Hydroxynitrile lyase-catalyzed addition of HCN to 2-substituted cyclopentanones

Article abstract of DOI:10.1016/j.tetasy.2004.10.010

A systematic investigation of the stereoselectivity of hydroxynitrile lyases (HNLs) catalyzed addition of HCN to a variety of monosubstituted cyclopentanones yielding the corresponding cyanohydrins is presented. With PaHNL from bitter almond as catalyst, the HCN addition to 2-alkyl cyclopentanones 1b-d is highly (R)-selective, leading to the cis-(1R,2S)- and trans-(1R,2R)-diastereomers. The addition to the sterically less demanding methyl compound 1a is far less selective. With MeHNL from cassava, the expected (S)-selectivity of the HCN addition is very high for the cyclopentanones 1c-d with larger substituents, but only for the cis-(1S,2R)- and not the trans-(1S,2S)-diastereomers. Dynamic kinetic resolution was observed for the MeHNL-catalyzed addition of HCN to the racemic alkyl 2-oxocyclopentane carboxylates 4a and 4b. Continuous equilibration via keto-enol tautomerism and the preferred enzymatic conversion of the (R)-enantiomers of the ketones 4 results in the formation of the cis-(1R,2S)-diastereomers in >50% yield. The absolute configurations of the synthesized cyanohydrins were determined by X-ray crystallography of O-p-bromobenzoyl derivatives.

Full text of DOI:10.1016/j.tetasy.2004.10.010

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3731–3742
Hydroxynitrile lyase-catalyzed addition of HCN to 2-substituted
cyclopentanonesq
Christoph Kobler and Franz Effenberger*
Institut fu¨r Organische Chemie der Universita¨t Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
Received 28 July 2004;accepted 11 October 2004
Abstract—A systematic investigation of the stereoselectivity of hydroxynitrile lyases (HNLs) catalyzed addition of HCN to a variety
of monosubstituted cyclopentanones yielding the corresponding cyanohydrins is presented. With PaHNL from bitter almond as cat-
alyst, the HCN addition to 2-alkyl cyclopentanones 1b–d is highly (R)-selective, leading to the cis-(1R,2S)- and trans-(1R,2R)-dia-
stereomers. The addition to the sterically less demanding methyl compound 1a is far less selective. With MeHNL from cassava, the
expected (S)-selectivity of the HCN addition is very high for the cyclopentanones 1c–d with larger substituents, but only for the cis-
(1S,2R)- and not the trans-(1S,2S)-diastereomers. Dynamic kinetic resolution was observed for the MeHNL-catalyzed addition of
HCN to the racemic alkyl 2-oxocyclopentane carboxylates 4a and 4b. Continuous equilibration via keto-enol tautomerism and the
preferred enzymatic conversion of the (R)-enantiomers of the ketones 4 results in the formation of the cis-(1R,2S)-diastereomers in
>50% yield. The absolute configurations of the synthesized cyanohydrins were determined by X-ray crystallography of O-p-bromo-
benzoyl derivatives.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
prepared stereoselectively by applying HNLs as cata-
lysts.1 With PaHNL from bitter almonds, the HCN
addition to the carbonyl group is (R)-selective, while
with (S)-MeHNL from cassava, (S)-selectivity is
observed.1
The stereoselectivity of the hydroxynitrile lyase-cata-
lyzed cyanohydrin formation of monosubstituted cyclic
ketones is of general interest for the synthesis of biolog-
ically active compounds as well as for learning more
about the stereochemistry of cyanogenesis of cyclic
ketones.
The stereoselectivity of the MeHNL-catalyzed addition
of HCN to various monosubstituted cyclohexanones
can be explained with the specific orientation of the
cyclohexanones in the active site of the enzyme.1,3 Since
the steric requirements of cyclohexanones and cyclopen-
tanones are markedly different, the stereochemistry of
HNL-catalyzed additions to substituted cyclopenta-
nones is of general interest in this connection. Addition-
ally, 1-hydroxycyclopentanone carboxylic acids, which
could be derived from the corresponding cyanohydrins,
are biologically active building blocks in pharmaceuti-
cals.5 We have therefore investigated comprehensively
the HNL-catalyzed addition of HCN to 2-substituted
cyclopentanones. The (R)-PaHNL-catalyzed addition
of HCN to rac-2-methylcyclopentanone described in a
patent is the only example of this type of reaction.6
The exact stereochemistry however of the thereby ob-
tained cyanohydrin could not be determined.6 Recently
in a patent, the HNL-catalyzed addition of HCN to
tetrahydrofuranones and tetrahydrothiophenones have
been described.7
4-Substituted cyclohexanone cyanohydrins, which are
important precursors for potent herbicides and insecti-
cides,2 can be obtained as cis/trans-mixtures by chemical
addition of HCN to the corresponding cyclohexanones.
With hydroxynitrile lyases (HNL) as catalysts, the HCN
addition is surprisingly highly stereoselective.3 By using
(R)-PaHNL from bitter almond (Prunus amygdalus)
trans-addition almost exclusively occurred, whereas with
(S)-MeHNL from cassava (Manihot esculenta) cis-addi-
tion is preferred.3 Cyanohydrins of 2-substituted cyclo-
hexanones, which are interesting precursors of various
compounds with pharmacological activity,4 can be
q See Ref. 1.
*
Corresponding author. Tel.: +49 711 685 4265;fax: +49 711 685
4269;e-mail: franz.effenberger@po.uni-stuttgart.de
Part of dissertation, Universita¨t Stuttgart, 2004.
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.10.010

3732
C. Kobler, F. Effenberger / Tetrahedron: Asymmetry 15 (2004) 3731–3742
2. Results and discussion
2.2. (R)-PaHNL- and (S)-MeHNL-catalyzed addition of
HCN to racemic 2-alkyl cyclopentanones rac-1a–e
2.1. Chemical addition of HCN to 2-alkyl substituted
cyclopentanones 1
The HNL-catalyzed additions of HCN to 2-alkyl cyclo-
pentanones 1 have been performed under optimized
standard conditions.9 In order to estimate the extent
of chemical addition, for each substrate the reaction
was also carried out under the same conditions but
without an enzyme (blank experiment). In contrast to
the chemical addition, where only cis/trans-addition
was expected, HNL-catalysis should cause R/S-selectiv-
ity concerning the newly formed stereogenic center at
the 1-position. One should therefore expect (R)-selectiv-
ity by using (R)-PaHNL10a yielding the cis-(1R,2S)
and trans-(1R,2R)-diastereomers and (S)-selectivity by
applying (S)-MeHNL10b to give the cis-(1S,2R)- and
the trans-(1S,2S)-diastereomer 2 as depicted in Scheme
2.
Before starting the enzyme-catalyzed reactions, we
investigated the chemical addition of HCN, prepared
in situ in aqueous solution from KCN with acetic
acid,8 to racemic 2-alkyl cyclopentanones rac-1a–e yield-
ing the corresponding cyanohydrins 2a–e (Scheme 1,
Table 1).
O
NC
OH
HO
CN
R
R
R
KCN, AcOH
H2O, rt
+
rac-1a-e
rac-cis-2a-e
Ac2O
rac-trans-2a-e
pyridine
<DMAP>
1, 2, 3
R =
NC
OH
NC
OH
R
R
(R)-selective
NC
OAc
AcO
CN
a
b
c
d
e
Me
+
+
R
R
Et
PaHNL
n-Pr
Allyl
n-Bu
+
O
cis -(1R,2S)-
trans -(1R,2R)-
2a-e
2a-e
R
HCN
rac-cis-3a-e
rac-trans-3a-e
iPr2O, rt
Scheme 1.
rac-1a-e
NC
OH
NC
OH
R
R
(S)-selective
MeHNL
Table 1. HCN addition to racemic 2-alkyl cyclopentanones rac-1a–e
to the corresponding cyanohydrins 2a–e and subsequent acetylation to
the O-acetyl derivatives 3a–e
cis -(1S,2R)-
trans -(1S,2S)-
2a-e
2a-e
Scheme 2.
Ketones
rac-1 R =
Cyanohydrins 2
O-Acetyl
derivatives 3
Yield
(%)
rac-cis:
rac-trans
rac-cis:
rac-trans
Table 2 summarizes the results of the (R)-PaHNL-cata-
lyzed addition of HCN to racemic 2-alkyl cyclopenta-
nones rac-1a–e. The cyclopentanones 1b–d react highly
(R)-selectively to give almost exclusively the cis-
(1R,2S)- and trans-(1R,2R)-diastereomers of 2b,c and
2d, even after long reaction times. The HCN addition
to methyl compound 1a however is far less selective.
In this case, the time dependent formation of the four
diastereomers is interesting. Whereas the ratios of the
unexpected (1S,2S)- and (1S,2R)-stereoisomers only
slightly change when increasing the reaction time one
observes an increase of the trans-(1R,2R) and decrease
of the cis-(1R,2S)-diastereomer with longer reaction
times (Table 2). These results could be due to an increas-
ing domination of the chemical addition of HCN,
where the trans-products are favored (Table 1). How-
ever since this cis- to trans-isomerization is not observed
for the corresponding (1S)-stereoisomers, an (R)-
PaHNL-catalyzed transformation of the cis-(1R,2S)-
to the trans-(1R,2R)-diastereomer 2a is more likely.
As the substituents become larger, the substrate selectiv-
ity decreases (Table 2). Butyl-derivative 1e, for example,
is no longer a substrate for (R)-PaHNL. It is also note-
worthy that even after very long reaction times (168h),
the PaHNL-catalyzed conversion rates of cyclopenta-
nones 1 to the corresponding cyanohydrins do not
exceed 80%.
1a
1b
1c
1d
1e
Methyl-
Ethyl-
2a
2b
2c
2d
2e
88
87
76
74
71
23:77
31:69
33:67
29:71
30:70
3a
21:79
33:67
31:69
28:72
28:72
3b
3c
3d
3e
n-Propyl-
Allyl-
n-Butyl-
The yields and cis/trans ratios presented in Table 1 are
obtained as follows. The reaction mixture was stirred
for 48h and the cyanohydrins, which formed are then
extracted with ether. The yields given in Table 1 are
the residues obtained after evaporation of ether. Acetyl-
ation of the crude cyanohydrins rac-2a–e to the corre-
sponding O-acetyl derivatives rac-3a–e was performed
with acetic anhydride and pyridine, catalyzed by 4-
dimethylaminopyridine (DMAP). The O-acetyl cyano-
hydrins rac-3a–e are stable and can be used for GC
measurements. On an achiral phase, the cis/trans-iso-
mers and on a chiral phase all four possible stereoiso-
mers, can be separated chromatographically. The
yields and isomer ratios of cyanohydrins 2a–e deter-
mined by NMR spectroscopy given in Table 1 are com-
parable with the yields and the isomer ratios obtained
for the corresponding isolated O-acetyl cyanohydrins
3a–e.

C. Kobler, F. Effenberger / Tetrahedron: Asymmetry 15 (2004) 3731–3742
Table 2. (R)-PaHNL-catalyzed addition of HCN to rac-2-alkyl cyclopentanones 1a–e
3733
rac-1 R =
t (h)
Cyanohydrin 2
cis-(1S,2R)
Blank experiment
Conv. (%) cis:trans
Conv. (%)
cis-(1R,2S)
trans-(1R,2R)
trans-(1S,2S)
1a
1b
Methyl-
1
5
6
21
59
72
46.2
45.0
32.1
30.1
4.0
5.5
5.5
7.0
11.5
12.7
24.9
29.6
38.3
36.8
37.5
33.3
48
168
8
13:87
Ethyl-
1
3
5
15
32
60
81
47.7
47.4
44.6
42.9
47.7
2.9
0.8
0.2
0.2
0.1
48.6
50.9
54.4
56.2
50.1
0.8
0.9
0.8
0.7
2.1
8
24
147
8
2
35:65
n.d.
1c
1d
n-Propyl-
5
48
2
16
42
49
42.9
23.6
24.3
31.4
<0.1
0.7
56.9
75.0
71.4
56.0
<0.1
0.7
168
336
0.1
1.0
4.2
11.6
Allyl-
5
48
10
35
48
59
61
44.0
38.7
40.0
44.0
44.8
2.3
0.2
0.1
0.2
1.2
51.8
60.9
58.8
53.1
48.3
1.9
0.2
1.1
2.7
5.7
96
168
336
4
13:87
n.d.
1e
n-Butyl-
168
<2
n.d.
n.d.
n.d.
n.d.
<2
Table 3 summarizes the results of the (S)-MeHNL-cata-
lyzed cyanohydrin formation of 2-alkyl cyclopentanones
1.
larger substituents, but only for the cis-(1S,2R)-diaste-
reomers not the trans-(1S,2S)-diastereomers (Table 3).
Since the chemical addition, which preferentially yields
trans-products (Table 1), can be excluded (Table 3,
blank experiment) the orientation and fixation of cyclo-
pentanones 1 in the active site of the enzyme must be the
reason for these unexpected results.11
The conversion rates are considerably faster than the
rates with (R)-PaHNL as catalyst (Table 2). Larger sub-
stituents in the substrate also diminish the conversion
rates but to a much lesser extent when compared to
the (R)-PaHNL-catalyzed reactions (Table 2). Even 1e,
with the sterically demanding n-butyl residue, gives after
48h reaction time, 47% conversion whereas with
PaHNL, no reaction at all occurs. The expected (S)-
selectivity is very high for cyclopentanones 1c and d with
2.3. (R)-PaHNL- and (S)-MeHNL-catalyzed addition of
HCN to racemic alkyl 2-oxocyclopentanecarboxylates 4
Prior to the enzyme-catalyzed reactions, we investi-
gated the chemical addition of HCN to racemic alkyl
Table 3. (S)-MeHNL-catalyzed addition of HCN to rac-2-alkyl cyclopentanones 1a–e
rac–1 R =
t (h)
Cyanohydrin 2
cis-(1S,2R)
Blank experiment
Conv. (%) cis:trans
Conv. (%)
cis-(1R,2S)
trans-(1R,2R)
trans-(1S,2S)
1a
1b
1c
1d
1e
Methyl-
1
2
3
4
53
79
83
89
6.3
7.4
38.8
37.1
35.3
33.3
12.5
13.7
15.2
16.9
42.4
41.7
40.7
39.5
8.8
10.3
ꢀ1
n.d.
Ethyl-
1
3
6
8
43
78
89
87
11.8
14.8
18.2
19.9
49.3
47.1
45.0
44.1
1.6
2.5
3.7
4.4
37.4
35.6
33.1
31.6
ꢀ1
n.d.
n.d.
n-Propyl-
Allyl-
1
5
10
31
44
51
12.3
13.2
14.5
14.6
68.7
66.5
60.9
60.0
0.7
0.3
0.3
0.3
18.3
20.0
24.3
25.5
24
48
<1
1
5
9
23
73
76
22.7
22.3
28.8
28.5
61.0
54.1
47.1
43.8
0.9
1.7
1.7
2.9
15.4
21.9
22.4
24.8
24
48
<1
<1
n.d.
n.d.
n-Butyl-
24
48
41
47
15.8
10.7
61.5
63.0
0.1
0.1
22.6
26.2

3734
C. Kobler, F. Effenberger / Tetrahedron: Asymmetry 15 (2004) 3731–3742
2-oxocyclopentanecarboxylates 4a–f affording the corre-
sponding cyclopentanone cyanohydrins 5a–f (Scheme 3,
Table 4).
In the HNL-catalyzed additions of HCN to alkyl 2-oxo-
cyclopentanecarboxylates 4, one should expect (R)-
selectivity by using PaHNL10a yielding the cis-(1S,2R)-
and the trans-(1R,2R)-diastereomers 5 and (S)-selectiv-
ity by applying MeHNL10b to give the cis-(1R,2S)-
and the trans-(1S,2S)-diastereomers 5 concerning the
newly formed stereogenic center at the 2-position
(Scheme 4).
O
O
O
O
NC
OH
AcO
CN
2
2
2
R
R
R
KCN, AcOH
H2O, rt
O
O
O
+
3
1
3
1
3
1
4
5
4
5
4
5
rac-4a-f
rac-cis-5a-f
rac-trans-5a-f
The PaHNL-catalyzed addition of HCN to cyclopenta-
nones 4a–f under optimized reaction conditions have
shown that only methyl ester 4a is a reasonable substrate
for PaHNL. The conversion rates for esters 4b–f are
below 10% even after long reaction times. The time
dependent formations of the stereoisomers in the
PaHNL-catalyzed reaction6 of the methylester 4a are
summarized in Table 5.
pyridine
Ac2O
R
<DMAP>
AcO
4, 5, 6
R =
a
b
c
d
e
f
Me
Et
n-Pr
i-Pr
Allyl
i-Bu
O
O
NC OAc
CN
2
2
R
O
O
3
1
+
3
4
1
4
5
5
rac-cis-6a-f
rac-trans-6a-f
Scheme 3.
Table 5. (R)-PaHNL-catalyzed addition of HCN to racemic methyl 2-
oxocyclopentane carboxylate rac-4a
Cyanohydrin 5a
Table 4. HCN addition to racemic alkyl 2-oxocyclopentane carboxyl-
ate rac-4a–f to the corresponding cyanohydrins 5a–f and subsequent
acetylation to the O-acetyl derivatives 6a–f
t
Conv. cis:
cis-
cis-
trans-
trans-
(h) (%) trans (1S,2R) (1R,2S) (1R,2R) (1S,2S)
Ketones
rac-4 R =
Cyanohydrins 5
O-Acetyl
derivatives 6
1
7
83:17 80.0
77:23 73.3
72:28 68.7
56:44 49.3
45:55 36.3
41:59 30.4
2.9
3.5
9.5
12.7
14.9
22.4
28.4
29.2
7.6
10.5
12.8
22.0
27.1
30.3
5
18
24
38
47
7
3.6
6.3
Yield (%) rac-cis:
rac-trans
rac-cis:
rac-trans
24
36
8.2
10.1
4a Methyl-
4b Ethyl-
4c n-Propyl-
5a 89
5b 90
5c 90
45:55
38:62
64:36
56:44
56:44
59:41
6a 48:52
6b 38:62
6c 64:36
6d 59:41
6e 58:42
168 79
4d iso-Propyl- 5d 95
4e Allyl- 5e 86
4f iso-Butyl- 5f 75
In contrast to the reactions of 2-alkyl cyclopentanones 1
where practically no change in stereoisomer ratios,
depending on reaction times were observed, the change
in the case of the methyl 2-oxocyclopentane carboxylate
4a was considerable. Whereas after 1h, the expected
(R)-selectivity was fairly high (>80%), it decreased
sharply with longer reaction times. After 168h it was
almost at equilibrium between all possible stereoisomers
(Table 5).
6f
62:38
As can be seen from Table 4, cis- and trans-addition
products are formed in practically equal amounts. For
characterization and determining the distribution of
stereoisomers for the enzyme-catalyzed reaction, the
crude stereoisomeric cyanohydrin mixtures 5a–f were
transferred to the stable O-acetyl cyanohydrins 6a–f
(Table 4). From GCs of the O-acetyl derivatives 6a–f
on chiral and achiral phases in combination with
NMR spectra of the cyanohydrins 5a–f, it was possible
to determine the ratios of all stereoisomers formed in
the described HNL-catalyzed additions of HCN to the
cyclopentanone derivatives rac-4a–f.
The results of the MeHNL-catalyzed additions of HCN
to the cyclopentanones rac-4a,b,d are summarized in
Table 6.
The conversion rates of the MeHNL-catalyzed reactions
clearly show, that cyclopentanones 4 are much better
O
OH
O
OH
NC
NC
2
2
(R)-selective
OR
OR
OR
OR
+
+
3
1
3
1
PaHNL
4
5
4
5
trans -(1R,2R)-
O
cis -(1S,2R)-
O
5a-f
5a-f
2
HCN
OR
3
1
iPr2O, rt
4
5
O
O
NC
OH
NC
OH
rac-4a-f
2
2
(S)-selective
3
1
5
3
1
MeHNL
4
4
5
trans -(1S,2S)-
cis -(1R,2S)-
5a-f
5a-f
Scheme 4.

C. Kobler, F. Effenberger / Tetrahedron: Asymmetry 15 (2004) 3731–3742
3735
Table 6. (S)-MeHNL-catalyzed addition of HCN to racemic alkyl 2-oxocyclopentane carboxylate rac-4
rac-4 R =
t (h)
Cyanohydrin 5
cis-(1S,2R)
Blank experiment
Conv. (%) cis:trans
Conv. (%)
cis-(1R,2S)
trans-(1R,2R)
trans-(1S,2S)
4a
4b
4d
Methyl-
1
3
28
45
53
74
7.9
7.7
7.1
7.4
89.1
91.0
91.2
88.4
1.1
0.7
0.8
2.0
1.9
0.6
0.9
2.2
8
28
4
28:72
Ethyl-
1
3
29
54
73
86
5.4
8.2
90.2
86.5
79.6
64.8
0.5
0.2
0.3
0.9
3.9
5.1
6.5
8.1
8
28
13.6
26.2
5
31:69
n.d.
i-Propyl-
3
6
28
33
47
3.7
5.0
91.8
92.3
84.5
0.1
0.8
0.4
4.4
1.9
1.6
24
13.5
<1
substrates for MeHNL than for PaHNL (Tables 5 and
6). The stereoselectivity of the MeHNL-catalyzed
HCN-addition to racemic alkyl 2-oxocyclopentane
carboxylates rac-4a,b, and d is particularly noteworthy.
At conversion rates of ꢁ50%, only one main diastereo-
mer namely the cyanohydrins 5a,b and d with a
cis-(1R,2S)-configuration (Table 6) was obtained. Since
starting ketones 4 are racemic, the trans-(1S,2S)-diaste-
reomers 5a,b, and d should be obtained in comparable
ratios with the (S)-selective MeHNL as catalyst. From
these results it is obvious, that the (R)-enantiomers of
racemic ketones 4 are by far better substrates for
MeHNL than the (S)-enantiomers and therefore the
preferred formation of the (1R,2S)-configurated cyano-
hydrins 5 can be explained. Since b-ketoesters can easily
isomerize via the tautomeric enols, the transformation
of the (S)- into the highly reactive (R)-enantiomers of
ketones 4 is explainable. For ethyl derivative 4b, the
amount of enol ranges from 2% to 8%, depending on
the solvent.12 The described formation is a new and
interesting example of the dynamic kinetic resolution
in enzyme-catalyzed reactions.13
Figure 1. ORTEP view of cis-(1S,2R)-1-(4-bromobenzoyloxy)-2-meth-
ylcyclopentanecarbonitrile cis-(1S,2R)-2a0.
2.4. Assignment of the absolute configuration of cyano-
hydrins 2 and 5
MeHNL-catalyzed reaction product of 4b after
recrystallization.14
The structure determinations were performed on
compounds 2a, 5a, and 5b. The cis/trans-mixtures
obtained in the HNL-catalyzed reactions were reacted
with p-bromobenzoyl chloride to give the corresponding
O-benzoyl derivatives, which can be separated by
column chromatography. After recrystallization, the
pure enantiomers cis-(1S,2R)-2a0, trans-(1S,2S)-2a0,
cis-(1R,2S)-5a0, and cis-(1R,2S)-5b0 were obtained as
single crystals suitable for X-ray structure determination
(Figs. 1–4, Table 7).14 The absolute configurations were
elucidated from diffraction data using anomalous
dispersion.
3. Conclusions
With the reactions performed it has been shown that the
addition of HCN to 2-substituted cyclopentanones, to
yield the corresponding cyanohydrins, can be strongly
catalyzed by hydroxynitrile lyases (HNLs). The HCN-
additions to racemic 2-alkyl cyclopentanones 1b–d,
catalyzed by PaHNL from bitter almonds, are highly
(R)-selective yielding almost exclusively the cis-
(1R,2S)- and trans-(1R,2R) stereoisomeric cyanohydrins
2b–d, respectively. With the sterically less demanding
methyl derivate 1a the stereoselectivity is lower,
especially for the formation of the trans-(1R,2R)-diaste-
reomer. In comparison to PaHNL as catalyst, the
reactions catalyzed by MeHNL from cassava were con-
siderably faster. The expected (S)-selectivity with
MeHNL was observed perfectly for the formation of
By correlation of the GC data of the O-acetyl derivatives
on achiral and chiral phases and analyses of NMR data,
an unambiguous assignment of the structures for all
prepared cyanohydrins 2 and 5 was possible (see Sec-
tion 4). X-ray structure determination was also per-
formed for the pure cyanohydrin (1R,2S)-5b of the

3736
C. Kobler, F. Effenberger / Tetrahedron: Asymmetry 15 (2004) 3731–3742
Figure 4. ORTEP view of cis-(1R,2S)-2-(4-bromobenzoyloxy)-2-cyano-
cyclopentane carboxylic acid ethyl ester cis-(1R,2S)-5b0.
Figure 2. ORTEP view of trans-(1S,2S)-1-(4-bromobenzoyloxy)-2-
methylcyclopentanecarbonitrile trans-(1S,2S)-2a0.
4. Experimental
4.1. Materials and methods
Melting points were determined on a Buchi SMP-20 and
¨
1
are uncorrected. Unless otherwise stated, H and 13C
NMR spectra were recorded on a Bruker AC 250 F
(250MHz) and ARX 500 (500MHz) in CDCl3 with
TMS as the internal standard. 13C NMR multiplicities
were determined with DEPT experiments. Optical rota-
tions were measured with a Perkin–Elmer polarimeter
241 LC in a thermostated glass cuvette (l = 10cm).
Chromatography was performed using silica gel, grain
size 0.040–0.063mm (Fluka). Diastereomeric excess:
GC separations were conducted using (a) capillary glass
columns (20m) with OV 1701, carrier gas 0.4–0.6bar
hydrogen;(b) a Chiraldex B-PM (permethylated) col-
umn (30m · 0.32mm), carrier gas 0.6–1.0bar hydrogen;
(c)
a
Chiraldex B-TA and G-TA column
(30m · 0.32mm), carrier gas hydrogen.
Cyclopentanones 1b–e,15 and 4c–f16,17 were prepared
according to literature procedures. Ketones 1a, 4a, and
4b are commercially available. Racemic cyanohydrins
were performed according to a procedure developed by
van der Gen et al.,8 but the reaction times were always
48h. 1H and 13C NMR data of the racemic cyanohydrins
are reported in Tables 9 and 10. For the performance of
the elemental analysis of the cyanohydrins, the O-acetyl-
ated cyanohydrins 3c, 6a, and 6c–6e were used (Table 8).
1H and 13C NMR data of the O-acetylated cyanohydrins
are reported in Table 11. The O-acetylated derivatives
were prepared using acetic anhydride and dimethylamino-
pyridine (for conditions see determination of conversion
rates and isomeric ratio). All yields are not optimized.
Figure 3. ORTEP view of cis-(1R,2S)-2-(4-bromobenzoyloxy)-2-cyano-
cyclopentane carboxylic acid methyl ester cis-(1R,2S)-5a0.
the trans-(1S,2S)- but not for the cis-(1S,2R)-stereoiso-
meric cyanohydrins 2b–e.
Racemic 2-oxocyclopentane carboxylates 4a–f are excel-
lent substrates for MeHNL but not for PaHNL. In most
cases, cyanohydrins 5a–f with a cis-(1R,2S)-configura-
tion were obtained with conversion rates of about
50%. These results can be rationalized via a fast enoliza-
tion of the starting racemic b-ketoesters 4a–f and a fast
and preferred reaction of the (R)-enantiomers to the
cyanohydrins 5a–f.
4.2. General procedure for the (R)-PaHNL-catalyzed
preparation of cyclopentanone cyanohydrins 2 and 5
In conclusion it is possible to selectively prepare each of
the four stereoisomeric 2-substituted cyclopentanone
cyanohydrins by HNL-catalyzed HCN additions to the
corresponding cyclopentanone derivatives.
A solution of (R)-PaHNL (100U per 100mg support,
total 200U, 83.0lL) was added to cellulose [Elcema-

C. Kobler, F. Effenberger / Tetrahedron: Asymmetry 15 (2004) 3731–3742
3737
Table 7. X-ray crystal data collection and refinement for cis-(1S,2R)-2a0, trans-(1S,2S)-2a0, cis-(1R,2S)-5a0, and cis-(1R,2S)-5b0
cis-(1S,2R)-2a0
trans-(1S,2S)-2a0
cis-(1R,2S)-5a0
cis-(1R,2S)-5b0
Formula
FW
C14H14NO2Br
308.17
Orthorhombic
P212121
7.3146(17)
10.356(2)
18.537(4)
90
C14H14NO2Br
308.17
Monoclinic
P21
C15H14NO4Br
352.18
Orthorhombic
P212121
7.3709(4)
10.3865(5)
20.604(3)
90
C16H16NO4Br
366.21
Crystal system
Space group
Monoclinic
C2
˚
a (A)
7.107(3)
12.500(5)
15.674(5)
90
29.459(6)
7.4626(14)
7.7420(11)
90
˚
b (A)
˚
c (A)
a (ꢁ)
b (ꢁ)
c (ꢁ)
90
90
95.85(3)
90
90
90
103.322(13)
90
3
˚
V (A )
1404.1(5)
4
1.458
1385.2(9)
4
1.478
1577.4(3)
4
1.483
1656.2(5)
4
1.469
Z
qcalcd (mgmÀ3
F(000)
)
624
2.921
2.20–26.00
624
2.961
2.09–25.00
712
3.689
4.29–68.00
744
2.498
2.70–27.50
l (mmÀ1
)
h Range (ꢁ)
Data collectiona
Reflections collected/unique
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices
10966/2752
2752/0/164
1.059
9742/4878
4878/1/326
1.058
2678/2287
2287/24/191
1.123
2068/2030
2030/1/200
1.061
[I > 2r(I)]
R1 = 0.0362
wR2 = 0.0721
R1 = 0.0499
wR2 = 0.0768
À0.021(12)
0.359
R1 = 0.0393
wR2 = 0.0790
R1 = 0.0579
wR2 = 0.0845
À0.005(8)
0.383
R1 = 0.0602
wR2 = 0.1687
R1 = 0.0644
wR2 = 0.1756
À0.07(5)
R1 = 0.0541
wR2 = 0.1174
R1 = 0.0925
wR2 = 0.1320
À0.02(3)
R indices (all data)
Absolute structure parameter
Largest diff.
˚
Peak and hole (eA
0.560
0.431
À3
)
À0.288
À0.355
À0.489
À0.273
a T = 293K, Nicolet P3 diffractometer, MoKa (l = 0.71073) or Siemens P4 diffractometer, CuKa (l = 1.54178) radiation.
Cellulose P100PSC, Degussa: 1g soaked in 10mL
of 0.02M sodium citrate buffer, pH3.3, for 2h, and fil-
tered off] followed by addition of diisopropyl ether
(5mL), substrate 1 or 4 (1mmol), and anhydrous
HCN18 (150lL, 3.9mmol). After stirring at room
temperature for the times given in Tables 2 and 5, the
support was filtered off, washed twice with diethyl
ether, and the combined filtrates concentrated under
vacuum.
Table 8. Yields and elemental analysis of racemic acetylated cyano-
hydrins 3 and 6
Compound Yield Mol. formula
(%)
Calcd/found
(mol. weight)
C
H
N
O
rac-3c
rac-6a
rac-6c
rac-6d
rac-6e
rac-6f
52
68
71
89
51
68
C
11H17NO2
(195.26)
67.66
67.42
56.87 56.87 6.63 30.30
8.78 7.17 16.39
8.78 6.89
C10H13NO4
(211.22)
57.02
60.24
60.12
60.24
60.02
60.75
60.81
61.64
61.77
6.22 6.53
7.16 5.85 26.75
7.19 5.81
C
(239.27)
12H17NO4
4.3. General procedure for the (S)-MeHNL-catalyzed
preparation of cyclopentanone cyanohydrins 2 and 5
C12H17NO4
(239.27)
7.16 5.85 26.75
7.15 5.73
C
12H15NO4
(237.26)
13H19NO4
(253.30)
6.37 5.90 26.97
6.48 5.89
A solution of (S)-MeHNL (100U per 100mg support,
total 200U, 76.4lL) was added to nitrocellulose [Pro-
Celloidin (Fluka): 1g (dry), soaked in 50mL of 0.02M
sodium citrate buffer, pH3.3, for 0.5h;the buffer was
decanted and nitrocellulose centrifuged (5700g for
30min) and dried under high vacuum for 5h], followed
after 15min by the addition of diisopropyl ether
(5mL), substrate 1 or 4 (1mmol), and anhydrous
HCN18 (150lL, 3.9mmol). The reaction was performed
as described above.
C
7.56 5.53 25.27
7.53 5.45
catalyzed and the chemically prepared cyanohydrins
are identical.
4.5. Determination of conversion rates and isomeric ratio
(acetylation)
4.4. Blank experiment
The chemical HCN addition was performed analogously
to the enzymatic reaction. However, the enzyme solu-
tion was replaced by the same volume of 0.02M sodium
acetate buffer, pH5.4. The reaction times correspond
with those of the (R)-PaHNL- and (S)-MeHNL-cata-
To a solution of the crude cyclohexanone cyanohydrins
2 or 5 (10lL) in CH2Cl2 (500lL) was added acetic anhy-
dride (50lL) and dimethylaminopyridine (15mg). The
reaction mixture was allowed to stand at room temper-
ature for 30min. The mixture was then filtered through a
silica gel column (3 · 0.5cm) with CH2Cl2 (4mL).
1
lyzed reaction. H and 13C NMR data of the enzyme

Table 9. Spectroscopic data of the 2-alkyl substituted cyanohydrins 2
Compound 1H NMR (250MHz) (J inHz): d
13C NMR (62.9MHz): d
rac-2a
1.15 (d, 3J = 6.8Hz, 0.6H, cis-CH3), 1.16 (d, 3J = 6.9Hz, 2.4H, trans-CH3),
1.41–1.49 (m, 1H, CH), 1.77–1.91 (m, 2H, 2CH), 1.98–2.30 (m, 4H, 4CH),
2.75 and 2.98 (br s, 1H, OH)
12.20 (cis-C6H3), 16.37 (trans-C6H3), 20.55 (trans-C4H2), 21.49 (cis-C4H2), 30.24 (cis-C3H2),
30.73 (trans-C3H2), 39.21 (trans-C5H2), 40.13 (cis-C5H2), 45.54 (trans-C2H), 45.56 (cis-C2H),
74.83 (cis-C1), 78.65 (trans-C1), 120.83 (trans-CN), 121.90 (cis-CN)
rac-2b
1.00 (d, 3J = 7.4Hz, 2.1H, trans-CH2CH3), 1.04 (d, 3J = 7.4Hz, 0.9H, cis-CH2CH3), 12.47 (trans-CH2CH3), 12.64 (cis-CH2CH3), 20.68 (trans-C4H2), 21.26, 21.32 (cis-C4H2),
1.32–1.49 (m, 2H, CH2CH3), 1.72–2.28 (m, 7H, 7CH), 2.65 and 3.15 (br s, 1H, OH) (cis-CH2CH3), 24.46 (trans-CH2CH3), 28.25 (cis-C3H2), 28.48 (trans-C3H2), 40.10 (trans-C5H),
40.65 (cis-C5H), 52.50 (cis-C2H2), 52.54 (trans-C2H2), 74.14 (cis-C1), 78.28 (trans-C1), 120.97
(trans-CN), 122.21 (cis-CN)
rac-2c
rac-2d
rac-2e
0.88–1.03 (m, 3H, CH2CH2CH3), 1.30–1.59 (m, 4H, CH2CH2CH3, CH2CH2CH3),
1.60–2.51 (m, 7H, 7CH), 2.98 (br s, 1H, OH)
14.14 (trans-CH2CH2CH3), 14.27 (cis-CH2CH2CH3), 20.70 (trans-C4H2), 21.17
(trans-CH2CH2CH3), 21.30 (cis-CH2CH2CH3), 21.41 (cis-C4H2), 28.49 (cis-C3H2), 28.83
(trans-C3H2), 30.33 (cis-CH2CH2CH3), 33.56 (trans-CH2CH2CH3), 40.08 (trans-C5H2), 40.56
(cis-C5H2), 50.53 (cis-C2H), 50.64 (trans-C2H2), 74.41 (cis-C1), 78.47 (trans-C1), 120.90
(trans-CN), 122.10 (cis-CN)
1.41–1.61 (m, 1H, CH), 1.66–2.59 (m, 8H, 8CH), 2.80 and 3.19 (br s, 1H, OH),
5.00–5.26 (m, 2H, CH2CH@CH2), 5.71–5.98 (m, 1H, CH2CH@CH2)
20.12 (trans-C4H2), 21.43 (cis-C4H2), 28.54 (cis-C3H2), 28.66 (trans-C3H2), 32.95
(cis-CH2CH@CH2), 35.79 (trans-CH2CH@CH2), 39.73 (trans-C5H2), 40.77 (cis-C5H2),
50.01 (trans-C2H), 50.04 (cis-C2H), 74.14 (cis-C1), 78.46 (trans-C1), 116.99 (cis-CH2CH@CH2),
117.61 (trans-CH2CH@CH2), 120.68 (trans-CN), 121.97 (cis-CN), 136.10 (cis-CH2CH@CH2),
136.13 (cis-CH2CH@CH2)
0.87–0.95 (m, 3H, CH2CH2CH2CH3), 1.17–1.57 (m, 6H, CH2CH2CH2CH3,
CH2CH2CH2CH3, CH2CH2CH2CH3), 1.60–2.44 (m, 7H, 7CH), 2.48 and
2.93 (br s, 1H, OH)
13.96 (cis-CH2CH2CH2CH3), 14.00 (trans-CH2CH2CH2CH3), 20.70 (trans-C4H2), 21.42
(cis-C4H2), 22.76 (trans-CH2CH2CH2CH3), 22.88 (cis-CH2CH2CH2CH3), 27.87 (cis-
CH2CH2CH2CH3), 28.56 (cis-C3H2), 28.89 (trans-C3H2), 30.21 (trans-CH2CH2CH2CH3),
30.26 (cis-CH2CH2CH2CH3), 31.12 (trans-CH2CH2CH2CH3), 40.09 (trans-C5H2), 40.57 (cis-
C5H2), 50.75 (cis-C2H), 50.86 (trans-C2H), 74.40 (cis-C1), 78.46 (trans-C1), 120.96 (trans-CN),
122.13 (cis-CN)

Table 10. Spectroscopic data of the cyanohydrins 5
Compound 1H NMR (500MHz) (J inHz): d
13C NMR (125.8MHz): d
rac-5a
1.80–2.42 (m, 6H, 6CH), 2.94–3.06 (m, 1H, C1Hax), 3.81
(s, 1.5H, cis-CH3), 3.82 (s, 1.5H, trans-CH3), 4.85 (br s, 1H, OH)
19.89 (trans-C4H2), 21.66 (cis-C4H2), 24.89 (trans-C5H2), 26.92 (cis-C5H2), 38.71 (trans-C3H2), 39.32
(cis-C3H2), 52.60 (trans-CH3), 52.64 (cis-C1H), 52.65 (cis-CH3), 55.55 (trans-C1H), 72.64 (cis-C2),
75.98 (trans-C2), 120.11 (trans-CN), 120.59 (cis-CN), 172.09 (trans-COO), 173.91 (cis-COO)
rac-5b
1.30–1.35 (m, 3H, CH2CH3), 1.83–1.94 (m, 2H, 2CH), 1.97–2.43
(m, 4H, 4 CH), 2.94–3.15 (m, 1H, C1Hax), 3.80 (br s, 0.6H, OH),
4.23–4.31 (m, 2H, CH2CH3), 4.93 (br s, 0.4H, OH)
14.07 (cis-CH2 CH3), 14.15 (trans-CH2CH3), 19.97 (trans-C4H2), 21.64 (cis-C4H2), 24.98 (trans-C5H2),
26.94 (cis-C5H2), 38.81 (trans-C3H2), 39.38 (cis-C3H2), 52.72 (cis-C1H), 55.57 (trans-C1H), 61.77
(trans-CH2CH3), 61.87 (cis-CH2CH3), 72.68 (cis-C2), 75.99 (trans-C2), 120.09 (trans-CN), 120.65
(cis-CN), 171.60 (trans-COO), 173.52 (cis-COO)
rac-5c
rac-5d
0.97 (t, 3J = 7.4Hz, 2.0H, cis-CH2CH2CH3), 1.00 (t, 3J = 7.4Hz,
1.0H, trans-CH2CH2CH3), 1.64–2.46 (m, 8H, CH2CH2CH3, 6CH),
2.94–3.06 (m, 1H, C1Hax), 3.87 (br s, 0.4H, OH), 4.17 (t, 3J = 6.7Hz,
1.3H, cis-CH2CH2CH3), 4.18 (t, 3J = 6.7Hz, 0.7H, trans-CH2CH2CH3),
4.93 (br s, 0.6H, OH)
10.28 (cis-CH2CH2CH3), 10.35 (trans-CH2CH2CH3), 19.90 (trans-C4H2), 21.83 (cis-CH2CH2CH3),
21.89 (trans-CH2CH2CH3), (cis-C4H2), 24.94 (trans-C5H2), 26.94 (cis-C5H2), 38.74 (trans-C3H2), 39.36
(cis-C3H2), 52.75 (cis-C1H), 55.58 (trans-C1H), 61.29 (trans-CH2CH2CH3), 61.34 (cis-CH2CH2CH3),
72.66 (cis-C2), 75.96 (trans-C2), 120.12 (trans-CN), 120.66 (cis-CN), 171.68 (trans-COO),
173.58 (cis-COO)
1.24–1.33 (m, 6H, CH(CH3)2), 1.82–2.43 (m, 6H, 6CH), 2.91–2.98
(m, 1H, C1Hax), 3.81 (br s, 0.4H, OH), 5.01 (br s, 0.6H, OH), 5.11–5.17
(m, 1H, CH(CH3)2)
20.22 (trans-C4H2), 21.59 (cis-C4H2), 21.65 (cis-CH(CH3)2), 21.70 (trans-CH(CH3)2), 21.74
(cis-CH(CH3)2)*, 21.78 (trans-CH(CH3)2)*, 25.25 (trans-C5H2), 26.82 (cis-C5H2), 38.98 (trans-C3H2),
39.43 (cis-C3H2), 52.84 (cis-C1H), 55.62 (trans-C1H), 69.47 (trans-CH2(CH3)2), 69.71(cis-CH2 (CH3)2),
72.67 (cis-C2), 75.84 (trans-C2), trans-120.19 (trans-CN), 120.72 (cis-CN), 171.22 (trans-COO), 173.00
(cis-COO)
rac-5e
1.78–2.52 (m, 6H, 6CH), 2.97–3.09 (m, 1H, C1Hax), 3.79 (br s, 0.5H, OH),
19.93 (trans-C4H2), 21.64 (cis-C4H2), 24.99 (trans-C5H2), 26.99 (cis-C5H2), 38.77 (trans-C3H2), 39.36
4.69–4.73 (m, 2H, CH2CH@CH2), 4.81 (br s, 0.5H, OH), 5.27–5.41 (m, 2H, (cis-C3H2), 52.77 (cis-C1H), 55.53 (trans-C1H), 66.23 (trans-CH2CH@CH2), 66.26 (cis-CH2CH@CH2),
CH2CH@CH2), 5.85–6.03 (m, 1H, CH2CH@CH2)
72.65 (cis-C2), 75.91 (trans-C2), 119.35 (cis-CH2CH@CH2), 119.39 (trans-CH2CH@CH2), 120.05
(trans-CN), 120.58 (cis-CN), 131.07 (cis-CH2CH@CH2), 131.36 (trans-CH2CH@CH2), 171.29
(trans-COO), 173.09 (cis-COO)
rac-5f
0.93–0.98 (m, 6H, CH2CH(CH3)2), 1.80–2.47 (m, 7H, 6CH, CH2CH(CH3)2), 18.94 (cis-CH2CH(CH3)2), 18.96 (cis-CH2CH(CH3)2)*, 19.06 (trans-CH2CH(CH3)2), 19.08
2.95–3.07 (m, 1H, C1Hax), 3.86–4.06 (m, 2.5H, OH, CH2CH(CH3)2), 4.91
(br s, 0.5H, OH)
(trans-CH2CH(CH3)2)trans-C4H2), 21.64 (cis-C4H2), 24.91 (trans-C5H2), 26.40 (cis-C5H2), 27.47
(trans-CH2CH(CH3)2), 27.64 (cis-CH2CH(CH3)2), 38.69 (trans-C3H2), 39.36 (cis-C3H2), 52.80
(cis-C1H), 55.59 (trans-C1H), 71.41 (cis-C2), 71.70 (cis-CH2CH(CH3)2), 72.65 (trans-CH2CH(CH3)2),
75.94 (trans-C2), 120.13 (trans-CN), 120.65 (cis-CN), 171.67 (trans-COO), 173.49 (cis-COO)
* Rotamers.

Table 11. Spectroscopic data of the O-acetylated cyanohydrins 3 and 6
Compound 1H NMR (250MHz) (J inHz): d
13C NMR (62.9MHz): d
rac-3c
rac-6a
rac-6c
0.93–0.98 (m, 3H, CH2CH2CH3), 1.26–1.53 (m, 4H, CH2CH2CH3, CH2CH2CH3),
1.66–1.91 (m, 3H, 3 CH), 1.93–2.67 (m, 4H, CH), 2.10–2.12 (m, 3H, COOCH3)
14.10 (trans-CH2CH2CH3), 14.23 (cis-CH2CH2CH3), 21.05, 21.18, 21.26, 21.42 (C4H2,
CH2CH2CH3), 28.19, 28.83 (C3H2), 30.31 (cis-CH2CH2CH3), 33.32 (trans-CH2CH2CH3),
37.63, 37.79 (C5H2), 48.94, 50.80 (C2H2), 77.73 (cis-C1), 80.89 (trans-C1), 117.56
(trans-CN), 119.18 (cis-CN), 169.14 (cis-COOCH3), 169.29 (trans-COOCH3)
1.81–2.23 (m, 4H, 4CH), 2.08 and 2.13 (s, 3H, OCOCH3), 2.25–2.33 (m, 0.5H, CH),
2.46 (t, 3J = 7.7Hz, 1H, CH), 2.56–2.64 (m, 0.5H, CH) 3.27 (t, 3J = 7.8Hz, 0.5H, CH),
3.35 (t, 3J = 8.6Hz, 0.5H, CH), 3.77 and 3.79 (s, 3H, COOCH3)
20.79 (cis-OCOCH3), 20.92 (trans-OCOCH3), 21.45 (cis-C4H2), 21.97 (trans-C4H2), 25.86
(cis-C5H2), 27.00 (trans-C5H2), 38.26 (trans-C3H2), 38.31 (cis-C3H2), 52.39 (cis-COOCH3),
52.53 (trans-COOCH3), 53.59 (cis-C1H), 54.09 (trans-C1H), 76.29, 77.96 (C2), 116.68
(trans-CN), 117.96 (cis-CN), 168.61, 168.82, 169.62, 171.19 (COOCH3, OCOCH3)
3
0.976 and 0.982 (t, Jt1 = 3Jt2 = 7.4Hz, 3H, CH2CH2CH3), 1.63–2.69 (m, 8H,
10.38 (trans-CH2CH2CH3), 10.46 (cis-CH2CH2CH3), 20.79 (cis-OCOCH3), 20.92
(trans-OCOCH3), 21.84, 21.89, 21.94 (C4H2), (CH2CH2CH3), 25.72 (cis-C5H2), 26.94
(trans-C5H2), 38.26 (C3H2), 53.85 (cis-C1H), 54.11 (trans-C1H), 67.02 (cis-CH2CH2CH3),
67.19 (trans-CH2CH2CH3), 76.38 (cis-C2), 77.96 (trans-C2), 116.67 (trans-CN), 117.96
(cis-CN), 168.56, 169.13 (cis-COO), (cis-OCOCH3), 168.79, 170.76 (trans-COO),
(trans-OCOCH3)
CH2CH2CH3, 6CH), 2.08 and 2.13 (s, 3H, OCOCH3), 3.23–3.37 (m, 1H, C1Hax),
4.04–4.23 (m, 2H, CH2CH2CH3)
3
cis-6d
rac-6e
1.28 and 1.29 (d, Jd1 = 3Jd2 = 6.3Hz, 6H, CH(CH3)2), 1.82–2.25 (m, 4H, 4CH), 2.08
20.76 (OCOCH3), 21.55 (C4H2), 21.68, 21.71 (CH(CH3)2), 25.61 (C5H2), 38.22
(C3H2), 53.87 (C1H), 69.01 (CH(CH3)2), 76.54 (C2), 117.98 (CN), 168.52 (COO).
(OCOCH3)
(s, 3H, OCOCH3), 2.46 (m, 3J = 7.6Hz, 2H, CH), 3.30 (t, 3J = 8.7Hz, 1H, C1Hax),
5.07 (sept, 3J = 6.3Hz, 1H, CH(CH3)2)
1.82–2.34 (m, 4H, 4CH), 2.07 and 2,13 (s, 3H, OCOCH3), 2,47 (t, 3J = 7.6Hz, 1H, CH), 20.78 (cis-OCOCH3), 20.92 (trans-OCOCH3), 21.45, 21.89 (C4H2), 25.78, 27.00 (C5H2),
2.57–2.84 (m, 1H, CH), 3.25–3.42 (m, 1H, C1Hax), 4.58–4.77 (m, 2H, CH2CH@CH2),
5.24–5.43 (m, 2H, CH2CH@CH2), 5.86–6.04 (m, 1H, CH2CH@CH2)
38.20, 39.26 (C3H2), 53.67, 54.01 (C1H), 65.93, 66.16 (CH2CH@CH2), 76.32 (cis-C2), 77.89
(trans-C2), 116.62 (trans-CN), 117.95 (cis-CN), 118.70 (cis-CH2CH@CH2), 118.88
(trans-CH2CH@CH2), 131.58 (cis-CH2CH = CH2), 131.60 (trans-CH2CH@CH2), 168.60,
168.81, 170.41 (COO), (OCOCH3)
rac-6f
0.96–0.99 (m, 6H, CH2CH(CH3)2), 1.75–2.71 (m, 7H, 6CH, CH2CH(CH3)2), 2,08 and
2,13 (s, 3H, OCOCH3), 3.24–3.38 (m, 1H, C1Hax), 3.88–4.05 (m, 2H, CH2CH(CH3)2)
19.06, 19.07 (CH2CH(CH3)2), 20.81 (cis-OCOCH3), 20.91 (trans-OCOCH3), 21.53
(cis-C4H2), 21.83 (trans-C4H2), 25.70 (cis-C5H2), 26.85 (trans-C5H2), 27.62
(trans-CH2CH(CH3)2), 27.70 (cis-CH2CH(CH3)2), 38.23 (trans-C3H2), 38.33 (cis-C3H2),
54.01 (cis-C1H), 54.14 (trans-C1H), 71.57 (cis-CH2CH(CH3)2), 71.63 (trans-CH2CH(CH3)2),
76.33 (cis-C2), 77.92 (trans-C2), 116.69 (trans-CN), 117.97 (cis-CN), 168.55, 169.07
(cis-COO), (cis-OCOCH3), 168.79, 170.68 (trans-COO), (trans-OCOCH3)

C. Kobler, F. Effenberger / Tetrahedron: Asymmetry 15 (2004) 3731–3742
3741
Conversion and isomeric ratio were directly determined
from the filtrate by gas chromatography.
Br, 22.69;O, 18.17. Found: C, 51.16;H, 4.14;N 3.83;
Br, 22.53.
4.6. General procedure for the preparation of the
p-bromobenzoylated derivatives 2a0, 5a0, and 5b0
4.6.4. cis-(1R,2S)-1-(4-Bromobenzoyloxy)-2-cyanocyclo-
pentanecarboxylic acid ethyl ester cis-(1R,2S)-
5b0. Reaction time: 14d at room temperature, Rf =
To a solution of 2a, 5a, or 5b (10.70, 1.77, or 2.84mmol,
diastereomeric ratio given in Tables 3 and 6 in 1:1 pyr-
idine/CH2Cl2 (20–80mL) was added dimethylaminopyr-
idine (ca. 0.2equiv) and p-bromobenzoyl chloride
(2.0equiv), and the reaction mixture stirred for the time
given. Water (20–50mL) was then added, the layers sep-
arated, and the aqueous layer extracted with diethyl
ether (3 · 50mL). The combined extracts were washed
with diluted HCl until neutral and then dried over
Na2SO4 and concentrated. The residue was chromato-
graphed on silica gel with petroleum ether–ethyl acetate
(50:1 for 2a0, 5:1 for 5a0, and 7:1 for 5b0) and
recrystallized.
0.21, yield: 56% cis-5b0, mp 93ꢁC (diisopropyl ether),
20
½aŠ ¼ À1:9 (c 1.0, CHCl3). 1H NMR (500MHz): d
D
3
1.23 (t, J = 7.1Hz, 3H, CH2CH3), 1.87–2.01 (m, 2H,
2CH), 2.13–2.20 (m, 1H, CH), 2.30–2.38 (m, 1H, CH),
2.52–2.67 (m, 2H, 2 CH), 3.44 (t, 3J = 8.9Hz, 1H,
C1Hax), 4.19–4.25 (m, 2H, CH2CH3), 7.59–7.83 (m,
4H, HPh). 13C NMR (125.8MHz): d 14.21 (CH2CH3),
21.76 (C4H2), 25.81 (C5H2), 38.38 (C3H2), 54.19 (C1H),
61.64 (CH2CH3), 77.11 (C2), 117.75 (CN), 127.51,
129.42, 131.32, 132.16 (CPh), 163.40 (OCO), 169.08
(COOEt). Anal. Calcd for C16H16NO4Br (366.21): C,
52.48;H, 4.40;N, 3.82;Br, 21.82;O, 17.48. Found: C,
52.52;H, 4.49;N 3.76;Br, 21.73.
4.6.1. cis-(1S,2R)-1-(4-Bromobenzoyloxy)-2-methylcyclo-
pentanecarbonitrile cis-(1S,2R)-2a0. Reaction time: 14d
Acknowledgements
at room temperature, Rf = 0.05, yield: 33% cis-2a0, mp
20
73ꢁC (diisopropyl ether), ½aŠ ¼ þ0:5 (c 1.0, CHCl3).
This work was supported by the Fonds der Chemischen
Industrie and the Degussa AG. The authors thank Dr.
Wolfgang Frey for X-ray crystallographic analysis,
and Dr. Angelika Baro for the help with preparing the
manuscript.
D
3
1H NMR (500MHz): d 1.29 (d, J = 6.8Hz, 3H, CH3),
1.59–1.67 (m, 1H, CH), 1.78–1.90 (m, 2H, 2CH), 2.05–
2.12 (m, 1H, CH), 2.43–2.56 (m, 3H, CH), 7.60–7.87
(m, 4H, HPh). 13C NMR (125.8MHz): d 13.06 (CH3),
21.42 (C4H2), 31.01 (C3H2), 37.40 (C5H2), 46.01 (C2H),
78.79 (C1), 118.80 (CN), 128.22, 129.01, 131.15, 132.03
(CPh), 163.90 (OCO). Anal. Calcd for C14H14NO2Br
(308.17): C, 54.56;H, 4.58;N, 4.55;Br, 25.93;O,
10.38. Found: C, 54.56;H, 4.56;N 4.56;Br, 25.89.
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20
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