Asymmetric Synthesis of Merck’s Potent hNK1 Antagonist and Its Stereoisomers via Tandem Acylation/[3,3]-Rearrangement of 1,2-Oxazine N-Oxides

Asymmetric Synthesis of Merck’s Potent hNK1 Antagonist and Its Stereoisomers via Tandem Acylation/[3,3]-Rearrangement of 1,2-Oxazine N-Oxides Full article

Journal

Journal of Organic Chemistry
ISSN: 1520-6904 , E-ISSN: 0022-3263

Output data

Year: 2020, Volume: 85, Number: 17, Pages: 11060-11071 Pages count : 12 DOI: 10.1021/acs.joc.0c01322

Authors

Dorokhov Valentin S ¹ , Nelyubina Yulia V ² , Ioffe Sema L ¹ , Sukhorukov Alexey Yu ^1,3

Affiliations

1	N. D. Zelinsky Institute of Organic Chemistry, Leninsky prospect, 47, Moscow 119991, Russia
2	A. N. Nesmeyanov Institute of Organoelement Compounds, Vavilov str. 28, Moscow 119991, Russia
3	Plekhanov Russian University of Economics, Stremyanny per. 36, Moscow 117997, Russia

An asymmetric total synthesis of Merck’s hNK1 antagonist and three of its stereoisomers was accomplished in 10 steps. The synthesis involves a stereoselective assembly of 1,2-oxazine N-oxide by the [4 + 2]-cycloaddition, site-selective C–H oxygenation using a novel tandem acylation/[3,3]-rearrangement process and the reductive 1,2-oxazine ring contraction into a pyrrolidine ring as key stages. Using this strategy, the fused pyrrolidine subunit was constructed with exceptionally high regio- and stereoselectivities. The approach described here can be used to access enantiopure 3,4-disubstituted prolinols, which are frequently found in pharmaceutically relevant molecules and organocatalysts.

Dorokhov V.S. , Nelyubina Y.V. , Ioffe S.L. , Sukhorukov A.Y.
Asymmetric Synthesis of Merck’s Potent hNK1 Antagonist and Its Stereoisomers via Tandem Acylation/[3,3]-Rearrangement of 1,2-Oxazine N-Oxides
Journal of Organic Chemistry. 2020. V.85. N17. P.11060-11071. DOI: 10.1021/acs.joc.0c01322 WOS Scopus OpenAlex

Web of science:	WOS:000569376800004
Scopus:	2-s2.0-85092164047
OpenAlex:	W3048935909

DB	Citing
OpenAlex	12
Scopus	10
Web of science	10