Solvent and catalyst free route to 3-indolyl glycoconjugates: Synthesis of sugar tethered isoxazolines and isoxazoles from 3-indolyl nitroalkanes

Article abstract of DOI:10.1039/c4ra02825b

An expedient, solvent and catalyst free strategy for the synthesis of sugar based bis(indolyl)methanes and indolyl nitroalkanes has been developed. The protocol works well within a wide range of substrates, and tolerates various N/O protecting groups. The

Full text of DOI:10.1039/c4ra02825b

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Solvent and catalyst free route to 3-indolyl
glycoconjugates: synthesis of sugar tethered
isoxazolines and isoxazoles from 3-indolyl
nitroalkanes†
Cite this: RSC Adv., 2014, 4, 27988
a
a
a
K. Karthikeyan,ab R. Senthil Kumar, P. Dheenkumar and Paramasivan T. Perumal
*
An expedient, solvent and catalyst free strategy for the synthesis of sugar based bis(indolyl)methanes and
indolyl nitroalkanes has been developed. The protocol works well within a wide range of substrates, and
tolerates various N/O protecting groups. The sugar tethered nitroalkanes were converted to the
corresponding nitrile oxides, and subsequently transformed to novel isoxazolines and isoxazoles by
cycloaddition with appropriate dipolarophiles.
Received 31st March 2014
Accepted 5th June 2014
DOI: 10.1039/c4ra02825b
www.rsc.org/advances
attractive scaffolds due to the synthetic versatility of nitro
groups.12,13 Indole is commonly used for Michael addition
Introduction
because many of its derivatives are found in nature and have
versatile biological activity.14 Traditionally, Michael addition of
indole to nitro alkenes is catalyzed by strong bases and
Brønsted acids.15 Recently, Lewis acids have been used to
catalyze Michael addition with high yields.16
Since both indoles and carbohydrates display useful bio-
logical activities, any synthesis that couples both indole and
carbohydrate scaffolds will be quite interesting in the antici-
pation of the biological properties of the resultant product.
At the beginning of the new century, it was widely acknowledged
that there is a growing need for the development of environ-
mentally benign processes in the chemical industry.1,2 Many
traditional organic solvents are volatile and are ecologically
harmful. Hence, non conventional reaction media for chemical
reactions are oen highly sought aer alternatives. These
include neat reaction, water, ionic liquids, eutectic melts,
though the neat reaction is thus far proved to be the best.1
Solvent-free reactions have several advantages such as reduced
pollution, lower cost, operational safety, etc.3 Due to its non-
toxicity, non-ammability and abundant availability, water is
the generally preferred alternative.4 However, lower solubility of
reactants oen makes water-mediated reactions less yielding.
Reaction under neat condition eliminates this issue because the
reacting species are directly in contact, leading to more effective
collision. Thus, yields are oen superior when compared with
water or even conventional organic solvents as the media.
The 3-substituted indole moiety is ubiquitous in natural
products and possesses signicant biological properties.5–9
Various synthetic strategies assisted by protic and Lewis acids,
ionic liquids, ion exchange resin and rare earth metal have been
described in the literature for bis(indolyl)methanes.10 Michael
addition is one of the most atom economic reactions in organic
synthesis.11 Among the Michael acceptors, nitro olens are very
Results and discussion
In continuation of our studies in the eld of heterocyclic
chemistry,17 we herein report the synthesis of novel 3-indolyl
glycoconjugates, sugar-based isoxazolines and isoxazoles.
Synthesis of sugar tethered bis(indolyl)methanes
When indole 1a (2 mmol) was treated with the aldehyde 2a
(1 mmol) in solvents such as acetonitrile, chloroform,
bis(indolyl)methane was not formed. With the use of Lewis or
Brønsted acid catalyst, the desired product was obtained in poor
yields. This may be attributed to the partial quenching of the
acid catalyst by the multi oxygenated carbohydrate aldehyde. To
circumvent the abovementioned problem, the reaction was
attempted in the absence of catalyst and under neat conditions.
aOrganic Chemistry Division, CSIR-Central Leather Research Institute, Adyar, At room temperature and stirring for 5–6 hours, the bis(indolyl)
Chennai, 600 020, India. E-mail: ptperumal@gmail.com; Fax: +91 44 24911539;
methane 3a was obtained in 20% yield, and unreacted starting
Tel: +91 44 24437223
materials accounted for the remainder of the mixture. However,
bDepartment of Chemistry, B. S. Abdur Rahman University, Vandalur, Chennai-600
when the temperature of the reaction increased to 70 ꢀC, the
048, India
yield of 3a increased to a maximum of 94% (Scheme 1). To
gauge the scope of this methodology, a variety of substituted
indoles 1a–j were reacted with the aldehydes 2a, b, and the
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectrum of all compounds and NOESY spectrum of compounds 7d and 8d. See
DOI: 10.1039/c4ra02825b
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their individual moieties, would be anticipated to display useful
biological properties, and hence might serve as attractive
targets for medicinal chemists in drug discovery. With the
abovementioned objective in mind, we prepared a suitable
Michael acceptor starting from D-glucose,19 and studied its
Michael addition with various indoles. Literature report reveals
numerous procedures using either Lewis or Brønsted acid as
catalysts for the Michael addition of indoles to electron de-
cient olens. However, the use of Lewis acids, such as indium
trichloride, indium triate, bismuth trichloride, for model
reactions did not yield the desired adduct probably because of
the deactivation of Lewis acids by the multioxygenated carbo-
hydrate moiety, as mentioned earlier. On the other hand,
Brønsted acid catalysed reactions were attempted but the
desired adducts were obtained in low yield because of the acidic
pH of the medium, which favours the acetal cleavage of the
sugar moiety. Encouraged by the bis(indolyl) methane protocol,
we subsequently attempted the reaction under neat conditions
in the absence of a catalyst. The reaction at room temperature
did not give the product. However, when heated to 70 ꢀC the
desired Michael adducts were obtained in good to excellent
yield. The reaction was highly stereoselective and only the
D-gluco isomers were obtained in all the cases (Scheme 2 and
Table 2). The stereochemistry of the products was assigned
from NMR characterization and correlation with our earlier
work.20
Scheme 1 Synthesis of bis(indolyl)methanes.
corresponding bis(indolyl)methanes were obtained in good to
excellent yields (3a–l, Table 1). The nature of the substitution on
the indole ring showed some effect on product yields and
reactions times. Unsubstituted indole gave a maximum of 94%
yield, whereas the relatively deactivated counterparts, namely
the 5-bromo and 5-cholor derivatives, gave 82% and 83% of the
corresponding bis(indolyl)methanes, respectively. With
N-substituted indoles such as N-Me, N-propargyl and N-Et, the
yield of bis(indolyl)methanes were around 90%.
Michael addition of indoles to sugar derived nitrovinyl
Carbohydrate derived chiral Michael acceptors were used in the
conjugate addition of carbon and hetero nucleophiles for the
synthesis of various amino, thio and carbasugars.18 However,
the addition of heteroaromatics, such as indole, pyrrole, to such
chiral Michael acceptors are not much explored. Such adducts,
considering the synthetic versatility and biological activity of
Synthesis of sugar tethered isoxazoles and isoxazolines
The in situ generation of sugar-tethered nitrile oxides21 from the
corresponding primary nitroalkanes and their regioselective
Table 1 Synthesis of bis(indolyl)methanes
Entry
R
R1
R2
R3
H
Product Time (h) Yielda %
1
2
3
4
5
6
7
8
Bn
Bn
Bn
Bn
H
H
H
H
H
H
H
H
H
H
H
Me
H
3a
3.0
3.0
4.5
4.5
2.5
4.5
3.0
3.5
4.5
4.5
3.5
4.0
94
91
82
83
90
89
92
88
80
89
92
90
Table 2 Synthesis of glycosyl nitroalkanes
Indole (1)
OMe 3b
Br
Cl
H
H
H
H
H
H
H
H
3c
3d
3e
3f
Entry Nitrovinyl (4) R1
R2 Product (5) Time (min) Yielda %
Bn Me
Bn Propargyl
Bn Et
1
2
3
4
5
6
4a (Bn)
4a
4a
4a
4a
Bn
H
Me
4-Br-Bn
Et
H
5a
30
40
35
60
30
30
84
80
86
70
86
75
3g
3h
3i
Me 5b
Bn
H
H
H
H
5c
5d
5e
9
Bn Br-Bn
Bn Propargyl Me
Et
Et
10
11
12
3j
3k
3l
H
Me
H
H
4b (Et)
H
Me 5f
a
a
Isolated yield aer column chromatography.
Isolated yield aer column chromatography.
Scheme 2 Synthesis of glycosyl nitroalkanes.
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Scheme 3 Synthesis of glycosyl isoxazolines.
Table 3 Synthesis of glycosyl isoxazolines
Method A
dr ratiob
7
Method B
dr ratiob
7
Entry
Nitro alkanes 5
R3
Product 7, 8
8
Yielda %
8
Yielda %
1
2
3
4
5a
5b
5c
5d
Me
Me
Me
Me
7a, 8a
7b, 8b
7c, 8c
7d, 8d
65
60
64
56
35
40
36
44
74
68
78
64
72
63
74
58
28
37
24
42
80
78
81
72
a
Isolated yield aer column chromatography. b Determined by the 1H NMR spectrum of reaction mixture.
conversion to isoxazolines and isoxazoles has been achieved. assigned to H-3a0 and H-6a0 protons, respectively. The doublet
Thus, the treatment of nitroalkanes 5a–f with di-tert-butyl at d 4.61 (J ¼ 9.9 Hz) and doublet of doublet at d 5.11 (J ¼ 9.9, 3.1
dicarbonate or ethyl chloroformate in the presence of 20 mol% Hz) were attributed to H-5 and H-4 protons, respectively. In the
equivalents of 4-dimethylaminopyridine (when using ethyl 1H NMR spectrum of the minor diastereoisomer 8d, the two
chloroformate, Et3N (1 equiv.) was also added) and an excess of doublets at d 3.75 (J ¼ 9.2 Hz) and 4.93 (J ¼ 9.2 Hz) were
a dipolarophile such as N-methyl maleimide 6a or diethyl- assigned to H-3a0 and H-6a0 protons, respectively. The doublet
acetylene dicarboxylate 10 at room temperature yielded the at d 4.44 (J ¼ 9.9 Hz) and doublet of doublet at d 4.98 (J ¼ 9.9, 3.1
isoxazolines 7a–d, 8a–d (Scheme 3 and Table 3) or isoxazoles Hz) were attributed to H-5 and H-4 protons, respectively.
9a–c (Scheme 4 and Table 4).
Stereochemical elucidation of the diastereoisomers (7d, 8d)
Structural and stereochemical studies of diastereoisomers 7
The stereochemistry of the diastereoisomers 7d and 8d were
assigned by the NOESY experiment. In the NOESY spectrum of
the major diastereoisomer 7d no correlation between H-3a0 and
H-5 protons was observed but minor diastereoisomer 8d
showed that H-3a0 proton correlates with H-5 proton. From the
abovementioned information, protons H-3a0 and H-5 are trans
in the major diastereoisomer 7d and cis in the minor diaste-
reoisomer 8d.
and 8
The systematic structural analysis of the two isomers to eluci-
date the exact regio and stereochemistry was performed using
1H, 13C and 2D NMR spectroscopic techniques.
Structural assignment of diastereoisomers (7d, 8d)
In the 1H NMR spectrum of the major diastereoisomer 7d, two
doublets at d 4.02 (J ¼ 9.9 Hz) and 5.06 (J ¼ 9.2 Hz) were
Table 4 Synthesis of glycosyl isoxazoles
Yielda %
Entry
Nitro alkanes 5
Product 9
Method A
Method B
1
2
3
5a
5e
5f
9a
9b
9c
70
74
68
82
80
70
a
Isolated yield aer column chromatography.
Scheme 4 Synthesis of glycosyl isoxazoles.
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(m, 2H), 6.04 (d, 1H, J ¼ 3.8 Hz), 6.89 (t, 1H, J ¼ 7.6 Hz), 6.95–
6.98 (m, 2H), 7.03 (t, 1H, J ¼ 7.6 Hz), 7.11 (t, 1H, J ¼ 7.6 Hz), 7.16
(dd, 2H, J ¼ 6.9, 3.8 Hz), 7.22–7.23 (m, 2H), 7.25–7.28 (m, 4H),
Structural assignment of isoxazoles 9b
In the 1H NMR spectrum of 9b, the two triplets at d 1.09 (J ¼ 6.9
Hz) and d 1.36 (J ¼ 6.9 Hz) ppm and two quartets at d 4.07 (J ¼
6.9 Hz) and d 4.39 (J ¼ 6.9 Hz) ppm were assigned to the CH3
and CH2 of the two ethyl groups, respectively. The doublet at d
5.16 (J ¼ 10.7 Hz) ppm and the doublet of doublet at d 5.23 (J ¼
10.7, 3.1 Hz) ppm were assigned to H-5 and H-4 protons,
respectively.
7.46 (d, 1H, J ¼ 8.4 Hz), 7.63 (d, 1H, J ¼ 7.6 Hz), 7.90 (s, 2H). 13
C
NMR (125 MHz, CDCl3): d 26.4, 27.1, 32.9, 71.7, 81.6, 82.2, 83.1,
105.4, 110.9, 111.1, 111.5, 116.6, 117.7, 118.9, 119.3, 119.9,
120.0, 121.6, 121.9, 122.1, 122.1, 126.9, 127.5, 127.7, 129.4,
136.2, 136.6, 137.8; MS m/z ¼ 495 M+ + 1; anal. calcd for
C
31H30N2O4 (494.22): C, 75.28; H, 6.11; N, 5.66. Found: C, 75.34;
H, 6.15; N, 5.71.
Conclusions
3-(((3aR,5R,6S,6aR)-6-(Benzyloxy)-tetrahydro-2,2-dimethyl-
furo[2,3-d][1,3]dioxol-5-yl)(5-methoxy-1H-indol-3-yl)methyl)-5-
In conclusion, we have developed an efficient synthetic protocol
for sugar-tethered bis-indolyl methanes. The key features of the
protocol include solvent and catalyst free reaction condition,
reduced reaction times, high yields and wide substrate scope.
Further, stereoselective Michael addition was achieved with
various indoles and sugar-tethered Michael acceptors. The
adducts were converted to the corresponding chiral isoxazolines
and isoxazoles. The structure and stereochemistry of the prod-
ucts were assigned by NMR studies.
methoxy-1H-indole (3b). Pale yellow solid; Mp ¼ 194 ꢀC; [a]D26
¼
ꢂ82.23 (c 0.2, CHCl3); IR 3414, 2934, 2361, 1631, 1579, 1468
1
cmꢂ1; H NMR (500 MHz, CDCl3): d 1.34 (s, 3H), 1.59 (s, 3H),
3.54 (s, 3H), 3.60 (s, 3H), 3.75 (d, 1H, J ¼ 2.3 Hz), 4.04 (d, 1H, J ¼
11.5 Hz), 4.38 (d, 1H, J ¼ 11.5 Hz), 4.59 (d, 1H, J ¼ 3.9 Hz), 4.99
(d, 1H, J ¼ 10.7 Hz), 5.11 (dd, 1H, J ¼ 10.7, 2.3 Hz), 6.08 (d, 1H, J
¼ 3.8 Hz), 6.69 (dd, 1H, J ¼ 8.5, 2.3 Hz), 6.77 (dd, 1H, J ¼ 8.4, 2.4
Hz), 6.90–6.93 (m, 2H), 7.04–7.06 (m, 2H), 7.11–7.13 (m, 4H),
7.24–7.26 (m, 3H), 7.89 (brs, 1H), 7.93 (brs, 1H); 13C NMR (125
MHz, CDCl3): d 26.4, 27.1, 32.8, 55.6, 55.8, 71.9, 81.8, 82.4, 83.3,
101.1, 102.2, 105.5, 111.5, 111.5, 111.7, 111.9, 112.3, 116.4,
117.7, 122.8, 122.8, 127.5, 127.5, 127.7, 127.8, 128.4, 137.2,
131.8, 137.8, 153.4, 153.9; MS m/z ¼ 555 M+ + 1; anal. calcd for
Experimental section
IR measurements were performed on KBr pellets for solids
using Perkin Elmer Spectrum RXI FT-IR. The H and 13C NMR
1
C
33H34N2O6 (554.24): C, 71.46; H, 6.18; N, 5.05. Found: C, 71.40;
spectra were recorded using CDCl3 with JEOL 500 MHz and
Bruker 500 MHz high resolution NMR spectrometer. CDCl3 was
used as the solvent for the NMR spectral measurements, and
spectra were recorded in ppm using TMS as the internal stan-
dard. Multiplicities are abbreviated as follows: singlet (s),
doublet (d), triplet (t), multiplet (m), and broad (br). The masses
were analyzed by an electrospray ionisation method with a
Thermo Finnigan Mass spectrometer. Melting points were
determined in capillary tubes and are uncorrected. Elemental
analyses were performed using a Thermo Finnigan FLASH EA
1112 CHN analyzer. Analytical TLC was performed on the pre-
coated plastic sheets of silica gel G/UV-254 of 0.2 mm thickness
(Macherey-Nagel).
H, 6.14; N, 5.11.
3-(((3aR,5R,6S,6aR)-6-(Benzyloxy)-tetrahydro-2,2-dimethyl-
furo[2,3-d][1,3]dioxol-5-yl)(5-bromo-1H-indol-3-yl)methyl)-5-
bromo-1H-indole (3c). Orange solid; Mp ¼ 140 ꢀC; [a]D26
¼
ꢂ29.71 (c 0.2, CHCl3); IR: 3418, 2931, 1724, 1458 cmꢂ1; 1H NMR
(500 MHz, CDCl3): d 1.31 (s, 3H), 1.57 (s, 3H), 3.74 (d, 1H, J ¼ 3.0
Hz), 4.14 (d, 1H, J ¼ 10.7 Hz), 4.44 (d, 1H, J ¼ 10.5 Hz), 4.62 (d,
1H, J ¼ 3.8 Hz), 4.92 (d, 1H, J ¼ 10.7 Hz), 5.04 (dd, 1H, J ¼ 13.0,
2.3 Hz), 6.03 (d, 1H, J ¼ 3.8 Hz), 6.96 (d, 1H, J ¼ 8.4 Hz), 7.02 (d,
2H, J ¼ 1.5, Hz), 7.07 (dd, 1H, J ¼ 8.4, 1.5 Hz), 7.10–7.12 (m, 2H),
7.18 (dd, 1H, J ¼ 8.4, 1.5 Hz), 7.23–7.26 (m, 3H), 7.64 (s, 1H),
7.67 (s, 1H), 8.02 (brs, 1H), 8.04 (brs, 1H); 13C NMR (125 MHz,
CDCl3): d 26.3, 27.0, 32.8, 71.9, 81.9, 82.8, 105.3, 111.7, 112.4,
112.73, 112.77, 112.8, 115.7, 116.6, 122.1, 122.2, 123.1, 123.7,
124.5, 125.0, 127.8, 127.9, 128.4, 128.5, 128.8, 134.8, 135.2,
General procedure for the synthesis of bis-indolyl methanes
A
mixture of 3-O-benzyl-1,2-O-isopropylidene-xylopenta- 137.3; MS m/z ¼ 651 M+ + 1, 653 M+ + 3, 655 M+ + 5; anal. calcd
dialdoses 2a, b (1.00 mmol) and indoles 1a–j (2.00 mmol) was for C31H28Br2N2O4 (650.04): C, 57.07; H, 4.33; N, 4.29. Found: C,
stirred at 70 ꢀC under neat condition for 2.5–4.5 h. The residue 57.11; H, 4.28; N, 4.35.
was dissolved in ethyl acetate (20 mL) and given a brine (1 ꢁ
3-(((3aR,5R,6S,6aR)-6-(Benzyloxy)-tetrahydro-2,2-dimethyl-
20 mL) and water wash (2 ꢁ 20 mL). The ethyl acetate layer was furo[2,3-d][1,3]dioxol-5-yl)(5-chloro-1H-indol-3-yl)methyl)-5-
dried over anhydrous Na2SO4, and the removal of solvent under chloro-1H-indole (3d). Yellow solid; Mp ¼ 126 ꢀC; [a]D26
¼
reduced pressure provided a crude product, which was puried ꢂ119.48 (c 0.18, CHCl3); IR 3408, 2944, 1716, 1423 cmꢂ1
;
1H
by ash column chromatography with ethyl acetate : petroleum NMR (500 MHz, CDCl3): 1.33 (s, 3H), 1.59 (s, 3H), 3.76 (d, 1H, J ¼
ether (20 : 80) as an eluent to obtain the bis-indolyl methanes 2.3 Hz), 4.13 (d, 1H, J ¼ 11.4 Hz), 4.45 (d, 1H, J ¼ 11.4 Hz), 4.64
3a–l in 80–94% yield.
(d, 1H, J ¼ 4.6 Hz), 4.94 (d, 1H, J ¼ 11.4 Hz), 5.06 (dd, 1H, J ¼
3-(((3aR,5R,6S,6aR)-6-(Benzyloxy)-tetrahydro-2,2-dimethyl- 10.3, 2.3 Hz), 6.04 (d, 1H, J ¼ 3.8 Hz), 6.93–6.98 (m, 3H), 7.02 (d,
furo[2,3-d][1,3]dioxol-5-yl)(1H-indol-3-yl)methyl)-1H-indole (3a). 1H, J ¼ 2.2 Hz), 7.05 (dd, 1H, J ¼ 9.1, 2.3 Hz), 7.09–7.13 (m, 4H),
Yellow solid; Mp ¼ 132 ꢀC; [a]D26 ¼ ꢂ91.90 (c 0.2, CHCl3); IR 7.26–7.27 (m, 2H), 7.49 (d, 1H, J ¼ 1.5 Hz), 7.52 (d, 1H, J ¼ 2.3
3402, 2929, 2324, 1078 cmꢂ1; 1H NMR (500 MHz, CDCl3): d 1.32 Hz), 8.01 (s, 1H), 8.02 (s, 1H); 13C NMR (125 MHz, CDCl3): 26.3,
(s, 3H), 1.57 (s, 3H), 3.71 (d, 1H, J ¼ 2.3 Hz), 4.13 (d, 1H, J ¼ 12.2 27.0, 32.8, 71.9, 81.7, 81.9, 82.9, 105.3, 111.7, 112.3, 112.4, 115.7,
Hz), 4.41 (d, 1H, J ¼ 11.5 Hz), 4.58 (d, 1H, J ¼ 3.8 Hz), 5.10 116.7, 118.9, 119.1, 121.9, 122.0, 123.3, 123.8, 124.7, 125.2,
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127.7, 127.8, 127.9, 128.2, 128.5, 134.5, 134.9, 137.3; MS m/z ¼ Hz), 4.11 (d, 1H, J ¼ 12.3 Hz), 4.36 (d, 1H, J ¼ 11.5 Hz), 4.53 (d,
563 M+ + 1; anal. calcd for C31H28Cl2N2O4 (562.14): C, 66.08; H, 1H, J ¼ 4.6 Hz), 5.02 (d, 1H, J ¼ 11.5 Hz), 5.48 (dd, 1H, J ¼ 11.5,
5.01; N, 4.97. Found: C, 66.13; H, 5.09; N, 5.91.
3.8 Hz), 6.02 (d, 1H, J ¼ 3.8 Hz), 6.91–6.98 (m, 3H), 7.02 (t, 1H, J
3-(((3aR,5R,6S,6aR)-6-(Benzyloxy)-tetrahydro-2,2-dimethyl- ¼ 7.7 Hz), 7.08 (d, 1H, J ¼ 6.9 Hz), 7.14 (d, 1H, J ¼ 8.4 Hz), 7.17–
furo[2,3-d][1,3]dioxol-5-yl)(1-methyl-1H-indol-3-yl)methyl)-1- 7.18 (m, 2H), 7.26–7.31 (m, 3H), 7.51 (s, 1H) 7.57 (s, 1H), 7.66
26
(dd, 2H, J ¼ 7.7 Hz); 13C NMR (125 MHz, CDCl3): d 12.5, 13.1,
ꢀ
methyl-1H-indole (3e). Pale yellow solid; Mp ¼ 120 C; [a]D
¼
ꢂ86.70 (c 0.2, MeOH); IR: 2922, 2346, 1465 cmꢂ1
;
1H NMR 26.2, 26.7, 26.9, 33.1, 71.4, 80.1, 81.7, 82.5, 105.3, 110.0, 110.1,
(500 MHz, CDCl3): 1.33 (s, 3H), 1.60 (s, 3H), 3.66 (s, 3H), 3.74 (m, 111.8, 111.9, 119.2, 119.5, 119.7, 120.2, 120.4, 127.5, 127.9,
4H), 4.12 (d, 1H, J ¼ 12.2 Hz), 4.42 (d, 1H, J ¼ 12.2 Hz), 4.59 (d, 128.2, 128.5, 131.5, 131.6, 135.1, 138.0; MS m/z ¼ 523 M+ + 1;
1H, J ¼ 3.85 Hz), 5.05–5.12 (m, 2H), 6.05 (d, 1H, J ¼ 3.8 Hz), 6.89 anal. calcd for C33H34N2O4 (522.35): C, 75.84; H, 6.56; N, 5.36.
(s, 1H), 6.92 (t, 1H, J ¼ 8.4 Hz), 6.99 (t, 1H, J ¼ 7.6 Hz), 7.10 Found: C, 75.64; H, 6.60; N, 5.42.
(t, 1H, J ¼ 7.6 Hz), 7.06–7.13 (m, 3H), 7.19–7.20 (m, 2H), 7.24–
1-(4-Bromobenzyl)-3-((1-(4-bromobenzyl)-1H-indol-3-yl)-
((3aR,5R,6S,6aR)-6-(benzyloxy)-tetrahydro-2,2-dimethylfuro[2,3-
7.27 (m, 4H), 7.50 (d, 1H, J ¼ 7.6 Hz), 7.68 (d, 1H, J ¼ 7.6 Hz); 13
C
NMR (125 MHz, CDCl3): 26.4, 27.1, 32.6, 32.8, 71.6, 81.6, 82.1, d][1,3]dioxol-5-yl)methyl)-1H-indole (3i). Green colour solid; Mp
83.3, 105.5, 108.9, 109.1, 113.4, 115.5, 116.5, 118.4, 118.8, 120.1, ¼ 78–80 ꢀC; [a]D27 ¼ 95.4 (0.86, CHCl3); 1H NMR (500 MHz,
120.2, 121.2, 121.4, 126.5, 126.7, 127.5, 127.6, 127.9, 128.3, CDCl3): d 1.32 (s, 3H), 1.54 (s, 3H), 3.69 (s, 1H), 4.07 (d, 1H, J ¼
136.8, 137.3, 137.8; MS m/z ¼ 523 M+ + 1; anal. calcd for 11.5 Hz), 4.45 (d, 1H, J ¼ 11.5 Hz), 4.58 (d, 1H, J ¼ 3.1 Hz), 5.12–
C
33H34N2O4 (522.25): C, 75.84; H, 6.56; N, 5.36. Found: C, 75.78; 5.17 (m, 4H), 5.25 (s, 2H), 6.04 (d, 1H, J ¼ 3.1 Hz), 6.81 (d, 2H, J ¼
H, 6.50; N, 5.42.
8.4 Hz), 6.88–6.90 (m, 3H), 6.95–6.98 (m, 2H), 7.03 (t, 1H, J ¼ 7.6
3-(((3aR,5R,6S,6aR)-6-(Benzyloxy)-tetrahydro-2,2-dimethyl- Hz), 7.07 (d, 1H, J ¼ 7.6 Hz), 7.11–7.18 (m, 4H), 7.25–7.27 (m,
furo[2,3-d][1,3]dioxol-5-yl)(1-(prop-2-ynyl)-1H-indol-3-yl)methyl)- 4H), 7.33 (d, 2H, J ¼ 8.4 Hz), 7.37 (d, 2H, J ¼ 7.6 Hz), 7.41 (d, 1H,
1-(prop-2-ynyl)-1H-indole (3f). Colour less solid; Mp ¼ 62–64 ꢀC; J ¼ 8.4 Hz), 7.59 (d, 1H, J ¼ 7.6 Hz); 13C NMR (125 MHz, CDCl3):
[a]2D6 ¼ ꢂ6.0 (0.64, CHCl3); 1H NMR (500 MHz, CDCl3): d 1.32 (s, d 26.3, 26.9, 33.4, 49.1, 49.3, 71.7, 81.4, 82.5, 105.4, 109.3, 109.5,
3H), 1.58 (s, 3H), 2.32 (t, 1H, J ¼ 2.3 Hz), 2.35 (t, 1H, J ¼ 2.3 Hz), 11.4, 115.9, 116.7, 118.8, 119.2, 120.2, 120.4, 121.1, 121.4, 121.5,
3.71 (s, 1H), 4.14 (d, 1H, J ¼ 11.5 Hz), 4.42 (d, 1H, J ¼ 11.5 Hz), 121.8, 126.1, 126.2, 127.3, 127.6, 128.1, 128.2, 128.3, 131.7,
4.57 (d, 1H, J ¼ 3.9 Hz), 4.75 (t, 2H, J ¼ 2.3 Hz), 4.82 (d, 2H, J ¼ 131.8, 136.6, 136.7, 136.9, 137.2; MS m/z ¼ 831 M+ + 1, 833 M+ +
3.1 Hz), 5.08 (s, 2H), 6.05 (d, 1H, J ¼ 3.8 Hz), 6.93 (t, 1H, J ¼ 6.9 3, 835 M+ + 5; anal. calcd for C45H40Br2N2O4 (830.14): C, 64.91;
Hz), 6.99 (t, 1H, J ¼ 7.6 Hz), 7.07 (s, 1H), 7.12 (t, 1H, J ¼ 7.6 Hz), H, 4.84; N, 3.36. Found: C, 64.95; H, 4.98; N, 3.33.
7.17–7.21 (m, 4H), 7.25–7.28 (m, 4H), 7.34 (d, 1H, J ¼ 8.4 Hz),
3-(((3aR,5R,6S,6aR)-6-(Benzyloxy)-tetrahydro-2,2-dimethyl-
7.47 (d, 1H, J ¼ 7.6 Hz), 7.62 (d, 1H, J ¼ 7.6 Hz); 13C NMR (125 furo[2,3-d][1,3]dioxol-5-yl)(2-methyl-1-(prop-2-ynyl)-1H-indol-3-
MHz, CDCl3): d 26.4, 26.9, 32.9, 35.4, 35.8, 71.8, 73.2, 73.4, 78.0, yl)methyl)-2-methyl-1-(prop-2-ynyl)-1H-indole
(3j).
Brown
78.3, 81.6, 82.2, 83.0, 105.4, 109.1, 109.2, 111.4, 116.1, 117.0, colour solid; Mp ¼ 188–190 ꢀC; [a]D27 ¼ ꢂ84.3 (0.56, CHCl3); 1H
119.0, 120.3, 121.5, 121.8, 125.2, 125.3, 127.5, 127.6, 127.9, NMR (500 MHz, DMSO-d6): d 1.24 (s, 3H), 1.48 (s, 3H), 2.39 (s,
128.5, 136.1, 136.4, 137.8; MS m/z ¼ 571 M+ + 1; anal. calcd for 3H), 2.41 (s, 3H), 3.19 (s, 1H), 3.23 (s, 1H), 3.46 (s, 1H), 4.07 (d,
C
37H34N2O4 (570.25): C, 77.87; H, 6.01; N, 4.91. Found: C, 77.94; 1H, J ¼ 11.5 Hz), 4.46 (d, 1H, J ¼ 11.5 Hz), 4.70 (d, 1H, J ¼ 3.8
H, 6.11; N, 4.83.
Hz), 4.84 (d, 1H, J ¼ 11.5 Hz), 4.88–5.02 (m, 4H), 5.43 (d, 1H, J ¼
3-(((3aR,5R,6S,6aR)-6-(Benzyloxy)-tetrahydro-2,2-dimethyl- 11.5 Hz), 5.88 (d, 1H, J ¼ 3.8 Hz), 6.88 (t, 2H, J ¼ 8.4 Hz), 6.97–
furo[2,3-d][1,3]dioxol-5-yl)(1-ethyl-1H-indol-3-yl)methyl)-1-ethyl- 7.03 (m, 2H), 7.17 (d, 2H, J ¼ 6.9 Hz), 7.24–7.30 (m, 3H), 7.36 (d,
1H-indole (3g). Colour less solid; Mp ¼ 60–62 ꢀC; [a]D27 ¼ ꢂ11.3 1H, J ¼ 8.4 Hz), 7.43 (d, 1H, J ¼ 7.6 Hz), 7.52 (d, 1H, J ¼ 8.4 Hz),
(0.70, CHCl3); 1H NMR (500 MHz, CDCl3): d 1.33 (s, 3H), 1.37 (t, 7.62 (d, 1H, J ¼ 8.4 Hz); 13C NMR (125 MHz, DMSO-d6): d 11.2,
3H, J ¼ 6.9 Hz), 1.43 (t, 3H, J ¼ 6.9 Hz), 1.59 (s, 3H), 3.71 (s, 1H), 26.5, 26.9, 32.3, 32.5, 33.9, 71.1, 74.8, 79.6, 80.1, 80.2, 81.3, 82.1,
4.06 (q, 2H, J ¼ 6.9 Hz), 4.10–4.14 (m, 3H), 4.42 (d, 1H, J ¼ 11.5 105.0, 109.6, 110.0, 110.8, 112.1, 112.4, 119.2, 119.3, 119.5,
Hz), 4.58 (d, 1H, J ¼ 3.8 Hz), 5.11 (s, 2H), 6.06 (d, 1H, J ¼ 3.8 Hz), 120.4, 120.7, 120.8, 127.0, 127.6, 127.9, 128.0, 128.7, 133.1,
6.90 (t, 1H, J ¼ 8.4 Hz), 6.97 (t, 1H, J ¼ 7.6 Hz), 6.99 (s, 1H), 7.08 133.2, 135.9, 136.3, 138.2; MS m/z ¼ 599 M+ + 1; anal. calcd for
(t, 1H, J ¼ 7.7 Hz), 7.14–7.17 (m, 3H), 7.21–7.29 (m, 6H), 7.47 (d,
C39H38N2O4 (598.28): C, 78.24; H, 6.40; N, 4.68. Found: C, 78.35;
1H, J ¼ 7.7 Hz), 7.65 (d, 1H, J ¼ 8.4 Hz); 13C NMR (125 MHz, H, 6.38; N, 4.73.
CDCl3): d 15.5, 15.6, 26.3, 27.0, 32.9, 40.8, 40.9, 71.7, 81.6, 82.3,
3-(((3aR,5R,6S,6aR)-6-Ethoxy-tetrahydro-2,2-dimethylfuro-
83.2, 105.4, 108.9, 109.1, 111.3, 115.4, 116.3, 118.2, 118.6, 120.2, [2,3-d][1,3]dioxol-5-yl)(1H-indol-3-yl)methyl)-1H-indole
(3k).
120.3, 120.9, 121.1, 124.9, 125.0, 127.4, 127.5, 127.6, 128.1, Colour less solid; Mp ¼ 100–102 ꢀC; [a]D28 ¼ ꢂ58.7 (0.72, CHCl3);
128.3, 135.9, 136.2, 137.8; MS m/z ¼ 551 M+ + 1; anal. calcd for 1H NMR (500 MHz, CDCl3): d 1.09 (t, 3H, J ¼ 6.9 Hz), 1.34 (s, 3H),
C
35H38N2O4 (550.28): C, 76.34; H, 6.96; N, 5.09. Found: C, 76.42; 1.59 (s, 3H), 2.92–2.97 (m, 1H), 3.38–3.41 (m, 1H), 3.48 (s, 1H),
H, 6.88; N, 5.11.
4.53 (d, 1H, J ¼ 3.8 Hz), 5.04 (s, 2H), 6.03 (d, 1H, J ¼ 3.8 Hz), 6.90
3-(((3aR,5R,6S,6aR)-6-(Benzyloxy)-tetrahydro-2,2-dimethyl- (t, 1H, J ¼ 6.9 Hz), 6.99–7.07 (m, 3H), 7.12 (t, 1H, J ¼ 7.7 Hz),
furo[2,3-d][1,3]dioxol-5-yl)(2-methyl-1H-indol-3-yl)methyl)-2- 7.19–7.25 (m, 3H), 7.46 (d, 1H, J ¼ 7.7 Hz), 7.75 (d, 1H, J ¼ 7.7
methyl-1H-indole (3h). Yellow colour solid; Mp ¼ 112–114 C; Hz), 7.92 (s, 1H), 7.97 (s, 1H); 13C NMR (125 MHz, CDCl3): d 15.2,
ꢀ
[a]2D7 ¼ 175.7 (0.62, CHCl3); 1H NMR (500 MHz, CDCl3): d 1.30 (s, 26.4, 27.1, 32.7, 65.5, 81.8, 82.2, 83.2, 105.5, 111.0, 111.1, 111.4,
3H), 1.59 (s, 3H), 2.13 (s, 3H), 2.29 (s, 3H), 3.70 (d, 1H, J ¼ 2.3 116.8, 117.9, 119.2, 119.8, 121.6, 121.8, 121.9, 122.3, 126.9,
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127.5, 136.0, 136.6; MS m/z ¼ 433 M+ + 1; anal. calcd for 11.4 Hz, OCHHPh), 4.84 (d, 1H, J ¼ 4.2 Hz, H-2), 5.01 (t, 1H, J ¼
C
26H28N2O4 (432.20): C, 72.20; H, 6.53; N, 6.48. Found: C, 72.32; 11.4 Hz, CHHNO2), 5.76 (d, 1H, J ¼ 3.8 Hz, H-1), 6.89 (t, 1H, J ¼
H, 6.50; N, 6.49.
6.9 Hz, Ar-H), 6.97 (t, 1H, J ¼ 7.6 Hz, Ar-H), 7.24 (d, 1H, J ¼ 8.4
3-(((3aR,5R,6S,6aR)-6-Ethoxy-tetrahydro-2,2-dimethylfuro- Hz, Ar-H), 7.32 (t, 1H, J ¼ 6.8 Hz, Ar-H), 7.38 (t, 2H, J ¼ 8.0 Hz,
[2,3-d][1,3]dioxol-5-yl)(1-methyl-1H-indol-3-yl)methyl)-1-methyl- Ar-H), 7.45 (d, 2H, J ¼ 6.9 Hz, Ar-H), 7.59 (d, 1H, J ¼ 6.5 Hz, Ar-
1H-indole (3l). Green Colour solid; Mp ¼ 70–72 ꢀC; [a]D28
¼
H), 10.85 (s, 1H, NH); 13C NMR (125 MHz, DMSO-d6): d 11.9,
ꢂ88.3 (0.82, CHCl3); 1H NMR (500 MHz, CDCl3): d 1.10 (t, 3H, J 26.7, 27.1, 35.7, 71.0, 76.6, 78.8, 79.7, 80.8, 81.7, 104.4, 106.2,
¼ 6.9 Hz), 1.34 (s, 3H), 1.60 (s, 3H), 2.91–2.96 (m, 1H), 3.37–3.41 111.2, 111.3, 118.3, 118.9, 120.5, 128.4, 128.6, 128.9, 134.2,
(m, 1H), 3.47 (d, 1H, J ¼ 3.1 Hz), 3.69 (s, 3H), 3.73 (s, 3H), 4.52 135.8, 138.2; MS m/z ¼ 453 M+ + 1; anal. calcd for C25H28N2O6
(d, 1H, J ¼ 3.8 Hz), 4.98–5.06 (m, 2H), 6.02 (d, 1H, J ¼ 3.8 Hz), (452.19): C, 66.36; H, 6.24; N, 6.19. Found C, 66.45; H, 6.20; N,
6.92 (t, 1H, J ¼ 8.4 Hz), 6.97 (s, 1H), 7.07–7.12 (m, 2H), 7.16–7.20 6.16.
(m, 3H), 7.25 (d, 1H, J ¼ 6.9 Hz), 7.49 (d, 1H, J ¼ 7.7 Hz), 7.80 (d,
3-((1R)-1-((3aR,5R,6S,6aR)-6-(Benzyloxy)-tetrahydro-2,2-
1H, J ¼ 7.7 Hz); 13C NMR (125 MHz, CDCl3): d 15.2, 26.4, 27.1, dimethylfuro[3,2-d][1,3]dioxol-5-yl)-2-nitroethyl)-1-methyl-1H-
32.4, 32.8, 81.7, 82.3, 83.4, 105.6, 108.9, 109.0, 111.2, 115.8, indole (5c). Orange solid; Mp 189–191 ꢀC; IR (cmꢂ1): 3372, 2954,
116.8, 118.4, 118.6, 119.9, 120.2, 121.2, 121.3, 126.3, 126.9, 2346, 1550, 1352, 759; [a]2D8 ¼ ꢂ176.9 (c 0.2, CHCl3); H NMR
1
127.5, 127.9, 136.7, 137.3; MS m/z ¼ 461 M+ + 1; anal. calcd for (500 MHz, CDCl3): d 1.33 (s, 3H, isopropylidene-CH3), 1.48 (s,
C
28H32N2O4 (460.24.): C, 73.02; H, 7.00; N, 6.08. Found: C, 72.88; 3H, isopropylidene-CH3), 3.63 (s, 3H, indole-CH3), 3.92 (d, 1H, J
H, 7.05; N, 6.01.
¼ 3.0 Hz, H-3), 4.45 (d, 1H, J ¼ 11.5 Hz, OCHHPh), 4.48–4.52 (m,
1H, H-5), 4.63–4.67 (m, 2H, H-4, H-2), 4.75 (d, 1H, J ¼ 11.5 Hz,
OCHHPh), 4.83 (dd, 1H, J ¼ 13.0, 3.9 Hz, CHHNO2), 4.90 (dd,
1H, J ¼ 13.0, 9.2 Hz, CHHNO2), 5.98 (d, 1H, J ¼ 3.8 Hz, H-1), 6.71
(s, 1H, Ar-H), 7.13 (t, 1H, J ¼ 7.6 Hz, Ar-H), 7.22–7.28 (m, 2H, Ar-
Experimental procedure for the synthesis of chiral
nitroalkanes 5a–f
To a solution of 5, 6-dideoxy-5, 6-anhydro-6-nitro-3-O-benzyl- H), 7.40–7.47 (m, 5H, Ar-H), 7.64 (d, 1H, J ¼ 8.4 Hz, Ar-H); 13C
1,2-O-isopropylidene-D-glucofuranose 4a–b (1.00 mmol) in NMR (125 MHz, CDCl3): d 26.3, 26.9, 32.9, 35.5, 71.6, 76.8, 80.3,
dichloromethane, indole 1 (1.00 mmol) was added and stirred 81.4, 81.9, 104.9, 109.6, 109.8, 111.8, 118.7, 119.5, 122.0, 126.9,
for uniform mixing. The solvent was then evaporated under 127.2, 128.4, 128.6, 128.9, 137.0; MS m/z ¼ 453 M+ + 1; anal.
reduced pressure and the mixture was heated under neat calcd for C25H28N2O6 (452.19): C, 66.36; H, 6.24; N, 6.19. Found:
condition at 70 ꢀC for an appropriate amount of time. Aer the C, 66.28; H, 6.18; N, 6.28.
completion of the reaction, the residue was subjected to column
1-(4-Bromobenzyl)-3-((1R)-1-((3aR,5R,6S,6aR)-6-(benzyloxy)-
chromatography over silica gel using ethylacetate–petroleum tetrahydro-2,2-dimethylfuro[3,2-d][1,3]dioxol-5-yl)-2-nitroethyl)-
ether (25/75) as an eluent to obtain the pure product 5a–f.
1H-indole (5d). Colourless solid; Mp 115–117 ꢀC; IR (cmꢂ1);
1-Benzyl-3-((1R)-1-((3aR,5R,6S,6aR)-6-(benzyloxy)-tetrahydro- 3377, 2951, 2347, 1555, 1357, 759; [a]2D8 ¼ ꢂ130.4 (c 0.90,
2,2-dimethylfuro[3,2-d][1,3]dioxol-5-yl)-2-nitroethyl)-1H-indole CHCl3); 1H NMR (500 MHz, CDCl3): d 1.31 (s, 3H, iso-
(5a). Colourless solid; Mp 101–103 ꢀC; IR (cmꢂ1): 3377, 2952, propylidene-CH3), 1.48 (s, 3H, isopropylidene-CH3), 3.80 (d, 1H,
1
2348, 1551, 1354, 756; [a]2D8 ¼ ꢂ78.9 (c 0.52, CHCl3); H NMR J ¼ 3.1 Hz, H-3), 4.21 (d, 1H, J ¼ 11.5 Hz, OCHHPh), 4.53–4.56
(500 MHz, CDCl3): d 1.30 (s, 3H, isopropylidene-CH3), 1.47 (s, (m, 1H, H-5), 4.58–4.61 (m, 2H, H-2, OCHHPh), 4.64 (dd, 1H, J ¼
3H, isopropylidene-CH3), 3.80 (d, 1H, J ¼ 3.1 Hz, H-3), 4.22 (d, 6.9, 3.8 Hz, H-4), 4.93–4.95 (m, 2H, CH2NO2), 5.16 (d, 1H, J ¼
1H, J ¼ 11.5 Hz, OCHHPh), 4.52–4.56 (m, 1H, H-5), 4.58–4.60 (m, 16.1 Hz, NCHHPh), 5.25 (d, 1H, J ¼ 16.1 Hz, NCHHPh), 5.98 (d,
2H, OCHHPh, H-2), 4.65 (dd, 1H, J ¼ 6.9, 3.8 Hz, H-4), 4.89–4.90 1H, J ¼ 3.8 Hz, H-1), 6.81 (s, 1H, Ar-H), 7.02 (d, 2H, J ¼ 7.6 Hz, Ar-
(m, 2H, –CH2NO2), 5.15 (d, 1H, J ¼ 16.1 Hz, NCHHPh), 5.25 (d, H), 7.13 (t, 1H, J ¼ 7.6 Hz, Ar-H), 7.21 (t, 1H, J ¼ 6.9 Hz, Ar-H),
1H, J ¼ 16.1 Hz, NCHHPh), 5.96 (d, 1H, J ¼ 3.8 Hz, H-1), 6.80 (s, 7.25–7.36 (m, 9H, Ar-H); 13C NMR (125 MHz, CDCl3): d 26.3,
1H, Ar-H), 7.04 (d, 2H, J ¼ 7.6 Hz, Ar-H), 7.13 (t, 1H, J ¼ 7.6 Hz, 26.9, 35.3, 50.1, 71.7, 76.6, 80.1, 81.4, 82.5, 104.8, 110.1, 110.7,
Ar-H), 7.19 (t, 1H, J ¼ 6.9 Hz, Ar-H), 7.24–7.36 (m, 9H, Ar-H), 7.66 111.8, 118.9, 119.8, 122.2, 126.1, 126.8, 127.4, 127.9, 128.1,
(d, 1H, J ¼ 7.6 Hz, Ar-H); 13C NMR (125 MHz, CDCl3): d 26.3, 128.4, 128.8, 128.9, 136.8, 136.9, 137.5; MS m/z ¼ 607 M+ + 1;
26.9, 35.4, 50.0, 71.8, 76.6, 80.2, 81.3, 82.4, 104.9, 110.0, 110.6, anal. calcd for C31H31BrN2O6 (606.14): C, 61.29; H, 5.14; N, 4.61.
111.9, 118.8, 119.9, 122.3, 126.2, 126.9, 127.5, 127.8, 128.0, Found: C, 61.40; H, 5.16; N, 4.64.
128.4, 128.8, 128.9, 136.7, 136.9, 137.4; MS m/z ¼ 529 M+ + 1;
3-((R)-1-((3aR,5R,6S,6aR)-6-(Benzyloxy)-tetrahydro-2,2-di-
anal. calcd for C31H32N2O6 (528.23): C, 70.44; H, 6.10; N, 5.30. methylfuro[3,2-d][1,3]dioxol-5-yl)-2-nitroethyl)-1-ethyl-1H-
Found: C, 70.52; H, 6.08; N, 5.12.
indole (5e). Viscous liquid; IR (cmꢂ1): 3376, 2964, 2348, 1555,
3-((1R)-1-((3aR,5R,6S,6aR)-6-(Benzyloxy)-tetrahydro-2,2- 1352, 758; [a]2D8 ¼ ꢂ16.3 (c 0.40, CHCl3); 1H NMR (500 MHz,
dimethylfuro[3,2-d][1,3]dioxol-5-yl)-2-nitroethyl)-2-methyl-1H- CDCl3): d 1.34 (s, 3H, isopropylidene-CH3), 1.39 (t, 3H, J ¼ 7.6
indole (5b). Yellow solid; Mp 207–209 ꢀC; IR (cmꢂ1): 3372, 2937, Hz, NCH2CH3), 1.50 (s, 3H, isopropylidene-CH3), 3.91 (d, 1H, J ¼
2346, 1553, 1350, 751; [a]2D8 ¼ ꢂ84.7 (0.2, CHCl3); 1H NMR 3.1 Hz, H-3), 4.05 (q, 2H, J ¼ 7.6 Hz, NCH2CH3), 4.46 (d, 1H, J ¼
(500 MHz, DMSO-d6): d 1.21 (s, 3H, isopropylidene-CH3), 1.31 (s, 11.5 Hz, OCHHPh), 4.53–4.57 (m, 1H, H-5), 4.66–4.68 (m, 2H, H-
3H, isopropylidene-CH3), 2.24 (s, 3H, indole-CH3), 4.02 (d, 1H, J 4, H-2), 4.76 (d, 1H, J ¼ 11.5 Hz, OCHHPh), 4.88–4.95 (m, 2H,
¼ 3.0 Hz, H-3), 4.04–4.09 (m, 1H, H-5), 4.59 (d, 1H, J ¼ 11.4 Hz, –CH2NO2), 6.00 (d, 1H, J ¼ 3.1 Hz, H-1), 6.82 (s, 1H, Ar-H), 7.14
–OCHHPh), 4.64–4.67 (m, 2H, H-4, CHHNO2), 4.77 (d, 1H, J ¼ (t, 1H, J ¼ 7.6 Hz, Ar-H), 7.24 (t, 1H, J ¼ 7.6 Hz, Ar-H), 7.33 (d,
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1H, J ¼ 8.4 Hz, Ar-H), 7.39–7.48 (m, 5H, Ar-H), 7.66 (d, 1H, J ¼ 1727, 1660, 1495, 1382, 1196, 1044; [a]2D6 ¼ ꢂ66.9 (1.10, CHCl3);
8.4 Hz, Ar-H); 13C NMR (125 MHz, CDCl3): d 15.5, 26.3, 26.8, 1H NMR (500 MHz, CDCl3): d 1.26 (s, 3H, isopropylidene-CH3),
35.5, 41.1, 71.7, 76.8, 80.3, 81.4, 82.2, 104.9, 109.7, 109.9, 111.8, 1.43 (s, 3H, isopropylidene-CH3), 2.46 (s, 3H, N–CH3), 4.03 (d,
118.8, 119.5, 121.9, 125.2, 127.4, 128.2, 128.5, 128.9, 136.1, 1H, J ¼ 9.9 Hz, H-3a0), 4.36 (d, 1H, J ¼ 12.2 Hz, OCHHPh), 4.43
137.1; MS m/z ¼ 467 M+ + 1; anal. calcd for C26H30N2O6 (466.21): (d, 1H, J ¼ 3.1 Hz, H-3), 4.58–4.63 (m, 3H, H-2, H-5, OCHHPh),
C, 66.94; H, 6.48; N, 6.00. Found: C, 66.74; H, 6.46; N, 6.12.
5.05 (d, 1H, J ¼ 9.9 Hz, H-6a0), 5.13 (dd, 1H, J ¼ 9.9, 3.1 Hz, H-4),
3-((1R)-1-((3aR,5R,6S,6aR)-6-Ethoxy-tetrahydro-2,2-dimethyl- 5.28 (s, 2H, NCH2Ph), 5.87 (d, 1H, J ¼ 3.8 Hz, H-1), 7.10 (t, 1H, J
furo[3,2-d][1,3]dioxol-5-yl)-2-nitroethyl)-2-methyl-1H-indole ¼ 6.9 Hz, Ar-H), 7.15–7.18 (m, 3H, Ar-H), 7.22–7.25 (m, 3H, Ar-
(5f). Yellow solid; Mp 160–162 C; IR (cmꢂ1): 3378, 2957, 2343, H), 7.27–7.30 (m, 5H, Ar-H), 7.36 (t, 2H, J ¼ 6.9 Hz, Ar-H), 7.81 (d,
ꢀ
1576, 1350, 759; [a]3D0 ¼ ꢂ129.60 (0.60, CHCl3); 1H NMR 1H, J ¼ 7.6 Hz, Ar-H); 13C NMR (125 MHz, CDCl3): d 24.8, 26.4,
(500 MHz, DMSO-d6): d 1.17–1.19 (m, 6H, isopropylidene-CH3, 26.9, 35.9, 50.3, 56.3, 71.5, 78.4, 80.2, 82.2, 82.3, 104.7, 108.9,
OCH2CH3), 1.28 (s, 3H, isopropylidene-CH3), 2.25 (s, 3H, indole- 110.2, 111.6, 119.4, 119.9, 122.1, 126.5, 126.9, 127.1, 127.5,
CH3), 3.45–3.51 (m, 1H, OCHHCH3), 3.70–3.75 (m, 1H, 127.6, 127.7, 128.5, 128.6, 128.8, 137.1, 137.2, 154.3, 170.4,
OCHHCH3), 3.88 (d, 1H, J ¼ 3.1 Hz, H-3), 3.97–4.01 (m, 1H, H-5), 172.5; MS m/z ¼ 622 M+ + 1; anal. calcd for C36H35N3O7 (621.25):
4.60 (dd, 1H, J ¼ 10.7 Hz, J ¼ 3.1 Hz, H-4), 4.68 (d, 1H, J ¼ 3.8 Hz, C, 69.55; H, 5.67; N, 6.76. Found: C, 69.41; H, 5.69; N, 6.85.
H-2), 4.79 (dd, 1H, J ¼ 12.2, 4.6 Hz, –CHHNO2), 5.01 (t, 1H, J ¼
(3aS,6aR)-3-((R)-(1-Benzyl-1H-indol-3-yl)((3aR,5R,6S,6aR)-6-
11.4 Hz, –CHHNO2), 5.72 (d, 1H, J ¼ 3.8 Hz, H-1), 6.90 (t, 1H, J ¼ (benzyloxy)-tetrahydro-2,2-dimethylfuro[3,2-d][1,3]dioxol-5-yl)-
7.6 Hz, Ar-H), 6.97 (t, 1H, J ¼ 7.6 Hz, Ar-H), 7.23 (d, 1H, J ¼ 8.4 Hz, methyl)-5-methyl-3aH-pyrrolo[3,4-d]isoxazole-4,6(5H,6aH)-
Ar-H), 7.56 (d, 1H, J ¼ 7.6 Hz, Ar-H), 10.84 (s, 1H, –NH); 13C NMR dione (8a). Colourless solid; Mp ¼ 66–68 C; IR (cmꢂ1): 2987,
ꢀ
(125 MHz, DMSO-d6): d 15.7, 26.7, 27.1, 35.9, 65.0, 76.9, 79.1, 1725, 1665, 1497, 1381, 1197, 1048; [a]2D6 ¼ +30.9 (0.54, CHCl3);
81.4, 81.8, 104.4, 106.6, 111.1, 111.4, 118.3, 118.9, 120.5, 134.1, H NMR (500 MHz, CDCl3): d 1.29 (s, 3H, isopropylidene-CH3),
135.9; MS m/z ¼ 391 M+ + 1; anal. calcd for C20H26N2O6 (390.18): 1.42 (s, 3H, isopropylidene-CH3), 2.20 (s, 3H, N–CH3), 3.75 (d,
C, 61.53; H, 6.71; N, 7.18. Found C, 61.65; H, 6.75; N, 7.06.
1H, J ¼ 9.2 Hz, H-3a0), 4.24 (d, 1H, J ¼ 3.1 Hz, H-3), 4.38 (d, 1H, J
¼ 11.5 Hz, OCHHPh), 4.45 (d, 1H, J ¼ 9.9 Hz, H-5), 4.71 (d, 1H, J
¼ 3.8 Hz, H-2), 4.76 (d, 1H, J ¼ 11.5 Hz, OCHHPh), 4.91 (d, 1H, J
¼ 9.2 Hz, H-6a0), 5.00 (dd, 1H, J ¼ 9.9, 3.8 Hz, H-4), 5.23 (s, 2H,
NCH2Ph), 5.94 (d, 1H, J ¼ 3.8 Hz, H-1), 7.01 (t, 1H, J ¼ 6.9 Hz, Ar-
Experimental procedure for glycosyl isoxazolines 7a–d, 8a–d
and glycosyl isoxazoles 9a–c
Using di-tert-butyl dicarbonate [(BOC)2O] and 4-dimethyla- H), 7.05–7.08 (m, 2H, Ar-H), 7.15 (d, 3H, J ¼ 7.7 Hz, Ar-H), 7.23–
minopyridine (DMAP) catalyst. Di-tert-butyl dicarbonate 7.29 (m, 3H, Ar-H), 7.32–7.39 (m, 5H, Ar-H), 7.64 (d, 1H, J ¼ 7.6
(1.5 mmol) and N-methyl maleimide 6a (1.5 mmol) or dieth- Hz, Ar-H); 13C NMR (125 MHz, CDCl3): d 24.4, 26.4, 26.9, 36.5,
ylacetylene dicarboxylate 10 (3 mmol) were dissolved in CH3CN 50.2, 57.5, 72.2, 78.9, 81.4, 82.0, 82.6, 104.9, 108.6, 109.9, 111.7,
(5 mL), and DMAP (0.2 mmol) was added. The nitro compound 119.4, 119.7, 121.7, 126.9, 127.1, 127.6, 128.2, 128.3, 128.6,
5a–f (1 mmol) dissolved in CH3CN (5 mL) was added in portions 128.7, 128.8, 136.8, 137.3, 137.5, 153.8, 170.1, 172.5; MS m/z ¼
over a period of 1 h at room temperature to the dipolarophile 622 M+ + 1; anal. calcd for C36H35N3O7 (621.25): C, 69.55; H,
solution, and the reaction was allowed to proceed for further 3 5.67; N, 6.76. Found: C, 69.70; H, 5.71; N, 6.52.
h. Aer the completion of the reaction, the solvent was evapo-
(3aR,6aS)-3-((R)-((3aR,5R,6S,6aR)-6-(Benzyloxy)-tetrahydro-
rated under reduced pressure and the products were separated 2,2-dimethylfuro[3,2-d][1,3]dioxol-5-yl)(2-methyl-1H-indol-3-yl)-
by column chromatography using silica gel (100–200 mesh) methyl)-5-methyl-3aH-pyrrolo[3,4-d]isoxazole-4,6(5H,6aH)-
with ethyl acetate–petroleum ether as an eluent to obtain iso- dione (7b). Colourless solid; Mp ¼ 210–212 ꢀC; IR (cmꢂ1): 2979,
xazolines 7a–d, 8a–d or isoxazoles 9a–c.
1728, 1661, 1499, 1384, 1197, 1044; [a]2D7 ¼ ꢂ13.4 (0.68, CHCl3);
Using ethyl chloroformate and 4-dimethylaminopyridine 1H NMR (500 MHz, CDCl3): d 1.23 (s, 3H, isopropylidene-CH3),
(DMAP) catalyst. Et3N (1.2 mmol), DMAP (0.2 mmol) and 1.37 (s, 3H, isopropylidene-CH3), 2.49 (s, 6H, N–CH3, indole-
N-methyl maleimide 6a (1.5 mmol) or diethylacetylene dicarbox- CH3), 3.81 (d, 1H, J ¼ 9.2 Hz, H-3a0), 4.36 (d, 1H, J ¼ 11.5 Hz,
ylate 10 (3 mmol) were dissolved in CH2Cl2 (5 mL). The nitro OCHHPh), 4.41–4.46 (m, 2H, H-3, H-5), 4.59–4.61 (m, 2H, H-2,
compound 5a–f (1 mmol) and ethyl chloroformate (2 mmol) dis- OCHHPh), 4.87 (d, 1H, J ¼ 9.9 Hz, H-6a0), 5.12 (dd, 1H, J ¼ 9.9,
solved in CH2Cl2 (5 mL) were added in portions over a period of 1 3.1 Hz, H-4), 5.82 (d, 1H, J ¼ 3.8 Hz, H-1), 7.00–7.58 (m, 3H, Ar-
h at room temperature to the dipolarophile solution, and the H), 7.21 (d, 2H, J ¼ 7.7 Hz, Ar-H), 7.25–7.28 (m, 1H, Ar-H), 7.34
reaction was allowed to proceed for another 3 h. The reaction (t, 2H, J ¼ 6.9 Hz, Ar-H), 7.50 (s, 1H, Ar-H), 7.91 (s, 1H, NH); 13
C
mixture was washed with water and dil. HCl. The organic layer was NMR (125 MHz, CDCl3): d 11.8, 24.8, 26.4, 26.9, 29.7, 35.3, 56.4,
dried over anhydrous Na2SO4, and the solvent was removed under 71.6, 78.3, 79.9, 82.3, 82.4, 104.5, 110.8, 111.7, 117.5, 119.5,
reduced pressure to give a crude product, which was puried by 121.1, 126.6, 127.7, 128.5, 135.0, 135.5, 137.6, 154.2, 170.6,
column chromatography with ethyl acetate–petroleum ether as an 172.6; MS m/z ¼ 546 M+ + 1; anal. calcd for C30H31N3O7 (545.22):
eluent to obtain isoxazolines 7a–d, 8a–d or isoxazoles 9a–c.
(3aR,6aS)-3-((R)-(1-Benzyl-1H-indol-3-yl)((3aR,5R,6S,6aR)-6-
C, 66.04; H, 5.73; N, 7.70. Found: C, 66.21; H, 5.74; N, 7.79.
(3aS,6aR)-3-((R)-((3aR,5R,6S,6aR)-6-(Benzyloxy)-tetrahydro-
(benzyloxy)-tetrahydro-2,2-dimethylfuro[3,2-d][1,3]dioxol-5-yl)- 2,2-dimethylfuro[3,2-d][1,3]dioxol-5-yl)(2-methyl-1H-indol-3-yl)-
methyl)-5-methyl-3aH-pyrrolo[3,4-d]isoxazole-4,6(5H,6aH)- methyl)-5-methyl-3aH-pyrrolo[3,4-d]isoxazole-4,6(5H,6aH)-
dione (7a). Colourless solid; Mp ¼ 100–102 ꢀC; IR (cmꢂ1): 2981, dione (8b). Viscous liquid; IR (cmꢂ1): 2997, 1721, 1669, 1497,
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1384, 1195, 1047; [a]D27 ¼ +108.4 (0.28, CHCl3); 1H NMR (500
MHz, CDCl3): d 1.27 (s, 3H, isopropylidene-CH3), 1.36 (s, 3H,
isopropylidene-CH3), 1.92 (s, 3H, indole-CH3), 2.43 (s, 3H,
NCH3), 3.66 (d, 1H, J ¼ 8.4 Hz, H-3a0), 4.23 (d, 1H, J ¼ 9.9 Hz, H-
5), 4.37–4.39 (m, 2H, H-3, OCHHPh), 4.71 (d, 1H, J ¼ 3.8 Hz, H-2),
4.77 (d, 1H, J ¼ 11.5 Hz, OCHHPh), 4.95 (d, 1H, J ¼ 8.4 Hz, H-6a0),
5.04 (dd, 1H, J ¼ 9.9, 3.1 Hz, H-4), 5.90 (d, 1H, J ¼ 3.8 Hz, H-1),
6.90 (t, 1H, J ¼ 6.9 Hz, Ar-H), 6.97 (t, 1H, J ¼ 7.6 Hz, Ar-H), 7.03 (d,
1H, J ¼ 7.6 Hz, Ar-H), 7.18 (d, 1H, J ¼ 7.7 Hz, Ar-H), 7.32–7.39 (m,
4H, Ar-H), 7.43 (d, 1H, J ¼ 7.6 Hz, Ar-H), 8.12 (s, 1H, NH); 13C
NMR (125 MHz, CDCl3): d 12.2, 26.4, 26.8, 29.7, 31.9, 36.3, 57.7,
72.4, 79.1, 80.8, 82.4, 82.6, 104.8, 110.5, 111.7, 117.7, 119.6,
120.6, 128.2, 128.3, 128.7, 135.2, 136.7, 137.6, 153.1, 169.9, 172.5;
MS m/z ¼ 546 M+ + 1; anal. calcd for C30H31N3O7 (545.22): C,
66.04; H, 5.73; N, 7.70. Found: C, 65.95; H, 5.73; N, 7.84.
4,6(5H,6aH)-dione (7d). Colourless solid; Mp ¼ 70–72 ꢀC; IR
(cmꢂ1): 2993, 1727, 1664, 1496, 1381, 1197, 1048; [a]2D8 ¼ ꢂ69.9
(1.22, CHCl3); 1H NMR (500 MHz, CDCl3): d 1.26 (s, 3H, iso-
propylidene-CH3), 1.41 (s, 3H, isopropylidene-CH3), 2.47 (s, 3H,
NCH3), 4.02 (d, 1H, J ¼ 9.9 Hz, H-3a0), 4.35 (d, 1H, J ¼ 12.3 Hz,
OCHHPh), 4.42 (d, 1H, J ¼ 3.8 Hz, H-3), 4.57–4.59 (m, 2H, H-2,
OCHHPh), 4.61 (d, 1H, J ¼ 9.9 Hz, H-5), 5.06 (d, 1H, J ¼ 9.2 Hz,
H-6a0), 5.11 (dd, 1H, J ¼ 9.9, 3.1 Hz, H-4), 5.21 (s, 2H, NCH2Ph),
5.86 (d, 1H, J ¼ 3.8 Hz, H-1), 7.01 (d, 2H, J ¼ 8.4 Hz, Ar-H), 7.11 (t,
1H, J ¼ 7.6 Hz, Ar-H), 7.16 (t, 1H, J ¼ 8.4 Hz, Ar-H), 7.19–7.23 (m,
3H, Ar-H), 7.26–7.29 (m, 2H, Ar-H), 7.35 (t, 2H, J ¼ 7.6 Hz, Ar-H),
7.41 (d, 2H, J ¼ 8.4 Hz, Ar-H), 7.79 (d, 1H, J ¼ 7.6 Hz, Ar-H); 13
C
NMR (125 MHz, CDCl3): d 24.8, 26.3, 26.9, 35.9, 49.7, 56.3, 71.5,
78.4, 80.1, 82.2, 82.3, 104.6, 109.3, 110.1, 111.6, 119.5, 120.1,
121.6, 122.3, 126.5, 127.1, 127.6, 128.5, 128.6, 128.7, 131.9,
136.2, 136.9, 137.5, 154.2, 170.4, 172.5; MS m/z ¼ 700 M+ + 1, 702
M+ + 3; anal. calcd for C36H34BrN3O7 (699.16): C, 61.72; H, 4.89;
N, 6.00. Found: C, 61.85; H, 4.91; N, 6.05.
(3aR,6aS)-3-((R)-((3aR,5R,6S,6aR)-6-(Benzyloxy)-tetrahydro-
2,2-dimethylfuro[3,2-d][1,3]dioxol-5-yl)(1-methyl-1H-indol-3-yl)-
methyl)-5-methyl-3aH-pyrrolo[3,4-d]isoxazole-4,6(5H,6aH)-
dione (7c). Colourless solid; Mp ¼ 86–88 C; IR (cmꢂ1): 2997,
ꢀ
(3aS,6aR)-3-((R)-(1-(4-Bromobenzyl)-1H-indol-3-yl)((3aR,5R,
6S,6aR)-6-(benzyloxy)-tetrahydro-2,2-dimethylfuro[3,2-d][1,3]-
dioxol-5-yl)methyl)-5-methyl-3aH-pyrrolo[3,4-d]isoxazole-
4,6(5H,6aH)-dione (8d). Colourless solid; Mp ¼ 78–80 ꢀC; IR
(cmꢂ1): 2997, 1721, 1669, 1495, 1385, 1198, 1047; [a]2D8 ¼ ꢂ1.2
(1.02, CHCl3); 1H NMR (500 MHz, CDCl3): d 1.29 (s, 3H, iso-
propylidene-CH3), 1.41 (s, 3H, isopropylidene-CH3), 2.19 (s, 3H,
NCH3), 3.75 (d, 1H, J ¼ 9.2 Hz, H-3a0), 4.26 (d, 1H, J ¼ 3.8 Hz, H-
3), 4.38 (d, 1H, J ¼ 11.5 Hz, OCHHPh), 4.44 (d, 1H, J ¼ 9.9 Hz, H-
5), 4.71 (d, 1H, J ¼ 3.8 Hz, H-2), 4.76 (d, 1H, J ¼ 11.5 Hz,
OCHHPh), 4.93 (d, 1H, J ¼ 9.2 Hz, H-6a0), 4.98 (dd, 1H, J ¼ 9.9,
3.1 Hz, H-4), 5.16 (s, 2H, NCH2Ph), 5.94 (d, 1H, J ¼ 3.8 Hz, H-1),
7.00–7.03 (m, 3H, Ar-H) 7.06–7.08 (m, 3H, Ar-H), 7.32–7.40 (m,
7H, Ar-H), 7.62 (d, 1H, J ¼ 7.6 Hz, Ar-H); 13C NMR (125 MHz,
CDCl3): d 24.4, 26.4, 26.9, 36.5, 49.6, 57.5, 72.8, 79.0, 81.2, 82.0,
82.5, 104.9, 108.8, 109.8, 111.7, 119.3, 119.8, 121.4, 121.9, 127.0,
128.2, 128.3, 128.5, 128.6, 128.7, 131.8, 136.4, 136.6, 137.5,
153.6, 170.2, 172.5; MS m/z ¼ 700 M+ + 1, 702 M+ + 3; anal. calcd
for C36H34BrN3O7 (699.16): C, 61.72; H, 4.89; N, 6.00. Found: C,
61.88; H, 4.90; N, 6.25.
1729, 1665, 1497, 1384, 1197, 1044; [a]2D7 ¼ ꢂ108.3 (1.70, CHCl3);
1H NMR (500 MHz, CDCl3): d 1.25 (s, 3H, isopropylidene-CH3),
1.42 (s, 3H, isopropylidene-CH3), 2.46 (s, 3H, NCH3), 3.74 (s, 3H,
indole-CH3), 4.01 (d, 1H, J ¼ 9.2 Hz, H-3a0), 4.35 (d, 1H, J ¼ 12.2
Hz, OCHHPh), 4.42 (d, 1H, J ¼ 3.8 Hz, H-3), 4.56 (d, 1H, J ¼ 9.9
Hz, H-5), 4.59–4.62 (m, 2H, H-2, OCHHPh), 5.00 (d, 1H, J ¼ 9.2
Hz, H-6a0), 5.10 (dd, 1H, J ¼ 9.9, 3.1 Hz, H-4), 5.86 (d, 1H, J ¼ 3.8
Hz, H-1), 7.10 (t, 1H, J ¼ 6.9 Hz, Ar-H), 7.18 (s, 1H, Ar-H), 7.21–
7.24 (m, 3H, Ar-H), 7.29 (d, 2H, J ¼ 7.7 Hz, Ar-H), 7.36 (t, 2H, J ¼
6.9 Hz, Ar-H), 7.78 (d, 1H, J ¼ 8.4 Hz, Ar-H); 13C NMR (125 MHz,
CDCl3): d 24.7, 26.4, 26.9, 32.9, 35.8, 56.3, 71.5, 78.3, 80.3, 82.2,
82.3, 104.6, 108.2, 109.7, 111.6, 119.2, 119.6, 121.9, 126.5, 126.8,
127.6, 128.2, 128.9, 137.5, 137.6, 154.4, 170.5, 172.6; MS m/z ¼
546 M+ + 1; anal. calcd for C30H31N3O7 (545.22): C, 66.04; H,
5.73; N, 7.70. Found: C, 66.14; H, 5.77; N, 7.64.
(3aS,6aR)-3-((R)-((3aR,5R,6S,6aR)-6-(Benzyloxy)-tetrahydro-
2,2-dimethylfuro[3,2-d][1,3]dioxol-5-yl)(1-methyl-1H-indol-3-yl)-
methyl)-5-methyl-3aH-pyrrolo[3,4-d]isoxazole-4,6(5H,6aH)-
dione (8c). Colourless solid; Mp ¼ 90–92 C; IR (cmꢂ1): 2996,
ꢀ
1727, 1661, 1490, 1384, 1196, 1048; [a]2D8 ¼ ꢂ68.9 (1.32, CHCl3);
1H NMR (500 MHz, CDCl3): d 1.29 (s, 3H, isopropylidene-CH3),
1.43 (s, 3H, isopropylidene-CH3), 2.33 (s, 3H, NCH3), 3.70 (s, 3H,
indole-CH3), 3.79 (d, 1H, J ¼ 9.2 Hz, H-3a0), 4.18 (d, 1H, J ¼ 3.8
Hz, H-3), 4.40 (d, 1H, J ¼ 11.5 Hz, OCHHPh), 4.49 (d, 1H, J ¼ 9.9
Hz, H-5), 4.70 (d, 1H, J ¼ 3.8 Hz, H-2), 4.75 (d, 1H, J ¼ 11.5 Hz,
OCHHPh), 4.91 (d, 1H, J ¼ 9.2 Hz, H-6a0), 4.99 (dd, 1H, J ¼ 9.9,
3.1 Hz, H-4), 5.93 (d, 1H, J ¼ 3.8 Hz, H-1), 6.98 (s, 1H, Ar-H), 7.03
(t, 1H, J ¼ 7.6 Hz, Ar-H), 7.15 (t, 1H, J ¼ 7.6 Hz, Ar-H), 7.21–7.24
(m, 1H, Ar-H), 7.32–7.37 (m, 5H, Ar-H), 7.62 (d, 1H, J ¼ 8.4 Hz,
Ar-H); 13C NMR (125 MHz, CDCl3): d 24.6, 26.4, 26.9, 32.8, 36.2,
57.3, 72.1, 79.1, 81.2, 81.9, 82.3, 104.9, 108.2, 109.3, 111.7, 119.2,
119.4, 121.6, 126.8, 128.2, 128.4, 128.7, 129.0, 137.3, 137.4,
153.9, 170.3, 172.5; MS m/z ¼ 546 M+ + 1; anal. calcd for
Diethyl
3-((R)-(1-benzyl-1H-indol-3-yl)((3aR,5R,6S,6aR)-6-
(benzyloxy)-tetrahydro-2,2-dimethylfuro[3,2-d][1,3]dioxol-5-yl)-
methyl)isoxazole-4,5-dicarboxylate (9a). Viscous liquid; IR
(cmꢂ1): 2989, 1727, 1667, 1496, 1382, 1198, 1041; [a]2D6 ¼ +249.9
(0.58, CHCl3); 1H NMR (500 MHz, CDCl3): d 1.05 (t, 3H, J ¼ 7.6
Hz, COOCH2CH3), 1.29 (s, 3H, isopropylidene-CH3), 1.37 (t, 3H,
J ¼ 7.6 Hz, COOCH2CH3), 1.46 (s, 3H, isopropylidene-CH3),
3.89–4.00 (m, 2H, COOCH2CH3), 4.22–4.24 (m, 2H, H-3,
OCHHPh), 4.39 (q, 2H, J ¼ 7.6 Hz, COOCH2CH3), 4.58 (d, 1H, J ¼
11.5 Hz, OCHHPh), 4.67 (d, 1H, J ¼ 3.8 Hz, H-2), 5.12–5.27 (m,
4H, H-5, H-4, NCH2Ph), 5.94 (d, 1H, J ¼ 3.8 Hz, H-1), 7.00–7.02
(m, 2H, Ar-H), 7.05 (d, 2H, J ¼ 6.9 Hz, Ar-H), 7.08 (t, 1H, J ¼ 7.6
Hz, Ar-H), 7.15–7.17 (m, 3H, Ar-H), 7.20–7.27 (m, 6H, Ar-H), 7.72
(d, 1H, J ¼ 7.6 Hz, Ar-H); 13C NMR (125 MHz, CDCl3): d 13.8,
14.1, 26.5, 27.0, 34.7, 50.1, 61.6, 62.9, 71.9, 81.3, 81.8, 82.3,
105.1, 109.8, 111.4, 111.7, 114.8, 119.5, 119.9, 121.8, 126.9,
127.3, 127.6, 127.8, 127.9, 128.1, 128.4, 128.8, 136.9, 137.2,
137.5, 156.7, 160.1, 160.2, 162.8; MS m/z ¼ 681 M+ + 1; anal.
C
30H31N3O7 (545.22): C, 66.04; H, 5.73; N, 7.70. Found: C, 66.01;
H, 5.74; N, 7.78.
(3aR,6aS)-3-((R)-(1-(4-Bromobenzyl)-1H-indol-3-yl)((3aR,5R,
6S,6aR)-6-(benzyloxy)-tetrahydro-2,2-dimethylfuro[3,2-d][1,3]-
dioxol-5-yl)methyl)-5-methyl-3aH-pyrrolo[3,4-d]isoxazole-
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calcd for C39H40N2O9 (680.27): C, 68.81; H, 5.92; N, 4.12. Found:
C, 68.92; H, 5.93; N, 4.31.
A. P. Downie, C. L. Raston and J. L. Scott, J. Am. Chem. Soc.,
2001, 123, 8701; (d) G. W. V. Cave, C. L. Raston and J. L. Scott,
Chem. Commun., 2001, 2159.
Diethyl 3-((R)-((3aR,5R,6S,6aR)-6-(benzyloxy)-tetrahydro-2,2-
dimethylfuro[3,2-d][1,3]dioxol-5-yl)(1-ethyl-1H-indol-3-yl)-
methyl)isoxazole-4,5-dicarboxylate (9b). Viscous liquid; IR
(cmꢂ1): 2999, 1727, 1664, 1491, 1388, 1198, 1046; [a]2D7 ¼ +162.4
(0.88, CHCl3); 1H NMR (500 MHz, CDCl3): d 1.09 (t, 3H, J ¼ 6.9
Hz, COOCH2CH3), 1.29 (s, 3H, isopropylidene-CH3), 1.36 (t, 3H,
J ¼ 7.6 Hz, COOCH2CH3), 1.43 (t, 3H, J ¼ 6.9 Hz, NCH2CH3), 1.47
(s, 3H, isopropylidene-CH3), 3.97–4.03 (m, 2H, NCH2CH3), 4.07
(q, 2H, J ¼ 6.9 Hz, COOCH2CH3), 4.22–4.25 (m, 2H, H-3,
OCHHPh), 4.39 (q, 2H, J ¼ 6.9 Hz, COOCH2CH3), 4.59 (d, 1H, J ¼
11.5 Hz, OCHHPh), 4.68 (d, 1H, J ¼ 3.8 Hz, H-2), 5.16 (d, 1H, J ¼
10.7 Hz, H-5), 5.23 (dd, 1H, J ¼ 10.7, 3.1 Hz, H-4), 5.95 (d, 1H, J ¼
3.8 Hz, H-1), 6.99 (s, 1H, Ar-H), 7.03 (t, 1H, J ¼ 7.6 Hz, Ar-H), 7.13
(t, 1H, J ¼ 7.6 Hz, Ar-H), 7.18–7.27 (m, 6H, Ar-H), 7.73 (d, 1H, J ¼
7.6 Hz, Ar-H); 13C NMR (125 MHz, CDCl3): d 13.9, 14.1, 15.4,
26.5, 27.0, 34.5, 40.9, 61.6, 62.9, 71.9, 81.6, 81.9, 82.2, 105.1,
109.4, 110.8, 111.7, 114.7, 119.1, 119.9, 121.5, 126.5, 127.3,
127.9, 128.1, 128.4, 136.4, 137.2, 156.8, 160.1, 163.0; MS m/z ¼
619 M+ + 1; anal. calcd for C34H38N2O9 (618.26): C, 66.01; H,
6.19; N, 4.53. Found: C, 66.22; H, 6.11; N, 4.41.
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J. Auge, Top. Curr. Chem., 1999, 206, 1; (c) U. M. Lindstrom,
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Diethyl
3-((R)-((3aR,5R,6S,6aR)-6-ethoxy-tetrahydro-2,2-
9 (a) J. E. Monckton and D. A. McCormick, J. Neurophysiol.,
2002, 87, 2124; (b) C.-M. Vacker, P. Fettier, C. Creminon,
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dimethylfuro[3,2-d][1,3]dioxol-5-yl)(2-methyl-1H-indol-3-yl)-
methyl)isoxazole-4,5-dicarboxylate (9c). Viscous liquid; IR (KBr):
3476, 2931, 2345, 1727, 1556, 1349, 751 cmꢂ1; [a]D30 ¼ +139.34 10 (a) P. T. Perumal and R. Nagarajan, Tetrahedron, 2002, 58,
(0.54, CHCl3); 1H NMR (500 MHz, CDCl3): d 1.01 (t, 3H, J ¼ 6.9
Hz, COOCH2CH3), 1.12 (t, 3H, J ¼ 7.6 Hz, COOCH2CH3), 1.27 (s,
3H, isopropylidene-CH3), 1.33 (t, 3H, J ¼ 7.6 Hz, OCH2CH3), 1.41
(s, 3H, isopropylidene-CH3), 2.42 (s, 3H, indole-CH3), 3.16–3.19
(m, 1H, OCHHCH3), 3.57–3.61 (m, 1H, OCHHCH3), 4.05–4.08
(m, 2H, COOCH2CH3), 4.20 (d, 1H, J ¼ 3.1 Hz, H-3), 4.36 (q, 2H, J
¼ 7.6 Hz, COOCH2CH3), 4.59 (d, 1H, J ¼ 3.8 Hz, H-2), 4.98 (d,
1H, J ¼ 9.9 Hz, H-5), 5.26 (dd, 1H, J ¼ 9.9, 3.1 Hz, H-4), 5.88 (d,
1H, J ¼ 3.8 Hz, H-1), 6.95 (t, 1H, J ¼ 6.9 Hz, Ar-H), 7.00 (t, 1H, J ¼
8.4 Hz, Ar-H), 7.16 (d, 1H, J ¼ 6.9 Hz, Ar-H), 7.62 (d, 1H, J ¼ 8.4
1229; (b) M. Chakrabarty, N. Ghosh, R. Basak and
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Hz, Ar-H), 7.83 (s, 1H, NH); 13C NMR (125 MHz, CDCl3): 13.9, 11 (a) B. M. Trost, Acc. Chem. Res., 2002, 35, 695; (b) B. M. Trost,
14.0, 14.9, 26.5, 27.1, 29.8, 34.2, 61.7, 62.8, 65.9, 80.8, 82.3, 82.9,
104.9, 110.3, 111.6, 118.7, 119.4, 120.8, 123.5, 127.6, 133.4,
Science, 1991, 254, 1471; (c) L. T. An, J. P. Zou, L. L. Zhang
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135.4, 155.6, 156.7, 160.5, 162.9; MS m/z ¼ 543 M+ + 1; anal. 12 (a) N. Ono, The nitro group in organic synthesis, Wiley, New
calcd for C28H34N2O9 (542.33): C, 61.98; H, 6.32; N, 5.16. Found
C, 61.90; H, 6.35; N, 5.31.
York, 2001; (b) D. Seebach, E. W. Colvin, F. Lehr and
T. Weller, Chimia, 1979, 33, 1; (c) G. Calderari and
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13 O. M. Berner, L. Tedeschi and D. Enders, Eur. J. Org. Chem.,
2002, 12, 1877.
Acknowledgements
Authors K.K. and R.S.K. are thankful to the Council of Scientic 14 (a) R. J. Sundberg, The Chemistry of Indoles, Academic Press,
and Industrial Research, New Delhi, India for the research
fellowship.
New York, 1996; (b) A. Casapullo, G. Bifulco, I. Bruno and
R. Riccio, J. Nat. Prod., 2000, 63, 447; (c) T. R. Garbe,
M. Kobayashi, N. Shimizu, N. Takesue, M. Ozawa and
H. Yukawa, J. Nat. Prod., 2000, 63, 596; (d) B. Bao, Q. Sun,
X. Yao, J. Hong, C. O. Lee, C. J. Sim, K. S. Im and
J. H. Jung, J. Nat. Prod., 2005, 68, 711.
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