A stereoselective route to aza-C-aryl glycosides from arynes and chiral nitrones

Article abstract of DOI:10.1002/ejoc.201200685

Arynes are regarded as potential and versatile intermediates in organic synthesis. These highly-reactive, strained and kinetically unstable species have numerous applications in synthetic chemistry. In this article, a highly-diasteroselective and efficient 1,3-dipolar cycloaddition reaction between a range of arynes and sugar-derived cyclic nitrones leading to an interesting class of sugar-based benzo[d]isoxazolines is described. These benzo[d]isoxazolines upon selective N-O bond cleavage provide various substituted aza-C-aryl glycosides in good yield. These substituted pyrrolidine derivatives are chiral aminophenols and could be potential chiral ligands and organocatalysts in asymmetric synthesis.

Full text of DOI:10.1002/ejoc.201200685

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FULL PAPER
DOI: 10.1002/ejoc.201200685
A Stereoselective Route to Aza-C-aryl Glycosides from Arynes and Chiral
Nitrones
Rama Kanwar Khangarot[a] and Krishna P. Kaliappan*[a]
Keywords: Glycosides / Cycloaddition / Nitrogen heterocycles / Cyclic nitrones / Arynes
Arynes are regarded as potential and versatile intermediates
in organic synthesis. These highly-reactive, strained and ki-
netically unstable species have numerous applications in
synthetic chemistry. In this article, a highly-diasteroselective
and efficient 1,3-dipolar cycloaddition reaction between a
range of arynes and sugar-derived cyclic nitrones leading to
an interesting class of sugar-based benzo[d]isoxazolines is
described. These benzo[d]isoxazolines upon selective N–O
bond cleavage provide various substituted aza-C-aryl glycos-
ides in good yield. These substituted pyrrolidine derivatives
are chiral aminophenols and could be potential chiral ligands
and organocatalysts in asymmetric synthesis.
make analogues of several naturally occurring aryl-substi-
tuted polyhydroxylated pyrrolidines (1–5, Figure 1).[10]
Herein, we report a facile 1,3-dipolar cycloaddition reaction
of various arynes with sugar-derived cyclic nitrones to syn-
thesize benzo[d]isoxazolines and a range of hydroxyaryl-
substituted polyhydroxy-pyrrolidines (Scheme 1). This ap-
proach is complimentary to the direct addition of organo-
Introduction
Arynes,[1] once mainly the subject of structural curiosity,
now attract the attention of synthetic chemists as reactive
intermediates and are now widely employed as reaction
partners in organic synthesis. Early syntheses of arynes suf-
fered from several shortcomings such as harsh conditions,
multiple reaction steps, limited availability of starting mate-
rials and were often low yielding.[2] However, a mild pro-
cedure involving fluoride promoted ortho-elimination of o-
(trimethylsilyl)aryl triflates developed by Kobayashi, led to
a renaissance of the chemistry of arynes.[3] Among the vari-
ety of reactions that arynes[4] undergo, 1,3-dipolar cycload-
dition reactions[5] deserve special mention owing to their
ability to produce pharmaceutically important nitrogen
containing heterocycles. Several dipoles have been systemat-
ically studied for their reactivity with arynes, leading to
interesting heterocycles. However, only a few nitrones,
mostly achiral ones, have been investigated as dipole part-
ners for arynes.[6]
Nitrones have long been used as building blocks in or-
ganic synthesis.[7] We and others have explored sugar-de-
rived cyclic nitrones for highly diastereoselective 1,3-dipolar
cycloaddition reactions.[8] Thus, based on our recent success
on the utility of sugar-derived cyclic nitrones,[9] we envi-
sioned that the reaction of these nitrones with arynes would
lead to benzo[d]isoxazolines, which upon cleavage of N–O
bond would afford o-hydroxyaryl-substituted pyrrolidines.
Furthermore, this method could be an attractive strategy to
Figure 1. Aryl-substituted polyhydroxy-pyrrolidine natural prod-
ucts.
[a] Department of Chemistry, Indian Institute of Technology
Bombay,
Powai, Mumbai 400076, India
Fax: +91-22-2572-3480
E-mail: kpk@chem.iitb.ac.in
Scheme 1. 1,3-Dipolar cycloaddition reaction between sugar-de-
rived cyclic nitrones and arynes, and their subsequent N–O bond
cleavage.
Homepage: http://www.chem.iitb.ac.in/~kpk/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200685.
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R. K. Khangarot, K. P. Kaliappan
FULL PAPER
metallic reagents to cyclic nitrones leading to aryl-substi- of sugar-derived cyclic nitrones,[9,10] is well documented. To
tuted polyhydroxy-pyrrolidines.[11] However, our strategy realize the feasibility of this reaction readily accessible
provides an additional hydroxy group in the aryl ring and nitrone 10 (from d-xylose) was chosen to identify suitable
thus the resultant aminophenols with other hydroxy groups, reaction conditions under which to perform the 1,3-dipolar
which are already protected, could serve as potential organo- cycloaddition reaction with simple benzyne. To begin with,
catalysts and as chiral ligands in asymmetric synthesis.[11] KF was chosen as the fluoride source and the reaction was
When we were concluding our investigation, Larock and
co-workers reported the synthesis of benzisoxazolines by
the coupling of arynes with nitrones.[6a]
Table 1. 1,3-Dipolar cycloaddition reaction between sugar-derived
cyclic nitrones and benzyne.[a,b]
Results and Discussion
The success of this strategy, which depends on the easy
availability of the starting materials and in the preparation
[a] 1,3-Dipolar cycloadducts were synthesized from the respective
cyclic nitrones and benzyne by using CsF in CH3CN at room temp.
[b] Yields are given in parentheses.
Scheme 2. 1,3-Dipolar cycloaddition reaction between d-xylose-de-
rived cyclic nitrone and benzyne.
Table 2. 1,3-Dipolar cycloaddition reaction between sugar-derived cyclic nitrones and arynes.[a,b]
[a] 1,3-Dipolar cycloadducts were synthesized from the respective cyclic nitrones and benzyne by using CsF in CH3CN at room temp.
[b] Yields are given in parentheses.
2
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A Stereoselective Route to Aza-C-aryl Glycosides
carried out in the presence of 18-crown-6. Unfortunately, (87% and 94%, respectively) whereas treatment with nitro-
under these conditions only a complex mixture of products nes 13 and 14 led to cycloadducts 27 and 29 in good yields
was obtained. By using TBAF as the fluoride source lead (79% and 72%, respectively). In a similar way, aryne pre-
to some of the required product but the yield was far from cursors 20 and 21 were treated with nitrones 10, 13, ent-10
satisfactory. Gratifyingly, when nitrone 10 and o-(trimethyl-
silyl)phenyltriflate 11 were mixed in CH3CN in the presence
of CsF at room temperature, desired product 12 was ob-
tained in 76% yield (Scheme 2).
Table 3. Screening of reaction conditions for the N–O bond cleav-
age of benzo[d]isoxazoline.
After identifying optimized reaction conditions, we
sought to probe the generality of this reaction with other
nitrones (13, ent-10 and 14) and o-(trimethylsilyl)phenyl-
triflate 11 (Table 1). Nitrone ent-10 reacted smoothly to
provide desired product 16 in excellent yield (85%), whereas
nitrones 13 and 14 furnished benzo[d]isoxazolines in good
yields (68% and 71%, respectively).
Entry
Reaction conditions
Yield of 38 [%]
Precursor 18 gave good results with nitrones 10, 13, ent-
10 and 14, furnishing cycloadduct 22 in excellent yield and
23, 24 and 25 in good yields, respectively (Table 2). 4,5-Di-
fluorobenzyne precursor 19, which represents an example
of an aryne with a strongly electron-withdrawing group,
was then investigated. Reaction of 19 with nitrones 10 and
ent-10 afforded desired products 26 and 28 in excellent yield
1
2
3
4
5
6
7
NiCl2·6H2O, NaBH4, MeOH, 0.5 h
Mo(CO)6, CH3CN, H2O, reflux, 24 h
LiAlH4, diethyl ether (or) THF, reflux
Zn, AcOH, H2O, room temp., 24 h
Zn, sonication, 40 °C, 2 h
62[c]
40
0
33[c]
21[c]
Zn, In, aq. NH4Cl, MeOH, reflux, 24 h 56[c]
Zn, AcOH, H2O, 70 °C, 2 h
83
Table 4. Reductive N–O bond cleavage of benzo[d]isoxazolines.[a,b]
[a] O-protected aza-C-aryl glycosides were synthesized from the respective cycloadducts by using Zn dust, acetic acid and H2O at 70 °C.
[b] Yields are given in parentheses. [c] Yields are based on recovered starting materials.
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R. K. Khangarot, K. P. Kaliappan
FULL PAPER
and 14 to afford cycloadducts 30–37 in good to excellent nes and arynes to afford a range of chiral benzo[d]isoxazol-
yields. ines that were further converted into a library of O-pro-
Having successfully synthesized a variety of sugar-de- tected aza-C-aryl glycosides upon reductive N–O bond
rived benzo[d]isoxazolines, next we turned our attention to cleavage. The cycloaddition reaction was highly diastereo-
transforming these intermediates into the corresponding O- selective and furnished only a single isomer in all the cases.
protected aza-C-aryl glycosides through cleavage of the N– Thus, this two-step protocol is a potential route to various
O bond. Although the cleavage of N–O bond and removal natural and synthetic compounds with an aryl-substituted
of benzyl groups could be performed simultaneously, we polyhydroxy-pyrrolidine framework. Furthermore, the ami-
were looking for specific reaction conditions to selectively nophenols obtained after N–O bond cleavage might find
cleave of N–O bond. Initially, cycloadduct 12 was chosen potential applications in organocatalysis and also as chiral
and treated with NiCl2·6H2O and NaBH4 in MeOH at ligands in organic synthesis. Efforts are underway in our
–40 °C for 30 min.[12] Expected product 38 was obtained in laboratory to utilize these new chiral amino alcohols in
low yield with significant recovery of cycloadduct 12 asymmetric synthesis.
(Table 3, Entry 1). Attempts to cleave the N–O bond with
Mo(CO)6 in CH3CN and H2O under reflux conditions[13]
Experimental Section
did not significantly improve the yield (Table 3, Entry 2).
Contrary to our expectations, treatment with LAH in ether
and THF[14] under reflux conditions also failed to deliver
the required product (Table 3, Entry 3). Attempted re-
ductive cleavage of the N–O bond in the presence of Zn
dust under various conditions with different additives was
also not helpful either at room temperature,[15] or under
sonication at 40 °C[16] (Table 3, Entries 4, 5 and 6).[17]
Eventually, treatment of cycloadduct 12 with Zn dust, ace-
tic acid and water at 70 °C for 2 h[18] paved the way for
smooth formation of product 38 in 83% yield (Table 3, En-
try 7). Thus, a combination of Zn and aqueous acetic acid
at 70 °C was identified as the best conditions for the re-
ductive cleavage of the N–O bond. We employed these opti-
mized conditions to other sugar-derived benzo[d]isoxazol-
ines, and in all cases we observed fully protected aza-C-aryl
glycosides in good to excellent yields (Table 4).
General Methods: All starting materials and reagents were obtained
from commercial suppliers and used without further purification.
Tetrahydrofuran was distilled from sodium benzophenone ketyl
and toluene from sodium. Dichloromethane, hexane and acetoni-
trile were freshly distilled from calcium hydride. All solvents for
routine isolation of products and chromatography were reagent
grade and glass distilled. Air and moisture sensitive reactions were
performed under an argon/UHP nitrogen atmosphere. Flash
chromatography was performed with silica gel (100–200 mesh,
Aceme) with indicated solvents. All reactions were monitored by
thin-layer chromatography carried out on 0.25 mm Merck silica
plates (60F-254) with the use of UV light as a visualizing agent
and 7% ethanolic phosphomolybdic acid and heat as developing
agents. Optical rotations were recorded on Rudolph Autopol IV
digital polarimeter. HRMS were recorded with a micromass ESI
Time of Flight (TOF) mass spectrometer. IR spectra were recorded
on a Perkin–Elmer Spectrum One FTIR spectrometer. H and 13C
1
NMR spectra were recorded either Bruker AV 400 MHz instrument
in CDCl3. The following abbreviations are used in reporting NMR
spectroscopic data: s, singlet; br, broad; d, doublet; t, triplet; q,
quartet; dd, doublet of doublets; dt, doublet of triplets; td, triplet
of doublets; ABq, AB quartet; m, multiplet.
After the successful cleavage of the N–O bond, we moved
on to study the removal of the benzyl groups to synthesize
aryl-substituted polyhydroxy-pyrrolidines (Scheme 3). Our
initial attempts under standard conditions, such as Pd-C/
H2 in acidic MeOH and Pd(OH)2-C/H2 in acidic MeOH,
did not provide the desired product which is in agreement
with the literature precedence[19] that indicates that the pres-
ence of an amine group suppresses the hydrogenolysis of O-
benzyl groups. Pleasingly, the use of BBr3 in dichlorometh-
ane[20] successfully cleaved all the benzyl groups to furnish
the desired product in 88% yield. This condition could be
extended to cleave benzyl groups of other sugar-derived
benzo[d]isoxazolines to a series of aryl-substituted polyhy-
droxy-pyrrolidines.
General Procedure for Cycloaddition: Nitrone (1 mmol) was added
to a suspension of CsF (6 mmol) in dry CH3CN (15 mL). Then, a
solution of aryne precursor (1.5 mmol) in CH3CN (5 mL) was
added and the obtained mixture was stirred at room temperature
for 1 h. After completion of the reaction (monitored by TLC), the
reaction mixture was treated with a saturated aqueous solution of
NaCl. The organic layer was separated and the aqueous layer was
extracted with ethyl acetate (2ϫ10 mL). The combined organic ex-
tracts were washed with brine, dried with Na2SO4, filtered and con-
centrated under vacuum to obtain the crude product, which was
purified by flash column chromatography.
(1S,2S,3S,9bS)-1,2-Bis(benzyloxy)-3-(benzyloxymethyl)-1,2,3,9b-
tetrahydrobenzo[d]pyrrolo[1,2-b]isoxazole (12): Following the gene-
ral procedure, starting from nitrone 10 (50 mg, 0.12 mmol) and
aryne precursor 11 (54 mg, 0.18 mmol), cycloadduct 12 was ob-
tained as a white solid (45 mg, 76%) after purification by silica gel
column chromatography (6% ethyl acetate/hexanes). Rf = 0.5 (10%
ethyl acetate/hexanes); m.p. 81–82 °C. [α]2D0 = 61.0 (c = 1.00,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.40–7.09 (m, 17 H),
6.95 (td, J = 7.4, 0.8 Hz, 1 H), 6.82 (d, J = 8.0 Hz, 1 H), 4.97 (d,
J = 2.7 Hz, 1 H), 4.74–4.51 (m, 6 H), 4.29 (dd, J = 4.8, 3.2 Hz, 1
H), 4.23 (dd, J = 7.9, 4.8 Hz, 1 H), 3.80 (dd, J = 10.5, 4.4 Hz, 1
Scheme 3. Removal of benzyl groups.
Conclusions
In summary, we have reported the successful 1,3-dipolar
cycloaddition reaction between sugar-derived cyclic nitro- H), 3.72 (dd, J = 10.5, 4.0 Hz, 1 H), 3.44–3.40 (m, 1 H) ppm. 13C
4
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A Stereoselective Route to Aza-C-aryl Glycosides
NMR (100 MHz, CDCl3): δ = 156.1, 138.4, 138.0, 137.6, 129.2,
128.7, 128.5, 128.4, 128.1, 128.0, 127.9, 127.8, 127.7, 127.0, 123.6,
ing the general procedure, starting from nitrone 10 (40 mg,
0.10 mmol) and aryne precursor 18 (50 mg, 0.15 mmol), cycload-
122.1, 108.9, 88.2, 81.6, 73.6, 72.7, 72.6, 72.5, 71.0, 68.0 ppm. IR duct 22 was obtained as a white solid (45 mg, 90%) after purifica-
(neat): ν = 3019, 2928, 2865, 1654, 1454, 1363, 1286, 1111, 1026, tion by silica gel column chromatography (6% ethyl acetate/hex-
˜
928, 881, 851, 669 cm–1. HRMS (ESI): calcd. for C32H31NO4 (M anes). Rf = 0.5 (10 % ethyl acetate/hexanes); m.p. 112–113 °C.
1
+ 1)+ 494.2331; found 494.2338.
[α]2D0 = 51.2 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ =
7.40–7.22 (m, 13 H), 7.13–7.11 (m, 2 H), 6.78 (s, 1 H), 6.62 (s, 1
H), 4.91 (d, J = 2.9 Hz, 1 H), 4.71, 4.66 (ABq, J = 11.5 Hz, 3 H),
4.59, 4.54 (ABq, J = 11.5 Hz, 3 H), 4.26–4.20 (m, 2 H), 3.79 (dd,
J = 10.4, 4.2 Hz, 1 H), 3.71 (dd, J = 10.4, 3.9 Hz, 1 H), 3.39–3.35
(m, 1 H), 2.21 (s, 3 H), 2.18 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 154.5, 138.4, 138.2, 137.8, 137.7, 130.1, 128.7, 128.5,
128.4, 128.1, 128.0, 127.7, 127.7, 127.7, 124.1, 124.2, 109.9, 88.2,
(1S,2R,3S,9bS)-1,2-Bis(benzyloxy)-3-(benzyloxymethyl)-1,2,3,9b-
tetrahydrobenzo[d]pyrrolo[1,2-b]isoxazole (15): Following the gene-
ral procedure, starting from nitrone 13 (50 mg, 0.12 mmol) and
aryne precursor 11 (54 mg, 0.18 mmol), cycloadduct 15 was ob-
tained as a white solid (60 mg, 68%) after purification by silica gel
column chromatography (6% ethyl acetate/hexanes). Rf = 0.5 (10%
ethyl acetate/hexanes); m.p. 108–109 °C. [α]2D0 = 32.4 (c = 1.00,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.37–7.26 (m, 15 H),
7.17 (td, J = 8.0, 0.7 Hz, 1 H), 7.09 (d, J = 7.5 Hz, 1 H), 6.88 (td,
J = 7.5, 0.8 Hz, 1 H), 6.75 (d, J = 8.1 Hz, 1 H), 5.06 (d, J = 5.5 Hz,
1 H), 4.78–4.52 (m, 6 H), 4.24 (t, J = 4.2 Hz, 1 H), 4.07 (m, 1 H),
4.02 (d, J = 9.4 Hz, 1 H), 3.86 (dd, J = 9.4, 5.8 Hz, 1 H), 3.61–3.56
(m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 156.1, 138.3,
138.2, 137.7, 129.2, 128.7, 128.5, 128.4, 128.1, 128.1, 128.0, 127.9,
127.8, 127.8, 126.7, 123.4, 121.7, 108.2, 100.1, 85.6, 74.0, 73.6, 72.7,
81.6, 73.6, 72.7, 72.6, 72.4, 70.7, 68.1, 20.3, 19.5 ppm. IR (neat): ν
˜
= 3028, 2926, 2857, 1605, 1494, 1453, 1366, 1308, 1216, 1144, 1125,
1094, 1029, 863, 694 cm–1. HRMS (ESI): calcd. for C34H35NO4 (M
+ 1)+ 522.2644; found 522.2658.
(1S,2R,3S,9bS)-1,2-Bis(benzyloxy)-3-(benzyloxymethyl)-7,8-dimeth-
yl-1,2,3,9b-tetrahydrobenzo[d]pyrrolo[1,2-b]isoxazole (23): Follow-
ing the general procedure, starting from nitrone 13 (40 mg,
0.10 mmol) and aryne precursor 18 (50 mg, 0.15 mmol), cycload-
duct 23 was obtained as a white solid (35 mg, 70%) after purifica-
tion by silica gel column chromatography (6% ethyl acetate/hex-
anes). Rf = 0.5 (10 % ethyl acetate/hexanes); m.p. 125–126 °C.
67.8 ppm. IR (neat): ν = 3071, 2922, 2851, 1652, 1596, 1457, 1361,
˜
1218, 1154, 1098, 1016, 960, 698 cm–1. HRMS (ESI): calcd. for
C32H31NO4 (M + 1)+ 494.2331; found 494.2307.
[α]2D0 = 49.6 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ =
1
(1R,2R,3R,9bR)-1,2-Bis(benzyloxy)-3-(benzyloxymethyl)-1,2,3,9b-
tetrahydrobenzo[d]pyrrolo[1,2-b]isoxazole (16): Following the gene-
ral procedure, starting from nitrone ent-10 (60 mg, 0.14 mmol) and
aryne precursor 11 (65 mg, 0.21 mmol), cycloadduct 16 was ob-
tained as a white solid (60 mg, 85%) after purification by silica gel
column chromatography (6% ethyl acetate/hexanes). Rf = 0.5 (10%
ethyl acetate/hexanes); m.p. 89–90 °C. [α]2D0 = –80.8 (c = 0.50,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.39–7.17 (m, 14 H),
7.13–7.09 (m, 3 H), 6.95 (td, J = 7.4, 0.7 Hz, 1 H), 6.82 (d, J =
8.0 Hz, 1 H), 4.97 (d, J = 2.7 Hz, 1 H), 4.74–4.51 (m, 6 H), 4.29
(dd, J = 4.7, 3.3 Hz, 1 H), 4.23 (dd, J = 8.0, 4.8 Hz, 1 H), 3.80 (dd,
J = 10.4, 4.3 Hz, 1 H), 3.72 (dd, J = 10.4, 4.0 Hz, 1 H), 3.44–3.40
(m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 156.1, 138.4,
138.0, 137.6, 129.2, 128.7, 128.5, 128.4, 128.1, 128.0, 127.9, 127.8,
127.81, 127.76, 127.01, 123.61, 122.11, 108.9, 88.2, 81.5, 73.6, 72.7,
7.38–7.26 (m, 15 H), 6.76 (s, 1 H), 6.55 (s, 1 H), 5.00 (d, J = 5.3 Hz,
1 H), 4.78–4.51 (m, 6 H), 4.23 (t, J = 4.3 Hz, 1 H), 4.06–4.01 (m,
2 H), 3.84 (dd, J = 9.4, 5.7 Hz, 1 H), 3.57–3.52 (m, 1 H), 2.19 (s,
3 H), 2.16 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 154.5,
138.4, 138.3, 137.9, 137.7, 129.7, 128.6, 128.5, 128.4, 128.1, 128.0,
128.0, 127.9, 127.8, 124.0, 123.9, 109.1, 85.6, 74.0, 73.6, 72.6, 71.5,
70.6, 67.9, 20.3, 19.4 ppm. IR (neat): ν = 3271, 3030, 2926, 2867,
˜
1666, 1489, 1454, 1371, 1217, 1151, 1101, 1013, 695 cm–1. HRMS
(ESI): calcd. for C34H35NO4 (M + 1)+ 522.2644; found 522.2656.
(1R,2R,3R,9bR)-1,2-Bis(benzyloxy)-3-(benzyloxymethyl)-7,8-di-
methyl-1,2,3,9b-tetrahydrobenzo[d]pyrrolo[1,2-b]isoxazole (24): Fol-
lowing the general procedure, starting from nitrone ent-10 (40 mg,
0.10 mmol) and aryne precursor 18 (50 mg, 0.15 mmol), cycload-
duct 24 was obtained as a white solid (40 mg, 70%) after purifica-
tion by silica gel column chromatography (6% ethyl acetate/hex-
anes). Rf = 0.5 (10 % ethyl acetate/hexanes); m.p. 112–113 °C.
72.6, 72.5, 71.0, 68.0 ppm. IR (neat): ν = 3016, 2920, 2853, 1652,
˜
1452, 1366, 1217, 1124, 1034, 879, 695 cm–1. HRMS (ESI): calcd.
for C32H31NO4 (M + 1)+ 494.2331; found 494.2331.
[α]2D0 = –49.0 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ =
1
7.39–7.23 (m, 13 H), 7.13–7.11 (m, 2 H), 6.78 (s, 1 H), 6.62 (s, 1
H), 4.91 (s, 1 H), 4.71, 4.67 (ABq, J = 11.5 Hz, 3 H), 4.59, 4.54
(ABq, J = 11.5 Hz, 3 H), 4.26–4.20 (m, 2 H), 3.79 (dd, J = 10.4,
4.2 Hz, 1 H), 3.71 (dd, J = 10.5, 3.9 Hz, 1 H), 3.39–3.35 (m, 1 H),
2.21 (s, 3 H), 2.18 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 154.5, 138.5, 138.2, 137.8, 137.7, 130.1, 128.7, 128.5, 128.4, 128.1,
128.0, 127.7, 127.7, 127.7, 124.3, 124.2, 109.9, 88.2, 81.6, 73.6, 72.7,
(1R,2R,3S,9bR)-1,2-Bis(benzyloxy)-3-(benzyloxymethyl)-1,2,3,9b-
tetrahydrobenzo[d]pyrrolo[1,2-b]isoxazole (17): Following the gene-
ral procedure, starting from nitrone 14 (50 mg, 0.12 mmol) and
aryne precursor 11 (54 mg, 0.18 mmol), cycloadduct 17 was ob-
tained as an oil (42 mg, 71%) after purification by silica gel column
chromatography (6% ethyl acetate/hexanes). Rf = 0.5 (10% ethyl
acetate/hexanes). [α]2D0 = –52.2 (c = 1.00, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.40–7.25 (m, 13 H), 7.21–7.09 (m, 4 H),
6.91 (td, J = 7.4, 0.8 Hz, 1 H), 6.78 (d, J = 8.0 Hz, 1 H), 5.25 (d,
J = 5.6 Hz, 1 H), 4.66–4.54 (m, 4 H), 4.49, 4.38 (ABq, J = 12.1 Hz,
2 H), 4.24 (dd, J = 5.7, 2.1 Hz, 1 H), 3.96 (t, J = 9.2 Hz, 1 H), 3.88
(dd, J = 9.2, 5.1 Hz, 1 H), 3.76–3.72 (m, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 157.2, 138.4, 138.0, 137.8, 128.9, 128.6,
128.5, 128.0, 128.0, 127.9, 127.7, 127.7, 125.4, 123.4, 121.0, 108.0,
72.6, 72.4, 70.7, 68.1, 20.3, 19.5 ppm. IR (neat): ν = 3028, 2924,
˜
2857, 1654, 1453, 1366, 1216, 1094, 1029, 694 cm–1. HRMS (ESI):
calcd. for C34H35NO4 (M + 1)+ 522.2644; found 522.2659.
(1R,2R,3S,9bR)-1,2-Bis(benzyloxy)-3-(benzyloxymethyl)-7,8-di-
methyl-1,2,3,9b-tetrahydrobenzo[d]pyrrolo[1,2-b]isoxazole (25): Fol-
lowing the general procedure, starting from nitrone 14 (50 mg,
0.12 mmol) and aryne precursor 18 (60 mg, 0.18 mmol), cycload-
duct 25 was obtained as a colorless oil (45 mg, 72%) after purifica-
tion by silica gel column chromatography (6% ethyl acetate/hex-
anes). Rf = 0.5 (10% ethyl acetate/hexanes). [α]2D0 = –47.6 (c = 1.00,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.32–7.24 (m, 13 H),
7.17–7.14 (m, 2 H), 6.88 (s, 1 H), 6.59 (s, 1 H), 5.18 (d, J = 5.8 Hz,
1 H), 4.62–4.51 (m, 5 H), 4.80 (d, J = 12.3 Hz, 1 H), 4.21 (dd, J =
81.9, 81.1, 73.7, 72.9, 72.3, 70.8, 69.8, 67.8 ppm. IR (neat): ν =
˜
3060, 3029, 2923, 2857, 1599, 1479, 1455, 1364, 1242, 1217, 1098,
698 cm–1. HRMS (ESI): calcd. for C32H31NO4 (M + 1)+ 494.2331;
found 494.2318.
(1S,2S,3S,9bS)-1,2-Bis(benzyloxy)-3-(benzyloxymethyl)-7,8-dimeth-
yl-1,2,3,9b-tetrahydrobenzo[d]pyrrolo[1,2-b]isoxazole (22): Follow-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20685
/KAP1
Date: 10-09-12 10:50:28
Pages: 12
R. K. Khangarot, K. P. Kaliappan
FULL PAPER
5.9, 2.2 Hz, 1 H), 4.07 (dd, J = 5.0, 2.2 Hz, 1 H), 3.96 (t, J = (ESI): calcd. for C32H29NO4F2 (M + 1)+ 530.2143; found 530.2124.
9.1 Hz, 1 H), 3.85 (dd, J = 9.2, 5.0 Hz, 1 H) 2.21 (s, 3 H), 2.18 (s,
(1R,2R,3S,9bR)-1,2-Bis(benzyloxy)-3-(benzyloxymethyl)-7,8-di-
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 155.5, 138.4, 138.1,
fluoro-1,2,3,9b-tetrahydrobenzo[d]pyrrolo[1,2-b]isoxazole (29): Fol-
137.9, 137.4, 128.9, 128.6, 128.5, 128.1, 127.9, 127.9, 127.8, 127.7,
lowing the general procedure, starting from nitrone 14 (40 mg,
127.1, 126.2, 120.6, 109.0, 81.9, 81.0, 73.6, 72.8, 72.3, 70.6, 69.4,
0.10 mmol) and aryne precursor 19 (48 mg, 0.14 mmol), cycload-
67.8, 20.4, 19.5 ppm. IR (neat): ν = 3021, 2924, 2862, 1655, 1493,
˜
duct 29 was obtained as a white solid (36 mg, 72%) after purifica-
tion by silica gel column chromatography (6% ethyl acetate/hex-
anes). Rf = 0.5 (10% ethyl acetate/hexanes); m.p. 99–100 °C. [α]2D0
1454, 1366, 1263, 1208, 1091, 1028, 694 cm–1. HRMS (ESI): calcd.
for C34H35NO4 (M + 1)+ 522.2644; found 522.2620.
1
= 67.6 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.35–
(1S,2S,3S,9bS)-1,2-Bis(benzyloxy)-3-(benzyloxymethyl)-7,8-di-
fluoro-1,2,3,9b-tetrahydrobenzo[d]pyrrolo[1,2-b]isoxazole (26): Fol-
lowing the general procedure, starting from nitrone 10 (50 mg,
0.12 mmol) and aryne precursor 19 (60 mg, 0.18 mmol), cycload-
duct 26 was obtained as a white solid (55 mg, 87%) after purifica-
tion by silica gel column chromatography (6% ethyl acetate/hex-
anes). Rf = 0.5 (10 % ethyl acetate/hexanes); m.p. 119–120 °C.
7.25 (m, 13 H), 7.12–7.10 (m, 2 H), 6.86 (td, J = 9.0, 0.6 Hz, 1 H),
6.58 (dd, J = 10.1, 6.2 Hz, 1 H), 5.16 (d, J = 5.6 Hz, 1 H), 4.62–
4.47 (m, 5 H), 4.32 (d, J = 12.1 Hz, 1 H), 4.17 (dd, J = 5.7, 2.0 Hz,
1 H), 4.08 (dd, J = 4.9, 2.0 Hz, 1 H), 3.93 (t, J = 9.1 Hz, 1 H), 3.83
(dd, J = 9.2, 5.2 Hz, 1 H), 3.72–3.69 (m, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 152.8, 152.7, 152.1, 151.9, 149.6, 149.5,
146.9, 146.7, 144.5, 144.4, 138.2, 137.8, 137.4, 128.6, 128.5, 128.2,
128.1, 128.0, 127.9, 127.8, 127.8, 118.5, 118.5, 118.4, 118.4, 113.5,
113.3, 97.7, 97.5, 81.5, 80.8, 73.7, 73.0, 72.4, 70.7, 69.9, 67.6 ppm.
[α]2D0 = 40.8 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ =
1
7.41–7.23 (m, 13 H), 7.13 (d, J = 3.0 Hz, 1 H), 7.11 (d, J = 2.0 Hz,
1 H), 6.75–6.71 (m, 1 H), 6.62 (dd, J = 9.9, 6.1 Hz, 1 H), 4.91 (s,
1 H), 4.67–4.53 (m, 6 H), 4.21–4.16 (m, 2 H), 4.59, 3.75–3.68 (m,
2 H), 3.47–3.43 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
152.2, 151.9, 149.6, 149.4, 147.6, 147.4, 145.1, 144.9, 138.2, 137.8,
137.3, 128.8, 128.5, 128.4, 128.0, 127.8, 121.9, 111.8, 111.6, 98.6,
IR (neat): ν = 3032, 2926, 2868, 1645, 1500, 1455, 1359, 1256, 1208,
˜
1154, 1102, 865, 698 cm–1. HRMS (ESI): calcd. for C32H29NO4F2
(M + 1)+ 530.2143; found 530.2142.
(1S,2S,3S,9bS)-1,2-Bis(benzyloxy)-3-(benzyloxymethyl)-6,9-dimeth-
yl-1,2,3,9b-tetrahydrobenzo[d]pyrrolo[1,2-b]isoxazole (30): Follow-
ing the general procedure, starting from nitrone 10 (50 mg,
0.12 mmol) and aryne precursor 20 (60 mg, 0.18 mmol), cycload-
duct 30 was obtained as a white solid (40 mg, 65%) after purifica-
tion by silica gel column chromatography (6% ethyl acetate/hex-
98.4, 87.8, 81.7, 73.6, 72.7, 71.6, 68.0 ppm. IR (neat): ν = 3030,
˜
2923, 2865, 1713, 1494, 1454, 1345, 1244, 1207, 1152, 1125, 1046,
1032, 866, 695 cm–1. HRMS (ESI): calcd. for C32H29NO4F2 (M +
1)+ 530.2143; found 530.2123.
(1S,2R,3S,9bS)-1,2-Bis(benzyloxy)-3-(benzyloxymethyl)-7,8-di-
fluoro-1,2,3,9b-tetrahydrobenzo[d]pyrrolo[1,2-b]isoxazole (27): Fol-
lowing the general procedure, starting from nitrone 13 (60 mg,
0.14 mmol) and aryne precursor 19 (70 mg, 0.18 mmol), cycload-
duct 27 was obtained as a white solid (60 mg, 79%) after purifica-
tion by silica gel column chromatography (6% ethyl acetate/hex-
anes). Rf = 0.5 (10 % ethyl acetate/hexanes); m.p. 123–124 °C.
anes). Rf = 0.5 (10% ethyl acetate/hexanes); m.p. 81–82 °C. [α]2D0
=
53.4 (c = 1.00, CHCl3). 1H NMR (400 MHz, CDCl3): δ = δ = 7.39–
7.26 (m, 10 H), 7.25–7.21 (m, 3 H), 7.08–7.06 (m, 2 H), 6.88 (d, J
= 7.5 Hz, 1 H), 6.61 (d, J = 7.5 Hz, 1 H), 4.98 (d, J = 3.0 Hz, 1
H), 4.70–4.57 (m, 4 H), 4.54, 4.47 (ABq, J = 11.5 Hz, 2 H), 4.31
(t, J = 3.4 Hz, 1 H), 4.26 (dd, J = 5.7, 3.8 Hz, 1 H), 3.79 (d, J =
5.3 Hz, 2 H), 3.72 (dd, J = 10.7, 5.3 Hz, 1 H), 2.16 (s, 3 H), 2.13
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 154.0, 138.3,
138.1, 137.7, 131.3, 130.2, 128.6, 128.5, 128.4, 128.0, 128.0, 127.8,
127.7, 127.6, 124.7, 123.0, 115.9, 86.9, 82.8, 73.6, 73.4, 72.5, 72.1,
1
[α]2D0 = 45.6 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ =
7.40–7.26 (m, 15 H), 6.75–6.71 (m, 1 H), 6.55 (dd, J = 10.0, 6.1 Hz,
1 H), 4.97 (d, J = 5.8 Hz, 1 H), 4.77–4.45 (m, 6 H), 4.24 (t, J =
4.1 Hz, 1 H), 4.01–3.97 (m, 2 H), 3.81 (dd, J = 9.3, 5.7 Hz, 1 H),
3.57–3.53 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 152.2,
152.1, 151.9, 151.8, 149.7, 149.6, 147.2, 147.1, 144.8, 144.7, 138.1,
138.1, 137.4, 128.8, 128.5, 128.5, 128.4, 128.1, 128.0, 128.0, 127.9,
127.9, 121.6, 121.6, 121.6, 121.5, 111.5, 111.3, 98.0, 97.8, 85.2, 76.7,
72.0, 68.7, 18.3, 15.2 ppm. IR (neat): ν = 3031, 2927, 2233, 1651,
˜
1405, 1260, 1041, 916, 700 cm–1. HRMS (ESI): calcd. for
C34H35NO4 (M + 1)+ 522.2644; found 522.2627.
(1S,2R,3S,9bS)-1,2-Bis(benzyloxy)-3-(benzyloxymethyl)-6,9-dimeth-
yl-1,2,3,9b-tetrahydrobenzo[d]pyrrolo[1,2-b]isoxazole (31): Follow-
ing the general procedure, starting from nitrone 13 (50 mg,
0.12 mmol) and aryne precursor 20 (60 mg, 0.18 mmol), cycload-
duct 31 was obtained as a white solid (50 mg, 80%) after purifica-
tion by silica gel column chromatography (6% ethyl acetate/hex-
anes). Rf = 0.5 (10 % ethyl acetate/hexanes); m.p. 110–111 °C.
74.1, 73.7, 72.8, 71.1, 71.0, 67.6 ppm. IR (neat): ν = 3032, 2922,
˜
2867, 2351, 1636, 1499, 1349, 1207, 1143, 1102, 924, 864, 696 cm–1.
HRMS (ESI): calcd. for C32H29NO4F2 (M + 1)+ 530.2143; found
530.2130.
(1R,2R,3R,9bR)-1,2-Bis(benzyloxy)-3-(benzyloxymethyl)-7,8-di-
fluoro-1,2,3,9b-tetrahydrobenzo[d]pyrrolo[1,2-b]isoxazole (28): Fol-
lowing the general procedure, starting from nitrone ent-10 (50 mg,
0.12 mmol) and aryne precursor 19 (60 mg, 0.18 mmol), cycload-
duct 28 was obtained as a white solid (60 mg, 94%) after purifica-
tion by silica gel column chromatography (6% ethyl acetate/hex-
anes). Rf = 0.5 (10 % ethyl acetate/hexanes); m.p. 118–119 °C.
1
[α]2D0 = 39.8 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ =
7.37–7.15 (m, 15 H), 6.87 (d, J = 7.5 Hz, 1 H), 6.60 (d, J = 7.5 Hz,
1 H), 5.07 (d, J = 5.5 Hz, 1 H), 4.70–4.44 (m, 6 H), 4.30 (t, J =
4.2 Hz, 1 H), 4.08–02 (m, 2 H), 3.90 (dd, J = 9.5, 6.0 Hz, 1 H),
3.74–3.70 (m, 1 H), 2.21 (s, 3 H), 2.13 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 154.4, 138.3, 138.3, 137.6, 131.6, 130.3,
128.6, 128.5, 128.5, 128.1, 128.0, 127.9, 127.8, 124.6, 122.7, 115.5,
1
[α]2D0 = –36.2 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ =
7.41–7.24 (m, 13 H), 7.13 (d, J = 3.0 Hz, 1 H), 7.11 (d, J = 1.9 Hz,
1 H), 6.75–6.71 (m, 1 H), 6.62 (dd, J = 9.9, 6.1 Hz, 1 H), 4.91 (s,
1 H), 4.67–4.53 (m, 6 H), 4.20–4.18 (m, 2 H), 3.75–3.68 (m, 2 H),
3.48–3.43 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 152.0,
151.9, 149.7, 149.6, 147.5, 147.3, 145.1, 144.9, 138.2, 137.8, 137.3,
128.8, 128.5, 128.5, 128.4, 128.0, 127.9, 127.8, 127.8, 121.9, 121.9,
121.8, 121.8, 111.8, 111.6, 98.6, 98.4, 87.8, 81.7, 73.6, 72.7, 72.7,
84.9, 73.8, 73.6, 72.5, 71.7, 71.0, 67.9, 18.6, 15.2 ppm. IR (neat): ν
˜
= 3029, 2916, 2860, 1587, 1497, 1454, 1365, 1308, 1257, 1202, 1138,
1029, 990, 695 cm–1. HRMS (ESI): calcd. for C34H35NO4 (M +
1)+ 522.2644; found 522.2628.
(1R,2R,3R,9bR)-1,2-Bis(benzyloxy)-3-(benzyloxymethyl)-6,9-di-
methyl-1,2,3,9b-tetrahydrobenzo[d]pyrrolo[1,2-b]isoxazole (32): Fol-
72.6, 71.6, 68.0 ppm. IR (neat): ν = 3029, 2922, 2856, 1645, 1493, lowing the general procedure, starting from nitrone ent-10 (50 mg,
˜
1454, 1316, 1245, 1208, 1152, 1095, 1046, 866, 695 cm–1. HRMS
0.12 mmol) and aryne precursor 20 (60 mg, 0.18 mmol), cycload-
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20685
/KAP1
Date: 10-09-12 10:50:28
Pages: 12
A Stereoselective Route to Aza-C-aryl Glycosides
duct 32 was obtained as a white solid (45 mg, 73%) after purifica-
1452, 1288, 1142, 1099, 1030, 696 cm–1. HRMS (ESI): calcd. for
C33H31NO6 (M + 1)+ 538.2230; found 538.2224.
tion by silica gel column chromatography (6% ethyl acetate/hex-
anes). Rf = 0.5 (10% ethyl acetate/hexanes); m.p. 82–83 °C. [α]2D0
=
Compound 36: Following the general procedure, starting from
nitrone ent-10 (40 mg, 0.10 mmol) and aryne precursor 21 (50 mg,
0.14 mmol), cycloadduct 36 was obtained as a white solid (40 mg,
78%) after purification by silica gel column chromatography (8%
ethyl acetate/hexanes). Rf = 0.45 (10% ethyl acetate/hexanes); m.p.
1
–62.7 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.39–
7.21 (m, 13 H), 7.08–7.06 (m, 2 H), 6.88 (d, J = 7.5 Hz, 1 H), 6.61
(d, J = 7.5 Hz, 1 H), 4.98 (d, J = 3.0 Hz, 1 H), 4.70–4.45 (m, 6 H),
4.31 (t, J = 3.3 Hz, 1 H), 4.25 (dd, J = 5.7, 3.8 Hz, 1 H), 3.79 (d,
J = 5.7 Hz, 2 H), 3.76–3.70 (m, 1 H), 2.16 (s, 3 H), 2.13 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 154.1, 138.3, 138.1,
137.8, 131.3, 130.2, 128.6, 128.5, 128.4, 128.0, 128.0, 127.8, 127.7,
127.6, 124.7, 123.0, 115.9, 87.0, 82.8, 73.6, 73.4, 72.5, 72.1, 72.0,
1
111–112 °C. [α]2D0 = –11.9 (c = 1.00, CHCl3). H NMR (400 MHz,
CDCl3): δ = 7.40–7.14 (m, 15 H), 6.46 (s, 1 H), 6.37 (s, 1 H), 5.91
(dd, J = 3.3, 1.3 Hz, 2 H), 4.88 (d, J = 2.2 Hz, 1 H), 4.69–4.52 (m,
6 H), 4.21–4.18 (m, 2 H), 3.76 (dd, J = 10.4, 4.3 Hz, 1 H), 3.70
(dd, J = 10.4, 4.1 Hz, 1 H), 3.45–3.40 (m, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 151.0, 148.6, 143.1, 138.4, 138.0, 137.6,
128.7, 128.5, 128.4, 128.2, 128.0, 127.9, 127.8, 127.7, 117.6, 103.1,
101.8, 92.2, 87.9, 81.6, 73.6, 72.8, 72.7, 72.5, 71.0, 68.1 ppm. IR
68.7, 18.3, 15.1 ppm. IR (neat): ν = 3030, 2921, 2872, 1587, 1454,
˜
1359, 1216, 1150, 1097, 1028, 967, 695 cm–1. HRMS (ESI): calcd.
for C34H35NO4 (M + 1)+ 522.2644; found 522.2629.
(1R,2R,3S,9bR)-1,2-Bis(benzyloxy)-3-(benzyloxymethyl)-6,9-di-
methyl-1,2,3,9b-tetrahydrobenzo[d]pyrrolo[1,2-b]isoxazole (33): Fol-
lowing the general procedure, starting from nitrone 14 (60 mg,
0.14 mmol) and aryne precursor 20 (72 mg, 0.22 mmol), cycload-
duct 33 was obtained as a colorless oil (45 mg, 60%) after purifica-
tion by silica gel column chromatography (6% ethyl acetate/hex-
anes). Rf = 0.5 (10% ethyl acetate/hexanes). [α]2D0 = 54.4 (c = 0.50,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.36–7.27 (m, 10 H),
7.26–7.21 (m, 3 H), 6.97–6.95 (m, 2 H), 6.88 (d, J = 7.5 Hz, 1 H),
6.59 (d, J = 7.5 Hz, 1 H), 5.24 (d, J = 4.6 Hz, 1 H), 4.65–4.55 (m,
4 H), 4.39, 4.27 (ABq, J = 12.0 Hz, 2 H), 4.17 (dd, J = 4.1, 0.8 Hz,
1 H), 4.11 (dd, J = 4.7, 0.8 Hz, 1 H), 3.98–3.94 (m, 2 H), 3.89–3.85
(m, 1 H), 2.14 (s, 3 H), 2.06 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 155.3, 138.4, 138.1, 137.7, 131.5, 130.2, 128.6, 128.5,
128.4, 128.0, 128.0, 127.9, 127.8, 127.7, 127.6, 121.6, 121.3, 114.9,
81.3, 81.3, 73.6, 73.0, 72.0, 72.0, 70.6, 67.8, 19.0, 15.3 ppm. IR
(neat): ν = 3021, 2923, 2852, 2139, 1645, 1450, 1250, 1149, 1118,
˜
1030, 692 cm–1. HRMS (ESI): calcd. for C33H31NO6 (M + 1)+
538.2230; found 538.2222.
Compound 37: Following the general procedure, starting from
nitrone 14 (50 mg, 0.12 mmol) and aryne precursor 21 (60 mg,
0.18 mmol), cycloadduct 37 was obtained as a colorless oil (35 mg,
55%) after purification by silica gel column chromatography (8%
ethyl acetate/hexanes). Rf = 0.45 (10% ethyl acetate/hexanes).
1
[α]2D0 = 15.2 (c = 0.25, CHCl3). H NMR (400 MHz, CDCl3): δ =
7.36–7.27 (m, 15 H), 7.18–7.16 (m, 15 H), 6.57 (s, 1 H), 6.35 (s, 1
H), 5.91 (m, 2 H), 5.13 (d, J = 5.8 Hz, 1 H), 4.62–4.38 (m, 6 H),
4.19 (dd, J = 5.8, 2.2 Hz, 1 H), 4.07 (dd, J = 5.2, 2.2 Hz, 1 H), 3.93
(t, J = 9.2 Hz, 1 H), 3.82 (dd, J = 9.2, 5.2 Hz, 1 H), 3.73–3.68 (m,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 151.0, 148.6, 143.1,
138.4, 138.0, 137.6, 128.7, 128.5, 128.4, 128.2, 128.0, 127.9, 127.8,
127.7, 117.6, 103.1, 101.8, 92.2, 87.9, 81.6, 73.6, 72.8, 72.7, 72.5,
(neat): ν = 3031, 2924, 2856, 1455, 1262, 1217, 1093, 1075, 1028,
˜
877, 697 cm–1. HRMS (ESI): calcd. for C34H35NO4 (M + 1)+
522.2644; found 522.2633.
71.0, 68.1 ppm. IR (neat): ν = 2950, 2923, 2853, 2137, 2098, 1642,
˜
1585, 1474, 1297, 1216, 1095, 1039, 698 cm–1. HRMS (ESI): calcd.
for C33H31NO6 (M + 1)+ 538.2230; found 538.2242.
Compound 34: Following the general procedure, starting from
nitrone 10 (40 mg, 0.10 mmol) and aryne precursor 21 (50 mg,
0.14 mmol), cycloadduct 34 was obtained as a white solid (40 mg,
78%) after purification by silica gel column chromatography (8%
ethyl acetate/hexanes). Rf = 0.45 (10% ethyl acetate/hexanes); m.p.
116–117 °C. [α]2D0 = 16.1 (c = 1.00, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.42–7.13 (m, 15 H), 6.46 (d, J = 0.7 Hz, 1 H), 6.37
(s, 1 H), 5.91 (dd, J = 3.3, 1.3 Hz, 2 H), 4.89 (d, J = 2.2 Hz, 1 H),
4.69–4.52 (m, 6 H), 4.21–4.18 (m, 2 H), 3.77 (dd, J = 10.4, 4.3 Hz,
General Procedure for N–O Bond Cleavage: Zn powder (40 mmol)
was added to benzo[d]isoxazoline (1 mmol) in AcOH/H2O (1:1,
30 mL) and the mixture was heated to 70 °C. After 2 h the mixture
was cooled to room temperature, filtered and washed with CH2Cl2.
The solvent was evaporated and ammonia solution (20 mL) and
CH2Cl2 (20 mL) were added. The aqueous layer was extracted with
CH2Cl2 (3ϫ20 mL) and the combined organic layers were dried
with anhydrous Na2SO4, filtered and concentrated under vacuum
to obtain the crude product, which was purified by basic alumina
flash column chromatography.
1 H), 3.70 (dd, J = 10.4, 4.1 Hz, 1 H), 3.45–3.41 (m, 1 H) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 151.0, 148.6, 143.1, 138.4, 138.1,
137.6, 128.7, 128.5, 128.4, 128.2, 128.0, 127.9, 127.8, 127.7, 117.6,
103.1, 101.8, 92.2, 87.9, 81.6, 73.6, 72.8, 72.7, 72.5, 71.0, 68.1 ppm.
2-((2S,3S,4S,5S)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)pyrrolidin-
2-yl)phenol (38): Following the general procedure, starting from cy-
cloadduct 12 (30 mg, 0.06 mmol) and Zn dust (157 mg, 2.4 mmol),
phenol 38 was obtained as a colorless oil (25 mg, 83%) after purifi-
cation by basic alumina column chromatography (10% ethyl acet-
IR (neat): ν = 3035, 2930, 1966, 1648, 1451, 1279, 1120, 1029,
˜
697 cm–1. HRMS (ESI): calcd. for C33H31NO6 (M + 1)+ 538.2230;
found 538.2220.
Compound 35: Following the general procedure, starting from ate/hexanes). Rf = 0.4 (10% ethyl acetate/hexanes). [α]2D0 = –34.2 (c
nitrone 13 (40 mg, 0.10 mmol) and aryne precursor 21 (50 mg,
0.14 mmol), cycloadduct 35 was obtained as a white solid (40 mg,
78%) after purification by silica gel column chromatography (8%
ethyl acetate/hexanes). Rf = 0.45 (10% ethyl acetate/hexanes); m.p.
105–106 °C. [α]2D0 = 26.4 (c = 1.00, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.39–7.24 (m, 15 H), 6.56 (s, 1 H), 6.30 (s, 1 H), 5.90
(s, 2 H), 4.95 (d, J = 5.4 Hz, 1 H), 4.77–4.51 (m, 6 H), 4.23 (t, J =
= 1.00, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.37–7.24 (m,
14 H), 7.22–7.13 (m, 3 H), 7.05 (dd, J = 7.5, 1.5 Hz, 1 H), 6.84
(dd, J = 8.1, 0.9 Hz, 1 H), 6.79 (td, J = 7.4, 1.0 Hz, 1 H), 4.57–
4.47 (m, 4 H), 4.40, 4.36 (ABq, J = 11.4 Hz, 2 H), 4.27–4.20 (m, 2
H), 3.86 (t, J = 4.2 Hz, 1 H), 3.57–3.47 (m, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 158.1, 138.0, 137.8, 137.7, 129.8, 129.1,
128.9, 128.7, 128.6, 128.5, 128.2, 128.1, 127.9, 127.9, 123.1, 120.7,
4.3 Hz, 1 H),4.02–3.98 (m, 2 H), 3.81 (dd, J = 9.0, 5.8 Hz, 1 H), 119.0, 117.3, 115.4, 88.4, 84.1, 73.3, 73.0, 72.1, 69.2, 64.9,
3.59–3.55 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 150.9, 60.2 ppm. IR (neat): ν = 3623, 3308, 3062, 3030, 2926, 2856, 1612,
˜
148.5, 142.8, 138.3, 138.2, 137.7, 128.7, 128.5, 128.4, 128.2, 128.1,
128.0, 127.9, 127.8, 117.1, 110.1, 102.9, 101.7, 9.5, 85.5, 74.0, 73.6,
1590, 1494, 1475, 1455, 1363, 1258, 1207, 1026, 909, 698 cm–1
.
HRMS (ESI): calcd. for C32H33NO4 (M + 1)+ 496.2488; found
496.2493.
72.7, 71.7, 70.7, 67.8 ppm. IR (neat): ν = 2920, 2852, 2125, 1634,
˜
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20685
/KAP1
Date: 10-09-12 10:50:28
Pages: 12
R. K. Khangarot, K. P. Kaliappan
FULL PAPER
2-[(2S,3S,4R,5S)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)pyrrolidin-
2-yl]phenol (39): Following the general procedure, starting from cy-
1 H), 7.15 (d, J = 1.6 Hz, 1 H), 6.79 (s, 1 H), 6.65 (s, 1 H), 4.58–
4.46 (m, 4 H), 4.44, 4.35 (ABq, J = 11.3 Hz, 2 H), 4.22–4.21 (m, 2
cloadduct 15 (30 mg, 0.06 mmol) and Zn dust (159 mg, 2.4 mmol), H), 3.85 (dd, J = 4.8, 3.1 Hz, 1 H), 3.54–3.48 (m, 3 H), 2.19 (s, 3
phenol 39 was obtained as a white solid (27 mg, 90%) after purifi-
H), 2.14 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 155.7,
cation by basic alumina column chromatography (10% ethyl acet-
138.1, 138.0, 137.8, 137.3, 129.9, 128.7, 128.6, 128.5, 128.1, 128.0,
ate/hexanes). Rf = 0.4 (10 % ethyl acetate/hexanes); m.p. 107– 127.9, 127.9, 127.9, 126.7, 120.2, 118.4, 88.7, 84.2, 73.3, 73.0, 72.1,
108 °C. [α]2D0 = –23.9 (c = 1.00, CHCl3). 1H NMR (400 MHz,
69.3, 64.6, 60.2, 19.7, 18.8 ppm. IR (neat): ν = 3430, 3020, 2927,
˜
CDCl3): δ = 7.37–7.24 (m, 14 H), 7.22–7.13 (m, 3 H), 7.08 (dd, J 2857, 1652, 1495, 1454, 1369, 1308, 1217, 1100, 1022, 668 cm–1.
= 8.2, 1.6 Hz, 1 H), 6.79 (s, 1 H), 6.77 (s, 1 H), 4.78 (d, J = 11.6 Hz,
1 H), 4.57–4.49 (m, 4 H), 4.48, 4.40 (ABq, J = 11.8 Hz, 2 H), 4.10
(t, J = 4.1 Hz, 1 H), 3.96 (dd, J = 7.8, 4.3 Hz, 1 H), 3.76–3.67 (m,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.2, 138.3, 138.0,
137.9, 128.9, 128.7, 128.6, 128.5, 128.5, 128.0, 128.0, 128.0, 127.9,
127.8, 127.7, 123.4, 119.0, 117.2, 84.9, 73.7, 73.5, 73.1, 68.6, 63.6,
HRMS (ESI): calcd. for C34H37NO4 (M + 1)+ 524.2801; found
524.2805.
2-[(2S,3S,4R,5S)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)pyrrolidin-
2-yl]-4,5-dimethylphenol (43): Following the general procedure,
starting from cycloadduct 23 (36 mg, 0.07 mmol) and Zn dust
(180 mg, 2.8 mmol), phenol 43 was obtained as a white solid
(33 mg, 91 %) after purification by basic alumina column
chromatography (10% ethyl acetate/hexanes). Rf = 0.4 (10% ethyl
acetate/hexanes); m.p. 137–138 °C. [α]2D0 = –14.0 (c = 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.36–7.21 (m, 14 H), 7.19 (d, J
= 2.8 Hz, 1 H), 7.17 (d, J = 1.8 Hz, 1 H), 6.81 (s, 1 H), 6.59 (s, 1
H), 4.76 (d, J = 2.8 Hz, 1 H), 4.57–4.40 (m, 6 H), 4.09 (t, J =
4.2 Hz, 1 H), 3.94 (dd, J = 7.4, 4.3 Hz, 1 H), 3.76–3.66 (m, 3 H),
2.18 (s, 3 H), 2.13 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 155.7, 138.4, 138.0, 136.9, 129.7, 128.6, 128.5, 128.4, 127.9, 127.9,
127.9, 127.8, 126.7, 120.5, 118.3, 85.3, 73.6, 73.5, 73.2, 68.6, 63.3,
57.9 ppm. IR (neat): ν = 3623, 3308, 3062, 3030, 2926, 2856, 1612,
˜
1590, 1494, 1475, 1455, 1363, 1258, 1207, 1026, 909, 698 cm–1
.
HRMS (ESI): calcd. for C32H33NO4 (M + 1)+ 496.2488; found
496.2481.
2-[(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)pyrrolid-
in-2-yl]phenol (40): Following the general procedure, starting from
cycloadduct 16 (50 mg, 0.10 mmol) and Zn dust (265 mg,
4.05 mmol), phenol 40 was obtained as a colorless oil (45 mg, 90%)
after purification by basic alumina column chromatography (10%
ethyl acetate/hexanes). Rf = 0.4 (10% ethyl acetate/hexanes). [α]2D0
58.0, 19.7, 18.8 ppm. IR (neat): ν = 3456, 3326, 3032, 3010, 2922,
˜
1
= 19.1 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.39–
2858, 2857, 1661, 1453, 1356, 1308, 1279, 1213, 1158, 1119, 1101,
1063, 1027, 801, 696, 668 cm–1. HRMS (ESI): calcd. for
C34H37NO4 (M + 1)+ 524.2801; found 524.2801.
7.20 (m, 14 H), 7.20–7.09 (m, 3 H), 7.06 (dd, J = 7.5, 1.6 Hz, 1 H),
6.84 (dd, J = 8.1, 1.1 Hz, 1 H), 6.79 (td, J = 7.5, 1.1 Hz, 1 H),
4.57–4.47 (m, 4 H), 4.40, 4.36 (ABq, J = 11.4 Hz, 2 H), 4.27–4.05
(m, 2 H), 3.86 (t, J = 4.2 Hz, 1 H), 3.62–3.45 (m, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 158.1, 138.0, 137.8, 137.7, 129.8,
129.1, 128.9, 128.7, 128.6, 128.5, 128.2, 128.1, 127.9, 127.9, 123.1,
119.1, 117.3, 115.4, 88.4, 84.1, 73.3, 73.0, 72.1, 69.2, 64.9,
2-[(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)pyrrolid-
in-2-yl]-4,5-dimethylphenol (44): Following the general procedure,
starting from cycloadduct 24 (40 mg, 0.08 mmol) and Zn dust
(200 mg, 3.06 mmol), phenol 44 was obtained as a colorless oil
(35 mg, 87 %) after purification by basic alumina column
chromatography (10% ethyl acetate/hexanes). Rf = 0.4 (10% ethyl
acetate/hexanes). [α]2D0 = 17.1 (c = 0.50, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.36–7.18 (m, 14 H), 7.17 (d, J = 2.0 Hz,
1 H), 7.16 (d, J = 1.6 Hz, 1 H), 6.79 (s, 1 H), 6.65 (s, 1 H), 4.57–
4.46 (m, 4 H), 4.45, 4.35 (ABq, J = 11.4 Hz, 2 H), 4.21–4.20 (m, 2
H), 3.85 (dd, J = 4.7, 3.1 Hz, 1 H), 3.55–3.48 (m, 3 H), 2.19 (s, 3
H), 2.14 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 155.7,
138.1, 138.0, 137.8, 137.3, 129.9, 128.7, 128.5, 128.5, 128.1, 128.0,
127.9, 127.9, 127.9, 126.7, 120.1, 118.4, 88.7, 84.2, 73.3, 73.0, 72.1,
60.2 ppm. IR (neat): ν = 3439, 3329, 3062, 3029, 2927, 2859, 1657,
˜
1589, 1494, 1473, 1454, 1364, 1258, 1217, 1094, 908, 698 cm–1
.
HRMS (ESI): calcd. for C32H33NO4 (M + 1)+ 496.2488; found
496.2480.
2-[(2R,3R,4R,5S)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)pyrrolid-
in-2-yl]phenol (41): Following the general procedure, starting from
cycloadduct 17 (30 mg, 0.06 mmol) and Zn dust (150 mg,
2.3 mmol), phenol 41 was obtained as a colorless oil (25 mg, 83%)
after purification by basic alumina column chromatography (10%
ethyl acetate/hexanes). Rf = 0.4 (10% ethyl acetate/hexanes). [α]2D0
69.3, 64.6, 60.2, 19.7, 18.8 ppm. IR (neat): ν = 3306, 3030, 2923,
˜
1
= 20.7 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.37–
2860, 2857, 1628, 1585, 1497, 1363, 1263, 1207, 1091, 1028, 877,
807, 698, 660 cm–1. HRMS (ESI): calcd. for C34H37NO4 (M + 1)+
524.2801; found 524.2820.
7.27 (m, 8 H), 7.24–7.19 (m, 3 H), 7.15 (td, J = 8.2, 1.6 Hz, 1 H),
6.95–6.93 (m, 2 H), 6.88 (dd, J = 7.5, 1.6 Hz, 1 H), 6.84 (dd, J =
8.2, 0.8 Hz, 1 H), 6.74 (dd, J = 7.4, 1.1 Hz, 1 H), 4.66 (d, J =
4.6 Hz, 1 H), 4.60–4.42 (m, 4 H), 4.1 (s, 2 H), 4.03 (dd, J = 4.8,
1.4 Hz, 1 H), 3.96–3.92 (m, 2 H), 3.71–3.62 (m, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 160.1, 138.0, 137.9, 137.9, 128.6,
128.6, 128.3, 128.1, 127.9, 127.9, 127.8, 127.7, 127.6, 120.7, 118.4,
117.1, 84.5, 82.3, 73.4, 72.5, 72.4, 68.1, 64.0, 58.6 ppm. IR (neat):
2-[(2R,3R,4R,5S)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)pyrrolid-
in-2-yl]-4,5-dimethylphenol (45): Following the general procedure,
starting from cycloadduct 25 (40 mg, 0.08 mmol) and Zn dust
(210 mg, 3.2 mmol), phenol 45 was obtained as a colorless oil
(35 mg, 87 %) after purification by basic alumina column
chromatography (10% ethyl acetate/hexanes). Rf = 0.4 (10% ethyl
acetate/hexanes). [α]2D0 = 28.4 (c = 0.50, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.36–7.19 (m, 14 H), 6.97–6.95 (m, 1 H),
6.65 (s, 1 H), 6.61 (s, 1 H), 4.59–4.41 (m, 5 H), 4.18 (s, 2 H), 4.02
(dd, J = 4.8, 1.4 Hz, 1 H), 3.92 (dd, J = 4.7, 1.4 Hz, 1 H), 3.70–
3.61 (m, 2 H), 2.20 (s, 3 H), 2.12 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 157.7, 138.1, 138.0, 136.8, 129.3, 128.6,
128.5, 128.3, 128.0, 127.9, 127.7, 127.6, 126.1, 118.2, 117.7, 84.4,
ν = 3445, 3328, 3060, 3030, 2924, 2857, 1657, 1590, 1494, 1470,
˜
1262, 1094, 698 cm–1. HRMS (ESI): calcd. for C32H33NO4 (M +
1)+ 496.2488; found 496.2490.
2-[(2S,3S,4S,5S)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)pyrrolidin-
2-yl]-4,5-dimethylphenol (42): Following the general procedure,
starting from cycloadduct 22 (42 mg, 0.08 mmol) and Zn dust
(235 mg, 3.6 mmol), phenol 42 was obtained as a colorless oil
(37 mg, 87 %) after purification by basic alumina column 82.4, 73.4, 72.4, 72.4, 68.2, 63.7, 58.6, 19.7, 18.8 ppm. IR (neat): ν
˜
chromatography (10% ethyl acetate/hexanes). Rf = 0.4 (10% ethyl
acetate/hexanes). [α]2D0 = –10.0 (c = 1.00, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.36–7.25 (m, 14 H), 7.17 (d, J = 2.2 Hz,
= 3366, 3027, 2927, 2856, 1788, 1748, 1663, 1454, 1217, 1095, 941,
825, 698, 669 cm–1. HRMS (ESI): calcd. for C34H37NO4 (M + 1)+
524.2801; found 524.2797.
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20685
/KAP1
Date: 10-09-12 10:50:28
Pages: 12
A Stereoselective Route to Aza-C-aryl Glycosides
2-[(2S,3S,4S,5S)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)pyrrolidin-
2-yl]-4,5-difluorophenol (46): Following the general procedure,
starting from cycloadduct 26 (30 mg, 0.06 mmol) and Zn dust
(157 mg, 2.4 mmol), phenol 46 was obtained as a colorless oil
4.50 (m, 3 H), 4.50, 4.46 (ABq, J = 11.9 Hz, 2 H), 4.27, 4.17 (ABq,
J = 12.3 Hz, 2 H), 4.00 (dd, J = 4.6, 1.4 Hz, 1 H), 3.93–3.90 (m, 1
H); 3.88 (dd, J = 4.5, 1.4 Hz, 1 H), 3.69 (dd, J = 9.7, 5.6 Hz, 1 H),
4.00 (dd, J = 9.7, 8.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
(24 mg, 80 %) after purification by basic alumina column δ = 156.7, 156.6, 151.2, 151.0, 148.7, 148.6, 144.4, 144.3, 142.1,
chromatography (10% ethyl acetate/hexanes). Rf = 0.4 (10% ethyl
142.0, 137.9, 137.8, 137.6, 128.7, 128.6, 128.4, 128.2, 128.0, 127.9,
127.9, 127.8, 127.77, 116.2, 115.9, 115.7, 105.8, 105.6, 84.1, 81.7,
acetate/hexanes). [α]2D0 = –27.8 (c = 1.00, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.38–7.24 (m, 14 H), 7.17–7.15 (m, 2 H), 73.50, 72.6, 72.5, 68.1, 63.5, 58.9 ppm. IR (neat): ν = 3466, 3328,
˜
6.79 (dd, J = 10.8, 8.8 Hz, 1 H), 6.60 (dd, J = 11.8, 7.0 Hz, 1 H),
4.55–4.37 (m, 6 H), 4.16–4.11 (m, 2 H), 3.85 (t, J = 3.5 Hz, 1 H),
3064, 3031, 2924, 2857, 1623, 1520, 1496, 1454, 1396, 1363, 1279,
1151, 1111, 1028, 698 cm–1. HRMS (ESI): calcd. for C32H31NO4F2
3.54–3.47 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 154.6, (M + 1)+ 532.2299; found 532.2301.
154.4, 149.1, 148.9, 147.0, 146.8, 144.7, 144.6, 142.4, 142.3, 137.8,
2-[(2S,3S,4S,5S)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)pyrrolidin-
137.6, 137.5, 129.8, 129.5, 128.7, 128.6, 128.6, 128.5, 128.5, 128.2,
128.1, 128.1, 127.9, 127.9, 127.9, 127.4, 121.9, 118.5, 116.6, 116.5,
106.2, 106.0, 88.4, 83.9, 73.4, 73.1, 72.3, 68.9, 64.1, 60.3 ppm. IR
2-yl]-3,6-dimethylphenol (50): Following the general procedure,
starting from cycloadduct 30 (23 mg, 0.04 mmol) and Zn dust
(115 mg, 1.7 mmol), phenol 50 was obtained as a colorless oil
(18 mg, 78 %) after purification by basic alumina column
chromatography (10% ethyl acetate/hexanes). Rf = 0.4 (10% ethyl
acetate/hexanes). [α]2D0 = –28.4 (c = 1.00, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 12.08 (s, 1 H), 7.36–7.25 (m, 10 H), 7.25–
7.21 (m, 3 H), 7.09–7.07 (m, 3 H), 6.94 (d, J = 7.5 Hz, 1 H), 6.55
(d, J = 7.5 Hz, 1 H), 4.62–4.56 (m, 3 H), 4.56, 4.49 (ABq, J =
11.9 Hz, 1 H), 4.37–4.30 (m, 3 H), 3.82 (dd, J = 5.1, 3.6 Hz, 1 H),
(neat): ν = 3736, 3324, 3027, 2927, 2855, 1628, 1516, 1364, 1215,
˜
1094, 875, 698 cm–1. HRMS (ESI): calcd. for C32H31NO4F2 (M +
1)+ 532.2299; found 532.2302.
2-[(2S,3S,4R,5S)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)pyrrolidin-
2-yl]-4,5-difluorophenol (47): Following the general procedure,
starting from cycloadduct 27 (30 mg, 0.06 mmol) and Zn dust
(156 mg, 2.4 mmol), phenol 47 was obtained as a white solid
(20 mg, 67 %) after purification by basic alumina column 3.62–3.58 (m, 1 H), 3.53 (t, J = 9.4 Hz, 1 H), 3.47 (dd, J = 9.4,
chromatography (10% ethyl acetate/hexanes). Rf = 0.4 (10% ethyl
4.2 Hz, 1 H), 2.26 (s, 3 H), 2.19 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 156.9, 138.1, 138.0, 137.8, 134.7, 129.8, 128.7, 128.5,
acetate/hexanes); m.p. 94–95 °C. [α]2D0 = –21.1 (c = 0.50, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.37–7.25 (m, 14 H), 7.18–7.15 128.4, 128.1, 127.9, 127.9, 127.8, 127.8, 127.7, 123.9, 120.8, 120.8,
(m, 2 H), 6.84 (dd, J = 11.0, 9.0 Hz, 1 H), 6.54 (dd, J = 11.9,
7.0 Hz, 1 H), 4.78 (d, J = 11.6 Hz, 1 H), 4.57–4.36 (m, 6 H), 4.06
(t, J = 4.0 Hz, 1 H), 3.88 (dd, J = 8.3, 4.0 Hz, 1 H), 3.69–3.61 (m,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 154.6, 154.5, 148.8,
148.7, 142.4, 138.1, 137.8, 137.4, 128.7, 128.6, 128.1, 128.1, 128.1,
128.0, 128.0, 127.9, 118.7, 116.6, 116.4, 106.0, 105.8, 85.1, 76.5,
88.6, 83.9, 73.3, 73.2, 72.0, 69.6, 59.7, 59.6, 20.1, 15.8 ppm. IR
(neat): ν = 3321, 3063, 3031, 2924, 2859, 1620, 1585, 1454, 1361,
˜
1270, 1206, 1095, 1028, 909, 801 cm–1. HRMS (ESI): calcd. for
C34H37NO4 (M + 1)+ 524.2801; found 524.2801.
2-[(2S,3S,4R,5S)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)pyrrolidin-
2-yl]-3,6-dimethylphenol (51): Following the general procedure,
starting from cycloadduct 31 (30 mg, 0.06 mmol) and Zn dust
(156 mg, 2.4 mmol), phenol 51 was obtained as a white solid
(26 mg, 86 %) after purification by basic alumina column
chromatography (10% ethyl acetate/hexanes). Rf = 0.4 (10% ethyl
acetate/hexanes); m.p. 119–120 °C. [α]2D0 = –41.4 (c = 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 12.69 (s, 1 H), 7.36–7.25 (m, 10
H), 7.09–7.05 (m, 3 H), 7.09 (d, J = 3.7 Hz, 1 H), 7.08 (d, J =
2.1 Hz, 1 H), 6.92 (d, J = 7.6 Hz, 1 H), 6.55 (d, J = 7.6 Hz, 1 H),
73.8, 73.6, 73.4, 68.5, 68.1, 62.6, 58.0 ppm. IR (neat): ν = 3336,
˜
3027, 2924, 2853, 1623, 1519, 1495, 1456, 1336, 1215, 1119,
698 cm–1. HRMS (ESI): calcd. for C32H31NO4F2 (M + 1)+
532.2299; found 532.2298.
2-[(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)pyrrolid-
in-2-yl]-4,5-difluorophenol (48): Following the general procedure,
starting from cycloadduct 28 (30 mg, 0.06 mmol) and Zn dust
(157 mg, 2.4 mmol), phenol 48 was obtained as a colorless oil
(20 mg, 67 %) after purification by basic alumina column 4.86 (d, J = 7.9 Hz, 1 H), 4.59–4.47 (m, 4 H), 4.36 (d, J = 11.7 Hz,
chromatography (10% ethyl acetate/hexanes). Rf = 0.4 (10% ethyl
1 H), 4.15 (t, J = 4.4 Hz, 1 H), 4.07 (dd, J = 8.0, 4.4 Hz, 1 H),
3.78–3.74 (m, 2 H), 3.71–3.67 (m, 1 H), 2.29 (s, 3 H), 2.16 (s, 3
acetate/hexanes). [α]2D0 = 10.4 (c = 1.00, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.37–7.26 (m, 14 H), 7.17–7.15 (m, 2 H), H) ppm. 13C NMR (100 MHz, CDCl3): δ = δ = 157.0, 138.5, 138.2,
6.79 (dd, J = 10.8, 8.8 Hz, 1 H), 6.60 (dd, J = 11.8, 7.0 Hz, 1 H),
4.55–4.37 (m, 6 H), 4.16–4.11 (m, 2 H), 3.85 (t, J = 3.5 Hz, 1 H),
138.0, 135.0, 129.5, 128.6, 128.5, 128.4, 128.0, 127.9, 127.8, 127.6,
127.5, 123.7, 121.1, 120.7, 84.7, 77.6, 73.7, 73.4, 73.3, 68.6, 59.2,
3.54–3.48 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 154.6, 57.3, 20.0, 15.7 ppm. IR (neat): ν = 3290, 3030, 2923, 2858, 2697,
˜
154.4, 148.9, 147.0, 137.8, 137.6, 137.5, 128.7, 128.6, 128.6, 128.2,
128.1, 128.1, 128.0, 118.5, 116.7, 116.5, 106.2, 106.0, 88.5, 83.9,
2321, 1725, 1581, 1454, 1367, 1311, 1268, 1210, 1115, 1094, 801,
697 cm–1. HRMS (ESI): calcd. for C34H37NO4 (M + 1)+ 524.2821;
73.4, 73.1, 72.3, 68.9, 64.1, 60.3 ppm. IR (neat): ν = 3401, 3318, found 524.2801.
˜
3027, 2924, 2854, 2853, 2346, 1666, 1517, 1455, 1215, 1095,
2-[(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)pyrrolid-
698 cm–1. HRMS (ESI): calcd. for C32H31NO4F2 (M + 1)+
532.2299; found 532.2294.
in-2-yl]-3,6-dimethylphenol (52): Following the general procedure,
starting from cycloadduct 32 (42 mg, 0.08 mmol) and Zn dust
(210 mg, 3.2 mmol), phenol 52 was obtained as a colorless oil
(37 mg, 88 %) after purification by basic alumina column
chromatography (10% ethyl acetate/hexanes). Rf = 0.4 (10% ethyl
acetate/hexanes). [α]2D0 = 27.3 (c = 1.00, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 12.06 (d, J = 6.5 Hz, 1 H), 7.37–7.20 (m,
13 H), 7.09 (d, J = 2.6 Hz, 1 H), 7.07 (d, J = 2.8 Hz, 1 H), 6.95 (d,
J = 7.6 Hz, 1 H), 6.55 (d, J = 7.6 Hz, 1 H), 4.62–4.55 (m, 4 H),
2-[(2R,3R,4R,5S)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)pyrrolid-
in-2-yl]-4,5-difluorophenol (49): Following the general procedure,
starting from cycloadduct 29 (20 mg, 0.04 mmol) and Zn dust
(99 mg, 1.5 mmol), phenol 49 was obtained as a white solid (17 mg,
85%) after purification by basic alumina column chromatography
(10% ethyl acetate/hexanes). Rf = 0.4 (10% ethyl acetate/hexanes);
m.p. 91–92 °C. [α]2D0 = 28.6 (c = 1.00, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.37–7.27 (m, 8 H), 7.25–7.22 (m, 6 H), 6.98–6.95 (m, 4.48 (d, J = 11.9 Hz, 1 H), 4.37–4.29 (m, 3 H), 3.83 (dd, J = 5.1,
2 H), 6.61 (dd, J = 12.3, 7.0 Hz, 1 H), 6.57–6.55 (m, 1 H), 4.59– 3.6 Hz, 1 H), 3.63–3.59 (m, 1 H), 3.54 (t, J = 9.5 Hz, 1 H), 3.48
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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/KAP1
Date: 10-09-12 10:50:28
Pages: 12
R. K. Khangarot, K. P. Kaliappan
(dd, J = 9.5, 4.3 Hz, 1 H), 2.26 (s, 3 H), 2.19 (s, 3 H) ppm. 13C dust (146 mg, 2.24 mmol), phenol 56 was obtained as a colorless
FULL PAPER
NMR (100 MHz, CDCl3): δ = 156.9, 138.1, 138.0, 137.8, 134.7,
129.8, 128.7, 128.5, 128.4, 128.1, 127.9, 127.9, 127.8, 127.8, 127.7,
123.9, 120.8, 88.6, 83.9, 73.3, 73.2, 72.0, 69.6, 59.7, 20.1, 15.8 ppm.
oil (18 mg, 60 %) after purification by basic alumina column
chromatography (15% ethyl acetate/hexanes). Rf = 0.35 (10% ethyl
acetate/hexanes). [α]2D0 = 18.5 (c = 0.25, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.38–7.26 (m, 14 H), 7.24–7.17 (m, 2 H),
6.51 (s, 1 H), 6.41 (s, 1 H), 5.87 (dd, J = 4.1, 1.3 Hz, 1 H), 4.69 (s,
1 H), 4.55–4.41 (m, 5 H), 4.18 (dd, J = 7.6, 4.6 Hz, 1 H), 4.12 (d,
J = 7.6 Hz, 1 H), 3.82 (t, J = 4.6 Hz, 1 H), 3.53–3.47 (m, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 153.3, 147.8, 140.1, 138.0, 137.8,
137.7, 128.7, 128.6, 128.6, 128.5, 128.3, 128.1, 127.9, 127.8, 127.8,
127.1, 114.1, 108.2, 100.9, 99.5, 88.5, 84.0, 73.3, 73.1, 72.1, 69.2,
IR (neat): ν = 3324, 3030, 2924, 2857, 1615, 1585, 1454, 1361, 1311,
˜
1270, 1207, 1090, 1072, 1028, 801, 698 cm–1. HRMS (ESI): calcd.
for C34H37NO4 (M + 1)+ 524.2801; found 524.2791.
2-[(2R,3R,4R,5S)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)pyrrolid-
in-2-yl]-3,6-dimethylphenol (53): Following the general procedure,
starting from cycloadduct 33 (25 mg, 0.05 mmol) and Zn dust
(130 mg, 2.0 mmol), phenol 53 was obtained as a colorless oil
(21 mg, 84 %) after purification by basic alumina column
chromatography (10% ethyl acetate/hexanes). Rf = 0.4 (10% ethyl
acetate/hexanes). [α]2D0 = 15.6 (c = 1.00, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.37–7.26 (m, 9 H), 7.24–7.17 (m, 5 H),
6.94–6.89 (m, 3 H), 6.47 (d, J = 7.5 Hz, 1 H), 4.84 (d, J = 4.5 Hz,
1 H), 4.58, 4.52 (ABq, J = 12.0 Hz, 2 H), 4.48 (s, 2 H), 4.11, 4.03
(ABq, J = 12.3 Hz, 2 H), 4.04 (d, J = 1.5 Hz, 1 H), 3.99 (dd, J =
4.5, 1.5 Hz, 1 H), 3.96–3.93 (m, 1 H), 3.71–3.62 (m, 2 H), 2.19 (s,
3 H), 2.04 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.9,
138.1, 138.0, 138.0, 133.1, 129.4, 128.7, 128.6, 128.3, 128.1, 127.9,
127.8, 127.8, 127.6, 123.8, 119.9, 117.8, 82.7, 81.6, 73.3, 72.6, 72.3,
64.8, 60.0 ppm. IR (neat): ν = 3736, 3365, 2926, 2857, 1749, 1650,
˜
1477, 1363, 1215, 1155, 945, 697 cm–1. HRMS (ESI): calcd. for
C33H33NO6 (M + 1)+ 540.2386; found 540.2375.
6-[(2R,3R,4R,5S)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)pyrrolid-
in-2-yl]benzo[d][1,3]dioxol-5-ol (57): Following the general pro-
cedure, starting from cycloadduct 37 (30 mg, 0.06 mmol) and Zn
dust (157 mg, 2.4 mmol), phenol 57 was obtained as a colorless oil
(23 mg, 77 %) after purification by basic alumina column
chromatography (15% ethyl acetate/hexanes). Rf = 0.35 (10% ethyl
acetate/hexanes). [α]2D0 = 1.4 (c = 1.0, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.36–7.20 (m, 17 H), 7.05–7.02 (m, 1 H), 6.55 (s, 1 H),
6.42 (s, 1 H), 5.88 (dd, J = 4.4, 1.4 Hz, 2 H), 4.58–4.37 (m, 5 H),
4.21 (s, 1 H), 4.06–4.00 (m, 2 H), 3.94 (dd, J = 5.5, 1.8 Hz, 1 H),
3.79 (dd, J = 9.4, 4.3 Hz, 1 H), 4.07 (t, J = 9.4 Hz, 1 H), 3.58–3.54
(m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 152.8, 147.8,
140.2, 138.2, 138.1, 137.7, 128.6, 128.5, 128.0, 127.9, 127.9, 127.8,
127.8, 127.7, 108.1, 100.9, 100.1, 99.5, 89.18, 73.8, 72.6, 71.4, 70.2,
67.9, 60.5, 58.1, 19.6, 16.0 ppm. IR (neat): ν = 3460, 2925, 2857,
˜
1617, 1454, 1270, 1217, 1092, 1028, 699 cm–1. HRMS (ESI): calcd.
for C34H37NO4 (M + 1)+ 524.2801; found 524.2794.
6-[(2S,3S,4S,5S)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)pyrrolidin-
2-yl]benzo[d][1,3]dioxol-5-ol (54): Following the general procedure,
starting from cycloadduct 34 (30 mg, 0.06 mmol) and Zn dust
(146 mg, 2.24 mmol), phenol 54 was obtained as a colorless oil
(16 mg, 53 %) after purification by basic alumina column
chromatography (15% ethyl acetate/hexanes). Rf = 0.35 (10% ethyl
acetate/hexanes). [α]2D0 = 5.76 (c = 0.25, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.51–7.26 (m, 14 H), 7.19–7.17 (m, 2 H),
6.51 (s, 1 H), 6.41 (s, 1 H), 5.87 (dd, J = 4.0, 1.2 Hz, 1 H), 4.55–
4.42 (m, 6 H), 4.18 (dd, J = 7.6, 4.6 Hz, 1 H), 4.12 (d, J = 7.6 Hz,
1 H), 3.82 (t, J = 4.6 Hz, 1 H), 3.53–3.45 (m, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 153.1, 147.3, 139.9, 138.1, 137.7, 137.7,
128.4, 128.3, 128.3, 127.8, 127.8, 127.7, 127.7, 127.6, 114.2, 107.9,
100.6, 99.1, 84.7, 73.5, 73.3, 73.0, 68.4, 63.3, 57.6 ppm. IR (neat):
67.7, 60.3 ppm. IR (neat): ν = 3323, 3029, 2924, 2854, 2137, 1631,
˜
1476, 1455, 1361, 1215, 1185, 1093, 1039, 860, 698 cm–1. HRMS
(ESI): calcd. for C33H33NO6 (M + 1)+ 540.2386; found 540.2386.
(2R,3R,4R,5R)-2-(Hydroxymethyl)-5-(2-hydroxyphenyl)pyrrolidine-
3,4-diol (58): A solution of compound 40 (75 mg, 0.15 mmol) in
3 mL of anhydrous CH2Cl2 is cooled to 0 °C and then BBr3
(113 mg, 0.45 mmol, 1 m solution in CH2Cl2) was added dropwise.
The mixture was warmed to room temperature for 0.5 h before
quenching with distilled water. The mixture was filtered and con-
centrated under vacuum to get the crude product. The crude com-
pound was purified by basic resin to obtain polyhydroxy-pyrrol-
idine 58 as a white solid (30 mg, 88%). Rf = 0.2 (10% methanol/
ethyl acetate). [α]2D0 = 21.8 (c = 2.0, H2O); m.p. 130–131 °C. 1H
NMR (400 MHz, D2O): δ = 6.89–6.82 (m, 2 H), 6.51–6.46 (m, 2
H), 4.18 (dd, J = 9.6, 8.1 Hz, 1 H), 3.98 (d, J = 9.6 Hz, 1 H), 3.69
(t, J = 8.2 Hz, 1 H), 3.51–3.46 (m, 2 H), 3.42–3.35 (m, 1 H) ppm.
13C NMR (100 MHz, D2O): δ = 155.0, 131.5, 130.2, 120.5, 118.4,
ν = 3730, 3390, 3027, 2961, 2928, 2857, 1732, 1454, 1374, 1283,
˜
1218, 1166, 1113, 953, 697 cm–1. HRMS (ESI): calcd. for
C33H33NO6 (M + 1)+ 540.2386; found 540.2385.
6-[(2S,3S,4R,5S)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)pyrrolidin-
2-yl]benzo[d][1,3]dioxol-5-ol (55): Following the general procedure,
starting from cycloadduct 35 (30 mg, 0.05 mmol) and Zn dust
(146 mg, 2.24 mmol), phenol 55 was obtained as a white solid
(25 mg, 83 %) after purification by basic alumina column
chromatography (15% ethyl acetate/hexanes). Rf = 0.35 (10% ethyl
acetate/hexanes); m.p. 93–94 °C. [α]2D0 = –17.9 (c = 0.40, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.40–7.26 (m, 14 H), 7.20–7.18
(m, 2 H), 6.54 (s, 1 H), 6.35 (s, 1 H), 5.86 (dd, J = 6.0, 1.4 Hz, 2
H), 4.76 (d, J = 11.6 Hz, 1 H), 4.56–4.45 (m, 6 H), 4.07 (t, J =
4.1 Hz, 1 H), 3.71–3.64 (m, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 153.3, 147.5, 140.1, 138.3, 137.9, 137.9, 128.6, 128.5,
128.5, 128.0, 128.0, 127.9, 127.9, 127.8, 114.4, 108.1, 100.8, 99.3,
116.1, 76.3, 73.8, 62.5, 61.3, 57.5 ppm. IR (neat): ν = 3497, 2870,
˜
2714, 1650, 1465, 1374, 1211, 1045, 921, 828, 770 cm–1. HRMS
(ESI): calcd. for C11H15NO4 (M + 1)+ 226.1079; found 226.1079.
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data including 1H and 13C NMR spectra for
all the compounds.
Acknowledgments
85.0, 73.7, 73.5, 73.2, 68.6, 63.5, 57.8 ppm. IR (neat): ν = 3337,
˜
3030, 2925, 2856, 2139, 1632, 1477, 1455, 1365, 1247, 1215, 1182,
1151, 1089, 1039, 865, 698 cm–1. HRMS (ESI): calcd. for
C33H33NO6 (M + 1)+ 540.2386; found 540.2386.
We thank the Department of Science and Technology (DST), New
Delhi for financial support. K. P. K. thanks the DST for the award
of a Swarnajayanti fellowship, and AstraZeneca Research Founda-
tion for partial financial support. R. K. K. thanks the Council of
Scientific and Industrial Research (CSIR), New Delhi for a fellow-
ship.
6-[(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)pyrrolid-
in-2-yl]benzo[d][1,3]dioxol-5-ol (56): Following the general pro-
cedure, starting from cycloadduct 36 (30 mg, 0.05 mmol) and Zn
10
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20685
/KAP1
Date: 10-09-12 10:50:28
Pages: 12
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Received: May 21, 2012
Published Online: ᭿
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11

Job/Unit: O20685
/KAP1
Date: 10-09-12 10:50:28
Pages: 12
R. K. Khangarot, K. P. Kaliappan
FULL PAPER
Dipolar Cycloaddition Reactions
R. K. Khangarot,
K. P. Kaliappan* ............................. 1–12
A Stereoselective Route to Aza-C-aryl Gly-
cosides from Arynes and Chiral Nitrones
An efficient strategy for the synthesis of a
variety of aza-C-aryl glycosides is de-
scribed. This strategy involves a stereo-
selective 1,3-dipolar cycloaddition reaction
between arynes and sugar-derived cyclic
nitrones followed by reductive N–O bond
cleavage and removal of benzyl groups.
Keywords: Glycosides / Cycloaddition / Ni-
trogen heterocycles
Arynes
/ Cyclic nitrones /
12
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