Synthesis of Chiral α‐Mercapto‐β‐acylamido Esters via One‐Pot Asymmetric Hydrosilylation−transacylation of α‐Acylthio‐β‐Enamino Esters

Abstract

Chiral α-mercapto-β-amino acid derivatives are highly significant for the development of new synthetic methodology and pharmaceutics. Until now, only a few catalytic asymmetric transformations for the synthesis of optically active α-mercapto-β-amino acid derivatives have been developed. In continuation of our ongoing research on asymmetric hydrosilylation, herein we report a one-pot asymmetric hydrosilylation-transacylation of N-unprotected α-acylthio-β-enamino esters by employing a chiral picolinamide Lewis base as a catalyst. The reactions afforded a wide variety of α-mercapto-β-acylamido esters with good yields (up to 99%) in good diastereoselectivities (> 20 : 1 d.r.) and moderate to good enantioselectivities (up to 86% ee). Furthermore, the absolute configuration of one product was determined and the configurations of other products were assigned by analogy. Finally, based on the absolute configuration of the product, a mechanism was proposed.[a] Dr.A solution of trichlorosilane (31 μL, 0.3 mmol, 3.0 equiv.) in 120 μL of DCM was added to a stirred solution of the corresponding αacylthio-β-enamino ester 1 (0.1 mmol), BzOH (0.3 mmol) and catalyst 2 j (0.02 mmol) in DCM (1.0 mL) at 0°C. The mixture was stirred at the same temperature for 24 h. Then the reaction mixture was treated with water at room temperature for 1 hour. Afterwards the mixture was extracted with DCM. The combined extracts were washed with brine and dried over anhydrous Na 2 SO 4 . The solvent was removed in vacuo. The residue was subjected to flash column chromatography (silica gel, PE/EA = 20 : 1) to give the desired product. The dr and ee values were determined using established HPLC techniques with chiral stationary phases.

Rational Design of Simple Organocatalysts for the HSiCl3 Enantioselective Reduction of (E)-N-(1-Phenylethylidene)aniline

“…The integration of Equation ( 1) provides the kinetic model (Equation ( 2)). Although in one instance, nonlinear effects (NLE) have indicated the participation of two catalyst molecules in the mechanism [59], NLE data have confirmed in most instances the involvement of one single catalyst molecule in the mechanism, in particular for catalytic systems related to the ones in this study and involving a dual activation mechanism [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43].…”

“…Chang-ing the solvent from CH 2 Cl 2 to CHCl 3 in this kind of reaction often provides lower ee values and slower reaction rates [54,[56][57][58], but slower kinetics can enable more accurate NMR kinetic analyses and reduce the contribution of the uncatalyzed reaction. The rate constants were calculated considering a simultaneous contribution of the uncatalyzed and catalyzed reactions with first-order rate equations in both substrate and reagent, in agreement with most mechanistic studies (Scheme 2 and Equation ( 1)) [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42]. Although for axially chiral biscarboline-based alcohols, the participation of two molecules of HSiCl 3 has been included in the reaction mechanism, to consider the quantitative reaction of this reagent with alcohols to produce hydrogen, this could be discarded in our case, as this process was not observed [43].…”

“…Thus, the organocatalytic reduction of ketimines with trichlorosilane provides an efficient methodology for the asymmetric preparation of amines [24][25][26]. Different organocatalysts have been reported and evaluated against a series of benchmark ketimines [27][28][29][30][31][32][33] and related substrates, in particular enamines [34][35][36][37][38][39], to compare their reactivity and selectivity. Some of them have provided very good levels of asymmetric induction, but their development was often based on empirical approaches, where structural modifications were sequentially tested until the required level of chiral induction was achieved.…”

Mannich-Type Reaction of α-Sulfanyl N-tert-Butanesulfinylimidates: Diastereoselective Access to α-Mercapto-β-amino Acid Derivatives

“…Procedure for the Preparation of Compound 7. (2R,3R)-3-((4-Methylphenyl)sulfonamido)-3-phenyl-2-(phenylthio)propanamide (7). Compound 6a (108.9 mg, 0.2 mmol, 1.0 equiv) was dissolved in THF/H 2 O (6 mL, v/v = 5:1), and iodine (10.1 mg, 0.04 mmol, 0.2 equiv) was added.…”

“…Recently, several asymmetric catalytic methods have been developed for the enantioselective synthesis of α-mercapto-β-amino acid analogues, such as chiral secondary amine-catalyzed aminosulfenylation of α,β-unsaturated aldehydes, chiral picolinamide-catalyzed hydrosilylation–transacylation of α-acylthio-β-enamino esters, and reactions involving imine addition, which include the organocatalytic reaction between α-thio-acetaldehydes with imines, the chiral bis­(imidazoline)–palladium-catalyzed reaction of α-(phenylthio)­acetonitriles with imines, and the reaction of α-diazo esters, thiols, and imines cocatalyzed by rhodium­(II) and chiral phosphoric acid . Methods using chiral starting materials have also been reported, such as ring opening of chiral oxazoline-5-carboxylate using thiolacetic acid and conjugate addition of homochiral lithium amides to cinnamate, followed by enolate trapping with electrophilic sulfur sources …”