Highly Enantioselective Aldol Reactions between Acetaldehyde and Activated Acyclic Ketones Catalyzed by Chiral Primary Amines

Abstract

Highly enantioselective cross-aldol reactions between acetaldehyde and activated acyclic ketones are reported for the first time. Various acyclic ketones, such as saturated and unsaturated keto esters, reacted with acetaldehyde in the presence of a chiral primary amine and a Brønsted acid to afford optically enriched tertiary alcohols in good yields and with excellent enantioselectivities. Trifluoromethyl ketones were tolerable under the reaction conditions, thereby affording the trifluoromethyl carbinol in good-to-excellent yields and enantioselectivities. Structural modification of the chiral amines from the same chiral source switched the stereoselectivity of the products. The utility of aldol chemistry was demonstrated in the brief synthesis of functionally enriched δ-lactones. Theoretical calculations on the transition-state structure indicated that the protonated tertiary amine could effectively activate the carbonyl group of a keto ester to promote the addition process through hydrogen-bonding interaction and, simultaneously, provide an appropriate attacking pattern for the approach of the keto ester to the enamine, which is formed from acetaldehyde and the chiral catalyst, on a particular face, resulting in high enantioselectivity.

Enantioselective aldol reactions of α,β-unsaturated ketones with trifluoroacetophenone catalyzed by a chiral primary amine

“…As recorded in Table 3, the primary amine 1d exhibited generally high to excellent enantioselectivities ranging from 83% to 93% ee and good yields for most of a,b-unsaturated ketones tested (entries [1][2][3][4][5][6][7][8][9][10][11], with the exception of the case involving heteroaromatic substrates, in which moderate yields were obtained (entries 12 and 13). Extending these reaction conditions to other trifluoroacetophenones was highly successful, giving rise to trifluoromethylated b-hydroxycarbonyl compounds with 86-99% ee (entries 14-17).…”

“…10 Very recently, these chiral amines were successfully applied in cross aldol reactions of acetaldehyde with unsaturated keto-esters, yielding enantiomerically enriched tertiary alcohols with excellent enantioselectivity. 11 In our continuous efforts toward exploring primary amine catalyzed aldol reactions with ketones and synthesizing trifluoromethylated organic compounds, we herein report a cross aldol of a,b-unsaturated ketones with trifluoroacetophenone to allow the synthesis of trifluoromethylated b-hydroxycarbonyl compounds bearing a quaternary carbon stereogenic center.…”

ChemInform Abstract: Acetaldehyde: A Small Organic Molecule with Big Impact on Organocatalytic Reactions

“…The au-thors reported also the asymmetric aldol reaction of an aromatic CF 3 ketone and of aC F 3 -tethered a,b-unsaturated ketonew ith acetaldehyde,w hich gave the corresponding aldol products in high yields and enantioselectivities( Scheme6). [12] The first applicationo ft his smalle nolizable aldehyde in the direct cross-aldol reaction with a-ketophosphonates was reportedb yZ hao and co-workers to afford a-hydroxyphosphonate derivatives, knowna sh ighly biologically active compounds. The screening of catalysts and additives showedt hat the 9-amino-9-deoxy-epi-quinine catalyst 7 in combination with 4-methoxybenzoic acid (MBA) as an additive provided the aldol products in moderate to high yields and excellent enantioselectivities (Scheme 7).…”

Synthesis of Optically Enrichedβ-Trifloromethyl-δ-lactones through Asymmetric Aldol Reactions of Acetaldehyde with Unsaturated Trifluoromethyl Ketones as the Key Steps

“…该手性伯胺可以有效催化丙酮与芳香醛、酮酸酯以 及不饱和酮酸酯的不对称 Aldol 反应 [12] (Scheme 2). 最 近, 我们首次发现, 该手性伯胺催化剂能有效催化乙醛 与活泼非环状酮化合物, 如不饱和酮酸酯、三氟甲基酮 等的高对映选择性 Aldol 反应 [13] (Scheme 3) .…”

“…c Determined by chiral HPLC. [12] . c Determined by chiral HPLC and the ee in parentheses is for the crystallization from hexane/ethyl acetate.…”