Enantioselective Cross‐Aldol Reaction with Ketones and Non‐Enolizable Ketones Catalyzed by Tetrapeptides

Abstract

An efficient strategy shaping the construction of (R)-3-alkyl-3hydroxyindolin-2-one and (S)-5-trifluoromethyl-4-hydroxy-4-arylpentan-2-one derivatives catalyzed by the β-turn tetrapeptide catalyst under mild conditions was developed. Various isatins and ketones could participate in this reaction, and the desired adducts were obtained with excellent yield (up to 99 %) and moderate to high enantioselectivity (ee up to 85 %) and excellent diastereoselectivity (dr up to > 20 : 1). Moreover, a series of trifluoromethyl ketones with ketones also could participate in this reaction, and the resulting β-trifluoromethylβ-hydroxy ketones with excellent yields and moderate enantioselectivities (ee up to 58 %) were obtained. In addition, the strategy afforded better results than natural papain.

Aldol Insights: The Route to Chiral Synthesis of 3‐Substituted 3‐Hydroxy‐2‐Oxindoles

“…Wang and colleagues developed an efficient strategy for the synthesis of ( R )‐3‐alkyl‐3‐hydroxyindolin‐2‐one and ( S )‐5‐trifluoromethyl‐4‐hydroxy‐4‐arylpentan‐2‐one derivatives using a β ‐turn tetrapeptide catalyst under mild conditions. The reaction accommodated various isatins and ketones, yielding desired adduct 6 a with excellent yields (up to 99 %), moderate to high enantioselectivity ( ee up to 85 %), and dr up to >20 : 1 [55] . Explored various isatins with different substituents, observed position‐dependent effects on enantioselectivity and diastereoselectivity.…”

“…The reaction accommodated various isatins and ketones, yielding desired adduct 6 a with excellent yields (up to 99 %), moderate to high enantioselectivity (ee up to 85 %), and dr up to > 20 : 1. [55] Explored various isatins with different substituents, observed position-dependent effects on enantioselectivity and diastereoselectivity. Furthermore, the method extended to trifluoromethyl ketones, producing β-trifluoromethyl-β-hydroxy ketones with excellent yields and moderate enantioselectivities (ee up to 58 %) (Scheme 32).…”

Prolinamide and Prolinamide Tagged with Ionic Liquid Intercalated in Bentonite Clay, a Recyclable Catalyst for Asymmetric Aldol Reactions

“…), the aldol product was obtained in lower yield (98 % to 18 %) with lower ee (Table 3, entries 1 vs 14 and 15). We also varied different catalyst loading from 2-20 mol% of CIL 2 a and the use of 10 mol% catalyst loading of CIL 2 a was found to be optimum in terms of yield and ee of the product 6 a (Table 3, entries [16][17][18]. The aldol reaction of isatin (4 a) and acetone (5 a) catalyzed by CIL 2 a (10 mol %) was carried out at different temperatures to improve the enantioselectivity of the product (Table 4).…”

“…[8] A highly efficient Nhetero aryl sulfonyl prolinamide for the synthesis of Rconvolutamydine (ee up to 99 %) was reported by Nakamura. [9] A variety of organocatalysts have been used for the direct asymmetric aldol reaction of isatin and ketone including prolines, [10] prolinamides, [5b] carbohydrate-derived alcohols, [11] quinidine-thioureas, [12] chiral amines as organocatalysts, [13] amino alcohols, [14] N-aryl, N-heteroaryl pyrrolidine amides, [15] natural amino-acid salts, [16] tetrapeptides, [17] and chiral norephedrine-based β-amino alcohols, [18] etc. The problem associated with these organocatalysts is that they are either expensive or require a few steps for their synthesis.…”