Total Syntheses of (+)‐Polygalolide A and (+)‐Polygalolide B: Elucidation of the Absolute Stereochemistry and Biogenetic Implications

The total syntheses of (+)‐polygalolide A and (+)‐polygalolide B have been completed by using a carbonyl ylide cycloaddition strategy. Three of the four stereocenters, including two consecutive tetrasubstituted carbon atoms at C2 and C8, were incorporated through internal asymmetric induction from the stereocenter at C7 by a Rh₂(OAc)₄]‐catalyzed carbonyl ylide formation/intramolecular 1,3‐dipolar cycloaddition sequence. The arylmethylidene moiety of these natural products was successfully installed by a Mukaiyama aldol‐type reaction of a silyl enol ether with a dimethyl acetal, followed by elimination under basic conditions. We have also developed an alternative approach to the carbonyl ylide precursor based on a hetero‐Michael reaction. This approach requires 18 steps, and the natural products were obtained in 9.8 and 9.3 % overall yields. Comparison of specific rotations of the synthetic materials and natural products suggests that polygalolides are biosynthesized in nearly racemic forms through a 5+2] cycloaddition between a fructose‐derived oxypyrylium zwitterion with an isoprene derivative.