- Expedient access to the okadaic acid architecture: A novel synthesis of the C1-C27 domain
-
A newly designed synthetic entry to the C1-C27 domain of okadaic acid has been developed. This incorporates substantial improvements in the preparations of the key okadaic acid building blocks representing the C3-C8, C9-C14, and C16-C27 portions. The synthesis of the C3-C8 lactone used (R)-glycidol as the origin of the C4 stereogenic center and featured a late-stage optional incorporation of the C7 hydroxyl group. The complementary C9-C14 fragment was synthesized in a concise route from (R)-3-tert-butyldimethylsilyloxy-2-methylpropanal and propargyl bromide. Assembly of the C3-C14 spiroketal-containing intermediate from the constituent fragments revealed a dramatic effect of C7 functionalization upon spiroketalization efficiency. In contrast, both (9E)- and (9Z)-enones converged readily to the C8 spiroketal upon treatment with acid. Modifications to the central C16-C27 fragment of okadaic acid included the early replacement of benzylic protecting groups by more suitable functionalities to facilitate both the generation of the C15-C27 intermediate and the deprotection of the final products. These modular building blocks were deployed for the synthesis of the C1-C27 scaffold of 7-deoxyokadaic acid. This work demonstrates improvements in the formation of versatile okadaic acid intermediates, as well as a reordering of fragment couplings. This alternative order of coupling was designed to promote the late stage incorporation of nonnatural lipophilic extensions from the C27 terminus.
- Dounay,Urbanek,Frydrychowski,Forsyth
-
p. 925 - 938
(2007/10/03)
-
- Efficient synthesis of okadaic acid. 2. Synthesis of the C1-C14 domain and completion of the total synthesis
-
Described here are the full details of the preparation of a synthetic intermediate representing carbons 1' 14 (C1-C14) of the marine natural product okadaic acid (1), the coupling of this fragment with the previously prepared C15-C38 domain, and the completion of an efficient total synthesis of 1. The C1-C14 intermediate was prepared in 11 steps and ~20% overall yield from a functionalized δ-valerolactone derivative representing C3-C8 of 1. This featured a classic spiroketalization strategy to construct the highly substituted 1,7-dioxaspiro-[5.5]undec-4-ene system, followed by incorporation of the intact C1-C2 α-hydroxyl, α-methyl carboxylate moiety using cis-(S)- lactate pivalidene enolate. The complete C1-C14 intermediate was converted into 1 in five additional steps. Coupling of the C1-C14 fragment with the C15-C38 domain of 1 via C14 aldehyde and C15 β-keto phosphonate moieties provided the complete carbon skeleton of 1 bearing a ketone at C16 and a mixed-methyl acetal at C19. Reduction of the C16 ketone using Corey's (S)- CBS/BH3 system and subsequent acid-triggered spiroketalization formed the Central 1,6-dioxaspiro[4.5]decane ring system. Saponification of the C1-C2 pivalidene group and final reductive cleavage of the three benzyl ethers using lithium di-tert-butylbiphenylide in THF provided 1 in 48% yield from the C1-C14 aldehyde, and in 26 steps and ~2% overall yield in the longest linear sequence from the C22-C27 synthon methyl 3-O-benzyl-α-D- altropyranoside.
- Sabes, Steven F.,Urbanek, Rebecca A.,Forsyth, Craig J.
-
p. 2534 - 2542
(2007/10/03)
-