Design and synthesis of 1,2,3-triazole-fused chiral medium-ring benzo-heterocycles, scaffolds mimicking benzolactams

Article abstract of DOI:10.1021/jo3004327

Based on amide-triazole bioequivalence principle, 1,2,3-triazole-fused chiral medium ring benzo-heterocycles capable of mimicking benzolactams were designed. Their syntheses were accomplished by cycloaddition of different sugar-derived azidoalkynes. While triazole-fused eight-membered benzo-heterocycles were formed by exclusive intramolecuclar [3 + 2] cycloaddition, attempted preparation of seven-membered analogues led to some intermolecular cycloaddition resulting in a dimeric macrocyclic product, in addition to intramolecular cycloaddition furnishing the expected heterocycle.

Full text of DOI:10.1021/jo3004327

Note
pubs.acs.org/joc
Design and Synthesis of 1,2,3-Triazole-Fused Chiral Medium-Ring
Benzo-Heterocycles, Scaffolds Mimicking Benzolactams
Nirmal Das Adhikary and Partha Chattopadhyay*
Chemistry Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, India
S
* Supporting Information
ABSTRACT: Based on “amide-triazole bioequivalence” prin-
ciple, 1,2,3-triazole-fused chiral medium ring benzo-hetero-
cycles capable of mimicking benzolactams were designed.
Their syntheses were accomplished by cycloaddition of
different sugar-derived azidoalkynes. While triazole-fused
eight-membered benzo-heterocycles were formed by exclusive
intramolecuclar [3 + 2] cycloaddition, attempted preparation
of seven-membered analogues led to some intermolecular
cycloaddition resulting in a dimeric macrocyclic product, in addition to intramolecular cycloaddition furnishing the expected
heterocycle.
1,2,3-Triazoles display a wide range of biological activities
including anti-HIV activity,1 antimicrobial activity against
Gram-positive bacteria,2 and selective β3 adrenergic receptor
agonism.3 These heteroarenes have proved particularly valuable
as genuine amide surrogates (amide−triazole bioequivalence
principle) in bioactive molecules because of their physicochem-
ical properties (peptide isosteres), in addition to their
remarkable metabolic stability.4 A number of studies reveal
that the 1,4-disubstituted triazole regioisomer effectively mimics
a trans amide bond,5 while the 1,5-disubstituted analogue does
it for a cis isomer (Figure 1).6 From a synthetic point of view,
known where the designed benzolactams can effectively mimic
teleocidines.7 1,2,3-Triazoles have also found various industrial
applications as dyes, corrosion inhibitors (of copper and copper
alloys), photostabilizers, photographic materials, and agro-
chemicals.8 On the other hand, benzofused aza-heterocycles are
described as “privileged structures” due to their capacity to bind
to multiple receptors with high affinity.9 Among them, benzo-
fused seven- and eight-membered rings are receiving a great
deal of attention as these structural units are also found in
numerous natural products and are components of a number of
biologically interesting molecules.10 For example, benzoxazo-
cine11 and benzodiazocine12 rings are often present in
pharmaceutical agents as a core structural motif. 1,5-
Benzoxazepine derivatives also exhibit a wide range of
bioactivity.13 It is a small wonder therefore that fusion of
1,2,3-triazoles with medium-ring benzo-heterocycles leads to
products that display an interesting range of biological
properties, as in the anxiolytic agents14 alprazolam and
estazolam, and the antidepressant agent15 triazolam.
Therefore, synthesis of 1,2,3-triazole-fused benzo-hetero-
cycles has been of growing interest in recent times.16 Although
there are several reported procedures for the synthesis of
triazole-fused five-, six-, and seven-membered benzo-hetero-
cycles, methods for the synthesis of triazole-fused eight-
membered benzo-heterocycles are scarce17 and deal with
achiral substrates only. The methodologies employing chiral
substrates mainly focus on the synthesis of triazoles fused to
heterocycles, not benzo-heterocycles.18 The chiron approach to
the synthesis of chiral target molecules involves the use of
sugars as starting materials.19 A key element in this strategy is
the ability to form optically active heterocycles20 and
carbohydrate-based mimetics.21 The design and synthesis of
Figure 1. (a) 1,4-Disubstituted and (b) 1,5-disubstituted triazoles
capable of mimicking trans and cis amides, respectively, and (c)
proposed 1,5-disubstituted triazole-fused benzo-heterocycle, capable of
mimicking benzolactams.
creation of a cis amide bond in a small to medium ring could be
challenging, whereas 1,5-disubstituted triazole moieties are easy
to access by simple azide−alkyne thermal cycloaddition
(formation of 1,4-regioisomer is less favorable in this case
due to strain induced in the ring). Thus, it is profitable to
attempt the preparation of triazole-fused benzo-heterocycles, an
alternate type of structures capable of mimicking benzolactams
(Figure 1), inspired by the fact that compared to the widely
applied peptidomimetics, small molecule mimetics are also
Received: February 29, 2012
© XXXX American Chemical Society
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novel benzolactams possessing broad biological activities were
accomplished starting from D-glucose. However, their synthesis
suffers either from regioselectivity considerations20c or from the
less favorable nature of the intramolecular SNAr reaction
employed during cyclization requiring N-alkylated amide20a,b
(cis amide).22 In continuation of our research activities related
to the synthesis of benzannulated chiral medium-ring
heterocycles,11c,12,13,23 we conceptualized that an intramolecu-
lar [3 + 2] cycloaddition of sugar derived azidoalkynes would
lead to highly functionalized 1,5-disubstituted 1,2,3-triazole-
fused chiral benzo-heterocycles, an effective scaffold capable of
mimicking sugar derived medium-ring benzolactams. Herein we
report our preliminary synthetic results using different sugar
derived azidoalkynes.
contained those for triazole protons (δ = 7.87, 7.82); formation
of the desired product was supported by ESIMS analysis. Thus,
compounds 3a,b underwent exclusive intramolecular cycliza-
tion to afford triazole-fused benzoxazocines 4a,b in excellent
yields (Scheme 1).
After achieving success with 1,2,3-triazole-fused furobenzox-
azocines, synthesis of fused pyranobenzoxazocine was attemp-
ted. With D-mannose as chiral precursor, conversion to alcohol
5 was done by the reported sequence of reactions (Scheme
2).25 Reaction of 5 with 2-azidobenzyl bromide then afforded 4-
Scheme 2. Synthesis of 1,2,3-Triazole-Fused
a
Pyranobenzoxazocine Derivative
The starting materials 1,2:5,6-di-O-isopropylidene-α-D-gluco-
furanose (1a) and 1,2:5,6-di-O-isopropylidene-α-D-allofuranose
(1b) were separately reacted with 2-azidobenzyl bromide to
give 3-O-(2-azidobenzyl) glucofuranoside 2a and 3-O-(2-
azidobenzyl) allofuranoside 2b (Scheme 1). Selective removal
Scheme 1. Synthesis of 1,2,3-Triazole-Fused Furo-
a
Benzoxazocine Derivatives
a
Reagents and conditions: (i) NaH, dry DMF, O °C, 15 min, then 2-
azidobenzyl bromide, rt, 6 h; (ii) TBAF, THF, reflux, 4 h; (iii) Dess−
Martin periodinane, dry DCM, rt, 4 h; (iv) dimethyl (1-diazo-2-
oxopropyl)phosphonate [CH3COCN2PO(OMe)2] (Bestmann’s re-
agent), K2CO3, MeOH, rt, 12 h; (v) dry DMF, 120 °C, 2 h, N2.
O-(2-azidobenzyl) mannopyranoside 6. Deprotection of the
silyl ether (to 7) with TBAF/THF followed by Dess−Martin
oxidation led to the intermediate aldehyde, which was treated
with Bestmann’s reagent to yield the desired azidoalkyne 8.
Heating 8 at 120 °C in DMF (20 mL/mmol) gratifyingly
afforded the 1,2,3-triazole-fused pyrano-benzoxazocine 9 by
exclusive intramolecular [3 + 2] cycloaddition (Scheme 2).
Next, the focus was to synthesize 1,2,3-triazole-fused
furobenzodiazocines and furobenzodiazocinones by similar
intramolecular [3 + 2] cycloadditions. For this, the starting
material 3-amino-3-deoxy-1,2:5,6-di-O-isopropylidene-α-D-glu-
cofuranoside (10)12 was nosylated and the resulted nosyl
amide derivative (11) was methylated to give 3-deoxy-3-(N-(4-
nitrophenylsulfonyl)-N-methylamino)-1,2:5,6-di-O-isopropyli-
dene-α-D-glucofuranoside 12 (Scheme 3). Conversion of 12 to
the nosylamido alkyne 13 was smoothly achieved following the
procedure used to convert 2 to 3. The nosyl group in 13 was
then removed using thiophenol in dry acetonitrile to obtain
aminoalkyne 14, which was reacted with 2-azidobenzyl bromide
or 2-azidobenzoyl chloride to give the azidoalkynes 15 and 16,
respectively. Intramolecular [3 + 2] cycloaddition of 15 and 16
gave 1,2,3-triazole fused furobenzodiazocine 17 and furobenzo-
diazocinone 18 derivatives exclusively and in excellent yield
(Scheme 3).
a
Reagents and conditions: (i) NaH, dry DMF, O °C, 15 min, then 2-
azidobenzyl bromide, rt, 6 h; (ii) 70% AcOH (v/v), rt, overnight; (iii)
aq NaIO4, MeOH, rt, 45 min; (iv) dimethyl (1-diazo-2-oxopropyl)-
phosphonate [CH3COCN2PO(OMe)2] (Bestmann’s reagent),
K2CO3, MeOH, rt, 12 h; (v) dry DMF, 120 °C, 2 h, N2.
of the 5,6-O-isopropylidene moiety from 2a,b was smoothly
effected with 70% aqueous HOAc at 25 °C. Oxidation of the
resulting diols with NaIO4 furnished the intermediate aldehyde,
which was treated with Bestmann’s reagent24 to afford the
desired alkynes 3a,b in good yields (Scheme 1). The structures
of 3a,b were supported by spectroscopic data, compared with
data of similar compounds.5a Intramolecular azide−alkyne [3 +
2] cycloaddition strategy was utilized for the cyclization of the
azidoalkynes to form 1,2,3-triazole fused furo-benzoxazocine
derivatives. After screening a variety of solvents and reaction
conditions (temperature, concentration) it was found that
heating of azidoalkynes at 120 °C in DMF (20 mL/mmol) was
most effective for the cyclization. TLC analysis showed the
formation of one product only, the 1H NMR spectrum of which
lacked the peaks for alkyne protons (δ = 2.60, 2.53) but
B
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Scheme 3. Synthesis of 1,2,3-Triazole-Fused
Furobenzodiazocine and Furobenzodiazocinone
Derivatives
Scheme 4. Synthesis of 1,2,3-Triazole-Fused
Furobenzoxazepine Derivative and Macrocycle
a
a
a
Reagents and conditions: (i) Tf2O, Py, dry DCM, −10 °C, 1 h, N2;
(ii) 2-azidophenol, K2CO3, dry CH3CN, reflux, 6 h; (iii) 70% AcOH
(v/v), rt, overnight; (iv) aq. NaIO4, MeOH, rt, 45 min; (v) dimethyl
(1-diazo-2-oxopropyl)phosphonate [CH3COCN2PO(OMe)2] (Best-
mann’s reagent), K2CO3, MeOH, rt, 12 h; (vi) dry DMF, 120 °C, 2 h,
N2.
generated carbonyl group with NaBH4, and acetylation
furnished 1,2,3-triazole fused chiral benzoxazocine derivative
23, which may mimic the 1,5-benzoxazocinone derivative 24
(Scheme 5).
a
Reagents and conditions: (i) NsCl (4-nitrophenylsulfonyl chloride),
Et3N, dry DCM, rt, 2 h; (ii) NaH, dry DMF, 0 °C, 15 min, then, CH3I,
rt, 6 h, N2; (iii) 80% AcOH (v/v), rt, overnight; (iv) aq. NaIO4,
MeOH, rt, 45 min; (v) dimethyl (1-diazo-2-oxopropyl)phosphonate
[CH3COCN2PO(OMe)2] (Bestmann’s reagent), K2CO3, MeOH, rt,
12 h; (vi) dry CH3CN, PhSH, K2CO3, rt, 3 h, N2; (vii) 2-azidobenzyl
bromide, K2CO3, dry CH3CN, rt, 6 h, N2; (viii) 2-azidobenzoyl
chloride, Et3N, dry DCM, rt, 8 h, N2; (ix) dry DMF, 120 °C, 2 h; N2.
Scheme 5. Conversion of 4a to 1,2,3-Triazole-Fused
a
Benzoxazocine Derivative
After successfully synthesizing triazole-fused eight-membered
heterocycles, we next focused on extending our methodology
for the synthesis of seven membered analogues. For this, the
starting material 1,2:5,6-di-O-isopropylidene-α-D-allofuranose
(1b) was converted to its triflate derivative, which was
subsequently reacted with 2-azidophenol to give 3-O-(2-
azidophenyl)-1,2:5,6-di-O-isopropylidene-α-D-glucofuranoside
(19, Scheme 4). Usual functional group manipulation then
afforded the desired alkyne 20 (Scheme 4). However, in this
case, heating of 20 in DMF followed by TLC analysis showed
formation of two distinct products. NMR analysis of purified
products showed disappearance of the signal for the alkyne
proton (δ = 2.55) and appearance of triazole proton signals
instead (δ = 7.92, 8.18). ESIMS analysis identified them as
momomeric and dimeric products. Thus heating of compound
20 produced both intramolecularly cyclized monomeric
product 21 and intermolecularly cyclized dimeric product 22.
As use of dilute reaction condition (30 mL DMF/mmol of 20)
did not effectively suppress the formation of 22, it was assumed
that the conformational rigidity present in 20, compared to the
previous azidoalkynes, was responsible for the formation of
dimeric product 22.26
a
Reagents and conditions: (i) CH3CN/H2O/H2SO4 (18:5:2), rt, 24 h;
(ii) aqueous NaIO4, MeOH, rt, 45 min (iii) NaBH4, MeOH, rt, 3 h;
(iv) Ac2O, pyridine, rt, 12 h.
In conclusion, based on the reasoning that 1,5-disubstituted
1,2,3-triazole-fused benzoheterocycles could be an alternate
type of structure mimicking benzolactams (“amide-triazole
bioequivalence”), we have designed 1,2,3-triazole-fused chiral
medium ring benzo-heterocycles for synthesis. Cycloaddition
using different sugar-derived azidoalkynes was resorted to for
their synthesis. Triazole-fused eight-membered rings were
generated by exclusive intramolecular cycloaddition of
azidoalkynes, whereas cycloaddition in case of seven-membered
rings was both intramolecular, generating the desired 1,2,3-
triazole-fused heterocycle, and intermolecular, resulting in a
macrocycle. The synthesized triazole-fused chiral benzoxazo-
cine was smoothly converted to the corresponding chiral
benzoxazocine derivative. We hope that the approach would be
effective enough to design triazole-fused heterocycles capable of
mimicking the corresponding benzolactams present in small
molecule drug candidates and thus will have profound
significance in drug discovery.
As a logical extension of our methodology, we next
investigated the feasibility of synthesizing 1,2,3-triazole fused
chiral functionalized benzo-heterocycles from the obtained
annulated sugar derivatives. Thus, subjecting 4a to a sequence
of reactions involving removal of the 1,2-O-isopropylidene
group, cleavage of the diol with NaIO4, reduction of the
C
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(300 MHz, CDCl3): δ 1.31 (s, 3H), 1.48 (s, 3H), 2.60 (d, J = 2.1 Hz,
1H), 4.02 (d, J = 3.0 Hz, 1H), 4.60−4.63 (m, 1H), 4.73 (s, 2H), 4.84−
4.85 (m, 1H), 5.97 (d, J = 3.6 Hz, 1H), 7.12−7.53 (m, 4H). 13C NMR
(75 MHz, CDCl3): δ 26.2, 26.7, 69.7, 70.5, 75.8, 81.1, 83.5, 84.4,
104.5, 112.0, 117.9, 125.3, 128.9, 129.2, 131.7, 143.0. IR νmax (film):
3278, 2986, 2933, 2124, 1588, 1497, 1457 cm−1. ESIMS: m/z 338 [M
+ Na]+. Anal. Calcd for C16H17N3O4: C, 60.94; H, 5.43; N, 13.33.
Found: C, 60.68; H, 5.27; N, 13.11.
(3aR,5R,6R,6aR)-6-(2-Azidobenzyloxy)-5-ethynyl-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxole (3b). Oil. Yield: 0.39
g, 62% (eluent PS/EA, 8:1). [α]2D5 = +28.7 (c 0.55, CHCl3). 1H NMR
(300 MHz, CDCl3): δ 1.34 (s, 3H), 1.55 (s, 3H), 2.53 (d, J = 1.8 Hz,
1H), 4.54 (d, J = 4.2 Hz, 1H), 4.58 (dd, J = 13.2, 3.9 Hz, 1H), 4.62−
4.67 (m. 1H), 4.72 (d, J = 4.2 Hz, 1H), 4.76 (d, J = 3.6 Hz, 1H), 5.78
(d, J = 3.6 Hz, 1H), 7.09−7.54 (m, 4H) ppm. 13C NMR (75 MHz,
CDCl3): δ 26.3, 26.7, 67.7, 68.0, 72.2, 77.4, 82.6, 82.9, 103.8, 113.3,
118.0, 125.6, 129.2, 129.9, 132.8, 144.2. IR νmax (film): 3270, 2987,
2933, 2124, 1588, 1496, 1457 cm−1. ESIMS: m/z 338 [M + Na]+.
Anal. Calcd for C16H17N3O4: C, 60.94; H, 5.43; N, 13.33. Found: C,
60.66; H, 5.31; N, 13.17.
EXPERIMENTAL SECTION
■
General Procedure for the Synthesis of Compounds 2a,b
and 6. NaH (200 mg, 60% suspension in oil, 5 mmol) was added to a
solution of each of 1a,b and 5 (4 mmol) in 20 mL of DMF at 0 °C,
and the solution was stirred for 15 min. Then, 2-azidobenzyl bromide
(1.05 g, 5 mmol) was added, and stirring was continued for 6 h at rt.
The reaction mixture was diluted with H2O and extracted with ethyl
acetate (3 × 30 mL). The ethyl acetate extract was washed with H2O,
dried, concentrated, and column chromatographed over silica gel
(100−200 mesh) to afford 2a,b and 6.
(3aR,5R,6S,6aR)-6-(2-Azidobenzyloxy)-5-(2,2-dimethyl[1,3]-
dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole
(2a). Oil; yield 1.33 g, 85% [eluent petroleum sprit (PS) 60−80 °C/
ethyl acetate (EA), 11:1]. [α]2D5 = −36.8 (c 0.5, CHCl3). H NMR
1
(300 MHz, CDCl3): δ 1.32 (s, 3H), 1.35 (s, 3H), 1.42 (s, 3H), 1.50 (s,
3H), 3.97−4.03 (m. 2H), 4.07−4.10 (m, 1H), 4.12−4.16 (m, 1H),
4.36 (dd, J = 13.8, 6.0 Hz, 1H), 4.56 (d, J = 12.3 Hz, 1H), 4.62 (d, J =
3.6 Hz, 1H), 4.66 (d, J = 12.3 Hz, 1H), 5.90 (d, J = 3.6 Hz, 1H), 7.11−
7.44 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 25.3, 26.2, 26.72, 26.78,
67.3, 67.5, 72.3, 81.1, 81.8, 82.4, 105.2, 108.9, 111.7, 117.9, 124.6,
128.8, 129.0, 129.6, 137.8. IR νmax (film): 2985, 2934, 2123, 1587,
1488, 1455 cm−1. ESIMS: m/z 414 [M + Na]+. Anal. Calcd for
C19H25N3O6: C, 58.30; H, 6.44; N, 10.74. Found: C, 58.06; H, 6.28;
N, 10.58.
(3aR,5R,6S,6aR)-5-Ethynyl-6-(N-4-nitrobenzenesulfonyl-N-
methylamino)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole
1
(13). Foamy solid. Yield: 0.445 g, 58% (eluent PS/EA 4:1). H NMR
(300 MHz, CDCl3): δ 1.27 (s, 3H), 1.50 (s, 3H), 2.35 (d, J = 2.4 Hz,
1H), 2.95 (s, 3H), 4.46 (d, J = 3.9 Hz, 1H), 4.64 (d, J = 5.1 Hz, 1H),
4.96 (dd, J = 5.1, 2.1 Hz, 1H), 5.88 (d, J = 3.9 Hz, 1H), 8.06 (d, J = 8.7
Hz, 2H), 8.37 (d, J = 8.7 Hz, 2H). 13C NMR (150 MHz, CDCl3): δ
25.9, 26.4, 32.1, 65.5, 69.6, 76.2, 77.7, 83.5, 104.3, 111.9, 124.3, 128.6,
134.4, 145.5. ESIMS: m/z 405 [M + Na]+. Anal. Calcd for
C16H18N2O7S: C, 50.26; H, 4.74; N, 7.33. Found: C, 50.12; H, 4.66;
N, 7.21.
(3aR,5R,6R,6aR)-6-(2-Azidobenzyloxy)-5-(2,2-dimethyl[1,3]-
dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole
(2b). Oil; yield 1.285 g, 82% (eluent PS/EA, 9:1). [α]2D5 = +54.8 (c 0.2,
1
CHCl3). H NMR (300 MHz, CDCl3): δ 1.34 (s, 3H), 1.36 (s, 3H),
1.57 (s, 3H), 1.58 (s, 3H), 3.89−3.94 (m, 1H), 3.97−4.04 (m, 2H),
4.13 (dd, J = 8.4, 3.0 Hz, 1H), 4.36−4.41 (m, 1H), 4.58 (d, J = 12.3
Hz, 1H), 4.63 (d, J = 4.2 Hz, 1H), 4.71 (d, J = 12.3 Hz, 1H), 5.78 (d, J
= 3.6 Hz, 1H), 7.12−7.48 (m, 4H). 13C NMR (75 MHz, CDCl3): δ
25.1, 25.9, 26.57, 26.77, 64.8, 67.2, 74.6, 77.4, 77.7, 77.8, 103.8, 109.5,
112.8, 118.0, 124.7, 128.7, 129.2, 130.2, 138.1. IR νmax (film): 2985,
2928, 2124, 1587, 1488, 1455 cm−1. ESIMS: m/z 414 [M + Na]+.
Anal. Calcd for C19H25N3O6: C, 58.30; H, 6.44; N, 10.74. Found: C,
58.02; H, 6.26; N, 10.56.
Methyl 4-O-(2-Azidobenzyl)-6-O-(tert-butyldimethylsilyl)-
2,3-O-isopropylidene-α-D-mannopyranoside (6). Oil; yield
1.515 g, 79% (eluent PS/EA, 11:1). [α]2D5 = +25.3 (c 0.3, CHCl3).
1H NMR (300 MHz, CDCl3): δ 0.06 (s, 3H), 0.07 (s, 3H), 0.89 (s,
(3aR,5R,6S,6aR)-6-(2-Azidophenoxy)-5-ethynyl-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxole (20). Colorless oil.
Yield: 0.373 g, 62% (eluent PS/EA, 9:1). [α]2D5 = = −26.2 (c 0.2,
1
CHCl3). H NMR (300 MHz, CDCl3): δ 1.28 (s, 3H), 1.53 (s, 3H),
2.55 (d, J = 2.4 Hz, 1H), 4.70 (d, J = 3.9 Hz, 1H), 4.76 (d, J = 3.0 Hz,
1H), 5.01−5.03 (m, 1H), 6.05 (d, J = 3.6 Hz, 1H), 6.91−7.44 (m,
4H). 13C NMR (75 MHz, CDCl3): δ 26.2, 26.5, 72.7, 75.6, 80.9, 81.7,
84.2, 104.6, 112.6, 122.1, 124.4, 124.9, 129.6, 134.7, 146.5. IR νmax
(film): 3279, 2986, 2936, 2120, 1598 cm−1. ESIMS: m/z 324 [M +
Na]+. Anal. Calcd for C15H15N3O4: C, 59.79; H, 5.02; N, 13.95.
Found: C, 59.55; H, 4.88; N, 13.77.
9H), 1.36 (s, 3H), 1.52 (s, 3H), 3.37 (s, 3H), 3.47−3.56 (m, 2H), 3.74
(dd, J = 12.3, 4.8 Hz, 1H), 3.89 (dd, J = 11.1, 1.8 Hz, 1H), 4.11 (d, J =
5.7 Hz, 1H), 4.29 (d, J = 6.0 Hz, 1H), 4.55 (d, J = 12.0 Hz, 1H), 4.82
(d, J = 12.0 Hz, 1H), 4.89 (s, 1H), 7.09−7.40 (m, 4H). 13C NMR (75
MHz, CDCl3): δ −5.4, −5.2, 18.2, 25.8, 26.2, 26.9, 54.5, 62.6, 68.2,
69.5, 75.7, 75.9, 78.7, 97.9, 109.2, 117.9, 124.5, 128.9, 129.6, 129.9,
137.8. IR νmax (film): 2932, 2858, 2435, 2122, 1586, 1458 cm−1.
ESIMS: m/z 502 [M + Na]+. Anal. Calcd for C23H37N3O6Si: C, 57.59;
H, 7.78; N, 8.76. Found: C, 57.37; H, 7.62; N, 8.58.
General Procedure for the Synthesis of Compounds 3a,b,
13, and 20. Each of compounds 2a,b, 12, and 19 (2 mmol) was
dissolved in aqueous HOAc (70%, v/v, 60 mL, 80% for 12), and the
solution was stirred overnight at rt. HOAc was distilled off using
toluene, and the resulting diol was dissolved in methanol (10 mL),
cooled to 0 °C, and slowly treated with a solution of NaIO4 (513 mg,
2.4 mmol) in water (5 mL). The reaction mixture was stirred for 45
min, filtered, evaporated, and extracted with CHCl3 (4 × 30 mL). The
organic layer was washed with water, dried, and evaporated to afford
the crude aldehyde which was dissolved in dry methanol (10 mL) and
treated with K2CO3 (550 mg, 4 mmol) followed by dimethyl (1-diazo-
2-oxopropyl)phosphonate (660 mg, 3 mmol) at rt. After 12 h, the
mixture was filtered, concentrated, extracted with ethyl acetate (30
mL), washed sequentially with saturated NH4Cl (20 mL) and water
(20 mL), dried (Na2SO4), concentrated, and subjected to silica gel
column chromatography to afford the desired azidoalkynes 3a,b, 13,
and 20, respectively.
General Procedure for the Synthesis of Compounds 4a,b, 9,
17, 18, 21, and 22. Each of compounds 3a,b, 8, 15, 16, and 20 (1
mmol) was dissolved in DMF (20 mL) and heated at 120 °C for 2 h.
The solution was diluted with H2O and extracted with Et2O (3 × 30
mL). The combined ether extract was washed with H2O, dried,
concentrated, and column chromatographed over silica gel to afford
4a,b, 9, 17, 18, 21, and 22, respectively.
(10aS,10bR,13aR,14aR)-12,12-Dimethyl-10a,10b,13a,14a-
tetrahydro-9H-[1,3]dioxolo[4′,5′:4,5]furo[3,2-b]benzo[f ]-
[1,2,3]triazolo[5,1-d][1,5]oxazocine (4a). Crystalline solid. Mp:
198−200 °C. Yield: 0.29 g, 92% (eluent PS/EA, 4:1). [α]2D5 = = −17.3
(c 0.25, CHCl3). 1H NMR (300 MHz, CDCl3): δ 1.25 (s, 3H), 1.47 (s,
3H), 4.09 (s, 1H), 4.50 (s, 2H), 4.62 (d, J = 3.3 Hz, 1H), 5.19 (s, 1H),
5.95 (s, 1H), 7.44−7.69 (m, 4H), 7.87 (s, 1H). 13C NMR (75 MHz,
CDCl3): δ 26.0, 26.8, 68.2, 74.8, 79.1, 84.5, 104.4, 112.1, 126.7, 130.4,
130.5, 130.8, 131.3, 134.3, 136.2, 136.6. IR νmax (film): 2985, 2938,
1732, 1499, 1466, 1379, 1217 cm−1. ESIMS: m/z 316 [M + H]+. Anal.
Calcd for C16H17N3O4: C, 60.94; H, 5.43; N, 13.33. Found: C, 60.64;
H, 5.31; N, 13.13.
(10aR,10bR,13aR,14aR)-12,12-Dimethyl-10a,10b,13a,14a-
tetrahydro-9H-[1,3]dioxolo[4′,5′:4,5]furo[3,2-b]benzo[f ]-
[1,2,3]triazolo[5,1-d][1,5]oxazocine (4b). Crystalline solid. Mp:
204−208 °C. Yield: 0.28 g, 89% (eluent PS/EA, 3:1). [α]2D5 = +22.5 (c
1
0.4, CHCl3). H NMR (300 MHz, CDCl3): δ 1.25 (s, 3H), 1.44 (s,
3H), 3.71 (dd, J = 8.4, 4.2 Hz, 1H), 3.94 (d, J = 13.2 Hz, 1H), 4.75 (d,
J = 8.4 Hz, 1H), 4.86 (d, J = 3.9 Hz, 1H), 4.91 (d, J = 13.2 Hz, 1H),
5.97 (d, J = 3.6 Hz, 1H), 7.57−7.64 (m, 4H), 7.82 (s, 1H). 13C NMR
(75 MHz, CDCl3): δ 26.0, 26.5, 70.3, 73.2, 79.1, 84.3, 103.3, 113.8,
126.7, 130.4, 130.6, 130.9, 132.2, 132.9, 134.5, 138.0. IR νmax (film):
(3aR,5R,6S,6aR)-6-(2-Azidobenzyloxy)-5-ethynyl-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxole (3a). Oil. Yield: 0.38
g, 60% (eluent PS/EA, 9:1). [α]2D5 = −32.7 (c 0.4, CHCl3). H NMR
1
D
dx.doi.org/10.1021/jo3004327 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
2986, 2931, 1499, 1466, 1378, 1253 cm−1. ESIMS: m/z 316 [M + H]+.
Anal. Calcd for C16H17N3O4: C, 60.94; H, 5.43; N, 13.33. Found: C,
60.58; H, 5.29; N, 13.17.
PS/EA, 6:1). [α]2D5 = +41.5 (c 0.45, CHCl3). H NMR (300 MHz,
CDCl3): δ 1.38 (s, 3H), 1.55 (s, 3H), 2.09 (t-like, 1H), 3.37 (s, 3H),
3.54−3.64 (m, 2H), 3.74−3.86 (m, 2H), 4.14 (d, J = 5.7 Hz, 1H), 4.30
(d, J = 6.0 Hz, 1H), 4.58 (d, J = 11.7 Hz, 1H), 4.83 (d, J = 11.7 Hz,
1H), 4.92 (s, 1H), 7.10−7.41 (m, 4H) ppm. 13C NMR (75 MHz,
CDCl3): δ 26.2, 27.9, 54.8, 62.6, 68.2, 68.4, 75.6, 76.7, 78.5, 98.1,
109.3, 118.0, 124.6, 129.1, 129.2, 130.2, 138.1. IR νmax (film): 3483,
2987, 2928, 2434, 2123, 1586 cm−1. ESIMS: m/z 366 [M + H]+. Anal.
Calcd for C17H23N3O6: C, 55.88; H, 6.34; N, 11.50. Found: C, 55.64;
H, 6.20; N, 11.36.
1
(3bR,5S,5aS,8aS,8bS)-5-Methoxy-7,7-dimethyl-3b,5,5a,-
8a,8b,10-hexahydro-[1,3]dioxolo[4′,5′:4,5]pyrano[3,2-b]-
benzo[f ][1,2,3]triazolo[5,1-d][1,5]oxazocine (9). Crystalline solid.
Mp: 235−238 °C. Yield: 0.305 g, 85% (eluent PS/EA, 3:1); [α]D25
=
1
+29.6 (c 0.2, CHCl3). H NMR (300 MHz, CDCl3): δ 1.37 (s, 3H),
1.54 (s, 3H), 3.29 (s, 3H), 3.45−3.51 (m, 1H), 3.85 (d, J = 12.3 Hz,
1H), 4.11 (d, J = 5.7 Hz, 1H), 4.13 (d, J = 4.2 Hz, 1H), 4.38 (d, J = 9.3
Hz, 1H), 4.80 (d, J = 12.9 Hz, 1H), 5.04 (s, 1H), 7.50−7.73 (m, 4H),
7.95 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 26.0, 27.8, 55.7, 64.8,
68.4, 74.6, 76.3, 81.0, 97.9, 110.0, 126.2, 130.0, 130.6, 131.3, 132.7,
134.4, 139.3. IR νmax (film): 2926, 1604, 1500, 1460, 1377 cm−1.
ESMS: m/z 360 [M + H]+. Anal. Calcd for C18H21N3O5: C, 60.16; H,
5.89; N, 11.69. Found: C, 59.90; H, 5.71; N, 11.53.
Methyl 4-O-(2-Azidobenzyl)-5-ethynyl-2,3-O-isopropyli-
dene-α-D-mannopyranoside (8). To a stirring solution of 7 (0.73
g, 2 mmol) in dry CH2Cl2 (20 mL) was added Dess−Martin
periodinane (1.3 g, 3 mmol) at rt, and stirring was continued for 4 h.
The reaction was quenched at 0 °C by stirring with a solution of
Na2S2O3 (4.0 g in 25 mL of water) and NaHCO3 (saturated, aq, 25
mL) for 10 min and extracted with CH2Cl2 (3 × 30 mL). The organic
extract was washed with H2O, dried, and concentrated to give the
crude aldehyde which was treated with Bestmann’s reagent as earlier
procedure to give alkyne 8 as oil. Yield: 0.416 g, 58% (eluent PS/EA,
(10aS,10bR,13aR,14aS)-10,12,12-Trimethyl-9,10,10a,10b,-
13a,14a-hexahydro-[1,3]dioxolo[4′,5′:4,5]furo[2,3-c]benzo[g]-
[1,2,3]triazolo[1,5-a][1,5]diazocine (17). Foamy solid. Yield: 0.3 g,
91% (eluent PS/EA, 4:1). [α]2D5 = −19.3 (c 0.32, CHCl3). H NMR
1
11:1). [α]2D5 = +35.2 (c 0.4, CHCl3). H NMR (300 MHz, CDCl3): δ
1
(300 MHz, CDCl3): δ 1.37 (s, 3H), 1.55 (s, 3H), 2.26 (s, 3H), 3.53 (d,
J = 12.6 Hz, 1H), 3.71 (d, J = 3.9 Hz, 1H), 3.73 (d, J = 12.6 Hz, 1H),
4.92 (s, 1H), 5.47 (d, J = 4.8 Hz, 1H), 5.86 (s, 1H), 7.42−7.58 (m,
4H), 7.77 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 26.0, 26.6, 41.2,
55.6, 68.9, 76.1, 77.2, 104.4, 111.1, 123.9, 126.0, 128.6, 129.3, 129.4,
131.5, 136.8, 143.6. IR νmax (film): 2924, 2855, 1668, 1496, 1460, 1377
cm−1. ESIMS: m/z 351 [M + Na]+. Anal. Calcd for C17H20N4O3: C,
62.18; H, 6.14; N, 17.06. Found: C, 61.94; H, 5.98; N, 16.92.
1.35 (s, 3H), 1.48 (s, 3H), 2.47 (d, J = 2.1 Hz, 1H), 3.43 (s, 3H), 3.57
(dd, J = 9.6, 7.2 Hz, 1H), 4.09 (d, J = 5.7 Hz, 1H), 4.22 (d, J = 6.0 Hz,
1H), 4.31 (dd, J = 9.6, 1.8 Hz, 1H), 4.76 (d, J = 12.3 Hz, 1H), 4.87 (d,
J = 12.3 Hz, 1H), 4.91 (s, 1H), 7.10−7.52 (m, 4H). 13C NMR (75
MHz, CDCl3): δ 26.2, 27.7, 55.5, 60.0, 68.7, 73.8, 75.3, 77.6, 78.9,
80.6, 98.3, 109.6, 117.9, 124.6, 128.9, 129.3, 130.0, 137.8. IR νmax
(film): 3277, 2988, 2931, 2123, 1587, 1495, 1456 cm−1. ESIMS: m/z
382 [M + Na]+. Anal. Calcd for C18H21N3O5: C, 60.16; H, 5.89; N,
11.69. Found: C, 59.94; H, 5.73; N, 11.51.
3-Deoxy-3-(N-4-nitrobenzenesulfonylamino)-1,2:5,6-di-O-
isopropylidene-α-D-glucofuranose (11). A solution of 10 (2.075 g,
8 mmol) in anhydrous CH2Cl2 (25 mL) was treated at rt with Et3N (1
mL) and NsCl (1.94 g, 8.8 mmol) and stirred for 2 h. Dilution with
CH2Cl2 (30 mL) and evaporation of the washed (saturated aqueous
NaHCO3, 1 × 20 mL, and saturated aqueous NaCl, 1 × 20 mL)
organic solution afforded a crude residue which was column
chromatographed over silica gel to obtain 11 as a colorless solid.
(10aS,10bR,13aR,14aS)-10,12,12-Trimethyl-10,10a,13a,14a-
tetrahydro[1,3]dioxolo[4′,5′:4,5]furo[2,3-c]benzo[g][1,2,3]-
triazolo[1,5-a][1,5]diazocin-9(10bH)-one (18). Foamy solid.
Yield: 0.287 g, 84% (eluent PS/EA, 2:1). [α]2D5 = −12.5 (c 0.23,
1
CHCl3). H NMR (300 MHz, CDCl3): δ 1.36 (s, 3H), 1.48 (s, 3H),
2.89 (s, 3H), 4.34 (d, J = 4.2 Hz, 1H), 5.09 (d, J = 3.6 Hz, 1H), 5.31
(d, J = 3.9 Hz, 1H), 6.15 (d, J = 3.6 Hz, 1H), 7.57−7.68 (m, 4H), 7.84
(s, 1H). 13C NMR (75 MHz, CDCl3): δ 25.7, 26.3, 30.8, 65.5, 76.4,
82.4, 104.9, 112.2, 127.2, 128.3, 131.2, 131.4, 132.6, 132.8, 132.9,
134.5, 168.0. IR νmax (film): 2988, 2927, 2857, 2128, 1652, 1469, 1381
cm−1. ESIMS: m/z 365 [M + Na]+. Anal. Calcd for C17H18N4O4: C,
59.64; H, 5.30; N, 16.37. Found: C, 59.48; H, 5.14; N, 16.23.
(2R,3R,3aS,10aR)-2,3-(Isopropylidenedioxy)-[1,5:9,10]-1,2,3-
triazolo-2,3,3a,10a-tetrahydrofuro[3,2-c][1,5]benzoxazepine
(21). Colorless solid. Mp: 177−179 °C. Yield: 0.108 g, 36% (eluent
1
Mp: 143−145 °C. Yield: 3.27 g, 92% (eluent PS/EA 3:1). H NMR
(300 MHz, CDCl3): δ 1.16 (s, 3H), 1.27 (s, 3H), 1.31 (s, 3H), 1.48 (s,
3H), 3.69 (dd, J = 8.4, 4.8 Hz, 1H), 3.75 (dd, J = 6.6, 3.6 Hz, 1H),
3.99−4.11 (m, 3H), 4.80 (d, J = 3.9 Hz, 1H), 5.40 (d, J = 6.6 Hz, 1H),
5.89 (d, J = 3.6 Hz, 1H), 8.12 (d, J = 8.7 Hz, 2H), 8.36 (d, J = 8.7 Hz,
2H). 13C NMR (75 MHz, CDCl3): δ 24.5, 26.0, 26.4, 59.2, 67.1, 72.2,
77.9, 84.7, 104.4, 109.6, 112.3, 124.1, 128.8, 145.1, 150.1. ESIMS: m/z
467 [M + Na]+. Anal. Calcd for C18H24N2O9S: C, 48.64; H, 5.44; N,
6.30. Found: C, 48.42; H, 5.36; N, 6.18.
PS/EA, 3:1). [α]2D5 = −14.8 (c 0.22, CHCl3). H NMR (300 MHz,
1
CDCl3): δ 1.25 (s, 3H), 1.35 (s, 3H), 4.94−4.98 (m, 2H), 5.56 (d, J =
3.3 Hz, 1H), 5.61 (d, J = 3.6 Hz, 1H), 7.21−7.42 (m, 3H), 7.92 (s,
1H), 7.97−8.06 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 26.2, 26.9,
72.8, 84.2, 89.1, 104.5, 112.4, 122.6, 123.7, 126.2, 129.7, 131.4, 131.9,
134.7, 147.3. IR νmax (film): 2988, 2927, 1599, 1502, 1468, 1378 cm−1.
ESIMS: m/z 324 [M + Na]+. Anal. Calcd for C15H15N3O4: C, 59.79;
H, 5.02; N, 13.95. Found: C, 59.47; H, 4.92; N, 13.75.
3-Deoxy-3-(N-4-nitrobenzenesulfonyl-N-methylamino)-
1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (12). To a sol-
ution of 11 (2.22 g, 5 mmol) in 25 mL of DMF at 0 °C was added
NaH (0.3 g, 60% suspension in oil, 7.5 mmol), and the solution was
stirred for 15 min. Then, methyl iodide (0.9 mL, 2 g, 15 mmol) was
added and the mixture stirred for 6 h at rt, diluted with H2O, and
extracted with ethyl acetate (3 × 30 mL). The ethyl acetate extract was
washed with aqueous Na2S2O3, H2O, dried, concentrated, and column
chromatographed over silica gel to afford 12 as a colorless solid. Mp:
168−171 °C. Yield: 1.925 g, 84% (eluent PS/EA 4:1). 1H NMR (300
MHz, CDCl3): δ 1.26 (s, 3H), 1.29 (s, 3H), 1.38 (s, 3H), 1.51 (s, 3H),
2.82 (s, 3H), 3.98−4.16 (m, 4H), 4.46 (d, J = 3.6 Hz, 1H), 4.62 (d, J =
4.5 Hz, 1H), 5.82 (d, J = 3.6 Hz, 1H), 8.12 (d, J = 9 Hz, 2H), 8.36 (d, J
= 9 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 25.3, 25.8, 26.3, 26.7,
32.5, 62.9, 67.2, 72.1, 80.3, 82.9, 104.7, 109.6, 111.7, 124.1, 129.0,
144.5, 150.1. ESIMS: m/z 481 [M + Na]+. Anal. Calcd for
C19H26N2O9S: C, 49.77; H, 5.72; N, 6.11. Found: C, 49.59; H, 5.64;
N, 6.05.
(3bR,4aR,7aR,7bS,17aR,20aR,20bS)-6,6,19,19-Tetramethyl-
3b,4a,7a,7b,16b,17a,20a,20b-octahydro[1,3]dioxolo[4′,5′:4,5]-
furo[2,3-f ][1,3]dioxolo[4′,5′:4,5]furo[2,3-m]dibenzo[b,i]bis-
([1,2,3]triazolo)[1,5-d:1′,5′-k][1,8,4,11]dioxadiaza-
cyclotetradecine (22). Colorless solid. Mp: 240−244 °C. Yield:
1
0.145 g, 24% (eluent PS/EA, 2:1). [α]2D5 = −3.7 (c 0.28, CHCl3). H
NMR (300 MHz, CDCl3): δ 1.40 (s, 3H), 1.65 (s, 3H), 4.85 (d, J =
3.3 Hz, 1H), 5.17 (s, 1H), 5.82 (s, 1H), 6.18 (s, 1H), 7.14−7.42 (m,
3H), 7.99 (d, J = 6.9 Hz, 1H), 8.18 (s, 1H). 13C NMR (75 MHz,
CDCl3): δ 26.2, 26.5, 75.6, 80.9, 81.7, 104.6, 112.5, 112.6, 122.1, 124.4,
124.9, 126.2, 129.6, 142.1, 146.5. IR νmax (film): 2979, 2930, 1597,
1503, 1378 cm−1. HRMS: calcd for [C30H30N6O8+Na]+ 625.2023,
found 625.2051.
Methyl 4-O-(2-Azidobenzyl)-2,3-O-isopropylidene-α-D-man-
nopyranoside (7). A mixture of silyl ether 6 (1.438 g, 3 mmol) and
TBAF (1.1 mL, 3.7 mmol) in dry THF (15 mL) was heated at reflux
for 4 h. Excess THF was distilled off, and the residue was diluted with
water and extracted with CH2Cl2 (3 × 15 mL). The organic extract
was washed with H2O, dried (Na2SO4), concentrated, and column
chromatographed to afford alcohol 7 as oil. Yield: 0.82 g, 75% (eluent
(3aR,5R,6S,6aR)-5-Ethynyl-6-methylamino-2,2-dimethyl-
tetrahydrofuro[2,3-d][1,3]dioxole (14). A solution of 13 (0.382 g,
1 mmol) in anhydrous MeCN (15 mL) was treated with K2CO3 (0.54
g, 4 mmol, 4 equiv) in the presence of PhSH (0.3 mL, 3 mmol, 3
equiv), and the resulting reaction mixture was stirred for 3 h at rt. The
E
dx.doi.org/10.1021/jo3004327 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
mixture was diluted with ethyl acetate (20 mL), filtered, evaporated,
and column chromatographed over silica gel to afford 14 as a colorless
oil. Yield: 0.125 g, 63% (eluent PS/EA 2:1). H NMR (300 MHz,
CDCl3): δ 1.32 (s, 3H), 1.50 (s, 3H), 1.68 (brs, 1H), 2.54 (s, 3H),
2.64 (d, J = 1.8 Hz, 1H), 3.14 (d, J = 3.9 Hz, 1H), 4.56 (d, J = 3.9 Hz,
1H), 4.92 (dd, J = 3.6, 2.4 Hz, 1H), 5.90 (d, J = 3.6 Hz, 1H). 13C
NMR (75 MHz, CDCl3): δ 26.0, 26.7, 34.6, 67.2, 70.8, 77.6, 77.9, 82.4,
104.9, 111.6. ESIMS: m/z 220 [M + Na]+. Anal. Calcd for
C10H15NO3: C, 60.90; H, 7.67; N, 7.10. Found: C, 60.74; H, 7.53;
N, 6.98.
125.7, 129.5, 149.3. IR νmax (film): 2987, 2108, 1589, 1496, 1377,
1233, 1162 cm−1. ESIMS: m/z 400 [M + Na]+. Anal. Calcd for
C18H23N3O6: C, 57.29; H, 6.14; N, 11.13. Found: C, 57.05; H, 5.98;
N, 11.01.
1
(3R,4R)-3-Acetoxy-4-(acetoxymethyl)-[1,5:1,2]-[1,2,3-triazo-
lo]-3,4,6-trihydrobenzo[c][1,5]oxazocine (23). Compound 4a
(0.5 mmol) was dissolved in 25 mL of CH3CN/H2O (18:5)
containing 8% H2SO4 and stirred at rt for 24 h. The acidic solution
was neutralized with solid NaHCO3 and filtered, and the filtrate was
evaporated in vacuo. The residue was dissolved in a minimum volume
of MeOH and treated dropwise at 0 °C with an aqueous solution of
NaIO4 (128 mg, 0.6 mmol) with stirring for 1 h. Usual workup
followed by NaBH4 reduction in MeOH afforded the diol. This was
acetylated with Ac2O (0.3 mL) and pyridine (2 mL) at rt for 12 h to
furnish a crude product, which was purified by silica gel flash
chromatography to afford 23 as a gummy material. Yield: 0.07 g, 42%
(eluent PS/EA, 2:1). [α]2D5: +37.8 (c 1.2, CHCl3). 1H NMR (300
MHz, CDCl3): δ 1.60 (s, 3H), 2.12 (s, 3H), 3.97 (d, J = 6.0 Hz, 1H),
4.08−4.30 (m, 3H), 4.79 (d, J = 11.7 Hz, 1H), 6.12 (s, 1H), 7.57−7.69
(m, 4H), 7.80 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 19.9, 20.7, 62.6,
64.0, 68.1, 77.2, 125.5, 129.9, 130.4, 131.5, 132.3, 133.3, 135.5, 135.8,
168.9, 170.4. IR νmax (film): 2924, 2855, 1742, 1530, 1460, 1372 cm−1.
ESI: m/z 354 [M + Na]+. Anal. Calcd for C16H17N3O5: C, 58.00; H,
5.17; N, 12.68. Found: C, 57.72; H, 5.03; N, 12.36.
(3aR,5R,6S,6aR)-6-(N-(2-Azidobenzyl)-N-methylamino)-5-
ethynyl-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole (15). A
solution of 14 (0.099 g, 0.5 mmol) in anhydrous CH3CN (8 mL) at rt
was treated with K2CO3 (0.27 g, 2 mmol, 4 equiv) and 2-azidobenzyl
bromide (0.12 g, 0.6 mmol), and the mixture was stirred for 6 h under
N2 atmosphere. The mixture was filtered, concentrated and extracted
with ethyl acetate (3 × 10 mL). The organic layer was washed with
H2O, dried (Na2SO4), evaporated, and column chromatographed over
silica gel to afford 15 as oil. Yield: 0.134 g, 82% (eluent PS/EA, 12:1).
[α]2D5 = −23.5 (c 0.25, CHCl3). H NMR (300 MHz, CDCl3): δ 1.33
1
(s, 3H), 1.49 (s, 3H), 2.37 (s, 3H), 2.66 (d, J = 2.1 Hz, 1H), 3.43 (d, J
= 5.4 Hz, 1H), 3.68 (d, J = 14.1 Hz, 1H), 3.84 (d, J = 14.1 Hz, 1H),
4.79 (d, J = 3.9 Hz, 1H), 4.97 (dd, J = 5.4, 2.1 Hz, 1H), 5.92 (d, J = 3.9
Hz, 1H), 7.10−7.58 (m, 4H). 13C NMR (75 MHz, CDCl3): δ 26.0,
26.7, 38.9, 53.3, 70.6, 71.4, 76.5, 78.3, 81.0, 104.6, 111.1, 118.0, 124.7,
128.2, 129.9, 130.4, 138.2. IR νmax (film): 3286, 2986, 2931, 2857,
2122, 1587 cm−1. ESIMS: m/z 351 [M + Na]+. Anal. Calcd for
C17H20N4O3: C, 62.18; H, 6.14; N, 17.06. Found: C, 61.98; H, 5.96;
N, 16.88.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for compounds 2a, 4a, 6, 8, 9, 11−
15, 17−19, and 21−23. This material is available free of charge
via the Internet at http://pubs.acs.org.
(3aR,5R,6S,6aR)-6-(2-Azidobenzoyl)methylamino-5-ethynyl-
2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole (16). A solution
of 14 (0.099 g, 0.5 mmol) in anhydrous CH2Cl2 (5 mL) was treated at
rt with Et3N (0.2 mL) and cooled to 0 °C. To it was added dropwise a
solution of 2-azidobezoyl chloride (0.11 g, 0.6 mmol) in CH2Cl2 (5
mL), and the resulting solution was stirred for 8 h under N2
atmosphere. The reaction mixture was cooled to 0 °C and diluted
with CH2Cl2 (10 mL) and washed successively with 2 N HCl (20
mL), H2O (20 mL), and saturated NaHCO3 (20 mL), dried,
evaporated, and column chromatographed over silica gel to afford
16 as a gummy material. Yield: 0.128 g, 75% (eluent PS/EA, 9:1).
AUTHOR INFORMATION
Corresponding Author
*Fax: +91-33-24735197. E-mail: partha@iicb.res.in.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
[α]2D5 = −18.6 (c 0.32, CHCl3). H NMR (300 MHz, CDCl3): δ 1.35
1
■
Financial assistance from the Department of Science and
Technology (DST), New Delhi, is gratefully acknowledged.
N.D.A. thanks the Council of Scientific and Industrial Research
(CSIR) for providing a research fellowship. We acknowledge
Dr. B. Achari, formerly at the CSIR-Indian Institute of
Chemical Biology, for his interest in this work.
(s, 3H), 1.48 (s, 3H), 2.79 (d-like, 1H), 2.89 (s, 3H), 4.34 (d, J = 3.9
Hz, 1H), 5.08 (d, J = 3.9 Hz, 1H), 5.31 (d, J = 4.2 Hz, 1H), 6.04 (d, J
= 3.6 Hz, 1H), 7.06−7.68 (m, 4H). 13C NMR (75 MHz, CDCl3): δ
25.8, 26.4, 30.9, 65.5, 76.5, 77.9, 82.4, 84.8, 104.9, 112.3, 127.9, 128.4,
129.3, 131.2, 132.6, 132.9, 168.0. IR νmax (film): 3278, 2988, 2936,
2128, 1644, 1478, 1380 cm−1. ESIMS: m/z 365 [M + Na]+. Anal.
Calcd for C17H18N4O4: C, 59.64; H, 5.30; N, 16.37. Found: C, 59.42;
H, 5.16; N, 16.19.
REFERENCES
■
(3aR,5R,6S,6aR)-6-[(2-azidophenoxy)-5-(2,2-dimethyl[1,3]-
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