Catalytic Enantioselective Aldol‐type Reaction of β‐Ketosters with Acetals

Abstract

Optically active b-oxycarbonyl compounds are useful intermediates in synthetic organic chemistry and great efforts have been devoted to the development of catalytic asymmetric aldol reactions. Excellent methods have been developed with secondary amines as well as chiral Lewis acids, whereby ketones and their silyl derivatives react with aldehydes in a highly enantioselective manner.[1] In contrast, readily enolizable 1,3-dicarbonyl compounds, such as b-ketoesters and malonates, have rarely been used as nucleophiles [2] because of the insufficient nucleophilicity of the metal enolates of such compounds; a plausible alternative explanation is that the products are unstable and readily undergo retro-aldol reactions (Scheme 1). Because of these general difficulties, there are only a few examples of the synthesis of optically active boxymalonates by using p-allyl Pd chemistry, [3] aldol reactions, [4] and oxy-Michael reactions. [5] As for catalytic aldol reactions of 1,3-dicarbonyl compounds, we recently reported a catalytic asymmetric hydroxymethylation of b-ketoesters by using paraformaldehyde as a C1 unit. [6,7] However, reactions with less reactive aldehydes were difficult to perform (vide infra), and we were unable to find literature precedent on similar reactions.Previously, we showed that chiral Pd enolates formed by the reaction of chiral Pd II -bisphosphine complexes 1 with bketoesters were accompanied by the formation of a protic acid (Scheme 1).[8] We envisaged that this proton might activate acetals to give an oxonium intermediate, which would undergo an aldol-type reaction with the b-ketoester. Since the product is O protected, we expected that the undesired retroaldol reaction would be suppressed. The use of an acetal as a synthetic equivalent of an aldehyde has been extensively investigated in Lewis acid mediated or catalyzed aldol-type reactions with silyl enolates. [9] In general, chiral induction is hard to achieve in these reactions because the chiral Lewis acid interacts only weakly with the prochiral electrophile (Scheme 2). To our knowledge, an asymmetric version of this type of reaction has not been reported. Herein, we disclose the first example of a catalytic asymmetric aldol-type reaction of acetals by using chiral Pd II and Pt II complexes, where the chiral metal enolates of prochiral b-ketoesters are the key intermediates.We chose tert-butyl-2-oxo-cyclohexane carboxylate (2 a) and cinnamaldehyde diethyl acetal (3 a)[10a] as model substrates (Table 1). The reaction of 2 a with 3 a was carried out in the presence of 10 mol % of Pd-binap complex 1 a (binap = 2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl) in THF at 0 8C. As expected, the desired aldol-type adduct 4 aa was obtained in excellent yield. To our delight, the enantioselectivity of the product was excellent (98 %), although the diastereoselectivity was insufficient (Table 1, entry 1). When the reaction was carried out at À20 8C the diastereoselectivity was improved (Table 1, entry 2). As shown in entry 3 in Table 1, the amounts of the...

Synthetic Strategies and Cascade Reactions of 2‐Cyanobenzophenones for the Access to Diverse 3,3‐Disubstituted Isoindolinones and 3‐Aryl‐3‐Hydroxyisoindolinones

“…Taking advantage from our preliminary works,,, we firstly focused on the reaction of malonate esters. The aldol‐type additions of malonates are surprisingly rare, because of the poor reactivity of the enolates of such compounds toward the carbonyl group ,. Usually, only Knoevenagel condensation products are obtained under harsh reaction conditions,, even if benzophenone 3 n , tested in a control experiment, was not reactive (Scheme ).…”

Chiral Pd aqua complex-catalyzed asymmetric C–C bond-forming reactions: a Brønsted acid–base cooperative system

“…The reaction was complete within 3 h, affording the aldol-type compound in 85% yield with 99% ee (major). 39 As shown in Scheme 24, various acetals underwent the reaction with cyclic b-ketoesters in a highly enantioselective manner (up to 99% ee). In addition to simple alkyl acetals, allyl and benzyl acetals could be without difficulty.…”

“…When the diethyl acetal of acrolein was used, the formal 1,4-adduct was produced as a major product instead of an aldol-type product, probably because the terminal position of the oxonium intermediate would be more sterically accessible (Scheme 25). 39 In contrast to cyclic substrates, the reaction of less reactive acyclic b-ketoesters did not reach completion, and decomposition of the catalyst was observed. We speculated that the Pd complex tended to undergo reduction by alcohol derived from the starting acetals, because complexation of the substrates and the catalyst might be slow.…”

Asymmetric catalytic construction of fully substituted carbon stereocenters using acyclic α-branched β-ketocarbonyls: the “Methyl Rule” widely exists

“…A transition state favoring Re-face addition was proposed (Scheme 28). 33 The asymmetric aldol reaction between β-ketoesters and formaldehyde was reported by Shibasaki and co-workers in 2009, using a homodinuclear Ni 2 -Schiff base complex (C20). The resulting hydroxyethylated adducts can be obtained with good to excellent ee values (Scheme 29).…”