An Achiral‐Acid‐Induced Switch in the Enantioselectivity of a Chiral cis‐Diamine‐Based Organocatalyst for Asymmetric Aldol and Mannich Reactions

Abstract

From a practical point of view, the development of a novel approach for the asymmetric synthesis of both enantiomeric products through catalytic asymmetric transformations with the same chiral catalyst would be very useful.[1] Various types of chiral metal complexes have already been introduced. [2] However, strictly speaking, many of these examples have employed a distinct three-dimensional association between a chiral ligand and different metals, or vice versa. In marked contrast, an initial effort for the synthetic application of chiral organocatalysts has appeared very recently, but has not been developed to a synthetically useful level. [3] In this context, we explored the capability of an additive to induce an unexpected inversion in catalyst selectivity for certain asymmetric transformations catalyzed by a single chiral organocatalyst. Herein we present the first practical example of such a system, employing achiral, organic acids as reliable additives in asymmetric, direct aldol reactions catalyzed by a chiral, cisdiamine-based, Tf-amido organocatalyst of type 1 (Tf = trifluoromethanesulfonyl Scheme 1). [4][5][6][7] Initally, the asymmetric direct aldol reaction of cyclohexanone and a-keto ester 3 a was carried out with organocatalyst 1 a to establish the optimum reaction conditions. The treatment of cyclohexanone 2 a and a-keto ester 3 a with 20 mol % of 1 a in methanol at 0 8C gave the corresponding aldol products 4 a in moderate yields; the major isomer, syn-4 a, was obtained with high enantioselectivity (Table 1, entry 1). We had previously observed a remarkable enhancement in enantioselectivity for the asymmetric conjugate addition of heterosubstituted aldehydes to vinyl sulfones by using bulky benzoic acid additives under the influence of a structurally rigid, trans-diamine-based, Tf-amide catalyst with a dihydroanthracene framework. [8] This finding prompted us to test a series of benzoic acid derivatives to probe their potential for the reversal of enantioselectivity in these products as well. [a]Entry Additive [b] Yield [c] [%] d.r. [d] (syn/anti) aldol ee [e] [%]

Organocatalytic Asymmetric α-Chlorination of 1,3-Dicarbonyl Compounds Catalyzed by 2-Aminobenzimidazole Derivatives

“…This assumption was based on the fact that the reaction using catalyst 1 with NCS and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dienone as chlorine source rendered the corresponding product 5a with opposite configurations. The same stereodivergent [38][39][40][41][42] behavior was observed with catalyst 2.…”

“…the corresponding product 5a with opposite configurations. The same stereodivergent [38][39][40][41][42] behavior was observed with catalyst 2. Finally, and based on previous studies from our group on which chiral 2-aminobenzimidazolederived organocatalysts were employed in different reactions, tentative mechanisms can be proposed for methods A and B (Figures 2 and 3).…”

Solvent‐Induced Reversal of Enantioselectivity in the Synthesis of Succinimides by the Addition of Aldehydes to Maleimides Catalysed by Carbamate‐Monoprotected 1,2‐Diamines

“…These results are always unexpected and serendipitous. [1] Thus, a few examples of switching the enantioselectivity of an organocatalyzed process by changing counteranions in the catalyst, [2] adding bases, [3] acids [4] or other additives [5] or even by light irradiation, [6] have been reported.…”

Design and Synthesis of Chiral Zn2+ Complexes Mimicking Natural Aldolases for Catalytic C–C Bond Forming Reactions in Aqueous Solution

“…Although only trace amounts of aldol product 11 were obtained under neat conditions (entry 1), the reaction was accelerated in the case of 9 /H 2 O (95/5) to give 11 in 79% yield with 89% ee (2 R , 1′ R ), while the anti / syn ratio was almost 1:1 (entry 2). When 5 mol % TFA was added, the diastereo- and enantioselectivity of syn - 11 were improved (entry 3) [37,38] (as was confirmed by 1 H-NMR that 45 ( l -ZnL 13 ) did not decompose under these conditions). Among the alcohol solvents tested (MeOH, EtOH, and 2-propanol), MeOH gave anti - 11 in 72% ee (2 S , 1′ R ) with an anti / syn ratio of 82/18 (entries 4–6).…”