Practical asymmetric synthesis of α-methylserine derivatives under mild phase-transfer conditions

Article abstract of DOI:10.1016/j.tetlet.2008.07.013

The enantioselective methylation reaction of phenyloxazoline tert-butyl ester 5 using (R)-4b as a catalyst under mild phase-transfer conditions provides optically active α-methylserine derivatives in moderate yields with high enantioselectivity. Other α-alkylated serine derivatives are also achievable in high yields with high enantioselectivity by using catalytic amount of (R)-4b.

Full text of DOI:10.1016/j.tetlet.2008.07.013

Tetrahedron Letters 49 (2008) 5461–5463
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Tetrahedron Letters
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Practical asymmetric synthesis of a-methylserine derivatives
under mild phase-transfer conditions
Keiji Nakayama a, Keiji Maruoka b,
*
a Process Technology Research Laboratories, Daiichisankyo CO., LTD, Hiratsuka, Kanagawa 254-0014, Japan
b Department of Chemistry, Graduate School of Science, Kyoto Univercity, Sakyo, Kyoto 606-8502, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective methylation reaction of phenyloxazoline tert-butyl ester 5 using (R)-4b as a catalyst
Received 10 June 2008
Revised 28 June 2008
Accepted 2 July 2008
Available online 4 July 2008
under mild phase-transfer conditions provides optically active
yields with high enantioselectivity. Other -alkylated serine derivatives are also achievable in high yields
with high enantioselectivity by using catalytic amount of (R)-4b.
Ó 2008 Elsevier Ltd. All rights reserved.
a-methylserine derivatives in moderate
a
In recent years,
ied for their important roles in biological and synthetic chemistry.1
Particularly, -methylserine derivatives are quite useful for the
synthesis of bioactive natural products such as (+)-conagenin2
and the design of bioactive peptidemimetics.3
-Methylserine is
found to be a promising residue in the design of peptides, showing
a well-defined and specific conformation.4 Moreover, in the inves-
tigation of FTY7205 analogues possessing immunosuppressive
a
-alkylated serines have been extensively stud-
fer catalysts to furnish
a
-alkylated serine derivatives with high
-methylserine
enantioselectivity.7,8 However, the preparation of
a
a
derivatives, which are required for our purpose, is not described
in the paper. Accordingly, we first followed reaction conditions
using chiral phase-transfer catalyst (R,R)-3a for the desired meth-
ylation reaction. Attempted reaction of phenyloxazoline tert-butyl
ester 5 with methyl iodide (5.0 equiv) in the presence of powdered
KOH (5.0 equiv) and 1 mol % of (R,R)-3a in toluene at 0 °C resulted
in the formation of methylation product 6a in low yield (5%), and
the enantiomeric excess of 6a was revealed to be moderate (67%
ee, entry 1 in Table 1). The use of CsOHꢀH2O as base increased
the chemical yield with similar enantioselectivity (entry 2). How-
ever, catalyst (R,R)-3b showed the disappointingly low enantio-
selectivity (entry 3).
a
activity, optically active
a-methylserine-derived compound 2
clearly exhibits the different bioactivity from the other enantio-
mer. Accordingly, the investigation of practical enantioselecitive
synthetic methods for
a-methylserine has been crucially impor-
tant in pharmaceutical development, but only a few methods are
found to be practical.6
NH2
HO
F
CO2R
N
F
Ph
OH
Ar
Ar
FTY-720
O
O
1
Br
Br
F
a
N
Ar :
N
NH2
HO
CF3
NH2
CO2R
HO
Ar
Ar
FTY-720 Analogues : 2
Optically Active
α-Methylserine Derivatives
(
(
R,R)-3a
R,R)-3b
(
(
R
)-4a
CF3
R)-4b
b
OH OH
H
N
CO2H
OH
O
Bioactive Peptidemimetics
With these preliminary results in hand, we examined the
screening of binaphthyl-modified phase-transfer catalysts9 and
reaction conditions. For example, the structurally simplified cata-
lyst (R)-4a, which was recently developed in our laboratory as
powerful alkylation catalyst,10 gave better enantiomeric excess
with CsOHꢀH2O (5.0 equiv) as base (entry 4). Moreover, use of
3,30-bis(3,5-bis(trifluoromethyl)phenyl)-substituted catalyst (R)-
4b (1 mol %) gave over 80% ee (entry 5).11 At lower temperature
(+)-Conagenin
Recently, Jew and Park reported asymmetric alkylation of phe-
nyloxazoline derivatives with several efficient chiral phase-trans-
* Corresponding author. Tel./fax: +81 75 753 4041.
E-mail address: maruoka@kuchem.kyoto-u.ac.jp (K. Maruoka).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.013

5462
K. Nakayama, K. Maruoka / Tetrahedron Letters 49 (2008) 5461–5463
Table 1
Enantioselective alkylation of 5 with various alkyl halides using chiral PTC
CO2But
N
CO2But
PTC (1mol%)
base, solvent
N
R—X
+
R
O
O
6a : R = Me
5
6b : R = CH2CH=CH2
6c : R = CH2C CH
6d : R = CH2Ph
Entrya
R–X
Catalyst
Base
Conditions (solvent, °C, h)
Product
Yieldb (%)
ee (%)c
1
2
3
4
5
6
7
8
MeI
MeI
MeI
MeI
MeI
MeI
MeI
MeI
(R,R)-3a
(R,R)-3a
(R,R)-3b
(R)-4a
(R)-4b
(R)-4b
(R)-4b
(R)-4b
KOH
Toluene, 0, 22
Toluene, 0, 22
Toluene, 0, 22
Toluene, 0, 22
Toluene, 0, 22
Toluene, ꢁ10, 22
CPME,e ꢁ10, 22
CPME,e ꢁ30, 22
6a
6a
6a
6a
6a
6a
6a
6a
5
35
20
40
67
62
8
77
81
86
88
90
CsOHꢀH2O
CsOHꢀH2O
CsOHꢀH2O
CsOHꢀH2O
CsOHꢀH2O
CsOHꢀH2O
CsOHꢀH2O
34
68 (66)d
63
55
Br
Br
9
(R)-4b
CsOHꢀH2O
Toluene, ꢁ10, 5
6b
97
81
10
(R)-4b
CsOHꢀH2O
Toluene, ꢁ10, 8
6c
96
94
Br
11
(R)-4b
(R)-4b
CsOHꢀH2O
CsOHꢀH2O
Toluene, ꢁ10, 8
Toluene, ꢁ30, 14
6d
6d
90
87
94
96
Br
12
a
The reaction was carried out with RX (5.0 equiv) and base (5.0 equiv), in the presence of catalyst in toluene or CPME (0.33 M) under the given conditions.
HPLC assay yield.
The ee was determined by chiral-phase HPLC analysis (Daicel Chiralcel OD-H and hexane/2-propanol as solvent).
Isolated yield after column chromatography in entry 6.
Use of CPME (0.15 M) as solvent.
b
c
d
e
(ꢁ10 °C), the enantioselectivity was further improved (entry 6 vs
5). Finally, the reaction using cyclopentyl methyl ether (CPME) at
ꢁ30 °C afforded 6a in 90% ee (entry 8).12
References and notes
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With the optimum reaction conditions in hand, asymmetric
alkylation of phenyloxazoline tert-butyl ester 5 was carried out
with 5.0 equiv of other alkyl halides in toluene in the presence of
only 1 mol % of (R)-4b with high enantioselectivity of up to 96%
ee (entries 9–12).
Reduction of 6a with lithium aluminum hydride (LiAlH4) and
subsequent hydrogenation easily produced the corresponding
alcohol 73b in 60% yield, which is a key intermediate for RST-
7912,13 possessing immunosuppressive activity (Scheme 1).
In summary, we have shown an efficient enantioselective syn-
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a
are easily transformed into various biologically active compounds.
CO2But
H
OH
N
O
1) LiAlH4
N
Ph
Ph
2) Pd/C, H2
O
6a
7
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60% yield
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O
HO
NH2
O
RST-7912
Scheme 1.

K. Nakayama, K. Maruoka / Tetrahedron Letters 49 (2008) 5461–5463
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