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Synfacts 2012; 8(3): 0233
DOI: 10.1055/s-0031-1290175
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of (+)-Sertraline

Contributor(s):
Philip Kocienski
Lee SH, Kim IS, Li QR, Dong GR, Jeong LS, Jung YH * Sungkyunkwan University, Suwon, University of Ulsan and Ewha Womans University, Seoul, Republic of Korea
Stereoselective Amination of Chiral Benzylic Ethers Using Chlorosulfonyl Isocyanate: Total Synthesis of (+)-Sertraline.

J. Org. Chem. 2011;
76: 10011-10019
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Further Information

Publication History

Publication Date:
20 February 2012 (online)

 
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Key words

sertraline - stereoselective amination - benzylic ethers - chlorosulfonyl isocyanate

Significance

Key steps in this small-scale, six-step synthesis of (+)-sertraline (19% overall yield) are (1) the kinetic resolution of the racemic ketone E using the (R)-(+)-2-methyl-CBS-oxazaborolidine catalyst D and N,N-diethylaniline borane as reducing agent, and (2) the reaction of benzyl ether F with chlorosulfonyl isocyanate to give carbamate I.


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Comment

The retention of configuration observed in the latter reaction arises from the formation of the tight ion pair H that allows front-side attack by an SN i mechanism involving a four-center transition state. A further 11 examples of the reaction are reported all proceeding with good yield (70–89%) and high ee (88 to >99%). Benzylic methyl ethers give the corresponding methyl ­carbamates.


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