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Direct Access to N‐Unprotected α‐ and/or β‐Tetrasubstituted Amino Acid Esters via Direct Catalytic Mannich‐Type Reactions Using N‐Unprotected Trifluoromethyl Ketimines
Author(s) -
Sawa Masanao,
Morisaki Kazuhiro,
Kondo Yuta,
Morimoto Hiroyuki,
Ohshima Takashi
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201703516
Subject(s) - stereocenter , chemistry , enantioselective synthesis , organocatalysis , nucleophile , catalysis , trifluoromethyl , lewis acids and bases , combinatorial chemistry , mannich reaction , organic chemistry , thiourea , medicinal chemistry , alkyl
Direct catalytic C−C bond‐forming addition to N‐unprotected ketimines is an efficient and straightforward method of synthesizing N‐unprotected tetrasubstituted amines that eliminates prior protection/deprotection steps and allows facile transformation of the products. Despite its advantages, however, N‐unprotected ketimines have difficulties in C−C bond‐forming reactions, and only a limited number of reactions and substrates are reported compared with their N‐protected counterparts. Herein we report that N‐unprotected trifluoromethyl ketimines are effective for C−C bond‐forming reactions using Mannich‐type reactions as a model case. We demonstrate that Lewis acid catalysis was effective for promoting reactions with various N‐unprotected trifluoromethyl ketimines, and thiourea organocatalysis was effective for promoting highly enantioselective reactions with various carbonyl nucleophiles, providing direct access to various N‐unprotected α‐ and/or β‐tetrasubstituted amino acid esters. Furthermore, direct construction of vicinal tetrasubstituted chiral carbon stereocenters was achieved for the first time in a highly enantio‐ and diastereoselective manner. These results demonstrate the potential of N‐unprotected ketimines as substrates applicable to many other addition reactions.