Total Synthesis of Estradiol Methyl Ether and Its Five-Pot Synthesis with an Organocatalyst

Seitaro Koshino, Eunsang Kwon, Yujiro Hayashi

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Enantioselective total synthesis of estradiol methyl ether has been accomplished in a highly diastereo- and enantioselective manner. The key reaction is diphenylprolinol silyl ether mediated domino Michael/aldol reaction to afford bicyclo[4.3.0]nonane derivatives with A, C, and D rings of the steroids as a single isomer with excellent enantioselectivity. Each reaction was optimized, and the total synthesis could be accomplished in 12 pots with 10 purifications using silica gel, resulting in an overall yield of 6.8 %. The reaction sequence and reaction conditions were then optimized in terms of pot economy, whereupon estradiol methyl ether could be synthesized using five reaction vessels with four purifications in an overall yield of 15 %. Notably, six reactions, namely, oxidation, hydrogenation, formation of acid chloride, Friedel–Crafts reaction, deprotection, and reduction could be carried out in the last one-pot sequence.

Original languageEnglish
Pages (from-to)5629-5638
Number of pages10
JournalEuropean Journal of Organic Chemistry
Volume2018
Issue number41
DOIs
Publication statusPublished - 2018 Nov 8

Keywords

  • Domino reactions
  • Organocatalysis
  • Pot economy
  • Steroids
  • Total synthesis

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Organic Chemistry

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