A Series of New C2-symmetric Amino Alcohols withMulticoordination Groups: Promising Catalysts for

Synthesis of Both Enantiomers in the Borane-MediatedReduction of Prochiral Ketones

YAN ZHOU,1 YA-WEN WANG,1 WEI DOU,1 DONG ZHANG,1 AND WEI-SHENG LIU1,2*1College of Chemistry and Chemical Engineering and State Key Laboratory of Applied Organic Chemistry,

Lanzhou University, Lanzhou 730000, People’s Republic of China2State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing 210093, China

ABSTRACT A series of new C2-symmetric amino alcohols with multicoordinationgroups have been synthesized and successfully applied as catalysts in the borane asym-metric reduction of prochiral ketones in refluxing toluene, providing the correspondingsecondary alcohols with up to 90% ee. An unusual temperature-dependent reversal ofstereochemistry was also observed. Chirality 21:657–662, 2009. VVC 2008 Wiley-Liss, Inc.

KEY WORDS: C2-symmetric; amino alcohols; prochiral ketones; reversal; reduction

INTRODUCTION

Catalytic reductions with boron-containing Lewis acidshave been thoroughly investigated,1–4 and occupy a spe-cial place in the history of asymmetric reduction of prochi-ral ketones for obtaining enantiomerically pure secondaryalcohols.5,6 In fact, since the introduction of the first struc-turally more rigid (S)-proline-based b-amino alcohol byItsuno et al. in 1981,7 the study of catalysts derived fromprolinol remains an active research area. New derivativessuch as sulfonyl prolinol,8 polymer-supported sulfona-mide,9 imidazolium-tagged sulfonamide,10 phosphina-mides,11 squaric prolinols,12–14 amides15, polymer-sup-ported prolinol16, and N-alkyl prolinols17 have beenreported and good enantioselectivities were obtained. Cat-alysts with C2-symmetry have also received much attentionand have been successfully applied in the borane-mediatedreduction.18–21 To develop versatile chiral catalysts, weherein reported the synthesis of prolinol-based C2-symmet-ric amino alcohols with multicoordination groups and theirapplication in the catalytic borane-mediated reduction ofprochiral ketones.

EXPERIMENTAL SECTIONGeneral Methods

Melting points were taken on an X-6 melting point appa-ratus and the data were uncorrected. IR spectra wereobtained on a Nicolet FT-170SX spectrometer with KBrdisc. 1H NMR and 13C NMR spectra were recorded on aDRX-300 MHz spectrometer with tetramethylsilane (TMS)serving as internal standard. Electron ionization massspectra were obtained on a Hewlett-Packard HP5988Amass spectrometer. ESI-MS was recorded on a Mariner1

biospectrometer. HRMS data were measured with ESItechniques (Bruker Apex II). Elemental analyses were car-

ried out on an Elementar Vario EL instrument. Opticalrotations were measured on a Perkin–Elmer 341 Polarime-ter. The ee value determination was carried out using chi-ral HPLC on Daicel Chiralcel1 OD-H, OB-H, AD-H andOJ-H columns with a Waters1 996 UV-detector. The abso-lute configuration of the major enantiomer was assignedaccording to the sign of the specific rotation. All reactionswere carried out under an argon atmosphere. THF and tol-uene was dried over sodium and freshly distilled beforeuse. Borane-dimethyl sulfide was obtained from Acros.

Preparation of the Chiral Ligands 5-9

1,4-bis(Bromomethyl)-2,3-dimethoxynaphthalene 1:Compound 1 was prepared according to the literature22 asa colorless prism in 70% yield; mp 187–1888C (literature22

mp 1898C); 1H NMR (300 MHz, CDCl3): d 8.07–8.04 (dd, J5 3.6, 6.6 Hz, 2H), 7.60–7.57 (dd, J 5 3.6, 6.6 Hz, 2H),5.03 (s, 4H), 4.04 (s, 6H); 13C NMR (75 MHz, CDCl3): d150.49 129.12, 127.22, 126.19, 124.04, 60.94, 23.92; MS(EI): m/z: 374 (M1).

1,4-bis(Bromomethyl)-2,3-diethoxynaphthalene 2: Com-pound 2 was prepared according to the literature22 as acolorless prism in 78% yield; mp 144–1468C (literature22

mp 1508C dec.); 1H NMR (300 MHz, CDCl3): d 8.07–8.04

*Correspondence to: W.-S. Liu, College of Chemistry and Chemical Engi-neering and State Key Laboratory of Applied Organic Chemistry, LanzhouUniversity, Lanzhou 730000, People’s Republic of China.E-mail: liuws@lzu.edu.cn

Contract grant sponsor: College of Chemistry and Chemical Engineeringand State Key Laboratory of Applied Organic Chemistry, Lanzhou Univer-sity, China.Contract grant sponsor: NSFC; Contract grant numbers: 20431010,20621091, 20771048, J0630962.

Received for publication 8 April 2008; Accepted 16 July 2008DOI: 10.1002/chir.20652Published online 30 October 2008 in Wiley InterScience(www.interscience.wiley.com).

CHIRALITY 21:657–662 (2009)

VVC 2008 Wiley-Liss, Inc.

(dd, J 5 3.3, 6.6 Hz, 2H), 7.59–7.55 (dd, J 5 3.3, 6.6 Hz,2H), 5.05 (s, 4H), 4.24 (q, J 5 7.5 Hz, 4H), 1.50 (t, J 5 7.5Hz, 6H); 13C NMR (75 MHz, CDCl3): d 149.84, 129.11,127.18, 126.04, 124.11, 69.46, 24.34, 15.92; MS (EI): m/z:402 (M1).

1,4-bis(Bromomethyl)-2,3-di-n-butoxynaphthalene 3:Compound 3 was prepared according to the literature22 asa colorless prism in 74% yield; mp 89–918C (literature22

mp 93–948C dec.); 1H NMR (300 MHz, CDCl3): d 8.07–8.03 (m, 2H), 7.60–7.54 (m, 2H), 5.04 (s, 4H), 4.16 (q, J 56.6 Hz, 4H), 1.92–1.83 (m, 4H), 1.65–1.55 (m, 4H), 1.03 (t,J 5 7.5 Hz, 6H); 13C NMR (75 MHz, CDCl3): d 105.10,129.17, 127.13, 126.00, 124.10, 73.70, 32.51, 24.32, 19.31,14.02; MS (EI): m/z: 458 (M1).

(S)-a,a-Diphenyl-2-pyrrolidinemethanol 4: Compound 4was prepared according to the literature procedures 23,24

in 65% overall yield as a colorless solid. [a]D20 5 255

(c 0.33, CH3OH) [literature23 [a]D21 5 254.3 (c 0.261,

CH3OH)]; mp 77–788C [literature23 mp 79–79.58C]; 1HNMR (300 MHz, CDCl3): d 1.54–1.67 (m, 2H ), 1.69–1.79(m, 2H ), 2.91–3.07 (m, 2H), 4.26 (t, J 5 7.5Hz, 1H),7.14–7.19 (m, 2H), 7.25–7.32 (m, 4H), 7.50 (d, J 5 8.1Hz, 2H), 7.58 (d, J 5 8.1 Hz, 2H); MS (ESI): m/z:254.2[M11]1.

1,4-bis[(2S)-(Hydroxydiphenylmethyl)-pyrrolidin-1-ylmethyl]-2,3-dialkoxynaphthalene 5–7; General Procedure: Dibro-mide (1 mmol) was added in one portion to a stirred andcooled solution of (S)-a,a-diphenyl-2-pyrrolidinemethanol4 (506 mg, 2 mmol) and K2CO3 (276 mg, 2 mmol) in dryDMF (10 ml). The ice bath was removed after the addi-tion, and the resulting mixture was allowed to stir at roomtemperature for 12 h before it was diluted with water(50 ml). The white precipitate was filtered, dried in vacuo,and purified by column chromatography on silica gel(EtOAc-Pet ether 5 1:30).

1,4-bis[(2S)-(Hydroxydiphenylmethyl)-pyrrolidin-1-ylmethyl]-2,3-dimethoxynaphthalene 5: White solid; yield: 84%; mp215–2178C; [a]D

20 5 160 (c 0.265, CHCl3); IR (KBr):3335, 2933, 2852, 1452, 1379, 1281, 1191, 1103, 1040, 752,705 cm21; 1H NMR (300MHz, CDCl3): d 8.01 (d, J 5 8.1Hz, 4H), 7.64 (d, J 5 8.1Hz, 4H), 7.50–7.47 (m, 2H),7.42–7.28 (m, 6H), 7.19–7.14 (m, 4H), 4.89 (br s, 2H),4.23, 4.20 (dd, J 5 4.8, 9.0 Hz, 2H), 3.96, 3.62 (AB sys-tem, J 5 11.4 Hz, 4H), 3.82 (s, 6H), 2.66–2.57 (m, 2H),2.49–2.42 (m, 2H), 1.99–1.89 (m, 2H), 1.72–1.63 (m, 2H),1.55–1.43 (m, 4H); 13C NMR (75 MHz, CDCl3): d 150.59,148.51, 147.03, 129.89, 128.22, 128.08, 126.90, 126.65,126.06, 125.87, 125.13, 124.63, 77.94, 71.44, 60.80, 53.37,30.03, 23.82; HRMS (ESI): M1H1, 719.3843; Found,719.3846.

1,4-bis[(2S)-(Hydroxydiphenylmethyl)-pyrrolidin-1-ylmethyl]-2,3-diethoxynaphthalene 6: White solid; yield: 85%; mp124–1258C; [a]D

20 5 149 (c 0.275, CHCl3); IR (KBr): 3393,2969, 2866, 1442, 1377, 1280, 1100, 1037, 752, 705 cm21;1H NMR (300 MHz, CDCl3): d 7.99 (d, J 5 7.8 Hz, 4H),7.63 (d, J 5 8.1 Hz, 4H), 7.40–7.25 (m, 12H), 7.17–7.12 (m,4H), 4.82 (br s, 2H), 4.22–4.12 (m, 4H), 3.96, 3.59 (AB sys-tem, J 5 11.7 Hz, 4H), 3.79–3.74 (dd, J 5 6.9, 8.7 Hz, 2H),2.67–2.59 (m, 2H), 2.46–2.39 (m, 2H), 1.97–1.90 (m, 2H),1.68–1.45 (m, 6H), 1.40 (t, J 5 6.9 Hz, 6H); 13C NMR (75

MHz, CDCl3): d 149.81, 148.51, 146.98, 129.89, 128.20,128.06, 127.12, 126.67, 126.04, 125.89, 125.23, 125.12,124.53, 77.98, 71.65, 69.29, 53.88, 50.79, 30.07, 23.89, 15.83;HRMS (ESI): M1H1, 747.4156; Found, 747.4165.

1,4-bis[(2S)-(Hydroxydiphenylmethyl)-pyrrolidin-1-ylmethyl]-2,3-di-n-butoxynaphthalene 7: White solid; yield: 87%; mp86–878C; [a]D

20 137 (c 0.285, CHCl3); IR (KBr): 3412, 2952,2867, 1444, 1435, 1372, 1280, 1185, 1109, 1068, 1025, 750,702 cm21; 1H NMR (300 MHz, CDCl3): d 8.00 (d, J 5 7.8Hz, 4H), 7.64 (d, J 5 6.6 Hz, 4H), 7.41–7.36 (m, 6H), 7.32–7.26 (m, 6H), 7.16 (t, J 5 6.9 Hz, 4H), 4.83 (br s, 2H),4.20–4.12 (m, 4H), 3.96 (d, J 5 11.7 Hz, 2H), 3.64–3.58 (m,4H), 2.69–2.61 (m, 2H), 2.45–2.42 (m, 2H), 1.97–1.83 (m,2H), 1.81–1.73 (m, 4H), 1.67–1.46 (m, 10H), 1.05 (t, J 57.5 Hz, 6H); 13C NMR (75 MHz, CDCl3): d 150.06, 148.55,147.00, 129.94, 128.21, 128.05, 127.00, 126.67, 125.90,125.15, 124.53, 77.93, 73.57, 71.78, 53.80, 50.74, 32.49,30.12, 23.90, 19.45, 14.08; HRMS (ESI): M1H1, 803.4782;Found, 803.4785.

Amino alcohol catalysts 8 and 9: General Procedure: 1-Bromomethyl-2-n-butoxynaphthalene or 1-bromomethyl-naphthalene (2 mmol) was added in one portion to astirred and cooled solution of (S)-a,a-diphenyl-2-pyrrolidi-nemethanol 4 (506 mg, 2 mmol) and K2CO3 (276 mg,2 mmol) in dry DMF (10 ml). The ice bath was removedafter the addition and the resulting mixture was allowed tostir at room temperature for 12 h before it was diluted withwater (50 ml). The white precipitate was filtered, dried invacuo, and purified by column chromatography on silicagel (EtOAc-Pet ether).

1-[(2S)-(Hydroxydiphenylmethyl)-pyrrolidin-1-ylmethyl]-2-n-butoxynaphthalene 8: White solid; yield: 86%; mp 96–978C. [a]D

20 5 147 (c 0.395, CHCl3); IR (KBr): 3335, 2964,2934, 2868, 1624, 1596, 1511, 1462, 1367, 1273, 1238, 1075,811, 748, 702 cm21; 1H NMR (300 MHz, CDCl3): d 7.99 (d,J 5 8.1 Hz, 2H), 7.70–7.62 (m, 4H), 7.48 (d, J 5 8.7 Hz,1H), 7.38–7.24 (m, 6H), 7.19–7.11 (m, 3H), 5.01 (br s, 1H),4.22–4.17 (dd, J 5 5.4, 9.0 Hz, 1H), 4.11–3.99 (m, 3H), 3.58(d, J 5 11.7 Hz, 1H), 2.70–2.62 (m, 1H), 2.55–2.52 (m, 1H),1.96–1.89 (m, 1H), 1.85–1.78 (m, 2H), 1.70–1.47 (m, 5H),1.03 (t, J 5 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d154.64, 148.70, 147.17, 133.48, 128.96, 128.80, 128.16,128.03, 127.94, 126.54, 125.92, 125.19, 124.55, 123.28,120.26, 114.06, 77.85, 71.55, 68.80, 53.74, 49.69, 31.73,30.10, 23.82, 19.42, 13.95; MS (ESI): m/z: 466.2[M1H]1;Anal. Calcd. for C32H35NO2: C, 82.54; H, 7.58; N, 3.01;Found: C, 82.30; H, 7.38; N, 2.97.

1-[(2S)-(Hydroxydiphenylmethyl)-pyrrolidin-1-ylmethyl]-naphthalene 9: White solid; yield: 85%; mp 124–1258C.[a]D

20 5 162 (c 0.265, CHCl3); IR (KBr): 3298, 3058, 2962,2878, 2806, 1596, 1491, 1446, 1383, 1111, 1033, 878, 792,770, 704 cm21; 1H NMR (300 MHz, CDCl3): d 7.90 (d, J 56.9 Hz, 2H), 7.78 (d, J 5 8.7 Hz, 1H), 7.71 (d, J 5 8.7 Hz,1H), 7.62 (d, J 5 7.8 Hz, 3H), 7.46–7.23 (m, 8H), 7.18–7.06(m, 2H), 4.88 (br s, 1H), 4.17–4.12 (dd, J 5 4.8, 9.6 Hz,1H), 3.93, 3.51 (AB system, J 5 12.9 Hz, 2H), 2.67–2.61(m, 1H), 2.49–2.40 (m, 1H), 2.03–1.89 (m, 1H), 1.77–1.68(m, 1H), 1.62–1.52 (m, 2H); 13C NMR (75 MHz, CDCl3): d148.24, 146.89, 135.34, 133.56, 131.79, 128.29, 128.20,128.11, 127.78, 127.14, 126.59, 126.15, 125.75, 125.54,

658 ZHOU ET AL.

Chirality DOI 10.1002/chir

125.26, 125.06, 124.48, 78.07, 71.44, 59.24, 55.55, 29.81,23.99; MS (ESI): m/z: 394.2[M1H]1; Anal. Calcd. forC28H27NO: C, 85.46; H, 6.92; N, 3.56; Found: C, 85.31; H,6.66; N, 3.31.

Typical Procedure for the Reduction ofProchiral Ketones

BH3�SMe2 (0.3 ml, 2 M) was added dropwise to a solu-tion of 7 (0.05 mmol) in dry toluene (3 ml) under argon at08C. The resulting solution was warmed to the specifiedtemperature, and then stirred for another 1 h. A solutionof the ketone (0.5 mmol) in dry toluene (3 ml) was addeddropwise over a period of 1 h. After reacting for another1 h, the reaction mixture was cooled and decomposed bydropwise addition of MeOH (5 ml). When gas emissionceased, the solvent was evaporated and the product waspurified by column chromatography on silica gel (petro-leum ether/ethyl acetate 8:1) to afford the correspondingsecondary alcohol. The enantiomeric excesses were deter-mined by HPLC with chiral columns.

RESULTS AND DISCUSSION

A series of new C2-symmetric amino alcohols 5–7 withmulticoordination groups were easily prepared from N-alkylation of (S)-a,a-diphenyl-2-pyrrolidinemethanol23,24 4(Scheme 1). Treatment of (S)-a,a-diphenyl-2-pyrrolidine-methanol 4 with 1,4-bis(bromomethyl)-2,3-dialkoxynaph-thalene 1–3 using K2CO3 as base in DMF afforded thecorresponding chiral prolinol derivatives 5–7 as whitesolid in 84–87% yields. Dibromides 1–3 were synthesizedaccording to the literature procedures22 in 70–78% yields.

Initially, the C2-symmetric ligands 5–7 were evaluatedin the asymmetric reduction of acetophenone using a bor-ane complex generated in situ in THF at reflux for 1 h. Asthe results summarized in Table 1 (entries 1–3) show,ligand 7, which possesses more flexible substituent at theoxygen atom, gave a higher enantioselectivity. Ligand 7was selected and the reduction of acetophenone was fur-ther investigated under various reaction conditions. Theenantiomeric excess was sensitive to the solvent. Whenthe reduction was carried out in toluene at reflux, anobvious increase of ee was observed (Table 1, entries 3and 4). Apart from the solvent, the ratio of the catalystsaffected the enantioselectivity. An increase in the catalystloading from 5 to 10 mol % resulted in increase in enantio-selectivity (Table 1, entries 4 and 5). Furthermore increas-ing the catalyst loading from 10 to 15 mol % resulted inalmost identical enantioselectivity. The best reaction con-ditions were chosen (Table 1, entry 5).

To extend the scope of the reduction, we subjectednumerous ketones to the borane-mediated asymmetricreduction under the optimum reaction conditions. Theresults are summarized in Table 2. An electron-withdraw-ing group on the phenyl ring was beneficial to high enan-tioselectivity (Table 2, entries 2–4). p-Methoxyacetophe-none gave a much lower enantioselectivity, which couldbe rationalized to the coordination of the heteroatom withthe boron atom in the catalyst and borane (Table 2, entry5).28–30 Probably because of steric effects, 1-acetonaph-

Scheme 1. Synthesis of catalyst 5–7.

TABLE 1. Enantioselective borane reduction of acetophenonea

Entry Ligand (mol %) Solvent T (8C) Yield (%)b ee (%)c Config.d

1 5 (5%) THF Reflux 84 7 R2 6 (5%) THF Reflux 82 12 R3 7 (5%) THF Reflux 85 16 R4 7 (5%) Toluene Reflux 83 68 R5 7 (10%) Toluene Reflux 84 78 R6 7 (15%) Toluene Reflux 82 78 R

aReaction carried out with 0.5 mmol scale, molar ratio of PhCOCH3/BH3�SMe2 51:1.2.bYield determined after chromatographic purification.cee determined by HPLC (Daicel Chiracel OD-H Column).dThe absolute configuration of the product was determined by comparison of the sign of the specific rotation to the literature data.25

659SERIES OF NEW C2-SYMMETRIC AMINO ALCOHOLS

Chirality DOI 10.1002/chir

thone and ketones containing substituents at the orthoposition gave lower enantioselectivities (Table 2, entries6–8). The symmetric reduction of the cyclic ketone a-tetra-lone (entry 9) and the aliphatic ketone benzylacetone(entry 10) produced a moderate degree of enantioselectiv-ity.

We also applied catalyst 7 to the asymmetric reductionof representative prochiral a-halo ketones to provide theresulting secondary alcohols in 80–90% enantiomericexcesses (Table 3).

The efficiency of ligand 7 as a chiral source in the asym-metric reduction of acetophenone was examined at lowertemperature (Table 4). When the temperature was

decreased to 258C (Table 4, entry 1), to our surprise theresulting 1-phenylethanol was obtained in 20% ee, with anopposite configuration, that is, the (S)-configuration.Decreasing the temperature to room temperature led toimprovement in selectivity (30% ee) (Table 4, entry 3). Fur-ther cooling the reaction to 08C resulted in slower reduc-tion and the ee for the product was lower than for reactionat room temperature (Table 4, entry 3 vs. 2). It wasobserved that a decrease in the catalyst loading from 10 to5 mol % at room temperature resulted in a decrease in theenantioselectivity. Lower ee was obtained when the reduc-tion was carried out in THF than in toluene (Table 4, entry5 vs. 4).

Thus when ligand 7 was applied in toluene at reflux,(R)-1-phenylethanol was obtained in 78% ee, whereas atroom temperature (S)-1-phenylethanol was obtained in30% ee. This remarkable temperature-dependant reversalof stereoselectivity makes the chiral ligand 7 with multi-coordination groups a promising catalyst for the synthesisof both enantiomers in the borane-mediated reduction ofprochiral ketones.

The temperature of the reaction is an important variablein determining the levels of selectivity in enantioselectivetransformations. To the best of our knowledge, the exam-ples of reversal of enantioselectivity with changes in tem-

TABLE 2. Enantioselective reduction of ketonesa

Entry Ketones Yield (%)b ee (%)c Config.d

1 Acetophenone 84 78 R2 40-Nitroacetophenone 88 85e R3 40-Fluoroacetophenone 86 85e R4 40-Bromoacetophenone 86 85e R5 40-Methoxyacetophenone 83 56 R6 20-Chloroacetophenone 85 65 R7 20-Methoxyacetophenone 88 61e R8 1-Acetonaphthtone 84 37 R9 a-Tetralone 84 66 R

10 Benzylacetone 89 74f R

aReaction carried out with 0.5 mmol scale, molar ratio of PhCOCH3/BH3.SMe2 5 1:1.2.bYield determined after chromatographic purification.cee determined by HPLC (Daicel Chiralcel OD-H Column).dThe absolute configuration of the product was determined by comparisonof the sign of the specific rotation to the literature data.11,25–27eee determined by HPLC (Daicel Chiralcel OB-H Column).fee determined by HPLC (Daicel Chiralcel AD-H Column).

TABLE 3. Asymmetric reduction of prochirala-halo ketonesa

Entry R X Yield (%)b ee (%)c Config.d

1 Ph Br 86 82 S2 Ph Cl 90 80 S3 p-CH3Ph Br 87 90 S4 p-CH3Ph Cl 86 87 S5 p-BrPh Br 92 90e S6 p-ClPh Br 90 85e S7 p-NO2Ph Br 85 85f S

aReaction carried out with 0.5 mmol scale, molar ratio of PhCOCH3/BH3.SMe2 51:1.2.bYield determined after chromatographic purification.cee determined by HPLC (Daicel Chiracel OD-H Column).dThe absolute configuration of the product was determined by comparisonof the sign of the specific rotation to the literature data.25,28–30eee determined by HPLC (Daicel Chiracel OJ-H Column).fee determined by HPLC (Daicel Chiracel OD-H Column) analysis of thecorresponding acetate.

TABLE 4. Enantioselective borane reduction ofacetophenone at low temperaturea

Entry 7 mol % Solvent T (8C) Yield (%)b ee (%)c Config.d

1 10% Toluene 25 84 20 S2 10% Toluene rte 82 30 S3 10% Toluene 0 85 26 S4 5% Toluene rte 86 28 S5 5% THF rte 84 15 S

aReaction carried out with 0.5 mmol scale, molar ratio of PhCOCH3/BH3�SMe2 5 1:1.2.bYield determined after chromatographic purification.cee determined by HPLC (Daicel Chiracel OD-H Column).dThe absolute configuration of the product was determined by comparisonof the sign of the specific rotation to the literature data.25ert � 188C.

Fig. 1. Amino alcohol catalysts 8 and 9.

660 ZHOU ET AL.

Chirality DOI 10.1002/chir

perature are rare.32–39 In a recent work on enantioselectiveborane-mediated reduction of prochiral ketones, Basavaiahet al.31,40 reported that their catalysts containingN��(C¼¼NH)��N and N��(C¼¼NH)��O frameworks exhib-ited temperature dependant reversal of stereoselectivity.

To further understand the structural effect of new C2-symmetric amino alcohol ligands on the temperature-dependent reversal of stereochemistry, the mono prolinolanalogue 8 (Fig. 1) was synthesized and applied to theasymmetric borane reduction of acetophenone in tolueneat refluxing temperature and at room temperature. As theresults in Table 5 show, reversal of enantioselectivity withchange in temperature was also observed. When thereduction was carried out in the presence of 10 mol % ofthe ligand 8 at reflux, higher ee was obtained than usingthe C2-symmetric ligand 7 (Table 5, entry 3 vs. 1). How-ever, the chiral amino alcohol 8 was found to be a lesseffective catalyst when the reduction was carried out atroom temperature (Table 5, entry 4 vs. 2). From theseresults, it may indicate that the C2-symmetry is not the fac-tor responsible for the reversal of stereochemistry. Weassume that the n-butoxy group at the g-position of chiralamino alcohol may play an important role. Thus, chiralligand 9 without n-butoxy was synthesized. As the results,summarized in Table 5, show, reversal of stereochemistrywas observed, and ligand 9 gave lower enantioselectivityas compared with ligands 7 and 8 at reflux as well as atroom temperature (Table 5, entry 6 vs. 2 and 4, entry 5 vs.3 and 1). Although it is difficult to ascertain the possiblereason for the temperature dependent reversal of stereo-chemistry from these studies, it suggests that catalystswith more coordination groups provide higher ees at lowtemperature.

In summary, a series of new C2-symmetric amino alco-hols with multicoordination groups have been synthesizedand one was successfully applied as catalysts in the borane

asymmetric reduction of prochiral ketones in refluxing tol-uene, affording the chiral secondary alcohols with up to90% ee. An unusual temperature-dependent reversal ofstereochemistry was also observed. Although ligand 7 pro-vides much lower ee at room temperature than at hightemperature (1108C), with respect to the reversal of stereo-selectivity, it is a promising catalyst for synthesis of bothenantiomers in the borane-mediated reduction of prochiralketones. Work towards development of a suitable chiralcatalytic source providing high levels of temperature-dependent stereodirectionality and understanding the mech-anism of this phenomenon is underway in our laboratory.

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TABLE 5. Enantioselective borane reductionof acetophenonea

Entry Ligand (mol %) T (8C) Yield (%)b ee (%)c Config.d

1 7 (5%) Reflux 83 68 R2 7 (5%) rte 82 28 S3 8 (10%) Reflux 80 83 R4 8 (10%) rte 82 17 S5 9 (10%) Reflux 84 57 R6 9 (10%) rte 83 13 S

aReaction carried out with 0.5 mmol scale, molar ratio of PhCOCH3/BH3�SMe2 5 1:1.2.bYield determined after chromatographic purification.cee determined by HPLC (Daicel Chiracel OD-H Column).dThe absolute configuration of the product was determined by comparisonof the sign of the specific rotation to the literature data.25ert � 188C.

661SERIES OF NEW C2-SYMMETRIC AMINO ALCOHOLS

Chirality DOI 10.1002/chir

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662 ZHOU ET AL.

Chirality DOI 10.1002/chir