Thioamide‐Substituted Cinchona Alkaloids as Efficient Organocatalysts for Asymmetric Decarboxylative Reactions of MAHOs

Abstract

A new class of thioamide‐substituted cinchona derivatives is reported. A convergent and practical approach was developed to insert the thioamide functional group onto the cinchonidine from readily available dithioesters. These organocatalysts were effective in asymmetric decarboxylative Mannich and protonation reactions of α‐amido‐substituted malonic acid half oxyesters (MAHOs), affording α,β‐ and α‐amino acid derivatives, respectively, in good yields and stereoselectivities.

Europhtal: An industrial cobalt phthalocyanine complex as the efficient catalyst for synthesis of thioamides by one‐pot reaction of mercaptans and amines

“…In view of the great practical and synthetic applicability of thioamides, the synthesis of such compounds has become an attractive goal for organic synthesis. There are several procedures based on different strategies reported in the literature for their synthesis, which include three component coupling reactions of aldehydes or ketones, amines, and elemental sulfur (Willgerodt–Kinder reactions) [ 12 ] ; thionation of amides using Lawesson's reagent or P 4 S 10 [ 13 ] ; thiolysis of iminium salts and nitriles with H 2 S, NaSH, or (NH 4 ) 2 S [ 14 ] ; Friedel–Crafts reaction with metal thiocyanates [ 15 ] ; thioacylation of amines using alkyldithioic acids [ 16–18 ] ; a four‐component condensation of isocyanides, CS 2 , primary amines, and aldehydes [ 19 ] ; and reduction of N ‐arylimino‐1,2,3‐dithiazoles by LiAlH 4 . [ 20 ] In addition, reaction of dibenzyl disulfides with amines as recent strategy has been employed, and a few methods using I 2 or S 8 as catalyst have been developed.…”

Substituted Malonic Acid Half Oxyesters (SMAHOs): Green Nucleophiles for Organic Synthesis

“…In all cases, the anti diastereomer was the major one. The same group subsequently developed conditions for an enantioselective version allowing to identify the use of a thioamide Cinchona derivative as a good catalyst [101] . However, the scope of this enantioselective version remains very limited, as only one example was described with moderate stereoselection.…”

Decarboxylative Mannich Reactions with Substituted Malonic Acid Half-Oxyesters

“…13 Compound 3ad. 22 Following GP3 performed with SMAHO 2d (56 mg, 0.25 mmol, 1.0 equiv) and imine 1a (65 mg, 0.25 mmol, 1.0 equiv), the desired product was obtained after purification by FC Compound 3af. Following GP3 performed with SMAHO 2f (43 mg, 0.25 mmol, 1.0 equiv) and imine 1a (65 mg, 0.25 mmol, 1.0 equiv), the desired product was obtained after purification by FC [V(SiO 2 ) = 50 mL, Cy/EA: 90/10 (250 mL), 80/20 (500 mL)] as a pale yellow glue (55 mg, 57%, d.r.…”

“…Enantioselective versions were then developed by Ma using either a thiourea catalyst for their addition to trifluoromethyl ketimines or a chiral Cu­(I) complex catalyst in the case of cyclic aldimines. , However, the use of substituted MAHOs (SMAHOs) in decarboxylative Mannich reactions remains elusive. The only examples required very particular reagents such as 2-amido MAHOs. , Such a reaction would however constitute attractive access to β 2,3 amino acid derivatives, which constitute valuable precursors for the preparation of peptidomimetics or β-lactams. , Although the use of MAHOs led to β 3 amino acid derivatives, no general method has been reported for the preparation of the disubstituted analogues. Moreover, none of the above-mentioned contributions exploit the intrinsic multicomponent potential character of the Mannich reaction .…”

“…The only examples required very particular reagents such as 2-amido MAHOs. 21,22 Such a reaction would however constitute attractive access to β 2,3 amino acid derivatives, which constitute valuable precursors for the preparation of peptidomimetics or β-lactams. 23,24 Although the use of MAHOs led to β 3 amino acid derivatives, no general method has been reported for the preparation of the disubstituted analogues.…”