Stereoselective synthesis of chirally deuterated (S)-D-(6- 2H1)glucose

Article abstract of DOI:10.1016/j.carres.2004.02.010

Chirally deuterated (S)-D-(6-²H₁)glucose has been prepared in good overall yield from D-(6,6′-²H ₂)glucose by a short, five-step synthesis from D-(6,6- ²H₂)glucose utilizing (R)-(+)-Alpine-Borane [(R)-9-[(6,6-dimethylbicyclo[3.1.1]hept-2-yl)methyl]-9- borabicyclo[3.3.1]nonane]. Suitably protected methyl 2,3,4-tri-O-benzyl-D-(6,6- ²H₂)glucopyranoside was prepared and the deuterated O-6 primary alcohol was oxidized to an aldehyde by Swern oxidation. Stereoselective reduction with nondeuterated (R)-(+)-Alpine-Borane gave methyl 2,3,4-tri-O-benzyl-(6S)-D-(6-²H₁)glucopyranoside, which was deprotected under standard conditions to afford the title compound. The key stereoselective reduction step was achieved in 90% yield. The preparation uses economical, commercially available starting materials and will be useful for elucidating biosynthetic mechanisms.

Full text of DOI:10.1016/j.carres.2004.02.010

Carbohydrate
RESEARCH
Carbohydrate Research 339 (2004) 1173–1178
Stereoselective synthesis of chirally deuterated (S)-
D
-(6-2H1)glucose
Lin Xu and Neil P. J. Price*
Department of Pharmacology and Physiology, University of Rochester Medical Center,
601 Elmwood Avenue, Rochester, NY 14642, USA
Received 6 January 2004; accepted 3 February 2004
Abstract—Chirally deuterated (S)-
five-step synthesis from
-(6,6-2H2)glucose utilizing (R)-(+)-Alpine-Boraneâ [(R)-9-[(6,6-dimethylbicyclo[3.1.1]hept-2-yl)methyl]-9-
borabicyclo[3.3.1]nonane]. Suitably protected methyl 2,3,4-tri-O-benzyl-
-(6,6-2H2)glucopyranoside was prepared and the deuter-
ated O-6 primary alcohol was oxidized to an aldehyde by Swern oxidation. Stereoselective reduction with nondeuterated (R)-(+)-
Alpine-Boraneâ gave methyl 2,3,4-tri-O-benzyl-(6S)- -(6-2H1)glucopyranoside, which was deprotected under standard conditions
D D
-(6-2H1)glucose has been prepared in good overall yield from -(6,60-2H2)glucose by a short,
D
D
D
to afford the title compound. The key stereoselective reduction step was achieved in 90% yield. The preparation uses economical,
commercially available starting materials and will be useful for elucidating biosynthetic mechanisms.
Ó 2004 Elsevier Ltd. All rights reserved.
Keywords: Chirally deuterated glucose; Alpine-Boraneâ; 9-[(6,6-Dimethylbicyclo[3.1.1]hept-2-yl)methyl]-9-borabicyclo[3.3.1]nonane; NMR spec-
troscopy; Mass spectrometry
1. Introduction
An alternative procedure was introduced by Ohrui
and co-workers.8 Perbenzoylated 1,6-anhydro-b-
-glu-
D
Chirally deuterated sugars have been widely used to
elucidate mechanisms of biosynthesis and of chemical
reactions.1–3 Selective deuteration has also been used to
confirm assignments of complex NMR or mass spectra,4
and have been particularly useful in biosynthetic studies
of aminocyclitol antibiotics.2;5 To date, however, there
are very few reported syntheses for regio and stereo-
specifically deuterated pyranoses. The first reported fully
chemical synthesis of (6R)- and (6S)-(6-2H1)glucose by
Kakinuma required the preparation of an acetylene
intermediate, 3-O-benzyl-5,6-dideoxy-1,2-O-isopropyl-
copyranose was photobrominated with bromine in car-
bon tetrachloride. This reaction proceeded regio and
stereospecifically at H-6exo to give (6S)-1,6-anhydro-
2,3,4-tri-O-benzoyl-6-bromo-b-
88% yield. Reduction with tri-n-butyltindeuteride also
D
-glucopyranose
in
proceeded stereospecifically to generate 1,6-anhydro-
2,3,4-tri-O-benzoyl-(6S)-b-
same procedure was later used to synthesize (6S)-
2H1)galactopyranose9 and (5S)- -(5-2H1)ribofuranose.10
D
-(6-2H1)glucopyranose. This
D
-(6-
D
Reported yields were satisfactory, but the photoactiva-
tion step required rather specialized apparatus, and the
cost of the deuterated reagent is high.
idene-a-D
-xylo-(6-2H1)hex-5-ynofuranose, achieved by
treatment of the corresponding 6,60-dibromoolefin with
n-butyllithium, followed by quenching with deuterated
water.6 The yield for this step was low to moderate, and
poorly impacted the overall yield. The key steps here
were analogous to the classical synthesis of chiral acetic
acid by Cornforth et al.7
A more recent preparation of N-acetyl-(6R)-(6-
2H1)glucosamine11 made use of the stereoselective
reducing agent, Alpine-Boraneâ [(R)-9-[(6,6-dimethyl-
bicyclo[3.1.1]hept-2-yl)methyl]-9-borabicyclo-[3.3.1]-
nonane introduced by Brown and Ramachandran.12
The key step in this synthesis was a stereoselective
* Corresponding author at present address: USDA-ARS-NCAUR,
1815, N. University St., Peoria, IL 61604, USA. Tel.: +1-309-681-
6246; fax: +1-309-681-6427; e-mail: pricen@ncaur.usda.gov
B-Isopinocampheyl-9-borabicyclo[3.3.1]nonane is the nomenclature
used by Brown and co-workers, as well as by Aldrich Chemical
Company.
0008-6215/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2004.02.010

1174
L. Xu, N. P. J. Price / Carbohydrate Research 339 (2004) 1173–1178
reduction of a suitably protected C-6-aldehydo-GlcNAc
derivative with (R)-(+)-Alpine-Borane-dâ [(R-9-[(6,6-
dimethylbicyclo[3.1.1]hept-2-yl)methyl]-9-borabicyclo-
[3.3.1]nonane-d)]. Chirally deuterated N-acetyl-(6R)-(6-
2H1)glucosamine was obtained in good yield, but
required the pre-synthesis of (R)-(+)-Alpine-Borane-dâ
from (+)-pinene.13 A similar approach has been applied
to the synthesis of 1,2:3,4-di-O-isopropylidene-(6R)-
were chosen to minimize the loss of deuterium. Initially,
we used a trityl group to protect O-6 of the glucopyr-
anoside 2, followed by benzylation at O-2, O-3, and O-4.
Subsequent de-tritylation of O-6 with HBr gave mix-
tures of 3 and 4 in 30% yield. To improve the yield, we
chose another approach introduced by Ohrui et al.1
Primary alcohol O-6 of the methyl
D
-(6,6-2H2)gluco-
pyranoside (2) was protected by a tert-butyldimethylsilyl
group. Sodium hydride and benzyl bromide were then
added to the reaction mixture to introduce the 2,3,4-tri-
O-benzyl protecting groups. The tert-butyldimethylsilyl
group was removed by refluxing in tetrabutylammonium
fluoride solution to give mixtures of 3 and 4 in 60% yield
a-
D
-(6-2H1)galactopyranose.14
Here we describe a straightforward synthesis of
(6S)- -(6,6-
-(6-2H1)glucose from -(6,6-2H2)glucose.
2H2)Glucose was partially protected as methyl 2,3,4-
tri-O-benzyl-
-(6,6-2H2)glucopyranoside using the tert-
D
D
D
D
butyldimethylsilyl group for transient protection of O-6.
The primary alcohol O-6 was subsequently oxidized to
the aldehyde by Swern oxidation and stereoselectively
reduced with nondeuterated (R)-(+)-Alpine-Boraneâ to
(Scheme 1). Methyl 2,3,4-tri-O-benzyl-D
-(6,6-2H2)-
glucopyranoside can also be prepared with similar yield
by stereoselective ring cleavage of methyl 2,3-di-O-benz-
yl-4,6-O-benzylidene-D-glucopyranoside with LiAlH4–
AlCl3.17
Two isomers 3 and 4 were separated by reversed-
phase chromatography to simplify NMR assignment of
the products. HPLC analysis showed the isomer ratio of
3 and 4 was 77:23. The anomeric proton of 3 has a
chemical shift d 4.55 and a coupling constant 3.5 Hz.
The low vicinal coupling constant for the downfield
anomeric proton resonance suggested that 3 is the
a-isomer. Accordingly, the anomeric proton of 4 has a
chemical shift d 4.34 and a vicinal coupling constant
7.8 Hz confirming that 4 is the b-isomer. Compound 3
was oxidized to methyl 6-aldehydo-2,3,4-tri-O-benzyl-
yield methyl 2,3,4-tri-O-benzyl-(6S)-
anosides 6 and 7. After deprotection of the methyl and
benzyl groups, (6S)-
-(6-2H1)glucose was formed. Two-
D
-(6-2H1)glucopyr-
D
dimensional NMR techniques such as COSY, HSQC,
and HMBC provided fully assigned NMR data for each
intermediate and product.
2. Results and discussion
The starting material
cially available. It can also be simply prepared by
reduction of 1,2-O-isopropylidene-a- -glucurono-6,3-
lactone with lithium aluminum deuteride and further
D
-(6,6-2H2)glucose is commer-
D
a-
D
-(6-2H1)glucopyranoside 5 in 95% yield under the
standard Swern conditions.18 The H NMR spectrum
of 5 showed a signal at d 9.48 ppm indicative of an
aldehydic deuterium.
2
hydrolysis.15
D
-(6,6-2H2)Glucose was first converted to
-(6,6-2H2)glucopyranosides by refluxing
-(6,6-2H2)glucopyr-
anoside was also synthesized by reduction of methyl
a- -glucopyranosiduronic acid methyl ester with
sodium borodeuteride.16 Appropriate protecting groups
the methyl
D
with methanolic 4% HCl. Methyl
D
The key step in our synthesis of (6S)-D
-(6-2H1)glucose
is a stereoselective reduction of the protected C-6-alde-
hydo glycoside 5. Compound 5 was not especially stable
and was easily hydrated to the gem-diol. Therefore, 5
D
D
OH
O
D
OH
O
O
D
b,c
d
D
D
HO
OR
O
BnO
BnO
OCH
OCH
3
HO
3
BnO
BnO
OH
1, R = H
OBn
OBn
5, α isomer
3, α isomer
a
2, R = CH3
4, β isomer
β isomer (not purified)
D
OH
O
D
OH
O
H
BnO
BnO
D
OH
O
H
g
e
H
f
OCH
3
HO
OH
HO
OCH
3
HO
OBn
HO
OH
OH
8, α isomer
β isomer (not purified)
6, α isomer
9
7, β isomer
Scheme 1. Reagents and conditions: (a) CH3OH–4% HCl, reflux; (b) (1) Et3N, DMAP, t-BDMSiCl–DMF, rt, 3 h; (2) Et3N, NaH, BnBr, rt, 6 h; (c)
(Butyl)4NþFÀ, THF–EtOH, reflux, 3 h; (d) (1) DMSO, (COCl)2, )60 °C, 20 min; (2) Et3N–CH2Cl2, )60 °C, 15 min; (e) 1) (R)-(+)-Alpine-Borane–
CH2Cl2, rt, 24 h; (2) NaOH–30% H2O2, rt, 1 h; (f) H2, Pd/C, EtOH, rt, 24 h; (g) 1 N HCl/H2O, 80 °C, 12 h.

L. Xu, N. P. J. Price / Carbohydrate Research 339 (2004) 1173–1178
1175
(A)
(B)
H6proS
H6proR
H5
H6R
(C)
ppm (f1)
4.00
3.90
3.80
3.70
3.60
3.50
Figure 1. Detail of the 400 MHz 1H NMR spectra of nondeuterated methyl 2,3,4-tri-O-benzyl-a-
-(6,6-2H2)glucopyranoside (B), and methyl 2,3,4-tri-O-benzyl-(6S)-a- -(6-2H1)glucopyranoside (C) in CDCl3 is shown. Selected resonances are
labeled as H-6proR (3.68 ppm), H-6proS (3.74 ppm), H-5 (3.63 ppm), and H-6R (3.67 ppm).
D
-glucopyranoside (A), methyl 2,3,4-tri-O-benzyl-a-
D
D
was reduced immediately with (R)-(+)-Alpine-Boraneâ
to form 6 in 90% yield. The 1H and 2H NMR spectra of
6 showed that the reduction was highly stereoselective.
In Figure 1, nondeuterated methyl 2,3,4-tri-O-benzyl-
known methyl 2,3,4-tri-O-benzyl-(6R)-b-D
-(6-2H1)-
glucopyranoside has a chemical shift at d 3.87 ppm.
However, 7 did not have a proton resonance at d
3.87 ppm, and instead 7 had H-6 with chemical shift at
d 3.71 ppm. Moreover, the 2H NMR spectrum of 7
showed a deuterium atom with chemical shift at
d 3.87 ppm. The 13C NMR spectrum of 7 was the same
as that of the known methyl 2,3,4-tri-O-benzyl-(6R)-b-
a-D-glucopyranoside has H-6proR and H-6proS with
chemical shifts d 3.68 and 3.76 ppm, respectively.
Assignment of the chemical shifts of H-6proR and
H-6proS is based on the known methyl 2,3,4-tri-
O-benzyl-(6R)-a-
D
-(6-2H1)glucopyranoside,4 in which
D
-(6-2H1)glucopyranoside.4 These evidences confirm
H-6(S) showed a chemical shift of d 3.74 ppm. Because
both protons on C-6 of 3 are replaced by deuterium, no
1H NMR signal was observed in the range of 3.68–
3.74 ppm. H-5 (3.63 ppm) of 3 showed a doublet signal
coupled only to H-4 (J4;5 10 Hz), also indicating the
absence of H-6 protons. In compound 6, a proton with
chemical shift d 3.67 ppm was observed coupled to H-5
that the absolute configuration of H-6 in 7 is R, and
therefore compound 7 is assigned as methyl 2,3,4-tri-
O-benzyl-(6S)-b-D
-(6-2H1)glucopyranoside.
The stereoselectivity of Alpine-Boraneâ is a conse-
quence of coordination between the boron atom and the
substrate carbonyl, which holds the substrate in a
favored conformation for hydride addition to occur
in a highly stereoselective manner. For (R)-(+)-Alpine-
Boraneâ this leads to hydride addition to the si-face,
1
(3.64 ppm) by H–1H COSY. The double-doublet split
of H-5 confirmed that H-5 was coupled with H-4 and
with a single H-6 proton. The proton was assigned to
H-6R due to its chemical shift. This assignment was
further confirmed by a 2D 1H–13C HSQC experiment, in
which H-6R was correlated to C-6 (61.5 ppm). The C-6
carbon was observed as a triplet with a normal 13C–2H
1J coupling constant 21.6 Hz. Furthermore, no proton
signal showed at 3.74 ppm (H-6S) in the 1H NMR
ultimately resulting in (6S)-D
-(6-2H1)glucopyranose.
The antipodal reagent, (S)-())-Alpine-Boraneâ pro-
motes hydride addition to the carbonyl re-face, and
assuming no steric restriction to the co-ordination
complex, might therefore provide a useful route to the
R-isomer, (6R)-D
-(6-2H1)glucopyranose.
Removal of the 2,3,4-O-benzyl groups from 6 was
accomplished by reaction with palladium-on-charcoal
2
spectrum, and a deuterium signal at 3.77 ppm in the H
NMR spectrum for 6 suggested that H-6S was replaced
by deuterium and that the stereoselectivity of reduction
by (R)-(+)-Alpine-Boraneâ was almost 100%.
under hydrogen atmosphere to give methyl (6S)-a-D-(6-
2H1)glucopyranoside (8) in 92% yield. Compound 8
showed a deuterium resonance at d 3.60 ppm in the
2H NMR spectrum and a triplet C-6 resonance at
Accordingly, the b-isomer 4 was also oxidized to the
aldehyde under Swern conditions, and reduction with
d
duced (6S)-
62.3 ppm. Acid-catalyzed hydrolysis of
D
8 pro-
-(6-2H1)glucose in 85% yield. The
1
(R)-(+)-Alpine-Boraneâ gave 7. Compared with the H
NMR spectrum of the known methyl 2,3,4-tri-O-benzyl-
normal ratio of a and b-isomers (36:64) in deuterated
(6R)-b-
D
-(6-2H1)glucopyranoside,4 7 has all the same
proton signals except for H-6. The H-6S proton for the
water was observed in the 1H NMR spectrum. The
assignment of NMR data to (6S)-a-D
-(6-2H1)glucose

1176
L. Xu, N. P. J. Price / Carbohydrate Research 339 (2004) 1173–1178
1
2
and (6S)-b-
D
-(6-2H1)glucose was based on H, 13C, and
3.68 (br, H-6, pro-R); electrospray-ion trap-MS: calcd
for C28H302H2O6: m=z 466. Found: m/z 467 [M+H]þ,
2D COSY, HSQC, and HMBC spectra. The synthetic
(6S)-
-(6-2H1)glucose was successfully incorporated
into tunicamycin by fermentation of S. chartreuses
D
489 [M+Na]þ.
(work in progress).
3.3. Methyl 2,3,4-tri-O-benzyl-b-D
-(6,6-2H2)glucopyr-
anoside (4)
3. Experimental
Compound 4 was synthesized as described above for 3;
25
D
½aŠ +7.9° (c 1.2, CHCl3); 1H NMR (CDCl3, 400 MHz):
3.1. General methods
d 3.35 (d, 1H, J4;5 9.6 Hz, H-5), 3.39 (dd, 1H, J1;2 7.8, J2;3
9.0 Hz, H-2), 3.56 (s, 3H, OCH3), 3.58 (dd, 1H, J3;4 9.0,
All reactions were carried out under dry N2 except where
noted. All solvents were distilled from drying agents.
Reagents were purchased from Aldrich Chemical Co.
and VWR Scientific. Alpine-Boraneâ is a trade name of
Aldrich Chemical Co. Normal-phase column chroma-
tography was performed on Silica Gel 60 (230–400 mesh,
EM Science). Reversed-phase column chromatography
was performed on Bakerbonde C18 (40 lm, J. T. Baker).
The specific optical rotation values were measured on a
Perkin–Elmer 241 polarimeter at 25 °C. 1H, 13C, COSY,
HMBC, and HSQC NMR data were recorded on a
Bruker Avance 400 with Me4Si as the internal standard
except where noted. MS analyses were performed with
an Agilent LC/MSD ion-trap mass spectrometer (Agi-
lent Technologies) with an electrospray-ionization
interface operated in the positive-ion mode.
J
4;5 9.6 Hz, H-4), 3.66 (t, 1H, J2;3 ¼ J3;4 9.0 Hz, H-3), 4.34
(d, 1H, J1;2 7.8 Hz, H-1), 4.63 (d, 1H, J 10.9 Hz, H-4a-
Bn), 4.70 (d, 1H, J 10.9 Hz, H-2a-Bn), 4.80 (d, 1H,
J 10.9 Hz, H-3a-Bn), 4.85 (d, 1H, J 10.9 Hz, H-4b-Bn),
4.90 (d, 1H, J 10.9 Hz, H-2b-Bn), 4.92 (d, 1H, J 10.9 Hz,
H-3b-Bn), 7.26–7.34 (Ph); 13C NMR (CDCl3, 100 MHz):
d 57.3 (OCH3), 61.7 (br, C-6), 74.8 (C-4ab), 74.9 (C-5),
75.1 (C-2ab), 75.7 (C-3ab), 77.5 (C-4), 82.3 (C-2), 84.4
(C-3), 104.8 (C-1), 127.6 (Ph), 127.7 (Ph), 127.8 (Ph),
127.9 (Ph), 128.0 (Ph), 128.4 (Ph), 128.5 (Ph), 137.9 (Ph),
2
138.4 (Ph), 138.5 (Ph); H NMR (CDCl3, 61.4 MHz):
2
2
d 3.86 (br, H-6, pro-S), 3.71 (br, H-6, pro-R); electro-
spray-ion trap-MS: calcd for C28H302H2O6: m=z 466.
Found: m=z 467 [M+H]þ, 489 [M+Na]þ.
3.4. Methyl 2,3,4-tri-O-benzyl-a-D
-gluco-(6-2H1)hexodi-
aldo-1,5-pyranoside (5)
3.2. Methyl 2,3,4-tri-O-benzyl-a-D
-(6,6-2H2)glucopyr-
anoside (3)
Compound 3 (500 mg, 1.07 mmol) was oxidized,
according to the procedure described by Singh et al.,18 to
25
D
-(6,6-2H2)Glucose (2 g, 11.1 mmol) was suspended into
4% HCl in abs MeOH solution, and the solution was
refluxed until no
-(6,6-2H2)glucose was detected. After
give 5 (470 mg, 1.02 mmol); ½aŠ +14.1° (c 1.0, CHCl3);
D
1H NMR (C6D6, 400 MHz): d 3.07 (s, 3H, OCH3), 3.45
(dd, 1H, J1;2 3.38, J2;3 9.56 Hz, H-2), 3.60 (dd, 1H, J3;4
8.75, J4;5 10.2 Hz, H-4), 4.11 (d, 1H, J4;5 10.2 Hz, H-5),
4.24 (dd, 1H, J2;3 9.56, J3;4 8.75 Hz, H-3), 4.47 (d, 1H,
J2a;2b 12.0 Hz, H-2a), 4.53 (d, 1H, J2a;2b 12.0 Hz, H-2b),
4.63 (d, 1H, J1;2 3.38 Hz, H-1), 4.68 (d, 1H, J4a;4b 11.0 Hz,
H-4a), 4.82 (d, 1H, J3a;3b 11.3 Hz, H-3a), 4.86 (d, 1H,
J4a;4b 11.0 Hz, H-4b), 5.01 (d, 1H, J3a;3b 11.3 Hz, H-3b),
7.13–7.23 (C6H5), 7.32–7.36 (Ph); 13C NMR (C6D6,
100 MHz): d 55.3 (OCH3), 72.9 (C-2ab), 74.4 (C-5), 75.0
(C-4ab), 75.6 (C-3ab), 77.9 (C-4), 80.3 (C-2), 81.8 (C-3),
98.5 (C-1), 126.2–128.6 (Ph), 138.6 (Ph), 138.9 (Ph),
D
cooling, the solution was evaporated in vacuo to a syrup
(2 g) and was used directly in the next reaction without
further purification. The synthesis of 3 and 4 from this
syrup was accomplished as described by Ohrui et al.1
Isomers 3 and 4 were separated on a preparative
reversed-phase C18 column with 68:32 MeOH–water as
eluent to yield 3 (2.36 g, 5.06 mmol) and 4 (0.70 g,
25
D
1.50 mmol); ½aŠ +19° (c 1.1, CHCl3); 1H NMR (CDCl3,
400 MHz): d 3.35 (s, 3H, OCH3), 3.48 (dd, 1H, J1;2 3.5,
J
2;3 9.3 Hz, H-2), 3.51 (dd, 1H, J3;4 9.3, J4;5 10.0 Hz, H-4),
2
3.63 (d, 1H, J4;5 10.0 Hz, H-5), 3.99 (t, 1H, J2;3 ¼ J3;4
9.3 Hz, H-3), 4.55 (d, 1H, J1;2 3.5 Hz, H-1), 4.62 (d, 1H,
J4a;4b 11.0 Hz, H-4a-Bn), 4.65 (d, 1H, J3a;3b 12.0 Hz,
H-3a-Bn), 4.79 (d, 1H, J3a;3b 12.0 Hz, H-3b-Bn), 4.86 (d,
1H, J2a;2b 10.7 Hz, H-2a-Bn), 4.87 (d, 1H, J4a;4b 11.0 Hz,
H-4b-Bn), 4.98 (d, 1H, J2a;2b 10.7 Hz, H-2b-Bn), 7.27–
7.36 (C6H5); 13C NMR (CDCl3, 100 MHz): d 55.2
(OCH3), 61.5 (br, C-6), 70.4 (C-5), 73.4 (C-2ab), 75.0 (C-
4ab), 75.7 (C-3ab), 77.0 (C-4), 79.9 (C-2), 81.9 (C-3),
98.1 (C-1), 127.6 (Ph), 127.8 (Ph), 127.9 (Ph), 128.0 (Ph),
128.1 (Ph), 128.4 (Ph),128.5 (Ph), 138.1 (Ph), 138.7 (Ph);
139.4 (Ph), 196.5 (C-6); H NMR (C6D6, 61.4 MHz):
d 9.48 (s, 2H-6); electrospray-ion trap-MS: calcd for
C28H292HO6: m=z 463. Found: m=z 464 [M+H]þ, 486
[M+Na]þ.
3.5. Methyl 2,3,4-tri-O-benzyl-(6S)-a-D
-(6-2H1)gluco-
pyranoside (6)
Compound 6 was synthesized as described by Falcone-
Hindley and Davis11 with some modifications. To a
solution of aldehyde 5 (470 mg, 1.02 mmol) in CH2Cl2 at
room temperature was added a 0.5 M solution of R-(+)-
2
2H NMR (CDCl3, 61.4 MHz): d 3.75 (br, H-6, pro-S),

L. Xu, N. P. J. Price / Carbohydrate Research 339 (2004) 1173–1178
1177
Alpine-Boraneâ in THF (6 mL, 3 mmol). The reaction
mixture was stirred at room temperature until 5 was not
detected by mass spectrometry (usually 24 h). Acetal-
dehyde was added to quench the excess Alpine-Boraneâ.
After the solution was stirred for 1 h, the solvent was
evaporated in vacuo, and the residue was redissolved in
THF (20 mL). To the solution were added 3 M NaOH
(20 mL) and 30% H2O2 (20 mL). The solution was stir-
red for 1 h, and THF was removed in vacuo. The
aqueous solution was extracted with CH2Cl2. Following
removal of CH2Cl2 the residue was chromatographed on
a silica gel column using 60:40 hexane–EtOAc and fol-
lowed by a preparative reversed-phase C18 column with
68:32 MeOH–water as eluent to give 6 (425 mg,
3.7. Methyl (6S)-a-D
-(6-2H1)glucopyranoside (8)
To a solution of 6 (360 mg, 0.77 mmol) in EtOH (40 mL)
was added 200 mg of 10% (w/w) palladium-on-charcoal
catalyst. The solution was stirred under hydrogen
atmosphere (1 L H2 balloon) for 24 h. The reaction
mixture was filtered, and filtrate was concentrated in
vacuo. The residue was passed through a Sephadex LH-
20 column with MeOH as eluent to yield 8 (138 mg,
25
D
0.71 mmol); ½aŠ
+158° (c 1.1, H2O); 1H NMR
(CD3OD, 400 MHz): d 3.28 (dd, 1H, J3;4 8.85, J4;5
9.82 Hz, H-4), 3.37 (s, 3H, OCH3), 3.40 (dd, 1H, J1;2
3.74, J2;3 9.64 Hz, H-2), 3.50 (dd, 1H, J4;5 9.82, J5;6 5.57,
H-5), 3.59 (t, J2;3 9.64, J3;4 8.85 Hz, H-3), 3.64 (d, J5;6
5.57, H-6R), 4.65 (d, 1H, J1;2 3.74 Hz, H-1); 13C NMR
(CD3OD, 100 MHz): d 55.5 (OCH3), 62.3 (t, JC–D
21.1 Hz, C-6), 71.6 (C-4), 73.3 (C-5), 73.4 (C-2), 75.0 (C-
25
1
0.91 mmol) in 90% yield; ½aŠ +18.5° (c 1.2, CHCl3); H
D
NMR (CDCl3, 400 MHz): d 3.36 (s, 3H, OCH3), 3.50
(dd, 1H, J1;2 3.54, J2;3 9.26 Hz, H-2), 3.52 (t, 1H,
J3;4 ¼ J4;5 9.46 Hz, H-4), 3.64 (dd, 1H, J4;5 9.46, J5;6
4.05 Hz, H-5), 3.67 (d, 1H, J5;6 4.05 Hz, H-6R), 4.01 (dd,
1H, J2;3 9.26, J3;4 9.46 Hz, H-3), 4.56 (d, 1H, J1;2 3.54 Hz,
H-1), 4.64 (d, 1H, J4a;4b 11.0 Hz, H-4a-Bn), 4.67 (d, 1H,
J3a;3b 12.0 Hz, H-3a-Bn), 4.81 (d, 1H, J3a;3b 12.0 Hz,
H-3b-Bn), 4.84 (d, 1H, J2a;2b 11.0 Hz, H-2a-Bn), 4.89 (d,
1H, J4a;4b 11.0 Hz, H-4b-Bn), 4.99 (d, 1H, J2a;2b 11.0 Hz,
H-2b-Bn), 7.27–7.38 (Ph); 13C NMR (CDCl3, 100 MHz):
d 55.1 (OCH3), 61.5 (t, JC–D 21.6 Hz, C-6), 70.5 (C-5),
73.4 (C-2ab), 75.0 (C-4ab), 75.7 (C-3ab), 77.0 (C-4), 79.9
(C-2), 81.9 (C-3), 98.1 (C-1), 127.6 (Ph), 127.8 (Ph),
127.9 (Ph), 128.0 (Ph), 128.1 (Ph), 128.4 (Ph),128.5 (Ph),
2
3), 101.1 (C-1); H NMR (CD3OD, 61.4 MHz): d 3.60
(s, 2H6, S); electrospray-ion trap-MS: calcd for
C7H132HO6: m=z 195. Found: m=z 196 [M+H]þ, 218
[M+Na]þ.
3.8. (6S)-D
-(6-2H1)Glucose (9)
Compound 8 (396 mg, 2.02 mmol) was dissolved in 1 M
HCl (70 mL) and heated at 80 °C for 12 h. The reaction
mixture was cooled to room temperature and neutral-
ized with Amberlite IRA-67 resin. The solution was
filtered, and the filtrate was concentrated in vacuo. The
residue was chromatographed on Sephadex LH-20 with
MeOH as eluent to yield 9 (312 mg, 1.72 mmol) as a
2
138.1 (Ph), 138.7 (Ph); H NMR (CDCl3, 61.4 MHz):
2
d 3.77 (s, H-6, S); electrospray-ion trap-MS: calcd for
25
C28H312HO6: m/z 465. Found: m=z 466 [M+H]þ, 488
white solid; ½aŠ +55° (c 1.2, H2O); H NMR (D2O–
1
D
[M+Na]þ.
acetone-d6 400 MHz): d 3.15 (t, 1H, J1;2 ¼ J2;3 7.94 Hz,
H-2b), 3.28 (m, 1H, H-4a), 3.29 (m, 1H, H-4b), 3.35 (m,
1H, H-3b), 3.36 (m, 1H, H-5b), 3.43 (dd, 1H, J1;2 3.38,
J2;3 10.0 Hz, H-2a), 3.61 (d, 1H, H-6b), 3.62 (m, 1H,
H-3a), 3.65 (d, 1H, J5;6 3.70 Hz, H-6a), 3.74 (dd, 1H, J4;5
10.0, J5;6 3.70 Hz, H-5a), 4.55 (d, 1H, J1;2 7.94 Hz, H-1b),
5.14 (d, 1H, J1;2 3.38 Hz, H-1a); 13C NMR (D2O–ace-
tone-d6 100 MHz): d 60.5 (t, JC–D 22 Hz, C-6a), 60.8 (t,
JC–D 22 Hz, C-6b), 69.9 (C-4a), 69.9 (C-4b), 71.6 (C-5a),
71.7 (C-2a), 73.0 (C-3a), 74.4 (C-2b), 76.0 (C-3b), 76.1
(C-5b), 92.3 (C-1a), 96.1 (C-1b); electrospray-ion trap-
MS: calcd for C6H112HO6: m/z 181. Found: m=z 182
[M+H]þ, 204 [M+Na]þ.
3.6. Methyl 2,3,4-tri-O-benzyl-b-
-(6S)-(6-2H1)gluco-
pyranoside (7)
D
Compound 7 was synthesized as described above for 6;
25
D
½aŠ +8.2° (c 1.2, CHCl3); 1H NMR (CDCl3, 400 MHz):
d 3.37 (dd, 1H, J4;5 9.6, J5;6 4.6 Hz, H-5), 3.40 (dd, 1H,
J1;2 7.8, J2;3 9.1 Hz, H-2), 3.57 (s, 3H, OCH3), 3.58 (dd,
1H, J3;4 9.1, J4;5 9.6 Hz, H-4), 3.67 (t, 1H, J2;3 ¼ J3;4
9.1 Hz, H-3), 3.71 (d, 1H, J5;6 4.6 Hz, H-6R), 4.36 (d, 1H,
J1;2 7.8 Hz, H-1), 4.64 (d, 1H, J 10.9 Hz, H-4a-Bn), 4.71
(d, 1H, J 10.9 Hz, H-2a-Bn), 4.81 (d, 1H, J 10.9 Hz, H-
3a-Bn), 4.87 (d, 1H, J 10.9 Hz, H-4b-Bn), 4.91 (d, 1H, J
10.9 Hz, H-2b-Bn), 4.94 (d, 1H, J 10.9 Hz, H-3b-Bn),
7.26–7.34 (Ph); 13C NMR (CDCl3, 100 MHz): d 57.3
(OCH3), 61.7 (t, JC–D 22 Hz, C-6), 74.8 (C-4ab), 74.9 (C-
5), 75.1 (C-2ab), 75.7 (C-3ab), 77.5 (C-4), 82.3 (C-2),
84.4 (C-3), 104.8 (C-1), 127.6 (Ph), 127.7 (Ph), 127.8
(Ph), 127.9 (Ph), 128.1 (Ph), 128.4 (Ph), 128.5 (Ph), 137.9
(Ph), 138.4 (Ph), 138.5 (Ph); 2H NMR (CDCl3,
Acknowledgements
We wish to thank Dr. Sandip Sur (Dept. of Chemistry,
University of Rochester) for assistance in obtaining the
400 MHz spectra, Dr. M. W. Anders (Dept. Pharma-
cology and Physiology, University of Rochester) for the
^ ꢀ
use of the Agilent LC-ESI-MS, and Dr. Greg Cote
(NCAUR–USDA, Peoria, IL) for preliminary reviewing
the manuscript.
2
61.4 MHz): d 3.87 (s, H-6, S); electrospray-ion trap-
MS: calcd for C28H312HO6: m=z 465. Found: m=z 466
[M+H]þ, 488 [M+Na]þ.

1178
L. Xu, N. P. J. Price / Carbohydrate Research 339 (2004) 1173–1178
10. Ohrui, H.; Misawa, T.; Meguro, H. Agric. Biol. Chem.
1984, 48, 1825–1829.
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