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Catalytic Asymmetric Synthesis of Morpholines. Using Mechanistic Insights To Realize the Enantioselective Synthesis of Piperazines

TitleCatalytic Asymmetric Synthesis of Morpholines. Using Mechanistic Insights To Realize the Enantioselective Synthesis of Piperazines
Publication TypeJournal Article
Year of Publication2016
AuthorsLau, YYin, Zhai, H, Schafer, LL
JournalJOURNAL OF ORGANIC CHEMISTRY
Volume81
Pagination8696-8709
Date PublishedOCT 7
ISSN0022-3263
Abstract

An efficient and practical catalytic approach for the enantioselective synthesis of 3-substituted morpholines through a tandem sequential one-pot reaction employing both hydroamination and asymmetric transfer hydrogenation reactions is described. Starting from ether-containing aminoalkyne substrates, a commercially available bis(amidate)bis(amido)Ti catalyst is utilized to yield a cyclic imine that is subsequently reduced using the Noyori-Ikariya catalyst, RuCl {[}(S,S)-Ts-DPEN] (eta(6)-p-cymene), to afford chiral 3-substituted morpholines in good yield and enantiomeric excesses of >95%. A wide range of functional groups is tolerated. Substrate scope investigations suggest that hydrogen-bonding interactions between the oxygen in the backbone of the ether-containing substrate and the {[}(S,S)-Ts-DPEN] ligand of the Ru catalyst are crucial for obtaining high ee's. This insight led to a mechanistic proposal that predicts the observed absolute stereochemistry. Most importantly, this mechanistic insight allowed for the extension of this strategy to include N as an alternative hydrogen bond acceptor that could be incorporated into the substrate. Thus, the catalytic, enantioselective synthesis of 3-substituted piperazines is also demonstrated.

DOI10.1021/acs.joc.6b01884