An efficient synthesis of triazolo-carbohydrate mimetics and their conformational analysis

Article abstract of DOI:10.1039/b803924k

A chemical library of 1,2,3-triazole fused carbohydrate mimetics was constructed. To synthesize enantiomerically pure mimetics, we developed a stereo- or diastereodivergent synthetic route from d-glucose, d-mannose and d-galactose as chiral sources. In th

Full text of DOI:10.1039/b803924k

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www.rsc.org/obc | Organic & Biomolecular Chemistry
An efficient synthesis of triazolo-carbohydrate mimetics and their
conformational analysis†
Hikaru Yanai, Shun Obara and Takeo Taguchi*
Received 6th March 2008, Accepted 14th April 2008
First published as an Advance Article on the web 19th May 2008
DOI: 10.1039/b803924k
A chemical library of 1,2,3-triazole fused carbohydrate mimetics was constructed. To synthesize
enantiomerically pure mimetics, we developed a stereo- or diastereodivergent synthetic route from
D-glucose, D-mannose and D-galactose as chiral sources. In this synthesis, an In(OTf)3-catalyzed
tandem azidation–1,3-dipolar cycloaddition reaction of 1,1-dimethoxyhex-5-yne derivatives with
TMSN3 was used as the key step to construct the 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyridine
framework. Additionally, NMR was used to carry out a conformational analysis of the synthesized
mimetics, which are of structural interest since they have an N,O-acetal moiety in place of the anomeric
position of normal pyranosides.
Introduction
1,2,3-Triazole derivatives are attracting much attention from
medicinal chemists due to their interesting biological properties,
such as antibacterial and antitumor activities, and glycosidase
inhibition.1,2 The isolation of triazole-containing compounds from
nature has not been reported, therefore, these compounds can only
be obtained by chemical synthesis. A number of methodologies to
Fig. 1 Structures of D-glucose and triazolo-glucose mimetics.
construct 1,2,3-triazole ring systems have already been reported.
Among these methodologies, the 1,3-dipolar cycloaddition of
organic azides to carbon–carbon multiple bonds, namely the
Huisgen reaction, is one of the most important reactions.3
Recently, Meldal et al. and Sharpless et al. independently re-
ported that, under mild conditions, Cu(I) complexes catalyze the
intermolecular Huisgen reaction of terminal alkynes and organic
azides to give 1,4-disubstituted 1,2,3-triazoles with excellent regio-
and chemoselectivities.4,5 However, due to the rapid formation
of dimerized products through intermolecular cycloaddition, it is
essentially difficult to apply Cu(I) catalysts to the intramolecular
Huisgen reaction.6 Bicyclic triazoles, which would be prepared by
the intramolecular Huisgen reaction of x-azidoalkyne derivatives,
are also interesting compounds in medicinal chemistry. For exam-
ple, Vasella et al. and Wong et al. reported the synthesis of car-
bohydrate mimetics having a 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-
a]pyridine framework and their inhibition properties against sev-
eral glycosidases (Fig. 1).7,8 However, the construction of a bicyclic
triazole framework by the intramolecular Huisgen type reaction
under simple thermal conditions remains a problematic step in
these syntheses. Therefore, the development of active catalysis for
the intramolecular Huisgen reaction is one of the challenges in
synthetic organic chemistry. Recently, we reported that indium(III)
triflate [In(OTf)3] nicely catalyzes the tandem azidation–1,3-
dipolar cycloaddition reaction of x,x-dialkoxyalkyne derivatives
with TMSN3 to give alkoxylated bicyclic 1,2,3-triazole products
(Scheme 1).9 In this reaction procedure, the isolation of potentially
explosive organic azides was not needed.10 Additionally, the mild
Lewis acidity and chemical stability of In(OTf)3 encouraged us to
apply this reaction to more complex substrates.11 Consequently,
we designed triazolo-carbohydrate mimetic A, which is not only a
potential synthetic intermediate of Vasella’s triazolo-mimetics but
also a structurally interesting mimic having an N,O-acetal moiety
as an equivalent to the anomeric position in normal pyranosides.
Herein we disclose the stereodivergent synthesis of A through
the tandem azidation–1,3-dipolar cycloaddition reaction of highly
oxygenated 1,1-dimethoxyhex-5-yne derivatives with TMSN3.
Scheme 1 In(OTf)3-catalyzed tandem azidation–1,3-dipolar cycloaddi-
tion reaction.
Results and discussion
Stereodivergent synthesis of triazolo-glucose/idose mimetics
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences,
1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. E-mail: taguchi@
ps.toyaku.ac.jp; Fax: +81 42 676 3257; Tel: +81 42 676 3257
† Electronic Supplementary Information (ESI) available: Preparative pro-
cedures for 6b, 6c, ent-5b and ent-5c, and NMR spectra of new compounds.
Enantiomerically pure 1,1-dimethoxyhex-5-yne derivative 4a was
synthesized in three steps from the chiral building block 1a,
which was easily prepared from D-glucose in multi-gram scale
(Scheme 2).12 That is, under acidic conditions, 1a was converted
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Scheme 2 Synthesis of 6a. Reagents and conditions: (a) HC(OMe)3, pTsOH, rt, 6 h, 91%; (b) OsO4, NMO, acetone–tBuOH–H2O (20 : 5 : 1), rt, 7 h, then
NaIO4, rt, 1 h, 79%; (c) CH3COC(N2)P(O)(OMe)2, K2CO3, MeOH, rt, 2 h, 76%; (d) TMSN3, In(OTf)3 (5 mol%), ClCH2CH2Cl, 0 ◦C, 4 h, then 80 ◦C,
8 h, 75% (a : b = 1 : 1.2); (e) TMSN3, In(OTf)3 (5 mol%), hexane, 0 ◦C, 4 h, then 60 ◦C, 16 h, 82% (a : b = 1.4 : 1); (f) Pd(OH)2/C, H2 (1 atm.), MeOH,
rt, 11 h.
to dimethyl acetal 2a in 91% yield by reaction with trimethyl
orthoformate. Catalytic dihydroxylation of 2a using an OsO4–4-
methylmorpholine N-oxide (NMO) system and an oxidative work-
up by NaIO4 provided the 5,5-dimethoxypentanal derivative 3a
in 79% yield. The homologation of 3a was achieved by Ohira–
Bestmann conditions using a CH3COC(N2)P(O)(OMe)2–K2CO3
system to give the 1,1-dimethoxyhex-5-yne derivative 4a in 76%
yield.13 In the presence of 5 mol% of In(OTf)3, the reaction of
4a and 5.0 molar equivalents of TMSN3 in 1,2-dichloroethane
at 0 ◦C for 4 h resulted in the complete consumption of 4a
(by TLC). Without isolation of the a-azido ether intermediate,
followed by silylation using the standard procedure produced the
silyl ether 7a in 94% yield over two steps. Catalytic dihydroxylation
of 7a and oxidative work-up gave the aldehyde 8a in 96% yield,
then 8a was converted to the 5,5-dimethoxypentan-1-ol derivative
9a in 89% yield over two steps via dimethyl acetalization and
desilylation by fluoride. According to the preparation of 4a, the
homologation reaction of aldehyde ent-3a, which was prepared
by the Dess–Martin oxidation of 9a, gave ent-4a. The tandem
azidation–1,3-dipolar cycloaddition reaction of ent-4a catalyzed
by In(OTf)3 gave essentially the same results as in the case of 4a
(78% yield, a : b = 1 : 1.2).
◦
further heating of the reaction mixture at 80 C for 8 h gave the
tribenzylated gluco-mimic 5a in 75% yield with low b-selectivity
(a: b = 1 : 1.2).14 Interestingly, the reaction of 4a in hexane instead
of 1,2-dichoroethane resulted in a change of diastereoselectivity.
That is, in hexane, the tandem azidation–1,3-dipolar cycloaddition
Diastereodivergent synthesis of triazolo-carbohydrate mimetics
Next, we carried out the diastereodivergent synthesis of triazolo-
carbohydrate mimetics from D-mannose and D-galactose. Mimet-
ics 4b and ent-4c, and 4c and ent-4b, were easily prepared from D-
mannose and D-galactose respectively, according to the synthetic
procedures for 4a and ent-4a (see Experimental section). The
results of the tandem azidation–1,3-dipolar cycloaddition reaction
are summarized in Table 1. Compared to the case of 4a, the
reactions of 4b and 4c gave better results. By the reaction of 4b at
◦
reaction of 4a for 16 h at 60 C provided the cycloadduct 5a in
82% yield with a-selectivity (a: b = 1.4 : 1). After chromatographic
separation of the anomeric mixture 5a, 5a-a and 5a-b were stirred
under a H2 atmosphere (1 atm.) in the presence of 40 mol% of
Pd(OH)2 on carbon for 11 h at room temperature to give 6a-a and
6a-b respectively in excellent yield without epimerization at the
anomeric position.
◦
80 C for 11 h, manno-mimic 5b was obtained in 91% yield as a
As shown in Scheme 3, the latent symmetry of 1a also enabled us
to synthesize an enantiomer of 4a (ent-4a). NaBH4 reduction of 1a
mixture of anomeric diastereomers in a ratio of 1.2 : 1 (entry 1).
Interestingly, the reaction at room temperature for 24 h gave only
Scheme 3 Synthesis of ent-5a. Reagents and conditions: (a) NaBH4, MeOH, rt, 2 h; (b) TBSCl, imidazole, DMF, rt, 3 h, 94% over 2 steps; (c) OsO4,
NMO, acetone–tBuOH–H2O (20 : 5 : 1), rt, 6 h, then NaIO4, rt, 1 h, 96%; (d) HC(OMe)3, pTsOH, rt, 45 min; (e) TBAF, THF, rt, 8 h, 89% over 2 steps; (f)
Dess–Martin periodinane, CH2Cl2, rt, 2 h, 96%; (g) CH3COC(N2)P(O)(OMe)2, K2CO3, MeOH, rt, 2 h; (h) TMSN3, In(OTf)3 (5 mol%), ClCH2CH2Cl,
0
◦C, 4 h, then 80 ◦C, 8 h, 78% (a : b = 1 : 1.2).
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Table 1 Tandem azidation–1,3-dipolar cycloaddition reactions of 1,1-dimethoxyhex-5-yne 4
Entry
1
4
Temp./◦C
80
Time/h
12
5
Yielda
91
a : bb
1.2 : 1
2
rt
rt
60
16
120
24
26
39
66
b-only
1 : 1.1
1 : 1.1
3
4c
5
80
12
86
1.3 : 1
6
80
8
90
1 : 1.8
7c
8
60
80
12
8
63
89
1.3 : 1
1 : 2.2
a Isolated yield. b Based on 1H-NMR. c Solvent: hexane.
the b-anomer 5b-b as the sole cycloadduct in 26% yield (entry 2),
although a prolonged reaction time (120 h) at room temperature
remarkably decreased the b-selectivity (entry 3).15 In addition,
carrying out the reaction in hexane for 24 h at 60 ◦C resulted in low
b-selectivity with a reasonable product yield (66% yield, a : b = 1 :
1.1) (entry 4). Likewise, the reaction of 4c in 1,2-dichloroethane
gave the galacto-mimic 5c in 90% yield with moderate b-selectivity
and the reaction in hexane gave 5c in 63% yield with a-selectivity
(entry 6, a : b = 1 : 1.8; entry 7, a : b = 1.3 : 1). gulo-Mimic
ent-5b and altro-mimic ent-5c were also obtained in 86% and 89%
yield, respectively (entry 5, a : b = 1.3 : 1; entry 8, a : b = 1 : 2.1).
Furthermore, manno- and galacto-cycloadducts 5b and 5c were
debenzylated by the above hydrogenolysis conditions to give triols
6b and 6c in excellent yield without epimerization at the anomeric
position (Fig. 2).
Fig. 2 Synthesized manno- and galacto-mimetics.
Concerning the observed diastereoselectivity, we propose the
mechanism of tandem azidation–1,3-dipolar cycloaddition reac-
tion. An example with the 1,1-dimethoxyhex-5-yne derivative 4b
is shown in Scheme 4. It was found that the 1H NMR of a
crude mixture obtained by the reaction of 4b with 5.0 molar
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Scheme 4 Proposed reaction mechanism.
equivalents of TMSN3 in the presence of 5 mol% of In(OTf)3
at room temperature for 2.5 h, showed the formation of (1R)-
azido ether and a mixture of (1S)-products, consisting of (1S)-
azido ether and (1S)-bicyclic triazole 5b-b. The ratio of (1R)-
azido ether to (1S)-products was 1.8 : 1. This finding clearly
supported the fact that (1R)-azido ether is a preferable product
in the azidation step, while its intramolecular cycloaddition does
not occur at room temperature due to the destabilization of
its transition state by the axial-methoxy group. On the other
hand, the (1S)-azido ether smoothly converts to the bicyclic
triazole 5b-b having S configuration at the anomeric position.16
Prolonged reaction at room temperature should result in the
epimerization of the initially formed 5b-b at the anomeric position,
catalyzed by In(OTf)3.9 With the reaction at a higher temperature,
both diastereomers of the a-azido ether should stereospecifically
convert to the corresponding cycloadduct 5b, which finally falls
into an appropriate ratio of a- and b-isomers via an epimerization
process after the formation of 5b-b from (1S)-azido ether and 5b-a
from (1R)-azido ether.
J2,3 10.6, J3,4 7.1 Hz for 6a-a and J1,2 6.8, J2,3 9.5, J3,4 8.4 Hz for
6a-b. Furthermore, NOESY spectra of b-gluco-mimic 6a-b also
showed a strong correlation between H1 and H3, which supports
2
its H3 conformation, and a weak correlation between H1 and
H2, although an NOE correlation between H3 and H4 was not
observed. Since the H1–H2 correlation cannot be assigned to
2
its H3 conformation, we proposed that the b-gluco-mimic 6a-b
2
exists as an equilibrium mixture of the H3 conformer and the
1,4B conformer.17 Furthermore, in tribenzyl ether 5a-b (400 MHz,
in CDCl3), small coupling constants, J1,2 4.0, J2,3 6.2 and J3,4
7.4 Hz, and a relatively weak NOE correlation between H1 and
H3, compared to a strong NOE correlation between H1 and
H2, supported the assignment of the 1,4B conformation to this
molecule. A similar tendency was also observed in the NMR
spectra of galacto-mimetic 6c. That is, the a-anomer occupies
the relatively stable 2H3 conformation, while the b-anomer exists
2
as an equilibrium mixture between the H3 conformer and the
1,4B conformer.18 Previously, we confirmed that the anomeric
effect of the triazolic N–C–O system is notably stronger than
that of an O–C–O system such as in 2-methoxytetrahydropyran
derivatives.19 The present conformational behavior of triazolo-
carbohydrate mimetics can be attributeted to the anomeric effect
of the triazolic N–C–O moiety. In a-anomers, the anomeric effect
Conformational analysis of the triazolo-carbohydrate mimetics
Based on NMR studies of triazolo-carbohydrate mimetics 6 in
D2O (600 MHz), their unique conformational behaviors were
revealed (Fig. 3). In both anomers of gluco-mimetic 6a, 3J coupling
constants and NOE correlation between H2 and H4 clearly
indicated that these mimetics occupy 2H3 conformations: J1,2 3.2,
2
of the triazolic N–C–O moiety stabilizes the H3 conformation.
In contrast, this anomeric effect possibly destabilizes the 2H3
conformation of b-anomers to form detectable amounts of 1,4B
conformers.
Fig. 3 Conformations of triazolo-glucose mimics 6a.
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(2S,3S,4R)-Tri(benzyloxy)-5,5-dimethoxypentanal (3a). To a
solution of 4-methylmorpholine N-oxide (NMO, 3.9 g, 34 mmol),
tert-butyl alcohol (20 mL) and 2a (9.3 g, 20 mmol) in acetone
(640 mL), a solution of OsO4 in H2O (0.11 M, 90 mL, 1.7 mmol)
was added. After being stirred for 7 h at room temperature,
the resultant mixture was treated with NaIO4 (40 g) for 1 h at
room temperature. The reaction mixture was filtered through a
pad of celite. Afterwards, the filtrate was extracted with EtOAc
(100 mL × 3) and the organic layer was washed with brine
(100 mL), dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel (hexane–EtOAc = 10 : 1) to give aldehyde 3a (7.36 g,
15.8 mmol) in 79% yield. Colorless oil. [a]2D5 (c 1.00, CHCl3) +2.48;
Conclusion
We achieved the stereodivergent synthesis of triazole-fused glu-
cose/idose mimetics through a tandem azidation–1,3-dipolar
cycloaddition reaction. According to the common synthetic
route, a chemical library of triazolo-carbohydrate mimetics with
stereochemical diversity was also constructed. Since the present
triazolo-carbohydrate mimetics have an sp3-hybridized anomeric
carbon, the existence of the anomeric effect at the triazolic N–C–
O system was expected. NMR experiments in D2O of the present
gluco- and galacto-mimetics showed that the a-anomers occupy the
relatively stable 2H3 conformation. In contrast, the b-anomers exist
as unstable 2H3 conformers in equilibrium with 1,4B conformers.
1
IR (neat) m 3031, 2932, 1729, 1455, 1092, 734 cm−1; H NMR
(400 MHz, CDCl3) d 3.29 (3H, s), 3.43 (3H, s), 3.69–3.74 (1H, m),
3.84 (1H, dd, J = 5.7, 2.9 Hz), 3.99–4.04 (1H, m), 4.45–4.52 (3H,
m), 4.56 (1H, d, J = 11.7 Hz), 4.62 (1H, d, J = 11.7 Hz), 4.68
(1H, d, J = 10.7 Hz), 4.78 (1H, d, J = 12.0 Hz), 7.19–7.37 (15H,
m), 9.72 (1H, d, J = 3.4 Hz); 13C NMR (100 MHz, CDCl3) d 54.3,
56.5, 72.9, 73.7, 73.9, 77.3, 79.5, 80.3, 105.4, 127.4, 127.8, 127.9,
127.9, 128.1, 128.3, 128.3, 128.4, 128.4, 137.4, 137.6, 137.9, 200.1;
MS (ESI-TOF) m/z 487 [M + Na]+; HRMS calcd for C28H32O6Na
[M + Na]+, 487.2097; found, 487.2094.
Experimental
General and materials
In(OTf)3 is commercially available. All reactions were carried
out under an argon atmosphere. H and 13C NMR spectra were
1
taken on a Bruker dpx400 spectrometer, and chemical shifts were
reported in parts per million (ppm) using CHCl3 (7.26 ppm)
in CDCl3 or sodium 3-trimethylsilylpropionate-2,2,3,3-d4 (TSP)
(0.00 ppm) in D2O for 1H NMR, and CDCl3 (77.01 ppm) or TSP
(0.00 ppm) in D2O for 13C NMR as an internal standard, respec-
tively. Infrared (IR) spectra were recorded on JASCO FT/IR-
620 or JASCO FT/IR-4100 infrared spectrophotometers. Mass
spectra (MS) were obtained on a Micromass LCT (ESI-TOF).
Medium pressure liquid chromatography (MPLC) was performed
using prepacked columns (KUSANO prepacked column Si-10,
40 × 300 mm i. d., silica gel, 50 lm) with a UV detector.
(2R,3S,4R)-2,3,4-Tri(benzyloxy)-1,1-dimethoxyhex-5-yne (4a).
To a solution of 3a (0.93 g, 2.0 mmol) in MeOH (20 mL), K2CO3
(0.83 g, 6.0 mmol) and Ohira–Bestmann reagent (1.34 g, 7.0 mmol)
were added. After being stirred for 2 h at room temperature,
the reaction mixture was filtered through a pad of celite and
the resulting filtrate was concentrated under reduced pressure.
Purification of the residue by column chromatography on silica gel
(hexane–EtOAc = 10 : 1) followed by MPLC (hexane–EtOAc =
10 : 1) gave 4a in 76% yield (700.1 mg, 1.52 mmol). Colorless oil.
[a]2D5 (c 1.00, CHCl3) −37.8; IR (neat) m 3282, 3063, 2930, 1454,
1
1096, 1027, 736, 697 cm−1; H NMR (400 MHz, CDCl3) d 2.54
Preparation of triazolo-glucose mimic (6a)
(1H, d, J = 2.0 Hz), 3.28 (3H, s), 3.48 (3H, s), 3.95 (2H, d, J = 7.6
Hz), 4.51–4.63 (3H, m), 4.68 (2H, brd, J = 11.1 Hz), 4.89 (1H, d,
J = 11.5 Hz), 4.90 (1H, d, J = 11.1 Hz), 4.99 (1H, d, J = 11.1 Hz),
7.23–7.44 (15H); 13C NMR (100 MHz, CDCl3) d 54.2, 56.3, 71.5,
71.6, 74.9, 75.3, 76.1, 79.2, 80.5, 81.2, 105.5, 127.4, 127.7, 128.1,
128.1, 128.2, 128.2, 128.3, 137.6, 138.6, 138.7; MS (ESI-TOF) m/z
483 [M + Na]+; HRMS calcd for C29H32O5Na [M + Na]+, 483.2147;
found, 483.2144.
(2R,3S,4R)-2,3,4-Tri(benzyloxy)-1,1-dimethoxyhex-5-ene (2a).
(2R,3S,4R)-2,3,4-Tribenzyloxyhex-5-enal 1a (24 mmol, 10.0 g)12
was treated with p-toluenesulfonic acid monohydrate
(pTsOH·H2O, 200 mg, 20 lmol) in trimethyl orthoformate
(200 mL) for 45 min at room temperature. The reaction mixture
was quenched with saturated NaHCO3 aqueous solution
(200 mL), followed by extraction with EtOAc (150 mL × 3).
The organic layer was washed with brine (100 mL), dried over
MgSO4, and evaporated. The residue was purified by column
chromatography on silica gel (hexane–EtOAc = 20 : 1) to give
2a in 91% yield (10.1 g, 21.8 mmol). Colorless oil. [a]2D5 (c 1.00,
CHCl3) −22.8; IR (neat) m 3031, 2908, 1496, 1454, 1072, 735 cm−1;
1H NMR (400 MHz, CDCl3) d 3.25 (3H, s), 3.42 (3H, s), 3.58
(1H, dd, J = 6.6, 3.0 Hz), 3.73 (1H, dd, J = 7.4, 3.0 Hz), 4.16
(1H, m), 4.41 (1H, J = 11.7 Hz), 4.47 (1H, J = 6.6 Hz), 4.55 (1H,
d, J = 11.6 Hz), 4.61 (1H, d, J = 11.7 Hz), 4.67 (1H, d, J = 11.6
Hz), 4.86 (1H, d, J = 11.6 Hz), 4.92 (1H, d, J = 11.5 Hz), 5.23
(1H, brd, J = 17.6 Hz), 5.25 (1H, dd, J = 10.6, 1.8 Hz), 5.77
(1H, ddd, J = 17.6, 10.6, 7.7 Hz), 7.25–7.36 (15H, m). 13C NMR
(100.6 MHz, CDCl3) d 54.5, 56.1, 70.7, 73.9, 75.0, 78.8, 81.3,
81.9, 105.6, 119.1, 127.29, 127.34, 127.4, 127.8, 127.9, 128.16,
128.18, 128.3, 138.6, 139.0, 139.1. MS (ESI-TOF) m/z 485 [M +
Na]+. HRMS calcd for C29H34NaO5 [M + Na]+, 485.2304; found:
485.2282.
(4R,5S,6R,7R)-4,5,6-Tri(benzyloxy)-7-methoxy-4,5,6,7-tetra-
hydro[1,2,3]triazolo[1,5-a]pyridine (5a-a) and (4R,5S,6R,7S)-4,5,6-
tri(benzyloxy)-7-methoxy-4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]-
pyridine (5a-b). To a suspension of In(OTf)3 (14.1 mg, 25 lmol)
in 1,2-dichloroethane (5.0 mL), TMSN3 (317 lL, 2.5 mmol) and a
solution of 4a (230 mg, 0.50 mmol) in 1,2-dichloroethane (2.0 mL)
were added at 0 ◦C. After being stirred for 4 h at the same
temperature, the resulting mixture was heated at 80 ◦C for 8 h. The
reaction mixture was quenched with H2O, extracted with EtOAc
and dried over MgSO4. Evaporation of the organic layer followed
by purification by column chromatography on silica gel (hexane–
EtOAc = 2 : 1) gave a mixture of anomers. This anomeric mixture
was separated by MPLC (hexane–EtOAc = 1 : 1) to give 5a-b
(96.6 mg, 0.205 mmol, 41% yield) and 5a-a (80.1 mg, 0.170 mmol,
34% yield). 5a-a was◦the more polar isomer. White amorphous
solid. Mp. 97.9–99.8 C; [a]2D5 (c 0.52, CHCl3) −32.4; IR (neat) m
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3062, 3030, 2932, 1454, 1363, 1203, 1162, 1096, 739, 698 cm−1; 1H
NMR (400 MHz, CDCl3) d 3.54 (3H, s), 3.75 (1H, dd, J = 10.1,
3.2 Hz), 4.50 (1H, dd, J = 10.1, 6.9 Hz), 4.73–4.80 (4H, m), 4.87
(1H, d, J = 11.0 Hz), 4.91 (1H, d, J = 12.1 Hz), 5.12 (1H, d, J =
11.0 Hz), 5.56 (1H, d, J = 3.2 Hz), 7.29–7.42 (15H, m), 7.52 (1H,
s). 13C NMR (100 MHz, CDCl3) d 58.1, 72.8, 73.5, 73.7, 75.5, 78.1,
79.4, 84.7, 127.9, 128.1, 128.1, 128.2, 128.2, 128.4, 128.5, 128.6,
128.7, 132.6, 133.4, 137.2, 137.2, 138.1; MS (ESI-TOF) m/z 472
[M + H]+; HRMS calcd for C28H30N3O4 [M + H]+, 472.2236;
found, 472.2214. 5a-b was the less polar isomer. Colorless oil. [a]D25
(c 0.50, CHCl3) −34.6; IR (neat) m 3062, 3031, 1454, 1359, 1224,
was added at 0 ◦C. After being stirred at room temperature for
3 h, the reaction mixture was quenched with H2O (25 mL) and
extracted with hexane (25 mL × 3). The combined organic layer
was dried over MgSO4 and evaporated. The residue was purified
by column chromatography on silica gel (hexane–EtOAc = 50 :
1) to give the TBS ether 7a in 94% yield (2.76 g, 4.70 mmol).
Colorless oil. [a]2D5 (c 1.01, CHCl3) −7.96; IR (neat) m 3031, 2928,
2856, 1455, 1254, 1092, 1028, 837, 733, 697 cm−1; 1H NMR
(400 MHz, CDCl3) d 0.00 (6H, s), 0.88 (9H, s), 3.61–3.75 (4H, m),
4.16 (1H, t, J = 6.6 Hz), 4.41 (1H, d, J = 11.5 Hz), 4.56 (1H, d,
J = 11.7 Hz), 4.63 (1H, d, J = 11.7 Hz), 4.71 (2H, d, J = 11.8
Hz), 4.83 (1H, d, J = 11.5 Hz), 5.25 (1H, brd, J = 14.7 Hz), 5.28
(1H, brd, J = 8.0 Hz), 5.77–5.89 (1H, m), 7.23–7.38 (15H, m);
13C NMR (100 MHz, CDCl3) d −5.5, 18.1, 25.9, 62.7, 70.7, 73.0,
75.1, 80.0, 81.1, 81.5, 118.6, 127.4, 127.4, 127.8, 128.0, 128.1,
128.2, 128.2, 128.4, 135.7, 138.5, 138.8, 138.9; MS (ESI-TOF)
m/z 555 [M + Na]+; HRMS calcd for C33H44NaO4Si [M + Na]+,
555.2907; found, 555.2884.
1
1156, 1090, 739, 698 cm−1; H NMR (400 MHz, CDCl3) d 3.61
(3H, s), 3.83 (1H, dd, J = 7.4, 6.2 Hz), 4.02 (1H, dd, J = 6.2,
4.0 Hz), 4.69 (1H, d, J = 11.5 Hz), 4.73 (1H, d, J = 11.5 Hz), 4.75
(1H, d, J = 11.4 Hz), 4.79 (1H, d, J = 11.4 Hz), 4.81 (1H, d, J =
7.4 Hz), 4.83 (1H, d, J = 11.6 Hz), 4.88 (1H, d, J = 11.6 Hz), 5.60
(1H, d, J = 4.0 Hz), 7.29–7.38 (15H, m), 7.60 (1H, s); 13C NMR
(100 MHz, CDCl3) d 58.5, 73.8, 73.8, 74.0, 74.4, 80.9, 82.5, 88.9,
127.9, 128.0, 128.0, 128.1, 128.1, 128.5, 128.6, 128.6, 130.8, 134.5,
137.1, 137.3, 137.6; MS (ESI-TOF) m/z 472 [M + H]+; HRMS
calcd for C28H30N3O4 [M + H]+, 472.2236; found, 472.2213.
(2S,3R,4S)-2,3,4-Tri(benzyloxy)-5-{[tert-butyl(dimethyl)silyl]-
oxy}pentanal (8a). Aldehyde 8a was obtained in 96% yield
(2.30 g, 4.30 mmol) by the reaction of 7a (2.4 g, 4.5 mmol), OsO4
(0.11 M in H2O, 4.0 mL, 0.44 mmol) and NMO (1.4 g, 12 mmol) in
a mixture of acetone (65 mL), H2O (15 mL) and tert-butyl alcohol
(2 mL) for 6 h at room temperature, followed by treatment of the
reaction mixture with NaIO4 (10 g) for 1 h at the same temperature.
Colorless oil. [a]2D5 (c 1.03, CHCl3) −11.1; IR (neat) m 3031, 2952,
2857, 1731, 1455, 1255, 1092, 1028, 838, 735, 697 cm−1; 1H NMR
(400 MHz, CDCl3) d 0.00 (6H, s), 0.89 (9H, s), 3.55–3.61 (1H, m),
3.67–3.77 (2H, m), 3.92 (1H, dd, J = 5.4, 1.6 Hz), 3.98–4.03 (1H,
m), 4.47–4.55 (3H, m), 4.59 (1H, d, J = 11.8 Hz), 4.67 (1H, d, J =
11.8 Hz), 4.79 (1H, d, J = 12.0 Hz), 7.23–7.38 (15H, m), 9.73 (1H,
d, J = 1.6 Hz); 13C NMR (100 MHz, CDCl3) d −5.5, −5.5, 18.1,
25.8, 61.6, 72.9, 73.1, 74.1, 78.2, 78.7, 81.2, 127.7, 128.0, 128.2,
128.4, 128.4, 137.3, 137.7, 138.0, 200.7; MS (ESI-TOF) m/z 557
[M + Na]+; HRMS calcd for C32H42NaO5Si [M + Na]+, 557.2699;
found, 557.2687.
(4R,5S,6R,7R)-4,5,6-Trihydroxy-7-methoxy-4,5,6,7-tetrahydro-
[1,2,3]triazolo[1,5-a]pyridine (6a-a). To a suspension of 20%
Pd(OH)2 on carbon (50 mg) in MeOH (1.0 mL), a solution of
5a-a (33.1 mg, 70 lmol) in MeOH (2.0 mL) was added. After
being stirred at room temperature for 11 h under a H2 atmosphere
(1 atm.), the reaction mixture was filtered. The filtrate was
concentrated under reduced pressure, and purified by column
chromatography on silica gel (CHCl3–MeOH = 10 : 1) to give
6a-a (13.8 mg, 68.8 lmol) in 96% yield. Colorless oil. [a]2D5 (c
1.00, CH3OH) +71.5; IR (neat) m 3031, 2908, 1496, 1454, 1072,
1
735 cm−1; H NMR (400 MHz, D2O) d 3.65 (3H, s), 4.07–4.12
(1H, m), 4.14 (1H, dd, J = 10.6, 7.1 Hz), 4.82 (1H, d, J = 7.1 Hz),
5.90 (1H, d, J = 3.2 Hz), 7.90 (1H, s); 13C NMR (100 MHz, D2O)
d 60.5, 68.4, 71.1, 73.5, 88.6, 134.2, 138.3; MS (ESI-TOF) m/z
202 [M + H]+; HRMS calcd for C7H12N3O4 [M + H]+, 202.0828;
found, 202.0821.
tert-Butyl(dimethyl){[(2S,3R,4S)-2,3,4-tri(benzyloxy)-5,5-dime-
thoxypentyl]oxy}silane. This compound was obtained in 100%
yield (3.90 g, 3.89 mmol) by the reaction of 8a (2.1 g, 3.9 mmol)
and HC(OMe)3 (10 mL) in the presence of pTsOH·H2O (100 mg)
for 45 min at room temperature. Colorless oil. [a]2D5 (c 1.00,
CHCl3) +7.20; IR (neat) m 3031, 2929, 2856, 1454, 1254, 1090,
(4R,5S,6R,7S)-4,5,6-Trihydroxy-7-methoxy-4,5,6,7-tetrahydro-
[1,2,3]triazolo[1,5-a]pyridine (6a-b). This compound was
prepared according to the synthesis of 6a-a and obtained in 95%
yield (12.2 mg, 60.6 lmol) by the reaction of 5a-b (30.1 mg,
64 lmol), Pd(OH)2 on carbon (20 w/w%, 50 mg) and H2 (1 atm.)
in MeOH (2.5 mL). Colorless oil. [a]2D5 (c 0.50, CH3OH) −26.6;
1
1028, 836, 733, 697 cm−1; H NMR (400 MHz, CDCl3) d 0.00
1
IR (neat) m 3031, 2908, 1496, 1454, 1072, 735 cm−1; H NMR
(6H, s), 0.88 (9H, s), 3.26 (3H, s), 3.43 (3H, s), 3.58 (1H, dd, J =
10.9, 5,5 Hz), 3.68–3.74 (2H, m), 3.75–3.81 (1H, m), 3.83–3.88
(1H, m), 4.45 (1H, d, J = 6.2 Hz), 4.63 (1H, d, J = 11.7 Hz),
4.65 (1H, d, J = 11.4 Hz), 4.66 (1H, d, J = 11.7 Hz), 4.73 (2H,
d, J = 11.7 Hz), 4.87 (1H, d, J = 11.5 Hz), 7.21–7.39 (15H, m);
13C NMR (100 MHz, CDCl3) d −5.4, 18.2, 25.9, 54.2, 55.9, 63.4,
72.9, 74.0, 74.6, 78.2, 78.3, 80.4, 105.5, 127.3, 127.4, 127.4, 127.9,
128.1, 128.1, 128.3, 138.7, 138.8, 138.9; MS (ESI-TOF) m/z 603
[M + Na]+; HRMS calcd for C34H48NaO6Si [M + Na]+, 603.3118;
found, 603.3132.
(400 MHz, D2O) d 3.83 (3H, s), 3.85 (1H, dd, J = 9.5, 8.4 Hz),
4.09 (1H, dd, J = 9.5, 6.8 Hz), 4.89 (1H, d, J = 6.8 Hz), 5.67
(1H, d, J = 6.8 Hz), 7.87 (1H, s); 13C NMR (100 MHz, D2O) d
60.9, 67.9, 73.6, 75.6, 92.5, 133.2, 139.0; ESI-MS (m/z) 202 [M +
H]+; HRMS calcd for C7H12N3O4 [M + H]+, 202.0828; found,
202.0821.
Preparation of triazolo-idose mimic (ent-5a)
tert-Butyl(dimethyl){[(2S,3S,4R)-2,3,4-tri(benzyloxy)hex-5-enyl]-
oxy}silane (7a). To
a
solution of (2S,3S,4R)-2,3,4-tris-
(2S,3R,4S)-2,3,4-Tri(benzyloxy)-5,5-dimethoxypentan-1-ol (9a).
(benzyloxy)hex-5-en-1-ol (2.1 g, 5.0 mmol),20 which was prepared
by NaBH4 reduction of 1a, and imidazole (510 mg, 7.5 mmol) in
DMF (5 mL), tert-butylchlorodimethylsilane (905 mg, 6.0 mmol)
To
a
solution of tert-butyl(dimethyl){[(2S,3R,4S)-2,3,4-tris-
(benzyloxy)-5,5-dimethoxypentyl]oxy}silane (3.9 g, 3.9 mmol) in
THF (5.0 mL), tetrabutylammonium fluoride (TBAF, 1.0 M in
2684 | Org. Biomol. Chem., 2008, 6, 2679–2685
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THF, 7.5 mL, 7.5 mmol) was added. After being stirred for
8 h at room temperature, the reaction mixture was evaporated.
The residue was dissolved in H2O (20 mL) and extracted with
EtOAc (20 mL × 3). The organic layer was washed with brine,
dried over Na2SO4 and concentrated under reduced pressure.
Chromatographic purification of the resulting residue on silica
gel (hexane–EtOAc = 3 : 1) gave alcohol 7a in 89% yield (1.66 g,
3.47 mmol). Colorless oil. [a]2D5 (c 1.00, CHCl3) −0.03; IR (neat)
V. V. Fokin, Angew. Chem., Int. Ed., 2006, 45, 1435–1439; (c) Y. Bourne,
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Int. Ed., 2002, 41, 3041–3044.
1
m 3460, 3030, 2933, 1454, 1070, 1028, 735, 698 cm−1; H NMR
(400 MHz, CDCl3) d 2.13 (1H, brs, OH), 3.31 (3H, s), 3.43–3.52
(1H, m), 3.50 (3H, s), 3.65–3.72 (2H, m), 3.73–3.79 (1H, m), 3.88–
3.93 (1H, m), 4.57 (1H, d, J = 6.3 Hz), 4.61–4.73 (4H, m), 4.81 (1H,
d, J = 11.4 Hz), 4.93 (1H, d, J = 11.4 Hz), 7.26–7.43 (15H, m);
13C NMR (100 MHz, CDCl3) d 54.2 56.0, 61.7, 72.8, 73.7, 74.6,
77.6, 78.4, 79.5, 105.3, 127.6, 127.7, 127.9, 128.2, 128.4, 138.3,
138.3, 138.4; MS (ESI-TOF) m/z 489 [M + Na]+; HRMS calcd
for C28H34NaO6 [M + Na]+, 489.2253; found: 489.2259.
(2R,3R,4S)-2,3,4-Tri(benzyloxy)-5,5-dimethoxypentanal (ent-
3a). To a solution of 9a (1.4 g, 3.0 mmol) in CH2Cl2, Dess-
Martin periodinane (DMP, 1.87 g, 4.5 mmol) was added. After
being stirred for 2 h at room temperature, the reaction mixture was
treated with pentane (15 mL) and filtered through a pad of celite.
The filtrate was concentrated under reduced pressure. Purification
of the residue by column chromatography on silica gel (hexane–
EtOAc = 5 : 1) gave the 5,5-dimethoxypentanal derivative ent-3a
in 96% yield (1.34 g, 2.88 mmol). The physical data of ent-3a were
coincident with those of 3a, except for the specific optical rotation:
[a]2D5 (c 1.10, CHCl3) −2.46.
(2S,3R,4S)-2,3,4-Tri(benzyloxy)-1,1-dimethoxyhex-5-yne (ent-
4a). This compound was prepared from ent-3a under the same
conditions as in the case of 4a. The physical data of ent-4a were
coincident with those of 4a, except for the specific optical rotation:
[a]2D5 (c 1.06, CHCl3) +39.6.
(4S,5R,6S,7S)-4,5,6-Tri(benzyloxy)-7-methoxy-4,5,6,7-tetrahy-
dro[1,2,3]triazolo[1,5-a]pyridine (ent-5a-a) and (4S,5R,6S,7R)-
4,5,6-tri(benzyloxy)-7-methoxy-4,5,6,7-tetrahydro[1,2,3]triazolo-
[1,5-a]pyridine (ent-5a-b). These compounds were prepared
according to the synthetic procedure for 5a and obtained in 78%
yield (ent-5a-a 70.7 mg, 0.15 mmol, 30% yield; ent-5a-b 113.2 mg,
0.24 mmol, 48% yield) by the reaction of ent-4a (230.1 mg,
0.50 mmol) and TMSN3 (317 lL, 2.5 mmol) in the presence of
In(OTf)3 (13.9 mg, 25 lmol) in 1,2-dichloroethane (7.0 mL). The
physical data of ent-5a-a were coincident with those of 5a-a,
except for the specific optical rotation: [a]2D5 (c 0.49, CHCl3) +32.1.
The physical data of ent-5a-b were also coincident with those of
5a-b, except for the specific optical rotation: [a]2D5 (c 0.50, CHCl3)
+34.1.
9 H. Yanai and T. Taguchi, Tetrahedron Lett., 2005, 46, 8639–8643.
10 For an intramolecular cycloaddition of azidoalkyne derivatives derived
from monosaccharides under thermal conditions, see: F. Dolhem, F.
Tahli, C. Lie`vre and G. Demailly, Eur. J. Org. Chem., 2005, 5019–5023.
11 H. Yanai, S. Saito and T. Taguchi, Tetrahedron, 2005, 61, 7087–7093.
12 M. Kleban, U. Kautz, J. Greul, P. Hilgers, R. Kugler, H.-Q. Dong and
V. Jaeger, Synthesis, 2000, 1027–1033.
13 S. Ohira, Synth. Commun., 1989, 19, 561–564.
14 Under simply thermal conditions, the intramolecular cycloaddition of
the isolated a-azido ether needed a prolonged reaction time (24 h) for
the complete consumption of the a-azido ether (5a 77%, a : b = 1.4 :
1). This finding indicates that In(OTf)3 accelerates the reaction rate of
the cycloaddition step.
15 The formation of cycloadduct at room temperature was observed only
in the reaction of 4b.
16 C. Herdeis and J. Telser, Eur. J. Org. Chem., 1999, 1407–1414.
17 For an example of the detection of an equilibrium between boat and
chair conformers by NOESY spectra see: T. Sakakibara, T. Suganuma
and Y. Kajihara, Chem. Commun., 2007, 3568–3570.
18 NOESY spectra of both a-manno-mimetic 6b-a and b-manno-mimetic
6b-b showed weak H3–H4 correlations. This finding strongly indicates
the low stability of these 2H3 conformers.
19 H. Yanai, Y. Dobashi, M. Nakayashiki, and T. Taguchi, unpublished
result.
Notes and References
1 (a) W.-Q. Fan, A. R. Katritzky, 1,2,3-Triazoles, In Comprehensive
Heterocyclic Chemistry II, ed. A. R. Katritzky, C. W. Rees, E. F.
and V. Scriven, Elsevier, Oxford, 1996, vol. 4, 1–126, pp. 905–1006;
(b) M. Whiting, J. Muldoon, Y.-C. Lin, S. M. Silverman, W. Lindstrom,
A. J. Olson, H. C. Kolb, M. G. Finn, K. B. Sharpless, J. H. Elder and
20 J. D
e´sire´ and J. Prandi, Eur. J. Org. Chem., 2000, 3075–3084.
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