d-Penicillamine and l-cysteine derived thiazolidine catalysts: an efficient approach to both enantiomers of secondary alcohols

Abstract

D-Penicillamine derived thiazolidine ligands were prepared in a two-step synthetic sequence and used in the enantioselective alkylation of a variety of aromatic aldehydes with diethylzinc at room temperature. Excellent ee, up to >99%, and nearly complete conversions were observed. Structurally analogous L-cysteine derived thiazolidine ligands were also synthesized and tested for comparative purposes, resulting in very good, albeit slightly lower selectivities, up to 89%. The combined use of these two types of thiazolidines constitutes a very interesting strategy for synthesizing both (S) and (R) enantiomers of chiral secondary alcohols, thus leading the way to a myriad of useful optically active products with opposite absolute configurations.

Deciphering the mechanism behind efficient enantioselective ethylation with thiazolidine‐based amino alcohols

“…The first important observation that can be made is that the main configuration of the product does not always rely on the stereochemistry of the starting material, unlike what is verified with the use of esterified thiazolidines as ligands. [ 58,59 ] Although l ‐cysteine derivatives always lead to ( S )‐1‐phenylpropan‐1‐ol, d ‐penicillamine derivatives originate both enantiomers of the chiral alcohol.…”

“…Thiazolidines 3b–g , 3h , and 3i were prepared according to established procedures and presented spectroscopic data in agreement with those previously described. [ 58,59 ] d ‐Penicillamine methyl ester hydrochloride was prepared according to a described procedure and used directly. [ 71 ]…”

“…[65][66][67][68][69][70] Thiazolidines 3b-g, 3h, and 3i were prepared according to established procedures and presented spectroscopic data in agreement with those previously described. [58,59] D-Penicillamine methyl ester hydrochloride was prepared according to a described procedure and used directly. [71] 2.2 | General procedure for the synthesis of C4-esterified thiazolidines 3a and 4c [72] To a solution of L-cysteine or D-penicillamine methyl ester hydrochloride, 1 or 2, (2.0 mmol) in water (2.00 ml), was added triethylamine (2.0 mmol, 0.28 ml) or potassium bicarbonate (2.0 mmol, 0.20 g) and a solution of trimethylacetaldehyde (2.0 mmol, 0.22 ml) in ethanol (1.50 ml).…”

“…The C4-esterified thiazolidines with opposite configuration, depending on their preparation from L-cysteine or D-penicillamine, showed remarkable efficiency as ligands for the enantioselective ethylation of aldehydes, mainly those derived from D-penicillamine. [58][59][60][61][62] The fact that amino alcohol ligands are the most studied for this reaction prompted us to further modify the thiazolidine ring in order to obtain C4-hydroxymethyl derivatives, available in a two-step sequence and subject of scarce reports in the literature (Scheme 2). [63,64] The catalytic efficiency of these new thiazolidines in the enantioselective ethylation of aldehydes was screened and optimized, and the steric and electronic effects of different substituents at C2 were analyzed.…”

Chiral Thiazolidine based Organocatalysts: Synthesis and Application in Asymmetric Aldol Reactions

“…[14] More recently, Schneider et al developed several chiral thiazolidine-derived organocatalysts that were used in aldol reactions. [15,16] In this context, and in the continuation of our studies on the use of thiazolidines for asymmetric catalysis, [17] a series of new thiazolidine organocatalysts were synthesized and tested in asymmetric aldolic reactions. The results of these studies are described in this paper.…”