Synthesis of the C-Glycoside Analogue of a Novel Sialyl Lewis X Mimetic

Article abstract of DOI:10.1021/jo991898h

Sialyl Lewis X (sLe^x) mimetics that can function as selectin antagonists have received considerable attention in connection with the development of novel antiinflammatory therapies. An interesting structure that emerged from the studies of the Wong group is the 1,1-Gal-Man disaccharide 2, reported to bind E-selectin 5 times more strongly than sLe^x. The C-glycoside derivative 3 is of interest both as a conformational probe for selectin binding and as a hydrolytically stable analogue. Herein we illustrate a novel methodology for β-C-galacto-disaccharides in the synthesis of 3. The protocol has as a key step a novel oxocarbenium ion-enol ether cyclization to give a Cl-substituted galactal.

Full text of DOI:10.1021/jo991898h

2544
J . Org. Chem. 2000, 65, 2544-2547
Syn th esis of th e C-Glycosid e An a logu e of a Novel Sia lyl Lew is X
Mim etic
Xuhong Cheng, Noshena Khan, and David R. Mootoo*
Department of Chemistry, Hunter College/ CUNY, 695 Park Avenue, New York, New York 10021
Received December 9, 1999
Sialyl Lewis X (sLex) mimetics that can function as selectin antagonists have received considerable
attention in connection with the development of novel antiinflammatory therapies. An interesting
structure that emerged from the studies of the Wong group is the 1,1-Gal-Man disaccharide 2,
reported to bind E-selectin 5 times more strongly than sLex. The C-glycoside derivative 3 is of
interest both as a conformational probe for selectin binding and as a hydrolytically stable analogue.
Herein we illustrate a novel methodology for â-C-galacto-disaccharides in the synthesis of 3. The
protocol has as a key step a novel oxocarbenium ion-enol ether cyclization to give a C1-substituted
galactal.
The implication of sialyl Lewis X (sLex, 1)-selectin
interaction as an initial event in the inflammation
response has led to innovative approaches to antiinflam-
matory therapies.1,2 One area that has received consider-
able attention is the design of mimetics of sLex that can
function as selectin antagonists.2,3 Although non-carbo-
hydrate structures have been examined, the majority of
approaches have focused on carbohydrate-type ligands
of varying degrees of similarity to sLex. An interesting
structure that emerged from the studies of the Wong
group is the 1,1-Gal-Man disaccharide (2), which was
reported to bind E-selectin 5 times more strongly than
sLex 4 (Figure 1).
The general model for sLex interaction with E-selectin
assumes key contact points at the 4- and 6-OH groups of
galactose, the COOH of sialic acid, and the hydroxyl
groups of fucose. It is believed that the GlcNHAc residue
acts as a conformationally restricted spacer that main-
tains the binding regions on the fucose and the COOH
in a preferred spatial disposition. Accordingly, it has been
suggested that the galactose sector in both sLex and 2
interacts with E-selectin in similar way and that the
mannose residue of 2 acts as an isotere of the fucose
moiety of sLex.4 Although much simpler than sLex, 2 is
still reasonably complex, a feature that is relevant to the
issue of binding specificity. We were especially interested
in the C-glycoside analogue 3, since it is expected to be
more flexible about the intersaccharide linkage5 and
therefore could serve as a conformational probe in the
search for more effective ligands. Of course, the hydrolytic
F igu r e 1.
stability of 3 presents an additional advantage for drug
development.6 Herein, we describe the details of our novel
C-glycosidation methodology, as applied to the synthesis
of 3.7
Our strategy centers on the stereoselective hydrobo-
ration of a C1-substituted galactal 5.8 The concept of
using a glycal as a precursor to 2-oxygenated C-glycosides
is a known one, which was originally devised because of
the high coupling efficiency of 1-lithio glycals with
aldehydo aglycone partners.8a The more direct approach
of using 2-O-substituted glycosyl anions is limited by
problems of â-elimination.9 Our synthesis of C1-substi-
tuted glycals is different from other methods10-12 in that
(1) Springer, T. A.; Larsky, L. A. Nature 1991, 349, 196-197.
Phillips, M. L.; Nudelman, E.; Gaeta, F. C. A.; Perez, M.; Singhal, A.
K.; Hakomori, S.-I.; Paulson, J . C. Science 1990, 250, 1130-1135.
(2) Musser, J . H.; Anderson, M. B.; Levy, D. E. Curr. Pharm. Design
1995, 1, 221-232. Boschelli, D. H. Drugs Future 1995, 20, 805-816.
Roy, R. In Carbohydrates in Drug Design; Witczak, Z. J ., Nieforth, K.
A., Eds.; Marcel Dekker: New York, 1997; pp 83-105.
(3) (a) Simanek, E. E.; McGarvey, G. J .; J ablonowski, J . A.; Wong,
C.-H. Chem. Rev. 1998, 98, 833-862. (b) Kretzschmar, G.; Toepfer,
A.; Huls, C.; Krause, M. Tetrahedron 1997, 53, 2485-2494.
(4) Hiruma, K.; Kajimoto, T.; Weitz-Schmidt, G.; Ollmann, I.; Wong,
C.-H. J . Am. Chem. Soc. 1996, 118, 9265-9270.
(6) (a) Nagy, J . O.; Wang, P.; Gilbert, J . H.; Schaefer, M. E.; Hill, T.
G.; Callstrom, M. R.; Bednarski, M. D. J . Med. Chem. 1992, 35, 4501-
02. (b) Mortell, K. H.; Weatherman, R. V.; Kiessling, L. L. J . Am. Chem.
Soc. 1996, 118, 2297-2298.
(7) Khan, N.; Cheng, X.; Mootoo, D. R. J . Am. Chem. Soc. 1999, 121,
4918-4919.
(8) (a) Schmidt, R. R.; Dietrich, H. Liebigs Ann. Chem. 1994, 975-
981. Eisele, T.; Ishida, M.; Hummel, G.; Schmidt, R. Liebigs Ann. Chem.
1995, 2113-2121. (b) Postema, M. H. D.; Calimente, D. Tetrahedron
Lett. 1999, 40, 4255-4259.
(5) For discussions on the conformational properties of O- vs
C-glycosides: (a) Ravishankar, R.; Surolia, A.; Vijayan, M.; Lim, S.;
Kishi, Y. J . Am. Chem. Soc. 1998, 120, 11297-11303. (b) Mart´ın-
Lomas, M.; Imberty, A.; Can˜ada, F. J .; J imenez-Barbero, J . J . Am.
Chem. Soc. 1998, 120, 1309-1318.
(9) (a) Beau, J .-M.; Gallagher, T. Top. Curr. Chem. 1997, 187, 1-54.
(b) Mazeas, D.; Skrydstrup, T.; Beau, J .-M. Angew. Chem., Int. Ed.
Engl. 1995, 34, 909-912. (c) Frey, O.; Hoffmann, M.; Wittmann, V.;
Kessler, H.; Uhlmann, P.; Vasella, A. Helv. Chim. Acta 1994, 77, 2060-
2069.
10.1021/jo991898h CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/23/2000

C-Glycoside of a Novel Sialyl Lewis X Mimetic
J . Org. Chem., Vol. 65, No. 8, 2000 2545
Sch em e 1
Sch em e 2
Sch em e 3
the glycal is formed via an intramolecular oxocarbenium
ion-alkene cyclization in an acetal-enol ether precursor
9. This idea was spawned from successes with related
dioxolenium ion cyclizations.13 An important aspect of
this plan is that â-C-galactosides could be accessed in a
convergent fashion from a 1-thio-1,2-O-isopropylidene
acetal (TIA) 7 and a carboxylic acid 8 (Scheme 1).
The key reaction in the synthesis of 7 was the Suarez
fragmentation of an anomeric alkoxy radical.14 The
known D-lyxose derivative 1015 was converted to the
monosilylated ether 11. Treatment of 11 with iodoben-
zene diacetate (DIB) led to the 1-O-acetyl-1,2-O-isopro-
pylidene acetal 12 in 90% yield. Acetal exchange on 12,
under controlled conditions with thiophenol and boron
trifluoride etherate, followed by mild base treatment of
the crude product, provided 7 in high yield. The overall
synthesis of 7 from D-lyxose was achieved in 65% yield,
spanned four “one-pot” operations, and involved simple
procedures, thereby facilitating multigram batches of 7.
The acid component 8 was obtained via oxidative cleav-
age of the C-allyl mannoside 1316 via the published
procedure.17 (Scheme 2).
The two-step operation provided enol ether 9 in 85% yield
from 7. The key cyclization reaction was carried out by
treatment of 9 with methyl triflate in the presence of 2,6-
di-tert-butyl-4-methylpyridine (DBMP). The glycal 5 was
obtained in 88% yield as a single stereo- and regioisomer.
No evidence was observed for isomers containing the
trans-isopropylidene or the exocyclic alkene. The high
efficiency of this reaction is presumably related to favor-
able entropy and ring strain effects of the cyclic oxocar-
benium ion 6 on the cyclization step and regioselective
deprotonation of the glycosyl cation derived therefrom.
The latter selectivity may be a consequence of unfavor-
able A(1,3) interactions in the exocyclic alkene product.20
Hydroboration of 5 provided the C-glycoside 4 as a single
diastereomer in 83% yield. The structure of 4 was
DCC-mediated coupling18 of 7 and 8 (1.1 equiv) led to
the ester 14, which was treated with Tebbe reagent.19
(10) For reviews on C-glycoside synthesis: (a) Du, Y.; Linhardt, R.
J .; Vlahov, J . R. Tetrahedron 1998, 54, 9913-9959. (b) Togo, H.; He,
W.; Waki, Y.; Yokoyama, M. Synlett 1998, 700-717. (c) Postema, M.
H. D. C-Glycoside Synthesis; CRC Press: Boca Raton, 1995. (d) Levy,
D.; Tang, C. The Synthesis of C-Glycosides; Elsevier/Pergamon: Oxford,
1995 and ref 9a.
(11) Recent examples of C-glycosides with less substituted aglycone
segments: (a) Ben, R. N.; Orellana, A.; Arya, P. J . Org. Chem. 1998,
63, 4817-4820. (b) Griffin, F. K.; Murphy, P. V.; Paterson, D. E.;
Taylor, R. J . K. Tetrahedron Lett. 1998, 39, 8179-8182. (c) Belica, P.
S.; Franck, R. W. Tetrahedron Lett. 1998, 39, 8225-8228. (d) Evans,
D. A.; Trotter, B. W.; Cote´, B. Tetrahedron Lett. 1998, 39, 1709-1712.
J ohnson, C. R.; J ohns, B. A. Synlett 1997, 1406-1408. Spencer, R. P.;
Schwartz, J . J . Org. Chem. 1997, 62, 4024-4025.
(12) Recent examples of C-glycosides with sugar-type aglycone
segments: (a) Bazin, H. G.; Du, Y.; Polat, T.; Linhardt, R. J . J . Org.
Chem. 1999, 64, 7254-7259. (b) Pham Huu, D.-P.; Petrusova, M.;
BeMiller, J . N.; Petrus, L. Tetrahedron Lett. 1999, 40, 3053-3056. (c)
J arreton, O.; Skrydstrup, T.; Espinosa, J . F.; J immene´z-Barbero, J .;
Beau, J .-M. Chem. Eur. J . 1999, 5, 430-441. (d) Dondoni, A.; Kleban,
M.; Zuurmond, H.; Marra, A. Tetrahedron 1998, 39, 7991-7994. (e)
Rubinstenn, G.; Mallet, J .-M.; Sinay¨, P. Tetrahedron Lett. 1998, 39,
3697-3700. (f) Rekai, El-D.; Rubinstenn, G.; Mallet, J .-M.; Sinay¨, P.
Synlet 1998, 831-834. (g) Zhu, H.; Vogel, P. Tetrahedron Lett. 1998,
39, 31-34. (h) Witczak, Z. J .; Chhabra, R.; Chojnacki, J . Tetrahedron
1997, 38, 2215-2218 (i) Sutherlin, D. P.; Armstrong, R. W. J . Org.
Chem. 1997, 62, 5267-5283. (j) Wei, A.; Haudrechy, A.; Audin, C.; J un,
H.; Bretel, H.-N.; Kishi, Y. J . Org. Chem. 1995, 60, 2160-2169 and
refs 8 and 9.
1
confirmed by H COSY analysis of the acetate 15. The
coupling constants (J 1′,2′ ) 9.2, J 2′,3′ ) 7.5, J 3′,4′ ) 5.1, and
J 4′,5′ ) 2.2 Hz) are in agreement with those expected for
the 3,4-O-isopropylidene 1â-galacto residue.21
The alcohol 4 was next converted to the desired acid
3. Acidic hydrolysis of 4 afforded the triol 16, which was
subjected to selective alkylation of the 3′-OH, using
methyl bromoacetate and dibutyltin oxide.4 Partial chro-
matographic purification of the crude product afforded
an approximately 1:1 mixture. The 1H NMR of this
mixture did not show the methoxy signals for the
expected alkylation product, and it was presumed that
the components were the regiosomeric O-2 and O-4
(16) Hosomi, A.; Sakata, Y.; Sakurai, H. Tetrahedron Lett. 1984, 25,
2383-2386.
(17) Wong, C.-H.; Moris-Varas, F.; Hung, S.-C.; Marron, T. G.; Lin,
C.-C.; Gong, K. W.; Weitz-Schmidt, G. J . Am. Chem. Soc. 1997, 119,
8152-8158.
(18) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17,
522-523.
(19) Pine, S. H.; Pettit, R. J .; Geib, G. D.; Cruz, S. G.; Gallego, C.
H.; Tijerina, T.; Pine, R. D. J . Org. Chem. 1985, 50, 1212-1218.
(20) For a discussion of A(1,3) strain effects on the 1-methylcyclo-
hexene/methylenecyclohexane equilibrium: Eliel, E. L.; Wilen, S. H.
Stereochemistry of Organic Compounds; Wiley-Interscience: New York,
1994; p 737.
(13) Khan, N.; Xiao, H.; Zhang, B.; Cheng, X.; Mootoo, D. R.
Tetrahedron 1999, 55, 8303-8312. Shan, W.; Wilson, P.; Liang, W.;
Mootoo, D. R. J . Org. Chem. 1994, 59, 7986-7992.
(14) De Armas, P.; Francisco, C. G.; Suarez, E. Angew. Chem., Int.
Ed. Engl. 1992, 31, 772-774. Francisco, C. G.; Friere, R.; Gonzalez,
C. C.; Suarez, E. Tetrahedron Asymmetry 1997, 8, 1971-1972.
(15) Levene, P. A.; Tipson, R. S. J . Biol. Chem. 1936, 115, 731-747
(21) For example, see: Barili, P. L.; Catelani, G.; D′Andrea, F.;
Mastrorilli, E. J . Carbohydr. Chem. 1997, 16, 1001-1010.

2546 J . Org. Chem., Vol. 65, No. 8, 2000
Cheng et al.
EtOAc/petroleum ether); 1H NMR (300 MHz, CDCl3) δ 1.05
(s, 9H), 1.46, 1.505 (both s, 3H ea), 2.10 (s, 3H), 3.82 (m, 2H),
4.51 (m, 1H), 4.58 (d, J ) 7.0 Hz, 1H), 5.25 (m, 1H), 6.21 (d, J
) 1.5 Hz, 1H), 7.40, 7.60 (both m, 10H), 8.05 (s, 1H); ESMS
509 (M + Na).
Sch em e 4
BF3‚OEt2 (1.3 mL, 12.4 mmol) was slowly added to a solution
of 12 (5 g, 10.3 mmol) and thiophenol (2.12 mL, 20.6 mmol) in
anhydrous CH2Cl2 (50 mL) at -78 °C under an atmosphere of
argon. The reaction mixture was warmed to -40 °C and stirred
at this temperature for 1 h or until TLC indicated complete
disappearance of the starting material. Triethylamine (5 mL)
was then added, and the reaction mixture was diluted with
saturated aqueous NaHCO3 and extracted with ether. The
organic phase was washed with brine, then dried (Na2SO4),
filtered, and evaporated under reduced pressure. The crude
material was dissolved in methanolic ammonia (100 mL) and
stirred at room temperature for 30 min. Most of the solvent
was removed under reduced pressure, and the residue was
diluted with water and extracted with ether. The organic phase
was washed with brine, then dried (Na2SO4), filtered, and
evaporated under reduced pressure. Flash chromatography of
the residue provided 7 (4.7 g, 90%): colorless oil; Rf 0.50 (10%
EtOAc/petroleum ether); 1H NMR (300 MHz, CDCl3) δ 1.07
(s, 9H), 1.47, 1.49 (both s, 6H), 2.32 (br s, 1H, D2O ex), 3.80
(m, 3H), 4.18 (dd, J ) 2.0, 7.0 Hz, 1H), 5.44 (d, J ) 7.0 Hz),
7.20-7.80 (m, 15H); 13C NMR (75 MHz, CDCl3) δ 19.5, 26.3,
27.1, 27.5, 65.3, 70.1, 80.4, 85.4, 111.5, 127.6, 127.9, 129.1,
129.9, 132.0, 133.3, 134.0, 135.7; ESMS 531 (M + Na).
FABHRMS calcd for C23H31O4Si (M - SC6H5) 399.1992, found
399.1992.
Th ioa ceta l Ester 14. DCC (1.20 g, 5.15 mmol) was added
at 0 °C to a solution of alcohol 7 (2.00 g, 3.94 mmol), acid 817
(3.00 g, 5.15 mmol), and DMAP (48.3 mg, 0.40 mmol) in
anhydrous benzene (50 mL). The reaction mixture was warmed
to room temperature and stirred for 1.5 h. The mixture was
then diluted with ether (15 mL) and filtered. The filtrate was
washed with 0.1 N aqueous HCl and brine, dried (Na2SO4),
filtered, and evaporated under reduced pressure. The residue
was purified by flash chromatography to give 14 (4.1 g, 97.2%
from 7): colorless oil; Rf 0.60 (15% EtOAc/petroleum ether);
IR (neat) 1732 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.02 (s, 9H),
1.38, 1.43 (both s, 3H ea), 2.52 (dd, J ) 8.0, 14.0 Hz, 1H), 2.65
(dd, J ) 4.8, 14.0 Hz, 2H), 3.63 (m, 2H), 3.75 (m, 4H) 3.86 (m,
1H), 4.30-4.60 (m, 11H), 5.24 (m, 1H), 5.30 (d, J ) 6.6 Hz),
7.10-7.70 (m, 35H); 13C NMR (75 MHz, CDCl3) δ 20.1, 27.2,
27.7, 28.1, 37.3, 63.0, 69.6, 69.7, 72.2, 72.6, 72.9, 73.9, 74.1,
75.0, 76.3, 76.4, 80.0, 85.7, 112.3, 128.2, 128.4, 128.5, 128.7,
129.0, 129.1, 129.7, 130.5, 133.4, 133.7, 133.8, 134.2, 136.3,
136.4, 138.7, 138.8, 139.0, 139.3, 170.8. FABHRMS: calcd for
lactone derivatives of 17. Indeed, basic hydrolysis and
acidification of the crude mixture afforded the desilylated
acid 17 as a single product in 57% overall yield from 16.
Exhaustive hydrogenolysis of 17 provided, in 76% yield,
a compound for which the physical data (1H COSY, 13C
NMR, MS) was consistent with the title compound 3
(Scheme 4).
In summary, the C-glycoside analogue of a novel sLex
mimetic has been prepared, via a highly convergent
approach, from the readily available 1-thio-1,2-O-isopro-
pylidene precursor 7. Compound 7 is a general synthon
for â-C-galactosides and is currently being applied to
other C-glycoside targets. The conformational and bio-
logical properties of 3 are currently under investigation.22
Exp er im en ta l Section
Gen er a l. Unless otherwise noted, TLC was performed on
aluminum sheets precoated with silica gel 60 (HF-254, E.
Merck) to a thickness of 0.25 mm. Flash column chromatog-
raphy was performed using Kieselgel 60 (230-400 mesh, E.
Merck) and usually employed a stepwise solvent polarity
gradient, correlated with TLC mobility. The spots were visual-
ized by UV or charring with a solution of ammonium molyb-
date(VI) tetrahydrate (12.5 g) and cerium(IV) sulfate tetrahy-
drate (5.0 g) in 10% aqueous H2SO4 (500 mL). NMR spectra
were recorded on 300, 400, or 500 MHz instruments with
residual CHCl3 or C6H6 as the internal standard.
C
65H72O10SSiNa (M + Na) 1095.4513, found 1095.4514.
Th ioa ceta l En ol Eth er 9. A solution of Tebbe reagent in
1-Th io-1,2-O-isop r op ylid en e Aceta l 7. A solution of 2,3-
O-isopropylidene-D-lyxofuranose 1015 (2.7 g, 14 mmol), TBDP-
SCl (3.7 mL, 14 mmol), and imidazole (1.9 g, 28 mmol) in
anhydrous DMF (25 mL) was stirred at 50 °C for 1.5 h. The
reaction mixture was then diluted with water and extracted
with ether. The combined organic phase was washed with
brine, dried (Na2SO4), filtered, and evaporated under reduced
pressure. The residue was purified by flash chromatography
to give 11 (5.7 g, 95%): colorless oil; Rf ) 0.20 (10% EtOAc/
THF (15 mL, 0.5 M, 7.5 mmol) was added dropwise under an
argon atmosphere at -78 °C to a solution of ester 14 (4.1 g,
3.8 mmol) and pyridine (0.3 mL) in anhydrous 3:1 toluene/
THF (80 mL). The reaction mixture was warmed to room
temperature, stirred at this temperature for 1 h, and then
slowly poured into a solution of 1 N aqueous NaOH at 0 °C.
The resulting suspension was extracted with ether, and the
organic phase was washed with brine, dried (Na2SO4), filtered,
and concentrated under reduced pressure. Flash chromatog-
raphy of the residue on basic alumina (Brockmann I, 150
mesh) provided enol ether 9 (3.6 g, 88%): colorless oil; Rf 0.65
(15% EtOAc/petroleum ether); [R]D 21.6 (c 1.44, CHCl3); IR
1
petroleum ether); H NMR (300 MHz, CDCl3) δ 1.06 (s, 9H),
1.26, 1.35 (both s, 3H ea), 3.94 (m, 2H), 4.33 (m, 1H), 4.58 (d,
J ) 7.0 Hz, 1H), 4.75 (m, 1H), 5.35 (s, 1H), 7.38, 7.70 (both m,
10H).
A solution of 11 (9.5 g, 21.6 mmol) in anhydrous cyclohexane
(120 mL) containing diacetoxyiodobenzene (8.54 g, 26.5 mmol)
and iodine (5.89 g, 23.2 mmol) was stirred under an atmos-
phere of argon at room temperature for 3 h. The reaction
mixture was then diluted with water and extracted with ether.
The organic phase was washed with aqueous Na2S2O3 and
brine, then dried (Na2SO4), filtered, and evaporated under
reduced pressure. The residue was purified by flash chroma-
tography to give 12 (10.0 g, 95%): clear oil; Rf ) 0.45 (10%
1
(neat) 1667, 1626 cm-1; H NMR (400 MHz, CDCl3) δ 1.05 (s,
9H), 1.38, 1.44 (both s, 3H ea), 2.20 (dd, J ) 6.4, 14.3 Hz, 1H),
2.34 (dd, J ) 8.4, 14.3 Hz, 1H), 3.54-3.94 (m, 10H), 4.19 (m,
1H), 4.36 (m, 1H), 4.38-4.55 (m, 8H), 4.77 (d, J ) 9.8 Hz, 1H),
5.45 (d, J ) 7.0 Hz, 1H), 7.10-7.75 (m, 35H); 13C NMR (75
MHz, C6D6) δ 19.9, 27.1, 27.6, 28.1, 36.8, 62.4, 70.8, 71.7, 72.3,
72.4, 74.1, 74.7, 74.8, 75.4, 76.1, 77.2, 79.3, 80.9, 85.3, 112.3,
127.8, 128.2, 129.5, 130.4, 130.5, 132.7, 133.8, 134.0, 135.0,
136.4, 139.6, 139.7, 139.9, 140.1, 159.0; FABHRMS calcd for
C
66H74O9SSiNa (M + Na) 1093.4721, found 1093.4719.
(22) For a preliminary analysis of the solution conformation of
deprotected 4: Asensio, J . L.; Can˜ada, F. J .; Cheng, X.; Khan, N.;
Mootoo, D. R.; J ime´nez-Barbero, J . Chem. Eur. J ., in press.
3,4-O-Isop r op lylid en e-6-O-ter t-b u t yld ip h en ylsilyl-2-
d eoxy-D-a r a b in o-h ex-1-en op yr a n osyl 1-Ca r b a -2,3.4,6-

C-Glycoside of a Novel Sialyl Lewis X Mimetic
J . Org. Chem., Vol. 65, No. 8, 2000 2547
tetr a -O-ben zyl-R-D-m a n n op yr a n osid e 5. Enol ether 9 (3.6
g, 3.4 mmol), 2,6-di-tert-butyl-4-methylpyridine (6.3 g, 40
mmol), and freshly activated, powdered 4A molecular sieves
(1.0 g) in anhydrous CH2Cl2 (100 mL) were stirred for 15 min
at room temperature under an argon atmosphere and then
cooled to 0 °C. Methyl triflate (3.7 mL, 33 mmol) was then
introduced, and the mixture was warmed to room temperature
and stirred for an additional 18 h, at which time triethylamine
(5 mL) was added. The mixture was diluted with ether, washed
with saturated aqueous NaHCO3 and brine, dried (Na2SO4),
filtered, and evaporated under reduced pressure. Flash chro-
matography of the residue on basic alumina (Brockmann I,
150 mesh) provided 5 (2.8 g, 88%): clear oil; Rf 0.55 (15%
EtOAc/petroleum ether); [R]D 17.6 (c 1.28, CHCl3); IR (neat)
1689, 1682 cm-1; 1H NMR (400 MHz, C6D6) δ 1.18 (s, 9H), 1.35,
1.54 (both s, 3H ea), 2.25 (m, 2H), 3.73 (dd, J ) 2.9, 4.0 Hz,
1H), 3.80 (dd, J ) 2.9, 7.7 Hz, 1H), 3.9 (m, 4H), 4.14 (m, 2H),
4.21 (t, J ) 7.3 Hz, 1H), 4.29 (d, J ) 6.2 Hz, 1H), 4.42-4.58
(m, 9H), 4.64 (d, J ) 2.6 Hz, 1H), 4.74 (apparent d, J ) 12 Hz,
1H), 7.00-7.40 (m, 26H), 7.70 (m, 4H); 13CNMR (75 MHz,
CDCl3) δ 19.5, 27.0, 28.6, 35.0, 63.0, 69.6, 69.7, 71.4, 71.6, 71.7,
72.1, 73.6, 74.0, 74.4, 75.1, 75.4, 75.7, 77.9, 100.0, 110.2, 127.6,
127.7, 127.8, 127.9, 128.0, 128.2, 128.4, 128.5, 130.0, 135.7,
135.8, 138.5, 138.6, 152.5; FABHRMS calcd for C60H69O9Si (M
+ H) 961.4711, found 961.4708.
d, J ) 14 Hz, 1H), 2.20 (m, partially hidden under br s at δ
2.24, 1H), 2.24 (br s, 1H, D2O ex), 2.52 (br s, 1H, D2O ex), 3.17
(m, 1H), 3.31 (br d, J ) 9.2 Hz, 1H), 3.46 (t, J ) 5.5 Hz, 1H),
3.50 (br s, 1H), 3.65 (m, 3H), 3.72-3.98 (m, 5H), 4.10 (m, 2H,
D2O ex 1H), 4.40-4.70 (m, 8H), 4.80 (apparent d, J ) 11 Hz,
1H), 7.15-7.55 (m, 26H), 7.70 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ 20.0, 27.5, 27.6, 29.9, 61.1, 64.1, 69.7, 69.9, 70.6, 70.7,
70.8, 71.0, 72.5, 72.6, 72.7, 72.8, 73.0, 73.3, 73.4, 74.4, 75.0,
75.7, 75.9, 76.1, 76.3, 76.5, 76.6, 78.2, 78.5, 78.9, 79.2, 128.2,
128.3, 128.5, 128.6, 128.7, 128.9, 129.1, 129.1, 129.3, 129.4,
129.5, 130.3, 133.9, 134.2, 136.2, 136.3, 136.6, 136.7, 138.0,
138.8; ESMS 961.5 (M + Na).
3-O-Ca r boxym eth yl-6-O-ter t-bu tyld ip h en ylsilyl-â-D-ga -
la ctop yr a n osyl 1-Ca r ba -2,3.4,6-tetr a -O-ben zyl-r-D-m a n -
n op yr a n osid e 17. A mixture of triol 16 (130 mg, 0.14 mmol),
dibutyltin oxide (32 mg, 0.14 mmol), and anhydrous toluene
(5 mL) was heated at reflux in a Dean-Stark apparatus for 1
h. The solvent was evaporated in vacuo, and the residue was
dissolved in dry toluene (3 mL). n-Bu4NI (40 mg, 0.14 mmol)
and methyl 2-bromoacetate (0.1 mL, 0.42 mmol) were added,
and the solution was heated at reflux for 1 h, at which time
the volatiles were removed under reduced pressure to give a
brown syrup. Partial purification of this material by flash
chromatography provided an approximately 1:1 mixture (100
mg) of two components, Rf 0.45 and 0.35 (30% EtOAc/
petroleum ether).
3,4-O-Isop r op lylid en e-6-O-ter t-bu tyld ip h en ylsilyl-â-D-
galactopyr an osyl 1-Car ba-2,3.4,6-tetr a-O-ben zyl-r-D-m an -
n op yr a n osid e 4. BH3‚Me2S (10 mL of a 1 M solution in
CH2Cl2, 10 mmol) was added at 0 °C to a solution of glycal 5
(2.3 g, 2.5 mmol) in anhydrous THF (50 mL) under an
atmosphere of argon. The mixture was warmed to room
temperature and stirred for an additional 1 h at this temper-
ature. At that time the solution was recooled to 0 °C and
treated with a mixture of 3 N NaOH (10 mL) and 30% aqueous
H2O2 (10 mL) for 30 min. The mixture was then diluted with
ether and washed with saturated aqueous NaHCO3 and brine.
The organic extract was dried (Na2SO4), filtered, and evapo-
rated under reduced pressure. Flash chromatography of the
residue provided 4 (2.0 g, 83%): white solid; Rf 0.30 (15%
EtOAc/petroleum ether); [R]D 22.9 (c 2.10, CHCl3); IR (neat)
3391 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.10 (s, 9H), 1.41 (s,
3H), 1.56 (m, buried under s at δ1.58), 1.58 (s, 3H), 2.22 (m,
1H), 3.19 (m, 1H), 3.56 (m, 2H), 3.64-4.22 (m, 9H), 4.12 (d, J
) 5.5 Hz, 1H, D2O ex), 4.36 (d, J ) 5.5 Hz, 1H), 4.42-4.84 (m,
9H), 7.10-7.85 (m, 30H); 13C NMR (75 MHz, CDCl3) δ 20.1,
27.3, 27.6, 29.3, 30.4, 63.7, 70.2, 70.5, 72.2, 72.5, 72.9, 73.6,
74.1, 74.6, 74.9, 76.1, 76.9, 77.6, 77.8, 78.9, 80.7, 109.9, 128.2,
128.3, 128.4, 128.5, 128.6, 128.8, 128.9, 129.1, 130.3, 134.2,
134.4, 136.3, 136.4, 138.3, 138.8, 138.9; FABHRMS calcd for
The mixture obtained in the previous step was treated with
a 1:1 mixture of aqueous 3 N NaOH/ethanol (2 mL). After 1
h, the reaction mixture was neutralized with aqueous 2 N HCl.
The solvent was then removed under reduced pressure, and
the residue was purified by chromatography to give 17 (60 mg,
57% from 16): clear oil; Rf 0.20 (30% methanol/EtOAc); IR
(neat) 3368, 1729 cm-1 1H NMR (400 MHz, CD3OD) δ 1.86
;
(m, 1H), 2.14 (m, 1H), 3.14 (br t, J ) 7.0 Hz, 1H), 3.30 (m, 1H
partially hidden under residual CD2HOD), 3.38 (t, J ) 6.5 Hz,
1H), 3.64-3.86 (m, 9H), 4.08 (d, J ) 3.0 Hz, 1H), 4.19 (ABq,
∆δ ) 0.13 ppm, J ) 14.4 Hz, 2H), 4.36 (m, 1H), 4.45-4.58 (m,
6H), 4.63, 4.72 (both apparent d, J ) 12, 11 Hz resp, 1H ea),
7.30 (m, 20H); 13C NMR (75 MHz, CD3OD) δ 35.0, 64.9, 70.4,
72.4, 73.3, 74.3, 74.5, 74.9, 76.2, 76.6, 77.1, 78.1, 78.9, 80.7,
81.3, 81.4, 87.0, 87.3, 130.4, 130.9, 130.9, 130.9, 131.1, 141.2,
141.4, 141.5, 179.5; FABHRMS calcd for C48H50O12Na (M +
Na) 781.3200, found 781.3202.
3-O-Ca r b oxym et h yl-â-D-ga la ct op yr a n osyl 1-Ca r b a -r-
D-m a n n op yr a n osid e 3. A mixture of acid 17 (35 mg, 0.05
mmol), 20% Pd on carbon (35 mg), formic acid (0.1 mL), and
methanol (2 mL) was stirred under an atmosphere of hydrogen
(balloon) for 12 h. The reaction mixture was then purged with
argon and filtered through a bed of Celite. The filtrate was
concentrated in vacuo, and the residue was purified by
Sephadex LH-20 chromatography (H2O). Lyophilization of the
column extracts provided 3 (14 mg, 76%): white powder; [R]D
C
60H71O10Si (M + H) 979.4817, found 979.4818.
2-O-Acetyl-3,4-O-isop r op lylid en e-6-O-ter t-bu tyldiph en -
ylsilyl-â-D-ga la ctop yr a n osyl 1-Ca r ba -2,3.4,6-tetr a -O-ben -
zyl-r-D-m a n n op yr a n osid e 15. 1H NMR (300 MHz, CDCl3)
δ 1.17 (s, 9H), 1.28, 1.61 (both s, 3H ea), 1.70 (s, 3H), 2.08 (m,
1H), 3.58 (dt, J ) 4.8, 9.4 Hz, 1H), 3.73 (dd, J ) 2.6, 5.5 Hz,
1H), 3.76-3.92 (m, 4H), 3.98 (dd, J ) 5.1, 7.3 Hz, 1H), 4.08
(m, 3H), 4.17 (dd, J ) 7.7, 9.5 Hz, 1H), 4.2 (dd, J ) 2.2, 5.1
Hz, 1H), 4.34-4.54 (m, 8H), 4.59 (apparent d, J ) 12.1 Hz,
1H), 5.38 (dd, J ) 7.7, 9.2 Hz, 1H), 7.10-7.90 (m, 26H), 7.82
(m, 4H).
6-O-ter t-Bu tyldiph en ylsilyl-â-D-galactopyr an osyl 1-Car -
ba -2,3.4,6-tetr a -O-ben zyl-r-D-m a n n o-p yr a n osid e 16. A so-
lution of 1 M HCl in ether (3 mL) was added to a solution of
4 (500 mg, 0.51 mmol) in dry methanol (50 mL). The reaction
mixture was stirred at room temperature for 20 min, and then
neutralized by addition of a solution of sodium methoxide in
methanol. Removal of the volatiles under reduced pressure and
flash chromatography of the residue provided 16 (300 mg,
63%): clear oil; Rf 0.50 (50% EtOAc/petroleum ether); IR (neat)
3369 cm-1; 1HNMR (400 MHz, CDCl3) δ 1.05 (s, 9H), 1.39 (br
1
+57 (c 0.75, 1:1 methanol/H2O); H NMR (500 MHz, D2O) δ
1.90 (dt, J ) 7.5, 15 Hz, 1H), 2.11 (ddd, J ) 1.5, 7.5, 15 Hz,
1H), 3.31 (dt, J ) 3.0, 8.0 Hz, 1H), 3.4 (dt, J ) 3.0, 9.5 Hz,
1H), 3.53-3.74 (m, 7H), 3.79 (m, 2H), 3.91 (br s, 1H), 4.08 (d,
J ) 3.0 Hz, 1H), 4.11 (ABq, ∆δ ) 0.04 ppm, J ) 12 Hz, 2H),
4.19 (t, J ) 7.0 Hz, 1H); 13C NMR (75 MHz, D2O) δ 34.1, 64.7,
65.0, 69.4, 70.8, 71.6, 73.2, 73.9, 74.3, 77.5, 79.1, 80.8, 81.7,
86.6, 181.5; FABMS 421 (M + Na).
Ack n ow led gm en t . This investigation was sup-
ported by NIH grants RR 03037 (RCMI) and GM 57865.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
data for compounds 3, 4, 9, and 14-17. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O991898H