Synthesis of L-glucose from D-gulono-1,4-lactone

Article abstract of DOI:10.1016/S0008-6215(99)00192-5

An efficient method for the synthesis of L-glucose from D-gulono-1,4-lactone via 1,2,3,4,5-penta-O-benzyl/acetyl/benzoyl-D-gulitol is described in 34-53% overall yield. Copyright (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0008-6215(99)00192-5

www.elsevier.nl/locate/carres
Carbohydrate Research 321 (1999) 116–120
Note
Synthesis of
L
-glucose from
D
-gulono-1,4-lactone
Ja´nos Hajko´ , Andra´s Lipta´k a,*, Vince Pozsgay b
a
a Research Group for Carbohydrates of the Hungarian Academy of Sciences, PO Box 55,
H-4010 Debrecen, Hungary
b Laboratory of De6elopmental and Molecular Immunity,
National Institute of Child Health and Human De6elopment, National Institutes of Health, Bethesda,
MD 20892-2720, USA
Received 7 June 1999; accepted 24 July 1999
Abstract
An efficient method for the synthesis of
benzoyl-
L
-glucose from
D
-gulono-1,4-lactone via 1,2,3,4,5-penta-O-benzyl/acetyl/
D
-gulitol is described in 34–53% overall yield. © 1999 Elsevier Science Ltd. All rights reserved.
Keywords: Monosaccharide; -Glucose; Unnatural carbohydrate
L
Unnatural carbohydrates have been gaining
increasing importance as synthons for the
preparation of chiral natural products [1,2]
and their analogs [3,4] and as probes in the
study of biological processes [5]. One of the
most important unnatural monosaccharides is
As part of our program [14] aimed at the
development of glycoconjugate vaccines
against diseases caused by Shigella sonnei, we
have reported syntheses of the monosaccharide
components of the O-specific polysaccharide
of this bacterium, using
starting material [14a]. The logic of our syn-
thetic plan is that -glucose is related to -gu-
L-glucose as a key
L
-glucose (1), which has been targeted by
many investigators using a variety of chemical
L
D
and/or enzymatic methods. The initial ap-
lose through inverted oxidation states of their
respective C-1 and C-6 carbon atoms. Thus,
proaches involved chain elongation of -ara-
L
binose by the cyanohydrin [6] and the
nitromethane procedures [7,8]. Other protocols
conversion of C-6 of
hydo function and reduction of its C-1 to a
hydroxymethyl group should lead to -glu-
D
-gulose into an alde-
include reduction of
L
-glucono-6,3-lactone [9],
-glucose and -ara-
L
multistep syntheses from
D
L
cose. Here we describe how this idea was tested
and put into practice.
binose [10], an iterative two-carbon extension
cycle consisting of asymmetric epoxidation fol-
lowed by regioselective and stereospecific ring
opening [11], asymmetric Diels–Alder reaction
[12], and enzymatic syntheses [13].
Commercially available
D
-gulono-1,4-lac-
tone (2) was selected as the starting material.
Regioselective protection of O-6 by a trityl
group [15] (“3) followed by reduction [16]
with NaBH4 gave the corresponding gulitol
derivative 4, which was isolated as its acetate 5
in 76% overall yield from 1. Routine replace-
* Corresponding author. Tel.: +36-52-512-900/2256; fax:
+36-52-512-913.
E-mail address: liptaka@tigris.klte.hu (A. Lipta´k)
0008-6215/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(99)00192-5

J. Hajko´ et al. / Carbohydrate Research 321 (1999) 116–120
117
ment of the acetyl groups of 5 by benzyls in a
two-step sequence [(i) NaOMe–MeOH; (ii)
BnBr–NaH] afforded compound 6 from
which hydrolytic removal [17] of the trityl
group furnished the alcohol 7 in 59% overall
yield from 2 (six steps). Next, compound 7
was oxidized by the CrO3–pyridine complex
in the presence of Ac2O [18] to afford the
aldehyde derivative 8. As the final step in this
sequence, catalytic hydrogenolysis of benzyl
groups provided 1 in 84% yield. Although the
ether-protected intermediates did afford the
targeted 1, the overall yield was moderate
(34% from 2, eight steps). In the hope of
higher overall yields, the use of O-acyl-pro-
tected intermediates were examined next.
Thus, 4 was benzoylated (“9), then the fully
Kieselgel 60 (0.063–0.2 mm, E. Merck). Thin-
layer chromatography (TLC) was performed
on Kieselgel 60 F254 (E. Merck) plates. Com-
pounds were visualized by spraying with aq
50% sulfuric acid followed by heating. Optical
rotations were measured with a Perkin–Elmer
1
241 polarimeter at room temperature (rt). H
and 13C NMR spectra were recorded at 200
and 50 MHz nominal frequencies in CDCl3
solutions using Me4Si as the internal refer-
ence, except where indicated otherwise. The
mass spectra were recorded in the chemical
ionization mode using NH3 as the ionizing
gas.
6-O-Trityl-
D
-gulono-1,4-lactone (3).—A so-
lution of -gulonic g-lactone (2, 10 g, 56
D
mmol) and TrCl (18.7 g, 67 mmol) in dry
pyridine (80 mL) was stirred overnight at rt.
The reaction mixture was diluted with
CH2Cl2, and neutralized with 4 M aq HCl.
The mixture was extracted with water. The
organic layer was dried (MgSO4) and concen-
trated. The residue was used directly in the
next reaction. Selected 13C NMR: l 175.98
(C-1), 87.06 (CPh3), 79.34, 70.74, 70.52, 69.45
(C-2,3,4,5), 63.61 (C-6).
acylated
D-gulo-derivatives 5 and 9 were de-
tritylated with 7:3 HCO2H–Et2O [19] and
BF3·Et2O [20] to give alditols 10 and 11, re-
spectively. Dess–Martin oxidation [21] of al-
cohols 10 and 11 proved to be superior to
other oxidation methods and afforded the de-
sired aldehydes 12 and 13, respectively, in
clean reactions. On the other hand, attempted
oxidation of 11 with either Me2SO–Ac2O [22]
or pyridine–SO3 in Me2SO in the presence of
Et3N [23] was accompanied by rapid elimina-
tion [24] of a benzoyl group from the newly
formed aldehyde 13. In the final steps,
NaOMe-promoted trans-esterification re-
moved the acyl protecting groups from 12 and
13 to afford 1 in 53 (six steps) and 43% overall
yields (eight steps), respectively, from the
commercially available precursor 2.
6-O-Trityl- -gulitol (4).—To a solution of
D
crude 3 in dry MeOH (200 mL) was added
NaBH4 (6.4 g, 168 mmol) and NaOMe (0.6 g,
11 mmol) at 0 °C. The mixture was stirred
overnight, then the excess of NaBH4 was de-
composed with glacial AcOH. The mixture
was concentrated. MeOH was added to and
evaporated from the residue several times. The
residue was used for the next step without
further purification. Selected 13C NMR
(CD3OD): l 87.91 (CPh3), 74.20, 73.97, 73.00,
70.80 (C-2,3,4,5), 66.20, 64.79 (C-1,6).
In conclusion, we have developed a simple
protocol for the preparation of the unnatural
sugar -glucose. Our method uses inexpensive
L
reagents and avoids the formation of
diastereomeric mixtures that were reported in
many previously described approaches. These
advantages, combined with high overall yields
should make our approach a competitive one
to other methods reported previously.
1,2,3,4,5-Penta-O-acetyl-6-O-trityl- -guli-
D
tol (5).—A solution of crude 4 in dry pyridine
(150 mL) and Ac2O (100 mL) was stirred
overnight at rt. The reaction mixture was con-
centrated. Toluene was added to and evapo-
rated from the residue several times. A
solution of the residue in CH2Cl2 was ex-
tracted with water. The organic phase was
dried (MgSO4) and concentrated. The residue
was used directly in the next reaction. A por-
tion of the crude product was purified by
column chromatography (49:1“9:1 CH2Cl2–
acetone) to give 5; [h]D −29.6° (c 0.47,
1. Experimental
General.—Organic solutions were concen-
trated under reduced pressure at 40 °C (bath).
Column chromatography was performed on

118
J. Hajko´ et al. / Carbohydrate Research 321 (1999) 116–120
1ab,2,3,4,5,6ab), 2.01 (s, 1 H, OH); 13C NMR: l
138.56–138.21 (Cquat), 128.24–127.51 (5 Ph),
79.27 (2C), 78.94, 78.58 (C-2,3,4,5), 74.67,
73.78, 73.27, 72.61, 71.91 (5 PhCH2), 69.57
(C-1), 61.73 (C-6); MS m/z 650 [M+NH4]+.
Anal. Calcd for C41H44O6: C, 77.82; H, 7.01.
Found: C, 78.01; H, 7.04.
1
CHCl3); H NMR: l 7.48–7.18 (m, 15 H, 3
Ph), 5.88 (dd), 5.33 (dd), 5.03 (m) (4 H, H-
2,3,4,5), 4.23 (dd, 1 H, H-1a), 4.06 (dd, 1 H,
H-1b), 3.25 (m, 2 H, H-6ab), 2.10–1.97 (5 s, 15
H, 5 CH3CO); 13C NMR: l 170.40, 170.02,
169.73, 169.65, 169.36 (5 CꢀO), 143.38 (Cquat),
128.54–127.12 (3 Ph), 86.75 (CPh3), 71.30,
68.26 (3C) (C-2,3,4,5), 61.67, 61.42 (C-1,6),
20.77–20.44 (5 CH3CO); MS m/z 652 [M+
NH4]+. Anal. Calcd for C35H38O11: C, 66.24;
H, 6.03. Found: C, 66.05; H, 6.01.
2,3,4,5,6-Penta-O-benzyl-aldehydo- -glucose
L
(8).—To a stirred mixture of dry CH2Cl2 (15
mL) and dry pyridine (1.8 mL, 22.3 mmol)
,
containing powdered 4 A molecular sieves
1,2,3,4,5-Penta-O-benzyl-6-O-trityl-
D
-gulitol
(0.55 g) was added finely powdered CrO3 (1.11
g, 11.1 mmol) at 0 °C. The suspension was
stirred for 20 min and was then treated, suc-
cessively, with a solution of 7 (1.76 g, 2.8
mmol) in dry CH2Cl2 (10 mL) and Ac2O (1.05
mL, 11.1 mmol) added dropwise. After 30
min, the mixture was diluted with Et2O (80
mL), and was filtered through a layer of silica
using EtOAc as the eluant. Column chromato-
graphic purification of the residue (4:1 hex-
ane–EtOAc) afforded 8 (1.2 g, 69%); [h]D
−2.9° (c 0.42, CHCl3); 13C NMR (90 MHz):
l 200.68 (C-1), 138.43–137.30 (Cquat), 129.69–
126.65 (5 Ph), 80.77, 79.95, 78.07, 77.14 (C-
2,3,4,5), 73.98, 73.59, 73.27, 72.97, 71.68 (5
PhCH2), 68.44 (C-6); MS m/z 648 [M+
NH4]+. Anal. Calcd for C41H42O6: C, 78.07;
H, 6.71. Found: C, 77.90; H, 6.69.
(6).—To a solution of crude 5 (4 g, approxi-
mately 6.3 mmol) in MeOH (100 mL) was
added NaOMe (pHꢀ8–9) at rt. The mixture
was stirred for 3 h and was then concentrated.
To a solution of the residue in DMF (30 mL)
were added successively 60% NaH (1.9 g 47.5
mmol) and BnBr (4.5 mL, 37.9 mmol) at 0 °C.
The mixture was stirred overnight. The mix-
ture was treated with MeOH and diluted with
toluene. The solution was extracted succes-
sively with 1 M H2SO4 and water, was dried
(MgSO4), and concentrated. The residue was
used directly in the next reaction. A portion of
the residue was purified by column chro-
matography (49:1“19:1 hexane–EtOAc) to
give 6; [h]D −10.6° (c 0.38, CHCl3); 1H
NMR: l 7.56–7.16 (m, 40 H, 8 Ph), 4.84–4.31
(m, 10 H, 5 PhCH2), 4.15–3.33 (m, 8 H,
1,2,3,4,5-Penta-O-benzoyl-6-O-trityl- -guli-
D
13
H-1ab,2,3,4,5,6ab); C NMR: l 143.86, 138.60
tol (9).—To a solution of 5 (4 g, approxi-
mately 6.3 mmol) in MeOH (100 mL) was
added NaOMe (pHꢀ8–9) at rt. The mixture
was stirred for 3 h followed by concentration.
To a stirred solution of the residue in dry
pyridine (15 mL), BzCl (5.6 mL, 48.2 mmol)
was added dropwise at 0 °C. The mixture was
stirred overnight then was diluted with
CH2Cl2. The resulting solution was extracted
with water, dried (MgSO4), and concentrated.
A portion of the residue was purified by
column chromatography (17:3 hexane–
EtOAc) to give 9; [h]D −27.2° (c 0.47,
CHCl3); 13C NMR (90 MHz): l 165.91–
164.78 (5 CꢀO), 143.33 (Cquat), 133.56–126.96
(8 Ph), 86.94 (CPh3), 72.58, 69.33 (3C) (C-
2,3,4,5), 62.49, 61.94 (C-1,6); MS m/z 962
[M+NH4]+. Anal. Calcd for C60H48O11: C,
76.26; H, 5.12. Found: C, 76.10; H, 5.13.
(Cquat), 128.68–126.87 (8 Ph), 8 (CPh3),
79.60–79.02 (C-2,3,4,5), 74.79, 73.97, 73.17,
72.84, 71.62 (5 PhCH2), 69.65 (C-1), 63.16
(C-6); MS m/z 892 [M+NH4]+. Anal. Calcd
for C60H58O6: C, 82.35; H, 6.68. Found: C,
82.55; H, 6.70.
1,2,3,4,5-Penta-O-benzyl- -gulitol (7).—A
D
solution of crude 6 in 80% aq AcOH (50 mL)
was stirred at 60 °C for 2 h. The mixture was
cooled and kept at 4 °C overnight. The solids
were removed by filtration. The filtrate was
diluted with CH2Cl2 and the resulting solution
was neutralized with K2CO3. The organic
layer was washed with water, dried (MgSO4),
and concentrated. Purification of the residue
by column chromatography (4:1 hexane–
EtOAc) afforded 7 (2.34 g, 59% for six steps);
1
[h]D +3.4° (c 0.81, CHCl3); H NMR: l
7.37–7.19 (m, 25 H, 5 Ph), 4.79–4.41 (m, 10
H, 5 PhCH2), 4.00–3.46 (m, 8 H, H-
1,2,3,4,5-Penta-O-benzoyl-
To a solution of crude 9 (1.80 g) in dry
D
-gulitol (11).—

J. Hajko´ et al. / Carbohydrate Research 321 (1999) 116–120
119
CH2Cl2 (80 mL) were added successively
BF3·Et2O (0.25 mL) and dry MeOH (0.8 mL).
The mixture was stirred for 2 h and then
diluted with CH2Cl2. The solution was ex-
tracted successively with satd aq NaHCO3
solution and water, was dried (MgSO4), and
(8:5:1 CH2Cl2–MeOH–H2O) gave 1 (43 mg,
84%); [h]D −52.2° (c 0.44, H2O, equilibrium),
lit. −52.6° [7], −52.0° [8a], −53° [9], −
52.9° [10a], −52° [12]; Anal. Calcd for
C6H12O6: C, 40.00; H, 6.71. Found: C, 40.10;
H, 6.69.
concentrated.
Column
chromatographic
(B) A solution of 5 (1.27 g, approximately
2.0 mmol) in 7:3 HCOOH–Et2O (10 mL) was
stirred at rt for 20 min and was then diluted
with Et2O. The resulting solution was succes-
sively extracted with satd aq NaHCO3 solu-
tion and water, dried (MgSO4), and
concentrated (“10). The residue was used in
the preparation of 12 without further treat-
ment. A solution of 10 (0.90 g, approximately
2.0 mmol) in dry CH2Cl2 (12 mL) was added
to a stirred solution of 1,1,1-triacetoxy-1,1-di-
hydro-1,2-benziodoxol-3(1H)-one (1.26 g, 3.0
mmol) in dry CH2Cl2 (15 mL). After 1 h, the
reaction mixture was diluted with Et2O and
poured into satd aq NaHCO3 (60 mL) con-
taining Na2S2O3 (12 g). The mixture was
stirred until the solids dissolved. The organic
layer was extracted with water, dried
purification of the residue (7:3 hexane–
EtOAc) afforded 11 (0.81 g, 61% for six
1
steps); [h]D −37.5° (c 0.36, CHCl3); H NMR
(360 MHz): l 8.03–7.87 (m, 10 H), 7.50–7.20
(m, 15 H, 5 Ph), 6.23 (m), 5.87 (m), 5.59 (m),
4.84 (dd), 4.56 (dd), 4.09 (dd) (8 H, H-
13
1ab,2,3,4,5,6ab), 2.77 (bs, 1 H, OH); C NMR
(90 MHz): l 165.91–165.22 (5 CꢀO), 133.54–
128.10 (5 Ph), 73.56, 70.01, 69.64, 69.11 (C-
2,3,4,5), 62.48, 60.87 (C-1,6); MS m/z 720
[M+NH4]+. Anal. Calcd for C41H34O11: C,
70.08; H, 4.88. Found: C, 70.25; H, 4.89.
L
-Glucose (1).—(A) A mixture of 8 (125
mg, 0.2 mmol), 5% Pd–C (200 mg) and EtOH
(4 mL) was stirred under H2 at rt for 12 h, and
then filtered through a layer of Celite. Column
chromatographic purification of the residue
Scheme 1. Reagents and conditions: (a) TrCl, pyridine; (b) NaBH4, NaOMe, MeOH; (c) Ac2O, pyridine, 76% for three steps; (d)
1. NaOMe, MeOH 2. BnBr, NaH; (e) 1. NaOMe, MeOH 2. BzCl, pyridine; (f) 6, 80% AcOH, 59% for six steps; (g) 5, 7:3
HCOOH–Et2O; (h) 9, MeOH, BF3Et2O, CH2Cl2, 61% for six steps; (i) 7, CrO3, pyridine, Ac2O, CH2Cl2, 69%; (j) 10 or 11,
Dess–Martin periodinane; (k) 8, 5% Pd–C/H2, EtOH, 84%; (l) 12 or 13, NaOMe, MeOH, 70% from 5 or 71% from 11.

120
J. Hajko´ et al. / Carbohydrate Research 321 (1999) 116–120
[2] M. Bols, Carbohydrate Building Blocks, Wiley, New
York, 1996.
[3] W.A. Szarek, J.K.N. Jones, Ger. Offen. 2,816,268; Chem.
Abstr., 90 (1979) 121973m.
[4] A.F. Hadfield, A.C. Sartorelli, Carbohydr. Res., 72
(1979) 235–242.
[5] H. Shibuya, M. Kurosu, K. Minagawa, S. Katayama, I.
Kitagawa, Chem. Pharm. Bull., 41 (1993) 1534–1544.
[6] E. Fischer, Ber. Dtsch. Chem. Ges., 23 (1890) 2611–2624.
[7] J.C. Sowden, H.O.L. Fischer, J. Am. Chem. Soc., 69
(1947) 1963–1965.
[8] (a) R. Kuhn, P. Klesse, Chem. Ber., 91 (1958) 1989–
1991. (b) V. B´ılik, Chem. Z6esti, 26 (1972) 187–189.
[9] W. Sowa, Can. J. Chem., 47 (1969) 3931–3934.
[10] (a) W.A. Szarek, G.W. Hay, D.M. Vyas, E.R. Ison,
L.J.J. Hronowski, Can. J. Chem., 62 (1984) 671–674. (b)
M. Shiozaki, J. Org. Chem., 56 (1991) 528–532. (c) P.
Smid, D. Noort, H.J.G. Broxterman, N.C.R. van
Straten, G.A. van der Marel, J.H. van Boom, Recl. Tra6.
Chim. Pays-Bas, 111 (1992) 524–528.
(MgSO4), and concentrated to give 12 (0.90 g).
To solutions of 12 (0.9 g) in MeOH (10 mL)
was added NaOMe (pHꢀ8–9) at rt. After 3
h, the solution was neutralized with Amberlite
IR-120 (H+) followed by filtration and con-
centration. Column chromatographic purifica-
tion of the residue afforded amorphous 1 [191
mg, 53% from 2 (six steps)]. Treatment of a
sample by Ac2O and pyridine afforded
1,2,3,4,6-penta-O-acetyl- -glucopyranose as a
L
45/55 mixture of the a and b anomers (1H
NMR); [h]D −44.8° (c 0.87, CHCl3), lit. −
54.5°, a/b=4/5 [10c]; MS m/z 408 [M+
NH4]+. Anal. Calcd for C16H22O11: C, 49.23;
H, 5.68. Found: C, 49.35; H, 5.69.
(C) To a stirred solution of Dess–Martin
periodinane (0.42 g, 1.0 mmol) in dry CH2Cl2
(5 mL) was added a solution of 11 (0.35 g,
0.50 mmol) in dry CH2Cl2 (4 mL) at rt. After
1 h, the reaction mixture was diluted with
Et2O and the resulting solution was poured
into satd aq NaHCO3 (20 mL) containing
Na2S2O3 (4 g). The mixture was processed as
described for compound 12 to afford 13 (0.35
g), 13 was then deacetylated as described
[11] S.Y. Ko, A.W.M. Lee, S. Masamune, L.A. Reed III,
K.B. Sharpless, F.J. Walker, Tetrahedron, 46 (1990)
245–264.
[12] M. Bednarski, S. Danishefsky, J. Am. Chem. Soc., 108
(1986) 7060–7067.
[13] (a) C.R. Johnson, A. Golebiowski, D.H. Steensma, J.
Am. Chem. Soc., 114 (1992) 9414–9418. (b) R.L. Root,
J.R. Durrwachter, C.-H. Wong, J. Am. Chem. Soc., 107
(1985) 2997–2999. (c) R. Alajar´ın, E. Garc´ıa-Junceda,
C.-H. Wong, J. Org. Chem., 60 (1995) 4294–4295.
[14] (a) A. Medgyes, E. Farkas, A. Lipta´k, V. Pozsgay,
Tetrahedron, 53 (1997) 4159–4178. (b) Gy. Batta, A.
Lipta´k, R. Schneerson, V. Pozsgay, Carbohydr. Res., 305
(1997) 93–99.
.
above (B) and gave amorphous 1 [64 mg, 71%
from 11 (two steps)] (Scheme 1).
[15] B. Helferich, Ad6. Carbohydr. Chem., 3 (1948) 79–111.
[16] M.L. Wolfrom, H.B. Wood, J. Am. Chem. Soc., 73
(1951) 2933–2934.
[17] R. Kuhn, H. Rudy, F. Weygand, Ber. Dtsch. Chem. Ges.,
69 (1936) 1546–1547.
Acknowledgements
[18] P.J. Garegg, B. Samuelsson, Carbohydr. Res., 67 (1978)
267–270.
[19] M. Bessodes, D. Komiotis, K. Antonakis, Tetrahedron
Lett., 27 (1986) 579–580.
[20] C. du Mortier, O. Varela, R.M. de Lederkremer, Carbo-
hydr. Res., 189 (1989) 79–86.
[21] (a) D.B. Dess, J.C. Martin, J. Org. Chem., 48 (1983)
4155–4156. (b) D.B. Dess, J.C. Martin, J. Am. Chem.
Soc., 113 (1991) 7277–7287. (c) R.E. Ireland, L. Liu, J.
Org. Chem., 58 (1993) 2899.
We thank the Mizutani Foundation and the
Howard Hughes Medical Institute for finan-
cial support and the Hungarian Scientific Re-
search Fund (OTKA) for a postdoctoral
fellowship to J.H.
References
[22] J.D. Albright, L. Goldman, J. Am. Chem. Soc., 87 (1965)
4214–4216.
[23] J.R. Parikh, W. von, E. Doering, J. Am. Chem. Soc., 89
(1967) 5505–5507.
[24] G.M. Cree, D.W. Mackie, A.S. Perlin, Can. J. Chem., 47
(1969) 511–512.
[1] (a) M. Kluge, B. Schneider, D. Sicker, Carbohydr. Res.,
298 (1997) 147–152. (b) E.R. Marinez, E.K. Salmassian,
T.T. Lau, C.G. Gutierrez, J. Org. Chem., 61 (1996)
3548–3550.