Conformational constraint in natural product synthesis.

Natural products that exhibit significant biological activity often possess complex molecular structures such as caged frameworks, strained motifs, inherent instability, and many stereogenic carbon centers, etc. Achievement of those total syntheses always requires the powerful methodologies and judicious strategies to fulfill the stereochemical requirements of the target compounds. Building on our successful stereo-controlled syntheses, we have established the concept of conformational constraint, which renders the approach of reactants under a controlled manner during the bond-forming process through the best orbital overlap. Important factors that affect the proper orientation of substrates are (i) acyclic allyl strain, (ii) stereoelectronic effect, (iii) chelation control, etc. Established methodologies include (i) heteroatom directed conjugate addition for diastereoselective C-C bond formation, (ii) 100% α-selective C-glycosidation by using alkynyl-silane, (iii) cobalt acetylene chemistry for medium-size ring formation, followed by its functional group transformation. The author has named such total concept as conformational constraint and has illustrated it with the finished examples of total syntheses. These examples are taken from maytansine, okadaic acid, tautomycin, tetrodotoxin, ciguatoxin, etc.