Synthesis and application of C2-symmetrical bis-β-amino alcohols based on the octahydro-cyclopenta[b]pyrrole system in the catalytic enantioselective addition of diethylzinc to benzaldehyde

Article abstract of DOI:10.1016/S0957-4166(99)00475-9

Asymmetric catalytic ethylation of benzaldehyde utilizing a series of new, tetradental bis-β-amino alcohols based on the octahydro- cyclopenta[b]pyrrole system - derived from an industrial waste material - is presented. Attention is focused on steric aspects of the catalyst(-precursor) structure. Furthermore, the catalytic efficiency of the ethylene-bridged, C₂-symmetrical bis-β-amino alcohols is compared to related 'monomeric' structures. Potent chiral ligands, which are highly effective even at concentrations of below 2 mol%, have been developed reaching excellent enantioselectivities up to 100% ee. (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(99)00475-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 4437–4445
Synthesis and application of C2-symmetrical bis-β-amino
alcohols based on the octahydro-cyclopenta[b]pyrrole system in
the catalytic enantioselective addition of diethylzinc to
benzaldehyde
Suzanne Wassmann,a Jörg Wilken b and Jürgen Martens c,∗
aGesellschaft für Biotechnologische Forschung (GBF), Mascheroder Weg 1, 38124 Braunschweig, Germany
bRiedel-de Haën GmbH, AlliedSignal, Wunstorfer Straße 40, 30926 Seelze, Germany
cFachbereich Chemie der Universität Oldenburg, Carl-von-Ossietzky-Straße 9-11, D-26129 Oldenburg, Germany
Received 21 October 1999; accepted 25 October 1999
Abstract
Asymmetric catalytic ethylation of benzaldehyde utilizing a series of new, tetradental bis-β-amino alcohols
based on the octahydro-cyclopenta[b]pyrrole system — derived from an industrial waste material — is presented.
Attention is focused on steric aspects of the catalyst(-precursor) structure. Furthermore, the catalytic efficiency of
the ethylene-bridged, C2-symmetrical bis-β-amino alcohols is compared to related ‘monomeric’ structures. Potent
chiral ligands, which are highly effective even at concentrations of below 2 mol%, have been developed reaching
excellent enantioselectivities up to 100% ee. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
In the context with our on-going studies on the utilization of industrial waste materials, we used (all-
R)-11 in the synthesis of new cost-effective enantioselective catalysts that exhibit high reactivity and
enantioselectivity and which are suitably designed for various applications. Ligands derived from the
proline analogous octahydro-cyclopenta[b]pyrrole system have been successfully applied in a variety
of asymmetric transformations, among them the enantiocontrolled catalytic diethylzinc addition to
aldehydes (best result reached so far: 100% ee at 10 mol% catalyst concentration),2 the enantioselective
oxazaborolidine-catalyzed reduction of ketones (best result: 91% o.p.),3 the ruthenium-catalyzed transfer
hydrogenation (86% ee)4 and the palladium-induced enantioselective protonation reaction (72% ee).5
∗
Corresponding author. E-mail: martens@uni-oldenburg.de
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00475-9
tetasy 3111

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These positive results inspired us to search for even more powerful calalysts based on (all-R)-1 for the
enantioselective ethylation reaction.
Some of our previously published efforts have focused on the evaluation of structural features
governing the extent of the chiral induction generated by β-amino alcohols: based on the bicyclic
backbone, which provides a limited flexibility and beneficial steric factors, the correlation of up to
four internal stereogenic centers, the variation of the α-substitution, the N-methylation and the ring-
size of an additional cycloalkanol subunit in the ligand structure were tested.2d,e In this paper, the study
is extended to tetradental, C2-symmetrical bis-β-amino alcohols. As a result, a new structure, (all-R)-5,
is one of the most efficient ligands which has been developed to date for the enantioselective alkylation
of benzaldehyde by diethylzinc (Scheme 1).6
Scheme 1. (a) Cyclohexene/Pd/C in MeOH/H2O7
2. Results and discussion
Sterically constrained tetradental ligands bearing two β-amino alcohol subunits are prepared starting
from the amino acid (all-R)-2 — obtained after recrystallization and hydrogenolytic cleavage of the
benzyl ester function of (all-R)-11 — by dimerization via 1,2-dibromoethane/K2CO3 in 4.5 M aqueous
NaOH7 followed by esterification with SOCl2/MeOH (Scheme 2). The resulting diester intermediate
(all-R)-4 reacted with Grignard reagents yielding the ethylene-bridged structures (all-R)-5–7 containing
a double tert-amino–tert-alcohol framework. The product isolation is performed by flash chromatography
on silica gel (yield: 23–42%).
A different approach had to be used for the synthesis of related structures (all-R)-8, (all-R)-9 and (all-
S)-10 (Scheme 3). These compounds were obtained starting from corresponding, previously described7
sec-amino alcohols by coupling of two amine units via 1,2-dibromoethane/K2CO3 in acetonitrile. Further
details are given in the Experimental section.
According to a typical procedure, catalysts 5–10 and related ligands 11–14 were tested in the
enantioselective addition of diethylzinc to the model substrate benzaldehyde at room temperature
(see Scheme 4). The results are given in Table 1. These results show that the (R)-enantiomer of
1-phenylpropan-1-ol is preferentially obtained with (all-R)-1 derived catalysts in 29–82% yield and
enantiomeric excesses varying from 7 to 100%.
A comparison of structures 6, 8 or 9 to related ‘monomeric’ β-amino alcohols with a secondary or
tertiary amino function (R=H or CH3) does not indicate a generally favored C2 symmetry for the inductive
efficiency (for example, see the bis-amino alcohols in comparison with the corresponding N-methylated

S. Wassmann et al. / Tetrahedron: Asymmetry 10 (1999) 4437–4445
4439
Scheme 2. Synthesis of ligands 5–7 starting from (all-R)-2: (a) dibromoethane, K2CO3, 4.5 M aq. NaOH; (b) SOCl2, MeOH,
2.1 equiv. Et3N; (c) Grignard-reaction (PhMgBr, BrMg(CH2)4MgB EtMgBr), aq. NH4Cl, chromatographic separation
Scheme 3. New, tetradental bis-β-amino alcohols 8–10 based on (all-R)-2 and (S)-proline
structures: 8 and 117 (R1, R2=CH2Ph), 9 and 122e (R1=Ph, R2=H) or 6 and 132d (R1, R2=-(CH2)4-); the
individual results are 8 vs. 11: 54:90%; 9 vs. 12: 65:68% and 6 vs. 13: 90:99% ee) (Scheme 5).
Only the already highly effective ligand 142a is further improved by the dimerization via the ethylene
bridge in structure 5: with a catalyst concentration of 5 mol%, an enantiomeric excess of 99% for 14
(Table 1, entry 10) and 100% for 5 (entry 9) is obtained. At a lower concentration of 1 mol% the
superiority of ligand 5 becomes more obvious: the results are 45% (14, entry 13) and 88% ee (5, entry
12). Even at a catalyst concentration of 2 mol% the enantiomeric excess obtained with 5 (entry 11) is still
100%.
Noteworthy is the significantly increased yield of 1-phenylpropan-1-ol from 29% (obtained with 14,
entry 10) to 73 and 82% (5, entries 9 and 12), respectively.
Neither an additional, fourth stereogenic center resulting in a secondary alcohol group (and a favored
(all-R)-configuration2e) in ligand 9 (65% ee) nor a decreased conformational flexibility introduced by
the rigid cyclopentanol subunit in compound 6 (90% ee) improves — compared to the corresponding
ligands 5 and 7 (100 and 91% ee), respectively — the stereodifferentiating properties originating from the

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Table 1
Enantioselective addition of diethylzinc to benzaldehyde in the presence of bis-β-amino alcohols 5–10
and β-amino alcohols 11–14; product: 1-phenylpropanol-1-ol
Scheme 4. Enantioselective catalytic ethylation of benzaldehyde in the presence of optically active ligands 5–10 (the results are
given in Table 1)
bicyclic (2R,3aR,6aR)-fragment. Thus, a flexible, sterically demanding α-bis-substitution at the hydroxyl
function seems to be crucial for the enhancement of the stereocontrol.
The condensed, second ring in the octahydro-cyclopenta[b]pyrrole system — further enhancing the
rigidity — positively influences the stereocontrol in the enantioselective ethylation step: compared to the
(S)-proline derived compound (all-S)-10 (ee values: 41 and 7%; entries 16 and 17), the analogous (all-

S. Wassmann et al. / Tetrahedron: Asymmetry 10 (1999) 4437–4445
4441
Scheme 5. Catalyst precursors 11–14
R)-2 derived system (all-R)-6 leads to a drastically increased enantioselectivity (90 and 47% ee, entries
6 and 7).
In conclusion, (all-R)-5 is the most efficient catalyst-precursor derived from (all-R)-octahydro-
cyclopenta[b]pyrrole-2-carboxylic acid benzyl ester (all-R)-1 which has been developed so far for
the ethylation of benzaldehyde by diethylzinc. Even at concentrations of 2 mol% 1-phenylpropan-1-
ol is obtained with 100% ee in good chemical yields. Furthermore, compound 5 is another example
of the extraordinary enhancement of stereoselectivity in asymmetric synthesis by the non-stereogenic
diarylhydroxy-methyl subunit.8
3. Experimental
All reactions were carried out in oven dried glassware under 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
1
polarimeter. IR spectra were recorded on a Philips PU 9706 spectrophotometer. The H NMR and 13C
NMR spectra were registered on a Bruker AM 300 spectrometer using TMS as internal standard. Mass
spectra were recorded on a Finnigan-MAT 212 (data system 300; CI, isobutane). Elemental analyses (C,
H, N) were performed on a Carlo Erba Stumentalione (MOD 1104) analyzer. Gas chromatography (GC)
was conducted on a Shimadzu GC-15a equipped with a 25 m chiral column (SGE Cydex-B, ωi=0.25
mm, film thickness: 0.25 µm, 1 µl product in n-hexane, detection: FID, carrier gas: nitrogen). The starting
material (all-R)-octahydro-cyclopenta[b]pyrrole-2-carboxylic acid benzyl ester (all-R)-1 was obtained
from Hoechst AG. Commercially available chemicals were used.
The starting materials for the synthesis of compounds 8–10 were prepared according to previously
published procedures. Furthermore, structures (all-R)-11,7 (αR,βR)-12,2e (all-R)-132d and (all-S)-142a
were also tested in the enantioselective ethylation of benzaldehyde.
3.1. (all-R)-1,2-Bis(methyloctahydro-cyclopenta[b]pyrrol-1-yl-2-carboxylate)ethane (all-R)-4
To a solution of (all-R)-37 (20.0 g, 59.5 mmol) in methanol (150 ml), thionyl chloride (21.2 g,
178.4 mmol) is added at 0–5°C. Stirring is continued for 2 h at 0°C and 48 h at room temperature.
The solvent is removed under reduced pressure and the residue is recrystallized twice from methanol.
The dihydrochloride intermediate (21.3 g, 47.5 mmol) is suspended in dichloromethane (150 ml) and
triethylamine (10.1 g, 100 mmol) is added with stirring at room temp. After addition of diethyl ether

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(30 ml), triethylamine hydrochloride is removed by filtration. The filtrate is washed with water and dried
with MgSO4. Evaporation of the solvent under reduced pressure gives the pure title compound. Yield:
16.9 g (78%); [α]2D0=+111.2 (c 1.56, CH2Cl2); IR (NaCl): ν=1740 cm−1 (C_O); 1H NMR (CDCl3, 300
MHz): δ=1.15–1.28, 1.42–1.55, 1.64–1.75 (3m, 14H, 2×H40, 2×H400, 2×H50, 2×H500, 2×H60, 2×H600,
H3a0, H3a00), 2.13–2.26 (m, 2H, H30, H300), 2.51–2.67 (m, 4H, 2×H1, 2×H2), 2.67–2.85 (m, 2H, H30,
H300), 3.04–3.09 (m, 2H, H6a0, H6a00), 3.16–3.27 (m, 2H, H20, H200), 3.15 (s, 6H, 2×OCH3); 13C NMR
(CDCl3): δ=24.2, 32.6, 34.4, 37.1 (C30, C300, C40, C400, C50, C500, C60, C600), 41.6 (C3a0, C3a00), 51.7
(C1, C2), 53.2 (2×OCH3), 68.4, 70.7 (C20, C200, C6a0, C6a00), 174.1 (2×C_O); MS (CI, i-butane): m/z
(%)=365 (100) [MH+]; anal. calcd for C20H32N2O2 (364.4): C, 65.89; H, 8.85; N, 7.69; found: C, 65.81;
H, 8.43; N, 7.44.
3.2. (all-R)-1,2-Bis[2-(diphenyl-methanol-yl)octahydro-cyclopenta[b]pyrrol-1-yl]ethane (all-R)-5
To a freshly prepared Grignard-solution consisting of bromobenzene (31.1 g, 198.2 mmol) and
magnesium (4.8 g, 198.2 mmol) in dry THF (350 ml), (all-R)-4 (4.5 g, 124 mmol; dissolved in 100
ml of dry THF) is added dropwise at 0–5°C within 1.5 h under argon atmosphere. The reaction mixture
is kept at room temperature for 80 h and the reaction is then quenched by the addition of a sat. aqueous
NH4Cl-solution (250 ml). After phase separation and extraction of the aqueous layer with toluene (40
ml), the combined organic phases are dried with MgSO4 and finally concentrated in vacuo. The resulting
yellow solid is recrystallized from dichloromethane/methanol. Yield (not optimized): 1.73 g (23%); mp:
20
1
238–239°C; [α]D =+70.7 (c 1.01, CH2Cl2); IR (NaCl): ν=3260 cm−1 (OH); H NMR (CDCl3, 300
MHz): δ=1.04–1.77 (4m, 16H, H30, H300, 2×H40, 2×H400, 2×H50, 2×H500, 2×H60, 2×H600, H3a0,
H3a00), 1.91–2.10 (2m, 4H, 2×H1, 2×H2), 2.19–2.25 (m, 2H, H30, H300), 2.44–2.53 (m, 2H, H6a0,
H6a00), 3.83 (d, J=14 Hz, 2H, H20, H200), 4.95–5.15 (s, 2H, 2×OH), 7.05–7.75 (m, 20H, aromat.-H); 13
C
NMR (CDCl3): δ=23.8, 32.1, 35.1, 35.9 (C30, C300, C40, C400, C50, C500, C60, C600), 39.9 (C3a0, C3a00),
51.1 (C1, C2), 70.6, 72.0 (C20, C200, C6a0, C6a00), 74.8 (2×COH), 125.1, 125.3, 126.0, 126.1, 127.8,
128.2 (2×6 aromat.-C), 147.1, 148.9 (2×2 q. aromat.-C); MS (CI, i-butane): m/z (%)=613 (100) [MH+];
anal. calcd for C42H48N2O2 (612.1): C, 82.31; H, 7.89; N, 4.57; found: C, 81.59; H, 7.96; N, 4.12.
3.3. (all-R)-1,2-Bis[2-(cyclopentan-1-ol-1-yl)octahydro-cyclopenta[b]pyrrol-1-yl]ethane (all-R)-6
To a Grignard-solution consisting of 1,4-dibromobutane (11.1 g, 51.4 mmol) and magnesium (2.5,
102.7 mmol) in dry THF (500 ml), (all-R)-4 (2.3 g, 6.4 mmol; dissolved in 250 ml of dry THF)
is added dropwise at –5 to 0°C within 2 h. The reaction mixture is then kept at room temperature
for 80 h and hydrolyzed with sat. aqueous NH4Cl-solution. After phase separation and extraction
of the aqueous layer with toluene (40 ml), the combined organic phases are dried with MgSO4 and
concentrated in vacuo. The resulting brown crude oil is purified by column chromatography (silica gel
60, eluents: n-hexane:triethylamine 9:1, TLC: Rf-value: 0.90). Further purification was performed by
recrystallization from ethanol/diethyl ether. Yield (not optimized): 1.09 g (41%); mp: 83°C; [α]2D0=+59.3
(c 1.00, CH2Cl2); IR (NaCl): ν=3320–3440 cm−1 (OH); 1H NMR (CDCl3, 300 MHz): δ=1.29–2.01 (m,
32H, H30, H300, 2×H40, 2×H400, 2×H50, 2×H500, 2×H60, 2×H600, H3a0, H3a00, 8×CH2, cyclopentyl),
2.45–2.62 (m, 2H, 1×H30, 1×H300), 2.65–2.79 (m, 4H, 2×H1, 2×H2), 2.91–3.05 (m, 2H, H6a0, H6a00),
3.32 (d, J=14 Hz, 2H, H20, H200), 3.74 (s, 2H, 2×OH); 13C NMR (CDCl3): δ=22.7, 23.8, 24.4, 32.3, 35.2,
35.4, 37.7, 40.7 (C30, C300, C40, C400, C50, C500, C60, C600, 8×CH2, cyclopentyl), 41.2 (C3a0, C3a00),
53.8 (C1, C2), 72.4, 73.5 (C20, C200, C6a0, C6a00), 80.1 (2×COH); MS (CI, i-butane): m/z (%)=417 (100)

S. Wassmann et al. / Tetrahedron: Asymmetry 10 (1999) 4437–4445
4443
[MH+]; anal. calcd for C26H44N2O2 (416.3): C, 74.95; H, 10.64; N, 6.72; found: C, 74.32; H, 10.36; N,
6.55.
3.4. (all-R)-1,2-Bis[2-(pentan-3-ol-3-yl)octahydro-cyclopenta[b]pyrrol-1-yl]ethane (all-R)-7
To a freshly prepared Grignard-solution consisting of bromoethane (17.6 g, 161.1 mmol) and magne-
sium (3.92, 161.1 mmol) in dry THF (300 ml), (all-R)-4 (3.67 g, 10.1 mmol; dissolved in 100 ml of dry
THF) is added dropwise at 0–5°C within 0.5 h. The reaction mixture is then heated at reflux temperature
for 40 h. The heating bath is removed and a sat. aqueous NH4Cl-solution (200 ml) is added at room
temperature. After phase separation the aqueous layer is extracted with toluene (40 ml). The combined
organic phases are dried (MgSO4) and concentrated in vacuo. The crude solid is recrystallized from small
amounts of methanol. Yield (not optimized): 1.79 g (42%), colorless solid; mp: 109–111°C; [α]2D0=+64.2
(c 1.02, CH2Cl2); IR (NaCl): ν=3480 cm–1 (OH); 1H NMR (CDCl3, 300 MHz): δ=0.79–0.92 (m, 12H,
4×CH3), 1.21–1.36, 1.38–1.76 (2m, 22H, 2×H40, 2×H400, 2×H50, 2×H500, 2×H60, 2×H600, H3a0,
H3a00, 4×CH2), 1.82–1.94 (m, 2H, 1×H30, 1×H300), 2.46–2.61 (m, 2H, H30, H300), 2.62–2.76, 2.77–3.00
(2m, 8H, H6a0, H6a00, 2×H1, 2×H2, 2×OH), 3.05–3.17 (m, 2H, H20, H200); 13C NMR (CDCl3): δ=7.7,
8.0 (4×CH3), 23.8, 26.2, 30.4, 30.8 (C30, C300, C40, C400, C50, C500, C60, C600), 29.9, 30.8 (4×CH2),
40.8 (C3a0, C3a00), 60.0 (C1, C2), 72.3, 74.1 (C20, C200, C6a0, C6a00), 74.8 (2×COH); MS (CI, i-butane):
m/z (%)=421 (100) [MH+]; anal. calcd for C26H48N2O2 (420.2): C, 74.23; H, 11.50; N, 6.66; found: C,
74.53; H, 10.93; N, 6.60.
3.5. (all-R)-1,2-Bis[2-(1,3-diphenylpropan-2-ol-2-yl)octahydro-cyclopenta[b]pyrrol-1-yl]ethane
(all-R)-8
To a suspension of (all-R)-2-(octahydro-cyclopenta[b]pyrrol-20-yl)-1,3-diphenylpropan-2-ol7 (1.5 g,
4.7 mmol) and potassium carbonate (0.64 g, 4.7 mmol) in dry acetonitrile (50 ml), 1,2-dibromoethane
(0.44 g, 2.35 mmol) is added dropwise within 30 min at 70°C. Stirring is continued at a constant
temperature for 48 h. The solvent is removed in vacuo, the residue dissolved in dichloromethane (60
ml) and washed twice with water (20 ml). After drying with MgSO4 and evaporation of the solvent
the resulting crude oil is purified by column chromatography (silica gel 60, eluents: n-hexane:ethyl
acetate 9:1, with addition of triethylamine (10 ml) per 1 litre of the solvent mixture, TLC: Rf-value:
0.28). The resulting colorless solid is recrystallized from ethanol. Yield (not optimized): 0.56 g (36%);
20
1
mp: 145–148°C; [α]D =−38.8 (c 1.01, CH2Cl2); IR (NaCl): ν=3560 cm–1 (OH); H NMR (CDCl3,
300 MHz): δ=1.34–1.74 (m, 16H, H30, H300, 2×H40, 2×H400, 2×H50, 2×H500, 2×H60, 2×H600, H3a0,
H3a00), 2.10–2.24 (m, 4H, 2×H1, 2×H2), 2.39–2.49 (m, 2H, H30, H300), 2.63–2.72, 2.73–2.93 (2m, 8H,
4×CH2Ph), 3.10–3.19 (m, 4H, H6a0, H6a00, 2×OH), 3.32 (d, J=14 Hz, 2H, H20, H200), 7.16–7.27 (m,
20H, aromat.-H); 13C NMR (CDCl3): δ=24.0, 32.6, 35.2, 35.5 (C30, C300, C40, C400, C50, C500, C60,
C600), 40.2, 40.3 (4×CH2Ph), 44.8 (C3a0, C3a00), 54.9 (C1, C2), 70.7, 72.7 (C20, C200, C6a0, C6a00),
77.2 (2×COH), 126.0, 126.2, 127.8, 128.0, 130.6, 131.1 (2×6 aromat.-C), 137.9, 138.0 (2×2 q. aromat.-
C); MS (CI, i-butane): m/z (%)=669 (100) [MH+]; anal. calcd for C46H56N2O2 (668.2): C, 82.59; H,
8.44; N, 4.19; found: C, 83.09; H, 8.42; N, 4.05.
3.6. (all-R)-1,2-Bis[2-(1-phenyl-methanol-yl)octahydro-cyclopenta[b]pyrrol-1-yl]ethane (all-R)-9
To a suspension of (all-R)-2-(octahydro-cyclopenta[b]pyrrol-20-yl)-10-phenyl-methanol3d (0.87 g, 4.0
mmol) and potassium carbonate (0.55 g, 4.0 mmol) in dry acetonitrile (50 ml), 1,2-dibromoethane (0.37

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S. Wassmann et al. / Tetrahedron: Asymmetry 10 (1999) 4437–4445
g, 2.0 mmol; in 25 ml dry acetonitrile) is added dropwise within 30 min at 65°C. Stirring is continued at
85°C for 40 h under argon. The solvent is removed in vacuo, the residue dissolved in dichloromethane (50
ml) and washed twice with water (20 ml). After drying with MgSO4 and evaporation of the solvent the
resulting crude solid is purified by column chromatography (silica gel 60, eluents: n-hexane:triethylamine
9:1, TLC: Rf-value: 0.32). Yield (not optimized): 0.58 g (63%); mp: 94–97°C; [α]2D0=−4.0 (c 1.00,
1
CH2Cl2); IR (NaCl): ν=3040–3280 cm–1 (OH); H NMR (CDCl3, 300 MHz): δ=1.32–1.95 (m, 16H,
1×H30, 1×H300, 2×H40, 2×H400, 2×H50, 2×H500, 2×H60, 2×H600, H3a0, H3a00), 2.32–2.49, 2.52–2.74
(2m, 4H, 2×H1, 2×H2), 2.85–3.19 (m, 6H, 1×H30, 1×H300, 2×CHOH, H6a0, H6a00), 4.61 (d, J=14 Hz,
2H, H20, H200), 7.05–7.52 (m, 10H, aromat.-H); 13C NMR (CDCl3): δ=24.3, 32.3, 34.0, 37.5 (C30, C300,
C40, C400, C50, C500, C60, C600), 40.5 (C3a0, C3a00), 57.1 (C1, C2), 73.0, 75.6 (C20, C200, C6a0, C6a00),
76.2 (2×COH), 126.2, 126.9, 128.1 (2×3 aromat.-C), 143.9 (2×1 q. aromat.-C); MS (CI, i-butane): m/z
(%)=461 (100) [MH+]; anal. calcd for C30H40N2O2 (460.2): C, 78.22; H, 8.75; N, 6.08; found: C, 78.04;
H, 8.66; N, 5.98.
3.7. (all-S)-1,2-Bis[2-(cyclopentan-1-ol-1-yl)pyrrolidon-1-yl]ethane (all-S)-10
To a suspension of (S)-10-(pyrrolidin-2-yl)cyclopentanol9 (2.0 g, 12.9 mmol) and potassium carbonate
(1.78 g, 12.9 mmol) in dry acetonitrile (150 ml), 1,2-dibromoethane (1.2 g, 6.45 mmol; in 25 ml dry
acetonitrile) is added dropwise within 30 min at 80°C. Stirring is continued at 80°C for 48 h under
argon atmosphere. The solvent is removed in vacuo, the residue dissolved in dichloromethane (50 ml)
and washed twice with water (20 ml). After drying and evaporation of the solvent the resulting crude oil
is purified by column chromatography (silica gel 60, eluent: n-hexane:ethyl acetate:triethylamine 8:1:1,
TLC: Rf-value: 0.42). Yield (not optimized): 0.46 g (21%), highly viscous oil; [α]2D0=−27.2 (c 2.05,
1
CH2Cl2); IR (NaCl): ν=3300–3500 cm−1 (OH); H NMR (CDCl3, 300 MHz): δ=1.35–1.85 (m, 24H,
8×CH2, 2×H30, 2×H300, 2×H40, 2×H400), 2.32–2.41, 2.45–2.63 (2m, 4H, 2×H1, 2×H2), 2.70–2.82,
2.85–3.05 (2m, 4H, 2×H50, 2×H500), 3.12–3.15 (m, 2H, H20, H200), 3.92 (s, 2H, 2×OH); 13C NMR
(CDCl3): δ=23.6, 24.0, 25.2, 28.0 (8×C, cyclopentyl), 35.6, 38.6 (C30, C300, C40, C400), 56.0, 58.6 (C1,
C2, C50, C500), 71.9 (C20, C200), 84.2 (2×COH); MS (CI, i-butane): m/z (%)=337 (100) [MH+]; anal.
calcd for C20H36N2O2 (336.4): C, 71.38; H, 10.78; N, 8.32; found: C, 71.24; H, 10.43; N, 8.15.
3.8. General procedure
Enantiocontrolled addition of diethylzinc to benzaldehyde in the presence of catalytic amounts of
amino alcohols 5–14 (the results are summarized in Table 1) is described below.
Under argon atmosphere a solution of 1.0 mmol of the respective catalyst precursor (alternatively
0.5, 0.25 or 0.1 mmol, i.e. 10, 5, 2 or 1 mol% of amino alcohols 5–14) in anhydrous toluene (20 ml)
is prepared. After cooling to −40°C (with ethanol/liquid nitrogen), 18.2 ml (20 mmol) of a 1.1 M
diethylzinc solution in toluene are added within 10 min. After 30 min with stirring at constant temperature
the clear solution is allowed to warm to room temperature. Then freshly distilled benzaldehyde (1.06 g,
10 mmol), dissolved in anhydrous toluene (20 ml), is added over a 30-min period. The mixture is stirred
for an additional 40 h and quenched at 0°C by the addition of 60 ml 2N aqueous HCl. After separation of
the layers, the water phase is extracted with diethyl ether (3×40 ml) and the combined organic extracts
are subsequently washed with 3.9% NaHSO3-solution (3×40 mL), saturated aqueous NaHCO3-solution
and finally with brine. After drying with MgSO4 solvents are removed under reduced pressure and the
residual oil is purified by distillation in vacuo (chemical yields of 1-phenylpropan-1-ol: between 29 and
82%). The enantiomeric excess (ee) is determined by chiral GC analysis performed on a Shimadzu GC-

S. Wassmann et al. / Tetrahedron: Asymmetry 10 (1999) 4437–4445
4445
15a instrument (25 m chiral column: SGE Cydex-B, ωi=0.25 mm, film thickness: 0.25 µm, 1 µl product
in n-hexane, detection: FID, carrier gas: nitrogen).
Acknowledgements
We express our thanks to Degussa AG, Hoechst AG, Witco GmbH and the Fonds der Chemischen
Industrie for generously providing the chemicals and for financial support.
References
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