Sarawak Medichem Pharmaceuticals, Inc.

David Zembower

Michael T Flavin

Ze-Qi Xu

Albert Khilevich

John D Rizzo

Lin Lin

Shuyuan Liao

Darko Brankovic

Jinjun Liu

Sergey Dzekhster

Aye Mar

Vilayphone Vilaychack

Vilayphone Vilaychak

Calanolide analogues that demonstrate potent antiviral activity against many viruses are provided. Also provided is a method of using calanolide analogues for treating or preventing viral infections. The calanolide analogues provided are obtained via syntheses employing chromene 4 and chromanone 7 as key intermediates.

Calanolide analogues and methods of their use

A method of preparing (+)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. According to the disclosed method, chromene 4 intermediate was subjected to a chlorotitanium-mediated aldol reaction with acetaldehyde to selectively produce (.+-.)-8a. Separation and enzyme-mediated resolution of (.+-.)-8a produced (+)-8a. Cyclization of (+)-8a under neutral Mitsunobu conditions followed by Luche reduction of (+)-7 produced (+)-calanolide A in high yield and enantiomeric purity. The method of the invention has been extended to produce potent antiviral calanolide A analogues.

Method for the preparation of (+)-calanolide A and analogues thereof

Method for the preparation of (+)-calanolide a and analogues thereof

A method of preparing (+)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. According to the disclosed method, chromene 4 intermediate was subjected to a chlorotitanium-mediated aldol reaction with acetaldehyde to selectively produce (.+-.)-8a. Separation and enzyme-mediated resolution of (.+-.)-8a produced (+)-8a. Cyclization of (+)-8a under neutral Mitsunobu conditions followed by Luche reduction of (.+-.)-7 produced (+)-calanolide A in high yield and enantiomeric purity. The method of the invention has been extended to produce potent antiviral calanolide A analogues.

(+)-calanolide A and analogues thereof

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Oak Park, IL, United States of America

David Zembower