An Enantioselective Recyclable Polystyrene-Supported Threonine-Derived Organocatalyst for Aldol Reactions

DOI: 10.1002/adsc.201400033

An Enantioselective Recyclable Polystyrene-SupportedThreonine-Derived Organocatalyst for Aldol Reactions

Andrea H. Henseler,a Carles Ayats,a and Miquel A. Peric�sa,b,*a Institute of Chemical Research of Catalonia (ICIQ), Avda. Pa�sos Catalans, 16. E-43007, Tarragona, Spain

Fax: (+34)-977-920-222; phone: (+ 34)-977-920-247; e-mail: [email protected] Departament de Qu�mica Org�nica, Universitat de Barcelona (UB), E-08028 Barcelona, Spain

Received: January 9, 2014; Published online: && &&, 0000

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400033.

Abstract: A series of primary amino acids covalentlysupported onto polystyrene through alkyne–azide cy-cloaddition reactions has been synthesized and eval-uated as catalysts in asymmetric aldol reactions. Apolymer-supported threonine behaves as an easily re-cyclable, highly reactive and stereoselective (up to99% ee) catalyst in the aldol reaction of both cyclicand acyclic ketone donors with aromatic aldehydesin aqueous environments. While cyclic ketones react

with anti diastereoselectivity, syn adducts are pre-dominantly obtained with acyclic substrates. The het-erogenized threonine catalyst has been used for thesequential synthesis of a small library of enantiopurealdol products.

Keywords: aldol reaction; amino acids; organocataly-sis; polymers; supported catalysts

Introduction

Catalyst immobilization onto different solid sup-ports[1] such as polymers,[2] nanoparticles[3] or mesopo-rous materials[4] represents an attractive approach to-wards increased sustainability in catalytic asymmetricsynthesis. Thus, simplicity of catalyst separation, recy-cling and, as a consequence thereof, reduced effectivecatalyst loading are the main advantages offered byimmobilized catalytic species. Proline and its deriva-tives have found ample use in asymmetric organoca-talysis as highly selective organocatalysts in asymmet-ric synthesis.[5] Natural primary amino acids and theirderivatives, in turn, have found more limited applica-tion as organocatalysts, and only recently has theiruse in aldol,[6] Michael,[7] Mannich,[6e,u,8] a-amination[9]

and cyanosilylation[10] reactions been reported.[11] Incontrast to polymer-supported proline-derived orga-nocatalysts,[12] to the best of our knowledge, there areno examples of solid-supported primary amino acidsused in enantioselective catalysis. If one considersthat organocatalytic processes mediated by primaryamino acids often require catalyst loadings of up to30%,[6b,d,g,l,q] the interest in immobilizing these speciesand decreasing through recycling the effective catalystloading becomes evident.

Until now, only a few examples of recyclable pri-mary amino acid-derived organocatalysts are known.

They involve soluble species and in all cases extrac-tion of the catalyst is required for recovery and re-use.[6h,m–o,r,v] In contrast with this, solid-supported cata-lysts would offer the advantage of easy recovery bysimple filtration and could allow the implementationof continuous flow processes.[13] Anchoring of highlypolar organocatalysts (such as free amino acids) isalso advantageous because common solubility prob-lems of the homogeneous counterparts can be easilycircumvented. Thus, functional polystyrene resinsswell in the presence of organic reagents in a varietyof solvents including water.

The asymmetric aldol reaction catalyzed by aminoacids is one of the most powerful methods to formcarbon-carbon bonds in nature and in synthetic organ-ic chemistry.[14] While a better catalytic activity ofthreonine compared to other primary amino acids ascatalysts for aldol reactions has been noted in someinstances,[6h,u,v,15] examples are also known where otheramino acids such as serine or phenylalanine displaya superior catalytic performance in these proces-ses.[6j,n,16] In the context of our efforts towards the de-velopment of a basic toolkit of solid-supported orga-nocatalytic species with improved sustainability char-acteristics,[12p,r,17] we report herein the first synthesis ofa series of highly selective primary amino acid-de-rived, polystyrene-supported analogues for asymmet-ric aldol reactions.

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Results and Discussion

The performance of immobilized organocatalysts im-portantly depends on the level of cross-linking of thepolymer matrix.[12p,r] Therefore, polystyrene (PS) sup-ported catalysts 1–6 were prepared via “click” reac-tions[12c,j,l,p,r,18,19] with Merrifield resins with two differ-ent levels of cross-linking [1% and 8% 1,4-divinylben-zene (DVB)]. The synthesis of catalysts 1a and 1b asa representative example is depicted in Scheme 1. Forcomparison purposes, homogeneous unnatural aminoacid 1c[20] was also prepared and tested in catalysis(Figure 1).

The series of catalysts was initially evaluated in thereaction of para-nitrobenzaldehyde 9a with cyclohexa-none 10a (Table 1). According to previous experiencewith polymer-supported proline,[12r] a DMF-watermixture was used as solvent. We found that in thecase of cysteine-derived systems (1a–c) the supportedderivatives (1a, b) showed a significantly higher activ-ity than their homogeneous analogue 1c (entries 1–3).A similar behaviour, suggesting a cooperative effectof polymer backbone, triazole linker and catalyticunit was already noted for proline.[12c,j] Catalysts 4a,b were synthesized from l-serine-b-lactone via ring-opening with NaN3.

[21] These molecules were designed

to feature a close structural similarity with immobi-lized trans-4-azidoproline, since resins incorporatingthis species via CuAAC reaction depict optimal cata-lytic performance in aqueous aldol reactions.[12j,r] Sur-prisingly enough, no catalytic activity was observedwith catalysts 4a, b (Table 1, entries 8 and 9). In turn,catalysts 5a, b derived from 5-hydroxytryptophan cat-alyzed the test reaction with moderate to high levelsof activity and stereoselectivity (Table 1, entries 10and 11).

PS-supported threonine derivatives 6a, b, whichonly differ from the serine-derived resins 2a, b by anadditional methyl group, showed the best catalyticperformance (Table 1, entry 12) and approached andeven surpassed the selectivity displayed by immobi-lized prolines. Based on these results, the threonine-derived catalyst 6a involving slightly cross-linkedpolystyrene (1% DVB) was selected for optimizationstudies.

To further improve reaction rates and stereoselec-tivities, the influence of the amount of water in thesolvent system was studied (Table 2). Interestingly,catalyst 6a remains active over the full range ofwater/DMF binary mixtures. In pure water and inpure DMF (entries 1 and 2) the recorded diastereose-lectivity is not optimal, and the results with anhydrousDMF (entry 3) suggest that water is crucial to acceler-ate the reaction. The accelerating effect of water in

Scheme 1. Synthesis of catalytic resins 1a and 1b.

Figure 1. Primary amino acid-derived catalysts developed inthis study.

Table 1. Catalyst screening for the asymmetric aldol reactionof para-nitrobenzaldehyde 9a with cyclohexanone 10a.

Entry Catalyst Conv.[a] anti :syn[b] ee[c]

1 1a 38 82:18 642 1b 38 81:19 513 1c – – –4 2a 31 88:12 795 2b 45 92:8 816 3a 52 83:17 577 3b 74 76:24 608 4a – – –9 4b – – –10 5a 50 83:17 5111 5b – – –12 6a 70 93:7 9613 6b 73 83:17 93

[a] In [%]; determined by 1H NMR spectroscopy of thecrude mixture.

[b] Determined by 1H NMR spectroscopy on the crude mix-ture.

[c] In [%]; determined by HPLC using a chiral stationaryphase after purification.

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catalysis by primary amino acids has been previouslyobserved.[6b,d,i–k,s] In these studies, the beneficial effectof water is described as the result of a hydrophobicinteraction, which assembles catalyst and reagents ina polar aqueous environment.[6s] Although this effectmight be enhanced by the hydrophobic polystyrenebackbone of catalyst 6a, the possible role of the tri-ACHTUNGTRENNUNGazole linker in establishing a hydrogen bond networkwith the hydrophilic amino acid residue througha small number of water molecules should also beconsidered.[12j] The optimal performance with respectto yield and selectivity was achieved in a mixture ofwater and DMF (8:92, Table 2, entry 6). When thecatalyst loading is increased to 20 mol% (Table 2,entry 7), the reaction time could be decreased toeight hours.

On the basis of these findings, the optimized reac-tion conditions [20 mol% of catalyst in water/DMF(8:92)] were used in further aldol reactions. The scopeof catalyst 6a was examined in aldol reactions of a rep-resentative set of ketones, including both cyclic andacyclic examples, with aromatic aldehydes (Table 3).The reaction of cyclohexanone 10a with a series of ar-omatic aldehydes provided anti-aldol products ingood to excellent yields and enantioselectivities (upto >99% ee and 88:12 dr). Notably, good yields andhigh levels of stereoselectivity could also be achievedwith electron-rich aldehydes (Table 3, entries 7 and8). Other cycloalkanones (entries 9–11) performednearly equally well in this reaction. Thus, the directaldol reaction of cyclopentanone 10b, cycloheptanone10c and tetrahydropyran-4-one 10d with para-nitro-

benzaldehyde 9a afforded the corresponding anti-aldol products with good yields and enantioselectivi-ties, albeit with low to moderate diastereoselectivity.

While many studies on amino acid-catalyzed aldolreactions have been limited to cyclohexanone orcyclic ketones as a donor component, the use of 6awith acyclic ketones in front of aromatic aldehydes(entries 12–15) was also tested. Reactions with acyclicketones afforded the corresponding syn-aldol prod-ucts with moderate to excellent enantioselectivities.Contrary to proline, primary amino acids preferential-ly mediate aldol reactions with acyclic ketones via(Z)-enamine intermediates, thus yielding syn-aldolproducts.[6f] Therefore, primary amino acid catalysis inasymmetric aldol reactions with acyclic ketones canbe considered complementary to proline catalysis.

The aldol reaction of para-nitrobenzaldehyde 9aand acetone 10e proceeded in the presence of catalyst6a albeit with moderate yield and enantioselectivity.Hydroxyacetone 10f could also be applied as a sub-strate to afford syn-1,2-diols, which are importantbuilding blocks for numerous biologically active mole-cules.[6u] Notably, catalyst 6a also allows for the forma-tion of the corresponding syn-1,2-diols derived fromprotected dihydroxyacetone, which are particularly in-teresting substrates during the synthesis of carbohy-drates.[6e]

These are, in fact, the first examples of aldol reac-tions involving hydroxyacetone or dihydroxyacetoneperformed by an insoluble, polymer-supported cata-lyst. When the highly polar nature of the correspond-ing aldol products is considered, the advantages forpurification derived from the easy separation of theinsoluble catalyst become clearly apparent.

As already mentioned, the use of immobilized cata-lysts offers the inherent advantages of easy recoveryand reuse. In the present case, we explored the recy-clability of catalyst 6a in the test reaction of para-ni-trobenzaldehyde 9a with cyclohexanone 10a. Thestandard reaction conditions of Table 3 (20 mol% of6 a, 8 h reaction time) were used in these experiments.After each run, the catalyst could be recovered bysimple filtration and reused in the next cycle bysimple addition of fresh reactants and solvent. Asshown in Figure 2, resin 6a was recycled five times, af-fording the aldol product with constant stereoselectiv-ity and only marginal erosion in conversion (from 99to 90%) for a constant reaction time.

As a further demonstration of the synthetic poten-tial of 6a, we planned to use this immobilized catalystfor the sequential synthesis of a small library of enan-tioenriched aldol products. From a general perspec-tive, the fast and directed synthesis of closely relatedenantiopure compounds is a common need in discov-ery-oriented industries, such as the pharmaceutical,agrochemical or high-performance materials sectors.For its easy separation from the reaction mixture, im-

Table 2. Solvent effects on the aldol reaction of para-nitro-benzaldehyde 9a with cyclohexanone 10a catalyzed by resin6a.

Entry Solvent Yield[a] anti :syn[b] ee[c]

1 H2O 65 80:20 942 DMF 33 68:32 933 anh. DMF 27 76:24 934 H2O/DMF (92:8) 54 86:14 945 H2O/DMF (50:50) 62 92:8 936 H2O/DMF (8:92) 72 92:8 967[d] H2O/DMF (8:92) 90 91:9 96

[a] Isolated yield in [%].[b] Determined by 1H NMR spectroscopy on the crude mix-

ture.[c] In [%]; determined by HPLC using a chiral stationary

phase after purification.[d] 20 mol% of catalyst 6a was used and the reaction time

was reduced to 8 h.

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Table 3. Asymmetric aldol reactions with different aldehydes and ketones catalyzed by 6a.

Entry Product Yield[a] anti :syn[b] ee[c] Time

1 90 88:12 95 8 h

2 87 88:12 94 30 h

3 90 87:13 95 16 h

4 81 88:12 94 16 h

5 94 78:22 95 39 h

6 74 78:22 94 48 h

7 75 69:31 99 72 h

8 70 68:32 92 72 h

9 75 58:42 89 8 h

10 76 68:32 73 55 h

11 78 80:20 89 40 h

12[d] 79 – 46 96 h

13 86 25:75 85 24 h





mobilized catalysts with high activity profile and goodrecycling characteristics present unique advantagesfor this application and provide a satisfactory re-sponse to this demand.

To simultaneously show the scalability of the reac-tion, these experiments were performed using a singlesample of 0.500 g (0.52 mmol) of catalyst 6a and2.6 mmol of each reactant aldehyde. We have repre-sented in Scheme 2 the way in which the library ofaldol products was prepared. The resin was initiallyswollen with DMF/water (92:8), the first reactantpartners (9a and 10a) were added in the same propor-tion used in the general procedure (1:5 molar ratio),and the reaction mixture was shaken for the reactiontime specified in Table 3 for this combination of reac-tants. After separation of the reaction mixture by fil-tration, washing the resin with ethyl acetate (4 �4 mL), and vacuum drying, the whole procedure wassequentially repeated with 9a/10b, 9c/10a, and with9a/10f. The results obtained for the whole library

Table 3. (Continued)

Entry Product Yield[a] anti :syn[b] ee[c] Time

14 96 21:79 78 24 h

15[e,f] 73 12:88 87 96 h

[a] Isolated yield in [%].[b] Determined by 1H NMR spectroscopy on the crude mixture.[c] In [%]; determined by HPLC using a chiral stationary phase after purification.[d] Reaction performed in acetone (25.0 equiv.) as reactant and solvent.[e] 7.0 equiv. of the ketone were used.[f] The ee was determined after acetylation (see the Supporting Information for details).

Figure 2. Asymmetric aldol reactions of para-nitrobenzalde-hyde 9a with cyclohexanone 10a in a series of identical recy-cling experiments. Light bars: conversion [%]; black bars:dr [%]; grey bars: ee [%].

Scheme 2. Catalyst recycling in the sequential synthesis of a small library of enantioenriched aldol adducts.





have been summarized in Scheme 2, and essentiallyreplicate those obtained individually for the samefour adducts 11aa, 11ab, 11ca, and 11af (see entries 1,9, 3, and 13 in Table 3).

Conclusions

In summary, anchoring strategies for a series of pri-mary amino acids onto polystyrene resins using “clickchemistry” have been developed. Out of the differentimmobilized catalysts prepared, polystyrene-support-ed threonine 6a shows the best performance in asym-metric aldol reactions in aqueous environments withenantioselectivities of up to 99%.

We have also shown that catalyst 6a allows aldol re-actions of aromatic aldehydes with a variety of ke-tones including different cyclic ketones, hydroxyace-tone and protected dihydroxyacetone generating aldolproducts of high enantiomeric purity with anti- orsyn-selectivity depending on the cyclic or acyclicnature of the ketone donor. The catalyst can be re-covered by filtration and reused five times withoutshowing any symptoms of deactivation. From an op-erational point of view, the ease of catalyst separationhas a very positive impact on the isolation of highlypolar aldol products like those derived from hydrox-yacetone. An interesting application arising from thecombination of these characteristics in 6a is the use ofthis heterogenized catalyst for the sequential synthesisof focused libraries of enantiopure aldol products.

Experimental Section

General Remarks

Liquid aldehydes were purified by distillation prior to use.Other commercial reagents were used as received and all re-actions were carried out under air, unless stated otherwise.Elemental analyses of the polystyrene (PS) resins were per-formed on a LECO CHNS 932 micro-analyzer at the Uni-versidad Complutense de Madrid, Spain. The degree offunctionalization was calculated on the basis of elementalanalysis.[22] The spectroscopic data of all aldol products wereidentical to data reported in the literature.

Typical Procedure for the Synthesis of Catalyst 1a

(R)-2-[(tert-Butoxycarbonyl)amino]-3-(prop-2-yn-1-yl-thio)-propanoic acid 7[19] (468 mmol, 468 mg, 1.4 equiv.), DIPEA(2.3 mL, 12.9 mmol, 10.0 equiv.) and CuI (14 mg, 75 mmol,6 mol%) were added to a suspension of azidomethyl poly-styrene 8a, b[12p] (1.0 g, 1.3 mmol, f=1.29 mmol g�1,1.0 equiv., 1% DVB) in a solvent mixture of THF/DMF(1:1) and the mixture was shaken at 40 8C for 30 h. The reac-tion was monitored by FT-IR spectroscopy. When the IR

band of the azide (2092 cm�1) had completely disappeared,the reaction product was filtered off and the resin was suc-cessively washed with 1 N HCl, H2O (until pH neutral),H2O/MeOH (1:1), MeOH, MeOH/THF (1:1), THF andDCM. The solid was dried under vacuum at 40 8C for 24 h.Elemental analysis (%): N 5.15, C 76.39, H 7.25; f=0.92 mmol g�1. The N-Boc-protected polystyrene resin wasswollen in DCM (10 mL). After 10 min shaking, trifluoro-acetic acid (1.1 mL) was added and the reaction vessel wasshaken at room temperature for 3 h. The reaction was moni-tored by FT-IR spectroscopy. When the IR band of the Bocgroup had completely disappeared, the reaction product wasfiltered off and suspended in a solvent mixture of MeOH/H2O (1:1) and 1 N NaOH was added dropwise until pH 6.The solid was filtered and washed successively with H2O,H2O/MeOH (1:1), MeOH, MeOH/THF (1:1), THF andDCM. The solid was dried in vacuo at 40 8C for 24 h. Ele-mental analysis (%): N 5.82, C 75.83, H 7.00; f=1.04 mmol g�1.

Synthesis of Catalysts 1b–6a, b

Amino acid-derived catalysts 1b–6a, b were prepared ac-cording to the procedure used for catalyst 1a. Experimentaldetails, spectra and spectroscopic data are provided in theSupporting Information.

General Procedure for the Asymmetric AldolReactions

The polystyrene-supported amino acid (20 mol%) was swol-len in a mixture of DMF/H2O (92 mL:8 mL). Aldehyde 9(314 mmol) and ketone 10 (1.6 mmol, 5.0 equiv.) wereadded, and the reaction mixture was shaken at room tem-perature. After the indicated time, the resin was filtered off,washed with ethyl acetate (3 � 1 mL), and dried undervacuum. The combined liquid phases were dried over anhy-drous magnesium sulfate and concentrated under reducedpressure. Conversion and diastereomeric ratio were deter-mined by performing 1H NMR spectroscopy on the crudesamples after removal of the resin. The aldol products werepurified by column chromatography. The enantiomericexcess was determined by HPLC on a chiral stationaryphase after purification. For the recycling experiments thedried resin could be used in the next reaction without fur-ther treatment. The up-scaled experiments were conductedunder identical conditions.

Characterization of Aldol Products

All obtained aldol products are literature known. 1H NMRand HPLC spectra are provided in the Supporting Informa-tion.

Acknowledgements

This work was funded by MINECO (grants CTQ2008-00947/BQU and CTQ2012-38594-C02-01), DEC (grant2009SGR623), and ICIQ Foundation. C. A. thanks MICINNfor a Juan de la Cierva postdoctoral fellowship. A. H. Hthanks the MECD for an FPU fellowship.





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9An Enantioselective Recyclable Polystyrene-SupportedThreonine-Derived Organocatalyst for Aldol Reactions

Adv. Synth. Catal. 2014, 356, 1 – 9

Andrea H. Henseler, Carles Ayats, Miquel A. Peric�s*




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An Enantioselective Recyclable Polystyrene-Supported Threonine-Derived Organocatalyst for Aldol Reactions