Enzymatic desymmetrization of 2-amino-2-methyl-1,3-propanediol: Asymmetric synthesis of (S)-N-Boc-N,O-isopropylidene-α-methylserinal and (4R)-methyl-4-[2-(thiophen-2-yl)ethyl]oxazolidin-2-one

Article abstract of DOI:10.1016/j.tetasy.2005.07.037

We report herein, the novel enzymatic desymmetrization of 2-tert-butoxycarbonylamino-2-methyl-1,3-propanediol 1. This method makes it possible to prepare (S)-N-Boc-N,O-isopropylidene-α-methylserinal 3, which is a chiral building block for the synthesis of a variety of α-substituted alanine derivatives. Moreover, optically active (4R)-methyl-4-[2-(thiophen-2- yl)ethyl]oxazolidin-2-one 4, one of the key intermediates in the synthesis of a novel immunosuppressant, has been prepared by this methodology.

Full text of DOI:10.1016/j.tetasy.2005.07.037

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3139–3142
Enzymatic desymmetrization of 2-amino-2-methyl-1,3-propanediol:
asymmetric synthesis of (S)-N-Boc-N,O-isopropylidene-a-methyl-
serinal and (4R)-methyl-4-[2-(thiophen-2-yl)ethyl]oxazolidin-2-one
Takashi Tsuji, Yukiko Iio, Toshiyasu Takemoto and Takahide Nishi*
Medicinal Chemistry Research Laboratories, Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
Received 8 June 2005; accepted 6 July 2005
Available online 28 September 2005
Abstract—We report herein, the novel enzymatic desymmetrization of 2-tert-butoxycarbonylamino-2-methyl-1,3-propanediol 1.
This method makes it possible to prepare (S)-N-Boc-N,O-isopropylidene-a-methylserinal 3, which is a chiral building block for
the synthesis of a variety of a-substituted alanine derivatives. Moreover, optically active (4R)-methyl-4-[2-(thiophen-2-yl)ethyl]oxaz-
olidin-2-one 4, one of the key intermediates in the synthesis of a novel immunosuppressant, has been prepared by this methodology.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
In recent years, a great deal of attention has been
focused on the synthesis of a,a-disubstituted a-amino
acids with a view to design and synthesize short chain
peptides for the purpose of enhanced properties and
beneficial physiological effects.1 Moreover, a,a-disubsti-
tuted a-amino acids themselves are known as powerful
enzyme inhibitors.2 Chiral N-Boc-N,O-isopropylidene-
a-methylserinal 3, for example, is known to be a poten-
tial building block for the synthesis of enantiomerically
pure a-substituted alanines.3 Additionally, a,a-disubsti-
tuted a-amino alcohols, are also recognized as signifi-
cant components of biologically active compounds.4
(4R)-Methyl-4-[2-(thiophen-2-yl)ethyl]oxazolidin-2-one
4 is one of the key intermediates in the synthesis of a
novel immunosuppressant bearing the a,a-disubstituted
a-amino alcohol moiety.5 Accordingly, the synthetic
importance as well as biological interest for the con-
struction of optically active quaternary carbon centers
has been recognized.6 In this context and as a part of
our research program, we have been interested in the
study and development of the methodology for the syn-
thesis of 3 and 4.
Among a number of synthetic methods to achieve this
aim, the enzymatic desymmetrization of achiral 2-ami-
no-2-methyl-1,3-propanediol leading to the enantiome-
rically enriched monoester was considered attractive.
Desymmetrization reactions have the advantage over
conventional kinetic resolution reactions in the terms
of the potential ability to achieve high enantiomeric
excess (ee) and also obtain up to 100% conversion.
Although many successful examples of similar desym-
metrizations of 2-monosubstituted 1,3-propanediols
have already been reported,7 to the best of our knowl-
edge, there are only a few examples of such desymmetri-
zation methods applied to prochiral compounds bearing
a quarternary carbon center.8 In this regard, we first
focused our attention on the enzymatic desymmetrization
of 2-amino-2-methyl-1,3-propanediol bearing a quarter-
nary carbon center for the synthesis of (S)-N-Boc-N,
O-isopropylidene-a-methylserinal 3 and (4R)-methyl-4-
[2-(thiophen-2-yl)ethyl]oxazolidin-2-one 4 (Scheme 1).
2-t-Butoxycarbonylamino-2-methyl-1,3-propanediol 19
was selected as a substrate to set up the experimental
conditions for the lipase-catalyzed desymmetrization
using vinyl n-hexanoate as an acylating agent in i-Pr2O
at ambient temperature. As shown in Table 1, from
among the numerous commercial lipases screened,
immobilized lipase from Pseudomonas sp. (TOYOBO)
clearly showed the best result (88% yield, 89% ee, entry
*
Corresponding author. Tel.: +81 3 3492 3131; fax: +81 3 5436
8563; e-mail: takahi@shina.sankyo.co.jp
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.07.037

3140
T. Tsuji et al. / Tetrahedron: Asymmetry 16 (2005) 3139–3142
Me
HO
OH
NHBoc
1
Me
NH
Me
O
CHO
Me
S
O
O
R
O
OH
NHBoc
NBoc
O
3
4
2
Scheme 1.
1).10 Other lipases gave relatively moderate yields and
ee. It is noteworthy that when lipases from Rhizopus
arrhizus and Mucor javanicus were used for this reaction,
there was a preference to yield (S)-2 with the opposite
configuration, though the ee was moderate (entries 7
and 8). The ee of (R)-2 could be determined by chiral
HPLC analysis [column, ChiralCel OF (4.6/ · 250
mm); eluent, 70:30 n-hexane–2-propanol mixture; flow
rate, 0.5 mL/min; tR of (S)-isomer, 8.2 min; tR of (R)-
isomer, 10.5 min].
provided the best result (entry 2). Acylating reagents hav-
ing either a shorter or longer alkanoyl group than that of
the n-hexanoyl group, gave poor results (entries 9–13).
Having determined the optimal conditions for the lipase-
catalyzed desymmetrization of 1, we sought to apply this
method to the synthesis of (S)-N-Boc-N,O-isopropyl-
idene-a-methylserinal 3 (Scheme 2). Recently, several
studies on the synthesis of 3 have been reported, but
the procedures often required many steps.11 The hydro-
xyl group of (R)-2 was protected with tert-butyldi-
phenylsilyl chloride (TBDPSCl) and the subsequent
hydrolysis of the ester group was achieved by treatment
with 1 M NaOH solution resulting in 84% yield over two
steps. The acetonide formation of 5 took place with the
use of 2,2-dimethoxypropane in CH2Cl2 with boron tri-
fluoride etherate as a catalyst. Subsequent treatment
with tetrabutylammonium fluoride (TBAF) gave alcohol
6 in 73% yield over two steps. Finally, the oxidation of
alcohol 6 under Swern conditions was completed to give
the required (S)-N-Boc-N,O-isopropylidene-a-methyl-
serinal 3 in 96% yield.12 As a result, 3 was prepared in
61% overall yield from compound (R)-2 in only five
steps.
Immobilized lipase from Pseudomonas sp. was chosen
for further optimization of this reaction. To increase
enantioselectivity, we examined various combinations
of acylating reagents and solvents (Table 2). Although
several solvents were examined for the reaction, no dras-
tic solvent effects in terms of yields or ee were observed.
The best yield was obtained in the case of CH2Cl2 as the
solvent used, but the ee was not very high (entry 7).
Amongst all the solvents examined, i-Pr2O and
t-BuOMe gave the highest ee (entries 2 and 3). Acylating
reagents were also explored. Yields and ee values varied
according to the length of the vinyl ester side chain.
Consequently, it was found that using vinyl n-hexanoate
Table 1.
O
O
Me
n-C5H11
O
Me
HO
OH
NHBoc
n-C5H11
O
OH
NHBoc
Lipase
i-Pr2O, room temperature
(R)-2
1
Entry
Lipase
Yield (%)
% ee of (R)-2
1
2
3
4
5
6
7
8
Immobilized lipase from Pseudomonas sp.a
Lipase, immobilized on cellulose from Pseudomonas sp.b
Lipase from Chromobacterium viscosumc
Lipase from hog pancreasc
88
89
45
32
17
32
45
24
89
84
35
35
58
20
51 (S)
37 (S)
Lipase from Penicillium roquefortic
Lipase AK ÔAmanoÕ 20d
Lipase from Rhizopus arrhizusc
Lipase from Mucor javanicusc
a Lipase from TOYOBO.
b Lipase from Sigma.
c Lipase from Fluka.
d Lipase from AMANO.

T. Tsuji et al. / Tetrahedron: Asymmetry 16 (2005) 3139–3142
3141
Table 2.
O
R
O
Immobilized lipase
from Pseudomonus sp.
O
Me
Me
HO
OH
R
O
OH
NHBoc
Solvent
room temperature
NHBoc
(R)-2
1
Entry
R
Solvent
Yield (%)
% ee of (R)-2
1
2
3
4
5
6
7
8
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C5H11
CH3
n-C3H7
n-C7H15
n-C9H19
(CH3)3C
—
83
88
84
82
87
89
95
78
43
52
86
60
69
77
89
89
86
81
79
78
77
62
72
82
71
53
i-Pr2O
t-BuOMe
n-Hexane
Toluene
Et2O
CH2Cl2
THF
9
i-Pr2O
i-Pr2O
i-Pr2O
i-Pr2O
i-Pr2O
10
11
12
13
i) TBDPSCl, NEt3
i) 2,2-dimethoxypropane
O
Me
CH2Cl2
BF3-Et2O, CH2Cl2
Me
HO
OTBDPS
n-C5H11
O
OH
NHBoc
ii) 1M NaOH
84 %
ii) TBAF, THF
73 %
NHBoc
(R)-2
5
Me
Me
CHO
DMSO, oxalyl chloride
OH
O
O
NBoc
NBoc
NEt3, CH2Cl2
96 %
6
3
Scheme 2.
In the course of our studies to synthesize a novel immu-
nosuppressant, (4R)-methyl-4-[2-(thiophen-2-yl)ethyl]-
oxazolidin-2-one 4 was recognized as one of the key
intermediates.5 Compound (R)-2 was converted to enan-
tiomerically pure 4 as follows: after oxidation of the pri-
mary alcohol with PCC in CH2Cl2, Wittig condensation
with phosphonium salt 8 was performed in the presence
of t-BuOK in THF at 0 ꢁC to give 9 in good yield.
Deprotection of the ester group of 9 followed by treat-
ment with t-BuOK in THF provided 10 in 81% yield.
-BrPh3+P
O
O
O
S
Me
Me
Me
PCC, MS 4Å
CH2Cl2
8
CHO
n-C5H11
O
OH
NHBoc
n-C5H11
O
n-C5H11
O
S
t-BuOK, THF
96 %
NHBoc
NHBoc
95 %
(R)-2
7
9
Me
NH
Me
i) 1M NaOH
THF-MeOH
H2/10% Pd-C
S
S
O
O
NH
ii) t-BuOK, THF
81 %
MeOH
91 %
O
O
10
4
Recrystallization from n-hexane-AcOEt
>99% ee
Scheme 3.

3142
T. Tsuji et al. / Tetrahedron: Asymmetry 16 (2005) 3139–3142
1998, 54, 9341; (h) Neri, C.; Williams, J. M. J. Tetra-
hedron: Asymmetry 2002, 13, 2197; (i) Neri, C.; Williams,
J. M. J. Adv. Synth. Catal. 2003, 345, 835; (j) Batovska, D.
I.; Tsubota, S.; Kato, Y.; Asano, Y.; Ubukata, M.
Tetrahedron: Asymmetry 2004, 15, 3551, and references
cited therein.
4 was then obtained in 91% yield by treating 10 with
10% Pd–C in MeOH under a hydrogen atmosphere.
The desired enantiomerically pure 4 was obtained by
single recrystallization from n-hexane and AcOEt to
25
increase the ee to >99% {½aꢀD ¼ þ7:8 (c 2.0, CHCl3)}.
The ee value of 4 was determined by chiral HPLC anal-
ysis [column, ChiralCel OD-H (4.6/ · 250 mm); eluent,
60:40 n-hexane–2-propanol mixture; flow rate, 0.5 mL/
min; tR of (S)-isomer, 16.8 min; tR of (R)-isomer,
17.6 min] (Scheme 3).
8. (a) Fadel, A.; Arzel, P. Tetrahedron: Asymmetry 1997, 8,
283; (b) Akai, S.; Naka, T.; Takebe, Y.; Kita, Y.
Tetrahedron Lett. 1997, 38, 4243; (c) Guanti, G.; Nari-
sano, E.; Riva, R. Tetrahedron: Asymmetry 1998, 9, 1859;
(d) Alexandre, F.-R.; Huet, F. Tetrahedron: Asymmetry
1998, 9, 2301, and references cited therein.
9. Compound 1 was synthesized from commercially available
2-amino-2-methyl-1,3-propanediol by treatment with
Boc2O in CH2Cl2 at room temperature in 90% yield.
10. Typical enzymatic desymmetrization procedure: 2-t-But-
oxycarbonylamino-2-methyl-1,3-propanediol 1 (200 mg,
0.97 mmol) was dissolved in i-Pr2O (2 mL), and vinyl
n-hexanoate (0.16 mL, 1.02 mmol) and lipase [immobilized
lipase from Pseudomonas sp. (TOYOBO; 0.67 U/mg)]
(20 mg) then added followed by stirring for 3 h at room
temperature. After the insoluble substances in the reac-
tion mixture were removed by filtration, the filtrate
was concentrated, and the residue purified by flash silica
gel column chromatography (eluent, n-hexane–AcOEt =
10:1–7:3) to give (R)-2 (260 mg, 88% yield) as a colorless
oil. The absolute configuration of (R)-2 was determined
by the comparison of the specific rotation with that of
the known compound, (2R)-t-butoxycarbonylamino-
2-methyl-3-buten-1-ol, which can be easily synthesized
3. Conclusion
In conclusion, we have demonstrated the enzymatic
desymmetrization of 2-amino-2-methyl-1,3-propanediol.
Using this enzymatic reaction, an efficient and practical
method for the preparation of (S)-N-Boc-N,O-isopropyl-
idene-a-methylserinal 3 and (4R)-methyl-4-[2-(thiophen-
2-yl)ethyl]oxazolidin-2-one 4 has been achieved.
References
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24
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1
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