Synthesis of peptidomimetics based on iminosugar and β-D- glucopyranoside scaffolds and inhibiton of HIV-protease

Article abstract of DOI:10.1016/j.tet.2004.05.080

Synthetic routes to peptidomimetic compounds derived from saccharide scaffolds are described. The regioselective introduction of pivaloyl groups was achieved from N-benzyloxycarbonyl protected 1-deoxymannojirimycin or via D-fructopyranosides. The results from biological evaluation of the saccharide derivatives as HIV-protease inhibitors are included.

Full text of DOI:10.1016/j.tet.2004.05.080

Tetrahedron 60 (2004) 6597–6608
Synthesis of peptidomimetics based on iminosugar and
b-D-glucopyranoside scaffolds and inhibiton of HIV-protease
*
Florence Chery, Linda Cronin, Julie L. O’Brien and Paul V. Murphy
Department of Chemistry, Centre for Synthesis and Chemical Biology, Conway Institute of Biomolecular and Biomedical Research,
University College Dublin, Belfield, Dublin 4, Ireland
Received 8 April 2004; revised 12 May 2004; accepted 27 May 2004
Abstract—Synthetic routes to peptidomimetic compounds derived from saccharide scaffolds are described. The regioselective introduction
of pivaloyl groups was achieved from N-benzyloxycarbonyl protected 1-deoxymannojirimycin or via D-fructopyranosides. The results from
biological evaluation of the saccharide derivatives as HIV-protease inhibitors are included.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
of b-D-glucopyranosides and 1-deoxymannojirimycin and
the results of their evaluation as HIV protease inhibitors.
Several aspartic acid proteases1 are of interest as therapeutic
targets. Examples include renin, HIV-1 protease and
memapsin 2 (b-secretase) which are respectively involved
in hypertension,2 viral infection and Alzheimer’s disease.3
Only in the case of the HIV-1 protease have inhibitors of
this class of enzymes attained clinical importance.4 This is
due mostly to the lack of bioavailability of the potent
inhibitors, which is caused in many cases by the high
peptide character of these compounds. Also, despite the
successes of using protease inhibitors for treatment of HIV,
there remain a number of problems with current therapies.
Consequently much work is being carried out to develop
new anti-HIV agents. Previously the design and synthesis of
b-D-glucopyranoside and b-D-mannopyranoside as pepti-
domimetic based inhibitors has been reported from our
group. Peptidomimetic research is concerned with develop-
ing bioactive agents which have improved pharmacokinetic
properties over peptides.5 The general principle is that
pharmacophoric groups are grafted onto a non-peptide
scaffold, which orient them in the direction of their binding
subsites. Researchers at the University of Pennsylvania
were first to validate b-D-glucopyranose (e.g., 2), its
enantiomer and a diastereomer (b-D-mannopyranose) as
scaffolds suitable for providing bioactive compounds that
bind to peptide receptors.6 This has led to other groups
utilising sugar scaffolds in peptidomimetic and other
research.7,8 Herein we describe the synthesis of conjugates
2. Results and discussion
2.1. Design of second generation carbohydrate based
peptidomimetics
The glucoside 1 and mannoside 3 (Fig. 1) are examples of
carbohydrate conjugates9 that have demonstrated a modest
inhibition of HIV-1 protease; their design and synthesis has
been described previously.10 It was hypothesized by us that
1 and 3 may be binding competitively in the active site of
the enzyme, that the hydrophobic groups attached to the
sugar scaffold were thus oriented into enzyme subsites and
that the 2-OH group of the mannopyranose or glyco-
pyranose was hydrogen bonding with the catalytic aspartate
residues in the active site.11 Compounds 2 and 4 were
selected for synthesis in order to obtain support for this
assumption and to try to develop more potent saccharide
derivatives.
Thus it was expected that 2 would bind with higher affinity
than the b-D-glucopyranoside 1 because the iminosugar
would be a charged hydrogen bond donor, contrasting with
1 where the pyranose oxygen atom has hydrogen bond
acceptor potential (Fig. 1). Molecular modelling indicated
that the protonated nitrogen of 3 would hydrogen bond with
a carbonyl group of the HIV protease amide backbone if the
molecule bound as predicted. b-D-Glucopyranosides of the
type 4 would be expected to show improved activity
when compared to 2 (and other mannosides and glucosides
that have been evaluated previously); molecular
Keywords: Peptidomimetic; Azasugar; Iminosugar; Glucopyranoside; HIV-
protease.
*
Corresponding author. Tel.: þ35317162504; fax: þ35317162127;
e-mail address: paul.v.murphy@ucd.ie
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.080

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F. Chery et al. / Tetrahedron 60 (2004) 6597–6608
Scheme 1. Reagents and conditions: (a) CbzCl, NaHCO3, dioxane, H2O,
74%; (b) PivCl, Py. 2 h; (c) 10% Pd–C, H2, MeOH; (d) K2CO3, BnBr,
DMF.
ing selectively at O-2 and O-6. The chemical behaviour of
the DMJ derivative 6 was not comparable with methyl a-D-
mannopyranoside which gave 14 as a result of pivaloylation
at O-3 and O-6 (Scheme 2). Attempts to alter the
regioselectivity of the pivaloylation by using (Bu3Sn)2O/
PivCl led only to intractable product mixtures or the
recovery of 6. Attempts to obtain pivaloylated products
from 717 were not successful. However, it was possible to
convert 8 into 2,6-di-O-pivaloylated DMJ derivative 10 and
subsequent N-benzylation gave 11; in a similar way 9 was
converted into monopivaloylated derivative 13 via 12
(Scheme 1). In general the reactions of DMJ derivatives
were low yielding, especially if crude rather than purified
DMJ was used. The products from 5 were also prone to
decomposition. These difficulties led us to investigate
alternative routes to 2.
Figure 1. Design of iminosugar 2 and glucopyranoside peptidomimetics 4.
modeling indicated that the valine residue attached to the
glucopyranose C-6, would have additional binding inter-
actions with the enzyme.
2.2. Synthesis from 1-deoxymannojirimycin
The first approach taken towards 2 involved investigation of
1-deoxymannojirimycin (DMJ) as a starting compound.
Syntheses of 5 were thus first carried out as described
previously.12,13 The nitrogen atom of 5 was then protected
2.3. Synthesis of iminosugar conjugates from D-fructose
One of the shortest syntheses of DMJ has been achieved by
Stu¨tz and co-workers from D-fructose.18 Based on this route
we proposed (Scheme 2) that the azidofructofuranoside 15
would be a viable intermediate for synthesis of 2 and that it
could be prepared from 16 (Scheme 3).
with Cbz according to literature procedure14 giving 6.15
A
61:25 mixture of the diester 8 and monoester 9 was obtained
when 6 was reacted with trimethylacetyl chloride in
pyridine at 0 8C,16 regioselective di-O-pivaloylation occur-

F. Chery et al. / Tetrahedron 60 (2004) 6597–6608
6599
the 4-OH of 19 and introduction of a second levulinate
group at O-5 and gave 20. The 1,2-di-O-isopropylidene was
next removed using aqueous TFA and another regioselec-
tive pivaloylation at O-1 gave 21. Reaction of 21 with
triphenylphosphine-bromine as described by Stu¨tz gave the
6-deoxy-6-bromofructose derivative 22 (93%). The levuli-
nate groups were then removed using hydrazine hydrate to
give furanose 23 and its subsequent reaction with sodium
azide in DMF gave the desired intermediate 15. The
catalytic hydrogenation of 15 gave the 3,6-di-O-pivaloy-
lated DMJ 24 (22%), which was then converted to the N-
benzyl derivative 2 using potassium carbonate and benzyl
bromide in DMF (60%).
Scheme 2. Reagents and conditions: (a) PivCl (2 equiv.), Py. 2 h.
Other potential intermediates such as 25 were prepared but
the selective removal of the acetates could not be achieved
in our hands. Also the reaction of 25 with sodium azide led
to decomposition and resulted in an intractable product
mixture.
Scheme 3. Retrosynthetic analysis.
The use of the levulinate protecting group was ultimately
successful (Scheme 4). Thus 18 was first prepared by the
DCC-DMAP promoted coupling of levulinic acid19 with 17,
which is obtained from D-fructose.20 Selective deprotection
of the 4,5-di-O-isopropylidene group using 80% aqueous
acetic acid at 45 8C gave 19. Regioselective pivaloylation of
2.4. Synthesis of b-D-glucopyranosides
Phenyl b-D-glucopyranoside was used as the starting
compound for the synthesis of 4a–e (Schemes 5 and 6).
The 3-O-benzyl derivative 26 was prepared as described
previously.9 The 2-OH group was then reacted with
TIPSOTf in dichloromethane in presence of 2,6-lutidine to
Scheme 4. Reagents and conditions: (a) Levulinic acid, DCC (2 equiv.),
DMAP (cat.), THF, 91%; (b) 80% AcOH, 45 8C, 4 h; (c) PivCl (1.1 equiv.,
Py. 278 8C to RT overnight, 98%; (d) Levulinic acid (1.8 equiv.), DCC
(2 equiv.), DMAP (cat.), THF, 77%; (e) TFA/H2O (4:1), 2 h, 85%; (f) PivCl
(1.2 equiv.), Py. 15 h, 90%; (g) PPh3Br2, Py. CH2Cl2, 3 h, heat at reflux,
93%; (h) NH2NH2·H2O, AcOH, H2O, 0 8C, 66%, (i) NaN3, DMF, rt, 48 h,
53%; (j) 10% Pd–C, H2, MeOH, 22%; (k) K2CO3 (0.6 equiv.), BnBr
(1.15 equiv.), DMF, 60%.
Scheme 5. Reagents and Conditions: (a) TIPSOTf, 2,6-lutidine, CH2Cl2;
(b) TFA, CH2Cl2, r.t.; (c) Ac2O, Py, r.t., 66% for two steps; (d) NaOMe,
MeOH, r.t.; (e) TsCl, Py, 0 8C, 85% for two steps; (f) NaN3, DMF, 80 8C,
72% (g) NaH, R’I or R’Br, DMF, 0 8C to r.t., 30–94%.

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2.5. Evaluation of iminosugars and glucopyranosides as
HIV protease inhibitors
The HIV-1 protease inhibition data22 data for sugar
derivatives prepared during the course of this study are
provided in Table 1. The IC50 value for pepstatin, a known
inhibitor of HIV-protease, was 4.3–7.4 mM in this assay.
The glucoside 1, prepared and evaluated previously, showed
modest inhibition (24% at 1.0£1024 M) and was the most
potent of the series of saccharides evaluated,23 all new
compounds being less potent at 1.0£1024 M. It would seem
that the modest inhibition observed for these carbohydrates
and for those described previously may be due to them
having a different mode of action than that hypothesized;
structural modifications that were expected to increase
binding at the active site did not lead to any improvement in
inhibitory activity.
Scheme 6. Reagents and Conditions: (a) Lindlar catalyst, H2, EtOH:EtOAc;
(b) AcVal–OH (L-isomer), BOP-Cl, DIPEA, CH2Cl2, 33–79%, two steps
(c) TBAF, THF, 0 8C, 44–88%.
Table 1. % Inhibition of HIV-1 protease by sugar derivatives at 1£1024 Ma
Compound
% Inhibitionb
give 27. Removal of the benzylidene group followed by
acetylation21 gave 28. This was followed by deacetylation
and regioselective tosylation to give 29. Reaction of this
tosyl derivative with sodium azide in DMF gives 6-deoxy-6-
azido derivative 30a, which when treated with NaH in DMF
in the presence of the appropriate alkyl iodide or bromide
gave 30b–e.
1
2
24
8
14
19
20
4a
4b
4c
4d
4e
33
16
Not active
11
Azides 30a–e were reacted with Lindlar catalyst in the
presence of H2 and the resulting amine coupled to AcVal–
OH (L-isomer) using BOP–Cl in dichloromethane in the
presence of DIPEA (28–66% over two steps) giving 31a–e
and subsequent removal of the TIPS protecting group was
accomplished using TBAF in THF to give 4a–e (65–96%).
The 13C NMR spectra of 31a–e and 4a–e contained two
signal sets indicating that each sample was a mixture of
diasteroisomers (,2:1), resulting from epimerization of the
chiral centre of the valine residue (Scheme 6).
a
IC50 value for pepstatin in this assay was 4.3–7.4 mM.
Values are mean of two experiments.
b
3. Summary
In summary, a series of b-D-glucopyranosides have been
prepared and a synthetic approach with potential to be
further developed towards diversely functionalized
1-deoxymannojirimycin derivatives has been described.
The saccharides show modest inhibitory activity for the
HIV-1 protease indicating the design of potent carbohydrate
peptidomimetics, related to those described herein, as
inhibitors of aspartic proteases will not be trivial.
In addition the Boc protected derivative 32 was prepared by
coupling of 30b with BocVal–OH using HBTU, HOBt in
presence of DIPEA. Subsequent removal of the silyl
protecting group gave 33 (Scheme 7).
4. Experimental
4.1. General
Optical rotations were determined at the sodium D line at
1
23 8C. Chemical shifts in H NMR spectra are reported
relative to internal Me4Si in CDCl3 (d 0.0) or HOD for D2O
(d 4.84) or CD2HOD (d 3.36) for 1H and CDCl3 (d 77.0) or
1
CD3OD (d 47.7) for 13C. H NMR signals were assigned
with the aid of COSY. 13C NMR signals were assigned with
the aid of DEPT. Coupling constants are reported in Hertz.
The IR spectra were recorded using either a thin film
between NaCl plates or KBr discs, as specified. Thin layer
chromatography (TLC) was performed on aluminium sheets
precoated with silica gel 60 (HF254, E. Merck) and spots
visualized by UV and charring with H2SO4–EtOH (1:20).
Flash column chromatography was carried out with silica
gel 60 (0.040–0.630 mm, E. Merck) and using a stepwise
solvent polarity gradient (EtOAc–petroleum ether
unless otherwise stated) correlated with TLC mobility.
Scheme 7. Reagents and Conditions: (a) Lindlar catalyst, H2, EtOH:EtOAc;
(b) BocVal–OH (L-isomer), HOBt, HBTU, DIPEA, CH2Cl2, 18% two
steps; (c) TBAF, THF, 0 8C, 66%.

F. Chery et al. / Tetrahedron 60 (2004) 6597–6608
6601
Chromatography solvents used were EtOAc and MeOH
(Riedel–deHaen) and petroleum ether (bp 40–60 8C, BDH
laboratory supplies). Toluene (Aldrich) and CH2Cl2
(Riedel–deHaen) benzene (Aldrich) and CH2Cl2 reaction
solvents were freshly distilled from calcium hydride and
anhydrous DMF was used as purchased from Sigma-
Aldrich. Phenyl b-D-glucopyranoside was purchased from
Sigma-Aldrich. MS is Electrospray MS unless otherwise
stated.
7.25–7.31 (m, 5H, Ph), 5.08 (AB d, 2H, J¼212.3 Hz,
CH2), 4.61 (t, 1H, J¼10.5 Hz, H-5), 4.51 (broad d, 1H,
J6a–6b¼29.6 Hz, H-6a), 3.94–4.10 (m, 5H, H-1b, H-2-4,
H-6b), 3.08 (t, 1H, J¼211.7 Hz, H-1b), 1.06 (s, 9H, Piv);
13C NMR (75 MHz, CDCl3): d 179.1 (s, Piv CvO), 156.8
(s, Cbz CvO), 136.2 (s, aromatic C), 128.5, 128.2, 127.8
(each d, aromatic CH), 70.5, 69.4, 64.5, (each d, C-2-4),
67.7 (t, C-6), 60.9 (t, C-1), 55.9 (d, C-5), 39.8 (t, CH2), 38.7
(s, Me3C), 27.0 (q, Piv CH3); IR: 3700–3100 (broad), 2970,
2909, 1728, 1682, 1538, 1479, 1431, 1281, 1164, 1058, 854,
765 cm21. LRMS: 404.1 [MþNa]þ. Anal. Calcd for
C19H27NO7: C, 59.83; H, 7.14; N, 3.67. Found: C, 59.58;
H, 7.14; N, 3.49.
4.1.1. N-Benzyloxycarbonyl-1,5-dideoxy-1,5-imino-D-
mannitol 6. 1-Deoxymannojirimycin (115 mg, 0.7 mmol)
was dissolved in a mixture of dioxane/water (1:1, 12 mL),
then NaHCO3 was added (1.75 equiv.) and benzylchloro-
formate (1.54 equiv.).18 The mixture was stirred for 18 h at
room temperature. The dioxane was then evaporated and the
aqueous layer was extracted with dichloromethane to
remove excess reagent. The aqueous phase was evaporated
and the residue purified by chromatography (EtOAc/
MeOH/water, 90:8:2 then 85:10:5) to give 6 (155 mg,
74%, clear syrup); [a]D¼þ1 (c 0.7, MeOH); 1H NMR
(300 MHz, CD3OD): d 7.30–7.42 (m, 5H, Ph), 5.14 (AB d,
2H, J¼213.5 Hz, CH2), 4.31 (t, 1H, J¼6.6 Hz, H-5), 4.03
(dd, 1H, J2–1a¼4.5 Hz, J1a–1b¼213.2, H-1a), 3.96–3.88
(m, 4H, H-2-4, H-6a), 3.75 (dd, 1H, J5–6b¼5.1 Hz,
J6a–6b¼211.1 Hz, H-6b), 3.14 (dd, 1H, J¼11.7,
213.2 Hz, H-1b); 13C NMR (75 MHz, CD3OD) d 158.3
(s, CO) 138.2 (s, aromatic C), 129.5, 128.9, 128.7 (each d,
aromatic CH), 71.9, 71.0, 65.6, (each d, C-2-4), 68.4 (t, Cbz
CH2), 61.2 (t, C-6), 60.5 (d, C-5), 41.5 (t, C-1); LRMS:
296.0 [M2H]2. Acetylation of 6 (52 mg) with pyridine
(0.5 mL), Ac2O (0.5 mL) and DMAP (2 mg) followed
by removal of volatile reagents by distillation and
purification of the residue by chromatography gave an
analytical sample of 2,3,4,6-tetra-O-acetyl-N-benzyloxy-
carbonyl-1,5-dideoxy-1,5-imino-D-mannitol; [a]D¼241 (c
1.7, CHCl3). Anal. Calcd for C24H27NO10: C, 56.77; H,
5.85; N, 3.01. Found: C, 56.37; H, 5.66; N, 3.04.
4.1.3. 2,6-Di-O-pivaloyl-1,5-dideoxy-1,5-imino-D-manni-
tol 10. Pivalic acid ester 8 (150 mg, 0.32 mmol) was
dissolved in MeOH (5 mL), then 10% Pd–C was added
(30 mg). The mixture was stirred at room temperature
overnight under H2. The solvent was evaporated and the
residue purified by chromatography (EtOAc then EtOAc/
MeOH/H2O 90:8:2, 85:10:5) to give title compound 10
(66 mg, 61%, colourless gum); 1H NMR (300MHz,
CD3OD): d 5.16 (broad s, 1H, H-2, 4.47 (dd, 1H, J5–6a
3.6 Hz, J6a–6b¼211.4 Hz, H-6a), 4.21 (dd, 1H, J5–6b
¼
¼
2.4 Hz, J6a–6b¼211.4 Hz, H-6b), 3.65–3.74 (m, 2H, H-3,
H-4), 3.09 (dd, 1H, J1a–2¼2.7 Hz, J1a–1b¼214.7 Hz,
H-1a), 2.92 (dd, 1H, J1b–2¼2.7 Hz, J1a–1b¼214.7 Hz,
H-1b), 2.72 (dt, 1H, J¼9.3, 3.0 Hz, H-5), 1.31, 1.30 (each
s, each 9H, Piv); 13C NMR (75MHz, CD3OD) d 178.0,
178.4 (each s, CvO), 73.6, 72.4, 68.7, 58.9 (each d, C-2-5),
63.5, 46.8, (each t, C-1, C-6), 38.8, 38.7 (each s, Me3C),
26.4, 26.3 (each q, CH3); HRMS: Found 332.2067, required
332.2073. [MþH]þ.
4.1.4. N-Benzyl-2,6-di-O-pivaloyl-1,5-dideoxy-1,5-imino-
D-mannitol 11. Iminosugar 10 (55 mg, 0.167 mmol) was
dissolved in DMF (1 mL), then K2CO3 (0.6 equiv.) was
added followed by benzyl bromide (1.15 equiv.) and the
mixture stirred for 4 h at 60 8C. The solvent was then
evaporated and the residue purified by chromatography
(petroleum ether/EtOAc 7:3 then 1:1) to give the title
compound (50 mg, 71%, colourless gum); [a]D¼293 (c
4.1.2. 2,6-Di-O-pivaloyl-N-benzyloxycarbonyl-1,5-
dideoxy-1,5-imino-D-mannitol 8 and 6-O-pivaloyl-N-
benzyloxycarbonyl-1,5-dideoxy-1,5-imino-D-mannitol 9.
To a stirred solution of 6 (149 mg, 0.5 mmol) in pyridine
(3 mL) at 0 8C was slowly added PivCl (2 equiv.). After 1 h
further PivCl was added (2 equiv.) and after 3 h the reaction
mixture was diluted with ethyl acetate and methanol. The
solvent was removed under reduced pressure and the residue
purified by chromatography (petroleum ether/EtOAc 1:1,
then 0:1) to give in order of elution 8 (25%) and 9 (61%)
both as colourless gums. Analytical data for 8: [a]D¼24 (c
1.4, CHCl3); 1H NMR (300 MHz, CDCl3): d 7.19–7.28 (m,
5H, Ph), 5.07 (AB d, 2H, J¼213.5 Hz, CH2), 4.98–5.05
(m, 1H, H-2), 4.61 (t, J¼11.1 Hz, H-5), 4.51 (d, 1H,
J6a–6b¼29.9 Hz, H-6a, 4.06–4.13 (m, 2H, H-1a, H-6b),
3.94–4.02 (m, 2H, H-3, H-4),), 3.19 (t, 1H, J1b–2¼12.9 Hz,
J1a–1b¼212.9 Hz, H-1b), 1.13, 1.03, (2s, each 9H each
Piv); 13C NMR (75 MHz, CDCl3) d 178.6, 177.5 (each s, Piv
CvO), 156.4 (s, Cbz CvO), 136.3 (s, aromatic C), 128.5,
128.1, 127.9 (each d, aromatic CH), 69.3, 69.1, 67.6 (each d,
C-2-4), 67.7 (t, C-6), 60.8 (t, C-1), 56.2 (d, C-5), 39.0, 38.7
(each s, each Me3C), 37.3 (t, CH2), 27.2, 27.1 (each q, Piv
CH3); LRMS: 488.1 [MþNa]þ. Analytical data for 9:
1
0.33, CHCl3); H NMR (300 MHz, CDCl3): d 7.27–7.38
(m, 5H, Ph), 5.12 (broad s, 1H, H-2), 4.73 (dd, 1H,
J5–6a,0.5 Hz, J6a–6b¼212.6 Hz, H-6a), 4.56 (d, 1H,
J6a–6b¼212.6 Hz, H-6b), 4.30 (d, 1H, J¼217.4 Hz,
C(H)H), 3.67–3.79 (m, 2H, H-3, H-4), 3.09 (d, 1H,
J¼217.4 Hz, C(H)H), 2.99 (dd, 1H, J1a–2¼3.6 Hz,
J1a–1b¼213.2 Hz, H-1a), 2.44 (d, 1H, J¼8.4 Hz, H-5),
2.26 (dd, 1H, J1b–2¼2.8 Hz, J1a–1b¼213.2 Hz, H-1b),
1.26, 1.30 (2s, each 9H each, Piv); 13C NMR (75 MHz,
CDCl3) d 178.5, 179.5 (each s, CvO), 138.7 (s, aromatic
C), 128.4, 128.3, 127.4, 127.2 (each d, aromatic CH), 74.0,
69.4, 69.2, 65.8 (each d, C-2-5), 60.5, 56.6, 52.9 (each t,
CH2, C-1, C-6), 39.0 (Me3C), 27.3, 27.2, (each q, CH3); IR:
3441 (broad), 2971, 2930, 2873, 2799, 1726, 1480, 1286,
1155, 1087, 1031, 910 cm21; HRMS: Found 422.2547,
required 422.2543 [MþH]þ.
4.1.5. 6-O-Pivaloyl-1,5-dideoxy-1,5-imino-D-mannitol 12.
Pivalic acid ester 9 (150 mg, 0.39 mmol) was dissolved was
dissolved in MeOH (5 mL), then 10% Pd/C was added
(30 mg). The mixture was stirred at room temperature
1
[a]D¼24 (c 2.0, CHCl3); H NMR (300 MHz, CDCl3): d

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F. Chery et al. / Tetrahedron 60 (2004) 6597–6608
overnight under H2. The residue obtained from evaporation
of solvent purified by chromatography (EtOAc then EtOAc/
MeOH/H2O 90:8:2 then 85:10:5) to give 12 (60 mg, 62%,
colourless gum); 1H NMR (300 MHz, CD3OD): d 4.41 (dd,
1H, J5–6a¼3.9 Hz, J6a–6b¼211.4 Hz, H-6a), 4.28 (d, 1H,
J5–6b,0.5 Hz, J6a–6b¼211.4 Hz, H-6b), 3.97 (broad s, 1H,
H-2), 3.70 (t, 1H, J¼9.6 Hz, H-4), 3.50 (d, 1H,
J2–3¼2.1 Hz, H-3), 3.09 (d, 1H, J1a–1b¼212.3 Hz, H-1a),
2.87 (d, 1H, J1a–1b¼212.3 Hz, H-1b), 2.74 (broad d, 1H,
J¼9.6 Hz, H-5), 1.29 (s, 9H, Piv); 13C NMR (75 MHz,
CD3OD) d 178.5 (CvO), 74.9, 68.8, 68.2 (C-2-4), 63.2
(C-1, C-6), 59.1 (C-5), 49.0, 38.7 (Me3C), 26.2 (CH3); IR:
3600–3000 (broad), 2970, 2874, 1725, 1286, 1161,
1068 cm21. HRMS: Found 248.1486, required 248.1489.
[MþH]þ.
4.1.8. 3-O-Levulinoyl-1,2-O-isopropylidene-b-D-fructo-
pyranose. Ester 18 (1.8 g, 5 mmol) was dissolved in 80%
AcOH and the mixture was heated at 45 8C for 4 h. The
solvent was evaporated and toluene then added and
evaporated to remove residual water and AcOH. The
residue was purified by chromatography (petroleum ether/
AcOEt 1:1) to give the title compound 19 (1.04 g, 65%,
white solid); [a]D¼270 (c 2.2, CHCl3); 1H NMR
(300 MHz, CDCl3): d 5.21 (d, 1H, J3–4¼9.6 Hz, H-3),
3.97–4.03 (m, 6H, H-1a, H-3, H-4, H-6a), 3.89 (d, 1H,
J1a–1b¼29.3 Hz, H-1b), 3.84 (dd, 1H, J5–6b¼1.2 Hz,
J6a–6b¼212.6 Hz, H-6b), 2.82–2.87 (m, 2H, CH2), 2.54–
2.70 (m, 2H, CH2), 2.20 (s, 3H, Lev CH3), 1.48, 1.43 (each
s, 6H, isopropylidene CH3); 13C NMR (75 MHz, CDCl3) d
207.8 (s, CvO, ketone), 173.4 (s, CvO, ester), 111.9 (s,
isopropylidene C), 104.3 (s, C-2), 71.9, 69.8, 69.4, (each d,
C-3-5), 71.9, 63.9 (each t, C-1, C-6), 38.4, 28.2, (each t,
CH2CH2), 29.8 (q, Lev CH3), 26.1, 26.5 (each q,
isopropylidene CH3); LRMS 341.2 [MþNa]þ. Anal.
Calcd for C14H22O8: C, 52.82; H, 6.97. Found: C, 53.08;
H, 6.88.
4.1.6. N-Benzyl-6-O-pivaloyl-1,5-dideoxy-1,5-imino-D-
mannitol 13. Pivalic acid ester 12 (50 mg, 0.2 mmol) was
dissolved in DMF (1 mL), then K2CO3 (0.6 equiv.) and
benzyl bromide (1.15 equiv.) were added. The mixture was
stirred for 4 h at 60 8C. Then solvent was evaporated and the
residue purified by chromatography (petroleum ether/
AcOEt 7:3, 1:1) to give 13 (50 mg, 73%, colourless gum);
[a]D¼281 (c 0.4, CHCl3); 1H NMR (300 MHz, CDCl3): d
7.23–7.34 (m, 5H, Bn), 4.60 (d, 1H, J6a–6b¼212.3 Hz,
H-6a), 4.51 (dd, 1H, J5–6b¼3.0 Hz, J6a–6b¼212.3 Hz,
H-6b), 4.18 (d, 1H, J¼213.2 Hz, CH2), 3.79 (broad s, 1H,
H-2), 3.63 (t, 1H, J¼9.0 Hz, H-4), 3.41 (dd, 1H, J¼2.4,
9.0 Hz, H-3), 3.24 (d, 1H, J¼213.2 Hz, CH2), 2.90 (dd, 1H,
J1a–2¼23.6 Hz, H-1a), 2.41 (broad d, 1H, J4–5¼9.0 Hz,
H-5), 2.20 (d, 1H, J1a–1b¼213.2 Hz, H-1b), 1.23 (s, 9H,
Piv); 13C NMR (75 MHz, CDCl3): d 178.9 (s, CvO), 138.1
(s, aromatic C), 128.8, 128.6, 127.4, (each d, aromatic CH),
75.6, 69.5, 67.7, 65.7 (each d, C-2-5), 61.3, 57.0, 54.7 (each
t, CH2, C-1, C-6), 38.9 (s, Me3C), 27.3 (q, Piv); IR: 3407
(broad), 2972, 2924, 2803, 1725, 1480, 1453, 1397, 1286,
1160, 1097 cm21; HRMS: Found 338.1968, required
338.1967 [MþH]þ.
4.1.9. 3,5-Di-O-levulinoyl-4-O-pivaloyl-1,2-O-isopropyl-
idene-b-D-fructopyranose 20. Fructose derivative 19
(800 mg, 2.5 mmol) was dissolved in pyridine and
CH2Cl2, (20 mL, 1:1) and the mixture was stirred at
278 8C; PivCl (1.1 equiv.) was then added slowly. The
temperature was allowed to slowly increase to room
temperature overnight. The mixture was diluted with
chloroform (5 mL) and washed with cold 5% HCl, then
with 5% NaHCO3. After drying over MgSO4, the solution
was evaporated and the residue purified by chromatography
(petroleum ether/EtOAc 6:4 then 1:1) to give 3-O-
levulinoyl-4-O-pivaloyl-1,2-O-isopropylidene-b-D-fructo-
pyranose (0.991 g, 98%, white gum); [a]D¼2116 (c 1.7,
CHCl3); 1H NMR (300 MHz, CDCl3): d 5.47 (d, 1H,
J3–4¼10.5 Hz, H-3), 5.17 (dd, 1H, J¼3.0, 10.5 Hz, H-4),
4.13 (m, 1H, H-5), 4.07 (dd, 1H, J5 – 6a¼1.2 Hz,
J6a–6b¼212.6 Hz, H-6a), 3.99 (d, 1H, J1a–1b¼29.3 Hz,
H-1a), 3.91 (d, 1H, J1a–1b¼29.3 Hz, H-1b), 3.80 (dd, 1H,
J5–6b¼1.8 Hz, J6a–6b¼212.6 Hz, H-6b), 2.45–2.83 (m,
4H, CH2CH2), 2.18 (s, 3H, Lev CH3), 1.49, 1.45 (2s, 6H,
each isopropylidene), 1.20 (s, 9H, Piv); 13C NMR (75 MHz,
CDCl3) d 206.0 (s, CvO, ketone), 177.5, 172.2, (each s,
each CvO, ester), 112.2 (s, isopropylidene C), 104.5 (C-2),
71.7, 63.9, (each t, C-1, C-6), 71.6, 67.9, 66.7, (each d, C-3-
5), 38.9 (s, Me3C), 37.8, 27.9, (each t, CH2CH2), 29.7 (q,
Lev CH3), 27.1 (q, Piv CH3), 26.5, 26.1 (each q,
isopropylidene CH3); LRMS: 425.15 [MþNa]þ. This
intermediate (933 mg, 2.3 mmol) was dissolved in THF
(30 mL) and DCC (2 equiv.), levulinic acid (1.8 equiv.) and
DMAP (10%) were added and the mixture was stirred
overnight at rt. The reaction mixture was then filtered, the
solvent removed and the residue purified by chromato-
graphy (toluene/EtOAc 9:1 then 8:2) to give 20 (893 mg,
4.1.7. 3-O-Levulinoyl-1,2:4,5-di-O-isopropylidene-b-D-
fructopyranose 18. Fructose derivative 1720 (1.0 g,
3.8 mmol) was dissolved in THF (30 mL) then DCC
(2 equiv.), levulinic acid (1.8 equiv.) and DMAP (10%)
were added, the reaction was stirred overnight at room
temperature. The mixture was then filtered and the solvent
removed and the residue purified by chromatography
(toluene/EtOAc 9:1 then 85:15) to give title compound 18
(1.25 g, 91%, colourless oil); [a]D¼2143 (c 5.1, CHCl3);
1H NMR (300 MHz, CDCl3): d 5.04 (d, 1H, J3–4¼7.8 Hz,
H-3), 4.21 (dd, 1H, J4–5¼5.4 Hz, J3–4¼7.8 Hz, H-4), 4.15
(dd, 1H, J5–6a¼1.8 Hz, J4–5¼5.4 Hz, H-5), 4.07 (dd, 1H,
J5–6a¼1.8 Hz, J6a–6b¼213.2 Hz, H-6a), 3.99 (d, 1H,
J6a–6b¼213.2 Hz, H-6b), 3.86 (d, 1H, J1a–1b¼29.3 Hz,
H-1a), 3.80 (d, 1H, J1a–1b¼29.3 Hz, H-1b), 2.47–2.87 (m,
4H, CH2CH2), 2.11 (s, 3H, Lev CH3), 1.46, 1.42, 1.36, 1.28
(each s, 12H, isopropylidene CH3); 13C NMR (75 MHz,
CDCl3) d 206.2 (s, CvO, ketone), 172.4 (s, CvO ester),
109.6, 112.1 (each s, isopropylidene C), 103.6 (s, C-2), 74.8,
73.7, 70.9 (each d, C-3-5), 71.5, 60.3 (each t, C-1, C-6),
37.9, 28.0 (each t, CH2CH2), 29.7 (q, Lev CH3), 27.8, 26.6,
26.4, 25.9 (each q, isopropylidene CH3); MS: 381.2
[MþNa]þ. Anal. Calcd for C17H26O8: C, 56.97; H, 7.31.
Found: C, 56.92; H, 7.15.
1
77%, colourless oil); H NMR (300 MHz, CDCl3): d 5.46
(d, 1H, J3–4¼10.5 Hz, H-3), 5.41 (d, 1H, J4–5¼3.0 Hz,
H-5), 5.31 (dd, 1H, J4–5¼3.0 Hz, J3–4¼10.5 Hz, H-4), 4.64
(d, 1H, J6a – 6b¼213.2 Hz, H-6a), 4.03 (d, 1H,
J1a–1b¼29.0 Hz, H-1a), 3.98 (d, 1H, J1a–1b¼29.0 Hz,
H-1b), 2.57–2.82 (m, 8H, CH2CH2), 3.80 (d, 1H,
J6a–6b¼213.2 Hz, H-6b), 2.23 (s, 6H, Lev CH3), 1.53,
1.51 (2s, 6H, isopropylidene CH3), 1.18 (s, 9H, Piv); 13C

F. Chery et al. / Tetrahedron 60 (2004) 6597–6608
6603
NMR (75 MHz, CDCl3): d 206.1, 205.9 (each s, CvO, Lev
ketone), 177.3 (s, CvO, Piv), 172.2, 171.9 (each s, CvO,
Lev ester), 112.3 (s, isopropylidene C), 71.7, 62.3 (each t,
C-1, C-6), 69.3, 68.9, 66.8 (each C-3-5), 104.5 (s, C-2), 38.8
(s, Me3C), 37.8, 28.0, 27.9 (each t, CH2CH2), 29.8, 29.7
(each q, Lev CH3), 26.9 (q, Piv CH3), 26.5, 26.0 (each q,
isopropylidene CH3); [a]D¼293 (c, 2.3, CHCl3); LRMS:
518.2 [MþH2O]þ 523.1 [MþNa]þ. Anal. Calcd for
C24H36O11: C, 57.59; H, 7.25. Found: C, 57.95; H, 7.30.
ester), 171.9, 171.1 (s, CvO Lev ester), 96.7 (s, C-2), 69.4,
68.4, 67.5 (each d, C-3-5), 65.1, 61.6 (each t, C-1, C-6),
38.9, 38.8 (each s, Me3C), 37.7, 27.8 (each t, CH2CH2),
29.8, 29.7 (each q, Lev CH3), 26.9, 27.1 (each q, Piv CH3);
LRMS: 562.3 [MþH2O]þ, 567.21 [MþNa]þ, 583.19
[MþK]þ. Anal. Calcd for C26H40O12: C, 57.34; H, 7.40.
Found: C, 57.04; H, 7.35.
4.1.11. 6-Bromo-6-deoxy-3,5-di-O-levulinoyl-1,4-di-O-
pivaloyl-D-fructose 22. Fructose derivative 21 (2.5 g,
4.59 mmol) was dissolved in dry CH2Cl2¼(50 mL) then
pyridine (0.5 mL) and triphenylphosphane dibromide
(1.3 equiv.) were added, and the mixture was stirred whilst
heating at reflux for 3 h. Satd. aq. NaHCO3¼was then added
slowly to the cooled solution and the organic layer
consecutively washed with 5% HCl and 5% NaHCO3.
After drying over sodium sulfate, the solvent was removed
under reduced pressure and the residue purified by
chromatography (petroleum ether/ EtOAc 7:3 then 6:4) to
give 22 (2.59 g, 93%, colourless gum); [a]D¼þ17 (c 2.3,
CHCl3); 1H NMR (300 MHz, CDCl3): d 5.68 (dd, 1H,
J4–5¼9.3 Hz, J3,4¼2.1 Hz, H-4, 5.49 (d, 1H, J3–4¼2.1 Hz,
H-3), 4.78 (d, 1H, J1a–1b¼217.4 Hz, H-1b), 5.28 (ddd, 1H,
J¼4.5, 9.3, 3.3 Hz, H-5), 4.84 (d, 1H, J1a–1b¼217.4 Hz,
H-1a), 3.64 (dd, 1H, J5–6a¼3.3 Hz, J6a–6b¼211.7 Hz,
H-6a), 3.45 (dd, 1H, J6a–6b¼211.7 Hz, J5–6b¼4.5 Hz,
H-6b), 2.56–2.82 (m, 8H, CH2CH2), 2.18 (each s, 6H,
Lev CH3), 1.19, 1.28 (each s, 18H, Piv); 13C NMR (75 MHz,
CDCl3): d 206.2, 206.1 (s, CvO Lev ketone), 197.8 (s,
C-2), 177.2, 176.8 (s, CvO, Piv), 171.8, 171.4, (s, CvO
Lev ester), 73.9, 69.2, 68.8 (each d, C-3-5), 67.1 (t, C-1),
38.9, 38.8 (q, Me3C), 31.4 (t, C-6), 37.9, 37.8, 27.9, 27.6
(each t, CH2CH2), 29.7 (q, Lev CH3), 27.2, 26.8 (each q, Piv
CH3); LRMS: 625.2 [MþH2O]þ, 630.2 [MþNa]þ, 646.2,
[MþK]þ. Anal. Calcd for C26H39BrO11: C, 51.41; H, 6.47;
Br, 13.15. Found: C, 51.11; H, 6.19; Br, 13.06.
4.1.10. 3,5-Di-O-levulinoyl-1,4-di-O-pivaloyl-b-D-fructo-
pyranose 21. Fructose derivative 20 (700 mg) was dis-
solved in TFA/H2O 4:1 (10 mL) and the mixture stirred at
room temperature for 2 h. The reaction mixture was then
evaporated and coevaporated with toluene. The residue was
purified by chromatography (petroleum ether/AcOEt 1:1
then 0:1) and gave 3,5-di-O-levulinoyl-4-O-pivaloyl-b-D-
fructopyranose (85%, white solid) and 1,5-di-O-levulinoyl-
4-O-pivaloyl-b-D-fructopyranose (11%, heavy syrup,
resulting from migration of levulinate from O-3). Analytical
data for the 3,5-di-O-levulinate: 1H NMR (300 MHz,
CDCl3): d 5.27–5.40 (m, 3H, H-3-5), 4.16 (d, 1H,
J6a–6b¼213.2 Hz, H-6a), 3.84 (d, 1H, J6a–6b¼213.2 Hz,
H-6b), 3.64 (d, 1H, J¼211.7 Hz, H-1a), 3.56 (d, 1H,
J1a–1b¼211.7 Hz, H-1b), 2.47–2.80 (m, 8H, CH2CH2),
2.20, 2.19 (2s, 6H, Lev CH3), 1.12 (s, 9H, Piv); 13C NMR
(75 MHz, CDCl3): d 207.3, 206.9 (each s, CvO, Lev
ketone), 177.3 (s, CvO, Piv ester), 172.2, 171.9 (each s,
CvO Lev ester), 97.3 (s, C-2), 69.5, 68.2, 68.1 (each d,
C-5), 65.3, 61.5 (each t, C-1, C-6), 38.8 (s, Me3C), 29.9,
29.8 (each q, Lev CH3), 37.9, 37.8, 27.9 (each t, CH2CH2),
26.9 (q, CH3, Piv); [a]D¼274 (c 1.6, CHCl3); LRMS:
483.15 [MþNa]þ. Anal. Calcd for C21H32O11: C, 54.78; H,
7.00. Found: C, 54.79; H, 7.10. Analytical data for the 1,5-
di-O-levulinate: [a]D¼256 (c 2.1, CHCl3); 1H NMR
(300 MHz, CDCl3): d 5.28 (dd, 1H, J¼3.6, 1.8 Hz, H-5),
5.21 (dd, 1H, J4–5¼3.6 Hz, H-4), 4.45 (d, 1H,
J1a–1b¼211.4 Hz, H-1a), 4.21 (d, 1H, J1a–1b¼211.4 Hz,
H-1b), 4.14 (dd, 1H, J5–6a¼0.9 Hz, J6a–6b¼212.9 Hz,
H-6a), 3.88 (d, 1H, J3–4¼10.2 Hz, H-3), 3.75 (dd, 1H,
J5–6b¼1.8 Hz, H-6b), 2.62–2.85 (m, 8H, CH2CH2¼Lev),
2.19, 2.21 (each s, 6H, Lev CH3), 1.19 (s, 9H, Piv); 13C
NMR (75 MHz, CDCl3): d 206.4, 207.7 (each s, CvO, Lev
ketone), 178.3 (s, CvO, Piv ester), 173.0, 171.9 (s, CvO
Lev ester), 97.2 (s, C-2), 70.4, 69.6, 68.1 (each d, C-3, C-4,
C-5), 66.4, 61.7 (each t, C-1, C-6), 38.9 (s, Me3C), 38.2,
37.8, 27.9 (each t, CH2CH2), 29.8 (q, Lev CH3), 27.0 (q,
CH3, Piv); LRMS: 483.15 [MþNa]þ. The 3,5-di-O-
levulinate (579 mg, 1.25 mmol) was dissolved in pyridine
(5 mL), and PivCl (1.2 equiv.) added and the mixture was
stirred at room temperature overnight. The reaction was
diluted with CH2Cl2 and consecutively washed with 5%
HCl and 5% NaHCO3. After drying over magnesium
sulfate, the solution was concentrated under reduced
pressure and the residue chromatographed (petroleum
ether/EtOAc, 1:1) to give 21 (616 mg, 90%, white solid;
[a]D¼238 (c 2.8, CHCl3); 1H NMR (300 MHz, CDCl3): d
5.43 (d, 1H, J3–4¼10.2 Hz, H-3), 5.24–5.28 (m, 2H, H-4,
H-5), 4.11 (d, 1H, J6a–6b¼213.2 Hz, H-6a), 4.04 (s, 2H,
H-1a, H-1b), 3.69 (d, 1H, J6a–6b¼213.2 Hz, H-6b), 2.66–
2.48 (m, 8H, CH2CH2), 2.11 (each s, 6H, Lev), 1.05, 1.17
(each s, 18H, Piv); 13C NMR (75MHz, CDCl3) d 206.3,
206.5 (s, CvO, Lev ketone), 177.5, 178.4 (s, CvO, piv
4.1.12. 6-Bromo-6-deoxy-1,4-di-O-pivaloyl-b-D-fructo-
furanose 23. Fructose derivative 22 (1.331 g, 2.19 mmol)
was dissolved in pyridine (10 mL) and acetic acid (5 mL),
cooled to 0 8C then hydrazine hydrate (3 equiv.) was added
and the mixture stirred until reaction was judged complete
by TLC analysis. The mixture was then diluted with
dichloromethane (25 mL) and washed with a cold 5%
aqueous HCl, then with 5% aqueous NaHCO3. After drying
over MgSO4, the solvent was evaporated and the residue
purified by chromatography (petroleum ether/AcOEt 7:3) to
give the title compound 23 (593 mg, 66%, colourless
powder); 1H NMR (300 MHz, CDCl3): d 4.96 (t, 1H,
J¼4.8 Hz, H-4), 4.19–4.28 (m, 2H, H-1a, H-1b), 4.09–4.16
(m, 2H, H-3, H-5), 3.85 (broad d, 1H, OH), 3.57–3.69 (m,
2H, H-6a, H-6b), 1.24, 1.22 (each s, 18H, Piv); 13C NMR
(75 MHz, CDCl3) d 179.9, 178.3 (each s, CvO), 102.3 (s,
C-2), 83.3, 79.9, 77.6 (each d, C-3-5), 64.9 (t, C-1), 38.7,
38.9 (Me3C), 33.2 (t, C-6), 27.0, 27.1 (each q, CH3); HRMS:
Found 409.0855, required 409.0862 [M2H]2.
4.1.13. 6-Azido-6-deoxy-1,4-di-O-pivaloyl-b-D-fructo-
furanose 15. Bromide 23 (50 mg, 0.115 mmol) was
dissolved in DMF (1 mL) and then NaN3 (20 equiv.) was
added. The mixture was stirred for 2 days at room
temperature. Then solvent was then evaporated and the
residue chromatographed (petroleum ether/EtOAc, 7:3) to

6604
F. Chery et al. / Tetrahedron 60 (2004) 6597–6608
give the title compound 15 (23 mg, 53%, colourless gum);
1H NMR (300 MHz, CDCl3): d 4.95 (t, 1H, J¼4.8 Hz, H-4),
4.21–4.31 (m, 2H, H-1a, H-1b), 4.14 (d, 1H, J3–4¼5.4 Hz,
H-3), 4.02–4.07 (m, 1H, H-5), 3.61 (dd, 1H, J5–6a¼5.7 Hz,
J6a–6b¼212.9 Hz, H-6a), 3.53 (dd, 1H, J5–6b¼4.2 Hz,
J6a–6b¼212.9 Hz, H-6b), 1.22, 1.24 (each s, each 9H,
Piv); 13C NMR (75 MHz, CDCl3): d 179.4, 178.4 (each s,
CvO), 102.1 (s, C-2), 81.3, 80.7, 76.7 (each d, C-3-5), 65.1
(t, C-1), 53.4 (t, C-6), 38.9, 38.8 (each s, Me3C), 27.1, 27.0
(each q, CH3),; IR: 3450 (broad), 2973, 2936, 2875, 2103,
1730, 1482, 1461, 1399, 1367, 1285, 1150, 1039, 942, 770,
635 cm21; HRMS: Found 327.1779, required 327.1771
[MþH]þ.
(2£100 mL). It was then concentrated and purified by
chromatography to give 27 (quant. yield, white solid); mp
120–121 8C; [a]D¼251.8 (c 0.09, CH2Cl2); 1H NMR
(300 MHz, CDCl3): d 7.47–7.01 (m, 15H, aromatic H), 5.59
(s, 1H, CHC6H4), 5.17 (d, 1H, J1,2¼7.2 Hz, H-1), 4.85 (AB
d, 2H, J¼211.3 Hz, OCH2Ph), 4.37 (dd, 1H, J5,6a¼4.8 Hz,
J6a,6b¼210.4 Hz, H-6a), 4.05 (t, 1H, J¼7.4 Hz, H-2), 3.78
(m, 3H), 3.63 (dd, 1H, J¼4.5, 9.2 Hz), 1.11–1.02 (m, 21H);
13C NMR (CDCl3): d 156.7, 139.0, 137.5 (each s, each
aromatic C) 129.7, 129.2, 128.5, 128.4, 127.9, 127.6, 126.2,
122.5, 116.1 (each d, aromatic CH), 101.5, 100.9, 82.7, 82.2
(each d), 75.3 (d), 74.9 (t), 69.1 (t), 66.1 (d), 18.4, 18.3, 13.1;
IR (KBr): 2944, 2867, 1598, 1493, 1389, 1223, 1093,
1027 cm21. HRMS-CI: Found 591.3142, required 591.3141
[MþH]þ.
4.1.14. N-Benzyl-3,6-di-O-pivaloyl-1,5-dideoxy-1,5-
imino-D-mannitol 2. The azide 15 (100 mg, 0.27 mmol)
was dissolved in MeOH (5 mL), then 10% Pd–C (30 mg)
was added and the mixture stirred at room temperature
overnight under H2. The mixture was filtered and solvent
evaporated and the residue purified by chromatography
(EtOAc then EtOAc/MeOH/H2O 90:8:2 then 85:10:5) to
give 24 (19.5 mg, 22%, colourless gum); 1H NMR
(300 MHz, CD3OD): d 4.75 (dd, 1H, J2–3¼3.0 Hz, H-3),
4.41 (dd, 1H, J5–6a¼4.2 Hz, J6a–6b¼211.4 Hz, H-6a), 4.28
(dd, 1H, J5–6b¼2.4 Hz, J6a–6b¼211.4 Hz, H-6b), 4.07
(broad s, 1H, H-2), 3.93 (t, 1H, J3–4¼J4–5¼9.9 Hz, H-4),
3.06 (dd, 1H, J1a–2¼3.0 Hz, J1a–1b¼213.8 Hz, H-1a),2.96
(d, 1H, J1a–1b¼213.8 Hz, H-1b), 2.79 (dt, 1H,
J4–5¼9.3 Hz, J¼3.2 Hz, H-5), 1.30, 1.31 (each s, each
9H, Piv); 13C NMR (75 MHz, CD3OD): d 178.5, 178.3
(each s, CvO), 76.8, 65.9, 65.3, 59.4 (each C-2-5), 62.7,
49.0 (each t, C-1, C-6), 38.7 (s, Me3C), 26.2, 26.1 (each q,
CH3); LRMS: 332.2 [MþH]þ, 354.2 [MþNa]þ. This
intermediate (25 mg, 0.076 mmol) was dissolved in DMF
(1 mL) and then K2CO3 (0.6 equiv.) and benzyl bromide
(1.15 equiv.) were added and the mixture stirred for 4 h at
60 8C. The solvent was then evaporated and the residue
purified by chromatography (petroleum ether/EtOAc, 7:3,
1:1) to give the title compound (19 mg, 60%, colourless
4.1.16. Phenyl 4,6-di-O-acetyl-3-O-benzyl-2-O-tri-
isopropylsilyl-b-D-glucopyranoside 28. Glucoside 27
(12.0 g, 20.3 mmol) was dissolved in wet 30% TFA/
CH2Cl2 solution (240 mL) and the mixture was stirred for
6 h until judged complete by TLC analysis. Pyridine
(200 mL) was added, followed by acetic anhydride
(200 mL). After 16 h the solution was concentrated and
chromatography gave 28 (7.86 g, 66% for two steps, white
1
solid); [a]D¼264.2 (c 0.26, CHCl3), H NMR (300 MHz,
CDCl3): d 7.27–7.15 (m, 10H, aromatic H), 5.03 (t, 1H,
J¼9.4 Hz, H-4), 4.92 (d, 1H, J1,2¼7.5 Hz, H-1), 4.68 (AB d,
2H, J¼211.7 Hz, OCH2Ph), 4.13 (dd, 1H, J5,6a¼6.3 Hz,
J6a,6b¼212.2 Hz, H-6a), 4.01 (m, 2H, H-6b, H-2), 3.68
(ddd, 1H, J¼2.6, 6.3, 12.2 Hz, H-5), 3.59 (t, 1H, J¼8.8 Hz,
H-3), 1.94 and 1.77 (each s, CH3), 1.02–0.92 (m, 21H,
TIPS); 13C NMR (CDCl3): d 170.9, 169.9 (each s, CvO),
156.6, 138.6 (each s, aromatic C) 129.6, 128.5, 127.7, 127.5,
122.5, 116.4 (each d, aromatic CH), 100.2 (d, C-1), 84.1 (d),
75.4 (t, CH2Ph), 75.3, 72.2, 70.7 (each d), 62.9 (t, C-6), 20.9,
20.9 (each d), 18.4, 18.3, 13.3; IR (NaCl): 2946, 2887, 1745,
1599, 1498, 1366, 1228, 1057, 884, 783 cm21. HRMS-CI:
Found 604.3301, required 604.3306 [MþNH4]þ.
1
gum); H NMR (300 MHz, CDCl3): d 7.26–7.38 (m, 5H,
4.1.17. Phenyl 3-O-benzyl-6-O-tosyl-2-O-triisopropyl-
silyl-b-D-glucopyranoside 29. Diacetate 28 (1.82 g,
3.1 mmol) was dissolved in methanol (100 mL) and sodium
(0.1 g) was added. The solution was stirred for 5 min and
then amberlite IR-120 (plus) ion exchange resin was added,
which after 5 min was filtered and the solvent removed. The
residue was dissolved in pyridine (20 mL) and cooled to
0 8C. Tosyl chloride (4.0 g, 20.6 mmol) was added and the
mixture stirred for 3 h and then diluted with EtOAc
(60 mL). The excess tosyl chloride was removed by several
aqueous washes (100 mL each). After drying and filtration
the EtOAc was removed and residue purified by chroma-
tography to give 29 (1.73 g, 85%, clear syrup); [a]D¼265.8
(c 0.44, CHCl3), 1H NMR (300 MHz, CDCl3): d 7.70–6.92
(m, 14H, aromatic H), 4.85 (AB d, 2H, J¼212.0 Hz,
OCH2Ph), 4.98 (d, 1H, J1,2¼7.3 Hz, H-1), 4.77 (dd, 1H,
J5,6a¼2.05 Hz, J6a,6b¼211.7 Hz, H-6a), 4.35 (dd, 1H,
J5,6b¼6.1 Hz, J6a,6b¼211.7 Hz, H-6b), 3.97 (t, 1H,
J¼8.0 Hz, H-2), 3.64 (ddd, 1H, J¼2.1, 9.9, 6.1 Hz, H-5),
3.59 (dd, 1H, J4,3¼8.7 Hz, J4,5¼9.9 Hz, H-4), 3.45 (t, 1H,
J¼8.7 Hz, H-3), 2.38 (s, 3H, CH3), 2.25 (br s, 1H, OH),
1.14–1.04 (m, 21H); 13C NMR (CDCl3): d 156.5, 144.9,
138.8, 132.7 (each s, each aromatic C) 129.9, 129.6, 128.9,
128.2, 128.1, 127.9, 122.4, 116.6 (each d, aromatic CH),
Ph), 4.68 (dd, 1H, J2–3¼3.0 Hz, J3–4¼9.0 Hz, H-3), 4.61
(dd, 1H, J5–6a¼3.3 Hz, J6a–6b¼212.6 Hz, H-6a), 4.54 (dd,
1H, J5–6b¼3.0 Hz, J6a–6b¼212.6 Hz, H-6b), 4.15 (d, 1H,
J¼213.2 Hz, CH2), 3.86–3.91 (m, 2H, H-2, H-4), 3.35 (d,
1H, J¼213.2 Hz, CH2), 2.87 (dd, 1H, J1a–2¼4.5 Hz,
J1a–1b¼212.0 Hz, H-1a), 2.55 (dt, 1H, J¼3.0, 9.5 Hz,
H-5), 2.33 (broad d, 1H, J1a–1b¼212.0 Hz, H-1b), 1.25 (s,
18H, Piv); 13C NMR (75 MHz, CDCl3) d 178.0, 177.8 (each
s, Piv CvO), 136.8 (each s, aromatic C), 127.9, 127.7,
127.6, 126.5 (each d, aromatic CH), 77.2, 67.4, 65.9, 65.8,
(each d, C-2-5), 59.3, 55.8, 52.9 (each t, CH2, C-1, C-6),
38.1, 37.9 (each s, Me3C), 26.2, 26.1 (each q, CH3); HRMS:
Found 422.5345, required 422.5351 [MþH]þ.
4.1.15. Phenyl 3-O-benzyl-4,6-O-benzylidene-2-O-tri-
isopropylsilyl-b-D-glucopyranoside 27. To
a stirred
solution of 26 (11.5 g, 26.5 mmol) and 2,6-lutidine
(18.5 mL, 159 mmol) in CH2Cl2 (120 mL) at 0 8C was
added triisopropylsilyl triflate (28.5 mL, 160 mmol). The
solution was allowed to warm to room temperature and the
reaction was allowed to stir overnight. The solution was
then diluted with CH2Cl2 (50 mL) and washed with a satd.
soln of NH4Cl (2£100 mL) and then washed with water

F. Chery et al. / Tetrahedron 60 (2004) 6597–6608
6605
99.7 (d, C-1), 85.9 (d), 75.4 (t), 74.9, 73.5, 69.6 (each d),
68.9 (t), 21.8, 18.4, 18.3, 13.4; IR (film on NaCl): 3471,
2945, 2856, 1588, 1495, 1359, 1232, 1174, 1070, 883, 748,
668 cm21. HRMS: Found 679.2740, required 679.2737.
[MþNa]þ.
(each d), 75.5 (t), 75.3 (d), 75.1 (t), 74.9 (d), 51.7, 23.7 (each
t), 18.4 (2s), 13.4, 10.7; IR (KBr): 2941, 2866, 2101, 1599,
1495, 1232, 1163, 1097 cm21. HRMS-CI: Found 587.3631,
required 587.3629 [MþNH4]þ.
4.1.21. Phenyl 6-azido-6-deoxy-3-O-benzyl-4-O-isobutyl-
2-O-triisopropylsilyl-b-D-glucopyranoside 30d. Reaction
of azide 30a (0.28 g, 0.53 mmol) with 1-bromo-2-methyl-
propane as described for preparation of 30b gave unreacted
30a (0.165 g, 54%) and 30d (90 mg, 30%, clear syrup);
[a]D¼256.8 (c 0.96, CHCl3); 1H NMR (300 MHz, CDCl3):
d 7.38–7.00 (m, 10H, aromatic H), 5.03 (d, 1H,
J1,2¼7.3 Hz, H-1), 4.92 (s, 2H, OCH2Ph), 4.03 (t, 1H,
J¼8.5 Hz), 3.65–3.54 (m, 4H), 3.44 (dd, 1H, J6a,5¼6.6 Hz,
J6a,6b¼212.8 Hz, H-6a), 3.36 (t, 1H, J¼9.4 Hz), 3.22 (t, 1H,
J¼7.3 Hz), 1.76 (m, 1H, isobutyl CH), 1.29–1.02 (m, 21H,
4.1.18. Phenyl 6-azido-6-deoxy-3-O-benzyl-2-O-tri-
isopropylsilyl-b-D-glucopyranoside 30a. Tosylate 29
(1.7 g, 2.6 mmol) was dissolved in DMF (52 mL) and
sodium azide (1.36 g, 21 mmol) was added. The suspension
was stirred and heated at 90 8C for 16 h, after which the
reaction was complete. The solution was diluted with
EtOAc (50 mL) and the excess sodium azide removed with
several aqueous washes (50 mL). Filtration through silica
gave 30a (0.98 g, 72%, clear syrup); [a]D¼2147.6 (c 0.49,
CHCl3), 1H NMR (300 MHz, CDCl3): d 7.44–7.03 (m,
10H, aromatic H), 5.08 (d, 1H, J1,2¼7.2 Hz, H-1), 4.90 (AB
d, 2H, J¼211.8 Hz, OCH2Ph), 4.11 (t, 1H, J¼8.0 Hz, H-2),
3.57–3.39 (m, 5H, H-3, 4, 5, 6a, 6b), 2.42 (broad s, 1H,
OH), 1.21–1.10 (m, 21H, TIPS); 13C NMR (CDCl3): d
156.5, 138.9 (each s, aromatic C) 129.7, 128.9, 128.2, 127.9,
122.5, 116.0 (each d, aromatic CH), 100.0 (d, C-1), 86.3 (d),
75.5 (t), 75.3, 75.0, 70.9 (each d), 51.9 (t), 18.4, 18.3, 13.5;
IR (KBr): 2943, 2885, 2101, 1598, 1495, 1236, 1072, 883,
753, 695 cm21. HRMS-CI: Found 545.3159, required
545.3159 [MþNH4]þ.
TIPS), 0.89, 0.83 (each d, 6H, J¼6.6 Hz, isobutyl CH3); 13
C
NMR (CDCl3): d 156.5, 139.0 (each s, aromatic C) 129.6,
128.4, 127.5, 127.2, 122.4, 116.1 (each d, aromatic CH),
100.1 (d, C-1), 86.2 (d), 80.1 (t), 79.4 (d), 75.4 (t), 75.3, 74.0
(each d), 51.7 (t, C-6), 19.6, 19.4, 18.4, 18.3, 13.4. HRMS-
CI: Found 601.3789, required 601.3785 [MþNH4]þ.
4.1.22. Phenyl 6-azido-6-deoxy-3,4-di-O-benzyl-2-O-tri-
isopropylsilyl-b-D-glucopyranoside 30e. Reaction of
azide 30a (0.1 g, 0.19 mmol) with 1-bromo-2-methyl-
propane as described for preparation of 30b gave 30e
(97 mg, 81%, clear syrup); [a]D¼245 (c 0.16, CHCl3); 1H
NMR (300 MHz, CDCl3): d 7.36–6.96 (m, 15H, aromatic
H), 5.07 (d, 1H, J1,2¼7.5 Hz, H-1), 5.00 (AB d, 2H,
J¼211.0 Hz, OCH2Ph), 4.75 (AB d, 2H, J¼211.1 Hz,
OCH2Ph), 4.13 (t, 1H, J¼6.9 Hz), 3.67 (m, 3H), 3.53 (dd,
1H, J¼213.0, 2.0 Hz), 3.37 (dd, 1H, J¼6.2, 213.0 Hz),
1.10–1.00 (m, 21H, TIPS); 13C NMR (CDCl3): d 156.5,
138.9, 137.9 (each s, aromatic C) 129.7, 128.7, 128.5, 128.2,
128.2, 127.6, 127.3, 122.5, 116.1 (each d, aromatic CH),
100.2 (d, C-1), 86.4, 78.9 (each d), 75.6 (d), 75.6, 75.3 (each
t), 74.6 (d), 51.6 (t), 18.5, 18.4, 13.5; IR (KBr): 3414, 2925,
2867, 2100, 1599, 1495, 1454, 1231, 1163, 1071, 751,
694 cm21. HRMS-CI: Found 635.3626, required 635.3629
[MþNH4]þ.
4.1.19. Phenyl 6-azido-6-deoxy-3-O-benzyl-4-O-methyl-
O-triisopropylsilyl-b-D-glucopyranoside 30b. Azide 30a
(0.1 g, 0.19 mmol) was dissolved in anhyd. DMF (5 mL)
and cooled to 0 8C. Sodium hydride (60% in mineral oil,
0.19 g) was added and the suspension was stirred for
20 min. Methyl iodide (0.2 mL, 1.4 mmol) was then added
and the mixture warmed to room temperature. After 3 h the
reaction was quenched by careful addition of methanol. The
solution was then diluted with ethyl acetate (30 mL) and
washed with water (2£30 mL). Chromatography gave
recovered 30a (14 mg, 12%) and 30b (90 mg, 88%, clear
1
syrup); [a]D¼2114 (c 0.2, CHCl3); H NMR (300 MHz,
CDCl3): d 7.38–6.96 (m, 10H, aromatic H), 4.98 (d, 1H,
J1,2¼7.4 Hz, H-1), 4.88 (s, 2H, OCH2Ph), 3.98 (t, 1H,
J¼8.0 Hz, H-2), 3.57–3.37 (m, 7H, H-3, 5, 6a, 6b, OMe),
3.25 (t, 1H, J4,5¼9.0 Hz, H-4), 1.09–0.99 (m, 21H, TIPS);
13C NMR (CDCl3): d 156.6, 138.9 (each s, aromatic C)
129.6, 128.5, 127.6, 127.4, 122.5, 116.5 (each d, aromatic
CH), 100.2 (d, C-1), 86.1, 81.3 (each d), 75.5 (t, CH2Ph),
75.3, 74.7, 61.6 (each d), 51.7 (t), 18.4, 18.3, 13.4; IR (KBr):
2942, 2866, 2100, 1599, 1495, 1360, 1283, 1231, 1160,
1092, 1066 cm21; HRMS-CI: Found 559.3314, required
559.3316 [MþNH4]þ.
4.1.23. Phenyl 6-(N-acetylvalinyl)amino-6-deoxy-3-O-
benzyl-b-D-glucopyranoside 4a. Azide 30a (0.23 g,
0.43 mmol) was dissolved in EtOH:EtOAc (5:3, 15 mL)
and Lindlar catalyst (0.4 g) was added. The suspension was
stirred under H2 (1 atm) for 2.5 h, then filtered and the
solvent removed. The residue was dissolved in dichloro-
methane and added to a solution of Ac-Val-OH (0.13 g,
0.6 mmol), BOP–Cl (0.16 g, 0.63 mmol) and DIPEA
(0.28 mL) which had been stirred for 5 min in dichloro-
methane (10 mL) at rt. The reaction was complete after 5 h
as judged by TLC analysis and purification by chromato-
graphy gave 31a (50 mg, 79%, clear syrup); [a]D¼243 (c
4.1.20. Phenyl 6-azido-6-deoxy-3-O-benzyl-4-O-propyl-
2-O-triisopropylsilyl-b-D-glucopyranoside 30c. Reaction
of azide 30a (0.21 g, 0.4 mmol) with 1-bromopropane as
described for preparation of 30b gave 30c (0.18 g, 79%,
clear syrup); [a]D¼253.3 (c 0.23, CHCl3); 1H NMR
(300 MHz, CDCl3): d 7.36–6.96 (m, 10H, aromatic H),
4.99 (d, 1H, J1,2¼7.4 Hz, H-1), 4.89 (s, 2H, OCH2Ph), 3.99
(t, 1H, J¼7.0 Hz), 3.76 (dd, 1H, J¼6.7, 8.7 Hz), 3.67–3.37
(m, 6H), 1.56 (m, 2H, CH2CH3), 1.16–1.06 (m, 21H, TIPS),
0.89 (t, 3H, J¼7.2 Hz, CH2CH3); 13C NMR (CDCl3): d
156.6, 138.0 (each s, aromatic C) 129.6, 128.4, 127.5, 127.2,
116.1 (each d, aromatic CH), 100.2 (d, C-1), 86.2, 79.4
1
0.075, CHCl3); H NMR (300 MHz, CDCl3): d 7.30–6.90
(m, 10H, aromatic H), 6.10–6.38 (overlapping signals, 2H,
NH), 4.90 (AB d, 2H, J¼211.4 Hz, OCH2Ph), 4.90 (d, 1H,
J1,2¼7.5 Hz, H-1), 4.20 (dd, 1H, J¼6.9, 8.8 Hz,
NHCHCH(Me)2), 3.29–3.85 (m, 3H), 3.67–3.36 (m, 3H),
3.28 (dd, 1H, J¼2.9, 214.0 Hz), 2.01 (m, 1H, (Me)2CH),
1.92 (s, 3H, Ac), 0.99–0.91 (m, 21H, TIPS), 0.80 and 0.83
(2£d, 6H, J¼7.0 Hz, (CH3)2CH); 13C NMR (75 MHz,
CDCl3): 173.1, 170.5 (each s, CvO), 156.4, 139.1 (each s,

6606
F. Chery et al. / Tetrahedron 60 (2004) 6597–6608
aromatic C), 129.5, 128.1, 127.4, 127.3, 122.1, 115.5, (each
d, aromatic C), 99.8 (d, C-1), 84.7, 74.7 (each d), 74.3 (t,
CH2Ph), 71.5 (d), 58.4 (t, C-6), 40.2, 30.9, 29.7, 22.9, 19.2,
18.1, 18.0, 12.9; LRMS: 665.4 [MþNa]þ. This intermediate
(50 mg, 0.078 mmol) was dissolved in anhyd. THF (2.5 mL)
and cooled to 0 8C. Tetrabutylammonium fluoride (38 mg,
0.15 mmol) was added and the solution was stirred for
30 min. The solvent was removed and the residue purified
by chromatography to give 4a (25 mg, 65%, white solid);
[a]D¼235.2 (c 0.38, MeOH); 1H NMR (300 MHz,
CD3OD): d 7.45–6.98 (m, 10H, aromatic H), 4.93 (d, 1H,
J1,2¼7.6 Hz, H-1), 4.90 (AB d, 2H, J¼11.1 Hz, OCH2Ph),
4.14 (d, 1H, J¼7.0 Hz), 3.44–3.64 (m, 4H), 3.37 (t, 1H,
J¼9.0 Hz), 2.03 (s, 3H, Ac), 2.00 (m, 1H, (CH3)2CH),
0.90–0.88 (m, 6H, (CH3)2CH); 13C NMR (CD3OD): d
174.4, 173.4 (each s, CvO), 159.1, 140.5 (each s, aromatic
C) 130.6, 129.2, 129.1, 128.5, 123.5, 117.8 (each d,
aromatic CH), 102.1 (d, C-1), 85.7, 75.9, 75.1, 72.8 (each
d, C-2-5), 76.1 (t), 60.6 (d), 41.6 (t, C-6), 31.8, (d), 22.5,
19.8, 18.6; HRMS-CI: Found 487.2443, required 487.2444;
[MþH]þ.
140.3 (each s, aromatic C) 130.6, 129.3, 129.1, 128.6, 123.5,
117.7 (each d, aromatic CH), 101.9 (d, C-1), 86.0, 82.0,
75.5, 74.8 (each d, C-2-5), 76.2 (t, CH2Ph), 61.2 (d), 60.7
(q), 41.2 (t, C-6), 31.8 (d, (CH3)2CH), 22.5, (q, Ac), 19.8,
18.5 (each q, (CH3)2CH); d 13C NMR (CDCl3, selected data
for minor diastereoisomer): d 173.8, 173.9 (each s, CvO),
159.1, (s, aromatic C) 130.5, 129.1, 123.6, 118.0 (each d,
aromatic CH), 102.3 (d, C-1), 85.9, 81.8, 75.1 (each d), 76.2
(t), 61.1 (d), 60.3 (q), 41.1 (t); IR (KBr): 3330, 2924, 2859,
1655, 1565, 1497, 1233, 1104, 1077, 766, 567 cm21
.
HRMS-CI: Found 501.2600, required 501.2601; [MþH]þ.
4.1.26. Phenyl 6-(N-acetylvalinyl)amino-6-deoxy-3-O-
benzyl-4-O-propyl-2-O-triisopropylsilyl-b-D-gluco-
pyranoside 31c. Azide 30c (0.178 g, 0.31 mmol) was
treated as described for 30a and gave the title compound
31c (50 mg, 23%, clear syrup); [a]D¼27.2 (c 0.27, CHCl3);
1H NMR (300 MHz, CDCl3): d 7.40–6.96 (m, 10H,
aromatic H), 6.37 (d, 1H, J¼8.8 Hz, NH, minor diastereo-
isomer), 6.22 (d, 1H, J¼8.6 Hz, NH, major diastereo-
isomer), 6.20 (t, 1H, J¼5.5 Hz, NH), 5.05 and 5.01 (2d, 1H,
J1,2¼7.5 Hz, H-1), 4.91 (s, 2H, OCH2Ph), 4.20 (t, 1H,
J¼6.5 Hz, CHCH(Me)2), 3.97 (t, 1H, J¼8.7 Hz), 3.84 (ddd,
1H, J¼2.9, 5.8, 213.6 Hz, H-6a), 3.29–3.72 (m, 3H), 3.24
(t, J¼9.0 Hz, 1H), 2.06 (m, 1H), 1.98 (s, 3H), 1.55 (m, 2H),
0.87–1.15 (m, 30H); 13C NMR (CDCl3): 171.2, 170.1 (each
s, CvO), 156.1, 138.7 (each s, aromatic C), 129.6, 128.1,
127.3, 127.0, 122.3, 115.3 (each d, aromatic CH), 99.2 (d,
C-1), 85.8, 79.9 (each d), 75.2 (t), 74.9 (d), 74.8 (t), 74.0,
73.6 (d), 58.6 (t, C-6), 40.2 (t), 31.1, 23.5, 23.1, 19.1, 18.1,
18.0, 13.1, 10.4; IR (film on NaCl); 3286, 2962, 1642, 1547,
1370, 1231, 1092 cm21; HRMS-FAB: Found 707.4062,
required 707.4068 [MþNa]þ.
4.1.24. Phenyl 6-(N-acetylvalinyl)amino-6-deoxy-3-O-
benzyl-4-O-methyl-2-O-triisopropylsilyl-b-D-gluco-
pyranoside 31b. Azide 30b (0.17 g, 0.3 mmol) was treated
as described for 30a and gave the title compound 31b
(0.117 g, 66%, clear syrup) as a mixture of diasteroisomers;
[a]D¼28.7 (c 0.3, CHCl3); 1H NMR (300 MHz, CDCl3): d
7.37–6.90 (m, 10H, aromatic H), 6.10–6.23 (overlapping
signals, 2H, NH), 5.00 and 5.02 (each d, 1H, J1,2¼7.5 Hz,
H-1), 4.88 (s, 2H, OCH2Ph), 4.13–4.21 (2 overlapping t,
1H, J¼8.5 Hz), 3.99 and 3.98 (each t, 1H, J¼8.0 Hz), 3.82
(ddd, 1H, J¼3.7, 6.3, 13.7 Hz, H-6a), 3.56 (t, 1H,
J¼9.5 Hz), 3.48 (s, 3H, OCH3), 3.41–3.56 (m, 3H), 3.14
(t, 1H, J¼9.0 Hz, H-4), 2.05 (m, 1H, CH(Me)2), 1.97 (s, 3H,
Ac), 1.08–0.90 (m, 27H); 13C NMR (75 MHz, CDCl3,
major isomer): 171.2, 170.1 (each s, CvO), 156.0 (s,
aromatic C), 129.6, 128.1, 127.4, 127.3, 122.3, 115.4, (each
d, aromatic C), 99.2 (d, C-1), 85.7, 81.7 (each d), 75.3 (t,
CH2Ph), 74.9, 73.4, 60.8, 58.6 (each d), 40.1 (t, C-6), 31.5,
31.1 29.7, 23.2, 19.1, 18.1, 13.1; 13C NMR (75 MHz,
CDCl3, selected signals for minor isomer); d 171.1, 170.0
(each s, CvO), 156.2 (s, aromatic C), 129.5, 128.1, 127.3,
127.2, 122.4, 115.6, (each d, aromatic CH), 99.6 (d, C-1),
85.6, 81.4 (each d), 75.2 (t, CH2Ph), 74.8, 73.8, 60.8, 58.3
(each d), 40.0 (t, C-6), 31.9, 29.7, 23.2, 19.1, 18.2, 13.1; IR
(NaCl plates): 3288, 2930, 1634, 1557, 1373, 1231,
4.1.27. Phenyl 6-(N-acetylvalinyl)amino-6-deoxy-3-O-
benzyl-4-O-propyl-b-D-glucopyranoside 4c. Glucoside
31c (0.11g, 0.16 mmol) was treated as described for 31a
to give the title compound 4c (37 mg, 44%, white solid);
[a]D¼222.5 (c 0.18, MeOH); 1H NMR (500 MHz,
CD3OD): d 7.41–6.98 (m, 10H, aromatic H), 4.90 (AB d,
2H, J¼211.0 Hz, OCH2Ph), 4.92 (d, 1H, J1,2¼7.2 Hz,
H-1), 4.15 (d, 1H, J¼6.8 Hz), 3.51–3.80 (m, 5H), 3.16 (t,
1H, J¼8.6 Hz), 2.15 (m, 1H), 1.98 (s, 3H), 1.54 (m, 2H),
0.92–0.87 (m, 6H); 13C NMR (CD3OD, major diastereo-
isomer): d 173.9, 173.4 (each s, CvO), 159.2, 140.3 (each s,
aromatic C) 130.6, 129.3, 128.9, 128.6, 123.5, 117.7 (each
d, aromatic CH), 101.95 (d, C-1), 76.3 (t), 76.25 (t), 86.1,
80.4, 75.8, 75.5, 74.9, 60.6 (each d), 41.2 (t), 31.8, 24.6,
22.4, 19.8, 10.9; 13C NMR (CD3OD, selected data for minor
diastereoisomer): d 173.8, 173.3 (each s, CvO), 159.2,
140.3 (each s, each aromatic C) 130.5, 129.3, 128.9, 128.5,
123.6, 118.0 (each d, each aromatic CH), 102.3 (d, C-1),
86.0, 80.2, 75.8, 75.5, 75.2, 60.3 (each d), 41.1 (t, C-6), 30.8,
24.6, 19.8, 11.0; HRMS-CI: Found 529.2917, required
529.2914; [MþH]þ.
1103 cm21
; HRMS-FAB: Found 679.3755, required
679.3755, [MþNa]þ.
4.1.25. Phenyl 6-(N-acetylvalinyl)amino-6-deoxy-3-O-
benzyl-4-O-methyl-b-D-glucopyranoside 4b. Glucoside
31b (0.11 g, 0.17 mmol) was treated as described for 31a
to give 4b (75 mg, 88%, white solid); [a]D¼20.2 (c 0.05,
1
MeOH); H NMR (500 MHz, CD3OD): d 7.44–7.02 (m,
10H, aromatic H), 4.88 (d, 1H, J1,2¼7.6 Hz, H-1), 4.85 (AB
d, 2H, J¼211.1 Hz, OCH2Ph), 4.10 (d, 1H, J¼6.8 Hz,
CHCH(Me)2), 3.59–3.49 (m, 4H), 3.36 (s, 3H), 3.07 (t, 1H,
J¼8.4 Hz), 2.08 (s, 3H, Ac), 1.97 (m, 1H, (CH3)2CH),
0.90–0.86 (m, 6H, (CH3)2CH); 1H NMR (500 MHz,
CD3CN, selected data) d 6.68 (br s, 1H, NH) and 6.55 (d,
1H, J¼6.3 Hz, NH): 13C NMR (75 MHz, CDCl3, major
diastereoisomer): d 174.0, 173.4 (each s, CvO), 159.1,
4.1.28. Phenyl 6-(N-acetylvalinyl)amino-6-deoxy-3-O-
benzyl-4-O-isobutyl-2-O-triisopropylsilyl-b-D-gluco-
pyranoside 31d. Azide 30d (0.137 g, 0.23 mmol) was
treated as described for 30a and gave the title compound
31d (60 mg, 38%, white solid); [a]D¼215 (c 0.21, CHCl3);
1H NMR (300 MHz, CDCl3):
d
7.40–6.90 (m,
10H, aromatic H), 6.37 (d, 1H, J¼8.7 Hz, NH, minor

F. Chery et al. / Tetrahedron 60 (2004) 6597–6608
6607
diastereoisomer), 6.25 (d, 1H, J¼8.7 Hz, NH, major
diastereoisomer), 5.50 (t, 1H, J¼5.5 Hz, NH), 5.00 and
5.03 (each d, 1H, J1,2¼7.3 Hz, H-1), 4.88 (s, 2H, OCH2Ph),
4.16 (2d, 1H, J¼6.4 Hz), 3.94 (t, 1H, J¼7.8 Hz), 3.86 (ddd,
1H, J¼2.8, 6.1, 213.5 Hz, H-6a), 3.17–3.59 (m, 5H), 1.96
(s, 3H), 1.78 (m, 1H), 0.86–1.08 (m, 33H); 13C NMR
(75 MHz, CDCl3): 171.5, 170.1 (each s, CvO), 156.2,
138.8 (each s, aromatic C), 129.7, 128.2, 127.3, 127.1,
127.0, 122.3 (each d, aromatic CH), 115.7, 115.4 (each d),
99.6 (d, C-1), 85.8 (d), 80.0 (t), 79.9 (d), 75.1 (t), 73.7, 58.6
(each d), 40.2 (t), 31.2, 29.1, 23.2, 19.4, 19.2, 19.1, 18.2,
18.1, 13.2; HRMS-FAB: Found 721.4224, required
721.4224; [MþNa]þ.
(s, 1H), 0.93 (m, 6H); 13C NMR (CD3OD, major
diastereoisomer): d 174.0, 173.5 (each s, CvO), 159.2,
140.2, 139. 8 (each s, aromatic C) 130.6, 129.4, 129.3 (2s),
129.2, 129.1, 128.8, 123.5, 117.7 (each d, aromatic CH),
102.0 (d, C-1), 86.3 (d), 79.9, 76.3 (t) 74.8 76.0, 75.7, 74.8,
60.7 (each d), 41.1 (t), 31.8, 22.5, 19.9, 18.6; 13C NMR
(CD3OD, selected data for minor diastereoisomer): d 173.9,
173.3 (each s, CvO), 159.1, 140.3, 139.7 (each s, aromatic
C) 130.7, 130.6, 129.4, 129.22, 129.2, 129.1, 128.7, 123.7,
118.0 (each d, aromatic CH), 102.4 (d, C-1), 86.2 (d), 79.6,
76.3 (each t), 75.9, 75.7, 75.1, 60.4 (each d), 41.1 (t, C-6),
22.5, 19.8; IR (film on NaCl); 3304, 2945, 1641, 1545,
1496, 1384, 1232, 1059.4 cm21
; HRMS-Cl: Found
577.2916, required 577.2914; [MþH]þ.
4.1.29. Phenyl 6-(N-acetylvalinyl)amino-6-deoxy-3-O-
benzyl-4-O-isobutyl-b-D-glucopyranoside 4d. Glucoside
31e (60 mg, 0.086 mmol) was treated as described for 31a to
give the title compound 4e (39 mg, 83%, white solid); mp:
209–210 8C; [a]D¼217.1 (c 0.24, MeOH); 1H NMR
(500 MHz, CD3OD): d 7.41–7.0 (m, 10H, aromatic H),
4.89 (AB d, 2H, J¼210.9 Hz, OCH2Ph), 4.93 (d, 1H,
J1,2¼7.3 Hz, H-1), 4.14 and 4.16 (each d, 1H, J¼6.8 Hz),
3.48–3.70 (m, 8H), 1.82 (m, 1H), 1.99 (s, 3H), 0.90–0.89
(m, 6H); 13C NMR (CD3OD, major diastereoisomer): d
172.5, 170.0 (each s, CvO), 155.9, 138.4 (each s, aromatic
C) 129.2, 129.1, 127.9, 127.5, 122.0, 116.3 (each d,
aromatic C), 100.5 (d, C-1), 84.8, 78.9, 74.1, 73.5 (each d,
C-2-5), 79.4 (t), 74.8 (t), 59.2 (d), 39.8 (t), 30.4, 28.9, 21.1,
18.4, 18.3, 17.1; 13C NMR (CD3OD, selected data for minor
diastereoisomer): d 116.6 (d, aromatic C), 101.0 (d, C-1); IR
(film on NaCl); 3300, 2957, 2430, 1637, 1544, 1495, 1370,
1235, 1066, 751, 698 cm21; HRMS-Cl: Found 543.3075,
required 543.3072; [MþH]þ
4.1.32. Phenyl 6-(N-tert-butoxycarbonylvalinyl)amino-
6-deoxy-3-O-benzyl-4-O-methyl-2-O-triisopropylsilyl-b-
D-glucopyranoside 32. Azide 30b (0.13 g, 0.24 mmol) was
dissolved in EtOH:EtOAc (5:3, 9 mL) and Lindlar catalyst
(0.22 g) was added and the suspension was stirred under
hydrogen (1 atm) for 6 h, then filtered and solvent removed.
The residue was dissolved in dichloromethane and added to
a mixture of BocVal–OH (14 mg, 0.063 mmol), HOBT
(9 mg, 0.07 mmol), HBTU (26 mg, 0.07 mmol) and DIPEA
(16 mg, 0.12 mmol) which had been stirred for 5 min in
dichloromethane (12 mL) at rt. The reaction was judged
complete by TLC analysis after 0.5 h and the title compound
(31 mg, 18%, white solid) as obtained after chromatography
of the residue; [a]D¼225.2 (c 0.29, CHCl3); mp: 120–
121 8C; 1H NMR (300 MHz, CDCl3): d 7.45–6.9 (m, 10H,
aromatic H), 6.17 (broad s, 1H, NH), 5.00 (d, 1H,
J1,2¼7.3 Hz, H-1), 4.95–5.0 (broad s, 1H, NH); 4.83 (d,
2H, J¼211.3 Hz, OCH2Ph), 3.93 (t, 1H, J¼8.3 Hz), 3.74–
3.88 (m, 2H) 3.42–3.56 (m), 3.48 (s, 3H), 3.13 (t, 1H,
J¼9.1 Hz), 2.07 (m, 1H), 1.43 (s, 9H), 1.15–0.98 (m, 21H,
TIPS), 0.84 and 0.89 (2 d, J¼6.8 Hz, 6H, CH(CH3)2); 13C
NMR (CDCl3): d 171.5 (s, CvO), 156.3, 138.8 (each s,
aromatic C), 129.7, 128.2, 127.4, 127.2, 122.4, 115.6, (each
d, aromatic CH), 99.6 (d, C-1), 85.8, 81.6 (each d), 77.5 (t,
CH2Ph), 77.1, 76.7, 75.3, 75.0, 73.7, 60.9 (each d), 40.0 (t,
C-6), 30.9, 29.7, 28.4, 19.3, 17.6, 18.2, 18.1, 13.6; IR (film
on NaCl); 3420, 2941, 1655, 1495, 1355, 1233, 1067,
4.1.30. Phenyl 6-(N-acetylvalinyl)amino-6-deoxy-3,4-di-
O-benzyl-2-O-triisopropylsilyl-b-D-glucopyranoside
31e. Glucoside 30e (0.21 g, 0.33 mmol) was treated as
described for 30a to give the title compound 31e (78 mg,
1
31%, clear syrup); [a]D¼24.0 (c 0.25, CHCl3); H NMR
(300 MHz, CDCl3): d 7.40–6.93 (m, 15H, aromatic H), 6.37
(d, J¼8.7 Hz, NH, minor diastereoisomer), 6.28 (d, 1H,
J¼8.7 Hz, NH, major diastereoisomer), 6.22 (t, 1H,
J¼5.5 Hz), 5.04 (d, 1H, J1,2¼7.4 Hz, H-1), 4.92 (AB d,
2H, J¼211.5 Hz, OCH2Ph), 4.66 (AB d, 2H, J¼210.6 Hz,
OCH2Ph), 4.10–4.20 (m, 2H); 4.04 and 4.05 (each t, 1H,
J¼7.5 Hz), 3.32–3.80 (m, 3H), 3.46 (t, 1H, J¼9.1 Hz), 2.03
(m, 1H), 1.95 (s, 3H), 0.85–1.09 (m, 27H); 13C NMR
(CDCl3): 171.3, 170.1 (each s, CvO), 156.0, 138.5, 137.6
(each s, aromatic C), 129.6, 128.4, 128.0, 127.9, 127.3,
126.99, 126.9 122.3, 115.3 (each d, aromatic C), 99.2 (d,
C-1), 85.9, 79.3 (each d), 75.3 (t), 75.1 (d), 74.9 (t), 73.3,
58.6 (each d), 40.0 (t, C-6), 31.1, 23.1, 19.2, 18.3, 18.0, 13.1;
HRMS-FAB: Found 755.4065, required 755.4068;
[MþNa]þ.
884 cm21
;
HRMS-FAB: Found 737.4169, required
737.4173; [MþNa]þ. Anal. Calcd for C39H62N2O8Si: C,
65.51; H, 8.74; N, 3.92; Found: C, 65.28; H, 8.81; N, 3.63.
4.1.33. Phenyl 6-(N-tert-butoxycarbonylvalinyl)amino-
6-deoxy-3-O-benzyl-4-O-methyl-2-b-D-glucopyranoside
33. TIPS protected 32 (25 mg, 0.035 mmol) was dissolved
in anhyd. THF (2 mL) and cooled to 0 8C. Tetrabutyl-
ammonium fluoride (18 mg, 0.07 mmol) was added and the
solution was stirred for 30 min. The solvent was then
removed and purified by chromatography to give the title
compound 33 (13 mg, 66%, white solid): [a]D¼240 (c
0.085, CD3OD); 1H NMR (500 MHz, CD3OD): d 7.80 (1H,
broad s), 7.43–6.97 (m, 10H, aromatic H), 6.51 (d, 1H,
J¼7.7 Hz), 4.88 (AB d, 2H, J¼211.0 Hz, OCH2Ph), 5.00
(d, 1H, J1,2¼7.5 Hz, H-1), 3.86 (t, 1H, J¼7.8 Hz), 3.54 (s,
3H, OMe), 3.45–3.60 (m, 4H), 3.09 (t, 1H, J¼8.8 Hz), 2.06
(m, 1H), 1.45 (s, 9H), 0.9–0.85 (2d, 6H, J¼6.8 Hz,
CH(Me)2); 13C NMR (CD3OD): d 178.0, 173.4 (each s,
CvO), 157.6, 138.9 (each s, aromatic C) 129.2, 127.9,
127.6, 127.2, 122.0, 116.3 (each d, aromatic CH), 100.5 (d,
4.1.31. Phenyl 6-(N-acetylvalinyl)amino-6-deoxy-3, 4-O-
benzyl-b-D-glucopyranoside 4e. Valine derivative 31e
(66 mg, 0.1 mmol) was treated as described for 31a to
give 4e (40 mg, 77%, white solid); [a]D¼22.7 (c 0.15,
1
CH3CN); H NMR (500 MHz, CD3OD): d 7.40–6.98 (m,
15H, aromatic H), 4.88 (AB d, 2H, J¼211.0 Hz, OCH2Ph),
4.80 (d, 1H, J1,2¼7.6 Hz, H-1, overlapping with HOD), 4.16
(d, 1H, J¼6.88 Hz), 3.32–3.72 (m, 8H), 2.02 (m, 1H), 1.96

6608
F. Chery et al. / Tetrahedron 60 (2004) 6597–6608
7. (a) Ghosh, M.; Dulina, R. G.; Kakarla, R.; Sofia, M. J. J. Org.
Chem. 2000, 65, 8387. (b) Wunberg, T.; Kallus, C.; Opatz, T.;
Henke, S.; Schmidt, W.; Kunz, H. Angew. Chem., Int. Ed.
Engl. 1998, 37, 2503. (c) Boer, J.; Gottschling, S. H. B.;
Kessler, H. Angew. Chem., Int. Ed. Engl. 2001, 40, 3870.
(d) Wessel, H. P.; Banner, D.; Gubernator, K.; Hilpert, K.;
Myller, K.; Tschopp, T. Angew. Chem., Int. Ed. Engl. 1997,
C-1), 84.7, 80.4 (each d), 74.8 (t), 74.1, 73.3, 59.8, 48.5 (d),
46.8 (q), 39.5 (t), 29.4, 27.4, 18.5, 16.9, 19.8, 18.5; IR (film
between NaCl plates); 3335, 2927, 2480, 1681, 1650, 1496,
1420, 1238, 1172, 1087, 762, 622 cm21; HRMS2Cl: Found
559.3024, required 559.3020; [MþH]þ.
Acknowledgements
´
36, 751. (e) Moitessier, N.; Dufour, S.; Chretien, F.; Thiery,
J. P.; Maigret, B.; Chapleur, Y. Bioorg. Med. Chem. 2001, 9,
511. (f) Papageorgiou, C.; Haltiner, R.; Bruns, C.; Petcher, T. J.
Bioorg. Med. Chem. Lett. 1992, 2, 135. (g) LeDiguarher, T.;
Boudon, A.; Elwell, C.; Paterson, D. E.; Billington, D. C.
Bioorg. Med. Chem. Lett. 1996, 6, 1983. (h) Sofia, M. J.;
Hunter, R.; Chan, T. Y.; Vaughan, A.; Dulina, R.; Wang,
H. M.; Gange, D. J. Org. Chem. 1998, 63, 2802. (i) Hanessian,
S.; Huynh, H. K. Synlett 1999, 1, 102. (j) Nakayama, K.;
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8. (a) Peri, F.; Cipolla, L.; Forni, E.; Nicotra, F. Monatsh. Chem.
2002, 133, 369–382. (b) Krueger, E. B.; Hopkins, T. P.;
Keaney, M. T.; Walters, M. A.; Boldi, A. M. J. Comb. Chem.
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We thank Enterprise Ireland (SC/2002/225) for a basic
research grant and IRCSET for a award of a postdoctoral
fellowship to FC.
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a different assay for each study. See Refs. 10,19.