TOTA BY»THg8IB Of TAXOL AMD AKALOGCTB THEREOF

This application is a continuation-in-part of U.S. Serial No. 07/860,792, filed March 30, 1992, the contents o which are hereby incorporated by reference into this application.

Background of the Invention

Throughout this application, various publications are referenced by Arabic numerals within parentheses. Full citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entirety are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.

The chemistry and pharmacology of the potent anticancer diterpenoid taxol 1 (1) , isolated from the yew tree, Taxus brevifolia. has been reviewed extensively (2, 3, 4, 5) . Taxol is currently undergoing phase II trials (6) and has shown very encouraging antitu or activity, especially against ovarian and breast cancers (4, 5).

Unfortunately, the natural availability of taxol is extremely limited. The increasing demand of taxol for the treatment of patients and the desirability of analogs to determine the real pathway of its mode of action has made the total synthesis or hemi-synthesis of taxol and its analogs a high priority over the last ten years (2, 3, 7).

Attempts at the he i-synthesis of taxol have been based on using an extract from the leaves of the yew tree, 10- deacetylbaccatin III, as the starting material (3). Structural modifications of taxol have also been performed using taxol as the starting material itself, or 10-deacetylbaccatin III (3) . In addition, there has been limited success in synthesizing the taxane skeleton or framework (2, 3, 7).

However, due to the complex structure of taxol, i.e. the vast functionalities and the buildup of the highly strained middle ring system, the various efforts at the total syntheses of this tetracyclic compound have not been successful (2, 3).

The inventors have overcome the difficulties faced by others and have been able to synthesize taxol via three routes. The present invention provides three basic routes for the total synthesis of taxol, important intermediates as well as analogues of taxol. These analogues include structures with nortaxane ring systems containing an aromatic moiety in lieu of the taxol C ring.

aimimitTY of the Jnvβntion

The present invention provides a compound having the structure:

wherein X is H, OH, 0, or 0SiR ₃ ; and Y is 0 or -OCH ₂ CH ₂ 0-; wherein R is an alkyl or aryl group.

The present invention also provides a compound having the structure:

wherein each X is independently the same or different and is H, OH, O, or OSiR ₃ ; Y is O or -OCH ₂ CH ₂ 0-; Z is OH, O, or _O TM _S ; and E is H, CN-, C0 ₂ R, CHO, or CH ₂ OR'; wherein R' is H, _CO R, R, or SiR ₃ and R is an alkyl or aryl group.

The present invention further provides a compound having the structure:

wherein each X is independently the same or different and is H, OH, 0, or OSiR ₃ ; Y is H, 0, or -OCH ₂ CH ₂ 0-; E is H, CN, C0 ₂ R, CHO, or CH ₂ OR'; R ¹ is H, OH, OCOR, OR or 0SiR ₃ ; and R ² is H, CH ₂ OSiR ₃ , CH ₂ SR, or CH ₂ SOR; wherein R' is H, _CO R, R, or SiR ₃ and R is an alkyl or aryl group.

Additionally, the present invention provides a compound having the structure :

wherein each X is independently the same or different and is H, OH, O, OR or 0SiR ₃ ; Y is O or -OCH ₂ CH ₂ 0-; E is _C N, _C02 R, CHO, or CH ₂ 0R'; R ¹ is H, COR, or SiR ₃ ; and R ² is H, _C OR, or SiR ₃ ; wherein R ^« is H, COR, R, or SiR ₃ and R is an alkyl or aryl group.

The present invention also provides a compound having the structure:

wherein X is H, OH, 0, OR, or OSiR ₃ ; and R ¹ , R ² , R ³ , R«, _an d R ⁵ are independently the same or different and are H, COR, SiR ₃ , or R; wherein R is an alkyl or aryl group; with the proviso that X, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are not OAc, H, Ac, COPh, H, and PhCH(BzNH)CH(OH)CO-, respectively..

The present invention also provides processes for synthesizing the compounds above.

In addition, the present invention also provides a process for synthesizing a compound having the structure:

which comprises :

(a) treating a compound having the structure:

under suitable conditions to form a compound having the structure:

(b) treating the compound formed in step (a) under suitable conditions to form a compound having the structure:

and (c) treating the compound formed in step (b) under suitable conditions to form the compound having the structure:

The present invention also provides a compound having the structure:

wherein X ₄ is H, OR, O, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R ₂ and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS.

The present invention also provides a compound having the structure:

wherein X ₃ and X ₄ are independently the same or different and are H, OR, 0, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R ₂ and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS.

Moreover, the present invention provides a compound having the structure:

wherein X ₄ is H, OR, O, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; R ₂ and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; and R ₄ is PhCH(BzNH)CH(OH)CO-, O, an alkyl, or aryl group; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS.

The present invention also provides a compound having the structure:

wherein X ₄ is H, OR, 0, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; R ₂ and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; and R ₄ is PhCH(BzNH)CH(OH)CO-, 0, an alkyl, or aryl group; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS.

The present invention further provides a compound having the structure:

wherein X ₄ is H, OR, 0, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R ₂ and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS.

In addition, the present invention provides a compound having the structure:

wherein X ₄ is H, OR, O, -0CH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R _j , R ₂ , and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS.

The presert invention also provides a compound having the structure:

wherein X ₂ , X ₃ , and X ₄ are independently the same or different and are H, OR, 0, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S- ; and R _α , R ₂ , and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS.

The present invention also provides a compound having the structure:

wherein X _α , X ₂ , X ₃ , and X ₄ are independently the same or different and are H, OR, O, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH CH ₂ S-; and R ₂ , R ₂ , and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl,.TBS, TES, TMS, or TBDPS.

The present invention also provides a compound having the structure:

wherein X _j and X ₅ are independently the same or different and are H, OR, 0, -OCH ₂ CH ₂ 0- , or -SCH ₂ CH ₂ CH ₂ S- ; wherein R is H, acyl , alkyl , aryl , TBS , TES, TMS , or TBDPS.

The present invention further provides a compound having the structure:

wherein X _1# X ₂ , and X ₅ are independently the same or different and are H, OR, 0, -0CH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and M is H or a metal; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS.

Additionally, the present invention provides a compound having the structure:

wherein X , X ₂ , and X ₃ , are independently the same or different and are H, OR, 0, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R ₂ and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS.

The present invention further provides processes for synthesizing the compounds above.

Finally, the present invention provides a process for synthesizing a compound having the structure:

which comprises:

(a) synthesizing a compound having the structure:

(b) treating the compound formed in step (a) under suitable conditions to form a compound having the structure:

(c) contacting the compound formed in step (b) with lithiodithiane under suitable conditions to form a compound having the structure:

(d) deketalizing the compound formed in step (c) under suitable conditions to form a compound having the structure:

(e) contacting the compound formed in step (d) with methoxyvinyllithium under suitable conditions to form a compound having the structure:

(f) heating the compound formed in step (e) under suitable conditions to form a compound having the structure:

(g) reducing and esterifying the compound formed in step (f) under suitable conditions to form a compound having the structure:

(h) oxidizing the compound formed in step (g) under suitable conditions to form a compound having the structure:

(i) removing the thioketal of the compound formed in step (h) under suitable conditions to form a compound having the structure:

(j) treating the compound formed in step (i) under suitable conditions to form a compound having the structure:

(k) treating the compound formed in step (j) under suitable conditions to form a compound having the structure:

and (1) treating the compound formed in step (k) under suitable conditions to form the compound having the structure :

The present invention provides a compound having the structure:

wherein X is 0, -OO^CI^O-, -SCH _j CH _j S-, or -OCH ₂ CH ₂ s-; wherein R ¹ is a linear or branched chain alkyl or arylalkyl group, or an aryl group; wherein R ² is a trimethylsilyl, triethylsilyl, or t-butyldimethylsilyl group, or a linear or branched chain alkyl group; and wherein R ³ is a linear or branched chain alkyl or alkylaryl group, or an aryl group.

The present invention also provides a compound having the structure:

wherein R is a trimethylsilyl, triethylsilyl, or t- butyldimethylsilyl group, or a linear or branched chain alkyl or arylalkyl group; wherein R ¹ is a linear or branched chain alkyl or arylalkyl group, or an aryl group; wherein R ² is a trimethylsilyl, triethylsilyl, or t-butyldimethylsilyl group, or a linear or branched chain alkyl group; and

wherein R ³ is a linear or branched chain alkyl or alkylaryl group, or an aryl group.

The present invention further provides a compound having the structure:

wherein X is H, OH, a linear or branched acyl group, an aroyl group, Br, I, Cl, or F; wherein Y is 0 or _S ; wherein R is a trimethylsilyl, triethylsilyl, or t-butyldimethyl _¬ silyl group, or a linear or branched chain alkyl or arylalkyl group; wherein R ¹ is a linear or branched chain alkyl or arylalkyl group, or an aryl group; wherein R ² is a trimethylsilyl, triethylsilyl, or t-butyldimethylsilyl group, or a linear or branched chain alkyl group; and wherein R ³ is a linear or branched chain alkyl or alkylaryl group, or an aryl group.

The present invention further provides a compound having the structure:

wherein X is OTf, Cl, Br, I, or F; wherein Y is 0 or S; wherein Z is H-, o, or S; wherein R ¹ is a linear or branched chain alkyl or arylalkyl group, or an aryl group; wherein R ² is a trimethylsilyl, triethylsilyl, or t-butyldimethylsilyl group, or a linear or branched chain alkyl group; and wherein R ³ is a linear or branched chain alkyl or alkylaryl group, or an aryl group.

The present invention also provides a compound having the structure:

wherein X is OTf, Cl, Br, I, or F; wherein Y is O or S; wherein R ¹ is a linear or branched chain alkyl or arylalkyl group, or an aryl group; wherein R ² is a trimethylsilyl, triethylsilyl, or t-butyldimethylsilyl group, or a linear or branched chain alkyl group; wherein R ³ is a linear or

branched chain alkyl or alkylaryl group, or an aryl group; and wherein R* is H, a linear or branched chain alkyloxyalkyl group, a linear or branched chain alkyl or arylalkyl group, or an aryl group.

The present invention further provides a compound having the structure:

wherein X is CH _j , O or S; wherein Y is O or S; wherein R ¹ is a linear or branched chain alkyl or arylalkyl group, or an aryl group; wherein R ² is a trimethylsilyl, triethylsilyl, or t-butyldimethylsilyl group, or a linear or branched chain alkyl group; wherein R ³ is a linear or branched chain alkyl or alkylaryl group, or an aryl group; and wherein ⁴ is H, a linear or branched chain alkyloxyalkyl group, a linear or branched chain alkyl or arylalkyl group, or an aryl group.

The present invention also provides a compound having the structure:

wherein X is CH ₂ , 0 or S; wherein Y is 0 or S; wherein R ¹ is a linear or branched chain alkyl or arylalkyl group, or an aryl group; wherein R ² is a trimethylsilyl, triethylsilyl, or t-butyldimethylsilyl group, or a linear or branched chain alkyl group; wherein R ³ is a linear or branched chain alkyl or alkylaryl group, or an aryl group; wherein R* is H, a linear or branched chain alkyloxyalkyl group, a linear or branched chain alkyl or arylalkyl group, or an aryl group; and wherein R ⁵ is a linear or branched chain acyl group, or an aroyl group.

The present invention also provides a compound having the structure:

wherein X is CIL,, 0, S, IL,, H, OH, a linear or branched chain acyl group, or a linear or branched chain alkoxy group; wherein R ² is a trimethylsilyl, triethylsilyl, or t- butyldimethylεilyl group, or a linear or branched chain alkyl group ^; and wherein R ³ is a linear or branche _d chain alkyl or alkylaryl group, or an aryl group.

The present invention provides a process for synthesizing a compound having the structure:

which comprises (a) synthesizing a compound having the structure:

(b) treating the compound of step (a) under suitable conditions to form a compound having the structure:

(c) treating the compound formed in step (b) under suitable conditions to form a compound having the structure:

(d) treating the compound formed in step (c) under suitable conditions to form a compound having the structure:

(e) treating the compound formed in step (d) under suitable conditions to form a compound having the structure:

(f) treating the compound formed in step (e) under suitable conditions to form a compound having the structure:

(g) reducing the compound formed in step (f) under suitable conditions to form a compound having the structure:

(h) acetalizing the compound formed in step (g) un _d er suitable conditions to form a compound having the structure:

(i) treating the compound formed in step (h) under suitable conditions to form a compound having the structure:

(j) treating the compound formed in step (h) under suitable conditions to form a compound having the structure:

(k) deacetalizing the compound of step (j) under suitable acidic conditions to form a compound having the structure:

(1) reacting the compound formed in step (k) with an organometallic compound having the structure:

wherein M is selected from a group consisting of Li, K, Cs, MgBr, and MgCl, under suitable conditions to form a compound having the structure:

(m) treating the compound of step (l) under suitable conditions to form a compound having the structure:

(n) dehalogenating the compound formed in step (1) under suitable conditions to form a compound having the structure:

(o) treating the compound of step (n) under suitable conditions to form a compound having the structure:

(p) treating the compound formed in step (o) under suitable conditions to form a compound having the structure:

(q) oxidizing the compound formed in step (p) under suitable conditions to form a compound having the structure:

(r) contacting the compound formed by step (q) with a chiral reducing agent under suitable conditions to form a compound having the structure:

(s) reacting the compound formed in step (r) under suitable conditions to form a compound having the structure:

(t) cyclizing the compound of step (u) with an organometallic reagent under suitable conditions to form a compound having the structure:

(u) oxidizing the compound formed in step (t) under suita _b le conditions to form a compound having the structure:

(v) reducing the compound formeφin step (u) under suita _b le conditions to form a compound having the structure:

0

(w) acylating the compound formed in step (v) under suitable conditions to form a compound having the structure:

(x) hydrolyzing the compound formed in step (w) under suitable conditions to form a compound having the structure:

(y) benzoylating the compound formed in step (x) under suitable conditions to form the compound having the structure:

(z) reacting the compound formed in step (y) under suitable acidic conditions to form a compound having the structure:

(aa) esterifying the compound formed in step ₍ z ₎ with a compound having the structure:

OR wherein R is selected from a group consisting o _f trimethylsilyl, triethylsilyl , and t-butyldimet _h y _l si _l y _l , under suitable conditions to form the compound _h avin _g t _h e structure :

(bb) deprotecting the compound formed in step (aa) under suitable conditions to form a compound having the structure:

The invention provides a compound having the structure:

wherein X is OTf, Cl, Br, I, or F; wherein Y is o or S; wherein Z is H ₂ , 0, or S; wherein R ² is a trimethylsilyl, triethylsilyl, or t-butyldimethylsilyl group, or a linear or branched chain alkyl group; and wherein R ³ is a linear or branched chain alkyl or alkylaryl group, or an aryl group.

The invention also provides a compound having the structure:

wherein X is H ₂ , 0, or S; wherein Y is 0 or S; wherein R is a trimethylsilyl, triethylsilyl, or t-butyldimethylsilyl group, or a linear or branched chain alkyl or arylalkyl group; wherein R ² is a trimethylsilyl, triethylsilyl, or t- butyldimethylsilyl group, or a linear or branched chain alkyl group; and wherein R ³ is a linear or branched chain alkyl, arylalkyl or alkylaryl group, or an aryl group.

The invention further provides a compound having the structure:

OH wherein X is H ₂ , O, H, OH, OAe, or S; wherein Y is O or S; wherein R is a trimethylsilyl, triethylsilyl, or t-butyldi¬ methylsilyl group, or a linear or branched chain alkyl or arylalkyl group; wherein R ² is a trimethylsilyl, triethyl¬ silyl, or t-butyldimethylsilyl group, or a linear or branched chain alkyl group; and wherein R ³ is a linear or branched chain alkyl, arylalkyl or alkylaryl group, or an aryl group.

naacription -~f +*■* riσurea

fj ire 1. Retrosynthetic analysis of Route 1 total synthesis of taxol. The functional groups are defined as follows: R ¹ = H, COR, SiR ₃ , or R; R ² = OSiR ₃ , SR, or SOR; E = CN, C0 ₂ R, _C HO, or CH ₂ R'; X - H,H, H,OH, H,OSiR ₃ , or 0; Y = O or - _OC H ₂ CH ₂ 0-; R' - H, COR, SiR ₃ , or R; and R = alkyl, aryl.

Fiσure 2. A-ring synthesis and extension to aldehyde 5; preparation of the dienophile 7; Diels-Alder reaction with model four-carbon diene l-methoxy-3-trimethylsilyloxy-l,3- butadiene (Danishefsky's diene), and Michael addition of a cyano fragment onto the enone function of the adduct.

Figure 3. Oxidation of dienophile 7 leading to dione 13 and Diels-Alder reaction with model four-carbon diene.

Figure 4. Allylic oxidation of A-ring (preparation of compounds 17 and 23) ; deketalization of A-ring (preparation of compound 19) ; preparation of aldehyde 21 and acetylenic compounds 22 and 24.

_F igure 5. Extension of aldehyde 5 to the trisubstituted dienophiles 28 and 30.

_F igure ₆ . Preparation of aldehyde 5. (a) KHMDS, PhNTf ₂ , THF, 82*; (b) Bu ₃ SnCH=CH ₂ , cat. Pd(PPh ₃ ) ₄ , THF, 91%; (c) ₉ -BBN, THF, 94%; (d) Swern, 94%.

_F igure 7. Preparation of compounds 7 and 10. (a) BrMgC ₍ Me)-CH ₂ , THF, 89%; (b) Swern, 96%; (c) Danishefsky's diene, then H*, 81%; (d) p-TsOH, THF-water, 89%; (e) Et ₂ AlCN, benzene, 72%.

jgure 8. Preparation of compounds 12 and 15. (a) KHMDS, F. Davis oxaziridine, 87%; (b) Danishefsky•s diene, then H*, 95%; (c) Swern, 69%; (d) H*, p-TsOH, THF-water, 79%.

F ^{igure 9} * Preparation of compounds 25, 26, 28, and 30. (a) CrCl ₂ , cat. NiCl ₂ , DMF, 60-70%; (b) Swern, 82-88%.

Fiσure 10. Preparation of compounds 18 and 23. (a) TBDMSC1, NEt ₃ , CH ₂ C1 ₂ , 76%; (b) Cr0 ₃ -3,5-DMP, CH ₂ C1 ₂ , 37- 48%; (c) p-TsOH, Me ₂ CO, water, 82%.

Figure 11. Preparation of compounds 19, 21, 22, and 24.

Figure 12. Total synthesis of Taxol.

Figure 13. Retrosynthetic analysis of Route 2(a) total synthesis of taxol.

Figure 14. Retrosynthetic analysis of Route 2(b) total synthesis of taxol.

Figure 15. Preparation of compounds 68 and 69.. (a) TBSOTf/2,6-lutidine/CH ₂ Cl ₂ /0 ^β C;97%; (b) i) BH ₃ -THF ii) H ₂ 0 ₂ /NaOH; (c) 10 mol % TPAP/NMO/powdered 4 A molecular sieves/CH ₂ Cl _2; (d) 3% NaOMe in MeOH; 76% overall for steps b-d; (e) i) KHMDS/THF/-78 ^β c/30 min ii) PhNTf ₂ /-78»C/l h; 81%; (f) DMF/ 3 eq. Hϋnig's base/ 40 eq. anh. MeOH/ 8 mol% Pd(OAc) ₂ / 16 mol% Ph ₃ P/2 psi CO/4 h; 73%; (g) DIBAH/hexanes/-78%*C; 99%; (h) 5 mol% Os0 ₄ /NMO/acetone/H ₂ 0; 66%; (i) i) TMSCl/pyr/CH ₂ Cl ₂ /-78 ^β C to rt ii) Tf ₂ 0/-78 ^β C to rt iii) ethylene glycol/40 ^β C/12 h; 69% overall; (j) TBAF/THF/reflux/10 h; 93%; (k) 1 eq. collidium tosylate/acetone:H ₂ 0 (12:1)/reflux/120 h; 84%; (1) i) 2 eq. LDA/THF/-78 ^» C/1.5 h ii) 2.3 eq. TMSC1/-78* to rt; (m) i) 1.1 eq. Pd(OAc) ₂ /MeCN/reflux ii) MeOH/K ₂ C0 ₃ ; 77% overall; (n) TBSCl/imidazole/DMF/80 ^# C; 57%; (o) TMSCl/pyr/CH ₂ Cl ₂ ;88%; (p) i) KHMDS/THF/-78-C ii) N-

phenylsulfonyl phenyloxaziridine iii) H ₂ θ -78°C to rt;

77%; (q) i) LDA/THF/-78°C ii) TMSCl/-78 ^β C to rt (r) i)

0 ₃ /CH ₂ Cl ₂ /-78 ^β C ii) Ph ₃ P/-78°C to rt; 36%.

Figure 16. Total synthesis of taxol from dialdehyde 69.

(a) ethylene glycol, PPTS; (b) i) XVII (X ₂ = SCH ₂ CH _j CH ₂ S;

M = Li) ; ii) Swern; (c) acetone, PPTS; (d) i) X (R, = MOM;

M = Li) ; ii) Swern; (e) xylene, reflux; (f) i) NaBH ₄ ; ii) BzCl/pyr; (g) i) Se0 ₂ /dioxane; ii) Swern; (h) i) L- selectride; ii) BnBr/NaH; iii) Raney Ni; (i) i)KHMDS; then N-phenyl phenylsulfonyloxaziridine; ii) TBAF; iii)

Ac ₂ 0/pyr/DMAP; (j) i) I^/Pd-C; ii) See (49); (k)

LiOH/H ₂ 0/THF; (1) dilute acid/ H ₂ 0.

Figure 17. Mimics of taxol. (a) Ac ₂ 0/Pyr; (b) L- selectride/THF/78 ^β C; (c) See (49); (d) TBAF/THF; (e) dilute acid/H ₂ 0; (f) BzCl/pyr.

Figure 18. Preparation of compound 116. (a) 1:1 THF:3N HC1; (b) TMSCN, KCN (cat), 18-crown-6; (c) DIBAL-H; (d) 2-lithiostyrene; (e) TBAF, THF; (f) (C0C1) ₂ DMSO, Et ₃ N; (g) NaBH _« , EtOH; (h) 2,2-DIMETHOXYPROPANE, CSA; (i) 0 ₃ ; (j) CH ₂ -CHMgBr; (k) Pd(OAc) ₂ , KjCO _j , DMF. R,, R,, R ₃ and R« are independently the same or different and are H, Br, Cl, F, I, OH, C0 ₂ R, or a linear or branched chain alkyl, alkoxyalkyl, amino-alkyl, hydroxyalkyl, aryl, or arylalkyl group, where R is a linear or branched chain alkyl, hydroxyalkyl, or alkoxyalkyl group.

Figure 19 . Total synthesis of taxol . (a) KH, BnBr, THAI; (b) TsOH, HjO/acetone; (c) TMSOTf , Et ₃ N; (d) Pd (OAc) ₂ , DMF ; (e) TMSOTf , EtjN; ( f ) 0 ₃ ; (g) HO (CH ₂ ) ₂ OH, TsOH, (EtO) ₃ CH; (h) CHj-CHMgBr; (i) KH, BnBr, TBAI ; (j ) TsOH , HjO/acetone ; ( k) 3 - l ithio - l - cyano- l - ftr-.-methyl ) siloxy-2 , 2 , 6 - trimethylcyclohexane THF, - 78°C, then TBAF, THF, rt; (1) nBuLi , C0 ₂ , then I ₂ ; (m) Bu ₃ SnH,

AIBN; (n) KjC0 ₃ , MeOH; (o) KHMDS, PhNTf ₂ ; (p) Cr0 ₃ , DMP;

(q) [R]-CBS; (r) MOMBr, iPr ₂ NEt; (s) (PPh ₃ ) ₂ Pd(OAc) ₂ , Et ₃ N,

THF; (t) 0 ₃ ; (u) Hj _, Pd/C; (v) Ac ₂ 0, AcCl, pyr; (w) H,0, pyr; (x) BzCl, Et ₃ N; (y) TFA, CH ₂ C1 ₂ ; (z) BzNHCHPhCH(OTES)C0 ₂ H; (aa) TBAF, THF.

Figure 20. Preparation of Nortaxol . (a) CH ₂ =CH-MgBr; (b) TsOH, H ₂ 0, acetone; (c) 3 -lithio- 1-cyano- 1-

(trimethyl)siloxy-2,2,6-trimethyl cyclohexane, THF, 78°C, then TBAF, TAF, r.t.; (d) nBuLi, C0 ₂ then I ₂ ; (e) Bu ₃ SnH, AIBN; (f) MeOH; (g) KHMDS, Ph Tf ₂ ; (h) C0 ₃ , DMP; (i) [R]-CBS; (j) MOM-Br; (k) (PPh ₃ ) ₂ Pd (OAe) ₂ , Et ₃ N, THF; (1) 0 ₃ ; (m) H ₂ , Pd/C; (n) ACjO, AcCl,pyr; (o) H ₂ 0, pyr; (p) BzCl, Et ₃ N; (q) TFA, CH ₂ C1 ₂ ; (r) BzNHCHPhCH(OTES)C0 ₂ H; (s) TBAF, THF.

pifcailed Dβae _r jptlon of the Inv _?r »^ _n

The present invention provides a compound having the structure:

wherein X is H, OH, 0, or OSiR ₃ ; and Y is o or -0CH ₂ CH ₀ -; wherein R is an alkyl or aryl group.

The present invention also provides a compound having the structure:

wherein each X is independently the same or different an _d is H, OH, O, or 0SiR ₃ ; Y is O or -OCH ₂ CH ₂ 0-; Z is OH, _O , or OTMS; and E is H, CN, C0 ₂ R, CHO, or CH ₂ OR ^« ; wherein R« is H, COR, R, or SiR ₃ and R is an alkyl or aryl group.

The present invention further provides a compound having the structure:

wherein each X is independently the same or different and is H, OH, 0, or 0SiR ₃ ; Y is H, 0, or -OCH ₂ CH ₂ 0-; E is H, CN, C0 ₂ R, CHO, or CH ₂ 0R'; R ¹ is H, OH, OCOR, OR or OSiR ₃ ; and R ² is H, CH ₂ OSiR ₃ , CH ₂ SR, or CH ₂ SOR; wherein R' is H, COR, R, or SiR ₃ and R is an alkyl or aryl group.

Additionally, the present invention provides a compound having the structure:

wherein each X is independently the same or different and is H, OH, 0, OR or OSiR ₃ ; Y is O or -OCH ₂ CH ₂ 0-; E is CN, C0 ₂ R, CHO, or CH ₂ OR'; R ¹ is H, COR, or SiR ₃ ; and R ₂ is H, COR, or SiR ₃ ; wherein R' is H, COR, R, or SiR ₃ and R is an alkyl or aryl group.

The present invention also provides a compound having the structure:

wherein X is H, OH, O, OR, or OSiR ₃ ; and R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are independently the same or different and are H, COR, SiR ₃ , or R; wherein R is an alkyl or aryl group; with the proviso that X, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are not OAe, H, Ac, COPh, H, and PhCH(BzNH)CH(OH)CO-, respectively.

The present invention also provides a process for synthesizing an aldehyde having the structure:

wherein Y is 0 or -OCH CH ₂ 0-; which comprises:

(a) triflating a ketoketal having the structure:

wherein Y is O or -OCH ₂ CH ₂ 0-; under suitable conditions to form an enol triflate having the structure:

(b) reacting the enol triflate formed in step (a) with vinyltributylstannane under palladium (O) catalysis, under suitable conditions to form a diene having the structure:

(c) reacting the diene formed in step (b) by

hydroboration/oxidation under suitable conditions to form an alcohol having the structure:

(d) contacting the alcohol formed in step (c) with a first protecting group under suitable conditions to form a protected alcohol having the structure: Group

(e) oxidizing the protected alcohol formed in step (d) under suitable conditions to form an enone having the structure: -Protecting Group

(f) reducing the enone formed in step (e) under suitable conditions to form an allylic alcohol having the structure: Group

(g) contacting the allylic alcohol formed in step (f) with a second protecting group under suitable conditions to form a protected alcohol having the structure:

(h) treating the protecte a coho formed in step (g) under suitable conditions to selectively remove the first protecting group to form an alcohol having the structure:

OH

Protecting Group-O III.'

and (i) oxidizing the alcohol formed in step (h) to form the aldehyde having the structure:

Protecting Group-O

In the above process and the various processes which follow, the suitable conditions necessary for the various reactions and treatments may be found in the Experimental Details Section which follows. However, it is within the confines of the present invention that the specific reactants and solvents provided as well as the specific conditions necessary for reaction or treatment may be substituted with other suitable reactants, solvents and conditions well known to those skilled in the art.

In step (a) above, the "triflating" of the ketoketal is performed by reacting the ketoketal with a suitable trifating agent, preferably, N-phenyl-trifluoromethane sulfoni ide. In step (b) above, the enol triflate formed in step (a) is coupled under palladium (O) catalysis with vinyl-tri-n-butylstannane leading to the diene. In step

(c) , the diene is preferably hydroborated with 9-BBN, to give, after basic hydroparoxide work-up, the alcohol. In step (d) , the alcohol is treated with a protecting group, preferably TBDMSC1, or another suitable protecting group to form the protected alcohol. In step (e) , the oxidizing of the protected alcohol is preferably performed via -3,5- dimethylpyrazole mediated allylic oxidation in the presence of a chromium trioxide complex. In step (f) , the enone is preferably reduced with borane in the presence of a catalytic amount of chiral oxazoborolidine to give the allylic alcohol. In step (g) , the alcohol function of the allylic alcohol is preferably protected with a TBDMS group. In step (h) , the first protecting group is preferably removed by selective desilylation of the primary hydroxyl. In step (i) , the alcohol is preferably oxidized by the method of Swern to form the aldehyde.

The present invention also provides a process for synthesizing a diketo dienophile having the structure:

wherein Y is O or -OCH ₂ CH ₂ 0-; and E is -CH ₂ OR', CN, C0 ₂ R, or CHO; wherein R' is H, COR, R, or SiR ₃ and R is an alkyl or aryl group; which comprises:

(a) synthesizing an aldehyde having the structure:

according to the process above;

(b) coupling the aldehyde formed in step (a) with a compound having the structure:

wherein E is -CH ₂ OR' , CN, C0 ₂ R, or CHO; wherein R' is H,

COR, R, or SiR ₃ and R is an alkyl or aryl group; under suitable conditions to form an allylic alcohol having the structure:

(c) oxidizing the allylic alcohol formed in step (b) under suitable conditions to form an enone having the structure:

Protecting

(d) treating the enone formed in step (c) under suitable conditions to form a hydroxyketone having the structure:

and (e) oxidizing the hydroxyketone formed in step (d) under suitable conditions to form the diketo dienophile having the structure:

In step (a) above, the aldehyde may be synthesized by the previous process or other processes deter inable by those skilled in the art. In step (b) , the coupling is preferably performed by a nickel chloride catalyzed chromium (II) chloride promoted coupling of the iodide compound, preferably vinyl iodide, with the aldehyde to afford the allylic alcohol. In step (c) , the alcohol is preferably oxidized by Swern oxidation (oxalyl chloride, dimethylsulfoxide, triethylamine, dichloromethane) to form the enone, which is converted in step (d) into the hydroxyketone by preferably adding KHMDS followed by N- phenylsulfonyl-phenyloxaziridine. In step (e) , the hydroxyketone is preferably oxidized using oxalyl chloride and DMSO followed by triethylamine to form the diketo dienophile.

The present invention also provides a process for synthesizing a compound having the structure:

Protecting Group-

wherein Y is o or -OCH ₂ CH ₂ 0- ; E is -CH ₂ 0R' , CN , C0 ₂ R, or CHO; R ¹ is H , COR, R, or SiR ₃ ; and R ² is 0SiR ₃ , SR, or SOR; wherein R' is H, COR, R, or SiR ₃ and R is an alkyl or aryl group; which comprises:

(a) synthesizing a diketo dienophile having the structure:

according to the process above;

and (b) coupling the diketo dienophile formed in step (a) with a diene having the structure :

wherein R ¹ is H, COR, R, or SiR ₃ ; and R ² is OSiR ₃ , SR, or SOR; wherein R is an alkyl or aryl group; to form the compound

In step ( di i i synthesized by the previous process or other processes determinable by those skilled in the art. In step (b) , Diels-Alder cycloaddition of the diketo dienophile with the diene followed by acidic work-up yields an adduct in which the primary silyl ether is selectively cleaved affording the alcohol. Alternatively, fluoride mediated work-up of the Diels-Alder reaction between the diketo dienophile and the diene produces the compound directly.

The present invention also provides a process for synthesizing a compound having the structure:

wherein R ¹ is H, COR, R, or SiR ₃ ; and R ² is OSiR ₃ , SR, or SOR; wherein R is an alkyl or aryl group; which comprises:

(a) synthesizing a compound having the structure:

Protecting

according to

(b) oxidizing the compound formed in step (a) under suitable conditions to form an aldehyde having the structure:

n step (b) under suitable conditions to form the compound having the structure:

In step (a) above, the compound may be synthesized by the previous process or other processes determinable by those skilled in the art. In step (b) , the compound of step (a ₎ is preferably oxidized using oxalyl chloride and DM _SO followed by triethylamine to form the aldehyde. In step (c) , the deketalizaton preferably involves treating the ketal with p-toluenesulfonic acid in aqueous tetrahydrofuran to form the compound in which the protecting group, preferably the TBDMS ether, is concomitantly removed.

The present invention also provides a process for synthesizing, a compound having the structure:

wherein X is SiR ₃ ; and R ² is

OSiR ₃ , SR, or SOR; wherein R is an alkyl or aryl group; which comprises:

( a ) synthesizing a compound having the structure :

according to the process a ove ;

and (b) coupling the compound formed in step (a) by intramolecular pinacolic coupling under suitable conditions to form a compound having the structure:

In step (a) above, the compound may be synthesized by the previous process or other processes determinable by those skilled in the art. In step (b) , the pinacolic coupling preferably involves the samarium diiodide promoted intramolecular coupling which is assisted by both the presence of the free hydroxy1 group at C-13 (numbering refers to the taxol skeleton) , and the cyclic enediolate samarium species, formed by the complexation of the diketo system at C-9,10 with excess reagent. Concomitantly, the ketone at C-5 might be reduced.

The present invention also provides a process for synthesizing a compound having the structure:

wherein R ¹ is H, COR, R, or SiR ₃ ; wherein R is an alkyl or aryl group; which comprises:

(a) synthesizing a compound having the structure:

according to the process above;

(b) treating the compound formed in step (a) under suitable conditions to form a compound having the structure:

(c) oxidizing the compound formed in step (b) under suita _b le conditions to form a compound having the structure:

(d) reducing the compound formed in step (c) under suitable conditions to form a compound having the structure:

(e) treating the compound formed in step (d) under suitable conditions to form a compound having the structure:

and (f) treating the compound formed in step (e) under suitable conditions to form the compound having the structure:

In step (a) above, the compound may be synthesized by the previous process or other processes determinable by those skilled in the art. In step (b) , sequential selective protection of the hydroxyl groups, preferably by the addition of Ac ₂ C/Py, TMSCl/NEt ₃ , TBDMSCl/NEt ₃ , and H*, of the compound synthesized in step (a) at Cι- _lθ , _C - _l (temporary) and C-13, leads to the formed compound. In step (c) , the compound is preferably oxidized using oxalyl chloride and DMSO followed by triethylamine. In step (d) , o-hydroxy at C-2 is preferably εtereoselectively reduced using 2n(BH ₄ ) ₂ . In step (e) , the compound is sequentially protected, preferably by the addition of TMSCl/NEt ₃ , BzCl/Py, H ^* , and NaH/BnBr. In step (f) , the treating preferably comprises the reduction at C-5, the oxidation of the sulfide at C-20- to the sulfoxide and its elimination upon heating, followed by the osmium tetroxide catalyzed bis-hydroxylation of the allylic alcohol.

The present invention also provides a process for synthesizing a compound having the structure:

which comprises:

(a) synthesizing a compound having the structure:

according to the process above;

and (b) treating the compound formed in step ₍ a ₎ under suitable conditions to form the compound having the structure:

In step (a) above, the compound may be synthesized by the previous process or other processes determinable by those skilled in the art. In step (b) , the compound of step (a) is converted to the hydroxy oxetane by known procedures (11,12).

The present invention also provides a process for synthesizing a compound having the structure:

which comprises:

(a) synthesizing a compound having the structure:

according to the process of above;

(b) treating the compound formed in step (a) under suitable conditions to form a compound having the structure:

(c) treating the compound formed in step (a) under _. suitable conditions to form a compound having the structure:

and (d) treating the compound formed in step (c) under suitable conditions to form a compound having the structure:

In step (a) above, the compound may be synthesized by the previous process or other processes known to those skilled in the art. in step (b) , the hydroxy group at c- ₄ an _d the protecting group, TBDMSO, at C-13 are readily converte _d into corresponding acetoxy and hydroxy groups by the ad _d ition o _f Ac ₂ 0/Py. and TBAF. In step (c) , the side chain attachment at C-13 is accomplished by known protocols (49) . in step (d) , the sequential selective deprotection of hydroxyl groups at C-l and C-7 by adding H ₂ /Pd/C produces taxol.

In addition, the present invention also provides a process for synthesizing a compound having the structure:

which comprises:

(a) treating a compound having the structure:

under suitable conditions to form a compound having the structure:

(b) treating the compound formed in step (a) under suitable conditions to form a compound having the structure:

and (c) treating the compound formed in step (b) under suitable conditions to form the compound having the structure:

In step (a) , the hydroxy group at C-4 and the protecting group, TBDMSO, at C-13 are readily converted into corresponding acetoxy and hydroxy groups by the addition of Ac ₂ 0/Py. and TBAF. In step (b) , the side chain attachment at C-13 is accomplished by known protocols (49) . In step (c) , the sequential, selective deprotection of hydroxyl groups at C-l and C-7 by adding H ₂ /Pd/C produces taxol.

The present invention also provides a process for synthesizing a compound having the structure:

which comprises treating a compound having the structure:

under suitable conditions to form the compound having the structure:

In process above, the starting compound is converted to the hydroxy oxetane by known procedures (11,12).

The present invention also provides a process _f or synthesizing a compound having the structure:

wherein R ¹ is H, COR, R, or SiR ₃ ; wherein R is an alkyl or aryl group; which comprises:

₍ a) treating a compound having the structure:

wherein X is O or OH; and R ¹ is H, COR, R, or SiR ₃ ; wherein R is an alkyl or aryl group;

under suitable conditions to form a compound having the structure:

(b) oxidizing the compound formed in step (a) under suitable conditions to form a compound having the structure:

( c) reducing the compound formed in step (b) under suitable conditions to form a compound having the structure:

(d) treating the compound formed in step (c) under suita _b le conditions to form a compound having the structure:

and (e) treating the compound formed in step (d) under suitable conditions to form the compound having the structure:

In step (a) , sequential selective protection of the hydroxyl groups, preferably by the addition of Ac ₂ 0/Py, TMSCl/NEt ₃ , TBDMSCl/NEt ₃ , and H ^* , of the starting compound at C-10, C- _l (temporary) and C-13, leads to the formed compound. In step (b) , the compound is preferably oxidized using oxalyl chloride and DMSO followed by triethylamine. In step (c) , ct-hydroxy at C-2 is preferably stereoselectively reduced using Zn(BH ₄ ) . In step (d) , the compound is sequentially protected, preferably by the addition of TMSCl/NEt ₃ , BzCl/Py, H*, and NaH/BnBr. In step (e) , the treating preferably comprises the reduction at C-5, the oxidation of the sulfide at C-20 to the sulfoxide, and its elimination upon heating, followed by the osmium tetroxide catalyzed bis-hydroxylation of the allylic alcohol.

The present invention also provides a process for synthesizing a compound having the structure:

wherein R ¹ is H, COR, R, or SiR ₃ ; R ² is OSiR ₃ , SR, or SOR; and X is OH or O; wherein R is an alkyl or aryl group;

which comprises coupling a compound having the structure:

wherein R ¹ is H, COR, R, or SiR ₃ ; and R ² is OSiR ₃ , SR, or SOR; wherein R is an alkyl or aryl group; by intramolecular pinacolic coupling under suitable conditions to form a compound having the structure:

In process above, the pinacolic coupling preferably involves the samarium diiodide promoted intramolecular coupling which is assisted by both the presence of the free hydroxyl group at C-13 (numbering refers to the taxol skeleton) , and the cyclic enediolate samarium species, formed by the complexation of the diketo system at C-9,10 with excess reagent. Concomitantly, the ketone at C-5 might be reduced.

The present invention also provides a process for synthesizing a compound having the structure:

wherein R ¹ is H, COR, R, or SiR ₃ ; and R ² is OSiR ₃ , SR, or SOR; wherein R is an alkyl or aryl group; which comprises:

(a) oxidizing a compound having the structure:

Protecting

wherein R ¹ is K, COR, R, or SiR ₃ ; and R ² is OSiR ₃ , SR, or SOR; wherein R is an alkyl or aryl group;

under suitable conditions to form an aldehyde having the structure:

Protecting

and (b) deketalizing the aldehyde formed in step (a) under suitable conditions to form the compound having the structure:

In step (a) , the starting compound is preferably oxidized using oxalyl chloride and DMSO followed by triethyla ine to form the aldehyde. In step (b) , the deketalizaton preferably involves treating the ketal with p- toluenesulfonic acid in aqueous tetrahydrofuran to form the compound in which the protecting group, preferably the TBDMS ether, is concomitantly removed.

The present invention further provides a process for synthesizing a compound having the structure:

wherein Y is O or -OCH ₂ CH ₂ 0-; E is -CH ₂ OR', CN, C0 ₂ R, or CHO; R ¹ is H, COR, R, or SiR ₃ ; and R ² is OSiR ₃ , SR, or SOR; wherein R' is K, COR, R, or SiR ₃ and R is an alkyl or aryl group; which comprises coupling a diketo dienophile having the structure:

wherein Y is 0 or -OCH ₂ CH ₂ 0-; and E is -CH ₂ OR\ CN, C0 ₂ R, or CHO; wherein R« is H, COR, R, or SiR ₃ and R is an alkyl or aryl group;

with a diene having the structure:

wherein R ¹ is H, COR, R, or SiR ₃ ; and R ² is OSiR ₃ , SR, or SOR; wherein R is an alkyl or aryl group;

to form

In proc of the diketo dienophile with the diene followed by acidic work-up yields an adduct in which the primary silyl ether is selectively cleaved affording the alcohol. Alternatively, fluoride mediated work-up of the Diels-Alder reaction between the diketo dienophile and the diene produces the compound directly.

The present invention also provides a process for synthesizing a diketo dienophile having the structure:

wherein Y is 0 or -OCH ₂ CH ₂ 0-; and E is -CH ₂ OR' , CN, co ₂ R, or CHO; wherein R ^« is H, COR, R, or SiR ₃ and R is an alkyl or aryl group; which comprises:

(a) coupling an aldehyde having the structure:

Protecting Group-O

wherein Y is 0 or -OCH ₂ CH ₂ 0- ;

with a compound having the structure:

wherein E is -CH ₂ OR', CN, C0 ₂ R, or CHO; wherein R» is H, COR, R, or SiR ₃ and R is an alkyl or aryl group;

under suitable conditions to form an allylic alcohol having the structure:

(b) oxidizing the allylic alcohol formed in step (a) under suitable conditions to form an enone having the structure:

(c) treating the enone formed in step (b) under suitable conditions to form a hydroxyketone having the structure:

and (d) oxidizing the hydroxyketone formed in step ( c) under suitable conditions to form the diketo dienophile having the

In step (a) , the coupling is preferably performed by a nickel chloride catalyzed chromium (II) chloride promoted coupling of the iodide compound, preferably vinyl iodide, with the aldehyde to afford the allylic alcohol. In step (b) , the alcohol is preferably oxidized by Swern oxidation (oxalyl chloride, di ethylsulfoxide, triethylamine, dichloroπtethane) to form the enone, which is converted in step (c) into the hydroxyketone by preferably adding KHMDS followed by N-phenylsulfonyl-phenyloxaziridine. In step (d) , the hydroxyketone is preferably oxidized using oxalyl chloride and DMSO followed by triethylamine to form the diketo dienophile.

The present invention also provides a process for synthesizing a compound having the structure:

wherein each X is independently the same or different and is H, OH, 0, OR, or 03iR ₃ ; Y is O or -OCH ₂ CH ₂ θ- _; and E is H, - CH ₂ OR\ CN, C0 ₂ R, or CHO; wherein R ^« is H, COR, R, or SiR and R is an alkyl or aryl group; which comprises coupling an aldehyde having the structure:

wherein X is H, OH, 0, OR, or 0SiR ₃ ; and Y is o or OCH ₂ CH ₂ 0-; wherein R is an alkyl or aryl group;

with a compound having the structure:

wherein E is -CH ₂ OR ^« , CN, C0 ₂ R, or CHO; wherein R' is H, COR, R, or SiR ₃ and -R is an alkyl or aryl group;

under suitable conditions to form the compound having the structure:

The present invention also provides a process for synthesizing a compound having the structure:

wherein each X is independently the same or different and is H, OH, 0, OR, or 0SiR ₃ ; Y is 0 or -OCH ₂ CH ₂ 0-; E is H, - CH ₂ OR\ CN, C0 ₂ R, or CHO; R ¹ is H, COR, R, or SiR ₃ ; and R ² is OSiR ₃ , SR, or SOR; wherein R' is H, COR, R, or SiR ₃ and R is an alkyl or aryl group; which comprises contacting a compound having the structure:

wherein each X is independently the same or different and is H, OH, O, OR, or OSiR ₃ ; Y is O or -OCH ₂ CH ₂ 0-; and E is H, - CH ₂ OR', CN, C0 ₂ R, or CHO; wherein R' is H, COR, R, or SiR ₃ and R is an alkyl or aryl group;

with a compound having the structure:

wherein R ¹ is H, ^CO R, R, or SiR ₃ ; and R* _is osiR ₃ , _S R, or SOR; wherein R is an alkyl or aryl group;

un ^d er suita ^b le con ^d itions to form the compoun _{d h} avin _g t _h e structure:

The present invention also provides a process for synthesizing a compound having the structure:

wherein each X is independently the same or different and is H, OH, 0, OR, or OSiR ₃ ; Y is O or -OCH ₂ CH ₂₀ -; E is H, - ^C H ₂ 0R\ CN, C0 ₂ R, or CHO; R ¹ is H, COR, or _S iR ₃ ; and R ² ' is H, ^C OR, or SiR ₃ ; wherein R - is H, COR, R, or SiR ₃ and R is an alkyl or aryl group; which comprises treating a compound having the.structure:

wherein each X is independently the same or different and is H, OH, 0, OR, or OSiR ₃ ; Y is 0 or -OCH ₂ CH ₂ 0-; E is H, - CH ₂ OR\ CN, C0 ₂ R, or CHO; R* is H, COR, R, or SiR ₃ ; and R ² is 0SiR ₃ , SR, or SOR; wherein R ^« is H, COR, R, or SiR ₃ and R is an alkyl or aryl group;

under suitable conditions to form the compound having the structure:

The present invention also provides a process for synthesizing a compound having the structure:

wherein X is H, OH, o, OR, or OSiR ₃ ; and R ¹ , R ² , R- _t R«, and R ⁵ are independently the same or different and are H, COR, SiR3, or R; wherein R is an alkyl or aryl group; which comprises treating a compound having the structure:

wherein each X is independently the same or different and is H, OH, 0, OR, or OSiR ₃ ; Y is O or -OCH ₂ CH ₂ 0-; E is H, - CH ₂ OR\ CN, C0 ₂ R, or CHO; R ¹ is H, COR, or SiR ₃ ; and R ² is H, COR, or SiR ₃ ; wherein R' is H, COR, R, or SiR ₃ and R is an alkyl or aryl group;

under suitable conditions to form the compound having the structure:

The present invention also provides a compound having the structure:

wherein X ₄ is H, OR, 0, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH _2C H _2S -; and R ₂ and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; w _h erein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDP _S .

The present invention further provides a compound having the structure:

wherein X ₃ and X ₄ are independently the same or di _f ferent and are H, OR, O, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R ₂ and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS.

In addition, the present invention provides a compound having the structure:

wherein X ₄ is H, OR, O, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; R ₂ and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; and R ₄ is PhCH(BzNH)CH(OH)CO-, O, an alkyl, or aryl group; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS.

The present invention also provides a compound having the structure:

wherein X ₄ is H, OR, 0, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; R ₂ an _d R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; and R ₄ is PhCH(BzNH)CH(OH)CO-, 0, an alkyl, or aryl group; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS.

The present invention also provides a compound having the structure:

wherein X ₄ is H, OR, 0, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R ₂ and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS.

The present invention also provides a compound having the structure:

wherein X ₄ is H, OR, 0, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R ₂ , R ₂ , and R ₃ are independently the same or different and are

H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS.

The present invention further provides a compound having the structure:

wherein X ₂ , X ₃ , and X ₄ are independently the same or different and are H, OR, 0, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R _j , R ₂ , and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS.

Moreover, the present invention provides a compound having the structure:

wherein X _λ , X ₂ , X ₃ , and X ₄ are independently the same or different and are H, OR, 0, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R _j , R ₂ , and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS.

The present invention also provides a compound having the structure:

wherein X _α and X^» are independently the same or differen _t and are H, OR, 0, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS.

The present invention also provides a compound having the structure:

wherein X _α , X ₂ , and "X ₅ are independently the same or different and are H, OR, 0, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and M is H or a metal; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS.

The present invention further provides a compound having the structure:

wherein X _lr X ₂ , and X ₃ are independently the same or different and are H, OR, 0, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R ₂ and R ₃ are independently the same or different and are H,

acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS.

The present invention also provides a process or synthesizing a compound having the structure:

wherein R is H or TBS; which comprises:

(a) treating a compound having the structure:

under suitable conditions to form a compound having the structure:

(b) contacting the compound formed in step (a) with TBS under suitable conditions to form a compound having the structure:

(c) contacting the compound formed in step (b) under suitable conditions to form a compound having the structure:

(d) triflating the compound formed in step (c) under suitable conditions to form a compound having the structure:

(e) treating the compound formed in step (d) by carbomethoxylation under suitable conditions to form a compound having the structure:

(f) reducing the compound formed in step (e) under suitable conditions to form a compound having the structure:

(g) treating the compound formed in step (f) by oxmylation under suitable conditions to form a compound having the structure:

and (h) contacting the compound formed in step (g) un _d er suitable conditions to form the compound having the structure:

In step (a) , the, starting compound is treated by deconjugative ketalization and hydroboration/oxidation, in step (b) , the equatorial secondary alcohol of the compound formed in step (a) (a pro C-7 hydroxyl in the C-ring of taxol) is protected by treating with t-butyldimethylsilyl (TBS) ether. In step (c) , the treating comprises the hydroboration/oxidization of the compound formed in step ₍ b ₎ according to the reported protocol (33), followed _b y tetrapropylammoniu perruthenate catalyzed oxidation ( ₃₉ , 40) to give the cis and trans-fused ketones which converge to the trans compound after base catalyzed equilibration. In step (d) , for the purpose of one carbon homologation, the compound formed in step (c) is converted to the enol triflate, preferably by O-sulfonylation of its potassium enolate with N-phenyltrifluoromethane sulfonimide (41, 42, 43). In step (e) , the treating comprises palladium catalyzed carbomethoxylation (44) to yield the unsaturated ester. In step (f) , this ester is readily reduced with a reducing agent, preferably, DIBAH, to the corresponding allylic alcohol. In step (g) , the treating comprises the osmylation of the alcohol under catalytic conditions to

yield the triol. In step (h) , the triol is converted to the oxetane by preferably treating with TMSCl/pyridine in CH ₂ C1 ₂ , Tf ₂ 0, and ethylene glycol (45). The TBS ether is removed with tetrabutylammonium fluoride.

The present invention also provides a process for synthesizing a compound having the structure:

which comprises:

(a) synthesizing a compound having the structure

according to the process above;

(b) removing the ketal of the compound formed in step (a) under suitable conditions to form a compound having the structure:

(c) treating the compound formed in step (b) under suitable conditions to form a compound having the structure:

⁽ d ⁾ treating the compound formed in step (c) under suitable conditions to form a compound having the structure:

and (e) treating the compound formed in step <d ₎ under suitable conditions to form the compound having the structure:

In step (a) , the compound is synthesized by the process above or other processes determinable by those skilled in the art. In step (b) , the ketal is removed under mildly acidic conditions (collidinium tosylate) to maintain the integrity of both the TBS ether and the oxetane ring. In step (c) , the ketone is subsequently converted to the corresponding enone by treating its silyl enol ether ₍ 4 ₆₎ with Pd(OAc) ₂ (47, 48). In step (d) , the tertiary alcohol of the compound is protected with TBS by treating with an excess of TBSC1, followed by the treatment of potassium bis(trimethylsilyl) amide in step (e) .

The present invention also provides a process for synthesizing a compound having the structure:

which comprises:

(a) synthesizing a compound having the structure

according to the suitable process above;

(b) treating the compound formed in step (a) under suitable conditions to form a compound having the structure:

(c) treating the compound formed in step (b) under suitable conditions to form a compound having the structure:

In step ⁽ a) , the compound is synthesized by the relevant process above or other processes determinable by those skilled in the art. In step (b) , the treating is effected by treatment with TBSCl/imidazole/DMF. In step _(C) , the treating is effected by degradation of the compoun _d formed in step ⁽ b) to the dialdehyde by ozonolysis of- the trimethylsilyl dienol ether.

The present invention also provides a process for synthesizing a compound having the structure:

wherein X ₄ is H, OR, 0, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH _2S -; and R ₂ and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

which comprises treating a compound having the structure:

wherein X ₄ is H, OR, O, -0CH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R ₂ and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

under suitable conditions to form the compound having the structure:

ao-

In the process above, the treating comprises methyllithium (Et ₂ 0/-78 ^β C) addition.

The present invention also provides a process for synthesizing a compound having the structure:

wherein X ₄ is H, OR, O, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R ₂ and R ₃ are independently the same or different and are H acyl, alkyl, aryl, TBS ^' , TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

which comprises treating a compound having the structure:

wherein X ₄ is H, OR, O, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S.-; and R ₂ and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS.; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

under suitable conditions to form the compound having the structure:

The present invention also provides a process for synthesizing a compound having the structure:

wherein X ₄ is H, OR, 0, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R ₂ , R ₂ , and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

which comprises:

(a) synthesizing a compound having the structure:

wherein X ₄ is H, OR, 0, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R ₂ and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; according to the

suitable process above;

and (b) treating the compound formed in step ₍ a ₎ under suitable conditions to form the compound having the structure:

In step (a) , the compound may be synthesized by the relevant process above or other processes determinable by those skilled in the art. The treating in step (b) involves degradation by ozonolysis followed by lead tεtraacetate.

The present invention also provides a process for synthesizing a compound having the structure:

wherein X ₃ and X ₄ are independently the same or different and are H, OR, 0, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R ₂ and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

which comprises:

(a) synthesizing a compound having the structure:

wherein X ₄ is H, OR, 0, -0CH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R ₂ and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; according to the suitable process above;

and (b) treating the compound formed in step (a) un _d er suitable conditions to form the compound having the structure:

In step (a) , the compound may be synthesized by the relevant process above or other processes determinable by those skilled in the art. The treating in step (b) involves homologation by methoxymethylene Wittig followed by oxidation.

The present invention also provides a process for synthesizing a compound having the structure:

wherein X ₂ , X ₃ , and X ₄ are independently the same or different and are H, OR, 0, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R _1# R ₂ , and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

which comprises:

(a) synthesizing a compound having the structure:

wherein X ₄ is H, OR, O, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R _1# R ₂ , and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, ~r TBDPS; according to the suitable process above;

and (b) contacting the compound formed in step (a) with a compound having the structure:

wherein X ₂ is H, OR, O, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and M is a metal; wherein.R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; under suitable conditions to form the compound having the structure:

In step (a) , the compound may be synthesized by the suitable process above or other processes determinable by those skilled in the art. The contacting in step (b) comprises the

nucleophilic attack of the compound synthesized in step ₍ a ₎ with the compound in step (b) .

The present invention also provides a process for synthesizing a compound having the structure:

wherein X ₂ , χ ₃ , and X ₄ are independently the same or different and are H, OR, O, -OCH ₂ CH ₂ θ-, or -SCH ₂ CH ₂ CH ₂ S-; an _d R _a# R , and R ₃ are independently the same or different an _d are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

which comprises:

(a) synthesizing a compound having the structure:

wherein X ₃ and X ₄ are independently the same or different and are H, OR, O, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R ₂ and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; according to the suitable process above;

(b) contacting the compound formed in step (a) with a compound having the structure:

95/12567

86 -

wherein M is a metal; under suitable conditions to form the compound having the structure:

wherein X ₂ , X ₃ , and X ₄ are independently the same or different and are H, OR, 0, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R ₂ and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

and (c) contacting the compound formed in step (b) with a compound having the structure:

OR,

=(

wherein R _: is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; and M is a metal; under suitable conditions to form the compound having the structure:

95/12567

- 87-

In step (a), the compound may be synthesized by the suita _b le process above or other processes determinable by those skilled in the art. The contacting in step (b) involves the addition of the metallated diene to the aldehyde function of the compound formed in step (a) . The contacting in step ₍ c ₎ involves the addition of the two carbon acyl-anion to t _h e compound formed in step (b) .

The present invention also provides a process for synthesizing a compound having the structure:

wherein X 2' ^k 3' a ently the same or different and are H, OR, 0, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R _α , R ₂ , and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

which comprises:

(a) synthesizing a compound having the structure:

wherein X ₄ is H, OR, O, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R ₂ and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; according to the suitable process above;

(b) contacting the compound formed in step (a) with compound having the structure:

wherein X ₂ is H, OR, O, - ^¥ OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and M is a metal; wherein R is H, acyl, alkyl, aryl, TBS, TE _S , TMS, or TBDPS; under suitable conditions to form the compound having the structure:

wherein X ₂ , χ ₃ , and X ₄ are independently the same or different and are H, OR, O, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R ₂ and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

and (c) contacting the compound formed in step (b) with a compound having the structure:

OR,

=<

wherein R _: is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; and M is a metal; under suitable conditions to form the compound having the structure:

In step (a) , the compound may be synthesized by the suitable process above or other processes determinable by those skilled in the art. The contacting in step (b) involves the addition of the metallated diene to the aldehyde function o _f the compound formed in step (a). The contacting in step _(C) involves the addition of the two carbon acyl-anion, preferably, methoxyvinyllithium, to the compound formed in step (b) .

The present invention also provides a process for synthesizing a compound having the structure:

wherein X _α , χ ₂ , χ ₃ , and X ₄ are independently the same or different and are H, OR, o, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R _α , R ₂ , and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

which comprises:

(a) synthesizing a compound having the structure:

wherein X 2' ^k 3' the same or different and are H, OR, 0, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R _{l t} R ₂ , and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein

R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDP _S ; according to one of the suitable processes above;

and (b) coupling the compound formed in step (a) by intra _¬ molecular coupling under suitable conditions to form the compound having

In step (a) , the compound may be synthesized by the suita _b le processes above or other processes determinable by those skilled in the art. In step (b) , the contacting comprises the intra-molecular Diels-Alder coupling of the compound formed in step (a) by thermal or Lewis acid catalyzed Diels- Alder cyclization.

The present invention further provides a process for synthesizing a compound having the structure:

wherein Xi *2' and X- are independently the same or different and are H, OR, O, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R ₂ and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

which comprises:

(a) synthesizing a compound having the structure:

95/12567

- 91 *

wherein X ₃ and X ₄ is H, OR, 0, -OCH ₂ CH ₂ 0-, or -SCH _2C H _2C H _2S -; and R ₂ and R ₃ are the independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDP _S ; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; according to the suitable process above;

and (b) contacting the compound formed in step (a) with a compound having the structure:

wherein X ₂ and X ₅ are independently the same or different and are K, OR, 0, -0CH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; under suitable conditions to form the compound having the structure:

In step (a) , the compound may be synthesized by the suitable process above or other processes determinable by those skilled in the art. In step (b) , the contacting is performed by Nozaki-Nishi (13,14) coupling of the enol triflate with the compound formed in step (a) .

95/12567

- 92 -

The present invention also provides a process for synthesizing a compound having the structure:

wherein X _a , X ₂ , and X ₃ are independently the same or different and are H, OR, O, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ s-; an _d R ₂ and R ₃ are independently the same or different an _d are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

which comprises:

(a) synthesizing a compound having the structure:

wherein X ₄ is H, OR, O, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R ₂ and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; according to the suitable process above;

and (b) contacting the compound formed in step (a) with a compound having the structure:

wherein X _λ , X ₂ , and X ₅ are independently the same or different and are H, OR, 0, -OCH ₂ CH ₂ o-, or -S _C H _2C H _2C H ₂ S-; and M is a metal; wherein R is H, acyl, alkyl, aryl, TB _S , TE _S TMS, or TBDPS; under suitable conditions to form a compoun _d having the structure:

In step (a) , the compound may be synthesized by the suita _b le process above or other processes determinable by those skilled in the art. In step (b) , the contacting is performed by nucleqphilic addition of the enol to the compound formed in step (a) .

The present invention also provides a process for synthesizing a compound having the structure:

wherein X _lf X ₂ , X ₃ , and X ₄ are independently the same or different and are H, OR, O, -OCH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R _χ , R ₂ , and R ₃ are independently the same or different and are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS;

which comprises:

(a) synthesizing a compound having the structure:

wherein X _1# χ ₂ , χ ₃ , and X ₄ are independently the same or different and are H, OR _r 0, -0CH ₂ CH ₂ 0-, or -SCH ₂ CH ₂ CH ₂ S-; and R ₂ and R ₃ are independently the same or different an _d are H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; wherein R is H, acyl, alkyl, aryl, TBS, TES, TMS, or TBDPS; according to the suitable processes above;

and (b) reacting the compound formed in step (a ₎ by reductive coupling to form the compound having the structure:

In step (a) , the compound may be synthesized by the suitable processes above or other processes determinable by those skilled in the art. In step (b) , the reacting is performed by reductive coupling using samariu (II) iodide or titanium(III) chloride.

The present invention also provides a process for synthesizing a compound having the structure:

which comprises:

(a) synthesizing a compound having the structure:

according to the suitable process above;

(b, treating the compound formed in _ste p _(a) under suitable cond ⁱ t ⁱ ons to form a compound having the structure:

(c) contacting the compound formed in step (b) with lithiodith ns to form a compound having the

(d) deketa in step _(c , under su ⁱ table conditions to form a compound having the structure:

(e) contacting the compound formed in step (d) with methoxyvinyllithiu under suitable conditions to form a compound having the structure:

(f) heating the compound formed in step (e) under suita _b le conditions to structure:

(g) reducing and esterifying the compound formed in step (f ₎ under suitable conditions to form a compound having the structure:

(h) oxidizing the compound formed in step (g) under suitable conditions to form a compound having the structure:

( i) removing the thioketal of the compound formed in step

th ⁾ un ^d er suitable conditions to form a compoun _d having t _h e structure:

⁽ j ⁾ treating the compound formed in step (i) un _d er suita _ble con ^d itions to form a compound having the structure:

⁽ k ⁾ treating the compound formed in step (j) un _d er suita _b le con ^d itions to form a compound having the structure:

and (1 ⁾ treating the compound formed in step ₍ k ₎ under suitable conditions to form the compound having the structure :

In step (a) , the compound may be synthesized by the suitable process above or other processes determinable by those skilled in the art. In step (b) , the treating comprises the selective ketalization of the less hindered aldehyde of step (a) . In step (c) , the contacting comprises the addition of lithiodithiane VII followed by Swern oxidation. m step (d), the contacting comprises deketalizing the compound formed in step (c) by the addition of acetone then PPTS. m step (e) , the compound formed in step (d) is contacted with vinyllithium. In step (f) , heating will cyclize the compound formed in step (e) to. the tricyclic compound _, m step (g), the compound formed in step (f) _is reduced by stereoselective reduction after benzoylation of the newly generated (α) secondary alcohol. In step (h) , the compound formed in step (g) is oxidized by Allylic oxidation, followed by Swern oxidation if necessary, in step (i) , the thioketal is removed by subsequent benzyl protection and Raney nickel reduction. In step (j), the treating comprises Franklin Davis hydroxylation of the potassium enolate of the compound formed in step (i) to give the corresponding hydroxyketone in which the oxaziridine approaches from the convex face. In step (k) , the treating comprises fluoride induced desilyation with TBAF, peracetylation, hydrogenolysis of the benzyl ether and subsequent side chain coupling. In step (1), the treating comprises selectively removing the acetate at C-7, which in turn is doubly deprotected by simultaneous removal of the MOM and EE groups to give taxol.

/12567

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The present invention provides a compound having the structure:

wherein X is 0, -OCH^O-, -SO^CI^S-, or -OCH^S-; wherein R ¹ is a linear or branched chain alkyl or arylalkyl group, or an aryl group; wherein R ² is a trimethylsilyl, triethylsilyl, or t-butyldimethylsilyl group, or a linear or branched chain alkyl group; and wherein R ³ is a linear or branched chain alkyl or alkylaryl group, or an aryl group.

The present invention also provides a compound having the structure:

wherein R is a trimethylsilyl, triethylsilyl, or t- butyldimethylsilyl group, or a linear or branched chain alkyl or arylalkyl group; wherein R ¹ is a linear or branched chain alkyl or arylalkyl group, or an aryl group; wherein R ² is a trimethylsilyl, triethylsilyl, or t-butyldimethylsilyl group, or a linear or branched chain alkyl group; and

/12567

- 100 - wherein R ³ is a linear or branched chain alkyl or alkylaryl group, or an aryl group.

The present invention further provides a compound having the structure:

wherein X is H, OH, a linear or branched acyl group, an aroyl group, Br, I, Cl, or F; wherein Y is O or S; wherein R is a trimethylsilyl, triethylsilyl, or t-butyldimethyl¬ silyl group, or a linear or branched chain alkyl or arylalkyl group; wherein R ¹ is a linear or branched chain alkyl or arylalkyl group, or an aryl group; wherein R ² is a trimethylsilyl, triethylsilyl, or t-butyldimethylsilyl group, or a linear or branched chain alkyl group; and wherein R ³ is a linear or branched chain alkyl or alkylaryl group, or an aryl group.

The present invention further provides a compound having the structure:

wherein X is OTf, Cl, Br, I, or F; wherein ϊ is o or S; wherein Z is H _j , 0, or S; wherein R ¹ is a linear or branched chain alkyl or arylalkyl group, or an aryl group; wherein R ² is a trimethylsilyl, triethylsilyl, or t-butyldimethylsilyl group, or a linear or branched chain alkyl group; and wherein R ³ is a linear or branched chain alkyl or alkylaryl group, or an aryl group.

The present invention also provides a compound having the structure:

wherein X is OTf, Cl, Br, I, or F; wherein Y is 0 or S; wherein R ¹ is a linear or branched chain alkyl or arylalkyl group, or an aryl group; wherein R ² is a trimethylsilyl, triethylsilyl, or t-butyldimethylsilyl group, or a linear or branched chain alkyl group; wherein R ³ is a linear or

12567

- 102 - branched chain alkyl or alkylaryl group, or an aryl group; and wherein R* is H, a linear or branched chain alkyloxyalkyl group, a linear or branched chain alkyl or arylalkyl group, or an aryl group.

The present invention further provides a compound having the structure:

wherein is CH _j , O or S; wherein Y is O or S; wherein R ¹ is a linear or branched chain alkyl or arylalkyl group, or an aryl group; wherein R ² is a trimethylsilyl, triethylsilyl, or t-butyldimethylsilyl group, or a linear or branched chain alkyl group; wherein R ³ is a linear or branched chain alkyl or alkylaryl group, or an aryl group; and wherein R* is H, a linear or branched chain alkyloxyalkyl group, a linear or branched chain alkyl or arylalkyl group, or an aryl group.

567

^■ 103 -

The present invention also provides a compound having the structure:

wherein X is CI^, 0 or S; wherein Y is O or S; wherein R ¹ is a linear or branched chain alkyl or arylalkyl group, or an aryl group; wherein R ² is a trimethylsilyl, triethylsilyl, or t-butyldimethylsilyl group, or a linear or branched chain alkyl group; wherein R ³ is a linear or branched chain alkyl or alkylaryl group, or an aryl group; wherein R* is H, a linear or branched chain alkyloxyalkyl group, a linear or branched chain alkyl or arylalkyl group, or an aryl group; and wherein R ⁵ is a linear or branched chain acyl group, or an aroyl group.

The present invention also provides a compound having the structure:

wherein X is CH ₂ ,,, 0,, S,, H ^« ,2,, Hn,. _O ^O HH, _a - lιi- _. n~ear or branched chain acyl group or a linear or branched chain alkoxy group- here ⁱ n R* _{is a} trimethylsilyl, triethylsilyl _r ' butyld ⁱ methylsilyl group, or a linear o _b ranche _d Iha n ^' alky group ^; an ^d wherein R ³ _{is a} li _near or _b ranche _d cha _in alkyl or alkylaryl group, or an aryl group.

The present invention provides a process for synthesizinα . compound having the structure: ^ ^h es ⁱ zmg a

which comprises (a) synthesizing a compound having the structure:

(b) treating the compound of steo „

— ⁱⁱ - to _te . _c∞pound S^^ T^

⁽ e ⁾ treating the compoun ^d formed in step ₍ d ₎ under suitable cond ⁱ t ⁱ ons to form a compound having the structure:

⁽ f ⁾ treating the compound formed in step (e ₎ under suita _b le con ^di t ⁱ ons to form a compound having the structure:

TttSO

⁽ g ⁾ reducing the compound formed in step ₍ f _{) mdGT suitable} cond ⁱ t ⁱ ons to form a compound having the structure:

(h) acetalizing the compound formed in step (g) under suitable conditions to form a compound having the structure:

(i) treating the compound formed in step (h) under suitable conditions to form a compound having the structure:

(j) treating the compound formed in step (i) under suitable conditions to form a compound having the structure:

(k) deacetalizing the compound of _ste p _{(j) uaάmr suitable} acidic conditions to form a compound having the structure:

(1) reacting the compound formed in step (k) with an organometallic compound having the structure:

wherein M is selected from a group consisting of Li, K, Cs, MgBr, and MgCl, under suitable conditions to form a compound having the structure:

(m) treating the compound of step (i) under suitable conditions to form a compound having the structure:

(n) dehalogenating the compound formed in step (1) under suitable conditions to form a compound having the structure:

(o) treating the compound of step (n) un _d er suitable conditions to form a compound having the structure:

(p) treating the compound formed in step (o) under suitable conditions to form a compound having the structure:

(q) oxidizing the compound formed in step (p) under suitable conditions to form a compound having the structure:

(r) contacting the compound formed by step (q) with a chiral reducing agent under suitable conditions to form a compound having the structure:

(s) reacting the compound formed in step (r) under suitable conditions to form a compound having the structure:

(t) cyclizing the compound of step (u) with an organometallic reagent under suitable conditions to form a compound having the structure:

(u) oxidizing the compound formed in step (t) under suitable conditions to form a compound having the structure:

(v) reducing the compound formedoin step (u) under suitable conditions to form a compound having the structure:

0

(w) acylating the compound formed in step (v) under suitable conditions to form a compound having the structure:

(x) hydrolyzing the compound formed in step (w) under suitable conditions to form a compound having the structure:

(y) benzoylating the compound formed in step (x) under suitable conditions to form the compound having the structure:

(z) reacting the compound formed in step (y) under suitable acidic conditions to form a compound having the structure:

(aa) esterifying the compound formed in step (z) with a compound having the structure:

Ph 0

Bz*

N OH H

OR wherein R is selected from a group consisting of trimethylsilyl, triethylsilyl, and t-butyldimethylsilyl, under suitable conditions to form the compound having the structure:

(bb) deprotecting the compound formed in step (aa) under suitable conditions to form a compound having the structure:

In one embodiment, the invention provides the process wherein M in step (1) is Li. in another embodiment, the invention provides the process wherein the organometallic

reagent of step (t) is a Pd(II) complex. In yet another embodiment, the invention provides the process wherein the Pd(II) complex is (PPh ₃ ) ₂ Pd(OAc) ₂ . In still another embodiment, the invention provides the process wherein R in step (aa) is triethylsilyl.

The preparation of the compound of step (a) has been described (Magee, T.V. , et al., J. Orσ. Che .. 57. 3274 (1992)). In step (b) the treating may be performed using a non-nucleophilic base such as potassium hydride followed by addition of benzyl bromide. In step (c) suitable conditions include a mild acid such as p-toluenesulfonic acid in the presence of water and acetone. In step (d) suitable conditions include trimethylsilyl triflate and a non- nucleophilic base such as triethylamine. In step (e) suitable conditions include palladium acetate in DMF. In step (f) suitable conditions include trimethylsilyl triflate and triethylamine. In step (g) suitable conditions include any reagent capable of cleaving double bonds to carbonyls, such as ozone. In step (h) suitable conditions include ethylene diol, p-toluene sulfonic acid, and triethyl orthoformate. In step (i) suitable conditions include a vinyl lithium or vinyl Grignard reagent. In step (j) suitable conditions include using a non-nucleophilic base such as potassium hydride followed by addition of benzyl bromide. In step (k) suitable acidic conditions are those typically used for hydrolysis of acetals, such as p- toluenesulfonic acid in acetone and water. In step (1) suitable conditions include use of a dipolar solvent such as THF at low temperatures, preferably at -78°C. In step (m) suitable conditions include use of n-butyl lithium and carbon dioxide, followed by treatment with iodine. In step (n) suitable conditions include use of dehalogenating conditions well known in the art, such as tributyltin hydride and a radical initiator such as AIBN. In step (o)

suitable conditions include use of potassium carbonate in methanol. In step (p) suitable conditions include potassium hexamethyldisilazide and phenyl amino triflate. In step (q) suitable conditions include a variety of oxidants such as chromium oxide. In step (r) suitable conditions for the stereospecific reduction is use of [RJ-CBS (R-1,3,2- oxazaborolidine) as described in Corey, E.J., et al., Tetrahedron Letters. 33, 4141 (1992) . In step (s) suitable conditions include use of methoxymethyl bromide and ethyldi- isopropylamine. Other ethers are known in the art and may be employed. In step (t) suitable conditions for Heck cyclization include use of a palladium salt, such as (PPh ₃ ) ₂ Pd(OAc) ₂ in the presence of triethylamine in THF. An alternative method is to use (Bu ₃ Sn) ₂ CuCNLi ₂ , followed by iodine treatment and then PPl^J _j Pd(OAc) ₂ . In step (u) suitable conditions include the use of ozone or another mild reagent for cleaving olefins. In step (v) suitable conditions include use of hydrogen gas in the presence of palladium on carbon. In step (w) acylation may be effected using acetic anhydride and acetyl chloride in the presence of pyridine. In step (x) suitable conditions for hydrolysis include use of water and pyridine. In step (y) suitable conditions for benzoylation include benzoyl chloride and triethylamine. In step (z) suitable conditions for deprotection include trifluoroacetic acid in dichloromethane. In step (aa) suitable conditions for esterification are well known in the art, and include use of a dehydrating agent such as diisopropylaminocarbodiimide. In step (bb) suitable conditions for deprotection include use of a fluoride salt such as tetrabutylammonium fluoride in THF.

The invention provides a compound having the structure:

wherein X is OTf, Cl, Br, I, or F; wherein Y is 0 or S; wherein Z is H _j , 0, or S; wherein R ² is a trimethylsilyl, triethylsilyl, or t-butyldimethylsilyl group, or a linear or branched chain alkyl group; and wherein R ³ is a linear or branched chain alkyl or alkylaryl group, or an aryl group.

The invention also provides a compound having the structure:

wherein X is H ₂ , O, or S; wherein Y is O or S; wherein R is a trimethylsilyl, triethylsilyl, or t-butyldimethylsilyl group, or a linear or branched chain alkyl or arylalkyl group; wherein R ² is a trimethylsilyl, triethylsilyl, or t- butyldimethylsilyl group, or a linear or branched chain alkyl group; and wherein R ³ is a linear or branched chain alkyl, arylalkyl or alkylaryl group, or an aryl group.

The invention further provides a compound having the structure:

OH wherein X is H ₂ , O, H, OH, OAe, or S; wherein Y is o or S; wherein R is a trimethylsilyl, triethylsilyl, or t-butyldi¬ methylsilyl group, or a linear or branched chain alkyl or arylalkyl group; wherein R ² is a trimethylsilyl, triethyl¬ silyl, or t-butyldimethylsilyl group, or a linear or branched chain alkyl group; and wherein R ³ is a linear or branched chain alkyl, arylalkyl or alkylaryl group, or an aryl group.

The invention provides a process for synthesizing a compound having the structure:

wherein X is O or S; wherein R ² is H, or a trimethylsilyl, triethylsilyl, or t-butyldimethylsilyl group, or a linear or branched chain alkyl group; and wherein R ³ is a linear or branched chain alkyl, acyl, arylalkyl or alkylaryl group, or

an aryl group, which comprises (a) synthesizing a compound having the structure:

as described hereinaboye; BnO

(b) treating the compound of step (a) under suitable conditions to form a compound having the structure:

(c) treating the compound formed in step (b) under suitable conditions to form a compound having the structure:

(d) reacting the compound formed in step (c) with a compound having the structure:

wherein M is selected from a group consisting of Li, K, _C s, MgBr, and MgCl, and R is selected from a group consisting of trimethylsilyl, triethylsilyl, and dimethyl-t-butylsilyl, linear or branched chain alkyl, arylalkyl, or aryl, under suitable conditions to form a compound having the structure:

(e) treating the compound formed in step (d) under suitable conditions to form a compound having the structure:

wherein X is selected from a group consisting of Br, I, Cl, and F;

(f) dehalogenating the compound formed in step (e) under suitable the structure:

0

(g) treating the compound formed in step (f) with a basic reagent under suitable conditions to form a compound having the structure:

(h) treating the compound formed in step (g) under suitable conditions to form a compound having the structure:

wherein X is selected from a group consisting of OTf Br Cl, I, and F;

⁽ i ⁾ oxidizing the compound formed in step (h ₎ un _d er suitable conditions to form a compound having the structure:

wherein X is selected from a group consisting of _O Tf, Br Cl, I, and F;

⁽ j ⁾ reducing the compound formed in step (i) under suitable conditions to form a compound having the structure:

wherein X is selected from a group consisting of _O Tf, Br Cl, I, and F;

⁽ k ⁾ treating the compound formed in step ₍ j ₎ under suitable conditions to form a compound having the structure:

wherein R is a linear or branched chain alkyl, alkoxyalkyl, or alkylaryl group, ^, or an aryl group; and wherein X is selected from a group consisting of OTf, Br, _C l, i, an _d F _;

⁽ 1 ⁾ reacting the compound of step (k) with an organometallic reagent under suitable conditions to form a compoun _d having the structure:

(m) oxidizing the compound formed in step (1) under suitable conditions to form a compound having the structure:

(n) reducing the compound of step (m) under suita _b le con ditions to form a compound having the structure:

⁽ o) acylating the compound formed in step (n) un _d er suita _b le conditions to form a compound having the structure:

⁽ p ⁾ hydrolyzing the compound of step (o ₎ un _d er suitable conditions to form a compound having the structure:

(q) benzoylating the compound formed in step (p) under suitable conditions to form a compound having the structure:

⁽ r ⁾ deprotecting the compound of step (q) under suita _b le conditions to form a compound having the structure:

(s) reacting the compound formed in step (r) with a compound having the structure:

H

OR wherein R is selected from a group consisting of trimethylsilyl , triethylsilyl , an _d t- butyldimethylsilyl,under suitable conditions to form a compound having the structure:

⁽ t ⁾ deprotecting the compound formed in step _(s) under suitable conditions to form a compound having the structure:

In one embodiment, the invention provides the process wherein R in step (d) is trimethylsilyl. m another embodiment, the invention provides the process wherein X in step ⁽ e ⁾ is I. In yet another embodiment, the invention provides the process wherein the basic reagent in step ₍ g ₎ is potassium car ^b onate. m another embodiment, the invention provides the process wherein X in step ₍ h ₎ is _O Tf. In another embodiment, the invention provides the process wherein the organometallic reagent in step ₍ 1 ₎ i _{s a Pd(} ii ₎ complex. In yet another embodiment, the invention provi _d es the process wherein the Pd(II) complex is (PPh^Pd _O Ac ₎ .

In step ⁽ b ⁾ suitable conditions include use of ittig or Peterson olefination conditions well known in the art. in step ⁽ c ⁾ suitable acidic conditions are those typically used for hydrolysis of acetals, such as p-toluenesulfonic acid in acetone an ^d water. In step (d) suitable conditions include use of a dipolar solvent such as THF at low temperatures prefera ^b ly at -7 ^8βC . m step (e) suitable con _d ition^ inclu ^d e use of n- ^b utyl lithium and carbon dioxide, followed by treatment with iodine or another halogen. in step (f ₎ suitable conditions include use of dehalogenating conditions well known in the art, such as tributyltin hydride and a radical initiator such as AIBN. m step ₍ g ₎ suitable conditions include use of potassium carbonate in methanol.

In step (h) suitable conditions inclu _d e potassium hexamethyldisilazide and phenyl amino triflate. in step ₍ i ₎ suitable conditions include a variety of oxidants such as chromium oxide. In step (j) suitable conditions for stereospecific reduction is use of [R _] - _C B _{S (} R- _{i 3} 2- oxazaborolidine) as described in Corey, E. _J . et a _l Tetrahedron Letters, 33_, 4141 (1992). In step ₍ k ₎ suita _b le conditions include use of methoxymethyl bromide an _d ethyldi- isopropylamine. Other ethers are known in the art and may be employed. In step (1) suitable conditions for Heck cyclization include use of a palladium salt, such as (PPh ₃ ) ₂ Pd(OAc) ₂ in the presence of triethylamine in THF. An alternative method is to use (Bu ₃ Sn) ₂ CuCNLi ₂ , followe _{d b} y io ^d ine treatment and then (PPh ₃ ) ₂ Pd(OAc) ₂ . in step ₍ m ₎ suitable conditions include the use of ozone or another mild reagent for cleaving olefins. in step ₍ n ₎ suitable conditions include use of hydrogen gas in the presence of palladium on carbon. In step (o) acylation may _b e effecte _d using acetic anhydride and acetyl chloride in the presence of pyridine. In step (p) suitable conditions for hy _d rolysis include use of water and pyridine. m step ₍ q ₎ suitable conditions for benzoylation include benzoyl chloride and triethylamine. In step (r) suitable conditions for ^d eprotection include trifluoroacetic acid in dichloromethane. In step (s) suitable conditions for esterification are well known in the art, and include use of a dehydrating agent such as diisopropylaminocarbodiimi _d e. In step (t) suitable conditions for deprotection include use of a fluoride salt such as tetrabutylammonium fluoride in THF.

The following Experimental Details Section is set forth to aid in an understanding of the invention. This section is not intended to, and should not be construe _d to, limi _t in any way the invention set forth in the claims which follow tthhperrMeaffrtoerr.

Egp«7»-imental Details Section

General Procedures

All air and moisture sensitive reactions were performed in a flame-dried apparatus under an argon atmosphere unless otherwise noted. Air sensitive liquids and solutions were transferred via syringe or canula. Whenever possible, reactions were monitored by thin-layer chromatography (TL _C) . Gross solvent removal was performed in vacuo under aspirator on a Buchi rotary evaporator, and traces of solvent were removed on a high vacuum oil pump (0.1-0.5 mmHg) .

Physical Pata

Melting points (mp) were uncorrected and performed in soft glass capillary tubes using a Electrothermal series I _A 9 ₁₀₀ digital melting point apparatus.

Infrared spectra (IR) were performed with a Perkin-Elmer 1600 series Fourier-Transform (FT) . Samples were prepared as neat films on NaCl plates unless otherwise noted. Absorption bands are reported in wavenumbers (cm ^-1 ) , and are described in abbreviations: s = strong; m - medium; w = weak; br = broad. Only relevant, assignable bands are reported.

Proton nuclear magnetic resonance ( ¹ H NMR) spectra were determined using a Bruker AMX-400 spectrometer at 40 ₀ MHz. Chemical shifts are reported in parts per million (d ₎ downfield from tetramethylsilane (TMS: d = 0) using residual CHC1 ₃ as a lock reference (d - 7.25). Resonances are presented in the following form: d in ppm (multiplicity, coupling constant = J, integral) . Multiplicities are abbreviated in the usual fashion: s = singlet; d = doublet; t =- triplet; q ^« quartet; m = multiplet; br = a descriptor for a multiplicity meaning broad.

- 131 -

Carbon nuclear magnetic resonance ( ¹³ c NMR) spectra were performed on a Bruker AMX-400 spectrometer at _l oo MHz with composite pulse decoupling. Samples were prepare _d as wit _h -H NMR and chemical shifts are reported in 8 re _l ative to TMS (8 = 0) ; the residual CHC1 ₃ was used as an internal reference (8 = 77.0).

All mass spectral analyses were performed at _C olum _b ia University at the Department of Chemistry. High resolution mass spectra (HRMS) were determined by electron impact ionization (El) on a JEOL JMS-DX 303HF mass spectrometer with perfluorokerosene (PFK) as an internal standard. Low resolution mass spectra (MS) were determined by either electron impact ionization (El) or chemical ionization ₍ Cl ₎ using the indicated carrier gas (NH ₃ or CH ₄₎ on a Delsi-Nermag R-10-10 mass spectrometer. For GCM _S , a DB-5 fused capillary column (30m, 0.25m thickness) was used with helium as the carrier gas. Typical conditions were a temperature program from 60°-250 ^β C at 40 ^β c/min.

Chromatoσraphv

Thin layer chromatography (TLC) was performed using precoated glass plates (silica gel 60, 0.25 mm thickness ₎ . Visualization was done by illumination with 254 nm _U V lamp, or by immersion in anisaldehyde stain (9.2 mL p-anisaldehyde in 3.5 mL HOAc, 12.5 L concentrated H ₂ S0 ₄ and 338 mL ₉ 5% EtOH) and heating to colorization.

Flash silica gel chromatography was carried out according to the protocol of Still (8) .

Solvents and Reagents

Unless otherwise noted, all solvents and reagents were commercial grade and were used as received from the suppliers indicated in the experiment ls. The following are

- 132 - exceptions, and all were distilled under Ar using the drying methods listed in parentheses: CH ₂ C1 ₂ (CaH ₂ ) ; PhH ₍ CaH ₂₎ ; THF (Na, PhCOPh as indicator); Et ₂ 0 (Na, Ph _CO Ph as indicator) ; diioprop lamine (CaH ₂ ) .

A solution of potassium bis(trimethylsilyl)amide (KHMDS, 12.9 g, 64.7 mmol, 1.5 eq) in tetrahydrofuran (anhydrous, 200 mL) was cooled to 0 ^# C under nitrogen using an ice-bath and was stirred for 15 minutes. To this solution was added

dropwise a solution of the known ketoketal 1 (9) (8.546 g, 43.16 mmol, 1.0 eq) in tetrahydrofuran (50 mL) and the mixture was stirred for 2 hours at o ^β C until no more precipitate appeared. Then N-phenyl trifluoromethane- sulfonimide (PhNTf ₂ , 25 g, 70 mmol, 1.62 eq) was added portionwise giving immediately a pale brown homogeneous solution. TLC (ethyl acetate/hexaneε, 1:4) showed total disappearance of the starting ketoketal and formation of a slightly less polar product as well as N-phenyl trifluoromethanesulfonamide (PhNHTf) , the by product derived from the imide. The solution was then warmed to room

^• temperature, diluted with ether (200 mL) and washed with brine (2 x 100 mL) . The aqueous layers were combined and washed with ether (2 x 200 mL) and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (600 L of silica gel, 40-65 μ, dichloro ethane/hexanes, 1:3) to give 11.73 g (82.4%) of the triflate 2 as a pale yellow oil.

'H NMR (CDC1 ₃ , 400MHZ): 8 3.99 (ε, 4H) , 2.22 (brt, J=6.5 Hz, 2H) , 1.80 (brt, J=6.5 HZ, 2H) , 1.78 (s, 3H) , 1.18 (s, 6H) .

¹³ C NMR, CDC1 ₃ , 8 17.42, 20.88, 26.56, 28.11, 44.48, 65.26, 111.42, 113.93, 117.10, 120.28, 123.45, 125.27, 146.77.

HRMS calcd. for C ₁₂ H ₁₇ 0 ₅ F ₃ S: 330.0749; found: 330.0735.

MS 41(38), 55(35), 69(30), 86(100), 165(56), 180(27), 330(10), 93(38), 99(41), 107(37), 137(25).

IR (neat, thin film, cm ^"1 ) 2989.1, 2950.8, 2888.5, 1689.9, 1471.2, 1454.6, 1402.3.

R _f = 0.56 (ethyl acetate/hexanes, 3:7).

Pre ^p arati ^p p f ^< ^ ^{iene 3t}

To a solution of triflate 2 (8.43 g, 25.54 mmol, 1 eq) , vinyltributylstannane (12.15 g, 11.2 mL, 38.32 mmol, 1.5 eq) and lithium chloride (anhydrous, 3.25 g, 76.64 mmol, 3 eq) in tetrahydrofuran (anhydrous, 150 mL) was added tetrakis(triphenylphosphine)palladium(0) (Pd(PPh ₃ ) _4# 1.48 g, 1.28 mmol, 5 mol%) and the green mixture was refluxed for 24 hours. The mixture was then cooled to room temperature. Work up A: the mixture was diluted with ethyl acetate (50 mL) and washed with brine (2 x 100 mL) . The aqueous layers were combined and extracted with ethyl acetate (3 x 50 mL) and the combined organic layers were dried over magnesium sulfate, filtered, concentrated under vacuum and purified by two successive silica gel chromatographies (each time 500 mL of silica gel, 40-65 μ, ether/hexanes, 5:95) to give 4.85 g (91.4%) of the diene 3 as a pale yellow oil. To avoid the second chromatography due to the presence of a large quantity of chlorotributylstannane, basic treatment was employed: work up B: the majority of the by-product was removed by adding l,8-diazabicyclo[5.4.0)undec-7-ene (DBU,

1.5 eq) after cooling the mixture to room temperature. It was then diluted with ether (600 mL) and washed with IN sodium hydroxide (3 x 150 mL) , brine (200 mL) , dried over magnesium sulfate , filtered and concentrated in vacuo . The residue was triturated with ether (3 x 100 mL) and the combined etheral layers were concentrated in vacuo and found to be devoid of tin by-products. Flash chromatography (same conditions) gave similar yield of diene 3.

^: H NMR (CDC1 ₃ , 400MHZ): 8 6.15 (m, 1H) , 5.27 (dd, J=11.2,

2.6 HZ,1H) , 4.99 (dd, J=17.6, 2.6 Hz, 1H) , 2.18 (m, 2H) , 1.78 (t, J=6.7, 2H) , 1.71 (d, J=0.9HZ, 3H) , 1.05 (s, 6H) .

¹³ C NMR, CDCI3, 8 20.92, 22.87, 26.70, 30.67, 42.04, 64.94, 112.08, 118.78, 126.98, 135.02, 137.46.

IR (neat, thin film, cm ^"1 ) 3078.0, 2976.0, 2878.7, 1621.5,

1469.8, 1451.7.

HRMS calcd. for C ₁₃ H ₂₀ O ₂ : 208.1463; found 208.1459.

MS 41(35) , 55(30) , 86(30) , 87(40) , 107(100) , 122(28) , 208(51) .

R _f = 0.45 (ethyl acetate/hexanes 1:4).

preparation of alco ol 4.

A three-necked 500 mL flask was charged with a solution of the diene 3 (23 mmol, 4.79 g) in anhydrous tetrahydrofuran ₍ 25 mL) , and then with a 9-borabicyclo[3,3.1)nonane (9-BBN, ₀ . ₅ M solution in tetrahydrofuran, 138.2 mL, 69.1 mmol, 3 eq ₎ and the mixture was immediately refluxed for 1.5 hours. TL _{C (} ethyl acetate/hexanes, 1:1) showed total disappearance of the starting material. The mixture was then cooled to room temperature and ethanol (40 mL) was added, followed by ₆ N sodium hydroxide (15 mL) , then dropwise 30% hydrogen peroxide (28 mL) , maintaining a gentle reflux. After one _h our, the mixture had cooled to room temperature, diluted with ether (100 mL) and washed with brine (2 x 200 mL) . The aqueous layers were back extracted with ether (3 x 100 mL) an _d t _h e combined organic layers were dried over magnesium sulfate, filtered and evaporated. Flash chromatography of the residue (silica gel, 40-65 μ, 600 mL, ethyl acetate/hexanes, 1:5, then 1:4, then 1:3, then 1:2) gave pure alcohol 4 (4.886 g, 93.9%) as a pale yellow oil.

-H NMR (CDC1 ₃ , 400MHz): 8 3.947-3.99 (m, 4H) , 3.609 (t, J=8 H _Z , 2H ₎ , ₃ .609 (t, J=8 HZ, 2H) , 2.345 (t, J=8 Hz, 2H) , 2.108 ₍ t, J« ₆ . ₆ HZ, 2H), 1.747 (t, J-6.7 Hz, 2H) , 1.677 (S,3H), 1.058 (S, 6H) .

¹³ _C NMR, CDC1 ₃ , 8 19.82, 22.72, 26.68, 30.60, 32.36, 40.09, ₆ 2.27, 64.84, 112.21, 128.43, 132.05.

IR (neat, thin film, cm ^"1 ) 3471.5, 2953.2, 2882.3, 1477.1, 1379.6, 1355.5, 1208.4, 1140.6, 1089.2, 1056.0, 949.7, 906.2.

HRMS Calcd. for C _α3 H ₂ 0 ₃ ^: 226.1569; found: 226.1568.

MS 43(76) , 55(39) , 86(100) , 87(75) , 97(28) , 107(28) , 125(26) , 196(20) , 226(15).

R _f = 0.43 (ethyl acetate:hexanes, 1:1).

Preparation of aldehyde 5.

A 50 mL round bottom flask was charged with 5 L of dichloromethane and 1 mL of a 2M solution of oxalyl chloride in dichloromethane (2 mmol, 2 eq) , and the solution was cooled to -60 ^β C. To this cooled solution was added dropwise dimethylsulfoxide (0.71 mL, 781 mg, 10 mmol, 5 eq) and the mixture was stirred 15 minutes at -60 ^C C. A solution of the alcohol 4 (226 mg, 1 mmol, 1 eq) in dichloromethane (2mL) was added dropwise, and the mixture was stirred at -60°C for 15 minutes. Triethylamine (1.4 mL, 1.012 g, 10 mmol, 5 eq) was added and the mixture was allowed to warm to room temperature before being diluted with water (10 mL) and ether (10 mL) . The aqueous phase was extracted with ether (10 mL) and the combined organic layers were washed with 0.1N hydrochloric acid (10 mL) , then brine (10 mL) , dried over magnesium sulfate, filtered and evaporated. Flash chromatography of the residue (silica gel, 40-65 μ, 100 mL, ether/hexanes 15:85) gave pure aldehyde 5 (210 mg) in 93.7% yield, as a pale yellow oil.

'H NMR (CDC1,, 400MHZ): 8 9.535 (t, J=2.4 Hz, 1H) , 3.948-4.031 (m, 4H) , 3.116 (brs, 2H) , 2.213 (t, J=6.6 Hz, 2H), 1.792 (t, J=6.6 Hz, 2H) , 1.622 (s, 3H) , 1.032 (s, 6H)

¹³ C NMR, CDC1 ₃ , 8 19.72, 22.38, 26.57, 30.70, 43.87, 64.79, 111.67, 127.80, 131.18, 200.65.

-137-

IR (neat, thin film, cm ^"1 ) 2883.1, 2717.3, 1722.1, 1472.2, 1427.2, 1380.5, 1357.1, 1327.3, 1306.4, 1208.5, 1141.0, 1086.7, 1056.4, 991.4, 949.9, 906.2.

HRMS Calcd. for C ₁₃ H ₀ O ₃ : 224.1412; found: 224.1393.

MS 41(26) , 73(20) , 86(85), 87(100) , 95(18) , 224(48) .

R _f = 0.75 (ethyl acetate/hexanes, 1:1) .

Preparation of alcohol 6.

A dry 100 mL flask equipped with stir bar was charged with a solution of aldehyde 5 (1.0 gm; 4.5 mmol) in tetrahydrofuran (25 mL) . The solution was cooled to 0 ^β C, and a solution of the grignard reagent derived from 2-bromopropene (0.64M in tetrahydrofuran; 7.7 mL, l.l eq.) was added dropwise over 5 minutes. When the addition was complete the mixture was stirred at 0 ^β C an additional 30 minutes and then at room temperature for 30 minutes. TLC (ethyl acetate/hexanes, 1:5) indicated that all the starting aldehyde (r _r =0.27) had been consumed, and showed the appearance of a new product (r _f =0.14). Saturated ammonium chloride (40 mL) was added, and the mixture partitioned between ethyl acetate (100 mL) and water (100 mL) . The aqueous phase was decanted and the organic phase washed with brine (2 x 100 mL) , dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. Purification of the residue by flash chromatography (150 mL of silica gel eluted with ethyl acetate/hexanes, 1:5) gave the allylic alcohol 6 (1.1 gm; 4.0 mmol; 89%) as a pale yellow oil.

-H NMR (CDC1 ₃ , 400MHZ): 8 5.00 (brs, 1H) , 4.81 (brε, 1H) ,

4.22 (dd, J=10.2, 3.6 Hz, 1H) , 3.92-4.02 (m, 4H) , 2.42 (dd, J=14.2, 10.2 HZ, 1H) , 2.08-2.32 (m, 4H) , 1.80 (s, 3H) ,

1.73-1.88 (m, 2H) , 1.72 (S, 3H) , 1.11 (s, 3H) , 1.10 (s, 3H) .

¹³ C NMR, CDCI3, 8 17.87, 20.59, 22.73, 22.61, 29.60, 30.79, 35.25, 43.18, 64.89, 74.45, 109.88, 112.31, 130.62, 132.34, 147.71.

IR (neat, thin film, cm ^"1 ) 3454.0, 2926.6, 1715.5, 1651.5, 1452.9, 1379.0, 1356.2, 1209.6, 1134.3, 1088.0, 1058.4, 991.6, 901.6.

HRMS Calcd for C ₁₆ H ₂₆ 0 ₃ : 266.1882; found: 266.1886.

MS 87(70), 99(46) , 109(23), 168(28) , 196(45) , 205(24) , 235(18), 249(100) , 266(4) , 267(34) .

R _f = 0.43 (ethyl acetate/hexanes, 1:1) .

P eparation of enone 7-

A 2M solution of oxalyl chloride in dichloromethane (170 μL, 0.34 mmol, 2 eq) in 1 mL of anhydrous dichloromethane were cooled under nitrogen to -60 ^β C. Dimethylsulfoxide (71 μl, 6 eq) was added, and after 15 minutes, a solution of the alcohol 6 (45 mg, 0.17 mmol, 1 eq) in dichloromethane (1 mL ₎ . After 30 minutes, triethylamine (0.5 mL, excess) was added, and the mixture was allowed to warm to room temperature. It was then diluted with ether and water (5 mL each) and the etheral layer was washed with 0.1 N hydrochloric acid (10 mL) . The aqueous phase was then extracted with ether (2 x 5 mL) and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated. Flash chromatography of the residue (100 mL of silica gel, 40-65 μ, ethyl acetate/hexanes, 1:4) gave 43 mg (96%) of the enone 7 as a pale yellow oil.

^: H NMR (CDCI3, 400MHz): 8 6.00 (brs, 1H) , 5.74 (brs, 1H) , 3.92-4.02 (m, 4H) , 3.47 (brs, 2H) , 2.20 (brt, J=6.4 Hz, 2H) ,

1.89 (s, 3H), 1.79 (t, J= 6.6 Hz, 2H) , 1.49 (s, 3H) , 0.97 (S, 6H).

¹³ _C NMR, CDCI ₃ , 8 17.94, 20.10, 22.53, 26.76, 30.55, 37.07, ₄ 2. ₉₀ , 64.88, 112.09, 123.27, 129.68, 130.07, 144.82, 199.04.

IR (neat, thin film, cm" ¹ ) 2926.5, 1686.1, 1452.0, 1336.0, 12 ₀ 8.5, 1130.1, 1088.6, 1063.6, 902.4.

HRMS Calcd for C ₁₆ H ₂₄ 0 ₃ : 264.1725; found: 264.1719.

MS 69(85), 86(100), 87(51), 99(25), 109(30), 135(25), 150(23), 163(18), 178(24), 221(16), 264(32).

R _f = 0.65 (ethyl acetate/hexanes, 1:1).

Preparation of adduct 8.

A solution of enone 7 (28 mg, 0.106 mmol) and diene (0.424 mmol, ₄ eq) in deuterated benzene (0.5 mL) was added into a _b ase washed sealable NMR tube. The extent of the reaction was monitored by studying the disappearance of the starting enone _b y NMR of the whole mixture. After 2.5 days at 125 ^» C, the pale brown solution did not contain any more starting material and showed a 2:1 ratio of 2 products. The mixture was evaporated to dryness and treated with a 0.1N hydrochloric acid/tetrahydrofuran mixture (1 mL, 1:4 vol) and stirred at room temperature for 30 minutes. The mixture was then poured into a saturated hydrogenocarbonate solution

₍ 5 mL ₎ and extracted with dichloromethane (3 x 10 mL) . The com _b ined organic layers were dried over magnesium sulfate, filtered and evaporated. Flash chromatography of the residue (100 mL of silica gel, ethyl acetate/hexanes, 1:2) gave 2 ₈ .5 mg of enone 8 (81%) as a pale yellow oil.

^: H NMR ₍ CDCI ₃ , 400MHz): 8 7.02 (dd, J= 10.2, 1.05 Hz, IH) , ₆ .05 ₍ d, J=10.2 HZ, IH) , 3.92-4.02 (m, 4H) , 3.31 (s, 2H) , 2.54 ₍ m, IH), 2.43 (m, 2H) , 2.20 (t,. J-6.6 Hz, 2H) , 1.91 (m, IH ₎ , 1.78 (t, J-6.6 HZ, 2H) , 1.43 (S, 3H) , 1.42 (s, 3H) , ₀ .94 (S, 3H), 0.93 (s, 3H) .

--C NMR, CDC1 ₃ , d 15.24, 19.96, 22.52, 25.24, 26.68, 30.54, 32.63, 34.79, 38.83, 42.80, 49.95, 64.91, 111.85, 128.60, 129.21, 130.44, 152.24, 198.43, 206.76.

IR (neat, thin film, cm ^"1 ) 2924.4, 1716.1, 1679.9, 1604.4, 1456.1, 1356.7, 1270.8, 1088.8, 1057.2.

MS 41(18) , 55(19) , 67(19), 79(22) , 81(41) , 86(100) , 87(53) , 109(80) , 110(93) , 121(40) , 137(70) , 195(32) , 223(40) , 289(23) , 332(92).

HRMS Calcd for C ₂₀ H ₂₈ O ₄ : 332.1988; found: 332.1960.

R _f = 0.36 (ethyl acetate/hexanes 1:1) .

Pre aration of triPP? ? ■

The ketal 8 (183 mg, 0.55 mmol) was stirred 3 hours at 45 ^β C in 4 mL of a 1:1 vol mixture of tetrahydrofuran and water in presence of p-toluenesulfonic acid (104 mg, 0.55 mmol). NMR analysis of aliquots allowed monitoring of the reaction. After three hours, all ^' the starting ketal has disappeared. The mixture was then diluted with ether (20 mL) , washed with sodium hydrogenocarbonate (sat. , 20 mL) . The aqueous layer was extracted with ether (20 mL) and the combined organic layers were washed with brine (20 mL) , dried over magnesium sulfate, filtered and evaporated, to give pure deketelized product 9 (141.4 mg, 89.1%) , as a colorless oil.

¹ H NMR (CDC1 ₃ , 400MHz) : 8 7.04 (dd, J=10.2, 1.2 Hz, IH) , 6.08 (d, J=10.2 HZ, IH) , 3.36 (brε, 2H) , 2.50-2.63 (m, 3H) ,

2.40-2.49 (m, 4H) , 1.96 (ddd, J=10.5, 13.2, 5.2 Hz, IH) ,

1.53 (s, 3H), 1.53 (s, 3H) , 1.45 (S, 3H) , 1.054 (S, 3H) , 1.047 (s, 3H) .

¹³ C NMR, CDC1 ₃ , 8 20.00, 24.13, 24.16, 25.06, 31.38, 32.47, 34.62, 35.80, 38.76, 47.28, 49.87, 128.61, 129.30, 131.64, 151.79, 198.07, 206.62, 214.11.

IR (thin film, cm ^'1 ) 2968.8, 2927.7, 2871.4, 1712.6, 1682.7,

1605.6, 1463.4, 1415.0, 1377.7, 1323.2, 1228.6, 1091.9,

1032.7, 1018.5, 807.1.

MS 41(28) , 43(19), 53(20), 55(18), 67(17) , 79(19) , 81(50) , 110(100) , 123(53) , 136(5), 151(8), 288(20) .

HRMS Calcd for C _lβ H ₂₄ 0 ₃ : 288.1725; found: 288.1716.

R _f = 0.36 (ethyl acetate/hexanes 1:1).

Preparation of Compound 10.

To a solution of enone 9 (45 mg, 0.156 mmol) in benzene

(anhydrous 2 mL) was added dropwise at room temperature l.l mL of a IM solution of diethylaluminium cyanide in toluene (7 eq) . After 10 minutes at room temperature, IN sodium hydroxide was added (5 mL) and the mixture was stirred vigorously. Dichloromethane (5 mL) was added, and the aqueous phase was extracted with more dichloromethane (5 mL) . The combined layers were washed with brine (10 mL) , dried over .magnesium ^' sulfate, filtered and evaporated. _C rude NMR showed a 3:1 ratio of 2 products as well as a small amount of remaining starting enone 9. Flash chromatography of the residue (50 mL of silica gel, 40-65μ, ethyl acetate/hexanes, 1:4-1:2) gave 3 fractions; starting enone 9 (9 mg, 20%) , and two cyanides, trans (9 mg, 19%) and cis (28 mg, 57%) by comparison to the methyl group. Based on starting material recovery, the yield of cyanides products is 96%.

-H NMR (CDC1 ₃ , 400MHZ): 8 3.50 (d, J=19.1 Hz, IH - AB system), 3.36 (d. J=19.1 Hz, IH - AB system), 3.06 (dd, J=15, ₁ 0 HZ, IH) , 2.99 (dd, J=10, 4.6, IH) , 2.68 (dd, J=15, 4.6 H _Z , IH), 2.61 (t, J=6.7 Hz, 2H) , 2.42-2.51 (m, 4H) , 2. ₃ 0-2.40 (m, IH) , 1.93-2.06 (m, IH) , 1.61 (s, 3H) , 1.59 (s, 3H) , 1.09 (s, 3H) , 1.08 (s, 3H) .

¹³ C NMR, CDCI ₃ , 8 20.16, 23.74, 24.22, 24.37, 31.47, 33.01, 35.88, 36.89, 37.12, 37.24, 40.04, 47.34, 49.39, 118.72, 12 ₈ .08, 132.32, 204.35, 207.14, 213.96.

IR (neat, thin film, cm ^"1 ) 2969.8, 2925.0, 2240.5, 1712.2, 1465.0, 1418.8, 1319.3, 1091.9, 1031.6, 1018.9, 916.1, 732.8.

MS 109(4), 123(9), 179(10), 273(15), 299(13), 315(27), 316(100), 317(17).

HRMS Calcd. for C ₁₉ H ₂₅ 0 ₃ N: 315.1835; found: 315.1818.

R _£ = 0.18 (ethyl acetate/hexanes 1:1) (trans isomer of 10 : 0.38)

Preparation of hvdroxy enone 11.

To a solution of potassium bis(trimethylsilyl)amide (KHMDS,

66 mg, 0.33 mmol, 3 eq) in tetrahydrofuran (anhydrous, 2mL) cooled to -78 ^β C under nitrogen, was added a solution of the enone 7 (29 mg, 0.11 mmol, 1 eq) in tetrahydrofuran (3 mL) . After 15 minutes, a solution of N-phenylsulfonyl phenyloxaziridine (86 mg, 0.33 mmol, 3 eq) was added to the green solution which was then decolored. The reaction was stirred 30 minutes .at -78 ^β C before being quenched with saturated solution of ammonium chloride (2 mL) and warmed to room temperature. The mixture was diluted with ether (10 mL) washed with brine (10 mL) , dried over magnesium sulfate, filtered and concentrated under reduce pressure. Flash chromatography of the residue (100 mL silica gel, 40-65 μ, ethyl acetate/hexanes, 1:2) gave 26.7 mg of the hydroxyenone 11 (87%).

-H NMR (CDCI ₃ , 400MHZ): 86.07 (s, IH) , 5.77 (brs, IH) , 5.08 (s, IH) , 4.15 (brs, IH) , 3.89-4.00 (m, 4H), 2.19 (t, J= 6.6 HZ, 2H) , 1.96 (d, J=0.7 Hz, 3H) , 1.68-1.86 (m, 2H) , 1.63 (s, 3H), 1.21 (s, 3H), 1.05 (s, 3H) .

¹³ C NMR, CDC1 _3> 8 18.83, 20.23, 22.98, 23.95, 26.54, 31.62, 43.74, 65.01, 74.56, 111.82, 125.95, 133.68, 135.87, 141.43, 204.31.

IR (neat, thin film, cm ^"1 ) 3447.1, 2884.8, 1664.0, 1067.4, 1571.0, 1451.4, 1376.5, 1298.2, 1208.8, 1162.5, 1136.6, 1087.3, 1058.9, 1034.0, 949.5.

MS 41(100), 43(32), 69(32), 86(58), 107(100), 121(70), 149(43), 167(35), 211(82), 252(3), 280(20).

HRMS Calcd for C ₁₆ H ₂ 0 ₄ : 280.1675; found: 280.1676.

R _f = 0.54 (ethyl acetate/hexanes, 1:1).

Preparation of compound 12.

The glassware was washed with IN sodium hydroxide, distilled water, and was then dried in the oven (140°C) . A sealable NMR tube containing a mixture of the enone 11 (23 mg, 0.082 mmol) andl-methoxy-3-trimethylsilyloxy-l,3-butadiene (0.424 mmol, 5.2 eq) in a solution of deuterated benzene was heated 3 hours at 140 ^β C. NMR analysis showed total disappearance of the starting enone, but no evidence of any Diels-Alder adducts were found in the spectrum. The mixture was then directly applied to a column of silica gel (50 mL, silica gel, 40-65 μ, ethyl acetate/hexanes, 1:4) and eluted with the same solvent to give 23 mg (80%) of enone 12 as a pale yellow oil.

-H NMR (CDC1 _3# 400MHz): 8 5.07 ( , IH) , 5.05 (m, IH) , 4.74 (s, IH) , 3.92-4.03 (m, 4H) , 2.11-2.27 ( , 2H) , 1.75-1.92 (m, 2H), 1.79 (s, 3H), 1.61 (s, 3H) , 1.21 (s, 3H) , 1.035 (ε, 3H) , 0.14 (s, 9H) .

¹³ C NMR, CDC1 ₃ , 8 0.03, 18.05, 21.33, 22.52, 24.53, 26.69, 30.37, 41.28, 65.13, 83.28, 111.43, 115.79, 130.44, 130.87, 143.02, 207.40.

IR (neat, thin film, cm ^"1 ) 2955.9, 1694.8, 1250.4, 1101.9, 889.0, 842.7.

MS 73(8) , 87(9), 137(19) , 181(22), 209(100) , 307(6) , 352(2) .

HRM _S Calcd for C ₁₉ H ₃₂ 0 ₄ Si: 352.2070; found: 352.2051.

R _f = 0.71 (ethy1 acetate/hexanes, 1:1).

Preparation of Compound- 13.

Dichloromethane (anhydrous, 2 mL) and oxalyl chloride (0.35 mL of a 2M solution in dichloromethane, 0.7 mmol, 2.3 eq) were cooled under nitrogen at -60 ^β C. Dimethylsulfoxide

(0.15 mL, 2.14 mmol, 7 eq) was then added slowly and after ₁ 5 minutes, a solution of the alcohol 11 (85 mg, 0.3 mmol, ₁ eq in dichloromethane, 2 mL) . After 30 minuteε at -60 ^β - -50 ^β C, triethylamine (1 ml, excess) was added, and the mixture was allowed to warm to room temperature. Ether (10 mL) and water (10 mL) were added and the organic phase was washed with 0.1N hydrochloric acid (10 mL) . The aqueous layers were combined and extracted with ether (2 x lOmL) . The combined organic layers were washed with brine (20 mL) , dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash chromatography of the residue (50 mL silica gel, 40--65 μ, ethyl acetate/hexanes 1:4) gave the dione 13 (58 mg, 69%) as a yellow oil.

-H NMR (CDC1 ₃ , 400MHZ): 8 6.20 (m, IH) , 6.10 (dq, J=0.7, 0.9 H _Z , IH) , 3.95-4.02 (m, 4H) , 2.30 (brt, J=6.7 Hz, 2H) , 1.94 (dd, J=1.4, 0.9 Hz, 3H) , 1.82 (t, J=6.7 Hz, 2H) , 1.67 (s, 3H) , 1.18 (s, 6H) .

¹³ C NMR, CDC1 ₃ , 8 17.18, 21.40, 22.88, 26.34, 31.67, 42.07, 65.10, 111.17, 131.23, 138.44, 139.54, 139.68, 193.76, 197.76.

IR ₍ neat, thin film, cm" ¹ ) 2980.0, 2957.7, 2883.8, 1668.7,

1454.4, 1378.0, 1259.9, 1213.0, 1137.4, 1110.6, 1042.9.

MS 41(88) , 43(28) , 45(30) , 67(32) , 69(30) , 87(29) , 137(50) , 181(30) , 209(100), 278(18).

HRMS Calcd for C ₁₆ H ₂₂ 0 ₄ : 278.1518; found: 278.1515.

R _f = 0.58 (ethyl acetate/hexanes 1:1).

Preparation of adduct 14.

In a base washed NMR tube with a screwable teflon joint, a solution of enone 13 (48 mg, 0.172 mmol) and diene (0.69 mmol, 4 eq) in deuterated benzene (0.5 mL) was heated at 80 ^# C. After 3 hours, NMR analysis showed that the reaction was complete. The solvent was evaporated and the residue was treated with C.1N hydrochloric acid/tetrahydrofuran (2 mL, 1:4 vol) for 30 minutes. The mixture was then poured into a saturated solution of sodium hydrogenocarbonate (20 mL) and extracted with dichloromethane (2 x 20 mL) . The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give enone 14 as a yellow oil (crude 95%) which showed satisfactory purity (NMR) .

-H NMR (CDCl _3f 400MHZ) : 8 7.27 (dd, J*=10.2, 1.2 Hz, IH) , 6.00 (d, J=10.2 HZ, IH) , 3.92-4.02 (m, 4H) , 2.60 (m, IH) ,

2.46 (m, 2H) , 2.25 (m, 2H) , 1.97 (dt, J=13.6, 8, 8 Hz, IH) ,

1.82 (m, 2H) , 1.55 (s, 3H) , 1.47 (s, 3H) , 1.09 (s, 3H) , 1.03 (s, 3H).

¹³ C NMR, CDC1 ₃ , 8 20.92, 22.25, 23.38, 25.22, 26.34, 30.66, 32.59, 34.38, 42.01, 47.98, 65.06, 65.11, 110.75, 129.32, 135.73, 136.37, 151.04, 196.32, 197.91, 198.14.

IR (neat, thin film, cm ^"1 ) 2922.9, 2852.6, 1684.9, 1456.0, 1380.1, 1228.1, 1137.1, 1103.1, 1049.1, 992.3, 825.2.

MS 41(20), 55(25), 67(28), 81(27), 86(23), 87(25), 95(20),

137 ( 40 ) , 181 ( 28 ) , 209 ( 100 ) , 346 ( 18 ) .

HRMS Calcd for C ₂₀ H ₂₆ 0 ₅ : 346.1780; found: 346.1792.

R _f = 0.40 (ethyl -acetate/hexanes, 1:1).

Preparation of- Compound 15.

The ketal 14 (56 mg, 0.16 mmol) was treated with p- toluenesulfonic acid (30 mg, 0.16 mmol) at 60°C for 21 hours in a tetrahydrofuran/water mixture (1:1 vol, 2 mL) and the reaction waε monitored by NMR analyεis of aliquots. The mixture waε then diluted with ether (10 mL) and poured into saturated hydrogenocarbonate (5 mL) . The aqueous layer was extracted with ether (10 mL) and the combined organic layers were washed with brine (10 mL) , dried over magnesium sulfate, filtered and evaporated. Flash chromatography of the residue (50 mL of silica gel 40-65 μ, ethyl acetate/hexanes 1:4) gave 2 fractions, remaining starting ketal (5 mg) and tetraone 15 (35.4 mg, 0.117 mmol, 73.3%, 79.4% based on starting material recovery) , as a yellow oil.

-H NMR (CDCl _3r 400MHZ) : 8 7.25 (dd, J=10.2, 1.1 Hz, IH) , 6.04 (d, J«=10.2 HZ, IH) , 2.58-2.68 (m, 3H) , 2.40-2.57 (m, 4H) , 2.02 (ddd, J=13.4, 10, 5.7 Hz, IH) , 1.60 (s, 3H) , 1.58 (s, 3H) , 1.23 (s, 3H) , 1.17 (s, 3H) .

¹³ C NMR, CDC1 ₃ , 8 21.47, 24.07, 25.02, 25.18, 31.29, 32.51, 34.34, 34.97, 46.07, 48.02, 129.61, 135.77, 138.37, 150.64, 195.04, 197.90, 198.13, 211.80.

IR (thin film, cm ^"1 ) 2971.6, 2930.1, 1680-1720, 1461.8, 1379.4, 1230.8, 1210.1, 1127.0, 1033.7, 874.5, 827.8, 803.6.

MS (CH ₄ ) 165(100) , 303(79), 304(20).

HRMS. Calcd for C ₁₈ H ₂₂ 0 ₄ : 302.1518; Calcd for M+H (C _1B H ₂₃ 0 ₄ ) : 303.1596. found: 303.1586.

R _f - 0.44 (ethyl acetate/hexanes, i:i).

preparation of Compound 16.

A 25 mL flask was charged with a solution of the alco _h ol ₄ (226 mg, 1 mmol) in dichloromethane (5 ml) , triethylamine (anhydrous, 121 mg, 1.2 eq) , 4-dimethylaminopyridine (12 mg, 0.1 eq) , and the mixture was cooled to 0°C under nitrogen. A solution of t-butylchlorodimethylsilane (166 mg, 1.1 eq) in dichloromethane (3 mL) was added, and the mixture was stirred for 1 hour at room temperature and was then washed with 5% sodium hydrogenocarbonate (10 mL) and brine (10 mL) . The aqueous layers were extracted with dichloromethane (10 mL) and the combined organic layers were dried over magnesium sulfate, filtered, and evaporated. Flash chromatography of the residue (100 mL, silica gel, 40-65 μ, 5% ether in hexanes) gave 16 (280 mg, 76% yield) as a clear oil.

^: H NMR (CDCI ₃ , 400MHZ) : 8 3.94-4.05 (m, 4H) , 3.61 (t, J=8.5 HZ, 2H) , 2.33 (t, J=8.5 Hz, 2H) , 2.12 (t, J=6.6 Hz, 2H) , 1.76 (t, J=6.6 HZ, 2H) , 1.69 (s, 3H) , 1.08 (s, 6H) , 0.93 (s, 9H) , 0.09 (S, 6H) .

¹³ C NMR, CDC1 ₃ ,8 -5.21, 18.32, 19.76, 22.60, 25.98, 26.67, 30.55, 32.87, 43.05,-62.74, 64.83, 112.11, 127.80, 132.44.

HRMS Calcd for C ₁₉ H ₃₆ 0 ₃ Si : 340.2434 ; found : 340.2447.

MS 73(50), 75(53), 86(50), 165(95), 197(100), 239(27), 283(25), 297(12), 325(10), 340(13).

IR (neat, thin film, cm ^"1 ) 2952.9, 1253.8, 1079.1, 835.5, 774.4.

R _f = 0.59 (ethyl acetate/hexanes 1:4)

pypparation of ΠOP? 7.

Chromium trioxide (275 mg, 2.76 mmol, 20 eq) was suspended in anhydrous dichloromethane (4 mL) and cooled to -23 ^β C (carbon tetrachloride/solid carbon dioxide bath) . After 10 minutes, 3 ,5-dimethylpyrazole (265 mg, 2.76 mmol, 20 eq) was added in one portion. The suspension then became a red-brown solution. After 20 minutes of stirring at -2 ^β C, a solu _t ion of the olefin 16 (47 mg, 0.13 mmol, l eq) in dichloromethane (3 mL) was added and the mixture was then stirred one hour between -20 and -10 ^β C. Sodium hydroxide of (6N, 1 mL) was added and the mixture was stirred 30 minutes at 0°C. After dilution with water and dichloromethane, the aqueous phase was re-extracted with dichloromethane (5 mL) and the combined organic layers were washed with 0.1N hydrochloric acid, then brine, and were then dried over magnesium sulfate. Filtration, evaporation, and flash chromatography (60 mL, silica gel, 40-65 μ, ethyl acetate/hexanes 1:4) gave 23.3 mg (48%) of enone 17 as a pale yellow oil.

^: H NMR (CDC1 ₃ , 400MHz): 8 3.93-4.03 (m, 4H) , 3.71 (t, J=8 HZ, 2H) , 2.74 (S, 2H) , 2.61 (t, J=8 Hz, 2H) , 1.85 (s, 3H) , 1.24 (s, 6H) , 0.92 (s, 9H) , 0.09 (s, 6H) .

¹³ C NMR, CDC1 ₃ , 8 -5.29, 11.94, 18.28, 21.72, 25.90, 34.52, 43.93, 45.78, 61.26, 65.23, 111.71, 131.73, 159.03, 196.57.

IR (neat, thin film, cm ^"1 ) 2928.0, 2881.6, 2856.1, 1673.3, 1611.4, 1471.7, 1335.1, 1252.3, 1130.9, 1073.7, 836.1, 776.5.

MS 43(26), 73(73), 75(70), 89(46), 179(78), 253(49), 268(100) , 297(20) , 354(4), 355(18).

HRMS Calcd for C ₁₉ H ₃₄ 0 ₄ Si: 354.2227; found: 354.2225.

R _f = 0.23 (ethyl acetate/hexanes, 1:4).

PropT_-n.fr.ion of compound ?.8.

The enone 17 (5.4 mg, 0.0153 mmol) was stirred in acetone (1 mL) in the presence of p-toluenesulfonic acid (19 mg, 0.1 mmol) and water (50 μl) • After 4 hours at room temperature, TLC showed that all the starting material has disappeared. T _h e mixture was then diluted with 2 mL of ether, washed with 2 L of saturated aqueous solution of sodium hydrogenocarbonate. The organic phase was then washed with 2 L of brine, dried over magnesium sulfate filtered and evaporate to give alcohol 18 (3 mg, 82%).

-H NMR (CDC1 ₃ , 400MHZ): 8 3.92-4.02 (m, 4H) , 3.77 (t, J=7.8 Hz, 2H), 2.73 (s, 2H), 2.65 (t, J=7.8 Hz, 2H) , 1.85 (ε, 3H) , 1.24 (S, 6H) .

MS (CH ₄ ) 87(58), 179(50), 211(20), 223(22), 241(M+l, 100) 269(M+l+28, 24), 281(M+l+40, 11).

HRMS Calcd for C ₁₃ H ₂₀ 0 ₄ : 240.1362; found: 240.1382.

Preparation of Com ^p ound 19.

Heating the ketal 4 (44 mg, 0.195 mmol) in 2 mL of a 1:1 ₍ vol) mixture of water and tetrahydrofuran at 45 ^β C gave, after dilution with ether, waεhing with εaturated sodium _h y _d rogenocarbonate then brine, drying over magnesium sulfate, filtration and evaporation, the pure ketone 19 as a colorless oil. TLC did not allow monitoring of the outcome of the reaction. NMR analysis of aliquots indicated that 2 hours were sufficient for completion of the hydrolysis which was quantitative.

-K NMR (CDC1 ₃ , 400MHZ^ : 8 3.64 (t, J=8.1 Hz, 2H) , 2.53 (t, J= ₇ H _Z , 2H) , 2.40 (t, J-8.1 Hz, 2H) , 2.35 (t, J«=7 Hz, 2H) , 2. ₀₈ ( _b rs, IH) , 1.76 (s, 3H), 1.18 (s, 6H) .

¹³ _C NMR, CDCI ₃ , 8 19.87, 24.54, 31.57, 32.45, 35.93, 47.82, ₆ 2.16, 129.70, 132.48, 215.34.

IR (neat, thin film, cm ^"1 ) 3409.7, 2969.5, 2929.3, 1712.2, 1471.1, 1446.0, 1378.3, 1357.6, 1039.5.

MS 41(45) , 55(40) , 81(56) , 96(42) , 107(44) , 124(100) , 137(18) , 149(20) , 182(30).

HR Calcd for C ₁₁ H ₁₈ 0 ₂ : 182.1307; found: 182.1318.

R _f = 0.43 (ethyl acetate/hexanes 1:1) .

Preparation of diol 20.

A solution of the diene 3 (214 mg, 1.03 mmol) and N-methylmorpholine-N-oxide (NMO, 127 mg, 1.08 mmol, 1.05 eq) was stirred in an acetone-water mixture (8:1 vol, 5 mL) while bubbling nitrogen through the solution. Then a 0.1M solution of osmium tetroxide in t-butanol (l mL, 0.1 mmol, 0.097 eq) was added and stirring and nitrogen bubbling was continued 3 hours until TLC (ethyl acetate/hexanes, 1:1 vol) showed total disappearance of the starting diene leading to a much more polar product. The reaction was then quenched with saturated sodium hydrogenosulfite (10 mL) then diluted with ethyl acetate (10 mL) and water (15 mL) . The agueouε phase was extracted (4 x 20 mL ethyl acetate) and the combined organic layers were dried over magnesium sulfate, filtered and evaporated to give quantitatively pure diol 20 which crystallized when refrigerated.

-H NMR (CDC1 ₃ , 400MHZ): 8 4.38 (dd, J=10, 3 Hz, IH) , 3.90-4.02 (m, 4H) , 3.88 (dd, J=11.7, 10 Hz, IH) , 3.51 (dd, J=11.7, 3 HZ, IH) , 3.45 (brs, 2H) , 1.92-2.23 (m, 2H) , 1.84 (ε, 3H) , 1.60-1.80 ( , 2H) , 1.18 (s,, 2H) , 1.02 (ε, 3H) .

¹³ C NMR, CDCl _3r 8 20.93, 21.50, 23.26, 26.34, 31.61 42.78, 64.73, 64.87, 65.60, 72.23, 111.87, 132.17, 135.12.

HRMS Calcd for C ₁₃ H ₂₂ 0 ₄ : 242.1518; found: 242.1518.

MS 86(100) , 87(62) , 107(25) , 125(44) , 150(18) , 167(15), 211(52), 212(38) , 242(15).

IR (Chloroform, cm ^"1 ) 3617, 3455.3, 2960.1, 2887.0, 1708.1, 1472.7, 1453.6, 1428.1, 1381.6, 1356.2, 1207.9, 1139.8,

1055.1.

R _f = 0.26 (ethyl acetate/hexanes, 1:1).

Melting point: 100-101 ^β C.

Preparation of aldehyde 21.

To a stirred solution of diol 20 (51 mg, 0.21 mmol) and

N-methylmorpholine-N-oxide (NMO, 27 mg, 0.23 mmol) was added molecular sieves (4 angstroms, powdered) and tetrapropylammoniu perruthenate (TPAP, 7.4 mg, 0.1 eq, 0.021 mmol). After 10 minutes, the green color turned to a grey-black color. The mixture was applied to a silica gel column (70 mL, silica gel, 40-65 μ, ethyl acetate/hexanes, 1:4) which was eluted with the same solvent to give 24.5 mg (56%) of the aldehyde 21.

-H NMR (CDC1 ₃ , 400MHz): 8 10.08 (ε, IH) , 3.99 (brs, 4H) , 2.40 (t, J=6.6 Hz, 2H) , 2.11 (ε, 3H) , 1.80 (t, J=6.6 Hz, 2H) , 1.26 (S, 6H) .

¹³ C NMR, CDC1 ₃ , 8 18.88, 21.83, 26.17, 33.62, 41.41, 65.67, 111.54, 139.30, 153.88, 192.00.

IR (neat, thin film, cm ^'1 ) 2883.0, 1725.8, 1673.6, 1614.0, 1463.9, 1379.0, 1266.5, 1210.4, 1144.7, 1096.3, 1050.9.

HRMS Calcd for C ₁₂ H ₁₈ 0 ₃ : 210.1256; found: 210.1253.

MS 49(100), 51(27), 83(20), 86(30), 87(40), 181(3), 182(3), 183(3), 209(3), 210(4), 211(5).

R _f = 0.70 (ethyl acetate/hexanes, 1:1).

Preparation of Compound 22.

To a room temperature solution of ketoketal l (9) ₍₃ . ₉₇₂ g, 20.06 mmol) in tetrahydrofuran (anhydrous, 50 mL) was a _dd e _d a solution of sodium acetylide in xylene and mineral _' oil (18% wt, 10.7 mL, d = 0.884, 35 mmol, 1.75 eq) and the mixture was stirred for 5 hours under nitrogen. It was then diluted with ether (100 mL) , washed with brine (3 x 1 ₀₀ mL ₎ . The aqueous layers were back extracted (3 x 100 mL of ether ₎ and the combined organic layers were dried over magnesium sulfate, filtered and evaporated. Flash chromatography of the residue (150 mL, silica gel, 40-65 μ, ethyl acetate/hexanes, 1:4) gave 3.365 g (74.9%) of white crystals of tertiary alcohol 22.

-E NMR (CDCI ₃ , 400MHZ): 8 3.89-4.03 ( , 4H) , 2.40 (s, IH ₎ , 1.93-2.04 (m, IH) , 1.78 (m, IH) , 1.39-1.58 (m, 3H) , 1.24 (ε, 3H) , 1.16 (S, 3H) , 1.12 (d, J=8.8 H∑, 3H) .

¹³ C NMR, CDCI ₃ , 8 16.25, 16.93, 22.15, 26.03, 29.81, 35.78, 45.51, 64.02, 65.48, 72.20, 78.23, 84.73, 112.51.

HRMS Calcd for C ₁₃ H ₂₀ O ₃ : 224.1412; found: 224.1409.

MS 53(38), 55(38), 86(20), 99(48) , 207(100), 224(16).

IR (Chloroform, cm ^"1 ) 3489.6, 3306.7, 2981.4, 2936.9, 2891.2, 1452.0, 1390.1, 1379.6.

R _f = 0.38 (ethyl acetate/hexanes, 1:4).

Melting point 107-108°C (hexanes) .

Prenaration of compound 23.

Chromium trioxide (1 g, 10 mmol, 20 eq) was suspended in dichloromethane (10 mL) and cooled to -23 ^β C. 3,5-Dimethyl- pyrazole (DMP, 0.96 g, 20 eq) was then added and the mixture was stirred 20 minutes at -23 ^β C. The enol triflate _{2 (16} 5 mg, 0.5 mmol) waε dissolved in dichloromethane (2 mL) and the solution was added to the red-brown solution of Crθ ₃ -DMP complex. After being stirred at room temperature, a pale new spot appeared on the TCL, but the mixture was mostly composed of the remaining triflate 2. No further disappearance of starting material was observed even after 2 days of reflux. The mixture was then cooled to room temperature; 3 mL of 6N sodium hydroxide was added and the mixture was stirred at 0 ^* C for 30 minutes. After dilution with water (20 mL) and dichloromethane (20 mL) , the aqueous phase was extracted with dichloromethane (20 mL) , and the combined organic layers were washed with 0.1N hydrochloric acid (2 x 20 mL) , brine (20 mL) , dried over magnesium sulfate, filtered and concentrated in vacuo . Flash chromatography (60 mL, silica gel, 40-65μ, ethyl acetate/hexaneε, 1:5) gave 2 fractionε, starting triflate (79 mg, 48%) and a fraction constituted with 2 products (62 mg, 36%) having one of them being the desired enone ₂ 3 constituting half of the fraction.

^: H NMR (CDC1 ₃ , 400MHZ): 8 3.95-4.04 (m, 4H) , 2.81 (s, 2H) , 1.91 (S, 3H) , 1.33 (s, 6H) .

HRMS Calcd for C ₁₂ H ₁₅ 0 ₆ F ₃ : 344.0541; found: 344.0512.

R _{ = 0.34 (ethyl acetate/hexanes, 1:4).

Preparation of envne 24.

A εolution of the triflate 2 (180 mg, 0.546 mmol), ethynyltributylstannane (1.092 mmol, 344 mg, 0.316 mL, 2 eq) , lithium chloride (anhydrous, 69 mg, 1.63 mmol, 3 eq) and tetrakis(triphenylphosphine) palladium(0) , (Pd(PPh ₃ ) ₄ ,

63 mg, 0.1 eq) in anhydrous THF (3 mL) was refluxed 1 day. After being cooled to room temperature, the mixture was diluted with ethyl acetate (30 mL) and washed with brine (2 x 50 mL) . The aqueous layer was extracted with ethyl acetate (2 x 30 mL) and the combined organic layers were dried over magnesium sulfate, filtered and evaporate _d . Flash chromatography of the reεidue (ioo ml, silica gel, 40-65 μ, 5% ether in hexanes) gave the enyne 24 as a pale yellow oil (77 mg, 69%) .

-H NMR (CDC1 ₃ , 400MHZ): 8 3.97 (brε, 4H) , 3.03 (ε, IH) , ₂ . ₂₃ (t, J=6.6 HZ, 2H) , 1.90 (ε, 3H) , 1.76 (t, J=6.6 Hz, ₂ H) , 1.16 (s, 6H) .

¹³ C NMR, CDCI ₃ , 8 22.00, 23.19, 26.62, 30.35, 41.69, 64. ₉₈ , 80.20, 81.76, 111.17, 125.60, 141.15.

HRMS Calcd for C ₁₃ H ₁₈ 0 ₂ : 206.1307; found: 206.1325.

MS 41(50), 42(50), 43(55), 49(76), 51(48), 86(100), 87(25), 105(29), 119(24), 134(26), 163(12), 206(24).

IR (neat, thin film, cm ^"1 ) 3302.9, 2978.4, 1466.9, 1380. ₈ , 1356.5, 1212.0, 1143.8, 1085.8, 1057.6, 992.0, 949.0, 907.2.

R _£ - 0.59 (ethyl acetate/hexanes, 1:4)

General procedure for Nozaki-Kishi couplings. Preparation of allylic alcohols 25. 26. 27 and 29 and enones 28 and 30. To a IM solution of anhydrous chromium chloride (4-6 eq.) containing 0.1% (wt) of nickel chloride in anhydrous dimethylformamide, waε added a IM solution of either aldehyde 5 or benzaldehyde (1 eq.) and the iodoolefin (2-3eq.) in anhydrous dimethylformamide. Reactions involving £-iodocrotonitrile had to be heated at 80 ^β c while methyl £-iodocrotonate reacted at room temperature. After 12 to 1 ₆ hours, water was added and the mixture was extracted with

ether. After washings with water and brine, drying over magnesium sulfate and evaporation of the solvent, flash chromatography (ethyl acetate/hexanes, 1:2) gave allylic alcohols 25 (25), 26, 27 and 29 in 59 to 66% yield.

Regular Swern oxidation (oxalyl chloride, dimethylεulfoxide, triethylamine, dichloromethane) of allylic alcohols 27 and 29 gave enones 28 and 30 respectively in 82% and 88% yield after flash chromatography (ethyl acetate/hexanes, 1:4).

Data for allvlic alcohol 25 (2~ ..

^: H NMR, 400 MHz, CDC1 ₃ , TMS, d 1.86 (s, 3H) , 5.12 (s, IH) ,

5.81 (brs, IH) , 7.27-7.40 (m, 5H) .

¹³ C NMR, CDC1 ₃ , 8 17.92, 76.97, 94.87, 117.03, 126.88, 128.89, 128.97, 139.76, 164.01.

IR (neat, thin film) 3443.3, 3064.2, 3030.5, 2920.8, 2856.1, 2220.7, 1633.3, 1493.9, 1061.4, 1019.4.

MS 51(40), 68(53), 77(86), 79(61), 105(59), 107(42), 130(36), 144(22), 158(26), 172(30), 173(100).

HRMS Cacd. for C ₁₂ H ₁₁ ON: 173.0841; found: 173.0838.

R _f ■ 0.5 (ethyl acetate/hexanes, 1:1).

Data for allvlic alcohol 26.

- NMR, 400 MHZ, CDC1 ₃ , TMS, 8 1.97 (d, J = l.l Hz, 3H) , 3.71 (S, 3H), 5.11 (s, IH) , 6.26 (rs, IH) , 7.31-7.35 (m, 5H) .

¹³ C NMR, CDCI3, 8 15.52, 51.05, 78.38, 114.63, 126.89, 128.30, 128.67, 140.63, 158.75, 167.30.

IR (neat, thin film) 3463.9, 3028.4, 2949.6, 1718.9, 1653.9, 1493.3, 1435.6, 1219.6, 1150.2.

MS 69(15), 85(16) , 101(100) ι ~~ _{t t n \} ' ¹² 9 ⁽ 20), 145(21) , 188(15), 206(10) .

HRMS Cacd. for C ₁₂ H ₁₄ 0 ₃ : 206.0943; found: 20 ₆ .0941.

R _f = 0.53 (ethyl acetate/hexanes, l:i ₎ .

Data for allylic alcohol 27.

-H NMR ⁽ CDC1 ₃ , 400MHZ ⁾ : 8 5.60 (brs, IH) , 4.23 (dd, J=10.2, 4.1 HZ, IH), 3.91-4.01 (m, 4H) , 2.11-2.47 (m, 5H) , 2.08 (d, J= 0.8 H ^Z , 3H), 1.72-1.86 (m, 2H) , 1.68 (s, 3H) , 1.10 ₍ s,' 3H) , 1.08 (s, 3H) .

13C NMR, CDC1 ₃ , 8 17.63, 20.68, 22.57, 23.94, 26.55, 30.83, 34.83, 43.22, 64.99, 65.04, 72.78, 93.92, 112.13, 117.29,' 130.95, 132.84, 165.58.

IR ⁽ neat, thin film) 3461.6, 2956.5, 2884.1, 2218.0, 1632.9, 1475.9, 1442.8, 1381.2, 1356.3, 1210.2, 1134.1, 1088.3,' 1058.0.

MS 86(100), 109(40), 168(22), 196(60), 276(6), 291 ₍ 8)

HRMS Cacd. for C ₁₇ H ₂₅ 0 ₃ N: 291.1835; found: 291.1812.

R _f = 0.54 (ethyl acetate/hexaneε, 1:1).

Data for allylic alcohol 29.

-H NMR (CDC1 ₃ , 400MHZ) : 8 6.04 (brε, IH) , 4.25 (dd, J=9.9, 4.6 HZ, IH), 3.93-4.01 ( , 4H) , 3.71 (ε, 3H) , 2.11-2.47 (m, 5H), 2.19 (S, 3H), 1.73-1.86 (m, 2H) , 1.71 (s, 3H) , 1.11 (ε, 3H) , 1.10 (S, 3H) .

13C NMR, CDC1 ₃ , 8 15.20, 20.71, 22.82, 23.82, 26.64, 30.91, 35.14, 43.28, 50.92, 65.00, 65.04, 74.75, 112.23, 113.58, 131.59, 132.10, 160.68, 167.49.

IR (neat, thin film) 3455.9, 2951.0, 1717.7, 1650.I, i43 _{4 2} 1380.5, 1355.0, 1218.4, 1147.3, 1087.8, 1057.5.

MS 86(87), 87(86), 109(58) , 134(41) , 168(61) , 196 ₍ 100 ₎ 293(28), 324(17).

HRMS Cacd . for C ₁₈ H ₂₈ 0 ₅ : 324 . 1937 ; found : 324 . 1929 .

R _f = 0.56 ( ethyl acetate/hexanes , 1 : 1) .

Data for enone 28 . ^l H NMR (CDC1 ₃ , 400MHZ): 8 6.17 (q, J.I.J. _H z, IH) , 3.92-4.01 (a, 4H), 3.42 (s, 2H), 2.25 (d, J=l.i Hz, 3H) , 2.21 ₍ t, J=6.7 HZ, 2H), 1.79 (t, J-6.7 Hz, 2H) , 1.48 (s,' ₃ H), 0.95 (ε, 6H) .

13C NMR, CDC1 ₃ , 8 16.90, 20.16, 22.55, 26.64, 30.54, 38.23, 42.88, 64.95, 105.4, 111.74, 115.60, 128.77, 130.92, 156.41,' 196.39.

IR (neat, thin film) 2964.0, 2884.2, 2220.4, 1694.3, 1609.6, 1471.8, 1359.5, 1209.9, 1143.0, 1130.8, 1088.4, 1080.4.

MS 66(48), 86(100), 87(83), 94(58), 99(90). 109(93), 190(67), 203(22), 246(21), 289(100).

HRMS Calcd. for C ₁₇ H ₂₃ 0 ₃ N: 289.1678; found: 289.4692

Rf - 0.72 (ethyl acetate/hexaneε, 1:1).

Data for enone 30.

-H NMR (CDCI3, 400MHZ): 8 6.58 (q, J-1.4 Hz, IH) , 3.94-4.04 (m, 4H), 3.80 (S, 3H), 3.46 (s, 2H) , 2.27 (d, J-1.4 Hz, 3H) , 2.21 (t, J-6.6 HZ, 2H) , 1.79 (t, J=6.6 Hz, 2H) , 1.48 (s,' 3H) , 0.95 (S, 6H) .

¹³ C NMR, CDCI ₃ , 8 13.88, 20.14, 22.54, 26.72, ₃₀ .55, 38.07, 42.93, 51.74, 64.94, 111.92, 123.81, 129.39, 1 ₃₀ .7 ₇ , 151.60, 166.67, 199.51.

IR (neat, thin film) 2951.5, 2883.0, 1726.5, 169 ₂ . ₅ , ₁₆₃₉ . ₉ , 1435.1, 1356.1, 1216.0, 1087.9, 1060.0.

MS 86(100), 87(40), 99(43), 109(40), 127(42), 22 ₃₍ 42 ₎ , 236(20), 279(12), 322(30).

HRMS Calc. for C ₁₈ H ₂₆ 0 ₅ : 322.1780; found: ₃₂ 2. ₁₇₇₉ .

Rf = 0.82 (ethyl acetate/hexanes, 1:1).

Discussion

A retrosynthetic analysis of taxol 1 total synthesiε given in Figure 1 involves the following key steps:

1. Formation of the B-ring is achieved through an intra _¬ molecular ketyl radical cyclization of II. This cyclization might be asεisted by cyclic reductive protection of the o-dione (C ₉ -C ₁₀ , numbering refers to taxol structure ₎ , deprotection of which would lead to the hydroxy ketone functionality needed in the target.

2. Construction of the D-ring involves an intramolecular oxetane formation via the triol (ii, 12) which can be obtained from III through an elimination - re _d uction process.

3. Formation of the C-ring is achieved by the Diels-Alder reaction between dienophile IV and diene V. The regioselectivity of the cycloaddition is controlled by the carbonyl group at C ₉ on the dienophile and both oxygenated functions of the diene.

4. Dienophile IV is o ^b tained via Nozaki-Kishi ₍ 1 ₃ 14 coupling of io ^d oolefin vτi and aldehyde vi _f ollowe _d b oxidation.

5. Preparation of aldehyde VI involves palla _d ium ₍₀₎ catalyzed coupling ⁽ 15 ⁾ of vinyltributylstannane _and triflate VTII prepared from the known ketotetal ix _(i6) .

In the context of this general scheme, the following steps are set forth in Figures 2-5:

1. A-ring synthesis and extension to the aldehyde _{5 (C} f. Figure 2) .

2. Preparation of the dienophile 7, Diels-Alder reaction with model four-carbon diene l-methoxy-3-trimethylsilyloxy- 1,3-butadiene (Danishefsky's diene) , and Michael addition of a cyano fragment onto the enone function of the adduct ₍ cf. Figure 2) .

3. Further oxidation of dienophile 7 leading to dione 1 ₃ and Diels-Alder reaction with model four-carbon diene ₍ cf . Figure 3) .

4. Allylic oxidation of A-ring (preparation of compoun _d s 17 and 23, cf. Figure 4).

5. Deketalization of A-ring (preparation of compound ₁₉ , cf . Figure 4) .

6. Preparation of aldehyde 21 and acetylenic compounds 2 ₂ and 24 which may be valuable intermediates in other synthetic schemes toward taxol ( cf . Figure ₄ ).

7. Extension of aldehyde 5 to the trisubstituted dienophiles 28 and 30 ( cf . Figure 5).

Results

The first important intermediate is the alde _h yde _{5 (} cf. Figure 6) which contains all the functionalities neede _d in the A-ring except the oxygen atom at C-13 which can _b e introduced later through an allylic oxidation process (vi _d e infra) . Treatment of the known ketoketal l (16) with potassium bis(trimethylsilyl) mide and N-phenyl trifluoromethanesulfoni ide gave the enol triflate _{2 (} 82% ₎ which reacted with vinyltributylstannane under palladium ₍₀₎ catalysis (15) leading to the diene 3 in 91% yield. Hydroboration of diene 3 (9-borabicyclo[3.3.l)nonane, 9 ₄ % ₎ gave alcohol 4 which was oxidized (Swern, 94%) to the aldehyde 5. TPAP oxidation (17) of 4 gave 5 in only 71% yield.

In order to study the Diels-Alder reaction for the construction of the C-ring, aldehyde 5 was extended to the disubstituted dienophile 7 (cf. Figure 7) . Grignard derivative of 2-bromopropene addition onto aldehyde 5 gave the allylic alcohol 6 (89%) . Addition of either the lithio or the cerio derivative gave 6 in low yields. Swern oxidation of the alcohol 6 gave the enone 7 in 96% yield.

Cycloaddition of 7 with l-methoxy-3-trimethylsilyloxy- 1,3-butadiene (Danishefky's diene) (18) in benzene (2.5 days, 125*C) gave after acidic work-up the enone 8 (81%) which was deketalized (p-toluenesulfonic acid, tetrahydrofuran, water, 89%) to the ene trione 9. Hydrocyanation of the enone functionality of 9 with diethylaluminium cyanide (19) gave, besides a small amount cf starting material, the desired cis cyanoketone 10 and its trans isomer in a 3:1 ratio in a 96% overall yield. Compound 10 contains 19 out of the 20 carbon atomε of the target. Trapping of the enolate during the Michael addition of the cyanide anion by a carbon electrophile might be an alternative to the use of a five-carbon diene for the

introduction of the carbon atom at position 2 ₀ .

Introduction of the oxygen atom at C-10 was trie _d startin _g from diene 3 after bis-hydroxylation to diol 20 (vi _d e infra ₎ without success. Attempted selective oxidation un _d er regular or modified Swern conditions (oxalyl chloride or trifluoroacetic anhydride, addition of triethylamine at various temperatures) (20, 21) gave the undesired hy _d roxy ketone. This lead us to study the oxidation of the enone ₇ .

Treatment of the enone 7 with potassium bis(trimethylsilyl)- amide and N-(phenylsulfonyl) phenyloxaziridine (22, 23) gave the hydroxy ketone 11 (87%) which did not cyclize ₍ cf . Figure 8) with l-methoxy-3- trimethylsilyloxy-l,3-butadiene (Danishefky ¹ s diene) (18) but lead to the transpose _d silylated hydroxy ketone 12 (80%) . Further oxidation of the hydroxy ketone 11 (Swern, 69%) gave the α-dione 1 ₃ which showed a much higher reactivity toward the same diene as above, giving in only 3 hrε at 80°C and after acidic work-up the adduct 14 in 95% yield. Deketalization of trione 1 ₄ gave the tetraone 15 (p-tolueneεulfonic acid, tetrahydrofuran, water, 79%) .

Unfortunately, the α-dione functionality did not survive an attempted hydrocyanation of compound 15. Protection of the hydroxy ketone 11 with t-butyldimethylsilyl group gave a dienophile which showed a much lower reactivity than the simple enone 7. Thus, we studied the extension of the aldehyde 5 to trisubεtituted dienophiles. Since the Nozaki-Kishi coupling (13, 14) of iodocrotonitrile or iodocrotonate had never been described, a preliminary study of this chromium chloride promoted reaction catalyzed _b y nickel chloride was done with benzaldehyde (cf. Figure 9 ₎ , giving allylic alcohols 25 and 26 is about 70% yield. Thiε coupling iε a new route for the preparation of γ-hydroxy-α,β-unsaturated esters and nitriles (24, 25 ₎ .

Allylic alcoholε 27 and 29 were obtained in comparable yield

from aldehyde 5. These compounds were then oxidized to the enoneε 28 and 30 respectively in 82% and 88% yield. We are currently studying the behavior of these enones in Diels-Alder reactions as well as the further oxidation to the correεponding dioneε.

Besides the straightforward route to taxol skeleton described to this point, various functionalizations in which the most important is the allylic oxidation of the A-ring have been achieved. The presence of the side chain at position 13 is known to be indispensable for any biological activity. A model reaction has been studied on the protecte _d alcohol 16.

Alcohol ⁴ was silylated (t-butylchlorodimethylεilane, triethylamine, 76%) to compound 16 which was oxidized to the enone 17 (48%) by action of the complex formed with chromium trioxide and 3,5-diroethylpyrazole (10, 26) . Deεilylation of the enone 17 (p-toluenesulfonic acid, acetone, water, ₈ 2% ₎ gave the hydroxy enone 18 . The same conditionε as above for the allylic oxidation of 16 were applied to the enol triflate 2 which gave compound 23 in 37% yield (cf. Figure 10) .

The ketal on A-ring showing fairly strong resistance to weak acids, a model reaction for the deketalization was studie _d on alcohol 4 which upon treatment with p-toluenesulfonic acid (tetrahydrofuran, water) gave the hydroxy ketone ₁₉ in quantitative yield ( cf. Figure 11).

In order to obtain intermediates similar to aldehyde 5 but containing an extra oxygen atom at C-10, bis-hydroxylation of the diene 3 (catalytic osmium tetroxide, N-methyl morpholine N-oxide, 98%) gave diol 20. Attempted selective oxidation of this diol was unsuccessful either under _S wern conditions (vide supra) either upon treatment with catalytic tetrapropylammonium perruthenate (17) and N-methyl

morpholine N-oxide. In the later case, cleavage of the dioi waε observed giving aldehyde 21 i _n 56% yield ₍ cf Fi ¬ ll) . ^{* 19αre}

Finally, in or ^d er to study how various acetylenic intermediates could be linked to an preforme _d A-ring, t _h e two following reactions were achieved. Addition of so _d ium acetylide to the ketoketal 1 gave the tertiary alcohol ₂₂ in ⁷ 5% yield. Eneyne 24 was obtained in 69% yiel _d from the enol triflate ² via palladium (0) catalyzed coupling with ethynyltributylstannane (15).

Total S ^y nthesis of Taxol as n pj-ted in _F i _rr _ _.r o - -

^S ummary: The strategy of the total synthesis of taxol ^d epicted in Figure 12 is based on the following key steps or sequences.

1. Extension of the ketoketal 1 to the aldehyde 34 correctly oxidized at c-13, and further extension to the α-diketo dienophile 39.

2. Diels-Alder between 39 and diene ₄₀ .

3. Intramolecular pinacolic coupling of ₄₄ giving ₄ 5, containing the ABC subskeleton of taxol.

4. Elaboration of the triol 50 and its conversion to the hydroxy oxetane 51 (11,12).

Potassium enolate of ketoketal l was treated with N-Phenyl trifluoromethane sulfonimide to give the enol triflate ₂ which was coupled under palladium (0) catalysis with vinyl- tri-n-butylstannane leading to diene 3. Hydroboration of 3 with 9-BBN gives after basic hydroperoxide work-up the alcohol 4 which upon treatment with TBDMSC1 is converted to the protected alcohol 16. Chromium trioxide complex with

3,5-dimethylpyrazole mediated allylic oxidation of 1 ₆ gives enone 17 which is reduced with borane in the presence of catalytic amount of chiral oxazoborolidine to give the allylic alcohol 31. Protection of the alcohol function of ³¹ with a TBDMS group followed by selective desilyation o _f the primary hydroxyl gives alcohol 33 which is oxidize _d to the aldehyde ³ 4. Nickel chloride catalyzed chromium chloride promoted coupling of vinyl iodide 35 with aldehyde ³⁴ affordε the allylic alcohol 36 which is oxidize _d to the enone 37 and further oxidized to the diketo dienophile ₃₉ . Diels-Alder cycloaddition of 39 with diene ₄₀ followe _d by acidic work-up yields adduct 41 in which the primary εilyi ether iε selectively cleaved affording alcohol ₄₂ . Alternatively, fluoride mediated work-up of the Diels-Alder reaction between 39 and 40 produces 42 directly. _O xidation of ⁴² to the aldehyde 43 followed by ύeketalizaton affordε ⁴⁴ in which the TBDMS ether is concomitantly removed. ^S amarium diiodide promoted intramolecular coupling is asεisted by both the presence of the free hydroxyl group at ^C -1 ^{3 (} numbering refers to the taxol skeleton) an _d the cyclic enediolate samarium species formed by complexation of the diketo system at C-9,10 with excess reagent. Concomitantly, the ketone at C-5 is also reduced leading to 45. _S equential selective protection of the hydroxyl groups of 45 at c-1 ₀ c-l (temporary) and. C-13, leads to triol ₄ 6 which upon oxidation produces 47. Stereoselective α-hydroxy directe _d reduction of the ketone at C-2 of 47 leads to ₄₈ which is sequentially protected to give 49. Reduction at _C -5, oxidation of the sulfide at C-20 to the sulfoxide and its elimination upon heating, followed by the osmium tetroxide catalyzed bis-hydroxylation of the intermediate allylic alcohol produces the triol 50. Accordingly to the known procedures (11,12), 50 is converted to the hydroxy oxetane 51 in which the free hydroxyl group at c-13 is released after acetylation of the tertiary alcohol at c-4 and desilylation. Side chain attachment according to known protocols followed by sequential selective deprotection of

hydroxyl groups at C-l and C-7 produces taxol.

Route 2 Synthesis

Synthesis of Compound 55.

The alcohol 54 (33) (13.0 g, 58.0 mmol) was disso _l ve _d in anhydrous CH ₂ C1 ₂ (80 mL) and the resulting solution coole _d to 0 ^β C, whereupon 2,6-lutidine (19.o mL, 17.5g, 1 ₆₃ mmol ₎ waε added followed by dropwise addition of tert-butyldimethylsilyl trifluoromethanesulfonate (l7.0mL, 19.6g, 74.0 mmol) . The solution was maintained at 0 ^# C for 30 minutes before addition of H ₂ 0 (100 mL) , and the mixture allowed to come to room temperature. The layers were separated and the aqueous phase repeatedly extracte _d with CH ₂ C1 ₂ (3 x 75mL) . The combined organic phases were washe _d with 10% CuS0 ₄ (aq) , then dried over MgS0 ₄ and the solvent removed in vacuo . The resulting oil was chromatographed (5% Et ₂ 0 in hexanes) to yield 55 (19 g, 56 mmol, 97%).

TLC (20% EtOAc in hexanes) : Rf = 0.55.

HRMS m/z (M ^* ) for C ₁₉ H ₃₄ 0 ₃ Si calcd. 338.2275, foun _d 338.2282.

IR (film): 1665(w), 1251(S), 1106(s), 1090(ε), 107 _l (s), 812(a), 801(m) cm" ¹ .

^: H NMR (CDC1 ₃ , 400 MHZ): 8 5.27 (brs, IH) , 3.99 - 3.88 (m, 4H) , 3.55 (dd,J = 11.9, 3.7 Hz, IH) , 2.49 (dq, J = 14.0,. ₃ .1 HZ, IH) , 2.14 (dd, J - ^~ 14.0, 2.9 Hz, IH) , 2.20 - 2.10 (m, 1 H), 2.03 - 1.97 (m, 1 H) , 1.88 (dt, J « 13.3, 3.4 Hz, IH) , 1.76 (qd, J = 13.7, 4.2 Hz, IH) , 1.71 - 1.66 (m, 2H)., 1.61 - 1.53 (m, IH) , 1.32 (td, J ^» 13.5, 4.3 Hz, IH) , 1.05 (s, 3H) , 0.88 (S, 9H) , 0.04 (s, 3H) , 0.03 (s, 3H) .

¹³ C NMR (CDCI ₃ , 100 MHZ): 8 139.4, 121.4, 109.5, 78.1, 64.4, 64.2, 41.3, 39.6, 35.7, 30.9, 27.6, 25.9, 24.8, 18.0,

17 . 0 , -4 . 0 , -4 . 8 .

Synthesis of Compound 56.

The alkene 55 (i.964g, 5.81 mmol) was disεolved in an _h y _d rous THF: (20 mL) and cooled to 0 ^» C, whereupon 1.0 M BH ₃ TH _{F (5} . ₉ mL, 5.9 mmol) was added dropwise to the stirred mixture. The mixture was allowed to come to room temperature an _d stirred overnight. After cooling to 0 ^β C, H ₂ 0 (0.2 mL ₎ was added dropwise, followed immediately by 2.5 ml of ₃ M Na _O H and subsequently 2.5 mL of 30% H ₂ 0 ₂ (aq) . The ice bath was removed and the mixture stirred for 3.5 h. After addition of Et ₂ 0 (lOOmL) and H ₂ 0 (100 mL) , the layers were separated. The aqueous layer was extracted repeatedly with Et _{20 (4} x 5 ₀ mL) , and the combined organic layers washed with _b rine. After concentration in vacuo to a viscous oil, the crude product was dissolved in undistilled CH ₂ C1 ₂ (100 mL ₎ and treated with powdered 4A molecular sieves (9g; Aldrich ₎ , 4-methylmorpholine N-oxide (2.7g) , and tetrapropylammonium perruthenate catalyst (120 mg) while under N ₂ . After 2 hours, the mixture was filtered through Celite and concentrated in vacuo ^* to a dark green oil. The crude product was dissolved in MeOH (100 mL) and treated with 2 ₀ mL of 3% NaOMe in MeOH for 10 h. After concentration in vacuo , the resulting oil was dissolved in Et ₂ 0 (100 mL ₎ and washed with H ₂ 0 (2 x -100 mL) and brine. The Et ₂ 0 layer was dried (MgS0 ₄ ) , concentrated in vacuo , and chromatographed (30% Et ₂ 0 in hexanes) to give trans-fused ketone 56 as the major product (1.571g, 4.43 mmol, 76% from the alkene ₎ .

TLC (20% EtOAc in hexanes): Rf = 0.34.

HRMS m/z (M ^* ) for C ₁₉ H ₃₄ 0 ₄ Si calcd. 354.2226, found 354.2214.

IR (film): 1716(s), 1110(S), 1093(s), 1051(s) cm" ¹ .

-H NMR (CDCI ₃ , 400 MHZ): 8 3.97 - 3.87 (m, 4H) , 3.7 _{8 (} dd,

11.1, 5 HZ, IH), 2.46 (dd, J = 12.3, .7Hz , IH) , 2.41 - 2.27 (m, 2H), 2.00 - 1.58 (m, 7H) , 1.42 (td, J = 13. _{4/ 4#9} Hz, IH), 0.88 (s, 9H) , 0.78 (s, 3H) , 0.07 (ε, 6H) .

¹³ C NMR ( CDC1 ₃ , 100 MHz) : 8 210.4, 109. ₀ , ₇₇ . , ₆₄ . ₃ 64.2, 52.2, 42.4, 38.9, 35.1,30.7, 30.5, 29.6, 25. ₈ , _. 1 ₈ . ₀ ^ 10.6, -4.1, -4.8.

Synthesis of Compound 57. The ketone 56 (6.00g, 16.9 mmol) was dissolved in anhydrous THF (100 mL) and cooled to -78 ^« C. Solid potassium bis(trimethylsilyl)amide (4.2g, 21 mmol; Aldrich ₎ was weighed out separately under a N ₂ atmosphere, dissolve _d in anhydrous THF (50 mL) , and transferred via cannula to the cooled ketone solution. After 30 min, solid N-phenyltrifluoromethanesulfonimide (6.68g, 18.7 mmol ₎ was added in one portion. The mixture was maintained at -78 ^# c for 1 h, after which H ₂ 0 (40 mL) was added and the resulting mixture was allowed to come to room temperature. Upon addition of Et ₂ 0 (100 mL) , the layers were separated. The aqueous layer was re-extracted with Et ₂ 0 (5 X 8 ₀ mL ₎ . The combined organic layers were washed with brine, dried over MgS0 ₄ , and concentrated in vacuo. The resulting oil was chromatographed (1:1 CH ₂ C1 ₂ : hexanes) to give pure enol triflate 57 (6.68g, 13.74 mmol, 81%).

TLC (1:1 CH ₂ C1 ₂ : hexaneε) : Rf = 0.37.

HRMS m/z (M ^* ) for C ₂₀ H ₃₃ O ₆ SF ₃ Si calcd. 486.171 ₉ , foun _d 486.1735.

IR (film): 1686 (w) , 1420(s), 1210(s), 1143(e), 87 ₈₍ s ₎ , 838(s) cm" ¹ *

'HHKR (CDCI ₃ , 400 MHz) : 8 5.61 (td, J = 5.1, 2.9 Hz, IH ₎ , 3.99 - 3.91 (m, 4 H) , 3.54 (dd, J « 9.4, 6.4 Hz, IH) , 2.67 (d quintet, J = 13.5, 3.1 Hz, IH) , 2.35 (dtd, J _* ■ 17.8, 6.0,

2.8 HZ, IH), 2.14 ⁽ dqd, J - 17.9, 4.5, 2.8 Hz, IH ₎ , 1.8 ₄ - 1.76 (m, 3H), 1.67 ⁽ d quintet, J « 13.5, 2.5 Hz, IH) , 1.59 .(t, J ^« = 13.3 HZ, IH ⁾ , 1.24 (td, J = 14.7, 4.6 Hz, IH ₎ , ₀ . ₈₈ (ε, 3H) , 0.87 (ε, 9H) , 0.04 (s, 3H) , 0.03 (s, ₃ H ₎ .

¹³ CNMR (CDC1 ₃ , 100 MHZ): 8 149.0, 130.0, ₁₁ 6. ₂ , ₁₀₈ . ₄ , 74.3, 64.5, 64.2, 42.7, 39.1, 33.0, 31.3, 30.9, ₃₀ . ₆ , 2 ₅ . ₈ , 18.0, 9.0, -4.1, - 4.8.

Synthesis of Compound 58.

The enol triflate 57 (2.865g, 5.895 mmol) was dissolved in anhydrous DMF (25 mL) and to this solution was added N, W-diisopropylethylamine (2.8 mL, 2.1g, 16 mmol) and powdered 4 A molecular sieves (l.lg). To this slurry was added anhydrous MeOH (lOmL, 7.91g, 247 mmol). The system was purged with carbon monoxide for 5 min, whereupon triphenylphosphine (240 mg, 0.916 mmol) and Pd(OAc _{)2 (} 102 mg, 0.454 mmol) were added. The purging was discontinued, and the system was kept under ca. 2 psi of CO for ₃ -4 hours. The slurry was filtered through Celite and H ₂ 0 ₍ 5 ₀ mL ₎ was added to the. filtrate, followed by Et ₂ 0 (65 mL) ₍ The crude ^: H NMR showed the presence of a minor product, thought to be the sis-fused isomer) . After separation, the aqueous layer was re-extracted with Et ₂ 0 (4 x 30 mL) . The combined organic layerε were waεhed with brine, dried over Mg _S04 , and concentrated in vacuo . Chromatography (15% Et ₂ 0 in hexanes ₎ yielded pure methyl ester 58 (l.702g, 4.298 mmol, 73% ₎ .

TLC (40% EtOAc in hexanes): Rf = 0.76 (UV active ₎ .

HRMS m/Z (M ^* ) for C ₂₁ H ₃₆ 0 ₅ Si calcd. 396.2332, found 396.2345.

IR (film): 1718 (S) , 1637(w), 1250(s), 1110(s) , ..1 ₀ 71 ₍ s ₎ cm ^-1 .

-H NMR (CDCI ₃ , 400 MHz): 8 6.54 (quintet, J = 2.6 Hz, IH ₎ , 4.03-3.91 (complex, 4H) , 3.68 (s, 3H) , 3.50 (dd, J = ₉ .6;

6.4 HZ, IH), 2.54 (d quintet, J -= 13.3, 2.9 Hz, IH) , 2.32

(a, 2H), 2.14 ( , IH) , 1.82 (m, 2H) , 1.68 (m, ι _H ) , 1.40 J _t

J - 7.2 Hz, IH), 1.25 ⁽ , IH) , 0.89 (ε, 9H) , 0.82 (s 3H ₎ '

0.02 (s, 6H)

13

C NMR (CDCI3, 100 MHZ): 8 167.8, 136.5, 132.9, 109.1 74.8, 64.3, 64.1, 51.4, 41.1, 37.7, 33.4, 33.1, 31.5, 31. ₀ ' 25.8, 20.7, 18.0, 9.0, -4.1, -4.8.

s ^y nthesis of Compound 59.

The methyl ester 58 (3.97g, 10.0 mmol) was dissolved in anhydrous hexanes (50 mL) with gentle warming. The solution was coole ^d to - ⁷ 8 ^# C and treated with 30 mL of ₁ . ₀ M DIBAL in hexanes ⁽ Aldrich ⁾ . After 1.5 h, the reaction mixture was quenched with H ₂ 0 (60 mL) followed by _l N H _C 1 ₍ 4 ₀ mL ₎ and allowed to warm to room temperature. The mixture was extracted repeatedly with EtOAc (4 x 100 mL) . The organic layer was washed with brine (2 x 50 mL) , dried over MgS0 ₄ , and concentrated in vacuo to a semi-crystalline product. Chromatographic purification (5% MeOH in CH ₂ C1 ₂₎ led to the allylic alcohol 57 (3.66g, 9.95 mmol, 99%) as a white solid (mp « 92-9 ^β C) .

TLC (5% MeOH in CH ₂ C1 ₂ ): Rf = 0. ₃ 2.

HRMS m/Z ⁽ M+) for C ₂₀ H ₃₆ O ₄ Si calcd. 368.2383, found ₃₆ 8.2377.

IR ⁽ film ⁾ : 3416(s), 1472 (m) , 1360(m), 1250(m ₎ , H _{06 (} s ₎ , 1072(s), 872(m), 836(s), 774(s) cm" ¹ .

-HiJKR ⁽ CDCI3, 400 MHZ): 85.57 (m, IH) , 4.03-3.92 ₍ complex, 6H ⁾ , 3.53 ⁽ dd, J = 9.8, 6.5 Hz, IH) , 2.49 (br d, IH ₎ , 2.23 ⁽ br d, IH), 2.02 (m, IH) , 1.90 (dt, J = 12.9, 2.5 Hz, IH ₎ , 1.83 (dq, J - 13.0, 2.5 Hz, IH) , 1.75 (dd, J = 1 ₃ .7, ₄ .7 Hz, IH), 1.67 (d quintet, J - 13.8, 2.5 Hz, IH) , 1.56 ₍ t, J _* 13.2 HZ, IH), 1.21 (td, J - 12.8, 4.5 Hz, IH) , ₀ .87 ₍ ε, 9H ₎ , 0.79 (s, 3H), 0.02 (s, 6H).

¹³ CNMR (CDCI3, 100 MHZ): 8 137.9, 123.1, 109.4, 75.8, 65.1 64.3, 64.2, 41.7, 37.4, 33.3, 33.2, 32.2, 30.8, 25.8, 18. θ' 8.9, -4.0, -4.8.

Synthesis of Compound 60.

The allylic alcohol 59 (3.56g, 9.67 mmol) was dissolved in 200 mL of acetone/H ₂ 0 (8/1), and to this solution was 4-methylmorpholine N-oxide (2.4g, 20 mmol). The system was purged with N ₂ for 10 minutes before 5 mL of a 0.1 g solution of Os0 ₄ in tert-butyl alcohol was added. After stirring for 12 h at room temperature the reaction flask was cooled to 0-C and 50 mL of 10% NaHS0 ₃ (aq) was added. The resulting brown slurry was extracted with EtOAc (5 x 100 mL). The combined extracts were washed with brine, dried over MgS0 ₄ and concentrated in vacuo to a light brown solid. ¹ HNMR analysis of the crude product, showed a 4:1 mixture of triols. Chromatography (5% MeOH in CH ₂ C1 ₂ ) gave the major triol 60 (2.56g, 6.36 mmol, 66%) as a white crystalline powder (mp = 117-118 ^» C).

TLC ⁽ 10% MeOH in CH ₂ C1 ₂ ) : Rf = 0.39 (Rf of minor triol = 0.32) .

IR (film): 3441(s), 1256(m), 1102 (s), 864 (m) , 835(m) cm" ¹ .

HRMS m/z (M*) for C ₂₀ H ₃₈ 0 ₆ Si calcd. 402.2438, found 402.2447.

-H NMR (CDCI ₃ , 400 MHZ): 8 4.00 (br s, IH) , 3.98-3.90 ₍ m, 4H), 3.77 (dd, J = 11.5, 5.5 Hz, IH) , 3.56 (m, 2H) , 2.06 (dd, J ^■ 14.7, 2.7HZ, IH), 1.87 (m, 2H) , 1.80-1.70 (M, 2H) , 1.62 (m, 2H), 1.52 (t, J = 13.2 Hz, IH) , 1.29 (td, J = 12.6, 6.4 HZ, IH), 0.87 (ε, 9H) , 0.82 (s, 3H) , 0.06 (s, 3H) , 0.04 (S, 3H).

¹³ C NMR (CDCI3, 100 MHZ): 8 109.3, 73.7, 69.4, 64.3, 64.2, 62.0, 42.5, 38.8, 38.0, 34.8, 30.9, 30.1, 25.9, 18.0, 12.3,

-4 . 0 , -4 . 8 .

S ^y nthesis ~Ψ Cmnmind 61.

T ^h e triol ⁶ 0 (536 mg, 1.33 mmol) was dissolved in _C H _C l ₍₄ 5 mL ⁾ an ^d anhydrous pyridine (I.15 mL, 1 ₄ .2 mmol ₎ an _d ² the resulting solution was cooled to -78 ^» C, whereupon freshly distilled chlorotrimethylsilane (0.236 mL, 1. ₈₆ mmol ₎ was added and the mixture allowed to come to room temperature for 1 h. TL ^C monitoring (40% EtOAc in hexanes) reveale _d the presence of what was presumed to be the primary trimethylsilyl ether intermediate (Rf = o.54) along with a trace amount of the disilyl ether byproduct ₍ Rf = ₀ .86- primary and secondary alcohols etherified) . The mixture was cooled to -78 ^« c and treated with trifluoromethanesulfonic anhydride ⁽ 5.75 mL of a 1.0 M stock solution in _C H ₂ ci ₂₎ and allowed to come to room temperature for 1 h. TL _C monitoring ⁽⁴⁰ % Et ^O Ac in hexanes) indicated complete conversion of the initial intermediate to its triflate (Rf = 0.85 ₎ . The mixture was finally treated with ethylene glycol ₍₆ mL ₎ and refluxed for 12 h. Mater (20 mL) and brine ₍ 2 ₀ mL ₎ were added and the layerε were separated. The aqueous layer was extracted repeatedly with CH ₂ C1 ₂ (6 x 15 mL) . The combined organic layers were washed with brine, drie _d over Na _2S04 , an ^d concentrated in vacuo . -HHKR analysis of the cru _d e yellow oil showed the desired oxetane 61 to be the major product by a ⁶ :1 margin over the migration byproduct ₆ 2. The mixture was chromatographed (gradient elution of ₄₀ % to ⁶⁰ % EtOAc in hexanes) to obtain pure 61 (353 mg, ₀ . ₉ 1 ₉ mmol, 69%) as a white solid.

TLC (40% EtOAc in hexanes): Rf of 61 = ₀ .17; Rf _{0 62 «} 0.30.

HRMS of 61 m/z ⁽ M ^* + 1) for C ₂₀ H ₃₇ O ₅ Si calcd. 385.241 ₀ , found 385.2410. HRMS of 62 m/z (M ⁺ ) for C ₂₀ H _36O5S ; calc _d . 384.2332, found 384.2323.

IR (film) of 61: 3416 ⁽ br), 1094(s) , 859(B) , 836(S) , 774(S) cm" ¹ . IR (film) of 62: 3456(br), 17lθ(s), 1253(E) , 1094 (vs) , 863(s), 836(S) , 775(ε) cm" ¹ .

-H NMR of 61 (CDC1 ₃ , 400 MHz): 8 4.78 (dd, J = 9.1, 2.2 Hz, IH) , 4.46 (d, J = 7.6 HZ, IH) , 4.26 (d, J = 7.6 Hz, IH ₎ , 3.96 - 3.89 (m, 4H) , 3.44 (dd, J = 10.6, 7.24Hz, IH) , 2.27 (ddd, J = 16.3, 9.2, 7.1 Hz, IH) , 1.88 (ddd, J = 15.1, 10.7, 2.4 HZ, IH) , 1.83-1.72 (m, 2H) , 1.68-1.55 (m, 5H) , 1.21 (s, 3H) , 0.87 (s, 9H) , 0.02 (ε, 6H) .

¹³ C NMR Of 61 (CDC1 ₃ , 100 MHz): 8 108.8, 88.1, 76.4, 74.0, 64.4, 64.3, 46.7, 37.6, 36.5, 30.9, 30.2, 29.7, 25.8, 18.0, 9.5, -4.0, -4.8.

-H NMR Of 62 (CDC1 ₃ , 400 MHz) : 8 3.95-3.81 (m, 4H) , 3.63-3.56 ( , 2H) , 2.58-2.48 (m, 3H) , 1.91 (quintet, J = 5.0 Hz, IH) , 1.81-1.60 (m, 5H) , 1.40 (td, J = 13.0, 5.3 Hz, IH) , 0.85 (S, 9H) , 0.72 (S, 3H) , 0.05 (s, 6H) .

¹³ C NMR of 62 (CDCI ₃ , 100 MHz) : 8 213.0, 108.9, 64.3, 64.2, 62.1, 52.3, 49.1, 42.9, 35.0, 33.7, 30.1, 29.4, 25.7, 17.9, 10.6, -4.1, -4.8.

Synthesis of Compound 63.

Oxetane 61 (20 mg, 0.052 mmol) was diεsolved in anhydrous THF (2 mL) and treated with 1.0 M tetrabutyl ammonium fluoride in THF (0.100 mL, 0.100 mmol). The mixture was heated to reflux for 12 h, cooled to room temperature, and chromatographed directly (EtOAc as eluant) to give 63 (13 mg, 0.048 mmol, 93%). Recrystallization from CHC1 ₃ yielded a fine, white crystalline solid from which a single crystal x-ray was obtained.

mp ■= 232 ^β C (dec).

TLC (EtOAc): Rf = 0.18.

HRMS m/Z (M*) for C _α4 H ₂₂ 0 ₅ calcd. 270.1467, found 270.1478

- NMR (CDC1 ₃ , 400 MHZ): 8 4.83 (dd, J ■ 2.9, 9.0 Hz, IH ₎ , 4.46 (d, J ^« = 7.6 HZ, IH), 4.28 (d, J ■= 7.5 Hz, IH ₎ , 3.99-3.89 (m, 4H) , 3.50 (m, IH) , 2.44 (quintet, J = 8 Hz, IH) , 1.90-1.60 (m, 6H), 1.41-1.29 (m, 2H) , 1.25 (s, 3H ₎ .

¹³ C NMR (CD3OD, 100 MHZ): 8 110.1, 89.9, 77.8, 76.8, 74.4, 65.3, 65.2, 47.7, 38.3, 37.6, 37.3, 32.0, 30.7, 9.9.

Synthesis of Compound 64.

The ketal 61 (1.320g, 3.438 mmol) was dissolved in 12 mL of acetone and 1 mL of H ₂ 0. To this solution was added collidinium tosylate (0.70g, 2.4 mmol) and the mixture was heated to reflux. Due to the sluggishness of the deketallization, more collidinium tosylate (0.60g, 2.0 mmol) and H ₂ 0 (1 mL) were added over a period of 120 h. The majority of starting ketal was consumed during this period, as monitored by TLC (Rf of 61 with EtOAc eluant = 0.52; Rf of 64 = 0.65). The mixture was cooled to room temperature and concentrated in vacuo to remove most of the acetone. To the crude product was added H ₂ 0 (10 mL) and EtOAc (50 mL) and the layers were separated. The aqueous phase was repeatedly extracted with EtOAc (5 x 40 mL) and the combined organic phases were washed with brine, dried over MgS0 ₄ , and concentrated in vacuo. Chromatography (40% EtOAc in hexanes) yielded pure 64 as a white solid (0.985g, 2.8 ₉ 7 mmol, 84%). Recrystallization from n-pentane/CH ₂ cl ₂ (10/1) gave fine white needles (mp = 152 ^β C) .

IR (film): 3375(S), 1710(S), 1253(6), 1083(S), 940(m) , 836(S), 772(S) cm" ¹ .

HRMS m/z (M*+l) for C ₁₈ H ₃₃ 0 ₄ Si calcd. 341.2148, found 341.2154.

~H NMR (CDCI ₃ , 400 MHZ): 8 4.80 (d, J = 7.9 Hz, IH) , 4.55

(d, J - ⁷ .8 HZ, IH ⁾ , 4.27 (d, J = 7.8 Hz, IH ₎ , ₃ . _{46 (dd} , J * ^• = 10.6, 7.2 HZ, IH), 2.48 (td, J = 15. ₂ , ₆ . ₄ Hz, IH ₎ , 2.38-2.29 ⁽ m, 5H), 2.13 (dd, J ^■ = 13.0, 5.3 Hz, IH ₎ , ₁ . ₉₄₍ t! J - 13.2 HZ, IH) , 1.72 (dd, J ^« = 11.5, 5.9 Hz, IH ₎ , ι. _{38 (S} [ 3H), 1.33 (td, J = 13.6, 4.5 Hz, IH) , 0.88 (ε, ₉ H ₎ , ₀ . _{03 (} s,' 3H) , 0.01 (ε, 3H) .

¹³ C NMR (CDCI ₃ , 100 MHZ): 8 210.4, 88.0, 76.1, 74. ₀ , 48.7, 38.7, 37.7, 37.6, 37.4, 36.7, 25.8, 17.9, 9. ₆ , -4. ₀ , - ₄ . ₉ '

Synthesis of Compound 65.

Freεhly distilled diisopropylamine (0.150 mL, ₁₀₈ mg, ₁ . ₀₇ mmol ⁾ was charged to a 10 mL roundbottom flask containing ₃ mL anhydrous THF. The solution was cooled to -7 ₈ ^β _C and treated with n-BuLi (0.355 mL, 2.5 M in hexanes, ₀ . ₈₈₈ mmol). After 15 min at -78 ^» C, ketone 64 ( ₁₄₂ mg, ₀ . ₄₁₈ mmol) in 2 mL anhydrous THF was transferred via cannula to the lithium diisopropylamide solution. After 1.5 h chlorotrimethylsilane (0.120 mL, 103 mg, 0. ₉ 45 mmol ₎ was added and the reaction mixture warmed to room temperature for 1 h, whereupon it was poured into n-pentane/H _{20 (} 5 mL/5 mL) and extracted. The aqueous layer was re-extracted with n-pentane (3 x 5 mL) . The combined organic layers were washed with brine, dried over MgS0 ₄ , and concentrated in vacuo to the crude enol ether, which waε redissolved in anhydrous acetonitrile (4mL) at reflux. After dissolution of the enol ether, Pd(OAc) ₂ (105 mg, 0.468 mmol) was added and the resulting mixture maintained at reflux for 5 h. At this time, MeOH (3 mL) and K ₂ C0 ₃ powder (200 mg, 1.45 mmol ₎ were added while maintaining reflux for 1 h. After cooling to room temperature, the slurry was filtered through _C elite (MeOH wash) and the filtrate concentrated in vacuo to a yellow oil. Chromatography (3% MeOH in CH ₂ C1 ₂ ) yielded the desired enone 65 (109 mg, 0.322 mmol, 77%) contaminated with a trace amount of an unidentified byproduct.

TLC (20% EtOAc in hexanes): Rf «= 0.14 (UV active).

HRHS m/z (M ^* +l) for C ₁₈ H ₃₁ 0 ₄ Si calcd. 339. ₁₉₉₂ , found 339.1986

IR (film): 3413 (S) , 1681 (s) , 1256 (s) , 1069 ₍ s ₎ , ₈₃₇ (s), 776 (s) cm" ¹ .

^l H NMR (CDC1 ₃ , 400 MHZ): 8 7.12 (d, J = 10.2 Hz, IH ₎ , 5. ₉₀ (d, J = 10.2 Hz, IH) , 4.83 (dd, J = 8.8, 1.6 Hz, IH ₎ , ₄ .5 ₄ (d, J - 7.8 HZ, IH), 4.34 (d, J = 7.8 Hz, IH) , 3.65 ₍ dd, J = 10.0, 7.6 HZ, IH), 2.72 (s, IH) , 2.48-2.37 (m, 3H ₎ , 2. ₀ 7 (ddd, J - 12.7, 6.0, 0.8 Hz, IH) , 1.93 (ddd, J = 15.3, 10.0, 1.9 HZ, IH), 1.39 (s, 3H) , 0.92 (s, 9H) , 0.06 (s, 6H ₎ .

¹³ C NMR (CDCI ₃ , 100 MHZ): 8 199.1, 157.2, 126. ₈ , ₈₇ . ₇ , 76.7, 73.4, 72.1, 45.6, 37.3, 33.3, 25.8, 18.0, 11. ₃ , - ₃ . ₉ , -5.0.

Synthesis of Compound 66.

Alcohol 65 (144 mg, 0.426 mmol) was dissolved in 2 mL anhydrous DMF and the resulting solution treated with i idazole (200 mg, 2.9 ^' 4 mmol) and tert-butyldimethylsilyl chloride (215 mg, 1.43 mmol). The mixture was heated to 80 ^β C for 12 h, then poured into Et ₂ 0 (lu mL) and H ₂ 0 ₍ 5 L) and extracted. The aqueous layer was re-extracted with Et, ₀ (5 x 10 mL) . The combined organic phases were washe _d with brine, dried over MgS0 ₄ , and concentrated in vacuo. Chromatography (5% EtOAc in hexanes) yielded the desired silyl ether 66 (110 mg, 0.243 mmol, 57%) along with starting alcohol 65 (25 mg, 0.074 mmol, 17% recovered).

TLC (5% EtOAc in hexanes): Rf = 0.18 (UV active).

HRMS m/z (M ^* +l) for C ₂₄ H ₄₅ 0 ₄ Si ₂ calcd 453.2857, found 453.2905.

IR (film): 1684(s), 1255(s), 1094(s), 836(s), 775(s) cm" ¹ .

-H NMR (CDCI ₃ , 400 MH ^Z) : 87.10 (d, J = 10.0 Hz, IH ₎ , 5. ₈₉ (d, J - 10.1 HZ, IH ⁾ , 4. ⁸⁹ (d, J - 8.0 Hz, IH ₎ , ₄ .42 ₍ d, J = 7.3 Hz, IH), 4.37 (d, J = 7.2 Hz, IH) , 3.6 _{4 (dd} , _J = ' ₅ 7.9 HZ, IH), 2.42-2.34 (m, 3H) , 2.02 (t, J *= ₈ . ₀ Hz, ι _H) ' 1.92 (ddd, J - 15.5, 9.6, 1.4 Hz, IH) , 1.39 (ε, ₃ H ₎ , ₀ . ₉₂ (s, 9H), 0.87 (ε, 9H) , 0.13 (ε, 3H) , 0.10 (ε, 3H) , ₀ . ₀₈ . ₍ s, 3H) , 0.07 (s, 3H) .

13 C NMR ⁽ CDCL ₃ , 100 MHZ): 8198.9, 157.0, 126.7, 8 ₆ . ₆ , 7 ₆ .6, 74.7, 72.3, 47.2, 41.3, 37.5, 33.2, 25.7, 25.5, 1 ₈ . ₀ , ₁₇ . ₉ ' 11.2, -3.0, -3.1, -3.9, -5.1.

Synthesis of Compound 67.

To alcohol 65 (85 mg, 0.251 mmol) in 2mL anhydrous _C H _2C 1 was added anhydrous pyridine (0.026 mL, 25 mg, 0. ₃ 2 mmol ₎ at 0 ^β C followed by chlorotrimethylsilane (0.036 mL, 31 mg, ₀ . ₂₈ mmol) . The reaction mixture was warmed to room temperature for 1 h, then poured into H ₂ 0 (5 mL) and extracte _d with CH ₂ C1 ₂ (3 x 15 mL) . The combined CH ₂ C1 ₂ layers were washe _d with brine, dried over MgS0 ₄ , and concentrated in vacuo . Chromatography (5% EtOAc in hexanes) yielded pure _{66 (9} 1 mg, 0.222 mmol, 88%) .

TLC (40% EtOAc in hexanes): Rf = 0.83 (UV active ₎

-H NMR (CDC1 ₃ ; 400 MHZ): 8 7.09 (d, J = 10.1 Hz, IH ₎ , 5.8 ₉ (d, J = 10.1 HZ, IH), 4.91 (d, J = 7.5 Hz, IH) , ₄ . _{43 (} dd, J = 10.8 HZ, 7.6 HZ, 2H) , 3.65 (dd, J = 9.5, 8.0 Hz, IH ₎ , 2.43-2.36 (m, 3H) , 2.04 (t, J = 8.6 Hz, IH) , 1.92 (d _d d, J = 15.5, 9.6, 1.4 Hz, IH) , 1.39 (s, 3H) , 0.92 (ε, 9H) , ₀ .1 _{6 (} ε, 9H) , 0.07 (ε, 3H) , 0.06 (ε, 3H) .

Svntheεis of Compound 68.

To enone 67 (6 mg, 0.0146 mmol) dissolved in anhydrous THF (1 mL) and cooled to -78 ^β C was added dropwise potassium bis(trimethylsilyl)amide (0.035 mL of 0.5 M solution in toluene, 0.0175 mmol). After 30 min a yellow color

developed, and a solution of tf-phenylεul onyl phenyloxi±iridine (10 mg, 0.038 mmol) in THF (l mL) was added slowly down the side of the flask. After 10 in, H ₂ o

(l mL) was added and the mixture was allowed to warm to room temperature for 30 min, whereupon it waε poured inro EtO _A c

(5 mL) and brine (5 mL) in a εeparatory funnel and subsequently extracted. The aqueous phase was re-extracted with EtOAc ( x 5 mL) . The combined organic phases were washed with brine, dried over MgS0 ₄ , concentrated in vacua , and chromatographed (gradient elution, 20% to 40% Et _O Ac in

CH ₂ C1 ₂ ) to give pure diol 68 as a white solid (4 mg, 0.0113 mmol, 77%) .

TLC (20% EtOAc in CH ₂ C1 ₂ ) : Rf - 0.13 (UV active).

IR (film): 3461(s), 1691(S), 1255(m), 1157(s), 1 ₁₀₀₍ s ₎ , 1045(m), 869(S), 838(s), 776(s) cm" ¹ .

-H NMR (CDClj, 400 MHZ) : 8 7.20 (d, J = 10.1 Hz, IH) , ₆ . ₀ 1 (d, J « 10.1 HZ, IH) , 4.88 (d, J « 8.5 Hz, IH) , 4.61 (d, J = 7.2 HZ, IH), 4.56 (d, J - 7.3 Hz, IH) , 4.53 (dd, J «= 13. ₀ , 1.2 HZ, IH), 4.03 (s, IH) , 3.76 (d, J = 1.3 Hz, IH) , 3. ₆₈ (dd, J ^~ 9.6, 7.7 Hz, IH) , 2.43 (quintet, J •= 7.8 Hz, IH ₎ , 2.07 (d, J = 13.0 HZ, IH) , 1.93 (ddd, J = 15.4, 9.8, ₁ . ₄ HZ, IH), 1.53 (s, 3H) , 0.92 (ε, 9H) , 0.06 (s, 3H) , 0. ₀ 5 ₍ s, 3H) .

13C NMR (CDC13, 100 MHz) : £ 199.3, 158.9, 123.0, 85.0, 76. ₈ , 72.8, 71.9, 70.4, 52.0, 43.0, 37.2, 25.7, 18.0, 11.7, -3. ₉ , -5.1.

Synthesis of Compound 69.

Freshly distilled diisopropylamine (0.018 mL, 13 mg, 0.13 mmol) was charged to a dry 5 L roundbottom flask containing 1 mL anhydrous THF. The solution was cooled to -78 ^# C and treated with n-BuLi (0.032 mL of 2.5 M in hexaneε, 0.080 mmol). After 15 min at -78 ^# C, enone 15 (18.0 mg, 0.0398

mmol ⁾ , dissolve ^d m 1 mL THF, waε transferre _{d i} nto t _h e lithium diiεopropyl mide solution via cannula Aft maintaining at - ⁷⁸ - ^C for ⁴⁵ min, chlorotrimet _h ylεilan ⁽⁰ . ⁰ 15 mL, 13 mg, ⁰ .1 ² mmol ⁾ was added an _d t _h e reac _ti on mixture allowed to come to room tempera _t ure _f or _{i h} , whereupon it was poured into n-pentane (5 mL) an _d H ₂ o ₍₅ mL ₎ an ^d extracted. The aqueous layer was re-extrac _t e _d w _ith n-pentane (3 x 5 mL) and the combined organic layers were washed with brine, dried over MgS0 ₄ , and concentrate _d m vacuo . The crude product was dissolved in anhy _d rous _C H _2C 1 (1 mL) and to the resulting solution was added anhydrous NaHC0 ₃ powder (20 mg, 0.24 mmol). The slurry was coole _d to -78 ^» C and purged with ozone until a light _b lue color persisted, whereupon excess ozone waε purge _d with _N Triphenylphosphine (27 mg, 0.12 mmol) was added and the mixture was allowed to come to room temperature for 1.5 h, at which time it waε filtered through cotton and concentrated in vacuo to a yellow oil. Chromatography (CH ₂ C1 ₂ as eluant) yielded dialdehyde 69 (6. ₃ mg, ₀ . ₀₁₄ mmol, 36%).

TLC (CH ₂ C1 ₂ ): Rf = 0.27.

HRMS m/z (M ^* +l) for C ₂₂ H ₄₃ 0 ₅ Si ₂ calcd 443.265 ₀ , foun _d 443.2613.

IR (film) 2723 (w), 1728 (S), 1472 (m), 1257 (s), 1174 ₍ m) , 1098(S), 837(S), 777(s) cm ^"1 .

'H NMR (CDC1 ₃ , 400 MHz) : 8 9.66 (ε, IH) , 9.60 (d, J = 0.4 HZ, IH) , 4.90 (dd, J - 8.3, 2.0 Hz, IH) , 4.63 (dd, J = 7.4, 1.0 HZ, IH), 4.36 (d, J - 7.4 Hz, IH) , 4.00 (dd, J = 9.2, 6.6 HZ, IH), 2.97 (s, IH) , 2.31 (ddd, J = 15.1, 8.2, 6.6 Hz, IH), 1.94 (ddd, J = 15.3, 9.2, 2.2 Hz, IH) , 1.52 (s, 3H) , 0.89 (S, 9H), 0.85 (S, 9H) , 0.19 (s, 3H) , 0.18 (s, 3H) , 0.03 (S, 3H) , -0.02 (S, 3H).

^xi Z NMR (CDClj, 100 MHz) : b 206.4, 200.2, 87.1, 79. ₁ , 7 ₃ . _2, 71.7, 62.0, 51.5, 36.0, 25.5, 17.8, 10.B, -2.9, - ₄ .2, - 5.3.

Preparation of 107

The l,2- ioxolane 106 (2.05g, 6.65πmol) waε dissolved in 1:1 THF:3N HCl (50xnL) and the mixture was heated at reflux for O.Sh. After cooling, the mixture was diluted with ether (200 mL) and H ₂ 0 (lOOmL) and the layers were separated. The aqueous layer was washed with ether (2 x lOOmL) and the combined organic layers were washed with saturated NaHCO,, brine, dried over MgS0 ₄ , and concentrated in vacuo. Purification of the residue by flash chromatography (SiO,; 9:1 hexane; EtOAc; R^O.35) afforded 1.6Bg(96A) of the ketone 107 (clear oil).

IR (neat cm ^*1 ) 2972, 2928, 1720, 1631, 1461, 1343, 1254, 905.

Η HXR (400 MHz, CDClj) 62.60 ( , 2H) , 2.53 ( , 2H) , 2.01

(s, 3H) , 1.27 (s, 6H) .

^,J C MMR (100 MHz, CDClj) δ 208.7, 137.8, 112.5, 52.1, 35.5,

31.8, 30.3, 28.0. HJUJS Calcd for ^H _o 0I: (M ^* ) 264.0011. Found 264.0017.

Preparation of 108

The ketone 107 (1.62g, 6.13ιπ ol) was dissolved in anhydrous CH _j Cl ₃ (41xnL) , cooled to 0 ^β C, and to this solution was added TMSCN (1.23mL, 9.20xπmol) followed by KC _N (4 ₀ mg, 0.6iππnol) and 18-crown-6 (40 mg, O.lSπmol) . After 0.5h, the mixture was treated with H ₂ 0 (5xnL) and the layers separated. The aqueous layer was washed with CH,C1 (1 x 20mL) , ^~nA the combined organic layerε were dried over MgS0 ₄ . Piltration through florisil and

concen ^t ra ^t ion of the filtrate in vacuo a _* *orde _d 2. ¹⁹ g ⁽ 98% ⁾ of the trimethylsilyl cyanohydrm 1 _Q B ^" ] _C 1~ - oil) .

IR ⁽ neat, cm ^"1) 2975, 1631, 1253, 1133, 8 ₄ 6. »H HHR ⁽⁴ 0 ⁰ MHz, ODCl ₃ ⁾ 0 2.46 (dt, j- ^' ₇ . _7; ^" ι ₈ 2 _H - IH _' 2.32 ⁽ dt, J=5.3;18.2 Hz, IH) , 2.06 (dd, _j . _{S 4 8} 2H ⁾ , 1.91 ⁽ s, 3H), 1.37 _(ε , 3H) , 1. _{14 (fi< 3E;} ^' , _2? ^'

9H) ^ϋ CHKR ⁽ 100 MHz, CDC1, ⁾ fl 131.3, 115.4. 105.5, ₆ 6. ₆ , ₄₁ 6 25.6, 25.3, 25.0, 23.4, 19.2, -4.1.

HBK ^S Calcd for CIBBBHOSII: ( _M+ ) 363. ₀ 515. _FOu n _d - 363.0527.

Preparation of 109

The tri ethylsiyl cyanohydrin 108 (2.l3g, 5.86 mmol ₎ was dissolved in anhydrous hexane (120mL) , cooled to -7 _8<* c, and to this solution was added DIBAL-H (β.SOmL _{; 1} 0M solution in hexane, ^' 8.8O mol) dropwise over a perio ^" of 0.25h. Af ^t er 6.5h, the mixture was diluted with ether ⁽ 120mL ⁾ , treated with Si0 ₂ gel (27g) , and slowly allowed to warm to RT over a period of lOh. The mixture was poured into H ₂ 0 ⁽ ISOmL ⁾ and the layers were separated The aqueous layer was washed with ether (2x100 mL ₎ and the combined organic layers were dried over MgS0 ₄ and concentrated in vacuo. Purification of the residue by flash chroma ^t ography ⁽ Si0 ₂ : 9:1 hexane; Et ₂ 0 _; R _θ .69 ₎ afforded 1.99g ⁽ 93% ⁾ of the aldehyde 109 (clear oil ₎ ^"

IR ⁽ neat, cπr' ⁾ 2953, 1734, 1632, 1459, 1249, 842. Η ^{fflffi (} 400 MHz, CDC1, ⁾ 6 9.75 (s, IH) 2.32 (m, 2H ₎ , 1. ₉₂ ⁽ s, 3H ⁾ , 1.91 ⁽ m, 2H ⁾ , 1.15 (ε, 3H) , 1.10 (s, 3H ₎ ' 0.15 (s, 9H) . "CMffi ⁽ 100 MHz, CDC1, ⁾ 0203.6, 136.8, 114.0, 82.0, 45.8, 30.7, 30.4, 27.3, 27.1, 26.3, 2.32.

HEMS Calcd for C^SiO,!: (M+) 366.0512. Found: 366.0531 _,

Preparation of no and in

2 -Bromostyrene ⁽ 567mg , 3 . iθxπmol ) in 5 : ₁ TH * *- r ^■r -*-L_.jU - _. (v 6 _w 11 U was cooled to -7 _{8 C} , and treated dropwise with nBu i ⁽ 1.93mL, 1.6M in hexane, 3.lθmmol). After 0.5 _t he yellow slurry was rapidly transferred via cannula _t o 1 78°C solution of the aldehyde 109 (955mg, 2. 1*^1 _{) <n} THF ⁽ 26mL ⁾ . After O.lh, H,0 (20mL) and ether ₍ somL ₎ were added to the mixture and the layers were separated. The aqueous layer was washed with ether (2 x 50mL ₎ , an _{d t} he com ^b ine ^d organic layers were dried over _M gS0 ₄ , an _d concen ^t ra ^t ed in vacuo . The residue was dissolve _d 'i THF ⁽ 50mL ⁾ and to this solution was added TBAF (2.70mL _l OM in THF, 2.70mmol ⁾ . After O.lh, the solution was concentrated in vacuo and purification of the residue by flash chromatography ⁽ Si0 ₂ ; 3:2 CH _j Cl-; _pet ether _; no ^* r-0.27, 111 R^0.14 ⁾ afforded 542mg (52V) of the syn-diol 110 ⁽ clear oil ⁾ and 283mg (27V) of the anti-diol 111 {white oil) .

Data for 110

IR ⁽ neat cm ^'1) 3540, 3462, 2976, 2938, 2907, 1714, _{1 G2} S , 1365, 1001, 911.

»H XR ⁽ 400 MHz, CDC1, ⁾ δ 7.66 (m, 1 H) , 7.46 ₍ m, 1 H ₎ , 7.33 ⁽ m, 2 H ⁾ , 7.19 ⁽ dd, J-11.0; 17.4 Hz, IH) , s'.58 ₍ d. J-17.4 Hz, IH ⁾ 5.44 ⁽ d, J-3.0 Hz, 1 H) 5.34 ₍ d, J-10.9 Hz, 1 H ⁾ , 2.25 ⁽ dd, J-4.9;8.0 Hz, 2H) , 2.10 ₍ dt, J-8.3; 13.8 Hz, 1 H ⁾ , 1.94 ⁽ d, 1 H, J-3.1 Hz, IH) , 1.78 ₍ dt,' J-4.8;13.9 Hz ⁾ , 1.35 ⁽ s, 3 H) , 1.32 (s, 3H) , 1.26 _(β 1 H) .

^U C NKE ⁽ 100 MHz, ODC1,) δ 138.7, 138.3, 137.9, 135.8, 128.0, 127.6, 127.5, 126.5, 117.0, 76.7, 72.3, 47.3,' 31.3, 29.9, 27.5, 27.2, 23.8.

ΞBMS Calcd for 0,^0,1: ⁽ M+) 398.0743. Found 39 ₈ .0750.

Data for 111

IR ⁽ XBr, cm ^"1) 3495, 3323, 2976, 2950, 1624, _{1406, 101} 5 _, 912, 889. ^l H HMR ⁽ 400 MHz, CDC1 ₃ ⁾ 6 7.65 (br s, 1 H) , 7.45 (d, J= ₇ . ₃ Hz, 1 H ⁾ , 7.32 ⁽ , 2H ⁾ , 7.00 (br s, 1 H) , 5.62 (d, J=17.2 Hz, IH ⁾ , 5.35 ⁽ d, J-11.0 Hz, 1 H) , 5.28 (br s, ₁ H) , 2. ₃ 1 ⁽ b s, IH ⁾ , 2.10 ⁽ dt, J-6.7;18.0 Hz) , 1.87 (s, 3 H) , ₁ .80 ⁽ ap dt, 1 H) , 1.40 ⁽ m, 2 H) , 1.39 (s, 3H) , 1.3 ₄ (s, 3 H ₎ .

^U C HMR ⁽ 100 MHz, CDC1 ₃ ⁾ δ 139.4, 137.8, 136.9, 134.3, 128.2, 128.10, 128.06, 126.3, 117.5, 76.0, 70.3, 48.3, 31.1, 29.8, 28.1, 27.6, 27.1.

HRMS Calcd for CnHgC^I: (M-c)398.0743. Found: 39 ₈ . ₀₇₄ 5.

Preparation of 112

A solution of oxalyl chloride (342μL, 3.92mmol) in CH ₂ Cl ₂ ⁽ 25mL ⁾ at -7B ^β C was treated with DMSO ( ₁ .39mL, 19.6mmol). After 0.25h, a solution of 110 (777 mg, 1.96mmol ⁾ in CHjCl ₂ (5mL) was added. After 0.5h, Et ₃ N ⁽ 2.87mL, 20.6mmol ⁾ was introduced and the mixture was allowed to warm to RT and stir for I2h. Addition of sat'd NaHCOj ⁽ lO L ⁾ and the layers were separated. The organic layer was washed saturated NH ₄ C1, brine, and dried over M3S0 ₄ . Removal of solvent in vacuo and purification of the residue by flaβh chromatography (Si0 _2: 95:5 hexane:EtOAc; Rf-0.27 4:1 hexane:ether) afforded 546mg (71%) of the ketone 112 (yellow oil) .

IR (neat, cm- ¹ ) 3461, 2974, 1676, 1458, 1370, 1228, 900. ^l H HMR (400 MHZ, CDClj) δ 7.61 (d, J-7.9 Hz, IH) , ₇ .461 (d, J-7.8 Hz, IH) , 7.41 (t, J-7.6 Hz, 1 H) , 7.27 (5, J-7.7 Hz, IH) 6.79 ⁽ dd, J-11.0; 17.3 Hz, 1 H) , 5.7 ₁ (d,

J-17.3 Hz, IH ⁾ , 5.34 ⁽ d, J-11.0 Hz, 1 H) , 3.41 is, 1 H ₎ , 2.31 ⁽ m, 2 H ⁾ , 1.99 ⁽ m, 2H) , 1.81 (s, 3 H) , 1.20 ₍ s, 3H ₎ ^,3 C HMR ⁽ 100 MHz CDC1 ₃ δ 209.2, 138.4, 137.3, 136.C, 13 ₄ .3, 130.0, 126.5, 126.4, 126.2, 117.3, 114.7, 82.5, ₄ 6. _7, 30.9, 30.0, 28.3, 27.7

HRMS Calcd for C„H ₂ ,0 ₂ I: ⁽ M+) 396.0586. Found: 396.0576.

Reduction of 112 - Preparation of 110 and 111

A solution of 112 ⁽ 138mg, 0.35mmol) in EtOH ₍ 4mL ₎ at 0°C was treated with NaBH, ⁽ 13mg, 0.35mmol) and the resulting mixture was allowed to warm to RT and stir for 2.5h. Addition of 0.2N HCl ⁽ 3mL) and ether (40mL) and the layers were separated. The aqueous layer was washed with ether ⁽ 2x ^l 0m ⁾ and the organic extracts were combined and dried

⁽ MgSo ₄ ⁾ . The solvent was removed in vacuo and purification of the residue by flash chromatography ₍ Si0 ₂ :

3:2 CHjClj: pet ether) afforded 66mg (48V) of the syn-diol

110 and 60 mg (43%) of the aπti-diol 111.

Preparation of 113

The aπti-diol 111 ⁽ 100 mg, 0.251 mmol) was dissolved in 1,2-dimethoxypropane ⁽ 5mL ⁾ and to this solution was added ⁽ IR ⁾ - ⁽ - ⁾ -ιo-camphorsulfonic acid (5 mg, 0.02 mmol ₎ . The mixture was heated at 70°C for I3h, allowed to cool to RT, then filtered through basic Alumina using CH _j Cl as eluent. The filtrate was concentrated in vacuo and purification cf the residue by flash chromatography ₍ SiO, _; 9:1 hexane; ether; RfO.53) afforded 102 mg (93V ₎ of the acetonide 113 (clear oil) .

IR ⁽ neat, cm ^'1) δ 2983, 1626, 1378, 1241, 1216, 1054, 909, Θ86. 'H HMR ⁽ 400 Mz, CDC1, ⁾ δ 7.75 (m, IH) , 7.43 ( , IH ₎ , 7.30 ⁽ m, 2H ⁾ , 7.09 ⁽ dd, J-11.0; 17.2 Hz, IH) , 5.62 (dd, J-l.l;

17.2 Hz) , 5.52 (S, IH) , 5.42 (dd, J-1.2; 11.0 Hz, 1 H) , 2.31 (br s, l H) , 2.15 ⁽ m, 1 H) , 1.72 (m, 5 K) , 1.61 (ε, 3 H) , 1.50 (s, 3 H) , 1.37 (S, 3 H) , 1.03 (br s, 3 H) . ^I3 C HMR (100 MHz) b 138.2, 137.4, 135.2, 133.6, 12E.Ξ, 128.3, 127.2, 127.0, 117.4, 106.2, 85.6, 75.9, 44.5, 30.8, 30.1, 29.0, 27.4, 26.8, 25.5. HRMS Calcd for C^H^O,!: <M+ ⁾ 438.1056. Found: 436.1068.

Preparation of 114

The acetonide 113 (84mg, 0.l9mmol) was dissolved in CH ₂ C1, <4mL) , cooled to -78 ^β C and treated with 0 ₃ until a blue solution resulted. The excess 0 ₃ was removed by bubbling N, through the solution which was subsequently treated with triphenylphosphine (55mg, 0.21 mmol) and allowed to warm to RT. After 4 h, the solution was concentrated in vacuo and purification of the residue by flash chromatography (SiO,; 9:1 hexane: ether; R _f O.24) afforded 83mg (9BV) of the aldehyde 114 (white solid; m.p.-169-171 °C) .

IR ( Br, cm" ¹ ) 2980, 1697, 1574, 1371, 1240, 1031, 885. 'H HMR (400 MHz, CDC1 ₃ ) δ 10.29 (s, 1 H) , 7.96 (d, J-7.8 Hz, 1 H) , 7.83 (dd, J-1.2 Hz, 1 H) , 7.59 (t, J-7.6 Hz, 1 H), 7.49 (t, J-7.4 Hz, 1 H) , 6.32 (s, 1 H) , 2.16 (br s,

1 H) , 2.06 (m, 1 H) , 1.68 (m, 2 H) , 1.66 (s, 6 H) , 1.51

(s, 3H) , 1.37 (br s, 3 H) , 1.12 (br s, 3H) . ^α C HMR (400 MHZ, CDC1 ₃ ) δ 191.6, 138.6, 138.0, 134.7,

132.8, 129.7, 128.4, 106.7, 86.0, 74.5, 44.6, 30.6, 30.0, 29.0, 27.5, 26.8, 25.7.

HRMS Calcd for C^H^I; (M+) 440.0849. Found: 440.0844.

Preparation of 115

The aldehyde 114 (lSlmg, 0.343mmol) was dissolved in anhydrous THF (6mL) , cooled to -78 ^β C, and treated with

^■ IBS-

vinyl magnesium bromide ⁽ Si4μL, l.OM in THF, 0.5i ₄ mmol) dropwise over a period of 0.1 h. After l h, _t he mix _t ure was quenched by addition of saturated NH _« C1 (2 mL) an _d ether (20mL ⁾ . The aqueous phase was washed wi _t h e _t her ( ₂ x 20 mL ⁾ , and the combined organic phases were washed with brine, dried over MgS0 ₄ , filtered through Celi _t e, an _d concentrated in vacuo to afford 158 mg (98%) of _th e allylic alcohol 115 (white solid, m.p.=i69- _l 7 °C) as α single diastereoisomer (>95V de) .

IR ⁽ neat, cm ^"1) 3470, 2983, 1636, 1453, 1379, 1240, 1217,

1057, 1026, 908, 88£. .

'H HMR (400 MHz, CDC1 ₃ ) δ 7.76 (d, J=7.8 Hz, ₁ H) , 7.59

⁽ dd, J-1.4; 7.8 Hz, 1 H) , 7.31 (m, 2 H) , 6.0 ₁ (ddd, J-5.5; 10.4; 17.2 Hz. 1 H) , 5.59 (s, 1 H) , 5.37 (s, ₁ H) , 5.22 ⁽ d, J-17.2 Hz, 1 H) , 5.16 (d, J-10.3 Hz, ₁ H) , 2. ₀ 8

⁽ m, 4 H ⁾ , 1.60 ⁽ s, 6 H), 1.45 (s, 3 H) , 1.33 (s, 3 H) ,

1.28 (br s, 3 H) .

^IJ C HMR ⁽ 100 MHz, CDC1 ₃ ) δ 141.2, 140.1, 133.1, 128.6,

128.1, 127.1, 125.9,. 115.3, 106.1, 86.0, 75.6, 71.2,

44.5, 30.7, 30.3, 29.0, 27.6, 26.7, 25.8.

HRMS Calcd for CJOHJSO-,1: (M+) 440.0848. Found: ₄₄ 0.08 ₄₄ .

Preparation of 116

The allylic alcohol 115 ⁽ 60.5mg, 0.129mmol) was dissolved in anhydrous DMF ⁽ 3mL) and to this solution was added anhydrous KjC0 ₃ ⁽ 89mg, 0.645mmol) . The mixture was heated at 80 ^β C and treated with Pd(OAc) ₂ (4.7mg, 0.021mmol) in portions over 46h so as to maintain a dark amber reaction mixture. The mixture was poured into cold H _j O (25mL) and ether ⁽ 25mL ⁾ , and the layers were separated. The aqueous layer was washed with ether (3 x 25mL) , and the combined organic layers were dried over MgS0 ₄ and concentrated in vacuo. Purification of the residue by flash chromatography ⁽ Si0 ₂ ; 95:5 hexane:ether, R^θ. ₁ 2) affor _d e _d

35mg (80%) of the product 116 (It. yellow solid; m.p.=126-128 ^β C) .

IR (KBr, cm" ¹ ) 29B4, 1674, 1644, 1597, 1378, 1241, 1217, 1064, 1046, 979.

Η HMR (400 MHz, CDC1 ₃ ) δ 7.62 (dd, J-0.7; 7.9 Hz, 1 K) , 7.38 (m, 1 H) , 7.23 ( , 2 H) , 6.43 (d, J-2.1 Hz, 1 H) . 5.29 (d, J-2.1 Hz, 1 H) , 4.97 (s, 1 H) , 2.37 (m, 1 H) , 2.21 (ddd, J-4.4; 10.5; 14.4 Hz, 1 H) , 1.79 (m, 1 H _. . 1.57 (s, 3 H) , 0.80 (d, J-1.2 Hz, 3 H)

°C HMR (100 MHZ, CDC1 ₃ ) δ 198.9, 147.6, 140.4, 137.3, 135.9, 133.8, 129.5, 128.1, 127.2, 124.2, 124.0, 106.5, 88.2, 77.7, 39.9, 28.4, 28.0, 26.5, 25.5, 24.B, 22.4, 21.7. HRMS Calcd for - (M+) 338.1882. Found: 338.1883.

Preparation of 117

The hydroxy ketone 112 (60mg, O.lS mol) was dissolved in anhydrous THF (3mL) and to this was added triethylamine (84 μL, 0.60 mmol) and. (PPH ₃ ) ₂ Pd(OAe) ₂ (22.6mg, 0.030mmol) . The mixture was heated at reflux for 44 h, cooled to RT, and concentrated in vacuo. Purification of the residue by flash chromatography (Si0 ₂ ; 4:1 hexane: EtOAc; R _f 0.26) afforded 24mg (40%) of recovered 7 and 2lmg (52%) OF 117 (yellow oil) .

IR (neat, cm- ¹ ) 3458, 3060, 2959, 2915, 1652, 1592, 1463,

1184, 1081, 1048, 942, 897.

»H HMR (400 MHZ, CDC1 ₃ ) δ 7.78 (d, J-B.O Hz, 1 H) , 7.57 (dd, J-1.3; 7.8 Hz, 1 H) , 7.44 (dt, J-1.4; 7.3 Hz), 7.31

(dt, J-l.l, € . 6 Hz, 1 H) , 6.00 (s, 1 H) , 5.02 (s, 1 H) ,

2.65 (m, 2 H) ,

2.45 (S, 1 H) , 2.06 (m, 2 H) , 1.57 (d, J-0.9 Hz, 3 H) ,

1.23 (S, 3 H) , 1.00 (s, 3 H) . ^U C HMR (100 MHz, CDC1 ₃ ) δ 205.5, 144.4, 142.8, 139.5,

138.6, 137.7, 132.6, 131.0, 128.2, 123.4, 111.0, 84.7,

38.9, 31.3, 28.2, 22.8, 21.3, 21.2.

HRM ^S Calcd for ⁽ M+) 268.1463. Found _: 268. ₁₄ 5 ₃ .

Data for 118

IR ⁽ neat, cm ^"1) 2955, 2929, 2857, 17C7, ₁ 472, ₁ 463, 125 ₇ ,

1168, 1095, 837, 776, 735.

Η HMR ⁽ 400 MHz, CDC1 ₃ ⁾ δ 10.6 (d, J-3.9 Hz, IH) , 4.8 _{4 (} d,

J=5.5 Hz, IH ⁾ , 4.55 ⁽ d, J-7.3 Hz, IH) , 4.4 ₀ (d, J- ₇ .3, IH ⁾ , 3.84 ⁽ t, J-4.8 Hz, 1 H) , 3.69 ( , 2H ₎ , 2.44 ₍ d,

J-3.9 Hz, IH ⁾ , 2.26 ⁽ m, IH) , 1.92 (m, IH) , 1.52 ₍ m, IH ₎ ,

1.08 ⁽ s, 3H ⁾ , 0.88 ⁽ s, 27H) , 0.12-0.04 (singlets, 18H ₎ .

¹³ C HMR ⁽ 100 MHz ⁾ , CDC1 ₃ ) δ 204.58, 86.87, 78.8 ₁ , 73.09,

7 ⁰ .51, 63.97, 58.98, 40.56, 40.17, 33.22, 25.9 ₁ , 25. ₇ 5, 25.67, 20.06, 18.18, 17.99, 17.83, -2.81, -2.99, - ₄ . ₁₇ , -

4.97, -5.43, -5.47.

HRMS Calcd for (M+) 572.3749. Found: 572.3727.

Preparation of 119

A dry 25 mL pear-shaped flask was charged with 120 ₍ 29mg, 0.052mmol ⁾ . To this was added 5mL of THF and the resulting solution was cooled to -78 ^β C under a nitrogen a ^t mosphere. The mixture was treated with tert-butyl li ^t hium ⁽ 153μL, 1.7 M solution in pentane, 0.26mmol ₎ and stirred for thirty minutes at -78 ^β C. The -78 ^β C bath was replaced with a 0 ^β C bath and the mixture was allowed to stir until nitrogen evolution ceased (-O.lh). The yellow-orange mixture was then treated drpowise with a solution of 118 ⁽ 15mg, 0.026mmol) in THF (500μL ₎ . The faint yellow mixture was stirred for thirty minutes at 0 ^β C before quenching with U-0 (4mL) and ether (4mL ₎ . The organic layer was separated and the water layer was extracted with ether. The extracts were combined dry over MgS0 ₄ . Removal of solvent in vacuo and purification of the residue by flash chromatography (Si0 _2; 93 _{:7 pe} t

- 186 -

ether:ether, Rf-0.33, 9:1 hexane:EtOAc) afforded 15 mg ⁽ 69% ⁾ of the allyiic alcohol 119 (clear oil) .

IR ⁽ neat, cm ^"1) 3492, 3055, 2857, 1471, 1256, 1089, 63c _, 775, 738. ^l H HMR ⁽ 400 MHz, CDC1 ₃ ⁾ δ 5.92 (t, J-3.5 Hz, IK) , ₄ .80 ₍ ά _, J-10.1 Hz, IH ⁾ , 4.28 ⁽ d, J-10.2 Hz, IH) , 4.19 (ε, 2K ₎ , 4.09 ⁽ d, J-7.9 Hz, IH ⁾ , 3.94 (br. s, IH) , 3.77 ₍ br. d, J-10.1 Hz, IH ⁾ , 3.67 ⁽ , 4H) , 2.72 ( , 2H) , 2.62 ₍ d, J-io Hz, IH ⁾ , 2.34 ⁽ m, IH ⁾ , 1.99 (m, 2H) , 1.75 (m, IH ₎ , 1.75 ⁽ s, 3H ⁾ , 1.21 ⁽ s, 3H ⁾ , 1.16 (s, 3H) , 0.85-1.0 (singlets, 36H) , 0.0-0.2 (singlets, 24H) .

^U C HMR ⁽ 100 MHZ, CDC1 ₃ ⁾ δ 144.35, 136.14, 128.36, 119.30, 81.88, 73.44, 73.10, 59.30, 58.88, 51.89, 43.01, 39.42, 37.74, 33.70, 30.04, 27.64, 26.63, 26.10, 25.96, 25.89, 25.85, 23.12, 19.05, 18.35, 18.18, 18.04, 17.98, -2.61, - 2.71, -4.44, -4.79, -5.37, -5.46, -5.50. HRMS Calcd for C^H^Si,: 838.5815. Found: 838.5805.

piscussion

This disclosure presents a synthesis of a potential c, uring fragment of l, starting from the Wieland-Kiescher ketone (27) , with appendages for the potential elaboration of t _h e remaining A and B rings.

A retrosynthetic analysis of l is given in Figure 1 ₃ . Functional group interchange yields the general structure I which is the product of an intra-molecular Diels-Al _d er cycloaddition of II for the simultaneous construction o _f rings A and B (28) . Cycloaddition precursor II is assembled by three main pathways as designated by bond cleavages given in the Figure, i.e. pathway ι, b + e, or 1 + c.

KEX: For all R _a , a ^« = 1, 2, 3 ... , R = H, acyl, alkyl, aryl, TBS, TES, TMS, and/or TBDPS unless otherwise specified. For all X _a , a ^« 1, 2, 3 ..., X -= H,H; H,OR; 0,0; OCH ₂ CH ₂ 0; and/or SCH ₂ CH ₂ CH ₂ S unless otherwise specified.

Bond a would result from a nucleophilic attack of V∑u (M - metal; X ₂ « SCH ₂ CH ₂ CH ₂ S; H _r H) (29) upon aldehyde III, which in turn is derived from degradation of olefin VI. The degradation precursor VI is the product of methyllithium addition to the central intermediate, enone VII. Bond b is formed by addition of the known metallated diene IX to the aldehyde function in V, which is the homologation product derived from aldehyde IV. Introduction of the dienophile (bond e) results from addition of a two carbon acyl-anion equivalent such as X.

An alternative route invokes an entirely different construction of the general tetracyclic intermediate I in which the B-ring is formed via a reductive coupling of the

dicarbonyl intermediate XI (Figure 14). Assem _b ly of t _h e cyclization precursor XI is achieved by coupling a pre-formed A-ring synthons χil or X∑∑i po) . Pat _h way a represents Nozaki-Kishi (13, 14) coupling of enol _t riflate with aldehyde V. Alternatively, pathway b is possi _b le _b y nucleophilic addition of XIII M « metal; x, ■= H,H; X, = SCHjCHjCHjS; X ₅ ^« OCH ₂ CH ₂ 0) to aldehyde ιv.

All of the aforementioned routes require the synt _h esis of intermediates containing C,D-ring system and equippe _d with appropriate functionality to elaborate the remaining A and B rings.

Pesultg

We began on the assumption that the ketone (27) offere _d a viable substrate for the construction of the C,D portion of 1, given its ready conversion to 54 (Figure 15) (for ketone production, see (31, 32) 7 for deconjugative ketalization and hydroboration/oxidation, see (33), and its availa _b ility in optically active form, see (34, 35, 36, 37)). The equatorial secondary alcohol of 54 (a pro C-7 hydroxyl in the C-ring of 1) was protected as the t-butyldimethylsilyl (TBS) ether (38) to give 55. The olefin of 55 was hydroborated and oxidized according to the reported protocol (33) to give a mixture of diastereo eric alcohols. Tetrapropylammoniu perruthenate catalyzed oxidation ₍₃ 9, 40) gave the cis and trans-fused ketones which converged to the trans 56 after base catalyzed equilibration. For the purpose of one carbon homologation, 56 was converted to the enol triflate 57 by -sulfonylation of its potassium enolate with N-phenyltrifluoromethane sulfonimide (41, 42,.43). Palladiua catalyzed carbomethoxylation (44) of 57 yielded the unsaturated ester 51, which was readily reduced with DIBAH to the corresponding allylic alcohol 59. Osmylation of 59 under catalytic conditions yielded a 4:1 diastereomeric ratio of triolε, 60 being the major product.

After isolation by flash chromatography (8), triol ₆₀ waε converted in one pot to oxetane 61 (45) . Careful εilylation of the primary alcohol waε achieved with TMS _C 1/pyri _d ine m ^C H ₂ C1 ₂ ⁽ - ⁷ 8-C to rt) as monitored by TLC; t _h e solution was cooled back to -78*C and treate _d wit _h trifluoromethanesulfonic anhydride. After warming to r _t TL ^C indicated that the secondary alcohol had been conver _t e _d to its triflate. While fluoride treatment tended to promote the migration of the hydroxymethyl function to give ₆₂ , it waε observed that alcoholic desilylation yielde _d oxetane _€i as the major product, the best result being achieved with ethylene glycol (analysis of the crude -n NMR spectrum indicated a ca. 6:1 ratio of €1:63). The desired oxetane ₆ 1 was isolated in 69% overall yield rom triol so. Removal of the TBS ether with tetrabutylammonium fluoride gave _d iol ₆₃ , of which a single crystal x-ray was obtained confirming the structure. It will be noted that compounds 6 ₁ an _{d 63} are the first synthesized subunits containing the full complement of oxygenε corresponding to the C,D section of taxol 1.

Having constructed pro C and D rings of l, we sought to unravel appendages useful to the introduction of rings A and B. To this end, the ketal of 61 was removed un _d er mildly acidic conditions (collidinium tosylate) to maintain t _h e integrity of both the TBS ether and the oxetane ring. Ketone 64 was subsequently converted to the corresponding enone 65 by way of its silyl enol ether (46) with Pd _(O Ac ₎₂ (47, 48). The tertiary alcohol of 65 was protected as t _h e TBS ether, though only under forcing conditions (DMF/imidazole/80 ^# C/12 h) , with an excess of TBS _C l to give 66. Degradation of 66 to dialdehyde 69 was accomplishe _{d b} y ozonolysis of the silyl dienol ether, albeit in low isolated yield (36%).

^W ith a view to obtaining the needed oxygenation a _{t C} -2, an _d in the interest of exploring alternative degradative pathways, we studied the oxidation of the enone sys _t em. T _h e tertiary alcohol of €5 waε readily converte _d to t _h e correspon ^d ing TMS ether tt. The potassium dienola _t e of _ββ was generated with potassium bis(trimethylsilyl) mide an _d subsequently treated with the Davis oxaziradine to give diol ⁶⁹ after aqueous workup. Formally, C-4 of 69 can be viewed as corresponding in stereochemistry to C-2 of ι.

Total S ^y nthesis of Taxol froττ, Diai^y^ ₁₈ m ^ _r --, • _] - _]

^S elective ketalization of the less hindered aldehy _d e of ₆₉ gives 70. Addition of the lithiodithiane vn ₍ x = ^SC H ₂ ^C H ₂ ^C H ₂ S; M - Li) followed by Swern oxidation yiel _d s ₇₁ . Release of the ketal of 71 to aldehyde 72 followe _d by addition of the vinyllithium X ( _χ . _M0 M; M - Li ₎ produces the Diels-Alder precursor 73. upon heating, 7 ₃ will cyclize to the tricyclic 74. Stereoselective reduction of the less hindered ketone of 74 yields 75 after benzoylation of the newly generated ⁽ a) secondary alcohol. Allylic oxidation in the A-ring of 75, followed by Swern oxidation if necessary, gives enone 76. The A-ring carbonyl reduces to the α configuration using a bulky borohydride. Subsequent benzyl protection and Raney nickel reduction of the thioketal produces 77. Franklin Davis hydroxylation of the potassium enolate of ketone 77 gives the corresponding hydroxy ketone in which the oxaziridine approaches from the convex face. After fluoride induced desilyation with TBAF, peracetylation yields 71. Hydrogenolysis of the benzyl ether and subsequent side chain coupling produces 79. The acetate at C-7 is selectively removed to to, which in turn is doubly deprotect ^β d by simultaneous removal of the MOM and EE groups to give taxol.

Simnle Mimics of Taxol

In Figure 17 are given syntheses of simple taxol mim _i cs w ^h ic ^h contain two critical features of taxol i _t sel _f , namely the side chain and the acetoxyoxetane.

^A cetylation of 64 gives gl. Reduction of the ketone of _βi with a bulky hydride (L-selectride) produces alcohol ₈₂ . ^C oupling of the side-chain using the method of Denis et al. ⁽ 4 ⁹⁾ yields mimic 85 after removal of the TBS and EE groups. The procedures are the same for the unsaturated series ₍₆₅ to 90) .

Diol ⁶⁸ is ^b enzoylated at the less hindere _d secon _d ary alcohol to give 91, leaving the tertiary position open to subsequent acetylation, yielding 92. The same reduction/coupling/ eprotection sequence described above is applied to 92 giving mimic 96.

The goal of a synthesis of baccatin III and thence taxol (1) continues to engage the attention of many laboratories. ² - '' ^x While it is unlikely that tne availability of taxol will be affected by a total synthesis, there is certainly every possibility that interesting and useful new analogs could become accessible if synthetic mastery of the system is gained. The complex chemical issues associated with surmounting the obstacles bestriding any total synthesis of taxol have encouraged many new strategic and methodological departures. ^{il U}

Herein we describe approaches to the synthesis of taxol analogs, and eventually taxol itself, by attaching the future A and C rings through a one- arbon spacer. This spacer carbon corresponds to the C-j carbon of the taxane skeleton. We start with a route in which the C, carbon v;as appended to C, and joined to a lithiated version of C ₃ (Figure 19) . The already described iodoketal 108" was converted to 109, in.87% yield. This compound reacted with 2-lithiostyrene ⁶⁰ to produce a 79% yield of a 2:1 mixture of 110 and 111, respectively. Only the latter

(vide infra) compound was a competent intermediate to reach the taxane- ike series. Recycling of the unwanted

110 was accomplished by oxidation to 112 and reduction to the 110:111 mixture. The alcohol functions of 111 were engaged as the isopropylidene derivative 113. The vinyl group was converted to the vinyl carbinol 115 aβ a single diastereoisαmer" in two operations. In the key step, reaction of 115 with palladiu (II) acetate, ^β "° under the conditions shown, afforded an 80% yield of ill secondary alcohol.** The structure of 116 was proven by an X-ray cryβtallographic determination. ⁴⁵ It is interesting to that 117, the corresponding C,-Cj diastereoisαmer of 115, which was synthesized from HO in the same way as 115 was derived from 111, failed to undergo any discernable

intramolecular Heck reaction.

The versatility of the Heck process waε fur _t her demonstrated in the case of hydroxyketone 112 (Fiσure I _S , bottom) . This compound reacted, as shown, to afford _t he B-nor-C-aryl taxane analog 117 in 52% yield (92% based on recovered 112) . To the best of our knowledge compound 117 is the first such B-nor taxane structure to have been prepared.

Before contemplating the application of this type of an intramolecular Heck reaction to the synthesis of taxols containing the full substructure, it would be necessary to demonstrate the feasibility of forming the C,, C-,, and C ₃ linkage in a context where ring C were appropriately substituted (Figure 19, bottom). Toward this end the vinyllithium derivative 121" was coupled to aldehyde 119,** derived in a straightforward way from the previously described building block 118. " In the event, coupling under the conditions shown, afforded a 60% yield of a single stereoisαmer 120.** While 120 is not necessarily the optimal intermediate for paving the way for an intramolecular Heck reaction, the feasibility and stereospecificity of the C,-C, bond formation from readily available intermediates argue well for testing this and related possibilities.

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15

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35

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- 196 -

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46. The free tertiary hydroxyl served, as the lithium alcoholate, to direct the lithium enolate formation to the regiochemically desired position. ₍ When the alcohol was silylated, a significant amount of the undesired enone was formed). The lithio-dianion was subsequently trapped with excess TMSCl to give the disilyl enol ether. During the course of subsequent oxidation, the majority of the tertiary silyl ether was concomitantly removed. After consumption of starting

aterial (TLC) , MeOH and K _j CO _j were added to comple _t e the desilyation process to give 65.

47. Ito, Y. ; Hirao, T. ; Saegusa, T.J. Qrσ. Cher.. 1 ₉₆₇ , 43, 1011.

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60. A 0.35M solution of 2-lithiostyrene was prepared dropwise addition of nBuLi to a -78 ^* c solution of 2- bromostyrene in 5:1 THF:diethyl ether.

61. The relative configuration of the secondary carbinols, 9 and 11, and the origins of this remarkable stereoselectivity remain to be determined.

62. Heck, R.F. "Palladium Reagents in Organic Synthesis," Academic Press; 1985, 179.

63. For a recent example, see: McClure, K.F.; Danishefsky, S.J. J. Am. Chem. s _7r , ₁₉₉₃ , _{115^ 6094}

64. The oxidation of alcohols in the presence of palladium(II) salts is certainly well precedented ^6- and a minor amount (5-10%) of the eyclized allylic alcohol was also obtained.

65. Crystal data for compound 10: crystallizes in the triclinic P, (no. 2) with a-8.124 (l) A, b*=i7.932 (1) A, c=7.3217 (9) A, cr-91.986 (8)*, 0=114.637 (9) A Y-79.358 (8)', and V-951.7 (2)', . with Z=2 and p _Mle d ^« 1.181 g/crn ³ . A total of 3067 reflection were collected in the +h, ±k, ±1 octants in the range of 5'≤θ<120 ^* . The structure was solved using direct methods and refined in full-matrix least- squares techniques for a final R « 0.052 and R «= 0.057. All measurements were made on a RIGAKU AFC5S

diffractometer with graphite monochromate _{d C} u Kα (1.54178 A) radiation.

66. Compound 15 was prepared from the previously reported 13 ¹⁰ by the following transformations: ₍ i ₎

KHMDS, TBSCl, THF, -78 ' C (ii) 0 ₃ , -78- _C , PPh ₃ , then 3N HCl. (iii) TMSCHN ₂ . (iv) PPTS, MeOH, 7 ₀ ' _C . ₍ v ₎ LAH, EtjO, 0-C. (vi) o-N0 ₂ C ₆ H ₄ SeCN, CH _? C1 ₂ , Bu ₃ P. ₍ vii ₎ H^, THF. (viii) PPTS, 1^0, acetone, (ix) LAH, Et _?0 . (X) TBSCl, EtjN, DMAP. (ix) 0 ₃ , PPh ₃ , _C H _2C 1 ₂ . _A n account of this and related degradations of ₁₃ is currently being prepared: DiGrandi, M.J. ; Isaacs, R.C.A. ^; Coburn, CA. ; Danishefsky, S.J. unpublis _h e _d results.

67. Magee, T.V. ; Bornmann, W.G. ; Isaacs, R. _C .A. _; Danishefsky, S.J. J. ore. e _.p _τ ι ₉₉₂ , 5 ₇ , ₃₂₇₄ .

68. On the basis of the previous findings, ² *- ^2b the stereochemistry at the secondary carbinol center would be formulated as s, _f in the enantiomer shown.