Synthesis of C-linked analogues of β-D-galactopyranosyl-(1→3)-D- galactopyranosides and of β-D-galactopyranosyl-(1→3)-D-galactal

Article abstract of DOI:10.1016/j.tetasy.2004.09.029

Efficient and stereoselective methods for the preparation of C-disaccharides, such as 2 and 3c, have been developed. C-linked disaccharide derivatives mimicking O-β-d-galactopyranosyl-(1→3)-d- galactopyranosides (end groups in Core-B structures of biologically important proteoglycans) have been obtained from isolevoglucosenone and β-d-galactopyranosylcarbaldehyde derivatives. The β-d- galactopyranosyl-(1→3)-CH(OH)-d-galactal derivatives 3a (4,6-di-O-acetyl-3-C-[(1R)-1,3,4,5,7-penta-O-acetyl-2,6-anhydro-d-glycero-l- manno-heptito1-1-C-yl]-3-deoxy-d-galactal), 3b (4,6-di-O-benzyl-3-C-[(1R)-2,6- anhydro-1,3,4,5,7-penta-O-benzyl-d-glycero-l-manno-heptitol-1-C-yl] -3-deoxy-d-galactal) and the β-d-galactopyranosyl-(1→3)-CH ₂-d-galactal 3c (4,6-O-diacetyl-3-C-) [6-O-acetyl-2,3,4-tri-O-(tert- butyl)dimethylsilyl-β-d-galactopyranosylmethyl]-3-deoxy-d-galactal have been prepared. One of them, 3a, has been shown to be a suitable agent for the O-glycosidation and the construction of glycoconjugates bearing the β-d-Galp-(1→3)-CH(OH)-d-Galp-O moiety.

Full text of DOI:10.1016/j.tetasy.2004.09.029

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3573–3585
Synthesis of C-linked analogues of
b-D-galactopyranosyl-(1!3)-D-galactopyranosides and of
b-D-galactopyranosyl-(1!3)-D-galactal
Raynald Demange,ꢀ Loay Awad and Pierre Vogel*
`
´
Laboratoire de glycochimie et de synthese asymetrique, Swiss Federal Institute of Technology (EPFL), BCH,
CH-1015 Lausanne-Dorigny, Switzerland
Received 17 August 2004; accepted 30 September 2004
Available online 22 October 2004
Abstract—C-linked disaccharide derivatives mimicking O-b-D-galactopyranosyl-(1!3)-D-galactopyranosides (end groups in Core-B
structures of biologically important proteoglycans) have been obtained from isolevoglucosenone and b-D-galactopyranosylcarbal-
dehyde derivatives. The b-D-galactopyranosyl-(1!3)-CH(OH)-D-galactal derivatives 3a (4,6-di-O-acetyl-3-C-[(1R)-1,3,4,5,7-penta-
O-acetyl-2,6-anhydro-D-glycero-L-manno-heptito1-1-C-yl]-3-deoxy-D-galactal), 3b (4,6-di-O-benzyl-3-C-[(1R)-2,6-anhydro-1,3,4,5,7-
penta-O-benzyl-D-glycero-L-manno-heptitol-1-C-yl]-3-deoxy-D-galactal) and the b-D-galactopyranosyl-(1!3)-CH2-D-galactal 3c
(4,6-O-diacetyl-3-C-) [6-O-acetyl-2,3,4-tri-O-(tert-butyl)dimethylsilyl-b-D-galactopyranosylmethyl]-3-deoxy-D-galactal have been
prepared. One of them, 3a, has been shown to be a suitable agent for the O-glycosidation and the construction of glycoconjugates
bearing the b-D-Galp-(1!3)-CH(OH)-D-Galp-O moiety.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
sides.10,11 An isomer of 2 (a-methyl a-galactopyranosyl,
(S)-hydroxymethylene linker) had been prepared al-
ready in 1992 by Schmidt and Beyerbach.12 Their method
involved the direct lithiation of 3,4,6-O-tribenzyl 2-phe-
nylsulfinyl-D-galactal with methyl 2,4,6-O-tribenzyl-3-
deoxy-a-D-galactopyranosyl bearing a b-carbaldehyde
groupat C(3). We had applied the Oshima–Nozaki cou-
pling reaction of enones and aldehydes13 to a 2,3,4,6-O-
tetrabenzyl-b-D-glucopyranosylcarbaldehyde and isolevo-
glucosenone 414 and obtained 2,3-anhydro-3-C-[(lS)-2,6-
anhydro-D-glycero-D-gulo-heptitol-l-C-yl]-b-D-gulopyra-
nose15 and a fluorinated derivative.16 We will show now
that 2,3,4,6-O-tetrabenzyl-5a and 2,3,4,6-O-tetra [(tert-
butyl)dimethylsilyl]-b-D-galactopyranosylcarbaldehyde
5b17,18 can be condensed with isolevoglucosenone 4
(Scheme 1) to produce enones 6a and 6b, respectively
(Baylis–Hillmann type of products) which can be readily
converted into C-linked analogues of b-D-galactopyrano-
syl-(1!3)-D-galactal derivatives 3a–3c. The carbon lin-
ker is a hydroxymethylene groupin 3a and 3b, and a
methylene groupin 3c. Galactal 3b was converted into
b-D-galactopyranosyl-(1!3)-CH(OH)-D-galactopyrano-
sides 2 and 17 and into b-D-galactopyranosyl-(1!3)-
CH(OH)-D-talopyranosides 16. Galactal 3a was converted
Carbohydrates regulate the cell/cell1 and cell/invader2
interactions, and play a crucial role in the construction
of multicellular organs and organisms. With a growing
understanding of the precise function that cell-surface
carbohydrates play in disorders such as inflammation,
viral and bacterial infections, to cancer, numerous car-
bohydrate analogues have now been developed and en-
tered into clinical studies.3 Disaccharide mimetics such
as C-linked disaccharides and oligosaccharides contain-
ing them offer the advantage of being resistant to acidic
and enzymatic hydrolysis.4,5 They are potential inhibi-
tors of glycosidases and glycosyltransferases.6 The disac-
charide
O-b-D-galactopyranosyl-(1!3)-O-b-D-galac-
topyranosyl 1 is found as an end groupin Core-B struc-
tures of a large number of proteoglycans7 and has been
isolated from a variety of other sources.8 We report
herein efficient syntheses of protected forms 2 of C-
linked analogues of 1, including the b-D-galactopyrano-
syl-(1!3)-D-galactal derivatives 3, compounds suitable
for O-glycosidation9 and for the preparation of C-glyco-
*
Corresponding author. Tel.: +41 216939371; fax: +41 216939375;
e-mail: pierre.vogel@epfl.ch
ꢀ Address: SICPA, CH 1008 Prilly.
into b-D-galactopyranosyl-(1!3)-CH(OH)-2-deoxy-D-
lyxo pyranoside a-O-conjugated with L-serine 21.
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.09.029

3574
R. Demange et al. / Tetrahedron: Asymmetry 15 (2004)3573–3585
in toluene containing silica gel, a smooth elimination of
BnO
OH
O
OH
O
OBn
O
OBn
O
HO
HO
HO
O
BnO
BnO
BnO
acetic acid occurred with the formation of galactal 3a
isolated in 82% yield after flash chromatography. Ex-
change of the acetyl groups for benzyl groups was done
by treating 3a with MeOH/Na2CO3 at 20ꢁC for 90min,
followed by solvent removal and reaction of the polyol
with NaH in DMF and then with benzyl bromide and
Bu4Nl. This gave 3b in 76% yield for the two steps.
O R'
OR
O R'
R
OH
OH
OBn
OBn
1
2
R'O
OR'
O
RO
RO
X
O
OR
Galactal 3b reacted with dimethyldioxirane in acetone at
0ꢁC. The unstable intermediate epoxide (Brigl anhy-
dride) reacted with MeOH to give semi-protected [free
at OH at C(2)] methyl b-D-galactopyranoside, which
was not isolated but benzylated under standard condi-
tions to furnish the perbenzylated C-disaccharide 2
3a R = R' = Ac, X = OAc
3b R = R' =Bn, X = OBn
3c R = TBS, R' = Ac, X = H
2. Results and discussion
1
(Scheme 2) in 71% yield (three steps). The H NMR
Slow addition of Et2AlI in solution in toluene to a mix-
ture of 4 and aldehydes 5a and 5b in CH2Cl2 (À80ꢁC)
led to the formation of enones 6a and 6b in 73% and
95% yield, respectively. These reactions imply the for-
mation of aluminum enolate 7, which adds to aldehydes
5a and 5b following the Zimmerman–Traxler model 819
(steric factors control the diastereoselectivity) giving
iodo-aldols 9 which are unstable and eliminate HI dur-
ing aqueous work-up( Scheme 1).
spectrum of 2 (vicinal H/H coupling constants) proved
its structure. Interestingly, when 3b was epoxidized with
meta-chloroperbenzoic acid (Scheme 3), the intermedi-
ate epoxide reacted with MeOH to give the semi-pro-
tected C-disaccharide 16 in 52% yield together with
20% of 17 (Scheme 2). This is a C-linked analogue of
(b-D-galactopyranosyl) (1!3)-(methyl a-D-talopyrano-
side). The preferred a-face epoxidation of galactal 3b
with dimethyldioxirane is to be expected for steric rea-
sons. The preferred b-face epoxidation of 3b with m-
CPBA can be attributed to hydrogen bridging of the
peracid with the 4- or 6-benzyloxy group. To further test
the usefulness of our C-galactopyranosyl(1!3)galactal
derivatives, we reacted peracetate 3a with Z-Ser-OBn
and Fmoc-Ser-OBn (semiprotected forms of L-serine)
in the presence of I(sym-collidine)2ClO4(Lemieuxꢁs,21
Thiemꢁs22 haloglycosidations). This produced iodo-talo-
pyranosides 18 (72%) and 19 (70%), respectively. At-
tempts to displace the iodide of 18 and 19 by all kinds
of azides (NaN3/DMF, LiN3/DMF, tetramethylguadi-
nium azide/DMF, Me3SiN3/Bu4NF/THF, azidoada-
mantane/DMF) led to products of decomposition and/
or to the a-D-threo-hex-2-enopyranoside 20.23 Radical
dehalogenation24 of 18 with Bu3SnH/AlBN generated
the 2-deoxy-a-galactopyranoside 21 in 72% yield
(Scheme 3).25
Attempts to reduce both the C@C and C@O double
bonds of enones 6a and 6b by direct methods [NaBH4,
LiAlH(t-BuS)3, cat. hydrogenation followed by hydride
reduction] led to mixtures of diastereomeric products.
Addition of thiophenol to 6a catalyzed by Et3N gener-
ated a single adduct 10 that could not be isolated be-
cause the thiophenol was eliminated readily at 20ꢁC.
Thus the crude adduct 10 was treated directly with
NaBH4 at 0ꢁC to produce a single diol 11 that was iso-
lated in 81% yield.15 Desulfurization of 11 with Raney
nickel in THF gave diol 12 (87% yield). It was converted
into its acetonide 13 (62%) under standard conditions.
1
The 2-D-NOESY H NMR spectrum of 13 confirmed
its structure and of its precursor (3J3,4 = 8.2Hz). More-
over, its 13C NMR spectrum showed dC(Me) = 25.5,
27.5ppm, typical for a 1,4-anti-disubstitution of the
1,3-dioxane moiety.20 A Birch reduction of the benzyl
ethers of 12, followed by acetylation provided hexaace-
tate 14 in 88% yield. Treatment of 14 with Ac2O and
CF3COOH gave a 1:0.3 mixture of a/b pyranosides
15a and 15b. When this mixture was heated under reflux
We have also explored the possibility of generating b-D-
galactopyranosyl-C(1!3)galactal, in which there is a
carbon linker in a methylene rather than a hydroxy-
methylene group. In the presence of Raney nickel in
OR
OR
RO
RO
RO
RO
O
O
O
HO
Et2AlI
CH2Cl2
O
O
O
O
+
O
CHO
OR
OR
6a R = Bn
4
5a R = Bn
5b R = (t-Bu)Me2Si = TBS
6b R = TBS
Et2AlI
Al
O
OR
O
RO
RO
O
O
O
HO
O
+ 5
O
O
H
O
O
O
OR
H
AlEt2
R H
I
I
I
7
8
9
Scheme 1.

R. Demange et al. / Tetrahedron: Asymmetry 15 (2004)3573–3585
3575
OBn
O
BnO
BnO
O
O
HO
HO
2. NaBH4
MeOH
0°C, 2 h
(81%)
OBn
O
O
BnO
BnO
HO
1. PhSH/CH2Cl2
Et3N (cat.)
O
O
6a
OBn
OBn
SPh
0°C, 1 h
X
10
11 X = SPh
12 X = H
Ra-Ni (87%)
Mea
H
H
H
H6
Meb
O
O
4
OBn O
H
OAc
O
AcO
AcO
1
O
O
AcO
H 3'
Me2C(OMe)2
pyrH+/TsO-
(62%)
1. Na/NH3
2. Ac2O/pyr.
DMAP
2
O
12
1'H
12
2'
3
BnO
AcO
H
H
4'
5'
H
O
OAc
H
BnO
(88%)
6'
H
7'
OBn
14
13
OAc
O
OR
OR
Ac2O
CF3COOH
20°C, 4 h
(81%)
AcO
AcO
OR
OAc
O
AcO
AcO
OR
RO
PhMe, SiO2
∆ (82%)
O
14
3b
O
OAc
RO
OAc
15α,β
OR
H
3a R = Ac
3b R = Bn
1. MeOH/Na2CO3, 20°C, 1.5 h
2. NaH, BnBr, Et4NI, DMF
(76%, 2 steps)
O O
OBn
1.
, 0°C
BnO 6
OBn
BnO 7'
Bn5O'
BnO
2'
2. MeOH
3. NaH, BnBr
DMF, Bu2NI
4
5
6'
O
O
1
OMe
3' OBn 1'
2 OR
4'
3
(75%, 3 steps)
2 R = Bn
17 R = H
Scheme 2.
OBn
OBn
O
BnO
BnO
BnO
OH
O
BnO
mCPBA
MeOH, CH2Cl2
+
17 (20%)
3b
OBn
OMe
16 (52%)
OAc
OAc
O
AcO
AcO
AcO
AcO
X
O
COOBn
I(symcollidine)2ClO4
MS 4Å, CH2Cl2
NHR
+
RHN
3a
OAc
O
OBn
OH
O
Z-Ser-OBn R = BnOCO
Fmoc-Ser-OBn R = Fmoc
18 R = BnOCO (72%) X = I
19 R = Fmoc (70%) X = I
21 R = Fmoc, X = H
Bu3SnH, AIBN
OAc
O
AcO
AcO
OAc
OAc
O
AcO
NaN3, DMF
18
20°C, 16 h
COOBn
NHR
20 (R = BnOCO)
OAc
O
(90%)
Scheme 3.
THF, the TBS-protected C-galactoside 6b was reduced
quantitatively into a mixture of aldols from which 22
and 23 were isolated (flash chromatography) in 57%
and 43% yield, respectively. The crude mixture of
22 and 23 was treated with CH3SO2Cl/pyridine and a
catalytical amount of DMAP. This led to the formation
of a mixture of unstable enones 24 that were not isolated
but treated with Raney nickel in aqueous THF at 20ꢁC.
This produced a mixture of ketones from which pure
25 and 26 were isolated in 43% and 44% yield, respec-
tively. Reduction of 25 with LiBH4 in THF gave alco-
hol 27 in 79% yield, the structure of which (1,6-
anhydro-2-deoxy-D-lyxo configuration) was given by
its 1H NMR spectrum. Treatment of 27 with triethylsilyl

3576
R. Demange et al. / Tetrahedron: Asymmetry 15 (2004)3573–3585
O
O
O
OR
O
OR
H
O
RO
RO
RO
RO
O
O
X
Ra-Ni
THF
O
+
6b
X
OR
OR
22 X = OH (57%)
25 X = H (43%)
23 X = OH (43%)
26 X = H (44%)
O
O
OR
O
RO
RO
O
MsCl, pyr.
DMAP
H
22 + 23
OR
Ra-Ni
H2O/THF
24
25 + 26
OR
O
OAc
O
RO
RO
RO
RO
HO
AcO
OAc
O
O
Et3SiOTf
Ac2O
-20°C
LiBH4/THF
-78→ -20°C
O
25
OAc
OR
27
OR
28α,β
R = TBS
AcO
OAc
O
OAc
O
TBSO
TBSO
TBSO
3c
Scheme 4.
trifluoromethanesulfonate and acetic anhydride ring-
opened the 1,6-anhydro moiety and acetylated the D-lyx-
ose derivative without formation of furanosides. The
mixture of a- and b-pyranosides 28a,b thus obtained,
was not purified but directly treated with silica gel in
benzene heated under reflux. This produced the C-linked
analogue of b-D-galactopyranosyl-(1!3)-D-galactal 3c
in 60% yield (Scheme 4).
4.2. 1,6-Anhydro-3-C-[(1R)-2,6-anhydro-3,4,5,7-tetra-O-
benzyl-D-glycero-L-manno-heptitol-1-C-yl]-2,3-dideoxy-
b-D-glycero-hex-2-en-4-ulopyranose 6a
A solution of Et2AlI (1M) in toluene (8.5mL, 8.5mmol)
was added dropwise in 90min to a stirred solution of
aldehyde 517 (3.53g, 6.4mmol) and isolevoglucosenone
4 (1.21g, 9.5mmol) in anhydrous CH2Cl2 (24mL)
cooled to À80ꢁC under an Ar atmosphere. After stirring
at À80ꢁC for 19h, the cooling bath was removed and
Et2O (80mL) and then 1M aq HCl (60mL) added under
vigorous stirring (red mixture becomes yellowish). After
the addition of H2O (50mL), the aqueous phase was ex-
tracted with Et2O (3 · 50mL). The combined organic
phases were washed with brine (100mL) and dried over
MgSO4. Solvent evaporation, FC (8:2 then 7:3 light
petroleum/EtOAc) afforded 3.17g (73%) of a white
3. Conclusion
The Oshima–Nozaki condensation of b-D-galactopyrano-
sylcarbaldehyde derivatives with isolevoglucosenone
has allowed the efficient and highly stereoselective
synthesis of C-linked disaccharides mimicking
b-D-Galp(1!3)-D-Galp. Useful b-D-galactopyrano-
syl(1!3)-CH(OH)-galactal and b-D-galactopyranosyl-
(1!3)-CH2-D-galactal derivatives have been prepared
and shown to be suitable for further derivatization and
O-glycosidations.
25
25
solid; mp46–48 ꢁC. ½aŠ ¼ þ78, ½aŠ ¼ þ52,
589
546
25
25
½aŠ ¼ þ225, ½aŠ ¼ þ573 (c 0.12, CHCl3). UV
435 405
(MeCN) 243 (6000), 213 (18500). IR (KBr) 3420, 3030,
2870, 1695, 1455, 1365, 1095, 910, 735, 700cmÀ1. H
1
NMR (400MHz, CDCl3) d 7.36–7.25 (m, 20H, ArH),
3
7.04 (dd, J1,2 = 3.4, J1 ,2 = 1.4, H-2), 5.75 (d,
4
0
4. Experimental
4.1. General
3J1,2 = 3.4, H-1), 4.98–4.35 (m, 9H, 4 O–CH2–Ph, H-
3
3
10), 4.66 (dd, J5,6exo = 6.1, J5,6endo = 1.1, H-5), 4.15
3
3
(dd, J3 ,4 = 9.5, J2 ,3 = 9.5, H-30), 3.92–3.88 (m, 2H,
0
0
0
0
3
3
H-50, Hexo-6), 3.64 (dd, J3 ,4 = 9.5, J4 ,5 = 2.7, H-40),
0
0
0
0
3
3
3.58 (dd, J2 ,3 = 9.5, J1 ,2 = 1.5, H-20), 3.51 (dd,
0
0
0
0
See Ref. 25; THF and Et2O were distilled from sodium
and benzophenone; toluene from CaH2; MeOH from
magnesium. Electrospray mass analyses were recorded
on a Finnigan MAT.SSQ710C spectrometer in the pos-
itive ionization mode. High resolution FAB mass spec-
tra were recorded on a FAB-LSIMS (University of
Seville, Spain). Elemental analyses were performed by
the Ilse Beetz Laboratory, Kronach, Germany. Signal
2J = 8.2, J5,6endo = 1.1, Hendo-6), 3.48–3.45 (m, 3H,
3
H-60, H2-70). 13C NMR (100.6MHz, CDCl3)
d 194.5 (s, C-4), 142.1 (d, 165, C-2), 138.5, 138.4,
138.2, 137.8, 137.8 (5s, 4Carom, C-3), 128.4–127.5 (20d,
CHarom), 96.8 (d, 177, C-1), 84.6 (d, 138, C-40), 79.2
(d, 160, C-5), 79.0 (d, 141, C-20), 77.3 (d, 143, C-60),
75.1 (t, 142, O–CH2–Ph), 74.5 (t, 143, O–CH2–Ph),
74.5 (d, 142, C-30), 74.0 (d, 144, C-50), 73.4 (t, 141, O–
CH2–Ph), 72.4 (t, 142, O–CH2–Ph), 69.3 (t, 142, C-70),
1
assignments in H NMR spectra are confirmed by 2D-
COSY and NOESY spectra.

R. Demange et al. / Tetrahedron: Asymmetry 15 (2004)3573–3585
3577
66.0 (d, 147, C-10), 62.2 (t, 154, C-6). CI-MS (NH3) m/z
697 (1, [M+18]+), 570 (1), 451 (1), 181 (4), 91 (71), 83
(100). Anal. Calcd for C41H42O9: C, 72.55; H, 6.24.
Found: C, 72.50; H 6.28.
(br s, H-1), 4.92–4.42 (m, 8H, 4OCH2Ph), 4.40 (br dd,
0
3
3
J4,5 = 5.2, J5,6exo = 4.8, H-5), 4.35 (d, J1 ,3 = 10.1, H-
3
3
3
10), 4.28 (br dd, J3,4 = 6.2, J4,5 = 5.2, H-4), 4.18 (d,
2J = 7.9, Hendo-6), 4.08 (dd, J3 ,4 = 9.4, J2 ,3 = 9.4, H-
3
3
0
0
0
0
3
30), 3.94 (d, J4 ,5 = 2.3, H-50), 3.64–3.50 (m, 5H, H-40,
0
0
3
H-60, Hexo-6, H2-70), 3.35 (d, J2 ,3 = 9.4, H-20),
0 0
4.3. 1,6-Anhydro-3-C-[(1R)-2,6-anhydro-3,4,5,7-tetra-O-
benzyl-D-glycero-L-manno-heptitol-1-C-yl]-2,3-dideoxy-
2-phenylthio-b-D-galacto-pyranose 11
3
3
2.31 (dddd, J1 ,3 = 10.1, J2endo,3 = 7.2, J3,4 = 6.2,
3
0
3J2exo,3 = 3.6, H-3), 1.81 (ddd, 2J = 14.7, J2endo,3
=
3
3
7.2, J1,2endo = 2.4, Hendo-2), 1.66 (br dd, 2J = 14.7,
3J2exo,3 = 3.6, Hexo-2). 13C NMR (100.6MHz, CDCl3)
d 138.5, 138.2, 138.1, 137.7 (4s, 4Carom), 128.5–127.5
(20d, CHarom), 99.9 (d, 169, C-1), 84.6 (d, 137, C-40),
78.4 (d, 142, C-20), 77.0 (d, 143, C-60), 75.5 (t, 145,
OCH2Ph), 75.3 (d, 157, C-5), 74.4 (t, 144, OCH2Ph),
74.1 (d, 147, C-30), 73.6 (t, 142, OCH2Ph), 73.5 (d,
142, C-50), 72.4 (t, 141, OCH2Ph), 71.2 (d, 148, C-10),
69.3 (d, 147, C-4), 68.9 (t, 144, C-70), 63.9 (t, 151, C-
6), 35.1 (d, 132, C-3), 32.2 (t, 128, C-2). CI-MS (NH3)
m/z 701 (3, [M+18]+), 684 (2, [M+1]+), 633 (2), 581
(1), 485 (1), 181 (8), 91 (100). Anal. Calcd for
C41H46O9: C, 72.11; H, 6.79. Found: C, 72.16; H, 6.77.
Triethylamine (61lL, 0.43mmol) was added to a solu-
tion of enone 6 (1.42g, 2.1mmol) and thiophenol
(0.24mL, 2.3mmol) in 9mL of CH2Cl2 cooled to 0ꢁC.
The reaction mixture was stirred at 0ꢁC for 1h at which
point 9mL of MeOH and 164mg of NaBH4 (4.3mmol)
were added and the reaction mixture stirred for 2h at
0ꢁC. Then, CH2Cl2 (30mL) and 1M aq HCl (6mL)
were added under stirring. After the addition of H2O
(30mL), the aqueous phase was extracted with CH2Cl2
(3 · 20mL). The combined organic phases were washed
with a satd aq soln of NaHCO3 (40mL), brine (40mL)
and dried over MgSO4. Solvent evaporation, FC (7:3
light petroleum ether/EtOAc) afforded 1.33g (81%)
25
25
25
of 11, colorless oil. ½aŠ ¼ À15, ½aŠ ¼ À19, ½aŠ
¼
4.5. 1,6-Anhydro-3-C-[(1R)-2,6-anhydro-3,4,5,7-tetra-O-
benzyl-D-glycero-L-manno-heptitol-1-C-yl]-2,3-dideoxy-
b-D-lyxo-hexopyranose-10,4-acetonide 13
589
546
435
25
405
(8300), 216 (18600). IR (film) 3375, 3030, 2870, 1455,
À34, ½aŠ ¼ À42 (c 0.27, CHCl3). UV (MeCN) 255
.
1365, 1210, 1115, 910, 735, 695cmÀ1 1H NMR
(400MHz, CDCl3) d 7.42–7.18 (m, 25H, ArH), 5.60 (s,
H-1), 4.95–4.39 (m, 8H, 4 OCH2Ph), 4.57–4.52 (m,
A mixture of 12 (47mg, 0.07mmol), 2,2-dimethoxypro-
pane (1.3mL), dry acetone (1.3mL) and PPTS (13mg)
was stirred at 20ꢁC for 2h. After the addition of CH2Cl2
(10mL) and H2O (20mL), the aqueous phase was ex-
tracted with CH2Cl2 (3 · 10mL). The combined organic
extracts were washed with a satd aq soln of NaHCO3
(20mL), brine (20mL) and dried over MgSO4. Solvent
3
3
2H, H-10, H–C4), 4.36 (dd, J5,6exo = 5.3, J4,5 = 5.3,
2
H-5), 4.17 (d, J = 7.7, Hendo-6), 4.03 (dd, J3 ,4 = 9.4,
3
0
0
3
3
J2 ,3 = 9.4, H-30), 3.87 (d, J4 ,5 = 2.5, H-50), 3.53 (dd,
0
0
0
0
2J = 7.7, J5,6exo = 5.3, Hexo-6), 3.51 (dd, J3 ,4 = 9.4,
3
3
0
0
3
J4 ,5 = 2.5, H-40), 3.38–3.36 (m, 2H, H2-70), 3.29–3.27
0
0
3
(m, 2H, H-2, H-60), 3.07 (d, J2 ,3 = 9.4, H-20), 2.20–
2.15 (m, H-3). 13C NMR (100.6MHz, CDCl3) d 138.4,
138.2, 137.9, 137.5, 134.6 (5s, 5 Carom), 132.3–127.4
(25d, CHarom), 102.9 (d, 177, C-1), 84.6 (d, 137, C-40),
79.2 (d, 141, C-20), 76.6 (d, 145, C-60), 75.7 (t, 142,
OCH2Ph), 74.8 (d, 158, C-5), 74.4 (t, 145, OCH2Ph),
74.2 (d, 142, C-30), 73.6 (t, 141, OCH2Ph), 73.2 (d,
143, C-50), 72.4 (t, 142, OCH2Ph), 69.9, 67.2 (2d, 147,
149, C-10, C-4), 68.5 (t, 144, C-70), 62.9 (t, 152, C-6),
50.8 (d, 144, C-2), 41.4 (d, 131, C-3). CI-MS (NH3) m/
z 792 (4, [M+1]+), 682 (4), 593 (3), 399 (3), 253 (4),
181 (8), 91 (100). Anal. Calcd for C47H50O9S: C,
71.37; H, 6.37. Found: C, 71.38; H, 6.42.
evaporation, FC (8:2 light petroleum ether/EtOAc)
0
0
25
589
afforded 31mg (62%) of 13, colorless oil. ½aŠ ¼ þ1,
25
25
435
25
405
½aŠ ¼ þ3, ½aŠ ¼ þ5, ½aŠ ¼ þ8 (c 0.24, CHCl3).
546
UV (MeCN) 212 (15400). IR (film) 3030, 2865, 1495,
1455, 1365, 1210, 1135, 1100, 1030, 910, 735, 695cmÀ1
.
1H NMR (400MHz, CDCl3) d 7.34–7.26 (m, 20H,
ArH), 5.48 (d, J1,2exo = 4.0, H-1), 5.03–4.44 (m, 8H,
3
3
3
4OCH2Ph), 4.51 (br dd, J43,5 = 6.4, J5,6exo = 5.7, H-5),
4.43 (br dd, J3,4 = 8.2, J4,5 = 6.4, H-4), 4.29 (d,
3
2J = 7.7, Hendo-6), 4.14 (dd, J3 ,4 = 9.4, J2 ,3 = 9.4, H-
3
3
0
0
0
0
3
3
30), 4.11 (dd, J1 ,3 = 11.2, J1 ,2 = 2.1, H-10), 3.97 (d,
0
0
0
3
J4 ,5 = 2.2, H-50), 3.63–3.57 (m, 4H, H-40, Hexo-6, H2-
0
0
3
3
70), 3.26 (m, H-60), 3.25 (dd, J2 ,3 = 9.4, J1 ,2 = 2.1,
0
0
0
0
3
H-20), 2.58 (dddd,
J1 ,3 = 11.2, 3J2exo,3 = 9.6,
0
3
4.4. 1,6-Anhydro-3-C-[(1R)-2,6-anhydro-3,4,5,7-tetra-O-
benzyl-D-glycero-L-manno-heptitol-1-C-yl]-2,3-dideoxy-
b-D-lyxo-hexopyranose 12
3J3,4 = 8.2, J2endo,3 = 5.0, H-3), 1.90 (ddd, 2J = 14.8,
3
2
3J2exo,3 = 9.6, J1,2exo = 4.0, Hexo-2), 1.44 (dd, J = 14.8,
3J2endo,3 = 5.0, Hendo-2), 1.41 (s, 3H, Hb-3), 1.31 (s, 3H,
Ha-3). 13C NMR (100.6MHz, CDCl3) d 138.9, 138.9,
138.3, 138.0 (4s, 4Carom), 128.4–127.3 (20d, CHarom),
100.6 (s, Cacetonide), 99.9 (d, 170, C-1), 85.5 (d, 137,
C-40), 77.7, 77.7 (2d, 140, 140, C-20, C-60), 74.8 (t, 145,
OCH2Ph), 74.2 (d, 147, C-30), 74.1 (t, 146, OCH2Ph),
73.6 (d, 150, C-50), 73.5 (t, 141, OCH2Ph), 72.2 (t, 141,
OCH2Ph), 72.0 (d, 155, C-5), 69.8 (d, 145, C-10), 69.1
(t, 145, C-70), 65.2 (d, 148, C-4), 62.9 (t, 150, C-6),
30.7 (t, 127, C-2), 28.4 (d, 134, C-3), 27.5 (q, 129,
Me(b)acetonide), 25.5 (q, 126, Me(a)acetonide). CI-MS
(NH3) m/z 741 (28, [M+18]+), 573 (7), 181 (7), 91
(100). Anal. Calcd for C44H50O9: C, 73.11; H, 6.97.
Found: C, 73.09; H, 7.04.
A solution of 11 (935mg, 1.18mmol) in THF (70mL)
was treated with Raney nickel (ꢀ7g) and the suspension
stirred for 1h at 20ꢁC. When the reaction was complete
(TLC 1:1 light petroleum ether/EtOAc), the solid was fil-
tered off and washed with EtOAc. The filtrate and the
washing were combined and dried over MgSO4. Solvent
evaporation, FC (3:2 light petroleum ether/EtOAc)
25
589
afforded 701mg (87%) of 12, colorless oil. ½aŠ ¼ þ3,
25
546
25
25
405
½aŠ ¼ À7, ½aŠ ¼ À9, ½aŠ ¼ À12 (c 0.15, CHCl3).
435
UV (MeCN) 210 (15300). IR (film) 3390, 3030, 2870,
1
1455, 1360, 1210, 1105, 865, 735, 695cmÀ1. H NMR
(400MHz, CDCl3) d 7.38–7.24 (m, 20H, ArH), 5.43

3578
R. Demange et al. / Tetrahedron: Asymmetry 15 (2004)3573–3585
3
3
3
0
0
0
0
0
0
4.6. 4-O-Acetyl-1,6-anhydro-3-C-[(1R)-1,3,4,5,7-penta-
O-acetyl-2,6-anhydro-D-glycero-L-manno-heptitol-1-C-
yl]-2,3-dideoxy-b-D-lyxo-hexopyranose 14
J4 ,5 = 3.1, H-50), 5.17 (dd, J3 ,4 = 9.9, J2 ,3 = 9.9,
H-30), 5.15–4.97 (m, 3H, H-10, H-4, H-40), 4.26–3.80
3
(m, 6H, H-5, H-60, H2-6, H2-70), 3.59 (dd, J2 ,3
0
0
=
3
9.9, J1 ,2 = 2.4, H-20), 2.79 (m, H-3), 2.17–1.97 (25H,
0
0
3
Metallic Na (530mg, 23mmol) was added to liquid NH3
(30mL, condensed at À78ꢁC). A solution of 12 (642mg,
0.94mmol) in anhydrous THF (8mL) was added drop-
wise under stirring. After stirring at À78ꢁC for 40min,
solid NH4Cl (1.3g) was added and the cooling bath re-
moved. Once at 20ꢁC, the residue was taken in MeOH
and purified by FC (2:1 CH2Cl2/MeOH) affording an
oil that was mixed with Ac2O (6mL), pyridine (9mL),
4-dimethylaminopyridine (0.5mg) and stirred at 20ꢁC
for 15h. Solvent evaporation in vacuo gave a residue,
which was taken in toluene (10mL) and the solvent
evaporated to dryness in vacuo. The latter operation
was repeated and the residue purified by FC (1:1 light
petroleum ether/EtOAc) affording 475mg (88%, two
Hax-2, 8 MeCOO), 1.69 (dd, 2J = 13.0, J2eq,3 = 3.3,
3
Heq-2). For the anomer 15b: d 5.76 (dd, J1,2ax = 9.8,
3
3
J1,2eq = 2.5, H-1), 5.41 (d, J4 ,5 = 3.2, H-50), 2.58
0
0
(m, H-3). 13C NMR (100.6MHz, CDCl3) data for the
anomer 15a: d 170.5–168.8 (8s, –COO), 91.1 (d, 174,
C-1), 76.2 (d, 138, C-20), 75.1 (d, 141, C-60), 72.6 (d,
148, C-40), 70.5 (d, 144, C-5), 67.8, 64.1 (2d, 147, 157,
C-10, C-4), 67.1 (d, 154, C-50), 64.5 (d, 156, C-30), 63.2,
60.7 (2t, 150, 153, C-6, C-70), 33.3 (d, 134, C-3), 26.0
(t, 130, C-2), 20.9–20.5 (8q, 130, CH3COO). For the ano-
mer 15b: d 93.1 (d, 165, C-1), 37.9 (d, 128, C-3), 27.5 (t,
130, C-2). CI-MS (NH3) m/z 695 (76, [M+18]+), 634 (65),
617 (100), 556 (10), 496 (20). Anal. Calcd for C29H40O18:
C, 51.48; H, 5.96. Found: C, 51.47; H, 6.08.
25
25
steps), white solid, mp 84–86ꢁC. ½aŠ ¼ þ24, ½aŠ
¼
589
546
25
435
25
405
þ28, ½aŠ ¼ þ46, ½aŠ ¼ þ57 (c 0.28, CHCl3). UV
4.8. 4,6-Di-O-acetyl-3-C-[(1R)-1,3,4,5,7-penta-O-acetyl-
2,6-anhydro-D-glycero-L-manno-heptitol-1-C-yl]-3-
deoxy-D-galactal 3a
(MeCN) final absorbance: 194 (e = 1500). IR (KBr)
3470, 2975, 1750, 1375, 1245, 1120, 1085, 1050, 1030,
945, 910, 595cmÀ1 1H NMR (400MHz, CDCl3) d
.
3
3
5.58 (d, J1,2endo = 5.7, H-1), 5.41 (d, J4 ,5 = 3.4, H-50),
A mixture of 15a,b (354mg, 0.52mmol) and silica gel
(1.2g) in toluene (13mL) was heated under reflux for
6h in a flask equipped with a Dean–Stark apparatus.
After cooling to 20ꢁC and evaporation of the solvent,
a FC (1:1 light petroleum ether/EtOAc) afforded
263mg (82%) of 3a, white solid, mp83–85 ꢁC.
0
0
3
3
0
J1 ,3 = 10.6,
0
0
5.27 (dd,
0
J1 ,2 = 2.2, H-10), 5.14
3
3
(dd, J3 ,4 = 10.0, J2 ,3 = 9.9, H-30), 5.11 (m, H-4),
0
0
0
3
5.01 (dd, J3 ,4 = 10.0, J4 ,5 = 3.4, H-4 ), 4.80 (dd,
3
0
0
0
0
0
3J4,5 = 7.8, J5,6exo = 4.7, H-5), 4.21 (dd, 2J = 11.4,
3
J6 ,7 a = 7.5, Ha-70), 4.08 (dd, 2J = 11.4, J6 ,7 b = 5.7,
3
3
0
0
0
0
25
589
25
546
25
435
25
405
2
Hb-70), 3.85 (m, H-60), 3.84 (d, J = 7.7, Hendo-6), 3.52
½aŠ ¼ þ17, ½aŠ ¼ þ21, ½aŠ ¼ þ30, ½aŠ ¼ þ32
3
3
(dd, J2 ,3 = 9.9, J1 ,2 = 2.2, H-2 ), 3.43 (dd, J = 7.7,
2
0
0
0
0
0
(c 0.25, CHCl3). UV (MeCN) final absorbance: 204
(e = 8800). IR (KBr) 1750, 1650, 1435, 1370, 1240,
3J5,6exo = 4.7, Hexo-6), 2.49 (dddd, J2,3endo = 11.7,
3
J1 ,3 = 10.6, 3J = 6.5, 3J = 5.2, H-3), 2.18–1.97 (19H,
1055cmÀ1 1H NMR (400MHz, CDCl3) d 6.51 (dd,
.
4 3
3
0
2
3
3
Hexo-2, 6 MeCOO), 1.53 (dd, J = 13.2, J2endo,3 = 11.7,
Hendo-2). 13C NMR (100.6MHz, CDCl3) d 170.8,
170.2, 170.1, 170.0, 169.6, 169.5 (6s,-COO), 98.3 (d,
174, C-1), 76.9 (d, 142, C-20), 75.3 (d, 141, C-60), 72.6
(d, 148, C-40), 72.2 (d, 158, C-5), 68.4 (d, 154, C-4),
68.0 (d, 149, C-10), 67.4 (d, 153, C-50), 64.6 (d, 156, C-
30), 62.7 (t, 152, C-6), 61.6 (t, 149, C-70), 30.9 (t, 129,
C-2), 30.5 (d, 133, C-3), 20.7–20.5 (6q, 130, CH3COO).
CI-MS (NH3) m/z 592 (100, [M+18]+), 515 (35). Anal.
Calcd for C25H34O15: C, 52.26; H, 5.96. Found: C,
52.19; H, 6.00.
J1,2 = 6.3, J1,3 = 2.5, H-1), 5.43 (d, J4 ,5 = 3.3, H-50),
0 0
3
5.29 (d, J3,4 = 3.1, H-4), 5.13 (dd, J3 ,4 = 9.6,
3
0
0
3
J2 ,3 = 9.6, H-30), 5.12 (m, H-10), 5.03 (dd,
J3 ,4 = 9.6, J4 ,5 = 3.3, H-40), 4.49 (br d, J1,2 = 6.3,
0
0
3
3
3
0
0
0
0
H-2), 4.24–4.07 (m, 4H, H-5, Ha-6, H2-70), 3.99 (dd,
2J = 10.3, J5,6b = 6.2, Hb-6), 3.89 (dd, J6 ,7 a = 7.0,
3
3
0
0
3
3
3
J6 ,7 b = 6.2, H-60), 3.71 (dd, J2 ,3 = 9.6, J1 ,2 = 2.4,
0
0
0
0
0
0
3
H-20), 3.19 (br d, J1 ,3 = 10.7, H-3), 2.18, 2.08, 2.06,
2.05, 2.04, 1.99, 1.97 (7s, 21H, 7 MeCOO). 13C NMR
(100.6MHz, CDCl3) d 171.0–169.5 (7s, –COO), 145.0
(d, 190, C-1), 96.5 (d, 165, C-2), 76.4 (d, 146, C-20),
75.4 (d, 143, C-60), 74.7 (d, 146, C-5), 72.8 (d, 148, C-
40), 67.7, 64.7 (2d, 150, 155, C-10, C-30), 67.5 (d, 153,
C-50), 63.4 (t, 148, C-6), 63.2 (d, 152, C-4), 62.5 (t,
150, C-70), 36.0 (d, 130, C-3), 20.9–20.5 (7q, 130, 7 Me-
COO). CI-MS (NH3) m/z 634 (100, [M+18]+), 617 (43,
[M+1]+), 557 (18), 496 (34). Anal. Calcd for
C27H36O16: C, 52.60; H, 5.89. Found: C, 52.53; H, 5.92.
0
4.7. 1,4,6-Tri-O-acetyl-3-C-[(1R)-1,3,4,5,7-penta-O-acet-
yl-2,6-anhydro-D-glycero-L-manno-heptitol-1-C-yl]-2,3-
dideoxy-a-D-lyxo-hexopyranose 15a,b
A mixture of 14 (445mg, 0.77mmol), Ac2O (16mL) and
CF3COOH (3.8mL) was stirred at 20ꢁC for 4h. This
was poured onto ice (20mL) and neutralized with a satd
aq soln of NaHCO3 (pH8). The mixture was extracted
with EtOAc (3 · 30mL). The combined organic extracts
were washed with brine (50mL) and dried over MgSO4.
Solvent evaporation, FC (1:2 light petroleum ether/
EtOAc) afforded 422mg (81%) of a colorless oil, a
4.9. 4,6-Di-O-benzyl-3-C-[(1R)-1,3,4,5,7-penta-O-benzyl-
2,6-anhydro-D-glycero-L-manno-heptitol-1-C-yl]-3-
deoxy-D-galactal 3b
To a solution of 3a (850mg, 1.37mmol) in MeOH
(35mL) was added Na2CO3 (830mg, 7.8mmol). The
reaction mixture was stirred at 20ꢁC for 1.5h, filtrated,
and the solvent evaporated. The crude polyol dissolved
in anhyd DMF (12mL) was added dropwise at 0ꢁC to
a suspension of NaH (0.7g, 15mmol, 55% dispersion
in paraffin) in DMF (5mL). After 20min, benzyl bro-
25
25
1:0.3 mixture of 15a/15b. ½aŠ ¼ þ51, ½aŠ ¼ þ59,
589
546
25
435
25
405
½aŠ ¼ þ98, ½aŠ ¼ þ118 (c 0.26, CHCl3). UV
(MeCN) final absorbance: 194 (e = 1800). IR (film)
2970, 1750, 1435, 1370, 1235, 1115, 1055, 940,
755cmÀ1 1H NMR (400MHz, CDCl3) data for the
.
3
anomer 15a: d 6.27 (d, J1,2ax = 1.8, H-1), 5.44 (d,

R. Demange et al. / Tetrahedron: Asymmetry 15 (2004)3573–3585
3579
25
26mg (71%, 3 steps) of 2, colorless oil. ½aŠ ¼ þ24,
mide (1.5mL, 13mmol) in DMF (2.5mL) and tetrabut-
ylammonium iodide (30mg) were added. The reaction
mixture was brought to 20ꢁC and stirred for 15h. After
completion of the reaction, the mixture was cooled to
0ꢁC, quenched with H2O (50mL) and extracted with
Et2O (3 · 50mL). The combined organic phases were
washed with brine (3 · 50mL) and dried over MgSO4.
Solvent evaporation, FC (9:1 then 8.5:1.5 light petro-
leum/EtOAc) afforded 994mg (76%, 2 steps) of 3b,
589
25
546
25
435
25
405
½aŠ ¼ þ28, ½aŠ ¼ þ51, ½aŠ ¼ þ60 (c 0.25, CHCl3).
UV (MeCN) 254 (2000), 216 (22000). IR (film) 3090,
3065, 3030, 2920, 2860, 1495, 1455, 1360, 1210, 1095,
990, 735, 695cmÀ1 1H NMR (400MHz, CDCl3) d
.
7.37–7.08 (m, 40H, ArH), 5.00–4.32 (m, 16H,
3
8OCH2Ph), 4.42 (m, H-10), 4.32 (d, J1,2 = 9.5, H-1),
3
3
4.21 (dd, J3 ,4 = 9.5, J2 ,3 = 9.5, H-30), 4.09 (d,
0
0
0
0
3
3
J3,4 = 1.8, H-4), 3.89 (d, J4 ,5 = 2.3, H-50), 3.71–3.67
0
0
3
25
25
25
3
0
0
0
0
colorless oil. ½aŠ ¼ À2:0, ½aŠ ¼ À3:5, ½aŠ ¼ À12,
(m, 2H, H-2, H-50), 3.66 (dd, J2 ,3 = 9.5, J1 ,2 = 2.1,
589
546
435
25
405
217 (16700). IR (film) 3065, 3030, 2865, 1650, 1495,
½aŠ ¼ À19 (c 0.26, CHCl3). UV (MeCN) 258 (2000),
1455, 1360, 1250, 1095, 735, 695cmÀ1
H-20), 3.59–3.57 (m, 3H, H2-6, Ha-70), 3.53 (s, 3H,
3
OCH3), 3.52 (m, Hb-70), 3.42 (dd, J3 ,4 = 9.5,
0
0
3
3
3
0
0
0
0
0
0
.
1H NMR
J4 ,5 = 2.3, H-40), 3.08 (dd, J6 ,7 a = 7.4, J6 ,7 b = 5.8,
3
3
3
0
(400MHz, CDCl3) d 7.30–7.02 (m, 35H, ArH), 6.39
(dd, J1,2 = 6.2, J1,3 = 2.5, H-1), 4.97–4.31 (m, 14H, 7
H-60), 2.41 (dt, J2,3 = 9.5, J1 ,3 = 9.5, J3,4 = 1.8, H-3).
13C NMR (100.6MHz, CDCl3) d 139.2, 139.2, 139.1,
138.8, 138.8, 138.5, 138.2, 138.1 (8s, 8Carom), 128.4–
126.8 (40d, CHarom), 106.8 (d, 161, C-1), 84.9 (d, 135,
C-40), 81.1 (d, 141, C-20), 77.2 (d, C-2), 76.6 (d, C-5),
76.1 (d, C-60), 75.8 (d, C-30), 74.9, 74.4, 74.2 (3t, 3
OCH2Ph), 74.1, 74.05, 73.9 (3d, C-10, C-4, C-50), 74.0,
73.3, 73.2, 71.9, 69.7 (5t, 5 OCH2Ph), 69.2 (t, C-6),
68.9 (t, C-70), 56.8 (q, 142, OCH3), 44.5 (d, 122, C-3).
Electrospray-MS (+, 50:50:1 MeCN/H2O/AcOH) m/z
1113.8 (17, [M+Na]+), 1108.3 (53, [M+18]+), 1059.4
(35).
3
4
3
OCH2Ph), 4.45 (d, J1,2 = 6.2, H-2), 4.29 (dd,
3
3
3
3
J1 ,3 = 10.3, J1 ,2 = 2.3, H-10), 4.22 (dd, J3 ,4 = 9.5,
0
0
0
0
0
3
3
J2 ,3 = 9.5, H-30), 4.04 (br t, J5,6a = 6.4, J5,6b = 6.4,
0
0
3
H-5), 4.00 (d, J = 2.2, H-50), 3.96 (br s, H-4), 3.67–
3.50 (m, 6H, H-40, H2-70, H-20, Ha-6, H-60), 3.38 (dd,
2J = 9.5, J5,6b = 6.4, Hb-6), 3.26 (br d, J1 ,3 = 10.3, H-
3). 13C NMR (100.6MHz, CDCl3) d 144.1 (d, 188, C-
1), 139.2, 139.0, 138.6, 138.5, 138.4, 137.9, 137.9 (7s,
7Carom), 128.4–127.0 (35d, CHarom), 98.3 (d, 162, C-2),
84.8 (d, 138, C-40), 79.1 (d, 138, C-20), 77.2 (d, 141, C-
60), 76.9 (d, 144, C-5), 75.2 (d, 147, C-30), 75.2 (t, 144,
OCH2Ph), 74.6 (t, 139, OCH2Ph), 74.3 (t, 144,
OCH2Ph), 74.1 (d, 143, C-50), 73.5 (t, 137, OCH2Ph),
73.5 (d, 147, C-10), 73.3 (t, 141, OCH2Ph), 72.3 (t, 137,
OCH2Ph), 70.4 (d, 145, C-4), 69.5 (t, 142, C-6), 69.0
(t, 143, C-70), 67.1 (t, 143, OCH2Ph), 35.0 (d, 127, C-
3). CI-MS (NH3) m/z 971 (3, [M+18]+), 861 (5), 723
(7), 616 (4), 445 (3), 181 (7), 91 (100). Anal. Calcd for
C62H64O9: C, 78.13; H, 6.77. Found: C, 78.15; H, 6.84.
3
3
0
4.11. Methyl 4,6-di-O-benzyl-1,3-C-[(1R)-1,3,4,5,7-
penta-O-benzyl-2,6-anhydro-D-glycero-L-manno-heptitol-
1-C-yl]-3-deoxy-a-D-talo-pyranoside 16
Galactal 3b (104mg, 0.11mmol) was dissolved in anhy-
drous MeOH (1mL) and CH2Cl2 (30lL) and the result-
ing solution cooled to 0ꢁC. mCPBA (32mg, 0.13mmol)
was added and the reaction mixture stirred at 0ꢁC for
1.5h, until TLC indicated complete consumption of
the glycal. After the addition of CH2Cl2 (15mL), H2O
(10mL), and NaHCO3 (10mL), the aqueous phase was
extracted with CH2Cl2 (15mL, three times). The com-
bined organic extracts were washed with brine (20mL)
and dried over MgSO4. Solvent evaporation afforded a
mixture of methyl glycosides. The major product 16
(52%) being the one for which epoxidation occurred
on the b face was contaminated with a mixture of 17
(mixture of anomers) (20%) for which epoxidation oc-
curred on the a face. FC (7.5:2.5 light petroleum/
EtOAc) afforded 55mg (52%) of pure 16, colorless oil.
4.10. Methyl 2,4,6-tri-O-benzyl-3-C-[(1R)-1,3,4,5,7-
penta-O-benzyl-2,6-anhydro-D-glycero-L-manno-heptitol-
1-C-yl]-3-deoxy-b-D-galacto-pyranoside 2
Galactal 3a (90mg, 0.09mmol) was dissolved in 1.8mL
of CH2Cl2, and the resulting solution was cooled to
0ꢁC. A solution of dimethyldioxirane (ꢀ0.05M in ace-
tone, 3.5mL, 0.17mmol) was added dropwise. The reac-
tion mixture was stirred at 0ꢁC for 1h, until TLC
indicated complete consumption of the glycal. The solu-
tion was evaporated with a stream of dry N2 and the res-
idue dried in vacuo to afford the 1,2-anhydro sugar. The
1,2-anhydro sugar was dissolved in 2.0mL of anhydrous
MeOH, and 300lL of CH2Cl2 and the solution stirred
at 20ꢁC for 4.5h. The MeOH was removed in vacuo
to afford methyl glycoside 17. A part of the crude methyl
glycoside (33mg, 0.03mmol) dissolved in anhydrous
DMF (0.3mL) was added dropwise at 0ꢁC to a suspen-
sion of NaH (9mg, 0.2mmol, 55% dispersion in paraf-
fin) in DMF (0.2mL). After 20min, benzyl bromide
(16lL, 0.14mmol) in DMF (0.1mL) and tetrabutylam-
monium iodide (2mg) were added. The reaction mixture
was brought to 20ꢁC and stirred for 15h. After comple-
tion of the reaction, the mixture was cooled to 0ꢁC,
quenched with H2O (10mL), and extracted with Et2O
(3 · 10mL). The combined organic phases were washed
with brine (3 · 10mL) and dried over MgSO4. Solvent
evaporation, FC (8:2 light petroleum/EtOAc) afforded
25
589
25
546
25
435
25
405
½aŠ ¼ þ29, ½aŠ ¼ þ40, ½aŠ ¼ þ65, ½aŠ ¼ þ79 (c
0.11, CHCl3). UV (MeCN) 251 (2300), 215 (25400). IR
(film) 3500, 3030, 2910, 2865, 1495, 1455, 1360, 1210,
1095, 1060, 910, 735, 695cmÀ1 1H NMR (400MHz,
.
CDCl3) d 7.36–7.11 (m, 35H, ArH), 5.05–4.73 (m, 7H,
3
OCH2Ph), 4.69 (s, H-1), 4.68 (dd, J1 ,3 = 11.1,
0
3
J1 ,2 = 2.6, H-10), 4.60–4.45 (m, 7H, OCH2Ph), 4.30
0
0
3
3
(dd, J3 ,4 = 9.5, J2 ,3 = 9.6, H-30), 4.05–4.02 (m, 3H,
0
0
0
0
3
3
H-50, H-5, H-4), 3.77 (dd, J2 ,3 = 9.6, J1 ,2 = 2.6, H-
0
0
0
0
20), 3.74–3.58 (m, 7H, H-40, H-2, H-60, H23-6, H2-70),
3
0
3.33 (s, 3H, OCH3), 2.82 (dt, J1 ,3 = 11.1, J2,3 = 2.0,
3J3,4 = 2.0, H-3). 13C NMR (100.6MHz, CDCl3) d
139.2, 139.0, 138.9, 138.4, 138.1, 138.0, 137.7 (7s,
7Carom), 128.4–127.0 (35d, CHarom), 101.7 (d, 169, C-
1), 84.9 (d, 139, C-40), 78.6 (d, 141, C-20), 77.4 (d, 144,
C-60), 75.3 (t, 143, OCH2Ph), 75.2 (d, 141, C-30), 74.9
(t, 142, OCH2Ph), 74.6 (t, 141, OCH2Ph), 74.5 (d, 142,

3580
R. Demange et al. / Tetrahedron: Asymmetry 15 (2004)3573–3585
1
C-50), 73.5, 69.9 (2d, 145, 147, C-4, C-5), 73.4 (t, 141,
OCH2Ph), 73.3 (t, 139, OCH2Ph), 72.4 (t, 144,
OCH2Ph), 71.2 (d, 143, C-10), 69.3, 69.2 (2t, 143, 143,
C-6, C-70), 67.9 (d, 149, C-2), 66.9 (t, 146, OCH2Ph),
54.9 (q, 139, OCH3), 35.0 (d, 125, C-3). CI-MS (NH3)
m/z 1018 (1, [M+17]+), 909 (1), 723 (1), 181 (7), 91 (100).
595cmÀ1. H NMR (400MHz, CDCl3) d 7.79–7.31 (m,
13H, ArH), 6.05 (d, JN,C* = 7.7, H–N), 5.38 (dd,
3
3
3
J4 ,5 = 3.2, J5 ,6 = 1.0, H-50), 5.32–5.16 (m, 2H,
0
0
0
0
3
OCH2Ph), 5.27 (dd, J1 ,3 = 12.0, J1 ,2 = 1.9, H-1 ),
3
0
0
0
0
3
3
5.23 (s, H-1), 5.10 (dd, J3 ,4 = 9.7, J2 ,3 = 9.7, H-30),
0
0
0
0
3
3
3
5.03 (dd, J3 ,4 = 9.7, J4 ,5 = 3.2, H-40), 5.02 (d, J3,4
=
0
0
0
0
3
3
2.8, H-4), 4.61 (dt, JC*,N = 7.7, JC*,H2-Ser = 2.8, H–
C*), 4.41–4.38 (m, 2H, H2-Fmoc), 4.26–4.23 (m, 2H,
H-Fmoc), Ha-70, 4.10–3.95 (m, 5H, Ha-6, Hb-70, H2-
4.12. N-[(Benzyloxy)carbonyl]-O-{4,6-di-O-acetyl-3-C-
[(1R)-1,3,4,5,7-penta-O-acetyl-2,6-anhydro-D-glycero-L-
manno-heptitol-1-C-yl]-2,3-dideoxy-2-iodo-a-D-talo-pyr-
anosyl}-L-serine phenylmethyl ester 18
2
3
Ser, H-5), 3.88 (dd, J = 11.4, J5,6b = 8.2, Hb-6), 3.68
0
3
3
3
(d, J2,3 = 3.9, H-2), 3.56 (dd, J2 ,3 = 9.7, J1 ,2 = 1.9,
0
0
0
3
H-20), 3.55 (m, H-60), 2.44 (ddd, J1 ,3 = 12.0,
0
3
A solution of galactal 3a (44mg, 0.071mmol) and Z-Ser-
OBn (30mg, 0.091mmol) in CH2Cl2 (2mL) was stirred
3J2,3 = 3.9, J3,4 = 2.8, H-3), 2.15, 2.07, 2.06, 2.03, 1.99,
1.98, 1.97 (7s, 21H,
7
MeCOO). 13C NMR
˚
for 30min at 20ꢁC in the presence of powdered 4A
(100.6MHz, CDCl3) d 170.6–169.4 (8s, –COO), 155.8 (s,
HN–COO), 143.8, 143.8, 141.3, 141.3, 135.4 (5s, 5Carom),
128.7–120.0 (13d, CHarom), 102.2 (d, 175, C-1), 75.3
(d, 140, C-20), 74.9 (d, 141, C-60), 72.6 (d, 148, C-40),
69.9 (d, 152, C-10), 68.4 (d, 146, C-5), 68.4 (t, 148,
CH2-Ser), 67.3, 67.3 (2t, 149, OCH2Ph, CH2-Fmoc),
67.1 (d, 152, C-50), 64.5 (d, 155, C-30), 63.0 (t, 150, C-
6), 62.5 (d, 150, C-4), 60.2 (t, 149, C-70), 54.4 (d, 140,
C*), 47.0 (d, 133, CH-Fmoc), 35.4 (d, 128, C-3), 20.8–
20.4 (7q, 1d, 130, CH3COO, C-2). Electrospray-MS
(+, 50:50:1 MeCN/H2O/AcOH) m/z 1182 (20,
[M+Na]+), 1159 (100, [M]+). Anal. Calcd for
C52H58O21NI: C, 53.85; H, 5.04. Found: C, 53.93; H,
5.02.
molecular
sieves
(20mg).
I(sym-collidine)2ClO4
(176mg, 0.375mmol) was added, the reaction stirred
for 2h at 20ꢁC and then filtered. The filtrate was washed
with 10% aq soln of Na2S2O3 (5mL), brine (10mL), and
dried over MgSO4. Solvent evaporation, FC (6:4 light
petroleum/EtOAc) afforded 55mg (72%) of 18, colorless
1
oil. H NMR (400MHz, CDCl3) d 7.43–7.32 (m, 10H,
ArH), 5.91 (d, 3JN,C* = 7.9, H–N), 5.36 (dd,
3
3
J4 ,5 = 2.2, J5 ,6 = 0.9, H-50), 5.31–5.08 (m, 4H, 2
0
0
0
0
3
3
OCH2Ph), 5.25 (dd, J1 ,3 = 10.2, J1 ,2 = 2.3, H-10),
0
0
0
3
3
5.20 (s, H-1), 5.07 (dd, J3 ,4 = 9.6, J2 ,3 = 9.6, H-30),
0
0
0
0
3
3
5.01 (dd, J3 ,4 = 9.6, J4 ,5 = 2.2, H-40), 5.00 (m, H-4),
4.59 (dt, JC*,N = 7.9, JC*,H2-Ser = 2.8, H–C*), 4.19
0
0
0
0
3
3
2
3
2
(dd, J = 11.2, J6 ,7 a = 8.7, Ha-70), 4.12 (dd, J = 11.5,
0
0
3J5,6a = 3.3, Ha-6), 4.02–3.96 (m, 4H, H-5, Hb-70, H2-
4.14. N-[(Benzyloxy)carbonyl]-O-{4,6-di-O-acetyl-3-C-
[(1R)-1,3,4,5,7-penta-O-acetyl-2,6-anhydro-D-glycero-L-
manno-heptitol-1-C-yl]-2,3-dideoxy-a-D-threo-hex-2-eno-
pyranosyl}-L-serine phenylmethyl ester 20
Ser), 3.87 (dd, 2J = 11.5, J5,6b = 8.3, Hb-6), 3.67 (d,
3
3J2,3 = 3.7, H-2), 3.57–3.53 (m, 2H, H-20, H-60), 2.39
3
3
3
0
(ddd, J1 ,3 = 10.2, J2,3 = 3.7, J3,4 = 3.0, H-3), 2.15–
1.97 (7s, 21H, 7 MeCOO). 13C NMR (100.6MHz,
CDCl3) d 170.6, 170.5, 170.2, 170.2, 170.1, 170.1,
169.6, 169.4 (8s, –COO), 155.7 (s, HN–COO), 136.1,
135.5 (2s, 2Carom), 128.7–128.1 (10d, CHarom), 102.0
(d, C-1), 75.3, 74.8 (2d, C-20, C-60), 72.6 (d, C-40), 69.8
(d, C-10), 68.3 (d, C-5), 68.2 (t, CH2-Ser), 67.2, 67.1
(2t, 2OCH2Ph), 67.0 (d, C-50), 64.4 (d, C-30), 63.0 (t,
C-6), 62.5 (d, C-4), 60.1 (t, C-70), 54.3 (d, C*), 35.3 (d,
C-3), 20.8–20.3 (7q, 1d, CH3COO, C-2). Electrospray-
MS (+, 50:50:1 MeCN/H2O/AcOH) m/z 1089.5 (40,
[M+18]+), 1072.1 (100, [M]+), 743.4 (15).
Glycoconjugate 18 (7.5mg, 0.007mmol) was dissolved
in DMFd7 (350lL, reaction followed by 1H NMR)
and NaN3 (1.6mg, 0.025mmol) then added. After 16h
at 20ꢁC, only one product formed cleanly (by 1H
NMR). Evaporation and FC (5:5 light petroleum/
EtOAc) afforded 7mg (90%) of 20, white solid, mp
25
25
25
52–55ꢁC. ½aŠ ¼ À42, ½aŠ ¼ À43, ½aŠ ¼ À81,
589
546
435
25
405
(9000), 197 (17200). IR (KBr) 2975, 1750, 1370, 1230,
½aŠ ¼ À104 (c 0.094, CHCl3). UV (MeCN) 262
1050, 700cmÀ1. H NMR (400MHz, CDCl3) d 7.40–
7.30 (m, 10H, ArH), 5.84 (d, JN,C* = 8.8, H–N), 5.80
1
3
3
(d, J1,2 = 2.4, H-2), 5.45 (d, J4,5 = 1.1, H-4), 5.41 (d,
3
4.13. N-[(9H-Fluoren-9-ylmethoxy)carbonyl]-O-{4,6-di-
O-acetyl-3-C-[(1R)-1,3,4,5,7-penta-O-acetyl-2,6-anhy-
dro-D-glycero-L-manno-heptitol-1-C-yl]-2,3-dideoxy-2-
iodo-a-D-talo-pyranosyl}-L-serine phenylmethyl ester 19
3
J4 ,5 = 3.0, H-50), 5.30–5.25 (m, 2H, H-10, H-30), 5.24–
0
0
5.12 (m, 4H, OCH2Ph), 5.02–4.99 (m, 2H, H-1, H-40),
4.60 (dt, JC*,N = 8.8, JC*,H2-Ser = 2.8, H–C*), 4.18–
3
3
3.95 (m, 7H, H-5, H2-70, H2-Ser, H2-6), 3.76 (br t,
3
3
3
H-60),
3.43
(dd,
0
0
0 0
J2 ,3 = 9.8,
A solution of galactal 3a (94mg, 0.15mmol) and Fmoc-
Ser-OBn (81mg, 0.19mmol) in CH2Cl2 (4.3mL) was
stirred for 30min at 20ꢁC in the presence of powdered
J6 ,H2À7 = 6.3,
J1 ,2 = 2.3, H-20), 2.19, 2.09, 2.08, 2.03, 1.99, 1.99,
0
0
1.97 (7s, 21H, 7 MeCOO). 13C NMR (100.6MHz,
CDCl3) d 170.5, 170.3, 170.2, 170.1, 169.9, 169.9,
169.8, 169.5 (8s, –COO), 155.9 (s, HN–COO),
136.0, 135.3, 133.8 (3s, 2Carom, C-3), 128.6–128.1 (11d,
10CHarom, C-2), 94.8 (d, 169, C-1), 79.2 (d, 144, C-20),
75.1 (d, 143, C-60), 72.1 (d, 146, C-40), 69.5, 65.1 (2d,
150, 154, C-10, C-30), 69.4 (t, 147, CH2-Ser), 68.0 (d,
146, C-5), 67.4 (d, 153, C-50), 67.3 (t, 145, OCH2Ph),
67.1 (t, 148, OCH2Ph), 63.0 (d, 149, C-4), 62.3 (t, 150,
C-6), 61.6 (t, 147, C-70), 54.5 (d, 140, C*), 20.7–20.5
(7q, 130, CH3COO). CI-MS (NH3) m/z 961 (62,
˚
4A molecular sieves (30mg). I(sym-collidine)2ClO4
(350mg, 0.75mmol) was added, the reaction stirred 2h
at 20ꢁC and then filtered. The filtrate was washed with
a 10% aq soln of Na2S2O3 (10mL), brine (20mL) and
dried over MgSO4. Solvent evaporation, FC (5:5 light
petroleum/EtOAc) afforded 120mg (70%) of 19, white
25
589
25
546
25
435
solid, mp87–90 ꢁC. ½aŠ ¼ þ45, ½aŠ ¼ þ54, ½aŠ
¼
25
405
þ92, ½aŠ ¼ þ109 (c 0.19, CHCl3). UV (MeCN)
299 (7500), 288 (6600), 265 (22400), 209 (49200). IR
(KBr) 3400, 2965, 1750, 1520, 1370, 1235, 1055, 740,

R. Demange et al. / Tetrahedron: Asymmetry 15 (2004)3573–3585
3581
[M+18]+), 615 (90), 337 (100), 91 (92). Anal. Calcd for
C45H53O21N: C, 57.26; H, 5.66. Found: C, 57.27; H, 5.70.
HCl (5mL), H2O (5mL), and brine (5mL), dried over
MgSO4, and concentrated in vacuo. FC (9:1, light
petroleum ether/EtOAc) 6.9g (95%), colorless oil.17 Rf =
25
589
4.15. N-[(9H-Fluoren-9-ylmethoxy)carbonyl]-O-[4,6-di-
O-acetyl-3-C-[(1R)-1,3,4,5,7-penta-O-acetyl-2,6-anhy-
dro-D-glycero-L-manno-heptitol-1-C-yl]-2,3-dideoxy-a-D-
lyxo-hexopyranosyl]-L-serine phenylmethyl ester 21
0.38 (light petroleum ether/EtOAc). ½aŠ ¼ þ79,
25
546
25
435
25
405
½aŠ ¼ þ85, ½aŠ ¼ þ330, ½aŠ ¼ þ710 (c 0.24,
CHCl3). 1H NMR (400MHz, CDCl3) d 7.39 (dd,
3
4
J1,2 = 3.5, J1 ,2 = 1.0, H-2), 5.83 (d, J1,2 = 3.5, H-1),
3
0
3
4.75 (dd, J5,6 = 6.4, J5,6 = 1.3, H-5), 4.45 (dd,
3
3
3
2
J3 ,4 = 8.6, J2 ,3 = 7.0, H-30), 4.26 (d, J = 12.4, Ha-
0
0
0
0
To a solution of 19 (58mg, 0.05mmol) in dry benzene
(250lL) under an argon atmosphere was added Bu3SnH
(30lL, 0.113mmol) and AIBN (3mg). The solution was
stirred for 45min at 55ꢁC and then, concentrated
in vacuo to afford a residue which was purified by FC
(5:5 light petroleum/EtOAc) to provide 37mg (72%) of 21,
3
3
4
70), 4.23 (ddd, J1 ,2 = 7.0, J1 ,OH = 6.7, J1 ,2 = 1.0, H-
0
0
0
0
10), 4.06 (dd, 2J = 8.3, J5,6exo = 6.4, Hexo-6), 3.99 (d,
3
3
3
3
3
J3 ,4 = 8.6, H-40), 3.96 (d, J5 ,6 = 4.1, H-50), 3.91 (t,
0
0
0
0
J1 ,2 = 3J2 ,3 = 7.0, H-20), 3.80 (dd,
3
0
0
0
0
0 0
J5 ,6 = 4.1,
J6 ,7 b = 1.9, H-60), 3.75 (dd, 2J = 12.4, J6 ,7 b = 1.9,
3
0
0
0
0
25
25
2
3
Hb-70), 3.81 (dd, J = 10.2, J6 ,7 a = 12.7, Ha-70), 3.65
0 0
white solid, mp84–86 ꢁC. ½aŠ ¼ þ31, ½aŠ ¼ þ39,
589
546
25
435
25
405
2
3
3
0
(dd, J = 8.3, J5,6endo = 1.3, Hendo-6), 2.94 (d, J1 ,OH =
½aŠ ¼ þ64, ½aŠ ¼ þ76 (c 0.18, CHCl3). UV
(MeCN) 299 (8100), 288 (7000), 264 (24400), 211
(35700). IR (KBr) 3450, 2965, 1750, 1520, 1370, 1240,
6.7, OH), 0.94, 0.93, 0.90, 0.90 (4s, 36H, 4 t-Bu), 0.14,
0.12, 0.10, 0.09, 0.08, 0.07, 0.06, 0.05 (8s, 24H, 4Me2Si).
13C NMR (100.6MHz, CDCl3) d 194.5 (s, C-4), 143.5 (s,
165, C-2), 137.0 (s, C-3), 96.9 (d, 177, C-1), 79.7 (d, 141,
C-20), 79.1 (d, 160, C-5), 73.1 (d, 143, C-60), 70.5 (d, 144,
C-50), 67.3 (d, 142, C-30), 67.1 (d, 147, C-10), 66.9 (d,
138, C-40), 62.3 (t, 154, C-6), 58.2 (t, 142, C-70), 25.9,
25.89, 25.85, 25.7 (4q, 125, (CH3)3CSi), 18.2, 18.1,
17.9, 17.0 (4s, (CH3)3CSi), À4.4, À4.6, À4.7, À4.9,
À5.0, À5.1, À5.3, À5.5 (8q, 118, CH3Si). CIMSHR
m/z found 797.43190 (calcd for C37H74O9Si4 + Na:
797.4307). Anal. Calcd for C37H74O9Si4: C, 57.32; H,
9.62. Found: C, 57.24; H, 9.56.
1055, 805, 745, 595cmÀ1. H NMR (400MHz, CDCl3)
1
3
d 7.79–7.30 (m, 13H, ArH), 6.04 (d, JN,C* = 8.1, H–
3
N), 5.38 (d, J4 ,5 = 3.1, H-50), 5.32–5.14 (m, 2H,
0
0
3
3
OCH2Ph), 5.16 (dd, J3 ,4 = 9.8, J2 ,3 = 9.8, H-30),
0
0
0
0
3
3
4.98 (dd, J3 ,4 = 9.8, J4 ,5 = 3.1, H-40), 4.96 (dd,
0
0
0
0
3
3
J1 ,3 = 10.6, J1 ,2 = 2.1, H-10), 4.90 (s, H-4), 4.84 (d,
0
0
0
3J1,2ax = 3.5, H-1), 4.61 (dt, JC*,N = 8.1, JC*,H2-Ser
2.7, H–C*), 4.40–4.37 (m, 2H, H2-Fmoc), 4.26–4.22
=
3
3
(m, 2H, H-Fmoc, Ha-70), 4.14 (dd, 2J = 11.1,
J6 ,7 b = 5.3, Hb-70), 4.05 (dd, 2J = 11.2, J5,6a = 3.4,
Ha-6), 3.98–3.92 (m, 3H, H2-Ser, H-5), 3.85 (dd,
3
3
0
0
2J = 11.2, J5,6b = 8.1, Hb-6), 3.63 (dd, J6 ,7 a = 7.8,
3
3
0
0
3
3
3
J6 ,7 b = 5.3, H-60), 3.45 (dd, J2 ,3 = 9.8, J1 ,2 = 2.1,
4.17. 1,6-Anhydro-3-{(1S)-2,6-anhydro-3,4,5,7-tetra-O-
[(tert-butyl)dimethylsilyl]-D-glycero-L-manno-heptitol-1-
C-yl}-2,3-dideoxy-b-D-glycero-hexopyranos-4-ulose 22
and 1,6-anhydro-3-{(1R)-2,6-anhydro-3,4,5,7-tetra-O-
[(tert-butyl)dimethylsilyl]-D-glycero-L-manno-heptitol-1-
C-yl}-2,3-dideoxy-b-D-erythro-hexopyran-4-ulose 23
0
0
0
0
0
0
3
H-20),
2.73
(ddd,
3J2ax,3 = 12.8,
J1 ,3 = 10.6,
0
3J2eq,3 = 3.6, H-3), 2.16, 2.06, 2.04, 2.00, 1.99, 1.98,
1.97 (7s, 21H, CH3COO), 1.76 (ddd, 2J = 12.8,
3
2
3J2ax,3 = 12.8, J1,2ax = 3.5, Hax-2), 1.35 (dd, J = 12.8,
3J2eq,3 = 3.6, Heq-2). 13C NMR (100.6MHz, CDCl3) d
170.7–169.6 (8s, –COO), 155.8 (s, HN–COO), 143.8,
143.8, 141.2, 141.2, 135.5 (5s, 5Carom), 128.6–120.0
(13d, CHarom), 96.7 (d, 167, C-1), 76.3 (d, 144, C-20),
74.9 (d, 141, C-60), 72.7 (d, 148, C-40), 68.8 (d, 148, C-
5), 68.0 (d, 142, C-10), 68.0 (t, 146, CH2-Ser), 67.3 (t,
148, CH2-Fmoc), 67.1 (d, 150, C-50), 67.1 (t, 146,
OCH2Ph), 64.7 (d, 157, C-30), 64.5 (d, 153, C-4), 63.6
(t, 147, C-6), 60.4 (t, 149, C-70), 54.5 (d, 141, C*), 47.0
(d, 135, CH-Fmoc), 33.2 (d, 129, C-3), 27.0 (t, 131, C-
2), 20.8–20.6 (7q, 130, CH3COO). Electrospray-MS (+,
50:50:1 MeCN/H2O/AcOH) m/z 1156.4 (18, [M+Na]+),
1034.3 (100, [M+1]+). Anal. Calcd for C52H59O21N: C,
60.40, H, 5.75. Found: C, 60.42; H, 5.91.
One hundred and three milligrams of an aqueous sus-
pension of Raney Nickel was added to a stirred solution
of compound 10 (103mg, 0.129mmol) in tetrahydrofu-
ran (1.11mL) and the mixture was further stirred at
20ꢁC until complete conversion of the starting material
(TLC control). The mixture diluted with Et2O (200mL)
and filtrated through a pad of silica gel. FC (9.5:0.5,
light petroleum ether/EtOAc), afforded 59mg (57%) of
22 and 45mg (43%) of 23, both as colorless oil. Data
of 22: Rf = 0.16, (9.5:0.5, light petroleum ether/EtOAc).
25
25
25
25
½aŠ ¼ þ4, ½aŠ ¼ þ3, ½aŠ ¼ À1, ½aŠ ¼ À10 (c
589
0.42, CHCl3). IR (film) 3405, 2955, 2860, 1715, 1460,
546
435
405
1360, 1265, 1095, 835, 775cmÀ1. H NMR (400MHz,
1
3
6.12 (s, H-1), 4.50 (dd, J5 ,6 = 2.2,
0
0
4.16. 1,6-Anhydro-3-C-{(1R)-2,6-anhydro-3,4,5,7-tetra-
O-[(tert-butyl)dimethylsilyl]-D-glycero-L-manno-heptitol-
1-C-yl}-2,3-dideoxy-b-D-glycero-hex-2-enopyran-4-ulose
6b
CDCl3)
d
3
3
J6 ,7 = 9.7, H-60), 4.42 (d, J5,6 = 5.4, H-5), 4.22 (dd,
0
0
3
3
2
3
J6 ,7 = 2.7, J = 11.8, H-7a0), 4.20 (dd, J3 ,4 = 2.7,
0
0
0
0
J2 ,3 = 2.7, H-3), 4.0 (d, 2J = 8.9, Hexo-6), 3.85 (m,
0
0
3
3H, Hendo-6, H-40, H-10), 3.75 (t, J2 ,3 = 2.7,
0
0
3
3
2
J1 ,2 = 3.2, H-20), 3.70 (dd, J6 ,7 = 1.61, J = 11.8, H-
0
0
0
0
A 1M solution of Et2AlI in toluene (12mL, 12mmol)
was added dropwise to a mixture of 5b15 (6g, 9.40mmol)
and 4 (2mg, 15.9mmol) in CH2Cl2 (100mL) at À78ꢁC.
The solution was stirred at this temperature for 12h and
diluted with Et2O (10mL). Two molar aq HCl (0.5mL)
was added and the phases separated. The aqueous phase
was extracted with Et2O (2 · 10mL). The combined
organic phases were washed sequentially with 2M aq
3
70), 3.55 (d, J5 ,6 = 9.7, H-50), 3.07 (m, H-3), 2.51 (m,
Hendo-2), 2.13 (m, Hexo-2), 0.97, 0.97, 0.91, 0.88 (4s,
36H, 4 t-Bu), 0.15, 0.14, 0.14, 0.12, 0.08, 0.07, 0.01,
0.01 (8s, 24H, 4Me2Si). 13C NMR (100.6MHz, CDCl3)
d 206.0 (s, C-4), 102.0 (d, 173, C-1), 79.5 (d, 141, C-
20), 79.5 (d, 163, C-5), 73.2 (d, 147, C-10), 70.2 (d, 146,
C-40), 67.3 (d, 141, C-30), 66.8 (t, 106, C-6), 65.2 (d,
0
0

3582
R. Demange et al. / Tetrahedron: Asymmetry 15 (2004)3573–3585
146, C-60), 64.7 (d, 140, C-50), 58.5 (t, 145, C-70), 44.4 (d,
125, C-3), 32.2 (t, 128, C-2, t-Bu), 18.4, 18.3, 18.1, 18.0
(4s, t-Bu), À4.4, À4.6, À4.8, À4.9, À5.0, À5.0, À5.3,
À5.3, À5.5 (8q, 118, 4Me2Si). CIMSHR m/z found
799.4464 (calcd for C37H76O9Si4 + Na: 799.4442).
2955, 2895, 2855, 1730, 1470, 1255, 1095, 835,
775cmÀ1 1H NMR (400MHz, CDCl3) d 5.70 (d,
3J = 5.4, H-1), 4.53 (dd, J5,6exo = 5.4, J5,6endo = 0.5,
.
3
3
3
3
H-5), 4.19 (dd, J5 ,6 = 2.7, J4 ,5 = 6.5, H-50), 4.15
0
0
0
0
3
(dd,
0
J6 ,7 = 9.7, 2J = 11.8, Ha-70), 4.00 (d,
0 0
3
3
J1 ,2 = 10.5, H-20), 3.88 (t, J6 ,7 = 7.5, H-60), 3.77
(dd, J = 7.3, J = 0.5, Hendo-6), 3.72 (dd, J = 3.2, H-
0
2
0
0
3
3
Data of 23: Rf = 0.16 (9.5:0.5, light petroleum ether/
25
589
25
546
25
435
25
405
3
EtOAc). ½aŠ ¼ þ10, ½aŠ ¼ þ9, ½aŠ ¼ þ14, ½aŠ
¼
40), 3.72 (m, Hexo-6), 3.65 (m, H-70), 3.49 (d, J = 3.5,
þ16 (c 0.44, CHCl3). IR (film) 3405, 2955, 2860, 1715,
1460, 1360, 1265, 1095, 835, 775cmÀ1 1H NMR
(400MHz, CDCl3) 6.12 (s, H-1), 4.50 (dd,
H-30), 2.92 (m, H-3), 2.68 (m, Hexo-2), 1.67 (dd,
3
.
2J = 12.9, J = 8.06, Hb-10), 1.46 (m, Ha-10), 1.30 (m,
d
Hendo-2), 0.97, 0.97, 0.91, 0.88 (4s, 36H 4 t-Bu), 0.15,
0.14, 0.14, 0.12, 0.08, 0.07, 0.01, 0.01 (8s, 24H, 4Me2Si).
13C NMR (100.6MHz, CDCl3) d 213 (s, C-4), 100.1 (d,
173, C-1), 79 (d, 141, C-60), 79 (d, 163, C-5), 74 (d, 147,
C-30), 74 (d, 146, C-40), 67 (d, 141, C-50), 67 (t, 106, C-6),
65 (d, 146, C-20), 58 (d, 145, C-70), 39 (d, 125, C-3), 36 (t,
128, C-2), 30 (t, 128, C-10), 18.4, 18.3, 18.1, 18.0 (4s, 4 t-
BuSi), À4.4, À4.6, À4.8, À4.9, À5.0, À5.0, À5.3, À5.3,
À5.5 (8q, 118, 4Me2Si). CIMSHR m/z found 783.4542
(calcd for C37H76O8Si4 + Na: 783.4515).
3
3
3
J5 ,6 = 2.2, J6 ,7 = 9.7, H-60), 4.42 (d, J5,6 = 5.4, H-
0
0
0
0
3
2
5), 4.22 (dd, J6 ,7 = 2.7, J = 11.8, Ha-70), 4.20 (dd,
0
0
3
3
J3 ,4 = 2.7, J2 ,3 = 2.7, H-3), 4.0 (d, J = 8.9, Hexo-6),
2
0
0
0
0
3
3.85 (m, 3H, Hendo-6, H-40, H-10), 3.75 (t, J2 ,3 = 2.7,
0
0
3
3
2
J1 ,2 = 3.2, H-20), 3.70 (dd, J6 ,7 = 1.6, J = 11.8, H-
0
0
0
0
3
70), 3.55 (d, J5 ,6 = 9.7, H-50), 3.07 (m, H-3), 2.51 (m,
Hendo-2), 2.13 (m, Hexo-2), 0.97, 0.97, 0.91, 0.88 (4s,
36H, 4 t-Bu), 0.15, 0.14, 0.14, 0.12, 0.08, 0.07, 0.01,
0.01 (8s, 24H, 4 Me2Si). 13C NMR (100.6MHz, CDCl3)
d 206 (s, C-4), 102 (d, 173, C-1), 79.5 (d, 141, C-20), 79.5
(d, 163, C-5), 73.2 (d, 147, C-10), 70.2 (d,146, C-40), 67.3
(d, 141, C-30), 66.8 (t, 106, C-6), 65.2 (d, 146, C-60), 64.7
(d, 140, C-50), 58.5 (t, 144.6, C-70), 44.4 (d, 125, C-3),
32.2 (t, 128, C-2), 18.4, 18.3, 18.1, 18.0 (4s, 4 Me3CSi),
À4.4, À4.6, À4.8, À4.9, À5.0, À5.0, À5.3, À5.3, À5.5
(8q, 118, 4 Me2Si). CIMSHR m/z found 799.4464 (calcd
for C37H76O9Si4 + Na: 799.4442).
0
0
Data of 26: colorless oil. IR (film) 2955, 2895, 2855,
1730, 1470, 1255, 1095, 835, 775cmÀ1. CIMSHR m/z
found 783.4521 (calcd for C37H76O8Si4 + Na: 783.4515).
4.20. 1,6-Anhydro-3-C-{2,6-anhydro-1-deoxy-3,4,5,7-
tetrakis-O-[(tert-butyl)dimethylsilyl]-D-glycero-L-manno-
heptitol-1-C-yl}-2,3-dideoxy-b-D-lyxo-hexopyranose 27
4.18. 1,6-Anhydro-3-C-{2,6-anhydro-3,4,5,7-1-deoxy-
tetrakis-O-[(tert-butyl)dimethylsilyl]-D-glycero-L-manno-
heptitol-1-C-ylidene}-2,3-dideoxy-b-D-glycero-hexopy-
ran-4-ulose 24
A THF solution of LiBH4 (0.56mL, 1.13mmol) was
a solution of 25 (0.140mg,
added dropwise to
0.188mmol) in THF (5mL) at À78ꢁC. The mixture
was stirred for 4h, from À78 to 15ꢁC. A satd aq soln
of NH4Cl (25mL) was then added. The reaction mixture
was warmed to 20ꢁC at which point a satd soln of so-
dium potassium tartarate (25mL) was added. The aque-
ous phase was then extracted with CH2Cl2 (3 · 100mL).
The combined organic phases were dried and concen-
trated in vacuo. FC (light petroleum ether/Et2O 9:1)
Methanesulfonyl chloride (98%, 0.370mL, 4.76mmol)
was added to a stirred solution of 22 and 23 (0.74g,
0.959mmol) in dry pyridine (15mL) containing DMAP
(50mg) under an Ar atmosphere. The mixture was stir-
red for 14h and then quenched by the addition of 20%
aq soln of CuSO4Æ5H2O solution (30mL). The solution
was extracted with CH2Cl2 (3 · 50mL), and the com-
bined organic phases washed with 2M aq HCl
(3 · 30mL), dried over MgSO4, and then concentrated
in vacuo to yield 24 as an unstable colorless oil, which
was used without further purification in the next step.
25
25
110mg (79%), colorless oil. ½aŠ ¼ þ4, ½aŠ ¼ þ7,
589
546
25
25
½aŠ ¼ þ9, ½aŠ ¼ þ11 (c 0.08, CHCl3). IR (film)
435 405
3425, 2955, 2855, 1620, 1470, 1360, 1130, 865, 835,
775, 740cmÀ1. H NMR (400MHz, CDCl3) d 5.57 (s,
1
H-1), 4.48 (m, Hexo-6), 4.54 (m, H-20), 4.42 (t,
3
J6 ,7 = 4.6, H-60), 4.29 (m, H-40), 4.26 (m, H-4), 4.24
0
0
(m, Ha-70), 3.95 (d, 3J5,6endo = 2.5, 3J3,5 = 6.8,
4.19. 1,6-Anhydro-3-{2,6-anhydro-1-deoxy-3,4,5,7-tetra-
kis-O-[(tert-butyl)dimethylsilyl]-D-glycero-L-manno-hept-
itol-1-C-yl}-2,3-dideoxy-b-D-threo-hexopyran-4-ulose 25
and 1,6-anhydro-3-{2,6-anhydro-1-deoxy-3,4,5,7-tetrakis-
O-[(tert-butyl)dimethylsilyl]-D-glycero-L-manno-heptitol-
1-C-yl}-2,3-dideoxy-b-D-erythro-hexopyran-4-ulose 26
3
3
J5,6exo = 9.6, H-5), 3.88 (t, J5 ,6 = 3.1, H-50), 3.73 (dd,
0
0
2J = 12.3, J5,6endo = 2.5, Hendo-6), 3.70 (ddd, 3J = 2.5,
3
3
3
J6 ,7 = 1.6, Hb-70), 3.46 (d, J3 ,4 = 3.7, H-30), 2.99
0
0
0
0
3
3
3
(ddd, J = 6.8, J = 12.3, J = 18.5, H-3), 2.03 (m, Ha-
10), 1.99 (m, Hendo-2), 1.83 (m, Hb-10), 1.66 (m, Hendo
-
2), 0.97, 0.97, 0.91, 0.88 (4s, 36H, 4 t-Bu), 0.15, 0.14,
0.14, 0.12, 0.08, 0.07, 0.01, 0.01 (8s, 24H, 4Me2Si). 13C
NMR (100.6MHz, CDCl3) d 101.5 (d, 173, C-1), 78.1
(d, 163, C-5), 75.6 (d, 141, C-60), 74.4 (d, 147, C-30),
73.8 (d, 141, C-50), 69.2 (d, 146, C-40), 67.5 (d, 141, C-
4), 64.8 (d, 144.6, C-70), 64.5 (d, 146, C-20), 58.6 (t,
106, C-6), 36.5 (t, 128, C-2), 34.6 (t, 128, C-10), 30.8
(d, 125, C-3), 18.4, 18.3, 18.1, 18.0 (4s, 4 t-BuSi), À4.4,
À4.6, À4.8, À4.9, À5.0, À5.0, À5.3, À5.3, À5.5 (8q,
118, 4Me2Si). CIMSHR m/z found 785.4662 (calcd for
C37H78O8Si4 + Na: 785.4671).
Raney Nickel (1g) in aqueous suspension was added to
a stirred solution of 24 (0.9g, 1.19mmol) in THF (5mL).
The mixture was stirred at 20ꢁC until complete conver-
sion of 24 (TLC control). The mixture was diluted with
Et2O (200mL) and filtrated through a pad of Celite. FC
(9:0.5:0.5 light petroleum ether/Et2O/CH2Cl2): 390mg
(43%) of 25, and 400mg (44%) of 26.
25
589
25
546
Data of 25: colorless oil. ½aŠ ¼ À10, ½aŠ ¼ À13,
25
435
25
405
½aŠ ¼ À44, ½aŠ ¼ À73 (c 0.21, CHCl3). IR (film):

R. Demange et al. / Tetrahedron: Asymmetry 15 (2004)3573–3585
3583
4.21. 4,6-Di-O-acetyl-3-C-{7-O-acetyl-2,6-anhydro-1-
References
deoxy-3,4,5-tri-O-[(tert-butyl)dimethylsilyl]-D-glycero-L-
manno-heptitol-1-C-yl}-2,3-dideoxy-a,b-D-lyxo-hexopy-
ranosyl acetate 28a,b
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A catalytic amount of triethylsilyl triflate (1.3lL) was
added dropwise via a syringe to a solution of compound
27 (0.12g, 0.157mmol) in acetic anhydride (2mL) cooled
at 0ꢁC. The mixture was stirred at 0ꢁC for 30min, and
then a satd aq soln of NaHCO3 added. The mixture was
extracted with CH2Cl2 (3 · 10mL). The organic layers
were dried over MgSO4, concentrated in vacuo and
coevaporated with toluene in vacuo. The oily product
¼
25
589
obtained was used directly in the next step. ½aŠ
25
25
25
þ50, ½aŠ ¼ þ51, ½aŠ ¼ þ99, ½aŠ ¼ þ118 (c 0.21,
546
CHCl3). CIMSHR m/z found 857.4334 (calcd for
435
405
C39H74O13Si3 + Na: 857.4309).
4.22. 4,6-Di-O-acetyl-3-C-{7-O-acetyl-2,6-anhydro-1-
deoxy-3,4,5-tri-O-[(tert-butyl)dimethylsilyl]-D-glycero-L-
manno-heptitol-1-C-yl}-3-deoxy-D-galactal 3c
Silica gel (870mg) was added to a solution of 28a,b
(0.286g, 0.315mmol) in toluene (10mL) and the mixture
heated under reflux for 3h. Filtration, washing with
CH2Cl2 (100mL), concentration in vacuo, FC
(9:0.5:0.5,
light
petroleum
ether/Et2O/CH2Cl2)
25
589
gave 160mg (60%) of yellowish oil. ½aŠ ¼ À7,
25
546
25
435
25
405
½aŠ ¼ À10, ½aŠ ¼ À27, ½aŠ ¼ À40 (c 0.09, CHCl3).
1H NMR (400MHz, CDCl3) d 6.38 (dd, J1,2 = 6.2,
3
4J1,3 = 2.7, H-1), 5.49 (d, J3,4 = 3.4 H-4), 5.16 (dd,
3
3J6exo,6endo = 12.6, J5,6exo = 9.9, Hexo-6), 4.72 (dt,
3
3J1,2 = 6.2, J2,3 = 3.9, 4J = 1.6, C–H2), 4.30–3.94 (m,
3
7H, H-5, Hendo-6, H-20, H-50, H-60, Ha-70, Hb-70), 3.72
3
3
(t, J3 ,4 = 4.0, H-40), 3.40 (d, J3 ,4 = 4.0, H-30), 2.70
(br s, C-3), 2.10 (s, 6H, 2 Ac), 2.06 (s, 3H, Ac), 1.58
(m, Ha-10), 1.25 (m, Hb-10), 0.95, 0.94, 0.93 (3s, 27H, 3
t-Bu), 0.12, 0.12, 0.12, 0.10, 0.09, 0.06 (8s, 6H, 3Me2Si).
13C NMR (100.6MHz, CDCl3) d 171.0, 170.7, 170.3 (3
Ac), 142.2 (d, 148, C-1), 104 (d, 146, C-2), 75.8 (d,
142, C-50), 74.4 (d, 146, C-40), 74.1 (d, 147, C-20), 73.5
(d, 147, C-30), 67.1 (d, 163, C-5), 65.6 (d, 142, C-60),
65.0 (d, 142, À4), 63.4 (d, 145, C-70), 60.2 (t, 106, C-
6), 32.9 (d, 125, C-3), 32.3 (t, 128, C-10), 26.1, 25.8,
25.6, (3s, 3 Me(Ac)), 21.1, 20.8, 20.7, (3s, 3 t-BuSi),
À4.4, À4.5, À4.7, À4.72, À5.0, À5.1 (6q, 118, 3 Me2Si).
CIMSHR m/z found 797.4151 (calcd for C37H70O11-
Si3 + Na: 797.4123).
0
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Acknowledgements
We are grateful to the Swiss National Science Founda-
´ ´
tion (Grant No. 200020-100002), and the ꢂOffice Federal
de lꢁEducation et de la Scienceꢁ (Bern, COST D13/0001/
99) for generous support. We thank the University of
Lausanne and Mrs. Antoinette Charon for a Peace
grant in favor of L.A. We thank also Prof. I. Robina,
Universidad de Sevilla, Spain, for discussions and help
with the HRMS. We thank also Mr. M. Rey, F. Sepu´l-
veda and Miss C. Buhlmann for technical help.
¨

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