Asymmetric synthesis of all stereoisomers of a-methylthreonine using an organocatalytic steglich rearrangement reaction as a key step

Article abstract of DOI:10.1055/s-0029-1217140

An efficient synthetic route to all four stereoisomers of a-methylthreonine has been established. Each type of stereoisomer has been isolated in diastereomerically pure form and with an enantiomeric excess of at least 86% ee. The key step in this multi-st

Full text of DOI:10.1055/s-0029-1217140

4208
PAPER
Asymmetric Synthesis of All Stereoisomers of a-Methylthreonine Using an
Organocatalytic Steglich Rearrangement Reaction as a Key Step
Asymmetric
S
r
ynthesis
i
of
a
-M
e
ethylthreon
d
ine rich R. Dietz, Harald Gröger*
Department of Chemistry and Pharmacy, University of Erlangen-Nuremberg, Henkestr. 42, 91054 Erlangen, Germany
Fax +49(9131)8521165; E-mail: harald.groeger@chemie.uni-erlangen.de
Received 28 April 2009
stereoselective methods for their preparation already ex-
Abstract: An efficient synthetic route to all four stereoisomers of
a-methylthreonine has been established. Each type of stereoisomer
has been isolated in diastereomerically pure form and with an enan-
tiomeric excess of at least 86% ee. The key step in this multi-step
ist,4a–g the synthesis of such types of amino acids 3 is still
challenging. One of the most important representatives of
this class is a-methylthreonine (4; Figure 1), which is
synthesis is an enantioselective organocatalytic Steglich rearrange- used as a key building block for the preparation of phar-
ment reaction of O-acetylated azlactones. The Steglich rearrange-
maceutically relevant molecules such as potential enzyme
inhibitors.4h,i Here we report a new synthetic route to all
ment was also extended to other substrates.
Key words: acylation, amino acids, asymmetric catalysis, rear-
four stereoisomers of a-methylthreonine (4; Figure 1), in
rangements, stereoselective synthesis
high enantiomeric excesses up to 89% by means of an or-
ganocatalytic enantioselective Steglich rearrangement re-
action as a key step.5
a-Amino b-hydroxy acids 1 represent an important class
The synthetic concept, which is shown in Scheme 1, is
based on the use of azlactone 5 as an easily accessible
starting material. The key step of this route is an enantio-
of amino acids that occur naturally in proteinogenic (e.g.
threonine, serine) and non-proteinogenic forms. Such
types of molecules are also integrated as structural motifs
selective organocatalytic Steglich rearrangement, which
in complex natural products such as antibiotics, e.g. van-
represents an acyl migration (step B) from oxygen to car-
bon, thus forming a quarternary stereogenic center. Sub-
comycin and chloramphemicol.1 Furthermore, a-amino b-
hydroxy acids are useful chiral building blocks in organic
sequent ring opening and diastereoselective reduction
chemistry. The amino acids could be efficiently prepared
with borohydrides (steps C and D) then delivers the
l-diastereomer as the major diastereomer. The formation
by chemocatalytic as well as by enzymatic methods.2 An-
other important class of amino acids are a,a-dialkylated
of l-9 as the major diastereomer was proven in prelimi-
amino acids 2. As peptides containing these amino acids
nary work when starting from racemic product 7.5 Access
often show an enhanced stability under metabolic condi-
to the minor diastereomers of type u-9 should be given by
inversion of the b-stereogenic center when starting from
the l-diastereomer.
tions, a,a-dialkylated amino acids are used in the synthe-
sis of protein-based drugs, and numerous methods for
their synthesis exist.3
Since asymmetric Steglich rearrangement is the key step
within this multi-step synthesis, we studied in detail the
impact of different types of catalysts on this reaction. In
OH
OH
CO2H
R
CO2H
*
CO2H
R
*
*
*
R
*
our preliminary work we found that the dimethylami-
nopyridine derivative (S)-10 and (S)-tetramisole [(S)-12]
were able to catalyse this reaction enantioselectively.5 En-
couraged by these results, we focused on a detailed inves-
tigation of these and related catalysts for enantioselective
acyl migration according to step B in Scheme 1 starting
from prochiral O-acetylated azlactone 6.
NH2
R
NH2
R
NH2
1
2
3
OH
OH
OH
OH
CO2H
CO2H
CO2H
CO2H
NH2
(2S,3R)-4
NH2
(2R,3R)-4
NH2
(2S,3S)-4
NH2
(2R,3S)-4
To start with the commercially available catalysts (S)-10
and (S)-11, which were developed by the Fu group and
turned out to be highly efficient for a range of asymmetric
reactions,6 these compounds were employed as catalysts
to give generally high conversions (up to 95%) at a low
catalytic loading of only 2 mol% (Table 1). However, the
resulting enantioselectivities remained in a moderate
range and did not exceed 50% ee. In general, both higher
enantioselectivities and higher conversions were obtained
with the Fu-catalyst (S)-11 compared to the initially tested
catalyst (S)-10. For example, in the presence of 2 mol% of
(S)-10 in dichloromethane as a solvent, azlactone 6 rear-
Figure 1 Structure of different types of amino acids 1–3 and all ste-
reoisomers of a-methylthreonine 4
The aim of our work was to prepare amino acids that com-
bine the structural motifs of both the above mentioned
classes of amino acids, namely b-hydroxy a-amino acids
bearing a quaternary a-carbon of type 3. Although elegant
SYNTHESIS 2009, No. 24, pp 4208–4218
x
x.
x
x
.
2
0
0
9
Advanced online publication: 20.11.2009
DOI: 10.1055/s-0029-1217140; Art ID: T08709SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Asymmetric Synthesis of a-Methylthreonine
4209
Table 1 Enantioselective Acetyl Migration in Steglich Rearrange-
ment Using Fu-Type Catalysts (S)-10 and (S)-11a
O
O
O
N
O
O
N
Me2N
N
step A
step B
Ph
Ph
N
N
5
6
Fe
Fe
Ph
Ph
Ph
or
Ph
O
O
O
Ph
O
*
*
(S)-10
Oi-Pr
NHCOPh
(S)-11
O
O
O
N
O
O
catalyst (S)-10 or (S)-11
step D
step C
(2 mol%)
Ph
8
O
N
N
O
solvent, r.t., 3 h
7
Ph
Ph
(S)-7
OH
O
OH
O
6
Oi-Pr
NHCOPh
(2S,3S)-9
Oi-Pr
NHCOPh
(2R,3R)-9
or
Entrya
Catalyst
(S)-10
(S)-10
(S)-11
(S)-11
(S)-11
Solvent
Conv. (%)b ee (%)c
inversion
inversion
1
2
3
4
5
CH2Cl2
84
93
95
92
94
25
30
41
20
50
major diastereomers
tert-amyl alcohol
CH2Cl2
hydrolysis
hydrolysis
hydrolysis
MTBE
OH
O
OH
O
OH
O
OH
O
tert-amyl alcohol
OH
OH
OH
OH
NH2
NH2
(2S,3S)-4
NH2
NH2
a For experimental details, see experimental section.
(2S,3R)-4
b All conversions given in the table are product-related conversions;
consumption of substrate 6 was complete in all cases (>95%) accord-
ing to NMR spectroscopic data.
(2R,3R)-4
(2R,3S)-4
Scheme 1 Concept for the synthesis of all a-methylthreonine ste-
reoisomers of type 4
c Enantiomeric excess was determined after DMAP-catalyzed ring
opening to keto ester (S)-8.
ranged to the desired key intermediate 7 with 84% conver-
sion and 25% ee (Table 1, entry 1), whereas under
identical reaction conditions the product (S)-7 was formed
with 95% conversion and 41% ee when using catalyst (S)-
11 (entry 3). When carrying out the reaction in tert-amyl
alcohol (TAA), which was reported to be an excellent sol-
vent for enantioselective Steglich rearrangements of
alkoxycarbonyl and benzyloxycarbonyl groups,6b the
enantioselectivity further increased up to 50% ee when us-
ing the Fu catalyst (S)-11 (entry 5).
When using (R)-13 as an organocatalyst, similar conver-
sion and enantioselectivity was obtained (up to 61% ee,
entries 5–7). The catalyst (R)-13 led to the opposite enan-
tiomeric form of 7 compared to the use of (S)-tetramisole
[(S)-12]. Since the R-enantiomer of tetramisole is not
commercially available, (R)-benzotetramisole [(R)-13]
represents an advantageous complementary catalyst to
(S)-12, thus offering access to both enantiomers of the de-
sired product 7 with enantiomeric excesses of about 60%
ee by means of these organocatalysts (S)-12 and (R)-13.
We observed a further improvement in the enantioselec-
tivity when using (S)-tetramisole [(S)-12] as a catalyst.
Notably, (S)-12 represents an economically attractive and
commercially readily available organocatalyst, since this
molecule is produced on large scales for medicinal and
veterinarian purposes in enantiomerically pure form as a
hydrochloride under the trade name ‘Levamisole’. As an
organocatalyst, (S)-12 was introduced by Birman et al. for
kinetic resolution processes.7 In the presence of a catalytic
amount (32 mol%) of (S)-12, we observed enantioselec-
tivities up to 63% ee in the asymmetric Steglich rear-
rangement of 6 (Table 2, entries 1 and 2). In order to
further improve the reaction rate we increased the reaction
temperature. Whereas at 40 °C the reaction was complet-
ed within one day, the enantioselectivity turned out to be
somewhat lower (entry 3). A further catalyst with a related
structure, which was also introduced by the Birman group,
is (R)-benzotetramisole [(R)-13];7 this catalyst can be eas-
ily synthesized (and is also commercially available).
The introduction of a tert-butyl group into a chiral catalyst
is a well-known technology in order to improve selectivi-
ty.8 For this reason, we decided to examine the new tetra-
misole analogue catalyst (S)-14 as an organocatalyst. This
compound was synthesized in an analogous manner to
(R)-13, starting from (S)-tert-leucinol instead of (R)-phe-
nylglycinol. However, (S)-14 showed very low catalytic
activity in the Steglich rearrangement of 6 (entry 8); even
after one week reaction time, conversion did not exceed
35%. Complete consumption of the substrate 6, however,
is essential, because the catalyst for the ring opening
(DMAP) would otherwise rearrange the remaining sub-
strate, leading to racemic product and thus decreasing the
overall enantiomeric excess of the product 7.
Next, we studied the substrate range of this type of asym-
metric Steglich rearrangement. Toward this end, O-acy-
lated azlactones 15a–d were prepared via their azlactones
from the corresponding amino acids (for details, see ex-
Synthesis 2009, No. 24, 4208–4218 © Thieme Stuttgart · New York

4210
F. R. Dietz, H. Gröger
PAPER
lysts (S)-10 and (S)-11. In addition, higher catalytic
loadings (20 mol% compared to 2 mol% with substrate 6)
were required, and the enantioselectivity was lower. For
example, the desired product 16c was obtained at 80%
conversion and with 24% ee when using 20 mol% of (S)-
11 as a catalyst (Table 3, entry 3). Tetramisole-type cata-
lysts (S)-12 and related (R)-13 were not able to complete
consumption of the substrate (data not shown). When us-
ing azlactone 15d, bearing a benzoyl group, which would
allow access to a-methyl b-phenyl serine, Steglich rear-
rangement only proceeded very slowly with catalyst (S)-
11 in a catalytic loading of 20 mol%. Complete consump-
tion of 15d was achieved after a reaction time of one
week. Product-related conversion and yield, however,
were only moderate even though the enantiomeric excess
was comparable to those using substrate 6 (entry 4). In
summary, it has been demonstrated that the Steglich rear-
rangement of several substrates proceeds enantioselec-
tively, with O-acylated azlactone 6 being the most
suitable substrate tested so far.
Table 2 Enantioselective Acetyl Migration in Steglich Rearrange-
ment Using Birman-Type Catalysts [(S)-12, (R)-13 and (S)-14]a
N
H
N
Ph
H
Ph
S
N
S
N
(R)-13
(S)-12
N
S
N
(S)-14
O
O
O
O
catalyst (S)-12, (R)-13 or (S)-14
*
(32 mol%)
N
O
O
N
solvent, T, t
Ph
Ph
7
6
Entrya Catalyst
Solvent
Temp
Time
(h)
Conv.
(%)b
ee
(%)c
1
2
3
4
5
6
7
8
(S)-12
(S)-12
(S)-12
(S)-12
(R)-13
(R)-13
(R)-13
(S)-14
CH2Cl2
CDCl3
CH2Cl2
TAA
r.t.
68
48
82
80
84
74
69
79
84
35
59
r.t.
63
40 °C
r.t.
24
52
After successfully constructing the first stereogenic center
(at the amino moiety) by means of Steglich rearrange-
ment, the next step toward the desired stereoisomers of a-
methylthreonine (4) required the development of a meth-
od for the construction of the second stereogenic center in
the b-position via diastereoselective reduction of the keto
moiety. Initial experiments were carried out using race-
mate rac-8. Initially, we tried to use borane as reducing
agent, applying the CBS reduction methodology.11,12
However, these reduction experiments were unsuccessful,
and led to the formation of complex crude reaction mix-
tures due to side reactions (presumably, for example, re-
duction of the ester moiety in rac-8).
24
60
CH2Cl2
CDCl3
TAA
r.t.
96
50
r.t.
48
61
r.t.
24
52
CH2Cl2
r.t.
168
n.d.d
a For experimental details, see experimental section.
b All conversions given in the table are product-related conversions;
consumption of substrate 6 was in the range of 95–100%, except for
entry 8 (93%) according to NMR spectroscopic data.
c Enantiomeric excess was determined after DMAP-catalyzed ring
opening to keto ester 8. The absolute configuration was S for entries
1–4 and R for entries 5–7.
As we had good experiences using sodium borohydride as
reducing agent during our initial synthesis of racemic a-
methylthreonine,5 we decided to continue using borohy-
drides as reducing agent. In 1979, Umino et al. reported
that the use of enantiomerically pure N-protected amino
acids as chiral additives to sodium borohydride leads to an
enantioselective reduction of ketones.13 Later, this method
was enhanced by using three equivalents of an N-protect-
ed amino acid.14 As N-Boc-proline was reported to be one
of the most efficient additives, we reduced racemic b-
keto-a-amino acid ester rac-8 using sodium borohydride
and three equivalents of L-N-Boc-proline as reducing
agent. The diastereomeric ratio of the reaction improved
to 80:20 (at 62% conversion) compared to 73:27 (at 100%
conversion) when using only borohydride but, even more
important, we were able to obtain the main product (R,R)-
9 with a conversion of 62%, in 40% yield and with an
enantiomeric excess of 36% ee, thus indicating an asym-
metric induction of the reducing agent (Scheme 2). Unfor-
tunately, it was not possible to improve the relative low
conversions by applying longer reaction times or more
equivalents of the reducing agent.
d n.d. = not determined.
perimental section).9 In these experiments we carried out
the Steglich rearrangement of 15 under in situ-formation
of 16, followed by (non-selective) ring-opening to b-keto
a-amino esters 17. Yields and enantioselectivities were
determined for 17a–d (Table 3).
Azlactone 15a, bearing an a-branched alkyl side chain on
C4, did not undergo Steglich rearrangement using (S)-11
as a chiral organocatalyst (Table 3, entry 1). This observa-
tion is in accordance with reports in the literature about
Steglich rearrangements of alkoxycarbonyl and benzyl-
oxycarbonyl groups.10 In contrast, we were pleased to find
that azlactone 15b, bearing a sterically demanding isobu-
tyl group at the C4-position of the azlactone, undergoes
Steglich rearrangement with a high enantioselectivity of
85% ee when using (S)-12 as a catalyst (entry 2). Reaction
rates were, however, lower compared to those for azlac-
tone 6, bearing a methyl group, and yields are low due to
decomposition in the ring-opening step.
Furthermore, we tried to rearrange acyl groups other than
acetyl. The rearrangement of the butanoyl group of sub-
strate 15c only worked when applying the Fu-type cata-
These results showed that the combination of an enan-
tioselective organocatalytic Steglich rearrangement and
subsequent diastereoselective reduction using sodium
Synthesis 2009, No. 24, 4208–4218 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of a-Methylthreonine
4211
Table 3 Enantioselective Acyl Migration in Steglich Rearrangement of Azlactones 15a–da
O
R2
R2
O
R1
O
(S)-11 (20 mol%) or
(S)-12 (32 mol%)
O
O
DMAP
R3OH
Ph
O
O
R3
Ph
Ph
O
N
N
solvent, r.t.
N
O
R1
H
R2
R1
O
15a–d
16a–d
17a–d
a R1 = i-Pr, R2 = Me, R3 = i-Pr
b R1 = i-Bu, R2 = Me, R3 = Me
c R1 = Me, R2 = n-Pr, R3 = i-Pr
d R1 = Me, R2 = Ph, R3 = i-Pr
Entrya
Substrate
15a
Catalyst
Solvent
CDCl3
TAA
Time
7 d
Conv. to 16 (%)b Yield of 17 (%)c ee (%)d
1
2
3
4
(S)-11
(S)-12
(S)-11
(S)-11
<5
59
80
48
n.d.e
17
n.d.e
85
15b
75 h
24 h
7 d
15c
CDCl3
CDCl3
54
24
15d
29
45
a For experimental details, see experimental section.
b All conversions given in the table are product-related conversions; consumption of 15a–d was complete in all cases (>90%) except entry 1
according to NMR spectroscopic data.
c Yield after chromatography.
d Enantiomeric excess was determined after DMAP-catalyzed ring opening to keto ester 17a–d.
e n.d. = not determined.
borohydride and N-Boc-proline as reducing agent is a initial enantioselective Steglich rearrangement in chloro-
suitable and practical synthetic route towards (enantio- form (Scheme 3). To ensure complete consumption of
merically enriched) a-methylthreonine. Furthermore, azlactone 6, we applied a longer reaction time of 70 hours.
asymmetric induction is possible at both stages, thus of- After subsequent ring opening in the presence of DMAP
fering the potential for obtaining a high ‘overall’ enantio- as a catalyst and subsequent column chromatography, the
meric excess.
b-keto ester (S)-8 was obtained in 53% yield with an enan-
tiomeric excess of 71% ee. The enantiomeric excess of the
ester (S)-8 in this experiment, which was performed on a
4.0 mmol scale, was higher compared to the enantiomeric
excess obtained in the small scale experiment (0.23 mmol
scale; see Table 2, entry 2), since the reaction time had
been extended to ensure complete conversion. The reduc-
tion was carried out using sodium borohydride and D-
Boc-proline as a chiral additive, leading to isopropyl
(S,S)-2-benzoylamino-3-hydroxy-2-methylbutyrate [(S,S)-
9] in 39% yield after chromatography. This reduction pro-
ceeded diastereoselectively, with a diastereomeric ratio of
88:12, yielding the product (S,S)-9 with an enantiomeric
excess of 89% ee. Hydrolysis of diastereomerically pure
and enantiomerically enriched ester [(S,S)-9] with 86% ee
gave diastereomerically pure (S,S)-a-methylthreonine
[(S,S)-4] in 72% yield and with 86% ee.
To prove the power of this new synthetic route and to
study the suitability of enantiomerically enriched b-keto-
a-amino acid ester 8 (resulting from asymmetric Steglich
rearrangement) in the diastereoselective reduction, we fo-
cused on the synthesis of both enantiomers of l-a-meth-
ylthreonine in high enantiomeric excess starting from
easily available azlactone 6 using this developed two-step
synthesis (enantioselective organocatalytic Steglich rear-
rangement followed by diastereoselective reduction).
Boc
O
N
NaBH4 + 3
THF
OH
2 h, r.t.
BocN
O
(R,R)-a-Methylthreonine was prepared in an analogous
manner using (R)-benzotetramisole [(R)-13] as catalyst
for the Steglich rearrangement. The intermediate isopro-
pyl (R)-2-benzoylamino-2-methyl-3-oxobutyrate [(R)-8]
was obtained in 56% yield and with an enantiomeric ex-
cess of 70% ee after subsequent ring-opening (Scheme 4).
Reduction with a sodium borohydride complex bearing L-
Boc-proline as a ligand, led to isopropyl (R,R)-2-benzoyl-
amino-3-hydroxy-2-methylbutyrate [(R,R)-9] in 32%
yield as the major diastereomer in 89% ee after chroma-
tography. Hydrolysis in hydrochloric acid and subsequent
purification on ion-exchange resin led to diastereomeri-
O
Boc
Boc
N
O
B
O
O
N
H
O
O
OH
O
O
*
Oi-Pr
NHCOPh
Oi-Pr
NHCOPh
THF, 0 °C, 20 h
62% conversion
dr 80:20
rac-8
(R,R)-9 (36% ee)
40% yield
Scheme 2 Diastereoselective reduction of b-keto a-amino ester rac-
8
For the synthesis of (S,S)-a-methylthreonine, we used (S)-
tetramisole [(S)-12] in a catalytic amount of 30 mol% for
Synthesis 2009, No. 24, 4208–4218 © Thieme Stuttgart · New York

4212
F. R. Dietz, H. Gröger
PAPER
O
O
O
O
O
O
(S)-12
(30 mol%)
CHCl3
O
OH
O
OH
O
SOCl2, THF
Oi-Pr
1. HCl (6 M)
reflux, 24 h
DMAP (9 mol%)
i-PrOH
0 °C to r.t., 12 h
Oi-Pr
NHCOPh
O
N
O
N
OH
O
N
r.t., 70 h
r.t., 20 h
Oi-Pr
60 °C, 3 h
2. Dowex
50WX8
NH2
NHCOPh
Ph
Ph
(S)-7
(not isolated)
(S)-8 (71% ee)
Ph
(R,S)-4
91% yield
(88% ee)
(R,S)-18
62% yield
(88% ee)
(R,R)-9
(89% ee)
53% yield
over 2 steps
6
O
OH
O
1. HCl (6 M)
Na[B(D-Boc-Pro)3H]
THF, 0 °C, 20 h
reflux, 3 d
OH
O
OH
O
OH
O
SOCl2, THF
0 °C to r.t., 12 h
1. HCl (6 M)
reflux, 24 h
2. Dowex 50WX8
Oi-Pr
Oi-Pr
NHCOPh
O
N
OH
OH
Oi-Pr
50% conversion
dr 88:12
60 °C, 3 h
2. Dowex
50WX8
NH2
NH2
NHCOPh
(S,S)-9 (89% ee)
major diastereomer
39% yield
Ph
(S,S)-4 (86% ee)
72% yield
(S,S)-9
(S,R)-18
60% yield
(89% ee)
(S,R)-4
87% yield
(89% ee)
(89% ee)
Scheme 3 Synthesis of (S,S)-a-methylthreonine [(S,S)-4]
Scheme 5 Synthesis of (R,S)-a-methylthreonine [(R,S)-4] and
(S,R)-a-methylthreonine [(S,R)-4]
O
O
O
O
O
O
(R)-13
(30 mol%)
CHCl3
88% ee. Starting from (S,S)-9 with 89% ee, the oxazoline
formation leads to diastereomerically pure (S,R)-18 with
89% ee in 60% yield. Subsequent hydrolysis furnished di-
astereomerically pure (S,R)-a-methylthreonine [(S,R)-4]
in 87% yield and with 89% ee.
DMAP (9 mol%)
i-PrOH
Oi-Pr
NHCOPh
N
O
O
N
r.t., 20 h
r.t., 95 h
Ph
(R)-8 (70% ee)
Ph
56% yield
6
(R)-7
(not isolated)
over 2 steps
OH
O
In conclusion, we have developed an efficient synthetic
route towards all four stereoisomers of a-methylthreonine
(4). The desired stereoisomers of type 4 have been ob-
tained in diastereomerically pure form and with high
enantiomeric excesses in the range of 86–89% ee. The key
step in this multi-step synthesis is an enantioselective or-
ganocatalytic Steglich rearrangement reaction of O-acety-
lated azlactones. The substrate spectrum of this type of
Steglich rearrangement was also studied.
1. HCl (6 M)
reflux, 3 d
2. Dowex 50WX8
Na[B(L-Boc-Pro)3H]
THF, 0 °C, 20 h
OH
O
Oi-Pr
NHCOPh
OH
43% conversion
dr 88:12
NH2
(R,R)-9 (89% ee)
major diastereomer
(R,R)-4 (89% ee)
89% yield
32% yield
Scheme 4 Synthesis of (R,R)-a-methylthreonine [(R,R)-4]
cally pure (R,R)-a-methylthreonine [(R,R)-4] in 89%
yield and with 89% ee.
Materials and reagents were used without further purification.
Chromatography was performed using Merck silica gel 60 (40–63
nm). Benzotetramisole (13) was synthesized according to the liter-
ature.7 As 4-acyl-4-alkyl-2-phenyloxazol-5-ones (7 and 16a–d) are
not stable under chromatography conditions, they were only charac-
terized by 1H NMR and afterwards further transformed into the cor-
responding, stable 2-benzoylamino-2-alkyl-3-oxo esters (8 and
17a–d), which were completely characterized. For the same reason,
analysis of enantiomeric excess was performed with compounds 8,
17a–d.
1H and 13C NMR spectra were recorded on Jeol JNM GX 400, Jeol
JNM EX 400, Bruker Avance 300 and Bruker Avance 400 spec-
trometers. Chemical shifts (d) are reported in ppm using TMS as a
reference. A Micromass Zabspec spectrometer was used for FAB
mass spectrometry measurements using 3-nitrobenzyl alcohol as
matrix. Analytical HPLC was performed using Daicel Chiralcel
OD, OJ-H and Chiralpak AD-H (4 mm, 250 mm) columns.
With respect to formation of the remaining two dia-
stereomers, namely the R,S- and S,R-stereoisomers of
a-methylthreonine (4), application of the diastereoselec-
tive reduction of 8 turned out to be difficult. Those
diastereomers represent the minor diastereomers and at-
tempts to reverse the diastereoselectivity in the reducing
step were not successful. Thus, we focused on the prepa-
ration of the R,S- and S,R-diastereoisomers starting from
the major R,R- and S,S-diastereoisomers, respectively, by
inversion of the absolute configuration of the stereogenic
centers in the b-position. Such a concept has previously
been successfully applied by Hamada et al. for the inver-
sion of configuration of the b-hydroxy group of a protect-
ed b-hydroxy a-amino acid of type 1 in the synthesis of all
four stereoisomers of 3-hydroxyleucine.15 Using this tech-
nique, preparation of oxazole 18 by dehydration with thio-
nyl chloride, subsequent ring-opening and deprotection
with hydrochloric acid, led to the desired remaining dia-
4-Methyl-2-phenyloxazol-5-yl Acetate (6)
4-Methyl-2-phenyloxazol-5(4H)-one17 (5; 4.0 g, 22.8 mmol) and
AcCl (2.5 mL, 2.7 g, 34.4 mmol) were dissolved in absolute THF
stereoisomers (R,S)-a-methylthreonine [(R,S)-4] and (70 mL) and cooled in an ice bath. Et3N (4.8 mL, 3.5 g, 34.6 mmol)
in THF (20 mL) was added dropwise over 10 min, then the solution
was stirred for 1 h at 0 °C and the precipitated white solid was fil-
tered off. The solvent was evaporated, and the residue was dis-
solved in MTBE (50 mL) and washed with 1 M HCl (50 mL). The
(S,R)-a-methylthreonine [(S,R)-4; Scheme 5]. The (R,S)-
oxazole [(R,S)-18] could be isolated in 62% yield, when
starting with (R,R)-9. The enantiomeric excess of this
product (88% ee) was nearly the same as that of the start-
ing material. Hydrolysis in hydrochloric acid and work up
using ion-exchange resin led to diastereomerically pure
(R,S)-a-methylthreonine [(R,S)-4] in 91% yield and with
organic layer was dried over MgSO4 and the solvent was evaporat-
ed, yielding a white solid. The NMR spectroscopic properties of 6
are in accordance with those reported by Steglich and Höfle.16
Synthesis 2009, No. 24, 4208–4218 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of a-Methylthreonine
4213
Yield: 4.05 g (81%).
1H NMR (400 MHz, CDCl3): d = 2.09 (s, 3 H), 2.35 (s, 3 H), 7.38–
7.41 (m, 3 H), 7.90–7.92 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 10.3, 13.4, 18.1, 35.3, 120.5,
125.8, 127.4, 128.7, 130.1, 145.9, 155.0, 170.0.
MS (FAB): m/z = 248 [MH+], 177 [MH+ – COCH2CH2CH3].
Anal. Calcd for C14H15NO3: C, 68.56; H, 6.16; N, 5.71. Found: C,
68.92; H, 6.23; N, 5.62.
4-Isopropyl-2-phenyloxazol-5-yl Acetate (15a)
4-Isopropyl-2-phenyloxazol-5(4H)-one17 (2.5 g, 12.3 mmol) and
AcCl (960 mL, 1.06 g, 13.5 mmol) were dissolved in absolute THF
(40 mL) and cooled in an ice bath. Et3N (1.9 mL, 1.4 g, 13.5 mmol)
in THF (10 mL) was added dropwise over 10 min. The solution was
stirred for 1 h at 0 °C and the precipitated white solid was filtered
off. The solvent was evaporated, and the residue was dissolved in
MTBE (30 mL) and washed with 1 M HCl (30 mL). The organic
layer was dried over MgSO4 and the solvent was evaporated, yield-
ing an orange oil, which was purified by column chromatography
(EtOAc–cyclohexane, 1:10).
4-Methyl-2-phenyloxazol-5-yl Benzoate (15d)
4-Methyl-2-phenyloxazol-5(4H)-one17 (5; 1.0 g, 5.7 mmol) and
benzoyl bromide (739 mL, 1.16 g, 6.3 mmol) were dissolved in ab-
solute THF (20 mL) and cooled in an ice bath. Et3N (870 mL, 632
mg, 6.3 mmol) in THF (10 mL) was added dropwise over 10 min,
then the solution was stirred for 4 h at 0 °C and the precipitated
white solid was filtered off. The solvent was evaporated, and the
residue was dissolved in MTBE (30 mL) and washed with 1 M HCl
(30 mL). The organic layer was dried over MgSO4 and the solvent
evaporated. The crude product was purified by column chroma-
tography (EtOAc–cyclohexane, 1:6), yielding a white solid. The an-
alytical data of 15d are identical to those reported by Steglich and
Höfle.16
Yield: 1.28 g (42%); Rf = 0.45 (EtOAc–cyclohexane, 1:10).
IR (powder film): 3066, 2966, 2881, 1784, 1653 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.25 (d, J = 7.0 Hz, 6 H), 2.32 (s,
3 H), 2.82 (sept, J = 7.0 Hz, 1 H), 7.38–7.40 (m, 3 H), 7.91–7.94 (m,
2 H).
13C NMR (100 MHz, CDCl3): d = 20.1, 21.0, 25.4, 118.6, 125.9,
127.6, 128.6, 129.8, 130.0, 144.2, 155.0, 167.8.
MS (FAB): m/z = 246 [MH+], 204 [MH+ – COCH3].
Yield: 880 mg (55%); Rf = 0.33 (EtOAc–cyclohexane, 1:6).
1H NMR (400 MHz, CDCl3): d = 2.16 (s, 3 H), 7.40–7.42 (m, 3 H),
7.51–7.55 (m, 2 H), 7.66–7.70 (m, 1 H), 7.94–7.97 (m, 2 H), 8.19–
8.21 (m, 2 H).
rac-4-Acetyl-4-methyl-2-phenyloxazol-5-one (rac-7)
5-Acetyloxy-4-methyl-2-phenyloxazole (6; 2.0 g, 9.3 mmol) and
DMAP (90 mg, 0.7 mmol) were dissolved in CH2Cl2 (50 mL) at r.t.
After 3 h stirring, the solvent was removed to give 7 as a yellow oil.
The analytical data of rac-7 are in accordance with those reported
by Steglich and Höfle.16
4-Isobutyl-2-phenyloxazol-5-yl Acetate (15b)
4-Isobutyl-2-phenyloxazol-5(4H)-one17 (1.85 g, 8.5 mmol) and
AcCl (670 mL, 740 mg, 9.4 mmol) were dissolved in absolute THF
(30 mL) and cooled in an ice bath. Et3N (1.3 mL, 950 mg, 9.4 mmol)
in THF (10 mL) was added dropwise over 10 min. The solution was
stirred for 1 h at 0 °C and the precipitated white solid was filtered
off. The solvent was evaporated, and the residue was dissolved in
MTBE (30 mL) and washed with 1 M HCl (30 mL). The organic
layer was dried over MgSO4 and the solvent was evaporated, yield-
ing a white solid.
Yield: 2.05 g (quantitative, purity >95%).
1H NMR (400 MHz, CDCl3): d = 1.69 (s, 3 H), 2.26 (s, 3 H), 7.46–
7.59 (m, 3 H), 8.00–8.02 (m, 2 H).
Isopropyl rac-2-Benzoylamino-2-methyl-3-oxobutyrate (rac-8)
Yield: 1.91 g (86%); mp 45–47 °C.
IR (powder film): 3061, 2961, 2868, 1791, 1729, 1660 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.93 (d, J = 6.8 Hz, 6 H), 2.02 (m,
1 H), 2.29 (d, J = 6.8 Hz, 2 H), 2.33 (s, 3 H), 7.38–7.40 (m, 3 H),
7.91–7.94 (m, 2 H).
rac-4-Acetyl-4-methyl-2-phenyloxazol-5-one
(rac-7,
1.5 g,
6.9 mmol) and DMAP (90 mg, 0.7 mmol) were dissolved in i-PrOH
(40 mL). The reaction mixture was stirred for 16 h and the excess of
i-PrOH was removed in vacuo. The resulting crude product was pu-
rified by column chromatography (EtOAc–cyclohexane, 1:3) to
give a colorless oil.
13C NMR (100 MHz, CDCl3): d = 20.1, 22.2, 27.5, 33.9, 124.0,
125.9, 127.4, 128.7, 130.1, 146.2, 155.1, 167.5.
Yield: 1.62 g (84%); Rf = 0.36 (EtOAc–cyclohexane, 1:3).
MS (FAB): m/z = 260 [MH+], 218 [MH+ – COCH3].
HPLC (Chiralcel OD column; hexanes–i-PrOH, 97:3; 1.0 mL/min):
tR = 9.0, 10.8 min.
IR (thin film): 3412, 3327, 2984, 1722, 1664 cm–1.
Anal. Calcd for C15H17NO3: C, 69.48; H, 6.61; N, 5.40. Found: C,
69.65; H, 6.63; N, 5.17.
1H NMR (400 MHz, CDCl3): d = 1.18 (d, J = 6.3 Hz, 3 H), 1.21 (d,
J = 6.3 Hz, 3 H), 1.79 (s, 3 H), 2.21 (s, 3 H), 5.08 (sept, J = 6.3 Hz,
1 H), 7.40–7.44 (m, 2 H), 7.47–7.51 (m, 1 H), 7.71 (br s, 1 H),
7.78–7.81 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 19.9, 21.30, 21.32, 23.9, 68.6,
70.5, 127.1, 128.6, 131.9, 133.6, 166.0, 168.7, 200.4.
4-Methyl-2-phenyloxazol-5-yl Butyrate (15c)
4-Methyl-2-phenyloxazol-5(4H)-one17 (5; 1.0 g, 5.7 mmol) and bu-
tanoyl chloride (600 mL, 610 mg, 5.7 mmol) were dissolved in ab-
solute THF (20 mL) and cooled in an ice bath. Et3N (791 mL, 575
mg, 5.7 mmol) in THF (5 mL) was added dropwise over 10 min,
then the solution was stirred for 2 h at 0 °C and the precipitated
white solid was filtered off. The solvent was evaporated, and the
residue was dissolved in MTBE (30 mL) and washed with 1 M HCl
(30 mL). The organic layer was dried over MgSO4 and the solvent
evaporated. The crude product was purified by column chromatog-
raphy (EtOAc–cyclohexane, 1:3), yielding a colorless oil.
MS (EI): m/z = 278 [MH+], 234 [MH+ – COCH3].
Anal. Calcd for C15H19NO4: C, 64.97; H, 6.91; N, 5.05; Found: C,
64.61; H, 6.88; N, 4.89.
rac-4-Acetyl-4-isopropyl-2-phenyloxazol-5-one (rac-16a)
Yield: 1.0 g (72%); Rf = 0.38 (EtOAc–cyclohexane, 1:3).
5-Acetyloxy-4-isopropyl-2-phenyloxazole
(15a;
100
mg,
0.4 mmol) and DMAP (5 mg, 0.04 mmol) were dissolved in CH2Cl2
(5 mL) at r.t. After 3 h stirring, the solvent was removed to give
crude 16a as yellow oil, which was applied for ring opening to 17a.
The analytical data of rac-16a are in accordance with those reported
by Steglich and Höfle.16
IR (powder film): 3069, 2968, 2934, 2880, 1791, 1752, 1660 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.04 (t, J = 7.4 Hz, 3 H), 1.74–1.84
(m, 2 H), 2.08 (s, 3 H), 2.59 (t, J = 7.2 Hz, 2 H), 7.39–7.42 (m, 3 H),
7.90–7.93 (m, 2 H).
Synthesis 2009, No. 24, 4208–4218 © Thieme Stuttgart · New York

4214
F. R. Dietz, H. Gröger
PAPER
Yield: 102 mg (quantitative, purity >70%).
Yield: 210 mg (quantitative, purity ~90%).
1H NMR (300 MHz, CDCl3): d = 0.90 (d, J = 6.8 Hz, 3 H), 1.03 (d,
J = 6.8 Hz, 3 H), 2.32 (s, 3 H), 2.76 (sept, J = 6.8 Hz, 1 H), 7.47–
7.60 (m, 3 H), 8.03–8.07 (m, 2 H).
1H NMR (300 MHz, CDCl3): d = 0.85–0.90 (m, 3 H), 1.55–1.63 (m,
2 H), 1.70 (s, 3 H), 2.42–2.69 (m, 2 H), 7.46–7.62 (m, 3 H), 8.01–
8.04 (m, 2 H).
Isopropyl rac-2-Benzoylamino-2-isopropyl-3-oxobutyrate (rac-
17a)
Isopropyl rac-2-Benzoylamino-2-methyl-3-oxohexanoate (rac-
17c)
rac-4-Acetyl-4-isopropyl-2-phenyloxazol-5-one (rac-16a, 102 mg),
containing DMAP and side products was dissolved in i-PrOH (5
mL). The reaction mixture was stirred for 16 h and the excess of
i-PrOH was removed in vacuo. The resulting crude product was pu-
rified by column chromatography (EtOAc–cyclohexane, 1:6) to
give a colorless oil.
A sample of the mixture from the reaction mentioned above (210
mg), containing 4-butyryl-4-methyl-2-phenyloxazol-5-one (rac-
16c; ~90%), and DMAP (~10%) were dissolved in i-PrOH (5 mL).
The reaction mixture was stirred for 16 h, then the excess alcohol
was removed in vacuo. The resulting crude product was purified by
column chromatography (EtOAc–cyclohexane, 1:3) to give pure
racemic rac-17c as a colorless oil.
Yield: 75 mg (61%); Rf = 0.20 (EtOAc–cyclohexane, 1:6).
Yield: 140 mg (56%); Rf = 0.53 (EtOAc–cyclohexane, 1:3).
IR (thin film): 3391, 2974, 2935, 2881, 1722, 1668 cm–1.
HPLC (Chiralpak AD-H-column; hexanes–i-PrOH, 97:3; 1.0 mL/
min): tR = 13.3, 14.9 min.
IR (thin film): 3408, 2968, 2937, 2880, 1745, 1718, 1664 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.86 (t, J = 7.4 Hz, 3 H), 1.16 (d,
J = 6.3 Hz, 3 H), 1.19 (d, J = 6.3 Hz, 3 H), 1.57–1.66 (m, 2 H), 1.78
(s, 3 H), 2.41–2.56 (m, 2 H), 5.07 (sept, J = 6.3 Hz, 1 H), 7.39–7.43
(m, 2 H), 7.46–7.50 (m, 1 H), 7.76 (br s, 1 H), 7.77–7.80 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 13.4, 17.0, 19.8, 21.32, 21.34,
38.0, 68.5, 70.3, 127.0, 128.6, 131.8, 133.7, 165.9, 168.7, 202.7.
MS (FAB): m/z = 307 [MH+].
1H NMR (400 MHz, CDCl3): d = 0.86 (d, J = 6.8 Hz, 3 H), 1.01 (d,
J = 6.8 Hz, 3 H), 1.19 (d, J = 6.3 Hz, 3 H), 1.22 (d, J = 6.3 Hz, 3 H),
2.14 (s, 3 H), 2.85 (sept, J = 6.8 Hz, 1 H), 5.11 (sept, J = 6.3 Hz,
1 H), 7.42–7.53 (m, 4 H), 7.80–7.82 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 17.7, 18.3, 21.3, 24.7, 26.8, 32.7,
70.3, 74.6, 127.1, 128.7, 131.9, 133.9, 166.4, 168.0, 199.1.
MS (EI): m/z = 306 [MH+], 262 [MH+ – i-PrOH], 201 [MH+ – Ph-
CO], 158 [MH+ – i-PrOH – PhCO].
Anal. Calcd for C17H23NO4: C, 66.86; H, 7.59; N, 4.59. Found: C,
67.58; H, 7.79; N, 4.57.
Anal. Calcd for C17H23NO4: C, 66.86; H, 7.59; N, 4.59. Found: C,
66.39; H, 7.57; N, 4.39.
rac-4-Acetyl-4-isobutyl-2-phenyloxazol-5-one (rac-16b)
5-Acetyloxy-4-isobutyl-2-phenyloxazole (15b; 400 mg, 1.4 mmol)
and DMAP (15 mg, 0.1 mmol) were dissolved in CH2Cl2 (20 mL)
at r.t. After 4 h stirring, the solvent was removed to give crude rac-
16b as a yellow oil, which was applied for ring opening to rac-17b.
rac-4-Benzoyl-4-methyl-2-phenyloxazol-5-one (rac-16d)
4-Methyl-2-phenyloxazol-5-yl benzoate (15d; 260 mg, 0.93 mmol)
and DMAP (23 mg, 0.19 mmol) were dissolved in CH2Cl2 (5 mL)
at r.t. After 5 h stirring, the solvent was removed to give crude 16d
as a yellow oil, which was applied for ring opening to rac-17c.
Yield: 402 mg (quantitative, purity >85%).
1H NMR (400 MHz, CDCl3): d = 0.86–0.91 (m, 6 H), 1.61–1.73 (m,
1 H), 1.97–2.02 (m, 1 H), 2.19–2.25 (m, 1 H), 2.28 (s, 3 H), 7.48–
7.51 (m, 2 H), 7.57–7.61 (m, 1 H), 8.02–8.05 (m, 2 H).
Yield: 280 mg (quantitative, purity ~70%).
1H NMR (300 MHz, CDCl3): d = 1.89 (s, 3 H), 7.43–7.59 (m, 6 H),
8.01–8.20 (m, 4 H).
Methyl rac-2-Benzoylamino-2-isobutyl-3-oxobutyrate (rac-17b)
4-Acetyl-4-isopropyl-2-phenyloxazol-5-one (rac-16b; 380 mg),
and DMAP (80 mg, 0.6 mmol) were dissolved in CH2Cl2 (50 mL).
MeOH (5 mL) was added and the reaction mixture was stirred for
16 h. The excess solvent was removed in vacuo, then the resulting
crude product was purified by column chromatography (EtOAc–
cyclohexane, 1:3) to give pure racemic rac-17b as a colorless oil.
Isopropyl rac-2-Benzoylamino-2-methyl-3-oxo-3-phenylpro-
panoate (rac-17d)
A sample of the mixture from the reaction mentioned above (280
mg), containing 4-benzoyl-4-methyl-2-phenyloxazol-5-one (rac-
16d; ~70%), DMAP (~10%) and deacylated side product were dis-
solved in i-PrOH (20 mL). The reaction mixture was stirred for 16
h, then the excess alcohol was removed in vacuo. The resulting
crude product was purified by column chromatography (EtOAc–
cyclohexane, 1:3) to give pure racemic rac-17d as a white solid.
Yield: 137 mg (32%); Rf = 0.47 (EtOAc–cyclohexane, 1:3).
HPLC (Chiralcel OJ-H-column; hexanes–i-PrOH, 90:10; 1.0 mL/
min): tR = 12.2, 19.9 min.
Yield: 100 mg (33%); mp 128–130 °C; Rf = 0.46 (EtOAc–cyclo-
hexane, 1:3).
IR (thin film): 3408, 2961, 1749, 1722, 1664 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.83–0.86 (m, 6 H), 1.46–1.55 (m,
1 H), 2.22 (s, 3 H), 2.37–2.42 (m, 1 H), 2.49–2.54 (m, 1 H), 3.76 (s,
3 H), 7.43–7.54 (m, 3 H), 7.75 (br s, 1 H), 7.81–7.84 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 23.1, 23.6, 24.3, 24.4, 39.5, 53.5,
72.1, 127.2, 128.8, 132.1, 133.4, 165.9, 169.8, 200.6.
HPLC (Chiralcel OJ-H-column; hexanes–i-PrOH, 90:10; 1.0 mL/
min): tR = 13.7, 29.4 min.
IR (powder film): 3408, 2984, 1737, 1698, 1652 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.06 (d, J = 6.3 Hz, 3 H), 1.15 (d,
J = 6.3 Hz, 3 H,), 1.95 (s, 3 H), 5.12 (sept, J = 6.3 Hz, 1 H), 7.34–
7.49 (m, 6 H), 7.71–7.73 (m, 2 H), 7.93–7.95 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 21.2, 21.3, 22.0, 66.8, 71.0, 127.0,
128.4, 128.56, 128.58, 131.8, 133.0, 133.6, 134.4, 165.4, 170.3,
192.1.
MS (FAB): m/z = 292 [MH+].
Anal. Calcd for C16H21NO4: C, 65.96; H, 7.27; N, 4.81. Found: C,
65.53; H, 7.36; N, 4.65.
rac-4-Butyryl-4-methyl-2-phenyloxazol-5-one (rac-16c)
4-Methyl-2-phenyloxazol-5-yl butyrate (15c; 200 mg, 0.8 mmol)
and DMAP (20 mg, 0.16 mmol) were dissolved in CH2Cl2 (5 mL)
at r.t. After 3 h stirring, the solvent was removed to give crude rac-
16c as a yellow oil, which was applied for ring opening to rac-17c.
MS (FAB): m/z = 341 [MH+].
Anal. Calcd for C20H21NO4: C, 70.78; H, 6.24; N, 4.13. Found: C,
70.71; H, 5.97; N, 3.92.
Synthesis 2009, No. 24, 4208–4218 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of a-Methylthreonine
4215
Isopropyl rac-2-Benzoylamino-3-hydroxy-2-methylbutyrate
(rac-l-9, rac-u-9)
troscopic properties are in accordance with those reported by
Avenoza et al.4g
Isopropyl 2-benzoylamino-2-methyl-3-oxobutyrate (rac-8, 100 mg,
0.36 mmol) was dissolved in absolute THF (5 mL) and cooled in an
ice bath. After adding NaBH4 (7.2 mg, 0.18 mmol), the mixture was
stirred at ice-bath temperature for 2 h. Subsequently, dilute HCl was
added until no further hydrogen was evolved. After addition of H2O
the reaction mixture was extracted with MTBE (3 × 10 mL). Re-
moval of the solvent furnished a crude product of the resulting race-
mic diastereomers l-9 and u-9 (diastereomeric ratio of 73:27),
which were separated by column chromatography (EtOAc–cyclo-
hexane, 1:3) to give both diastereomers as white solids.
Yield: 70 mg (73%).
1H NMR (400 MHz, D2O): d = 1.27 (d, J = 6.6 Hz, 3 H), 1.42 (s,
3 H), 4.19 (q, J = 6.6 Hz, 1 H).
(S)-N-(Thiazolyl-2)-2-hydroxy-1-tert-butylethylamine
A pressure tube charged with 2-chlorobenzothiazole (1.32 mL, 1.72
g, 10.1 mmol), (S)-tert-leucinol (1.23 g, 10.4 mmol), DIPEA (2.7
mL, 15 mmol) and a stir bar was flushed with nitrogen several
times, stoppered and heated at 130 5 °C for 24 h. After cooling the
tube to r.t., the viscous reaction mixture was treated with CH2Cl2
(10 mL) and left at r.t. to dissolve overnight. The diluted reaction
mixture was applied directly to a chromatographic column (i-PrOH–
CH2Cl2, 2.5%) to afford a white solid.
rac-l-9
Yield: 60 mg (60%); mp 70–71 °C; Rf = 0.16 (EtOAc–cyclohexane,
1:3).
Yield: 1.48 g (58%); mp 155–157 °C; [a]D –34.8 (c 1.0, MeOH).
HPLC (Chiralcel OD column; hexanes–i-PrOH, 97:3; 1.0 mL/min):
tR = 9.9, 12.5 min.
IR (powder film): 3516, 3242, 2984, 1706, 1633 cm–1.
IR (powder film): 3223, 3196, 2964, 2891, 1722, 1668, 1644, 1598,
1522 cm–1.
1H NMR (400 MHz, CD3OD): d = 0.97 (s, 9 H), 3.52 (dd, J = 8.1,
11.3 Hz, 1 H), 3.77–3.78 (m, 1 H), 3.85 (dd, J = 3.5, 11.4 Hz, 1 H),
6.95–7.00 (m, 1 H), 7.14–7.19 (m, 1 H), 7.32–7.34 (m, 1 H), 7.48–
7.50 (m, 1 H).
13C NMR (100 MHz, CD3OD): d = 27.4, 35.7, 63.0, 67.2, 118.8,
121.7, 122.5, 126.9, 131.2, 153.3, 170.9.
1H NMR (400 MHz, CDCl3): d = 1.07 (d, J = 6.5 Hz, 3 H), 1.25–
1.29 (m, 6 H), 1.69 (s, 3 H), 4.14–4.22 (m, 1 H), 5.09 (sept, J = 6.4
Hz, 1 H), 5.49 (d, J = 10.1 Hz, 1 H), 7.41–7.45 (m, 2 H), 7.49–7.53
(m, 1 H), 7.61 (br s, 1 H), 7.79–7.81 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 18.8, 20.1, 21.4, 65.9, 70.5, 71.2,
127.2, 128.7, 132.1, 133.9, 168.0, 173.6.
MS (FAB): m/z = 251 [MH+], 233 [MH+ – H2O].
MS (FAB): m/z = 280 [MH+].
Anal. Calcd for C13H18N2OS: C, 62.37; H, 7.25; N, 11.19; S, 12.81.
Found: C, 62.24; H, 7.31; N, 11.09; S, 12.35.
Anal. Calcd for C15H21NO4: C, 64.50; H, 7.58; N, 5.01. Found: C,
64.14; H, 7.58; N, 4.93.
(S)-2,3-Dihydro-2-tert-butylimidazo[2,1-b]benzothiazole (14)
A solution of (S)-N-(thiazolyl-2)-2-hydroxy-1-tert-butylethylamine
(0.63 g, 2.5 mmol) in anhydrous CH2Cl2 (25 mL) was cooled to 0 °C
under a nitrogen atmosphere and treated with Et3N (1.05 mL, 7.5
mmol) followed by MsCl (0.29 mL, 3.75 mmol). The mixture was
stirred at 0 °C for 1 h and then warmed to r.t.; MeOH (0.15 mL) was
then added to quench the excess amount of MsCl, then Et3N (3.5
mL) was added and the mixture was refluxed overnight. The cooled
mixture was washed with a small amount of H2O, dried over
Na2SO4 and evaporated in vacuo. The crude product was purified by
chromatography (i-PrOH–hexanes, 5% containing 1% Et3N) to give
the crude product as a white solid. The compound was recrystallized
(MTBE–hexanes), yielding a white solid.
rac-u-9
Yield: 16 mg (16%); mp 111–112 °C; Rf = 0.06 (EtOAc–cyclohex-
ane, 1:3).
IR (powder film): 3412, 3331, 2976, 1733, 1640 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.20–1.26 (m, 9 H), 1.57 (s, 3 H),
3.71 (br s, 1 H), 4.13–4.19 (m, 1 H), 5.09 (sept, J = 6.0 Hz, 1 H),
6.86 (br s, 1 H), 7.38–7.42 (m, 2 H), 7.46–7.50 (m, 1 H), 7.74–7.77
(m, 2 H).
13C NMR (100 MHz, CDCl3): d = 17.8, 18.5, 21.56, 21.62, 64.6,
69.6, 71.3, 127.1, 128.6, 131.7, 134.5, 167.9, 172.2.
MS (FAB): m/z = 280 [MH+].
Yield: 280 mg (48%); mp 75–76 °C; [a]D20 –154.9 (c 1.0, MeOH).
IR (powder film): 2957, 2903, 2864, 1606, 1475 cm–1.
Anal. Calcd for C15H21NO4: C, 64.50; H, 7.58; N, 5.01. Found: C,
64.13; H, 7.61; N, 4.87.
rac-l-a-Methylthreonine (rac-l-4)
1H NMR (400 MHz, CDCl3): d = 0.95 (s, 9 H), 3.52–3.56 (m, 1 H),
3.73–3.78 (m, 1 H), 4.29–4.34 (m, 1 H), 6.63 (d, J = 7.8 Hz, 1 H),
6.90 (dd, J = 7.7, 7.7 Hz, 1 H), 7.14 (dd, J = 7.7, 7.7 Hz, 1 H), 7.22
(d, J = 7.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 25.8, 34.3, 45.4, 82.7, 108.1,
121.1, 123.0, 126.4, 127.2, 137.3, 165.0.
A mixture of rac-l-9 (106 mg, 0.38 mmol) in HCl (6 M, 10 mL) was
refluxed for 3 d then, after cooling to r.t., the mixture was washed
with MTBE (10 mL). The aqueous phase was evaporated to dryness
and the resulting hydrochloride was converted into free rac-l-4 by
ion-exchange resin (Dowex 50WX8; eluent: 1 M ammonia). The
spectroscopic properties are in accordance with those reported by
Avenoza et al.4g
MS (FAB): m/z = 233 [MH+], 175 [MH+ – t-Bu].
Anal. Calcd for C13H16N2S: C, 67.20; H, 6.94; N, 12.06; S, 13.80.
Found: C, 66.91; H, 7.05; N, 11.96; S, 13.55.
Yield: 45 mg (89%).
1H NMR (400 MHz, D2O): d = 1.14 (d, J = 6.6 Hz, 3 H), 1.36 (s,
3 H), 3.96 (q, J = 6.6 Hz, 1 H).
Enantioselective Steglich Rearrangement of 6 Using Fu-Type
Catalysts 10 and 11; Typical Procedure (Table 1, entry 1)
5-Acetyloxy-4-methyl-2-phenyloxazole (6; 50 mg, 0.23 mmol) and
(S)-4-dimethylaminopyridinyl(pentaphenylcyclopentadienyl)iron
[(S)-10; 4 mg, 0.005 mmol] were dissolved in CH2Cl2 (1 mL) and
stirred at r.t. for 3 h. Subsequently, the solvent was removed to give
4-acetyl-4-methyl-2-phenyloxazol-5-one (7; 52 mg) as an oily
crude product. The conversion (84%) was determined by 1H NMR
spectroscopy. The enantioselectivity (25% ee) was determined by
rac-u-a-Methylthreonine (rac-u-4)
A mixture of rac-u-9 (200 mg, 0.72 mmol) in HCl (6 M, 20 mL) was
refluxed for 3 d. After cooling to r.t., the mixture was washed with
MTBE (20 mL). The aqueous phase was evaporated to dryness and
the resulting hydrochloride was converted into free rac-u-4 by ion-
exchange resin (Dowex 50WX8; eluent: 1 M ammonia). The spec-
Synthesis 2009, No. 24, 4208–4218 © Thieme Stuttgart · New York

4216
F. R. Dietz, H. Gröger
PAPER
chiral HPLC chromatography after derivatization to isopropyl 2-
benzoylamino-2-methyl-3-oxobutyrate (8), which was performed
as follows: The crude product was dissolved in i-PrOH (5 mL) and
DMAP (5 mg, 4.1 mmol) was added. After 16 h stirring, the solvent
was evaporated in vacuo. The spectroscopic properties are in accor-
dance with those of the racemic products rac-7 and rac-8. Reactions
were stirred until complete consumption of substrate 6 was ob-
served.
After shaking this mixture for 7 d, conversion was determined by 1H
NMR spectroscopy. The mixture was rotary evaporated, dissolved
in i-PrOH (5 mL) and DMAP (10 mg, 0.08 mmol) was added. After
an additional 16 h stirring, the solvent was evaporated to give crude
17d, which was purified by column chromatography (cyclohexane–
EtOAc, 3:1). The spectroscopic properties are in accordance with
those of the racemic compound rac-17d.
Yield: 18 mg (29%); 45% ee.
Enantioselective Steglich Rearrangement of 6 Using Birman-
Type Catalysts 12–14; Typical Procedure (Table 2, entry 1)
5-Acetyloxy-4-methyl-2-phenyloxazole (6; 50 mg, 0.23 mmol) and
(S)-tetramisole [(S)-12; 15 mg, 0.07 mmol] were dissolved in
CH2Cl2 (1 mL) and stirred at r.t. for 68 h. Subsequently, the solvent
was removed to give 4-acetyl-4-methyl-2-phenyloxazol-5-one (7;
63 mg) as a crude oily product. The conversion (82%) was deter-
Isopropyl (S)-2-Benzoylamino-2-methyl-3-oxobutyrate [(S)-8]
5-Acetyloxy-4-methyl-2-phenyloxazole (6; 880 mg, 4.0 mmol) and
(S)-tetramisol [(S)-12; 248 mg, 1.2 mmol] were dissolved in CHCl3
(17 mL). After stirring this mixture for 70 h, i-PrOH (21.5 mL) and
DMAP (44 mg, 0.36 mmol) were added. After an additional 16 h
stirring, the solvent was evaporated to give crude (S)-8, which was
purified by column chromatography (cyclohexane–EtOAc, 3:1).
The spectroscopic properties are in accordance with those of the ra-
cemic compound rac-8.
1
mined by H NMR spectroscopy. The enantioselectivity (59% ee)
was determined by chiral HPLC chromatography after derivatiza-
tion to isopropyl 2-benzoylamino-2-methyl-3-oxobutyrate (8),
which was performed as follows: The crude product was dissolved
in i-PrOH (5 mL) and DMAP (5 mg, 4.1 mmol) was added. After
16 h stirring, the solvent was evaporated in vacuo. The spectroscop-
ic properties are in accordance with those of the racemic products
rac-7 and rac-8. Reactions were stirred until complete consumption
of substrate 6 was observed (except Table 2, entry 8).
Yield: 588 mg (53%); 71% ee.
Isopropyl (S,S)-2-Benzoylamino-3-hydroxy-2-methylbutyrate
[(S,S)-9]
NaBH4 (106 mg, 2.79 mmol) was suspended in absolute THF (15
mL) and cooled in an ice-bath. D-N-Boc-proline (1800 mg, 8.36
mmol) in THF (30 mL) was added through an additional funnel. Af-
ter 2 h stirring at r.t., the mixture was cooled in an ice bath and iso-
propyl (S)-2-benzoylamino-2-methyl-3-oxobutyrate [(S)-8; 580
mg, 2.09 mmol, 71% ee] in THF (30 mL) was added dropwise. Af-
ter 20 h stirring at ice-bath temperature, the excess NaBH4 was
quenched by adding HCl (2 M) and most of the solvent was evapo-
rated. The resulting aqueous solution was basified with NaHCO3
and extracted with EtOAc (3 × 50 mL). After drying of the com-
bined organic phases over MgSO4, the solvent was removed to give
a crude mixture of starting material (S)-8 and both diastereomers of
product 9. The diastereomeric ratio and conversion were deter-
Enantioselective Steglich Rearrangement of Substrate 15a
5-Acetyloxy-4-isopropyl-2-phenyloxazole (15a; 50 mg, 0.20
mmol) and (S)-11 (15 mg, 0.04 mmol) were dissolved in CDCl3 (1
mL). After shaking this mixture for 7 d, conversion was determined
1
by H NMR spectroscopy. As conversion was lower than 5%, no
further reaction or purification was carried out.
Enantioselective Steglich Rearrangement of Substrate 15b:
Synthesis of Methyl 2-Benzoylamino-2-isobutyl-3-oxobutyrate
(17b)
1
mined by H NMR spectroscopy. Diastereomerically pure (S,S)-9
5-Acetyloxy-4-isobutyl-2-phenyloxazole (15b, 104 mg, 0.40
mmol) and (S)-tetramisol [(S)-12; 26 mg, 0.13 mmol] were dis-
solved in tert-amyl alcohol (2 mL). After stirring this mixture for 75
h, the solvent was removed to give crude 16b. Conversion was de-
termined by 1H NMR spectroscopy. The mixture was dissolved in
CH2Cl2 (4 mL), and DMAP (10 mg, 0.08 mmol) and MeOH (200
mL) were added. After an additional 16 h stirring, the solvent was
evaporated to give crude 17b, which was purified by column chro-
matography (EtOAc–cyclohexane, 1:4). The spectroscopic proper-
ties are in accordance with those of the racemic compound rac-17b.
was obtained after column chromatography (cyclohexane–EtOAc,
3:1). The spectroscopic properties are in accordance with those of
the racemic compound rac-l-9.
Yield: 230 mg (39%); 89% ee.
(S,S)-a-Methylthreonine [(S,S)-4]
Isopropyl
(S,S)-2-benzoylamino-3-hydroxy-2-methylbutyrate
[(S,S)-9; 126 mg, 0.45 mmol, 86% ee] was dissolved in HCl (6 M,
10 mL) and refluxed for 60 h. After cooling to r.t., the mixture was
washed with MTBE (10 mL). The aqueous phase was evaporated to
dryness and the resulting hydrochloride was converted into free
(S,S)-4 by ion-exchange resin (Dowex 50WX8; eluent: 1 M ammo-
nia). The spectroscopic properties are in accordance with those giv-
en above for the racemic compound rac-l-4 and those reported by
Avenoza et al.4g Enantiomeric excess was examined by optical ro-
tation.
Yield: 21 mg (17%); 85% ee.
Enantioselective Steglich Rearrangement of Substrate 15c:
Synthesis of Isopropyl 2-Benzoylamino-2-methyl-3-oxohex-
anoate (17c)
4-Methyl-2-phenyloxazol-5-yl butyrate (15c; 50 mg, 0.20 mmol)
and (S)-11 (15 mg, 0.04 mmol) were dissolved in CDCl3 (1 mL).
After shaking this mixture for 24 h, conversion was determined by
1H NMR spectroscopy. The mixture was rotary evaporated, dis-
solved in i-PrOH (5 mL) and DMAP (10 mg, 0.08 mmol) was
added. After an additional 16 h stirring, the solvent was evaporated
to give crude 17c, which was purified by column chromatography
(EtOAc–cyclohexane, 1:3). The spectroscopic properties are in ac-
cordance with those of the racemic compound rac-17c.
Yield: 43 mg (72%); 86% ee; [a]D20 +10.0 (c 0.85, H2O).
Isopropyl (R)-2-Benzoylamino-2-methyl-3-oxobutyrate [(R)-8]
5-Acetyloxy-4-methyl-2-phenyloxazole (6; 861 mg, 4.0 mmol) and
(R)-benzotetramisol [(R)-13; 300 mg, 1.2 mmol] were dissolved in
CHCl3 (17 mL). After stirring this mixture for 95 h, i-PrOH (21.5
mL) and DMAP (43 mg, 0.35 mmol) were added. After an addition-
al 16 h stirring, the solvent was evaporated to give crude (R)-8,
which was purified by column chromatography (cyclohexane–
EtOAc, 3:1). The spectroscopic properties are in accordance with
those of the racemic compound rac-8.
Yield: 33 mg (54%); 24% ee.
Enantioselective Steglich Rearrangement of Substrate 15d:
Synthesis of Isopropyl 2-Benzoylamino-2-methyl-3-oxo-3-phe-
nylpropanoate (17d)
4-Methyl-2-phenyloxazol-5-yl benzoate (15d; 50 mg, 0.18 mmol)
and (S)-11 (14 mg, 0.036 mmol) were dissolved in CDCl3 (1 mL).
Yield: 615 mg (56%); 70% ee.
Synthesis 2009, No. 24, 4208–4218 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of a-Methylthreonine
4217
Isopropyl (R,R)-2-Benzoylamino-3-hydroxy-2-methylbutyrate
[(R,R)-9]
(R,S)-4-Isopropoxycarbonyl-4,5-dimethyl-2-phenyl-1,3-oxazo-
line [(R,S)-18]
NaBH4 (109 mg, 2.89 mmol) was suspended in absolute THF (15
mL) and cooled in an ice bath. L-N-Boc-proline (1868 mg, 8.68
mmol) in THF (30 mL) was added through an additional funnel. Af-
ter 2 h stirring at r.t., the mixture was cooled in an ice bath and iso-
propyl (R)-2-benzoylamino-2-methyl-3-oxobutyrate [(R)-8; 600
mg, 2.17 mmol, 70% ee) in THF (30 mL) was added dropwise. Af-
ter 20 h stirring at ice-bath temperature, the excess NaBH4 was
quenched by adding HCl (2 M) and most of the solvent was evapo-
rated. The resulting aqueous solution was basified with NaHCO3
and extracted with EtOAc (3 × 50 mL). After drying the combined
organic phases over MgSO4, the solvent was removed to give a
crude mixture of starting material (R)-8 and both diastereomers of
product 9. The diastereomeric ratio and conversion were deter-
mined by 1H NMR spectroscopy. Diastereomerically pure (R,R)-9
was obtained after column chromatography (cyclohexane–EtOAc,
3:1). The spectroscopic properties are in accordance with those of
the racemic compound rac-l-9.
Isopropyl
(R,R)-2-benzoylamino-3-hydroxy-2-methylbutyrate
[(R,R)-9; 180 mg, 0.7 mmol, 89% ee] was dissolved in THF (5 mL)
and cooled in an ice-bath. After SOCl2 (73 mL, 119 mg, 1.0 mmol)
was added, the mixture was allowed to come to r.t. overnight. After
an additional 3 h stirring at 60 °C, the solution was cooled in an ice-
bath and the excess SOCl2 was quenched with sat. NaHCO3 (30 mL)
and the mixture was extracted with EtOAc (3 × 30 mL). The com-
bined organic phases were washed with H2O and brine, dried over
Na2SO4 and evaporated. The crude product was purified by column
chromatography (cyclohexane–EtOAc, 9:1) to yield a colorless oil.
The spectroscopic properties are in accordance with those of the ra-
cemic compound rac-u-18.
Yield: 105 mg (62%); 88% ee.
(S,R)-4-Isopropoxycarbonyl-4,5-dimethyl-2-phenyl-1,3-oxazo-
line [(S,R)-18]
Isopropyl
(S,S)-2-benzoylamino-3-hydroxy-2-methylbutyrate
Yield: 195 mg (32%); 89% ee.
[(S,S)-9; 230 mg, 0.8 mmol, 89% ee] was dissolved in THF (8 mL)
and cooled in an ice bath. After SOCl2 (91 mL, 152 mg, 1.2 mmol)
was added, the mixture was allowed to come to r.t. overnight. After
an additional 3 h stirring at 60 °C, the solution was cooled in an ice
bath and the excess SOCl2 was quenched with sat. NaHCO3 (40 mL)
and the mixture was extracted with EtOAc (3 × 40 mL). The com-
bined organic phases were washed with H2O and brine, dried over
Na2SO4 and evaporated. The crude product was purified by column
chromatography (cyclohexane–EtOAc, 9:1) to yield a colorless oil.
The spectroscopic properties are in accordance with those of the ra-
cemic compound rac-u-18.
(R,R)-a-Methylthreonine [(R,R)-4]
Isopropyl
(R,R)-2-benzoylamino-3-hydroxy-2-methylbutyrate
[(R,R)-9; 106 mg, 0.38 mmol, 89% ee] was dissolved in HCl (6 M,
10 mL) and refluxed for 60 h. After cooling to r.t., the mixture was
washed with MTBE (10 mL) and the aqueous phase was evaporated
to dryness. The resulting hydrochloride was converted into free
(R,R)-4 by ion-exchange resin (Dowex 50WX8; eluent: 1 M ammo-
nia). The spectroscopic properties are in accordance to those given
above for the racemic compound rac-l-4 and those reported by
Avenoza et al.4g Enantiomeric excess was examined by optical ro-
tation.
Yield: 127 mg (60%); 89% ee.
Yield: 45 mg (89%); 89% ee; [a]D20 –10.4 (c 0.85, H2O).
(R,S)-a-Methylthreonine [(R,S)-4]
(R,S)-4-Isopropoxycarbonyl-4,5-dimethyl-2-phenyl-1,3-oxazoline
[(R,S)-18; 100 mg, 0.38 mmol, 88% ee] was dissolved in HCl (6 M,
15 mL) and refluxed for 24 h. After cooling to r.t., the mixture was
washed with MTBE (2 × 10 mL) and the aqueous phase was evap-
orated to dryness. The resulting hydrochloride was converted into
free (R,S)-4 by ion-exchange resin (Dowex 50WX8; eluent: 1 M
ammonia). The spectroscopic properties are in accordance to those
given above for the racemic compound rac-u-4 and those reported
by Avenoza et al.4g Enantiomeric excess was examined by optical
rotation.
rac-u-4-Isopropoxycarbonyl-4,5-dimethyl-2-phenyl-1,3-oxazo-
line (rac-u-18)
Isopropyl rac-l-2-benzoylamino-3-hydroxy-2-methylbutyrate (rac-
l-9; 140 mg, 0.5 mmol) was dissolved in THF (5 mL) and cooled in
an ice bath. After SOCl2 (55 mL, 89 mg, 0.75 mmol) was added, the
mixture was allowed to come to r.t. overnight. After an additional 3
h stirring at 60 °C, the solution was cooled in an ice bath and the ex-
cess SOCl2 was quenched with sat. NaHCO3 (30 mL). The mixture
was extracted with EtOAc (3 × 20 mL) and the combined organic
phases were washed with H2O and brine, dried over Na2SO4 and
evaporated. The crude product was purified by column chromato-
graphy (cyclohexane–EtOAc, 9:1) to yield a colorless oil.
Yield: 46 mg (91%); 88% ee; [a]D20 +11.8 (c 0.75, H2O).
(S,R)-a-Methylthreonine [(S,R)-4]
Yield: 94 mg (72%).
(S,R)-4-Isopropoxycarbonyl-4,5-dimethyl-2-phenyl-1,3-oxazoline
[(S,R)-18; 127 mg, 0.49 mmol, 89% ee] was dissolved in HCl (6 M,
15 mL) and refluxed for 24 h. After cooling to r.t., the mixture was
washed with MTBE (2 × 10 mL) and the aqueous phase was evap-
orated to dryness. The resulting hydrochloride was converted into
free (S,R)-4 by ion-exchange resin (Dowex 50WX8; eluent: 1 M
ammonia). The spectroscopic properties are in accordance to those
given above for the racemic compound rac-u-4 and those reported
by Avenoza et al.4g Enantiomeric excess was examined by optical
rotation.
HPLC (Chiralcel OJ-H-column; hexanes–i-PrOH, 90:10; 1.0 mL/
min): tR = 8.9, 12.5 min.
IR (thin film): 2984, 1725, 1644 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.23 (d, J = 6.3 Hz, 6 H), 1.39 (s,
3 H), 1.40 (d, J = 6.7 Hz, 3 H), 4.95 (q, J = 6.7 Hz, 1 H), 5.03 (sept,
J = 6.3 Hz, 1 H), 7.32–7.36 (m, 2 H), 7.40–7.44 (m, 1 H), 7.92–7.93
(m, 2 H).
13C NMR (100 MHz, CDCl3): d = 15.2, 19.2, 21.4, 68.8, 75.4, 80.7,
127.6, 128.2, 128.4, 131.5, 163.7, 173.3.
Yield: 56 mg (87%); 89% ee; [a]D20 –11.9 (c 0.75, H2O).
MS (FAB): m/z = 262 [MH+], 220 [MH+ – i-Pr].
Acknowledgment
Anal. Calcd for C15H19NO3: C, 68.94; H, 7.33; N, 5.36. Found: C,
68.50; H, 7.38; N, 5.33.
F.R.D. gratefully thanks the Evonik Stiftung for a scholarship
award. The authors gratefully thank Prof. Dr. G. C. Fu and Dr. J. G.
Ruble for personal communications and Evonik-Degussa GmbH for
donation of chemicals.
Synthesis 2009, No. 24, 4208–4218 © Thieme Stuttgart · New York

4218
F. R. Dietz, H. Gröger
PAPER
(6) (a) For a review of planar chiral DMAP derivatives in
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subsequent ring-closure reaction according to literature
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Synthesis 2009, No. 24, 4208–4218 © Thieme Stuttgart · New York