Catalytic asymmetric synthesis of (S)-oxybutynin and a versatile intermediate for antimuscarinic agents

Article abstract of DOI:10.1016/j.tet.2004.08.081

A practical synthesis of (S)-oxybutynin, a muscarinic receptor antagonist, using catalytic enantioselective cyanosilylation of cyclohexyl phenyl ketone (9a) as a key step is described. The key reaction proceeded with 94% ee using 1 mol% of Gd-1 catalyst,

Full text of DOI:10.1016/j.tet.2004.08.081

Tetrahedron 60 (2004) 10497–10504
Catalytic asymmetric synthesis of (S)-oxybutynin and a versatile
intermediate for antimuscarinic agents
a,
Shuji Masumoto,a Masato Suzuki,a Motomu Kanaia,b, and Masakatsu Shibasaki
*
*
aGraduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
bPRESTO, Japan Science and Technology Corporation (JST), Kawaguchi, Saitama-ken, Japan
Received 24 June 2004; revised 28 July 2004; accepted 23 August 2004
Available online 17 September 2004
Abstract—A practical synthesis of (S)-oxybutynin, a muscarinic receptor antagonist, using catalytic enantioselective cyanosilylation of
cyclohexyl phenyl ketone (9a) as a key step is described. The key reaction proceeded with 94% ee using 1 mol% of Gd-1 catalyst, and was
performed on a 100 g-scale. In addition, a short catalytic enantioselective synthesis of the versatile intermediate for Scios Nova analogues of
antimuscarinic agents (7) is described. Application of the catalytic enantioselective cyanosilylation to ketones containing two sterically
similar substituents on the carbonyl group is also discussed.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
thecin5 (an important anticancer drug) were achieved using
these reactions as key steps.
In 2000, we developed a general catalytic enantioselective
cyanosilylation of ketones using a catalyst derived from
ligand 1 and Ti(OiPr)4 in a 1:1 ratio (Scheme 1).1,2 (R)-
Ketone cyanohydrins are obtained with high enantio-
selectivity through a presumed dual activation3 transition
state depicted as 3, which was suggested based on kinetic
studies and results using a control catalyst lacking the Lewis
base moiety. The efficiency (enantioselectivity and catalyst
turnover number) of the Ti-catalyzed reaction was further
improved by developing a tuned ligand 2 containing an
electron-withdrawing benzoyl group at the catechol
moiety.4 For the synthesis of (S)-ketone cyanohydrins, we
developed a catalyst prepared from 1 and Gd(OiPr)3 in a 1:2
ratio.5 This (S)-selective Gd-catalyst is more reactive than
the (R)-selective Ti-catalyst. Mechanistic studies suggested
that the active catalyst is a 2:3 complex of gadolinium
cyanide and 1, and the reaction proceeds through an
intramolecular cyanide transfer from the nucleophilic
gadolinium cyanide activated by the phosphine oxide, to
the ketone activated by the Lewis acidic gadolinium cyanide
(4). These reactions are practical and of broad substrate
scope, and the catalytic enantioselective syntheses of
fostriecin6 (a natural anticancer compound) and campto-
Oxybutynin (Ditropan: 5) is a widely utilized muscarinic
receptor antagonist for the treatment of urinary urgency,
frequency, and incontinence.7 A number of derivatives have
been synthesized mainly by modifying the ester (or the
amide) and the cycloalkyl parts (for examples, see Fig. 1).8
Some of these analogues have improved M3-receptor
subtype selectivity and thus the side effects caused by
antagonizing other subtypes, such as M1- and M2-receptors,
are minimized. A structurally common feature of oxy-
butynin and related compounds is the chiral tertiary
a-hydroxy carbonyl moiety. Although oxybutynin is
currently prescribed in racemic form, the (S)-enantiomer
is proposed to have an improved therapeutic profile.
Therefore, there is a high demand for the development of
an efficient enantioselective synthetic route. Previously
reported methods utilized diastereoselective reactions that
require a stoichiometric amount of chiral auxiliary or a
chiral starting material to construct the chiral stereocenter of
5.9 We reported the first practical catalytic enantioselective
synthesis of the key synthetic intermediate 11, utilizing
catalytic cyanosilylation of the ketone as a key step.10 Our
synthesis produced high enantioselectivity (up to 94% ee)
from cyclohexyl phenyl ketone (9a). Based on the high
enantioselectivity obtained from a ketone containing two
sterically similar substituents (phenyl and cyclohexyl), we
investigated the applicability of the Gd-catalyst to other
related ketones. Among the substrates studied, excellent
enantioselectivity (97% ee) was obtained from cyclobutyl
phenyl ketone (9f). This finding led us to apply the catalytic
Keywords: Oxybutynin; Muscarinic receptor antagonist; a-Hydroxy
carboxylic acid; Catalytic enantioselective cyanosilylation; Ketones;
Practical synthesis.
* Corresponding authors. Tel.: C81-3-5841-4830; fax: C81-3-5684-5206;
e-mail addresses: mshibasa@mol.f.u-tokyo.ac.jp;
kanai@mol.f.u-tokyo.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.08.081

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S. Masumoto et al. / Tetrahedron 60 (2004) 10497–10504
Scheme 1. Catalytic enantioselective cyanosilylation of ketones.
enantioselective cyanosilylation to a short synthesis of the
versatile synthetic intermediate for Scios Nova analogues
(for example, see 7)8b of subtype-selective antimuscarinic
agents. This paper describes the details of these syntheses.
2. Results and discussion
2.1. Catalytic enantioselective synthesis of (S)-
oxybutynin
Substrate 9a for the oxybutynin synthesis is an extremely
challenging ketone with respect to the induction of
enantioselectivity. In general, to achieve high enantio-
selectivity of a nucleophilic addition to carbonyl com-
pounds, the chiral catalyst needs to differentiate two lone
pairs of the carbonyl oxygen atom for the coordination to
the Lewis acid metal of the chiral catalyst. In the case of
ketone 9a, however, the difference in the steric demand of
these lone pairs is not sufficient because these lone pairs are
cis to sterically similar phenyl or cyclohexyl groups.11
Figure 1.
Despite the expected difficulties, the catalytic enantio-
selective cyanosilylation of ketone 9a proceeded at K60 8C
Table 1. Catalytic enantioselective cyanosilylation of ketone 9a
Entry
Cat. (!mol%)
Temperature (8C)
Time (h)
Yield (%)a
ee (%)b
1
2
5
5
1
1
K60
K40
K40
K40
21
1.5
50
40
96
99
99
100
95
91
85
94
3
4c
a
Isolated yield.
Determined by chiral HPLC analysis.
The ketone was added prior to TMSCN (see Section 4 for details). In other entries, ketones were added at the last stage.
b
c

S. Masumoto et al. / Tetrahedron 60 (2004) 10497–10504
10499
for 21 h in the presence of 5 mol % of Gd-catalyst, affording
the desired (S)-10a in 96% yield with 95% ee (Table 1, entry
1, catalyst concentrationZ0.075 M, ketone concentrationZ
1.5 M). The absolute configuration of 10a was determined
after conversion to carboxylic acid 11, and by comparing the
optical rotation with the reported value.9a This is the same
enantioselectivity as obtained with other previously studied
simple ketones such as acetophenone,5 suggesting that the
catalyst recognizes the cyclohexyl group as being smaller
than the phenyl group. For comparison of the reactivity, we
investigated the reaction using the (R)-selective Ti-catalyst;
however the Ti-complex did not promote the reaction of 9a
at low temperature. The reaction proceeded at room
temperature with the Ti-catalyst, and (R)-10a was obtained
in 96% yield with only 7% ee (36 h).
recovered ligand can be reused many times without any loss
of efficiency.
Having established a practical method for the catalytic
enantioselective cyanosilylation of the ketone, the next task
was to convert the cyanide to the carboxylic acid. The
conversion was initially problematic, however, probably
due to steric hindrance. Acidic hydrolysis or alcoholysis
gave predominantly ketone 9a through the elimination of
HCN. Basic hydrolysis after conversion to the THP-
protected cyanohydrin resulted in no reaction. Therefore,
we investigated the reduction–oxidation procedure
(Scheme 2). Careful reduction of 10a with DIBAL-H in
toluene, desilylation with 4 M HCl aq in THF, followed by
oxidation with NaClO2 gave the known a-hydroxy
carboxylic acid 11 in 80% overall yield (3 steps).
Chemically pure 11 was obtained through a base/acid
aqueous workup without silica gel column chromatography.
Recrystallization from CH2Cl2/hexane gave an enantio-
merically pure intermediate for oxybutynin synthesis.12
To improve the practicality of the Gd-catalyzed ketone
cyanosilylation for (S)-oxybutynin synthesis, we decreased
the catalyst loading. Using 1 mol% Gd-catalyst, however,
resulted in a sluggish reaction at K60 8C, giving the product
in 39% yield with 64% ee (9 days, catalyst concentrationZ
0.015 M, ketone concentrationZ1.5 M). Increasing the
reaction temperature to K40 8C and using a higher
concentration, the reaction proceeded to completion to
give the product in 99% yield with 85% ee (entry 3, catalyst
concentrationZ0.075 M, ketone concentrationZ7.5 M).
We hypothesized that the decrease in enantioselectivity
with the lower amount of catalyst was due in part to the
initial heat generation when a large amount of substrate
ketone was added in one portion to a mixture of the catalyst
and TMSCN, following the previous general procedure.
Therefore, we first added the substrate ketone to the catalyst,
then cooled the reaction temperature to K40 8C, added the
solvent, and slowly added the TMSCN (over 15 min). This
procedure improved the results and the product was
obtained with 94% ee (entry 4). The reaction and
purification procedures are practical and we performed the
reaction on a 100 g-scale. After the usual aqueous workup,
the crude oil was purified through short-pad silica gel
column chromatography (Scheme 2). Pure 10a was obtained
with EtOAc/hexane (1:20) elution, followed by MeOH/
CHCl3 (1:15) elution to obtain the ligand-containing
fraction (a mixture of ligand 1 and the silylated ligand).
The pure ligand 1 was recovered in 98% yield after acidic
desilylation (1 M HCl aq in THF) and recrystallization. The
2.2. Catalytic enantioselective cyanosilylation of ketones
containing two sterically similar substituents on the
carbonyl carbon
The unusually high enantio-differentiation ability of the
catalyst on the apparently difficult substrate 9a led us to
study the applicability of the Gd-catalyzed enantioselective
cyanosilylation to other ketones containing two sterically
similar substituents on the carbonyl carbon. High to
excellent enantioselectivity was obtained except in the
cases of cyclopentyl phenyl ketone (9e–H: entry 4) and
isopropyl phenyl ketone (9l–H: entry 14: Table 2). Even
simple linear ketone 9n gave the product with 85% ee (entry
17). Therefore, differentiation of the two carbonyl oxygen
lone pair by the Gd-1 catalyst might be due mainly to the
electronic characteristics of the two substituents on the
carbonyl group.11 Some of the products obtained with high
enantioselectivity should be very useful for synthesizing
new chiral oxybutynin analogues (for example, see
Section 4).
The sharp contrast in the enantiomeric excess of 10e–H and
10l–H, and products from other ketones is intriguing from a
mechanistic point of view. The results cannot be explained
from the ground state structure difference, based on the
Scheme 2. Practical catalytic enantioselective synthesis of (S)-oxybutynin key intermediate.

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S. Masumoto et al. / Tetrahedron 60 (2004) 10497–10504
Table 2. Catalytic enantioselective cyanosilylation of ketones containing sterically similar substituents
Entry
1
Ketone
Temperature (8C)
K40
Time (h)
22
Yieldb (%)
eec (%)
94
9b
99
9c
2
K40
K40
1
5
96
99
83
94
9d
3
4
K40
64
87
22
9e-H (XZH)
5d
6e
7f
9e-D
9e-D
9e-D (XZD)
K40
K40
K40
1
1
18
99
99
99
95
95
78
9f
8
K40
2
99
97
9g
9
K40
K40
48
1
97
89
82
95
10
9h (R0ZMe)
9i (R0ZEt)
9j (R0-Pr)
9k (R0ZBu)
11
12
13
K60
K60
K60
14
2.5
14
93
94
91
97
97
87
14
K40
K40
20
1
99
81
38
96
9l-H (XZH)
15g
16
9l-D (XZD)
9m
K60
2.5
90
87
80
85
9n
17
K40
1
a The absolute configuration of the product was temporarily assigned based on the analogy to 10a.
b Isolated yield.
c Determined by chiral HPLC analysis.
d 85%-D.
e 65%-D.
f 21%-D.
g 80%-D.

S. Masumoto et al. / Tetrahedron 60 (2004) 10497–10504
10501
2.3. Short-step synthesis of a versatile intermediate for
subtype-selective muscarinic receptor antagonists
The research group of Scios Nova Inc., reported a series of
compounds with M3-subtype-selective antimuscarinic
activity.8b These compounds contain a tertiary alcohol
with phenyl and cyclobutyl groups as substituents on the
tetrasubstituted carbon (for example, see 7) as the common
structure. These compounds were readily synthesized using
the methyl ketone 12 as a versatile synthetic intermediate;
a-bromination followed by the substitution with amines.
Although the Scios Nova group reported promising
biological activities using racemic compounds, it is highly
probable that the (S)-enantiomer possesses higher potency
than the (R)-enantiomer, based on the analogy to oxy-
butynin. Thus, we developed a short synthetic route to (S)-
12, using the catalytic enantioselective cyanosilylation of
ketone 9f. As described in the above section, the
corresponding precursor cyanohydrin 10f was obtained
with excellent enantioselectivity (97% ee: Table 2, entry 6).
The addition of MeLi to 10f15 followed by hydrolysis with
silica gel gave the methyl ketone 12 with no decrease in
enantioselectivity (91% yield over 2 steps). Thus, a two-step
catalytic enantioselective synthesis of the versatile inter-
mediate for subtype-selective antimuscarinic lead com-
pounds from commercially available ketone 9f was
achieved (Scheme 4).
Scheme 3.
comparison of the most stable conformation of these
substrates; molecular modeling studies indicated that
9e–H and 9l–H contain similar conformation and electronic
characteristics to other ketones. The reactivity-enantio-
selectivity relation indicated a general trend in that high
enantioselectivity was obtained when the reactions pro-
ceeded smoothly (Table 2). To explain this trend, we
hypothesized that the asymmetric catalyst might act as a
¨
Bronsted base to deprotonate the starting ketones. Based on
the analogy from the fact that the equilibrium acidity of
nitrocyclopentane is significantly higher (pKa units of ca. 2)
than nitrocyclobutane or nitrocyclohexane due to the
difference in the released strain energy in the nitronate
formation,13 it might be reasonable to assume that the
a-proton of 9e–H is more acidic than that of 9a or 9f. Thus,
9e–H (and maybe 9l–H) might be more prone to
deprotonation. This competitive deprotonation pathway
might cause a ligand exchange to produce a less
enantioselective catalyst (Scheme 3). Based on this
hypothesis, we planned to utilize a deuterium kinetic
isotope effect to prevent the undesired deprotonation.14 As
we expected, the reactions using 9e–D and 9l–D proceeded
rapidly and the products were obtained with up to 95 and
96% ee, respectively (Table 2, entry 5 vs entry 4 and entry
15 vs entry 14). Even using the starting ketone with 21%
deuterium incorporation at the a-position, the enantio-
selectivity was significantly higher than the non-deuterated
one (entry 7 vs entry 4). Thus, the enantioselectivity of the
product should be determined by the population ratio of
the highly enantioselective Gd-1 and ligand-exchanged
catalyt(s) with reduced enantioselectivity (see Scheme 3),
as well as the reaction kinetics promoted by these
complexes. To our knowledge, this is the first example of
a dramatic advantage using an isotope effect in catalytic
enantioselective reactions. The results provide very import-
3. Conclusions
We developed a practical synthetic route for an important
pharmaceutical, (S)-oxybutynin. The chiral center of the
core tertiary a-hydroxy carboxylic acid was constructed by
the catalytic enantioselective cyanosilylation of ketones
using 1 mol% of Gd-1 complex. These procedures are
suitable for large-scale synthesis with minimal silica gel
column chromatography purification. In addition, a two-step
catalytic enantioselective synthesis of the versatile inter-
mediate for subtype-selective antimuscarinic compounds
(Scios Nova analogues) was developed. Furthermore, the
excellent enantioselectivity obtained in the reaction of
ketones containing two sterically similar substituents
indicated that the Gd-1 catalyst differentiates the electronic
characteristics of the substituents. There was a dramatic
deuterium isotope effect on the reaction kinetics and
enantioselectivity in the case of ketones 9e and 9l, which
suggested that ketone deprotonation might be a possible
competitive pathway for some ketones. Based on these new
¨
ant insight for a new use of the Gd-catalyst as a Bronsted
base.
¨
findings, studies to develop a new chiral Bronsted base
catalyst are currently ongoing.
Scheme 4. Short-step synthesis of versatile intermediate for subtype-selective antimuscarinic compounds.

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S. Masumoto et al. / Tetrahedron 60 (2004) 10497–10504
4. Experimental
the bath temperature was increased to K40 8C and the
solution was stirred for 11 h. After the reaction was
completed, satd NH4Cl aq was added, followed by the
addition of 1 M HCl. After stirring for 30 min, the product
was extracted with Et2O. The organic layer was washed
with brine, dried over Na2SO4, and concentrated. The
residue was dissolved in THF (30 ml) and 4 M HCl aq
(30 ml) was added at room temperature for desilylation
(2 h). Extraction with EtOAc, successive wash with satd
NaHCO3 aq and brine, and evaporation of the organic
solvent gave the corresponding hydroxy aldehyde, which
was subjected to the following oxidation. NaClO2 (79%,
2.99 g, 26.1 mmol) was added portionwise to a solution of
the residue, 2-methyl-2-butene (8.1 ml), and NaH2PO4
4.1. 100 g-Scale cyanosilylation of 9a
Gd(OiPr)3 (5.31 mmol, 0.2 M stock solution in THF,
purchased from Kojundo Chemical Laboratory Co., Ltd.
Fax: C81-492-84-1351) in THF (26.6 ml) was added to a
suspension of chiral ligand 1 (4.51 g, 10.6 mmol) in THF
(106 ml) in an ice bath and the mixture was stirred for
30 min at 45 8C. After cooling to room temperature, THF
was evaporated and the residue was dried for 6 h under
vacuum (5 mmHg). To this catalyst powder, ketone 9a
(100 g, 0.531 mol) was added. Propionitrile (71 ml) and
TMSCN (85 ml, 0.637 mol) were successively added at
K40 8C, and the mixture was stirred for 40 h at K40 8C.
H2O was added to quench the reaction (caution: HCN is
generated), and the product and the ligand were extracted
with EtOAc. The combined organic layers was washed with
brine and dried over Na2SO4. Evaporation of the solvent
gave a crude oil, which was purified through short pad SiO2
column chromatography (450 g; EtOAc/hexaneZ1:20) to
give pure 10a as a colorless oil (152 g, 100% yield). The
ligand and the silylated ligand were eluted from the column
with CHCl3/MeOHZ15:1, treated with HCl aq in THF,
extracted, and purified by recrystallization to recover pure
ligand 1 in 98% yield.
t
(2.09 g, 17.4 mmol) in BuOH (50 ml) and H2O (12.5 ml)
for 15 min in an ice bath, and the mixture was stirred for 1 h
at room temperature. After cooling in an ice bath, 2 M
NaOH aq was added until pH was greater than 10, and the
solution was slowly added to Na2SO3 (4.84 g, 38.4 mmol) in
H2O (80 ml). tBuOH was evaporated under reduced
pressure and the water layer (pH O10) was washed with
Et2O (!3). The water layer was acidified with conc. HCl to
pHZ1 and extracted with EtOAc. The organic layer was
washed with brine and dried over Na2SO4. Filtration and
evaporation of the solvent gave a white powder of 11
(3.28 g, 80%). The enantiomeric excess of 11 was
determined by chiral HPLC [DAICEL CHIRALPAK AS,
hexane/2-propanol/TFAZ95:5:0.1, 1.0 ml/min, tR 7.3
(minor) and 10.6 min (major)]. Enantiomerically pure
(O99% ee) 11 was obtained by recrystallization from
4.2. General procedure for the conversion to benzoyl
amide for ee determination
1
CH2Cl2/hexane (1:30) in 85% yield. H NMR (CDCl3) d
To a solution of 10a (16.7 mg, 0.0581 mmol) in THF
(0.2 ml) was added LiAlH4 (6.3 mg, 0.166 mmol) at room
temperature, and the resulting mixture was stirred at 40 8C
for 1 h H2O (1 drop), 15% NaOH (1 drop) and H2O
(3 drops) were successively added to the reaction mixture in
an ice bath and ether (2 ml) was added to the resulting
mixture. After stirring at room temperature for 30 min, Et3N
(2 drops) and benzoyl chloride (14 ml, 0.121 mmol) were
added to the reaction mixture in an ice bath. After stirring
for 20 min, water was added and the mixture was extracted
with EtOAc. The organic layer was washed with satd
NaHCO3 and brine, dried over Na2SO4 and concentrated to
give a crude product, which was purified by preparative
TLC (EtOAc/hexane, 1:3) to give the corresponding
benzoyl amide.
7.64 (d, 2H, JZ7.6 Hz), 7.36–7.33 (m, 2H), 7.29–7.26 (m,
1H), 2.29–2.23 (m, 1H), 1.83–1.81 (m, 1H), 1.67–1.61 (m,
3H), 1.49–1.41 (m, 1H), 1.38–1.29 (m, 1H), 1.21–1.02 (m,
4H); 13C NMR (C6D6) d 180.71, 140.04, 128.36, 127.88,
126.09, 81.21, 45.88, 27.55, 26.43 (overlap), 26.29, 25.60;
mp 142–143 8C; EI-MS m/z 234 (MC); EI-HRMS calcd
for C14H18O3 (MC): 234.1256, Found: 234.1257; [a]2D7Z
C21.8 (cZ1.00, EtOH) (O99% ee) (lit.9c [a]22DZC22.6
(EtOH)).
4.3. General procedure for the catalytic asymmetric
cyanosilylation of ketones
Gd(OiPr)3 (0.015 mmol, 0.2 M stock solution in THF) in
THF (75 ml) was added to a suspension of chiral ligand 1
(12.7 mg, 0.030 mmol) in THF (0.3 ml) in an ice bath and
the mixture was stirred for 30 min at 45 8C. After cooling to
room temperature, THF was evaporated and the residue was
dried for 1 h under vacuum (5 mmHg). Propionitrile
(0.2 ml) was added to this catalyst powder, and TMSCN
(60 ml, 0.45 mmol) and a ketone (0.300 mmol) were added
at K40 or K60 8C, and the mixture was stirred at the
temperature shown in Table 2 until the starting ketone
disappeared on TLC. Workup and purification procedures
are the same as for the large-scale reaction (vide supra). ee
was determined after conversion to the corresponding
benzoyl amide (1. LAH, THF, 2. benzoyl chloride, Et3N).
4.2.1. Cyclohexyl(phenyl)[(trimethylsilyl)oxy]aceto-
nitrile (10a). Colorless oil; H NMR (CDCl3) d 7.47–7.45
1
(m, 2H), 7.39–7.32 (m, 3H), 2.03–1.99 (m, 1H), 1.82–1.79
(m, 1H), 1.75–1.68 (m, 2H), 1.65–1.62 (m, 1H), 1.39–1.35
(m, 1H), 1.21–1.02 (m, 5H), 0.09 (s, 9H); 13C NMR (CDCl3)
d 140.33, 128.60, 128.35, 125.96, 120.35, 79.71, 50.84,
27.49, 27.40, 26.13, 26.09, 26.07, 0.97; EI-MS m/z 287
(MC); EI-HRMS calcd for C17H25NOSi (MC): 287.1705,
Found: 287.1705; [a]D27ZK19.4 (cZ1.41, CHCl3) (94%
ee). HPLC (the corresponding benzoyl amide; DAICEL
CHIRALPAK AD-H, hexane/2-propanolZ9:1, 1.0 ml/min)
tR 18.9 min (major), 20.8 min (minor).
4.2.2. (2S)-Cyclohexyl(hydroxy)phenylacetic acid (11).
DIBAL-H (1.0 M in toluene, 34.8 ml, 34.8 mmol) was
added dropwise to a solution of cyanohydrin 10a (5.00 g,
17.4 mmol) in toluene (50 ml) at K78 8C for 75 min. Then,
4.3.1. Cyclohexyl(4-methoxyphenyl)[(trimethylsilyl)oxy]
acetonitrile (10b). Colorless oil; 1H NMR (CDCl3) d 7.39–
7.36 (m, 2H), 6.90–6.87 (m, 2H), 3.82 (s, 3H), 2.04–2.01
(m, 1H), 1.82–1.80 (m, 1H), 1.73–1.68 (m, 2H), 1.65–1.63

S. Masumoto et al. / Tetrahedron 60 (2004) 10497–10504
10503
(m, 1H), 1.38–1.35 (m, 1H), 1.22–1.00 (m, 5H), 0.09 (s,
9H); 13C NMR (CDCl3) d 159.79, 132.40, 127.24, 120.50,
113.67, 79.43, 55.41, 50.90, 27.52 (overlap), 26.17, 26.12,
26.10, 1.02; EI-MS m/z 317 (MC); EI-HRMS calcd
for C18H27NO2Si (MC): 317.1811, found: 317.1807;
[a]2D7ZK20.8 (cZ1.16, CHCl3) (94% ee). HPLC (the
corresponding benzoyl amide; DAICEL CHIRALCEL
OD-H, hexane/2-propanolZ9:1, 1.0 ml/min) tR 13.2 min
(minor), 17.4 min (major).
d 141.53, 128.83, 128.64, 125.41, 120.35, 75.64, 24.17,
3.02, 2.74, 1.14; EI-MS m/z 245 (MC); EI-HRMS calcd
for C14H19NOSi (MC): 245.1236, found: 245.1233;
[a]24DZK12.2 (cZ1.23, CHCl3) (82% ee). HPLC (the
corresponding benzoyl amide; DAICEL CHIRALPAK
AD-H, hexane/2-propanolZ9:1, 1.0 ml/min) tR 16.3 min
(minor), 37.1 min (major).
4.3.7.
Phenyl-2-[(trimethylsilyl)oxy]pentanenitrile
(10i).16 HPLC (the corresponding benzoyl amide; DAICEL
CHIRALPAK AS, hexane/2-propanolZ9:1, 1.5 ml/min) tR
15.3 min (major), 21.0 min (minor).
4.3.2. Cyclohexyl[4-(trifluoromethyl)phenyl] [(tri-
methylsilyl)oxy]acetonitrile (10c). Colorless oil; 1H
NMR (CDCl3) d 7.65 (d, 2H, JZ8.4 Hz), 7.60 (d, 2H, JZ
8.4 Hz), 1.97–1.95 (m, 1H), 1.83–1.80 (m, 1H), 1.72 (m,
2H), 1.66–1.64 (m, 1H), 1.40–1.38 (m, 1H), 1.22–1.05 (m,
5H), 0.13 (s, 9H); EI-MS m/z 355 (MC); EI-HRMS calcd for
C18H24F3NOSi (MC): 355.1579, Found: 355.1577;
[a]26DZK14.2 (cZ1.98, CHCl3) (83% ee). HPLC (the
corresponding benzoyl amide; DAICEL CHIRALPAK
AD-H, hexane/2-propanolZ9:1, 1.0 ml/min) tR 14.4 min
(major), 22.6 min (minor).
4.3.8. Phenyl-2-[(trimethylsilyl)oxy]hexanenitrile (10k).
Colorless oil; 1H NMR (CDCl3) d 7.52–7.50 (m, 2H), 7.40–
7.33 (m, 3H), 2.04–1.99 (m, 1H), 1.93–1.87 (m, 1H), 1.52–
1.43 (m, 1H), 1.35–1.24 (m, 3H), 0.87 (t, 3H, JZ7.2 Hz),
0.13 (s, 9H); HPLC (the corresponding benzoyl amide;
DAICEL CHIRALPAK AS-H, hexane/2-propanolZ9:1,
1.0 ml/min) tR 22.9 min (major), 27.5 min (minor).
4.3.9. 3-Methyl-2-phenyl-2-[(trimethylsilyl)oxy] butane-
nitrile (10l).17 GC (Varian Chirasil DEX CB (0.25 mm!
25 m), column temperatureZ100 8C (isothermal), injector
temperatureZ250 8C, detector temperatureZ280 8C, inlet
pressureZ1.3 kg/cm2): tR 25.9 min (major), 27.7 min
(minor).
4.3.3. Cycloheptyl(phenyl)[(trimethylsilyl)oxy] aceto-
nitrile (10d). Colorless oil; H NMR (CDCl3) d 7.50–7.48
1
(m, 2H), 7.39–7.32 (m, 3H), 2.08–2.04 (m, 1H), 1.97–1.92
(m, 1H), 1.82–1.75 (m, 1H), 1.65–1.40 (m, 8H), 1.33–1.22
(m, 2H), 0.07 (s, 9H); 13C NMR (CDCl3) d 140.64, 128.64,
128.42, 126.15, 120.65, 80.02, 52.34, 29.34, 28.75, 28.28,
27.92, 26.69, 26.68, 1.02; EI-MS m/z 301 (MC); EI-HRMS
calcd for C18H27NOSi (MC): 301.1862, found: 301.1862;
[a]26DZK27.9 (cZ0.31, CHCl3) (94% ee). HPLC (the
corresponding benzoyl amide; DAICEL CHIRALPAK
AD-H, hexane/2-propanolZ9:1, 1.0 ml/min) tR 18.1 min
(major), 23.3 min (minor).
4.3.10. 3,3-Dimethyl-2-phenyl-2-[(trimethylsilyl)oxy]
butanenitrile (10m).18 GC (Varian Chirasil DEX CB
(0.25 mm!25 m), column temperatureZ100 8C (iso-
thermal), injector temperatureZ250 8C, detector tempera-
tureZ280 8C, inlet pressureZ1.3 kg/cm2): tR 31.7 min
(major), 33.5 min (minor).
4.3.4. Cyclopentyl(phenyl)[(trimethylsilyl)oxy] aceto-
nitrile (10e). Colorless oil; H NMR (CDCl3) d 7.52–7.49
4.3.11. 2-Propyl-2-[(trimethylsilyl)oxy]-3-pentenenitrile
(10n). Colorless oil; 1H NMR (CDCl3) d 6.05–5.98 (m, 1H),
5.39 (dq, JZ1.7, 15.5 Hz, 1H), 1.81–1.75 (m, 4H), 1.69–
1.61 (m, 1H), 1.56–1.47 (m, 1H), 1.46–1.36 (m, 1H), 0.94 (t,
JZ7.5 Hz, 3H), 0.18 (s, 9H); 13C NMR (CDCl3) d 131.27,
128.25, 120.33, 73.65, 45.23, 17.29, 13.70, 1.31; IR (neat,
cmK1) 2963; ESI-MS m/z 234 (MCNaC); EI-HRMS calcd
for C11H21NOSi (MC): 211.1392, Found: 211.1396;
[a]22DZC3.6 (cZ2.87, CHCl3) (80% ee). HPLC
(DAICEL CHIRALPAK AS-H, hexane/2-propanolZ9:1,
1.0 ml/min) tR 14.4 min (minor), 16.8 min (major).
1
(m, 2H), 7.39–7.31 (m, 3H), 2.43–2.36 (m, 1H), 1.77–1.62
(m, 4H), 1.58–1.46 (m, 2H), 1.44–1.39 (m, 2H), 0.10 (s,
9H); 13C NMR (CDCl3) d 141.28, 128.60, 128.49, 125.55,
120.72, 79.10, 53.72, 28.28 (overlap), 25.68, 25.62, 1.04;
EI-MS m/z 273 (MC); EI-HRMS calcd for C16H23NOSi
(MC): 273.1549, found: 273.1553; [a]26DZK5.8 (cZ0.48,
CHCl3) (22% ee). HPLC (the corresponding benzoyl amide;
DAICEL CHIRALPAK AD-H, hexane/2-propanolZ9:1,
1.0 ml/min) tR 15.9 min (major), 18.1 min (minor).
4.3.5. Cyclobutyl(phenyl)[(trimethylsilyl)oxy]aceto-
nitrile (10f). Colorless oil; H NMR (CDCl3) d 7.46 (m,
4.4. General procedure for preparation of a-D ketones
(9e-D and 9l-D)
1
2H), 7.37–7.3 (m, 3H), 2.71 (m, 1H), 2.18 (m, 1H), 2.03 (m,
1H), 1.87–1.73 (m, 4H), 0.14 (s, 9H); 13C NMR (CDCl3) d
140.04, 128.63, 128.54, 125.18, 120.34, 77.76, 47.79, 23.32,
23.13, 16.51, 1.06; EI-MS m/z 259 (MC); EI-HRMS calcd
for C15H21NOSi (MC): 259.1392, found: 259.1401;
[a]25DZK7.0 (cZ0.60, CHCl3) (97% ee). HPLC (the
corresponding benzoyl amide; DAICEL CHIRALCEL
OJ-H, hexane/2-propanolZ9:1, 1.0 ml/min) tR 8.5 min
(major), 10.3 min (minor).
To a solution of KHMDS (0.5 M solution in toluene, 1.2 ml,
0.60 mmol), a ketone (0.50 mmol) was added at room
temperature, and the mixture was stirred for 3.5 h in the case
of 9e and 10 h in the case of 9l. After cooling in an ice bath,
CD3OD (0.2 ml, 5.0 mmol) was added, and the mixture was
stirred for 10 min. Satd NH4Cl was added, and the product
was extracted with EtOAc. The combined organic layers
were dried over Na2SO4. Filtration, evaporation of the
solvent, and purification through silica gel column chroma-
tography (EtOAc/hexaneZ1:19) gave the deuterated
ketone. The D-incorporation ratio was determined to be
4.3.6. Cyclopropyl(phenyl)[(trimethylsilyl)oxy] aceto-
nitrile (10g). Colorless oil; H NMR (CDCl3) d 7.57–7.55
1
1
(m, 2H), 7.41–7.34 (m, 3H), 1.41–1.35 (m, 1H), 0.86–0.81
(m, 1H), 0.70–0.57 (m, 3H), 0.14 (s, 9H); 13C NMR (CDCl3)
87% for 9e-D and 80% for 9l-D, respectively, based on H
NMR analysis.

10504
S. Masumoto et al. / Tetrahedron 60 (2004) 10497–10504
1009–1012. (h) Chen, F.; Feng, Z.; Qin, B.; Zhang, G.; Jiang,
Y. Org. Lett. 2003, 5, 949–952. (i) Shen, Y.; Feng, X.; Li, Y.;
Zhang, G.; Jiang, Y. Eur. J. Org. Chem. 2004, 129–137.
3. Shibasaki, M.; Kanai, M.; Funabashi, K. Chem. Commun.
2002, 1989.
4.4.1. Synthesis of methyl ketone 12. To a solution of the
cyanohydrin 10f (100 mg, 0.386 mmol) in ether (0.5 ml),
MeLi$LiBr (1.5 M in ether, 0.39 ml, 0.578 mmol) was
added in an ice bath. The reaction temperature was allowed
to increase to room temperature for 3 h, and the reaction was
continued at room temperature for 1 h. Silica gel was added,
and the resulting suspension was stirred for 15 min.
Filtration, evaporation, and purification through silica gel
column chromatography gave the product methyl ketone in
91% yield as a colorless oil.
4. Hamashima, Y.; Kanai, M.; Shibasaki, M. Tetrahedron Lett.
2001, 42, 691–694.
5. (a) Yabu, K.; Masumoto, S.; Yamasaki, S.; Hamashima, Y.;
Kanai, M.; Du, W.; Curran, D. P.; Shibasaki, M. J. Am. Chem.
Soc. 2001, 123, 9908–9909. (b) Yabu, K.; Masumoto, S.;
Kanai, M.; Curran, D. P.; Shibasaki, M. Tetrahedron Lett.
2002, 43, 2923. (c) Yabu, K.; Masumoto, S.; Kanai, M.;
Shibasaki, M. Heterocycles 2003, 59, 369. Ligands 1 and 2 are
commercially available from Junsei Chemical Co., Ltd. Fax:
C81-3-3270-5461 (Tokyo, Japan).
4.4.2. 1-Cyclobutyl-1-hydroxy-1-phenyl-propan-2-one
(12). Colorless oil; 1H NMR (CDCl3) d 7.39–7.41 (m,
2H), 7.34 (m, 2H), 7.28 (m, 1H), 4.70 (s, 1H), 3.47 (quintet,
JZ8.3 Hz, 1H), 2.16 (m, 1H), 2.04 (m, 1H), 2.03 (s, 3H),
1.94 (m, 2H), 1.75–1.83 (m, 2H); 13C NMR (CDCl3) d
208.67, 139.85, 128.59, 127.78, 126.59, 83.09, 38.75, 23.50,
22.59, 20.56, 17.64; IR (neat, cmK1) 3460, 1705; EI-MS m/z
204 (MC), 186 (MC1-OH), 161 (MKCOCH3); EI-HRMS
calcd for C11H13O (MKCOCH3): 161.0961, found:
161.0322; [a]22DZC149.0 (cZ1.76, CHCl3) (97% ee).
HPLC (DAICEL CHIRALPAK AS-H, hexane/2-propa-
nolZ99:1, 1.0 ml/min) tR 6.9 min (minor), 7.4 min (major).
6. Fujii, K.; Maki, K.; Kanai, M.; Shibasaki, M. Org. Lett. 2003,
5, 733.
7. Thompson, I. M.; Lauvetz, R. Urology 1976, 8, 452–454.
8. For examples, see: (a) Carter, J. P.; Noronha-Blob, L.; Audia,
V. H.; Dupont, A. C.; McPherson, D. W.; Natalie, K. J.;
Rzeszotarski, W. J.; Spagnuolo, C. J.; Waid, P. P.; Kaiser, C.
J. Med. Chem. 1991, 34, 3065–3074. (b) Kaiser, C.; Audia,
V. H.; Carter, J. P.; McPherson, D. W.; Waid, P. P.; Lowe,
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9. (a) Grover, P. T.; Bhongle, N. N.; Wald, S. A.; Senanayake,
C. H. J. Org. Chem. 2000, 65, 6283–6287. (b) Mitsuya, M.;
Ogino, Y.; Ohtake, N.; Mase, T. Tetrahedron 2000, 56,
9901–9907. (c) Senanayake, C. H.; Fang, Q. K.; Grover, P.;
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Acknowledgements
Financial support was provided by RFTF of Japan Society
for the Promotion of Science and PRESTO of Japan Science
and Technology Corporation (JST).
10. For a preliminary communication, see: Masumoto, S.; Suzuki,
M.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2002, 43,
8647–8651.
11. Corey et al. reported that electronic characteristics can
determine the effective size of the carbonyl substituents:
Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1995, 36,
9153–9156.
References and notes
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McConville, F. X.; Vandenbossche, C. P.; Senanayake, C. H.;
U.S., 6140529.
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