Synthesis of C2-symmetrical bis-β-amino alcohols from (R)-cysteine and their application in enantioselective catalysis

Article abstract of DOI:10.1016/S0957-4166(98)00106-2

Six new sulfur-containing C₂-symmetrical bis-β-primary and sec-amino- tert-alcohols have been synthesized from (R)-cysteine and applied successfully in the enantiocontrolled catalytic addition of diethylzinc to benzaldehyde. The resulting 1-phe

Full text of DOI:10.1016/S0957-4166(98)00106-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1409–1417
Synthesis of C2-symmetrical bis-β-amino alcohols from
(R)-cysteine and their application in enantioselective catalysis†
Michael Kossenjans and Jürgen Martens ∗
Fachbereich Chemie der Universität Oldenburg, Carl-von-Ossietzky-Straße 9-11, D-26129 Oldenburg, Germany
Received 12 February 1998; accepted 12 March 1998
Abstract
Six new sulfur-containing C2-symmetrical bis-β-primary and sec-amino-tert-alcohols have been synthesized
from (R)-cysteine and applied successfully in the enantiocontrolled catalytic addition of diethylzinc to benzalde-
hyde. The resulting 1-phenyl-1-propanol could be obtained in good enantiomeric excess of up to 94%. Using the
same chiral auxiliaries in the enantioselective borane reduction of acetophenone afforded 1-phenyl-1-ethanol in
enantiomeric excesses of up to 82%. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
The stereoselective synthesis of optically active secondary alcohols is a well studied theme in organic
chemistry. In this connection, the enantioselective addition of diethylzinc1 to various aldehydes and
the enantiocontrolled catalytic reduction of prochiral ketones using modified borane reagents2 have
been intensively investigated over the last decade. In both model reactions, β-amino alcohols (usually
prepared from α-amino acids) are often used as chiral auxiliaries.1,2 In the last few years sulfur-
containing ligands like thioether-derivatives from (R)-cysteine,3 (R)-cystine,4 (S)-penicillamine4 and
(S)-methionine,4 amino thiols5 or sulfoxides6 have gained more and more interest as catalysts in these
stereoselective reactions.
However, to the best of our knowledge, this paper is the first report on the synthesis of bis-β-
amino tert-alcohols, starting from (R)-cysteine 1, and the application of these C2-symmetrical sulfides in
enantioselective catalysis.
∗
†
Corresponding author. E-mail: martens@uni-oldenburg.de
This paper is dedicated to Heribert Offermanns on the occasion of his 60th birthday.
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00106-2

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2. Results and discussion
The synthesis of the C2-symmetrical ligands 7–12 is shown in Scheme 1: (R)-cysteine 1 was first
converted into the bridged bis-amino acid methyl ester 2 by treatment with 1,2-dibromoethane followed
by esterification with methanol and thionylchloride.7,8 The reaction of 2 with different Grignard reagents
to give the desired chiral ligands 7–9 was not very successful. Low yields and the formation of by-
products made it necessary to protect the primary amino groups of 2 by reaction with (Boc)2O in the
presence of triethylamine, resulting in the carbamate 3. The β-bis-amino alcohols 4–6 were obtained in
moderate to good yields (60% to 87%, see experimental section) by addition of the respective Grignard
reagent (10 equiv.) to 3. Deprotection of the amino group by treatment with trifluoroacetic acid in
dichloromethane gave the C2-symmetrical β-primary amino-tert-alcohols 7–9 after basification with aq.
NaOH and extractive work-up. Reduction of the N-Boc-protected intermediates 4–6 with excess LiAlH4
in refluxing THF afforded the N-methylated bis-sec-amino-tert-alcohols 10–12.
Scheme 1.
According to a typical procedure (see experimental section), the catalysts 7–12 were tested in the
enantioselective addition of diethylzinc to benzaldehyde at room temperature (Scheme 2). As can be

M. Kossenjans, J. Martens / Tetrahedron: Asymmetry 9 (1998) 1409–1417
1411
seen from Table 1, the enantiomeric excesses of the obtained 1-phenyl-1-propanol range from 18% to
94%.
Scheme 2.
Using the β-primary amino alcohols 7–9 in the ethylation of benzaldehyde, only low excesses of one of
the enantiomers (18–38%, entries 1–3) were obtained. Also, the absolute configurations of the enriched
sec alcohols were not uniform. A predominant formation of (S)-1-phenyl-1-propanol was observed in
the presence of the corresponding N-methylated β-sec-amino alcohols 10–12 (entries 4–8). In the case
of catalysts 10 and 11 the additional N-alkylation shows no significant improvement of the enantiomeric
excess, but in agreement with some of our previously published results,3f,j ligand 12 again clarifies the
advantage of the N-methylation: with a catalyst concentration of 5 mol% the inductive efficiency strongly
increased from 38% to 86% e.e. (entries 3 and 7). Apparently a sterically demanding α-substitution
(R=phenyl) combined with a secondary amino function seems to be crucial for the enhancement of the
stereocontrol. So the enantiomeric excess could be increased to 94% with 12 at a concentration of 10
mol% and, as expected, it decreased to 74% at 2.5 mol% (entries 6 and 8).
Table 2 shows the results of the homogenous catalytic reduction of acetophenone as model substrate
(Scheme 3) with in situ formed oxazaborolidine catalysts derived from ligands 7–12, respectively.
Conversion of these bis-β-amino alcohols to oxazaborolidines was accomplished by treatment with
BH3·THF and no further isolation or purification was carried out (see experimental section).
In contrast to the partially increased inductive efficiency of the ligands in the ethylation of benz-
aldehyde by an additional N-methylation, a drastic decrease of the enantiomeric excess was observed
when the same β-sec-amino alcohols were used in the reduction of acetophenone (ligands 11 and 12;
entries 15 and 16). The best result was obtained with the primary amino alcohol 7 at a concentration
of 5 mol% (82% e.e.; entry 10). Neither a bulky α-substitution (R=phenyl, 9 and 12) nor a decreased
conformative flexibility, caused by a rigid cyclopentanol fragment [R, R=–(CH2)4–, 8 and 11] improved
the stereocontrol in the formation of 1-phenylethan-1-ol.
In summary, the presented C2-symmetrical bis-β-amino alcohols 7–12 have different capabilities
concerning their inductive efficiency in the addition of diethylzinc to benzaldehyde and the borane
Table 1
Enantioselective addition of diethylzinc to benzaldehyde; product: 1-phenylpropan-1-ola

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Table 2
Enantioselective reduction of acetophenone at 25°C; product: (R)-1-phenylethan-1-ola
Scheme 3.
reduction of acetophenone. Noteworthy is the significant importance of a secondary amino function as
well as a bulky α-hydroxy-substitution for good e.e.s in the ethylation of benzaldehyde and a secondary
amino group combined with a less sterically demanding α-substitution in the borane reduction.
3. Experimental section
All reactions were carried out in oven-dried glassware under an argon atmosphere using anhydrous
solvents. Thin layer chromatography was carried out on silica gel (60 F254, Merck) and spots located
with UV light or iodine vapors. Melting points were taken on a melting point apparatus according
to Dr. Linström and are uncorrected. Optical rotations were measured on a Perkin–Elmer automatic
polarimeter. IR spectra were recorded on a Philips PU 9706 spectrophotometer. The 1H-NMR and 13C-
NMR spectra were registered on a Bruker AM 300 spectrometer using TMS as the internal standard. Mass
spectra were recorded on a Finnigan-MAT 212 (data system 300; CI, isobutane). Elemental analyses (C,
H, N, S) were performed on a Carlo Erba Stumentalione (MOD 1104) analyzer. Gas chromatography
(GC) was performed using a Shimadzu (GC-15A) instrument, 25 m column: SGE Cydex-B (chiral),
ωi=0.25 mm, film thickness 0.25 µm, 1 µl product in n-hexane, detection: FID, carrier gas: nitrogen.
The starting material (R)-cysteine (chemical and enantiomeric purity >99%) was obtained from Degussa
AG. Borane/THF complex was supplied from Aldrich and diethylzinc from Witco GmbH. Commercially
available chemicals were used.
3.1. (2R,9R)-2,9-Diamino-4,7-dithia-decandiacid-methylester dihydrochloride 2
To a suspension of 60.5 g (0.5 mol) (R)-cysteine in 400 mL of 2 N NaOH and 300 mL of ethanol, 46.95
g (0.25 mol) of 1,2-dibromoethane was added slowly at r.t. After stirring for 24 h at ambient temperature

M. Kossenjans, J. Martens / Tetrahedron: Asymmetry 9 (1998) 1409–1417
1413
the suspension was basified cautiously (pH 10) with conc. HCl. The precipitate was filtered off, washed
with cold water and ether and dried in vacuo. Without further purification and characterization, 111.4 g
(0.33 mol) of the resulting bridged bis-amino acid hydrochloride was suspended in 800 mL methanol and
cooled to 0°C. Under vigorous stirring, 119.1 g (1 mol) SOCl2 was added over 3 h. After the reaction
mixture had been allowed to warm to r.t., it was stirred for another 12 h. The solvent was evaporated
in vacuo and the crude product was purified by recrystallization from methanol/methyl-tert-butylether.
The C2-symmetrical bis-amino acid methylester hydrochloride 2 was obtained as a yellow solid. Yield:
109.7 g (59%); m.p. 165°C; [α]D20=+1.6 (c=2.18, CH3OH); IR (KBr): ν=3300–3600 cm−1 (NH); 1740
1
(CO); H-NMR (D2O, 300 MHz): δ=2.87 (m, 4H, 2×CH2S); 3.16 (dd, J=4.4 Hz, J=14.85 Hz, 2H,
2×CH2CHN); 3.28 (dd, J=7.15 Hz, J=14.85 Hz, 2H, 2×CH2CHN); 4.43 (dd, J=4.4 Hz, J=7.15 Hz, 2H,
2×CHN); 4.64 (s, 6H, 2×OCH3); 13C-NMR (D2O, 75.47 MHz): δ=31.49, 31.84 (2×CH2SCH2); 52.82,
54.40 (2×OCH3, 2×CHN); 169.44 (CO); MS (CI, i-butane): m/z (%)=297 (100) [MH+]; anal. calc. for
C10H20N2O4S2 (296.4): C, 40.52; H, 6.80; N, 9.45; S, 21.64. Found: C, 40.10; H, 6.91; N, 9.42; S, 21.52.
3.2. (2R,9R)-2,9-Di-(tert-butoxycarbonyl)-amino-4,7-dithia-decandiacid-methylester 3
Under an argon atmosphere, 15.0 g (40.6 mmol) of the bis-amino acid methylester hydrochloride 2 was
suspended in 400 mL anhydrous THF. Et3N (18.04 g, 178.6 mmol) was added dropwise to the stirred
reaction mixture. The resulting white suspension was cooled to 0°C and a solution of (Boc)2O (17.27 g,
79.17 mmol) in 120 mL anhydrous THF was added over 60 min. The mixture was allowed to warm to r.t.
and stirred for 14 h. The solvent was removed in vacuo, and the residue portioned between Et2O (200 mL)
and water (100 mL). The aqueous phase was extracted with Et2O (2×100 mL) and the combined organic
layers were washed with 2 N HCl (2×60 mL), saturated NaHCO3 (2×80 mL) and brine (60 mL). Drying
(MgSO4) and evaporation of the solvent under reduced pressure afforded the N-Boc protected bis-amino
acid methylester 3 as a yellow oil which slowly crystallized at r.t. Yield: 18.70 g (93%); m.p. 58°C;
[α]D20=+17.6 (c=1.03, CH2Cl2); IR (NaCl): ν=3380 cm−1 (NH); 1670–1800 (CO); 1H-NMR (CDCl3,
300 MHz): δ=1.42 (s, 18H, 2×C(CH3)3); 2.68 (s, 4H, 2×CH2S); 2.94 (m, 4H, 2×CH2CHN); 3.73 (s,
6H, 2×CH3); 4.48 (m, 2H, 2×CHN); 13C-NMR (CDCl3, 75.47 MHz): δ=28.25 (2×C(CH3)3); 32.45,
34.48 (2×CH2SCH2); 52.53, 53.41 (2×OCH3, 2×CHN); 80.16 (2×C(CH3)3); 155.05 (2×CO); 171.30
(2×CO); MS (CI, i-butane): m/z (%)=497 (100) [MH+]; anal. calc. for C20H36N2O8S2 (496.6): C, 48.37;
H, 7.31; N, 5.64; S, 12.91. Found. C, 48.29; H, 7.36; N, 5.50; S, 12.64.
3.3. Products 4–6; general procedure
A Grignard reagent was prepared under an argon atmosphere from magnesium (200 mmol) and
ethyl or phenyl bromide (200 mmol) or 1,4-dibromobutane (100 mmol) in dry THF (400 mL). The
N-Boc-bis-amino acid methylester 3 (20 mmol in 100 mL dry THF) was added to this solution over
90 min at r.t. After complete addition the resulting solution was refluxed for 12 h, cooled and stirred
for another 3 h at ambient temperature. The reaction mixture was cooled to 0°C and hydrolyzed with
saturated NH4Cl solution (100 mL) and water (100 mL). The organic layer was separated and the
aqueous layer was extracted with Et2O (2×100 mL). The combined organic extracts were finally washed
with brine (100 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. The
obtained crude products were purified by recrystallization from dichloromethane/n-hexane or by column
chromatography. The individual work-up is described below.

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3.3.1. (4R,11R)-4,11-Di-(tert-butoxycarbonyl)-amino-3,12-diethyl-6,9-dithia-tetradecan-3,12-diol 4
Work-up: purification by column chromatography (silica gel 60, eluent: n-hexane:EtOAc=3:2, Rf-
value: 0.41); yield: 7.29 g (66%); m.p. 93°C; [α]D20=−53.6 (c=1.04, CH2Cl2); IR (KBr): ν=3500–3300
1
cm−1 (OH, NH); 1670 (CO); H-NMR (CDCl3, 300 MHz): δ=0.78–0.91 (m, 12H, 4×CH2CH3);
1.33–1.64 (m, 8H, 4×CH2CH3); 1.43 (s, 18H, 2×C(CH3)3); 2.44 (s, 2×OH); 2.53–2.97 (m, 8H,
2×CH2SCH2); 3.73 (m, 2H, 2×CHN); 5.03 (s, 2H, 2×NH); 13C-NMR (CDCl3, 75.47 MHz): δ=7.58,
7.79 (4×CH2CH3); 27.55, 27.83 (4×CH2CH3); 28.36 (2×C(CH3)3); 32.55, 33.04 (2×CH2SCH2); 76.99
(2×COH); 79.37 (2×C(CH3)3); 156.28 (2×CO); MS (CI, i-butane): m/z (%)=553 (96) [MH+], 453 (100)
[MH+−C(O)OtBu]; anal. calc. for C26H52N2O6S2 (552.8): C, 56.48; H, 9.48; N, 5.07; S, 11.60. Found:
C, 56.69; H, 9.62; N, 5.05; S, 11.32.
3.3.2. (1R,8R)-1,8-Di-(tert-butoxycarbonyl)-amino-1,8-di-(10 -hydroxycyclopentyl)-3,6-dithia-octan 5
Work-up: purification by column chromatography (silica gel 60, eluent: n-hexane:EtOAc:CHCl3=
35:50:15, Rf-value: 0.68); yield: 8.24 g (60%); m.p. 150°C; [α]D20=−75.1 (c=1.03, CH2Cl2); IR (KBr):
ν=3600–3200 cm−1 (OH, NH); 1650 (CO); 1H-NMR (CDCl3, 300 MHz): δ=1.19–1.88 (m, 16H, 2×c-
pentyl-CH2); 1.44 (s, 18H, 2×C(CH3)3); 2.41–3.23 (m, 4H, 2×CH2SCH2); 3.86 (m, 2H, 2×CHN); 4.95
(m, 2H, 2×NH); 13C-NMR (CDCl3, 75.47 MHz): δ=28.38 (2×C(CH3)3); 23.53, 23.99, 30.99, 32.87,
36.14, 38.08 (8×c-pentyl-CH2, 2×CH2SCH2); 56.15 (2×CHN); 79.63 (2×C(CH3)3); 84.41 (2×COH);
156.39 (2×CO); MS (CI, i-butane): m/z (%)=549 (100) [MH+]; anal. calc. for C26H48N2O6S2 (548.8):
C, 56.90; H, 8.82; N, 5.10; S, 11.68. Found: C 57.03; H, 8.81; N, 5.14; S, 11.61.
3.3.3. (2R,9R)-2,9-Di-(tert-butoxycarbonyl)-amino-1,1,10,10-tetraphenyl-4,7-dithia-decan-1,10-diol 6
Work-up: purification by recrystallization from dichloromethane:n-hexane; yield: 12.98 g (87%); m.p.
1
193°C; [α]20D=−61.2 (c=0.97, CH2Cl2); IR (KBr): ν=3400 cm−1 (NH, OH); 1660 (CO); H-NMR
(CDCl3, 300 MHz): δ=1.25 (s, 18H, 2×C(CH3)3); 2.48–2.57 (m, 3H, 6×CH2S); 2.75 (dd, J=3.01 Hz,
J=13.99 Hz, 2H, 2×CH2S); 4.08 (s, breit, 2H, 2×OH); 4.69 (m, 2H, 2×CHN); 7.08–7.47 (m, 20H,
aromat.-H); 13C-NMR (CDCl3, 75.47 MHz): δ=28.25 (2×C(CH3)3); 32.17, 33.16 (2×CH2SCH2); 56.14
(2×CHN); 79.79 (2×COH); 81.18 (C(CH3)3); 125.29, 125.69, 126.91, 127.05, 127.88, 128.15, 128.52
(20×aromat.-C); 144.72, 144.99 (4×q.-aromat.-C); 156.05 (2×CO); MS (CI, i-butane): m/z (%)=745
(100) [MH+]; anal. calc. for C42H52N2O6S2 (744.6): C, 67.75; H, 7.04; N, 3.76; S, 8.61. Found: C,
67.51; H, 7.04; N, 3.78; S, 8.58.
3.4. Products 7–9; general procedure
A portion of the respective N-Boc-protected amino alcohol 4–6 (10 mmol) was dissolved in 10 mL
CH2Cl2, 15 mL CF3CO2H was added at 0°C, and the resulting mixture was stirred overnight at r.t.
All volatile materials were removed in vacuo, the residue was taken up in 40 mL of 2 N NaOH and
after stirring for 15 min the resulting suspension was extracted with CH2Cl2 (4×25 mL). The combined
organic layers were dried over anhydrous MgSO4. Evaporation in vacuo afforded the crude bis-amino
alcohol which was purified by column chromatography or recrystallization (see below for individual
work-ups).
3.4.1. (4R,11R)-4,11-Diamino-3,12-diethyl-6,9-dithia-tetradecan-3,12-diol 7
Starting material: 1.27 g (2.3 mmol) 4; work-up: purification by column chromatography (silica gel
60, eluent: methanol:n-hexane=13:0.5, Rf-value: 0.46); yield: 0.63 g (78%); [α]D20=−115.2 (c=1.08,
1
CH2Cl2); IR (NaCl): ν=3600–3000 cm−1 (OH, NH); H-NMR (CDCl3, 300 MHz): δ=0.87 (t, J=7.57

M. Kossenjans, J. Martens / Tetrahedron: Asymmetry 9 (1998) 1409–1417
1415
Hz, 6(3)H, 2×CH2CH3); 0.88 (t, J=7.52 Hz, 6(3)H, 2×CH2CH3); 1.28–1.62 (m, 8H, 4×CH2CH3);
2.34–2.43 (m, 2H, 2×CHN); 2.71–2.92 (m, 8H, 2×CH2SCH2); 3.46 (s, 2H, OH); 13C-NMR (CDCl3,
75.47 MHz): δ=7.53, 7.63 (4×CH2CH3); 26.41, 27.99 (2×CH2CH3); 32.33, 35.40 (2×CH2SCH2); 54.51
(2×CHN); 74.68 (2×COH); MS (CI, i-butane): m/z (%)=353 (100) [MH+]; anal. calc. for C16H36N2O2S2
(352.6): C, 54.50; H, 10.29; N, 7.94; S, 18.19. Found: C, 54.32; H, 10.18; N, 7.85; S, 18.26.
3.4.2. (1R,8R)-1,8-Diamino-1,8-di-(10 -hydroxycyclopentyl)-3,6-dithia-octan 8
Starting material: 4.60 g (8.36 mmol) 5; work-up: purification by recrystallization from
dichloromethane:n-hexane; yield: 2.83 g (98%); m.p. 86°C; [α]D20=−110.9 (c=1.22, CH2Cl2); IR
1
(KBr): ν=3600–3100 cm−1 (OH, NH); H-NMR (CDCl3, 300 MHz): δ=1.2–1.87 (m, 16H, 8×c-
pentyl-CH2); 2.22 (s, 4H, 2×NH2); 2.43 (dd, J=10.59 Hz, J=12.87 Hz, 2H, 2×CHN); 2.63–2.95
(m, 8H, 2×CH2SCH2); 13C-NMR (CDCl3, 75.47 MHz): δ=23.61, 23.92, 31.99, 35.47, 35.84, 38.96
(8×c-pentyl-CH2, 2×CH2SCH2); 57.50 (2×CHN); 83.11 (2×COH); MS (CI, i-butane): m/z (%)=349
(100) [MH+]; anal. calc. for C16H32N2O2S2 (348.6): C, 55.13; H, 9.25; N, 8.04; S, 18.40. Found: C,
55.08; H, 9.26; N, 7.99; S, 18.39.
3.4.3. (2R,9R)-2,9-Diamino-1,1,10,10-tetraphenyl-4,7-dithia-decan-1,10-diol 9
Starting material: 7.45 g (10 mmol) 6; work-up: purification by recrystallization from
dichloromethane:n-hexane; yield: 4.05 g (74%); m.p. 128°C; [α]D20=−175.5 (c=1.03, CH2Cl2);
1
IR (KBr): ν=3100–3600 cm−1 (OH, NH); 1590 (C–C aromat.); H-NMR (CDCl3, 300 MHz): δ=2.40
(dd, J=10.74 Hz, J=13.51 Hz, 2H, 2×CH2CHN); 2.57 (m, 6H, 2×CH2CHN, 4×CH2S); 4.02 (dd,
J=2.4 Hz, J=10.2 Hz, 2H, 2×CHN); 7.17–7.64 (3m, 20H, aromat.-H); 13C-NMR (CDCl3, 75.47 MHz):
δ=31.66, 33.89 (2×CH2SCH2); 55.53 (2×CHN); 78.33 (2×COH); 125.12, 125.55, 126.69, 126.91,
128.28, 128.54 (20×aromat.-C); 143.65, 146.40 (4×q.-aromat.-C); MS (CI, i-butane): m/z (%)=545
(100) [MH+]; anal. calc. for C32H36N2O2S2 (544.8): C, 70.55; H, 6.66; N, 5.14; S, 11.77. Found: C,
70.48; H, 6.67; N, 5.08; S, 11.91.
3.5. Products 10–12; general procedure
To a suspension of 2.28 g (60 mmol) lithium aluminiumhydride in 100 mL THF — stirred for 1 h under
reflux then cooled to r.t. — 3.0 mmol of the respective N-tert-butoxycarbonyl derivative 4–6 (dissolved
in 20 mL THF) was added dropwise over 30 min at r.t. under an argon atmosphere. The reaction mixture
was heated under reflux for 24 h. The heating bath was removed and aqueous KOH (10%) was added
cautiously at r.t. to destroy excess reducing reagent. After an additional 2 h under reflux, the resulting
white suspension was filtered, the solids were intensively washed with ethyl acetate and the combined
organic layers were concentrated in vacuo to afford colourless or slightly yellow oils as crude products.
In all cases further purification was accomplished by column chromatography on silica gel.
3.5.1. (4R,11R)-4,11-Di-(monomethyl)-amino-3,12-diethyl-6,9-dithia-tetradecan-3,12-diol 10
Starting material: 1.66 g (3.0 mmol) 4; eluent: n-hexane:triethylamine=6:4, Rf-value: 0.15; yield:
1
0.84 g (74%); [α]D20=−50.1 (c=1.29, CH2Cl2); IR (NaCl): ν=3600–3100 cm−1 (OH, NH); H-NMR
(CDCl3, 300 MHz): δ=0.86 (t, J=7.54 Hz, 6(3)H, 2×CH2CH3); 0.88 (t, J=7.46 Hz, 6(3)H, 2×CH2CH3);
1.23–1.66 (m, 8H, 4×CH2CH3); 2.42–2.53 (m, 2H, 2×CHN); 2.55 (s, 6H, 2×NCH3); 2.76–2.71 (m,
8H, 2×CH2SCH2); 13C-NMR (CDCl3, 75.47 MHz): δ=7.68 (4×CH2CH3); 27.06, 28.36 (4×CH2CH3);
32.95, 34.16 (2×CH2SCH2); 37.91 (2×NCH3); 63.63 (2×CHN); 75.21 (2×COH); MS (CI, i-butane):

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M. Kossenjans, J. Martens / Tetrahedron: Asymmetry 9 (1998) 1409–1417
m/z (%)=381 (100) [MH+]; anal. calc. for C18H40N2O2S2 (380.7): C, 56.80; H, 10.59; N, 7.36; S, 16.85.
Found: C, 56.85; H, 10.51; N, 7.36; S, 16.90.
3.5.2. (1R,8R)-1,8-Di-(monomethyl)-amino-1,8-di-(10 -hydroxycyclopentyl)-3,6-dithia-octan 11
Starting material: 2.74 g (5.0 mmol) 5; eluent: MTBE:triethylamine=8:2, Rf-value: 0.17; yield: 1.23 g
(65%); [α]D20=−109.9 (c=1.13, CH2Cl2); IR (NaCl): ν=3600–3000 cm−1 (OH, NH); 1H-NMR (CDCl3,
300 MHz): δ=1.26–1.89 (m, 16H, 8×c-pentyl-CH2); 2.35–2.52 (m, 8H, 2×CHN, 2×NCH3); 2.73–2.92
(2m, 8H, 2×CH2SCH2); 13C-NMR (CDCl3, 75.47 MHz): δ=23.36, 23.68, 32.28, 34.23, 36.15, 37.05
(8×c-pentyl-CH2, 2×CH2SCH2); 40.11 (2×NCH3); 66.14 (2×CHN); 83.07 (2×COH); MS (CI, i-
butane): m/z (%)=377 (100) [MH+]; anal. calc. for C18H36N2O2S2 (376.6): C, 57.40; H, 9.63; N, 7.44;
S, 17.03. Found: C, 57.23; H, 9.62; N, 7.41; S, 17.10.
3.5.3. (2R,9R)-2,9-Di-(monomethyl)-amino-1,1,10,10-tetraphenyl-4,7-dithia-decan-1,10-diol 12
Starting material: 5.0 g (6.7 mmol) 6; eluent: n-hexane:triethylamine=7:3, Rf-value: 0.32; yield: 2.96
g (77%); m.p. 112°C; [α]D20=−103.3 (c=1.69, CH2Cl2); IR (KBr): ν=3500–3100 cm−1 (OH, NH);
1H-NMR (CDCl3, 300 MHz): δ=1.59, 4.74 (2s, 4H, 2×NH, 2×OH); 2.16 (s, 6H, 2×NCH3); 2.34 (dd,
J=9.38 Hz, J=13.65 Hz, 2H, 2×CHN); 2.53 (s, 4H, 2×CH2SCH2CHN); 2.74 (dd, J=2.69 Hz, J=13.65
Hz, 2H, 2×SCH2CHN); 3.61 (dd, J=2.69 Hz, J=9.38 Hz, 2H, 2×SCH2CHN); 7.16–7.36, 7.53–7.68 (2m,
20H, 4×aromat.-H); 13C-NMR (CDCl3, 75.47 MHz): δ=32.12, 34.20 (2×CH2SCH2); 36.82 (2×NCH3);
65.56 (2×CHN); 78.21 (2×COH); 125.38, 125.75, 126.65, 126.73, 128.21, 128.29 (aromat.-C); 144.65,
146.98 (q.-aromat.-C); MS (CI, i-butane): m/z (%)=573 (100) [MH+]; anal. calc. for C34H40N2O2S2
(572.8): C, 71.29; H, 7.04; N, 4.89; S, 11.19. Found: C, 71.47; H, 7.03; N, 4.91; S, 11.29.
3.6. Enantioselective addition of diethylzinc to benzaldehyde (typical procedure)
Under an argon atmosphere, 10 mmol of a 1.1 M solution of diethylzinc in anhydrous toluene (9.1 mL,
10 mmol of a 1.1 M solution) was added to a solution of the respective amount of catalyst (0.1 mmol, 0.5
mmol or 1 mmol; see Table 1) in dry toluene (10 mL) at −15°C. After 30 min with stirring at constant
temperature, the clear solution was allowed to warm to r.t. and then 0.53 g (5 mmol) of freshly distilled
benzaldehyde, dissolved in 10 mL abs. toluene, was added over a period of 15 min. The mixture was
stirred for an additional 24 h and quenched at 0°C with 20 mL of 2 N aqueous HCl. After separation of the
layers, the aqueous layer was extracted with diethyl ether (3×20 mL) and the combined organic extracts
were subsequently washed with 3.9% NaHSO3 solution (3×20 mL), saturated aqueous NaHCO3 solution
and finally with brine. After drying with MgSO4, the solvents were removed under reduced pressure and
the residue distilled (Kugelrohr) to afford pure 1-phenyl-1-propanol. The obtained secondary alcohol was
analysed by chiral gas chromatography (GC). The absolute configuration of the product was determined
via chiral GC analysis by comparison with authentic samples. Temperature programme: 100°C, 4°C/min
up to 125°C, 10 min isothermal, retention times: (R)-1-phenyl-1-propanol: 13.12 min, (S)-1-phenyl-1-
propanol: 13.46 min.
3.7. Enantioselective reduction of acetophenone (typical procedure)
In a typical procedure, a mixture of 5 mmol of acetophenone in dry THF (10 mL) was slowly added
to a solution of the catalyst (0.5 mmol) and borane–THF complex (5.5 mmol, 5.5 mL of a 1.0 M of
BH3 in THF) in dry THF (10 mL) within 30 min at r.t. After stirring for 4 h at 24°C the reaction
mixture was hydrolysed at 0°C with 2 N HCl (20 mL) and extracted with diethyl ether (2×20 mL).

M. Kossenjans, J. Martens / Tetrahedron: Asymmetry 9 (1998) 1409–1417
1417
The combined organic layers were successively washed with 2 N NaOH (20 mL) and brine, dried over
MgSO4 and concentrated under reduced pressure. The obtained crude product was distilled in vacuo
(Kugelrohr) to afford the corresponding chiral secondary alcohol which was analysed by chiral gas
chromatography (GC). The absolute configuration of the product was determined via chiral GC analysis
by comparison with authentic samples. Temperature programme: 100°C, 5°C/min up to 140°C, 5 min
isothermal, retention times: (R)-1-phenyl-1-ethanol: 7.98 min, (S)-1-phenyl-1-ethanol: 8.12 min.
Acknowledgements
Thanks are due to Degussa AG, Witco GmbH and the Fonds der Chemischen Industrie for the generous
provision of chemicals and support.
References
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