Cooperative Asymmetric Catalysis Using Thioamides toward Truly Practical Organic Syntheses

Abstract

Asymmetric catalysis has established its unwavering position in organic chemistry as a particularly efficient strategy for the production of enantiomerically enriched compounds. For a truly practical synthetic protocol, however, asymmetric catalysis must be endowed with high atom economy and sustainability. Cooperative activation is a powerful strategy to drive efficient asymmetric catalysis without the use of stoichiometric activating reagents, leading to asymmetric catalysis with minimum waste production. This review summarizes the utility of thioamides as an emerging functional group class in cooperative asymmetric catalysis. Soft Lewis acid/hard Brønsted base cooperative catalysts, in which thioamides serve as either electrophiles or pronucleophiles, promote asymmetric CC bond‐forming reactions with perfect atom economy.

Streamlined Catalytic Asymmetric Synthesis of Atorvastatin

“…The catalyst components ( R , R )‐Ph‐BPE, mesitylcopper, and 2,2,5,7,8‐pentamethylchroman‐6‐ol ( 10 ) are commercially available materials and work as a precatalyst 9. 12b Initially, the ( R , R )‐Ph‐BPE/mesitylcopper complex chemoselectively deprotonated thioamide 3 to generate ( R , R )‐Ph‐BPE/Cu–enolate with the liberation of mesitylene. Subsequently, the aldol addition proceeded with aldehyde 4 to generate ( R , R )‐Ph‐BPE/Cu–aldolate 11 , which functioned as a soft Lewis acid/hard Brønsted base cooperative catalyst in the following catalytic cycles 12b.…”

“…[9] In this direct aldol methodology, [10] chemoselective activation of thioamide by a soft-soft interaction of the Cu + and a sulfur atom allowed for the exclusive generation of the thioamide enolate even in the presence of enolizable aldehydes 4 (Scheme 1a). [11][12][13] Direct transformation of the thioamide functionality of aldol adduct (R)-5 into b-ketoester 6 and the subsequent diastereoselective reduction of the ketone produced the requisite syn-1,3-diol 7. [9] The major drawbacks of this first-generation synthetic route are 1) the use of costly chiral bisphosphine ligand, Ph-BPE; and 2) the lengthy reaction sequence associated with unproductive protection/deprotection steps and the introduction of an amino group.…”

Cyanomethylation of β‐Alkoxyaldehydes: Toward a Short Synthesis of Atorvastatin

“…Most of the synthetic strategies are based on the use of linear precursor 2 as a common key intermediate (Figure ), via a wide range of approaches such as optical resolution and chiral auxiliary, chiral pool, enzymatic catalysis, and asymmetric catalysis . In this context, we have previously reported the catalytic asymmetric total synthesis of atorvastatin using thioamide aldol chemistry (Scheme a) . The key C−C bond formation was accomplished by a Cu(I)/bisphosphine catalytic system, which chemoselectively promoted the enolization of the thioamide in the presence of the enolizable aldehyde .…”

Synthesis and characterization of bifunctional surfaces with tunable functional group pairs

“…In spite of its importance, the number of examples where precise placement of multiple functional groups is achieved in synthetic catalysts is limited e.g. [1][2][3][4][5][6][7][8], particularly in heterogeneous systems [8][9][10][11][12][13][14].…”

“…It is recognized that controlled separation distance between functional groups is essential in order for cooperativity to occur in catalysis [11,12]. Common methods of surface functionalization often produce random distributions on surfaces, such as the "one-pot" cocondensation of a mixture of tetraorthosilicate functional group precursors, such as the examples in [6], or sequential or concurrent post-synthesis grafting of functional groups, e.g. [7].…”