1716
J . Org. Chem. 2002, 67, 1716-1718
Sch em e 1
P r ep a r a tion of En a n tiop u r e Keton es a n d
Alcoh ols Con ta in in g a Qu a ter n a r y
Ster eocen ter th r ou gh P a r a llel Kin etic
Resolu tion of â-Keto Nitr iles
J uan R. Dehli and Vicente Gotor*
Departamento de Quı´mica Orga´nica e Inorga´nica,
Universidad de Oviedo, c/ J ulia´n Claverı´a, 8.
33006 Oviedo, Spain
vgs@sauron.quimica.uniovi.es
Received November 20, 2001
We decided then to merge both targets, and we chose
racemic 1-methyl-2-oxocycloalkanecarbonitriles 1 as sub-
strates for the bioreduction process. According to Prelog’s
rule,10 the formal introduction of the hydride would take
place from the re face of the carbonyl group, yielding the
corresponding alcohol of 2S configuration, which would
represent a parallel kinetic resolution (PKR): (R)-1 would
give u-2 and (S)-1, l-2 (see Scheme 1). Although this kind
of resolution is not completely new,11 the scarce biocata-
lytic examples described thus far do not allow for the
recuperation of the optically active substrate.12 In our
case, mild oxidation of the alcohol would let us recover
the enantioenriched ketone, which is what gives our
process additional value because compounds such as 1
are interesting building blocks for the preparation of
natural products13 and conformationally restricted amino
acids.14
Among the microorganisms tested at analytical scale15
for the bioreduction of (()-1a , the fungus Mortierella
isabellina NRRL 1757 gave the most satisfactory results.
Thus, after 2 h, a mixture of u-2a (>99% ee) and l-2a
(73% ee) was obtained in a 42:58 diastereomeric ratio.
To achieve efficient preparative-scale experiments at
gram scale, the substrate concentration was increased
to 10 g/L (75 mM) without any change as far as stereo-
chemistry was concerned. In a typical example, 1 g of
(()-1a was subjected to bioreduction using resting cells
grown in 100 mL of culture for 48 h16 and resuspended
in 100 mL of distilled water.17 After 7 h at 28 °C and 200
Abstr a ct: Racemic 1-methyl-2-oxocycloalkanecarbonitriles
have been subjected to bioreduction by the fungus Mortier-
ella isabellina NRRL 1757 through a parallel kinetic-
resolution process. The u and l alcohols thus obtained (up
to >99% ee) were easily separated and oxidized to the R and
S ketones, respectively. The process can be then repeated
so that both enantiomers of the ketone and two epimers of
the alcohol can be obtained in their enantiopure forms.
The asymmetric construction of molecules with qua-
ternary carbon stereocenters has represented a very
challenging and dynamic area in organic synthesis over
the past decade.1 Despite the numerous reports on
bioreduction of ketones, mainly by baker’s yeast,2 re-
ported in the literature, very few examples have made
use of bioreduction as a means to obtain optically active
compounds with fully substituted carbons, and in most
cases with only moderate success.3
On the other hand, the importance of optically active
â-hydroxy nitriles as suitable synthons for the prepara-
tion of γ-amino alcohols (like the antidepressant fluox-
etine)4 is steadily growing. Thus, recently, methodologies
have been developed to prepare these alcohols via clas-
sical kinetic resolution,5 dynamic kinetic resolution,6
reduction,7 alkylation-reduction,8 and addition9 pro-
cesses.
* Corresponding author.
(1) (a) Fuji, K. Chem. Rev. 1993, 93, 2037. (b) Corey, E. J .; Guzman-
Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388.
(2) (a) Servi, S. Synthesis 1990, 1. (b) Csuk, R.; Gla¨nzer, B. I. In
Stereoselective Biocatalysis; Patel, R. N., Ed.; Marcel Dekker, Inc.: New
York, 2000; Chapter 19, p 527.
(3) (a) Brooks, D. W. J . Org. Chem. 1982, 47, 2820. (b) Brooks, D.
W.; Woods, K. W. J . Org. Chem. 1987, 52, 2036. (c) Brooks, D. W.;
Mazdiyasni, H.; Grothaus, P. G. J . Org. Chem. 1987, 52, 3223. (d)
Fuhshuku, K.; Funa, N.; Akeboshi, T.; Ohta, H.; Hosomi, H.; Ohba,
S.; Sugai, T. J . Org. Chem. 2000, 65, 129.
(10) Prelog, V. Pure Appl. Chem. 1964, 9, 119.
(11) (a) Vedejs, E.; Chen, X. J . Am. Chem. Soc. 1997, 119, 2584. (b)
Eames, J . Angew. Chem., Int. Ed. 2000, 39, 885. (c) Bertozzi, F.; Crotti,
P.; Macchia, F.; Pineschi, M.; Feringa, B. L. Angew. Chem., Int. Ed.
2001, 40, 930.
(12) See, for example: (a) Konigsberg, K.; Alphand, V.; Furstoss,
R.; Griengl, H. Tetrahedron Lett. 1991, 32, 499. (b) Petit, F.; Furstoss,
R. Tetrahedron: Asymmetry 1993, 4, 1341. (c) Mischitz, M.; Faber, K.
Tetrahedron Lett. 1994, 35, 81.
(4) Koenig, T. M.; Mitchell, D. Tetrahedron Lett. 1994, 35, 1339.
(5) (a) Itoh, T.; Takagi, Y.; Nishiyama, S. J . Org. Chem. 1991, 56,
1521. (b) Itoh, T.; Takagi, Y.; Murakami, Y. J . Org. Chem. 1996, 61,
2158.
(6) Pa`mies, O.; Ba¨ckvall, J .-E. Adv. Synth. Catal. 2001, 343, 726.
(7) (a) Itoh, T.; Fukuda, T.; Fujisawa, T. Bull. Chem. Soc. J pn. 1989,
62, 3851. (b) Mehmandoust, M.; Buisson, D.; Azerad, R. Tetrahedron
Lett. 1995, 36, 6461. (c) Florey, P.; Smallridge, A. J .; Ten, A.; Trewhella,
M. A. Org. Lett. 1999, 1, 1879. (d) Dehli, J . R.; Gotor, V. Tetrahedron:
Asymmetry 2000, 11, 3693.
(8) (a) Itoh, T.; Takagi, Y.; Fujisawa, T. Tetrahedron Lett. 1989, 30,
3811. (b) Gotor, V.; Dehli, J . R.; Rebolledo, F. J . Chem. Soc., Perkin
Trans. 1 2000, 307. (c) Dehli, J . R., Gotor, V. Tetrahedron: Asymmetry
2001, 12, 1485.
(9) Soai, K.; Hirose, Y.; Sakata, S. Tetrahedron: Asymmetry 1992,
3, 677.
(13) Enders, D.; Zamponi, A.; Raabe, G.; Runsink, J . Synthesis 1993,
725 and references therein.
(14) Westermann, B.; Walter, A.; Diedrichs, N. Angew. Chem., Int.
Ed. 1999, 38, 3384.
(15) Typically, the substrate (1 g/L), solvated in ethanol (1% v/v),
was added to a suspension of resting cells in 35 mL of distilled water.
This mixture was then shaken (200 rpm) at 28 °C, and the reaction
was monitored by chiral GC.
(16) (a) Quiro´s, M.; Rebolledo, F.; Liz, R.; Gotor, V. Tetrahedron:
Asymmetry 1997, 8, 3035. (b) Quiro´s, M.; Rebolledo, F.; Gotor, V.
Tetrahedron: Asymmetry 1999, 10, 473.
(17) Recently, special emphasis has been placed on the substitution
of plain water for buffers, which simplifies the downstream processing
of a hypothetical industrial application. See, for example: Genzel, Y.;
Archelas, A.; Broxterman, Q. B.; Schulze, B.; Furstoss, R. J . Org. Chem.
2001, 66, 538.
10.1021/jo011092t CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/02/2002