Synthesis of substituted septanosyl-1,2,3-triazoles

Article abstract of DOI:10.1016/j.carres.2007.03.026

A carbohydrate-based oxepine, derived from 2-deoxy-d-arabino-hexopyranose, was used to prepare a family of septanosyl-1,2,3-triazoles in four steps. DMDO mediated epoxidation of the oxepine followed by trapping of the intermediate 1,2-anhydroseptanose by

Full text of DOI:10.1016/j.carres.2007.03.026

Carbohydrate Research 342 (2007) 1366–1372
Note
Synthesis of substituted septanosyl-1,2,3-triazoles
Steve Castro, Emily C. Cherney, Nicole L. Snyder and Mark W. Peczuh*
Department of Chemistry, University of Connecticut, U-3060, 55 North Eagleville Road, Storrs, CT 06269, United States
Received 16 February 2007; received in revised form 22 March 2007; accepted 26 March 2007
Available online 2 April 2007
Abstract—A carbohydrate-based oxepine, derived from 2-deoxy-D-arabino-hexopyranose, was used to prepare a family of septanos-
yl-1,2,3-triazoles in four steps. DMDO mediated epoxidation of the oxepine followed by trapping of the intermediate 1,2-anhydro-
septanose by sodium azide gave the b-substituted glycosyl azide. The septanosyl azide was then reacted with a number of alkynes
under thermal Huisgen or copper(I) mediated reaction conditions. Hydrogenolysis of benzyl protecting groups gave substituted
septanosyl-1,2,3-triazoles. The new septanose-based structures were then evaluated as potential glycosidase inhibitors.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Keywords: Septanose carbohydrates; Glycosidase; Triazole
A comprehensive list of protein–carbohydrate interac-
tions includes mono-, oligo-, and polysaccharides bound
by lectins (as ligands) and also by carbohydrate process-
ing enzymes such glycosyltransferases and glycosidases
(as substrates). Such interactions are integral to a num-
ber of biological processes such as cell–cell communica-
tion,1 synthesis of cell-wall polysaccharides,2 protein
folding,3 and glycoprotein synthesis.4 Our group has be-
come interested in evaluating the potential for unnatu-
ral, ring expanded carbohydrates to participate in
protein–carbohydrate interactions with natural proteins.
These investigations should deepen the understanding of
the role molecular topology plays in protein–carbohy-
drate interactions generally. Specifically, we are inter-
ested in correlating the conformational preferences of
septanose carbohydrates with their ability to be bound
by lectins and carbohydrate processing enzymes.
We recently reported on the binding of methyl sept-
anosides by the model plant lectin Concanavalin A
(ConA).5 In contrast to its preference for alpha over
beta configured pyranosides, ConA bound methyl b-D-
glycero-D-septanosides in preference to methyl a-D-gly-
cero-D-septanosides. Our earlier conformational analy-
sis of these monosaccharides6 showed that: (i) both the
alpha and beta configured methyl septanosides took
up conformations that resembled the bound conforma-
tion of the natural ligands, and; (ii) the methyl septano-
side structures were stable. That is, they populated one
unique conformation as a large (>90) percent of the
Boltzmann distribution of conformers. Overall, the
investigation suggested septanose carbohydrates could
serve as ligands for a variety of natural proteins.
As an extension of that original investigation of
protein–septanose interactions, we wanted to know if
septanoses could inhibit glycosidase enzymes. This
exploration would inform the fundamental protein–sep-
tanose interaction question and could also serve as a
starting point for the development of a new class of
inhibitors. Some recent investigations served to motivate
our efforts. For example, para-nitrophenyl septan-
osides were shown to be substrates for natural glycosi-
dases.7 Also, a number of groups have reported on the
glycosidase inhibitory activity of polyhydroxylated
azepanes.8–10
Here we report the synthesis of a family of septanosyl
1,2,3-triazoles from a carbohydrate-based oxepine. The
synthetic strategy borrowed from previous reports of
pyranosyl triazoles,11,12 which have themselves been
shown to be glycosidase inhibitors.12 Septanosyl 1,2,3-
triazoles and the known azepane glycosidase inhibi-
tors share a polyhydroxylated seven-membered ring
*
Corresponding author. E-mail: mark.peczuh@uconn.edu
0008-6215/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2007.03.026

S. Castro et al. / Carbohydrate Research 342 (2007) 1366–1372
1367
R2
R1
N
N
OBn
OBn
O
OBn
O
N3
N
a
b
c or d
O
BnO
BnO
BnO
BnO
BnO
BnO
OH
OH
7 R1 = H R2 =
O
3 R1 = R2 = CO2Et
4 R1 = H R2 = C4H9
5 R1 = H R2 = C6H11
1
2
O
OH
O
6 R1 = H R2 = Ph
O
Scheme 1. Reagents and conditions: (a) DMDO, CH2Cl2, 0 ꢁC; (b) NaN3, DMF/H2O, rt, 22%, two steps; (c) diethyl acetylene dicarboxylate,
toluene, 110 ꢁC, 70%; (d) alkyne, Cu(OAc)2, sodium ascorbate, t-BuOH/H2O, rt, 52–70%.
structure, with the addition of a basic nitrogen found
O
only in the azepanes. Based on our familiarity with the
low energy conformations of the related methyl septano-
sides, we wanted address the issue of flexibility that has
been argued to be operative with the polyhydroxylated
azepane glycosidase inhibitors.
O
O
O
O
O
a
b
R
O
OH
OH
O
O
Oxepine 113 served as the starting material for the syn-
thesis of the septanosyl 1,2,3-triazoles (Scheme 1). Epox-
idation of 1 provided a 1,2-anhydroseptanose, which
was not isolated, but carried directly onto the next step
in the synthesis. Attack on the epoxide using tetrabutyl-
ammonium azide in methylene chloride14 was sluggish
with approximately 8–10% yield after 48 h at room tem-
perature. Switching to sodium azide under reported con-
ditions15 gave septanosyl azide 2 in 22% over two steps.
The low yield for this process is ascribed to the low sol-
ubility of sodium azide in the mixed DMF/H2O solvent
where water may also compete as a nucleophile. Consis-
tent with the earlier preparation of methyl 3-deoxy-b-D-
glycero-D-guloseptanoside from oxepine 1,5 azide 2 was
assigned as being in the beta anomeric configuration,
arising from SN2 attack on the a-1,2-anhydroseptanose.
The glycosyl azide was then reacted with alkynes under
two separate types of reaction conditions to form pro-
tected triazoles. Huisgen dipolar cycloaddition16,17 of 2
with diethyl acetylene dicarboxylate in refluxing toluene
provided triazole 3 in 69% yield.
The other triazoles were prepared by reaction of azide
2 with terminal alkynes using the Cu(I) mediated
addition reaction.18,19 Reaction of 2 with commer-
cially available 1-hexyne, cyclohexylacetylene, or
phenylacetylene provided triazoles 4, 5, and 6 in 65%,
70%, and 65% yields, respectively. The regiochemistry
of these adducts was confirmed by COSY and HMBC
spectroscopy on the hexyne adduct 4. An alkyne pre-
pared by halovinylation and elimination of 2,3:4,6-di-
O-isoproylidene-D-mannopyranose was also used in
the addition reaction (Scheme 2).20 Addition under the
Cu(I) conditions with this new alkyne provided the cor-
responding triazole in 52% yield. Hydrogenolysis of the
benzyl protecting groups of 3–7 provided the deprotec-
13
R =
R =
14
15
Cl
Scheme 2. Reagents and conditions: (a) ClCH2PPh3, n-BuLi, HMPA,
THF, 0 ꢁC to rt, 61%; (b) n-BuLi, THF, 3 h, 68%.
ted septanosyl 1,2,3-triazoles (>95%) 8–12 (Fig. 1).
After hydrogenolysis of 7, it was noted that one of the
acetonide protecting groups was removed over the
course of the reaction. The regiochemistry of this
deprotection was rationalized in terms of the distinct
13C chemical shift of the two (five-membered ring vs
six-membered ring) acetonides,21 and HMBC analysis
of 12.
Each of the triazoles 8–12 was then evaluated for
activity against a battery of glycosidases. Standard
UV-based assays measured inhibition by the triazoles
on the activity of a-glucosidase (Saccharomyces cerevi-
siae), b-glucosidase (almonds), a-galactosidase (green
coffee beans), b-galactosidase (Aspergillus oryzae),
a-mannosidase (Canavalia ensiformis), b-mannosidase
(snail acetone powder), or b-N-acetylglucosaminidase
(C. ensiformis) on their corresponding para-nitrophenyl
glycosides.22 No inhibition of activity was noted under
the assay conditions up to a concentration of 1 mM of
8–12. Our current efforts are aimed at further evaluation
of the potential activity of the septanosyl triazoles and
the identification of inhibitors that include a septanose
as a structural feature. The lack of activity in the mole-
cules reported here prevents a substantive analysis on
the importance of any alleged flexibility in seven-
membered ring glycosidase inhibitors. New results will
be reported in due course.

1368
S. Castro et al. / Carbohydrate Research 342 (2007) 1366–1372
N
N
N
N
N
OR
OR
N
O
O
O
CO2Et
CO2Et
RO
RO
RO
O
N
N
N
RO
5 R = Bn
N
N
OH
10 R = H
OH
OR
N
OH
OR1
O
R2O
O
4 R = Bn
9 R = H
RO
RO
R1O
R1O
OR2
OH
8 R = H
OH
N
3 R = Bn
7 R1 = Bn R2 = -C(CH3)2-
12 R1 = R2 = H
N
OR
N
O
RO
RO
OH
6 R = Bn 11 R = H
Figure 1.
1. Experimental
1.3. 4,5,6-Tri-O-benzyl-3-deoxy-b-D-glycero-D-gulo-
septanosyl azide (2)
1.1. General methods
Oxepine 1 (0.130 g, 0.302 mmol) was dried via azeotro-
pic distillation from toluene (3 · 5 mL) under reduced
pressure and dissolved in dry CH2Cl2 (5 mL). The solu-
tion was cooled in an ice bath to 0 ꢁC and a DMDO
solution (0.38 mL, 0.24 M) was added dropwise. The
mixture was stirred at 0 ꢁC for 30 min and the solvent
was removed under reduced pressure. The residue was
dissolved in DMF (3 mL) and NaN3 (0.573 g,
6.04 mmol) in water (2 mL) was added. After 4 h, water
(5 mL) was added to the solution and it was extracted
with ethyl acetate (EtOAc, 2 · 15 mL). The organic lay-
ers were dried (Na2SO4) and solvent was removed under
reduced pressure. The material was purified by column
chromatography, using 1:3 EtOAc–hexanes as eluent
to give a clear and colorless oil (0.120 g, 22%).
Rf = 0.51 (1:3, EtOAc–hexanes); [a]D ꢀ2.90 (c 1.2,
Unless stated otherwise, all reactions were conducted at
room temperature (rt) under nitrogen atmosphere.
DMDO was generated as described.23 Reactions were
˚
monitored by TLC (silica gel, 60 A, F254, 250 lm). Visu-
alization was conducted either under UV light or by
charring with 2.5% p-anisaldehyde in H2SO4, acetic
acid, and ethanol solution. Preparative chromatography
˚
was conducted on silica gel (60 A, 32–63 lm). Melting
points are uncorrected. Optical rotations were measured
1
at 22 2 ꢁC. H NMR spectra were collected at 300 or
400 MHz with chemical shifts referenced to (CH3)4Si
(dH 0.00 ppm), CHCl3 (dH 7.27 ppm), or CD3OD (dH
3.31 ppm). 13C NMR were collected at 75 or 100 MHz
and referenced to CDCl3 (dC 77.2 ppm) or CD3OD (dC
49.0 ppm).
1
CHCl3); H NMR 400 MHz (CDCl3): d 7.36–7.15 (m,
1.2. 1,6-Anhydro-4,5,7-tri-O-benzyl-2,3-dideoxy-D-gluco-
sept-1-enitol (1)
15H), 4.67–4.47 (m, 6H), 4.32 (d, 1H, J = 11.39 Hz),
3.8–3.78 (m 3H), 3.65–3.57 (m, 3H), 2.23 (ddd, 1H,
J = 14.7, 7.5, 3.6 Hz) 1.90 (dd, 1H, J = 14.6, 9.6 Hz);
13C NMR 100 MHz (CDCl3): d 138.4, 138.3, 137.9,
128.7 (2), 128.6, 128.1 (2), 128.0 (2), 127.9, 97.2, 82.1,
80.1, 75.9, 73.7, 72.9, 71.5, 71.4, 70.1, 32.1; ESIMS
m/z calcd for [M+Na]+: 512.2156. Found: 512.2170.
1,6-Anhydro-4,5,7-tri-O-benzyl-2,3-dideoxy-D-gluco-
sept-1-enitol (1) was synthesized by the route previously
reported.13 Rf = 0.59 (1:3, EtOAc–hexanes); [a]D +14.7
1
(c 0.8, CHCl3); H NMR 400 MHz (CDCl3): d 7.44–
7.19 (m, 15H), 6.50 (dd, 1H, J = 6.4, 1.1 Hz), 4.73 (d,
1H, J = 12.2 Hz), 4.68–4.59 (m, 4H), 4.56 (d, 1H,
J = 2.8 Hz), 4.40 (d, 1H, J = 11.2 Hz), 4.15–4.11 (m,
1H), 3.79–3.69 (m, 4H), 2.65 (ddd, 1H, J = 17.1, 3.5,
1.8 Hz), 2.39 (ddd, 1H, J = 16.9, 13.6, 6.8 Hz); 13C
NMR 100 MHz (CDCl3): d 148.6, 138.7, 138.0, 128.6,
128.5, 128.2, 128.0 (2), 127.9, 127.8, 127.7, 103.3, 82.6,
79.6, 78.2, 77.7, 73.5, 72.9, 71.1, 70.7, 25.7; FABMS
m/z calcd for [M+H]+: 431.2222. Found: 431.2206.
1.4. 1-(40,50,60-Tri-O-benzyl-30-deoxy-b-D-glycero-D-
gulo-septanosyl)-[1,2,3]-trizaole-4,5-dicarboxylic acid
diethyl ester (3)
Azide 2 (0.032 g, 0.065 mmol) was dried via azeotropic
distillation from toluene (3 · 5 mL) under reduced
pressure and dissolved in dry toluene (5 mL). To the

S. Castro et al. / Carbohydrate Research 342 (2007) 1366–1372
1369
solution, diethyl acetylene dicarboxylate (0.011 mL,
1.7. 4-Cyclohexyl-1-(40,50,60-tri-O-benzyl-30-deoxy-b-D-
glycero-D-gluco-septanosyl)-1,2,3-trizaole (5)
0.065 mmol) was added dropwise and the mixture was
heated to 110 ꢁC for 24 h and then cooled to rt. The
reaction mixture was concentrated under reduced pres-
sure and the material was purified by column chroma-
tography, using 1:1 EtOAc–hexanes as eluent to give a
clear and colorless oil (0.030 g, 70%). Rf = 0.11 (1:3,
Triazole 5 was isolated in 70% yield as a clear syrup.
Rf = 0.72 (1:1, EtOAc–hexanes); [a]D +26.7 (c 4.8,
1
CHCl3); H NMR 400 MHz (CDCl3): d 7.58–7.21 (m,
16H), 5.43 (d, 1H, J = 8.24 Hz), 4.69 (ddd, 2H,
J = 15.74, 9.61, 7.03 Hz), 4.58 (dd, 3H, J = 12.52,
4.48 Hz), 4.52 (d, 1H, J = 11.84 Hz), 4.37 (d, 1H,
J = 11.40 Hz), 3.98 (dd, 2H, J = 7.74, 4.05 Hz), 3.69
(dd, 2H, J = 10.20, 2.60 Hz), 3.60 (ddd, 2H, J = 16.37,
6.55, 4.39 Hz), 2.76 (s, 1H), 2.46 (ddd, 1H, J = 14.63,
7.78, 3.88 Hz), 2.19 (dd, 1H, J = 14.76, 9.20 Hz), 2.04
(d, 2H, J = 9.20 Hz), 1.79 (dd, 3H, J = 25.75,
12.14 Hz), 1.51–1.26 (m, 5H); 13C NMR 100 MHz
(CDCl3): d 138.1, 137.7, 128.6 (3), 128.1, 128.0, 127.9,
127.8, 119.3, 94.7, 82.6, 80.4, 75.7, 73.4, 72.9, 71.3,
68.9, 35.3, 32.9, 32.6, 26.2, 26.1; ESIMS m/z calcd for
[M+Na]+: 620.3095. Found: 620.3103.
1
EtOAc–hexanes); [a]D ꢀ46.7 (c 2.9, CHCl3); H NMR
400 MHz (CDCl3): d 7.37–7.21 (m, 15H), 5.93 (d, 1H,
J = 8.80 Hz), 5.10–5.06 (m, 1H), 4.69 (d, 1H,
J = 12.1 Hz), 4.58 (dd, 2H, J = 12.3, 2.7 Hz), 4.47–
4.18 (m, 8H), 4.07 (dd, 1H, J = 11.0, 4.8 Hz), 3.98 (dd,
1H, J = 5.7, 5.7 Hz), 3.8 (dd, 1H, J = 6.0, 6.0 Hz),
3.60–3.57 (m, 2H), 2.83 (d, 1H, J = 4.4 Hz), 2.47 (ddd,
1H, J = 14.8, 7.5, 4.4 Hz), 2.21 (dd, 1H, J = 14.6,
9.2 Hz), 1.42 (t, 3H, J = 7.1, 7.1 Hz), 1.34 (t, 3H,
J = 7.1, 7.1 Hz) ; 13C NMR 100 MHz (CDCl3): d
138.9 (2), 138.4, 138.3, 128.6 (2), 128.4, 128.3, 128.2,
128.0, 127.9 (2), 127.7 (2), 108.3, 79.8, 79.7, 79.3, 75.8,
74.7 (2), 74.3, 73.9, 73.8, 70.2, 56.2.
1.8. 4-Phenyl-1-(40,50,60-tri-O-benzyl-30-deoxy-b-D-
glycero-D-gluco-septanosyl)-1,2,3-trizaole (6)
1.5. Procedure for preparation of triazoles 4–7
Azide 2 (1.00 mmol) and the appropriate alkyne
(1.00 mmol) were dissolved in a solution of water and
t-BuOH (1:1) such that the azide was at a concentra-
tion of 0.5 M (2–3 mL). To this solution was added
sodium ascorbate (0.40 mmol) and Cu(OAc)2 (0.20
mmol). The reaction was allowed to stir at rt overnight.
After, water (20 mL) was added to dilute the solution
and the mixture was then extracted with CH2Cl2
(3 · 20 mL). The organic layer was washed with satd
NaHCO3 and aq NaCl and then dried over Na2SO4.
The organic layer was concentrated under reduced pres-
sure and purified by flash column chromatography (1:1,
EtOAc–hexanes).
Triazole 6 was isolated in 65% yield as a clear syrup.
Rf = 0.63 (1:1, EtOAc–hexanes); [a]D +39.8 (c 4.7,
CHCl3); H NMR 400 MHz (CDCl3): d 8.06 (d, 1H,
1
J = 21.72 Hz), 7.73 (d, 2H, J = 6.16 Hz), 7.42–7.24 (m,
18H), 5.53 (d, 1H, J = 8.32 Hz), 4.75 (d, 2H,
J = 12.08 Hz), 4.62 (dd, 2H, J = 11.66, 3.98 Hz), 4.56
(dd, 2H, J = 22.45, 10.52 Hz), 4.39 (d, 1H,
J = 11.36 Hz), 4.04–4.03 (m, 2H), 3.72 (dd, 2H,
J = 10.33, 2.99 Hz), 3.63 (dd, 2H, J = 14.94, 6.02 Hz),
2.50 (ddd, 1H, J = 14.46, 7.80, 4.00 Hz), 2.36 (dd, 1H,
J = 14.78, 9.02 Hz); 13C NMR 100 MHz (CDCl3): d
147.7, 138.2, 138.1, 137.7, 130.3, 128.9, 128.6 (2),
128.3, 128.1, 128.0 (2), 127.9 (2), 125.8, 119.5, 94.9,
82.8, 80.4, 75.8, 73.5, 73.0, 71.4, 71.3, 69.0, 32.8; ES
m/z calcd for [M+Na]+: 614.2625. Found: 614.2614.
1.6. 4-Butyl-1-(40,50,60-tri-O-benzyl-30-deoxy-b-D-
glycero-D-gluco-septanosyl)-1,2,3-trizaole (4)
Triazole 4 was isolated in 65% as a clear syrup.
Rf = 0.65 (1:1, EtOAc–hexanes); [a]D +26.5 (c 6.2,
CHCl3); H NMR 400 MHz (CDCl3): d 7.60–7.21 (m,
1.9. 4-(2,3:4,6-Di-O-isopropylidene-mannosyl)-1-(4,5,6-
tri-O-benzyl-3-deoxy-b-D-glycero-D-glucoseptanosyl)-
1,2,3-trizaole (7)
1
16H), 5.46 (d, 1H, J = 8.19 Hz), 4.75–4.66 (m, 2H),
4.57 (dd, 4H, J = 8.19, 9.28 Hz), 4.40 (t, 1H,
J = 12.90 Hz), 3.99 (dd, 2H, J = 9.67, 5.70 Hz), 3.85
(s, 1H), 3.69 (dd, 1H, J = 10.80, 3.16 Hz), 3.61 (dd,
2H, J = 11.32, 5.64 Hz), 2.71 (t, 2H, J = 7.72 Hz), 2.46
(ddd, 1H, J = 14.53, 7.80, 3.86 Hz), 2.20 (dd, 1H,
J = 14.69, 9.08 Hz), 1.65 (ddd, 2H, J = 14.76, 7.42,
7.42 Hz), 1.42 (ddd, 2H, J = 14.74, 7.33, 7.33 Hz), 0.97
(t, 3H, J = 7.32 Hz); 13C NMR 100 MHz (CDCl3): d
138.1 (2), 137.7, 128.6, 128.5 (2), 128.1, 128.0, 127.9,
127.8, 120.4, 94.6, 82.5, 80.3, 75.8, 73.4, 72.9, 71.3,
71.2, 68.9, 32.7, 31.5, 25.3, 22.3, 13.9; ESIMS m/z calcd
for [M+Na]+: 594.2938. Found: 594.2945.
Triazole 7 was isolated in 52% yield as a white solid. [a]D
+18.4 (c 4.0, CHCl3); H NMR 400 MHz (CDCl3): d
1
7.93 (s, 1H), 7.35–7.19 (m, 15H), 5.56 (s, 1H), 5.46 (d,
1H, J = 9.24 Hz), 4.75 (s, 1H), 4.68 (d, 1H, J =
11.95 Hz), 4.59 (d, 2H, J = 13.36 Hz), 4.51 (dd, 2H,
J = 15.47, 11.58 Hz), 4.15 (dd, 1H, J = 14.20,
7.12 Hz), 3.97 (s, 2H), 3.87–3.81 (m, 2H), 3.60 (t, 2H,
J = 10.28 Hz), 3.54 (dd, 2H, J = 18.79, 8.70 Hz), 3.30
(s, 1H), 2.45 (d, 1H, J = 16.27, 7.18 Hz), 1.60 (d, 4H,
J = 10.20 Hz), 1.49 (s, 3H), 1.27 (t, 4H, J = 10.06),
1.00 (s, 2H); 13C NMR 100 MHz (CDCl3): d 138.2,
138.0, 137.6, 128.7, 128.2, 128.0 (2), 109.7, 98.5, 94.8,

1370
S. Castro et al. / Carbohydrate Research 342 (2007) 1366–1372
82.9, 82.8, 80.0, 76.5, 76.0, 73.4, 73.0, 72.3, 71.4, 71.2,
69.1, 65.0, 63.7, 32.8, 28.6, 26.8, 25.9, 18.6.
by the addition of satd aq NH4Cl (50 mL). The mixture
was concentrated and the residue extracted with CH2Cl2
(3 · 20 mL). The organic layer was dried with Na2SO4
and concentrated. Purification by flash column chroma-
tography (1:2 to 1:1, EtOAc–hexanes) gave the alkyne
1.10. 1-Chloro-3,4:5,7-di-O-isopropylidene-1,2-dideoxy-
D-manno-hept-1-enitol (14)
1
15 (0.137 g) in 68% yield. H NMR 300 MHz (CDCl3):
A solution of chloromethyltriphenylphosphonium chlo-
ride (15.4 mmol) in 10 mL dry THF was cooled to 0 ꢁC.
To this solution was added n-BuLi (9.60 mL,
15.4 mmol) and HMPA (2.67 mL, 15.4 mmol) dropwise.
After 10 min, a solution of 2,3:4,6-di-O-isopropylidene-
b-D-mannopyranose24 (1.00 g, 3.8 mmol) in dry THF
(10 mL) was added. The reaction was allowed to come
to rt with stirring overnight. After, excess base was
quenched by the addition of satd NH4Cl (100 mL).
The mixture was concentrated and the residue extracted
with CH2Cl2 (3 · 40 mL). The organic layer was dried
with Na2SO4 and concentrated. Purification by column
chromatography (1:4, EtOAc–hexanes) led to the trans
and cis vinyl chlorides 14 (0.66 g) in 61% combined
yield. The vinyl chlorides were routinely used as the
mixture of trans and cis isomers in the subsequent
reaction.
d 4.87 (dd, 1H, J = 6.33, 2.13 Hz), 4.31 (dd, 1H, J =
6.29, 3.29 Hz), 3.87–3.75 (m, 3H), 3.59 (dd, 1H, J =
10.53, 8.34 Hz), 2.92 (s, 1H), 1.48 (d, 6H, J = 17.11),
1.33 (d, 6H, J = 16.11 Hz); 13C NMR 100 MHz
(CDCl3): d 110.4, 98.6, 79.3, 76.3, 76.1, 73.2, 67.2,
64.8, 63.5, 28.2, 26.5, 26.0, 19.1.
1.14. General hydrogenolysis procedure
10% Pd/C (0.005–0.010 g) was added to a solution of
the protected triazole 3–7 (0.05 mmol) in CH3OH
(6 mL). The reaction was placed under an H2 atmo-
sphere via a balloon and the mixture was stirred for
4 h at rt. The balloon was removed from the flask and
the mixture was filtered through a short pad of Celite.
The Celite was washed with additional CH3OH
(4 · 5 mL). The solvent was removed from the combined
filtrates by rotary evaporation under reduced pressure to
give the deprotected triazoles 8–12 in the yields
indicated.
1.11. trans-1-Chloro-3,4:5,7-di-O-isopropylidene-1,2-
dideoxy-D-manno-hept-1-enitol (14-trans)
[a]D ꢀ0.5 (c 4.5, CHCl3); 1H NMR 400 MHz (CDCl3): d
6.35 (d, 1H, J = 13.36 Hz), 6.24 (dd, 1H, J = 8.28,
13.32 Hz), 4.71 (t, 1H, J = 7.76 Hz), 4.39 (dd, 1H,
J = 7.30, 1.34 Hz), 4.12 (dd, 1H, J = 10.73, 8.40 Hz),
4.00 (d, 2H, J = 5.36), 3.45 (d, 1H, J = 6.99 Hz), 2.18
(s, 1H), 1.52–1.36 (m, 12H); 13C NMR 100 MHz
(CDCl3): d 130.0, 123.5, 109.6, 76.9, 76.7, 76.3, 70.7,
67.4, 27.0, 26.9, 25.4, 24.6.
1.15. 1-(30-Deoxy-b-D-glycero-D-gluco-septanosyl)-1,2,3-
trizaole-4,5-dicarboxylic acid diethyl ester (8)
The product was isolated as a clear, colorless oil (100%).
1H NMR 400 MHz (CD3OD):
d 5.93 (d, 1H,
J = 8.1 Hz), 5.05 (dd, 1H, J = 8.49, 4.5 Hz), 4.51 (dd,
2H, J = 14.3, 7.1 Hz), 4.44 (dd, 2H, J = 14.3, 7.2 Hz),
4.03 (dd, 1H, J = 8.7, 8.7 Hz), 3.83 (dd, 1H, J = 11.9,
2.2 Hz), 3.76 (m, 1H), 3.62 (dd, 1H J = 11.9, 6.34 Hz),
3.38 (m, 1H), 2.30 (ddd, 1H, J = 14.7, 10.1, 4.7 Hz),
2.09 (dd, 1H, J = 4.6, 3.3 Hz), 1.43 (dd, 6H, J = 15.3,
7.2 Hz); 13C NMR 100 MHz (CD3OD): d 161.5, 159.9,
141.1, 132.5, 94.8, 87.7, 76.3, 70.9, 68.8, 64.4, 64.1,
63.1, 39.3, 14.5, 14.3; ES m/z [M+Na]+ calcd
412.1327, found 412.1315.
1.12. cis-1-Chloro-3,4:5,7-di-O-isopropylidene-1,2-di-
deoxy-D-manno-hept-1-enitol (14-cis)
[a]D ꢀ100.4 (c 2.3, CHCl3); 1H NMR 400 MHz
(CDCl3): d 6.21 (dd, 1H, J = 7.28, 1.28 Hz), 6.09 (t,
1H, J = 7.12 Hz), 5.26 (m, 1H), 4.59 (dd, 1H,
J = 23.86, 7.34 Hz), 4.13 (dd, 1H, J = 14.22, 7.06 Hz),
3.91 (m, 1H), 3.62 (dd, 1H, J = 12.76, 11.00 Hz), 3.44
(dd, 1H, J = 22.49, 7.99 Hz), 2.37 (s, 1H), 1.56–1.33
(m, 12H); 13C NMR 100 MHz (CDCl3): d 129.8,
121.2, 109.6, 98.8, 76.3, 75.2, 73.7, 65.0, 63.2, 28.6,
26.6, 26.0, 19.4.
1.16. 4-Butyl-1-(30-deoxy-b-D-glycero-D-gluco-septanos-
yl)-1,2,3-trizaole (9)
The product was isolated as a white solid (99%).
Mp = 159–161 ꢁC; [a]D +20.6 (c 3.3, CH3OH); 1H
NMR 300 MHz (CD3OD): d 7.93 (s, 1H), 5.59 (d, 1H,
J = 7.77 Hz), 4.59 (ddd, 1H, J = 8.08, 4.25, 4.25 Hz),
4.03 (t, 1H, J = 8.00 Hz), 3.85 (dd, 1H, J = 11.75,
2.21 Hz), 3.74 (dd, 1H, J = 7.65, 2.32 Hz), 3.63 (dd,
1H, J = 11.77, 6.36 Hz), 3.42 (dd, 1H, J = 8.86,
7.46 Hz), 3.33 (dd, 1H, J = 3.13, 1.54 Hz), 2.72 (t, 2H,
J = 7.76 Hz), 2.26 (ddd, 1H, J = 14.47, 9.98, 4.41 Hz),
2.09 (ddd, 1H, J = 14.54, 4.95, 1.35 Hz), 1.68 (ddd,
1.13. 3,4:5,7-Di-O-isopropylidene-1,2-dideoxy-D-manno-
hept-1-ynitol (15)
A solution of the vinyl chlorides 14 (0.230 g, 0.80 mmol)
was dissolved in dry THF (3 mL) and cooled to ꢀ78 ꢁC.
To this solution was added n-BuLi (2.88 mL, 4.6 mmol)
dropwise. After 3 h the reaction mixture was quenched

S. Castro et al. / Carbohydrate Research 342 (2007) 1366–1372
1371
2H, J = 15.17, 7.56, 7.56 Hz), 1.42 (dq, 2H, J = 22.31,
Acknowledgements
7.36 Hz), 0.97 (t, 3H, J = 7.32 Hz); 13C NMR
100 MHz (CD3OD): d 149.3, 130.9, 122.3, 95.6, 86.8,
76.5, 71.3, 70.3, 64.3, 38.9, 32.8, 26.1, 23.4, 14.2; ES
m/z [M+Na]+ calcd 324.1530, found 324.1539.
E.C.C. thanks the National Science Foundation
(N.S.F.) for an REU summer research stipend (CHE-
0354012). This work was supported by the University
of Connecticut Research Foundation and an N.S.F.
CAREER award to M.W.P. (CHE-0546311).
1.17. 4-Cyclohexyl-1-(30-deoxy-b-D-glycero-D-gluco-
septanosyl)-1,2,3-trizaole (10)
Supplementary data
The product 10 was isolated as a slightly yellow glass
(99%). [a]D +22.0 (c 2.6, CH3OH); H NMR 400 MHz
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.carres.
2007.03.026.
1
(CD3OD): d 7.92 (s, 1H), 5.60 (d, 1H, J = 7.72 Hz),
4.60 (dt, 1H, J = 7.80, 4.20 Hz), 4.04 (t, 1H,
J = 8.32 Hz), 3.86 (d, 1H, J = 10.24 Hz), 3.75 (t, 1H,
J = 6.66 Hz), 3.64 (dd, 1H, J = 11.76, 6.32 Hz), 3.44
(t, 1H, J = 8.14 Hz), 3.35 (d, 1H, J = 15.25 Hz), 2.76
(s, 1H), 2.27 (ddd, 1H, J = 14.26, 10.05, 4.13 Hz),
2.12–2.05 (m, 2H), 1.93–2.86 (m, 3H), 1.59–1.40 (m,
5H); 13C NMR 100 MHz (CD3OD): d 154.5, 121.0,
95.6, 86.9, 76.4, 71.3, 70.3, 64.3, 38.9, 36.7, 34.2 (2),
27.4, 27.2; ES m/z [M+Na]+ calcd 350.1686, found
350.1690.
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