Efficient synthesis of a stereochemically defined carbohydrate scaffold: Carboxymethyl 2-acetamido-6-azido-4-O-benzyl-2-deoxy-α-D-glucopyranoside

Full text of DOI:10.1021/jo001183a

J . Org. Chem. 2000, 65, 8387-8390
8387
Efficien t Syn th esis of a Ster eoch em ica lly
Defin ed Ca r boh yd r a te Sca ffold :
Ca r boxym eth yl 2-Aceta m id o-6-Azid o-
4-O-Ben zyl-2-d eoxy-r-D-Glu cop yr a n osid e
Manuka Ghosh,*,† Richard G. Dulina,
Ramesh Kakarla,‡ and Michael J . Sofia‡
Resu lts a n d Discu ssion
Intercardia Research Laboratories, 8 Cedar Brook Drive,
Cranbury, New J ersey 08852
The design of scaffold 1 involved incorporation of a
carboxymethyl group at C-1, a free hydroxyl group at C-3,
and an azido functionality at C-6 on the modified hexose
backbone. These three functional groups offer the desired
chemoselectivity necessary for rapid combinatorial solid-
phase synthesis and create the ultimate “three-point
binding motif” in a relatively few number of synthetic
steps.
mghosh@nrgn.com
Received August 4, 2000
In tr od u ction
Although natural products remain a rich source of new
lead compounds for drug discovery, the ability to rapidly
perform structure-function studies is limited by the
synthesis. The combinatorial chemistry approach has
become well-established among modern drug discovery
strategies especially where generation of a large number
of structurally diverse molecules is necessary in a short
period of time for high throughput screening programs.1
Such approaches can facilitate the identification of
ligands that bind to biological receptors, promoting the
chemical understanding of cellular processes. Recently,
we have disclosed a new strategy for the construction of
broad screening libraries using a carbohydrate-based
universal pharmacophore mapping library strategy.2
Hexoses are readily available in enantiomerically pure
form and offer a conformationally rigid pyran backbone
with three-dimensional arrangement of substituents. For
small molecule receptor ligands such a well-defined
spatial arrangement of functional groups, classically
defined as the “three-point motif”, is necessary for the
selective recognition between molecule and its protein
receptors. Moreover, hexose derivatives have demon-
strated high affinity to several pharmacologically impor-
tant receptors (e.g., G-protein-coupled receptors),3 which
clearly suggest the potential of monosaccharides as three-
dimensional chemical platforms for strategic generation
of combinatorial libraries. However, success of such a
strategy relies heavily on the development of carbohydrate-
based novel chemical entities with appropriate spatial
arrangements for diversification. Herein we describe the
design and efficient synthesis of a monosaccharide scaf-
fold 1, containing three diversity sites that allow develop-
ment of libraries with distinct chiral molecular recogni-
tion motifs.
The synthesis of compound 1 is outlined below. A
modified Fisher glycosidation of 2-acetamido-2-deoxy-D-
glucose with acidic allyl alcohol in the presence of BF3‚
Et2O under reflux (10h) provided 2 as a 9:1 (R: â) mixture
of anomers which after crystallization (EtOH/Et2O) fur-
nished the desired R-anomer 2 in 63% yield (Scheme 1).
Since, the target 6-azido-glucopyranoside 1 possesses
a free C-3 hydroxyl group and a benzyl-protected C-4
hydroxyl group, a regioselective reductive ring-opening
of the corresponding 4,6-O-benzylidene acetal appeared
to be appropriate for incorporation of the 4-O-benzyl ether
substituent. Thus, treatment of allyl 2-acetamido-2-
deoxy-R-D-glucopyranoside (2) with benzaldehyde dim-
ethyl acetal in the presence of catalytic amount of TsOH
(DMF, 60 °C) under reduced pressure afforded the 4,6-
O-benzylidene acetal 3 in 83% yield. Acetylation of
compound 3 under usual conditions (Ac2O, pyr, DMAP)
furnished the 3-O-acetyl-4,6-benzylidene derivative 4
(72%). The next step in the synthetic sequence was the
ring-opening of the benzylidene acetal to obtain the
desired 4-O-benzyl derivative. The most useful and
widely utilized method for differentiating the C-4 and C-6
hydroxyl groups of sugars involve reductive ring-opening
of a rather easily available 4,6-O-benzylidene acetal.4
However, this usually produces the 6-O-benzyl regioiso-
mer predominantly due to attack of the electrophile at
the secondary hydroxyl oxygen (4-O, thermodynamic
control).4a,f,I,k On the other hand, reported conditions for
the production of 4-O-benzyl derivatives4a,f,k-n are often
less chemoselective4a and offer unsatisfactory regioselec-
tivity4k or yield.4f Reductive ring-opening of benzylidene
acetal of fully protected 4,6-O-(4-methoxybenzylidene)-
hexopyranoside with combination of NaCNBH3-TMSCl
in acetonitrile has been reported to give the 4-O-(4-
methoxybenzyl)ethers in good yield and regioselectivity.4d,e
† Correspondence/current address: Neurogen Corporation, 35 North-
east Industrial Rd., Branford, CT 06405. Tel: 203-488-8201. Fax: 203-
481-5290.
(3) For some pioneering work in this area, see: (a) Hirschmann,
R.; Nicolaou, K. C.; Pietranico, S.; Leahy, E. M.; Salvino, J .; Arison,
B.; Cichy, M. A.; Spoors, P. G.; Shakespear, W. C.; Sprengeler, P. A.;
Hamley, P.; Smith, A. B., III.; Reisine, T.; Raynor, K.; Maechler, L.;
Donaldson, C.; Vale, W.; Freidinger, R. M.; Cascieri, M. A.; Strader,
C. D. J . Am. Chem. Soc. 1993, 115, 12550-12568. (b) Hirschmann,
R.; Wenqing, Y.; Cascieri, M. A.; Strader, C. D.; Maechler, L.; Cichy-
Knight, M. A.; Hynes, J ., J r.; van Rijn, R, D,; Sprengeler, P. A.; Smith,
A. B., III J . Med. Chem. 1996, 39, 2441-2448. (c) von Roedern, E. G.;
Lohof, E.; Hessler, G.; Hoffmann, M.; Kessler, H. J . Am. Chem. Soc.
1996, 118, 10156-10167. For some recent reports on the use of
carbohydrates as multifunctional chiral scaffolds, see: (d) Kallus, C.;
Opatz, T.; Wunberg, T.; Schmidt, W.; Henke, S.; Kunz, H. Tetrahedron
Lett. 1999, 7783. (e) Wunberg, T.; Kallus, C.; Opatz, T.; Henke, S.;
Schmidt, W.; Kunz, H. Angew. Chem., Int. Ed. 1998, 37, 2503.
‡ Current address: Bristol-Myers Squibb Company, 5 Research
Parkway, Wallingford, CT 06492.
(1) For recent reviews, see: (a) Gallop, M. A.; Barrett, R. W.; Dower,
W. J .; Fodor, S. P. A.; Gordon, E. M. J . Med. Chem. 1994, 37, 1233-
1251. (b) Gordon, E. M.; Barrett, R. W.; Dower, W. J .; Fodor, S. P. A.;
Gallop, M. A. J . Med. Chem. 1994, 37, 1385-1400. (c) Thompson, L.
A.; Ellman, J . A. Chem. Rev. 1996, 96, 555. (d) Balkenhohl, F.; von
dem Bussche-Hu¨nnefeld, C.; Lansky, A.; Zechel, C. Angew. Chem., Int.
Ed. Engl. 1996, 35, 2288. (d) Hermkens, P. H. H.; Ottenheijm, H. C.
J .; Rees, D. C. Tetrahedron 1997, 53, 5643.
(2) (a) Sofia, M. J .; Hunter, R.; Chan, T. Y.; Vaughan, A.; Dulina,
R.; Wang, H.; Gange, D. J . Org. Chem. 1998, 63, 2802-2803. (b) Sofia,
M. J . Drug Discovery Today 1996, 1 (3), 27-34. (c) Sofia, M. J . Mol.
Diversity 1998, 3, 75-94.
10.1021/jo001183a CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/28/2000

8388 J . Org. Chem., Vol. 65, No. 24, 2000
Notes
Sch em e 1
Interestingly, compound 4 under identical experimental
conditions (NaCNBH3-TMSCl) showed the opposite re-
gioselectivity, giving the 6-O-benzyl regioisomer 5 in 76%
yield. This striking reversal of regioselectivity could be
attributed to the enhanced transition state stabilization
of the electrophile (TMS+) by the neighboring C-3 acetoxy
group.5 The acetal-opening with LAH/AlCl3 reagent
system has been used to obtain 4-O-benzyl ether deriva-
tive in the presence of benzyl or allyl ether.4a However,
reduction of acetal 4 with LAH/AlCl3 under carefully
controlled conditions gave 4-O-benzyl ether derivative 6
in only 25% yield due to competitive reductive and
hydrolytic pathways. The “borane-amine complex/Lewis
acid” combination have also been reported to be either
nonselective (BH3‚Me3N-AlCl3),4f or low-yielding (BH3‚
Me2NH-BF3‚Et2O).4k Recently, a combination of BH3/
Bu2BOTf has been used for reductive cleavage of 4,6-O-
benzylidene acetals of hexopyranosides to the correspond-
ing 4-O-benzyl ethers in modest yields.4l However, to
avoid potential problems associated with scale-up and for
ease of handling, we needed to develop a mild, selective,
and stable reagent system for this transformation. In-
terestingly, treatment of compound 4 with H3B‚NMe3/
Me2BBr at -78 °C afforded the desired 4-O-benzyl
derivative 7 in 90% yield (column chromatography)
without affecting other protecting groups.6 The high
regioselectivity of the process could be rationalized
considering the controlled reactivity of H3B‚NMe3/
Me2BBr reagent system. Although AlCl3 and BF3‚Et2O
have similar steric environments compared to Me2BBr,
moderate acidity of Me2BBr proved optimal for prefer-
ential coordination to the least hindered oxygen (6-O,
kinetic control) of the benzylidene acetal prior to opening
of the acetal. For the subsequent reduction, on the other
hand, the H3B‚NMe3 complex was conveniently chosen
as a stable and modest hydride source. This procedure
turned out to be very mild to surrounding functionalities
and was used to obtain multigram quantities of 7.
Next, we needed to convert the 6-OH group to a better
leaving group, to introduce the 6-azido functionality in
an SN2 fashion. A brief attempt to convert compound 7
to the corresponding triflate 8 using triflic anhydride in
the presence of pyridine led to the formation of the
trifloromethanesulfinyl ester. Such an unexpected sulfi-
nyl ester formation under similar conditions have been
reported recently with a mechanistic explanation.7 How-
ever, treatment of 6-OH derivative 7 with TsCl in Py in
the presence of catalytic amount of DMAP provided the
fully protected 6-tosyl-gluco derivative 8a in 72% yield
(Scheme 2). Nucleophilic displacement of tosyl group with
azide (NaN3) was achieved in DMF or DMSO at 90 °C
within 3 h (70-80%). At this point, we needed to perform
the oxidation of C1-O-allyl substituent to the desired
carboxymethyl derivative. Use of oxidants, such as
KMnO4, was not suitable for this purpose due to the
presence of the benzyl ether functionality in 9. Although
ozonolytic cleavage of olefin in the presence of an azido
functionality has been reported, to our knowledge, use
of ruthenium for oxidation of such a system has no
literature precedence. Thus, catalytic ruthenium trichlo-
ride-mediated modified Sharpless conditions (RuCl3‚H2O/
NaIO4 oxidant in CCl4:CH3CN:H2O) appeared to be most
practical for large scale oxidation of 9.8 However, when
compound 9 was treated with cat. amount of RuCl3‚H2O
in the presence of 8 equiv of co-oxidant NaIO4, the 4-O-
benzoate acid derivative 10 was obtained exclusively due
(4) (a) Gelas J . Adv. Carbohydr. Chem. Biochem. 1981, 39, 71. (b)
Garegg, P. J .; Hultberg, H.; Wallin, S. Carbohydr. Res. 1982, 108, 97-
101. (c) Mikami, T.; Asano, H.; Mitsunobu, O. Chem. Lett. 1987, 2033.
(d) J ohansson, R.; Samuelsson, B. J . Chem. Soc., Chem. Commun.
1984, 201-202. (e) J ohansson, R.; Samuelsson, B. J . Chem. Soc., Perkin
Trans 1 1984, 2371-2374. (f) Ek, M.; Garegg, P. J .; Hultberg, H.;
Oscarson, S. J . Carbohydr. Chem. 1983, 2, 305. (g) Wanner, M. J .;
Williard, N. P.; Koomen, G. J .; Pandit, U. K. Tetrahedron 1987, 43,
2549. (i) DeNinno, M. P.; Etienne, J . B.; Duplantier, K. C. Tetrahedron
Lett. 1995, 36, 669-672. (h) Brewster, J . H. In Comprehensive Organic
Synthesis; Trost, B. M.; Fleming, I., Eds.; 1991; Vol. 8, pp 224-227.
(k) Oikawa, M.; Liu, W.-C.; Nakai, Y.; Koshida, S.; Fukase, K.;
Kusumoto, S. Synlett. 1996, 1179. (l) J iang, L.; Chan, T.-H. Tetrahedron
Lett. 1998, 39, 355-358. (m) For the use of a polymeric hydride source
namely polymethylhydrosiloxane (PMHS), see: Chandrasekhar, S.;
Ravindra Reddy, Y.; Raji Reddy, Ch. Chem. Lett. 1998, 1273. (n) For
a recent use of trialkylsilane derivatives including PS-DES as hydride
source, see: Sakagami, M.; Hamana, H. Tetrahedron. Lett. 2000, 41,
5547.
(6) For cleavage of acetals and ketals using dimethylboron bromide,
see: Guindon, Y.; Yoakim, C.; Morton, H. E. J . Org. Chem. 1984, 49,
3912-3920.
(7) Netscher, T.; Bohrer, P. Tetrahedron Lett. 1996, 37, 8359-8362.
(8) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J .
Org. Chem. 1981, 46, 3936-3938.
(5) For an example of improved selectivity due to the 3-acetoxy group
during Grignard addition to 4-oxosugar, see: Thoma, G.; Schwarzen-
bach, F.; Duthaler, R. O. J . Org. Chem. 1996, 61, 514-524.

Notes
J . Org. Chem., Vol. 65, No. 24, 2000 8389
Sch em e 2
3.72-3.54 (m, 2H, H-2, H-6,), 3.52-3.32 (m, 3H, H-6, H-3, H-5),
3.11(t, J ) 9.0 Hz, 1H, H-4), 1.82 (s, 3H, NCOCH3); 13C NMR
(75 MHz, DMSO-d6) δ 163.58, 134.69, 116.53, 95.99 (C-1), 72.99
(C-5), 70.92 (C-3), 70.63, 66.87 (C-4), 60.87 (C-6), 53.79 (C-2),
22.65; EIMS m/z 262 (MH+), 260.2 (M - 1+).
to over oxidation. A carefully controlled reaction condi-
tions using 4.0 equiv of NaIO4 and with reduced reaction
time (2 h), however, provided the desired acid 12 and the
intermediate aldehyde 11 in 1:3 ratio. Although aldehyde
11 was easily separated and further oxidized, this
mixture was routinely oxidized further under J ones
conditions to obtain acid 12, cleanly.9 The conditions are
mild, catalytic in ruthenium, and suitable for scale-up
purposes with a very simple postreaction workup. Fi-
nally, deacetylation of 3-O-acetyl group of 12 using
NaOMe/MeOH provided the desired product 1.
In conclusion, we have described a highly efficient
synthesis of scaffold 1 with appropriate orientation of the
functional group triad for the generation of broad spec-
trum libraries. The described approach is amenable for
multigram-scale preparation in the laboratory and gave
access to a library of 12000 compound for broad spectrum
screening. The regioselective ring-opening of the ben-
zylidene acetal to obtain the 4-O-benzyl derivative using
H3B‚NMe3/Me2BBr, and efficient oxidation of the 1-O-
allyl to the 1-O-carboxymethyl group in the presence of
a benzyl ether as well as an azido functionality, are the
two noteworthy transformations of the synthetic scheme
and may find broader application for the preparation of
highly functionalized carbohydrate derivatives.
Allyl 2-Acet a m id o-4,6-O-b en zylid in e-2-d eoxy-r-D-glu -
cop yr a n osid e (3). To a solution of compound 2 (26 g, 101.5
mmol) in anhydrous DMF (200 mL) are added benzaldehyde
dimethylacetal (45 mL, 304.5 mmol) and TsOH (2 g), and the
mixture is heated at 60 °C under reduced pressure (ca. 10 mm/
Hg) for constant removal of MeOH formed. After 3 h, the reaction
mixture is cooled, poured into saturated solution of NaHCO3 (500
mL) to precipitate out the product as solid, filtered, and washed
with Et2O to furnish compound 3 (30 g, 86%) as a white
crystalline solid;1H NMR (300 MHz, DMSO-d6) δ 8.11 (d, J )
6.0 Hz, 1H, NH), 7.5-7.3 (m, 5H, ArH), 5.98-5.83 (m, 1H, vinylic
CH), 5.62 (s, 1H, PhCH), 5.35, 5.18 (2d, J ) 17.4, 10.5 Hz, 2H,
vinylic CH2), 5.30 (brs, 1H, 3-OH), 4.79 (d, J ) 3.0 Hz, 1H, H-1),
4.22-4.15 (m, 2H, H-2, allylic CH2), 3.96 (dd, J ) 13.5, 5.4 Hz,
1H, allylic CH2), 3.91-3.41 (m, 5H, H-6, H-3, H-5, H-4), 1.87 (s,
3H, NCOCH3); 13C NMR (75 MHz, DMSO-d6) δ 169.74, 162.45,
137.79, 134.48, 129.56, 129.24, 128.95, 128.10, 126.47, 111.92,
100.98, 96.90 (C-1), 82.00 (C-5), 68.08, 67.64, 67.24, 62.83 (C-6),
54.43 (C-2), 22.62; EIMS m/z 350 (MH+), 348.3 (M - 1+).
Allyl 2-Aceta m id o-3-O-a cetyl-4,6-O-ben zylid in e-2-d eoxy-
r-D-glu cop yr a n osid e (4). To a solution of compound 3 (29.3 g,
84.19 mmol) in anhydrous pyridine (200 mL) are added Ac2O
(11.9 mL, 102 mmol) and DMAP (4 g). The resulting mixture is
stirred at room temperature for 2.5 h under nitrogen and then
poured into ice-cold water. The precipitated white solid is
filtered, washed repeatedly with water to remove residual
pyridine, and redissolved in CH2Cl2. The organic layer is dried
over anhydrous Na2SO4 and then concentrated to obtain com-
pound 4 (23 g, 72%) as a solid; 1H NMR (300 MHz, CDCl3) δ
7.51-7.31 (m, 5H, ArH), 6.02-5.98 (brs, 1H, NH), 5.94-5.81
(m, 1H, vinylic CH), 5.52 (s, 1H, PhCH), 5.35, 5.22 (2d, J ) 10.2,
12.0 Hz, 2H, vinylic CH2), 5.31-5.25 (m, 1H, H-3), 4.87 (d, J )
3.0 Hz, 1H, H-1), 4.36 (td, J ) 9.6, 3.6 Hz, 1H, H-2), 4.28 (dd J
) 9.9, 4.5 Hz, 1H, H-6), 4.19 (dd, J ) 12.0, 6.0 Hz, 1H allylic
CH2,), 3.98 (dd, J ) 12.9, 6.6 Hz, 1H, allylic CH2), 3.91 (dd, J )
9.9, 4.5 Hz, 1H, H-6), 3.77 (t, J ) 10.2, 1H, H-5), 3.72 (t, J ) 9.3
Exp er im en ta l Section
Gen er a l Meth od s. All moisture-sensitive reactions were
carried out under an atmosphere of nitrogen in oven-dried
glassware. THF was freshly distilled from sodium-benzophe-
none ketyl; ethyl acetate, toluene, and CH2Cl2 were freshly
distilled from CaH2. Products were routinely analyzed by 1H and
13C NMR spectroscopy and by liquid chromatography (LC) with
light-scattering (LSD) and mass spectrometry (MS) detectors.
1H NMR spectra were obtained at 300 MHz, and 13C NMR
spectra were obtained at 75.4 MHz.
Allyl 2-Aceta m id o-2-d eoxy-r-D-glu cop yr a n osid e (2). A
mixture of 2-acetamido-2-deoxy-D-glucose (50 g, 226 mol), allyl
alcohol (500 mL, dried over molecular sieve), and BF3‚Et2O (8
mL, 67.8 mmol) is refluxed for 2 h. Allyl alcohol (100 mL,
containing 5% of concd HCl) is then added to the above, and
the reaction is heated under reflux for 10 h. The reaction mixture
is concentrated under reduced pressure, and the resulting
gummy residue is crystallized from EtOH-Et2O to afford
compound 2 (37 g, 63%) as a light brown solid. 1H NMR (300
MHz, DMSO-d6) δ 7.79(d, J ) 6.0 Hz, 1H, NH), 5.94-5.78 (m,
1H, vinylic CH), 5.28, 5.13 (2d, J ) 17.4, 10.5 Hz, 2H, vinylic
CH2), 4.65 (d, J ) 3.3 Hz, 1H, H-1), 4.07 (dd, J ) 13.8, 3.0 Hz,
1H, allylic CH2), 4.87 (dd, J ) 14.1, 4.8 Hz, 1H, allylic CH2),
Hz, 1H, H-4), 2.05 (s, 3H, OCOCH3), 1.96 (s, 3H, NCOCH3); 13
C
NMR (75 MHz, CDCl3) δ 171.19, 169.99, 136.82, 133.07, 128.94,
128.05, 126.01, 118.15, 101.36, 96.91 (C-1), 78.85 (C-5), 70.11
(C-3), 68.65, 68.46 (C-4), 62.79 (C-6), 52.32 (C-2), 23.01, 20.76;
EIMS m/z 392 (MH+), 390.3 (M - 1+).
Allyl 2-Acet a m id o-3-O-a cet yl-6-O-b en zyl-2-d eoxy-r-D-
glu cop yr a n osid e (5). To a suspension of compound 4 (4.9 g,
10 mmol), NaCNBH3 (60 mmol), and 3 Å molecular sieves in
anhydrous acetonitrile (200 mL) at 0 °C is dropwise added
TMSCl (60 mmol) and then stirred for 5 h at room temperature.
The reaction mixture is filtered through a pad of Celite, poured
into a saturated solution of NaHCO3, and extracted three times
with methylene chloride. The methylene chloride extract is dried
over anhydrous Na2SO4 and concentrated, and the residue is
purified by column chromatography (EtOAc) to obtain compound
5 (3.0 g, 60%) as an oil;1H NMR (300 MHz, CD3OD) δ 7.78 (d, J
(9) For an example of ozonolytic functionalization of O-allyl glyco-
sides, see: Park. W. K. C.; Auer, M.; J aksche, H.; Wong, C.-H. J . Am.
Chem. Soc. 1996, 118, 10150.

8390 J . Org. Chem., Vol. 65, No. 24, 2000
Notes
) 6.0 Hz, 1H, NH), 7.42-7.21 (m, 5H, ArH), 6.01-5.86 (m, 1H,
vinylic CH), 5.43 (d, J ) 6.3 Hz, 1H, C-4-OH), 5.33, 5.17 (2d, J
) 17.1, 10.5 Hz, 2H, vinylic CH2), 4.51 (s, 2H, PhCH2), 5.00 (dd,
J ) 11.1, 9.3 Hz, 1H, H-3), 4.69 (d, J ) 3.6 Hz, 1H, H-1), 4.12
(dd, J ) 13.5, 4.8 Hz, 1H, H-2), 4.03-3.93 (m, 2H, allylic CH,
H-6), 3.73-3.58 (m, 2H, allylic CH, H-6), 3.46-3.32 (m, 2H, H-4,
H-5), 1.95 (s, 3H, OCOCH3), 1.80 (s, 3H, NCOCH3); 13C NMR
(75 MHz, CD3OD) δ 173.36, 173.04, 138.99, 134.73, 129.17,
128.90, 128.59, 128.54, 118.20, 97.34 (C-1), 74.74 (C-3), 74.30
(C-5), 72.31, 69.84 (C-4), 69.59, 69.35 (C-6), 52.87 (C-2), 22.56,
20.91; EIMS m/z 394 (MH+), 392.3 (M - 1+).
Allyl 2-Aceta m id o-4-O-ben zyl-2-d eoxy-r-D-glu cop yr a n o-
sid e (6). To a suspension of LAH (250 mg, 6.56 mmol) in
anhydrous CH2Cl2 (32 mL) and Et2O (90 mL) under argon are
added the acetal 4 (2.0 g, 5.11 mmol) and AlCl3 (875 mg, 6.56
mmol), and the reaction is stirred under reflux for 20 h. The
reaction mixture is quenched with EtOAc (15 mL), filtered
through a pad of Celite, and then concentrated. The residue is
purified by column chromatography on silica gel using 5%
MeOH-CH2Cl2 as eluent to obtain compound 6 (440 mg, 25%)
as a white solid; 1H NMR (300 MHz,CD3OD) δ 7.59-7.21 (m,
5H, ArH), 6.11-5.82 (m, 1H, vinylic CH), 5.28,5.15 (2d, J ) 17.1,
9.6 Hz, 2H, vinylic CH2), 4.93, 4.83(2d, J ) 10.8, 11.0 Hz, 2H,
PhCH2), 4.64 (d, J ) 10.5 Hz, 1H, H-1), 4.18-3.93 (m, 2H, allylic
CH2), 3.89-3.58 (m, 5H, H-2, H-3, H-5, H-6), 3.43 (t, J ) 9.0
Hz, 1H, H-4), 1.98 (s, 3H, OCOCH3); 13C NMR (75 MHz, CD3-
OD) δ 173.81, 140.07, 135.54, 130.05, 129.43, 129.16, 128.78,
127.65, 117.73, 97.70, 80.18 (C-5), 76.16 (C-3), 73.39, 73.20 (C-
4), 69.75, 69.24 (C-6), 62.44, 55.77 (C-2), 22.71; EIMS m/z 352
(MH+), 350.3 (M - 1+).
Allyl 2-Acet a m id o-3-O-a cet yl-4-O-b en zyl-2-d eoxy-r-D-
glu cop yr a n osid e (7). To a cooled (-78 °C) solution of com-
pound 4 (10.0 g, 25.5 mmol) in CH2Cl2 under argon is added a
solution of H3B‚NMe3 complex (7.4 g, 102 mmol) in toluene (50
mL) followed by Me2BBr (7.44 mL, 64 mmol). After stirring for
30 min, 200 mL of 0.5 M sodium phosphate buffer (pH 7.3) is
added, and the solution is allowed to warm to room temperature.
The organic layer is washed with saturated NaHCO3 solution
and water, dried (Na2SO4), and evaporated. The residue is
chromatographed on silica gel using EtOAc to obtain compound
7 (9 g, 90%) as a white solid; 1H NMR (300 MHz, CD3OD) δ 7.41-
7.22 (m, 5H, ArH), 6.02-5.84 (m, 1H, vinylic CH2), 5.33, 5.20
(2d, J ) 17.1, 10.5 Hz, 2H, vinylic CH2), 5.30 (m, 1H, H-3), 4.81
(d, J ) 3.9 Hz, 1H, H-1), 4.67, 4.60 (2d, J ) 11.7, 11.6 Hz, 2H,
PhCH2), 4.22-4.16 (m, allylic CH2, H-6), 4.12-3.88 (m, 1H,
allylic CH2), 3.86-3.68 (m, 3H, H-4, H-5, H-6), 1.92 (s, 3H, OAc),
1.90 (s, 3H, NHCOCH3); 13C NMR (75 MHz, CD3OD) δ 173.35,
172.24, 139.49, 135.15, 129.36, 129.31, 128.90, 128.77, 128.66,
128.58, 118.15, 97.50 (C-1), 77.50 (C-3), 75.66 (C-5), 74.51, 73.01
(C-4), 69.29, 61.75 (C-6), 53.34 (C-2), 22.44, 20.95; EIMS m/z 394
(MH+), 392.3 (M - 1+).
mixture is poured into ice-water and extracted with methylene
chloride. The combined organic layer is washed with water and
brine, dried (Na2SO4), and evaporated. The residue is purified
by column chromatography on silica gel, eluting with 50% EtOAc
in hexane to obtain compound 9 (4.0 g, 75%) as a white solid;
1H NMR (300 MHz, CDCl3) δ 7.39-7.21 (m, 5H, ArH), 5.97-
5.79 (m, 2H, NH, vinylic CH), 5.31, 5.21 (2d, J ) 9.9, 10.5 Hz,
2H, vinylic CH2), 5.26-5.25 (m, 1H, H-3), 5.85 (d, J ) 3.9 Hz,
1H, H-1), 4.65, 4.57 (2d, J ) 11.1, 11.1 Hz, 2H, PhCH2), 4.28
(td, J ) 9.6, 3.6 Hz, 1H, H-2), 4.18, 3.99 (2dd, J ) 12.6, 5.1,
12.9, 6.0 Hz, 2H, allylic CH2), 3.87 (ddd, J ) 9.6, 5.4, 2.4 Hz,
1H, H-5), 3.64 (t, J ) 9.0 Hz, 1H, H-4), 3.48 (dd, J ) 12.9, 2.1
Hz, 1H, H-5), 3.64 (t, J ) 9.0 Hz, 1H, H-4), 3.48 (dd, J ) 12.9,
2.1 Hz, H-6), 3.36 (dd, J ) 13.2, 5.4 Hz, 1H, H-6), 1.98 (s, 3H,
OAc), 1.94 (S, 3H, NCOCH3); 13C NMR (75 MHz, CDCl3) δ
170.88, 169.77, 137.21, 132.93, 128.26, 127.78, 127.64, 127.57,
117.93, 96.02, 76.28, 74.70, 73.33, 70.23, 68.25, 51.86, 50.79,
22.83, 20.63; EIMS m/z 419.3 (MH+), 417.3 (M - 1+).
Car boxym eth yl 2-Acetam ido-3-O-acetyl-6-azido-4-O-ben -
zyl-2-d eoxy-r-D-glu cop yr a n osid e (12). To a solution of com-
pound 9 (4 g, 9.6 mmol) in a mixture of CCl4 (20 mL), CH3CN
(20 mL), and H2O (30 mL) is added NaIO4 (8.4 g,39.36 mmol).
To this biphasic solution is added RuCl3‚3H2O (43 mg, 2.2 mol
%), and the resulting mixture is stirred vigorously for 2 h at
room temperature. After dilution with 50 mL of CH2Cl2, the
reaction mixture is filtered through a pad of Celite, and the
phases are separated. The aqueous layer is extracted twice with
CH2Cl2. The combined organic layer is washed with water and
brine, dried (Na2SO4), and concentrated to obtain the mixture
of aldehyde 11 and acid 12. This crude mixture is chromato-
graphed on silica gel eluting with a gradient of MeOH in CH2-
Cl2 to obtain aldehyde 11 (2.7 g, 67%) and acid 12 (1 g, 25%).
J ones reagent (1.17 M, 10 mL, 8.54 mmol) is added to a
solution of compound 11 (2.7 g, 5.97 mmol) in acetone (30 mL),
and the mixture is subjected to sonication for 30 min. After TLC
analysis, excess reagent is quenched with 2-propanol (100 mL),
and the chromate salt is filtered off through a pad of Celite. The
green solid residue obtained after concentration is purified by
flash chromatography, eluting with 20% methanol/methylene
chloride to afford compound 12 as a white foamy solid (2.4 g,
86%). The overall yield for the two-step oxidation is 82%; 1H
NMR (300 MHz, CD3OD) δ 7.49-7.19 (m, 5H, ArH), 5.32 (t, J
) 9.9 Hz, 1H, H-3), 4.96 (brs, 1H, NH), 4.82 (brs, 1H, H-1), 4.60
(s, 2H, PhCH2), 4.23-4.11 (m, 2H, H-2, CH2CO2), 4.01-3.81 (m,
2H, CH2CO2, H-5), 3.62 (t, J ) 9.3 Hz, 1H, H-4), 3.53-2.28 (m,
2H, H-6), 1.94 (s, 3H, OAc), 1.91 (s, 3H, NCOCH3); 13C NMR
(75 MHz, CD3OD) δ 173.45, 172.03, 139.25, 129.44, 128.95,
128.89, 98.81 (C-1), 78.17 (C-3), 75.77 (C-5), 74.73, 71.94 (C-4),
53.24 (C-6), 52.26 (C-2), 22.59, 20.94. Fab-MS m/z 437.3 (MH+),
434.8(M - 1+).
Car boxym eth yl 2-Acetam ido-6-azido-4-O-ben zyl-2-deoxy-
r-D-glu cop yr a n osid e (1). To a stirred solution of 12 (3.4 g,6.8
mmol) in anhydrous methanol (40 mL) is added sodium meth-
oxide (365 mg, 6.8 mmol). The reaction mixture is stirred for 45
min at room temperature by which time all the starting material
has been consumed (TLC analysis). Excess base is neutralized
with Amberlite-H resin, filtered, concentrated, and purified by
silica gel chromatography, eluting with 25% MeOH in CH2Cl2
to afford compound 1 as a brownish foamy solid (2.5 g, 83%); 1H
NMR (300 MHz, CD3OD) δ 7.39-7.19 (m, 5H, ArH), 4.79 (d, J
) 11.1 Hz, 1H, H-1), 4.14 (d, J ) 15.9 Hz, 1H, CH2CO2), 4.07 (d,
J ) 10.8 Hz, 1H, H-2), 3.93 (d, J ) 14.1 Hz, 1H, CH2CO2), 3.90
(t, j ) 8.7 Hz, 1H, H-3), 3.82-3.72(m, 1H, H-5), 3.48-3.24 (m,
3H, H-6, H-4), 2.05 (s,3H, NCOCH3); 13C NMR (75 MHz, CD3-
OD) δ 178.07, 174.02, 139.67, 129.31, 129.08, 128.74, 98.87 (C-
1), 80.28 (C-5), 75.98 (C-3), 73.89, 71.99 (C-4), 67.53, 55.19 (C-
6), 52.55 (C-2), 22.90; FAB-MS m/z 395 (MH+), 392.8 (M - 1+).
Anal. Calcd for C17H22N4O7: C, 51.77; H, 5.62; N, 14.21. Found:
C, 51.52; H, 5.44; N, 14.42.
Allyl 2-Aceta m id o-3-O-a cetyl 4-O-ben zyl-2-d eoxy-6-O-
tosyl-r-D-glu cop yr a n osid e (8a ). To a solution of compound 7
(9.0 g, 23 mmol) in pyridine (100 mL) are added TsCl (13.0 g,
63 mmol) and DMAP (3 g). The reaction mixture is stirred at
room temperature for 6 h, poured into ice-water, and then
extracted with methylene chloride. The organic layer is washed
with brine, dried (Na2SO4), and evaporated. The residue is
chromatographed on silica gel using EtOAc as elutent to obtain
compound 8a (8.0 g, 72%) as a gummy liquid; 1H NMR (300 MHz,
CDCl3) δ 7.35-7.28 (m, 7H, ArH), 7.21-7.18 (m, 2H, ArH), 5.88-
5.72 (m, 2H, vinylic CH, NH), 5.27, 5.18 (2d, J ) 5.4, 12.0 Hz,
2H, vinylic CH2), 5.26-5.24 (m, 1H, H-3), 4.73 (d, J ) 3.6 Hz,
1H, H-1), 4.60, 4.52 (2d, J ) 10.8, 11.1 Hz, 2H, PhCH2), 4.28
(dd, J ) 4.2,10.8 Hz, H-6), 4.22-4.04 (m, 4H, H-2, H-6, allylic
CH2), 3.93-3.81 (m, 2H, allylic CH2, H-5), 3.63 (t, J ) 9.3 Hz,
1H, H-4), 2.44 (s, 3H, ArMe), 1.98 (s, 3H, OAc), 1.93 (s, 3H,
NCOCH3); 13C NMR (75 MHz, CDCl3) δ 171.10, 169.90, 144.91,-
137.16, 132.96, 132.59, 129.73, 128.39, 127.91, 127.87, 127.70,
118.10, 96.13 (C-1), 75.11 (C-3), 74.80 (C-5), 73.44, 68.79 (C-4),
68.97, 68.03 (C-6), 51.88 (C-2), 23.04, 21.54, 20.79; EIMS m/z
548.3 (MH+), 546.5 (M - 1+).
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 2-7, 8a , 9, and 12. This material is
available free of charge via the Internet at http://pubs.acs.org.
Allyl 2-Acetam ido-3-O-acetyl-6-azido-4-O-ben zyl-2-deoxy-
r-D-glu cop yr a n osid e (9). To a solution of compound 8a (7.0
g, 12.9 mmol) in DMF (50 mL) is added NaN3 (8.0 g, 129 mmol),
and the suspension is stirred at 90 °C for 3 h. The reaction
J O001183A