Stereocontrolled 1,3-addition reaction of silyl ketene acetal to sugar nitrone: Synthesis of D-gluco-homo-1-deoxynojirimycin and L-ido-homo-1-deoxynojirimycin

Article abstract of DOI:10.1016/S0040-4020(00)00981-9

The 1,3-addition reaction of silyl ketene acetal 6 to D-glucose derived nitrone 7 followed by reductive cleavage of the N-O bond afforded D-gluco- and L-ido-β-amino ester derivatives of 9a and 9b. The diastereoselectivity in addition reaction was improved

Full text of DOI:10.1016/S0040-4020(00)00981-9

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 39±46
Stereocontrolled 1,3-addition reaction of silyl ketene acetal to
sugar nitrone: synthesis of d-gluco-homo-1-deoxynojirimycin and
l-ido-homo-1-deoxynojirimycin
*
Nabendu N. Saha, Vijaya N. Desai and Dilip D. Dhavale
Department of Chemistry, Garware Research Centre, University of Pune, Pune 411 007, India
Received 9 August 2000; revised 27 September 2000; accepted 12 October 2000
AbstractÐThe 1,3-addition reaction of silyl ketene acetal 6 to d-glucose derived nitrone 7 followed by reductive cleavage of the N±O bond
afforded d-gluco- and l-ido-b-amino ester derivatives of 9a and 9b. The diastereoselectivity in addition reaction was improved as well as
altered by making use of different Lewis acids. Reduction of the ester group in 9a followed by hydrogenolysis gave amino alcohol 12a.
Selective N-Cbz protection, hydrolysis and intramolecular reductive amination afforded d-gluco-homo-1-deoxynojirimycin 1d.
Analogously, b-amino ester 9b was converted to l-ido-homo-1-deoxynojirimycin 1c. q 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
reported the synthesis of 1-deoxy-l-ido-homonojirimycin
1c.4a Our approach (Scheme 1) involved highly diastereo-
selective intramolecular Michael addition of in situ
generated N-benzyl substituted sugar amine, from d-glucose
derived hemiacetal 2, to a,b-unsaturated ester and domino
lactonisation to yield lactone 3 as the only isolable product
with the homoazasugar ring skeleton having 1C4 conforma-
tions. Reduction of the lactone functionality and removal of
the protecting groups afforded 1-deoxy-l-ido-homonojiri-
mycin 1c with 4C1 conformation. As a part of our continuing
interest in this area,4 we are now describing a divergent
synthetic route to 1c and 1-deoxy-d-gluco-homonojirimycin
1d.
The term `iminosugars' is currently being used to describe
monosaccharide analogues having a nitrogen atom instead
of the ring oxygen atom. These iminosugars (azasugars),
namely nojirimycin 1a and 1-deoxynojirimycin 1b (Fig. 1)
are glycosidase inhibitors with promising medicinal
applications in the treatment of diabetes, obesity and viral
infections including HIV-1, the virus responsible for AIDS.1
The worldwide intense search for potential drugs against
AIDS has resulted in the development of new method-
ologies enabling the synthesis of a plethora of natural and
unnatural nojirimycin analogues.2
We visualized that, the 1-deoxy piperidine ring skeleton
with requisite homologated side chain could be built up
In recent years, synthesis and evaluation of homoazasugars
with a CH2-homologation either at C1 or at C5 have
received much attention.3 In this context, we have recently
Figure 1.
Keywords: piperidines; alkaloids; amino sugars; enzymes inhibitors;
nitrones.
* Corresponding author. Tel.: 1020-565-6061; fax: 1020-565-3899;
e-mail: ddd@chem.unipune.esnet.in
Scheme 1.
0040±4020/01/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00981-9

40
N. N. Saha et al. / Tetrahedron 57 (2001) 39±46
i.e. the [312] cycloaddition reactions have also been
exploited by us.5 In particular, the TMSOTf catalysed
[312] cycloaddition of aldonitrones with silylated nucleo-
philes for the synthesis of isooxazolidines has been studied
in detail. There, we have observed that the transfer of silyl
group from TMSOTf to nitrone oxygen leads to the forma-
tion of N-silyloxyiminium ions wherein, the activation
energy for the formation of C±C bond has been reduced
considerably leading to regio- and stereo-selective cyclo-
addition of electron rich alkenes under mild conditions.
We have now studied the 1,3-addition reaction of silyl
ketene acetal 6 to nitrone 7 under different reaction condi-
tions and demonstrated its applicability in the synthesis of
homo-1-deoxynojirimycins 1c and 1d.
2. Results and discussion
The desired sugar nitrone 7 was readily prepared by the
reaction of 1,2-O-isopropylidene-3-O-benzyl-a-d-xylo-
pento-dialdose with N-benzylhydroxylamine hydrochloride,
in the presence of sodium acetate in ethanol±water, as
reported earlier by us4c (Scheme 3). The 1,3-addition reac-
tion of silyl ketene acetal 6 to nitrone 7 in dichloromethane
at 258C for 24 h afforded an inseparable diastereomeric
mixture of O-silyloxy-b-amino esters 8a and 8b
(d-gluco:l-idoˆ36:64)9 in 95% yield (Table 1, entry 1).
The product showed single spot on TLC (Rfˆ0.69, hexane/
Scheme 2.
by the reductive amination of C1 aldehyde with the C5
amino group of the hemiacetal 4 (Scheme 2). The
compound 4 could be obtained by the reduction of
the ester group and the cleavage of acetonide group in 5.
The synthesis of sugar b-amino ester 5 would thus be the
key step in the process. It is possible that this can be
achieved by 1,3-addition reaction of silyl ketene acetal 6
with sugar nitrone 7 which in turn could be easily derived
from d-glucose. It remained a matter of practicability
whether the addition reaction could be performed stereo-
selectively to obtain the sugar b-aminoester 5 with required
d-gluco or l-ido diastereomer in excess.
1
ethyl acetateˆ3/1) but the H NMR (300 MHz) was not
assignable due to the overlap of signals. The formation of
b-silyloxyamino ester, indicated by strong ester carbonyl
stretching frequency at 1740 cm21 in the IR spectrum,
precludes the formation of isoxazolidine in the reaction
sequence.
Performing the reactions using CH3CN as a solvent at
different reaction temperature (08C to re¯ux temperature)
led to a moderate change of stereoselectivity in favour of
l-ido-isomer (Table 1, entry 2,3). In order to increase or
alter the diastereoselectivity, we investigated the in¯uence
of solvent and various Lewis acids. In this respect, the effect
of TMSOTf was ®rst examined. As shown in Table 1, the
individual reactions of 6 with 7 were performed in the
presence of 0.1 or 1.2 equiv. of TMSOTf using either
CH2Cl2 or CH3CN as the solvent (Table 1, entries 4±7).
Excellent chemical yield with good diastereoselectivity
(d-gluco:l-idoˆ23:77), in favour of l-ido isomer, was
achieved by using 1.2 equiv. of TMSOTf in a binary
mixture of CH2Cl2 and CH3CN at 2788C (entry 5). We
presumed that these TMSOTf promoted cycloaddition
reactions proceed with the formation of O-silyloxy inter-
mediate leading to the product formation in a non-chelation
controlled manner.10
After evaluation of the addition reactions of silyl ketene
acetals to chiral and achiral nitrones, performed by us5
and reported by others,6±8 it was felt that the con®guration
at the pro-chiral nitrone carbon could be in¯uenced if the
reaction system was properly designed. In view of this, we
have anticipated that the addition of silyl ketene acetal 6 to
nitrone 7 could be stereocontrolled under different chelation
and non-chelation conditions by the use of suitable Lewis
acids. The chelation-controlled pathway should favour one
con®guration while the Felkin±Anh stereoselectivity should
lead to the other con®guration at the newly generated C5
asymmetric carbon centre.
Although, nitrones are widely used as the starting
compounds in the synthesis of natural and unnatural
amino compounds,7 their utility in the synthesis of poly-
hydroxylated indolizidine, pyrrolidine and piperidine
alkaloids have received limited attention.8 In this context,
we have recently reported on the diastereoselective nucleo-
philic addition of methylmagnesium chloride to d-glucose
derived nitrone 7 to give 5,6-dideoxy-1,2-O-isopropylidene-
3-O-benzyl-5-(N-hydroxy)benzylamino-a-d-gluco-furanose.
The d-gluco derivative which was obtained in major amount
(d-gluco:l-idoˆ88:12) was subsequently elaborated to
6-deoxynojirimycin.4c The other aspect of nitrone chemistry
The sugar nitrone 7 possesses two alkoxy substituents
namely the furanose ring oxygen at the a-position and
benzyloxy group (at C3) at the b-position with respect to
CvN bond. These alkoxy substituents are considered to be
promising chelating groups prone to enhance or alter the
stereoselectivity of the cycloaddition reactions.5,7 This
prompted us to make use of metal chelating Lewis acids
such as ZnCl2, ZnI2 and MgBr2 in the subsequent reactions.
The use of either ZnCl2 or ZnI2, under various conditions of

N. N. Saha et al. / Tetrahedron 57 (2001) 39±46
41
Scheme 3.
temperature, solvent and mole proportions did not alter the
diastereoselectivity (preponderance of l-ido isomer 8b)
however, the observed stereoselectivity was poor (Table 1,
entries 8±15). Surprisingly, the replacement of ZnCl2
with MgBr2 altered the stereochemical course of the
addition reaction (Table 1, entries 16±19). The best
result was obtained by the use of 2.5 equiv. of MgBr2 in a
binary mixture of CH2Cl2 and CH3CN at 2108C which
afforded 8a as the major product (8a:8bˆ76:24) in 94%
yield (entry 18). No signi®cant effect was observed when
Table 1. Lewis acid catalysed addition of silyl ketene acetal 6 to nitrone 7
Run
Lewis acid (equiv.)
Solventa
Conditions
Temp. 8C
Yieldb (%)
8a:8b
time h
1
2
3
4
5
6
7
8
±
±
±
CH2Cl2
CH3CN
CH3CN
CH2Cl2
CH2Cl21CH3CN
CH2Cl21CH3CN
CH3CN
CH2Cl2
CH2Cl2
25
25
80
278
278
278
25
278
240
240
240
278
240
240
240
278
210
210
210
24
20
4
1.5
1.5
15
2.0
24
2.0
2.0
2.0
24
2.0
2.0
2.0
24
95
95
80
94
93
96
36:64
34:66
30:70
34:66
23:77
31:69
25:75
TMSOTf (1.2)
TMSOTf (1.2)
TMSOTf (0.1)
TMSOTf (0.1)
ZnCl2 (1.2)
ZnCl2 (1.2)
ZnCl2 (1.2)
ZnCl2 (3.0)
ZnI2 (1.2)
ZnI2 (1.2)
ZnI2 (1.2)
ZnI2 (3.0)
MgBr2 (1.2)
MgBr2 (1.2)
MgBr2 (2.5)
MgBr2(2.5)
93
No reaction
94
96
85
No reaction
92
91
83
No reaction
90
94
90
9
40:60
42:58
45:55
10
11
12
13
14
15
16
17
18
19
CH2Cl21CH3CN
CH2Cl21CH3CN
CH2Cl2
CH2Cl2
50:50
46:54
46:54
CH2Cl21CH3CN
CH2Cl21CH3CN
CH2Cl2
CH2Cl2
CH2Cl21CH3CN
CH3CN
2.0
2.0
2.0
60:40
76:24
74:26
a CH2Cl21CH3CN in the ratio 1:1.
b Yields refer to the isolated yields after column chromatography.

42
N. N. Saha et al. / Tetrahedron 57 (2001) 39±46
the reaction was performed in CH3CN as a solvent (entry
19).
2.1. Explanation for the observed diasteroselectivity
According to Felkin±Anh12 model two conformations A
and B (Fig. 2) were considered. Although, transition state
A is preferred over B,13 the attack of the bulky silyl ketene
acetal, along the BuÈrgi±Dunitz trajectory14 from the Re face
is disfavored by the C3-benzyloxy substituent. This explains
why d-gluco isomer 8a is obtained as a minor product.
However, in the alternate transition state B, the attack of
the silyl ketene acetal from the opposite face of the bulky
C3-benzyloxy group (Si face) is strongly favored due to the
minimised steric non-bonded interactions, leading to the
preferential formation of the l-ido-isomer 8b as the major
product.
The determination of the d-gluco/l-ido diastereomeric ratio,
at the newly generated C5 stereocentre, in the 1,3-addition
reaction of 6 and 7 was not possible with the inseparable
mixture of b-silyloxy amino esters 8a and 8b. Therefore, the
crude mixture of b-silyloxy amino esters 8a and 8b was
subjected to N±O bond reductive cleavage by treatment
with zinc/copper couple in acetic acid±water at 708C for
1 h and the diastereomeric mixture of N-benzyl b-amino
esters 9a and 9b was separated by ¯ash chromatography
(91% yield). Although, b-amino esters 9a and 9b were
1
isolated in the pure form, their H NMR data could not
discriminate the d-gluco and l-ido isomers. As a result,
the con®gurational assignment at C5 was made in the next
stage. Thus, reduction of the ester functionality in b-amino
esters 9a and 9b, individually, with LAH in THF afforded
b-aminoalcohols 10a and 10b, respectively. Assignment of
the con®guration at C5 was made on the basis of comparison
The stereochemical outcome in the bivalent metal assisted
reaction could be explained by considering the chelated
transition states involving the metal complexation with
nitrone oxygen and proximate alkoxy groups.6 Two confor-
mations C and D (Fig. 2) are therefore considered. The
a-chelation of nitrone oxygen with furanose ring oxygen,
in a six membered transition state, is represented in model C
while the b-chelation with the benzyloxy substituent at C3
resembles the model D. For the reaction in the presence of
MgBr2, we assume that the reactive transition state that
resembles the complexation of magnesium hydroxylamine
with the C3 benzyloxy group prevails (b-chelated model D)
wherein; Re facial nucleophilic addition, from the small
group, gives the observed d-gluco stereoselectivity (anti-
product). In the case of ZnCl2 and ZnI2 mediated addition
reactions with nitones, with a- and b-alkoxy substituents
in the proximity, earlier workers have shown that the
a-chelation model explains the observed stereoselectivity.6
Thus, nucleophilic attack from the preferred Si face in
conformer C affords the syn-adduct albeit in poor
selectivity. Other workers also noted an analogous observa-
tion wherein a bidentate Lewis acid precomplex the nitrones
and a-chelated conformation leads to syn-adducts while the
b-chelated one affords the anti-adducts.7g
1
of their H NMR spectra. It is known that, for a series of
given C5 epimeric pairs, derived from d-gluco-furanose, the
vicinal coupling constants between H4 and H5 in l-ido
isomers (threo-relationship) are constantly larger than
those of the corresponding d-gluco isomers (erythro
relationship).11 The higher value of J4,5 observed in dia-
stereomer 10b (9.5 Hz) as compare to 10a (6.9 Hz) indi-
cated the l-ido con®guration for 10b and d-gluco
con®guration for 10a. This assignment was further
supported by comparison of the H3 chemical shifts in
both the isomers. The chemical shift of H3 is reported to
be diagnostic such that in the l-ido- the H3 resonates signi®-
cantly up®eld (d,3.6) as compared to that in the d-gluco-
con®guration (d,4.0).11 In 10b, H3 appeared considerably
up®eld (at d 3.86) as compare to 10a (at d 4.03) further
supporting the l-ido- and d-gluco-con®guration at C5 to
10b and 10a, respectively.
2.2. Synthesis of d-gluco- and l-ido-homo-1-deoxynojiri-
mycins
The C5 amino alcohols 10a and 10b with respective
d-gluco- and l-ido-con®gurations are the true intermediates
for the synthesis of higher homologues of 1-deoxynojiri-
mycin. Thus, in the subsequent steps, the one pot deprotec-
tion of N- and O-benzyl groups in 10a, by treatment with
10% Pd/C in the presence of ammonium formate as a hydro-
gen donor in methanol, afforded amino alcohol 11a in 91%
yield. The removal of the 1,2-O-isopropylidene functional-
ity in 11a with TFA±water followed by hydrogenation with
10% Pd/C resulted into a complex mixture of products.
Therefore, C5±NH2 functionality in 11a was protected
with Cbz group using benzyl chloroformate in the presence
of sodium bicarbonate in ethanol±water to obtain N-Cbz
protected amino alcohol 12a in 95% yield. Finally,
hydrolysis of 12a with TFA±water at 08C to 258C for 2 h
afforded a hemiacetal which was directly subjected to
hydrogenolysis using 10% Pd/C wherein deprotection of
the N-Cbz group, intramolecular amine cyclisation, imine
formation and reduction of the imino group in one pot gave
d-gluco-homo-1-deoxynojirimycin 1d as a pale yellow
Figure 2.

N. N. Saha et al. / Tetrahedron 57 (2001) 39±46
43
1
solid. In the H NMR spectra, appearance of two triplets
fraction), ethyl acetate and methanol were puri®ed and dried
before use. N-Benzylhydroxylamine, N-benzylamine,
HMDS, HMPA, LAH, Cbz-Cl were purchased from Aldrich
and/or Fluka. Sugar nitrone 6 was prepared from 1,2-O-
isopropylidene-3-O-benzyl-a-d-xylo-pento-dialdose in 78%
yield as reported earlier.4c
with large coupling constants- one at d 3.08 corresponds
to H4 (J4,5ˆJ3,4ˆ9.5 Hz) and other at d 3.27 for H3
(J3,4ˆJ2,3ˆ9.5 Hz) indicated trans diaxial relation with the
adjacent protons. In the amino alcohol 10a the relative
stereochemistry of the substituents at C2, C3 and C3, C4
is trans and the same stereochemistry is retained in the
product formation. The appearance of eight line pattern
(ddd) at 2.51 d corresponding to H5 with J4,5ˆ9.5 Hz,
3.1. General procedure for the cycloaddition of silyl
ketene acetal 6 to nitrone 7 in the presence of Lewis acid
0
J5,6ˆ8.8 Hz and J5,6 ˆ3.3 Hz con®rmed the trans diaxial
relative disposition of H4 and H5 protons. This con®rms
that the C5 substituent (±CH2CH2OH) is oriented
equatorially [(5R)-con®guration] and the compound 1d
To a solution of nitrone 7 (1 equiv.) in dichloromethane
(5 mL) was added Lewis acid (0.1, 1.2 or 3.0 equiv.) at
08C and the reaction mixture was stirred for 30 min. After
cooling (2788C or 2108C) silyl ketene acetal 6 (1.3 equiv.)
in solvent (5 mL) was added and stirred for required time at
speci®c temperature (Table 1). After completion of the reac-
tion, as monitored by TLC, a saturated solution of aqueous
NH4Cl (2 mL) was added and the reaction mixture was
extracted with organic solvent. The combined organic
layer washed with water and brine and dried over anhydrous
Na2SO4. Solvent removal afforded a diastereomeric mixture
of 8a and 8b as a thick liquid, which was puri®ed by column
chromatography using pet. ether/ethyl acetate (7:3) as an
eluent (yield 83±96%).
4
has the C1 conformation.
In an analogous reaction sequence, the pure N-benzyl amino
alcohol 10b on hydrogenolysis gave 11b, which on selective
N-protection afforded N-Cbz-amino alcohol 12b. In the next
step, removal of the acetonide group followed by the hydro-
genolysis afforded l-ido-homo-1-deoxynojirimycin 1c in
1
78% yield from 10b. Since the H NMR spectrum of 1c is
very different from 1d, it was thought that 1c could exit in
the 1C4 conformation. However, appearance of two distinct
doublet of doublets for H1a at d 2.62 (J1a,1eˆ13.3 Hz;
J1a,2ˆ8.2 Hz) and for H1e at d 2.88 (J1e,1aˆ13.3 Hz;
J1e,2ˆ4.2 Hz) were informative. The large coupling constant
(J1a,2ˆ8.2 Hz) for the H1 axial proton requires trans diaxial
relationship with H2 proton. This clearly requires H2 proton
to be axial and suggestive of the fact that compound 1c exits
3.1.1. Ethyl 3-O-benzyl-5-aminobenzyl-1,2-O-isopropyl-
idene-a-d-gluco-hept-furanuronate (9a). Ethyl 3-O-
benzyl-5-aminobenzyl-1,2-O-isopropylidene-b-l-ido-
hept-furanuronate (9b). Copper(II) acetate (0.02 g,
0.110 mmol) was added to a stirred solution of zinc dust
(0.25 g, 3.85 mmol) in glacial acetic acid (1 mL) under
N2. The mixture was stirred at room temperature for
15 min until the colour disappeared. A mixture of 8a and
8b (0.45 g, 0.77 mmol) in glacial acetic acid (1 mL) and
water (0.3 mL) was added, the reaction mixture was heated
at 708C for 1 h and then cooled to room temperature. After
the sodium salt of EDTA (0.1 g) was added, the mixture was
stirred for 10 min and then made alkaline (pHˆ10) by addi-
tion of 3 M NaOH. Extraction with chloroform (3£10 ml)
and usual workup gave a thick oil. Flash chromatographic
puri®cation by elution with pet. ether/ethyl acetate (98/2)
gave 9a (0.109 g, 31%) as a thick colourless oil: Rfˆ0.47
(hexane/EtOAcˆ6/4); [a]Dˆ242.16 (c 0.44, CHCl3); IR
(neat) 3330, 1730; 1H NMR (300 MHz) d 1.27 (t,
Jˆ7.2 Hz, 3H), 1.33 (s, 3H), 1.50 (s, 3H), 1.66 (bs, 1H,
exchanges with D2O), 2.61 (dd, Jˆ6.7, 15.7 Hz, 1H), 2.83
(dd, Jˆ4.2, 15.7 Hz, 1H), 3.55 (ddd, Jˆ4.2, 6.7, 8.8 Hz 1H),
3.75 (d, Jˆ12.8 Hz, 1H), 3.87 (d, Jˆ12.8 Hz, 1H), 4.12 (d,
Jˆ3.0 Hz, 1H), 4.15 (q, Jˆ7.2 Hz, 2H), 4.20 (dd, Jˆ3.0,
8.8 Hz, 1H), 4.56 (d, Jˆ11.6 Hz, 1H), 4.62 (d, Jˆ3.7 Hz,
1H), 4.70 (d, Jˆ11.6 Hz, 1H), 5.92 (d, Jˆ3.7 Hz, 1H),
7.15±7.35 (m, 10H).
4
1
in C1 conformation. The H and 13C NMR spectral and
analytical data was also found to be in consonance with
4
the data reported earlier by us4a thus con®rming the C1
conformation with (5S) con®guration.
In conclusion, we have demonstrated that the 1,3-addition
reaction of silyl ketene acetal 6 with d-glucose derived
nitrone 7 can be stereocontrolled by the use of appropriate
Lewis acid under chelation and non-chelated controlled
pathways. The two-diastereomeric sugar b-aminoesters
thus obtained were successfully utilized in the synthesis of
d-gluco-homo-1-deoxynojirimycin and l-ido-homo-1-
deoxynojirimycin. Work is in progress to demonstrate the
applicability of this methodology in the synthesis of
castanospermine.
3. Experimental
1H NMR (300 MHz, 500 MHz) and 13C NMR (75 MHz,
125 MHz) spectra were recorded using CDCl3 as a solvent
unless otherwise stated. Chemical shifts are reported in ppm
(d) relative to internal standard Me4Si. IR spectra (n, cm21
)
were measured as thin ®lms or nujol mulls or KBr pellets.
Optical rotations were recorded at 258C. Whenever required
the reactions were carried out in oven-dried glassware under
dry N2. On work up, reaction mixture was extracted with
organic solvents, evaporated at reduced pressure with rotary
evaporator. Thin layer chromatography was performed on
0.25 mm pre-coated silica gel; ¯ash chromatography was
carried out on silica gel 200±400 mesh and column chro-
matography on silica gel 100±200 mesh. The organic
solvents such as n-hexane, THF, diethyl ether, methylene
chloride, chloroform, petroleum ether (pet. ether, 60±708C
13C NMR (75 MHz) d 14.2, 26.3, 26.8, 35.7, 51.2, 52.5,
60.2, 72.0, 81.6, 81.7, 82.0, 104.7, 111.5, 126.8, 127.7,
127.8, 128.0, 128.2, 128.4, 137.4, 140.5, 172.3. Anal.
Calcd for C26H33NO6: C, 68.55; H, 7.30. Found: C, 68.79;
H, 7.55.
Futher elution with pet. ether/ethyl acetateˆ95/5 gave 9b
(0.21 g, 60%) as a pale yellow solid: mp 70±728C; Rfˆ0.36
(Hexane/EtOAcˆ6/4); [a]Dˆ226.25 (c 0.32, CHCl3); IR
(nujol) 3337, 1731; 1H NMR (300 MHz) d 1.25 (t,

44
N. N. Saha et al. / Tetrahedron 57 (2001) 39±46
Jˆ7.1 Hz, 3H), 1.35 (s, 3H), 1.51 (s, 3H), 1.80 (bs, 1H,
exchanges with D2O), 2.33 (dd, Jˆ6.7, 14.8 Hz, 1H), 2.45
(dd, Jˆ4.6, 14.8 Hz, 1H), 3.55 (ddd, Jˆ4.6, 6.7, 8.8 Hz,
1H), 3.86 (ABq, Jˆ12.7 Hz, 2H), 3.97 (d, Jˆ3.1 Hz, 1H),
4.12 (q, Jˆ7.1 Hz, 2H), 4.26 (dd, Jˆ3.1, 8.8 Hz, 1H), 4.47
(d, Jˆ11.8 Hz, 1H), 4.67 (d, Jˆ3.9 Hz, 1H), 4.72 (d,
Jˆ11.8 Hz, 1H), 5.97 (d, Jˆ3.9 Hz, 1H), 7.22±7.45 (m,
10H); 13C NMR (75 MHz) d 14.0, 26.1, 26.6, 36.3, 51.4,
53.6, 60.2, 71.2, 81.5, 81.6, 82.1, 104.7, 111.4, 126.6, 127.7,
127.8, 128.0, 128.1, 128.3, 136.9, 140.4, 171.5. Anal. Calcd
for C26H33NO6: C, 68.55; H, 7.30. Found: C, 68.72; H, 7.40.
column chromatography. Elution with CHCl3/MeOH (95/5)
gave amine 11a (0.29 g, 91%) as a thick liquid: Rfˆ0.67
(CHCl3/MeOHˆ1/1); [a]D1ˆ221.6 (c 0.5, MeOH); IR
(neat) 3750±3150 (broad); H NMR (300 MHz) d 1.36 (s,
3H), 1.51 (s, 3H), 1.75±1.85 (m, 1H), 1.92±2.03 (m, 1H),
3.42±3.49 (m, 1H), 3.78 (t, Jˆ6.2 Hz, 1H), 4.12 (dd, Jˆ7.3,
2.6 Hz, 1H), 4.40 (d, Jˆ2.6 Hz, 1H), 4.70 (d, Jˆ3.6 Hz,
1H), 6.05 (d, Jˆ3.6 Hz, 1H); 13C NMR (125 MHz) d
27.6, 28.1, 36.1, 50.2, 61.2, 76.4, 83.8, 87.1, 107.0, 115.2.
Anal. Calcd for C10H19NO5: C, 51.49; H, 8.21. Found: C,
51.47; H, 8.41.
3.1.2. 3-O-Benzyl-5,6-dideoxy-5-(N-benzyl)amino-1,2-O-
isopropylidene-a-d-gluco-hepto-1,4-furanose 10a. To an
ice cooled suspension of LAH (0.20 g, 5.49 mmol) in dry
THF (5 mL) was added a solution of 9a (0.5 g, 1.1 mmol) in
dry THF (5 mL) over a period of 10 min. The reaction
mixture was warmed to room temperature and stirred for
2 h. Ethyl acetate (10 mL) was added at 08C, stirred for
10 min and the reaction was quenched with saturated solu-
tion of NH4Cl (2 mL). The solution was ®ltered, the residue
washed with ethyl acetate (5 mL) and workup as usual.
Flash chromatography (CHCl3/MeOHˆ98/2) gave 10a
(0.4 g, 87%) as a thick liquid: Rfˆ0.77 (CHCl3/MeOHˆ9/
1); [a]Dˆ230.38 (c 0.65, CHCl3); IR (nujol) 3750±3340
3.1.5. 5,6-Dideoxy-5-amino-1,2-O-isopropylidene-b-l-ido-
hepto-1,4-furanose 11b. A stirred solution of 10b (0.4 g,
0.97 mmol), 10%Pd/C (0.4 g), ammonium formate (0.43 g,
6.89 mmol) in dry methanol (10 mL) was re¯uxed for 1.5 h.
Workup as in the case of 11a, puri®cation by column chro-
matography and eluting with CHCl3/MeOH (95/5) gave 11b
(0.29 g, 89%) as a thick liquid: Rfˆ0.39 (CHCl3/MeOHˆ1/
1); [a]Dˆ211.14 (c 0.28, MeOH); IR (neat) 3800±3300
1
(broad); H NMR (300 MHz) d 1.32 (s, 3H), 1.48 (s, 3H),
1.75±1.90 (m, 2H), 2.50±3.00 (bs, exchanges with D2O,
4H), 3.40±3.48 (m, 1H), 3.75±3.89 (m, 2H), 4.08 (bs,
1H), 4.28 (bd, Jˆ2.0 Hz, 1H), 4.49 (d, Jˆ3.3 Hz, 1H),
5.95 (d, Jˆ3.3 Hz, 1H); 13C NMR (125 MHz) d 27.7,
28.1, 37.0, 49.6, 61.0, 76.4, 86.2, 87.5, 106.8, 115.0; Anal.
Calcd for C10H19NO5: C, 51.47; H, 8.21. Found: C, 51.38;
H, 8.36.
1
(broad); H NMR (300 MHz) d 1.33 (s, 3H), 1.50 (s, 3H),
1.77±1.83 (m, 2H), 2.85±2.90 (bs, 2H, exchanges with
D2O), 3.32±3.40 (m, 1H), 3.79 (d, Jˆ12.3 Hz, 1H), 3.75±
3.90 (m, 2H), 3.94 (d, Jˆ12.3 Hz, 1H), 4.03 (d, Jˆ3.3 Hz,
1H), 4.20 (dd, Jˆ3.3, 6.9 Hz, 1H), 4.48 (d, Jˆ11.5 Hz, 1H),
4.64 (d, Jˆ3.8 Hz, 1H), 4.69 (d, Jˆ11.5 Hz, 1H), 5.95 (d,
Jˆ3.8 Hz, 1H), 7.15±7.35 (m, 10H); 13C NMR (75 MHz) d
26.2, 26.8, 31.9, 51.8, 56.9, 62.5, 71.8, 81.4, 81.6, 82.2,
104.7, 111.5, 127.1, 127.5, 128.0, 128.2, 128.5, 128.7,
136.8, 139.8. Anal. Calcd for C24H31NO5: C, 69.71; H
7.56. Found: C, 69.49; H, 7.77.
3.1.6. 5,6-Dideoxy-5-(N-benzoxycarbonyl)amino-1,2-O-
isopropylidene-a-d-gluco-hepto-1,4-furanose 12a. To a
stirred solution of 11a (0.12 g, 0.515 mmol) and NaHCO3
(0.12g, 1.428 mmol) in ethanol±water (2 mL, 1:1), at 08C,
was added benzyl chloroformate (0.131 g, 0.770 mmol).
The mixture was stirred at 258C for 6 h, quenched with
water and extracted with chloroform (3£10 mL). Usual
workup and puri®cation by column chromatography (pet
ether/ethylacetateˆ1/1) gave 12a as a thick liquid (0.18 g,
95%): Rfˆ0.71 (CHCl3/MeOHˆ9/1); [a]Dˆ158.56 (c
0.32, MeOH); IR (neat) 3600±3300, 1693; 1H NMR
(300 MHz, CDCl31D2O) d 1.32 (s, 3H), 1.49 (s, 3H),
1.80±1.92 (m, 1H), 2.00±2.18 (m, 1H), 3.80±4.06 (m,
4H), 4.09 (bs, 1H), 4.57 (d, Jˆ3.6 Hz, 1H), 5.10 (ABq,
Jˆ12.1 Hz, 2H), 5.91 (d, Jˆ3.6 Hz, 1H), 7.30±7.41 (m,
5H); 13C NMR (125 MHz, CDCl31D2O) d 26.1, 26.8,
32.9, 47.6, 59.4, 67.3, 74.0, 81.7, 84.4, 104.8, 111.5,
128.1, 128.3, 128.5, 135.9, 157.8. Anal. Calcd for
C18H25NO7: C, 58.84; H, 6.86. Found: C, 58.63; H, 7.09.
3.1.3. 3-O-Benzyl-5,6-dideoxy-5-(N-benzyl)amino-1,2-O-
isopropylidene-b-l-ido-hepto-1,4-furanose 10b. The
reaction of 9b (0.5 g, 1.1 mmol) with LAH (0.20 g,
5.49 mmol) under the same conditions as reported for 9a.
Flash chromatography (CHCl3/MeOHˆ96/4) afforded 10b
(0.95 g, 84%) as a thick liquid: Rfˆ0.48 (CHCl3/MeOHˆ9/
1); [a]Dˆ232.65 (c 0.65, CHCl3); IR (neat) 3250±3600
(broad); 1H NMR (300 MHz, CDCl31D2O) d 1.33 (s,
3H), 1.50 (s, 3H), 1.38±1.65 (m, 2H), 3.38 (m, 1H), 3.69±
3.82 (m, 2H), 3.86 (d, Jˆ3.1 Hz, 1H), 3.89 (ABq,
Jˆ12.1 Hz, 2H), 4.24 (dd, Jˆ3.1, 9.5 Hz, 1H), 4.41 (d,
Jˆ11.7 Hz, 1H), 4.66 (d, Jˆ3.8 Hz, 1H), 4.70 (d,
Jˆ11.7 Hz, 1H), 5.96 (d, Jˆ3.8 Hz, 1H), 7.21±7.39 (m,
10H); 13C NMR (75 MHz) d 26.2, 26.8, 29.5, 50.8, 56.8,
62.3, 71.8, 81.4, 81.7, 81.9, 104.8, 111.7, 127.1, 128.1,
128.2, 128.5, 128.6, 136.9, 139.7. Anal. Calcd for
C24H31NO5: C, 69.71; H, 7.56. Found: C, 69.73; H, 7.61.
3.1.7. 5,6-Dideoxy-5-(N-benzoxycarbonyl)amino-1,2-O-
isopropylidene-b-l-ido-hepto-1,4-furanose 12b. Reaction
of b-amino alcohol 11b (0.15 g, 0.644 mmol), NaHCO3
(0.15 g, 1.785 mmol) with benzyl chloroformate (0.179 g,
1.049 mmol) under the same conditions as for 11a afforded
a compound which on column chromatographic puri®cation
using pet. ether/ethyl acetate (1/1) as an eluent gave 12b
(0.19 g, 80%) as a thick liquid: Rfˆ0.24 (CHCl3/MeOHˆ9/
1); [a]Dˆ260.65 (c 0.25, MeOH); IR (neat) 3700±3200,
3.1.4. 5,6-Dideoxy-5-amino-1,2-O-isopropylidene-a-d-
gluco-hepto-1,4-furanose 11a. To a stirred suspension of
10a (0.35 g, 0.847 mmol), 10% Pd/C (0.35 g) in dry metha-
nol (10 mL) was added ammonium formate (0.38 g,
6.01 mmol). The reaction mixture was re¯uxed for 1 h and
cooled to room temperature. The catalyst was ®ltered
through celite and washed with methanol (5 mL). The
®ltrate was evaporated to afford oil, which was puri®ed by
1
1695; H NMR (200 MHz, CDCl31D2O) d 1.30 (s, 3H),
1.48 (s, 3H), 1.35±2.00 (m, 2H), 3.60±3.75 (m, 2H),
4.00±4.25 (m, 3H), 4.52 (d, Jˆ4.0 Hz, 1H), 5.10 (AB
quartet, Jˆ12.0 Hz, 2H), 5.93 (d, Jˆ4.0 Hz, 1H), 7.30±7.41
(m, 5H); 13C NMR (125 MHz, CDCl31D2O) d 26.0, 26.6,

N. N. Saha et al. / Tetrahedron 57 (2001) 39±46
45
A.; Raymond, A. D.; Fellows, L. E.; Tyms, A. S.; Petursson,
S.; Namgoong, S. K.; Ramsden, N. G.; Smith, P. W.; Son, J. C.;
Wilson, F.; Witty, D. R.; Jacob, G. S.; Rademacher, T. W.
FEBS Lett. 1988, 237, 128±132. (g) Datema, R.; Olofsson, S.;
Romero, P. A. Pharmacol. Ther. 1987, 33, 221±286; (h) Kino,
N.; Inamura, N.; Nakahara, K.; Tsurumi, T.; Adachi, K.;
Shibata, T.; Terano, H.; Kohsaka, M.; Aoki, H.; Imanaka,
H. J. Antibiot. 1985, 38, 936.
35.0, 47.5, 58.4, 66.9, 74.5, 81.8, 85.3, 104.4, 111.4, 127.9,
128.0, 128.4, 136.2, 157.5; Anal. Calcd for C18H25NO7: C,
58.84; H, 6.86. Found: C, 58.60; H, 7.04.
3.1.8. 1,5,6-Trideoxy-1,5-imino-d-gluco-heptitol 1d. An
ice cooled solution of 12a (0.16 g, 0.436 mmol) in TFA±
H2O (2 mL, 3:2) was warmed up to 258C and stirred for 2 h.
TFA was evaporated at high vacuum to yield a hemiacetal
which was directly used in the next reaction. To a solution
of hemiacetal in methanol (5 mL) was added 10% Pd/C
(0.02 g) and the solution was hydrogenolysed (70 psi) at
room temperature for 16 h. The catalyst was ®ltered,
washed with methanol and the combined ®ltrate concen-
trated to a residue. The residue was washed with chloroform
(3£2 mL) and then puri®ed by column of amberlite IR 400A
(OH2) resin eluting with distilled water to yield a colorless
semisolid 1d (0.070 g, 90%): Rfˆ0.37 (EtOH/H2Oˆ3/2);
2. (a) Aoyagi, S.; Fujimaki, S.; Kibayashi, C. J. Chem. Soc.,
Chem. Commun. 1990, 1457±1459. (b) Hughes, A. B.;
Rudge, A. J. Natural Product Reports, 1994, 135±162 and
references cited therein. (c) Wong, C.-H.; Provencher, L.;
Porco, J. A.; Jung, S.-H.; Wang, Y.-F.; Chen, L.; Wang, R.;
Steensma, D. H. J. Org. Chem. 1995, 60, 1492±1501.
(d) Rassu, G.; Pinna, L.; Spano, P.; Culeddu, N.; Casiraghi
G.; Fava, G. G.; Ferrari, M. B.; Pelosi, G. Tetrahedron 1992,
48, 727±742; (e) Herdeis, C.; Schiffer, T. Tetrahedron 1996,
52, 14745±14756. (f) Compernolle, F.; Joly, G.; Peeters, K.;
Toppet, S.; Hoomaert, G.; Kilonda, A.; Bila, B. Tetrahedron
1997, 53, 12739±12754. (g) Asano, N.; Nash, R. J.;
Molyneux, R. J.; Fleet, G. W. J. Tetrahedron Asymmetry
2000, 11, 1645±1680 and reference cited therein.
1
[a]Dˆ18.7 (c 0.2, H2O); IR (KBr) 3650±2900; H NMR
(300 MHz, CDCl31D2O) d 1.46±1.60 (m, 1H), 1.95±2.12
(m, 1H), 2.41 (dd, Jˆ11.0, 12.5 Hz, 1H), 2.51 (ddd, Jˆ3.3,
8.8, 9.5 Hz, 1H), 3.04 (dd, Jˆ5.5, 12.5 Hz, 1H), 3.08 (t,
Jˆ9.5 Hz, 1H), 3.27 (t, Jˆ9.5 Hz, 1H), 3.48 (ddd, Jˆ5.5,
9.5, 11.0 Hz, 1H), 3.50±3.80 (m, 2H); 13C NMR (125 MHz)
d 36.4, 51.5, 59.8, 61.5, 73.5, 77.6, 81.0. Anal. Calcd for
C7H15NO4: C, 47.44; H, 8.53. Found: C, 47.60; H, 8.75.
3. (a) Kite, G. C.; Fellows, L. E.; Fleet, G. W. J.; Liu, P. S.;
Sco®eld, A. M.; Smith, N. G. Tetrahedron Lett. 1988, 29,
6483±6486; (b) Winchester, B.; Barker, C.; Baines, S.;
Jacob, G. S.; Namgoong, S. K.; Fleet, G. W. J. Biochem. J.
1990, 265, 277±282; (c) Rhinehart, B. L.; Robinson, K. M.;
Liu, P. S.; Payne, J.; Wheatley, M. E.; Wagner, S. R.
J. Pharmacol. Exp. Therap. 1987, 241, 915±920. (e) Fleet,
G. W. J.; Namgoong, S. K.; Barker, C.; Baines, S.; Jacob,
G. S.; Winchester, B. Tetrahedron Lett. 1989, 30, 4439±
4442. (f) Bruce, I.; Fleet, G. W. J.; di Bello, I. C.; Winchester,
B. Tetrahedron Lett. 1989, 30, 7257±7260; Szolesanyl, P.;
Gracza, T.; Koman, M.; Pronayova, N.; Liptaj, T. J. Chem.
Soc., Chem. Commun. 2000, 471±472.
3.1.9. 1,5,6-Trideoxy-1,5-imino-l-ido-heptitol 1c. An ice
cooled solution of 12b (0.075 g, 0.204 mmol) in TFA±
water (2 mL, 3:2) was warmed to 258C and stirred for 2 h.
After work up, as in case of 1d, the hemiacetal was directly
hydrogenolysed in methanol using 10% Pd/C (0.01 g) for
16 h. Work up as in case of 1d afforded a foaming solid
(0.034 g, 94%): mp 132±1358C; Rfˆ0.20 (EtOH/H2Oˆ3/
1
2); [a]Dˆ213.85 (c 0.8, H2O); IR (KBr) 3400±2900; H
NMR (300 MHz, CDCl31D2O) d 1.62±1.78 (m, 2H), 2.62
(dd Jˆ8.2, 13.3 Hz, 1H), 2.88 (dd Jˆ4.2, 13.3 Hz, 1H),
3.04±3.14 (m, 1H), 3.40±3.57 (m, 3H), 3.59±3.76 (m,
2H); 13C NMR (125 MHz) d 30.94, 46.73, 55.15, 62.13,
73.22, 74.51, 75.26; Anal. Calcd for C7H15NO4: C, 47.44;
H, 8.53. Found: C, 47.25; H, 8.74.
4. (a) Desai, V. N.; Saha, N. N.; Dhavale, D. D. J. Chem. Soc.,
Chem. Commun. 1999, 1719±1720. (b) Dhavale, D. D.; Saha,
N. N.; Desai, V. N. J. Org. Chem. 1997, 62, 7482±7484.
(c) Dhavale, D. D.; Desai, V. N.; Sindkhedkar, M. D.; Mali,
R. S.; Castellari, C.; Trombini, C. Tetrahedron: Asymmetry
1997, 8, 1475±1478.
5. (a) Camiletti, C.; Dhavale, D. D.; Gentilucci, L.; Trombini, C.
J. Chem. Soc., Perkin Trans. 1 1993, 3157±3165. (b) Camiletti,
C.; Dhavale, D. D.; Donati, F.; Trombini, C. Tetrahedron Lett.
1995, 36, 7293. (c) Dhavale, D. D.; Trombini, C. Heterocycles
1992, 34, 2253±2258. (d) Dhavale, D. D.; Donati, F.;
Trombini, C. J. Chem. Soc., Chem. Commun. 1992, 1268±
1270.
Acknowledgements
We are grateful to Professor M. S. Wadia for helpful discus-
sion. V. N. D. and N. N. S. are thankful to UGC and CSIR
respectively for fellowship. We gratefully acknowledge the
help of TIFR and IIT, Mumbai for use of high resolution
NMR facility.
6. (a) Kita, Y.; Tamura, O.; Ito, F.; Kishino, H.; Miki, T.; Kohno,
M.; Tamura, Y. Chem Pharm Bull 1989, 37, 2002±2007.
(b) Tomoda, S.; Takeuchi, Y.; Nomura, Y. Chem. Lett.
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Kohno, M.; Tamura, Y. J. Chem. Soc., Chem. Commun.
1988, 761±763. (e) Dondoni, A.; Junquera, F.; Merchan,
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Merino, P.; Tejero, T. Tetrahedron Lett. 1993, 34, 5475±
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