New access to C-branched sugars and C-disaccharides under indium promoted barbier-type allylations in aqueous media

Full text of DOI:10.1021/jo001217e

3206
J . Org. Chem. 2001, 66, 3206-3210
and environmentally friendly solvent8 but more especially
New Access to C-Br a n ch ed Su ga r s a n d
because unique reactivities and selectivities are often
exhibited in water. Among them, organometallic reac-
tions in aqueous media have been developed and their
application in organic synthesis has been increasingly
explored.9 From this perspective, indium chemistry has
captured much recent attention largely due to the
discovery that indium can mediate the smooth coupling
of allylic halides with aldehydes to give the corresponding
homoallylic alcohols in aqueous media.10 This reaction
has been applied to the synthesis of carbohydrates11 and
many natural products.12
C-Disa cch a r id es u n d er In d iu m P r om oted
Ba r bier -typ e Allyla tion s in Aqu eou s Med ia
Yves Canac,* Eric Levoirier, and Andre´ Lubineau*
Laboratoire de chimie organique multifonctionnelle, associe´
au CNRS (UMR 8614), Institut de chimie mole´culaire,
Universite´ Paris-Sud, Baˆt. 420, 91405 Orsay Cedex, France
lubin@icmo.u-psud.fr.
Received August 9, 2000
We wish to report here a very convenient protocol for
the preparation of 2-C-branched sugars and C-disaccha-
rides under indium-promoted Barbier-type allylations in
aqueous media.
The efficient formation of carbon-carbon bonds with
good, and preferably predictable, stereocontrol is still a
synthetic challenge in organic chemistry. In carbohydrate
chemistry, C-branched sugars which represent a very
attractive class of compounds because of their occurrence
in nature,1 or because they are found as subunits in many
natural products,2 require such a stereoselective C-C
bond creation onto generally base- or acid-sensitive
compounds due to their multifunctional character. Inter-
est in C-branched sugars also comes from the fact that
they are extensively used as a starting point in the total
synthesis of natural products.3
Among the many methods developed for the synthesis
of C-glycosides4 or C-branched sugars during the last 20
years, some have been efficient, although they still
remain relatively complex, generally requiring many
steps5 and sometimes the use of toxic tin and mercury
compounds.6 Furthermore, problems are frequently en-
countered with the stereochemical control at the C-
branching point.7
Resu lts a n d Discu ssion
The construction of the key compound for the allyla-
tion reaction, 4-bromo-2-enopyranoside 2, is described in
Scheme 1. We started from the 2-enopyranoside 1 ob-
tained by Ferrier rearrangement of 3,4,6-tri-O-acetyl-D-
glucal with ethanol in 80% yield.13
After O-deacetylation of 1, selective tert-butyldimeth-
ylsilylation at O-6 was carried out in 90% yield.14 The
intermediate 4-bromoderivative prepared by inversion of
the 4-hydroxyl group under standard bromination condi-
tions (triphenylphosphine, carbon tetrabromide), was
then treated by tetrabutylammonium fluoride to give the
desired 4-bromo-2-enopyranoside 2 in 69% overall yield.
As expected, only the diastereoisomer with the bromine
atom in a C-4 axial position was isolated.
We then tested the allylation reactions with several
aldehydes whose results are shown in Table 1. First, we
examined the reaction of the bromo-derivative 2 with
benzaldehyde under indium-promoted Barbier-type con-
ditions.
Recently, organic reactions in water have received
much attention, not only because water is an economical
(1) (a) Chapleur, Y.; Che´tien, F. in Preparative Carbohydrate
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262. (b) Yoshimura, J .; J . Adv. Carbohydr. Chem. Biochem. 1984, 42,
69. (c) Celmer, W. D. Pure Appl. Chem. 1971, 28, 413.
The reaction took place in H2O at room temperature
in 2 h to give 3 in 95% yield as a unique stereoisomer
(2) (a) Hanessian, S. Total Synthesis of Natural Products: The
Chiron Approach; Pergamon Press: Oxford, 1983. (b) Fraser-Reid, B.
Acc. Chem. Res. 1996, 29, 57. (c) Rauter, A.; Ferreira, M.; Borges, C.;
Duarte, T.; Piedade, F.; Silva, M.; Santos, H. Carbohydr. Res. 2000,
325, 1.
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J . Org. Chem. 1994, 59, 715. (d) Alonso, R. A.; Burgey, C. S.; Rao, B.
V.; Vite, G. D.; Vollerthun, R.; Zottola, M. A.; Fraser-Reid, B. J . Am.
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1976, 33, 111. (b) Postema, M. H. D. Tetrahedron 1992, 48, 8545. (c)
Levy, D. E.; Tang, C. The Chemistry of C-Glycosides; Pergamon:
Oxford, 1995. (d) Postema, M. H. D. C-Glycoside synthesis; CRC
Press: London, 1995. (e) Beau, J . M.; Gallagher, T. Top. Curr. Chem.
1997, 187, 1-54. (f) Nicotra, F. Top. Curr. Chem. 1997, 187, 55-83.
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Fraser-Reid, B.; Magdzinski, L.; Molino, B. F.; Mootoo, D. R. J . Org.
Chem. 1987, 52, 4495. (c) Lawrence, A. J .; Pavey, J . B. J .; Cosstick,
R.; O’Neil, I. A. J . Org. Chem. 1996, 61, 9213. (d) Dondoni, A.; Kniezo,
L.; Martinkova. M.; Imrich, J . Chem. Eur. J . 1997, 3, 424. (e) Sinay,
P. Pure Appl. Chem. 1997, 69, 459.
(8) (a) Li, C. J . Chem. Rev. 1993, 93, 2023. (b) Lubineau, A.; Auge`,
J .; Queneau, Y. Synthesis 1994, 741. (c) Lubineau, A. Chem. Ind. 1996,
123. (d) Li, C. J .; Chan T. H. Organic Reactions in Aqueous Media;
J ohn Wiley & Sons: New York, 1997. (e) Grieco, P. A. Organic
Synthesis in Water; Blackie Academic & Profesionnal: Glascow,
1998.
(9) (a) Chan, T. H.; Li, C. J .; Lee, M. C.; Wei, Z. Y. Can. J . Chem.
1994, 72, 1181. (b) Ref 8a.
(10) (a) Li, C. J .; Chan, T. H. Tetrahedron, 1999, 55, 11149. (b)
Cintas, P. Synlett 1995, 1087. (c) Li, C. J . Tetrahedron, 1996, 52, 5643.
(d) Chan, T. H.; Isaac, M. B. Pure Appl. Chem. 1996, 68, 919. (e)
Paquette, L. A. In Green Chemistry: Frontiers in Beningn Chemical
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dron Lett. 1991, 32, 7017.
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Schmid, W.; Whitesides, G. M. J . Am. Chem. Soc. 1991, 113, 6674. (c)
Chan, T. H.; Xin, Y. C.; von Itzstein, M. J . Org. Chem. 1997, 62, 3500.
(d) Gordon, D. M.; Whitesides, G. M. J . Org. Chem. 1993, 58, 7937.
(12) (a) Paquette, L. A.; Rothhaar, R. R.; Issac, M.; Rogers, L. M.;
Rogers, R. D. J . Org. Chem. 1998, 63, 5463. (b) Chan, T. H.; Lu, W.
Tetrahedron Lett. 1998, 39, 8605. (c) Yi, X. H.; Meng, Y.; Hua, X. G.;
Li, C. J . J . Org. Chem. 1998, 63, 7472. (d) Loh, T. P.; Cao, G. Q.; Pei,
J . Tetrahedron Lett. 1998, 39, 1453.
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10.1021/jo001217e CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/03/2001

Notes
J . Org. Chem., Vol. 66, No. 9, 2001 3207
Sch em e 1a
a
Conditions: (a) Et3N, CH3OH, H2O, 96%; (b) TBSCl, pyri-
dine, 90%; (c) CBr4, (C6H5)3P, CH2Cl2, 75%; (d) (C4H9)N+F-, THF,
92%.
F igu r e 1.
Sch em e 3
Ta ble 1
yieldd dr:
entry
RCHOa
PhCHO
HCHO
CH3(CH2)2CHO
12
15
products solventsb condc
(%) S/Re
1
2
3
4
5
3
A
A
A
B
B
2; RT
1; RT
4; RT
4; RT
12; RT
95
97
71
94
55
1/0
6
This reaction was extended to other aldehydes. In the
case of formaldehyde (Table 1, entry 2), the C-2 axial
product 6 was obtained in the same conditions and in
quantitative yield as a single compound, with the reac-
tion being only faster (1 h). With butyraldehyde (Table
1, entry 3), two new products, 8a ,b , were formed in
equal amounts and both correspond to the expected C-2
axial adduct. However, poor selectivity at C-7 was
observed, probably due to lower reactivity and a decrease
in the steric hindrance around the carbonyl group. In this
case, using butyraldehyde, two minor compounds were
obtained, 10a ,b (85:15, 8%), whose structures were
determined by spectroscopic analysis. For both com-
8a ,b
1/1
0/1
1/1
13
16a ,b
a
b
RCHO (2 equiv), In (2 equiv). Solvent system: A, H2O; B,
H2O/THF (1/1). c Conditions: reaction time (h); temperature (°C).
Isolated yields. e Diastereomeric ratio calculated by 1H and 13C
d
NMR.
Sch em e 2a
1
pounds, the H NMR spectra exhibited a singlet for the
H-1 signals, indicating axial alkylation at C-2 and
showing the presence of the following three double
bonds: the expected 3,4-double bond, a double bond
with cis geometry, and another with trans geometry. In
fact, they result from the condensation of the alde-
hyde 9 onto the starting 4-bromo-2-enopyranoside 2.
Aldehyde 9 comes from the elimination of the ethoxy
group on the intermediate allyl indium as shown in
Scheme 3. In the transition state leading to the major
diastereoisomer 10a , the bulky substituent is, as ex-
pected, oriented away from the pyranosidic ring in an
equatorial position (C-7, S), whereas it must be in an
unfavorable axial position for the minor isomer (C-7, R).
This is supported by a large coupling constant (J 2,7 9.5
Hz) for the major diastereoisomer. The formation of
these two minor compounds 10a ,b comes from a lower
reactivity of butyraldehyde in comparison to that of
benzaldehyde and formaldehyde, which allow the allyl
indium intermediate to decompose to aldehyde 9 before
reacting with butyraldehyde. Furthermore, when the
4-bromo-2-enopyranoside 2 was treated with indium
alone without any aldehyde, the C-2 axial adducts
10a ,b, epimers at C-7, were obtained in near quantitative
yields (45% isolated, theoretical 50%) in an identical 85:
15 ratio.
a
Conditions: (a) C6H5CHO, ZnCl2, CH2Cl2.
resulting from complete regio- and diastereoselectivity
(Table 1, entry 1). The structure of 3 was deduced from
an 1H NMR analysis which exhibited a singlet for the
H-1 signal, indicating an axial alkylation at C-2.15
Furthermore, the presence of a 3,4-double bond was
supported by an allylic coupling between H-3 and H-5.
These data indicate alkylation at the γ position with syn
stereochemistry relative to the bromine atom. The con-
figuration of the second new stereogenic center at the C-7
position was deduced as (S) after introducing a ben-
zylidene group to the C-1 and C-7 hydroxyl groups to give
compound 4 (Scheme 2). In this reaction and under these
experimental conditions, it is interesting to note the
predominant formation of the unsaturated 2-C-anhydro-
derivative 5 to be used later (vide infra).
In compound 4, the bulky substituent (phenyl group
at C-7) is ideally oriented away from the pyranosidic ring
in an equatorial position. This is supported by the J 1,2
2.9 Hz value indicating a cis relationship between the
two six-membered cycles and the J 2,7 ) 10.7 Hz value
showing a transdiaxial antiperiplanar orientation of the
C-2 and C-7 hydrogen atoms.
)
Next, we examined the reaction between the 4-bromo-
2-enopyranoside 2 and the 3-O-Benzyl-1,2-O-isopropy-
lidene-R-D-xylo-dialdose 12.16 The reaction was conducted
From a mechanistic point of view, our results can be
explained by the formation of the currently accepted six-
membered cyclic transition state between the carbonyl
compound and the allylindium sugar moiety,8-10 with the
phenyl group in an equatorial position as depicted in
Figure 1. The C-7 (S) configuration in 3 was further
supported by X-ray crystallography.
(15) Valverde, S.; Bernabe, M.; Gomez, A. M.; Puebla P. J . Org.
Chem. 1992, 57, 4546.
(16) (a) Wolfrom, M. L.; Hanessian, S. J . Org. Chem. 1962, 27, 1800.
(b) Horton, D.; Swanson, F. O. Carbohydr. Res. 1970, 14, 159.

3208 J . Org. Chem., Vol. 66, No. 9, 2001
Notes
F igu r e 2.
Sch em e 4a
a
Conditions: (a) OsO4, NMO, CH3COCH3/H2O, 88%.
Sch em e 5a
in an H2O/THF mixture because of the poor solubility of
the aldehyde in pure water. In this case, the reaction was
as efficient as with benzaldehyde and the C-2 axial
adduct 13 was obtained as a single diastereoisomer in
94% yield (Table 1, entry 4). Formation of the benzylidene
derivative 14 onto the C-1 and C-7 hydroxyl groups
showed that the configuration of new stereogenic center
C-7 (R) was opposite to that observed in the case of the
reaction with benzaldehyde. Indeed, the very small
coupling constant between H-2 and H-7 (J 2,7 < 1 Hz) in
the benzylidene derivative 14, indicating a cis relation-
ship, confirms this attribution. In this case, a chelated
transition state has taken place, with the bulky substitu-
ent (sugar moiety) oriented toward the pyranosidic ring
in an axial position. At this stage, it is worth pointing
out that in product 3 (C-7, S) whose structure was
assigned by X-ray and on the basis of the formation of
the benzylidene derivative 4, the J 2,7 value was greater
than that in compound 13 (C-7, R). Considering these
criteria, it is therefore possible to assign the C-7 config-
uration of other similar adducts as it has already been
postulated.17
The formation of 13 in which C-7 has an (R) configu-
ration could be explained by a chelation of the indium
atom with the aldehyde carbonyl and an oxygen atom in
12 either via a six-membered cyclic chair transition state
(C-3′ oxygen) or a five-membered cyclic transition state
(endocyclic oxygen) which both favored the formation of
the C-2 axial adduct with C-7 (R) configuration (Figure
2). In this case, the chelating factor overrides the steric
effects, since the bulky substituent (sugar moiety) is in
an unfavorable axial position in the cyclic chair transition
state.
a
Conditions: (a) m-CPBA, CH2Cl2, 89%; (b) CH3COOH, Ac2O,
BF3.OEt2, 65%.
adduct was obtained but with no diastereoselectivity at
C-7, and a mixture of the two corresponding diastereo-
isomers 16a ,b (50/50) was isolated in 55% yield. The
moderate value of this yield can be explained by the lower
reactivity of the â-C-linked 2,3,4,6-tetra-O-benzyl-â-D-
glucosyl aldehyde 15 in comparison to that with previous
aldehydes, as well as by the enhanced formation of the
adducts 10a ,b (85:15, 29%) in the reaction. This lower
reactivity in Barbier-type allylation was further demon-
strated through the reaction with the simple allyl bro-
mide which required 24 h (66% yield) with aldehyde 15
compared to 2 h (98% yield) when aldehyde 12 was used
(data not shown).
As mentioned previously, the formation of the two
diastereoisomers 16a ,b was obtained from a six-mem-
bered cyclic chair transition state between the carbonyl
compound and the allylindium sugar moiety with both
the chelating and steric effects operating at the same
time to give the C-7 (R) and C-7 (S) diastereoisomers,
respectively. Compounds 6, 8a ,b, 10a ,b, and 16a ,b were
acetylated respectively to 7, 9a ,b, 11a ,b, and 17a ,b for
full characterization including elemental analyses.
In fact, all these allylation reactions led to unsaturated
analogues of C-branched sugars or C-disaccharides which
need to be further elaborated to real sugars. Accordingly,
cis-hydroxylation with osmium tetroxide of the C-
branched sugar 3 gave, with complete stereoselectivity,
the 2-C-altrose 18 in 88% yield (Scheme 4).
Finally, to obtain the analogues of the C-oligosaccha-
rides, we turned our attention to the reaction between
the 4-bromo-2-enopyranoside 2 and the â-C-linked 2,3,4,6-
tetra-O-benzyl-â-D-glucosyl aldehyde 15.18 The reaction,
conducted in an H2O/THF mixture at room temperature
(Table 1, entry 5), was slower than with previous alde-
hydes and required 12 h. As before, only the C-2 axial
More interestingly, as shown in Scheme 5, treatment
of the unsaturated 2-C-anhydro-derivative 5 with 3-chlo-
roperoxy-benzoic acid led to a mixture of epoxides 19,
which under acetolysis conditions (Ac2O, BF3-Et2O) led
to the opening of both the anhydro and the epoxide rings
to give the 2-C-mannose, 20, as a single diastereoisomer
(58% overall yield).
(17) Yu, K. L.; Handa, S.; Tsang, R.; Fraser-Reid, B. Tetrahedron,
1991, 47, 189.
(18) (a) Sanchez, M. E. L.; Michelet, V.; Besnier, I.; Geneˆt, J . P.
Synlett, 1994, 705. (b) Dondoni, A.; Scherrmann, M. C. J . Org. Chem.
1994, 59, 6404.
In conclusion, the above results show that C-branched
sugars or C-oligosaccharides are obtainable through

Notes
J . Org. Chem., Vol. 66, No. 9, 2001 3209
(m, 5H). 13C NMR (62.9 MHz, CDCl3) δ 15.1, 46.1, 63.4, 64.8,
68.8, 75.1, 96.7, 125.3, 126.4, 127.4, 127.8, 128.5, 142.1. MS (EI)
m/z: 287.1 (M + Na)+. Anal. Calcd for C15H20O4: C, 68.16; H,
7.63; O, 24.21. Found: C, 68.06; H, 7.73; O, 24.04.
indium-promoted Barbier-type allylations in aqueous
media. Alkylation always occurs at the γ position, with
syn stereochemistry relative to the bromine atom via a
cyclic six-membered chair transition state.
Work is currently in progress in our laboratory to
extend this methodology to other bromo-enopyranosides
and C-formyl-glycosides. This method seems very general
and should open the door to interesting prospects for the
synthesis of many different C-oligosaccharides.
1,7-O-Ben zylid en e-2-C-[(S)-1-p h en yl-1-h yd r oxym eth yl]-
3,4-d id eoxy-â-D-t h r eo-h ex-3-en op yr a n osid e (4) a n d 1,6-
An h yd r o-2-C-[(S)-1-p h en yl-1-h yd r oxym eth yl]-3,4-d id eoxy-
â-D-th r eo-h ex-3-en op yr a n osid e (5). To a solution of 3 (190
mg, 0.719 mmol) in CH2Cl2 (5 mL) under argon were added zinc
chloride (117 mg, 0.863 mmol) and benzaldehyde (365µL, 3.59
mmol). The suspension was stirred at room-temperature over-
night, then quenched with a saturated aqueous solution of
NaHCO3 and extracted with CH2Cl2. The organic phase was
washed several times with a saturated aqueous NH4+Cl- solu-
tion, dried (MgSO4), and then concentrated. Flash chromatog-
raphy of the residue (petroleum ether/ethyl acetate: 10/1 to 1/1)
gave first 5 (108 mg, 69%) then 4 (47 mg, 20%).
Exp er im en ta l Section
Gen er a l Met h od s a n d Ma t er ia ls. All moisture sensitive
reactions were performed under argon using oven-dried glass-
ware. If necessary, solvents were dried and distilled prior to use.
Reactions were monitored on silica gel 60 F254. Detection was
performed using UV light, iodine, and/or 5% sulfuric acid in
ethanol, followed by heating. Flash chromatography was per-
formed on silica gel 6-35µm. 1H and 13C NMR spectra were
recorded at room temperature with Bruker AC 200, 250 or AM
400 spectrometers. Chemical shifts are reported in δ vs Me4Si
for 1H NMR spectra (external reference for D2O) and relative to
the CDCl3 resonance at 77.00 ppm for 13C NMR spectra in CDCl3
and relative to Me4Si for 13C NMR spectra in D2O. Melting points
were measured on a Reichert apparatus and were uncorrected.
Optical rotations were measured on an Electronic Digital J asco
DIP-370 Polarimeter. Mass spectra were recorded in positive
mode on a Finnigan MAT 95 S spectrometer using electrospray
ionization. Elemental analyses were performed at the Service
Central de Microanalyses du CNRS (Gif-sur-Yvette, France).
Acetylation was performed in pyridine with Ac2O (2:1, v/v)
and kept at room-temperature overnight. After several coevapo-
rations with toluene, the crude product was purified by flash
chromatography (petroleum ether/ethyl acetate).
4. White solid. [R]28D: +24.7° (c 1.2, CH2Cl2). 1Η ΝΜR (250
MHz, CDCl3) δ 2.63-2.70 (m, 1H), 3.79 (dd, J ) 6.3, 11.5 Hz,
1H), 3.90 (dd, J ) 3.4 Hz, 1H), 4.59 (m, 1H), 4.91 (d, J ) 10.7
Hz, 1H), 5.39 (d, J ) 2.9 Hz, 1H), 5.44 (dddd, J ) 2.9, 6.8, 10.3
Hz, 1H), 5.73 (d, J ) 10.3 Hz, 1H), 6.33 (s, 1H), 7.35-7.62 (m,
10H). 13C NMR (62.9 MHz, CDCl3) δ 41.0, 65.0, 76.7, 81.0, 94.9,
95.3, 125.7, 126.3, 127.0, 128.1, 128.2, 128.3, 128.9, 137.6, 138.7.
MS (EI) m/z: 347.1 (M + Na)+. Anal. Calcd for C20H20O4: C, 74.06;
H, 6.21; O, 19.73. Found: C, 73.86; H, 6.27; O, 19.89.
5. Colorless oil. [R]26D: +8.3° (c 1.3, CH2Cl2). 1Η ΝΜR (200
MHz, CDCl3) δ 2.94-2.98 (m, 1H), 3.35 (d, J ) 6.8 Hz, 1H), 3.77
(m, 1H), 4.02 (d, J ) 6.3 Hz, 1H), 4.68 (t, J ) 4.4 Hz, 1H), 4.80
(t, J ) 6.8 Hz, 1H), 5.45 (td, J ) 2.0, 9.8 Hz, 1H), 5.63 (t, J )
2.0 Hz, 1H), 6.10 (dddd, J ) 2.0, 4.4, 9.8 Hz, 1H), 7.29-7.40 (m,
5H). 13C NMR (50.3 MHz, CDCl3) δ 49.3, 71.1, 72.6, 74.4, 101.7,
126.1, 126.7, 127.7, 128.5, 129.7, 133.5. Anal. Calcd for C13H14O3:
C, 71.54; H, 6.47; O, 21.99. Found: C, 71.74; H, 6.52; O, 22.16.
Eth yl 2-C-[Hyd r oxym eth yl]-3,4-d id eoxy-R-D-th r eo-h ex-
3-en op yr a n osid e (6). Colorless oil (97%). [R]27D: +24.6° (c 1.2,
1
Eth yl 4-Br om o-2,3,4-tr id eoxy-R-D-th r eo-h ex-2-en op yr a -
n osid e (2). To a solution of ethyl 6-O-(tert-butyldimethylsilyl)-
2,3-dideoxy-R-D-erythro-hex-2-enopyranoside14 (750 mg, 2.6 mmol)
in CH2Cl2 (10 mL) maintained under argon at -78 °C were
added (C6H5)3P (1.02 g, 3.9 mmol) and CBr4 (948 mg, 2.86 mmol).
The suspension was stirred at 0 °C for 2 h then quenched with
a saturated aqueous solution of NaHCO3 and extracted with
CH2Cl2. The organic phase was dried (MgSO4) then concentrated.
The crude residue was dissolved in THF (10 mL) and then
treated at 0 °C with a solution of NBu4+F- (1M in THF, 3.12
mL). The mixture was stirred at room temperature for 3h and
then quenched with water and extracted with Et2O. The organic
phase was washed several times with saturated aqueous
NH4Cl solution, dried (MgSO4), and then concentrated. Flash
chromatography of the residue (petroleum ether/ethyl acetate:
3/1 to 1/1) gave 2 (425 mg, 69%).White crystals, mp 92-93 °C
CH2Cl2). Η ΝΜR (250 MHz, CDCl3) δ 1.20 (t, J ) 7.0 Hz, 3H),
2.26-2.29 (m, 1H), 2.76 (m, 2H), 3.49-3.84 (m, 6H), 4.23 (m,
1H), 4.96 (s, 1H), 5.75 (s, 2H). 13C NMR (62.9 MHz, CDCl3) δ
15.1, 41.6, 63.3, 63.4, 64.6, 68.9, 98.2, 124.5, 127.8. MS m/z: 211.1
(M + Na)+.
Eth yl 2-C-[Hyd r oxym eth yl]- 6,7-d i-O-a cetyl-3,4-d id eoxy-
R-D-th r eo-h ex-3-en o-pyr an oside (7). Colorless oil (93%). [R]29
:
D
1
+69.6° (c 1.3, CH2Cl2). Η ΝΜR (200 MHz, CDCl3) δ 1.20 (t, J
) 7.0 Hz, 3H), 2.02 (s, 3H), 2.04 (s, 3H), 2.34-2.41 (m, 1H), 3.54
(qd, J ) 7.0, 9.7 Hz, 1H), 3.75-3.92 (m, 2H), 4.05-4.14 (m, 3H),
4.32-4.36 (m, 1H), 4.88 (s, 1H), 5.73 (s, 2H). 13C NMR (50.3 MHz,
CDCl3) δ 15.1, 20.8, 38.9, 63.6, 64.5, 65.5, 66.7, 96.7, 123.9, 127.2,
170.7, 170.8. MS (EI) m/z: 295.1 (M + Na)+. Anal. Calcd for
C13H20O6: C, 57.34; H, 7.40; O, 35.25. Found: C, 57.22; H, 7.48;
O, 35.19.
Eth yl 2-C-[(R,S)-1-Hyd r oxybu tyl]-3,4-d id eoxy-R-D-th r eo-
3-en op yr a n osid e (8a ,b). Colorless oil (71%). 1Η ΝΜR (200
MHz, CDCl3) δ 0.92 (t, J ) 6.3 Hz, 6H), 1.22 (t, J ) 7.0 Hz, 6H),
1.32-1.53 (m, 4H), 1.80-1.87 (m, 4H), 2.09-2.16 (m, 1H), 2.24-
2.27 (m, 1H), 2.80 (brs, 1H), 3.50-3.89 (m, 10H), 4.26 (m, 2H),
4.93 (s, 1H), 5.11 (s, 1H), 5.78-5.87 (m, 4H). 13C NMR (50.3 MHz,
CDCl3) δ 14.0, 15.1, 18.8, 19.2, 36.9, 37.1, 43.6, 44.8, 63.2, 63.3,
64.5, 64.8, 68.7, 69.1, 72.4, 72.6, 96.7, 100.1, 123.0, 125.5, 127.3,
128.5. MS (EI) m/z: 253.1 (M + Na)+.
27
(CH2Cl2). [R]D : -283° (c 1.05, CH2Cl2). 1Η ΝΜR (250 MHz,
CDCl3) δ 1.25 (t, J ) 7.0 Hz, 3H), 2.00 (brs, 1H), 3.57 (dq, J )
7.1, 9.5 Hz, 1H), 3.74 (dd, J ) 5.4, 11.2 Hz, 1H), 3.80-3.95 (m,
2H), 4.09 (m, 1H), 4.48 (dd, J ) 1.9, 5.4 Hz, 1H), 5.14 (d, J )
3.1 Hz, 1H), 5.83 (dd, J ) 10.0 Hz, 1H), 6.22 (dd, J ) 5.6 Hz,
1H). 13C NMR (50.3 MHz, CDCl3) δ 15.2, 44.4, 63.9, 65.0, 68.5,
93.9, 127.4, 129.3. Anal. Calcd for C8H13O3Br: C, 40.53; H, 5.53;
O, 20.24. Found: C, 40.99; H, 5.46; O, 20.21.
Gen er a l P r oced u r e for Rea ction of 2 w ith Ald eh yd es.
To a solution of 4-bromo-2-enopyranoside 2 in H2O (system A)
or THF/H2O (1/1) (system B) were added indium powder (2
equiv) and the corresponding aldehyde (2 equiv). The suspension
was stirred at room temperature until the reaction was complete,
as judged by consumption of the 4-bromo-2-enopyranoside 2 (see
Table 1). The reaction was then quenched with a saturated
aqueous NaHCO3 solution, filtered, and concentrated. Flash
chromatography of the residue (petroleum ether/ethyl acetate:
4/1 to 1/3) gave the corresponding 2-C-branched sugars.
Eth yl 2-C-[(S)-1-P h en yl-1-h yd r oxym eth yl]-3,4-d id eoxy-
R-D-th r eo-h ex-3-en op yr a n osid e (3). White crystals (95%), mp
139-140 °C (CH2Cl2). [R]27D: +101.8° (c 1.2, CH2Cl2). 1Η ΝΜR
(250 MHz, CDCl3) δ 1.20 (t, J ) 7.0 Hz, 3H), 2.47-2.51 (m, 1H),
3.46-3.59 (m, 1H), 3.65 (dd, J ) 5.4, 11.2 Hz, 1H), 3.74-3.87
(m, 2H), 4.28 (m, 1H), 4.64 (d, J ) 7.3 Hz, 1H), 5.13 (s, 1H),
5.43-5.51 (m, 1H), 5.73 (dd, J ) 1.2, 10.5 Hz, 1H), 7.25-7.31
E t h yl 6,7-Di-O-a cet yl-2-C-[(R ,S)-1-h yd r oxyb u t yl]-3,4-
dideoxy-R-D-th r eo-3-en opyr an oside (9a,b). Colorless oil (91%).
1Η ΝΜR (250 MHz, CDCl3) δ 0.87 (t, J ) 7.3 Hz, 6H), 1.19 (t, J
) 7 Hz, 6H), 1.20-1.65 (m, 8H), 2.03 (s, 6H), 2.06 (s, 6H), 2.28-
2.36 (m, 2H), 3.51 (qd, J ) 7.3, 9.7 Hz, 2H), 3.70-3.84 (m, 2H),
4.06-4.22 (m, 4H), 4.30-4.34 (m, 2H), 4.78 (s, 1H), 4.90 (s, 1H),
4.90-5.03 (m, 2H), 5.76 (m, 4H). 13C NMR (62.9 MHz, CDCl3) δ
13.7, 13.9, 15.0, 18.1, 19.0, 20.7, 20.8, 21.0, 21.1, 32.9, 33.2, 42.5,
42.8, 63.1, 63.3, 65.5, 65.6, 66.0, 66.3, 73.5, 74.3, 96.7, 96.8, 123.9,
124.1, 126.9, 170.3, 170.5, 170.8. MS (EI) m/z: 337.2 (M + Na)+.
Anal. Calcd for C16H26O6: C, 61.13; H, 8.34; O, 30.53. Found:
C, 60.91; H, 8.43; O, 30.81.
Eth yl 2-C-[(R,S)-5-Hyd r oxyp en ta -1(cis),3(tr a n s)-d ien yl]-
3,4-d id eoxy-R-D-th r eo-h ex-3-en o-p yr a n osid e (10a ,b). To a
stirred solution of 4-bromo-2-enopyranoside 2 (100 mg, 0.421
mmol) in H2O (3 mL) was added indium powder (145 mg, 1.26
mmol). After 3 h at room temperature, the reaction was

3210 J . Org. Chem., Vol. 66, No. 9, 2001
Notes
quenched with a saturated aqueous NaHCO3 solution, filtered,
and concentrated. Flash chromatography of the residue (petro-
leum ether/ethyl acetate: 3/1 to 0/1) gave a 85/15 mixture of
10a ,b (51 mg, 45%).
) 1.0, 5.4 Hz, 1H), 5.75 (m, 1H), 5.91 (m, 1H), 7.15-7.45 (m,
20H). 13C NMR (62.9 MHz, CDCl3) δ 15.1, 20.9, 21.1, 42.0, 63.5,
65.6, 66.7, 68.8, 70.1, 73.3, 74.9, 75.0, 75.6, 77.7, 78.1, 78.3, 79.4,
87.7, 97.0, 125.0, 126.5, 127.5-128.4, 137.1-138.4, 170.0, 170.1.
Anal. Calcd for C47H54O11: C, 71.01; H, 6.85; O, 22.14. Found:
C, 70.83; H, 6.92; O, 22.28.
Colorless oil. 1Η ΝΜR for 10a (C-7 (S); major diastereoisomer).
(200 MHz, CD3OD) δ 1.21 (t, J ) 7.0 Hz, 3H), 2.04-2.11 (m,
1H), 3.48-3.65 (m, 3H), 3.76-3.93 (m, 1H), 4.08-4.15 (m, 3H),
4.48 (t, J ) 9.5 Hz, 1H), 5.14 (s, 1H), 5.37 (t, J ) 10.3 Hz, 1H),
5.54-5.62 (m, 1H), 5.70-5.89 (m, 2H), 6.12 (t, J ) 11.2 Hz, 1H),
6.55 (dd, J ) 11.2, 14.9 Hz, 1H).13C NMR for 10a (50.3 MHz,
CD3OD) δ 15.5, 46.8, 63.2, 64.3, 65.5, 69.5, 70.6, 98.1, 125.2,
127.0, 128.3, 131.0, 132.4, 135.6. MS (EI high resolution) for
10a,b m/z: Calcd for C14H22O5 Na: 293.13715. Found: 293.13649.
Eth yl 6,7-Di-O-a cetyl-2-C-[(R,S)-5-h yd r oxyp en ta -1(cis),
3(t r a n s)-d ie n y l]-3,4-d id e o x y -R-D -t h r e o -h e x -3-e n o p y -
r a n osid e (11a ,b). Colorless oil (91%). 1Η ΝΜR for 11a (C-7 (S),
major stereoisomer) (200 MHz, CDCl3) δ 1.23 (t, J ) 7.0 Hz,
3H), 2.00-2.08 (3s, 9H), 2.38 (m, 1H), 3.46-3.59 (m, 1H), 3.74-
3.84 (m, 1H), 4.05-4.25 (m, 2H), 4.35 (m, 1H), 4.55-4.62 (m,
2H), 4.83 (s, 1H), 5.31 (m, 1H), 5.56 (t, J ) 8.9 Hz, 1H), 5.65-
5.85 (m, 3H), 6.14 (t, J ) 11.2 Hz, 1H), 6.65 (m, 1H). 13C NMR
for 11a (50.3 MHz, CDCl3) δ 15.1, 20.8, 21.1, 42.8, 63.7, 64.3,
65.6, 66.8, 70.4, 96.3, 123.9, 127.2, 128.5, 130.1, 132.0, 169.8,
170.7, 170.8. Anal. Calcd for C20H28O8: C, 60.59; H, 7.12.
Found: C, 61.13; H, 7.25.
17b. Colorless oil. [R]27D: +16.8° (c 1.2, CH2Cl2). 1Η ΝΜR (250
MHz, CDCl3) δ 1.18 (t, J ) 7 Hz, 3H), 2.03 (s, 6H), 2.63 (m, 1H),
3.36-3.81 (m, 9H), 4.03 (dd, J ) 6.3, 11.2 Hz, 1H), 4.19 (dd, J
) 3.9 Hz, 1H), 4.32 (m, 1H), 4.47-4.95 (m, 8H), 4.90 (s, 1H),
5.38 (dd, J ) 1.0, 7.8 Hz, 1H), 5.79-5.82 (m, 2H), 7.17-7.34 (m,
20H). 13C NMR (62.9 MHz, CDCl3) δ 15.1, 20.8, 21.0, 40.2, 63.5,
65.7, 66.7, 68.8, 73.3, 75.0, 75.7, 78.0, 78.7, 79.0, 79.5, 87.4, 96.9,
125.3, 127.1, 127.1-128.4, 137.7-138.3, 169.8, 170.9. Anal.
Calcd for C47H54O11: C, 71.01; H, 6.85. Found: C, 71.41; H, 7.34.
Eth yl 2-C-[(S)-1-P h en yl-1-h yd r oxym eth yl]-R-D-a ltr op y-
r a n osid e (18). To a solution of 3 (200 mg, 0.757 mmol) in
acetone/water (8/1, 5 mL) were added 4-methylmorpholine-N-
oxide monohydrate (204 mg, 1.51 mmol) and osmium tetroxide
(0.2M/THF, 190 µL, 0.05 eq). The reaction mixture was stirred
overnight at room temperature then diluted with AcOEt and
washed several times with a saturated aqueous Na2SO3 solution.
The organic phase was dried (MgSO4) then concentrated. Flash
chromatography of the residue (petroleum ether/ethyl acetate:
1/1 to 0/1) gave the triol 18 (198 mg, 88%). White crystals, mp
25
Con d en sa tion w ith Ald eh yd e 12. Com p ou n d 13. Colorless
122-124 °C (CH3OH/CH2Cl2). [R]D : +25.5° (c 1.2, CH3OH).
oil (94%). [R]27
:
+5.5° (c 1.2, CH2Cl2). 1Η ΝΜR (250 MHz,
1Η ΝΜR (250 MHz, CD3OD) δ 1.22 (t, J ) 7.1 Hz, 3H), 2.36
(ddd, 1H), 3.24 (t, J ) 2.9 Hz, 1H), 3.50 (ddd, J ) 7.3, 9.8, 9.8
Hz, 1H), 3.60 (dd, J ) 3.4 Hz, 1H), 3.75-3.90 (m, 4H), 4.63 (d,
J ) 9.7 Hz, 1H), 5.27 (s, 1H), 7.30-7.39 (m, 5H). 13C NMR (62.9
MHz, CD3OD) δ 15.3, 53.2, 63.0, 64.6, 65.7, 70.1, 70.4, 72.8, 99.3,
127.8, 129.0, 129.7, 144.0. MS (EI) m/z: 321.1 (M + Na)+. Anal.
Calcd for C15H22O6: C, 60.39; H, 7.43; O, 32.18. Found: C, 59.77;
H, 7.46; O, 32.14.
D
CDCl3) δ 1.21 (t, J ) 7 Hz, 3H), 1.31 (s, 3H), 1.47 (s, 3H), 2.66
(m, 1H), 3.43-3.88 (m, 4H), 4.04-4.11 (m, 2H), 4.19 (dd, J )
1.9, 9.3 Hz, 1H), 4.29 (m, 1H), 4.59 (d, J ) 3.9 Hz, 1H), 4.63 (d,
J ) 11.2 Hz, 1H), 4.71 (d, 1H), 5.00 (s, 1H), 5.90 (d, 1H), 5.89-
5.93 (m, 2H), 7.20-7.40 (m, 5H). 13C NMR (62.9 MHz, CDCl3) δ
15.1, 26.3, 26.9, 40.4, 63.2, 64.2, 69.0, 69.3, 72.4, 80.0, 81.5, 82.4,
100.2, 105.0, 111.7, 122.6, 127.7, 127.9, 128.5, 129.2, 137.5. MS
(EI) m/z: 459.2 (M + Na)+. Anal. Calcd for C23H32O8: C, 63.29;
H, 7.39; O, 29.32. Found: C, 62.95; H, 7.56; O, 29.95.
1,3,4,6,7-P e n t a -O-a ce t yl-2-C-[(S )-1-p h e n yl-1-a ce t oxy-
m eth yl]-R-D-m a n n op yr a n ose (20). To a cooled (0 °C) solution
of 5 (80 mg, 0.366 mmol) in CH2Cl2 (5 mL) was added 3-chlo-
roperoxy-benzoic acid (126 mg, 0.734 mmol). After stirring
overnight at 40 °C, the reaction mixture was diluted with
CH2Cl2 and then washed with a saturated aqueous NaHCO3
solution. The organic phase was dried (MgSO4) and then con-
centrated to give a crude mixture of epoxide 19 (1/15). Acetic
acid (2 mL) and acetic anhydride (0.5 mL) were then added,
followed by a catalytic amount of BF3.OEt2. After heating at 55
°C overnight, the reaction mixture diluted with ether was
washed several times successively with a saturated aqueous
NaHCO3 solution and a saturated aqueous NH4+Cl- solution.
The organic phase was dried (MgSO4) and then concentrated.
Flash chromatography (petroleum ether/ethyl acetate: 5/1 to 1/1)
of the residue gave 20 (102 mg, 58%). Colorless oil. [R]27D: -4.9°
Ben zylid en e Der iva tive (14). The primary hydroxyl group
in compound 13 (87 mg, 0.2 mmol) was first regioselectively
acetylated with Ac2O (21µL, 0.22 mmol) in pyridine (300µL) for
12 h at 0 °C. After coevaporation with toluene, flash chroma-
tography gave the monoacetylated compound (92 mg, 97%) Then,
following the same experimental protocol described for the prep-
aration of compound 4, except that the reaction was quenched
after 2 h at room temperature, compound 14 was obtained as a
1
colorless oil (26 mg, 24%). [R]27D: -21° (c 1.0, CH2Cl2). Η ΝΜR
(250 MHz, CDCl3) δ 1.25 (s, 3H), 1.41 (s, 3H), 2.00 (s, 3H), 2.60
(m, 1H), 4.03 (s, 1H), 4.21 (m, 2H), 4.32 (d, J ) 11.0 Hz, 1H),
4.35 (d, 1H), 4.45 (m, 1H), 4.50 (d, J ) 12.2 Hz, 1H), 4.58 (d, J
) 3.7 Hz, 1H), 4.64 (d, 1H), 5.37 (s, 1H), 5.50 (s, 1H), 5.84 (d,
1H), 5.83-5.95 (m, 2H), 7.18-7.52 (m, 10H). 13C NMR (62.9
MHz, CDCl3) δ 21.0, 26.3, 26.9, 34.1, 67.3, 70.9, 72.4, 73.2, 76.9,
80.9, 82.3, 95.6, 99.5, 105.0, 112.0, 122.2, 126.1, 127.6, 128.2,
128.5, 128.6, 128.9, 130.2, 133.6, 137.3, 137.4, 170.9. MS (EI)
m/z: 561.2 (M + Na)+. Anal. Calcd for C30H34O9: C, 66.90; H,
6.36; O, 26.74. Found: C, 66.76; H, 6.61; O, 27.04.
1
(c 1.1, CH2Cl2). Η ΝΜR (250 MHz, CDCl3) δ 1.65 (s, 3H), 2.03
(s, 3H), 2.12 (s, 3H), 2.14 (s, 6H), 2.91-2.97 (m, 1H), 4.00-4.08
(m, 1H), 4.19 (m, 2H), 5.30 (dd, J ) 5.6, 9.5 Hz, 1H), 5.50 (t, J
) 9.5 Hz, 1H), 6.03 (d, J ) 8.3 Hz, 1H), 6.29 (s, 1H), 7.27-7.33
(m, 5H). 13C NMR (50.3 MHz, CDCl3) δ 20.2, 20.6, 20.7, 20.9,
21.1, 45.5, 62.5, 65.8, 69.7, 70.4, 72.0, 91.3, 126.8, 128.3, 128.7,
138.3, 168.6, 169.2, 169.5, 170.1, 170.7. MS (EI) m/z: 503.0 (M
+ Na)+. Anal. Calcd for C23H28O11: C, 57.50; H, 5.87. Found:
C, 57.55; H, 6.02.
Con d en sa tion w ith Ald eh yd e 15. Following the general
procedure, a 1:1 mixture of compounds 16a ,b was obtained as a
colorless oil (55%) which was directly peracetylated and partially
separated by flash chromatography (petroleum ether-AcOEt,
2/8) to give first the pure C-7 (S) stereoisomer 17a followed by
the C-7 (R) stereoisomer 17b (96%).
Ack n ow led gm en t. We thank CNRS and the Uni-
versity of Paris-Sud for financial supports, Nicole Le
Goff for helpful technical assistance, and Giliane
Bouchain for preliminary experiments.
17a . Colorless oil. [R]27D: +24.9° (c 1.1, CH2Cl2). 1Η ΝΜR (250
MHz, CDCl3) δ 1.19 (t, J ) 7 Hz, 3H), 2.05 (s, 3H), 2.12 (s, 3H),
2.57 (m, 1H), 3.37-3.56 (m, 4H), 3.62-3.82 (m, 5H), 4.08 (dd, J
) 3.9, 11.2 Hz, 1H), 4.22 (dd, J ) 6.3 Hz, 1H), 4.34 (m, 1H),
4.48-4.67 (m, 4H), 4.81-4.92 (m, 4H), 5.03 (s, 1H), 5.46 (dd, J
J O001217E