Stereoselective synthesis of C-glycosyl analogues of phenylalanine

Article abstract of DOI:10.1016/S0040-4020(02)00831-1

Condensation of 1-[4,6-di-O-(tert-butyldimethylsilyl)-2,3-dideoxy-α-D-erythro-hex-2- enopyranosyl]-4-bromobenzene (2) with methyl 2-acetamidoacrylate in the presence of Pd(OAc)₂, P(C₆H₄-O-CH₃)₃, and AgNO₃, afforded the unsaturated C-glycosyl enamido ester 3d in 80% yield. Reduction of compound 3d in the presence of [Rh(COD)(R,R)-(Et-DuPHOS)]OTf gave the corresponding unsaturated C-glycosyl (R)-phenylalanine derivative, when the [Rh(COD)(S,S)-(Et-DuPHOS)]OTf catalyst gave the C-glycosyl (S)-phenylalanine derivative, in 67 and 79% yield, respectively. Bis-hydroxylation of compound 4, followed by acetylation afforded the C-mannopyranosyl phenylalanine derivative 5 in overall 30% yield.

Full text of DOI:10.1016/S0040-4020(02)00831-1

Tetrahedron 58 (2002) 7539–7544
Stereoselective synthesis of C-glycosyl analogues of phenylalanine
*
Xin Xu, Ghada Fakha and Denis Sinou
` ´ ´
Laboratoire de Synthese Asymetrique, Associe au CNRS, ESCPE Lyon, Universite Claude Bernard Lyon I,
´
´
43, Boulevard du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
Received 17 May 2002; revised 19 June 2002; accepted 3 July 2002
Abstract—Condensation of 1-[4,6-di-O-(tert-butyldimethylsilyl)-2,3-dideoxy-a-D-erythro-hex-2-enopyranosyl]-4-bromobenzene (2) with
methyl 2-acetamidoacrylate in the presence of Pd(OAc)2, P(C6H4-O-CH3)3, and AgNO3, afforded the unsaturated C-glycosyl enamido ester
3d in 80% yield. Reduction of compound 3d in the presence of [Rh(COD)(R,R )-(Et-DuPHOS)]OTf gave the corresponding unsaturated
C-glycosyl (R )-phenylalanine derivative, when the [Rh(COD)(S,S )-(Et-DuPHOS)]OTf catalyst gave the C-glycosyl (S )-phenylalanine
derivative, in 67 and 79% yield, respectively. Bis-hydroxylation of compound 4, followed by acetylation afforded the C-mannopyranosyl
phenylalanine derivative 5 in overall 30% yield. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
paper a palladium(0)-catalyzed access to C-glycosyl
analogues of phenylalanine.
O-Linked glycopeptides are involved in various cellular and
biological processes.1,2 However, glycopeptides are chemi-
cally and enzymatically unstable, since they contain the
natural O- or N-glycosidic linkage. This is a problem which
limits their uses in many cases. One way to circumvent this
drawback is the use of C-analogues of O-glycosylated
aminoacids, in order to increase their stability towards
hydrolysis. Another benefit relative to these compounds is
their uses as probe and understanding of the mechanisms
of a number of key cellular processes. This simple trans-
formation of a O-glycosidic bond to a C-glycosidic bond
could effectively provide very useful informations on the
specific role of the carbohydrate moiety of glycopeptides.
These C-glycosylated amino acids can also be readily
incorporated into larger and biological more relevant
molecular frameworks, in order to modify these glyco-
peptides. In this context, much effort has been devoted to the
development of new technologies for the construction of
some C-glycosyl amino acids.3 Different approaches to
the synthesis of C-glycosyl glycine,4–9 C-glycosyl ala-
nine,10–13 C-glycosyl serine,14–29 C-glycosyl asparagine,22,
2. Results and discussion
We described previously the stereospecific access to various
unsaturated a- and b-C-arylglycosides via the condensation
of an aryl Grignard reagent with p-tert-butylphenyl 4,6-di-
O-(tert-butyldimethylsilyl)-2,3-dideoxy-a-D-erythro-hex-
2-enopyranoside (1); a palladium catalyst complex,
obtained by mixing PdCl2(CH3CN)2 and dppf, allowed the
formation of the corresponding a-configurated C-glycoside,
whereas the b-anomer was obtained in the presence of the
catalyst NiCl2(dppe).37 Among the functionalized C-aryl
glycosides obtained, C-p-bromophenyl D2-glycopyrano-
sides are of particular interest, since the presence of the
bromide on the aromatic ring allows a lot of transformation,
for instance in the presence of a palladium or a nickel
complex. Condensation of carbohydrate 1 with the Grignard
reagent BrMgC6H4-p-Br in the presence of PdCl2(CH3CN)2þ
dppf as the catalyst afforded the unsaturated a-C-aryl
glycoside 2 in 30% yield. One of the most useful
transformation of compound 2 would be the Heck reaction
of this derivative in the presence of various esters,
unsaturated ketones, or nitriles.
29–31
C-glycosyl tyrosine,32 as well as more complex
C-glycosyl amino acids,30,33–35 have been described in the
literature. We have previously described a new access to
C-glycosyl glycine via a palladium(0)-catalyzed alkylation
of 2,3-unsaturated aryl glycoside with ethyl nitroacetate
or with N-(diphenylmethylene)glycine ethyl ester.36
According to our continuous interest in the synthesis of
C-glycosyl analogues of amino acids, we describe in this
In order to test the feasibility of this Heck reaction using
a-C-p-bromophenyl glycoside 2, we performed the con-
densation first in the presence of methyl acrylate as the
unsaturated substrate (Scheme 1). Condensation occurred
readily in the presence of a catalytic amount of Pd(OAc)2
and PPh3 in dimethylformamide as the solvent at 1008C
to give the corresponding coupling product 3a in 60%
yield after purification by column chromatography (Table 1,
entry 1). It is to be noticed that only the E-isomer was
Keywords: C-aryl glycoside; C-glycosyl phenylalanine; Heck reaction.
*
Corresponding author. Tel.: þ33-4-72-448183; fax: þ33-4-78898914;
e-mail: sinou@univ-lyon1.fr
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00831-1

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X. Xu et al. / Tetrahedron 58 (2002) 7539–7544
Scheme 1. Synthesis of C-glycosyl phenylalanine analogues Reagents: (i) BrMg-C6H4-4-Br, PdCl2(CH3CN)2, dppf, THF, 258C. (ii) CH2vCHR1R2,
Pd(OAc)2, PAr3, NEt3, DMF, D. (iii) H2, [Rh(COD)(Et-DuPHOS]OTf. (iv) OsO4, CH3COCH3, H2O. (v) Ac2O, C5H5N.
Table 1. Heck-coupling reaction of C-bromophenyl carbohydrate 2 with
various alkenes
0.2 equiv. of PPh3, no formation of the desired product was
detected (Table 1, entry 4); addition of silver carbonate
(2 equiv.) allowed the formation of compound 3d in 14%
yield (Table 1, entry 5). However, when P(C6H4-o-CH3)3
(0.4 equiv.) was used as the ligand, instead of PPh3, the
desired product 3d was obtained in 33% yield after column
chromatography (Table 1, entry 6). When this ligand was
combined with silver carbonate (2 equiv.), the yield in 3d
increased to 80% (Table 1, entry 7). Since a single
stereoisomer was obtained in this condensation as shown
from the NMR spectra, the Z configuration was attributed to
3d, according to the previous results in this field.38–43
Entry
Alkene
Phosphine Additive Yield 3 (%)
1
2
3
4
5
6
7
R1¼H, R2¼CO2Me
R1¼H, R2¼COMe
R1¼H, R2¼CN
PPh3
PPh3
PPh3
No
No
No
No
3a (60)
3b (82)
3c (63)
3d (0)
a
R1¼NHCOMe, R2¼CO2Me PPh3
R1¼NHCOMe, R2¼CO2Me PPh3
AgNO3 3d (14)
3d (33)
b
R1¼NHCOMe, R2¼CO2Me P(o-tolyl)3 No
b
R1¼NHCOMe, R2¼CO2Me P(o-tolyl)3 AgNO3 3d (80)
[2]/[alkene]/[Pd(OAc)2]/[NEt3]/[additive]¼10:20:1:2:80:20; T¼1008C;
12 h.
a
19 h.
[Pd]/[P(o-tolyl)3]¼1:3.
b
In order to reduce the C-glycosyl enamide ester 3d to the
C-glycosyl amino acid 4, we used [Rh(COD)(Et-DuPHOS)]-
OTf as the hydrogenation catalyst. The DuPHOS-Rhþ
catalyst seems effectively to be the appropriate candidate for
this reduction, since it has been shown that it reduced a
variety of enamides with excellent chiral inductions.44
Moreover, this catalyst has been successfully applied in
the reduction of some C-glycosyl enamide precursors.19 The
reduction was performed in MeOH as the solvent and under
10 bar H2. When the reduction was performed using
(R,R)-Et-DuPHOS or (S,S)-Et-DuPHOS as the chiral ligand
under 10 bar H2, two different compounds, resulting from
the reduction of the double bond of the enamido moiety
only, were produced in 67 and 64% yield, respectively.
These two diastereoisomers show small differences in the
1H NMR spectra, and particularly the signal corresponding
to the ester group; according to these spectra, we postulated
that this C-glycosyl amino acid was produced in .95% de
in the two cases. The reaction was also performed under
5 bar H2 to give the expected product in 79% yield, and
more than 95% de. According to the results of Burk et al.44
we postulated that reduction of compound 3d using the two
enantiomeric catalysts [Rh(COD)(R,R )-(Et-DuPHOS)]OTf
and [Rh(COD)(S,S )-(Et-DuPHOS)]OTf gave the (R )- and
(S )-glycosyl amino acid 4, respectively.
detected, characterized by a coupling constant J¼16.2 Hz
for the ethylenic proton.
This Heck reaction was then extended to methyl vinyl
ketone and acrylonitrile under exactly the same conditions
(Table 1, entries 2, 3). The unsaturated functionalized
C-aryl glycosides 3b and 3c were obtained in 82 and 63%
yield after column chromatography, respectively. Only the
stereoisomer E was obtained as shown by the coupling
constant J¼16.2 and 16.7 Hz for the ethylenic proton of 3b
and 3c, respectively.
We then turned our attention to the condensation of
bromophenyl glycoside 2 with methyl 2-acetamido acrylate,
in order to obtain C-glycosidic dehydrophenylalanine
methyl ester derivatives. Although several methods
appeared recently in the literature concerning the prepa-
ration of dehydroaminoacids using a palladium-catalyzed
vinylation, this condensation seemed more difficult under
the usual Heck reaction conditions.38–43
Effectively when the condensation was performed at 1008C
for 12 h in the presence of 0.1 equiv. of Pd(OAc)2 and

X. Xu et al. / Tetrahedron 58 (2002) 7539–7544
7541
Then we try to bis-hydroxylated the unsaturated carbohydrate
moiety of compound 4. Bis-hydroxylation of compound 4
in a mixture of acetone/water using a catalytic amount of
OsO4 in the presence of N-methyl-morpholine gave a diol,
which was directly acetylated. Purification by column
chromatography gave the C-mannopyranosyl amino acid
derivative 5 in 30% yield. The attribution of the manno
configuration to this compound was mainly based on
the coupling constants observed for H-1 (J1,2¼2.2 Hz) and
H-4 (J4,3¼8.8 Hz), characteristics of an equatorial–
equatorial and an axial–axial disposition for the
hydrogens, and so a manno configuration. This configu-
ration is also in agreement with a bis-hydroxylation on the
less hindered side of the double bond of the unsaturated
carbohydrate.
and dppf (48.8 mg, 0.088 mol) in 4 mL of THF was added at
room temperature a solution of the Grignard reagent
prepared from magnesium (128 mg, 5.2 mmol) and 1,4-di-
bromobenzene (1028.6 mg, 4.36 mmol) in 10 mL of THF.
The reaction was followed by TLC. After disappearance of
the starting material, diethyl ether (100 mL) was added, the
ethereal solution was washed with water (2£20 mL), and
dried. Concentration and column chromatography on silica
gel, using petroleum ether/dichloromethane as the eluent,
furnished 135.6 mg of compound 2 (yield 30%). Oil; Rf 0.33
(petroleum ether/dichloromethane 2/1); [a ]2D5¼212.8 (c
1
1.9, CHCl3); H NMR (CDCl3, 200 MHz) d 0.04 (s, 3H,
SiCH3), 0.06 (s, 3H, SiCH3), 0.09 (s, 3H, SiCH3), 0.11 (s,
3H, SiCH3), 0.89 (s, 9H, SiMe3), 0.91 (s, 9H, SiMe3), 3.37
(ddd, J¼8.0, 6.3, 2.4 Hz, 1H, H-5), 3.68 (dd, J¼11.1,
6.3 Hz, 1H, H-6), 3.87 (dd, J¼11.1, 2.4 Hz, 1H, H-6), 4.18
(dd, J¼8.4, 1.7 Hz, 1H, H-4), 5.10 (bs, 1H, H-1), 5.85 (d,
J¼10.4 Hz, 1H, H-2), 6.05 (d, J¼10.4 Hz, 1H, H-3), 7.32
(d, J¼8.6 Hz, 2H, Harom), 7.42 (d, J¼8.6 Hz, 2H, Harom);
13C NMR (CDCl3, 50 MHz) d 25.1 (SiMe), 25.0 (SiMe),
24.6 (SiMe), 24.1 (SiMe), 18.1 (SiCMe3), 18.5 (SiCMe3),
25.9 (SiCMe3), 26.1 (SiCMe3), 63.4 (C-6), 64.3 (C-4), 73.1
(C-5), 74.8 (C-1), 121.6 (C-Br), 127.9, 129.6, 130.9, 132.9,
and 139.5 (C-2, C-3, Carom).
3. Conclusion
In conclusion, a Heck-coupling reaction of an appropriate
C-p-bromophenyl unsaturated glycoside led with good
yields to the corresponding C-glycosyl enamide ester.
Hydrogenation of this unsaturated substrate using
[Rh(COD)(Et-DuPHOS]OTf as the catalyst produced the
corresponding unsaturated C-glycosylphenylalanine with a
high ed, and having the D- or the L-stereochemistry at the
a-amino acid center, depending on the catalyst precursor.
Bis-hydroxylation of this compound, followed by acetyl-
ation of the resulting diol, gave the C-manno pyranosyl
phenylalanine derivative. Experiments to explore the
potentiality of this new methodology and his extension to
the b-anomer are under way and will be reported in due
course.
Anal. Calcd for C24H41O3BrSi2 (513.67): C, 56.12; H, 8.05.
Found: C, 56.26; H, 7.99.
4.2. General procedure
A solution of C-p-bromophenyl glycoside 2 (309 mg,
0.6 mmol) and the unsaturated substrate (1.2 mmol) in
DMF (4 mL) was heated at 1008C in the presence of
Pd(OAc)2 (13.5 mg, 1.2 mmol), monophosphine (0.2 mmol),
NEt3 (0.67 mL, 4.8 mmol), and eventually AgNO3 (204.8 mg,
1.2 mmol) for the indicated time. After being cooled to room
temperature, water (10 mL) was added, and the solution was
treated by Et2O (3£15 mL). Evaporation of the solvent
under reduced pressure gave an oil that was purified by
column chromatography on silica gel using the indicated
solvent to give the coupled product 3.
4. Experimental
4.1. General methods
All reactions were monitored by thin-layer chromatography
carried out on 0.25 mm silica gel plates (60 F-254, Merck).
Compounds were visualized under UV light (254 nm) or by
spraying with an H2SO4 solution and heating. Column
chromatography was performed on silica gel 60 (40–63
mesh, Merck). NMR spectra were recorded on Bruker AC
200 and AM 300 spectrometers, and chemical shifts are
given in ppm on the d scale from internal tetramethylsilane.
Reactions involving palladium complexes were carried out
in a Schlenk tube under a nitrogen atmosphere. THF was
distilled from sodium/benzophenone and stored under a
nitrogen atmosphere. Pd(OAc)2, triphenylphosphine,
tri(o-tolyl) phosphine, methyl acrylate, methyl vinyl ketone,
acrylo-nitrile, methyl 2-acetamidoacrylate, [Rh(COD)(R,R)-
(Et-DuPHOS)]OTf, and [Rh(COD)(S,S )-(Et-DuPHOS)]-
OTf are from commercial source. p-tert-Butylphenyl
4,6-di-O-(tert-butyldimethylsilyl)-2,3-dide-oxy-a-D-ery-
thro-hex-2-enopyranoside (1) was prepared as already
described.37
4.2.1. Methyl 3-[4{4,6-di-O-(tert-butyldimethylsilyl)-2,3-
dideoxy-a-D-erythro-hex-2-enopyranosyl}phenyl]pro-
penoate (3a). Oil; Rf 0.24 (petroleum ether/dichloro
methane 1/2); [a]D25¼231.4 (c 1.2, CH2Cl2); 1H NMR
(CDCl3, 300 MHz) d 0.03 (s, 3H, SiCH3), 0.05 (s, 3H,
SiCH3), 0.08 (s, 3H, SiCH3), 0.11 (s, 3H, SiCH3), 0.88 (s,
18H, SiCMe3), 3.39 (ddd, J¼8.1, 6.3, 2.2 Hz, 1H, H-5), 3.69
(dd, J¼11.0, 6.3 Hz, 1H, H-6), 3.81 (s, 3H, OCH3), 3.86 (dd,
J¼11.0, 2.2 Hz, 1H, H-6), 4.16 (ddd, J¼8.1, 1.8, 1.8 Hz,
1H, H-4), 5.27 (bs, 1H, H-1), 5.89 (ddd, J¼10.3, 1.8, 1.8 Hz,
1H, H-3), 6.06 (ddd, J¼10.3, 3.3, 1.8 Hz, 1H, H-2), 6.43 (d,
J¼16.2 Hz, 1H, vCH–), 7.50 (bs, 4H, C6H4), 7.68 (d, J¼
16.2 Hz, 1H, C6H4–CHv); 13C NMR (CDCl3, 50 MHz) d
25.3 (SiMe), 25.2 (SiMe), 24.7 (SiMe), 24.2 (SiMe),
18.0 (SiCMe3), 18.4 (SiCMe3), 25.8 (SiCMe3), 25.9
(SiCMe3), 51.7 (OCH3), 63.3 (C-6), 64.2 (C-4), 73.2 (C-1),
74.9 (C-5), 117.7 (vCH–CO2), 127.8, 127.9, 128.1, 131.2,
133.5, 142.9, and 144.6 (C6H4–CHv, C-2, C-3), 165.0 (CO).
4.1.1. 1-[4,6-Di-O-(tert-butyldimethylsilyl)-2,3-dideoxy-
a-D-erythro-hex-2-enopyranosyl]-4-bromophenyl (2). To
a solution of the unsaturated carbohydrate 1 (447 mg,
0.88 mmol) and PdCl2(CH3CN)2 (22.8 mg, 0.088 mmol)
Anal. Calcd for C28H46O5Si2 (518.84): C, 64.82; H, 8.94.
Found: C, 64.88; H, 8.86.

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X. Xu et al. / Tetrahedron 58 (2002) 7539–7544
4.2.2. 4-[4{4,6-Di-O-(tert-butyldimethylsilyl)-2,3-di-
deoxy-a-D-erythro-hex-2-enopyranosyl}phenyl]-2-oxo-
but-3-ene (3b). Oil; Rf 0.29 (petroleum ether/ethyl acetate
131.8, 132.1, 132.8, 133.0, and 143.6 (C6H4–C Hv, C-2,
C-3), 165.8 (CO2), 169.3 (COCH3).
1
10/1); [a ]2D5¼þ12.9 (c 0.9, CH2Cl2); H NMR (CDCl3,
HRMS m/z (FAB) calcd for [M2H]þ (C30H48NO6Si2)
574.3020, found 574.3024.
300 MHz) d 0.04 (s, 3H, SiCH3), 0.06 (s, 3H, SiCH3), 0.09
(s, 3H, SiCH3), 0.11 (s, 3H, SiCH3), 0.89 (s, 18H, SiCMe3),
2.39 (s, 3H, COCH3), 3.40 (ddd, J¼8.1, 6.6, 2.2 Hz,
1H, H-5), 3.71 (dd, J¼11.0, 6.6 Hz, 1H, H-6), 3.87 (dd,
J¼11.0, 2.2 Hz, 1H, H-6), 4.16 (bd, J¼8.1 Hz, 1H,
H-4), 5.28 (bs, 1H, H-1), 5.90 (ddd, J¼10.5, 1.8, 1.8 Hz,
1H, H-3), 6.07 (ddd, J¼10.5, 3.1, 1.8 Hz, 1H, H-2), 6.72
(d, J¼16.2 Hz, 1H, vCH–), 7.51 (bs, 4H, C6H4), 7.52 (d,
J¼16.2 Hz, 1H, C6H4–CHv); 13C NMR (CDCl3, 50 MHz)
d 25.3 (SiMe), 25.2 (SiMe), 24.7 (SiMe), 24.2 (SiMe),
18.0 (SiCMe3), 18.4 (SiCMe3), 25.8 (SiCMe3), 26.0
(SiCMe3), 27.8 (COC H3), 63.3 (C-6), 64.2 (C-4), 73.2
(C-1), 75.0 (C-5), 127.0 (vC HCO), 127.1, 127.9, 128.2,
129.2, 130.3, 141.6, and 143.2 (C6H4–CHv, C-2, C-3),
198.0 (CO).
4.3. Hydrogenation of unsaturated compound 3d
An autoclave was charged with compound 3d (90 mg,
0.16 mmol), and catalyst [Rh(COD)(Et-DuPHOS]OTf
(2.5 mg, 3.5£1023 mmol). After five vacuum/H2 cycles,
ethanol (7 mL) was added, and the reactor was pressurized
to an initial pressure of 5–10 bar hydrogen. The reaction
was allowed to stir at room temperature for 24 h.
Evaporation of the solvent followed by column chroma-
tography on silica using a mixture of petroleum ether/ethyl
acetate as the eluent gave the C-glycosyl phenylalanine
methyl ester 4.
4.3.1. Methyl (2R )-2-acetamido-3-[4{4,6-di-O-(tert-
butyldimethylsilyl)-2,3-dideoxy-a-D-erythro-hex-2-eno-
pyranosyl}phenyl]propanoate (4). Oil; Rf 0.44 (petroleum
HRMS m/z (FAB) calcd for [M2H]þ (C28H45O4Si2)
501.2856, found 501.2855.
1
ether/ethyl acetate 1/1); [a ]2D5¼214.1 (c 1.9, CH2Cl2); H
4.2.3. 3-[4{4,6-Di-O-(tert-butyldimethylsilyl)-2,3-di-
deoxy-a-D-erythro-hex-2-enopyranosyl}phenyl]propene-
nitrile (3c). Oil; Rf 0.44 (petroleum ether/ethyl acetate
NMR (CDCl3, 300 MHz) d 0.06 (s, 3H, SiCH3), 0.07 (s, 3H,
SiCH3), 0.11 (s, 3H, SiCH3), 0.13 (s, 3H, SiCH3), 0.91 (s,
9H, SiCMe3), 0.92 (s, 9H, SiCMe3), 2.02 (s, 3H, COCH3),
3.14 (dd, J¼14.0, 6.7 Hz, 1H, CH2), 3.16 (dd, J¼14.0,
6.7 Hz, 1H, CH2), 3.43 (ddd, J¼8.2, 6.5, 2.5 Hz, 1H,
H-5), 3.70 (dd, J¼11.1, 6.5 Hz, 1H, H-6), 3.76 (s, 3H,
NHCOCH3), 3.88 (dd, J¼11.1, 2.5 Hz, 1H, H-6), 4.18 (ddd,
J¼8.2, 3.9, 1.9 Hz, 1H, H-4), 4.91 (m, 1H, CHNH), 5.27
(bs, 1H, H-1), 5.89 (ddd, J¼10.3, 3.9, 1.9 Hz, 1H, H-3), 5.93
(m, 1H, NH), 6.06 (ddd, J¼10.3, 3.2, 1.9 Hz, 1H, H-2),
7.08–7.41 (m, 4H, C6H4); 13C NMR (CDCl3, 50 MHz) d
25.3 (SiMe), 25.1 (SiMe), 24.7 (SiMe), 24.2 (SiMe),
18.0 (SiCMe3), 18.4 (SiCMe3), 23.2 (COC H3), 25.8
(SiCMe3), 26.0 (SiCMe3), 37.4 (C6H4C H2), 52.3
(CO2C H3), 53.1 (CHNH), 63.3 (C-6), 64.2 (C-4), 73.2
(C-1), 74.7 (C-5), 127.6, 128.4, 129.2, 130.0, 134.9, and
139.3 (C6H4, C-2, C-3), 169.7 (CO2), 172.1 (COCH3); m/z
(EI) 579 [MþH]þ, 577 [M2H]þ, 463 [M2SiMe2CMe3]þ.
1
10/1); [a ]2D5¼252.2 (c 1.1, CH2Cl2); H NMR (CDCl3,
300 MHz) d 0.04 (s, 3H, SiCH3), 0.06 (s, 3H, SiCH3), 0.09
(s, 3H, SiCH3), 0.11 (s, 3H, SiCH3), 0.88 (s, 9H, SiCMe3),
0.89 (s, 9H, SiCMe3), 3.38 (ddd, J¼14.7, 6.6, 2.3 Hz, 1H,
H-5), 3.70 (dd, J¼11.0, 6.6 Hz, 1H, H-6), 3.86 (dd, J¼11.0,
2.3 Hz, 1H, H-6), 4.16 (ddd, J¼14.7, 3.7, 1.8 Hz, 1H, H-4),
5.28 (bs, 1H, H-1), 5.87 (d, J¼16.7 Hz, vCHCN), 5.91 (dd,
J¼10.3, 3.7, 1.8 Hz, 1H, H-3), 6.05 (ddd, J¼10.3, 2.9,
1.8 Hz, 1H, H-2), 7.40 (d, J¼16.7 Hz, 1H, C6H4–CHv),
7.43 (d, J¼8.2 Hz, 2H, C6H4), 7.52 (d, J¼8.2 Hz, 2H,
C6H4); 13C NMR (CDCl3, 50 MHz) d 25.3 (SiMe), 25.1
(SiMe), 24.7 (SiMe), 24.2 (SiMe), 18.0 (SiCMe3), 18.4
(SiCMe3), 25.8 (SiCMe3), 26.0 (SiCMe3), 63.3 (C-6), 64.1
(C-4), 73.1 (C-1), 75.0 (C-5), 96.2 (vCH–CN), 118.2
(CN), 127.4, 128.0, 131.3, 132.7, 144.0, 148.3, and 150.3
(C6H4–CHv, C-2, C-3).
4.3.2. Methyl (2S )-2-acetamido-3-[4{4,6-di-O-(tert-
butyldimethylsilyl)-2,3-dideoxy-a-D-erythro-hex-2-eno-
pyranosyl}phenyl]propanoate (4). Oil; Rf 0.44 (petroleum
Anal. Calcd for C27H43NO3Si2 (485.82): C, 66.75; H, 8.92.
Found: C, 66.84; H, 8.88.
ether/ethyl acetate 1/1); [a ]2D5¼þ31.7 (c 2.5, CH2Cl2); H
1
4.2.4. Methyl 2-acetamido-3-[4{4,6-di-O-(tert-butyldi-
methylsilyl)-2,3-dideoxy-a-D-erythro-hex-2-enopyrano-
syl}phenyl]propenoate (3d). Oil; Rf 0.24 (petroleum
NMR (CDCl3, 300 MHz) d 0.05 (s, 3H, SiCH3), 0.07 (s, 3H,
SiCH3), 0.11 (s, 3H, SiCH3), 0.13 (s, 3H, SiCH3), 0.91 (s,
9H, SiCMe3), 0.92 (s, 9H, SiCMe3), 2.02 (s, 3H, COCH3),
3.12 (dd, J¼14.0, 5.4 Hz, 1H, CH2), 3.16 (dd, J¼14.0,
5.8 Hz, 1H, CH2), 3.43 (ddd, J¼8.4, 6.3, 2.2 Hz, 1H,
H-5), 3.73 (dd, J¼11.1, 6.3 Hz, 1H, H-6), 3.78 (s, 3H,
NHCOCH3), 3.88 (dd, J¼11.1, 2.2 Hz, 1H, H-6), 4.17 (ddd,
J¼8.4, 1.9, 1.9 Hz, 1H, H-4), 4.91 (m, 1H, CHNH), 5.27
(bs, 1H, H-1), 5.89 (ddd, J¼10.4, 1.9, 1.9 Hz, 1H, H-3), 5.92
(m, 1H, NH), 6.06 (ddd, J¼10.4, 1.9, 1.9 Hz, 1H, H-2), 7.07
1
ether/ethyl acetate 2/1); [a ]2D5¼217.1 (c 0.9, CH2Cl2); H
NMR (CDCl3, 300 MHz) d 0.04 (s, 3H, SiCH3), 0.05 (s, 3H,
SiCH3), 0.08 (s, 3H, SiCH3), 0.10 (s, 3H, SiCH3), 0.90 (s,
18H, SiCMe3), 2.10 (s, 3H, COCH3), 3.40 (ddd, J¼8.1, 6.2,
2.6 Hz, 1H, H-5), 3.70 (dd, J¼11.0, 6.2 Hz, 1H, H-6), 3.80
(s, 3H, NHCOCH3), 3.86 (dd, J¼11.0, 2.6 Hz, 1H, H-6),
4.16 (ddd, J¼8.1, 1.8, 1.5 Hz, 1H, H-4), 5.30 (bs, 1H, H-1),
5.85 (ddd, J¼10.5, 1.5, 1.5 Hz, 1H, H-3), 6.07 (ddd, J¼10.5,
3.0, 1.8 Hz, 1H, H-2), 6.90 (bs, 1H, NH), 7.36–7.45
(m, 5H, C6H4–CHv); 13C NMR (CDCl3, 50 MHz) d 25.3
(SiMe), 25.1 (SiMe), 24.7 (SiMe), 24.2 (SiMe), 18.0
(SiCMe3), 18.4 (SiCMe3), 22.0 (COC H3), 25.8 (SiCMe3),
26.0 (SiCMe3), 52.7 (COOC H3), 63.3 (C-6), 64.1 (C-4),
73.2 (C-1), 74.9 (C-5), 125.4, 125.6, 127.5, 127.9, 131.1,
(d, J¼8.0 Hz, 2H, C6H4), 7.39 (d, J¼8.0 Hz, 2H, C6H4); 13
C
NMR (CDCl3, 50 MHz) d 25.3 (SiMe), 25.1 (SiMe), 24.7
(SiMe), 24.2 (SiMe), 18.0 (SiCMe3), 18.4 (SiCMe3), 23.1
(COC H3), 25.8 (SiCMe3), 26.0 (SiCMe3), 37.4 (C6H4C H2),
52.3 (CO2C H3), 53.1 (CHNH), 63.3 (C-6), 64.2 (C-4), 73.2
(C-1), 74.7 (C-5), 127.6, 128.3, 129.2, 130.7, 134.9, and
139.3 (C6H4, C-2, C-3), 169.6 (CO2), 172.0 (COCH3).

X. Xu et al. / Tetrahedron 58 (2002) 7539–7544
7543
6. Simchen, G.; Pu¨rkner, E. Synthesis 1990, 525–527.
7. Colombo, L.; Casiraghi, G.; Pittalis, A.; Rassu, G. J. Org.
Chem. 1991, 56, 3897–3900.
Anal. Calcd for C30H51NO6Si2 (577.91): C, 62.35; H, 8.90.
Found: C, 63.32; H, 8.97.
8. Casiraghi, G.; Colombo, L.; Rassu, G.; Spanu, P. J. Org.
Chem. 1991, 56, 6523–6527.
4.3.3. Methyl (2S )-2-acetamido-3-[4{4,6-di-O-(tert-
butyldimethylsilyl)-2,3-di-O-acetyl-a-D-mannopyrano-
syl}phenyl] propanoate (5). To a solution of unsaturated
compound (2S )-4 (220 mg, 0.4 mmol) in a mixture of
acetone/water (5 mL/1 mL) was added N-methyl morpho-
line oxide (178 mg, 1.6 mmol), and then OsO4 (4.4 mg,
0.017 mmol). After being stirred at room temperature until
all the starting material disappeared, an aqueous solution
of sodium bisulfite (5 mL) was added. After 30 min, an
aqueous solution of sodium chloride was added (40 mL),
and the organic product was extracted with dichloromethane
(2£50 mL). Evaporation of the solvent gave the crude diol.
This diol was stirred in the presence of C5H5N (2 mL) and
acetic anhydride (2 mL) for 24 h; addition of a saturated
aqueous solution of cuprous sulfate (5 mL), followed by
extraction with CH2Cl2 (4£50 mL), evaporation of the
solvent, and purification by column chromatography on
silica using a mixture petroleum ether/ethyl acetate as the
eluent gave 83 mg of compound 5 as an oil (yield 30%). Oil;
Rf 0.51 (petroleum ether/ethyl acetate 1/2); [a]2D5¼þ73.0 (c
9. Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G.
Tetrahedron: Asymmetry 1995, 6, 371–374.
¨
10. Kessler, H.; Wittmann, V.; Koch, M.; Kottenhahn, M. Angew.
Chem., Int. Ed. Engl. 1992, 31, 902–904.
11. Gurjar, M. K.; Mainkar, A. S.; Syamala, M. Tetrahedron:
Asymmetry 1993, 4, 2343–2346.
12. Axon, S. P.; Beckwith, A. L. J. J. Chem. Soc., Chem. Commun.
1995, 549–550.
13. Vincent, S. P.; Schleyer, A.; Wong, C.-H. J. Org. Chem. 2000,
65, 4440–4443.
14. Petrus, L.; BeMiller, J. N. Carbohydr. Res. 1992, 230,
197–200.
15. Bertozzi, C. R.; Hoeprich, Jr. P. D.; Bednarski, M. D. J. Org.
Chem. 1992, 57, 6092–6094.
16. Bertozzi, C. R.; Cook, D. G.; Kobertz, W. R.; Gonzales-
Scarano, F.; Bednarski, M. D. J. Am. Chem. Soc. 1992, 114,
10639–10641.
17. Dorgan, B. J.; Jackson, R. F. W. Synlett 1996, 859–861.
18. Herpin, T. F.; Motherwell, W. B.; Weibel, J.-M. J. Am. Chem.
Soc. 1997, 119, 9897–9898.
1
1.3, CH2Cl2); H NMR (CDCl3, 300 MHz) d 0.02 (s, 3H,
SiCH3), 0.04 (s, 3H, SiCH3), 0.07 (s, 3H, SiCH3), 0.08 (s,
3H, SiCH3), 0.80 (s, 9H, SiCMe3), 0.95 (s, 9H, SiCMe3),
1.98 (s, 3H, COCH3), 2.05 (s, 3H, COCH3), 2.10 (s, 3H,
COCH3), 3.07 (dd, J¼13.9, 5.9 Hz, 1H, CH2), 3.13 (dd,
J¼13.9, 5.5 Hz, 1H, CH2), 3.34 (ddd, J¼8.8, 4.8, 2.9 Hz,
1H, H-5), 3.67–3.70 (m, 1H, H-3), 3.72 (s, 3H, NHCOCH3),
3.80 (dd, J¼11.0, 2.9 Hz, 1H, H-6), 3.86 (dd, J¼11.0,
4.8 Hz, 1H, H-6), 4.13 (dd, J¼8.8, 8.8 Hz, 1H, H-4), 4.81–
4.94 (m, 2H, CHNH, H-2), 4.95 (d, J¼2.2 Hz, 1H, H-1),
5.96 (m, 1H, NH), 7.10 (d, J¼8.1 Hz, 2H, C6H4), 7.45 (d,
J¼8.1 Hz, 2H, C6H4); 13C NMR (CDCl3, 50 MHz) d 25.3
(SiMe), 25.0 (SiMe), 24.9 (SiMe), 24.5 (SiMe), 18.1
(SiCMe3), 18.4 (SiCMe3), 20.9 (COCH3), 21.2 (COCH3),
23.2 (NHCOCH3), 25.7 (SiCMe3), 25.9 (SiCMe3), 37.5
(C6H4CH2), 52.4 (CO2C H3), 53.0 (CHNH), 62.3 (C-6),
66.3, 69.5, 73.3, 75.5, and 76.3 (C-1, C-2, C-3, C-4, C-5),
126.9, 129.7, 130.0, and 130.4 (C6H4), 169.7 (CO2), 170.4
(COCH3), 170.5 (COCH3), 172.0 (COCH3).
19. Debenham, S. D.; Debenham, J. S.; Burk, M. J.; Toone, E. J.
J. Am. Chem. Soc. 1997, 119, 9897–9898.
20. Dondoni, A.; Marra, A.; Massi, A. Chem. Commun. 1998,
1741–1742.
21. Dondoni, A.; Marra, A.; Massi, A. Tetrahedron 1998, 54,
2827–2832.
22. Dondoni, A.; Massi, A.; Marra, A. Tetrahedron Lett. 1998, 39,
6601–6604.
23. Dondoni, A.; Marra, A.; Massi, A. J. Org. Chem. 1999, 64,
933–944.
24. Lay, L.; Meldal, M.; Nicotra, F.; Panza, L.; Russo, G. Chem.
Commun. 1997, 1469–1470.
25. Tedebark, U.; Meldal, M.; Panza, L.; Bock, K. Tetrahedron
Lett. 1998, 39, 1815–1818.
26. Urban, D.; Skrydstrup, T.; Beau, J.-M. Chem. Commun. 1998,
955–956.
27. Fuchss, T.; Schmidt, R. R. Synthesis 1998, 753–758.
28. Arya, P.; Ben, R. N.; Qin, H. Tetrahedron Lett. 1998, 39,
6131–6134.
HRMS m/z (FAB) calcd for [MþH]þ (C34H58NO10Si2)
696.3599, found 696.3607.
29. Campbell, A. D.; Paterson, D. E.; Raynham, T. M.; Taylor,
R. J. K. Chem. Commun. 1999, 1599–1600.
30. Burkhart, F.; Hoffmann, M.; Kessler, H. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1191–1192.
Acknowledgments
31. Dondoni, A.; Mariotti, G.; Marra, A. Tetrahedron Lett. 2000,
41, 3483–3487.
ˆ
One of us (X. X.) thanks the Region Rhone-Alpes for a
fellowship.
32. Pearce, A. J.; Ramaya, S.; Thorn, S. N.; Bloomberg, G. B.;
Walter, D. S.; Gallagher, T. J. Org. Chem. 1999, 64,
5453–5462.
33. Hoffmann, M.; Burkhart, F.; Hessler, F.; Kessler, G. Helv.
Chim. Acta 1996, 79, 1519–1532.
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