Epoxide Homologation, reductive

Sundarababu Baskaran of -Madras offers (Organic Lett. 5 583,2003) an alternative route to indolizidines. Exposure of the epoxide 7 to Lewis acid followed by reduction leads to 11 as a single diastereomer. The authors hypothesize that this rearrangement is proceeding via intermediates 8 -10. Tosylation of 11 followed by homologation leads to the Dendrobatid alkaloid 12. 

The required chain extension of 12 was accomplished via deprotonation with NaH and condensation with aldehyde 7 to afford the Diels-Alder precursor 13 in 50% yield. Thermolysis of triene 13 and lactam 3 in xylene at 170 C for four days resulted in the desired cycloaddition to 14. Chromatographic purification permitted isolation of pure 14 in addition to a small amount of an exo isomer (>4 1 ratio). Acid treatment induced cleavage of both the silyl ether and acetonide. Reprotection of the diol and selective epoxidation of the A olefin produced 15 in 64% yield from 12. Epoxide 12 was then transformed to the isomeric allylic alcohol 16 by conversion of the alcohol to the bromide followed by reductive elimination. Protecting-group manipulation and subsequent oxidation the gave aldehyde 17, which was homologated and hydrolyzed to give seco acid 18 in 32% overall yield from 16. 

Scheme 3 shows the flexibility of this approach in more detail. Possible electrophiles for addition to metalated intermediate 4 include iodine to give the halogenated aromatic ring 6, Weinreb amides (e.g., 9) to access the aromatic ketone 10, DMF to give aldehyde 11, or various aldehydes, e.g., 8, 12, 15, or 16, to give differently substituted benzylic alcohols, e.g., 7, 13, 14, and 17, with diverse additional functional handles for further homologation. All these products may be readily further elaborated. Possible transformations include reductions, iodolactonizations, aldol reactions, allylation, epoxidation, or direct lactonization reactions. 

The flrst total synthesis of the benzoquinonoid ansamycin antibiotic herbimycin A has been reported.3 7 Methyl a-D-mannopyranoside played a key role in the synthesis of die C(9)-C(15) segment 56 (mannose numbering) which required legioselective reduction of the C(2)-branched epoxide 55 followed by homologation at C(6) (sugar numbering) (Scheme 13). 

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