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

• Published in: Chemical record 2020-12, Vol.20 (12), p.1410-1429
• Main Authors: Ashida, Yuichiro, Tanabe, Yoo
• Format: Article
• Language: English
• Subjects: (E)- and (Z)-stereocomplementary and parallel synthesis; (E)- and (Z)-α,β-unsaturated esters; Chemical reactions; Cross coupling; Cyclopropane; Drug syntheses; Esters; Ketoesters; Organic chemistry; Reagents; Synthetic methods; Tamoxifen
• ISSN: 1527-8999; 1528-0691
• DOI: 10.1002/tcr.202000076

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. We achieved a variety of (E)‐, (Z)‐stereocomplementary syntheses of (E)‐ and (Z)‐α,β‐unsaturated esters from highly accessible (E)‐, (Z)‐stereodefined enol tosylates derived from β‐oxoesters. The preparation of (E)‐, (Z)‐enol tosylates is implemented by using inexpensive reagents under mild conditions (Step 1). The highly stereoretentive synthesis of (E)‐ and (Z)‐α,β‐unsaturated esters involves Suzuki‐Miyaura, Negishi, Sonogashira cross‐couplings (Step 2). This strategy was applied for parallel drug syntheses of (E)‐ and (Z)‐zimelidine and tamoxifen. Representative successful utilizations by other groups are also introduced.