Dkt. No. 0575/81382-A-PCT/JPW/GJG/ML

SYNTHESIS OF THE POTENT IMMUNOSUPPRESSANT AGENTS DALESCONOL A AND B

This application claims priority of U.S. Provisional Application No. 61/338 551, filed February 18, 2010, the contents of which are hereby incorporated by reference.

The invention disclosed herein was made with government support under grant number R01- GM849 4 awarded by the National Institutes of Health. Accordingly, the U.S Government has certain rights in this invention.

Throughout this application, certain publications are referenced in brackets. Full citations for these publications may be found immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to describe more fully the state of the art to which this invention relates.

Background of the Invention

Seeking to identify new classes of potent immunosuppressants, Tan and co-workers recently isolated and characterized dalesconol A and B (1 and 2, Figure 1) from a culture of Daldinia eschsholzii IFB-TL01 residing inside the gut of the mantis species Tenodora aridifolia. ^li Apart from possessing an unprecedented carbon-based skeleton containing seven fused rings of various size, these isolates indeed possessed immunosuppressive activity (ICso values of 0.16 μg/mL and 0.25 μg mL, respectively), levels comparable to that of the clinically utilized cyclosporin A (IC50 = 0.06 μ^ητΐ..), but with significantly reduced background cytotoxicity Intriguingly, racemic mixtures of either 1 or 2 were found to be more potent than their separated enantiomers. She, Lin and colleagues obtained the same natural products (1 and 2) from a marine-based endophytic fungus (Sporothrix sp. #4335) that grew on the inshore mangrove tree Kandelia candel, naming them as sporothrin A and B; ¹⁴¹ they also isolated and characterized a related metabolite (sporothrin C, 3) Their activity screens revealed that 1 was a potent acetylcholinesterase inhibitor and that both 1 and 2 possessed modest antitumor activity. As such, members of this structurally novel natural product family could serve as valuable leads for future pharmaceutical development. 2

Described herein are the first total syntheses of dalesconoi A and B (1 and 2) through an expedient and scalable route capable of providing the material supplies needed for more thorough biochemical applications.

Summary of the Invention

Disclosed are compounds having the structure:

e

wherein

bonds α, β, γ, δ, ω, η, χ, ε, κ, and μ are each present or absent; when bond β is present, is absent, R3 is H, -OR ₁₉ , or together with R ₂ form an unsubstituted or substituted aryl ring,

wherein R| ₉ is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic; when bond β is absent, is present, Ry is O; when bond γ is absent, R4 is present and is H;

when bond γ is present, R4 is absent; when bond a is present, bond δ is absent, R| ₂ is present and is H;

when bond a is absent, bond δ is present, R| ₂ is absent;

when bonds ε and η are absent, bonds ω, χ, and μ are present, and Rj6 is O; when bonds ε and η are present, bonds ω, χ, and μ are absent, and R|« is H or -OR20. wherein R ₂ o is H, alkyl, alkenyl. alkynyl, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

Ri is H. -OR21, or together with R ₂ form an unsubstituted or substituted aryl ring, wherein R2 ₁ is H, alkyl. alkenyl, alkynyl, cycloalkyl, cycloalkenyl,

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

R ₂ together with R| or R ₃ form an unsubstituted or substituted aryl ring;

R ₅ , R6, R ₇ , Rg, Rq, Rio. i i _* Ri3. Ri4. i7 _% Ri8. are each, independently, H, -OH, -OR22, alkyl, alkenyl, alkynyl, -SR22, -N(R2 ₂ >2, -SO2R22, -CO2R22, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen,

wherein R ₂₂ is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl.

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

R i5 and Ri6 are each, independently, H, -OR ₂₂ , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or together form a heterocyclic ring; wherein each instance of alkyl, alkenyl, alkynyl, is branched or unbranched, substituted or unsubstituted; or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof. Also disclosed are compounds having the structure: 5

bond a is present or absent;

bond γ is present or absent;

R ₅ , Rft, R ₇ , Re, R9, Rio, Ri I , Rii. Ri4, R15. R17, Ris, are each, independently, H, -OH, -

OR ₂₂ , alkyl, alkenyl, a!kynyl, -SR ₂₂ , -N(R ₂ 2)2, -SO2R22, -CO2R22, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen,

or Rt and R ₇ together form =0;

when bond β is present, R _½ is O;

when bond β is absent, R½ is -OR22;

wherein R ₂₂ is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

wherein each instance of alkyl, alkenyl, alkynyl, is branched or unbranched, substituted or unsubstituted;

R38, Rw, R40, and R41 are each, independently, H, -OH, -OR42, alkyl, alkenyl, alkynyl, -SR42, -N(R 2>2, -SO2R42, -CO2R42, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen,

wherein R 2 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, 6

or an enantiomer diastereomer, or pharmaceutically acceptable salt thereof.

Also disclosed is a composition free of bacterial or fungal extract comprising the compounds as well as naturally occurring compounds which can be synthesized by the methods herein, as welt as the process of synthesis.

7

Brief Description of the Figures

Figure 1. Scheme 1 - Retrosynthetic analysis of the dalesconols (1 and 2) based on an attempt to utilize key intermediate 5, a variant of 6 which has already led to a variety of resveratrol-derived polycyclic natural products (7-9).

Figure 2. Scheme 2 - Synthesis of key phenolic building blocks 11, 16, and 18. Figure 3. Scheme 3 - Total synthesis of dalesconol B (2).

Figure 4. Scheme 4 - Unique skeletal rearrangements deriving from differential protection of the phenols which afford 28 and 30.

Figure 5. Scheme 5 - Total synthesis of dalesconol A (1).

Figure 6. Additional analogs prepared for screening activities.

8

Detailed Description of the Invention

This invention provides compound having the structure:

R ₂

wherein

bonds α, β, γ, δ. ω, η, χ, ε. κ, and μ are each present or absent;

when bond β is present, κ is absent, Ri is H, -OR 19, or together with R ₂ form an unsubstituted or substituted aryl ring,

wherein R19 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

when bond β is absent, κ is present, R3 is O;

when bond γ is absent, R4 is present and is H;

when bond γ is present, R4 is absent;

when bond a is present, bond δ is absent, R12 is present and is H;

when bond a is absent, bond δ is present, R ₁ 2 is absent;

when bonds ε and η are absent, bonds OX χ, and μ are present, and R½ is O; when bonds ε and η are present, bonds co, χ, and μ are absent, and Rie is H or -OR20 wherein R20 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

Ri is H, -OR2 ₁ , or together with R ₂ form an unsubstituted or substituted aryl ring, 9 wherein R ₂ i is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

R ₂ together with R| or R ₃ form an unsubstituted or substituted aryl ring;

R5, Re, R7, Rs. 9, io, Ri in Ri3. Ru, R17, Ri8. are each, independently, H, -OH, -OR22, alkyl, alkenyl, alkynyl, -SR22, -N(R22b, -SO2R22, -CO2R22. cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen,

wherein R ₂ ? is H, alkyl, alkenyl, alkynyl cycloalkyl, cycloalkenyl,

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

or R ₆ and R7 together form =0;

Ris and R| ₆ are each, independently, H, -OR ₂₂ , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or together form a heterocyclic ring; wherein each instance of alkyl, alkenyl, alkynyl, is branched or unbranched, substituted or unsubstituted;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

In an embodiment, the compound has the structure:

wherein R ₂ 3, R24, R25. and R½ are each, independently, H, -OH, -OR ₂₇ , alkyl, alkenyl, alkynyl, -SR27, - (R27>2. -SO2R27. -CO2R27, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl. unsubstituted or substituted heterocyclic, or halogen,

wherein R ₂₇ is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

embodiment, the compound has the structure:

28. R29. R30, and R31 are each, independently, H, -OH, -OR32, alkyl, alkenyl, alkynyl, -SR32, - (R32)2, -SO2R32, -C02R32, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen,

wherein R32 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

embodiment, the compound has the structure:

bond γ is present or absent;

R33, Rj , R.¾: and R36 are each, independently, H, -OH, -OR37, alkyl, alkenyl, alkynyl, -SR37, -N(R37>2, SO2R37, -CO2R37, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen,

wherein R37 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof. embodiment, the compound has the structure:

wherein

R38. R39, R40 and R41 are each, independently, H, -OH, -OR42, alkyl, alkenyl, alkynyl, -SR42, -N(R42h, -SO2R42, -CO2R42, cycloalkyl, cycloalkenyl, unsubsiituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen,

wherein R42 is H, alkyl, alkenyl, alkynyl cycloalkyl, cycloalkenyl,

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

In an embodiment,

Ri5 and Ri ₆ together form a heterocyclic ring;

R∑3» R24. R25, and R26 are each, independently, H, -OH, -OR27, wherein R27 is alkyl; or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

In an embodiment,

R 15 and R 16 together form an acetonide ring;

R3, R5, R¾, R ₇ , Re, R9, io. Ri i» Ri3. Ri4» Ri7. Rie. R23. R∑4» R25. and R¾ are each, independently, H, -OH, or -OCH3,

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

In an embodiment,

Ri5 and Ri6 together form a heterocyclic ring:

R28, R29, R30, and R31 are each, independently, H, -OH, -OR32, wherein R32 is alkyl; or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

In another embodiment,

Ri is H;

Ri5 and R|6 together form an acetonide ring;

R5, Re, R7, Rg, R Rio _* Ri I. Ri3. Ri4 Ri7. Ri8. R28. R29» R3o» and R31 are each, independently, H, -OH, or -OCH3,

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof. In an embodiment, the compound has the structure

HjCO

In an embodiment,

bond γ is present or absent;

R33. R34. R351 and R¾> are each, independently, H, -OH, -OR 37

wherein R37 is aikyl;

or an enantiomer, diastereomer or pharmaceutically acceptable salt thereof.

In another embodiment,

bond γ is present or absent;

R5, R$, R7, Re, R9, Rio Ri I, i3. Ri4, R15. Ri6. R17. R|8» 33» R34, R35t and R36 are each, independently, H, -OH, -OCH3, or -OCH ₂ OCH ₃ ;

or an enantiomer. diastereomer or pharmaceutically acceptable salt thereof.

In an embodiment,

R3g, R3 . R 0, and R4! are each, independently, H or -OH;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

In another embodiment, R ₃ , 1*6, R7, Rg. R¾ Rio. RI I , Ri3. Ri . R 15, R17, Ri«. Rj», R.19. R40, and R41 are each, independently, H or -OH;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof. bodiment, the compound has the structure

bond a is present or absent;

bond γ is present or absent;

R ₅ , Re, R7, e, R9, Rio, Ri I, i3, Ri4, i5, Ri7, Ri8, are each, independently, H, -OH, OR22, alkyl, alkenyl, alkynyl, -SR22, -N(R ₂₂ )2, -SO2R22, -CO2R22, cycloalkyl. cycloalkenyl. unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen,

or R and R ₇ together form =0; when bond β is present, R| ₆ is O;

when bond β is absent, Ri is -OR22; wherein R ₂₂ is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic; wherein each instance of alkyl, alkenyl, alkynyl, is branched or unbranched, substituted or unsubstituted;

R.w R39 R 0, and R 1 are each, independently, H, -OH, -OR42. alkyl, alkenyl, alkynyl, -SR42, - (R42>2. -SO2R42, -CO2R42. cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen,

wherein R42 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic,

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

In an embodiment, the compound has the structure:

wherein

bond μ is present or absent;

bond γ is present or absent;

bond ω is present or absent;

R _g , R ₉ , Rio, RI I, Rn, Ri4. Ris, Ri7, Rie, are each, independently, H, -OH, -OR22, alkyl, alkenyl, alkynyl, -SR22, - (R2 >2, -SO2R22, -CO2R22, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen,

when bond μ is present, R½ is O;

when bond μ is absent, R| _¾ is -OR22;

wherein R22 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

wherein each instance of alkyl, alkenyl, alkynyl, is branched or unbranched, substituted or unsubstituted;

R38, RTO, R40, and R41 are each, independently, H, -OH, -OR42, alkyl, alkenyl, alkynyl, -SR42, - (R42>2, -SO2R42. -CO2R42, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen, wherein R ₄ 2 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl. unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic,

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

In an embodiment, bond μ is present, Ri6 is O.

In an embodiment,

bond ω is present;

bond γ is absent;

R ₉ , R1 ₁ , Ri i, R|4. R|7, Rig, R38, R and R ₄ 0 are each, independently, H;

R ₈ , Rio, Ri5. and R41 are each, independently, -OR2 ₂ ;

wherein R22 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic,

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

In an embodiment, the compound has the structure

wherein

bond μ is present or absent;

bond γ is present or absent;

bond ω is present or absent;

Re, R¾ Rio. Ri i, Ri3, Ri4» R15. R17, Rie. are each, independently, H, -OH, -OR22, alkyl, alkenyl, alkynyl, -SR22. - (R22>2. -SO2R22, -C02R22. cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen,

when bond μ is present, Ri is O;

when bond μ is absent, R|6 is -OR22; wherein R22 is H, alkyl, alkenyl, alkynyt, cycloalky!, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

wherein each instance of alkyl, alkenyl, alkynyl, is branched or unbranched, substituted or unsubstituted:

R38, R39. R-w. and R 1 are each, independently, H, -OH, -OR42, alkyl, alkenyl, alkynyl, -SR42. -N(R4?>2, -SO2R42, -CO2R42, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen,

wherein R42 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic,

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

In an embodiment,

bond μ is present, Ri ₆ is O;

bond co is present;

R¾, R||. Rn, R]4, R|7, Rig, R ₃₈ . R39, and R40 are each, independently, H;

R¾, Rio, Ri5. and R41 are each, independently, -OR ₂₂ ;

wherein R22 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic,

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

This invention provides a composition free of bacterial or fungal extract comprising a compound having the structure: 22

bonds α, β, γ, δ, ω, η, χ, ε, , and μ are each present or absent;

when bond β is present, is absent, R3 is H, -OR ₁ , or together with R2 form an unsubstituted or substituted aryl ring,

wherein R1 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

when bond β is absent, κ is present, R3 is O;

when bond γ is absent, R ₄ is present and is H;

when bond γ is present, R4 is absent;

when bond a is present, bond δ is absent, R12 is present and is H;

when bonds ε and η are absent, bonds co. χ, and μ are present, and R _½ is O;

when bonds ε and η are present, bonds (O, χ. and μ are absent, and R| ₆ is H or -OR20, wherein R20 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

Ri is H, -OR21, or together with R2 form an unsubstituted or substituted aryl ring, wherein R21 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

R2 together with R| or R3 form an unsubstituted or substituted aryl ring; 23

R ₅ , R&, R7, R». R<*, Rio. Ri i, Ri3, i , R17, Rie. are each, independently, H, -OH, -OR22, alkyl. alkenyl, alkynyl, -SR22, -N(R2 . -SO2R22. -CO2R22 cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen,

wherein R2 ₂ is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

or Re and R ₇ together form =0;

Ri5 and R i6 are each, independently, H, -OR ₂₂ , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl. unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or together form a heterocyclic ring; wherein each instance of alkyl, alkenyl, alkynyl, is branched or unbranched, substituted or unsubstituted;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

In an embodiment of the composition, the compound has the structure

wherein

R23. R2 » R25. and R26 are each, independently, H, -OH, -OR27, alkyl, alkenyl, alkynyl, -SR27 -N(R27>2. -SO2R27 -CO2R27. cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen. 24

wherein R27 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl unsubstituted or substituted heterocyclic;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

In an embodiment of the composition, the compound has the structure

wherein

R28 ¾ . R30, and R31 are each independentl H, -OH OR32, alkyl, alkenyl, alkynyl -SR32, -N R32>2 -SO2R32 -CO2R32 cycloalkyl cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl. unsubstituted or substituted heterocyclic or halogen,

wherein R32 is H, alkyl alkenyl alkynyl, cycloalkyl cycloalkenyl

unsubstituted or substituted aryl. unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic:

or an enantiomer. diastereomer. or pharmaceutically acceptable salt thereof.

In an embodiment of the composition, the compound has the structure 25

R

R 'β

wherein

bond γ is present or absent;

R33, R34. R3 ₅ . and R% are each, independently, H, -OH, -OR ₃₇ , alkyl, alkenyl, alkynyl -SR37, -N(R37>2, SO2R37, -CO2R37, cycloalkyl, cyctoalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen,

wherein R37 is H, alkyl. alkenyl, alkynyl, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

In an embodiment of the composition, the compound has the structure

26

R.i8. R39, R40. and R41 are each, independently, H, -OH, -OR42, alkyl, alkenyl, alkynyl, -SR42, -N(R42>2. -SO2R42. -CO2R42, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen,

wherein R42 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

In an embodiment of the composition,

Ri5 and R i6 together form a heterocyclic ring;

R23, R24, R25. and R26 are each, independently, H, -OH, -OR27, wherein R27 is alkyl; or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

In an embodiment of the composition,

Ri5 and R|6 together form an acetonide ring;

R3, R5, Re, R7, Re» R9, Rio» RI I . Ri3. i4» R17. Ri8» R23, R24, R25. and R2 are each, independently, H, -OH, or -OCH3,

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

In an embodiment of the composition, the compound has the structure: 27

In an embodiment of the composition,

Ri5 and R i6 together form a heterocyclic ring;

R28, R29, R¾), and R31 are each, independently, H, -OH, -OR32, wherein R _¾ is alkyl; or an enantiomer, diastereomer. or pharmaceutically acceptable salt thereof.

In an embodiment of the composition,

Ri is H;

R 15 and R 16 together form an acetonide ring;

Rs, Re, R7. Re. R9. Rio. Ri I . Ri3. Ri4- R i7> Rie, R28. R29, R30 and R31 are each, independently, H, -OH, or -OCH3,

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof. In an embodiment of the composition, the compound has the structure:

embodiment of the composition, 28 bond γ is present or absent;

R33, Rj4 R35, and R¾ are each, independently, H, -OH, -OR37, wherein R37 is alkyl; or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof. In an embodiment of the composition,

bond γ is present or absent;

R5, Re, R ₇ , Re, R9. Rio _* RI I . R i3» i . Ris. Ri6» i7» Ris, R33. R34. R35. and R.% are each, independently, H, -OH, -OCH3 or -OC^OCH^

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

In an embodiment of the composition, the compound has the structure:

In an embodiment of the composition

R$ and R7 are each H, or together form =0·

38, R39, 0, and R41 are each, independently, H or -OH;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof. 29

In an embodiment of the composition,

Rs, Re, Rq, Rio, Ri i, Ri3. Ri4, Ria» Ri7, Rig. 38. R3 R40. and R41 are each, independently. H or -OH;

R6 and R? are each H, or together form =0;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof. embodiment of the composition, the compound has the structure

This invention provides a compound having the structure:

wherein

bond φ is present or absent;

R42. R43. R 4, 1*45» R47t R 81 R49t R51. R52. Rs3» RM» R55. Rse. s7» Rss, R59, a d R<JO are each, independently, H, OH, alkyl, alkenyl, alkynyl, -OR^j, -SR _$ i, - (R«i)2, -

SO2R ₁ , -COiR _ft i, cycloalkyl, cycloalkenyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heterocyclyl, or halogen; or R49 and R50 together form a heterocyclic ring,

wherein each occurrence of R< _¾ i are, independently, H, alkyl, alkenyl, or alkynyl;

R46 is OH,

wherein each occurence of alkyl, alkenyl, alkynyl is branched or unbranched, substituted or unsubstituted;

or an enantiomer, diastereomer, or salt thereof. bodiment,

bond φ is present or absent;

R42. R43. 44» 45 R47. 48. R49. Rso. R51. R52. 53» s4» Rss. s6» R57. ss. R59, and R¾o are each, independently, H, OH, -OR ₆ i; or R49 and Rso together form a heterocyclic ring,

wherein R*i is alkyl;

R46 is OH,

wherein each occurrence of alkyl, alkenyl, alkynyl is branched or unbranched, substituted or unsubstituted; or an enantiomer, diastereomer, or salt thereof.

In an embodiment,

bond φ is present or absent;

1¾42» R43» R44, R45. R 7, R48, R49, R50. R51. s2» SJ. Rs4» Rss, R56. s7 _* R58, s9- and R#) are each, independently. H, OH, -OCH¾, -OCH ₂ OCH ₃ . -OCH ₂ phenyl; or R49 and R50 together form an acetonide ring;

R46 is OH,

or an enantiomer, diastereomer, or salt thereof.

In an embodiment, the compound has the structure:

This invention provides a compound having the structure: 32

wherein

Re?, Rei. RM, and R*7 are each, independently, H or -ORee,

R ₆ 5 is halogen;

R66 is -CH ₂ P(0)(OR ₆₈ ) ₂ or -CH^CC^Ra CHzCC^Rai;

wherein each occurrence of R^s is each, independently, branched unbranched, substituted or unsubstituted alk l.

In an embodiment,

R62, 63. Rfi4, and Re7 are each, independently, H or -OCH3, R65 is Br,

Rtt is -CH2P(0)(OCH ₂ CH3)2 or CH=C(C0 ₂ CH ₂ CH ₃ )CH ₂ C02CH2CH3.

In an embodiment.

R ₆₂ and R<s4 are each H;

R63 and R^i are each -OCH3:

R« i Br;

R66 is -CH ₂ P(OKOCH ₂ CH3)2.

In an embodiment,

R«3, R - and R 7 are each H;

R ₆₂ is -OCH3;

R« i Br;

R^ is -CH=C(C0 ₂ CH ₂ CH ₃ )CH ₂ CC½CH ₂ CH ₃ .

In an embodiment,

R«, 63 and RM are each H;

R ₆₇ is OCH ₃ ;

R<55 is Br; 33

R66 is -CH ₂ P<0)(OCH ₂ CH3)7. This invention provides a compound having the structure:

^R 70

wherein

R<S8 and R<» are each, independently, alkyl, -C(=0)R72, or -CH2OR ₇ 2,

R70 and R71, are each independently, H, halogen, -CH(=0), or -CO2R72,

wherein each occurrence of R7 is, independently, branched or unbranched. substituted or unsubstituted alkyl.

In an embodiment.

Res and Re9 are each, independently, -CH ₃ , -C(=0)CH3, -CH2OCH3, or -CH ₂ -phenyl; R70 and R71, are each independently. H, Br, -CH(=0), or -C0 ₂ CH ₂ CH ₃ .

In an embodiment,

es is -C(=0)CH3;

Rw is -CH ₃ ;

R70 is Br;

R71 is -CO2CH2CH3.

In an embodiment,

Ri» is -CH ₃ ;

R69 is -CH2OCH3;

R70 is Br,

R71 is H.

In an embodiment,

R<i8 is -CH3;

R« is -CH ₂ -phenyl; 34

R ₇ o is H;

R ₇ , is -CH(=0).

This invention provides a compound having the structure:

R ₃ is H or -OR i9,

wherein R1 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

R5. R$, R ₇ , Re, R » Rio, Ri i, |6» Ri7i Ri8, R23, R24, R25. R?6» are each, independently,

H, - OH, -OR1 ₂ , alkyl, alkenyl, alkynyl, -SR ₂₂ , -N(R ₂₂ ) ₂ , -S0 ₂ R ₂₃ , -C0 ₂ R ₂₂ , cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen,

wherein R ₂₂ is H, alkyl alkenyl, alkynyl, cycloalkyl, cycloalkenyl,

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

wherein each instance of alkyl, alkenyl, alkynyl is branched or unbranched, substituted or unsubstituted;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

In an embodiment,

R ₃ is -ORi9, 35 wherein R 1 is alkyl;

Rs. Re, R7. Rs. 9, Rio. RI I, Ri6. Ri7, Rie, R23, R24. R25, R26. are each, independently, H, -OH, or -OR22

wherein R ₂ 2 is alkyl;

In another embodiment,

R is -OCH ₃ ;

Rs, R«, R7, Rs, Ro, Rio, RI I , Ri6, 17. Rie, R23, R24, R25. R26 are each, independently, H, -OH, or OCH3. embodiment, the compound has the structure:

wherein

bond γ is present or absent; 36

R ₅ , Re, R7, e, R<», Rio. i I , R i3, Ri4, Rn, Rie» are each, independently, H, -OH, -OR22, alkyl, alkenyl, alkynyl, -SR22. -N(R22>2 _* -SO2R22, -CO2R22. cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl. unsubstituted or substituted heteroary!, unsubstituted or substituted heterocyclic, or halogen,

wherein R _?? is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

Ri5 and R|¾ are each, independently, H, -OR22, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or together form a heterocyclic ring;

R33, Rj4. R35. and R36 are each, independently, H, -OH, -OR37, alkyl, alkenyl, alkynyl, -SR37. - (R37>2, -SO2R37, CO2R37, cycloalkyl. cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen,

wherein R37 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

wherein each instance of alkyl, alkenyl, alkynyl, is branched or unbranched, substituted or unsubstituted;

comprising:

a) contacting a compound having the structure

wherein

bond φ is absent; 37

I¾42, R*3. R44, 45» R47. R4S, R49, R50. R51. Rs2. Rs3» R54, 551 56. Rs7» 58. 59, and R«) are each, independently, H, OH, alkyl, alkenyl, alkynyl, - Rei, -SR^i, -N(Rei 2, - S0 ₂ Rn, -CO2R61, cycloalkyl cycloalkenyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl. a substituted or unsubstituted heterocyclyl or halogen; or R49 and R50 together form a heterocyclic ring,

wherein each occurrence of R ₆ i are, independently, H alkyl, alkenyl, or alkynyl;

R46 is OH,

wherein each occurence of alkyl, alkenyl, alkynyl is branched or unbranched, substituted or unsubstituted,

with a suitable acid;

b) contacting the product of step a) with Phl(0 Ac>2 to form the compound;

so as to thereby prepare the compound. embodiment, the process further comprises:

c) contacting the product of step b) with hydrogen gas in the presence of a palladium catalyst. embodiment, the compound prepared has the structure:

38

wherein 39

R ₅ , Rft, R7, Re. R9. Rio, Ri i. Ri3, i , R 17. Rie. are each, independently, H, -OH, -OR22, alkyl, alkenyl, alkynyl. -SR22, -N(R ₂₂ )2, -SO2R22, -CO2R22, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen; or R« and R7 together form =0,

wherein R22 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

R i5 is H, -OR ₂₂ , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or together form a heterocyclic ring;

R38 R39. 40, and R41 are each, independently, H, -OH, -OR42. alkyl, alkenyl, alkynyl, -SR42. -N(R 2>2, -SO2R42, -CO2R42, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen,

wherein R42 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

comprising:

a) contacting a compound having the structure

wherein

bond γ is absent;

Rs, R , R7, Re, R9, Rio, R11, Ri3. R , R17, Rie. are each, independently, H, -OH, -OR22, alkyl, alkenyl, alkynyl, -SR22. - (R ₂ 2)2, -SO2R22, -CO2R22, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen,

wherein R22 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

R i5 and Ri6 are each, independently, H, -OR2?, alky I, alkenyl, alkynyl cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or together form a heterocyclic ring;

R33, R34. 35. and R36 are each, independently, H, -OH -OR37 alkyl, alkenyl, alkynyl, -SR37, - (R37>2, -SO2R37, -CO2R37, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen,

wherein R37 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

wherein each instance of alkyl, alkenyl, alkynyl, is branched or unbranched.

substituted or unsubstituted;

with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone to form the compound;

so as to thereby prepare the compound. bodiment, the compound prepared has the structure:

42

wherein R _{2 i} is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

Ri2 is H;

R5, R«, R ₇ . Re, Ro. Rio, R11. t3, Ri4, R17. Ri8, are each, independently, H, -OH, -OR22, alkyl, alkenyl, alkynyl, -SR22, -N(R22>2, -SO2R22, -CO2R22, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryi, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen.

wherein R 2 is H, alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl,

unsubstituted or substituted aryl. unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic:

R)5 and Rie are each independently, H, -OR ₂₂ , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or together form a heterocyclic ring;

28, R29, R30, and R31 are each, independently, H, -OH, -OR32, alkyl, alkenyl, alkynyl, -SR32, -N(R37>2, -SO2R3? -CO2R32, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl unsubstituted or substituted heterocyclic, or halogen,

wherein R¾ ₂ is H, alkyl, alkenyl. alkynyl, cycloalkyl, cycloalkenyl,

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic:

comprising:

a) contacting a compound having the structure

43 wherein

bond φ is absent;

R 2. R43. R . R45» 1*47·. R48. R . R50, Rsi> R52. Rs3. R54. RSS» RS6- R57. Rs8» Rs . and eo are each, independently, H, OH, alky], alkenyl, alkynyl, -ORei, -SR«i, -N(R ₆ ih» - SO2R ₆₁ , -CO ₂ R ₆₁ , cycloalkyl, cycloalkenyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heterocyclyl, or halogen; or R49 and R50 together form a heterocyclic ring,

wherein each occurrence of R i are, independently, H, alky I, alkenyl, or alkynyl;

R46 is OH,

wherein each occurence of alkyl, alkenyl, alkynyl is branched or unbranched, substituted or unsubstituted,

with a suitable acid to form the compound;

so as to thereby prepare the compound.

In an embodiment, the compound prepared has the structure

'3

This invention provides a process for preparing a compound having the structure 44

wherein

R ₃ is H or -OR |9,

wherein R19 is H, alkyl, alkenyl, alkynyl, cycioalkyl, cycloalkenyl,

unsubstituted or substituted aryl. unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

R ₅ , Re, R7. Re, Rg, Rio, I I . R16. R17, Ris, R23, 2 , R25, R26, are each, independently, H, -OH, -OR22, alkyl, alkenyl, alkynyl, -SR22. -N(R _;2 )2, -SO2R22, -CO2R22, cycioalkyl, cycloalkenyl. unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen,

wherein R ₂₂ is H, alkyl, alkenyl, alkynyl, cycioalkyl, cycloalkenyl,

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

wherein each instance of alkyl, alkenyl, alkynyl, is branched or unbranched, substituted or unsubstituted;

comprising:

a) contacting a compound having the structure

45

wherein

R ₃ is H or -OR,9,

wherein R1 is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

R ₅ , R«, R7, e R9, Rio, Rn. R13. Ri , Ri7, R18, are each, independently, H, -OH, -OR22, alkyl, alkenyl, alkynyl, -SR22, -N(R??)2, -SO2R2?, -CO2R22. cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen,

wherein R ₂₂ is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,

unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic;

Ri2 is H,

R15 and Ri6 are each, independently, H, -OR ₂₂ , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or together form a heterocyclic ring;

R2.1. R24, R25. and R26 are each, independently, H, -OH, -OR27, alkyl, alkenyl, alkynyl, -SR27, -N(R2 >2, -SO2R27, -CO2R27. cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic, or halogen, 46

wherein R27 is H, alkyl, alkenyl, nikynyl, cycloalkyl, cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heterocyclic; with a suitable acid to form the compound;

so as to thereby prepare the compound.

In an embodiment, the compound prepared has the structure:

This invention provides a composition comprising dalescanol and the compound disclosed herein.

The compounds of the present invention include all hydrates, solvates, and complexes of the compounds used by this invention. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein. Compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone The compounds described in the present invention are in racemic form or as individual enantiomers The enantiomers can be separated using known techniques, such as those described in Pure and Applied Chemistry 69, 1469-1474. (1997) IUPAC. In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention. In cases wherein compounds may exist in tautomeric forms such as keto-enol tautomers each tautomeric form 47

is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.

It will be noted that the structure of the compounds of this invention includes an asymmetric carbon atom and thus the compounds occur as racemates, racemic mixtures, and isolated single enantiomers. All such isomeric forms of these compounds are expressly included in this invention. Each stereogenic carbon may be of the R or S configuration. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemical ly controlled synthesis, such as those described in "Enantiomers, Racemates and Resolutions" by J. Jacques, A. Collet and S. Wilen, Pub. John Wiley & Sons. NY, 1981. For example, the resolution may be carried out by preparative chromatography on a chiral column.

The subject invention is also intended to include all isotopes of atoms occurring on the compounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

It will be noted that any notation of a carbon in structures throughout this application, when used without further notation, are intended to represent all isotopes of carbon, such as ^,2 C, ^l3 C, or ^, C. Furthermore, any compounds containing ^l3 C or ^,4 C may specifically have the structure of any of the compounds disclosed herein.

It will also be noted that any notation of a hydrogen in structures throughout this application, when used without further notation, are intended to represent all isotopes of hydrogen, such as Ή, ² H, or ³ H. Furthermore, any compounds containing ² H or ³ H may specifically have the structure of any of the compounds disclosed herein.

Isotopically-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art using appropriate isotopically-labeled reagents in place of the non- labeled reagents employed. 48

As used herein, "alkyl" includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and may be unsubstituted or substituted. Thus, C|-C„ as in "C|-C„ alkyl" is defined to include groups having 1, 2, n-

1 or n carbons in a linear or branched arrangement. For example, Ci-C*. as in "Ci-Ce alkyl" is defined to include groups having 1, 2, 3, 4, 5, or 6 carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, pentyl, hexyl, and octyl.

As used herein, "alkenyl" refers to a non-aromatic hydrocarbon radical, straight or branched, containing at least 1 carbon to carbon double bond, and up to the maximum possible number of non-aromatic carbon-carbon double bonds may be present, and may be unsubstituted or substituted. For example, ' C ₂ -C ₆ alkenyl" means an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms, and up to 1, 2, 3, 4, or 5 carbon-carbon double bonds respectively. Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.

The term "alkynyl" refers to a hydrocarbon radical straight or branched, containing at least 1 carbon to carbon triple bond, and up to the maximum possible number of non-aromatic carbon-carbon triple bonds may be present, and may be unsubstituted or substituted. Thus, "C ₂ -C ₆ alkynyl" means an alkynyl radical having 2 or 3 carbon atoms and 1 carbon-carbon triple bond, or having 4 or 5 carbon atoms and up to 2 carbon-carbon triple bonds, or having

6 carbon atoms and up to 3 carbon-carbon triple bonds. Alkynyl groups include ethynyl, propynyl and butynyl.

"Alkylene", "alkenylene" and "alkynylene" shall mean, respectively, a divalent alkane, alkene and alkyne radical, respectively. It is understood that an alkylene, alkenylene, and alkynylene may be straight or branched. An alkylene, alkenylene, and alkynylene may be unsubstituted or substituted.

As used herein, "aryl" is intended to mean any stable monocyclic, bicyclic or polycyclic carbon ring of up to 10 atoms in each ring, wherein at least one ring is aromatic, and may be unsubstituted or substituted. Examples of such aryl elements include phenyl, p-toluenyl (4- methylphenyl), naphthyl, tetrahydro-naphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. In cases where the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring. phenoxy; arylalkyloxy, such as benzyloxy (phenylmethoxy) and p-trifluoromethylbenzyloxy (4-trifluoromethylphenylmethoxy); heteroaryloxy groups; sulfonyl groups, such as trifluoromethanesulfonyl, methanesulfony), and p-toluenesulfonyl; nitro, nitrosyl; mercapto; sulfanyl groups, such as methylsulfanyl, ethylsulfanyl and propylsulfanyl; cyano; amino groups, such as amino, methylamino, dimethylamino, ethylamino, and diethylamino; and carboxyl. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.

"Free of bacterial extract" with regard to a composition, as used herein _* means that the composition is absent any amount of dalesconol containing-bacterial material. Thus only synthetically produced compounds and compositions are free of dalescanol containing- bacterial extract. Any compound or compositions isolated from a bacterium, such as Daldinia sp., would always contain at least some trace amount of bacterial extract or bacterial material, such as bacterial cell components etc.. and are not free of bacterial extract. "Free of fungal extract" with regard to a composition, as used herein, means that the composition is absent any amount of dalesconol containing-fungal material. Thus only synthetically produced compounds and compositions are free of dalescanol containing-fungal extract. Any compound or compositions isolated from a fungus, such as Sporothrix sp., would always contain at least some trace amount of fungal extract or fungal material, such as fungal cell components etc., and are not free of bacterial extract.

The term "acid" refers to acids under both the Bronsted-Lowry and the Lewis definitions of acids. Under the Bronsted-Lowry definition, acids are defined as proton (H*) donors. Examples of Bronsted-Lowry acids include, but are not limited to, inorganic acids such as 52

hydrofluoric, hydrochloric, hydrobromic, hydroiodic, perchloric, hypochlorous, sulfuric, sulfurous, sulfamic, phosphoric, phosphorous, nitric, nitrous, and the like; and organic acids such as formic, acetic, trifluoroacetic, p-toluenesulfonic. camphorsulfonic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. Under the Lewis definition, an acid is an electron acceptor capable of accepting electron density by virtue of possessing unoccupied orbitals. Examples of Lewis acids include, but are not limited to, metal salts such as AlCb, FeCl ₃ , FeC ^« Si0 ₂ , CrCl ₂ , HgCl ₂ , CuCI, TiCl ₄ , Yb(Otfi), InOTf, TiCl ₂ (OiPr)2, and Ti(OiPr) ₄ ; organometallic species such as trimethylaluminum and dimethylaluminum chloride; and boron species such as BH ₃ , B(Et) ₃ , BF ₃ , BF ₃ -OEt ₂ , BBr ₃ , B(OMe) ₃ , and B(OiPr) ₃ .

Examples of bases include, but are not limited to, alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert- butoxide, potassium tert-butoxide, lithium methoxide; alkali metal hydrides, such as lithium hydride, sodium hydride, and potassium hydride; alkali metal bicarbonates and carbonates, such as sodium bicarbonate, sodium carbonate, lithium bicarbonate, lithium carbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, and cesium bicarbonate; organolithium bases, such as methyllithium, n-butyllithium, s-butyl lithium, tert-butyllithium, isobutyllithium. phenylltthium, ethyllithium, n-hexyllithium, and isopropyllithium; amide bases, such as lithium amide, sodium amide, potassium amide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, lithium diethylamide, lithium dicyclohexylamide, and lithium 2,2,6,6-tetramethylpiperidide; and amine bases, such as pyridine, 4-(dimethylamino)pyridine, trimethylamine, diethylamine, triethylamine, diisopropylethylamine, 1.8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5- diazabicyclo[4.3.0|non-5-ene (DBN), L4-diazabicyclo[2.2.2]octane (DABCO), and the like. As used herein, abbreviations are defined as follows:

Ac = acetyl

4-DMAP = 4-(dimethylamino)pyridine

DABCO = l,4-diazabicyclo[2.2.2]octane

DBU = l,8-diazabicyclo[5.4.0]undec-7-ene 53

DBN = 1 ,5-diazabicyclo|4.3.01non-5 ene

DMF = Λ .W-dimethylformamide

EDC = ^V-ethyl- V'-(3-dimethylaminopropyl)carbodiiiT-ide

TB AF = tetra-/i-butylammonium fluoride

TBS = ½#t-butyldimethylsilyl

TMS = trimethylsilyl

Tf - trifluoromethanesulfonyl

HMDS = potassium bis(trimelhylsilyl)amide or potassium hexamethyldisilazide

AIBN = Ι,Γ-azobisisobutyronitrile

9-BBN = 9-borabicyclo[3.3.1 |nonane

D1BA = diisobutylaluminum

PDBBA = potassium diisobutyl-terf-butoxyaluminum hydride

MOM = methoxymethyl

DDQ = 2,3-dichloro-5,6-dicyano- l,4-benzoquinone

TFE = 2,2.2-trifluoroethanol

THF = tetrahydrofuran

MeOH = methanol

DCE = 1,2-dichIoroethane

Ph = phenyl

Me = methyl

Et = ethyl

iPr = isopropyl

n-Bu = n-butyl

i-Bu = isobutyl

s- B u = sec-but l

t-Bu = ½r/-butyl

Ms = methanesulfonyl

Ts = p-toluenesulfonyl

SET = single electron transfer

In choosing the compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents, i.e. R|, R2, etc. are to be chosen in conformity with well-known principles of chemical structure connectivity. .54

The various R groups attached to the aromatic rings of the compounds disclosed herein may be added to the rings by standard procedures, for example those set forth in Advanced Organic Chemistry: Part B: Reaction and Synthesis, Francis Carey and Richard Sundberg, (Springer) 5 ^th ed. Edition. (2007), the content of which is hereby incoporated by reference.

The compounds of the instant invention may be in a salt form. As used herein, a "salt" is a salt of the instant compounds which has been modified by making acid or base salts of the compounds. In the case of compounds used for treatment of cancer, the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols. The salts can be made using an organic or inorganic acid. Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, 54uinine, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like. Phenolate salts are the alkaline earth metal salts, sodium, potassium or lithium. The term "pharmaceutically acceptable salt" in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate. and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", /. Pharm. Sci. 66: 1-19).

The compositions of this invention may be administered in various forms, including those detailed herein. The treatment with the compound may be a component of a combination therapy or an adjunct therapy, i.e. the subject or patient in need of the drug is treated or given another drug for the disease in conjunction with one or more of the instant compounds. This combination therapy can be sequential therapy where the patient is treated first with one drug and then the other or the two drugs are given simultaneously. These can be administered independently by the same route or by two or more different routes of administration depending on the dosage forms employed. 55

As used herein, a "pharmaceutically acceptable carrier" is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the animal or human. The carrier may be liquid or solid and is selected with the planned manner of administration in mind. Liposomes are also a pharmaceutically acceptable carrier.

The dosage of the compounds administered in treatment will vary depending upon factors such as the pharmacodynamic characteristics of a specific chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect.

A dosage unit of the compounds may comprise a single compound or mixtures thereof with ant i- cancer compounds, or tumor growth inhibiting compounds, or with other compounds also used to treat neurite damage. The compounds can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by injection or other methods, into the cancer, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.

The compounds can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral, rectal, topical, intravenous or direct injection or parenteral administration. The compounds can be administered alone but are generally mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used. In one embodiment the carrier can be a monoclonal antibody. The active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, 56

coloring agents, flavoring agents, flow- inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non- effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavorants and coloring agents. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen

Specific examples of pharmaceutical acceptable carriers and excipients that may be used to formulate oral dosage forms of the present invention are described in U. S. Pat. No. 3.903,297 to Robert, issued Sept 2, 1975. Techniques and compositions for making dosage forms useful in the present invention are described- in the following references: 7 Modem Pharmaceutics. Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2 ^nd Edition (1976); Remington's Pharmaceutical Sciences, 17 ^th ed. (Mack Publishing Company, Easton, Pa , 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity. Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers. Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed , 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modem Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.). All of the aforementioned publications are incorporated by reference herein.

Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow- inducing agents, and melting agents. For instance, for oral administration in the dosage unit form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as 57

lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. The compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. The compounds may be administered as components of tissue-targeted emulsions.

The compounds may also be coupled to soluble polymers as targetable drug carriers or as a prodrug. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylasparta-midephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacytates, and crosslinked or amphipathic block copolymers of hydrogels.

The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parentally, in sterile liquid dosage forms. Gelatin capsules may contain the active ingredient compounds and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate. stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar 58

coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract

For oral administration in liquid dosage form, the oral drug components are combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol glycerol, water, and the like. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

The compounds of the instant invention may also be administered in intranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen.

Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen. 59

The compounds and compositions of the invention can be coated onto stents for temporary or permanent implantation into the cardiovascular system of a subject.

Those having ordinary skill in the art of organic synthesis will appreciate that modifications to the general procedures shown herein can be made to yield structurally diverse compounds. For example, where aryl rings are present, all positional isomers are contemplated and may be synthesized using standard aromatic substitution chemistry. The number and types of substituents may also vary around the aryl rings. Furthermore, where alkyl, alkenyl, and alkynyl groups are present, the chain length may be modified using methods well known to those of ordinary skill in the art. Suitable organic transformations are described in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (Wiley-Interscience; 6 ^th edition, 2007), the content of which is hereby incoporated by reference.

The compounds and compositions of the present invention are useful in the synthesis of compounds that possess activity as immunosuppressants and that do not appear to suffer from cytotoxic effects. For example, in terms of the in vitro inhibitory effects for the ConA- induced proliferation of mouse spleen cells, evaluating activity versus cytotoxic effects, dalesconol A has a selectivity factor greater than 500 with 59uinine59e59ne A having a value of 187. In general terms, almost all clinical immunosuppressants come from nature, with recent examples including FK-506 and rapamycin. The compounds and compositions of the present invention possess an entirely different architecture, a far simpler one in fact, from which to begin more advanced studies and to develop unique immunosuppressive properties relative to those agents already in the clinic. The compounds and compositions of the present invention are prepared in large quantities in a bare modicum of steps, ensuring that plenty of material exists for thorough biology evaluation; in advance of these endeavors, such molecules were essentially unavailable for exploration. This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter. Experimental Details

All reactions were carried out under an argon atmosphere with dry solvents under anhydrous conditions, unless otherwise noted. Dry tetrahydrofuran (THF) acetonitrile (MeCN), toluene, benzene, diethyl ether (Et ₂ 0) and methylene chloride (CH ₂ CI ₂ ) were obtained by passing commercially available pre-dried, oxygen-free formulations through activated alumina columns. Yields refer to chromatographically and spectroscopically (Ή and ^{l 3} C NMR) homogeneous materials unless otherwise stated. Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated. Reactions were magnetically stirred and monitored by thin- layer chromatography (TLC) carried out on 0.25 mm E. Merck silica gel plates (60F-254) using UV light as visualizing agent and an ethanolic solution of phosphomolybdic acid and cerium sulfate, and heat as developing agents. SiliCycle silica gel (60, academic grade, particle size 0.040-0.063 mm) was used for flash column chromatography. Preparative thin-layer chromatography (PTLC) separations were carried out on 0.50 mm E. Merck silica gel plates (60F-254). NMR spectra were recorded on Bruker DRX-300, DRX-400 DMX-500 instruments and calibrated using residual undeuterated solvent as an internal reference. The following abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, br = broad, AB = AB quartet, app = apparent. IR spectra were recorded on a Perkin-Elmer 1000 series FT-IR spectrometer. High-resolution mass spectra (HRMS) were recorded in the Columbia University Mass Spectral Core facility on a JOEL HX110 mass spectrometer using the MALDI (matrix- assisted laser-desorption ionization) technique.

Example 1. Synthesis of Delascanol B

Phosphonate 11. 3,5-dimethoxybromobenzene (10.0 g, 46.1 mmol, 1.0 equiv) was dissolved in DMF (21 mL, 277 mmol, 6.0 equiv) and cooled to 0 °C. POCl ₃ (12.8 mL, 138 mmol, 3.0 equiv) was added dropwise, and the now orange reaction contents were warmed to 90 °C and stirred for 6 h. Upon completion, the reaction contents were poured into ice water (100 mL), quenched by the slow addition of solid KOH until a pH 14 was obtained, and allowed to stir for 12 h. Once achieved, the crude material was extracted with Et ₂ 0 (3 x 100 mL). The combined organic extracts were then washed with water (3 x 75 mL) and brine (75 mL), dried (MgSOj), and concentrated to give the desired aldehyde (11.2 g, 99% yield) as a white solid.' ¹ ' Pressing forward without any additional purification, this newly prepared material (11.2 g, 45.7 mmol, 1.0 equiv) was suspended in MeOH (250 mL) and cooled to 0 °C. NaBHi (3.45 g, 91.4 mmol, 2.0 equiv) was added portionwise and the reaction contents were stirred for 30 min at 0 °C. Upon completion, the reaction contents were poured into water (100 mL) and the residual organic solvent was concentrated. The reaction contents were redissolved in EtOAc (150 mL), poured into water (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (75 mL) and brine (75 mL), dried (MgS0 ₄ ), and concentrated to give the desired alcohol ( 10.8 g. 96%) as a white solid. R _{/ =} _ 0.44 (silica gel, hexanes EtOAc, 1/1); 1R (film) 3327 (br), 2941, 2834, 1609, 1568, 1456, 141 1, 1215, 1148, 1033, 1000; Ή NMR (400 MHz, CDCI3) δ 6.70 (d, J = 2.4 Hz, 1 H), 6.41 (d, J = 2.4 Hz, 1 H), 4.80 (d, J = 6.0 Hz, 2 H), 3.83 (s, 3 H), 3.79 (s, 3 H), 2.17 (t, / = 6.4 Hz, 1 H); ^l3 C NMR (75 MHz, CDCI3) δ 160.6, 159.5, 125.5, 121.5, 108.9, 98.3, 59.9, 55.9, 55.6; HRMS (MALDI-FTMS) calcd for C ₉ H,,Br03 ⁺ [M*] 245.9892, found 245.9907. Pressing forward without any additional purification, this newly prepared material (10.8 g, 43.9 mmol, 1.0 equiv) was dissolved in Et ₂ 0 (350 mL) and pyridine (0.53 mL, 6.58 mmol, 0.15 equiv) and ΡΒΓ ₃ (4.15 mL, 43.9 mmol, 1.0 equiv) were added sequentially at 25 °C. The reaction contents were then stirred for 4 h at 25 °C. Upon completion, the reaction contents were quenched by the addition of water (200 mL), and extracted with EtOAc (3 x 75 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried (MgS0 ₄ ), and concentrated to give the desired bromide (13.1 g, 96%) as a white solid. [Note: this product quickly decomposes on standing once it is neat and should be carried forward immediately]. Finally, KHMDS (0.5 M in toluene, 152 mL, 75.8 mmol, 1.8 equiv) was added to a stirred solution of diethyl phosphite ( 10.8 mL, 84.2 mmol, 2.0 equiv) in THF (60 mL) at 0 °C, and the resultant solution was stirred for 15 min. A solution of the freshly 62

prepared bromide ( 13.1 g, 42.1 mmol, 1.0 equiv) in THF (60 mL) was then added, and the reaction contents were stirred for 12 h with slow warming to 25 °C. Upon completion, the reaction contents were quenched with saturated NH4CI (75 mL), poured into water (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (75 mL) and brine (75 mL), dried (MgSC , and concentrated to give phosphonate 11 (14.6 g, 94%) as a colorless oil. 11: R _/ = 0.20 (silica gel, EtOAc); 1R (Film) v, 2981, 2937, 2906, 2839, 1603, 1569, 1485, 1463, 1438, 1412, 1303, 1276, 1224, 1200, 1159, 1034, 965; Ή NMR (400 MHz, CDCI ₃ ) δ 6.68 (d, J = 2.4 Hz, 1 H), 6.36 (d, J = 2.4 Hz, 1 H), 4.01 (dq, J = 7.2, 7.2 Hz, 4 H), 3.77 (s, 3 H), 3.73 (s, 3 H), 3.36 (d, J = 21.6 Hz, 2 H), 1.22 (t, J = 7.2 Hz, 6 H); ^,3 C NMR (75 MHz, CDC ) 5 159.5, 158.8, 125.5 (d, J = 6.9 Hz), 113.9 (d, J = 10.4 Hz). 109.0, 98.0. 61.7 (d, J = 5.9 Hz), 55.6 (d, J = 23.5 Hz), 27.5 (d, J = 140.3 Hz). 16.3 (d, J = 5.6 Hz); HRMS ( M ALDI-FTMS) calcd for C| ₃ H ₂ |BrP0 ₅ ⁺ [M + H ^* ] 367.0310, found 367.0319. Phosphonate 13. Triethyl phosphonoacetate (8.93 mL, 44.6 mmol, 1.0 equiv) was dissolved in THF (100 mL) at 25 °C and the resultant solution was cooled to 0 °C. NaH (60% dispersion in mineral oil, 1.96 g, 49.1 mmol, 1.1 equiv) was added portionwise and the resultant suspension was allowed to stir for 10 min at 0 °C. f -Butyl bromoacetate (7.91 mL, 53.5 mmol, 1.2 equiv) was then added dropwise, and the solution was allowed to stir for 4 h with slow warming to 25 °C. During this time, the formation of a white precipitate occurred. Upon completion, the reaction contents were quenched with saturated NH ₄ CI (75 mL), poured into water (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (75 mL) and brine (75 mL), dried (MgSC ), and concentrated. The resultant crude, colorless oil was purified by flash column chromatography (silica gel, CH ₂ Cl ₂ MeOH, 19/1) to give phosphonate 13 (14.9 g, 99%) as a colorless oil. Alternatively, this material can be purchased commercially.

Diester 14. A/e/ -anisaldehyde (6.06 g, 44.6 mmol, 1.0 equiv) was dissolved in AcOH (10 mL), Br ₂ (2.75 mL, 53.6 mmol, 1.2 equiv) was then added dropwise, and the resultant solution was stirred for 36 h at 25 °C. Upon completion, the reaction contents were quenched with saturated Na ₂ S0 ₃ (50 mL), poured into water (20 mL), and extracted with Et ₂ 0 (5 x 30 mL). The combined organic layers were then washed with water (3 x 25 mL) and brine (30 mL), dried (MgS0 ₄ ), and concentrated to give the desired aldehyde 12 (9.49 g, 99% yield) as a dark yellow solid. Alternatively, this aldehyde 12 can be purchased commercially. Next, 63

aldehyde 12 (9.49 g, 44.2 mmol, 1.0 equiv) was dissolved in CH ₃ CN (200 mL) and then this solution was added to a stirred solution of phosphonate 13 (14.9 g, 44.2 mmol, 1.0 equiv), LiCl (2.44 g, 57.4 mmol, 1.3 equiv), and DBU (6.59 mL, 44.2 mmol, 1.0 equiv) at 25 °C. The resultant dark yellow solution was stirred for 12 h at 25 °C. Upon completion, the reaction contents were quenched by the addition of saturated NH CI (100 mL) and the organic solvent was concentrated. The contents were redissolved in EtOAc (50 mL), poured into water (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried (MgSOi), and concentrated to give diester 14 ( 17.5 g, 99% yield) as a yellow oil. 14: R/= 0.57 (silica gel, hexanes/EtOAc, 4/1); IR (film) 2979, 2936, 1724, 1643, 1590, 1569, 1465, 1285, 1238, 1194, 1156, 1097, 1019; Ή NMR (400 MHz, CDC1 ₃ ) δ 7.80 (s, 1 H), 7.47 (d. J = 8.8 Hz, 1 H), 6.94 (d, J = 2.8 Hz, 1 H), 6.77 (dd, J = 8.8, 2.8 Hz, 1 H), 4.29 (q, J = 7.2 Hz, 2 H), 3.76 (s, 3 H), 3.33 (s, 2 H), 1.45 (s, 9 H), 1.35 (t, J = 7.2 Hz, 3 H); ^,3 C NMR (75 MHz, CDCI ₃ ) δ 170.2, 166.9, 158.7, 140.6, 136.3, 133.3. 128.3 116.5, 1 15.0, 114.3, 81.1, 61.2, 55.5 35.2, 28.0, 14.2; HRMS (MALDI-FTMS) calcd for C , ₈ H ₂ 3Br0 ₅ ⁺ [M ⁺ | 398.0729, found 398.0746.

Naphthoate 15. Diester 14 (17.5 g, 43.8 mmol, 1.0 equiv) was dissolved in TFA (90% in water, 50 mL) and allowed to stir for 90 min at 25 °C. Upon completion, the reaction contents were concentrated and azeotroped with toluene (3 x 100 mL) to give the desired crude monoacid intermediate as a yellow solid. This newly formed material was immediately dissolved in Ac ₂ 0 (200 mL), NaOAc (5.03 g, 61.4 mmol, 1.4 equiv) was added at 25 °C, and the resultant yellow suspension was warmed to 140 °C and stirred at that temperature for 60 min. Upon completion, the darkened reaction contents were cooled to 25 °C and the organic solvent was concentrated. The reaction contents were redissolved in EtOAc (75 mL), poured into water (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried (MgS0 ₄ ), and concentrated. The resultant crude brown solid was purified by flash column chromatography (silica gel, hexanes EtOAc, 3/2) to give 15 (13.4 g, 83% yield) as a yellow solid. 15: R/ = 0.20 (silica gel, hexanes/EtOAc, 4/1); IR (film) 2979, 1769, 1718, 1597, 1572, 1506, 1356, 1277. 1248, 1212, 1092, 1023, 766; Ή NMR (400 MHz, CDCI3)□ 8.88 (d, J = 1.6 Hz, 1 H), 7.74 (d, J = 8.4 Hz, 1 H), 7.73 (d, J = 1.6 Hz, 1 H), 6.81 (d, J = 8.4 Hz, 1 H), 4.45 (q, J = 7.2 Hz, 1 H), 3.93 (s, 3 H), 2.38 (s, 3 H), 1.44 (t, J = 7.2 Hz, 3 H); ^,3 C NMR (75 MHz, CDCI ₃ ) δ 169.9, 165.4, 155.0, 147.0, 134.0, 131.1, 129.4, 128.4, 122.5, 119.8, 115.1, 108.7, 61.5, 56.4, 20.8, 14.3: HRMS (MALDI-FTMS) calcd for C| ₆ H,5Br0 ₅ ⁺ [M ⁺ ] 366.0103, found 366.0107. 64

Aldehyde 16. Naphthoate 15 ( 13.4 g, 36.S mmol, 1.0 equiv) was dissolved in MeOH ( ISO ntiL) and CH ₂ C1 ₂ (75 mL) at 25 °C. Pd/C (10%, 3.88 g. 3.65 mmol, 0.1 equiv) was added, and the reaction contents were placed under an atmosphere of H ₂ . After stirring the resultant suspension for 24 h at 25 °C, the reaction contents were filtered through a pad of Celtte and NaOMe (5.94 g 1 10 mmol, 3.0 equiv) was added portionwise to the filtrate at 0 °C. The resultant solution was warmed to 25 °C and allowed to stir for 2 h. Upon completion, the contents were cooled to 0 °C, quenched with the addition of 1 M HC1 (200 mL), and concentrated. The reaction contents were redissolved in EtOAc (75 mL), poured into water (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried (MgSC ), and concentrated to give the desired product (8.38 g, 99%) as a yellow solid. Pressing forward without any additional purification, this newly prepared material (8.38 g, 36.1 mmol, 1.0 equiv) was dissolved in DMF (75 mL), cooled to 0 °C, and BnBr (8.57 mL, 72.2 mmol, 2.0 equiv) and NaH (60% dispersion in mineral oil, 2.89 g, 72.2 mmol, 2.0 equiv) were added sequentially. The reaction contents were stirred for 1 h at 0 °C, warmed to 25 °C, and then quenched with saturated NH»C1 (50 mL). The contents were then poured into water (200 mL) and extracted with Et7<_) (5 x 50 mL). The combined organic extracts were washed with water (5 x 100 mL) and brine ( 100 mL), dried (MgSO. , and concentrated. The resultant crude orange oil was purified by flash column chromatography (silica gel, hexanes/Et ₂ 0, 3/2) to give the desired benzyl-protected product (8.95 g, 77% yield) as a yellow solid. A portion of this material (8.28 g, 25.7 mmol, 1.0 equiv) was dissolved in THF (130 mL) and cooled to -20 °C. A precooled (-30 °C) solution of 0.5 M PDBBA in THF/toluene [1/1, 46.2 mL, 23.1 mmol, 0.9 equiv, prepared by mixing KO/-Bu (1.0 M in THF, 23.1 mL, 23.1 mmol, 0.9 equiv) and DIBAL-H (1.0 M in toluene, 23.1 mL, 23.1 mmol, 0.9 equiv) at 25 °C for 2 h] was then added. The reaction contents were quickly warmed to 0 °C and stirred for 90 min at 0 °C. Upon completion, the reaction contents were quenched with 1 M HC1 (300 mL), poured into water (50 mL), and extracted with Et ₂ 0 (3 x 50 mL). The combined organic extracts were washed with water (75 mL) and brine (75 mL), dried (MgSO-»), and concentrated. The resultant crude yellow solid was purified by flash column chromatography (silica gel, hexanes/Et ₂ 0, 4 1) to give aldehyde 16 (5.03 g, 67% yield) as a yellow solid. 16: R/= 0.49 (silica gel, hexanes/EtOAc, 4/1); 1R (film) ν^θόΐ, 2935, 2838, 1687, 1581, 1512, 1498, 1463, 1354, 1279, 1101, 1076, 737; Ή NMR (400 MHz, CDCI ₃ ) δ 10.06 (s, 1 H), 7.88 (d, 7 = 1.6 Hz, 1 H), 7.63 (d, J = 7.2 Hz, 2 H), 7.55-7.34 (m, 6 H), 7.03 (dd, J = 7.6, 1.2 Hz, 1 65

H), 5.27 (s, 2 H), 3.97 (s. 3 H); ^{l 3} C NMR (75 MHz. CDC1 ₃ ) δ 192.0. 157.4, 157.2, 137.0, 136.6, 134.7, 128.7. 128.4, 127.7. 127.6. 126.8, 122.1, 109.6 102.0, 77.0, 70.9, 56.3: HRMS (MALDI-FTMS) calcd for C| ₉ H| ₆ 0^ [M ⁺ ] 292.1099, found 292.1093. Aldehyde 18. Solid OH (100 g, 1780 mmol, 18.4 equiv) was heated to 210 °C in a stainless steel pot until a partial melt formed. NaOH (20.0 g, 500 mmol, 5.15 equiv) was then added, at which time the melt became transparent. 1 ,8-Naphthosultone (20.0 g, 97.0 mmol, 1.0 equiv) which had been recrystallized from CH ₂ C1 ₂ was then added in a single portion at 210 ^Q C followed by vigorous stirring for 5 min during which time yellow gaseous clouds were evolved. The darkly colored reaction contents were kept at 210 °C with occasional manual stirring for 40 min: upon completion the reaction contents were slowly cooled to 0 °C. Water ( 1.4 L) and concentrated H2SO ₄ (150 mL) were added to slowly dissolve the dark, solid reaction contents. The resultant aqueous phase was extracted with Et ₂ 0 (5 x 300 mL), and the combined oiganic extracts were then washed with water (400 mL) and brine (400 mL), dried (MgS0 ₄ ), and concentrated. The resultant crude brown solid was purified by flash column chromatography (silica gel, hexanes Et ₂ 0, 1/1) to give 1,8-naphthalenediol (8.23 g, 53% yield) as a white solid. This reaction was repeated several times to obtain large quantities of the desired product Next, 1,8-naphthalenediol (14.84 g, 92.8 mmol, 1.0 equiv) was dissolved in THF (200 mL) and cooled to 0 °C NaH (60% dispersion in mineral oil, 3.71 g, 92.8 mmol, 1.0 equiv) was added portionwise and the reaction contents were stirred at 0 °C for 10 min; Me ₂ S0 ₄ (8.77 mL, 92.8 mmol, 1.0 equiv) was then added dropwise at 0 °C The reaction contents were stirred for 14 h with slow warming from 0 °C to 25 °C. Upon completion, the contents were quenched by the addition of saturated NH ₄ CI (100 mL). They were then poured into water ( 100 mL) and extracted with EtOAc (3 x 50 mL) The combined organic extracts were washed with water (75 mL) and brine (75 mL), dried (MgS0 ₄ ), and concentrated. The resultant crude grey solid was purified by flash column chromatography (silica gel, hexanes/Et ₂ 0, 2/1) to give the monomethylated product (16.0 g, 99%) as a white solid R/= 0.71 (silica gel, hexanes/EtOAc, 2/1); IR (film) 3361 (br), 3057, 2945, 2843 1739, 1630, 1612, 1582, 1452, 1404, 1261, 1196, 11 19, 1076, 964, 813, 753, 674- Ή NMR (400 MHz, CDCI3) δ 9.34 (s, 1 H), 7.43 (dd, J = 8.0, 0.8 Hz, t H), 7.36 (app t, J = 8.0 Hz, 1 H), 7.31 (app t, /= 8.0 Hz, 1 H), 7.30 (dd, / = 8.0, 1.2 Hz, 1 H), 6.89 (dd, J = 7.6, 1 2 Hz, 1 H), 6.78 (d, 7= 8.0 Hz, 1 H), ^,3 C NMR (75 MHz, CDC1 ₃ ) δ 156.2, 154.5, 136.7, 127.7, 125.6, 121.8, 118.8, 115.1. 110.4, 103.9, 56.1; HRMS (MALDI-FTMS) calcd for C,iH _l0 O2 ⁺ [M ⁺ ] 174.0681, found 174.0673. This monomethylated product (16.0 g 92 0 mmol, 1.0 equiv) 66 was dissolved in CH ₃ CN (300 mL) at 25 °C, NBS (16.4 g, 92.0 mmol, 1.0 equiv) was added in a single portion, and the resultant solution was stirred for 1 h at 25 °C. Upon completion, the reaction contents were concentrated and the resultant crude grey solid was purified by flash column chromatography (silica gel, hexanes/Et ₂ 0, 1/1) to give the desired brominated product (23.0 g, 98%) as a yellow solid.' ²¹¹ This brominated product (23.0 g, 91.1 mmol, 1.0 equiv) was dissolved in D F (75 mL) and cooled to 0 °C. NaH (60% dispersion in mineral oil, 4.36 g, 109 mmol, 1.2 equiv) was added slowly and the resultant yellow solution was stirred for 10 min at 0 °C. MOMC1 (10.4 mL, 137 mmol, 1.5 equiv) was then added and the resultant suspension was stirred for 1 h at 0 °C. Upon completion, the reaction contents were quenched with saturated NaHC0 ₃ (75 mL), and then were poured into water ( 100 mL) and extracted with Et?0 (5 x 50 mL). The combined organic extracts were washed with water (5 x 50 mL) and brine (75 mL), dried (MgS0 ₄ ), and concentrated to give a crude yellow solid which was purified by flash column chromatography (silica gel, hexanes Et ₂ 0, 1/1) to give the desired MOM-protected product (26.8 g, 99%) as a yellow solid. This newly prepared material (26.8 g, 90.2 mmol, 1.0 equiv) was dissolved in THF (560 mL), cooled to -78 °C. and H-BuLi (1.6 M in hexanes. 67.7 mL 108 mmol, 1.2 equiv) was added dropwise. The resultant darkened reaction contents were stirred for 20 min at -78 °C. DMF (27.8 mL, 361 mmol, 4.0 equiv) was then added dropwise, quickly lightening the color of the solution, and the reaction contents were stirred for 1.5 h at -78 °C. Upon completion, the reaction contents were quenched with saturated NH4CI (100 mL), poured into water (100 mL), and the organic solvent was removed by rotary evaporation. The crude reaction mixture was redissolved in Et ₂ 0 (100 mL) and extracted with Et ₂ 0 (3 x 75 mL). The combined organic extracts were washed with water (5 x 75 mL) and brine (100 mL), dried (MgS0 ₄ ), and concentrated. The resultant crude brown solid was purified by flash column chromatography (silica gel, hexanes CH ₂ Cl ₂ , 1/2) to give aldehyde 18 (21.3 g, 96%) as a yellow solid. 18: R _f = 0.41 (silica gel, hexanes/EtOAc, 2/1); IR (film) 2937, 1680, 1616, 1574, 1518, 1277, 1219, 1152, 11 12, 1058; Ή NMR (400 MHz, CDCI3) δ 10.22 (s, 1 H), 8.97 (dd, / = 8.0, 0.8 Hz, 1 H), 7.88 (d, J = 8.0 Hz, 1 H), 7.59 (dd. J = 8.4, 8.0 Hz, 1 H), 7.13 (d, / = 8.4 Hz, 1 H), 6.99 (dd, J = 8.0, 0.8 Hz, 1 H), 5.41 (s, 2 H), 3.98 (s, 3 H), 3.60 (s, 3 H); ^,3 C NMR (75 MHz, CDC ) δ 192.1, 160.1, 157.6, 139.2, 135.1, 129.8, 125.4, 117.9, 117.2, 108.7, 107.7, 95.3, 56.6, 56.4; HRMS (MALDI-FTMS) calcd for C,4H _I4 0 ⁺ [M ⁺ J 246.0892, found 246.0901.

Key Triaryl Intermediate 19. Phosphonate 11 (5.84 g, 15.9 mmol, 1.0 equiv) was dissolved in THF (65 mL) at 25 °C and cooled to -78 °C. KOi-Bu (1.0 M in THF, 17.5 mL, 17.5 67 mmol, 1. 1 equiv) was added dropwise and the resultant yellow solution was stirred for 20 min at -78 °C. A solution of aldehyde 16 (4.65 g, 15.9 mmol, 1.0 equiv) in THF (50 mL) was added dropwise to the stirring reaction contents, and the dark yellow solution was allowed to stir for 2 h with slow warming to 25 °C. Upon completion, the reaction contents were quenched with saturated NH ₄ CI (50 mL) and poured into EtOAc (75 mL) and water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (75 mL) and brine (75 mL), dried (MgSQ*), and concentrated. The resultant crude yellow solid was purified by flash column chromatography (silica gel, hexanes/Et20, 3/1) to give the desired Zs-olefin (6.99 g, 87%) as a yellow solid. A portion of this freshly prepared olefin (6.80 g, 13.5 mmol, 1.0 equiv) was dissolved in THF (70 mL) at 25 °C, cooled to -78 °C, and n-BuLi ( 1.6 M in hexanes, 12.6 mL, 20.2 mmol, 1.5 equiv) was then added dropwise. The resultant darkened reaction contents were then stirred for 20 min at -78 °C. A solution of aldehyde 18 (6.62 g, 26.9 mmol, 2.0 equiv) in THF (50 mL) was then added dropwise and the resultant orange solution was stirred for 4 h with slow warming from -78 °C to 25 °C. Upon completion, the reaction contents were quenched with saturated NH ₄ CI (75 mL), poured into water (100 mL), and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (75 mL) and brine (75 mL), dried (MgSO-t), and concentrated. The resultant crude orange solid was purified by flash column chromatography (silica gel, hexanes/EtOAc, 1/1) to give the key triaryl intermediate 19 (6.09 g, 67%) as a yellow foam. 19: /= 0.37 (silica gel, hexanes/EtOAc, 1/1); IR (film) v^ 3426 (br), 2936, 2835, 1584, 1463, 1272, 1 151, 1101, 1056, 1029, 751; Ή NMR (400 MHz, CDCI ₃ ) δ 7.74 (d, J = 8.4 Hz, 1 H), 7.56 (d, / = 7.2 Hz, 2 H), 7.42-7.31 (m, 5 H), 7.28 (dd. J = 8.4, 8.0 Hz, 1 H), 7.20 (dd, J = 8.0, 0.8 Hz, 1 H), 7.08 (d, 7 = 16.4 Hz, 1 H), 7.08 (s, 1 H), 7.00 (d, J = 8.0 Hz, 1 H), 6.93 (d, J = 16.8 Hz, 1 H), 6.89 (d, J = 2.4 Hz, 1 H), 6.80-6.78 (m, 2 H), 6.76 (d, J = 8.0 Hz, 1 H), 6.68 (d, / = 1.2 Hz, 1 H), 6.52 (d, J = 2.8 Hz, 1 H), 5.26 (d, J = 6.4 Hz, 1 H), 5.23 (d, J = 6.4 Hz, 1 H), 4.86 (d, J = 12.0 Hz, 1 H), 4.82 (d, J = 1 1.6 Hz, 1 H), 3.90 (s, 3 H), 3.88 (s, 3 H). 3.85 (s, 3 H), 3.82 (s, 3 H), 3.57 (s, 3 H), 2.34 (d, J = 4.4 Hz, 1 H); ^,3 C NMR (75 MHz, CDCI3) 6 159.7, 159.1, 157.3, 157.0, 156.0, 154.2, 143.3, 137.6, 137.4, 136.1, 134.9, 132.7, 128.2, 127.9, 127.4, 127.2 (2 C), 126.5, 126.4, 122.0, 120.9, 120.0, 1 18.9, 1 17.6, 1 17.3, 1 16.1, 1 12.3, 106.4, 106.2, 105.1 , 104.0, 97.9, 96.6, 71.0, 70.1, 56.4, 56.1 (2 C), 55.7, 55.3; HRMS (MALDI-FTMS) calcd for C ₄ 2l (£>s [M*l 672.2723, found 672.2698. 68

Dalesconol B Core (22). Triaryl intermediate 19 (5.69 g, 8.47 mmol, 1.0 equiv) was dissolved in EtOAc (40 mL) and EtOH (60 mL) at 25 °C. Solid Pd/C (10%, 9.01 g, 8.47 mmol, 1.0 equiv) was added and the reaction flask was charged with an atmosphere of H ₂ gas at 25 °C. The reaction contents were stirred for 45 min at 25 °C. filtered through a pad of Celite, and the filtrate was concentrated. The resultant crude yellow foam was immediately redissolved in TFE (65 mL) and cooled to -^5 °C. TFA (0.65 mL, 8.47 mmol, 1.0 equiv) was then added dropwise and the resultant dark purple solution was stirred for 15 min at -45 °C. Upon completion, Phl(OAc) _? (3.00 g, 9.32 mmol, 1.1 equiv) was added and the resultant dark green solution was stirred for an additional 20 min at -45 °C. Upon completion, the reaction contents were quenched with saturated Na ₂ SC>3 (25 mL) and saturated NaHCOj (25 mL), poured into water ( 100 mL), and extracted with EtOAc (3 x 75 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried (MgSO. , and concentrated. The resultant crude red foam was purified by flash column chromatography (silica gel, hexanes EtOAc, 1/2) to give the polycyclic enone 22 (1.50 g, 32%) as a yellow solid 22: R/ = 0.38 (silica gel, hexanes EtOAc, 1 :3); IR (film) v^ 2938. 2835, 1658, 1593, 1465. 1431, 1267, 1150, 1089, 1064; Ή NMR (400 MHz, CDCIj) δ 7.25 (app t, J = 8.0 Hz, 1 H), 7.06 (d, J = 7.6 Hz, 1 H). 6.88 (dd, / = 7.6, 1.2 Hz, 1 H), 6.86 (d, J = 8.8 Hz, 1 H), 6.84 (d, J - 8.0 Hz, 1 H), 6.84 (d, J = 8.0 Hz, 1 H), 6.36 (d. / = 2.0 Hz, 1 H), 6.30 (dd, J = 7.6, 0.4 Hz, 1 H). 6.21 (d, J = 2.4 Hz. 1 H), 6.10 (d, J = 1.2 Hz, 1 H), 5.31 (s, 2 H), 4.91 (d, J = 1.2 Hz, 1 H), 4.01 (s, 3 H), 3.95 (s, 3 H), 3 74 (s, 3 H), 3.71 (s. 3 H), 3.63 (s, 3 H), 2.76 (dd, J = 14.4, 6.4 Hz, 1 H), 2 47 (dd, J = 14.4, 7.6 Hz, 1 H), 2.27 (ddd, J = 10.0, 10.0, 7.6 Hz, 1 H), 1.55 (m, 1 H); ^,3 C NMR (75 MHz, CDC1 ₃ ) δ 185.0, 159.4, 158.3 (2 C), 157.8, 155.6, 155.0, 151.9, 143.1, 141.2, 139.4, 139.0, 133.6, 131.1, 121.9, 121.4, 1 19.9, 119.4, 118.9, 115.9, 1 15.1, 109.4. 108.0, 97.7, 96.9, 77.2, 70.0, 59.6, 56.5, 56.3, 56.1. 55.6, 55.2, 35.7. 19.7; HRMS (MALDI-FTMS) calcd for C35H33 V [M + H*] 565.2226, found 565.2223.

Hydrogenated core 23. Enone 22 (0.500 g, 0.887 mmol, 1.0 equiv) was dissolved in EtOAc (5 mL) and EtOH (15 mL) and Pd/C (10%, 0.471 g, 0.443 mmol, 0.5 equiv) was added. The reaction flask was charged with an atmosphere of H ₂ gas at 25 °C and the reaction contents were stirred for 2 h at 25 °C. Upon completion, the reaction contents were filtered through a

Celite pad, the filtrate was concentrated, and the resultant yellow solid was purified by flash column chromatography (silica gel, hexanes EtOAc, 1/2) to give the desired reduction product 23 (0.420 g, 84%) as a yellow solid 23: R/ = 0.46 (silica gel, hexanes/EtOAc, 1/3); IR (film) v _m „ 2939, 2835. 1678, 1593, 1464, 1432, 1269, 1149. 1070, 969, 736; Ή NMR 69

(400 MHz, CDCI3) δ 7.20 (app t, J = 8.0 Hz, 1 H), 7.04 (d, J = 7.6 Hz, 2 H), 6.94 (d, J = 8.0 Hz, 1 H), 6.84 (dd, J = 8.0, 1.2 Hz, 1 H), 6.82 (d, J = 8.4 Hz, 1 H), 6.39 (d, J = 2.4 Hz, 1 H), 6.35 (d. J = 2.4 Hz, 1 H), 6.04 (d, J = 7.2 Hz, 1 H), 5.30 (s, 2 H), 4.60 (s, 1 H), 4.03 (s, 3 H), 3.91 (s, 3 H), 3.78 (s, 3 H), 3.71 (s, 3 H). 3.62 (s, 3 H), 3.20-3. 13 (m, 1 H), 2.60 (dd, / = 14.4, 6.0 Hz, 1 H), 2.33 (dd, J = 18.4, 6.0 Hz, I H), 2.22 (dd, J = 18.4, 14.0 Hz, 1 H), 1.81-1.74 (m 1 H), 1.64- 1.57 (m, 1 H), 1.39-1.31 (m, 1 H); ¹³ C NMR (75 MHz. CDC1 ₃ ) δ 198.2, 159.8, 158.8, 157.9. 157.2, 154.6. 151.6, 143.2, 142.4, 14 L.4, 139.1 , 134.2, 120.9 (2 C), 120.6, 1 19.8. 1 19.6, 1 15.6. 1 15.4, 1 10.0, 107.9, 107.6, 97.7, 97.0, 77.2, 64.7, 56.7, 56.4, 56.1, 55.7, 55.4, 45.8, 39.1 , 27.6, 19.1 ; HRMS (MALDI-FTMS) calcd for 0, ₅ Η ₃ 4θ7 ⁺ [M ⁺ ] 566.2305, found 566.2304.

Desoxo dalesconol B (24). Intermediate 23 (0.200 g, 0.353 mmol, 1.0 equiv) was dissolved in THF (20 mL) at 25 °C and cooled to 0 °C. Concentrated HC1 ( 1.16 mL, 14.1 mmol, 40.0 equiv) was added dropwise and the reaction contents were allowed to stir for 3 h with slow warming from 0 °C to 25 °C. Upon completion, the reaction contents were quenched with water (30 mL), poured into EtOAc (30 mL), and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with water (50 mL) and brine (25 mL), dried (MgSO-i), and concentrated. The resultant crude brown solid was purified by flash column chromatography (silica gel, hexanes/EtOAc, 1/2) to give the desired mono deprotected phenol (0.183 g, 99%) as a yellow oil. Pressing forward, a portion of this material (0.082 g, 0.157 mmol, 1.0 equiv) was dissolved in CH ₂ C1 ₂ (8 mL) at 25 °C and DDQ (0.042 g. 0.152 mmol. 0.97 equiv) was added. The reaction contents were allowed to stir for 1 h at 25 ^C C, at which time they were then cooled to -78 °C and BBr$ (1.0 M in CH ₂ C1 ₂ , 3.14 mL, 3.14 mmol, 20 equiv) was added dropwise. The resultant solution was stirred for an additional 12 h with slow warming from -78 °C to 25 °C. Upon completion, the reaction contents were quenched by the addition of water ( 15 mL), poured into EtOAc (20 mL), and extracted with EtOAc (3 x 1 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried (MgS0 ₄ ), and concentrated. The resultant crude brown solid was purified by flash column chromatography (silica gel, CH ₂ Cl ₂ MeOH, 19/1) to give the desired demethylated compound 24 (0.053 g, 73%) as a dark orange solid. 24: R = 0.24 (silica gel, CH ₂ Cl ₂ /MeOH,

19/1); fR (film) ν,,,» 3425 (br), 3364 (br), 2918, 2850, 1643, 1609, 1564, 1527, 1452, 1231, 1 195, 1 169, 1015, 668; Ή NMR (400 MHz, acetone-i¾) δ 12.71 (s, 1 H), 10.84 (br s, 1 H), 8.40 (br s, 1 H), 8.32 (br s, 1 H), 7.70 (d, J = 9.6 Hz, 1 H), 7.53 (d, J = 8.4 Hz, 1 H), 7.24 (app t, J = 8.0 Hz, 1 H), 6.77 (d, J = 8.4 Hz, 1 H), 6.74 (dd, J = 8.4. 1.2 Hz, 1 H), 6.70 (d, J - 9.6 Hz, 1 H), 6.49 (d, J = 2.4 Hz, 1 H), 6.46 (d, J = 2.4 Hz. 1 H), 6.35 (dd, J = 7.6, 0.8 Hz, 1 H), 3.80 (dd, J = 18.0, 5.2 Hz, 1 H), 3.38 (dd, J = 15.2, 7.6 Hz, 1 H), 2.74 (dd, J = 18.0, 2.0 Hz, 1 H), 2.53-2.48 (m, 1 H), 2.31 (dd, J = 15.2, 1 1.6 Hz, 1 H), 2.13-2.07 (m, 1 H), 1.92-1.83 (m, 1 H); ^,3 C NMR (75 MHz, acetone-i/ ₆ ) δ 204.7, 189.9, 165.8, 163.8, 159.5, 156.6, 155.6, 144.1, 142.6, 140.1, 138.0, 137.3, 135.8, 133.7, 132.1. 130.3, 1 18.9 (2 C). 117.3, 1 17.0, 1 13.9, 1 12.6, 104.2, 64.7, 46.8 (2 C). 34.5, 25.3; HRMS (MALDI-FTMS) calcd for C»H ₂ o0 ₆ ⁺ |M ⁺ 1 464.1260, found 464.1268.

Dalesconol B (2). Deprotected compound 24 ( 1 1.0 mg, 0.024 mmol, 1.0 equiv) was dissolved in THF (1 mL), cooled to 0 °C, and HMDS (0.5 M in toluene, 0.24 mL _r 0.120 mmol, 5.0 equiv) was added dropwise. The resultant dark purple solution was then stirred for 3 min at 0 °C, at which time MOMC1 (0.036 mL, 0.480 mmol, 20 equiv) was added and the solution slowly lightened to yellow as it was stirred for 20 additional min at 0 °C Upon completion, Et ₃ N (0.170 mL. 1.20 mmol, 50 equiv) and MeOH (0.049 mL, 1.20 mmol, 50 equiv) were added sequentially, and the reaction contents were stirred for 20 min at 25 °C during which time a precipitate was formed slowly. Upon completion, saturated NaHCOj ( 1 mL) was added and the reaction contents were stirred for 5 min more at 25 °C at which point they were poured into water (2 mL) and extracted with EtOAc (3 x 5 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried (MgSO- , and concentrated. The resultant crude yellow oil was purified by flash column chromatography (silica gel, C^C /MeOH, 19/1) to give the desired protected material (14.0 mg, 91%) as a yellow solid. A portion of this material (7.0 mg, 0.01 1 mmol, 1.0 equiv) was dissolved in CH ₂ C1 ₂ (0.5 mL) at 25 °C open to air. ₂ C0 ₃ (15.0 mg, 0.109 mmol, 10.0 equiv), -BuOOH (5.5 M in decanes, 0.050 mL, 0.273 mmol, 25 equiv), and Pd(OAc) ₂ (2.45 mg, 0.0109 mmol, 1.0 equiv) were added sequentially and the reaction contents were allowed to stir for 24 h at 25 °C at which time more f-BuOOH (5.5 M in decanes, 0.050 mL, 0.273 mmol, 25.0 equiv) and Pd(OAc)2 (2.45 mg, 0.011 mmol, 1.0 equiv) were added. After 24 h of additional stirring at 25 °C, a third portion of /-BuOOH (5.5 M in decanes, 0.050 mL, 0.273 mmol. 25 0 equiv) and Pd(OAc)2 (2 45 mg, 0.011 mmol, 1.0 equiv) were added. After another 24 h of stirring at 25 °C the reaction contents were quenched with the addition of water (2 mL), poured into EtOAc (2 mL), and extracted with EtOAc (3 x 5 mL) The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried (MgS0 ₄ ), and concentrated The resultant crude yellow oil was purified by preparative thin-layer chromatography (silica gel, CH ₂ Cl ₂ /MeOH, 97/3) to give the desired product (3.0 mg, 42%) as a yellow solid. This procedure was repeated several times to obtain large quantities of the desired product. This material (30.0 mg, 0.046 mmol, 1.0 equiv) was then dissolved in CH2CI2 ( 1 mL) at 25 °C and solid NaHCC>3 (38.3 mg, 0.457 mmol, 10.0 equiv) and Dess-Martin periodinane (96.7 mg, 0.228 mmol, 5.0 equiv) were added sequentially. The reaction contents were stirred for 2 h at 25 °C at which point they were quenched with the addition of saturated a ₂ S0 ₃ (5 mL), and poured into water (5 mL), and extracted with EtOAc (3 x 5 mL). The combined organic extracts were washed with 1 M NaOH (5 mL), water (5 mL), and brine (5 mL), dried (MgSO-i), and concentrated to give MO -protected dalesconol B (30.0 mg, 99% yield) as a yellow solid. A portion of this material (28.0 mg, 0.043 mmol, 1.0 equiv) was dissolved in CH2CI2 (4 mL), cooled to -78 °C, and then BBr, (1.0 M in CH ₂ C1 ₂ , 1 07 mL, 1.07 mmol, 25.0 equiv) was added quickly and the purple reaction contents were allowed to stir for 15 min at -78 *C. Upon completion, the now brown reaction contents were poured into water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with water ( 10 mL) and brine (10 mL), dried (MgS0 ₄ ), and concentrated. The resultant crude orange solid was purified by column chromatography (silica gel, CH ₂ Cl ₂ /MeOH, 19/1) to give dalesconol B (2, 15.0 mg, 73% yield) as a red solid. 2: R/ = 0.35 (silica gel, CH ₂ Cl ₂ /MeOH, 19/1); IR (Film) 3520 (br), 3300 (br), 3020 (br), 2918, 2849, 1704, 1646, 1613, 1524, 1453, 1260, 1218, 1 197, 845; Ή NMR (300 MHz, acetone-<k) δ 12.61 (br s, 1 H), 12.24 (br s, 1 H), 8.05 (d, J = 9.9 Hz, 1 H), 7.66 (d, J = 8.1 Hz, 1 H), 7.14 (app t, J = 8.1 Hz, 1 H), 6.83 (d, J = 8.4 Hz, 1 H), 6.79 (d, J = 9.9 Hz, 1 H), 6.66 (d, J = 7.5

Hz, 1 H), 6.66 (d, J = 2.1 Hz, 1 H), 6.27 (d, J = 2.4 Hz, 1 H), 6.03 (d, J = 6.9 Hz, 1 H), 3.50 (dd, J = 16.8, 6.9 Hz, 1 H), 3.39 (dd, J = 13.8, 7.5 Hz, 1 H), 3.12 (br m, 1 H), 2.91 (dd, / = 16.8, 4.5 Hz, 1 H), 2.75 (dd J = 13.5, 2.7 Hz, 1 H); ^l3 C NMR (100 MHz, acetone-i ₆ ) δ 204.2, 203.0, 189.7, 166.4, 164.3, 163.7, 162.4, 159.7, 144.9, 143.2, 142.1, 139.5, 137.8, 135.4, 133.3, 132.9, 128.7, 119.5, 118.3, 116.9, 115.2, 114.7, 114.2, 113.2, 104.5, 65.0, 50.4, 42.8, 37.2; HRMS (MALDI-FTMS) calcd for C2 ₉ H, ₉ (V [M+H 479.1131, found 479.1154. The spectroscopic data for 2 matched that as described by Lin and co-workers;' ²³¹ a full comparison table of NMR data is provided at the end of this section. Example 2. Skeletal Rearrangement

Skeletal Rearrangement Product 28. Triaryl intermediate 25 (8.0 mg, 0.014 mmol, 1.0 equiv) was dissolved in CH2CI2 (0.5 mL) and cooled to -78 °C. Methanesulfonic acid (0.007 mL, 0.113 mmol, 8.0 equiv) was then added at -78 °C and the resultant solution was stirred 72

for I h with slow warming to 0 °C. Upon completion, the reaction contents were quenched with saturated NaHCC>3 (2 mL), poured into water (2 mL), and extracted with EtOAc (3 5 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried (MgSO-j), and concentrated. The resultant crude yellow oil was purified by preparative thin layer chromatography (silica gel, hexanes EtjO, 2/1) to give the cyclized and rearranged product 28 (6.0 mg, 77% yield) as a colorless oil. The product was crystallized from CH ₂ Cl ₂ /MeOH (1/1) to obtain material suitable for X-ray crystallographic analysis.

Skeletal rearrangement 30. Intermediate 29 (18.0 mg, 0.032 mmol, 1.0 equiv) was dissolved in CH ₂ C1 ₂ (1.0 mL) and cooled to -78 °C. BF ₃ »OEt ₂ (0.040 mL 0.320 mmol, 10.0 equiv) was added dropwise and the resultant red solution was stirred for 7 h with slow warming to 25 °C. Upon completion, the reaction contents were quenched with saturated NaHCOi (2 mL), poured into water (2 mL), and extracted with EtOAc (3 x 5 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried (MgS0 ₄ ), and concentrated. The resultant crude yellow oil was purified by flash column chromatography (silica gel, hexanes Et ₂ 0, 2/1) to give the polycyclic product 30 (9.8 mg, 59% yield) as a colorless oil. The product was crystallized from CH ₂ Cl ₂ /MeOH (1/1) to obtain material suitable for X-ray crystallographic analysis. Phosphonate 31. -Anisaldehyde (10.0 g, 73.4 mmol, 1.0 equiv) was dissolved in EtOH (150 mL) at 25 ^C C, MAT-dimemylethylenediamine (8.70 mL, 80.8 mmol, 1.1 equiv) was added, and the reaction contents were stirred at 25 °C for 24 h before being filtered through a pad of MgS0 ₄ and concentrated to afford the desired imidazolidine (15.0 g, 99% yield) as a white solid. Without any additional purification, this material (15.0 g, 72.8 mmol, 1.0 equiv) was dissolved in Et ₂ 0 (250 mL) and cooled to -40 °C. f-BuLi (1.7 M in pentane. 100 mL 170 mmol, 2.34 equiv) was then added dropwise over 1 h at -40 °C. Upon completion, the resultant orange reaction contents were warmed slowly to -20 °C. stirred for an additional 7 h, and then transferred by cannula over 5 min into a flask containing (CBrCl ₂ )2 (55.3 g, 170 mmol, 2.34 equiv) in Et ₂ 0 (250 mL) at 0 °C. The reaction contents were then stirred for 12 h, during which time they were warmed to 25 °C; upon completion, the solution was recooled to 0 °C and 1 M HCI (500 mL) was added slowly. The resultant solution was stirred for 1 h at 0 °C, quickly warmed to 25 °C, and then quenched by the addition of water (500 mL). The reaction contents were then extracted with EtOAc (3 x 250 mL), and the combined organic extracts were washed with water (500 mL) and brine (250 mL). dried (MgSO-i), and 73 concentrated.' ²³ ' The resultant crude yellow solid was purified by flash column chromatography (silica gel, hexanes EtOAc, 9/1) to give the desired brominated product 28 (8.12 g, 52% yield) as a white solid. This material (8.12 g, 37.8 mmol, 1.0 equiv) was suspended in MeOH (100 mL) at 25 °C and cooled to 0 °C. NaBHj (2.88g , 75.6 mmol, 2.0 equiv) was added portionwise and the reaction contents were stirred for 1 h at 0 °C. Upon completion, the reaction contents were quenched with water (100 mL) and concentrated. The reaction contents were redissolved in EtOAc ( 100 mL), poured into water (100 mL), and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water ( 150 mL) and brine (50 mL), dried (MgSO- , and concentrated to afford the desired alcohol (7.83 g, 96%) as a white solid. Pressing forward without any additional purification, this newly prepared material (7.83 g, 36.1 mmol, 1.0 equiv) was dissolved in EtjO (180 mL) and pyridine (0.437 mL, 5.41 mmol, 0.15 equiv) and PBr^ (3.41 mL, 36.1 mmol, 1.0 equiv) were added sequentially at 25 °C. The reaction contents were then stirred for 4 h at 25 °C. Upon completion, the reaction contents were quenched by the addition of water (100 mL), poured into water ( 100 ml), and extracted with EtOAc (3 x 150 mL). The combined organic extracts were washed with water (200 mL) and brine (100 mL), dried (MgS0 ₄ ), and concentrated to give the desired bromide (10.0 g, 99%) as a white solid. [Note: This product quickly decomposes on standing once it is neat and should be carried forward immediately. | Finally, KHMDS (0.5 M in toluene, 129 mL, 64.5 mmol, 1.8 equiv) was added to a solution of diethyl phosphite (9.19 mL, 71.4 mmol, 2.0 equiv) in THF (100 mL) at 0 °C and stirred for 15 min. To this solution was added dropwise a solution of the freshly prepared bromide (10.0 g, 35.7 mmol, 1.0 equiv) dissolved in THF (100 mL), and the reaction contents were stirred for 12 h with slow warming to 25 °C. Upon completion, the reaction contents were quenched with saturated NH ₄ CI (150 mL), poured into water (150 mL), and extracted with EtOAc (3 x 150 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried (MgS0 ₄ ), and concentrated to give the phosphonate 31 (10.79 g, 90%) as a colorless oil. 31: R/ = 0.21 (silica gel, EtOAc); IR (film) v _max 2981, 1589, 1572, 1466, 1435, 1267, 1082, 965, 864, 771 ; Ή NMR (400 MHz, CDCI3) δ 7.18 (d, / = 8.0 Hz, 1 H), 7.07 (app dt, J = 8.0, 2.4 Hz, 1 H), 6.81 (d, J = 8.4 Hz, 1 H), 4.05 (dq, J = 7.2, 7.2 Hz, 4 H), 3.85 (s, 3 H), 3.50 (d, J = 22.0 Hz, 2 H), 1.26 (t, J = 7.2 Hz, 6 H); ^l3 C NMR (75 MHz, CDCI ₃ ) δ 158.4 (d, J = 5.4 Hz). 128.6 (d, J = 3.8 Hz), 125.8 (d, J = 7.5 Hz), 125.0 (d, J = 3.5 Hz), 121.6 (d, J = 10.6 Hz), 109.4 (d, J = 3.4 Hz), 61.9 (d, J = 6.5 Hz), 55.9, 28.3 (d, J = 139.0 Hz), 16.3 (d, J = 6.4 Hz); HRMS (MALDI-FTMS) calcd for Ci ₂ H| ₉ BrP0 ₄ ⁺ [M + H ^* ] 337.0204, found 337.0189. 74

Key Triaryl Intermediate 32. Phosphonate 31 (6.07 g, 18.0 mmol, 1.0 equiv) was dissolved in THF (75 mL) and cooled to -78 °C. KOf-Bu (1.0 M in THF, 19.8 mL, 19.8 mmol, 1.1 equiv) was added dropwise and the resultant yellow solution was stirred for 20 min at -78 °C. A solution of aldehyde 14 (5.26 g, 18.0 mmol, 1.0 equiv) in THF (35 mL) was then added dropwise, and the resultant dark yellow solution was stirred for an additional 3 h with slow warming to 25 °C. Upon completion, the reaction contents were quenched with saturated NH ₄ CI (75 mL), poured into water (75 mL), and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried (MgSO- , and concentrated. The resultant crude yellow solid was purified by column chromatography (silica gel. hexanes/Et ₂ 0, 3/1) to give the desired E-disposed olefin (6.76 g, 79%) as a yellow solid. A portion of this olefin (6.68 g, 14.1 mmol, 1.0 equiv) was dissolved in THF (75 mL), cooled to -78 "C, and n-BuLi (1.6 M in hexanes, 13.3 mL, 21.2 mmol, 1.5 equiv) was added dropwise. The resultant darkened reaction contents were stirred for 20 min at -78 °C. A solution of aldehyde 18 (6.94 g, 28.2 mmol, 2.0 equiv) in THF (40 mL) was then added dropwise at -78 °C and the resultant orange solution was stirred for 4 h with slow warming to 25 °C. Upon completion, the reaction contents were quenched with saturated NH4CI (100 mL), poured into water (100 mL), and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried (MgS0 ₄ ), and concentrated. The resultant crude orange solid was purified by flash column chromatography (silica gel, hexanes/EtOAc, 1/1) to give the key triaryl intermediate 32 (4.62 g, 51%) as a yellow foam. 32: R = 0.65 (silica gel, hexanes EtOAc, 1:1); IR (film) v,™* 3425 (br), 2935, 2834, 1616, 1584, 1465, 1381, 1272, 1101, 1073, 1054, 750; Ή NMR (400 MHz, CDC1 ₃ ) δ 7.68 (d. J = 8.4 Hz, 1 H), 7.57 (d, J = 7.6 Hz, 2 H), 7.42-7.29 (m, 7 H), 7.25-7.22 (m, 2 H), 7.19 (d. J = 16.8 Hz, 1 H), 7.14 (d, 7 = 1.2 Hz, 1 H), 7.02 (d, J = 8.0 Hz, 1 H), 7.01 (d, J = 16.4 Hz, 1 H), 6.94 (dd, J = 8.0, 1.2 Hz, 1 H), 5.26 (d, J = 6.4 Hz, 1 H), 5.24 (d, J = 6.0 Hz, 1 H), 4.93 (d, J = 12.8 Hz, 1 H), 4.89 (d, J = 12.4 Hz, 1 H), 3.92 (s, 3 H), 3.90 (s, 3 H), 3.86 (s, 3 H), 3.58 (s, 3 H), 2.25 (d, J = 4.8 Hz, 1 H); ^,3 C NMR (75 MHz, CDCI ₃ ) δ 157.8, 157.3, 157.1, 156.1, 154.2, 142.3, 137.6, 137.4, 135.8, 134.8, 134.5, 132.9, 128.2, 128.0, 127.4, 127.2, 127.1, 126.6, 126.2. 124.9, 122.2, 121.0, 120.4, 119.9, 1 18.9, 1 16.2, 112.4, 110.1, 106.3 (2 C), 105.3, 96.7, 77.2, 71.1, 70.2, 56.4, 56.2 (2 C), 55.7; HRMS (MALDI-FTMS) calcd for C ₄ iH ₃₈ 0 ₇ ⁺ [M ⁺ ] 642.2618, found 642.2644. 75

Dalesconol A Core (33). Triaryl intermediate 32 (1.51 g, 2.35 mmol, 1.0 equiv) was dissolved in EtOAc (14 mL) and EtOH (21 mL) at 25 °C. Solid Pd/C (10%, 2.50 g, 2.35 mmol, 1.0 equiv) was added and the reaction flask was charged with an atmosphere of H ₂ gas at 25 °C. The reaction contents were stirred for 1 h at 25 °C, filtered through a pad of Celite, and the filtrate was concentrated. The resultant crude yellow foam was immediately redissolved in TFE (18 mL) and cooled to -45 °C. TFA (0.18 mL, 2.35 mmol, 1.0 equiv) was added dropwise and the resultant dark purple solution was stirred for 15 min at -45 °C Upon completion, PhI(OAc)2 (0.834 g, 2.59 mmol, 1.1 equiv) was added and the resultant dark green solution was stirred for an additional 20 min at -45 °C. Upon completion, the reaction contents were quenched with saturated Na ₂ SO.11 (15 mL) and saturated NaHCO _. t (15 mL), poured into water (30 mL), and extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried (MgSO_ , and concentrated. The resultant crude green foam was purified by flash column chromatography (silica gel, hexanes/EtOAc, 1/2) to give the cyclized core (0.337 g, 27%) as an orange foam. A portion of this enone (0.082 g, 0.154 mmol, 1.0 equiv) was dissolved in EtOAc (2 mL) and EtOH (6 mL) and Pd/C ( 10%, 0.082 g 0.077 mmol, 0.5 equiv) was added. The reaction flask was charged with an atmosphere of H? gas at 25 °C and the reaction contents were stirred for 2 h at 25 °C which point more Pd C (10%, 0.082 g, 0.077 mmol, 0.5 equiv) was added and the flask was filled with a fresh atmosphere of H ₂ gas. After 2 h of additional stirring at 25 °C, the reaction contents were filtered through a Celite pad, concentrated, and the resultant crude yellow foam was purified by flash column chromatography (silica gel, hexanes EtOAc, 1/2) to give the desired product (0.054 g, 65% yield) as a yellow foam. This product (0.054 g, 0.100 mmol, 1.0 equiv) was dissolved in THF (6 mL) at 25 °C and cooled to 0 °C. Concentrated HC1 (0.248 mL, 3.00 mmol, 30.0 equiv) was added dropwise and the reaction contents were allowed to stir for 2 h with slow warming to 25 °C. Upon completion, the reaction contents were quenched with water (6 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried (MgS0 ₄ ), and concentrated. The resultant crude brown oil was purified by flash column chromatography (silica gel, hexanes/EtOAc, 1/2) to give the free phenol 33 (0.049 g, 99% yield) as a yellow oil. 33: R/= 0.50 (silica gel, hexanes EtOAc, 1/3); 1R (film) v. 3447 (br), 2935, 1678, 1610, 1587, 1464, 1428, 1263, 1072, 1038, 819, 746; Ή NMR (400 MHz, CDCI ₃ ) δ 8.41 (s, 1 H), 7.20 (app t, J = 8.4 Hz, 1 H), 7.08 (app t, J = 7.6 Hz, 1 H), 7.00 (d, J = 7.6 Hz, 1 H), 6.86 (d, J = 7.6 Hz, 1 H), 6.83-6.79 (m, 4 H), 6.76 (d, J = 7.6 Hz, 1 H), 6.06 (d, J = 7.6 Hz, 1 H), 4.66 (s, 1 H), 4.11 (s, 3 H), 3.90 (s, 3 H), 3.73 (s, 3 H), 3.18-3 11 (m, 1 76

H), 2.71 (dd, J = 13.6, 6.4 Hz 1 H), 2.32 (dd, J = 18.4, 6.0 Hz, 1 H), 2.06 (dd, J = 18.4, 14.0 Hz, 1 H), 1.83-1.66 (m, 2 H), 1.38 (ddd, J = 12.4, 12.4, 7.6 Hz, 1 H); ^,3 C NMR (75 MHz, CDCI ₃ ) 5 198.1, 159.7, 157.1. 156.8, 154.2, 151.7, 142.6, 142.3, 141.7, 135.3, 134.3, 127.6, 127.0, 122.6, 122.1, 120.6, 120.2, 1 19.4, 1 12.0, 110.6, 109.9, 105.6, 77.2, 64.6, 57.0, 56.1, 56.0, 55.7, 45.7, 38.9, 27.3, 19.5; HRMS (MALDI-FTMS) calcd for C ₃ 2H ₂₈ C [M ⁺ ] 492.1937. found 492.1937.

Dalesconol A (1). Intermediate 33 (32.0 mg, 0.065 mmol, 1.0 equiv) was dissolved in benzene (1 mL) at 25 °C, DDQ (18.0 mg, 0.013 mmol, 1.0 equiv) was added, and the reaction contents were stirred for 1 h at 25 °C. Upon completion, the reaction contents were quenched by the addition of 1 M NaOH (2 mL) and water (2 mL) and extracted with EtOAc (3 5 mL). The combined organic extracts were washed with 1 M NaOH (2 x 5 mL), water (10 mL), and brine (10 mL), dried (MgSO_j), and were concentrated. The resultant crude yellow solid was purified by flash column chromatography (silica gel, C^Cfe/MeOH, 1 /1) to give the desired quinone methide intermediate (24.5 mg, 77%) as a yellow solid. A portion of this material (5.0 mg, 0.010 mmol, 1.0 equiv) was dissolved in CH2CI2 (0.5 mL) at 25 °C open to air. ₂ CO ₃ (14.1 mg, 0.102 mmol 10.0 equiv), /-BuOOH (5.5 M in decanes, 0.046 mL, 0.255 mmol, 25.0 equiv), and Pd(OAc)2 (2.3 mg, 0.010 mmol, 1.0 equiv) were added sequentially and the reaction contents were allowed to stir for 24 h at 25 °C at which time more -BuOOH (5.5 M in decanes, 0.046 mL, 0.255 mmol, 25.0 equiv) and Pd(OAc)2 (2.3 mg, 0.010 mmol, 1.0 equiv) were added. After 24 h of additional stirring at 25 °C a third portion of i-BuOOH (5.5 M in decanes, 0.046 mL, 0.255 mmol, 25.0 equiv) and Pd(OAc (2.3 mg, 0.010 mmol, 1.0 equiv) were added. After another 24 h of stirring at 25 °C, the reaction contents were quenched with the addition of water (2 mL) and extracted with EtOAc (3 5 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried (MgSO-O, and concentrated. The resultant crude yellow oil was purified by preparative thin layer chromatography (silica gel, C^Ch/MeOH, 97/3) to give the desired product (2.1 mg, 41%) as a yellow oil. This material (2.1 mg, 0.004 mmol, 1.0 equiv) was dissolved in CH ₂ C1 ₂ (0.5 mL) and solid NaHC0 ₃ (3.5 mg, 0.042 mmol, 10.0 equiv) and Dess-Martin periodinane (8.8 mg, 0.021 mmol, 5.0 equiv) were added sequentially at 25 °C. The reaction contents were stirred for 2 h at 25 °C. Upon completion, the reaction contents were quenched with the addition of saturated Na ₂ SOj (5 mL), poured into water (5 mL), and extracted with EtOAc (3 x 5 mL). The combined organic extracts were washed with 1 M NaOH (5 mL), water (5 mL), and brine (5 mL), dried MgS0 ₄ ), and concentrated to give 77

protected dalesconol A (2.1 mg, 99% yield) as a yellow oil. This material (2.1 mg, 0.004 mmol, 1.0 equiv) was dissolved in CH ₂ CI ₂ (1 mL), cooled to -78 ^< C, and BBr ₃ (1.0 M in CH ₂ CI ₂ , 0.064 mL 0.064 mmol, 15.0 equiv) was added dropwise. The resultant purple solution was stirred for 5 h with slow warming to 25 °C. Upon completion, the reaction contents were quenched by the addition of water (2 mL) and extracted with EtOAc (3 x 5 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried (MgS0 ₄ ), and concentrated. The resultant crude orange oil was purified by preparative thin layer chromatography (silica gel, hexanes EtOAc, 3/1) to give dalesconol A (1, 1.3 mg, 66% yield) as a red solid. 1: R/ = 0.47 (silica gel, hexanes EtOAc, 2/1); IR (film) 3550 (br), 3220 (br), 3059, 2921, 2850, 1714, 1644, 1612, 1557, 1525. 1474, 1450, 1264, 1221, 1165, 846, 820; Ή NMR (400 MHz, CDCI ₃ ) 5 12.13 (s, 1 H), 12.00 (s, 1 H), 10.71 (s, 1 H), 7.84 (d, / = 9.6 Hz, 1 H), 7.45 (app t, J = 8.0 Hz, 1 H), 7.28 (m, specific multiplicity obscured by solvent residual peak, 1 H), 7.04 (app t, J = 8.0 Hz, 1 H), 6.97 (d, J = 7.6 Hz, 1 H), 6.94 (d, J = 8.4 Hz, 1 H), 6.86 (d, J = 8.4 Hz, 1 H), 6.80 (d, J = 10.0 Hz, 1 H), 6.71 (d. J = 7.6 Hz, 1 H), 5.86 (d, J = 7.6 Hz, 1 H), 3.30 (dd, J = 16.8, 6.0 Hz, 1 H), 3.28 (dd, J = 12.8, 7.2 Hz, 1 H), 2.99 (br m, I H), 2.89 (dd, / = 16.0, 5.0 Hz, 1 H), 2.84 (dd, J = 13.0, 3.2 Hz, 1 H); ^,3 C NMR (150 MHz, CDCI ₃ ) δ 204.5, 201.0, 188.7, 162.7, 162.1, 159.3, 143.5, 141.3, 140.1, 137.2, 136.2, 135.4. 133.6, 133.2 (2 C), 132.0, 127.3, 124.0, 120.2 118.4 (2 C), 117.2, 117.0, 115.2, 113.6, 64.1, 50.0, 42.3, 36.6; HRMS (MALDI-FTMS) calcd for C ₂ 9H| ₉ 0 ₆ ⁺ [M + H ^* ] 463.1 182, found 463.1201. The spectroscopic data for 1 matched that as described by Lin and co-workers; ¹²³ ' a full comparison table of NMR data is provided at the end of this section

Example 3. By-Products and Derivatives Oxidized By-Product 34. Dalesconol B (2, 5.0 mg, 0.0105 mmol, 1.0 equiv) was suspended in DMSO-i/« (0.4 mL) under ambient atmosphere at 25 °C and allowed to stand without stirring for 6 months. The sample was concentrated under a stream of air and purified by preparative thin layer chromatography (silica gel, CHaCfe/MeOH AcOH, 98 2 0.1) to give dehydrodalesconol B (34, 2.0 mg, 40% yield) as a red solid. 34: Ή NMR (400 MHz, CDCI ₃ ) δ 12.89 (s, 1 H), 12.36 (s, 1 H), 7.68 (d, J = 9.6 Hz, 1 H), 7.32 (app t. / = 8 4 Hz, 1 H), 7.19 (d, / = 8.0 Hz, 1 H), 6.83 (d, J = 8.4 Hz, 2 H), 6.80 (s, 1 H), 6.73 (d, J = 9.6 Hz, 1 H), 6.61 (dd, J = 8.0, 1.0 Hz, 1 H), 6.60 (d, J = 2.4 Hz, 1 H), 6.36 (d, J = 2.4 Hz, 1 H), 3.52 (d, / = 12.8 Hz, 1 H), 3.42 (d, J = 12.8 Hz, 1 H); ^{, 3} C NMR (150 MHz, CDCI ₃ ) δ 197.9, 190.0, 78

187.6, 167.0, 164.8, 162.1. 158.4, 153.4, 151.8, 145.1, 141.3, 137.4, 136.6, 136.2, 134.7, 133.6, 133.5, 129.0, 128.5, 1 16.9, 116.1 1 15.8, 115.3, 113.7, 1 1 1.0, 1 10.3, 104.0, 66.5, 49.4

Phenol Derivative 35. Core enone 22 can be MOM deprotected exactly as detailed above for core ketone 23 and purified by the use of preparative thin layer chromatography (silica gel, CHCIi/THF, 94/6) to give free phenolic enone 35. 35: Ή NMR (500 MHz. CDCh) δ 8.42 (s, 1 H), 7.26 (multiplicity obscured by solvent residual peak, 1 H), 6.89 (dd. J = 8.5. 1.0 Hz, 1 H), 6.86 (d, J = 7.5 Hz, 1 H), 6.84 (d, J = 8.5 Hz, 1 H), 6.80 (d, J = 7.5 Hz, 1 H), 6.78 (d, J = 8.0 Hz, 1 H). 6.35 (d, J = 2.0 Hz, 1 H), 6.30 (d, J = 8.0 Hz, 1 H), 6.20 (d, J = 2.0 Hz, 1 H), 6.09 (s, 1 H), 4.91 (s, 1 H), 4.09 (s. 3 H), 3.95 (s, 3 H), 3.73 (s, 3 H), 3.71 (s, 3 H), 2.77 (dd, J = 14.5, 7.0 Hz, 1 H), 2.47 (dd, J = 14.5, 7.5 Hz, 1 H), 2.31-2.24 (m, 1 H), 1.62-1.56 (m, 1 H).

Derivative 36. During the hydrogenation of the core enone (formed from Friedel-Crafts cascade on intermediate 32) leading to dalesconol A (1), a small amount (10 to 20%) of the resultant ketone is further reduced to one diastereomer of a benzyl ic alcohol, presumably with hydrogen approaching from the same face as that of the desired alkene reduction. This over- reduced product (compound 36) can be isolated by preparative thin layer chromatography (silica gel, CHCI3 THF 97/3). 36: ^l H NMR (400 MHz, CDClj) δ 7.13 (app t, J = 8.0 Hz, 1 H), 7.04 (d, J = 7.6 Hz, 1 H), 6.97 (app t, / = 8.0 Hz, 1 H), 6.86 - 6.83 (m, 4H), 6.80 (d, J = 8.0 Hz, 1 H), 6.69 (d, J = 8.0 Hz, 1 H), 6.05 (d, J = 7.6 Hz, I H), 5.29 (s, 2H), 5.04 (dd, / = 10.0, 7.6 Hz. 1 H), 4.83 (d, J = 1.2 Hz, 1 H), 4.21 (s, 1 H), 4.00 (s. 3 H), 3.89 (s, 3 H), 3.74 (s, 3 H), 3.62 (s, 3 H), 2.66 (dd, J = 14.0, 6.0 Hz, 1 H), 2.55 (dd, / = 13.6, 8.0 Hz, 1 H), 1.82- 1.75 (m, 2 H), 1.70-1.61 (m, I H), 1.47-1.35 (m, 2 H).

Desoxo-dalesconol A (37). After DDQ-mediated oxidation of phenolic intermediate 33 to a p-quinone methide, the resultant material can be subjected to BBr ₃ deprotection to give an alternative natural product analog of dalesconol A (1). In the event, oxidized 33 (35.0 mg, 0.071 mmol, 1.0 equiv) was dissolved in CH ₂ C1 ₂ (3.5 mL), cooled to -78 °C, and BBr ₃ (1.0 M in CH2CI2. 1 07 mL, 1.07 mmol, 15.0 equiv) was added dropwise. The resultant purple solution was stirred for 15 h with slow warming to 25 °C. Upon completion, the reaction contents were quenched by the addition of water (5 mL) and extracted with EtOAc (3 5 mL). The combined organic extracts were washed with water (10 mL) and brine (5 mL), dried (MgS0 ₄ ), and concentrated. The resultant crude orange solid was purified by 79 preparative thin layer chromatography (silica gel, CHjCb/MeOH AcOH, 98/2/0.1 ) to give A?. w-dalesconol A (37, 1.3 mg, 66% yield) as an orange solid. 37: Ή NMR (400 MHz, CDCl ₃ ) δ 12.69 (s. 1 H), 10.84 (s, 1 H), 8.50 (s, 1 H), 7.63 (d, J = 9.6 Hz, 1 H), 7.55 (d, J = 8.4 Hz, 1 H), 7.21 (app t, J = 8.0 Hz, 1 H), 7.15 (app t, J = 7.6 Hz, 1 H), 6.97 (dd, J = 7.6. 1.2 Hz, 1 H) 6.90 (dd. J = 8.0, 1.2 Hz, 1 H), 6.77 (d, J = 8.4 Hz, I H), 6.72 (dd. J = 8.4 0.8 Hz, 1 H), 6.68 (d, J = 9.6 Hz, 1 H), 6.36 (dd, J = 7.6, 0.8 Hz, 1 H), 3.81 (dd. J = 18.0, 5.2 Hz, 1 H), 3.50 (dd, J = 15.2, 7.6 Hz, 1 H). 2.75 (dd, J - 18.0, 2.0 Hz, 1 H), 2.57-2.52 (m, 1 H), 2.40 (dd, J = 15.2, 1 1.6 Hz, 1 H), 2.17-2.1 1 (m, 1 H), 1.95-1.85 (m, 1 H).

Table 1. NMR Spectral Data Comparison of Natural and Synthetic Dalesconol A (1) in CDCb; Coupling Constants (J) in Hz.

Ή "C

Natural

Natural dalesconol A Synthetic dalesconol A Synthetic dalesconol A dalesconol A

12.13 (br s) 12.13 (s) 204.5 204.5

11.99 (brs) I2.00(s) 201.0 201.0

10.70 (brs) 10.71 (s) 188.6 188.7

7.84 (d. J = 10.0) 7.84 (d.7 = 9.6) 162.7 162.7

7.45 (dd.7 = 8.4.7.6) 7.45 (app 1.7 = 8.0) 162.0 162.1

7.28 (d, 7 = 8.4) 7.28 (d.7 = 8.0) 159.3 159.3

7.04 (dd 7 = 8.4.7.6) 7.04 (app t.7 = 8.0) 143.6 143.5

6.97 (d, 7 = 7.6) 6.97 (d.7 = 7.6) 141.4 141.3

6.94 (d, 7 = 8.4) 6.94 (d.7 = 8.4) 140.1 140.1

6.85 (d.7 = 8.4) 6.86 (d.7 = 8.4) 137.2 137.2

6.80 (d, 7 = 10.0) 6.80 (d.7= 10.0) 136.2 136.2

6.71 (d.7 = 8.4) 6.71 (d,7 = 7.6) 135.4 135.4

5.86 (d.7 = 7.6) 5.86 (d.7 =7.6) 133.5 133.6

3.30 (dd, 7 = 16.0.6.0) 3.30 (dd, 7= 16.8, 6.0) 133.2

133.2 (2 C)

3.28 (dd,7 = 13.0.7.0) 3.28 (dd, 7= 12.8, 7.2) 133.2

2.99 (dddd.7 = 7.0.6.0.5.0, 3.0) 2.99 (br m) 132.1 132.0

2.90 (dd, 7 = 16.0,5.0) 2.89 (dd, 7= 16.5.0) 127.3 127.3

2.84 (dd.7= 13.0.3.0) 2.84 (dd.7= 13.3.2) 124.0 124.0

120.3 120.2

118.5

118.4(2 C)

118.4

117.2 117.2

117.0 117.0

115.2 115.2

113.6 113.6

64.2 64.1

50.0 50.0

42.3 42.3

36.6 36.6

Table 2. NMR Spectral Data Comparison of Natural and Synthetic Dalesconol B (2) in acetone-Je; Coupling Constants (J) in Hz.

*Note that all

signals are 1.0

ppm lower than

reported

as (hey were not

referenced

to the same

solvent ppm. 83

respect to Ref. 5. Note that the natural dalesconol B ^L, C peaks were recalibrated for this comparison.

Discussion

Synthesis of Delascanol B

As part ot a program seeking to identify new classes of potent immunosuppressants. Tan and co-workers recently isolated and characterized dalesconol A and B (1 and 2, Figure 1) from a culture of Daldinia es hsholiii IFB-TLOl residing inside the gut of the mantis species Tenodora aridifolia ^ Apart from possessing an unprecedented carbon-based skeleton containing seven fused rings of various sizes, these isolates indeed possessed immunosuppressive activity (IC50 values of 0.16 pg/mL and 0.25 pg/mL. respectively), levels comparable to that of the clinically utilized cyclosporin A (ICso = 0.06 pg/mL), but with significantly reduced background cytotoxicity.' ²¹¹ Intriguingly, racemic mixtures of either 1 or 2 were found to be more potent than their separated enantiomers.' ³¹ Subsequently, She, Lin and colleagues obtained the same natural products (1 and 2) from a marine-based endophytic fungus (Sporothrix sp. #4335) that grew on the inshore mangrove tree Kandelia candel, naming them as sporothrin A and B; ^(4] they also isolated and characterized a related metabolite (sporothrin C, 3). Their activity screens revealed that 1 was a potent acetylcholinesterase inhibitor and that both 1 and 2 possessed modest antitumor activity. As such, members of this structurally novel natural product family could serve as valuable leads for future pharmaceutical development. The Examples disclosed herein describe the first total syntheses of dalesconol A and B (1 and 2) through an expedient and scalable route capable of providing the material supplies needed for more thorough biochemical applications.

As revealed in Figure 1, the synthetic approach to the dalesconols (1 and 2) was based primarily on the idea that an appropriately protected form of 5 could be converted into their complete cores (such as that represented by 4) in a single, cascade-based operation. That key step would employ among its operations a Friedel-Crafts cyclization initiated by ionization of its hydroxyl function followed by an oxidative C-C bond forming event; these processes would utilize the starred position within 5 as both nucleophile and electrophile to transform it into the lone quaternary carbon of the natural products. Subsequent adjustments in oxidation state would then complete the target molecules. 84

The envisioned cascade (i.e. S→4) shows that the power of the general structural subtype represented by 5 and 6 as precursors to controllably access structurally and biosynthetically diverse architectures is enhanced. Synthesis began with the preparation of three phenolic precursors, hoping to unite them smoothly into a defined form of 5 via the retrosynthetic disconnections indicated in Figure 1, targeting dalesconol B (2) specifically. Following several rounds of protecting group selections to achieve proper reactivity in later steps (vide infra), fragments 11, 16, and 18 were smoothly prepared from commercial materials in 4, 5, and 5 linear steps, respectively, as shown in Figure 2. Given the conventional nature of many of these operations, detailed discussion of the entire sequence is not warranted. However, the following should be noted: 1) each fragment was readily synthesized on multigram scale; 2) extensive efforts to form a variant of 14 via Stobbe condensations (with a free carboxylic acid instead of the /-butyl ester) proved low yielding and capricious, particularly on scale;' ⁷¹ 3) attempted DIBAL-H reduction of the ester within 15 to the aldehyde failed, with only the reagent formed by admixing DIBAL-H with KOi-Bu ¹⁸¹ (PDBBA) giving the desired chemoselectivity; ^l9] and 4) commercial sultone 17 had to be recrystallized prior to use to achieve a successful alkali fusion reaction en route to 18. ^[ ' ⁰¹ The above-described fragments were then united into key intermediate 19 (a fully defined form of retron 5, cf. Figure 1) in 58% overall yield via an initial Horner- Wads worth- Emmons olefination between the anion derived from 11 and aldehyde 16. followed by halogen-lithium exchange and nucleophilic attack onto the aldehyde function of 18 (Figure 3). Methods to convert this material into the entire dalesconol framework were investigated. Following extensive studies, this goal was indeed realized; Figure 3 presents the sequence in its current level of optimization.

In the event, compound 19 was taken up in a mixture of EtOAc and EtOH (2/3) and subjected to 1 atmosphere of H ₂ gas in the presence of a full equivalent of Pd C (10%); under these specific conditions, the benzyl protecting group was excised and the double bond uniting the A and B rings was reduced in quantitative yield. Use of any other solvent combinations or ratios, as well as catalytic loadings of palladium, led to significant amounts of material in which the alcohol group on the carbon bridging the A and E rings was reduced as well. Next, 86

oxidation with Dess-Martin periodinane, followed by MOM-ether cleavage with BBrj in CH2CI1, completed the target molecule (2) in 73% overall yield.' ¹⁷ ' Thus, a total of 15 linear operations, with only half of these occurring after the preparation of key intermediate 19, were needed to achieve the total synthesis. To date, over 20 mg of dalesconol B (2) have been prepared.

Skeletal Rearrangement

It is important to stress, however, that the sequence delineated above, particularly the cascade-based sequence converting 19 into 22, required several generations of approaches to achieve. The main challenge, as observed on numerous occasions, was that subtle alteration of reaction conditions and/or the mere alteration or absence of a single protecting group afforded a number of unanticipated skeletal rearrangements. For instance, exposure of a molecule with a free B-ring phenol (i.e 25, Figure 4) to a stronger acid than used above (MeSOjH in CH2CI2) led to an alternate 7-membered ring adduct (i.e. 28). Without being bound by theory, it is believed that this structure, one whose connectivities were confirmed by X-ray crystallographic analysis, is the product of a reuO-Friedel^rafts/Friedel-Crafts sequence as 26 was observed during the course of the reaction, though it could not be isolated in any significant quantity. Based on the evaluation of a number of crystal structures of related intermediates, materials of general architecture 28 appear to have significantly less steric strain than those like 26. ^,I8J Indeed, even 21 (cf. Figure 3) can rearrange into such products if appropriate care is not taken (in terms of total reaction stir time, temperature, or equivalents of acid used) Similarly, when efforts were made to deprotect the ketal within compound 29 and similar materials with B-nng phenol protection (which prevented their initial rearrangement into materials like 28), both protic and Lewis acidic conditions led to deprotection and concomitant rearrangement to unique polycycle 30.

Synthesis of Delascanol A

Finally, the developed sequence could be applied to prepare dalesconol A (1) as well. As shown in Figure 5, the synthesis was achieved starting with phosphonate 31,' ¹⁹¹ obtained from oanisaldehyde. through the same general sequence of events as described above for dalesconol B (2). Interestingly, though there is one fewer phenol in the A-ring within all of these intermediates, no fundamental change in reactivity was observed, though some differences in reaction time and temperature were required for individual steps to reach completion. As a testament to the strength of the developed chemistry, the first attempt to 87 execute this sequence with just 100 mg of o-anisaldehyde, led to the preparation of a characterizable amount of dalesconol A (1). The yields and experimental description for this synthesis shown in Figure 5 represent a second, larger scale push of material which ultimately provided the target molecule.

In conclusion, a short, direct route to dalesconol A and B (1 and 2) that is capable of providing suitable quantities of both natural products, as well as several analogs, to enable a fuller evaluation of their biochemical potential has been developed. Key elements of the sequence include a one-pot cascade process which sequentially forged two rings and the lone quaternary carbon to complete the entire polycyclic core of the targets from an acyclic material, a unique benzyl ic oxidation to fashion the final oxygen atom of the targets, and the demonstration that alteration in phenol protection and/or reaction conditions can afford a number of unique structures in addition to the target molecules. Indeed, the ability to obtain not only 22, but also 28 and 30 from intermediates of general structure 5 and 6 reaffirms their power as privileged starting materials for the controlled generation of a variety of distinct architectures. ¹²⁰ '

Furthermore, additional four compounds were obtained and characterized. These compounds, shown in Figure 6, are the result of the oxidation of dalesconol B (2) itself upon standing (34) for 6 months in deuterated solvent, as well as other side-products and deprotected analogs obtained through the sequence itself. (35-37).

It is noted that X-ray crystal structures has been obtained a compound having the strutrure

OMe

O e

, and for compounds 28 and 30, which have been deposited with the CCDC under the numbers 779330, 779331, and 779332, respectively. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.acuk/data_request/cif. 88

The biological activity particularly the immunosuppressive activity, of the following compounds was studied:

92

References

ΤΠ Y. L. Zhang, H. . Ge, W. Zhao, H. Dong. Q. Xu. S. H. Li, S. Li, J. Zhang, Y. C.

Song, X Tan, Angew. Chem. 2008, 120, 5907 - 5 10; Angew. Chem. Int. Ed. 2008, 47, 5823 - 5826.

[2] For a recent total synthesis of cyclosporin A, see: X. Wu, J. L. Stockdill, P. Wang, S

J. Danishefsky, J. Am. Chem. Soc. 2010, 132, 4098 - 4100.

13) This unique biological activity can perhaps be explained if both enantiomers can enter the binding pocket, a phenomenon that was only just recently observed. M. Mentel,

W. Blankenfeldt, R. Breinbauer, Angew. Chem 2009, 121, 9248 - 9251; Angew.

Chem. Int. Ed. 2009, 48, 9084 - 9087.

[4J L. Wen, X. Cai, F. Xu, Z. She, W L. Chan, L. L. P. Vrijmoed, E B. G Jones Y. Lin,

J. Org. Chem 2009, 74, 1093 - 1098.

[51 a) S. A. Snyder, A. L Zografos Y. Lin, Angew Chem 2007, 119, 8334 - 8339;

Angew. Chem. Int. Ed. 2007, 46 8186 - 8191; b) S. A. Snyder, S. P. Breazzano, A G

Ross, Y. Lin, A. L. Zografos, J Am. Chem. Soc. 2009, 131, 1753 - 1765.

[6] For the isolation and characterization of these 3 particular natural products, see: a)

Baba, K. Maeda, Y. Tabata, M. Doi, M. ozawa, Chem. Pharm. Bull 1988, 36, 2977

- 2983, b) Y Guo-Xun, Pl nta Medico 2005, 71, 569; c) Y. Ohshima, Y. Ueno, .

Hisamachi, M. Takeshita. Tetrahedron 1993, 49, 5801 - 5804

[7) For a related Stobbe condensation, see: a) J. L. Bloomer. W. Stagliano, J. A

Gazzillo, J. Org. Chem. 1993, 58, 7906 - 7912. The preparation and use of phosphonate 13 was inspired by the following article: b) M. Tamiya, Ohmori, M.

Kitamura, H. Kato, T. Arai M. Oorui, K. Suzuki, Chem. Eur. J. 2007, 13, 9791 -

9823.

[81 a) M. Chae J. Song, D. An Bull Kor. Chem Soc 2007, 28, 2517 - 2518. The sodium and lithium analogs have been made as well: b) J. I. Song. D. K An, Chem. Lett. 2007, 36, 886 - 887: c) M. S. Kim, Y. M. Choi, D. K. An, Tetrahedron Lett. 2007, 45, 5061 - 5064.

[91 A sequence using LiAlH* to completely reduce the ester of 15, followed by Dess- Martin oxidation, afforded a commensurate yield of product, albeit at the cost of an additional synthetic step. 93

L 101 For recent uses of the alkali fusion reaction, see: a) M. Poirier, . Simard, J. D.

Wuest, Organometallics 1996, 15, 1296 - 1300; b) S. A. Snyder, Z.-Y. Tang, R.

Gupta, J. Am. Chem. Soc. 2009, 131, 5744 - 5745.

[ 1 1 ] With the double bond present, or with any oxidized form of the double bond, the desired Friedel-Crafts cyclization could not be achieved. Thus, though a decrease in oxidation state was required before a penultimate oxidation event to complete the targets, that change proved absolutely necessary in this case.

[ 12] The use of PhI(OAc)2 to forge such types of systems is, of course, well known. For selected examples, see: a) Y. ita, T. Takada, M. Gyoten, H. Tohma, M. H. Zenk, J. Eichhorn, J. Org. Chem. 1996. 61, 5857 - 5864; b) Y. Kita, M. Arisawa, M. Gyoten,

M. Nakajima, R. Hamada. H. Tohma, T. Takada, J. Org. Chem. 1998, 63, 6625 -

6633; c) H. Tohma, H. orioka, S. Takizawa, M. Arisawa, Y. Kita, Tetrahedron

2001, 57, 345 - 352; d) I. R. Baxendale, S. V. Ley, C. Piutti, Angew. Chem. 2002,

114, 2298 - 2301 ; Angew. Chem. Int. Ed. 2002, 41, 2194 - 2197; e) C. J. Lion, D. A. Vasselin, C. H. Schwalbe. C. S. Matthews, M. F. G. Stevens, A. D. Westwell, Org.

Biomol. Chem. 2005, 3, 3996 - 4001; I. R. Baxendale, J. Deeley, C. M. Griffiths- Jones. S. V. Ley, S. Saaby, G. K. Tranmer, Chem. Comm. 2006, 2566 - 2568; g) D.

R. Kelly, S. C. Baker, D. S. King, D. S. de Silva, G. Lord, J. P. Taylor, Org. Biomol.

Chem. 2008, 6, 787 - 796. However, to the best of our knowledge, the transformation has never been used in such a cascade-based event as described here. For excellent reviews on such reactions in synthesis, see: h) L. Pouysegu, D. Deffieux, S. Quideau.

Tetrahedron 2010, 66, 2235 - 2261 ; i) S. Quideau, L. Pouysegu, D. Deffieux, Curr.

Org. Chem. 2004, 8, 1 13 - 148.

[ 13] Molecular modeling suggested that there would be a preference for the desired approach of hydrogen in this reaction, though the overall bias was not profound. For precedent that the desired hydrogenation could be achieved without loss of the benzylic ketone, see: a) T. Kametani, H. Kondoh, M. Tsubuki, T. Honda, J. Chem.

Soc. Perkin Trans. I 1990, 5 - 10; b) D. H. Miles, D.-S. Lho, V. Chittawong, A. M.

Payne, J. Org. Chem. 1990, 55, 4034 - 4036. Nevertheless, this reaction could be capricious, with over-reduction easily achieved if the reaction was not carefully monitored, particularly on scale-up.

[ 14] For a general reference on DDQ, see: D. R. Buckle in Encyclopedia of Reagents for

Organic Synthesis (Ed.: L. A. Paquette), Vol. 3, pp. 1299 - 1704, 1995, Chichester

John Wiley and Sons. 94

[ 151 a) J.-Q. Yu, E. J. Corey, Org. Lett. 2002, 4, 2727 - 2730; b) J.-Q. Yu, E. J Corey, J.

Am. Chem. Soc. 2003, 125. 3232 - 3233.

[ 16) Only one other oxidant, Mn(OAc)i, delivered similar material without the formation of significant amounts of by-products: T. . M. Shing, Y.-Y. Yeung, P. L. Su, Org

Lett. 2006, 8, 3149 - 3151. Other oxidants which failed to effect this transformation include DDQ (in the presence and absence of water), Jones reagent, Ag20, N- bromosuccinimide, and eerie ammonium nitrate (CAN).

[ 17] The permethylated form of 24 could also be oxidized to a ketone over 2 steps under the reported conditions; however, despite numerous attempts, it could never be fully deprotected to dalcsconol B (2); the non-hydrogen bound phenol within ring A proved resistant to cleavage over several attempts.

118J See the Supporting Information section for these structures. Based on MMFF94 calculations, rearranged compound 28 is approximately 6.8 kcal/mol more stable than

26.

[ 19] See the Supporting Information section for the synthetic route.

[201 For a recent review on the concept of privileged architectures in drug discovery and development, see: M. Welsch, S. A. Snyder, B. S. Stockwell, Curr. Opin. Chem. Biol. 2010, 74, 347 - 361.

[21] W. Zhang B. I. Wilke, J. Zhan K. Watanabe, C. N. Boddy, Y. Tang, J. Am. Chem.

Soc. 2007, 129, 9304.

[221 M C. Carreno, J. L. Garcia Ruano, G. Sanz, M. A. Toledo, A. Urbano, Synlett 199 ,

1241.

[23] M. Rawat, V. Prutyanov, W. D. Wullf, Am. Chem. Soc. 2006, 128, 11044.