Selective protecting group manipulations on the 1-deoxynojirimycin scaffold

Article abstract of DOI:10.1016/j.tet.2007.04.070

Iminosugars are inhibitors of glycoprocessing and are of interest as scaffolds for medicinal chemistry, as their successful application as peptide mimetics has shown. The synthesis of novel peptidomimetics based on 1-deoxynojirimycin (DNJ) requires practical strategies that allow introduction of amino acid side chains or pharmacophore groups at each of its hydroxyl groups or to the nitrogen atom. This paper describes one approach towards achieving selective protection and deprotection at the hydroxyl and amino groups of?DNJ and a novel synthesis of DNJ from l-sorbose is included.

Full text of DOI:10.1016/j.tet.2007.04.070

Tetrahedron 63 (2007) 6827–6834
Selective protecting group manipulations on the
1-deoxynojirimycin scaffold
a
Elisa Danieli, Jerome Lalot and Paul V. Murphy
b
b,
*
ˆ
ꢀ
aDepartment of Organic Chemistry ‘Ugo Schiff’, University of Florence, via della Lastruccia 13, 50019 Sesto Fiorentino,
Florence, Italy
bCentre for Synthesis and Chemical Biology, UCD School of Chemistry and Chemical Biology, UCD Conway Institute,
University College Dublin, Belfield, Dublin 4, Ireland
Received 26 January 2007; revised 1 April 2007; accepted 19 April 2007
Available online 25 April 2007
Abstract—Iminosugars are inhibitors of glycoprocessing and are of interest as scaffolds for medicinal chemistry, as their successful
application as peptide mimetics has shown. The synthesis of novel peptidomimetics based on 1-deoxynojirimycin (DNJ) requires practical
strategies that allow introduction of amino acid side chains or pharmacophore groups at each of its hydroxyl groups or to the nitrogen
atom. This paper describes one approach towards achieving selective protection and deprotection at the hydroxyl and amino groups of DNJ
and a novel synthesis of DNJ from L-sorbose is included.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
grafted strategically to functional groups on the DMJ scaf-
fold. The synthesis of molecules based on iminosugars
thus requires practical strategies that allow introduction of
substituents at each of the hydroxyl groups or to the
nitrogen atom of iminosugars so that structure–activity
relationships may be established. Such strategies would
also facilitate the synthesis of novel analogues of iminosu-
gars for investigation as glycosidase inhibitors or for other
purposes.11 Herein, we describe one approach towards
Monosaccharides and their derivatives have been receiving
increased attention as scaffolds for the synthesis of novel
compounds. Such carbohydrate derivatives have been mainly
designed to modulate protein–protein and peptide–protein
interactions (peptidomimetics) although carbohydrate–pro-
tein (glycomimetics) and carbohydrate–nucleic acid interac-
tions (aminoglycoside mimetics) have also been of interest.
1-Deoxynojirimycin (DNJ) 11 is a naturally occurring mem-
ber of the iminosugars, which constitute polyhydroxylated
heterocycles containing an endocyclic nitrogen atom. The
polyhydroxylated piperidines are true structural analogues
of pyranosides and the substitution of the ring oxygen of
the corresponding pyranose with a nitrogen atom renders
these compounds stable to glucosidases, but does not prevent
their recognition by glycosidases2 and glycosyltransferases.3
Consequently, derivatives of DNJ have found clinical appli-
cation4 and analogues are of interest for treatment of HIV
infection, hepatitis C virus infection, diabetes and other
metabolic disorders.5 In addition, DNJ derivatives, which
have pharmacophoric groups attached are potentially bioac-
tive compounds,6–8 and preliminary studies using iminosu-
gar based scaffolds bioactive molecule synthesis indicate
promise in this regard.9 For example, the Lys-Trp mimetic
2, based on 1-deoxymannojirimycin (DMJ) as a scaffold,
is a ligand for somatostatin receptors.10 In this compound,
the amino acid side chains of lysine and tryptophan are
H2N
O
NH2
O
O
H
N
H
N
H
S
N
H
N
H
O
N
H
N
O
O
O
H
N
H
N
H
NH
O
O
H2N
O
O
NH2
N
O
S
H
N
H
N
H
OH
N
O
N
H
HO2C
HO
OH
O
HO
Somatostatin
HO
HO
NH
HO
N
O
HO
NH
OH
HO
NH2
Trp-Lys mimetic based on DMJ 2
Somatostatin receptor ligand
DNJ 1
Glucosidase inhibitor
* Corresponding author. Tel.: +353 1 7162504; e-mail: paul.v.murphy@
ucd.ie
Chart 1.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.070

6828
E. Danieli et al. / Tetrahedron 63 (2007) 6827–6834
achieving selective protection and deprotection strategies for
12 including an alternative preparation of 1 from L-sorbose.
group in less than 1 h at atmospheric pressure. The satisfac-
tory purification of 1 was achieved by chromatography using
an acid ion exchange resin (Dowex-50-X8) as the stationary
phase, which unlike the use of silica gel as stationary phase,
did not lead to loss of product. The overall yield of 1 using
this sequence of reactions was 30% in seven steps from
L-sorbose,17 and the sequence is suitable for preparation of
gram quantities of 1. Also the sequence used herein, where
selective alkylation of the 1-OH and 3-OH groups of sorbose
and subsequent formation of the piperidine are possible,
could, in principle, be used to regioselectively introduce
pharmacophoric groups to 1; however, this was not exploited
during the course of this study.
1
2. Results and discussion
Strategies where pharmacophoric groups can be introduced
at the desired position of an iminosugar could involve intro-
duction of the pharmacophoric group to a suitable precursor
followed by formation of the piperidine ring, or the synthesis
could begin from the iminosugar itself and involve both
chemo- and regioselective reactions of the amine and hy-
droxyl groups. The work described herein focuses more on
the latter approach and a practical synthesis of DNJ was thus
first required.13 Our group has developed a synthesis of DNJ
from 6-deoxy-hex-5-enopyranosyl azides but scale-up of this
route to provide multi-gram quantities of DNJ was not
practical and thus a novel approach was developed from
L-sorbose (Scheme 1). The bis-acetonide 3 was first pre-
pared14 and subsequent benzylation of the C-1 hydroxyl
group and regioselective hydrolysis of one acetonide group
gave the dihydroxylated derivative 4. A cyclic sulfite was
generated from the reaction of 4 with thionyl chloride and
reaction of this sulfite with sodium azide at 110 ꢀC in
DMF gave, after aqueous work-up and purification, the 6-
azido-L-sorbofuranose derivative 5.15 Hydrolysis of the ace-
tonide located at C-2 and C-3 hydroxyl groups promoted by
the acidic ion exchange resin Dowex-50-X8-100 (H+)16 gave
the 6-azido-1-O-benzylated sorbofuranose derivative 6. Cat-
alytic hydrogenation using Pd(OH)2 adsorbed on charcoal in
methanol led to formation of the 6-O-benzylated derivative 7
without any loss of the benzyl group occurring in these con-
ditions. Various attempts to convert 7 to 1 were investigated
by catalytic hydrogenation; this included using different cat-
alysts (Pd–C or Pd(OH)2–C), pressures (100 psi and 90 bar)
and temperatures (25–100 ꢀC), but the benzyl group could
not be removed. The addition of acetic acid to reaction mix-
tures led to degradation. Finally 7 was converted to 1 by cat-
alytic hydrogenolysis in methanol in the presence of HCl
(1.0–1.4 mol equiv), which facilitated removal of the benzyl
With gram quantities of 1 in hand, our attention turned to an
investigation of its selective protection and deprotection re-
actions. Firstly a Boc protecting group was introduced onto
the nitrogen atom of 1 and subsequent reaction of the prod-
uct with the dimethylacetal of anisaldehyde in acetonitrile in
the presence of a catalytic amount of camphorsulfonic acid
gave the benzylidene derivative 8 in good yield. Next a vari-
ety of reactions to differentiate the two secondary hydroxyl
groups of 8 were investigated. The most satisfactory of these
approaches was a regioselective benzoylation, which gave 9
via reaction of the dibutyltin ketal derivative obtained from 8
with benzoyl chloride. The main product, the 2-O-benzoyl-
ated derivative 9, was separated from a minor amount of the
3-O-benzoylated isomer (2-OBz–3-OBz 10:1) by chromato-
graphy. Other attempts at obtaining highly regioselective re-
actions were less successful. For example, the benzylation of
8 using dibutyltin oxide and benzyl bromide (1.1 equiv)18
gave a mixture of the two mono-benzylated ethers with low
regioselectivity (2-OBn–3-OBn, 1.4:1). The reaction of 8
with pivaloyl chloride (1 equiv) in presence of pyridine
gave a mixture of mono- and di-O-pivaloylated products,19
whereas the reaction of 8 with TIPSOTf in presence of 2,6-
lutidine gave either recovery of substantial amounts of
unreacted 8 (using 1.0 equiv TIPSOTf) or gave a mixture
of mono- and di-O-silylated products (using 1.5 equiv
TIPSOTf). Reaction of 9 was next investigated, given that
benzoylation was the most satisfactory approach and benzyl-
ation using benzyl bromide in presence of silver oxide gave
10 in 74% yield (Scheme 2).
1. BnBr, NaH,
OH
O
OBn
O
dry DMF, 0 °C,
2h
O
O
O
HO
2. 60% AcOH,
2h, 60 °C, 62%,
two steps
O
O
O
HO
Boc
N
1. (Boc)2O,
DMF, 15 h, 61%
3
O
4
1
OBn
O
1. SOCl2, py
O
2. CSA, CH3CN, 3h, 87%
O
OH
DOWEX 50X8
CH3CN/H2O
80 °C,2h, 92%
dry THF, 0 °C, 2h
OH
N3
HO
OMe
MeO
8
2. NaN3, DMF,
110 °C, 16 h,
82% two steps
O
MeO
OMe
1. Bu2SnO, dry MeOH,
reflux, then toluene
5
2. dry Et3N , BzCl,
dry CH2Cl2, 1.5 h, 86%
OBn
OH
O
H
O
20% Pd(OH)2-C,
H2, MeOH, 12h
Boc
Boc
N
N
O
N
O
N3
HO
BnBr, Ag2O
OH
4A MS, dry CH2Cl2
, 48 h, 74%
HO
OH
O
O
OBz
OBz
7
OH
6
OBn
OH
MeO
MeO
9
10
20% Pd(OH)2-C, H2,
HCl (1 mol eq.) MeOH
2h, 78% over two steps
Scheme 2.
Reactions of 10 were investigated (Scheme 3). The benzoyl
ester of 10 was hydrolysed selectively using potassium hy-
droxide in methanol to give 11 in high yield. Attempts to
1
Scheme 1.

E. Danieli et al. / Tetrahedron 63 (2007) 6827–6834
6829
Boc
N
selected hydroxyl groups of DNJ. In addition, a series of or-
thogonally protected DNJ derivatives are described and con-
ditions for the selective manipulation of three protecting
groups (N-Boc, methoxybenzylidene and Bz) are provided.
The approach has potential for synthesis of pharmacologi-
cally interesting structures, including glycosidase inhibitors
and peptidomimetics based on DNJ.
KOH, MeOH,
3h, 99%
O
10
O
OH
OBn
MeO
11
Me3NBH3,
TMSOTf,
AlCl3, CH2Cl2-
Et2O
2,6-lutidine,
dry CH2Cl2,
61%
0 °C, 30 min,
43%
Boc
N
H
N
3. Experimental section
3.1. General
O
O
HO
OBz
O
OBz
MeO
OBn
OBn
MeO
12
13
NMR spectra were recorded with a Varian 300, 400, 500 or
600 MHz spectrometers. Chemical shifts are reported rela-
tive to internal Me4Si in CDCl3 (d 0.0) or HOD for D2O (d
Scheme 3.
1
4.79) for H and D2O (d 77.16) for 13C. 13C signals were
effect selective cleavage of the methoxybenzylidene group of
10 using DIBAL-H were investigated but reductive hydroly-
sis of the benzoyl ester was a competing reaction. The reduc-
tive cleavage of the methoxybenzylidene group of 10, to give
the 6-O-methoxyphenylmethyl derivative 12, was achieved
in moderate yield using borane–trimethyl amine complex
in presence of aluminium trichloride at 0 ꢀC in dichloro-
methane–ether.20 The structure of this regioisomer was
assigned using COSY, which showed correlation between
the proton of the 4-hydroxyl group and the proton at C-4. A
selective deprotection of the Boc group of 10 using TMSOTf
and 2,6-lutidine21 gave amine 13, proving to be useful for the
chemoselective removal of the Boc group in presence of the
acid sensitive methoxybenzylidene group (Scheme 3).
1
assigned with the aid of DEPT-135. H NMR signals were
assigned with the aid of COSY. Mass spectra were recorded
on a Micromass LCT KC420 or Micromass Quattro. TLC
was performed on aluminium sheets precoated with Silica
Gel 60 (HF254, E. Merck) and spots visualised by UV and
charring with 1:20 H2SO4–EtOH. Chromatography was car-
ried out with Silica Gel 60 (0.040–0.630 mm, E. Merck) and
employed a stepwise solvent polarity gradient correlated
with the TLC mobility. Chromatography solvents used were
EtOAc (Riedel de Haen), cyclohexane and MeOH (Sigma–
Aldrich). Anhydrous DMF was used as purchased from
Sigma–Aldrich. THF, dichloromethane and methanol were
used as obtained from a Pure-SolvÔ solvent purification
system.
The allylation of 11 with sodium hydride and allyl bromide
gave 14 (Scheme 4). The chemoselective deprotection of the
Boc group of 14 using TMSOTf and 2,6-lutidine gave amine
15. The reaction of 11 with TIPSOTf in presence of 2,6-
lutidine gave 16 (53%) when the TIPSOTf was added por-
tionwise (total added was 4.5 equiv) during the course of
reaction (20 h). If all the TIPSOTf (4.0 equiv), which was re-
quired to ensure the complete conversion of 11 (TLC analy-
sis) to product, were added in one portion at the beginning of
the reaction then the exchange of the tert-butyl group for
TIPS was observed and the silyl carbamate 17 was isolated.22
3.1.1. 1-O-Benzyl-2,3:4,6-di-O-isopropylidene-a-L-
sorbofuranose. To 3 (35.92 g, 138 mmol) in dry DMF
(508 mL), NaH (60% dispersion in mineral oil, 11.06 g,
276 mmol) was added slowly at 0 ꢀC. Then benzyl bromide
(32.9 mL, 276 mmol) was added dropwise and the reaction
was allowed to stir at 0 ꢀC for 2 h. The mixture was then
poured into ice and the aqueous phase extracted with diethyl
ether (3ꢁ400 mL). The organic extracts were combined and
dried (MgSO4), filtered, the solvent was removed in vacuo
and the residue was purified by chromatography (EtOAc–
cyclohexane, 1:15, Rf 0.12) to afford the title compound
1
In summary, an alternative synthesis of DNJ in 30% overall
yield is described from L-sorbose that also offers the oppor-
tunity for strategic grafting of pharmacophoric groups at
as a colourless syrup (35.2 g, 73%); H NMR (400 MHz,
CDCl3) d 7.33 (m, 4H, aromatic H), 7.27 (m, 1H, aromatic
H), 4.72 (d, 1H, J ꢂ12.3 Hz, CH2Ph), 4.59 (d, 1H,
TMSOTf,
H
NaH, allyl bromide
Boc
2,6-lutidine,
N
DMF dry, rt, 1h,
N
O
dry CH2Cl2, 80%
99%
O
11
O
O
O
O
OBn
OBn
MeO
15
MeO
14
TIPSOTf 2,6-lutidine,
dry CH2Cl2
O
OTIPS
Boc
N
52%
O
N
O
O
OTIPS
O
OTIPS
OBn
OBn
MeO
17
MeO
16
Scheme 4.

6830
E. Danieli et al. / Tetrahedron 63 (2007) 6827–6834
J ꢂ12.3 Hz, CH2Ph), 4.51 (s, 1H, H-3), 4.31 (d, 1H, J4,5
2.2 Hz, H-4), 4.08 (m, 1H, H-5), 4.05 (dd, 1H, J6a,6b
ꢂ13.4 Hz, J6a,5 2.3 Hz, H-6a), 3.99 (d, 1H, J6a,6b
ꢂ13.4 Hz, H-6b), 3.80 (d, 1H, J1a,1b ꢂ10.9 Hz, H-1a),
3.73 (d, 1H, J1b,1a ꢂ10.9 Hz, H-1b), 1.52 (s, 3H, CH3),
1.42 (s, 3H, CH3), 1.41 (s, 3H, CH3), 1.29 (s, 3H, CH3);
13C NMR (100 MHz, CDCl3) d 138.4 (aromatic C), 128.5
(3ꢁC, aromatic CH), 127.8 (2ꢁd, aromatic CH), 114.3
(C), 112.5 (C), 97.5 (C), 84.5 (CH), 73.8 (CH2), 73.5
(CH), 72.3 (CH), 70.1 (CH2), 60.5 (CH2), 29.1 (C), 27.8
(CH3), 26.7 (CH3), 18.8 (CH3); ESI-HRMS: Calcd for
C19H27O6 351.1808; found m/z 351.1797 [M+H]+.
J6a,5 6.1 Hz, J6a,6b ꢂ12.8 Hz, H-6a), 3.49 (dd, 1H, J6b,5
7.1 Hz, J6b,6a ꢂ12.8 Hz, H-6b), 1.51 (s, 3H, CH3), 1.29 (s,
3H, CH3); 13C NMR (CDCl3, 100 MHz) d 136.4 (C), 129.0
(2ꢁCH), 128.6 (CH), 128.2 (2ꢁCH), 112.8 (2ꢁC), 86.8
(CH), 80.9 (CH), 74.7 (CH), 74.3 (CH2), 71.6 (CH2), 49.9
(CH2), 27.3 (CH3), 26.2 (CH3); ESI-HRMS: Calcd for
C16H21N3O5Na 358.1379, found m/z 358.1387 [M+Na]+.
3.1.4. 6-Azido-6-deoxy-1-O-benzyl-a-L-sorbofuranose 6.
To 5 (5.0 g, 14.9 mmol) in CH3CN–H2O (1:4, 500 mL) was
added Dowex-50-X8-100 (H+) (29 g) and the mixture was
stirred whilst heating at reflux for 3 h. The solvent was then
evaporated under diminished pressure and the residue was
purified by column chromatography (EtOAc–cyclohexane,
3:7 then 1:1, Rf ¼0.28) to afford 6 as a white solid (4.1 g,
92%); 1H NMR (CDCl3, 500 MHz) d 7.38–7.31 (m, 5H, aro-
matic H), 4.63 (2ꢁd, 2H, J ꢂ11.8 Hz, CH2Ph), 4.35 (dd, 1H,
J5,6a 5.0 Hz, J5,6b 5.9 Hz, J5,4 10.7 Hz, H-5), 4.12 (m, 1H,
H-4), 4.04 (s, 1H, H-3), 3.67 (d, 1H, J1a,1b ꢂ9.9 Hz, H-1a),
3.61 (d, 1H, J1b,1a ꢂ9.9 Hz, H-1b), 3.51 (dd, 1H, J6a,5
5.1 Hz, J6a,6b ꢂ12.9 Hz, H-6a), 3.46 (dd, 1H, J6b,5 6.0 Hz,
J6b,6a ꢂ12.9 Hz, H-6b), 3.42 (d, 1H, JOH,4 9.6 Hz, OH),
2.82 (br s, 1H, OH); 13C NMR (CDCl3, 75 MHz) d 136.5
(C), 128.5 (2ꢁCH), 128.1 (CH), 127.9 (2ꢁCH), 102.3 (C),
78.2 (CH), 78.1 (CH), 76.7 (CH), 72.4 (CH2), 73.8 (CH2),
50.2 (CH2). ESI-HRMS: Calcd for C13H17N3O5Na
318.1066, found m/z 318.1060 [M+Na]+.
3.1.2. 1-O-Benzyl-2,3-O-isopropylidene-a-L-sorbofura-
nose 4. To 1-O-benzyl-2,3:4,6-di-O-isopropylidene-a-L-sor-
bofuranose (35.15 g, 100.3 mmol), aqueous AcOH (60%,
576 mL) was added. The mixture was stirred at 60 ꢀC for
2 h. The solvent was then removed under diminished pres-
sure and the residue purified by column chromatography
(EtOAc–cyclohexane, 2:3, Rf 0.23) to afford 4 as a white
1
solid (26.64 g, 85%); H NMR (CDCl3, 400 MHz) d 7.40–
7.31 (m, 5H, aromatic H), 4.68 (d, 1H, J ꢂ11.6 Hz,
CH2Ph), 4.60 (d, 1H, J ꢂ11.6 Hz, CH2Ph), 4.43 (s, 1H, H-
3), 4.36 (dt, 1H, J5,4 2.9 Hz, J5,6a 5.2 Hz, J5,4 5.2 Hz, H-5),
4.17 (dd, 1H, J4,5 2.9 Hz, J4,OH 10.9 Hz, H-4), 3.93 (m,
2H, H-6), 3.84 (d, 1H, J1a,1b ꢂ10.0 Hz, H-1a), 3.73 (d, 1H,
JOH,4 10.9 Hz, OH), 3.64 (d, 1H, J1a,1b 10.0 Hz, H-1b),
1.51 (s, 3H, CH3), 1.31 (s, 3H, CH3); 13C NMR (CDCl3,
100 MHz) d 136.8 (C), 128.9 (2C), 128.5 (CH), 128.2
(2CH), 112.8 (C), 112.6 (C), 87.1 (CH), 82.0 (CH), 75.7
(CH), 74.3 (CH2), 71.7 (CH2), 61.6 (CH2), 27.4 (CH3),
26.3 (CH3); ESI-HRMS: Calcd for C16H22O6Na 333.1314,
found m/z 333.1328 [M+Na]+.
3.1.5. 1,5-Dideoxy-1,5-imino-D-glucitol 1. Sorbose deriva-
tive 6 (2.78 g, 9.41 mmol) was dissolved in MeOH
(110 mL), and Pd(OH)2–C 20% (670 mg) was added; the re-
action mixture was stirred under an atmosphere of hydrogen
(1 atm) at room temperature for 12 h. Filtration and removal
of solvent gave a residue containing 6-O-benzyl-1,5-di-
deoxy-1,5-imino-D-glucitol. The residue was then dissolved
in MeOH (110 mL) and a 1.2 M methanolic solution of HCl
(11.2 mL) was then added and the resulting mixture was
stirred at room temperature under hydrogen (1 atm) for
2 h. The reaction mixture was then filtered through Celite
and evaporated in vacuo. The residue was dissolved in
1.0 M methanolic solution of HCl (28 mL) and the solvent
was evaporated. The residue, dissolved in H2O, was intro-
duced to a Dowex-50W-X8-100 (H+) packed ion-exchange
column (pre-washed with MeOH and H2O), washed with
water (200 mL) and MeOH (100 mL) and then the product
was eluted with 0.6 M aqueous solution of NH4OH. The
combined pure fractions were evaporated in vacuo to give
1 (1.28 g, 84%) as a pale orange solid. The NMR data of
the free amine 1 were in excellent agreement to those re-
ported in literature;23 1H NMR (D2O, 400 MHz) d 3.70
(dd, 1H, J6a,5 2.9 Hz, J6a,6 ꢂ11.6 Hz, H-6a), 3.50 (dd, 1H,
J6b,5 6.3 Hz, J6a,6b ꢂ11.6 Hz, H-6b), 3.36 (ddd, 1H, J2,1b
5.2 Hz, J2,3 9.1 Hz, J2,1a 10.8 Hz, H-2), 3.19 (t, 1H, J3,4
9.0 Hz, J3,2 9.1 Hz, H-3), 3.10 (dd, 1H, J4,3 9.5 Hz, J4,5
9.4 Hz, H-4), 2.98 (dd, 1H, J1b,2 5.2 Hz, J1b,1a ꢂ12.3 Hz,
H-1b), 2.41 (ddd, 1H, J5,6a 2.9 Hz, J5,6b 6.3 Hz, J5,4
9.4 Hz, H-5), 2.33 (dd, 1H, J1a,2 10.8 Hz, J1a,1b ꢂ12.3 Hz,
H-1a); 13C NMR (D2O, 100 MHz) d 79.4, 72.7, 72.1 (each
CH), 62.8 (CH2), 61.9 (CH), 50.4 (CH2).
3.1.3. 6-Azido-6-deoxy-1-O-benzyl-2,3-O-isopropyl-
idene-a-L-sorbofuranose 5. To 4 (16.8 g, 54.2 mmol) in
dry THF (180 mL) was added dry pyridine (10.5 mL,
130 mmol). The reaction mixture was stirred at 0 ꢀC, and
SOCl2 (4.73 mL, 65.0 mmol) in dry THF (23 mL) was added
dropwise and then the reaction mixture was stirred at 0 ꢀC for
2 h. The solution was then filtered through Celite and washed
with cold THF. The solvent was removed under diminished
pressure and the crude product was dissolved in dichlorome-
thane (300 mL) and washed with H2O (300 mLꢁ3). The
organic layer was then dried (MgSO4), filtered and the sol-
vent was removed under diminished pressure, whilst keeping
the temperature of the water bath below 35 ꢀC, and the resi-
due dissolved in DMF (300 mL). Sodium azide (10.6 g,
163 mmol) was then added and the reaction mixture was
stirred at 110 ꢀC overnight. The DMF was removed under
diminished pressure and the residue dissolved in Et2O
(200 mL), washed with water (150 mLꢁ3) and the organic
layer was dried (MgSO4), filtered, and the solvent was then
removed under diminished pressure. The residue was
purified by column chromatography (EtOAc–cyclohexane,
1
1:5, Rf 0.17) to afford 5 as a white solid (15 g, 82%); H
NMR (CDCl3, 500 MHz) d 7.39–7.38 (m, 2H, aromatic H),
7.37–7.31 (m, 3H, aromatic H), 4.67 (d, 1H, J ꢂ11.8 Hz,
CH2Ph), 4.60 (d, 1H, J ꢂ11.8 Hz, CH2Ph), 4.43 (s, 1H,
H-3), 4.35 (ddd, 1H, J5,4 2.5 Hz, J5,6a 6.1 Hz, J5,6b 7.1 Hz,
H-5), 4.07 (dd, 1H, J4,5 2.5 Hz, J4,OH 11.9 Hz, H-4), 3.83
(d, 1H, J1a,1b ꢂ9.9 Hz, H-1a), 3.61 (d, 1H, J1a,1b ꢂ9.9 Hz,
H-1b), 3.55 (d, 1H, JOH,4 ꢂ11.9 Hz, OH), 3.53 (dd, 1H,
3.1.6. N-(tert-Butoxycarbonyl)-1,5-dideoxy-1,5-imino-D-
glucitol. To 1 (306 mg, 1.9 mmol) in DMF (4.5 mL),
Boc2O (495 mg, 2.27 mmol) was added and the mixture

E. Danieli et al. / Tetrahedron 63 (2007) 6827–6834
6831
was stirred at room temperature overnight. The solvent was
then evaporated under diminished pressure and the residue
was purified by flash column chromatography (CH2Cl2–
MeOH, 14:1) to give the title compound (303 mg, 61%) as
4.5 Hz, J6a,6b ꢂ11.1 Hz, H-6a), 4.13 (dd, 1H, J6a,6b
ꢂ11.1 Hz, J6b,5 10.6 Hz, H-6b), 4.00–3.95 (m, 2H, H-1a,
H-3), 3.83 (d, 1H, J4,5 10.2 Hz, H-4), 3.80 (s, 3H, CH3),
3.49 (dd, 1H, J1b,2 7.9 Hz, J1b,1a ꢂ14.5 Hz, H-1b), 3.44
(dt, 1H, J5,6a 4.6 Hz, J5,4 10.2 Hz, J5,6b 10.4 Hz, H-5), 2.82
1
a white solid; H NMR (CD3OD, 600 MHz) d 4.10 (dd,
t
1H, J5,6b 5.6 Hz, J5,6b 9.3 Hz, H-5), 3.90 (d, 1H, J1a,1b
ꢂ13.9 Hz, H-1a), 3.80 (dd, 1H, J6a,5 9.3 Hz, J6a,6b
ꢂ11.4 Hz, H-6a), 3.77 (dd, 1H, J6b,5 5.6 Hz, J6b,6a ꢂ11.4 Hz,
H-6b), 3.75 (m, 1H, H-4), 3.66 (m, 2H, H-2, H-3), 3.38
(dd, 1H, J1b,2 1.8 Hz, J1b,1a ꢂ13.9 Hz, H-1b), 1.47 (s, 9H,
tBu); 13C NMR (CD3OD, 150 MHz) d 158.2 (C), 81.4 (C),
72.4, 71.5, 70.6 (each CH), 61.3 (CH2), 61.2 (CH), 44.3
(CH2), 28.8 (3ꢁCH3). ESI-HRMS: Calcd for C11H20NO6
262.1291, found m/z 262.1280 [MꢂH]ꢂ.
(br s, 1H, OH), 1.44 (s, 9H, Bu); 13C NMR (CDCl3,
75 MHz) d 170.2, 165.8, 160.3, 155.0 (each C), 133.4
(CH), 129.8 (2ꢁCH), 129.6 (C), 128.4 (2ꢁCH), 127.6
(2ꢁCH), 113.7 (2ꢁCH), 101.9 (CH), 81.2 (C), 80.1, 74.2,
73.9 (each CH), 69.8 (CH2), 55.3 (CH3), 52.6 (CH), 44.8
(CH2), 28.3 (3ꢁCH3); ESI-HRMS: Calcd for C26H32NO8
486.2128, found m/z 486.2133 [M+H]+.
3.1.9. 2-O-Benzoyl-3-O-benzyl-N-tert-butoxycarbonyl-
1,5-dideoxy-1,5-imino-4,6-O-(4-methoxybenzylidene)-D-
glucitol 10. To 9 (338 mg, 0.7 mmol) in dry CH2Cl2
3.1.7. N-tert-Butoxycarbonyl-1,5-dideoxy-1,5-imino-4,6-
O-[4-methoxybenzylidene]-D-glucitol 8. N-tert-Butoxy-
˚
(3.5 mL), in the presence of 4A molecular sieves and under
a nitrogen atmosphere, was added Ag2O (480 mg,
carbonyl-1,5-dideoxy-1,5-imino-D-glucitol
(200 mg,
0.76 mmol), camphorsulfonic acid (4.2 mg) and anisalde-
hyde dimethylacetal (258 mL, 1.5 mmol) in MeCN (4 mL)
were stirred for 2 h at room temperature. Triethylamine
(4 mL) was added and the solution was stirred for a further
30 min, the solvent was removed under diminished pressure
and the residue purified by flash column chromatography
(EtOAc–cyclohexane, 1:1) to give 8 (251 mg, 87%) as
2.1 mmol) and benzyl bromide (166 mL, 1.4 mmol) drop-
wise. The mixture was stirred at room temperature for 48 h
and was then filtered through Celite and the solvent was
evaporated under diminished pressure and chromatography
of the residue (EtOAc–cyclohexane, 1:7) gave 10 as a white
solid (295 mg, 74%); 1H NMR (CDCl3, 500 MHz) d 7.98 (d,
2H, J 8.0 Hz, aromatic H), 7.57 (t, 1H, J 7.3 Hz, aromatic H),
7.43 (d, 2H, J 8.8 Hz, aromatic H), 7.42 (dd, 2H, J 7.4,
8.1 Hz, aromatic H), 7.32 (m, 2H, aromatic H), 7.25–7.23
(m, 3H, aromatic H), 6.91 (d, 2H, J 8.8 Hz, aromatic H),
5.59 (s, 1H, benzylidene H), 5.20 (ddd, 1H, J2,1b 3.0 Hz,
J2,1a 3.5 Hz, J2,3 6.0 Hz, H-2), 4.85 (dd, 1H, J6a,5 4.3 Hz,
J6a,6b ꢂ10.4 Hz, H-6a), 4.82 (s, 2H, CH2Ph), 4.03 (dd, 1H,
J4,3 8.5 Hz, J4,5 10.5 Hz, H-4), 3.96 (t, 1H, J6b,5 10.2 Hz,
J6b,6a ꢂ10.4 Hz, H-6b), 3.82 (s, 3H, OMe), 3.80–3.76 (m,
2H, H-1a, H-3), 3.72 (dd, 1H, J1b,2 3.0 Hz, J1b,1a
ꢂ14.2 Hz, H-1b), 3.54 (ddd, 1H, J5,6a 4.3 Hz, J5,6b 10.2 Hz,
1
a white solid; H NMR (CDCl3, 500 MHz) d 7.41 (d, 2H,
J 8.7 Hz, aromatic H), 6.90 (d, 2H, J3,2 8.7 Hz, aromatic
H), 5.51 (s, 1H, benzylidene CH), 4.77 (dd, 1H, J6a,5
4.6 Hz, J6a,6b ꢂ11.5 Hz, H-6a), 4.40 (dd, 1H, J6b,5
10.8 Hz, J6b,6a ꢂ11.2 Hz, H-6b), 4.28 (dd, 1H, J1,2 4.9 Hz,
J1a,1b ꢂ13.4 Hz, H-1a), 3.81 (s, 3H, OMe), 3.65 (m, 1H,
H-2), 3.56 (m, 2H, H-3, H-4), 3.19 (ddd, 1H, J5,6a 4.6 Hz,
J5,6b 10.2 Hz, J5,4 9.8 Hz, H-5), 2.73 (br s, 1H, OH), 2.69
(dd, 1H, J1b,2 10.5 Hz, J1b,1a ꢂ13.4 Hz, H-1b), 2.46 (br s,
t
1H, OH), 1.46 (s, 9H, Bu); 13C NMR (CDCl3, 100 MHz)
t
d 160.4, 154.4, 130.1 (each C), 127.9 (2ꢁCH), 113.9
(2ꢁCH), 101.7 (CH), 81.4 (C), 80.4 (CH), 77.2 (CH), 69.9
(CH2), 69.7 (CH), 55.5 (CH3), 55.0 (CH), 49.5 (CH2), 28.6
(3ꢁCH3). ESI-HRMS: Calcd for C19H28NO7 382.1866,
found m/z 382.1884 [M+H]+.
J5,4 10.5 Hz, H-5), 1.40 (s, 9H, Bu); 13C NMR (CDCl3,
75 MHz) d 165.2, 160.0, 155.7, 137.9 (each C), 133.3
(CH), 130.1 (C), 129.8 (2ꢁCH), 129.6 (C), 128.4 (2ꢁCH),
128.3 (2ꢁCH), 128.0 (2ꢁCH), 127.7 (CH), 127.4
(2ꢁCH), 113.6 (2ꢁCH), 101.4 (CH), 81.1 (C), 80.3 (CH),
79.8 (CH), 73.1 (CH2), 72.5 (CH), 70.3 (CH2), 55.3 (CH3),
51.3 (CH), 43.9 (CH2), 28.2 (3ꢁCH3). ESI-HRMS: Calcd
for C33H38NO8 576.2597, found m/z 576.2584 [M+H]+.
3.1.8. 2-O-Benzoyl-N-tert-butoxycarbonyl-1,5-dideoxy-
1,5-imino-4,6-O-(4-methoxybenzylidene)-D-glucitol 9.
Benzylidene 8 and Bu2SnO were pre-dried under vacuum
over KOH overnight. Then to a mixture of 8 (700 mg,
1.8 mmol) and Bu2SnO (914 mg, 3.7 mmol), under a nitro-
gen atmosphere, was added MeOH (7 mL, pre-dried over
3.1.10. 3-O-Benzyl-N-tert-butoxycarbonyl-1,5-dideoxy-
1,5-imino-4,6-O-[4-methoxybenzylidene]-D-glucitol 11.
To 10 (150 mg, 0.26 mmol) in MeOH (4.0 mL), was added
KOH in MeOH (40 mg in 4.3 mL, 0.71 mmol) and the mix-
ture was stirred at room temperature for 3 h. Amberlite IR-
120 (H+) was then added until the solution was neutral.
The mixture was then filtered and the solvent evaporated.
The residue was purified by chromatography (EtOAc–cyclo-
hexane, 1:3 then 1:1) to give 11 (123 mg, 99%) as a white
solid; 1H NMR (CDCl3, 500 MHz) d 7.43 (d, 2H, J 8.7 Hz,
aromatic H), 7.35 (m, 4H, aromatic H), 7.32 (m, 1H, aro-
matic H), 6.92 (d, 2H, J 8.7 Hz, aromatic H), 5.58 (s, 1H,
benzylidene H), 5.00 (d, 1H, J ꢂ11.6 Hz, CH2Ph), 4.76
(dd, 1H, J6a,5 4.5 Hz, J6a,6b ꢂ11.1 Hz, H-6a), 4.71 (d, 1H,
J ꢂ11.6 Hz, CH2Ph), 4.44 (dd, 1H, J6b,5 10.5 Hz, J6b,6a
ꢂ11.1 Hz, H-6b), 4.19 (dd, 1H, J1a,2 4.8 Hz, J1a,1b
ꢂ13.4 Hz, H-1a), 3.83 (s, 3H, OMe), 3.84–3.80 (m, 1H,
H-4), 3.66 (m, 1H, H-2), 3.48 (dd, 1H, J3,2 8.1 Hz, J3,4
8.3 Hz, H-3), 3.26 (ddd, 1H, J5,6a 4.5 Hz, J5,6b 10.5 Hz,
˚
4A molecular sieves) and the mixture was heated at reflux
overnight. The volatile materials were then evaporated and
toluene was evaporated from the residue (ꢁ2). The residue
was dissolved in anhydrous CH2Cl2 (7 mL) and placed un-
der a nitrogen atmosphere. Dry Et3N (291 mL, 2.09 mmol)
and BzCl (213 mL, 1.836 mmol) were then added and the
mixture was stirred for 1.5 h at room temperature. Aqueous
NaHCO3 was then added, the organic layer washed with
brine, dried (MgSO4), filtered and the solvent removed under
diminished pressure. Chromatography of the residue
(EtOAc–cyclohexane, 1:6) gave 9 (770 mg, 86%) as a white
solid; 1H NMR (CDCl3, 500 MHz) d 8.03 (d, 2H, J 8.5 Hz,
aromatic H), 7.57 (t, 1H, J 7.5 Hz, aromatic H), 7.44 (dd,
2H, J 7.9, 8.5 Hz, aromatic H), 7.43 (d, 2H, J 8.5 Hz, aro-
matic H), 6.86 (d, 2H, J 8.5 Hz, aromatic H), 5.56 (s, 1H,
benzylidene H), 5.05 (m, 1H, H-2), 4.79 (dd, 1H, J6a,5

6832
E. Danieli et al. / Tetrahedron 63 (2007) 6827–6834
J5,4 10.1 Hz, H-5), 2.79 (dd, 1H, J1b,2 10.1 Hz, J1b,1a
1H, H-3), 3.83 (s, 3H, OMe), 3.73–3.67 (overlapping of sig-
nals, 2H, H-4 and H-6b), 3.50 (dd, 1H, J1a,2 5.3 Hz, J1a,1b
ꢂ13.6 Hz, H-1a), 2.88 (dt, 1H, J5,6a 4.4 Hz, J 9.2, 9.2 Hz,
H-5), 2.72 (dd, 1H, J1b,2 10.8 Hz, J1b,1a ꢂ12.0 Hz, H-1b);
13C NMR (CDCl3, 100 MHz) d 165.9, 160.2, 138.4 (each
CH), 133.4 (CH), 130.3 (C), 130.0 (2ꢁCH), 128.6
(2ꢁCH), 128.4 (2ꢁCH), 128.3 (2ꢁCH), 127.8 (CH),
127.5 (2ꢁCH), 113.8 (2ꢁCH), 101.5 (CH), 83.9 (CH),
80.1 (CH), 76.7 (C), 74.8 (CH2), 73.3 (CH), 69.8 (CH2),
55.5 (CH3), 54.1 (CH), 48.0 (CH2). ESI-HRMS: Calcd for
C28H30NO6 476.1995, found m/z 476.2579 [M+H]+.
t
ꢂ13.4 Hz, H-1b), 2.29 (br s, 1H, OH), 1.47 (s, 9H, Bu);
13C NMR (CDCl3, 125 MHz) d 160.3, 154.6, 138.6, 130.4
(each s), 128.8 (2ꢁCH), 128.3 (2ꢁCH), 128.2 (CH), 127.5
(2ꢁCH), 113.9 (2ꢁCH), 101.2 (CH), 84.6 (CH), 81.3 (CH),
81.2 (C), 75.0 (CH2), 70.0 (C), 69.6 (CH), 55.5 (CH), 55.3
(C), 49.3 (CH2), 28.6 (3ꢁCH3); ESI-HRMS: Calcd for
C26H34NO7 472.2335, found m/z 472.2354 [M+H]+.
3.1.11. 2-O-Benzoyl-3-O-benzyl-N-tert-butoxycarbonyl-
1,5-dideoxy-1,5-imino-6-O-[4-methoxybenzyl]-D-glucitol
12. A suspension of AlCl3 (185 mg, 1.39 mmol) in ether
(2.1 mL) was added, over 15 min, to a stirred mixture of
10 (200 mg, 0.35 mmol), Me3NBH3 (152 mg, 2.1 mmol)
3.1.13. 2-O-Allyl-3-O-benzyl-N-tert-butoxycarbonyl-1,5-
dideoxy-1,5-imino-4,6-O-[4-methoxybenzylidene]-D-glu-
citol 14. To 11 (150 mg, 0.32 mmol) in dry DMF (10 mL)
was added portionwise, at 0 ꢀC, sodium hydride (60% min-
eral oil, 25 mg, 0.64 mmol) and the mixture was stirred for
a few minutes and then allyl bromide (41 mL, 0.48 mmol)
was added dropwise. The mixture was allowed to attain
room temperature and was then stirred under a nitrogen at-
mosphere for 1 h. A few drops of methanol were added
and the solvent was evaporated under diminished pressure
and the residue purified by column chromatography
(EtOAc–cyclohexane, 1:4) to give 14 (163 mg, >99%) as
˚
and 4A molecular sieves in CH2Cl2 (7 mL) and ether
(1.4 mL) at 0 ꢀC. The mixture was then stirred for 30 min
at 0 ꢀC and then filtered through Celite and washed with
aqueous NaHCO3 and water. The organic phase was dried
(MgSO4) and the solvent was removed under diminished
pressure and the residue purified by column chromatography
(EtOAc–cyclohexane, 1:5) to give 12 as a colourless oil
1
(86 mg, 43%); H NMR (CDCl3, 400 MHz) d 7.98 (d, 2H,
J 8.2 Hz, aromatic H), 7.57 (t, 1H, J 7.5 Hz, aromatic H),
7.43 (dd, 2H, J 7.5, 8.2 Hz aromatic H), 7.33–7.28 (m, 5H,
aromatic H), 7.22 (d, 2H, J 8.6 Hz, aromatic H), 6.86 (d,
2H, J 8.6 Hz, aromatic H), 5.14 (m, 1H, H-2), 4.70 (d, 1H,
J ꢂ11.7 Hz, CH(H)2Ar), 4.64 (d, 1H, J ꢂ11.7 Hz,
CH(H)Ar), 4.49 (d, 1H, J ꢂ11.6 Hz, C(H)HAr), 4.43 (d,
1H, J ꢂ11.6 Hz, CH(H)2Ar), 4.34 (dd, 1H, J5,4 11.2 Hz,
J5,6b 5.8 Hz, H-5), 4.25 (d, 1H, J1a,1b ꢂ15.1 Hz, H-1a),
4.07 (dd, 1H, J4,OH 6.0 Hz, J4,5 11.2 Hz, H-4), 3.80 (s, 3H,
CH3), 3.81–3.77 (overlapping of signals, 2H, H-6a, H-3),
3.70 (dd, 1H, J6b,5 5.8 Hz, J6b,6a ꢂ10.0 Hz, H-6b), 3.36
(dd, 1H, J1b,2 2.6 Hz, J1b,1a ꢂ15.1 Hz, H-1b), 2.66 (d, 1H,
1
a colourless oil; H NMR (CDCl3, 500 MHz) d 7.42 (d,
2H, J 8.7 Hz, aromatic H), 7.35 (d, 2H, J 7.0 Hz, aromatic
H), 7.32–7.28 (m, 3H, aromatic H), 6.90 (d, 2H, J 8.7 Hz,
aromatic H), 5.89 (ddt, 1H, J 5.5, 5.5, 10.5, 16 Hz, allyl CH),
5.54 (s, 1H, benzylidene H), 5.28 (dd, 1H, J 1.4, 16.0 Hz, al-
lyl CH(H)), 5.17 (dd, 1H, J 1.4, 10.5 Hz, allyl CH(H)), 4.82
(d, 1H, J ꢂ11.5 Hz, C(H)HPh), 4.75 (d, 1H, J ꢂ11.5 Hz,
C(H)HPh), 4.74 (dd, 1H, J6a,5 4.5 Hz, J6a,6b ꢂ11.0 Hz, H-
6a), 4.12 (dd, 1H, J 5.5, ꢂ12.5 Hz, allyl C(H)HO), 4.06
(dd, 1H, J6b,5 10.5 Hz, J6b,6a ꢂ11.0 Hz, H-6b), 4.31 (dd,
1H, J 5.5, 12.5 Hz, allyl C(H)HO), 3.84 (dd, 1H, J4,3
8.5 Hz, J4,5 10.5 Hz, H-4), 3.81 (s, 3H, OMe), 3.73 (dd,
1H, J1a,2 3.0 Hz, J1a,1b ꢂ14.0 Hz, H-1a), 3.61 (dd, 1H, J3,2
5.0 Hz, J3,4 8.5 Hz, H-3), 3.51 (m, 1H, H-2), 3.36 (dt, 1H,
J5,6a 4.5 Hz, J5,4 10.5 Hz, J5,6b 10.5 Hz, H-5), 3.35 (d, 1H,
t
JOH,4 6.0 Hz, OH), 1.29 (s, 9H, Bu); 13C NMR (CDCl3,
100 MHz) d 164.4, 158.2, 154.3, 136.5 (each C), 132.4
(CH), 129.2 (2ꢁC), 128.7 (2ꢁCH), 128.2 (2ꢁCH), 127.5
(2ꢁCH), 127.5 (2ꢁCH), 126.9 (C), 126.7 (2ꢁCH), 112.8
(2ꢁCH), 79.1 (C), 77.1 (CH2), 71.7 (2ꢁCH2), 71.6 (CH),
66.6 (CH), 66.2 (CH), 55.6 (CH), 54.2 (CH3), 40.2 (CH2),
27.1 (3ꢁCH3). ESI-HRMS: Calcd for C33H40NO8
578.2754, found m/z 578.2759 [M+H]+.
t
J1b,1a ꢂ13.8 Hz, H-1b), 1.46 (s, 9H, Bu); 13C NMR
(CDCl3, 100 MHz) d 158.9, 154.2 (each C), 137.4 (CH),
133.5 (C), 129.2 (C), 127.3 (2ꢁCH), 126.9 (2ꢁCH), 126.6
(CH), 126.3 (2ꢁCH), 116.0 (CH2), 112.5 (2ꢁCH), 100.1
(CH), 81.2 (CH), 79.8 (CH), 79.7 (C), 76.3 (CH), 72.9
(CH2), 69.5 (CH2), 69.1 (CH2), 54.2 (CH3), 51.4 (CH),
43.7 (CH2), 27.3 (3ꢁCH3); ESI-HRMS: Calcd for
C29H38NO7 512.2648, found m/z 512.2628 [M+H]+.
3.1.12. 2-O-Benzoyl-3-O-benzyl-1,5-dideoxy-1,5-imino-
4,6-O-[4-methoxybenzylidene]-D-glucitol 13. To 10
(50 mg, 0.09 mmol) in CH2Cl2 (1 mL) were added, under
a nitrogen atmosphere and at 0 ꢀC, 2,6-lutidine (60 mL,
0.54 mmol) and, dropwise, TMSOTf (36 mL, 0.2 mmol).
The mixture was allowed to attain room temperature and
was stirred for 12 h and then poured into aqueous NaHCO3
and then extracted with CH2Cl2 (ꢁ2). The combined organic
layers were washed with brine, dried (MgSO4) and the sol-
vent was evaporated under diminished pressure. The residue
was purified by column chromatography (EtOAc–cyclohex-
ane, 1:3) to give 13 (25 mg, 61%) as a white solid; 1H NMR
(CDCl3, 400 MHz) d 7.97 (d, 2H, J 7.8 Hz, aromatic H), 7.58
(t, 1H, J 7.2 Hz, aromatic H), 7.45 (d, 2H, J 8.8 Hz, aromatic
H), 7.44 (dd, 2H, J 6.8, 8.2 Hz, aromatic H), 7.25–7.14 (m,
5H, aromatic H), 6.92 (d, 2H, J 8.8 Hz, aromatic H), 5.59
(s, 1H, benzylidene H), 5.15 (ddd, 1H, J2,1a 5.5 Hz, J2,3
10.4 Hz, J2,1b 10.8 Hz, H-2), 4.88 (d, 1H, J ꢂ11.8 Hz,
C(H)HPh), 4.77 (d, 1H, J ꢂ11.8 Hz, C(H)HPh), 4.32 (dd,
1H, J6a,5 4.4 Hz, J6a,6b ꢂ10.4 Hz, H-6a), 3.87–3.80 (m,
3.1.14. 2-O-Allyl-3-O-benzyl-1,5-dideoxy-1,5-imino-4,6-
O-[4-methoxybenzylidene]-D-glucitol 15. To 14 (313 mg,
0.618 mmol) in dry CH2Cl2 (15 mL), under a nitrogen atmo-
sphere at 0 ꢀC, were added 2,6-lutidine (423 mL, 3.65 mmol)
and TMSOTf (232 mL, 1.24 mmol) dropwise. The mixture
was stirred at room temperature overnight and was then
poured into aqueous NaHCO3 and extracted with CH2Cl2.
The organic layer was washed with brine, dried (MgSO4)
and the solvent was removed under diminished pressure.
The crude was purified by column chromatography
(EtOAc–cyclohexane, 1:2 then 3:1), to give 15 (204 mg,
80%) as a colourless oil; 1H NMR (CDCl3, 600 MHz)
d 7.42 (d, 2H, J 8.4 Hz, aromatic H), 7.38 (d, 2H, J
7.4 Hz, aromatic H), 7.30 (dd, 2H, J 6.6, 7.7 Hz, aromatic
H), 7.27–7.24 (m, 1H, aromatic H), 6.9 (d, 2H, J 8.4 Hz,

E. Danieli et al. / Tetrahedron 63 (2007) 6827–6834
6833
aromatic H), 5.92 (ddt, 1H, J 6.0, 6.0, 10.6, 16.2 Hz, allyl
Supplementary data
CH), 5.53 (s, 1H, benzylidene H), 5.29 (dd, 1H, J 1.2,
16.8 Hz, allyl C(H)H), 5.18 (dd, 1H, J 1.2, 10.4 Hz, allyl
CH(H)), 4.91 (d, 1H, J ꢂ11.4 Hz, C(H)HPh), 4.81 (d, 1H,
J ꢂ11.4 Hz, CH(H)Ph), 4.24 (dd, 1H, J6a,5 4.2 Hz, J6a,6b
ꢂ10.8 Hz, H-6a), 4.23 (dd, 1H, J 6.0, ꢂ12.6 Hz, allyl
OCH(H)), 4.16 (dd, 1H, J 6.0, ꢂ12.6 Hz, allyl OCH(H)),
3.82 (s, 3H, OMe), 3.61 (dd, 1H, J6b,5 10.2 Hz, J6b,6a
ꢂ10.8 Hz, H-6b), 3.60 (dd, 1H, J3,2 7.2 Hz, J3,4 7.8 Hz, H-
3), 3.50 (dd, 1H, J4,3 8.7 Hz, J4,5 9.0 Hz, H-4), 3.46 (ddd,
1H, J2,1a 5.4 Hz, J2,3 8.3 Hz, J2,1b 10.8 Hz, H-2), 3.30 (dd,
1H, J1a,2 5.4 Hz, J1a,1b ꢂ12.0 Hz, H-1a), 2.75 (ddd, 1H,
J5,6a 4.2 Hz, J5,4 9.6 Hz, J5,6b 11.8 Hz, H-5), 2.60 (dd, 1H,
J1b,2 10.8 Hz, J1b,1a ꢂ12.0 Hz, H-1b), 1.61 (br s, 1H, NH);
13C NMR (CDCl3, 100 MHz) d 160.2, 139.1, 135.2 (each
C), 135.2 (CH), 130.6 (C), 128.5 (2ꢁCH), 128.2 (2ꢁCH),
127.7 (CH), 127.5 (2ꢁCH), 117.2 (CH2), 113.8 (CH),
101.4 (CH), 83.7 (CH), 83.5 (CH), 79.4 (CH), 75.4 (CH2),
72.5 (CH2), 70.1 (CH2), 55.5 (CH3), 54.2 (CH), 49.2
(CH2). ESI-HRMS: Calcd for C24H30NO5 412.2124, found
m/z 412.2138 [M+H]+.
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.04.070.
References and notes
1. Asano, N.; Nash, R. J.; Molyneaux, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 1645–1680.
2. For reviews on glycosidase inhibition, see: Refs. 1,3 and (a)
Ganem, B. Acc. Chem. Res. 1996, 29, 340–347; (b)
Heightman, T. D.; Vasella, A. T. Angew. Chem., Int. Ed.
1999, 38, 750–770; (c) Lillelund, V. H.; Jensen, H. H.; Liang,
X.; Bols, M. Chem. Rev. 2002, 102, 515–553; (d) Greimel, P.;
Spreitz, J.; Stutz, A. E.; Wrodnigg, T. M. Curr. Top. Med.
Chem. 2003, 3, 513–523.
3. For a recent review on iminosugar based glycosyltransferase
inhibitors, see: Compain, P.; Martin, O. R. Curr. Top. Med.
Chem. 2003, 3, 541–560.
4. Kingma, P. J.; Menheere, P. P.; Sels, J. A.; Nieuwenhuijzen
Kruseman, A. C. Diabetes Care 1992, 15, 478–483.
5. (a) Hughes, A. B.; Rudge, A. J. Nat. Prod. Rep. 1994, 135–
162; (b) Winchester, B.; Fleet, G. W. J. Glycobiology 1992,
2, 199–210.
6. For recent reviews, see: (a) Meutermans, W.; Thanh Le, G.;
Becker, B. ChemMedChem 2006, 1, 1164–1194; (b) Cipolla,
L.; Peri, F.; La Ferla, B.; Redaelli, C.; Nicotra, F. Curr. Org.
Synth. 2005, 2, 153–173; (c) Dunne, J. L.; Murphy, P. V.
Curr. Org. Synth. 2006, 3, 403–437.
3.1.15. 3-O-Benzyl-N-tert-butoxycarbonyl-1,5-dideoxy-
1,5-imino-4,6-O-[4-methoxybenzylidene]-2-O-triisopro-
pylsilyloxy-1-D-glucitol 16. To 11 (53 mg, 0.11 mmol) and
2,6-lutidine (39 mL, 0.34 mmol) in anhydrous CH2Cl2 at
0 ꢀC, was added TIPSOTf (46 mL, 0.17 mmol) dropwise un-
der a nitrogen atmosphere. The mixture was stirred at room
temperature under a nitrogen atmosphere with the same
amount of 2,6-lutidine and TIPSOTf being again added at
4 and 8 h and stirring continued overnight. The reaction mix-
ture was washed with 5% NH4Cl and water and the organic
phase was dried (MgSO4) and the solvent removed. The
residue was purified by column chromatography (EtOAc–
cyclohexane, 1:15) to give 16 (37 mg, 52%) as a colourless
7. For the first application of pyranosides as peptidomimetics, see:
(a) Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Salvino, J.;
Leahy, E. M.; Sprengeler, P. A.; Furst, G.; Smith, A. B., III;
Strader, C. D.; Cascieri, M. A.; Candelore, M. R.; Donaldson,
C.; Vale, W.; Maechler, L. J. Am. Chem. Soc. 1992, 114,
9217; (b) Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.;
Leahy, E. M.; Salvino, J.; Arison, B.; Cichy, M. A.; Spoors,
P. G.; Shakepseare, W. C.; Sprengler, P. A.; Hamley, P.;
Smith, A. B.; Reisine, T.; Raynor, K.; Maechler, L.;
Donaldson, C.; Vale, W.; Freidinger, R. M.; Cascieri, M. R.;
Strader, C. D. J. Am. Chem. Soc. 1993, 115, 12550–12568.
8. For examples of solid phase synthesis of prospecting libraries
using pyranoside derivatives, see: (a) Wunberg, T.; Kallus,
C.; Opatz, T.; Henke, S.; Schmidt, W.; Kunz, H. Angew.
Chem., Int. Ed. 1998, 37, 2503–2505; (b) Sofia, M. J.;
Hunter, R.; Chan, T. Y.; Vaughan, A.; Dulina, R.; Wang,
H. M.; Gange, D. J. Org. Chem. 1998, 63, 2802–2803; (c)
Jain, R.; Kamau, M.; Wang, C.; Ippolito, R.; Wang, H.;
Dulina, R.; Anderson, J.; Gange, D.; Sofia, M. Bioorg. Med.
Chem. Lett. 2003, 13, 2185–2189; (d) Opatz, T.; Kallus, C.;
Wunberg, T.; Kunz, H. Tetrahedron 2004, 60, 8613–8626.
9. (a) Le Merrer, Y.; Poitout, L.; Depezay, J.-C.; Dosbaa, I.;
Geoffroy, S.; Foglietti, M.-J. Bioorg. Med. Chem. Lett. 1996,
6, 1667–1672; (b) Chery, F.; Cronin, L.; O’Brien, J. L.;
Murphy, P. V. Tetrahedron 2004, 60, 6597–6608; (c) Tsukida,
T.; Moriyama, H.; Inoue, Y.; Kondo, H.; Yoshino, K.;
Nishimura, S. Bioorg. Med. Chem. Lett. 2004, 14, 1569–
1572; (d) Timmer, M. S. M.; Verhelst, S. H. L.; Grotenbreg,
G. M.; Overhand, M.; Overkleeft, H. S. Pure Appl. Chem.
2005, 77, 1173–1181.
1
oil; H NMR (CDCl3, 400 MHz) d 7.40 (d, 2H, J 8.8 Hz,
aromatic H), 7.34–7.25 (m, 5H, aromatic H), 6.89 (d, 2H,
J 8.8 Hz, aromatic H), 5.54 (s, 1H, benzylidene H), 4.88
(d, 1H, J ꢂ11.2 Hz, CH(H)Ph), 4.86 (dd, 1H, J6a,5 4.4 Hz,
J6a,6b ꢂ10.8 Hz, H-6a), 4.72 (d, 1H, J ꢂ11.2 Hz, CH(H)Ph),
4.06 (dd, 1H, J6b,5 10.4 Hz, J6a,6b ꢂ10.8 Hz, H-6b), 3.93 (m,
1H, H-2), 3.86 (dd, 1H, J4,3 8.5 Hz, J4,5 10.4 Hz, H-4), 3.80
(s, 3H, OMe), 3.71 (dd, 1H, J1a,2 2.8 Hz, J1a,1b ꢂ13.3 Hz, H-
1a), 3.56 (dd, 1H, J3,2 4.4 Hz, J3,4 8.6 Hz, H-3), 3.41 (dt, 1H,
J5,6a 4.4 Hz, J5,6b 10.4 Hz, J5,4 10.4 Hz, H-5), 3.33 (dd, 1H,
J1b,2 7.2 Hz, J1b,1a ꢂ13.3 Hz, H-1b), 1.45 (s, 9H, tBu), 1.07
(s, 18H, TIPS), 1.02 (m, 3H, TIPS); 13C NMR (CDCl3,
100 MHz) d 158.9, 154.1, 137.5, 129.3 (each C), 127.2
(2ꢁCH), 126.9 (2ꢁCH), 126.5 (CH), 126.3 (2ꢁCH),
112.5 (2ꢁCH), 100.1 (CH), 82.9 (CH), 80.8 (CH), 79.6
(C), 73.2 (CH2), 70.5 (CH3), 69.4 (CH2), 54.3 (CH), 50.9
(CH), 47.2 (CH2), 27.3 (3ꢁCH3), 17.0 (6ꢁCH3), 11.3
(3ꢁC). ESI-HRMS: Calcd for C35H54NO7Si 628.3670,
found m/z 628.4121 [M+H]+.
Acknowledgements
Funding was provided by Science Foundation Ireland (Pro-
gramme Grant 03/IBN/B352) and the Astellas USA Founda-
tion. The authors thank the staff of the NMR Centre at UCD
and Dr. Dilip Rai for high resolution mass spectrometry
measurements.
10. Gouin, S. G.; Murphy, P. V. J. Org. Chem. 2005, 70, 8527–
8532.
11. For examples where protected 1-deoxynojirimycin derivatives
have been useful, see: (a) Boeshagen, H.; Heiker, F. R.;

6834
E. Danieli et al. / Tetrahedron 63 (2007) 6827–6834
Schueller, A. M. Carbohydr. Res. 1987, 164, 141–148; (b)
12–15; (b) Behling, J.; Farid, P.; Medich, J. R.; Scaros, M. G.;
Prunier, M.; Weier, R. M.; Khanna, I. Synth. Commun. 1991,
21, 1383–1386; (c) Beaupere, D.; Stasik, B.; Uzan, R.;
Demailly, G. Carbohydr. Res. 1989, 191, 163–166.
18. Van der Ven, J. G. M.; Wilkmans, J. C. H. M.; Kamerling,
J. P.; Vliegenthart, J. F. G. Carbohydr. Res. 1994, 253,
121–139.
19. Jiang, L.; Chan, T. H. J. Org. Chem. 1998, 63, 6035–6038.
20. Garegg, P. J. Preparative Carbohydrate Chemistry; Hanessian,
S., Ed.; Marcel Dekker: New York, NY, 1997; pp 53–67.
21. Nakatani, H.; Oshita, J.; Ishigami, K.; Watanabe, H.; Kitahara,
T. Tetrahedron 2006, 62, 160–165.
22. The conversion of an N-Boc group in presence of TBDMSOTf
to a silyl carbamate has been reported. Sakaitani, M.; Ohfune,
Y. Tetrahedron Lett. 1985, 26, 5543–5546.
23. Straub, A.; Effenberger, F.; Fischer, P. J. Org. Chem. 1990, 55,
3929–3932.
Blattner, R.; Furneaux, R. H.; Pakulski, Z. Carbohydr. Res.
2006, 341, 2115–2125; (c) Kiso, M.; Ando, K.; Inagaki, H.;
Ishida, H.; Hasegawa, A. Carbohydr. Res. 1995, 272, 159–178.
12. Chery, F.; Murphy, P. V. Tetrahedron Lett. 2004, 45, 2067–
2069.
13. For a recent review on synthesis of iminosugars containing six-
membered rings, see: Afarinkia, K.; Bahar, A. Tetrahedron:
Asymmetry 2005, 16, 1239–1287.
14. Kartha, K. P. R. Tetrahedron Lett. 1986, 3415–3416.
15. The yield of the azide via the cyclic sulfite reported was the best
achieved. However, in the hands of other co-workers lower
yields were obtained (w60%, two steps).
16. For the deprotection on a 10 g scale, the use of Dowex-50-X8
was found to be more efficient than Dowex-50-X4.
17. For previous syntheses of 1-deoxynojirimycin from L-sorbose,
see: (a) Tian, L.-L.; Li, Z.-J.; Li, H. Yingyong Huaxue 2004, 21,