Stereocontrolled α-alkylation of fully protected L-serine

Article abstract of DOI:10.1002/ejoc.200400207

Diastereoselective alkylation of the (2S,4S) and (2R,4S) diastereomers of 3-tert-butyl 4-methyl 2-tert-butyl-1,3-oxazolidine-3,4-dicarboxylate (1a/b) is reported. Formation of both diastereomers of these oxazolidines was achieved by changing the order of protection steps, and their relative and absolute configurations were determined by NOESY spectroscopy. The use of the bulky ring substituent tBu together with Boc as the N-protecting group led to the exclusive formation of only one alkylated diastereomer. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400207

FULL PAPER
Stereocontrolled α-Alkylation of Fully Protected -Serine
L
[a]
[b]
[a]
[b]
Martin Brunner, Pauli Saarenketo, Thomas Straub, Kari Rissanen, and
Ari M. P. Koskinen*[
a]
Keywords: Amino acids / Alkylation / Diastereoselectivity / Heterocycles / X-ray diffraction
Diastereoselective alkylation of the (2S,4S) and (2R,4S) di-
troscopy. The use of the bulky ring substituent tBu together
astereomers of 3-tert-butyl 4-methyl 2-tert-butyl-1,3-oxazoli- with Boc as the N-protecting group led to the exclusive for-
dine-3,4-dicarboxylate (1a/b) is reported. Formation of both
diastereomers of these oxazolidines was achieved by chan-
ging the order of protection steps, and their relative and
absolute configurations were determined by NOESY spec-
mation of only one alkylated diastereomer.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
Myriocin,[1] mycestericins,[2] and sphingofungins[3] are
sphingosine-related metabolites with strong antifungal and
immunosuppressive activity (Figure 1). In the course of our
[
4]
studies to obtain these derivatives of -serine stereoselec-
[
5]
tively, we became interested in α-substituted amino acids.
Stereoselective α-alkylation according to the principle of
self-regeneration of stereocentres (SRS)[ is a particularly
convenient methodology for our purposes. The necessary
transient stereocentre can be introduced by forming oxazol-
idines of type 1. Although such oxazolidines have been pre-
pared previously, we report herein a new series of alkylation
products where the variation of the ring substituent influ-
ences the preference for diastereoselection. In contrast to
recent literature reports, we have not only regenerated the
configuration at the defined stereocentre, but we have also
prepared the products of inversion.[
6,7]
Figure 1. Sphingosine-related metabolites
ing.[9] Among the two ring forms the amount of the cis
epimer was always higher than the trans epimer and, unlike
[
10]
for the thiazolidines,
no reaction condition could be
found to obtain predominantly the trans product.[ Both
diastereomers of the oxazolidines used in our alkylation
studies were prepared according to standard methods (1a)
or using a slightly modified literature procedure (1b).[
Compound 1a was isolated from a 3:1 mixture together
with 1b, while 1b was obtained in diastereomerically pure
9]
8]
11,12]
Results and Discussion
[8]
form in three steps (Scheme 1). In fact, 1a was a 9:1 mix-
ture of rotamers while 1b was observed in only one rotam-
Oxazolidines derived from serine esters are prone to ring-
chain tautomerism, and equilibrium studies of methyl and
ethyl esters with aromatic aldehydes in CDCl3 showed
three-component tautomeric mixtures where the open-
chain, Schiff-base intermediate was typically predominat-
[
13]
eric form.
We deduced the relative configurations of 1a/
b from NOESY experiments where correlation was ob-
served for the acetal proton at C2 with tBu at C2 and with
[
14]
[15]
Heq at C5 only in 1a.
An ORTEP-3
plot of 1a con-
firmed the trans configuration of the C2 and C4 ring sub-
stituents from the NOESY observations. The X-ray struc-
ture of 1a shows that bulky ester and tBu groups shield the
five-membered ring of the oxazolidine and that the large
ring substituent on C2 shields one face of the oxazolidine
[
a]
Laboratory of Organic Chemistry, Helsinki University of
Technology,
P. O. Box 6100, 02150 Espoo, Finland
Fax: ϩ358-9-451-2538
E-mail: ari.koskinen@hut.fi
[
b]
X-ray crystallography: Laboratory of Organic Chemistry, (Figure 2). The nitrogen atom of the oxazolidine ring is al-
University of Jyväskylä,
˚
most planar and is found to be 0.25(0.01) A above the plane
4
0351 Jyväskylä, Finland
[
16]
defined by carbon atoms C2, C4 and C6.
The observed
Fax: ϩ358-14-260-2672
E-mail: kari.rissanen@jyu.fi
planarity of the nitrogen is probably due to delocalized elec-
Eur. J. Org. Chem. 2004, 3879Ϫ3883
DOI: 10.1002/ejoc.200400207
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3879

M. Brunner, P. Saarenketo, T. Straub, K. Rissanen, A. M. P. Koskinen
The relative and, by inference, absolute configurations of
FULL PAPER
tron density of the conjugated p-orbitals of the carbamate
moiety. Adaptation of the ring conformation and orien- 3a/b were obtained from NOESY experiments and con-
tation of the C4-ester substituent for better overlap of the firmed by NMR data of 1a/b and the crystal structure of
p-orbitals is seen in the torsion angles C2ϪN3ϪC6ϪO7 1a. The correlation in the NOESY spectrum of 1b between
[
12.8(6)°] and C4ϪN3ϪC6ϪO8 [Ϫ22.3(5)°].
the methyl protons of the tBu and the acetal proton at C2
as well as the Heq at C5 is observed in 4b, too (Figure 3).
Therefore, the newly introduced substituent is necessarily
trans to the tBu ring substituent. We assigned compounds
5
to 7 in an analogous manner. Product pairs 3a/b to 7a/b
are enantiomers, as confirmed by their identical NMR spec-
tra and opposite signs of optical rotation. The yields and
selectivities of the reactions are shown in Table 1.
Scheme 1. Conditions: i) (Boc)
2
O, CH
2 2
Cl /MeOH, room temp.; ii)
pivalaldehyde, PPTS, toluene, reflux; iii) 2,2-dimethylpropanal,
pentane/TEA, reflux; iv) (Boc)
LDA, RX (see Table 1), THF, Ϫ78 °C
2
O, TEA/ THF, room temp.; v)
Figure 3. NOESY spectrum of 4b
Table 1. Diastereoselective alkylation of diastereomers 1a and 1b
Entry
1
RX
Product
Yield[a]
dr[b]
1
2
3
4
5
6
7
8
9
a
a
a
a
a
b
b
b
b
b
D
MeI
Allyl bromide
BnBr
BrCH
2
O
3a
4a
5a
6a
7a
3b
4b
5b
6b
7b
n.d.
87
30 (67)
11
20
(64)
92
45 (79)
(25)
(67)
mixture
99:1
99:1
one isomer
one isomer
99:1
99:1
99:1
99:1
99:1
Figure 2. ORTEP-3 plot of 1a
Subsequent alkylation reactions of the ester enolates of
1
a and 1b were performed under standard conditions
[
8]
2
CO
2
Me
(Scheme 1). Addition of 110 mol % of LDA was sufficient
D
2
O
to deprotonate 1b but not 1a, where H4 is sterically more
hindered. However, the alkylation yields were only modest.
Increasing the amount of base to 200 mol % led to im-
proved yields for all alkylated products 3Ϫ7. In each case
only one diastereomer was obtained as the sole alkylation
MeI
Allyl bromide
BnBr
1
0
BrCH
2
CO
2
Me
[a]
[b]
Yields after chromatography; crude yields in parentheses. Dia-
1
product ( H NMR spectroscopy and HPLC). However, the
1
stereomeric ratio (dr) determined by H NMR spectroscopy.
alkylation products of the a series gave systematically lower
yields, indicating a more hindered electrophilic attack to the
enolate of 1a, which was also observed upon deuteration of
the enolates of 1a/b. We also observed different side prod- Conclusion
ucts. While 3b was accompanied only by starting material,
an additional product from protonation with inversion of
In summary, formation of both diastereomers of 3-tert-
configuration was observed for 3a. The yields for alky- butyl 4-methyl 2-tert-butyl-1,3-oxazolidine-3,4-dicarboxyl-
lations with more hindered electrophiles decreased rapidly, ate (1a/b) was achieved by two different routes where the
and benzylation (products 6a/b) was accompanied by sig- reversal of the order of protection steps is the directive tool.
[17]
nificant amounts of 1-bromo-1,2-diphenylethane. In con- The stereoelectronic properties cause the ring nitrogen atom
trast to literature reports,[ the use of DMPU as a cosol- in 1a to be nearly planar, as shown by an X-ray structure.
8a]
[18]
vent did not improve the situation.
The observed structural and conformational properties of
3880
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org Eur. J. Org. Chem. 2004, 3879Ϫ3883

Stereocontrolled α-Alkylation of Fully Protected L-Serine
FULL PAPER
1
a/b were utilized to achieve diastereoselective alkylation re- and (Boc)
2
O (17.4 mL, 75.0 mmol, 200 mol %) was added dropwise
while the formed CO
tion mixture was allowed to warm to room temp. overnight, and
then poured onto a mixture of ice (ca. 10 g) and saturated NaHCO
solution (50 mL). Et O (50 mL) was added and the organic layer
was washed with saturated NaHCO solution (4 ϫ 20 mL) and
dried over Mg SO . Evaporation of the solvent and drying in vacuo
gave the crude product. The excess of (Boc) O was distilled to give
2
was passed through a silicon trap. The reac-
actions with high drs and good yields. Further examples of
the SRS principle and practical applications in the synthesis
of natural compounds will be reported in due course.
3
2
3
2
4
Experimental Section
2
2
0
1
b (9.7 g, 90 mol %) as the only product. [α]
D
ϭ Ϫ30 (c ϭ 0.3,
ϭ 0.19 (hexane/EtOAc, 4:1). H NMR: δ ϭ 5.00 (s, 1
General Remarks: All reactions with moisture-sensitive compounds
were conducted in flame-dried glassware under an atmosphere of
1
MeOH). R
f
H), 4.67 (br. m, 1 H), 4.24 (dd, J ϭ 5.6, 8.6 Hz, 1 H), 4.11 (t, J ϭ
8
NMR: δ ϭ 170.9, 155.1, 97.6, 81.3, 68.3, 59.7, 52.2, 37.7, 28.2, 25.8
5
ppm. HRMS (C14H26NO ): calcd. 288.1810 [M ]; found 288.1823.
argon. Solvents were dried by distillation from LiAlH
from Na (toluene) or used as purchased (pentane, CH
4
(THF) or
Cl ). n-Bu-
13
.6 Hz, 1 H), 3.73 (s, 3 H), 1.45 (s, 9 H), 0.91 (s, 9 H) ppm.
C
2
2
tyllithium solution in hexanes (2.5 ) was purchased from Aldrich
in Sure-Seal containers. Starting materials that were commercially
ϩ
available were used without purification. Allyl bromide, benzyl bro- General Procedure for Alkylation: A 50 mL flask was placed under
mide and methyl bromoacetate were passed through a short col-
umn of basic Al prior to use. Melting points are uncorrected
and were determined with recrystallized samples. NMR spectra
were recorded from CDCl solutions at room temp. with an instru-
ment operating at 400 MHz/100 MHz ( H/ C). Analytical thin-
layer chromatography (TLC) was performed on SiO
Ar and charged with THF (35 mL) and diisopropylamine (DIPA)
with a syringe. The solution was cooled to Ϫ78 °C (isopropanol/
dry ice) and nBuLi was added dropwise. The colorless reaction mix-
ture was stirred at 0 °C for 15 min, then cooled to Ϫ78 °C and 1
in THF (5 mL) was slowly added to the solution. After stirring for
2
O
3
3
1
13
60 F254 plates 45 min at Ϫ78 °C, the electrophile was added. The reaction mixture
2
and visualization was accomplished with a 254 nm UV light or by
staining with ninhydrin (0.3 g ninhydrin, 100 mL 1-butanol) or
was allowed to warm up to room temp. overnight and then poured
into a mixture of a semisaturated solution of NH Cl (30 mL) and
Et O (80 mL). The organic layer was separated, washed with dis-
tilled water (4 ϫ 50 mL) and dried over Mg SO . Evaporating the
formed using the indicated solvent system on Merck silica gel 60 solvent and drying in vacuo gave the crude product, which was
4
acidic PMA (1.0 g phosphomolybdic acid hydrate, 5% H
2
SO
4
, 100
2
mL EtOH) followed by heating. Flash chromatography was per-
2
4
(particle size 0.040Ϫ0.063 mm; 230Ϫ400 mesh ASTM). Low- and
purified by flash chromatography (FC) using mixtures of hexane/
high-resolution mass spectra were obtained with a JEOL-DX303
mass spectrometer with a direct inlet probe in EI mode at 50 V.
Elemental analysis was performed with a PerkinϪElmer Elemental
Analyser 2400CHN. Optical rotations were measured with a
PerkinϪElmer Polarimeter 343.
EtOAc, or hexane/acetone as eluent.
(
2R,4R)-3-tert-Butyl 4-Methyl 2-tert-Butyl-4-deuterio-1,3-oxazolid-
ine-3,4-dicarboxylate (3a): DIPA (0.11 mL, 0.8 mmol, 210 mol %),
nBuLi (1.96  in n-hexanes, 0.39 mL, 0.8 mmol, 210 mol %), 1a
(
2
110.0 mg, 0.38 mmol, 100 mol %), D O (0.02 mL, 1.1 mmol, 290
(2R,4S)-3-tert-Butyl 4-Methyl 2-tert-Butyl-1,3-oxazolidine-3,4-di-
mol %). FC (hexane/EtOAc, 8:1) gave an inseparable mixture of
carboxylate (1a): A 100 mL flask was charged with N-(1,1-di-
3a, 1a and -serine derivative ent-1b.
methylethoxycarbonyl)--serine methyl ester[ (1.1 g, 5.0 mmol,
19]
(
2S,4S)-3-tert-Butyl 4-Methyl 2-tert-Butyl-4-deuterio-1,3-oxazolid-
1
2
00 mol %), toluene (20 mL), PPTS (63 mg, 0.25 mmol, 5 mol %),
,2-dimethylpropanal (2.2 mL, 20.0 mmol, 400 mol %) and tri-
ine-3,4-dicarboxylate (3b): DIPA (0.13 mL, 0.9 mmol, 190 mol %),
nBuLi (2.10  in n-hexanes, 0.44 mL, 0.9 mmol, 190 mol %), 1b
methyl orthoformate (0.83 mL, 8.0 mmol, 150 mol %). The reac-
tion mixture was stirred for 4 d at 90 °C. After cooling to room
(
2
133.8 mg, 0.47 mmol, 100 mol %), D O (0.02 mL, 1.1 mmol, 235
mol %). FC (hexane/EtOAc, 8:1) gave pure 3b (35.3 mg, 26%) as a
brown oil accompanied by a side product identified as the product
temp. and subsequent extraction with a solution of 10% NaHCO
2 ϫ 20 mL) and then brine (20 mL), the organic layer was dried
over Mg SO . Evaporating the solvent and drying in vacuo gave
3
(
2
0
of β-elimination. [α]
D 3 f
ϭ Ϫ29 (c ϭ 1, CHCl ). R ϭ 0.20 (hexane/
2
4
1
EtOAc, 8:1). H NMR: δ ϭ 5.03 (s, 1 H), 4.26 (d, J ϭ 8.6 Hz, 1
H), 4.13 (d, J ϭ 8.6 Hz, 1 H), 3.75 (s, 3 H), 1.47 (s, 9 H), 0.92 (s,
H) ppm. C NMR: δ 171.4, 155.5, 98.0, 81.7, 68.7, 60.1, 52.7,
the crude product, which contained a 3:1 mixture of diastereomers.
Separation by flash chromatography (hexane/EtOAc, 4:1) gave 1a
1
3
9
3
0
(
0.85 g, 60%). [α]2
D
ϭ Ϫ57 (c ϭ 0.5, MeOH). R
f
ϭ 0.17 (hexane/
8.2, 28.6, 26.2 ppm.
1
EtOAc, 4:1). m.p. 64Ϫ65 °C (Hex). H NMR (major rotamer): δ ϭ
5
3
.17 (br. s, 1 H), 4.33 (m, 2 H), 4.00 (d, J ϭ 7.2 Hz, 1 H), 3.73 (s, (2R,4R)-3-tert-Butyl 4-Methyl 2-tert-Butyl-4-methyl-1,3-oxazolid-
13
H), 1.43 (br. s, 9 H), 0.93 (s, 9 H) ppm. C NMR (major rot-
ine-3,4-dicarboxylate (4a): DIPA (0.06 mL, 0.4 mmol, 115 mol %),
amer): δ ϭ 172.0, 154.0, 96.8, 81.0, 70.4, 60.5, 52.3, 39.0, 28.1, 26.0 nBuLi (2.08  in n-hexanes, 0.20 mL, 0.41 mmol, 115 mol %), 1a
ϩ
ppm. MS (EI): m/z (%) ϭ 288 [M ], 272, 232, 214, 200, 188, 174,
72, 160, 146 (100), 130, 128, 112, 102, 86, 70, 57. C14
calcd. C 58.46, H 8.77, N 4.88; found C 58.04, H 8.72, N 4.66.
(100.4 mg, 0.35 mmol, 100 mol %), methyl iodide (0.07 mL,
1
H25NO
5
:
1.1 mmol, 315 mol %). FC (hexane/EtOAc, 8:1) gave pure 4a
2
0
1
(25.5 mg, 25%) as a brown oil. [α]D ϭ ϩ4 (c ϭ 0.4, CHCl ). H
3
NMR: δ ϭ 5.09 (s, 1 H), 4.25 (d, J ϭ 8.0 Hz, 1 H), 3.80 (d, J ϭ
(
2S,4S)-3-tert-Butyl 4-Methyl 2-tert-Butyl-1,3-oxazolidine-3,4-di-
carboxylate (1b): NEt (5.75 mL, 41.3 mmol, 110 mol) was added
to a suspension of 2 (5.83 g, 37.5 mmol, 100 mol %) and pentane
50 mL). The reaction mixture was boiled at reflux until no further
water was collected in a DeanϪStark trap. The Et N·HCl salt was
filtered, washed with Et O (3 ϫ 30 mL) and the organic layer dried
over Mg SO . Evaporating the solvent and drying in vacuo gave a
8
.0 Hz, 1 H), 3.75 (s, 3 H), 1.62 (s, 3 H), 1.43 (s, 9 H), 1.00 (s, 9
3
1
3
H) ppm. C NMR: δ ϭ 172.9, 154.1, 97.4, 81.2, 77.5, 66.8, 52.8,
3
2
ϩ
9.6, 28.5, 26.9, 21.7 ppm. MS (EI): m/z (%) ϭ 302 [M ϩ H ],
(
96, 228, 214, 202, 186, 160 (100), 114, 100, 84, 69, 58. HRMS
3
ϩ
15 5
(C H28NO ): calcd. 302.1967 [M ϩ H ]; found 302.1977.
2
2
4
(2S,4S)-3-tert-Butyl 4-Methyl 2-tert-Butyl-4-methyl-1,3-oxazolid-
ine-3,4-dicarboxylate (4b): DIPA (0.11 mL, 0.8 mmol, 215 mol %),
nBuLi (2.1  in n-hexane; 0.37 mL, 0.78 mmol, 210 mol %), 1b
(110.0 mg, 0.37 mmol, 100 mol %), methyl iodide (0.06 mL,
coloured oil (8.87 g) containing a 1:1 mixture of epimers. A 100
mL flask was charged with the epimer mixture (7.0 g, 37.5 mmol,
1
00 mol %) and THF (20 mL). The solution was cooled to 0 °C
Eur. J. Org. Chem. 2004, 3879Ϫ3883
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3881

M. Brunner, P. Saarenketo, T. Straub, K. Rissanen, A. M. P. Koskinen
.0 mmol, 270 mol %). Pure 4b (103.0 mg, 92%) was obtained as a 81.3, 74.1, 67.5, 52.7, 51.9, 39.1, 37.7, 36.9, 28.1, 26.6 ppm. MS
FULL PAPER
1
20
ϩ
brown oil. [α]
EtOAc, 1:1).
D
ϭ Ϫ5 (c ϭ 0.4, CHCl
3
). R
f
ϭ 0.58 (hexane/ (EI): m/z (%) ϭ 360 [M ϩ H ], 302, 286, 272, 260, 246, 202, 186,
7
170, 157, 142 (100), 110, 82, 69, 57. HRMS (C17H28NO ): calcd.
ϩ
3
58.1865 [M Ϫ H ]; found 358.1793.
(
2R,4R)-3-tert-Butyl 4-Methyl 4-Allyl-2-tert-butyl-1,3-oxazolidine-
3,4-dicarboxylate (5a): DIPA (0.10 mL, 0.7 mmol, 200 mol %), X-ray Crystallographic Study of 1a: The data were recorded on a
nBuLi (2.03  in n-hexane, 0.35 mL, 0.71 mmol, 200 mol %), 1a
100.7 mg, 0.35 mmol, 100 mol %), allyl bromide (0.08 mL,
.0 mmol, 290 mol %). FC (hexane/EtOAc, 18:1) gave pure 5a using Denzo-SMN. The structure was solved by direct methods
Nonius Kappa CCD diffractometer using graphite-monochrom-
˚
ated Mo-Kα radiation (λ ϭ 0.71073 A). The data were processed
(
1
[20]
2
0
[21]
2
(33.8 mg, 30%) as a brown oil. [α]
D
ϭ Ϫ15 (c ϭ 1.0, CHCl
.10 (hexane/EtOAc, 9:1). H NMR: δ ϭ 5.86 (m, 1 H), 5.20 (m, 2 techniques (SHELXL-97). The hydrogen atoms were calculated
at their ideal positions and refined as riding atoms with isotropic
.6 Hz, 1 H), 3.78 (s, 3 H), 3.16 (br. s, 1 H), 2.74 (dd, J ϭ 6.0 Hz, temperature factors 1.2 (CH and CH ) or 1.5 (CH ) times the cor-
3
). R
f
ϭ
(SHELXS-97)
and refined on F by full-matrix least-squares
1
[22]
0
H), 5.09 (s, 1 H), 4.26 (dd, J ϭ 8.6, 1.6 Hz, 1 H), 4.09 (d, J ϭ
8
1
1
2
3
H), 1.47 (s, 9 H), 1.01 (s, 9 H) ppm. 13C NMR: δ ϭ 172.6, 153.5,
32.4, 120.0, 98.4, 81.3, 75.7, 69.0, 52.8, 39.9, 31.3, 28.6, 26.9 ppm. of 1a was not defined, as shown by the meaningless value of Flack’s
responding carbon temperature factor. The absolute configuration
ϩ
MS (EI): m/z (%) ϭ 328 [M ϩ H ], 300, 285, 270, 254, 242, 228, x parameter [0.1(2.5)]. An absorption correction was not applied.
12, 198, 186, 171 (100), 130, 110, 82, 69, 57. HRMS (C17 ):
Crystal data: C H NO , M ϭ 287.35, orthorhombic, space
2
H30NO
5
1
4
25
5
r
ϩ
˚
calcd. 328.2133 [M ϩ H ]; found 328.2096.
group P2 2 2 , a ϭ 5.9326(2), b ϭ 10.1145(7), c ϭ 26.3519(17) A,
1 1 1
˚
3
V ϭ 1581.25(16) A , Z ϭ 4, T ϭ 173(2) K, F(000) ϭ 624, µ ϭ
(
2S,4S)-3-tert-Butyl 4-Methyl 4-Allyl-2-tert-butyl-1,3-oxazolidine-
Ϫ1
3
0
1
3
.091 mm . Data collection: crystal size 0.38 ϫ 0.13 ϫ 0.13 mm ,
73(2) K, index ranges Ϫ7 Յ h Յ 7, Ϫ13 Յ k Յ 10, Ϫ34 Յ l Յ
4, Θ range 3.07Ϫ27.51°, 10166 measured reflections, 3627 unique
3
,4-dicarboxylate (5b): DIPA (0.11 mL, 0.8 mmol, 210 mol %),
nBuLi (2.10  in n-hexane, 0.37 mL, 0.78 mmol, 205 mol %), 1b
110.3 mg, 0.38 mmol, 100 mol %), allyl bromide (0.08 mL,
.0 mmol, 265 mol %). FC (hexane/EtOAc, 18:1) gave pure 5b
(
1
2
2
(
R
int ϭ 0.1295), R(F ) ϭ 0.0974, wR(F ) ϭ 0.2099 for 2167 ob-
served reflections [F Ͼ 4σ(F )].
o
o
2
0
(
0
D 3 f
55.9 mg, 45%) as a brown oil. [α] ϭ ϩ12 (c ϭ 1, CHCl ). R ϭ
CCDC-230045 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge CB2
.58 (hexane/EtOAc, 4:1).
(
2R,4R)-3-tert-Butyl 4-Methyl 4-Benzyl-2-tert-butyl-1,3-oxazolid-
ine-3,4-dicarboxylate (6a): DIPA (0.08 mL, 0.6 mmol, 210 mol %),
nBuLi (2.10  in n-hexane, 0.29 mL, 0.58 mmol, 200 mol %), 1a
1EZ, UK; Fax: ϩ44-1223-336033; E-mail: deposit@ccdc.cam.a-
c.uk.
(
0
80.0 mg, 0.28 mmol, 100 mol %), benzyl bromide (0.09 mL,
.8 mmol, 290 mol %). Crude product: 180 mg, containing an in-
separable mixture of 6a (11%) and 1-bromo-1,2-diphenylethane
(
89%).
Acknowledgments
This research was financially supported by the Ministry of Edu-
cation of Finland (Graduate School of Bioorganic Chemistry Pro-
gram) and the National Technology Agency (TEKES, Finland).
(
2S,4S)-3-tert-Butyl 4-Methyl 4-Benzyl-2-tert-butyl-1,3-oxazolidine-
3
,4-dicarboxylate (6b): DIPA (0.15 mL, 1.1 mmol, 220 mol %),
nBuLi (2.10  in n-hexane, 0.50 mL, 1.05 mmol, 210 mol %), 1b
149.9 mg, 0.51 mmol, 100 mol %), benzyl bromide (0.15 mL,
(
1
2
[
1] [1a]
.3 mmol, 250 mol %). FC (hexane/EtOAc, 18:1) gave 6b (48.0 mg,
D. Kluepfel, J. Bagli, H. Baker, M.-P. Charest, A. Kudelski,
2
0
[1b]
5%) as a brown oil. [α]
D
ϭ ϩ73 (c ϭ 1, CHCl
3
). R
f
ϭ 0.51 (hex-
S. N. Sehgal, C. V e´ zina, J. Antibiot. 1972, 25, 109Ϫ115.
F.
1
ane/EtOAc, 1:1). H NMR (major rotamer): δ ϭ 7.32Ϫ7.27 (m, 4
H), 7.23 (m, 2 H), 4.65 (s, 1 H), 4.18 (dd, J ϭ 8.8, 0.8 Hz, 2 H),
3
H), 1.01 (s, 9 H) ppm. C NMR (major rotamer): δ ϭ 172.7, 153.5,
1
2
Aragozzini, P. L. Manachini, R. Craveri, B. Rindone, C. Scola-
stico, Tetrahedron 1972, 28, 5493Ϫ5498. [ T. Fujita, K. Inoue,
S. Yamamoto, T. Ikumoto, S. Sasaki, R. Toyama, K. Chiba, Y.
Hoshino, T. Okumoto, J. Antibiot. 1994, 47, 208Ϫ215.
1c]
.83 (s, 3 H), 3.69 (m, 1 H), 3.39 (d, J ϭ 14.2 Hz, 1 H), 1.55 (s, 9
13
[2] [2a]
S. Sasaki, R. Hashimoto, M. Kiuchi, K. Inoue, T. Ikumoto,
36.4, 130.7, 128.7, 127.3, 98.0, 81.5, 74.2, 70.0, 52.9, 39.9, 28.7,
R. Hirose, K. Chiba, Y. Hoshino, T. Okumoto, T. Fujita, J.
ϩ
7.0, 25.3 ppm. HRMS (C21
H32NO
5
): calcd. 378.2280 [M ϩ H ];
[2b]
Antibiot. 1994, 47, 420Ϫ433.
T. Fujita, N. Hamamichi, M.
found 328.2273.
Kiuchi, T. Matsuzaki, Y. Kitao, K. Inoue, R. Hirose, M.
Yoneta, S. Sasaki, K. Chiba, J. Antibiot. 1996, 49, 846Ϫ853.
(
2R,4R)-3-tert-Butyl 4-Methyl 4-Methoxycarbonyl-2-tert-butyl-1,3-
[3] [3a]
F. VanMiddlesworth, R. A. Giacobbe, M. Lopez, G. Garr-
oxazolidine-3,4-dicarboxylate (7a): DIPA (0.04 mL, 0.5 mmol, 200
mol %), nBuLi (2.03  in n-hexane, 0.23 mL, 0.5 mmol, 200
mol %), 1a (75.8 mg, 0.26 mmol, 100 mol %), methyl bromoacetate
ity, J. A. Bland, K. Bartizal, R. A. Fromtling, J. Polishook, M.
Zweerink, A. M. Edison, W. Rozdilsky, K. E. Wilson, R. L.
Monaghan, J. Antibiot. 1992, 45, 861Ϫ867. [ W. S. Horn, J.
L. Smith, G. F. Bills, S. L. Raghoobar, G. L. Helms, M. B.
Kurtz, J. A. Marrinan, B. R. Frommer, R. A. Thornton, S. M.
Mandala, J. Antibiot. 1992, 45, 1692Ϫ1696.
3b]
(0.06 mL, 0.7 mmol, 270 mol %). FC (hexane/acetone, 18:1) gave a
3
:1 mixture of 1a and 7a. R ϭ 0.12 (hexane/EtOAc, 8:1).
f
[
[
4]
5]
(2S,4S)-3-tert-Butyl 4-Methyl 4-Methoxycarbonyl-2-tert-butyl-1,3-
M. Brunner, T. Straub, P. Saarenketo, K. Rissanen, A. M. P.
oxazolidine-3,4-dicarboxylate (7b): DIPA (0.10 mL, 0.7 mmol, 190
mol %), nBuLi (2.03  in n-hexane, 0.35 mL, 0.71 mmol, 190
mol %), 1b (107.5 mg, 0.37 mmol, 100 mol %), methyl bromoacet-
ate (0.09 mL, 1.0 mmol, 270 mol %). FC (hexane/acetone, 18:1)
Koskinen, Lett. Org. Chem. 2004, 1, 266Ϫ268.
[5a]
For recent reviews, see:
C. Cativiela, M. D. D ´ı az-de-Vil-
[5b]
legas, Tetrahedron: Asymmetry 1998, 9, 3517Ϫ3599.
viela, M. D. D ´ı az-de-Villegas, Tetrahedron: Asymmetry 2000,
C. Cati-
11, 645Ϫ732.
2
0
gave 7b (89.4 mg, 67% yield). [α]
D
ϭ ϩ51 (c ϭ 1, CHCl
.22 (hexane/EtOAc, 9:1). H NMR: δ ϭ 4.98 (s, 1 H), 4.41 (br. d,
J ϭ 8.6 Hz, 1 H), 4.27 (d, J ϭ 8.6 Hz, 1 H), 3.77 (s, 3 H), 3.68 (s,
H), 3.20Ϫ3.00 (br. s, 1 H), 2.97 (d, J ϭ 14.1 Hz, 1 H), 1.46 (s, 9
3
). R
f
ϭ
[6]
D. Seebach, A. R. Sting, M. Hoffmann, Angew. Chem. Int. Ed.
Engl. 1996, 35, 2708Ϫ2748; Angew. Chem. 1996, 108,
1
0
2880Ϫ2921.
[7]
1
For a corresponding principle, see: K. Fuji, T. Kawabata,
Chem. Eur. J. 1998, 4, 373Ϫ376.
13
H), 1.01 (s, 9 H) ppm. C NMR: δ ϭ 170.9, 170.7, 153.1, 97.4,
3882
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3879Ϫ3883

Stereocontrolled α-Alkylation of Fully Protected L-Serine
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[20]
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[
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Received March 29, 2004
Eur. J. Org. Chem. 2004, 3879Ϫ3883
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3883