Saturday, December 10, 2011

Partial Synthesis of Withanolide A From Pregnenolone

            Gademann and co-workers have disclosed a stereocontrolled preparation of withanolide A from a readily available steroid precursor. Their partial synthesis proceeds in 13 steps with minimal use of protecting groups and accomplishes stereoselective elongation of the steroid (C17) side chain as well as oxidative elaboration of the western A/B decalin substructure. Among the synthetic challenges associated with this task is the establishment of stereocenters at C20, a quaternary center, and C22, which is incorporated into the alpa,beta-unsaturated valerolactone (dihydropyrone) in the side chain. Ikekawa’s partial synthesis of withanolide D (structure shown above) provides a strong precedent for pregnane side-chain homologation of this sort and Gademann clearly benefits from the knowledge gained in pioneering synthetic campaigns. What makes the synthesis of withanolide A significant is the stereocontrolled functionalization of rings A and B of pregnenolone, which entails installation of a very sensitive enone and an alpha-hydroxy epoxide. These structural motifs are unique as compared to other withanolides that have succumbed to synthesis and, thus, a novel synthetic strategy is required to access this important candidate for the therapeutic treatment of neurodegenerative disease (see previous post for details). Gademann and co-workers expertly apply the Schenck O2 ene reaction and Wharton carbonyl transposition to complete the synthesis of the target molecule along with non-natural analogues in quantities sufficient for evaluation of neuritogenic properties and secretase inhibition activity.
The synthesis is initiated by a highly diastereoselective addition of lithiated 1,3-dithiane to the C20-keto group of 3beta-OTBS pregnenolone. Gademann and co-workers do not comment on the stereochemical outcome of this conversion except to say that the product is known. A 1978 review article by Jerzy Wicha provides a detailed rationale for the addition of sterically bulky nucleophiles to the 20-ketone of the steroid system, a reaction with a rich history dating back to Woodward’s total synthesis of cholesterol (JACS 1951). This stereochemical result is best explained by ‘steric approach’ control, which favors attack of the carbonyl from ‘outside of the molecule,’ or, in other words, from the C16 side. The observed diastereoselectivity, dictated by the conformational transition state model shown above, generally predominates for the addition of bulky nucleophiles to C17 non-hydroxylated (i.e. 17alpha-H) steroidal 20-ketones.
Two subsequent synthetic operations generate the MOM-protected alpha-hydroxy aldehyde which is elaborated to the lactone with excellent diastereoselectivity by a tandem vinylogous aldol/lactonization reaction. This method was developed by Ikekawa for the partial synthesis of withanolide D, recorded in 1984. The reaction seems to proceed through a transition state comparable to Cram’s cyclic chelate model.
Stereoselective oxyfunctionalization of the A/B ring junction position (C5) on the alpa-face is accomplished by implementation of the Schenck ene reaction with singlet oxygen, generated in situ from molecular oxygen in the presence of a porphyrin sensitizer with irradiation (Na lamp). Generally, diastereoselectivity in the photooxygenation of steroids is governed mainly by steric shielding by the angular methyl groups. Conformational rigidity also contributes to pi-facial selectivity, as hydrogen atoms perpendicular to the plane of the double bond are accessible only from one face of the molecule. In this case, the alpha-oriented allylic alcohol is generated in good isolated yield although the diastereomeric ratio of products is not provided by the authors.
The key step of the synthesis was the Wharton carbonyl transposition of the advanced bis-epoxy ketone intermediate. Exposure to hydrazine furnished the rearranged allylic alcohol and subsequent PDC oxidation completed the synthesis of withanolide A (50% yield over two steps). This partial synthesis effort is notable for its practicality (13 steps), high level of stereocontrol and pragmatic choice of a simple and abundant starting material derived from Nature’s chiral pool.

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