Linear synthesis of a protected H-type II pentasaccharide using glycosyl phosphate building blocks

Article abstract of DOI:10.1021/jo015987h

A linear synthesis of a fully protected H-type II blood group determinant pentasaccharide utilizing glycosyl phosphate and glycosyl trichloroacetimidate building blocks is reported. Envisioning an automated solid-phase synthesis of blood group determinants, the utility of glycosyl phosphates in the stepwise construction of complex oligosaccharides, such as the H-type II antigen, is demonstrated. Installation of the central glucosamine building block required the screening of a variety of nitrogen protecting groups to ensure good glucosamine donor reactivity and protecting group compatibility. The challenge to differentiate C2 of the terminal galactose in the presence of other hydroxyl and amine protecting groups prompted us to introduce the 2-(azidomethyl)benzoyl group as a novel mode of protection for carbohydrate synthesis. The compatibility of this group with traditionally employed protecting groups was examined, as well as its use as a C2 stereodirecting group in glycosylations. The application of the 2-(azidomethyl)benzoyl group along with a systematic evaluation of glycosyl donors allowed for the completion of the pentasaccharide and provides a synthetic strategy that is expected to be generally amenable to the solid support synthesis of blood group determinants.

Full text of DOI:10.1021/jo015987h

J . Org. Chem. 2001, 66, 8165-8176
8165
Lin ea r Syn th esis of a P r otected H-Typ e II P en ta sa cch a r id e Usin g
Glycosyl P h osp h a te Bu ild in g Block s
Kerry Routenberg Love, Rodrigo B. Andrade, and Peter H. Seeberger*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
seeberg@mit.edu
Received J uly 30, 2001
A linear synthesis of a fully protected H-type II blood group determinant pentasaccharide utilizing
glycosyl phosphate and glycosyl trichloroacetimidate building blocks is reported. Envisioning an
automated solid-phase synthesis of blood group determinants, the utility of glycosyl phosphates in
the stepwise construction of complex oligosaccharides, such as the H-type II antigen, is demon-
strated. Installation of the central glucosamine building block required the screening of a variety
of nitrogen protecting groups to ensure good glucosamine donor reactivity and protecting group
compatibility. The challenge to differentiate C2 of the terminal galactose in the presence of other
hydroxyl and amine protecting groups prompted us to introduce the 2-(azidomethyl)benzoyl group
as a novel mode of protection for carbohydrate synthesis. The compatibility of this group with
traditionally employed protecting groups was examined, as well as its use as a C2 stereodirecting
group in glycosylations. The application of the 2-(azidomethyl)benzoyl group along with a systematic
evaluation of glycosyl donors allowed for the completion of the pentasaccharide and provides a
synthetic strategy that is expected to be generally amenable to the solid support synthesis of blood
group determinants.
In tr od u ction
Heliobacter pylori was shown to recognize the Leb antigen
in the gastric epithelium, and this interaction is essential
for bacterial infection leading to gastric ulcers and adeno-
carcinoma.8-10 The H-type II antigenic structure has been
implicated in infection of humans with cholera.11
Carbohydrates play an important role in many cellular
processes, such as recognition, adhesion, and signaling
between cells.1 These processes may be initiated by car-
bohydrates existing as part of a glycoprotein or glycolipid
on the cell surface. One class of glycolipids, glycosphin-
golipids (GSLs), is essential for cellular adhesion and
recognition. The Lewis antigens, a group of fucosylated,
ceramide containing GSLs, have been implicated in a
variety of normal cellular adhesion processes, as well as
adhesion associated with different disease states, includ-
ing many types of metastatic cancer.2,3
Lewis blood group oligosaccharides (Figure 1) occur as
cell surface carbohydrates on healthy leukocytes.4 White
blood cells, are essential for the repair of tissue in the
vicinity of an injury and subsequent defense against
possible microbial infection. The recruitment of leuko-
cytes to a site of injury is brought about in a series of
signaling steps. In response to the cytokines released
by the damaged tissue, the endothelium expresses the
two proteins E- and P-selectin on its surface. These
selectins recognize carbohydrate ligands containing the
Lex and Lea sequences, including sialylated and sulfated
variants.4,5
Lewis antigens like many other glycosphingolipids,3
are tumor markers in human cancers including adeno-
carcinoma,12,13 colorectal cancer,14 pancreatic cancer,15
and breast cancer.16 Although GSLs are present in both
cancerous and normal cellular tissue, their composition
and density are altered in tumors.2 Aberrant glycosyla-
tion in tumor cells helps to promote motility and adhesion
necessary for tumor-cell invasion and progression.2
The widespread biological implications of Lewis anti-
gens have rendered them targets of intense study. Since
only small amounts of pure oligosaccharides can be
obtained from natural sources due to microheterogeneity,
chemical synthesis is the best way to procure appreciable
(6) Holgersson, J .; J oval, P.-A.; Breimer, M. J . Biol. Chem. 1991,
110, 120.
(7) Karlsson, K.-A. Annu. Rev. Biochem. 1989, 58, 309.
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1993, 262, 1892.
(9) Applemelk, B.; Monteiro, M.; Martin, S.; Moran, A.; Vander-
brouke-Grauls, C. Trends Microbiol. 2000, 8, 565.
(10) Wang, G.; Ge, Z.; Rasko, D.; Taylor, D. Mol. Microbiol. 2000,
36, 1187.
(11) Newburg, D. S. Current Med. Chem. 1999, 6, 117.
(12) Hakomori, S.; Nudelman, E.; Levery, S.; Reiji, K. J . Biol. Chem.
1984, 259, 4672.
(13) Blaszczyk, M.; Pak, K.; Hereyl, M.; Sears, H.; Steplewski, Z.
Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 3552.
(14) Nishihara, S.; Hiraga, T.; Ikehara, Y.; Kudo, T.; Iwasaki, H.;
Morozumi, K.; Akamatsu, S.; Tachikawa, T.; Hiashi, N. Glycobiology
1998, 9, 607.
(15) Tempero, M.; Uchida, E.; Takasaki, H., Burnett, D.; Steplewski,
Z.; Pour, P. Cancer Res. 1987, 47, 5501.
In addition to their role in the inflammatory response,
the Lewis antigens are present on the surface of the
endothelium lining of the gastrointestinal tract6 where
they are the point of attachment for pathogenic bacteria.7
(1) Varki, A. Glycobiology 1993, 3, 97.
(2) Hakomori, S.; Zhang, Y. Chem. Biol. 1997, 4, 97.
(3) Hakomori, S. Adv. Cancer Res. 1989, 52, 257.
(4) Simanek, E.; McGarvey, G.; J ablanowski, J .; Wong, C.-H. Chem.
Rev. 1998, 98, 833.
(5) Phillips, L.; Nudleman, E.; Gaeta, F.; Perez, M.; Singhal, A.;
Hakomori, S.; Paulson, J . Science 1990, 250, 1130.
(16) Ura, Y.; Dion, A.; Williams, C.; Olsen, B.; Redfield, E.; Ishida,
M.; Herlyn, M.; Major, P. Int. J . Cancer 1992, 50, 57.
10.1021/jo015987h CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/06/2001

8166 J . Org. Chem., Vol. 66, No. 24, 2001
Love et al.
in synthesis of the Lex trisaccharide and SLex tetrasac-
charides.22,23 The entire family of tri- and tetrameric
Lewis antigens, including SLex, were assembled via the
glycal assembly method.24 Schmidt disclosed Lewis an-
tigen syntheses using trichloroacetimidate donors in a
block coupling strategy to maximize convergence while
exploring a host of amine-protecting groups for construc-
tion of the core glucosamine building block, including
azide,25 tetrachlorophthaloyl,26 dimethylmaleoyl,27 and
trichloroethoxycarbonyl (Troc).28
Recently, we addressed the need for efficient glycosy-
lating agents that could be prepared in differentially
protected form. Using a one-pot procedure, glycosyl phos-
phates were readily prepared from glycals and shown to
selectively and efficiently form a host of glycosidic
linkages.29-32 The scope of these building blocks in the
context of the synthesis of complex carbohydrates in
solution and on solid support has yet to be demonstrated.
Another factor of crucial importance for the synthesis of
complex carbohydrates is the differential protection of
hydroxyl and amino groups. The exploration of novel
modes of protection that are orthogonal to existing
protecting groups and withstand glycosylation conditions
is expected to increase synthetic flexibility in the prepa-
ration of branched structures.
Here we describe the linear solution-phase synthesis
of a fully protected H-type II pentasaccharide. Three
major challenges were addressed during the course of the
synthesis. A strictly linear strategy for the assembly of
oligosaccharides from the reducing end was explored in
anticipation of an automated solid-phase synthesis method
following this paradigm. Second, glycal-derived glycosyl
phosphates were utilized for the installation of glycosidic
linkages. Finally, a variety of protecting groups for
masking the amino group of the central glucosamine
moiety were tested; a new 2-(azidomethyl)benzoate ester
hydroxyl protecting group was employed as a participat-
ing, selectively removable entity. The compatibility of the
2-(azidomethyl)benzoate group with other commonly used
protective groups in natural products synthesis, as well
as its applicability as a stereodirecting group in glyco-
sylation reactions with glycosyl phosphates, glycosyl
F igu r e 1. Lewis blood group oligosaccharides (R ) ceramide).
(22) Lin, C.-C.; Shimazaki, M.; Hack, M.-P.; Aoki, S.; Wang, R.;
Kimura, T.; Ritzen, H.; Takayama, S.; Wu, S.-H.; Weitz-Schmidt, G.;
Wong, C.-H. J . Am. Chem. Soc. 1996, 118, 6826.
(23) Kondo, H.; Aoki, S.; Ichikawa, Y.; Halcomb, R.; Ritzen, H.;
Wong, C.-H. J . Org. Chem. 1994, 59, 864.
amounts of material for biological investigations. The
Lewis blood group antigens have served as a synthetic
challenge prompting the development of new methods for
oligosaccharide synthesis since the seminal work by
Lemieux in the mid 1970s.17,18 Advances in oligosaccha-
ride chemistry, including the development of novel gly-
cosyl donors and a host of new protecting groups, have
since eased the synthesis of complex, branched carbohy-
drates. Hasegawa reported the first synthesis of the sLex
antigen in 1991, utilizing thiogylcosides for the instal-
lation of glycosidic linkages.19 Thioglycosides also have
been used in combination with selective protection in a
one-pot, two-step glycosylation to construct the trimeric
antigens in good yield.20 Kahne and co-workers21 synthe-
sized the Lea, Leb, and Lex trisaccharides using a single
set of sulfoxide donors. Glycosyl phosphites served well
(24) (a) Danishefsky, S.; Gervay, J .; Peterson, J .; McDonald, F.;
Koseki, K.; Oriyama, T.; Griffith, D. J . Am. Chem. Soc. 1992, 114, 8329.
(b) Danishefsky, S.; Gervay, J .; Peterson, J .; McDonald, F.; Koseki,
K.; Griffith, D.; Oriyama, T.; Marsden, S. J . Am. Chem. Soc. 1995,
117, 1940. (c) Danishefsky, S.; Behar, V.; Randolph, J .; Lloyd, K. J .
Am. Chem. Soc. 1995, 117, 5701.
(25) (a) Bommer, R.; Kinzy, W.; Schmidt, R. Liebigs Ann. Chem.
1991, 425. (b) Toepfer, A.; Schmidt, R. Tetrahedron Lett. 1992, 33, 5161.
(c) Windmuller, R.; Schmidt, R. Tetrahedron Lett. 1994, 35, 7927. (d)
Hummel, G.; Schmidt, R. Tetrahedron Lett. 1997, 38, 1173.
(26) (a) Castro-Palomino, J .; Schmidt, R. Tetrahedron Lett. 1995,
36, 5343. (b) Lay, L.; Manzoni, L.; Schmidt, R. Carbohydr. Res. 1998,
310, 157.
(27) (a) Aly, R.; Castro-Palomina, J .; Ibrahim, E.-S.; El-Ashry, E.-
S.; Schmidt, R. Eur. J . Org. Chem. 1998, 2305, 5. (b) Aly, R.; Ibrahim,
E.-S.; El-Ashry, E.-S.; Schmidt, R. Carbohydr. Res. 1999, 316, 121.
(28) Gege, C.; Oscarson, S.; Schmidt, R. Tetrahedron Lett. 2001, 42,
377.
(29) For a detailed description of necessary considerations when
performing solid-phase oligosaccharide synthesis, see: Plante, O. J .;
Palmacci, E. R.; Seeberger, P. H. Science 2001, 291, 1523.
(30) Hewitt, M. C.; Seeberger, P. H. J . Org. Chem. 2001, 66, 4233.
(31) Plante, O. J .; Andrade, R.; Seeberger, P. H. Org. Lett. 1999, 1,
211.
(17) Lemieux, R.; Driguez, H. J . Am. Chem. Soc. 1975, 97, 4063.
(18) Lemieux, R.; Driguez, H. J . Am. Chem. Soc. 1975, 97, 4069.
(19) Kameyama, A.; Ishida, H.; Kiso, M.; Hasegawa, A. J . Carbo-
hydr. Chem. 1991, 10, 549.
(20) Tsukida, T.; Yoshida, M.; Kurokawa, K.; Nakai, Y.; Achiha, T.;
Kiyoi, T.; Konda, H. J . Org. Chem. 1997, 62, 6876.
(32) Plante, O. J .; Palmacci, E. R.; Andrade, R. B.; Seeberger, P. H.
J . Am. Chem. Soc. 2001, 123, 9545.
(21) Yan, L.; Kahne, D. J . Am. Chem. Soc. 1996, 118, 9239.

Synthesis of an H-Type II Pentasaccharide
J . Org. Chem., Vol. 66, No. 24, 2001 8167
Sch em e 1. Retr osyn th esis of P r otected H-Typ e II P en ta sa cch a r id e
Sch em e 2. Syn th esis of La ctose Disa cch a r id es
trichloroacetimidates, and thioglycosides is discussed.
for conversion to the corresponding glycosyl phosphate
The strategy described here for the synthesis of the
H-type II pentasaccharide is representative of the as-
sembly of blood group determinant oligosaccharides in
solution and on solid support.
4 via the one-pot procedure for phosphate preparation.31
Galactose phosphate building block 9 was prepared in
a manner analogous to that for glucose donor 4. Depro-
tection of peracetylated galactal was followed by regio-
selective benzylation of the C4 and C6 hydroxyls using
benzyl bromide and sodium hydride at 0 °C.34 Although
the yield of the desired galactal was low (34%), three
other synthetically useful galactals (tri-O-benzyl galactal
(21%), 3,6-di-O-benzyl galactal (11%), and 3,4-di-O-benzyl
galactal (10%)) were also obtained from this procedure
after silica column chromatography. Protection of the 4,6-
di-O-benzyl galactal as the silyl ether using TBSCl and
imidazole afforded 7 and subsequent conversion to the
glycosyl phosphate produced 9 in good yield.
A reducing end building block was prepared by cou-
pling glucose phosphate 4 with 4-penten-1-ol under the
agency of TBSOTf. Deprotection with TBAF yielded
acceptor 11, ready for coupling with galactose phosphate
9. Union of acceptor 11 and galactosyl phosphate 9
furnished disaccharide 12 in good yield. Removal of the
silyl ether in 12, however, proved difficult and could not
Resu lts a n d Discu ssion
Our retrosynthetic analysis of the H-type II pentasac-
charide followed a markedly different path from previous
routes that had been striving for maximum convergence
(Scheme 1). In keeping with our goal of automating
solution-phase protocols in a solid-phase paradigm, five
glycosyl donors served as building blocks for a sequential
synthesis, adding one donor at a time to a growing
oligosaccharide chain. Since this solution-phase synthesis
was used as a study for future automation, we were
cognizant of constraints in solid-phase oligosaccharide
chemistry in developing reaction conditions for the
incorporation of glycosyl phosphate and trichloroacetimi-
date donors.29
Syn th esis of th e La ctose Disa cch a r id e. Two glycal-
derived glycosyl phosphate donors were required to
construct the lactose portion of the molecule (Scheme
2). The first donor, glucosyl phosphate 4, was derived
from readily available 3,6-di-O-benzyl glucal 1.33 Silyla-
tion of 1 yielded differentially protected glycal 2 ready
(33) Park, T. K.; Kim, I. J .; Hu, S.; Bilodeau, M. T.; Randolph, J . T.;
Kwon, O.; Danishefsky, S. J . J . Am. Chem. Soc. 1996, 118, 11488.
(34) Kessler, H.; Kling, A.; Kottenhahn, M. Angew. Chem., Int. Ed.
Engl. 1990, 29, 425.

8168 J . Org. Chem., Vol. 66, No. 24, 2001
Love et al.
1
Sch em e 3. Syn th esis of a 2-Azid o Glu cosa m in e
Don or
be achieved using standard conditions (TBAF/THF). H
NMR analysis of the crude product indicated the migra-
tion of the pivaloyl ester from the C2 to the C3 hydroxyl
of galactose to form an inseparable mixture of disaccha-
rides. A host of other deprotection conditions (TBAF/
AcOH, 1% HCl/MeOH, sat. HCl/ether) failed to cleanly
liberate disaccharide 12 from the C3 TBS ether.
Reevaluation of the synthetic route in light of difficul-
ties with protecting group removal proved silyl ethers
incompatible with both the solution-phase synthesis and
subsequent solid-phase automation. Therefore, levulinate
esters were chosen as the temporary protecting groups
in the synthesis of both building blocks for the lactose
portion of the Lewis antigens. Levulinate esters are
readily removed in the presence of other esters with
hydrazine.
Sch em e 4. Syn th esis of Glu cosyl Oxa zolin e
Don or 19
Glycosyl phosphates 5 and 10 were synthesized from
glycals substituting the Lev group for the TBS (Scheme
2). Formation of disaccharide 13, followed by treat-
ment with hydrazine35 yielded desired lactose disaccha-
ride 14. With 14 in hand, our focus turned to the con-
struction of the â-(1 f 4) glucosamine linkage bridging
the lactose and the antigenic portions of the Lewis
oligosaccharides.
Develop m en t of a Glu cosa m in e Bu ild in g Block .
The branched nature of the Lewis antigens around
the central glucosamine residue mandates a diverse pro-
tecting group scheme for this monosaccharide building
block. The choice of amine protecting group is essential
since it determines the overall protecting group strategy.
Previous syntheses of the Lewis antigens relied often on
protection of the amine in the form of an azide,25 owing
to the stability of this group to basic conditions required
for removal of esters typically used for temporary protec-
tion of hydroxyl groups. Following these examples, we
initially chose 2-azido glucosamine donor 17 for instal-
lation of the â-(1 f 4) glucosamine linkage.
and the N-acetate in a single step. While oligosaccharide
oxazolines are readily prepared using a variety of meth-
ods,39 their synthetic utility has been limited. Model
donor 19 (Scheme 4), derived from peracetylated glu-
cosamine,39 was activated with triflic acid40 in the pres-
ence of several secondary alcohols as acceptors but
yielded no coupling products.
Given the failure of both C2 azido glucosamine donor
17 and glucosyl oxazoline 19 to yield coupling products,
additional nitrogen-protecting groups were investigated.
Protection of the glucosamine nitrogen with a dimethyl-
maleoyl (DMM) group was recently reported to effectively
mask the glucosamine nitrogen while ensuring trans
glycosylation products.27 Installation of the DMM group
using dimethyl maleic anhydride, followed by global
acetylation produced 20 (Scheme 5). Further elaboration
of 20 in a manner analogous to that used in preparing
17 afforded 23. Conversion of 23 to glycosyl trichloro-
acetimidate 24 proceeded in modest yield (65%). While
24 proved an acceptable donor in initial model studies,
unsatisfactory yields (38% impure product) of trisaccha-
ride 25 were obtained when coupling 24 with lactose
acceptor 14 was attempted (Scheme 6). In addition, loss
of the DMM group was encountered when coupled
products were subjected to benzylation with benzyl
bromide and sodium hydride. These factors, along with
poor yields reported previously for the removal of DMM
from complex oligosaccharides27b rendered the DMM
group unattractive for amine protection in the context
of this synthesis.
The synthesis commenced with known compound 1536
by acetylation of the C3 hydroxyl position and regiose-
lective ring opening of the benzylidene using TES and
TFA,37 followed by protection of the C4 hydroxyl to yield
differentially protected monosaccharide 16. Removal of
the anomeric silyl ether and reaction of the lactol with
trichloroacetonitrile in the presence of catalytic DBU
afforded 17. Reaction of donor 17 with a series of model
compounds using BF3-OEt2 at a range of temperatures
was unsuccessful. Increased Lewis acidity of the activator
had no effect on the outcome of the glycosylation reaction,
but resulted in increased donor decomposition. The lack
of success with the C2 azido donor, while disappointing,
was not surprising in light of the fact that ester protected
2-azido glucosamines are only weakly active donors.38
Donor activity can be increased by introduction of allyl
and benzyl ethers as hydroxyl protecting groups, but was
not possible in this case in light of the required branching
pattern.
Inadequate performance of donors employing the afore-
mentioned base-stable amine-protecting groups in cou-
pling reactions with lactose acceptor 14 prompted us to
consider the use of the phthaloyl group for amine protec-
tion. The phthaloyl group is commonly used for the
protection of glucosamines in the context of oligosaccha-
ride syntheses; it is readily installed and functions well
as a C2 participating group to ensure â-selectivity of
glycosylation reactions. Since the phthalimide group is
Since most naturally occurring glucosamines are N-
acetates, we next investigated glucosamine oxazolines as
glycosyl donors for installation of the â-(1 f 4) linkage
(35) Zhu, T.; Boons, G.-T. Tetrahedron Asymm. 2000, 11, 199.
(36) Topefer, A.; Kinzy, W.; Schmidt, R. R. Liebigs Ann. Chem. 1994,
449.
(37) DeNinno, M. P.; Etienne, J . B.; Duplantier, K. C. Tetrahedron
Lett. 1995, 36, 669.
(38) (a) Schmidt, R. Angew. Chem., Int. Ed. Engl. 1986, 25, 212. (b)
van Boeckel, C.; Beetz, T.; van Aelst, S. Tetrahedron 1984, 40, 4097.
(39) (a) Nakabayashi, S.; Warren, C.; J eanloz, R. Carbohydr. Res.
1986, 150, C7. (b) Warren, C.; J eanloz, R. Carbohydr. Res. 1980, 92,
85. (c) Strivastard, V. Carbohydr. Res. 1982, 103, 286.
(40) Heskamp, B.; der Marel, G.; van Boom, J . J . Carbohydr. Chem.
1995, 14, 1265.

Synthesis of an H-Type II Pentasaccharide
J . Org. Chem., Vol. 66, No. 24, 2001 8169
Sch em e 5. Syn th esis of a Dim eth yl Ma leoyl-P r otected Don or
Sch em e 6. Syn th esis of H-Typ e II Cor e
Tr isa cch a r id es
Sch em e 8. Syn th esis of 2-(Azid om eth yl)ben zoyl
(AZMB) Ch lor id e
Sch em e 7. Syn th esis of a P th a lim id e-P r otected
Glu cosa m in e Don or
pivaloyl esters were disqualified as participating groups
since the basic conditions required for their removal were
not compatible with the phthalimide and ester groups
present in the existing trisaccharide. The need for a
participating group that could be selectively removed in
the presence of other esters prompted us to develop the
2-(azidomethyl)benzoyl (AZMB) group42 for carbohydrate
synthesis.
2-(Azid om eth yl)ben zoyl a s a n Or th ogon a l a n d
P a r ticip a tin g C2 P r otectin g Gr ou p for Oligosa c-
ch a r id e Assem bly. The development of new protecting
groups that are stable during glycosylation reactions and
can be selectively removed in high yield under conditions
orthogonal to other protecting groups are of utmost
importance for oligosaccharide synthesis. Traditional
modes of hydroxyl protection, such as esters or ethers,
rely on varying degrees of basic or acidic conditions for
their removal. Protective groups that may be removed
using neutral conditions offer an additional dimension
of orthogonality to existing groups. “Assisted cleavage”
involves the unmasking of a latent functionality, which
in turn facilitates the indirect removal of the protecting
group.43 Following this paradigm, reduction of the azide
in the 2-(azidomethyl)benzoyl group to the corresponding
amine induces intramolecular cyclization and expulsion
of the hydroxyl moiety.42
not completely stable under basic conditions, it was not
selected initially in anticipation of problems during re-
moval of ester protecting groups. In light of the develop-
ment of a novel 2-(azidomethyl)benzoyl protecting group
(vide infra) the use of base was no longer mandatory
during the late stages of the synthesis and allowed for
the use of phthaloyl as amine protecting group. Glycosyl
trichloroacetimidate building block 30 was prepared
using standard protecting group manipulations via known
n-pentenyl glycoside intermediates41 (Scheme 7). Glyco-
sylation of lactose acceptor 14 employing glycosyl trichlo-
roacetimidate 30 at -20°C afforded trisaccharide 26 in
good yield (87%) albeit an excess of donor 30 (3 equiv)
was required. Removal of the C4 levulinate ester using
hydrazine acetate readily furnished trisaccharide 27 in
98% yield (Scheme 7).
Completion of the protected H-type II pentasaccha-
ride required addition of a galactosyl donor capable of
fashioning the â-(1 f 4) linkage between the galac-
tose and glucosamine building blocks, followed by fuco-
sylation of the C2 position of this newly installed
galactose moiety. The nature of the C2 participating
group was of crucial importance. Acetate, benzoate, and
Synthesis of the 2-(azidomethyl)benzoyl chloride (AZMB-
Cl) commenced with bromination of commercially avail-
able methyl 2-methylbenzoate with NBS in the presence
of benzoyl peroxide to afford 32 (Scheme 8). Displacement
of the bromide with sodium azide, followed by saponifica-
tion, yielded 2-azidomethyl benzoic acid 33. Conversion
of the 33 to AZMB-Cl 34 was achieved by treatment with
(42) (a) Wada, T.; Ohkabso, A.; Mochizuki, A.; Sekine, M. Tetrahe-
dron Lett. 2001, 42, 1069. (b) Arasappan, A.; Fuchs, P. L. J . Am. Chem.
Soc. 1995, 117, 177.
(41) Handlon, A. L.; Fraser-Reid, B. J . Am. Chem. Soc. 1993, 115,
3796.
(43) Greene, T. W.; Wutz, P. G. M. In Protecting Groups in Organic
Synthesis, 3rd ed.; J ohn Wiley & Sons: New York, 1999.

8170 J . Org. Chem., Vol. 66, No. 24, 2001
Love et al.
Ta ble 1. Com p a tibility of AZMB w ith Com m on ly Used
Hyd r oxyl a n d Am in e P r otectin g Gr ou p s
AZMB group were synthesized. The donors were acti-
vated following standard protocols32,44,45 to fashion dis-
accharides 54 and 60. The AZMB group proved stable to
activation conditions and exclusively â-linked glycosidic
products were obtained. Cleavage of AZMB from disac-
charide 54 was carried out to highlight its utility as a
removable C2 participating group.
Com p letion of th e H-Typ e II P en ta sa cch a r id e. To
achieve the completion of the desired pentasaccharide
structure, a galactose unit had to be connected onto the
C4 position of the central glucosamine followed by
fucosylation of the C2 position of the newly installed
galactose. In exploring this chemistry, we initially focused
on a simpler trisaccharide model system 66 (Scheme 10)
that constitutes the antigenic trisaccharide portion of
H-type II without the reducing end lactose.
Given our success using the AZMB group as a C2
participating group with a variety of glycosyl donors, we
chose to equip the galactose building block to be con-
nected to the central glucosamine with this protective
group. Galactosyl phosphate 61 was prepared via the one-
pot procedure from tri-O-benzyl galactal.31 Glycosylation
of the C4 position of glucosamine 62 using galactose
phosphate 61 proceeded in excellent yield to afford
disaccharide 63 (Scheme 10). Removal of the C2 AZMB
group did not cause any unexpected problems and
furnished disaccharide acceptor 64.
Fucosylation of the C2 hydroxyl of the terminal galac-
tose is the final step for completion of H-type II oligosac-
charides. As in most glycoconjugates, Lewis group anti-
gens contain exclusively R-(1,2-cis) fucosidic linkages.
This cis linkage poses a synthetic challenge since C2
participating groups cannot be employed.46 The use of
fucosyl phosphates32 to establish this difficult linkage was
addressed in the context of the Lewis antigen synthesis.
Fucosylation using dibutyl perbenzylated fucose phos-
phate32 resulted as expected in an inseparable mixture
of diasteriomers upon reaction with a model acceptor.
Similar results had been obtained previously with other
fully benzylated fucose donors such as fucosyl bromides,47
trichloroacetimidates,36 fluorides,48 thioglycosides,49 and
n-pentenyl glycosides.50 The problem of stereocontrol
during fucosylation was addressed by introduction of a
C4 ester protecting group following precedence with other
glycosylating agents47 to create fucosyl phosphate donor
65.32 Using model disaccharide 64 as acceptor, fucosyla-
tion with 65 (1.6 equiv) under the agency of stoichiomet-
ric amounts of TBSOTf provided protected H-type II
trisaccharide 66 in excellent yield with complete R-se-
lectivity. It is interesting to note that the corresponding
fucosyl trichloroacetimidate donor failed to ensure com-
plete R-selectivity in glycosylation reactions.51
Reaction conditions: a36 (1 equiv) and hydrazine acetate (1
equiv) in MeOH/CH2Cl2 at room temperature for 40 min. b37 (1
equiv); Pd(II)chloride (2.5 equiv), and sodium acetate (7 equiv) in
acetic acid (90% aqueous) at 70 °C for 1.5 h. c38 (1 equiv) and
TFA (15 equiv.) at room temperature for 1 h. d43 (0.1 M) in a 1:3:3
TFA/THF/H2O solution.
thionyl chloride. Installation of the AZMB group was
achieved quantitatively by reaction of the free hydroxyl
group with the AZMB-Cl and a stoichiometric amount
of DMAP. Removal of AZMB is equally facile under
Staudinger conditions for reduction of the azide (PBu3
and water).
The compatibility of the AZMB group with traditionally
used protecting groups for oligosaccharide synthesis was
examined (Table 1). Differentially protected monosac-
charides 35-38 were used to explore orthogonality with
other modes of protection including esters, silyl ethers,
p-methoxybenzyl (PMB) ethers, and allyl ethers. AZMB
was not affected by conditions used for the removal of
any of these groups. Similarly, all groups remained intact
during AZMB removal from a model monosaccharide.
Cleavage of AZMB in the presence of phthaloyl and
trichloroethoxycarbonyl (Troc) amine protecting groups
afforded high yields of deprotected monosaccharides 47
and 48. The possibility of AZMB removal in the presence
of acetate, levinulate, and phthaloyl groups was particu-
larly notable since these protecting groups were used in
preparation of the H-type II pentasaccharide.
After establishing the feasibility of all synthetic trans-
formations for the construction of the antigenic portion
of the oligosaccharide target on a trisaccharide model,
(44) Garegg, P. J . Adv. Carbohydr. Chem. Biochem. 1997, 52, 179.
(45) Schmidt, R. R. Adv. Carbohydr. Chem. Biochem. 1994, 50, 21.
(46) Flowers, H. M. Carbohydr. Res. 1983, 119, 75.
(47) Dejter-J uszynski, M.; Flowers, H. M. Carbohydr. Res. 1971, 18,
219.
(48) Nicolaou, K. C.; Hummel, C. W.; Bockovich, N. J .; Wong, C.-H.
J . Chem. Soc., Chem. Commun. 1991, 10, 870.
(49) Lonn, H. Carbohydr. Res. 1995, 139, 105.
(50) Udodong, U. E.; Srinivas, R. C.; Fraser-Reid, B. Tetrahedron
1992, 48, 4713.
In addition to its utility as a temporary protecting
group, we intended to demonstrate the ability of the
AZMB group to function as a stereodirecting entity
during glycosylation reactions utilizing different glycosyl
donors. Glycosyl phosphate 52, thioglycoside 57, and
glycosyl trichloroacetimidate 59 each containing a C2
(51) Andrade, R. Dissertation, Massachusetts Institute of Technol-
ogy, 2001.

Synthesis of an H-Type II Pentasaccharide
J . Org. Chem., Vol. 66, No. 24, 2001 8171
Sch em e 9. Com p a tibility of AZMB w ith Activa tion Con d ition s for Glycosyl Don or s a n d C2 P a r ticip a tion
in Glycosyla tion
Sch em e 10. Syn th esis of H-Typ e II Tr isa cch a r id e 66
Sch em e 11. Com p letion of th e H-Typ e II P en ta sa cch a r id e
we focused our attention on the final steps of the pen-
tasaccharide assembly (Scheme 11). Galactosylation of
trisaccharide acceptor 27 afforded tetrasaccharide 67 in
92% yield. Reduction of the azide using Staudinger con-
ditions cleanly removed the AZMB protecting group in
67 to yield desired tetrasaccharide acceptor 68. Fucosy-
lation of the tetrasaccharide 68 was carried out at low
temperatures using phosphate 65 to yield 94% of the
desired H-type II pentasaccharide 69 in fully protected
form.

8172 J . Org. Chem., Vol. 66, No. 24, 2001
Love et al.
4,6-Di-O-ben zyl-3-O-levu lin yl-ga la cta l 8. Levulinic acid
(0.77 g, 6.66 mmol) and DMAP (0.856 g, 6.97 mmol) were
dissolved in 25 mL of CH2Cl2 and cooled to 0 °C. After 10 min,
DIPC (0.99 mL, 6.34 mmol) was added with vigorous stirring.
After five additional minutes, a solution of 4,6-di-O-benzyl
galactal (2.07 g, 6.34 mmol) in 25 mL of CH2Cl2 was added to
the levulinic acid solution via cannula, and the mixture was
left to slowly warm to room temperature. After 12 h, the
reaction mixture was diluted with EtOAc and flushed through
a plug of silica gel. The filtrate was concentrated, and the
residue was purified by flash silica gel chromatography (40%
EtOAc/hexanes) to afford 2.57 g (95%) of 8 as a white solid.
[R]D: -21.09° (c ) 2.15, CH2Cl2); IR (thin film): 3030, 2916,
Con clu sion s
In summary, the solution-phase synthesis of a fully
protected H-type II pentasaccharide was accomplished
using a linear glycosylation strategy as a model for the
automated synthesis of this molecule. This synthesis
demonstrates the utility of glycal-derived glycosyl phos-
phates, along with glycosyl trichloroacetimidates, in the
synthesis of complex oligosaccharides. Different protect-
ing group patterns for masking the amino group of the
central glucosamine moiety were tested. Introduction of
a new hydroxyl protecting group, a 2-(azidomethyl)ben-
zoate ester, allowed for the straightforward synthesis of
the target pentasaccharide. The synthetic strategy de-
scribed here for the H-type II pentasaccharide is exem-
plary for the preparation of blood group determinant
oligosaccharides in solution and on solid support.
2870, 1719, 1645 cm-1 1H NMR (400 MHz, CDCl3): 7.36-
;
7.27 (m, 10 H), 6.45 (dd, J ) 6.2, 1.4 Hz, 1 H), 5.52-5.49 (m,
1 H), 4.78-4.74 (m, 2 H), 4.55 (d, J ) 11.9 Hz, 2 H), 4.46 (d,
J ) 12.0 Hz, 1 H), 4.29-4.26 (m, 1 H), 4.03-4.01 (m, 1 H),
3.77 (dd, J ) 10.3, 7.5 Hz, 1 H), 3.62 (dd, J ) 10.3, 4.7 Hz, 1
H), 2.73-2.69 (m, 2 H), 2.58-2.55 (m, 2 H), 2.16 (s, 3 H); 13C
NMR (100 MHz, CDCl3): 206.5, 172.5, 145.8, 144.4, 138.0,
137.9, 128.7, 128.6, 128.6, 128.5, 128.3, 128.2, 128.0, 127.9,
127.8, 98.6, 75.6, 73.5, 73.2, 70.7, 67.9, 65.7, 38.0, 30.0, 28.2;
ESI-MS: m/z (M + Na)+ calcd 447.1784, obsd 447.1758.
Dibu tyl 4,6-d i-O-ben zyl-3-O-levu lin yl-2-O-p iva loyl-â-D-
ga la ctop yr a n osyl P h osp h a te 10. Galactal 8 (0.622 g, 1.46
mmol) was azeotroped with toluene (3 × 3 mL) and then dried
under vacuum for 1 h. A solution of 8 in CH2Cl2 (15 mL) was
cooled to 0 °C, and dimethyl dioxirane (27 mL of a 0.08 M
solution in acetone, 2.19 mmol) was added. After 20 min,
volatiles were removed under vacuum, and the resulting
residue was dried for 10 min. The residue was redissolved in
CH2Cl2 (40 mL) and cooled to -78 °C, and a solution of dibutyl
phosphate (0.35 mL, 1.76 mmol) in CH2Cl2 (5 mL) was added
dropwise over a period of 5 min. After 10 min, the solution
was warmed to 0 °C, and DMAP (0.716 g, 5.86 mmol) and
pivaloyl chloride (0.36 mL, 2.93 mmol) were added. After 30
min the reaction mixture was diluted with EtOAc (100 mL)
and filtered through a plug of silica gel. The filtrate was
concentrated, and the residue was purified by flash silica gel
chromatography (30% EtOAc/hexanes) to yield 0.984 g (94%)
of 10 as a white solid. [R]D: +16.22° (c ) 1.57, CH2Cl2); IR
(thin film): 2962, 2873, 1742, 1720, 1028 cm-1; 1H NMR (400
MHz, CDCl3): 7.36-7.26 (m, 10 H), 5.45 (dd, J ) 10.4, 7.9
Hz, 1 H), 5.24 (dd, J ) 7.8, 7.1 Hz, 1 H), 5.03 (dd, J ) 10.5,
3.1 Hz, 1 H), 4.76 (d, J ) 11.6 Hz, 1 H), 4.43 (dd, J ) 18.6,
11.8 Hz, 2 H), 4.05-3.95 (m, 4 H), 3.76 (dd, J ) 6.8, 6.8 Hz, 1
H), 3.59 (dd, J ) 7.1, 2.8 Hz, 1 H), 2.70-2.63 (m, 2 H), 2.48-
2.43 (m, 2 H), 2.15 (s, 3 H), 1.62-1.57 (m, 4 H), 1.39-1.31 (m,
4H), 1.20 (s, 9 H), 0.91 (t, J ) 7.5 Hz, 3 H), 0.88 (t, J ) 7.4 Hz,
3 H); 13C NMR (100 MHz, CDCl3): 206.2, 177.1, 172.1, 138.2,
137.7, 128.6, 128.5, 128.3, 128.0, 128.0, 127.9, 96.9, 75.3, 74.1,
73.9, 73.8, 73.6, 69.4, 68.2, 68.1, 68.0, 67.7, 39.0, 37.7, 32.3,
32.2, 32.1, 29.9, 27.9, 27.9, 27.2, 18.8, 13.8, 13.7; 31P NMR (120
MHz, CDCl3): -2.45; ESI-MS: m/z (M + Na)+ calcd 757.3329,
obsd 757.3350.
Exp er im en ta l Section
Gen er a l Meth od s. All chemicals were reagent grade and
used as supplied unless otherwise noted. Dichloromethane
(CH2Cl2), tetrahydrofuran (THF), and toluene were purified
by a J T Baker Cycle-Tainer Solvent Delivery System. Analyti-
cal thin-layer chromatography was performed on E. Merck
silica gel 60 F254 plates (0.25 mm). Compounds were visualized
by dipping the plates in a cerium sulfate-ammonium molyb-
date solution followed by heating. Liquid column chromatog-
raphy was performed using forced flow of the indicated solvent
on Silicycle silica (230-400 mesh). 1H NMR spectra were
obtained using a Bruker-400 NMR spectrometer (400 MHz)
or a Varian VXR-500 (500 MHz) and are reported in parts per
million (δ) relative to CDCl3 (7.27 ppm). Coupling constants
(J ) are reported in hertz. 13C NMR spectra were obtained using
a Bruker-400 NMR spectrometer (100 MHz) or a Varian VXR-
500 (125 MHz) and are reported in δ relative to CDCl3 (77.23
ppm) as an internal reference. 31P spectra were obtained using
a Varian VXR-300 NMR spectrometer (120 MHz) or a Varian
VXR-500 (200 MHz) and are reported in δ relative to H3PO4
(0.0 ppm) as an external reference. Optical rotations were
measured at 24 °C.
Dibu t yl 3,6-Di-O-b en zyl-4-O-levu lin yl-2-O-p iva loyl-â-
D-glu cop yr a n osyl P h osp h a te 5. 3,6-Di-O-benzyl-4-O-levuli-
nyl-glucal 3 (2.34 g, 5.5 mmol) was azeotroped with toluene
(3 × 5 mL) and then dried under vacuum for 1 h. A solution
of 3 in CH2Cl2 (40 mL) was cooled to 0 °C, and dimethyl
dioxirane (103 mL of a 0.08 M solution in acetone, 8.3 mmol)
was added. After 20 min, volatiles were removed under
vacuum, and the resulting residue was dried for 10 min. The
residue was redissolved in CH2Cl2 (40 mL) and cooled to -78
°C, and a solution of dibutyl phosphate (1.3 mL, 6.6 mmol) in
CH2Cl2 (5 mL) was added dropwise over a period of 5 min.
After 10 min, the reaction mixture was warmed to 0 °C, and
DMAP (2.69 g, 22 mmol) and pivaloyl chloride (1.35 mL, 11
mmol) were added. The solution was left to slowly warm to
room temperature and after 2 h was diluted with EtOAc (100
mL) and filtered through a plug of silica gel. The filtrate was
concentrated, and the residue was purified by flash silica gel
chromatography (25% EtOAc/hexanes) to yield 3.518 g (89%)
of 5 as a white solid. [R]D: +0.98° (c ) 2.10, CH2Cl2); IR (thin
film): 2962, 2874, 1745, 1719, 1029 cm-1; 1H NMR (400 MHz,
CDCl3): 7.35-7.22 (m, 10 H), 5.28 (dd, J ) 7.8, 7.1 Hz, 1 H),
5.22-5.17 (m, 2 H), 4.65 (d, J ) 11.3 Hz, 1 H), 4.57 (d, J )
11.3 Hz, 1 H), 4.49 (dd, J ) 13.3, 11.8 Hz, 2 H), 4.07-3.98 (m,
4 H), 3.80-3.72 (m, 2 H), 3.63-3.56 (m, 2 H), 2.67-2.50 (m, 2
H), 2.44-2.36 (m, 1 H), 2.32-2.24 (m, 1 H), 2.12 (s, 3 H), 1.65-
1.53 (m, 4 H), 1.42-1.32 (m, 4 H), 1.21 (s, 9 H), 0.92 (t, J )
7.4 Hz, 3 H), 0.87 (t, J ) 7.4 Hz, 3 H); 13C NMR (100 MHz,
CDCl3): 206.3, 176.8, 171.6, 138.0, 137.9, 128.5, 128.5, 128.0,
127.8, 127.7, 96.7, 80.3, 74.1, 73.8, 73.7, 72.3, 70.3, 69.2, 68.3,
68.1, 39.0, 37.9, 32.3, 32.3, 32.2, 30.0, 28.0, 27.3, 18.8, 13.8,
13.7; 31P NMR (120 MHz, CDCl3): -2.34; ESI-MS: m/z (M +
Na)+ calcd 757.3329, obsd 757.3320.
n -P en ten yl 4-O-ter t-Bu tyld im eth ylsilyl-3,6-d i-O-ben -
zyl-2-O-p iva loyl-â-D-glu cop yr a n osid e. Phosphate 4 (0.350
g, 0.47 mmol) was azeotroped with toluene (3 × 3 mL) and
dried under vacuum for 1 h. The residue was dissolved in
CH2Cl2 (5 mL), along with 4-penten-1-ol (58 µL, 0.56 mmol),
and the solution was cooled to -78 °C. TBSOTf (108 µL, 0.47
mmol) was added, and after 30 min the reaction mixture was
neutralized with Et3N and concentrated in vacuo. The residue
was purified by flash silica gel chromatography (25% EtOAc/
hexanes) to yield 262 mg (89%) of n-pentenyl 4-O-tert-bu-
tyldimethylsilyl-3,6-di-O-benzyl-2-O-pivaloyl-â-D-glucopyrano-
side. [R]D: +4.77 (c ) 0.73, CH2Cl2); IR (thin film): 2947, 2851,
1742, 1140, 1057 cm-1 1H NMR (400 MHz, CDCl3): 7.35-
;
7.21 (m, 10 H), 5.85-5.75 (m, 1 H), 5.09 (dd, J ) 9.2, 8.0 Hz,
1 H), 5.01 (ddd, J ) 18.7, 3.4, 1.6 Hz, 1 H), 4.97-4.94 (m, 1
H), 4.71-4.64 (m, 3 H), 4.54 (d, J ) 12.3 Hz, 1 H), 4.43 (d, J
) 7.9 Hz, 1 H), 3.88 (dt, J ) 9.4, 6.5 Hz, 1 H), 3.78 (dd, J )
9.4, 6.5 Hz, 1 H), 3.65 (app t, J ) 9.1 Hz, 1 H), 3.60-3.45 (m,
4 H), 2.13-2.07 (m, 2 H), 1.71-1.60 (m, 2 H), 1.13 (s, 9 H),
0.83 (s, 9 H), -0.04 (s, 3 H), -0.10 (s, 3 H); 13C NMR (100 MHz,

Synthesis of an H-Type II Pentasaccharide
J . Org. Chem., Vol. 66, No. 24, 2001 8173
CDCl3) 177.0, 138.3, 138.3, 128.6, 128.3, 127.8, 127.4, 127.1,
115.0, 101.3, 83.5, 77.5, 74.7, 73.6, 71.3, 69.6, 69.1, 39.0, 30.3,
29.1, 27.3, 26.1, 18.2, -3.7, -4.7; ESI-MS: m/z (M + Na)+ calcd
626.3639, obsd 626.3620.
Hz, 1H), 3.86 (dt, J ) 9.6, 6.4 Hz, 1H), 3.72-3.70 (m, 2H),
3.61 (app t, J ) 9.1 Hz, 1 H), 3.49-3.41 (m, 2H), 3.37-3.26
(m, 3H), 2.69-2.65 (m, 2H), 2.45 (app t, J ) 6.3 Hz, 2H), 2.15
(s, 3H), 2.13-2.06 (m, 2H), 1.68-1.63 (m, 2H), 1.18 (s, 18H);
13C NMR (100 MHz, CDCl3): 206.3, 177.0, 176.8, 172.1, 138.9,
138.6, 138.3, 138.1, 138.0, 128.7, 128.6, 128.4, 128.2, 128.2,
128.0, 128.0, 127.9, 127.7, 127.7, 127.1, 115.0, 101.5, 99.7, 81.0,
75.3, 75.2, 74.6, 74.5, 74.3, 73.7, 73.5, 73.3, 72.4, 70.2, 69.1,
68.0, 67.7, 39.0, 38.9, 37.7, 30.2, 29.9, 28.9, 27.9, 27.3; ESI-
MS: m/z (M + Na)+ calcd 1059.5076, obsd 1059.5043.
n -P en ten yl 3,6-Di-O-ben zyl-4-O-levu lin yl-2-O-p iva loyl-
â-D-glu cop yr a n osid e. Phosphate 5 (0.220 g, 0.306 mmol) was
azeotroped with toluene (3 × 3 mL) and dried under vacuum
for 1 h. The residue was dissolved in CH2Cl2 (5 mL), along
with 4-penten-1-ol (29 mg, 0.337 mmol), and the solution was
cooled to -78 °C. TBSOTf (70 µL, 0.306 mmol) was added, and
after 10 min the reaction mixture was neutralized with Et3N
and concentrated in vacuo. The residue was purified by flash
silica gel chromatography (25% EtOAc/hexanes) to yield 160
mg (88%) of n-pentenyl 3,6-di-O-benzyl-4-O-levulinyl-2-O-
pivaloyl-â-D-glucopyranoside. [R]D: -15.66° (c ) 1.70, CH2Cl2);
n -P en ten yl 4,6-Di-O-ben zyl-2-O-p iva loyl-â-D-ga la cto-
p yr a n osyl-(1 f 4)-3,6-d i-O-ben zyl-2-O-p iva loyl-â-D-glu -
cop yr a n osid e 14. A solution of hydrazine acetate (14 mg, 0.19
mmol) in MeOH (0.3 mL) was added to a solution of 13 (175
mg, 0.17 mmol) in CH2Cl2 (3 mL), and the resulting solution
was stirred for 90 min at room temperature. The reaction
mixture was diluted with CH2Cl2 (5 mL) and concentrated in
vacuo. The crude product was purified by flash silica gel
chromatography (25% EtOAc/hexanes) to yield 156 mg (98%)
of 14. [R]D: -32.05° (c ) 0.40, CH2Cl2); IR (thin film): 3529,
1
IR (thin film): 2975, 2879, 1743, 1722, 1151 cm-1; H NMR
(400 MHz, CDCl3): 7.34-7.21 (m, 10 H), 5.85-5.74 (m, 1 H),
5.12-5.07 (m, 2 H), 5.04-4.99 (m, 1 H), 4.98-4.95 (m, 1 H),
4.63 (d, J ) 11.3 Hz, 1 H), 4.58-4.52 (m, 3 H), 4.43 (d, J ) 7.9
Hz, 1 H), 3.88 (dt, J ) 9.5, 6.4 Hz, 1 H), 3.76 (t, J ) 9.4 Hz, 1
H), 3.65-3.57 (m, 3 H), 3.47 (dt, J ) 9.5, 6.8 Hz, 1 H), 2.65-
2.52 (m, 2 H), 2.41 (ddd, J ) 17.3, 7.6, 6.0 Hz, 1 H), 2.29 (dt,
J ) 17.3, 6.4 Hz, 1 H), 2.12 (s, 3 H), 2.12-2.06 (m, 3 H), 1.71-
1.63 (m, 2 H), 1.21 (s, 9 H); 13C NMR (100 MHz, CDCl3): 206.4,
176.8, 171.8, 138.3, 138.2, 128.5, 128.5, 128.0, 127.8, 127.8,
127.7, 115.1, 101.4, 80.6, 73.8, 73.8, 73.5, 72.5, 71.0, 69.8, 69.4,
39.0, 37.9, 30.2, 30.0, 29.0, 28.0, 27.4; ESI-MS: m/z (M + Na)+
calcd 633.3034, obsd 633.3018.
2969, 1736, 1137, 1064 cm-1 1H NMR (400 MHz, CDCl3):
;
7.36-7.13 (m, 20H), 5.85-5.74 (m, 1H), 5.04-4.92 (m, 5H),
4.76 (d, J ) 12.1 Hz, 1H), 4.62 (s, 2H), 4.52 (d, J ) 10.8 Hz,
1H), 4.47 (d, J ) 12.1 Hz, 1H), 4.41 (d, J ) 8.0 Hz, 1H), 4.37
(dd, J ) 8.0 Hz, 1H), 4.35 (d, J ) 11.8 Hz, 1H), 4.25 (d, J )
11.7 Hz, 1H), 4.03 (dd, J ) 9.4, 9.3 Hz, 1H), 3.86 (dt, J ) 9.6,
6.4 Hz, 1H), 3.79 (dd, J ) 8.5, 3.4 Hz, 2H), 3.74 (dd, J ) 10.7,
1.6 Hz, 1H), 3.59 (dd, J ) 9.2, 9.2 Hz, 1H), 3.47-3.31 (m, 6H),
2.17 (d, J ) 10.5 Hz, 1H), 2.12-2.06 (m, 2H), 1.70-1.62 (m,
2H), 1.20 (s, 9H), 1.17 (s, 9H); 13C NMR (100 MHz, CDCl3):
176.8, 139.1, 138.3, 138.1, 137.9, 128.7, 128.7, 128.6, 128.2,
128.1, 128.0, 127.9, 127.6, 127.2, 115.0, 101.5, 99.7, 81.1, 76.7,
75.7, 75.5, 75.4, 74.5, 74.1, 73.8, 73.6, 73.3, 72.4, 69.1, 68.1,
67.8, 39.1, 38.9, 30.3, 29.0, 27.4, 27.3; ESI-MS: m/z (M + Na)+
calcd 961.4714, obsd 961.4744.
n -P en ten yl 3,6-Di-O-ben zyl-2-O-p iva loyl-â-D-glu cop y-
r a n osid e 11. Method A: A solution of n-pentenyl 4-O-tert-
butyldimethylsilyl-3,6-di-O-benzyl-2-O-pivaloyl-â-D-glucopy-
ranoside (1.75 g, 2.78 mmol) in THF (30 mL) was treated with
TBAF (5.56 mL of a 1.0 M solution in THF, 5.56 mmol). After
30 min, the mixutre was diluted with water (50 mL), extracted
with EtOAc (3 × 50 mL), dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by silica gel
chromatography (20% EtOAc/hexanes) to yield 1.26 g (89%)
of 11. [R]D: -20.94° (c ) 1.31, CH2Cl2); IR (thin film): 3492,
ter t-Bu tyld im eth ylsilyl 3-O-Acetyl-6-O-ben zyl-2-d eoxy-
2-a zid o-4-O-levu lin yl-â-D-glu cop yr a n osid e-3-O-ben zoyl-
6-O-b en zyl-4-O-levu lin oyl-2-d eoxy-2-p h t h a lim id o-â-D-
glu cop yr a n osyl tr ich lor oa cetim id a te 30. To a stirred
solution of 29 (1.90 g, 2.83 mmol) in 50 mL of CH3CN/H2O
(8:1) was added NBS (1.51 g, 8.51 mmol), and the reaction
mixture was stirred for 5 h at room temperature. After
addition of Na2S2O3 (7 mL of a saturated aqueous solution),
the reaction mixture was partitioned between EtOAc and
water and the aqueous phase was extracted once with EtOAc.
The combined organic phases were washed with saturated
NaHCO3 and brine and dried over Na2SO4. Upon filtration and
concentration, the crude product was purified by flash silica
gel column chromatography (40% EtOAc/hexanes) to afford
3-O-benzoyl-6-O-benzyl-4-O-levulinoyl-2-deoxy-2-phthalimido-
â-D-glucopyranoside (1.10 g, 66% yield), which was used
immediately in the next step. To a stirred solution of 3-O-
benzoyl-6-O-benzyl-4-O-levulinoyl-2-deoxy-2-phthalimido-â-D-
glucopyranoside (1.10 g, 1.89 mmol) and trichloroacetonitrile
(1.89 mL, 18.91 mmol) in 20 mL of CH2Cl2 under N2 was added
DBU (60 µL, 0.38 mmol). The reaction mixture was stirred at
room temperature for 2 h and then concentrated. The crude
product was purified by flash silica gel column chromatography
(30% f 40% EtOAc/hexanes with 1% triethylamine) to afford
27 (620 mg, 45% yield). [R]D: +88.2° (c ) 2.42, CH2Cl2); IR
(thin film): 2921, 1779, 1720, 1681, 1386 cm-1; 1H NMR (500
MHz, CDCl3): 8.68 (s, 1H), 7.85 (d, J ) 7.5 Hz, 1H), 7.82-
7.64 (m, 4H), 7.51 (m, 1H), 7.38-7.29 (m, 8H), 6.72 (d, J ) 9.0
Hz, 1H), 6.17 (dd, J ) 9.0, 10.5 Hz, 1H), 5.53 (t, J ) 9.5 Hz,
1H), 4.80 (dd, J ) 9.0, 10.7 Hz, 1H), 4.62 (d, J ) 12.0 Hz, 1H),
4.59 (d, J ) 12.0 Hz, 1H), 4.14 (m, 1H), 3.79 (dd, J ) 3.0, 11.2
Hz, 1H), 3.71 (dd, J ) 5.0, 11.2 Hz, 1H), 2.59-2.28 (m, 4H),
2.00 (s, 3H); 13C NMR (125 MHz, CDCl3): 206.0, 171.4, 165.8,
160.7, 138.0, 134.4, 133.5, 131.4, 130.0, 128.8, 128.5, 128.2,
127.8, 123.8, 93.8, 74.5, 73.6, 71.2, 69.4, 68.2, 68.2, 53.9, 37.9,
29.6, 28.0; FAB-MS: m/z (M + Na)+ calcd 767.0936, obsd
767.0932.
2922, 1733, 1130, 1071 cm-1 1H NMR (400 MHz, CDCl3):
;
7.38-7.28 (m, 10 H), 5.83-5.74 (m, 1 H), 5.06-4.98 (m, 2 H),
4.96 (dd, J ) 10.3, 1.7 Hz, 1 H), 4.74 (d, J ) 11.4 Hz, 1 H),
4.69 (d, J ) 11.4 Hz, 1 H), 4.63 (d, J ) 12.1 Hz, 1 H), 4.58 (d,
J ) 12.0 Hz, 1 H), 4.40 (d, J ) 8.0 Hz, 1 H), 3.85 (dt, J ) 9.5,
6.5 Hz, 1 H), 3.80-3.70 (m, 3 H), 3.58-3.44 (m, 3 H), 2.69 (d,
J ) 1.3 Hz, 1 H), 2.12-2.06 (m, 2 H), 1.70-1.62 (m, 2H), 1.22
(s, 9 H); 13C NMR (100 MHz, CDCl3): 177.0, 138.4, 138.3,
138.0, 128.7, 128.7, 128.0, 128.0, 127.8, 115.1, 101.5, 83.0, 74.6,
74.3, 73.9, 72.8, 72.1, 70.6, 69.3, 39.0, 30.3, 29.0, 27.4; ESI-
MS: m/z (M + Na)+ calcd 535.2666, obsd 535.2645. Method
B: A solution of hydrazine acetate (20 mg, 0.27 mmol) in
MeOH (0.3 mL) was added to a solution of pentenyl 3,6-di-O-
benzyl-4-O-levulinyl-2-O-pivaloyl-â-D-glucopyranoside (160 mg,
0.27 mmol) in CH2Cl2 (3 mL) and was stirred for 90 min at
room temperature. The reaction mixture was diluted with
CH2Cl2 (5 mL) and concentrated in vacuo. The crude product
was purified by flash silica gel chromatography (25% EtOAc/
hexanes) to afford 109 mg (81%) of 11.
n -P en ten yl 4,6-Di-O-ben zyl-3-O-levu lin yl-2-O-p iva loyl-
â-D-galactopyr an osyl-(1 f 4)-3,6-di-O-ben zyl-2-O-pivaloyl-
â-D-glu cop yr a n osid e 13. Monosaccharide 11 (109 mg, 0.22
mmol) and glycosyl phosphate 10 (190 mg, 0.26 mmol) were
azeotroped with toluene (3 × 3 mL) and then dried under
vacuum for 1 h. Dichloromethane (5 mL) was added, the
solution was cooled to -78 °C, and TBSOTf (55 µL, 0.242
mmol) was added. After 30 min, the mixture was neutralized
with Et3N and concentrated in vacuo. The residue was purified
by flash silica gel chromatography (25% EtOAc/hexanes) to
yield 175 mg (90%) of 13. [R]D: -11.51° (c ) 3.95, CH2Cl2); IR
(thin film): 3027, 2977, 1745, 1723, 1138 cm-1; 1H NMR (400
MHz, CDCl3): 7.38-7.24 (m, 13H), 7.23-7.19 (m, 4H), 7.16-
7.13 (m, 1H), 7.09-7.06 (m, 2H), 5.85-5.74 (m, 1H), 5.35 (dd,
J ) 10.5, 7.9 Hz, 1H), 5.04-4.94 (m, 4H), 4.83 (dd, J ) 10.5,
3.1 Hz, 1H), 4.74 (app t, J ) 11.9 Hz, 2H), 4.52-4.44 (m, 4H),
4.36 (d, J ) 8.0 Hz, 1H), 4.30 (d, J ) 11.8 Hz, 1H), 4.17 (d, J
) 11.8 Hz, 1H), 4.04 (app t, J ) 9.2 Hz, 1H), 3.92 (d, J ) 2.9
n -P en t en yl 3-O-Ben zoyl-6-O-b en zyl-4-O-levu lin oyl-2-
d eoxy-2-p h th a lim id o-â-D-glu cop yr a n osyl-(1 f 3)-4,6-d i-
O-ben zyl-2-O-p iva loyl-â-D-ga la ctop yr a n osyl-(1 f 4)-3,6-

8174 J . Org. Chem., Vol. 66, No. 24, 2001
Love et al.
d i-O-ben zyl-2-O-p iva loyl-â-D-glu cop yr a n osid e 26. To a
stirred solution of 14 (77 mg, 0.082 mmol) and 30 (180 mg,
0.248 mmol) in 2.5 mL of CH2Cl2 under N2 at -30 °C was
added TMSOTf (8 µL, 0.044 mmol). The reaction was stirred
at -30 °C for 5 min and warmed to -15 °C over the course of
10 min. Triethylamine (15 µL) was added, the solution was
concentrated, and the crude product purified by flash silica
column chromatography (30% f 40% EtOAc/hexanes) to afford
26 (107 mg, 87% yield). [R]D: -5.7° (c ) 2.16, CH2Cl2); IR (thin
film): 2869, 1730, 1387, 1267, 1144 cm-1; 1H NMR (500 MHz,
CDCl3): 7.79 (d, J ) 7.0 Hz, 1H), 7.78-7.59 (m, 4H), 7.47 (t,
J ) 7.0 Hz, 1H), 7.38-7.21 (m, 26H), 7.07 (t, J ) 8.0 Hz, 1H),
6.97 (t, J ) 8.0 Hz, 1H), 6.14 (dd, J ) 9.0, 10.7 Hz, 1H), 5.77
(m, 1H), 5.40 (d, J ) 8.0 Hz, 1H), 5.31 (t, J ) 9.5 Hz, 1H),
5.10 (dd, J ) 5.0, 11.5 Hz, 1H), 5.03 (d, J ) 11.0 Hz, 1H), 4.97
(m, 1H), 4.94 (m, 1H), 4.92 (m, 1H), 4.87 (d, J ) 10.5 Hz, 1H),
4.70 (d, J ) 12.0 Hz, 1H), 4.57-4.42 (m, 2H), 4.43 (d, J ) 12.0
Hz, 1H), 4.28 (m, 2H), 4.17 (d, J ) 11.5 Hz, 1H), 4.00 (t, J )
9.5 Hz, 2H), 3.94 (m, 1H), 3.86 (dd, J ) 3.0, 10.0 Hz, 1H), 3.81
(m, 1H), 3.74 (dd, J ) 7.5, 10.5 Hz, 1H), 3.67 (m, 2H), 3.46-
3.38 (m, 3H), 3.33-3.27 (m, 3H), 2.62-2.23 (m, 4H), 2.03 (s,
3H), 2.12-2.01 (m, 2H), 1.65-1.59 (m, 2H), 1.14 (s, 9H), 1.09
(s, 9H); 13C NMR (125 MHz, CDCl3): 206.0, 176.6, 176.5, 171.5,
165.6, 139.1, 138.7, 138.3, 138.2, 137.9, 137.8, 134.0, 133.4,
130.0, 129.9, 128.8, 128.6, 128.5, 128.4, 128.3, 128.2, 128.0,
127.9, 127.8, 127.6, 127.3, 126.9, 123.7, 114.8, 101.3, 99.4, 98.1,
80.9, 77.6, 76.8, 75.3, 74.6, 74.3, 73.7, 73.5, 72.3, 70.6, 70.2,
69.0, 68.9, 68.4, 68.2, 55.3, 38.8, 38.7, 37.8, 30.1, 29.6, 28.8,
27.9, 27.2, 27.1; FAB-MS: m/z (M + Na)+ calcd 1544.6551, obsd
1544.6523.
1H NMR (500 MHz, CDCl3): 8.01 (d, J ) 7.0 Hz, 1H), 7.51 (t,
J ) 7.5 Hz, 1H), 7.47 (d, J ) 7.5 Hz, 1H), 7.38 (t, J ) 7.5 Hz,
1H), 4.79 (s, 2H), 3.84 (s, 3H); 13C NMR (125 MHz, CDCl3):
167.1, 137.3, 132.7, 131.6, 129.7, 128.7, 128.1, 53.11, 52.21;
FAB-MS: m/z (M + Na)+ calcd 214.0587, obsd 214.0591. To a
stirred solution of methyl 2-(azidomethyl)benzoate (15.0 g,
78.45 mmol) in 192 mL of THF/H2O (10:1) was added LiOH‚
H2O (16.2 g, 41.96). The reaction mixture was stirred at room
temperature for 60 h, diluted with H2O, and extracted twice
with CH2Cl2. The aqueous phase was acidified with 2 N HCl,
and the precipitated acid was extracted three times with
CH2Cl2. The combined organic phases were washed with brine,
dried over Na2SO4, filtered, and concentrated to afford 33 (13.5
g, 97%) in analytically pure form. Characterization data were
consistent with that previously reported.42
2-(Azid om eth yl)ben zoyl Ch lor id e 34. 2-(Azidomethyl)-
benzoic acid 33 (10.45 g, 59 mmol) was dissolved in CHCl3 (100
mL), and thionyl chloride (12.9 mL, 177 mmol) was added. The
reaction mixture was heated to reflux for 5 h, cooled, and
concentrated in vacuo using a base trap. The resulting residue
was coevaporated with toluene (3 × 15 mL) to yield 11.15 g of
34 (97%). IR (thin film): 3071, 2962, 2105, 1769, 1201 cm-1
;
1H NMR (400 MHz, CDCl3): 8.33 (dd, J ) 8.0, 1.2 Hz, 1 H),
7.70 (td, J ) 7.6, 1.3 Hz, 1 H), 7.61 (dd, J ) 7.6, 0.5 Hz, 1 H),
7.54 (td, J ) 7.9, 1.3 Hz, 1 H), 4.76 (s, 2 H); 13C NMR (100
MHz, CDCl3): 138.5, 135.2, 134.7, 131.7, 130.0, 129.7, 128.8,
53.2; ESI-MS: m/z ) (M + Na)+ calcd 195.0200, obsd 195.0217.
P r otection of Alcoh ols w ith AZMB. Gen er a l P r oce-
d u r e A. A solution of the alcohol (1.0 equiv) in CH2Cl2 (10
mL/mmol alcohol) was stirred at room temperature, and
DMAP (2 equiv) was added, followed by a solution of the
2-(methylazido)benzoyl (AZMB) chloride 34 (1.5 equiv) in
CH2Cl2 (1 mL). After 10 min, the reaction mixture was diluted
with CH2Cl2 and washed twice with saturated aqueous
NaHCO3 and once with water. The organic layer was dried
(Na2SO4), filtered, and concentrated in vacuo. The crude
product was purified by flash silica gel column chromatogra-
phy.
n -P en ten yl 3-O-Ben zoyl-6-O-ben zyl-2-d eoxy-2-p h th a l-
im id o-â-D-glu cop yr a n osyl-(1 f 3)-4,6-d i-O-b en zyl-2-O-
p iva loyl-â-D-ga la ctop yr a n osyl-(1 f 4)-3,6-d i-O-ben zyl-2-
O-p iva loyl-â-D-glu cop yr a n osid e 27. To a stirred solution of
26 (54 mg, 0.036 mmol) in 2 mL of CH2Cl2 at room temperature
under N2 was added a solution of hydrazine acetate (90 µL,
0.40 M) in MeOH. The reaction mixture was stirred at room
temperature for 3 h and concentrated, and the crude product
was purified by flash silica column chromatography (50%
EtOAc/hexanes) to afford 27 (49 mg, 98% yield). [R]D: -24.4°
(c ) 1.20, CH2Cl2); IR (thin film) 3481, 2868, 1726, 1386, 1272
Clea va ge of 2-(Azid om eth yl)ben zoa te Ester s. Gen er a l
P r oced u r e B. To a solution of the ester in THF (10 mL/
mmol ester) was added water (5 equiv), followed by tributyl
phosphine (3 equiv). After 30 min, the reaction mixture was
diluted with CH2Cl2 and washed once with saturated aque-
ous NaHCO3 and twice with water. The organic layer was
dried (Na2SO4), filtered, and concentrated in vacuo. The
crude product was purified by flash silica gel column chroma-
tography.
1
cm-1; H NMR (500 MHz, CDCl3): 7.87 (d, J ) 7.0 Hz, 1H),
7.82-7.59 (m, 4H), 7.48 (t, J ) 7.0 Hz, 1H), 7.42-7.20 (m,
26H), 7.08 (t, J ) 8.0 Hz, 1H), 6.96 (t, J ) 8.0 Hz, 1H), 5.99
(dd, J ) 8.5, 11.0 Hz, 1H), 5.78 (m, 1H), 5.37 (d, J ) 8.5 Hz,
1H), 5.12 (dd, J ) 8.0, 10.0 Hz, 1H), 5.07 (d, J ) 11.0 Hz, 1H),
5.01 (m, 1H), 4.95 (m, 1H), 4.87 (d, J ) 10.5 Hz, 1H), 4.73 (d,
J ) 12.0 Hz, 1H), 4.64 (d, J ) 12.0 Hz, 1H), 4.62 (d, J ) 12.0
Hz, 1H), 4.50 (d, J ) 11.0 Hz, 1H), 4.48 (m, 2H), 4.34-4.27
(m, 4H), 4.23 (d, J ) 12.0 Hz, 1H), 4.03 (t, J ) 9.0 Hz, 1H),
3.99-3.81 (m, 7H), 3.70 (m, 2H), 3.41-3.39 (m, 2H), 3.35-
3.29 (m, 3H), 2.13-2.02 (m, 2H), 1.78 (bs, 1H), 1.70-1.59 (m,
2H), 1.16 (s, 9H), 1.13 (s, 9H); 13C NMR (125 MHz, CDCl3):
176.7, 176.6, 167.1, 139.2, 138.8, 138.2, 138.0, 137.7, 134.0,
133.6, 130.0, 128.8, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2,
128.1, 128.0, 127.9, 127.7, 127.3, 126.9, 123.8, 114.9, 101.3,
99.5, 98.0, 81.0, 77.4, 75.4, 75.2, 75.0, 74.7, 74.4, 74.0, 73.9,
73.8, 73.7, 73.6, 72.5, 72.3, 71.9, 70.0, 68.9, 68.4, 68.3, 55.0,
38.9, 38.8, 30.1, 28.9, 27.3, 27.2, 27.1; FAB-MS: m/z (M + Na)+
calcd 1446.6183, obsd 1446.6122.
Meth yl 2-O-Acetyl-6-O-(2-(a zid om eth yl)ben zoyl)-3,4-d i-
O-ben zyl-â-D-glu cop yr a n osid e 35. 6-(2-(Azidomethyl)ben-
zoyl)-O-3,4-di-O-benzyl-â-D-glucopyranoside 49 (117 mg, 0.22
mmol) was dissolved in CH2Cl2 (2 mL), and DMAP (29 mg,
0.26 mmol) and acetic anhydride (25 µL, 0.26 mmol) were
added. After 1 h at room temperature, the reaction mixture
was diluted with CH2Cl2 (20 mL) and washed with saturated
aqueous NaHCO3 (20 mL) and water (20 mL). The organic
layer was dried over Na2SO4, filtered, and concentrated. The
crude product was purified by flash silica gel column chroma-
tography (30% EtOAc/hexanes) to yield 120 mg of 35 (95%).
[R]D: +50.52° (c ) 3.62, CH2Cl2); IR (thin film): 3031, 2884,
2102, 1747, 1719 cm-1; 1H NMR (400 MHz, CDCl3): 7.99 (app
d, J ) 7.8 Hz, 1 H), 7.57 (app t, J ) 7.5 Hz, 1 H), 7.49 (app d,
J ) 7.5 Hz, 1 H), 7.42 (app t, J ) 7.6 Hz, 1 H), 7.35-7.23 (m,
10 H), 5.04-5.00 (m, 1 H), 4.86-4.74 (m, 4 H), 4.71 (d, J )
11.3 Hz, 1 H), 4.63-4.55 (m, 2 H), 4.45 (dd, J ) 11.9, 4.4 Hz,
1 H), 4.34 (d, J ) 7.9 Hz, 1 H), 3.75-3.7 (m, 3 H), 3.46 (s, 3
H), 2.00 (s, 3 H); 13C NMR (100 MHz, CDCl3): 169.9, 166.4,
138.0, 137.6, 137.5, 133.2, 131.5, 130.0, 128.7, 128.7, 128.5,
128.4, 128.4, 128.3, 128.1, 102.0, 83.2, 77.8, 75.4, 73.2, 63.5,
57.0, 53.2, 21.2; ESI-MS: m/z (M + Na)+ calcd 598.2160, obsd
598.2168.
2-(Azid om eth yl)ben zoic Acid 33. To a stirred solution of
methyl 2-methyl benzoate (4.29 g, 28.56 mmol,) in 100 mL of
CCl4 were added NBS (5.1 g, 28.65) and a catalytic amount of
benzoyl peroxide (55 mg, 0.227 mmol). The reaction mixture
was refluxed for 24 h and allowed to cool to room temperature.
Filtration and concentration afforded crude bromide 32, which
was taken up in 80 mL of anhydrous EtOH before NaN3 (1.86
g, 28.65 mmol) was added, and the reaction mixture was
stirred for 48 h at room temperature under N2. The reaction
was quenched with brine and extracted twice with EtOAc. The
combined organic phases were dried over Na2SO4, filtered, and
concentrated. The crude product was purified by flash silica
column chromatography (2% f 5% f 10% EtOAc/hexanes) to
afford 4.58 g (84% for two steps) of methyl 2-(azidomethyl)-
Met h yl 2-O-Acet yl-3,4-d i-O-b en zyl-â-D-glu cop yr a n o-
sid e 39. General procedure B using methyl 2-O-acetyl-6-O-
(2-(azidomethyl)benzoyl)-3,4-O-benzyl-â-D-glucopyranoside 35
(68 mg, 0.118 mmol), water (10 µL, 0.59 mmol), and PBu3 (90
µL, 0.355 mmol) afforded 39 (45 mg, 92%) after purification
benzoate. IR (thin film): 2952, 2109, 1739, 1434, 1263 cm-1
;

Synthesis of an H-Type II Pentasaccharide
J . Org. Chem., Vol. 66, No. 24, 2001 8175
by flash silica gel column chromatography (25% EtOAc/
hexanes). Characterization data were consistent with that
previously reported.54
reaction mixture was neutralized by addition of Et3N, filtered
through a plug of silica, and concentrated in vacuo. The crude
product was purified by flash silica gel column chromatography
(25% EtOAc/hexanes) to yield 54 (97 mg, 88%).
Dibu tyl 2-O-(2-(Azid om eth yl)ben zoyl)-3,4,6-tr i-O-ben -
zyl-â-D-glu cop yr a n osyl P h osp h a te 52. 3,4,6-Tri-O-benzyl
glucal (402 mg, 0.965 mmol) was azeotroped with toluene (3
× 5 mL) and then dried under vacuum for 1 h. A solution of
the glucal in CH2Cl2 (10 mL) was cooled to 0 °C, and dimethyl
dioxirane (20 mL of a 0.08 M solution in acetone, 1.44 mmol)
was added. After 20 min, volatiles were removed under
vacuum, and the resulting residue was dried for 10 min. The
residue was redissolved in CH2Cl2 (10 mL) and cooled to -78
°C, before a solution of dibutyl phosphate (0.23 mL, 1.16 mmol)
in CH2Cl2 (5 mL) was added dropwise over a period of 5 min.
After 10 min, the solution was warmed to 0 °C, and DMAP
(472 mg, 3.86 mmol) and AZMB chloride (377 mg, 1.93 mmol)
were added. After 10 min, the reaction mixture was diluted
with EtOAc (100 mL) and filtered through a plug of silica gel.
The filtrate was concentrated, and the residue was purified
by flash silica gel chromatography (20% EtOAc/hexanes) to
yield 52 (547 mg, 71%) as a white solid. [R]D +17.26° (c ) 1.04,
3,4,6-Tr i-O-ben zyl-â-D-glu cop yr a n osyl-(1 f 6)-1,2;3,4-
d iisop r op ylid en e-r-D-ga la ctop yr a n osid e 55. General pro-
cedure B using disaccharide 54 (121 mg, 0.142 mmol), water
(13 µL, 0.71 mmol), and PBu3 (100 µL, 0.426 mmol) yielded
55 (86 mg, 88%) after purification by flash silica gel column
chromatography (15% EtOAc/hexanes). Characterization data
were consistent with previously reported data.55
Dibu tyl 2-O-(2-(Azid om eth yl)ben zoyl)-3,4,6-tr i-O-ben -
zyl-â-D-ga la ctop yr a n osid e P h osp h a te 61. To a stirred
solution of tri-O-benzyl-D-galactal (505 mg, 1.214 mmol) in 10
mL of CH2Cl2 at 0 °C under N2 was added a solution of
dimethyldioxirane in acetone (23 mL, 0.08 M). The reaction
mixture was stirred for 15 min at 0 °C, and the volatiles were
removed in vacuo. After 1 h under vacuum at 0 °C, 10 mL of
CH2Cl2 were added, and the reaction mixture was cooled to
-78 °C and stirred for 10 min. To the reaction vessel was
added a solution of dibutyl phosphate (277 µL, 1.396 mmol)
in CH2Cl2 (2 mL) dropwise over 5 min and the reaction mixture
was warmed to 0 °C over 5 min. After stirring for 10 min at 0
°C, DMAP (445 mg, 3.642 mmol) was added followed by a
solution of AZMB chloride (475 mg, 2.428 mmol) in CH2Cl2 (2
mL) dropwise over 5 min. The reaction was warmed to room
temperature and stirred for 3 h. The reaction mixture was
diluted with hexanes to precipitate DMAP salts, filtered, and
washed several times with 40% EtOAc/hexanes. The crude
product was concentrated and purified by flash silica column
chromatography (40% EtOAc/hexanes with 1% triethylamine)
to afford of 61 (603 mg, 62% yield). [R]D: +24.2° (c )3.46,
CH2Cl2); IR (thin film) 2960, 2102, 1729, 1259, 1082 cm-1; 1H
NMR (500 MHz, CDCl3): 8.02 (d, J ) 7.7 Hz, 1H), 7.61-7.54
(m, 3H), 7.19-7.04 (m, 16H), 5.72 (dd, J ) 8.0, 10.0 Hz, 1H),
5.35 (t, J ) 8.0 Hz, 1H), 5.02 (d, J ) 11.5 Hz, 1H), 4.83 (d, J
) 15.5 Hz, 1H), 4.79 (d, J ) 15.0 Hz, 1H), 4.68 (d, J ) 8.5 Hz,
1H), 4.66 (d, J ) 8.5 Hz, 1H), 4.47 (d, J ) 11.5 Hz, 1H), 4.46
(s, 2H), 4.08 (d, J ) 1.5 Hz, 1H), 4.07-3.99 (m, 2H), 3.81-
3.62 (m, 6H), 1.62-1.56 (m, 2H), 1.38-1.29 (m, 4H), 1.10-
1.02 (m, 2H), 0.89 (t, J ) 7.5 Hz, 1H), 0.69 (t, J ) 7.5 Hz, 1H);
13C NMR (125 MHz, CDCl3): 165.1, 138.4, 138.1, 137.7, 137.4,
133.1, 131.4, 129.5, 128.6, 128.4, 128.3, 128.1, 128.0, 127.8,
127.7, 97.0, 79.7, 74.8, 74.4, 73.6, 72.2, 72.0, 68.0, 67.9, 32.1,
32.0, 31.9, 31.8, 18.6, 18.4, 13.7, 13.4; 31P NMR (200 MHz,
CDCl3): -2.26; FAB-MS: m/z (M+) calcd 824.3282, obsd
824.3264.
CH2Cl2); IR (thin film): 2961, 2102, 1729, 1076, 1028 cm-1
;
1H NMR (400 MHz, CDCl3): 8.01 (dd, J ) 7.9, 1.1 Hz, 1 H),
7.59 (td, J ) 7.8, 1.3 Hz, 1 H), 7.55-7.53 (m, 1 H), 7.41-7.30
(m, 9 H), 7.23-7.21 (m, 2 H), 7.15-7.10 (m, 5 H), 5.42-5.33
(m, 2 H), 4.86-4.79 (m, 3 H), 4.73 (d, J ) 15.1 Hz, 1 H), 4.65-
4.62 (m, 3 H), 4.55 (d, J ) 12.0 Hz, 1 H), 4.09-4.03 (m, 2 H),
3.94-3.89 (m, 1 H), 3.83-3.72 (m, 4 H), 3.70-3.65 (m, 1 H),
1.63-1.58 (m, 2 H), 1.39-1.27 (m, 4 H), 1.08-1.03 (m, 2 H),
0.89 (t, J ) 7.4 Hz, 3 H), 0.69 (t, J ) 7.4 Hz, 3 H); 13C NMR
(100 MHz, CDCl3): 164.9, 138.4, 138.0, 137.9, 137.7, 133.3,
131.4, 129.4, 128.7, 128.6, 128.4, 128.2, 128.1, 128.1, 127.9,
96.7, 82.3, 77.6, 75.9, 75.3, 75.3, 73.7, 73.5, 73.4, 68.3, 68.2,
68.1, 53.1, 32.2, 32.1, 32.0, 31.9, 18.7, 18.4, 13.7, 13.5; 31P NMR
(120 MHz, CDCl3): -2.21; ESI-MS: m/z (M + Na)+ calcd
824.3283, obsd 824.3299.
2-O-(2-(Azid om et h yl)b en zoyl)-3,4,6-t r i-O-b en zyl-â-D-
glu cop yr a n osyl-(1 f 6)-1,2;3,4-d iisop r op ylid en e-r-D-ga -
la ctop yr a n osid e 54. Method A: Phosphate 52 (75 mg, 0.094
mmol) and 1,2;3,4-diisopropylidene-R-D-galactopyranoside 53
(21 mg, 0.079 mmol) were coevaporated in toluene (3 × 1 mL)
and then dried under vacuum for 1 h. After addition of
CH2Cl2 (1 mL), the solution was cooled -78 °C, and TBSOTf
(20 µL, 0.087 mmol) was added. After 10 min, the mixture was
neutralized with Et3N and concentrated in vacuo. The residue
was purified by flash silica gel chromatography (10% EtOAc/
hexanes) to yield 53 (75 mg, 94%). [R]D -22.76° (c ) 1.96,
CH2Cl2); IR (thin film): 3030, 2933, 2102, 1728, 1073 cm-1
;
n -P en ten yl 2-O-(2-(Azid om eth yl)ben zoyl)-3,4,6-tr i-O-
b en zyl-â-D-ga la ct op yr a n osyl-(1 f 4)-3-O-b en zoyl-6-O-
b en zyl-2-d eoxy-2-p h t h a lim id o-â-D-glu cop yr a n osyl-(1 f
3)-4,6-d i-O-ben zyl-2-O-p iva loyl-â-D-ga la ctopyr a n osyl-(1 f
4)-3,6-d i-O-ben zyl-2-O-p iva loyl-â-D-glu cop yr a n osid e 67.
To a stirred solution of 27 (31 mg, 0.022 mmol) and galactosyl
phosphate 61 (66 mg, 0.127 mmol) in 2.5 mL of CH2Cl2 under
N2 at -60 °C was added TMSOTf (23 µL, 0.127 mmol). The
reaction was stirred at -60 °C for 5 min and allowed to warm
to -50 °C over 5 min. Triethylamine (30 µL) was added, the
solution was concentrated, and the crude product was purified
by flash silica column chromatography (10% EtOAc/toluene)
to afford 67 (41.2 mg, 92% yield). [R]D: -11.5° (c ) 1.95,
CH2Cl2); IR (thin film): 2870, 2102, 1733, 1077 cm-1; 1H NMR
(500 MHz, CDCl3): 7.83 (d, J ) 7.5 Hz, 1H), 7.78 (d, J ) 7.5
Hz, 1H), 7.62-7.58 (m, 6H), 7.42-7.02 (m, 44H), 6.92 (t, J )
7.0 Hz, 1H), 6.10 (t, J ) 9.0 Hz, 1H), 5.77 (m, 1H), 5.51 (t, J
) 9.5 Hz, 1H), 5.34 (d, J ) 8.5 Hz, 1H), 5.07 (t, J ) 8.0 Hz,
1H), 5.02 (d, J ) 11.5 Hz, 1H), 4.96 (d, J ) 11.0 Hz, 1H), 4.92
(d, J ) 15.0 Hz, 1H), 4.90 (d, J ) 17.5 Hz, 1H), 4.83 (m, 2H),
4.76 (d, J ) 15.0 Hz, 1H), 4.69 (d, J ) 12.0 Hz, 1H), 4.60 (d,
J ) 8.0 Hz, 1H), 4.57 (d, J ) 12.5 Hz, 1H), 4.44 (m, 3H), 4.36
(t, J ) 7.5 Hz, 1H), 4.32-4.27 (m, 4H), 4.21-4.05 (m, 4H),
4.05 (s, 2H), 3.98 (t, J ) 9.0 Hz, 1H), 3.57 (d, J ) 10.5 Hz,
1H), 3.44-3.36 (m, 5H), 3.32-3.26 (m, 3H), 3.08 (m, 1H), 3.02
1H NMR (400 MHz, CDCl3): 7.96 (dd, J ) 7.6, 1.1 Hz, 1 H),
7.59-7.53 (m, 2 H), 7.40-7.29 (m, 9 H), 7.22-7.13 (m, 7 H),
5.39 (d, J ) 5.0 Hz, 1 H), 5.31-5.27 (m, 1 H), 4.85-4.77 (m, 4
H), 4.70-4.65 (m, 3 H), 4.62-4.58 (m, 2 H), 4.49 (dd, J ) 8.4,
2.4 Hz, 1 H), 4.22 (dd, J ) 5.0, 2.4 Hz, 1 H), 4.16 (dd, J ) 7.9,
1.8 Hz, 1 H), 4.07 (dd, J ) 11.1, 4.0 Hz, 1 H), 3.90-3.88 (m, 1
H), 3.84-3.82 (m, 2 H), 3.80-3.79 (m, 2 H), 3.71 (dd, J ) 11.1,
7.2 Hz, 1 H), 3.58-3.56 (m, 1 H), 1.27 (s, 3 H), 1.21 (s, 3 H),
1.20 (s, 3 H); 13C NMR (100 MHz, CDCl3): 165.5, 138.3, 138.1,
138.0, 132.7, 131.5, 129.0, 128.8, 128.6, 128.4, 128.2, 128.0,
127.8, 109.4, 108.6, 101.5, 96.3, 82.9, 78.2, 75.4, 75.2, 73.8, 73.7,
71.3, 70.7, 70.5, 68.8, 67.6, 53.2, 26.1, 25.8, 25.6, 24.4; ESI-
MS: m/z (M + Na)+ calcd 874.3521, obsd 874.3496. Method
B: Thiogylcoside 57 (85 mg, 0.13 mmol) and galactopyranoside
53 (41 mg, 0.16 mmol) were coevaporated in toluene (3 × 1
mL) and then dried under vacuum for 1 h. The residue was
dissolved in CH2Cl2 (1 mL) and activated powdered molecular
sieves (4 Å, 200 mg) were added to the solution. The reaction
mixture was cooled to 0 °C and NIS (36 mg, 0.16 mmol) was
added, followed by triflic acid (2 µL, 0.016). After 10 min, the
(52) Schmidt, R. R.; Wegmann, B.; J ung, K.-H. Liebigs Ann. Chem.
1991, 121.
(53) Nashed, M., A.; Slite, C. W.; Kiso, M.; Anderson, L. Carbohydr.
Res. 1980, 82, 237.
(54) Plante, O. J .; Buchwald, S. J .; Seeberger, P. H. J . Am. Chem.
Soc. 2000, 122, 7148.
(55) Love, K. R.; Seeberger, P. H. Synthesis 2001, 317.

8176 J . Org. Chem., Vol. 66, No. 24, 2001
Love et al.
(t, J ) 8.5 Hz, 1H), 2.92 (m, 1H), 2.12-2.01 (m, 2H), 1.68-
1.59 (m, 2H), 1.10 (s, 9H); 13C NMR (125 MHz, CDCl3): 176.7,
176.6, 165.0, 164.9, 139.2, 138.8, 138.7, 138.4, 138.3, 138.0,
138.0, 137.9, 137.7, 133.9, 133.0, 132.9, 131.0, 130.0, 129.8,
129.6, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 127.9, 127.8,
127.7, 127.6, 127.6, 127.5, 127.3, 126.9, 114.9, 101.3, 101.2,
99.5, 97.9, 81.0, 80.0, 76.6, 75.5, 75.1, 74.7, 74.6, 74.5, 74.4,
73.7, 73.6, 73.5, 73.3, 72.8, 72.4, 72.3, 72.2, 71.7, 71.5, 71.3,
68.9, 68.3, 67.8, 67.0, 55.6, 53.1, 38.9, 38.8, 30.2, 28.9, 27.3,
27.2, 25.7; FAB-MS: m/z (M + Na)+ calcd 2037.8552, obsd
2037.8478.
was added, the solution was concentrated, and the crude
product purified by flash silica column chromatography (10%
EtOAc/toluene) to afford 69 (13.9 mg, 94%). [R]D: -32.7° (c )
1.16, CH2Cl2); IR (thin film): 2930, 2869, 1732, 1387, 1268
cm-1 1H NMR (500 MHz, CDCl3): 7.81-7.57 (m, 4H), 7.71
;
(d, J ) 8.5 Hz, 1H), 7.35-6.90 (m, 49H), 6.02 (dd, J ) 9.0,
11.0 Hz, 1H), 5.77 (m, 1H), 5.60 (d, J ) 3.5 Hz, 1H, He-1), 5.39
(d, J ) 8.5 Hz, 1H, Hc-1), 5.36 (dd, J ) 3.0, 10.5 Hz, 1H), 5.28
(d, J ) 3.0 Hz, 1H), 5.15 (dd, J ) 7.5, 10.2 Hz, 1H), 5.09 (d, J
) 11.0 Hz, 1H), 5.05-4.99 (m, 2H), 4.91 (d, J ) 8.0 Hz, 1H),
4.87 (d, J ) 11.0 Hz, 1H), 4.72 (d, J ) 12.0 Hz, 1H), 4.71 (d,
J ) 14.0 Hz, 1H), 4.68 (d, J ) 12.0 Hz, 1H), 4.59 (d, J ) 12.5
Hz, 1H), 4.57 (d, J ) 12.5 Hz, 1H), 4.52 (d, J ) 12.5 Hz, 1H),
4.48-4.41 (m, 3H), 4.38 (d, J ) 7.5 Hz, 1H, Hd-1), 4.35 (d, J )
8.0 Hz, 1H, Hb-1), 4.33-4.30 (m, 4H), 4.29 (d, J ) 7.5 Hz, 1H,
Ha-1), 4.20 (d, J ) 11.5 Hz, 1H), 4.18-4.11 (m, 4H), 4.03-
3.96 (m, 5H), 3.83-3.78 (m, 3H), 3.74-3.65 (m, 4H), 3.49 (t, J
) 6.5 Hz, 1H), 3.46-3.38 (m, 4H), 3.32-3.28 (m, 3H), 3.24 (dd,
J ) 4.5, 9.0 Hz, 1H), 3.05 (dd, J ) 5.0, 9.0 Hz, 1H), 2.68 (t, J
) 9.0 Hz, 1H), 2.14-2.01 (m, 2H), 1.66-1.59 (m, 2H), 1.27 (d,
J ) 6.5 Hz, 3H), 1.18 (s, 9H), 1.16 (s, 9H), 1.14 (s, 9H), 1.09 (s,
9H); 13C NMR (125 MHz, CDCl3): 177.8, 177.6, 176.7, 176.6,
165.2, 139.4, 138.9, 138.8, 138.4, 138.3, 138.2, 138.0, 137.7,
134.0, 132.3, 130.4, 130.0, 128.7, 128.6, 128.5, 128.4, 128.2,
128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 127.4, 127.3, 126.9,
126.3, 123.8, 114.9, 101.3 (Ca-1), 100.2 (Cd-1), 99.7 (Cb-1), 98.5
(Cc-1), 97.1 (Ce-1), 83.6, 81.1, 77.6, 77.4, 75.6, 75.3, 75.2, 74.5,
74.3, 73.7, 73.6, 73.5, 73.4, 73.2, 72.7, 72.5, 72.4, 72.2, 71.8,
71.5, 71.4, 70.8, 70.4, 70.3, 68.9, 68.6, 68.4, 67.7, 67.4, 65.2,
55.4, 39.2, 38.9, 38.8, 30.2, 29.9, 28.9, 27.4, 27.3, 27.2, 15.5;
ESI-MS: m/z (M + 2Na)2+ calcd 1153.0106, obsd 1153.0107.
n -P en ten yl 3,4,6-Tr i-O-ben zyl-â-D-ga la ctop yr a n osyl-(1
f 4)-3-O-ben zoyl-6-O-ben zyl-2-d eoxy-2-p h th a lim id o-â-D-
glu cop yr a n osyl-(1 f 3)-4,6-d i-O-ben zyl-2-O-p iva loyl-â-D-
ga la ctop yr a n osyl-(1 f 4)-3,6-d i-O-ben zyl-2-O-p iva loyl-â-
D-glu copyr an oside 68. General procedure B using tetrasacch-
aride 67 (45 mg, 0.022 mmol), water (4 µL, 0.225 mmol), and
PBu3 (30 µL, 0.112 mmol) after purification by flash silica gel
column chromatography (30% EtOAc/hexanes) afforded 68 (40
mg, 96%). [R]D: -18.1° (c 1.35, CH2Cl2); IR (thin film): 3387,
2868, 2360, 1733, 1070 cm-1; 1H NMR (500 MHz, CDCl3): 7.79
(d, J ) 8.5 Hz, 1H), 7.67-7.58 (m, 4H), 7.41-7.13 (m, 41H),
7.11 (d, J ) 7.0 Hz, 1H), 7.07 (t, J ) 7.5 Hz, 1H), 6.93 (t, J )
7.5 Hz, 1H), 6.55 (dd, J ) 9.0, 11.0 Hz, 1H), 5.77 (m, 1H), 5.39
(d, J ) 8.0 Hz, 1H), 5.11 (t, J ) 10.0 Hz, 1H), 5.04 (d, J ) 10.5
Hz, 1H), 4.99 (d, J ) 18.5 Hz, 1H), 4.93 (d, J ) 12.5 Hz, 1H),
4.90 (d, J ) 9.5 Hz, 1H), 4.86 (d, J ) 10.5 Hz, 1H), 4.74 (d, J
) 8.0 Hz, 1H), 4.72 (d, J ) 8.0 Hz, 1H), 4.64 (d, J ) 9.0 Hz,
1H), 4.60 (d, J ) 9.0 Hz, 1H), 4.52 (d, J ) 11.5 Hz, 1H), 4.47
(d, J ) 13.0 Hz, 1H), 4.44 (d, J ) 12.5 Hz, 1H), 4.39 (d, J )
12.0 Hz, 1H), 4.37 (d, J ) 8.5 Hz, 1H), 4.33-4.27 (m, 6H), 4.18
(d, J ) 12.0 Hz, 1H), 4.17 (d, J ) 7.0 Hz, 1H), 4.06-3.99 (m,
6H), 3.88-3.80 (m, 4H), 3.79 (d, J ) 1.5 Hz, 1H), 3.68 (s, 2H),
3.46-3.38 (m, 3H), 3.36-3.22 (m, 2H), 3.21 (dd, J ) 2.5, 9.7
Hz, 1H), 2.97 (d, J ) 8.0 Hz, 1H), 2.79 (s, 1H), 2.73 (q, J ) 4.5
Hz, 1H), 2.10-2.01 (m, 2H), 1.67-1.59 (m, 3H), 1.14 (s, 9H),
1.10 (s, 9H); 13C NMR (125 MHz, CDCl3): 176.8, 176.7, 165.1,
139.3, 139.0, 138.9, 138.3, 138.1, 137.9, 137.8, 133.0, 130.0,
129.9, 128.7, 128.6, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8,
127.7, 127.5, 127.4, 126.9, 114.9, 104.0, 101.4, 99.6, 98.2, 81.8,
81.1, 75.6, 75.3, 74.8, 74.6, 74.5, 74.4, 73.8, 73.7, 73.6, 73.3,
73.0, 72.5, 72.4, 72.1, 72.0, 71.8, 71.7, 69.0, 68.4, 67.1, 55.6,
39.0, 38.9, 30.2, 29.0, 27.3, 27.2; FAB-MS: m/z (M + Na)+ calcd
1878.8120, obsd 1878.8152.
Ack n ow led gm en t. Financial support from the do-
nors of the Petroleum Research Fund, administered by
the American Chemical Society (ACS-PRF 34649-G1),
for partial support of this research; the Mizutani
Foundation for Glycoscience; the NIH (Biotechnology
Training Grant for K.R.L.); and NSF (Predoctoral Fel-
lowship for R.B.A.) is gratefully acknowledged. Funding
for the MIT-DCIF Inova 501 was provided by NSF
(Award no. CHE-9808061). Funding for the MIT-DCIF
Avance (DPX) 400 was provided by NIH (Award no.
1S10RR13886-01). Funding for the MIT-DCIF Mercury
300 was provided by NSF (Award no. CHE-9808061)
and NSF (Award no. DBI-9729592).
n -P en ten yl 2-O-Ben zyl-3,4-d i-O-p iva loyl-r-L-fu cop yr a -
n osyl-(1 f 2)-3,4,6-tr i-O-ben zyl-â-D-ga la ctop yr a n osyl-(1
f 4)-3-O-ben zoyl-6-O-ben zyl-2-d eoxy-2-p h th a lim id o-â-D-
glu cop yr a n osyl-(1 f 3)-4,6-d i-O-ben zyl-2-O-p iva loyl-â-D-
ga la ctop yr a n osyl-(1 f 4)-3,6-d i-O-ben zyl-2-O-p iva loyl-â-
D-glu copyr an oside 69. To a stirred solution of tetrasaccharide
acceptor 68 (12.1 mg, 0.0065 mmol) and fucosyl phosphate 65
(39.7 mg, 0.0645 mmol) in 1.5 mL of CH2Cl2 under N2 at -55
°C was added TBSOTf (15 µL, 0.0645 mmol). The reaction was
stirred at this temperature for 10 min. Triethylamine (60 µL)
Su p p or tin g In for m a tion Ava ila ble: Detailed experi-
mental procedures and compound characterization data, in-
cluding 1H NMR, 13C NMR, and 31P NMR spectral data for all
described compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O015987H