Conversion of glucosamine to galactosamine and allosamine derivatives: Control of inversions of stereochemistry at C-3 and C-4

Article abstract of DOI:10.1021/jo010210+

The reactions of sodium benzoate with a series of trimesylates derived from glucosamine have been examined in an attempt to gain facile access to galactosamine analogues. Trimesylate 17, in which the amino group was protected as a phthalimide, underwent double displacement at positions 4 and 6 to give the dibenzoate 18 with the desired galactosamine configuration. In contrast, trimesylates 21 and 27, in which the amino groups were protected as acetamides, unexpectedly underwent double displacement at positions 3 and 6, giving products 22 and 28, respectively, with allosamine configurations.

Full text of DOI:10.1021/jo010210+

5102
J . Org. Chem. 2001, 66, 5102-5105
Con ver sion of Glu cosa m in e to Ga la ctosa m in e a n d Allosa m in e
Der iva tives: Con tr ol of In ver sion s of Ster eoch em istr y a t C-3 a n d
C-4
Ross P. McGeary,†,‡ Karen Wright,§ and Istvan Toth*,†,‡,§
School of Pharmacy, The University of Queensland, Brisbane, QLD 4072, Australia, Alchemia Pty Ltd,
3 Hi-Tech Court, Brisbane Technology Park, Eight Mile Plains, Qld 4113, Australia,
and The School of Pharmacy, University of London, 29-39 Brunswick Square, London WC1N 1AX, U.K.
i.toth@pharmacy.uq.edu.au
Received February 26, 2001
The reactions of sodium benzoate with a series of trimesylates derived from glucosamine have
been examined in an attempt to gain facile access to galactosamine analogues. Trimesylate 17, in
which the amino group was protected as a phthalimide, underwent double displacement at positions
4 and 6 to give the dibenzoate 18 with the desired galactosamine configuration. In contrast,
trimesylates 21 and 27, in which the amino groups were protected as acetamides, unexpectedly
underwent double displacement at positions 3 and 6, giving products 22 and 28, respectively, with
allosamine configurations.
In tr od u ction
derivatives for application to carbohydrate-based librar-
ies.
Galactosamine is a commonly occurring constituent of
natural oligosaccharides and glycoproteins, found R-linked
to serine or threonine on O-glycans and â-linked in
glycosphingolipids. We required access to a range of
suitably protected derivatives of galactosamine, as part
of a program directed at solid-phase carbohydrate chem-
istry.1 However, due to the expense of galactosamine, we
decided to develop a synthetic route to this amino sugar
from the readily available and inexpensive glucosamine.
There are reports of the conversion of protected glu-
cosamines to their epimeric galactosamines, but all
published routes suffer from either excessive length, poor
yields, or the need for harsh reaction conditions. Gross
et al. converted a 4,6-dimesylate derivative of glu-
cosamine to the corresponding galactosamine by a double
displacement with potassium acetate.2 More recently, an
enzymic deacetylation of the primary 6-acetate of an
N-acetylglucosamine derivative was employed as the key
step in a synthetic sequence culminating in the displace-
ment of a 4-triflate by cesium acetate,3 and Takeda and
Horito have shown that a 4-triflate of a glucosamine
derivative can undergo intramolecular displacement by
neighboring acyl groups to give a product with the
galactosamine configuration.4 Our aim was to develop a
high-yielding, relatively short route to galactosamine
Allosamine (2-amino-2-deoxyallose) is a relatively rare
amino sugar. It is not commercially available, and only
in 1986 was it found to exist naturally, constituting the
disaccharide moiety of the powerful and selective chiti-
nase inhibitor, allosamidin.5
Resu lts a n d Discu ssion
Our first synthetic strategy to the galactosamine donor
7 is shown in Scheme 1. The thioacetate 16 was deacety-
lated with sodium methoxide in methanol, and then the
resulting thiolate was methylated in situ with io-
domethane to give the thioether 2 in excellent yield.
Protection of the 4- and 6-hydroxyl groups of compound
2 as the benzylidene derivative proved to be difficult, and
after much experimentation the best conditions found
employed camphorsulfonic acid as a catalyst in neat
benzaldehyde, which gave the acetal 3 in moderate yield.
Conversion of the remaining hydroxyl group of compound
3 to the benzoate ester was accomplished with benzoic
anhydride in pyridine to give compound 4, and then the
benzylidene acetal was removed with warm aqueous
acetic acid to give the diol 5. Conversion of compound 5
to the dimesylate 6 was achieved with methanesulfonyl
chloride in pyridine.
Displacement of the mesylate groups in compound 6
was attempted with several nucleophiles, including ni-
trite ion and acetate ion, without success. However,
conversion of the dimesylate 6 to the tribenzoate was
accomplished with sodium benzoate in hot DMF, giving
compound 7 with the desired galactosamine configura-
tion, in very good yield.
* To whom correspondence should be addressed. Tel: +61-7-3365-
1386. Fax: +61-7-3365-1688.
† The University of Queensland.
‡ Alchemia Pty Ltd.
§ University of London.
(1) Drinnan, N.; West, M. L.; Broadhurst, M.; Kellam, B.; Toth, I.
Tetrahedron Lett. 2001, 42, 1159-1162.
(2) Gross, P. H.; du Bois, F.; J eanloz, R. W. Carbohydr. Res. 1967,
4, 244-248.
In an attempt to shorten the synthetic route, we
envisioned a procedure whereby we would take advan-
(3) Chaplin, D.; Crout, D. H. G.; Bornemann, S.; Hutchinson, D. W.;
Khan, R. J . Chem. Soc., Perkin Trans. 1 1992, 235-237.
(4) Takeda, Y.; Horito, S. Poster presented at the 20th International
Carbohydrate Symposium, Hamburg, Germany, Aug 27-Sep 1,
2000.
(5) Sakuda, S.; Isogai, A.; Matsumoto, S.; Suzuki, A. Tetrahedron
Lett. 1986, 27, 2475-2478.
(6) Falconer, R. A.; J ablonkai, I.; Toth, I. Tetrahedron Lett. 1999,
40, 8663-8666.
10.1021/jo010210+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/27/2001

Conversion of Glucosamine to Galactosamine and Allosamine Derivatives
J . Org. Chem., Vol. 66, No. 15, 2001 5103
Sch em e 1a
To investigate the possible differing reactivities of
glucosamine substrates possessing N-protection with
differing electron-withdrawing strengths, we examined
the reactions of the N-acetyl 21, the N-benzyloxycarbonyl
23, and the N-phthaloyl derivatives 17 of glucosamine.
The route to the trimesylate 17 is outlined in Scheme
3. Reaction of glucosamine hydrochloride 13 with phthalic
anhydride in aqueous sodium bicarbonate gave the
phthaloyl derivative 14 in moderate yield.10 Acetylation
of compound 14 under standard conditions afforded the
crystalline tetraacetate 15, which was obtained as a 5:1
mixture of R/â anomers. Tetraacetate 15 was converted
to the triol 16 via the intermediate anomeric bromide,10
and mesylation of compound 16 gave the crystalline
trimesylate 17. When the trimesylate 17 was stirred in
hot DMF with an excess of sodium benzoate, the diben-
zoate 18, possessing the required galactosamine config-
uration, was obtained in almost quantitative yield. This
result demonstrated that the phthaloyl protecting group
on the amine of compound 17 did not participate in the
displacement of the mesylate at position 3, as had been
anticipated (Scheme 2). Indeed, substitution at position
3 of compound 17 was prevented.
a
Reagents and conditions: (a) NaOMe, MeOH, rt; (b) MeI, rt;
(c) PhCHO, CSA, rt; (d) (PhCO)2O, pyridine, DMAP, 0 °C to rt; (e)
HOAc, H2O, 65 °C; (f) MsCl, CH2Cl2, pyridine, -15 °C to rt; (g)
NaOBz, DMF, 140 °C. Bz ) benzoyl; Dde ) 1-(4,4-dimethyl-2,6-
dioxocyclohexylidene)ethyl; CSA ) camphorsulfonic acid.
Sch em e 2
We have also examined the analogous displacement
reaction of the N-acetylglucosamine derivative 21. This
compound (21) was prepared by the route outlined in
Scheme 4. Refluxing N-acetylglucosamine 19 with acidic
ion-exchange resin in methanol led to the methyl glyco-
side 20,11 obtained as the pure R-anomer after two
recrystallizations from 2-propanol. The triol 20 was
converted to the crystalline trimesylate 21 with meth-
anesulfonyl chloride in pyridine.12 Treatment of com-
pound 21 under the same conditions used to convert
trimesylate 17 to compound 18 (sodium benzoate in hot
DMF) gave an unexpected result. Unlike the case of
compound 17, where the mesylate at position 4 was
displaced and the mesylate at position 3 was unreactive,
compound 21 displayed the opposite reactivity. Thus, the
4-mesylate group of compound 21 proved to be unreac-
tive, and the 3-mesylate underwent displacement to give
the dibenzoate 22, with the allosamine configuration.
Again it seems that the N-acetyl group did not participate
in the 3-mesylate displacement as had been anticipated.
The lack of reactivity of the 3-mesylate of compound 17,
when compared with trimesylate 21, was most likely due
to a combination of steric and dipolar effects.
tage of the protecting group on the amine to control the
stereochemistry at position 3, via neighboring group
participation. Our plan was to use the N-acyl group of
compound 8 to displace the mesylate at the position 3,
forming an intermediate oxazolinium ion 9. This would
be opened by subsequent intermolecular attack by the
benzoate nucleophile, giving compound 10 with overall
retention of configuration at position 3. In conjunction
with inversion of configuration at position 4, this proce-
dure would result in the product 10 having the required
galactosamine configuration (Scheme 2). There is some
literature precedence to support this hypothesis. For
example, the triflate 11 has been shown to undergo facile
ring closure to the oxazolidinone 12 by warming in
pyridine solution7 (eq 1), and similar reactions, also in
the glucosamine series, have been reported.8,9 We are not
aware, however, of any examples of carbohydrate-derived
oxazolinium ions such as 9 reacting intermolecularly with
nucleophiles.
The reaction of the trimesylate 23 derived from N-
benzyloxycarbonylglucosamine was also examined. Reac-
13
tion of the trimesylate 23
with sodium benzoate in
DMF at 140 °C led only to decomposition, and no
identifiable products could be isolated. When the reaction
was repeated, but at a lower temperature, the monoben-
(10) Kochetkov, N. K.; Byramova, N. E.; Tsvetkov, Yu. E.; Backi-
nowsky, L. V. Tetrahedron 1985, 41, 3363-3375.
(11) Galemmo, R. A.; Horton, D. Carbohydr. Res. 1983, 119, 231-
240.
(12) Brimacombe, J . S.; Da’Aboul, I.; Tucker, L. C. N. Carbohydr.
Res. 1972, 25, 522-525.
(13) Raghit, G. J . Carbohydr. Nucleosides Nucleotides 1975, 2, 153.
(7) Tsuchiya, T.; Shitara, T. Carbohydr. Res., 1982, 109, 59-72.
(8) Sano, H.; Iimura, S.; Tsuchiya, T.; Umezawa, S. Bull. Chem. Soc.
J pn. 1978, 51, 3661-3662.
(9) Rhoads, W. D.; Gross, P. H. Carbohydr. Res. 1969, 11, 561-
564.

5104 J . Org. Chem., Vol. 66, No. 15, 2001
McGeary et al.
Sch em e 3a
Sch em e 5a
a
Reagents and conditions: (a) 33% HBr/AcOH, rt; (b) MeOH,
rt; (c) MsCl, pyridine, 4 °C; (d) NaOBz, DMF, 140 °C.
in a reaction analogous to that shown in Scheme 4 for
the R-anomer 21.
a
Reagents and conditions: (a) phthalic anhydride, NaHCO3,
Con clu sion s
H2O, rt; (b) Ac2O, pyridine, rt; (c) 33% HBr/AcOH, rt; (d) MeOH,
rt; (e) MsCl, 0 °C to rt; (f) NaOBz, DMF, 140 °C.
We have shown that the nature of the protecting group
on the amino group of glucosamine derivatives can
profoundly affect the reactivities of mesylate groups
present elsewhere in the molecule. These differing reac-
tivities have allowed us to prepare either galactosamine
or allosamine derivatives, in short, high-yielding routes,
from inexpensive glucosamine.
Sch em e 4a
Exp er im en ta l Section
Gen er a l Meth od s. Reactions were carried out under argon
atmosphere. Solvents were dried according to established
procedures by distillation under argon from an appropriate
drying agent. Commercially available starting materials and
1
reagents were purchased from Aldrich Chemical Co., Inc. H
NMR spectra were obtained using either a Bruker AM 500
instrument or a Varian Gemini 300 instrument. 13C NMR were
obtained on a Varian Gemini 300 instrument. Chemical shifts
are expressed in ppm (δ). Coupling constants are reported in
Hz. FAB-MS were obtained on a VG Analytical ZAB-SE
instrument, using either 3-nitrobenzyl alcohol or thioglycerol
with NaI solution added when no protonated species were
observed. Electrospray MS were obtained on a Perkin-Elmer
API 3000 instrument using acetonitrile-water as the mobile
phase.
a
Reagents and conditions: (a) Dowex (H+), MeOH, reflux; (b)
MsCl, pyridine, 4 °C; (c) NaOBz, DMF, 140 °C.
zoate 24, arising from single displacement of the primary
mesylate of compound 23 by benzoate ion, was obtained
in excellent yield (eq 2; (a) NaOBz, DMF, 100 °C).
Meth yl 3,4,6-Tr is-O-ben zoyl-2-(1-(4,4-d im eth yl-2,6-d i-
oxocycloh exylid en e)eth yla m in o)-2-d eoxy-1-th io-â-D-glu -
cop yr a n osid e (7). The dimesylate 6 (640 mg, 0.98 mmol) and
sodium benzoate (1.0 g, 6.9 mmol) were suspended in DMF
(20 mL), and the mixture was stirred at 140 °C for 24 h. The
mixture was cooled and filtered, and then the filtrate was
concentrated and the residue was taken up in EtOAc and
refiltered. The filtrate was concentrated to give the tribenzoate
7 as a colorless oil (600 mg, 89%). Rf (1:1 EtOAc/hexane): 0.60.
Anal. Calcd for C38H39NO9S: C, 66.56; H, 5.73; N, 2.04.
Found: C, 66.49; H, 5.75; N, 2.01. FABMS: 708 (M + Na)+,
We initially attributed the remarkable difference in
reactivities of the trimesylates 17 and 21 to their differ-
ent amine protection. However, since compound 17 is a
â-glucoside and compound 21 is an R-glucoside, it was
conceivable that the configuration of the anomeric group
at position 1 was influencing the reactivities of the
mesylate groups in these molecules. To clarify this
ambiguity, we prepared the trimesylate 27 (the C-1
epimer of 21) and examined its reactivity under the same
reaction conditions, which led to the dibenzoates 18 and
22. The synthetic route to the trimesylate 27 is shown
1
686 (MH)+. H NMR (500 MHz, (CDCl3) 0.95, 6H, s, 2 × Me;
2.30, 3H, s, SMe; 2.36, 4H, s, 2 × CH2; 2.57, 3H, s, NCMe;
4.35-4.41, 3H, m, H5,6,6; 4.66-4.69, 1H, m, H2; 4.86, 1H, d
(J 9.8), H1; 5.52, 1H, dd (J 10.3, 3.2), H3; 5.99, 1H, d (J 3.3),
H4; 7.29-8.12, 15H, m, 15 × Ar-H; 14.01, 1H, br s, NH.
Meth yl 2-P h th a lim id o-2-d eoxy-4,6-bis-(O-ben zoyl)-3-
(O-m eth a n esu lfon yl)-â-D-ga la ctop yr a n osid e (18). Proce-
dure as for compound 7. Scale: 1.26 mmol. Product 18: a tan
foam, 790 mg (98%). ES-MS: 610 (MH)+, 627 (M + NH4)+,
3
in Scheme 5. The tetraacetate 25 was converted to the
anomeric bromide, and then this was reacted with
methanol, leading to the â-methyl glycoside 26. Com-
pound 26 was converted to the trimesylate 27 with
methanesulfonyl chloride in pyridine, and this, when
heated with sodium benzoate in hot DMF, gave the
dibenzoate 28, possessing the allosamine configuration,
1
632 (M + Na) +. H NMR (500 MHz, CDCl3) 2.85, 3H, s, SMe;
3.50, 3H, s, OMe; 4.34, 1H, t (J 6.5), H5; 4.42, 1H, dd (J 11.3,
6.6), H6A; 4.68, 1H, dd (J 11.5, 6.2), H6B; 4.69, 1H, dd (J 11.1,
8.4), H2; 5.38, 1H, d (J 8.4), H1; 5.80, 1H, dd (J 11.1, 3.6), H3;
5.97, 1H, d (J 3.2), H4; 7.35-8.16, 14H, m, 14 × Ar-H. 13C

Conversion of Glucosamine to Galactosamine and Allosamine Derivatives
J . Org. Chem., Vol. 66, No. 15, 2001 5105
NMR (75 MHz, CDCl3) 38.3, 52.0, 56.9, 61.9, 68.1, 70.9, 73.1,
99.2, 123.3, 123.4, 128.3, 128.6, 129.3, 129.6, 129.9, 131.5,
133.1, 133.7, 134.1, 165.6, 165.8. HRMS (TOF) calcd for
10H, m, 10 × Ar-H. 13C NMR (75 MHz, CDCl3): 38.4, 38.9,
53.9, 55.5, 62.2, 67.2, 67.8, 73.5, 77.7, 98.3, 128.3, 128.4, 128.6,
129.5, 129.6, 133.0, 135.9, 155.6, 165.9. HRMS (TOF): calcd
for C25H32NO12S2 (M + H)+ 588.1209, found 588.1198.
C
30H31N2O11S (M + NH4)+ 627.1649, found 627.1629.
Meth yl 2-Aceta m id o-2-d eoxy-3,6-bis-(O-ben zoyl)-4-(O-
Meth yl 2-Aceta m id o-2-d eoxy-3,5-bis-(O-ben zoyl)-4-(O-
m eth a n esu lfon yl)-â-D-a llop yr a n osid e (28). Procedure as
for compound 7. Scale: 0.628 mmol. Product 28: purified by
flash chromatography and elution with 50-100% EtOAc in
hexane to give a pale yellow oil, 140 mg (43%). Rf (3:1 EtOAc/
m eth a n esu lfon yl)-r-D-a llop yr a n osid e (22). Procedure as
for compound 7. Scale: 1.26 mmol. Product 22: purified by
flash chromatography and elution with 0-1% MeOH in EtOAc
1
to give a brown gum, 210 mg (32%). ES-MS: 522 (MH)+. H
hexane): 0.47. ES-MS: 522 (MH)+, 539 (M + NH4) +, 548 (M
NMR (500 MHz, CDCl3): 2.03, 3H, s, Ac; 3.06, 3H, s, SMe;
3.41, 3H, s, OMe; 4.30, 1H, ddd (J 10.5, 4.1, 2.0), H5; 4.33,
1H, br dt (J 9.0, 3.6), H2; 4.40, 1H, t (J 2.9), H3; 4.53, 1H, dd
(J 12.3, 4.3), H6A; 4.68, 1H, dd (J 12.3, 2.0), H6B; 4.80, 1H, d
(J 4.1), H1; 4.82, 1H, dd (J 10.3, 3.0), H4; 6.49, 1H, d (J 9.0),
NH; 7.40-7.58 and 8.03-8.06, 10H, m, 10 × Ar-H. 13C NMR
(75 MHz, CDCl3): 22.9, 38.7, 49.0, 56.1, 62.5, 62.6, 68.9, 74.3,
98.7, 128.4, 128.5, 128.6, 132.9, 133.0, 133.2, 166.1, 170.0.
HRMS (TOF): calcd for C24H28NO10S (M + H)+ 522.1434,
found 522.1414.
+
+ Na)
.
1H NMR (500 MHz, CDCl3): 1.93, 3H, s, Ac; 3.03,
3H, s, SMe; 3.51, 3H, s, OMe; 4.30-4.36, 1H, m, H5; 4.41, 1H,
dt (J 3.0, 8.0), H2; 4.49, 1H, dd (J 4.4, 12.3), H6A; 4.76, 1H, dd
(J 3.0, 12.3), H6B; 4.81, 1H, d (J 7.9), H1; 5.12, 1H, dd (J 3.0,
8.9), H4; 5.96, 1H, d (J 8.1), NH; 6.04, 1H, t (J 3.0), H3; 7.43-
7.66 and 8.05-8.10, 10H, m, 10 × Ar-H. 13C NMR (75 MHz,
CDCl3): 23.0, 29.6, 38.9, 51.2, 56.3, 62.6, 69.4, 71.3, 73.1, 100.3,
128.4, 128.5, 128.9, 129.5, 129.7, 129.8, 133.2, 133.9, 165.3,
166.0, 170.0. HRMS (TOF): calcd for C24H28NO10S (M + H)+
522.1434, found 522.1436.
Meth yl
6-O-Ben zoyl-2-ben zyloxyca r bon yla m in o-2-
d e oxy-3,4-b is-(O-m e t h a n e su lfon yl)-r-D -glu cop yr a n o-
sid e (24). Procedure as for compound 7, except that compound
2313 was heated at 100 °C. Scale: 1.26 mmol. Product 24:
purified by dissolving in a small amount of EtOAc/hexane (1:
1) and filtering through a plug of silica. Evaporation of the
filtrate gave a colorless foam, 730 mg (96%). Rf (1:1 EtOAc/
hexane): 0.50. ES-MS: 588 (MH)+, 605 (M + NH4)+, 610 (M
Ack n ow led gm en t. We thank Mr. Alun J ones of the
Institute for Molecular Bioscience, U.Q., for accurate
mass measurements.
Su p p or tin g In for m a tion Ava ila ble: The detailed ex-
perimental procedures and characterization data for com-
pounds 2-6, 14-17, 20, 21, 26, and 27 and the 1H NMR
spectra of compounds 22, 24, and 28. This information is
available free of charge via the Internet at http://pubs.acs.org.
1
+ Na)+. H NMR (300 MHz, CDCl3): 2.85, 3H, s, SMe; 3.15,
3H, s, SMe; 3.36, 3H, s, OMe; 4.06-4.20, 2H, m, H2 and H5;
4.52, 1H, dd (J 4.2, 12.4), H6A; 4.75, 1H, d (J 3.4), H1; 4.78,
1H, br d (J 12.1), H6B; 4.90, 1H, t (J 9.5), H3; 4.93, 1H, t (J
9.6), H4; 5.04, 1H, d (J 12.1), PhCHA; 5.17, 1H, d (J 12.1),
PhCHB; 5.43, 1H, d (J 9.9), NH; 7-28-7.56 and 8.06-8.09,
J O010210+