Efficient enantioselective synthesis of (2R,3R)- and (2S,3S)-3-hydroxyleucines and their diastereomers through dynamic kinetic resolution

Article abstract of DOI:10.1016/S0957-4166(01)00306-8

(2R,3R)- and (2S,3S)-3-Hydroxyleucines, components of cyclodepsipeptides, papuamides and polyoxypeptins, were efficiently synthesized along with their diastereomers from the corresponding β-keto-α-amino acid ester through dynamic kinetic resolution using RuCl₂(binap)-catalyzed hydrogenation.

Full text of DOI:10.1016/S0957-4166(01)00306-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1757–1762
Efficient enantioselective synthesis of (2R,3R)- and
(2S,3S)-3-hydroxyleucines and their diastereomers through
dynamic kinetic resolution
Kazuishi Makino, Naoki Okamoto, Osamu Hara and Yasumasa Hamada*
Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received 4 June 2001; accepted 29 June 2001
Abstract—(2R,3R)- and (2S,3S)-3-Hydroxyleucines, components of cyclodepsipeptides, papuamides and polyoxypeptins, were
efficiently synthesized along with their diastereomers from the corresponding b-keto-a-amino acid ester through dynamic kinetic
resolution using RuCl2(binap)-catalyzed hydrogenation. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
(Fig. 1). The (2R,3S)-diastereomer has also been used
as a building block in the synthesis of lactacystin, a
neurotrophic agent.3e
Naturally occurring (2R,3R)- and (2S,3S)-3-hydroxy-
leucines are found as components of the ester tether
linkage in cyclodepsipeptides, such as papuamides1 of
marine origin and polyoxypeptins2 of microbial origin
Several groups have already reported enantioselective
approaches to these important 3-hydroxyleucines,3,4
OH
O
OH
H
N
OH
O
N
H
HO
O
OH
O
H
HN
O
O
H
N
NH HN
N
H
O
O
HN
HN
H
N
H
NH2
N
HO
O
O
O
O
O
O
OH
O
O
N
H
OMe
N
HN
N
H
NH
NH
O
O
O
MeO
O
O
NH
OH
O
OH
H
OH
N
N
Polyoxypeptin A 2
Papuamide A 1
Me
O
OH
NH2
NH2
OH
OH
OH
O
OH
O
(2R,3R)-3
(2S,3S)-3
Figure 1.
* Corresponding author. Fax: +81-43-290-2987; e-mail: hamada@p.chiba-u.ac.jp
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00306-8

1758
K. Makino et al. / Tetrahedron: Asymmetry 12 (2001) 1757–1762
including Sharpless asymmetric epoxidation,3a,e,4a enan-
tioselective aldol condensation,3b,i diastereoselective
aldol condensation,3c,h Sharpless asymmetric dihydrox-
ylation,3d,4c alkylation of the serinal derivatives,3f,g alkyl-
ation of chiral 2-hydroxyisobutyraldehyde,3j Sharpless
asymmetric aminohydroxylation4b and asymmetric
Strecker methods.4d Some of these methods are
stereoselective but require careful handling and prob-
lems with the use of some large-scale processes remain
to be solved. In connection with our efforts to synthe-
size papuamides, cyclodepsipeptides with anti-HIV and
cytotoxic activities, and polyoxypeptins, cyclodepsipep-
tides with apoptosis-inducing activity, we needed
(2R,3R)- and (2S,3S)-3-hydroxyleucines in large quan-
tities. Herein, we report a simple and efficient method
for the preparation of (2R,3R)- and (2S,3S)-3-hydroxy-
leucines and their diastereomers from the correspond-
ing b-keto-a-amino acid ester through dynamic kinetic
resolution using RuCl2(binap)-catalyzed hydrogenation.
phorazidate and potassium carbonate sesquihydrate
with similar efficiency.7 Acid-catalyzed cleavage of 4
with p-toluenesulfonic acid (TsOH) proceeded cleanly
under reflux in methanol and gave the b-keto-a-amino
acid ester 5 in quantitative yield. First, we attempted
the formation and stereoselective hydrogenation of the
oxazolone 6, which directly produces the desired stereo-
chemistry of the 3-hydroxyleucine. Reaction of 5 with
triphosgene in the presence of triethylamine in THF at
−50°C gave the oxazolone 6 in 87% yield. Unfortu-
nately, the stereoselective hydrogenation of 6 using
several catalysts, such as Rh-BINAP and Rh-DIOP,
was sluggish and failed to afford the erythro-3-hydroxy-
leucine derivative in productive yield.
Next, we focussed on the stereoselective reduction of
the b-keto-a-amino acid ester 5. Protection of 5 using
benzoyl chloride and triethylamine in tetrahydrofuran
(THF) at the nitrogen function provided the 2-benzoyl-
amino-3-oxopentanoate 7 in 99% yield. Alternatively,
the N-tert-butoxycarbonyl derivative of 7 was obtained
by NꢀC acyl migration reaction developed by us.8 The
double acylated substrate 9 for the migration was pre-
pared by acylation of methyl glycinate hydrochloride
with isovaleryl chloride and subsequent N-tert-butoxy-
carbonylation with di-tert-butyl dicarbonate in the
presence of N,N-dimethylaminopyridine (DMAP) in
acetonitrile in 69% yield. NꢀC Acyl migration of 9 was
carried out by treatment with lithium hexamethyldisi-
lazide (2.5 equiv.) in the presence of N,N-dimethyl-
propyleneurea (DMPU) in THF at −78°C to afford the
b-keto-a-amino acid ester 10 in 96% yield. Interestingly,
the tert-butoxycarbonyl group in the double acylated
substrate 9 was observed to serve as a non-transfer
group.
2. Results and discussion
The key features of our synthesis are (1) the prepara-
tion of the b-keto-a-amino acid esters from the 4-
methoxycarbonyloxazole or by novel acyl migration of
the N,N-diacylglycine ester (Scheme 1) and (2) stereose-
lective reduction of the b-keto-a-amino acid ester using
the RuCl2(binap)-catalyzed hydrogenation methodol-
ogy developed by Noyori,5 as illustrated in Scheme 2.
Treatment of isovaleric anhydride with methyl iso-
cyanoacetate in the presence of diazabicyclo-
[4.3.0]undecene (DBU) afforded the oxazole 46 in
80% yield, which was also obtained from isovaleric acid
and methyl isocyanoacetate by use of diphenyl phos-
NH2•HOTs
CO2Me
TsOH
CO2Me
O
DBU
OMe
+
NC
MeOH
reflux
overnight
N
O
O
80%
O
O
O
O
5
4
NHCOPh
OMe
PhCOCl
triphosgene
Et3N, THF
-50°C
CO2Me
NH
Et3N, THF
O
O
99% (2 steps)
7
87%
O
6
Cl
O
O
H
Boc
N
Boc2O
N
O
OMe
OMe
HCl•NH2CH2CO2Me
LHMDS (2.5 eq)
DMAP
CH3CN
O
O
9
8
69% in two steps
NHBoc
OMe
O
O
DMPU (2 eq), THF
96%
10
Scheme 1.

K. Makino et al. / Tetrahedron: Asymmetry 12 (2001) 1757–1762
1759
NHCOPh
H2 (100 atm)
NHCOPh
OMe
RuCl2[(S)-binap](dmf)n
OMe
O
O
CH2Cl2, 50°C, 48 h
OH
O
100% single diastereomer
99% e.e.
(-)-11
7
6 N HCl
reflux, 50 h
85%
SOCl2
THF, 0° to 60°C, 86%
Ph
N
NH2
NH2
6 N HCl
O
OMe
OH
OH
reflux, 24 h
85%
O
OH
O
OH
O
(2R,3S)-12
(-)-13
(2R,3R)-3
58% overall yield
in 6 steps
67% overall yield
in 5 steps
H2 (100 atm)
RuCl2[(R)-binap](dmf)n
(+)-11
95% (98% e.e.)
7
CH2Cl2, 50°C, 48 h
SOCl2
6 N HCl
reflux 46 h
THF, 0 °C to 60 °C
68%
84 %
NH2
NH2
OH
6 N HCl
(+)-13
OH
reflux 24 h
87%
OH
O
OH
O
(2S,3S)-3
45% overall yield
in 6 steps
(2S,3R)-12
63% overall yield
in 5 steps
Scheme 2.
diastereoisomer (−)-12 were also synthesized with
similar efficiency by use of an analogous procedure.
The key hydrogenation of 7 using RuCl2((S)-binap) in
methylene chloride was found to be sluggish and
required higher temperature (Scheme 2). Finally, the
reaction at 50°C for 48 h gave the (2R,3S)-3-hydroxy-
leucine derivative (−)-11 in 100% yield. The enan-
tiomeric excess (e.e.) of 11 was shown to be 99% by
HPLC analysis using a chiral column. The absolute
stereostructure of 11 was unambiguously determined
after conversion to the corresponding 3-hydroxyleucine.
Thus, (−)-11 was hydrolyzed with 6N aqueous hydro-
chloric acid under reflux for 50 h to give (2R,3S)-3-
hydroxyleucine (+)-12, which was confirmed by
comparison with the values reported by others.3e Inver-
sion of the C(3) stereochemistry of (−)-11 was effected
by treatment with thionyl chloride in THF at 0°C and
then heating to 60°C to furnish the oxazoline (−)-13
with the stereochemistry (2R,3R)-3-hydroxyleucine in
86% yield. The thus obtained (−)-13 was hydrolyzed
with 6N aqueous hydrochloric acid under reflux to
afford (2R,3R)-3-hydroxyleucine ((−)-3) in 85% yield
which was identical with that reported.3e The overall
yields of (−)-3 and (+)-12 are 58% and 67%, respec-
tively. (2S,3S)-3-Hydroxyleucine (+)-3 and the (2S,3R)-
3. Conclusion
We have succeeded in the efficient synthesis of (2R,3R)-
and (2S,3S)-3-hydroxyleucines applicable to large-scale
production in six steps with high overall yields. Using
the same procedure, the (2R,3S)- and (2S,3R)-3-
hydroxyleucines, are also available with high overall
yields in five steps.
4. Experimental
Melting points are uncorrected. IR spectra were recorded
on a JASCO FT/IR-230 spectrometer. NMR spectra
were recorded on JEOL JNM GSX400A, JNM
GSX500A, and JNM ECP400 spectrometers. FAB mass
spectra were obtained with a JEOL JMS-HX-110A
spectrometer. Optical rotations were determined on a
JASCO DIP-140 polarimeter. Column chromatography
was carried out with silica gel BW-820MH (Fuji silysia).

1760
K. Makino et al. / Tetrahedron: Asymmetry 12 (2001) 1757–1762
4.1. 4-Methoxycarbonyl-5-(1-methylethyl)-1,3-oxazole 4
4.4. Methyl N-tert-butoxycarbonyl-N-isobutyrylglyci-
nate 9
Prepared according to the literature procedure.6
To a mechanically stirred suspension of methyl glyci-
nate hydrochloride (10.11 g, 80.5 mmol) in ether (32
mL) at 0°C was added saturated aqueous potassium
carbonate (64 mL) and isovaleroyl chloride (17 mL, 161
mmol), and the mixture was stirred at 0°C for 3 h. The
reaction mixture was extracted three times with ether
(150 mL) and the organic layer was washed with satu-
rated aqueous sodium hydrogen carbonate, water, and
saturated brine. The aqueous phase was saturated with
sodium chloride and extracted with ethyl acetate (150
mL). The combined extracts were dried over sodium
sulfate, filtered, and concentrated in vacuo to give the
crude methyl N-isobutyrylglycinate 8 as a colorless oil
(10.3 g), which was used directly in the next reaction.
4.2. Methyl 2-benzoylamino-4-methyl-3-oxopentanoate
7
A mixture of the oxazole (4, 958 mg, 5.66 mmol) and
TsOH·H2O (2.14 g, 11.26 mmol) in MeOH (15 mL) was
heated under reflux overnight. The mixture was cooled
to rt and concentrated in vacuo. The residue was
triturated with ether and filtered to afford methyl 2-
amino-4-methyl-3-oxopentanoate toluenesulfonic acid
salt (2.46 g, quant.) as colorless solids. The crude
material was used for the next step without further
purification.
A suspension of the TsOH salt 5 (2.46 g) in THF (15
mL) was cooled to 0°C. Benzoyl chloride (0.7 mL, 6.03
mmol) and triethylamine (2.4 mL, 17.2 mmol) was
slowly added. After stirring overnight, the reaction
mixture was quenched with water (1 mL) and diluted
with ethyl acetate–n-hexane (5:1). The mixture was
washed with aqueous hydrochloric acid (1N), water,
saturated aqueous sodium hydrogen carbonate, and
saturated brine, dried over sodium sulfate, filtered, and
concentrated in vacuo. The residue was purified by
column chromatography (30 g, ethyl acetate–n-hex-
ane=1:2.5 to 1:1) to give N-benzoyl derivative 7 as a
colorless oil (1.43 g, 99%); IR (neat): 3409, 1754, 1660,
The crude 8 was dissolved in acetonitrile (32.5 mL) at
20°C and di-tert-butyl dicarbonate (21.86 g, 100.2
mmol) followed by N,N-dimethylaminopyridine (807
mg, 6.6 mmol) was added. After stirring at 20°C for 6.5
h, the reaction mixture was condensed in vacuo and the
residue was dissolved in ethyl acetate (300 mL). The
organic layer was washed with potassium hydrogen
sulfate (20 mL) and brine, then dried over sodium
sulfate, filtered, and concentrated in vacuo to give the
crude product (18.6 g) as a orange oil. Chromato-
graphic purification (250 g, ethyl acetate–n-hexane=
1:6) gave the title compound 9 as a colorless oil (14.3 g,
1
1
1516, 1484 cm−1; H NMR (400 MHz, CDCl3): l 1.15
69%); IR (neat): 1743, 1701 cm−1; H NMR (500 MHz,
(3H, d, J=6.8 Hz), 1.26 (3H, d, J=7.1 Hz), 3.14 (1H,
heptet, J=6.8 Hz), 3.84 (3H, s), 5.62 (1H, d, J=6.8
Hz), 7.31 (1H, d, J=5.4 Hz), 7.44–7.50 (2H, m), 7.52–
7.56 (1H, m), 7.84–7.87 (2H, m); 13C NMR (100 MHz,
CDCl3): l 17.6, 18.8, 37.7, 53.2, 61.0, 127.2, 128.6,
132.0, 133.0, 166.7, 166.9, 205.0. HRMS calcd for
C14H18NO4: 264.1236 (M++1). Found: 264.1237.
CDCl3): l 1.19 (6H, d, J=7.0 Hz), 1.50 (9H, s), 3.73
(3H, s), 3.74 (1H, septet, J=6.7 Hz), 4.44 (2H, s). Anal.
calcd for C12H21NO5: C, 55.58; H, 8.16; N, 5.40.
Found: C, 55.56; H, 8.15; N, 6.01%.
4.5. Methyl 2-tert-butoxycarbonylamino-4-methyl-3-
oxopentanoate 10
4.3. 4-Methoxycarbonyl-5-(1-methylethyl)-1,3-oxazol-2-
one 6
To a stirred solution of methyl N-tert-butoxycarbonyl-
N-isobutyrylglycinate (433 mg, 1.7 mmol) in THF at
−78°C under an argon atmosphere was added DMPU
(0.40 mL, 3.3 mmol) followed by lithium hexamethyl-
disilazide (1 M solution in THF, 4.25 mL, 4.25 mmol)
over 10 min. After stirring at −78°C for 1.5 h, the
reaction mixture was quenched with saturated aqueous
ammonium chloride (24 mL). The mixture was
extracted three times with ethyl acetate (50 mL). The
organic layer was washed with water and saturated
brine, dried over sodium sulfate, filtered, and concen-
trated in vacuo to give the crude product as a yellow
oil. Chromatographic purification (90 g, ethyl acetate–
n-hexane=1:4) of the residue gave the title compound
10 (414 mg, 96%) as colorless crystals; mp 43–45°C
(ethyl acetate–n-hexane); IR (KBr): 3320, 1729, 1720,
To a stirred mixture of the TsOH salt 5 (prepared as
described above, 850 mg, 2.57 mmol) and Et3N (1.07
mL, 7.70 mmol) in THF (8.8 mL) was cooled to −50°C
and a solution of triphosgene (266 mg, 0.90 mmol) in
THF (4.0 mL) was added via cannula. After stirring for
30 min, the reaction mixture was diluted with ether (90
mL) and saturated aqueous NH4Cl (50 mL) was added.
The aqueous phase was separated and extracted with
ether (3×60 mL). The combined organic extracts were
washed with brine (60 mL), dried over sodium sulfate,
and concentrated in vacuo. The residue was purified by
column chromatography (25 g, n-hexane–ethyl ace-
tate=2:1) to give the oxazolone 6 as colorless solids
(411 mg, 87%); mp 74–76°C (ether–n-hexane); IR
(KBr): 3226, 3143, 2979, 1762, 1721, 1661, 1316, 1032
cm−1; 1H NMR (400 MHz, CDCl3): l 1.25 (6H, d,
J=7.1 Hz, CH(CH3)2), 3.50 (1H, septet, J=7.0 Hz,
CH(CH3)2), 3.88 (3H, s, CO2CH3), 8.70 (1H, s, NH);
13C NMR (100 MHz, CDCl3): l 19.7, 25.4, 112.2,
154.4, 154.5, 159.1. HRMS calcd for C8H11NO4:
185.0688. Found: 185.0692.
1
1687, 1535 cm−1; H NMR (500 MHz, CDCl3): l 1.10
(3H, d, J=6.7 Hz), 1.19 (3H, d. J=7.0 Hz), 1.44 (9H,
s), 3.03 (1H, septet, J=6.7 Hz), 3.80 (3H, s), 5.19 (1H,
d, J=7.6 Hz), 5.69 (1H, br s). Anal. calcd for
C12H21NO5: C, 55.58; H, 8.16; N, 5.40. Found: C,
55.50; H, 8.15; N, 5.37%.

K. Makino et al. / Tetrahedron: Asymmetry 12 (2001) 1757–1762
1761
4.6. Methyl (2R,3S)-2-benzoylamino-3-hydroxy-4-
methylpentanoate (−)-11
was purified by column chromatography (25 g, ethyl
acetate–n-hexane=1:3) to give the oxazoline 13 as a
colorless oil (241 mg, 86%); [h]2D4=−97.5 (c 0.90,
CHCl3); IR (neat): 2964, 1747, 1645, 698 cm−1; 1H
NMR (400 MHz, CDCl3): l 0.97 (3H, d, J=6.6 Hz),
1.06 (3H, d, J=6.6 Hz), 2.09 (1H, m), 3.77 (3H, s), 4.54
(1H, dd, J=7.9, 9.9 Hz), 4.95 (1H, d, J=9.9 Hz), 7.42
(2H, m), 7.50 (1H, m), 8.00 (2H, m); 13C NMR (100
MHz, CDCl3): l 18.7, 19.6, 29.2, 52.1, 70.6, 87.6, 127.2,
128.3, 128.5, 131.8, 166.6, 170.5. HRMS (FAB) calcd
for C14H18NO3: 248.1287 (M++1). Found: 248.1289.
RuCl2[(S)-binap](dmf)n
was
prepared
from
[RuCl2(C6H6)]2 (72 mg, 0.144 mmol) and (S)-binap (189
mg, 0.302 mmol) according to the literature.5 The
resulting red–brown catalyst was dried in vacuo at 60°C
for 1 h. A degassed solution of N-benzoyl b-keto-a-
amino ester 7 (7.60 g, 28.9 mmol) in dichloromethane
(6.0 mL) was added to the catalyst under an argon
atmosphere. The mixture was hydrogenated at 50°C
under hydrogen pressure (100 atm) for 64 h. The sol-
vent was removed in vacuo and the residue was purified
by column chromatography (350 g, ethyl acetate–n-hex-
ane=1:3 to 1:2) to give methyl (2R,3S)-2-benzoyl-
amino-3-hydroxy-4-methylpentanoate 11 as a yellow–
green oil (7.66 g, 100%). An analytically pure sample
was obtained by further purification using column
chromatography. HPLC analysis using a CHIRALCEL
OD-H and hexane–iPrOH (85:15, 0.5 mL/min) as an
eluent indicated to be 99% e.e. (retention times:
(2R,3S): 10.1 min; (2S,3R): 16.6 min); [h]2D4=−27.8 (c
0.85, CHCl3); IR (neat): 3388, 1747, 1650, 1531 cm−1;
1H NMR (400 MHz, CDCl3): l 0.97 (3H, d, J=6.8
Hz), 1.03 (3H, d, J=6.6 Hz), 1.76 (1H, m), 2.80 (1H,
m), 3.75 (3H, s), 3.84 (1H, m), 5.04 (1H, dd, J=2.0, 9.3
Hz), 7.14 (1H, m), 7.40 (2H, m), 7.50 (1H, m), 7.84
(2H, m); 13C NMR (100 MHz, CDCl3): l 18.9, 31.1,
52.5, 54.7, 77.4, 127.2, 128.5, 131.8, 133.6, 167.8, 172.2.
HRMS (FAB) calcd for C14H20NO4: 266.1392 (M++1).
Found: 266.1370.
4.9. (4S,5S)-4-Methoxycarbonyl-5-(1-methylethyl)-2-
phenyl-1,3-oxazoline (+)-13
Prepared according to the procedure described above
for (−)-13. Yield 68%; [h]2D4=+94.9 (c 1.25, CHCl3); IR
(neat): 2964, 1746, 1644, 698 cm−1; 1H NMR (400
MHz, CDCl3): l 1.02 (3H, d, J=6.6 Hz), 1.06 (3H, d,
J=6.3 Hz), 2.09 (1H, m), 3.77 (3H, s), 4.54 (1H, dd,
J=7.8, 9.8 Hz), 4.95 (1H, d, J=9.8 Hz), 7.40–7.43 (2H,
m), 7.48–7.52 (1H, m), 7.98–8.00 (2H, m); 13C NMR
(100 MHz, CDCl3): l 18.8, 19.6, 29.3, 52.1, 70.6, 87.6,
127.2, 128.3, 128.5, 131.8, 166.6, 170.5. HRMS (FAB)
calcd for C14H18NO3: 248.1287 (M++1). Found:
248.1272.
4.10. (2R,3R)-3-Hydroxyleucine (−)-3
A mixture of the oxazoline (−)-13 (167 mg, 0.629 mmol)
in 6N hydrochloric acid (11.5 mL) was heated to reflux
for 24 h. The resulting solution was cooled to 25°C and
washed with ether (20 mL). The aqueous layer was
concentrated in vacuo. The residue was purified by
Dowex 50W-X4 ion-exchange resin (H+ form) using 2N
pyridine as an eluant to give (2R,3R)-3-hydroxyleucine
3 as colorless powder (79 mg, 85%); mp 224–228°C
(MeOH) (lit.3e 225–228°C); [h]D26=−21.6 (c 1.15, H2O)
(lit.3e [h]D26=−22.0 (c 0.96, H2O)); IR (KBr): 3437, 3080,
4.7. Methyl (2S,3R)-2-benzoylamino-3-hydroxy-4-
methylpentanoate (+)-11
Prepared according to the procedure described above
for (−)-11. Yield 95% (e.e.=98%); [h]2D4=+27.2 (c 0.92,
CHCl3); IR (neat): 3417, 2598, 1747, 1645 cm−1; 1H
NMR (400 MHz, CDCl3): l 1.01 (3H, d, J=6.8 Hz),
1.05 (3H, d, J=6.6 Hz), 1.79 (1H, m), 2.22 (1H, d,
J=4.4 Hz), 3.79 (3H, s), 3.85 (1H, ddd, J=1.7, 4.4, 9.0
Hz), 5.05 (1H, dd, J=1.7, 9.0 Hz), 6.86 (1H, d, J=9.0
Hz), 7.43–7.47 (2H, m), 7.51–7.55 (1H, m), 7.83–7.86
(2H, m); 13C NMR (100 MHz, CDCl3): l 18.9, 31.1,
52.5, 54.7, 74.4, 127.2, 128.5, 131.8, 133.7, 167.8, 172.2.
HRMS (FAB) calcd for C14H20NO4: 266.1392 (M++1).
Found: 266.1404.
1
2961, 1626 cm−1; H NMR (400 MHz, D2O): l 0.82
(3H, d, J=6.6 Hz), 0.83 (3H, d, J=6.6 Hz), 1.75–1.84
(1H, m), 3.39 (1H, dd, J=3.1, 9.2 Hz), 3.77 (1H, d,
J=3.1 Hz); 13C NMR (100 MHz, D2O): l 18.6, 30.2,
57.1, 76.1, 171.8. HRMS (FAB, glycerol matrix) calcd
for C6H14NO3: 148.0974 (M++1). Found: 148.0963.
Anal. calcd for C6H13NO3: C, 48.97; H, 8.90; N, 9.52.
Found: C, 48.78; H, 8.87; N, 9.25%.
4.8. (4R,5R)-4-Methoxycarbonyl-5-(1-methylethyl)-2-
phenyl-1,3-oxazoline (−)-13
4.11. (2S,3S)-3-Hydroxyleucine (+)-3
A solution of the ester (−)-11 (300 mg, 1.13 mmol) in
THF (11.3 mL) was cooled to 0°C. Thionyl chloride (88
mL, 1.21 mmol) was added to the solution at 0°C. The
reaction mixture was allowed to warm gradually to
25°C. After stirring for 12 h, the mixture was heated to
60°C for 2.5 h with stirring. The reaction mixture was
cooled to 0°C and quenched by addition of saturated
aqueous sodium hydrogen carbonate (14 mL). The
aqueous layer was extracted with ethyl acetate (3×20
mL). The combined organic extracts were washed with
water (20 mL) and saturated brine (20 mL), dried over
sodium sulfate, and concentrated in vacuo. The residue
Prepared according to the procedure described above
for (−)-3. Yield 87%; mp 225–228°C (MeOH); [h]2D0=
+20.9 (c 1.03, H2O); IR (KBr): 3452, 3086, 1628, 1560
1
cm−1; H NMR (400 MHz, D2O): l 0.83 (3H, d, J=6.6
Hz), 0.84 (3H, d, J=6.6 Hz), 1.80 (1H, m), 3.40 (1H,
dd, J=3.2, 9.1 Hz), 3.78 (1H, d, J=3.1 Hz); 13C NMR
(100 MHz, D2O): l 18.5, 18.6, 30.2, 57.1, 76.1, 171.8.
HRMS (FAB, glycerol matrix) calcd for C6H14NO3:
148.0974 (M++1). Found: 148.0983. Anal. calcd for
C6H13NO3: C, 48.97; H, 8.90; N, 9.52. Found: C, 48.01;
H, 9.00; N, 9.26%.

1762
K. Makino et al. / Tetrahedron: Asymmetry 12 (2001) 1757–1762
4.12. (2R,3S)-3-Hydroxyleucine (+)-12
References
A mixture of N-benzoyl-3-hydroxyleucine methyl ester
(−)-11 (100 mg, 1.131 mmol) in aqueous hydrochloric
acid (6N, 6.9 mL) was heated under reflux for 50 h. The
resulting solution was cooled to 25°C and washed with
ether (10 mL). The aqueous layer was concentrated in
vacuo. The residue was purified by Dowex 50W-X4
ion-exchange resin (H+ form) using 2N pyridine as an
eluant to give (2R,3S)-3-hydroxyleucine 12 as a color-
less powder (47 mg, 85%): mp 202–205°C (MeOH)
(lit.3e 213–214°C); [h]D27=+4.1 (c 1.14, H2O) (lit.3e
[h]2D6=+3.5 (c 1, H2O)); IR (KBr): 3316, 2961, 1637,
1. Ford, P. W.; Gustafson, K. R.; McKee, T. C.; Shigematsu,
N.; Maurizi, L. K.; Pannell, L. K.; Williams, D. E.; de
Silva, E. D.; Lassota, P.; Allen, T. M.; Soest, R. V.;
Anderson, R. J.; Boyd, M. R. J. Am. Chem. Soc. 1999,
121, 5899–5909.
2. Umezawa, K.; Nakazawa, K.; Ikeda, Y.; Naganawa, H.;
Kondo, S. J. Org. Chem. 1999, 64, 3034–3038 and refer-
ences cited therein.
3. For the synthesis of (2R,3R)- and (2S,3S)-3-hydrox-
yleucines, see: (a) Caldwell, C. G.; Bondy, S. S. Synthesis
1990, 34–36; (b) Corey, E. J.; Lee, D. H.; Choi, S. Tetra-
hedron Lett. 1992, 33, 6735–6738; (c) Kanemasa, S.; Mori,
T.; Tatsukawa, A. Tetrahedron Lett. 1993, 34, 8293–8296;
(d) Hale, K. J.; Manaviazar, S.; Delisser, V. M. Tetra-
hedron 1994, 50, 9181–9188; (e) Nagamitsu, T.; Sunazuka,
T.; Tanaka, H.; Omura, S.; Sprengeler, P. A.; Smith, III,
A. B. J. Am. Chem. Soc. 1996, 118, 3584–3590; (f)
Williams, L.; Zhang, Z.; Shao, F.; Carroll, P. J.; Joullie`,
M. M. Tetrahedron 1996, 52, 11673–11694; (g) Laib, T.;
Chastanet, J.; Zhu, J. J. Org. Chem. 1998, 63, 1709–1713;
(h) Panek, J. S.; Masse, C. E. J. Org. Chem. 1998, 63,
2382–2384; (i) Horikawa, M.; Busch-Petersen, J.; Corey,
E. J. Tetrahedron Lett. 1999, 40, 3843–3846; (j) Adams, Z.
M.; Jackson, R. F. W.; Palmer, N. J.; Rami, H. K.;
Wythes, M. J. J. Chem. Soc., Perkin Trans. 1 1999,
937–947.
1
1509 cm−1; H NMR (400 MHz, D2O): l 0.78 (3H, d,
J=6.6 Hz), 0.83 (3H, d, J=6.4 Hz), 1.53–1.62 (1H, m),
3.58 (1H, d, J=8.4 Hz), 3.65 (1H, s); 13C NMR (100
MHz, D2O): l 17.4, 18.4, 30.2, 56.9, 75.1, 173.4.
HRMS (FAB, glycerol matrix) calcd for C6H14NO3:
148.0974 (M++1). Found: 148.0986. Anal. calcd for
C6H13NO3·6/5H2O: C, 42.69; H, 9.20; N, 8.30. Found:
C, 42.98; H, 8.87; N, 8.23%.
4.13. (2S,3R)-3-Hydroxyleucine (−)-12
Prepared according to the procedure described above
for (+)-12. Yield 84%; mp 203–206°C (MeOH) (lit.3e
213–214°C); [h]2D7=−4.3 (c 1.10, H2O); IR (KBr): 3317,
1
2952, 1637, 1525 cm−1; H NMR (400 MHz, D2O): l
0.83 (3H, d, J=6.6 Hz), 0.88 (3H, d, J=6.6 Hz), 1.63
(1H, m), 3.63 (1H, dd, J=3.9, 7.8 Hz), 3.70 (1H, d,
J=3.9 Hz); 13C NMR (100 MHz, D2O): l 17.4, 18.4,
30.2, 56.9, 75.1, 173.4. HRMS (FAB, glycerol matrix)
calcd for C6H14NO3: 148.0974 (M++1). Found:
148.0996. Anal. calcd for C6H13NO3·H2O: C, 43.63; H,
9.15; N, 8.48. Found: C, 43.70; H, 9.21; N, 8.28%.
4. For the synthesis of (2R,3S)- and (2S,3R)-3-hydrox-
yleucines, see: (a) Jung, M. E.; Yung, Y. H. Tetrahedron
Lett. 1989, 30, 6637–6640; (b) Panek, J. S.; Masse, C. E.
Angew. Chem., Int. Ed. 1999, 38, 1093–1095; (c) Soucy, F.;
Grenier, L.; Behnke, M. L.; Destree, A. T.; McCormack,
T. A.; Adams, J.; Plamondon, L. J. Am. Chem. Soc. 1999,
121, 9967–9976; (d) Davis, F. A.; Srirajan, V.; Fanelli, D.
L.; Portonovo, P. J. Org. Chem. 2000, 65, 7663–7666. See
also references 3e and 3f.
5. For hydrogenation using RuCl2(binap) catalyst, see: Noy-
ori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc.
Jpn. 1995, 68, 36–55.
Acknowledgements
6. Suzuki, M.; Iwasaki, T.; Miyoshi, M.; Okumura, K.;
Matsumoto, K. J. Org. Chem. 1973, 38, 3571–3575.
7. Hamada, Y.; Shioiri, T. Tetrahedron Lett. 1982, 23, 235–
236.
8. Hara, O.; Ito, M.; Hamada, Y. Tetrahedron Lett. 1998, 39,
5537–5540.
This work was financially supported in part by research
grants from the Ministry of Education, Science and
Culture, Japan (to Y.H.) and the Nagase Science and
Technology Foundation. The authors would like to
thank Ms. Miyuki Furukawa and Ms. Ai Kondo for
their preliminary assistance.
.