A short and economical synthesis of orthogonally protected C-linked 2-deoxy-2-acetamido-α-D-galactopyranose derivatives

Article abstract of DOI:10.1021/jo051938j

A short and high-yielding synthesis has been devised to prepare C-linked 2-deoxy-2-acetamido-α-D-galactopyranose derivative 3. One of the main advantages of this approach is that it employs commercially available and inexpensive D-glucosamine as the starting material. The key steps include a highly stereoselective C-allylation followed by epimerization of the C-4 hydroxyl group. Building block 3 and orthogonally protected C-linked 2-deoxy-2-acetamido-α-D-galactopyranose derivative 2 were obtained in 44% overall yield (six steps) and 29% overall yield (eight steps), respectively. This represents a significant improvement over previously reported syntheses.

Full text of DOI:10.1021/jo051938j

A Short and Economical Synthesis of
Orthogonally Protected C-Linked
-Deoxy-2-acetamido-r-D-galactopyranose
Derivatives
Although many methods have been developed to prepare
C-linked carbohydrate derivatives, the synthesis of C-linked
6
glycosylamine derivatives is still lengthy and inefficient. The
2
preparation of C-linked 2-deoxy-2-acetamido-R-D-galactopyra-
nose derivatives is especially difficult due to the incompatibility
of C-2 nitrogen protecting groups with most C-glycosylation
7
Vincent R. Bouvet and Robert N. Ben*
strategies. Currently available syntheses of C-linked 2-deoxy-
2
-acetamido-R-D-galactopyranose derivatives utilize glucosyl
Department of Chemistry, UniVersity of Ottawa,
8
9
derivatives (via oxime intermediates) or galactosyl pyranose
derivatives (via galactal intermediates) as starting materials. The
Ottawa, Ontario KIN 6N5, Canada
latter approach often introduces a C-2 acetamide precursor via
robert.ben@science.uottawa.ca
9
a
9b
9c-f
azido nitration, azido chlorination, or azido selenation,
and these intermediates are then subjected to stereoselective
ReceiVed September 15, 2005
9
g
carbon-carbon bond-forming reactions. For instance, acetylenic,
9
h
9h
9i
9j-l
allylic, allenic, cyano, and other derivatives
have been
prepared after azidonitration or chlorination of the appropriate
9
m,n
glycal. Similarly, a number of C-linked GalNHAc derivatives
9
including C-linked disaccharide GalNHAc derivatives ° have
been prepared via azido selenation of galactal. C-Linked
N-acetylgalactosamine derivatives have also been prepared via
7
,10,11a
11b
direct Keck allylation
of N-acetylgalactosamine.
(
3) (a) Shulman, M. L.; Shiyan, S. D.; Khorlin, A. Y. Carbohydr. Res.
1
974, 33, 229. (b) Chmielewski, M.; Bemiller, J. N.; Ceretti, D. P.
Carbohydr. Res. 1981, 97, C1-C4. (c) Myers, R. W.; Lee, Y. C. Carbohydr.
Res. 1986, 152, 143. (d) Bemiller, J. N.; Yadav, M. P.; Kalabokis, V. N.;
Myers, R. W. Carbohydr. Res. 1990, 200, 111. (e) Kuan, S. F.; Byrd, J. C.;
Basbaum, C.; Kim, Y. S. J. Biol. Chem. 1989, 264, 19271. (f) Byrd, J. C.;
Dahiya, R.; Huang, J.; Kim, Y. S. Eur. J. Cancer 1995, 31A, 1498. (g)
Hennebicq-Reig, S.; Lesuffleur, T.; Capon, C.; De Bolos, C.; Kim, I.;
Moreau, O.; Richet, C.; Hemon, B.; Recchi, M. A.; Maes, E.; Aubert, J.
P.; Real, F. X.; Zweibaum, A.; Delannoy, P.; Degand, P.; Huet, G. Biochem.
J. 1998, 334, 283. (h) Zanetta, J. P.; Gouyer, V.; Maes, E.; Pons, A.; Hemon,
B.; Zweibaum, A.; Delannoy, P.; Huet, G. Glycobiology 2000, 10, 565.
A short and high-yielding synthesis has been devised to
prepare C-linked 2-deoxy-2-acetamido-R-D-galactopyranose
derivative 3. One of the main advantages of this approach
is that it employs commercially available and inexpensive
D-glucosamine as the starting material. The key steps include
a highly stereoselective C-allylation followed by epimeriza-
tion of the C-4 hydroxyl group. Building block 3 and
orthogonally protected C-linked 2-deoxy-2-acetamido-R-D-
galactopyranose derivative 2 were obtained in 44% overall
yield (six steps) and 29% overall yield (eight steps),
respectively. This represents a significant improvement over
previously reported syntheses.
(4) (a) Lee, Y. C.; Lee, R. T. Acc. Chem. Res. 1995, 28, 321. (b) Dwek,
R. A. Chem. ReV. 1996, 96, 683. (c) Imperiali, B.; Shannon, K. L.; Rickert,
K. W. J. Am. Chem. Soc. 1992, 114, 7942. (d) Imperiali, B. Acc. Chem.
Res. 1997, 30, 452. (e) Seitz, O. ChemBioChem 2000, 1, 214.
(
5) (a) Varki, A. Glycobiology 1993, 3, 97. (b) Lis, H.; Sharon, N. Eur.
J. Biochem. 1993, 218, 1. (c) McEver, R. Glycoconjugate J. 1997, 14, 585.
6) For representative approaches see: (a) Nicotra, F.; Russo, G.;
(
Ronchetti, F.; Toma, T. Carbohydr. Res. 1983, 124, C5-C7. (b) Giannis,
A.; Sandhoff, K. Carbohydr. Res. 1987, 171, 201-210. (c) Carcano, M.;
Nicotra, F.; Panza, L.; Russo, G. J. Chem. Soc., Chem. Commun. 1989,
297. (d) Grondin, R.; Leblanc, Y.; Hoogsteen, K. Tetrahedron Lett. 1991,
Since the early 1970s, many syntheses of C-linked carbohy-
32, 5021. (e) Leteux, C.; Veyrieres, A. J. Chem. Soc., Perkin Trans. 1 1994,
2647. (f) Kim, K.; Hollingsworth, R. I. Tetrahedron Lett. 1994, 35, 1031.
drate derivatives have been reported.1
a-c,2
The interest in these
(
g) Hoffman, M.; Kessler, H. Tetrahedron Lett. 1994, 35, 6067.
compounds stems from their applications as glycosidase inhibi-
(7) Roe, B. A.; Boojamra, C. G.; Griggs J. L.; Bertozzi, C. J. Org. Chem.
tors3 and their attractiveness as intermediates for probing
1996, 61, 6442.
4
(8) (a) Cipolla, L.; La Ferla, B.; Lay, L.; Peri, F.; Nicotra, F.
Tetrahedron: Asymmetry 2000, 11, 295. (b) Cipolla, L.; Lay, L.; Nicotra,
F. J. Org. Chem. 1997, 62, 6678.
carbohydrate-peptide and/or carbohydrate-lipid interactions
in biological systems.1 The enhanced stability of C-linked
pyranoses toward basic and acid media as well as resistance to
enzymatic degradation makes them ideally suited for this
(9) For representative approaches, see: (a) Lemieux, R. U.; Ratcliffe,
R. M. Can. J. Chem. 1979, 57, 1244 (b) Bovin, N. V.; Zurabyan, S. E.;
Khorlin, A. Y. Carbohydr. Res. 1981, 98, 25. (c) Czernecki, S.; Randria-
mandimby, D. Tetrahedron Lett. 1993, 34, 7915. (d) Czernecki, S.; Ayadi,
E.; Randriamandimby, D. J. Org. Chem. 1994, 59, 8256. (e) Santoyo-
Gonzalez, F.; Calvo-Flores, F. G.; Garc y´ a-Mendoza, P.; Hernandez-Mateo,
F.; Isac-Garc y´ a, J.; Robles-D y´ az, R. J. Org. Chem. 1993, 58, 6122. (f)
Giuliano, R. M.; Davis, R. S.; Boyko, W. J. J. Carbohydr. Chem. 1994,
13, 1135. (g) Dondoni, A.; Mariotti, G.; Marra, A. J. Org. Chem. 2002, 67,
4475. (h) Bertozzi, C. R.; Bednarski, M. D. Tetrahedron Lett. 1992, 33,
3109. (i) Hoffmann, M. G.; Schmidt, R. R. Liebigs Ann. Chem. 1985, 2403.
(j) Burkhart, F.; Kessler, H. Tetrahedron Lett. 1998, 39, 255. (k) Urban,
D.; Skrysdstrup, T.; Beau, J.-M. J. Org. Chem. 1998, 63, 2507. (l) Sh a¨ fer,
A.; Thiem, J. J. Org. Chem. 2000, 65, 24. (m) Grant, L.; Liu, Y.; Walsh,
K. E.; Walter, D. S.; Gallagher, T. Org. Lett. 2002, 4, 4623 (n) Rubinstenn,
G.; Esnault, J.; Mallet, J.-M.; Sina y¨ , P. Tetrahedron: Asymmetry 1997, 8,
1327. (o) Sanmartin, R.; Tavassoli, K. E.; Walsh, K. E.; Walter, D. S.;
Gallagher, T. Org. Lett. 2000, 2, 4051.
5
purpose.
(1) (a) Postema, M. H. D. Tetrahedron 1992, 48, 8545. (b) Postema, M.
C-Glycoside Synthesis; CRC Press: Boca Raton, 1995. (c) Levy, D.; Tang,
C. The Chemistry of C-Glycosides; Pergamon: Oxford, 1995. (d) Togo,
H.; He, W.; Waki, Y.; Yokoyama, M. Synlett 1998, 700. (e) Skrydstrup,
T.; Vauzeilles, B.; Beau, J.-M. In Carbohydrates in Chemistry and Biology.
The Chemistry of Saccharides; Ernst, B., Hart, G. W., Sina y¨ , P., Eds.; Wiley-
VCH: New York, 2000; Vol. 1, Chapter 20, pp 495-530.
(2) (a) San Martin, R.; Tavassoli, B.; Walsh, K. E.; Walter, D. S.;
Gallagher, T. Org. Lett. 2000, 2, 4051 and references therein. (b) Grant,
L.; Liu, Y.; Walsh, K. E.; Walter, D. S.; Gallagher, T. Org. Lett. 2002, 4,
623 and references therein. (c) For a recent review on “Synthetic methods
of amino C-Glycosides”, see: Xie, J. Recent Res. DeVel. Organic Chem.
999, 3, 505.
4
1
1
0.1021/jo051938j CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/06/2006
J. Org. Chem. 2006, 71, 3619-3622
3619

SCHEME 1. Preparation and Allylation of Intermediate 5
SCHEME 2. Preparation and Allylation of Intermediate 7
strategies and explore a novel synthetic route to access C-linked
2
-deoxy-2-acetamido-R-D-galactopyranose derivatives 2 and 3
starting from commercially available and inexpensive D-
glucosamine.
The proposed strategy installed an allyl group at the anomeric
position and inverted the stereochemistry at C-4 late in the
synthesis. The inversion of stereochemistry at C-4 of various
As part of our ongoing studies toward the rational design
and synthesis of C-linked antifreeze glycoprotein analogues, we
required large quantities of C-linked 2-deoxy-2-acetamido-R-
D-galactopyranose derivatives. On the basis of literature pre-
cedent, we chose to perform a direct allylation on N-acetylga-
lactosamine derivative 5 (Scheme 1).1 Chloropyranose 5 was
generated from N-acetylgalactosamine 4, which in turn was
14a,b
pyranose derivatives
oligosaccharides.
has been well studied on O-linked
In fact, a similar inversion has been
14c-e
reported in the synthesis of C-linked 2-acetamido-2-deoxy-R-
D-galactose where the C-2 acetamido group was introduced
8a
using an oxime early in the synthesis. This approach was also
1b
attractive in that the C-3 hydroxyl group of 2 and 3 would be
unprotected and available for a glycosidic coupling after the
migration/epimerization sequence.
9
a
prepared via azido nitration of the corresponding glycal.
Unfortunately, in our hands, conversion of 4 to 6 via
generation of chloro intermediate 5 failed to proceed with yields
greater than 14% even when previously reported optimal
conditions (3 equiv of allyl tributylstannane and 0.15 molar
equiv of AIBN) were employed.1 Changes in temperature and
The first step in the synthesis centers on the preparation of
2
-acetamido-3,4,6-tri-O-acetyl-2-deoxy-R-D-glucopyranosyl chlo-
12b,c
ride 8 (Scheme 3) from D-glucosamine in 78% yield.
Compound 8 was smoothly converted into C-linked derivative
1b
10a
9
via Keck allylation in 73% yield as a R/â mixture (12/1)
1
2
different Lewis acids also failed to improve the yield of 6.
of diastereomers. Optimized conditions for this allylation utilized
.8 equiv of allyl tributylstannane and 0.3 equiv of AIBN in
Generation of 5 starting from D-galactosamine produced a
similar result. Next, we explored the possibility of performing
either a Keck allylation1 or photochemical-mediated radical
allylation on bromo derivative 7 (Scheme 2). Unlike chloro
intermediate 5, we were able to purify bromo derivative 7 using
silica gel chromatography. However, when 7 was subjected to
a Keck allylation, the only product obtained was the bicyclic
4
refluxing THF. While the R/â ratios are not as high as those
1a
12c
previously reported, these conditions have advantages in that
no polymer byproducts are observed. Furthermore, the amount
of allylstannane in the reaction mixture can be reduce by half
7
compared to the Bertozzi procedure. Deacetylation furnished
intermediate 1, which was readily converted into C-linked
13
oxazoline. A photochemically-mediated allylation improved
the yield of 6 only slightly (42%). While this sequence seems
attractive given that only one anomer is generated, preparation
of the requisite starting material (2-acetamido-l,3,4,6-tetra-O-
acetyl-2-deoxy-R,â-D-galactopyranose) is not trivial. For in-
stance, preparation from D-galactosamine hydrochloride is only
2
-deoxy-2-acetamido-R-D-galactopyranose derivatives 2 and 3.
With respect to the latter, the C-6 and C-3 hydroxyls were
selectively protected using 2 equiv of pivaloyl chloride to furnish
2 in 92% yield as an inseparable R/â mixture (12:1). Inversion
1
of the C-4 hydroxyl group was accomplished by treatment with
triflic anhydride followed by stirring in water overnight leading
to C-linked 2-acetamido-R-D-galactose derivative 3 in six steps
and an overall yield of 44%. The inversion of the C-4 hydroxyl
1
2a
one step,
but galactosamine is prohibitively expensive.
Furthermore, the preparation from galactose pentaacetate re-
9a
quires five to seven steps, with tedious purifications by column
chromatography. Consequently, this approach was abandoned.
14
group has been studied using various adjacent esters and is
rationalized as outlined in Scheme 4. Intramolecular displace-
ment of the triflate via the carbonyl oxygen of the pivaloyl group
at C-2 produces dioxolenium ion intermediate A. Hydration
occurs from the least hindered face to give hemi-ortho ester
intermediate B after proton transfer. Intermediate B collapses
1
0
Given that Keck allylation of D-glucosamine derivatives has
been reported, we decided to combine different literature
(
10) McGarvey, G. J.; Schmidtmann, F. W.; Benedum, T. E.; Kizer, D.
E. Tetrahedron Lett. 2003, 44, 3775.
11) (a) Keck, G. E.; Yates, J. B. J. Am. Chem. Soc. 1982, 104, 5829.
b) Cui, J.; Horton, D. Carbohydr. Res. 1998, 309, 319.
12) (a) Tarasiejska, Z.; Jeanloz, R. W. J. Am. Chem. Soc. 1958, 80,
325. (b) Heidlas, J. E.; Lees, W. J.; Pale, P.; Whitesides, G. M. J. Org.
(
(
(13) Ponten, F.; Magnusson, G. J. Org. Chem. 1996, 61, 7463.
(14) (a) Binkley, R. W.; Sivik, M. R. J. Org. Chem. 1986, 51, 2621. (b)
Binkley, R. W. J. Org. Chem. 1991, 56, 3892. (c) Lay, L.; Nicotra, F.;
Panza, L.; Russo, G. HelV. Chim. Acta 1994, 77, 509. (d) Lubineau, A.;
Bienayme, H. Carbohydr. Res. 1991, 212, 267. (e) Nashed, M. A.; El-
Sokkary, R. I.; Rateb, L. Carbohydr. Res. 1984, 131, 47.
(
6
Chem. 1992, 57, 146. (c) Horton, D. Methods Carbohydr. Chem. 1972, 6,
82. (d) Baker, B. R.; Joseph, J.; Schaub, R. E.; Williams, J. H. J. Org.
Chem. 1954, 19, 1786.
2
3
620 J. Org. Chem., Vol. 71, No. 9, 2006

SCHEME 3. Synthesis of the C-Linked 2-Deoxy-2-acetamido-r-D-galactopyranose Derivatives 2 and 3
SCHEME 4. Stereoselectivity in the Ring Opening of
Hemiortho ester Intermediates B and C
and boron trifluoride etherate afforded the R-anomer of 11 in
77% yield after purification by column chromatography. Inver-
sion of the C-4 hydroxyl group and migration of the pivaloyl
protecting group was accomplished by treatment with triflic
anhydride in refluxing dichloroethane/water to afford orthogo-
nally protected C-linked 2-deoxy-2-acetamido-R-D-galacto-
pyranose derivative 2 in 83% yield. This route required only
eight steps and produced 2 in 29% overall yield.
In summary, the synthesis of intermediates 2 and 3 can be
accomplished in eight and six steps, respectively, with an overall
yield of 29% and 44%. To date, the most efficient synthesis of
3
starting from D-glucose was carried out in 14 steps and 11%
8a
overall yield, and no syntheses using D-glucosamine have been
reported. The synthetic sequence is amenable to large scale and
consequently could be used to generate large quantities of 3 as
well as differentially protected galactosamine derivative 2. In
both cases, a diastereomeric mixture (R/â anomers) is carried
through until late into the synthesis where facile purification
by column chromatography furnishes products with the desired
R-configuration. Other attractive features of this approach
include the fact that D-glucosamine is inexpensive, and all steps
in the synthetic sequences are high yielding. In summary, this
strategy affords a fast, efficient, and affordable synthesis of 2
and 3, which are useful building blocks to synthesize different
polysaccharide targets.
with the assistance of two primary stereoelectronic effects15
resulting in formation of axial ester 3 as the R-anomer after
purification by column chromatography. While the correspond-
ing equatorial ester 13 can be formed via intermediate C, this
product is not observed due to severe steric interactions between
the tert-butyl group and the pyranose ring. In addition, collapse
of intermediate B to form 3 furnishes an ester with the more
stable “Z” conformation, while collapse of intermediate C
produces an ester 13 with the less stable “E” ester conformation.
Preparation of orthogonally protected C-linked 2-deoxy-2-
acetamido-R-D-galactopyranose derivative 2 is possible by
conversion of 1 to benzylidene acetal 10 in 80% overall yield,
via the benzylidene acetal intermediate (84% yield) and
subsequent pivaloylation (95% yield). The diastereomeric
Experimental Section:
2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-r-d-glucopyranosyl
1
2a,b
chloride (8) (r:â ) 3:1):
white powder (26.4 g, 72.3 mmol,
1
3
78% yield); (R anomer) H NMR (300 MHz, CDCl ) δ 6.16 (d, J
)
3.6 Hz, 1H), 5.84 (d, J ) 8.7 Hz, 1H), 5.29 (t, J ) 10.1 Hz,
1
H), 5,18 (t, J ) 9.1 Hz, 1H), 4.54-5.15 (m, 1H), 4.25-4.23 (m,
2
H), 4.10 (d, J ) 10.5 Hz), 2.07 (s, 3H), 2.02 (bs, 6H), 1.96 (s,
3
H); 13C NMR (56 MHz, CDCl
3
) δ 171.6, 170.8, 170.3, 169.3,
9
NH
3.8, 71.1, 70.3, 67.1, 61.3, 53.7, 23.3, 20.9, 20.8, 20.7 LRMS (ES,
+
+
4
) m/z 330.1 (M - Cl).
-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-r-d-glucopyran-
3
7
osyl)propene (9) (r: â ) 12:1): white powder (4.4 g, 11.9 mmol,
1
73% yield); (R anomer) H NMR (500 MHz, CDCl
) 8.5 Hz, 1H), 5.82-5.74 (m, 1H), 5.16-5.10 (m, 3H), 4.94 (t, J
7.5 Hz, 1H), 4.13 (dt, J ) 10 Hz, J ) 5 Hz, 1H), 4.08 (dd, J
) 12, 7.5 Hz, 1H), 4.01 (dt, J ) 3.1, J ) 7.4 Hz, 1H), 3.93-3.89
m, 1H), 3.72 (dt, J ) 7.5 Hz, J ) 3.5 Hz, 1H), 2.31-2.25 (m,
H), 2.16-2.11 (m, 1H), 1.87 (bs, 9H), 1.78 (s, 3H); C NMR
125 MHz, CDCl ) δ 170.8, 170.7, 170.0, 169.2, 133.4, 117.6, 71.2,
0.3, 70.0, 68.2, 61.8, 50.4, 31.8, 23.1, 20.8, 20.8, 20.7; LRMS
3
) δ 6.63 (d, J
)
t
d
mixture (R/â ) 12:1) was used directly in the next step.
Selective cleavage of benzylidene acetal16 10 using triethylsilane
t
d
(
t
d
1
3
1
(
15) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Pergamon Press Ltd.: Oxford, 1983; p 83.
16) (a) DeNinno, M. P.; Etienne, J. B.; Daplantier, K. C. Tetrahedron
(
3
7
(
+
+
+
+
(
4
ES, NH ) m/z: 372.1 (M + H), 394.1 (M + Na), 765.1 (2M
Lett. 1995, 36, 669. (b) Debenham, S. D.; Toone, E. J. Tetrahedron:
Asymmetry 2000, 11, 385. (c) Barroca, N.; Jacquinet, J.-C. Carbohydr. Res.
+
8
+ Na); HRMS m/z calcd for C14H20NO (M - allyl) 330.1189,
2
002, 337, 673.
found 330.1188.
J. Org. Chem, Vol. 71, No. 9, 2006 3621

3
-(2-Acetamido-4,6-benzylidene-2-deoxy-r-d-glucopyran-
12 Hz, 1H) 4.47 (d, J ) 12 Hz, 1H), 4.35-4.31 (m, 1H), 4.17-
4.13 (m, 1H), 4.08-4.03 (m, 1H), 3.95 (dd, J ) 3.3, 7.2 Hz, 1H),
3.71 (dd, J ) 6.8 Hz, J ) 10.4 Hz, 1H), 3.51 (dd, J ) 4.2 Hz, J
osyl)propene (r: â ) 12:1): white powder (172 mg, 518 µmol,
4% yield); H NMR (500 MHz) (CD OD) δ 7.60-7.33 (m, 5H),
3
.82-5.74 (m, 1H), 5.60 (s, 1H), 5.15 (dd, J ) 1.5, 17 Hz, 1H),
.07 (d, J ) 10 Hz, 1H), 4.18-4.09 (m, 3H), 3.87 (t, J ) 8.0 Hz,
H), 3.71 (t, J ) 10 Hz, 1H), 3.62-3.58 (m, 1H), 3.52 (t, J ) 8.0
Hz, 1H), 2.61-2.55 (m, 1H), 2.32-2.27 (m, 1H), 1.98 (bs, 3H);
C NMR (125 MHz, CD
27.9, 127.5, 126.0, 115.7, 101.6, 83.0, 74.2, 68.7, 67.7, 63.4, 54.2,
0.3, 20.1; LRMS (CI, Isobutylene) m/z 334.2 (M + H), 316 (M
OH); HRMS m/z calcd for C15
1
8
5
5
3
) 10.5 Hz, 1H), 3.42 (bs, 1H), 2.36-2.30 (m, 1H), 2.18 (dt, J )
t
1
3
6.3 Hz, J
(125 MHz, CDCl
128.1, 117.7, 73.7, 73.7, 71.4, 69.0, 67.9, 67.8, 52.3, 39.3, 33.2,
d
) 15.3 Hz, 1H), 1.99 (bs, 3H), 1.16 (bs, 9H); C NMR
) δ 178.4, 171.3, 137.8, 134.2, 128.7, 128.1,
3
13
+
+
3
OD) δ 172.1, 137.6, 132.5, 129.2, 128.4,
27.3, 23.4; LRMS (CI, Isobutylene) m/z 420 (M + H), 401 (M
+
1
3
-
- 18); HRMS m/z calcd for C20
H28NO
6
(M - allyl) 378.1916,
+
+
found 378.1916.
+
H18NO
8
(M - allyl) 292.1185,
3-(2-Acetamido-2-deoxy-6,3-dipivaloyl-r-d-glucopyranosyl)-
found 292.1185.
-(2-Acetamido-4,6-benzylidene-2-deoxy-3-pivaloyl-r-d-glu-
copyranosyl)propene (10) (r: â ) 12:1): white powder (148 mg,
propene (12) (r: â ) 12:1): compound 12 was obtained as an
1
3
inseparable R/â mixture (1.54 g, 3.74, 92% yield); H NMR (300
MHz, CDCl ) δ 6.18 (d, J ) 8.4 Hz, 1H), 5.81-5.68 (m, 1H),
3
1
3
7
5
5
(
2
54 µmol, 95% yield); (R anomer) H NMR (300 MHz, CDCl
3
) δ
5.12-4.92 (m, 3H), 4.52 (dd, J ) 6.3, 12 Hz, 1H), 4.23-4.11 (m,
.41-7.31 (m, 5H), 5.97 (d, J ) 7.5 Hz, 1H), 5.75-5.61 (m, 1H),
.54 (s, 1H), 5.19 (t, J ) 10.2 Hz, 1H), 5.05 (d, J ) 7.2 Hz, 1H),
.01 (s, 1H), 4.42-4.34 (m, 1H), 4.31-4.20 (m, 2H), 3.76-3.66
3H), 3.76 (dt, J ) 6,9 J ) 2.7, 1H), 3.5 (t, J ) 7.5 Hz, 1H),
t
d
2.47-2.37 (m, 1H), 2.29-2.22 (m, 1H), 1.91 (bs, 3H), 1.19 (bs,
18H); 13C NMR (75 MHz, CDCl ) δ 180.1, 179.6, 170.4, 134.1,
3
m, 2H), 3.60 (dd, J ) 4.2, 9.6 Hz, 1H), 2.53-2.41 (m, 1H), 2.34-
.25 (m, 1H), 1.89 (bs, 3H), 1.17 (bs, 9H); 13C NMR (56 MHz,
CDCl ) δ 180.4, 170.3, 137.2,133.6, 129.1, 128.4, 126.0, 117.8,
01.3, 79.9, 74.4, 70.1, 69.4, 64.1, 53.4, 39.3, 30.9, 27.2, 23.2;
LRMS (CI, H ) m/z 418 (M + H), (M + K) 458; HRMS m/z
calcd for C23
117.8, 72.9, 72.5, 72.1, 68.8, 63.2, 51.4, 39.4, 32.0, 27.6, 27.4, 23.6,
+
+
23.6; LRMS (ES, H ) m/z 414.2 (M + H).
3
3-(2-Acetamido-2-deoxy-6,4-dipivaloyl-r-d-galactopyranosyl)-
propene (3):8 H NMR (300 MHz, CDCl ) δ 5.86 (d, J ) 7.5 Hz,
a 1
1
3
+
+
+
1H), 5.81-5.68 (m, 1H), 5.13-5.03 (m, 3H), 4.59 (t, J ) 10.2
Hz, 1H), 4.38-4.32 (m, 1H), 4.18-4.08 (m, 2H), 4.01 (dd, J )
3.6, 6.3 Hz, 1H), 3.98 (d, J ) 3.9 Hz, 1H), 2.35-2.25 (m, 1H),
+
6
H31NO (M ) 417.2151, found 417.2151.
3
-(2-Acetamido-6-O-benzyl-2-deoxy-3-pivaloyl-r-d-gluco-
1
3
pyranosyl)propene (11) (r: â > 98:2): white powder (R-anomer,
2.21-2.12 (m, 1H), 1.98 (bs, 3H), 1.21 (bs, 9H) 1.16 (bs, 9H); C
1
3
7
(
9
4
3
1
1
7
3 mg, 87 µmol, 77% yield); H NMR (300 MHz, CDCl
3
) δ 7.31-
NMR (75 MHz, CDCl ) δ 178.3, 178.2, 171.3, 134.1, 117.3, 70.7,
3
.21 (m, 5H), 6.28 (d, J ) 8.7 Hz, 1H), 5.81-5.67 (m, 1H), 5.09
68.7, 67.3, 61.0, 60.5, 52.2, 39.1, 38.7, 27.2, 27.2, 23.0, 23.0; LRMS
+
+
+
+
d, J ) 17.1 Hz, 1H), 5.05 (d, J ) 9.3 Hz, 1H), 4.99 (dd, J ) 7.5,
(ES, H ) m/z 414.1 (M + H), 436.1 (M + Na), 849.2 (2M +
.6 Hz, 1H), 4.55 (d, J ) 12 Hz, 1H), 4.49 (d, J ) 12 Hz, 1H),
.24-4.16 (m, 1H), 4.09-4.04 (m, 1H), 3.75-3.68 (m, 3H), 3.60-
.56 (m, 1H), 3.05 (bs, 1H), 2.53-2.41 (m, 1H), 2.34-2.19 (m,
Na).
Acknowledgment. This work was supported by a grant from
the NIH (RO1GM60319), the Natural Science and Engineering
Research Council (NSERC), and the Canada Research Chair
Program (CRC). R.N.B. holds a Tier 2 CRC in medicinal
chemistry.
H), 1.87 (bs, 3H), 1.17 (bs, 9H); 13C NMR (56 MHz, CDCl
) δ
3
80.1, 170.1, 137.8, 134.0, 128.6, 128.0, 127.9, 117.5, 73.9, 72.9,
2.5, 71.8, 70.6, 70.5, 51.6, 39.2, 31.4, 27.2, 23.3 LRMS (CI,
Isobutylene) m/z 420 (M + H), 401 (M - 18); HRMS m/z calcd
+
+
+
for C20
-(2-Acetamido-6-O-benzyl-2-deoxy-4-pivaloyl-r-d-galacto-
pyranosyl)propene (2): white powder (2.32 g, 5.54 mmol, 83%
6
H28NO (M - allyl) 378.1916, found 378.1916.
3
Supporting Information Available: Experimental procedures
and spectroscopic data for compounds 2, 3, and 8-12. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
yield); H NMR (500 MHz, CDCl ) δ 7.32-7.27 (m, 5H), 6.10 (d,
3
J ) 7.5 Hz, 1H), 5.80-5.72 (m, 1H), 5.18 (t, J ) 3.6 Hz, 1H),
5
.08 (d, J ) 13.2 Hz, 1H), 5.05 (d, J ) 7.8 Hz, 1H), 4.53 (d, J )
JO051938J
3
622 J. Org. Chem., Vol. 71, No. 9, 2006