SolutionsEpothilone
Exercise 1
In the retrosynthesis of epothilone A, why is the epoxide introduced at the end, by epoxidation of epothilone C, rather than carried from the start in a fragment?
The epoxide is sensitive to acids, nucleophiles and organometallics, and would not survive the aldol, esterification and metathesis well; moreover, the C12=C13 alkene is the one formed in the ring-closing metathesis. Epoxidizing it at the end with dimethyldioxirane takes advantage of the conformation of the macrocycle, which favours attack on one face. It applies the rule of introducing delicate groups as late as possible.
Exercise 2
Count the stereocentres of epothilone A. If each were formed without control (1:1 mixture), what fraction of the product would be the natural stereoisomer? What does that teach about planning?
It has seven stereocentres (C3, C6, C7, C8, C12, C13 and C15), i.e. 27 = 128 stereoisomers; without control, only 1/128 (less than 1%) would be the natural one. That is why the retrosynthesis of a natural product must decide, besides the bonds, how each stereocentre is set: from chiral starting materials, with chiral auxiliaries or asymmetric catalysts, or by induction from the substrate itself.