Stereodirecting effect of the pyranosyl C-5 substituent in glycosylation reactions

Article abstract of DOI:10.1021/jo900662v

(Chemical Equation Presented) The stereodirecting effect of the glycosyl C-5 substituent has been investigated in a series of D-pyranosyl thioglycoside donors and related to their preferred positions in the intermediate ³H₄ and

Full text of DOI:10.1021/jo900662v

Stereodirecting Effect of the Pyranosyl C-5 Substituent in
Glycosylation Reactions
Jasper Dinkelaar, Ana Rae de Jong, Robert van Meer, Mark Somers, Gerrit Lodder,
Herman S. Overkleeft, Jeroen D. C. Code´e,* and Gijsbert A. van der Marel*
Leiden Institute of Chemistry, Leiden UniVersity, P.O. Box 9502, 2300 RA Leiden, The Netherlands
marel_g@chem.leidenuniV.nl
ReceiVed March 30, 2009
The stereodirecting effect of the glycosyl C-5 substituent has been investigated in a series of D-pyranosyl
3
4
thioglycoside donors and related to their preferred positions in the intermediate H4 and H3 half-chair
oxacarbenium ions. Computational studies showed that an axially positioned C-5 carboxylate ester can
3
stabilize the H4 half-chair oxacarbenium ion conformer by donating electron density from its carbonyl
function into the electron-poor oxacarbenium ion functionality. A similar stabilization can be achieved
by a C-5 benzyloxymethyl group, but the magnitude of this stabilization is significantly smaller than for
the C-5 carboxylate ester. As a result, the preference of the C-5 benzyloxymethyl to occupy an axial
position in the half-chair oxacarbenium ions is much reduced compared to the C-5 carboxylate ester. To
minimize steric interactions, a C-5 methyl group prefers to adopt an equatorial position and therefore
favors the 4H3 half-chair oxacarbenium ion. When all pyranosyl substituents occupy their favored position
in one of the two intermediate half-chair oxacarbenium ions, highly stereoselective glycosylations can
be achieved as revealed by the excellent ꢀ-selectivity of mannuronate esters and R-selectivity of
6-deoxygulosides.
Introduction
acid6 oligomers as fragments of the alginate polymer. In a
sulfonium ion mediated preactivation glycosylation procedure,7
the ꢀ-1,4-D-mannuronic acid linkages (4) were introduced with
high stereoselectivity using a suitably protected thiomannuronate
ester donor (e.g., 1, Scheme 1). At the time, we assumed that
in analogy with the thorough mechanistic studies of the group
of Crich on the glycosylating properties of 4,6-O-benzylidene-
thiomannoside donors, this stereochemical outcome can be
explained by an SN2-like attack of the nucleophile on the
putative axial R-triflate 2 or on the corresponding contact ion
Uronic acids, aldohexoses having their primary hydroxyl
oxidized to a carboxylic acid, are widely spread constituents of
naturally occurring polysaccharides.1 For instance, the biologi-
cally important glycosaminoglycans are characterized by dimeric
repeating units, in which one of the residues is either a
D-glucuronic acid or a L-iduronic acid.2 Alginate (composed of
D-mannuronic acid and L-guluronic acid residues)3 and pectin
(D-galacturonic acid)4 are examples of the class of homogly-
curonans that contain solely uronic acids. Recently, we reported
the syntheses of ꢀ-1,4-D-mannuronic acid5 and R-1,4-L-guluronic
(4) Mohnen, D. In ComprehensiVe Natural Products Chemistry; Barton, D.,
Nakanishi, K., Meth-Cohn, O., Eds.; Elsevier Science Publishers BV: Amsterdam,
1999; Vol. 3, pp 497-527.
(5) van den Bos, L. J.; Dinkelaar, J.; Overkleeft, H. S.; van der Marel, G. A.
J. Am. Chem. Soc. 2006, 128, 13066–13067.
(6) Dinkelaar, J.; van den Bos, L. J.; Hogendorf, W. F. J.; Lodder, G.;
Overkleeft, H. S.; Code´e, J. D. C.; van der Marel, G. A. Chem.sEur. J. 2008,
14, 9400–9411.
(1) van den Bos, L. J.; Code´e, J. D. C.; Litjens, Dinkelaar, J.; Overkleeft,
H. S.; van der Marel, G. A. Eur. J. Org. Chem. 2007, 3963–3976.
(2) (a) Hacker, U.; Nybakken, K.; Perimon, N. Nat. ReV. Mol. Cell Biol.
2005, 6, 530–541. (b) Laurent, T. C.; Fraser, J. R. E. FASEB J. 1992, 6, 2397–
2404. (c) Gama, C. I.; Tully, S. E.; Sotogaku, N.; Clark, P. M.; Rawat, M.;
Vaidehi, N.; Goddard, W. A.; Nishi, A.; Hsieh-Wilson, L. C. Nat.Chem. Biol.
2006, 2, 467–473.
(3) Moe, S. T.; Draget, K. I.; Skjak-Braek, G.; Smidsrød, O. In Food
Polysaccharides and Their Applications; Stephen, A. M., Eds.; Marcel Dekker,
Inc.: New York, 1995; pp 245-286.
(7) (a) Code´e, J. D. C.; Litjens, R. E. J. N.; Den Heeten, R.; Overkleeft,
H. S.; van Boom, J. H.; van der Marel, G. A. Org. Lett. 2003, 5, 1519–1522. (b)
Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015–9020.
4982 J. Org. Chem. 2009, 74, 4982–4991
10.1021/jo900662v CCC: $40.75  2009 American Chemical Society
Published on Web 06/02/2009

Pyranosyl C-5 Substituent in Gly1cosylation Reactions
SCHEME 1. Glycosylations with Mannuronate and Guluronate Ester Donors
SCHEME 2. Stereoselectivity of C-5-Functionalized
Pyranosides
pair.8 The electron-withdrawing capacity of the C-5 carboxylate9
serves to destabilize the (solvent separated) oxocarbenium ion
3a,b, resulting in a shift of the equilibrium to the side of the
R-triflate 2.5
Application of the same type of glycosylation procedure to
the suitably protected thioguluronic ester donor 5 (the C-5
epimer of D-mannose) gave the R-linked product (8),6 albeit
with reduced stereoselectivity and yield. The stereochemical
outcome of the glycosylation of 5 cannot be explained by
invoking R-triflate 6 as the product-forming intermediate, since
SN2-like attack on the axial triflate 6 would result in the
formation of the ꢀ-product (1,2-trans). Puzzled by the effect of
the C-5 carboxylate ester on the stereochemistry of these
glycosylations, our attention was attracted to the work of
Woerpel and co-workers on the stereoselectivity of pyranosyl
oxacarbenium ions in C-glycosylation reactions.10 From their
doequatorial positions, whereas electron-withdrawing substit-
uents at these positions preferentially adopt an axial orientation,
C-2 alkoxy substituents again prefer an equatorial orientation.12c
To establish the stereodirecting effect of the C-5 carboxylate
ester, we studied the condensations of pyranoside 9 (Scheme
2) having a single carboxylate subtituent at C-5 and its “non-
oxidized” counterpart 10 having a methylene oxybenzyl group
at this position.16 It turned out that the C-5 ester is 1,5-cis
directing, while the C-5 methylene oxybenzyl functionalized
pyranose exhibits little selectivity. The stereochemical outcome
of these glycosylations can be explained with the half-chair
oxocarbenium ions 11 and 12 as product-forming intermediates.
Attack of an incoming nucleophile on these ions occurs along
a pseudoaxial trajectory with a facial selectivity which allows
the formation of the lower energy chair product, as opposed to
a twist-boat product originating from attack from the other side
of the oxacarbenium ion.14b The formation of the 1,5-cis-
products of 13 and 14 arises from the 3H4 (11a and 12a)
conformer, indicating that the C-5 carboxylate prefers to occupy
an axial position in the oxacarbenium ion intermediate.
3
work it became apparent that the relative stability of the H4
11
4
and H3 half-chair conformers of the intermediate oxacarbe-
nium ions12 is of prime importance for the stereochemical
outcome of these reactions.13 Provided that there are no
prohibitive steric interactions in the transition state, the isomeric
ratio of the addition products reflects the relative ground-state
energies of the product-forming oxacarbenium ions.14 The sta-
bility of the half-chair conformers is determined by the nature
and the configuration of the substituents on the pyranose
ring.12c,15 Alkyl groups at C3 and C4 prefer to adopt pseu-
(8) (a) Crich, D.; Sun, S. J. Org. Chem. 1996, 61, 4506–4507. (b) Crich, D.;
Sun, S. J. Org. Chem. 1997, 62, 1198–1199. (c) Crich, D.; Sun, S. J. Am. Chem.
Soc. 1997, 119, 11217–11223. (d) Crich, D.; Sun, S. J. Am. Chem. Soc. 1998,
120, 435–436. (e) Crich, D.; Cai, W. J. Org. Chem. 1999, 64, 4926–4930. (f)
Crich, D.; de la Mora, M.; Vinod, A. U. J. Org. Chem. 2003, 68, 8142–8148.
(g) Crich, D.; Chandrasekera, N. S. Angew. Chem., Int. Ed. 2004, 43, 5386–
5389. (h) Crich, D.; Vinogradova, O. J. Org. Chem. 2006, 71, 8473–8480. (i)
Crich, D.; Li, L. J. Org. Chem. 2007, 72, 1681–1690.
(9) Garegg, P. J.; Olsson, L.; Oscarson, S. J. Org. Chem. 1995, 60, 2200–
2204.
In the mannuronate ester 3H4 oxacarbenium ion (3a), the axial
preference of the C-5 ester can be accommodated keeping all
other substituents in their most favorable orientations (Scheme
1). The 3H4 conformer will therefore be substantially more stable
(10) (a) Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem.
Soc. 2000, 122, 168–169. (b) Ayala, L.; Lucero, C. G.; Romero, J. A. C.; Tabacco,
S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 15521–15528. (c)
Chamberland, S.; Ziller, J. W.; Woerpel, K. A. J. Am. Chem. Soc. 2005, 127,
5322–5323. (d) Lucero, C. G.; Woerpel, K. A. J. Org. Chem. 2006, 71, 2641–
2647. (e) Yang, M. T.; Woerpel, K. A. J. Org. Chem. 2009, 74, 545–553.
(11) (a) Lemiuex, R. U.; Huber, G. Can. J. Chem. 1955, 33, 128–133. (b)
Be´rces, A.; Whitfield, D. M.; Nukada, T. Tetrahedron 2001, 57, 477–491.
(12) (a) Andrews, C. W.; Fraser-Reid, B.; Bowen, J. P. J. Am. Chem. Soc.
1991, 113, 8293–8298. (b) Woods, R. J.; Andrews, C. W.; Bowen, J. P. J. Am.
Chem. Soc. 1992, 114, 850–858. (c) Woods, R. J.; Andrews, C. W.; Bowen,
J. P. J. Am. Chem. Soc. 1992, 114, 859–864. (d) Ionescu, A. R.; Whitfield, D. M.;
Zgierski, M. Z.; Nukada, T. Carbohydr. Res. 2006, 341, 2912–2920.
(13) (a) Nukada, T.; Be´rces, A.; Whitfield, D. M. Carbohydr. Res. 2002,
337, 765–774. (b) Whitfield, D. M. Carbohydr. Res. 2007, 342, 1726–1740.
(14) (a) Stevens, R. V.; Lee, A. W. M. J. Am. Chem. Soc. 1979, 101, 7032–
7035. (b) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Pergamon: New York, 1983; pp 209-221.
4
than the corresponding H3 half-chair (3b), and nucleophilic
attack on 3a leads to the formation of the 1,2-cis products. Thus,
besides R-triflate 2 (Scheme 1), oxacarbenium ion 3a can also
be at the basis of the selectivity displayed by mannuronate esters.
In the L-guluronate case, the C-5 ester can only adopt its
(15) For conformationally locked mannuronate ester oxacarbenium ions see:
Code´e, J. D. C.; de Jong, A.-R.; Dinkelaar, J.; Overkleeft, H. S.; van der Marel,
G. A. Tetrahedron 2009, 65, 3780–3788.
(16) Code´e, J. D. C.; van den Bos, L. J.; de Jong, A.-R.; Dinkelaar, J.; Lodder,
G.; Overkleeft, H. S.; van der Marel, G. A. J. Org. Chem. 2009, 74, 38–47.
J. Org. Chem. Vol. 74, No. 14, 2009 4983

Dinkelaar et al.
the calculations are reported in Figure 1. Both the MP2 and
MP3 calculations show that the methyl ester oxacarbenium ion
3H4 conformer (15 and 16), in which the ester occupies an axial
position, is more stable than the corresponding equatorial ester
oxacarbenium ion (17). The orientation of the ester is also of
importance: conformer 15, in which the ester carbonyl is
pointing toward the ring oxygen, was calculated to be ap-
proximately 3.5 kcal/mol more stable than the equatorial
conformer, whereas conformer 16, having the methoxy group
oriented toward the oxacarbenium ion, is isoenergetic with
the equatorial conformer.22,23 The stability of 15 results from
the donation of electron density from the carbonyl group to the
electron-depleted oxacarbenium ion function. The axial prefer-
ence of the C-5 ester with its carbonyl directed to the electron-
depleted anomeric center, is of similar magnitude as the axial
preference of C-3 and C-4 alkoxy groups.12c The axially oriented
methyloxy methylene pyranosyl oxacarbenium 18, with the
alkoxy group situated above the ring,10e was also calculated to
be the most stable conformer, although the difference between
the axial and equatorial conformer was significantly smaller
when compared to the C-5 ester system. The axially (20) and
equatorially (21) oriented C-5 methyl oxacarbenium ions differ
in energy by approximately 1 kcal/mol, in favor of the equatorial
substituent. A similar value has previously been reported by
Bowen and co-workers for the same system.12c
FIGURE 1. Calculated relative energies of C-5-substituted pyranosyl
oxacarbenium ions. (a) The experimental error in these calculations is
approximately (1 kcal/mol.
favorable axial position in the 4H3 half-chair (7b), in which all
other substituents are in their disfavored positions (Scheme 1).
3
In the alternative H4 conformer (7a), the C-2, C-3, and C-4
are favorably oriented while placing the C-5 ester in the more
destabilizing equatorial position. The guluronate ester oxacar-
benium ion half-chairs will therefore be closer together in
ground-state energy, and the selectivities of the glycosylations
involving these intermediates is less pronounced. The effect of
the C-5 ester does not outweigh the combined electronic effects
of the substituents at C-2, C-3, and C-4,12c and therefore, the
3H4 half-chair (7a), which leads to 1,2-cis selective condensa-
The trend17 revealed by the calculations is in line with the
experimental results described above in Scheme 2. The C-5 ester
prefers to adopt an axial position in the oxacarbenium inter-
3
mediate, thereby stabilizing the H4 conformer relative to its
4H3 counterpart. The stabilization is large enough to overrule
the unfavorable steric interactions that develop in the transition
state when the nucleophile approaches this half-chair conformer
form the ꢀ-face. The 1,5-cis product is thus preferentially
formed. The small preference of the methylene oxybenzyl group
in pyranoside 18 to occupy an axial position does not lead to
the selective formation of the 1,5-cis product. In this case, steric
interactions between the incoming nucleophile and the C-5
substituent in the transition state counterbalance the ground-
state preferences of the half-chair oxacarbenium ions.
4
tions, is preferred over its H3 counterpart (7b).
To investigate the magnitude of the stereodirecting effect of
the C-5 substituent in glycosylations in more detail, we here
present a study toward the glycosylation properties of a set of
thioglycosides having a carboxylate methyl ester, a methylene
benzyl ether, or a methyl group at C-5. To this end, D-manno-,
D-gulo-, D-gluco-, and D-galacto-configured 1-thioglycosides,
1-thiouronic acids, and 1-thio-6-deoxythioglycosides were syn-
thesized17 and glycosidated with both a primary and a secondary
glycosyl acceptor.
(21) Gaussian 03, ReVision C.02; Frisch, M. J.; Trucks, G. W.; Schlegel,
H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.;
Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi,
J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson,
G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa,
J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo,
J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli,
C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.;
Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.;
Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.;
Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.;
Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.;
Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; and Pople,
J. A. Gaussian, Inc., Wallingford, CT, 2004.
Results and Discussion
First, theoretical support was sought for the effect of ester,
methylene ether,18 and methyl functions at C-5 on the stability
of the oxacarbenium ion half chairs (Figure 1). To this end, the
geometries of the C-5-functionalized pyranosyl half-chair ox-
acarbenium ions were optimized and their relative energies
calculated. Second-order Mo¨ller-Plesset (MP2) geometry op-
timizations19 were performed using the 6-311+G** basis set
in Spartan 04.20 The MP2 and MP3 gas-phase energy calcula-
tions of the geometry- optimized conformers were performed
using Gaussian 03.21 The effect of the solvent (dichloromethane)
was taken into account by application of the polarizable
continuum model (PCM) at the MP2 level, which leveled the
energy differences to some extent (vide infra). The results of
(22) It should be noted that the level of theory deployed in our study provides
the relative energies with an error of approximately 1 kcal/mol. Therefore, care
should be taken with the interpretation of small energy differences.
(23) The relative energies of the pyranosyl oxacarbenium ion, functionalized
with a CF3 substituent at C-5, were also calculated. MP2 and MP3 calculations
showed the equatorial CF3 to be the most stable by 0.23 and 0.25 kcal/mol,
respectively. Application of the PCM model led to a difference in energy of 1.1
kcal/mol in favor of the equatorial conformer. These results indicate that the
axial preference of C-5 carboxylate is a result of the stabilization of the positive
charge at the anomeric center by the ester and is not caused by its electron-
withdrawing nature. The small difference in stability of the C-5-CF3 half chair
oxacarbenium ions was translated in the stereochemical outcome of the
condensation reaction of 1-phenylsulfanyl-5-trifluoromethyltetrahydropyran with
benzyl alcohol, which proceeded without any selectivity to provide 1-benzyloxy-
5-trifluoromethyltetrahydropyran as an R/ꢀ mixture (1:1.2).
(17) See Supporting Information for experimental details.
(18) The methylene benzyloxy function of the glycosides used in this study
are replaced by a methylene methoxy group in the pyranosyl oxacarbenium ions
to simplify the calculations.
(19) Møller, C.; Plesset, M. S. Phys. ReV. 1934, 46, 618–622.
(20) Spartan’04; Wavefunction, Inc.: Irvine, CA.
4984 J. Org. Chem. Vol. 74, No. 14, 2009

Pyranosyl C-5 Substituent in Gly1cosylation Reactions
TABLE 1. Study of the C-5 Substituent Effect in the Mannose Series
b
donor
acceptor
22: R ) COOMea
23: R ) CH2OBnb
24: R ) CH3
mannose (22-24)
25
26
27: R/ꢀ ) 0/1 (77%)
30: R/ꢀ ) 0/1 (58%)
28: R/ꢀ ) 1/2 (71%)
31: R/ꢀ ) 1/1.5 (52%)
29: R/ꢀ ) 1/1.7 (71%)
32: R/ꢀ ) 1/1 (65%)
a Reagents and conditions: Ph2SO, TTBP, DCM, -60 °C to -45 °C, Tf2O, 10 min, then -78 °C, nucleophile, to 0 °C. b Reagents and conditions:
Ph2SO, TTBP, DCM, -78 °C, Tf2O, 10 min, nucleophile, to 0 °C.
SCHEME 3. Mannosyl Oxacarbenium Ions
Next, the stereodirecting effect of three C-5 substituents
(methyl ester, methylene oxybenzyl, and methyl) on the
glycosylation properties of a set of epimeric perbenzylated
D-pyranosides was investigated. First, the mannose series was
investigated. Phenyl 1-thio-ꢀ-D-mannuronate ester 22, the cor-
responding D-mannose 23, and 6-deoxy-D-mannose (D-rham-
nose) 24 were condensed with both the primary alcohol 25 and
the secondary alcohol 26 using a diphenylsulfoxide (Ph2SO)-
trifluoromethanesulfonic anhydride (Tf2O) activation procedure.
3
allow nucleophilic attack on the H4 conformer, despite of the
The coupling conditions for all three donors were identical
steric interactions that develop in the product-forming transition
except for the activation temperature: mannuronate ester 22 was
state, and the sole formation of the 1,2-cis product is observed.
activated starting at -60 °C and warming to -45 °C over a
In mannose, the difference in stability between the 3H4
period of 15 min, before addition of the acceptor at -78 °C
conformer (34a) and its 4H3 counterpart (34b) is less pro-
and very slow warming to 0 °C, at which temperature the
nounced, and the nucleophilic attack more sensitive to steric
effects. Because steric interactions in the transition state leading
reaction was quenched. The more reactive mannose donor 23
and rhamnose donor 24 were preactivated at -78 °C for 10
min after which the acceptor was added at the same temperature.
The results of these condensations are summarized in Table 1.
Mannuronate ester 22 yielded solely the 1,2-cis (ꢀ-linked)
to the 1,2-trans product are smaller than in the transition state
which leads to the 1,2-cis-linked dimer,10d,e a Curtin-Hammett/
Winstein-Holness kinetic scenario,26 in which product forma-
4
tion arises from the higher energy H3 conformer (34b), can
products 27 and 30 independent of the nature of the acceptor.
account for the formation of the 1,2-trans product in this case.
Tetrabenzylmannose 23 showed a significant drop in selectivity
Because the methyl group prefers an equatorial orientation in
but maintained a slight preference for the formation of the 1,2-
the oxacarbenium ion intermediate, the difference in stability
cis product. The cis selectivity for the glycosylation involving
3
4
between the H4 (35a) and H3 (35b) conformers of rhamnose
is further minimized, and more product is formed from the 4H3
oxacarbenium ion.
the primary acceptor 25 was slightly better than for the
secondary acceptor 26. Although the 1,2-cis selectivity of donor
23 is not unprecedented,24 it stands in contrast to the perception
that perbenzylated mannose donors are 1,2-trans selective (R-
selective) in glycosylation reactions.25 The condensations of
D-rhamnose 24 showed a further decrease of 1,2-cis product
formation, and also here the secondary acceptor gave more
R-product. The anomeric ratios of the glycosylations in Table
1 reflect the expected stability differences of the respective
oxacarbonium ion conformers (Scheme 3). In the 3H4 conformer
of mannuronic ester (33a) all substituents are situated in a
favorable position, making this conformer considerably more
stable than the 3H4 half-chair. The ground-state energy difference
of the mannuronate half-chair conformers is large enough to
Execution of glycosylation reactions of 25 and 26 with
D-gulose derivatives 36-38 shows an R-selectivity that increases
slightly in going from the carboxylate methyl ester 36, to
methylene benzyl ether 37, to 6-deoxy 38 (Table 2). For both
tetrabenzyl (37) and the 6-deoxy (38) gulose the R-selectivity
is slightly diminished when secondary alcohol 26 is used instead
of primary acceptor 25. On the contrary, for the guluronic acid
methyl ester (36) glycosylations this effect is reversed.
The stereochemical outcome of the glycosylations in Table
2 can be rationalized with the oxacarbenium ions 45-47
(Scheme 4) as product-forming intermediates. Although the
degree of influence of the substituents on the stereoselectivity
seems to be reduced, the trend based on the relative stabilities
(24) (a) Plante, O. J.; Palmacci, E. R.; Andrade, R. B.; Seeberger, P. H. J. Am.
Chem. Soc. 2001, 123, 9545–9554. (b) Doores, K. J.; Davis, B. G. Org. Biomol.
Chem. 2008, 6, 2692–2696. (c) Teumelsan, N.; Huang, X. J. Org. Chem. 2007,
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2692.
(25) (a) ComprehensiVe Glycoscience; KamerlingJ. P., Ed.; Elsevier: Oxford,
2007; Vol. 1. (b) The Organic Chemistry of Sugars; Levy, D. E.,; Fu¨gedi, P.,
Eds.; CRC Press: Boca Raton, 2006. (c) Handbook of Chemical Glycosylations
AdVances in StereoselectiVity and Therapeutic ReleVance; Demchenko, A. V.,
Ed.; Wiley-VCH: Weinheim, 2008. (d) Gouyette, C.; Neumann, J. M.; Fauve,
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Venugopal, R. G. Tetrahedron 1991, 47, 6435–6448. (f) Li, Z.-J.; Huang, H.-
Q.; Cai, M.-S. J. Carbohydr. Chem. 1996, 15, 501–506. (g) Ding, X.; Yang, G.;
Kong, F. Carbohydr. Res. 1998, 310, 135–140.
27
3
4
of the H4 and the H3 conformers is again confirmed. The
gulosylations may proceed by an axial attack of the nucleophile
on the 4H3 conformer, leading to the cis-product (Scheme 4).28
The H3 oxacarbenium ion of 6-deoxygulose 47b has all the
substituents positioned in such a manner that they all contribute
4
favorably to the stability of this conformer, and the gulosylations
(26) Seeman, J. I. Chem. ReV. 1983, 83, 83–134.
(27) It is of interest to note that previous studies with L-gulose similar
stereoselectivities were obtained, indicating that double stereo differentiation is
no issue in these condensations (see ref 6).
J. Org. Chem. Vol. 74, No. 14, 2009 4985

Dinkelaar et al.
TABLE 2. Study of the C-5 Substituent Effect in the Gulose Series
b
donor
acceptor
36: R ) COOMea
37: R ) CH2OBnb
38: R ) CH3
gulose (36-38)
25
26
39 R/ꢀ ) 1/0.33 (86%)
42 R/ꢀ ) 1/0.17 (63%)
40 R/ꢀ ) 1/0.10(76%)
43 R/ꢀ ) 1/0.12 (70%)
41 R/ꢀ ) 1/0.08 (67%)
44 R/ꢀ ) 1/0.15 (70%)
a Reagents and conditions: Ph2SO, TTBP, DCM, -45 °C, Tf2O 10 min, then -78 °C, nucleophile, to 0 °C. b Reagents and conditions: Ph2SO, TTBP,
DCM, -78 °C, Tf2O 10 min, nucleophile, to 0 °C.
SCHEME 4. Gulosyl Oxacarbenium Ions
occupying an unfavorable position, making none of them highly
favorable based on electronic grounds. In addition, destabilizing
steric interactions are present in all oxacarbenium ions and in
all product-forming transition states, except in the 4H3 glucose
half-chair 67b. The stereochemical outcome of the glycosyla-
tions are thus a delicate balance between electronic and steric
factors in both the ground state of the oxacarbenium ions and
the resulting transition states. Furthermore, the reactivity of the
acceptor is of decisive influence.31
of this donor are therefore the most cis selective. The stereo-
selectivity of gulose 37 and in particular guluronic ester 36 is
less pronounced, as in the H3 conformer (45b) the carboxylic
Conclusion
4
The study described here investigated the stereodirecting
capacity of glycosyl C-5 substituents in systems that were devoid
of any other stereodirecting factors. In pyranosyl oxacarbenium
ion intermediates possessing a half-chair conformation, a C-5
ester prefers to occupy a pseudoaxial position. As such it can
donate electron density through space to the electron-depleted
oxacarbenium ion, thereby stabilizing this intermediate. A C-5
methylene alkoxy substituent is also capable of such an
energetically favorable interaction, but the magnitude of this
stabilization is significantly smaller than that of the C-5 ester
functionality. A C-5 alkyl group prefers to adopt an equatorial
position because of steric reasons. When the stereodirecting
effect of the C-5 substituent works in concert with the other
functional groups on the pyranose ring, highly selective
condensations are achieved. This is exemplified by the glycosi-
dations of mannuronate ester 22 and 6-deoxy guloside 38. In
systems having conflicting substituent preferences, steric factors
ester does not occupy its favored axial position (Scheme 4).
The erosion in stereoselectivity caused by the unfavorable
positioning of the C-5 substituent is considerably less in the
gulose series than in the mannose series. This may be due to
the difference in steric interactions that develop in the transition
states of the nucleophilic additions to the respective oxacarbe-
3
nium ions. Axial attack of a nucleophile on the mannose H4
oxacarbenium ions 33a-35a leads to 1,3-diaxial interactions
with both the C-3 and C-5 substituents,12c which are absent in
the transition state of the 4H3 half-chairs 33b-35b (Scheme 3).
For gulose, both half-chair conformers give rise to one 1,3-
diaxial interaction in the transition states and are therefore
sterically equally demanding (Scheme 4).
The results reported above for mannuronic acid donor 22 and
6-deoxygulose donor 38 indicate that highly stereoselective
glycosylations can be obtained when all the substituents occupy
3
4
a favorable position in either the H4 or the H3 oxacabenium
ion conformer. To further assess the effect of the substituent at
C-5 on the stereochemical outcome of glycosylation reactions,
three other epimers have been examined. D-Gluco-, D-allo-, and
D-galacto-configured 1-thioglycosides and the corresponding
1-thiouronic acids were prepared and glycosidated with the same
primary and secondary acceptor as used in the manno- and gulo-
series. The results of these condensations are summarized in
Table 3. Clearly, almost all of the condensations proceed with
poor stereoselectivity.24d,e,29,30 Furthermore, the nature of the
acceptor has a profound effect on the stereochemical outcome
of the glycosylations and no clear effect of the C-5 substituent
can be distilled from the data reported in Table 3.
(29) Similar selectivities have been reported before in condensations of
tetrabenzyl glucopyranosyl and tetrabenzyl galactopyranosyl donors. See, for
example: (a) Milat, M. L.; Zollo, P. A.; Sinay¨, P. Carbohydr. Res. 1982, 100,
263–271. (b) Hinklin, R. J.; Kiessling, L. L. J. Am. Chem. Soc. 2001, 123, 3379–
3380. (c) Meloncelli, P. J.; Williams, T. M.; Hartmann, P. E.; Stick, R. V.
Carbohydr. Res. 2007, 342, 1793–1804. (d) Mukaiyama, T.; Takeuchi, K.;
Maeshima, H.; Saitoh, T. HelV. Chem. Acta 2000, 83, 1901–1918. (e) Choudhury,
A. K.; Mukherjee, I.; Mukhopadhyay, B.; Roy, N. J. Carbohydr. Chem. 1999,
18, 361–367. (f) Kartha, K. P. R.; Aloui, M.; Field, R. A. Tetrahedron Lett.
1996, 37, 5175–5178.
(30) The high R-selectivity in the condensation of tetrabenzyl galactopyra-
nosyl donors and the galactosyl C3-OH has been observed before. See, for
example: (a) Wang, J.-Q.; Chen, X.; Zhang, W.; Zacharek, S.; Chen, Y.; Wang,
G. P. J. Am. Chem. Soc. 1999, 121, 8174–8181. (b) Hanessian, S.; Huynk, H. K.;
Reddy, G. V.; Duthaler, R. O.; Katopodis, A.; Streiff, M. B.; Kinzy, W.; Oehrlein,
R. Tetrahedron 2001, 57, 3281–3290. (c) Ramos, D.; Rollin, R.; Klaffke, W. J.
Org. Chem. 2001, 66, 2948–2956. (d) Litjens, R. E. J. N.; Hoogerhout, R.;
Filippov, D. V.; Code´e, J. D. C.; Van den Bos, L. J.; Van den Berg, R. J. B. H.
N.; Overkleeft, H. S.; Van der Marel, G. A. J. Carbohydr. Res. 2005, 24, 755–
769. (e) Ratcliffe, R. M.; Kamth, V. P.; Yeske, R. E.; Gregson, J. M.; Fang,
Y. R.; Palcic, M. M. Synthesis 2004, 14, 2293–2296.
When we consider the structures of the half-chair oxacarbe-
nium ions involved in the condensations in Table 3 (Scheme
5), it can be seen that all of them have one or more substituents
(28) The high R-selectivity of L-gulose has been observed in previous syntheses
involving L-gulose donors. For examples of the synthesis of bleomycin, see: (a)
Katano, K.; An, H.; Aoyagi, Y.; Overhand, M.; Sucheck, S. J.; Stevens, W. C., Jr.;
Hess, C. D.; Zhou, X.; Hecht, S. M. J. Am. Chem. Soc. 1998, 120, 11285–11296.
(b) Boger, D. L.; Honda, T. J. Am. Chem. Soc. 1994, 116, 5647–5656. See for
the synthesis of an L-gulose alginate tetramer: (c) Chi, F.-C.; Kilkarni, S. S.;
Zulueta, M. M. L.; Hung, S.-C. Chem. Asian J. 2009, 3, 386–390.
(31) (a) Bele´n Cid, M.; Alfonso, F.; Alonso, I.; Mart´ın-Lomas, M. Org.
Biomol. Chem. 2009, 7, 1471–1481. (b) Bele´n Cid, M.; Alfonso, I.; Alonso, F.;
Bonilla, J. B.; Lo´pez-Prados, J.; Mart´ın-Lomas, M. Eur. J. Org. Chem. 2006,
3947–3959. (c) Xia, C.; Yao, Q.; Schu¨mann, J.; Rossy, E.; Chen, W.; Zhu, L.;
Zhang, W.; De Libero, G.; Wang, P. G. Bioorg. Med. Chem. Lett. 2006, 16,
2195–2199. (d) Crich, D.; Dudkin, V. J. Am. Chem. Soc. 2001, 121, 6819–
6825.
4986 J. Org. Chem. Vol. 74, No. 14, 2009

Pyranosyl C-5 Substituent in Gly1cosylation Reactions
TABLE 3. Study of the C-5 Substituent Effect in the Glucose, Galactose, and Allose Series
donor
acceptor
R ) COOMea
R ) CH2OBnb
glucose (48, 49)
25
26
25
26
25
26
50: R/ꢀ ) 1/1.4 (68%)
52: R/ꢀ ) 1/0.6 (86%)
56: R/ꢀ ) 1/0.4 (91%)
58: R/ꢀ ) 1/0 (52%)
62: R/ꢀ ) 1/2.3 (49%)
64: R/ꢀ ) 1/0.4 (86%)
51: R/ꢀ ) 1/1.4 (75%)
53: R/ꢀ ) 1/1.7 (89%)
57: R/ꢀ ) 1/0.5 (92%)
59: R/ꢀ ) 1/0.6 (65%)
63: R/ꢀ ) 1/3 (67%)
65: R/ꢀ ) 1/0.1 (72%)
Allose (54, 55)
Galactose (60, 61)
a Reagents and conditions: Ph2SO, TTBP, DCM, -45 °C, Tf2O, 10 min, then -78 °C, nucleophile, to 0 °C. b Reagents and conditions: Ph2SO, TTBP,
DCM, -78 °C, Tf2O, 10 min, nucleophile, to 0 °C.
SCHEME 5. Glucosyl, Galactosyl, and Allosyl
Oxacarbenium Ions
dried over MgSO4, filtered, and concentrated in vacuo. Purification
by size-exclusion and column chromatography yielded the corre-
sponding dimer.
Methyl 2,3,4-Tri-O-benzyl-6-O-(methyl 2,3,4-tri-O-benzyl-ꢀ-
D-mannopyranosyluronate)-r-D-glucopyranoside (27). Donor 22
(86 mg, 0.15 mmol) was condensed with acceptor 25 according to
the general procedure for glycosylations of thioglycuronates,
yielding ꢀ-linked disaccharide 27 (80 mg, 58%) as an amorphous
white solid: [R]22D ) +9.4 (c ) 0.016, DCM); IR (neat) 729, 795,
860, 910, 1026, 1049, 1157, 1120, 1238, 1265, 1362, 1454, 1497,
1
1605, 1747, 2862, 2924, 3032 cm-1; H NMR (400 MHz) δ )
3.31 (s, 3H, C-1-OCH3), 3.39-3.43 (m, 3H, H-3′, H-4, H-6), 3.50
(d, 1H, J ) 9.2 Hz, H-2), 3.70-3.77 (m, 6H, CO2CH3, H-5, H-5′,
H-2′), 4.01 (t, 1H, J ) 8.8 Hz, H-3), 4.11-4.03 (m, 2H, H-1′, H-6),
4.21 (t, 1H, J ) 9.2 Hz, H-4′), 4.47-4.56 (m, 4H, CH2 Bn, H-1),
4.66 (d, 1H, J ) 11.6 Hz, CH2 Bn), 4.77-4.91 (m, 5H, CH2 Bn),
4.96 (d, 1H, J ) 10.0 Hz, CH2 Bn), 5.02 (d, 1H, J ) 10.8 Hz, CH2
Bn), 7.20-7.46 (m, 30 H, HPh); 13C NMR (100 MHz) δ ) 52.4
(CO2CH3), 55.1 (C-1-OCH3), 68.6 (C-6), 69.7 (C-5), 71.7 (CH2
Bn), 73.3 (C-5′or C-2′), 73.4 (CH2 Bn), 73.8 (CH2 Bn), 74.8 (CH2
Bn), 75.2 (CH2 Bn), 75.3 (C-5′or C-2′), 75.8 (CH2 Bn), 75.8 (C-
4′), 77.6 (C-3′or C-4), 79.9 (C-2), 81.3 (C-3′or C-4), 82.2 (C-3),
97.8 (C-1), 102.1 (C-1′), 127.6-128.5 (CH arom), 138.0 (Cq Ph),
138.1 (Cq Ph), 1383 (Cq Ph), 138.3 (Cq Ph), 138.5 (Cq Ph), 138.88
(Cq Ph), 168.7 (CdO CO2Me); 13C-GATED NMR (100 MHz) δ
) 97.8 (JC-1, H-1 ) 167 Hz, C-1), 102.1 (JC-1′, H-1′ ) 155 Hz, C-1′);
HRMS [M + Na]+ calcd for C56H60O12Na 947.39770, found
947.39853.
in both the ground state of the oxacarbenium ion half-chair and
product-forming transition states become important for the
outcome of the reaction. The mechanistic insight described here
can aid in the design of stereoselective glycosylation strategies.
Experimental Section
General Procedure for Glycosylations of Thioglycosides
and 6-Deoxythioglycosides. A solution of donor, diphenyl sulfoxide
(1.1 equiv), and tri-tert-butylpyrimidine (2.5 equiv) in DCM (0.05
M) was stirred over activated MS 3 Å for 30 min. The mixture
was cooled to -78 °C before triflic acid anhydride (1.1 equiv) was
added. The mixture was stirred for 10 min at -78 °C followed by
addition of acceptor (1.5 equiv) in DCM (0.1 M). The reaction
mixture was allowed to warm to 0 °C, and Et3N (0.15 mL) was
added. The reaction mixture was diluted with DCM and washed
with NaHCO3 (aq). The aqueous layer was extracted twice with
DCM, and the collected organic layers were dried over MgSO4,
filtered, and concentrated in vacuo. Purification by size-exclusion
and column chromatography yielded the corresponding dimer.
General Procedure for Glycosylations of Thioglycuronates.
A solution of donor, diphenyl sulfoxide (1.1 equiv), and tri-tert-
butylpyrimidine (2.5 equiv) in DCM (0.05 M) was stirred over
activated MS 3 Å for 30 min. The mixture was cooled to -60 °C
before triflic acid anhydride (1.1 equiv) was added. The mixture
was warmed to -45 °C and then cooled to -78 °C followed by
addition of acceptor (1.5 equiv) in DCM (0.1 M). Stirring was
continued, the reaction mixture was allowed to warm to 0 °C, and
Et3N (0.15 mL) was added. The reaction mixture was diluted with
DCM and washed with NaHCO3 (aq). The aqueous layer was
extracted twice with DCM, and the collected organic layers were
p-Methoxyphenyl 2-O-Menzyl-3-O-(methyl 2,3,4-tri-O-benzyl-
ꢀ-D-mannopyranosyluronate)-4,6-benzylidene-ꢀ-D-galactopyra-
noside (30). Donor 22 (86 mg, 0.15 mmol) was condensed with
acceptor 26 according to the general procedure for glycosylations
of thioglycuronates, yielding ꢀ-linked disaccharide 30 (107 mg,
77%) as an amorphous white solid: [R]22D ) -8.5 (c ) 2, DCM);
IR (neat) 729, 895, 1003, 1061 1096, 1219, 1265, 1366, 1508, 1747,
1
3055 cm-1; H NMR δ ) 3.15 (d, 1H, J 9.2 Hz, H-3′), 3.53 (s,
1H, H-5), 3.62 (s, 1H, H-2′), 3.66-3.75 (m, 4H, H-5′, CO2CH3),
3.77 (s, 3H, CO2CH3), 3.84 (dd, 1H, J ) 2.8 Hz, 9.6 Hz, H-3),
4.05-4.10 (m, 2H, H-2, H-6), 4.18 (t, 1H, J ) 9.6 Hz, H-4′), 4.27
(d, 1H, J ) 10.0 Hz, CH2 Bn), 4.34-4.37 (m, 3H, H-4, H-6, CH2
Bn), 4.60 (d, 1H, J, 10.4 Hz, CH2 Bn), 4.70 (s, 1H, H-1′), 4.81-4.97
(m, 5H, H-1, CH2 Bn), 5.61 (s, 1H, CHPh benzylidene), 6.83 (d,
2H, J ) 8 Hz, H arom), 7.05-7.07 (m, 3H, H arom), 7.16-7.40
(m, 22H, H arom), 7.51-7.70 (m, 2H, H arom); 13C NMR (100
MHz) δ ) 52.3 (CO2CH3), 55.6 (OCH3 pMP), 66.6 (C-5), 68.9
(C-6), 71.7 (C-2′), 71.7 (CH2 Bn), 73.3 (CH2 Bn), 75.2 (CH2 Bn),
75.6 (C-4′), 75.8 (C-4, C-5), 77.7 (C-3), 79.1 (C-2), 82.0 (C-3′),
100.8 (CHPh benzylidene), 103.1 (C-1′, C-1), 114.5 (CH arom
pMP), 118.8 (CH arom pMP), 126.3-128.8 (CH arom), 130.9 (Cq
Ph), 151.4 (Cq Ph), 155.4 (Cq Ph), 168.7 (CdO CO2Me); 13C-
J. Org. Chem. Vol. 74, No. 14, 2009 4987

Dinkelaar et al.
GATED NMR (100 MHz) δ ) 100.8 (JC-1,
) 152 Hz, C-1),
acceptor 26 as described in the general procedure for glycosylations
of thioglycosides, affording the title compound 32 (86 mg, 65%)
as a mixture of anomers (R/ꢀ: 1/1): IR (neat) 694, 732, 995, 1026,
1061, 1218, 1454, 1504, 2341, 2873 cm-1; 1H NMR (400 MHz) δ
H-1
103.2 (JC-1′,
) 155 Hz, C-1′); HRMS [M + Na]+ calcd for
H-1′
C55H56O13Na 947.36131, found 947.36214.
Methyl 2,3,4-Tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-r/ꢀ-
D-mannopyranoside)-r-D-glucopyranoside (28). Mannopyrano-
side 23 (95 mg, 0.15 mmol) was condensed with acceptor 25
according to the general procedure for glycosylations of thiogly-
cosides, yielding disaccharide 28 (105 mg, 71%) as a mixture of
anomers (R/ꢀ: 1/2): IR (neat) 729, 895, 1042, 1069, 1265, 1362,
1454, 1497, 2870 cm-1; 1H NMR (400 MHz) δ ) 3.30 (s, 1.55 H,
C-1R-OCH3), 3.33 (s, 3H, C-1ꢀ-OCH3), 3.36-3.47 (m, 5H), 3.51
(dd, 1H, J ) 9.6 Hz, 3.2 Hz, H-3′ꢀ), 3.58-3.62 (m, 2H), 3.65-3.73
(m, 3H), 3.76-3.85 (m, 5H), 3.95-4.04 (m, 2H, H-4′, H-3), 4.11
(s, 1H, H-1′ꢀ), 4.16 (d, 1H, J ) 10.8 Hz), 4.42-4.71 (m, 14H),
4.75-5.03 (m, 10H), 7.13-7.42 (m, 53 H); 13C NMR (100 MHz)
δ ) 55.0 (OCH3 ꢀ), 55.0 (OCH3 R), 65.7, 68.2, 69.0, 69.7, 71.5,
71.8, 71.9, 72.0, 72.4, 73.6, 74.5, 74.7, 74.9, 75.0, 75.1, 75.6, 75.7,
75.9, 77.6, 79.5, 79.8, 79.9, 82.1, 82.2, 97.7 (C-1 ꢀ), 97.7 (C-1 R)
98.2 (C-1′R), 101.4 (C-1′ ꢀ), 127.3-128.4 (CH arom), 138.0 (Cq
Ph), 138.1 (Cq Ph), 138.2 (Cq Ph), 138.3 (Cq Ph), 138.3 (Cq Ph),
138.4 (Cq Ph), 138.6 (Cq Ph), 138.6 (Cq Ph), 138.6 (Cq Ph), 138.6
(Cq Ph), 138.8 (Cq Ph), 151.5 (Cq Ph), 151.6 (Cq Ph), 155.3 (Cq
Ph); 13C-GATED NMR (100 MHz) δ ) 98.2 (J ) 164 Hz), 101.4
(J ) 158 Hz); HRMS [M + NH4]+ calcd for C62H70O11N
1004.49434, found 1004.49572.
) 1.26 (d, 3H, J ) 4.8 Hz, C-6), 1.35 (d, 3H, J ) 6 Hz, C-6); 13
C
NMR (100 MHz) δ ) 17.9 (C-6′ ꢀ), 18.0 (C-6′ R), 93.4 (C-1′ R),
102.5 (C-1′ ꢀ); 13C-GATED NMR (100 MHz) δ ) 97.7 (JC-1, H-1
)
166 Hz, C-1′ R), 103.2 (JC-1′, H-1′ ) 154 Hz, C-1′ ꢀ); HRMS [M +
Na]+ calcd for C54H56O11Na 903.3715, found 903.3712.
Methyl 2,3,4-Tri-O-benzyl-6-O-(methyl 2,3,4-tri-O-benzyl-r/
ꢀ-L-gulopyranosyluronate)-r-D-glucopyranoside (39). Guluronic
acid 36 (114 mg, 0.20 mmol) was glycosylated with glucoside 25
(139 mg, 0.30 mmol) as described in the general procedure for
glycosylations of thioglycuronates, yielding 39 (115 mg, 73%) as
a mixture of anomers (R/ꢀ: 1/0.33): IR (neat) 731, 808, 910, 1026,
1047, 1070, 1207, 1265, 1304, 1358, 1439, 1454, 1497, 1732, 1765,
2876, 3030 cm-1; 1H NMR (400 MHz) δ ) 3.28 (s, 3H, CH3 OMe),
3.33 (s, 1H, CH3 OMe), 3.39 (dd, 1H, J ) 3.6 Hz, 9.6 Hz),
3.49-3.53 (m, 0.3H), 3.59 (s, 3H, CH3 COOMe), 3.61-3.65 (m,
1.3H), 3.66 (s, 1H, CH3 COOMe), 3.68-3.73 (m, 1H), 3.75-3.77
(m, 2.2H), 3.80-3.82 (m, 1.6H), 3.85-3.87 (m, 1.3H), 3.90-4.02
(m, 3.6H), 4.22-4.99 (m, 18 H), 5.16 (d, 1H, J ) 4 Hz, H-1′); 13
C
NMR (100 MHz) δ ) 51.9 (CH3 COOMe), 51.9 (CH3 COOMe),
54.8 (CH3 OMe), 54.9 (CH3 OMe), 67.4, 67.6, 68.2, 70.1, 70.3,
71.2, 72.5, 72.6, 72.9, 72.9, 73.0, 73.1, 73.2, 73.2, 73.4, 74.6, 74.7,
74.8, 75.5, 75.5, 75.7, 76.4, 76.9, 77.9, 78.1, 79.8, 80.0, 81.9, 82.0,
97.7 (C-1), 97.8 (C-1), 98.0 (C-1′ R), 101.0 (C-1′ ꢀ), 127.3-128.3
(CH arom), 137.4-138.8 (Cq arom), 169.3 (Cq COOMe), 170.0
(Cq COOMe); HRMS [M + Na]+ calcd for C56H60O12Na 947.3977,
found 947.3985.
p-Methoxyphenyl 2-O-Benzyl-3-O-(2,3,4,6-tetra-O-benzyl-r/
ꢀ-D-mannopyranoside)-4,6-benzylidene-ꢀ-D-galactopyranoside
(31). Mannopyranoside 23 (95 mg, 0.15 mmol) was glycosylated
with acceptor 26 as described in the general procedure for
glycosylations of thioglycosides, affording the title compound 31
(77 mg, 52%) as a mixture of anomers (R/ꢀ: 1/1.6): IR (neat) 729,
826, 899, 999, 1026, 1061, 1219, 1265, 1366, 1454, 1504, 2858
p-Methoxyphenyl 2-O-Benzyl-3-O-(methyl 2,3,4-tri-O-benzyl-
r/ꢀ-L-gulopyranosyluronate)-4,6-benzylidene-ꢀ-D-galactopyra-
noside (42). Guluronic acid 36 (114 mg, 0.20 mmol) was
glycosylated with galactoside 26 (139 mg, 0.30 mmol) as described
in the general procedure for glycosylations of thioglycuronates,
yielding 42 (124 mg, 79%) as a mixture of anomers (R/ꢀ: 1/0.1):
IR (neat) 731, 826, 908, 997, 1026 1065, 1078, 1175, 1217, 1265,
1
cm-1; H NMR (400 MHz) δ ) 3.22 (dd, 1.6 H, J ) 2.4 Hz, 9.2
Hz, H-3′ꢀ), 3.35-3.41 (m, 4H), 3.60 (d, 1H, J ) 10.4 Hz),
3.67-3.73 (m, 4H), 3.77-3.84 (m, 13H), 3.88-3.910 (m, 1.6 H),
4.00-4.07 (m, 7H), 4.22-4.23 (m, 1.6 H), 4.27-4.40 (m, 10 H),
4.48-4.69 (m, 14 H), 4.76-4.79 (m, 3H), 4.82-4.88 (m, 3.5 H),
4.91-4.95 (m, 6H), 5.09 (s, 1H, H-1′R), 5.44 (s, 1H, CHPh R
benzylidene), 5.58 (s, 1.6 H, CHPh ꢀ benzylidene), 6.80-6.83 (m,
4H, CH arom pMP), 7.01-7.40 (m, 27 H, 2 H arom Ph), 7.48-7.49
(m, 1H, H arom Ph), 7.53-7.58 (m, 1H, H arom Ph); 13C NMR
(100 MHz) δ ) 55.6 (OCH3 pMP), 66.2, 66.7, 68.1, 68.9, 69.0,
69.2, 69.9, 71.0, 71.3, 71.5, 72.1, 72.3, 72.7, 72.8, 73.3, 73.4, 74.3,
74.8, 74.9, 75.2, 75.7, 75.7, 76.1, 78.0, 78.9, 79.9, 82.8, 93.3 (C-
1′R), 100.8 (CHPh benzylidene ꢀ), 101.0 (CHPh benzylidene R),
102.8 (C-1′ ꢀ), 103.1 (C-1), 114.4 (CH arom pMP), 114.5 (CH
arom pMP), 118.8 (CH arom pMP), 118.9 (CH arom pMP),
126.3-139.0 (CH arom), 130.9 (CH arom), 137.7 (Cq Ph), 138.0
(Cq Ph), 138.0 (Cq Ph), 138.1 (Cq Ph), 138.2 (Cq Ph), 138.2(Cq
Ph), 138.3 (Cq Ph), 138.4 (Cq Ph), 138.5 (Cq Ph), 138.6 (Cq Ph),
138.8 (Cq Ph), 151.5 (Cq Ph), 151.6 (Cq Ph), 155.3 (Cq Ph); 13C-
GATED NMR (100 MHz) δ ) 93.3 (J ) 171 Hz, C-1′R), 102.8
(J ) 156 Hz, C-1′ꢀ); HRMS [M + NH4]+ calcd for C61H66O12N
1004.45795, found 1004.45932.
1
1306, 1366, 1439, 1454, 1506, 175, 2870, 3030 cm-1; H NMR
(400 MHz) δ ) 3.43 (s, 3H, CH3 COOMe), 3.45 (bs, 1H), 3.72 (s,
3H, CH3 pMP), 3.88-3.90 (m, 1H), 3.93-3.99 (m, 2H), 4.01-4.02
(m, 2H), 4.05-4.08 (m, 1H, H-6), 4.30-4.39 (m, 5H), 4.46 (m,
2H), 4.55-4.68 (m, 4H), 4.84-4.90 (m, 2H), 4.97 (d, 1H, J ) 1.6
Hz), 5.39 (d, 1H, J ) 3.6 Hz, H-1′), 5.56 (s, 1H, CHPh), 6.75-7.56
(m, 29H); 13C NMR (100 MHz) δ ) 51.6 (CH3 COOMe), 55.5
(CH3 OMe), 66.3, 67.6, 69.2, 70.9, 71.6, 72.4, 72.6, 73.3, 73.4,
74.6, 74.9, 76.3, 77.4, 92.9 (C-1′), 100.8 (CHPh), 103.0 (C-1), 114.3
(CH arom pMP), 118.9 (CH arom pMP), 126.2-128.7 (CH arom),
137.5-138.6 (Cq arom), 151.6 (Cq pMP), 155.1 (Cq pMP), 169.7
(Cq COOMe); HRMS [M + Na]+ calcd for C55H56O13Na 947.36131,
found 947.36184.
Methyl 2,3,4-Tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-r/ꢀ-
L-gulopyranoside)-r-D-glucopyranoside (40). Gulopyranoside 37
(127 mg, 0.20 mmol) was condensed with acceptor 25 according
to the general procedure for glycosylations of thioglycosides,
yielding disaccharide 40 (150 mg, 76%) as a mixture of anomers
(R/ꢀ: 1/0.1): IR (neat) 733, 820, 908, 1026, 1047, 1069, 1194, 1207,
Methyl 2,3,4-Tri-O-benzyl-6-O-(2,3,4-tri-O-benzyl-r/ꢀ-D-
rhamnopyranoside)-r-D-glucopyranoside (29). Rhamnopyrano-
side 24 (79 mg, 0.15 mmol) was glycosylated with acceptor 25 as
described in the general procedure for glycosylations of thiogly-
cosides, affording the title compound 29 (94 mg, 71%) as a mixture
of anomers (R/ꢀ: 1/1.7): IR (neat) 732, 694, 1006, 1026, 1053,
1
1310, 1327, 1360, 1454, 1497, 2870, 3030, 3063 cm-1; H NMR
(400 MHz) δ ) 3.28 (s, 3H, OMe), 3.41 (dd, 1H, J ) 3.6 Hz, 9.6
Hz), 3.54 (m, 2H), 3.60 (bs, 1H), 3.66-3.78 (m, 3H), 3.81-3.82
(m, 2H), 3.95 (t, 1H, J ) 9.2 Hz), 4.00 (dd, 1H, J ) 4.0 Hz, 11.6
Hz), 4.34-4.56 (m, 8H), 4.63-4.71 (m, 4H), 4.75 (d, 1 H, J ) 12
Hz, CH2 Bn), 4.79 (d, 1 H, J ) 10.8 Hz, CH2 Bn), 4.93 (d, 1 H, J
) 10.8 Hz, CH2 Bn), 5.06 (bs, 1H, H-1′), 7.12-7.36 (m, 35H, H
arom); 13C NMR (100 MHz) δ ) 54.9 (OMe), 65.7, 66.9, 68.7,
70.4, 70.9, 72.7, 73.1, 73.2, 73.2, 73.9, 74.8, 75.5, 75.6, 77.9, 70.1,
82.0, 97.7 (C-1 or C-1′), 97.9 (C-1 or C-1′),127.2-128.9 (CH
arom), 137.9-139.0 (Cq arom); HRMS [M + NH4]+ calcd for
C62H70O11N 1004.49434, found 1004.49581.
1
1068, 1362, 1454, 2866 cm-1; H NMR (400 MHz) δ ) 1.25 (d,
1.75 H, J ) 4.8 Hz, C-6 R), 1.35 (d, 3 H, J ) 6 Hz, C-6 ꢀ);13C
NMR (100 MHz) δ ) 17.8 (C-6′ ꢀ), 17.9 (C-6 R′), 98.2(C-1′ R),
101.2 (C-1′ ꢀ); 13C-GATED NMR (100 MHz) δ ) 98.2 (JC-1′, H-1′
) 168 Hz, C-1′ R), 103.2 (JC-1′, H-1′ ) 153 Hz, C-1′ ꢀ); HRMS [M
+ Na]+ calcd for C55H60O10Na 903.4079, found 903.4077.
p-Methoxyphenyl 2-O-Benzyl-3-O-(2,3,4-tri-O-benzyl-r/ꢀ-D-
rhamnopyranoside)-4,6-benzylidene-ꢀ-D-galactopyranoside (32).
Rhamnopyranoside 24 (79 mg, 0.15 mmol) was glycosylated with
4988 J. Org. Chem. Vol. 74, No. 14, 2009

Pyranosyl C-5 Substituent in Gly1cosylation Reactions
p-Methoxyphenyl 2-O-Benzyl-(2,3,4,6-tetra-O-benzyl-r/ꢀ-L-
gulopyranoside)-4,6-benzylidene-ꢀ-D-galactopyranoside (43). Gu-
lopyranoside 37 (127 mg, 0.20 mmol) was glycosylated with
acceptor 26 according to the general procedure for glycosylations
of thioglycosides, yielding disaccharide 43 (138 mg, 70%) as a
mixture of anomers (R/ꢀ: 1/0.12): IR (neat) 731, 824, 872, 910,
997, 1026, 1065, 1080, 1173, 1217, 1265, 1308, 1367, 1454, 1506,
2866, 3030 cm-1; 1H NMR (400 MHz) δ ) 3.30 (s, 1H), 3.37 (dd,
1H, J ) 6 Hz, 10 Hz), 3.53 (bs, 1H), 3.61 (dd, 1H, J ) 7.2 Hz,
10.4 Hz), 3.74 (s, 3H, CH3 pMP), 3.88-3.92 (m, 2H), 4.00-4.08
(m, 3H), 4.22 (d, 1 H, J ) 12 Hz, CH2 Bn), 4.28-4.46 (m, 8H),
4.57-4.64 (m, 3H), 4.68 (d, 1 H, J ) 10.8 Hz, CH2 Bn), 4.77 (m,
2H), 4.86 (d, 1 H, J ) 10.8 Hz, CH2 Bn), 5.32 (d, 1 H, J ) 3.2 Hz,
H-1′), 5.51 (s, 1H, CHPh), 6.77-7.54 (m, 34H, H arom); 13C NMR
(100 MHz) δ ) 55.5 (OCH3 pMP), 65.2, 66.3, 69.1, 69.3, 70.6,
71.3, 72.4, 72.5, 72.6, 73.3, 73.7, 74.6, 74.7, 76.0, 76.3, 91.9 (C-
1′), 101.0 (CHPh), 102.9 (C-1), 114.3 (CH arom pMP), 118.9 (CH
arom pMP), 126.3-128.8 (CH arom), 137.7-139.1 (Cq arom),
151.8 (Cq pMP), 155.1(Cq pMP); HRMS [M + Na]+ calcd for
C61H62O12Na 1009.41335, found 1009.41396.
H), 3.67 (s, 3H, OCH3 ꢀ), 3.67-3.86 (m, 6H), 3.94-4.01 (m, 2.5
H), 4.12 (dd, 1H, J ) 1.6 Hz, 10.8 Hz), 4.29 (d, 0.7 H, J ) 10.0
Hz), 4.38 (d, 1.1 H, J ) 7.6 Hz, H-1′ꢀ), 4.50 (d, J ) 11.6 Hz),
4.55-4.60 (m, 4.6 H), 4.72-4.83 (m, 4.2 H), 4.72-4.83 (m, 8.9
H), 4.88-4.98 (m, 6 H), 7.17-7.35 (m, 55H, H arom); 13C NMR
(100 MHz) δ ) 52.3 (CO2CH3 R or ꢀ), 52.3 (CO2CH3 R or ꢀ),
66.5 (C-6 R or ꢀ), 68.8 (C-6 R or ꢀ), 69.7 (OCH3 R or ꢀ), 70.3
(OCH3 R or ꢀ), 72.5, 73.2, 73.3, 74.4, 74.8, 74.8, 74.9, 74.9, 75.5,
75.6, 75.6, 77.9, 79.1, 79.3, 79.5, 79.8, 78.0, 80.8, 81.5, 81.8, 82.0,
83.8, 97.7 (C-1′R), 97.9 (C-1 R and ꢀ), 104.0 (C-1′ꢀ), 127.5-128.4
(CH arom Ph), 137.8 (Cq Ph), 138.0 (Cq Ph), 138.1 (Cq Ph), 138.2
(Cq Ph), 138.2 (Cq Ph), 138.7 (Cq Ph), 168.7 (CdO CO2Me); HRMS
[M + Na]+ calcd for C56H60O12Na: 947.39770, found 947.39850.
p-Methoxyphenyl 2-O-Benzyl-3-O-(methyl 2,3,4-tri-O-benzyl-
r/ꢀ-D-glucopyranosyluronate)-4,6-benzylidene-ꢀ-D-galactopyra-
noside (52). Donor 48 (114 mg, 0.2 mmol) was glycosylated with
acceptor 26 as described as in the general procedure for glycosy-
lations of thioglycuronates, yielding disaccharide 52 (159 mg, 86%)
as a mixture of anomers (R/ꢀ: 1/0.6): IR (neat) 737, 826, 914, 991,
1030, 1088, 1180, 1219, 1288, 1366, 1454, 1508, 1747, 2203, 2870,
1
Methyl 2,3,4-Tri-O-benzyl-6-O-(2,3,4-tri-O-benzyl-r/ꢀ-D-an-
tiaropyranoside)-r-D-glucopyranoside (41). Antiaromatic pyra-
noside 38 (79 mg, 0.15 mmol) was glycosylated with acceptor 25
as described in the general procedure for glycosylations of
thioglycosides, affording the title compound 41 (89 mg, 67%) as a
mixture of anomers (R/ꢀ: 1/0.08): IR (neat) 633, 694, 1026, 1069,
3032 cm-1; H NMR (400 MHz) δ ) 3.49 (s, 1.2 H), 3.53 (s, 0.6
H), 3.54-3.67 (m, 4.6 H), 3.70-3.73 (m, 3.2 H), 3.75-3.83 (m,
6.7 H), 3.85-3.87 (d, J ) 6.8 Hz), 3.97 (dd, 1.5 H, J ) 3.6 Hz, J
) 10 Hz, H-3′R), 4.05 (dd, 0.7 H, J ) 3.6 Hz, J ) 10 Hz, H-3′ꢀ),
4.10-4.25 (m, 5H), 4.37-4.42 (m, 3.4 H), 4.80-4.88 (m, 3.6 H),
4.91-5.10 (m, 2.5 H), 5.13 (d, 0.6 H, J ) 7.3 Hz, H-1′ꢀ), 5.29 (d,
1H, J ) 3.6 Hz, H-1′R), 5.60 (s, 1H, CHPh benzylidene R), 5.67
(s, 0.6 H, CHPh benzylidene ꢀ), 6.85-6.88 (m, 3.7 H, H arom
pMP), 7.09-7.40 (m, 47 H, H arom), 7.45-7.48 (m, 2.4 H, H
arom), 7.62-7.64 (m, 3.6 H, H arom); 13C NMR (100 MHz) δ )
52.2 (CO2CH3 R), 52.3 (CO2CH3 ꢀ), 55.5 (OCH3 pMP), 66.2, 66.5,
68.8, 69.2, 70.2, 71.2, 72.1, 74.1, 74.4, 74.7, 74.9, 75.0, 74.4, 75.0,
75.5, 75.7, 75.9, 76.5, 78.6, 78.8, 79.2, 79.7, 80.9, 81.0, 83.5, 92.7
(C-1′R), 100.6, 101.3, 103.0 (C-1 R and ꢀ), 103.1, 103.4 (C-1′R),
114.4 (CH arom pMP), 118.8 (CH arom pMP), 126.2-129.0 (CH
arom Ph), 137.5 (Cq Ph), 137.7 (Cq Ph), 137.8 (Cq Ph), 138.0 (Cq
Ph), 138.0 (Cq Ph), 138.1 (Cq Ph), 138.2 (Cq Ph), 138.3 (Cq Ph),
138.4 (Cq Ph), 151.4 (Cq Ph), 151.5 (Cq Ph), 155.2 (Cq Ph), 155.3
(Cq Ph), 169.1 (CdO CO2Me ꢀ), 170.3 (CdO CO2Me R); HRMS
[M + Na]+ calcd for C55H56O13Na 947.36131, found 947.36208.
Methyl 2,3,4-Tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-r/ꢀ-
D-glucospyranoside)-r-D-glucopyranoside (51). Donor 49 (127
mg, 0.2 mmol) was glycosylated with acceptor 25 in the same way
as described in the general procedure for glycosylations of
thioglycosides, affording the title compound 51 (148 mg, 75%) as
a mixture of anomers (R/ꢀ: 1/1.4): IR (neat) 737, 826, 910, 1042,
1069, 1157, 1207, 1265, 1327, 1362, 1454, 1497, 1585, 2870, 2905,
3032, 3063 cm-1; 1H NMR (400 MHz) δ ) 3.29 (s, 5.1 H, OCH3),
3.41-3.44 (m, 1 H), 3.47-3.52 (m, 5.4 H, OCH3), 3.54-3.63 (m,
4H), 3.71-4.00 (m, 10 H), 4.14 (d, 1H, J ) 10 Hz), 4.31 (d, 1 H,
J ) 7.6 Hz, H-1′ꢀ), 4.34-4.44 (m, 3.6 H), 4.50-4.63 (m, 6.6 H),
4.75-4.86 (m, 6.5 H), 4.90-4.97 (m, 4H), 5.00 (d, 1.4 H, J ) 3.2
Hz, H-1′R), 7.15-7.32 (m, 35 H, 35 × H arom); 13C NMR (100
MHz) δ ) 55.0 (OCH3 R), 55.1 (OCH3 ꢀ), 66.3, 68.5, 68.6, 68.9,
69.3, 69.8, 70.2, 72.4, 72.7, 72.8, 73.2, 73.3, 73.4, 73.5, 74.5, 74.7,
74.7, 74.9, 75.0, 75.1, 75.6, 75.6, 76.5, 77.9, 78.1, 78.2, 78.2, 78.8,
80.1, 81.9, 82.0, 82.2, 97.8 (C-1′R), 104.2 (C-1′ꢀ), 127.3- 128.3
(CH arom), 137.8 (Cq Ph), 138.0 (Cq Ph), 138.1 (Cq Ph), 138.1 (Cq
Ph), 138.3 (Cq Ph), 138.4 (Cq Ph), 138.7 (Cq Ph), 138.7 (Cq Ph),
138.8 (Cq Ph); HRMS [M + NH4]+ calcd for C62H70O11N:
1004.49434, found 1004.49587.
1
1358, 2341, 2870, 3028 cm-1; H NMR (400 MHz) δ ) 1.07 (d,
3H, J ) 6.4 Hz, H-6′), 3.29 (s, 3H, CH3 OMe), 3.31-3.33 (m,
1H), 3.43 (dd, 1H, J ) 3.6 Hz, 9.6 Hz), 3.66-3.78 (m, 3H),
3.81-3.82 (m 2H), 3.93-4.00 (m 2H), 4.30 (dq, 1H, J ) 1.2 Hz,
6.4 Hz, H-5′), 4.39 (d, 1H, J ) 12 Hz, CH2 Bn), 4.47-4.81 (m,
12H), 4.93 (d, 1H, J ) 10.8 Hz, CH2 Bn), 5.00 (d, 1H, J ) 2.8 Hz,
H-1′), 7.13-7.38 (m, 30H, H arom); 13C NMR (100 MHz) δ )
15.6 (C-6′), 54.9 (CH3 OMe), 62.7 (C-5′), 66.9 (C-6), 70.1, 71.1,
72.7, 73.1, 73.3, 73.5, 73.9, 74.8, 75.5, 77.7, 77.9, 80.1, 82.0, 97.8
(C-1′), 97.9 (C-1), 127.0-128.8 (CH arom), 137.9-139.0 (Cq
arom); HRMS [M + Na]+ calcd for C55H60O10Na 903.4079, found
903.4073.
p-Methoxyphenyl 2-O-Benzyl-3-O-(2,3,4-tri-O-benzyl-r/ꢀ-D-
antiapyranoside)-4,6-benzylidene-ꢀ-D-galactopyranoside (44). An-
tiaromatic pyranoside 38 (79 mg, 0.15 mmol) was glycosylated with
acceptor 26 as described in the general procedure for glycosylations
of thioglycosides, affording the title compound 44 (93 mg, 70%)
as a mixture of anomers (R/ꢀ: 1/0.15): IR (neat) 694, 733, 995,
1
1026, 1060, 1219, 1454, 1504, 2341, 2870 cm-1; H NMR (400
MHz) δ ) 0.91 (d, 3H, J ) 6.8 Hz, H-6′), 3.24 (d, 1H, J ) 2.4
Hz), 3.45 (s, 1H), 3.73 (s, 3H, CH3 pMP), 3.87-3.92 (m, 2H),
3.96 (dd, 1H, J ) 3.6 Hz, 10 Hz), 4.03-4.07 (m, 2H), 4.32-4.39
(m, 4H), 4.45 (q, 1H, J ) 6 Hz, H-5′), 4.49 (d, 1H, J ) 12 Hz,
CH2 Bn), 4.57 (d, 1H, J ) 12 Hz, CH2 Bn), 4.62 (d, 1H, J ) 11.6
Hz, CH2 Bn), 4.69 (d, 1H, J ) 10.8 Hz, CH2 Bn), 4.73 (d, 1H, J
) 10.8 Hz, CH2 Bn), 4.85 (d, 1H, J ) 11.6 Hz, CH2 Bn), 4.90 (d,
1H, J ) 7.6 Hz, H-1), 5.24 (d, 1H, J ) 3.6 Hz, H-1′), 5.52 (s, 1H,
CHPh), 6.76-7.54 (m, 29H, H arom); 13C NMR (100 MHz) δ )
55.5 (CH3 pMP), 65.2 (C-5′), 66.3, 69.1, 69.3, 70.6, 71.3, 72.4,
72.5, 72.6, 73.3, 73.7, 74.6, 74.7, 76.0, 76.3, 91.9 (C-1′), 101.0
(CHPh), 102.9 (C-1), 114.3 (CH pMP), 118.9 (CH pMP),
126.3-128.8 (CH arom), 137.7-139.1 (Cq arom), 151.8 (Cq pMP),
155.1 (Cq pMP); HRMS [M + Na]+ calcd for C54H56O11Na
903.3715, found 903.3712.
Methyl 2,3,4-Tri-O-benzyl-6-O-(methyl 2,3,4-tri-O-benzyl-r/
ꢀ-D-glucopyranosyluronate)-r-D-glucopyranoside (50). Donor 48
(114 mg, 0.2 mmol) was condensed with acceptor 25 following
the general procedure for glycosylations of thioglycuronates, giving
disaccharide 50 (0.14 mmol, 68%) as a mixture of anomers (R/ꢀ:
1/1.4): IR (neat) 737, 914, 1030, 1072, 1088, 1157, 1138 1200,
p-Methoxyphenyl-2-O-Benzyl-(2,3,4,6-tetra-O-benzyl-r/ꢀ-D-
glucospyranoside)-4,6-benzylidene-ꢀ-D-galactopyranoside (53).
Donor 49 (127 mg, 0.2 mmol) was condensed with acceptor 26
according to the general procedure for glycosylations of thiogly-
cosides, delivering disaccharide 53 (176 mg, 89%) as a mixture of
anomers (R/ꢀ: 1/1.7): IR (neat) 737, 826, 1003, 1030, 1065, 1219,
1
1285, 1358, 1454, 1497, 1751, 2912, 3032, 3063 cm-1; H NMR
1
(400 MHz) δ ) 3.35 (s, 3H, CO2CH3 ꢀ), 3.37 (s, 1.9 H, CO2CH3
R), 3.42-3.60 (m, 1.6 H), 3.48-3.56 (m, 3.5 H), 3.57-3.65 (m, 5
1362, 1454, 1504, 2866, 3032 cm-1; H NMR (400 MHz) δ )
3.37-3.41 (m, 3H), 3.48-3.59 (m, 5H), 3.61-3.69 (m, 3.8 H),
J. Org. Chem. Vol. 74, No. 14, 2009 4989

Dinkelaar et al.
3.73 (s, 3H, OCH3 ꢀ), 3.74 (s, 1.8 H, OCH3 R), 3.90 (dd, 0.8 H, J
) 3.6 Hz, 10.0 Hz), 3.97-4.01 (m, 2.2 H), 4.03-4.06 (d, 0.8 H,
J ) 8.0 Hz), 4.10-4.19 (m, 3.3 H), 4.26-4.35 (m, 4.3 H),
4.44-4.51 (m, 4H), 4.54-4.60 (m, 3.6 H), 4.78-4.89 (m, 8.9 H),
4.95-5.04 (m, 4.8 H), 5.21 (d, 1H, J ) 3.6 Hz, H-1′R), 5.55 (s,
0.6 H, CHPh benzylidene R), 5.60 (s, 1H, CHPh benzylidene ꢀ),
6.79-6.82 (m, 3.7 H, H arom pMP), 7.03-7.36 (m, 60 H, H arom),
7.60-7.62 (m, 3.6 H, H arom); 13C NMR (100 MHz) δ ) 55.5
(OCH3 pMP ꢀ), 55.5 (OCH3 pMP R), 66.3, 66.6, 68.3, 68.8, 68.9,
69.8, 71.2, 71.8, 73.0, 74.1 (R), 74.4 (CH2Ph R), 74.4 (CH2 Bn
ꢀ), 74.4 (CH2 Bn ꢀ), 74.8 (ꢀ), 74.9 (CH2 Bn R), 74.9 (CH2 Bn ꢀ),
75.5 (CH2 Bn ꢀ), 75.6 (CH2 Bn R), 75.6 (CH2 Bn R), 75.9 (ꢀ),
76.2 (ꢀ), 76.5 (R), 77.5 (R), 77.7 (ꢀ), 78.7 (ꢀ), 79.2 (R), 81.6 (ꢀ),
81.9 (R), 84.4 (ꢀ), 92.0 (1′ R), 100.6 (CHPh benzylidene), 101.4
(CHPh benzylidene), 103.2 (C-1 ꢀ), 103.2 (C-1 R), 103.5 (C-1′
ꢀ); HRMS [M + Na]+ calcd for C61H62O12Na 1009.41335, found
1009.41410.
Methyl 2,3,4-Tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-r/ꢀ-
D-allopyranoside)-r-D-glucopyranoside (57). Allopyranoside 55
(95 mg, 0.15 mmol) was condensed with acceptor 25 according to
the general procedure for glysolylations of thioglycosides, yielding
disaccharide 57 (136 mg, 92%) as a mixture of anomers (R/ꢀ: 1/0.5):
IR (neat) 729, 910, 1026, 1049, 1072, 1207, 1265, 1327, 1362,
1
1454, 1497, 2870, 3032 cm-1; H NMR (600 MHz) δ ) 3.26 (s,
3H), 3.31-3.33 (m, 2H), 3.39 (dd, 0.5 H, J ) 3.6 Hz, 9.6 Hz,
H-2R), 3.43-3.46 (m, 1.6 H), 3.51 (dd, 1H, J ) 3.6 Hz, 9.6 Hz,
H-2ꢀ), 3.55-3.60 (m, 2.5 H), 3.65-3.74 (m, 6.3 H), 3.93 (t, 1H,
J ) 9.0 Hz), 3.97-4.00 (m, 1.5 H), 4.11 (m, 0.4 H), 4.17-4.18
(m, 1.5 H), 4.23-4.25 (m, 1H), 4.37 (d, 1H, J ) 7.6 Hz), 4.37 (d,
0.5 H, J ) 7.6 Hz), 4.44 (d, 1H, J ) 8.0 Hz), 4.48-4.69 (m, 13
H), 4.73 (d, 0.5 H), 4.77-4.85 (m, 4.3 H), 4.90-4.97 (m, 3.2 H),
5.1 (d, 1H, J ) 3.0 Hz, H-1′ R), 7.07-7.36 (m, 53H, 5 H arom);
13C NMR (125 MHz) δ ) 54.9 (OCH3 ꢀ), 55.1 (OCH3 R), 66.2
(R), 66.6, 68.1, 68.6, 69.4, 69.9, 70.4, 70.6, 70.8 (CH2 Bn R), 71.5
(CH2Ph ꢀ), 72.6 (CH2 Bn ꢀ), 72.8 (R), 73.3 (CH2 Bn ꢀ), 73.3 (CH2
Bn R), 73.4 (CH2 Bn R), 73.5 (CH2 Bn R), 74.0 (CH2 Bn R), 74.4
(R), 74.5 (CH2 Bn R), 74.6 (ꢀ), 74.8 (CH2 Bn R), 75.0 (CH2 Bn
ꢀ), 75.5 (CH2 Bn R), 75.6 (ꢀ), 75.6 (R), 75.6 (CH2 Bn ꢀ), 76.7 (ꢀ),
77.8 (ꢀ), 77.8 (R), 79.0 (ꢀ), 79.6 (ꢀ), 80.1 (R), 82.0 (R), 97.6 (C-
1′R), 97.9 (C-1 R), 98.0 (C-1 ꢀ), 101.1 (C-1′ꢀ), 127.0-128.4 (CH
arom), 137.8 (Cq Ph), 138.1 (Cq Ph), 138.1 (Cq Ph), 138.3 (Cq Ph),
138.3 (Cq Ph), 138.4 (Cq Ph), 138.5 (Cq Ph), 138.7 (Cq Ph), 138.8
(Cq Ph), 138.9 (Cq Ph), 139.0 (Cq Ph), 137.4 (Cq Ph); 13C-GATED
Methyl 2,3,4-Tri-O-benzyl-6-O-(methyl 2,3,4-tri-O-benzyl-r/
ꢀ-D-allopyranosyluronate)-r-D-glucopyranoside (56). Alluronic
acid 54 (86 mg, 0.15 mmol) was condensed with glucoside 25 (105
mg, 0.225 mmol, 1.5 equiv) following the general procedure for
glycosylations of thioglycuronates, yielding 56 (126 mg, 76%) as
a mixture of anomers (R/ꢀ: 1/0.4): IR (neat) 737, 914, 1026, 1072,
1088, 1161, 1204, 1281, 1327, 1362, 1454, 1497 1747, 2905, 3032,
1
3063 cm-1; H NMR (400 MHz) δ ) 3.26 (s, 3H, C-1-OCH3R),
3.30 (s, 1.1 H, C-1-OCH3 ꢀ), 3.37 (dd, 1H, J ) 3.6 Hz, 9.6 Hz),
3.45-3.53 (m, 2H), 3.56 (dd, 1H, J ) 2.4 Hz, 9.6 Hz), 3.67-3.68
(m, 4H), 3.70 (s, 3H, CO2CH3 R), 3.91-3.99 (m, 2H), 4.06-4.17
(m, 0.4 H), 4.15 (m, 1H), 4.38 (d, 1H, J ) 12.0 Hz, CH2 Bn),
4.42-4.70 (m, 10H), 4.73-4.98 (m, 3H), 5.08 (d, 1H, J ) 4.0 Hz,
H-1R), 7.10-7.37 (m, 45H, 4 H arom); 13C NMR (100 MHz) δ )
52.1 (OCH3 ꢀ), 52.1 (OCH3 R), 54.9 (CO2CH3 R), 55.1 (CO2CH3
ꢀ), 67.1 (R), 67.2 (C-6 R), 68.5 (C-6 ꢀ), 69.9 (ꢀ), 70.4 (CR), 70.8
(CH2 Bn R), 71.2 (CH2 Bn R), 71.9 (CH2 Bn ꢀ), 72.5 (ꢀ), 72.9
(CH2 Bn ꢀ), 73.2 (ꢀ), 73.3 (CH2 Bn ꢀ), 74.0 (CH2 Bn ꢀ), 74.5 (ꢀ),
75.0 (CH2 Bn R, 76.0 (R), 76.9 (R), 77.2 (ꢀ), 77.8 (R), 77.9 (ꢀ),
78.3 (ꢀ), 79.7 (ꢀ), 80.1 (R), 82.0 (R), 97.8 (C-1′R), 97.9 (C-1 R),
101.3 (C-1′ ꢀ); 13C GATED NMR (100 MHz) δ ) 97.8
NMR (100 MHz) δ ) 97.6 (JC-1′R,
) 167 Hz), 101.1
H-1′R
(JC-1′ꢀ, H-1′ꢀ ) 162 Hz); HRMS [M + NH4]+ calcd for C62H70O11N
1004.49434, found 1004.49594.
p-Methoxyphenyl 2-O-Benzyl-(2,3,4,6-tetra-O-benzyl-r/ꢀ-D-
allopyranoside)-4,6-benzylidene-ꢀ-D-galactopyranoside (59). Al-
lopyranoside 55 (95 mg, 0.15 mmol) was condensed with acceptor
26 according to the general procedure for glycosylations of
thioglycosides, affording disaccharide 59 (105 mg, 71%) as a
mixture of anomers (R/ꢀ: 1/0.56). R Isomer: [R]22D ) +11.3 (c )
0.6, DCM); IR (neat) 729, 826, 907, 999, 1026, 1061, 1096, 1146,
1
1180, 1219, 1265 1366, 1393, 1454, 1504, 2866, 3032 cm-1; H
NMR (400 MHz) δ ) 3.40-3.45 (m, 3H, H-5, H-6′, H-6′),
3.56-3.59 (m, 2H, H-2′, H-4′), 3.76 (s, 3H, OCH3 pMP), 3.98-4.00
(m, 2H, H-3, H-2), 4.08 (d, 1H, J ) 11.2 Hz, CH2 Bn), 4.32-4.59
(m, 10H, H-4, H-3′, H-5′, CH2 Bn), 4.66 (d, 1H, J ) 11.6 Hz, CH2
Bn), 4.78-4.83 (m, 2H, H-1, CH2 Bn), 4.99 (d, 1H, J ) 11.6 Hz,
CH2 Bn), 5.30 (d, 1H, J ) 4.0 Hz, H-1′), 5.57 (s, 1H, CHPh
benzylidene), 6.78-6.80 (m, 2H, H arom), 7.02-7.36 (m, 28H, H
arom), 7.44-7.47 (m, 2H, H arom), 7.55-7.57 (m, 2H, H arom);
13C NMR (100 MHz) δ ) 55.6 (OCH3 pMP), 65.9 (C-5′), 66.4
(C-5), 68.7 (C-6′), 69.3 (C-6), 70.6 (CH2 Bn), 70.6 (CH2 Bn), 71.6
(C-4), 73.0 (CH2 Bn), 73.5 (C-3), 74.2 (CH2 Bn), 74.6 (C-4′or C-2′),
74.7 (C-3 or C-2), 74.8 (CH2 Bn), 76.2 (C-3 or C-2), 76.8 (C-2′ or
C-4′), 92.4 (C-1′), 100.9 (CHPh benzylidene), 103.1 (C-1), 114.3
(CH arom pMP), 118.9 (CH arom pMP), 126.3-129.1 (CH arom),
137.7 (Cq Ph), 138.0 (Cq Ph), 138.2 (Cq Ph), 138.4 (Cq Ph), 138.5
(Cq Ph), 139.4 (Cq Ph), 151.8 (Cq pMP), 155.1 (Cq pMP); 13C-
(JC-1′R,
) 167 Hz, C-1′R), 97.9 (JC-1R,
) 166 Hz, C-1R);
H-1R
H-1′R
HRMS [M + NH4]+ calcd for C56H64O12N 942.44230, found
942.44368.
p-Methoxyphenyl 2-O-Benzyl-3-O-(methyl 2,3,4-tri-O-benzyl-
r-D-allopyranosyluronate)-4,6-benzylidene-ꢀ-D-galactopyrano-
side (58). Alluronic acid 54 (86 mg, 0.15 mmol) was glycosylated
with galactoside 26 (105 mg, 0.225 mmol, 1.5 equiv) as described
in the general procedure for glycosylations of thioglycuronates
giving R-linked disaccharide 58 (72 mg, 52%) as transparent oil:
[R]22D ) +26.3 (c ) 0.2, DCM); IR (neat) 729, 826, 895, 999,1030,
1061, 1096, 1180, 1215, 1265, 1366, 1454, 1508, 1744, 2866, 3055
1
cm-1; H NMR (400 MHz) δ ) 3.46 (s, 1H, H-5), 3.54 (s, 3H,
CO2CH3), 3.58 (t, 1H, J ) 3.6 Hz, H-2′), 3.61 (dd, 1H, J ) 9.6
Hz, 2.4 Hz, H-4′), 3.75 (s, 3H, OCH3 pMP), 3.99-4.09 (m, 3H,
H-2, H-4, H-6), 4.27 (m, 1H, H-3′), 4.34-4.40 (m, H-3, H-6, CH2
Bn), 5.52 (d, 1H, J ) 11.6 Hz, CH2 Bn), 4.56 (d, 1H, J ) 10.4 Hz,
CH2 Bn), 4.61 (d, 1H, J ) 11.2 Hz, CH2 Bn), 4.71 (d, 1H, J )
10.4 Hz, CH2 Bn), 4.80 (d, 1H, J ) 11.6 Hz, CH2 Bn), 4.89-4.95
(m, 3H, H-5′, H-1, CH2 Bn), 5.33 (d, 1H, J ) 4.0 Hz, H-1′), 5.55
(s, 1H, CHPh benzylidene), 6.77 (d, 2H, J ) 9.2 Hz, H arom),
7.00 (d, 2H, J ) 6.8 Hz, H arom), 7.02-7.30 (m, 23H, 2 H arom),
7.51-7.58 (m, 2H, H arom); 13C NMR (100 MHz) δ ) 52.1
(CO2CH3), 55.6 (OCH3 pMP), 66.3 (C-5), 67.0 (C-5′), 69.3 (C-6),
70.8 (CH2 Bn), 71.0 (CH2 Bn), 71.5 (C-3), 73.2 (C-3′), 74.1 (CH2
Bn), 75.0 (CH2 Bn), 75.4 (C-2), 76.0 (C-4), 76.3 (C-2′), 77.0 (C-
4′), 92.5 (C-1′), 101.0 (CHPh benzylidene), 102.8 (C-1), 114.3 (CH
arom pMP), 118.8 (CH arom pMP), 126.3, 137.1-128.9 (CH arom),
137.7-139.0 (Cq arom), 151.7 (Cq pMP), 155.1 (Cq pMP), 171.5
(CdO CO2Me); 13C-GATED NMR (100 MHz) δ ) 92.4 (JC-1′, H-1′
GATED NMR (100 MHz) δ ) 92.4 (JC-1′,
) 162 Hz, C-1′),
H-1′
103.1 (JC-1,
) 154 Hz, C-1); HRMS [M + NH4]+ calcd for
H-1
C61H66O12N 1004.45795, found 1004.45933. ꢀ Isomer: [R]22
)
D
+32.3 (c ) 1.2, DCM); IR 737, 826, 1003, 1092 1223, 1366, 1454,
1504, 2866 cm-1; 1H NMR (400 MHz) δ ) 3.31 (dd, 1H, J ) 7.6
Hz, 2.4 Hz, H-2′), 3.42-3.46 (m, 2H, H-4′, H-5), 3.65 (dd, 1H, J
) 4.8 Hz, 10.8 Hz, H-6′), 3.73 (dd, 1H, J ) 10.8 Hz, 2.0 Hz, H-6),
3.76 (s, 3H, OCH3 pMP), 3.96-3.99 (m, 2H, H-3, H-6), 4.04-4.14
(m, 3H, H-5′, H-2, H-3′), 4.29-4.34 (m, 2H, H-6, H-4), 4.43 (d,
1H, J ) 11.6 Hz, CH2 Bn), 4.49 (d, 1H, J ) 8.8 Hz, CH2 Bn),
4.58 (d, 1H, J ) 12.4 Hz, CH2 Bn), 4.76 (d, 1H, J ) 12.0 Hz, CH2
Bn), 4.80-4.93 (m, 6H, H-1, CH2 Bn), 5.42 (d, 1H, J ) 8.0 Hz,
H-1′), 5.56 (s, 1H, CHPh benzylidene), 6.79 (d, 2H, J ) 6.8 Hz, H
arom), 7.02-7.39 (m, 32H, 3 H arom), 7.39-7.61 (m, 2H, H arom);
13C NMR (100 MHz) δ ) 55.6 (OCH3 pMP), 66.6 (C-4′), 69.0
(C-6), 69.53 (C-6′), 71.4 (CH2 Bn), 72.0 (C-5′), 72.9 (CH2 Bn),
) 164 Hz, C-1′), 102.7 (JC-1,
) 160 Hz, C-1); HRMS [M +
H-1
NH4]+ calcd for C55H60O13N 942.40592, found 942.40719.
4990 J. Org. Chem. Vol. 74, No. 14, 2009

Pyranosyl C-5 Substituent in Gly1cosylation Reactions
73.4 (CH2 Bn), 74.2 (CH2 Bn), 74.4 (C-2), 75.2 (CH2 Bn), 75.7
(C-5), 77.0 (C-4), 77.3 (C-4), 78.3 (C-3′), 78.7 (C-2′), 100.8 (CHPh
benzylidene), 101.9 (C-1′), 103.3 (C-1), 114.4 (CH arom pMP),
119.1 (CH arom pMP), 126.4-128.7 (CH arom), 137.8 (Cq Ph),
138.2 (Cq Ph), 138.3 (Cq Ph), 138.4 (Cq Ph), 138.7 (Cq Ph), 139.1
(Cq Ph), 151.7 (Cq pMP), 155.3 (Cq pMP); HRMS [M + NH4]+
calcd for C61H66O12N 1004.45795, found 1004.45938.
pMP), 168.8 (CdO CO2Me R); HRMS [M + NH4]+ calcd for
C55H60O13N 942.40592, found 942.40733.
Methyl 2,3,4-Tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-r/ꢀ-
D-galactopyranoside)-r-D-glucopyranoside (63). Galactoside 61
(127 mg, 0.20 mmol) was condensed with glucoside 25 (139 mg,
0.30 mmol, 1.5 equiv) according to the general procedure for
glycosylations of thioglycosides, yielding 63 (132 mg, 67%) as a
mixture of anomers (R/ꢀ: 1/3): IR (neat) 733, 818, 910, 1026, 1065,
1092, 1157, 1207, 1265, 1362, 1454, 1497, 1585, 1605, 1956, 2870,
3032, 3063 cm-1; 1H NMR (400 MHz) δ ) 3.33 (s, 3H, OCH3 ꢀ),
3.35 (s, 1H, OCH3 R), 3.43-3.73 (m, 12 H), 3.71-3.84 (m, 1.7
H), 3.96-4.02 (m, 1.7 H), 4.18 (d, 1H, J ) 10.4 Hz, CH2 Bn),
4.35 (d, 1H, J ) 8.0 Hz, H-1′ ꢀ), 4.40-4.47 (m, 0.7 H), 4.50-4.66
(m, 8 H), 4.69-4.84 (m, 8 H), 4.91 (m, 1.6 H, CH2 Bn), 4.97 (m,
2 H, CH2 Bn and C-1′ R), 7.13-7.42 (m, 59H, 5 H arom); 13C
NMR (100 MHz) δ ) 55.1 (OCH3 R), 55.1 (OCH3 ꢀ), 66.0, 68.4,
68.5, 69.8, 70.2, 70.3, 72.3 (CH2 Bn), 73.3 (CH2 Bn), 74.8 (CH2
Bn), 74.9 (CH2 Bn), 75.0, 75.4 (CH2 Bn), 75.6 (CH2 Bn), 75.6
(CH2 Bn), 77.5, 77.7, 77.8, 77.9, 79.7, 79.9, 80.1, 81.6, 81.9, 82.0,
84.7, 97.2 (C-1′R), 97.9 (C-1 R), 98.0 (C-1 ꢀ), 103.7 (C-1′ꢀ),
127.5-128.4 (CH arom), 138.0 (Cq Ph), 138.1 (Cq Ph), 138.1 (Cq
Ph), 138.2 (Cq Ph), 138.3 (Cq Ph), 138.3 (Cq Ph), 138.5 (Cq Ph),
138.8 (Cq Ph); HRMS [M + NH4]+ calcd for C62H70O11N
1004.49434, found 1004.49583.
Methyl 2,3,4-Tri-O-benzyl-6-O-(methyl 2,3,4-tri-O-benzyl-r/
ꢀ-D-galactopyranosyluronate)-r-D-glucopyranoside (62). Galac-
turonic acid 60 (114 mg, 0.20 mmol) was condensed with glucoside
25 (139 mg, 0.30 mmol) as described in the general procedure for
glycosylations of thioglycuronates yielding 62 (91 mg, 49%) as a
mixture of anomers (R/ꢀ: 1/2.3): IR (neat) 733, 818, 914, 1026,
1049, 1068, 1092, 1211, 1269, 1358, 1454, 1497, 1605, 1732, 1767,
1
2870, 3032 cm-1; H NMR (400 MHz) δ ) 3.28 (s, 3 H, OCH3
R), 3.29 (s, 8 H, OCH3 ꢀ), 3.40 (dd, 1H, J ) 3.6 Hz, J ) 9.6 Hz),
3.44-54 (m, 10 H), 3.58 (s, 3H, CO2CH3 R), 3.62 (s, 7H, OCH3
pMP, CO2CH3 ꢀ), 3.65 (dd, 2H, J ) 5.6 Hz, 10.8 Hz), 3.85-3.89
(m, 7H), 3.91-4.02 (m, 5H), 4.06 (dd, 1H, J ) 3.6 Hz, 9.6 Hz),
4.20-4.23 (m, 6H), 4.29 (d, 2H, J ) 8.0 Hz), 4.40 (bs, 1H),
4.50-4.72 (m, 16 H), 4.73-4.83 (m, 4 H), 4.97 (dd, 6H, J ) 2.0
Hz, 10.8 Hz), 5.07 (d, 1H, J ) 3.6 Hz, H-1′R), 7.18-7.36 (m, 16
H, H arom Ph); 13C NMR (100 MHz) δ ) 53.0 (OCH3 C-1-OCH3),
55.0 (OCH3 CO2CH3), 66.8 (C-6 R), 68.6 (C-6 ꢀ), 69.9 (ꢀ), 70.1
(R), 70.7 (R), 72.7 (CH2 Bn R), 72.9 (CH2 Bn R), 73.2 (CH2 Bn
R), 73.2 (CH2 Bn ꢀ), 73.8 (ꢀ), 74.4, 74.7 (CH2 Bn R), 74.9 (ꢀ),
75.0 (CH2 Bn ꢀ), 75.5 (CH2 Bn ꢀ), 75.6 (CH2 Bn R), 75.8 (R),
76.5 (R), 77.2 (R), 77.8 (R), 79.8 (ꢀ), 78.0 (R), 81.3 (ꢀ), 81.9 (ꢀ),
82.0 (R), 97.7 (C-1 ꢀ), 97.7 (C-1 R), 98.1 (C-1′R), 103.7 (C-1′ꢀ),
137.3-128.3 (CH arom), 138.0-138.8 (Cq arom), 168.4 (CdO
CO2CH3 ꢀ), 169.2 (CdO CO2CH3 R); HRMS [M + NH4]+ calcd
for C56H64O12N 942.44230, found 942.44373.
p-Methoxyphenyl 2-O-Benzyl-(2,3,4,6-tetra-O-benzyl-r/ꢀ-D-
galactospyranoside)-4,6-benzylidene-ꢀ-D-galactopyranoside (65).
Galactoside 61 (127 mg, 0.20 mmol) was glycosylated with
galactoside 26 (139 mg, 0.30 mmol, 1.5 equiv) following the general
procedure for glycosylations of thioglycosides, giving disaccharide
65 (0.142 mg, 72%) as a mixture of anomers (R/ꢀ: 1/0.1): IR (neat)
737, 826, 907, 999, 1061, 1099, 1223, 1312, 1366, 1454, 1504,
1
2168, 2866, 3032 cm-1; H NMR (400 MHz) δ ) 5.24 (d, 1H, J
) 3.6 Hz, H-1′R), 5.50 (s, 1H, CHPh-R benzylidene), 5.55 (s, 0.1
H, CHPh-ꢀ benzylidene). R Anomer: 3.25-3.29 (m, 2H, H-5, H-6′),
3.53-3.57 (m, 1H, H-6′), 3.69 (d, 1H, J ) 2.0 Hz, H-4′), 3.73 (s,
3H, OCH3 pMP), 3.88 (dd, 1H, J ) 3.2 Hz, 10.0 Hz, H-3),
3.92-3.99 (m, 2H, H-3′, H-6), 4.07 (d, 1H, J ) 3.6 Hz, H-2′),
4.09-4.14 (m, 1H, H-2), 4.18 (t, 1H, J ) 6.4 Hz, H-5′), 4.26-4.29
(m, 4H, H-6, H-4, CH2 Bn), 4.53 (d, 1H, J ) 11.6 Hz, CH2 Bn),
4.58 (m, 2H, CH2 Bn), 4.66 (d, 1H, J ) 12.0 Hz, CH2 Bn),
4.76-4.81 (m, 3H, H-1, CH2 Bn), 4.92 (d, 1 H, CH2 Bn), 5.01 (d,
1H, J ) 10.8 Hz, CH2 Bn), 5.24 (d, 1H, J ) 3.6 Hz, H-1′R), 5.50
(s, 1H, CHPh-R benzylidene), 6.79 (d, 2H, J ) 2.0 Hz, H arom
pMP), 6.81 (d, 2H, J ) 2.0 Hz, H arom pMP), 7.01-7.37 (m, 28
H, 2 H arom Ph), 7.52-7.55 (m, 2H, H arom Ph); 13C NMR (100
MHz) δ ) 55.5 (OCH3 pMP), 66.2 (C-5 or C-5′), 69.3 (C-5 or
C-5′), 69.2 (C-6 or C-6′), 69.3 (C-6 or C-6′), 71.3 (C-4), 71.9 (CH2
Bn), 72.6 (CH2 Bn), 72.9 (CH2 Bn), 73.7 (C-3), 74.6 (CH2 Bn),
75.1 (C-4), 75.2 (CH2 Bn), 76.0 (C-2′), 76.8 (C-2), 78.5 (C-3), 92.6
(C-1′ R), 100.5 (C-1′ꢀ), 101.2 (CHPh benzylidene), 103.1 (C-1 R),
103.6 (C-1 ꢀ); HRMS [M + NH4]+ calcd for C61H66O12N
1004.45795, found 1004.45943.
p-Methoxyphenyl 2-O-Benzyl-3-O-(methyl 2,3,4-tri-O-benzyl-
r/ꢀ-D-allopyranosyluronate)-4,6-benzylidene-ꢀ-D-galactopyra-
noside (64). Galacturonic acid 60 (114 mg, 0.20 mmol) was
glycosylated with glucoside 26 (139 mg, 0.30 mmol, 1.5 equiv) as
described in the general procedure for glycosylations of thiogly-
curonates yielding 64 (159 mg, 86%) as a mixture of anomers (R/
ꢀ: 1/0.4): IR (neat) 737, 826, 922, 999, 1030, 1065, 1096 1219,
1
1366, 1396, 1454, 1504, 1759, 2870, 3032 cm-1; H NMR (400
MHz) δ ) 3.31 (s, 0.7 H, pMP ꢀ), 3.41-3.44 (m, 2H), 3.45 (s,
3H, pMP R), 3.56 (s, 1H, CO2CH3 ꢀ), 3.72 (s, 3H, CO2CH3 R),
3.83 (s, 0.4 H), 3.87 (dd, 1H, J ) 3.2 Hz, J ) 10.0 Hz), 3.95 (dd,
1H, J ) 2.8 Hz, 10.0 Hz), 4.01-4.07 (m, 3H), 4.09-4.17 (m, 3H),
4.28-4.32 (m, 2H), 4.34 (d, 0.4 H, J ) 3.6 Hz), 4.50-4.55 (m,
1.4 H), 4.60 (d, 3H, J ) 12.0 Hz), 4.67 (d, 2H, J ) 11.2 Hz, CH2
Bn), 4.74-4.92 (m, 6H), 4.97 (d, 0.4 H, J ) 8.0 Hz, H-1′ꢀ), 4.53
(d, 1 H, J ) 11.2 Hz, CH2 Bn R), 5.05 (d, 0.4 H, J ) 11.6 Hz,
CH2 Bn ꢀ), 5.28 (d, 1H, J ) 3.6 Hz, H-1′R), 0.55 (s, 1H, CHPh
benzylidene R), 5.61 (s, 0.4 H, CHPh benzylidene ꢀ), 6.78 (d, 3H,
J ) 2.0 Hz, H arom pMP R, pMP ꢀ), 6.80 (s, 3H, J ) 2.0 Hz, H
arom pMP R, pMP ꢀ), 7.02-7.39 (m, 38.5 H, H arom), 7.54-7.56
(m, 2H, H arom), 7.60-7.60 (m, 0.8 H, H arom); 13C NMR (100
MHz) δ ) 51.7 (OCH3 pMP R), 52.0 (OCH3 pMP ꢀ), 55.5
(CO2CH3 R, CO2CH3 ꢀ), 66.3 (R), 66.6 (ꢀ), 68.7 (CH2 Bn ꢀ), 69.1
(CH2 Bn R), 70.5 (R), 71.3 (R), 72.2 (CH2 Bn), 73.2 (CH2 Bn),
73.8 (R), 74.3 (CH2 Bn), 74.6 (CH2 Bn), 74.7 (CH2 Bn), 75.1 (ꢀ),
75.2 (CH2 Bn), 75.3 (R), 75.5 (ꢀ), 76.2 (R), 76.8 (R), 77.6 (R),
78.3 (ꢀ), 79.1 (ꢀ), 81.0 (ꢀ), 93.0 (C-1′R), 100.5 (CHPh benzylidene
ꢀ), 101.1 (CHPh benzylidene R), 103.0 (C-1′ꢀ), 103.1 (C-1 R,
C-1ꢀ), 114.3 (CH arom pMP), 118.6 (CH arom pMP), 126.1-128.8
(CH arom), 137.6-138.5 (Cq arom), 151.4 (Cq pMP), 155.2 (Cq
Acknowledgment. We thank The Netherlands Organisation
for Scientific Research (NWO) for financial support (VENI
fellowship to J.D.C.C.).
Supporting Information Available: General experimental
procedures, synthesis of the glycosyl donors, and NMR spectra
of all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO900662V
J. Org. Chem. Vol. 74, No. 14, 2009 4991