Enantioselective Direct Aldol Reactions Catalyzed by Cinchonine-derived Prolinamides

Chinese Journal of Chemistry, 2009, 27, 930—936 Full Paper

* E-mail: [email protected]; Tel.: 0086-817-2568081; Fax: 0086-817-2562029 Received April 16, 2008; revised January 10, 2009; accepted March 4, 2009. Project supported by the National Natural Science Foundation of China (No. 20772097), Sichuan Provincial Science Foundation for Outstanding

Youth (No. 05ZQ026-008) and the Key Project of the Education Department of Sichuan Province, China (No. 2006A081).

© 2009 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Enantioselective Direct Aldol Reactions Catalyzed by Cinchonine-derived Prolinamides

ZHAO, Jing(赵晶) CHEN, Aijun(陈爱军) LIU, Quanzhong*(刘全忠)

Laboratory of Applied Chemistry and Pollution Control Technology, College of Chemistry and Chemical Engineering, China West Normal University, Nanchong, Sichuan 637002, China

Highly enantioselective aldol reactions catalyzed by cinchonine-derived prolinamides are reported. Both cyclic and acyclic ketones were reacted with various aldehydes furnishing the desired aldol products in up to 90% yield with excellent enantioselectivities (up to 95%) and moderate diastereoselectivities (up to 3.6/1) in the case of cyclic ketones. A possible mechanism that elucidates the excellent observed enantioselectivities is presented.

Keywords aldol reaction, cinchonine-derived prolinamide, mechanism

Introduction

Asymmetric aldol reactions are attractive method-ologies for the rapid access to optically enriched β-hydroxyl ketones and have been widely employed in the synthesis of complex molecules.1 The importance of organocatalysis in asymmetric transformations has been demonstrated by the facile preparation of the catalysts, the mild reaction conditions, and the environmentally benign aspects as compared to metal catalysis.2 In the recent period past, a great deal of effort on the develop-ment of organocatalyzed aldol reactions has been made and impressive results have been achieved.3 Among the reagents used in direct aldol reactions, proline has been widely employed as a versatile organocatalyst.3a,4 How-ever, proline or other amino acids also suffer from in-herent drawbacks such as poor solubility in nonpolar solvents and difficulties in modulating reactivity through structure modifications. To address these prob-lems, the development of new organocatalysts has re-ceived much attention. Maruoka and coworkers5 re-ported a novel amino acid derived from optically pure binaphthol. Various amines, most of which are synthe-sized from optically pure proline, have also been em-ployed in the direct aldol reactions.3x,3y,6 Recently, Cheng7 developed a simple primary-tertiary diamine- Brønsted acid catalyst that has been successfully applied to direct aldol reactions, and this catalytic system was highly efficient for both linear and cyclic aliphatic ke-tones. Prolinamides have also received great success for their easy preparation and high efficiency.3m,3o-3q,8

Cinchonine-derived amines have been employed in asymmetric transformations.9 In our efforts toward the potential application of cinchonine-derived amines to organic transformations, we found the amine 1 in com-

bination with triflic acid to be an effective catalyst in direct aldol reactions. However, only cyclic ketones and electron deficient aldehydes were tolerated in our sys-tem.10 In studies of enamine catalysis, replacement of the carboxylate functionality greatly changed the effi-ciency of the catalyst. We conjectured that cin-chonine-based prolinamides might improve our methods. Herein, we report the logical extension of our previous work, that is, enantioselective direct aldol reactions catalyzed by prolinamide 2 (Figure 1) derived from cin-chonine and optically pure proline.

Figure 1 The catalysts used in the present work.

Experimental

Unless otherwise noted, materials were purchased from commercial suppliers and used without further purification. Cyclohexanone and acetone were freshly distilled. All solvents were purified according to stan-dard methods unless otherwise stated. 1H NMR and 13C NMR spectra were recorded on a Bruker-300 (300 MHz) spectrometer in CDCl3 unless otherwise stated. Chemi-cal shifts are reported with the solvent resonance as an internal standard (CDCl3, δ: 7.26). (s＝singlet, d＝doublet, t＝triplet, m＝multiplet or unresolved, brs＝broad singlet, coupling constant(s) in Hz, integration). 13C NMR chemical shifts are reported with the internal

Aldol reaction Chin. J. Chem., 2009 Vol. 27 No. 5 931


chloroform signal at δ＝77.0 as a standard. Mass spectra were obtained using an electrospray ionization (ESI) mass spectrometer. Chiral HPLC was performed on a Waters 2996 series instrument with chiral columns (Chirapak AD-H, AS-H, OJ-H columns, Daicel Chemi-cal Ind., Ltd.). Optical rotations were measured on a Perkin-Elmer 341 digital polarimeter and are reported as follows.

Preparation of catalyst 2

To a stirred solution of (S)-Boc-proline (0.946 g, 4.4 mmol) and Et3N (0.62 mL, 4.4 mmol) in dry THF (30 mL) was added ClCOOEt (0.42 mL, 4.4 mmol) in drops at 0 .℃ After 0.5 h, a solution of 9-amino-(9-deoxy)- epicinchonine (1.288 g, 4.2 mmol) in dry THF (10 mL) was added in drops. The resulting mixture was stirred at room temperature for 4 h. After the completion of the reaction (monitored by TLC), the solvent was evapo-rated. Water (20 mL) and DCM (20 mL) were sequen-tially added to the residue. The organic phase was sepa-rated and the aqueous solution was extracted with DCM (20 mL×3). The combined organic layer was washed with brine (20 mL) and dried over anhydrous Na2SO4. Removal of the solvent afforded the crude product which was directly submitted to the deprotection of the Boc group (12 mL of trifluruoacetic acid in 20 mL of CH2Cl2 at room temperature for 12 h). The reaction was quenched with water (20 mL), the organic phase was separated and the aqueous layer was extracted with DCM (20 mL×3). The combined organic layer was washed with brine, dried (Na2SO4) and purified by flash chromatography (DCM/MeOH, 10/1, V/V) affording the desired product as white solid in 87% yield. m.p. 174—176 ℃, 20

D[ ]α ＋90.0 (c 1.36, CHCl3); 1H NMR (300

MHz, CDCl3) δ: 8.83 (d, J＝4.5 Hz, 1H), 8.37 (d, J＝8.4 Hz, 2H), 8.09 (d, J＝8.4 Hz, 1H), 7.67 (t, J＝7.2 Hz, 1H), 7.56 (t, J＝7.4 Hz, 1H), 7.39 (d, J＝4.5 Hz, 1H), 5.81—5.92 (m, 1H), 5.37 (br, 1H), 5.04—5.11 (m, 2H), 3.63 (dd, J＝8.4, 5.7 Hz, 1H), 3.04—3.14 (m, 1H), 2.80—2.96 (m, 7H), 2.20—2.28 (m, 1H), 1.89—2.01 (m, 2H), 1.60—1.75 (m, 3H), 1.44—1.51 (m, 2H), 1.20—1.27 (m, 1H), 0.94—1.03 (m, 1H); 13C NMR (75 MHz, CDCl3) δ: 174.7, 149.9, 148.4, 147.1, 140.3, 130.2, 129.0, 127.2, 126.5, 123.5, 119.2, 114.7, 60.7, 59.6, 49.2, 47.1, 47.0, 39.3, 30.4, 27.3, 26.3, 25.9, 25.8, 25.7; IR (KBr) v: 3311, 3065, 2938, 2873, 1655, 1592, 910, 769 cm－1; HRMS (ESI-HRMS) calcd for (C24H30N4O＋H) 391.2498, found 391.2499.

General procedure for the direct aldol reaction

To a mixture of catalyst 2 (0.025 mmol) and TFA (0.025 mmol) was added ketone (1 mL). The reaction mixture was stirred for 5 min in a closed system and then aldehyde (0.25 mmol) was added. The reaction mixture was stirred for 9—166 h (monitored by TLC), quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (15 mL×3). The combined organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo. The crude

product was purified by flash column chromatography to give the pure aldol adduct. Diastereo-selectivities were determined by 1H NMR analysis of the crude aldol product.

4-Hydroxy-4-(4-nitrophenyl)butan-2-one (5a) Reaction time: 24 h, the crude product was purified by flash column chromatography (Vhexane/Vethyl acetate＝3/1) to give the pure aldol adduct, 79% yield, 93% ee, 20

D[ ]α＋62.5 (c 0.02, CHCl3);

1H NMR (300 MHz, CDCl3) δ: 8.20 (d, J＝8.8 Hz, 2H), 7.53 (d, J＝8.8 Hz , 2H), 5.26 (dd, J＝7.3, 4.9 Hz, 1H), 3.61 (br, 1H), 2.84—2.86 (m, 2H), 2.22 (s, 3H). HPLC analysis on Chiralcel AS-H (Vhexane/Vi-PrOH＝70/30, 1.0 mL/min, λ＝254 nm, 20

℃), tR(major)＝11.3 min and tR(minor)＝14.2 min.

4-Hydroxy-4-(2-nitrophenyl)butan-2-one (5b) Reaction time: 56 h; the crude product was purified by flash column chromatography (Vhexane/Vethyl acetate＝3/1) to give the pure aldol adduct, 79% yield, 91% ee, 20

D[ ]α －1.8 (c 0.46, CHCl3);

1H NMR (400 MHz, CDCl3) δ: 7.95 (dd, J＝8.2, 1.2 Hz, 1H), 7.89 (dd, J＝7.9, 1.2 Hz, 1H), 7.66 (t, J＝7.6 Hz, 1H), 7.44 (dd, J＝8.4, 1.4 Hz, 1H), 5.67 (dd, J＝9.4, 2.0 Hz, 1H), 3.79 (br, 1H), 3.11 (dd, J＝17.7, 3.4 Hz, 1H), 3.03 (dd, J＝17.7, 9.4 Hz, 1H), 2.23 (s, 3H). HPLC analysis on Chiralcel AS-H (Vhexane/Vi-PrOH＝7/3, 1.0 mL/min, λ＝254 nm, 20 ℃), tR(minor)＝6.5 min and tR(major)＝8.5 min.

4-Hydroxy-4-(3-nitrophenyl)butan-2-one (5c) Reaction time: 43 h; the crude product was purified by flash column chromatography (Vhexane/Vethyl acetate＝3/1) to give the pure aldol adduct, 79% yield, 90% ee, 20

D[ ]α＋59.3 (c 0.49, CHCl3);

1H NMR (400 MHz, CDCl3) δ: 8.21—8.23 (m, 1H), 8.09—8.12 (m, 1H), 7.69 (dd, J＝7.7, 4.8 Hz, 1H), 7.51 (t, J＝8.0 Hz, 1H), 5.25 (dd, J＝6.1, 2.1 Hz, 1H), 3.69 (br, 1H), 2.87 (d, J＝5.7 Hz, 2H), 2.21 (s, 3H). HPLC analysis on Chiralcel OJ-H (Vhexane/Vi-PrOH＝80/20, 1.0 mL/min, λ＝254 nm, 20

℃), tR(major)＝18.8 min and tR(minor)＝21.2 min.

4-Hydroxy-4-(4-(trifluoromethyl)phenyl)butan-2- one (5d) Reaction time: 48 h; the crude product was purified by flash column chromatography (Vhexane/ Vethyl acetate＝3/1) to give the pure aldol adduct, 69% yield, 87.5% ee, 20

D[ ]α ＋45.0 (c 0.48, CHCl3); 1H NMR

(300 MHz, CDCl3) δ: 7.59 (d, J＝8.1 Hz, 2H), 7.46 (dd, J＝8.1, 0.6 Hz, 2H), 5.19 (dd, J＝7.4, 4.8 Hz, 1H), 3.63 (br, 1H), 2.83 (t, J＝3.6 Hz, 2H), 2.19 (s, 3H). HPLC analysis on Chiralcel AS-H (hexane/i-PrOH＝80/20, 1.0 mL/min, λ＝220 nm, 20 ℃), tR(major)＝9.9 min and tR(minor)＝12.5 min.

4-(4-Chlorophenyl)-4-hydroxybutan-2-one (5e) Reaction time: 24 h, the crude product was purified by flash column chromatography (Vhexane/Vethyl acetate＝3/1) to give the pure aldol adduct, 79% yield, 95% ee, 20

D[ ]α＋109.3 (c 0.22, CHCl3);

1H NMR (300 MHz, CDCl3) δ: 7.62 (dd, J＝1.8, 1.2 Hz, 1H), 7.18—7.33 (m, 3H), 5.50 (dd, J＝9.6, 2.0 Hz, 1H), 3.56 (br, 1H), 2.98 (dd, J＝17.7, 2.0 Hz, 1H), 2.67 (dd, J＝17.7, 9.6 Hz, 1H), 2.21 (s, 3H). HPLC analysis on Chiralcel AS-H (Vhexane/Vi-PrOH＝10/1, 1.0 mL/min, λ＝220 nm, 20 ℃),

932 Chin. J. Chem., 2009, Vol. 27, No. 5 ZHAO, CHEN & LIU


tR(major)＝9.6 min and tR(minor)＝13.2 min. 4-Hydroxy-4-(4-cyanophenyl)butan-2-one (5f)

Reaction time: 72 h, the crude product was purified by flash column chromatography (Vhexane/Vethyl acetate＝3/1) to give the pure aldol adduct, 74% yield, 90% ee, 20

D[ ]α＋76.9 (c 0.03, CHCl3);

1H NMR (300 MHz, CDCl3) δ: 7.65 (dd, J＝8.3, 1.9 Hz, 2H), 7.48 (dd, J＝8.3, 4.8 Hz, 2H), 5.21 (dd, J＝7.1, 4.9 Hz, 1H), 3.32 (br, 1H), 2.83 (dd, J＝4.9, 2.4 Hz, 2H), 2.21 (s, 3H). HPLC analysis on Chiralcel AS-H (Vhexane/Vi-PrOH＝70/30, 1.0 mL/min, λ＝220 nm, 20 ℃), tR(major)＝8.0 min and tR(minor)＝13.5 min.

4-Hydroxy-4-(4-bromophenyl)butan-2-one (5g) Reaction time: 96 h; the crude product was purified by flash column chromatography (Vhexane/Vethyl acetate＝3/1) to give the pure aldol adduct, 41% yield, 89% ee, 20

D[ ]α＋52.8 (c 0.02, CHCl3);

1H NMR (300 MHz, CDCl3) δ: 7.44—7.48 (m, 2H), 7.21—7.26 (m, 2H), 5.11 (dd, J＝7.9, 4.4 Hz, 1H), 3.41 (br, 1H), 2.80—2.83 (m, 2H), 2.19 (s, 3H). HPLC analysis on Chiralcel AS-H (Vhexane/Vi-PrOH＝85/15, 1.0 mL/min, λ＝220 nm, 20 ℃), tR(major)＝7.0 min and tR(minor)＝8.3 min.

4-Hydroxy-4-p-tolylbutan-2-one (5h) Reaction time: 96 h, the crude product was purified by flash column chromatography (Vhexane/Vethyl acetate＝3/1) to give the pure aldol adduct, 34% yield, 86% ee, 20

D[ ]α ＋62.3 (c 0.02, CHCl3);

1H NMR (300 MHz, CDCl3) δ: 7.25 (d, J＝8.5 Hz, 2H), 7.16 (d, J＝8.3 Hz, 2H), 5.12 (dd, J＝9.0, 3.5 Hz, 1H), 3.59 (br, 1H), 2.76—2.93 (m, 2H), 2.34 (s, 3H), 2.18 (s, 3H). HPLC analysis on Chiralcel AS-H (Vhexane/Vi-PrOH＝85/15, 1.0 mL/min, λ＝220 nm, 20 ℃), tR(major)＝6.7 min and tR(minor)＝7.9 min.

2-(α-Hydroxy-p-nitrobenzy)cyclohexanone (5i) Reaction time: 30 h, the crude product was purified by flash column chromatography (Vhexane/Vethyl acetate＝5/1) to give the pure aldol adduct, 96% yield, 87% ee, anti/syn＝3.6/1; 1H NMR (300 MHz, CDCl3) δ: 8.18—8.23 (m, 2H), 7.48—7.53 (m, 2H), 4.89 (dd, J＝8.4, 3.1 Hz, 1H), 4.08 (d, J＝3.1 Hz, 1H), 2.35—2.59 (m, 3H), 2.09—2.10 (m, 1H), 1.78—1.87 (m, 1H), 1.53—1.61 (m, 3H), 1.30—1.40 (m, 1H). HPLC analysis on Chiralcel AD-H (Vhexane/Vi-PrOH＝95/5, 1.0 mL/min, λ＝254 nm, 20 ℃), tR(minor)＝53.0 min and tR(major)＝71.4 min, t'R(minor)＝47.9 min and t'R(major)＝36.8 min.

2-(α-Hydroxy-p-trifluorobenzy)cyclohexanone (5j) Reaction time: 47 h, the crude product was purified by flash column chromatography (Vhexane/Vethyl acetate＝15/1) to give the pure aldol adduct, 93% yield, 87% ee, anti/syn＝3.6/1; 1H NMR (300 MHz, CDCl3) δ: 7.61 (d, J＝8.1 Hz, 2H), 7.44 (d, J＝8.0 Hz, 2H), 4.84 (d, J＝8.6 Hz, 1H), 4.05 (br, 1H), 2.57—2.64 (m, 1H), 2.35—2.59 (m, 3H), 2.07—2.14 (m, 1H), 1.52—1.79 (m, 3H), 1.25—1.39 (m, 1H). HPLC analysis on Chiralcel AD-H (Vhexane/Vi-PrOH＝90/10, 0.5 mL/min, λ＝220 nm, 20 ℃), tR(minor)＝22.2 min and tR(major)＝28.0 min, t'R(minor)＝17.1 min and t'R(major)＝14.7 min.

2-(α-Hydroxy-o-chlorobenzy)cyclohexanone (5k) Reaction time: 119 h, the crude product was purified by

flash column chromatography (Vhexane/Vethyl acetate＝15/1) to give the pure aldol adduct. 85% yield, 81% ee, anti/syn＝3.4/1; 1H NMR (300 MHz, CDCl3) δ: 7.18—7.56 (m, 4H), 5.35 (d, J＝8.1 Hz, 1H), 4.05 (br, 1H), 2.66—2.68 (m, 1H), 2.33—2.45 (m, 2H), 2.07—2.08 (m, 1H), 1.54—1.83 (m, 5H). HPLC analysis on Chiralcel AD-H (Vhexane/Vi-PrOH＝90/10, 0.5 mL/min, λ＝220 nm, 20 ℃), tR(major)＝23.8 min and tR(minor)＝27.7 min, t'R(minor)＝13.4 min and t'R(major)＝14.8 min.

2-(α-Hydroxy-m-nitrobenzy)cyclohexanone (5l) Reaction time: 72 h, the crude product was purified by flash column chromatography (Vhexane/Vethyl acetate＝5/1) to give the pure aldol adduct, 96% yield, 85% ee, anti/syn＝1/1.4; 1H NMR (300 MHz, CDCl3) δ: 8.14—8.21 (m, 2H), 7.67 (d, J＝7.7 Hz, 1H), 7.53 (t, J＝7.9 Hz, 1H), 4.89 (dd, J＝8.5, 3.0 Hz, 1H), 4.12 (d, J＝3.1 Hz, 1H), 2.36—2.66 (m, 3H), 2.09—2.15 (m, 1H), 1.80—1.86 (m, 1H), 1.54—1.71 (m, 3H), 1.25—1.44 (m, 1H). HPLC analysis on Chiralcel AD-H (Vhexane/Vi-PrOH

＝95/5, 1.0 mL/min, λ＝254 nm, 20 ℃), tR(major)＝43.9 min and tR(minor)＝58.7 min, t'R(minor)＝39.1 min and t'R(major)＝34.9 min.

2-(α-Hydroxy-o-nitrobenzyl)cyclohexanone (5m) Reaction time: 107 h, the crude product was purified by flash column chromatography (Vhexane/Vethyl acetate＝7/1) to give the pure aldol adduct, 94% yield, 90% ee, anti/syn＝1/2.1; 1H NMR (300 MHz, CDCl3) δ: 7.84 (d, J＝8.2 Hz, 1H), 7.76 (d, J＝7.8 Hz, 1H), 7.63 (t, J＝7.4 Hz, 1H), 7.42 (t, J＝7.4 Hz, 1H), 5.44 (d, J＝7.1 Hz, 1H), 3.80 (br, 1H), 2.71—2.79 (m, 1H), 2.28—2.47 (m, 2H), 2.06—2.12 (m, 1H), 1.82—1.86 (m, 1H), 1.52—1.79 (m, 4H). HPLC analysis on Chiralcel AD-H (Vhexane/Vi-PrOH＝90/10, 1.0 mL/min, λ＝254 nm, 20

℃), tR(major)＝20.2 min and tR(minor)＝21.9 min. The other enantiomers are not determination.

Results and discussion

The organocatalyst 2 was readily prepared from op-tically pure amine 1; the readily available amine 1 or its pseudo-enantiomer was condensed with Boc-protected proline followed by the deprotection with TFA, which afforded the optically pure amine 2 in an 87% yield (two steps).

The catalyst 2 was firstly employed in the direct al-dol reaction of 4-nitrobenzaldehyde with acetone (Table 1), which proceeded smoothly in 72% yield and 63% ee when 10 mol% of catalyst 2 was used (Entry 1) at room temperature. However, 84% ee was observed when the reaction was conducted in the presence of TFA (10 mol%, Entry 2). Various acids were further investigated and the results were listed in Table 1 (Entries 3—8). Among the acids surveyed, trifluoroacetic acid was the best of the choice (Entry 2). Only 65% ee was obtained when 10 mol% triflic acid was employed. Acetic acid and chloro substituted acids gave less desired outcomes. Benzoic acid gave only 17% ee under the identical con-ditions. These results indicate that the acidity and the amount of the acids had considerable effects on the re-



activity of the catalyst. For example, 5 mol% of trifluoroacetic acid afforded 84% yield with ee un-changed, while the yield and ee decreased significantly when the amount of acid was increased to 15 mol% (Entries 9, 10). Apparently, more acid led to the forma-tion of the ammonium salt of 2, retarding the formation of enamine, and thus decelerating the aldol reaction (En-tries 2 vs. 9—11).

Table 1 Reactions between p-nitrobenzaldehyde and acetone

Entry Acid Time/h Yielda/% ee b/%

1 — 12 72 63

2c TFA 7.5 91 84

3c TfOH 31 11 65

4c AcOH 11 82 37

5c ClCH2COOH 8 92 62

6c Cl3CCOOH 22 86 56

7c PhCOOH 6.5 94 17

8c TsOH 10 93 77

9d TFA 5.5 84 84

10e TFA 48 31 78

11 f TFA 48 24 72 a Isolated yield; b determined by chiral HPLC; c 10 mol% of acid used unless otherwise stated; d 5 mol% of TFA used; e 15 mol% of TFA used; f 20 mol% of TFA used.

Next, we fixed the amount of TFA at 10 mol% and screened the effects of solvents (Table 2). The reaction proceeded very slowly in DMSO and DCM in low yields and ee values. Other solvents showed less desired yields and enantioselectivities than the neat condition. The neat condition (using acetone as solvent) was thus chosen in terms of enantioselectivity and yield of the reaction.

Table 2 Effects of solvent

Entry Solvent Time/h Yield/% ee/%

1 Neat 5.5 91 84

2 CH2Cl2 48 79 59

3 THF 10 62 60

4 H2O 4 82 37

5 DMSO 70 Trace —

6 DMF 9 74 75

7 CH3CN 12 79 75

8 CHCl3 11 84 61

We then investigated the effects of temperature on the reaction (Table 3). When the reaction was carried out at －18 ℃, we obtained 93% ee (Entry 4, Table 3). However, the enantioselectivity dropped to 91% when the reaction was carried out at －40 ℃. Generally, the enantioselectivities of reaction only slightly depended on the reaction temperature (Entries 1—5). To our sur-prise, 95% ee was obtained when 5 mol% of catalyst was used in the presence of 5 mol% of TFA, albeit in a low yield and requiring a long reaction time (Entry 6). In terms of yield, reaction time, and enantioselectivities, 10 mol% of catalyst in combination with 10 mol% of trifluoroacetic acid, ketone as solvent, and －18 ℃ were chosen as the optimal conditions.

Table 3 Effects of temperaturea

Entry Temperature/℃ Time/h Yield/% ee/%

1 r.t. 5.5 91 84

2 15 10 84 84

3 0 11 79 88

4 －18 24 79 93

5 －40 46 62 91

6b －18 30 67 95

7c －18 22 89 93

8d －18 21 67 89 a 10 mol% of catalyst in combination with 10 mol% of trifluoroacetic acid was used unless otherwise stated. b 5 mol% of catalyst used; c 15 mol% of catalyst used; d 20 mol% of catalyst used.

With the optimal conditions in hand, the scope of the reaction with regard to variation of the aryl substituents of aldehydes was investigated (10 mol% of catalyst, 10 mol% of TFA and neat conditions, Table 4). Elec- tron-withdrawing substituents in the aromatic ring al-lowed for good yields and enantioselectivities. For ex-ample, 3- and 2-nitrobenzaldehydes afforded high yields and ee (Entries 2, 3). Electron enriched aldehydes such as 4-methylbenzaldehyde afforded low yield (34%), but with good enantioselectivity. Electron enriched alde-hydes such as 4-methoxybenzaldehyde were not good substrates under the optimal conditions. Next cyclohex-anone was investigated, which provided the corre-sponding products in high yields with moderate enanti-oselectivities and good diastereoselectivities. For exam-ple, cyclohexanone was reacted with p-nitrobenzaldehyde affording the corresponding product in an ex-cellent yield with 86% ee and the trans-isomer was fa-vorably formed with 3.4/1 de in the presence of 10 mol% catalyst in combination with 10 mol% triflic acid



(Entry 9, Table 4). The aldehydes with electron-withdrawing substituents at the o-, m- or p-position of the aromatic ring all afforded high yields and good enanti-oselectivities. It is noteworthy that 3-nitrobenzaldehyde and 2-nitrobenzaldehyde were reacted with cyclohexa-none providing syn products with 1.4 and 2.1 de, re-spectively (Entries 12, 13).

To elucidate the effects of the structure of the cata-lysts on the enantioselectivities of the reaction, we also synthesized catalyst 6, which was derived from L-proline and cinchonidine, a pseudo-enantiomer of cinchonine. When the catalyst 6 was applied to the di-rect aldol reaction of nitrobenzaldehyde acetone, the same enantiomer was obtained with only 74% ee. Thus the chiralities of both proline and the cinchonine struc-ture affected the enantioselectivities. From the results, the configuration of the aldol product stems from the structure of the proline motif and the enantioselectivities depend greatly on the structure of the cinchonine deriva-tive used in the catalysts. When the chirality of the proline matched that of the cinchona, high enantioselec-tivity was observed. Based on these observations,11 a plausible transition state was proposed (Figure 2).

In the transition state, acetone was condensed with the proline motif forming the enamine and the nitrobenzaldehyde was activated by formation of a

Figure 2 A plausible transition state in the aldol reaction.

hydrogen bond to the hydrogen of the amide nitrogen atom. As a result, the enamine attacks from the re-face of the aldehyde, yielding the corresponding R-product.

Conclusion

We have demonstrated an enantioselective aldol re-action catalyzed by readily prepared cinchonine-based prolinamides. The absolute configuration of the proline motif in the catalyst dictated the absolute configuration of the aldols. High enantioselectivities were observed when their chiralities matched. Under optimal condi-tions, aldehydes with electron-withdrawing substituents were reacted with acetone and cyclohexanone, affording the corresponding products in good yields and with good to excellent enantioselectivities.

Table 4 Reactions between aldehyde and ketone

Entry Compd. Aldehyde Ketonea Yield/% ee/%

1 5a 4-Nitrobenzaldehyde Acetone 79 93

2 5b 2-Nitrobenzaldehyde Acetone 89 91

3 5c 3-Nitrobenzaldehyde Acetone 81 90

4 5d 4-Trifluoromethylbenzaldehyde Acetone 69 88

5 5e 2-Chlorobenzaldehyde Acetone 76 95

6 5f 4-Cyanobenzaldehyde Acetone 74 90

7 5g 4-Bromobenzaldehyde Acetone 41 89

8 5h 4-Methylbenzaldehyde Acetone 34 86

9 5i 4-Nitrobenzaldehyde Cyclohexanone 86 87,10 (3.4/1)

10 5j 4-Trifluoromethylbenzaldehyde Cyclohexanone 93 87,4 (3.6/1)

11 5k 2-Chlorobenzaldehyde Cyclohexanone 85 81,54 (3.4/1)

12 5l 3-Nitrobenzaldehyde Cyclohexanone 96 4,85 (1/1.4)

13 5m 2-Nitrobenzaldehyde Cyclohexanone 94 90,nd (1/2.1) a Unless otherwise stated, the reaction was carried out with 0.25 mmol of substituted benzaldehyde and 13.6 or 9.6 mmol of acetone or cyclohexanone, respectively. The enantioselectivity was measured using chiral HPLC, de was measured according to 1H NMR of crude product, and the absolute configuration of product was assigned as R by comparison of retention time or optical rotations.5a,5e

References

1 (a) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem.

Rev. 2007, 107, 5471. (b) Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc. 1990, 112, 7001.



(c) Enders, D.; Grondal, C. Angew. Chem., Int. Ed. 2005, 44, 1210. (d) Ibrahem, I.; Zou, W.; Xu, Y.; Córdova, A. Adv. Synth. Catal. 2006, 348, 211. (e) Enders, D.; Voith, M.; Lenzen, A. Angew. Chem., Int. Ed. 2005, 44, 1304. (f) Suri, J. T.; Ramachary, D. B.; Barbas, C. F., III. Org. Lett. 2005, 7, 1383.

2 For reviews of enantioselective organocatalysis see: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 113, 3726. (b) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (c) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520.

3 (a) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123, 5260. (b) Saito, S.; Nakadai, M.; Yamamoto, H. Synlett 2001, 1245. (c) Krattiger, P.; McCarthy, C.; Pfaltz, A.; Wennemers, H. Angew. Chem., Int. Ed. 2003, 42, 1722. (d) Kofoed, J.; Nielsen, J.; Reymond, J.-L. Bioorg. Med. Chem. Lett. 2003, 13, 2445. (e) Cobb, A. J. A.; Shaw, D. M.; Ley, S. V. Synlett 2004, 558. (f) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew. Chem., Int. Ed. 2004, 43, 1983. (g) Lacoste, E.; Landais, Y.; Schenk, K.; Verlhac, J.-B.; Vincent, J.-M. Tetrahedron Lett. 2004, 45, 8035. (h) Berkessel, A.; Koch, B.; Lex, J. Adv. Synth. Catal. 2004, 346, 1141. (i) Mangion, I. K.; Northrup, A. B.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2004, 43, 6722. (j) Shi, L.-X.; Sun, Q.; Ge, Z.-M.; Zhu, Y.-Q.; Cheng, T.-M.; Li, R.-T. Synlett 2004, 2215. (k) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84. (l) Wang, W.; Li, H.; Wang, J. Tetrahedron Lett. 2005, 46, 5077. (m) Chimni, S. S.; Mahajan, D.; Babu, V. V. S. Tetrahedron Lett. 2005, 46, 5617. (n) Bellis, E.; Kokotos, G. Tetrahedron 2005, 61, 8669. (o) Chen, J.-R.; Lu, H.-H.; Li, X.-Y.; Cheng, L.; Wan, J.; Xiao, W.-J. Org. Lett. 2005, 7, 4543. (p) Samanta, S.; Liu, J.; Dodda, R.; Zhao, C.-G. Org. Lett. 2005, 7, 5321. (q) Gryko, D.; Lipinski, R. Adv. Synth. Catal. 2005, 347, 1948. (r) Silva, F.; Sawicki, M.; Gouverneur, V. Org. Lett. 2006, 8, 5417. (s) Guillena, G.; Hita, M. C.; Njera, C. Tetrahedron: Asym-metry 2006, 17, 729. (t) Raj, M.; Vishnumaya; Ginotra, S. K.; Singh, V. K. Org. Lett. 2006, 8, 4097. (u) Gryko, D.; Kowlaczyk, B.; Zawadzki, L. Synlett 2006, 1059. (v) Cheng, C.; Sun, J.; Wang, C.; Zhang, Y.; Wei, S.; Jiang, F.; Wu, Y. Chem. Commun. 2006, 215. (w) Gu, L.; Yu, M.; Wu, X.; Zhang, Y.; Zhao, G. Adv. Synth. Catal. 2006, 348, 2223.

(x) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 734. (y) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 958. (z) Gu, Q.; Jiang, L. X.; Wang, Q.; Wu, X. Chin. J. Org. Chem. 2008, 28, 1416 (in Chinese).

4 (a) List, B.; Lerner, R. A.; Barbas III, C. F. J. Am. Chem. Soc. 2000, 122, 2395. (b) Corvoda, A.; Zhou, B.; Ibrahem, I.; Reyes, E.; Engqvist, M.; Liao, W.-W. Chem. Commun. 2005, 3586. (c) Jiang, Z.; Liang, Z.; Wu, X.; Lu, Y. Chem. Commun. 2006, 2801. (d) Corvoda, A.; Zhou, B.; Dziedzic, P.; Ibrahem, I.; Reyes, E.; Xu, Y. Chem. Eur. J. 2006, 12, 5385. (e) List, B. Synlett 2001, 1675. (f) Gröger, H.; Wilken, J. Angew. Chem., Int. Ed. 2001, 40, 529. (g) Movassaghi, M.; Jacobsen, E. N. Science 2002, 298, 582. (h) Paraskar, A. S. Synlett 2003, 582. (i) List, B. Chem. Commun. 2006, 819.

5 (a) Kano, T.; Takai, J.; Tokuda, O.; Maruoka, K. Angew. Chem., Int. Ed. 2005, 44, 3055. (b) Kano, T.; Tokuda, O.; Maruoka, K. Tetrahedron Lett. 2006, 47, 7423.

6 (a) Hayashi, Y.; Sekizawa, H.; Yamagushi, J.; Gotoh, H. J. Org. Chem., 2007, 72, 6493. (b) Davies, S. G.; Sheppard, R. L.; Smith, A. D.; Thoson, J. E. Chem. Commun. 2005, 3802. (c) Tang, Z.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Org. Lett. 2006, 8, 1263.

7 (a) Luo, S.-Z.; Xu, H.; Li, J.-Y.; Zhang, L.; Cheng, J.-P. J. Am. Chem. Soc. 2007, 129, 3074. (b) Luo, S.; Li, Y.; Xu, H.; Cheng, J.-P. Chem. Eur. J. 2008, 14, 1273.

8 (a) Tang, Z.; Jiang, F.; Yu, L.-T.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003, 125, 5262. (b) Tang, Z.; Jiang, H.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Ji-ang, Y.-Z.; Wu, Y.-D. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5755. (c) Guo, H.-M.; Cun, L.-F.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z. Chem. Commun. 2005, 1450. (d) 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, 9285. (e) He, L.; Tang, Z.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Tetrahedron 2006, 62, 346. (f) Jiang, M.; Zhu, S.-F.; Yang, Y.; Gong, L.-Z.; Zhou, X.-G.; Zhou, Q.-L. Tetrahedron: Asymmetry 2006, 17, 384. (g) Tang, Z.; Marx, A. Angew. Chem., Int. Ed. 2007, 46, 7297.

9 (a) Brunner, H.; Bugler, J.; Nuber, B. Tetrahedron: Asymme-try 1995, 7, 1699. (b) Xie, J.-W.; Chen, W.; Li, R.; Zeng, M.; Du, W.; Yue, L.; Chen, Y.-C.; Wu, Y.; Zhu, J.; Deng, J.-G. Angew. Chem., Int. Ed. 2007, 46, 389. (c) Xie, J.-W.; Yue, L.; Chen, W.; Du, W.; Zhu, J.; Deng,



J.-G.; Chen, Y.-C. Org. Lett. 2007, 9, 413. (d) Connon, S. J.; McCooey, S. H. Org. Lett. 2007, 9, 599. (e) Bartoli, G.; Bosco, M.; Carlone, A.; Pesciaioli, F.; Sambri, L.; Melchiorre, P. Org. Lett. 2007, 9, 1403. (f) Mase, N.; Tanaka, F.; Barbas III, C. F. Org. Lett. 2003, 5, 4369.

10 Zheng, B.-L.; Liu, Q.-Z.; Guo, C.-S.; Wang, X.-L.; He, L. Org. Biomol. Chem. 2007, 5, 2913.

11 (a) Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am.

Chem. Soc. 2003, 125, 2475. (b) Rankin, K. N.; Gauld, J. W.; Boyd, R. J. J. Phys. Chem. A 2002, 106, 5155. (c) Bahmanyar, S.; Houk, K. N. Org. Lett. 2003, 5, 1249. (d) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123, 12911. (e) Calderoń, F.; Doyaguëz, E. G.; Cheong, P. H.; Fernańdez-Mayoralas, A.; Houk, K. N. J. Org. Chem. 2008, 73, 7916.

(E0804162 Lu, Y.)

Documents

Enantioselective Direct Aldol Reactions Catalyzed by Cinchonine-derived Prolinamides