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Total Synthesis of Estradiol Methyl Ether and Its Five‐Pot Synthesis with an Organocatalyst
Author(s) -
Koshino Seitaro,
Kwon Eunsang,
Hayashi Yujiro
Publication year - 2018
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201800910
Subject(s) - chemistry , enantioselective synthesis , aldol reaction , total synthesis , silyl ether , yield (engineering) , organic chemistry , ether , catalysis , silylation , materials science , metallurgy
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.