Synthesis and conformational analysis of 6-C-methyl-substituted 2-acetamido-2-deoxy-β-D-glucopyranosyl mono- and disaccharides

Article abstract of DOI:10.1021/jo0485841

(Chemical Equation Presented). Several 6-C-substituted 2-acetamido-2-deoxy- β-D-glucopyranosides (β-D-GlcNAc monosaccharides 1a-3a and 1,4-linked disaccharides 1b-3b) were studied by solution NMR spectroscopy. Conformational analysis of the (6S)- and (6R)

Full text of DOI:10.1021/jo0485841

Synthesis and Conformational Analysis of 6-C-Methyl-Substituted
2-Acetamido-2-deoxy-â-D-glucopyranosyl Mono- and Disaccharides
Jihane Achkar, Isabel Sanchez-Larraza, Carol A. Johnson, and Alexander Wei*
Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907-2084
alexwei@purdue.edu
Received August 12, 2004
Several 6-C-substituted 2-acetamido-2-deoxy-â-D-glucopyranosides (â-D-GlcNAc monosaccharides
1a-3a and 1,4-linked disaccharides 1b-3b) were studied by solution NMR spectroscopy. Confor-
mational analysis of the (6S)- and (6R)-C-methyl-substituted â-D-GlcNAc monosaccharides indicates
that the stereodefined methyl groups impose predictable conformational biases on the exocyclic
C-5-C-6 bond, as determined by 1H-1H and 13C-1H coupling constants. Variable-temperature NMR
experiments in methanol-d4 were performed to determine ∆∆H and ∆∆S values derived from the
two lowest energy conformers. These indicate that while the influence of 6-C-methyl substitution
on conformational enthalpy is in accord with the classic principles of steric interactions,
conformational preference in solution can also be strongly affected by other factors such as solvent-
solute interactions and solvent reorganization.
Introduction
for designing interfaces with selective recognition proper-
ties, or for directing the supramolecular architecture of
polysaccharides such as chitin.
Protein-carbohydrate and carbohydrate-carbohydrate
interactions play essential roles in the recognition of cell
surfaces and polysaccharides in the extracellular matrix.1
For pyranosidic carbohydrates, the exocyclic C-5 hy-
droxymethyl substituent has particular significance and
often provides key interactions at biological interfaces.2,3
The exocyclic C-5-C-6 bond is known to be torsionally
flexible;3 however, a number of systems recognize or
require specific orientations. For example, the polymor-
phic forms of the crystalline polysaccharide chitin (â-1,4-
linked poly-N-acetyl-D-glucosamine) are likely deter-
mined by hydrogen bonding between interstrand O-6
hydroxyl groups, which are in turn directed by the C-5
hydroxymethyl conformations.4-6 There is also strong
evidence that the O-6 hydroxyl is intimately involved in
stabilizing the interaction between chitin and various
chitinases.7 Understanding the factors which affect the
conformation of the C-5-C-6 bond may reveal insights
The conformation of this exocyclic bond can be ratio-
nally biased by introducing a small but sterically de-
manding methyl group at the (6S)- or (6R)-position (see
Figure 1). This conformational director destabilizes stag-
gered rotamers via 1,3-diaxial-like interactions, which
increases steric repulsion energies by 1-3 kcal/mol.8 The
steric director approach has been used to probe the effect
of conformational bias on protein-carbohydrate binding
and enzymatic hydrolysis, using 6-C-substituted gluco-
and galactopyranosides9 and related 1,6-linked oligosac-
charide derivatives.10
Here we describe the conformational analysis of 6-C-
monodeuterated and 6-C-methyl-substituted 2-aceta-
mido-2-deoxy-â-D-glucopyranosyl (â-D-GlcNAc) monosac-
charides (1a-3a) and their corresponding 1,4-linked
disaccharides (1b-3b), using vicinal coupling constants
from variable-temperature nuclear magnetic resonance
(1) Bioorganic Chemistry: Carbohydrates; Hecht, S. M., Ed.; Oxford
University Press: Oxford, UK, 1999.
(7) van Aalten, D. M. F.; Komander, D.; Synstad, B.; Gaseidnes, S.;
Peter, M. G.; Eijsink, V. G. H. Proc. Natl. Acad. Sci. U.S.A. 2001, 98,
8979-8984.
(8) (a) Eliel, E. L.; Gilbert, E. C. J. Chem. Am. Soc. 1969, 91, 5487-
5495. (b) Corey, E. J.; Feiner, N. F. J. Org. Chem. 1980, 45, 765-780.
(c) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic
Compounds; Wiley: New York, 1994; Chapter 10 and references
therein.
(2) Adelhorst, K.; Bock, K. Acta Chem. Scand. 1992, 46, 1114-1121.
(3) Bock, K.; Duus, J. Ø. J. Carbohydr. Chem. 1994, 13, 513-543.
(4) Blackwell, J. In Methods in Enzymology; Wood, W. A., Kellogg,
S. T., Eds.; Academic Press: San Diego, CA, 1988; Vol. 161, pp 435-
442.
(5) Minke, R.; Blackwell, J. J. Mol. Biol. 1978, 120, 167-181.
(6) Gardner, K. H.; Blackwell, J. Biopolymers 1975, 14, 1581-1595.
10.1021/jo0485841 CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/25/2004
214
J. Org. Chem. 2005, 70, 214-226

6-C-Methyl-Substituted Mono- and Disaccharides
SCHEME 1. Synthesis of 6-C-Substituted
Monosaccharidesa
FIGURE 1. Staggered gt, tg, and gg conformations of 6-C-
substituted â-D-GlcNAc derivatives 1-3.
a Reagents and conditions: (a) (i) AcOH, THF:H2O, 45 °C, (ii)
TBS-Cl, Et3N, imidazole, CH2Cl2:THF (93%, two steps); (b) (i)
dihydropyran, PPTS, CH2Cl2, (ii) n-Bu4NF, THF (76%, two steps);
(c) 7: (i) (COCl)2, DMSO, CH2Cl2, -78 °C, Et3N, 0 °C (62%), (ii)
NaBD4, CH2Cl2:MeOH, -10 °C (6S:6R 2:1), (iii) p-TsOH, MeOH
(46%, two steps); (d) 8: (i) (COCl)2, DMSO, CH2Cl2, -78 °C, Et3N,
0 °C, (ii) AlMe3, CuCN, THF, -55 °C to rt (6S:6R 6:1), (iii) p-TsOH,
MeOH (25%, three steps); (e) 9: (i) and (ii) same as (d), (iii) (COCl)2,
DMSO, CH2Cl2, -78 °C; Et3N, 0 °C (81%), (iv) ZnCl2, i-Bu2AlH,
THF, -78 °C (6S:6R 1:6), (v) p-TsOH, MeOH (44%, two steps); (f)
(i) (CH2NH2)2, n-BuOH, 100 °C, (ii) Ac2O, pyridine (10: 74%, 11:
87%, 12: 93%, two steps); (g) NaOMe, MeOH:CH2Cl2 (1:1, v/v)
(1a: 71%, 1b: 98%, 1c: 100%). Selected acronyms: All ) allyl,
Phth ) phthalimido, PMP ) p-methoxyphenyl, TBS ) tert-
butyldimethylsilyl, THP ) tetrahydropyranyl.
FIGURE 2. (6R)-C-Methyl-substituted glucosamine in Gene-
ticin (G418).
(VT-NMR) spectroscopy. A previous analysis of these
compounds at 298 K in methanol-d4 has established that
the stereodefined 6-C-methyl group imposes a strong
conformational bias on the C-5-C-6 bond, with predict-
able outcomes for the lowest energy conformations.11 In
this article, further evaluation of 3JH,H coupling constants
over a wide temperature range (229-320 K) permits
these conformational preferences to be described in
thermodynamic terms with use of three-state conformer
models. Parametrized Karplus analyses of this type allow
us to estimate relative differences in enthalpy, which is
pertinent for understanding conformational effects in
crystal polymorphism and ligand-receptor binding. With
respect to the latter, it is interesting to note that
aminoglycoside antibiotics in the gentamicin family
including Geneticin (G418) possess 6-C-methyl-substi-
tuted glucosamines (see Figure 2).12,13 A recent X-ray
crystal structure of G418 complexed to an RNA fragment
suggests that the (6R)-C-methyl group may destabilize
a specific G-C base pair.13 Conformational analysis of
these units may contribute toward structure-activity
studies of gentamicin analogues, whose medicinal utility
is hampered by the evolution of drug-resistant bacterial
strains.14
Results and Discussion
Synthesis. Multigram quantities of protected glu-
cosamine derivative 4 were prepared from glucosamine
hydrochloride according to literature procedures (see
Scheme 1).15 Reductive cleavage of the 4,6-O-p-methoxy-
benzylidene acetal with borane and Bu2BOTf to the
corresponding 4-O-p-methoxybenzyl (PMB) ether16 were
problematic due to the reactivity of the allyl ether at 0
°C;17 however, the 4,6-diol could be regioselectively
protected as 6-O-tert-butyldimethylsilyl (TBS) ether 5,
then converted to 4-O-tetrahydropyranyl (THP)-protected
primary alcohol 6 in 71% overall yield from 4.
Compound 6, which served as the common intermedi-
ate for the 6-C-substituted â-D-GlcNAc derivatives, was
(9) (a) Lemieux, R. U.; Wong, T. C.; Thøgerson, H. Can. J. Chem.
1982, 60, 81-86. (b) Lough, C.; Hindsgaul, O.; Lemieux, R. U.
Carbohydr. Res. 1983, 120, 43-53.
(10) (a) Lindh, I.; Hindsgaul, O. J. Am. Chem. Soc. 1991, 113, 216-
223. (b) Sabesan, S.; Neira, S.; Davidson, F.; Duus, J. Ø.; Bock, K. J.
Am. Chem. Soc. 1994, 116, 1616-1634. (c) Spohr, U.; Le, N.; Ling,
C.-C.; Lemieux, R. U. Can J. Chem. 2001, 79, 238-255.
(11) Achkar, J.; Sanchez-Larraza, I.; Wei, A. Carbohydr. Res. 2002,
337, 83-86.
(14) Wright, G. D.; Davies, J. Trends Microbiol. 1997, 5, 234-240.
(15) (a) Kiso, M.; Anderson, L. Carbohydr. Res. 1985, 136, 309-
323. (b) El-Sokkary, R. I.; Silwanis, B. A.; Nashed, M. A.; Paulsen, H.
Carbohydr. Res. 1990, 203, 319-323. (c) Herna´ndez-Torres, J. M.;
Liew, S.-T.; Achkar, J.; Wei, A. Synthesis 2002, 487-490.
(16) Jiang, L.; Chan, T.-H. Tetrahedron Lett. 1998, 39, 355-358.
(17) Herna´ndez-Torres, J. M.; Achkar, J.; Wei, A. J. Org. Chem.
2004, 69, 7206-7211.
(12) Berdy, J.; Pauncz, J. K.; Vajna, Z. M.; Horvath, G.; Gyimesi,
J.; Koczka, I. J. Antibiot. 1977, 30, 945-954.
(13) Vicens, Q.; Westhof, E. J. Mol. Biol. 2003, 326, 1175-1188.
J. Org. Chem, Vol. 70, No. 1, 2005 215

Achkar et al.
TABLE 1. Stereoselectivity of Methyl Addition to
Glucosamine-Derived Aldehydea
SCHEME 2. Synthesis of 6-C-Substituted
Disaccharidesa
reagent
(equiv)
additive
(equiv)b
yield,c
%
8:9
entry
R
solvent
(6S:6R)d
1
2
3
4
5
6
MeMgI (2) THP
THF
25
60
60
0
54
40
4:1
4:1
3:1
AlMe3 (6)
AlMe3 (4)
AlMe3 (4)
AlMe3 (5)
AlMe3 (5)
THP
Bn
CH2Cl2
CH2Cl2
CH2Cl2
MEM
THP
THP
CuCN (0.2) THF
CuCN (1) THF
5:1
6:1
a See Experimental Section for standard reaction conditions.
b Equivalents in parentheses relative to aldehyde. c Combined yield
after methylation and THP deprotection. d In the case of R ) THP,
both diastereomers yielded mixtures of 6S and 6R epimers.
a Reagents and conditions: (a) 13: TBS-Cl, Et3N, imidazole,
CH2Cl2:THF (89%); (b) 14, 15: (i) p-MeOC6H4CH(OMe)2, cam-
phorsulfonic acid, 4A mol sieves, toluene, 90 °C, (ii) NaBH3CN,
HCl, THF:Et2O, 4A mol sieves, -30 °C (14: 43%, 15: 27%, two
steps); (c) 16 (2 equiv), TMSOTf, 4A mol sieves, CH2Cl2, -30 °C
(17: 51%, 18: 98%, 19: 78%); (d) 1b: n-Bu4NF, THF; (e) 2b, 3b:
DDQ, t-BuOH, pH 7 buffer, CH2Cl2; (f) (i) (CH2NH2)2, n-BuOH,
100 °C, (ii) Ac2O, pyridine, (iii) NaOMe, MeOH:CH2Cl2 (1b: 99%,
2b: 79%, 3b: 71%, four steps). Selected acronyms: All ) allyl,
Phth ) phthalimido, PMB ) p-methoxybenzyl, TBS ) tert-
butyldimethylsilyl.
oxidized to the corresponding aldehyde with Swern
conditions.18 This was reduced with NaBD4 and depro-
tected at O-4 to yield 6-C-d-substituted diol 7 as a 7:3
6S:6R mixture of diastereomers, with 6S- or 6R-stereo-
3
chemical assignments based on J5,6 coupling constants
of the corresponding 4,6-O-isopropylidene acetal deriva-
3
tive (3J5,6R ) 5.2 Hz, J5,6S ) 10.2 Hz). Monodeuteration
simplifies the coupling of H-5 to H-6R and H-6S to two-
spin systems, making conformational analysis straight-
forward. Next, the aldehyde was reacted with methyl
Grignard reagents, which have been shown to add to
similar substrates in good yields and stereoselectivity;9
unfortunately, the aldehyde proved to be a remarkably
poor electrophile. After a broad survey of nucleophiles
and reaction conditions (see Table 1 for selected condi-
tions), we were able to achieve methylation with 6:1 6S:
6R stereoselectivity using AlMe3 in the presence of a
stoichiometric amount of CuCN in THF at low temper-
atures, in 40% yield over two steps from 6.19
ing that bulky reducing agents such as NaAl(OCH2CH2O-
CH3)2H2, LiAl(sBu)3H, or LiAl(OtBu)3H did not deliver
the desired 6R epimer with high selectivities, whereas
several other conditions produced the 6S-epimer prefer-
entially. Diols 7-9 were then transformed into â-D-Glc-
NAc derivatives 10-12 in excellent yields by ethylene-
diamine-mediated cleavage of the phthalimide group and
peracetylation. Last, methanolysis afforded the desired
6-C-substituted â-D-GlcNAc monosaccharides 1a-3a in
quantitative yields.
To determine the relative influence of a neighboring
glycosidic unit at C-4 on sidechain conformations, disac-
charides 1b-3b were also synthesized (see Scheme 2).
Monodeuterated diol 7 was protected as 6-O-TBS ether
13, whereas 6-C-methyl-substituted diols 8 and 9 were
protected as 4,6-O-p-methoxybenzylidene acetals, and
converted to their respective 6-O-PMB ethers 14 and 15
by reductive cleavage under acidic conditions.21 These
alcohols were coupled straightforwardly with trichloro-
acetimidate 1622 to produce the protected â-1,4-linked
disaccharides 17-19 in excellent yields. Global depro-
tection, peracetylation, and methanolysis afforded the
desired 6-C-substituted â-D-GlcNAc disaccharides 1b-
3b in high overall yields.
The 4-O-THP group had an important role in the reac-
tion outcome. Replacing this group with benzyl ether
caused the stereoselectivity to drop to a 3:1 6S:6R ratio,
whereas the 4-O-methoxyethoxymethyl (MEM)-protected
aldehyde was unreactive to AlMe3. The chiral THP group
did not drastically influence methylation stereochemistry,
as both diastereomers yielded the 6S-epimer as the major
product.
Separation of the C-6 diastereomers was achieved upon
cleavage of the THP group and recrystallization of the
(6S)-C-methyl â-D-GlcNAc precursor 8. Assignments of
C-6 stereochemistry were confirmed by vicinal coupling
constant analysis of the corresponding 4,6-O-anisylidene
3
acetals (from 8: 3J5,6 ) 5.7 Hz; 9: J5,6 ) 9.2 Hz). Larger
quantities of the (6R)-C-methyl derivative 9 were ob-
tained by oxidation of the diastereomeric 6-C-methyl
adducts and reduction of the corresponding methyl
ketone under chelate-controlled conditions with use of
iBu2AlH in the presence of ZnCl2 with 6:1 6R:6S stereo-
selectivity,20 followed by THP cleavage and careful sepa-
ration by silica gel chromatography. It is worth mention-
Conformational Analysis. The influence of C-6 sub-
stituents on side chain conformations in methanol-d4 was
evaluated primarily by 3JH,H coupling constant analysis,
using empirically parametrized Karplus equations de-
veloped by Altona and co-workers.23 Conformational
analyses of the hydroxymethyl C-5-C-6 bond in pyra-
(18) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978,
43, 2480-2482.
(21) Johansson, R.; Samuelsson, B. J. Chem. Soc., Chem. Commun.
1984, 201-202.
(19) Flemming, S.; Kabbara, J.; Nickisch, K.; Westermann, J.; Mohr,
J. Synlett 1995, 183-185.
(22) Grundler, G.; Schmidt, R. R.; Michel, J. Carbohydr. Res. 1984/
1985, 135, 203-218.
(20) Frenette, R.; Monette, M.; Bernstein, M. A.; Young, R. N.;
Verhoeven, T. R. J. Org. Chem. 1991, 56, 3083-3089.
(23) Haasnoot, C. A. G.; de Leeuw, F. A. A. M.; Altona, C.
Tetrahedron 1980, 36, 2783-2792.
216 J. Org. Chem., Vol. 70, No. 1, 2005

6-C-Methyl-Substituted Mono- and Disaccharides
FIGURE 3. Parametrized Karplus relationships describing C-5-C-6 conformations as a function of 3J5,6, based on the empirical
formulations of Haasnoot et al.23 C-5 hydroxymethyl and C-5 hydroxyethyl conformations were evaluated by using Karplus curves
parametrized for 1,2-dialkoxypropanes3 (left) and 1,2-dialkoxybutanes (right), respectively.
TABLE 2. Assignment of Selected JH,H and JC,H Values
nosides are typically based on Karplus curves param-
to Staggered Conformers about the Exocyclic C-5-C-6
etrized for 1,2-dialkoxypropanes. These produce dihedral
Bond
angles as a function of two coupling constants 3J5,6R and
a
b
c
3JH-5,H-6
2JC-6,H-5
3JC-7,H-5
3J5,6S, which reflect the weighted average of staggered
conformations.3 In the case of 6-C-methyl-substituted
pyranosides, the hydroxyethyl C-5-C-6 bond must be
considered as a 1,2-dialkoxybutane, which produces a
Karplus relationship with a significantly reduced ampli-
tude (see Figure 3). Coupling constant analysis of hy-
droxyethyl C-5-C-6 conformations rests on a single 3J5,6
value, and requires additional data to produce a unique
dihedral angle solution. To this end, geminal and vicinal
13C-1H coupling constants (2JC,H and 3JC,H) obtained from
proton-coupled 13C NMR spectra were employed as sup-
porting constraints. Empirical measurements compiled
by Serianni24 and Murata25 provide a set of limiting 3JC,H
values complementary to the parametrized Karplus
equations, and can be useful for defining rotamers with
significant contributions to the time-averaged conforma-
tions.
(6S)-C-CH3 substitution (2a,b)
gtd
tgd
ggd
9.2
2.6
0.7
L
L
S
S
L
S
(6R)-C-CH3 substitution (3a,b)
gte
tge
gge
2.3
9.1
1.4
L
L
S
L
S
S
a 3
J
H,H
values (in Hz) are derived from Karplus relationships
parametrized for 1,2-dialkoxybutanes (Figure 3), with a standard
2
deviation of 0.5 Hz.23 b Correlation of JC,H values with the
dihedral angle defined by H-6 and O-5 suggests “L” (-4 to -6 Hz)
and “S” (0 to +2 Hz) values.24,25 c Correlation of 3JC,H values with
the dihedral angle defined by H-7 and C-5 suggests “L” (+5 to +7
Hz) and “S” (+1 to +3 Hz) values.24,25 d gt, tg, and gg defined by
O5-C5-C6-O6 dihedral angles of +60°, +170°, and -60°,
respectively. e gt, tg, and gg defined by O5-C5-C6-O6 dihedral
angles of +60°, +175°, and -70°, respectively.
Conformational analysis about the C-5-C-6 bond was
performed based on the relative populations of the three
staggered conformers gt, tg, and gg (see Figure 1).26
Individual rotamers of 6-C-methyl â-D-GlcNAc deriva-
3
study have JH,H values consistent with stable chair
conformations, permitting conformational analysis to be
modeled on a diamond lattice framework.28
3
tives (2a,b and 3a,b) were correlated with JH,H values
Coupling constant analysis of compounds 1-3 at 298
K was presented in an earlier communication11 and is
briefly summarized here. In accord with previous re-
derived from the Karplus curves at the relative minima
determined by semiempirical methods (see below), supple-
2
3
mented by “large” and “small” JC,H and JC,H coupling
constants as defined by Serianni24 and Murata.25 Despite
their limited precision, JC,H couplings allow each stag-
gered conformer to be defined by a unique set of coupling
constant parameters (see Table 2).27 Last, we note that
the ring protons of all â-D-GlcNAc derivatives in this
(27) It has been shown that 13C-1H coupling constants can be used
to support parametrized Karplus relationships for quantifying the
relative populations of staggered conformers, particularly for C-O-
C-H couplings. However, the amount of empirical data available to
support such relationships for C-C-C-H couplings is presently
limited. Also technical limitations arise when collecting
2,3
J
values
C,H
at low temperatures on natural abundance compounds. See: (a)
Spoormaker, T.; de Bie, M. J. A. Recl. Trav. Chim. 1978, 97, 85-87.
(b) Spoormaker, T.; de Bie, M. J. A. Recl. Trav. Chim. Pays-Bas 1979,
98, 380-388. (c) Spoormaker, T.; de Bie, M. J. A. Recl. Trav. Chim.
Pays-Bas 1980, 99, 154-160. (d) Mulloy, B.; Frenkiel, T. A.; Davies,
D. B. Carbohydr. Res. 1988, 184, 39-46. (e) Tvaroska, I.; Gajdos, J.
Carbohydr. Res. 1995, 271, 151-162. (f) Bose, B.; Zhao, S.; Stenutz,
R.; Cloran, F.; Bondo, P. B.; Bondo, G.; Hertz, B.; Carmichael, I.;
Serianni, A. S. J. Am. Chem. Soc. 1998, 120, 11158-11173.
(24) Podlasek, C. A.; Wu, J.; Stripe, W. A.; Brondo, P. B.; Serianni,
A. S. J. Am. Chem. Soc. 1995, 117, 8635-8644.
(25) Matsumori, N.; Kanedo, D.; Murata, M.; Nakamura, H.; Ta-
chibana, K. J. Org. Chem. 1999, 64, 866-876.
(26) Conformational analysis of the C5-C6 bond is more accurate
when conformers are assumed to adopt slightly nonstaggered geom-
etries. See: Rockwell, G. D.; Grindley, T. B. J. Am. Chem. Soc. 1998,
120, 10953-10963.
J. Org. Chem, Vol. 70, No. 1, 2005 217

Achkar et al.
TABLE 3. Selected JH,H and JC,H Coupling Constants
for 6-C-Substituted â-D-GlcNAc Mono- and Disaccharides
at 298 Ka
stant; in the case of the (6S)-C-methyl derivative, the
relative minima were switched. We thus elected to carry
out conformational analyses using a three-conformer
model under two limiting assumptions: one with the two
minor isomers being isoenergetic, the other with a free-
energy difference of 0.5 kcal/mol between minor isomers.
These assumptions necessarily limited the precision of
the analyses, but could otherwise enable a reliable
assessment of conformational stability in thermodynamic
terms.
b
c
c
compd
3JH-5,H-6
2JC-6,H-5
3JC-7,H-5
1a
6.2, 2.6
4.9, 2.0
1.8
1bd
2a
2.9
2.3
4.2
4.5
1.6
1.2
3.4
3.8
2be
3a
1.5
3.9
2.4
3bf
a 1H NMR spectra were acquired at 600 MHz in CD3OD unless
otherwise noted. Proton-coupled 13C NMR spectra were acquired
at 500 MHz in CD3OD unless otherwise noted. b In Hz ((0.25 Hz).
c In Hz ((0.3 Hz). d 1H NMR in CD3OD:D2O (3:1, v/v). e 13C NMR
in CD3OD:D2O (5:3, v/v). f 13C NMR in CD3OD:D2O (5:1, v/v).
Distributions of staggered conformers about the C-5-
C-6 bonds were calculated by using the Karplus relation-
ships defined in Figure 3, with dihedral angles for gt, tg,
and gg based on the minima calculated for methyl â-D-
GlcNAc derivatives in methanol (see Table 4). For the
6-C-monodeuterated derivatives 1a and 1b, an unre-
stricted three-conformer model could be derived from two
3J5,6 values, with dihedral angles for gt, tg, and gg defined
at +60°, +170°, and -65°, respectively (see Figure 4d).26
The negative tg values are artifacts of the parametriza-
tion; nevertheless, the population ratios of gg vs gt are
expected to be slightly more accurate than those derived
from earlier analyses, whose populations are based on
dihedral angles of +60°, +180°, and -60°.3,29 For the 6-C-
methyl derivatives 2a,b and 3a,b, three-conformer mod-
ports,29 the C-5-C-6 bond of monodeuterated â-D-GlcNAc
derivatives 1a and 1b preferred the gg and gt conformers
over the tg conformer, which is destabilized by 1,3-
diaxial-like interactions between O-4 and O-6 (see Figure
1). By comparison, the C-5-C-6 bond in (6S)-C-methyl
â-D-GlcNAc derivatives 2a and 2b had a clear preference
for the gg conformation over gt or tg, whereas that of (6R)-
C-methyl â-D-GlcNAc derivatives 3a and 3b preferred gt
3
over tg or gg (see Table 3 for J5,6 and selected JC,H
3
values). It is noteworthy that the J5,6 values of disac-
3
els were based on a single J5,6 value using the limiting
charides 2b and 3b at 298 K indicate a stronger prefer-
ence for their lowest energy conformations (gg and gt,
respectively) than their monosaccharides 2a and 3a. At
first glance, this suggests that the neighboring C-4
glycosidic unit has a greater steric interaction with the
C-6 methyl group than the C-4 hydroxyl, but a more
detailed examination reveals this not to be the case (see
below).
assumptions above, with dihedral angles for gt, tg, and
gg defined at +60°, +170°, and -60° for 2a,b and at +60°,
+175°, and -70° for 3a,b (see Figure 4e,f).
In all cases, the 6-C-methyl-substituted derivatives
favored the sterically least encumbered conformations,
regardless of temperature (gg for 2a,b and gt for 3a,b).
The population ratios of the two lowest energy conformers
were used to determine relative free-energy differences
(-∆∆G) based on each three-conformer model (see Table
4). In the case of (6S)-C-methyl monosaccharide 2a,
-∆∆G values for the lower limiting case were found to
be on the order of 0.5 kcal/mol, whereas those for the
upper limiting case were on the order of 1.1 kcal/mol. A
similar situation was observed for (6S)-C-methyl disac-
charide 2b, albeit with slightly greater free-energy dif-
ferences. For (6R)-C-methyl monosaccharide 3a, the
-∆∆G values were less affected by the choice of three-
conformer model but more affected by temperature, with
values ranging between 0.3 and 1.4 kcal/mol. Last, in the
case of (6R)-C-methyl disaccharide 3b, the preference for
the lowest energy conformation was overwhelming (-∆∆G
> 1.9 kcal/mol), to the extent that the accuracy of
thermodynamic analysis was limited by the parametrized
Karplus equation itself. It should be noted that the
uncertainty of ∆∆G increases rapidly as the J5,6 value
approaches the lower limit set by the parametrized
Karplus equation (2.3 Hz for 3a,b). Furthermore, in some
cases the J5,6 value lay below this limit, which suggests
that the preferred orientation of the C-5-C-6 bond in
disaccharide 3b is distorted away from a staggered gt
conformation, as opposed to the model (6R)-C-methyl
monosaccharide used for Figure 4f.
To obtain quantitative estimates of the relative con-
formational energies, VT-NMR studies were conducted
in methanol-d4 between 230 and 320 K and applied
toward three-conformer models. The latter proved to be
a challenge in the case of the (6S)- and (6R)-C-methyl-
substituted compounds: a first-order analysis based on
experimentally measured interaction energies8 indicated
a difference of less than 0.5 kcal/mol between the minor
staggered conformers. This was confirmed by molecular
mechanics (AMBER) calculations of conformational ener-
gies as a function of dihedral angle about the C-5-C-6
bond of methyl â-D-GlcNAc derivatives, in the gas phase
(ꢀ ) 1; see Figure 4a-c) or in a dielectric continuum
representing methanol (ꢀ ) 32.6; see Figure 4d-f).30 The
most stable conformations of the 6-C-methyl-substituted
compounds were favored by more than 1 kcal/mol over
the next lowest energy conformer; however, the relative
energies of the minor conformers were less clearly
defined. In the low-dielectric simulations, energy differ-
ences between minor conformers were 0.5 kcal/mol or
less, with rotational barriers on the order of 4-6 kcal/
mol. Both the energy differences and rotational barriers
were reduced upon increasing the media dielectric con-
(28) (a) Prelog, V. Pure Appl. Chem. 1964, 9, 119-130. (b) Prelog,
V. Angew. Chem., Int. Ed. Engl. 1989, 28, 1147-1152. (c) Wei, A.;
Haudrechy, A.; Audin, C.; Jun, H.-S.; Haudrechy-Bretel, N.; Kishi, Y.
J. Org. Chem. 1995, 60, 2160-2169 and references therein.
(29) (a) Perkins, S. J.; Johnson, L. N.; Phillips, D. C.; Dwek, R. A.
Carbohydr. Res. 1977, 59, 19-34. (b) Nishida, Y.; Hori, H.; Ohrui, H.;
Meguro, H. Carbohydr. Res. 1987, 170, 106-111.
Linear free-energy relationships were determined for
all compounds except 3b (see Figure 5), whose J5,6 values
coincided with the lower limit imposed by the Karplus
equation parametrized for 1,2-dialkoxybutanes. Least-
squares analyses of the corresponding van’t Hoff plots
yielded approximate ∆∆H and ∆∆S values (see Table 5),
(30) Kirschner, K. N.; Woods, R. J. Proc. Natl. Acad. Sci. U.S.A.
2002, 98, 10541-10545.
218 J. Org. Chem., Vol. 70, No. 1, 2005

6-C-Methyl-Substituted Mono- and Disaccharides
FIGURE 4. Potential energy curves for 6-C-substituted â-D-GlcNAc derivatives as a function of dihedral angle. Gas-phase
conformational energies were calculated by using molecular mechanics (Amber) with ꢀ ) 1 (a-c); conformations in methanol
were simulated by using ꢀ ) 32.6 (d-f).
which revealed additional insights into the forces influ-
encing the conformational preference of the exocyclic
C-5-C-6 bond. First, the -∆∆H values for the monosac-
charides (1a, 2a) are comparable to or greater than those
for the corresponding disaccharides (1b, 2b). This indi-
cates that the presence of the O-4 glycoside does not have
a significant steric influence on the conformation of the
C-5-C-6 bond; indeed, in the case of 2b the enthalpic
difference is much less than that predicted on the basis
of steric interactions alone (see above). Second, the -∆∆H
value of (6R)-C-methyl â-D-GlcNAc 3a is much larger
than can be accounted for based on increased 1,3-diaxial-
like interactions. It should be noted that the same is also
true for the relative free energy difference of disaccharide
3b.
Our observations indicate that the C-5-C-6 conforma-
tions are influenced by solvation effects.31 These can be
described in terms of solvent-solute interactions and
solvent reorganization, i.e., the restructuring of solvent
molecules around the cavity occupied by the solute.
Solvent-solute interactions can affect conformational
preferences if the quality of key polar interactions is
J. Org. Chem, Vol. 70, No. 1, 2005 219

Achkar et al.
3
TABLE 4. J5,6 Coupling Constants, Conformer
Distributions, and Relative Free Energy Differences As
Determined by VT-NMR Spectroscopy
b
b
compd
Ta J5,6S J5,6R
gt
tg
gg
57
-∆∆Gc
1a
239 1.76 6.15 55
258 2.20 6.15 53
278 2.20 5.72 49
302 2.64 6.16 52
320 2.63 6.16 52
239 1.66 4.61 38
248 1.72 4.77 40
258 2.05 4.65 38
278 1.97 4.65 38
302 2.04 4.93 41
320 2.04 4.93 41
-12
-6
0.02 (0.06)
0.00 (0.07)
0.09 (0.08)
-0.04 (0.09)
-0.04 (0.09)
0.31 (0.06)
0.29 (0.07)
0.32 (0.07)
0.34 (0.08)
0.30 (0.08)
0.32 (0.09)
1.11 (0.20)
1.10 (0.18)
1.12 (0.18)
1.17 (0.18)
1.08 (0.17)
0.57 (0.23)
0.54 (0.21)
0.53 (0.21)
0.57 (0.22)
0.44 (0.21)
1.16 (0.22)
1.25 (0.24)
1.31 (0.25)
1.29 (0.23)
1.41 (0.25)
1.44 (0.24)
0.63 (0.25)
0.71 (0.27)
0.77 (0.28)
0.73 (0.25)
0.85 (0.28)
0.86 (0.27)
1.31 (0.85)
1.35 (0.95)
0.82 (0.24)
0.60 (0.20)
0.29 (0.20)
0.08 (0.22)
1.37 (0.84)
1.41 (0.94)
0.94 (0.21)
0.77 (0.17)
0.55 (0.15)
0.42 (0.15)
53
57
49
49
74
71
69
70
67
67
-6
-1
-1
1bd
-12
-11
-7
-8
-8
-8
2ae (tg ) gt) 230
1.48
1.63
1.78 10
1.83 11
2.08 13
7.5
9
7.5 85
250
9
10
11
13
21
23
25
25
29
7
82
277
80
298
78
319
74
2af (tg > gt) 230
1.48
1.63
1.78 10
1.83 10.5
2.08 13
1.41
1.41
1.40
1.54
1.53
1.60
1.41
1.41
1.40
1.54
1.53
1.60
7
8.5
72
250
68.5
65
277
298
64.5
58
319
2be (tg ) gt) 230
247
7
7
86
86
7
258
6.5
8
6.5 87
278
8
8
84
84
302
8
320
8.5
6.5
6.5
6.5
8
8.5 83
2bf (tg > gt) 230
247
19
18
17
74.5
75.5
76.5
258
278
19.5 72.5
302
8
18
19
5
5
15
20
74
72.5
5
5
15
20
320
8.5
3ae (tg ) gg) 229 2.60
233 2.59
269 3.19
278 3.49
302 3.93
320 4.18
3af (tg > gg) 229 2.60
233 2.59
269 3.19
278 3.49
302 3.93
320 4.18
3be (tg ) gg) 230 2.05
248 2.14
258 2.18
278 2.33
302 2.43
320 2.56
90
90
70
60
45
36
94
94
81
74
63.5
57
27.5 27.5
32
32
4.5 1.5
4.5 1.5
FIGURE 5. Van’t Hoff plots describing conformational prefer-
ences of the C-5-C-6 bond for 6-C-substituted â-D-GlcNAc
derivatives. (a) gg vs gt for 6-C-d-substituted â-D-GlcNAc
monosaccharide 1a (filled circles) and disaccharide 1b (open
squares). (b) gg vs tg for (6S)-C-methyl-substituted â-D-GlcNAc
monosaccharide 2a, with tg ) gt (filled circles) or tg > gt (open
squares). (c) gg vs tg for (6S)-C-methyl-substituted â-D-GlcNAc
disaccharide 2b, with tg ) gt (filled circles) or tg > gt (open
squares). (d) gt vs tg for (6R)-C-methyl-substituted â-D-GlcNAc
3a, with tg ) gg (filled circles) or tg > gg (open squares).
14
5
18.5 7.5
25.5 11
29.5 13.5
99
96
91
0.5 0.5
2.9g
2.3g
1.9g
2
2
4.5 4.5
a Calibrated temperatures in K. b Coupling constants in Hz
((0.25 Hz). c Free-energy difference between the two lowest energy
conformations, in kcal/mol (uncertainties in parentheses). d Con-
formational analysis performed in 3:1 CD3OD:D2O. e Conformer
populations calculated assuming minor conformers are equal in
energy. f Conformer populations calculated assuming minor con-
formers have a free-energy difference of 0.5 kcal/mol. g The ac-
curacy of these values is affected by the lower limit set by the
parametrized Karplus equation. See Experimental Section for
further details.
Both solvent-solute interactions and solvent reorga-
nization may have a significant influence on the relative
changes in conformational enthalpies and entropies for
6-C-methyl-substituted derivatives 2a,b (gg vs tg,gt) and
3a,b (gt vs tg,gg). Solvation entropy should in principle
favor the minor tg conformer, because the consolidation
of polar and nonpolar groups reduces the size of the
solvophobic cavity. However, the protruding 6-C-methyl
group increases the size of the solvophobic pocket and is
sensitive to local environmental factors, whereas solvent
reorganization can account for large changes in solvation
enthalpy and entropy in rough proportion to the solvent-
exposed surface area of the solute.32 Recent simulations
on the solvation energies of hydrocarbons in water as a
function of conformation (cavity size) indicate that changes
in solvation free energies are dominated by entropic
changes in solvent reorganization.33
(31) Others have commented on the influence of solvation on
conformational equilibria: (a) Lemieux, R. U.; Pavia, A. A.; Martin, J.
C.; Watanabe, K. A. Can. J. Chem. 1969, 47, 4427-4439. (b) Praly,
J.-P.; Lemieux, R. U. Can. J. Chem. 1987, 65, 213-223. (c) Gregoire,
F.; Wei, S. H.; Streed, R. W.; Brameld, K. A.; Fort, D.; Hanely, L. J.;
Walls, J. D.; Goddard, W. A.; Roberts, J. D. J. Am. Chem. Soc. 1998,
120, 7537-7543.
(32) Cabani, S.; Gianni, P.; Mollica, V.; Lepori, L. J. Solution Chem.
1981, 10, 563-595.
(33) Gallichio, E.; Kubo, M. M.; Levy, R. M. J. Phys. Chem. B 2000,
104, 6271-6285.
220 J. Org. Chem., Vol. 70, No. 1, 2005

6-C-Methyl-Substituted Mono- and Disaccharides
TABLE 5. Thermodynamic Values Describing
) +60°; tg ) +170°; gg ) -70°) based on the relative minima
calculated for methyl â-D-GlcNAc in methanol (see Figure 4d)
and Karplus relationships parametrized for 1,2-dialkoxypro-
panes (see Figure 3). Populations were derived with eqs 1-3:
Conformational Preferences about the C-5-C-6 Bonda
b
∆∆Grt
∆∆Hb
∆∆Sc
1a: gg vs gt
1b: gg vs gtd
+0.04 (0.09) -0.21 (0.23) -0.72 (0.84)
-0.30 (0.08) -0.27 (0.08)
0.14 (0.30)
0.16 (0.46)
10.68% gt + 1.30% gg + 3.53% tg ) J5,6R
3.07% gt + 2.33% gg + 10.36% tg ) J5,6S
gt + gg + tg ) 100
(1)
(2)
(3)
2a: gg vs tg (tg ) gt) -1.17 (0.18) -1.07 (0.12)
2a: gg vs tg (tg > gt) -0.57 (0.22) -0.78 (0.15) -0.92 (0.56)
2b: gg vs tg (tg ) gt) -1.41 (0.25) -0.50 (0.12)
2b: gg vs tg (tg > gt) -0.85 (0.28) -0.09 (0.13)
2.97 (0.44)
2.45 (0.50)
3a: gt vs tg (tg ) gg) -0.29 (0.20) -4.62 (0.18) -14.26 (0.66)
3a: gt vs tg (tg > gg) -0.55 (0.15) -4.01 (0.19) -11.41 (0.72)
Conformer populations for (6S)-C-CH3-substituted compounds
were calculated by using three-conformer models with limiting
assumptions described in the main text, based on Karplus
relationships parametrized for 1,2-dialkoxybutanes (see Figure
3). For the case in which the two minor conformers are equal
in energy (tg ) gt), populations were derived with eqs 4 and
5:
1
a Thermodynamic values were derived from H NMR coupling
constants obtained at 600 MHz in CD3OD from 229 to 320 K.
Values for ∆∆H and ∆∆S were obtained from a linear least-
squares fit of the data plotted in Figure 5. Uncertainties (in
parentheses) for ∆∆G (rt ) 298 or 302 K) were derived by using
3
indeterminate errors from JH,H measurements ((0.25 Hz); un-
certainties for ∆∆H and ∆∆S were obtained from linear regression
analysis and do not include propagation of indeterminate error.
b In kcal/mol. c In cal‚mol/K. d Compound was dissolved in 3:1
CD3OD:D2O.
11.8% tg + 0.7% gg ) J5,6
2 tg + gg ) 100
(4)
(5)
likely to have an adverse effect on solvation reorganiza-
tion. Furthermore, solvation enthalpy disfavors the tg
conformer, because fewer well-defined hydrogen bonds
between solvent molecules around the solute cavity and
the hydroxyl groups at C-4 and C-6 are possible.
For the case in which the two minor conformers differ in
energy by 0.5 kcal/mol (tg > gt), populations were derived with
eqs 6-8:
9.2% gt + 2.6% tg + 0.7% gg ) J5,6
gt + tg + gg ) 100
(6)
(7)
(8)
The conformational preferences of the 6-C-methyl-
substituted â-D-GlcNAc derivatives can now be evaluated
in the context of both steric interactions and solvent
effects. In the case of (6S)-C-methyl-substituted monosac-
charide 2a, the minor changes in entropy indicate that
the preference for gg over the higher energy conformers
is due mostly to local steric interactions, with solvation
having little influence. In the case of (6S)-C-methyl-
substituted disaccharide 2b, ∆∆H is decreased and
accompanied by a rise in ∆∆S, indicating significant
changes in solvation energy. In particular, the positive
change in entropy implies that the minor conformations
require greater solvent reorganization. Last, in the case
of (6R)-C-methyl-substituted monosaccharide 3a, the
preference for the gt conformer is clearly strengthened
by additional solvent-solute interactions. The addition
of a bound solvent molecule to the gt conformer is
accompanied by a large and negative change in entropy.
In summary, a thermodynamic analysis of the confor-
mational preferences of the C-5-C-6 bond in 6-C-
substituted â-D-GlcNAc derivatives reveals the complex
balance of forces which influence their solution conforma-
tions. Overall, our results support the application of
classical steric interactions to predict preferred confor-
mations in polar solvents at ambient temperatures, and
confirm the validity of the steric director concept. How-
ever, solvent-solute interactions and solvent reorganiza-
tion can have a considerable impact on conformational
enthalpies and entropies, and may significantly alter the
conformational behavior of compounds with very similar
structures.
gt ) tg‚e-0.5/RT
Conformer populations for (6R)-C-CH3-substituted compounds
were calculated in a similar manner. For the case in which
the two minor conformers are equal in energy (tg ) gg),
populations were derived with eqs 9 and 10:
2.3% gt + 10.5% tg ) 3J5,6
gt + 2 tg ) 100
(9)
(10)
For the case in which the two minor conformers differ in
energy by 0.5 kcal/mol (tg > gg), populations were derived with
eqs 11-13:
2.3% gt + 9.1% tg + 1.4% gg ) 3J5,6
gt + tg + gg ) 100
(11)
(12)
(13)
gg ) tg‚e-0.5/RT
Allyl 3-O-Acetyl-2-deoxy-4,6-O-(p-methoxybenzylidene)-
2-phthalimido-â-D-glucopyranoside (4). A solution of allyl-
2-deoxy-2-phthalimido-3,4,6-tri-O-acetyl-â-D-glucopyrano-
side11 (10.2 g, 21.5 mmol) in CH2Cl2 (130 mL) was treated with
NaOMe (8 mL, 1 M solution in MeOH) at -5 °C. The reaction
was stirred for 2 h at 0 °C, and then poured onto a column of
activated Dowex 50X-W H+ ion-exchange resin. Elution with
spectral grade MeOH (500 mL) followed by solvent evaporation
affords the crude triol in 93% yield (6.98 g) as a white solid.
The intermediate triol and activated 4A molecular sieves
were suspended in toluene (80 mL) and treated with p-
anisaldehyde dimethylacetal (4.70 mL, 29.7 mmol) and cam-
phorsulfonic acid (426 mg, 1.83 mmol). The reaction mixture
was stirred at 90 °C for 20 h, diluted with EtOAc, filtered over
Celite, and quenched with water. A basic aqueous workup
(EtOAc) followed by recrystallization (EtOAc/hexanes, 60/140
mL) afforded the desired acetal as a white solid in 88% yield
(8.13 g).
Experimental Section
1
NMR Conformational Analysis. Chemical shifts for H
and 13C NMR spectra are reported (in parts per million)
relative to CDCl3 (δ 7.24 and 77.0 ppm, respectively) or CD3-
OD (δ 3.30 and 49.0 ppm, respectively).
Staggered conformer populations for 6-C-d-substituted com-
pounds were calculated by using a three-conformer model (gt
The acetal intermediate (8.00 g, 17.1 mmol) was dissolved
in pyridine (40 mL) and treated with Ac2O (40 mL) at 0 °C.
J. Org. Chem, Vol. 70, No. 1, 2005 221

Achkar et al.
The reaction mixture was stirred at room temperature for 24
h, quenched with EtOH (100 mL), and concentrated to dryness.
The crude residue was recrystallized (EtOAc/hexanes, 10/100
mL) to afford 4 as yellow needles in 68% yield (5.93 g). [R]D
-20 (c 1, CHCl3); IR (thin film) ν 2877, 1777, 1742, 1717, 1615,
1.89 and 1.87 (2 s, 3H), 1.80-1.30 (6 H); 13C NMR (75 MHz,
CDCl3) δ 169.9, 169.4, 167.5, 133.9, 133.2, 133.2, 130.9, 123.0,
116.9, 116.9, 102.0, 100.1, 96.8, 96.7, 75.5, 75.1, 74.6, 74.5, 72.9,
71.6, 69.6, 69.4, 65.0, 62.4, 61.2, 60.9, 54.6, 30.8, 30.8, 24.8,
24.5, 20.7, 20.3, 20.1, 19.1; HRMS (ESI) calcd for C24H29NO9
[M + Na]+ 498.1740, found 498.1746.
1386, 1251, 1226, 1101, 1034, 991, 722 cm-1 1H NMR (300
;
Allyl 3-O-Acetyl-2-deoxy-(6R/6S)-C-2H-2-phthalimido-
â-D-glucopyranoside (7). Primary alcohol 6 (200 mg, 0.421
mmol) was oxidized by the usual Swern procedure to afford
the corresponding aldehyde (124 mg, 0.262 mmol, 62% yield)
after purification by flash chromatography on silica gel (Et2O).
A solution of aldehyde (114 mg, 0.241 mmol) in MeOH/CH2-
Cl2 (5 mL, 3:2 v/v) was treated with NaBD4 (30.0 mg, 0.717
mmol) at -10 °C. The reaction mixture was stirred for 1 h.
Excess reagent was destroyed with acetone (5 mL) and the
reaction quenched with saturated NH4Cl solution (12 mL).
Aqueous workup (EtOAc) and purification by flash column
chromatography on silica gel (30-50% EtOAc gradient in
hexanes) afforded 4-O-THP-protected monodeuterated inter-
mediate alcohol in 69% isolated yield.
The monodeuterated intermediate (79.1 mg, 0.166 mmol)
was dissolved in spectral grade MeOH (5 mL) and treated with
p-toluenesulfonic acid (31.6 mg, 0.166 mmol). The reaction
mixture was stirred for 1 h at room temperature, then diluted
with CHCl3 (12 mL) and quenched at 0 °C with saturated
NaHCO3 solution (12 mL). Aqueous workup (CHCl3) and
solvents removal afforded compound 7 in 67% yield (45.5 mg)
in pure form without further purification. 1H NMR (300 MHz,
CDCl3) δ 7.84 (m, 2 H), 7.72 (m, 2 H), 5.69 (m, 1 H), 5.63 (dd,
1 H, J ) 8.8, 10.7 Hz), 5.39 (d, 1 H, J ) 8.4 Hz), 5.11 (dm, 1
H, J ) 17.2 Hz), 5.03 (dm, 1 H, J ) 10.4 Hz), 4.25 (ddt, 1 H,
J ) 4.1, 12.9, 1.4 Hz), 4.24 (ddt, 1 H, J ) 6.1, 12.9, 1.3 Hz),
4.23 (dd, 1 H, J ) 8.4, 10.7 Hz), 3.97-3.74 (m, 2 H), 3.60 (ddd,
1 H, J ) 3.9, 4.7, 9.8 Hz), 3.20 (br s, 1 H), 2.25 (br s, 1 H), 1.87
(s, 3 H); 13C NMR (75 MHz, CDCl3) δ 171.3, 167.8, 134.2, 133.4,
131.4, 123.5, 117.6, 97.2, 75.4, 73.6, 70.2, 67.0, 62.2, 61.9, 54.7,
20.6; HRMS (EI) calcd for C19H20DNO8 [M + H]+ 393.1408,
found 393.1409.
Allyl 3-O-Acetyl-2-deoxy-(6S)-C-methyl-2-phthalimido-
â-D-glucopyranoside (8). A solution of oxalyl chloride (0.55
mL, 6.31 mmol) in CH2Cl2 (6.6 mL) at -78 °C was treated with
a solution of DMSO (0.89 mL, 12.6 mmol) in CH2Cl2 (1.8 mL).
The reagents were stirred for 15 min. A solution of primary
alcohol 6 (1 g, 2.10 mmol) in CH2Cl2 (6 mL) was added over
20 min via syringe pump. After being stirred for 30 min, the
reaction mixture was treated with Et3N (2.64 mL, 18.9 mmol)
at -78 °C, allowed to reach 0 °C over 20 min, then diluted in
C6H6/Et2O (20 mL, 4:1 v/v) and quenched with saturated NH4-
Cl solution (18 mL). Upon standard aqueous workup, the
residue was azeotroped with toluene (thrice) to afford the
desired aldehyde in quantitative crude yield.
A suspension of crude aldehyde (996 mg, 2.10 mmol) and
CuCN (188 mg, 2.10 mmol) in anhydrous THF (20 mL) was
stirred at room temperature for 10 min, cooled to -55 °C, then
treated with AlMe3 (5.26 mL, 2 M solution in hexanes) and
allowed to reach room temperature overnight. The reaction
mixture was diluted with Et2O (20 mL) and quenched with
saturated Na/K-tartrate/NH4Cl (24 mL, 1:1 v/v) solution at 0
°C. The biphasic mixture was stirred for 30 min or until the
aqueous phase turned blue. Aqueous workup (EtOAc) followed
by flash chromatography on silica gel (30-50% EtOAc gradient
in hexanes) afforded the desired methyl adduct as a 6:1
mixture of (6S):(6R) diastereomers in 40% isolated yield (402
mg) over two steps.
MHz, CDCl3) δ 7.83 (m, 2 H), 7.71 (m, 2 H), 7.36 (d, 2 H, J )
8.7 Hz), 6.86 (d, 2 H,, J ) 8.7 Hz), 5.86 (dd, 1 H, J ) 8.9, 10.4
Hz), 5.68 (m, 1 H), 5.48 (s, 1 H), 5.45 (d, 1 H, J ) 8.5 Hz), 5.12
(dm, 1 H, J ) 17.2 Hz), 5.03 (dm, 1 H, J ) 10.4 Hz), 4.37 (dd,
1 H, J ) 4.3 Hz, 10.2 Hz), 4.30 (dd, 1 H,, J ) 8.5 Hz), 4.26
(ddt, 1 H, J ) 5.0, 12.9, 1.5 Hz), 4.02 (ddt, 1 H, J ) 6.2, 12.9,
1.3 Hz), 3.82 (t, 1 H, J ) 9.8 Hz), 3.78 (s, 3 H), 3.75 (t, 1 H, J
) 9.0 Hz), 3.72 (m, 1 H), 1.86 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 170.0, 167.5, 160.1, 134.1, 133.2, 131.4, 129.4, 127.5,
123.4, 117.7, 113.5, 101.5, 97.7, 79.1, 70.2, 69.7, 68.5, 66.1, 55.3,
55.2, 20.5; HRMS (EI) calcd for C27H27NO9 [M + H]+ 510.1764,
found 510.1753.
Allyl 3-O-Acetyl-6-O-(tert-butyldimethylsilyl)-2-deoxy-
2-phthalimido-â-D-glucopyranoside (5). A solution of 4
(7.27 g, 14.3 mmol) in AcOH/THF/H2O (100 mL, 8:1:1 v/v/v)
was heated to 45 °C for 5 h, evaporated to dryness, and
azeotroped with toluene. Upon basic aqueous workup (CHCl3),
the solid residue was washed with cold hexanes to afford the
intermediate diol in 97% yield. The crude diol (5.40 g, 13.8
mmol) was dissolved in anhydrous THF/CH2Cl2 (80 mL, 1:3
v/v) and treated with Et3N (3.26 mL, 23.4 mmol), imidazole
(94 mg, 1.38 mmol), then TBSCl (3.12 g, 20.7 mmol). The
reaction mixture was stirred at room temperature for 16 h,
then diluted with CH2Cl2 (100 mL) and quenched with
saturated aqueous NaHCO3 solution (100 mL). Product extrac-
tion (CH2Cl2) was followed by 5% CuSO4 aqueous solution (50
mL), water (50 mL), and brine (50 mL) washes. The crude
residue was purified by flash chromatography on silica gel
(EtOAc/hexanes, 1:2 v/v) to afford 5 in 96% yield (6.72 g). [R]D
-9 (c 1, CHCl3); IR (thin film) ν 3481, 2930, 2857, 1778, 1747,
1718, 1387, 1231, 1114, 1067, 1040, 837, 779, 722 cm-1 1H
;
NMR (300 MHz, CDCl3) δ 7.78 (m, 2 H), 7.66 (m, 2 H), 5.66
(m, 1 H), 5.61 (dd, 1 H, J ) 8.8, 10.7 Hz), 5.37 (d, 1 H, J ) 8.5
Hz), 5.06 (dm, 1 H, J ) 17.3 Hz), 4.97 (dm, 1 H, J ) 10.4 Hz),
4.20 (ddt, 1 H, J ) 5.0, 12.9, 1.5 Hz), 4.15 (dd, 1 H, J ) 8.5,
10.7 Hz), 3.99 (ddt, 1 H, J ) 6.2, 12.9, 1.3 Hz), 3.90 (dd, 2 H,
J ) 4.9, 11.7 Hz), 3.71 (t, 1 H, J ) 9.8 Hz), 3.57 (dt, 1 H, J )
4.9, 9.8 Hz), 3.44 (br s, 1 H), 1.84 (s, 3 H), 0.87, 0.86, 0.85 (3
s, 9 H), 0.07, 0.06 (2 s, 6 H); 13C NMR (75 MHz, CDCl3) δ 170.9,
167.7, 134.1, 133.4, 131.4, 123.3, 117.3, 96.8, 74.6, 73.5, 71.7,
69.7, 64.1, 54.5, 25.7, 20.5, 18.1, -5.5, -5.6; HRMS (ESI) calcd
for C25H35NO8Si [M + Na]+ 528.2030, found 528.2021.
Allyl 3-O-Acetyl-2-deoxy-2-phthalimido-4-O-tetrahy-
dropyranyl-â-D-glucopyranoside (6). A solution of 5 (6.72
g, 13.3 mmol) in CH2Cl2 (65 mL) was treated with 3,4-dihydro-
2H-pyran (12.1 mL, 0.133 mol) and PPTS (84.6 mg, 0.332
mmol). The reaction was stirred at room temperature for 20
h, then diluted with CH2Cl2 (65 mL) and quenched with
saturated NaHCO3 solution (60 mL). Product extraction (CH2-
Cl2) and standard aqueous workup followed. The crude residue
was dissolved without further purification in anhydrous THF
(70 mL) and treated with n-Bu4NF (20 mL, 1 M solution in
THF). The reaction mixture was stirred at room temperature
for 1 h, then filtered over a silica gel plug (EtOAc). After
solvent evaporation, the crude residue was coevaporated with
CHCl3 (thrice), then washed with cold hexanes (3 × 50 mL) to
afford primary alcohol 6 as a mixture of diastereoisomers in
76% yield (4.78 g) over two steps. 1H NMR (300 MHz, CDCl3)
δ 7.82 (m, 2 H), 7.70 (m, 2 H), 5.73 (dd, 1 H, J ) 8.6, 10.6 Hz),
5.69 (m, 1 H), 5.42 (d, 1 H, J ) 8.5 Hz), 5.12 (dm, 1 H, J )
17.2 Hz), 5.04 (dm, 1 H, J ) 10.4 Hz), 4.66 and 4.56 (dd, 1 H,
J ) 3.0, 4.0 Hz), 4.24 (ddt, 1 H, J ) 5.3, 12.9, 1.4 Hz), 4.21
(dd, 1 H, J ) 8.5, 10.6 Hz), 4.04 (ddt, 1 H, J ) 6.0, 12.9, 1.3
Hz), 3.93 (ddd, 1 H, J ) 2.6, 5.0, 11.1 Hz), 3.86 (t, 1 H, J ) 9.2
Hz), 3.76 (m, 2 H), 3.62 (ddd, 1 H, J ) 2.6, 3.9, 4.6 Hz), 3.42
(ddd, J ) 3.9, 5.9, 11.1 Hz), 2.00 (dd, 1 H, J ) 5.0, 5.9 Hz),
A solution of methyl adduct (0.40 g, 0.821 mmol) in spectral
grade MeOH (8 mL) was treated with p-toluenesulfonic acid
(156 mg, 0.821 mmol). The reaction mixture was stirred at
room temperature for 1 h, then diluted with CHCl3 (12 mL)
and quenched with saturated NaHCO3 solution (24 mL) at 0
°C. Aqueous workup (CHCl3) afforded a 6:1 mixture of (6S):
(6R) diols as judged by 1H NMR spectroscopy. The crude
residue was dissolved in anhydrous THF (1 mL), and tritu-
222 J. Org. Chem., Vol. 70, No. 1, 2005

6-C-Methyl-Substituted Mono- and Disaccharides
rated with cold hexanes (10 mL) to afford (6S)-C-methyl
epimer 8 as a white solid in 63% isolated yield (209 mg). [R]D
+1 (c 0.9, CHCl3); IR (thin film) ν 3474, 2924, 1777, 1747, 1716,
temperature for 20 h, then quenched with EtOH (24 mL) at 0
°C and concentrated to dryness. Purification by flash column
chromatography on silica gel (1.25-5% EtOH gradient in
CHCl3) afforded peracetylated monosaccharide 12 in 93%
isolated yield over two steps (66.7 mg). Monosaccharides 7
(21.2 mg, 53.9 µmol) and 8 (42.4 mg, 0.105 mmol) were
converted to peracetates 10 (15.5 mg, 74% yield over two steps)
and 11 (36.7 mg, 87% yield over two steps) by the same
procedure.
Allyl 2-N-acetyl-2-deoxy-(6R/6S)-C-2H-3,4,6-tri-O-acetyl-
â-D-glucopyranoside (10): 1H NMR (300 MHz, CDCl3) δ 5.94
(m, 1 H), 5.48 (br d, 1 H, J ) 8.5 Hz), 5.27 (dd, 1 H, J ) 9.5,
10.3 Hz), 5.25 (dm, 1 H, J ) 17.2 Hz), 5.17 (dm, 1 H, J ) 10.4
Hz), 5.04 (t, 1 H, J ) 9.9 Hz), 4.69 (d, 1 H, J ) 8.2 Hz), 4.31
(ddm, 1 H, J ) 5.0, 12.9 Hz), 4.21 (d, 0.7 H, J ) 4.3 Hz), 4.13
(d, 0.3 H, J ) 2.4 Hz), 4.06 (ddm, 1 H, J ) 6.9, 12.9 Hz), 3.85
(dt, 1 H, J ) 10.3, 8.2 Hz), 3.66 (dd, 1 H, J ) 3.4, 9.9 Hz), 2.06
(s, 3 H), 2.01 (s, 3 H), 2.00 (s, 3 H), 1.92 (s, 3 H); 13C NMR (75
MHz, CDCl3) δ 170.8, 170.7, 170.1, 169.4, 133.5, 117.8, 99.6,
72.3, 71.7, 69.9, 68.7, 54.7, 23.3, 20.7, 20.6, 20.6; HRMS (ESI)
calcd for C17H24DNO9 [M + Na]+ 411.1490, found 411.1499.
Allyl 2-N-acetyl-2-deoxy-(6S)-C-methyl-3,4,6-tri-O-acetyl-
â-D-glucopyranoside (11): [R]D -21 (c 0.5, CHCl3); IR (thin
film) ν 3318, 2937, 2877, 1747, 1666, 1537, 1432, 1375, 1305,
1253, 1146, 1054 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.85 (m,
1 H), 5.47 (br d, 1 H, J ) 8.7 Hz), 5.27 (dd, 1 H, J ) 9.6, 10.5
Hz), 5.23 (dm, 1 H, J ) 17.2 Hz), 5.16 (dm, 1 H, J ) 10.4 Hz),
5.05 (t, 1 H, J ) 9.9 Hz), 5.02 (dq, 1 H, J ) 2.1, 6.6 Hz), 4.70
(d, 1 H, J ) 8.4 Hz), 4.33 (ddt, 1 H, J ) 5.2, 12.9, 1.5 Hz), 4.10
(ddt, 1 H, J ) 6.4, 12.9, 1.2 Hz), 3.81 (q, 1 H, J ) 9.5 Hz), 3.43
(dd, 1 H, J ) 2.1, 9.9 Hz), 2.02 (s, 3 H), 1.98 (s, 3 H), 1.95 (s,
3 H), 1.90 (s, 3 H), 1.28 (d, 3 H, J ) 6.6 Hz); 13C NMR (75
MHz, CDCl3) δ 170.8, 170.6, 170.2, 169.3, 133.6, 117.8, 99.9,
74.7, 72.5, 70.0, 68.3, 66.1, 55.1, 23.3, 21.0, 20.7, 20.5, 15.7;
HRMS (ESI) calcd for C18H27NO9 [M + Na]+ 424.1584, found
424.1587.
Allyl 2-N-acetyl-2-deoxy-(6R)-C-methyl-3,4,6-tri-O-acetyl-
â-D-glucopyranoside (12): [R]D +1 (c 1, CHCl3); IR (thin film)
ν 3297, 3090, 2950, 2877, 1741, 1665, 1552, 1432, 1375, 1305,
1258, 1237, 1144, 1072, 1041 cm-1; 1H NMR (300 MHz, CDCl3)
δ 5.85 (br d, 1 H, J ) 8.7 Hz), 5.82 (m, 1 H), 5.21 (dm, 1 H, J
) 17.2 Hz), 5.17 (dd, 1 H, J ) 9.5, 10.5 Hz), 5.14 (dm, 1 H, J
) 10.4 Hz), 4.91 (t, 1 H, J ) 10.1 Hz), 4.88 (dq, 1 H, J ) 2.0,
6.6 Hz), 4.59 (d, 1 H, J ) 8.4 Hz), 4.27 (ddt, 1 H, J ) 5.0, 12.9,
1.5 Hz), 4.05 (ddt, 1 H, J ) 6.4, 12.9, 1.0 Hz), 3.88 (q, 1 H, J
) 9.6 Hz), 3.58 (dd, 1 H, J ) 2.0, 10.1 Hz), 1.99 (s, 6 H), 1.97
(s, 3 H), 1.89 (s, 3 H), 1.22 (d, 3 H, J ) 6.6 Hz); 13C NMR (75
MHz, CDCl3) δ 170.8, 170.2, 170.1, 169.5, 133.6, 117.6, 99.5,
74.4, 72.7, 69.6, 69.3, 69.0, 54.3, 23.2, 21.1, 20.6, 20.6, 13.5;
HRMS (ESI) calcd for C18H27NO9 [M + H]+ 402.1764, found
402.1781.
1
1493, 1452, 1387, 1232, 1032, 755 cm-1; H NMR (300 MHz,
CDCl3) δ 7.83 (m, 2 H), 7.71 (m, 2 H), 5.71 (m, 1 H), 5.62 (dd,
1 H, J ) 9.0, 10.5 Hz), 5.39 (d, 1 H, J ) 8.5 Hz), 5.12 (dm, 1
H, J ) 17.2 Hz), 5.05 (dm, 1 H, J ) 10.4 Hz), 4.22 (ddm, 1 H,
J ) 4.1, 12.9 Hz), 4.21 (dd, 1 H, J ) 8.5, 10.5 Hz), 4.16 (br q,
1 H, J ) 6.6 Hz), 4.05 (ddt, 1 H, J ) 6.3, 12.9, 1.5 Hz), 3.92
(br t, 1 H, J ) 9.8 Hz), 3.37 (dd, 1 H, J ) 1.7, 9.8 Hz), 3.19 (br
s, 1 H), 2.22 (br s, 1 H), 1.91 (s, 3 H), 1.34 (d, 3 H); 13C NMR
(75 MHz, CDCl3): δ 171.3, 165.0, 134.2, 133.5, 131.5, 123.5,
117.7, 97.3, 77.6, 73.9, 70.3, 69.5, 65.6, 54.7, 20.7, 19.7; HRMS
(ESI) calcd for C20H23NO8 [M + H]+ 405.1424, found 405.1427.
Allyl 3-O-Acetyl-2-deoxy-(6R)-C-methyl-2-phthalimido-
â-D-glucopyranoside (9). Primary alcohol 6 (1.0 g, 2.10
mmol) was oxidized by the usual Swern procedure to the
corresponding aldehyde. Subsequent treatment of the crude
aldehyde with AlMe3 (5.3 mL, 2 M in hexanes) in the presence
of CuCN (188 mg, 2.10 mmol) in anhydrous THF (20 mL)
afforded the corresponding secondary alcohol (521 mg, 61%
yield over two steps) according to the above-described proce-
dure. A solution of oxalyl chloride (0.74 mL, 8.5 mmol) in CH2-
Cl2 (8.5 mL) at -78 °C was treated with a solution of DMSO
(1.2 mL, 17 mmol) in CH2Cl2 (2.4 mL). The reagents were
stirred for 25 min. A solution of secondary alcohol (0.5 g, 1.0
mmol) in CH2Cl2 (3 mL) was added over 20 min via syringe
pump. After 20 min, the reaction solution was treated with
Et3N (2.8 mL, 20.2 mmol) at -78 °C, allowed to reach 0 °C
over 20 min, then diluted with C6H6/Et2O (25 mL, 4:1 v/v) and
quenched with saturated NH4Cl solution (24 mL). Aqueous
workup (CH2Cl2) followed by flash chromatography on silica
gel (10-40% EtOAc gradient in hexanes) afforded intermediate
methyl ketone in 81% yield (404 mg) as a mixture of diaster-
eomers.
A solution of methyl ketone (0.32 g, 0.66 mmol) in anhydrous
THF (12 mL) was treated with ZnCl2 (0.84 mL, 1 M solution
in THF) and cooled to -78 °C. After 10 min, i-Bu2AlH (2.65
mL, 1 M solution in hexanes) was added dropwise. The
reaction mixture was stirred for 30 min at -78 °C, then
quenched with EtOAc (20 mL) and treated with Na2SO4‚10H2O
(4 g). The suspension was stirred at room temperature for 1
h, diluted with Et2O (50 mL), filtered over Celite, and
evaporated to dryness. The crude residue was dissolved in
MeOH (5 mL) and treated with p-toluenesulfonic acid (125 mg,
0.66 mmol) according to the procedure described above to
afford a 6:1 mixture of (6R):(6S)-C-methyl epimers as judged
by 1H NMR spectroscopy. The desired (6R)-C-methyl diol 9 was
separated by flash chromatography on silica gel (10-20%
acetone gradient in toluene) in 44% yield over two steps (119
mg). [R]D +2 (c 1, CHCl3); IR (thin film) ν 3474, 2935, 1777,
1
1747, 1716, 1468, 1387, 1231, 1033, 722 cm-1; H NMR (300
Typical Deacetylation Procedure (1a-3a). A solution
of monosaccharide 10 (9.0 mg, 23.2 µmol) in CH2Cl2/MeOH (2
mL, 1:1 v/v) was treated with NaOMe (8.5 µL, 1 M in MeOH)
at 0 °C. The reaction mixture was stirred at room temperature
for 20 h, diluted with MeOH (10 mL), and neutralized with
activated acidic Dowex 50X-W H+ ion-exchange resin (25 mg).
The resin beads were filtered off and thoroughly rinsed with
MeOH (3 × 15 mL). The filtrate was evaporated to dryness,
affording monosaccharide 1a as a white solid in 71% yield (4.3
mg). Similarly, monosaccharides 11 (57.0 mg, 0.142 mmol) and
12 (66.7 mg, 0.166 mmol) afforded polyols 2a (38.2 mg, 98%
yield) and 3a (46.1 mg, quantitative yield), respectively, with
the same procedure.
MHz, CDCl3) δ 7.84 (m, 2 H), 7.71 (m, 2 H), 5.71 (m, 1 H),
5.63 (dd, 1 H, J ) 8.8, 10.7 Hz), 5.38 (d, 1 H, J ) 8.4 Hz), 5.12
(dm, 1 H, J ) 17.2 Hz), 5.06 (dm, 1 H, J ) 10.4 Hz), 4.22 (dd,
1 H, J ) 8.4, 10.7 Hz), 4.21 (ddt, 1 H, J ) 5.3, 12.9, 1.4 Hz),
4.08 (q, 1 H, J ) 6.2 Hz), 4.05 (ddm, 1 H, J ) 6.1, 12.9, 1.5
Hz), 3.78 (t, 1 H, J ) 9.5 Hz), 3.40 (dd, 1 H, J ) 6.4, 9.5 Hz),
2.70 (br s, 2 H), 1.92 (s, 3 H), 1.34 (d, 3 H, J ) 6.2 Hz); 13C
NMR (75 MHz, CDCl3) δ 171.4, 165.0, 134.3, 133.5, 131.5,
123.6, 117.7, 97.2, 77.2, 73.6, 73.5, 70.3, 70.2, 54.6, 20.7, 19.4;
HRMS (ESI) calcd for C20H23NO8 [M + H]+ 406.1502, found
405.1427, calcd [M + Na]+ 428.1321, found 428.1331.
General Procedure for Phthalimide Cleavage and
Acetylation (10-12). In a typical procedure, a solution of
monosaccharide 9 (72.7 mg, 0.179 mmol) in n-BuOH (5 mL)
was treated with ethylenediamine (0.96 mL, 14.3 mmol). The
reaction mixture was stirred at 100 °C in a pressure tube for
20 h, then concentrated to dryness, coevaporated with toluene
(thrice), and dried under high vacuum for 1 h. The crude amine
was dissolved in pyridine (4.5 mL) and treated with Ac2O (3
mL) at 0 °C. The reaction mixture was stirred at room
Allyl 2-N-acetyl-2-deoxy-(6R/6S)-C-2H-â-D-glucopyra-
noside (1a): 1H NMR (500 MHz, CD3OD) δ 5.89 (m, 1 H,
vinylic H-â), 5.27 (dm, 1 H, J ) 17.3 Hz, cis-vinylic H-γ), 5.13
(dm, 1 H, J ) 10.5 Hz, trans-vinylic H-γ′), 4.44 (d, 1 H, J1,2
)
8.4 Hz, H-1), 4.34 (ddm, 1 H, J ) 4.8, 13.3 Hz, allylic H-R),
4.07 (ddm, 1 H, J ) 5.7, 13.3 Hz, allylic H-R′), 3.86 (d, 0.3 H,
J5,6S ) 2.6 Hz, H-6S), 3.67 (m, 1.7 H, H-2 and H-6R), 3.45 (dd,
1 H, J3,4 ) 8.7 Hz, J2,3 ) 10.3 Hz, H-3), 3.31 (buried, 1 H, H-4),
J. Org. Chem, Vol. 70, No. 1, 2005 223

Achkar et al.
3.25 (dd, 1 H, J5,6R ) 6.2 Hz, J4,5 ) 9.7 Hz, H-5), 1.97 (s, 3 H,
COCH3); 13C NMR (125 MHz, CD3OD) δ 173.9, 135.7, 117.1,
102.0, 78.1, 76.2, 72.3, 70.8, 62.7, 57.5, 23.1; HRMS (EI) calcd
for C11H18DNO6 [M + H]+ 263.1353, found 263.1354.
Allyl 2-N-acetyl-2-deoxy-(6S)-C-methyl-â-D-glucopyra-
noside (2a): 1H NMR (500 MHz, CD3OD) δ 5.90 (m, 1 H,
vinylic H-â), 5.26 (dm, 1 H, J ) 17.2 Hz, cis-vinylic H-γ), 5.14
filtered over Celite, then quenched with a 0.5 M HCl aqueous
solution. Basic aqueous workup (EtOAc) followed by flash
chromatography on silica gel (10-50% EtOAc gradient in
hexanes) afforded acceptor 14 as a white solid in 61% yield
(60.8 mg). [R]D -13 (c 0.5, CHCl3); IR (thin film) ν 3475, 2917,
1
1777, 174, 1718, 1613, 1514, 1387, 1246, 1044, 722 cm-1; H
NMR (300 MHz, CDCl3) δ 7.82 (m, 2 H), 7.69 (m, 2 H), 7.27
(d, 2 H, J ) 8.7 Hz), 6.87 (d, 2 H, J ) 8.7 Hz), 5.69 (m, 1 H),
5.66 (dd, 1 H, J ) 9.0, 10.7 Hz), 5.34 (d, 1 H, J ) 8.4 Hz), 5.09
(dm, 1 H, J ) 17.2 Hz), 5.02 (dm, 1 H, J ) 10.4 Hz), 4.63 (d,
1 H, J ) 11.5 Hz), 4.43 (d, 1 H, J ) 11.5 Hz), 4.22 (m, 1 H),
4.22 (dd, 1 H, J ) 8.4, 10.7 Hz), 4.01 (m, 1 H), 3.97-3.89 (m,
2 H), 3.79 (s, 3 H), 3.50 (dd, 1 H, J ) 3.2, 9.7 Hz), 2.84 (d, 1 H,
J ) 2.7 Hz), 1.90 (s, 3 H), 1.32 (d, 3 H, J ) 6.4 Hz); 13C NMR
(125 MHz, CDCl3) δ 170.9, 159.4, 134.1, 133.6, 131.5, 129.9,
129.6, 123.5, 117.5, 113.9, 97.3, 75.4, 73.6, 72.5, 70.9, 69.9, 69.4,
55.3, 54.6, 20.7, 14.6; HRMS (EI) calcd for C28H31NO9 [M +
H]+ 526.2077, found 526.2066.
(dm, 1 H, J ) 10.5 Hz, trans-vinylic H-γ′), 4.43 (d, 1 H, J1,2
)
8.4 Hz, H-1), 4.30 (ddt, 1 H, J ) 5.0, 13.3, 1.6 Hz, allylic H-R),
4.05-4.10 (m, 2 H, allylic H-R′ and H-6), 3.68 (dd, 1 H, J1,2
8.4 Hz, J2,3 ) 10.3 Hz, H-2), 3.56 (dd, 1 H, J3,4 ) 8.9 Hz, J4,5
)
)
9.6 Hz, H-4), 3.45 (dd, 1 H, J3,4 ) 8.9 Hz, J2,3 ) 10.3 Hz, H-3),
3.01 (dd, 1 H, J5,6 ) 1.8 Hz, J4,5) 9.6 Hz, H-5), 1.98 (s, 3 H,
COCH3), 1.28 (d, 3 H, J6,7 ) 6.6 Hz, CH3); 13C NMR (125 MHz,
CD3OD) δ 173.9, 135.8, 117.1, 102.2, 79.6, 76.4, 71.8, 70.9, 65.9,
57.5, 23.1, 20.1; HRMS (ESI) calcd for C12H21NO6 [M + Na]+
298.1267, found 298.1265.
Allyl 2-N-acetyl-2-deoxy-(6R)-C-methyl-â-D-glucopyra-
noside (3a): 1H NMR (500 MHz, CD3OD) δ 5.89 (m, 1 H,
vinylic H-â), 5.27 (dm, 1 H, J ) 17.3 Hz, cis-vinylic H-γ), 5.13
Allyl 3-O-Acetyl-2-deoxy-6-O-(p-methoxybenzyl)-(6R)-
C-methyl-2-phthalimido-â-D-glucopyranoside (15). (6R)-
C-Me-substituted acetal (220 mg) was obtained in 76% isolated
yield from diol 9 (225 mg, 0.555 mmol) by the above-described
procedure. The acetal intermediate (45.0 mg, 85.9 µmol) was
treated with NaBH3CN (3 × 32.7 mg, 1.56 mmol) and HCl (5
mL, ca. 1 M solution in Et2O) over a 6-h period according to
the above-described procedure. Alcohol 15 was isolated in 35%
yield (15.9 mg), along with unreacted starting material (14.4
mg, 32%). [R]D +53 (c 0.45, CHCl3); IR (thin film) ν 3852, 3752,
2936, 1777, 1746, 1718, 1616, 1513, 1387, 1228, 1043, 721
(dm, 1 H, J ) 10.5 Hz, trans-vinylic H-γ′), 4.42 (d, 1 H, J1,2
)
8.4 Hz, H-1), 4.32 (ddt, 1 H, J ) 4.9, 13.3, 1.6 Hz, allylic H-R),
4.07 (ddt, 1 H, J ) 5.8, 13.3, 1.4 Hz, allylic H-R′), 4.05 (dq, 1
H, J5,6 ) 3.9 Hz, J6,7 ) 6.5 Hz, H-6), 3.66 (dd, 1 H, J1,2 ) 8.4
Hz, J2,3 ) 10.3 Hz, H-2), 3.44 (dd, 1 H, J3,4 ) 8.7 Hz, J2,3
)
10.3 Hz, H-3), 3.30 (dd, 1 H, J3,4 ) 8.7 Hz, J4,5 ) 9.7 Hz, H-4),
3.20 (dd, 1 H, J5,6 ) 3.9 Hz, J4,5 ) 9.7 Hz, H-5), 1.97 (s, 3 H,
COCH3), 1.24 (d, 3 H, J6,7 ) 6.5 Hz, CH3); 13C NMR (125 MHz,
CD3OD) δ 173.9, 135.8, 117.1, 102.1, 79.6, 76.3, 74.4, 70.8, 69.0,
57.4, 23.1, 17.7; HRMS (ESI) calcd for C12H21NO6 [M + Na]+
298.1267, found 298.1262.
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.85 (m, 2 H), 7.73 (m, 2
H), 7.27 (d, 2 H, J ) 8.5 Hz), 6.90 (d, 2 H, J ) 8.5 Hz), 5.75
(m, 1 H), 5.65 (dd, 1 H, J ) 8.7, 10.6 Hz), 5.42 (d, 1 H, J ) 8.4
Hz), 5.15 (dm, 1 H, J ) 17.2 Hz), 5.09 (dm, 1 H, J ) 10.4 Hz),
4.68 (d, 1 H, J ) 11.1 Hz), 4.44 (d, 1 H, J ) 11.1 Hz), 4.25
(ddt, 1 H, J ) 5.3, 12.9, 1.0 Hz), 4.22 (dd, 1 H, J ) 8.4, 10.6
Hz), 4.07 (ddt, 1 H, J ) 6.2, 12.9, 1.0 Hz), 3.87 (dq, 1 H, J )
6.0, 7.3 Hz), 3.82 (s, 3 H), 3.78 (dd, 1 H, J ) 8.7, 9.3 Hz), 3.43
(dd, 1 H, J ) 7.3, 9.3 Hz), 1.92 (s, 3 H), 1.41 (d, 3 H, J ) 6.0
Hz); 13C NMR (75 MHz, CDCl3) δ 170.5, 167.8, 159.5, 134.1,
133.5, 131.5, 129.6, 129.1, 123.4, 117.6, 114.0, 97.0, 77.6, 76.2,
73.3, 73.2, 70.4, 70.1, 55.2, 54.5, 20.6, 16.5; HRMS (EI) calcd
for C28H31NO9 [M + H]+ 526.2077, found 526.2057.
Allyl 3-O-Acetyl-6-O-(tert-butyldimethylsilyl)-2-deoxy-
(6R/6S)-C-2H-2-phthalimido-â-D-glucopyranoside (13). A
solution of 7 (30.5 mg, 0.078 mmol) in CH2Cl2/THF (750 µL,
3:1 v/v) was treated with Et3N (18.4 µL, 0.132 mmol), imidazole
(1.3 mg, 0.019 mmol), then TBSCl (41.0 mg, 0.272 mmol). The
reaction mixture was stirred at room temperature for 20 h,
then diluted with CH2Cl2 (50 mL) and quenched with satu-
rated NaHCO3 solution (12 mL). Product extraction (CH2Cl2)
was followed by 5% CuSO4 aqueous solution (50 mL), water
(50 mL), and brine (50 mL) washes. The crude residue was
purified by flash column chromatography on silica gel (10-
40% EtOAc gradient in hexanes) to afford acceptor 13 in 89%
2-Deoxy-2-phthalimido-3,4,6-tri-O-acetyl-r/â-D-glucopy-
ranosyl Trichloroacetimidate (16).17 A solution of tetra-
O-acetyl-2-deoxy-2-phthalimido-â-D-glucopyranoside (1.5 g,
3.14 mmol) in anhydrous DMF (10 mL) was treated with
hydrazine acetate (0.68 g, 7.41 mmol). The reaction mixture
was stirred at room temperature for 3 h, then cooled to 0 °C
and quenched with saturated NaHCO3 solution (36 mL).
Standard aqueous workup (CHCl3) and purification over a
silica gel plug (30-50% EtOAc gradient in hexanes, 0.2% Et3N)
afforded the corresponding lactol in 35% yield. The lactol (471
mg, 1.09 mmol) was azeotroped with toluene (thrice), dried
under high vacuum overnight, and dissolved in CH2Cl2 (10
mL). The solution was treated with 4A molecular sieves, CCl3-
CN (3.25 mL. 32.4 mmol), then Cs2CO3 (106 mg, 0.324 mmol).
The reaction mixture was stirred at room temperature for 3
h, diluted with CH2Cl2 (50 mL), filtered over Celite, then
quenched with saturated NaHCO3 solution (50 mL). Standard
aqueous workup (CH2Cl2) followed by flash chromatography
over silica gel (25-50% EtOAc gradient in hexanes, 0.2% Et3N)
afforded imidate donor 16 in 74% isolated yield (461.5 mg).
1H NMR (300 MHz, CDCl3) δ 8.64 (s, 1 H), 7.84 (m, 2 H), 7.72
(m, 2 H), 6.61 (d, 1 H, J ) 9.0 Hz), 5.90 (dd, 1 H, J ) 9.2, 10.7
Hz), 5.26 (dd, 1 H, J ) 9.2, 10.1 Hz), 4.61 (dd, 1 H, J ) 9.0,
10.7 Hz), 4.37 (dd, 1 H, J ) 4.3, 12.4 Hz), 4.18 (dd, 1 H, J )
2.2, 12.4 Hz), 4.05 (ddd, 1 H, J ) 2.2, 4.3, 10.1 Hz), 2.10 (s, 3
H), 2.05 (s, 3 H), 1.88 (s, 3 H).
1
yield (35.1 mg). H NMR (300 MHz, CDCl3) δ 7.82 (m, 2 H),
7.70 (m, 2 H), 5.69 (m, 1 H), 5.63 (dd, 1 H, J ) 8.7, 10.7 Hz),
5.38 (d, 1 H, J ) 8.4 Hz), 5.09 (dm, 1 H, J ) 17.2 Hz), 5.02
(dm, 1 H, J ) 10.4 Hz), 4.22 (ddt, 1 H, J ) 5.0, 12.9, 1.5 Hz),
4.20 (dd, 1 H, J ) 8.4, 10.7 Hz), 4.01 (ddt, 1 H, J ) 6.2, 12.9,
1.4 Hz), 3.95 (d, 0.7 H, J ) 4.9 Hz), 3.87 (d, 0.3 H, J ) 5.9 Hz),
3.78 (br t, 1 H, J ) 9.5 Hz), 3.58 (dd, 1 H, J ) 5.4, 9.5 Hz),
3.35 (br s, 1 H), 1.89 (s, 3 H), 0.90 (s, 9 H), 0.10, 0.09 (2 s, 6
H); 13C NMR (75 MHz, CDCl3) δ 171.0, 167.8, 134.1, 133.5,
131.5, 123.4, 117.5, 97.0, 74.1, 73.5, 72.4, 69.9, 64.6, 54.6, 25.8,
20.6, 18.2, -5.4, -5.5; HRMS (EI) calcd for C25H34DNO8Si [M
+ H]+ 507.2273, found 507.2276.
Allyl 3-O-Acetyl-2-deoxy-6-O-(p-methoxybenzyl)-(6S)-
C-methyl-2-phthalimido-â-D-glucopyranoside (14). Diol 8
(179 mg, 0.441 mmol) and 4A molecular sieves were suspended
in toluene (5 mL) and treated with p-anisaldehyde dimethy-
lacetal (1.4 mL, 8.83 mmol) and camphorsulfonic acid (25.6
mg, 0.110 mmol). The reaction mixture was stirred at 90 °C
for 3 h, then diluted with EtOAc (50 mL) and filtered over
Celite. Basic aqueous workup (EtOAc) followed by flash
chromatography on silica gel (10-40% EtOAc gradient in
hexanes, 0.2% Et3N) afforded (6S)-C-Me-substituted acetal as
a white solid in 71% yield (165 mg).
A suspension of the acetal (99 mg, 0.19 mmol) and 4A
molecular sieves in anhydrous THF (7 mL) was cooled to -30
°C and treated with NaBH3CN (83.2 mg, 1.32 mmol). HCl (2
mL, ca. 1 M solution in Et2O) was added dropwise to the
reaction mixture, and repeated every 30 min over 1.5 h
reaction time. The reaction mixture was diluted with Et2O,
Glycosidic Coupling (17-19). In a typical procedure, both
imidate donor 16 (134.1 mg, 0.23 mmol) and acceptor 14 (60.8
mg, 0.11 mmol) were azeotroped with toluene (thrice), dried
under high vacuum for 45 min, then dissolved in CH2Cl2 (2
224 J. Org. Chem., Vol. 70, No. 1, 2005

6-C-Methyl-Substituted Mono- and Disaccharides
mL) and treated with 4A activated molecular sieves. The
suspension was stirred at room temperature for 15 min then
cooled to -30 °C and treated with TMSOTf (64 µL, 0.5 M
solution in CH2Cl2). The reaction mixture was stirred at -30
°C for 2 h, then quenched with Et3N (24 µL, 0.17 mmol),
filtered over Celite, and concentrated to dryness. The crude
residue was purified by flash column chromatography on silica
gel (25-60% EtOAc gradient in hexanes) to afford disaccharide
18 in 98% isolated yield (107 mg). Similarly, acceptors 13 (40.0
mg, 0.079 mmol) and 15 (84.0 mg, 0.16 mmol) were respec-
tively converted into disaccharides 17 (37.1 mg, 51% isolated
yield) and 19 (118.3 mg, 78% isolated yield) with the same
procedure.
20.6, 20.6, 20.5, 20.3, 14.2; HRMS (ESI) calcd for C48H50N2O18
[M + Na]+ 965.2956, found 965.2944.
Allyl N-Acetyl-4-O-(N-acetyl-2-deoxy-â-D-glucopyrano-
syl)-2-deoxy-(6R/6S)-C-2H-â-D-glucopyranoside (1b). A so-
lution of disaccharide 17 (37.5 mg, 40.6 µmol) in anhydrous
THF was treated with TBAF (183 µL, 1 M solution in THF).
The reaction mixture was stirred at room temperature for 20
h, then evaporated to dryness. The crude residue was coevapo-
rated with CHCl3 (thrice), dissolved in n-BuOH (5 mL), and
treated with ethylenediamine (0.44 mL, 6.6 mmol) according
to the above-described procedure. The resulting free amine
intermediate was dissolved in pyridine (3 mL) and treated with
Ac2O (2 mL) also according to the above-described procedure.
Column chromatography on silica gel (1.25-5% EtOH gradient
in CHCl3) afforded the desired peracetylated C-6 monodeu-
terated disaccharide intermediate (27.2 mg, 99% over three
steps): [R]D +4 (c 1, CHCl3); IR (thin film) ν 3289, 2920, 1745,
1661, 1541, 1372, 1233, 1047 cm-1; 1H NMR (500 MHz, CDCl3)
δ 6.28 (d, 1 H, J ) 9.1 Hz), 5.97 (d, 1 H, J ) 9.5 Hz), 5.81 (m,
1 H), 5.22 (dm, 1 H, J ) 17.2 Hz), 5.18 (dd, 1 H, J ) 9.4, 10.3
Hz), 5.15 (dm, 1 H, J ) 10.4 Hz), 5.11 (dd, 1 H, J ) 8.2, 9.7
Hz), 5.01 (t, 1 H, J ) 9.6 Hz), 4.59 (d, 1 H, J ) 8.2 Hz), 4.50
(d, 1 H, J ) 7.8 Hz), 4.34 (dd, 1 H, J ) 4.3, 12.3 Hz), 4.27 (ddt,
1 H, J ) 5.0, 13.1, 1.5 Hz), 4.23 (d, 1 H, J ) 5.6 Hz), 4.01 (ddt,
1 H, J ) 6.1, 13.1, 1.4 Hz), 4.00 (dd, 1 H, J ) 2.4, 12.3 Hz),
3.88-3.79 (m, 2 H), 3.72 (t, 1 H, J ) 8.9 Hz), 3.65 (ddd, 1 H,
J ) 2.4, 4.3, 9.6 Hz), 3.61 (dd, 1 H, J ) 5.6, 8.9 Hz), 2.10 (s, 3
H), 2.05 (s, 3 H), 2.03 (s, 3 H), 1.98 (s, 3 H), 1.97 (s, 3 H), 1.94
(s, 3 H), 1.91 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 171.0,
170.8, 170.7, 170.6, 170.3, 169.3, 133.5, 117.6, 101.1, 99.9, 99.7,
76.1, 72.7, 72.4, 72.3, 71.7, 69.7, 68.1, 62.3, 61.7, 54.7, 53.4,
23.2, 20.9, 20.7, 20.6.
Allyl 3-O-acetyl-6-O-(tert-butyldimethylsilyl)-2-deoxy-
4-O-(2-deoxy-2-phthalimido-3,4,6-tri-O-acetyl-â-D-glucopy-
ranosyl)-(6R/6S)-C-2H-2-phthalimido-â-D-glucopyrano-
1
side (17): H NMR (300 MHz, CDCl3) δ 7.87-7.64 (m, 8 H),
5.74 (dd, 1 H, J ) 9.0, 10.5 Hz), 5.63 (dd, 1 H, J ) 9.0, 10.6
Hz), 5.63 (m, 1 H), 5.48 (d, 1 H, J ) 8.4 Hz), 5.24 (d, 1 H, J )
8.4 Hz), 5.08 (dd, 1 H, J ) 9.0, 10.1 Hz), 5.02 (dm, 1 H, J )
17.2 Hz), 4.97 (dm, 1 H, J ) 10.4 Hz), 4.42 (dd, 1 H, J ) 4.6,
12.3 Hz), 4.19 (dd, 1 H, J ) 8.4, 10.5 Hz), 4.11 (ddt, 1 H, J )
5.0, 12.9, 1.4 Hz), 4.10 (dd, 1 H, J ) 8.4, 10.6 Hz), 4.04 (dd, 1
H, J ) 2.7, 12.3 Hz), 4.00 (t, 1 H, J ) 9.9 Hz), 3.92 (ddt, 1 H,
J ) 6.3, 12.9, 1.3 Hz), 3.78 (ddd, 1 H, J ) 2.7, 4.6, 10.1 Hz),
3.62 (d, 0.3 H, J ) 1.5 Hz), 3.40 (d, 0.7 H, J ) 3.5 Hz), 3.31
(dd, 1 H, J ) 2.5, 9.9 Hz), 2.06 (s, 3 H), 1.98 (s, 3 H), 1.89 (s,
3 H), 1.79 (s, 3 H), 0.90 (s, 9 H), 0.05 and 0.04 (2 s, 6 H).
Allyl 3-O-acetyl-2-deoxy-4-O-(2-deoxy-2-phthalimido-
3,4,6-tri-O-acetyl-â-D-glucopyranosyl)-6-O-(p-methoxy-
benzyl)-(6S)-C-methyl-2-phthalimido-â-D-glucopyrano-
side (18): [R]D -12 (c 1, CHCl3); IR (thin film) ν 2950, 1734,
1717, 1684, 1653, 1559, 1540, 1507, 1457, 1046, 668 cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.85-7.68 (m, 8 H), 7.41 (d, 2 H, J
) 8.7 Hz), 6.91 (d, 2 H, J ) 8.7 Hz), 5.68 (m, 1 H), 5.61 (dd, 1
H, J ) 9.2, 10.7 Hz), 5.59 (dd, 1 H, J ) 9.0, 10.7 Hz), 5.22 (d,
1 H, J ) 8.5 Hz), 5.16 (d, 1 H, J ) 8.4 Hz), 5.05 (dm, 1 H, J )
17.2 Hz), 4.99 (dd, 1 H, J ) 9.2, 10.4 Hz), 4.98 (dm, 1 H, J )
10.1 Hz), 4.67 (d, 1 H, J ) 11.3 Hz), 4.41 (d, 1 H, J ) 11.3 Hz),
4.22 (dd, 1 H, J ) 6.5, 12.3 Hz), 4.20 (t, 1 H, J ) 9.0 Hz), 4.18
(dd, 1 H, J ) 8.4, 10.7 Hz), 4.17 (m, 1 H), 4.11 (dd, 1 H, J )
8.5, 10.7 Hz), 3.98 (ddt, 1 H, J ) 6.4, 12.9, 1.6 Hz), 3.86 (dd,
1 H, J ) 2.0, 12.3 Hz), 3.82 (s, 3 H), 3.65 (dq, 1 H, J ) 2.1, 6.4
Hz), 3.24 (dd, 1 H, J ) 2.1, 9.8 Hz), 2.90 (ddd, 1 H, J ) 2.0,
6.5, 10.4 Hz), 2.03 (s, 3 H), 1.97 (s, 3 H), 1.88 (s, 3 H), 1.79 (s,
3 H), 1.19 (d, 3 H, J ) 6.4 Hz); 13C NMR (75 MHz, CDCl3) δ
170.5, 170.2, 169.4, 167.5, 159.0, 134.4, 134.1, 133.6, 131.4,
129.0, 123.6, 123.4, 117.6, 113.7, 97.1, 95.9, 73.4, 71.4, 71.2,
70.6, 69.9, 69.6, 68.4, 61.3, 55.2, 55.0, 54.9, 20.6, 20.5, 20.5,
20.4, 15.2; HRMS (ESI) calcd for C48H50N2O18 [M + Na]+
965.2956, found 965.2959.
A solution of C-6 monodeuterated disaccharide peracetate
(25.4 mg, 37.6 µmol) in CH2Cl2/MeOH (3 mL, 1:1 v/v) was
treated with NaOMe (25 µL, 1 M in MeOH) according to the
above-described procedure to afford monodeuterated disac-
charide 1b as a white solid in quantitative yield (17.5 mg). 1H
NMR (600 MHz, CD3OD:D2O, v/v 3:1) δ 5.88 (m, 1 H, vinylic
H-â), 5.27 (dm, 1 H, J ) 17.3 Hz, vinylic H-γ), 5.17 (dm, 1 H,
J ) 10.6 Hz, vinylic H-γ′), 4.52 (d, 1 H, J1′,2′ ) 8.5 Hz, H-1′),
4.46 (d, 1 H, J1,2 ) 8.3 Hz, H-1), 4.31 (ddt, 1 H, J ) 4.9, 13.3,
1.6 Hz, allylic H-R), 4.08 (ddt, 1 H, J ) 5.9, 13.3, 1.4 Hz, allylic
H-R′), 3.91 (dd, 1 H, J5′,6′a ) 2.2 Hz, J6′a,6′b ) 12.1 Hz, H-6′a),
3.80 (d, 0.3 H, J5,6S ) 2.0 Hz, H-6S), 3.74 (dd, 1 H, J1,2 ) 8.3
Hz, J2,3 ) 10.4 Hz, H-2), 3.73 (dd, 1 H, J1′,2′ ) 8.5 Hz, J2′,3′
)
10.4 Hz, H-2′), 3.67 (dd, 1 H, J5′,6′b ) 6.3 Hz, J6′a,6′b ) 12.1 Hz,
H-6′b), 3.64 (dd, 1 H, J3,4 ) 8.3 Hz, J2,3 ) 10.4 Hz, H-3), 3.63
(d, 0.7 H, J5,6R ) 4.9 Hz, H-6R), 3.55 (dd, 1 H, J3,4 ) 8.3 Hz,
J4,5 ) 9.7 Hz, H-4), 3.48 (dd, 1 H, J3′,4′ ) 8.5 Hz, J2′,3′ ) 10.4
Hz, H-3′), 3.41 (ddd, 1 H, J5′,6′a ) 2.2 Hz, J5′,6′b ) 6.3 Hz, J4′,5′
) 9.9 Hz, H-5′), 3.36 (m, 2 H, H-4′ and H-5), 2.04 (s, 3 H,
COCH3), 1.99 (s, 3 H, COCH3); 13C NMR (75 MHz, CD3OD/
D2O, 4:1 v/v) δ 174.4, 174.2, 135.3, 117.7, 103.2, 101.8, 81.4,
78.0, 76.3, 75.6, 74.2, 71.8, 71.1, 62.4, 61.3, 57.2, 56.5, 23.2,
23.1; HRMS (ESI) calcd C19H31DN2O11 [M + Na]+ 488.1967,
found 488.1975.
Allyl 3-O-acetyl-2-deoxy-4-O-(2-deoxy-2-phthalimido-
3,4,6-tri-O-acetyl-â-D-glucopyranosyl)-6-O-(p-methoxy-
benzyl)-(6R)-C-methyl-2-phthalimido-â-D-glucopyrano-
side (19): [R]D +7 (c 1, CHCl3); IR (thin film) ν 2943, 1778,
1749, 1718, 1612, 1514, 1498, 1387, 1228, 1144, 1046, 722
6-C-Methyl-Substituted Disaccharides (2b, 3b). A solu-
tion of disaccharide 18 (91.8 mg, 97.4 µmol) in CH2Cl2 (5.5 mL)
was treated with pH 7 buffer (0.41 mL), t-BuOH (0.19 mL,
1.95 mmol), and DDQ (71 mg, 0.31 mmol) at 0 °C. The
heterogeneous solution was stirred at room temperature for
20 h, then diluted with CH2Cl2 (15 mL) and quenched with
saturated NaHCO3 solution (12 mL) at 0 °C. Standard aqueous
workup (CH2Cl2) followed by flash column chromatography on
silica gel (25-70% EtOAc gradient in hexanes) afforded the
free 6-OH disaccharide intermediate in 80% isolated yield (63.8
mg).
According to the previously described procedure, a solution
of the disaccharide intermediate (50.4 mg, 61.2 µmol) in
n-BuOH (5.5 mL) was treated with ethylenediamine (0.65 mL,
9.80 mmol) affording the free amine intermediate, which was
then dissolved in pyridine (3 mL) and treated with Ac2O (2
1
cm-1; H NMR (500 MHz, CDCl3) δ 7.81 (m, 4 H), 7.69 (m, 4
H), 7.03 (d, 2 H, J ) 8.7 Hz), 6.80 (d, 2 H, J ) 8.7 Hz), 5.75
(dd, 1 H, J ) 7.9, 10.7 Hz), 5.67 (dd, 1 H, J ) 9.2, 10.4 Hz),
5.64 (m, 1 H), 5.45 (d, 1 H, J ) 8.4 Hz), 5.24 (d, 1 H, J ) 8.5
Hz), 5.12 (t, 1 H, J ) 9.3 Hz), 5.02 (dm, 1 H, J ) 17.2 Hz),
4.96 (dm, 1 H, J ) 10.4 Hz), 4.38 (dd, 1 H, J ) 4.0, 12.3 Hz),
4.21 (dd, 1 H, J ) 8.4, 10.7 Hz), 4.15 (ddt, 1 H, J ) 5.0, 13.0,
1.4 Hz), 4.12 (dd, 1 H, J ) 8.5, 10.4 Hz), 4.09 (d, 2 H, J ) 11.6
Hz), 4.01 (dd, 1 H, J ) 2.1, 12.3 Hz), 3.94 (ddt, 1 H, J ) 6.4,
13.0, 1.6 Hz), 3.78 (s, 3 H), 3.76-3.70 (m, 3 H), 3.52 (dq, 1 H,
J ) 1.0, 6.6 Hz), 2.04 (s, 3 H), 1.96 (s, 3 H), 1.91 (s, 3 H), 1.80
(s, 3 H), 0.96 (d, 3 H, J ) 6.6 Hz); 13C NMR (125 MHz, CDCl3)
δ 170.5, 170.1, 169.8, 169.3, 167.7, 159.0, 134.4, 134.1, 133.5,
131.3, 130.5, 128.8, 123.6, 123.4, 117.6, 113.6, 96.9, 96.7, 76.5,
75.2, 73.4, 71.9, 71.3, 70.6, 70.4, 69.8, 68.3, 61.4, 55.2, 54.8,
J. Org. Chem, Vol. 70, No. 1, 2005 225

Achkar et al.
mL). Column chromatography on silica gel (1.25-5% EtOH
gradient in CHCl3) afforded the desired (6S)-C-CH3-substituted
peracetylated disaccharide intermediate (42.8 mg, quantitative
yield over two steps): [R]D -53 (c 1, CHCl3); IR (thin film) ν
3347, 2940, 1745, 1664, 1532, 1431, 1375, 1231, 1150, 1048
J3,4 ) 8.6 Hz, J2,3 ) 10.2 Hz, H-3), 3.42 (dd, 1 H, J3′,4′ ) 8.4
Hz, J2′,3′ ) 10.2 Hz, H-3′), 3.35 (dm, 1 H, J4′,5′ ) 9.3 Hz, H-5′),
3.34 (t, 1 H, J3′,4′ ) J4′,5′ ) 8.8 Hz, H-4′), 3.08 (dd, 1 H, J5,6
)
1.5 Hz, J4,5 ) 9.4 Hz, H-5), 1.99 (s, 3 H, COCH3), 1.96 (s, 3 H,
COCH3), 1.29 (d, 3 H, J6,7 ) 6.6 Hz, CH3); 13C NMR (125 MHz,
CD3OD/D2O, v/v 5:3) δ 174.7 (CO), 174.7 (CO), 134.9 (C-â),
118.4 (C-γ), 103.1 (C-1′), 101.6 (C-1), 81.4 (C-4), 77.8 (C-5), 77.5
(C-5′), 75.1 (C-3′), 74.0 (C-3), 71.4 (C-4′), 71.3 (C-R), 64.9 (C-
6), 62.1 (C-6′), 56.9, 56.3 (C-2/2′), 23.2, 22.9 (NHAc), 19.9 (CH3);
HRMS (ESI) calcd for C20H34N2O11 [M + Na]+ 501.2060, found
501.2063.
1
cm-1; H NMR (500 MHz, CDCl3) δ 6.19 (d, 1 H, J ) 9.6 Hz),
5.83 (m, 1 H), 5.46 (d, 1 H, J ) 9.5 Hz), 5.31 (dq, 1 H, J ) 1.1,
6.6 Hz), 5.23 (dq, 1 H, J ) 17.4, 1.6 Hz), 5.18 (dm, 1 H, J )
10.4, 1.6 Hz), 5.03 (t, 1 H, J ) 9.6 Hz), 5.01 (dd, 1 H, J ) 10.7,
8.8 Hz), 4.91 (t, 1 H, J ) 10.2 Hz), 4.39 (d, 1 H, J ) 8.4 Hz),
4.34 (dd, 1 H, J ) 4.1, 12.4 Hz), 4.30 (ddt, 1 H, J ) 11.7, 5.2,
1.6 Hz), 4.16 (q, 1 H, J ) 8.4 Hz), 4.09 (ddt, 1 H, J ) 6.4, 11.7,
1.6 Hz), 4.09 (q, 1 H, J ) 8.4 Hz), 4.04 (d, 1 H, J ) 8.4 Hz),
3.98 (dd, 1 H, J ) 2.3, 12.4 Hz), 3.54 (t, 1 H, J ) 9.6 Hz), 3.51
(m, 1 H), 3.27 (dd, 1 H, J ) 8.6, 9.6 Hz), 2.16 (s, 3 H), 2.05 (s,
3 H), 1.99 (s, 3 H), 1.98 (s, 3 H), 1.97 (s, 3 H), 1.96 (s, 3 H),
192 (s, 3 H), 1.30 (d, 3 H); 13C NMR (125 MHz, CDCl3) δ 172.0,
171.0, 170.8, 170.6, 170.1, 169.9, 169.2, 133.6, 117.9, 102.6,
100.4, 77.4, 76.1, 73.2, 72.8, 72.0, 70.0, 67.8, 66.7, 61.6, 54.0,
53.5, 23.3, 23.0, 21.6, 20.7, 20.6, 20.6, 20.5, 16.6; HRMS (ESI)
calcd for C30H44N2O16 [M + H]+ 689.2769, found 689.2742.
Disaccharide 19 (117.6 mg, 0.125 mmol) was converted to
the corresponding (6R)-C-CH3-substituted peracetate inter-
mediate in a similar fashion (63.0 mg, 74% yield over three
steps): [R]D -36 (c 1, CHCl3); IR (thin film) ν 3341, 2940, 1744,
1687, 1666, 1537, 1431, 1372, 1233, 1151, 1047 cm-1; 1H NMR
(500 MHz, CDCl3) δ 6.25 (d, 1 H, J ) 8.2 Hz), 6.09 (d, 1 H, J
) 9.4 Hz), 5.82 (m, 1 H), 5.35 (t, 1 H, J ) 10.0 Hz), 5.22 (dq,
1 H, J ) 17.2, 1.5 Hz), 5.14 (m, 2 H), 5.05 (t, 1 H, J ) 9.5 Hz),
5.01 (t, 1 H, J ) 8.1 Hz), 4.79 (d, 1 H, J ) 8.2 Hz), 4.42 (d, 1
H, J ) 7.7 Hz), 4.34 (dd, 1 H, J ) 4.8, 12.4 Hz), 4.26 (ddt, 1 H,
J ) 4.8, 13.2, 1.5 Hz), 4.05 (ddt, 1 H, J ) 6.1, 13.2, 1.5 Hz),
4.01 (t, 1 H, J ) 8.6 Hz), 4.00 (dd, 1 H, J ) 2.1, 12.4 Hz), 3.70
(m, 1 H), 3.67 (q, 1 H, J ) 8.2 Hz), 3.60 (q, 1 H, J ) 7.7 Hz),
3.53 (dd, 1 H, J ) 2.9, 12 Hz), 2.03 (s, 3 H), 2.01 (s, 6 H), 1.97-
1.96 (2 s, 6 H), 1.93 (s, 3 H), 1.89 (s, 3 H), 1.26 (d, 3 H, J ) 6.5
Hz); 13C NMR (125 MHz, CDCl3) δ 171.2, 170.6, 170.6, 170.4,
170.3, 169.5, 133.7, 117.3, 100.1, 99.8, 76.2, 75.4, 72.6, 71.9,
71.7, 69.4, 68.9, 68.4, 61.9, 55.4, 53.1, 23.2, 23.1, 21.2, 20.7,
20.6, 20.6, 13.8; HRMS (ESI) calcd for C30H44N2O16 [M + H]+
689.2769, found 689.2739.
A solution of (6S)-C-CH3-substituted disaccharide peracetate
(65.0 mg, 94.4 µmol) in CH2Cl2/MeOH (6 mL, 1:1 v/v) was
treated with NaOMe (60 µL, 1 M in MeOH) according to the
above-described procedure, affording disaccharide 2b as a
white solid in 99% yield (45.0 mg). Similarly, (6R)-C-CH3-
substituted disaccharide peracetate (63.0 mg, 91.5 µmol)
afforded disaccharide 3b (43.0 mg, 96% yield).
Allyl N-acetyl-4-O-(N-acetyl-2-deoxy-â-D-glucopyrano-
syl)-2-deoxy-(6S)-C-methyl-â-D-glucopyranoside (2b): 1H
NMR (600 MHz, CD3OD) δ 5.89 (m, 1 H, vinylic H-â), 5.26
(dq, 1 H, J ) 1.6, 17.3 Hz, cis-vinylic H-γ), 5.14 (dq, 1 H, J )
10.5, 1.6 Hz, trans-vinylic H-γ′), 4.50 (d, 1 H, J1′,2′ ) 8.4 Hz,
H-1′), 4.40 (d, 1 H, J1,2 ) 8.5 Hz, H-1), 4.29 (ddt, 1 H, J ) 5.0,
13.3, 1.5 Hz, allylic H-R), 4.07 (ddt, 1 H, J ) 5.8, 13.3, 1.5 Hz,
allylic H-R′), 3.91 (dq, 1 H, J5,6 ) 1.5 Hz, J6,7 ) 6.6 Hz, H-6),
3.90 (dd, 1 H, J5′,6′a ) 2.3 Hz, J6′a,6′b ) 11.8 Hz, H-6′a), 3.74
(dd, 2 H, J1,2 ) J1′,2′ ) 8.5 Hz, J2,3 ) J2′,3′ ) 10.2 Hz, H-2 and
H-2′), 3.65 (dd, 1 H, J5′,6′b ) 6.1 Hz, J6′a,6′b ) 11.8 Hz, H-6′b),
3.64 (dd, 1 H, J3,4 ) 8.6 Hz, J4,5 ) 9.4 Hz, H-4), 3.59 (dd, 1 H,
Allyl N-acetyl-4-O-(N-acetyl-2-deoxy-â-D-glucopyrano-
syl)-2-deoxy-(6R)-C-methyl-â-D-glucopyranoside (3b): 1H
NMR (600 MHz, CD3OD) δ 5.88 (m, 1 H, vinylic H-â), 5.27
(dq, 1 H, J ) 17.3, 1.8 Hz, cis-vinylic H-γ), 5.13 (dq, 1 H, J )
10.5, 1.8 Hz, trans-vinylic H-γ′), 4.50 (d, 1 H, J1′,2′ ) 8.4 Hz,
H-1′), 4.40 (d, 1 H, J1,2 ) 8.4 Hz, H-1), 4.34 (ddt, 1 H, J ) 4.8,
13.4, 1.8 Hz, allylic H-R), 4.08 (ddt, 1 H, J ) 5.8, 13.4, 1.8 Hz,
allylic H-R′), 4.02 (dq, 1 H, J5,6 ) 2.4 Hz, J6,7 ) 6.5 Hz, H-6),
3.91 (dd, 1 H, J5′,6′a ) 2.3 Hz, J6′a,6′b ) 11.8 Hz, H-6′a), 3.72
(dd, 1 H, J1,2 ) 8.4 Hz, J2,3 ) 10.2 Hz, H-2), 3.65 (dd, 1 H, J1′,2′
) 8.4 Hz, J2′,3′ ) 10.4 Hz, H-2′), 3.62 (dd, 1 H, J5′,6′b ) 6.7 Hz,
J6′a,6′b ) 11.8 Hz, H-6′b), 3.60 (dd, 1 H, J3,4 ) 7.9 Hz, J2,3
)
10.2 Hz, H-3), 3.48 (dd, 1 H, J3′,4′ ) 8.6 Hz, J2′,3′ ) 10.4 Hz,
H-3′), 3.39 (dd, 1 H, J5,6 ) 2.4 Hz, J4,5 ) 9.7 Hz, H-5), 3.35
(dm, 1 H, J4′,5′ ) 9.8 Hz, H-5′), 3.33 (dd, 1 H, J3,4 ) 7.9 Hz, J4,5
) 9.7 Hz, H-4), 3.28 (dd, 1 H, J3′,4′ ) 8.6 Hz, J4′,5′ ) 9.8 Hz,
H-4′), 2.01 (s, 3 H, COCH3), 1.96 (s, 3 H, COCH3), 1.22 (d, 3
H, J6,7 ) 6.5 Hz, CH3); 13C NMR (125 MHz, CD3OD/D2O, v/v
5:1) δ 174.5 (CO), 174.3 (CO), 135.3 (C-â), 117.8 (C-γ), 103.0
(C-1′), 101.9 (C-1), 83.3 (C-4), 78.4 (C-5), 77.9 (C-5′), 75.3 (C-
3′), 74.6 (C-3), 71.8 (C-4′), 71.0 (C-R), 66.8 (C-6), 62.4 (C-6′),
57.3 (C-2′), 56.4 (C-2), 23.3, 23.2 (NHAc), 16.3 (CH3); HRMS
(ESI) calcd for C20H34N2O11 [M + Na]+ 501.2060, found
501.2060.
Acknowledgment. This work was supported by the
American Chemical Society Petroleum Research Foun-
dation (33341-G4, 36069-AC1), the American Cancer
Society (IRG-58-006-41), the American Heart Associa-
tion Midwest Affiliates (30399Z), and the National
Science Foundation (CHE-0243496). J.A. thanks the
American Heart Association Midwest Affiliates for
financial support in the form of a predoctoral fellowship
(0110248Z). Support from the Purdue Cancer Center is
also gratefully acknowledged. We thank Dr. Klaas
Hallenga, Dr. Edwin Rivera, and Mr. Scott A. Bradley
of the Purdue Interdepartmental NMR Facility and Dr.
Karl V. Wood of the Purdue Mass Spectrometry Center
for their assistance, and Prof. Paul G. Wenthold for
helpful discussions on error analysis.
Supporting Information Available: Spectroscopic data
for title compounds 1a-3b and synthetic intermediates 4-19,
1
including H, 13C, {1H}-coupled-13C, DQF-COSY, and HMQC
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO0485841
226 J. Org. Chem., Vol. 70, No. 1, 2005