Preliminary investigation of the yeast-mediated reduction of β-keto amides derived from cyclic amines as potential resolution methodology

Article abstract of DOI:10.1016/j.tetasy.2008.02.021

2-Methylpiperidine and 2-cyclohexylpiperidine were converted to their respective β-keto amides by treatment with diketene. Several strains of yeast were used to reduce the racemic β-keto amides. The unreacted enantiomers were separated from the β-hydroxy

Full text of DOI:10.1016/j.tetasy.2008.02.021

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 672–681
Preliminary investigation of the yeast-mediated reduction of b-keto
amides derived from cyclic amines as potential resolution methodology
Rachel E. Saxon, Hannes Leisch and Tomas Hudlicky*
Department of Chemistry and Centre for Biotechnology, Brock University, 500 Glenridge Avenue, St. Catharines, Ontario, Canada L2S 3A1
Received 7 December 2007; accepted 19 February 2008
Abstract—2-Methylpiperidine and 2-cyclohexylpiperidine were converted to their respective b-keto amides by treatment with diketene.
Several strains of yeast were used to reduce the racemic b-keto amides. The unreacted enantiomers were separated from the b-hydroxy
amides, the amides cleaved, and the extent of resolution was determined for the cyclic amines. Detailed experimental and spectral data
are provided for all compounds.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
investigations reported on the extent of asymmetric induc-
tion at a prochiral center contained within the alkoxide
part of the molecule. The distance of this center (d1) from
the site of the enzymatic reduction remains constant.
The reduction of b-keto esters and other dicarbonyl
compounds by enzymes from natural yeast strains is well
established.1 Further advances in this field provided recom-
binant strains that are either (R)- or (S)-specific for the
configuration of the resulting b-hydroxy carbonyl com-
pounds.2 These biotransformations yield valuable chiral
building blocks and, in those instances where additional
unsaturation is present in the substrates, are superior to
other methods of reduction such as Noyori hydro-
genation.3
In 1991, we reported the first example of the resolution of
racemic alcohols by the yeast-mediated reduction of their
keto esters,6 as shown in Figure 2. We found that reason-
able levels of enantiomeric enrichment were produced for
those alcohols containing larger groups.7 An application
of this methodology in the field of pyrrolizidine alkaloid
synthesis led to the concise preparation of several natural
products.8,9 Keto ester 9 was reduced to b-hydroxy ester
10, as shown in Figure 3.
The next logical step was to investigate asymmetric induc-
tion at remote stereogenic centers in the keto ester portion,4
as indicated in Figure 1. The results of these experiments
showed that the enantiomeric excess at remote centers de-
creases with the increasing distance (d2) of such centers
from the reaction site.5 Surprisingly, there have been no
At longer reaction times, the unreduced enantiomer 11 was
racemized, via the enolized dienic ester 12a, possibly
formed by an intramolecular abstraction of the proton
from the enolized b-keto ester 12b. Thus, all the mass of
OH
O
R1
R
R2
R3
d2
d1
O
O
O
2
R1
R
R2
R3
O
O
O
R1
R
R2
R3
1
O
3
Figure 1. Enantiomeric enrichment at prochiral centers as a function of distance from the reduction site; lim ðeeÞ ¼ 0.
d2!1
*
Corresponding author. E-mail: thudlicky@brocku.ca
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.02.021

R. E. Saxon et al. / Tetrahedron: Asymmetry 19 (2008) 672–681
673
OH
O
HO R* (+)
OR*
4
O
O
6
7
HO R*
OR*
O
O
4
5
HO R* (-)
OR*
4
Figure 2. Yeast-mediated resolution of alcohols via the reduction of b-keto esters [(+) and (ꢀ) arbitrarily assigned].
O
O
O
H
OH
O
O
OH
OMe
CO2Me
12b
12a
N3
N3
O
O
O
O
O
O
CO2Me
OH
O
O
N3
11
CO2Me
CO2Me
O
OH
N3
N3
8
9
O
CO2Me
N3
10
CO2Me
HO
H
hastanacine
heliotridine
dihydroxyheliotridine
N
13
Figure 3. Asymmetric synthesis of pyrrolizidine alkaloids by [4+1] pyrroline annulation and yeast-mediated resolution of b-keto esters.
racemic 9 was converted to hydroxyl ester 10, whose fur-
ther reactions provided the pyrrolizidine ester 13, a precur-
sor to several naturally occurring alkaloids.
and converted them to the corresponding b-keto amides
by reaction with diketene, as shown in Scheme 1. The pro-
gress of the yeast-mediated reduction of 15 was followed by
GC/MS, and was stopped after 50% conversion of the
starting material. The reaction provided b-keto amide
15a and b-hydroxy amide 16a, which were separated by
flash column chromatography and converted to the free
amines by treating either b-keto amide 15a or b-hydroxy
amide 16a with an excess of LiAlH4 in refluxing dioxane.
Conversion of the amines to their Mosher amides did not
allow the estimation of the enantiomeric excess by 19F
In an extension of this method to similar reductions of b-
keto amides,10 we found that the extent of resolution of
conformationally flexible amides derived from acyclic
amines was lower than that found for b-keto esters of race-
mic alcohols. Herein, we report the preliminary results of
the reductions of b-keto amides derived from cyclic amines
as a means of their resolution. As cyclic amines containing
alkyl groups at C-2 are commonly used as organocata-
lysts,11 yeast-mediated reduction could potentially lead to
both enantiomers of such amines, not always available
from naturally derived substances.
1
NMR, H NMR, GC/MS, or HPLC, as no separation or
distinction of the diastereomeric compounds was achieved
by these methods. 19F NMR spectra of the diastereomeric
mixture showed only one signal for both compounds. No
suitable conditions were found for the separation of the
diastereomeric compounds by GC/MS or HPLC. The for-
mation of benzamide derivatives 17a and 17b, prepared by
the acylation of the free amines, led to a scalemic mixture,
which was separated by chiral HPLC. An enantiomerically
pure sample of 17a for HPLC analysis was easily obtained
2. Results and discussion
For our initial study, we chose two cyclic amines contain-
ing substituents of varying size a to the nitrogen atom

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R. E. Saxon et al. / Tetrahedron: Asymmetry 19 (2008) 672–681
diketene, DMAP,
N
Me
N
H
Me
NEt3, DCM, 0 ºC
O
O
14
15
86% yield
baker's yeast, glucose, yeast extract, H2O, 40 ºC
(COCl)2, DMSO,
N
Me
N
N
Me
Me
NEt3, DCM,
-78 ºC to rt
O
O
O
O
O
OH
15b
41% yield
15a
25-30% yield
16a
15-26% yield
1. LiAlH4, dioxane,
reflux
2. benzoyl chloride,
K2CO3, DCM, rt
1. LiAlH4, dioxane,
reflux
2. benzoyl chloride,
K2CO3, DCM, rt
N
R
Me
N
R
Me
14b, R = H
17b, R = Bz
14a, R = H
17a, R = Bz
15% ee
26% ee
Scheme 1. Yeast reduction of 2-methylpiperidine b-keto amide 15.
Table 1. Second yeast-reduction cycle of optically enriched 15a and 15b
by the acylation of commercially available (S)-2-methylpi-
peridine with benzoyl chloride, allowing the assignment of
the absolute configuration of the resolved amines.
baker's yeast
N
Me
N
O
Me
N
Me
+
O
O
O
The first cycle of the yeast reduction produced about 15%
ee in b-keto amide 15a and 26% ee in b-hydroxy amide 16a,
as determined at the stage of benzamides 17a and 17b. The
b-hydroxy amide 16a was oxidized in moderate yield by
means of standard Swern conditions12 to b-keto amide
15b. Both keto amides, enriched as noted above, were then
resubjected to the second cycle of yeast reduction.
O
15a, R =
15b, R =
OH
Me
Me
2nd Yeast-reduction cycle
b-Keto amidea
b-Hydroxy amidea
b-Keto amide 15a
(+)-15% ee
35–43% yield
(+)-25% ee
26–35% yield
(ꢀ)-12% ee
39% yield
(ꢀ)-2.5% ee
As expected, the second bioreduction of b-keto amide 15a
provided enrichment to 25% ee, as determined after amide
cleavage and acylation to the benzamide derivative. How-
ever, the results for the reduction of b-keto amide 15b, ob-
tained by the oxidation of b-hydroxy amide 16a, were quite
unexpected and revealed that the second yeast reduction
did not enrich further the enantiomeric purity of the (R)-
2-methylpiperidine. The results for both experiments are
shown in Table 1.
b-Keto amide 15b
(ꢀ)-26% ee
28–35% yield
(ꢀ)-2% ee
a Enantiomeric excess was determined by chiral HPLC, after the cleavage
of the amide and acylation with benzoylchloride to 17a and 17b,
respectively.
After the unexpected outcome of the second yeast-reduction
cycle, we examined the resolution of 2-cyclohexylpiperidine
18 by the reduction of b-keto amide 19, as shown in Scheme
2. The reduction of 19 produced higher enrichments in the
first cycle: 42% enantiomeric excess in 19a and 62% enantio-
meric excess in b-hydroxy amide 20a. The enantiomeric ex-
cess was determined after the conversion of 19a and 20a to
the corresponding benzamide derivatives 21a and 21b,
respectively. The second yeast-reduction cycles of com-
pounds 19a and 19b (19b was obtained upon the oxidation

R. E. Saxon et al. / Tetrahedron: Asymmetry 19 (2008) 672–681
675
diketene, DMAP,
N
N
H
NEt3, DCM, 0 ºC
O
O
18
19
83% yield
baker's yeast, glucose, yeast extract, H2O, 40 ºC
(COCl)2, DMSO,
N
N
N
NEt3, DCM,
-78 ºC to rt
O
O
O
O
O
OH
19a
29-50% yield
19b
40% yield
20a
40-45% yield
1. LiAlH4, dioxane,
1. LiAlH4, dioxane,
reflux
reflux
2. benzoyl chloride,
K2CO3, DCM, rt
2. benzoyl chloride,
K2CO3, DCM, rt
N
R
N
R
18b, R = H
21b, R = Bz
62% ee
18a, R = H
21a, R = Bz
42% ee
Scheme 2. Yeast reduction of 2-cyclohexylpiperidine b-keto amide 19.
of b-hydroxy amide 20a) showed a similar trend to the re-
sults obtained for the second yeast reduction cycle of the
2-methylpiperidine derivatives. The enantiomeric excess of
b-keto amide 19a, determined after amide cleavage and
acylation with benzoyl chloride, was enriched further to
72%. The reduction of b-keto amide 19b gave a slight de-
crease in the enantiomeric excess for both the b-keto amide
and b-hydroxy amide derivative, as shown in Table 2.
A third b-keto amide derivative, derived from 2-phenyl-
3,4-dihydro-2H-quinoline, was also subjected to bioreduc-
tion. The resulting b-keto amide 27a and the b-hydroxy
amide 28 were both isolated in racemic form.15 These re-
sults indicate that the yeast-mediated reduction of quino-
line derivative 27 showed no kinetic resolution and that
the reductase or reductases did not distinguish between
the (R)- and (S)-enantiomer.
The absolute stereochemistry of the 2-cyclohexylpiperidine
derivatives was determined by the synthesis of an enriched
standard 21a, via the hydrogenation of (R)-2-phenylpiperi-
dine 26, which was obtained by a literature procedure,13 as
shown in Scheme 3. Cyclocondensation of (R)-phenylgly-
cinol 22 with 5-phenyl-5-oxopentanoic acid 23, followed
by the reductive opening of cyclic amide 24 with 9-borabi-
cyclo[3.3.1] (9-BBN) yielded a mixture of two diastereomers
in a ratio of approximately six to four. Removal of the
After the promising results in the resolution of 2-cyclo-
hexylpiperidine with baker’s yeast, we investigated the biore-
duction and resolution with various yeast strains available
from wine cultures. The results are shown in Table 3.
The K1 V1116 and EC 1118 strains achieved only 33%
and 30% conversions, respectively, and no further conver-
sion was observed even after an incubation of two weeks.
In both cases the enantiomeric excess was lower than
for bioreduction with baker’s yeast from the local
supermarket.
benzylethanol group by hydrogenolysis afforded (R)-2-
23
phenylpiperidine 26 {½aꢁD ¼ þ3:6 (c 0.6, CHCl3), lit.13
22
½aꢁD ¼ þ63:8 (c 0.5, CHCl3)}, which was further hydroge-
nated and reacted with benzoyl chloride to give the enriched
standard 21a in 6% ee,14 sufficient for assigning absolute ste-
reochemistry to 21a by comparison. The absolute stereo-
chemistry of the alcohol portion was not determined, but
was assumed to be (S) as expected from the baker’s yeast
reduction of b-keto esters or b-keto amides.6,10
Biotransformations with CY 3079 and BA 11 strains fur-
nished the b-keto amides with slightly higher enantiomeric
excess compared to that obtained with baker’s yeast (49%
for CY 3079 and 41% for BA 11). In contrast, the enantio-
meric excess of the b-hydroxy amides was significantly low-
er in both the cases.

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R. E. Saxon et al. / Tetrahedron: Asymmetry 19 (2008) 672–681
Table 2. Second yeast-reduction cycle of enantiomerically enriched 19a
and 19b
amides; that is, the extent of the resolution of the adjacent
stereogenic center is a function of the steric bulk at the C-2
of the cyclic amine. At this time, we cannot explain the
unexpected decrease in the enantiomeric excess during the
second cycle of the yeast reduction of the keto amides
obtained by the reoxidation of enriched b-hydroxy amides.
As the mass balance of the reductions has not been com-
pletely accounted for, the lack of enrichment may be due
to either the loss of material during purification or possibly
due to unrelated metabolic processes operating during the
fermentation. The results reported here are only prelimin-
ary and are based on the resolution of two compounds con-
taining the substituents of differing A-values. A detailed
investigation of 5- and 6-membered cyclic amines contain-
ing substituents of different steric bulk in the 2-position will
be conducted to assess the practicality and potential of
using this methodology for providing resolved cyclic
amines for the use as catalysts. Further improvements will
also be considered by using recombinant yeast strains2 with
known (R)- or (S)-selectivity.
baker's yeast
N
N
O
N
+
O
O
O
O
19a, R =
19b, R =
OH
Cy
Cy
Cy = cyclohexyl
2nd Yeast-reduction cycle
b-Keto amidea b-Hydroxy amidea
40–48% yield
b-Keto amide 19a
28–36% yield
(+)-42% ee
(+)-72% ee
(ꢀ)-18% ee
b-Keto amide 19b
(ꢀ)-62% ee
28–36% yield
(ꢀ)-45% ee
48% yield
(ꢀ)-59% ee
a Enantiomeric excess was determined by chiral HPLC, after cleavage of
amide and acylation with benzoylchloride to 21a and 21b, respectively.
To compare the results with more traditional methods, we
investigated the reduction of b-keto amide derivatives of 2-
methylcyclopiperidine and 2-cyclohexylpiperidine with
known asymmetric reducing agents or catalysts. In the case
of Noyori’s catalyst,17 at a hydrogen pressure of up to
1400 psi, or borane reduction with Corey’s catalyst,18 only
the starting material could be recovered. In the case of b-
chlorodiisopinocampheylborane (DIP-Cl), the starting
material was degraded.
4. Experimental
All non-aqueous reactions were carried out in an argon
atmosphere using standard Schlenk techniques for the
exclusion of moisture and air. Methylene chloride was dis-
tilled from calcium hydride. THF, benzene, and toluene
were dried over potassium/benzophenone. Analytical thin
˚
layer chromatography was performed on Silicycle 60 A
250 lm TLC plates with F-254 indicator. Flash column
chromatography was performed using Natland 200–400
mesh silica gel. The two centrifuges used are the Beckman
Model TJ-6 centrifuge using 50 mL conical tubes and the
Eppendorf Centrifuge 5414 using 1.5 mL M.C. tubes. Melt-
ing points were recorded on a Hoover Unimelt apparatus
3. Conclusion
The yeast-mediated reduction of keto amides derived from
the two piperidines appears to follow principles similar to
those in the reduction of b-keto esters or acyclic b-keto
C6H5
C6H5
OH
C6H5
toluene, reflux
9-BBN
O
O
N
O
N
+
HOOC
OH
Dean Stark trap
THF, reflux
C6H5
NH2
22
24
23
25
Pd/C, H2
MeOH
H
N
H
N
benzoyl
chloride
N
PtO2, H2
O
EtOH, HCl
K2CO3, DCM
18a
21a
26
Scheme 3. Preparation of enantiomerically enriched standard 21a.
Table 3. Results of the bioreduction of 2-cyclohexylpiperidine b-keto amide with various yeast strains
Entry
Yeast strain
Ketone ee (%)
Alcohol ee (%)
Conversion (%)
1
2
3
4
5
baker’s yeast
42
32
23
49
41
62
46
—
26
30
50
33
30
50
50
K1 V1116 (Saccharomyces cerevisiae cerevisiae)16
EC 1118 (Saccharomyces cerevisiae bayanus)16
CY 3079 (Saccharomyces cerevisiae)16
BA 11 (Saccharomyces cerevisiae cerevisiae)16

R. E. Saxon et al. / Tetrahedron: Asymmetry 19 (2008) 672–681
677
and are uncorrected. IR spectra were obtained on a Per-
kin–Elmer One FT-IR spectrometer. Optical rotations
were measured on a Perkin-Elmer 341 polarimeter. The
GC/MS data were obtained on a Perkin-Elmer Clarus
500 Gas Chromatograph and Mass Spectrometer using a
Perkin Elmer Elite-5MS column, 10 m, 0.25 mm ID,
2 mL/min helium flow. For monitoring the conversion of
the yeast reduction the following temperature program
were used: for 2-methylpiperidine, 50 °C, 15 °C/min to
330 °C (2 min); for 2-cyclohexylpiperidine and 1,2,3,4-tet-
rahydro-2-phenylquinoline, 50 °C (2 min), 10 °C/min to
300 °C (3 min). Chiral HPLC analyses were performed on
Agilent 1100 Series HPLC with a Daicel Chiralpak AS-H
column, 1 mL/min flow, hexanes/isopropanol 9:1 at room
temperature, courtesy of Dr. C. Metallinos of Brock Uni-
versity. Retention times for the (2-methylpiperidin-1-yl)-
phenyl-methanone are 17.0 and 20.5 min, (2-cyclohexyl-
piperidin-1-yl)phenyl-methanone are 18.5 and 20.9 min,
and (3,4-dihydro-2-phenylquinolin-1(2H)-yl)-phenyl-meth-
183.1254. Anal. Calcd for C10H17NO2ꢂ1/6H2O: C, 64.49;
H, 9.38. Found: C, 64.69; H, 9.38.
4.1.2. 1-(2-Cyclohexyl-piperidin-1-yl)-butane-1,3-dione 19.
The crude product was purified by flash column chroma-
tography (hexanes/ethyl acetate 3:1?1:2) affording the title
compound (83%) as a clear, slightly yellow oil; Rf 0.4
(methylene chloride/hexanes/diethyl ether 8:1:4); IR m
3425, 3252, 2928, 2852, 2663, 1721, 1631, 1579, 1484,
1446, 1390, 1358, 1315, 1259, 1214, 1190, 1176, 1159,
1
1144, 1107, 1086, 1071, 1025, 1006; H NMR (300 MHz,
CDCl3) (two rotamers) d 15.0 (s, 0.3H), 5.13 (s, 0.3H),
4.54 (d, J = 12.3 Hz, 1H), 4.41 (d, J = 6.6 Hz, 1H), 3.33–
3.58 (m, 4H), 3.05 (t, J = 13.2 Hz, 1H), 2.54 (t,
J = 12.6 Hz, 1H), 2.26 (s, 4H), 1.25–2.04 (m, 24H), 1.10–
1.26 (m, 6H), 0.92–0.98 (m, 3H); 13C NMR (75 MHz,
CDCl3) d 202.8, 202.7, 165.4, 164.9, 59.6, 53.5, 50.8, 50.3,
42.5, 37.3, 35.4. 34.8, 30.4, 30.1, 30.0, 29.9, 29.6, 28.8,
26.4, 26.1, 26.1; MS (EI) m/z (%): 169 (13), 168 (74), 85
(16), 84 (100), 43 (15); HRMS calcd for C15H25NO2
251.1885, found 251.1882. Anal. Calcd for C15H25NO2ꢂ
1/4 H2O: C, 70.41; H, 10.05. Found: C, 70.68; H, 10.04.
1
anone are 19.9 and 22.6 min. H and 13C NMR spectra
were recorded on a Brucker (300 MHz or 600MHz) spec-
trometer. All chemical shifts are referenced to TMS or
residual undeuterated solvent. Mass spectra were per-
formed by Tim Jones, at Brock University. Combustion
analyses were carried out by Atlantic Microlabs, Norcross,
GA.
4.1.3. 1-(2-Phenyl-3,4-dihydro-2H-quinolin-1-yl)-butane-1,3-
dione 27. The crude product was purified by flash column
chromatography (hexanes/ethyl acetate 5:1) affording the
title compound (57%) as a yellow oil. Rf 0.7 (hexanes/ethyl
acetate 1:1); IR m 3425, 3062, 3028, 2951, 1721, 1635, 1603,
1581, 1491, 1454, 1411. 1380, 1358, 1316, 1251, 1208, 1179,
1157, 1115, 1074, 1030; 1H NMR (300 MHz, CDCl3) d 14.2
(s, 0.3H), 7.18–7.43 (m, 9H), 5.75 (s, 0.4H), 5.64 (t,
J = 8.1 Hz, 0.4H), 3.60–3.74 (m, 1H), 2.63–2.73 (m, 3H),
2.06 (s, 2H), 1.89 (s, 1H), 1.73–1.79 (m, 1H); 13C NMR
(75 MHz, CDCl3) d 202.6, 174.8, 171.6, 166.6, 143.4,
137.6, 128.4, 127.4, 126.7, 126.6, 126.0, 126.0, 125.8,
125.7, 125.4, 125.2, 124.8, 89.1, 88.8, 60.2, 56.6, 50.0,
34.3, 34.2, 30.4, 30.3, 26.6, 26.5, 26.5, 23.8, 21.7, 14.0;
MS (EI) m/z (%): 217 (27), 209 (10), 134 (10), 133 (100),
132 (69), 131 (15), 130 (13), 118 (14), 117 (10), 85 (15), 84
(11), 77 (12), 69 (13), 43 (57); HRMS calcd for
C19H19NO2 293.425, found 293.415.
4.1. General procedure for the formation of b-keto amides
The amine (10 mmol), DMAP (4.4 mmol), and triethyl-
amine (10 mmol) were dissolved in methylene chloride
(15 mL) and cooled to 0 °C. Diketene (30 mmol) was added
dropwise to the reaction mixture. After the addition was
complete, the reaction mixture was allowed to warm to
room temperature and stirred until complete conversion
of the starting material. The reaction was quenched by
the addition of 15% NaOH (15 mL). The mixture was ex-
tracted three times with methylene chloride. The organic
layers were combined and washed four times with 1 M
HCl and once with brine, then dried over anhydrous
MgSO4, and filtered. The solvent was evaporated under re-
duced pressure.
4.2. General procedure for the chemical reduction of b-keto
amides to racemic b-hydroxy amides
4.1.1.
1-(2-Methyl-piperidin-1-yl)-butane-1,3-dione
15.
The crude product was purified by Kugelrohr distillation
affording the title compound (86%) as a clear and colour-
less oil. Bp 140–150 °C (0.4 mmHg); Rf 0.5 (methylene
chloride/methanol 96:4); IR m 3483, 2939, 2865, 1721,
To a solution of the corresponding b-keto amide
(1.09 mmol) in MeOH (5 mL) was added NaBH4
(1.20 mmol) at 0 °C. The reaction mixture was allowed to
warm to room temperature over 30 min followed by the
addition of 1 M NaOH (2 mL).
1
1634, 1582, 1441, 1359, 1272, 1181, 1152, 1008; H NMR
(300 MHz, CDCl3) (two rotamers) d 15.0 (s, 0.3H), 5.08
(s, 0.3H), 4.78–4.92 (m, 1H), 4.43 (d, J = 11.5 Hz, 1H),
3.90–4.01 (m, 1H), 3.35–3.56 (m, 5H), 3.09 (dt, J = 13.0,
2.3 Hz, 1H), 2.64 (t, J = 13.0 Hz, 1H), 2.21 (d,
J = 6.8 Hz, 6H), 1.89 (s, 1H), 1.44–1.71 (m, 11H), 1.25–
1.43 (m, 2H), 1.18 (d, J = 6.9 Hz, 3H), 1.11 (d,
J = 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 202.8,
202.7, 164.9, 164.7, 50.7, 50.2, 49.3, 44.0, 41.7, 36.5, 30.6,
30.1, 30.0, 29.7, 26.1, 25.4, 22.1, 18.7, 18.5, 16.6, 15.5;
MS (EI) m/z (%): 183 (19), 168 (19), 140 (20), 98 (22), 97
(18), 85 (14), 84 (100), 56 (17), 55 (13), 43 (38), 42 (14),
41 (13); HRMS calcd for C10H17NO2 183.1259, found
The solvent was evaporated and the residue diluted with
H2O (5 mL). The aqueous layer was extracted three times
with methylene chloride. The organic layers were combined
and dried over anhydrous MgSO4, filtered, and the solvent
was evaporated under reduced pressure.
4.2.1.
3-Hydroxy-1-(2-methyl-piperidin-1-yl)-butan-1-one
16. The title compound obtained from the reaction did
not require further purification; it was obtained in 96%
yield as a clear and colourless oil. Rf 0.32 (hexanes/ethyl
acetate 1:1); IR m 3423, 2970, 2937, 2866, 1719, 1617,

678
R. E. Saxon et al. / Tetrahedron: Asymmetry 19 (2008) 672–681
1
1442, 1372, 1256, 1181, 1153, 1038; H NMR (600 MHz,
CDCl3) d 4.98 (s, 1H), 4.46 (d, J = 12.9 Hz, 2H), 4.03–
4.25 (m, 3H), 3.56 (d, J = 13.1 Hz, 1H), 3.07 (t,
J = 12.2 Hz, 1H), 2.63 (t, J = 14.2 Hz, 1H), 2.11–2.55 (m,
4H), 1.48–1.75 (m, 10H), 1.29–1.45 (m, 2H), 1.15–1.26
(m, 9H), 1.07–1.15 (m, 3H); 13C NMR (75 MHz, CDCl3)
d 170.9, 170.8, 64.3, 64.2, 64.1, 48.0, 47.9, 43.6, 43.5,
41.1, 40.6, 40.4, 36.0, 30.5, 29.7, 26.0, 25.4, 22.2, 22.1,
18.6, 16.5, 15.6, 15.5; MS (EI) m/z (%): 185 (21), 170
(12), 140 (10), 126 (12), 98 (11), 84 (100) 56 (13), 55 (12),
45 (15), 43 (19), 41 (13); HRMS calcd for C10H19NO2
185.1416, found 185.1421. Anal. Calcd for C10H19NO2:
C, 64.38; H, 10.34. Found: C, 64.49; H, 10.16.
was added to the reaction mixture to ensure further reduc-
tion of the starting material.
The conversion of the starting material was followed by
GC/MS. For GC/MS analysis, an aliquot of 2 mL was ta-
ken from the reaction mixture and centrifuged at
13,000 rpm for 2 min. The supernatant was extracted 2ꢃ
with chloroform (1 mL) and dried over anhydrous MgSO4.
The organic layer was filtered through a 9 in. pipette con-
taining glass wool and was used directly for GC/MS
analysis.
After 50% conversion had been achieved, the reaction mix-
ture was centrifuged at 4000 rpm for 13 min. The superna-
4.2.2. 1-(2-Cyclohexyl-piperidin-1-yl)-3-hydroxy-butan-1-
one 20. The residue was purified by flash column chroma-
tography (hexanes/ethyl acetate 2:1) affording the title
compound (85%) as a colourless oil. Rf 0.2 (methylene
chloride/hexanes/diethyl ether, 8:1:4); IR m 3401, 2928,
tant was decanted into a separatory funnel. The
centrifugate was suspended in chloroform, and the organic
solvent was decanted and used for the extraction of the
aqueous solution. The supernatant was either extracted five
times with chloroform/methylene chloride 1:4 or continu-
ously extracted with methylene chloride. The organic layers
were combined, dried over anhydrous MgSO4, filtered, and
the solvent was evaporated under reduced pressure. The
residue was purified by flash column chromatography
using methylene chloride/hexanes/diethyl ether 8:1:4 as
an eluent for the separation of 1-(2-methyl-piperidin-1-
yl)-butane-1,3-dione and 3-hydroxy-1-(2-methyl-piperidin-
1-yl)-butan-1-one; 1-(2-cyclohexyl-piperidin-1-yl)-butane-
1,3-dione and 3-hydroxy-1-(2-cyclohexyl-piperidin-1-yl)-
butan-1-one; and hexanes/ethyl acetate 9:1?2:1 for 1-(2-
phenyl-3,4-dihydro-2H-quinolin-1-yl)-butane-1,3-dione and
3-hydroxy-1-(2-phenyl-3,4-dihydro-2H-quinolin-1-yl)-butan-
1-one.
1
2852, 1614, 1448, 1371, 1248, 1189, 1121, 1012; H NMR
(600 MHz, CDCl3) d 4.52 (m, 2H), 4.38 (d, J = 6.3 Hz,
1H). 4.13–4.17 (m, 2H), 3.55 (d, J = 13.8 Hz, 1H), 2.95
(t, J = 4.5 Hz, 1H), 2.41–2.49 (m, 2H), 2.21–2.29 (m, 2H),
1.57–1.89 (m, 18H), 1.42 (m, 5H), 1.06–1.19 (m, 12H),
0.78–0.94 (m, 4H); 13C NMR (75 MHz, CDCl3) d 171.4,
171.3, 171.1, 171.0, 64.3, 64.2, 64.1, 58.3, 58.2, 53.1, 41.2,
40.8, 36.8, 36.7. 35.4, 35.3, 34.8, 30.4, 30.2, 29.6, 29.0,
29.8, 26.4; MS (EI) m/z (%): 170 (48), 85 (16), 84 (100),
41 (12); HRMS calcd for C15H27NO2 253.2042, found
253.2042, Anal. Calcd for C15H27NO2ꢂ1/4H2O: C, 69.86;
H, 10.75. Found: C, 69.51; H, 10.58.
4.2.3.
3-Hydroxy-1-(2-phenyl-3,4-dihydro-2H-quinolin-1-
yl)-butan-1-one 28. The residue was purified by flash col-
umn chromatography (hexanes/ethyl acetate 5:1) affording
the title compound (88%) as a white solid. Mp 118–126 °C
(methylene chloride); Rf 0.5 (hexanes/ethyl acetate 1:1); IR
m 3683, 3401, 3019, 2400, 1630, 1583, 1521, 1491, 1400,
In all the cases the analytical data of the isolated products
were found to be identical to compounds 15 and 16. In
addition, the following specific rotation values were ob-
22
tained: 15a, ½aꢁD ¼ þ7:65 (c 0.65, CHCl3); 15a (b-keto
22
amide recovered from second yeast cycle of 15a), ½aꢁD
¼
1
1215, 1047; H NMR (300 MHz, CDCl3) d 7.17–7.31 (m,
þ16:35 (c 2.00, CHCl3); 15b (b-keto amide recovered from
23
9H), 5.70 (s, 1H), 4.21–4.23 (m, 1H), 2.61–2.88 (m, 7H),
2.25–2.33 (m, 1H), 1.98–2.02 (m, 1H), 1.12–1.24 (m, 5H);
13C NMR (75 MHz, CDCl3) d 173.0, 172.5, 128.5, 127.5,
127.4, 126.9, 126.7, 126.7, 126.0, 125.9, 125.8, 64.5, 42.4,
42.3, 42.2, 34.5, 34.4, 26.6, 26.5, 22.3, 22.0; MS (EI) m/z
(%): 277 (10), 209 (45), 208 (17), 201 (13), 133 (100), 132
(65), 131 (14), 130 (28), 118 (11), 91 (11), 77 (16), 69 (38),
43 (19), 41 (17); HRMS calcd for C19H21NO 295.1572,
found 295.1574; Anal. Calcd for C19H21NO2ꢂ1/4H2O: C,
76.10; H, 7.23. Found: C, 75.92; H, 7.25.
second yeast cycle of 15b), ½aꢁD ¼ ꢀ0:6 (c 0.75, CHCl3);
22
16a, ½aꢁD ¼ þ53:6 (c 1.10, CHCl3); 16a (b-hydroxy amide
22
recovered from second yeast cycle of 15a), ½aꢁD ¼ þ27:6
(c 1.25, CHCl3); 16a(b-hydroxy amide recovered from sec-
23
ond yeast cycle of 15b), ½aꢁD ¼ þ44:3 (c 1.10, CHCl3); 19a,
22
½aꢁD ¼ þ15:1 (c 0.45, CHCl3); 19a (b-keto amide recovered
22
from second yeast cycle of 19a), ½aꢁD ¼ þ29:7 (c 1.10,
CHCl3); 19b(b-keto amide recovered from second yeast
23
cycle of 19b), ½aꢁD ¼ ꢀ17:1 (c 0.55, CHCl3); 20a,
24
½aꢁD ¼ þ7:2 (c 0.30, CHCl3); 20a (b-hydroxy amide recov-
22
ered from second yeast cycle of 19a), ½aꢁD ¼ þ2:6 (c 0.85,
4.3. General procedure for the reduction of b-keto amides
with baker’s yeast
CHCl3); 20a (b-hydroxy amide recovered from second
23
yeast cycle of 19b), ½aꢁD ¼ þ6:8 (c 1.00, CHCl3).
A mixture of glucose (12.00 g) and yeast extract (0.50 g) in
distilled water (400 mL) was warmed to 40 °C in a 1000-mL
Erlenmeyer flask. Fleischmann’s Traditional baker’s yeast
(10.00 g) was added to the mixture and allowed to hydrate
for 20 min before the addition of the substrate (400 mg) in
ethanol (2 mL). The mixture was shaken at 180 rpm at
40 °C on an orbital shaker. At 24 h intervals, a suspension
of yeast (2.00 g), glucose (3.40 g), and yeast extract (0.12 g)
in distilled water (80 mL), hydrated at 35 °C for 20 min,
4.4. General procedure for the reduction of b-keto amides
with selected yeast strains
Yeast (0.5 g) was rehydrated in autoclaved distilled water
(3 mL) for 15 min. A starter culture was prepared by the
addition of the hydrated yeast solution (150 lL) to Yeast
Peptone Dextrose (YPD) broth (3 mL) (10 g/L yeast ex-
tract, 20 g/L peptone, and 20 g/L glucose) and the culture

R. E. Saxon et al. / Tetrahedron: Asymmetry 19 (2008) 672–681
679
was incubated at 40 °C at 180 rpm in an orbital shaker
layers were combined, dried over anhydrous Na2SO4, and
filtered. The solvent was carefully reduced and the crude
reaction mixture (50 mg in 1 mL of DCM) was carried onto
the next step without further purification.
overnight.
YPD broth (200 mL) was inoculated with the starter cul-
ture. The mixture was shaken at 40 °C at 180 rpm for
20 min, before the addition of the substrate (200 mg) dis-
solved in ethanol (2 mL). Shaking was continued at 40 °C
with monitoring of the consumption of starting material
by GC/MS. At 24 h intervals, a suspension of yeast starter
culture (0.6 mL) in YPD broth (40 mL) was added to the
reaction mixture to ensure further reduction of the starting
material.
4.7. General procedure for the formation of benzamides
Potassium carbonate (484 mg, 3.5 mmol) was added in one
portion to the crude amine (0.7 mmol) in methylene chlo-
ride at 0 °C. Benzoyl chloride (147 mg, 1.05 mmol) was
added dropwise and the reaction mixture was allowed to
warm to room temperature. After complete consumption
of the starting material (TLC), the reaction mixture was
quenched by the addition of water. The aqueous layer
was extracted three times with methylene chloride. The
organic layers were combined, and washed with 1 M
NaOH and 1 M HCl. The organic layer was dried over
anhydrous MgSO4, filtered, and the solvent was evapo-
rated under reduced pressure.
After 50% conversion of the starting material, as detected
by GC/MS, the reaction mixture was worked up as de-
scribed in the general procedure for the reduction of b-keto
amides with baker’s yeast.
4.5. General procedure for the oxidation of b-hydroxy
amides
4.7.1. (S)-(2-Methyl-piperidin-1-yl)-phenyl-methanone 17a.
The crude product, using (S)-2-methylpiperidine (75 mg,
0.76 mmol) as the starting material, was purified by flash
column chromatography (hexanes/ethyl acetate 6:1?4:1)
Oxalyl chloride (1.08 mmol) in methylene chloride (8.0 mL)
was cooled to ꢀ65 °C, then DMSO (2.16 mmol) in methy-
lene chloride (2 mL) was added. The reaction mixture was
stirred at ꢀ65 °C for 10 min, before the b-hydroxy amide
(0.54 mmol) in methylene chloride (1.0 mL) was added.
After 15 min, triethylamine (5.4 mmol) was added drop-
wise. The reaction was warmed to 0 °C over 1 h and al-
lowed to stir at room temperature until no more starting
material was present by TLC. The reaction was quenched
by the addition of H2O (5 mL) and extracted four times
with methylene chloride. The organic layers were combined
and washed with 1 M HCl and brine. The organic layer was
dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure.
affording 125 mg (96%) of the title compound as a white
21
solid. ee = 96% (HPLC); ½aꢁD ¼ þ37:2 (c 0.95, CHCl3).
The analytical data were identical to the reported data in
the literature.19
The following compounds were prepared by the general
procedure for the formation of benzamides.
22
Compound 17a, ee = 15% (HPLC); ½aꢁD 2¼1 þ6:05 (c
1.40, CHCl3); 17b, ee = 26% (HPLC); ½aꢁD ¼ ꢀ8:7 (c
1.95, CHCl3); 17a (benzamide derived from b-keto amide
23
of second yeast cycle of 15a), ee = 25% (HPLC); ½aꢁD
¼
4.5.1. (R)-1-(2-Methyl-piperidin-1-yl)-butane-1,3-dione 15b.
Compound 15b was obtained in 41% yield, following the
general procedure for the oxidation of b-hydroxy amides
after purification by flash column chromatography (meth-
þ8:1 (c 0.45, CHCl3); 17b (benzamide derived from b-
hydroxy amide of second yeast cycle of 15a), ee = 12%
22
(HPLC); ½aꢁD ¼ ꢀ4:6 (c 0.25, CHCl3); 17b (benzamide
derived from b-keto amide of second yeast cycle of 15b),
ylene chloride/hexanes/diethyl ether 8:1:4). The analytical
22
23
ee = 2% (HPLC); ½aꢁD ¼ ꢀ0:8 (c 0.50, CHCl3); 17b (benz-
data were identical to compound 15; ½aꢁD ¼ ꢀ16:7 (c
amide derived from b-hydroxy amide of second yeast cycle
1.20, CHCl3).
22
of 15b), ee = 2.5% (HPLC); ½aꢁD ¼ ꢀ0:8 (c 0.40, CHCl3).
4.5.2. (S)-1-(2-Cyclohexyl-piperidin-1-yl)-butane-1,3-dione
19b. Compound 19b was obtained in 40% yield following
the general procedure for the oxidation of b-hydroxy
amides after purification by flash column chromatography
4.7.2. (2-Cyclohexyl-piperidin-1-yl)-phenyl-methanone 21.
The crude product was purified by flash column chroma-
tography (hexanes/ethyl acetate 6:1?4:1) affording
183 mg (88%) of the title compound as a white solid. Mp
86–90 °C (ethyl acetate); Rf 0.5 (hexanes/ethyl acetate
2:1); IR m 3676, 3466, 3245, 2994, 2927, 2874, 2662, 2467,
2158, 1958, 1886, 1810, 1734, 1724, 1624, 1577, 1494,
1443, 1452, 1372, 1345, 1304, 1276, 1263, 1242, 1215,
1119, 1073, 1028, 1000; 1H NMR (300 MHz, CDCl3) d
7.44 (s, 5H), 4.56 (m, 1H), 3.33–3.52 (dd, J = 12.9,
8.1 Hz, 1H), 2.70–3.03 (dt, J = 11.7, 12.6 Hz, 1H), 1.51–
1.80 (m, 11H), 1.41 (m, 1H), 0.98–1.31 (m, 4H), 0.57 (s,
1H); 13C NMR (75 MHz, CDCl3) d 171.3, 170.5, 137.3,
129.4, 128.9, 128.8, 128.5, 128.3, 126.6, 126.4, 60.3, 60.0,
53.3, 43.6, 37.5, 35.6, 35.0, 30.2, 29.5, 28.9, 26.5, 26.1,
25.5, 19.2, 14.2; MS (EI) m/z (%): 189 (17), 188 (79), 105
(100), 77 (24); HRMS calcd for C18H25NO 271.1936, found
(methylene chloride/hexanes/diethyl ether, 8:1:4). The ana-
22
lytical data were identical to compound 19; ½aꢁD ¼ ꢀ26:3 (c
0.75, CHCl3).
4.6. General procedure for the reductive cleavage of amides
To a solution of the corresponding amide (0.45 mmol) in
dioxane (2 mL) was added LiAlH4 (2.30 mmol) and the
reaction mixture was kept at reflux overnight until no more
starting material was present by TLC. The reaction was
cooled to room temperature and quenched by the addition
of H2O (0.1 mL), 15% NaOH (0.2 mL) and H2O (0.3 mL).
The reaction mixture was filtered and the filtrate was
extracted three times with methylene chloride. The organic

680
R. E. Saxon et al. / Tetrahedron: Asymmetry 19 (2008) 672–681
3. Noyori, R.; Ohkuma, T. Angew. Chem. 2001, 113, 40; Pavlov,
V. A.; Starodubtseva, E. V.; Vinogradov, M. G.; Ferapontov,
V. A.; Malyshev, O. R.; Heise, G. L. Russ. Chem. Bull. 2000,
49, 728.
4. For general papers on the topic: Seebach, D.; Sutter, M.;
Weber, R. H.; Zuger, M. F. Org. Synth. 1985, 1; Shieh, W.;
Sih, C. J. Tetrahedron: Asymmetry 1993, 4, 1259.
5. Kertesz, D. J.; Kluge, A. F. J. Org. Chem. 1988, 53, 4952;
Davies, G. H.; Gartenmann, C. C.; Leaver, J.; Roberts, S. M.;
Turner, M. K. Tetrahedron Lett. 1986, 27, 1093; Athanasiou,
N.; Smallridge, A. J.; Trewhella, M. A. J. Mol. Catal. B:
Enzym. 2001, 11, 893.
271.1935; Anal. Calcd for C18H25NO: C, 79.66; H 9.28.
Found: C, 79.27; H 9.35.
The following compounds were prepared by the general
procedure for the formation of benzamides. The analytical
data were identical to compound 21.
23
Compound 21a, ee = 42% (HPLC); ½aꢁD ¼ þ21:7 (c
22
0.30, CHCl3); 21b, ee = 62% (HPLC); ½aꢁD ¼ ꢀ41:9
(c 0.35, CHCl3); 21a (benzamide derived from b-keto
amide of second yeast cycle of 19a), ee = 72% (HPLC);
23
6. Hudlicky, T.; Tsunoda, T.; Gadamasetti, G.; Murry, J.;
Keck, G. J. Org. Chem. 1991, 56, 3619.
½aꢁD ¼ þ47:4 (c 0.25, CHCl3); 21b (benzamide derived
from b-hydroxy amide of second yeast cycle of 19a),
23
7. The surprising absence of such investigations until 1991 was
most likely due to the lack of yeast reductions of esters other
than those derived from methyl, ethyl, propyl, butyl and
benzyl alcohols, the most commonly used substrates.
8. Hudlicky, T.; Seoane, G.; Lovelace, T. C. J. Org. Chem. 1988,
53, 2094.
ee = 18% (HPLC); ½aꢁD ¼ ꢀ10:1 (c 0.60, CHCl3); 21b
(benzamide derived from b-keto amide of second yeast
23
cycle of 19b), ee = 45% (HPLC); ½aꢁD ¼ ꢀ29:7 (c 0.55,
CHCl3); 21b (benzamide derived from b-hydroxy amide
22
of second yeast cycle of 19b), ee = 59% (HPLC); ½aꢁD
¼
ꢀ32:4 (c 0.40, CHCl3).
9. Hudlicky, T.; Seoane, G.; Price, J. D.; Gadamasetti, K. (in
part) Synlett 1990, 433.
10. Hudlicky, T.; Gillman, G.; Andersen, C. Tetrahedron:
Asymmetry 1992, 3, 281.
Acknowledgements
11. (a) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res.
2004, 37, 580; (b) Enders, D.; Kipphardt, H.; Gerdes, P.;
Brena-Valle, L. J.; Bhushan, V. Bull. Soc. Chim. Belg. 1988,
97, 691; (c) Albertshofer, K.; Thayumanavan, R.; Utsumi, N.;
Tanaka, F.; Barbas, C. F., III Tetrahedron Lett. 2007, 48, 693.
12. Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
The authors are grateful to the following agencies for
financial support: Natural Science and Engineering Re-
search Council (NSERC), TDC Research Foundation,
Canada Foundation for Innovation (CFI), Ontario Inno-
vation Trust (OIT), Research Corporation, TDC Research,
Inc., and Brock University. We are indebted to Dr. Debra
Ingils and Dr. Gary Pigeau for providing various wine
yeast strains as well as Nu´ria Llor and Professor Joan Bos-
ch for providing additional information on the synthesis of
compound 26.
´
´
13. Amat, M.; Bassas, O.; Llor, N.; Canto, M.; Perez, M.;
Molins, E.; Bosch, J. Chem. Eur. J. 2006, 12, 7872.
14. We want to thank Nu´ria Llor and Professor Joan Bosch for
helpful advice for the synthesis of the enantiomerically
enriched standard 26. In repetition of this work, we were
unable to obtain the enantiomeric excess of 99% reported
(Ref. 13).
15. No resolution with yeast reduction was observed for 2-
phenyl-3,4-dihydro-2H-quinoline as substrate.
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N
H
Ph
N
Ph
O
O
27
yeast
reduction
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N
Ph
N
O
Ph
+
O
O
OH
27a
28

R. E. Saxon et al. / Tetrahedron: Asymmetry 19 (2008) 672–681
681
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