Stereocomplementary and Parallel Syntheses of Multi-Substituted (E)-, (Z)-Stereodefined α,β-Unsaturated Esters: Application to Drug Syntheses.

Ubiquitous α,β-unsaturated esters are well recognized as key structural olefin scaffolds in organic chemistry. (E)- and (Z)-steroselectivity is the most critical issue in their synthesis, however, (E)- and (Z)- stereocomplementary synthetic methods remain quite limited. The present account discloses general (E)-, (Z)-stereocomplementary syntheses of a variety of α,β-unsaturated esters from highly accessible (E)-, (Z)-stereodefined enol tosylates derived from β-ketoesters and α-formyl esters. Step 1 toward the stereocomplementary preparation of (E)-, (Z)-stereodefined enol tosylates is implemented by using inexpensive reagents under mild reaction conditions. Step 2 toward the highly stereoretentive synthesis of (E)- and (Z)-stereodefined α,β-unsaturated esters involves Suzuki-Miyaura, Negishi, Sonogashira, Iron-catalyzed, Mizoroki-Heck, and Buchwald-Hartwig cross-coupling reactions. Notably, this strategy was successfully applied for parallel drug syntheses of (E)- and (Z)-zimelidine, (E)- and (Z)-tamoxifen, and Merck's cyclopropane pharmacophore. Representative successful utilizations by other groups are also introduced.