Synthesis and Enzymatic Kinetic Resolution of α,α -Disubstituted Cyclic Hydroxy Nitriles

Article abstract of DOI:10.1021/jo035808r

Herein, we describe the diastereoselective synthesis of five- and six-membered α,α-disubstituted cyclic β-hydroxy nitriles and their resolution via enzymatic transesterification. By this method, all possible stereoisomers were obtained in enantiopure form and high yield.

Full text of DOI:10.1021/jo035808r

SCHEME 1a
Syn th esis a n d En zym a tic Kin etic
Resolu tion of r,r-Disu bstitu ted Cyclic
Hyd r oxy Nitr iles
Laura M. Levy and Vicente Gotor*
Departamento de Qu´ımica Orga´nica e Inorga´nica,
Facultad de Qu´ımica, Universidad de Oviedo,
J ulia´n Claverı´a, 8, 33071 Oviedo, Spain
a
Reagents and conditions: (i) 1.5 equiv of TiCl4, 1.5 equiv of
BH3‚py, DCM, -100 °C, 1 h; (ii) 3.2 equiv of CeCl3, 2 equiv of
LiEt3BH, THF, -100 °C, 2 h.
vgs@fq.uniovi.es
SCHEME 2
Received December 11, 2003
Abstr a ct: Herein, we describe the diastereoselective syn-
thesis of five- and six-membered R,R-disubstituted cyclic
â-hydroxy nitriles and their resolution via enzymatic trans-
esterification. By this method, all possible stereoisomers
were obtained in enantiopure form and high yield.
LiEt3BH as the nonchelating reagent to obtain the cis
diastereomers (Scheme 1).
The asymmetric construction of quaternary carbon
centers represents a challenging task in organic synthe-
sis.1 Despite numerous reports on bioreduction of ke-
tones2 and kinetic resolutions of secondary alcohols, very
few strategies utilize these two methods to obtain fully
substituted carbon atoms enantiomerically pure, and if
so, usually 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 flu-
oxetine)4 is steadily growing. Thus, methodologies have
been recently developed to prepare these alcohols via
classical5a or dynamic kinetic resolution,5b reduction,5c
alkylation-reduction,5d and addition processes.5e
Therefore, we decided to combine both targets and
chose racemic cis- and trans-1-alkyl-2-hydroxycyclo-
alkane nitriles 3 and 4 for the kinetic resolution via
enzymatic transesterification.
Keto nitriles 1 and 2 were synthesized via Thorpe-
Ziegler reaction using the corresponding dinitriles fol-
lowed by alkylation in R-position. After trying different
reagents in the subsequent diastereoselective reduction
(K-Selectride, Zn(BH4)2, CeCl3/NaBH4), Marcantoni’s and
Bartoli’s procedure for the reduction of keto esters6 gave
the best results. TiCl4/BH3‚py was used as the chelating
reagent to obtain the trans diastereomers and CeCl3/
Next, we carried out the resolution of racemic â-hy-
droxy nitriles trans-3, 4 by lipase Candida antarctica B
(CAL-B)-catalyzed enantioselective acylation using a
3-fold excess of vinyl acetate (VA) as the acyl donor in
tert-butyl methyl ether (TBME) at 30 °C (Scheme 2).
These conditions were chosen since they gave the best
results in our previous work on the resolution of cyclic
â-hydroxy esters.7
Under these reaction conditions, O-acylation of the
trans isomers (()-3a , 3b, 4a , and 4b took place smoothly,
and 50% conversion could be reached, yielding both the
substrates and the products in excellent enantiomeric
excess (ee g 99%), corresponding to excellent enantio-
selectivities (E > 200) in all cases (Table 1). With respect
to the ring size and the R-substituent, no difference in
the enantioselectivities could be observed. However,
CAL-B displayed a lower activity with R ) ally than with
R ) Me (compare entries 1, 2 with 3, 4). Furthermore,
CAL-B reacted more sluggishly with the six-membered
ring substrates in comparison to their five-membered
ring analogues (compare entry 1 with 2, Table 1).
The same methodology was then applied to the cis-
configurated â-hydroxy nitriles (()-3 and (()-4 (Scheme
3). In all cases, substrates and products were isolated in
very high yield and in excellent enantiomeric excess (ee
g 99%, E > 200) after 2-13 h (Table 2). Again, no
dependence of the enantioselectivity on the ring size was
observed. However, a considerably lower activity of
CAL-B toward (()-trans-4a , 4b in comparison to sub-
strates (()-cis-4a , 4b was obtained (compare entries 3
and 4 in Tables 1 and 2).
(1) (a) Fuji, K. Chem. Rev. 1993, 93, 2037. (b) Corey, E. J .; Guzman-
Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388.
(2) Czuk, R.; Glanzer, B. I. In Stereoselective Biocatalysis; Patel, R.
N., Ed.; Marcel Dekker, Inc.: New York, 2000; 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) Fuhshuku, K.;
Funa, N.; Akeboshi, T.; Ohta, H.; Hosomi, H.; Ohba, S.; Sugai, T. J .
Org. Chem. 2000, 65, 129. (d) Westermann, B.; Walter, A.; Raabe, G.;
Runsink, J . Synthesis 1993, 725.
(4) Koening, T. M.; Mitchell, D. Tetrahedron Lett. 1994, 35, 1339.
(5) (a) Itoh, T.; Tkagi, Y.; Nishiyama, S. J . Org. Chem. 1991, 56,
1521. (b) Pamies, O.; Backwall, J .-E. Adv. Synth. Catal. 2001, 343,
726. (c) Itoh, T.; Fukuda, T.; Fujisawa, T. Bull. Chem. Soc. J pn. 1989,
62, 3851. (d) Dehli, J . R.; Gotor, V. Tetrahedron: Asymmetry 2000,
11, 3693. (e) Soai, K.; Hirose, Y.; Sakata, S. Tetrahedron: Asymmetry
1992, 3, 677.
The assignment of the relative configuration of alcohols
4a and 4b has been done on the basis of their 13C NMR
1
and H-NOESY spectra, as had been previously reported
for substrates 3a and 3b (Figure 1).9 In the case of the
(7) Levy, L. M.; Dehli, J . R.; Gotor, V. Tetrahedron: Asymmetry
2003, 14, 2053.
(6) Marcantoni, E.; Alessandrini, S.; Malavolta, M.; Bartoli, G.;
Bellucci, M. C.; Sambri, L.; Dalpozzo, R. J . Org. Chem. 1999, 64, 1986.
(8) Chen, C. S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J . J . Am. Chem.
Soc. 1982, 104, 7294.
10.1021/jo035808r CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/27/2004
J . Org. Chem. 2004, 69, 2601-2602
2601

TABLE 1. CAL-B-Ca ta lyzed En a n tioselective Acyla tion of (()-tr a n s-â-Hyd r oxy Nitr iles
product substrate
yielda (%)
entry
n
R
substrate
t (h)
eeb (%)
yielda (%)
eeb (%)
cc (%)
Ec
1
2
3
4
1
2
1
2
Me
Me
allyl
allyl
(()-trans-3a
(()-trans-3b
(()-trans-4a
(()-trans-4b
4.0
12.5
34.0
30.0
40.5 (5a )
40.0 (5b)
42.5 (6a )
42 (6b)
>99
>99
>99
>99
47.0 (3a )
45.0 (3b)
48.5 (4a )
47.5 (4b)
>99
99
99
50
50
50
50
>200
>200
>200
>200
>99
a
b
After purification by flash column chromatography on SiO2. Determined by chiral GC. c Calculated from the e.e. of the substrate
and the product.8
TABLE 2. CAL-B-Ca ta lyzed En a n tioselective Acyla tion of (()-cis-â-Hyd r oxy Nitr iles
product
yielda (%)
substrate
yielda (%)
entry
n
R
substrate
t (h)
ee (%)b
eeb (%)
cc (%)
Ec
1
2
3
4
1
2
1
2
Me
Me
allyl
allyl
(()-cis-3a
(()-cis-3b
(()-cis-4a
(()-cis-4b
4
13
8
44.5 (7a )
43.0 (7b)
35.0d (8a )
49.0 (8b)
>99
>99
>99
>99
44.0 (3a )
44.0 (3b)
43.5 (4a )
40.5 (4b)
>99
99
>99
>99
50
50
50
50
>200
>200
>200
>200
8
a
b
After purification by flash column chromatography on SiO2. Determined by chiral GC. c Calculated from the ee of the substrate and
the product.8 Some of the product was lost during purification.
d
SCHEME 3
F IGURE 1. Relevant NOESY correlations observed for (()-
cis-4b and (()-trans-4b.
maining substrate (1S,2S)-4b. The differential shielding
obtained for the R-methylene group of enantiopure
Mosher derivative of (1S,2S)-4b and its enantiomer, (∆δ
) + 0.05 ppm, signal at 1.98 ppm for the Mosher
derivative of (1S,2S)-4b minus the signal at 1.93 ppm
for its enantiomer in Mosher derivative of racemic (()-
trans-4b) obtained from the Mosher derivative of racemic
(()-trans-4b is in good agreement with previous findings.
Where the positive sing of the ∆δ values indicates that
the product contained the alcohol (S)-configurated10 (see
the Supporting Information).
cis isomers (4a and 4b), the CN signal is considerably
deshielded in comparison to that of the corresponding
trans isomer because of the γ steric-compression effect
of the vicinal hydroxyl group.9b As expected, the opposite
effect is observed with the CH2 group (see the Supporting
Information). Also in the NOESY spectrum of compound
cis-4b a correlation between the CH2 group of the allyl
substituent and the CH group of the cycle could be
observed confirming the cis disposition of these two
groups, whereas no correlation was observed between the
same protons of the trans-4b diastereomer.
In summary, we have reported a novel resolution of
five- and six-membered cyclic â-hydroxy nitriles bearing
a quaternary center R to the nitrile utilizing lipase from
Candida antartica B as the biocatalyst for the enantio-
selective transesterification of these substrates. This
procedure allows, for the first time, a direct access to all
16 stereoisomers of these interesting building blocks in
enantiopure form and high yield.
Regardless of the R-substituent and the ring size,
CAL-B only reacted with substrates containing the
alcohol with the absolute configuration R. In the case of
hydroxy nitriles (1S,2S)-3a , b and (1R,2S)-3a , b, the
absolute stereochemistry was assigned by comparison of
the sign of their specific rotations with the published
data.9a The absolute configuration of the enzymatically
prepared (1R,2R)-6a ,b and (1S,2R)-8a ,b has been ten-
tatively assigned on the basis of two convergent criteria
or by a double-confirmation method:10 (a) the enantiotopic
preference displayed by CAL-B in the transesterification
of secondary alcohols following in all cases the Kazlaus-
kas’s rule;11 (b) using Mosher’s method for secondary
alcohols12 to determine the S-configuration of the re-
Ack n ow led gm en t. We thank Novo Nordisk Co. for
the generous gift of Ca lipase. Financial support of this
work by the Spanish Ministerio de Ciencia y Tecnolog´ıa
(Project No. PPQ-2001-2683) and by Principado de
Asturias (Project No. GE-EXP01-03) is gratefully ac-
knowledged.
(9) (a) Dehli, J . R.; Gotor, V. J . Org. Chem. 2002, 67, 1716. (b) Grant,
D. M.; Cheney, B. V. J . Am. Chem. Soc. 1967, 89, 5315.
(10) Ema, T.; Yoshii, M.; Korenaga, T.; Sakai, T. Tetrahedron:
Asymmetry 2002, 13, 1223.
(11) Kazlauskas, R. J .; Weissfloch, A. N. E.; Rappaport, A. T.; Cuccia,
L. A. J . Org. Chem. 1991, 56, 2656.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of new compounds, experimental procedures, and
experimental data. This material is available free of charge
via the Internet at http://pubs.acs.org.
(12) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512.
J O035808R
2602 J . Org. Chem., Vol. 69, No. 7, 2004