Catalytic Enantioselective Strecker Reaction of Isatin-Derived N-Unsubstituted Ketimines.

A catalytic enantioselective Strecker reaction of isatin-derived N-unsubstituted ketimines directly afforded the N-unprotected α-aminonitriles with a tetrasubstituted carbon stereocenter in up to 99% ee without requiring protection/deprotection steps. One-pot Strecker reactions from the parent carbonyl compounds were also realized with comparable yields and enantioselectivities. Direct transformations of the N-unprotected α-aminonitrile products streamlined the synthesis of unnatural amino acid derivatives and achieved the shortest one-pot stereoselective routes to a biologically active compound reported to date.

Catalytic Enantioselective Decarboxylative Mannich-Type Reaction of N-Unprotected Isatin-Derived Ketimines.

The first catalytic enantioselective decarboxylative Mannich-type reaction of N-unprotected ketimines is reported, directly providing N-unprotected 3-tetrasubstituted 3-aminooxindoles in high yield and ee without protection/deprotection steps. The utility of this reaction is demonstrated in the short step synthesis of (+)-AG-041R.

3-Mono-Substituted BINOL Phosphoric Acids as Effective Organocatalysts in Direct Enantioselective Friedel-Crafts-Type Alkylation of N-Unprotected α-Ketiminoester.

Although BINOL-derived phosphoric acids are among the most widely used chiral Brønsted acid organocatalysts, their structures are mostly limited to 3,3'-disubstituted ones and simple 3-mono-substituted ones without any polar functionalities on the 3-substituent have not been used in highly enantioselective reactions. This work reports such 3-mono-substituted analogues as effective organocatalysts in direct highly enantioselective Friedel-Crafts-type alkylation of N-unprotected α-ketiminoester. The origin of the observed high enantioselectivity with the 3-mono-substituted catalyst is also discussed.

Synthesis of 1-Tetrasubstituted 2,2,2-Trifluoroethylamine Derivatives via Palladium-Catalyzed Allylation of sp3 C-H Bonds.

This note describes the construction of tetrasubstituted carbon stereocenters via palladium-catalyzed allylation of sp3 C-H bonds of 2,2,2-trifluoroethylamine derivatives. The presence of 2-pyridyl group of the imines derived from 1-substituted-2,2,2-trifluoroethylamine was key to promoting the reaction efficiently, allowing an access to a variety of 1-allylated 2,2,2-trifluoroethylamine derivatives with tetrasubstituted carbon stereocenters.

Direct Access to N-Unprotected α- and/or ß-Tetrasubstituted Amino Acid Esters via Direct Catalytic Mannich-Type Reactions Using N-Unprotected Trifluoromethyl Ketimines.

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 ß-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.

Mechanistic Studies and Expansion of the Substrate Scope of Direct Enantioselective Alkynylation of α-Ketiminoesters Catalyzed by Adaptable (Phebox)Rhodium(III) Complexes.

Mechanistic studies and expansion of the substrate scope of direct enantioselective alkynylation of α-ketiminoesters catalyzed by adaptable (phebox)rhodium(III) complexes are described. The mechanistic studies revealed that less acidic alkyne rather than more acidic acetic acid acted as a proton source in the catalytic cycle, and the generation of more active (acetato-κ(2)O,O')(alkynyl)(phebox)rhodium(III) complexes from the starting (diacetato)rhodium(III) complexes limited the overall reactivity of the reaction. These findings, as well as facile exchange of the alkynyl ligand on the (alkynyl)rhodium(III) complexes led us to use (acetato-κ(2)O,O')(trimethylsilylethynyl)(phebox)rhodium(III) complexes as a general precatalyst for various (alkynyl)rhodium(III) complexes. Use of the (trimethylsilylethynyl)rhodium(III) complexes as precatalysts enhanced the catalytic performance of the reactions with an α-ketiminoester derived from ethyl trifluoropyruvate at a catalyst loading as low as 0.5 mol % and expanded the substrate scope to unprecedented α-ketiminophosphonate and cyclic N-sulfonyl α-ketiminoesters.

Rh-catalyzed direct enantioselective alkynylation of α-ketiminoesters.

A green way to amino acids: α-Tetrasubstituted α-amino acid derivatives are formed in high yield and enantioselectivity by using a Rh-catalyzed enantioselective alkynylation of α-ketiminoesters. This reaction, which involves a proton transfer and can be conducted at room temperature, has high substrate scope (see scheme; Cbz = benzyloxycarbonyl, Fmoc = 9-fluorenylmethyloxycarbonyl).