New aspects in the stereoselective ethynylation of β-C-glycoside aldehydes. Application to the synthesis of an ambruticin fragment

Article abstract of DOI:10.1002/ejoc.200300255

Stereoselective ethynylation of functionalized β-C-glycosyl aldehydes has been achieved with various organometallic alkynes, The diastereoselectivity is highly dependent on the organometallic alkyne and on the functionalization on the C-6 position of the

Full text of DOI:10.1002/ejoc.200300255

FULL PAPER
New Aspects in the Stereoselective Ethynylation of β-C-Glycoside Aldehydes.
Application to the Synthesis of an Ambruticin Fragment
[a]
[a]
[a]
[b]
´
Veronique Michelet,* Kouacou Adiey, Suzelle Tanier, Gilles Dujardin, and
[a]
ˆ
Jean-Pierre Genet*
Keywords: Alkylation / Alkynes / Ambruticin / Cyclopropanation / Glycosides / Palladium
Stereoselective ethynylation of functionalized β-C-glycosyl
aldehydes has been achieved with various organometallic
alkynes. The diastereoselectivity is highly dependent on the
organometallic alkyne and on the functionalization on the
C-6 position of the glycoside. The stereoselective reaction
conducted with ester-functionalized aldehyde, followed by
Mitsunobu reaction and two Pd-catalyzed regio- stereo- and
enantioselective alkylations afforded the ‘‘western’’ part of
ambruticin.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
Despite widespread interest among chemists, resulting in
the preparation of several fragments,[12] up to 2001, only
one total synthesis Ϫ by a Sinay¨ strategy[12c] Ϫ had been
published, by Kende’s group.[13] Kende’s condensation be-
tween a vinylalanecyclopropane and a fluoroglycoside with
a subsequent Julia olefination efficiently produced ambrut-
icin.
During the last two decades, the synthesis of C-glycosides
has become an area of intense study among carbohydrate
chemists and biochemists.[1] The discovery of naturally oc-
curring C-nucleosides with important pharmacological
properties, such as palytoxin,[2] spongistatin,[3] or ambrut-
icin,[4] has stimulated the development of new synthetic
methodologies.[5] Ambruticin (1), an antifungal antibiotic
discovered in the late 1970s, has been isolated from fermen-
tation extracts of Myxobacteria species Polyangium cellulo-
sum var. fulvum.[6] It exhibits a unique oral in vivo activity
against pathogens such as Coccidiodes immitis, Histoplasma
capsulatum, and Blastomyces dermatitidis.[6,7] Höfle’s group
showed that it displays potent inhibitory activity against the
yeast strain Hansenula anomala, and these workers have
also isolated analogues of (ϩ)-ambruticin carrying an am-
ino group on the C5 position from Myxobacteria Sorang-
ium cellulosum So ce10.[8] The mode of action of (ϩ)-am-
bruticin has been shown to be related to osmoregulation
in the same manner as that of pyrrolnitrin.[9] Its complete
structure was determined by elegant spectroscopic analy-
ses,[10] degradative studies and chemical transformation,
and by a single X-ray of a derivative.[11]
More recently, three groups have succeeded in the chal-
lenging total synthesis of ambruticin (Scheme 1). Martin[14]
and Lee[15] employed a common strategy based on C8ϪC9
and C13ϪC14 disconnections through the functionalization
of the A-ring aldehyde, a strategy that had previously been
reported by our group.[16] The B-ring was prepared either
by Doyle-Martin’s methodology or by Kende’s strategy,
respectively. The key step in the synthesis of the C-ring was
a ring-closing metathesis starting from a homoallylic chiral
epoxide[14] or (R)-3-hydroxy-2-methylpent-1-ene.[15] Joining
of parts A and B, and then C, was achieved by a
KocienskiϪJulia olefination with moderate to good selec-
tivity. Jacobsen[17] described a highly stereocontrolled total
synthesis based on the cleavage of the C8ϪC9 olefin, which
revealed two fragments, joining of which was again
achieved by a KocienskiϪJulia olefination. The elegant
functionalization of the BϪC ring precursor was originally
performed by asymmetric cyclopropanation and hydrofor-
mylation (C15). The synthesis of the A and C rings were
both achieved through an asymmetric hetero-DielsϪAlder
reaction.
[a]
`
´
Laboratoire de Synthese Selective Organique et Produits
Naturels, UMR 7573 CNRS, E.N.S.C.P.,
11 rue P. et M. Curie, 75231 Paris Cedex 05, France
Fax: (internat.) ϩ 33-1/44071062
As part of a program devoted towards the synthesis of
C-glycosides and vinylcyclopropanes, we have also for a
long time been interested in the unique oral antifungal am-
bruticin. In 1994 we had envisaged a totally different ap-
proach, based on long work on the synthesis of vinylcyclo-
propanes.[18] In collaboration with Dujardin’s group, in
E-mail: genet@ext.jussieu.fr
michelet@ext.jussieu.fr
[b]
`
Laboratoire de Synthese Organique, UPRES-A 6011 CNRS,
´
´
Universite du Mans, Faculte des Sciences,
BP 535, avenue Olivier Messiaen, 72017 Le Mans Cedex,
France
E-mail: dujardin@univ-lemans.fr
Eur. J. Org. Chem. 2003, 2947Ϫ2958
DOI: 10.1002/ejoc.200300255
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2947

ˆ
V. Michelet, K. Adiey, S. Tanier, G. Dujardin, J.-P. Genet
FULL PAPER
Scheme 1. Total syntheses of ambruticin
which highly efficient hetero-DielsϪAlder reactions have well as 4, we also selected the totally benzylated aldehyde 5
been developed,[19] we slightly modified our approach to and aldehydes 6 and 7 for our study (Scheme 3). Here we
the A ring by changing the functionalization and the prep- wish to report our results concerning the chain-elongation
aration (Scheme 2).[20] We had therefore envisaged a
C13ϪC14 disconnection to provide the ‘‘western’’ part,
which was seen as an entire building block 2 resulting from
the sequential alkylation/cyclopropanation of (1R,4R)-al-
lylic hydroxycarbonate 3, catalyzed by Pd0 complexes. We
had previously developed a methodology for cyclopropane
formation akin to an intramolecular TsujiϪTrost reaction.
Unfortunately, our efforts produced a C10ϪC11 cis isomer
fragment epi-2 instead of the trans counterpart: as we knew
that the configuration of the cyclopropane is dictated by
the absolute configuration of the carbon atom bearing the
free OH group,[18] we deduced that an unusual and unex-
pected stereoselectivity had occurred in the addition of the
ethynyl Grignard to the β-C-glycosyl aldehyde 4.[20]
We therefore decided to investigate this unprecedented
diastereoselectivity with different C-glycoside aldehydes. As Scheme 3. Functionalized β-C-glycosyl aldehydes
Scheme 2. Retrosynthesis of ambruticin
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Eur. J. Org. Chem. 2003, 2947Ϫ2958

Stereoselective Ethynylation of β-C-Glycoside Aldehydes
FULL PAPER
As shown in Table 1, the addition of the lithiated (R)-
of C-glycoside aldehydes, and their application to the pre- O-ethoxycarbonylbut-1-yn-3-ol (10a),[21] prepared by use of
paration of the western part of ambruticin with the correct LDA or tBuLi either in the presence or in the absence of 12-
absolute configuration on the cyclopropane at C10.
crown-4 in diethyl ether or THF gave no desired products
(Table 1, Entry 1). Only starting material, epimerized alde-
hyde, or de-O-benzylated aldehyde could be detected by 1H
NMR spectroscopy. We then turned our attention to less
basic organometallic derivatives. The Mg, Cu,[22] Ce,[23] or
Zn[24] derivatives (Table 1, Entry 2) gave no better results.
We next decided to test commercially available acetylenic
compounds such as phenylacetylene (10c) and trimethyl-
silylacetylene (10d) and were pleased to see that the ad-
dition of the Grignard reagents derived from phenylacety-
lene and trimethylacetylene gave the desired alcohols 11c/
12c and 11d/12d, respectively, in 60 and 73% yields (Table 1,
Entries 3, 4).[25] The diastereoselectivity could not be deter-
mined by 1H NMR spectroscopy but was assumed to follow
Cram’s chelation model.[25,26] The diastereomers 11 and 12
were isolated by chromatography on silica gel, the major
product 11 being less polar than 12. Having prepared an
optically pure silylated protected alcohol 10b, we studied
the reactivity of the aldehyde 5. Grignard derivatives gave
better results than Zn or Ce reagents (Table 1, Entries 5, 7).
Addition of an excess of MgBr2 (Table 1, Entry 4) gave bet-
ter diastereoselectivity and a better yield than the use of
ZnBr2 (Table 1, Entry 8) or CuI (Table 1, Entry 9). More-
over, when a powerful complexing cation agent such as
HMPT was used, the diastereoselectivity was reversed, as
expected (Table 1, Entry 10).[27]
Results and Discussion
Synthesis of Aldehydes
The preparations of aldehydes 4, 5, and 6 were described
previously.[16,20] We synthesized aldehyde 7 starting from
lactone 8.[19b] Addition of the anion of phenylacetylene to
the lactone, followed by Kishi deoxygenation, stereoselec-
tively afforded the C-glycoside 9 in 72% isolated yield
(Scheme 4). Semi-hydrogenation followed by the ozonolysis
of the resulting alkene gave the β-C-glycosyl aldehyde 7.
Scheme 4. Synthesis of aldehyde 7; a) nBuLi, PhCϵCH, THF, Ϫ78
°C Ϫ room temp., 95%; b) BF3·Et2O, Et3SiH, CH3CN/CH2Cl2,
Ϫ40 °C, 79%; c) Pd/Lindlar, H2 (1 atm), quinoline, EtOAc, room
temp., 100%; d) O3, CH2Cl2, Ϫ78 °C then Me2S, 58%
Chain-Elongation of Aldehydes
The optimized conditions were then tested on the func-
tionalized aldehydes 4, 6, and 7 (Scheme 6).
The MeLi/MgBr2 conditions, conducted at lower tem-
perature in order to avoid addition at the ester group, ef-
We first investigated the chain-elongating hydroxy alky-
lation of the aldehyde 5 with several alkynyl derivatives 10
(Scheme 5).
Scheme 5. Hydroxy alkylation of aldehyde 5 with various alkynyl derivatives
Table 1. Hydroxy alkylation of aldehyde 5 with various alkynyl derivatives
Entry Alkyne Conditions
Dia 11[a] Dia 12[a] Yield[b]
1
2
3
4
5
6
7
8
9
10a
10a
10c
10d
10b
10b
10b
10b
10b
10b
LDA, LDA/12-crown4, tBuLi, THF or Et2O, Ϫ78 °C Ϫ room temp.
LDA/MgBr2, tBuLi/ CuI, LDA/CeCl3, LDA/ZnBr2, THF or Et2O, Ϫ78 °C Ϫ room temp.
MeLi, MgBr2, 8 equiv. MgBr2, Et2O, Ϫ30 °C Ϫ room temp.
MeLi, MgBr2, 8 equiv. MgBr2, Et2O, Ϫ30 °C Ϫ room temp.
MeLi, MgBr2, 8 equiv. MgBr2, Et2O, Ϫ30 °C Ϫ room temp.
MeLi, ZnBr2, 8 equiv. ZnBr2, Et2O, 0 °C. Ϫ room temp.
MeLi, CeCl3, 8 equiv. CeCl3, THF, Ϫ78 °C Ϫ room temp.
MeLi, MgBr2, 8 equiv. ZnBr2, Et2O, Ϫ78 °C Ϫ room temp.
MeLi, MgBr2, 8 equiv. CuI, THF/Me2S, Ϫ78 °C Ϫ room temp.
MeLi, HMPT, Ϫ78 °C Ϫ room temp.
Ϫ
Ϫ
Ϫ
Ϫ
n.r.
n.r.
87
70
75
Ϫ
58
53
70
40
13
30
25
Ϫ
42
47
30
60
60%
73%
75%
n.r.
20%
47%
50%
50%
10
[a]
[b]
Diastereomeric ratio. Global isolated yield; n.r. no reaction.
Eur. J. Org. Chem. 2003, 2947Ϫ2958
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V. Michelet, K. Adiey, S. Tanier, G. Dujardin, J.-P. Genet
FULL PAPER
Scheme 6. Hydroxy alkylation of aldehydes 4, 6, and 7 with 10b
Table 2. Hydroxy alkylation of aldehydes 4, 6, and 7 with 10b
Entry
Aldehyde
(R,R) Isomer, (%)[a]
(S,R) Isomer, (%)[a]
Yield (%)[b]
1
2
3
4, R1 ϭ CO2Me, R2 ϭ R3 ϭ OBn
6, R1 ϭ CH2OBn, R2 ϭ R3 ϭ OBn
7, R1 ϭ OBn, R2 ϭ H, R3 ϭ OtBu
(R,R)-13, 12
(R,R)-14, 65
(R,R)-15, 80
(S,R)-13, 88
(S,R)-14, 35
(S,R)-15, 20
52[c]
73
50[d]
[a]
[b]
[c]
[d]
Diastereomeric ratio, isolated yield. Global yield. 28% SM recovered. 12% SM recovered.
ficiently afforded the two desired alcohols 13 in a 12:88 dia-
stereomeric ratio and 52% isolated yield, accompanied by
28% of starting material (Table 2, Entry 1). The 12:88 ratio
was this time in favor of the diastereomer (S,R)-13, which
was converted into an isomer of the C1ϪC13 part of am-
bruticin.[20] The aldehyde 6 was highly reactive at Ϫ30 °C
and correspondingly afforded (R,R)-14 and (S,R)-14 in 73%
yield. The 65:35 diastereoselectivity was in favor of the less
polar alcohol (R,R)-14, as in the case of aldehyde 5. Under
the same conditions, the alkylation of aldehyde 7 gave the
alcohols 15 in a moderate yield of 50% and a diastereomeric
ratio of 80:20, with 12% of starting material being reco-
vered.
Scheme 7. Synthesis of the tetra-O-benzylated western part of am-
bruticin; a) ClCO2CH2CHϭCH2, pyridine, CH2Cl2, 0 °C Ϫ room
temp., 95%; b) Bu4NF, THF, 0 °C Ϫ room temp., 92%; c) ClCO2Et,
pyridine, CH2Cl2, 0 °C Ϫ room temp., 92%; d) Pd(OAc)2 (20
mol %)/TPPTS, CH3CN/H2O (6:1), Et2NH, room temp., 83%; e)
Pd/C (10 mol %), pyridine (5 mol %), H2, room temp., MeOH,
70%; f) Pd(OAc)2 (10 mol %), dppe (15 mol %), NaCH(CO2Me)2,
THF, room temp., 43% (50% of SM recovered); g) 2,4-Cl2-
C6H3COCl, pyridine, CH2Cl2, 0 °C Ϫ room temp., 71%; h)
Pd(OAc)2 (10 mol %), dppe (15 mol %), DBU, THF, room temp.,
68%
Determination of Absolute Structures
Absolute Configuration of the Tetra-O-benzylated
Derivative
With the major alcohol 11b now to hand, we carried out
protection and deprotection and isolated alcohol 16 in 67%
overall yield. All attempts to obtain crystalline structures
were unsuccessful. Considering that the preparation of a
vinylcyclopropane would give us the answer concerning the
configuration of the major alcohol, we decided to carry out
the overall complete sequence to prepare the cyclopropane
(Scheme 7).
The alkyne 16 was semi-hydrogenated and then alkylated
under mild conditions by use of 10 mol % of [Pd(dppe)2]
and the sodium salt of dimethyl malonate. The alcohol 17
was isolated as a single diastereomer. The alkylation was
totally regio-, stereo-, and enantioselective, based on the
anti addition of Pd0 catalyst, anti-syn isomerization, and
anti addition of nucleophile.[28] This alcohol was then acti-
vated with 2,4-dichlorobenzoyl chloride and cyclized to give
Figure 1. Comparison of cyclopropanes 18 and epi-2
Absolute Configuration of the Functionalized Substrate
We had previously shown that the same sequence as de-
the cyclopropane 18. The reaction proceeds with a clean scribed on Scheme 7, starting with the major alcohol (S,R)-
chirality transfer from the CϪO bond to the newly formed 13, had produced an isomer of the “western” part of am-
CϪC bond.[29] The stereochemistry and the structure were bruticin, and so were able to deduce the (S) configuration
1
confirmed by H and 13C NMR and NOE experiments (Ja- of the stereogenic center bearing the alcohol. We took the
ϭ 7.5 Hz in 18 and 9.6 Hz in epi-2) (Figure 1).
minor isomer (R,R)-13 and were gratified to isolate crystal-
b
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Eur. J. Org. Chem. 2003, 2947Ϫ2958

Stereoselective Ethynylation of β-C-Glycoside Aldehydes
FULL PAPER
line compound 19 after protection with the allyloxycar- sists of three six-membered ring chelates, on which a si-face
bonyl chloride and removal of the silyl group (Scheme 8).
attack affords the (S) isomer as the major product
(Scheme 9).
Scheme 9. Cram chelation model on aldehyde 4
Scheme 8. Protection of alcohol (R,R)-13; a) ClCO2CH2CHϭ
CH2, pyridine, CH2Cl2, 0 °C Ϫ room temp., 95%; b) Bu4NF, THF,
O ° Ϫ room temp., 90%
In the case of the tetra-O-benzylated aldehyde 5, chel-
ation of MgL2 may give two intermediates, resulting from
α- or β-chelation. The major chelate with the oxygen of the
aldehyde and the oxygen of the pyran (α-chelation[25,30]) re-
sulted in a re-face attack of the ethynyl organometallic
(Scheme 10).
The ORTEP drawing of the crystal of compound 19 cor-
roborated the absolute stereochemistry of the minor alcohol
(Figure 2). It also confirmed that the major diastereomer
obtained upon hydroxyalkylation of the aldehyde 4 was (S),
which does not follow the commonly accepted Cram chel-
ation model.
Scheme 10. Cram chelation model on aldehyde 5
Synthesis of the Western Part of Ambruticin
The stereochemistry of the alcohol (S,R)-13 was ef-
ficiently inverted through a Mistunobu reaction[31] with use
of 4-nitrobenzoic acid, giving a 90% yield (Scheme 11). Re-
moval of the silyl group, followed by protection as an ethyl-
carbonate, provided the ester 20. Saponification was care-
fully performed with a catalytic amount of K2CO3 at room
temperature, avoiding cleavage of the carbonate moiety.
Semi-hydrogenation was then performed with deactivated
Pd/C, with careful control of the hydrogen volume. The
minor isomer (R,R)-13 was also converted into the same
intermediate 21 by a protectionϪdeprotection sequence and
Figure 2. ORTEP drawing of the crystal structure of the alcohol 19
Interpretation
The diastereoselectivity of the hydroxyalkylation reaction semi-hydrogenation. Similar spectral analyses were ob-
on substrates 4 and 5 may be explained through α- or β- tained from both ((S,R)-13 and (R,R)-13) transformations.
chelation.[25] The excess of MgBr2 activates the aldehyde The Pd-catalyzed step was smoothly conducted with
and provides a cyclic stable intermediate.
Pd(dppe)2 and methyl malonate sodium salt. Alcohol 22
Taking the presence of the ester function on compound was isolated in 80% yield as a unique diastereomer. Acti-
4 into account, β-chelation should be favored with MgL2 vation of the resulting alcohol, followed by final Pd-cycliza-
(L ϭ Br or alkynyl derivative). The rigid intermediate con- tion, gave the “western” part of ambruticin 2.
Eur. J. Org. Chem. 2003, 2947Ϫ2958
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V. Michelet, K. Adiey, S. Tanier, G. Dujardin, J.-P. Genet
FULL PAPER
Scheme 11. Synthesis of the western part of ambruticin; a) DEAD, PPh3, 4-NO2-C6H4-CO2H, 90%; b) Bu4NF, THF, 0 °C Ϫ room temp.,
80%; c) ClCO2Et, pyridine, CH2Cl2, 0 °C Ϫ room temp., 92% Ar ϭ 4-NO2-C6H4; d) K2CO3 2 mol % MeOH, room temp., 70%; e) Pd/
C (10 mol %), H2, room temp., EtOAc, 70%; f) Pd(OAc)2 (10 mol %), dppe (15 mol %), NaCH(CO2Me)2, THF, room temp., 80%; g)
2,4-Cl2-C6H3COCl, pyridine, CH2Cl2, 0 °C Ϫ room temp., 80%; h) Pd(OAc)2 (10 mol %), dppe (15 mol %), DBU, THF, room temp., 60%
transferred by cannula to a THF solution (45 mL) of lactone 8
(3.47 g, 11.9 mmol), also at Ϫ78 °C. The reaction mixture was
Conclusion
warmed to Ϫ40 °C over 1.5 h, and aqueous NH4Cl (10 mL) and
In conclusion, we have shown that the ethynylation of β-
diethyl ether (40 mL) were added. After the mixture had been
C-glycosyl aldehydes can be performed stereoselectively and
warmed to room temp., the aqueous phase was separated and ex-
is highly dependent on the substrate functionality at carbon
tracted with diethyl ether, and the combined organic phase was
6 of the pyranoside and on the alkynyl metal (Ce, Li, Mg).
washed with water and brine, dried (Na2SO4), and concentrated to
We have determined the stereochemistry of the major al-
cohols in the case of a C-6-benzylated aldehyde and an C-
afford crude lactol, which was purified by chromatography (SiO2,
cyclohexane/ethyl acetate, 8:2) to give the lactol as a colorless oil
6 ester aldehyde. Ethynylation of the functionalized A ring (4.43 g, 95%).1H NMR (250 MHz, CDCl3): δ ϭ 7.59Ϫ7.26 (m, 10
H), 4.6, 4.55 (2s, 2 H), 4.46 (m, 1 H), 4.10 (m, 1 H), 3.4 (m, 3 H),
2.96 (m, 2 H), 1.68 (m, 2 H), 1.25 (s, 9 H) ppm. 13C NMR
(63 MHz, CDCl3): δ ϭ 137.8, 131.2, 132.8, 130.5, 128.4, 128.1,
127.4, 127.3, 91.1, 88.1, 74.6, 74.5, 73.1, 67.0, 65.8, 60.1, 52.3, 38.7,
of ambruticin, followed by Mistunobu inversion and a two-
step Pd-catalyzed strategy, has created a unique method for
the preparation of the C1ϪC13 part of ambruticin. Further
studies are under investigation in our laboratory for the
synthesis of the C ring[32] and the completion of the total
synthesis and ambruticin analogues.
28.1 ppm. IR (neat): ν˜ ϭ 3345, 2220, 1380, 1365, 1260, 1210 cmϪ1
MS (CI, NH3): m/z ϭ 412 [M ϩ 18].
.
6-O-Benzyl-3-O-tert-butyl-2,4-dideoxy-1-(2-phenylethynyl)-D-gluco-
β-C-pyranose (9): A solution of lactol (1.7 g, 4.31 mmol) in a
CH3CN/CH2Cl2 solvent mixture (85:15, 65 mL) was cooled to Ϫ40
°C, and Et3SiH (3.44 mL, 21.6 mmol) was added. After 5 min,
BF3·Et2O (1.59 mL, 12.9 mmol) was added very slowly, and the
mixture was stirred at Ϫ40 °C for 2 h. After addition of Et3N
(3 mL, 21.6 mmol), the solution was warmed to room temp. and
was concentrated under reduced pressure. The residue was dis-
solved in CH2Cl2, washed with water and brine, dried with Na2SO4,
and concentrated to give crude C-glycoside, which was purified by
chromatography (SiO2, cyclohexane/ethyl acetate, 9:1) to afford 9
as a pale yellow solid (1.28 g, 79%). [α]2D0 ϭ ϩ4 (c ϭ 1.1, CHCl3);
m.p. 100Ϫ102 °C. 1H NMR (250 MHz, CDCl3): δ ϭ 7.45Ϫ7.24
(m, 10 H), 4.62, 4.54 (AB system, J ϭ 12 Hz, 2 H), 4.38 (dd, J ϭ
11.8, 2.1 Hz, 1 H), 3.69, 3.42 (m, 4 H), 2.12 (m, 1 H), 1.80 (m, 2
H), 1.27 (m, 1 H), 1.21 (s, 9 H) ppm. 13C NMR (63 MHz, CDCl3):
δ ϭ 137.8, 122.3, 131.6, 128.1, 127.9, 127.8, 127.6, 127.5, 127.3,
87.2, 84.3, 75.5, 73.7, 73.2, 72.8, 66.7, 66.5, 41.3, 37.0, 28.2 ppm.
IR (neat): ν˜ ϭ 2230 cmϪ1. MS (CI, NH3): m/z ϭ 379 [M ϩ 1], 396
Experimental Section
General: 1H NMR spectra were recorded with a Bruker AC-200,
AM-250, or AC-400 spectrometers at 200, 250, or 400 MHz,
respectively; chemical shifts (δ) are reported in ppm units, with ref-
erence to Me4Si, and coupling constants (J) are reported in Hertz
and refer to apparent peak multiplicities. 13C NMR spectra were
recorded with a Bruker AC-200, AM-250, or AC-400 instruments
at 50, 63, or 100 MHz, respectively. High-resolution mass spectra
´
were performed on a Varian MAT311 instrument at the Universite
Pierre et Marie Curie (Paris). Low-resolution mass measurements
were run with a Fisons Hewlett Packard 5989 instrument. Optical
rotations were recorded with a PerkinϪElmer 241 polarimeter at
589 nm. IR spectra were recorded with a IRFT-45 Bruker spectro-
photometer. Elemental analyses were carried out at the ‘‘Service
Regional de Microanalyse’’ (Universite Pierre et Marie Curie).
Thin-layer chromatography was carried out on silica gel plates
(Merck F254) and spots were detected by UV and/or use of vanillin.
´
[M
C25H34NO3: 396.2539; found 396.2540.
ϩ 18]. HRMS-DCI/NH3: [M ϩ
NH4]ϩ calculated for
Anhydrous THF and diethyl ether were distilled from over sodium/
benzophenone, and CH2Cl2 was distilled from over calcium hy-
dride.
6-O-Benzyl-3-O-tert-butyl-2,4-dideoxy-1-[(Z)-2-phenylethenyl]-D-
gluco-β-C-pyranose: Pd Lindlar (0.11 g, 10% in weight), and quino-
line (100 µL, 10% in weight) were added to a solution of 9 (1.11 g,
2.9 mmol) in ethyl acetate (25 mL), and the mixture was stirred
under hydrogen at room temp. for 16 h. After filtration through a
short plug of silica with diethyl ether as eluent, the solvent was
evaporated under reduced pressure. The crude product was purified
6-O-Benzyl-3-O-tert-butyl-2,4-dideoxy-1-(2-phenylethynyl)-α
and
-β- -Glucopyranose: nBuLi (5.2 mL, 2.5  solution in hexane) was
D
added at Ϫ78 °C to a THF solution (60 mL) of phenylacetylene
(1.43 mL, 13 mmol). The mixture was stirred for 15 min and then
2952
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 2947Ϫ2958

Stereoselective Ethynylation of β-C-Glycoside Aldehydes
FULL PAPER
by chromatography (SiO2, cyclohexane/ethyl acetate, 9:1) to give
4.90Ϫ4.52 (m, 10 H), 3.79Ϫ3.46 (m, 7 H), 2.73 (d, J ϭ 10.7 Hz, 1
H), 1.39 (d, J ϭ 6.5 Hz, 3 H), 0.88 (s, 9 H), 0.10, 0.09 (2s, 6 H)
the alkene as a pale yellow oil (1.11 g, 100%). [α]2D0 ϭ Ϫ37.3 (c ϭ
1, CHCl3). 1H NMR (200 MHz, CDCl3): δ ϭ 7.36Ϫ7.22 (m, 10 ppm. 13C NMR (63 MHz, CDCl3): δ ϭ 138.2, 138.0, 137.8, 137.7,
H), 6.61 (d, J ϭ 11.6 Hz, 1 H), 5.70 (dd, J ϭ 11.6, 8.6 Hz, 1 H),
4.58 (m, 2 H), 4.2 (m, 1 H), 3.6 (m, 4 H), 1.85Ϫ1.40 (m, 4 H), 1.19
128.2, 128.1, 127.7, 127.6, 127.5, 127.4, 127.3, 89.0, 86.6, 80.3, 80.0,
79.6, 78.9, 78.1, 75.3, 75.0, 74.8, 73.0, 68.6, 62.5, 58.7, 25.5, 25.2,
(s, 9 H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 138.3, 136.6, 132.3, 17.9, Ϫ4.7, Ϫ5.1 ppm. IR (neat): ν˜ ϭ 3450, 2100 cmϪ1. MS (CI,
131.5, 128.8, 128.5, 128.2, 127.6, 127.4, 127.2, 75.0, 73.7, 73.4, 73.3, NH3): m/z ϭ 754 [M ϩ 18]. HRMS-DCI/NH3: [M ϩ NH4]ϩ calcu-
72.3, 67.0, 41.0, 37.3, 28.3 ppm. IR (neat): ν˜ ϭ 1650 cmϪ1. MS (CI, lated for C45H60NO7Si: 754.4139; found 754.4133.
NH3): m/z ϭ 381 [M ϩ 1], 398 [M ϩ 18]. HRMS-DCI/CH4: [M ϩ
The hydroxy alkylation of aldehyde 5 (165 mg, 0.3 mmol) in the
presence of phenylacetylene (10c, 144 µL, 1.31 mmol) afforded the
diastereomers 11c (102 mg, colorless oil) and 12c (14 mg, colorless
oil). dr 87:13, Yield 60%.
H]ϩ calculated for C25H33O3: 381.2430; found 381.2424.
[6-O-Benzyl-3-O-tert-butyl-2,4-dideoxy- -gluco-β-C-pyranosyl]-
D
carbaldehyde (7): Ozone was bubbled at Ϫ78 °C through a CH2Cl2
solution (160 mL) of the alkene (1.03 g, 2.71 mmol) until saturation
(blue color in 10 min). Argon was then passed through to eliminate
the excess ozone, and Me2S (0.6 mL, 8.1 mmol) was added. The
reaction mixture was warmed to room temp. and concentrated un-
der reduced pressure. Column chromatography (SiO2, cyclohexane/
(1R)-1-(2,3,4,6-Tetra-O-benzyl-D-gluco-β-C-pyranosyl)-3-phenyl-
prop-2-yne (11c): [α]2D0 ϭ ϩ10 (c ϭ 1, CHCl3). 1H NMR (200 MHz,
CDCl3): δ ϭ 7.48Ϫ7.20 (m, 25 H), 5.03Ϫ4.56 (m, 9 H), 3.95Ϫ3.52
(m, 7 H), 3.09 (d, J ϭ 10.5 Hz, 1 H) ppm. 13C NMR (63 MHz,
CDCl3): δ ϭ 138.1, 137.9, 137.8, 137.6, 131.5, 128.3, 128.1, 128.0,
127.9, 127.7, 127.6, 127.5, 127.4, 127.3, 122.4, 87.9, 86.6, 84.9, 80.1,
79.0, 78.3, 78.0, 75.2, 75.1, 74.8, 73.1, 68.6, 62.1 ppm. IR (neat):
ν˜ ϭ 3390, 2233 cmϪ1. MS (CI, NH3): m/z ϭ 672 [M ϩ 18]. HRMS-
DCI/NH3: [M ϩ NH4]ϩ calculated for C43H46NO6: 672.3325;
found 672.3317.
ethyl acetate, 8:2) afforded 7 as a white solid (484 mg, 58%). [α]2D0
ϭ
1
ϩ19 (c ϭ 1, CHCl3); m.p. 105 °C. H NMR (200 MHz, CDCl3):
δ ϭ 9.66 (d, J ϭ 0.8 Hz, 1 H), 7.36Ϫ7.27 (m, 5 H), 4.63, 4.56 (AB
system, J ϭ 12.2 Hz, 2 H), 3.85 (ddd, J ϭ 12.2, 2.3, 0.8 Hz, 1 H),
3.73Ϫ3.45 (m, 4 H), 2.01, 1.79 (2m, 2 H), 1.33 (m, 2 H), 1.20 (s, 9
H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 201.1, 137.7, 128.1,
127.5, 127.4, 80.0, 75.5, 73.8, 73.3, 72.6, 66.6, 36.9, 35.0, 28.1 ppm.
IR (KBr): ν˜ ϭ 1735 cmϪ1. MS (EI): m/z ϭ 249 [M Ϫ tBu]ϩ.
HRMS-EI calculated for C14H17O4: [M Ϫ tBu] 249.112681;
found 249.112745.
(1S)-1-(2,3,4,6-Tetra-O-benzyl-D-gluco-β-C-pyranosyl)-3-phenyl-
prop-2-yne (12c): [α]2D0 ϭ ϩ8 (c ϭ 0.7, CHCl3). 1H NMR (250 MHz,
CDCl3): δ ϭ 7.40Ϫ7.22 (m, 25 H), 4.93Ϫ4.56 (m, 8 H), 4.92 (m, 1
H), 3.87Ϫ3.51 (m, 7 H), 3.00 (d, J ϭ 10 Hz, 1 H) ppm. 13C NMR
(63 MHz, CDCl3): δ ϭ 138.5, 138.4, 138.2, 138.0, 131.9, 128.6,
128.5, 128.4, 128.3, 128.0, 127.9, 127.8, 127.6, 127.3, 122.5, 87.0,
86.7, 86.4, 80.8, 79.9, 79.4, 78.4, 75.8, 75.5, 75.2, 73.4, 68.6, 63.4
ppm. IR (neat): ν˜ ϭ 3390, 2223 cmϪ1. MS (CI, NH3): m/z ϭ 672 [M
ϩ 18]. HRMS-DCI/NH3: [M ϩ NH4]ϩ calculated for C43H46NO6:
672.3325; found 672.3315.
General Procedure for the Hydroxy Alkylation of Aldehydes: Two
solutions of MgBr2 in diethyl ether (0.7 mL/mmol) were prepared,
by addition of 1,2-dibromoethane (8 equiv.) to magnesium (8
equiv.). The alkyne (4.4 equiv.) was added at Ϫ5 °C to a solution
of methyllithium (4 equiv.) in diethyl ether. After 30 minutes, the
first solution of MgBr2 was added and the resulted mixture was
cooled to Ϫ30 °C or Ϫ60 °C. The second solution of MgBr2 was
added to a solution of the aldehyde (1 equiv.) in diethyl ether
(3.5 mL/mmol). This mixture was then added to the Grignard ace-
tylenic reagent. The solution was stirred at Ϫ60 °C or Ϫ78 °C, was
warmed to room temperature, and was then slowly quenched with
cold aqueous NH4Cl. The aqueous phase was extracted with di-
ethyl ether. The organic phase was washed with water, dried
(Na2SO4), and concentrated under reduced pressure. Column chro-
matography (SiO2, cyclohexane/EtOAc, 8:2 then 7:3) afforded two
diastereomers.
The hydroxy alkylation of aldehyde 5 (800 mg, 1.45 mmol) in the
presence of trimethylsilylacetylene (10d, 900 µL, 6.38 mmol) af-
forded the diastereomers 11d (483 mg, colorless oil) and 12d
(206 mg, colorless oil). dr 70:30, Yield 73%.
(1R)-1-(2,3,4,6-Tetra-O-benzyl-D-gluco-β-C-pyranosyl)-3-trimethyl-
silylprop-2-yne (11d): [α]2D0 ϭ ϩ16 (c ϭ 1.1, CHCl3). 1H NMR
(250 MHz, CDCl3): δ ϭ 7.36Ϫ7.19 (m, 20 H), 4.96Ϫ4.54 (m, 8 H),
4.58 (dd, J ϭ 10.9, 1.8 Hz, 1 H), 3.83Ϫ3.38 (m, 7 H), 2.65 (d, J ϭ
10.9 Hz, 1 H), 0.16 (s, 9 H) ppm. 13C NMR (63 MHz, CDCl3): δ ϭ
138.5, 138.4, 138.2, 137.9, 128.6, 128.5, 128.4, 128.1, 128.0, 127.9,
127.8, 127.6, 104.6, 90.3, 87.0, 80.1, 79.6, 78.7, 78.4, 75.6, 75.4,
The hydroxy alkylation of aldehyde 5 (310 mg, 0.56 mmol) in the
presence of (R)-3-(tert-butyldimethylsilyloxy)but-1-yne (10b,
469 mg, 2.46 mmol) afforded the diastereomers 11b (226 mg, color-
less oil) and 12b (75 mg, colorless oil). dr 75:25, Yield 75%.
75.1, 73.4, 68.8, 62.5, Ϫ0.06 ppm. IR (neat): ν˜ ϭ 3400, 2205 cmϪ1
.
MS (CI, NH3): m/z ϭ 668 [M ϩ 18]. C40H46O6Si: calcd. C 73.8, H
7.12, found C 74.3, H 7.10.
(1R,4R)-1-(2,3,4,6-Tetra-O-benzyl-D-gluco-β-C-pyranosyl)-4-O-tert-
(butyldimethylsilyl)pent-2-yne-1,4-diol (11b): [α]2D0 ϭ ϩ41 (c ϭ 1.5,
(1S)-1-(2,3,4,6-Tetra-O-benzyl-D-gluco-β-C-pyranosyl)-3-trimethyl-
silylprop-2-yne (12d): [α]2D0 ϭ ϩ12 (c ϭ 1, CHCl3). 1H NMR
(250 MHz, CDCl3): δ ϭ 7.36Ϫ7.24 (m, 20 H), 4.92Ϫ4.55 (m, 8 H),
4.72 (dd, J ϭ 10.6, 3.2 Hz, 1 H), 3.84Ϫ3.65 and 3.51Ϫ3.46 (m, 7
H), 2.72 (d, J ϭ 10.6 Hz, 1 H), 0.16 (s, 9 H) ppm. 13C NMR
(63 MHz, CDCl3): δ ϭ 138.4, 138.2, 138.1, 128.6, 128.5, 128.4,
128.1, 128.0, 127.9, 127.8, 127.6, 127.7, 103.0, 91.8, 86.9, 80.4, 80.1,
79.5, 78.4, 75.9, 75.5, 75.2, 73.3, 68.5, 63.2, Ϫ0.05 ppm. IR (neat):
ν˜ ϭ 3385, 2200 cmϪ1. MS (CI, NH3): m/z ϭ 668 [M ϩ 18]. HRMS-
DCI/NH3: [M ϩ NH4]ϩ calculated for C40H50NO6Si: 668.3407;
found 668.3400.
1
CHCl3). H NMR (250 MHz, CDCl3): δ ϭ 7.35Ϫ7.17 (m, 20 H),
4.94Ϫ4.51 (m, 10 H), 3.76Ϫ3.33 (m, 7 H), 2.59 (d, J ϭ 11 Hz, 1
H), 1.40 (d, J ϭ 6.5 Hz, 3 H), 0.88 (s, 9 H), 0.1, 0.09 (2s, 6 H) ppm.
13C NMR (63 MHz, CDCl3): δ ϭ 138.2, 137.9, 137.8, 137.6, 128.2,
128.1, 128.0, 127.7, 127.6, 127.5, 127.4, 127.3, 87.2, 86.6, 81.8, 80.0,
78.9, 77.9, 76.9, 75.2, 75.0, 74.8, 73.2, 68.5, 61.2, 58.7, 25.5, 25.0,
17.9, Ϫ4.8, Ϫ5.2 ppm. IR (neat): ν˜ ϭ 3450, 2100 cmϪ1. MS (CI,
NH3): m/z ϭ 754 [M ϩ 18]. HRMS-DCI/NH3: [M ϩ NH4]ϩ calcu-
lated for C45H60O7NSi: 754.4139; found 754.4147.
(1S,4R)-1-(2,3,4,6-Tetra-O-benzyl-D-gluco-β-C-pyranosyl)-4-O-tert-
(butyldimethylsilyl)pent-2-yne-1,4-diol (12b): [α]2D0 ϭ ϩ28 (c ϭ 0.9,
The hydroxy alkylation of aldehyde 4 (525 mg, 1.3 mmol) in the
presence of (R)-3-(tert-butyldimethylsilyloxy)but-1-yne 10b (1.07 g,
1
CHCl3). H NMR (250 MHz, CDCl3): δ ϭ 7.35Ϫ7.18 (m, 20 H),
Eur. J. Org. Chem. 2003, 2947Ϫ2958
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2953

ˆ
V. Michelet, K. Adiey, S. Tanier, G. Dujardin, J.-P. Genet
FULL PAPER
5.72 mmol) afforded the diastereomers (R,R)-13 (80 mg, colorless The hydroxy alkylation of aldehyde 7 (318 mg, 1.04 mmol) in the
oil) and (S,R)-13 (343 mg, colorless oil), together with unchanged
aldehyde 4 (150 mg, 28%). dr 88:12, Yield 52%.
presence of (R)-3-(tert-butyldimethylsilyloxy)but-1-yne (10b)
(843 mg, 4.57 mmol) afforded the diastereomers (R,R)-15 (188 mg,
colorless oil) and (S,R)-15 (49 mg, colorless oil), together with un-
changed aldehyde 7 (37 mg). dr 80:20, Yield 50%.
(1R,4R)-1-[2,3-Di-O-benzyl-4,6-dideoxy-6-(methoxycarbonyl)-D-
gluco-β-C-pyranosyl]-4-O-(tert-butyldimethylsilyl)pent-2-yne-1,4-
1
diol [(R,R)-13]: [α]2D0 ϭ ϩ5 (c ϭ 1.1, CHCl3). H NMR (250 MHz,
(1R,4R)-1-[6-O-Benzyl-3-O-tert-butyl-2,4-dideoxy-D-gluco-β-C-py-
CDCl3): δ ϭ 7.39Ϫ7.28 (m, 10 H), 5.03, 4.62:4.70, 4.65 (2 AB sys-
tem, J ϭ 10.7, 11.6 Hz, 4 H), 4.56Ϫ4.53 (m, 2 H), 3.90Ϫ3.70 (m,
2 H), 3.68 (s, 3 H), 3.56 (app. t, J ϭ 9.3 Hz, 1 H), 3.20 (dd, J ϭ
2.8, 9.3 Hz, 1 H), 2.66, 2.46 (2dd, J ϭ 15.8, 7.3 Hz and 15.8, 5.8 Hz,
2 H), 2.26 (dd, J ϭ 12.7, 5.1 Hz, 1 H), 1.75 (broad s, 1 H),
1.45Ϫ1.39 (m, 1 H), 1.40 (d, J ϭ 6.5 Hz, 3 H), 0.90 (s, 9 H), 0.15,
0.14 (2s, 6 H) ppm. 13C NMR (63 MHz, CDCl3): δ ϭ 171.9, 138.2,
138.1, 128.3, 128.1, 127.9, 127.5, 88.8, 82.0, 80.5, 80.0, 78.4, 72.1,
75.2, 71.3, 61.8, 58.9, 51.7, 40.2, 36.3, 25.7, 25.3, 18.1, Ϫ4.6, Ϫ5.0
ppm. MS (CI, NH3): m/z ϭ 583 [M ϩ 1], 600 [M ϩ 18]. HRMS-
DCI/NH3: [M ϩ NH4]ϩ calculated for C33H50NO7Si: 600.3357;
found 600.3361.
ranosyl]-4-O-(tert-butyldimethylsilyl)pent-2-yne-1,4-diol [(R,R)-15]:
[α]2D0 ϭ ϩ31 (c ϭ 1, CHCl3). 1H NMR (250 MHz, CDCl3): δ ϭ
7.34Ϫ7.27 (m, 5 H), 4.56 (AB system, J ϭ 12.1 Hz, 2 H), 4.53Ϫ4.47
(m, 2 H), 3.67Ϫ3.46 (m, 4 H), 3.42 (dd, J ϭ 10, 4.3 Hz, 1 H), 2.37
(d, J ϭ 5.9 Hz, 1 H), 1.90Ϫ1.76 (m, 2 H), 1.60Ϫ1.25 (m, 2 H), 1.39
(d, J ϭ 6.5 Hz, 3 H), 1.23 (s, 9 H), 0.89 (s, 9 H), 0.11, 0.10 (2s, 6
H) ppm. 13C NMR (63 MHz, CDCl3): δ ϭ 138.2, 128.5, 127.8,
127.7, 88.7, 80.6, 78.1, 75.7, 73.8, 73.5, 73.3, 67.3, 64.9, 59.0, 37.6,
34.8, 28.6, 25.9, 25.4, 18.3, Ϫ4.39, Ϫ4.83 ppm. IR (neat): ν˜ ϭ 3450,
2100 cmϪ1. MS (CI, NH3): m/z ϭ 508 [M ϩ 18]. HRMS-DCI/
NH3: [M ϩ NH4]ϩ calculated for C28H50NO5Si: 508.3458; found
508.3447.
(1S,4R)-1-[2,3-Di-O-benzyl-4,6-dideoxy-6-(methoxycarbonyl)-D-
(1S,4R)-1-[6-O-Benzyl-3-O-tert-butyl-2,4-dideoxy-D-gluco-β-C-py-
gluco-β-C-pyranosyl]-4-O-(tert-butyldimethylsilyl)pent-2-yne-1,4-
ranosyl]-4-O-(tert-butyldimethylsilyl)pent-2-yne-1,4-diol [(S,R)-15]:
[α]2D0 ϭ ϩ12 (c ϭ 1, CHCl3). 1H NMR (250 MHz, CDCl3): δ ϭ
7.35Ϫ7.26 (m, 5 H), 4.55 (s, 2 H), 4.54 (dq, J ϭ 6.5, 1.4 Hz, 1 H),
4.28 (dd, J ϭ 7.7 Hz, 1.4 Hz, 1 H), 3.71Ϫ3.40 (m, 4 H), 3.37 (ddd,
J ϭ 11.6, 7.7, 1.8 Hz), 2.8 (broad s, 1 H), 2.01 (m, 1 H), 1.81 (m,
1 H), 1.40 (d, J ϭ 6.5 Hz, 3 H), 1.33Ϫ1.15 (m, 2 H), 1.20 (s, 9 H),
0.89 (s, 9 H), 0.11, 0.10 (2s, 6 H) ppm. 13C NMR (63 MHz, CDCl3):
δ ϭ 138.2, 128.5, 127.7, 88.9, 80.3, 78.9, 75.5, 73.9, 73.5, 73.1, 65.9,
59.0, 37.5, 36.7, 28.6, 25.9, 25.3, 18.3, Ϫ4.43, Ϫ4.86 ppm. IR (neat):
ν˜ ϭ 3470, 2110 cmϪ1. MS (CI, NH3): m/z ϭ 508 [M ϩ 18]. HRMS-
DCI/NH3: [M ϩ NH4]ϩ calculated for C28H50NO5Si: 508.3458;
found 508.3448.
1
diol [(S,R)-13]: [α]2D0 ϭ Ϫ20 (c ϭ 1, CHCl3). H NMR (400 MHz,
CDCl3): δ ϭ 7.38Ϫ7.26 (m, 10 H), 4.88, 4.59/4.71, 4.62 (2 AB sys-
tem, J ϭ 10.8, 11.5 Hz, 4 H), 4.60Ϫ4.53 (m, 2 H), 3.90Ϫ3.80 (m,
2 H), 3.68 (s, 3 H), 3.51 (app. t, J ϭ 9.5 Hz, 1 H), 3.41 (dd, J. ϭ
9.5, 3.2 Hz, 1 H), 2.63, 2.41 (2dd, J ϭ 15.8, 7.0 Hz and 15.8, 5.9 Hz,
2 H), 2.28 (dd, J ϭ 11.8, 4.8 Hz, 1 H), 1.65Ϫ1.63 (m, 1 H), 1.44
(d, J ϭ 6.4 Hz, 3 H), 0.92 (s, 9 H), 0.14, 0.13 (2s, 6 H) ppm. 13C
NMR (63 MHz, CDCl3): δ ϭ 170.9, 138.2, 138.1, 128.3, 128.1,
127.9, 127.5, 88.9, 88.8, 80.4, 80.2, 79.8, 75.1, 72.1, 71.4, 62.6, 58.9,
51.7, 40.0, 36.3, 25.7, 25.3, 18.1, Ϫ4.5; Ϫ4.9 ppm. MS (CI, NH3):
m/z ϭ 600 [M ϩ 18].
The hydroxy alkylation of aldehyde 6 (259 mg, 0.56 mmol) in the
presence of (R)-3-(tert-butyldimethylsilyloxy)but-1-yne (10b)
(469 mg, 2.46 mmol) afforded the diastereomers (R,R)-14 (171 mg,
colorless oil) and (S,R)-14 (96 mg, colorless oil). dr 65:35, Yield
73%.
(1R,4R)-1-O-Allyloxycarbonyl-1-(2,3,4,6-tetra-O-benzyl-D-
gluco-β؊C-pyranosyl)-4-O-(tert-butyldimethylsilyl)pent-2-yne-1,4-
diol: Allyloxycarbonyl chloride (52 µL, 0.49 mmol) was slowly ad-
ded at 0 °C to a CH2Cl2 (4.5 mL) solution of alcohol 11b (300 mg,
0.41 mmol) and pyridine (66 µL, 0.81 mmol). The solution was
stirred at 0 °C for 1 h and for 1 h at room temp. After completion,
the reaction mixture was washed with 5% aqueous HCl and brine
to pH ϭ 7. The organic phase was dried with MgSO4, filtered,
and concentrated under reduced pressure. Column chromatography
(SiO2, cyclohexane/EtOAc, 9:1) afforded the diprotected derivative
as a colorless oil (318 mg, 95%).[α]2D0 ϭ ϩ3 (c ϭ 1, CHCl3). 1H
NMR (250 MHz, CDCl3): δ ϭ 7.33Ϫ7.19 (m, 20 H), 5.92 (ddt, J ϭ
16.2, 10.5, 5.7 Hz, 1 H), 5.68 (t, J ϭ 1.8 Hz, 1 H), 5.38 (dq, J ϭ
16.2, 1.3 Hz, 1 H), 5.27 (dq, J ϭ 10.5, 1.3 Hz, 1 H), 4.93Ϫ4.54 (m,
10 H), 4.51 (qd, J ϭ 6.5, 1.6 Hz, 1 H), 3.77Ϫ3.45 (m, 7 H), 1.36
(d, J ϭ 6.5 Hz, 3 H), 0.86 (s, 9 H), 0.08Ϫ0.07 (2s, 6 H) ppm. 13C
NMR (63 MHz, CDCl3): δ ϭ 153.9, 138.2, 138.1, 137.8, 137.4,
131.1, 128.2, 128.0, 127.7, 127.6, 127.5, 127.3, 127.2, 127.1, 118.8,
89.2, 77.4, 86.8, 79.6, 78.8, 77.9, 77.2, 75.2, 74.9, 74.7, 73.2, 68.5,
68.4, 66.1, 58.7, 25.5, 24.8, 17.9, Ϫ4.82, Ϫ5.27 ppm. IR (neat): ν˜ ϭ
2225, 1750 cmϪ1. MS (CI, NH3): m/z ϭ 838 [M ϩ 18]. HRMS-
DCI/NH3: [M ϩ NH4]ϩ calculated for C49H64NO9Si: 838.4350;
found 838.4338.
(1R,4R)-1-[2,3-Di-O-benzyl-6-(benzyloxymethyl)-4,6-dideoxy-D-
gluco-β-C-pyranosyl]-4-O-(tert-butyldimethylsilyl)pent-2-yne-1,4-
diol [(R,R)-14]: [α]2D0 ϭ ϩ25 (c ϭ 1, CHCl3). H NMR (250 MHz,
1
CDCl3): δ ϭ 7.34Ϫ7.36 (m, 15 H), 5.03Ϫ4.49 (m, 8 H), 3.72Ϫ3.27
(m, 6 H), 2.60 (d, J ϭ 10.7 Hz, 1 H), 2.2Ϫ2.1 (m, 1 H), 1.95Ϫ1.75
(m, 2 H), 1.38 (d, J ϭ 6.5 Hz, 3 H), 1.25Ϫ1.35 (m, 1 H), 0.88 (s, 9
H), 0.11, 0.10 (2s, 6 H) ppm. 13C NMR (63 MHz, CDCl3): δ ϭ
138.2, 138.1, 137.9, 128.2, 128.1, 127.6, 127.5, 127.3, 87.1, 82.1,
80.6, 79.7, 78.6, 72.5, 75.0, 72.8, 71.0, 66.4, 61.8, 58.7, 36.5, 35.4,
25.5, 17.9, Ϫ4.7, Ϫ5.2 ppm. IR (neat): ν˜ ϭ 3450, 2100 cmϪ1. MS
(CI, NH3): m/z ϭ 645 [M ϩ 1], 662 [M ϩ 18]. HRMS-DCI/NH3:
[M ϩ H]ϩ calculated for C39H53O6Si: 645.3611; found 645.3609,
[M
ϩ
NH4]ϩ calculated for C39H56O6NSi: 662.3877; found
662.3871.
(1S,4R)-1-[2,3-Di-O-benzyl-6-(benzyloxymethyl)-4,6-dideoxy-D-
gluco-β-C-pyranosyl]-4-O-(tert-butyldimethylsilyl)pent-2-yne-1,4-
1
diol [(S,R)-14]: [α]2D0 ϭ ϩ10 (c ϭ 1, CHCl3). H NMR (200 MHz,
CDCl3): δ ϭ 7.33Ϫ7.27 (m, 15 H), 4.98Ϫ4.50 (m, 8 H), 3.58Ϫ3.43
(m, 6 H), 2.60 (d, J ϭ 10.8 Hz, 1 H), 2.2Ϫ2.1 (m, 1 H), 1.95Ϫ1.8
(1R,4R)-1-O-Allyloxycarbonyl-1-(2,3,4,6-tetra-O-benzyl-D-gluco-β-
(m, 2 H), 1.40 (d, J ϭ 6.5 Hz, 3 H), 1.20Ϫ1.30 (m, 1 H), 0.9 (s, 9 C-pyranosyl)pent-2-yne-1,4-diol: Tetrabutylammonium fluoride
H), 0.13, 0.12 (2s, 6 H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ (215 µL, 1 mol·LϪ1 in THF) was slowly added at 0 °C to a solution
138.1, 137.9, 128.5, 128.1, 127.5, 127.3, 87.3, 82.0, 80.6, 79.5, 78.9,
75.0, 72.8, 72.7, 71.3, 66.7, 61.4, 58.7, 36.5, 35.4, 25.3, 25.3, 17.8,
of the O-silyl compound (192 mg, 0.19 mmol) in THF (2 mL). The
solution was stirred at 0 °C for 1 h and at room temp. for 1 h, and
Ϫ4.6, Ϫ5.2 ppm. IR (neat): ν˜ ϭ 3445, 2100 cmϪ1. MS (CI, NH3): was then treated with water after completion. The aqueous phase
m/z ϭ 645 [M ϩ 1], 662 [M ϩ 18].
was extracted with diethyl ether. The organic phase was washed
2954
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 2947Ϫ2958

Stereoselective Ethynylation of β-C-Glycoside Aldehydes
FULL PAPER
with aqueous NaCl, dried over Na2SO4, filtered, and concentrated
under reduced pressure. Column chromatography (SiO2, cyclohex-
was evaporated under reduced pressure. Column chromatography
(SiO2, cyclohexane/EtOAc, 8:2) afforded the alkene as a colorless
ane/EtOAc, 7:3) afforded the alcohol as a colorless oil (132 mg, oil (55 mg, 70%). [α]2D0 ϭ ϩ5 (c ϭ 0.7, CHCl3). 1H NMR
92%).[α]2D0 ϭ ϩ6 (c ϭ 1, CHCl3). 1H NMR (250 MHz, CDCl3): (250 MHz, CDCl3): δ ϭ 7.35Ϫ7.16 (m, 20 H), 5.95 (app. dd, J ϭ
δ ϭ 7.38Ϫ7.15 (m, 20 H), 5.92 (ddt, J ϭ 16.1, 10.3, 5.8 Hz, 1 H),
5.62 (dd, J ϭ 2.3, 1.4 Hz, 1 H), 5.37 (dq, J ϭ 16.1, 1.3 Hz, 1 H), (2q, J ϭ 7.1 Hz, 2 H), 3.86 (app. t, J ϭ 9.3 Hz, 1 H), 3.77Ϫ3.66
5.26 (dq, J ϭ 10.3, 1.3 Hz, 1 H), 4.93Ϫ4.45 (m, 11 H), 3.74Ϫ3.49 (m, 3 H), 3.63Ϫ3.43 (m, 2 H), 3.18 (dd, J ϭ 9.3, 16 Hz, 1 H), 3.05
10, 8.7 Hz, 1 H), 5.51Ϫ5.46 (m, 2 H), 4.95Ϫ4.46 (m, 9 H), 4.17
(m, 7 H), 1.86 (d, J ϭ 5.2 Hz, 1 H), 1.38 (d, J ϭ 6.5 Hz, 3 H) ppm. (broad s, 1 H), 1.29 (t, J ϭ 7.1 Hz, 3 H), 1.27 (d, J ϭ 6.2 Hz, 3 H)
13C NMR (63 MHz, CDCl3): δ ϭ 153.9, 138.2, 138.0, 137.7, 137.4, ppm. 13C NMR (63 MHz, CDCl3): δ ϭ 154.8, 138.7, 138.3, 138.2,
131.0, 128.2, 128.1, 128.0, 127.7, 127.6, 127.4, 127.3, 119.0, 89.2,
86.8, 79.6, 78.8, 78.3, 78.1, 77.3, 75.3, 74.9, 74.8, 73.1, 68.6, 68.5,
66.1, 57.9, 23.5 ppm. IR (neat): ν˜ ϭ 3400, 2200, 1750 cmϪ1. MS
138.1, 132.5, 130.8, 128.6, 128.5, 128.4, 128.3, 128.1, 128.0, 127.8,
127.7, 127.6, 87.3, 81.0, 79.5, 78.5, 78.3, 75.6, 75.5, 75.1, 73.5, 70.6,
69.7, 64.8, 64.1, 20.6, 14.3 ppm. IR (neat): ν˜ ϭ 3450, 1735, 1641
(CI, NH3): m/z ϭ 724 [M ϩ 18]. HRMS-DCI/NH3: [M ϩ NH4]ϩ cmϪ1. MS (CI, NH3): m/z ϭ 714 [M ϩ 18].
calculated for C43H50NO9: 724.3486; found 724.3490.
Methyl
ranosyl)-6-hydroxy-2-(methoxycarbonyl)-3-methylhex-4-enoate (17):
C-pyranosyl)-4-O-(ethoxycarbonyl)pent-2-yne-1,4-diol: Ethyl chloro- Pd(OAc)2 (0.6 mg, 10% molar) and bis(diphenylphosphanyl)ethane
(3S,4E,6R)-6-(2,3,4,6-Tetra-O-benzyl-D-gluco-β-C-py-
(1R,4R)-1-O-Allyloxycarbonyl-1-(2,3,4,6-tetra-O-benzyl-D-gluco-β-
formate (20 µL, 0.21 mmol) was slowly added at 0 °C to a CH2Cl2
(2 mL) solution of alcohol (123 mg, 0.17 mmol) and pyridine (28
(1.7 mg, 1.5 equiv./Pd) were stirred in THF (0.1 mL) at 30 °C for
30 min. A THF (0.4 mL) solution of the alcohol (20 mg, 0.03
µL, 0.34 mmol). The solution was stirred at 0 °C for 1 h and at mmol) was added at room temp to this orange mixture. Dimethyl
room temp. for 1 h. After completion, the reaction mixture was
washed with 5% aqueous HCl and brine to pH ϭ 7. The organic
phase was dried with MgSO4, filtered, and concentrated under re-
duced pressure. Column chromatography (SiO2, cyclohexane/
malonate (5 µL, 0.04 mmol) was added to a THF (0.4 mL) suspen-
sion of NaH (2 mg, 0.04 mmol, 60% in oil). After 15 min at room
temp., the catalyst mixture was added to the anion of the dimethyl
malonate. After one hour the solution was treated with aqueous
NH4Cl. The aqueous phase was extracted with diethyl ether. The
EtOAc, 8:2) afforded the diprotected derivative as a colorless oil
(125 mg, 92%). [α]2D0 ϭ ϩ25 (c ϭ 1, CHCl3). H NMR (250 MHz, organic phase was dried with Na2SO4, filtered, and concentrated
CDCl3): δ ϭ 7.35Ϫ7.17 (m, 20 H), 5.92 (ddt, J ϭ 16.1, 10.3, 5.8 Hz, under reduced pressure. Column chromatography (SiO2, cyclohex-
1 H), 5.67 (dd, J ϭ 2, 1.3 Hz, 1 H), 5.41Ϫ5.24 (m, 3 H), 4.96Ϫ4.53 ane/EtOAc, 7:3) afforded 17 as a colorless oil (9 mg, 43%), while
1
(m, 10 H), 4.14 (q, J ϭ 7.3 Hz, 2 H), 3.75Ϫ3.47 (m, 7 H), 1.48 (d,
10 mg (50%) of starting material were recovered. [α]2D0 ϭ ϩ19 (c ϭ
J ϭ 6.5 Hz, 3 H), 1.26 (t, J ϭ 7.3 Hz, 3 H) ppm. 13C NMR
0.8, CHCl3). H NMR (250 MHz, CDCl3): δ ϭ 7.36Ϫ7.19 (m, 20
1
(63 MHz, CDCl3): δ ϭ 153.8, 138.2, 138.1, 137.7, 137.4, 131.0, H), 5.75Ϫ5.65 (m, 2 H), 4.94Ϫ4.49 (m, 8 H), 4.27 (d, J ϭ 3.7 Hz,
128.2, 128.0, 127.7, 127.6, 127.5, 127.4, 127.3, 127.2, 118.9, 86.8,
84.6, 80.0, 79.7, 78.6, 78.0, 77.3, 75.3, 74.9, 74.8, 73.2, 68.6, 68.4,
2 H), 3.73, 3.68 (2s, 6 H), 3.73Ϫ3.20 (m, 7 H), 3.31 (d, J ϭ 8.9 Hz,
1 H), 3.0 (m, 1 H), 2.0 (broad s, 1 H), 1.29 (d, J ϭ 6.7 Hz, 3 H)
ppm. 13C NMR (63 MHz, CDCl3): δ ϭ 168.7, 168.6, 138.6, 138.3,
138.2 (2C), 133.4, 131.3, 128.6, 128.5, 127.9, 127.8, 127.7, 87.1,
80.7, 79.1, 78.3 (2C), 75.6, 75.2, 75.1, 73.5, 70.1, 69.1, 57.7, 52.4,
52.3, 36.9, 18.1 ppm. IR (neat): ν˜ ϭ 3450, 1735, 1670 cmϪ1. MS
(CI, NH3): m/z ϭ 756 [M ϩ 18]. HRMS-DCI/NH3: [M ϩ NH4]ϩ
calculated for C44H54NO10: 756.3748; found 756.3746.
66.0, 63.9, 63.6, 20.8, 13.9 ppm. IR (neat): ν˜ ϭ 2219, 1735 cmϪ1
MS (CI, NH3): m/z ϭ 796 [M ϩ 18].
.
(1R,4R)-1-(2,3,4,6-Tetra-O-benzyl-D-gluco-β-C-pyranosyl)-4-O-
(ethoxycarbonyl)pent-2-yne-1,4-diol (16): A mixture of Pd(OAc)2
(6 mg) and TPPTS (112 mg) in water (0.4 mL) was added to a solu-
tion of the allyloxycarbonyl compound (125 mg, 0.16 mmol) and
diethylamine (36 µL, 0.35 mmol) in acetonitrile (2.4 mL). The re-
sulting mixture was vigorously stirred at room temperature until
completion of the reaction and was then evaporated under reduced
pressure. The resulting aqueous phase was extracted with ethyl
acetate, dried over Na2SO4, filtered, and concentrated under re-
duced pressure. Column chromatography (SiO2, cyclohexane/
Methyl (3S,4E,6R)-6-(2,3,4,6-Tetra-O-benzyl-D-gluco-β-C-pyran-
osyl)-6-(2,4-dichlorobenzoyloxy)-2-(methoxycarbonyl)-3-methylhex-
4-enoate: 2,4-Dichlorobenzoyl chloride (6 µL, 0.032 mmol) was
slowly added at 0 °C to a CH2Cl2 (2 mL) solution of alcohol 17
(20 mg, 0.027 mmol) and pyridine (4 µL, 0.054 mmol). The solu-
tion was stirred at 0 °C for 1 h and at room temp. for 1 h After
EtOAc, 7:3) afforded the alcohol 16 as a colorless oil (92 mg, 83%). completion, the reaction mixture was washed with 5% aqueous
[α]2D0 ϭ ϩ36 (c ϭ 1, CHCl3). 1H NMR (250 MHz, CDCl3): δ ϭ HCl and brine to pH ϭ 7. The organic phase was dried with
7.35Ϫ7.16 (m, 20 H), 5.35 (qd, J ϭ 6.7, 1.3 Hz, 1 H), 4.95Ϫ4.51
(m, 9 H), 4.21Ϫ4.13 (2q, J ϭ 7.3 Hz, 2 H), 3.76Ϫ3.37 (m, 7 H),
2.73 (d, J ϭ 10.9 Hz, 1 H), 1.51 (d, J ϭ 6.7 Hz, 3 H), 1.28 (t, J ϭ
MgSO4, filtered, and concentrated under reduced pressure. Column
chromatography (SiO2, cyclohexane/EtOAc, 8:2) afforded the ben-
zoyl derivative as a colorless oil (17 mg, 71%). [α]2D0 ϭ Ϫ9.5 (c ϭ
1
7.3 Hz, 3 H) ppm. 13C NMR (63 MHz, CDCl3): δ ϭ 153.9, 138.2, 0.9, CHCl3). H NMR (250 MHz, CDCl3): δ ϭ 7.79Ϫ7.13 (m, 23
137.9, 137.8, 137.5, 128.3, 128.2, 128.1, 127.7, 127.6, 127.5, 127.4,
127.3, 86.6, 84.3, 82.6, 79.7, 79.0, 78.0, 77.9, 75.2, 75.0, 74. 8, 73.1, 3.70, 3.55 (2s, 6 H), 3.30 (d, J ϭ 9.2 Hz, 1 H), 3.05 (m, 1 H), 1.06
68.5, 63.9, 63.8, 61.5, 21.1, 13.9 ppm. IR (neat): ν˜ ϭ 3450, 2200,
(d, J ϭ 6.7 Hz, 3 H) ppm. 13C NMR (63 MHz, CDCl3): δ ϭ 168.6,
H), 5.90Ϫ5.80 (m, 3 H), 4.94Ϫ4.47 (m, 8 H), 3.82Ϫ3.38 (m, 7 H),
1735 cmϪ1. MS (CI, NH3): m/z ϭ 712 [M ϩ 18]. HRMS-DCI/ 168.4, 163.6, 138.6, 138.5, 138.4, 138.2, 137.8, 137.7, 135.1, 132.7,
NH3: [M ϩ NH4]ϩ Calculated for C42H50NO9: 712.3486; found
712.3481.
131.1, 128.6, 128.5, 128.4, 128.3, 128.1, 128.0, 127.9, 127.8, 127.6,
127.2, 126.1, 87.3, 80.0, 79.7, 78.4, 77.6, 75.8, 75.4, 75.2, 73.6, 73.0,
68.8, 57.5, 52.5, 52.3, 37.1, 18.0 ppm. IR (neat): ν˜ ϭ 1735, 1670
cmϪ1. MS (CI, NH3): m/z ϭ 928 [M ϩ 18].
(1R,2Z,4R)-1-(2,3,4,6-Tetra-O-benzyl-D-gluco-β-C-pyranosyl)-4-O-
(ethoxycarbonyl)pent-2-ene-1,4-diol: Pyridine (3 µL, 5% weight) was
added to a solution of 16 (65 mg, 0.093 mmol) and Pd/C (7 mg,
Dimethyl (2S,3S)-2-Methyl-3-[(E)-2-(2,3,4,6-tetra-O-benzyl-D-gluco-
10% weight) in methanol (1.5 mL) and the reaction mixture was β-C-pyranosyl)ethenyl]cyclopropane-1,1-dicarboxylate (18): Pd-
stirred under hydrogen at room temp. After filtration through a
short plug of silica gel, with diethyl ether as eluent, the solvent
(OAc)2 (0.4 mg, 10% molar) and bis(diphenylphosphanyl)-
ethane, (1.1 mg, 1.5 equiv. Pd) were stirred in THF (0.1 mL) at 30
Eur. J. Org. Chem. 2003, 2947Ϫ2958
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2955

ˆ
V. Michelet, K. Adiey, S. Tanier, G. Dujardin, J.-P. Genet
FULL PAPER
°C for 30 min. To this orange mixture, containing the catalyst, was
added a THF (0.1 mL) solution of the benzoyl compound (15 mg,
contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge at www.ccdc.cam.ac.uk/
0.016 mmol) at room temp. DBU (4 µL, 0.023 mmol) was then conts/retrieving.html [or from the Cambridge Crystallographic
slowly added. After 1 h at room temp., the reaction mixture was
treated with aqueous NH4Cl. The aqueous phase was extracted
with diethyl ether. The organic phase was washed with brine, dried
with Na2SO4, and concentrated under reduced pressure. Column
chromatography (SiO2, cyclohexane/EtOAc, 8:2) afforded 18 as a
colorless oil (11.5 mg, 68%). [α]2D0 ϭ Ϫ42 (c ϭ 1.1, CHCl3). 1H
NMR (250 MHz, CDCl3): δ ϭ 7.36Ϫ7.15 (m, 20 H), 5.80 (dd, J ϭ
15.6, 7.1 Hz, 1 H), 5.51 (dd, J ϭ 15.6, 9.1 Hz, 1 H), 4.94Ϫ4.87 (m,
8 H), 3.75, 3.67 (2s, 6 H), 3.76Ϫ3.26 (m, 7 H), 2.40 (dd, J ϭ 9.1,
7.4 Hz, 1 H), 2.02 (m, 1 H), 1.10 (d, J ϭ 6.3 Hz, 3 H) ppm. 13C
NMR (63 MHz, CDCl3): δ ϭ 168.1, 138.7, 138.4, 138.3, 138.2,
130.9, 129.7, 128.6, 128.5, 128.4, 128.1, 128.0, 127.9, 127.8, 127.7,
127.6, 86.8, 82.5, 79.8, 78.8, 78.3, 75.7, 75.1, 75.0, 73.6, 69.1, 52.6,
41.8, 36.4, 27.6, 14.2 ppm. IR (neat): ν˜ ϭ 1740, 1672 cmϪ1. MS
(CI, NH3): m/z ϭ 738 [M ϩ 18]. HRMS-DCI/NH3: [M ϩ NH4]ϩ
calculated for C44H52NO9: 738.3642; found 738.3634.
Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; Fax:
(internat.) ϩ44-1223/336-033; E-mail: deposit@ccdc.cam.ac.uk].
(1R,4R)-1-[2,3-Di-O-benzyl-4,6-dideoxy-6-(methoxycarbonyl)-D-
gluco-β-C-pyranosyl]-4-O-tert-butyldimethylsilyl-1-O-(4-nitro-
benzoyl)pent-2-yne-1,4-diol: A THF solution of DEAD (0.3 mL, 0.5
mmol) and 4-nitrobenzoic acid (300 mg, 2.5 mmol) was slowly ad-
ded at 0 °C to a THF solution of triphenylphosphane (452 mg,
2.5 mmol) and alcohol (S,R)-13 (315 mg, 0.5 mmol). The resulting
mixture was stirred at 0 °C for 1 hand and was then warmed to
room temp. The solution was hydrolyzed with aqueous HCl (1 ).
The organic phase was washed with saturated aqueous Na2CO3
and brine, dried over Na2SO4, filtered, and concentrated under re-
duced pressure. Column chromatography (SiO2, cyclohexane/
EtOAc, 9:1) afforded the ester as a colorless oil (317 mg, 90%).
[α]2D0 ϭ ϩ33 (c ϭ 1, CHCl3). 1H NMR (200 MHz, CDCl3): δ ϭ
8.20, 8.08 (2d, J ϭ 8.8 Hz, 4 H), 7.37Ϫ7.22 (m, 10 H), 5.09 (app.
t, J ϭ 1.7 Hz, 1 H), 4.92, 4.54/4.73, 4.56 (2 AB system, J ϭ 10.4,
11.3 Hz, 4 H), 4.20 (qd, J ϭ 6.4, 1.7 Hz, 1 H), 3.95Ϫ3.76 (m, 2 H),
3.69 (s, 3 H),3.57Ϫ3.52 (m, 2 H), 2.73, 2.49 (2 dd, J ϭ 6.1, 7.0,
15.7 Hz, 2 H), 2.34 (dd, J ϭ 12.7, 1.7 Hz, 1 H), 1.65Ϫ1.50 (m, 1
H), 1.39 (d, J ϭ 6.5 Hz, 3 H), 0.88 (s, 9 H), 0.12, 0.11 (2s, 6 H)
ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 171.0, 163.3, 150.6, 138.1,
138.0, 135.1, 131.1, 128.3, 128.0, 127.8, 127.5, 123.5, 89.1, 80.7,
79.1, 78.2, 77.5, 75.0, 72.4, 71.6, 64.3, 60.0, 51.8, 40.2, 36.3, 26.9,
(1R,4R)-1-O-Allyloxycarbonyl-1-[2,3-di-O-benzyl-4,6-dideoxy-6-
(methoxycarbonyl)-D-gluco-β-C-pyranosyl]pent-2-yne-1,4-diol (19):
The protection of (R,R)-13 under the same conditions as used for
11b with allyloxycarbonyl chloride followed by the silyl deprotec-
tion afforded the alcohol 19 in 85% overall yield. [α]2D0 ϭ ϩ1.8 (c ϭ
1, CHCl3). 1H NMR (400 MHz, CDCl3): δ ϭ 7.34Ϫ7.26 (m, 10
H), 5.97Ϫ5.85 (m, 1 H), 5.61 (app. t, J ϭ 1.7 Hz, 1 H), 5.36 (dq,
J ϭ 1.3, 17.2 Hz, 1 H), 5.25 (dq, J ϭ 1.3, 9.2 Hz, 1 H), 4.90, 4.49/
4.69, 4.60 (2 AB system, J ϭ 10.2, 11.5 Hz, 4 H), 4.63Ϫ4.61 (m, 2
H), 4.50 (q, J ϭ 6.6 Hz, 1 H), 3.90Ϫ3.80 (m, 1 H), 3.76Ϫ3.73 (m,
1 H), 3.68(s, 3 H), 3.51 (app. t, J ϭ 9.6 Hz, 1 H), 3.45 (dd, J ϭ
9.6, 2.0 Hz, 1 H), 2.69, 2.43 (2dd, J ϭ 7.5, 5.9, 16.2 Hz, 2 H), 2.21
(ddd, J ϭ 1.8, 5.0, 12.7 Hz, 1 H), 1.46 (m, 1 H), 1.41 (d, J ϭ 6.6 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 171.6, 154.2, 138.3,
138.0, 131.3, 128.5, 128.4, 127.9, 127.8, 127.7, 119.3, 89.1, 81.3,
80.2, 78.8, 77.4, 75.5, 72.8, 71.8, 69.3, 66.4, 58.4, 51.9, 39.8, 36.3,
23.8 ppm. IR (neat): ν˜ ϭ 3448, 2200, 1740 cmϪ1. MS (CI, NH3):
m/z ϭ 570 [M ϩ 18]. HRMS-DCI/NH3: [M ϩ NH4]ϩ calculated
for C31H40NO9: 570.2703; found 570.2694.
26.8, 24.9, 19.2, Ϫ4.6, Ϫ5.0 ppm. IR (neat): ν˜ ϭ 2200, 1740 cmϪ1
MS (CI, NH3): m/z ϭ 749 [M ϩ 18].
.
(1R,4R)-1-[2,3-Di-O-benzyl-4,6-dideoxy-6-(methoxycarbonyl)-D-
gluco-β-C-pyranosyl]-1-O-(4-nitrobenzoyl)pent-2-yne-1,4-diol: The
alcohol derivative (227 mg, 85%) was obtained from the diester
(317 mg, 0.18 mmol) by the classic procedure for the removal of
silyl groups with tetrabutylammonium fluoride (80 µL, 1 mol·LϪ1
in THF). [α]2D0 ϭ ϩ1.5 (c ϭ 1, CHCl3). 1H NMR (200 MHz,
CDCl3): δ ϭ 8.30, 8.14 (2d, J ϭ 8.8 Hz, 4 H),7.36Ϫ7.16 (m, 10 H),
5.92 (app. t, J ϭ 1.7 Hz, 1 H), 4.9, 4.51/4.74, 4.64 (2 AB system,
J ϭ 10.5, 11.3 Hz, 4 H), 4.52 (qd, J ϭ 6.5, 1.6 Hz, 1 H), 3.96Ϫ3.76
(m, 2 H), 3.69 (s, 3 H), 3.64Ϫ3.47 (m, 2 H), 2.76, 2.55 (2dd, J ϭ
6.1, 7.0, 15.8 Hz, 2 H), 2.33 (dd, J ϭ 12.6, 1.7 Hz, 1 H), 1.60Ϫ1.55
(m, 1 H), 1.44 (d, J ϭ 6.4 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ ϭ 171.5, 163.4, 150.7, 137.9, 137.7, 134.8, 131.1, 128.6,
128.5, 128.3, 128.1, 127.9, 123.5, 88.9, 81.5, 80.1, 78.7, 77.2, 75.3,
72.8, 72.0, 64.3, 58.4, 52.3, 40.3, 36.7, 24.2 ppm. IR (neat): ν˜ ϭ
3400, 2200, 1740 cmϪ1. MS (CI, NH3): m/z ϭ 635 [M ϩ 18].
X-ray Crystal Structure Determination of 19: C31H36O9; Mr
ϭ
552.6, orthorhombic, P212121, a ϭ 10.408(5), b ϭ 11.796(10), c ϭ
24.554(9) A, V ϭ 3015(3) AϪ3, Z ϭ 4, Dx ϭ 1.22 Mg·mϪ3, λ(Mo-
Kα) ϭ 0.71069A, µ ϭ 0.83 cmϪ1, F(000) ϭ 800, T ϭ 223 K. The
˚
intensity data were collected with a Nonius CAD-4 automatic dif-
fractometer with use of graphite-monochromated Mo-Kα radi-
ation.[33] The cell parameters were obtained by fitting a set of 25-
high theta reflections. The data collection (2θmax ϭ 54°, scan ω/
(1R,4R)-1-[2,3-Di-O-benzyl-4,6-dideoxy-6-(methoxycarbonyl)-D-
2θ ϭ 1, tmax ϭ 60s, range hkl: h 0.12 k 0.14 l 0.29, intensity controls gluco-β-C-pyranosyl]-4-O-(ethoxycarbonyl)-1-O-(4-nitrobenzoyl)-
without appreciable decay (0.25%)] gave 2454 reflections, of which
pent-2-yne-1,4-diol (20): Compound 20 (229 mg, 90%) was obtained
1641 were independent with I Ͼ 2σ(I). After Lorenz and polariz-
by the classic procedure for the protection of the alcohol (228 mg,
ation corrections,[34] the structure was solved with SIR-97,[35] which 0.36 mmol) with ethyl chloroformate (0.1 mL) and pyridine (93 µL,
1
revealed the non-hydrogen atoms in the structure and the water 0.72 mmol). [α]2D0 ϭ ϩ29.7 (c ϭ 1, CHCl3). H NMR (400 MHz,
molecule. After anisotropic refinement, all the hydrogen atoms of
CDCl3): δ ϭ 8.14, 8.04 (2d, J ϭ 8.9 Hz, 4 H), 7.27Ϫ7.17 (m, 10
the structure were found by Fourier difference. The whole structure H), 5.90 (app. t, J ϭ 1.6 Hz, 1 H), 5.39 (q, J ϭ 6.6 Hz, 1 H), 4.83,
was refined with the aid of SHELXL-97[36] by full-matrix, least-
square techniques (use of F-square magnitude: x, y, z, βij for C and
O atoms, x, y, z for H atoms; 363 variables and 3019 observations
4.44 (2 AB system, J ϭ 10.5, 11.3 Hz, 4 H), 4.09 (q, J ϭ 7.1 Hz, 2
H),3.99Ϫ3.94 (m, 1 H), 3.78Ϫ3.75 (m, 2 H), 3.63 (s, 3 H), 3.58 (dd,
J ϭ 1.8, 9.5 Hz, 1 H), 2.68, 2.47 (2dd, J ϭ 6.7, 6.1, 15.5 Hz, 2 H),
2.27 (dd, J ϭ 3.3, 12.8 Hz, 1 H), 1.65Ϫ1.55 (m, 1 H), 1.39 (d, J ϭ
[1641 with I Ͼ 2σ(I)]; calcd. w ϭ 1/(σ2(F2o) ϩ (0.0528P)2
ϩ
0.0755P) where P ϭ (F2o Ϫ 2Fc2)/3 with the resulting R ϭ 0.042 and 6.7 Hz, 3 H), 1.2 (t, J ϭ 7.1 Hz, 3 H) ppm. 13C NMR (100 MHz,
SW ϭ 1.001 (residual ∆ρ Յ 0.166 eAϪ3). Atomic scattering factors
CDCl3): δ ϭ 170.9, 163.3, 154.1, 150.7, 138.1, 137.9, 134.8, 131.1,
from International tables for X-ray Crystallography (1992). OR-
128.9, 128.8, 128.7, 128.2, 123.8, 88.9, 81.3, 79.6, 78.7, 77.6, 75.3,
TEP view produced with PLATON-98.[37] All the calculations were 72.9, 71.9, 64.6, 64.4, 64.2, 52.2, 40.6, 36.6, 21.5, 14.5 ppm. IR
performed with a Silicon Graphic Indy computer. CCDC-112890
(neat): ν˜ ϭ 2220, 1735 cmϪ1. MS (CI, NH3): m/z ϭ 707 [M ϩ
2956
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2947Ϫ2958

Stereoselective Ethynylation of β-C-Glycoside Aldehydes
FULL PAPER
18]. HRMS-DCI/NH3: [M ϩ NH4]ϩ calculated for C37H43N2O12:
707.2816; found 707.2829.
tive (86 mg, 80%) was obtained from the alcohol 22 (93 mg, 0.16
mmol), by treatment with pyridine (26 µL, 0.3 mmol) and 2,4-di-
chlorobenzoyl chloride (55 µL, 0.03 mmol) by the same procedure
as used for the activation of 17. [α]2D0 ϭ ϩ3.8 (c ϭ 0.5, CHCl3). 1H
NMR (400 MHz, CDCl3): δ ϭ 7.80 (d, J ϭ 8.4 Hz, 1 H), 7.46 (d,
J ϭ 1.9 Hz, 1 H), 7.36Ϫ7.26 (m, 11 H), 5.87Ϫ5.69 (m, 3 H), 4.88,
4.49/4.79, 4.61 (2 AB system, J ϭ 10.1, 11.6 Hz, 4 H), 3.83Ϫ3.73
(m, 2 H), 3.70 (s, 3 H), 3.67, 3.68 (2s, 6 H), 3.47 (app. t, J ϭ 9.3 Hz,
1 H), 3.35 (dd, J ϭ 1.6, 9.3 Hz, 1 H), 3.29 (d, J ϭ 9.1 Hz, 1 H),
3.01Ϫ2.90 (m, 1 H), 2.68, 2.47 (2 dd, J ϭ 6.7, 6.1, 15.4 Hz, 2 H),
2.26 (dd, J ϭ 1.7, 12.3 Hz, 1 H), 1.43 (m, 1 H), 1.07 (d, J ϭ 6.7 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 171.2, 168.6, 168.3,
163.6, 138.5, 138.4, 138.2, 138.0, 136.2, 131.6, 129.9, 127.5, 127.4,
126.8, 126.7, 126.1, 126.0, 125.0, 79.6, 79.0, 76.4, 74.2, 72.0, 71.3,
70.4, 56.3, 51.3, 51.2, 50.7, 39.3, 35.9, 35.3, 16.3 ppm. IR (neat):
ν˜ ϭ 1735, 1665 cmϪ1. MS (CI, NH3): m/z ϭ 774 [M ϩ 18].
(1R,4R)-1-[2,3-Di-O-benzyl-4,6-dideoxy-6-(methoxycarbonyl)-D-
gluco-β-C-pyranosyl]-4-O-(ethoxycarbonyl)pent-2-yne-1,4-diol:
K2CO3 (2 mol %) was added at room temp. to a methanol solution
(1.5 mL) of alkyne 20 (220 mg, 0.3 mmol). The resulting mixture
was stirred for 15 min, filtered, and then evaporated under reduced
pressure. Column chromatography (SiO2, cyclohexane/EtOAc, 8:2)
afforded the alcohol as a colorless oil (153 mg, 70%). [α]2D0 ϭ ϩ39
1
(c ϭ 1, CHCl3). H NMR (400 MHz, CDCl3): δ ϭ 7.34Ϫ7.26 (m,
10 H), 5.36 (qd, J ϭ 1.9, 6.5 Hz, 1 H), 5.01, 4.61/4.70, 4.61 (2 AB
system, J ϭ 10.7, 11.5 Hz, 4 H), 4.21Ϫ4.15 (m, 3 H), 3.94Ϫ3.88
(m, 1 H), 3.76Ϫ3.64 (m, 2 H), 3.70 (s, 3 H), 3.34 (dd, J ϭ 1.7,
9.2 Hz, 1 H), 2.77 (broad s, 1 H), 2.66, 2.46 (2 dd, J ϭ 7.4, 5.8,
15.5 Hz, 2 H), 2.26 (ddd, J ϭ 1.6, 4.9, 12.8 Hz, 1 H), 1.53 (d, J ϭ
6.5 Hz, 3 H), 1.42Ϫ1.36 (m, 1 H), 1.24 (t, J ϭ 7.1 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ ϭ 171.0, 154.2, 138.3, 138.2,
128.6, 128.5, 128.2, 127.9, 127.8, 127.7, 84.7, 82.8, 80.5, 80.1, 78.6,
78.5, 72.4, 71.4, 64.3, 64.1, 62.0, 51.8, 43.5, 40.4, 21.5, 14.3 ppm.
IR (neat): ν˜ ϭ 3450, 2220, 1735 cmϪ1. MS (CI, NH3): m/z ϭ 558
Dimethyl (2S,3S)-2-Methyl-3-[(E)-2-(2,3-di-O-benzyl-4,6-dideoxy-6-
(methoxycarbonyl)-D-gluco-β-C-pyranosyl)ethenyl]cyclopropane-
1,1-dicarboxylate (2): Cyclopropane 2 (46 mg, 81%) was obtained
from the benzoyl derivative (86 mg, 0.1 mmol), by treatment with
Pd(OAc)2 (2.2 mg, 10% molar), bis(diphenylphosphanyl)ethane
(5.9 mg, 1.5 equiv. Pd), and DBU (30 µL, 0.2 mmol) by the same
procedure as used for the synthesis of 18. [α]2D0 ϭ Ϫ9.6 (c ϭ 1,
[M
C30H40NO9: 558.2703; found 558.2697.
ϩ 18]. HRMS-DCI/NH3: [M ϩ
NH4]ϩ calculated for
(1R,4R)-1-[2,3-Di-O-benzyl-4,6-dideoxy-6-(methoxycarbonyl)-D-
1
CHCl3). H NMR (400 MHz, CDCl3): δ ϭ 7.35Ϫ7.26 (m, 10 H),
gluco-β-C-pyranosyl]-4-O-(ethoxycarbonyl)pent-2-ene-1,4-diol (21):
Alkene 21 (105 mg) was obtained from the alkyne (150 mg, 0.27
mmol) and Pd/C (15 mg, 10% weight) by the same procedure as
used for the semi-hydrogenation of 16. [α]2D0 ϭ ϩ11 (c ϭ 1, CHCl3).
1H NMR (200 MHz, CDCl3): δ ϭ 7.38Ϫ7.26 (m, 10 H), 5.89Ϫ544
(m, 3 H), 5.03Ϫ4.59 (m, 5 H), 4.18 (q, J ϭ 7.1 Hz, 2 H), 3.85Ϫ3.62
(m, 6 H), 3.13 (dd, J ϭ 1.7, 9.2 Hz, 1 H), 2.66, 2.46 (2 dd, J ϭ 7.4,
5.8, 15.5 Hz, 2 H), 2.26 (ddd, J ϭ 1.6, 4.9, 12.6 Hz, 1 H), 1.53(d,
J ϭ 6.5 Hz, 3 H), 1.42Ϫ1.36 (m, 1 H), 1.24 (t, J ϭ 7.1 Hz, 3 H)
ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 171.2, 154.6, 138.4, 132.4,
130.5, 128.3, 128.1, 127.5, 127.4, 80.6, 80.5, 79.9, 72.4, 78.1, 72.2,
72.0, 66.0, 63.9, 51.6, 43.3, 40.2, 20.7, 14.1 ppm. IR (neat): ν˜ ϭ
3450, 1735, 1670 cmϪ1. MS (CI, NH3): m/z ϭ 560 [M ϩ 18].
5.76 (dd, J ϭ 6.5, 15.4 Hz, 1 H), 5.42 (ddd, J ϭ 0.7, 7.6, 15.4 Hz,
1 H), 4.84, 4.61/4.68, 4.63 (2 AB system, J ϭ 10.8, 11.5 Hz, 4 H),
3.80 (m, 1 H), 3.74 (S, 3 H), 3.66 (s, 6 H), 3.64Ϫ3.57 (m, 2 H), 3.14
(app. t, J ϭ 9.1 Hz, 1 H), 2.62, 2.42 (2 dd, J ϭ 6.1, 6.8, 15.5 Hz, 2
H), 2.44 (t, J ϭ 7.6 Hz, 1 H), 2.20 (ddd, J ϭ 1.7, 4.9, 12.7 Hz, 1
H), 2.02 (dq, J ϭ 7.6, 6.4 Hz, 1 H), 1.43Ϫ1.33 (m, 1 H), 1.11 (d,
J ϭ 6.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 171.3,
168.4, 138.5, 138.4, 131.2, 129.0, 128.5, 128.3, 128.1, 127.7, 82.4,
80.2, 79.2, 75.1, 71.8, 71.6, 52.6, 51.8, 40.5, 36.8, 36.3, 30.2, 26.9,
12.5 ppm. IR (neat): ν˜ ϭ 1735, 1675 cmϪ1. MS (CI, NH3): m/z ϭ
584 [M ϩ 18]. HRMS-DCI/NH3: [M ϩ H]ϩ Calculated for
C32H39O9: 567.2600; found 567.2596, [M ϩ NH4]ϩ calculated for
C32H42NO9: 584.2860; found 584.2856.
HRMS-DCI/NH3: [M
560.2860; found 560.2853.
ϩ
NH4]ϩ calculated for C30H42NO9:
Methyl (3S,4E,6R)-6-[2,3-Di-O-benzyl-4,6-dideoxy-6-(methoxy-
carbonyl)- -gluco-β-C-pyranosyl]-6-hydroxy-2-(methoxy-
Acknowledgments
K. Adiey is grateful to the Ministere de l’Education Nationale et
D
`
carbonyl)-3-methylhex-4-enoate (22): Compound 22 (93 mg, 80%)
was obtained from the carbonate derivative (105 mg, 0.2 mmol),
with Pd(OAc)2 (4.5 mg, 10% molar), bis(diphenylphosphanyl)-
ethane (12 mg, 1.5 equiv./Pd), dimethyl malonate (46 µL, 0.4
mmol), and NaH (17 mg, 0.44 mmol, 60% in oil) by the same pro-
cedure as used for the synthesis of 17. [α]2D0 ϭ ϩ5 (c ϭ 0.5, CHCl3).
1H NMR (400 MHz, CDCl3): δ ϭ 7.36Ϫ7.26 (m, 10 H, 5.66Ϫ564
(m, 2 H), 4.97, 4.61/4.69, 4.61 (2 AB system, J ϭ 10.8, 11.7 Hz, 4
H), 4.32Ϫ4.27 (m, 1 H), 3.83Ϫ3.79 (m, 2 H), 3.82 (S, 3 H), 3.67,
3.68 (2s, 6 H), 3.59 (app. t, J ϭ 9 Hz, 1 H), 3.29 (d, J ϭ 8.8 Hz, 1
H), 3.19 (dd, J ϭ 1.7, 9.2 Hz, 1 H), 2.96Ϫ2.94 (m, 1 H), 2.58 (d,
J ϭ 7.4 Hz, 1 H), 2.64, 2.44 (2 dd, J ϭ 7.4, 5.8, 15.5 Hz, 2 H), 2.22
(ddd, J ϭ 1.6, 4.9, 12.8 Hz, 1 H), 1.43Ϫ1.33 (m, 1 H), 1.07 (d, J ϭ
6.5 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 171.2, 168.7,
138.4, 133.2, 131.3, 128.9, 128.5, 128.0, 127.8, 127.7, 80.6, 78.5,
72.5, 70.4, 75.5, 71.8, 70.3, 58.0, 52.7, 52.1, 40.7, 36.8, 37.1, 18.3
ppm. IR (neat): ν˜ ϭ 3445, 1730, 1665 cmϪ1. MS (CI, NH3): m/z ϭ
602 [M ϩ 18].
´
ˆ
de l’Enseignement Superieur et Technologique de Cote d’Ivoire for
a grant (1997Ϫ2000). We are also thankful to Marie-Noelle Rager
(E.N.S.C.P.) for the nuclear Overhauser effects experiments and to
Jacqueline Waisserman (U.P.M.C.) for RX structure.
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2957

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