Synthetic route towards (5R,2′S,5′S,6′S)-ribosyl-diazepanone, an analogue core of the liposidomycins

Article abstract of DOI:10.1016/j.tetasy.2007.07.023

The synthesis of (5R,2′S,5′S,6′S)-ribosyl-diazepanone, an analogue core of liposidomycins is described. The core ribosyl seven-membered heterocycle of nucleoside antibiotic liposidomycins was formed by reductive amination of an α-ribosylamino ester derived from d-ribose, and an amino aldehyde derived from methyl 4-triisopropylsilyloxy-3-oxobutanoate, followed by a peptidic coupling reaction.

Full text of DOI:10.1016/j.tetasy.2007.07.023

Tetrahedron: Asymmetry 18 (2007) 1955–1963
Synthetic route towards (5R,20S,50S,60S)-ribosyl-diazepanone,
an analogue core of the liposidomycins
Bruno Drouillat, Yann Bourdreux, Delphine Perdon and Christine Greck*
Institut Lavoisier de Versailles, UMR CNRS 8180, Universite´ de Versailles St-Quentin-en-Yvelines, 45,
Avenue des Etats Unis, 78035 Versailles Ce´dex, France
Received 10 July 2007; accepted 25 July 2007
Abstract—The synthesis of (5R,20S,50S,60S)-ribosyl-diazepanone, an analogue core of liposidomycins is described. The core ribosyl
seven-membered heterocycle of nucleoside antibiotic liposidomycins was formed by reductive amination of an a-ribosylamino ester
derived from D-ribose, and an amino aldehyde derived from methyl 4-triisopropylsilyloxy-3-oxobutanoate, followed by a peptidic cou-
pling reaction.
ꢀ 2007 Elsevier Ltd. All rights reserved.
HO
1. Introduction
NH2
N
HO3SO
O
The liposidomycins are a family of complex nucleoside
antibiotics that can be isolated from Streptomyces griseo-
sporeus.1 They act by inhibiting phospho-N-acetyl-mura-
myl-pentapeptide-transferase (translocase I), an enzyme
involved in the lipid cycle of the biosynthesis of bacterial
peptidoglycan.2 The liposidomycin core structure was elu-
cidated by NMR and mass spectra studies of their degrada-
tion products, which revealed the presence of a 50-
substituted uridine, a 5-amino-5-deoxyribose and a disub-
stituted 1,4-diazepan-3-one.3 The liposidomycins B and C
are the major members of this family (Fig. 1). They display
only minor peripheral structural differences in their lipidic
side chain. The determination of the absolute configuration
of the ribosyl-diazepanone core, although initially uncer-
tain, has been the subject of various synthetic approaches.4
Knapp et al.5 suggested that the unassigned stereogenic
centres for the ribosyl-diazepanone of liposidomycins pre-
sented a (S)-configuration. The X-ray crystal analysis of
caprazol,6 the core structure of the caprazamycins, which
are nucleoside antibiotics structurally and biologically re-
lated to the liposidomycins and recently synthesized by
Matsuda,7 confirmed the stereochemical assignments for
the liposidomycin core structure.
O
O
O
O
NH
N
O
N
R2
HO2C
HO OH
R1
O
7
Liposidomycin B : R1 = H , R2 = CH3
Liposidomycin C : R1 = CH3 , R2 = H
O
O
HO2C
O
Figure 1. Structures of liposidomycins B and C.
The liposidomycins are potential lead compounds for the
design of novel antibiotics acting on peptidoglycan biosyn-
thesis. We designed a convergent synthesis of liposidomy-
cin core analogues using the same methodology to
control the stereochemistry at each of the stereocentres of
the two intermediates necessary for the synthesis of the
ribosyl seven-membered heterocycle. We have used this
pathway to synthesize (5R,20S,50S,60S)-ribosyl-diazepa-
none 1, the 5-epi analogue core of the liposidomycins.
Retrosynthetic analysis (Scheme 1) shows that the core can
be divided into two key intermediates 2 and 3. Each precur-
sor was obtained with complete anti selectivity at C2–C3
from the corresponding b-ketoesters 4 and 5 by asymmet-
ric hydrogenation in the presence of a chiral ruthenium
*
Corresponding author. Tel.: +33 139254474; fax: +33 139254452;
e-mail: greck@chimie.uvsq.fr
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.07.023

1956
B. Drouillat et al. / Tetrahedron: Asymmetry 18 (2007) 1955–1963
OMEM
O
O
O
MeO2C
OMe
OMe
MeO2C
HN
OMEM
O
O
O
O
O
O
4
1
OMe
2'
4'HN
5
2
4
3'
3
2
1'
N
5'
MEMOH2C
MEMO
O
O
7'
6'
OMEM
O
H
O
1
TIPSO
CO2Me
OMEM
NHCbz
5
3
Scheme 1. Retrosynthetic analysis of the 5-epi analogue of the ribosyl diazepanone core of the liposidomycins.
catalyst, followed by electrophilic amination8 of the result-
ing b-hydroxyester.
Aldehyde precursor 3 was obtained from prochiral b-keto-
ester 5 using anti-2-amino-1,3,4-butanetriol intermediates
(Scheme 3).13 The first step was the hydrogenation of b-
ketoester 5 in methanol at 40 ꢁC under a pressure of
10 bar in the presence of 2 mol % of (S)-BinapRuBr2. Un-
der these conditions, b-hydroxyester 9 was obtained in 92%
yield and complete enantioselectivity as confirmed by euro-
pium-complex NMR studies by comparison with the race-
mic mixture.14 The zinc enolate of 9 was generated using
methyl zinc bromide and lithium diisopropylamide at
ꢀ78 ꢁC before reaction with dibenzyl azodicarboxylate to
give anti diastereoisomer 10 in 70% yield and with complete
diastereoselectivity. In order to shorten the synthesis of 3,
we tried initially to protect the secondary alcohol of com-
pound 10 with a methoxyethoxymethyl group. Unfortu-
nately, this protection was not successful under
sufficiently mild conditions. The hydroxyl function was
protected as a tert-butyldimethylsilyl ether because degra-
dation products were formed during N–N bond cleavage
of the free alcohol. One-pot deprotection and cleavage of
the deprotected hydrazine derivative was achieved under
an atmospheric pressure of hydrogen by successively add-
ing Pd/C and Raney Ni as catalysts to the reaction mixture.
The resulting a-amino ester was protected with a benzyl-
oxycarbonyl group to afford 11 in 70% yield from 10.
Reduction of the ester function of 11 to 2-aminobutanetriol
proceeded in high yield and without detectable epimeriza-
tion by using calcium borohydride.15
2. Results and discussion
b-Ketoester 4 derived from D-ribose was hydrogenated in
methanol at 40 ꢁC under an atmospheric pressure in the
presence of 2 mol % of (S)-BinapRuBr2 to afford the corre-
sponding b-hydroxyester 6 in quantitative yield as a 95/5
diastereomeric mixture. Compound 6 was separated by
flash chromatography and isolated in 94% yield as a single
diastereomer. The catalyst, prepared in situ from commer-
cially available Ru(Cod)(2-methylallyl)2,9 was shown to
control the stereochemistry at the created hydroxyl cen-
tre.10 Electrophilic amination of the zinc enolate of 6 was
performed at ꢀ78 ꢁC with dibenzyl azodicarboxylate to
produce anti-diastereoisomer 7 in 56% yield and with com-
plete diastereoselectivity. Catalytic hydrogenolysis of the
benzyl carbamates and of the N–N bond under atmo-
spheric pressure occurred simultaneously in the presence
of Raney Ni. The benzophenone Schiff base of the resulting
a-amino-b-hydroxyester, formed by transimination with
benzophenone imine in the presence of methanolic HCl,
was reduced with sodium cyanoborohydride.11 Reductive
N-methylation with a formaldehyde aqueous solution12
afforded 8 in 94% yield from 7. Crystallographic analysis
of a tert-butyldimethylsilyl ether derivative of 8 shows an
anti-relationship between the two adjacent aminated and
hydroxylated carbons with C-5 (R) and C-6 (S) absolute
configurations.10 Protection of the hydroxyl function of 8
with a methoxyethoxymethyl group followed by hydrogen-
olysis of the benzhydryl group in ethanol with Pd/C as cat-
alyst gave a-ribosylamino ester 2 in 58% yield (Scheme 2).
At this point, two synthetic pathways were used to obtain
aldehyde 3. The first route involves the hydroxyl protection
of 12 as a methoxyethoxymethyl ether, followed by desilyl-
ation of the two silyl ethers by TBAF in THF afforded diol
13 in 85% yield. This full desilylation was necessary as it is
OH
OH
OH
a
c
O
O
OMe
b
O
d
OMe
MeO2C
MeO2C
CbzHN
MeO2C
Ph
OMe
4
2
N
NCbz
O
O
O
O
O
O
6
Ph
7
8
Scheme 2. Reagents and conditions: (a) H2 (1 atm), (S)-Binap RuBr2 2%, MeOH, 40 ꢁC, 16 h (94%); (b) (i) MeZnBr (1.1 equiv), THF, 1 h, 0 ꢁC; (ii) LDA
(2.2 equiv), THF, 1 h, 78 ꢁC; (iii) CbzN@NCbz (2 equiv), THF, 1.5 h, ꢀ78 ꢁC; (iv) satd aq NH4Cl (56%, de >95%); (c) (i) H2 1 atm, Raney Ni, MeOH,
18 h; (ii) Ph2C@NH (1.5 equiv), DCM, MeOH satd HCl, 18 h; (iii) MeCN, AcOH (9 equiv), NaBH3CN (4 equiv), 1.5 h, then aqueous HCHO (50 equiv),
1 h, 0 ꢁC (94%); (d) (i) DIPEA (5 equiv), MEMCl (5 equiv), DCM, 72 h; (ii) H2 1 atm, Pd/C, EtOH, 18 h (58%).

B. Drouillat et al. / Tetrahedron: Asymmetry 18 (2007) 1955–1963
1957
OH
OH
OTBDMS
CO2Me
a
b
TIPSO
CO2Me
c
d
TIPSO
CO2Me
5
TIPSO
NCbz
CbzHN
NHCbz
10
11
9
OH
OH
OTBDMS
f
e
HO
TIPSO
TIPSO
OMEM
NHCbz
OMEM
NHCbz
OH
NHCbz
14
12
13
g
OH
OMEM
j
i
h
TIPSO
TIPSO
OTBDMS
NHCbz
OMEM
NHCbz
3
16
15
Scheme 3. Reagents and conditions: (a) H2 (10 bar), (S)-Binap RuBr2 2%, MeOH, 40 ꢁC, 16 h (92%, ee >95%); (b) (i) MeZnBr (1.1 equiv) THF, 1 h, 0 ꢁC;
(ii) LDA (2.2 equiv), THF, 1 h, ꢀ78 ꢁC; (iii) CbzN@NCbz (2 equiv), THF, 1.5 h, ꢀ78 ꢁC; (iv) satd aq NH4Cl; (70%, de >95%); (c) (i) TBDMSOTf
(1.5 equiv), 2,6-lutidine (2 equiv), DCM, 2 h, ꢀ78 ꢁC; (ii) H2 (1 atm), Pd/C, MeOH, 1 h, then Raney Ni, 1 h; (iii) CbzCl (1.2 equiv), DMAP (1.2 equiv),
MeCN, 12 h (70%); (d) Ca(BH4)2 (7 equiv), THF/EtOH 1/1.2, ꢀ20 ꢁC, 15 min to rt, 18 h (91%); (e) (i) DIPEA (2.5 equiv), MEMCl (2.5 equiv), DCM,
16 h; (ii) TBAF (3 equiv), THF, 30 min, 0 ꢁC (85%); (f) TIPSOTf (1.05 equiv), imidazole (2.6 equiv), DMF, 16 h (87%); (g) DIPEA (5 equiv), MEMCl
(5 equiv), DCM, 48 h (70%); (h) NaH (4.5 equiv), DMF, 30 min, ꢀ20 ꢁC (42%); (i) (i) PTSAÆH2O (0.1 equiv), EtOH/THF 2/1, 3 h; (ii) DIPEA (10 equiv),
MEMCl (10 equiv), DCM, 16 h (72%); (j) (i) TBAF (1.5 equiv), THF, 10 min, 0 ꢁC; (ii) DMSO (3 equiv), (COCl)2 (1.1 equiv), DCM, 1 h, ꢀ78 ꢁC then
NEt3 (7.5 equiv), 15 min, ꢀ78 ꢁC (81%).
not possible to selectively cleave a primary triisopropylsilyl
ether in the presence of a secondary tert-butyldimethylsilyl
ether.16a The primary alcohol of 13 was regioselectively
silylated in 87% yield using 1.05 equiv of triisopropylsilyl
triflate in the presence of imidazole in DMF. Compound
14 was reacted with methoxyethoxymethyl chloride in the
presence of diisopropylethylamine to afford 15 in 70%
yield.
First, we accomplished the coupling of 2 and 3 using reduc-
tive amination conditions. However, ester deprotection un-
der basic conditions of the resulting adduct was
troublesome as noticed before by us17 and by Matsuda7
for the synthesis of caprazol. Thus, we first performed
the basic hydrolysis of the ester of 2. This reaction was
quantitative within 3 h at room temperature in the presence
of potassium hydroxide in a mixture H2O/MeOH 1/1.
After acidification, the reaction mixture was lyophilized
to give a-ribosylamino acid 17. Following our previously
described synthesis of two liposidomycin ribosyl-diazepa-
none C-60 deoxy derivatives, we treated 17 with an excess
of aldehyde 3 in the presence of sodium borohydride in ace-
tonitrile.17 Unfortunately, these reaction conditions led
only to the reduction of aldehyde 3 to the corresponding
primary alcohol with no reductive amination product.
A second pathway was developed to shorten the synthesis
of 15. We exploited the ability of the tert-butyldimethylsilyl
group to migrate under basic conditions16b and the possible
cleavage of a primary TBDMS ether in the presence of a
primary TIPS ether. We previously noticed that the benzy-
lation of compound 12 under classical conditions (NaH,
BnBr) occurred with migration of the silyl ether from the
secondary to the primary alcohol and the corresponding
product was isolated in 80% yield.13 Treatment of 12 with
sodium hydride in DMF at ꢀ20 ꢁC resulted in the migra-
tion of the TBDMS group to the primary alcohol. Com-
pound 16 was isolated in 42% yield and the remaining
starting material 12 was recycled. After selective cleavage
of the tert-butyldimethylsilyl ether of 16 using 0.1 equiv
of p-toluenesulfonic acid monohydrate in THF/EtOH,16c
the resulting diol was reacted with methoxyethoxymethyl
chloride in the presence of diisopropylethylamine to afford
15 in 72% yield.
We decided to attempt the reductive amination using the
benzyl ester of 17, which can later be hydrogenolyzed
together with the benzyl carbamate group. Treatment of
the crude ribosylamino acid 17 with an excess of benzyl
alcohol and hydroxybenzotriazole (HOBt) in the presence
of dimethylaminopyridine and 1-(3-dimethylaminopro-
pyl)-3-ethylcarbodiimide hydrochloride (EDC) in DCM
gave benzyl ester 18 in 55% yield from 2. At this point,
we used a stepwise reductive amination procedure where
amine 18 and an excess of 3 were first mixed together in
˚
dichloroethane in the presence of 3 A-MS and acetic acid.
Removal of the triisopropylsilyl ether group of 15 by
TBAF in THF followed by Swern oxidation of the primary
alcohol yielded aldehyde 3 in 81% yield.
The resulting imine was reduced using sodium triacetoxy-
borohydride18 to give compound 19 in 45% yield. Simulta-
neous hydrogenolysis of the benzyl ester and of the
benzylcarbamate of 19 in the presence of catalytic Pd/C
in EtOH/H2O followed by intramolecular peptidic cou-
pling with an excess of EDC and HOBt in the presence
of dimethylaminopyridine in DMF, led to the expected
Having completed the synthesis of the two compounds 2
and 3 with high enantio- and diastereoselectivities, we
had to accomplish the coupling of the two intermediates.

1958
B. Drouillat et al. / Tetrahedron: Asymmetry 18 (2007) 1955–1963
MEMO
Me
N
OMEM
OMEM
O
c
O
OMe
O
d
OMe
RO2C
1
MEMO
NHCbz
CO2Bn
HN
O
O
O
19
a
b
2: R = Me
17: R = H
18: R = Bn
Scheme 4. Reagents and conditions: (a) KOH (3 equiv), MeOH/H2O 1/1, 3 h (quantitative yield); (b) BnOH (10 equiv), HOBt (2 equiv), DMAP
˚
(0.2 equiv), EDCÆHCl (2.5 equiv), DCM, 4 days (55%); (c) 3 (2 equiv), 3 A-MS, AcOH, DCE, 24 h then NaBH(OAc)3 (2 equiv), 40 h then 3 (1.4 equiv),
48 h, then NaBH(OAc)3 (2 equiv), 18 h (45%); (d) (i) H2 (5 bar), Pd/C cat., EtOH/H2O 1/1, 5 h (quantitative yield); (ii) HOBt (3 equiv), DMAP
(0.4 equiv), EDC (3.5 equiv), DMF, 16 h (28%).
lactam 1 in 28% isolated yield from 19 (Scheme 4). This
yield is comparable to those obtained by Le Merrer4c for
the macrolactamization step or by Matsuda7 for the
macrocyclization step by reductive amination.
4.1.1. Methyl (methyl 6-deoxy-2,3-O-isopropylidene-5-oxo-
b-D-ribo-heptafuranosid)uronate 4. Compound 4 was pre-
pared according to Masamune’s procedure.20 Carbonyldi-
imidazole (8.6 g, 53.0 mmol) was added to a solution of
methyl
2,3-O-isopropylidene-b-D-ribofuranosiduronic
acid21 (8.5 g, 39.0 mmol) in dry THF (150 mL). The reac-
tion mixture was stirred for 7 h before adding the magne-
sium salt of monomethylmalonate (13.5 g, 52.3 mmol).
After stirring for 16 h, the solution was concentrated under
vacuum. The residue was treated with a 1 M aqueous solu-
tion of HCl (250 mL) cooled to 0 ꢁC. The aqueous layer
(pH 1) was extracted with ethyl acetate (5 · 100 mL). The
ethyl acetate extract was washed with a saturated aqueous
solution of sodium bicarbonate (50 mL), dried over sodium
sulfate and concentrated. The crude product was crystal-
lized from diisopropyl ether giving 7.5 g (27.4 mmol, 70%
yield) of the title compound as white crystals. In CDCl3,
3. Conclusion
We designed a convergent synthetic approach to the 5-epi
liposidomycin ribosyl-diazepanone analogue derivative 1
using the same strategy to control the stereochemistry at
each of the stereocentres of the ribosyl seven-membered
heterocycle. This methodology, based on the catalytic
hydrogenation of a b-ketoester followed by electrophilic
amination of the resulting b-hydroxyester to give an a-ami-
no-b-hydroxy ester with excellent anti stereoselectivity,
could be extended to generate other diastereomers of the
diazepanone of the liposidomycins by coupling different
anti-precursors. An approach to the synthesis of the natu-
ral ribosyl-diazepanone core is currently in progress.
1
7% of the enol form was detected by H and 13C NMR.
25
Mp 56 ꢁC; ½aꢁD ¼ ꢀ119 (c 1.1, CH2Cl2); IR (KBr): 2940,
1730, 1700, 1570, 1360, 1320, 1090 cmꢀ1
;
1H NMR
(200 MHz, CDCl3) d (ppm): 1.33 (s, 3H, CH3), 1.48 (s,
3H, CH3), 3.45 (s, 3H, OCH3), 3.52 (d, 1H, H-6a,
J6a,6b = 16.55 Hz), 3.75 (s, 3H, COOCH3), 3.77 (d, 1H,
4. Experimental
H-6b, J6a,6b = 16.55 Hz), 4.51 (d, 1H, H-2, J2,3
=
5.88 Hz), 4.65 (s, 1H, H-4), 5.03 (s, 1H, H-1), 5.22 (d,
3H, H-3, J2,3 = 5.88 Hz); 13C NMR (50 MHz, CDCl3) d
(ppm): 24.91, 26.35, 44.96, 52.42, 56.52, 80.50, 84.29,
89.65, 110.42, 112.66, 167.52, 201.69; MS (ESI+): m/z =
275 [M+H]+; Anal. Calcd for C12H18O7: C, 52.55; H,
6.57. Found: C, 52.52; H, 6.75.
4.1. General experimental methods
Solvents were distilled according to the literature.19 Flash
column chromatographic separations were carried out over
Merck silica gel 60 (0.035–0.070 mm). The solvent system is
given v/v. NMR spectra were recorded on a Bruker AC-
200 or Avance 300 spectrometer, and reported in parts
per million (d) relative to tetramethylsilane (0.00 ppm) as
the internal standard. Coupling constant (J) was reported
in Hertz (Hz). Abbreviations of multiplicity were as fol-
lows: s, singlet; d, doublet; t, triplet; q, quartet; m, multi-
plet; br, broad. Assignment was based on 1H–1H COSY
and HMQC NMR spectra. Optical rotations were recorded
at 25 ꢁC on a Perkin–Elmer 241 polarimeter (1 dm cell).
Melting points were measured by means of a capillary tube
4.1.2. Methyl (methyl 6-deoxy-2,3-O-isopropylidene-b-D-
allo-heptafuranosid)uronate
6. The
(S)-BinapRuBr2
catalyst was prepared under argon according to the litera-
ture.8a To bis-(2-methylallyl)-cycloocta-1,5-diene-ruthe-
nium(II) complex (16 mg, 0.050 mmol, 0.020 equiv) and
(S)-2,20-bis(diphenylphosphino)-1,10-binaphthyl (34 mg,
0.055 mmol, 0.022 equiv) in degassed acetone (2 mL) was
added a methanolic solution of hydrogen bromide (0.15–
0.18 M, 0.044 equiv). The reaction mixture was stirred for
1 h and the solution then concentrated under vacuum. A
solution of 4 (0.685 g, 2.50 mmol) in degassed methanol
(5 mL) was canulated into the (S)-BinapRuBr2 (2 mol %).
The reaction mixture was purged three times with hydro-
gen and vigorously stirred at rt. After 16 h, the solution
was concentrated under vacuum and the residue was puri-
fied by flash chromatography (Et2O/pentane 25/75) to
afford 0.648 g (2.35 mmol, 94% yield) of the title compound
immersed in an oil bath (Tottoli apparatus, Buchi). Infra-
¨
red spectra were recorded on a Nicolet Impact 400 D spec-
trometer in KBr discs or films. Routine mass spectra were
recorded on HP MS Engin 5989B mass spectrometer by
Vincent Steinmetz (ILV, Versailles). High-resolution mass
spectra were performed on a Q-TOF Ultima Bruker mass
´
spectrometer (Universite d’Amiens, France). Elemental
analyses were performed by the Service de Microanalyses
of ICSN, Gif-sur-Yvette, France.

B. Drouillat et al. / Tetrahedron: Asymmetry 18 (2007) 1955–1963
1959
as a solid. A sample was crystallized from diisopropyl
The filtrate was concentrated under vacuum and to the
resulting residue dissolved in dry acetonitrile (25 mL) was
added sodium cyanoborohydride (1.31 g, 20.81 mmol)
and acetic acid (2.7 mL, 47 mmol). After 1.5 h, the solution
was cooled to 0 ꢁC before adding a 37% aqueous solution
of formaldehyde stabilized with 10–15% methanol
(19 mL, 261 mmol). After 1 h, a saturated aqueous solution
of sodium bicarbonate (50 mL) was slowly added to the
reaction mixture. The aqueous layer was extracted with
ethyl acetate (3 · 50 mL). The ethyl acetate extract was
dried over sodium sulfate and concentrated. The residue
was purified by flash chromatography (EtOAc/pentane
ether/pentane 1/9 giving white needles. Mp 32 ꢁC;
25
½aꢁD ¼ ꢀ45 (c 1.0, CH2Cl2); IR (KBr): 3400, 2920, 1720,
1360, 1200, 1100 cmꢀ1 1H NMR (200 MHz, CDCl3) d
;
(ppm): 1.33 (s, 3H, CH3), 1.48 (s, 3H, CH3), 2.52 (dd,
1H, H-6a, J6a,6b = 16.08 Hz, J5,6a = 7.92 Hz), 2.66 (dd,
1H, H-6b, J6a,6b = 16.08 Hz, J5,6b = 3.63 Hz), 3.41 (s, 3H,
OCH3), 3.62 (d, 1H, OH, J5,OH = 10.01 Hz), 3.72 (s, 3H,
COOCH3), 4.07 (m, 1H, H-5), 4.10 (s, 1H, H-4), 4.59 (d,
1H, H-2, J2,3 = 6.24 Hz), 4.88 (d, 1H, H-3, J2,3
=
6.24 Hz), 4.98 (s, 1H, H-1); 13C NMR (50 MHz, CDCl3)
d (ppm): 24.48, 26.09, 37.77, 51.61, 55.70, 68.26, 80.36,
85.22, 89.57, 109.70, 111.97, 171.90; MS (ESI+): m/z =
277 [M+H]+; Anal. Calcd for C12H20O7: C, 52.17; H,
7.24. Found: C, 52.11; H, 7.44.
30/70) affording 2.32 g (4.92 mmol, 94% yield) of the title
25
compound as a white solid. Mp 134 ꢁC; ½aꢁD ¼ ꢀ105 (c
1
1.2, MeOH); H NMR (300 MHz, CDCl3) d (ppm): 1.25
(s, 3H, CH3), 1.36 (s, 3H, CH3), 3.44 (s, 3H, OCH3), 3.47
(d, 1H, H-6, J5,6 = 10.29 Hz), 3.78 (s, 3H, COOCH3),
4.09 (s, 1H, OH), 4.24 (d, 1H, H-5, J5,6 = 10.29 Hz), 4.52
(m, 3H, H-2, H-3, H-4), 4.99 (s, 1H, H-1), 5.14 (s, 2H,
H-1, (Ph)2CH), 7.15-7.29 (m, 6H, Ar-H), 7.46 (m, 4H,
Ar-H); 13C NMR (75 MHz, CDCl3) d (ppm): 24.47,
26.41, 36.13, 50.95, 55.71, 63.39, 71.03, 74.83, 79.96,
86.03, 88.23, 110.69, 111.68, 126.55, 127.02, 127.29,
127.58, 127.81, 128.53, 142.05, 142.82, 170.34; MS
(ESI+): m/z = 472 [M+H]+; Anal. Calcd for C26H33NO7:
C, 66.22; H, 7.05; N, 2.97. Found: C, 66.07; H, 7.23; N,
2.98.
4.1.3. Methyl (methyl 6-deoxy-6-N,N0-dibenzyloxycarbonyl-
hydrazino-2,3-O-isopropylidene-D-glycero-b-D-allo-heptafur-
anosid)uronate 7. To a solution of 6 (0.641 g, 2.32 mmol)
in dry THF (2.3 mL) at 0 ꢁC was added dropwise a solution
of MeZnBr (2.55 mmol) prepared from zinc bromide
(0.575 g, 2.55 mmol) in dry THF (2.6 mL) and methylli-
thium (1.65 mL, 2.64 mmol, 1.6 M sol in Et2O). After stir-
ring for 1 h, the reaction mixture was cooled to ꢀ78 ꢁC and
a solution of lithiumdiisopropylamide (5.10 mmol) in THF
(5.2 mL) was added dropwise. After a further 1 h at
ꢀ78 ꢁC, a solution of dibenzyl azodicarboxylate (1.38 g,
4.64 mmol) in THF (5 mL) was added dropwise, the reac-
tion mixture was stirred for 1.5 h, hydrolyzed at ꢀ78 ꢁC
with a saturated aqueous solution of ammonium chloride
(50 mL), warmed to rt, extracted into ethyl acetate
(3 · 70 mL), dried over sodium sulfate and concentrated.
The crude product was purified by flash chromatography
(Et2O/pentane 60/40) affording 0.746 g (1.30 mmol, 56%
yield) of the title compound as a solid. A sample was crys-
4.1.5. Methyl (methyl 6-deoxy-2,3-O-isopropylidene-5-O-
(2-methoxyethoxymethyl)-6-N-methylamino-D-glycero-b-D-
allo-heptafuranosid)uronate 2. To a solution of 8 (0.835 g,
1.77 mmol) in dichloromethane (10 mL) containing diiso-
propylethylamine (1.55 mL, 8.86 mmol) was added 2-meth-
oxyethoxymethyl chloride (1 mL, 8.86 mmol) at 0 ꢁC. The
reaction mixture was warmed to rt and stirred for 72 h.
The reaction mixture was hydrolyzed with a saturated
aqueous solution of sodium chloride (20 mL) and extracted
with ethyl acetate (4 · 20 mL). The ethyl acetate extract
was dried over sodium sulfate and concentrated. The resi-
due was purified by flash chromatography (Et2O/pentane
1/1) affording 0.813 g of the expected compound as an
oil. A solution of this oil (0.813 g, 1.45 mmol) in ethanol
(35 mL) containing 10% Pd/C (20 mg) was vigorously stir-
red under hydrogen for 18 h. After filtering, the solution
was concentrated under vacuum and the residue was puri-
fied by flash chromatography (EtOAc) affording 0.403 g
(1.025 mmol, 58% yield) of the title compound as a colour-
tallized from ether/pentane 8/2 giving white crystals. Mp
25
110 ꢁC; ½aꢁD ¼ ꢀ10 (c 1.0, CH2Cl2); IR (KBr): 3380,
1
2940, 1700, 1200, 1170, 1150 cmꢀ1; H NMR (300 MHz,
toluene-d8, 353 K) d (ppm): 1.31 (s, 3H, CH3), 1.63 (s,
3H, CH3), 3.36 (s, 3H, OCH3), 3.37 (s, 1H, OH), 3.55 (s,
3H, COOCH3), 4.45 (m, 1H, H-5), 4.66 (d, 1H, H-2,
J2,3 = 5.91 Hz), 4.81 (d, 1H, H-4, J4,5 = 8.19 Hz), 5.05 (d,
1H, H-4, J2,3 = 5.91 Hz), 5.15 (m, 3H, H-1 and PhCH2),
5.52 (d, 1H, H-6, J5,6 = 2.97 Hz), 6.97 (s, 1H, NH), 7.19
(m, 10H, Ar-H); 13C NMR (75 MHz, toluene-d8, 353 K)
d (ppm): 24.25, 25.75, 50.62, 54.32, 62.84, 66.88, 67.76,
71.85, 81.56, 84.93, 86.87, 109.90, 111.44, 127.41, 128.62,
135.61, 135.47, 155.38, 168.88; MS (ESI+): m/z = 575
[M+H]+; Anal. Calcd for C28H34N2O11: C, 58.53; H,
5.96; N, 4.88. Found: C, 58.41; H, 5.99; N, 4.88.
25
1
less oil. ½aꢁD ¼ þ1 (c 0.9, CH2Cl2); H NMR (300 MHz,
CDCl3) d (ppm): 1.31 (s, 3H, CH3), 1.48 (s, 3H, CH3),
2.39 (s, 3H, NCH3), 3.33 (s, 3H, OCH3), 3.39 (s, 3H,
OCH3), 3.60 (m, 4H, H-6, OCHaCH2O), 3.76 (m, 5H, H-
5, COOCH3 and OCHbCH2O), 4.25 (d, 1H, H-4,
J4,5 = 9.90 Hz), 4.57 (d, 1H, H-2, J2,3 = 6.00 Hz), 4.72 (d,
0
4.1.4. Methyl (methyl 6-deoxy-2,3-O-isopropylidene-6-[(N-
benzhydryl-N-methyl)amino]-D-glycero-b-D-allo-heptafurano-
sid)uronate 8. A solution of 7 (3 g, 5.22 mmol) in dry
methanol (115 mL) containing Raney Ni (1 g) was vigor-
ously stirred for 18 h under hydrogen. After filtering, the
solution was concentrated under vacuum. To the residue
dissolved in dry dichloromethane (21 mL) was added ben-
zophenone imine (1.31 mL, 7.83 mmol) and a saturated
methanolic solution of HCl (0.9 mL). The reaction mixture
was stirred for 18 h. The mixture was filtered and the white
solid residue was washed with dichloromethane (3 · 5 mL).
1H, OCHa O, J = 7.20 Hz), 4.76 (d, 1H, H-3, J2,3
=
0
6.00 Hz), 4.89 (d, 1H, OCHb O, J = 7.20 Hz), 4.98 (s, 1H,
H-1). 13C NMR (75 MHz, CDCl3) d (ppm): 24.97, 26.49,
35.13, 51.80, 55.82, 59.10, 64.29, 67.92, 71.64, 82.01,
83.28, 85.05, 85,91, 97.52, 110.06, 112.38, 171.98; MS
(ESI+): m/z = 394 [M+H]+; Anal. Calcd for C17H31NO9:
C, 51.90; H, 7.94; N, 3.56. Found: C, 52.07; H, 7.86; N,
3.40.

1960
B. Drouillat et al. / Tetrahedron: Asymmetry 18 (2007) 1955–1963
4.1.6. Methyl (3R)-3-hydroxy-4-(triisopropylsilyloxy)but-
anoate 9. Methyl 4-triisopropysilyloxy-3-oxobutanoate
(3.420 g, 11.86 mmol) was dissolved under argon in de-
gassed methanol (24 mL). This solution was canulated into
the (S)-BinapRuBr2 complex (2 mol %), prepared as previ-
ously described for 6. The reaction mixture was placed in
an autoclave, which was purged three times with hydrogen
and brought to a pressure of 10 bar. The autoclave was
heated to 40 ꢁC. After 16 h, magnetic stirring was stopped
and the autoclave was cooled to rt. The solution was con-
centrated under vacuum and the residue was purified by
flash chromatography (Et2O/cyclohexane 20/80) affording
nol (75 mL) was added and the mixture was warmed to rt.
The solution was concentrated under vacuum and the res-
idue was immediately purified by flash chromatography
(EtOAc/pentane 10/90) affording 4.25 g of the expected
compound as a colourless oil. A solution of this oil
(4.25 g, 6.04 mmol) in dry methanol (115 mL) containing
10% Pd/C (300 mg) was stirred under hydrogen for 1 h.
Raney Ni (4 g) was added to the reaction mixture, which
was vigorously stirred under hydrogen until TLC monitor-
ing showed complete transformation of the intermediate
hydrazine (about 1 h). After filtering, the solution was
concentrated under vacuum and the residue was purified
by flash chromatography (Et2O/pentane 15/85) affording
2.02 g of the expected compound as a colourless oil. To
a solution of this oil (2.02 g, 4.82 mmol) in acetonitrile
(25 mL) containing 4-dimethylaminopyridine (647 mg,
5.30 mmol) was added benzyl chloroformate (0.76 mL,
5.30 mmol) at 0 ꢁC. The reaction mixture was warmed to
rt and stirred for 12 h before adding methanol (50 mL).
The solution was concentrated under vacuum and the res-
idue was purified by flash chromatography (Et2O/cyclo-
3.163 g (10.91 mmol, 92% yield) of the title compound as
25
a pale yellow oil. ½aꢁD ¼ þ16 (c 1.3, EtOH); IR (film):
1
3405, 2945, 2863, 1741, 881 cmꢀ1; H NMR (200 MHz,
CDCl3) d (ppm): 1.06 (s, 21H, Si(CH(CH3)2)3), 2.50 (dd,
1H, H-2a, J2a,2b = 16 Hz, J2a,3 = 7.4 Hz), 2.59 (dd, 1H,
H-2b, J2a,2b = 16 Hz, J2b,3 = 5.3 Hz), 2.94 (br s, 1H, OH),
3.70 (m, 5H, CO2CH3 and H-4), 4.10 (m, 1H, H-3); 13C
NMR (50 MHz, CDCl3) d (ppm): 11.81, 17.93, 37.84,
51.77, 66.41, 68.74, 172.52; MS (ESI+): m/z = 291
[M+H]+; Anal. Calcd for C14H30O4Si: C, 57.89; H,
10.41. Found: C, 58.14; H, 10.58.
hexane 5/95) affording 2.39 g (4.32 mmol, 70% yield) of
25
the title compound as an oil. ½aꢁD ¼ þ24 (c 2.1, CH2Cl2);
IR (film): 3431, 3092, 3064, 3029, 2945, 2858, 1726, 1506,
4.1.7. Methyl (2S,3R)-2-N,N0-dibenzyloxycarbonylhydraz-
ino-3-hydroxy-4-(triisopropylsilyloxy)butanoate 10. To a
solution of 9 (3.23 g, 11.13 mmol) in dry THF (11 mL) at
892, 786 cmꢀ1 1H NMR (300 MHz, CDCl3) d (ppm)
;
0.07 (s, 6H, Si(CH3)2), 0.87 (s, 9H, SiC(CH3)3), 1.07, 1.08
(2s, 21H, Si(CH(CH3)2)3), 3.73 (m, 5H, CO2CH3 and H-
4), 4.09 (m, 1H, H-3), 4.49 (dd, 1H, H-2, J2,NH = 8.0 Hz,
J2,3 = 3.1 Hz), 5.12 (s, 2H, OCH2Ph), 5.85 (d, 1H,
NH, J2,NH = 8.0 Hz), 7.34 (m, 5H, Ar-H). 13C NMR
(75 MHz, CDCl3) d (ppm): ꢀ5.12, ꢀ4.63, 11.87, 17.94,
18.07, 25.63, 52.03, 57.62, 65.34, 66.77, 73.54, 127.81,
127.97, 128.42, 136.54, 155.92, 170.41; MS (ESI+):
m/z = 576 [M+Na]+; Anal. Calcd for C28H51NO6Si2: C,
60.72; H, 9.28; N, 2.53. Found: C, 60.42; H, 9.39; N, 2.39.
0 ꢁC was added dropwise
a solution of MeZnBr
(12.23 mmol) prepared from zinc bromide (2.75 g,
12.23 mmol) in dry THF (11 mL) and methyllithium
(8.8 mL, 14.08 mmol, 1.6 M sol in Et2O). After stirring
for 1 h, the reaction mixture was cooled to ꢀ78 ꢁC and a
solution of lithiumdiisopropylamide (24.46 mmol) in
THF (25 mL) was added dropwise. After a further 1 h at
ꢀ78 ꢁC, a solution of dibenzyl azodicarboxylate (6.63 g,
22.24 mmol) in THF (7 mL) was added dropwise, the reac-
tion mixture was stirred for 1.5 h, hydrolyzed at ꢀ78 ꢁC
with a saturated aqueous solution of ammonium chloride
(110 mL), warmed to rt, extracted into ethyl acetate, dried
over sodium sulfate and concentrated. The crude product
was purified by flash chromatography (EtOAc/pentane 5/
4.1.9. (2R,3R)-2-N-Benzyloxycarbonylamino-3-O-tert-butyl-
dimethylsilyl-4-O-(triisopropylsilyl)butane-1,3,4-triol
12.
A solution of 11 (2.52 g, 4.55 mmol) in dry ethanol
(30 mL) was canulated into a 500 mL round bottom flask
containing a suspension of calcium chloride (3.51 g,
31.62 mmol) in dry THF (25 mL). Sodium borohydride
(2.06 g, 54.45 mmol) was added slowly to the solution
cooled to ꢀ20 ꢁC. After stirring at ꢀ20 ꢁC for 1 h, the reac-
tion mixture was warmed to rt and stirred for 18 h. The
reaction mixture was hydrolyzed at 0 ꢁC with a saturated
aqueous solution of ammonium chloride (300 mL). The
organic layer was extracted with ethyl acetate (4 · 150 mL).
The ethyl acetate extract was washed with a saturated
aqueous solution of sodium chloride (200 mL), dried over
sodium sulfate and concentrated. The residue was purified
by flash chromatography (Et2O/pentane 30/70) affording
95) to afford 4.58 g (7.79 mmol, 70% yield) of the title com-
25
pound as an oil. ½aꢁD ¼ þ2 (c 1.7, EtOH); IR (film): 3472,
1
3088, 3062, 3032, 2934, 2863, 1755, 1712, 881 cmꢀ1; H
NMR (300 MHz, CDCl3)
d (ppm): 1.07 (s, 21H,
Si(CH(CH3)2)3), 3.05 (s, 1H, OH), 3.71 (s, 3H, CO2CH3),
3.89 (m, 2H, H-4), 4.23 (m, 1H, H-3), 5.02 (m, 1H, H-2),
5.16 (m, 4H, 2 · CO2CH2Ph), 7.08 (s, 1H, NH), 7.30 (m,
10H, Ar-H). 13C NMR (75 MHz, CDCl3) d (ppm): 11.91,
17.83, 52.14, 62.20, 64.17, 67.83, 68.62, 71.14, 127.81,
128.02, 128.21, 128.34, 128.44, 128.51, 135.51, 135.60,
155.91, 156.20, 170.23; MS (ESI+): m/z = 611 [M+Na]+;
Anal. Calcd for C30H44N2O8Si: C, 61.20; H, 7.53; N,
4.76. Found: C, 60.99; H, 7.63; N, 4.64.
2.18 g (4.15 mmol, 91% yield) of the title compound as
25
an oil. ½aꢁD ¼ þ7 (c 2.1, CH2Cl2); IR (film): 3416, 3092,
3064, 3029, 2868, 1705, 1506, 898, 785 cmꢀ1 1H NMR
;
4.1.8. Methyl (2S,3R)-2-N-benzyloxycarbonylamino-4-
triisopropylsilyloxy-3-(tert-butyldimethylsilyloxy)butanoate
11. tert-Butyldimethylsilyl triflate (2.15 mL, 9.34 mmol)
was added dropwise in 15 min at ꢀ78 ꢁC to a solution of
10 (3.63 g, 6.17 mmol) in dichloromethane (11 mL) con-
taining 2,6-lutidine (1.45 mL, 12.44 mmol). The reaction
mixture was stirred for 2 h at ꢀ78 ꢁC, after which metha-
(300 MHz, CDCl3) d (ppm): 0.08 (s, 6H, Si(CH3)2), 0.88
(s, 9H, SiC(CH3)3), 1.06, 1.07 (2s, 21H, Si(CH(CH3)2)3),
3.66–3.82 (m, 3H, H-1 and H-4a), 3.93 (m, 1H, H-2),
4.01–4.07 (m, 2H, H-3 and H-4b), 5.12 (s, 2H, OCH2Ph),
5.67 (d, 1H, NH, J2,NH = 7.81 Hz), 7.35 (m, 5H, Ar-H).
13C NMR (75 MHz, CDCl3) d (ppm): ꢀ5.11, ꢀ4.69,
11.81, 17.86, 17.93, 25.71, 53.52, 62.48, 65.10, 66.65,

B. Drouillat et al. / Tetrahedron: Asymmetry 18 (2007) 1955–1963
1961
74.55, 127.97, 128.00, 128.45, 129.14, 136.58, 156.29; MS
(ESI+): m/z = 548 [M+Na]+; Anal. Calcd for C27H51NO5-
Si2: C, 61.67; H, 9.78; N, 2.66. Found: C, 61.66; H, 9.92; N,
2.63.
J1a,1b = 10.02 Hz, J1b,2 = 3.66 Hz), 4.72 (s, 2H, OCH2O),
5.07 (d, 1H, OCH0Ph, JH ,H = 12.33 Hz), 5.15 (d, 1H,
0
00
OCH00Ph, JH ,H = 12.33 Hz), 5.56 (d, 1H, NH, J2,NH
=
0
00
8.48 Hz), 7.35 (m, 5H, Ar-H). 13C NMR (75 MHz, CDCl3)
d (ppm): 11.79, 17.91, 52.57, 58.96, 64.97, 66.69, 67.07,
67.37, 71.53, 71.69, 95.75, 127.99, 128.04, 128.46, 136.52,
156.18; MS (ESI+): m/z = 522 [M+Na]+; Anal. Calcd for
C25H45NO7Si C, 60.09; H, 9.08; N, 2.80. Found: C,
59.96; H, 9.18; N, 2.67.
4.1.10. (2R,3R)-2-N-Benzyloxycarbonylamino-1-O-(2-meth-
oxyethoxymethyl)butane-1,3,4-triol 13. To a solution of
12 (0.350 g, 0.666 mmol) in dichloromethane (4 mL) con-
taining diisopropylethylamine (0.31 mL, 1.666 mmol) was
added
2-methoxyethoxymethyl
chloride
(0.20 mL,
1.666 mmol) at 0 ꢁC. The reaction mixture was warmed
to rt and stirred for 16 h. The reaction mixture was hydro-
lyzed with a saturated aqueous solution of sodium chloride
(20 mL) and extracted with ethyl acetate (4 · 20 mL). The
ethyl acetate extract was dried over sodium sulfate and
concentrated. The residue was purified by flash chromato-
graphy (Et2O/pentane 4/6) affording 373 mg of the expected
compound as a colourless oil. To a solution of this oil
(0.361 g, 0.588 mmol) in THF (5 mL) at 0 ꢁC was slowly
added a 1 M solution of tetrabutylammonium fluoride in
THF (1.8 mL, 1.8 mmol). After 30 min, the reaction mix-
ture was hydrolyzed with a saturated aqueous solution of
sodium chloride (20 mL). The aqueous layer was extracted
with ethyl acetate (4 · 25 mL). The ethyl acetate extract
was dried over sodium sulfate, and concentrated under vac-
uum. The residue was purified by flash chromatography
(EtOAc/pentane 50/50) affording 0.195 g (0.569 mmol,
4.1.12. (2R,3R)-1-O-tert-Butyldimethylsilyl-2-N- benzyloxy-
carbonylamino-4-O-(triisopropylsilyl)butane-1,3,4-triol 16.
To a solution of 12 (2.18 g, 4.15 mmol) in N,N-dimethyl-
formamide (19 mL) cooled to ꢀ20 ꢁC was added sodium
hydride (448 mg, 18.63 mmol) over 30 min. After addition,
the reaction mixture was hydrolyzed at ꢀ20 ꢁC with a sat-
urated aqueous solution of ammonium chloride (60 mL)
and extracted with ethyl acetate (4 · 40 mL). The ethyl ace-
tate extract was dried over sodium sulfate and concen-
trated. The residue was purified by flash chromatography
(Et2O/pentane 20/80) affording 0.913 g (1.74 mmol, 42%
yield) of the title compound as an oil and 0.719 g
25
(1.36 mmol, 33%) of the starting material. ½aꢁD ¼ þ11 (c
1
1.3, EtOH); H NMR (300 MHz, CDCl3) d (ppm): 0.06,
0.07 (2s, 6H, Si(CH3)2), 0.83 (s, 9H, SiC(CH3)3), 1.12,
1.14 (2s, 21H, Si(CH(CH3)2)3), 3.08 (s, 1H, OH), 3.73–
3.90 (m, 5H, H-2, H-3, H-4a and H-1), 4.02 (d, 1H, H-
4b, J4a,4b = 8.85 Hz), 5.17 (s, 2H, OCH2Ph), 5.47 (d, 1H,
NH, J2,NH = 7.32 Hz), 7.33 (m, 5H, Ar-H). 13C NMR
(75 MHz, CDCl3) d (ppm): ꢀ5.62, 11.86, 17.98, 18.22,
25.87, 53.51, 62.51, 65.15, 66.64, 74.63, 128.58, 128.12,
128.03, 136.67, 156.15; MS (ESI+): m/z = 548 [M+Na]+;
Anal. Calcd for C27H51NO5Si2: C, 61.67; H, 9.78; N,
2.66. Found: C, 61.79; H, 9.64; N, 2.66.
85%) of the title compound as a white solid. Mp 46 ꢁC;
25
½aꢁD ¼ ꢀ2 (c 2.6, CH2Cl2); IR (KBr): 3742, 3064, 3029,
2924, 1700, 1531 cmꢀ1 1H NMR (300 MHz, CDCl3) d
;
(ppm): 3.04 (s, 1H, OH), 3.37 (s, 3H, CH3), 3.54–3.78 (m,
9H, H-1a, H-2, H-3, H-4, and OCH2CH2O), 4.10 (dd,
1H, H-1b, J1a,1b = 9.76 Hz, J1b,2 = 2.56 Hz), 4.71 (s, 2H,
OCH2O), 5.10 (d, 1H, OCH0Ph, JH ,H = 12.14 Hz), 5.16
0
00
(d, 1H, OCH00Ph, JH ,H = 12.14 Hz), 5.55 (d, 1H, NH,
J2,NH = 8.10 Hz), 7.35 (m, 5H, Ar-H). 13C NMR
(75 MHz, CDCl3) d (ppm): 52.06, 58.94, 62.96, 66.79,
67.14, 67.26, 70.74, 71.74, 95.48, 128.15, 128.31, 128.58,
136.09, 157.39; MS (ESI+): m/z = 366 [M+Na]+; Anal.
Calcd for C16H25NO7: C, 55.97; H, 7.34; N, 4.08. Found:
C, 56.14; H, 7.34; N, 3.91.
0
00
4.1.13. (2R,3R)-2-N-Benzyloxycarbonylamino-1,3-O-bis(2-
methoxyethoxymethyl)-4-O-(triisopropylsilyl)butane-1,3,4-
triol 15. Synthesis of 15 from 14: to a solution of 14
(0.210 g, 0.420 mmol) in dichloromethane (5 mL) contain-
ing diisopropylethylamine (0.36 mL, 2.104 mmol) was
added
2-methoxyethoxymethyl
chloride
(0.24 mL,
2.104 mmol) at 0 ꢁC. The reaction mixture was warmed
to rt and stirred for 48 h. The reaction mixture was hydro-
lyzed with a saturated aqueous solution of sodium chloride
(20 mL) and extracted with ethyl acetate (4 · 20 mL). The
ethyl acetate extract was dried over sodium sulfate and
concentrated. The residue was purified by flash chromato-
graphy (Et2O/pentane 4/6) affording 173 mg (0.294 mmol,
70%) of the title compound as a colourless oil. Synthesis
of 15 from 16: compound 16 (103 mg, 0.196 mmol) was dis-
solved in a 0.02 M p-toluenesulfonic acid monohydrate
2.3:1 solution of EtOH and THF (1 mL, 0.020 mmol) at
rt. The reaction was stirred for 3 h before adding a 5%
aqueous solution of sodium hydrogenocarbonate
(0.5 mL) and concentrated. The residue was purified by
flash chromatography (Et2O/pentane 20/80) affording
0.061 g of the expected compound as a colourless oil. To
a solution of this oil (0.061 g, 0.147 mmol) in dichloro-
4.1.11. (2R,3R)-2-N-Benzyloxycarbonylamino-1-O-(2-meth-
oxyethoxymethyl)-4-O-(triisopropylsilyl)butane-1,3,4-triol
14. To a solution of 13 (173 mg, 0.504 mmol) in N,N-
dimethylformamide (2 mL) containing imidazole (0.072 g,
1.310 mmol)
was
added
triisopropylsilyl
triflate
(0.117 mL, 0.529 mmol) at 0 ꢁC. The reaction mixture
was warmed and stirred for 16 h at rt. Methanol (1 mL)
was added at 0 ꢁC and the mixture was warmed to rt. After
adding ethyl acetate (25 mL), the organic layer was washed
with a saturated aqueous solution of sodium chloride
(2 · 10 mL), dried over sodium sulfate and concentrated
under vacuum. The residue was purified by flash chroma-
tography (Et2O/pentane 75/25) affording 0.218 g
(0.437 mmol, 87%) of the title compound as a colourless
25
oil. ½aꢁD ¼ ꢀ11 (c 2.1, CH2Cl2); IR (film): 3400, 3092,
3064, 3029, 2939, 2863, 1721, 1521, 886, 786 cmꢀ1 1H
;
NMR (300 MHz, CDCl3) d (ppm): 1.05, 1.07 (2s, 21H,
Si(CH(CH3)2)3), 3.37 (s, 3H, CH3), 3.54 (m, 2H, OCH2),
3.68 (m, 3H, H-1a and OCH2), 3.78 (m, 3H, H-3 and H-
4), 3.90 (m, 1H, H-2), 3.98 (dd, 1H, H-1b,
methane
(2 mL)
containing
diisopropylethylamine
(0.26 mL, 1.48 mmol) was added 2-methoxyethoxymethyl
chloride (0.17 mL, 1.48 mmol) at 0 ꢁC. The reaction mix-
ture was warmed to rt and stirred for 16 h. The reaction

1962
B. Drouillat et al. / Tetrahedron: Asymmetry 18 (2007) 1955–1963
mixture was hydrolyzed with a saturated aqueous solution
of sodium chloride (5 mL) and extracted with ethyl acetate
(4 · 5 mL). The ethyl acetate extract was dried over sodium
sulfate and concentrated. The residue was purified by flash
chromatography (Et2O/pentane 1/1) affording 83 mg
(0.141 mmol, 72% yield) of the title compound as a colour-
0.01 M aqueous solution of HCl, the solution was lyophi-
lized. To a suspension of the residue in dichloromethane
(6 mL) at 0 ꢁC was added benzyl alcohol (0.22 mL,
2.1 mmol), hydroxybenzotriazole (57 mg, 0.42 mmol), 2,5-
dimethylaminopyridine (5 mg, 0.041 mmol) and 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
25
1
less oil. ½aꢁ ¼ þ18 (c 1.2, CH2Cl2); H NMR (300 MHz,
CDCl3) d D(ppm): 1.04, 1.05 (2s, 21H, Si(CH(CH3)2)3),
3.31 (s, 3H, CH3), 3.37 (s, 3H, CH3), 3.51 (m, 4H,
2 · OCH2), 3.66 (m, 5H, H-1a, 2 · OCH2), 3.80 (m, 4H,
H-1b, H-3 and H-4), 4.08 (m, 1H, H-2), 4.69 (s, 2H,
OCH2O), 4.79 (m, 2H, OCH2O), 5.09 (s, 2H, OCH2Ph),
5.99 (dl, 1H, NH, J2,NH = 13.98 Hz), 7.34 (m, 5H, Ar-H).
13C NMR, (75 MHz, CDCl3) d (ppm): 11.70, 17.92,
51.84, 58.97, 64.54, 66.45, 66.87, 67.42, 71.67, 71.72,
79.23, 95.54, 95.95, 127.81, 127.94, 128.38, 136.77,
156.34; MS (ESI+): m/z = 610 [M+Na]+; Anal. Calcd for
C29H53NO9Si: C, 59.25; H, 9.09; N, 2.38. Found: C,
59.15; H, 9.01; N, 2.15.
(100 mg, 0.53 mmol). The reaction mixture was stirred for
4 days at rt and concentrated under vacuum. The residue
was purified by flash chromatography (methanol/dichloro-
methane 5/95 containing 1% NEt3) affording 0.055 g
(0.117 mmol, 55% yield) of the title compound as an oil.
½aꢁD ¼ ꢀ19 (c 1.3, CH2Cl2); H NMR (300 MHz, CDCl3)
d (ppm): 1.31 (s, 3H, CH3), 1.44 (s, 3H, CH3), 2.39 (s,
3H, NCH3), 3.34 (s, 3H, OCH3), 3.38 (s, 3H, OCH3),
25
1
3.52 (m, 3H, OCHaCH2), 3.56 (d, 1H, H-6, J5,6
=
1.7 Hz), 3.76 (m, 2H, H-5 and OCHbCH2O), 4.30 (d, 1H,
H-4, J4,5 = 10.2 Hz), 4.56 (d, 1H, H-2, J2,3 = 6.1 Hz),
0
0
0
4.70 (d, 1H, OCHa O, JHa ,Hb = 7.3 Hz), 4.76 (d, 1H, H-
0
0
0
3, J2,3 = 7.3 Hz), 4.86 (d, 1H, OCHb O, JHa ,Hb = 7.3 Hz),
4.97 (s, 1H, H-1). 13C NMR (75 MHz, CDCl3) d (ppm):
25.18, 26.53, 35.13, 55.69, 59.03, 64.47, 66.52, 67.84,
71.57, 81.95, 83.66, 85.00, 85.99, 97.50, 109.76, 112.37,
128.06, 128.10, 128.32, 128.42, 135.74, 171.51; HR-MS
(ESI+) calcd m/z for C23H35NO9Na: 492.2210 [M+Na]+,
found: 492.2210 [M+Na]+.
4.1.14.
(2R,3R)-3-N-Benzyloxycarbonylamino-2,4-bis(2-
methoxyethoxymethoxy)butanal 3. To a solution of 15
(1.25 g, 2.13 mmol) in THF (40 mL) at 0 ꢁC was slowly
added a 1 M solution of tetrabutylammonium fluoride in
THF (3.2 mL, 3.2 mmol). After 10 min, the solution was
concentrated under vacuum and the residue was purified
by flash chromatography (EtOAc/cyclohexane 50/50)
affording 0.901 g of the expected compound as a colourless
oil. To a solution of DMSO (0.44 mL, 6.27 mmol) in dry
dichloromethane (5.4 mL) cooled to ꢀ78 ꢁC was added
4.1.16. Benzyl (methyl 6-deoxy-2,3-O-isopropylidene-5-O-
(2-methoxyethoxymethyl)-6-N,N-{methyl[(20S,30R)-30-N-
benzyloxycarbonylamino-20-(2-methoxyethoxymethoxy)-40-
(2-methoxyethoxymethoxy)butyl]amino}-D-glycero-b-D-allo-
heptafuranosid)uronate 19. A solution of 18 (58 mg,
dropwise
a
solution of oxalyl chloride (0.20 mL,
2.30 mmol) in dichloromethane (5.4 mL). After 10 min, a
solution of the previous oil (0.901 g, 2.09 mmol) in dry
dichloromethane (9 mL) was added dropwise at ꢀ78 ꢁC
to the reaction mixture. After 1 h at ꢀ78 ꢁC, triethylamine
(2.2 mL, 15.7 mmol) was added. After stirring at ꢀ78 ꢁC
for 15 min, a saturated aqueous solution of ammonium
chloride (40 mL) was added to the reaction mixture. The
organic layer was extracted with ethyl acetate
(4 · 40 mL). The ethyl acetate extract was dried over so-
dium sulfate, and concentrated. The residue was purified
by flash chromatography (EtOAc/cyclohexane 50/50)
affording 0.749 g (1.75 mmol, 82% yield) of the title com-
pound as a colourless oil. ½aꢁD ¼ þ14 (c 1.3, EtOH); H
NMR (300 MHz, CDCl3) d (ppm): 3.23 (s, 3H, CH3),
3.30 (s, 3H, CH3), 3.55 (m, 4H, 2 · OCH2), 3.66 (m, 4H,
2 · OCH2), 3.70 (m, 3H, H-3 and H-4), 4.10 (d, 1H, H-2,
J2,3 = 4.2 Hz), 4.71 (s, 2H, OCH2O), 4.75 (m, 2H,
OCH2O), 5.03 (s, 2H, OCH2Ph), 5.69 (d, 1H, NH,
J3,NH = 9.0 Hz), 7.26 (m, 5H, Ar-H), 9.53 (s, 1 H, H-1).
13C NMR (75 MHz, CDCl3) d (ppm): 51.39, 59.02, 65.49,
66.99, 67.19, 68.08, 71.52, 71.69, 83.89, 96.61, 128.54,
128.20, 128.17, 136.37, 156.02, 199.36; HR-MS (ESI+)
calcd for C20H31NO9Na: 452.1897 [M+Na]+, found:
452.1906 [M+Na]+.
0.123 mmol) and 3 (107 mg, 0.25 mmol) in toluene
(10 mL) was stirred for 15 min before concentrating under
vacuum. To the residue dissolved in dichloroethane
˚
(12 mL) was added 3 A-MS (2 g) and acetic acid
(0.3 mL). The solution was stirred for 24 h before adding
sodium triacetoxyborohydride (53 mg, 0.25 mmol). After
40 h, 3 (76 mg, 0.18 mmol) was added and the solution
was stirred for 48 h before adding sodium triacetoxyboro-
hydride (38 mg, 0.18 mmol). After 18 h, the reaction mix-
ture was filtered, diluted with dichloromethane (10 mL)
and quenched by adding 5% aqueous solution of sodium
bicarbonate (10 mL). The product was extracted with
dichloromethane (2 · 10 mL). The organic extract was
dried over sodium sulfate and concentrated. The residue
was purified by flash chromatography (methanol/dichloro-
25
1
methane 3/97) affording 49 mg (0.055 mmol, 45% yield) of
25
the title compound as a colourless oil. ½aꢁD ¼ ꢀ16 (c 0.5,
1
CH2Cl2); H NMR (300 MHz, CDCl3) d (ppm): 1.26 (s,
3H, CH3), 1.44 (s, 3H, CH3), 2.36 (s, 3H, NCH3), 2.59
(dd, 1H, H-10a, J1 a,1 b = 13.89 Hz, J1 a,2 = 4.23 Hz), 2.75
0
0
0
0
(dd, 1H, H-10b, J1 a,1 b = 13.89 Hz, J1 b,2 = 7.71 Hz,),
3.35-3.37 (m, 13H, 4 · OCH3, H-30), 3.49-3.75 (m, 16H,
3 · O(CH2)2O, H-5, H-6, H-40), 3.98 (m, 1H, H-20), 4.47
(d, 1H, H-4, J4,5 = 6.07 Hz), 4.66-4.84 (m, 7H, H-2,
3 · OCH2O), 4.91 (s, 1H, H-1), 4.93 (m, 1H, H-3), 5.08
(m, 2H, OCH2Ph), 5.16 (m, 2H, OCH2Ph), 6.01 (d, 1H,
0
0
0
0
4.1.15. Benzyl (methyl 6-deoxy-2,3-O-isopropylidene-5-O-
(2-methoxyethoxymethyl)-6-N-methylamino-D-glycero-b-D-
allo-heptafuranosid)uronate 18. A solution of 2 (83 mg,
0.21 mmol) in a 1/1 mixture of methanol/water (2 mL) con-
taining potassium hydroxide (35 mg, 0.63 mmol) was stir-
red for 3 h. After acidification to pH 1 at 0 ꢁC with a
NH, J3 ,NH = 8.67 Hz), 7.34 (m, 10H, Ar-H). 13C NMR
0
(75 MHz, CDCl3) d (ppm): 25.03, 26.68, 39.77, 56.16,
58.91, 66.06, 66.54, 66.78, 67.37, 67.42, 67.55, 67.69,
71.56, 71.69, 67.84, 79.16, 79.77, 85.34, 86.32, 85.34,
85.45, 97.74, 110.38, 112.71, 127.91, 128.07, 128.18,

B. Drouillat et al. / Tetrahedron: Asymmetry 18 (2007) 1955–1963
1963
128.37, 128.47, 135.86, 156.35, 169.56; HR-MS (ESI+)
calcd for C43H66N2O17Na: 905.4259 [M+Na]+, found:
905.4246 [M+Na]+.
(b) Ubukata, M.; Kimura, K.; Isono, K.; Gregson, J. M.;
McCloskey, J. A. J. Org. Chem. 1992, 57, 6392–6403.
4. (a) Spada, M. R.; Ubukata, M.; Isono, K. Heterocycles 1992,
34, 1147–1167; (b) Kim, K. S.; Ahn, Y. H. Tetrahedron:
Asymmetry 1998, 9, 3601–3605; (c) Le Merrer, Y.; Gravier-
Pelletier, C.; Gerrouache, M.; Depezay, J.-C. Tetrahedron
Lett. 1998, 39, 385–388; (d) Gravier-Pelletier, C.; Milla, M.;
Le Merrer, Y.; Depezay, J.-C. Eur. J. Org. Chem. 2001, 16,
3089–3096; (e) Sarabia, F.; Martin-Ortiz, L.; Lopez-Herrera,
F. Org. Lett. 2003, 5, 3927–3930.
5. Knapp, S.; Moriello, G. J.; Doss, G. A. Org. Lett. 2002, 4,
603–606.
6. Miyake, T.; Igarashi, M.; Shidara, T.; Takahashi, Y. JP WO
2004-067544A1, 2004.
7. Hirano, S.; Ichikawa, S.; Matsuda, A. Angew. Chem., Int. Ed.
2005, 44, 1854–1856.
8. (a) Greck, C.; Bischoff, L.; Ferreira, F.; Pinel, C.; Piveteau,
E.; Geneˆt, J. P. Synlett 1993, 475–477; (b) Greck, C.;
Drouillat, B.; Thomassigny, C. Eur. J. Org. Chem. 2004, 7,
1377–1385, and references cited therein.
4.1.17. Methyl (5R)-5-O-(2-methoxyethoxymethyl)-5-C-
[(20S,50S,60S)-60-(2-methoxyethoxymethoxy)-50-(2-methoxy-
ethoxymethoxymethyl)-10-methyl-30-oxo-10,40-diazepan-20-yl]-
2,3-O-isopropylidene-b-D-ribofuranoside 1. A solution of
19 (49 mg, 0.055 mmol) in a 1/1 mixture of ethanol/
water (8 mL) containing Pd/C (25 mg) was stirred
vigorously at 25 ꢁC for 6 h under 5 bar hydrogen. After fil-
tering, the solution was concentrated under vacuum. To
the residue dissolved in dry N,N-dimethylformamide
(3 mL) cooled to 0 ꢁC was added hydroxybenzotriazole
(22 mg, 0.162 mmol), 2,5-dimethylaminopyridine (3 mg,
0.024 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbo-
diimide hydrochloride (37 mg, 0.193 mmol). The reaction
mixture was stirred for 16 h at 25 ꢁC before adding metha-
nol (1 mL). After 1 h, the solution was concentrated under
vacuum and the residue was purified by flash chromatogra-
phy (16 M ammonia solution/methanol/dichloromethane
9. (a) Geneˆt, J. P.; Pinel, C.; Ratovelomanana-Vidal, V.;
Mallart, S.; Pfister, X.; Cano De Andrade, M. C.; Laffitte,
J. A. Tetrahedron: Asymmetry 1994, 5, 665–674; (b) Geneˆt, J.
P.; Ratovelomanana-Vidal, V.; Canˇo de Andarade, C.;
Pfister, X.; Guerreiro, P.; Lenoir, J. Y. Tetrahedron Lett.
1995, 36, 4801–4804; (c) Ratovelomanana-Vidal, V.; Geneˆt, J.
P. J. Organomet. Chem. 1998, 567, 163–171.
0.25/2.5/100) affording 10 mg (0.016 mmol, 28% yield) of
25
the title compound as a colourless oil. ½aꢁD ¼ ꢀ10 (c 0.6,
1
CH2Cl2); H NMR (300 MHz, CDCl3) d (ppm): 1.31 (s,
3H, CH3), 1.47 (s, 3H, CH3), 2.53 (s, 3H, NCH3), 3.11
(m, 2H, H-70), 3.37–3.41 (m, 12H, 4 · OCH3), 3.56–3.91
(m, 14H, 3 · O(CH2)2O, H-20, H-60), 4.07 (m, 1H, H-5),
4.23 (m, 1H, H-50), 4.34 (d, 1H, H-4, J4,5 = 9.84 Hz),
4.59 (d, 1H, H-2, J2,3 = 6.36 Hz) 4.70–4.86 (m, 6H,
3 · OCH2O), 4.98–5.01 (m, 2H, H-1, H-3), 6.35 (s, NH).
13C NMR (75 MHz, CDCl3) d (ppm): 25.16, 26.52, 37.17,
55.71, 56.08, 59.01, 59.07, 63.45, 64.71, 65.67, 67.34,
67.51, 67.53, 67.74, 68.12, 70.02, 82.11, 85.74, 86.23,
110.27, 112.29, 177.72; HR-MS (ESI+) calcd for
C28H52N2O14Na: 663.3316 [M+Na]+, found: 663.3293
[M+Na]+.
10. Drouillat, B.; Poupardin, O.; Bourdreux, Y.; Greck, C.
Tetrahedron Lett. 2003, 44, 2781–2783.
11. O’Donnel, M. J.; Polt, R. L. J. Org. Chem. 1982, 47, 2663–
2666.
12. Chruma, J. J.; Sames, D.; Polt, R. Tetrahedron Lett. 1997, 38,
5085–5086.
13. Bourdreux, Y.; Drouillat, B.; Greck, C. Synlett 2005, 2086–
2088.
14. In the presence of the NMR shift complex tris[3-(trifluoro-
methylhydroxymethylene)-D-camphorato]-europium (molar
ratio b-hydroxyester/europium complex = 8/1; CCl4/
CDCl3 = 70/30), the methyl ester chemical shifts of the
racemic mixture obtained by reduction of 5 with sodium
borohydride were at 3.82 and 3.79 ppm using 1H NMR
analysis. Under the same analytical conditions, a single
methyl ester chemical shift at 3.82 ppm was observed for 9
obtained by hydrogenation of 5 in the presence of (S)-
BinapRuBr2 catalyst.
Acknowledgement
15. Guanti, G.; Banfi, L.; Narisano, E. Tetrahedron Lett. 1989,
30, 5507–5510.
`
Funding for this work was provided by the Ministere de la
Recherche through a grant to Y.B.
16. (a) Crouch, R. D. Tetrahedron: Asymmetry 2004, 28, 5833–
5871; (b) Protective Groups in Organic Synthesis; Greene, T.
W., Wuts, P. G. M., Eds., 3rd ed.; John Wiley & Sons: New
York, 1999; (c) Nelson, T. D.; Crouch, R. D. Synthesis 1996,
9, 1031–1069.
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