Enzymatic synthesis of enantiomerically enriched D- and L-3-silylated alanines by deracemization of DL-5-silylmethylated hydantoins

Article abstract of DOI:10.1016/S0957-4166(01)00028-3

The hydantoinase process was shown to be extendable to the production of highly lipophilic, silicon-containing amino acids. Two hydantoinases of different origin and stereoselectivities and one L-N-carbamoylase were used for the highly stereoselective bioconversion of (dimethyl)phenylsilyl- and 1-methyl-1-silacyclopentyl substituted alanine derivatives. The enantiomeric purities and absolute configuration of the products were determined with reference compounds that were synthesized with the aid of the Evans oxazolidinone auxiliary.

Full text of DOI:10.1016/S0957-4166(01)00028-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 157–165
Enzymatic synthesis of enantiomerically enriched
D
- and
L
-3-silylated alanines by deracemization of DL-5-silylmethylated
hydantoins
Richard J. Smith,a Markus Pietzsch,b Thomas Waniek,b Christoph Syldatkb and Stefan Bienza,*
aInstitute of Organic Chemistry, University of Zurich, CH-8057 Zurich, Switzerland
bInstitute of Biochemical Engineering, University of Stuttgart, D-70569 Stuttgart, Germany
Received 13 December 2000; accepted 15 January 2001
Abstract—The hydantoinase process was shown to be extendable to the production of highly lipophilic, silicon-containing amino
acids. Two hydantoinases of different origin and stereoselectivities and one
L-N-carbamoylase were used for the highly
stereoselective bioconversion of (dimethyl)phenylsilyl- and 1-methyl-1-silacyclopentyl substituted alanine derivatives. The enan-
tiomeric purities and absolute configuration of the products were determined with reference compounds that were synthesized with
the aid of the Evans oxazolidinone auxiliary. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
feature was in fact observed with a renin inhibitor,
where replacement of an -phenylalanine residue by
-3-(trimethylsilyl)alanine resulted in enhanced stability
of the peptide towards digestive proteolytic cleavage.
The inhibitory power of the compound was only mar-
ginally affected.7 The synthesis, and in particular the
stereoselective synthesis, of silicon-containing amino
acids is thus a field of growing activity.
L
Non-proteinogenic amino acids are important building
blocks for peptide chemistry.1–5 They mainly serve as
surrogates for natural counterparts, resulting in inter-
esting modified properties of the altered parent struc-
tures. Among the non-natural amino acids,
silicon-containing compounds are of increasing interest.
With their large hydrophobic groups they are expected
to offer several advantages when incorporated into
peptides, such as the prevention of hydrophobic pocket
collapse, higher lipophilicity, and enhanced stability
towards proteolytic enzymatic degradation.6 The latter
L
Several approaches towards optically active silicon-con-
taining amino acids have been published. Apart from
resolution of racemates,8,9 several stereoselective syn-
theses have been reported. The Scho¨llkopf, Seebach, or
Scheme 1.
* Corresponding author. E-mail: sbienz@oci.unizh.ch
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00028-3

158
R. J. Smith et al. / Tetrahedron: Asymmetry 12 (2001) 157–165
Myers methods of asymmetric a-alkylation of glycine
enolate equivalents,6,7,10,11 the Evans procedure of
asymmetric a-bromination of carboxylic acid deriva-
tives followed by substitution of the bromine atom,12
and Sibi’s method of b-substitution of serine
derivatives6 gave (in principle) access to either antipode
of the desired amino acid in high enantiomeric excesses
(e.e.). The overall yields attained with these methods,
however, were low, and (except for Sibi’s method,
which is, however, restricted to phenyl substituted
silanes) stoichiometric chiral auxiliaries had to be
employed.
acids DL-2a and DL-2b18 with the
L-N-carbamoylase to
yield the respective hydrolysis products (Scheme 1).
Both hydantoin substrates were accepted by the two
hydantoinases: however, DL-1a was converted at a
much higher rate than DL-1b. After 2 hours, 1a was
converted already to 50% while 80% of 1b was still
present. The difference in rate for the transformations
of the two compounds is not clear. It might be a
consequence of the different solubility of the two sub-
strates. Whereas DL-1a is readily soluble in the reaction
medium, DL-1b does not completely dissolve at 23°C.
We have recently shown that
lyl)alanine ( -3c or -3c) are accessible by deracemiza-
D
- or
L
-3-(trimethylsi-
The curve in Fig. 1 represents the kinetics of the
transformation of DL-1a with hydantoinase of B. ther-
moglucosidasius over 4 days. A bend in the curve is seen
after 50% conversion (ca. 2 hours). Evidently, the
enzyme-catalyzed hydrolysis of the accepted enan-
tiomeric form of 1a is faster than the racemization of its
antipode under the slightly basic reaction conditions.
After >50% conversion of the racemic samples and
complete consumption of one of the enantiomers, it was
in fact found that the hydantoins of type 1 were basi-
cally enantiomerically pure. The overall rate of the
transformation of DL-1a could possibly be slightly
enhanced by departing from the pH maximum of the
biotransformation and performing the reaction under
more basic conditions.
D
L
tion using the hydantoinase process.13 The
hydantoinase process consists of a cascade of two
hydrolytic enzymes, a hydantoinase and an N-car-
bamoylase (Scheme 1).14 The hydantoinase is responsi-
ble for the partial hydrolysis of hydantoins 1 to the
respective N-carbamoyl amino acids 2 and the N-car-
bamoylase for the subsequent deaminocarbonylation to
the corresponding amino acids 3. The deaminocarbony-
lation can also be effected by chemical means. Because
5-monosubstituted hydantoins 1 often racemize sponta-
neously under slightly alkaline conditions (for racem-
ization constants see Ref. 14), the enzymatically
accepted enantiomeric form of the hydantoin is con-
stantly resupplied from the racemate. Alternatively, a
hydantoin racemase can be involved in this conver-
sion.14 A theoretical yield of 100% is thus possible for
the formation of enantiomerically pure amino acids by
the dynamic kinetic resolution of racemic hydantoins.
All bioconversions with both hydantoinases and both
hydantoins delivered the
D-configured N-carbamoyl
amino acids of type 2 as the major products. The
enantioselectivities were virtually absolute for the
hydantoinase of B. thermoglucosidasius (e.e.s of >98%
for both substrates). For the hydantoinase of A. aures-
cens DSM 3745, which is known to change its enan-
tiomer selectivity depending on the substrate,14 the
extent of selectivity was substrate dependent: DL-1a
In particular, amino acid
D
-3c was obtained from
hydantoin DL-1c in 88% yield and with an enantiomeric
excess of 96% by this process.13
We show in the following that two further silicon-con-
taining amino acids (3a and 3b) with more bulky silicon
groups are also accessible in virtually enantiomerically
pure form by the hydantoinase process, that enzymes of
the hydantoinase process are thus not limited to the
conversion of only the simplest and most uncritical
silicon-containing hydantoin 1c and N-carbamoyl
amino acid 2c.
delivered the N-carbamoyl product
detectable amount of the -enantiomer (e.e. of >98%)
while -2b was produced from DL-1b together with its
D
-2a without a
L
D
2. Results and discussion
2.1. Biotransformations
For the extension of our foregoing study,13 the previ-
ously successfully applied hydantoinase from
Arthrobacter aurescens DSM 374515 in immobilized
form,16 which was reported to be
L-selective for the
conversion of DL-5-indolylmethylhydantoin and DL-5-
benzylhydantoin,14 the commercially available immobi-
lized
D-hydantoinase from Bacillus thermoglucosidasius
and the immobilized
L
-N-carbamoylase from A. aures-
cens DSM 374717 were investigated with the new sub-
strates. The racemic hydantoins DL-1a and DL-1b18
were thus treated in H2O at pH 8.5 with the two
hydantoinases, and the racemic N-carbamoyl amino
Figure 1. Kinetics of the transformation of DL-1a with
hydantoinase of B. thermoglucosidasius over a period of 4
days.

R. J. Smith et al. / Tetrahedron: Asymmetry 12 (2001) 157–165
159
antipode with an e.e. of 84%. The hydantoinase of A.
aurescens DSM 3745 preferred the -enantiomeric
forms of the hydantoins 1a and 1b, as was found for
the trimethylsilyl substituted hydantoin 1c. The trans-
formations thus parallel the reactions towards
methionine15 and contrast the conversions towards
tryptophan15 and phenylalanine.19
2.2. Analytical methods
D
Compounds of type 1, 2, and 3 were quantified by
reversed phase HPLC on a Gromasil ODS 1 PE
column according to May.15 E.e.s of compounds of
type 1 and 2 were measured by HPLC on a chiral
stationary phase. In contrast to the amino acids
and -/ -3b, the hydantoins -/ -1a and -/ -1b as well
as the N-carbamoyl amino acids -/ -2a and -/ -2b
D-/L-3a
D
L
D
L
D L
Deaminocarbonylation of racemic N-carbamoyl amino
acids DL-2a and DL-2b was effected by treatment of the
D
L
D L
could be separated on the Nucleodex b-PM column.
Therefore, the amino acids were transformed into the
respective N-carbamoyl amino acids to be analyzed.
Enantioselectivities were subsequently determined by
comparison of the N-carbamoyl amino acids deriving
from biotransformations with N-carbamoyl amino
acids of known absolute configuration deriving from
classical synthesis (see below).
two compounds with immobilized
L-N-carbamoylase
from A. aurescens DSM 3747 in the presence of H2O.
The reactions stopped for both substrates at 50% con-
version. Again, the rate of conversion of the
(dimethyl)phenylsilyl-containing substrate 2a was
markedly faster than that of the less soluble silacy-
clopentyl derivative 2b. As in the case of 3-(trimethylsi-
lyl)alanine, 3c, the reaction was completely L-selective:
solely one enantiomeric substrate was consumed, and
the remaining N-carbamoyl amino acids 2a and 2b
were found to be of virtually pure D-configuration (e.e.
2.3. Synthesis of the enantiomerically enriched amino
acids and N-carbamoyl amino acids
>98%), with no trace of their corresponding enan-
tiomers detectable by HPLC analysis.
The enantiomerically enriched reference compounds
2a, -2b, -3a, and -3b were synthesized in analogy to
L-
L
L
L
Scheme 2. (a) 1-Butenylmagnesium bromide, Et2O; (b) (butane-1,4-diyl)dimagnesium dibromide, Et2O; (c) O3, 2.5N NaOH in
MeOH, CH2Cl2, −60°C; (d) LiOH, H2O/THF 1:1, 0°C; (e) (1) NaH, THF, 23°C, (2) Me3COCl, 0°C, (3) (R)-4-benzyl-2-oxazolid-
inone, BuLi, −78°C; (f) (1) Bu2BOTf, iPr2NEt, CH2Cl2, −78“0°C, (2) NBS, CH2Cl2, −78°C; (g) N,N,N%,N%-tetra-
methylguanidinium azide, MeCN, 0°C; (h) LiOH, THF/H2O 3:1, 0°C; (i) PtO2, H2 (1 atm), EtOH/H2O 1:1; (j) (1) KOCN, H2O,
70°C, (2) HOAc, 10°C.

160
R. J. Smith et al. / Tetrahedron: Asymmetry 12 (2001) 157–165
a procedure of Walkup et al.12 (Scheme 2). The
required base structures, acids 7a and 7b, were prepared
as follows: treatment of chlorosilane 4a with homoallyl-
magnesium bromide afforded homoallylic silane 5a; the
respective silacyclopentyl substituted analogue 5b was
obtained from trichloro(methyl)silane 4b with 1 equiva-
lent of homoallyl Grignard reagent, followed by 1
equivalent of (butane-1,4-diyl)dimagnesium dibromide.
Ozonolysis of 5a and 5b in the presence of NaOH and
MeOH afforded esters 6a and 6b, which were readily
hydrolyzed to the respective acids 7a and 7b. (Ozonoly-
sis under neutral conditions and oxidative workup
directly afforded the two acids 7a and 7b, but in much
lower yield.) Acids 7a and 7b were then converted using
the Walkup procedure via the Evans amides 8a and 8b
and the bromo compounds 9a and 9b to the azido
products 10a and 10b.12 In contrast to Walkup’s
description, hydrolysis of compounds 10a and 10b to
DL-1a), DL-5-[(1-methyl-1-silacyclopentyl)methyl]oxaz-
olidin-2,4-dione DL-5-[(1-methyl-1-silacyclopentyl)-
(
methyl]hydantoin, DL-1b), DL-2-carbamoylamino-3-
[(dimethyl)phenylsilyl]propionic acid (DL-N-carbamoyl-
3-[(dimethyl)phenylsilyl]alanine, DL-2a), and DL-2-
carbamoylamino-3-(1-methyl-1-silacyclopentyl)propio-
nic acid (DL-N-carbamoyl-3-(1-methyl-1-silacyclopen-
tyl)alanine, DL-2b) were synthesized as described previ-
ously.18 Chemical manipulations were carried out under
argon in oven-dried glass equipment. For reactions,
Et2O and THF were freshly distilled from Na with
benzophenone ketyl as indicator; dry CH2Cl2 was pur-
chased from Merck AG and stored over molecular
sieves. Extracts were washed with satd aq. NH4Cl soln
and brine and were dried over MgSO4. Chromatogra-
phy: Merck silica gel 60 (40–63 mm). Optical rotation:
Perkin–Elmer polarimeter 241. Mp: Mettler FP5/FP52.
IR spectra: neat liquid films between NaCl plates for
liquids and as KBr presslings for solids; Perkin–Elmer
297 or 781; in cm−1. 1H NMR spectra in CDCl3; Bruker
AC-300 (300 MHz), ARX-300 (300 MHz), or AMX-
600 (600 MHz); l in ppm rel. to CHCl3 (l 7.26), J in
Hz. 13C NMR spectra in CDCl3; Bruker ARX-300
(75.5 MHz); l in ppm rel. to CDCl3 (l 77.0); multiplic-
ities from DEPT-135 and DEPT-90 experiments; the
interpretation of the NMR spectra is based on cross-
correlation with a number of reference samples. Mass
spectrometry (MS): Finnigan MAT 90 or Finnigan SSQ
700; electron-impact MS (EI MS) at 70 eV; chemical-
ionization MS (CI MS) with NH3 as the reactant gas;
molecular ions, quasi-molecular ions, and characteristic
fragments either with interpretation or ]20 rel.%; in
m/z (rel.%).
the acids
L
-11a and -11b could not be performed by
L
treatment with aqueous H2O2 and LiOH because
almost complete decomposition of the silicon-contain-
ing substrates occurred under these conditions. Hydro-
lysis with LiOH alone, however, afforded the desired
acids
azido groups of compounds
the desired amino acids -3a and
L
-11a and
L
-11b in good yields. Reduction of the
-11a and -11b to form
-3b was effected by
L
L
L
L
catalytic hydrogenation in aqueous EtOH over a PtO2
catalyst. Catalytic hydrogenation was far superior to
the alternative Staudinger reduction with Ph3P12,20 as it
afforded the products in almost quantitative yields and
in virtually pure form. Amino acids
finally transferred into the N-carbamoyl derivatives
L
-3a and -3b were
L
L
-2a and
L
-2b using a slightly modified procedure as
described earlier for the racemic compounds.18
4.2. Enzymes
3. Conclusion
Enriched hydantoinase from B. thermoglucosidasius
(Hyd 1, carrier-fixed) was a gift from Roche Diagnos-
tics (Penzberg, Germany). Hydantoinase from A. aures-
cens DSM 3745 was purified from recombinant
Escherichia coli and immobilized on Eupergit C250L.16
These investigations show that both hydantoinases and
-N-carbamoylase accept sterically demanding silicon-
L
containing amino acid derivatives of type 1 and 2. The
hydantoins as well as the N-carbamoyl amino acids
were transformed with high enantioselectivity into the
respective enantiomerically enriched hydrolysis prod-
ucts. Thus, the hydantoinase process is applicable for
the conversion of rather unusual, very lipophilic sub-
strates. For further investigations it would be of interest
L
-N-Carbamoylase from A. aurescens DSM 3747 was
purified from recombinant E. coli17 and immobilized on
EAH-Sepharose.16
4.3. Analytical methods
to test
D-N-carbamoylases as well as hydantoin
racemases described in the literature14 for their accep-
tance of these substrates.
The concentrations of compounds of type 1, 2, and 3
were determined with reversed-phase HPLC (RP-
HPLC) on a Gromsil ODS 1 PE column (5 mm, 250×
4.6 mm, Grom, Herrenberg, Germany) according to a
literature procedure15 with UV detection at 210 nm.
Eluent: aq. H3PO4 (85%, 7 mL) in H2O (2000 mL) and
MeOH (500 mL); flow rate: 1.0 mL min−1; retention
times: 66.1 min (DL-1a); 47.6 min (DL-1b); 59.5 min
4. Experimental
4.1. General
(
DL-2a); 41.3 min (DL-2b); 37.7 min (DL-3a); 22.7 min
DL-3b).
Unless otherwise stated, all chemicals were of reagent
grade and purchased from Fluka Chemie AG or Merck
AG. Aq. solns were prepared with ultrapure H2O
(NANOpure II, Fa. Barnstedt, Newton, MA, USA).
DL-5-{[(Dimethyl)phenylsilyl]methyl}oxazolidin-2,4-di-
(
The separation of the enantiomers of DL-1 and DL-2
was accomplished by chiral HPLC on an ET 200/4
Nucleodex b-PM column (Macherey–Nagel, Du¨ren,
Germany) with UV detection at 210 nm. Eluent A: aq.
one
(DL-5-{(dimethyl)phenylsilyl]methyl}hydantoin,

R. J. Smith et al. / Tetrahedron: Asymmetry 12 (2001) 157–165
161
H3PO4 (85%, 3 mL) in H2O (842 mL) and MeOH (211
4.6. Synthesis of the enantiomerically enriched refer-
ence compounds
mL), pH adjusted to 3.7 with concd aq. NaOH soln;
flow rate: 0.7 mL min−1; retention times: 168.4 min
(D
-1a); 176.2 min ( -1a). Eluent B: aq. H3PO4 (85%, 3
L
4.6.1. 4-[(Dimethyl)phenylsilyl]but-1-ene 5a. Neat 4-bro-
mobut-1-ene (6.82 g, 50.5 mmol) was added dropwise
to a suspension of Mg (1.24 g, 51.0 mmol) in Et2O (250
mL) at 23°C. After the exothermic reaction ceased, it
was stirred at 23°C for another 30 min. Neat
chloro(dimethyl)phenylsilane (4a, 8.5 g, 50.0 mmol) was
added dropwise, it was warmed to 40°C for 3 days, and
quenched with excess H2O. Extraction with Et2O and
distillation (50°C, 2 torr) via a Vigreux column afforded
5a as a colorless liquid (7.9 g, 41.8 mmol, 84%). IR:
3075m, 3050w, 3000w, 2960m, 2905m, 2890w, 2840w,
1640w, 1430m, 1410w, 1255s, 1120s, 1055m, 1025m,
1000w, 905m, 895m, 835s, 790s, 780m, 730m, 700s,
mL) in H2O (842 mL) and MeOH (563 mL), pH
adjusted to 3.7 with concd aq. NaOH soln; flow rate:
0.6 mL min−1; retention times: 96.1 min (
D
-1b); 77.8
-2a); 19.4 min
min (
L
-1b); 16.9 min (
D
-2a); 22.3 min (
L
(
D
-2b); 24.6 min (
L
-2b).
4.4. Biotransformations with hydantoinases
4.4.1. Biotransformation of DL-1a. Immobilized hydan-
toinase from A. aurescens DSM 3745 (232 mg) was
added to 0.5 mM soln of DL-1a (1 mL) in tris/HCl
buffer
(0.1
M,
pH
8.5,
tris=tris(hydroxy-
methyl)aminomethane), and the mixture was incubated
with shaking at 37°C for the bioconversion. At different
intervals, mixing was interrupted and samples (100 mL)
were drawn from the clear supernatant, diluted with
HPLC eluant (900 mL), centrifuged, and analyzed by
RP and chiral HPLC. Chiral HPLC revealed the for-
1
605s. H NMR: 7.54–7.51 (m, 2 arom. H); 7.38–7.35
(m, 3 arom. H); 5.89 (ddt, J=16.8, 10.3, 6.5, CHꢀ);
4.99 (d, J=17.1, 1H, CH2ꢀ); 4.90 (d, J=10.4, 1H,
CH2ꢀ); 2.13–2.05 (m, CH2CHꢀ); 0.90–0.85 (m, CH2Si);
0.30 (s, 2 MeSi). 13C NMR: 141.5 (d, CHꢀ); 139.2 (s,
arom. C); 133.6 (d, 2 arom. C); 128.3 (d, arom. C);
127.7 (d, 2 arom. C); 112.8 (t, H2Cꢀ); 27.9 (t,
CH2CHꢀ); 14.8 (t, CH2Si); −3.0 (q, 2 MeSi). EI MS:
175 (13, [M−Me]+), 135 (100, [M−C4H7]+), 121 (30), 105
(23). The spectral data of 5a are in agreement with
published data.21
mation of
>98% (no
reached after 125 min.
D
-2a and
L
-2a with an enantiomeric excess
L
-2a was detected). 50% conversion was
Analogously to above, DL-1a (1 mL of 0.5 mM soln in
tris/HCl buffer (0.1 M, pH 8.5)) was treated with
hydantoinase from B. thermoglucosidasius (35 mg) to
yield
D
-2a and
L
-2a in a ratio of 99:1. 50% conversion
4.6.2. 4-(1-Methyl-1-silacyclopentyl)but-1-ene 5b. Neat
4-bromobut-1-ene (20.65 g, 153.0 mmol) was added
dropwise to a suspension of Mg (3.79 g, 156.0 mmol) in
Et2O (150 mL) at 23°C. After the exothermic reaction
ceased, the mixture was stirred at 23°C for a further 30
min. The mixture was slowly transferred via a cannula
to a flask containing trichloro(methyl)silane 4b (22.4 g,
150.0 mmol) in Et2O (150 mL), and it was stirred for 15
h (soln A) at 23°C. In a separate flask, 1,4-dibromobu-
tane (33.7 g, 156.0 mmol) was added dropwise to a
suspension of Mg (7.61 g, 313.0 mmol) in Et2O (300
mL) at 23°C. After the exothermic reaction ceased, the
mixture was stirred for an additional 15 h at 23°C (soln
B). Solns A and B were simultaneously transferred via
cannulae to a flask that was kept at 23°C. The resultant
mixture was stirred for 24 h at 23°C (GC control) and
quenched by addition of a satd aq. NH4Cl soln (200
mL). Extraction with Et2O/pentane (1:1) and distilla-
tion (70°C, 26 torr) via a Vigreux column afforded 5b
as a colorless liquid (5.7 g, 36.8 mmol, 25%). IR:
3075w, 2935s, 2920s, 2895m, 2855m, 1640w, 1440w,
1405w, 1250m, 1070s, 1050m, 1030m, 1020m, 990w,
905m, 895m, 855w, 830m, 790m, 780m, 765m, 705m,
was reached after 122 min.
4.4.2. Biotransformation of DL-1b. Analogously to Sec-
tion 4.4.1, DL-1b (1 mL of 0.5 mM soln in tris/HCl
buffer (0.1 M, pH 8.5)) was treated with hydantoinase
from A. aurescens DSM 3745 (217 mg) and
toinase from B. thermoglucosidasius (35 mg) to yield
-2b and -2b in ratios of 92:8 and 99:1, respectively.
D-hydan-
D
L
50% conversions were reached after 8 and 6 h,
respectively.
4.5. Biotransformations with N-carbamoylase
4.5.1. Biotransformation of DL-2a. Analogously to Sec-
tion 4.4.1, DL-2a (1 mL of 0.5 mM soln in tris/HCl
buffer (0.1 M, pH 8.5)) was treated with immobilized
L
-N-carbamoylase from A. aurescens DSM 3747 (94
mg) to yield (presumably highly enriched) -3a. The
reaction stopped after consumption of 50% of the
starting material, leaving -2a and -2a in a ratio of
L
D
L
<1:99. 50% conversion was reached after 130 min;
sample preparation for HPLC analysis as described
above.
1
650m, 610m. H NMR: 5.89 (ddt, J=16.8, 10.3, 6.3,
CHꢀ); 5.00 (ddt, J=17.1, 2.0, 1.7, 1H, CH2ꢀ); 4.90
(ddt, J=10.1, 2.0, 1.3, 1H, CH2ꢀ); 2.15–2.05 (m,
CH2CHꢀ); 1.64–1.50 (m, 2 CH2CH2Si); 0.73–0.68 (m,
CH2Si); 0.65–0.42 (m, 2 CH2CH2Si); 0.08 (s, MeSi). 13C
NMR: 141.6 (d, CHꢀ); 112.8 (t, H2Cꢀ); 28.4 (t,
4.5.2. Biotransformation of DL-2b. Analogously to Sec-
tion 4.4.1, DL-2b (1 mL of 0.5 mM soln in tris/HCl
buffer (0.1 M, pH 8.5)) was treated with immobilized
L
-N-carbamoylase from A. aurescens DSM 3747 (67
mg) to yield (presumably highly enriched) -3b and
leaving -2b and -2b in a ratio of <1:99 after complete
L
CH2CHꢀ); 27.3 (t, 2 CH2CH2Si); 14.3 (t, CH2Si); 11.8
+
’
D
L
(t, 2 CH2CH2Si); −3.2 (q, MeSi). EI MS: 154 (1, M ),
transformation (50% conversion). 50% conversion after
195 min; sample preparation for HPLC analysis as
described above.
139 (7, [M−Me]+), 99 (100, [M−C4H7]+), 98 (29), 97
(79), 83 (22), 71 (45), 55 (29), 45 (25), 43 (39). Due to
high volatility, no microanalysis could be performed.

162
R. J. Smith et al. / Tetrahedron: Asymmetry 12 (2001) 157–165
4.6.3. Methyl 3-[(dimethyl)phenylsilyl]propionate 6a. A
stream of ozone was passed through a soln of 5a (0.16
g, 0.82 mmol) in a mixture of CH2Cl2 (50 mL) and
NaOH/MeOH (2.5 M, 1.6 mL) at −60°C until the blue
color of O3 persisted. Excess ozone was removed with a
stream of N2, and the mixture was allowed to warm to
23°C. H2O (3 mL) was added, and the mixture
extracted with Et2O. The solvent was carefully evapo-
rated (35°C, 200 mbar) and the residue chro-
matographed (Et2O/pentane 1:10) to give 6a as a
colorless liquid (0.15 g, 0.67 mmol, 82%). IR: 3070m,
3050m, 3000m, 2950s, 2920m, 2900m, 2880m, 2870m,
1780s, 1435s, 1425s, 1350m, 1290m, 1250s, 1210s,
1160s, 1115s, 1050m, 1025m, 1000w, 980w, 915w, 880w,
4.6.6. 3-(1-Methyl-1-silacylclopentyl)propionic acid 7b.
Analogously to Section 4.6.5, 6b (4.30 g, 23.1 mmol)
was treated with LiOH (23.1 mmol) for 15 h to give 7b
as a slightly yellow oil (3.11 g, 18.0 mmol, 78%). IR:
2935m, 2920m, 2895m, 2855m, 1710s, 1450w, 1425w,
1410w, 1285w, 1245m, 1075m, 1030w, 910w, 855w,
1
830m, 790w, 770m, 710w, 605s. H NMR: 2.39–2.33
(m, CH2CO); 1.60–1.50 (m, 2 CH2CH2Si); 0.97–0.91
(m, CH2Si); 0.61–0.47 (m, 2 CH2CH2Si); 0.10 (s, MeSi).
13C NMR: 180.6 (s, CO); 29.0 (t, CH2CO); 27.2 (t, 2
CH2CH2Si); 11.5 (t, 2 CH2CH2Si); 10.0 (t, CH2Si); −3.5
(q, MeSi). EI MS: 143 (44), 130 (33), 129 (22), 115
(100), 101 (31), 99 (30, [M−C3H5O2]+), 89 (29), 87 (29),
75 (20), 70 (32), 61 (26), 59 (47), 55 (24). Anal. calcd for
C8H16O2Si (172.092): C, 55.77; H, 9.36. Found: C,
55.84; H, 9.28%.
1
840s, 830s, 780s, 730s, 700s. H NMR: 7.54–7.48 (m, 2
arom. H); 7.40–7.34 (m, 3 arom. H); 3.63 (s, MeO);
2.34–2.28 (m, CH2CO); 1.15–1.09 (m, CH2Si); 0.31 (s, 2
MeSi). 13C NMR: 175.2 (s, CO); 138.1 (s, arom. C);
133.5 (d, 2 arom. C); 129.1 (d, arom. C); 127.8 (d, 2
arom. C); 51.5 (q, MeO); 28.6 (t, CH2CO); 10.9 (t,
CH2Si); −3.4 (q, 2 MeSi). EI MS: 207 (64, [M−Me]+),
151 (33), 145 (59, [M−C6H5]+), 135 (100, [M−C4H7O2]+),
121 (27), 117 (33), 105 (34), 91 (26), 89 (25), 59 (52), 57
(8), 43 (26). The spectral data of 6a are in agreement
with published data.22
4.6.7.
(R)-4-Benzyl-3-{3-[(dimethyl)phenylsilyl]propio-
nyl}oxazolidin-2-one 8a. A dispersion of NaH (60% in
oil, 0.15 g, 3.74 mmol) was added at 23°C to a soln of
7a (0.71 g, 3.40 mmol) in THF (17 mL) and the
resultant suspension cooled to 0°C, trimethylacetyl
chloride (0.43 g, 3.53 mmol) was added, and the mix-
ture was stirred for 2 h (soln A, this was then cooled to
−78 °C prior to the addition of soln B). In a separate
flask, BuLi (2 M in hexane, 1.9 mL, 3.8 mmol) was
added slowly at −78°C to a soln of (R)-4-benzyloxazo-
lidin-2-one (0.60 g, 3.36 mmol) in THF (17 mL), and
the mixture stirred for 30 min (soln B).
4.6.4. Methyl 3-(1-methyl-1-silacyclopentyl)propionate
6b. Analogously to Section 4.6.3, 5b (5.68 g, 36.8 mmol)
was treated with O3 in CH2Cl2 (250 mL) and NaOH/
MeOH (2.5 M, 15.2 mL) to give, after chromatography
(Et2O/pentane 1:10), 6b as a colorless liquid (4.32 g,
23.2 mmol, 63%). IR: 2935m, 2920m, 2895m, 2855m,
1745s, 1450w, 1435w, 1405w, 1355w, 1250m, 1210m,
1160w, 1125w, 1075m, 1045w, 1030m, 1020w, 860w,
Soln B was transferred by syringe into soln A, cooled to
−78°C. After stirring at −78°C for 1.5 h and at 23°C for
2 h, it was quenched with H2O, extracted with Et2O,
and chromatographed (AcOEt/hexane 1:9) to give 8a as
colorless crystals (1.04 g, 2.82 mmol, 84%). Mp 74.1–
75.0°C (hexane) (lit.12 62–64°C); [h]D=−37.9 (c 1.16,
CHCl3), lit.12 [h]D=−34.0 (c 2.0, CHCl3). IR: 3070s,
3025s, 2975s, 2950s, 2905s, 1950m, 1795s, 1700s,
1605m, 1530m, 1500s, 1475s, 1455s, 1425s, 1385s,
1295s, 1250s, 1200s, 1160s, 1110s, 1075s, 1050s, 1015s,
975s, 920s, 905s, 840s, 800s, 775s, 755s, 740s, 700s,
1
830m, 785m, 770m, 710w, 655m, 605s. H NMR: 3.68
(s, MeO); 2.36–2.30 (m, CH2CO); 1.61–1.51 (m, 2
CH2CH2Si); 0.97–0.92 (m, CH2Si); 0.61–0.48 (m, 2
CH2CH2Si); 0.10 (s, MeSi). 13C NMR: 175.5 (s, CO);
51.6 (q, MeO); 29.0 (t, CH2CO); 27.2 (t, 2 CH2CH2Si);
11.5 (t, 2 CH2CH2Si); 10.3 (t, CH2Si); −3.5 (q, MeSi).
EI MS: 157 (17), 130 (38), 99 (9, [M−C4H7O2]+), 59
(25), 57 (30), 56 (21), 45 (29), 43 (99), 41 (100). Due to
high volatility, no microanalysis could be performed.
1
620s. H NMR (600 MHz): 7.56–7.53 (m, 2 arom. H);
4.6.5. 3-[(Dimethyl)phenylsilyl]propionic acid 7a. A mix-
ture of 6a (3.15 g, 14.2 mmol) in THF (28.6 mL) and
aq. LiOH soln (0.5 m, 28.6 mL, 14.3 mmol) was stirred
at 23°C for 15 h. The solvent was evaporated, and the
residue carefully acidified with aq. HCl soln (1N) to pH
1. Extraction with Et2O and filtration through a plug of
SiO2 (Et2O) afforded 7a as a slightly yellow oil (2.96 g,
12.9 mmol, 91%). IR: 3070m, 3050m, 3020m, 3000m,
2950s, 2895m, 2880m, 1710s, 1490w, 1425s, 1405m,
1295m, 1260s, 1250s, 1220m, 1190m, 1165s, 1110s,
7.38–7.35 (m, 3 arom. H); 7.34–7.31 (m, 2 arom. H);
7.29–7.27 (m, 1 arom. H); 7.21–7.18 (m, 2 arom. H);
4.62–4.57 (symm. m, eight lines, HCN); 4.17–4.11 (m,
H2CO); 3.26 (dd, J=13.4, 3.4, 1 benzyl H); 2.95,
2.90 (AB of ABXY, JAB=16.8, JAX=JBY=9.8, JAY
BX=6.4, H2CCꢀO); 2.71 (dd, J=13.4, 9.8,
1 benzyl H); 1.16, 1.13 (XY of ABXY, JXY=16.8,
XA=JYB=9.8, YA=JXB=6.4, CH2Si); 0.34 (s,
=
J
J
J
2
MeSi). 13C NMR: 174.5 (s, CON); 153.3 (s, COO);
138.2, 135.4 (2s, 2 arom. C); 133.6, 129.4 (2d, 2×2
arom. C); 129.1 (d, arom. C); 128.9, 127.8 (2d, 2×2
arom. C); 127.3 (d, arom. C); 66.1 (t, CH2O); 55.2 (d,
CHN); 37.9 (t, CH2Ph); 30.3 (t, CH2CO); 10.2 (t,
CH2Si); −3.2 (q, 2 MeSi). CI MS: 384 (16, [M+NH4+
NH3−H2O]+), 367 (6, [M+NH4−H2O]+), 351 (10, [M+
NH3−H2O−Me]+), 289 (100, [M+NH3−H2O−Ph]+). The
spectral data of 8a are in agreement with published
data.12
1
1090s, 910m, 835s, 820s, 780s, 730s, 700s. H NMR:
7.52–7.47 (m, 2 arom. H); 7.37–7.34 (m, 3 arom. H);
2.35–2.29 (m, CH2CO); 1.13–1.07 (m, CH2Si); 0.31 (s, 2
MeSi). 13C NMR: 180.8 (s, CO); 137.9 (s, arom. C);
133.5 (d, 2 arom. C); 129.2 (d, arom. C); 127. 9 (d, 2
arom. C); 28.6 (t, CH2CO); 10.7 (t, CH2Si); −3.4 (q, 2
MeSi). CI MS: 226 (35, [M+NH4]+), 148 (100), 131 (22).
The spectral data are in agreement with published
data.12

R. J. Smith et al. / Tetrahedron: Asymmetry 12 (2001) 157–165
163
CHBr); 36.9 (t, CH2Ph); 23.5 (t, CH2Si); −2.5, −2.6 (2q,
2 MeSi). CI MS: 465/463 (88/84, [M+NH4]+), 448/446
(7/7, [M+H]+), 432/430 (16/15, [M−Me]+), 370/368 (100/
99, [M−Ph]+), 366 (30, [M−Br]+), 290 (20), 249 (30), 232
(22). The spectral data for 9a are in agreement with
published data.12
4.6.8. (R)-4-Benzyl-3-[3-(1-methyl-1-silacylopentyl)pro-
pionyl]oxazolidin-2-one 8b. Analogously to Section 4.6.7,
7b (0.20 g, 1.15 mmol) was deprotonated with NaH
(1.27 mmol), activated with trimethylacetyl chloride
(0.14 g, 1.20 mmol), and treated with lithiated (R)-4-
benzyloxazolidin-2-one (1.14 mmol) to give, after chro-
matography (AcOEt/hexane 1:9), 8b as a colorless oil,
which crystallized upon cooling to 4°C (0.31 g, 0.95
mmol, 83%). Mp 50.8–51.8°C (hexane); [h]D=−42.3 (c
2.47, CHCl3). IR (film): 3025w, 2935s, 2920m, 2895m,
2850m, 1785s, 1700s, 1605w, 1495w, 1480w, 1450m,
1435w, 1385s, 1365m, 1350m, 1325w, 1290w, 1250s,
1215s, 1195m, 1180m, 1160m, 1100m, 1075m, 1050m,
1030m, 1020m, 975w, 915w, 855w, 835m, 780m, 765m,
4.6.10. (4R,2%S)-4-Benzyl-3-[2-bromo-3-(1-methyl-1-sila-
cyclopentyl)propionyl]-oxazolidin-2-one 9b. Analogously
to Section 4.6.9, 8b (1.19 g, 3.61 mmol) was treated
with ethyldiisopropylamine (0.70 g, 5.39 mmol) and
dibutylboryl trifluoromethanesulfonate (5.32 mmol),
and the resulting boron enolate was brominated with
N-bromosuccinimide (0.86 g, 4.8 mmol) to give 9b as a
colorless oil (1.12 g, 2.73 mmol, 76%). [h]D=−37.5 (c
4.37, CHCl3). IR: 3085w, 3060w, 3025m, 2930s, 2855s,
2800w, 1780s, 1705s, 1605w, 1585w, 1495m, 1480m,
1450m, 1385s, 1345m, 1290m, 1260s, 1215s, 1195s,
1170m, 1105s, 1075m, 1050m, 1030m, 1020m, 975m,
920w, 865w, 835m, 775m, 760m, 735m, 705s, 650s,
1
750m, 735m, 705m, 660m, 600s. H NMR (600 MHz):
7.35–7.20 (m, 5 arom. H); 4.69–4.61 (m, HCN); 4.19
(dd, J=9.0, 7.6, 1 H, H2CO); 4.16 (dd, J=9.1, 3.0, 1 H,
H2CO); 3.30 (dd, J=13.4, 3.3, 1 benzyl H); 2.96, 2.91
(AB of ABXY, JAB=16.7, JAX=JBY=10.8, JAY=JBX
=
5.7, H2CCꢀO); 2.76 (dd, J=13.4, 9.6, 1 benzyl H);
1.60–1.56 (quint.-like m, 2 CH2CH2Si); 1.00, 0.95 (XY
of ABXY, JXY=14.6, JXA=JYB=10.8, JYA=JXB=5.7,
CH2Si); 0.66–0.51 (m, 2 CH2CH2Si); 0.12 (s, MeSi). 13C
NMR: 174.6 (s, CON); 153.4 (s, COO); 135.4 (s, arom.
C); 129.4, 128.9 (2d, 2×2 arom. C); 127.3 (d, arom. C);
66.1 (t, CH2O); 55.2 (d, CHN); 37.9 (t, CH2Ph); 30.7 (t,
CH2CO); 27.2 (t, 2 CH2CH2Si); 11.6 (t, 2 CH2CH2Si);
9.6 (t, CH2Si); −3.4 (q, MeSi). CI MS: 349 (17, [M+
NH4]+), 333 (22), 332 (100, [M+H]+), 262 (57). Anal.
calcd for C18H25NO3Si (331.482): C, 65.22; H, 7.60; N,
4.23. Found: C, 65.33; H, 7.49; N, 4.05%.
1
600s. H NMR: 7.34–7.17 (m, 5 arom. H); 5.93 (dd,
J=10.1, 6.0, HCBr); 4.72–4.59 (m, HCN); 4.22–4.12
(m, H2CO); 3.29 (dd, J=13.5, 3.4, 1 benzyl H); 2.76
(dd, J=13.5, 9.6, 1 benzyl H); 1.91 (dd, J=14.1, 10.1,
1 H, CH2Si); 1.58 (dd, J=14.1, 6.1, 1 H, CH2Si);
1.58–1.48 (m,
2
CH2CH2Si); 0.65–0.45 (m,
2
CH2CH2Si); 0.12 (s, MeSi). 13C NMR: 169.6 (s, CON);
152.4 (s, COO); 134.8 (s, arom. C); 129.4, 128.9 (2d,
2×2 arom. C); 127.4 (d, arom. C); 66.1 (t, CH2O); 55.2
(d, CHN); 42.6 (d, CHBr); 36.9 (t, CH2Ph); 27.0 (t, 2
CH2CH2Si); 22.3 (t, CH2Si); 12.3, 12.0 (2t,
2
CH2CH2Si); −2.8 (q, MeSi). CI MS: 429/427 (100/97,
[M+NH4]+), 412/410 (12/11, [M+NH4−Me]+), 349 (77),
332 (53), 330 (25), 279 (66), 249 (99), 195 (21). Anal.
calcd for C18H24BrNO3Si (410.378): C, 52.68; H, 5.89;
N, 3.41. Found: C, 52.84; H, 6.07; N, 3.27%.
4.6.9. (4R,2%S)-4-Benzyl-3-{2-bromo-3-[(dimethyl)phenyl-
silyl]propionyl}oxazolidin-2-one 9a. Ethyldiisopropyl-
amine (0.49 g, 3.85 mmol) and a soln of dibutylboryl
trifluoromethanesulfonate (1 M in CH2Cl2, 3.8 mL, 3.8
mmol) were added subsequently to a soln of 8a (1.01 g,
2.75 mmol) in CH2Cl2 (10 mL) at −78°C. The mixture
was allowed to warm to 0°C, kept at this temperature
for 4 h, and re-cooled to −78°C before the mixture was
transferred with a syringe to a soln of N-bromosuccin-
imide (0.61 g, 3.43 mmol, freshly recrystallized from
H2O) in CH2Cl2 (60 mL) at −78°C. After 2 h, satd aq.
NaHCO3 soln (10 mL) was added to the reddish soln,
and the mixture was allowed to warm to 23°C. Extrac-
tion with CH2Cl2, evaporation and chromatography
(AcOEt/hexane 5:95) afforded 9a as a colorless oil (0.91
g, 2.04 mmol, 75%). [h]D=−60.6 (c 0.85, CHCl3), lit.12
[h]D=−48.0 (c 0.8, CHCl3). IR: 3090w, 3065w, 3030w,
3000w, 2955w, 2920w, 2860w, 1780s, 1705s, 1605w,
1575w, 1495w, 1475w, 1455w, 1425m, 1385s, 1350m,
1290w, 1260s, 1210m, 1200s, 1170m, 1110m, 1105m,
1075w, 1050w, 1030w, 1015w, 1000w, 975w, 920w,
4.6.11. (4R,2%R)-3-{2-Azido-3-[(dimethyl)phenylsilyl]pro-
pionyl}-4-benzyloxazolidin-2-one 10a. A soln of tetra-
methylguanidinium azide (3.80 g, 24.0 mmol) in MeCN
(100 mL) was added dropwise to a soln of 9a (2.30 g,
5.15 mmol) in MeCN (50 mL) at 0°C. After 4 h, satd
aq. NaHCO3 soln (5 mL) was added, the mixture was
extracted with Et2O, evaporated and the residue chro-
matographed (AcOEt/hexane 1:9) to give 10a as color-
less crystals (1.41 g, 3.46 mmol, 67%). Mp
123.0–124.0°C (CHCl3) (lit.12 118–120°C); [h]D=−9.2 (c
3.38, CHCl3), lit.12 [h]D=+3.1 (c 5.0, benzene). IR:
3070w, 3025w, 2970w, 2110s, 1800s, 1695s, 1500w,
1455m, 1425m, 1385s, 1370s, 1295m, 1240s, 1210s,
1200s, 1115s, 1050m, 1020m, 990m, 895m, 880m, 860m,
1
840s, 805m, 760m, 735s, 705s, 670w, 645w, 615w. H
NMR: 7.62–7.56 (m, 2 arom. H); 7.42–7.16 (m, 8 arom.
H); 4.83 (dd, J=11.1, 4.2, HCN3); 4.73–4.63 (m, HCN);
4.28–4.16 (m, H2CO); 3.22 (dd, J=13.4, 3.4, 1 benzyl
H); 2.70 (dd, J=13.4, 9.5, 1 benzyl H); 1.61–1.26 (m,
CH2Si); 0.47, 0.46 (2s, 2 MeSi). 13C NMR: 172.4 (s,
CON); 152.7 (s, COO); 137.4, 134.8 (2s, 2 arom. C);
133.7, 129.4, 129.0, 127.9, 127.5 (5d, 10 arom. C); 66.7
(t, CH2O); 57.4 (d, CHN3); 55.1 (d, CHN); 37.6 (t,
CH2Ph); 18.8 (t, CH2Si); −2.9, −3.3 (2q, 2 MeSi). CI
MS: 426 (100, [M+NH4]+), 366 (100, [M−N3]+), 331 (72,
[M−Ph]+), 249 (26), 195 (30). The spectral data are in
agreement with published data.12
1
870w, 835s, 780w, 760m, 735m, 705s, 640m, 600s. H
NMR: 7.51–7.14 (m, 10 arom. H); 5.90 (dd, J=12.6,
4.2, HCBr); 4.16–4.08 (m, HCN); 4.04–3.83 (m, H2CO);
3.12 (dd, J=13.7, 3.4, 1 benzyl H); 2.67 (dd, J=13.7,
9.5, 1 benzyl H); 2.22 (dd, J=13.7, 12.6, 1 H, CH2Si);
1.65 (dd, J=14.1, 4.2, 1 H, CH2Si); 0.39 (s, 2 MeSi).
13C NMR: 169.1 (s, CON); 151.9 (s, COO); 136.4, 134.8
(2s, 2 arom. C); 134.2, 129.4 (2d, 2×2 arom. C); 129.3
(d, arom. C); 128.9, 127.7 (2d, 2×2 arom. C); 127.3 (d,
arom. C); 65.7 (t, CH2O); 54.7 (d, CHN); 42.0 (d,

164
R. J. Smith et al. / Tetrahedron: Asymmetry 12 (2001) 157–165
4.6.12.
(4R,2%R)-3-[2-Azido-3-(1-methyl-1-silacyclo-
6.6, HCN3); 1.61–1.56 (m, 2 CH2CH2Si); 1.31 (d, J=
4.2, CH2Si, 1 H); 1.28 (d, J=2.7, CH2Si, 1 H); 0.71–
0.57 (m, 2 CH2CH2Si); 0.19 (s, MeSi). 13C NMR: 178.0
(s, CO); 59.3 (d, CHN3); 27.0 (t, 2 CH2CH2Si); 18.1 (t,
CH2Si); 12.0, 11.9 (2t, 2 CH2CH2Si); −3.2 (q, MeSi). EI
MS: 114 (25), 101 (33), 99 (45), 98 (20), 97 (33), 88 (22),
87 (27), 86 (36), 85 (51), 74 (74), 71 (53), 70 (41), 61
(40), 60 (31), 59 (62), 55 (45), 45 (100), 44 (25), 43 (79),
42 (28), 41 (28), 31 (36), 29 (28), 28 (25). Anal. calcd for
C8H15N3O2Si (213.093): C, 45.05; H, 7.09; N, 19.70.
Found: C, 45.23; H, 6.87; N, 19.47%.
pentyl)propionyl]-4-benzyl-oxazolidin-2-one 10b. Analo-
gously to Section 4.6.11, 9b (0.75 g, 1.82 mmol) was
treated with tetramethylguanidinium azide (1.44 g, 9.07
mmol) to give 10b as a colorless oil (0.51 g, 1.36 mmol,
75%). [h]D=−8.8 (c 7.75, CHCl3). IR: 3085w, 3060w,
3025w, 2930s, 2855s, 2800w, 2110s, 1785s, 1705s,
1605w, 1585w, 1495w, 1480w, 1455m, 1385s, 1375s,
1350m, 1305w, 1290w, 1245s, 1215s, 1195s, 1155w,
1115m, 1075m, 1055w, 1030m, 1020m, 995w, 895m,
880m, 855w, 835m, 805w, 780m, 765m, 740m, 705m,
1
655m, 630m, 600m. H NMR: 7.41–7.16 (m, 5 arom.
H); 4.86 (dd, J=11.1, 4.2, HCN3); 4.76–4.68 (m, HCN);
4.31–4.20 (m, H2CO); 3.31 (dd, J=13.3, 3.0, 1 benzyl
H); 2.78 (dd, J=13.3, 9.6, 1 benzyl H); 1.66–1.57 (m, 2
CH2CH2Si); 1.42–1.18 (m, CH2Si); 0.81–0.53 (m, 2
CH2CH2Si); 0.24 (s, MeSi). 13C NMR: 172.6 (s, CON);
152.8 (s, COO); 134.8 (s, arom. C); 129.4, 129.0 (2d,
2×2 arom. C); 127.5 (d, arom. C); 66.7 (t, CH2O); 57.6
(d, CHN3); 55.2 (d, CHN); 37.7 (t, CH2Ph); 27.1, 27.0
(2t, 2 CH2CH2Si); 18.0 (t, CH2Si); 12.1, 11.8 (2t, 2
CH2CH2Si); −3.2 (q, MeSi). CI MS: 390 (85, [M+NH4]+),
345 (42), 331 (22), 330 (100, [M−N3]+), 279 (28), 195
(21), 116 (38), 73 (20), 61 (63). Anal. calcd for
C18H24N4O3Si (372.494): C, 58.04; H, 6.49; N, 15.04.
Found: C, 58.19; H, 6.62; N, 14.95%.
4.6.15.
(R)-2-Amino-3-[(dimethyl)phenylsilyl]propionic
-3-[(dimethyl)phenylsilyl]alanine) -3a. A soln
acid (=
L
L
of 11a (0.363 g, 1.45 mmol) in EtOH/H2O (20 mL, 1:1)
was treated with PtO2 (0.049 g, 0.21 mmol) and kept
under H2 (760 torr) for 3 h. The catalyst was removed
by filtering the mixture through cotton, and evapora-
tion of the solvent afforded pure
L
-3a as a colorless
solid (0.323 g, 1.45 mmol, 100%). Mp 207.8–209.2°C
(H2O, decomposition); [h]D=+36.2 (c 0.13, 1N aq. HCl
soln), lit.12 [h]D=+28.8 (c 0.5, HCl salt in H2O). The
spectral data of
L
-3a are identical with those of DL-3a
reported earlier.18
4.6.16. (R)-2-Amino-3-(1-methyl-1-silacyclopentyl)pro-
4.6.13.
(R)-2-Azido-3-[(dimethyl)phenylsilyl]propionic
pionic acid (=L-3-(1-methyl-1-silacyclopentyl)alanine) L-
acid -11a. A mixture of 10a (1.40 g, 3.42 mmol) and
L
3b. Analogously to Section 4.6.15, 11b (0.062 g, 0.29
LiOH·H2O (0.29 g, 6.90 mmol) in THF/H2O (94 mL,
3:1) was stirred for 1 h at 0°C. Satd aq. NaHCO3 soln
(20 mL) was added and the THF evaporated at 15 torr.
Extraction of the aq. residue with CH2Cl2 to remove
the auxiliary, acidification with aq. HCl soln (1N) to
pH 1, extraction with AcOEt, and filtration through a
mmol) was hydrogenated with PtO2 catalyst (0.050 g,
0.22 mmol) to yield -3b as a colorless solid (0.049 g,
L
0.26 mmol, 90%). Mp 241°C (H2O, start of decomposi-
tion); [h]D=+26.4 (c 1.00, 1N aq. HCl soln). The
spectral data of
L
-3b are identical with those of DL-3b
reported earlier.18
plug of SiO2 afforded -11a as a colorless oil (0.84 g,
L
3.38 mmol, 99%). [h]D=−13.3 (c 2.95, CHCl3), lit.12
[h]D=−9.2 (c 2.94, CHCl3). IR: 3070m, 3045m, 3020m,
2955s, 2895m, 2110s, 1720s, 1430s, 1420m, 1335m,
1300m, 1260s, 1250s, 1230s, 1190m, 1155w, 1115s,
1030w, 1020w, 1000w, 940m, 885s, 840m, 825s, 800m,
4.6.17. (R)-2-Carbamoylamino-3-[(dimethyl)phenylsilyl]-
propionic acid (= -N-carbamoyl-3-[(dimethyl)phenyl-
silyl]alanine) -2a. A mixture of -3a (0.110 g, 0.49
L
L
L
mmol) and KOCN (0.040 g, 0.50 mmol) in H2O (4 mL)
was stirred at 70°C for 3 h. The mixture was cooled to
10°C and AcOH (2 mL) was added. The precipitated
product was collected by filtration and dried at 10−2
1
735s, 700s, 595m. H NMR: 10.86 (s, HOOC); 7.57–
7.51 (m, 2 arom. H); 7.42–7.36 (m, 3 arom. H); 3.77
(dd, J=9.5, 6.1, HCN3); 1.45 (dd, J=14.9, 6.5, CH2Si,
1 H); 1.37 (dd, J=14.9, 9.5, CH2Si, 1 H); 0.43, 0.41 (2s,
2 MeSi). 13C NMR: 177.8 (s, CO); 136.9 (s, arom. C);
133.5 (d, 2 arom. C); 129.5 (d, 1 arom. C); 128.0 (d, 2
arom. C); 59.0 (d, CHN3); 18.8 (t, CH2Si); −2.7, −3.1
(2q, 2 MeSi). CI MS: 267 (18, [M+NH4]+), 178 (98), 152
(100). The spectral data of 11a are in agreement with
published data.12
torr to yield
mmol, 84%). The enantiomeric purity of
determined by chiral HPLC to exceed 99%. Mp 148.2–
L
-2a as a colorless solid (0.110 g, 0.41
L
-2a was
148.9°C (H2O); [h]D=+11.2 (c 0.74, MeOH). The spec-
tral data of
L
-2a are identical with those of DL-2a
reported earlier.18
4.6.18. (R)-2-Carbamoylamino-3-(1-methyl-1-silacyclo-
4.6.14. (R)-2-Azido-3-(1-methyl-1-silacyclopentyl)propio-
pentyl)propionic acid (=
silacyclopentyl)alanine)
4.6.17, -3b (0.88 g, 0.47 mmol) was treated with
KOCN (0.040 g, 0.50 mmol) to yield -2b as a color-
less solid (0.062 g, 0.27 mmol, 57%). The enantio-
meric purity of -2b was determined by chiral HPLC
to exceed 99%. Mp 142.8–143.4°C (H2O); [h]D=+5.5
(c 0.51, MeOH). The spectral data of
L
-N-carbamoyl-3-(1-methyl-1-
nic acid
L
-11b. Analogously to Section 4.6.13, 10b (0.27
L-2b. Analogously to Section
g, 0.74 mmol) was treated with LiOH·H2O (0.062 g,
1.47 mmol) to yield -11b as a colorless oil (0.148 g,
L
L
L
0.69 mmol, 94%). [h]D=−7.7 (c 4.05, CHCl3). IR:
2930s, 2895m, 2855m, 2800w, 2110s, 1720s, 1460w,
1450w, 1420m, 1405m, 1335w, 1305w, 1255s, 1245s,
1200m, 1190m, 1155w, 1075s, 1030m, 1020m, 945w,
925w, 885m, 860m, 835s, 805m, 780m, 715w, 655m,
L
L
-2b are iden-
tical in all respects with those of DL-2b reported ear-
1
595m. H NMR: 11.52 (s, HOOC); 3.88 (dd, J=8.8,
lier.18

R. J. Smith et al. / Tetrahedron: Asymmetry 12 (2001) 157–165
165
Acknowledgements
Appl. Microbiol. Biotechnol. 1996, 45, 51–55.
10. Handmann, V. I.; Merget, M.; Tacke, R. Z. Naturforsch.
2000, 55b, 133–138.
The authors would like to thank Dr. W. Tischer and
Dr. W. Bacher (Roche Diagnostics, Penzberg, Ger-
11. Myers, A. G.; Gleason, J. L.; Yoon, T.; Kung, D. W. J.
Am. Chem. Soc. 1997, 119, 656–673.
12. Walkup, R. D.; Cole, D. C.; Whittlesey, B. R. J. Org.
many) for the provision of the immobilized
D
-hydan-
toinase from B. thermoglucosidasius. Financial support
from the Swiss National Science Foundation, the
Novartis Stipendienfond and the Konrad-Adenauer-
Stiftung is gratefully acknowledged.
Chem. 1995, 60, 2630–2634.
13. Pietzsch, M.; Waniek, T.; Smith, R. J.; Bratovanov, S.;
Bienz, S.; Syldatk, C. Chem. Month. 2000, 131, 645–653.
14. Pietzsch, M.; Syldatk, C. In Enzyme Catalysis in Organic
Synthesis; Drauz, K.; Waldmann, H., Eds. Hydrolysis
and formation of hydantoins. VCH: Weinheim, 1995; pp.
409–431.
References
15. May, O.; Siemann, M.; Pietzsch, M.; Kiess, M.; Mattes,
R.; Syldatk, C. J. Biotechnol. 1998, 61, 1–13.
16. Ragnitz, K.; Syldatk, C.; Pietzsch, M., submitted.
17. Wilms, B.; Wiese, A.; Syldatk, C.; Mattes, R.; Altenbuch-
ner, J.; Pietzsch, M. J. Biotechnol. 1999, 68, 101–113.
18. Smith, R. J.; Bratovanov, S.; Bienz, S. Tetrahedron 1997,
53, 13695–13702.
1. Barrett, G. C. Chemistry and Biochemistry of the Amino
Acids; Chapman and Hall: London, 1985.
2. Duthaler, R. O. Tetrahedron 1994, 50, 1539–1650.
3. Ohfune, Y. Acc. Chem. Res. 1992, 25, 360–366.
4. Wagner, I.; Musso, H. Angew. Chem. 1983, 95, 827–839.
5. Williams, R. M. Synthesis of Optically Active h-Amino
Acids; Pergamon: New York, 1989.
19. Pietzsch, M.; Schwa¨mmle, A.; Syldatk, C., in prepara-
tion.
6. Sibi, M. P.; Harris, B. J.; Shay, J. J.; Hajra, S. Tetra-
hedron 1998, 54, 7221–7228.
20. Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2,
635–646.
21. Hudrlik, P. F.; Abdallah, Y. M.; Kulkarni, A. K.; Hudr-
lik, A. M. J. Org. Chem. 1992, 57, 6552–6556.
22. Fleming, I.; Ghosh, S. K. J. Chem. Soc., Perkin Trans. 1
1998, 2711–2720.
7. Weidmann, B. Chimia 1992, 46, 312–313.
8. Tsuji, Y.; Yamanaka, H.; Fukui, T.; Kawamoto, T.;
Tanaka, A. Appl. Microbiol. Biotechnol. 1997, 47, 114–
119.
9. Yamanaka, H.; Fukui, T.; Kawamoto, T.; Tanaka, A.
.
.