New C2-symmetric 2,4-bis(1-hydroxycyclopentyl)azetidines derived from (S)-1-phenylethylamine and their application in the enantioselective catalysis

Article abstract of DOI:10.1016/S0957-4166(00)00155-5

The synthesis of new tridental 2,4-bis(1-hydroxycyclopentyl)azetidines using (S)-1-phenylethylamine as starting material is described. These new structures have been successfully applied in the enantiocontrolled catalytic addition of diethylzinc to aromatic aldehydes reaching enantiomeric excesses of up to 85% for the resulting 1-arylpropan-1-ols. Attempts in the field of the enantioselective oxazaborolidine-catalyzed reduction of ketones employing azetidine alcohols as precatalysts are also included. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00155-5

Tetrahedron: Asymmetry 11 (2000) 2143±2148
New C2-symmetric 2,4-bis(1-hydroxycyclopentyl)azetidines
derived from (S)-1-phenylethylamine and their application in
the enantioselective catalysis
Jorg Wilken,a Silke Erny,b Suzanne Wassmannc and Jurgen Martensb,*
aHoneywell, Specialty Chemicals, Seelze GmbH, Wunstorfer Str. 40, 30926 Seelze, Germany
bFachbereich Chemie der Universitat Oldenburg, Carl-von-Ossietzky-Str. 9±11, 26129 Oldenburg, Germany
È
cGesellschaft fur Biotechnologische Forschung (GBF), Mascheroder Weg 1, 38124 Braunschweig, Germany
È
Received 19 March 2000; accepted 25 April 2000
Abstract
The synthesis of new tridental 2,4-bis(1-hydroxycyclopentyl)azetidines using (S)-1-phenylethylamine as
starting material is described. These new structures have been successfully applied in the enantiocontrolled
catalytic addition of diethylzinc to aromatic aldehydes reaching enantiomeric excesses of up to 85% for the
resulting 1-arylpropan-1-ols. Attempts in the ®eld of the enantioselective oxazaborolidine-catalyzed
reduction of ketones employing azetidine alcohols as precatalysts are also included. # 2000 Elsevier
Science Ltd. All rights reserved.
1. Introduction
Even though particularly ecient ligands for the enantiocontrolled ethylation by diethylzinc
have been reported, the design of new ligands has been continuously attracting research interest.1
In fact, from a practical viewpoint, it is still of strong current interest to develop highly e€ective
ligands meeting levels suitable for practical application.
Prompted by recent reports on the application of tridental, small-ring heterocycles such as
aziridine alcohols2 and 2,5-disubstituted pyrrolidine derivatives,3 we considered the utilization of
C2-symmetric azetidinyl-methanols4 as chiral catalysts in the addition of diethylzinc to aldehydes.
Here we report a facile synthesis of stereoisomeric pairs of 2,4-bis(1-hydroxycyclopentyl)azetidins
bearing two cyclopentanol substituents on the carbon atoms adjacent to the nitrogen. In addition,
results of their application as catalysts in two asymmetric transformations are described.
* Corresponding author. E-mail: juergen.martens@uni-oldenburg.de
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00155-5

2144
J. Wilken et al. / Tetrahedron: Asymmetry 11 (2000) 2143±2148
2. Results and discussion
The synthesis of aminoalcohols 4±6 and 7, 8 is accomplished in a two- or three-step sequence
starting from (S)-1-phenylethylamine (see Scheme 1 depicted below). Diastereomers 1±3 of
known con®guration are available by Yamamoto's procedure5 via ring-closure reaction with
methyl 2,4-dibromopentanedioate (Scheme 1). Each diastereomer is converted to the corresponding
bis(cyclopentanol) structure 4±6 by reaction of the respective diester with an excess of 5 equiv. of
the difunctional Grignard reagent 1,4-bis(bromomagnesio)butane in THF with yields ranging
from 54 to 82%.6 Finally, catalytic hydrogenolysis of (10S,2S,4S)-4 and (10S,2R,4R)-5 over
palladium hydroxide on carbon gives the secondary amines (2S,4S)-7 (yield: 49%) and (2R,4R)-8
(45%), respectively.
Scheme 1. (a) See Ref. 5; (b) 5 equiv. of BrMg(CH2)4MgBr in THF at re¯ux temperature for 18 h, puri®cation by
column chromatography (silica gel, eluents: n-hexane/ethyl acetate), isolated yields: (10S,2S,4S)-4: 82%, (10S,2R,4R)-5:
68% and (10S,2S,4R)-6: 54%; (c) (1) H2/Pd(OH)2/C 24 h at room temperature in MeOH, (2) puri®cation by column
chromatography (silica gel, eluents: ethyl acetate:ethanol 3:7), isolated yields: (2S,4S)-7: 49% and (2R,4R)-8: 45%
The enantioselective addition of diethylzinc to various aromatic aldehydes has been conducted
in the presence of the optically active (pre-)catalysts 4±6 (Table 1 gives a summary of the results).
In a typical procedure the reaction was carried out at ^30 to 110ꢀC for 40 h with a catalyst
concentration of 2±20 mol% relative to the respective aldehyde. In general, the chemical yields
obtained after fractional distillation ranged from moderate to good (61±85%, with the exception
of entries 14 and 15). The process optimization with respect to the reaction temperature and the
catalyst concentration using benzaldehyde as a model substrate is described in entries 1±9. Entry

J. Wilken et al. / Tetrahedron: Asymmetry 11 (2000) 2143±2148
2145
2 displays the best result in terms of enantioselectivity. At a reaction temperature of 0ꢀC with 10
mol% of ligand 4 the ethylation product 10a is obtained in 76% chemical yield and 77% e.e.7 The
di€erences in comparison with entries 8 and 9 Ð employing a catalyst concentration of 5 and 20
mol% Ð are only marginal (73 and 75% e.e., respectively).
Table 1
Enantioselective addition of diethylzinc to aromatic aldehydes (substrates 9a±e, see Scheme 2 depicted above) catalyzed
by ligands 4±6; products: 1-phenylpropan-1-ol 10a, 1-(4-chlorophenyl)propan-1-ol 10b, 1-(4-methylphenyl)propan-1-ol
10c, 1-(4-methoxy-phenyl)propan-1-ol 10d and 1-(2-furanyl)propan-1-ol 10e
Scheme 2. Enantioselective catalytic ethylation of various aldehydes in the presence of the optically active catalysts 4±6

2146
J. Wilken et al. / Tetrahedron: Asymmetry 11 (2000) 2143±2148
Furthermore, ligand 4 was also successfully tested for the conversion of other aromatic aldehydes
9b±e with a maximum e.e. value of 85% for the formation of 1-(4-chlorophenyl)propan-1-ol 10b
(entry 12).
A comparison between the structures 4, 5 and 6 (entries 2, 10 and 11) reveals the minor in¯uence
of the third, (S)-1-phenylethylamine derived stereogenic center on the asymmetric induction.
The best result is obtained with an (all-S)-con®guration of the three internal stereogenic centers in
ligand 4 (entry 2) with a predominant formation of the (S)-con®gurated ethylation product in
77% e.e. By changing to a less favored situation in terms of inductive capability (ligand 5) an only
slightly diminished result (entry 10: 73% e.e.) together with a (R)-con®guration of the addition
product is obtained. As expected structure 6 gives only a very low e.e. value (entry 11: 9% e.e.).
A second application chosen to test the inductive capabilities of the new structures is the
homogeneous catalytic reduction of various aromatic ketones with in situ formed oxazabor-
olidine catalysts8 derived from enantiomerically pure ligands 7 and 8, respectively. The conver-
sion of these b-amino bis-alcohols to oxazaborolidines is accomplished by treatment with BH3/
THF. No further puri®cation or characterization of the resulting intermediate was carried out. In
a representative procedure 1±5 mol% of 7 or 8 in THF are employed as precatalysts at a reaction
temperature of +30ꢀC in the reduction of acetophenone, o-chloro-acetophenone or propio-
phenone. In general, good chemical yields (76 to 91% after distillation) are reached whereas the
corresponding enantioselectivities are moderate to low with e.e. values only ranging from 35 to
54%.
In conclusion, the synthesis of a family of simple, tricyclic azetidine alcohols is described which
are attractive because of their ready availability in both enantiomeric forms (7 and 8) and due to
their bene®cial structural features (C2-symmetry, limited ¯exibility). These new chiral structures
eciently catalyze the diethylzinc addition to aromatic aldehydes with up to 85% e.e., which is
slightly below the results reported by Shi et al.4 for related C2-symmetric azetidines bearing two
¯exible methoxy groups.
3. Experimental
All reactions were carried out in oven dried glassware under an argon atmosphere using anhy-
drous 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. Linstrom and are uncorrected. Optical rotations were measured on a
Perkin±Elmer automatic polarimeter. IR spectra were recorded on a Philips PU 9706 spectro-
1
photometer. The H NMR and 13C NMR spectra were registrated on a Bruker AM 300 spec-
trometer 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. Commercially available chemicals were used.
The enantiocontrolled diethylzinc reactions9 and the oxazaborolidine catalyzed reductions10
were conducted according to previously published procedures.
3.1. General procedure: conversion of 1±3 to 4±6 with 1,4-bis(bromomagnesio)butane
To a freshly prepared Grignard reagent generated from 1.54 g (63.1 mmol) magnesium and
6.81 g (31.6 mmol) 1,4-dibromobutane in 50 ml dry THF is added dropwise a solution of

J. Wilken et al. / Tetrahedron: Asymmetry 11 (2000) 2143±2148
2147
1.75 g (6.3 mmol) of compounds 1±35 in 10 ml THF at room temperature. After the addition, the
reaction mixture is stirred at re¯ux temperature for 18 h. Then the reaction is hydrolyzed with an
aqueous solution of NH4Cl and the aqueous phase is extracted twice with 30 ml of diethyl ether.
The combined organic layers are washed with brine, dried with magnesium sulfate and con-
centrated in vacuo. The resulting crude products are puri®ed by column chromatography on
silica gel.
3.1.1. (10S,2S,4S)-1-[(S)-10-Phenethyl]-2,4-bis(1-hydroxycyclopentyl)azetidine (10S,2S,4S)-4
Column chromatography: n-hexane:ethyl acetate 6:4 (Rf-value: 0.54). Yield: 1.70 g (82%),
colorless solid; mp: 126±128ꢀC; ‰ꢀŠD20=^52.0 (c=1.01, CHCl3); IR (KBr): ꢁ=3640±3410 cm^1
(OH); 1H NMR (CDCl3, 300 MHz): ꢂ=1.11±1.88 (m, 16H, 8ÂCH2, cyclopentyl), 1.28 (d, J=7.1
Hz, 3H, PhCHCH3), 2.00±2.20 (m, 2H, CH2), 2.85 (s, 2H, OH), 3.65±3.80 (m, 2H, 2ÂCH), 4.45
(q, J=7.1 Hz, 1H, PhCHCH3), 7.10±7.40 (m, 5H, aromat.-H); 13C NMR (CDCl3): ꢂ=23.04
(PhCHCH3), 23.52, 25.20, 37.51, 40.55 (9ÂCH2), 56.23 (PhCHCH3), 66.92 (2ÂCH), 82.97
(2ÂCOH), 126.17, 126.42, 128.41 (aromat.-C), 146.55 (q. aromat.-C); MS (CI, i-butane): m/z
(%)=330 (100) [MH+]. Anal. calcd for C21H31NO2 (329.5): C, 76.55; H, 9.48; N, 4.25; found: C,
76.40; H, 9.48; N, 3.98.
3.1.2. (10S,2R,4R)-1-[(S)-10-Phenethyl]-2,4-bis(1-hydroxycyclopentyl)azetidine (10S,2R,4R)-5
Column chromatography: n-hexane:ethyl acetate 2:8 (Rf-value: 0.45). Yield: 1.41 g (68%),
slightly colored solid; mp: 113ꢀC; ‰ꢀŠD20=+5.1 (c=1.04, CHCl3); IR (KBr): ꢁ=3635±3400 cm^1
(OH); 1H NMR (CDCl3, 300 MHz): ꢂ=1.11±1.92 (m, 16H, 8ÂCH2, cyclopentyl), 1.45 (d, J=7.1
Hz, 3H, PhCHCH3), 1.96±2.07 (m, 2H, CH2), 2.77 (s, 2H, OH), 3.69±3.80 (m, 2H, 2ÂCH), 4.44
(q, J=7.1 Hz, 1H, PhCHCH3), 7.20±7.47 (m, 5H, aromat.-H); 13C NMR (CDCl3): ꢂ=19.25
(PhCHCH3), 23.06, 23.28, 25.03, 37.26, 39.10 (9ÂCH2), 55.23 (PhCHCH3), 66.78 (2ÂCH), 82.67
(2ÂCOH), 127.39, 128.21, 128.85 (aromat.-C), 141.47 (q. aromat.-C); MS (CI, i-butane): m/z
(%)=330 (100) [MH+]. Anal. calcd for C21H31NO2 (329.5): C, 76.55; H, 9.48; N, 4.25; found: C,
76.32; H, 9.55; N, 4.13.
3.1.3. (10S,2S,4R)-1-[(S)-10-Phenethyl]-2,4-bis(1-hydroxycyclopentyl)azetidine (10S,2S,4R)-6
Column chromatography: n-hexane:ethyl acetate 1:1 (Rf-value: 0.54). Yield: 1.12 g (54%), viscous
20
1
oil; ‰ꢀŠD =+7.3 (c=8.35, CHCl3); IR (KBr): ꢁ=3620±3400 cm^1 (OH); H NMR (CDCl3, 300
MHz): ꢂ=1.17±1.95 (m, 18H, 8ÂCH2, cyclopentyl, CH2, azetidine ring), 1.50 (d, J=7.1 Hz, 3H,
PhCHCH3), 2.80 (s, 2H, OH), 3.24±3.41 (m, 2H, 2ÂCH), 3.85 (q, J=7.1 Hz, 1H, PhCHCH3),
7.18±7.40 (m, 5H, aromat.-H); 13C NMR (CDCl3): ꢂ=16.54 (PhCHCH3), 20.67, 23.16, 24.43,
24.49, 35.37, 35.48, 38.82, 39.01 (9ÂCH2), 60.00, 62.76, 65.21 (3ÂCH), 82.06, 82.26 (2ÂCOH),
127.35, 127.97, 128.37 (aromat.-C), 142.81 (q. aromat.-C); MS (CI, i-butane): m/z (%)=330 (100)
[MH+]. Anal. calcd for C21H31NO2 (329.5): C, 76.55; H, 9.48; N, 4.25; found: C, 76.25; H, 9.40;
N, 4.01.
3.2. General procedure: synthesis of ꢃ-aminodiols 7 and 8 by catalytic hydrogenolysis of 4 and 5
A suspension of 1.47 g (4.46 mmol) of (10S,2S,4S)-4 or (10S,2R,4R)-5 dissolved in 30 ml
methanol and palladium hydroxide on charcoal is stirred under hydrogen atmosphere for 24 h at
room temperature. The catalyst is ®ltered o€ and washed twice with 50 ml methanol. The combined
methanol solutions are concentrated under reduced pressure yielding green, viscous oils. These

2148
J. Wilken et al. / Tetrahedron: Asymmetry 11 (2000) 2143±2148
crude products are further puri®ed by column chromatography (silica gel 60) utilizing ethyl acetate
and ethanol in a ratio of 3:7 as eluents.
3.2.1. (2S,4S)-2,4-Bis(1-hydroxycyclopentyl)azetidine (2S,4S)-7
Yield: 0.49 g (49%), colorless solid; mp: 127ꢀC; ‰ꢀŠD20=^40.2 (c=1.00, CHCl3); IR (KBr):
1
ꢁ=3620±3110 cm^1 (OH, NH); H NMR (CDCl3, 300 MHz): ꢂ=1.30±2.00 (m, 16H, 8ÂCH2,
cyclopentyl), 2.20±2.29 (m, 2H, CH2), 3.20 (s, 2H, 2ÂOH), 3.60±3.70 (m, 2H, 2ÂCH); 13C NMR
(CDCl3): ꢂ=22.89, 24.25, 24.47, 35.32, 37.67 (9ÂCH2), 62.35 (2ÂCH), 82.55 (2ÂCOH); MS (CI,
i-butane): m/z (%)=226 (100) [MH+]. Anal. calcd for C13H23NO2 (225.3): C, 69.30; H, 10.29; N,
6.22; found: C, 69.55; H, 10.41; N, 5.92.
3.2.2. (2R,4R)-2,4-Bis(1-hydroxycyclopentyl)azetidine (2R,4R)-8
Yield: 0.38 g (45%), colorless solid; mp: 125ꢀC; ‰ꢀŠD20=+37.8 (c=1.05, CHCl3); IR (KBr):
1
ꢁ=3640±3120 cm^1 (OH, NH); H NMR (CDCl3, 300 MHz): ꢂ=1.30±1.91 (m, 16H, 8ÂCH2,
cyclopentyl), 2.30±2.40 (m, 2H, CH2), 3.73±3.83 (m, 2H, 2ÂCH), 4.67 (s, 2H, 2ÂOH); 13C NMR
(CDCl3): ꢂ=22.29, 24.23, 24.56, 35.32, 37.76 (9ÂCH2), 63.15 (2ÂCH), 81.60 (2ÂCOH); MS (CI,
i-butane): m/z (%)=226 (100) [MH+]. Anal. calcd for C13H23NO2 (225.3): C, 69.30; H, 10.29; N,
6.22; found: C, 69.04; H, 10.11; N, 6.43.
Acknowledgements
We express our thanks to Degussa-Huls AG, Witco GmbH and the Fonds der Chemischen
Industrie for generously providing the chemicals and for ®nancial support.
References
1. (a) Noyori, R.; Kitamura, M. Angew. Chem. 1991, 103, 34; Angew. Chem., Int. Ed. Engl. 1991, 30, 49. (b) Soai, K.;
Niwa, S. Chem. Rev. 1992, 92, 833. (c) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley: New York,
1994. (d) Fitzpatrick, K.; Hulst, R.; Kellogg, R. Tetrahedron: Asymmetry 1995, 6, 1861. (e) Bolm, C.; Muniz, K.
J. Chem. Soc., Chem. Commun. 1999, 1295 and references cited therein.
2. (a) Willems, J. G. H.; Dommerholt, F. J.; Hammink, J. B.; Vaarhorst, A. M.; Thijs, L.; Zwanenburg, B.
Tetrahedron Lett. 1995, 36, 603. (b) Tanner, D.; Korno, H. T.; Guijarro, D.; Andersson, P. G. Tetrahedron 1998,
54, 14213. (c) Lawrence, C. F.; Nayak, S. K.; Thijs, L.; Zwanenburg, B. Synlett 1999, 10, 1571.
3. Shi, M.; Satoh, Y.; Makihara, T.; Masaki, Y. Tetrahedron: Asymmetry 1995, 6, 2109.
4. Shi, M.; Jiang, J.-K. Tetrahedron: Asymmetry 1999, 10, 1673.
5. Hoshino, J.; Hiraoka, J.; Hata, Y.; Sawada, S.; Yamamoto, Y. J. Chem. Soc., Perkin Trans. 1 1995, 693.
6. Reiners, I.; Wilken, J.; Martens, J. Tetrahedron: Asymmetry 1995, 12, 3063.
7. The linear correlation between o.p. and e.e. values was con®rmed for 1-phenylpropan-1-ol in the range from 0 to
100% o.p. See also: Kossenjans, M. Diploma Thesis, Universitat Oldenburg, 1996.
8. Corey, E. J.; Helal, C. J. Angew. Chem. 1998, 110, 2092; Angew. Chem., Int. Ed. Engl. 1998, 37, 1986 and
references cited therein.
9. Wassmann, S.; Wilken, J.; Martens, J. Tetrahedron: Asymmetry 1999, 10, 4437±4445.
10. Wilken, J.; Martens, J. Synth. Commun. 1996, 26, 4477±4485.