Aziridine carboxylate from D-glucose: Synthesis of polyhydroxylated piperidine, pyrrolidine alkaloids and study of their glycosidase inhibition

Article abstract of DOI:10.1039/b509216g

The D-glucose derived aziridine carboxylate 5 was obtained from (E)-ethyl-6-bromo-1,2-O-isopropylidene-3-O-benzyl-5-deoxy-α-D-xylo-5-eno- heptofuranuronate 4 through conjugate addition of benzylamine and in situ intramolecular nucleophilic expulsion of br

Full text of DOI:10.1039/b509216g

View Article Online / Journal Homepage / Table of Contents for this issue
A R T I C L E
Aziridine carboxylate from D-glucose: synthesis of polyhydroxylated
piperidine, pyrrolidine alkaloids and study of their glycosidase
inhibition†
Dilip D. Dhavale,*a K. S. Ajish Kumar,a Vinod D. Chaudhari,a Tarun Sharma,b
Sushma G. Sabharwalb and J. PrakashaReddyc
a Garware Research Centre, Department of Chemistry, University of Pune, Pune, 411 007, India
b Division of Biochemistry, Department of Chemistry, University of Pune, Pune, 411 007, India
c Division of Organic Chemistry, National Chemical Laboratory, Pune, 411 008, India.
E-mail: ddd@chem.unipune.ernet.in
Received 30th June 2005, Accepted 2nd August 2005
First published as an Advance Article on the web 12th September 2005
The D-glucose derived aziridine carboxylate 5 was obtained from (E)-ethyl-6-bromo-1,2-O-isopropylidene-3-
O-benzyl-5-deoxy-a-D-xylo-5-eno-heptofuranuronate 4 through conjugate addition of benzylamine and in situ
intramolecular nucleophilic expulsion of bromine. The regioselective aziridine ring-opening, using water as a
nucleophile, resulted in the a-hydroxy-b-aminoester 6, which was exploited in the synthesis of six and five membered
azasugars 1b/1c and 2b/2c, respectively. The glycosidase inhibitory activity of the title compounds was evaluated.
leading to the exclusive formation of a-hydroxy-b-aminoesters,
which represents promising chiral precursor to the synthesis of
Introduction
The aziridine carboxylic esters of type A (R1 = alkyl, aryl)
six and five membered azasugars. Although, aziridines have
play a vital role in the synthetic sequence due to their inherent
been widely exploited as intermediates in the synthesis of a
capability to undergo nucleophilic ring opening either at C3
number of biologically important compounds,12 only a few
or C2 giving an access to differentially substituted a- or b-
examples are known with sugar aziridines13 and, to the best
amino esters, respectively1 (Fig. 1). The weak electrophilic
of our knowledge, no report is available with D-glucose derived
nature of the aziridine carboxylate A is overpowered either
aziridine carboxylate of type A (R1 = D-gluco-furanose) in the
by incorporation of an electron-withdrawing group (e.g., R3 =
synthesis of azasugars.
sulfonyl) on the aziridinic nitrogen atom and/or by the use
Nitrogen-incorporated polyhydroxylated carbocylic ring sys-
of acidic reaction conditions. In general, nucleophiles such as
tems, commonly known as azasugars or iminosugars, are of
alcohols,2 Wittig reagents,3 thiols,4 indoles4,5 and amines6 attack
great importance as they often exhibit significant glycosi-
at the C3 carbon leading to the aziridine ring opening in the
dase inhibitory activity. Among these, the polyhydroxylated
usual conjugate addition pathway, thus yielding a-amino esters.
piperidine14 (e.g., 1-deoxynojirimycin 1a) and pyrrolidine15 (e.g.,
A few examples are known wherein organocuprates,7 malonates8
1,4-dideoxy-1,4-imino-L-arabinitol 2a) alkaloids selectively in-
and some indole derivatives9 react at both C3 and C2 of A
hibit glycosidase that modify glycoconjugates by hydrolyzing
to give a mixture of products. However, azidotrimethylsilane10
glycosidic linkages and are therefore potential candidates as
and lithium dimethylcuprate1 undergo regioselective aziridine
antiviral, antibacterial or, antimetastatic agents16 (Fig. 2). In
ring opening at the C2–N bond to give b-amino esters.11
the search for structure–activity relationship, a number of six
and five membered azasugar analogues of 1a and 2a were
synthesized and evaluated for their biological activities. In the
continuation of our work in the area of azasugars,17 we thought
of exploiting aziridine carboxylate A (R1 = D-gluco-furanose) in
In this context, we noticed an interesting observation in the
reaction of D-glucose-derived aziridine carboxylate A (R1
=
sugar), with water as a nucleophile. Under acidic conditions,
the aziridine ring opening took place at the C2 position
Fig. 1 Nucleophilic ring-opening of aziridine esters.
† Electronic supplementary information (ESI) available: General exper-
1
imental methods, crystallographic data for 5 and copies of H and 13C
NMR spectra of compounds 1b, 1c, 2b, 2b.HCl, 2c, 4, 5, 6, 7, 8, 9, 10.
See http://dx.doi.org/10.1039/b509216g
Fig. 2 Piperidine and pyrrolidine alkaloids.
3 7 2 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 7 2 0 – 3 7 2 6
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

View Article Online
the synthesis of 1-deoxy-L-ido-nojirimycin 1b, 1,4-dideoxy-1,4-
imino-L-xylitol 2b and one-carbon homologated 1,5-dideoxy-
1,5-imino-6-hydroxy-b-L-glycero-L-ido-heptitol 1c, 1,4-dideoxy-
1,4-imino-5-hydroxy-L-iditol 2c, with hydroxyl functionality at
the homologated carbon. Although compounds 1b and 2b are
known in the literature, compounds 1c and 2c, to the best of our
knowledge, are not reported so far.
We realized that the six membered piperidine alkaloids 1b
and 1c could be prepared from sugar aminal 6 by joining
the C5 amino group to carbon C1 by reductive amination,
while chopping of C1 and joining the C5 amino group to C2
will give an access to the five membered pyrrolidine alkaloids
2b and 2c (Scheme 1). Thus, the key intermediate for all
four target molecules is the a-hydroxy-b-amino ester 6 that
could be prepared from the aziridinyl precursor 5 following a
regioselective ring opening under acidic condition, using water
as a nucleophile. The main feature of this strategy lies in
the evolution of a masked nucleophilic center at C6 carbon
through aziridine ring formation that could be achieved by
intermolecular conjugate addition of benzylamine and concomi-
tant SN2 displacement of bromine. Our efforts in the successful
implementation of this method for the formation of piperidine
1b/1c and pyrrolidine alkaloids 2b/2c are reported herein.
Results and discussion
The Wittig olefination of a-D-xylo-pentodialdose 3 using
Ph3PCBrCOOEt in dichloromethane afforded the required bro-
mocarboxylate 4 in 77% yield.18,19 The exclusive formation of E-
isomer 4 was confirmed by 1H NMR spectra in which the vinylic
proton H5 appeared at downfield position (d 7.50)20 as well as the
H4 proton showed a considerable downfield shift and appeared
at d 5.05 (as compared to the normal position of d ∼ 4.0)
due to the diamagnetic anisotropic deshielding effect induced
by the ester carbonyl functionality,21 indicating the cis relative
orientation of carboxylate group and sugar moiety. In the next
step, compound 4 was treated with benzylamine (15 equiv.)
to give aziridine carboxylic ester 5 in 70% yield.22 The trans-
1
aziridine geometry of 5 was established by H NMR analysis
which showed a small vicinal coupling constant of H5 and H6
(J5,6 = 2.9 Hz) against the large Jvic (∼7.0 Hz) known for the cis-
aziridine derivative.23 Compound 5 was isolated as a colorless
solid and the single crystal X-ray analysis (Fig. 3) firmly estab-
lished the trans relative configuration, 5S and 6S, of the carboxy-
late group and the sugar functionality respectively. This one-pot
two-step reaction of 4 probably involves in situ generation of b-
aminoester, by the Re face attack of benzylamine at the prochiral
C5, that concomitantly undergoes SN2 type nucleophilic dis-
placement of the bromine (by rotation around C5–C6 bond) to
give the more stable trans-aziridine as the only isolable product.24
Subsequently, the aziridine ring-opening of 5 with water in
the presence of TFA (1 equiv.) in acetone afforded a-hydroxy-b-
aminoester 6 as the only product in 82% yield. The use of other
acids like HClO4 and H2SO4 afforded a mixture of products
probably due to the hydrolysis of the 1,2-acetonide functionality.
The formation of 6 with regioselective SN2-type aziridine
ring opening a to the carboxylate group in 5 is unusual, as a
nucleophilic solvent like water is known to afford essentially a-
aminoesters resulting from an attack at the b-position of the
carboxylate group. The observed regioselectivity in favour of b-
amino-a-hydroxy ester 8, with 5S, 6R absolute stereochemistry
could be explained by the preferential b-attack at the C6 carbon
atom, rather than at the C5 which is hindered due to the b-
oriented C3-OBn group.25 Although the spectral data of 6 were in
Scheme 1 Retrosynthetic analysis.
Fig. 3 ORTEP drawing of compound 5.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 7 2 0 – 3 7 2 6
3 7 2 1

View Article Online
agreement with the b-aminoester structure, further evidence was
obtained by converting 6 to the known azasugars 1-deoxy-L-ido-
nojirimycin 1b and 1,4-dideoxy-1,4-imino-L-xylitol 2b. Thus, as
shown in (Scheme 2), the reduction of the ester group by LAH in
6 followed by selective amine protection by benzylchloroformate
afforded the N-Cbz protected diol 7. The oxidative cleavage of
diol 7 with sodium periodate furnished an unstable aldehyde,
which was subjected to sodium borohydride reduction to yield
primary alcohol 8. The compounds 4 to 8 were obtained in
good yield and characterized by spectral/analytical techniques,
which were found to be in agreement with the structures.26 The
hydrolysis of the 1,2-acetonide functionality in 8 with TFA–
water followed by treatment with ammonium formate and 10%
Pd/C in MeOH gave 1-deoxy-L-ido-nojirimycin 1b as a thick
liquid. The analytical and spectral data of 1b were found to
be identical with those reported in the literature (observed
[a]D + 7.91 (c 0.25, MeOH), lit.,14s [a]D + 8.49 (c 0.5, MeOH)).
Compound 8 proved to be a valuable precursor for the five
membered pyrrolidine alkaloid 1,4-dideoxy-1,4-imino-L-xylitol
2b. Thus, cleavage of the 1,2-acetonide functionality in 8 by
TFA–water and treatment with sodium metaperiodate afforded
the one carbon degraded aminal that was directly subjected to
hydrogenation with 10% Pd/C in methanol to give 1,4-dideoxy-
1,4-imino-L-xylitol 2b as a viscous liquid. The reaction of 2b
with MeOH.HCl afforded the hydrochloride salt of 2b as a
sticky solid. The spectral and analytical data of 2b.HCl was
in agreement with that reported (observed [a]D −9.40 (c 0.74,
H2O), lit.,15b,d [a]D −9.9 (c 0.71, H2O)).
The utility of a-hydroxy-b-aminoester 6 was also demon-
strated by the synthesis of the new azasugar analogues 1c and
2c (Scheme 3). Thus, the reduction of the ester functionality in
6 with LAH in THF followed by treatment with ammonium
formate in the presence of 10% Pd/C, in methanol, afforded an
aminotriol that was reacted with benzylchloroformate to give the
N-Cbz protected triol 9. The cleavage of 1,2-acetonide group
and hydrogenation afforded 1,5-dideoxy-1,5-imino-6-hydroxy-
b-L-glycero-L-ido-heptitol 1c as a thick oil. In order to prepare
the new pyrrolidine alkaloid 1,4-dideoxy-1,4-imino-5-hydroxy-
L-iditol 2c the same protocol as in the synthesis of 2b was
followed. Thus, the N-Cbz protected triol 9 was reacted with
acetic anhydride in pyridine to give the tri-acetylated compound
10. The careful cleavage of 1,2-acetonide functionality in 10, at
0 ◦C with 95% TFA–water followed by oxidative cleavage of the
C1–C2 bond and treatment with ammonium formate and 10%
Pd/C in methanol yielded a product27 which on treatment with
sodium methoxide in methanol at 0 ◦C afforded 1,4-dideoxy-
1,4-imino-5-hydroxy-L-iditol 2c as a white solid.
Scheme 3 Reagents and conditions: (a) (i) LAH, THF, 0 to 25 ◦C, 2 h;
(ii) HCOONH4, 10% Pd/C, MeOH, reflux, 2 h; (iii) CbzCl, MeOH–H2O
(9 : 1), 0 to 25 ◦C, 3.5 h, 82%; (b) (i) TFA–H2O (2 : 1), 0 to 25 ◦C, 4 h;
(ii) H2, 10% Pd/C, 80 psi, 24 h, 75%; (c) Ac2O, py, DMAP, 0 to 25 ◦C, 6 h,
86%; (d) (i) TFA–H2O (9.5 : 0.5), 0 ◦C, 2.5 h; (ii) NaIO4, acetone–water
(5 : 1), 0 ◦C, 1.5 h; (iii) HCOONH4, 10% Pd/C, MeOH, reflux, 3 h;
(iv) NaOMe, MeOH, 25 ◦C, 3 h, 45%.
Conformational analysis
We have recently reported that the D-gluco-homo-1-
deoxynojirimycin and L-ido-homo-1-deoxynojirimycin exist in
4C1 and 1C4 conformations, respectively.17d,e The conformational
1
aspect of hitherto unknown 1c was studied by using H NMR
data wherein the assignment of signals and coupling constant
information were obtained from decoupling experiments. In
the 1H NMR spectrum of 1c, the appearance of a doublet
of doublets corresponding to the H1a proton with one large
geminal (J1a,1e = 14.3 Hz) and an other small vicinal (J1a,2
=
3.2 Hz) coupling indicated a cis axial–equatorial relationship
with the H2 proton. The initial geometry in the precursor 9
ensures that in the product 1c the substituent at C2/C3 should
be trans. Therefore, the proton at H3 should be equatorial. The
coupling constant value between H4 and H5 was evident from
the decoupling experiments and was found to be (J4,5 = 2.0 Hz).
The low coupling constant corresponds to the equatorial–axial
relationship between H4 and H5 protons, thus indicating the 1C4
conformation.
=
Scheme 2 Reagents and conditions: (a) PPh3 CBrCOOEt, CH2Cl2,
Glycosidase inhibitory study
25 ◦C, 12 h, 77%; (b) BnNH2, benzene, 10 to 20 ◦C, 6 h, 70%; (c) TFA
(1 equiv.), acetone–water (2 : 1), 25 ◦C, 24 h, 82%; (d) (i) LAH, THF,
0 to 25 ◦C, 2 h,; (ii) CbzCl, NaHCO3, MeOH–water, 0 to 25 ◦C, 6 h,
82%; (e) (i) NaIO4, acetone–water (3 : 1), 0 to 15 ◦C, 1.5 h; (ii) NaBH4,
EtOH, 15 ◦C, 15 min, 93%. (f) (i) TFA–water (6 : 4), 0 to 25 ◦C, 3 h;
(ii) HCOONH4, 10% Pd/C, MeOH, reflux, 1.5 h, 58%; (g) (i) TFA–water
(9.5 : 0.5), 0 ◦C, 4 h; (ii) NaIO4, acetone–water (8 : 2), 0 ◦C, 2 h.
(h) HCOONH4, 10% Pd/C, reflux, 3 h, 46%; (i) MeOH.HCl, 0 to
25 ◦C, 3 h, 98%.
The IC50 values were determined for the compounds 1b, c and
2b, c and are summarized in Table 1. All the compounds showed
inhibitory potencies in millimolar range. These results are in con-
sonance with the IC50 value reported by Katoet al. for compound
1b wherein it shows no inhibition in micromolar range.14s The
compound 2b showed selectivity towards a-glycosidases while
compound 1c is selective towards a-galactosidase.
3 7 2 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 7 2 0 – 3 7 2 6

View Article Online
Table 1 Inhibitory potencies of piperidine (1b/c) and Pyrrolidine
(2b/c) analogues
purchased from Sigma Chemicals Co. USA. a-Glucosidase and
b-galactosidase were extracted and purified from sweet almonds
and used.
IC50/mM
(E)-6-Bromo-ethyl-3-O-benzyl-5-deoxy-1,2-O-isopropylidene-
hept-5-eno-furanuronate 4. To the solution of a-D-xylo-
pentodialdose 3 (10 g, 35 mmol) in dry dichloromethane
(250 cm3) was added bromophosphorane, PPh3CBrCOOEt
Enzyme
1b
1c
2b
2c
a − Glucosidase(yeast)
NIa
2.57
3.19
4.72
NIa
51.8
2.88
10.31
22.6
NI
5.89
9.96
NI
b-Glucosidase (almond)
a-Galactosidase (almond)
a-Mannosidase (jack bean)
85.22
◦
NIa
(17.72 g, 43 mmol) and stirred at 25 C for 12 h. The reaction
187.5
mixture was concentrated on vacuum and purified by column
chromatography on silica (n-hexane–ethyl acetate = 95 : 5)
to afford alkene 4 (11 g, 77%) as a thick liquid (Found: C,
53.52; H, 5.32. Calc. for C19H23O6Br: C, 53.41; H, 5.43); Rf 0.67
(30% ethyl acetate–n-hexane); [a]D −103.0 (c 11.77, CHCl3);
vmax (neat)/cm−11741, 1230, 1637, 866 and 740. dH (300 MHz,
CDCl3) 1.36 (3H, t, J = 7.0 Hz, CH2CH3), 1.37 (3H, s, CH3)
1.55 (3H, s, CH3), 4.28 (1H, d, J = 3.2 Hz, H3), 4.34 (2H, q, J =
7.0 Hz, CH2CH3), 4.50 (1H, d, J = 11.8 Hz, OCH2Ph), 4.65
(1H, d, J = 11.8 Hz, OCH2Ph), 4.68 (1H, d, J = 3.6 Hz, H2),
5.05 (1H, dd, J = 6.5 and 3.2 Hz, H4), 6.06 (1H, d, J = 3.6 Hz,
H1), 7.23–7.44 (5H, m, Ar–H), 7.50 (1H, d, J = 6.5 Hz, H5);
dC (75 MHz, CDCl3) 14.2 (CH2CH3), 26.3, 26.9 (2 × CH3), 62.7
(OCH2CH3), 72.4 (OCH2), 80.5, 82.4, 82.7 (C2/C3/C4), 105.1
(C1), 111.9 (OCO), 116.6 (C6), 127.6 (strong), 127.8, 128.3
(strong), 136.8 (Ar–C), 141.3 (C5), 161.3 (CO).
a NI: Inhibition not observed under assay conditions. Data is average of
three sets of assay performed.
Conclusion
In conclusion, we have reported a new aziridine carboxylate
chiron synthon 5 from D-glucose and demonstrated that the
aziridine ring opening takes place a to the carboxylate although
the ring nitrogen is not activated with electron withdrawing
group. The utility of 5 is demonstrated in the synthesis of
six membered piperidine alkaloids 1b, c and five membered
pyrrolidine alkaloids 2b, c. The target molecules showed poor
glycosidase inhibition indicating that the L-azasugars with
hydroxyl functionality at the C6 side chain are not good
candidates for inhibition study.
Ethyl-3-O-benzyl-5,6-N-benzyl-E-aziridine-1,2-O-isopropyl-
idene-5,6-dideoxy-b-L-ido-heptofuranuronate 5. To a cooled
solution of 4 (0.4 g, 0.94 mmol) in dry benzene (0.4 cm3) was
added benzylamine (1.37 cm3, 1.4 mmol) drop by drop at 10 ◦C
and allowed to stirred well at 25 ◦C for 6 h, the excess of benzyl
amine was removed on vacuum and the reaction mixture was
diluted with ether and filtered. The filtrate was concentrated and
purified by column chromatography on silica (n-hexane–ethyl
acetate, 9 : 1) to afford 5 (0.29 g, 70%) as a white solid, mp
95–97 ◦C (Found: C, 68.80; H, 6.79. Calc. for C26H31NO6: C,
68.86; H, 6.89); Rf 0.52 (30% ethyl acetate–n-hexane); [a]D
−71.69 (c 0.27, CHCl3); vmax(KBr)/cm−1 1720.4, 1458.1 and
1242; dH (300 MHz, CDCl3) 1.18 (3H, t, J = 7.0 Hz, CH2CH3),
1.35 (3H, s, CH3), 1.48 (3H, s, CH3) 2.62 (1H, d, J = 2.9 Hz,
H6), 2.90 (1H, dd, J = 7.0, 2.9 Hz, H5), 3.60–4.00 (3H, m,
H3, H4, NCH2Ph), 4.06–4.20 (2H, m, CH2), 4.29 (1H, d,
J = 13.7 Hz, NCH2Ph), 4.54 (1H, d, J = 12.0 Hz, OCH2Ph),
4.67 (1H, d, J = 3.8 Hz, H2), 4.75 (1H, d, J = 12.0 Hz,
OCH2Ph), 6.04 (1H, d, J = 3.8 Hz, H1), 7.24–7.39 (10H, m,
Ar–H); dC (75 MHz, CDCl3) 13.9 (CH2CH3), 26.2, 26.8 (2 ×
CH3), 37.1 (C5), 45.0 (C6), 54.9 (NCH2Ph), 61.1(OCH2CH3),
71.8 (OCH2Ph), 82.1 (strong) (C2/C3/C4), 105.3 (C1), 111.7
(OCO), 126.8 (strong), 127.6, 127.9 (strong), 128.1, 128.2,
128.4, 137.2, 138.8 (Ar–C), 168.5 (CO).
Experimental
Single crystals of compound 5 suitable for X-ray diffraction were
selected directly from the analytical samples.
Crystal structure determination of compound 5
Crystal data‡. C26H31N1O6, M = 453.52, monoclinic, a =
3
˚
˚
˚
9.934(4) A, b = 5.408(2) A, c = 22.042(1), U = 1176.3(8) A ,
T = 293(2) K, space group P21, Z = 2, l(Mo Ka) = 0.091 mm−1,
5045 reflections measured, unique (Rint = 0.0408) which were
used in all calculations. The final wR(F2) was 0.1554 (all data).
The Flack parameter −0.6555 (with esd 3.0219) is inconclusive
and therefore no conclusions on the absolute structure can be
drawn
General methods
Melting points were recorded with Thomas Hoover melting
point apparatus and are uncorrected. IR spectra were recorded
with Shimadzu FTIR-8400 as a thin film or in nujol mull or using
KBr pellets and are expressed in cm−1. H (300 MHz) and 13C
1
(75 MHz) NMR spectra were recorded with Varian Mercury 300
using CDCl3 or D2O as a solvent. Chemical shifts were reported
in d unit (ppm) with reference to TMS as an internal standard
and J values are given in Hz. Elemental analysis were carried
out with Elemental Analyser Flash 1112. Optical rotations were
measured using a Bellingham Stanle◦y-ADP digital polarimeter
with sodium light (589.3 nm) at 25 C. Thin layer chromatog-
raphy was performed on Merck pre-coated plates (0.25 mm,
silica gel 60 F254). Column chromatography was carried out
with silica gel (100–200 mesh). The reactions were carried out
in oven-dried glassware under dry N2. Methanol, DMF, THF
were purified and dried before use. Petroleum ether (PE) that
was used is a distillation fraction between 40–60 ◦C. LAH,
CbzCl, 10% Pd–C were purchased from Aldrich and/or Fluka.
After decomposition of the reaction with water, the work-
up involves washing of combined organic layer with water,
brine, drying over anhydrous sodium sulfate and evaporation
of solvent at reduced pressure. For enzyme inhibition studies
substrates were purchased from Sigma Chemicals Co., USA. a-
Glucosidase from yeast and a-mannosidase from jack bean were
Ethyl-3-O-benzyl-5-(N-benzyl)amino-1,2-O-isopropylidene-b-
L-glycero-L-ido-heptofuranuronate 6. To
a solution of 5
(1 g, 2.20 mmol) in acetone–water (2 : 1, 20 cm3) at 10 ◦C
was added TFA (0.17 cm3, 2.20 mmol) and stirred well for
24 h at 25 ◦C. After neutralization of TFA with sat. sodium
bicarbonate solution, reaction mixture was concentrated on
rotavapor, extracted with dichloromethane (3 × 10 cm3). The
combined organic layer was concentrated to afford a pale yellow
liquid, which was purified by column chromatography on silica
(n-hexane–ethyl acetate = 4 : 1) to give 6 (0.82 g, 82.0%) as a
thick liquid (Found: C, 66.38; H, 7.10. Calc. for C26H33NO7:
C, 66.22; H, 7.05); Rf 0.56 (30% ethyl acetate–n-hexane); [a]D
−48.65 (c 0.19, CHCl3); vmax(neat)/cm−1 3050–3700 (broad),
2925, 1739, 1213; dH (300 MHz, CDCl3) 1.25 (3H, t, J = 7.0 Hz,
CH3), 1.36 (3H, s, CH3), 1.51 (3H, s, CH3), 2.20–3.20 (2H,
b s, NH/OH exchangeable with D2O,), 3.55 (1H, dd, J = 8.7,
3.5 Hz, H5), 3.86 (1H, d, J = 12.8 Hz, N–CH2Ph), 4.06 (1H,
d, J = 12.8 Hz, NCH2Ph), 4.08 (1H, d, J = 3.2 Hz, H3),
4.10–4.22 (3H, m, O–CH2CH3, H6), 4.30 (1H, dd, J = 8.7 and
3.2 Hz, H4), 4.52 (1H, d, J = 11.7 Hz, OCH2Ph), 4.68 (1H, d,
‡ CCDC reference numbers 276962. See http://dx.doi.org/10.1039/
b509216g for crystallographic data in CIF format.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 7 2 0 – 3 7 2 6
3 7 2 3

View Article Online
J = 3.9 Hz, H2), 4.74 (1H, d, J = 11.7 Hz, OCH2Ph), 5.99 (1H,
d, J = 3.9 Hz, H1), 7.27–7.42 (10H, m, Ar–H); dC (75 MHz,
CDCl3) 14.0, 26.2, 26.6 (CH3), 52.8 (N–CH2Ph), 59.3 (C5), 61.3
(O–CH2CH3), 70.1 (O–CH2Ph), 71.4 (C6), 80.8, 81.7 (strong)
(C2/C3/C4), 104.5 (C1), 111.5 (OCO), 127.0 (strong), 127.1,
127.8, 128.1, 128.3, 128.4, 128.5, 136.8, 138.8 (Ar–C), 172.8
(COOEt).
9 : 1) to yield alcohol 8 (0.11 g, 93%) in the form of white solid;
mp 97–99 C (Found: C, 69.77; H, 6.59. Calc. for C31H35NO7:
◦
C, 69.78; H, 6.61); Rf 0.34 (30% ethyl acetate–n-hexane); [a]D
+13.33 (c 0.15, CDCl3); mmax(KBr)/cm−1 3502 (broad), 2904,
1676, 1253; dH (300 MHz, CDCl3) 1.32 (3H, s, CH3), 1.49
(3H, s, CH3), 3.58–3.74 (3H, m, 2 × H6, H5), 4.15 (1H, d,
J = 1.9 Hz, H3), 4.22 (1H, d, J = 15.8 Hz, NCH2Ph), 4.47
(1H, d, J = 11.7 Hz, OCH2Ph), 4.62 (1H, d, J = 3.5 Hz, H2),
4.65 (1H, d, J = 11.7 Hz, OCH2Ph), 4.86 (1H, dd, J = 9.0 and
1.9 Hz, H4), 4.98 (1H, d, J = 15.8 Hz, NCH2Ph), 5.16 (2H,
ABq, J = 12.6 Hz, N–COOCH2Ph), 5.99 (1H, d, J = 3.5 Hz,
H1), 7.20–7.30 (15H, m, Ar–H); dC (75 MHz, CDCl3) 26.3,
26.7 (CH3), 53.7 (C5), 60.8 (NCH2Ph), 63.3 (N–COOCH2Ph),
67.4 (C6), 71.8 (O–CH2Ph), 77.7, 81.6, 81.9 (C2/C3/C4), 104.5
(C1), 111.7 (OCO), 127.2, 127.5, 127.6, 127.7, 127.9, 128.4,
136.1, 137.1, 137.9 (Ar–C), 157.6 (N–COOCH2Ph).
5-(N-Benzyl-benzoxycarbonyl)amino-3-O-benzyl-6,7-dihydroxy-
5deoxy-1,2-O-isopropylidene-b-L-glycero-L-ido-hepto-1,4-furanose
7. A solution of 6 (0.6 g, 0.24 mmol) in tetrahydrofuran
(2 cm3) was added cautiously drop by drop over 5 min
to a stirred solution of lithium aluminum hydride (0.19 g,
4.88 mmol) in THF (3 cm3) at 0 ◦C. The mixture was stirred
in an atmosphere of nitrogen for 2 h at 25 ◦C, and quenched
by careful addition of ethyl acetate and saturated aqueous
ammonium chloride, filtered, concentrated and dried. To this
reduced product (0.41 g, 0.93 mmol) in methanol–water (4 :
1) at 10 ◦C, sodium bicarbonate (0.22 g, 2.6 mmol) and
benzylchloroformate (0.16 cm3, 1.12 mmol) were added and
stirred for 6 h at 25 ◦C. The reaction mixture was concentrated
under vacuum and then extracted with dichloromethane
(4 × 10 cm3). The combined organic layers were dried and
evaporated under reduced pressure to leave a viscous liquid,
which was purified by column chromatography (n-hexane–ethyl
acetate = 7 : 3) afforded 7 (0.48 g, 88.88%) as a thick liquid
(Found: C, 68.00; H, 6.25. Calc. for C32H37NO8: C, 68.19; H,
6.62); Rf 0.50 (50% ethyl acetate–n-hexane); [a]D −18.88 (c 1.69,
CHCl3); vmax(neat)/cm−1 3150–3600 (broad), 2929, 1685, 1232;
1,5-Dideoxy-1,5-imino-(2S, 3R, 4R, 5S)-L-iditol (1-deoxy-L-
ido-nojirimycin) 1b. A cooled solution of 8 (0.18 g, 0.33 mmol)
in TFA–water (2 : 1, 3 mL) was stirred for 3 h at 25 ◦C. TFA was
co-evaporated with benzene to furnish a thick liquid, which was
treated with ammonium formate and 10% Pd/C in methanol at
reflux for 1.5 h. The reaction mixture was filtered, concentrated
and purified by column chromatography on silica (chloroform–
methanol, 1 : 1) to give 1b (0.032 g, 58.1%) as a thick liquid
(Found: C, 44.23; H, 8.00. Calc. for C6H13NO4: C, 44.16; H,
8.03); Rf 0.20 (60% methanol–chloroform); [a]D +7.9 (c 0.25,
MeOH), lit.14s [a]D +8.49 (c 0.5, MeOH)]; mmax(nujol)/cm−1 3200–
3600 (broad band); dH (300 MHz, D2O) 2.72 (1H, dd, J = 13.1
and 7.3 Hz, H1a), 2.91 (1H, dd, J = 13.1 and 3.3 Hz, H1e),
3.08–3.14 (1H, m, H5) 3.50–3.58 (2H, m, H6), 3.60–3.69 (3H,
m, H2/H3/H4); dC (75 MHz, D2O) 44.0 (C1), 56.3 (C5), 57.7
(C6), 69.2, 69.8, 71.3 (C2/C3/C4).
1
the H and 13C NMR of this compound showed a doubling
of signals due to restricted rotation around the C–N bond of
urethane hence only relatively high intensity signals are given.
dH (300 MHz, CDCl3) 1.34 (6H, s, CH3), 1.52 (3H, s, CH3),
1.60–2.20 (2H, b s, 2–OH, exchangeable with D2O), 3.10 (1H,
dd, J = 11.2 and 3.2 Hz, H5), 3.24–3.38 (1H, m, N–CH2Ph),
3.90–3.99 (1H, m, NCH2Ph), 4.14 (2H, m, H3, H4), 4.47 (2H,
d, J = 11.7 Hz, O–CH2Ph, H6), 4.67 (1H, d, J = 11.7 Hz,
O–CH2Ph), 4.70 (1H, d, J = 3.5 Hz, H2), 4.78 (2H, b s,
H7), 5.18 (2H, m, N–COOCH2Ph), 5.57 (1H, d, J = 3.5 Hz,
H1), 7.17–7.34 (15H, m, Ar–H); dC (75 MHz, CDCl3) 26.3,
26.5 (CH3), 54.9, 55.0 (N–CH2Ph/C5), 62.8 (O–CH2Ph), 67.3
(C6), 71.0 (C7), 81.8, 82.1(strong) (C2/C3/C4), 103.6 (C1),
111.4(OCO), 127.2, 127.4, 127.5, 127.6, 127.7, 128.2, 129.5,
136.0, 137.1, 137.4 (Ar–C), 157.1 (N–COOCH2Ph).
1,4-Dideoxy-1,4-imino-L-xylitol 2b. A solution of 8 (0.45 g,
0.84 mmol) in TFA–water (3 : 2, 5 cm3) was stirred for 4 h
at 25 ◦C. TFA was co-evaporated with benzene to furnish
hemiacetal as a thick liquid. To the cooled solution of hemiacetal
in acetone–water (5 : 1, 10 cm3) was added sodium metaperiodate
(0.17 g, 1.04 mmol). After stirring the reaction mixture for 2 h
at 20 ◦C the excess sodium metaperiodate was neutralized using
ethylene glycol (0.2 cm3). The reaction mixture was concentrated
and the residue was extracted with chloroform (3 × 15 cm3).
The combined organic layer was concentrated to afford a yellow
liquid, which was purified by column chromatography on silica
(n-hexane–ethyl acetate, 4 : 1) to give aldehyde as a thick liquid.
The aldehyde was directly subjected for ammonium formate
treatment in methanol (8 cm3) and 10% Pd/C (0.10 g). After
refluxing for 3 h the reaction mixture was filtered and purified
by column chromatography (chloroform–methanol, 1 : 1) to give
2b (0.049 g, 45.53%) as a thick liquid (Found: C, 44.90; H, 8.23.
Calc. for C5H11NO3: C, 45.1; H, 8.33); Rf 0.25 (60% methanol–
chloroform); [a]D −7.4 (c 0.54, MeOH); vmax(neat)/cm−1 3200–
3600 (broad); dH (300 MHz, D2O) 3.29 (1H, d, J = 12.9, 4.1 Hz,
H1a), 3.65 (1H, dd, J = 12.9 and 4.1 Hz, H1e), 3.85–3.95 (2H,
m, H4, H5a), 3.96–4.08 (1H, m, H5b), 4.33 (1H, m, H3), 4.34–
4.42 (1H, m, H2); dC (75 MHz, D2O) 50.4 (C1), 57.1 (C4), 62.9
(C5), 74.1, 74.2 (C2/C3).
Preparation of 5-(N -benzyl-benzoxycarbonyl)amino-3-O-
benzyl-5-deoxy-6-hydroxy-1,2-O-isopropylidene-b-L-ido-hexo-1,4-
furanose 8. 1. Conversion of diol 7 to 6-aldehydo-5-(N-benzyl-
benzoxycarbonyl)amino-3-O-benzyl-5-deoxy-1,2-O-isopropyl-
idene-b-L-ido-hexo-1,4-furanose To the Cbz protected product 7
(0.25 g, 0.36 mmol) in acetone–water (3 : 1, 5 cm3) was added
metaperiodate (0.09 g, 0.44 mmol) at 15 ◦C and stirred well for
1 h. Excess metaperiodate was decomposed by using ethylene
glycol (0.01 cm3), concentrated under vacuum extracted with
chloroform (4 × 10 cm3) and concentrated to afford a thick
liquid, which was purified by column chromatography on silica
(n-hexane–ethyl acetate, 4 : 1) to give aldehyde (0.17 g, 70%)
in the form of a thick liquid (Found: C, 70.02; H, 6.22. Calc.
for C31H33NO7: C, 70.04; H, 6.26.); Rf 0.56 (30% ethyl acetate–
n-hexane); [a]D + 12.21 (c 0.65, CDCl3); mmax(nujol)/cm−1
3200–3600 (broad); dH (300 MHz, CDCl3) and dC (75 MHz,
CDCl3) Both 1H NMR and 13C NMR spectra were very
complicated due to doubling of signals.
2. Convertion of aldehyde to 5-(N-benzyl-benzoxycarbonyl)-
amino-3-O-benzyl-5-deoxy-6-hydroxy-1,2-O-isopropylidene-b-L-
ido-hexo-1,4-furanose 8. To the solution of aldehyde (0.12 g,
0.28 mmol) in ethanol–water (2 : 1, 3 cm3) was added sodium
borohydride (0.01 g, 0.28 mmol) at 15 ◦C and stirred well for
15 min. Excess borohydride was quenched using sat. NH4Cl
solution, concentrated and extracted with chloroform and
purified by column chromatography (n-hexane–ethyl acetate =
1,4-Dideoxy-1,4-imino-L-xylitol hydrochloride 2b·HCl.
A
solution of 2b (0.012 g, 0.09 mmol) in methanolic hydrochloric
◦
acid (5 cm3) was stirred under nitrogen at 0 C and stirred for
3 h at 25 ◦C. The reaction mixture was concentrated on vacuum
to afford 2b·HCl (0.015 g, 98%) as a semi solid (Found: C, 36.5;
H, 7.4. Calc. for C5H12NO3Cl: C, 36.1; H, 7.3); [a]D −9.4 (c 0.74,
H2O), lit. [a]D −9.9 (c 0.71, H2O);15b,d mmax(nujol)/cm−1 3200–
3600 (broad); dH (300 MHz, D2O) 3.32 (1H, d, J = 12.9 Hz,
H1a), 3.68 (1H, dd, J = 12.9 and 4.4 Hz, H1b), 3.88–3.98 (2H,
m, H4, H5a), 4.05 (1H, dd, J = 15.4 and 8.5 Hz, H5b), 4.34
(1H, m, H3), 4.41 (1H, m, H2); dC (75 MHz, D2O) 52.7 (C1),
59.5 (C5), 65.2 (C4), 76.5, 76.6 (C2/C3).
3 7 2 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 7 2 0 – 3 7 2 6

View Article Online
5-(N-Benzoxycarbonyl)amino-3,6,7-trihydroxy-5-deoxy-1,2-
(1H, d, J = 3.5 Hz, H1), 7.29–7.37 (5H, m, Ar–H); dC (75 MHz,
CDCl3) 20.2, 20.4, 20.5 (COCH3), 25.8, 26.3 (CH3), 48.9 (C5),
61.7 (NCOOCH2Ph), 66.6 (C6), 71.4 (C7), 75.3, 76.5, 83.1
(C2/C3/C4), 104.0 (C1), 111.9 (OCO), 127.8, 128.2, 135.9
(Ar–C), 155.8 (NCOOCH2Ph), 169.6, 169.7, 170.3 (COCH3).
O-isopropylidene-b-L-glycero-L-ido-hepto-1,4-furanose 9.
A
solution of 6 (0.6 g, 0.24 mmol) in tetrahydrofuran (2 cm3) was
added cautiously drop by drop over 5 min to a stirred solution of
lithium aluminum hydride (0.19 g, 4.88 mmol) in THF (3 cm3)
◦
at 0 C. The mixture was stirred in an atmosphere of nitrogen
for 2 h at 25 ◦C, and quenched by careful addition of ethyl
acetate and saturated aqueous ammonium chloride, filtered,
concentrated and dried. To it dry ethanol (5 cm3), followed by
10% Pd/C (0.1 g) and ammonium formate (0.055 g, 6.96 mmol),
was added and refluxed for 2 h under nitrogen. The reaction
mixture was filtered through celite-540, concentrated and dried
to afford an amino triol. The amino triol was dissolved in
ethanol–water (4 : 1) at 10 ◦C, sodium bicarbonate (0.056 g,
0.67 mmol) and benzylchloroformate (0.041 cm3, 0.29 mmol)
were added and stirred for 3.5 h at 25 ◦C. The reaction
mixture was concentrated under vacuum and extracted with
dichloromethane (4 × 10 cm3). The combined organic layers
were dried and evaporated under reduced pressure to leave a
viscous liquid, which was purified by column chromatography
on silica (n-hexane–ethyl acetate, 7 : 3), afforded 9 (0.76 g,
82.6%) as a white solid, mp 132–135 ◦C (Found: C, 56.22;
H, 6.28. Calc. for C18H25NO8: C, 56.39; H, 6.57); Rf 0.37
(50% ethyl acetate–n-hexane); [a]D −13.33 (c 0.15, CHCl3);
mmax(KBr)/cm−1 3523–3477 (broad), 3413, 1706, 1521, 1238 and
1083; dH (300 MHz, CD3OD) 1.23 (3H, s, CH3), 1.42 (3H, s,
CH3), 3.59 (1H, dd, J = 11.7 and 5.8 Hz, H7a), 3.65 (1H, dd,
J = 11.7 and 3.2 Hz, H7b), 3.74 (1H, ddd, J = 7.3, 5.8 and
3.2 Hz, H6), 4.07 (1H, t, J = 7.3 Hz, H5), 4.22 (1H, d, J =
2.6 Hz, H3), 4.34 (1H, dd, J = 7.3 and 2.6 Hz, H4), 4.55 (1H,
d, J = 3.8 Hz, H2), 5.12 (2H, s, N-COOCH2Ph), 5.91 (1H, d,
J = 3.8 Hz, H1), 7.23–7.45 (5H, m, Ar–H); dC NMR (75 MHz,
CD3OD) 26.4, 27.0 (CH3), 53.5 (C5), 64.6 (NCOOCH2Ph),
67.6 (C7), 73.3 (C6), 76.3, 81.1, 87.0 (C2/C3/C4), 105.3(C1),
112.6 (OCO), 128.7, 128.8, 128.9, 129.4, 129.5, 138.3 (Ar–C),
159.0 (NCOOCH2Ph).
1,4-Dideoxy-1,4-imino-5-hydroxy-L-iditol 2c. A solution of
triacetate 10 (0.63 g, 1.13 mmol) in TFA–water (9.5 : 0.5,
5 cm3) was stirred at 0 ◦C for 3 h. TFA was co-evaporated
with benzene to furnish a hemiacetal as a thick liquid. To
the ice-cooled solution of hemiacetal in acetone–water (5 : 1,
10 cm3) was added NaIO4 (0.34 g, 1.59 mmol) and stirred well
for 1.5 h at 15 ◦C. Work up as usual and purified by column
chromatography on silica afforded aldehyde which was directly
treated with ammonium formate in the presence of catalytic
amount of 10% Pd/C in methanol and refluxed for 3 h to
yield mixture of acetylated product that was deacetylated using
sodium methoxide in methanol at 25 ◦C for 3 h and purified by
column chromatography (chloroform–methanol, 1 :◦1) afforded
2c (0.038 g, 45.23%) as a white solid; mp 118–120 C (Found:
C, 43.9; H, 8.02. Calc. for C6H13NO4: C, 44.1; H, 8.03); Rf
0.20 (60% methanol–chloroform); [a]D +8.75 (c 0.8, MeOH);
v
max(neat)/cm−13200–3600 (broad); dH (300 MHz, D2O) 2.66
(1H, dd, J = 12.8 and 1.0 Hz, H1a), 3.06 (1H, dd, J = 9.3
and 3.3 Hz, H4), 3.18 (1H, dd, J = 12.8 and 4.8 Hz, H1b), 3.44
(1H, dd, J = 11.9 and 6.5 Hz, H6a), 3.62 (1H, dd, J = 11.9
and 3.0 Hz, H6b), 3.69 (1H, ddd, J = 9.3, 6.5 and 3.3 Hz, H5),
4.00–4.06 (2H, m, H2, H3); dC (75 MHz, D2O) 51.2 (C1), 60.9
(C4), 63.9 (C6), 69.3 (C5), 75.9, 76.0 (C2/C3).
General procedure for inhibition assay
Inhibition potencies of 1b/1c and 2b/2c were determined by
measuring the residual hydrolytic activities of the glycosidases.
The substrates (Purchased from Sigma Chemicals Co. USA.)
namely p-nitrophenyl-a-D-glucopyranoside, p-nitrophenyl-b-D-
glucopyranoside and p-nitrophenyl-a-D-galactopyranoside, of
2 mM concentration were prepared in 0.025 M citrate buffer
with pH 6.0. p-Nitrophenyl-a-D-mannopyranoside of 2 mM
was prepared in 0.025 M citrate buffer with pH 4.0. The
test compound was preincubated with the respective enzyme
buffered at their optimal pH, for 1 h at 25 ◦C. The enzyme
reaction was initiated by the addition of 100 lL substrate.
Controls were run simultaneously in absence of test compound.
The reaction was terminated at the end of 10 min by the
addition of 0.05 M borate buffer (pH 9.8) and absorbance of the
liberated p-nitrophenol was measured at 405 nm using Shimadzu
Spectrophotometer UV-1601.28 One unit of glycosidase activity
is defined as the amount of enzyme that hydrolyzed 1 lmol of
p-nitrophenyl pyranoside per minute at 25 ◦C.
1,5-Dideoxy-1, 5-imino-6-hydroxy-b-L-glycero-L-ido-heptitol
1c. To the Cbz protected amino triol 9 (0.04 g, 0.10 mmol),
TFA–water (2 : 1, 3 cm3) was added at 0 ◦C and stirred well for
4 h at 25 ◦C. TFA was co-evaporated with benzene to furnish a
thick liquid. To a solution of above product in methanol (5 cm3)
was added 10% Pd/C (0.05 g) and hydrogenated at 80 psi for
24 h. The reaction mixture was filtered through celite-540 and
filtrate was concentrated under vacuum to afford product 1c
(0.027 g, 75%) as thick liquid (Found: C, 44.01; H, 7.73. Calc.
for C7H15NO5: C, 43.52; H, 7.83); Rf 0.20 (80% methanol–
chloroform); [a]D +1.28 (c 1.56, MeOH); vmax(nujol)/cm−1 3200–
3600 (broad); dH (300 MHz, D2O) 2.75 (1H, dd, J = 14.3 and
3.2 Hz, H1a), 2.87 (1H, dd, J = 7.9 and 2.0 Hz, H5), 2.91 (1H,
dd, J = 14.3 and 2.9 Hz, H1e), 3.49 (1H, dd, J = 12.0 and
6.4 Hz, H7a), 3.53–3.59 (1H, m, H2), 3.63 (1H, dd, J = 12.0
and 3.5 Hz, H7b), 3.71 (1H, ddd, J = 7.9, 6.4 and 3.5 Hz, H6),
3.74–3.80 (2H, m, H3, H4); dC NMR (75 MHz, D2O) 45.6 (C1),
54.3 (C5), 63.2 (C7), 67.7, 68.2, 68.9 (C2/C3/C4), 70.3 (C6).
Acknowledgements
We are grateful to Prof. M. S. Wadia for helpful discussion.
AKKS is thankful to CSIR, New Delhi for the Junior Research
Fellowship. We gratefully acknowledge UGC, New Delhi for the
grant to purchase high field (300 MHz) NMR facility.
3,6,7-Tri-O-acetyl-5-(N-benzoxycarbonylamino)-5-deoxy-1,2-
O-isopropylidine-b-L-glycero-L-ido-heptofuranose 10. To an
ice-cold solution of triol 9 (0.32 g, 0.83 mmol) in pyridine
(5 cm3), acetic anhydride (0.51 cm3, 4.98 mmol) was added
and stirred well for 6 h at 25 ◦C. The excess of pyridine and
acetic anhydride was removed under vacuum and purified by
column chromatography on silica (n-hexane–ethyl acetate, 4 :
1) to afford triacetate 10 (0.36 g, 86%) as a white solid; mp
109–111 ◦C (Found: C, 56.22; H, 6.28. Calc. for C19H25N3O7:
C, 56.01; H, 6.18); Rf 0.38 (30% ethyl acetate–n-hexane); [a]D
−24.77 (c 0.56, CHCl3); mmax(KBr)/cm−1 3338, 1728, 1537 and
1234; dH (300 MHz, CDCl3) 1.32 (3H, s, CH3), 1.50 (3H, s,
CH3), 1.93 (3H, s, COCH3), 2.08 (6H, s, COCH3), 4.18 (1H,
dd, J = 12.0 and 5.5 Hz, H5), 4.28–4.54 (4H, m, H4, H6, H7,
H2), 4.95–5.40 (5H, m, H3, H7, NCOOCH2Ph, NH), 5.93
References
1 For a recent review on aziridine carboxylic esters see: D. Tanner,
Angew. Chem., Int. Ed. Engl., 1994, 33, 599.
2 (a) K. Nakajima, M. Neya, S. Yamada and K. Okawa, Bull. Chem.
Soc. Jpn., 1982, 55, 3049; (b) J. Bodenan and R. Vessiere, Synthesis,
1992, 288.
3 J. E. Baldwin, R. M. Adlington and N. G. Robinson, J. Chem. Soc.,
Chem. Commun., 1987, 153.
4 (a) Nakajima, H. Oda and K. Okawa, Chem. Abs., 1974, 80, 70734t;
(b) Nakajima, H. Oda and K. Okawa, Bull. Chem. Soc. Jpn., 1983,
56, 520; (c) O. Ploux, M. Caruso, G. Chassaing and A. Marquet,
J. Org. Chem., 1988, 53, 3154.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 7 2 0 – 3 7 2 6
3 7 2 5

View Article Online
5 (a) K. Sato and A. P. Kozikowski, Tetrahedron Lett., 1989, 30, 4073;
(b) I. Shima, N. Shimazaki, K. Imai, K. Hemmi and M. Hashimoto,
Chem. Pharm. Bull., 1990, 38, 564.
6 K. Nakajima, T. Tanaka, K. Morita and K. Okawa, Bull. Chem. Soc.
Jpn., 1980, 53, 283.
7 J. E. Baldwin, R. M. Adlington, I. A. O’Neil, C. Schifield, A. C.
Spivey and J. B. Sweeney, J. Chem. Soc., Chem. Commun., 1989,
1852.
D. D. Dhavale, J. Org. Chem., 2001, 66, 1065; (g) N. T. Patil, J.
Tilekar and D. D. Dhavale, Tetrahedron Lett., 2001, 42, 747; (h) D. D.
Dhavale, N. T. Patil, S. John and S. Sabharwal, Bioorg. Med. Chem.,
2002, 10, 2155; (i) D. D. Dhavale, N. N. Saha, V. N. Desai and J. N.
Tilekar, Arkivoc, 2002(VIII), 91–105; (j) J. N. Tilekar, N. T. Patil, H. S.
Jadhav and D. D. Dhavale, Tetrahedron, 2003, 59, 1873; (k) D. D.
Dhavale, V. D. Chaudhari and J. N. Tilekar, Tetrahedron Lett., 2003,
44, 7321; (l) D. D. Dhavale, S. D. Markad, N. S. Karanjule and J.
Prakashareddy, J. Org, Chem., 2004, 69, 4760; (m) D. D. Dhavale,
S. M. Jachak, N. P. Karche and C. Trombini, SYNLETT, 2004,
1549; (n) V. D. Chaudhari, K. S. Ajish Kumar and D. D. Dhavale,
Tetrahedron Lett., 2005, 45, 8363; (o) N. S. Karanjule, S. D. Markad,
T. Sharma, S. G. Sabharwal, V. G. Puranik and D. D. Dhavale, J. Org.
Chem., 2005, 70, 1356.
8 Z. Bouayed, J. Chanet-Ray, S. Ducher and R. Vessiere, J. Heterocycl.
Chem., 1991, 28, 1757.
9 L. Dubois, M. Anita, E. Tourette and R. H. Dodd, J. Org. Chem.,
1994, 59, 434.
10 B. Zwanenburg, Pure Appl. Chem., 1999, 71, 423 and references
therein.
11 For regioselective ring opening at C2, see: P. Dauban, L. Dubois, E.
Tran Huu Dau and R. H. Dodd, J. Org. Chem., 1995, 60, 2035.
12 (a) T. Tanaka, K. Nakajima and K. Okawa, Bull. Chem. Soc. Jpn.,
1980, 53, 1352; (b) K. J. Shaw, J. R. Luly and H. Rapoport, J. Org.
Chem., 1985, 50, 4515; (c) P. Deshong and D. A. Kell, Tetrahedron
Lett., 1986, 27, 3979; (d) J. Legters, L. Thijs and B. Zwanenburg,
Tetrahedron, 1991, 47, 5287.
18 Tronchet et al. first reported the glycosylaziridine derivatives and
studied the ring opening and ring expansion to D2-oxazolines:
(a) J. M. J. Tronchet and M. A. M. Massoud, Heterocycles, 1989,
29, 3; (b) J. M. J. Tronchet, E. Winter-Mihaly, M. A. M. Massoud,
O. R. Martin, F. Barbalat-Rey, J. Ojha-Poncet and J. Giust, Helv.
Chim. Acta, 1981, 64, 2350 and references cited therein.
19 For preparation of bromophosphorane see: D. B. Denny and S. T.
Ross, J. Org. Chem., 1961, 27, 998.
13 P. Bisseret, C. Bouix-Peter, O. Jacques, S. Henriot and J. Eustache,
Org. Lett., 1999, 1, 1181.
20 (a) P. B. Woller and N. H. Cromwell, J. Org. Chem., 1970, 35, 888;
(b) Due to the presence of a sugar moiety in place of an electron
withdrawing aromatic ring the vinylic proton in sugar-derived bromo
alkene 4 appeared at comparatively low down field shift d 7.50.
21 (a) H. Gunther, NMR Spectroscopy, John Wiley & Sons, New York,
1987, p. 70; (b) W. Kemp, Organic Spectroscopy, Macmillan Press
Ltd., London, 1991, p. 122.
14 (a) S. Inouye, T. Tsuruoka, T. Ito and T. Niida, Tetrahedron, 1968,
24, 2125; (b) H. Iida, N. Yamazaki and C. Kibayashi, J. Org. Chem.,
1987, 52, 3337; (c) S. Aoyagi, S. Fujimaki, N. Yamazaki and C.
Kibayashi, J. Org. Chem., 1991, 56, 815; (d) T. Kajimoto, K. K. C.
Liu, R. L. Pederson, Z. Zhong, Jr. Ichikawa, J. A. Porco and C. H.
Wong, J. Am. Chem. Soc., 1991, 113, 6187; (e) A. J. Fairbanks, N. C.
Carpentor, G. W. J. Fleet, N. G. Ramsden, I. Cencide Bello, B. G.
Winchester, S. S. Aldaher and G. Nagahashi, Tetrahedron, 1992, 48,
3365; (f) R. Grandel and U. Kazmair, Tetrahedron Lett., 1997, 38,
8009; (g) P. L. Barili, G. Berti, G. Catelani, F. D’Andrea, F. De Rensis
and L. Ruccioni, Tetrahedron, 1997, 53, 3409; (h) Y. Xu and W. Zhou,
J. Chem. Soc., Perkin Trans. 1, 1997, 1, 741; (i) N. Asano, A. Kato, M.
Miyauchi, H. Kizu, Y. Kameda, A. A. Watson, R. J. Nash and G. W. J.
Fleet, J. Nat. Prod., 1998, 61, 625; (j) C. Schaller, P. Vogel and V. Jager,
Carbohydr. Res., 1998, 314(1–2), 25–35; (k) C. Uriel and F. Santoyo-
Gonzalez, Synlett, 1999, 5993; (l) L. B. Won, J. Ill-Yun, Y. M. Suk,
C. Sang Uk and P. Ki Hun, Synthesis, 2000, 9, 1305; (m) G. Godin,
P. Compain, G. Masson and O. R. Martin, J. Org. Chem., 2002, 67,
6960; (n) M. Bols, V. H. Lillelund, H. H. Jensen and X. Liang, Chem.
Rev., 2002, 102, 515; (o) M. S. Pino-Gonzalez, C. Assiego and F. J.
Loez-Herrera, Tetrahedron Lett., 2003, 44, 8353; (p) P. Somfai, P.
Marchand, S. Torsell and U. M. Lindstorm, Tetrahedron, 2003, 59,
1293; (q) O. V. Singh and H. Han, Tetrahedron Lett., 2003, 44, 2387;
(r) H. Ko, E. Kim, J. E. Park, D. Kim and S. Kim, J. Org. Chem.,
2004, 69, 112; (s) A. Kato, N. Kato, E. Kano, I. Adachi, K. Ikeda, L.
Yu, T. Okamoto, Y. Banba, H. Ouchi, H. Takahata and N. Asano,
J. Med. Chem., 2005, 48, 2036.
15 (a) S. V. Evans, L. E. Fellows, T. K. M. Shing and G. W. J. Fleet,
Phytochemistry, 1985, 24, 1953; (b) A. Hosaka, S. Ichikawa, H.
Shindo and T. Sato, Bull. Chem. Soc. Jpn., 1989, 62, 797; (c) V.
Jager and W. Hummer, Angew. Chem., Int. Ed. Engl., 1990, 29, 1171;
(d) P. van der Klein, W. Filemon, H. J. G. Broxterman, G. A. van der
Marel and J. H. van Boom, Synth. Commun., 1992, 22, 1763; (e) D. K.
Thompson, C. N. Hubert and R. H. Wightman, Tetrahedron, 1993,
49, 3827; (f) Y. Ryu and G. Kim, J. Org. Chem., 1995, 60, 103; (g) C.
Cinquin, M. Bortolussi and B. Robert, Tetrahedron: Asymmetry,
1996, 7, 3327; (h) M. Lombardo, S. Fabbroni and C. Trombini, J. Org.
Chem., 2001, 66, 1264; (i) R. Badorrey, C. Cativela, D. M. Diaz-de-
Villegas, R. Diez and A. J. Galvez, Tetrahedron Lett., 2004, 45, 719
and references cited therein.
22 During this reaction of 4 with benzyl amine two products were
obtained however, after chromatographic purification we could
isolate compound 5 as the major product. Our efforts to isolate the
other product in pure form were unsuccessful. To improve the yield,
we performed the reaction in the presence of lithium N-benzyl amide
at −78 ◦C that afforded unidentified product. The reaction of 4 with
benzylamine under neat condition afforded aziridine ester 5 in 52%
yield. The reaction in the presence of solvent like dichloromethane
and THF were sluggish and incomplete even after reflux for 24 h.
We have also attempted an alternate route to 5 via carbene insertion
to D-glucose derived imine using ethyldiazoacetate in the presence of
•
BF3 etherate that led to mixture of products.
23 (a) H.-D. Ambrosi, W. Duczek, M. Ramm, E. Grundemann, B.
Schulz and K. Jahnisch, Liebigs Ann. Chem., 1994, 1013; (b) A. E.
Rubin and K. B. Sharpless, Angew. Chem., Int. Ed. Engl., 1997, 36,
2637; (c) F. A. Davis, H. Liu, P. Zhou, T. Fang, G. V. Reddy and Y.
Zhang, J. Org. Chem., 1999, 64, 7559.
24 The D-glucose derived a,b-unsaturated ester namely (E + Z)-
ethyl-1,2-O-isopropylidene-3-O-benzyl 5,6-dideoxy-a-D-xylo-5-eno-
heptofuranuronoate is known to undergo conjugate addition of
amine derivatives at C5 preferentially from the Si face to give
L-ido configurated C5 amino ester. For reference see: G. V. M.
Sharma, V. G. Reddy, A. S. Chander and K. R. Reddy, Tetrahedron:
Asymmetry, 2002, 13, 21.
25 The effect of –OBn substituent at C3 was also noticed with substrate
I which under similar reaction conditions resulted into the regio-
selective ring opening at C6 carbon leading to the formation of
product II.
26 The 1H and 13C NMR spectra of the compounds 7 and 8 showed
doubling of signals due to the restricted rotation around C–N bond
of urethane functionality. This type of phenomenon is general with
N-Cbz protected compounds.17.
27 This product was found to be a mixture of compounds in which the
deacetylation has occurred at different positions as indicated by the
1H NMR spectrum of compounds.
28 L. Yu-The, and L. Suc-Chen, in Methods in Enzymology, ed.
V. Ginsberg, Academic Press, New York, 1972, vol. 28, part B,
p. 702.
16 (a) G. Legler, Adv. Carbohydr. Chem. Biochem., 1990, 48, 319;
(b) G. C. Look, C. H. Fotsch and C.-H. Wong, Acc. Chem. Res.,
1993, 26, 182.
17 (a) D. D. Dhavale, V. N. Desai, M. Sindkhedkar, R. S. Mali, C.
Castellari and C. Trombini, Tetrahedron: Asymmetry, 1997, 8, 1475;
(b) D. D. Dhavale, N. N. Saha and V. N. Desai, J. Org. Chem., 1997,
62, 7482; (c) V. N. Desai, N. N. Saha and D. D. Dhavale, J. Org.
Chem., 1999, 64, 1715; (d) V. N. Desai, N. N. Saha and D. D. Dhavale,
Chem. Commun., 1999, 1719; (e) N. N. Saha, V. N. Desai and D. D.
Dhavale, Tetrahedron, 2001, 57, 39; (f) N. T. Patil, J. N. Tilekar and
3 7 2 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 3 7 2 0 – 3 7 2 6