Stereoselective synthesis of (3S,4R)-3,4-dimethyl-(S)-glutamine and the absolute stereochemistry of the natural product from papuamides and callipeltin

Article abstract of DOI:10.1016/S0957-4166(01)00231-2

(3S,4R)-3,4-Dimethyl-(S)-glutamine, a common component of cyclodepsipeptides, papuamide A and callipeltin A, was stereoselectively prepared from (S)-pyroglutamic acid. The stereostructure of natural dimethylglutamine was unambiguously confirmed to be (2S,

Full text of DOI:10.1016/S0957-4166(01)00231-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1353–1358
Stereoselective synthesis of (3S,4R)-3,4-dimethyl-(S)-glutamine
and the absolute stereochemistry of the natural product from
papuamides and callipeltin†
Naoki Okamoto, Osamu Hara, Kazuishi Makino and Yasumasa Hamada*
Graduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Received 25 April 2001; accepted 21 May 2001
Abstract—(3S,4R)-3,4-Dimethyl-(S)-glutamine, a common component of cyclodepsipeptides, papuamide A and callipeltin A, was
stereoselectively prepared from (S)-pyroglutamic acid. The stereostructure of natural dimethylglutamine was unambiguously
confirmed to be (2S,3S,4R) by comparison of the CD and NMR spectra of the synthetic 3,4-dimethylpyroglutamic acid with the
hydrolysate of callipeltin A. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
1RF and also exhibit cytotoxicity against a number of
human cancer cell lines.
The novel cyclodepsipeptide papuamide A 1 and its
congeners1 were isolated from the marine sponge genus
Theonella, collected at Papua New Guinea by Boyd et
al. These cyclic heptapeptides have a unique structure
containing unusual amino acid residues. The structural
determination of papuamide A has not yet been com-
pleted and the stereostructures of some components
remain to be defined. Papuamides are known to inhibit
the infection of human T-lymphoblastoid cells by HIV-
Two unusual amino acids, b-methoxytyrosine and 3,4-
dimethylglutamine, of 1 are common components to
the cyclodepsipeptide callipeltin A,2 which was isolated
from a sponge collected at New Caledonia, and also
shows anti-HIV and cytotoxic activities. The
stereostructure of 3,4-dimethylglutamine was deter-
mined to be (2S,3S,4R) on the basis of a positive
Cotton effect of the hydrolysate, 3,4-dimethylpyroglu-
* Corresponding author. Tel./fax: +81 43 290 2987; e-mail: hamada@p.chiba-u.ac.jp
†
Dedicated to Professor Takayuki Shioiri on the occasion of retirement from Nagoya City University.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00231-2

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N. Okamoto et al. / Tetrahedron: Asymmetry 12 (2001) 1353–1358
tamic acid, from callipeltin A. The unique structure and
intriguing biological activities of these compounds led
us to explore their total synthesis. Herein, we report a
stereoselective synthesis of (3S,4R)-3,4-dimethyl-(S)-
glutamine (3,4-DiMeGln) in its protected form 2 and
the unambiguous determination of the absolute
stereostructure of natural 3,4-dimethylglutamine by
comparison of the CD spectra of the synthetic 3,4-
dimethylpyroglutamic acid with the hydrolysate of
callipeltin A. Recently, a synthesis of (3S,4R)-3,4-
dimethyl-(S)-glutamine as its protected derivative
through asymmetric Michael addition using a camphor-
sultam auxiliary has been reported.3 However, the
diastereoselection of the asymmetric synthesis for the
desired 3,4-dimethylglutamine is in the ratio 3:1 and
remains to be improved.
spectroscopic methods and elemental analyses. In par-
ticular, NOE experiments disclosed the stereostructures
of 5 and 6 as shown in Fig. 1. Conversion of the
trans-product to the desired cis-dimethyl lactam 7 was
achieved by deprotonation with LDA followed by
stereoselective protonation.8 Thus, treatment of trans-6
with LDA at −78°C followed by slow addition of
saturated aqueous ammonium chloride gave the cis-
product 7 in 77% yield. To deprotect the benzylidene
group, we first attempted transfer hydrogenolysis con-
ditions, which had already been applied for the
reported synthesis of AI-77-B.4a,b Unfortunately, the
deprotection was low yielding using this procedure and
the starting material was recovered in 46% yield with
38% yield of the desired 8. The benzylidene was eventu-
ally found to be efficiently cleaved by exposure to
excess trifluoroacetic acid at 20°C over 13 hours and
using this procedure 8 was formed in quantitative yield
(Scheme 1).
2. Results and discussion
To confirm the absolute stereostructure of the naturally
occurring 3,4-dimethylglutamine, the lactam 8 was con-
verted into 3,4-dimethylpyroglutamic acid, which was
obtained from the degradation product of callipeltin A.
The hydroxyl group of 8 was therefore oxidized with
As the starting material for the synthesis of (3S,4R)-
3,4-dimethyl-(S)-glutamine, we chose 3 as a chiral syn-
thon derived from (S)-glutamic acid. Bicyclic lactam 3
is a versatile synthon in the synthesis of a variety of
natural products4 and was prepared from (S)-pyroglu-
tamic acid according to Thottathil’s procedure.5 Intro-
duction of a double bond to the lactam was effected by
the method developed by us.4a,b We first attempted the
sequential introduction of two methyl groups to 4 by
conjugate addition with Gilman’s reagent followed by
trapping of the resulting enolate. However, the intro-
duction of the second methyl group completely failed.
Therefore, a stepwise procedure was employed for the
introduction of methyl groups at the 6- and 7-positions
of the bicyclic lactam 4.6
9
RuCl3–NaIO4 to provide the desired product 9 in 80%
yield. In the CD spectrum the synthetic 3,4-dimethylpy-
roglutamic acid showed a positive Cotton effect at 208
nm (q=+20054) in accordance with that of the natural
product. Additionally, its NMR spectrum was com-
pletely identical with that of the natural product.2 The
above results unambiguously show that the absolute
configuration of the 3,4-dimethylglutamine unit in the
natural products is (2S,3S,4R).
To complete the synthesis of 3,4-dimethylglutamine, the
hydroxyl and amine functions of the lactam were
respectively protected with tert-butyldimethylsilyl
(TBS) and tert-butoxycarbonyl (Boc) groups in good
yields. After deprotection of the silyl group, ring-open-
ing of lactam 10 into the carboxamide was carried out
by ammonolysis. Alcohol 10 was treated with 2.4%
ammonia–methanol for 24 hours at 55°C to give the
desired product with recovery of the starting material.
The obtained ring-opened product was directly oxidized
with RuCl3–NaIO4 to give N-Boc-3,4-dimethylglu-
tamine 2 in 81% yield without epimerization (Scheme
2).
Treatment of
4
with lithium dimethylcuprate
(Me2CuLi) in the presence of chlorotrimethylsilane7 at
−78°C preferentially provided the 6-methylated product
5 in 86% yield in a ratio of 19:1. After removal of the
unwanted diastereomer by chromatography, methyl-
ation of the bicyclic lactam 5 at the 7-position was
carried out by treatment with LDA at −78°C followed
by alkylation with iodomethane to afford trans-
dimethyl lactam 6 in 96% yield with stereoselection of
97:3. These results are not in accordance with those of
Hanessian’s report6 regarding the selectivities of the
conjugate addition and methylation at the 7-position
and also the values of specific rotation of 5 and 6. The
structures of 5 and 6 were unequivocally confirmed by
In summary, we have demonstrated the stereoselective
synthesis of (3S,4R)-dimethyl-(S)-glutamine 2 from
Figure 1.

N. Okamoto et al. / Tetrahedron: Asymmetry 12 (2001) 1353–1358
1355
Scheme 1.
Scheme 2.
(S)-pyroglutamic acid and unambiguously determined
that the naturally occurring 3,4-dimethylglutamine
residue in papuamides and callipeltins has (2S,3S,4R)
stereochemistry. Further investigation of other compo-
nents of the papuamides and callipeltins and their total
synthesis is actively under way.
3.1. (2R,5S,6S)-6-Methyl-2-phenyl-1-aza-3-oxabicy-
clo[3.3.0]octan-8-one 5
To a suspension of CuI (11.4 g, 59 mmol) in THF (344
mL) was added a solution of MeLi in ether (0.8 M, 105
mL, 59 mmol) at −78°C and the mixture was stirred at
0°C for 30 min. The resulting colorless solution was
cooled to −78°C and a solution of TMSCl (7.57 mL, 59
mmol) and the enone 4 (4 g, 19 mmol) in THF (30 mL)
was added. After stirring for 1 h the reaction mixture
was quenched with saturated aqueous NH4Cl (250 mL).
The aqueous phase was extracted with ether (3×120
mL). The combined organic extracts were washed with
saturated aqueous NH4Cl (3×100 mL), water (100 mL)
and saturated brine (150 mL), dried over Na2SO4 and
concentrated in vacuo. The residue was purified by
column chromatography on silica gel (120 g, n-hexane–
ethyl acetate=2:1) to give 5 as a colorless oil (3.78 g,
86%): [h]2D2=+228 (c 0.64, CHCl3) (lit.6 (6R)-enan-
tiomer: [h]D=−2.3 (c 1.47, CHCl3)); IR (neat) 2962,
3. 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. The CD spectrum was
recorded on a JASCO J-720WI spectrometer. Column
chromatography was carried out with silica gel BW-
820MH (Fuji silysia).

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N. Okamoto et al. / Tetrahedron: Asymmetry 12 (2001) 1353–1358
1
1710, 1453, 1350 cm−1; H NMR (400 MHz, CDCl3): l
1.22 (3H, d, J=6.8 Hz), 2.33–2.39 (1H, m), 2.46–2.69
(2H, m), 3.60 (1H, dd, J=7.0, 8.0 Hz), 3.62–6.77 (1H,
m), 4.20 (1H, dd, J=6.3, 8.3 Hz), 6.35 (1H, s), 7.30–
7.44 (5H, m); 13C NMR (100 MHz, CDCl3): l 19.16,
34.77, 42.31, 66.04, 70.77, 87.08, 125.95, 128.38, 128.49,
138.5, 177.5. HRMS (FAB, NBA) calcd for
C13H16NO2: 218.1181 (M+H+). Found: 218.1185.
128.3, 128.4, 138.4, 181.4. HRMS (FAB, NBA) calcd
for C14H18NO2: 232.1338 (M+H+). Found: 232.1329.
3.4. (3R,4S,5S)-3,4-Dimethyl-5-hydroxymethylpyrrol-
idin-2-one 8
To a stirred solution of benzylidene 7 (2.16 g, 9.3
mmol) in CH2Cl2 (300 mL) was added trifluoroacetic
acid (39 mL) at 20°C. The mixture was stirred at 20°C
for 16 h. The reaction mixture was concentrated in
vacuo. Water (20 mL) was added to the residue and the
mixture was stirred at 20°C for 1 min. Toluene was
added to the mixture and removed in vacuo. This
procedure was repeated three times. The residue was
purified by column chromatography on silica gel (40 g,
CHCl3–MeOH=20:1) to give alcohol 8 as a colorless
solid (1.33 g, 100%): mp 76–79°C; [h]2D4=+88.0 (c 0.48,
CHCl3); IR (KBr) 3855, 2977, 1664, 1321, 1074 cm−1:
1H NMR (400 MHz, CDCl3): l 1.02 (3H, d, J=7.3
Hz), 1.09 (3H, d, J=7.6 Hz), 2.25 (1H, sextet, J=7.1
Hz), 2.54 (1H, quintet, J=7.6 Hz), 3.30–3.35 (1H, m),
3.50 (1H, dd, J=7.3, 11.2 Hz), 3.74 (1H, dd, J=2.9,
11.4 Hz); 13C NMR (100 MHz, CDCl3): l 10.7, 13.8,
34.6, 39.8, 62.1, 64.6, 181.4. HRMS calcd for
C7H13NO2: 143.0946 (M+H+). Found: 143.0950.
3.2. (2R,5S,6S,7S)-6,7-Dimethyl-2-phenyl-1-aza-3-
oxabicyclo[3.3.0]octan-8-one 6
To a precooled (−78°C) solution of LDA, prepared
from n-BuLi in hexane (1.6 M solution, 15.1 mL, 4.17
mmol) and di-iso-propylamine (3.39 mL, 24 mmol) in
THF (40 mL) at −78°C, was added a solution of 5 (3.5
g, 16 mmol) in THF (20 mL). After stirring the mixture
for 30 min, iodomethane (2 mL, 32 mmol) was added in
one portion at −78°C and the mixture was stirred at the
same temperature for 1 h. The reaction was quenched
with saturated aqueous NH4Cl (30 mL) and extracted
with ethyl acetate (3×40 mL). The combined organic
extracts were washed with saturated brine (40 mL),
dried over Na2SO4 and filtered. The filtrate was concen-
trated in vacuo and the residue was purified by column
chromatography on silica gel (160 g, n-hexane–ethyl
acetate=3:1) to give 6 (3.59 g, 96%) as a colorless oil:
[h]2D2=+152 (c 0.75, CHCl3) (lit.5a (6R,7R)-enantiomer:
[h]D=−19 (c 0.7, CHCl3)); IR (neat) 2964, 2929, 1707,
3.5. (3R,4S,5S)-3,4-Dimethyl-5-tert-butyldimethyl-
siloxymethylpyrrolidin-2-one
To a stirred solution of alcohol 8 (200mg, 1.3 mmol) in
DMF (1.7 mL) were added TBSCl (232 mg, 1.54 mmol)
and imidazole (295 mg, 4.3 mmol) and the mixture was
stirred at 20°C for 48 h. The mixture was diluted with
ethyl acetate–n-hexane (4:1, 30 mL) and washed with
water (10 mL). The aqueous layer was extracted with
ethyl acetate–n-hexane (4:1, 20 mL×2). The combined
organic layer was washed with water, saturated brine,
dried over Na2SO4 and filtered. The filtrate was concen-
trated in vacuo and the residue was purified by column
chromatography on silica gel (15 g, n-hexane–ethyl
acetate=1:1) to give the desired silylether derivative
(215 mg, 66%) as colorless solid: mp 48–49°C; [h]2D7=
+54.3 (c 0.635, CHCl3); IR (KBr) 3293, 2930, 1654, 1254
1454, 1351 cm−1; H NMR (400 MHz, CDCl3): l 1.18
1
(3H, d, J=7.1 Hz), 1.20 (3H, d, J=6.6 Hz), 1.81–1.87
(1H, m), 2.47–2.52 (1H, m), 3.63–3.72 (2H, m), 4.17
(1H, dd, J=5.8, 7.8 Hz), 6.37 (1H, s), 7.29–7.38 (3H,
m), 7.42–7.44 (2H, m); 13C NMR (100 MHz, CDCl3): l
13.06, 16.83, 45.52, 47.32, 63.99, 70.85, 87.00, 126.1,
128.4, 128.5, 138.4, 179.1. HRMS (FAB, NBA) calcd
for C14H18NO2: 232.1338 (M+H+). Found: 232.1343.
3.3. (2R,5S,6S,7R)-6,7-Dimethyl-2-phenyl-1-aza-3-
oxabicyclo[3.3.0]octan-8-one 7
To a precooled (−78°C) LDA solution prepared from
n-BuLi in hexane (1.6 M solution, 13.8 mL, 22 mmol)
and di-iso-propylamine (13.8 mL, 22 mmol) in THF (40
mL) was added a solution of 6 (3.4 g, 14 mmol) in THF
(20 mL). After stirring the mixture for 30 min, satu-
rated aqueous NH4Cl (0.8 mL) was added dropwise
and the mixture was stirred at the same temperature for
1 h. The aqueous phase was separated and extracted
with ethyl acetate (3×40 mL). The combined organic
layers were washed with saturated brine (40 mL), dried
over Na2SO4 and concentrated in vacuo. The residue
was purified by column chromatography on silica gel
(120 g, n-hexane–ethyl acetate=2:1) to give 7 as a
colorless oil (2.26 g, 67%): [h]2D2=+154 (c 0.42, CHCl3);
1
cm−1; H NMR (400 MHz, CDCl3): l 0.06 (6H, s), 0.89
(9H, s), 1.03 (3H, d, J=7.2 Hz), 1.10 (3H, d, J=7.7
Hz), 2.20 (1H, m), 2.53 (1H, quintet, J=7.8 Hz), 3.28
(1H, m), 3.45 (1H, dd, J=8.0, 10.0 Hz), 3.69 (1H, dd,
J=4.0, 10.0 Hz), 5.78 (1H, br s); 13C NMR (100 MHz,
CDCl3): l −5.47 −5.46, 10.7, 14.2, 18.2, 25.8, 34.8, 39.4,
61.4, 65.8, 77.3, 180.0. HRMS (FAB, NBA) calcd for
C13H28NO2Si: 258.1889 (M+H+). Found: 258.1895.
3.6. (3R,4S,5S)-N-tert-Butoxycarbonyl-3,4-dimethyl-5-
tert-butyldimethylsiloxymethylpyrrolidin-2-one
To a stirred solution of the silylether derivative (192
mg, 0.7 mmol) in acetonitrile (8 mL) were added
DMAP (9 mg, 0.07 mmol) and (Boc)2O ( 0.19 mL, 0.8
mmol). The mixture was stirred for 24 h and diluted
with ethyl acetate (60 mL), washed with aqueous citric
acid (10%, 10 mL), water (10 mL) and saturated brine
(10 mL), dried over Na2SO4 and filtered. The filtrate
was concentrated in vacuo and the residue was purified
IR (neat) 3419, 2967, 1705, 1450, 1352 cm−1; H NMR
1
(400 MHz, CDCl3): l 1.09 (3H, d, J=6.8 Hz), 1.25
(3H, d, J=7.6 Hz), 2.40 (1H, sextet, J=7.1 Hz,), 2.69
(1H, quintet, J=7.6 Hz), 3.62 (1H, dd, J=7.1, 8.1 Hz),
3.76 (1H, q, J=6.6 Hz), 4.18 (1H, dd, J=6.5, 8.2 Hz),
6.37 (1H, s), 7.29–7.43 (5H, m); 13C NMR (100 MHz,
CDCl3): l 11.8, 13.6, 38.0, 44.9, 64.3, 70.4, 86.9, 125.9,

N. Okamoto et al. / Tetrahedron: Asymmetry 12 (2001) 1353–1358
1357
by column chromatography on silica gel (15 g, n-hex-
ane–ethyl acetate=3:1) to give the desired Boc deriva-
tive as colorless solid (256 mg, 96%): mp 40–41°C;
[h]2D7=−46.7 (c 1.12, CHCl3); IR (neat) 2931, 1789,
1755, 1712, 1366, 1310, 1159 cm−1: 1H NMR (400
MHz, CDCl3): l 0.04, (3H, s), 0.06 (3H, s), 0.88 (9H, s),
1.00 (3H, d, J=7.3 Hz), 1.09 (3H, d, J=7.5 Hz), 1.55
(9H, s), 2.45 (quintet, J=7.4 Hz), 2.99 (1H, quintet,
J=7.6 Hz), 3.68 (1H, m), 3.77 (1H, dd, J=2.6, 10.4
Hz), 3.87 (1H, dd, J=5.4, 10.4 Hz); 13C NMR (100
MHz, CDCl3): l −5.64, 9.97, 15.7, 18.0, 25.7, 28.0, 32.8,
40.5, 62.9, 64.6, 82.5, 150.4, 176.6. HRMS (FAB, NBA)
calcd for C18H36NO4Si: 358.2414 (M+H+). Found:
358.2395.
RuCl3·nH2O (0.4 mg, 0.002 mmol) was added. The
mixture was stirred for 8 h gradually warming to 20°C.
iso-Propanol (1.0 mL) was added and the mixture was
stirred at 20°C for 30 min. The resulting brownish oil
was filtered through a Celite pad, and the filtrate was
concentrated in vacuo. The residue was purified by
column chromatography on ODS silica gel with H2O–
MeOH (2:1) eluent to give N-Boc-3,4-dimethylglu-
tamine 11 as colorless solid (21 mg, 81%): mp
146–148°C; [h]2D1=+15.0 (c 0.56, MeOH); IR (neat)
1
3397, 2977, 1671, 1508, 1395, 1169 cm−1; H NMR (400
MHz, D2O): l 0.73 (3H, d, J=6.8 Hz), 1.02 (3H, d,
J=6.8 Hz), 1.25 (9H, s), 1.84 (1H, m), 2.34 (1H, m),
3.94 (1H, m); 13C NMR (100 MHz, D2O): l 14.31,
15.72, 28.25, 38.89, 43.26, 57.03, 82.11, 158.22, 177.38,
182.05. HRMS (FAB, NBA-NaI) calcd for
C12H22N2NaO5: 297.1426 (M+Na+). Found: 297.1441.
3.7. (3R,4S,5S)-N-tert-Butoxycarbonyl-3,4-dimethyl-5-
hydroxymethylpyrrolidin-2-one 10
To a stirred solution of the Boc derivative (90 mg, 0.25
mmol) in THF (0.27 mL) was added acetic acid (16 mL)
and a solution of TBAF in THF (1 M, 0.28 mL, 0.28
mmol). After stirring the mixture for 6 h, the mixture
was concentrated in vacuo and the residue was purified
by column chromatography on silica gel (15 g, n-hex-
ane–ethyl acetate=1:3) to give alcohol 10 as a colorless
oil (57 mg, 93%): [h]2D4=−47.8 (c 1.37, CHCl3); IR
(neat) 3491, 2976, 1769, 1714, 1370, 1306, 1156 cm−1;
1H NMR (400 MHz, CDCl3): l 1.02 (3H, d, J=7.3
Hz), 1.09, (3H, d, J=7.3 Hz), 1.54 (9H, s), 2.39 (1H,
quintet, J=7.3 Hz), 2.85 (1H, s, OH), 2.91 (1H, quin-
tet, J=7.3 Hz), 3.79 (3H, m); 13C NMR (100 MHz,
CDCl3): l 9.99, 15.3, 28.0, 32.8, 40.6, 63.5, 65.0, 83.3,
151.3, 176.5. HRMS (FAB, NBA) calcd for
C12H22NO4: 244.1549 (M+H+). Found: 244.1531.
3.10. (3S,4R)-3,4-Dimethyl-(S)-pyroglutamic acid 9
To a stirred solution of 8 (150 mg, 1.048 mmol) in
CH3CN (4.5 mL) and CCl4 (2.30 mL) was added a
solution of NaIO4 (609 mg, 3.248 mmol) in H2O (3.4
mL). The mixture was cooled to 0°C and RuCl3·nH2O
(6.0 mg, 0.023 mmol) was added. The mixture was
stirred for 8 h with gradual warming to 20°C. iso-
Propanol (3.0 mL) was added and the mixture was
stirred at 20°C for 0.5 h. The resulting brownish oil was
filtered through a Celite pad, and the filtrate was con-
centrated in vacuo. The residue was purified by ion-
exchange chromatography with 2N AcOH eluent to
give carboxylic acid 9 as a pale yellow solid (111 mg,
67%): mp 175–176°C; [h]2D6=+43.4 (c 0.83, MeOH); CD
[q]208 nm +20054 (c 0.001 M, H2O) (lit.2 [q]208 nm +1534
(c 0.001 M, H2O)); IR (neat) 3262, 2979, 1719, 1654,
1
3.8. (2R,3S,4S)-4-tert-Butoxycarbonylamino-3,4-
dimethyl-5-hydroxypentamide
1243 cm−1; H NMR (400 MHz, pyr-d5): l 1.15 (3H, d,
J=6.7 Hz), 1.18 (3H, d, J=7.1 Hz), 2.80 (1H, m), 2.85
1
(1H, m), 4.14 (1H, d, J=3.3 Hz); H NMR (400 MHz,
A 5 mL ampoule was charged with alcohol 10 (152 mg,
0.6 mmol) and ammonia in methanol (1.4 M, 3 mL).
The ampoule was heated at 55°C for 24 h, then the
reaction mixture was concentrated in vacuo. The
residue was purified by column chromatography on
silica gel (25 g, ethyl acetate–MeOH=20:1) to give the
desired amide as a colorless solid (59 mg, 36%): mp
143–144°C; [h]2D7=−27.7 (c 0.55, CHCl3); IR (KBr)
D2O): l 0.89 (3H, d, J=6.6 Hz), 0.97 (3H, d, J=6.2
Hz), 2.53 (2H, m), 3.80 (1H, d, J=3.9 Hz); 13C NMR
(100 MHz, D2O): l 9.43, 13.69, 37.98, 39.19, 61.38,
176.2, 183.8. HRMS (FAB, NBA) calcd for C7H12NO3:
158.0817 (M+H+). Found: 158.0808.
Acknowledgements
1
3407, 3299, 2975, 1693, 1666, 1543 cm−1; H NMR (400
MHz, CDCl3): l 0.94 (3H, d, J=7.0 Hz), 1.15 (3H, d,
J=7.0 Hz), 1.47 (9H, s), 1.72–1.67 (1H, m), 2.56 (1H,
dq, J=2.1, 7.0 Hz), 3.62 (1H, ddt, J=3.3, 10.1, 10.2
Hz), 3.72–3.83 (2H, m), 5.36 (1H, d, J=9.5 Hz), 5.47
(1H, s), 7.55 (1H, s); 13C NMR (100 MHz, CDCl3): l
11.91, 16.25, 28.32, 39.00, 39.39, 54.82, 62.80, 80.08,
157.6, 176.7. HRMS (FAB) calcd for C12H25N2O4:
261.1814 (M+H+). Found: 261.1799.
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 (to Y.H.).
References
3.9. (3S,4R)-N-tert-Butoxycarbonyl-3,4-dimethyl-(S)-
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glutamine 11
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