A facile and general synthesis of rare L-sugar lactones

Article abstract of DOI:10.1055/s-2007-977451

A facile and general synthesis of rare L-sugar lactones from D-sugars by selectively inverting C-5 was developed. Selective 1-deacylation of sugar perpivaloates by hydroxylamine is described. More practically, β-D-glucose pentaacetate could be transformed to L-idono-1,4-lactones by this simple procedure. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-977451

LETTER
1247
A Facile and General Synthesis of Rare L-Sugar Lactones
S
R
ynthesis of Rare
a
L
-
Sugar
L
w
a
Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA
Fax +1(517)3539334; E-mail: rih@afidtherapeutics.com; E-mail: rih@cem.msu.edu
b
Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA
Received 16 September 2006
Abstract: A facile and general synthesis of rare L-sugar lactones
from D-sugars by selectively inverting C-5 was developed. Selec-
tive 1-deacylation of sugar perpivaloates by hydroxylamine is de-
scribed. More practically, b-D-glucose pentaacetate could be
transformed to L-idono-1,4-lactones by this simple procedure.
Key words: L-sugar, aldonolactone, 1-deacylation
Except for a few configurations such as arabinose and xy-
lose, L-sugars are rare in nature. Some such as L-iduronic
1
acid, L-rhamnose and L-fucose are important components
in biological systems although they are found in very low
abundance. Some L-nucleosides have shown great potent
2
as antiviral agents. Practical and general methods for the
synthesis of L-sugars are therefore of interest. Ikegami et
al. developed a useful method of synthesizing L-hexoses
3
a
by inverting C-5 of D-glycono-1,5-lactones and a related
3
b
synthesis of L-ribose. The starting materials involved in
this synthesis, however, are relatively expensive. The sep-
aration of side products in Mitsunobu reactions is always
another issue. Lee et al. employed mesylate substitution to
invert certain position of sugar lactones to prepare rare
sugar such as L-ribose. Here we introduce a general and Figure 1 1H and 13C NMR spectra of the starting material (com-
4
pound 3) and the hydrolysis intermediate after refluxing in MeOH–
facile synthesis of L-sugar lactones from D-sugars.
1
H O for 24 h. (a) H NMR spectra comparison; (b) carbon NMR spec-
2
2
,3,4,6-Tetra-O-trimethylacetyl-D-glucose (1) was treated tra comparison. The H-5 signal in the proton spectrum of the unhydro-
with hydroxylamine (Scheme 1) hydrochloric acid salt in lyzed compound is at d = ca. 5 ppm and the H-6 signals are between
d = 4.0 and 4.6 ppm. Note the disappearance of the H-6 signals in (a)
pyridine to give an aldoxime 2. Treatment of 2 with meth-
anesulfonyl chloride afforded 5-O-methanesulfonyl-
and the appearance of new signals at d = ca. 4.1 ppm in (b). Note also
1
3
the shift of the C-6 signal in the C spectrum from d = ca. 61 ppm to
d = ca. 63 ppm.
2
,3,4,6-tetra-O-pivaloyl D-gluconitrile (3) with the 5-po-
sition derivatized to a good leaving group. Hydrolysis of
this orthogonally protected and derivatized D-gluconitrile
with hydrochloric acid in ethanol yielded L-idono-1,4-lac-
tone 4.
groups or the possible carboxylic acid/amide from nitrile
hydrolysis. To probe the reaction mechanism, compound
3
was refluxed in methanol–water for 24 hours and the so-
The acidic displacement of the mesyl (-OMs) group could lution turned acidic. NMR analyses of this hydrolysate
result from the attack of neighboring pivaloyl carbonyl (Figure 1) indicated that the OMs group had been
OH
OPiv
OMs
OPiv
OH
OPiv
O
HO
O
c
b
PivO
PivO
O
a
PivO
PivO
PivO
PivO
N
H
OH
N
OH
OPiv
PivO
OPiv
HO
OH
2
3
1
4
Scheme 1 Synthesis of L-idono-1,4-lactone from 2,3,4,6-tetra-O-trimethylacetyl-D-glucose (1). Reagents and conditions: a) hydroxylamine
hydrogen chloride salt, pyridine, 90%; b) MsCl, pyridine, 88%; c) HCl, EtOH–H O, 85%.
2
SYNLETT 2007, No. 8, pp 1247–1250
1
6.
0
5.
2
0
0
7
Advanced online publication: 08.05.2007
DOI: 10.1055/s-2007-977451; Art ID: S17406ST
©
Georg Thieme Verlag Stuttgart · New York

1
248
X. Song, R. I. Hollingsworth
LETTER
t-Bu
H2O
O
t-Bu
O
t-Bu
O
OH
O
OPiv
H2O
O
H+
O
S
t-Bu
O
PivO
O
PivO
PivO
3
O
PivO
O
N
+
N
N
PivO
PivO
PivO
5
6
7
R3
H2O, or intra-
molecular -OH
R2
OH
R1
PivO
HO
further hydrolysis
cyclization
HO
HO
N
4
PivO
COOH
H+
HO
8
9
R , R = OPiv, R3 = OH
1
2
or R , R = OPiv, R2 = OH
1
3
or R , R = OPiv, R1 = OH
2
3
Scheme 2 The proposed mechanism of formation of L-idono-1,4-lactone 4 by a simple acidic treatment of 5-O-methanesulfonyl-2,3,4,6-tetra-
O-pivaloyl D-gluconitrile 3.
removed but the nitrile group was still unchanged. This the 6-pivaloyl group is dominant because of the shift of
indicated that the OMs group was displaced by a neigh- both the proton and C-13 signals for this position.
boring pivaloyl groups.
The procedure described above is essentially applicable to
The proposed mechanism of the inversion of the 5-posi- all aldoses and should constitute a practical route towards
tion under acidic condition is shown in Scheme 2. It is L-aldonolactones since no expensive reagents and tedious
possible that the 5-position OMs is attacked intramolecu- separations are involved. Some other abundant aldoses
larly by the neighboring 4- or 6-pivaloyl group to give a were also subjected to this procedure and several other
mixture of tert-butyl-1,3-dioxolanylium cations 6 and 7. rare L-sugar lactones were synthesized (Table 1).
Intermediates 6 and 7 are quenched by water to give a
mixture of three possible D-gluconitrile tetrapivaloates.
We also explored the possibility of directly using sugar
perpivaloates as the starting materials. Hydrazine is wide-
Neighboring group participation in the displacement of
ly used in the selective 1-O-deacylation of protected sug-
5
OMs group has been reported by Acton et al., although
ars. Based on the structure similarity of hydrazine and
under basic condition. Both the pivaloyl groups and the
hydroxylamine, we proposed that hydroxylamine might
nitrile group are then completely hydrolyzed to give L-
also act as a deacylating reagent. Therefore it is possible
idonic acid, which spontaneously cyclize to L-idono-1,4-
that sugar oximes could be obtained directly from sugar
perpivaloate 19 by combining deacylation and oxime for-
lactone. It is clear from Figure 1 that the participation of
Table 1 Synthesis of L-Sugar Lactones from Sugar Pivaloates
Entry
1
Substrate
Intermediate
Product
Yield (%)
PivO
OPiv
O
PivO
PivO
OPiv
OH
OMs
CN
HO
O
PivO
PivO
OH
O
PivO
H
76
10
13
HO
OH
16
OPiv
PivO
OPiv
OH
OPiv
O
OPiv
OMs
HO
O
O
OH
PivO
H
2
3
CN
72
69
OPiv
PivO
HO
OH
O
1
1
14
1
7
O
OMs
O
PivO
OH
HO
PivO
CN
H
H
H
PivO
OPiv
HO
OH
PivO
OPiv
18
12
15
Synlett 2007, No. 8, 1247–1250 © Thieme Stuttgart · New York

LETTER
Synthesis of Rare L-Sugar Lactones
1249
OPiv
O
OPiv
O
OPiv
a
long reaction time
OH
PivO
PivO
PivO
PivO
PivO
PivO
OPiv
OH
N
OH
OPiv
OPiv
OPiv
19
1
2
Scheme 3 Treatment of glucose pentapivaloate with hydroxylamine. Reagents and conditions: a) freshly prepared hydroxylamine, pyridine,
r.t., 24 h, 85%.
OAc
OMs
OAc
OH
OAc
O
b
a
AcO
AcO
AcO
AcO
AcO
AcO
N
OAc
OH
N
OAc
AcO
22
OAc
21
20
c
d
R3
R2
OH
H
OH
OMs
d
R1
AcO
HO
O
O
HO
HO
N
AcO
N
HO
HO
OH
23
4
1
2
3
R , R = OAc, R = OH
complicated mixture
1
3
2
or R , R = OAc, R = OH
2
3
1
or R , R = OAc, R = OH
Scheme 4 Synthesis of L-idono-1,4-lactone from b-D-glucose pentaacetate. Reagents and conditions: a) hydroxylamine hydrogen chloride,
pyridine; 88%; b) MsCl, pyridine; 90%; c) MeCN–H O, reflux; d) HCl, EtOH, H O; 75%.
2
2
mation in the same step without separation of 1. Com- In summary, we developed a practical and general synthe-
pound 19 was successfully transformed into compound 1 sis of L-aldono-1,4-lactones from aldose perpivaloates
by treatment with hydroxylamine (Scheme 3) within 1 and peracetates by selectively inverting the C-5 positions.
day. However, formation of glucose oxime 2 from hy- Several rare-L-sugar lactones were prepared conveniently.
droxylamine is much slower than that from hydroxyl- It is highly possible that this methodology could be ap-
amine hydrochloride salt. This is not a surprise since it is plied in the synthesis of other rare sugars. It should be not-
well known that oxime formation is favored by lower pH ed that the acid-catalyzed displacement of mesyl groups
6
value. A similar result was observed with D-mannose and under similar conditions to form furans has been noted be-
7
D-galactose pentapivaloates.
fore. The intramolecular base-catalyzed displacement of
mesyl groups to form ethers is the norm.
To further improve the practicability of this procedure,
acetyl group was employed as the protecting group. Inter-
estingly, when b-D-glucose pentaacetate was treated with
hydroxylamine hydrogen chloride in pyridine, the sugar General Experimental Procedure for L-Aldonolactone Synthe-
sis
oxime 21 was yielded directly, greatly improving the effi-
ciency. Treatment with methanesulfonyl chloride afford-
ed oxime dehydration and 5-O-mesylation in the same
step to give 22. When 22 was subjected to the same hy-
Anomeric-free sugar tetrapivaloates (for D-gluco, D-manno and D-
galacto configurations) or tripivaloate (for D-ribo configuration)
was dissolved in pyridine [5 mL/g starting material (SM)] with hy-
droxylamine hydrogen chloride salt (1.2 g/g SM). The solution was
drolysis employed above for pivaloyl-protected sugar ni- stirred at r.t. for 24 h. Then, CH Cl (15 mL/g SM) was added and
2
2
triles, however, a complicated mixture was obtained the mixture was filtered. The filtrate was washed with H O, dried
2
and evaporated to afford the sugar oxime. The crude sugar oxime
(
Scheme 4). It is possible that under this condition, acetyl
was dissolved in pyridine (5 mL/g) and cooled to 0 °C. Then, MsCl
2.5 equiv) was added slowly. The mixture was warmed to r.t. slow-
groups were deprotected in the same rate as that for mesyl
groups, if not faster. This might trigger attack of the OMs
group by neighboring hydroxy groups, yielding compli-
cated anhydrosugars and products generated from their
(
ly and stirred for 8 h. It was then poured to cold NaHCO solution
3
and extracted by CH Cl . The organic layer was dried and evaporat-
2
2
ed to dryness. The residue was purified by flash column chromatog-
hydrolysis. This problem was successfully solved by re- raphy to afford the mesylated sugar nitrile. The mesylated sugar
fluxing 22 in acetonitrile and water first, which only dis- nitrile was refluxed in 1–3 N HCl in 1:1 mixture of EtOH and H O
2
for 4–16 h. The solution was then evaporated to dryness to yield the
place the OMs group. The resulted mixture was then
refluxed in acidic aqueous ethanol to yield L-idono-1,4-
lactone 4 in a similar yield as that when pivaloyl group
L-sugar lactone. They can be purified by flash column chromatog-
8
raphy. Their spectroscopic properties match those from literature.
was used as the protecting group.
Synlett 2007, No. 8, 1247–1250 © Thieme Stuttgart · New York

1
250
X. Song, R. I. Hollingsworth
LETTER
5
-O-Methanesulfonyl-2,3,4,6-tetra-O-pivaloyl-D-gluconitrile (3):
5-O-Methanesulfonyl-2,3,4,6-tetra-O-acetyl-D-gluconitrile (22):
[a]D +28.1 (c 1.8, CHCl3); HRMS–FAB: m/z calcd for
[
a]D +29.08 (c 0.8, CHCl ). HRMS–FAB: m/z calcd for
3
+
1
+
1
C H NO S: 591.2713; found: 592.2789 [MH ]. H NMR (500
C H NO S: 423.0835; found: 424.0911 [MH ]. H NMR (500
2
7
45
11
15 21 11
MHz, CDCl ): d = 1.24, 1.27, 1.29, 1.30 (4 × 9 H, 4 × s), 3.12 (3 H,
MHz, CDCl ): d = 2.13, 2.19, 2.23, 2.24, (4 × 3 H, 4 × s), 3.11 (3 H,
3
3
s), 4.12 (1 H, dd, J5 = 4.6 Hz, J = 13.0 Hz, H-6¢), 4.52 (1 H, dd,
s), 4.26 (1 H, dd, J = 5.6 Hz, J = 12.8 Hz, H-6¢), 4.41 (1 H, dd,
,6¢
6,6¢
5,6¢
6,6¢
J5,6 = 2.6 Hz, H-6), 4.93 (1 H, ddd, J4,5 = 7.5 Hz, H-5), 5.42 (1 H,
J5,6 = 2.8 Hz, H-6), 5.04 (1 H, ddd, J4,5 = 8.0 Hz, H-5), 5.34 (1 H,
dd, J2,3 = 7.0 Hz, J = 2.4 Hz, H-3), 5.61 (1 H, d, H-2), 5.70 (1 H,
dd, J2,3 = 6.4 Hz, J = 2.3 Hz, H-3), 5.61 (1 H, dd, H-4), 5.66 (1 H,
3,4
3,4
dd, H-4). 13C NMR (125 MHz, CDCl ): d = 26.76, 27.00, 27.04,
d, H-2). C NMR (125 MHz, CDCl ): d = 20.04, 20.45, 20.58,
13
3
3
3
1
1
8.89, 38.91, 39.08, 39.11, 39.21, 58.65, 61.23, 66.51, 67.08, 74.88,
13.94, 175.75, 176.38, 176.64, 177.82. IR: 2362, 2342, 1746,
481, 1368, 1218 cm .
20.62, 38.78, 58.23, 61.53, 66.49, 67.00, 74.50, 113.93, 167.99,
–
1
169.30, 169.70, 170.17. IR: 2362, 2340, 1756, 1372, 1216 cm .
–1
5
-O-Methanesulfonyl-2,3,4,6-tetra-O-pivaloyl-D-mannonitrile
Acknowledgment
1
(
1
13): [a] +0.95 (c 0.3, CHCl ). H NMR (500 MHz, CDCl ): d =
D
3
3
.18, 1.21, 1.22, 1.28 (4 × 9 H, 4 × s), 3.11 (3 H, s), 4.09 (1 H, dd,
This research was supported by a Strategic Grant from the Michigan
State University Foundation and by the Michigan State University
Research Excellence Fund.
J5,6¢ = 4.1 Hz, J = 13.1 Hz, H-6¢), 4.43 (1 H, dd, J = 2.4 Hz, H-
6
2
6,6¢
5,6
), 4.84 (1 H, ddd, J4,5 = 8.1 Hz, H-5), 5.30 (1 H, d, J = 7.3 Hz, H-
2,3
1
3
), 5.39 (1 H, dd, J3,4 = 2.0 Hz, H-4), 5.42 (1 H, dd, H-3). C NMR
(
3
1
125 MHz, CDCl ): d = 26.71, 26.91, 26.93, 27.00, 38.81, 39.04,
3
9.10, 39.13, 59.3, 61.41, 66.51, 67.23, 74.48, 114.29, 175.66, References
–1
76.45, 176.52, 177.63. IR: 2363, 2344, 1744, 1215 cm .
(
1) Essentials of Glycobiology; Varki, A.; Cummings, R.; Esko,
J.; Freeze, H.; Hart, G.; Marth, J., Eds.; Cold Spring Harbor:
New York, 1999, 653.
5
(
-O-Methanesulfonyl-2,3,4,6-tetra-O-pivaloyl-D-galactonitrile
1
14): H NMR (500 MHz, CDCl ): d = 1.17, 1.19, 1.23, 1.28 (4 × 9
3
H, 4 × s), 3.15 (3 H, s), 4.08 (1 H, dd, J = 7.0 Hz, J = 11.9 Hz,
(2) (a) Gumina, G.; Chong, Y.; Choo, H.; Song, G.; Chu, C. K.
Curr. Top. Med. Chem. 2002, 2, 1065. (b) Wang, P.; Hong,
J. H.; Cooperwood, J. S.; Chu, C. K. Antivir. Res. 1998, 40,
19. (c) Ashley, G. W. J. Am. Chem. Soc. 1992, 114, 9731.
(d) Mansuri, M. M.; Farina, V.; Starrett, J. E. Jr.; Benigni, D.
A.; Brankovan, V.; Martin, J. C. Bioorg. Med. Chem. Lett.
1991, 1, 65.
5
,6¢
6,6¢
H-6¢), 4.16 (1 H, dd, J = 5.8 Hz, H-6), 4.92 (1 H, ddd, J4,5 = 1.8
5
,6
Hz, H-5), 5.34 (1 H, d, J2,3 = 2.3 Hz, H-2), 5.36 (1 H, dd, J = 9.6
3,4
1
3
Hz, H-4), 5.63 (1 H, dd, H-3). C NMR (125 MHz, CDCl ): d =
2
6
3
6.68, 26.85, 26.90, 26.95, 38.72, 38.80, 38,96, 39.04, 39.08, 58.99,
1.86, 66.10, 66.76, 74.72, 114.00, 175.84, 176.10, 176.32, 177.62.
–
1
IR: 2363, 2344, 1744, 1482, 1366, 1216 cm .
(
3) (a) Takahashi, H.; Hitomi, Y.; Iwai, Y.; Ikegami, S. J. Am.
Chem. Soc. 2000, 122, 2995. (b) Takahashi, H.; Iwai, Y.;
Hitomi, Y.; Ikegami, S. Org. Lett. 2002, 4, 2401.
4) Lee, S. J.; Seo, M. J.; Jeong, N. C.; Kim, G. C.; Hong, H. W.;
Kim, S. A. US 6,448,415, 2002.
4
+
1
-O-Methanesulfonyl-2,3,5-tri-O-pivaloyl-D-ribonitrile (15): [a]
D
1
24.2 (c 2.4, CHCl ). H NMR (500 MHz, CDCl ): d = 1.23, 1.24,
3
3
.26 (3 × 9 H, 3 × s), 3.18 (3 H, s), 4.21 (1 H, dd, J = 4.6 Hz,
4
,5¢
(
J5,5¢ = 12.9 Hz, H-5¢), 4.53 (1 H, dd, J = 3.1 Hz, H-5), 5.12 (1 H,
4,5
ddd, J3,4 = 6.7 Hz, H-4), 5.43 (1 H, dd, J = 3.3 Hz, H-3), 5.79
2,3
(
3
1
1 H, d, H-2). 13C NMR (125 MHz, CDCl ): d = 26.76, 26.84, 27.01,
(5) Acton, E. M.; Ryan, K. J.; Goodman, L. J. Am. Chem. Soc.
964, 86, 5352.
(6) Haas, J. W. Jr.; Kadunce, R. E. J. Am. Chem. Soc. 1962, 84,
910.
3
1
8.88, 38.91, 39.02, 60.55, 61.44, 68.17, 74.64, 113.75, 175.82,
–
1
76.02, 177.64. IR: 2363, 2344, 1748, 1482, 1367, 1215 cm .
4
(
(
7) Hicks, A.; Fraser-Reid, B. Can. J. Chem. 1974, 52, 3367.
8) Angelotti, T.; Krisko, M.; O’Connor, T.; Serianni, A. S. J.
Am. Chem. Soc. 1987, 109, 4464.
Preparation of L-idono-1,4-lactone from b-D-glucose-penta-
acetate
It is essentially the same as the procedure described above except fi-
nal hydrolysis step. 5-O-Methanesulfonyl-2,3,4,6-tetra-O-acetyl-D-
gluconitrile (22) was first refluxed in MeCN–H O (4:1) for 12 h and
2
then evaporated, the residue was refluxed in 2 N HCl in 1:1 mixture
of EtOH and H O for 1 h to give L-idono-1,4-lactone.
2
Synlett 2007, No. 8, 1247–1250 © Thieme Stuttgart · New York

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