Synthesis of a potent antagonist of E-selectin.

Article abstract of DOI:10.1021/jo0110956

A synthesis of an antagonist of E-selectin previously reported by a group at Novartis Pharma in Basel is described. An important feature involves the formation of an ether linkage based on a Rh(II)-catalyzed reaction. Stereocontrolled glycosylations rely on the anomeric activation of 2-pyridylthio carbonate as leaving group for the attachment of beta-D-galactopyranosyl and alpha-L-fucopyranosyl units on a common 1,5-anhydro D-glucitol scaffold.

Full text of DOI:10.1021/jo0110956

3346
J . Org. Chem. 2002, 67, 3346-3354
Syn th esis of a P oten t An ta gon ist of E-Selectin
Stephen Hanessian,* Vincent Mascitti, and Olivier Rogel
Department of Chemistry, Universite´ de Montre´al, C.P. 6128, Succursale Centre-ville,
Montre´al, Que´bec H3C 3J 7 Canada
stephen.hanessian@umontreal.ca
Received November 21, 2001
A synthesis of an antagonist of E-selectin previously reported by a group at Novartis Pharma in
Basel is described. An important feature involves the formation of an ether linkage based on a
RhII-catalyzed reaction. Stereocontrolled glycosylations rely on the anomeric activation of 2-py-
ridylthio carbonate as leaving group for the attachment of â-D-galactopyranosyl and R-L-
fucopyranosyl units on a common 1,5-anhydro D-glucitol scaffold.
In tr od u ction
in an effort to develop antagonists to the natural recep-
tors such as E-selectin.5 Numerous carbohydrate-type6
and related structures consisting of hybrid molecules7
have been reported, with binding affinities in the low
micromolar level.8 A common design element has capital-
ized on the nature of the known pharmacophores involved
in the recognition between sialyl Lewisx and E-selectin.
Thus, the 3,4-hydroxyl groups of L-fucosyl and the 6-hy-
droxyl group of D-galactosyl units are essential for
The recruitment and extravasation of leukocytes from
the blood stream to the locus of inflammation in tissues
is an essential immune-modulated process leading to
beneficial effects and healing.1 However, excessive re-
cruitment and influx of leukocytes at the site of injury
may result in adverse reactions that can be manifested
in reperfusion injuries, stroke, rheumatoid arthritis,
asthma, diabetes, and other acute or chronic health
problems.2 The phenomenological and molecular basis for
initiating the physiological events associated with the
over-recruitment of leukocytes are reasonably well un-
derstood.3 Endothelial cells lining the inner walls of blood
vessels express adhesion molecules called E- and P-
selectin when activated or induced. The sialyl Lewisx
tetrasaccharide expressed on the surface of glycoproteins
of leukocytes are common epitopes recognized by the
selectins.4 In a cascade of events, leukocytes are recog-
nized by these physiological ligands through specific
interactions with pharmacophoric groups on the sialyl
Lewisx epitope. A rolling process of leukocytes on the
endothelial cells at the inner blood vessels ensues, leading
to excessive recruitment at the site of tissue inflamma-
tion. What follows is extravasation into the affected sites
with beneficial or adverse effects.
(5) For pertinent reviews, see: (a) Simanek, E. E.; McGarvey, G.
J .; J ablonski, J . A.; Wong, C.-H. Chem. Rev. 1998, 98, 833. (b) Roy, R.
In Carbohydrates in Drug Design; Witczak, Z. J ., Nieforth, K. A., Eds.;
Marcel Dekker: New York, 1997; p 83. (d) Musser, J . H.; Anderson,
M. B.; Levy, D. E. Curr. Pharm. Des. 1995, 1, 221.
(6) For selected examples, see ref 5; see also: (a) Ramphal, J . Y.;
Hiroshige, M.; Lou, B.; Gaudino, J . J .; Hayashi, M.; Chen, S. M.;
Chiang, L. C.; Gaeta, F. C. A.; De Frees, S. A. J . Med. Chem. 1996, 39,
1357. (b) Wong, C.-H.; Halcomb, R. L.; Ichikawa, Y.; Kajimoto, T.
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Kiso, M.; Hasegawa, A. J . Med. Chem. 1996, 39, 1339. (d) Vig, R. J ain,
R. K.; Piskorz, C. F.; Matta, K. L. J . Chem. Soc., Chem. Commun. 1995,
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Kiessling, L. L. J . Org. Chem. 1995, 60, 6254.
(7) For peptide and amino acid-based analogues, see: (a) Hanessian,
S.; Huynh, H. K.; Reddy, G. V.; McNaughton-Smith, G.; Ernst, B.; Kolb,
H. C.; Magnani J . L. Bioorg. Med. Chem. Lett. 1998, 8, 2803. (b)
Tsukida, T.; Moriyama, H.; Kurokawa, K.; Achiha, T.; Inoue, Y.; Kondo,
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Kondo, H. Bioorg. Med. Chem. Lett. 2000, 10, 1827. (d) Tsai, C.-Y.;
Park, W. K. C.; Weitz-Schmidt, G.; Ernst, B.; Wong, C.-H. Bioorg. Med.
Chem. Lett. 1998, 8, 2333. For analogues with partial carbohydrate
components, see: (e) Kaila, N.; Thomas, B. E., IV; Thakker, P.; Alvarez,
J . C.; Camphausen, R.; Crommie, D. Bioorg. Med. Chem. Lett. 2001,
10, 151. (f) Kretzchmar, G. Tetrahedron 1998, 54, 3765. (g) Murphy,
P. V.; Hubbard, R. E.; Manallack, D. T.; Montana, J . G.; Taylor, R. J .
K. Tetrahedron Lett. 1998, 39, 3273. (h) Hanessian, S.; Reddy, G. V.;
Huynh, H. K.; Pan, J .; Pedatella, S.; Ernst, B.; Kolb, H. C. Bioorg.
Med. Chem. Lett. 1997, 7, 2729. (i) Bamford, M. J .; Bird, M.; Gore, P.
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D.; Huryn, D. M. Tetrahedron Lett. 1996, 37, 3785. (k) Kaila, N.; Yu,
H.-A.; Xiang, Y. Tetrahedron Lett. 1995, 36, 5503. (l) Heskamp, B. M.;
Veeneman, G. H.; van der Marel, G. A.; van Boeckel, C. A. A.; van
Boom, J . H. Rec. Trav. Chim. Pays-Bas 1995, 114, 398. (m) Kogan, T.
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Tetrahedron 1997, 53, 2485.
Extensive studies on the design and synthesis of
molecules that mimic sialyl Lewisx have been reported
* To whom correspondence should be addressed. Tel: (514) 343-
6738. Fax: (514) 343-5728.
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64, 113. (c) Bevilacqua, M. D. Annu. Rev. Immunol. 1993, 11, 767. (d)
Paulson, J . C. In Adhesion, Its Role in Inflammatory Disease; Harlan,
J . M., Liu, D. Y., Eds.; Freeman, New York, 1992; Chapter 2, p 19.
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D. A.; Springer, T. A. Nature 1995, 374, 539. (b) Springer, T. A. Cell
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10.1021/jo0110956 CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/24/2002

Synthesis of a Potent Antagonist of E-Selectin
J . Org. Chem., Vol. 67, No. 10, 2002 3347
binding to a calcium ion.9 The carboxylic acid group is
involved in the formation of a salt bridge with an arginine
residue in the receptor. Extensive studies involving
molecular modeling,10 NMR,11 and X-ray crystallogra-
phy12 have delineated the importance of attaining an
optimal bioactive conformation for efficient binding to
E-selectin. Within the group of carbohydrate-type pseu-
dosaccharide antagonists, the incorporation of an R-L-
fucosyl and a â-D-galactosyl unit that strategically mimic
their counterparts in sialyl Lewisx appears to be essential
for good binding. The GlcNAc moiety can be replaced by
simple carboxylic13,14 or heterocyclic units.7a Perhaps the
most revealing modification was the replacement of the
N-acetylneuraminyl portion in sialyl Lewisx with an
S-cyclohexyl-2-propionic acid group attached as an R-ether
linkage to the C-4 position of D-gal.15,16 A series of related
analogues and their binding affinities expressed as IC50
values is shown in Figure 1. Starting with sialyl Lewisx
1 at IC50 ) 1000 µM, it is clear that considerable
flexibility exists with regard to the GlcNAc portion
provided the replacement motif is cyclic. The need for a
hydrophobic unit associated with the N-acetylneuraminyl
portion is evident in comparing glycolic acid and R-sub-
stituted variants. The most active analogue is repre-
sented by structure 2,16 which is represented in two
perspective drawings. This structure was arrived at by
refinements in the GlcNAc mimetic portion by replacing
it with an 1,5-anhydro-2-deoxy-D-xylo-hexitol unit,17 to
which were glycosidically linked â-D-gal and R-L-fucosyl
units at C-3 and C-4, respectively. The importance of
(9) (a) Tyrrell, D.; J ames, P.: Rao, N.; Foxall, Cl; Abbas, S.;
Dasgupta, F.; Nashed, M.; Hasegawa, A.; Kiso, M.; Asa, D.; Kidd, J .;
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5449. (d) Lin, Y.-C.; Hummel, C. W.; Huang, D.-H.; Ichikawa, Y.;
Nicolaou, K. C.; Wong, C.-H. J . Am. Chem. Soc. 1992, 114, 5452.
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Rumberger, J . M.; Lis, S.; Huang, K.-S.; Presky, D. H.; Familletti, P.
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Appl. Chem. 1997, 69, 1879.
F igu r e 1. Some E-selectin carbohydrate-based antagonists
(refs 16 and 18).
preorganization of the bioactive conformation of 2, as well
as multivalency was recently confirmed.16
The synthesis and biological evaluation of 2 and related
analogues was reported by Thoma and co-workers18 at
Novartis Pharma in Basel, jointly with Patton and
Magnani of Glycotech. Their synthesis strategy as il-
lustrated in Figure 2 relies on glycosylations with D-gal19
and R-L-fucosyl20 thioglycosides. The crucial R-glycolate
ether linkage was achieved by treatment of the 3,4-
(15) J anke, W.; Kolb, H. C.; Blommers, M. J . J .; Magnani, J . L.;
Ernst, B. Angew. Chem., Int. Ed. Engl. 1997, 36, 2603.
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R.; J ahnke, W.; Magnani, J . L.; Patton, J . T. Angew. Chem., Int. Ed.
2001, 40, 3644. (c) Thoma, G.; Duthaler, R. O.; Magnani, J . L.; Patton,
J . T. J . Am. Chem. Soc. 2001, 123, 10113.
(18) Thoma, G.; Kinzy, W.; Bruns, C.; Patton, J . T.; Magnani, J . L.;
Ba¨nteli, R. J . Med. Chem. 1999, 42, 4909.
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Chem. 1986, 51, 5472. (c) Giuliano, R. M.; J ordan, A. D., J r.; Gauthiere,
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1989, 193, 283.
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Carbohydr. Res. 1990, 201, 15.

3348 J . Org. Chem., Vol. 67, No. 10, 2002
Hanessian et al.
alternative methods for ether formation, not relying on
tin-mediated activation of hydroxyl groups was another
challenge.
Figure 3 shows critical disconnections starting with 2,
where glycoside formation relies on a stereocontrolled
R-L-fucosylation and â-D-galactosylation reactions with
a common 2-thiopyridyl carbonate (TOPCAT) leaving
group.27 Etherification would involve a RhII-catalyzed
carbene insertion reaction,28 followed by a Horner-
Wadsworth-Emmons extension and catalytic hydroge-
nation.
The readily available preferentially protected trimeth-
ylsilylethyl â-D-galactopyranoside 329 was treated with
methyl diazo(dimethoxyphosphoryl)acetate30 under RhII
catalysis31 to afford the 3-O-R-phosphonoacetate 5 as a
mixture of epimers in 72% yield (Scheme 1). Olefination
with cyclohexane carboxyaldehyde in the presence of
DBU and lithium chloride32 afforded 6 as a major isomer
in a 9:1 mixture in 97% yield as evidenced by NOE
studies. Hydrogenation with 20% palladium hydroxide
on carbon33 (Pearlman’s catalyst, Degussa), followed by
treatment with benzaldehyde dimethylacetal in the pres-
ence of fluoroboric acid34 led to a single isomer 7.
Benzoylation afforded a crystalline product 8, suitable
for single-crystal X-ray analysis as shown in the ORTEP
drawing in Scheme 1. Thus, the correct stereochemistry
at the R-cyclohexyl glycolate carbon atom was secured.
Scheme 2 shows the conversion of 8 into the required
activated glycosyl donor 11. In preliminary studies,
several conditions normally utilized to cleave silyl gly-
cosides such as TBAF/AcOH, TBAF/THF, or CsF/DMF,
with or without 18-crown-6, resulted in recovery of
starting material, even when heated (i.e., CsF/DMF,
MeCN, or THF). Cleavage was successfully achieved with
TFA in CH2Cl2 at 0 °C within 20 min, which also led to
the hydrolysis of the benzylidene acetal. Subsequent
steps involved acetal formation to 10 and esterification27
with di(S-2-pyridyl) thiocarbonate35 at the anomeric
center to give the glycosyl donor 11 as a pale yellow solid
in excellent yield.
F igu r e 2. Novartis Pharma disconnection of antagonist 2 (ref
18).
stannylidene acetal derived from the D-gal unit with the
triflate ester prepared from methyl 3-cyclohexyl-2R-
hydroxy propionate.21 This regioselective activation of
vicinal diols via organotin derivatives in SN2-type etheri-
fications is well-known.22 Further elaboration afforded
the intended target 2, which proved to be approximately
30 times more active than sialyl Lewisx in a static cell-
free E-selectin binding assay.
Our interest in the synthesis of 2 was motivated by a
number of considerations and challenges. Foremost
among these was the need to explore methodology that
did not utilize thioglycosides23 or other relatively labile
activating groups24 as glycosyl donors. Another factor was
to avoid organotin chemistry late in the synthesis, to
render a potential scale-up of the process practical.25 We
considered these issues as a good opportunity to apply
recently developed glycosylation methods that rely on the
remote activation concept26 utilizing shelf-stable and
often crystalline glycosyl donors. The exploration of
The acceptor disaccharide unit was prepared form the
readily available 1,5-anhydro-D-xylo-hexitol derivative
1317 (Scheme 3). Benzylation afforded 14, which was
subjected to reductive cleavage36 of the 4,6-O-benzylidene
acetal to afford the 6-O-benzyl derivative 15. Glycosyla-
tion with L-fucosyl 2-thiopyridyl carbonate donor 16
proceeded in nearly quantitative yield to give the desired
R-L-fucosylated disaccharide 17. Subsequent debenzoyl-
ation gave the desired acceptor 18.
(27) See, for example: (a) Hanessian, S.; Huynh, H. K.; Reddy, G.
V.; Duthaler, R. O.; Katopodis, A.; Streiff, M. B.; Kinzy, W.; Ohrlein,
R. Tetrahedron 2001, 57, 3281. (b) Lou, B.; Huynh, H. K.; Hanessian,
S. In Preparative Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel
Dekker: New York, 1997; Chapter 19, p 431.
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(28) For reviews, see: (a) Miller, D. J .; Moody, C. J . Tetrahedron
1995, 51, 10811. (b) Kirmse, W. In Advances in Carbene Chemistry;
Brinker, V., Ed.; J AI Press: Greenwich, CT, 1994; Vol. 1, p 1. (c)
Adams, J .; Spero, D. M. Tetrahedron 1991, 47, 1769.
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see: (c) David, S.; Hanessian, S. Tetrahedron 1985, 41, 643.
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Academic: Chichester, 1996; Chapter 4, p 82. (b) Garegg, P. Adv.
Carbohydr. Chem. Biochem. 1997, 52, 179.
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(25) For a discussion on large-scale synthesis of sialyl Lewisx, see:
Kretschmar, G.; Stahl, W. Tetrahedron 1998, 54, 6341.
(26) For a review, see: (a) Hanessian, S.; Lou, B. Chem. Rev. 2000,
100, 4443. Hanessian, S. In Preparative Carbohydrate Chemistry;
Hanessian, S., Ed.; Marcel Dekker: New York, 1997; Chapter 16, p
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Masamune S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 29, 2183.
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97.

Synthesis of a Potent Antagonist of E-Selectin
J . Org. Chem., Vol. 67, No. 10, 2002 3349
F igu r e 3. Disconnective analysis.
The â-D-galactosylation reaction required careful ex-
perimentation no doubt due to the hindered nature of
the hydroxyl group in 18. Under previously successful
conditions using silver triflate37 as promoter in the
presence of 4 Å molecular sieves, and tetramethylurea37a,b
as an acid scavenger, only low yields of the expected
trisaccharide 19 were obtained. Eventually, it was found
that pretreatment of the acceptor 18 with sodium hy-
dride, followed by addition of silver triflate, and finally
adding the donor 11 led to the target trisaccharide 19 in
∼50% yield (Scheme 4). Cleavage of the methyl ester
afforded the corresponding carboxylic acid 20 in quanti-
tative yield. Debenzoylation required refluxing in metha-
nol in the presence of sodium methoxide affording the
penultimate precursor 21 in excellent yield. Removal of
the benzyl ethers utilizing Pearlman’s catalyst33 under
60 psi of hydrogen in a mixture of aqueous dioxane
containing acetic acid, followed by conversion to the
sodium salt, afforded the target inhibitor 2 in quantita-
tive yield.
yields of two glycosylations utilizing the 2-thiopyridyl
carbonate group in the synthesis described herein was
also 73%. The critical etherification reaction in our
synthesis relied on the generation of a vinyl ether and a
highly stereoselective catalytic hydrogenation proceeding
in a combined yield of ∼90%. Overall, the synthesis of 2
is convergent, high yielding in many steps, with the
added advantage of a crystalline advanced intermediate,
thus adding an element of practicality.
Exp er im en ta l Section
Solvents were distilled under a positive pressure of dry
nitrogen before use and dried by standard methods; THF and
ether, from Na/benzophenone; and CH2Cl2, from CaH2. All
commercially available reagents were used without further
purification. All reactions were performed under nitrogen
atmosphere. NMR (1H, 13C) spectra were recorded on AMX-
300 and ARX-400 spectrometers. The term [(-)] in 13C data
refers to the sign of the corresponding peak in the DEPT 135
NMR experiment. Low- and high-resolution mass spectra were
recorded on Finningan MAT 900, VG Micromass, Ael-MS902,
or Kratos MS-50 spectrometers using fast atom bombardment
(FAB) or electrospray techniques. Optical rotations were
recorded on a Perkin-Elmer 241 polarimeter in a 1 dm cell at
ambient temperature. Analytical thin-layer chromatography
was performed on Merck 60F254 precoated silica gel plates.
Visualization was done by ultraviolet light and/or by staining
with ceric ammonium molybdate. Flash column chromatog-
raphy38 was performed using (40-60 µM) silica gel at increased
pressure.
We have described a new and practical synthesis of
the potent carbohydrate-based E-selectin inhibitor 2,
utilizing a strategy that avoids thioglycosides as glycosyl
donors and organotin activation late in the synthesis. The
combined yields of R-L-fucosylation and â-D-galactosyla-
tion reactions utilizing thioethyl anomeric activation in
the Novartis synthesis was 73%.18 Coincidentally the
Meth yl Dia zo(d im eth oxyp h osp h or yl)a ceta te (4).30 To
a suspension of t-BuOK (dried overnight under vacuum over
(37) (a) Hanessian, S.; Banoub, J . Carbohydr. Res. 1977, 53, C13.
(b) Methods. Carbohydr. Chem. 1980, 8, 243. See also: (c) Schuerch,
C.; Kronzer, F. J . Carbohydr. Res. 1973, 27, 379. For
a recent
application to glycopeptides, see: Polt, R.; Szabo´, L.; Treiberg, J .; Li,
Y.; Hruby, V. J . J . Am. Chem. Soc. 1992, 114, 10249.
(38) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

3350 J . Org. Chem., Vol. 67, No. 10, 2002
Hanessian et al.
Sch em e 1
Sch em e 3
dropwise at 5 °C. After further stirring for 2 h, the mixture
was filtered and concentrated, and the residue was purified
by flash chromatography on neutral alumina, eluting with
benzene/hexanes 1:1 to give 4 (3.9 g, 54%): bp 110 °C/10
1
mmHg (lit.30 bp 65-69 °C/0.002 Torr); H NMR (CDCl3, 400
3
MHz) δ 3.84 (d, 3H, CO2CH3), 3.81 (d, 6H, P(OCH3)2, J H-P
)
)
2
3.5 Hz); 13C NMR (CDCl3, 100 MHz) δ 163.5 (d, CO, J C-P
1
12.5 Hz), 128.4 (d, CN2, J C-P ) 81 Hz), 53.7 (d, P(OCH3)2,
2J C-P ) 6 Hz), 52.5 (s, OCH3); 31P NMR (CDCl3, 162 MHz) δ
13.8; IR (film, cm-1) 2134, 1711, 1288, 1029; HR-FABMS calcd
for C5H9O5N2PNa m/z 231.01468, found 231.01465.
2-(Tr im eth ylsilyl)eth yl O-2,4,6-Tr i-O-ben zyl-3-O-[(E)-
1-(m eth oxyca r bon yl)-2-cycloh exyleth ylen -1-oxy]-â-D-ga -
la ctop yr a n osid e (6). A mixture of 2-(trimethylsilyl)ethyl
2,4,6-tri-O-benzyl-â-D-galactopyranoside29 3 (4.67 g, 8.48 mmol),
methyl diazo(dimethoxyphosphoryl)acetate 4 (3.53 g, 2 equiv),
and rhodium(II) acetate dimer (150 mg, 2 mol %/4) in benzene
(280 mL) was refluxed for 5 h. After filtration on Celite and
concentration, the residue was purified by flash chromatog-
raphy on silica gel, eluting with ethyl acetate/hexanes 35:65,
to give a 1:1 diastereomeric mixture of phosphonates 5 and 5′
(4.43 g, 71.5%): HR-FABMS calcd for C37H51O11PSiNa m/z
753.28360, found 753.28296.
A solution of the above mixture (2.80 g, 3.82 mmol), lithium
chloride (dried under vacuum over P2O5 before use) (195 mg,
1.2 equiv), and DBU (distilled under reduced pressure over
CaH2 before use) (630 µL, 1.1 equiv) dissolved in acetonitrile
(38 mL) was stirred at rt for 30 min, and then cyclohexane
carboxaldehyde (510 µL, 1.1 equiv) was added dropwise at 0
°C and the mixture stirred at this temperature for 15 min
(formation of a yellow precipitate). The resulting mixture was
concentrated, redissolved in dichloromethane (50 mL), and
washed with saturated aqueous ammonium chloride (40 mL)
and 1 M aqueous hydrogen chloride (20 mL). The organic phase
was dried (sodium sulfate) and concentrated. The residue was
purified by flash chromatography on silica gel, eluting with
ethyl acetate/hexanes 1:9, to give a 9:1 inseparable mixture
of isomers (2.65 g, 97%). Data for the major isomer 6: [R]D
Sch em e 2
1
-13.8 (c 1.0, CHCl3); H NMR (CDCl3, 400 MHz, assigned by
COSY45) δ 7.41-7.28 (m, 15H, ArH), 5.51 (d, 1H, Hvinylic, J )
9.9 Hz), 4.98 (d, 1H, PhCHH-, J ) 11.7 Hz), 4.93 (d, 1H,
PhCHH-, J ) 10.8 Hz), 4.73 (d, 1H, PhCHH-, J ) 10.8 Hz),
4.64 (d, 1H, PhCHH-, J ) 11.7 Hz), 4.46 and 4.41 (AB, 2H,
PhCH2-, J ) 11.7 Hz), 4.41 (d, 1H, H-1, J 1,2 ) 7.6 Hz), 4.08-
4.00 (m, 2H, H-4 and -OCHHCH2TMS), 3.97 (dd, 1H, H-3,
J 3,2 ) 9.7 Hz, J 3,4 ) 2.9 Hz), 3.86 (dd, 1H, H-2), 3.75 (s, 3H,
OCH3), 3.63-3.55 (m, 4H, H-5, H-6, H-6A and -OCHHCH2-
TMS), 2.84 (m, 1H, -CH-), 1.71-1.68 (m, 6H, -CH2-), 1.36-
0.98 (2m, 6H, -CH2- and -CH2TMS), 0.03 (s, 9H, -Si(CH3)3);
13C NMR (CDCl3, 100 MHz) δ 164 (CO), 143.8, 138.9 (2C) and
138.1 (ArC), 128.5, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8,
P2O5) (5.17 g, 46.2 mmol) in toluene (200 mL) cooled at 0 °C
was added dropwise a solution of methyl (dimethoxyphospho-
ryl)acetate (7.00 g, 38.5 mmol) in toluene (20 mL) while
maintaining the temperature below 5 °C. The viscous mixture
was stirred for 1 h, and a solution of naphthalenesulfonyl
azide30 (9.05 g, 38.8 mmol) in toluene (20 mL) was added

Synthesis of a Potent Antagonist of E-Selectin
J . Org. Chem., Vol. 67, No. 10, 2002 3351
Sch em e 4
127.6 and 127.4 (ArCH), 103.5 (C-1), 82.7, 80.0, 73.8, 73.4 (C-2
to C-5), 75.0, 74.6, 73.5 [(-), PhCH2-], 69.0 and 67.6 [(-), C-6
and -OCH2CH2TMS], 51.7 (-OCH3), 36.0 (-CH-), 33.7, 33.5,
26.0, 25.9 (2C) [(-), -CH2-], 18.6 [(-), -CH2TMS], -1.3 [-Si-
(CH3)3]; IR (film, cm-1) 2926, 2852, 1724, 1249, 1216, 1102,
1076; HR-FABMS calcd for C42H56O8SiNa m/z 739.36422,
found 739.36364.
rt for 12 h. After concentration, the residue was purified by
flash chromatography on silica gel, eluting with ethyl acetate/
hexanes 2:8, to give 9 (104 mg, 99%) as a syrup: [R]D -37 (c
1.0, CHCl3); 1H NMR (CDCl3, 400 MHz, assigned by COSY45)
δ 7.50 (d, 2H, ArH, J ) 7.1 Hz), 7.35 (m, 3H, ArH), 5.59 (s,
1H, PhCH(O)(O)-), 4.66 (dd, 1H, H-2, J 2,3 ) 10.1 Hz, J 2,1
)
7.7 Hz), 4.58 (m, 1H, -OCHCO2Me), 4.57 (d, 1H, H-1), 4.37
(fdd, 1H, H-6, J 6,6A ) 12.5 Hz, J 6,5 ) 1.3 Hz), 4.33 (fd, 1H, H-4,
J 4,3 ) 3.1 Hz), 4.11 (fdd, 1H, H-6A, J 6A,5 ) 1.3 Hz), 4.10 (m,
1H, -OCHHCH2TMS), 3.78 (dd, 1H, H-3), 3.63 (m, 1H,
-OCHHCH2TMS), 3.53 (brs, 1H, H-5), 1.88-1.50 (m, 9H,
-CH2- and -CH-), 1.30-0.80 (m, 6H, -CH2- and -CH2-
TMS), 0.03 (s, 9H, -Si(CH3)3); 13C NMR (CDCl3, 100 MHz) δ
170.2 (CO), 137,5 (ArC), 129.3, 128.4 (2C) and 126.5 (2C)
(ArCH), 101.2 and 100.0 (PhCH(O)(O)- and C-1), 74.5, 74.1,
72.3, 71.4 and 66.8 (C-2 to C-5 and -OCHCO2Me), 69.3 and
67.7 [(-), C-6 and -OCH2CH2TMS], 38.6, 34.1, 32.1, 26.6, 26.4
and 26.1 [(-), -CH2-], 33.7 (-CH-), 18.2 [(-), -CH2TMS],
-1.2 [-Si(CH3)3]; IR (film, cm-1) 2925, 2853, 1756, 1251, 1049;
HR-FABMS calcd for C27H40O7SiNa m/z 527.24410, found
527.24440.
2-(Tr im eth ylsilyl)eth yl O-2-O-Ben zoyl-4,6-O-ben zyli-
den e-3-O-[(S)-1-(m eth oxycar bon yl)-2-cycloh exyleth yloxy]-
â-D-ga la ctop yr a n osid e (8). To a cold solution of 7 (300 mg,
559 µmol) in dichloromethane (5.6 mL) and pyridine (1.1 mL)
were added benzoyl chloride (325 µL, 5 equiv) and a catalytic
amount of DMAP at 0 °C. The mixture was stirred at rt
overnight. The excess of benzoyl chloride was quenched with
MeOH and the mixture concentrated under vacuum. The crude
product was redissolved in dichloromethane (25 mL), washed
with aqueous saturated ammonium chloride (20 mL) and
water (20 mL), and dried (sodium sulfate). After concentration,
the residue was purified by flash chromatography on silica gel,
eluting with ethyl acetate/hexanes 3:7, to give 8 (359 mg,
100%) as a white solid. White needle-shaped crystals were
obtained by recrystallization from a mixture of hexanes/ethyl
acetate: mp 160 °C; [R]D +10 (c 0.2, CHCl3); 1H NMR (CDCl3,
400 MHz, assigned by COSY45) δ 8.08 (d, 2H, ArH, J ) 7.1
Hz), 7.60-7.30 (3m, 8H, ArH), 5.61 (dd, 1H, H-2, J 2,3 ) 10.0
Hz, J 2,1 ) 8.0 Hz), 5.58 (s, 1H, PhCH(O)(O)-), 4.60 (d, 1H,
H-1), 4.46 (fd, 1H, H-4, J 4,3 ) 3.5 Hz), 4.35 (fdd, 1H, H-6, J 6,6A
) 12.3 Hz, J 6,5 ) 1.5 Hz), 4.13 (m, 1H, -OCHCO2Me), 4.11
(fdd, 1H, H-6A, J 6A,5 ) 1.5 Hz), 4.00 (m, 1H, -OCHHCH2TMS),
3.76 (dd, 1H, H-3), 3.58 (s, 3H, OCH3), 3.54 (m, 1H, -OCHHCH2-
TMS), 3.48 (brs, 1H, H-5), 1.57 (m, 1H, -CHHCHCO2Me-),
1.50-1.20 (m, 7H, -CH2- and -CHHCHCO2Me-), 0.95-0.75
(m, 5H, -CH2-, -CH- and -CH2TMS), 0.71-0.55 (m, 2H,
-CH2-), 0.08 (s, 9H, -Si(CH3)3); 13C NMR (CDCl3, 100 MHz)
δ 174.3 (CO2Me), 165.0 (PhCO), 138.0 and 130.4 (ArC), 133.1,
130.0 (2C), 129.0, 128.5 (2C), 128.2 (2C) and 126.7 (2C) (ArCH),
101.2 and 100.9 (PhCH(O)(O)- and C-1), 79.0, 78.3, 75.2, 71.9
and 66.9 (C-2 to C-5 and -OCHCO2Me), 69.2 and 66.8 [(-),
2-(Tr im eth ylsilyl)eth yl O-4,6-O-Ben zylid en e-3-O-[(S)-
1-(m eth oxyca r bon yl)-2-cycloh exyleth yloxy]-â-D-ga la cto-
p yr a n osid e (7). To a solution of 6 and its inseparable isomer
(1.07 g, 1.49 mmol) dissolved in methanol (21 mL) was added
palladium hydroxide on carbon (Degussa, 107 mg). The result-
ing mixture was hydrogenated under 60 psi at rt for 2 h. After
filtration on Celite and concentration, the residue was dis-
solved in DMF (15 mL) and cooled with an ice bath, and then
benzaldehyde dimethyl acetal (268 µL, 1.2 equiv) and tet-
rafluoroboric acid (54% in ether, 246 µL, 1.2 equiv) were
added.34 The mixture was stirred under nitrogen atmosphere
overnight at rt, and then triethylamine (270 µL, 1.3 equiv) was
added and the solvent evaporated. The residue was purified
by flash chromatography on silica gel, eluting with ethyl
acetate/hexanes 2:8 to give 7 (640 mg, 80%) as clear syrup:
[R]D -18.1 (c 0.95, CHCl3); 1H NMR (CDCl3, 400 MHz, assigned
by COSY45) δ 7.51 (d, 2H, ArH, J ) 7.1 Hz), 7.34-7.30 (m,
3H, ArH), 5.53 (s, 1H, PhCH(O)(O)-), 4.50 (dd, 1H, -OCHCO2-
Me, J ) 9.4, 3.6 Hz), 4.34 (fd, 1H, H-4, J 4,3 ) 3.5 Hz), 4.30 (d,
1H, H-6, J 6,6A ) 12.4 Hz), 4.26 (d, 1H, H-1, J 1,2 ) 7.8 Hz), 4.07
(d, 1H, H-6A), 4.05 (m, 1H, -OCHHCH2TMS), 3.95 (dd, 1H,
H-2, J 2,3 ) 9.6 Hz), 3.62 (s, 3H, OCH3), 3.55 (m, 1H,
-OCHHCH2TMS), 3.48 (dd, 1H, H-3), 3.39 (brs, 1H, H-5), 2.50
(brs, 1H, -OH), 1.90-1.50 (3m, 9H, -CH2- and -CH-),
1.30-0.80 (m, 6H, -CH2- and -CH2TMS), 0.00 (s, 9H, -Si-
(CH3)3); 13C NMR (CDCl3, 100 MHz) δ 174.7 (CO), 138,0 (ArC),
128.9, 128.0 (2C) and 126.6 (2C) (ArCH), 102.7 and 101.0
(PhCH(O)(O)- and C-1), 79.4, 77.0, 74.9, 70.8 and 66.6 (C-2 to
C-5 and -OCHCO2Me), 69.3 and 67.4 [(-), C-6 and -OCH2-
CH2TMS], 51.9 (-OCH3), 40.8, 33.9, 32.6, 26.6, 26.4 and 26.3
[(-), -CH2-], 33.9 (-CH-), 18.3 [(-), -CH2TMS], -1.2 [-Si-
(CH3)3]; IR (film, cm-1) 2923, 1741, 1249, 1113, 1051; HR-
FABMS calcd for C28H44O8SiNa m/z 559.27032, found 559.27057.
La ct on e Der iva t ive of 2-(Tr im et h ylsilyl)et h yl O-4,6-
O-Ben zylid en e-3-O-[(S)-1-(m eth oxyca r bon yl)-2-cycloh ex-
yleth yloxy]-â-D-ga la ctop yr a n osid e (9). To a cooled solution
of 7 (112 mg, 208.1 µmol) in THF (21 mL) was added at 0 °C
lithium hydroxide (17.5 mg, 2 equiv) dissolved in water (2 mL).
The mixture was stirred overnight at 7 °C (cold chamber) and
neutralized with Amberlite IR-120 (H+). After filtration and
concentration, the residue was dissolved in a mixture of acetic
anhydride (1.2 mL) and acetonitrile (4.6 mL)39 and stirred at
(39) (a) Zou, W.; J ennings, H. J . J . Carbohydr. Chem. 1996, 15, 257.
(b) Severn, W. B.; Richards, C. J . Am. Chem. Soc. 1993, 115, 1114.

3352 J . Org. Chem., Vol. 67, No. 10, 2002
Hanessian et al.
C-6 and -OCH2CH2TMS], 52.0 (-OCH3), 41.0, 33.8, 32.6, 26.4,
25.9 and 25.7 [(-), -CH2-], 33.3 (-CH-), 18.0 [(-), -CH2-
TMS], -1.3 [-Si(CH3)3]; IR (film, cm-1) 2924, 1731, 1267, 1096;
HR-FABMS calcd for C35H48O9SiNa m/z 663.29653, found
663.29590.
4.36 (dd, 1H, H-6, J 6,6A ) 10.4 Hz, J 6,5 ) 4.9 Hz), 4.06 (ddfd,
1H, H-1eq, J 1eq,1ax ) 12.0 Hz, J 1eq,2ax ) 5.2 Hz, J 1eq,2eq ) 1.5
Hz), 3.86 (t, 1H, H-4), 3.81 (t, 1H, H-6A), 3.71 (td, 1H, H-1ax,
J 1ax,2ax ) 12.0 Hz,, J 1ax,2eq ) 1.5 Hz), 3.54 (td, 1H, H-5, J 5,4
)
J 5,6A ) 10.0 Hz), 2.35 (ddt, 1H, H-2eq, J 2eq,2ax ) 13.0 Hz), 1.95
(tdd, 1H, H-2ax); 13C NMR (CDCl3, 100 MHz) δ ppm 165.8
(CO), 137.1 and 130.0 (ArC), 132.9, 129.6 (2C), 128.8, 128.2
(2C), 128.0 (2C) and 126.0 (2C) (ArCH), 101.4 (PhCH(O)
(O)-), 80.4, 71.8 and 71.5 (C-3 to C-5), 68.8 and 65.9 [(-), C-6
and C-1], 31.5 [(-), C-2]; IR (film, cm-1) 2866, 1719, 1452, 1315,
1270, 1133, 1103, 1014; HR-FABMS calcd for C20H20O5Na m/z
363.12084, found 363.12088.
2-O-Ben zoyl-4,6-O-b en zylid en e-3-O-[(S)-1-(m et h oxy-
car bon yl)-2-cycloh exyleth yloxy]-R-D-galactopyr an ose (10).
A solution of 8 (200 mg, 312 µmol) in dichloromethane (1.5
mL) and TFA (3.0 mL) was stirred at 0 °C for 30 min,
concentrated, and codistilled twice with toluene. The crude
product was dissolved in DMF (3.1 mL) cooled in an ice bath,
and then benzaldehyde dimethyl acetal (56 µL, 1.2 equiv) and
tetrafluoroboric acid (54% in ether, 47 µL, 1.1 equiv) were
added. The mixture was stirred under nitrogen atmosphere
for 6 h at rt, triethylamine (52 µL, 1.2 equiv) was added, and
the solvent was evaporated. The residue was purified by flash
chromatography on silica gel, eluting with ethyl acetate/
hexanes 1:1, to give a 4:1 R/â inseparable mixture of isomers
(115 mg, 68%) as a clear syrup. Data for the major R isomer
10: 1H NMR (CDCl3, 400 MHz, assigned by COSY45) δ 8.08
(d, 2H, ArH, J ) 7.3 Hz), 7.59-7.55 (m, 3H, ArH), 7.48-7.32
(2m, 5H, ArH), 5.67 (d, 1H, H-1, J 1,2 ) 3.5 Hz), 5.58 (s, 1H,
PhCH(O)(O)-), 5.54 (dd, 1H, H-2, J 2,3 ) 10.4 Hz), 4.53 (fd,
1H, H-4, J 4,3 ) 3.2 Hz), 4.31 (dd, 1H, -OCHCO2Me, J ) 9.1,
4.0 Hz), 4.23 (d, 1H, H-6, J 6,6A ) 12.5 Hz), 4.12 (dd, 1H, H-3),
4.06 (d, 1H, H-6A), 3.94 (brs, 1H, H-5), 3.64 (s, 3H, OCH3),
1.62-1.27 (m, 8H, -CH2- and -CHHCHCO2Me-), 1.00-0.60
(m, 5H, -CH2-, -CH-); 13C NMR (CDCl3, 100 MHz) δ 174.5
(CO2Me), 166.0 (PhCO), 137.9, 133.4, 129.9, 129.6 (2C), 129.0,
128.6 (2C), 128.2 (2C) and 126.5 (2C) (ArCH and ArC), 100.9
(PhCH(O)(O)-), 91.2 (C-1), 78.4, 75.7, 74.2, 71.8, 69.4 and 62.9
(C-2 to C-6 and -OCHCO2Me), 52.1 (-OCH3), 41.0, 33.8, 33.7,
32.8, 26.4, 26.1 and 25.8 (-CH2- and -CH-); HR-FABMS
calcd for C30H36O9Na m/z 563.22570, found 563.22667.
2-O-Ben zoyl-4,6-O-b en zylid en e-3-O-[(S)-1-(m et h oxy-
ca r b on yl)-2-cycloh exylet h yloxy]-â-D-ga la ct op yr a n osyl
2-Th iop yr id yl Ca r bon a te (11). A mixture of 10 and its â
isomer (99.3 mg, 183.7 µmol), di(S-2-pyridyl) thiocarbonate
(137 mg, 3 equiv), and triethylamine (77 µL, 3 equiv) in
dichloromethane (1.84 mL) was stirred at rt for 24 h. Concen-
tration and purification by flash chromatography on silica gel,
eluting with ethyl acetate/hexanes 1:1, gave 11 (100 mg, 80%)
as a yellow powder: [R]D +17.3 (c 1.1, CHCl3); 1H NMR (CDCl3,
400 MHz, assigned by COSY45) δ 8.52 (m, 1H, PyH), 8.07 (d,
2H, ArH, J ) 7.1 Hz), 7.70-7.30 (4m, 10H, ArH), 7.25 (m, 1H,
PyH), 5.87 (d, 1H, H-1, J 1,2 ) 8.3 Hz), 5.80 (dd, 1H, H-2, J 2,3
) 9.8 Hz), 5.61 (s, 1H, PhCH(O)(O)-), 4.56 (fd, 1H, H-4, J 4,3
) 3.2 Hz), 4.37 (dfd, 1H, H-6, J 6,6A ) 12.5 Hz, J 6,5 ) 1.3 Hz),
4.15 (m, 1H, -OCHCO2Me), 4.12 (dfd, 1H, H-6A, J 6A,5 ) 1.3
Hz), 3.81 (dd, 1H, H-3), 3.65 (brs, 1H, H-5), 3.63 (s, 3H, OCH3),
1.59 (m, 1H, -CHHCHCO2Me-), 1.50-1.20 (m, 7H, -CH2-
and -CHHCHCO2Me-), 1.00-0.58 (2m, 5H, -CH2-,
-CH-); 13C NMR (CDCl3, 100 MHz) δ 174.0 (CO2Me), 168.6
(-OC(O)S-), 164.7 (PhCO), 151.2 (PyC), 150.6 (PyCH), 137.9,
137.7, 133.8, 130.3, 130.0, 129.7, 129.3, 128.9, 128.5, 126.8 and
124.0 (PhCH PyCH and PhC), 101.4 and 95.2 (PhCH(O)(O)-
and C-1), 79.0, 78.9, 74.9, 70.5 and 68.2 (C-2 to C-5 and
-OCHCO2Me), 68.9 [(-), C-6], 52.3 (-OCH3), 41.1, 34.0, 32.9,
3-O-Ben zoyl-6-O-ben zyl-1,2-d id eoxy-D-glu cop yr a n ose
(15). Hydrogen chloride in diethyl ether was added at rt to 14
(1.31 g, 3.84 mmol) and sodium cyanoborohydride36 (966 mg,
4 equiv) in THF (87 mL) containing 4 Å molecular sieves until
the evolution of gas ceased. The mixture was filtered through
a Celite pad, diluted with dichloromethane (200 mL), and
washed with water and saturated aqueous hydrogen carbon-
ate. The organic layer was dried (sodium sulfate) and concen-
trated, and the resulting syrup was purified by flash chroma-
tography on silica gel, eluting with ethyl acetate/hexanes 3:7,
to give 15 (1.21 g, 92%) as a clear syrup: [R]D -28.4 (c 1.0,
1
CHCl3); H NMR (CDCl3, 400 MHz, assigned by COSY45) δ
8.06 (d, 2H, ArH, J ) 7.0 Hz), 7.57-7.29 (3m, 8H, ArH), 5.08
(ddd, 1H, H-3, J 3,2ax ) 11.4 Hz, J 3,4 ) 9.0 Hz, J 3,2eq ) 5.2 Hz),
4.61 (AB, 2H, PhCH2-, J ) 12.0 Hz), 4.05 (ddfd, 1H, H-1eq,
J 1eq,1ax ) 12.0 Hz, J 1eq,2ax ) 4.9 Hz, J 1eq,2eq ) 1.5 Hz), 3.78-
3.73 (m, 3H, H-4, H-6 and H-6A), 3.55 (td, 1H, H-1ax, J 1ax,2ax
) 12.0 Hz, J 1ax,2eq ) 2.0 Hz), 3.45 (dt, 1H, H-5, J 5,4 ) 9.4 Hz,
J 5,6 ) J 5,6A ) 4.0 Hz), 2.14 (ddt, 1H, H-2eq, J 2eq,2ax ) 12.0 Hz),
1.86 (tdd, 1H, H-2ax); 13C NMR (CDCl3, 100 MHz) δ 166.7
(CO), 137.7 and 129.7 (ArC), 133.1, 129.6 (2C), 128.2 (3C),
127.7 (2C) and 127.6 (2C) (ArCH), 79.0, 76.0 and 70.9 (C-3 to
C-5), 73.6, 70.1 and 65.3 [(-), PhCH2-, C-6 and C-1], 30.8 [(-),
C-2]; IR (film, cm-1) 3471, 2862, 1718, 1452, 1317, 1273, 1122,
1092, 1071, 1027; HR-FABMS calcd for C20H22O5Na m/z
365.13649, found 365.13638.
Di(S-2-p yr id yl) Th ioca r bon a te. To a cold solution (0 °C)
of 2-mercaptopyridine (8.89 g, 80 mmol) and triphosgene (3.95
g, 13.3 mmol) in dichloromethane (400 mL) was added drop-
wise triethylamine (12 mL, 86 mmol); the mixture was stirred
at this temperature for 30 min and then at rt for 1 h. The
mixture was concentrated, treated with cold saturated aqueous
bicarbonate, and extracted with 400 mL of ethyl acetate. After
being washed with water and brine, the organic layer was
dried (sodium sulfate), filtered, and concentrated to give the
product as a yellow solid that was dried in vacuo overnight.
Pale yellow needle-shaped crystals were obtained by recrys-
tallization from 2-propanol (8.32 g, 84%): mp 44 °C; 1H NMR
(CDCl3, 400 MHz) δ 8.57 (ddd, 2H, J ) 4.8, 1.9, 0.8 Hz), 7.69
(td, 2H, J ) 7.9, 1.9 Hz), 7.63 (dt, 2H, J ) 7.9, 1.1 Hz), 7.26
(ddd, 2H, J ) 7.3, 4.8, 1.3 Hz); 13C NMR (CDCl3, 100 MHz) δ
185.6 (CO), 150.6 (PyC), 150.5, 137.5, 130.5 and 124.2 (PyCH);
IR (film, cm-1) 3047, 1712, 1656, 1572, 1562, 1449, 1421, 1282,
1152, 1113, 1083, 1045; HR-FABMS calcd for C11H9ON2S2 m/z
249.01563, found 249.01553.
2,3,4-Tr i-O-ben zyl-â-L-fu copyr an osyl 2-Th iopyr idyl Car -
bon a te (16). A mixture of 2,3,4-tri-O-benzyl-L-fucopyranose40
(714 mg, 1.65 mmol), di(S-2-pyridyl) thiocarbonate (1.22 g, 3
equiv), and triethylamine (690 µL, 3 equiv) in dichloromethane
(16.5 mL) was stirred at rt for 24 h. Concentration and
purification by flash chromatography on silica gel, eluting with
ethyl acetate/hexanes 3:7, gave 16 (840 mg, 89%) as a yellow
powder: [R]D -9.3 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz,
assigned by COSY45) δ 8.60 (d, 1H, PyH, J ) 5.0 Hz), 7.72
(m, 2H, ArH), 7.41-7.25 (m, 16H, ArH), 5.66 (d, 1H, H-1, J 1,2
) 8.0 Hz), 5.00 (d, 1H, PhCHH-, J ) 11.6 Hz), 4.80 (s, 2H,
PhCH2-), 4.78 (AB, 2H, PhCH2-, J ) 11.9 Hz), 4.72 (d, 1H,
PhCHH-, J ) 11.6 Hz), 4.00 (t, 1H, H-2, J 2,3 ) 8.0 Hz), 3.68-
3.58 (m, 3H, H-3, H-4 and H-5), 1.22 (d, 3H, -CH3, J Me,5 ) 6.4
26.6, 26.2 and 25.9 [(-), -CH2-], 33.6 (-CH-); IR (film, cm-1
)
2924, 1736, 1264, 1112, 1062; HR-FABMS calcd for C35H39O8-
NSNa m/z 656.22940, found 656.22971.
3-O-Ben zoyl-4,6-O-ben zylid en e-1,2-d id eoxy-D-glu cop y-
r a n ose (14). To a cold (5 °C) solution of 4,6-O-benzylidene-
1,2-dideoxy-D-glucopyranoside17 13 (1.0 g, 4.24 mmol) in
dichloromethane (47 mL) were added triethylamine (1.77 mL,
3 equiv), a catalytic amount of DMAP, and benzoyl chloride
(1.0 mL, 2 equiv). The mixture was stirred at rt for 2 h, poured
into a separatory funnel, washed with water and brine, dried
(sodium sulfate), and filtered. After concentration, the residue
was purified by flash chromatography on silica gel, eluting
with ethyl acetate/hexanes 1:9, to give 14 (1.40 g, 97%) as a
clear syrup: [R]D -135.8 (c 0.5, CHCl3); 1H NMR (CDCl3, 400
MHz, assigned by COSY45) δ 8.08 (d, 2H, ArH, J ) 7.0 Hz),
7.57-7.33 (3m, 8H, ArH), 5.63 (s, 1H, PhCH(O)(O)-), 5.36
(ddd, 1H, H-3, J 3,2ax ) 10.9 Hz, J 3,4 ) 9.5 Hz, J 3,2eq ) 5.3 Hz),
(40) Dejter-J uszynski, M.; Flowers, H. M. Carbohydr. Res. 1971, 18,
219.

Synthesis of a Potent Antagonist of E-Selectin
J . Org. Chem., Vol. 67, No. 10, 2002 3353
Hz); 13C NMR (CDCl3, 100 MHz) δ 167.7 (CO), 151.4 (PyC),
149.9, 137.1, 129.1, 128.3, 128.2, 128.1, 127.6, 127.4 and 123.4
(PhCH and PyCH), 138.1, 138.0, 137.9 (PhC), 96.9 (C-1), 82.3,
77.5, 75.7 and 71.6 (C-2 to C-5), 75.2, 74.6 and 73.0 [(-),
PhCH2-], 16.5 (-CH3); IR (film, cm-1) 2874, 1736, 1573, 1497,
1454, 1422, 1102, 1062, 1021; HR-FABMS calcd for C32H33O4-
NSNa m/z 550.20280, found 550.20292.
sodium hydride (9 mg, 1.5 equiv), and the mixture was stirred
at 0 °C for 30 min. Silver triflate (42 mg, 1.1 equiv) was added,
the mixture stirred in the dark 15 min, 11 (66.3 mg, 0.7 equiv)
and 4 Å molecular sieves were then added, and the mixture
was allowed to warm to rt in the dark overnight. The mixture
was filtered through Celite, concentrated, redissolved in
dichloromethane (20 mL), and washed with saturated aqueous
ammonium cloride (10 mL) and brine (10 mL). The organic
phase was dried (sodium sulfate), concentrated, and purified
by flash chromatography on silica gel, eluting with ethyl
acetate/hexanes 6:4 gave 19 (55.3 mg, 48%) as a syrup: [R]D
(2,3,4-Tr i-O-ben zyl-R-L-fu cop yr a n osyl)-O-(1 f 4)-3-O-
ben zoyl-6-O-ben zyl-1,2-d id eoxy-D-glu cop yr a n ose (17). A
mixture of 15 (343 mg, 1.00 mmol), 16 (800 mg, 1.4 equiv),
1,1,3,3-tetramethylurea (170 µL, 1.4 equiv), and activated 4
Å molecular sieves in dichloromethane (38.5 mL) was stirred
overnight at rt and then cooled at 0 °C. Silver triflate (2.32 g,
9 equiv) was added to the reaction mixture, and the stirring
was continued 24 h at rt in the dark. The suspension was
treated with a few drops of pyridine, filtered through Celite,
and concentrated. Purification by flash chromatography on
silica gel, eluting with ethyl acetate/hexanes 2:8, gave 17 (758
1
-31.0 (c 0.6, CHCl3); H NMR (CDCl3, 400 MHz, assigned by
COSY45) δ 8.07 (dfd, 2H, ArH, J ) 8.3, 1.2 Hz), 7.68 (d, 2H,
ArH, J ) 7.0 Hz), 7.58 (t, 1H, ArH, J ) 7.0 Hz), 7.46 (t, 2H,
ArH, J ) 7.0 Hz), 7.40-7.10 (m, 23H, ArH), 5.67 (s, 1H,
PhCH(O)(O)-), 5.62 (t, 1H, H-2′, J 2′,1′ ) J 2′,3′ ) 8.8 Hz), 4.91
(q, 1H, H-5′′, J 5′′,Me ) 6.4 Hz), 4.85 (d, 1H, H-1′′, J 1′′,2′′ ) 3.3
Hz), 4.75 (d, 1H, PhCHH-, J ) 11.7 Hz), 4.66 (d, 1H,
PhCHH-, J ) 11.5 Hz), 4.65 (d, 1H, H-1′, J 1′,2′ ) 7.0 Hz), 4.57
(d, 1H, PhCHH-, J ) 11.5 Hz), 4.55 (d, 1H, PhCHH-, J )
11.7 Hz), 4.49 (fd, 1H, H-4′, J 4′,3′ ) 2.9 Hz), 4.34 (s, 2H, PhC-
H2-), 4.33 (d, 1H, H-6′, J 6′,6A′ ) 12.6 Hz), 4.22 (d, 1H, PhCHH-,
J ) 11.3 Hz), 4.18-4.13 (m, 2H, -OCHCO2Me and H-6A′),
3.97-3.88 (m, 2H, H-2′′ and H-3′′), 3.86-3.56 (m, 10H, H-1eq,
H-3, H-4, H-3′, H-6, H-6A, PhCHH- and -OCH3), 3.46 (s,1H,
H-5′), 3.31-3.24 (m, 3H, H-1ax, H-5 and H-4′′), 1.83 (brdd,
1H, H-2eq, J 2eq,2ax ) 12.0 Hz, J 2eq,3 ) 5.0 Hz), 1.67 (m, 1H,
-CHHCHCO2Me-), 1.52-1.27 (m, 8H, H-2ax, -CH2- and
-CHHCHCO2Me-), 1.26 (d, 3H, -CH3), 0.96-0.71 (m, 5H,
-CH2- and -CH-); 13C NMR (CDCl3, 100 MHz) δ 174.3 (CO2-
Me), 164.8 (PhCO), 140, 139.6, 138.9, 138.3 and 130.1 (ArC),
133.3, 129.9, 128.9, 128.8, 128.6, 128.4, 128.3, 128.2, 128.0,
127.9, 127.8, 127.7, 127.6, 127.3, 127.0 and 126.2 (ArCH and
ArC), 99.8, 99.3 and 97.6 (PhCH(O)(O)-, C-1′ and C-1′′), 80.4,
80.1, 78.9 (2C), 78.5, 78.3, 75.6, 75.1, 72.5, 71.6, 66.7 and 65.8
(C-3 to C-5, C-2′ to C-5′, C-2′′ to C-5′′ and -OCHCO2Me), 75.0,
74.7, 73.4, 71.3, 69.4, 68.4 and 66.6 [(-), PhCH2-, C-1, C-6
and C-6′], 52.1 (-OCH3), 41.0, 33.9, 32.6, 31.4, 26.4, 26.0 and
25.7 [(-), -CH2- and C-2], 33.4 (-CH-), 16.3 (-CH3); HR-
1
mg, > 98%) as a syrup: [R]D -48.6 (c 1.0, CHCl3); H NMR
(CDCl3, 400 MHz, assigned by COSY45) δ 8.08 (d, 2H, ArH, J
) 7.0 Hz), 7.65-7.20 (3m, 23H, ArH), 5.30 (ddd, 1H, H-3, J 3,2ax
) 11.0 Hz, J 3,4 ) 9.0 Hz, J 3,2eq ) 5.5 Hz), 5.07 (d, 1H, H-1′,
J 1′,2′ ) 3.5 Hz), 4.92 (d, 1H, PhCHH-, J ) 11.5 Hz), 4.84 (d,
1H, PhCHH-, J ) 11.6 Hz), 4.74 (AB, 2H, PhCH2-, J ) 11.7
Hz), 4.62 (d, 1H, PhCHH-, J ) 11.6 Hz), 4.58 (d, 1H,
PhCHH-, J ) 11.5 Hz), 4.46 (s, 2H, PhCH2-), 4.06 (dd, 1H,
H-1eq, J 1eq,1ax ) 11.6 Hz, J 1eq,2ax ) 4.0 Hz, J 1eq,2eq ) 0 Hz), 4.00
(dd, 1H, H-2′, J 2′,3′ ) 10.3 Hz), 3.95-3.84 (m, 5H, H-4, H-6,
H-6A, H-3′ and H-5′), 3.60-3.51 (m, 3H, H-1ax, H-5 and H-4′),
2.20 (brdd, 1H, H-2eq, J 2eq,2ax ) 11.0 Hz), 1.86 (brq, 1H, H-2ax,
J 2ax,1ax ) 11 Hz), 0.78 (d, 3H, -CH3, J Me,5′ ) 6.4 Hz); 13C NMR
(CDCl3, 100 MHz) δ 166.2 (CO), 138.9, 138.7 (2C), 138.4 and
130.5 (ArC), 133.1, 129.9, 128.4,128.3, 128.2, 128.0, 127.8,
127.7, 127.6 and 127.5 (ArCH), 99.4 (C-1′), 79.9, 79.5, 77.8,
76.6, 76.5, 74.6 and 67.2 (C-3 to C-5 and C-2′ to C-5′), 75.0,
74.2, 73.5, 72.9, 69.6, and 65.4 [(-), PhCH2-, C-6 and C-1],
31.6 [(-), C-2], 16.4 (-CH3); IR (film, cm-1) 3031, 2864, 1717,
1454, 1273, 1099, 1069, 1047, 1028; HR-FABMS calcd for
C
47H50O9Na m/z 781.33525, found 781.33512.
FABMS calcd for
1199.53391.
C70H80O16Na m/z 1199.53440, found
(2,3,4-Tr i-O-ben zyl-R-L-fu cop yr a n osyl)-O-(1 f 4)-6-O-
ben zyl-1,2-d id eoxy-D-glu cop yr a n ose (18). To a solution of
17 (758 mg, 1.00 mmol) in methanol (5 mL) was added 2 mL
(1.0 equiv) of a freshly prepared methanol solution of sodium
methoxide (0.5 M). The solution was stirred at 45 °C for 2 h
and neutralized with Amberlite IR-120 (H+). After filtration
and concentration, the resulting syrup was purified by flash
chromatography on silica gel, eluting with ethyl acetate/
hexanes 3:7, to give 18 (514 mg, 85%) as a white powder: [R]D
(2-O-Ben zoyl-4,6-O-ben zylid en e-3-O-[(S)-1-(oxyca r bo-
n yl)-2-cycloh exyleth yloxy]-â-D-ga la ctop yr a n osyl)-O-(1 f
3)-[(2,3,4-tr i-O-ben zyl-R-L-fu cop yr a n osyl)-O-(1 f 4)]-6-O-
ben zyl-1,2-d id eoxy-D-glu cop yr a n ose (20). To a cooled solu-
tion (0 °C) of 19 (94.2 mg, 80.06 µmol) in THF (8 mL) was
added lithium hydroxide (3.7 mg, 1.1 equiv) dissolved in water
(470 µL). The mixture was stirred at rt for 48 h and neutralized
with Amberlite IR-120 (H+). After filtration and concentration,
the residue was purified by flash chromatography on silica gel,
eluting with dichloromethane/methanol 14:1, to give 20 (93
mg, >98%) as a gum: [R]D -86.0 (c 0.2, CHCl3); 1H NMR (CD3-
OD, 400 MHz) δ ppm 8.16 (d, 2H, ArH, J ) 8.0 Hz), 7.74 (d,
2H, ArH, J ) 7.7 Hz), 7.65 (t, 1H, ArH, J ) 7.0 Hz), 7.53 (t,
2H, ArH, J ) 7.0 Hz), 7.40-7.19 (m, 23H, ArH), 5.75 (s, 1H,
PhCH(O)(O)-), 5.61 (t, 1H, H-2′, J 2′,1′ ) J 2′,3′ ) 9.0 Hz), 5.06
(q, 1H, H-5′′, J 5′′,Me ) 6.4 Hz), 4.83 (d, 1H, H-1′′, J 1′′,2′′ ) 3.8
Hz), 4.79 (d, 1H, H-1′, J 1′,2′ ) 8.0 Hz), 4.72 (d, 1H, J ) 11.9
Hz), 4.67 (d, 1H, J ) 11.4 Hz), 4.61 (d, 1H, J ) 11.6 Hz), 4.59
(brs, 1H, H-4′), 4.42 (t, 2H, J ) 11.4 Hz), 4.27-4.18 (m, 5H),
3.96-3.91 (m, 2H), 3.79-3.73 (m, 4H), 3.66-3.49 (m, 5H), 3.40
(brs, 1H), 3.20 (brd, 1H, J ) 9 Hz), 2.00 (brdd, 1H, H-2eq,
J 2eq,2ax ) 12.0 Hz, J 2eq,3 ) 4.0 Hz), 1.70-0.80 (2m, 14H, H-2ax,
-CH2- and -CH-), 1.26 (d, 3H, -CH3); 13C NMR (CDCl3, 100
MHz) δ 178.9 (CO2H), 166.7 (PhCO), 139.9, 139.6, 139.0, 138.3
(2C) and 129.9 (ArC), 134.0, 130.3, 129.2, 128.9, 128.6, 128.3,
128.1, 128.0, 127.9, 127.8, 127.6, 127.4, and 126.3 (ArCH),
100.1, 99.3 and 97.7 (PhCH(O)(O)-, C-1′ and C-1′′), 80.9, 80.7,
80.4, 79.0 (2C), 75.9, 75.8, 74.1, 72.7, 71.1, 66.8 and 66.7 (C-3
to C-5, C-2′ to C-5′, C-2′′ to C-5′′ and -OCHCO2H), 75.4, 74.9,
73.6, 71.7, 69.5, 68.6 and 66.0 [(-), PhCH2-, C-1, C-6 and C-6′],
41.7, 33.5, 31.8, 30.1, 26.7, 26.2 and 26.1 [(-), -CH2- and C-2],
34.0 (-CH-), 16.7 (-CH3); IR (film, cm-1) 2924, 1732, 1603,
1
-24.2 (c 1.1, CHCl3); H NMR (CDCl3, 400 MHz, assigned by
COSY45) δ 7.45-7.20 (m, 20H, ArH), 5.04 (d, 1H, PhCHH-,
J ) 11.4 Hz), 5.00 (d, 1H, H-1′, J 1′,2′ ) 3.8 Hz), 4.88 (d, 1H,
PhCHH-, J ) 11.9 Hz), 4.81 (d, 1H, PhCHH-, J ) 11.9 Hz),
4.78 (d, 1H, PhCHH-, J ) 12.1 Hz), 4.70 (d, 1H, PhCHH-, J
) 11.4 Hz), 4.68 (d, 1H, PhCHH-, J ) 11.7 Hz), 4.62 (brs,
1H, -OH), 4.42 (AB, 2H, PhCH2-, J ) 12.3 Hz), 4.15-4.07
(m, 2H, H-2′ and H-5′), 4.04 (dd, 1H, H-1eq, J 1eq,1ax ) 11.5 Hz,
J 1eq,2ax ) 4.0 Hz), 3.99 (dd, 1H, H-6, J 6,6A ) 10.5 Hz, J 6,5 ) 1.6
Hz), 3.93 (dd, 1H, H-3′, J 3′,2′ ) 10.2 Hz, J 3′,4′ ) 2.6 Hz), 3.74
(fd, 1H, H-4′), 3.73 (dd, 1H, H-6A, J 6A,5 ) 6.3 Hz), 3.63 (m,
1H, H-3), 3.50-3.40 (m, 2H, H-1ax and H-5), 3.28 (t, 1H, H-4,
J 4,3 ) J 4,5 ) 8.6 Hz), 2.03 (brdd, 1H, H-2eq, J 2eq,2ax ) 11.0 Hz,
J 2eq,3 ) 4.0 Hz), 1.73 (brq, 1H, H-2ax, J 2ax,1ax ) J 2ax,3 ) 11 Hz,
J 2ax,1eq ) 4 Hz), 1.22 (d, 3H, -CH3, J Me,5′ ) 6.4 Hz); 13C NMR
(CDCl3, 100 MHz) δ 138.7, 138.6, 138.4 (2C) (ArC), 128.5,
128.4, 128.3, 128.0, 127.9, 127.7, 127.6, 127.5 and 127.4
(ArCH), 99.7 (C-1′), 84.0, 79.0, 78.3, 77.4, 76.0, 71.9 and 68.0
(C-3 to C-5 and C-2′ to C-5′), 75.0, 73.8, 73.3, 73.2, 70.1, and
65.7 [(-), PhCH2-, C-6 and C-1], 32.8 [(-), C-2], 16.8 (-CH3);
HR-FABMS calcd for
677.30865.
C40H46O8Na m/z 677.30904, found
(2-O-Ben zoyl-4,6-O-b en zylid en e-3-O-[(S)-1-(m et h oxy-
ca r bon yl)-2-cycloh exyl-eth yloxy]-â-D-ga la ctop yr a n osyl)-
O-(1 f 3)-[(2,3,4-tr i-O-ben zyl-R-L-fu cop yr a n osyl)-O-(1 f
4)]-6-O-ben zyl-1,2-d id eoxy-D-glu cop yr a n ose (19). To a cold
solution of 18 (96 mg, 146.8 µmol) in THF (14.7 mL) was added
1452, 1365, 1268, 1097, 1057; HR-FABMS calcd for C69H78O16
-
Na m/z 1185.51880, found 1185.52240.

3354 J . Org. Chem., Vol. 67, No. 10, 2002
Hanessian et al.
(4,6-O-Ben zylid en e-3-O-[(S)-1-(oxyca r b on yl)-2-cyclo-
h exylet h yloxy]-â-D-ga la ct op yr a n osyl)-O-(1 f 3)-[(2,3,4-
tr i-O-ben zyl-R-L-fu cop yr a n osyl)-O-(1 f 4)]-6-O-ben zyl-
1,2-d id eoxy-D-glu cop yr a n ose (21). To a solution of 20 (44.1
mg, 37.93 µmol) in methanol (5.4 mL) was added 1.52 mL (20
equiv) of a freshly prepared methanol solution of sodium
methoxide (0.5 M). The solution was refluxed for 2 h and
neutralized with Amberlite IR-120 (H+). After filtration and
concentration, the resulting syrup was purified by flash
chromatography on silica gel, eluting with dichloromethane/
methanol 12:1, to give 21 (36 mg, 90%) as a gum: [R]D -107.2
(c 0.18, CH3OH); 1H NMR (CD3OD, 400 MHz, assigned by
COSY45) δ 7.66 (d, 2H, ArH, J ) 7.4 Hz), 7.40-7.10 (m, 23H,
concentration, the product was passed through an ion-
exchange resin column (Dowex in the sodium form); the
solution afforded after rinsing the column with water and
lyophilizing the eluate pure 2 as a sodium salt (14.4 mg, >98%)
1
as a white powder: [R]D -49.0 (c 1.06, H2O); H NMR (D2O
CH3OD as external standard δ ) 3.35 ppm, 400 MHz, assigned
by COSY45) δ 4.97 (d, 1H, H-1′′, J 1′′,2′′ ) 3.9 Hz), 4.77 (q, 1H,
H-5′′), 4.52 (d, 1H, H-1′, J 1′,2′ ) 7.9 Hz), 4.10-3.92 (m, 3H, H-3,
H-1eq and-OCHCO2Me), 3.92 (fd, 1H, H-4′, J 4′,3′ ) 3.0 Hz),
3.90-3.85 (m, 3H, H-6, H-6A and H-3′′), 3.82 (fd, 1H, H-4′′,
J 4′′,3′′ ) 3.0 Hz), 3.78 (dd, 1H, H-2′′, J 2′′,3′′ ) 10.5 Hz), 3.74 (brd,
2H, H-6′ and H-6A′, J ) 6 Hz), 3.64 (t, 1H, H-2′, J 2′,3′ ) 8.0
Hz), 3.62 (t, 1H, H-5′, J 5′,6′ ) J 5′,6A′ ) 6.0 Hz), 3.59 (t, 1H, H-4,
ArH), 5.68 (s, 1H, PhCH(O)(O)-), 5.01 (q, 1H, H-5′′, J 5′′,Me
)
J 4,3 ) J 4,5 ) 9.0 Hz), 3.50 (brt, 1H, H-1ax, J 1ax,2ax ) J 1ax,1eq )
6.4 Hz), 4.89 (d, 1H, H-1′′, J 1′′,2′′ ) 3.8 Hz), 4.72-4.67 (m, 3H,
-OCHCO2Me and 2 PhCHH-), 4.58 (d, 1H, PhCHH-, J )
11.9 Hz), 4.47 (d, 1H, PhCHH-, J ) 11.8 Hz), 4.45 (d, 1H,
PhCHH-, J ) 11.4 Hz), 4.42 (d, 1H, H-4′, J 4′,3′ ) 3.3 Hz), 4.36
(d, 1H, H-1′, J 1′,2′ ) 7.7 Hz), 4.22-4.15 (m, 3H, H-6′, H-6A′
and PhCHH-), 3.95-3.78 (m, 6H, H-1eq, H-3, H-6, H-2′, H-2′′
and H-3′′), 3.68 (t, 1H, H-4, J 4,3 ) J 4,5 ) 9.4 Hz), 3.60-3.47
(m, 4H, H-6A, H-3′, H-5′ and PhCHH-), 3.39 (brt, 1H, H-1ax,
J 1ax,2ax ) J 1ax,1eq ) 9.0 Hz), 3.31 (1H, H-4′′), 3.24 (m, 1H, H-5),
2.10 (brdd, 1H, H-2eq, J 2eq,2ax ) 12.0 Hz, J 2eq,3 ) 5.0 Hz), 2.00
(brd, 1H, J ) 11.0 Hz), 1.90-1.55 (m,6H), 1.45-1.20 (m,5H)
and 1.03-0.94 (m, 2H) (-CH2-, H-2ax and -CH-), 1.09 (d,
3H, -CH3); 13C NMR (CD3OD, 100 MHz) δ 178.3 (CO), 140.5,
140.4, 140.2, 139.7 and 139.3 (ArC), 129.6, 129.4, 129.3, 129.1,
129.0, 128.7, 128.6, 128.5, 128.4, 128.2 and 127.2 (ArCH),
102.1, 100.8 and 98.7 (PhCH(O)(O)-, C-1′ and C-1′′), 81.3, 80.4,
80.0 (2C), 78.5, 78.4, 76.9, 76.6, 74.6, 72.0, 67.9 and 67.7 (C-3
to C-5, C-2′ to C-5′, C-2′′ to C-5′′ and -OCHCO2H), 76.3, 75.4,
74.4, 72.4, 70.7, 69.5 and 66.8 [(-), PhCH2-, C-1, C-6 and C-6′],
41.9, 35.1, 33.8, 32.5, 27.7, 27.6 and 27.4 [(-), -CH2- and C-2],
35.4 (-CH-), 16.8 (-CH3); HR-FABMS calcd for C62H73O15 m/z
1057.49500, found 1057.49130.
11.5 Hz), 3.42-3.39 (m, 2H, H-5 and H-3′), 2.23 (brdd, 1H,
H-2eq, J 2eq,2ax ) 12.0 Hz, J 2eq,3 ) 4.0 Hz), 1.80 (m, 1H), 1.75-
1.50 (m, 8H), 1.35-1.10 (m, 6H) and 1.00-0.85 (m, 2H)
(-CH2-, H-2ax and -CH-), 1.21 (d, 3H, -CH3, J Me,5′′ ) 6.5
Hz); 13C NMR (D2O, CH3OD as external standard δ ) 49.6
ppm, 100 MHz) δ 183.1 (CO), 99.4 and 99.0 (C-1′ and C-1′′),
83.1, 80.4, 79.6, 76.0, 75.0, 74.6, 72.2, 70.1, 69.6, 68.3, 67.2
and 66.6 (C-3 to C-5, C-2′ to C-5′, C-2′′ to C-5′′ and -OCHCO2H),
65.5, 61.9 and 60.3 [(-), C-1, C-6 and C-6′], 41.5, 33.9, 32.2,
30.6, 26.5, 26.3, and 26.0 [(-), -CH2- and C-2], 33.6 (-CH-),
15.9 (-CH3); IR (KBr, cm-1) 3430, 2925, 1599, 1400, 1079; HR-
FABMS calcd for C27H46O15Na m/z 633.27344, found 633.27160.
Ack n ow led gm en t. We thank NSERC and Novartis
Pharma Process Group (Basel) for generous financial
support through the Medicinal Chemistry Chair pro-
gram. We thank Dr. Pong Mak and Dr. Gerhard Penn
and the Novartis group for their support and Dr. Michel
Simard (Universite´ de Montre´al, crystallography labo-
ratory) for X-ray structure determination. We appreciate
assistance from Novartis Pharma (Basel) for HRMS
data for some compounds.
(3-O-[(S)-1-(Oxyca r b on yl)-2-cycloh exylet h yloxy]-â-D-
ga la ctop yr a n osyl)-O-(1 f 3)-[R-L-fu cop yr a n osyl-O-(1 f
4)]-1,2-d id eoxy-D-glu cop yr a n ose Sod iu m Sa lt (2). To a
solution of 21 (25 mg, 23.6 µmol) dissolved in a mixture of
dioxane (5.50 mL) and water (2.40 mL) was added 20%
palladium hydroxide on carbon (Degussa, 18.0 mg) and acetic
acid (24 µL, 18 equiv). The resulting mixture was hydrogenated
under 60 psi at rt for 40 h. After filtration on Celite and
Su p p or tin g In for m a tion Ava ila ble: Copies of selected
1H and 13C spectra and X-ray structure determination data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O0110956