tert-Butyl esters of tripeptides based on Pro-Phe as organocatalysts for the asymmetric aldol reaction in aqueous or organic medium

Tetrahedron 70 (2014) 608e615

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tert-Butyl esters of tripeptides based on Pro-Phe as organocatalysts for the asymmetric aldol reaction in aqueous or organic medium Anastasia Psarra, Christoforos G. Kokotos *, Panagiota Moutevelis-Minakakis * Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis 15771, Athens, Greece

a r t i c l e i n f o

a b s t r a c t

Article history: Received 6 September 2013 Received in revised form 12 November 2013 Accepted 2 December 2013 Available online 7 December 2013

The enantioselective aldol reaction between ketones and aldehydes constitutes one the most common reaction models for the evaluation of novel organocatalysts. The last few years, it has been shown that the organocatalytic aldol reaction can be performed in water. A family of tripeptides consisting of proline, phenylalanine, and tert-butyl esters of amino acids was successfully employed in this asymmetric transformation. The products of the reaction between various ketones and aldehydes were obtained in high yields (up to 99%) with excellent diastereo- (up to 97:3 dr) and enantioselectivities (up to 99% ee). The C-terminal amino acid determines the ability of the tripeptide (Pro-Phe-AA-OtBu) to act efficiently in aqueous or organic medium. Ó 2013 Published by Elsevier Ltd.

Keywords: Aldol reaction Organocatalysis Prolinamides Water Ureas

1. Introduction The enantioselective aldol reaction is among the most commonly used CeC bond forming reactions in modern asymmetric catalysis.1 With the recognition of organocatalysis as the third branch of asymmetric catalysis, alongside the transition metal complexes catalysis and biocatalysis,2,3 a significant increase in the number of the studies concerning aldol reactions has been realized. Since List, Lerner, and Barbas employed proline as the catalyst in the intermolecular aldol reaction,4 proline, and proline derivatives containing bioisosteric groups like sulfonamides and tetrazoles have been frequently employed in organocatalytic transformations.5 Nowadays, it is well accepted that organocatalysts combining the prolinamide unit with functionalities able to act as hydrogen bond donors are among the most successful classes of catalysts employed in the aldol reaction. Representative examples of such prolinamides that efficiently catalyze the aldol reactions are shown in Fig. 1 (compounds 1e7).6e12 The five-membered secondary amine structure of the pyrrolidine ring enables the activation of carbonyl compounds through the formation of enamine intermediates, while incorporation of a chiral template provides extra interactions, while the bulky environment leads to enhanced selectivity. Another important family of prolinamides that have Fig. 1. Known prolinamide organocatalysts. * Corresponding authors. Tel.: þ30 210 7274484; fax: þ30 210 7274761 (P.M.-M.); tel.: þ30 210 7274281; fax: þ30 210 7274761 (C.G.K.); e-mail addresses: ckokotos@ chem.uoa.gr (C.G. Kokotos), [email protected] (P. Moutevelis-Minakakis). 0040-4020/$ e see front matter Ó 2013 Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.tet.2013.12.007

been less frequently exploited as potential organocatalysts are peptides.13 Although peptides were among the first organocatalysts employed in the aldol reaction, they found limited success, since in

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most cases low to moderate enantioselectivities were obtained.14,15 In particular, the dipeptide Pro-Phe has been studied and when DMSO is utilized as the solvent, moderate selectivities are obtained,14d except for a single case, where good enantioselectivities were obtained.14h Unfortunately, when the solvent is switched to water, the enantioselectivities and yields drop significantly.14c,f,h In the last few years, reactions where water is used as the solvent have attracted a great deal of attention because water is an abundant, safe, and environmentally friendly medium to carry out reactions.16 Since the pioneering work from the groups of Hayashi and Barbas,17 a variety of catalysts have been developed for the organocatalytic aldol reaction in the presence of water. Proline and proline derivatives have been mainly designed and employed in aqueous environment as the catalyst,9,18 but also a number of reports exist on the use of the other amino acid derivatives.19 2. Results and discussion Along with the catalytic activity of catalyst 5,10 the key factors that are responsible for high catalytic activity in prolinamideethioureas have been studied, concluding that catalyst 6 is an improved catalyst for the aldol reaction in organic solvents and all three potential hydrogen bond sites are involved and responsible for the enantioselection observed.11 We have also demonstrated that the combination of a prolinamide with an urea moiety provides similar modes of activation through hydrogen bonding as in catalyst 7.12 Bearing these in mind, and our previous endeavors in organocatalysis,20 we postulated that a tripeptide could be an efficient catalyst for the asymmetric aldol reaction. Coupled with the potential for enamine activation of the nucleophile deriving from the pyrrolidine ring of proline, a tripeptide possesses two potential hydrogen bond sites that can activate the electrophile. Along the same lines as our recent study,11 these additional activation can lead to increased enantioselectivity (Fig. 2). Furthermore, tripeptides can adopt a stable conformation that is highly dependant on the solvent and the containing amino acids. Thus, employing bulky tert-butyl esters of various amino acids at the C-terminus of the tripeptide, we could end up with tripeptides that will show catalytic activities in different solvents. Having as a goal, the identification of peptides that can catalyze the aldol reaction in either an organic or an aqueous medium, (S)-benzyloxycarbonyl protected proline (8) was coupled with (S)-methyl phenylalaninate (9) using dicyclohexyl carbodiimide (DCC) as a condensing agent in the presence of 1-hydroxybenzotriazole (HOBt). Saponification afforded the N-protected dipeptide 10. To the resulting dipeptide, a series of tert-butyl ester of amino acids were added under conventional peptide coupling conditions, affording the protected tripeptides 11aef. Finally, deprotection via hydrogenation afforded organocatalysts 12aef (Scheme 1).

Fig. 2. Design of the peptide-organocatalysts used in this study.

The synthesized organocatalyst 12a was then evaluated in the aldol reaction between cyclohexanone (13a) and 4-nitroben zaldehyde (14a) (Table 1). Following previously acquired

Scheme 1. Synthesis of the tripeptides 12aef.

Table 1 Enantioselective aldol reaction of cyclohexanone with 4-nitrobenzaldehyde using catalysts 12aa

Entry

Conditions

Yieldb (%)

drc

ee (%)d

1 2 3 4 5 6 7 8e 9 10e,f 11e,f 12e,g

Toluene, rt, 72 h THF, rt, 72 h MeOH, rt, 72 h H2O, rt, 48 h H2O/NaCl, rt, 48 h H2O/Heptyl4NþCl-, rt, 48 h H2O/NaBr, rt, 48 h H2O/NaBr, rt, 24 h H2O/NaBr, 0  C, 48 h H2O/NaBr, 0  C, 24 h H2O/NaBr, 10  C, 24 h H2O/NaBr, 0  C, 24 h

58 31 42 >99 >99 >99 >99 >99 97 98 82 92

85:15 88:12 72:28 85:15 83:17 75:25 90:10 92:8 96:4 93:7 94:6 92:8

91 82 89 86 88 89 89 89 92 93 95 92

a Catalyst (0.02 mmol) in solvent (1.0 mL), 4-NBA (0.014 mmol), aldehyde (0.14 mmol), and cyclohexanone (1.00 mmol). b Isolated yield. c The diastereomeric ratio (dr) was determined by 1H NMR spectroscopy of the crude reaction mixture. d The enantiomeric excess (ee) for the major isomer was determined by chiral HPLC. e 20 mol % additive. f 2 equiv of cyclohexanone. g 1.1 equiv of cyclohexanone, 4-NBA: 4-nitrobenzoic acid.

knowledge,12 toluene was employed as the solvent (entry 1, Table 1). Although high selectivities were obtained, prolonged reaction times were required to afford the products in mediocre yield. Other solvents provided similar results (entries 2 and 3, Table 1, see also Supplementary data). Fortunately, the use of water as the solvent led to quantitative yield (entry 4, Table 1). Having identified the potential to develop a tripeptide able to promote the aldol reaction in aqueous medium in high selectivities, a thorough examination of

610

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reaction conditions was undertaken (entries 5e12, Table 1 and Supplementary data). Among a number of different aqueous solutions, a saturated aqueous solution of NaBr provided the best results. Careful selection of the reaction temperature and the amount of the acid additive provided the best reaction conditions (entries 9e12, Table 1). It has to be highlighted that only 2 equiv of ketone are enough to afford the product in high yields and selectivities (entry 11, Table 1). Once the optimum reaction conditions in aqueous medium were identified, the catalytic behavior of the other tripeptides were evaluated, since it was interesting to study how the incorporation of other tert-butyl esters of amino acids on the catalyst backbone would affect the catalytic efficiency. Thus, catalysts 12aef were tested both in toluene and in aqueous conditions (Table 2). Tripeptide 12a, based on di-tert-butyl aspartate, provided the product in high yields and selectivities only in aqueous medium, while in toluene the yield was low (entries 1 and 2, Table 2). Although catalyst 12b, based on (S)-tert-butyl phenylglycinate, catalyzed the aldol reaction both in aqueous and organic media, it provided inferior selectivities (entries 3 and 4, Table 2). Changing to (R)-tertbutyl phenylglycinate, tripeptide 12c provided the product in quantitative yield, but the selectivities were slightly inferior when toluene was used as the solvent and compared to 12a (entry 5, Table 2). Decreasing the excess of ketone to 2 equiv had a positive impact in selectivities, while the yield remained high (entry 6 vs 5, Table 2). This catalyst provided the best results in organic solvents among the tripeptides bearing tert-butyl esters of amino acids tested. Furthermore, catalyst 12c could be also employed in the presence of water affording the product in slightly decreased selectivities (entry 7, Table 2). Among the other catalysts, serinebased 12d proved inferior in both reaction conditions, while catalysts 12e and 12f led to a further decrease in the catalytic activity (entries 8e13, Table 2). Table 2 Enantioselective aldol reaction of cyclohexanone with 4-nitrobenzaldehyde using catalysts 12aefa

We then turned our attention in exploring the substrate scope of the enantioselective aldol reaction by employing either catalyst 12a in aqueous environment or catalyst 12c in toluene (Table 3). A variety of substituted aromatic aldehydes can be employed with cyclohexanone leading to products from good to excellent yields and selectivities (entries 1e16, Table 3). Electron-withdrawing groups at any position of the aryl moiety led to good to excellent results (entries 1e10, Table 3), while the use of benzaldehyde or aromatic aldehydes para-substituted with halogens led to similar yields and selectivities (entries 11e16, Table 3). In all cases higher diastereoselectivities were obtained when the aqueous conditions along with catalyst 12a were employed. On the other hand and in most cases, slightly higher enantioselectivities were observed when catalyst 12c in toluene was utilized. Tetrahydropyran-4-one and tetrahydrothiopyran-4-one proved to be difficult substrates for catalyst 12a leading to lower yields and selectivities, while catalyst 12c delivered the products in high yields and selectivities (entries 17e20, Table 3). Disubstituted cyclohexanone at the 4-position required prolonged reaction time to deliver a mediocre yield and lower enantioselectivity (entries 21 and 22, Table 3). The desymmetrization of ketones is also possible utilizing organocatalyst 12a, since 4-methyl cyclohexanone delivered the product in high yield and with excellent selectivities, while catalyst 12c led to inferior results (entries 23 and 24, Table 3). Cyclopentanone was also utilized with some success, since very low enantioselectivities were observed (entries 25 and 26, Table 3). Moreover, in order to broaden the scope of this methodology, we investigated the reaction of acetone with 4-nitrobenzaldehyde (entries 27 and 28, Table 3). In aqueous environment no reaction took place, while the yield and enantioselectivity observed were not satisfactory when catalyst 12c was employed. A plausible transition-state model is proposed in Fig. 3. The secondary amine of the pyrrolidine ring activates the ketone through the formation of an enamine intermediate. It is likely that the electrophile is activated through a multiple hydrogen bonding network consisting of the two amide protons of the tripeptide. 3. Conclusions

Entry e

1 2 3e 4f 5 6g 7 8 9 10f 11f 12e 13e

Catalyst

Conditions

Yieldb (%)

drc

ee (%)d

12a 12a 12b 12b 12c 12c 12c 12d 12d 12e 12e 12f 12f

A B A B A A B A B A B A B

17 82 >99 >99 >99 99 >99 98 >99 12 63 Traces 7

98:2 94:6 70:30 80:20 83:17 88:12 88:12 90:10 86:14 87:13 90:10 d 85:15

95 95 75 88 94 96 93 92 83 n.d. 87 d n.d.

In conclusion, the synthesis of tripeptides based on proline, phenylalanine, and a series of tert-butyl esters of amino acids was carried out. The design of these catalysts was based on the efficient activation of ketones from the secondary amine of the proline residue via enamine formation and the high level of organization of the transition state when more than one potential hydrogen bond sites exist in the molecule of the catalyst. The evaluation of these tripeptides in the asymmetric aldol reaction was carried out. When di-tert-butyl aspartate was utilized, the tripeptide provided the aldol product in good to excellent yields and selectivities in saturated aqueous solution. When the tert-butyl (R)-phenylglycinate was utilized, the aldol product was obtained in similar high yields and selectivities but in toluene. The nature of the amino acid moiety at the C-terminus is of critical importance, since depending on the amino acid, different reaction conditions can be employed. 4. Experimental section

a

Conditions A: catalyst (0.02 mmol) in toluene (1.0 mL), 4-NBA (0.03 mmol), aldehyde (0.14 mmol), and cyclohexanone (1.40 mmol), 20  C, 24 h. Conditions B: catalyst (0.02 mmol) in H2O/NaBr (1.0 mL), 4-NBA (0.03 mmol), aldehyde (0.14 mmol), and cyclohexanone (0.28 mmol), 10  C, 24 h. b Isolated yield. c The diastereomeric ratio (dr) was determined by 1H NMR spectroscopy of the crude reaction mixture. d The enantiomeric excess (ee) for the major isomer was determined by chiral HPLC. e Reaction time 72 h. f Reaction time 48 h. g 2 equiv of cyclohexanone, 4-NBA: 4-nitrobenzoic acid, n.d.: not determined.

4.1. General information Organic solutions were concentrated under reduced pressure on € chi rotary evaporator. Chromatographic purification of proda Bu ucts was accomplished using column chromatography on Merck Kieselgel 60 F254 230e400 mesh. Thin-layer chromatography (TLC) was performed on aluminum backed silica plates (0.2 mm, 60 F254). Visualization of the developed chromatogram was performed by fluorescence quenching using ninhydrin stain. Melting points were

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Table 3 Enantioselective aldol reaction between ketones and aldehydes using catalyst 12a or 12ca

Fig. 3. Proposed transition-state model for the aldol reaction. Ar/conditions

Yieldb (%)

drc

1 2 3e 4e 5e 6e 7f 8f 9f 10f 11f 12f 13f 14f 15f 16f

4-NO2C6H4/A 4-NO2C6H4/B 3-NO2C6H4/A 3-NO2C6H4/B 2-NO2C6H4/A 2-NO2C6H4/B 4-CF3C6H4/A 4-CF3C6H4/B 3-CNC6H4/A 3-CNC6H4/B C6H5/A C6H5/B 4-FC6H4/A 4-FC6H4/B 4-BrC6H4/A 4-BrC6H4/B

82 99 64 67 40 47 78 80 54 58 61 86 78 62 58 53

94:6 88:12 95:5 92:8 89:11 90:10 94:6 88:12 93:7 88:12 90:10 88:12 97:3 86:14 93:7 88:12

95 96 91 93 97 97 86 90 97 94 75 85 90 97 77 67

17g

4-NO2C6H4/A

78 (15i)

90:10

82

18g

4-NO2C6H4/B

92 (15i)

92:8

85

19f

4-NO2C6H4/A

64 (15j)

96:4

89

20f

4-NO2C6H4/B

92 (15j)

96:4

98

Entry

Ketone

(15a) (15a) (15b) (15b) (15c) (15c) (15d) (15d) (15e) (15e) (15f) (15f) (15g) (15g) (15h) (15h)

ee (%)d

€ chi 530 hot stage apparatus and are undetermined on a Bu corrected. IR spectra were recorded on a Nicolet 6700 FT-IR spectrometer and are reported in terms of frequency of absorption (cm1). 1H and 13C NMR spectra were recorded on Varian Mercury (200 or 600 and 50 or 125 MHz) as noted, and are internally referenced to residual solvent signals (CDCl3 or (CD3)2SO). Data for 1H NMR spectroscopy are reported as follows: chemical shift (d parts per million), multiplicity (s¼singlet, d¼doublet, t¼triplet, q¼quadruplet, m¼multiplet, br s¼broad signal, bs m¼broad signal multiplet), integration, coupling constant and assignment. Wherever rotamers exist, are presented in brackets. Diastereomeric ratios were determined by 1H NMR spectroscopy (200 MHz). Data for 13 C NMR spectroscopy are reported in terms of chemical shift (d ppm). Mass spectra were recorded on a Finnigan Surveyor MSQ Plus, with only molecular ions and major peaks being reported with intensities quoted as percentages of the base peak. High Performance Liquid Chromatography (HPLC) was used to determine enantiomeric excesses and was performed on an Agilent 1100 Series apparatus using ChiralpakÒ AD-H, OD-H and AS-H columns. Optical rotations were measured on a Perkin Elmer 343 polarimeter. The configuration of the products has been assigned by comparison to literature data. Data for known compounds match literature data.

4.2. General procedure for the synthesis of the catalysts 21f

4-NO2C6H4/A

41 (15k)

82:18

72

22f

4-NO2C6H4/B

40 (15k)

89:11

85

23f

4-NO2C6H4/A

91 (15l)

97:3

99

24e

4-NO2C6H4/B

43 (15l)

70:30

82

25f

4-NO2C6H4/A

90 (15m)

37:63

12

26e

4-NO2C6H4/B

98 (15m)

37:63

27h

27e

4-NO2C6H4/A

e (15n)

d

d

28e

4-NO2C6H4/B

40 (15n)

d

a

71

Conditions A: 12a in H2O/NaBr. Conditions B: 12c in toluene. b Isolated yield. c The diastereomeric ratio (dr) was determined by 1H NMR spectroscopy of the crude reaction mixture. d The enantiomeric excess (ee) for the major isomer was determined by chiral HPLC. e Reaction time 48 h. f Reaction time 72 h. g Reaction time 120 h. h Major isomer syn: 27% ee, minor isomer anti: 97% ee.

4.2.1. (S)-2-[(S)-1-(Benzyloxycarbonyl)pyrrolidine-2-carboxamido]3-phenylpropanoic acid (10). An identical procedure was followed and compound data in agreement with Ref. 12. 4.2.2. (S)-Di-tert-butyl 2-((S)-2-((S)-1-((benzyloxy)carbonyl)pyrrolidine-2-carboxamido)-3-phenylpropanamido)succinate (11a). To a stirred solution of dipeptide 10 (1.29 g, 3.26 mmol) in dry CH2Cl2 (20 mL) at 0  C, 1-hydroxybenzotriazole (HOBt) (0.44 g, 3.26 mmol), H-Asp(OtBu)-OtBu (0.92 g, 3.26 mmol), Et3N (0.70 mL, 5.00 mmol), and dicyclohexyl carbodiimide (DCC) (0.72 g, 3.26 mmol) were added consecutively. The reaction mixture was left stirring at 0  C for 1 h and then warmed to rt and left stirring for 18 h. The solvents were evaporated under reduced pressure and the crude product was dissolved in EtOAc (30 mL). After filtration, the organic layer was washed with aqueous H2SO4 (5%, 20 mL), H2O (20 mL), aqueous NaHCO3 (5%, 20 mL), and brine (20 mL). After evaporation of the solvent, the crude ester was purified using column chromatography eluting with Pet. Ether/EtOAc (30:70). Mixture of rotamers 60:40. White solid; 1.80 g, 89% yield; Rf (AcOEt/Pet. Ether 7:3) 0.67; mp 92e94  C; ½a25 D 45.0 (c 1.0, CH3OH); IR (KBr) 3302, 2977, 2931, 1743, 1705, 1655, 1524, 1414, 1366, 1153 cm1; 1H NMR (600 MHz, DMSO-d6) d 8.42 (0.6H, d, J¼7.9 Hz, NH), 8.27 (0.4H, d, J¼8.0 Hz, NH), 8.07 (0.6H, d, J¼8.5 Hz, NH), 7.96 (0.4H, d, J¼8.3 Hz, NH), 7.36e7.05 (10H, m, ArH), 5.08 (0.4H, d, J¼12.7 Hz, OCHH), 5.00 (0.4H, d, J¼12.7 Hz, OCHH), 4.94 (0.6H, d, J¼13.1 Hz, OCHH), 4.77 (0.6H, d, J¼13.1 Hz, OCHH), 4.58 (0.6H, ddd, J¼8.7, 8.5 and 3.9 Hz, NCH), 4.52e4.41 (1.4H, m, NCH), 4.21e4.12 (1H, m, NCH), 3.38e3.25 (2H, m, 2 CHH), 3.04e2.92 (1H, m, CHH), 2.82e2.73 (1H, m, CHH), 2.66e2.58 (1H, m, CHH), 2.54e2.45 (1H, m, CHH), 2.08e2.00 (0.6H,

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m, CHH), 2.00e1.92 (0.4H, m, CHH), 1.72e1.58 (3H, m, 3 CHH), 1.37 [12.6H, s, (CCH3)3], 1.35 [5.4H, s, (CCH3)3]; 13C NMR (75 MHz, DMSO-d6) d 172.2 (172.0), 171.5 (171.3), 170.0 (169.9), 169.6 (169.5), 154.7 (154.2), 138.2 (138.1), 137.5 (137.3), 129.6 (129.5), 128.8 (128.6), 128.4 (128.3), 127.9 (128.2), 127.3 (127.8), 126.6 (126.5), 81.4, 80.9, 66.0 (66.4), 59.7 (60.4), 53.7 (53.9), 49.8, 47.5 (46.9), 37.5 (38.0), 31.4 (30.1), 29.5 (29.2), 28.1, 28.0, 24.0 (23.2); MS 624 (MþHþ, 100); HRMS exact mass calculated for [MþH]þ (C34H46N3O8) requires m/z 624.3279, found m/z 624.3284. 4.2.3. (S)-Benzyl 2-(((S)-1-(((S)-2-(tert-butoxy)-2-oxo-1phenylethyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)pyrrolidine-1-carboxylate (11b). Same procedure as above, but utilizing HPhg-OtBu (1.00 mmol). Mixture of rotamers 60:40. White solid; 0.50 g, 87% yield; Rf (AcOEt/Pet. Ether 1:1) 0.38; mp 99e101  C; ½a25 D 9.1 (c 1.0, CH3OH); IR (KBr) 3281, 2918, 2850, 1738, 1707, 1648, 1535, 1414, 1358, 1151 cm1; 1H NMR (600 MHz, DMSO-d6) d 8.67 (0.6H, d, J¼6.9 Hz, NH), 8.48 (0.4H, d, J¼7.0 Hz, NH), 8.07 (0.6H, d, J¼8.5 Hz, NH), 7.97 (0.4H, d, J¼8.5 Hz, NH), 7.41e7.31 (7H, m, ArH), 7.31e7.18 (5H, m, ArH), 7.16e7.06 (3H, m, ArH), 5.23 (0.4H, d, J¼7.0 Hz, NCH), 5.20 (0.6H, d, J¼7.0 Hz, NCH), 5.00 (0.4H, d, J¼12.7 Hz, OCHH), 4.92 (0.6H, d, J¼13.0 Hz, OCHH), 4.86 (0.4H, d, J¼12.7 Hz, OCHH), 4.76 (0.6H, d, J¼13.0 Hz, OCHH), 4.70 (0.6H, td, J¼9.6 and 4.2 Hz, NCH), 4.64 (0.4H, ddd, J¼9.7, 9.6 and 4.1 Hz, NCH), 4.16e4.06 (1H, m, NCH), 3.40e3.34 (1H, m, NCHH), 3.32e3.24 (1H, m, NCHH), 3.09 (0.4H, dd, J¼13.6 and 3.6 Hz, CHH), 3.02 (0.6H, dd, J¼13.9 and 4.0 Hz, CHH), 2.86e2.79 (1H, m, CHH), 2.06e1.97 (0.6H, m, CHH), 1.96e1.88 (0.4H, m, CHH), 1.68e1.61 (1H, m, CHH), 1.61e1.52 (2H, m, 2 CHH), 1.33 [3.6H, s, (CCH3)3], 1.32 [5.4H, s, (CCH3)3]; 13C NMR (125 MHz, DMSO-d6) d 172.3 (172.1), 171.6 (171.4), 169.8 (169.7), 154.2 (154.8), 138.3 (138.2), 137.5 (137.3), 136.7 (136.6), 129.7 (129.6), 129.0 (129.1), 128.8 (128.7), 128.6 (128.7), 128.3 (128.4), 128.1 (128.2), 128.1 (127.8), 127.4 (127.8), 126.6 (126.5), 81.6, 66.0 (66.4), 59.8 (60.5), 57.6, 53.6 (53.7), 47.5 (46.9), 37.8 (37.5), 31.4 (30.1), 27.9, 23.2 (24.0); MS 586 (MþHþ, 52); HRMS exact mass calculated for [MþH]þ (C34H40N3O6) requires m/z 586.2912, found m/z 586.2927. 4.2.4. (S)-Benzyl 2-(((S)-1-(((R)-2-(tert-butoxy)-2-oxo-1phenylethyl)amino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)pyrrolidine-1-carboxylate (11c). Same procedure as above, but utilizing (R)-H-Phg-OtBu (2.90 mmol). White solid; 1.56 g, 92% yield; Rf (AcOEt/Pet. Ether 6:4) 0.55; mp 100e102  C; ½a25 D 75.3 (c 1.0, CH3OH); IR (KBr) 3301, 2978, 2852, 1735, 1697, 1651, 1523, 1415, 1356, 1152 cm1; 1H NMR (200 MHz, CDCl3) d 7.41e6.82 (17H, m, ArH and 2 NH), 5.46e5.29 (1H, m, NCH), 5.22e4.92 (2H, m, OCHH), 4.71e4.57 (1H, m, NCH), 4.29e4.21 (1H, m, NCH), 3.49e3.29 (2H, m, NCHH), 3.29e2.81 (2H, m, CHH), 2.11e1.89 (2H, m, 2 CHH), 1.89e1.55 (2H, m, 2 CHH), 1.36 [9H, s, (CCH3)3]; 13C NMR (50 MHz, CDCl3) d 171.6 (171.8), 169.9 (170.0), 169.5 (169.7), 156.1 (156.0), 136.6, 136.5, 136.3, 129.1, 129.2, 128.6 (128.8), 128.5, 128.4, 128.1, 127.3 (127.1), 127.1 (127.0), 126.7 (126.9), 82.5 (82.6), 67.4 (67.3), 60.7 (60.4), 57.0 (56.9), 53.8 (53.7), 47.0 (47.4), 37.8 (37.7), 28.7 (28.6), 27.7, 24.3 (23.2); MS 586 (MþHþ, 54); HRMS exact mass calculated for [MþH]þ (C34H40N3O6) requires m/z 586.2912, found m/z 586.2925. 4.2.5. (S)-Benzyl 2-(((S)-1-(((S)-1,3-di-tert-butoxy-1-oxopropan-2-yl) amino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)pyrrolidine-1carboxylate (11d). Same procedure as above, but utilizing HSer(tBu)-OtBu (2.16 mmol). Mixture of rotamers 60:40. White solid; 1.10 g, 85% yield; Rf (AcOEt/Pet. Ether 7:3) 0.59; mp 106e108  C; ½a25 D 35.5 (c 1.0, CH3OH); IR (KBr) 3310, 2974, 2931, 1736, 1699, 1655, 1524, 1415, 1363, 1193 cm1; 1H NMR (200 MHz, DMSO-d6) d 8.15 (0.4H, d, J¼7.2 Hz, NH), 8.09 (0.6H, d, J¼8.3 Hz, NH), 8.05 (0.6H, d, J¼6.8 Hz, NH), 7.95 (0.4H, d, J¼8.3 Hz, NH), 7.38e7.05 (10H, m,

ArH), 5.08 (0.4H, d, J¼13.0 Hz, OCHH), 4.98 (0.4H, d, J¼13.0 Hz, OCHH), 4.93 (0.6H, d, J¼13.4 Hz, OCHH), 4.77 (0.6H, d, J¼13.4 Hz, OCHH), 4.72e4.53 (1H, m, NCH), 4.31e4.19 (1H, m, OCHH), 4.15e4.07 (1H, m, OCHH), 3.65e3.52 (1H, m, NCH), 3.47e3.18 (3H, m, NCH and NCHH), 3.09e2.91 (1H, m, CHH), 2.86e2.69 (1H, m, CHH), 2.05e1.96 (1H, m, CHH), 1.71e1.49 (3H, m, 3 CHH), 1.36 [9H, s, (CCH3)3], 1.09 [9H, s, (CCH3)3]; 13C NMR (50 MHz, DMSO-d6) d 172.5 (172.3), 172.0 (171.8), 169.9 (170.0), 154.5 (154.9), 138.5 (138.7), 137.7 (137.4), 129.8 (129.9), 128.8 (129.1), 128.5 (128.6), 128.1 (128.0), 127.6 (127.8), 126.8 (126.7), 81.3, 73.5, 66.3 (66.6), 62.3 (62.2), 60.0 (60.1), 58.4 (59.1), 54.1 (54.0), 47.7 (47.6), 37.9 (37.8), 31.7 (31.9), 28.3, 27.8, 23.4 (24.4); MS 596 (MþHþ, 42); HRMS exact mass calculated for [MþH]þ (C33H46N3O7) requires m/z 596.3330, found m/z 596.3341. 4.2.6. (S)-Benzyl 2-(((S)-1-(((2S,3R)-1,3-di-tert-butoxy-1-oxobutan2-yl)amino)-1-oxo-3-phenylpropan-2-yl)carbamoyl)pyrrolidine-1carboxylate (11e). Same procedure as above, but utilizing HThr(tBu)-OtBu (0.50 mmol). Mixture of rotamers 60:40. White solid; 0.28 g, 91% yield; Rf (AcOEt/Pet. Ether 7:3) 0.75; mp 105e107  C; ½a25 D 37.4 (c 0.8, CH3OH); IR (KBr) 3315, 2975, 2933, 1740, 1702, 1517, 1415, 1364, 1160 cm1; 1H NMR (200 MHz, CDCl3) d 7.48e7.09 (11H, m, ArH and NH), 6.61e6.41 (1H, m, NH), 5.22e4.92 (2H, m, OCHH), 4.81e4.62 (1H, m, OCH), 4.39e4.07 (3H, m, 3 NCH), 3.52e2.85 (4H, m, NCHH and CHH), 2.29e2.12 (0.6H, m, CHH), 2.08e1.62 (3.4H, m, 3.4 CHH), 1.46 [9H, s, (CCH3)3], 1.17e1.05 [12H, m, (CCH3)3 and CH3]; 13C NMR (50 MHz, CDCl3) d 171.4 (171.8), 170.7 (170.6), 169.4 (169.5), 156.9 (156.8), 136.7 (136.6), 136.3 (136.4), 129.3, 128.5 (128.6), 128.3 (128.4), 128.0 (128.1), 127.9 (128.0), 126.6 (126.9), 81.9, 73.8, 67.3, 67.1, 60.5 (60.7), 58.4 (56.7), 53.8 (53.7), 46.8 (47.3), 38.1 (38.2), 30.8 (30.9), 28.6, 28.1, 24.3 (23.2), 20.6 (21.1); MS 610 (MþHþ, 49); HRMS exact mass calculated for [MþH]þ (C34H48N3O7) requires m/z 610.3487, found m/z 610.3496. 4.2.7. (S)-Benzyl 2-(((S)-1-(((S)-1-(tert-butoxy)-1-oxo-3-(1-trityl1H-imidazol-4-yl)propan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl) carbamoyl)pyrrolidine-1-carboxylate (11f). Same procedure as above, but utilizing H-His(Trt)-OtBu (0.50 mmol). White solid; 0.33 g, 80% yield; Rf (AcOEt/Pet. Ether 8:2) 0.75; mp 75e78  C; ½a25 D 40.3 (c 0.67, CH3OH); IR (KBr) 3311, 2979, 2927, 1738, 1705, 1672, 1 1 1495, 1415, 1357, 1154 cm ; H NMR (200 MHz, CDCl3) d 7.80e7.52 (1H, m, NH), 7.41e7.21 (16H, m, ArH), 7.21e6.97 (11H, m, ArH), 6.61e6.52 (1H, m, NH), 5.15 (1H, d, J¼12.1 Hz, OCHH), 5.01 (1H, d, J¼12.1 Hz, OCHH), 4.85e4.69 (1H, m, NCH), 4.68e4.56 (1H, m, NCH), 4.31e4.17 (1H, m, NCH), 3.41e3.18 (3H, m, NCHH and CHH), 2.99e2.82 (3H, m, 3 CHH), 1.99e1.52 (4H, m, 4 CHH), 1.36 [9H, s, (CCH3)3]; 13C NMR (50 MHz, CDCl3) d 171.6 (171.4), 170.5 (170.3), 169.8 (169.9), 156.0 (155.9), 142.1, 140.5, 138.5 (138.4), 136.5 (136.4), 136.4 (136.3), 129.7, 129.5, 128.4, 128.1, 126.4, 119.3, 81.4, 70.3 (70.2), 67.3 (67.2), 60.6 (60.6), 53.6 (53.7), 53.0 (52.9), 46.7, 37.9 (38.0), 36.9 (37.0), 29.7, 28.0, 24.2; MS 832 (MþHþ, 38); HRMS exact mass calculated for [MþH]þ (C51H54N5O6) requires m/z 832.4069, found m/z 832.4078. 4.2.8. (S)-Di-tert-butyl 2-((S)-3-phenyl-2-((S)-pyrrolidine-2-carbo xamido)propanamido)succinate (12a). To a stirred solution of compound 11a (1.70 g, 2.70 mmol) in dry methanol (60 mL), 10% Pd/C (10 mol %) was added and the reaction mixture was left stirring at rt for 2 h under hydrogen atmosphere. After filtration through Celite, the solvent was evaporated to afford the desired product. Colorless oil; 1.10 g, 85% yield; Rf (nBuOH/AcOH/H2O 4:1:1) 0.62; ½a25 D 16.4 (c 1.0, CH3OH); IR (KBr) 3296, 2975, 2926, 1731, 1654, 1513, 1392, 1367, 1152 cm1; 1H NMR (600 MHz, DMSO-d6) d 8.55 (1H, d, J¼8.1 Hz, NH), 8.06 (1H, d, J¼8.9 Hz, NH), 7.23e7.16 (2H, m, ArH), 7.17e7.13 (3H, m, ArH), 4.57 (1H, td, J¼9.0 and 4.5 Hz, NCH), 4.52e4.43 (1H, m, NCH), 3.44 (1H, dd, J¼8.8 and 4.9 Hz, NCH), 3.01 (1H, dd, J¼13.8 and 4.3 Hz,

A. Psarra et al. / Tetrahedron 70 (2014) 608e615

CHH), 2.80e2.72 (2H, m, CHH and CHH), 2.64 (1H, dd, J¼16.3 and 5.9 Hz, CHH), 2.59e2.47 (2H, m, 2 CHH), 1.85e1.75 (1H, m, CHH), 1.48e1.38 (2H, m, 2 CHH), 1.38e1.32 (2H, m, CHH and NH), 1.37 [9H, s, (CCH3)3], 1.36 [9H, s, (CCH3)3]; 13C NMR (125 MHz, DMSO-d6) d 173.8, 171.2, 170.1, 169.6, 137.6, 129.8, 128.3, 126.8, 81.5, 80.9, 60.3, 52.8, 49.7, 47.0, 38.6, 37.5, 30.7, 28.1, 28.0, 25.9; MS 490 (MþHþ, 100); HRMS exact mass calculated for [MþH]þ (C26H40N3O6) requires m/z 490.2912, found m/z 490.2897. 4.2.9. (S)-tert-Butyl 2-phenyl-2-((S)-3-phenyl-2-((S)-pyrrolidine-2carboxamido)propanamido)acetate (12b). Same procedure as above, but utilizing 11b (0.77 mmol). Colorless oil; 0.29 g, 84% yield; Rf (nBuOH/AcOH/H2O 4:1:1) 0.63; ½a25 D þ5.9 (c 1.0, CH3OH); IR (KBr) 3299, 2976, 2928, 1735, 1649, 1517, 1392, 1369, 1152 cm1; 1H NMR (600 MHz, DMSO-d6) d 8.88 (1H, d, J¼7.2 Hz, NH), 8.09 (1H, d, J¼8.9 Hz, NH), 7.42e7.32 (5H, m, ArH), 7.22e7.14 (5H, m, ArH), 5.24 (1H, d, J¼7.2 Hz, NCH), 4.69 (1H, td, J¼9.1 and 4.4 Hz, NCH), 3.44 (1H, dd, J¼8.9 and 5.0 Hz, NCH), 3.05 (1H, dd, J¼13.7 and 4.3 Hz, NCHH), 2.81 (1H, dd, J¼13.7 and 9.3 Hz, NCHH), 2.77 (1H, dt, J¼10.1 and 6.6 Hz, CHH), 2.57 (1H, dt, J¼10.1 and 6.3 Hz, CHH), 1.85e1.75 (1H, m, CHH), 1.48e1.36 (2H, m, 2 CHH), 1.36e1.28 (2H, m, CHH and NH), 1.34 [9H, s, (CCH3)3]; 13C NMR (125 MHz, DMSO-d6) d 173.8, 171.3, 169.9, 137.7, 136.8, 129.8, 129.1, 128.7, 128.3, 128.1, 126.7, 81.7, 60.3, 57.4, 52.8, 47.0, 38.6, 30.7, 28.0, 25.8; MS 452 (MþHþ, 100); HRMS exact mass calculated for [MþH]þ (C26H34N3O4) requires m/z 452.2544, found m/z 452.2537. 4.2.10. (R)-tert-Butyl 2-phenyl-2-((S)-3-phenyl-2-((S)-pyrrolidine-2carboxamido)propanamido)acetate (12c). Same procedure as above, but utilizing 11c (2.39 mmol). Colorless oil; 0.89 g, 83% yield; Rf (nBuOH/AcOH/H2O 4:1:1) 0.62; ½a25 D 84.2 (c 1.1, CH3OH); IR (KBr) 3297, 2975, 2927, 1735, 1651, 1513, 1368, 1152 cm1; 1H NMR (200 MHz, CDCl3) d 8.12 (0.8H, d, J¼8.0 Hz, NH), 7.77 (0.2H, d, J¼8.5 Hz, NH), 7.34e7.04 (11H, m, ArH and NH), 5.37 (1H, d, J¼7.2 Hz, NCH), 4.69 (1H, td, J¼8.3 and 4.1 Hz, NCH), 3.75 (1H, dd, J¼8.2 and 4.8 Hz, NCH), 3.25e2.86 (3H, m, NCHH and CHH), 2.67 (1H, dt, J¼10.1 and 6.1 Hz, CHH), 2.12e1.91 (2H, m, CHH and NH), 1.72e1.36 (3H, m, 3 CHH), 1.35 [9H, s, (CCH3)3]; 13C NMR (50 MHz, CDCl3) d 175.4, 170.1, 169.5, 136.7, 136.6, 129.2, 128.7, 128.5, 128.1, 127.1, 126.7, 82.5, 60.1, 56.9, 53.8, 47.0, 37.0, 30.6, 27.7, 25.8; MS 452 (MþHþ, 100); HRMS exact mass calculated for [MþH]þ (C26H34N3O4) requires m/z 452.2544, found m/z 452.2535. 4.2.11. (S)-tert-Butyl 3-(tert-butoxy)-2-((S)-3-phenyl-2-((S)-pyrrolidine-2-carboxamido)propanamido)propanoate (12d). Same procedure as above, but utilizing 11d (1.60 mmol). Colorless oil; 0.64 g, 87% yield; Rf (nBuOH/AcOH/H2O 4:1:1) 0.67; ½a25 D 21.2 (c 0.76, CH3OH); IR (KBr) 3301, 2973, 2929, 1736, 1656, 1513, 1393, 1365, 1161 cm1; 1H NMR (200 MHz, CDCl3) d 8.05 (0.5H, d, J¼8.5 Hz, NH), 7.72 (0.5H, d, J¼8.9 Hz, NH), 7.38e7.05 (5H, m, ArH), 6.78e6.62 (1H, m, NH), 4.71e4.59 (1H, m, OCHH), 4.59e4.41 (1H, m, OCHH), 3.79e3.61 (1H, m, NCH), 3.58e3.42 (1H, m, NCH), 3.29e2.62 (5H, m, NCH, NCHH and CHH), 2.18e1.81 (3H, m, 2 CHH and NH), 1.71e1.22 (2H, m, 2 CHH), 1.44 [9H, s, (CCH3)3], 1.11 [9H, s, (CCH3)3]; 13C NMR (50 MHz, CDCl3) d 174.5 (174.4), 170.5 (170.6), 169.0 (168.9), 136.5 (136.6), 129.4 (129.3), 128.5 (128.4), 126.9 (126.8), 82.0 (81.9), 77.2, 64.5 (68.5), 62.0 (61.8), 53.5 (53.6), 53.2 (53.4), 47.0 (52.2), 38.0 (41.6), 30.2 (30.6), 28.0, 27.3, 24.1 (25.7); MS 462 (MþHþ, 100); HRMS exact mass calculated for [MþH]þ (C25H40N3O5) requires m/z 462.2962, found m/z 462.2951. 4.2.12. (2S,3R)-tert-Butyl 3-(tert-butoxy)-2-((S)-3-phenyl-2-((S)pyrrolidine-2-carboxamido)propanamido)butanoate (12e). Same procedure as above, but utilizing 11e (0.31 mmol). Yellow oil; 0.13 g, 88% yield; Rf (CHCl3/CH3OH 9:1) 0.34; ½a25 D 32.5 (c 0.89, CH3OH); IR (KBr) 3298, 2974, 2929, 1730, 1655, 1515, 1366, 1155 cm1; 1H

613

NMR (200 MHz, CDCl3) d 7.82e7.59 (1H, m, NH), 7.36e7.08 (5H, m, ArH), 6.68e6.52 (1H, m, NH), 4.91e4.41 (2H, m, OCH and NCH), 4.40e4.06 (2H, m, 2 NCH), 3.58e3.17 (2H, m, NCHH), 3.11e2.77 (2H, m, CHH), 2.31 (1H, br s, NH), 2.21e1.61 (4H, m, 4 CHH), 1.45 [9H, s, (CCH3)3], 1.18e1.08 [12H, m, (CCH3)3 and CH3]; 13C NMR (50 MHz, CDCl3) d 171.1 (171.2), 170.4 (170.8), 169.4 (169.5), 136.8 (136.7), 129.3 (129.5), 128.4 (128.2), 126.8 (126.7), 82.0 (82.2), 73.9, 67.1 (68.1), 58.4 (58.3), 57.6 (56.2), 54.1 (53.6), 46.5 (50.7), 38.0 (37.9), 30.2 (27.3), 28.6, 28.0, 23.9 (24.0), 20.7 (20.8); MS 476 (MþHþ, 100); HRMS exact mass calculated for [MþH]þ (C26H42N3O5) requires m/z 476.3119, found m/z 476.3108. 4.2.13. (S)-tert-Butyl 2-((S)-3-phenyl-2-((S)-pyrrolidine-2-carbox amido)propanamido)-3-(1-trityl-1H-imidazol-4-yl)propanoate (12f). Same procedure as above, but utilizing 11f (0.26 mmol) (no cleavage of the Trt-protecting group was observed under the reaction conditions employed). Yellow oil; 0.13 g, 72% yield; Rf (CHCl3/CH3OH 9:1) 0.29; ½a25 D 17.4 (c 0.6, CH3OH); IR (KBr) 3300, 2975, 2928, 1733, 1665, 1522, 1367, 1154 cm1; 1H NMR (200 MHz, CDCl3) d 8.65e7.63 (4H, m, ArH and NH), 7.42e6.95 (19H, m, ArH), 6.69e6.55 (1H, m, NH), 5.55e5.33 (1H, m, NCH), 4.91e4.52 (2H, m, 2 NCH), 3.51e3.19 (2H, m, NCHH), 3.19e2.81 (4H, m, 4 CHH), 2.41e2.31 (1H, m, CHH), 2.27e2.07 (2H, m, CHH and NH), 1.81e1.51 (2H, m, 2 CHH), 1.41 [3.6H, s, (CCH3)3], 1.34 [5.4H, s, (CCH3)3]; 13C NMR (50 MHz, CDCl3) d 170.9 (171.2), 169.7 (169.8), 166.5 (165.2), 141.8, 138.1, 137.2, 137.0, 135.2, 129.7, 129.4, 128.4, 128.3, 128.2, 128.1, 126.2, 120.0, 81.7 (81.1), 67.8 (66.3), 55.7 (56.1), 53.5 (54.5), 53.0 (52.8), 44.6, 40.5 (40.6), 38.3, 30.1 (29.4), 27.9, 23.6; MS 698 (MþHþ, 100); HRMS exact mass calculated for [MþH]þ (C43H48N5O4) requires m/z 698.3701, found m/z 698.3692. 4.3. General procedure for the aldol reaction Conditions A: To a stirred solution of catalyst 12a (10 mg, 0.02 mmol) in saturated aqueous NaBr (1.0 mL), 4-nitrobenzoic acid (4.6 mg, 0.028 mmol) was added. The reaction mixture was cooled to 10  C. The aldehyde (0.14 mmol) was added, followed by the ketone (0.28 mmol). The reaction mixture was left stirring at 10  C for 24e120 h. The solvent was evaporated and the crude product was purified using column chromatography eluting with the appropriate mixture of petroleum ether (40e60  C)/EtOAc to afford the desired product. Conditions B: To a stirred solution of catalyst 12c (9.3 mg, 0.02 mmol) in toluene (1.0 mL), 4-nitrobenzoic acid (4.6 mg, 0.028 mmol) was added. The reaction mixture was cooled to 20  C. The aldehyde (0.14 mmol) was added, followed by the ketone (0.28 mmol). The reaction mixture was left stirring at 20  C for 24e120 h. The solvent was evaporated and the crude product was purified using column chromatography eluting with the appropriate mixture of petroleum ether (40e60  C)/EtOAc to afford the desired product. 4.3.1. (S)-2-[(R)-Hydroxy-(4-nitrophenyl)methyl]-cyclohexanone (15a, Table 3, entry 2).12 Colorless oil, 34 mg, 99% yield; Rf (AcOEt/ Pet. Ether 4:6) 0.10; 1H NMR (200 MHz, CDCl3) anti d 8.20 (2H, d, J¼8.8 Hz, ArH), 7.51 (2H, d, J¼8.8 Hz, ArH), 4.87 (1H, d, J¼8.4 Hz, OCH), 4.09 (1H, br s, OH), 2.64e2.26 (3H, m, COCH and CHH), 2.17e1.29 (6H, m, 6 CHH); 13C NMR (50 MHz, CDCl3) d 214.6, 148.4, 127.9, 127.8, 123.4, 73.8, 57.0, 42.5, 30.6, 27.5, 24.5; HPLC analysis: Diacel Chiralpak AD-H, hexane/iPrOH 90:10, flow rate 1.0 mL/min, retention time: 25.15 (minor) and 33.10 (major), 96% ee. 4.3.2. (S)-2-[(R)-Hydroxy-(3-nitrophenyl)methyl]-cyclohexanone (15b, Table 3, entry 4).12 Colorless oil, 23 mg, 67% yield; Rf (AcOEt/ Pet. Ether 4:6) 0.20; 1H NMR (200 MHz, CDCl3) anti d 8.23e8.14 (2H, m, ArH), 7.67 (1H, d, J¼7.3 Hz, ArH), 7.55 (1H, d, J¼7.6 Hz, ArH), 4.90 (1H, d, J¼8.4 Hz, OCH), 4.11 (1H, br s, OH), 2.68e2.31 (3H, m, COCH

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and CHH), 2.17e1.32 (6H, m, 6 CHH); 13C NMR (50 MHz, CDCl3) d 214.6, 148.2, 143.1, 133.1, 129.2, 122.7, 121.9, 74.0, 57.0, 42.6, 30.6, 27.6, 24.6; HPLC analysis: Diacel Chiralpak AD-H, hexane/iPrOH 92:8, flow rate 1.0 mL/min, retention time: 25.15 (major) and 31.98 (minor), 93% ee. 4.3.3. (S)-2-[(R)-Hydroxy-(2-nitrophenyl)methyl]-cyclohexanone (15c, Table 3, entry 6).12 Yellow solid, 16 mg, 47% yield; mp 114e116  C {lit.: mp 116e11821}; Rf (AcOEt/Pet. Ether 3:7) 0.25; 1H NMR (200 MHz, CDCl3) anti d 7.91e7.72 (2H, m, ArH), 7.63 (1H, t, J¼6.5 Hz, ArH), 7.42 (1H, t, J¼6.6 Hz, ArH), 5.43 (1H, d, J¼7.1 Hz, OCH), 4.16 (1H, br s, OH), 2.85e2.01 (3H, m, COCH, CHH), 1.90e1.52 (6H, m, 6 CHH); 13C NMR (50 MHz, CDCl3) d 214.9, 136.5, 133.0, 128.9, 128.3, 128.2, 124.0, 69.7, 57.2, 42.8, 31.1, 27.7, 24.9; HPLC analysis: Diacel Chiralpak AD-H, hexane/iPrOH 95:5, flow rate 0.8 mL/min, retention time: 40.77 (major) and 42.92 (minor), 97% ee. 4.3.4. (S)-2-[(R)-Hydroxy-(4-(trifluoromethyl)phenyl)methyl]-cyclohexanone (15d, Table 3, entry 8).12 White solid, 30 mg, 80% yield; mp 73e75  C; Rf (AcOEt/Pet. Ether 4:6) 0.48; 1H NMR (200 MHz, CDCl3) anti d 7.61 (2H, d, J¼8.2 Hz, ArH), 7.44 (2H, d, J¼8.2 Hz, ArH), 4.84 (1H, d, J¼8.6 Hz, OCH), 4.03 (1H, br s, OH), 2.69e2.02 (4H, m, COCH and 3 CHH), 1.90e1.39 (5H, m, 5 CHH); 13C NMR (50 MHz, CDCl3) d 215.1, 144.9, 129.6 (q, J¼31.2 Hz), 127.3, 125.3 (q, J¼8.1 Hz), 123.9 (q, J¼271.4 Hz), 74.2, 57.2, 42.6, 30.7, 27.6, 24.7; 19F NMR (188 MHz, CDCl3) d 3.89 (S); HPLC analysis: Diacel Chiralpak AD-H, hexane/iPrOH 90:10, flow rate 0.5 mL/min, retention time: 22.19 (minor) and 27.37 (major), 90% ee. 4.3.5. (R)-3-[Hydroxy-(2-(S)-oxocyclohexyl)methyl]-benzonitrile (15e, Table 3, entry 9).12 Yellow solid, 17 mg, 54% yield; mp 66e68  C {lit.: mp 69e7218o}; Rf (AcOEt/Pet. Ether 3:7) 0.17; 1H NMR (200 MHz, CDCl3) anti d 7.68e7.38 (4H, m, ArH), 4.81 (1H, d, J¼8.5 Hz, OCH), 4.01 (1H, br s, OH), 2.65e2.03 (4H, m, COCH and 3 CHH), 1.87e1.22 (5H, m, 5 CHH); 13C NMR (50 MHz, CDCl3) d 214.6, 142.6, 131.5, 130.6, 129.1, 129.0, 118.7, 112.4, 73.9, 57.1, 42.6, 30.6, 27.6, 24.6; HPLC analysis: Diacel Chiralpak AD-H, hexane/iPrOH 95:5, flow rate 1.0 mL/min, retention time: 28.15 (minor) and 42.58 (major), 97% ee. 4.3.6. (S)-2-[(R)-Hydroxy-(phenyl)methyl]-cyclohexanone (15f, Table 3, entry 12).12 Colorless oil, 25 mg, 86% yield; Rf (AcOEt/Pet. Ether 4:6) 0.42; 1H NMR (200 MHz, CDCl3) anti d 7.51e7.21 (5H, m, ArH), 4.78 (1H, d, J¼8.8 Hz, OCH), 3.84 (1H, br s, OH), 2.70e2.31 (3H, m, COCH and CHH), 2.15e1.24 (6H, m, 6 CHH); 13C NMR (50 MHz, CDCl3) d 215.5, 140.8, 128.3, 127.8, 125.7, 74.7, 57.4, 42.6, 30.8, 27.8, 24.7; HPLC analysis: Diacel Chiralpak OD-H, hexane/iPrOH 90:10, flow rate 0.5 mL/min, retention time: 18.87 (major) and 27.38 (minor), 85% ee. 4.3.7. (S)-2-[(R)-Hydroxy-(4-(fluorophenyl)methyl])-cyclohexanone (15g, Table 3, entry 14).12 White solid, 19 mg, 62% yield; mp 66e68  C; Rf (AcOEt/Pet. Ether 4:6) 0.16; 1H NMR (200 MHz, CDCl3) anti d 7.33e7.27 (2H, m, ArH), 7.03 (2H, t, J¼8.7 Hz, ArH), 4.77 (1H, d, J¼8.4 Hz, OCH), 4.03 (1H, br s, OH), 2.65e2.31 (3H, m, COCH and CHH), 2.08e1.22 (6H, m, 6 CHH); 13C NMR (50 MHz, CDCl3) d 215.4, 162.3 (d, J¼246.2 Hz), 136.6, 128.5 (d, J¼5.1 Hz), 115.2 (d, J¼20.0 Hz), 74.1, 57.4, 42.6, 30.7, 27.7, 24.6; 19F NMR (188 MHz, CDCl3) d 48.12 (S); HPLC analysis: Diacel Chiralpak AD-H, hexane/iPrOH 90:10, flow rate 0.5 mL/min, retention time: 26.65 (minor) and 29.59 (major), 97% ee. 4.3.8. (S)-2-[(R)-Hydroxy-(4-(bromophenyl)methyl)]-cyclohexanone (15h, Table 3, entry 15).12 White solid, 23 mg, 58% yield; mp 89e91  C; Rf (AcOEt/Pet. Ether 3:7) 0.24; 1H NMR (200 MHz, CDCl3)

anti d 7.47 (2H, d, J¼8.5 Hz, ArH), 7.20 (2H, d, J¼8.5 Hz, ArH), 4.75 (1H, d, J¼8.6 Hz, OCH), 3.94 (1H, br s, OH), 2.61e2.13 (3H, m, COCH and CHH), 2.11e2.01 (1H, m, CHH), 1.88e1.24 (5H, m, 5 CHH); 13C NMR (50 MHz, CDCl3) d 215.2, 140.0, 131.5, 128.7, 121.7, 74.2, 57.3, 42.6, 30.7, 27.7, 24.7; HPLC analysis: Diacel Chiralpak AD-H, hexane/iPrOH 90:10, flow rate 0.5 mL/min, retention time: 30.57 (minor) and 35.29 (major), 77% ee. 4.3.9. (S)-3-[(R)-Hydroxy-[4-(nitrophenyl)methyl]dihydro-2H-pyran-4(3H)-one (15i, Table 3, entry 18).12 Pale yellow solid, 32 mg, 92% yield; mp 116e118  C; Rf (AcOEt/Pet. Ether 4:6) 0.16; 1H NMR (200 MHz, CDCl3) anti d 8.21 (2H, d, J¼8.8 Hz, ArH), 7.50 (2H, d, J¼8.8 Hz, ArH), 4.97 (1H, d, J¼8.2 Hz, OCH), 4.28e4.09 (1H, m, OCHH), 3.90e3.64 (3H, m, 2 OCHH and OH), 3.44 (1H, dd, J¼11.4, 9.8 Hz, OCHH), 3.02e2.41 (3H, m, 3 CHH); 13C NMR (50 MHz, CDCl3) d 209.2, 147.7, 147.4, 127.4, 123.8, 71.2, 69.7, 68.2, 57.5, 42.7; HPLC analysis: Diacel Chiralpak AD-H, hexane/iPrOH 80:20, flow rate 1.0 mL/min, retention time: 19.03 (minor) and 27.46 (major), 85% ee. 4.3.10. (S)-3-[(R)-Hydroxy-[4-(nitrophenyl)methyl]dihydro-2H-thiopyran-4(3H)-one (15j, Table 3, entry 20).12 Yellow solid, 34 mg, 92% yield; mp 137e139  C {lit.: mp 140e14122}; Rf (AcOEt/Pet. Ether 3:7) 0.13; 1H NMR (200 MHz, CDCl3) anti d 8.23 (2H, d, J¼8.3 Hz, ArH), 7.53 (2H, d, J¼8.3 Hz, ArH), 5.04 (1H, d, J¼7.9 Hz, OCH), 3.63 (1H, br s, OH), 3.07e2.91 (3H, m, COCH and CHH), 2.87e2.70 (2H, m, 2 CHH), 2.68e2.42 (2H, m, 2 CHH); 13C NMR (50 MHz, CDCl3) d 211.2, 147.7, 147.6, 127.7, 123.8, 73.1, 59.4, 44.7, 32.8, 30.7; HPLC analysis: Diacel Chiralpak AD-H, hexane/iPrOH 90:10, flow rate 1.0 mL/min, retention time: 48.22 (minor) and 71.13 (major), 98% ee. 4.3.11. (S)-7-[(R)-Hydroxy-4-(nitrophenyl)methyl]-1,4-dioxospiro [4.5]decan-8-one (15k, Table 3, entry 22).12 White solid, 17 mg, 40% yield; mp 89e91  C; Rf (AcOEt/Pet. Ether 3:7) 0.06; 1H NMR (200 MHz, CDCl3) anti d 8.21 (2H, d, J¼8.8 Hz, ArH), 7.49 (2H, d, J¼8.8 Hz, ArH), 4.92 (1H, d, J¼7.5 Hz, OCH), 4.04 (1H, br s, OH), 3.98e3.68 (4H, m, 4 OCHH), 2.91e2.74 (1H, m, COCH), 2.66e2.54 (1H, m, CHH), 2.51e2.42 (1H, m, CHH), 2.07e1.55 (3H, m, 3 CHH), 1.54e1.44 (1H, m, CHH); 13C NMR (50 MHz, CDCl3) d 213.1, 147.9, 127.8, 126.5, 123.6, 106.6, 73.8, 64.8, 64.5, 52.9, 38.8, 37.8, 34.3; HPLC analysis: Diacel Chiralpak AS-H, hexane/iPrOH 70:30, flow rate 1.0 mL/min, retention time: 16.34 (anti minor) and 26.41 (anti major), 85% ee. 4.3.12. (2S,4S)-2-[(R)-Hydroxy-(4-(nitrophenyl)methyl)]-4-methyl cyclohexanone (15l, Table 3, entry 23).23 Yellow solid, 34 mg, 91% yield; mp 99e101  C; Rf (AcOEt/Pet. Ether 3:7) 0.15; ½a25 D 6.8 (c 1.0, CHCl3); 1H NMR (200 MHz, CDCl3) anti d 8.22 (2H, d, J¼8.8 Hz, ArH), 7.51 (2H, d, J¼8.8 Hz, ArH), 4.92 (1H, d, J¼8.6 Hz, OCH), 3.99e3.87 (1H, br s, OH), 2.81e2.29 (3H, m, COCH and CHH), 2.15e1.29 (5H, m, 4 CHH, CH); 1.07 (3H, d, J¼7.1 Hz, CH3); 13C NMR (50 MHz, CDCl3) d 214.8, 148.4, 147.5, 127.8, 123.7, 73.9, 52.9, 38.3, 36.1, 33.0, 26.5, 18.2; HPLC analysis: Diacel Chiralpak OD-H, hexane/iPrOH 95:5, flow rate 1.0 mL/min, retention time: 48.43 (minor) and 54.58 (major), 99% ee. 4.3.13. (S)-2-[(R)-Hydroxy-(4-(nitrophenyl)methyl)]-cyclopentanone (15m, Table 3, entry 26).12 Pale yellow oil, 32 mg, 98% yield; Rf (AcOEt/Pet. Ether 4:6) 0.23; 1H NMR (200 MHz, CDCl3) d 8.21 (2H, d, J¼8.8 Hz, ArH), 7.52 (2H, d, J¼8.8 Hz, ArH), 5.42 (1H, s, OCH syn), 4.84 (1H, d, J¼9.2 Hz, OCH anti), 4.76 (1H, br s, OH anti), 2.69 (1H, br s, OH syn), 2.52e2.18 (3H, m, COCH and CHH), 2.15e1.83 (2H, m, 2 CHH), 1.78e1.55 (2H, m, 2 CHH); 13C NMR (50 MHz, CDCl3) d 214.6, 213.4, 149.2, 147.9, 147.4, 147.3, 127.2, 126.5, 123.0, 122.9, 73.5, 69.8, 57.0, 56.3, 42.5, 30.2, 27.7, 25.5, 24.6, 24.3; HPLC analysis: Diacel

A. Psarra et al. / Tetrahedron 70 (2014) 608e615

Chiralpak AD-H, hexane/iPrOH 95:5, flow rate 1.0 mL/min, retention time: 30.01 (syn major) and 41.68 (syn minor), 54.22 (anti minor) and 56.18 (anti major), syn isomer 27% ee, anti isomer 97% ee. 4.3.14. (S)-4-Hydroxy-4-(4-nitrophenyl)-butan-2-one (15n, Table 3, entry 28).21 Colorless oil, 12 mg, 40% yield; Rf (AcOEt/Pet. Ether 4:6) 1 0.14; [a]25 D þ36.9 (c 1.4, CHCl3); H NMR (200 MHz, CDCl3) d 8.20 (2H, d, J¼7.0 Hz, ArH), 7.52 (2H, d, J¼7.0 Hz, ArH), 5.25 (1H, m, OCH), 3.56 (1H, br s, OH), 3.01e2.71 (2H, m, CHHCO), 2.21 (3H, s, CH3CO); 13 C NMR (50 MHz, CDCl3) d 208.6, 149.9, 147.4, 126.4, 123.8, 68.9, 51.5, 30.7; HPLC analysis: Diacel Chiralpak AS-H, hexane/iPrOH 85:15, flow rate 1.0 mL/min, retention time: 32.69 (minor) and 42.78 (major), 71% ee. Acknowledgements C.G.K. gratefully acknowledges the Operational Program ‘Education and Lifelong Learning’ for financial support through the NSRF program ‘ENISXYSH METADIDAKTOPUN EPEYNHTUN’ (PE 2431) co-financed by ESF and the Greek State. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.tet.2013.12.007. References and notes 1. For a recent review on the aldol reaction, see: Trost, B. M.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600e1632. 2. For books, see: (a) Berkessel, A.; Groger, H. Asymmetric Organocatalysis-From Biomimetic Concepts to Powerful Methods for Asymmetric Synthesis; WileyVCH: Weinheim, Germany, 2005; (b) Dalko, P. I. Enantioselective Organocatalysis Reactions and Experimental Procedure; Wiley-VCH: Weinheim, Germany, 2007. 3. For selected reviews, see: (a) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471e5569; (b) Barbas, C. F., III. Angew. Chem., Int. Ed. 2008, 47, 42e47; (c) Bertelsen, S.; Jorgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178e2189; (d) Pihko, P. M.; Majander, I.; Erkkila, A. Top. Curr. Chem. 2010, 291, 29e75; (e) Giacalone, F.; Gruttadauria, M.; Agrigento, P.; Noto, R. Chem. Soc. Rev. 2012, 41, 2406e2447; (f) Aleman, J.; Cabrera, S. Chem. Soc. Rev. 2013, 42, 774e793. 4. List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395e2396. 5. For selected papers, see: (a) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123, 5260e5267; (b) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew. Chem., Int. Ed. 2004, 43, 1983e1986; (c) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84e96; (d) Berkessel, A.; Koch, B.; Lex, J. Adv. Synth. Catal. 2004, 346, 1141e1146; (e) Bellis, E.; Vasilatou, K.; Kokotos, G. Synthesis 2005, 2407e2413; (f) Barbayianni, E.; Bouzi, P.; Constantinou-Kokotou, V.; Ragoussis, V.; Kokotos, G. Heterocycles 2009, 78, 1243e1252; (g) Reis, O.; Eymur, S.; Reis, B.; Demir, A. S. Chem. Commun. 2009, 1088e1090; (h) Companyo, X.; Valero, G.; Crovetto, L.; Moyano, A.; Rios, R. Chem.dEur. J. 2009, 15, 6564e6568; (i) Tsandi, E.; Kokotos, C. G.; Kousidou, S.; Ragoussis, V.; Kokotos, G. Tetrahedron 2009, 65, 1444e1449; (j) El-Hamdouni, N.; Companyo, X.; Rios, R.; Moyano, A. Chem.dEur. J. 2010, 16, 1142e1148. 6. (a) Tang, Z.; Jiang, F.; Yu, L. T.; Cui, X.; Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z. J. Am. Chem. Soc. 2003, 125, 5262e5263; (b) Tang, Z.; Jiang, F.; Cui, X.; Gong, L. Z.; Mi, A. Q.; Jiang, Y. Z.; Wu, Y. D. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5755e5760. 7. Tang, Z.; Yang, Z. H.; Chen, X. H.; Cun, L. F.; Mi, A. Q.; Jiang, Y. Z.; Gong, L. Z. J. Am. Chem. Soc. 2005, 127, 9285e9289. 8. Gandgi, S.; Singh, V. K. J. Org. Chem. 2008, 73, 9411e9416.

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