Diastereoselective synthesis and antifungal activity of glycosyl isoxazolines

Article abstract of DOI:10.1081/CAR-200037331

Glycosyl nitrile oxides, generated in situ by reaction of glycosyl oximes (3a, 3b, 4) with N-chlorosuccinimide and DBU, on 1,3-dipolar cycloaddition with substituted alkenes resulted in glycosyl isoxazolines (5, 7-28) in diastereoselective manner. The ext

Full text of DOI:10.1081/CAR-200037331

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Diastereoselective Synthesis and
Antifungal Activity of Glycosyl
Isoxazolines
Ram Chandra Mishra a , Neetu Tewari a , Shyam Sunder Verma a ,
Rama Pati Tripathi a , Manish Kumar b & Praveen Kumar Shukla b
a Division of Medicinal Chemistry, Central Drug Research Institute,
Lucknow, 226001, India
b Medical Mycology, Central Drug Research Institute, Lucknow, India
Version of record first published: 18 Aug 2006.
To cite this article: Ram Chandra Mishra, Neetu Tewari, Shyam Sunder Verma, Rama Pati Tripathi,
Manish Kumar & Praveen Kumar Shukla (2004): Diastereoselective Synthesis and Antifungal Activity of
Glycosyl Isoxazolines, Journal of Carbohydrate Chemistry, 23:6-7, 353-374
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JOURNAL OF CARBOHYDRATE CHEMISTRY
Vol. 23, No. 6&7, pp. 353–374, 2004
Diastereoselective Synthesis and Antifungal Activity
of Glycosyl Isoxazolines#
Ram Chandra Mishra,1 Neetu Tewari,1 Shyam Sunder Verma,1
2
2
Rama Pati Tripathi,1, Manish Kumar, and Praveen Kumar Shukla
*
2
1Divisions of Medicinal Chemistry and Medical Mycology, Central Drug Research
Institute, Lucknow, India
CONTENTS
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
II. RESULTS AND DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . 355
A. Antifungal Evaluation of the Compounds . . . . . . . . . . . . . . . 360
B. Antifungal Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . 363
III. EXPERIMENTAL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364
ACKNOWLEDGMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . 372
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372
#CDRI Communication No.6460.
*
Correspondence: Rama Pati Tripathi, Division of Medicinal Chemistry, Central Drug Research
Institute, Lucknow 226001, India; Fax: þ91-522-2223938, 2223405; E-mail: rpt_56@yahoo.com.
353
DOI: 10.1081/CAR-200037331
0732-8303 (Print); 1532-2327 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

354
Mishra et al.
ABSTRACT
Glycosyl nitrile oxides, generated in situ by reaction of glycosyl oximes (3a, 3b, 4)
with N-chlorosuccinimide and DBU, on 1,3-dipolar cycloaddition with substituted
alkenes resulted in glycosyl isoxazolines (5, 7–28) in diastereoselective manner.
The extent of diastereoselection varies with the nature of substituents both in sugar
and alkenes. The compounds synthesized were screened in vitro against many
fungi wherein two of the compounds (12, 23) showed significant inhibition against
Sporothrix schenckii, Trychophyton mentagrophytes, and Cryptococcus neoformans
with MIC of 12.5 and 6.25 mg/mL, respectively.
Key Words: Cycloaddition; Isoxazoline; DBU; Antifungal activity.
INTRODUCTION
1,3-Dipolar cycloaddition reactions of nitrones and nitrile oxides with alkenes for the
synthesis of five membered heterocycles of synthetic and biological importance is known
for quite some time.[1–3] Isoxazolines, isosters of oxazolidinones, which are well-known
antibacterial agents, have recently been reported to be of great significance as antibacterial
and antifungal agents.[4,5]
The stereochemistry in 1,3-dipolar cycloadditions is controlled either by choosing an
appropriate substrate or controlling the geometry of the transition state during progress
of the reaction by agents acting as catalyst or co-catalyst. If the alkene, or the 1,3-
dipole, contains a chiral center(s), the approach towards one of the faces of the alkene or
1,3-dipole can be discriminated (diastereofacial selectivity) leading to a diastereoselectivity.
The exo/endo selectivity is also diastereoselectivity, but for clarity endo/exo or
cis-trans selectivity terms are preferred.
Existing reports for 1,3-dipolar additions using optically active nitrile oxides are
scanty but of great synthetic value.[6–8] Application of chiral nitrile oxides generated
in situ by reaction of oximes with N-bromosuccinimide in the presence of bases such as
pyridine or triethylamine to get isoxazolines diastereoselectively have recently been
reported[9] to prepare biologically active compounds. Synthetic application of carbo-
hydrate-derived chiral building blocks as precursors for the synthesis of nitrogenated
compounds such as amino sugars, alkaloids, and amino acids has been reported since
long ago.[10,11] Asymmetric 1,3-dipolar cycloaddition utilizing either chiral nitrile oxide
or chiral dipolarophile because of its versatility in the construction of diastereomerically
pure compounds like amino alcohol, b-hydroxy ketones, amino acids, and many anti-
biotics are of much importance.[12] Carbohydrate-derived chiral nitrones have been used
in asymmetric synthesis of fused or bridged isoxazoline, oxepans, and pyrans.[10] Keeping
the aforementioned facts in mind and in the continuation of our work on the development
of sugar derivatives as chemotherapeutic agents,[13] we were prompted to synthesize
glycosylated isoxazolines, which may serve as intermediates for the synthesis of a
variety of compounds. The compounds synthesized were screened against Candida
albicans, Candida parapsilosis (ATCC 22019), Cryptococcus neoformans, Aspergillus
fumigatus, Sporothrix schenckii, and Trychophyton mentagrophytes.

Glycosyl Isoxazolines
355
RESULTS AND DISCUSSION
The glycosyl oximes[14] (3a, 3b, 4) were prepared from the respective uloses (1a, 1b,
2) by reaction with hydroxylamine hydrochloride separately in good yields. Glycosyl
oximes on reaction with N-cholorosuccinimide led to the formation of intermediate
glycosyl hydroxamoyl chlorides, which on treatment with diazabicyclo undecene (DBU)
separately in situ resulted in glycosyl nitrile oxides. The intermediate nitrile oxides, so gene-
rated, on reaction with different dipolarophiles (alkenes) gave 3- glycosyl-2-isoxazolines in
good yields with varying diastereoselection.
Thus reaction of glycosyl ulose 1a with hydroxylamine hydrochloride resulted in
a 1 : 1 mixture of syn/anti oxime 3a, which on treatment with N-chlorosuccinimide
gave the intermediate glycosyl hydroxamoyl chloride. In situ reaction of the intermediate
hydroxamoyl chloride with DBU resulted in the formation of glycosyl nitrile oxide
(unisolated), which on treatment with ethyl acrylate at 08C gave a mixture of products
from which only two products could be isolated by column chromatography. The
faster-moving compound was found to be a diastereomeric mixture of 5-carbethoxy-3-
(30-O-methyl-10, 20-O-isopropylidene-tetrahydro-10, 40-furanos-40-yl)-isoxazole (5). The
two diastereomers formed were separated by repetitive column chromatography and
characterized individually. The structure of compound 5 was established on the basis of
spectral data and analysis. Compound 5 (major diastereoisomer) in IR spectrum exhibited
absorption band at 1744 and 1625 cm21, indicating the presence of COOEt and C55N moi-
eties, respectively. In the 1H NMR spectrum a dd signal for two protons at d 3.4 while a
one-proton m at d 4.99 accounted for the H-4 and H-5 of the isoxazoline ring, respectively.
In 13C NMR spectrum a signal corresponding to C55N appeared at d 157 and signals
corresponding to C-4 and C-5 of the isoxazoline ring appeared at d 40.0 and 87.0, respec-
tively, besides other usual signals. The minor diastereoisomer showed a dd for H-5 at d
5.00 with J ¼ 9.6 and 8.4 Hz, and an m at d 3.40–3.34 accounted for methylene
protons at C-4. In 13C NMR there were slight differecnces in d values of all the carbons.
The second product, isolated from column, was found to be a furoxan derivative (6, 20%)
formed by dimerization of the nitrile oxide. Its structure was also established on the basis
of spectroscopic data and analysis. MS (FAB) of compound 6 showed a peak at 431 cor-
1
responding to (M þ H)þ, while in the H NMR spectrum all the proton signals in sugar
moiety were duplicated and no proton signal corresponding to isoxazoline ring was
observed. It is appropriate to mention here that when triethyl amine was used as a base
instead of DBU in the aforementioned reaction, the yield of the isoxazoline is low and
furoxan is the major product. Further, formation of hydroxamoyl chloride in the presence
of triethyl amine is slow and always accompanied with a darkening of the reaction mixture
while with DBU, hydroxamoyl formation followed by the addition of alkene is completed
within 2–4 h and reaction mixture is comparatively clean.
Similarly, reaction of 3a with dipolarophiles including ethyl vinyl ether, vinyl acetate,
methyl vinyl ketone, acrylo nitrile, allyl bromide, 2-allyl phenol, 4-allyl anisole, allyl
alcohol, and crotonic acid separately resulted in the formation of respective glycosyl iso-
xazolines (7–14) as diastereomeric mixture in fair to good yields. Diastereomers could be
separated in the reaction of ethyl vinyl ether and acrylonitrile with 3a and characterized
1
individually as major (7, 10) and minor isomers. Minor isomer of 7 in H NMR shows
a d signal for H-5, while in major isomer it appeared as dd. Similarly for compound 10,
H-5 appeared as a t in the minor isomer while in major isomer as m at d 5.21.

356
Mishra et al.
It is interesting to note that the reaction of crotonic acid with 3a gave regioisomeric
glycosyl isoxazoline (15) with 4-carboxy and 5-methyl substituents as distereoisomeric
mixture. It is speculated that due to the electron-withdrawing effect of COOH, the
polarization is in such a manner that electron density is more at b carbon to carboxyl
group, which results in compound 15. However, the formation of other regioisomer in
minor amounts cannot be ruled out, because many unisolable products were observed
on tlc plates. The structure of the compound 15 was elucidated on the basis of IR, MS
(FAB), NMR spectral data and analysis. Compound 15 in the IR spectrum exhibited
absorption band at 3352, 1769, and 1658 cm21 indicating the presence of COOH and
C55N moieties, respectively. MS (FAB) showed peak at m/z 302 corresponding to
1
(M þ H)þ. In H NMR spectrum an m for one proton at d 7.22 accounted for the H-4
and another m at d 1.81 for H-5 of the isoxazoline ring. The 13C NMR spectrum
showed signals corresponding to COOH and C55N at d 164.4 and d 163.8, respectively,
while signals at d 149.5 & 118.5 accounted for C-4 and C-5 of the isoxazoline ring,
respectively, besides other usual signals for sugar moiety.
In the next attempt a glycosyl oxime with bulky 3-O-benzyl substituent was chosen as
starting material to see whether there is any improvement on diastereoselection due to
steric effect. Thus the reaction of oxime 3b with N-chlorosuccinimide leads to the
formation of intermediate hydroxamoyl chloride, which on treatment with DBU results
in the respective nitrile oxide and the latter, on in situ reaction with ethyl acrylate, gave
compound 16 in 75% yield as diastereomeric mixture. Some minor products, observed
on thin layer chromatography plates formed in the reaction, could not be isolated. The
structure of the compound 16 was elucidated on the basis of IR, FABMS, NMR spectral
data, and analysis. Compound 16 in the IR spectrum exhibited absorption band at 1744 and
1625 cm21, indicating the presence of COOEt and C55N moieties, respectively. The MS
(FAB) showed peak at m/z 392 corresponding to (M þ H)þ, and in the 1H NMR spectrum
an m for two protons at d 3.40 while a one-proton m at d 4.93 accounted the H-4 and H-5 of
the isoxazoline ring, respectively (Sch. 1). The 13C NMR showed two signals correspond-
ing to C55N at d 157.3 and 156.7 for each diastereomer, while signals at d 40.5 and d 40.5
accounted for C-4 of the two diastereomers and another signal at d 85.3 corresponded to
C-5 of the isoxazoline ring, respectively, besides other usual signals (Sch. 2).
Similar reaction of 3b with N-chlorosuccinimide followed by treatment with DBU
and subsequent cycloaddition of ethyl vinyl ether, vinyl acetate, methyl vinyl ketone, acry-
lonitrile, allyl bromide, 2-allyl phenol, 4-allyl anisole, and allyl alcohol separately resulted
in the formation of respective glycosyl isoxazolines (17–24) in good yield with marginal
diastereoselection (Tab. 1). The structures of all the products were determined on the basis
of spectroscopic data and analysis. However, reaction of 3b with crotonic acid here too
resulted in regioisomeric glycosyl isoxazoline (25) with 4-carboxyl and 5-methyl
substituents.
The 1H NMR spectrum of all the glycosyl isoxazolines, except compound 25, showed
characteristic signals for H-4 and H-5 of isoxazoline ring as d, dd, or m at around d 3.5 and
as t, dd, or m at around d 5.0, respectively, while H-40 (sugar ring) in all the compounds
appeared downfield at around d 5.1–5.2. In 13C NMR C-5 in all the compounds was
observed around d 65.0–87.0 (d 102.6 in compound 7) depending upon the nature of
substituents, while C-4 in these compounds appeared between d 37.0–41.0. All the com-
pounds showed (M þ H)þ peaks in their FAB MS. Only a marginal diastereoselection was
noticed in most of the cases. It is appropriate to mention here that all the spots observed on

Glycosyl Isoxazolines
357

358
Mishra et al.

Glycosyl Isoxazolines
359
Table 1. Glycosyl isoxazolines synthesized.
Entry
Compound no.
R
R1
R2
% Yield
Ratio of isomers#
1
2
5
7
CH3
CH3
COOC2H5
OC2H5
H
H
H
H
H
H
H
H
H
70
60
60
54
55
58
75
79
60
58
75
65
75
59
50
80
75
80
65
55
65
55
75
75 : 25
60 : 40
62 : 38
55 : 45
55 : 45
60 : 40
75 : 25
65 : 35
55 : 45
60 : 40
80 : 20
65 : 35
65 : 35
60 : 40
62 : 38
70 : 30
90 : 10
75 : 25
65 : 35
65 : 35
60 : 40
70 : 30
60 : 40
3
8
CH3
CH3
OCOCH3
COCH3
CN
4
9
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
CH3
CH3
6
CH2Br
7
CH3
CH3
CH2PhOH
CH2PhOCH3
CH2OH
CH3
8
9
CH3
CH3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
COOH
H
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
—
COOC2H5
OC2H5
H
OCOCH3
COCH3
CN
H
H
H
CH2Br
H
CH2PhOH
CH2PhOCH3
CH2OH
CH3
H
H
H
COOH
H
COOC2H5
CH2PhOH
CH2OH
—
—
H
H
1
#Determined on the basis of integration of H NMR signal.
tlc plates in the reactions could not be isolated, thus the possibility of regioisomeric
isoxazolines cannot be ruled out in few cases.
Compound 25 in its IR spectrum exhibited absorption bands at 3280, 1770, 1658, and
1587 cm21 corresponding to carboxylic acid and C55N moieties; MS (FAB) showed peak
corresponding to (M þ H)þ at m/z 378. In 1H NMR a broad singlet at d 9.64 exchangeable
with D2O corresponds to carboxyl proton, while H-4 and H-5 of the isoxazoline
ring appeared as m at d 7.13 and d 1.94 a m, respectively, beside other usual signals.
In 13C NMR spectrum of compound 25 signals corresponding to COOH and C55N of
the isoxazoline ring appeared at d 173.0 and 164.3, beside other usual signals.
Among all the compounds (5, 7–25) the maximum diastereoselection (9 : 1) was
noticed in reaction of 3b with 2-allyl phenol for compound 22. As changing the substituent in
the sugar ring did not improve the diastereoselection, we were curious to compare the dia-
stereoselectivity of furanose and pyranose skeletons at least with three alkenes, ethyl acry-
late, allyl alcohol, and 2-allyl phenol. Thus, galactopyranosyl oxime (4), obtained from the
galactopyranosyl ulose (2)[15] and hydroxylamine hydrochloride, on treatment with N-chlor-
osuccinimide resulted in the unisolated galactopyranosyl hydroxamoyl chloride, which on
addition of DBU gave glycosyl nitrile oxide and the latter on in situ reaction with ethyl acry-
late gave a diastereoisomeric mixture of galactopyranosyl isoxazolines (26) in 65% yield.
The structure of 26 was elucidated on the basis of IR, NMR, and MS spectral data. The

360
Mishra et al.
MS showed the peak at m/z 372 corresponding to (M þ H)þ, while the IR
spectrum exhibited an absorption band at 1745 cm21 and 1631cm21 corresponding to
1
COOEt and C55N of the isoxazoline ring, respectively. In the H NMR spectrum two m
were observed at d 4.82 and d 3.45, each accounting for diastereomeric H-5 and H-4,
respectively, in the isoxazoline ring, besides other usual signals.
Similar sequence of reactions of galactopyranosyl oxime with N-chlorosuccinimide
treatment with DBU followed by cycloaddition of 2-allyl phenol resulted in compound
27 as diastereomeric mixture (7 : 3). The structural elucidation was carried out using IR,
FABMS, and NMR spectroscopy. The IR spectrum exhibited absorption bands at 3467,
2985, and 1597 cm21 corresponding to –OH, ArCH, and C55N of the isoxazoline
1
moiety, while FAB MS showed (M þ H)þ at m/z 406. In the H NMR spectrum a
broad singlet at d 6.70 accounted for aromatic –OH, and two m at d 5.65 and 3.09
accounted for the H-5 and H-4 of the isoxazoline ring. 13C NMR showed characteristic
signals at d 158.2, 65.5, 65.8, and 37.2 for C55N, C-5 (diastereomeric), and C-4.
Similar cycloadditon of allyl alcohol with the nitrile oxide, generated from galactopyrano-
syl oxime, gave a diastereomeric mixture of isoxazoline 28 in 75% yield. Compound 28 in
IR exhibited absorption bands at 3469 cm21 and 1599 cm21, while FAB MS showed base
1
peak at 330 (M þ H)þ. In H NMR an m at d 4.67 for three protons accounted H-5 of
the isoxazoline ring and H-30 & H-50 of the sugar ring, while two dd at d 3.23 and 2.94
corresponded to H-4 of the isoxazoline ring. In 13C NMR signals at d 65.47 and 65.35
were accounted for diastereomeric C-5 and a signal at d 37.03 was assigned for C-4 of
the isoxazoline ring beside other usual signals.
Formation of two diastereoisomers, endo/exo or syn/anti, in different ratios could be
rationalized considering the Houk and Felkin Anh models of the transition states formed
during the reaction. The major products in allyl derivatives arise from a transition state I in
which the largest group occupies the anti position, the medium group the inside position,
and the smallest group the outside position,[2,16] the medium and smallest group being the
same proton in all the cases. The minor products may arise from the transition state II,
in which the location of the largest group is outside or inside. The outside position is
more sterically demanding than the inside due to the angle of approach of the nitrile
oxide oxygen.
Similarly for vinyl derivatives major products may be formed from the transition state
III and the minor products from a transition state IV if we consider the Houck model[2]
or Felkin model. However, if hyperconjugative effect is taken into consideration, the
transition state V gives the major isomer because the electron-withdrawing substituents
are known to occupy the inside or outside positions in order to exert minimal electron
withdrawal from the alkene, as this addition is presumed to be mildly electrophilic in
nature. Because outside position is more sterically demanding[16] the major product
arises from V while the minor one from VI (Fig. 1). As evident from the results and tran-
sition states proposed, the diastereoselectivity is mainly dependent on the size and nature
of substituent in alkene and almost independent of sugar substituents (Fig. 2).
Antifungal Evaluation of the Compounds
The minimum inhibitory concentration (MIC) for each compound against the
test fungi was determined using a broth micro-dilution technique as per guidelines

Glycosyl Isoxazolines
361

362
Mishra et al.

Glycosyl Isoxazolines
363
of NCCLS M-27A[17]. The MIC of standard antifungals and synthetic compounds
were measured in 96 well tissue culture plates (Cellstar Greiner Bio One, Germany)
using RPMI 1640 media buffered with MOPS (3-[N-Morpholino] propanesulfonic acid)
(Sigma Chemical Co.). Starting inocula of test cultures were maintained at 1.0–5.0 ꢀ
103 cfu/mL. All the compounds were tested between the range of 50–0.78 mg/mL.
Microtiter plates were incubated at 358C in a moist, dark chamber, and MICs were
recorded spectrophotometrically (Softmax prow 4.3, Versamax microplate reader,
Molecular Devices) after 48 h for Candida spp. and 72 h for Cryptococcus spp. and
mycelial fungi, while for T. mentegrophytes it was documented after 96 h.
Antifungal Activity
It is evident from the antifungal activity data (Tab. 2) that except compound 14 all the
compounds belonging to glycosyl isoxazolines exhibited inhibition of fungal growth at a
concentration ranging from 50 mg/mL to 6.25 mg/mL. A glycosyl isoxazoline (23) with
a hydrophobic 30-O-benzyl substituent in the sugar ring was found to be the most active
against the dermatophyte T. mentagrophytes (MIC 6.25 mg/mL). Compound 12 with
30-O-methyl substituent and compound 22 with a hydroxy substituent at C-5 of isoxazoline
moiety were less potent with an MIC value of 12.5 mg/mL, indicating the importance of
hydrophobicity in fungal growth inhibition. Because compound 23 is a diastereoisomeric
mixture and it was the most active compound in the series, we were interested to see
the activity of individual diastereoisomers. Repetitive column chromatography led to
separation of only the major isomer in pure form, and the minor isomer was always
contaminated with the major isomer. The pure major diastereoisomer and mixture of
minor and major isomers were screened separately. It was found that the major has an
Table 2. Antifungal activity of glycosylisoxazolines showing MIC against different fungal strains.
Compd. no.
Cn
Ss
Tm
Compd. no.
Cn
Ss
Tm
5
25 (50)
25 (25)
25
25 (25)
12.5 (25)
50
25 (25)
25 (6.25)
25
17
18
19
20
21
22
23
24
25
26
27
28
25
50
50
50
50
7
50
50
50
25
50
8
12.5
25
25
50
9
10
25
50 (25)
25
25
50
50 (25)
12.5
50
50 (6.25)
50
12.5
25
12.5
25
12.5
11
12
12.5
25
25 (25) .50 6.25 (.12.5)
25
nd
13
14
50
.50
50
50
12.5
25
nd
50
50
50
12.5
nd
.50
12.5
12.5
.50
50
25
15
16
12.5
25
50
50
Ketoconazole
0.12
0.50
0.25
12.5
50
Figures in ( ) indicate MIC for minor isomers in given cases.
Cn ¼ Cryptococcus neoformans; Tm ¼ Trychophyton mentagrophytes; Ss ¼ Sporothrix schenckii.
The compounds did not show any activity against Candidia albicans, Candida parapsilosis (ATCC
22019), and Aspergillus fumigatus at the concentrations tested.

364
Mishra et al.
MIC of 6.25 mg/mL while the minor isomer (contaminated with the major isomer) has an
MIC of .12.5 mg/mL. The dermatophytes including T. mentagrophytes in patients with
advanced HIV infection can extend to large area of the body,[18] hence this series of
compounds offers a lead to further optimization in order to get better and safer antiderma-
tophytic agents.
EXPERIMENTAL
General methods. Thin-layer chromatography was carried out on silica gel (Kiesel
60-F254, Merck) and spots were developed in iodine vapors and also by spraying with
5% sulfuric acid in alcohol followed by heating at 1008C. Column chromatography was
carried out on flash silica gel (230–400 mesh, Merck) using the indicated eluent. IR
spectra were recorded as thin films on KBr plates with a Perkin Elmer 881 spectro-
photometer. NMR spectra were recorded on Bruker spectrometers, 200 and 300 MHz,
and reference used was CDCl3. Chemical shifts were given as d ppm values and J
values were given in Hertz (Hz). Elemental analyses were performed on a Perkin-Elmer
2400 II elemental analyzer. The optical rotations were measured in a 1.0 dm tube with
Jasco dip-140 polarimeter in chloroform. The excess of the reagents or solvents were
evaporated under reduced pressure at a bath temperature between the ranges 558C
and 608C.
General Procedure for the preparation of compounds 3a, 3b & 4: 5-Deoxy-1,2-O-iso-
propylidene-3-O-methyl-5-oximinyl-a-D-xylofuranose (3a). A mixture of 1,2-O-iso-
propylidene-3-O-methyl-a-D-xylofuranos-5-ulose (1, 10.0 g, 49.5 mmol), hydroxylamine
hydrochloride (3.48 g, 50.0 mmol), and dimethyl aminopyridine (6.1 g, 50.0 mmol) in
ethanol and pyridine (25 mL each) was magnetically stirred at room temperature for
2 h. The solvent was evaporated under reduced pressure and the crude mass, thus obtained,
was dissolved in ethylacetate (2 ꢀ 100 mL), washed with water (2 ꢀ 20 mL), and dried
(Na2SO4). Solvents evaporated under reduced pressure to get syrup which on column
chromatography (SiO2) using hexane:ethyl acetate (17 : 3) as eluant afforded the required
compound 3a as colorless viscous oil, Rf 0.55 (hexane:ethyl acetate, 7 : 3); [a]D20–32.68
(c 0.175, CHCl3), MS (FAB) ¼ m/z 218 (M þ H)þ; IR (Neat): nmaxcm-1 3396, 2989,
2836, 2143, 1710, 1630, 1457, 1379; 1H NMR (CDCl3, 200 MHz): d 7.47
(d, J ¼ 7.3 Hz, 1H, CH55N, anti isomer), 6.90 (d, J ¼ 3.4 Hz, 1H, CH55N, syn isomer),
5.96 (d, J ¼ 2.5 Hz, 2H, diastereomeric H-1’), 5.20 (dd, J ¼ 3.4 and 3.3 Hz, 1H, H-4,
syn isomer), 4.73 (dd, J ¼ 7.3 and 3.3 Hz, 1H, H-4, anti isomer), 4.61 (d, J ¼ 2.5 Hz,
2H, H-2 of each isomer), 4.15 and 3.81 (d, J ¼ 3.3 Hz, 1H, H-3 of each isomer), 3.40
and 3.39 (s, 3H, OCH3 of each isomer), 2.10 (s, exchangable with D2O, 1H, N-OH),
1.51 and 1.33 [each s, 12H, C(CH3)2 of each isomer].
Anal. Calcd for C9H15NO5: C, 49.76; H, 6.96; N, 6.45. Found: C, 49.93; H, 7.11;
N, 6.32.
3-O-Benzyl-5-deoxy-1,2-O-isopropylidene-5-oximinyl-a-D-xylofuranose (3b). Color-
less Solid, Mp 1598C, Rf 0.65 (hexane:ethyl acetate, 7:3); [a]D20–42.78 (c 0.275,
CHCl3), MS (FAB) ¼ m/z 294 (M þ H)þ; IR (Neat): nmax cm21 3412, 3251, 2995,
1
2371, 2162, 1628, 1450, 1384; H NMR (CDCl3, 200 MHz): d 7.67 (s, 1H, CH55N),

Glycosyl Isoxazolines
365
7.30 (m, 5H, ArH), 6.98 (d, J ¼ 3.9 Hz, 1H, CH55N), 5.99 (d, J ¼ 3.7 Hz, 1H, H-1), 5.23
(m, 1H, H-4), 4.61 (m, 3H, H-2 and –OCH2Ph), 4.37 (d, J ¼ 3.2 Hz, 1H, H-3), 1.50 and
1.32 [s, 6H, C(CH3)2].
Anal. Calcd for C15H19NO5: C, 61.42; H, 6.53; N, 4.78. Found C, 61.65; H, 6.73;
N, 4.55.
6-Deoxy-1,2:3,4-di-O-isopropylidene-6-oximinyl-a-D-galactopyranose (4). Colorless
Solid, Mp 828C, Rf 0.60 (hexane:ethyl acetate, 7:3); [a]2D5 –53.48 (c 0.28, CHCl3); MS
(FAB) ¼ m/z 274 (M þ H)þ; IR (Neat): nmax cm21 3396, 2989, 2836, 2143, 1710,
1
1630, 1457, 1379; H NMR (CDCl3, 200 MHz): d 7.48 (d, J ¼ 7.3 Hz, 1H, CH55N, anti
isomer), 6.80 (d, J ¼ 3.4 Hz, 1H, CH55N, syn isomer) 5.57 (d, J ¼ 4.9 Hz, 2H, diastereo-
meric H-1’), 4.66 (m, 2H, H-3, and H-2), 4.33 (m, 2H, H-4, and H-5) 1.55, 1.51 and 1.33
[s, 12H, C(CH3)2 of each isomer].
Anal. Calcd for C12H19NO6: C, 52.74; H, 7.01; N, 5.13. Found: C, 52.74; H, 7.01;
N, 5.13.
General Procedure for the preparation of compounds 5, 7–28: 5(R,S)-Carbethoxy-3-
[(1’R, 2’R, 3’S, 4’R)-1’,2’-O-isopropylidene-3’-O-methyl-tetrahydrofuranos-4’-yl]-2-
isoxazoline (5). To a stirring solution of compound 3a (0.6 g, 2.76 mmol) in acetonitrile
(7.0 mL) at 08C N-chlorosuccinimide (0.37 g, 2.80 mmol) was added and stirring contin-
ued for 1.5 h. Conversion of the oxime to chloroxime was monitored by thin layer chrom-
atography. DBU (0.42 g, 2.76 mmol) was slowly added to the reaction mixture followed by
addition of ethyl acrylate (1.4 g, 14.0 mmol) and the reaction continued for 4 h. Solvent
was evaporated and the residue obtained was dissolved in ethyl acetate (50 mL),
washed with water (2 ꢀ 25 mL), and saturated solution of NaCl (2 ꢀ 25 mL), and dried
(Na2SO4). The solvent evaporated under reduced pressure to get a crude product, which
was chromatographed over SiO2 using hexane:ethyl acetate (17 : 3) as eluent to give com-
pound 5 major isomer as colorless oil, Rf 0.70 (hexane:ethyl acetate, 7:3); [a]2D5 þ49.18 (c
0.175, CHCl3), MS (FAB) ¼ m/z 316 (M þ H)þ; IR (Neat): nmax cm21 2985, 2362, 1744,
1
1625, 1540, 1377; H NMR (CDCl3, 200 MHz): d 5.96 (d, J ¼ 3.6 Hz, 1H, H-1’), 5.13
(d, J ¼ 3.6 Hz, 1H, H-4’) 4.99 (t, J ¼ 9.6 Hz, 1 H, H-5), 4.60 (d, J ¼ 3.6 Hz, 1H, H-2’),
4.24 (q, J ¼ 7.2 Hz, OCH2), 3.89 (d, J ¼ 3.6 Hz, 1H, H-3’), 3.40–3.36 (m, 2H, H-4 iso-
xazoline ring), 3.38 (s, 3H, OCH3), 1.50 and 1.33 [s, 3H, C(CH3)2], 1.28 (t, J ¼ 7.2 Hz,
–OCH2CH3).13C NMR (CDCl3): d 170.6 (C ¼ O), 157.1 (C ¼ N); 112.7 [C(CH3)2];
105.0 (C-1’); 87.3 (C-5), 81.8 (C-2’); 77.7 (C-4’); 76.2 (C-3); 62.2 (OCH2); 58.4
(OCH3), 40.5 (C-4); 27.2, 26.7 [.C(CH3)2] and 14.5 (CH2CH3).
1
Compound 5 minor isomer: MS (FAB) ¼ m/z 316 (M þ H)þ; H NMR (CDCl3,
200 MHz): d 5.97 (d, J ¼ 3.6 Hz, 1H, H-1’), 5.14 (d, J ¼ 3.3 Hz, 1H, H-4’) 5.00 (dd,
J ¼ 9.6 and 8.4 Hz, 1 H, H-5), 4.61 (d, J ¼ 3.6 Hz, 1H, H-2’), 4.25 (q, J ¼ 7.2 Hz,
OCH2), 3.91 (d, J ¼ 3.3 Hz, 1H, H-3’), 3.40–3.34 (m, 2H, H-4 isoxazoline ring), 3.38
(s, 3H, OCH3), 1.50 and 1.33 [s, 3H, C(CH3)2], 1.28 (t, J ¼ 7.2 Hz, –OCH2CH3).
Anal. Calcd for C14H21NO7: C, 53.33; H, 6.71; N, 4.44. Found: C, 53.46; H, 6.92; N, 4.31.
3,4-Bis-[(10R,20R,30S,40R)-10,20-O-isopropylidene-30-O-methyl-tetrahydrofuranos-
40-yl]-1,2,5-oxadizole-2-oxide (6). Colorless oil, Rf 0.40 (hexane:ethyl acetate, 7:3);
MS (FAB) ¼ m/z 431 (M þ H)þ; IR (Neat): nmax cm21 2988, 2839, 1609, 1475, 1379;
1H NMR (CDCl3, 200 MHz): d 6.07 and 6.01 (each d, J ¼ 3.6 Hz, each 1H, H-10), 5.55

366
Mishra et al.
and 5.28 (each d, J ¼ 3.0 and 3.3 Hz, each 1H, H-40), 4.67 (d, J ¼ 3.6 Hz, 2H, H-20), 4.17
and 3.89 (each d, J ¼ 3.0 and 3.3 Hz, each 1H, H-30), 3.33 and 3.29 (each s, each 3H,
OCH3), 1.53 and 1.36 [each s, each 6H, C (CH3)2].
Anal. Calcd for C18H26N2O10: C, 50.23; H, 6.09; N, 6.51; O, 37.17 Found: C, 50.43;
H, 6.37; N, 6.32.
5(R,S)-Ethoxy-3-[(10R,20R,30S,40R)-10,20-O-isopropylidene-30-O-methyltetrahydrofuranos-
40-yl]-2-isoxazoline (7). Major isomer: white solid m.p. 848C, Rf 0.65 (hexane:ethyl
acetate, 3 : 1); [a]2D5 –86.58 (c 0.275, CHCl3), MS (FAB) ¼ m/z 288 (M þ H)þ; IR
1
(Neat): nmax cm21 2983, 2362, 1616, 1453, 1378, 1300 H NMR (CDCl3, 200 MHz): d
5.96 (d, J ¼ 3.6 Hz, 1H, H-1), 5.55 (dd, J ¼ 6.5 and 2.3 Hz, 1H, H-5), 5.11
(d, J ¼ 3.2 Hz, 1H, H-40), 4.59 (d, J ¼ 3.6 Hz, 1H, H-20), 3.90 (d, J ¼ 3.2 Hz, 1H,
H-30), 3.84 and 3.55 (each m, 2H, –OCH2CH3), 3.36 (s, 3H, OCH3), 3.06 (dd, J ¼ 12.5
and 6.5 Hz, 1H, H- 4A), 2.98 (dd, J ¼ 12.5 and 2.3 Hz, 1H, H-4B),1.50 and 1.33 [s, 6H,
C (CH3)2], 1.28 (t, J ¼ 7.0 Hz, -CH2CH3).
Minor isomer: Colorless oil, Rf 0.67 (hexane:ethyl acetate, 3 : 1); [a]2D5 þ23.58
(c 0.275, CHCl3), MS (FAB) ¼ m/z 288 (M þ H)þ; IR (Neat): nmax cm21 2983, 2362,
1
1616, 1453, 1378, 1300 H NMR (CDCl3, 200 MHz): d 5.96 (d, J ¼ 3.3 Hz, 1H, H-1),
5.56 (d, J ¼ 6.0 Hz, 1H, H-5), 5.13 (d, J ¼ 2.7 Hz, 1H, H-40), 4.61 (d, J ¼ 3.3 Hz, 1H,
H-20), 3.90 (d, J ¼ 2.7 Hz, 1H, H-30), 3.83 and 3.56 (each m, 2H, –OCHA & –OCHB),
3.38 (s, 3H, –OCH3), 3.14 (dd, J ¼ 18.0 and 6.0 Hz, 1H, H-4A), 3.02 (d, J ¼ 18.0 Hz,
1H, H-4B), 1.52 and 1.35 [s, 6H, C (CH3)2], 1.20 (t, J ¼ 7.0 Hz, –CH2CH3). 13C NMR
(CDCl3): d 157.7 (C55N); 112.1 [C(CH3)2]; 105.1 (C-10); 102.6 (C-5), 86.7 (C-20); 81.4
(C-40); 76.0 (C-3); 63.3 (OCH2); 57.9 (OCH3), 42.3 (C-4); 26.8, 26.2 [.C(CH3)2] and
14.9 (CH2CH3).
Anal. Calcd for C13H21NO6: C, 54.35; H, 7.37; N, 4.88. Found: C, 54.71; H, 7.41;
N, 4.67.
5(R,S)-Acetoxy-3-[(10R,20R,30S,40R)-10,20-O-isopropylidene-30-O-methyltetrahy-
drofuranos-40-yl]-2-isoxazoline (8). Colorless oil, Rf 0.60 (hexane:ethyl acetate, 4 : 1);
[a]D25 – 38.68 (c 0.21, CHCl3), MS (FAB) ¼ m/z 302 (M þ H)þ; IR (Neat): nmax cm21
1
2992, 2258, 1775, 1635, 1564, 1458, 1379; H NMR (CDCl3, 200 MHz): d 6.68 (dd,
J ¼ 6.4 and 1.4 Hz, 1H, H-5), 5.98 (d, J ¼ 3.6 Hz, 1H, H-10), 5.16 (d, J ¼ 3.3 Hz, 1H,
H-40),4.63 (d, J ¼ 3.6 Hz, 1H, diastereomeric H-20), 3.93 (d, J ¼ 3.3 Hz, 1H, diastereo-
meric H-30), 3.41 and 3.35 (s, 3H, diastereomeric –OCH3), 3.26 (dd, J ¼ 6.4 and
1.4 Hz, 1H, H-4A) 3.16 (dd, J ¼ 16.6 Hz, 1H, H-4B) 2.05 (s, 3H, –COCH3), 1.51 and
1.34 [s, 6H, C (CH3)2].
Anal. Calcd for C13H19NO7: C, 51.82; H, 6.36; N, 4.65. Found: C, 52.12; H, 6.47;
N, 4.44.
5(R,S)-Acetyl-3-[(10R,20R,30S,40R)-10,20-O-isopropylidene-30-O-methyltetrahydrofuranos-
40-yl]-2-isoxazoline (9). Colorless oil, Rf 0.70 (hexane:ethyl acetate, 7:3); [a]2D5–34.78 (c
0.375, CHCl3), MS (FAB) ¼ m/z 286 (M þ H)þ; IR (Neat): nmax cm21 2988, 2362,
1
1722, 1627, 1438, 1376; H NMR (CDCl3, 200 MHz): d 5.96 (d, J ¼ 3.7 Hz, 1H, H-10),
5.10 (d, J ¼ 3.5Hz, 1H, diastereomeric H-40), 4.85 (m, 1H, H-5), 4.61 (d, J ¼ 3.7 Hz,
1H, diastereomeric H-20), 3.89 (d, J ¼ 3.5 Hz, 1H, diastereomeric H-30), 3.41 (s, 3H,
OCH3), 3.34 (m, 2H, H-4), 2.26 (s, 3H, COCH3), 1.50 and 1.34 [s, 6H, C(CH3)2].

Glycosyl Isoxazolines
367
Anal. Calcd for C13H19NO6: C, 54.73; H, 6.71; N, 4.91. Found: C, 54.97; H, 6.91;
N, 4.83.
5(R,S)-Cyano-3-[(10R,20R,30S,40R)-10,20-O-isopropylidene-30-O-methyltetrahydro-
furanos-40-yl]-2-isoxazoline (10). Major isomer: White solid, Mp 788C, Rf 0.55
(hexane : ethyl acetate, 7 : 3); [a]2D5 –21.08 (c 0.25, CHCl3), MS (FAB) ¼ m/z 269
1
(M þ H)þ; IR (Neat): nmax cm21 2933, 2950, 2845, 2362, 1638, 1453, 1383; H NMR
(CDCl3, 200 MHz):
d
5.97 (d, J ¼ 3.6 Hz, 1H, H-10), 5.21 (m, 1H, H-5),
5.17 (d, J ¼ 3.6 Hz, 1H, H-40), 4.64 (d, J ¼ 3.6 Hz, 1H, H-20), 3.95 (d, J ¼ 3.6 Hz, 1H,
H-30), 3.49 (m, 2H, H-4), 3.45 (s, 3H, OCH3), 1.51 and 1.35 [s, 6H, C (CH3)2]. 13C
NMR (CDCl3): d 158.0 (C55N); 117.5 (C;N); 112.9 [C(CH3)2]; 105.9 (C-10); 87.5 (C-
20); 81.9 (C-40); 75.6 (C-3); 66.3 (C-5); 58.8 (OCH3), 42.4 (C-4); 27.3, 26.6 [.C(CH3)2].
Anal. Calcd for C13H18N2O5: C, 55.31; H, 6.43; N, 9.92. Found: C, 55.58; H, 6.70;
N, 9.78.
Minor isomer: colorless oil, Rf 0.57, (hexane:ethyl acetate, 7:3); [a]2D5 –42.58 (c 0.30,
CHCl3), MS (FAB) ¼ m/z 269 (M þ H)þ; IR (Neat): nmax cm21 2933, 2950, 2845, 2362,
1
1638, 1453, 1383; H NMR (CDCl3, 200 MHz): d 5.97 (d, J ¼ 3.6 Hz, 1H, H-10), 5.21
(t, J ¼ 6.2 Hz, 1H, H-5), 5.17 (d, J ¼ 3.6 Hz, 1H, H-40), 4.64 (d, J ¼ 3.6 Hz, 1H, H-20),
3.95 (d, J ¼ 3.6 Hz, 1H, H-30), 3.49 (d, J ¼ 6.2 Hz, 2H, H-4), 3.45 (s, 3H, OCH3), 1.51
and 1.35 [s, 6H, C (CH3)2]. 13C NMR (CDCl3): d 157.8 (C55N); 117.4 (C;N); 112.9
[C(CH3)2]; 105.9 (C-10); 87.3 (C-20); 81.7 (C-40); 75.4 (C-3); 66.7 (C-5), 58.4 (OCH3),
42.2 (C-4); 27.3, 26.6 [.C(CH3)2].
5(R,S)-Bromomethyl-3-[(10R,20R,30S,40R)-10,20-O-isopropylidene-30-O-methyl-tetra-
hydrofuranos-40-yl]-2-isoxazoline (11). Colorless oil, Rf 0.60 (hexane:ethyl acetate,
7:3); [a]2D5 þ3.48 (c 0.4125, CHCl3), MS (FAB) ¼ m/z 336 (M þ H)þ; IR (Neat): nmax
cm21 2984, 2937, 2367, 1623, 1442, 1378; 1H NMR (CDCl3, 200 MHz): d 5.98
(d, J ¼ 3.7 Hz, 1H, diastereomeric H-10), 5.09 (d, J ¼ 3.6 Hz, 1H, H-40), 4.82 (m, 1H,
H-5), 4.62 (d, J ¼ 3.7 Hz, 1H, diastereomeric H-20), 3.90 and 3.95 (d, J ¼ 3.6 Hz, 1H, dia-
stereomeric H-30), 3.56, 3.40 (s, 3H, diastereomeric –OCH3), 3.30 (m, 2H, H-4), 1.50,
1.48, 1.34, and 1.32 [s, 6H, C (CH3)2]; 13C NMR (CDCl3): d 157.4 (C55N); 112.2
[C(CH3)2]; 105.9, 105.7 (C-10); 87.5 (C-5), 84.8 (C-20); 81.9, 81.8 (C-40); 79.5, 76.3
(C- 30); 59.2 and 58.3 (–OCH3), 40.7 (C-4); 33.2 (CH2Br), 27.3, 27.2 and 26.5
[.C(CH3)2].
Anal. Calcd for C12H18BrNO5: C, 42.87; H, 5.40; N, 4.17. Found: C, 43.12; H, 5.71;
N, 4.02.
5(R,S)-(2-Hydroxy phenylmethyl)-3-[(10R,20R,30S,40R)-10,20-O-isopropylidene-30-O-
methyl-tetrahydrofuranos-40-yl]-2-isoxazoline (12). Colorless oil, Rf 0.65
(hexane : ethyl acetate, 7:3); [a]D25 –34.28 (c 0.275, CHCl3); MS (FAB) ¼ m/z 350
1
(M þ H)þ; IR (Neat): nmax cm21 3404, 2936, 2364, 1599, 1454, 1376, 1220; H NMR
(CDCl3, 200 MHz): d 7.12 (m, 4H, ArH), 5.97 (d, J ¼ 3.8 Hz, 1H, H-10), 5.08 (m, 1H,
H-5), 4.84 (d, J ¼ 3.6 Hz, 1H, H-40), 4.60 (d, J ¼ 3.8 Hz, 1H, H-20), 3.87 (d, J ¼ 3.6 Hz,
1H, H-30), 3.46 (dd, J ¼ 5.1 and 1.4 Hz, 2H, CH2Ar), 3.40 (s, 3H, OCH3), 3.33 (m, 2H,
H-4), 1.49, 1.45, 1.35, and 1.30 [s, 6H, diastereomeric C(CH3)2]. 13C NMR (CDCl3): d
159.4, 158.9 (C55N); 155.6, 127.5 (ArC), 132.3, 132.0, 121.0, 120.9, 117.4,
117.3(ArCH), 112.7 [C(CH3)2]; 105.6, 105.7 (C-10); 87.4, 87.1 (C-5), 82.0 (C-20), 81.8

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Mishra et al.
(C-40), 76.3 (C-30), 58.4 (–OCH3), 40.6, 40.2 (ArCH2), 36.5, 36.2 (C-4), 27.3, 27.2 and
26.7 [C(CH3)2].
Anal. Calcd for C18H23NO6: C, 61.88; H, 6.64; N, 4.01. Found: C, 62.09; H, 6.92; N, 3.97.
5(R,S)-(4-Methoxy phenylmethyl)-3-[(10R,20R,30S,40R)-10,20-O-isopropylidene-30-O-
methyl-tetrahydrofuranos-40-yl]-2-isoxazoline (13). Colorless oil, Rf 0.65
(hexane:ethyl acetate, 3 : 1); [a]D25 217.68 (c 0.375, CHCl3), MS (FAB) ¼ m/z 364
(M þ H)þ; IR (Neat): nmax cm21 2987, 2936, 1612, 1514, 1458, 1377; 1H NMR
(CDCl3, 200 MHz): d 7.14 and 6.84 (d, J ¼ 6.6 Hz, 2H, ArH), 5.94 (d, J ¼ 3.7 Hz, 1H,
H-10), 5.07 (d, J ¼ 3.4 Hz, 1H, H-40), 4.70 (m, 1H, H-5), 4.59 (d, J ¼ 3.7 Hz, 1H, H-20),
3.87 (d, J ¼ 3.4 Hz, 1H, H-30), 3.78 (s, 3H, –ArOCH3), 3.35 (s, 3H, –OCH3), 2.98
(m, 2H, ArCH2), 2.84 (m, 2H, H-4), 1.50 and 1.33 [s, 6H, C (CH3)2].
Anal. Calcd for C19H25NO6: C, 62.80; H, 6.93; N, 3.85. Found: C, 62.98; H, 7.19;
N, 3.61.
5(R,S)-Hydroxymethyl-3-[(10R,20R,30S,40R)-10,20-O-isopropylidene-3-O-methyltetra-
hydrofuranos-40-yl]-2-isoxazoline (14). Colorless oil, Rf 0.35 (hexane:ethyl acetate,
3 : 2); [a]2D5–76.18 (c 0.3625, CHCl3), MS (FAB) ¼ m/z 274 (M þ H)þ; IR (Neat): nmax
1
cm21 H NMR (CDCl3, 200 MHz): d 5.98 (d, J ¼ 3.7 Hz, 1H, H-10), 5.09
(d, J ¼ 3.3 Hz, 1H, diastereomeric H-40), 4.80 (m. 1H, H-5), 4.62 (d, J ¼ 3.7 Hz, 1H,
H-20), 3.90 (d, J ¼ 3.5 Hz, 1H, H-30), 3.72 (dd, J ¼ 13.6 and 2.9 Hz, -CHAOH), 3.58
(dd, J ¼ 13.6 and 5.4 Hz, –CHBOH), 3.39 (s, 3 H, –OCH3), 3.18 (dd, J ¼ 18.0 and
10.8 Hz, –H-4A), 2.95 (dd, J ¼ 18.0 and 8.0 Hz, H-4B), 1.51 and 1.34 [s, 6H, C(CH3)2].
13C NMR (CDCl3): d 157.9 (C55N); 112.6 [C(CH3)2]; 105.6 (C-10); 87.19, 87.04 (C-5),
81.9 (C-20); 81.2 (C-40); 76.5, 76.4 (C-3); 64.0, 63.9 (CH2OH), 58.4 (OCH3), 37.7, 37.6
(C-4); 27.2, 26.6 [.C(CH3)2].
Anal. Calcd for C12H19NO6: C, 52.74; H, 7.01; N, 5.13. Found: C, 52.96; H, 7.32;
N, 5.01.
5(R,S)-Carboxy-3-[(10R,20R,30S,40R)-10,20-O-isopropylidene-30-O-methyltetrahydro-
furanos-40-yl]-2-isoxazoline (15). Colorless oil, Rf 0.40 (hexane:ethyl acetate, 1:1);
[a]D25–418 (c 0.4, CHCl3), MS (FAB) ¼ m/z 302 (M þ H)þ; IR (Neat): nmaxcm21 3352,
1
2937, 2362, 1769, 1709, 1658, 1622, 1447, 1378; H NMR (CDCl3, 200 MHz): d 9.76
(bs, exchangeable with D2O, 1H, –COOH), 7.22 (m, 1H, H-4), 5.99, 5.91
(d, J ¼ 3.6 Hz, 1H, diastereomeric H-10), 4.84 (d, J ¼ 3.3 Hz, 1H, H-40), 4.59
(d, J ¼ 3.6 Hz, 1H, H-20), 4.13 (d, J ¼ 3.3 Hz, 1H, H-30), 3.43 (s, 3H, -OCH3), 1.95
(d, J ¼ 6.9 Hz, 3H, CH3), 1.81 (m, 1H, H-5) 1.49 and 1.33 [s, H, C(CH3)2]. 13C NMR
(CDCl3): d 164.4 (C ¼ O), 163.8 (C55N); 149.5 (C-4), 118.6 (C-5), 113.3 [C(CH3)2];
106.09 (C-10); 84.8 (C-20); 81.9 (C-40); 81.3 (C-3); 59.4 and 58.6 (OCH3), 27.3, 26.7
[.C(CH3)2], 18.8 (CH3).
Anal. Calcd for C13H19NO7: C, 51.82; H, 6.36; N, 4.65. Found: C, 52.07; H, 6.54;
N, 4.48.
5(R,S)-Carbethoxy-3-[(10R,20R,30S,40R)-30-O-benzyl-10,20-O-isopropylidenetetrahydro-
furanos-40-yl]-2-isoxazoline (16). Colorless oil, Rf 0.70 (hexane:ethyl acetate, 7:3); [a]2D5
þ30.58 (c 0.4, CHCl3), MS (FAB) ¼ m/z 392 (M þ H)þ; IR (Neat): nmax cm21 2986,
1
2361, 1745, 1620, 1448, 1377, 1215. H NMR (CDCl3, 200 MHz): d 7.32 (m, 5H, ArH)

Glycosyl Isoxazolines
369
5.99 (d, J ¼ 3.7 Hz, 1H, H-10), 5.15 (d, J ¼ 3.2 Hz, 1H, H-40); 4.93 (t, J ¼ 9.3 Hz, 1H, H-5)
4.57 (m, 2H, OCHAPh and H-20), 4.17 (m, 4H, –OCH2, OCHBPh and H-30); 3.40 (m, 2H,
H-4); 1.49 and 1.32 [each s, each 3H, C (CH3)2], 1.25 (t, J ¼ 7.1 Hz, –OCH2CH3).13C
NMR (CDCl3, 50 MHz): d 170.6 (C22O), 157.3 and 156.7 (C55N); 137.3, (ArC), 129.0,
128.9, 128.5, 128.4, 128.0 (ArCH), 112.7 [C(CH3)2]; 105.7 (C-10); 85.3 (C-20); 84.8 (C-
40); 82.6, 82.57 (C-3); 72.8 (–OCH2Ph), 62.2, 62.0 (–OCH2), 40.6, 40.5 (C-4); 27.2,
26.7 [.C(CH3)2], 14.5 (CH3).
Anal. Calcd for C20H25NO7: C, 61.37; H, 6.44; N, 3.58. Found: C, 61.64; H, 6.57;
N, 3.32.
5(R,S)-Ethoxy-3-[(10R,20R,30S,40R)-30-O-benzyl-10,20-O-isopropylidene-tetrahydro-
furanos-40-yl]2-isoxazoline (17). Colorless oil, Rf 0.65 (hexane:ethyl acetate, 3:1); [a]2D0
–23.88 (c 0.275, CHCl3), MS (FAB) ¼ m/z 364 (M þ H)þ; IR (Neat): nmax cm21 2981,
2362, 1626, 1456, 1377; 1H NMR (CDCl3, 200 MHz): d 7.35 (m, 5H, ArH), 6.00
(d, J ¼ 3.1 Hz, 1H, diastereomeric H-10), 5.54 (m, 1H, diastereomeric H-5), 5.15
(d, J ¼ 3.3 Hz, 1H, H-40), 4.64 (m, 3H, H-20 and –OCH2Ph), 4.13 (d, J ¼ 3.3 Hz, 1H,
H-30), 3.86 and 3.53 (each m, 2H, –OCH2CH3), 1.49 and 1.33 [s, 6H, C (CH3)2].
Anal. Calcd for C19H25NO6: C, 62.80; H, 6.93; N, 3.85. Found: C, 62.96; H, 7.11;
N, 3.68.
5(R,S)-Acetoxy-3-[(10R,20R,30S,40R)-30-O-benzyl-10,20-O-isopropylidene-tetrahydro-
furanos-40-yl]-2-isoxazoline (18). Colorless oil, Rf 0.65 (hexane:ethyl acetate, 3:1);
[a]2D5 – 38.28 (c 0.738, CHCl3), MS (FAB) ¼ m/z 318 (M-OCOCH3)þ; IR (Neat): nmax
1
cm21 3022, 2937, 1751, 1610, 1456, 1377; H NMR (CDCl3, 200 MHz): d 7.34 and
7.21 (m, 5H, ArH), 6.66 (m, 1H, H-5), 6.00 (d, J ¼ 3.5 Hz, 1H, H-10), 5.20
(d, J ¼ 3.4 Hz,1H, H-40), 4.64 (m, 2H, –OCHAPh and H-20), 4.47 (d, J ¼ 11.6 Hz, 1H,
– OCHBPh), 4.17 (d, J ¼ 3.4 Hz, 1H, H-30), 3.23 (m, 2H, H-4), 2.03 and 1.90 (s, 3H, dia-
stereomeric COCH3), 1.50 and 1.33 [s, 6H, C (CH3)2]; 13C NMR (CDCl3): d 170.4, 169.9
(C22O), 158.0 (C55N); 137.4, 137.1 (ArC), 129.1, 128.9, 128.6, 128.4, 128.2, 128.0, 127.8
(ArCH), 112.8 ad 109.9 [C(CH3)2]; 105.8, 105.7 (C-10); 95.8, 95.7 (C-5); 85.2, 84.9 (C-20);
82.8, 82.6 (C-40); 76.3, 76.1 (C-30); 72.9, 72.7 (–OCH2Ph); 42.8, 42.6 (C-4); 27.3, 26.7
[.C(CH3)2], 21.4, 21.2 (COCH3).
Anal. Calcd for C19H23NO7: C, 60.47; H, 6.14; N, 3.71. Found: C, 60.68; H, 6.32;
N, 3.58.
5(R,S)-Acetyl-30-O-benzyl-3-[(10R,20R,30S,40R)-10,20-O-isopropylidene-tetrahydro-
furanos-40-yl]-2-isoxazoline (19). Colorless oil, Rf 0.65 (hexane:ethyl acetate, 3:1);
[a]D25–24.58 (c 0.2, CHCl3), MS (FAB) ¼ m/z 362 (M þ H)þ; IR (Neat): nmax cm21
1
2987, 2935, 2363, 1722, 1624, 1496, 1449, 1377; H NMR (CDCl3, 200 MHz): d 7.33
and 7.23 (m, 5H, ArH), 6.00 (d, J ¼ 3.7 Hz, 1H, H-10), 5.12 (m, 1H, diastereomeric
H-40), 4.81 (m, 1H, diastereomeric H-5), 4.61 (m, 3H, –OCH2Ph and H-20), 4.15, 4.13
(d, J ¼ 3.6 Hz, 1H, diastereomeric H-30), 3.29 (m, 2H, H-4), 2.25, 2.13 (s, 3H, diastereo-
meric COCH3), 1.50 and 1.33 [s, 6H, C(CH3)2].
Anal. Calcd for C19H23NO6: C, 63.15; H, 6.41; N, 3.88. Found: C, 63.44; H, 6.71;
N, 3.64.

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5(R,S)-Cyano-3-[(10R,20R,30S,40R)-30-O-benzyl-10,20-O-isopropylidene-tetrahydro-
furanos-40-yl]-2-isoxazoline (20). Colorless oil, Rf 0.60 (hexane:ethyl acetate, 7:3); [a]2D5
–21.98 (c 0.4875, CHCl3), MS (FAB) ¼ m/z 345 (M þ H)þ; IR (Neat): nmax cm21 2988,
2936, 2364, 1620, 1453, 1379, 1314, 1218; 1H NMR (CDCl3, 200 MHz): d 7.35 and 7.22
(m, 5H, ArH), 6.00 (d, J ¼ 3.7 Hz, 1H, H-10), 5.18 (d, J ¼ 3.5 Hz, 1H, diastereomeric
H-40), 5.08 (t, J ¼ 8.5 Hz, 1H, H-5), 4.65 (m, 2H, H-2 and –OCHBPh), 4.46
(d, J ¼ 11.6 Hz, 1H, –OCHAPh), 4.17 (d, J ¼ 3.5 Hz, 1H, H-30), 3.51 and 3.44 (d, 2H,
H-4), 1.51 and 1.34 [each s, each 3H, C(CH3)2]; 13C NMR (CDCl3): d, 157.9 (C55N);
136.7 (Ar-C), 129.2, 128.8, 128.6, 128.0 (Ar-CH), 117.0 (C55N), 112.9 [C(CH3)2];
105.9 (C-10); 85.4, 84.8 (C-40); 83.4 (C-20); 76.1, 75.7 (C-30); 73.1, 72.9 (–OCH2Ph),
66.3, 66.2 (C-5), 42.3 (C-4); 27.3, and 26.7 [.C(CH3)2].
Anal. Calcd for C19H22N2O5: C, 63.67; H, 6.19; N, 7.82. Found: C, 63.89; H, 6.34;
N, 7.66.
5(R,S)-Bromomethyl-3-[(10R,20R,30S,40R)-30-O-benzyl-10,20-O-isopropylidene-tetra-
hydrofuranos-40-yl]-2-isoxazoline (21). Colorless oil. Rf 0.65 (hexane:ethyl acetate,
7:3); [a]2D5 þ3.2 (c 0.98, CHCl3); MS (FAB) ¼ m/z 412 (M þ H)þ; IR (Neat):
1
nmax cm21 2985, 2365, 2144, 1631, 1452, 1377, 1312; H NMR (CDCl3, 200 MHz):
d 7.33 (m, 5H, ArH), 6.01 (d, J ¼ 3.6 Hz, 1H, H-10), 5.13 (d, J ¼ 3.5 Hz, 1H,
H-40), 4.80 (m, 1H, H-5), 4.66 (m, 2H, H-20 and –OCHAPh), 4.50 (d, J ¼ 11.6 Hz,
1H, –OCHBPh), 4.16 (d, J ¼ 3.5 Hz, 1H, diastereomeric H-30), 3.46 (dd, J ¼ 10.3 and
4.6 Hz, 1H, H-4A), 3.23 (m, 3H, H-4A and CH2Br), 1.55, 1.50, and 1.30 [s, 6H, C(CH3)2].
Anal. Calcd for C18H22BrNO5: C, 52.44; H, 5.38; N, 3.40. Found: C, 52.70; H, 5.57;
N, 3.32.
5(R,S)-(2-Hydroxy phenylmethyl)-3-[(10R,20R,30S,40R)-30-O-benzyl-10,20-O isopropylidene-
tetrahydrofuranos-40-yl]-2-isoxazoline (22). Colorless oil, Rf 0.70 (hexane:ethyl
acetate, 7:3); [a]2D5 –42.58 (c 0.15, CHCl3), MS (FAB) ¼ m/z 426 (M þ H)þ; IR
(Neat): nmax cm21 3395, 2985, 2366, 1592, 1493, 1456, 1377; 1H NMR (CDCl3,
200 MHz): d 7.32 (m, 9H, ArH), 6.60 (s, exchangeable with D2O, 1H, ArOH), 6.01,
5.97 (d, J ¼ 3.8 Hz, 1H, diastereomeric H-10), 5.07 (d, J ¼ 3.5 Hz, 1H, H-40), 4.87
(m, 1H, H-5), 4.61 (m, 3H, –OCH2Ph and diastereomeric H-20), 4.13, 4.08
(d, J ¼ 3.5 Hz, 1H, distereomeric H-3), 3.40 (d, J ¼ 6.4 Hz, 1H, –CHAPhOH), 3.16
(dd, J ¼ 18.8 and 10.2 Hz, 1H, H-4A) 2.95 (m, 2H, CHBPhOH and H-4B), 1.48, 1.47,
1.31 [s, 6H, diastereomeric C(CH3)2], 13C NMR (CDCl3): d 159.3 (C55N); 155.4,
149.5, 137.4 (ArC), 132.1, 130.7, 128.5, 128.3, 127.6, 121.0, and 117.4 (ArCH), 112.7
[C(CH3)2], 105.7, 105.6 (C-10), 85.2 (C-20), 83.0 (C-40), 81.9 (C-30), 78.4, 76.6 (C-5),
73.8 (OCH2Ph), 40.75 (CH2-Ar), 36.6, 36.4 (C-4), 27.38, 27.3, 26.8, and 26.73 [C(CH3)2].
Anal. Calcd for C24H27NO6: C, 67.75; H, 6.40; N, 3.29. Found: C, 67.96; H, 6.69;
N, 3.12.
5-(4-Methoxyphenylmethyl)-3-[(10R,20R,30S,40R)-30-O-benzyl-10,20-O-isopropylidene-
tetrahydrofuranos-40-yl]-2-isoxazoline (23). Major isomer: Colorless oil, Rf 0.70
(hexane:ethyl acetate, 3 : 1); [a]D25 þ8.648 (c 0.3125, CHCl3), MS (FAB) ¼ m/z 440
1
(M þ H)þ; IR (Neat): nmax cm21 2994, 2936, 2365, 1612, 1513, 1457, 1378; H NMR
(CDCl3, 200 MHz): d 7.30 (m, 6H, ArH), 6. 85 (m, 3H, ArH), 5.98 (d, J ¼ 3.4 Hz, 1H,
H-10), 5.12 (d, J ¼ 3.6 Hz, 1H, H-40), 4.65 (m, 3H, H-5, H-20 and –OCHAPh), 4.48

Glycosyl Isoxazolines
371
(d, J ¼ 11.7Hz, 1H, –OCHBPh), 4.16 (d, J ¼ 3.6 Hz, 1H, H-3), 3.78 (s, 3H, Ar-OCH3),
3.10–2.62 (m, 4H, CH2Ar and H-4), 1.42 and 1.26 [s, 6H, C(CH3)2]; 13C NMR (CDCl3):
d 158.8 (C55N); 137.4 (ArC), 130.69, 129.40, 128.6, 128.2, 127.9, and 114.4 (ArCH),
112.6 [C(CH3)2], 105.6 (C-10), 85.4 (C-20), 82.7 (C-40), 82.0 (C-30), 76.8 (C-5), 72.8
(OCH2Ph), 55.6 (Ar-OCH3), 40.70 (CH2-Ar), 40.3 (C-4), 27.28, and 26.73 [C(CH3)2].
Anal. Calcd for C25H29NO6: C, 68.32; H, 6.65; N, 3.19. Found: C, 68.54; H, 6.81;
N, 3.07.
5(R,S)-Hydroxymethyl-3-[(10R,20R,30S,40R)-30-O-benzyl-10,20-O-isopropylidenetetra-
hydrofuranos-40-yl]-2-isoxazoline (24). Colorless oil, Rf 0.40 (hexane:ethyl acetate, 3:2);
[a]2D5–118 (c 0.28, CHCl3), MS (FAB) ¼ m/z 350 (M þ H)þ; IR (Neat): nmaxcm21 3426,
1
2934, 2365, 1628, 1454, 1379; H NMR (CDCl3, 200 MHz): d 7.33, (m, 5H, ArH), 6.01
(d, J ¼ 3.3 Hz, 1H, H-10), 5.10 (d, J ¼ 3.3 Hz, 1H, H-40), 4.67 (m. 3H, H-5,–OCHAPh and
H-20), 4.51 (d, J ¼ 11.4 Hz, 1H,–OCHBPh), 4.15 (d, J ¼ 3.3 Hz, 1H, H-30), 3.58 (dd,
J ¼ 12.0 and 3.0 Hz, –CHAOH), 3.46 (dd, J ¼ 12.0 and 5.7 Hz, –CHBOH), 3.09 (dd,
J ¼ 17.4 and 10.8 Hz, –H-4A), 2.95 (dd, J ¼ 17.4 and 7.8 Hz, H-4B), 1.50 and 1.34 [s, 6H,
C(CH3)2]. 13C NMR (CDCl3): d 158.1, 157.9 (C55N); 137.3 (ArC), 129.0, 128.6, 128.3,
128.0 (ArCH), 112.7 [C(CH3)2], 105.7 (C-10), 85.2 (C-20), 82.6, 82.5 (C-40), 81.1 (C-30),
76.6 (C-5), 73.4 (OCH2Ph), 64.1, 63.9 (CH2OH), 37.7 (C-4), 27.25 and 26.70 [C(CH3)2].
Anal. Calcd for C18H23NO6: C, 61.88; H, 6.64; N, 4.01. Found: C, 62.06; H, 6.82;
N, 3.91.
5(R,S)-Carboxy-3-[(10R,20R,30S,40R)-30-O-benzyl-10,20-O-isopropylidenetetrahydrofura-
nos-40-yl]-2-isoxazoline (25). Colorless oil, Rf 0.45 (hexane:ethyl acetate, 1: 1); [a]D25–27.68
(c 0.1375, CHCl3), MS (FAB) ¼ m/z 378 (M þ H)þ; IR (Neat): nmax cm21 3280, 2984,
2933, 2362, 1770, 1708, 1658, 1587, 1481, 1379; 1H NMR (CDCl3, 200MHz): d 9.65 (bs,
1H, exchangeable with D2O, COOH), 7.23 (m, 5H, ArH), 7.13 (m, 1H, H-4), 6.00 (m, 1H,
diastereomeric H-10), 4.88 (d, J ¼ 3.2Hz, 1H, H-40), 4.60 (m, 3H, –OCH2 and H-20),
4.37, 4.10 (d, J ¼ 3.2 Hz, 1H, diastereomeric H-30), 1.94 (m, 1H, H-5), 1.47, 1.30 (s, 3H,
C(CH3)2], 1.27 (d, J ¼ 6.9 Hz, 3H, CH3).
Anal. Calcd for C19H23NO7: C, 60.47; H, 6.14; N, 3.71. Found: C, 60.47; H, 6.14;
N, 3.71.
5(R,S)-Ethoxy-3-[(10R,20R,30S,40R)-10,20:30,40-di-O-isopropylidenetetrahydropyr-
anos-50-yl]-2-isoxazoline (26). Colorless oil, Rf 0.65 (hexane:ethyl acetate, 4:1); [a]2D0
–
60.48 (c 0.275, CHCl3); MS (FAB) ¼ m/z 372 (M þ H)þ; IR (Neat): nmax cm21 2980,
2939, 2365, 1745, 1631, 1445, 1377, 1223; 1H NMR (CDCl3, 200 MHz): d 5.54
(d, J ¼ 4.9 Hz, 1H, H-10), 5.10 (m, 1H, H-50), 4.82 (m, 1H, H-5), 4.34 (dd, J ¼ 7.7 and
2.3 Hz, 1H, H-30), 4.33 (m, 4H, –OCH2, H-20 and H-40), 3.45 (m, 2H, H-4), 1.55, 1.46,
1.34, and 1.33 [s, 12H, C(CH3)2], 1.30 (t, J ¼ 7.1 Hz, 3H, CH3). 13C NMR (CDCl3,
50 MHz): d 170.8, 170.4 (C55O), 157.9 (C55N); 110.02, 109.48 [C(CH3)2]; 96.6 (C-10);
78.1 (C-20); 77.5, 76.8 (C-40); 70.6 (C-30); 71.0 (C-5); 69.4 (C-50); 62.15 (OCH2);
40.38, 40.18 (C-4); 26.4, 26.3, 25.2, and 24.6 [C(CH3)2].
Anal. Calcd for C17H25NO8: C, 54.98; H, 6.79; N, 3.77. Found: C, 55.22; H, 6.95;
N, 3.58.

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5(R,S)-(2-Hydroxy phenylmethyl)-3-[(10R, 20R, 30R, 40S) 10,20:30,40-di-O-isopropyli-
dene-tetrahydropyranos-50-yl]-2-isoxazoline (27). Colorless oil; Rf 0.65 (hexane:ethyl
acetate, 7:3); [a]2D0 –23.68 (c 0.2875, CHCl3); MS (FAB) ¼ m/z 405 (M þ H)þ; IR
(Neat): nmax cm21 3467, 2985, 2362, 1747, 1597, 1455, 1374; 1H NMR (CDCl3,
200 MHz): d 7.03 (m, 2H, ArH), 6.86 (m, 2H, ArH), 6.70 (bs, 1H, ArOH), 5.65 (m, 1H,
H-5), 5.55 (d, J ¼ 4.7 Hz, 1H, diastereomeric H-10), 4.62 (m, 2H, H-50 and H-30), 4.31
(m, 4H, H-20, H-40 and CH2Ar)), 3.09 (m, 2H, H-4), 1.51, 1.43, and 1.31 [s, 12H,
C(CH3)2]. 13C NMR (CDCl3, 50 MHz): d 158.2 (C55N); 145.6, 137.2 (ArC), 128.9,
128.4, 128.3 (ArCH) 109.6, 108.9 [C(CH3)2]; 96.1 (C-10); 80.2 (C-20); 73.5, 73.4 (C-40);
70.3 (C-30); 72.8 (C-50), 65.8, 65.5 (diastereomeric C-5), 40.4 (CH2Ar), 37.2 (C-4);
25.6, 25.3, 24.5, and 24.2 [.C(CH3)2].
Anal. Calcd for C21H27NO7: C, 62.21; H, 6.71; N, 3.45. Found: C, 62.31; H, 6.88;
N, 3.39.
5(R,S)-(Hydroxymethyl)-3-[(10R,20R,30R,40S)-10,20:30,40-tetrahydropyranos-50-yl]-
2-isoxazoline (28). Colorless solid Mp 1248C; Rf 0.35 (hexane:ethyl acetate, 7:3);
[a]D25–76.18 (c 0.3625, CHCl3); MS (FAB) ¼ m/z 330 (M þ H)þ; IR (Neat): nmax cm21
1
3469, 2985, 2929, 2362, 1744 1599, 1446, 1379; H NMR (CDCl3, 200 MHz): d 5.55
(d, J ¼ 4.9 Hz, 1H, H-10), 4.67 (m, 3H, H-5, H-50, and H-30), 4.34 (m, 2H, H-20, and
H-40), 3.66 (m, 2H, diastereomeric CH2OH), 3.23 (dd, J ¼ 17.5 and 10.4 Hz, 1H,
H-4A), 2.94 (dd, J ¼ 17.5 and 7.4 Hz, 1H, H-4B), 1.55, 1.46, and 1.34 [s, 12H,
C(CH3)2]. 13C NMR (CDCl3, 50 MHz): d 158.3 (C55N); 109.6, 108.9 [C(CH3)2]; 96.1
(C-10); 80.4 (C-20); 73.6, 73.5 (C- 40); 70.6 (C-30); 72.8 (C-50), 65.47 and 65.35 (diaster-
eomeric C-5), 63.7 (CH2OH), 37.03 (C-4); 25.9, 25.8, 24.7, and 24.2 [.C(CH3)2].
Anal. Calcd for C15H23NO7: C, 54.70; H, 7.04; N, 4.25. Found: C, 54.99; H, 7.23;
N, 4.17.
ACKNOWLEDGMENTS
Authors thank the director of CDRI, for his keen interest in the program; ICMR,
New Delhi, for financial support; and RSIC staff for spectral data and analysis.
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Received December 24, 2003
Accepted March 12, 2004