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Tripeptide-Catalyzed Asymmetric Aldol Reaction Between Α-Ketoesters and Acetone Under Acidic Cocatalyst-Free Conditions

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Tripeptide-Catalyzed Asymmetric Aldol Reaction Between Α-Ketoesters and Acetone Under Acidic Cocatalyst-Free Conditions catalysts Article Tripeptide-Catalyzed Asymmetric Aldol Reaction Between α-ketoesters and Acetone Under Acidic Cocatalyst-Free Conditions Kazumasa Kon 1, Hiromu Takai 2, Yoshihito Kohari 3,* and Miki Murata 1,2,3 1 Graduate School of Manufacturing Engineering, Kitami Institute of Technology, 165 Koen-Cho, Kitami, Hokkaido 090-8507, Japan; [email protected] 2 Graduate School of Materials Science and Engineering, Kitami Institute of Technology, 165 Koen-Cho, Kitami, Hokkaido 090-8507, Japan; [email protected] 3 School of Earth, Energy and Environmental Engineering, Faculty of Engineering, Kitami Institute of Technology, 165 Koen-Cho, Kitami, Hokkaido 090-8507, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-157-26-9432 Received: 17 April 2019; Accepted: 6 June 2019; Published: 9 June 2019 Abstract: Here, we report the tripeptide-catalyzed asymmetric aldol reaction between α-ketoesters and acetone under acidic cocatalysts-free conditions. H-Pro-Tle-Gly-OH 3g-catalyzed reactions between α-ketoesters and acetone resulted in up to 95% yield and 88% ee. Analysis of the transition state using density functional theory (DFT) calculations revealed that the tert-butyl group in 3g played an important role in enantioselectivity. Keywords: organocatalyst; aldol reaction; peptide catalyst; α-ketoesters 1. Introduction Optically active tertiary alcohols are partial structures present in various natural products and biologically active compounds [1–5]. Various synthetic methods for these compounds have been developed. Asymmetric nucleophile addition to functionalized ketones is one of the most useful synthetic methods, because highly functionalized optically active tertiary alcohols, which can undergo various transformations, can be obtained. For example, the direct asymmetric aldol reaction between α-ketoesters and acyclic ketones is a helpful asymmetric reaction, because it gives γ-keto-α-hydroxyesters, which can undergo various transformations [6–8]. Therefore, various asymmetric catalysts, such as bisprolinamide, primary amine, and diamine catalysts, have been developed for this reaction [9–17]. However, most catalysts require acidic cocatalysts for high enantioselectivity and high chemical yield. Thus, simpler catalytic systems that do not require acidic cocatalysts are needed. Nevertheless, the number of asymmetric catalysts that catalyze this reaction, under acidic cocatalyst-free conditions, is limited. Although Zhang et al. [18] reported a proline-catalyzed asymmetric aldol reaction between ethyl phenylglyoxylate and acetone under acidic cocatalyst-free conditions, this method was enantioselective to some degree [18]. To the best of our knowledge, for this reaction, an asymmetric catalyst displaying high enantioselectivity and chemical yield under acidic cocatalyst-free conditions has still not been reported. Following the introduction of a proline-catalyzed asymmetric aldol reaction of aldehydes reported by List et al. [19], prolinamide catalysts for this reaction have been actively developed [20,21]. Synthetic peptides in prolinamide catalysts, are recognized as effective catalysts for the direct asymmetric aldol reaction using aldehydes as electrophiles [22–33]. However, peptide catalysts for the direct asymmetric aldol reaction using ketones as electrophiles are limited [29,33–36]. Previously, we developed tripeptide catalysts (Supplementary Materials) that catalyzed the direct asymmetric aldol reaction of isatins or Catalysts 2019, 9, 514; doi:10.3390/catal9060514 www.mdpi.com/journal/catalysts Catalysts 2019, 9, 514 2 of 8 Catalysts 2019, 9, x FOR PEER REVIEW 2 of 9 trifluoromethyl ketones with acetone (Figure1a) [ 37,38]. These catalysts, under acidic cocatalyst-free conditions,conditions, displayed displayed good good enantioselectivity enantioselectivity and and kinetics kinetics in in these these reactions. reactions. Herein, Herein, we we will will report report α thethe direct direct asymmetric asymmetric aldol aldol reaction reaction between between-ketoesters α-ketoesters and and acetone acetone catalyzed catalyzed by by tripeptide tripeptide under under acidicacidic cocatalyst-free cocatalyst-free conditions conditions (Figure (Figure1b). 1b). Figure 1. (a) Our previous works; (b) this work. Figure 1. (a) Our previous works; (b) this work. 2. Results and Discussion 2. Results and Discussion In this study, we investigated the effect of the catalyst structure on the rate and enantioselectivity of theIn reaction this study, between we investigated methyl phenylglyoxylate the effect of the ca (talyst1a) and structure acetone on the (2) ra (Tablete and1 ,enantioselectivity entries 1–9). H-Pro-Gly-Gly-OHof the reaction between3a-catalyzed methyl reactionphenylglyoxylate progressed (1a to) and give acetone the corresponding (2) (Table 1, entries aldol adduct1–9). H-Pro-4a withGly-Gly-OH 61% yield and3a-catalyzed 31% ee (Table reaction1, entry progressed 1). To investigate to give the the corresponding e ffect of introducing aldol adduct a methyl 4a group with to61% theyield C-terminal and 31% amino ee (Table acid residue 1, entry in 1).3a To, H-Pro-Gly-Ala-OH investigate the effect3b- andof introducing H-Pro-Gly-D-Ala-OH a methyl group3c-catalyzed to the C- reactionsterminal were amino carried acid outresidue (Table in1 ,3a entries, H-Pro-Gly-Ala-OH 2 and 3). Both reactions3b- and H-Pro-Gly-D-Ala-OH displayed higher reaction 3c-catalyzed rates thanreactions the 3a -catalyzedwere carried reaction; out (Table however, 1, entries enantioselectivities 2 and 3). Both reactions of both reactionsdisplayed were higher not reaction improved, rates comparedthan the with3a-catalyzed that of the reaction;3a-catalyzed however, reaction. enantioselectivi H-Pro-Ala-Gly-OHties of both3d -reactions and H-Pro-D-Ala-Gly-OH were not improved, 3e-catalyzedcompared with reactions that introducedof the 3a-catalyzed a methyl reaction. group to H-Pro-Ala-Gly-OH the amino acid residue 3d- and adjacent H-Pro-D-Ala-Gly-OH to the proline residue3e-catalyzed in 3a. The reactions reaction introduced between 1a a methyland 2 gave group4a tohigher the amino enantioselectivity acid residue than adjacent the 3a to-catalyzed the proline reactionresidue (Table in 3a1., The entries reaction 4 and between 5). The 3d1a -catalyzedand 2 gave reaction 4a higher displayed enantioselectivity higher enantioselectivity than the 3a-catalyzed than thereaction3e-catalyzed (Table one. 1, entries However, 4 and the 5). reaction The 3d-catalyzed catalyzed by reaction H-Pro-Val-Gly-OH displayed higher3f and enantioselectivity H-Pro-Tle-Gly-OH than 3gthe, containing 3e-catalyzed bulkier one. isopropyl However, and the tertiary reaction butyl catalyzed groups by instead H-Pro-Val-Gly-OH of methyl groups, 3f and displayed H-Pro-Tle-Gly- higher enantioselectivitiesOH 3g, containing than bulkier the isopropyl3d-catalyzed and reaction tertiary butyl (Table groups1, entries instead 6–7). of Above methyl all, groups,3g-catalyzed displayed reactionshigher showedenantioselectivities the highest than enantioselectivity the 3d-catalyzed and reactionreaction rates(Table than 1, anyentries of the6–7). other Above catalyzed all, 3g- reactions.catalyzed From reactions these investigations, showed the highest it was discoveredenantioselec thattivity bulky and substitution reaction rates in L-amino than any acid of adjacent the other tocatalyzed proline residue reactions. played From an these important investigations, role in determiningit was discovered enantioselectivity. that bulky substitution From the in results,L-amino weacid decided adjacent that to the proline most eresiduefficient played catalyst an for importan this reactiont role wasin determining3g, in terms enantioselectivity. of enantioselectivity From and the theresults, reaction we rate decided obtained. that the most efficient catalyst for this reaction was 3g, in terms of enantioselectivityTo improve enantioselectivity, and the reaction we rate optimized obtained. the reaction conditions for a 3g-catalyzed reaction betweenTo1a improveand 2 (Table enantioselectivity,1, entries 8–21). we Thisoptimized reaction the was reaction carried conditions out in various for a 3g solvents-catalyzed (Table reaction1, entriesbetween 8–13). 1a Inand THF 2 (Table and diethyl 1, entries ether, 8–21). the This reaction reaction displayed was carried higher out enantioselectivity in various solvents than (Table in any 1, otherentries solvent 8–13). (Table In THF1, entries and diethyl 12 and ether, 13). The the reactionreaction in displayed THF and higher diethyl enantioselectivity ether at 0 ◦C produced than in4a any withother higher solvent enantioselectivity (Table 1, entries than 12 and that 13). at 20 The◦C. reac However,tion in THF thereaction and diethyl rate ether at 0 ◦ Cat in0 °C diethyl produced ether 4a with higher enantioselectivity than that at 20 °C. However, the reaction rate at 0 °C in diethyl ether was lower than that in THF at 0 ◦C. Therefore, we determined that the best solvent for this reaction waswas THF, lower in termsthan that of enantioselectivity in THF at 0 °C. Therefore, and reaction we ratedetermined (Table1, entriesthat the 14 best and solvent 15). The for reaction this reaction in THFwas at THF,15 inC terms did not of progress enantioselectivity (Table1, entry and reaction 16). The rate reaction (Table in 1, THF entries at 0 14C and was 15). also The slow reaction when in − ◦ ◦ theTHF catalytic at −15 amount °C did not was progress reduced (Table
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