Efficient synthesis of a key intermediate of neurokinin receptor antagonists using a bifunctional asymmetric catalyst

Article abstract of DOI:10.1055/s-2003-37123

We report herein an efficient synthetic method for the preparation of 2-[(2R)-arylmorpholin-2-yl]ethanol, a key intermediate of neurokinin receptor antagonists. Catalytic asymmetric cyanosilylation of ketone 3 using titanium complex 4 was employed to introduce the required stereochemistry.

Full text of DOI:10.1055/s-2003-37123

LETTER
353
Efficient Synthesis of a Key Intermediate of Neurokinin Receptor Antagonists
Using a Bifunctional Asymmetric Catalyst
Synthesis of
a
K
ey Inte
a
rmediate
o
k
f
N
eurokinin
o
Receptor to Takamura,*a Kazuo Yabu,a Takahide Nishi,a Hiroaki Yanagisawa,a Motomu Kanai,b Masakatsu Shibasakib
a
Medicinal Chemistry Research Laboratories, Sankyo Co., Ltd., Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
Fax +81(3)54368563; E-mail: takamu@shina.sankyo.co.jp
b
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 18 November 2002
novel morpholine analogues 1 exhibited high binding
affinities for NK1, NK2 and NK3 receptors were already
reported.2 Preliminary studies indicated that the stereo-
chemistry of the 2-substituents of the morpholine ring has
great impact on the binding activity to neurokinin recep-
tor, and the (R)-configuration has been shown to be an es-
sential requirement for more potent binding affinity. An
asymmetric synthetic method using Sharpless asymmetric
dihydroxylation and the Mitsunobu reaction was also de-
veloped for preparation of 2-[(2R)-arylmorpholin-2-
yl]ethanol 2, the key intermediate of 1.3 Although this
method is useful for the preparation of an optically active
form, it is not preferable for practical synthesis because of
the toxic osmium used in the asymmetric dihydroxyla-
tion.4 Meanwhile, some of the authors have developed a
highly enantioselective catalytic cyanosilylation of ke-
tones with broad substrate generality, using a Lewis acid
Lewis base bifunctional catalyst 4 (Figure 1).5 We now
describe a new efficient route to 2 (Scheme 1) using this
catalytic asymmetric cyanosilylation as a key step.
Abstract: We report herein an efficient synthetic method for the
preparation of 2-[(2R)-arylmorpholin-2-yl]ethanol, a key inter-
mediate of neurokinin receptor antagonists. Catalytic asymmetric
cyanosilylation of ketone 3 using titanium complex 4 was employed
to introduce the required stereochemistry.
Key words: asymmetric, catalysis, ketones, ligands, titanium
Introduction
The neurokinins are a family of neuropeptides comprising
substance P (SP), neurokinin A (NKA) and neurokinin B
(NKB), that share the common C-terminal sequence Phe-
X-Gly-Leu-Met-NH2 in 10- or 11-amino acid residue.
Based on the different orders of potency of natural neuro-
kinins, three distinct receptor subtypes, which belong to
the G-protein-coupled 7-transmembrane superfamily,
have been identified: NK1 (SP-preferring), NK2 (NKA-
preferring) and NK3 (NKB-preferring).1 The presence of
the various forms of neurokinin in the mammalian body is
associated with a variety of biological actions such as pain
transmission, vasodilation, smooth muscle contraction,
and neurogenic inflammation. Airway inflammation and
bronchoconstriction in asthma and chronic airway ob-
structive disease continue to be the major foci of clinical
interest in neurokinin research. Based on the speculation
that combined (NK1/NK2/NK3) neurokinine receptor an-
tagonist would be of greater benefit in the treatment of
pulmonary diseases than selective antagonist, a series of
Ph
Ph
O
P
O
O
i PrO
O
O
Ti
i
PrO
4
Figure 1 Catalyst 4
Cl
Cl
Cl
Cl
Catalytic
O
Asymmetric
Cyanosilylation
O
OTBS
HO
X
N
NH
N
Cl
R
O
O
Cl
3
2
1
Scheme 1 Retrosynthesis
Synlett 2003, No. 3, Print: 19 02 2003.
Art Id.1437-2096,E;2002,0,02,0353,0356,ftx,en;U11502ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

354
M. Takamura et al.
LETTER
O
O
.
EtO OEt
p-TsOH H2O
CH(OEt)3
CO2Et
CO2Et
MgCl2, Et3N
CO2Et
CO2K
Cl
+
EtOH
CH3CN, y. 82%
Cl
Cl
Cl
Cl
Cl
Cl
5
6
7
O
O
i) LiAlH4, THF
ii) TFA, y. 72%
TBSCl, Imidazole
DMF, y. 90%
OH
OTBS
Cl
Cl
Cl
Cl
8
3
Scheme 2 Synthesis of 3
Although excellent results were obtained from a wide
range of ketones by catalytic enantioselective cyano-
Results and Discussion
The synthetic procedure to the starting material of the cat- silylation using 4, there have been no precedents of using
alytic asymmetric cyanosilylation is shown in Scheme 2. an aryl alkyl ketone having a bulky t-butyldimethylsiloxy
At first we synthesized ethyl 3-(3,4-dichlorophenyl)-3- group at the end of the alkyl chain. Therefore, we were
oxo propionate 6 from acid chloride 5 and potassium ethyl pleased when we found that application of a representa-
malonate in 82% yield.6 The 3-oxo group of 6 was then tive procedure7 (10 mol% of catalyst 4, THF, 30 °C for 92
protected with diethylacetal and the obtained ester 7 was h) gave the product cyanohydrin trimethylsilylether 9 in
reduced with LiAlH4 followed by deprotection of the ace- 91% yield with 79% ee (Table 1, entry 1). The chemical
tal group to obtain alcohol 8 in 72% yield (3 steps). Pro- yield was determined after reduction to aminoalcohol 108
tection of alcohol 8 with a t-butyldimethylsilyl (TBS) because of decomposition of 9 to the starting ketone in
group provided a desired ketone 3 in 90% yield.
silica gel chromatography. Enantiomeric excess was de-
termined by chiral HPLC analysis after conversion to 10
Table 1 Catalytic Asymmetric Cyanosilylation of 3 Using Ti Complex
O
Ph2P(O)
HO
10 mol%
O
NH2
O
HO
X
TMSO CN
Ti(OiPr)4
10 mol%
BH3·SMe2
OTBS
OTBS
OTBS
TMSCN
+
THF, reflux
Cl
Cl
THF, –30 °C
Cl
Cl
Cl
Cl
3
(R) - 9
(R) - 10
ee (%)
Entry
1
X
Time (h)
92
Yield
91%
79
HO
2
92
67%
75
O
HO
HO
HO
3
4
113
111
quant.
quant.
86
89
F
F
Synlett 2003, No. 3, 353–356 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of a Key Intermediate of Neurokinin Receptor
355
Table 2 Catalytic Asymmetric Cyanosilylation of 3 Using Gd Complex
O
Ph2P(O)
HO
10 mol%
NH2
O
O
TMSO CN
HO
X
Gd(OiPr)3
5 mol%
BH3·SMe2
OTBS
OTBS
OTBS
TMSCN
+
THF, reflux
Cl
EtCN, –40 °C
Cl
Cl
Cl
Cl
Cl
(S) - 9
3
(S) - 10
Entry
1
X
Time (h)
Yield
ee (%)
81
4
quant.
HO
HO
HO
2
3
3
3
quant.
quant.
75
86
F
F
and its benzamide form. Next, we tried to tune up the after converting to the key intermediate 2. Next, to obtain
ligand in this asymmetric reaction. We selected ligands, the catalyst structure-activity relationship, we changed the
which have an electron deficient and bulky cathecol unit Lewis acid metal of this catalyst to Gd (Table 2).11,12 In
in place of the cathecol unit of 4 according to previous re- this case the absolute configuration of the obtained 10 was
ports.9,10 Surprisingly, the 4-benzoyl cathecol ligand, switched to an (S)-configuration as reported11 and using a
which is the current best ligand on the Ti-system, gave 9 difluoro cathecol ligand, comparable enantioselectivity
only in 67% yield with 75% ee (Table 1, entry 2). Then was obtained to the Ti-difluoro cathecol ligand system.
the ligand having a naphthalene-2,3-ol unit (Table 1, entry
3) or difluoro cathecol unit (Table 1, entry 4) was used,
and chemical yields were gratifyingly improved to quan-
titative yield in both cases. Enantiomeric excesses were
also improved to 86% ee and 89% ee, respectively. Abso-
lute configuration of the product was determined to be R
Synthetic procedure from (R)-10 to the key intermediate 2
is shown in Scheme 3. Amino alcohol (R)-10 was then
condensed with chloroacetyl chloride to amide 11. Ob-
tained 11 was converted to desired key intermediate 2 af-
ter ring construction using NaOEt, reduction with borane
dimethylsulfide complex and following deprotection of
Cl
HN
O
NH2
HO
TMSO
Cl
chloroacetyl chloride, i-Pr2EtN
OTBS
OTBS
CH2Cl2 , y. 76%
Cl
Cl
Cl
11
(R) - 10
Cl
Cl
O
Cl
Cl
i) BH3·SMe2, THF
ii) HCl, y. 91%
NaOEt
EtOH, y. 47%
TBSO
HO
NH
NH
iii) Recrystallization
O
O
12
2 (99% ee)
Scheme 3 Synthesis of 2
Synlett 2003, No. 3, 353–356 ISSN 0936-5214 © Thieme Stuttgart · New York

356
M. Takamura et al.
LETTER
was added using an ice bath, and the whole was stirred at
room temperature for 30 min. To this catalyst solution,
ketone 3 (180 mg, 0.54 mmol) in THF (0.9 mL) was added,
followed by the addition of (CH3)3SiCN (144 mL, 1.08
mmol) at 30 °C. The reaction was monitored by TLC, and
after the reaction period described in Table 2, pyridine (0.1
mL) and H2O (1 mL) were added. Usual workup gave the
crude cyanohydrintrimethylsilylether 9. 1H NMR (CDCl3, δ
in ppm): 0.02 (6 H, s), 0.16 (9 H, s), 0.84 (9 H, s), 2.08–2.15
(1 H, m), 2.20–2.28 (1 H, m), 3.60–3.66 (1 H, m), 3.73–3.79
(1 H, m), 7.35 (1 H, dd, J = 2.0 Hz, 8.5 Hz), 7.46 (1 H, d,
J = 8.5 Hz), 7.60 (1 H, d, J = 2.0 Hz).
the TBS group with 1 N HCl. The key intermediate 2 was
obtained without any loss of enantiomeric purity from 10
and recrystallization of 2 of 89% ee from a mixture of
n-hexane and ethyl acetate yielded 2 of >99% ee in the
form of white crystals.
In summary, an efficient synthesis of the key intermediate
2 of neurokinin receptor antagonist has been achieved by
the use of a bifunctional asymmetric catalyst. Further
work in this area is now in progress.
(8) 1H NMR (400 MHz, CDCl3) δ: 0.04 (3 H, s), 0.01 (3 H, s),
0.87 (9 H, s), 1.44 (2 H, br. s), 1.88 (1 H, ddd, J = 14.6 Hz,
3.7 Hz, 3.7Hz), 2.16 (1 H, ddd, J = 14.6 Hz, 10.2 Hz, 4.6 Hz),
2.86 (1 H, d, J = 13.1 Hz), 2.91 (1 H, d, J = 13.1 Hz), 3.53 (1
H, ddd, J = 10.3 Hz, 10.2 Hz, 3.7 Hz), 3.73 (1 H, ddd, J =
10.3 Hz, 4.6 Hz, 3.7 Hz), 4.91 (1 H, br. s), 7.22 (1 H, dd, J =
8.6 Hz, 2.2 Hz), 7.42 (1 H, d, J = 8.6 Hz), 7.56 (1 H, d, J =
2.2 Hz). 13C NMR (125 MHz, CDCl3) δ: 5.82, 5.77, 17.94,
25.70, 39.61, 53.27, 60.40, 77.21, 125.21, 128.28, 130.10,
130.59, 132.44, 145.46. IR (liquid film) cm1: 3454, 2954,
2930, 1092, 837. HRMS: 364.1275 (calcd for
C16H28NO2Cl2Si 364.1266).
(9) Hamashima, Y.; Kanai, M.; Shibasaki, M. Tetrahedron Lett.
2001, 42, 691.
(10) Masumoto, S.; Yabu, K.; Kanai, M.; Shibasaki, M.
Tetrahedron Lett. 2002, 43, 2919.
(11) Yabu, K.; Masumoto, S.; Yamasaki, S.; Hamashima, Y.;
Kanai, M.; Du, W.; Curran, D. P.; Shibasaki, M. J. Am.
Chem. Soc. 2001, 123, 9908.
(12) A representative procedure: To a suspension of the chiral
ligand (0.030 mmol) in THF (0.3 mL), Gd(i-PrO)3 (0.2 M
solution in THF, 75 mL, 0.015 mmol) was added at 0 °C, and
the mixture was stirred at 45 °C for 30 min. The solvent was
evaporated at ambient temperature, the resulting white
powder was dissolved in EtCN (0.1 mL), and (CH3)3SiCN
(60 mL, 1.5 equiv) was added at –40 °C. After stirring for 15
min, the reaction was started by adding a solution of ketone
3 (0.30 mmol) in EtCN (0.1 mL).
Acknowledgment
Financial support was provided by JSPS’s Research for the Future
Program.
References
(1) Regoli, D.; Boudon, A.; Fauchere, J.-L. Pharmacol. Rev.
1994, 46, 551; and references cited therein.
(2) Nishi, T.; Fukazawa, T.; Kurata, H.; Ishibashi, K.; Nakajima,
K.; Yamaguchi, T.; Itoh, K. Sankyo Co. Ltd, Japan, EP-
776893-A1, 1996.
(3) Nishi, T.; Ishibashi, K.; Nakajima, K.; Iio, Y.; Fukazawa, T.
Tetrahedron: Asymmetry 1998, 9, 3251.
(4) A synthetic method using iodoetherification and optical
resolution was already reported: Takemoto, T.; Yukiko lio,
Y.; Nishi, T. Tetrahedron Lett. 2000, 41, 1785.
(5) Hamashima, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2000, 122, 7412.
(6) Clay, R. J.; Collom, T. A.; Karrick, G. L.; Wemple, J.
Synthesis 1993, 290.
(7) A representative procedure: To a suspension of the chiral
ligand (0.0565 mmol) in toluene (1 mL) was added Ti(i-Pr)4
(16 mL, 0.054 mmol) at ambient temperature, and the whole
mixture was stirred at 75 °C for 1 h. After the yellow solution
was cooled to room temperature, toluene was evaporated
under reduced pressure. The resulting pale yellow residue
was further dried in vacuo for 1 h. The residue was dissolved
in THF (0.9 mL), then (CH3)3SiCN (14 mL, 0.108 mmol)
Synlett 2003, No. 3, 353–356 ISSN 0936-5214 © Thieme Stuttgart · New York