Kinetic enzymatic resolution of cyclopropane derivatives

Article abstract of DOI:10.1055/s-1999-2983

The kinetic enzymatic resolution of cyclopropane acetates was systematically investigated utilizing 16 different hydrolases. Best results were obtained with hydrolyses in the presence of Candida antarctica B lipase.

Full text of DOI:10.1055/s-1999-2983

LETTER
1981
Kinetic Enzymatic Resolution of Cyclopropane Derivatives
Jörg Pietruszka*, Thorsten Wilhelm, Andreas Witt
Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
Fax +711 685 4269; E-mail: joerg.pietruszka@po.uni-stuttgart.de
Received 13 October 1999
We then performed similar studies with racemic and enan-
tiomerically enriched cyclopropanol rac-4 and (1S,2S)-4
(75% ee) and acetates rac-5 and (1S,2S)-5 (75% ee), ob-
tained from cyclopropylboronic esters 6 and 7 (dr 88:12),
respectively (Scheme 1).5,6
Abstract: The kinetic enzymatic resolution of cyclopropane ace-
tates was systematically investigated utilizing 16 different hydro-
lases. Best results were obtained with hydrolyses in the presence of
Candida antarctica B lipase.
Key words: enzymes, enantiomeric resolution, cyclopropanes,
asymmetric synthesis, boron
Me
CO2i-Pr
CO2i-Pr
C5H11
O
O
C5H11
O
O
Kinetic resolutions using hydrolases have been extensive-
ly investigated and applied in organic synthesis.1 In view
of the increasing interest in cyclopropane derivatives it is
surprising that only a few successful examples are known
in cyclopropane chemistry. In general, except for meso-
configurated compounds, mediocre enantioselectivities
are obtained when the cyclopropane moiety contains the
only stereogenic unit in the molecule (e.g. compounds
1-3).2-4 We sought to optimize the kinetic resolution of 3
with various hydrolases (Table 1), solvents and reaction
temperatures. The best results were obtained with Mucor
miehei lipase (THF, phosphate buffer pH 7, 60 °C), but
enantioselectivity enhancements were unacceptable.
Me
Me
B
B
Me
7 (dr 88:12)
6
ref. 6a-c
ref. 5, 6d
C5H11
C5H11
OH
OH
(1S,2S)-4 (75% ee)
rac-4
Ac2O, pyridine
88%
C5H11
C5H11
OAc
OAc
(1S,2S)-5 (75% ee)
rac-5
O
AcO
Scheme 1
Ph
O
CO2Me
All attempts to selectively acetylate cyclopropanol rac-4
with vinyl acetate in the presence of an enzyme failed. At
67% (calculated) turnover, the enantiomeric excess of the
cyclopropanol (1R,2R)-4 was similar to that observed in
the diastereoselective approach using cyclopropylboronic
ester 7, nevertheless this route was still impractical. Better
results were obtained from hydrolysis, with CAL-B
(E = 44; THF, phosphate buffer pH 7, 60 °C) superior to
other enzymes (Scheme 2).7 Although these findings were
promising, it was obvious that by using this protocol enan-
tiomerically pure cyclopropanols could not be obtained in
just one cycle. However, since the enantiomerically en-
riched cyclopropanol (1S,2S)-4 is synthesized from cyclo-
propylboronic ester 7 as conveniently as the racemic
compound rac-4 from the corresponding ester 6, only one
enzymatic purification step gave the enantiomerically
pure product (1S,2S)-4 (ee >98%; turnover 78%).
E = 20; ref. 4a
E = 36; ref. 4b
E = 23; ref. 4c
1
2
3
Figure 1
Similar results could be obtained with the cyclo-
propanes 9 and 10, respectively. Again, racemic and enan-
tiomerically enriched compounds were both readily
synthesized from cinnamyl alcohol (8) (Scheme 3). In this
case the Simmons-Smith reaction was used,8 following the
Furukawa protocol to get rac-9 (83%),9 and utilizing the
Synlett 1999, No. 12, 1981–1983 ISSN 0936-5214 © Thieme Stuttgart · New York

1982
J. Pietruszka et al.
LETTER
ferior to the catalytic asymmetric cyclopropanation reac-
tion. Hydrolysis of rac-10 was achieved best in the
presence of CAL-B. In this case the selectivity could be
increased by changing the solvent from THF (E = 5.3),
pentane (E = 7.3) and toluene (E = 13) to dichlo-
romethane (E = 24). Again, the enantiomeric excess ob-
tained was not sufficient to get the enantiomerically pure
compound, but starting from the enantiomerically en-
riched (1'S,2'S)-10 (87% ee from the enantioselective cat-
alytic reaction) did efficiently yield the pure enantiomer
(ee >98%, 88% turnover, 77% yield).13
PCL, E = 13,
toluene, 40 °C
Ph
Ph
OH
Ph
Ph
OH
(1'R,2'R)-9
Ph
Ph
OAc
(1'S,2'S)-10
(53% ee)
vinyl acetate
rac-9
(78% ee)
OAc
OH
OAc
(1'R,2'R)-10
rac-10
(1'S,2'S)-9
(78% ee)
(82% ee)
CAL-B, E = 24
CH2Cl2, 40 °C,
phosphate buffer
Glc trace for the enantioseparation of cyclopropanol 4 and acetate 5
(dotted arrows: minor enantiomers). Conditions: 0.5 bar H2, 3 min
at 60 °C then 2 °C/min. Stationary phase: Bondex b (25 m glass
capillary).
turnover: 88%
yield: 77%
Ph
OAc
(1'R,2'R)-10
Ph
OH
(1'S,2'S)-9
(>98% ee)
Scheme 2
(87% ee)
Scheme 4
Denmark conditions10 to furnish (1’S,2’S)-9 (90%, 87%
ee) in the presence of ligand 11.11,12 The enantiomeric ex-
cess for these compounds was determined by hplc
(Chiracel OD, hexane:isopropanol 99.6:0.4 to 95:5).
Given that the maximum yield of a kinetic enzymatic res-
olution is <50% (exception: meso-compounds), versus an
enantioselective catalysis that does not yield enantiomer-
ically pure cyclopropanes, the herein reported combina-
tion of both would be the most efficient protocol. In
conclusion, we did not only get high E-values (for cyclo-
propanes) for the lipase-catalyzed transformation, but
could also propose a practical route to pure compounds.
The evaluation of the generality of this approach is cur-
rently under investigation in our laboratories.
1. Et2Zn, 0.1 eq. 11, CH2Cl2, 0 °C
2. ZnI2, CH2Cl2, 0 °C
3. Et2Zn, CH2I2, CH2Cl2, 0 °C
Ph
OH
(90%)
8
NHTs
NHTs
1. Et2Zn, CH2Cl2, 0 °C
2. Et2Zn, CH2I2, CH2Cl2, 0 °C
(83%)
11
Acknowledgement
The generous support of Prof. Dr. V. Jäger and Prof. Dr. Dr. h. c. F.
Effenberger (University of Stuttgart) is gratefully acknowledged.
We are greatly indepted to PD Dr. Uwe Bornscheuer for valuable
advice. This work was supported by the Fonds der Chemischen In-
dustrie, the Deutsche Forschungsgemeinschaft, the Boehringer In-
gelheim KG, the Novartis AG, the Degussa AG, the Bayer AG, the
Boehringer Mannheim GmbH and Amano Pharmaceutical Co., Ltd.
Ph
OH
Ph
OH
rac-9
(1'S,2'S)-9
(87% ee)
Ac2O, NEt3, DMAP, 97%
References and Notes
Ph
OAc
Ph
OAc
(1'S,2'S)-10
(87% ee)
rac-10
(1) (a) Faber, K. Biotransformation in organic chemistry - a
textbook; Springer: Heidelberg, 1997; (b) Schmid, R. D.;
Verger, R. Angew. Chem. 1998, 110, 1694; Angew. Chem. Int.
Ed. 1998, 37, 1608; (c) Drauz, K.; Waldmann, H. Enzyme
Catalysis in Organic Synthesis; Wiley-VCH: Weinheim,
1995; (d) Bornscheuer, U.; Kazlauskas, R. Hydrolases in
Organic Synthesis – Biotransformations with Lipases,
Esterases and Proteases; Wiley-VCH: Weinheim, 1999.
Scheme 3
Although the enzymatic conversion of alcohol rac-9 gave
slightly better selectivities (up to E = 13; PCL, toluene,
40 °C) than for cyclopropanol rac-4, these results were in-
Synlett 1999, No. 12, 1981–1983 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Kinetic Enzymatic Resolution of Cyclopropane Derivatives
1983
(2) (a) Varadarajan, S.; Mohapatra, D. K.; Datta, A. Tetrahedron
Lett. 1998, 39, 1075; (b) Itoh, T.; Emoto, S.; Kondo, M.
Tetrahedron 1998, 54, 5225.
Kleewein, A.; Faber, K. Tetrahedron: Asymmetry 1997, 8,
3251.
(8) (a) H. E. Simmons, R. D. Smith, J. Am. Chem. Soc. 1958, 80,
5323; (b) H. E. Simmons, R. D. Smith, J. Am. Chem. Soc.
1959, 81, 4256; (c) H. E. Simmons, T. L. Cairns, S. A.
Vladuchick, C. M. Hoiness, Org. React. (N.Y.) 1973, 20, 1.
(9) (a) Nishimura, J.; Furukawa, J.; Kawabata, N.; Kitayama, M.
Tetrahedron 1971, 1799; (b) Furukawa, J.; Kawabata, N.;
Nishimura, J. Tetrahedron Lett. 1966, 3353; (c) Furukawa, J.;
Kawabata, N.; Nishimura, J. Tetrahedron 1968, 53.
(10) (a) Denmark, S. E.; O'Connor, S. P. J. Org. Chem. 1997, 62,
3390; (b) Denmark, S. E.; O'Connor, S. P. J. Org. Chem. 1997,
62, 584; (c) Denmark, S. E.; Christenson, B. L.; Coe, D. M.;
O'Connor, S. P. Tetrahedron Lett. 1995, 36, 2215;
(3) (a) Ader, U.; Breitgoff, D.; Klein, P.; Laumen, K. E.;
Schneider, M. P. Tetrahedron Lett. 1989, 30, 1793; (b) Kasel,
W.; Hultin, P. G.; Jones, J. B. J. Chem. Soc., Chem. Commun.
1985, 1563; (c) Laumen, K.; Schneider, M. Tetrahedron Lett.
1985, 26, 2073; (d) Mohr, P.; Waespe-Sarcevic, N.; Tamm, C.
Helv. Chim. Acta 1983, 66, 2501; (e) Sabbioni, G.; Shea, M.
L.; Jones, J. B. J. Chem. Soc., Chem. Commun. 1984, 236;
(f) Sabbioni, G.; Jones, J. B. J. Org. Chem. 1987, 52, 4565;
(g) Schneider, M.; Engel, N.; Hönicke, P.; Heinemann, G.;
Görisch, H. Angew. Chem. 1984, 96, 55; Angew. Chem. Int.
Ed. 1984, 23, 67; (h) Walser, P.; Renold, P.; N'Goka, V.;
Hosseinzadeh, F.; Tamm, C. Helv. Chim. Acta 1991, 74, 1941.
(4) (a) Csuk, R.; Schabel, M. J.; von Scholz, Y. Tetrahedron:
Asymmetry 1996, 7, 3505; (b) Guibe-Jampel, E.; Rousseau,
G.; Blanco, L. Tetrahedron Letters 1989, 30, 67; (c) Barnier,
J.-P.; Blanco, L.; Rousseau, G.; Guibé-Jambel, E. J. Org.
Chem. 1993, 58, 1570.
(5) (a) Pietruszka, J.; Widenmeyer, M. Synlett 1997, 977;
(b) Luithle, J. E. A.; Pietruszka, J. Liebigs Ann./Recueil 1997,
2297.
(6) (a) Fontani, P.; Carboni, B.; Vaultier, M.; Carrié, R.
Tetrahedron Lett. 1989, 30, 4815; (b) Fontani, P.; Carboni, B.;
Vaultier, M.; Maas, G. Synthesis 1991, 605; (c) Hildebrand, J.
P.; Marsden, S. P. Synlett 1996, 893; (d) Imai, T.; Mineta, H.;
Nishida, S. J. Org. Chem. 1990, 55, 4986.
(7) The enantiomeric purity of the products was determined by
glc using a Bondex b stationary phase: Fischer, P.; Aichholz,
R.; Bölz, U.; Juzu, M.; Krimmer, S. Angew. Chem. 1990, 102,
439; Angew. Chem. Intl. Ed. Engl. 1990, 29, 427. Since in a
kinetic resolution the enantiomeric excess of product and
starting material varies as the reaction proceeds, it is more
meaningful to use the E-value (enantiomeric ratio; measures
the ability of the enzyme to distinguish between enantiomers)
to compare reactions (see ref. 1, cit. ref.). A simple program to
calculate the E-value for given enantiomeric ratios is available
free of charge at http://www-orgc.tu-graz.ac.at: Kroutil, W.;
(d) Denmark, S. E.; Christenson, B. L.; O'Connor, S. P.
Tetrahedron Lett. 1995, 36, 2219.
(11) Takahashi, H.; Yoshioka, M.; Shibasaki, M.; Ohno, M.; Imai,
N.; Kobayashi, S. Tetrahedron 1995, 51, 12013.
(12) Alternative synthesis of (3-phenylcyclopropyl)methanol
(93% ee) using equimolar amounts of a chiral modifier:
Charette, A. B.; Lebel, H. Org. Synth. 1998, 76, 86.
(13) Experimental Procedure: CAL-B (1.20 g; 'Chirazyme L 2')
was suspended in 40 mL phosphate buffer (pH 7) and 3.40 g
(17.5 mmol) (1'S,2'S)-10 (87% ee) in 20 mL CH2Cl2 was
added. After 22 h at 40 °C (monitored by hplc) the organic
layer was separated, the aqueous layer extracted with CH2Cl2,
and the combined layer dried over MgSO4. Chromatographic
separation (petroleum ether 40-60:EtOAc 9:1 to 3:1) followed
by Kugelrohr destillation (80 °C/0.5 torr) yielded 2.00 g (13.5
mmol, 77%) of the pure (3-phenylcyclopropyl)methanol
(1'S,2'S)-9 (>98% ee). The spectroscopic data were in full
agreement with those published previously; [a]20D = +86 (c
1.0, EtOH), C10H12O (148.20): calcd. C 81.04, H 8.16; found
C 81.03, H 8.21.
Article Identifier:
1437-2096,E;1999,0,12,1981,1983,ftx,en;L17299ST.pdf
Synlett 1999, No. 12, 1981–1983 ISSN 0936-5214 © Thieme Stuttgart · New York