PRINS REACTION AND COMPOUNDS USEFUL IN THE SYNTHESIS OF

HALICHONDRIN MACROLIDES AND ANALOGS THEREOF

Background

The invention relates to intermediates useful in the synthesis of pharmaceutically active macrolide compounds and methods of synthesizing macrolide compounds. Halichondrin B is a potent anticancer agent originally isolated from the marine sponge Halichondria okadai, and subsequently found in Axinella sp., Phakellia carteri , and Lissodendoryx sp. A total synthesis of halichondrin B was published in 1 992 (Aicher,

T. D. et al., J. Am. Chem. Soc. 1 14:31 62-3164). Further synthetic and structure-activity relationship studies have been disclosed in U.S. Patent Nos. 5,338,865 and 5,436,238 and in Towle et al., Annual Meeting of the American Association for Cancer Research, April 6-10, 2002, 5721 and Wanget al., Bioorg. Med. Chem.

Lett., 10:1029-1032, 2000. Eribulin mesylate (also called Halaven®, E7389, and the mesylate salt of B1939), a nontaxane microtubule dynamics inhibitor, is a structurally simplified, synthetic analog of halichondrin B. Methods and intermediates for the synthesis of certain halichondrin B analogs and intermediates are described in International Publication Nos. WO 2005/1 18565, WO 2009/046308, WO 2009/064029, and WO 2009/124237, WO 2015/066729, and WO 2016/179607; U.S. Patent No. 6,214,865; Austad et al., Synlett 24(3):333-337, 2013; Austad et al., Synlett. 24(3):327-332, 2013; and Chase et al., Synlett 24(3):323-326, 2013. New methods for the synthesis of halichondrin and its analogs (e.g., macrolide analogs) are desirable.

Summary of the Invention

In general, the present invention provides methods and compounds useful for the preparation of macrocyclic intermediates in the synthesis of a halichondrin macrolide or analog thereof. In particular, the methods disclosed herein may be useful in the preparation of a halichondrin macrolide or analog thereof through a synthesis including a C.23-C.24 bond-forming Prins reaction. Prins reaction precursors may be prepared using a Sakurai reaction, as described herein.

In one aspect, the invention provides a method of preparing a compound of formula (A):

(A),

where

each of D and D’ is independently H, optionally substituted alkyl, or OPi , provided that only one of D and D’ is OPi , where Pi is H, alkyl, a hydroxyl protecting group, and A is a C1 -6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1 , or A is a group of formula (1 ):

(1 ) ,

where

L is -(CH(OP ₂ ))-, -(C(OH)(OP ₂ ))-, or -C(O)-;

R ₂ is H and Pi is absent, H, alkyl, or a hydroxyl protecting group, or R ₂ and Pi combine to form a bond;

(i) R3 is H, and P ₂ is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;

(ii) R3 is -(CH ) _n NP P , where P3 is H or an N-protecting group, and (a) P is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P4 is H or an N-protecting group, (b) P and P4 combine to form an alkylidene, or (c) each of P and P4 is H;

(iii) R3 is -(CH ₂ )nOP5, where P ₂ is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P ₂ and P5, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or

(iv) Re and P ₂ combine to form an optionally substituted ethylene or a structure selected from the group consisting of:

protecting group;

E is H, optionally substituted alkyl, or optionally substituted alkoxy;

G is O, S, CH ₂ , or NRN, where RN is H, an N-protecting group, or optionally substituted alkyl; each Q1 is independently ORA, SRA, S0 ₂ RA, 0S0 ₂ RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRB(CO)NRBRA, NRB(CO)ORA, (CO)ORA, 0(C0)RA, (CO)NRBRA, or 0(C0)NRBRA, where each of R _A and Re is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;

n, when present, is 0, 1 , or 2;

k is 0 or 1 ;

Ri is -OP ₆ , -CH(Y) , or -CH (Y), where Rb is H or a hydroxyl protecting group;

FU is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl,

each P is independently H or a hydroxyl protecting group; and

RB is -CH CH -COORC, -CH=CH-COORc, -CH CH -SO RD, or -CH=CH-S0 ₂ RD; R6 is H, optionally substituted alkyl, or optionally substituted arylalkyl;

each Y is independently -COORc or -SO RD;

each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and

each RD, when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl.

The method includes producing the compound of formula (A) from a compound of formula (B), a compound of formula (C), and RsOH, where Rs is optionally substituted acyl. The compound of formula (B) is:

where all variables are as described for the compound of formula (A). The compound of formula (C) is:

R -R ,

(C)

OR7A

R O ··

here R is -CHO or ^7A L · _»

w : , and each R A is independently an optionally substituted alkyl. In some embodiments, the producing the compound of formula (A) includes reacting the compound of formula (B), the compound of formula (C), RsOH, and a Lewis acid (e.g., an oxophilic Lewis acid (e.g., boron trifluoride or a solvate thereof)).

In certain embodiments, the method further includes producing the compound of formula (B) including reacting a compound of formula (D), a compound of formula (E), and a second Lewis acid.

The compound of formula (D) is:

where all variables are as described for the compound of formula (B).

The compound of formula (E) is:

where Rs is silyl, and R6 is as described for the compound of formula (B).

In some embodiments, the second Lewis acid is an oxophilic second Lewis acid (e.g., boron trifluoride or a solvate thereof). In particular embodiments, the Lewis acid and the second Lewis acid are same. In further embodiments, the Lewis acid and the second Lewis acid are different.

In certain embodiments, the preparing the compound of formula (B) and the preparing the compound of formula (A) are performed as a single-pot transformation. In other embodiments, the method further includes epimerizing the product of reacting the compound of formula (D), the compound of formula (E), and the second Lewis acid.

In another aspect, the invention provides a method of preparing a compound of formula (B). The compound of formula (B) can be used as a reactant in the Prins reaction described herein. The method includes producing the compound of formula (B) from a compound of formula (D) and a compound of formula (E). The compound of formula (B) is:

where

each of D and D’ is independently H, optionally substituted alkyl, or OP1 , provided that only one of D and D’ is OP1 , where Pi is H, alkyl, a hydroxyl protecting group, and A is a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1 , or A is a group of formula (1 ):

(1 ) ,

where

L is -(CH(OP ₂ ))-, -(C(OH)(OP ₂ ))-, or -C(O)-;

R ₂ is H and Pi is absent, H, alkyl, or a hydroxyl protecting group, or R ₂ and Pi combine to form a bond;

(i) R3 is H, and P ₂ is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;

(ii) R3 is -(CH ₂ )nNP3P4, where P3 is H or an N-protecting group, and (a) P ₂ is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P4 is H or an N-protecting group, (b) P ₂ and P4 combine to form an alkylidene, or (c) each of P ₂ and P4 is H ;

(iii) R3 is -(CH ₂ ) _n OP5, where P ₂ is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P ₂ and P5, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or

(iv) R3 and P ₂ combine to form an optionally substituted ethylene or a structure selected from the group consisting of:

otecting group;

E is H, optionally substituted alkyl, or optionally substituted alkoxy;

G is O, S, CH , or NRN, where RN is H, an N-protecting group, or optionally substituted alkyl; each Q is independently ORA, SRA, SO RA, OSO RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRB(CO)NRBRA, NRB(CO)ORA, (CO)ORA, 0(C0)RA, (CO)NRBRA, or 0(C0)NRBRA, where each of R _A and RB IS independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;

n, when present, is 0, 1 , or 2;

k is 0 or 1 ;

R1 is -OPe, -CH(Y)2, or -CH2(Y), where RQ is H or a hydroxyl protecting group;

R6 is H, optionally substituted alkyl, or optionally substituted aryl; and

Y is independently -COORc or -SO RD;

Rc, when present, is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and

RD, when present, is optionally substituted aryl or optionally substituted non-enolizable alkyl. The compound of formula (D) is:

where all variables are as described for the compound of formula (B).

The compound of formula (E) is:

where Rs is silyl, and R6 is as described for the compound of formula (D).

In some embodiments, the producing the compound of formula (B) includes reacting the compound of formula (D), the compound of formula (E), and a Lewis acid (e.g., an oxophilic Lewis acid (e.g., boron trifluoride or a solvate thereof)). In certain embodiments, the method further includes epimerizing the product of reacting the compound of formula (D), the compound of formula (E), and the Lewis acid.

In yet another aspect, the invention provides methods of preparing a halichondrin macrolide or analog thereof.

In particular embodiments, the halichondrin macrolide or an analogue thereof is:

a halichondrin macrolide or analog thereof,

where

each of D and D’ is independently H, optionally substituted alkyl, or OPi , provided that only one of D and D’ is OPi , where Pi is H, alkyl, a hydroxyl protecting group, and A is a C saturated or C unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Qi , or A is a group of formula (1 ):

(1 )

where

L is -(CH(OP ₂ ))-, -(C(OH)(OP ₂ ))-, or -C(O)-;

R2 is H and Pi is absent, H, alkyl, or a hydroxyl protecting group, or R2 and Pi combine to form a bond;

(i) R ₃ is H, and P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;

(ii) Fh is -(CH2) _n NP ₃ P4, where P ₃ is H or an N-protecting group, and (a) P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P4 is H or an N-protecting group, (b) P2 and P4 combine to form an alkylidene, or (c) each of P2 and P4 is H ;

(iii) R ₃ is -(CH ₂ )nOP ₅ , where P is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P is H, optionally substituted alkyl, or a hydroxyl protecting group; or P and P , together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or

(iv) R ₃ and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:

otecting group;

each of A1 , A2, and A ₃ is independently H or OP”, where each P” is independently H or a hydroxyl protecting group;

E is H, optionally substituted alkyl, or optionally substituted alkoxy;

G is O, S, CH2, or NRN, where RN is H, an N-protecting group, or optionally substituted alkyl; each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRB(CO)NR _B RA, NRB(CO)ORA, (CO)ORA, 0(CO)RA, (CO)NRBRA, or 0(CO)NR _B RA, where each of RA and RB is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl; n, when present, is 0, 1 , or 2;

k is 0 or 1 ; and

Xi is -CH2- or -0-.

In certain embodiments, the method includes

(A) producing a compound of formula (IA) from a compound of formula (IIC), a compound of formula (III), and R5OH, where R5 is optionally substituted acyl ;

and

(B) producing the halichondrin macrolide or analog thereof from the compound of formula (IA).

The compound of formula (IA) is:

where

Ri is -OPs, -CH(Y)2, or -CH2(Y), where Rb is H or a hydroxyl protecting group, and each Y is independently -COORc or -SO2RD;

each P is independently H or a hydroxyl protecting group;

Re is -CH2CH2-COORC, -CH=CH-COORc, -CH2CH2-SO2RD, or -CH=CH-

SO2RD;

each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and

each RD, when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl;

R5 is optionally substituted acyl; and the remaining variables are as described for the halichondrin macrolide or analog thereof.

The compound of formula (IIC) is:

where all variables are as described for the compound of formula (IA).

The compound of formula (III) is:

R -R ,

(III) where R7 is -CHO or , where each R7A is independently an optionally substituted alkyl; and R4 is as described for the compound of formula (IA).

In particular embodiments, the method includes:

(A) producing a compound of formula (IVB) from a compound of formula (I IA), a compound of formula (MB), a compound of formula (IIIA), a compound of formula (IVA), and R5OH, where R5 is optionally substituted acyl;

(B) producing a compound of formula (IVC) from the compound of formula (IVB);

(C) producing a compound of formula (IVD) from the compound of formula (IVC);

and

(D) producing the halichondrin macrolide or analog thereof from the compound of formula (IVD). The compound of formula (IIA) is:

where

R1 is -OPB, -CH(Y)2, or -CH2(Y), where Rb is H or a hydroxyl protecting group, and each Y is independently-COORc or -SO2RD;

each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; each RD, when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl;

RE is is -CHO or -CH(i ₊ m)(ORF)(2-m),

where

m is 1 , and RF is a hydroxyl protecting group,

or

m is 0, and

(i) each RF is independently an alkyl or hydroxyl protecting group, or

(ii) both RF combine to form an alkylene;

and the remaining variables are as described for the halichondrin macrolide or analog thereof.

The compound of formula (MB) is:

where Rs is silyl.

The compound of formula (IMA) is:

R ₄ A-R ₇ ,

(IMA)

where

where Rc is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl, and each P ₇ is independently H or a hydroxyl protecting group;

R ₇ is -CHO or

where each R ₇ A is independently an optionally substituted alkyl.

The compound of formula (IVA) is:

where

each P ₉ is independently a hydroxyl protecting group;

R ₉ is -CHO or -COOH;

(a1 ) R10 is H or a hydroxyl protecting group, R is alkyl ether, and R12 is H;

(a2) R10 is H or a hydroxyl protecting group, and Rn and R12 combine to form a double bond;

or

(a3) R10 and Rn combine to form a bond, and R12 is H;

(b1 ) Ai and R14 combine to form oxo, R13 is H or a hydroxyl protecting group, and R15 is H;

or

(b2) Ai is H or -OP”, and:

(i) R13 is H or a hydroxyl protecting group, and R and R15 combine to form a double bond;

or

(ii) R13 and Ru combine to form a bond, and R15 is H or -OP”; and

(d ) R16 is H, and Pe is H or a hydroxyl protecting group;

or

(c2) R16 and Pe combine to form a double bond;

and

each P”, when present, is independently H or a hydroxyl protecting group.

The compound of formula (IVB) is:

where

Xi is -0-, -C(Y) ₂ -, -CH(Y)-, or -CH ₂ -;

X is oxo, or X , together with the atom to which it is attached, is -(CH(OPi ))-, where P is H or a hydroxyl protecting group; and

RG is

R is an optionally substituted acyl; and

X ₂ is H or -OHS-CSA-OHS-OH _^ OHS, where X ₂ A is -0-, -C(RH) ₂ - or— NR— , where each RH is independently H or -COORj, Ri is an A/-protecting group, and Rj is C alkyl ; and

the remaining variables are as described for the compound of formula (IIA) and the compound of formula (IVA).

The compound of formula (IVC) is:

where

Li is

where l_ ₂ and L combine to form a bond;

and the remaining variables are as described for the compound of formula (IVB).

The compound of formula (IVD) is:

where each of Ai and A is independently H or -OP”, and the remaining variables are as described for the compound of formula (IVC).

In further embodiments, step (A) includes:

(E) producing a compound of formula (IA) from the compound of formula (IIA), the compound of formula (IIIA), and R OH, where the compound of formula (IA) is:

where R A is as described for the compound of formula (IIIA), and the remaining variables are as described for the compound of formula (IA) above;

and

(F) producing the compound of formula (IVB) from the compound of formula (IF) and the compound of formula (IVA).

In yet further embodiments, step (E) includes reacting the compound of formula (IIA), the compound of formula (IMA), RsOH, and a Lewis acid (e.g., an oxophilic Lewis acid (e.g., boron trifluoride or a solvate thereof)). In still further embodiments, step (F) includes reacting R4A that is

In other mebodiments, step (F) includes reacting R4A that is a 1 ,2-reducing agent and further reacting with an allyl halide or allyl pseudohalide.

In yet other embodiments, Rg is -CHO, X1 is -C(Y)2-, -CH(Y)-, or -CH2-, and step (A) includes reacting Rg with R1 that is -CH(Y)2 or -CH2(Y) treated with a Brensted base. In still other embodiments, X1 is -0-, and step (A) includes esterifying R1 that is -ORb, where Rb is H, with R9 that is -COOH.

In some embodiments, step (B) includes reacting the compound of formula (IVB) with an olefin metathesis catalyst.

In particular embodiments, Pg is H, R16 is H, and step (C) includes:

oxidizing the compound of formula (IVC) to produce a compound of formula (IVCa):

where all variables are as described for the compound of formula (IVC);

and reacting the compound of formula (IVCa) with a 1 ,4-reducing agent to produce the compound of formula (IVD). In certain embodiments, the compound of formula (IVB) is, or is converted to, a compound of formula (IVBa) prior to producing the compound of formula (IVC), where the compound of formula (IVBa) is:

where all variables are as described for the compound of formula (IVB).

In further embodiments, the producing the halichondrin macrolide or analog thereof includes reacting the compound of formula (IVD) with a hydroxyl protecting group removing agent.

In yet further embodiments, the method includes:

(A) producing a compound of formula (VB) from a compound of formula (IIA), a compound of formula (MB), a compound of formula (NIB), a compound of formula (VA), and R5OH,

where Rs is optionally substituted acyl;

(B) producing a compound of formula (VC) from the compound of formula (VB),

and

(C) producing the halichondrin macrolide or analog thereof from the compound of formula (VC).

The compound of formula (IIA) is:

where

R1 is -OP ₆ , -CH(Y)2, or -CH2(Y), where Rb is H or a hydroxyl protecting group, and each Y is independently -COORc or -SO2RD;

each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;

RD, when present, is optionally substituted aryl or optionally substituted non-enolizable alkyl;

RE is is -CHO or -CH(i ₊ m)(ORF)(2-m),

where

m is 1 , and RF is a hydroxyl protecting group, or

m is 0, and

(i) each RF is independently an alkyl or hydroxyl protecting group, or

(ii) both RF combine to form an alkylene;

and the remaining variables are as described for the halichondrin macrolide or analog thereof. The compound of formula (MB) is:

where Rs is silyl.

The compound of formula (NIB) is:

R4B-R7,

(NIB)

where

R4B is but-3-en-1 -yl,

where each P7 is independently H or a hydroxyl protecting group;

and

R7 is -CHO or

OR ₇ A

R _7A 0 j

where each R ₇ A is independently an optionally substituted alkyl.

The compound of formula (VA) is:

where

a designates (R)-stereogenic center, and Z is a sulfonate, chloride, bromide, or iodide; or a designates (S)-stereogenic center, and Z is OR16, where R16 is a hydroxyl protecting group;

(a1 ) R 10 is a hydroxyl protecting group, R is alkyl ether, and R12 is H; (a2) R is a hydroxyl protecting group, and Rn and R combine to form a double bond;

or

(a3) R and R combine to form a bond, and R is H;

(b1 ) Ai and R combine to form oxo, R is a hydroxyl protecting group, and R is H;

or

(b2) Ai is H or -OP”, and:

(i) R is a hydroxyl protecting group, and RH and R combine to form a double bond;

or

(ii) R and R combine to form a bond, and R is H or -OP”;

Yi is iodide, bromide, or trifluoromethanesulfonate;

Rs is -CHO or -COOH;

each P is independently a hydroxyl protecting group, and X is oxo; or both Pg groups and X , together with the atoms to which each is attached, combine to form a ketal; and

each P” is independently a hydroxyl protecting group.

The compound of formula (VB) is:

where

Xi is -CH -, -CH(Y)-, -C(Y) -, or -0-, where each Y is independently -COORc or -SO RD; each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;

each RD, when present, is independently optionally substituted aryl or optionally substituted non- enolizable alkyl; and

RK is

Rs is optionally substituted acyl; and the remaining variables are as described for the compound of formula (VA) and the compound of formula (IIA).

The compound of formula (VC) is:

where

Li is

where l_2 and L3 combine to form a bond;

b designates (S)-stereogenic center, if a designates (R)-stereogenic center; and

b designates (R)-stereogenic center, if a designates (S)-stereogenic center; and the remaining variables are as described for the compound of formula (VB).

In certain embodiments, step (A) includes:

(D) producing a compound of formula (ID) from the compound of formula (IIA), the compound of formula (MB), the compound of formula (IIIB), and R5OH, where Rs is optionally substituted acyl, and where the compound of formula (ID) is:

where all variables are as described for the compound of formula (IIA), the compound of formula (MB), the compound of formula (I I IB), and R5OH;

and (E) producing the compound of formula (VB) from the compound of formula (ID) and the compound of formula (VA).

In some embodiments, the producing the compound of formula (ID) includes reacting the compound of formula (IIC), the compound of formula (NIB), R OH, and a Lewis acid (e.g., an oxophilic Lewis acid (e.g., boron trifluoride or a solvate thereof)).

In certain embodiments, step (D) includes a Sakurai reaction between the compound of formula (IIA) and the compound of formula (I IB) to produce a compound of formula (IIC), and a Prins reaction between the compound of formula (IIC), the compound of formula (NIB), and R5OH.

In further embodiments, the compound of formula (IIC) is:

where all variables are as described for the compound of formula (IIA).

In yet further embodiments, X1 is -CH2-, -CH(Y)-, or -C(Y)2-, and step (A) includes reacting R9, where Rg is -CHO, with R1 that is -CH(Y)2 or -CH2(Y) treated with a Bronsted base, to produce -CO-X1-. In still further embodiments, X1 is -0-, and step (A) includes esterifying Rg that is -COOH with R1 that is -ORb, where Rb is H, to produce -CO-X1-.

In other embodiments, step (B) includes reacting the compound of formula (VB) with a Cr(ll) salt and a Ni(ll) salt. In yet other embodiments, step (C) includes a step of nucleophilic ring-closing of the compound of formula (VC). In still other embodiments, both Pg groups and X3, together with the atoms to which each is attached, combine to form a ketal. In some embodiments, R and R combine to form a bond, and R is H. In certain embodiments, R _B is but-3-en-1 -yl, and step (A) includes reacting the but-3-en-1 -yl group with a dihydroxylating agent to produce R4B that is

cleaving the

^0P 7 through a reaction with a glycol cleaving agent. In particular embodiments, FUB is step (A) includes reacting the an oxidizing agent capable of converting an alcohol into a carbonyl group. In further embodiments, R4B is

, and step (A) includes cleaving the

O ^p 7 through a reaction with a glycol cleaving agent.

In yet further embodiments, the method includes:

(A) producing a compound of formula (IF) from a compound of formula ( 11 A) , a compound of formula

(MB), a compound of formula (NIC), and RsOH, where Rs is optionally substituted acyl;

(B) producing a compound of formula (IG) from the compound of formula (IF),

and

(C) producing the halichondrin macrolide or analog thereof from the compound of formula (IG) and one or more intermediates.

The compound of formula (IF) is:

where

Fti is -ORe, -CH(Y) , or -CH (Y), where Rb is H or a hydroxyl protecting group, and each Y is independently-COORc or -SC^Ro;

each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;

each RD, when present, is independently optionally substituted aryl or optionally substituted non- enolizable alkyl; , where Rc is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl, and each P7 is independently H or a hydroxyl protecting group;

R5 is optionally substituted acyl; and

the remaining variables are as described for the halichondrin macrolide or analog thereof.

The compound of formula (IIA) is:

where

R1 is -OPB, -CH(Y)2, or -CH2(Y), where Rb is H or a hydroxyl protecting group, and each Y is independently -COORc or -SO2RD;

each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;

RD, when present, is optionally substituted aryl or optionally substituted non-enolizable alkyl; RE is -CHO or— CH(i ₊ m)(0RF)(2-m),

where

m is 1 , and RF is a hydroxyl protecting group,

or

m is 0, and

(i) each RF is independently an alkyl or hydroxyl protecting group, or

(ii) both RF combine to form an alkylene; and

the remaining variables are as described for the compound of formula (IF).

The compound of formula (MB) is:

where Rs is silyl. The compound of formula (NIC) is:

R4C-R7,

(INC)

OR7A

where R ₇ is -CHO or ^R 7A ⁰ A , where each R _7A is independently an optionally substituted alkyl, and R4C is as described for the compound of formula (IF).

The compound of formula (IG) is:

the remaining variables are as described for the compound of formula (IF). In some embodiments, step (B) includes reacting R4C that is

In certain embodiments, step (B) includes reducing R4C that is

In further embodiments, step (B) includes reducing R4C that is

In yet further embodiments, step (B) includes reducing R4c that is -reducing agent to produce a carbonyl group in REI .

In still further embodiments, the step reducing R4C that is

In particular embodiments, step (B) includes reacting R4C that is with an oxidizing agent capable of converting an alcohol to a carbonyl group in

R .

In certain embodiments, the one or more intermediates is a compound of formula (VIA):

where

RIOA is -CH ₂ -CH=CH ₂ , -(CH ₂ ) -CH=CH , or -(CH ₂ ) ₃ -OPIO; each R10, R13, P9 and P10 is independently a hydroxyl protecting group;

Ai is H or -OP”; and

Yi is chloro, bromo, iodo, trifluoromethanesulfonate, or trialkylsilane;

and step (C) includes:

(D) producing a compound of formula (VIB) from the compound of formula (IG) and the compound of formula (VIA).

The compound of formula (VIB) is:

Ri is -ORe or -CH(Y), where Rb is H or a hydroxyl protecting group, and Y is -COORc or -CHO;

Ai and RH combine to form oxo, R13 is H or a hydroxyl protecting group, and R15 is H; or

Ai is H or -OP”, and:

(i) R13 is H or a hydroxyl protecting group, and Ru and R15 combine to form a double bond;

or

(ii) R13 and Ru combine to form a bond, and R15 is H or -OP”;

each P9 is independently a hydroxyl protecting group, and X3 is oxo or X3, together with the carbon atom to which it is attached, is -(CH(OP ))-, where Pn is H or a hydroxyl protecting group; or both P9 groups and X3, together with the atoms to which each is attached, combine to form a ketal; and

the remaining variables are as described for the compound of formula (VIA) and the compound of formula (IG).

In yet further embodiments, step (D) includes reacting the compound of formula (VIA) and the compound of formula (IG) with a Cr(ll) salt and a Ni(ll) salt. In still further embodiments, RIOA is -CH -CH=CH , and step (C) includes:

(E) producing a compound of formula (VIC) from the compound of formula (VIB) and R - CH CH=CH , where R is -COOH or a metallic or metalloid moiety;

(F) producing a compound of formula (VID) from the compound of formula (VIC);

and

(G) producing the halichondrin macrolide or analog thereof from the compound of formula (VID). The compound of formula (VIC) is:

X4 is oxo, or X4, together with the atom to which it is attached, is -(CH(OPi2))-, where P12 is H or a hydroxyl protecting group; and

the remaining variables are as described for the compound of formula (VIB).

The compound of formula (VID) is:

where

Li is

combine to form a bond; and

the remaining variables are as described for the compound of formula (VIC).

In some embodiments, R1 is -CH2(Y), X1 is -CH2-, X4 is oxo or -(CH(OPi2))-, and step (E) includes reacting the compound of formula (VIB) with Ri7-CH2CH=CH2, where R17 is a metallic or metalloid moiety. In other embodiments, R1 is -ORb, PB is H, X1 is -0-, X4 is oxo, and step (E) includes esterifying the compound of formula (VIB) with Ri7-CH2CH=CH2, where R17 is -COOH. In yet other embodiments, the producing step (F) includes reacting the compound of formula (VIC) with an olefin metathesis catalyst. In still other embodiments, step (G) includes reacting the compound of formula (VID) with a hydroxyl protecting group removing agent.

In certain embodiments, RIOA is -CH2-CH2-CH=CH2, R1 is -ORe or -CH2(Y), where Rb is H or a hydroxyl protecting group, and Y is -COORc, and step (C) includes:

(H) producing a compound of formula (VIE) from the compound of formula (VIB) and Ri7-CH=CH2, where R17 is -COOH or a metallic or metalloid moiety;

(I) producing a compound of formula (VIF) from the compound of formula (VIE);

and

(J) producing the halichondrin macrolide or analog thereof from the compound of formula (VIF).

The compound of formula (VIE) is:

Xi is -CH - or -0-; and

X4 is oxo, or X4, together with the atom to which it is attached, is -(CH(OPi ))-, where P is H or a hydroxyl protecting group; and

the remaining variables are as described for the compound of formula (VIB).

The compound of formula (VI F) is:

o form a bond; and

the remaining variables are as described for the compound of formula (VIE).

In some embodiments, step (I) includes reacting the compound of formula (VIE) with an olefin metathesis catalyst. In particular embodiments, step (J) includes reacting the compound of formula (VI F) with a hydroxyl protecting group removing agent.

In certain embodiments, RI OA is -(CH2)3-OPIO, and step (C) includes:

(K) producing a compound of formula (VIG) from the compound of formula (VIB) and (Rc0)2P(0)- CH -RP, where each Rc is indepenedently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl, and Rp is H or -COOH;

(L) producing a compound of formula (VIF) from the compound of formula (VIG);

and

(M) producing the halichondrin macrolide or analog thereof from the compound of formula (VIF). The compound of formula (VIG) is:

the remaining variables are as described for the compound of formula (VIB) and for (Rc0)2P(0)- CH ₂ -RP. The compound of formula (VIF) is:

where

Li is

combine to form a bond; and

X4 is oxo; and

the remaining variables are as described for the compound of formula (VIG). In further embodiments, the producing step (K) includes reacting the compound of formula (VIB) with (RC0)2P(0)-CH2-RP under Claisen reaction conditions, where Rp is H and R1 is -CH2(Y). In yet further embodiments, the producing step (K) includes esterifying the compound of formula (VIB) with (Rc0)2P(0)- CH2-RP, where Rp is -COOH and R1 is -ORb, where Pe is H. In still further embodiments, step (M) includes reacting the compound of formula (VIF) with a hydroxyl protecting group removing agent.

In some embodiments, step (C) includes:

(N) producing a compound of formula (VIIB) from the compound of formula (IG) and a compound of formula (VIIA);

(O) producing a compound of formula (VIIC) from the compound of formula (VIIB);

and

(P) producing the halichondrin macrolide or analog thereof from the compound of formula (VIIC).

The compound of formula (VIIA) is:

(VI I A)

where

(i) R10 is a hydroxyl protecting group, Rn is alkyl ether, and R12 is H;

(ii) R10 is a hydroxyl protecting group, and Rn and R12 combine to form a double bond;

or

(iii) R10 and R combine to form a bond, and R12 is H;

R ₉ is -CH2-OP” or -COOP”;

R13 and each Pg is independently a hydroxyl protecting group;

Ai is H or -OP”;

each P” is independently H or a hydroxyl protecting group; and

Yi is chloro, bromo, iodo, trifluoromethanesulfonate, or trialkylsilane.

The compound of formula (VI IB) is:

where

Ri is -ORe, -CH2(Y), or -CH(Y>2, where RQ is H or a hydroxyl protecting group, and Y is -COORc or

-CHO;

Ai and Ru combine to form oxo, R13 is H or a hydroxyl protecting group, and R15 is H; or

Ai is H or -OP”, and:

(i) R13 is H or a hydroxyl protecting group, and RH and R15 combine to form a double bond;

or

(ii) R13 and R14 combine to form a bond, and R15 is H or -OP”;

R ₉ is -CHO or -COOP”;

each P9 is independently a hydroxyl protecting group, and X3 is oxo or X3, together with the carbon atom to which it is attached, is -(CH(OP ))-, where Pn is H or a hydroxyl protecting group; or both P9 groups and X3, together with the atoms to which each is attached, combine to form a ketal; and

the remaining variables are as described for the compound of formula (IG) and the compound of formula (VIIA).

The compound of formula (VI IC) is:

where

Li is

where L2 and L3 combine to form a bond;

Xi is -CH2-, -CH(Y)-, -C(Y)2-, or -0-, where each Y is independently -COORc or -SO2RD; each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and each RD, when present, is independently optionally substituted aryl or optionally substituted non- enolizable alkyl;

X4 is oxo, or X4, together with the atom to which it is attached, is -(CH(OPi2))-, where P12 is H or a hydroxyl protecting group; and

the remaining variables are as described for the compound of formula (VI IB).

In certain embodiments, step (N) includes reacting the compound of formula (VIIA) and the compound of formula (IH) with a Cr(ll) salt and a Ni(ll) salt. In particular embodiments, step (O) includes an esterification reaction between R1 that is -ORb, where Pe is H, and R9 that is -COOH. In further embodiments, step (O) includes a reaction between R1 that is -CH(Y) ₂ or -CH ₂ (Y), and Rg that is -CHO. In yet further embodiments, step (P) includes reacting the compound of formula (VIIC) with a hydroxyl protecting group removing agent.

In still further embodiments, the method includes:

(A) producing a compound of formula (VIID) from a compound of formula (IIA), a compound of formula (MB), a compound of formula (NIC), a compound of formula (VI IA), and R5OH, where R5 is optionally substituted acyl;

(B) producing a compound of formula (VIIE) from the compound of formula (VI ID);

and

(C) producing the halichondrin macrolide or analog thereof from the compound of formula (VIIC).

The compound of formula (IIA) is:

(I I A)

where

R1 is -OP ₆ , -CH(Y)2, or -CH2(Y), where Rb is H or a hydroxyl protecting group, and each Y is independently-COORc or -SO2RD;

each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;

each RD, when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl;

RE is -CHO or -CH(i ₊ m)(ORF)(2-m),

where

m is 1 , and RF is a hydroxyl protecting group,

or

m is 0, and

(i) each RF is independently an alkyl or hydroxyl protecting group, or

(ii) both RF combine to form an alkylene; and the remaining variables are as described for the halichondrin macrolide or analog thereof.

The compound of formula (MB) is:

(I IB)

where Rs is silyl.

The compound of formula (MIC) is:

R4C-R7,

(INC)

where

where each P , when present, is independently H or a hydroxyl protecting group.

The compound of formula (VI IA) is:

(VI I A)

where

(i) R10 is a hydroxyl protecting group, Rn is alkyl ether, and R12 is H ;

(ii) R10 is a hydroxyl protecting group, and Rn and R12 combine to form a double bond; or

(iii) R10 and R11 combine to form a bond, and R12 is H ;

R ₉ is -CHO or -COOH ;

R13 and each Pg is independently a hydroxyl protecting group;

Ai is H or -OP”, where P” is H or a hydroxyl protecting group; and

Yi is chloro, bromo, iodo, trifluoromethanesulfonate, or trialkylsilane. The compound of formula (VI I D) is:

where

Xi is -CH2-, -CH(Y)-, -C(Y)2- or -0-, where each Y is independently -COORc or -SO2RD;

X4 is oxo, or X4, together with the atom to which it is attached, is -(CH(OPi2))-, where P12 is H or a hydroxyl protecting group;

RL is

R is— CHO or— CH OP ;

R5 is optionally substituted acyl; and

the remaining variables are as described for the compound of formula (IIA).

The compound of formula (VI I E) is:

where

where Lå and L3 combine to form a bond;

each Pg is independently a hydroxyl protecting group, and X3 is oxo or X3, together with the carbon atom to which it is attached, is -(CH(OP ))-, where Pn is H or a hydroxyl protecting group; and

the remaining variables are as described for the compound of formula (VI ID).

In some embodiments, step (A) includes:

(D) producing a compound of formula (IIC) from the compound of formula (IIA) and the compound of formula (MB);

(E) producing a compound of formula (IF) from the compound of formula (IIC), the compound of formula (NIC), and R5OFI;

and

(F) producing the compound of formula (VIIB) from the compound of formula (VI IA) and the compound of formula (IF).

The compound of formula (IIC) is:

where the variables are as described for the compound of formula (IIA).

The compound of formula (IF) is:

where the variables are as described for the compound of formula (IIC), the compound of formula (MIC), and RsOH. In certain embodiments, the producing the compound of formula (IF) includes reacting the compound of formula (IIC), the compound of formula (MIC), RsOH, and a Lewis acid (e.g., an oxophilic Lewis acid (e.g., boron trifluoride or a solvate thereof)). In particular embodiments, step (F) includes:

(G) producing a compound of formula (IH) from the compound of formula (IF); and

(H) producing the compound of formula (VI ID) from the compound of formula (IH) and the compound of formula (VI I A). The compound of formula (IH) is:

where the variables are as described for the compound of formula (IF). In some embodiments, the producing step (G) includes reacting the compound of formula (IF) with an allylic reducing agent.

In certain embodiments, step (A) includes reducing FUc that is -reducing agent.

In particular embodiments, step (A) includes reducing Ft4c that is -reducing agent to produce a reduction product, and reducing the reduction product with a 1 ,2-reducing agent. In further embodiments, step (A) includes reducing R4C that is allylic reducing agent to produce an acid product, and reducing the acid product with a 1 ,2-reducing agent capable of converting the carboxylic acid to an aldehyde. In yet further embodiments, step (A) includes cleaving R C that is

-reducing agent capable of converting the carboxylic acid to an aldehyde.

In still further embodimetns, step (A) includes an esterification reaction between R that is -OPB, where Re is H, and R that is -COOH. In other embodiments, step (A) includes a reaction between R that is -CH(Y or -CH (Y), and Rg that is -CHO. In yet other embodiments, step (B) includes reacting the compound of formulas (VIID) with a Cr(ll) salt and a Ni(ll) salt. In still other embodiments, step (C) includes reacting the compound of formula (VIIE) with a hydroxyl protecting group removing agent.

In some embodiments, the method includes:

(A) producing a compound of formula (VIIIB) from a compound of formula (VIIIA), a compound of formula (IIA), a compound of formula (MB), and a compound of formula (MIC), and R OH, where Rs is optionally substituted acyl ;

(B) producing a compound of formula (VIIIC) from the compound of formula (VIIIB);

and

(C) producing the halichondrin macrolide or analog thereof from the compound of formula (VIIIC).

The compound of formula (IIA) is:

where

Ri is -OP ₆ , -CH(Y) , or -CH (Y), where Rb is H or a hydroxyl protecting group, and each Y is independently-COORc or -SO RD; each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;

each RD, when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl;

RE is -CHO or— CH(i ₊ m)(ORF)(2-m),

where

m is 1 , and RF is a hydroxyl protecting group,

or

m is 0

(i) each RF is independently an alkyl or hydroxyl protecting group, or

(ii) both RF combine to form an alkylene; and

the remaining variables are as described for the halichondrin macrolide or analog thereof.

The compound of formula (MB) is:

where Rs is silyl.

The compound of formula (NIC) is:

R4C-R7,

(INC)

where

R4C is

each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;

each P ₇ , when present, is independently H or a hydroxyl protecting group;;

OR7A

R ₇ is -CHO or ^R 7AO A ^' r , where each R7A is independently an optionally substituted alkyl.

The compound of formula (VINA) is:

where

(i) R10 is a hydroxyl protecting group, R is alkyl ether, and R12 is H;

(ii) R10 is a hydroxyl protecting group, and R4 and Rs combine to form a double bond;

or

(iii) R10 and R11 combine to form a bond, and R12 is H;

R ₉ is -CHO or -COOH;

and

each P9 and R13 is independently a hydroxyl protecting group.

The compound of formula (VI I IB) is:

where

Rs is optionally substituted acyl; and

X3 is oxo or X3, together with the carbon atom to which it is attached, is -(CH(OP ))-, where P11 is H or a hydroxyl protecting group;

X4 is oxo, or X4, together with the atom to which it is attached, is -(CH(OPi2>)-, where P12 is H or a hydroxyl protecting group; and the remaining groups are as described for the compound of formula (IIA) and the compound of formula (VIIIA).

The compound of formula (VI 11C) is:

where

Li is

where l and L combine to form a bond;

At is H or -OP”, where P” is H or a hydroxyl protecting group; and

the remaining variables are as described for the compound of formula (VIIIB).

In certain embodiments, step (A) includes:

(D) producing a compound of formula (IIC) from the compound of formula (IIA) and the compound of formula (I IB) ;

(E) producing a compound of formula (IF) from the compound of formula (IIC), the compound of formula (MIC), and RsOH;

(F) producing a compound of formula (IJ) from the compound of formula (IF);

and

(G) producing the compound of formula (VIIIB) from the compound of formula (VIIIA) and the compound of formula (IJ).

The compound of formula (IIC) is:

where the variables are as described for the compound of formula (IIA).

The compound of formula (IF) is:

where the variables are as described for the compound of formula (IIA), the compound of formula (MIC), and RsOH.

The compound of formula (IJ) is:

where the variables are as described for the compound of formula (VIIIB).

In particular embodiments, step (D) includes reacting the compound of formula (MB), the compound of formula (IIA), and a Lewis acid (e.g., the Lewis acid is an oxophilic Lewis acid (e.g., boron trifluoride or a solvate thereof)). In further embodiments, step (E) includes reacting the compound of formula (IIC), the compound of formula (MIC), RsOH and a Lewis acid (e.g., the Lewis acid is an oxophilic Lewis acid (e.g., boron trifluoride or a solvate thereof)). In yet further embodiments, the Lewis acid in step (D) and the Lewis acid in step (E) are different. In still further embodiments, the Lewis acid in step (D) and the Lewis acid in step (E) are same.

In some embodiments, step (F) includes converting

using an allylic reducing agent. In particular embodiments, step (A) includes reacting R4C that is -reducing agent to produce a product, and reacting the product with a vinyl nucleophile. In certain embodiments, step (A) includes reacting FUc that is -reducing agent to produce a product, reducing the product with a 1 ,2-reducing agent to produce a reduced product, and reacting the reduced product with a vinyl nucleophile.

In further embodiments, step (A) includes reacting FUc that is allylic reducing agent to produce an acid, reducing the acid with a 1 ,2-reducing agent to produce a reduced product, and reacting the reduced product with a vinyl nucleophile.

In yet further embodiments, step (A) includes cleaving R4C that is a glycol cleaving agent to produce an aldehyde, reacting the aldehyde with (Rc0)2P(0)-CFl2-C00Rc to produce an enoate, reacting the enoate with a 1 ,4-reducing agent to produce a product, reducing the product with a 1 ,2-reducing agent to product a reduced product, and reacting the reduced product with a vinyl nucleophile.

In still further embodiments, step (A) includes an esterification reaction between Ri that is -OPB, where Rb is FI, and R9 that is -COOFI.

In other embodiments, step (A) includes a reaction between R1 that is -CH(Y)2 or -CH2(Y), and Rg, where Rg is -CHO. In yet other embodiments, step (B) includes reacting the compound of formula (VIIIB) with an olefin metathesis catalyst. In still other embodiments, step (C) includes reacting the compound of formula (VIIIC) with a hydroxyl protecting group removing agent.

In some embodiments, the method includes:

(A) producing a compound of formula (IXB) from a compound of formula (IXA), a compound of formula (MB), a compound of formula (IIA), a compound of formula (HIE), and RsOH, where Rs is optionally substituted acyl; and

(B) producing the halichondrin macrolide or analog thereof from the compound of formula (IXB). The compound of formula (IXA) is:

where

Rs is -CHO or -COOP”;

(a1 ) R10 is a hydroxyl protecting group, Rn is alkyl ether, and R12 is H;

(a2) R10 is a hydroxyl protecting group, and Rn and R12 combine to form a double bond;

or

(a3) R and Rn combine to form a bond, and R12 is H;

Ai and Rn combine to form oxo, R13 is H or a hydroxyl protecting group, and R15 is H; or

Ai is H or -OP”, and:

(i) R13 is H or a hydroxyl protecting group, and RH and R15 combine to form a double bond;

or

(ii) R13 and Rn combine to form a bond, and R is H or -OP”;

Ro is -CHO, -CH OP”, -CH=CH ₂ , -CH(OP”)CH ₂ OP”, -C(0)-CH ₂ P(0)(0RC)2, or halogen;

each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and

each P” is independently H or a hydroxyl protecting group; and

each P9 is independently a hydroxyl protecting group.

The compound of formula (IIA) is:

(I I A)

where

R is -OPs, -CH(Y) , or -CH (Y), where Rb is H or a hydroxyl protecting group, and each Y is independently-COORc or -SO RD;

each RD, when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl;

RE is -CHO or -CH(i ₊ m)(ORF)(2-m),

where

m is 1 , and RF is a hydroxyl protecting group,

or m is 0, and

(i) each RF is independently an alkyl or hydroxyl protecting group, or

(ii) both RF combine to form an alkylene; and

the remaining variables are as described for the halichondrin macrolide or analog thereof. The compound of formula (IIIE) is:

R4E-R7,

(II IE)

where

where

each P7 is independently H or a hydroxyl protecting group; and

Re is -CH CH -COORC, -CH=CH-COORc, -CH CH -SO RD, or -CH=CH-S0 ₂ RD; and

OR ₇ A

j

R is -CHO or R ₇ ACT ^ , where each R A is independently an optionally substituted alkyl.

The compound of formula (MB) is:

where Rs is silyl.

The compound of formula (IXB) is:

(IXB)

where

combine to form a bond;

R is optionally substituted acyl;

Ai and R combine to form oxo, R13 is H or a hydroxyl protecting group, and R15 is H; or

Ai is H or -OP”, and:

(i) R13 is H or a hydroxyl protecting group, and Ru and R15, together with the atoms to which each is attached, combine to form a double bond;

or

(ii) R13 and R14 combine to form a bond, and R15 is H or -OP”;

each P9 is independently H or a hydroxyl protecting group, and X3 is oxo, or X3, together with the atom to which it is attached, combines to form -(CH(OPn))-, where P11 is H or a hydroxyl protecting group;

or

both P9 and X3, together with the atoms to which each is attached, combine to form a ketal; R19A is H, -OP”, or Y, and R19B is H; or R and R , together with the atoms to which each is attached, combine to form a double bond; and

the remaining variables are as described for the compound of formula (IXA) and the compound of formula (IIA).

In some embodiments, step (A) includes reacting RE that is -CHO with the compound of formula (MB) and a first Lewis acid to produce a group of the structure

In certain embodiments, step (A) includes reacting the group of the structure

In particular embodiments, the first Lewis acid and/or second Lewis acid is an oxophilic Lewis acid (e.g., boron trifluoride or a solvate thereof). In further embodiments, the first Lewis acid is same as the second Lewis acid. In still further embodiments, the first Lewis acid is same as the second Lewis acid.

In other embodiments, step (A) includes converting FUE that is

, g g p Ro that is -C(0)-CH2P(0)(0Rc)2 under Horner-

Wadsworth-Emmons reaction conditions.

In yet other embodiments, step (A) includes reacting R4E that is with Ro that is -CHO under Claisen reaction conditions, where Re is -CH2CH2-COORC or

-CH2CH2-SO2RD.

In still other embodiments, step (A) includes converting R4E that is

group of the structure

H~ > _"„ /~ ^cHo

O , and reacting this group with Ro that is a halogen under Nozaki-Hiyama-Kishi reaction conditions, where Re, when present, is -CH2CH2-COORC or -CH=CH-COORc, and R14 and R15 combine to form a double bond.

In some embodiments, step (A) includes reacting R1 that is -ORQ and R9 under esterification reaction conditions to produce a group of the structure -Xi-C(O)-, where Rb is H, R9 is -COOH, and X1 is -0-. In certain embodiments, step (A) includes reacting R1 that is -CH(Y)2 or -CH2(Y) with Rg under Claisen reaction conditions to produce a group of the structure -Xi-C(O)-, where R9 is -CHO, and X1 is -C(Y)2- or - CH(Y)-, respectively. In particular embodiments, step (B) includes reacting the compound of formula (IXB) with a hydroxyl protecting group removing agent. In further embodiments, D’ is OP1 , where Pi is alkyl. In yet further embodiments, D is H. In still further embodiments, A is of the following structure:

Y^Rs

0P ₂ In other embodiments, k is 0. In yet other embodiments, R3 is -(CH2) _n NP3P4 or -(CH2) _n OP5, where n is 0. In still other embodiments, D’ is H. In some embodiments, A and D combine to form the following structure:

where, the bond to oxygen atom originates at the carbon atom, to which D is attached in formula (IA), and

where R3 is -(CH2)nNP3P4 or -(CH2)nOPs, where n is 2.

In certain embodiments, k is 1 , and E is optionally substituted alkyl. In particular embodiments, G is O.

In still another aspect, the invention provides a method of preparing an intermediate in the synthesis of a halichondrin macrolide or analog thereof.

In some embodiments, the intermediate is:

OR7A

where R _/ is -CHO or ^R 7A° Ai and

each R _7A is independently alkyl or a hydroxyl protecting group; or

both R _7A combine to form an optionally substituted alkylene.

In certain embodiments, the method includes:

(A) producing a compound of formula (Z2) from a compound of formula (Z1 ) and

O , where each Ro is independently optionally substituted alkyl, where the compound of formula (Z1 ) is:

(Z1 )

where

each R20A is independently a hydroxyl protecting group, or both R20A, together with the atoms to which each is attached, combine to form an acetal, ketal, cyclic carbonate, dicarbonyl-dioxo, or silylene- dioxo; each R B is independently a hydroxyl protecting group, or both R B, together with the atoms to which each is attached, combine to form an acetal, ketal, cyclic carbonate, dicarbonyl-dioxo, or silylene- dioxo;

P A is H;

P B is H or a hydroxyl protecting group;

and the compound of formula (Z2) is:

(B) producing a compound of formula (Z3) from the compound of formula (Z2) and

O

R GT' ''^ ²¹

^R21 ° nR

2 ¹ , where each R is independently optionally substituted alkyl, where the compound of formula (Z3) is:

(C) producing a compound of formula (Z4) from the compound of formula (Z3), where the compound of formula (Z4) is:

where X5 is a halogen;

(D) producing a compound of formula (Z5) from the compound of formula (Z4), where the compound of formula (Z5) is:

where

R A is H or a hydroxyl protecting group; and each R B is independently FI or a hydroxyl protecting group, or both R B, together with the atoms to which each is attached, combine to form an acetal, ketal, cyclic carbonate, dicarbonyl-dioxo, or silylene- dioxo;

(E) producing a compound of formula (Z ) from the compound of formula (Z5) and R AOFI

(F) producing a compound of formula (Z 7) from the compound of formula (Z6) and

O

R K ₂₂ oU" ^[ _| I ^> '^ ^COOR22

²² , where each R is independently optionally substituted alkyl, and the compound of formula (Z7) is:

and

(G) producing the compound of formula (Z) from the compound of formula (Z7). In particular embodiments, step (E) includes reacting the compound of formula (Z5) with R7AOH and a Bnansted acid. In further embodiments, step (F) includes reacting the compound of formula (Z6) with a glycol cleaving agent to produce an aldehyde product, and reacting the aldehyde product with

O

R n" ^f _| ⁾ '^' ^COOR22

^K22 ° OR

²² under Horner-Wadsworth-Emmons reaction conditions. In yet further embodiments, step (G) includes reacting the compound of formula (Z6) with a 1 ,4-reducing agent.

In still further embodiments, the intermediate is:

where R is -CHO or

each R ₇ A is independently alkyl or a hydroxyl protecting group; or

both R7A combine to form an optionally substituted alkylene;

Rs is -CH CH -COORC, -CH=CH-COORc, -CH CH -SO RD, or -CH=CH-S0 ₂ RD;

Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and

RD, when present, is independently optionally substituted aryl or optionally substituted non- enolizable alkyl.

In other embodiments, the method includes:

(A) producing a compound of formula (Z2) from a compound of formula (Z1 ) and

O

„ _n -P _' ^COOR ₀

^R °° ORo where each Ro is independently optionally substituted alkyl, where the compound of formula (Z1 ) is:

where

each R20A is independently a hydroxyl protecting group, or both R20A, together with the atoms to which each is attached, combine to form an acetal, ketal, cyclic carbonate, dicarbonyl-dioxo, or silylene- dioxo;

each R20B is independently a hydroxyl protecting group, or both R20B, together with the atoms to which each is attached, combine to form an acetal, ketal, cyclic carbonate, dicarbonyl-dioxo, or silylene- dioxo;

P A is H;

P B is H or a hydroxyl protecting group;

and the compound of formula (Z2) is:

(B) producing a compound of formula (Z3) from the compound of formula (Z2) and O , where each R is independently optionally substituted alkyl, where the compound of formula (Z3) is:

(C) producing a compound of formula (Z4) from the compound of formula (Z3), where the compound of formula (Z4) is:

where Xs is a halogen;

(D) producing a compound of formula (Z5) from the compound of formula (Z4), where the compound of formula (Z5) is:

where

R A is H or a hydroxyl protecting group; and

each R B is independently H or a hydroxyl protecting group, or both R B, together with the atoms to which each is attached, combine to form an acetal, ketal, cyclic carbonate, dicarbonyl-dioxo, or silylene- dioxo;

(E) producing a compound of formula (Z5A) from the compound of formula (Z5) and R7AOH, where the compound of formula (Z5A) is:

where R20A is H or a hydroxyl protecting group; and

each R20B is independently FI or a hydroxyl protecting group, or both R20B, together with the atoms to which each is attached, combine to form an acetal, ketal, cyclic carbonate, dicarbonyl-dioxo, or silylene- dioxo;

(F) producing a compound of formula (Z5B) from the compound of formula (Z5A), where the compound of formula (Z5B) is:

where R23 is FI or -OR20A;

and

(G) producing the compound of formula (Z8) from the compound of formula (Z5B) and

o o , in which each R ₂₂ is independently optionally substituted alkyl.

In further embodiments, step (E) includes reacting the compound of formula (Z5) with R7AOH and a Brensted acid. In yet further embodiments, step (F) includes reacting the compound of formula (Z5A), in which both R20B are H, with a glycol cleaving agent. In still further embodiments, step (E) or step (F) further includes reacting -OR20A, where R20A is optionally substituted acyl with an allylic reducing agent. In other embodiments, step (G) includes reacting the compound of formula (Z5B) with under Horner-Wadsworth-Emmons reaction conditions to produce the compound of formula (Z8), in which Rs is -CH=CH-COORc or -CH=CH-SC>2RD, respectively.

In yet other embodiments, step (G) further includes reacting the compound of formula (Z8), in which Rs is - CPI=CPI-COORc or -CPI=CPI-S02RD, with a 1 ,4-reducing agent to produce the compound of formula (Z8), in which Re is -CH ₂ CH ₂ -COORC or -CH2CH2-SO2RD, respectively. In still other embodiments, the producing the compound of formula (Z2) includes reacting the compound of formula (Z1 ) with under Horner-Wadsworth-Emmons reaction conditions. In some embodiments, step

(B) includes reacting the compound of formula (Z2) with a 1 ,2-reducing agent to produce a reduction product, and reacting the reduction product with

O

II

under Horner-Wadsworth-Emmons reaction conditions. In certain embodiments, step (C) includes substituting free hydroxyl group in the compound of formula (Z3) with a halogen. In particular embodiments, step (D) includes subjecting the compound of formula (Z4) to reductive metal conditions. In a further aspect, the invention provides the compounds of formula (II), (IID), (ME), (IIF), (IIG), (IIH), (lli), (IVAb), (VAb), (VIIAa), (VIAa), (VIIID), (IXD), (IXF), (IXG), (Z), (Z1 ), (Z2), (Z3), (Z4), (Z5), (Z5A), (Z5B), or (Z6).

The compound of formula (II) is:

where

each of D and D’ is independently H, optionally substituted alkyl, or OP1 , provided that only one of D and D’ is OP1 , where Pi is H, alkyl, a hydroxyl protecting group, and A is a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1 , or A is a group of formula (1 ):

(1 )

where

L is -(CH(OP ₂ ))-, -(C(OH)(OP ₂ ))-, or -C(O)-;

R2 is H and Pi is absent, H, alkyl, or a hydroxyl protecting group, or R ₂ and Pi combine to form a bond;

(i) R3 is H, and P ₂ is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;

(ii) R3 is -(CH ₂ ) _n NP3P4, where P3 is H or an N-protecting group, and (a) P ₂ is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P4 is H or an N-protecting group, (b) P ₂ and P4 combine to form an alkylidene, or (c) each of P ₂ and P4 is H ;

(iii) R3 is -(CH ₂ )nOP5, where P ₂ is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P ₂ and P5, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or

(iv) R3 and P ₂ combine to form an optionally substituted ethylene or a structure selected from the group consisting of:

otecting group;

E is H, optionally substituted alkyl, or optionally substituted alkoxy;

G is O, S, CH , or NRN, where RN is H, an N-protecting group, or optionally substituted alkyl; each Q is independently ORA, SRA, SO RA, OSO RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRB(CO)NRBRA, NRB(CO)ORA, (CO)ORA, 0(C0)RA, (CO)NRBRA, or 0(C0)NRBRA, where each of R _A and RB IS independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;

n, when present, is 0, 1 , or 2;

k is 0 or 1 ;

R is -ORe, -CH(Y) , or -CH (Y), where Re is H or a hydroxyl protecting group;

Rs is H, optionally substituted alkyl, or optionally substituted aryl; and

Y is independently -COORc or -SO RD;

Rc, when present, is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and

RD, when present, is optionally substituted aryl or optionally substituted non-enolizable alkyl. The compound of formula (VIIAa) is:

(VIIAa)

where

R7 is -CH2OPA, -CHO, or

OR ₇ A

RT 7A _A O'~ ^I A ^' < , where each R _7A is independently an optionally substituted alkyl;

R ₉ is -CH2-OP”, -CHO, or -COOP”;

(i) R10 is a hydroxyl protecting group, R is alkyl ether, and R12 is H;

(ii) R10 is a hydroxyl protecting group, and Rn and R12 combine to form a double bond; or

(iii) R10 and R11 combine to form a bond, and R12 is H;

Ai and R14 combine to form oxo, R13 is H or a hydroxyl protecting group, and R15 is H;

or

Ai is H or -OP”, and:

(i) R13 is H or a hydroxyl protecting group, and R14 and R15 combine to form a double bond;

or

(ii) R13 and R14 combine to form a bond, and R15 is H or -OP”;

each P” is independently H or a hydroxyl protecting group; and

each P ₉ is independently a hydroxyl protecting group, and X3 is oxo or X3, together with the carbon atom to which it is attached, is -(CH(OP ))-, where Pn is H or a hydroxyl protecting group; or both P9 groups and X3, together with the atoms to which each is attached, combine to form a ketal.

The compound of formula (VIAa) is:

where R7 is -CHO or

OR7A

R _7A 0. ί , where each R _7A is independently an optionally substituted alkyl;

RIOA is -CH2-CH=CH2, -(CH ₂ )2-CH=CH2, or -(CH ₂ )3-OPIO;

each of R10 and P10 is independently a hydroxyl protecting group;

Ai and R14 combine to form oxo, R13 is FI or a hydroxyl protecting group, and R15 is FI;

or

Ai is H or -OP”, and:

(i) R13 is H or a hydroxyl protecting group, and R14 and R15 combine to form a double bond;

or

(ii) R13 and R14 combine to form a bond, and R15 is H or -OP”;

and

each Pg is independently a hydroxyl protecting group, and X3 is oxo or X3, together with the carbon atom to which it is attached, is -(CH(OP ))-, where Pn is H or a hydroxyl protecting group; or both Pg groups and X3, together with the atoms to which each is attached, combine to form ketal.

The A compound of formula (IID) or (IIF) is:

where

each of D and D’ is independently FI, optionally substituted alkyl, or OP1 , provided that only one of D and D’ is OP1 , where Pi is FI, alkyl, a hydroxyl protecting group, and A is a C1 -6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 1 0 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1 , or A is a group of formula (1 ):

(1 )

where

L is -(CH(OP ₂ ))-, -(C(OH)(OP ₂ ))-, or -C(O)-;

R2 is FI and Pi is absent, FI, alkyl, or a hydroxyl protecting group, or R2 and Pi combine to form a bond;

(i) R3 is FI, and P2 is absent, FI, optionally substituted alkyl, or a hydroxyl protecting group; (ii) Fb is -(OH ₂ ) _P NR ₃ R4, where P3 is H or an N-protecting group, and (a) P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P4 is H or an N-protecting group, (b) P2 and P4 combine to form an alkylidene, or (c) each of P2 and P4 is H ;

(iii) F is -(CH ₂ ) _n OP ₅ , where P ₂ is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P ₂ and P5, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or

(iv) Fb and P combine to form an optionally substituted ethylene or a structure selected from the group consisting of:

otecting group;

E is H, optionally substituted alkyl, or optionally substituted alkoxy;

G is O, S, CPb, or NRN, where RN is H, an N-protecting group, or optionally substituted alkyl; each Q is independently ORA, SRA, SO RA, OSO RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRB(CO)NRBRA, NRB(CO)ORA, (CO)ORA, 0(C0)RA, (CO)NRBRA, or 0(C0)NRBRA, where each of R _A and RB IS independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;

n, when present, is 0, 1 , or 2;

k is 0 or 1 ;

Xi is -CH - or -0-;

X4 is oxo, or X4, together with the atom to which it is attached, is -(CH(OPI ₂ ))-, where Pi ₂ is FI or a hydroxyl protecting group; and

RE is -CHO or -CH(i _+m) (ORF)(2-m), where

m is 1 , and RF is a hydroxyl protecting group,

or

m is 0, and (i) each RF is independently an alkyl or hydroxyl protecting group, or

(ii) both RF combine to form an alkylene.

The compound of formula

where

each of D and D’ is independently H, optionally substituted alkyl, or OP , provided that only one of D and D’ is OP , where Pi is H, alkyl, a hydroxyl protecting group, and A is a C saturated or C unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q , or A is a group of formula (1 ):

L is -(CH(OP ₂ ))-, -(C(OH)(OP ₂ ))-, or -C(O)-;

R is H and Pi is absent, H, alkyl, or a hydroxyl protecting group, or R ₂ and Pi combine to form a bond;

(i) R3 is H, and P is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;

(ii) R3 is -(CH ) _n NP P , where P3 is H or an N-protecting group, and (a) P is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P4 is H or an N-protecting group, (b) P and P combine to form an alkylidene, or (c) each of P and P is H ;

(iii) R3 is -(CH ) _n OP , where P is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P and P5, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or

(iv) R and P combine to form an optionally substituted ethylene or a structure selected from the group consisting of:

otecting group;

E is H, optionally substituted alkyl, or optionally substituted alkoxy;

G is O, S, CH , or NRN, where RN is H, an N-protecting group, or optionally substituted alkyl; each Q is independently ORA, SRA, SO RA, OSO RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRB(CO)NRBRA, NRB(CO)ORA, (CO)ORA, 0(C0)RA, (CO)NRBRA, or 0(C0)NRBRA, where each of R _A and RB IS independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;

n, when present, is 0, 1 , or 2;

k is 0 or 1 ;

Xi is -CH - or -0-; and

X4 is oxo, or X4, together with the atom to which it is attached, is -(CH(OPi ))-, where P is H or a hydroxyl protecting group.

The compound of formula (IIH) is:

where

each of D and D’ is independently H, optionally substituted alkyl, or OP1 , provided that only one of D and D’ is OP1 , where Pi is H, alkyl, a hydroxyl protecting group, and A is a C1 -6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Qi , or A is a group of formula (1 ):

(1 )

where

L is -(CH(OP2))-, -(C(OH)(OP2))-, or -C(O)-;

R2 is H and Pi is absent, H, alkyl, or a hydroxyl protecting group, or R ₂ and Pi combine to form a bond;

(i) Fh is H, and P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;

(ii) Fh is -(CH ₂ ) _n NP ₃ P4, where P3 is FI or an N-protecting group, and (a) P2 is absent, FI, optionally substituted alkyl, or a hydroxyl protecting group, and P4 is FI or an N-protecting group, (b) P ₂ and P4 combine to form an alkylidene, or (c) each of P ₂ and P4 is FI ;

(iii) Fh is -(CH ₂ )nOP5, where P ₂ is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P5 is FI, optionally substituted alkyl, or a hydroxyl protecting group; or P ₂ and P5, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or

(iv) FI3 and P ₂ combine to form an optionally substituted ethylene or a structure selected from the group consisting of:

otecting group;

E is FI, optionally substituted alkyl, or optionally substituted alkoxy;

G is O, S, CFI ₂ , or NRN, where RN is FI, an N-protecting group, or optionally substituted alkyl; each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRB(CO)NRBRA, NRB(CO)ORA, (CO)ORA, 0(C0)RA, (CO)NRBRA, or 0(C0)NRBRA, where each of R _A and RB IS independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;

n, when present, is 0, 1 , or 2;

k is 0 or 1 ;

each Rc is indepenedently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;

Xi is -CH2- or -0-;

X is oxo, or X , together with the atom to which it is attached, is -(CH(OPi2»-, where P12 is H or a hydroxyl protecting group; and

RE is -CHO or -CH(i ₊ m)(ORF)( -m), where

m is 1 , and RF is a hydroxyl protecting group,

or

m is 0, and

(i) each RF is independently an alkyl or hydroxyl protecting group, or

(ii) both RF combine to form an alkylene.

The compound of formula (lli) is:

where

each of D and D’ is independently H, optionally substituted alkyl, or OP1 , provided that only one of D and D’ is OP1 , where Pi is H, alkyl, a hydroxyl protecting group, and A is a C saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1 , or A is a group of formula (1 ):

(1 )

where

L is -(CH(OP ₂ ))-, -(C(OH)(OP ₂ ))-, or -C(O)-;

R2 is H and Pi is absent, H, alkyl, or a hydroxyl protecting group, or R2 and Pi combine to form a bond;

(i) R is H, and P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group; (ii) Fb is -(OH ₂ ) _P NR ₃ R4, where P is H or an N-protecting group, and (a) P is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P is H or an N-protecting group, (b) P and P combine to form an alkylidene, or (c) each of P and P is H ;

(iii) F is -(CH ₂ ) _n OP ₅ , where P ₂ is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P is H, optionally substituted alkyl, or a hydroxyl protecting group; or P ₂ and P , together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or

(iv) Fb and P combine to form an optionally substituted ethylene or a structure selected from the group consisting of:

otecting group;

E is H, optionally substituted alkyl, or optionally substituted alkoxy;

G is O, S, CPb, or NRN, where RN is H, an N-protecting group, or optionally substituted alkyl; each Q is independently ORA, SRA, SO RA, OSO RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRB(CO)NRBRA, NRB(CO)ORA, (CO)ORA, 0(C0)RA, (CO)NRBRA, or 0(C0)NRBRA, where each of R _A and RB IS independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;

n, when present, is 0, 1 , or 2;

k is 0 or 1 ;

each Rc is indepenedently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and

Xi is -CH - or -0-. The compound of formula (VIIID) is:

where

each of D and D’ is independently H, optionally substituted alkyl, or OP1 , provided that only one of D and D’ is OP1 , where Pi is H, alkyl, a hydroxyl protecting group, and A is a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1 , or A is a group of formula (1 ):

(1 )

where

L is -(CH(OP ₂ ))-, -(C(OH)(OP ₂ ))-, or -C(O)-;

R2 is H and Pi is absent, H, alkyl, or a hydroxyl protecting group, or R ₂ and Pi combine to form a bond;

(i) R3 is H, and P ₂ is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;

(ii) R3 is -(CH ₂ ) _n NP3P4, where P3 is H or an N-protecting group, and (a) P ₂ is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P4 is H or an N-protecting group, (b) P ₂ and P4 combine to form an alkylidene, or (c) each of P ₂ and P4 is H ;

(iii) R3 is -(CH ₂ ) _n OP5, where P ₂ is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P ₂ and P5, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or

(iv) R3 and P ₂ combine to form an optionally substituted ethylene or a structure selected from the group consisting of:

each P’ is independently H or a hydroxyl protecting group;

E is H, optionally substituted alkyl, or optionally substituted alkoxy;

G is O, S, CH2, or NRN, where RN is H, an N-protecting group, or optionally substituted alkyl; each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRB(CO)NRBRA, NRB(CO)ORA, (CO)ORA, 0(C0)RA, (CO)NRBRA, or 0(C0)NRBRA, where each of R _A and RB IS independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;

n, when present, is 0, 1 , or 2;

k is 0 or 1 ;

Xi is -CH2-, -CH(Y)-, -C(Y)2-, or -0-, where each Y is independently -COORc or -SO2RD;

X4 is oxo, or X4, together with the atom to which it is attached, is -(CH(OPi2>)-, where P12 is H or a hydroxyl protecting group;

each P9 and R13 is independently a hydroxyl protecting group;

(i) R10 is a hydroxyl protecting group, Rn is alkyl ether, and R12 is H ;

(ii) R10 is a hydroxyl protecting group, and R4 and R5 combine to form a double bond; or

(iii) R10 and R11 combine to form a bond, and R12 is H;

R I is

R5 is optionally substituted acyl;

P13 is H or a hydroxyl protecting group; and

R4C is

where Rc is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and P7, when present, is independently H or a hydroxyl protecting group.

The compound of formula (IVAb) is:

where

each of D and D’ is independently H, optionally substituted alkyl, or OP1 , provided that only one of D and D’ is OP1 , where Pi is H, alkyl, a hydroxyl protecting group, and A is a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1 , or A is a group of formula (1 ):

(1 )

where

L is -(CH(OP ₂ ))-, -(C(OH)(OP ₂ ))-, or -C(O)-;

R ₂ is H and Pi is absent, H, alkyl, or a hydroxyl protecting group, or R ₂ and Pi combine to form a bond;

(i) R3 is H, and P ₂ is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;

(ii) R3 is -(CH ₂ )nNP3P4, where P3 is H or an N-protecting group, and (a) P ₂ is absent,

H, optionally substituted alkyl, or a hydroxyl protecting group, and P4 is H or an N-protecting group, (b) P ₂ and P4 combine to form an alkylidene, or (c) each of P ₂ and P4 is H ;

(iii) R3 is -(CH ₂ )nOP5, where P ₂ is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P ₂ and P5, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or

(iv) R3 and P ₂ combine to form an optionally substituted ethylene or a structure selected from the group consisting of:

otecting group;

E is H, optionally substituted alkyl, or optionally substituted alkoxy;

G is O, S, CH , or NRN, where RN is H, an N-protecting group, or optionally substituted alkyl; each Q is independently ORA, SRA, SO RA, OSO RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRB(CO)NRBRA, NRB(CO)ORA, (CO)ORA, 0(C0)RA, (CO)NRBRA, or 0(C0)NRBRA, where each of R _A and RB IS independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;

n, when present, is 0, 1 , or 2;

k is 0 or 1 ;

Xi is -CH -, -CH(Y)-, -C(Y) -, or -0-, where each Y is independently -COORc or -SO RD;;

each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;

each RD, when present, is independently optionally substituted aryl or optionally substituted non- enolizable alkyl;

X4 is oxo, or X4, together with the atom to which it is attached, is -(CH(OPi ))-, where P is H or a hydroxyl protecting group;

each P is independently a hydroxyl protecting group;

(a1 ) R10 is H or a hydroxyl protecting group, Rn is alkyl ether, and R12 is H;

(a2) R10 is H or a hydroxyl protecting group, and Rn and R12 combine to form a double bond; or

(a3) R and Rn combine to form a bond, and R is H;

(b1 ) Ai and RH combine to form oxo, R13 is H or a hydroxyl protecting group, and R15 is H;

or

(b2) Ai is H or -OP”, and: (i) R13 is H or a hydroxyl protecting group, and RH and R15 combine to form a double bond;

or

(ii) R13 and R14 combine to form a bond, and R15 is H or -OP”; and

(d ) R16 is H, and Rb is H or a hydroxyl protecting group;

or

(c2) R16 and Pe combine to form a double bond;

and

each P”, when present, is independently H or a hydroxyl protecting group.

The compound of formula (VAb) is:

where

each of D and D’ is independently H, optionally substituted alkyl, or OP1 , provided that only one of D and D’ is OP1 , where Pi is H, alkyl, a hydroxyl protecting group, and A is a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1 , or A is a group of formula (1 ):

L is -(CH(OP ₂ ))-, -(C(OH)(OP ₂ ))-, or -C(O)-;

R ₂ is H and Pi is absent, H, alkyl, or a hydroxyl protecting group, or R ₂ and Pi combine to form a bond;

(i) R3 is H, and P ₂ is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;

(ii) R3 is -(CH ₂ ) _n NP3P4, where P3 is H or an N-protecting group, and (a) P ₂ is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P4 is H or an N-protecting group, (b) P ₂ and P4 combine to form an alkylidene, or (c) each of P ₂ and P4 is H ;

(iii) R3 is -(CH ₂ ) _n OP5, where P ₂ is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P ₂ and P5, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or (iv) R and P combine to form an optionally substituted ethylene or a structure selected from the group consisting of:

otecting group;

E is H, optionally substituted alkyl, or optionally substituted alkoxy;

G is O, S, CH , or NRN, where RN is H, an N-protecting group, or optionally substituted alkyl; each Q is independently ORA, SRA, SO RA, OSO RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRB(CO)NRBRA, NRB(CO)ORA, (CO)ORA, 0(C0)RA, (CO)NRBRA, or 0(C0)NRBRA, where each of RA and RB IS independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;

n, when present, is 0, 1 , or 2;

k is 0 or 1 ;

a designates (f?)-stereogenic center, and Z is a sulfonate, chloride, bromide, or iodide; or a designates (S)-stereogenic center, and Z is OR , where R is a hydroxyl protecting group;

Xi is -CH -, -CH(Y)-, -C(Y) -, or -0-, where each Y is independently -COORc or -SO RD;

each P9 is independently a hydroxyl protecting group, and X3 is oxo; or both P9 groups and X3, together with the atoms to which each is attached, combine to form ketal;

Yi is iodide, bromide, or trifluoromethanesulfonate;

each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and

each RD, when present, is independently optionally substituted aryl or optionally substituted non- enolizable alkyl;

(a1 ) R10 is a hydroxyl protecting group, Rn is alkyl ether, and R12 is H;

(a2) R10 is a hydroxyl protecting group, and Rn and R12 combine to form a double bond;

or

(a3) R and Rn combine to form a bond, and R12 is H; (b1 ) Ai and R combine to form oxo, R is a hydroxyl protecting group, and R15 is H;

or

(b2) Ai is H or -OP”, and:

(i) R13 is a hydroxyl protecting group, and RH and R15 combine to form a double bond;

or

(ii) R13 and R14 combine to form a bond, and R15 is H or -OP”;

and

each P” is independently a hydroxyl protecting group.

The compound of formula (IXD) is:

where

each of D and D’ is independently H, optionally substituted alkyl, or OP , provided that only one of D and D’ is OP , where Pi is H, alkyl, a hydroxyl protecting group, and A is a C saturated or C unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q , or A is a group of formula (1 ):

L is -(CH(OP ₂ ))-, -(C(OH)(OP ₂ ))-, or -C(O)-;

R is H and Pi is absent, H, alkyl, or a hydroxyl protecting group, or R ₂ and Pi combine to form a bond;

(i) R3 is H, and P is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;

(ii) R3 is -(CH ) _n NP P , where P3 is H or an N-protecting group, and (a) P is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P is H or an N-protecting group, (b) P and P combine to form an alkylidene, or (c) each of P and P is H ;

(iii) R3 is -(CH ₂ )nOP5, where P is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and Ps is H, optionally substituted alkyl, or a hydroxyl protecting group; or P ₂ and P5, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or (iv) R3 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:

otecting group;

E is H, optionally substituted alkyl, or optionally substituted alkoxy;

G is O, S, CH2, or NRN, where RN is H, an N-protecting group, or optionally substituted alkyl; each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRB(CO)NRBRA, NRB(CO)ORA, (CO)ORA, 0(C0)RA, (CO)NRBRA, or 0(C0)NRBRA, where each of RA and RB IS independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;

n, when present, is 0, 1 , or 2; each Y is independently -COORc or -SO2RD;

each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;

each RD, when present, is independently optionally substituted aryl or optionally substituted non- enolizable alkyl;

X4 is oxo, or X4, together with the atom to which it is attached, is -(CH(OPi2»-, where P12 is H or a hydroxyl protecting group;

Ry is -CHO, -CH2OPA or re each RZA is independently an optionally substituted alkyl;

hydroxyl protecting group, Rn is alkyl ether, and R12 is H ;

hydroxyl protecting group, and Rn and R12 combine to form a double bond; or

(iii) R10 and R11 combine to form a bond, and R12 is H; Ai and RM combine to form oxo, F½ is H or a hydroxyl protecting group, and R15 is H; or

Ai is H or -OP”, and

(i) R is H or a hydroxyl protecting group, and RM and R15, together with the atoms to which each is attached, combine to form a double bond;

or

(ii) R13 and RM combine to form a bond, and R15 is H or -OP”; each P9 is independently H or a hydroxyl protecting group,

each P9 is independently a hydroxyl protecting group, and X3 is oxo, or X3, together with the atom to which it is attached, combines to form -(CH(OP ))-, where P11 is H or a hydroxyl protecting group; or both P9 and X3, together with the atoms to which each is attached, combine to form a ketal; and

R19A is H, -OP”, or Y, and R19B is H ; or Rm and Rm, together with the atoms to which each is attached, combine to form a double bond.

The compound of formula (IXF) is:

where

each of D and D’ is independently H, optionally substituted alkyl, or OP1 , provided that only one of D and D’ is OP1 , where Pi is FI, alkyl, a hydroxyl protecting group, and A is a C1-6 saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q1 , or A is a group of formula (1 ):

R ₂

V~'L'' ¾

(1 )

where

L is -(CH(OP ₂ ))-, -(C(OH)(OP ₂ ))-, or -C(O)-;

R ₂ is FI and Pi is absent, FI, alkyl, or a hydroxyl protecting group, or R ₂ and Pi combine to form a bond;

(i) R3 is FI, and P ₂ is absent, FI, optionally substituted alkyl, or a hydroxyl protecting group;

(ii) R3 is -(CFI ₂ ) _n NP3P4, where P3 is FI or an N-protecting group, and (a) P ₂ is absent, FI, optionally substituted alkyl, or a hydroxyl protecting group, and P4 is FI or an N-protecting group, (b) P ₂ and P4 combine to form an alkylidene, or (c) each of P ₂ and P4 is FI ; (iii) R3 is -(CH2)nOP5, where P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P2 and P5, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or

(iv) R3 and P2 combine to form an optionally substituted ethylene or a structure selected from the group consisting of:

otecting group;

E is H, optionally substituted alkyl, or optionally substituted alkoxy;

G is O, S, CH2, or NRN, where RN is H, an N-protecting group, or optionally substituted alkyl; each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRB(CO)NR _B RA, NRB(CO)ORA, (CO)ORA, 0(C0)RA, (CO)NRBRA, or 0(C0)NRBRA, where each of R _A and RB IS independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;

n, when present, is 0, 1 , or 2;

k is 0 or 1 ;

Xi is -CH2-, -CH(Y)-, -C(Y)2-, or -0-, where each Y is independently -COORc or -SO2RD;

X4 is oxo, or X4, together with the atom to which it is attached, is -(CH(OPi2»-, where P12 is H or a hydroxyl protecting group;

each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;

each RD, when present, is independently optionally substituted aryl or optionally substituted non- enolizable alkyl;

Ro is -CHO, -CH2OP”, -CH=CH ₂ , -CH(OP”)CH ₂ OP”, -C(0)-CH ₂ P(0)(0RC)2, or halogen;

(i) R10 is a hydroxyl protecting group, Rn is alkyl ether, and R12 is H ;

(ii) R10 is a hydroxyl protecting group, and Rn and R12 combine to form a double bond; or (iii) R10 and R11 combine to form a bond, and R12 is H;

Ai and Ru combine to form oxo, R13 is H or a hydroxyl protecting group, and R15 is H;

or

Ai is H or -OP”, and

(i) R13 is H or a hydroxyl protecting group, and Ru and R15, together with the atoms to which each is attached, combine to form a double bond;

or

(ii) R13 and Ru combine to form a bond, and R15 is H or -OP”; each Pg is independently H or a hydroxyl protecting group;

and

each of P”, P9, and P13 is independently H or a hydroxyl protecting group.

The compound of formula (IXG) is:

where

R7 is— CHO,— CH2OPA, or ere each RZA is independently an optionally substituted alkyl;

a hydroxyl protecting group, R is alkyl ether, and R12 is H ;

a hydroxyl protecting group, and Rn and R12 combine to form a double bond; or

(iii) R10 and R11 combine to form a bond, and R12 is H;

Ai and Ru combine to form oxo, R13 is H or a hydroxyl protecting group, and R15 is H;

or

Ai is H or -OP”, and

(i) R13 is H or a hydroxyl protecting group, and Ru and R15, together with the atoms to which each is attached, combine to form a double bond;

or

(ii) R13 and Ru combine to form a bond, and R15 is H or -OP”; each Pg is independently H or a hydroxyl protecting group,

each Pg is independently a hydroxyl protecting group, and X3 is oxo, or X3, together with the atom to which it is attached, combines to form -(CH(OPn))-, where Pu is H or a hydroxyl protecting group; or both P9 and X3, together with the atoms to which each is attached, combine to form a ketal; and Ri 9A is H, -OP”, or Y, and R19B is H; or R and Ri9B, together with the atoms to which each is attached, combine to form a double bond.

In a yet further aspect, the invention provides a compound of formula (Z), (Z1 ), (Z2), (Z3), (Z4), (Z5), (Z5A), (Z5B), or (Z6), as described herein.

In the halichondrin macrolide and halichondrin macrolide analog structures herein, when Pi is absent, each of D and D' is independently H or optionally substituted alkyl, and, when P2 is absent, L is -C(O)-.

Definitions

Compounds useful in the invention may be isotopically labeled compounds. Useful isotopes include hydrogen, carbon, nitrogen, and oxygen (e.g., ² H, ³ H, ¹³ C, ¹⁴ C, ^{1 5} N, ^{1 8} 0, and ¹⁷ 0). Isotopical ly-labeled compounds can be prepared by synthesizing a compound using a readily available isotopically-labeled reagent in place of a non-isotopically-labeled reagent.

For any of the following chemical definitions, a number following an atomic symbol indicates that total number of atoms of that element that are present in a particular chemical moiety. As will be understood, other atoms, such as hydrogen atoms, or substituent groups, as described herein, may be present, as necessary, to satisfy the valences of the atoms. For example, an unsubstituted C2 alkyl group has the formula -CH2CH3. When used with the groups defined herein, a reference to the number of carbon atoms includes the divalent carbon in acetal and ketal groups but does not include the carbonyl carbon in acyl, ester, carbonate, or carbamate groups. A reference to the number of oxygen, nitrogen, or sulfur atoms in a heteroaryl group only includes those atoms that form a part of a heterocyclic ring.

By“acetal” is meant -0-(CHR)-0-, where R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted arylalkyl, or R group is a bond to an enumerated carbon atom, as shown in Chart 1 , within the intermediate or within the halichondrin macrolide or analog thereof.

By“acetyl” is meant an acyl, in which R is -CXnPta-n, where n is 0, 1 , 2, or 3, and each X is independently alkoxy or halogen, provided that, when n is 3, each X is independently halogen, and, when n is 2, either both of the X groups are independently halogen or both of the X groups are independently alkoxy. An acetyl group may be substituted (i.e., n is 1 , 2, or 3) or unsubstituted (i.e., n is 0).

By“acyl” is meant -C(0)R, where R is H, alkyl, alkenyl, aryl, or arylalkyl. In exemplary acyl groups, R is H, C1-12 alkyl (e.g., C1 -8, C1 -6, C1-4, C2-7, C3-12, or C3-6 alkyl), C2-12 alkenyl (e.g., C2-8, C2-6, C2-4, C3-12, or C3-6 alkenyl), Ce-20 aryl (e.g., Ce-14, C6-10, Ce-20, or Cs-14 aryl), monocyclic C1 -6 heteroaryl (e.g., monocyclic C1-4 or C2-6 heteroaryl), C4-19 heteroaryl (e.g., C4-10 heteroaryl), (C6-i4)aryl(Ci-6)alkyl, (Ci-6)heteroaryl(Ci-6)alkyl, or (C4-9)heteroaryl(Ci-6)alkyl. As defined herein, any heteroaryl group present in an acyl group has from 1 to 4 heteroatoms selected independently from O, N, and S. An acyl group can be unsubstituted or substituted (e.g., optionally substituted acyl). In the optionally substituted acyl group, the substituent R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted arylalkyl. In some embodiments, acyl is C2-10 acyl. By“acylating agent” is meant a compound that reacts with an amine or a hydroxyl group to produce an amide or an ester, respectively. An acylating agent has a formula R-LG, where R is acyl, and LG is halogen, carbonate, or -OR’, where R’ is acyl.

By“alkoxide” is meant an anionic compound RO ^_ , where R is alkyl. A counterion for alkoxide can be an alkali metal cation, an alkali earth metal cation, or a tetraalkylammonium cation. Alkoxide can be optionally substituted in the same manner as alkyl.

By“alkoxy” is meant -OR, where R is alkyl. Alkoxy can be optionally substituted in the same manner as alkyl.

By“alkoxyalkyl” is meant -OR, where R is alkyl substituted by alkoxy. Each portion of the alkoxyalkyl can be optionally substituted in the same manner as alkyl.

By“alkoxyaryl” is meant -R’(R”) _n , where n is 1 or 2, R' is arylene and R” is alkoxy, as defined herein. R’ can be further optionally substituted in the same manner as aryl. R” can be optionally substituted in the same manner as alkyl.

By“alkoxyarylalkyl’’ is meant -R’(R”(R”’) _n ), where n is an integer from 1 to 3, R’ is alkylene, R” is arylene, and R’” is alkoxy, as defined herein. R’ can be optionally substituted in the same manner as alkyl. R” can be further optionally substituted in the same manner as aryl. R”’ can be optionally substituted in the same manner as alkyl.

By“alkyl” is meant a straight or branched chain saturated cyclic (i.e., cycloalkyl) or acyclic hydrocarbon group of from 1 to 12 carbons, unless otherwise specified. In some embodiments, alkyl is C alkyl.

Exemplary alkyl groups include C - , C - , C - , C - , C - , and C alkyl. Specific examples include methyl, ethyl, 1 -propyl, 2-propyl, 2-methyl-1 -propyl, 1 -butyl, 2-butyl, and the like. Alkyl group can be optionally substituted with 1 , 2, 3, or 4 substituents selected from the group consisting of halogen, hydroxy, alkoxy, aryloxy, arylalkyloxy, amino, oxo, alkylthio, alkylenedithio, alkylamino, [alkenyl]alkylamino, [aryl]alkylamino, [arylalkyl]alkylamino, dialkylamino, silyl, sulfonyl, cyano, nitro, carboxyl, and azido.

By“alkylamino” is meant -NHR, where R is alkyl. By“[alkenyl]alkylamino” is meant -NRR’, where R is alkyl, and R’ is alkenyl. By“[aryl]alkylamino” is meant -NRR’, where R is alkyl, and R’ is aryl. By

“[arylalkyl]alkylamino” is meant -NRR’, where R is alkyl, and R’ is arylalkyl. By“dialkylamino” is meant -NR , where each R is alkyl, selected independently.

By“alkylaryl” is meant -R’(R”) _n , where n is an integer from 1 to 3, R’ is arylene, and R” is alkyl. Alkylaryl can be optionally substituted in the same manner as defined for each R’ and R” group.

By“alkylene” is meant a multivalent alkyl group. Alkylene groups can be optionally substituted in the same manner as alkyl groups. Alkylene may be a divalent alkylene. For example, a Ci alkylene group is -CH -. By“alkylenedithio” is meant -S-alkylene-S-. Alkylenedithio can be optionally substituted in the same manner as an alkylene group.

By“alkylhaloaryl” is meant -R’(R”) _n -R”\ where n is an integer from 1 to 5 and R’ is arylene, R” is halogen, and R’” is alkylene, as defined herein. R’ can be further optionally substituted in the same manner as aryl.

R’” can be further optionally substituted in the same manner as alkyl.

By“alkylthio” is meant -SR, where R is alkyl. Alkylthio can be optionally substituted in the same manner as an alkyl group.

By“alkenyl” is meant a straight or branched chain cyclic or acyclic hydrocarbon group of, unless otherwise specified, from 2 to 12 carbons and containing one or more carbon-carbon double bonds. In some embodiments, alkenyl is C2-6 alkenyl. Exemplary alkenyl groups include C2-8, C2-7, C2-6, C2-4, C3-12, and C3-6 alkenyl. Specific examples include ethenyl (i.e. , vinyl), 1 -propenyl, 2-propenyl (i.e. , allyl), 2-methyl-1 - propenyl, 1 -butenyl, 2-butenyl (i.e., crotyl), and the like. Alkenyl group can be optionally substituted in the same manner as alkyl groups. Alkenyl groups, used in any context herein, may also be substituted with an aryl group.

By“amido” is meant -NHR, where R is acyl. Amido can be optionally substituted in the same manner as acyl.

By“aminal” is meant -O-CR2-NR’-, where each R is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted arylalkyl, or both R groups are together optionally substituted alkylene, and R’ is H or an /V-protecting group. In particular, R’ can be an N- protecting group (e.g., Boc).

By“amino” is meant -NR2, where N and R2 combine to form azido, or each R is independently H or an N- protecting group, or both R combine to form an A/-protecting group. Amino can be unmasked, when each R is H, or masked, when at least one R is not H. Thus, optionally masked amino can be masked or unmasked amino.

By“aminoalkyl” is meant -R’(R”) _n , where n is 1 or 2, R’ is alkylene, and R” is amino, as defined herein. R’ can be optionally substituted in the same manner as an alkyl group.

By“aryl” is meant a monocyclic or multicyclic ring system having one or more aromatic rings, where the ring system is carbocyclic. Exemplary aryl groups include C6-20, Ce-is, Ce-io, Ce-20, and Ce-i s aryl. A preferred aryl group is a Ce-io aryl group. Specific examples of carbocyclic aryl groups include phenyl, indanyl, indenyl, naphthyl, phenanthryl, anthracyl, and fluorenyl. Aryl group can be optionally substituted with 1 , 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, halogen, alkoxy, aryloxy, arylalkyloxy, alkylthio, alkylenedithio, alkylamino, [alkenyl]alkylamino, [aryl]alkylamino, [arylalkyl]alkylamino, dialkylamino, silyl, sulfonyl, cyano, nitro, carboxyl, and azido. By“arylalkyl” is meant -R’R”, where R’ is alkylene, and R” is aryl. Arylalkyl can be optionally substituted in the same manner as defined for each R’ and R” group.

By“arylalkyloxy” is meant -OR, where R is arylalkyl. Arylalkyloxy can be optionally substituted in the same manner as defined for arylalkyl.

By“arylene” is meant a multivalent aryl group. Arylene groups can be optionally substituted in the same manner as aryl groups. For example, a Ce arylene group is phenylene.

By“aryloxy” is meant -OR, where R is aryl. Aryloxy can be optionally substituted in the same manner as aryl.

By“azido” is meant -N3.

By“boronate” is meant -OB(R)0-, where R is alkyl, alkenyl, aryl, arylalkyl, alkoxy, or 2,6-diacetamidophenyl. Boronate can be substituted, when R is a substituted alkyl, substituted alkenyl, substituted aryl, substituted arylalkyl, or substituted alkoxy. Alternatively, boronate can be unsubstituted, when R is unsubstituted alkyl, unsubstituted alkenyl, aryl, unsubstituted arylalkyl, unsubstituted alkoxy, or 2,6-diacetamidophenyl.

By“carbamate” is meant a group, when a hydroxyl protecting group, having the formula -OC(0)NR2, or, when an amine protecting group, having the formula -NR’-C(0)OR, where each R and R’ is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted arylalkyl.

By“carbonate” is meant -OC(0)OR, where R is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted arylalkyl.

By“carbonyl” is meant -C(O)-.

By“carboxyl” is meant -C(0)OH, in free acid, ionized, or salt form.

By“carboxylic acid” is meant R-OH, where R is optionally substituted acyl.

By“carboxylic acid anhydride” is meant R-O-R, where each R is independently optionally substituted acyl.

By“cyclic carbonate” is meant -0C(0)0- that is part of a ring.

By“dicarbonyl” is meant -C(0)-C(0)-. Dicarbonyl-dioxo is -0C(0)-C00-

By“ester” is meant -OC(0)R, where -C(0)R is an optionally substituted acyl group. By“ether” is meant -OR, where R is alkyl, alkenyl, arylalkyl, silyl, or 2-tetrahydropyranyl. Ether can be optionally substituted as defined for each R group.

By“halichondrin macrolide” is meant a lactone including the structure of carbons 1 -30 as shown in Chart 1 , where carbons 29 and 30 form part of a five- or six-membered ring.

By“haloalkyl” is meant -R’(R”) _n , where n is an integer from 1 to 5 and R’ is alkylene and R” is halogen, as defined herein. R’ can be further optionally substituted in the same manner as alkyl

By“haloaryl” is meant -R’(R”) _n , where n is an integer from 1 to 5 and R’ is arylene and R” is halogen, as defined herein. R’ can be further optionally substituted in the same manner as aryl.

By“haloarylalkyl” is meant -R’(R”(R”’) _n ), where n is an integer from 1 to 5 and R’ is alkylene, R” is arylene, and R’” is halogen, as defined herein. R’ can be further optionally substituted in the same manner as alkyl. R” can be further optionally substituted in the same manner as aryl.

By“halogen” is meant fluoro, chloro, bromo, or iodo.

By“heterocyclic radical” is meant a 5-, 6- or 7-membered ring, unless otherwise specified, containing one, two, three, or four heteroatoms independently selected from the group containing nitrogen, oxygen, and sulfur. The 5-membered ring has zero to one double bonds, and the 6- and 7-membered rings have zero to two double bonds. Certain heterocyclyl groups include from 1 to 9 carbon atoms. Other such groups may include up to 12 carbon atoms. The term“heterocyclyl” also represents a heterocyclic compound having a bridged multicyclic structure in which one or more carbons and/or heteroatoms bridges two non-adjacent members of a monocyclic ring, e.g., a quinuclidinyl group. The term“heterocyclyl” includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one, two, or three carbocyclic rings, e.g., an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocyclic ring, such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl and the like. Examples of fused heterocyclyls include tropanes and 1 ,2,3,5,8,8a- hexahydroindolizine. Heterocyclics include pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidiniyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, thiazolidinyl, isothiazolyl, isoindazoyl, triazolyl, tetrazolyl, oxadiazolyl, purinyl, thiadiazolyl {e.g., 1 ,3,4-thiadiazole), tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, benzofuranyl, benzothienyl and the like. Still other exemplary heterocyclyls include: 2,3,4,5-tetrahydro-2-oxo-oxazolyl; 2,3-dihydro-2-oxo-1 H-imidazolyl; 2,3,4,5-tetrahydro-5-oxo-1 H- pyrazolyl {e.g., 2,3,4,5-tetrahydro-2-phenyl-5-oxo-1 H-pyrazolyl); 2,3,4,5-tetrahydro-2,4-dioxo-1 H-imidazolyl {e.g., 2,3,4,5-tetrahydro-2,4-dioxo-5-methyl-5-phenyl-1 H-imidazolyl); 2,3-dihydro-2-thioxo-1 ,3,4-oxadiazolyl {e.g., 2,3-dihydro-2-thioxo-5-phenyl-1 ,3,4-oxadiazolyl) ; 4,5-dihydro-5-oxo-1 /-/-triazolyl {e.g., 4,5-dihydro-3- methyl-4-amino 5-oxo-1 /-/-triazolyl) ; 1 ,2,3,4-tetrahydro-2,4-dioxopyridinyl {e.g., 1 ,2,3,4-tetrahydro-2,4-dioxo- 3,3-diethylpyridinyl); 2,6-dioxo-piperidinyl (e.g., 2,6-dioxo-3-ethyl-3-phenylpiperidinyl); 1 ,6-dihydro-6- oxopyridiminyl; 1 ,6-dihydro-4-oxopyrimidinyl (e.g., 2-(methylthio)-1 ,6-dihydro-4-oxo-5-methylpyrimidin-1 -yl);

1 ,2,3,4-tetrahydro-2,4-dioxopyrimidinyl (e.g., 1 ,2,3,4-tetrahydro-2,4-dioxo-3-ethylpyrimidinyl); 1 ,6-dihydro-6- oxo-pyridazinyl (e.g., 1 ,6-dihydro-6-oxo-3-ethylpyridazinyl); 1 ,6-dihydro-6-oxo-1 ,2,4-triazinyl (e.g., 1 ,6- dihydro-5-isopropyl-6-oxo-1 ,2,4-triazinyl); 2,3-dihydro-2-oxo-1 H-indolyl (e.g., 3,3-dimethyl-2,3-dihydro-2-oxo- 1 /7-indolyl and 2,3-dihydro-2-oxo-3,3’-spiropropane-1 /7-indol-1 -yl); 1 ,3-dihydro-1 -oxo-2/-/-iso-indolyl; 1 ,3- dihydro-1 ,3-dioxo-2H-iso-indolyl; 1 H-benzopyrazolyl (e.g., 1 -(ethoxycarbonyl)- 1 H-benzopyrazolyl); 2,3- dihydro-2-oxo-1 H-benzimidazolyl (e.g., 3-ethyl-2,3-dihydro-2-oxo-1 H-benzimidazolyl); 2,3-dihydro-2-oxo- benzoxazolyl (e.g., 5-chloro-2,3-dihydro-2-oxo-benzoxazolyl); 2,3-dihydro-2-oxo-benzoxazolyl; 2-oxo-2H- benzopyranyl; 1 ,4-benzodioxanyl; 1 ,3-benzodioxanyl ; 2,3-dihydro-3-oxo,4H-1 ,3-benzothiazinyl; 3,4-dihydro- 4-oxo-3/7-quinazolinyl (e.g., 2-methyl-3,4-dihydro-4-oxo-3/-/-quinazolinyl); 1 ,2,3,4-tetrahydro-2,4-dioxo-3H- quinazolyl (e.g., 1 -ethyl-1 ,2,3,4-tetrahydro-2,4-dioxo-3H-quinazolyl); 1 ,2,3,6-tetrahydro-2,6-dioxo-7 -/-purinyl (e.g., 1 ,2,3,6-tetrahydro-1 ,3-dimethyl-2,6-dioxo-7 /7 -purinyl); 1 ,2,3,6-tetrahydro-2,6-dioxo-1 /7-purinyl (e.g.,

1 ,2,3,6-tetrahydro-3,7-dimethyl-2,6-dioxo-1 /-/ -purinyl) ; 2-oxobenz[c,d|indolyl; 1 ,1 -dioxo-2H-naphth[1 ,8- naphthylenedicarboxamido. Fleterocyclic groups also include groups of the formula

F' is selected from the group consisting of -CH -, -CH O- and -0-, and G' is selected from the group consisting of -C(O)- and -(C(R’)(R”)) _V -, where each of R’ and R” is, independently, selected from the group consisting of hydrogen or alkyl of one to four carbon atoms, and v is one to three and includes groups, such as 1 ,3-benzodioxolyl, 1 ,4-benzodioxanyl, and the like. Any of the heterocyclyl groups mentioned herein may be optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of: (1 ) alkanoyl (e.g., formyl, acetyl, and the like); (2) alkyl {e.g., alkoxyalkylene,

alkylsulfinylalkylene, aminoalkylene, azidoalkylene, acylalkylene, haloalkylene (e.g., perfluoroalkyl), hydroxyalkylene, nitroalkylene, or thioalkoxyalkylene); (3) alkenyl ; (4) alkynyl ; (5) alkoxy (e.g.,

perfluoroalkoxy); (6) alkylsulfinyl ; (7) aryl; (8) amino; (9) aryl-alkylene; (10) azido; (1 1 ) cycloalkyl; (12) cycloalkyl-alkylene; (13) cycloalkenyl; (14) cycloalkenyl-alkylene; (1 5) halo; (16) heterocyclyl (e.g., heteroaryl); (17) (heterocyclyl)oxy; (18) (heterocyclyl)aza; (19) hydroxy; (20) oxo; (21 ) nitro; (22) sulfide; (23) thioalkoxy; (24) -(CH2) _q C02R ^A , where q is an integer from zero to four, and R ^A is selected from the group consisting of (a) alkyl, (b) aryl, (c) hydrogen, and (d) aryl-alkylene; (25) -(CH ) _q CONR ^B R ^c , where q is an integer from zero to four and where R ^B and R ^c are independently selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) aryl-alkylene; (26) -(CH ) _q SC> R ^D , where q is an integer from zero to four and where R ^D is selected from the group consisting of (a) alkyl, (b) aryl, and (c) aryl-alkylene; (27) - (CH ) _q SC> NR ^E R ^F , where q is an integer from zero to four and where each of R ^E and R ^F is, independently, selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) aryl-alkylene; (28) thiol; (29) aryloxy; (30) cycloalkoxy; (31 ) arylalkoxy; (31 ) heterocyclyl-alkylene (e.g., heteroaryl-alkylene); (32) silyl; (33) cyano; and (34) -S(0)R ^H where R ^H is selected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) aryl-alkylene. In some embodiments, each of these groups can be further substituted as described herein. For example, the alkylene group of an aryl-Ci-alkylene or a heterocyclyl-Ci-alkylene can be further substituted with an oxo group to afford the respective aryloyl and (heterocyclyl)oyl substituent group. In addition, when a heterocyclyl group is present in a bioreversible group of the invention it may be substituted with an ester, thioester, or disulfide group that is bound to a conjugating moiety, a hydrophilic functional group, or an auxiliary moiety as defined herein.

By“heterocyclic radical alkyl,” as used herein, represents an alkyl group substituted with a heterocyclic radical. The heterocyclic radical and alkyl portions may be substituted as the individual groups as described herein.

By“hydroxyalkyl” is meant -R’(R”) _n , where n 1 or 2, R’ is alkylene and R” is hydroxyl, as defined herein. R’ can be further optionally substituted in the same manner as alkyl.

By“hydroxyaryl” is meant— R’(R”) _n , where n is 1 or 2, R’ is arylene and R” is hydroxyl, as defined herein. R' can be further optionally substituted in the same manner as aryl.

By“hydroxyl” is meant -OH.

By“hydroxyl protecting group” is meant any group capable of protecting the oxygen atom to which it is attached from reacting or bonding. Hydroxyl protecting groups are known in the art, e.g., as described in Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-lnterscience, 4th Edition, 2006. Exemplary protecting groups (with the oxygen atom to which they are attached) are independently selected from the group consisting of esters, carbonates, carbamates, sulfonates, and ethers. In exemplary ester hydroxyl protecting groups, R of the acyl group is C1-12 alkyl (e.g ., C1-8, C1-6, C1-4, C2-7, C3-12, and C3-6 alkyl), C2-12 alkenyl (e.g., C2-8, C2-6, C2-4, C3-12, and C3-6 alkenyl), carbocyclic C6-20 aryl (e.g. , C6-15, Ce-io, Ce-2o, and Ce-is aryl), monocyclic C1-6 heteroaryl (e.g., C1-4 and C2-6 heteroaryl), C4-19 heteroaryl (e.g., C4-10 heteroaryl), (C ₆ -i ₅ )aryl(Ci - ₆ )alkyl, (C ₄ -i ₉ )heteroaryl(Ci^)alkyl, or (Ci- ₆ )heteroaryl(Ci- ₆ )alkyl. Specific examples of acyl groups for use in esters include formyl, benzoylformyl, acetyl (e.g., unsubstituted or chloroacetyl, trifluoroacetyl, methoxyacetyl , triphenylmethoxyacetyl, and p-chlorophenoxyacetyl), 3-phenylpropionyl , 4- oxopentanoyl, 4,4-(ethylenedithio)pentanoyl, pivaloyl (Piv), vinylpivaloyl, crotonoyl, 4-methoxy-crotonoyl, naphthoyl (e.g. , 1 - or 2-naphthoyl), and benzoyl (e.g., unsubstituted or substituted, e.g., p-methoxybenzoyl , phthaloyl (including salts, such a triethylamine and potassium), p-bromobenzoyl, and 2,4,6-trimethylbenzoyl). As defined herein, any heteroaryl group present in an ester group has from 1 to 4 heteroatoms selected independently from O, N, and S. In exemplary carbonate hydroxyl protecting groups, R is C1-12 alkyl (e.g. , C1-8, C1-6, C1-4, C2-7, C3-12, and C3-6 alkyl), C2-12 alkenyl (e.g., C2-8, C2-6, C2-4, C3-12, and C3-6 alkenyl), carbocyclic C6-20 aryl (e.g., Ce-15, Ce-i o, C8-20, and Ce-is aryl), monocyclic C1-6 heteroaryl (e.g ., C1-4 and C2-6 heteroaryl), C4-19 heteroaryl (e.g., C4-10 heteroaryl), (C6-1 s)aryl(Ci -6)alkyl , (C4-i9)heteroaryl(Ci-6)alkyl, or (Ci- ₆ )heteroaryl(Ci- ₆ )alkyl. Specific examples include methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl , 2- (trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, t-butyl, p-nitrobenzyl, and benzyl carbonates. As defined herein, any heteroaryl group present in a carbonate group has from 1 to 4 heteroatoms selected independently from O, N, and S. In exemplary carbamate hydroxyl protecting groups, each R is

independently H, C1-12 alkyl (e.g., C1-8, C1-6, C1-4, C2-7, C3-12, and C3-6 alkyl), C2-12 alkenyl (e.g., C2-8, C2-6, C2^, C3-12, and C3-6 alkenyl), carbocyclic C6-20 aryl (e.g. , C6-15, C6-10, Ce-2o, and Ce-is aryl), monocyclic C1-6 heteroaryl (e.g ., C1-4 and C2-6 heteroaryl), C4-19 heteroaryl (e.g., C4-10 heteroaryl), (C6-is)aryl(Ci-6)alkyl, (C - 1 s)heteroaryl(C i-6)alkyl , or (Ci-6)heteroaryl(Ci-e)alkyl. Specific examples include N-phenyl and N-methyl-N-(o- nitrophenyl) carbamates. As defined herein, any heteroaryl group present in a carbamate group has from 1 to 4 heteroatoms selected independently from O, N, and S. Exemplary ether hydroxyl protecting groups include C1-12 alkyl (e.g., C1-8, C1 -6, C1-4, C2-7, C3-12, and C3-6 alkyl), C2-12 alkenyl (e.g., C2-8, C2-6, C2-4, C3-12, and C3-6 alkenyl), (Ce-i5)aryl(Ci-6)alkyl, (C ₄ -i9)heteroaryl(Ci-6)alkyl, (Ci-6)heteroaryl(Ci-6)alkyl, (Ci-e)alkoxy(Ci- 6)alkyl, (C -6)alkylth io(Ci -e)alkyl , (C6-io)aryl(Ci-6)alkoxy(Ci-6)alkyl, and silyl (e.g., tri(Ci-6 alkyl)silyl, tri(C6-io aryl or C1 -6 heteroaryl)silyl, di(C6-io aryl or C heteroaryl)(Ci-6 alkyl)silyl, and (Ce-io aryl or C1 -6 heteroaryl)di(Ci-6 alkyl)silyl). Specific examples of alkylethers include methyl and t-butyl, and an example of an alkenyl ether is allyl. Ether hydroxyl protecting groups can be used to protect a carboxyl group (e.g., with a C1 -12 alkyl (e.g., C1-8, C1 -6, C1-4, C2-7, C3-12, and C3-6 alkyl), (Ce-i s)aryl(Ci -e)alkyl , (Ci-e)alkoxy(Ci-6)alkyl, (C1 -6)alkylthio(Ci-e)alkyl , or (C6-io)aryl(Ci-6)alkoxy(Ci-6)alkyl). Examples of alkoxyalkyls and alkylthioalkyls that can be used as ether hydroxyl protecting groups include methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, and b- (trimethylsilyl)ethoxymethyl. Examples of arylalkyl groups that can be used as ether hydroxyl protecting groups include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, triphenylmethyl (trityl), o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, naphthylmethyl, and 2- and 4-picolyl ethers. Specific examples of silylethers include trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBS), t- butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), and triphenylsilyl (TPS) ethers. An example of an arylalkyloxyalkylether is benzyloxymethyl ether. As defined herein, any heteroaryl group present in an ether group has from 1 to 4 heteroatoms selected independently from O, N, and S. Vicinal or 1 ,3-diols may be protected with a diol protecting group (e.g., to produce a“cyclic protected diol”), such as acetal (e.g., containing C1-6 alkylene), ketal (e.g., containing C3-6 alkylene or C3 6 cycloalkyl), cyclic silylene, cyclic carbonate, and cyclic boronate. Examples of acetal and ketal groups include methylene-dioxo, ethylidene- dioxo, benzylidene-dioxo, isopropylidene-dioxo, cyclohexylidene-dioxo, and cyclopentylidene-dioxo. An example of a cyclic silylene is di-t-butylsilylene. Another diol protecting group is 1 ,1 ,3,3- tetraisopropylsiloxanediyl. Examples of cyclic boronates include methyl, ethyl, phenyl, and 2,6- diacetamidophenyl boronates. Protecting groups may be substituted as is known in the art; for example, aryl and arylalkyl groups, such as phenyl, benzyl, naphthyl, or pyridinyl, can be substituted with C1-6 alkyl, Cue alkoxy, nitro, cyano, carboxyl, or halogen. Alkyl groups, such as methyl, ethyl, isopropyl, n-propyl, t-butyl, n- butyl, and sec-butyl, and alkenyl groups, such as vinyl and allyl, can also be substituted with oxo, arylsulfonyl, halogen, and trialkylsilyl groups. Preferred protecting groups are TBS and Piv. Protecting groups that are orthogonal are removed under different conditions, as is known in the art.

By“imido” is meant -NR , where each R is independently optionally substituted acyl.

By“ketal” is meant -O-CR -O-, where each R is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted arylalkyl, or both R groups are together optionally substituted alkylene, or each of the R groups is a bond to an enumerated carbon atom, as shown in Chart 1 , within the intermediate or within the halichondrin macrolide or analog thereof.

By“macrocyclic” is meant a compound containing at least one n-membered ring, where n is equal to or greater than 10. By“non-enolizable” is meant a group that, either alone or in combination with a group to which it is attached, cannot form an enol through a deprotonation/reprotonation sequence. For example, a“non-enolizable alkyl” can be bonded to a sulfone group or to a carbonyl group through a quaternary carbon atom (i.e., the carbon atom that is not bonded to a hydrogen atom).

By“A/-protecting group” is meant a group protecting a nitrogen atom in a molecule from participating in one or more undesirable reactions during chemical synthesis (e.g., oxidation reactions, or certain nucleophilic and electrophilic substitutions). Commonly used /V-protecting groups are disclosed in Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-lnterscience, 4th Edition, 2006. Exemplary A/-protecting groups include acyl (e.g., formyl, acetyl, trifluoroacetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2- bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, ochlorobutyryl, benzoyl, 4- chlorobenzoyl, and 4-bromobenzoyl); sulfonyl-containing groups (e.g., benzenesulfonyl, p-toluenesulfonyl, o- nitrobenzenesulfonyl, and p-nitrobenzenesulfonyl); carbamate forming groups (e.g., benzyloxycarbonyl, p- chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyl oxycarbonyl, 2,4- dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,

3.4.5-trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)-l -methylethoxycarbonyl, a,a-dimethyl-

3.5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl), arylalkyl (e.g., triphenylmethyl); silyl groups (e.g., trimethylsilyl); and imine-forming groups (e.g., diphenylmethylene). Preferred /V-protecting groups are acetyl, benzoyl, phenylsulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, o- nitrobenzenesulfonyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

By“oxo” or (O) is meant =0.

By“pharmaceutically acceptable salt” is meant a salt within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1 -19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.FH . Stahl and C.G. Wermuth), Wiley-VCPI, 2008. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts and the like. A preferred salt is the mesylate salt. By“pseudohalogen” is meant -O-SO R, where R is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl. Non-limiting examples of pseudohalogens include trifluoromethanesulfonate and nonaflate.

By“silyl” is meant -S1 R3, where each R is independently alkyl, alkenyl, aryl, or arylalkyl. Examples of silyl groups include tri(Ci-6 alkyl)silyl, tri(C6-io aryl or C heteroaryl)silyl, di(C6-io aryl or C heteroaryl)(Ci-6 alkyl)silyl, and (C aryl or Ci-s heteroaryl)di(Ci-6 alkyl)silyl. It will be understood that, when a silyl group includes two or more alkyl, alkenyl, aryl, heteroaryl, or arylalkyl groups, these groups are independently selected. As defined herein, any heteroaryl group present in a silyl group has from 1 to 4 heteroatoms selected independently from O, N, and S. Silyl can be optionally substituted in the same manner as defined for each R group.

By“silylene” is meant -S R -, where each R is independently alkyl, alkenyl, aryl, arylalkyl, or alkoxy. By “dialkylsilylene” is meant a silylene, where each R is alkyl. Silylene can be optionally substituted in the same manner as defined for each R group. Silylene-dioxo is a group having the formula -O-S R -O-.

By“strong base” is meant a Bnansted base, the conjugate acid of which has pKa that is greater than or equal to 13. Non-limiting examples of strong bases include alkyl alkali metals (e.g., butyl lithium or Schlosser’s base), Grignard reagents (e.g., alkyl magnesium halide), alkali or alkali earth alkoxides, alkali or alkali earth amides (e.g., diisopropylamide, tetramethylpiperidide, or bis(trimethylsilyl)amide), and phosphazene bases (e.g., Schwesinger base). Non-limiting examples of the alkali amides are lithium diisopropylamide, lithium tetramethylpiperidide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide.

By“sulfonamide” is meant -NR, where R is sulfonyl.

By“sulfonate” is meant -OS(0)2R, where R is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted arylalkyl. In exemplary sulfonates, R is C1 -12 alkyl (e.g., C1-8, C1 -6, C1-4, C2-7, C3-12, or C3-6 alkyl), C2-12 alkenyl (e.g., C2-8, C2-6, C2-4, C3-12, or C3-6 alkenyl), carbocyclic C6-20 aryl (e.g., Ce-15, Ce-io, C8-20, or CB-I S aryl), monocyclic C1 -6 heteroaryl (e.g., C1 -4 and C2-6 heteroaryl), C4-19 heteroaryl (e.g., C heteroaryl), (C6-is)aryl(Ci-6)alkyl, (C4-i9)heteroaryl(Ci-6)alkyl, or (Ci-e)heteroaryl(Ci- s)alkyl. As defined herein, any heteroaryl group present in a sulfonate group has from 1 to 4 heteroatoms selected independently from O, N, and S.

By“sulfonyl” is meant -S(0)2R, where R is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted arylalkyl, or silyl. Preferred R groups for sulfonyl are the same as those described above for sulfonates.

By“thioacetal” is meant -S-(CHR)-S-, where R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted arylalkyl. By“thioketal” is meant -S-(CR ₂ )-S-, where each R is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted arylalkyl.

By“triflate” is meant trifluoromethanesulfonate.

The pKa values recited herein refer to the pKa values of a conjugate Brensted acid in water at room temperature, unless stated otherwise.

References to compounds described herein encompass their salts, where applicable.

Detailed Description

The present invention provides compounds and methods that may be useful in the synthesis of halichondrin macrolides and analogs thereof (see Chart 1 ). Preferably, the halichondrin macrolide analog is eribulin or a salt thereof (e.g., eribulin mesylate). Preferably, the halichondrin macrolide is a halichondrin B macrolide. The carbon-atom numbering schemes for a halichondrin macrolide and analog thereof are shown in Chart 1 .

Chart 1

halichondrin macrolide halichondrin macrolide analog

in which each of D and D’ is independently H, optionally substituted alkyl, or OPi , provided that only one of D and D' is OPi , where Pi is H, alkyl, a hydroxyl protecting group, and A is a C saturated or C unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q , or A is a group of formula (1 ):

(1 ) ,

where

L is -(CH(OP ₂ ))-, -(C(OH)(OP ₂ ))-, or -C(O)-;

R ₂ is H and Pi is absent, H, alkyl, or a hydroxyl protecting group, or R ₂ and Pi combine to form a bond;

(i) R is H, and P ₂ is absent, H, optionally substituted alkyl, or a hydroxyl protecting group; (ii) Fb is -(OH ₂ ) _P NR ₃ R4, where P is H or an N-protecting group, and (a) P is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P is H or an N-protecting group, (b) P and P combine to form an alkylidene, or (c) each of P and P is H;

(iii) F is -(OH ₂ ) _P OR5, where P ₂ is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P is H, optionally substituted alkyl, or a hydroxyl protecting group; or P and

P , together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or

(iv) Fb and P combine to form an optionally substituted ethylene or a structure selected from the group consisting of:

otecting group; each of A , A , and A is independently H or OP”, where each P” is independently H or a hydroxyl protecting group;

E is H, optionally substituted alkyl, or optionally substituted alkoxy;

G is 0, S, CH , or NRN, where RN is H, an N-protecting group, or optionally substituted alkyl;

each Qi is independently ORA, SRA, S0 ₂ RA, 0S0 ₂ RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRB(CO)NR _B RA, NRB(CO)ORA, (CO)ORA, 0(C0)RA, (CO)NRBRA, or 0(C0)NRBRA, where each of RA and RB is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl; n, when present, is 0, 1 , or 2; and

k is 0 or 1 .

In the halichondrin macrolide and halichondrin macrolide analog structures, when Pi is absent, each of D and D’ is independently H or optionally substituted alkyl, and, when P ₂ is absent, L is -C(O)-. Prins Reaction

In one aspect, the invention provides a compound of formula (A) and methods of its preparation. The compound of formula (A) may be prepared from a compound of formula (B), a compound of formula (C), and RsOH, where Rs is optionally substituted acyl. For example, a compound of formula (B), a compound of formula (C), and RsOH may be subjected to Prins reaction conditions, e.g., as known in the art. For example, the compound of formula (B), the compound of formula (C), and RsOH may be reacted with a Lewis acid (e.g., an oxophilic Lewis acid (e.g., boron trifluoride or solvate thereof)).

The compound of formula (A) is:

where

each of D and D’ is independently H, optionally substituted alkyl, or OP , provided that only one of D and D’ is OP , where Pi is H, alkyl, a hydroxyl protecting group, and A is a C saturated or C2-6 unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q , or A is a group of formula (1 ):

(1 ) ,

where

L is -(CH(OP ₂ ))-, -(C(OH)(OP ₂ ))-, or -C(O)-;

R is H and Pi is absent, H, alkyl, or a hydroxyl protecting group, or R ₂ and Pi combine to form a bond;

(i) R is H, and P is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;

(ii) R3 is -(CH ) _n NP P , where P3 is H or an N-protecting group, and (a) P is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P is H or an N-protecting group, (b) P and P combine to form an alkylidene, or (c) each of P and P is H ;

(iii) R is -(CH )nOP , where P is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P and P5, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or

(iv) R3 and P combine to form an optionally substituted ethylene or a structure selected from the group consisting of:

otecting group;

E is H, optionally substituted alkyl, or optionally substituted alkoxy;

G is 0, S, CH2, or NRN, where RN is H, an N-protecting group, or optionally substituted alkyl;

each Q1 is independently ORA, SRA, SO2RA, OSO2RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRB(CO)NR _B RA, NRB(CO)ORA, (CO)ORA, 0(C0)RA, (CO)NRBRA, or 0(C0)NRBRA, where each of RA and RB is independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl; n, when present, is 0, 1 , or 2;

k is 0 or 1 ;

R1 is -ORe, -CH(Y)2, or -CH2(Y), where Rb is H or a hydroxyl protecting group;

R4 is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl,

each P7 is independently H or a hydroxyl protecting group; and Rs is -CH ₂ CH ₂ -COORC, -CH=CH-COORc, -CH2CH2-SO2RD, or -CH=CH-S0 ₂ RD; R5 is optionally substituted acyl;

R6 is H, optionally substituted alkyl, or optionally substituted arylalkyl;

each Y is independently -COORc or -SO2RD; each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and

each RD, when present, is independently optionally substituted aryl or optionally substituted non- enolizable alkyl.

In the compound of formula (A), when Pi is absent, each of D and D’ is independently H or optionally substituted alkyl, and, when P2 is absent, L is -C(O)-.

The compound of formula (B) is:

where all variables are as described for formula (A).

The compound of formula (C) is:

R -R ,

(C)

where

OR _7A

R O

R7 is -CHO or ^r A'-' , where each R7 _A is independently an optionally substituted alkyl, and R4 is as described for the compound of formula (A).

The compound of formula (B) may be prepared from a compound of formula (D) and a compound of formula (E). For example, the compound of formula (D) and the compound of formula (E) may be subjected to Sakurai reaction conditions, e.g., as known in the art. In certain embodiments, the compound of formula (D) may be reacted with the compound of formula (E) and a Lewis acid (e.g., an oxophilic Lewis acid (e.g., boron trifluoride or a solvate thereof)) to produce the compound of formula (B).

The compound of formula (D) is:

where

all variables are as described for the compound of formula (B).

where

Rs is silyl (e.g., MesSi-); and

Re is as described for the compound of formula (B).

The Sakurai reaction producing the compound of formula (B) introduces the secondary alcohol stereogenic center in the compound of formula (B). If the stereoselectivity of the Sakurai reaction is less than desirable, the Sakurai reaction product can be subjected to epimerization to enrich the product in the compound of formula (B) relative to its diastereomer. In a non-limiting example, the Sakurai reaction products (the compound of formula (B) and its C.27 diastereomer) can be reacted with an oxidizing agent capable of converting an alcohol to a carbonyl group (e.g., Dess-Martin periodinane) to give a compound of formula (F), and the compound (F) can then be subjected to enantioselective 1 ,2-reduction reaction conditions (e.g., Corey-Bakshi-Shibata reaction). Alternatively, if the diastereoselectivity of the Sakurai reaction favors the formation of the diastereomer of the compound of formula (B), the Mitsunobu reaction may be used to invert the secondary alcohol stereocenter in a diastereomeric Sakurai reaction product mixture.

where all variables are as described for formula (B).

Enantioselective 1 ,2-reduction reaction conditions are known in the art. In a non-limiting example, the enantioselective 1 ,2-reduction reaction is Corey-Bakshi-Shibata reaction. Corey-Bakshi-Shibata reduction can include reacting a ketone with CBS catalyst and borane or a solvate thereof. In a non-limiting example, (S)-CBS-oxazaborolidine catalyst can be used with borane or a solvate thereof (e.g., BFh HF) to control the stereochemistry of the resulting secondary alcohol in the preparation of the compound of formula (II) from the compound of formula (F).

Mitsunobu reaction conditions are known in the art. In a non-limiting example, the diastereomeric Sakurai reaction product mixture may be reacted with an azadicarboxylate compound (e.g., DIAD), phosphine (e.g., PPhe), and a carboxylic acid (e.g., 3,5-dinitrobenzoic acid) to produce a compound of formula (G):

where

RA _C is optionally substituted acyl; and

the remaining variables are as described for formula (B).

The compound of formula (G) may be converted to the compound of formula (B). In a non-limiting example, the compound of formula (G) may be subjected to alcoholysis or hydrolysis reaction conditions (e.g., Mg(OMe)2 in MeOH) to produce the compound of formula (B). Alternatively, the compound of formula (G) may be reacted with a 1 ,2-reducing agent to produce the compound of formula (B).

In the compounds described herein, R6 may be optionally substituted alkyl (e.g., methyl).

In the compounds described herein, D may be H. In the compounds described herein, D’ may be OP1 (e.g., Pi may be alkyl (e.g., methyl)). In the compounds described herein, G may be O.

In the compounds described herein, k may be 0, and Ri may be -CH2(Y), where Y may be -SO2RD where, RD is optionally substituted aryl (e.g., phenyl) or optionally substituted non-enolizable alkyl.

In the compounds described herein, E may be optionally substituted alkyl (e.g., methyl).

In the compounds described herein, D may be H, and A may be:

vy R ₃

OP ₂

In the compounds described herein, k may be 0, and R1 may be -CH(Y)2, or -CH2(Y). In the compounds described herein, R3 may be -(CH2) _n NP3P4 or -(CH2)nOP5, where n may be 0.

In the compounds described herein, A and D may combine to form the following structure:

where the bond to the oxygen atom originates at the carbon atom to which D is attached in formula (A) or formula (B). In the compounds described herein, R3 may be -(CH2)nNP3P4 or -(CH2)nOP5, and n is 2. In the compounds described herein, k may be 1 , and E may be optionally substituted alkyl (e.g., methyl). In the compounds described herein, Ri may be -CH2(Y), where Y may be -COORD, where RD may be optionally substituted alkyl (e.g., methyl). Preparation of Halichondrin Macrolides and Analogs Thereof

A halichondrin macrolide or analog thereof may be prepared as described herein and using methods and reactions known in the art. Non-limiting examples of methods and reactions useful for the preparation of a halichondrin macrolide or analog thereof include U.S. patent application publication Nos. 2016/0264594, 2015/0158881 , 201 1 /0184190, 201 1/00541 94, 2009/0203771 , and 2009/0198074; International patent application publication No. WO 2016/179607; U.S. patent Nos. 5,338,865, 5,436,238, 6,214,865, and

8,445,701 ; and in Towle et al ., Annual Meeting of the American Association for Cancer Research, April 6-10, 2002, 5721 ; Wang et al., Bioorg. Med. Chem. Lett., 10:1029-1032, 2000; Aicher et al., J. Am. Chem. Soc., 114:3162-3164, 1992; Ueda et al., J. Am. Chem. Soc., 136:5171 -5176; and Yamamoto et al., J. Am. Chem. Soc., 134:893-896, 2012.

As described herein, one of skill in the art can identify the sequence of reactions involving hydroxyl protecting group removing agents and Bronsted acids to convert the compounds described below into a halichondrin macrolide or analog thereof. One of skill in the art can recognize that certain functional groups require protecting groups known in the art to reduce or prevent undesired reactivity. One of skill in the art can select appropriate protecting groups to be used in the syntheses described herein.

Chart 2 illustrates the macrocycle disconnections that may be useful for the preparation of a halichondrin macrolide or analog thereof. Chart 2

a halichondrin macrolide or analog thereof

where Xi is -O- or -CH2-, and the remaining variables are as described in Chart 1 . Table 1 lists the macrocyclic retrosynthesis disconnections shown in Chart 2 and indicates corresponding exemplary bond-forming reactions as described herein. Any of these various reactions can be employed in the synthesis of halichondrin macrolide or analogs thereof. For example, these reactions may be employed to couple various fragments together or to form the macrocycle.

Table 1

The methods of preparing a halichondrin macrolide or analog thereof disclosed herein include a C.23-C.24 bond-forming Prins reaction either as a macrocylization step or as a step in the synthesis of non-macrocyclic intermediates. In some approaches, a halichondrin macrolide or analog thereof (e.g., eribulin or a salt thereof (e.g., eribulin mesylate)) may be prepared from the compound of formula (IA) using methods and reaction conditions known in the art.

A compound of formula (IA) may be produced from a compound of formula (I IA), a compound of formula (MB), a compound of formula (III), and RsOH. The compound of formula (IA) is:

where

Fti is -ORb, -CH(Y) , or -CH (Y), where Rb is H or a hydroxyl protecting group, and each Y is independently -COORc or -SO RD;

each P7 is independently H or a hydroxyl protecting group;

Rs is -CH2CH2-COORC, -CH=CH-COORc, -CH2CH2-SO2RD, or -CH=CH-S0 ₂ RD; each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and

each RD, when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl; and

Rs is optionally substituted acyl;

and the remaining variables are as described for the halichondrin macrolide or analog thereof (e.g., eribulin or a salt thereof (e.g., eribulin mesylate)).

In the compound of formula (IA), when Pi is absent, each of D and D’ is independently H or optionally substituted alkyl.

The compound of formula (IIA) is:

where

RE is -CHO or— CH(i _+m) (ORF)(2-m),

where

m is 1 , and RF is a hydroxyl protecting group,

or

m is 0, and

(i) each RF is independently an alkyl or hydroxyl protecting group, or

(ii) both RF combine to form an alkylene;

and

the remaining variables are as described for the compound of formula (IA). The compound of formula (MB) is:

(MB),

where Rs is silyl (e.g., MesSi-).

The compound of formula (III) is:

R -R ,

(III)

where

R _/ is -CHO or , where each R7A is independently an optionally substituted alkyl, and

R4 is as described for the compound of formula (IA).

Preparation of the compound of formula (IA) may include reacting the compound of formula (I IA) (in which RE is -CHO), the compound of formula (MB), and a Lewis acid (e.g., an oxophilic Lewis acid (e.g., boron trifluoride or a solvate thereof)) to produce a compound of formula (IIC):

where the variables are as described for the compound of formula (IA).

The compound of formula (III) and the compound of formula (IIC) may be reacted under Prins reaction conditions to produce the compound of formula (IA). Prins reaction conditions are known in the art. In a non-limiting example, the compound of formula (III) and the compound of formula (IIC) may be reacted with a Lewis acid (e.g., an oxophilic Lewis acid (e.g., boron trifluoride or a solvate thereof)).

The following describes exemplary conditions for macrocyclization at the indicated positions. These reaction conditions may also be used to couple two or more fragments prior to macrocyclization.

C.1-Xi Bond-forming Macrocyclization

A halichondrin macrolide or analog thereof (e.g., eribulin or a salt thereof (e.g., eribulin mesylate)) may be prepared through a C.0-C.1 or a 0-C.1 bond-forming macrocyclization according to the following synthesis strategy from a compound of formula (VIIB):

(VI IB)

where

(i) R10 is a hydroxyl protecting group, R is alkyl ether, and R12 is H;

(ii) R10 is a hydroxyl protecting group, and Rn and R12 combine to form a double bond;

or

(iii) R10 and R11 combine to form a bond, and R12 is H;

l_4 is

R1 is -OP ₆ , -CH2(Y), or -CH(Y)2, where Rb is H or a hydroxyl protecting group, and Y is -COORc or -CHO;

each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and

Ai and R14 combine to form oxo, R13 is H or a hydroxyl protecting group, and R15 is H;

or

Ai is H or -OP”, and:

(i) R13 is H or a hydroxyl protecting group, and R14 and R15 combine to form a double bond;

or

(ii) R13 and R14 combine to form a bond, and R15 is H or -OP”;

R5 is optionally substituted acyl;

Rg is -CHO or -COOP”;

each P” is independently H or a hydroxyl protecting group;

each Pg is independently a hydroxyl protecting group, and X3 is oxo or X3, together with the carbon atom to which it is attached, is -(CH(OP ))-, where P is H or a hydroxyl protecting group; or both P9 groups and X3, together with the atoms to which each is attached, combine to form a ketal;

and the remaining variables are as described for the halichondrin macrolide or analog thereof.

The compound of formula (VI IB) is converted to a compound of formula (VIIC):

(VI IC)

where

Li is

where L and L combine to form a bond;

Xi is -CH -, -CH(Y)-, -C(Y) -, or -0-;

X is oxo, or X , together with the atom to which it is attached, is -(CH(OPi ))-, where P is H or a hydroxyl protecting group;

and the remaining variables are as described for the compound of formula (VI IB).

Preparation of the compound of formula (VI IC) may include an esterification reaction between R that is - ORQ, where Re is H, and R9 that is -COOH. Alternatively, preparation of the compound of formula (VIIC) may include a reaction between R that is -CH(Y or -CH (Y), and Rg that is -CHO (e.g., under Claisen reaction conditions). Oxidation of the Claisen product (X , together with the atom to which it is attached, is - (CH(OPi ))-, where P is H) with an oxidizing agent capable of converting an alcohol to a carbonyl group may produce X that is oxo. Further desulfonylation or decarboxylation of this compound of formula (VIIC) may produce the compound of formula (VIIC), in which X is -CH -.

The compound of formula (VIIC) is then converted to the halichondrin macrolide or analog thereof using methods described herein and those known in the art, e.g., those described in US 5,338,865, US

2016/0264594, US 2009/0203771 , and WO 2016/179607. For example, preparation of the halichondrin macrolide or analog thereof may include reacting the compound of formula (VIIC) with a hydroxyl protecting group removing agent.

The compound of formula (VI IB) may be prepared from a compound of formula (VIIA), the compound of formula (IIA), the compound of formula (I IB), a compound of formula (INC), and R OH. The compound of formula (VIIA) is:

where

(i) R10 is a hydroxyl protecting group, Rn is alkyl ether, and R12 is H;

(ii) R10 is a hydroxyl protecting group, and Rn and R12 combine to form a double bond; or

(iii) R10 and R11 combine to form a bond, and R12 is H;

Rg is -CH2-OP”, -CHO, or -COOP”;

R13 and each P9 is independently a hydroxyl protecting group;

Ai is H or -OP”;

each P” is independently H or a hydroxyl protecting group; and

Yi is chloro, bromo, iodo, trifluoromethanesulfonate, or trialkylsilane.

The compound of formula (NIC) is:

R4C-R7,

(INC)

where

Ry is -CHO, -CH2OPA, each R _7A is independently an optionally substituted alkyl; and

Rc is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; PA is H or a hydroxyl protecting group; and

P , when present, is independently H or a hydroxyl protecting group.

Preparation of the compound of formula (VIIB) can be accomplished as follows. The compound of formula (NIC), in which R7 is -CH2OPA or may be converted to a compound of formula (HID): R4D-R7,

(HID)

where

FUD is

all remaining variables are as described for the compound of formula (NIC).

The compound of formula (MID) may be reacted with the compound of formula (VI I A) under Nozaki-Hiyama- Kishi reaction conditions (e.g., with a Cr(ll) salt and a Ni(ll) salt as described herein) to form a compound of formula (VIIAa):

(VIIAa)

where

R7 is— CH OPA,— CHO, or

and all remaining variables are as described for the compound of formula (VIIB) and the compound of formula (HID).

The compound of formula (VIIAa), in which R is -CHO, may be reacted with a compound of formula (IIC) and RsOH under Prins reaction conditions to form the compound of formula (VIIB).

Alternatively, preparation of the compound of formula (VIIB) can be accomplished by reacting the compound of formula (IG) and the compound of formula (VI I A) under Nozaki-Hiyama-Kishi reaction conditions (e.g., with a Cr(ll) salt and a Ni(ll) salt as described herein). The compound of formula (IG) is:

where

REI is

where Rs is optionally substituted acyl;

and the remaining variables are as described for the compound of formula (VI IB). The compound of formula (IG) may be formed from a compound of formula (IF):

where all variables are as described for the compound of formula (IG) and the compound of formula (MIC). R4C that is

R4C that is

producing this FUc may further include an esterification reaction after the reaction with an allylic reducing agent).

R4C that is

verting an alcohol to a carbonyl group in

In general, the method described herein includes an allylic reduction at C.25. This reaction can be performed at any point prior to the formation of the halichondrin macrolide or analog thereof. For example, using an allylic reducing agent.

C.2-C.3 and C.3-C.4 Bond-Forming Macrocyclizations

In another approach, a halichondrin macrolide or analog thereof (e.g., eribulin or a salt thereof (e.g., eribulin mesylate)) may be prepared through a C.2-C.3 or a C.3-C.4 bond-forming macrocyclization according to the following strategy.

In some embodiments, a halichondrin macrolide or analog thereof is prepared from a compound of formula (VIB) is:

where

l_4 is

R1 is -OP ₆ or -CH(Y), where Rb is H or a hydroxyl protecting group, and Y is -COORc or -CHO;

R5 is optionally substituted acyl;

RIOA is -CH ₂ -CH=CH ₂ , -(CH ₂ ) ₂ -CH=CH ₂ , or -(CH ₂ ) ₃ -OPIO;

each of R10 and P10 is independently a hydroxyl protecting group;

Ai and R14 combine to form oxo, R13 is H or a hydroxyl protecting group, and R15 is H;

or

Ai is H or -OP”, and:

(i) R13 is H or a hydroxyl protecting group, and R14 and R15 combine to form a double bond;

or

(ii) R13 and R14 combine to form a bond, and R15 is H or -OP”;

each P9 is independently a hydroxyl protecting group, and X3 is oxo or X3, together with the carbon atom to which it is attached, is -(CH(OPu))-, where Pu is H or a hydroxyl protecting group; or both P9 groups and X ₃ , together with the atoms to which each is attached, combine to form a ketal; and

the remaining variables are as described for the halichondrin macrolide or analog thereof.

The compound of formula (VIB) may be converted to the halichondrin macrolide or analog thereof (e.g., eribulin or a salt thereof (e.g., eribulin mesylate)) using reaction conditions known in the art, e.g., as described herein.

In particular embodiments, preparation of the halichondrin macrolide or analog thereof from the compound of formula (VIB) through C.3-C.4 bond-forming macrocyclization includes producing a compound of formula (VIC) from the compound of formula (VIB). The compound of formula (VIC) is

X4 is oxo, or X4, together with the atom to which it is attached, is -(CH(OPi2))-, where P12 is H or a hydroxyl protecting group; and

the remaining variables are as described for the compound of formula (VIB).

The compound of formula (VIC) may be prepared by reacting the compound of formula (VIB) with R17- CH2CH=CH2, where R17 is -COOH or a metallic or metalloid moiety. The compound of formula (VIB), in which R1 is -CH2(Y), may be reacted with Ri7-CH2CH=CH2, in which R17 is a metallic or metalloid moiety, to produce the compound of formula (VIC), in which X1 is -CH2-, and X4 is oxo or -(CH(OPi2))-. The compound of formula (VIB), in which R1 is -ORb, and Rb is H, may be esterified with Ri7-CH2CH=CH2, where R17 is -COOH, to produce the compound of formula (VIC), in which X1 is -0-, and X4 is oxo. The compound of formula (VIC) is then converted to a compound of formula (VID):

where

Li is

combine to form a bond;

and the remaining variables are as described for the compound of formula (VIC).

The compound of formula (VID) is produced through a reaction of the compound of formula (VIC) with an olefin metathesis catalyst.

The compound of formula (VID) may be converted to the halichondrin macrolide or analog thereof using methods described herein and those known in the art, e.g., those described in US 2016/0264594, US 2009/0203771 , and WO 2016/1 79607.

Preparation of the halichondrin macrolide or analog thereof may include reacting the compound of formula (VID) with a hydroxyl protecting group removing agent. A reaction of the compound of formula (VID) with a hydroxyl protecting group removing agent may lead to the C.3-C.4 double bond isomerization to give an enoate/enone described herein upon exposure to basic (e.g., isomerization mediated by a hydroxyl protecting group removing agent, such as a fluoride source) or acidic (e.g., isomerization mediated by a Bnansted acid) conditions. The resulting enoate/enone may undergo a reaction with a hydroxyl of -ORio.

In certain embodiments, preparation of the halichondrin macrolide or analog thereof from the compound of formula (VIB) through C.2-C.3 bond-forming macrocyclization includes producing a compound of formula (VIE) from the compound of formula (VIB). The compound of formula (VIE) is:

X4 is oxo, or X4, together with the atom to which it is attached, is -(CH(OPi2))-, where P12 is H or a hydroxyl protecting group; and

the remaining variables are as described for the compound of formula (VIB).

The compound of formula (VIB) may be converted to a compound of formula (VIE) through a reaction with Ri7— CH=CH2, where R17 is -COOH or a metallic or metalloid moiety. For example, the compound of formula (VIB), in which R1 is -CH2(Y), can be reacted with Ri7-CH2CH=CH2, where R17 is a metallic or metalloid moiety, to give the compound of formula (VIE), in which X1 is -CH2-, and X4 is oxo or -(CH(OPi2>)-.

Alternatively, the compound of formula (VIB), in which R1 is -ORb, and Rb is H, can be esterified with R17- CH2CH=CH2, where R17 is -COOH, to give the compound of formula (VIE), in which X1 is -0-, and X4 is oxo.

The compound of formula (VIE) may be converted to a compound of formula (VIF):

where Li is

combine to form a bond;

and the remaining variables are as described for the formula (VIE). The compound of formula (VI F) may be produced by a reaction of the compound of formula (VIE) with an olefin metathesis catalyst.

Alternatively, the compound of formula (VI F), in which X4 is oxo, may be prepared from a compound of formula (VIG):

each Rc is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;

and the remaining variables are as described for the compound of formula (VI F). The compound of formula (VIG) may be prepared by reacting the compound of formula (VIB) with

(RC0)2P(0)-CFI2-RP, where each Rc is indepenedently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl, and Rp is H or -COOH. For example, the compound of formula (VIB), in which R1 is -CH2(Y), may be reacted with (RC0)2P(0)-CH2-RP, in which Rp is H, under Claisen reaction conditions to produce the compound of formula (VIG). Alternatively, the compound of formula (VIB), in which R is -ORb, where RQ is H, may be esterified with (RC0)2P(0)-CH2-RP, in which Rp is -COOH, to produce the compound of formula (VIG).

The compound of formula (VIG) is then converted to the compound of formula (VI F), e.g., through a Horner- Wadsworth-Emmons reaction, where all variables are as described for the compound of formula (VIG).

The compound of formula (VI F) is then converted to the halichondrin macrolide or analog thereof using methods described herein and those known in the art, e.g., those described in US 2016/0264594, US 2009/0203771 , and WO 2016/1 79607.

The compound of formula (VIB) may be prepared from a compound of formula (VIA), a compound of formula (IIA), a compound of formula (MB), a compound of formula (INC), and RsOFI.

The compound of formula (VIA) is:

where

each Rio, R13, and P is independently a hydroxyl protecting group;

Ai is H or -OP”;

Yi is chloro, bromo, iodo, trifluoromethanesulfonate, or trialkylsilane; and

RIOA is as described for the compound of formula (VIB).

The compound of formula (IIA) is:

where

RE is -CHO or— CH(i _+m) (ORF)(2-m),

where

m is 1 , and RF is a hydroxyl protecting group,

or

m is 0, and

(i) each RF is independently an alkyl or hydroxyl protecting group, or

(ii) both RF combine to form an alkylene;

and the remaining varilables are as described for the compound of formula (VIB). The compound of formula (MB) is:

where Rs is silyl ;

The compound of formula (NIC) is:

R4C-R7,

(MIC)

where

R4C is where Rc is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl, and each P7 is independently H or a hydroxyl protecting group; and R7 is -CHO or

OR7A

R _7A O ί

where each R _7A is independently an optionally substituted alkyl;

Preparation of the compound of formula (VIB) includes a Sakurai reaction between RE that is -CHO and the compound of formula (MB) producing a group of the structure: . This product may then be reacted with the compound of formula (MIC) under Prins reaction conditions to produce a group of the structure: This group may be converted to

If the stereochemistry of the secondary alcohol in the Sakurai reaction product differs from the desired stereochemistry, this group may be subjected to epimerization reaction conditions described herein (e.g., oxidation followed by Corey-Bakshi-Shibata reduction; alternatively, Mitsunobu reaction may be used to invert the stereogenic center). is -CH(i +m)(ORF)(2-m), preparation of the compound of formula (IVB) may further include conversion of to -CHO under acetal deprotecting conditions, e.g., through a reaction with an aqueous Bronsted acid (e.g., when m is 0), or through oxidation using an oxidizing agent capable of converting an alcohol to a carbonyl group (e.g., when m is 1 ).

R4C that is

R4C that is

producing this R4c may further include an esterification reaction after the reaction with an allylic reducing agent). R4C that is

y g g p verting an alcohol to a carbonyl group in

In some embodiments, the compound of formula (VIB) is produced from the compound of formula (VIA) and a compound of formula (IG):

where

REI is

where Rs is optionally substituted acyl;

and the remaining variables are as described for the compound of formula (VIB). The compound of formula (VIA) is reacted with the compound of formula (IG) under Nozaki-Hiyama-Kishi reaction conditions to produce the compound of formula (VIB). For example, Nozaki-Hiyama-Kishi reaction on the compound of formula (VIA) and the compound of formula (IG) can include reacting the compound of formula (VIA) and the compound of formula (IG) with a Cr(ll) salt and a Ni(ll) salt. The compound of formula (IG) may be prepared from the compound of formula (IIA), the compound of formula (MB), the compound of formula (MIC), and RsOH, where Rs is optionally substituted acyl.

In further embodiments, the compound of formula (VIB) may be prepared according to the following strategy. The compound of formula (MIC) may be convered to the compound of formula ( ID) as described herein. Further, the compound of formula (MID) may be reacted with the compound of formula (VIA) under Nozaki- Hiyama-Kishi reaction conditions to produce a compound of formula (VIAa):

where all variables are as described for the compound of formula (VIB) and the compound of formula (MIC).

The compound of formula (VIAa), in which R is -CHO, may be reacted with a compound of formula (IIC) and R OH under Prins reaction conditions to form the compound of formula (VIB). In yet further embodiments, the compound of formula (VIC) may be prepared according to the following strategy. The compound of formula (IIA), in which RE is -CH(i _+m) (ORF)(2-m), may be reacted with R17- CH2CH=CH2, where R17 is -COOH or a metallic or metalloid moiety, to produce a compound of formula (IID):

where all variables are as described for the compound of formula (VIC).

For example, the compound of formula (IIA), in which R1 is -CH2(Y), may be reacted with Ri7-CH2CH=CH2, in which R17 is a metallic or metalloid moiety, to produce the compound of formula (VIC), in which X1 is - CH2-, and X4 is oxo or -(CH(OPi2))-. The compound of formula (IIA), in which R1 is -ORb, and Rb is H, may be esterified with Ri7-CH2CH=CH2, where R17 is -COOH, to produce the compound of formula (IID), in which Xi is -0-, and X is oxo.

The compound of formula (IID), in which RE is -CHO, may be reacted with the compound of formula (MB) under Sakurai reaction conditions to produce a compound of formula (ME):

where all variables are as described for the compound of formula (VIC). The compound of formula (ME) may be reacted with the compound of formula (VIAa) and R OH under Prins reaction conditions to produce the compound of formula (VIC), in which L is:

In still further embodiments, the compound of formula (VIE) may be prepared according to the following strategy. The compound of formula (IIA) may be converted to a compound of formula (I IF) through a reaction with Ri7-CH=CH2, where R is -COOH or a metallic or metalloid moiety. The compound of formula (IIF) is:

where all variables are as described for the compound of formula (VIE).

For example, the compound of formula (IIA), in which Ri is -CH (Y), can be reacted with Ri7-CH ₂ CH=CH ₂ , where R is a metallic or metalloid moiety, to give the compound of formula (IIF), in which Xi is -CH -, and X is oxo or -(CH(OPi ))-. Alternatively, the compound of formula (IIA), in which R is -ORb, and Rb is H, can be esterified with Ri7-CH2CH=CH2, where R is -COOH, to give the compound of formula (IIF), in which Xi is -0-, and X is oxo.

The compound of formula (IIF), in which RE is -CHO, may be reacted with the compound of formula (MB) under Sakurai reaction conditions to produce a compound of formula (IIG):

where all variables are as described for the compound of formula (VIE). The compound of formula (IIF) may be reacted with the compound of formula (VIAa) and RsOH under Prins reaction conditions to produce the compound of formula (VIE), in which l_6 is:

In some embodiments, the compound of formula (VIG) may be prepared according to the following strategy. The compound of formula (IIA) may be converted to a compound of formula (IIH) through a reaction with (RC0)2P(0)-CH2-RP, where each Rc is indepenedently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl, and Rp is H or -COOH. The compound of formula (IIH) is:

where

each Rc is indepenedently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;

X4 is oxo, or X4, together with the atom to which it is attached, is -(CH(OPi >)-, where P is H or a hydroxyl protecting group; and

all remaining variables are as described for the compound of formula (VIG).

The compound of formula (IIH), in which X is oxo, may be converted to a compound of formula (Mi) through a reaction with the compound of formula (MB) under Sakurai reaction conditions. The compound of formula (lli) is:

where all variables are as described for the compound of formula (IIH). The compound of formula (lli) may be reacted with the compound of formula (VIAa), in which RIOA is -CH - CH=CH or -(CH ₂ ) ₃ -OPIO, to produce a compound of formula (VIGa):

where

RIOA is— CH— CH=CH or— (CH2)3— OP ,

L7 is

and all remaining variables are as described for the compound of formula (VIG). The compound of formula (VIGa), in which RIOA is -CH -CH=CH , may be converted to the compound of formula (VIGa), in which RIOA is -(CFI ₂ ) ₃ -OPIO, and P is H, by hydroboration/oxidation reaction.

Hydroboration/oxidation reactions are known in the art. For example, 9-BBN or thexyl borane may be used for the hydroboration of RIOA, and sodium perborate or hydrogen peroxide and base may be used for the oxidation step providing -(CH ₂ )3-OPIO, and P is H. The compound of formula (VIGa), in which RIOA is - (CH2)3-OPIO, and P is FI, may be converted to the compound of formula (VIG).

In general, the method described herein includes an allylic reduction at C.25. This reaction can be performed at any point prior to the formation of the halichondrin macrolide or analog thereof. For example, may be converted using an allylic reducing agent.

C.12-C.13 Bond-forming Macrocyclization

In still another approach, a halichondrin macrolide or analog thereof may be prepared from the compound of of formula (VIIIB):

where

Xi is -CH2-, -CH(Y)-, -C(Y)2-, or -0-, where each Y is independently -COORc or -SO2RD;

X4 is oxo, or X4, together with the atom to which it is attached, is -(CH(OPi2»-, where P12 is H or a hydroxyl protecting group;each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;

each RD, when present, is independently optionally substituted aryl or optionally substituted non- enolizable alkyl;

(i) R ₁₀ is a hydroxyl protecting group, R ₁₁ is alkyl ether, and R ₁₂ is H;

(ii) R is a hydroxyl protecting group, and R and Rs combine to form a double bond;

or

(iii) R and R combine to form a bond, and R12 is H;

each P and R is independently a hydroxyl protecting group;

where

Rs is optionally substituted acyl; and X3 is oxo or X3, together with the carbon atom to which it is attached, is -(CH(OP ))-, where Pn is H or a hydroxyl protecting group;

and the remaining variables are as described for the halichondrin macrolide or analog thereof.

The compound of formula (VIIIB) can be subjected to ring closing metathesis to produce a compound of formula (VIIIC):

where

Ai is H or -OP”, where P” is H or a hydroxyl protecting group;

Li is

combine to form a bond; and

and the remaining variables are as described for the compound of formula (VI IB).

The halichondrin macrolide or analog thereof is then produced from the compound of formula (VIIIC), e.g. according to the methods decribed in WO 2016/179607.

In general, the fragments may be coupled in any order when forming compound (VIIIB). For example, the C.0-C.1 or 0-C.1 bond between fragment (II A) and fragment (VIIIA) can be formed, as described herein, prior to or after the Sakurai and/or Prins reaction. Similarly, installation of the C.13 olefin may occur before or after any of the Sakurai, Prins, and C.0-C.1 or 0-C.1 bond forming reactions.

In one embodiment, the compound of formula (VIIIB) is produced from a compound of formula (VIIIA), a compound of formula (IIA), and a compound of formula (I IB), a compound of formula (NIC), and RsOH. The compound of formula (IIA) is:

where R1 is -ORQ, -CH(Y)2, or -CH2(Y), where RQ is H or a hydroxyl protecting group, and each Y is independently-COORc or -SC^Ro;

each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;

each RD, when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl; and

RE is -CHO or -CH(i ₊ m)(ORF)(2-m), where

m is 1 , and RF is a hydroxyl protecting group,

or

m is 0, and

(i) each RF is independently an alkyl or hydroxyl protecting group, or

(ii) both RF combine to form an alkylene.

The compound of formula (VIIIA) is:

(VIIIA),

where

(i) R10 is a hydroxyl protecting group, R is alkyl ether, and R12 is H ;

(ii) Rio is a hydroxyl protecting group, and R4 and R5 combine to form a double bond; or

(iii) R10 and R11 combine to form a bond, and R12 is H;

R9 is -CHO or -COOH; and

each Pg and R13 is independently a hydroxyl protecting group.

The compound of formula (NIC) is:

R4C-R7,

(INC)

where

R7 is -CHO or each R A is independently an optionally substituted alkyl; and

where Rc is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and P7, when present, is independently H or a hydroxyl protecting group.

The compound of formula (MB) is:

where Rs is silyl.

In certain embodiments, a compound of formula (IIC) :

produced from the compound of formula (IIA) and the compound of formula (IIB), e.g., by reacting with a Lewis acid, such as an oxophilic Lewis acid (e.g., boron trifluoride or a solvate thereof).

A compound of formula (IF):

can be produced from the compound of formula (IIC), the compound of formula (MIC), and R5OH, e.g., by reacting with a Lewis acid, such as an oxophilic Lewis acid (e.g., boron trifluoride or a solvate thereof) (which may or may not be different from a Lewis acid used to react compounds of formulas (IIA) and (IIB)).

A compound of formula (IJ):

can be produced from the compound of formula (IF). The compound of formula (IF) may be converted to the compound of formula (IJ) using reaction conditions known in the art. For example, the compound of formula (IF) may be reacted with an allylic reducing agent to give the compound of formula (IJ). A non-limiting example of an allylic reducing agent is a palladium complex (e.g., Pd(PPh3)4) in combination with a formic acid salt (e.g., trialkylammonium formate). The compound of formula (VI I IB) can be produced from the compound of formula (VI II A) and the compound of formula (IJ) as described herein.

Preparation of the compound of formula (VI MB) may include an esterification reaction between Ri that is - OP ₆ , where Rb is H , and Rg that is -COOH. Alternatively, preparation of the compound of formula (VIIIB) may include a reaction between Ri that is -CH(Y or -CH (Y), and R that is -CHO (e.g., under Claisen reaction conditions). Oxidation of the Claisen product (X ₄ , together with the atom to which it is attached, is - (CH(OPi ))-, where P is H) with an oxidizing agent capable of converting an alcohol to a carbonyl group may produce X ₄ that is oxo. Further desulfonylation or decarboxylation of this compound of formula (VI IIB) may produce the compound of formula (VII IB), in which Xi is -CH -.

Alternatively, the compound of formula (VI IIB) may be produced from the compound of formula (I F) and the compound of formula (VIIIA). For example, a compound of formula (VII ID) may be produced from the compound of formula (I F) and the compound of formula (VIIIA) using methods described herein. The compound of formula (VIIID) is:

R5 is optionally substituted acyl;

P is FI or a hydroxyl protecting group;

and the remaining variables are as described for the compound of formula (IF) and the compound of formula (VIIIB).

Alternatively, the compound of formula (VI II D) may be prepared from the compound of formula (I IC) and the compound of formula (VIIIA) as follows. The compound of formula (IIC) may be protected with a hydroxyl protecting group to give a compound of formula (IIJ) :

where P13 is a hydroxyl protecting group, and the remaining variables are as described for the compound of formula (IIC).

The compound of formula (IIJ) may be reacted with the compound of formula (VIIIA) using methods described herein to produce the compound of formula (VIIID), in which RMI is: , where P ₁₃ is a hydroxyl protecting group.

The compound of formula (VIIID), in which RMI is , and P ₁₃ is H, may be reacted with the compound of formula (INC) and R ₅ OH under Prins reaction conditions to produce the compound of formula (VIIID), in which RMI is

The compound of formula (VIIID) may also be produced according to the following strategy. The compound of formula (IIA) and the compound of formula (VIIIA) may be converted to a compound of formula (VINE) using methods described herein. The compound of formula (VINE) is:

where all variables are as described for the compound of formula (VIIID) and the compound of formula (IIA). The compound of formula (VIIID), in which RMI is , may be converted to the compound of formula (VIIIB) as described herein.

In general, the method described herein includes an allylic reduction at C.25. This reaction can be performed at any point prior to the formation of the halichondrin macrolide or analog thereof.

In certain embodiments, the method includes converting using an allylic reducing agent.

Generally, the C.12 olefin can be introduced at any point prior to the metathesis reaction via several routes. For example, if FUc is

, , g g .g., produce the corresponding aldehyde, which can be reacted with a vinyl nucleophile.

If FUc is , the compound can be reduced with a 1 ,4-reducing agent (e.g., Stryker’s reagent), and the product can be reduced with a 1 ,2-reducing agent (e.g., DIBAL-H) to produce the corresponding aldehyde, which can be reacted with a vinyl nucleophile.

If R ₄ C is , the compound can be reacted with a glycol cleaving agent (e.g., NalCU), (Rc0)2P(0)-CFl2-C00Rc (under Florner-Wadsworth-Emmons reaction conditions), a 1 ,4-reducing agent (e.g., Stryker’s reagent), and a 1 ,2-reducing agent (e.g., DIBAL-FI) to produce the corresponding aldehyde, which can be reacted with a vinyl nucleophile. Vinyl nucleophiles are known in the art. Vinyl nucleophiles may be prepared in situ or in a separate reaction vessel. Reaction conditions for adding vinyl nucleophiles to carbonyl groups are known in the art.

The compound of formula (VIIIC) can be formed by reacting the compound of formula (VI MB) with an olefin metathesis catalyst.

The halichondrin macrolide may be produced from the compound of formula (VII 1C) using reaction conditions known in the art and those described herein. For example, the compound of formula (VIIIC) may be reacted with a hydroxyl protecting group removing agent to produce the halichondrin macrolide.

In general, the method described herein includes an allylic reduction at C.25. This reaction can be performed at any point prior to the formation of the halichondrin macrolide or analog thereof. For example,

using an allylic reducing agent.

C.13-C.14 Bond-forming Macrocyclization

In still another approach, a halichondrin macrolide or analog thereof (e.g., eribulin or a salt thereof (e.g., eribulin mesylate)) may be prepared from the compound of formula (VI ID) :

where

(i) R10 is a hydroxyl protecting group, R is alkyl ether, and R12 is H;

(ii) R10 is a hydroxyl protecting group, and Rn and R12 combine to form a double bond;

or

(iii) R10 and R11 combine to form a bond, and R12 is H;

Xi is -CH2-, -CH(Y)-, -C(Y) ₂ -, or -0-,

where each Y is independently -COORc or -SO2RD;

each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;

each RD, when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl; X4 is oxo, or X4, together with the atom to which it is attached, is -(CH(OPi2))-, where P12 is H or a hydroxyl protecting group;

Ai is H or -OP”, where P” is H or a hydroxyl protecting group;

Yi is chloro, bromo, iodo, trifluoromethanesulfonate, or trialkylsilane;

R13 and each P9 is independently a hydroxyl protecting group;

RL is

R18 is— CHO or— CH2OP7;

R5 is optionally substituted acyl; and

P7, when present, is independently H or a hydroxyl protecting group;

and the remaining variables are as described for the halichondrin macrolide or analog thereof.

The compound of formula (VI I D) is then converted to a compound of formula (VIIE):

where

Li is

where L2 and L3 combine to form a bond;

each P9 is independently a hydroxyl protecting group, and X3 is oxo or X3, together with the carbon atom to which it is attached, is -(CH(OPn))-, where Pn is H or a hydroxyl protecting group;

and the remaining variables are as described for the compound of formula (VI ID).

In certain embodiments, the compound of formula (VI I D) , in which Ris is -CHO, is subjected to Nozaki- Hiyama-Kishi reaction conditions to produce the compound of formula (VIIE). The compound of formula (VI I E) may then be converted to a halichondrin macrolide or analog thereof using methods described herein and those known in the art, e.g., those described in US 2009/0203771 , US 2016/0264594, and WO 2016/1 79607.

In general, the fragments may be coupled in any order when forming the compound of formula (VIID). For example, the C.0-C.1 or O-C.1 bond in the compounds of formula (VIID) can be formed, as described herein, prior to or after the Sakurai and/or Prins reaction. In some embodiments, a compound of formula (VIID) is produced from a compound of formula (I I A) , a compound of formula (I IB), a compound of formula (MIC), and R5OH, where R5 is optionally substituted acyl. The compound of formula (VI IA) is:

where

R9 is -CHO or -COOH; and

the remaining variables are as described for the compound of formula (VIID).

The compound of formula (IIA) is:

where

R1 is -OPB, -CH(Y)Z, or -CHz(Y),

where Pe is H or a hydroxyl protecting group, and each Y is independently -COORc or -SO2RD; each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;

each RD, when present, is independently optionally substituted aryl or optionally substituted non- enolizable alkyl;

and

RE is is -CHO or— CH(i _+m) (ORF)( -m),

where

m is 1 , and RF is a hydroxyl protecting group, or

m is 0, and (i) each RF is independently an alkyl or hydroxyl protecting group, or

(ii) both RF combine to form an alkylene. The compound of formula (MB) is:

where Rs is silyl

The compound of formula (NIC) is:

R4C-R7,

(INC)

where

R4C is

where each R7A is independently an optionally substituted alkyl; and

the remaining variables are as described for the compound of formula (VI ID).

Preparation of the compound of formula (VI ID) includes a Sakurai reaction between RE that is -CHO and the compound of formula (MB) producing a group of the structure: . This product may then be reacted with the compound of formula (MIC) under the Prins reaction conditions to produce a group of the structure: . This group may be converted to RL as described herein. If the stereochemistry of the secondary alcohol in the Sakurai reaction product differs from the desired stereochemistry, this group may be subjected to epimerization reaction conditions described herein (e.g., oxidation followed by Corey-Bakshi-Shibata reduction; alternatively, Mitsunobu reaction may be used to invert the stereogenic center). is -CH(i +m)(ORF)(2-m), preparation of the compound of formula (VII D) may further include conversion of to -CHO under acetal deprotecting conditions, e.g., through a reaction with an aqueous Bnansted acid (e.g., when m is 0), or through oxidation using an oxidizing agent capable of converting an alcohol to a carbonyl group (e.g., when m is 1 ).

Preparation of the compound of formula (VI ID) may include an esterification reaction between R that is - OP ₆ , where Rb is H, and Rg that is -COOH. Alternatively, preparation of the compound of formula (VIID) may include a reaction between R that is -CH(Y or -CPl (Y), and R that is -CPIO (e.g., under Claisen reaction conditions). Further desulfonylation or decarboxylation of this compound of formula (VIID) may produce the compound of formula (VIID), in which X is -CH -.

In some embodiments, preparation of the compound of formula (VIID) includes producing a compound of formula (IIC) from the compound of formula (IIA) and the compound of formula (MB) (e.g., under Sakurai reaction conditions). The compound of formula (IIC) is:

where all variables are as described for the compound of formula (IIA). The compound of formula (IIC) may be reacted with the compound of formula (MB), the compound of formula (NIC), and RsOH to produce a compound of formula (IF):

where all variables are as described for the compound of formula (IIA), the compound of formula (INC), and RsOH.

Preparation of the compound of formula (IF) may include a Prins reaction between the compound of formula (IIC), the compound of formula (IIC), and R5OH . The compound of formula (IF) may be converted to a compound of formula (IH):

where all variables are described for the compound of formula (IF).

In general, the method described herein includes an allylic reduction at C.25. This reaction can be performed at any point prior to the formation of the halichondrin macrolide or analog thereof. For example,

using an allylic reducing agent. In certain embodiments, the compound of formula (IF) may be reacted with an allylic reducing agent to produce the compound of formula (IH).

In the reactions described herein, the requisite transformations of groups FUc may be performed using reaction conditions known in the art. In some embodiments, the transformations of groups FUc are as described herein.

C.15-C.16 Bond-forming Macrocyclization

In one approach, the macrocyclization reaction is a carbon-carbon bond-forming reaction (e.g., olefin metathesis) that provides a C.15-C.16 bond in a halichondrin macrolide or analog thereof (e.g., eribulin or a salt thereof (e.g., eribulin mesylate)). A non-macrocyclic intermediate in the synthesis of the halichondrin macrolide or analog thereof (e.g., eribulin or a salt thereof (e.g., eribulin mesylate)) may be a compound of formula (IVB). The compound of formula (IVB) is:

where

each P ₉ is independently a hydroxyl protecting group;

(a1 ) R10 is H or a hydroxyl protecting group, R is alkyl ether, and R12 is H;

(a2) R10 is H or a hydroxyl protecting group, and Rn and R12 combine to form a double bond; or

(a3) R10 and Rn combine to form a bond, and R12 is H;

(b1 ) Ai and R14 combine to form oxo, R13 is H or a hydroxyl protecting group, and R15 is H; or

(b2) Ai is H or -OP”, and:

(i) R13 is H or a hydroxyl protecting group, and Ru and R15 combine to form a double bond;

or

(ii) R13 and R14 combine to form a bond, and R15 is H or -OP”; and

(d ) R16 is H, and Pe is H or a hydroxyl protecting group;

or

(c2) R16 and Ps combine to form a double bond;

each P”, when present, is independently H or a hydroxyl protecting group

Xi is -0-, -C(Y)2-,-CH(Y)-, or -CH2-, where each Y is independently-COORc or -SO2RD, where each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl, and each RD, when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl;

RG is

where

R5 is an optionally substituted acyl, and

X2 is H or -CH2-X2A-CH2-CH=CH2, where X2A is -0-, -C(RH)2-, or -NRi-, where each RH is independently H or -COORj, Ri is an A/-protecting group, and Rj is C1-6 alkyl;

and

X4 is oxo, or X4, together with the atom to which it is attached, is -(CH(OPi2))-, where P12 is H or a hydroxyl protecting group;

and the remaining variables are as described for the halichondrin macrolide or analog thereof. In some embodiments, the compound of formula (IVB) is a compound of formula (IVBa):

where all variables are as described in the compounds of formula (IVB). The compound of formula (IVB) (e.g., the compound of formula (IVBa)) is converted to the compound of formula (IVC) through an olefin metathesis reaction. The compound of formula (IVC) is:

where

Li is

where L2 and L3 combine to form a bond; and the remaining variables are as described for the compound of formula (IVB).

The compound of formula (IVC) is then converted to the compound of formula (IVD):

where each of Ai and A2 is independently H or -OP”, and the remaining variables are as described for the compound of formula (IVC).

The compound of formula (IVC) may be converted to the compound of formula (IVD) using reaction conditions known in the art. For example, the compound of formula (IVC) may be reacted with a 1 ,4- reducing agent to give the compound of formula (IVD).

Preparation of the compound of formula (IVD) may further include reacting the compound of formula (I VA) , (IVB), or (IVC), in which Pe and R16 are both H, with an oxidizing agent capable of converting an alcohol to a carbonyl group (e.g., Dess-Martin periodinane or a dimethylsulfonium compound) to give the compound of formula (IVA), (IVB), or (IVC), in which F¼ and Pe combine to form a double bond (e.g., the compound of formula IVCa)). If Pe is a hydroxyl protecting group, prior to oxidation, the compound of formula (IVA), (IVB), or (IVC) may be treated with a hydroxyl protecting group removing agent. In a non-limiting example, preparation of the compound of formula (IVD) includes oxidizing the compound of formula (IVC), in which P9 is H, R16 is H, with an oxidizing agent capable of converting an alcohol to a carbonyl group (e.g., Dess-Martin periodinane or a dimethylsulfonium compound) to give a compound of formula (IVCa):

where all variables are described for the compound of formula (IVC). The compound of formula (IVD) is then converted to the halichondrin macrolide or analog thereof using methods described herein and those known in the art, e.g., those described in US 2016/0264594 and WO 2016/179607.

If the compound of formula (IVD) includes hydroxyl protecting groups as Fte and/or Ps, these hydroxyl protecting groups can be removed with a hydroxyl protecting group removing agent. For example, a hydroxyl protecting group removing agent may be a fluoride source, if the hydroxyl protecting group is a silyl group.

If, in the compound of formula (IVD), each Pg is H, and X3 is oxo, the synthesis may further involve a reaction with a Bnansted acid (e.g., a Brensted acid having a pKa of 5 ± 3), e.g., after the reaction of the compound of formula (IVD) with a hydroxyl protecting group removing agent (e.g., to convert P9 from a hydroxyl protecting group into H).

If, in the compound of formula (IVD), X3 is oxo, R10 is a hydroxyl protecting group, and Rn and R12 combine to form a double bond, treatment with a hydroxyl protecting group removing agent can provide the compound of formula (IVD), in which R10 and Rn combine to form a bond, and R12 is H.

In general, the fragments may be coupled in any order when forming compound (IVB). For example, the C.0-C.1 or 0-C.1 bond between fragment (II A) and fragment (IVA) can be formed, as described herein, prior to or after the Sakurai and/or Prins reaction. Similarly, installation of the C.15 olefin may occur before or after any of the Sakurai, Prins, and C.0-C.1 or 0-C.1 bond forming reactions.

In certain embodiments, the compound of formula (IVB) is produced from a compound of formula (II A) , a compound of formula (I IB), a compound of formula (IIIA), a compound of formula (IVA), and R5OH.

The compound of formula (IVA) is:

R ;

Rg R-|0 OPg R ₁₃

(IVA)

where

Rg is -CHO or -COOH,

and the remaining variables are as described for the compound of formula (IVB). The compound of formula (IIA) is:

where

R1 is -ORQ, -CH(Y)2, or -CH2(Y), where RQ is H or a hydroxyl protecting group, and each Y is independently-

COORc or— SO2RD;

RE is is -CHO or -CH(i ₊ m)(ORF)(2-m),

where

m is 1 , and RF is a hydroxyl protecting group, or

m is 0, and (i) each RF is independently an alkyl or hydroxyl protecting group, or

(ii) both RF combine to form an alkylene;

and the remaining variables are as described for the compound of formula (IVB).

The compound of formula (MB) is:

where Rs is silyl.

The compound of formula (MIA) is:

R4A-R7,

(MIA)

where

R7 is -CHO or

where each R7A is independently an optionally substituted alkyl; and

where Rc is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl, and each P7 is independently H or a hydroxyl protecting group.

Preparation of the compound of formula (IVB) includes a Sakurai reaction between RE that is -CHO and the compound of formula (MB) producing a group of the structure: . This product may then be reacted with the compound of formula (IIIA) under Prins reaction conditions to produce a group of the structure: . This group may be converted to RG as described herein. If the stereochemistry of the secondary alcohol in the Sakurai reaction product differs from the desired stereochemistry, this group may be subjected to epimerization reaction conditions described herein (e.g., oxidation followed by Corey-Bakshi-Shibata reduction; alternatively, itsunobu reaction may be used to invert the stereogenic center). If RE is -CH (1 ₊ m) (ORF)< 2-m), preparation of the compound of formula (IVB) may further include conversion of RE to -CHO under acetal deprotecting conditions, e.g., through a reaction with an aqueous Brensted acid (e.g., when m is 0), or through oxidation using an oxidizing agent capable of converting an alcohol to a carbonyl group (e.g., when m is 1 ). Preparation of RG may include reacting R4A that is with a glycol cleaving agent, and subjecting the resulting product to Horner-

Wadsworth-Emmons reaction with (Rc0)2P(0)-CH2-C00Rc to produce R4A that is This reaction may be performed after Sakurai and Prins reactions. Preparation of RG may further include a reaction of R4A that is a 1 ,2-reducing agent and reacting the resulting product with an allyl halide or allyl pseudohalide. This reaction may be performed after Sakurai and Prins reactions.

Group RE may be converted to RG before or after the reaction of the compound of formula (IIA) with the compound of formula (IVA). For example, conversion of RE to RG before the reaction of the compound of formula (IIA) with the compound of formula (IVA) may be carried out via compounds of formulae (IB) and (1C), as described herein. Conversion of RE to RG after the reaction of the compound of formula (IIA) with the compound of formula (IVA) may be carried out via a compound of formula (IVAa):

where

Xi is -CH -, -CH(Y)-, -C(Y) -, or -0-, where each Y is independently -COORc or -SO RD;;

each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;

each RD, when present, is independently optionally substituted aryl or optionally substituted non- enolizable alkyl;

X is oxo, or X , together with the atom to which it is attached, is -(CH(0Pi2))-, where P is H or a hydroxyl protecting group; and

the remaining variables are as described for the compound of formulae (II A) and (IVA).

The compound of formula (IVAa), in which RE is -CHO, may be reacted with the compound of formula (MB) under Sakurai reaction conditions to produce a compound of formula (IVAb):

where all variables are as described for the compound of formula (IVAa).

A compound of formula (IVAc) may be produced from the compound of formula (IVAb), the compound of formula (IIIA), and RsOH. The compound of formula (IVAc) is:

where

RGI is

R5 is optionally substituted acyl, and

the remaining variables are as described for the compound of formula (IVAb).

For example, the compound of formula (IVAb) may be reacted with the compound of formula (IIIA) and R5OH under Prins reaction conditions to produce the compound of formula (IVAc), in which RGI is

The compound of formula (IVAc) may be converted to the compound of formula (IVB) as described herein. If the compound described herein (e.g., a Prins reaction product) includes:

the synthesis may further include reacting such compound with an allylic reducing agent to produce the group

A non-limiting example of an allylic reducing agent is a palladium complex (e.g., Pd(PPhi3)4) in combination with a formic acid salt (e.g., trialkylammonium formate). Alternatively, preparation of the compound of formula (IVB) may include producing a compound of formula (IA) from a compound of formula (I I A) , a compound of formula (IIIA), and RsOH. The compound of formula (IA) is:

where all variables are as described for the compound of formula (I IA), the compound of formula (IIIA), and RsOH. The compound of formula (IA) may be reacted with the compound of formula (IVA) to form the compound of formula (IVB). For example, the compound of formula (IA) may be converted to the compound of formula (IB), which may then be converted to the compound of formula (IC). The compound of formula (IB) is:

where all variables are as described for the compound of formula (IA).

Preparation of the compound of formula (IB) may include reacting the compound of formula (IA) with an allylic reducing agent. The compound of formula (IC) is:

where X2 is as described for the compound of formula (IVB), and the remaining variables are as described for the compound of formula (IB).

The compound of formula (IVB) may be prepared from the compound of formula (IC) and the compound of formula (IVA) as described herein.

Preparation of the compound of formula (IVB), in which Xi is -C(Y)å-, -CH(Y)-, or -CH2-, may include a reaction (e.g., Claisen reaction) between an intermediate (e.g., the compound of formula (IVA), in which Rg is -CHO) and another intermediate (e.g., the compound of formula (IIA), (IA), (IB), or (IC), in which R1 is - CH(Y)2 or -CH2(Y)) that was treated with a Bronsted base to produce an intermediate (e.g., the compound of formula (IVB), in which Xi is -C(Y)2-, -CH(Y)-, or -CH2-). If Xi in the compound of formula (IVB) is -CH2-, the preparation of the compound of formula (IVB) may further include a desulfonylation or decarboxylation reaction.

Alternatively, preparation of the compound of formula (IVB), in which Xi is -0-, may include a reaction (e.g., an esterification reaction) between an intermediate (e.g., the compound of formula (IVA), in which Fb is - COOH) and another intermediate (e.g., the compound of formula (IIA), (IA), (IB), or (IC), in which Ri that is - 0P ₆ , where Re is H) to produce an intermediate (e.g., the compound of formula (IVB), in which Xi is -0-).

Preparation of certain compounds of formula (IVB) or (IVC) may further involve conversion of the compound of formula (IVB) or (IVC), in which Ai is H, and RH and R15 combine to form a double bond, into the compound of formula (IVB) or (IVC), respectively, in which RM and A1 combine to form oxo. In a non-limiting example, the enone in the compound of formula (IVB) or (IVC), in which Ru and R15 combine to form a double bond can be converted into a C.12-C.13 epoxide using a nucleophilic peroxide agent, e.g., f-butyl hydroperoxide, which can then be converted into the compound of formula (IVB) or (IVC), in which A1 and R14 combine to form oxo, using methods known in the art, e.g., by reacting with a bidentate phosphine ligand and a source of Pd(0) (see, e.g., Muzart, J., Eur. J. Org. Chem., 4717-4741 , 201 1 ). Thus, the compound of formula (IVB) or (IVC), in which A1 is OP”, can be prepared. Other transformations may involve 0 oxygenation to produce the compound of formula (IVB) or (IVC), in which R15 is OP”.

In general, the method described herein includes an allylic reduction at C.25. This reaction can be performed at any point prior to the formation of the halichondrin macrolide or analog thereof. For example,

using an allylic reducing agent.

C.19-C.20 Bond-forming Macrocyclization

In another approach, the macrocyclization reaction can be a carbon-carbon bond-forming reaction (e.g., olefin metathesis) that provides a C.19-C.20 bond in a halichondrin macrolide or analog thereof (e.g., eribulin or a salt thereof (e.g., eribulin mesylate)). A non-macrocyclic intermediate in the synthesis of the halichondrin macrolide or analog thereof (e.g., eribulin or a salt thereof (e.g., eribulin mesylate)) may be a compound of formula (VB).

The compound of formula (VB) is:

where

a designates (R)-stereogenic center, and Z is a sulfonate, chloride, bromide, or iodide; or a designates (S)- stereogenic center, and Z is OR16, where R16 is a hydroxyl protecting group;

Xi is -CH2-, -CH(Y)-, -C(Y)2-, or -0-, where each Y is independently -COORc or -SO2RD;

each P9 is independently a hydroxyl protecting group, and X3 is oxo; or both Pg groups and X3, together with the atoms to which each is attached, combine to form a ketal;

Yi is iodide, bromide, or trifluoromethanesulfonate;

each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;

each RD, when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl;

RK is

where Rs is optionally substituted acyl;

(a1 ) R10 is a hydroxyl protecting group, R is alkyl ether, and R12 is H;

(a2) R10 is a hydroxyl protecting group, and Rn and R12 combine to form a double bond;

or

(a3) R10 and Rn combine to form a bond, and R12 is H;

(b1 ) Ai and R14 combine to form oxo, R13 is a hydroxyl protecting group, and R15 is H;

or

(b2) Ai is H or -OP”, and:

(i) R13 is a hydroxyl protecting group, and RH and R15 combine to form a double bond;

or

(ii) R13 and R14 combine to form a bond, and R15 is H or -OP”;

each P” is independently a hydroxyl protecting group; and the remaining variables are as described for the halichondrin macrolide or analog thereof.

The compound of formula (VB) is then converted to the compound of formula (VC) using reaction conditions known in the art. For example, the compound of formula (VB) may be subjected to Nozaki-Hiyama-Kishi reaction conditions known in the art to produce the compound of formula (VC). Nozaki-Hiyama-Kishi reaction on the compound of formula (VB) can include reacting the compound of formula (VB) with a Cr(ll) salt and a Ni(ll) salt. Ancillary ligands can be used in combination with the metal salts. In a non-limiting example, a substituted 1 ,10-phenanthroline can be used in combination with a Ni(ll) salt. Chiral ancillary ligands can be used to render the reaction stereoselective. In a non-limiting example, chiral N- (dihydrooxazolyl-phenyl)-sulfonamides can be used with a Cr(ll) salt to control the stereochemistry of the carbonyl carbon, to which a vinyl nucleophile is added in the course of Nozaki-Hiyama-Kishi reaction.

The compound of formula (VC) is:

where

Li is

where l and L combine to form a bond;

b designates (S)-stereogenic center, if a designates (fi)-stereogenic center;

and

b designates (R)-stereogenic center, if a designates (S)-stereogenic center;

and the remaining variables are as described for the compound of formula (IVB).

The compound of formula (VC) is then converted to the halichondrin macrolide or analog thereof using methods described herein and those known in the art, e.g., those described in US 2016/0264594, US 2009/0203771 , and WO 2016/1 79607.

The compound of formula (VC), in which Z is OR , R is a hydroxyl protecting group ester, a designates (S)-stereogenic center, and b designates (F?)-stereogenic center, can be converted to a compound of formula (VD):

where a designates (S)-stereogenic center, b designates (F?)-stereogenic center, Z is OR16, in which R16 is a hydroxyl protecting group (e.g., R16, together with the atom to which it is attached, combine to form an ester), RH is sulfonyl, and the remaining variables are as described for the compound of formula (VC).

The compound of formula (VC), in which Z is OR16, R16 is a hydroxyl protecting group ester, a designates (S)-stereogenic center, and b designates (R)-stereogenic center, may be converted to the compound of formula (VD), e.g., by reacting with a sulfonyl electrophile, such as a sulfonyl chloride or a sulfonyl anhydride. In the compound of formula (VD), a hydroxyl protecting group in Z may be removed, resulting in the formation of the C.16-C.20 furan ring in the structure of the halichondrin macrolide or analog thereof (e.g., eribulin or a salt thereof (e.g., eribulin mesylate)). In a non-limiting example, the concomitant removal of a hydroxyl protecting group in Z (e.g., if Z is an ester) and the formation of the C.16-C.20 furan ring in the structure of the halichondrin macrolide or analog thereof may be achieved by the treatment of the compound of formula (VD) with a strong base (e.g., a C1-6 alkoxide (e.g., KOMe)).

The compound of formula (VB), in which Z is a sulfonate, chloride, bromide, or iodide, a designates (S)- stereogenic center, and b designates (F?)-stereogenic center, may be converted to the halichondrin macrolide or analog thereof (e.g., eribulin or a salt thereof (e.g., eribulin mesylate)) directly upon formation of the compound of formula (VC), e.g., upon the reaction work up and/or purification (e.g., on silica gel).

If the compound of formula (VD) includes hydroxyl protecting groups as R3 and/or P5, these hydroxyl protecting groups can be removed with a hydroxyl protecting group removing agent. For example, a hydroxyl protecting group removing agent may be a fluoride source, if the hydroxyl protecting group is a silyl group.

If, in the compound of formula (VC), each P9 is H, and X3 is oxo, the synthesis may further involve a reaction with a Bronsted acid (e.g., a Brensted acid having a pKa of 5 ± 3), e.g., after the formation of the C.16-C.20 furan ring.

If, in the compound of formula (VC), (VD), or a C.16-C.20 furan cyclization product thereof, X3 is oxo, R13 is a hydroxyl protecting group, and RH and R15 combine to form a double bond, treatment with a hydroxyl protecting group removing agent can provide the compound of formula (VC), (VD), or a C.16-C.20 furan cyclization product thereof, in which R13 and RH combine to form a bond, and R15 is H. Preparation of the halichondrin macrolides or analogs thereof may further involve conversion of the compound of formula (VC), (VD), or a C.16-C.20 furan cyclization product thereof, in which Ai is H, and Ru and R15 combine to form a double bond, into the compound of formula (VC), (VD), or a C.16-C.20 furan cyclization product thereof, respectively, in which Ru and Ai combine to form oxo. In a non-limiting example, the enone in the compound of formula (VC), (VD), or a C.16-C.20 furan cyclization product thereof, in which X3 is oxo, and R14 and R15 combine to form a double bond, can be converted into a C.12-C.13 epoxide using a nucleophilic peroxide agent, e.g., f-butyl hydroperoxide, which can then be converted into the compound of formula (VC), (VD), or a C.16-C.20 furan cyclization product thereof, in which Ai and R combine to form oxo, using methods known in the art, e.g., by reacting with a bidentate phosphine ligand and a source of Pd(0) (see, e.g., Muzart, J., Eur. J. Org. Chem., 471 7-4741 , 201 1 ). Thus, the compound of formula (VC), (VD), or a C.16-C.20 furan cyclization product thereof, in which Ai is OP”, can be prepared. Other transformations may involve ooxygenation to produce the compound of formula (VC), (VD), or a C.16-C.20 furan cyclization product thereof, in which R15 is OP”.

In general, the fragments may be coupled in any order when forming compound (VB). For example, the C.0- C.1 or 0-C.1 bond between fragment (IIA) and fragment (VA) can be formed, as described herein, prior to or after the Sakurai and/or Prins reaction.

In some embodiments, the compound of formula (VB) is produced from a compound of formula (IIA), a compound of formula (I IB), a compound of formula (IIIB), and, R OH, where Rs is optionally substituted acyl.

The compound of formula (VA) is:

where

Rg is -CHO or -COOH;

and the remaining variables are as described for the compound of formula (VB).

The compound of formula (IIA) is:

where

R1 is -OPs, -CH(Y)2, or -CH2(Y), where Rb is H or a hydroxyl protecting group, and each Y is independently- COORc or -SO2RD;

each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;

each RD, when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl;

RE is is -CHO or -CH(i ₊ m)(ORF)(2-m),

where

m is 1 , and RF is a hydroxyl protecting group, or

m is 0, and (i) each RF is independently an alkyl or hydroxyl protecting group, or

(ii) both RF combine to form an alkylene;

and the remaining variables are as described for the compound of formula (VB).

The compound of formula (MB) is:

where Rs is silyl.

The compound of formula (NIB) is:

R4B-R7,

(NIB)

where

R7 is -CHO or

OR _7A

RTAO A ^' y

where each R A is independently an optionally substituted alkyl, and

R B is but-3-en-1 -yl,

where each P7 is independently H or a hydroxyl protecting group.

Preparation of the compound of formula (VB) includes a Sakurai reaction between RE that is -CHO and the compound of formula (MB) producing a group of the structure: . This product may then be reacted with the compound of formula (NIB) under Prins reaction conditions to produce a group of the structure: . This group may be converted to RK as described herein. If the stereochemistry of the secondary alcohol in the Sakurai reaction product differs from the desired stereochemistry, this group may be subjected to epimerization reaction conditions described herein (e.g., oxidation followed by Corey-Bakshi-Shibata reduction; alternatively, itsunobu reaction may be used to invert the stereogenic center). If RE is -CH (1 +m) (ORF)< 2-m), preparation of the compound of formula (VB) may further include conversion of RE to -CHO under acetal deprotecting conditions, e.g., through a reaction with an aqueous Bronsted acid (e.g., when m is 0), or through oxidation using an oxidizing agent capable of converting an alcohol to a carbonyl group (e.g., when m is 1 ). When R ₄ B is but-3-en-1 -yl, preparation of the compound of formula (VB) includes conversion of the but-3-en- 1 -yl group to -(CH2)2-CHO. For example, the but-3-en-1 -yl group may be reacted with a dihydroxylating agent to produce R ₄ B that is

OP ⁷ , and cleaving with a glycol cleaving agent. When R ₄ B is , preparation of the compound of formula (VB) includes conversion of to -(CH2)2-CHO, e.g., by reacting with an oxidizing agent capable of converting an alcohol into a carbonyl group.

When R ₄ B is

OP ⁷ , preparation of the compound of formula (VB) includes conversion of

OP ⁷ to -(CH2)2-CHO, e.g., using a glycol cleaving agent. If at least one P is a hydroxyl protecting group in the compound of formula (NIB), preparation of the compound of formula (VB) may futher include treating with a hydroxyl protecting group removing agent.

Group RE may be converted to RK before or after the reaction of the compound of formula (IIA) with the compound of formula (VA). For example, conversion of RE to RK before the reaction of the compound of formula (IIA) with the compound of formula (VA) may be carried out via compounds of formulae (ID) and (IE), as described herein. Conversion of RE to RK after the reaction of the compound of formula (IIA) with the compound of formula (VA) may be carried out via a compound of formula (VAa):

where all variables are as described for the compound of formulae (IIA) and (VA).

The compound of formula (VAa) may be reacted with the compound of formula (I IB) under Sakurai reaction conditions to produce a compound of formula (VAb):

where all variables are as described for the compound of formula (VA).

A compound of formula (VAc) may be prepared from the compound of formula (VAb), the compound of formula (NIB), and R OH through Prins reaction. The compound of formula (VAc) is:

where

RKI is

and the remaining variables are as described for the compound of formula (VA) and the compound of formula (NIB).

The compound of formula (VAc) may be converted to the compound of formula (VB) as described herein.

In particular embodiments, the Sakurai reaction product is a compound of formula (IIC):

where all variables are as described for the compound of formula (IIA).

In certain embodiments, the Prins reaction product is a compound of formula (ID):

where all variables are as described for the compound of formula (IIA), the compound of formula (IIIB), and RsOH.

In further embodiments, a compound of formula (IE) may be prepared from the compound of formula (ID) (e.g., the compound of formula (ID) is reacted with an allylic reducing agent to produce the compound of formula (IE)). The compound of formula (IE) is:

where all variables are as described for the compound of formula (ID).

The compound of formula (IE) may be reacted with the compound of formula (VA), as described herein, to produce the compound of formula (VB).

Preparation of the compound of formula (VB), in which Xi is -C(Y)2- -CH(Y)-, or -CH2-, may include a reaction (e.g., Claisen reaction) between an intermediate (e.g., the compound of formula (VA), in which R ₉ is -CHO) and another intermediate (e.g., the compound of formula (II A) , (ID), (IIC), or (IE), in which R1 is - CH(Y)2 or -CH2(Y)) that was treated with a Bronsted base to produce an intermediate (e.g., the compound of formula (VB), in which X1 is -C(Y)2-, -CH(Y)-, or -CH2-). If X1 in the compound of formula (VB) is -CH2-, the preparation of the compound of formula (VB) may further include a desulfonylation or decarboxylation reaction.

Alternatively, preparation of the compound of formula (VB), in which X1 is -0-, may include a reaction (e.g., an esterification reaction) between an intermediate (e.g., the compound of formula (VA), in which R ₉ is - COOH) and another intermediate (e.g., the compound of formula (I I A), (ID), (IIC), or (IE), in which R1 is - ORd, where Rb is H) to produce an intermediate (e.g., the compound of formula (VB), in which X1 is -0-).

In general, the method described herein includes an allylic reduction at C.25. This reaction can be performed at any point prior to the formation of the halichondrin macrolide or analog thereof. For example,

using an allylic reducing agent.

C.23-C.24 Macrocyclization

In another approach, a halichondrin macrolide or analog thereof may be prepared from the compound of formula (IXB): where X1 is -CH2-, -CH(Y)-, -C(Y)2- or -0-, each independently -COORc or -SO2RD;

each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;

each RD, when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl;

Li is

combine to form a bond;

R5 is optionally substituted acyl;

Ai and RM combine to form oxo, R13 is H or a hydroxyl protecting group, and R15 is H;

or

Ai is H or -OP”, and

(i) R13 is H or a hydroxyl protecting group, and Ru and R15, together with the atoms to which each is attached, combine to form a double bond;

or

(ii) R13 and R14 combine to form a bond, and R15 is H or -OP”; each P9 is independently H or a hydroxyl protecting group,

X3 is oxo, or X3, together with the atom to which it is attached, combines to form -(CH(OP ))-, where P is H or a hydroxyl protecting group; or both Pg and X3, together with the atoms to which each is attached, combine to form a ketal; and

R19A is H, -OP”, or Y, and R19B is H; or R19A and R19B, together with the atoms to which each is attached, combine to form a double bond.

The compound of formula (IXB) can be produced from a compound of formula (IXA), a compound of formula (MB), a compound of formula ( 11 A) , a compound of formula (HIE), and R5OH. The compound of formula (IXA) is:

where

R _s is -CHO or -COOP”;

(a1 ) R is a hydroxyl protecting group, R is alkyl ether, and R is H;

(a2) R is a hydroxyl protecting group, and Rn and R combine to form a double bond; or (a3) R and Rn combine to form a bond, and R is H;

Ai and RH combine to form oxo, R13 is H or a hydroxyl protecting group, and R15 is H;

or

Ai is H or -OP”, and:

(i) R is H or a hydroxyl protecting group, and R and R combine to form a double bond; or

(ii) R13 and RH combine to form a bond, and R15 is H or -OP”;

Ro is -CHO, -CH OP”, -CH=CH ₂ , -CH(OP”)CH ₂ OP”, -C(0)-CH ₂ P(0)(0RC)2, or halogen;

each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;

each P” is independently H or a hydroxyl protecting group; and

each P is independently a hydroxyl protecting group.

The compound of formula (IIA) is:

(I I A)

where

R is -ORQ, -CH(Y) ₂ , or -CH ₂ (Y), where RQ is H or a hydroxyl protecting group, and each Y is independently -COORc or— S0 ₂ RD;

each Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;

each RD, when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl;

RE is -CHO or -CH(i _+m) (ORF)( _{2 m)} , where

m is 1 , and RF is a hydroxyl protecting group,

or

m is 0, and

(i) each RF is independently an alkyl or hydroxyl protecting group, or (ii) both RF combine to form an alkylene.

The compound of formula (IIIE) is:

R4E-R7,

(IIIE)

where R4E is

where each P7 is independently H or a hydroxyl pr

COORc, -CH2CH2-SO2RD, or -CH=CH-S0 ₂ RD; and

R7 is -CHO or

OR7A

R _7A 0 A* , where each R7A is independently an optionally substituted alkyl.

The compound of formula (MB) is:

where Rs is silyl.

In some embodiments, the compound of formula (IXB) is produced according the following strategy. For example, a compound of formula (IXC) may be produced from the compound of formula (IXA), the compound of formula (I IA), in which RE is -CH(i _+m) (ORF)(2-m), the compound of formula (MB), and RsOH, as follows. The compound of formula (IXA) may be reacted with the compound of formula (I IA) to produce a compound of formula (IXC):

where

Xi is -CH2-, -CH(Y)-, -C(Y) ₂ - or -0-; X4 is oxo, or X4, together with the atom to which it is attached, is -(CH(OPi2))-, where P12 is H or a hydroxyl protecting group; and

the remaining variables are as described for the compound of formula (IXA) and the compound of formula (IIA).

Preparation of the compound of formula (IXC) may include an esterification reaction between R1 that is - ORQ, where Re is H , and R9 that is -COOP”, where P” is H. Alternatively, preparation of the compound of formula (IXC) may include a reaction between R1 that is -CH(Y)2 or -CH2(Y), and R9 that is -CHO (e.g. , under Claisen reaction conditions). Further, the compound of formula (IXC), in which X4, together with the atom to which it is attached, is -(CH(OPi2))-, where P12 is H, may be oxidized to produce the compound of formula (IXC), in which X4 is oxo. Reaction conditions useful for this oxidation are known in the art. Further desulfonylation or decarboxylation of this compound of formula (IXC) may produce the compound of formula (IXC), in which X1 is -CH2-.

The compound of formula (IXC) may be converted to a compound of formula (IXD):

where

R7 is -CHO, -CH2OPA or

the remaining variables are as described for the compound of formula (IXB).

The compound of formula (IXD) may be prepared from the compound of formula (IXC) and the compound of formula (IIIE) as follows. The compound of formula (II IE) may be converted to a compound of formula (IN F) :

R4F-R7,

(IM F)

where R4F is

OR7A

R _7A O ί , where each R A is independently an optionally substituted alkyl.

FUE that is

may be converted to R F that is ng a glycol cleaving agent.

R8 that is -CH=CH-COORc or -CH=CH-S02RD may be reacted with a 1 ,4-reducing agent to produce Rs that is -CH CH -COORC or -CH CH -SO RD, respectively. R E that is

reacted with an allylic reducing agent to produce

, which, upon reduction with a 1 ,2-reducing agent may produce R _4F that is A compound of formula (IXE) may be produced from the compound of formula (IMF) and the compound of formula (IXC). The compound of formula (IXE) is:

where all variables are as described for the compound of formula (IXC) and the compound of formula (IXD). R4F that is , where Rs is -CH CH -COORC or -CH CH^SC> RD, may be reacted with Ro that is -

CHO under Claisen reaction conditions. This reaction may produce the compound of formula (IXE), in which R19A is Y.

FUF that is may be reacted with Ro that is halogen under Nozaki-Hiyama-Kishi reaction conditions. This reaction may produce the compound of formula (IXE), in which X3, together with the atom to which it is attached, combines to form -(CH(OP ))-, where P is H.

R F that is may be reacted with Ro that is -C(0)-CH2P(0)(0Rc)2 under Horner-Wadsworth-

Emmons reaction conditions. This reaction may produce the compound of formula (IXE), in which R and R19B, together with the atoms to which each is attached, combine to form a double bond.

The compound of formula (IXE) may be converted to the compound of formula (IXD) by reacting with the compound of formula (I IB) under Sakurai reaction conditions.

The compound of formula (IXD), in which R7 is -CHO, may reacted with R5OH under Prins reaction conditions to produce the compound of formula (IXB), in which Li is:

In further embodiments, the compound of formula (IXD) may be prepared by reacting the compound of formula (IXC), in which is -CHO, with a compound of formula (MB) to produce a compound of formula (IXF):

where P13 is H or a hydroxyl protecting group; and the remaining variables are as described for the compound of formula (IXC).

The compound of formula (IXD) may be produced from the compound of formula (IXF) and the compound of formula (INF) as described herein. Preparation of the compound of formula (IXD) may further include converting P13 that is a hydroxyl protecting group to P13 that is FI. In yet further embodiments, the compound of formula (IXD) may be prepared as follows. A compound of formula (IXG) may be prepared from the compound of formula (IXA) and the compound of formula (INF) using methods described herein. The compound of formula (IXG) is:

where all variables are as described for the compound of formula (IXD) and the compound of formula (IXA).

The compound of formula (IXE) may be prepared from the compound of formula (IXG) and the compound of formula (IIA) using methods described herein. Preparation of the compound of formula (IXD) from the compound of formula (IXE) is then carried out as described herein.

The compound of formula (IXD) may be prepared from the compound of formula (IXG) and the compound of formula (IIC). For example, the compound of formula (IIC) may be protected with a hydroxyl protecting group to produce a compound of formula (IIJ):

where P is a hydroxyl protecting group, and the remaining variables are as described for the compound of formula (IIC).

The compound of formula (IXD) may be produced from the compound of formula (IIJ) and the compound of formula (IXG) using methods described herein.

In general, the methods described herein can include reacting RE that is -CHO with the compound of formula (MB) and a first Lewis acid (e.g., an oxophilic Lewis acid) to produce a group of the structure: , which may be reacted with R , R OH, and a second Lewis acid (e.g., an oxophilic Lewis acid)

(same as or different from the first Lewis acid) to produce a group of the structure: In other embodiments, R that is -ORb is reacted with R under esterification reaction conditions to produce a group of the structure -Xi-C(0)-, where Rb is H, Rg is -COOH, and X is -0-. Alternatively, R that is - CH(Y or -CH (Y) is reacted with Rg under Claisen reaction conditions to produce a group of the structure - Xi-C(0)-, where Rg is -CHO, and X is -C(Y) ₂ - or -CH(Y)-. The compound of formula (IXB) may also be accessed using methods and compounds described in PCT/US17/40401 .

In general, the method described herein includes an allylic reduction at C.25. This reaction can be performed at any point prior to the formation of the halichondrin macrolide or analog thereof. In certain embodiments, the compound of formula (IXB) is reacted with an allylic reducing agent to produce the halichondrin or analog thereof.

In general, the method described herein includes an allylic reduction at C.25. This reaction can be performed at any point prior to the formation of the halichondrin macrolide or analog thereof. For example, may be converted using an allylic reducing agent.

Compounds of Formula (Z) an

Compounds of formula (Z) and (Z8) may be used as the compound of formula (III) in the syntheses described herein.

Compound of Formula (Z)

The compound of formula (Z) is:

each R7A is independently alkyl or a hydroxyl protecting group; or

both R7A combine to form an optionally substituted alkylene.

The compound of formula (Z) may be prepared as described herein. For example, a compound of formula

O

11

P _{\ ^} -COORi ₉

(Z2) may be produced from a compound of formula (Z1 ) and ^{Rl 9} ° OR 1 ⁹ , where each R19 is independently optionally substituted alkyl.

The compound of formula (Z1 ) is:

where

each R20A is independently a hydroxyl protecting group, or both R20A, together with the atoms to which each is attached, combine to form an acetal, ketal, cyclic carbonate, dicarbonyl-dioxo, or silylene- dioxo;

each R20B is independently a hydroxyl protecting group, or both R20B, together with the atoms to which each is attached, combine to form an acetal, ketal, cyclic carbonate, dicarbonyl-dioxo, or silylene- dioxo; Pi A is H;

P B is H or a hydroxyl protecting group. The compound of formula (Z2) is:

where all variables are as described for the compound of formula (Z1 ).

O

I I

The compound of formula (Z1 ) may be reacted with under Horner-Wadsworth-Emmons reaction conditions to produce the compound of formula (Z2).

O

I I

P _{\ ^} .OR _2-|

R ₂₁ O Ί

A compound of formula (Z3) may be produced from the compound of formula (Z2) and OR 21 in which each R is independently optionally substituted alkyl. The compound of formula (Z3) is:

O

-P^ ,OR 21

R ₂ I O 1

where all variables are as described for the compound of formula (Z2) and for OR 21

O

R ^K 21 n ^ϋ " O ^l R^ ^0R21

The compound of formula (Z2) may be reacted with ²¹ under Horner-Wadsworth-Emmons reaction conditions to produce the compound of formula (Z3).

The compound of formula (Z3) may be converted to the compound of formula (Z4):

where X5 is a halogen, and

the remaining variables are as described for the compound of formula (Z3).

The free hydroxyl in the compound of formula (Z3) may be substituted with a halogen (e.g., iodide) as described herein. Reaction conditions for halogen substitution with a halogen are known in the art. In a non limiting example, the compound of formula (Z3) may reacted with a sulfonyl anhydride (e.g.,

trifluoromethanesulfonic anhydride or methanesulfonic anhydride) to produce the corresponding sulfonate (e.g., trifluoromethanesulfonate or methanesulfonate), which, upon reaction with a halide source (e.g., alkali iodide), may produce the compound of formula (Z4).

The compound of formula (Z4) may be converted to the compound of formula (Z5):

where all variables are as described for the compound of formula (Z4).

The compound of formula (Z4) may be subjected to reductive metal conditions to produce the compound of formula (Z5). Reductive metal conditions are known in the art. In a non-limiting example, the compound of formula (Z4) may be reacted with a metal capable of inserting into carbon-halogen bonds (e.g., Zn(0) or an alkyl lithium (e.g., ί-BuLi) in combination with a Brensted acid (e.g., acetic acid) to produce the compound of formula {Zb). When the metal is Zn(0), the Brensted acid is an ingredient of the reaction mixture. When the reaction is performed with an alkyl lithium, the Brensted acid is added to quench the reaction.

The compound of formula (Z5) may be reacted with R7AOH to produce the compound of formula (Z6):

where R7A is as described for the compound of formula (Z).

The compound of formula (Z5) may be reacted with R7AOH in the presence of a Brensted acid to produce the compound of formula (Z6).

O

I I

A compound of formula (Z7) may be produced from the compound of formula (Z6) and

in which each R22 is independently optionally substituted alkyl. The compound of formula (Z7) is:

R n"i^^ ^{COOR22 K22} ° riR

where all variables are as described for the compound of formula (Z) and for The compound of formula (Z6) may be reacted with a glycol cleaving agent to produce aldehyde (Z6A):

where all variables are as described for the compound of formula (Z5).

0

The aldehyde (Z6A) can be reacted with , in which each R22 is independently optionally substituted alkyl, under Horner-Wadsworth-Emmons reaction conditions to produce the compound of formula (Z7).

The compound of formula (Z) may be produced from the compound of formula (Z7). In a non-limiting example, the compound of formula (Z7) may be reacted with a 1 ,4-reducing agent to produce the compound of formula (Z).

Compound of Formula (Z8)

The compound of formula (Z8) is:

each R7A is independently alkyl or a hydroxyl protecting group; or

both R7A combine to form an optionally substituted alkylene; Re is -CH CH -COORC, -CH=CH-COORc, -CH CH -SO RD, or -CH=CH-S0 ₂ RD;

Rc, when present, is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and

RD, when present, is independently optionally substituted aryl or optionally substituted non-enolizable alkyl.

The compound of formula (Z8) may be prepared from the compound of formula (Z5) as follows.

The compound of formula (Z5) may be reacted with R7AOH in the presence of a Bronsted acid to produce the compound of formula (Z5A):

where

R20A is H or a hydroxyl protecting group;

each R20B is independently H or a hydroxyl protecting group, or both R20B, together with the atoms to which each is attached, combine to form an acetal, ketal, cyclic carbonate, dicarbonyl-dioxo, or silylene-dioxo; and all remaining variables are as described for the compound of formula (Z8).

The compound of formula (Z5A) may be converted to a compound of formula (Z5B):

where

R23 is H or -OR20A; and

all remaining variables are as described for the compound of formula (Z8). The compound of formula (Z5A), in which both R20B are H, can be reacted with a glycol cleaving agent to produce the compound of formula (Z5B). Conversion of -OR20A in formula (Z5A) to H in the compound of formula (Z5B) (R23 is H) can be achieved using allylic deoxygenation methods known in the art, e.g., using allylic reducing agents, when R A is a hydroxyl protecting group that is an ester. Alternatively, when R20A is H, -OR20A may be converted to H using deoxygenation reactions known in the art. Deoxygenation reactions are known in the art, e.g., Barton- McCombie deoxygenation and tin-free versions thereof (see, e.g., Chenneberg and Ollivier, Chimia, 70:67- 76, 2016). The reaction replacing -OR20A with H can be performed before or after the glycol cleavage. The compound of formula (Z5B) may be converted to the compound of formula (Z8), in which Re is -

CH=CH-COORc or -CH=CH-S0 ₂ RD, by a reaction

which each R22 is independently optionally substituted alkyl, under Horner-Wadsworth-Emmons reaction conditions. The compound of formula (Z8), in which Re is -CH=CH-COORc or -CH=CH-SC> RD, can be converted to the compound of formula (Z8), in which Re is -CH2CH2-COORC or -CH2CH2-SO2RD, respectively, by a reaction with a 1 ,4-reducing agent. A reaction replacing -OR20A with H can be performed before or after the Horner-Wadsworth-Emmons reaction and/or the reaction with a 1 ,4-reducing agent.

Further Compounds

The invention provides a compound of formula (II):

where

each of D and D’ is independently H, optionally substituted alkyl, or OP , provided that only one of D and D’ is OP , where Pi is H, alkyl, a hydroxyl protecting group, and A is a C1-6 saturated or C unsaturated hydrocarbon skeleton, the skeleton being unsubstituted or having from 1 to 10 substituents independently selected from the group consisting of cyano, halo, azido, oxo, and Q , or A is a group of formula (1 ):

(1 )

where

L is -(CH(OP ₂ ))-, -(C(OH)(OP ₂ ))-, or -C(O)-;

R is H and Pi is absent, H, alkyl, or a hydroxyl protecting group, or R and Pi combine to form a bond;

(i) R3 is H, and P is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;

(ii) R3 is -(CH2) _n NP ₃ P4, where P3 is H or an N-protecting group, and (a) P2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P4 is H or an N-protecting group, (b) P2 and P4 combine to form an alkylidene, or (c) each of P2 and P4 is H ;

(iii) R is -(CH ₂ )nOP5, where P is absent, H , optionally substituted alkyl, or a hydroxyl protecting group, and P5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P and P5, together with the atoms to which each is attached, combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or silylene-dioxo; or (iv) R and P combine to form an optionally substituted ethylene or a structure selected from the group consisting of:

otecting group;

E is H, optionally substituted alkyl, or optionally substituted alkoxy;

G is O, S, CH , or NRN, where RN is H, an N-protecting group, or optionally substituted alkyl; each Q is independently ORA, SRA, SO RA, OSO RA, NRBRA, NRB(CO)RA, NRB(CO)(CO)RA, NRB(CO)NRBRA, NRB(CO)ORA, (CO)ORA, 0(C0)RA, (CO)NRBRA, or 0(C0)NRBRA, where each of RA and RB IS independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic radical, or heterocyclic radical-alkyl;

n, when present, is 0, 1 , or 2;

k is 0 or 1 ;

R is -OPe, -CH(Y) , or -CH (Y), where Rb is H or a hydroxyl protecting group;

Re is H, optionally substituted alkyl, or optionally substituted aryl; and

Y is independently -COORc or -SO RD;

Rc, when present, is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; and

RD, when present, is optionally substituted aryl or optionally substituted non-enolizable alkyl.

The invention also provides the compounds of formula (IID), (HE), (IIF), (IIG), (I IH), (lli), (IVAb), (VAb),

(VIIAa), (VIAa), (VIIID), (IXD), (IXF), (IXG), (Z), (Z1 ), (Z2), (Z3), (Z4), (Z5), (Z5A), (Z5B), or (Z6).

Amination

Compounds disclosed herein, in which R is -(CPl )nOP , can be aminated to afford eribulin, as described herein. Amination conditions can be those known in the art. In a non-limiting example, C.35 hydroxyl in the compounds disclosed herein can be sulfonylated (e.g., by a reaction with a sulfonyl anhydride or a sulfonyl chloride) and reacted with a nitrogen source (e.g., ammonia, azide, sulfamic acid, urea (H NCONH ), or thiourea (H NCSNH )) to afford eribulin or a pharmaceutically acceptable salt thereof upon optional unmasking of the amino group (if the nitrogen source was azide, urea, or thiourea). In another non-limiting example, C.35 hydroxyl in the compounds disclosed herein can be halogenated (e.g., by Appel reaction or a reaction with thionyl chloride, sulfuryl chloride, phosphorus(lll) chloride, or phosphorus(V) oxychloride) and reacted with a nitrogen source (e.g., ammonia, azide, sulfamic acid, a phthalimide salt, urea (H NCONH ), or thiourea (H NCSNH )) to afford eribulin or a pharmaceutically acceptable salt thereof upon optional unmasking of the amino group (if the nitrogen source was azide, a phthalimide salt, urea, or thiourea).

Amino unmasking agents are further described herein. The amination reaction can provide a

pharmaceutically acceptable salt of eribulin directly. Alternatively, the amination reaction can provide eribulin in a free base form. A pharmaceutically acceptable salt of eribulin can be prepared from eribulin through a salification reaction as described herein.

Masked Amines and Amine Unmasking Agents

The compounds used in the methods of the invention can contain a masked or unmasked amine (e.g., at C.35 carbon of the structure of the halichondrin macrolide analog, such as eribulin). An unmasked amine is -NH . An amine can be masked using methods known in the art, e.g., by protecting the amine with an N- protecting group. Alternatively, an amine can be masked as a nitrogen-containing moiety, which can be reacted with an amine unmasking agent to afford an amine. Non-limiting examples of the nitrogen- containing moieties include azide and an imide (e.g., phthalimide). Amine unmasking agents can be those known in the art for removing /V-protecting groups from amines. In a non-limiting example, a Boc group can be removed using amine unmasking agents known in the art, e.g., a Bronsted acid (e.g., HCI in 1 ,4-dioxane or trifluoroacetic acid). When amine is masked as azide, the amine can be unmasked by subjecting the compound containing the masked amine to Staudinger reaction conditions (e.g., by contacting with a phosphine, such as trialkylphosphine, dialkylarylphosphine, alkyldiarylphosphine, or triarylphosphine) or by reacting the compound containing the masked amine with a reducing agent (e.g., LiAIEU). When amine is masked as an imide (e.g., phthalimide), the amine can be unmasked by reacting with an amine unmasking agent known in the art, e.g., hydrazine.

Oxidizing Agents Capable of Converting an Alcohol to a Carbonyl Group

Oxidizing agents capable of converting an alcohol to a carbonyl group are known in the art. Non-limiting examples of these oxidizing agents include Dess-Martin periodinane, TEMPO (in the presence of bleach or BAIB), a dimethylsulfonium compound (e.g., dimethylchlorosulfonium chloride), aluminum trialkoxide with an excess of a ketone (e.g., acetone), and catalytic tetrapropylammonium perruthenate (TPAP) (in the presence of A/-methylmorpholine oxide). The dimethylsulfonium compound can be prepared in situ under the conditions known for Parikh-Doering oxidation, Swern oxidation, Corey-Kim oxidation, or Pfitzner-Moffatt oxidation. Alternatively, the dimethylsulfonium compound can be prepared in situ by a reaction between trichloroacetic acid anhydride and dimethyl sulfoxide. An oxidation reaction of an alcohol to a carbonyl group (e.g., a ketone) can be performed using aluminum trialkoxide and an excess of a ketone (e.g., acetone) under the conditions known in the art for Oppenauer oxidation. Allylic and benzylic alcohols can also be oxidized with MnC> . Reducing Agents

Reducing agents that can be used in the methods of the invention are those known in the art. A reducing agent can be an electron-transfer reducing agent, a metal hydride, or a metalloid hydride. Non-limiting examples of electron-trannsfer reducing agent include alkali metals in oxidation state (0), alkali earth metals in oxidation state (0), alkali arenides, lanthanide (II) salts (e.g., SmE), Zn(0), Fe(0), and Mn(0). Non-limiting examples of metal hydrides and metalloid hydrides include boron hydride compounds (e.g., NaBFU, LiBhU, LiHBEt3, selectrides (e.g., L-selectride), and boranes (e.g., 9-BBN and alpine borane)), aluminum hydride compounds (e.g., LiAII- , Red-AI®, and alanes (e.g., diisobutylaluminum hydride (DIBAL))), hydrosilanes (e.g., PMHS and P ^SiFE), hydrostannanes (e.g., BusSnH), copper hydride complexes (e.g., Stryker’s reagent), palladium hydride complexes, platinum hydride complexes, iridium hydride complexes, rhodium hydride complexes, and ruthenium hydride complexes. Reducing agents can be formed in situ, e.g., a copper hydride complex can be formed by a reaction of a copper salt with, e.g., a boron hydride compound or a hydrosilane. Thus, some reducing reagents (e.g., boron hydride compounds, hydrosilanes, and hydrostannanes) can be used in combination with a catalytic quantity of a metal salt (e.g., Cu, Pd, Pt, Ir, Rh, or Ru salt). Alternatively, catalytic reducing agents can be metal salts (e.g., aluminum isopropoxide or a ruthenium complex) in combination with an alcohol, which undergo transfer hydrogenation of carbonyl- containing compounds without intermediacy of a metal hydride. Non-limiting examples of transfer hydrogenation reactions include Meerwein-Ponndorf-Verley reduction (e.g., using aluminum

isopropoxide/isopropanol) and Ru-catalyzed transfer hydrogenation (e.g., Hashiguchi et al., J. Am. Chem. Soc., 1 17:7562-7563, 1995).

When a substrate is an a,b-unsaturated carbonyl or sulfone compound (e.g., an a,b-enone or a vinyl sulfone), a reducing agent can be a 1 ,2-reducing agent or a 1 ,4-reducing agent. For example, a reaction between an a,b-unsaturated carbonyl compound and a 1 ,2-reducing agent can afford, e.g., an allylic alcohol (or an allylic amine, if the starting compound is an enamide), whereas a reaction between an a,b-unsaturated carbonyl compound and a 1 ,4-reducing agent can afford an a,b-saturated compound and can leave the carbonyl group intact after work up of the reaction mixture. Non-limiting examples of 1 ,2-reducing agents include metal hydrides and metalloid hydrides, e.g., aluminum hydride compounds, boron hydride compounds (e.g., CeCb with NaBFU), and ruthenium hydride complexes. Non-limiting examples of 1 ,4- reducing agents include boron hydride compounds (e.g., LiHBEt3 and L-selectride), hydrostannanes, copper hydride complexes (e.g., Stryker’s reagent), palladium hydride complexes, platinum hydride complexes, iridium hydride complexes, rhodium hydride complexes, and ruthenium hydride complexes. Non-limiting examples of the 1 ,4-reducing agents include copper (I) hydrides, which can be isolated (e.g., Stryker’s reagent) or prepared in situ (e.g., from a copper (I) or copper (II) salt and a hydride source). Catalytic quantities of a copper salt (either copper (I) or copper (II) salt) in combination with stoichiometric or superstoichiometric quantities of a hydride source (e.g., a borohydride salt, borane, PMHS, or a hydrosilane (e.g., Ph SiH )). A non-limiting example of the reaction conditions that can be used for 1 ,4-reduction is described, e.g., in Baker et al., Org. Lett., 1 0:289-292, 2008, the disclosure of which is incorporated herein by reference. Other metals can be used to catalyze 1 ,4-reduction, e.g., Ru, Pd, and Ir compounds.

Methods of the invention may include the use of selective reduction techniques to reduce some reactive groups with retention of other reactive groups. For example, a carboxylic acid may be reduced in the presence of esters and/or olefins using sodium borohydride and iodine. Alternatively, a carboxylic acid may be reduced in the presence of esters and/or 1 ,1 -disubstituted olefins by converting the carboxylic acid to a mixed anhydride (e.g., using N-methylmorpholine and /-butylchloroformate) and reducing the resulting mixed anhydride using borane reducing agents (e.g., 9-BBN).

A compound having an allylic leaving group (e.g., a carboxylate, a halide, or a sulfonate) can be treated with an allylic reducing agent to replace the leaving group with a hydrogen atom. A non-limiting example of allylic reducing agent is a palladium salt or complex (e.g., Pd(PPh3)4) in combination with a formic acid salt (e.g., trialkylammonium formate).

Hydroxyl Protecting Groups and Hydroxyl Protecting Group Removing Agents

Hydroxyl protecting groups can be as defined herein. In particular, a hydroxyl protecting group can be an acyl, a sulfonyl, an arylalkyl (e.g., benzyl or p-methoxybenzyl), an aryl (e.g., p-methoxyphenyl), or an optionally substituted silyl (e.g., TMS, TES, TBS, TIPS, TBDPS, or TPS). Hydroxyl protecting groups, hydroxyl protecting agents, and hydroxyl protecting reaction conditions can be selected to protect selectively certain hydroxyl groups in a compound, while leaving other hydroxyl groups unprotected. The choice of hydroxyl protecting groups for a compound can facilitate subsequent deprotection strategies, as some hydroxyl protecting groups can be removed in the presence of others using appropriate hydroxyl protecting group removing agents. Some of these strategies involving the choice of silyl hydroxyl protecting groups are discussed in, e.g., Silicon-Based Blocking Agents, Gelest, Inc., 201 1 .

Hydroxyl protecting group removing agents are those agents that can react with a compound having a protected hydroxyl group to afford the compound with a deprotected hydroxyl group. Hydroxyl protecting group removing agents and deprotection reaction conditions can be those known in the art. In a non-limiting example, hydroxyl masked as silyl ether can be unmasked by a reaction with a fluoride source (e.g., a fluoride salt, such as KF or TBAF). Alternatively, hydroxyl protected as TMS or TES ether can be deprotected by a reaction with a Bronsted acid (e.g., a carboxylic acid). In another non-limiting example, hydroxyl protected as an ester can be deprotected by a reaction with a base (e.g., alkali hydroxide (e.g., lithium hydroxide, sodium hydroxide, or potassium hydroxide) or C1 -6 alkoxide (e.g., alkali C1 -6 alkoxide or alkali earth C1 -6 alkoxide)). Alternatively, hydroxyl protected as an ester (e.g., pivaloyl ester) can be deprotected by a reaction with a 1 ,2-reducing agent (e.g., DIBAL-H). In yet another non-limting example, hydroxyl protected as an arylalkyl ether (e.g., 1 -arylalk-1 -yl ether) can be deprotected using a reduction reaction, e.g., with Pd/C and H2 or with Na/NH3. Alternatively, hydroxyl protected as an alkoxy-arylalkyl ether (e.g., MPM ether) can be deprotected by a reaction with 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone (DDQ).

In still another non-limiting example, hydroxyl protected as alkoxyalkyl ether (e.g., 1 -alkoxyalk-1 -yl) or THP ether can be deprotected by a reaction with a Bronsted acid. Cyclic protected diols, such as acetals or ketals (e.g., as 2-alkyl-1 ,3-dioxolane, 2,2-dialkyM ,3-dioxolane, 2-alkyl-1 ,3-dioxane, or 2,2-dialkyM ,3- dioxane), can be deprotected by a reaction with a Bronsted acid (e.g., a carboxylic acid).

Decarboxylation and Desulfonylation

The conditions for the decarboxylation reaction can be those known in the art, e.g., Krapcho decarboxylation or a sequence including deprotection, if Rc is not H, by converting Rc to H and subsequent protodecarboxylation. The conditions for the desulfonylation reaction can be those known in the art. For example, the desulfonylation reaction can include contacting the compound of formula (IA) or formula (IB) or an intermediate downstream of the compound of formula (IA) or formula (IB) with an electron-transferring reducing agent (e.g., Sml2; Cr(lll) salt and Mn(0); or Mg(0)). For exemplary desulfonylation conditions, see WO 2009/064029.

Nozaki-Hiyama-Kishi Reaction

Nozaki-Hiyama-Kishi reaction conditions that may be used in transformation described herein can be those known in the art. Nozaki-Fliyama-Kishi reaction can include reacting substrates (an aldehyde and a vinyl halide or pseudohalide) with a Cr(ll) salt and a Ni(ll) salt. Ancillary ligands can be used in combination with the metal salts. In a non-limiting example, a substituted 1 ,10-phenanthroline can be used in combination with a Ni(ll) salt. Chiral ancillary ligands can be used to render the reaction stereoselective. In a non-limiting example, chiral N-(dihydrooxazolyl-phenyl)-sulfonamides can be used with a Cr(ll) salt to control the stereochemistry of the carbonyl carbon, to which a vinyl nucleophile is added in the course of Nozaki- Hiyama-Kishi reaction.

Olefin Metathesis

Olefin metathesis catalysts are known in the art and include Ru-carbene complexes (e.g., Grubbs and Hoveyda-Grubbs catalysts). Olefin metathesis-competent catalysts that may be used in the olefin metathesis reactions described herein are known in the art (e.g., second generation Hoveyda-Grubbs-type catalysts, e.g., those in which the Ru-benzylidene moiety is modified to include electron-withdrawing and/or electron-donating groups). Non-limiting examples of the useful olefin metathesis reaction conditions are provided in, e.g., U.S. patent application publication No. 2016/0264594 and International patent application publication No. WO 2016/179607.

Salification

Eribulin mesylate can be produced by salification of eribulin, as describen herein. Salification reaction conditions are known in the art. Salification of eribulin can afford a pharmaceutically acceptable salt of eribulin (e.g., eribulin mesylate). In particular, salification reaction can involve contacting eribulin with a Bronsted acid (e.g., a pharmaceutically acceptable Bronsted acid (e.g., methanesulfonic acid)) to afford a pharmaceutically acceptable salt of eribulin (e.g., Handbook of Pharmaceutical Salts: Properties, Selection and Use, ed.: Stahl and Wermuth, Wiley-VCH/VHCA, Weinheim/Zurich, 2002). Pharmaceutically acceptable salts of eribulin, e.g., eribulin mesylate, can be formed by methods known in the art, e.g., in situ during the final isolation and purification of the compound or separately by reacting the free base group with a suitable organic acid. In one example, eribulin is treated with a solution of MsOH and NH4OH in water and acetonitrile. The mixture is concentrated. The residue is dissolved in DCM-pentane, and the solution is added to anhydrous pentane. The resulting precipitate is filtered and dried under high vacuum to provide eribulin mesylate.

Epimerizations

Epimerization reactions can be used to invert a stereogenic center having an undesired stereochemical identity. For example, through epimerization, Ft stereogenic center can be converted to S stereogenic center and vice versa. Epimerization of a stereogenic sp ³ -carbon bonded to one hydrogen atom and to one hydroxyl group can be achieved through a reaction sequence involving oxidation of the hydroxyl group to a carbonyl group followed by a 1 ,2-reduction reaction. The 1 ,2-reduction reaction can provide the desired stereochemical identity diastereoselectively, or the reaction can be carried out using a chiral catalyst, chiral auxiliary, or a chiral reducing agent. Non-limiting examples of chiral reducing agents include alpine borane and prapine borane. Non-limiting examples of 1 ,2-reduction reactions involving chiral catalysts are Corey- Bakshi-Shibata reduction, Noyori hydrogenation, and Noyori transfer hydrogenation, The oxidation/reduction reaction sequence can be carried out in situ using dynamic kinetic resolution. A dynamic kinetic resolution can further involve a reaction with a hydroxyl protecting agent, which removes the desired stereoisomer from the reduction/oxidation equilibrium. In a non-limiting example, a dynamic kinetic resolution of chiral secondary alcohols can involve reduction/oxidation equilibration using n ⁵ -Ph CpRu(CO) H in combination with enantioselective esterification using isopropenyl acetate catalyzed by a lipase enzyme (e.g., lipase B from Candida Antarctica, see, e.g., Martin-Matute et al., J. Am. Chem. Soc., 127:8817-8825, 2005). The following examples are meant to illustrate the invention. They are not meant to limit the invention in any way.

Examples

Example 1

, ,

combine to form a carbonyl.

An exemplary compound of formula (IA) can be prepared as shown in the above scheme. This compound may be useful as an intermediate in the synthesis of a halichondrin macrolide. Compound 1 was treated with compound 2 in the presence of BF3-OEt2 (exemplary Sakurai reaction conditions) to give compound 3.

Compound 5 can be prepared by treating compound 3 with compound 4 in the presence of BF ₃ OEt and methoxyacetic acid (exemplary Prins reaction conditions). Compound 7 can be prepared by treating compound 3 with compound 6 in the presence of BF ₃ OEt and methoxyacetic acid (exemplary Prins reaction conditions).

A halichondrin macrolide can be prepared from compound 5 or 7 using methods and intermediates disclosed, e.g., WO 2016/1 79607, the synthesis of which is hereby incorporated by reference and described herein. For example, compounds 5 and 7 may be converted to a halichondrin macrolide, as described for the compound of formula (VIIIC) in WO 2016/179607.

Example 2

An exemplary compound of formula (IA) for the synthesis of a halichondrin macrolide analog can be prepared as shown in this Example. Compound 8 was treated with compound 2 in the presence of BF3-OEt2 (exemplary Sakurai reaction conditions) to give compound 9.

The scheme above illustrates two exemplary synthetic routes that can be used to access compound 11 from compound 9. In one approach, compound 9 was reacted with Dess-Martin periodinane to afford enone 10, which, upon reduction with either (S)-(-)-2-methyl-CBS-oxazaborolidine and BH3THF or Zn(BH4)2, provided compound 11 as the major diastereomer. (S)-(-)-2-methyl-CBS-oxazaborolidine is:

Trimethyl(2-methylbuta-2,3-dien-1-yl)silane. Lithium chloride (4.0 g, 94 mmol) was charged a round bottom flask and dried with heating under vacuum. After cooling to room temperature, the flask was charged with diethyl ether (100 mL) and copper(l) cyanide (4.0 g, 45 mmol). The mixture was cooled to 0 °C and treated with 1 M TMSCLLMgCI (45.0 mL, 45.0 mmol) over 10 min maintaining the internal temperature below 5 °C. The mixture was stirred at 0 °C for 1 h. After cooling to -78 °C, the mixture was treated with 2-butynyl p-toluenesulfonate (10.0 g, 44.5 mmol) in 3 portions. The mixture was slowly warmed up to room temperature over 18 h. The reaction mixture was filtered through a celite pad and rinsed with diethyl ether. The filtrate was concentrated with slight vacuum (bath : 10 °C) to give the title compound (4.09 g, 65.3%). ¹ H NMR (400 MHz, CHLOROFORM-d) d 4.51 -4.58 (m, 2H), 1 .70 (t, J=3.13 Hz, 3H), 1 .33 (t, J= 2.54 Hz, 2H), 0.06 (s, 9H).

(S 3-((2R,3/?,4S,5S 5-((S 2-hydroxy-4-methyl-3-methylenepent-4-en-1-yl)-3-methoxy-4- ((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1 ,2-diyl dibenzoate. A mixture of (S)-3-

((2F?,3/ ^: ?,4S,5S 3-methoxy-5-(2-oxoethyl)-4-((phenylsulfonyl)methyl)tetrahydr ofuran-2-yl)propane-1 ,2-diyl dibenzoate (1 .61 g, 2.77 mmol) and trimethyl(2-methylbuta-2,3-dien-1 -yl)silane (0.78 g, 5.5 mmol) in CH2CI2 (32 mL) was cooled to -78 °C, treated with BF3-OEt2 (0.70 mL, 5.5 mmol) and stirred at -78 °C for 1 h. The reaction was quenched with sat. aq. NaHCC>3 (80 mL) and the mixture was extracted twice with MTBE (30 mL). The organic layers were combined, washed with brine (32.1 mL), and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate in n-heptane=10% to 50%) to give the title compound (960 mg, 53.5%) and a 1 :1 mixture of the title compound and its epimer (631 mg, 35%). Ή NMR (400 MHz, CHLOROFORM-d) d 8.04-8.10 (m, 2H), 7.97-8.04 (m, 2H), 7.88-7.96 (m, 2H), 7.64-7.72 (m, 1 H), 7.50-7.62 (m, 4H), 7.37-7.48 (m, 4H), 5.54-5.70 (m, 1 H), 5.27 (s, 1 H), 5.17 (s, 1 H), 4.99 (s, 1 H), 4.95 (s, 1 H), 4.63 (br d, J= 8.60 Hz, 1 H), 4.57 (d, .7=5.08 Hz, 2H), 3.87-3.97 (m, 2H), 3.76-3.85 (m, 1 H), 3.41

(s, 3H), 3.01 -3.19 (m, 2H), 2.52-2.63 (m, 1 H), 2.19-2.35 (m, 2H), 1 .93-2.03 (m, 1 H), 1 .88 (s, 3H), 1 .68-1 .79 (m, 1 H).

(S 3-((2R,3/?,4S,5S 3-methoxy-5-(4-methyl-3-methylene-2-oxopent-4-en-1 -yl)-4- ((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1 ,2-diyl dibenzoate. A solution of (¾)-3- ((2F?,3/T4S,5S,)-5-((S,)-2-hydroxy-4-methyl-3-methylenepent- 4-en-1 -yl)-3-methoxy-4- ((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1 ,2-diyl dibenzoate (0.63 g, 0.97 mmol) in CH2CI2 (12.6 mL) was treated with sodium bicarbonate (0.16 g, 1 .9 mmol) and Dess-Martin periodinane (0.495 g, 1 .1 7 mmol). After stirring at room temperature for 1 h, the reaction was quenched with sat. NaHCC>3 (6.3 mL) and 20% (w/v) aq. NaiSOe (6.3 mL), and extracted twice with MTBE (1 2.6 mL). The organic layers were combined, washed with brine (6.3 mL), and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate in n-heptane= 10% to 40%) to give the title compound (378 mg,

60%).

Ή NMR (400 MHz, CHLOROFORM-d) d 7.98-8.1 1 (m, 4H), 7.89-7.97 (m, 2H), 7.62-7.72 (m, 1 H), 7.50-7.62 (m, 4H), 7.35-7.49 (m , 4H), 5.54-5.69 (m, 3H), 5.08 (s, 1 H), 4.97 (s, 1 H), 4.57 (d, J=5.08 Hz, 2H), 3.97-4.05 (m, 2H), 3.90-3.96 (m , 1 H), 3.49 (dd, J= 3.91 , 14.07 Hz, 1 H), 3.42 (s, 3H), 3.05-3.24 (m, 2H), 2.98 (dd, J=7.03, 1 7.58 Hz, 1 H), 2.47-2.58 (m, 1 H), 2.1 8-2.35 (m, 2H), 1 .82-1 .91 (s, 3H).

(S)-3-((2ff,3/?,4S,5S)-5-((/7)-2-hydroxy-4-methyl-3-methylen epent-4-en-1-yl)-3-methoxy-4- ((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1 ,2-diyl dibenzoate. (S -CBS oxazaborolidine (0.056 g, 0.20 mmol) was dissolved in THF (5.8 mL) and treated with 1 M BH3-THF in THF (0.90 ml_, 0.90 mmol). The mixture was stirred at room temperature for 1 h. After cooling to -40 °C, the mixture was treated with a solution of (S)-3-((2R,3/7,4S 5S^-3-methoxy-5-(4-methyl-3-methylene-2-oxopent-4-en-1 -yl)-4- ((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1 ,2-diyl dibenzoate (0.29 g, 0.45 mmol) in THF (5.8 ml_) and stirred at a temperature between -30 and -1 5 °C for 3 h. The reaction was quenched with methanol (0.18 mL) and sat. aq. NH4CI (1 5 mL). The mixture was extracted twice with MTBE (29 mL), washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate in n-heptane= 1 0% to 50%) to give the title compound (120 mg, 41 %). Ή NMR (400 MHz, CHLOROFORM-d) d 7.95-8.09 (m, 4H), 7.86-7.93 (m, 2H), 7.62-7.72 (m, 1 H), 7.49-7.60 (m, 4H), 7.35-7.45 (m, 4H), 5.49-5.59 (m, 1 H), 5.30-5.37 (m, 1 H), 5.15-5.21 (m, 1 H), 4.99 (s, 1 H), 4.96 (s, 1 H), 4.58-4.65 (m, 1 H), 4.49-4.57 (m, 2H), 3.83-3.97 (m, 2H), 3.77-3.82 (m, 1 H), 3.36 (s, 3H), 3.03-3.15 (m, 2H), 2.60-2.70 (m, 1 H), 2.26 (t, J=6.44 Hz, 2H), 2.03-2.1 1 (m, 1 H), 1 .89 (s, 3H), 1 .71 -1 .83 (m, 1 H).

In another approach, compound 9 was subjected to Mitsunobu reaction with 3,5-dinitrobenzoic acid, DIAD, and PPhe to give compound 13. Alcoholysis of compound 13 with Mg(OMe) ₂ gave compound 11.

(S)-3-((2R,3/?,4S,5S)-5-((/?)-2-((3,5-dinitrobenzoyl)oxy) -4-methyl-3-methylenepent-4-en-1-yl)-3- methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propa ne-1 ,2-diyl dibenzoate. A solution of (S)-3-((2R,3/7,4S,5S -5-((S -2-hydroxy-4-methyl-3-methylenepent-4-en-1 -yl)-3-methoxy-4- ((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1 ,2-diyl dibenzoate (0.33 g, 0.51 mmol) in THF (13.2 mL) was treated with 3,5-dinitrobenzoic acid (0.65 g, 3.1 mmol) and triphenylphosphine (0.80 g, 3.1 mmol). The mixture was treated with DIAD (0.49 mL, 2.5 mmol) and stirred at room temperature for 20 h. The reaction was quenched with sat. aq. NaHC03 (6.6 mL) and extracted twice with MTBE (9.9 mL). The organic layers were combined, washed with brine, and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate in n-heptane= 10% to 30%) to give the title compound (235 mg, 55%).

Ή NMR (400 MHz, CHLOROFORM-d) d 9.13-9.17 (m, 2H), 9.10-9.13 (m, 1 H), 7.89-7.99 (m, 6H), 7.65-7.72 (m, 1 H), 7.50-7.62 (m, 4H), 7.35-7.45 (m, 4H), 5.98-6.08 (m, 1 H), 5.36-5.46 (m, 1 H), 5.31 (s, 1 H), 5.29 (s, 1 H), 5.27 (s, 1 H), 5.1 1 (s, 1 H), 4.43-4.49 (m, 2H), 3.83-3.92 (m, 2H), 3.69-3.77 (m, 1 H), 3.31 (s, 3H), 3.01 - 3.17 (m, 2H), 2.64-2.75 (m, 1 H), 2.28-2.37 (m, 2H), 2.07-2.28 (m, 2H), 1 .94 (s, 3H).

(S)-3-((2R,3/?,4S,5S)-5-((ff)-2-hydroxy-4-methyl-3-methylene pent-4-en-1-yl)-3-methoxy-4- ((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1 ,2-diyl dibenzoate. A solution of (S)- 3- ((2F?,3/ ^: ? 4S 5SJ-5-((i?J-2-((3,5-dinitrobenzoyl)oxy)-4-methyl-3-methylene pent-4-en-1 -yl)-3-methoxy-4- ((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1 ,2-diyl dibenzoate (0.235 g, 0.279 mmol) in methanol (4.7 mL) and THF (0.24 mL) was treated with 6-10% Mg(OMe) ₂ in methanol (0.22 g, 0.17 mmol) and stirred at room temperature for 1 h. The reaction mixture was diluted with MTBE (23.5 mL) and washed with sat. aq. NaHCC>3 (4.7 mL) and brine. The aqueous layer was extracted with MTBE (5 mL). The organic layers were combined, concentrated in vacuo, and purified by silica gel column chromatography (ethyl acetate in n- heptane=10% to 40%) to give the title compound (40 mg, 22%).

Ή NMR (400 MHz, CHLOROFORM-d) d 7.95-8.09 (m, 4H), 7.86-7.93 (m, 2H), 7.62-7.72 (m, 1 H), 7.49-7.60 (m, 4H), 7.35-7.45 (m, 4H), 5.49-5.59 (m, 1 H), 5.30-5.37 (m, 1 H), 5.15-5.21 (m, 1 H), 4.99 (s, 1 H), 4.96 (s,

1 H), 4.58-4.65 (m, 1 H), 4.49-4.57 (m, 2H), 3.83-3.97 (m, 2H), 3.77-3.82 (m, 1 H), 3.36 (s, 3H), 3.03-3.15 (m, 2H), 2.60-2.70 (m, 1 H), 2.26 (t, J=6.44 Hz, 2H), 2.03-2.1 1 (m, 1 H), 1 .89 (s, 3H), 1 .71 -1 .83 (m, 1 H).

(S)-3-((2R,3/?,4S,5S)-5-(((2S,6fi)-6-((fi)-3,4-bis(benzoylox y)butyl)-3-((2-methoxyacetoxy)methyl)-4- methyl-5, 6-dihydro-2H-pyran-2-yl)methyl)-3-methoxy-4-((phenylsulfonyl )methyl)tetrahydrofuran-2- yl)propane-1 ,2-diyl dibenzoate. A mixture of (S 3-((2R,3R,4S,5S 5-((S 2-hydroxy-4-methyl-3- methylenepent-4-en-1 -yl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-y l)propane-1 ,2-diyl dibenzoate (0.035 g, 0.054 mmol) and (F?)-5,5-dimethoxypentane-1 ,2-diyl dibenzoate (0.030 g, 0.081 mmol) in CH2CI2 (2.1 mL) was cooled to -30 °C and treated with methoxyacetic acid (0.062 mL, 0.81 mmol) and BF3-OEt2 (0.021 mL, 0.162 mmol). The mixture was stirred at a temperature between -30 and -20 °C for 1 .5 h, quenched with sat. aq. NaHCC>3 (3.5 mL) and extracted twice with MTBE (3.5 mL). The organic layers were combined, washed with brine (1 .8 mL), and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate in n-heptane= 20% to 50%) to give the title compound (21 mg, 37%).

¹ H NMR (400 MHz, CHLOROFORM-d) d 7.91 -8.06 (m, 8H), 7.87 (d, J=7.42 Hz, 2H), 7.60 (m, 1 H), 7.45-7.55 (m, 6H), 7.30-7.41 (m, 8H), 5.53-5.65 (m, 1 H), 5.42-5.52 (m, 1 H), 4.62-4.70 (m, 1 H), 4.40-4.57 (m, 5H), 4.05- 4.18 (m, 1 H), 3.98 (s, 2H), 3.90 (s, 2H), 3.71 -3.80 (m, 1 H), 3.40 (s, 3H), 3.37 (s, 3H), 3.28-3.36 (m, 1 H), 2.97-3.1 1 (m, 2H), 2.45-2.55 (m, 1 H), 2.10-2.28 (m, 2H), 1 .82-1 .99 (m, 3H), 1 .72-1 .82 (m, 1 H), 1 .67 (s, 3H), 1.44-1 .63 (m, 4H).

Compound 14 can be prepared by treating compound 11 with compound 4 in the presence of BF3-OEt2 and methoxyacetic acid (exemplary Prins reaction conditions):

(S)-3-((2R,3/?,4S,5S)-3-methoxy-5-(((2/?,6S)-3-((2-methox yacetoxy)methyl)-4-methyl-6-(2-((2S,5S)-3- methylene-5-(3-(pivaloyloxy)propyl)tetrahydrofuran-2-yl)ethy l)-5,6-dihydro-2H-pyran-2-yl)methyl)-4- ((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1 ,2-diyl dibenzoate. A mixture of (S)-3- ((2/?,3/ ^: ?,4S,5S)-5-((/7)-2-hydroxy-4-methyl-3-methylenepent-4- en-1 -yl)-3-methoxy-4-

((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1 ,2-diyl dibenzoate (71 mg, 0.1 1 mmol) and 3-((2S,5S)- 4-methylene-5-(3-oxopropyl)tetrahydrofuran-2-yl)propyl pivalate (43 mg, 0.15 mmol) in CH2CI2 (3 mL) was cooled to -30 °C and treated with methoxyacetic acid (0.13 ml, 1 .6 mmol) and BF3-OEt2 (0.042 ml, 0.33 mmol). After stirring at -20 to -30 °C for 2 h, the reaction was quenched with sat. NaHCC>3 (3.6 mL), and the resulting mixture was extracted twice with MTBE (3.6 mL). The organic layers were combined, dried over MgSC , and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate in n- heptane= 10% to 40%) to give the title compound (4 mg, 4%). Mass (M + Na ⁺ ): 757.4 Compound 15 can be prepared by treating compound 14 with an allylic reducing agent (e.g., Pd(PPh ₃ )4/HC02H/Et ₃ N). Alternatively, compound 16 can be prepared by treating compound 11 with compound 6 in the presence of BF3-OEt2 and methoxyacetic acid (exemplary Prins reaction conditions). Compound 17 can be prepared by treating compound 16 with an allylic reducing agent (e.g., Pd(PPh ₃ ) ₄ /HCC> ₂ H/Et ₃ N).

A halichondrin macrolide analog can be prepared from compound 15 or 17 using methods and intermediates disclosed, e.g., WO 2015/066729, the synthesis of which is hereby incorporated by reference and described herein. For example, compounds 15 and 17 may be converted to a halichondrin macrolide analog, as described for the compound of formula (VII E) in WO 2015/066729.

Example 3

An exemplary compound of formula (III) can be prepared as shown in the above scheme. Compound 18 was subjected to an aldol reaction with HCHO in the presence of K CO to afford compound 19. Compound 19 was treated with triethyl phosphonoacetate, which was deprotonated with CS CO , to afford compound 20.

Compound 21 can be prepared from compound 20 by treating with a 1 ,2-reducing agent (e.g., DIBAL-H) followed by an alkoxymethyl phosphonate, e.g., diethyl-(methoxymethyl)-phosphonate, under Wittig reaction conditions. Compound 22 can be prepared from compound 21 by treating with a sulfonyl halide or sulfonyl anhydride, e.g., Tf20, followed by a halide salt, e.g., Nal or Kl. Compound 23 can be prepared from compound 22 by treating with a reducing metal, e.g., elemental zinc, and a Bronsted acid, e.g., acetic acid. Compound 24 can be prepared from compound 23 by a reaction with methanol in the presence of a Brensted acid, e.g., FHCI. Compound 25 can be prepared from compound 24 by a reaction with a glycol cleaving agent, e.g., NalC , followed by a Florner-Wadsworth-Emmons reaction with alkylated

phosphonoacetate, e.g., trimethyl phosphonoacetate, that has been deprotonated with a base (e.g., NaFI or CS CO ). Compound 26 can be prepared from compound 25 by treating with a 1 ,4-reducing agent (e.g., Stryker’s reagent), followed by a cyclization reaction. The cyclization reaction may proceed spontaneously after the 1 ,4-reduction, e.g., on work-up or during purification.

Example 4

An exemplary intermediate of formula (IA) can be prepared from compounds 3 and 26. Compound 3 can be treated with compound 26 in the presence of BF3-OEt2 and methoxyacetic acid (exemplary Prins reaction conditions) to afford compound 27. Compound 27 can be treated with an allylic reducing agent (e.g., Pd(PPh3)4/HC02H/Et3N) to afford compound 28. Compound 28 can be converted to compound 29 using methods known in the art, e.g., using NaBFU/E or by converting the carboxylic acid in compound 28 to a mixed anhydride (e.g., using N-methylmorpholine and /-butylchloroformate) reducing the resulting mixed anhydride using borane reducing agents (e.g., 9-BBN).

A halichondrin macrolide can be prepared from compound 29 using methods and intermediates disclosed, e.g., WO 2016/179607, the synthesis of which is hereby incorporated by reference and described herein.

For example, compound 29 can be converted to a halichondrin macrolide, as described for the compound of formula (VI I ID) in WO 2016/179607. Example 5

An exemplary intermediate of formula (IA) can be preparation from compounds 11 and 26. Compound 11 can be treated with compound 26 in the presence of BF ₃ OEt and methoxyacetic acid (exemplary Prins reaction conditions) to afford compound 30. Compound 30 can be treated with an allylic reducing agent (e.g., Pd(PPh3)4/HCC>2H/Et3N) to afford compound 31. Compound 31 can be converted to compound 15 using methods known in the art, e.g., using NaBEU/ or by converting the carboxylic acid in compound 28 to a mixed anhydride (e.g., using N-methylmorpholine and /-butylchloroformate) and reducing the resulting mixed anhydride using borane reducing agents (e.g., 9-BBN).

A halichondrin macrolide analog can be prepared from compound 15 using methods and intermediates disclosed, e.g., WO 2015/066729, the synthesis of which is hereby incorporated by reference. For example, compound 15 may be converted to a halichondrin macrolide analog, as described for the compound of formula (VI IE) in WO 2015/066729. Example 6

(4-methyl-2,6-c/s-diphenyl-5,6-dihydro-2W-pyran-3-yl)meth yl 2-methoxyacetate. A mixture of trimethyl(2-methylbuta-2,3-dien-1 -yl)silane (0.050 g, 0.36 mmol) and benzaldehyde (0.1 1 mL, 1 .1 mmol) in CH2CI2 (4.0 mL) was cooled to -78 °C and treated with BF3-OEt2 (0.14 mL, 1 .1 mmol). The mixture was stirred at -78 °C for 1 .5 h . After addition of methoxyacetic acid (0.41 mL, 5.4 mmol), the mixture was warmed to -40 ¾ and then slowly warmed to -20 over 2 h with stirring. The reaction was quenched with sat. aq. NaHC03 (5.0 mL) and extracted twice with MTBE (5.0 mL). The organic layers were combined, washed with brine (2.5 mL), and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate in n-heptane= 5% to 15%) to give the title compound (53 mg, 42%).

Ή NMR (400 MHz, CHLOROFORM-d) d 7.34-7.44 (m, 4H), 7.20-7.33 (m, 6H), 5.31 (br s, 1 H), 4.65-4.76 (m , 2H), 4.13-4.23 (m, 1 H), 3.87 (d, J=16.41 Hz, 1 H), 3.72 (d, J=1 6.41 Hz, 1 H), 3.36 (s, 3H), 2.48-2.63 (m, 1 H), 2.1 6-2.31 (m , 1 H), 1 .85 (s, 3H).

(fi)-4-((2ff,6S)-5-((2-methoxyacetoxy)methyl)-4-methyl-6- phenyl-3,6-dihydro-2W-pyran-2-yl)butane-1 ,2- diyl dibenzoate. A mixture of trimethyl(2-methylbuta-2,3-dien-1 -yl)silane (0.057 g, 0.41 mmol) and benzaldehyde (0.034 mL, 0.34 mmol) in CH2CI2 (2 mL) was cooled to -78 °C and treated with BF3-OEt2 (0.13 mL, 1 .0 mmol). The mixture was stirred at -78 °C for 1 .5 h. After addition of methoxyacetic acid (0.39 mL,

5.1 mmol) and a solution of (ff)-5,5-dimethoxypentane-1 ,2-diyl dibenzoate (0.16 g, 0.44 mmol) in CH2CI2 (1 .2 mL), the mixture was stirred at -35 °C for 10 min and warmed up to -10 TD over 2 h. The reaction was quenched with sat. aq. NaHCC>3, extracted twice with MTBE (3.6 mL), washed with brine (1 .8 mL), and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate in n- heptane= 10%, 20% and 30%) to give the title compound (82 mg, 42%).

Ή NMR (400 MHz, CHLOROFORM-d) d 7.91 -8.06 (m, 4H), 7.46-7.59 (m, 2H), 7.32-7.45 (m, 6H), 7.19-7.31 (m, 3H), 5.84-5.93 (m, 1 H), 5.07-5.17 (m, 2H), 3.95-4.08 (m, 1 H), 3.78-3.87 (m, 2H), 3.70-3.77 (m, 2H), 3.64- 3.78 (m, 1 H), 3.34 (s, 3H), 2.15-2.31 (m, 2H), 1 .95-2.07 (m, 1 H), 1 .82-1 .94 (m, 2H), 1 .78 (s, 3H), 1 .58-1 .76 (m, 1 H).

W-((4-methyl-2,6-c/s-diphenyl-5,6-dihydro-2H-pyran-3-yl)meth yl)acetamide. A mixture of trimethyl(2- methylbuta-2,3-dien-1 -yl)silane (0.098 g, 0.70 mmol) and benzaldehyde (0.21 mL, 2.1 mmol) in CH2CI2 (2 mL) and acetonitrile (2 mL) was cooled to -40 °C and treated with BF ₃ -OEt2 (0.27 mL, 2.1 mmol). The mixture was slowly warmed up to -10 °C over 3 h. The reaction was quenched with sat. aq. NaHC03 (3.9 mL) and extracted twice with MTBE (3.92 mL). The organic layers were combined, washed with brine (4.90 mL), and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate in A/-heptane= 10% to 90%) to give the title compound (60 mg, 27%).

Ή NMR (400 MHz, CHLOROFORM-d) d 7.28-7.49 (m, 10H), 5.21 (br s, 1 H), 4.72 (dd, J= 3.12, 10.93 Hz, 1 H), 4.50 (br s, 1 H), 3.93 (dd, J=6.44, 14.25 Hz, 1 H), 3.41 (dd, J= 3.51 , 14.06 Hz, 1 H), 2.44-2.64 (m, 1 H),

2.15-2.28 (m, 1 H), 1 .83 (s, 3H), 1 .64 (s, 3H).

The experiments described herein show that Sakurai and Prins reactions can be performed as a single-pot Sakurai-Prins cascade reaction. Other Embodiments

Various modifications and variations of the described compositions and methods of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the invention.

Other embodiments are in the claims.