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 from 201, entry mol% 16). to 10The mol% reaction (Table in1 THF, entry at 0 17). °C Thewas increasealso slow and when decreasethe catalytic in the amountsamount was of 2 andreduced THF, from respectively, 20 mol% caused to 10 amol% reduction (Table in reaction1, entry rate17). (TableThe increase1, entries and decrease in the amounts of 2 and THF, respectively, caused a reduction in reaction rate (Table 1, entries 18–21). From all the reaction conditions tested, it was revealed that the optimum reaction was

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18–21). From all the reaction conditions tested, it was revealed that the optimum reaction was 3g (20 mol%)-catalyzed reaction using 2 (100 eq.) in THF (1 mL) at 0 ◦C, because this reaction gave 4a with 76% chemical yield and 88% ee under less acidic conditions (Table1, entry 16).

Table 1. Optimization of catalysts and reaction conditions.

Entry Catalyst Solvent Yield (%) a ee (%) b 1 H-Pro-Gly-Gly-OH 3a neat 61 31 2 H-Pro-Gly-Ala-OH 3b neat 81 30 3 H-Pro-Gly-D-Ala-OH 3c neat 70 26 4 H-Pro-Ala-Gly-OH 3d neat 50 38 5 H-Pro-D-Ala-Gly-OH 3e neat 49 34 6 H-Pro-Val-Gly-OH 3f neat 49 50 7 H-Pro-Tle-Gly-OH 3g neat 90 65 8 3g MeOH 40 30 9 3g MeCN 62 54 10 3g CHCl3 81 68 11 3g PhMe 44 70 12 3g THF 82 79 13 3g Et2O 74 82 14 c 3g THF 76 88 c 15 3g Et2O 45 88 16 d 3g THF — — 17 c,e 3g THF 39 89 18 c,f 3g THF 56 87 19 c,g 3g THF 57 89 20 c,h 3g THF 34 89 21 c,i 3g THF 56 83 a Isolated yield after preparative thin layer chromatography. b Determined by HPLC. Absolute conﬁguration of 4a was determined by comparing optical rotation between 4a and previous report [14]. c Reaction was carried out at d e f g 0 ◦C. Reaction was carried out at 15 ◦C. 3g (10 mol%) was used. 2 (150 eq.) was used. 2 (50 eq.) was used. h Reaction was carried out in THF (2− mL). i Reaction was carried out in THF (0.5 mL).

We also investigated the reaction between various α-ketoesters 1a–1h and 2 under optimized conditions (Table2). To reveal the e ﬀect of ester substituents, reactions of 1a–1c having various ester groups were carried out (Table2, entries 1–3). In reactions using 1a–1c as substrates with alkyl esters, the bulkier the alkyls esters were, the slower the reactions progressed. The substrates 1a–1c generated the corresponding aldol adducts 4a–4c with good enantioselectivities. To estimate the contribution of the methoxycarbonyl group of 1a, the reaction between acetophenone and acetone was carried out. This reaction was not progressed. To investigate the eﬀect of substituents on phenyl groups, reactions of 4-substituted α-ketoesters 1d–1g were carried out (Table2, entries 4–7). Reactions of 4-Cl 1d and 4-CF3 1e were faster than that of 1a, and especially that of 1e, which was completed after three days. However, enantioselectivities of reactions 1d and 1e were lower than that of the reaction of 1a (Table2, entries 4 and 5, respectively). In the reactions of 4-Me 1f and 4-MeO 1g, the reaction rates and enantioselectivities were also lower than that of the reaction of 1a (Table2, entries 6 and 7, respectively). The reactions of methyl pyruvate (1h) and methyl trimethylpyruvate as aliphatic α-ketoesters were investigated. The reaction between 1h and 2 gave corresponding aldol adduct 4h, with good chemical yield and medium enantioselectivity (Table2, entry 8). Additionally, the reaction of more bulky genusmethyl trimethylpyruvate (R1 = tBu) with 2 did not give corresponding aldol adduct. Cyclohexanone, 2-butanone, and acetophenone were applied as nucleophiles. These nucleophiles were not reacted. Catalysts 2019, 9, x FOR PEER REVIEW 4 of 9 CatalystsCatalysts2019 2019, 9, ,9 514, x FOR PEER REVIEW 44 ofof 8 9 Table 2. Substrate scope. Table 2. Substrate scope. Table 2. Substrate scope.

entry R1 R2 1 4 yield (%)a ee (%)b 1 2 a b Entry entry1 R PhR1 R MeR2 11a1 4a4 4yield76 (%) Yielda (%)ee88( (%)R)c b ee (%) 121 PhPhPh Me MeEt 1a1b1a 4b4a 4a 6376 7688( 82R )c 88(R) c 232 PhPhPh Et iPrEt 1b1c1b 4c4b 4b 3363 63 86 82 82 3 Ph iPr 1c 4c 33 86 43 4-ClPhPh MeiPr 1d1c 4d4c 8433 75 86 4 4-ClPh Me 1d 4d 84 75 d 54d 4-CF4-ClPh3Ph MeMe 1e1d 4e4d 9584 50 75 5 4-CF3Ph Me 1e 4e 95 50 656 4-MePhd 4-MePh4-CF3Ph Me MeMe 1f1f1e 4f4e 4f 2595 25 75 50 75 7 4-MeOPh76 4-MeOPh4-MePhMe MeMe 1g1g1f 4g4f 4g 1025 10 65 75 65 887 Me4-MeOPhMe Me MeMe 1h1h1g 4h4g 4h 9210 9239 65 39 a b c a Isolated Isolated yield yield after after preparative preparative8 thin layerMe thin chromatography. layerMe chromatography.1h b Determined4h 92 by Determined HPLC. c Absolute39 by HPLC. configuration Absolute of 4a wasconfigurationa Isolated determined yield byof comparingafter4a was preparative determined optical rotation thin by layercomparing between chromatography.4a and optical previous rotation report b Determined between [14]. d Reaction 4a by and HPLC. was previous demonstrated c Absolute report 3d for[14].configuration. d Reaction of was 4a demonstratedwas determined for by 3d comparing. optical rotation between 4a and previous report [14]. d Reaction was demonstrated for 3d. ItIt was was assumed assumed that that the the catalytic catalytic cycle cycle of of this this reaction reaction was was similar similar to to that that of of the the proline-catalyzed proline-catalyzed It was assumed that the catalytic cycle of this reaction was similar to that of the proline-catalyzed asymmetricasymmetric aldol aldol reaction reaction (Figure (Figure2a) [2a)9]. Therefore,[9]. Therefore,2 was 2 activated was activated by enamine by enamine formation formation by reacting by asymmetric aldol reaction (Figure 2a) [9]. Therefore, 2 was activated by enamine formation by withreacting the aminowith the group amino of group3g. The of 3g C–C. The bond C–C was bond then was formed then formed by nucleophilic by nucleophilic addition addition to the to1 theof reacting with the amino group of 3g. The C–C bond was then formed by nucleophilic addition to the enamine1 of enamine as anucleophile as a nucleophile to generate to generate the iminium the iminium cation. cation. Finally, Finally, the aldolthe aldol adduct adduct was was produced produced by 1 of enamine as a nucleophile to generate the iminium cation. Finally, the aldol adduct was produced theby hydrolysisthe hydrolysis of the of iminium the iminium cation. cation. In this In reaction, this reaction, the absolute the absolute configuration configuration of the aldol of adductthe aldol4 by the hydrolysis of the iminium cation. In this reaction, the absolute configuration of the aldol wasadduct determined 4 was determined at the C–C at bond the C–C formation bond step.formation step. adduct 4 was determined at the C–C bond formation step. ToTo understand understand the the e effectffect of oftert tert-leucine-leucine residue residue in in H-Pro-Tle-Gly-OH H-Pro-Tle-Gly-OH 3g3gon on enantioselectivity,enantioselectivity, originsTo ofunderstand enantioselectivity the effect of tert3g -leucineand H-Pro-Gly-Gly-OH residue in H-Pro-Tle-Gly-OH 3a were investigated. 3g on enantioselectivity, Specifically, origins of enantioselectivity of 3g and H-Pro-Gly-Gly-OH 3a were investigated. Specifically, transition transitionorigins of states enantioselectivity of the stereo-determining of 3g and C–CH-Pro-Gly-Gly-OH bond forming step 3a ofwere 3g- andinvestigated. 3a-catalyzed Specifically, reactions states of the stereo-determining C–C bond forming step of 3g- and 3a-catalyzed reactions between 1a betweentransition 1a states and 2of were the stereo-determininginvestigated via density C–C functionalbond forming theory step (DFT) of 3g calculations- and 3a-catalyzed (Figures reactions 2b and and 2 were investigated via density functional theory (DFT) calculations (Figures2b and3)[39,40]. 3)between [39,40]. 1a and 2 were investigated via density functional theory (DFT) calculations (Figures 2b and 3) [39,40].

FigureFigure 2. 2.( a(a)) A A plausible plausible catalytic catalytic cycle; cycle; ( b(b)) transition transition states states of of C–C C–C bond bond forming forming step step of of3a 3a-catalyzed-catalyzed reactionreactionFigure 2. between between (a) A plausible1a 1aand and2 2catalytic.. All All calculationscalculations cycle; (b) were weretransition carriedcarried states outout viaofvia C–C CPCM(acetone)CPCM(acetone)/B3LYP/6-31G(d’,p’)// bond forming/B3LYP step /of6-31G(d’,p’) 3a-catalyzed// B3LYPB3LYP/6-31G(d’,p’)reaction/6-31G(d’,p’) between 1a level level and of 2of.theory. All theory. calculations were carried out via CPCM(acetone)/B3LYP/6-31G(d’,p’)// B3LYP/6-31G(d’,p’) level of theory. Investigation of transition states of the stereo-determining C–C bond forming step of 3a-catalyzed Investigation of transition states of the stereo-determining C–C bond forming step of 3a- reactions between 1a and 2 via DFT calculations revealed that the major (R)-aldol adduct was produced catalyzedInvestigation reactions ofbetween transition 1a and states 2 via of DFT the calculationsstereo-determining revealed C–C that bondthe major forming (R)-aldol step adductof 3a- through 3a-TS-(R), and the minor (S)-aldol adduct was produced through 3a-TS-(S) in the 3a-catalyzed wascatalyzed produced reactions through between 3a-TS-( 1aR ),and and 2 thevia minorDFT calculations (S)-aldol adduct revealed was that produced the major through (R)-aldol 3a-TS-( adductS) in reaction (Figure2b). Like the experimental result where ( R)-aldol adduct was preferentially obtained thewas 3a produced-catalyzed through reaction 3a-TS-( (FigureR), and 2b). the Like minor the (Sexperimental)-aldol adduct result was producedwhere (R through)-aldol adduct 3a-TS-( Swas) in the 3a-catalyzed reaction (Figure 2b). Like the experimental result where (R)-aldol adduct was

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(Table1, entry 1), 3a-TS-(R) was the more stable transition state. To understand the origin of enantioselectivity of 3a, we focused on hydrogen bonds in transition states of the stereo-determining C–CCatalysts bond 2019 forming, 9, x FOR step. PEER Hydrogen REVIEW bonds a, b, and c were formed in both transition states. However,5 of 9 hydrogen bonds d and e were present in only 3a-TS-(R), and hydrogen bond f was present in only 3apreferentially-TS-(S). Namely, obtained3a-TS-( R(Table) had more1, entry hydrogen 1), 3a-TS-( bondsR) thanwas 3athe-TS-( moreS). Thisstable was transition the reason state. why To 3aunderstand-TS-(R) was the origin more stableof enantioselectivity transition state. of The 3a, investigationwe focused on of hydrogen transition bonds states ofin thetransition C–C bond states formingof the stereo-determining step of the 3g-catalyzed C–C bond reaction forming via DFT step. calculation Hydrogen foundbonds foura, b, transitionand c were states, formed such in both as 3gtransition-TS-(R)-1, states.3g-TS-( However,R)-2, 3g-TS-( hydrogenS)-1, and bonds3g-TS-( d andS)-2 e (Figurewere present3). When in only this 3a3g-TS-(-catalyzedR), and reactionhydrogen passedbond throughf was present3g-TS-( inR )-1only and 3a3g-TS-(-TS-(S).R )-2,Namely, the major 3a-TS-( (R)-aldolR) had adduct more hydrogen was obtained. bonds Similarly, than 3a when-TS-(S). thisThis3g -catalyzedwas the reason reaction why passed 3a-TS-( throughR) was the3g-TS-( moreS)-1 stable and transition3g-TS-(S)-2, state. the The minor investigation (S)-aldol adduct of transition was obtained.states of Focusing the C–C on bond conformations forming step of these of the transition 3g-catalyzed states, reaction3g in 3g -TS-(via DFTR)-1 andcalculation3g-TS-( Sfound)-1 had four a similartransition conformation states, such to as3a 3gin-TS-( the transitionR)-1, 3g-TS-( stateR)-2, of 3g the-TS-( C–CS)-1, bond and forming 3g-TS-( stepS)-2 of(Figure the 3a 3).-catalyzed When this reaction.3g-catalyzed However, reaction the presence passed ofthrough3g in these 3g-TS-( transitionR)-1 and states 3g-TS-( introducedR)-2, the steric major repulsion (R)-aldol between adduct the was tBuobtained. of tert-leucine Similarly, residue when and this the 3g carbonyl-catalyzed group reaction of proline passed residue, through causing 3g-TS-( destabilizationS)-1 and 3g-TS-( ofS these)-2, the transitionminor (S states.)-aldol In adduct contrast, was this obtained. steric repulsion Focusing was on mitigatedconformations in 3g -TS-(of theseR)-2 transition and 3g-TS-( states,S)-2, 3g due in to 3g- theTS-( changeR)-1 and in conformation 3g-TS-(S)-1 had influenced a similar by theconformationtBu group. to Due 3a toin thisthe changetransition of stericstate environmentof the C–C bond in theseforming transition step states,of the 3g3a-TS-(-catalyzedR)-2 and reaction.3g-TS-( SHowever,)-2 were more the presence stable than of3g 3g-TS-( in Rthese)-1 and transition3g-TS-( Sstates)-1. t Forintroduced that reason, steric it was repulsion concluded between that (S the)- and Bu (ofR)-aldol tert-leucine adducts residue were and formed the throughcarbonyl3g group-TS-( Sof)-2 proline and 3gresidue,-TS-(R)-2 causing in the 3g destabilization-catalyzed reaction, of these respectively. transition states. In contrast, this steric repulsion was t mitigatedFinally, in3g -TS-(3g-TS-(R)-2R)-2 and and3g -TS-(3g-TS-(S)-2S)-2, were due analyzed to the change and a comparison in conformation of their influenced Gibbs free by energy the Bu revealedgroup. thatDue3g to-TS-( this Rchange)-2 was of 2.2 steric kcal environment/mol more stable in these than transition3g-TS-(S)-2. states, This 3g di-TS-(fferenceR)-2 inand Gibbs 3g-TS-( freeS)- energy2 were was more larger stable than than that 3g between-TS-(R)-13a -TS-(and 3gR)-TS-( and S3a)-1.-TS-( ForS). that Moreover, reason, DFTit was calculations concluded reproduced that (S)- and the(R experimental)-aldol adducts results were such formed that through3g displayed 3g-TS-( higherS)-2 and enantioselectivity 3g-TS-(R)-2 in thanthe 3g3a-catalyzed, mainly because reaction, ofrespectively. the difference in stabilization caused by hydrogen bonds. In both 3g-TS-(R)-2 and 3g-TS-(S)-2, multipleFinally, hydrogen 3g-TS-( bondsR)-2 a,and b, and3g-TS-( c formed.S)-2 were Hydrogen analyzed bonds and a gcomparison and h formed of their only Gibbs in 3g -TS-(free energyR)-2. Therevealed conformational that 3g-TS-( changeR)-2 was of 3g 2.2by kcal/mol the introduction more stable of thantBu group3g-TS-( toS)-2.3a createdThis difference a larger in di Gibbsfference free inenergy the number was larger of hydrogen than that bonds between formed 3a-TS-( betweenR) and 3a3g-TS-(-TS-(SR).)-2 Moreover, and 3g-TS-( DFTS )-2calculations than that reproduced between 3athe-TS-( experimentalR) and 3a-TS-( resultsS). Hence, such di thatfference 3g displayed of stabilization higher by enantioselectivity hydrogen bonds than between 3a, mainly3g-TS-( Rbecause)-2 and of 3gthe-TS-( differenceS)-2 was larger in stabilization than that between caused3a -TS-(by hydrogenR) and 3a -TS-(bonds.S). FromIn both the above3g-TS-( results,R)-2 and we concluded3g-TS-(S)-2, thatmultiple the control hydrogen of 3g bondsconformation a, b, and c by formedtBu groups. Hydrogen played bonds an importantg and h formed rolein only the in production 3g-TS-(R)-2. t ofThe enantioselectivity. conformational change of 3g by the introduction of Bu group to 3a created a larger difference in the number of hydrogen bonds formed between 3g-TS-(R)-2 and 3g-TS-(S)-2 than that between 3a-

FigureFigure 3. 3.Transition Transition states states of of C–CC–C bondbond formingforming step of 3g3g-catalyzed-catalyzed reaction reaction between between 1a1a andand 2.2 All. Allcalculations calculations were were carried carried out out via via CPCM(acetone)/ CPCM(acetone)B3LYP/6-31G(d’,p’)///B3LYP/6-31G(d’,p’)// B3LYP/6-31G(d’,p’)B3LYP/6-31G(d’,p’) level level of oftheory.

TS-(R) and 3a-TS-(S). Hence, difference of stabilization by hydrogen bonds between 3g-TS-(R)-2 and 3g-TS-(S)-2 was larger than that between 3a-TS-(R) and 3a-TS-(S). From the above results, we concluded that the control of 3g conformation by tBu groups played an important role in the production of enantioselectivity.

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3. Materials and Methods

3.1. General Methods Column chromatography was carried out on a column packed with spherical silica gel 60N of neutral size, 40–50 µm. Thin layer chromatography was prepared using PLC Silica gel (60 F254, 1 mm, Merck). NMR spectra were recorded on a JEOL JNM-ECA600 spectrometer (1H, 600 MHz; 13C, 150 MHz). Chemical shifts of 1H NMR and 13C NMR signals, reported as δ ppm, were referenced to an internal standard SiMe4 or sodium 3-(trimethylsilyl)-1-propanesulfonate. HRMS were obtained at an ionization potential of 70 eV with a JEOL JMS-T100GCV spectrometer. Melting points were measured on an AS ONE ATM-01 melting-point apparatus. Optical rotations were measured by a JASCO P-1010 Polarimeter. HPLC analysis was performed with a Daicel Chiralpak AD-H column (25 cm 4.6 mm 5 µm) and Chiralpak OD-H column (25 cm 4.6 mm 5 µm). All reagents and × × × × solvents were purchased from commercial sources and used without puriﬁcation. Compounds 1a–1g were synthesized by the previously reported method [41,42]. Tripeptide catalysts were synthesized by the literature methods [37,38].

3.2. General Procedure for the Asymmetric Aldol Reaction between α-Ketoesters and Acetone A mixture of H-Pro-Tle-Gly-OH 3g (20 µmol, 5.7 mg), acetone (10 mmol, 0.74 mL), and THF (1.0 mL) was stirred at 0 ◦C for 10 min. To the resulting mixture, α-ketoester (0.1 mmol) was added. The mixture was stirred at 0 ◦C for six days and then ﬁltered to remove the catalyst. The resulting mixture was concentrated under reduced pressure. Preparative thin layer chromatography on silica gel using hexane/ethyl acetate as the eluent gave the aldol adduct. The enantiomeric excess of aldol adduct was determined by chiral HPLC.

4. Conclusions We have developed a direct asymmetric aldol reaction between α-ketoesters and acetone, catalyzed by a tripeptide under acidic cocatalyst-free conditions. The 3g-catalyzed reaction gave various aldol adducts with up to 95% yield and 88% ee. Investigation of the transition state via the C–C bond forming step by DFT calculations has revealed the role of the tBu group in 3g in determining enantioselectivity.

Supplementary Materials: The following are available online at http://www.mdpi.com/2073-4344/9/6/514/s1, 1. General; 2. Materials; 3. Preparation of the tripeptide catalysts; 4. General procedure for tripeptide-catalyzed asymmetric aldol reaction; 5. Computational Details; 6. Reference; 7. Copy of NMR spectra; 8. Copy of HPLC spectra; 9. Geometries and Cartesian Coordinates. Figure S1: Synthesis of tripeptide catalysts. Author Contributions: K.K. and M.M. designed the experiments. K.K. and Y.K. wrote the paper. K.K. and H.T. performed the experiments. All authors read and approved the final manuscript. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest.

References

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