Highly modular dipeptide-like organocatalysts for direct asymmetric aldol reactions in brine

Abstract

A novel series of dipeptide-like organocatalysts derived from proline, amino acids and primary amines have been prepared for direct asymmetric aldol reactions between various aromatic aldehydes and acetone to afford aldol products in good yields (up to 82%) and moderate enantioselectivities (up to 67% ee) with only 1 mol% of catalyst-loading in brine. Under the same conditions, the direct asymmetric aldol reactions of aromatic aldehydes and cyclohexanone give aldol products with high yields (up to 91%) and moderate to good enantioselectivities (up to 88% ee) and excellent diastereoselectivities (up to 99% dr). These organocatalysts are easily synthesized from commercially available materials in multi-gram scale with high modularity in their structural and stereogenic properties.

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Introduction

The direct aldol reaction is one of the most fundamental reactions for carbon–carbon bond formation.^1,2 Many efforts are devoted to develop a highly efficient asymmetric version of this important reaction both in metal³ or metal-free catalytic conditions.⁴ Since the prominent achievements of List and Barbas III on proline catalysis,⁵ a large number of organocatalysts have been prepared and applied in direct aldol reactions between various aldehydes and ketones to achieve excellent yields and enantioselectivities.^6–19

Peptides are common bio-molecules and constituents in living organisms, and play vital roles in variously biological activities. In modern organic synthesis, small peptides can be used as catalysts and ligands for enantioselective transformations²⁰ such as acylation,²¹ epoxidation,²² and cyclopropanation.²³ Undoubtedly, the research of organic synthesis in or on aqueous medium is attractive to chemists by its environmentally benign property and easily handled process.²⁴ Since Janda's²⁵ pioneering work on direct asymmetric aldol reactions in water, Barbas III,²⁶ Hayashi,²⁷ and Singh²⁸ et al. have independently developed enantioselective aldol reactions in aqueous media to achieve excellent results. Small peptides are also utilized as organocatalysts for direct asymmetric aldol reactions in water or brine to afford aldols in good yields and enantioselectivities,²⁹ and some elegant examples³⁰ are listed in Fig. 1. However, the high catalyst-loading (usually 10–30 mol%) and additives are necessary to ensure good yields and enantioselectivities in most cases, and the low-loading organocatalysts without any additive for the direct asymmetric aldol reactions under aqueous conditions are rare.

Fig. 1 Typical small peptides catalysed direct aldol reactions.

In this paper, we have presented the preparation and application of a novel class of highly modular dipeptide-like organocatalysts derived from proline, amino acids and primary amines for direct aldol reactions between various aromatic aldehydes and ketones in brine to provide aldol products in excellent yields and moderate to good enantioselectivities with only 1 mol% of catalyst-loading (Fig. 2). Different amino acid tethered proline-skeletons were compared and their catalytic behaviour was also evaluated in this study.

Fig. 2 Dipeptide-like organocatalysts in this study.

Results and discussion

Synthesis of dipeptide-like organocatalysts

The synthesis of these dipeptide-like organocatalysts is very straightforward and shown in Scheme 1. The coupling of the chiral (or achiral) primary amines 9 with different Boc-protected amino acids 10 under the mixed-anhydride conditions provides the intermediates 11 in high yields which directly followed the deprotection of Boc-group to afford the amines 12. The connection of 12 with Boc-proline can produce 13 which undergo the deprotection to yield the final dipeptide-like organocatalysts 14 (Fig. 3). Only one column chromatographic purification of the intermediates 13 needed in the third step. The organocatalysts 14b–e derived from L-proline and (S)-methylbenzylamine but containing different amino acid motifs in the middle part of the structures, are prepared for the detection of the steric effect on their chiral induction abilities in the direct aldol reactions. The family of 14f–h are synthesized from chiral methylbenzylamine, valine and proline but with different configurations to investigate the effect of the tunably stereogenic centers on aldol reactions. The organocatalyst 14i with the ending group of benzylamine is used in the direct aldol reaction to show the necessity of the chiral or achiral primary amine group in these dipeptide-like analogues. The catalyst 14a [from L-proline and (S)-methylbenzylamine] are used as catalysts for the comparison with the performance of the above dipeptide-like organocatalysts 14b–i in the direct aldol reactions.

Scheme 1 The synthetic route to 14c.

Fig. 3 The structures of organocatalysts 14a–i.

Direct aldol reactions by using dipeptide-like organocatalysts

With these above dipeptide-like organocatalysts 14b–i in hand, the direct aldol reaction of 4-nitrobenzyaldehyde and acetone was chosen as the model reaction for the test of the activities of catalysts. Initially, the reaction was performed under neat conditions at room temperature (r.t.) with catalysts L-proline (30 mol%), and 14a–e (5 mol% respectively), and the results are shown in the Table 1. From the Table 1, it was found that L-proline was the effective catalyst to give moderate yield (76%) and relatively good enantioselectivity (67% ee) of aldol product (Table 1, entry 1) but with a large amount of catalyst-loading. The catalyst 14a with slightly positive result of aldol reaction has good yield (87%) but with very low enantioselectivity (Table 1, entry 2, 20% ee). The catalyst 14b from L-proline, L-alanine and (S)-methylbenzylamine (L-Pro-L-Ala-S-amine) gives 82% yield and 37% ee of aldol product (Table 1, entry 3). With the increase of the steric hindrance of the middle part of the catalysts, the yield and the enantioselectivity of aldol adduct is also significantly increased (Table 1, entries 3–5). To our surprise, the most hindered t-Bu in the middle part of catalyst 14d affords lower yield and enantioselectivity than the catalyst 14c (L-Pro-L-Val-S-amine, LLS, Table 1, entry 4 vs. 5). The catalyst 14e with L-Phe in the middle part results the lower enantioselectivity than 14c (Table 1, entry 6 vs. 4). When the reaction is performed at −40 °C in neat acetone, the yield of aldol product is decreased but with the increase of the enantioselectivity (Table 1, entry 4 with 14c, 75% ee vs. 57% ee) and the sacrifice of reaction time (up to 3 days).

Table 1 The direct aldol reactions catalyzed by dipeptide-like organocatalysts 14 under neat conditions

Entry^a^,^b	Orgcat.	r.t.^b		−40 °C^c
		Yield (%)	ee (%)^d	Yield (%)	ee (%)^d
a 0.5 mmol of aldehyde 1a in 1.0 mL of acetone for every entry.b The reaction time is 24 h.c The reaction time is 3 days.d The enantiomeric excess (ee) of aldol product was determined by chiral HPLC with Chiralpak AS-H column.e 30 mol% of L-proline was used in entry 1.
1^e	L-Pro	76	67(R)	—	—
2	14a	87	20(R)	67	39(R)
3	14b	82	37(R)	62	59(R)
4	14c	92	57(R)	68	75(R)
5	14d	84	45(R)	65	61(R)
6	14e	84	41(R)	67	57(R)
7	14f	92	55(R)	63	80(R)
8	14g	94	57(S)	57	53(S)
9	14h	93	57(S)	61	49(S)
10	14i	90	49(R)	59	47(R)

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In order to investigate the effect of the tunable stereogenic centers of catalysts on aldol reactions, 14f (L-Pro-L-Val-R-amine, LLR), 14g (D-Pro-D-Val-S-amine, DDS), 14h (D-Pro-D-Val-R-amine, DDR) and 14i (L-Pro-L-Val-Bn, LLBn) were prepared respectively. The direct aldol reactions of 4-nitrobenzyaldehyde and acetone under neat condition at r.t. or at −40 °C were performed by using these above catalysts. It was found that the configuration of the chiral carbon atom in the terminal amine of catalysts is changed from (S)- to (R)-, the enantioselectivity of aldol product is slightly increased from 75% (r.t., with catalyst 14c) to 80% ee (−40 °C, with catalyst 14f, Table 1, entry 4 vs. 7). Switching the configuration of proline motif of catalysts from L- to D-, the configurations of aldol product are also changed to be their opposite configurations (Table 1, entries 4, 7 vs. 8, 9). When the terminal amine is achiral (catalyst 14i), the enantioselectivity of aldol product is decreased (Table 1, entry 10). These results indicate that the different stereogenic centers in these dipeptide-like catalysts can produce the obviously different enantioselective inductions and 14f is the best choice both at r.t. and −40 °C on the direct aldol reactions.

To the environmental benign concern, the direct aldol reaction was undertaken in brine at r.t. with the catalysts 14c, 14f–i. There is a decrease of at least 10% ee for every entry when changing from neat conditions to brine (Table 2, entries 1–5). The catalyst-loading is also investigated. Interestingly, the enantioselectivity of aldol product is obviously decreased to be 23% ee with 10 mol% of catalyst-loading of 14f (Table 2, entry 6 vs. entry 2), and this may due to the reaction switching from kinetic-control to thermodynamic-control.³¹ To our delight, when the amount of 14f is reduced to be 1 mol%, the aldol product is afforded in slightly lower yield (80%) but with relatively stable enantioselectivity (45% ee) comparison to 5 mol% of catalyst-loading (Table 2, entry 7 vs. entry 2). However, when the reaction was performed in water with 1 mol% of catalyst 14f, the enantioselectivity is decreased dramatically to 7.5% ee (Table 2, entry 8 vs. entry 7). This shows that these dipeptide-like organocatalysts are highly efficient for the direct aldol reactions in brine but with very poor performance in water.

Table 2 The direct aldol reactions in brine

Entry^a	Orgcat. (mol%)	Yield (%)	ee (%)^b
a 0.5 mmol of aldehyde 1a and 0.5 mL of acetone in 1.0 mL of brine for every entry.b The enantiomeric excess (ee) of aldol product was determined by chiral HPLC with Chiralpak AS-H column, the configuration of aldol product was assigned by comparison to the literature data.c The reaction was performed in water.
1	14c(5)	79	44(R)
2	14f(5)	80	45(R)
3	14g(5)	83	45(S)
4	14h(5)	82	45(S)
5	14i(5)	89	35(R)
6	14f(10)	85	23(R)
7	14f(1)	80	45(R)
8^c	14f(1)	77	7.5(R)

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By using only 1 mol% of dipeptide-like organocatalyst 14f, the direct aldol reactions of acetone and various aromatic aldehydes (Table 3) with electron-withdrawing or electro-donating group are suitable to brine medium at r.t. to produce aldol adducts in good yields (up to 82%) and moderate enantioselectivities (up to 67% ee).

Table 3 The direct aldol reactions between various aromatic aldehydes and acetone in brine with 1 mol% of catalyst 14f

Entry^a	Substrate	Product	Yield (%)	ee (%)^b
a 0.5 mmol of aldehyde 1 and 0.5 mL of acetone in 0.5 mL of brine for every entry.b The enantiomeric excess (ee) of aldol products 3a–j was determined by chiral HPLC with Chiralpak AD-H, OD-H and AS-H columns, the configuration of aldol product was assigned by comparison to the literature data.
1	1a R = 4-NO2	3a	80	45(R)
2	1b R = 2-NO2	3b	82	60(R)
3	1c R = 3-NO2	3c	80	56(R)
4	1d R = 4-Br	3d	75	51(R)
5	1e R = 3-Br	3e	78	52(R)
6	1f R = H	3f	60	54(R)
7	1g R = 2,4-dichloro	3g	67	41(S)
8	1h R = 4-Me	3h	61	54(R)
9	1i R = 3-OMe	3i	65	67(R)
10	1j R = 3,4,5-(OMe)3	3j	78	47(R)

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The direct aldol reaction of 4-nitrobenzyaldehyde and cyclohexanone (Table 4, entry 1) in water with 1 mol% of 14f afforded 15a in excellent diastereoselectivity (d.r. > 98%) and moderate enantioselectivity of anti-product (54% ee). However, switching the reaction solvent of water to brine, the enantioselectivity of 15a is significantly increased to 88% ee (Table 4, entry 2). The direct aldol reactions between various aromatic aldehydes 1a–k and cyclohexanone in brine with 1 mol% of catalyst 14f were smoothly performed at r.t. to furnish aldols 15a–k with moderate to good enantioselectivities (except benzaldehyde 1f, entry 7, 28% ee) and excellent diastereoselective ratios (Table 4, entries 2–12).

Table 4 The direct aldol reactions between various aromatic aldehydes 1a–k and cyclohexanone in brine with 1 mol% of catalyst 14f

Entry^a	Substrate	Product	Yield (%)	Anti : syn	ee (%)^d
a 0.5 mmol of aldehyde 1 and 0.5 mL of acetone in 0.5 mL of brine for entries 2 to 12.b The reaction was performed in 0.5 mL of acetone with 0.5 mL of water for entry 1.c For entry 12, the substrate 1k is 4-chlorobenzyaldehyde.d The enantiomeric excess (ee) of aldol products 15a–k was determined by chiral HPLC with Chiralpak AD-H column, the configuration of aldol product was assigned by comparison to the literature data.
1^b	1a	15a	81	98 : 2	54
2	1a	15a	82	96 : 4	88
3	1b	15b	89	99 : 1	68
4	1c	15c	92	99 : 1	65
5	1d	15d	85	98 : 2	77
6	1e	15e	86	99 : 1	76
7	1f	15f	72	98 : 2	28
8	1g	15g	87	99 : 1	78
9	1h	15h	76	95 : 5	84
10	1i	15i	81	97 : 3	67
11	1j	15j	80	89 : 11	66
12^c	1k	15k	91	91 : 9	81

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From the above reaction results, we have noticed that not only acetone but also cyclohexanone react with various aromatic aldehydes in brine to afford aldol adducts with superior enantioselectivities to those in water (Table 2, entry 7 vs. entry 8; Table 4, entry 2 vs. entry 1). This observation may due to the “salting-out effect” increasing “hydrophobic effect” which was found in the previous reports by Barbas III,²⁶ Hayashi²⁷ and Singh²⁸ et al. The OH groups of the surface water molecules in brine may form the proper amount of additional hydrogen bonds with two amide oxygen atoms to make the amidic NH more acidic resulting in a tight transition state in hydrophobic micro-surroundings to ensure the good enantioselectivity. When the aldol reaction was performed in water, a large amount of hydrogen bonds might form not only with two amide oxygen atoms but also with amidic NH groups to deteriorate the stable transition state leading to poor enantioseletivity. The proposed transition states are shown in Fig. 4.

Fig. 4 The proposed transition states in brine and in water.

In summary, we have prepared a novel series of dipeptide-like organocatalysts for the direct asymmetric aldol reactions of various aromatic aldehydes and acetone in brine with only 1 mol% of catalyst-loading to provide aldol products in good yields (up to 82%) and moderate enantioselectivities (up to 67% ee). Additionally, under the same reaction conditions, the direct asymmetric aldol reactions of various aromatic aldehydes with cyclohexanone afford the corresponding aldol adducts in high yields (up to 92%) and moderate to good enantioselectivities (up to 88% ee) with excellent diastereoselectivitives (d.r. up to 99%). These dipeptide-like organocatalysts are easily synthesized in multi-gram scale with high tunability in their structural and stereogenic properties. The more complex dipeptide-like organocatalysts with multi-hydrogen bonding sites are investigated in due course.

Experimental

General

Melting points are uncorrected and expressed in °C by MRS-2 melting point apparatus from Shanghai Apparatus Co., Ltd. ¹H NMR and ¹³C NMR spectra were measured in CDCl₃, solution on a Bruker AV-400 spectrometer using TMS as an internal reference. Coupling constant (J) values are given in Hz. Multiplicities are designated by the following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; br, broad; m, multiplet. High-resolution mass spectra were performed on a Bruker microTOF-Q II Mass Spectrometer with ES ionization (ESI). All commercially available reagents were used as received. Thin-layer chromatography on silica (with GF254) was used to monitor all reactions. Products were purified by flash column chromatography on silica gel purchased from Qingdao Haiyang Chemical Co., Ltd. Optical rotations were measured on a Perkin Elmer 343 polarimeter. Chiral High Performance Liquid Chromatography (HPLC) analyses were performed using an Agilent 1200 series apparatus and Chiralpak AD-H, OD-H and AS-H columns purchased from Daicel Chemical Industries. The configuration of the products has been assigned by comparison to the literature data or assigned by analogy. All reactions involving air- or moisture-sensitive species were performed in oven-dried Schlenk tubes under an inert atmosphere.

Typical synthetic procedure for preparation of dipeptide-like organocatalyst 14c

A solution of Boc-L-Val-OH (10c, 2.17 g, 10 mmol), Et₃N (1.52 g, 15 mmol) and isobutyl chloroformate (1.57 mL, 10 mmol) in dichloromethane (DCM, 25 mL) at 0 °C was stirred for 30 min, after which the (S)-(−)-1-phenylethylamine 9 (11 mmol) was added and stirred at this temperature for 2 h after which it was warmed to room temperature along with stirring overnight. The reaction was monitored by TLC, and then quenched with sat. aq. NH₄Cl (25 mL), and successively washed with H₂O, and brine. Aqueous phase extracted with dichloromethane (3 × 25 mL). The organic layers were dried over Na₂SO₄, filtered, and concentrated to give the crude 11c as light yellow glue which was directly deprotected by using trifluoroacetic acid (TFA, 4 mL, 52 mmol, 6 equiv.) in 30 mL of DCM to afford the crude product 12c without further purification. The coupling of Boc-L-Pro-OH (1.72 g, 8 mmol) with crude 12c was performed following the same procedure of the connection of 10c with 9 to yield the crude 13c as yellow wax (Alternatively, the crude 13c can be purified by a flash column chromatography with n-hexane/ethyl acetate = 1/1, V/V). This crude 13c was directly undergone the deprotection of Boc-group via TFA (4 mL, 52 mmol) in anhydrous DCM (30 mL) produced the crude product 14c which was purified by a flash column chromatography (n-hexane/ethyl acetate/Et₃N = 1/5/0.05, V/V) to provide the final dipeptide-like organocatalyst 14c (1.87 g, total yield 59% based on Boc-L-Val-OH).

(S)-N-((S)-1-phenylethyl)pyrrolidine-2-carboxamide³² (14a)

Compound 14a was prepared from Boc-L-Pro-OH and (S)-(−)-1-phenylethylamine. The same procedure as described above for the preparation of compound 14c was used.

Yield 72%; white solid; m.p. 145–147 °C; [α]²⁵_D = −91.8° (c = 0.50, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, J = 7.2 Hz, 1H), 7.36–7.34 (m, 5H), 5.11 (dd, J = 7.2, 1.6 Hz, 1H), 3.75 (dd, J = 5.6, 3.6 Hz, 1H), 3.07–3.01 (m, 1H), 2.96–2.90 (m, 1H), 2.21–2.12 (m, 2H), 1.99–1.92 (m, 1H), 1.78–1.50 (m, 2H), 1.09 (d, J = 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 173.95, 143.52, 128.59, 127.18, 126.15, 60.58, 48.03, 47.24, 30.74, 26.16, 22.17; HRMS(ESI⁺) calcd for C₁₃H₁₉N₂O [M + H]⁺ = 219.1497, found: 219.1498.

(S)-N-((S)-1-oxo-1-(((S)-1-phenylethyl)amino)propan-2-yl)pyrrolidine-2-carboxamide^29f (14b)

Compound 14b was prepared from Boc-L-Pro-OH, Boc-L-Ala-OH and (S)-(−)-1-phenylethylamine. The same procedure as described above for the preparation of compound 14c was used.

Yield 52%; white solid; m.p. 155–157 °C; [α]²⁵_D = −216.7° (c = 0.50, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 8.11 (d, J = 7.6 Hz, 1H), 7.37–7.26 (m, 5H), 6.96 (d, J = 7.2 Hz, 1H), 5.07 (t, J = 7.2 Hz, 1H), 4.44 (t, J = 7.2 Hz, 1H), 3.78–3.73 (m, 1H), 3.05–3.01 (m, 1H), 2.95–2.91 (m, 1H), 2.15–1.91 (m, 2H), 1.90 (br, 1H), 1.77–1.67 (m, 2H), 1.46 (d, J = 6.8 Hz, 3H), 1.36 (d, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 175.62, 171.26, 143.34, 128.64, 127.23, 126.05, 60.39, 48.90, 48.50, 47.27, 30.69, 26.21, 22.13, 17.73; HRMS(ESI⁺) calcd for C₁₆H₂₄N₃O₂ [M + H]⁺ = 290.1869, found: 290.1871.

(S)-N-((S)-3-methyl-1-oxo-1-(((S)-1-phenylethyl)amino)butan-2-yl)pyrrolidine-2-carboxamide^22a (14c, LLS)

Compound 14c was prepared from Boc-L-Pro-OH, Boc-L-Val-OH and (S)-(−)-1-phenylethylamine. Yield 59%; white solid; m.p. 141–142 °C; [α]²⁵_D = −98.2° (c = 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 8.25 (d, J = 8.8 Hz, 1H), 7.34–7.26 (m, 5H), 6.76 (d, J = 7.6 Hz, 1H), 5.10 (t, J = 7.2 Hz, 1H), 4.18 (t, J = 8.2 Hz, 1H), 3.77 (dd, J = 4.8, 4.4 Hz, 1H), 3.08–3.02 (m, 1H), 2.97–2.91 (m, 1H), 2.19–2.10 (m, 3H), 1.97–1.89 (m, 1H), 1.76–1.69 (m, 2H), 1.47 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 175.36, 170.37, 143.26, 128.61, 127.27, 126.14, 60.48, 58.47, 48.92, 47.31, 30.98, 30.68, 26.16, 21.92, 19.48, 18.12; HRMS(ESI⁺) calcd for C₁₈H₂₈N₃O₂ [M + H]⁺ = 318.2182, found: 318.2188.

(S)-N-((S)-3,3-dimethyl-1-oxo-1-(((S)-1-phenylethyl)amino) butan-2-yl)pyrrolidine-2-carboxamide (14d)

Compound 14d was prepared from Boc-L-Pro-OH, 3-Me-Boc-L-Val-OH and (S)-(−)-1-phenylethylamine. The same procedure as described above for the preparation of compound 14c was used. Yield 62%; white solid; m.p. 86–88 °C; [α]²⁵_D = −80.3° (c = 0.50, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 8.45 (d, J = 10.0 Hz, 1H), 7.37–7.26 (m, 5H), 6.94 (d, J = 5.6 Hz, 1H), 5.10 (t, J = 7.2 Hz, 1H), 4.31 (d, J = 10.0 Hz, 1H), 3.85 (br, 1H), 3.11–2.97 (m, 2H), 2.21–2.11 (m, 1H), 1.97–1.72 (m, 2H), 1.49–1.47 (m, 2H), 1.46 (d, J = 6.8 Hz, 3H), 0.93 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 174.43, 169.67, 143.43, 128.52, 127.19, 126.32, 60.48, 60.12, 58.40, 48.96, 47.20, 34.98, 30.96, 26.60, 26.04, 21.89, 18.44; HRMS(ESI⁺) calcd for C₁₉H₃₀N₃O₂ [M + H]⁺ = 332.2338, found: 332.2337.

(S)-N-((S)-1-oxo-3-phenyl-1-(((S)-1-phenylethyl)amino) propan-2-yl)pyrrolidine-2-carboxamide (14e)

Compound 14e was prepared from Boc-L-Pro-OH, Boc-L-Phe-OH and (S)-(−)-1-phenylethylamine. The same procedure as described above for the preparation of compound 14c was used.

Yield 53%; white solid, m.p. 107–109 °C; [α]²⁵_D = −15.4° (c = 0.50, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 8.09 (d, J = 7.8 Hz, 1H), 7.30–7.12 (m, 10H), 6.64 (d, J = 29.3, 7.5 Hz, 1H), 5.02 (t, J = 7.2 Hz, 1H), 4.60 (q, J = 8.0 Hz, 1H), 3.64 (dd, J = 4.0, 5.2 Hz, 1H), 3.20–2.77 (m, 4H), 2.07–2.02 (m, 2H), 1.75–1.68 (m, 1H), 1.64–1.49 (m, 2H), 1.36 (d, J = 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 175.71, 169.81, 143.26, 137.21, 129.28, 128.56, 127.17, 126.78, 126.02, 60.23, 58.42, 48.81, 47.09, 30.65, 25.92, 21.97, 18.44; HRMS(ESI⁺) calcd for C₂₂H₂₈N₃O₂ [M + H]⁺ = 366.2182, found: 366.2179.

(S)-N-((S)-3-methyl-1-oxo-1-(((R)-1-phenylethyl)amino)butan-2-yl)pyrrolidine-2-carboxamide (14f, LLR)

Compound 14f was prepared from Boc-L-Pro-OH, Boc-L-Val-OH and (R)-(+)-1-phenylethylamine. The same procedure as described above for the preparation of compound 14c was used.

Yield 67%; white solid, m.p. 132–133 °C; [α]²⁵_D = −23.5° (c = 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, J = 9.2 Hz, 1H), 7.28–7.20 (m, 5H), 6.90 (d, J = 8.0 Hz, 1H), 5.11 (t, J = 7.2 Hz, 1H), 4.23 (dd, J = 7.6, 1.6 Hz, 1H), 3.59 (dd, J = 4.8, 4.4 Hz, 1H), 3.03–2.97 (m, 1H), 2.94–2.89 (m, 1H), 2.23–2.05 (m, 2H), 1.94–1.86 (m, 2H), 1.73–1.66 (m, 2H), 1.49 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 175.58, 170.28, 143.18, 128.58, 127.15, 126.11, 60.41, 58.22, 48.73, 47.26, 30.95, 30.68, 26.17, 22.07, 19.52, 18.23; HRMS(ESI⁺) calcd for C₁₈H₂₇N₃O₂ [M + H]⁺ = 318.2182, found: 318.2182.

(R)-N-((R)-3-methyl-1-oxo-1-(((S)-1-phenylethyl)amino)butan-2-yl)pyrrolidine-2-carboxamide (14g, DDS)

Compound 14g was prepared from Boc-D-Pro-OH, Boc-D-Val-OH and (S)-(−)-1-phenylethylamine. The same procedure as described above for the preparation of compound 14c was used.

Yield 53%; white solid; m.p. 122–123 °C; [α]²⁵_D = +23.9° (c = 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 8.21 (d, J = 9.2 Hz, 1H), 7.30–7.20 (m, 5H), 6.93 (d, J = 8.0 Hz, 1H), 5.11 (t, J = 7.2 Hz, 1H), 4.23 (dd, J = 7.6, 1.6 Hz, 1H), 3.61 (dd, J = 5.2, 4.0 Hz, 1H), 3.04–2.98 (m, 1H), 2.94–2.90 (m, 1H), 2.23–2.05 (m, 3H), 1.93–1.85 (m, 1H), 1.70 (t, J = 6.8 Hz, 2H), 1.50 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 175.38, 170.23, 143.15, 128.57, 127.16, 126.11, 60.37, 58.34, 48.79, 47.24, 30.74, 26.12, 22.07, 19.51, 18.24; HRMS(ESI⁺) calcd for C₁₈H₂₈N₃O₂ [M + H]⁺ = 318.2182, found: 318.2187.

(R)-N-((R)-3-methyl-1-oxo-1-(((R)-1-phenylethyl)amino)butan-2-yl)pyrrolidine-2-carboxamide (14h, DDR)

Compound 14h was prepared from Boc-D-Pro-OH, Boc-D-Val-OH and (R)-(+)-1-phenylethylamine. The same procedure as described above for the preparation of compound 14c was used. Yield 56%; white solid; m.p. 141–143 °C; [α]²⁵_D = +98.8° (c = 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 8.27 (d, J = 9.2 Hz, 1H), 7.35–7.25 (m, 5H), 7.02 (d, J = 7.6 Hz, 1H), 5.10 (t, J = 7.2 Hz, 1H), 4.24 (dd, J = 7.6, 1.6 Hz, 1H), 3.74 (dd, J = 4.8, 4.4 Hz, 1H), 3.07–3.01 (m, 1H), 2.96–2.91 (m, 1H), 2.17–2.06 (m, 3H), 1.96–1.88 (m, 1H), 1.72 (t, J = 6.8 Hz, 2H), 1.46 (d, J = 7.2 Hz, 3H), 0.88 (d, J = 6.4 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 175.04, 170.42, 143.44, 128.85, 128.56, 127.19, 126.17, 60.46, 58.35, 48.92, 47.27, 30.98, 30.96, 26.08, 22.01, 19.44, 18.15; HRMS(ESI⁺) calcd for C₁₈H₂₈N₃O₂ [M + H]⁺ = 318.2182, found: 318.2187.

(S)-N-((S)-1-(benzylamino)-3-methyl-1-oxobutan-2-yl)pyrrolidine-2-carboxamide (14i)

Compound 14i was prepared from Boc-L-Pro-OH, Boc-L-Val-OH and benzylamine. The same procedure as described above for the preparation of compound 14c was used.

Yield 51%; white solid; m.p. 121–123 °C; [α]²⁵_D = −61.3° (c = 1.0, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 8.23 (d, J = 9.2 Hz, 1H), 7.35–7.32 (m, 5H), 6.75 (s, 1H), 4.49 (dd, J = 9.2, 5.6 Hz, 1H), 4.40 (dd, J = 9.2, 5.6 Hz, 1H), 4.19 (t, J = 8.4 Hz, 1H), 3.68 (dd, J = 4.2, 4.0 Hz, 1H), 3.06–3.00 (m, 1H), 2.96–2.91 (m, 1H), 2.28–2.19 (m, 1H), 2.15–2.07 (m, 1H), 1.93–1.86 (m, 2H), 1.75–1.68 (m, 2H), 0.95 (t, J = 7.2 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 172.25, 171.14, 138.12, 128.64, 127.74, 127.41, 60.33, 58.46, 47.21, 43.44, 30.88, 30.52, 28.27, 19.52, 18.45; HRMS(ESI⁺) calcd for C₁₇H₂₆N₃O₂ [M + H]⁺ = 304.2025, found: 304.2029.

Typical procedure for direct aldol reactions by using dipeptide-like organocatalyst 14f in brine

To a mixed solvents of sat. aq. brine (0.5 mL) and ketone (0.5 mL) was added aldehyde (0.5 mmol), and the corresponding catalyst 14f (1.6 mg, 0.005 mmol). The reaction mixture was stirred at 25 °C for 24 h. The mixture was then quenched with a solution of saturated NH₄Cl (0.5 mL), and extracted with ethyl acetate (3 × 10 mL). The combined organic layer was washed with brine and dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give a residue which was purified through a flash column chromatography with n-hexane/ethyl acetate (1 : 1, V/V) to afford the pure aldol adduct. All these aldol products are known compounds^29,33,34 and the enantiomeric excess (ee) of the aldol adduct was determined by chiral HPLC analysis. For HPLC spectra of compounds 3a–j and 15a–k, please refer to ESI.†

Acknowledgements

We thank the National Science Foundation of China (no. 21372259 and 21172262) for financial support of this work.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: ¹H, ¹³C NMR and HRMS of compounds 14a–i, HPLC charts of aldol products 3a–j and 15a–k can be found in the ESI. See DOI: 10.1039/c5ra07019h

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