Synthesis 2012; 44(15): 2424-2430
DOI: 10.1055/s-0031-1290396
paper
© Georg Thieme Verlag Stuttgart · New York

Thiol-Free Synthesis of Oseltamivir and Its Analogues via Organocatalytic Michael Additions of Oxyacetaldehydes to 2-Acylaminonitroalkenes

Juraj Rehák
a   Synkola Ltd., Mlynska dolina CH-2, 84215 Bratislava, Slovak Republic
,
Martin Huťka
b   Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University, Mlynska dolina CH-2, 84215 Bratislava, Slovak Republic, Fax: +421(2)60296337   Email: radovan.sebesta@fns.uniba.sk
,
Attila Latika
a   Synkola Ltd., Mlynska dolina CH-2, 84215 Bratislava, Slovak Republic
,
Henrich Brath
a   Synkola Ltd., Mlynska dolina CH-2, 84215 Bratislava, Slovak Republic
,
Ambroz Almássy
b   Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University, Mlynska dolina CH-2, 84215 Bratislava, Slovak Republic, Fax: +421(2)60296337   Email: radovan.sebesta@fns.uniba.sk
,
Viktória Hajzer
a   Synkola Ltd., Mlynska dolina CH-2, 84215 Bratislava, Slovak Republic
,
Július Durmis*
a   Synkola Ltd., Mlynska dolina CH-2, 84215 Bratislava, Slovak Republic
,
Štefan Toma
b   Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University, Mlynska dolina CH-2, 84215 Bratislava, Slovak Republic, Fax: +421(2)60296337   Email: radovan.sebesta@fns.uniba.sk
,
Radovan Šebesta*
b   Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University, Mlynska dolina CH-2, 84215 Bratislava, Slovak Republic, Fax: +421(2)60296337   Email: radovan.sebesta@fns.uniba.sk
› Author Affiliations
Further Information

Publication History

Received: 30 March 2012

Accepted after revision: 09 May 2012

Publication Date:
13 June 2012 (online)


Abstract

The organocatalytic addition of substituted oxyacetaldehydes to 2-acylaminonitroethenes proceeded with good to high diastereoselectivities and enantioselectivities. The resulting adducts reacted with ethyl 2-(diethoxyphosphoryl) acrylate to afford highly functionalized cyclohexenes. A thiol-free protocol for cyclization has been developed that leads to a separable mixture of two diastereoisomers. The unwanted diastereoisomer can be efficiently epimerized. The resulting cyclohexenes are precursors to oseltamivir and its analogues. The synthesis of the key reagent, 3-pentyloxyaldehyde, was also improved.