A convenient synthesis of novel glycosyl azetidines under mitsunobu reaction conditions

Article abstract of DOI:10.1080/00397911.2011.587079

A facile, simple, and high-yielding protocol for synthesis of novel glycosyl azetidines was developed from glycosyl-amino alcohols via intramolecular cyclization under Mitsunobu reaction conditions.

Full text of DOI:10.1080/00397911.2011.587079

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A Convenient Synthesis of Novel Glycosyl
Azetidines Under Mitsunobu Reaction
Conditions
Archana Singh a , Bhuwan B. Mishra a , Raju R. Kale a , Divya
Kushwaha a & Vinod K. Tiwari a
a Department of Chemistry, Centre of Advanced Study, Faculty of
Science, Banaras Hindu University, Varanasi, India
Accepted author version posted online: 20 Jan 2012.Published
online: 20 Aug 2012.
To cite this article: Archana Singh , Bhuwan B. Mishra , Raju R. Kale , Divya Kushwaha & Vinod
K. Tiwari (2012) A Convenient Synthesis of Novel Glycosyl Azetidines Under Mitsunobu Reaction
Conditions, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 42:24, 3598-3613, DOI: 10.1080/00397911.2011.587079
To link to this article: http://dx.doi.org/10.1080/00397911.2011.587079
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Synthetic Communications1, 42: 3598–3613, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.587079
A CONVENIENT SYNTHESIS OF NOVEL GLYCOSYL
AZETIDINES UNDER MITSUNOBU REACTION
CONDITIONS
Archana Singh, Bhuwan B. Mishra, Raju R. Kale,
Divya Kushwaha, and Vinod K. Tiwari
Department of Chemistry, Centre of Advanced Study, Faculty of Science,
Banaras Hindu University, Varanasi, India
GRAPHICAL ABSTRACT
Abstract A facile, simple, and high-yielding protocol for synthesis of novel glycosyl
azetidines was developed from glycosyl b-amino alcohols via intramolecular cyclization
under Mitsunobu reaction conditions.
Keywords DIAD=PPh3; glycosyl amino alcohol; glycosyl amino ester; glycosyl
azetidines; Mitsunobu reaction
INTRODUCTION
Azetidines, the saturated four-membered monocyclic aza-heterocycles, have a
special place in organic chemistry because of their occurrence in numerous biologi-
cally active natural products.[1] Apart from 2-azetidinone (b-lactams), they form a
core skeleton to carbapenem antibiotics, mugineic acid, penaresidin=penazetidine,
peptidyl polyoxins, and sphingosine classes of compounds obtained from numerous
marine organisms.[2] These four-membered monocyclic aza-heterocycles have found
diffuse applications in medicinal chemistry as pharmacological tools, in peptidomi-
metics as unnatural amino acids, and also in numerous natural products. The ability
of azetidines to undergo various transformations such as cycloaddition,[3,4] ring
expansion,[5] and ring opening[6] makes them highly valuable in organic synthesis.
In comparison to the chemistry of b-lactams, the chemistry of azetidines has not
Received March 25, 2011.
This article is dedicated to V.K.T.’s doctoral mentor, Dr. R. P. Tripathi, Senior Scientist at Central
Drug Research Institute, Lucknow, India.
Address correspondence to Vinod K. Tiwari, Department of Chemistry, Banaras Hindu University,
Varanasi 221 005, India. E-mail: vtiwari@ucdavis.edu; tiwari_chem@yahoo.co.in
3598

NOVEL GLYCOSYL AZETIDINES
3599
been much investigated and many of the efforts involving the azetidine nucleus have
been directed toward its synthesis only.[7,8]
The most important and easy synthetic protocol to obtain azetidines involves
the ring closure of amino alcohols (obtained by asymmetric reduction of b-amino
ketones or b-amino acids) induced by transformation of the hydroxyl moiety into
a good leaving group. Other important methods employed include the base-induced
intramolecular cyclization of N-alkylamino oxiranes,[9] stereospecific ring opening of
aziridines and subsequent ring closure with dimethyl sulfoxide,[10] metal-catalyzed
intramolecular NH-insertion of diazo compounds,[11] electroreductive intramole-
cular cross coupling of imines with alkoxycarbonyl compounds, Pd-catalyzed
coupling–cyclizations of allenes with phenyliodonium salts[12] or organic halides,[13]
cycloaddition reactions of imines and alkenes,[14] rearrangement of four-membered
or larger rings,[15] and reduction of azetidin-2-ones.[16a,b] However, these methods
have not been well investigated in the area of carbohydrate chemistry.
The reports on carbohydrate derivatives with azetidine rings are scarce.[16c] In
continuation of our efforts on development of carbohydrate-based potential che-
motherapeutic agents,[17–19] the present communication introduces azetidines in the
area of carbohydrate research and discloses a facile, simple, and high-yielding
protocol for the synthesis of some novel glycosyl azetidines starting from glycosyl
b-amino alcohols via intramolecular cyclization under Mitsunobu reaction conditions.
RESULTS AND DISCUSSION
The synthetic strategy starts from cheap and readily available D-glucose, which after
processing through a number of high-yielding steps such as isopropylidene protection, 3-
O-benzyl protection, selective 5,6-isopropylidene deprotection, NaIO4 oxidation, and
finally the Horner–Wadsworth–Emmons modification affords the glycosyl olefinic ester
(1R,2R,3S,4R)-ethyl (3-O-benzyl-1,2-O-isopropylidene-1,4-pentofuranose-4-yl)-hept-5-
enoate (1).[17a] The 1,4-conjugate addition of cyclopropyl amine to olefinic ester (1)
afforded (1R,2R,3S,4R)-ethyl [3-O-benzyl-5-cyclopropyl-amino-5,6-dideoxy-1,2-O-
isopropylidene]-a-D-gluco- and b-L-ido-hepto-furanuronate (2a and 2b) as a diastereo-
meric mixture (73:27) in good yield (Scheme 1).[17a–c] The diastereoselectivity was deter-
1
mined by comparing the signals in H NMR spectrum of crude product 2 obtained
after conjugate addition reaction. In the majority of the cases the major isomer of glycosyl
amino esters (2a–7a) were separated in pure form using column chromatography (SiO2),
whereas the minor isomer was contaminated with the major isomer. We tried with some
known suitable catalyst to achieve the better diastereoselectivity, where unfortunately the
InCl3 or amidine bases such as 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) or 1,4-diazabi-
cyclo[2.2.2]octane (DABCO) could not result in better selectivity. The InCl3-catalyzed
Scheme 1. Synthesis of glycosylated amino ester (2–7).

3600
A. SINGH ET AL.
Table 1. Conjugate addition of cyclopropyl amine to glycosyl olefinic ester 1
Diastereo selectivity
(major=minor isomer)
Glycosyl b-amino ester
Catalyst
Yield (%)
Time (h)
—
80
90
90
92
88
40
16
16
30
32
73:27
75:25
75:25
71:29
77:23
InCl3 (5 mm %)
InCl3 (10 mm %)
DBU
DABCO
conjugate addition of cyclopropyl amine to olefinic ester 1 afforded compound 2a with
almost similar selectivity; however, yield was improved and reaction time was also reduced
to 16 h (Table 1).
Thus, the predominant diastereoselectivity is only because of the presence of
the alkene–arene p stacking effect as described earlier on the basis of Felkin–
Anh-like transition-state model.[17a,b] Similarly, 1,4-conjugate addition of compound
1 with other aliphatic amines (viz, hexadecyl, n-octyl, n-butyl, cyclohexyl, and phe-
nylethyl amine) led to the formation of corresponding glycosyl b-amino esters (3–7)
in excellent yield.
Although the configuration at the newly formed stereogenic center at C-5 in
compounds 2–7 was difficult to assign at this stage because in the majority of the cases
the -OCH2 (q) peak was merged with H-4 (dd) signal and complicated to determine the
J
4,5 value. However, the configuration at C-5 was determined successfully after lithium
aluminum hydride (LAH) reduction of specific major or minor isomers to the corre-
sponding glycosyl amino alcohol (9–13), where J ¼ 9.6 Hz was calculated for amino
alcohol reduced from the major isomer while J ¼ 5.7 Hz for the minor isomer and thus
relative configuration was assigned as S and R for major (threo-) and minor (erythro-)
isomers, respectively. As the C-5 stereocenter is not involved in the reduction process,
the stereochemistry at this center would be the same as in the glycosyl amino esters
already established. The LAH reduction of glycosyl b-amino ester 2a affords the
corresponding glycosyl b-amino alcohol (1R,2R,3S,4R,5S)-[3-O-benzyl-5-cyclopro-
pylamino-5,6-dideoxy-1,2-O-isopropylidene-1,4-pentofuranos-4-yl]-b-L-ido-heptanol
(8) in 90% yield. 1H NMR spectrum of compound 8 exhibited signals corresponding to
15 proton resonances. An aromatic multiplet integrated to five protons appeared at d
7.33 was identified for the phenyl group whereas a doublet observed at d 5.95 (1H,
J ¼ 3.9 Hz) was evidenced for H-1. The two doublets of one proton each were
observed at d 4.72 (J ¼ 11.8 Hz) and 4.41 (J ¼ 11.8 Hz) were assigned for benzylic pro-
tons -OCHAPh and -OCHBPh, respectively. A doublet appearing at d 4.65 (1H,
J ¼ 3.9 Hz) was identified for H-2 while a double doublet integrated to one proton
observed at d 4.17 (J ¼ 9.6, 3.3 Hz) was evidenced for H-4. A doublet appearing at
d 3.82 (1H, J ¼ 3.3 Hz) was assigned for H-3 whereas a two-proton multiplet observed
at d 3.73 was identified for hydroxyl methylene protons (H-7). Similarly, multiplets of
one proton each observed at d 3.31 and d 2.43 were evidenced for H-5 and -NCH,
respectively. A multiplet integrated to eight protons appearing at d 1.43–1.33 was
assigned for corresponding two methyl resonances of isopropylidene unit and
methylene protons H-6 whereas four methylene protons of the cyclopropyl ring

NOVEL GLYCOSYL AZETIDINES
3601
Table 2. Glycosyl azetidines (14–19) synthesized from b-amino alcohols (8–13) via Scheme 2
Glycosyl amino
alcohol (8–13)a
Glycosyl
azetidines (14–19)
Yields
(%)b
Entry
Reaction conditions
1
PPh3=DEAD (1.2 eq)
45c
2
3
4
8
8
8
PPh3=DEAD (1.5 eq)
PPh3=DIAD (1.2 eq)
PPh3=DIAD (1.5 eq)
14
14
14
48
58
63
5
PPh3=DIAD (1.5 eq)
65
6
7
PPh3=DIAD (1.5 eq)
62
60
PPh3=DIAD (1.5 eq)
8
9
PPh3=DIAD (1.5 eq)
60
64
PPh3=DIAD (1.5 eq)
aDiastereoselectivity of conjugate additions was determined by comparative signal in 1H NMR spec-
trum of crude glycosyl b-amino ester (2–7), where InCl3 or DBU=DABCO could not result in better sel-
ectivity and the configuration was determined by J4,5 in 1H NMR spectrum of corresponding alcohols.
bYield refers the isolated product. All intramolecular cyclization reactions were carried out in anhydrous
THF for 12 h.
cIntermolecular cyclization of compound 8 using PPh3=DEAD results in comparatively poor yield of
compound 14.

3602
A. SINGH ET AL.
Scheme 2. Synthesis of N-substituted glycosyl azetidines (14–19).
resonated as a multiplet at d 0.46–0.39. Compound 8 exhibited a broad absorption
band at 3730 cmꢀ1 corresponding to OH group, and 20 carbon resonances appearing
in 13C NMR in addition to the molecular ion peak ( Mþ H)þ observed at m=z 364 in
the mass spectrum finally confirmed the structure. Similar LAH reduction of glycosyl
b-amino esters (3a–7a) results in the formation of corresponding glycosyl b-amino
alcohols (9–13) in excellent yield.
The esters and related compounds can be easily prepared by reaction of alcohol
and carboxylic acids under Mitsunobu reaction condition using azodicarboxylate
(DEAD) and triphenylphosphine (PPh3). To achieve the practical and easy synthesis
of novel glycosyl azetidines, we turned our attention to a related chemistry. The intra-
molecular cyclization of 8 with PPh3 in the presence of DEAD in anhydrous
tetrahydrofuran(THF) afforded 2-(3-O-benzyl-5,6-dideoxy-6-hydroxymethyl-1,2-O-
isopropylidene-b-L-ido-furanose)-1-cyclopropyl azetidine (14) in poor yield (Table 2).
However, intramolecular cyclization of glycosyl b-amino alcohols (8–13) using
DIAD not just increases the product yield significantly but also avoids various hazards
associated with the use of DEAD (e.g., toxic, shock sensitive, thermally unstable, etc).
Because the involved alcohols are of primary nature, inversion of configuration under
Mitsunobu reaction condition is not a problem. Based on the same methodology, vari-
ous glycosyl b-amino alcohols (8–13) were prepared from glycosyl amino esters (2–7)
having S stereochemistry at C-5 (major compound) and were cyclized intramolecularly
to afford corresponding glycosyl azetidines (14–19) in good yield under Mitsunobu
reaction condition using PPh3 and DIAD (Scheme 2). In 1H NMR spectrum, proton
resonances of glycosyl azetidines (14–19) resembled closely those observed in glycosyl
b-amino alcohols (8–13) with no significant difference except the multiplets corre-
sponding to hydroxyl methylene protons were now shifted upfield while the signal cor-
responding to –NCH disappeared. In addition to all the sugar carbon signals, the
peaks appeared at d 64.42 (C-10), 54.59 (C-30), and 37.69 (C-20) in 13C NMR of
compound 14 corresponding to azetidine ring and the mass spectra(MS) at m=z 346
(M þ H) with supported elemental analysis finally confirms the structure of synthe-
sized glycosyl azetidine (14). All the synthesized glycosyl amino esters (2–7), glycosyl
b-amino alcohols (8–13), and glycosyl azetidines (14–19) were purified by column
chromatography using silica gel and characterized through spectroscopic techniques
including IR, 1H NMR, 13C NMR, MS, and elemental analysis.
CONCLUSION
In conclusion, the novel glycosyl azetidines with different substitution patterns
on N-atoms have been synthesized through a simple, facile, and high-yielding proto-
col via intramolecular cyclization of glycosyl b-amino alcohols under Mitsunobu

NOVEL GLYCOSYL AZETIDINES
3603
reaction condition. The azetidine ring formation under the Mitsunobu reaction
offers several advantages including (a) the mild reaction conditions, (b) simple
workup procedure, and (c) good yields of the desired products. To the best of our
knowledge all the synthesized glycosyl azetidiens (14–19) are novel. Moreover, the
use of DIAD has also been disclosed for the first time in the construction of an
azetidine ring. The developed glycosyl azetidine may be useful in the development
of well-defined natural and synthetic imino sugar, where the work on this direction
is in progress in our laboratory.
EXPERIMENTAL
Glassware was dried over an open flame before use in connection with an inert
atmosphere (N2), and solvents were evaporated under reduced pressure at <55 ꢁC.
Unless otherwise stated, all materials were obtained from commercial suppliers
(Sigma Aldrich Company, SRL, and Spectrochem Pvt. Ltd.) and were used without
further purification. Silica gel (230–400 mesh) from commercial supplier Spectro-
chem Pvt. Ltd. was used for column chromatography. The thin-layer chromatogra-
phic(TLC) spots were visualized by spraying Liebermann–Burchard reagent and
iodine (I2) developer wherever applicable. IR spectra were recorded as KBr pellets
on a Perkin-Elemer RX-1 spectrometer. Elemental analyses were performed on a
Perkin-Elmer 2400 C, H, N analyzer, and results were found to be within ꢂ0.4%
of the calculated values. NMR spectra for the compounds were obtained on a Jeol
AL300 FT-NMR spectrometer (300 MHz for 1H, 75 MHz for 13C NMR) in CDCl3.
Chemical shifts are given in parts per million(ppm) downfield from internal tetra-
methylsilane(TMS); J values are given in hertz(Hz). The mass spectra were recorded
on a Jeol JMS D 300 spectrometer with accelerating potential of 3 kV and an ioniza-
tion potential of 30 eV or on a Jeol SX-102(EI=CI=FAB) mass spectrometer.
Syntheses of Glycosyl b-Amino Esters (2–7)
(1R,2R,3S,4R)-Ethyl [3-O-benzyl-5-cyclopropyl-amino-5,6-dideoxy-1,2-
O-isopropylidene]-a-D-gluco and b-L-ido-heptofuranuronate (2). A solution
of glycosyl olefinic ester 1 (3.48 g, 10.0 mmol) dissolved in EtOH (15 mL) was stirred
with cyclopropylamine (1.16 mL, 10.8 mmol) at room temperature (25 ꢁC). On com-
pletion of the reaction (monitored through TLC), the solvent was evaporated under
reduced pressure and the syrup thus obtained was dissolved in ethyl acetate (100 mL)
and washed with H2O (2 ꢃ 25 mL). The organic layer was dried over Na2SO4 and
concentrated under reduced pressure to obtain a crude product, which on silica-gel
column chromatography using n-hexane–EtOAc (80:20) as eluant afforded com-
pound 2 as a colorless solid in diastereomeric ratio 73:27 (yield: 80%); [a]D ¼
ꢀ60.0 (c, 0.30, CHCl3); IR (KBr): nmax cmꢀ1 3350 (NH), 2956 and 2918 (CH3 and
þ
1
=
CH2 stretching), 1730 (>C O); MS (FAB): 406 (M þ H) ; H NMR (300 MHz,
CDCl3): d ¼ 7.33 (m, 5 H, Ar-H), 5.94 (d, J ¼ 3.7 Hz, 1 H, H-1), 4.72 (d, J ¼ 12 Hz,
1 H, -OCHAPh), 4.64 (d, J ¼ 3.7 Hz, 1 H, H-2), 4.46 (d, J ¼ 12 Hz, 1 H, -OCHBPh),
4.22–4.07 (m, 3 H, H-4 and -OCH2), 3.91 (d, J ¼ 2.7 Hz, 1 H, H-3), 3.58 (m, 1 H,
H-5), 3.36–2.16 (m, 3 H, -NCH and H-6), 1.63 (bs, 1 H, NH), 1.48 and 1.32 [each
s, each 3 H, 2 ꢃ > C(CH3)2], 1.24 (t, J ¼ 7.1 Hz, 3 H, -OCH2CH3), 0.39–0.35 (m, 4

3604
A. SINGH ET AL.
13
=
H, CH2’s) ppm; C NMR (75 MHz, CDCl3): d ¼ 171.79 (>C O), 136.99, 128.47,
128.09, 127.99 (Ar-C), 111.57 [2 ꢃ > C(CH3)2], 104.78 (C-1), 81.82 (C-2), 81.74
(C-4), 81.49 (C-3), 71.49 (OCH2Ph), 60.28 (OCH2), 54.24 (C-5), 36.26 (C-6), 28.06
(NCH), 26.72 and 26.28 [2 ꢃ > C(CH3)2], 14.20 (OCH2CH3), 7.31 and 5.68 (2 ꢃ
CH2’s) ppm. Similar conjugate addition of cyclopropyl amine to olefinic acid 1 in
presence of catalytic amount of InCl3 results in the glycosyl amino ester 2 in the same
selectivity; however, the reaction time was reduced to 16 h.
(1R,2R,3S,4R)-Ethyl
[3-O-benzyl-5,6-dideoxy-5-(hexadec-1-yl-amino)-
1,2-O-isopropylidene]-a-D-gluco and b-L-ido-heptofuranuronate (3). Reac-
tion of olefinic ester 1 with hexadecylamine and workup as described previously gave
compound 3 as a colorless solid in diastereomeric ratio 65:35 (yield: 92%); [a]D ¼
ꢀ32.0 (c, 0.15, CHCl3); IR (KBr): nmax cmꢀ1 3332 (NH), 2921 and 2852 (CH3 and
þ
1
=
CH2 stretching), 1730 (>C O); MS (FAB): 591 [M þ 2] ; H NMR (300 MHz,
CDCl3): d ¼ 7.32 (m, 5 H, Ar-H), 5.91 (d, J ¼ 3.7 Hz, 1 H, H-1), 4.67 (d, J ¼ 11.8 Hz,
Hz, 1 H, -OCHAPh), 4.64 (d, J ¼ 3.7 Hz, 1 H, H-2), 4.47 (d, J ¼ 11.8 Hz, 1 H,
OCHBPh), 4.09–4.11 (m, 3 H, H-4 and OCH2), 3.92 (d, J ¼ 2.7 Hz, 1 H, H-3),
3.44 (m, 1 H, H-5), 2.50 and 2.36 (m, 4 H, H-6 and NHCH2), 1.58 (bs, 1 H, NH),
1.47 and 1.31 [each s, each 3 H, 2 ꢃ > C(CH3)2], 1.24 (m, 31 H, CH2’s and
-OCH2CH3), 0.87 (t, J ¼ 6.6 Hz, 3 H, CH2CH3) ppm; 13C NMR (75 MHz, CDCl3):
=
d ¼ 171.83 (>C O), 137.09, 128.47, 128.03 and 127.86 (Ar-C), 111.59 [>C(CH3)2],
104.80 (C-1), 82.11 (C-2), 81.82 (C-4), 81.72 (C-3), 71.47 (-OCH2Ph), 60.32
(OCH2CH3), 54.05 (C-5), 47.36 (NHCH2), 36.35 (C-6), 32.32, 30.83, 30.09, 27.75
and 23.08 (CH2’s), 26.74 and 26.31 [2 ꢃ > C(CH3)2], 14.18 and 14.10 (OCH2CH3
and CH2CH3) ppm.
(1R,2R,3S,4R)-Ethyl
[3-O-benzyl-5-octylamino-5,6-dideoxy-1,2-O-
isopropylidene]-a-D-gluco- and b-L-ido-heptofuranuronate (4). The reaction
of olefinic ester 1 with octylamine and workup as described previously gave a diaster-
eomeric mixture of compound 4 as a colorless oil (yield: 94%); [a]D ¼ ꢀ24.2 (c, 0.28,
CHCl3); IR: nmax cmꢀ1 3350 (NH),þ3040, 2990, 2880 (CH3 and CH2 stretching), 1730
1
=
(>C O); MS (FAB): 478 (M þ H) ; H NMR (300 MHz, CDCl3): d 7.33 (m, 5 H,
Ar-H), 5.89 (d, J ¼ 3.7 Hz, 1 H, H-1), 4.71 (d, J ¼ 12.0 Hz, 1 H, -OCHAPh), 4.64
(d, J ¼ 3.7 Hz, 1 H, H-2, major isomer), 4.51 (d, J ¼ 12.0 Hz, 1 H, -OCHBPh),
4.25–4.08 (m, 3 H, H-4 and -OCH2CH3), 3.97 (d, J ¼ 3.1 Hz, 1 H, H-3), 3.39 (m, 1
H, H-5), 2.75–2.30 (m, 4 H, -NHCH2, H-6A and H-6B), 1.54 [bs, 1 H,
0
-NH(CH2)7CH3], 1.49–1.27 [m, 18 H, 2 ꢃ >C(CH3)2 and CH2 s], 1.25 (t, J ¼ 7.1 Hz,
Hz, 3 H, -OCH2CH3), 0.87 [t, J ¼ 6.9 Hz, 3 H, -NH(CH2)7CH3] ppm; 13C NMR
=
(75 MHz, CDCl3): d ¼ 172.54 (>C O), 137.59, 128.49, 128.45 and 127.84 (Ar-C),
111.90 [>C(CH3)2], 105.00 (C-1), 82.80 (C-2), 82.20 (C-4), 81.63 (C-3), 72.22 (-O-
CH2Ph), 60.41 (-OCH2CH3), 52.66 (C-5), 47.00 (-NHCH2), 35.81 (C-6), 31.83,
0
30.69, 29.52, 26.80, 26.19, 22.65 (CH2 s), 27.33 and 26.35 [2 ꢃ > C(CH3)2], 14.24
(-OCH2CH3), 14.10 [-NH(CH2)7CH3] ppm. Anal. calcd. for C27H43NO6: C, 67.88;
H, 9.08; N, 2.93. Found: C, 67.96; H, 9.13; N, 2.88.
(1R,2R,3S,4R)-Ethyl
[3-O-benzyl-5-butylamino-5,6-dideoxy-1,2-O-
isopropylidene]-a-D-gluco- and b-L-ido-heptofuranuronate (5). Reaction of
olefinic ester 1 with n-butyl amine and workup as described previously gave a

NOVEL GLYCOSYL AZETIDINES
3605
diastereomeric mixture of compound 5 as a colorless oil; 90%); [a]D ¼ ꢀ42.3 (c, 0.18,
CHCl3); IR: nmax cmꢀ1 3350 (NH), 3040þ, 2990, 2880 (CH3 and CH2 stretching),
1730 (>C O); MS (FAB): 422 (M þ H) ; 1H NMR (300 MHz, CDCl3): d 7.32
=
(m, 5 H, Ar-H), 6.10 (d, J ¼ 3.7 Hz, 1 H, H-1, major isomer), 4.84 (d, J ¼ 12 Hz,
1 H, -OCHAPh), 4.69 (d, J ¼ 3.7 Hz, 1 H, H-2, major isomer), 4.58 (d, J ¼ 12 Hz,
1 H, -OCHBPh), 4.17–4.10 (m, 3 H, H-4 and -OCH2CH3), 3.22–3.20 (m, 2 H, H-5
and H-3), 2.65 (m, 2 H, -NHCH2), 2.38 and 2.32 (dd, J ¼ 15.6 Hz and 4.7 Hz, 1 H,
H-6A), 2.25 and 2.19 (dd, J ¼ 15.6 Hz and 6.6 Hz, 1 H, H-6B), 1.59 [bs, 1 H,
-NH(CH2)3CH3], 1.40–1.27 [m, 11 H, 2 ꢃ > C(CH3)2, NHCH2CH2CH2 and
OCH2CH3], 0.88 [t, J ¼ 7.2 Hz, 3 H, -NH(CH2)3CH3] ppm; 13C NMR (75 MHz,
=
CDCl3): d ¼ 172.20 (>C O), 137.51, 129.10, 128.42 and 128.14 (each Ar-C),
111.90 [>C(CH3)2], 105.21 (C-1), 82.63 (C-2), 82.26 (C-4), 82.12 (C-3), 71.88 (-O-
CH2Ph), 60.68 (OCH2CH3), 54.44 (C-5), 47.34 (NHCH2), 36.74 (C-6), 32.90
(NHCH2CH2), 27.14 and 26.73 [2 ꢃ > C(CH3)2], 20.81 [NH(CH2)2CH2CH3], 14.57
(OCH2CH3), 14.36 [NH(CH2)3CH3] ppm.
(1R,2R,3S,4R)-Ethyl [3-O-benzyl-5-cyclohexylamino-5,6-dideoxy-1,2-O-
isopropylidene]-a-D-gluco- and b-L-ido-heptofuranuronate (6). Reaction of
olefinic ester 1 with cyclohexylamine and workup as described previously gave a dia-
stereomeric mixture of compound 6 as colorless oil; [a]D ¼ ꢀ22.6 (c, 0.18, CHCl3);
IR: nmax cmꢀ1 3350 (NH), 3040, 2990, 2880 (CH3 and CH2 stretching), 1730
þ
1
=
(>C O); MS (FAB): 448 (M þ H) ; H NMR (300 MHz, CDCl3): d 7.33 (m, 5 H,
Ar-H), 5.93 (d, J ¼ 3.7 Hz, 1 H, H-1, major isomer), 4.70 (d, J ¼ 12 Hz, 1 H,
-OCHAPh), 4.64 (d, J ¼ 3.7 Hz, 1 H, H-2, major isomer), 4.45 (d, J ¼ 12 Hz, 1 H,
-OCHBPh), 4.12–4.07 (m, 3 H, H-4 and OCH2CH3), 3.93 (d, J ¼ 3.1 Hz, 1 H,
H-3), 3.40 (m, 1 H, H-5), 2.65 (m, 1 H, -NHCH), 2.38 and 2.32 (dd, J ¼ 15.6 Hz
and 4.7 Hz, 1 H, H-6A), 2.65 and 2.49 (dd, J ¼ 15.6 Hz and 6.6 Hz, 1 H, H-6B),
2.35 (m, 1 H, NHCH), 2.12–2.09 (m, 2H, 2 ꢃ CH2), 1.70 (bs, 1 H, -NH),
1.48–1.23 [s, 12 H, 2 ꢃ CH3 and cyclohexyl ring] ppm; 13C NMR (75 MHz, CDCl3):
=
d ¼ 172.20 (>C O), 137.51, 129.10, 128.42 and 128.14 (Ar-C), 111.90 [>C(CH3)2],
105.21 (C-1), 82.63 (C-2), 82.26 (C-4), 82.12 (C-3), 71.88 (-OCH2Ph), 60.68 (-O-
CH2CH3), 54.44 (C-5), 47.34 (-NHCH), 36.74, 33.4, 29.9, 25.6, and 25.5 (CH2’s),
27.14 and 26.73 [2 ꢃ > C(CH3)2], 14.57 (-OCH2CH3) ppm. Anal. calcd. for
C25H37NO6: C, 67.07; H, 8.34; N, 3.13. Found: C, 67.12; H, 8.41; N, 3.16.
(1R,2R,3S,4R)-Ethyl [3-O-benzyl-5-phenylethylamino-5,6-dideoxy-1,2-
O-isopropyl-idene]-a-D-gluco- and b-L-ido-heptofuranuronate (7). Conjugate
addition of phenylethylamine to olefinic ester 1 and workup as described previously
gave a diastereomeric mixture of compound 7 as a colorless oil; [a]D ¼ ꢀ18.0 (c, 0.11,
CHCl3); IR: nmax cmꢀ1 3350 (-NH), 302þ0, 2980, 2920 (CH3 and CH2 stretching),
1
=
1710, (>C O); MS (FAB): 470 (M þ H) ; H NMR (300 MHz, CDCl3): d ¼ 7.30
(m, 10 H, Ar-H), 5.93 (d, J ¼ 3.9 Hz, 1 H, H-1), 4.68 (d, J ¼ 12 Hz, 1 H, -OCHAPh),
4.62 (d, J ¼ 3.9 Hz, 1 H, H-2), 4.43 (d, J ¼ 12 Hz, 1 H, -OCHBPh), 4.19 and 4.16 (dd,
J ¼ 9.0 Hz and 3.3 Hz, 1 H, H-4), 4.10 (q, J ¼ 7.14 Hz, 2 H, -OCH2CH3), 3.90 (d,
J ¼ 3.19 Hz, 1 H, H-3), 3.48 (m, 1 H, H-5), 2.92 (t, 2 H, -NHCH2CH2Ph), 2.76 (t,
2 H, -NHCH2CH2Ph), 2.41 and 2.36 (dd, J ¼ 15.6 Hz and 4.8 Hz, 1 H, H-6A), 2.29
and 2.25 (dd, J ¼ 15.6 Hz and 6.6 Hz, 1 H, H-6B), 1.70 (bs, 1 H, -NH), 1.47 and,
1.31 [each s, each 3 H, 2 ꢃ > C(CH3)2], 1.20 (t, J ¼ 7.14 Hz, 3 H, -OCH2CH3)

3606
A. SINGH ET AL.
13
=
ppm; C NMR (75 MHz, CDCl3): d ¼ 172.80 (>C O), 141.07, 137.97, 128.86,
128.69, 128.42, 128.26, 128.12 and 127.27 (Ar-C), 111.98 [>C(CH3)2], 105.20
(C-1), 82.60 (C-2), 82.40 (C-4), 82.22 (C-3), 71.37 (-OCH2Ph), 60.26 (-OCH2CH3),
53.79 (C-5), 48.63 (CH2), 36.73 (C-6), 36.25 (NCH2), 26.68 and 26.24
[2 ꢃ > C(CH3)2], 14.10 (-OCH2CH3) ppm. Anal. calcd. for C27H35NO6: C, 69.05;
H, 7.52; N, 2.98. Found: C, 68.95; H, 7.57; N, 2.94.
Syntheses of Glycosyl b-Amino Alcohols (8–13)
(1R,2R,3S,4R,5S)-[3-O-Benzyl-5-cyclopropyl amino-5,6-dideoxy-1,2-O-
isopropylidene-1,4-pento-furanos-4-yl]-b-L-ido-heptanol (8). A solution of
major glycosyl amino ester 2a (0.5 g, 1.52 mmol) in anhydrous THF (5.0 ml) was
added drop-wise to the stirring slurry of LiAlH4 (0.058 g, 1.52 mmol) in anhydrous
THF (5.0 ml) at 0 ꢁC under a nitrogen atmosphere. The reaction mixture was stirred
for 30 min at 0 ꢁC followed by stirring for further 3 h at ambient temperature. On
completion of reaction, excess reducing agent was quenched by adding saturated
aqueous Na2SO4 solution and the reaction mixture was filtered. The solid cake
was washed with THF, and the filtrate was concentrated under reduced pressure fol-
lowed by extraction with chloroform (2 ꢃ 25 ml) and water (12 ml). The organic layer
was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give
a crude mass, which on silica-gel column chromatography using chloroform–
methanol (98:2) as eluent afforded glycosyl b-amino alcohol 8 as a colorless oil
(yield: 90%); [a]D ¼ ꢀ88.6 (c, 0.43, CHCl3); IR: nmax cmꢀ1 3730 (OH), 3350 (NH),
1
2970 and 2910 (CH2 and CH3 stretching); MS (FAB): 364 (M þ H)þ; H NMR
(300 MHz, CDCl3): d ¼ 7.33 (m, 5 H, Ar-H), 5.95 (d, J ¼ 3.9 Hz, 1 H, H-1), 4.72
(d, J ¼ 11.8 Hz, 1 H, -OCHAPh), 4.65 (d, J ¼ 3.9 Hz, 1 H, H-2), 4.41 (d, J ¼ 11.8 Hz,
Hz, 1 H, -OCHBPh), 4.17 (dd, J ¼ 9.6 and 3.3 Hz, 1 H, H-4), 3.82 (d, J ¼ 3.3 Hz, 1 H,
H-3), 3.73 (m, 2 H, H-7), 3.31 (m, 1 H, H-5), 2.43 (m, 1 H, NCH), 1.43–1.33 [m, 8 H,
>C(CH3)2 and H-6], 0.46–0.39 (m, 4 H, cyclopropyl ring CH2’s) ppm; 13C NMR
(75 MHz, CDCl3): d ¼ 136.80, 128.52, 128.26 and 128.15 (Ar-C), 111.54 [>C(CH3)2],
], 104.70 (C-1), 82.74 (C-2), 81.68 (C-4), 81.26 (C-3), 71.65 (OCH2Ph), 62.69 (C-7),
57.82 (C-5), 30.2 (C-6), 28.51 (CH), 26.65 and 26.14 [2 ꢃ > C(CH3)2], 6.44 and
6.42 (2 ꢃ CH2) ppm.
(1R,2R,3S,4R,5S)-[3-O-Benzyl-5,6-dideoxy-5-hexadecylamino-1,2-O-iso-
propylidene-1,4-pentofu-ranos-4-yl]-b-L-ido-heptanol (9). Reduction of glyco-
syl b-amino ester 3a (major isomer) with LiAlH4 and workup as described
previously gave corresponding glycosyl b-amino alcohol 9 as a colorless oil
(yield 90%), [a]D ¼ ꢀ27.0 (c, 0.50, CHCl3); IR: nmax cmꢀ1 3740 (OH), 3346 (NH),
1
2927 and 2856 (CH3 and CH2 stretching); MS (FAB): 548 (M þ H)þ; H NMR
(300 MHz, CDCl3): d ¼ 7.29 (m, 5 H, Ar-H), 5.93 (d, J ¼ 3.7 Hz, 1 H, H-1), 4.71
(d, J ¼ 11.6 Hz, 1 H, -OCHAPh), 4.65 (d, J ¼ 3.7 Hz, 1 H, H-2), 4.41 (d, J ¼ 11.6 Hz,
Hz, 1 H, –OCHBPh), 4.21 (dd, J ¼ 9.4 and 3.0 Hz, 1 H, H-4), 3.83 (d, J ¼ 3.0 Hz, 1 H,
H-3), 3.76 (m, 2 H, H-7), 3.26 (m, 1H, H-5), 2.70 (m, 2 H, NCH2), 1.53–1.25 (m, 36
H, 2 ꢃ > C(CH3)2, H-6, 14 ꢃ CH2’s), 0.87 (t, J ¼ 6.6 Hz, 3 H, -CH2CH3) ppm; 13C
NMR (75 MHz, CDCl3): d ¼ 136.5, 128.55, 128.33 and 128.04 (Ar-C), 111.64
[>C(CH3)2], 104.64 (C-1), 81.81 (C-2), 81.22 (C-4), 81.09 (C-3), 71.70 (–OCH2Ph),

NOVEL GLYCOSYL AZETIDINES
3607
62.31 (C-7), 57.12 (C-5), 46.11 (NCH2), 32.2, 30.0, 29.9, 29.8, 29.7, 29.4, 27.44 and
26.71 (CH2’s), 27.20 and 26.19 [2 ꢃ >C(CH3)2], 14.11 (CH2CH3) ppm.
(1R,2R,3S,4R,5S)-[3-O-Benzyl-5,6-dideoxy-5-octylamino-1,2-O-isopropyl-
idene-1,4-pentofuranos-4-yl]-b-L-ido-heptanol-(10). Reduction of glycosyl b-
amino ester 4a (major isomer) with LiAlH4 and workup as described previously gave
corresponding glycosyl b-amino alcohol 10 as colorless oil (yield 92%); [a]D ¼ ꢀ18.2
(c, 0.2, CHCl3); IR: nmax cmꢀ1 3330 (NH), 2929 and 2857 (CH3 and CH2 stretching);
1
MS (FAB): 436 (M þ H)þ; H NMR (300 MHz, CDCl3): d ¼ 7.33 (m, 5 H, Ar-H),
5.93 (d, J ¼ 3.8 Hz, 1 H, H-1), 4.70 (d, J ¼ 11.7 Hz, 1 H, -OCHAPh), 4.65 (d,
J ¼ 3.8 Hz, 1 H, H-2), 4.41 (d, J ¼ 11.7 Hz, 1 H, -OCHBPh), 4.21 (dd, J ¼ 9.6 and
3.0 Hz, 1 H, H-4), 3.82 (d, J ¼ 3.0 Hz, 1 H, H-3), 3.24 (m, 3 H, H-5 and NCH2),
1.50 (bs, 1 H, -NH), 3.69 (m, 2 H, H-7), 1.41–1.25 [m, 20 H, >C(CH3)2, H-6 and
6 ꢃ CH2’s] and 0.87 (t, J ¼ 6.9 Hz, 3 H, CH2CH3) ppm; 13C NMR (75 MHz, CDCl3):
d ¼ 136.85, 128.51, 128.18 and 128.00 (Ar-C), 111.59 [>C(CH3)2], 104.63 (C-1), 81.84
(C-2), 81.22 (C-4), 81.18 (C-3), 71.68 (OCH2Ar), 62.39 (C-7), 57.10 (C-5), 46.09
(NCH2), 31.78, 30.38, 29.19, 28.76, 27.19, 22.61 (CH2’s), 26.69 and 26.18
[>C(CH3)2], 14.05 (CH2CH3) ppm. Anal. calcd. for C25H41NO5: C, 68.93; H,
9.49; N, 3.22. Found: C, 68.97; H, 9.46; N, 3.25.
(1R,2R,3S,4R,5S)-[3-O-Benzyl-5,6-dideoxy-5-butylamino-1,2-O-isopro-
pylidene-1,4-pentofuranos-4-yl]-b-L-ido-heptanol (11). Reduction of glycosyl
b-amino ester 5a (major isomer) with LiAlH4 and workup as described previously
gave corresponding glycosyl b-amino alcohol 11 as a colorless oil (yield 90%);
[a]D ¼ ꢀ43.3 (c, 0.15, CHCl3); IR: nmax cmꢀ1 3346, 2927 and 2856 (CH3 and CH2
1
stretching); MS (FAB): 380 (M þ H)þ; H NMR (300 MHz, CDCl3): d ¼ 7.32 (m,
5 H, Ar-H), 5.94 (d, J ¼ 3.6 Hz, 1 H, H-1), 4.69 (d, J ¼ 11.6 Hz, 1 H, -OCHAPh),
4.64 (d, J ¼ 3.7 Hz, 1 H, H-2), 4.40 (d, J ¼ 11.6 Hz, 1 H, -OCHBPh), 4.20 (dd,
J ¼ 9.4 and 3.0 Hz, 1 H, H-4), 3.83 (d, J ¼ 3.0 Hz, 1 H, H-3), 3.72 (m, 2 H, H-7),
3.24 (m, 1 H, H-5), 2.75 (m, 2 H, NCH2), 1.53–1.25 (m, 12 H, >C(CH3)2, H-6
and 2 ꢃ CH2’s), 0.87 (t, J ¼ 6.9 Hz, 3 H, -CH2CH3) ppm; 13C NMR (75 MHz,
CDCl3): d ¼ 136.5, 129.1, 128.9 and 128.78 (Ar-C), 113.0 [>C(CH3)2], 105.4 (C-1),
82.2 (C-2), 81.4 (C-4), 79.72 (C-3), 72.3 (-OCH2Ph), 59.9 (C-7), 58.4 (C-5), 47.3
(NCH2), 32.2, 30.0, 29.9, 29.4, and 27.2 (CH2’s), 27.44 and 27.0 [2 ꢃ >C(CH3)2],
14.4 (CH2CH3) ppm.
(1R,2R,3S,4R,5S)-[3-O-Benzyl-5,6-dideoxy-5-cyclohexylamino-1,2-O-iso-
propylidene-1,4-pento-furanos-4-yl]-b-L-ido-heptanol (12). Reduction of gly-
cosyl b-amino ester 6a (major isomer) with LiAlH4 and workup as described
previously gave the corresponding glycosyl b-amino alcohol 12 as a colorless oil
(yield 90%); [a]D ¼ ꢀ14.9 (c, 0.23, CHCl3); IR: nmax cmꢀ1 3350 (NH), 2970 and
1
2910 (CH3 and CH2 stretching); MS (FAB): 406 (M þ H)þ; H NMR (300 MHz,
CDCl3): d ¼ 7.34 (m, 5 H, Ar-H), 5.92 (d, J ¼ 3.9 Hz, 1 H, H-1), 4.69 (d, J ¼ 11.8 Hz,
Hz, 1 H, -OCHAPh), 4.62 (d, J ¼ 3.9 Hz, 1 H, H-2), 4.53 (d, J ¼ 11.8 Hz, 1 H,
-OCHBPh), 4.10 (dd, J ¼ 9.6 and 3.0 Hz, 1 H, H-4), 3.84 (m, 1 H, H-3), 3.40 (m, 1
H, H-7 and 1 H, H-5), 2.72 (m, 1 H, NCH), 1.64 (bs, 1 H, NH), 1.49–1.33 [m, 7
H, >C(CH3)2 and H-6], 1.25–1.05 (m, 6 H, cyclohexyl ring protons) ppm; 13C
NMR (75 MHz, CDCl3): d ¼ 136.66, 128.31, 127.86 and 127.61 (Ar-C), 111.31

3608
A. SINGH ET AL.
[>C(CH3)2], 104.27 (C-1), 82.30 (C-2), 81.34 (C-4), 81.16 (C-3), 71.47 (OCH2Ph),
62.25 (C-7), 54.35 (C-5), 33.70 (NCH), 32.22, 25.67, 24.83 and 24.47 (CH2’s),
26.47 and 25.67 [>C(CH3)2] ppm. Anal. calcd. for C23H35NO5: C, 68.12; H, 8.70;
N, 3.45; Found: C, 68.09; H, 8.73; N, 3.41.
(1R,2R,3S,4R,5S)-[3-O-Benzyl-5,6-dideoxy-5-phenylethylamino-1,2-O-
isopropylidene-1,4-pento-uranos-4-yl]-b-L-ido-heptanol (13). Reduction of
glycosyl b-amino ester 7a (major isomer) with LiAlH4 and workup as described pre-
viously gave corresponding glycosyl b-amino alcohol 13 as colourless oil (yield 92%);
[a]D ¼ ꢀ27.0 (c, 0.16, CHCl3); IR: nmax cmꢀ1 3330 (NH), 2929 and 2857 (CH3 and
CH2 stretching); MS (FAB): 428 (M þ H)þ; 1H NMR (300 MHz, CDCl3):
d ¼ 7.29–7.15 (m, 10 H, Ar-H), 5.91 (d, J ¼ 3.8 Hz, 1 H, H-1), 4.47 (d, J ¼ 11.7 Hz,
1H, -OCHAPh), 4.24 (d, J ¼ 3.9 Hz, 1 H, H-2), 4.14 (d, J ¼ 11.7 Hz, 1 H, -OCHBPh),
3.67 (m, 2 H, H-4 and H-3), 3.26 (m, 2 H, H-7 and H-5), 2.83–2.70 (m, 4 H, NCH2
and PhCH2), 1.50–1.25 [m, 8H, >C(CH3)2 and H-6] ppm; 13C NMR (75 MHz,
CDCl3): d ¼ 137.3, 128.9, 128.5 and 128.4 (Ar-C), 111.70 [>C(CH3)2], 104.89
(C-1), 82.3 (C-2), 81.7 (C-4), 81.6 (C-3), 72.1 (OCH2Ar), 58.58 (C-7), 54.81 (PhCH2),
47.38 (C-5), 36.55 (NCH2), 26.90 and 26.20 [>C(CH3)2] ppm. Anal. calcd. for
C25H33NO5: C, 70.23; H, 7.78; N, 3.28; Found: C, 70.20; H, 7.74; N, 3.24.
Synthesis of Glycosyl Azetidines (14–19)
3-O-Benzyl-4-N-cyclopropyl azetidine-1,2-O-isopropylidene-b-L-ido-fur-
anose (14). A solution of (1R,2R,3S,4R,5S)-[3-O-benzyl-5-cyclopropylamino-
5,6-dideoxy-1,2-O-isopropylidene-1,4-pentofuranos-4-yl]-b-L-ido-heptanol (8, 0.5 g,
1.38 mmol) and DIAD (0.42 g, 2.07 mmol, 1.5 eq) in dry THF was stirred for
20 min at 0 ꢁC under anhydrous condition followed by dropwise addition of a freshly
prepared solution of PPh3 (0.54 g, 2.07 mmol) in dry THF. After complete addition
of PPh3, the reaction mixture was further stirred for 8–10 h at room temperature.
The reaction was monitored on TLC, which after completion was concentrated
under reduced pressure followed by extraction with chloroform (2 ꢃ 25 ml) and
water (12.5 ml). The organic layer was dried over anhydrous Na2SO4 and concen-
trated under reduced pressure to afford a crude mass, which on silica-gel column
chromatography and elution with chloroform–methanol (98:2) afforded glycosyl
azetidine 14 as a colorless oil (yield 63%); [a]D ¼ ꢀ28.6 (c, 0.13, CHCl3); MS
(FAB): 346 (M þ H)þ, 1H NMR (300 MHz, CDCl3): d ¼ 7.34 (m, 5 H, Ar-H), 5.92
(d, J ¼ 3.9 Hz, 1 H, H-1), 4.66 (d, J ¼ 11.8 Hz, 1 H, -OCHAPh), 4.64 (d, J ¼ 3.9 Hz,
Hz, 1 H, H-2), 4.48 (d, J ¼ 11.8 Hz, 1 H, -OCHBPh), 4.20 (dd, J ¼ 9.6 and 3.1 Hz, 1
H, H-4), 3.88 (d, J ¼ 3.1 Hz, 1 H, H-3), 3.57 (m, 1 H, H-10), 3.11 (m, 1 H, NCH), 1.80
(m, 2 H, H-30), 1.48–1.22 [m, 8 H, >C(CH3)2 and H-20], 0.42 (m, 4 H, cyclopropyl
ring CH2’s) ppm; 13C NMR (75 MHz, CDCl3): d ¼ 137.20, 128.48, 128.32 and
127.85 (Ar-C), 111.21 [>C(CH3)2], 105.43 (C-1), 82.04 (C-2), 81.76 (C-4), 81.44
(C-3), 71.67 (OCH2Ph), 64.42 (C-10), 54.59 (C-30), 47.50 (NCH), 37.69 (C-20),
26.57 and 26.15 [>C(CH3)2], 6.95 and 6.89 (cyclopropyl ring CH2) ppm. Anal. calcd.
for C20H27NO4: C, 69.54; H, 7.88; N, 4.05; Found: C, 69.86; H, 8.01; N, 3.98.
3-O-Benzyl-4-N-hexadecyl azetidine-1,2-O-isopropylidene-b-L-ido-fura-
nose (15). Intramolecular cyclization of glycosyl b-amino alcohol 9 using PPh3=

NOVEL GLYCOSYL AZETIDINES
3609
DIAD and workup as described previously gave the corresponding glycosyl azeti-
dene 15 as a colorless oil (yield 65%); [a]D ¼ ꢀ19.3 (c, 0.17, CHCl3); MS (FAB):
530 (M þ H)þ; 1H NMR (300 MHz, CDCl3): d ¼ 7.34 (m, 5 H, Ar-H), 5.95 (d,
J ¼ 3.7 Hz, 1 H, H-1), 4.65 (d, J ¼ 11.6 Hz, 1 H, -OCHAPh), 4.56 (d, J ¼ 3.7 Hz, 1
H, H-2), 4.41 (d, J ¼ 11.6 Hz, 1 H, -OCHBPh), 4.21 (dd, J ¼ 9.4 and 2.9 Hz, 1 H,
H-4), 3.86 (d, J ¼ 2.9 Hz, 1 H, H-3), 3.40 (m, 1 H, H-10), 2.76 (m, 2 H, NCH),
1.86 (m, 2 H, H-30), 1.53–1.25 [m, 34 H, >C(CH3)2, H-20, 14 ꢃ CH2’s], 0.87 (t,
J ¼ 6.7 Hz, 3 H, CH2CH3) ppm; 13C NMR (75 MHz, CDCl3): d ¼ 136.2, 128.12,
128.03 and 127.64 (Ar-C), 111.60 [>C(CH3)2], 104.14 (C-1), 81.81 (C-2), 81.22
(C-4), 81.09 (C-3), 71.70 (-OCH2Ph), 56.12 (C-10), 50.6 (C-30), 46.11 (NCH2),
31.30, 30.00, 29.91, 29.8, 29.7, 29.4, 27.44 and 27.2 (CH2’S), 26.71 and 26.19
[2 ꢃ >C(CH3)2], 14.11 (CH2CH3) ppm. Anal. calcd. for C33H55NO4: C, 74.80; H,
10.47; N, 2.65. Found: C, 74.58; H, 9.98; N, 2.71.
3-O-Benzyl-4-N-octyl azetidine-1,2-O-isopropylidene-b-L-ido-furanose
(16). Intramolecular cyclization of glycosyl b-amino alcohol 10 using PPh3=DIAD
and workup as described previously gave the corresponding glycosyl azetidene 16
as colorless oil (yield 62%); [a]D ¼ ꢀ21.6 (c, 0.14, CHCl3); MS (FAB): 418 (M þ H)þ;
1H NMR (300 MHz, CDCl3): d ¼ 7.33 (m, 5 H, Ar-H), 5.95 (d, J ¼ 3.8 Hz, 1 H, H-1),
4.65 (d, J ¼ 11.7 Hz, 1 H, -OCHAPh), 4.60 (d, J ¼ 3.8 Hz, 1 H, H-2), 4.41 (d,
J ¼ 11.7 Hz, 1 H, -OCHBPh), 4.20 (dd, J ¼ 9.6 and 3.0 Hz, 1 H, H-4), 3.82 (d,
J ¼ 3.0 Hz, 1 H, H-3), 3.24 (m, 2 H, H-30), 3.69 (m, 1 H, H-10 and 2 H, NCH2),
1.41–1.25 [m, 20 H, >C(CH3)2, H-20 and 6 ꢃ CH2’s], 0.87 (t, J ¼ 6.9 Hz, 3 H,
CH2CH3) ppm; 13C NMR (75 MHz, CDCl3): d ¼ 137.27, 128.42, 128.17 and
127.81 (Ar-C), 111.64 [>C(CH3)2], 105.47 (C-1), 84.92 (C-2), 81.85 (C-4), 81.50
(C-3), 71.75 (OCH2Ph), 65.03 (C-10), 59.42 (C-30), 51.89 (NCH2), 31.79, 30.34,
29.52, 29.24, 27.37 and 22.67 (CH2’s), 27.44 and 26.28 [>C(CH3)2], 14.06 (CH2CH3)
ppm. Anal. calcd. for C25H39NO4: C, 71.91; H, 9.41; N, 3.35. Found: C, 71.67; H,
9.40; N, 3.63.
3-O-Benzyl-4-N-butyl azetidine-1,2-O-isopropylidene-b-L-ido-furanose
(17). Intramolecular cyclization of glycosyl b-amino alcohol 11 using PPh3=DIAD
and workup as described previously gave corresponding glycosyl azetidene 17 as a
colorless oil (yield 60%); [a]D ¼ ꢀ20.1 (c, 0.21, CHCl3); MS (FAB): 362 (M þ H)þ;
1H NMR (300 MHz, CDCl3): d ¼ 7.33 (m, 5 H, Ar-H), 5.88 (d, J ¼ 3.6 Hz, 1 H,
H-1), 4.67 (d, J ¼ 11.6 Hz, 1 H, -OCHAPh), 4.62 (d, J ¼ 3.6 Hz, 1 H, H-2), 4.42 (d,
J ¼ 11.6 Hz, 1 H, -OCHBPh), 4.11 (dd, J ¼ 9.4 and 3.0 Hz, 1 H, H-4), 3.87 (d,
J ¼ 3.0 Hz, 1 H, H-3), 3.23 (m, 2 H, H-30), 3.14 (m, 1 H, H-10), 2.75 (m, 2 H,
NCH2), 1.53–1.25 [m, 12 H, >C(CH3)2, H-20, 2 ꢃ CH2’s], 0.87 (t, J ¼ 6.7 Hz, 3 H,
-CH2CH3) ppm; 13C NMR (75 MHz, CDCl3): d ¼ 136.5, 129.1, 128.9 and 128.78
(Ar-C), 113.0 [>C(CH3)2], 105.4 (C-1), 82.2 (C-2), 81.4 (C-4), 79.72 (C-3), 72.3
(–OCH2Ph), 60.09 (C-10), 58.44 (C-30), 49.30 (NCH2), 32.14, 30.10, 29.22, 29.13,
and 27.12 (CH2’s), 27.44 and 27.03 [2 ꢃ >C(CH3)2], 14.02(CH2CH3) ppm. Anal.
calcd. for C21H31NO4: C, 69.78; H, 8.64; N, 3.87. Found: C, 69.42; H, 9.07; N, 3.65.
3-O-Benzyl-4-N-cyclohexyl azetidine-1,2-O-isopropylidene-b-L-ido-
furanose (18). Intramolecular cyclization of glycosyl b-amino alcohol 12 using
PPh3=DIAD and workup as described previously gave the corresponding glycosyl

3610
A. SINGH ET AL.
azetidene 18 as a colorless oil (yield 60%); [a]D ¼ ꢀ17.0 (c, 0.15, CHCl3); MS
1
(FAB): 388 (M þ H)þ; H NMR (300 MHz, CDCl3): d ¼ 7.33 (m, 5 H, Ar-H),
5.92 (d, J ¼ 3.9 Hz, 1 H, H-1), 4.68 (d, J ¼ 11.8 Hz, 1 H, -OCHAPh), 4.64 (d,
J ¼ 3.9 Hz, 1 H, H-2), 4.48 (d, J ¼ 11.8 Hz, 1 H, -OCHBPh), 4.22 (dd, J ¼ 9.6 and
3.1 Hz, 1 H, H-4), 3.86 (m, 1 H, H-3), 3.56 (m, 1 H, H-10), 3.15 (m, 1 H, NCH),
2.25 (m, 2 H, H-30), 1.45–1.24 [m, 8 H, >C(CH3)2 and H-20], 1.22–1.05 (m, 6 H,
cyclohexyl ring protons) ppm; 13C NMR (75 MHz, CDCl3): d ¼ 136.66, 128.31,
127.86 and 127.61 (Ar-C), 111.58 [>C(CH3)2], 105.07 (C-1), 82.03 (C-2), 81.43
(C-4), 81.06 (C-3), 72.24 (OCH2Ph), 64.25 (C-10), 53.35 (C-30), 33.70 (NCH),
32.11, 25.56, 24.33 and 24.02 (CH2’s), 26.47 and 26.06 (>C(CH3)2) ppm. Anal.
calcd. for C23H33NO4: C, 71.29; H, 8.58; N, 3.61. Found: C, 71.08; H, 9.12; N,
3.39.
3-O-Benzyl-4-N-phenylethyl
azetidine-1,2-O-isopropylidene-b-L-ido-
furanose (19). Intramolecular cyclization of glycosyl b-amino alcohol 13 using
PPh3=DIAD and workup as described previously gave the corresponding glycosyl
azetidene 19 as a colorless oil (yield 64%); [a]D ¼ ꢀ19.6 (c, 0.23, CHCl3); MS
(FAB): 410 (M þ H)þ; 1H NMR (300 MHz, CDCl3): d ¼ 7.31–7.12 (m, 10 H,
Ar-H), 5.91 (d, J ¼ 3.9 Hz, 1 H, H-1), 4.64 (d, J ¼ 11.7 Hz, 1 H, -OCHAPh), 4.51
(d, J ¼ 3.9 Hz, 1 H, H-2), 4.39 (d, J ¼ 11.7 Hz, 1 H, -OCHBPh), 4.20 (m, 1 H,
H-4), 3.89 (m, 1 H, H-3), 3.48 (m, 1 H, H-10), 3.03–2.62 (m, 4 H, NCH2 and PhCH2),
1.60 (m, 2 H, H-30), 1.50–1.25 [m, 8 H, >C(CH3)2 and H-20]; 13C NMR (75 MHz,
CDCl3): d ¼ 137.3, 128.9, 128.5 and 128.4 (Ar-C), 111.58 [>C(CH3)2], 104.84
(C-1), 82.03 (C-2), 81.74 (C-4), 81.45 (C-3), 71.65 (OCH2Ar), 63.33 (C-10), 52.39
(PhCH2), 36.78 (NCH2), 33.98 (C-30), 26.80 and 26.16 [>C(CH3)2] ppm. Anal. calcd.
for C25H31NO4: C, 73.32; H, 7.63; N, 3.42. Found: C, 73.95; H, 7.52; N, 3.49.
ACKNOWLEDGMENTS
We thank CISC, BHU, and CDRI, Lucknow, for spectroscopic data of synthe-
sized molecules and Virendra Prasad for his scientific discussion. The Council of
Scientific and Industrial Research, New Delhi, is gratefully acknowledged for
financial support.
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