34-38
of salacinol,27-33 chain-extended analogues,
and other
SCHEME 1
analogues.34-38 Some of these derivatives exhibited interesting
biological properties.34,35,39,40
It was of interest to investigate the effect of introducing an
acetamido or an amine function at the C-2 position of salacinol
to broaden the scope of glycosidase inhibitory activities, in
particular, to target the hexosaminidase enzymes. Therefore, we
report herein the attempted synthesis of the 2-acetamido- (7)
and 2-amino- (8) substituted analogues of salacinol. These
derivatives were found to undergo ring opening reactions by
nucleophilic participation of the amide or amine moieties to
give acyclic amido or ammonium sulfates, respectively.
to give 11, and the 2-OH group of compound 11 was then
mesylated (12). The substitution of the mesylate in 12 by an
azide group did not proceed in MeOH; however, at 75 °C in
DMF, the substitution proceeded with inversion of configuration
at C-2 (13). The azide group in compound 13 was then reduced
to an amine by using triphenylphosphine (PPh3) in dioxane:
MeOH:H2O (10:3:1) to afford compound 14 in 70% yield;
acetylation then afforded compound 15 in 77% yield. The
alkylation reaction of compound 15 with 2,4-O-benzylidene-L-
erythritol-1,3-cyclic sulfate (9) did not proceed as expected.
Instead, the silyl protecting group was removed under the
reaction conditions. Therefore, we chose to replace this group
by benzyl ethers. The silyl protecting group in 15 was thus
removed, using tetra-n-butylammonium fluoride (TBAF), and
the crude product obtained was then subjected to benzylation
by using benzyl bromide and a mixture of BaO and Ba(OH)2‚
8H2O to afford compound 16 in 78% yield. A 1D-NOESY
experiment performed on compound 16 confirmed the stereo-
chemistry at C-2 by showing a correlation between H-2 and
H-4 of the five-membered ring. The alkylation reaction between
compound 16 and 2,4-O-benzylidene-L-erythritol-1,3-cyclic
sulfate (9) gave compound 18c in 87% yield. A 1D-NOESY
experiment performed on the coupled product showed no
correlation between H-1′ and H-1 (as would be expected for
the target compound 17); the latter result also confirms that the
five-membered ring had been opened to give an acyclic
thioether. The 13C NMR spectrum of the coupled product
indicated the presence of a carbonyl group, and a g-HMBC
spectrum showed a correlation between this carbonyl carbon
and H-2, and no correlation between the carbonyl carbon and
H-1, thus suggesting 18c as the product of the reaction. The IR
spectrum of this product suggested the presence of an OH group
as well as an amide carbonyl group, further corroboration of
the structure of 18c. The high-resolution mass spectrum
confirmed the molecular formula of compound 18c. The
microanalysis of compound 18c also confirmed the presence
of potassium as the counterion (Scheme 2).
The target compounds 7 and 8 could be obtained by
hydrogenolysis of the coupled product A, which has an
acetamide or an azide group at C-2 (Scheme 1). Compound A
could be synthesized, in turn, by the alkylation of a 2-azido- or
2-acetamido-1,4-anhydro-4-thio-D-arabinitol derivative (B) with
2,4-O-benzylidene-L-erythritol-1,3-cyclic sulfate (9). Compound
B could, in turn, be synthesized from the reaction of sodium
azide with a selectively protected 1,4-anhydro-4-thio-D-ribose
(C) unit in which C-2 bears a good leaving group. Compound
C could be obtained from 1,4-anhydro-4-thio-D-ribose (10),
which could be synthesized, in turn, from commercially
available D-ribose.41
1,4-Anhydro-4-thio-D-ribose (10) was synthesized from com-
mercially available D-ribose in 11 steps according to a literature
procedure.41 To introduce an azide group selectively at C-2 of
compound 10, the 3-OH and 5-OH groups were first protected
by using 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane in pyridine
(26) Kumar, N. S.; Pinto, B. M. Carbohydr. Res. 2005, 340, 2612-
2619.
(27) Ghavami, A.; Johnston, B. D.; Jensen, M. T.; Svensson, B.; Pinto,
B. M. J. Am. Chem. Soc. 2001, 123, 6268-6271.
(28) Johnston, B. D.; Ghavami, A.; Jensen, M. T.; Svensson, B.; Pinto,
B. M. J. Am. Chem. Soc. 2002, 124, 8245-8250.
(29) Liu, H.; Pinto, B. M. J. Org. Chem. 2005, 70, 753-755.
(30) Liu, H.; Pinto, B. M. Can. J. Chem. 2006, in press.
(31) Liu, H.; Pinto, B. M. Can. J. Chem. 2005, in press.
(32) Muraoka, O.; Ying, S.; Yoshikai, K.; Matsuura, Y.; Yamada, E.;
Minematsu, T.; Tanabe, G.; Matsuda, H.; Yoshikawa, M. Chem. Pharm.
Bull. 2001, 49, 1503-1505.
(33) Gallienne, E.; Gefflaut, T.; Bolte, J.; Lemaire, M. J. Org. Chem.
2006, 71, 894-902.
(34) Johnston, B. D.; Jensen, H. H.; Pinto, B. M. J. Org. Chem. 2006,
71, 1111-1118.
Scheme 3 shows the proposed mechanism for the formation
of 18c. Nucleophilic attack of the amide oxygen on C-1 of
compound 17 would result in opening of the five-membered
ring to give (18a), which could then react with water during
the processing and purification to give 18b. Further rearrange-
ment of the orthoaminal (18b) would result in 18c.
(35) Liu, H.; Sim, L.; Rose, D. R.; Pinto, B. M. J. Org. Chem. Submitted
for publication.
(36) Muraoka, O.; Yoshikai, K.; Takahashi, H.; Minematsu, T.; Lu, G.
X.; Tanabe, G.; Wang, T.; Matsuda, H.; Yoshikawa, M. Bioorg. Med. Chem.
2006, 14, 500-509.
(37) Gallienne, E.; Benazza, M.; Demailly, G.; Bolte, J.; Lemaire, M.
Tetrahedron 2005, 61, 4557-4568.
(38) Szczepina, M. G.; Johnston, B. D.; Yuan, Y.; Svensson, B.; Pinto,
B. M. J. Am. Chem. Soc. 2004, 126, 12458-12469.
(39) Pinto, B. M.; Johnston, B. D.; Ghavami, A.; Szczepina, M. G.; Liu,
H.; Sadalapure, K. U.S. patent application, filed June 25, 2004.
(40) Li, Y. J.; Scott, C. R.; Chamoles, N. A.; Ghavami, A.; Pinto, B.
M.; Turecek, F.; Gelb, M. H. Clin. Chem. 2004, 50, 1785-1796.
(41) Naka, T.; Minakawa, N.; Abe, H.; Kaga, D.; Matsuda, A. J. Am.
Chem. Soc. 2000, 122, 7233-7243.
To prevent the intramolecular nucleophilic participation of
the amide group observed in compound 18a, we next examined
the alkylation reaction of a 2-azido arabinitol derivative (Scheme
4). Starting from compound 13, the silyl protecting group was
substituted by benzyl protecting groups (19). The alkylation
reaction of compound 19 with 2,4-O-benzylidene-L-erythritol-
4672 J. Org. Chem., Vol. 71, No. 12, 2006