1-Thio-1,2-O-isopropylidene acetals: Novel precursors for the synthesis of complex C-glycosides [14]

Full text of DOI:10.1021/ja9843270

4918
J. Am. Chem. Soc. 1999, 121, 4918-4919
aldehydes are the most general but are only reliable for 2-deoxy
and Man-R-C-glycosides.11 Extension to the gluco and galacto
series is severely hampered by competing elimination of the
2-substituent. 2-Phenyl-sulfinyl-lithio glycals have been used to
address this problem, and high yields with complex aldehydes
have been obtained.12 However, the synthesis and handling of
these lithio reagents are not trivial, and the conversion of the
coupled product to the C-glycoside is somewhat cumbersome.
Herein we describe a highly convergent, de novo approach15-17
to â-C-galactosides, which alleviates these problems.
1-Thio-1,2-O-isopropylidene Acetals: Novel
Precursors for the Synthesis of Complex
C-Glycosides
Noshena Khan, Xuhong Cheng, and David R. Mootoo*
Department of Chemistry, Hunter College/CUNY
695 Park AVenue, New York, New York 10021
ReceiVed December 16, 1998
The methodology originates in our earlier observation that the
iodoetherification of C5 allylated 1,2-O-isopropylidene furanose
1 on treatment with IDCP gave the linked bis-ether 3, which may
be regarded as a “1-deoxy-L-galactopyranose.”18 The reaction was
extremely facile and proceeded in high yield with formation of
only a single THP isomer. The proposed mechanism for the
formation of 3 involves the intramolecular capture of the
isopropylidinated oxocarbenium ion 2 by the alkene residue.
(Scheme 1). The efficiency of the reaction apparently derives from
The implication of carbohydrates in important biological
mechanisms has led to interest in carbomimetic structures as
potential therapeutic agents and biochemical tools.1,2 First genera-
tion analogues of the native carbohydrate with functional group
replacements allow for systematic analysis of carbohydrate-
receptor contacts and are natural starting points.3 Among these
are C-glycosides, derivatives in which the exocyclic acetal oxygen
is replaced by a methylene.4 C-glycosides are expected to have
conformational and steric properties similar to those of the
O-analogues5,6 and are especially interesting as hydrolytically
stable carbomimetics or molecular scaffolding.7,8
Scheme 1
Application of existing C-glycoside methodologies4,9 toward
the synthesis of “true” C-glycosides10 of complex structures such
as glycolipids and disaccharides is not generally practical. The
most common approach to such structures involves the coupling
of sugar-derived THP components. This includes the addition of
C1 nucleophiles to aglycon aldehydes, C1 radicals to activated
or tethered aglycon alkenes, and aglycon nucleophiles to C1
electrophiles.11-14 These methods are often limited by experi-
mentally difficult or low-yielding coupling protocols and lengthy
processing sequences for the THP precursors and the coupled
product. Strategies based on C1-nucleophiles with aglycon
the cyclic nature of 2. This led to interest in less substituted 1,2-
O-isopropylidinated oxocarbenium ion precursors as potential
annulating synthons for highly oxygenated structures. Toward this
goal the 1-thio-1,2-O-isopropylidine 7 was prepared (Scheme 2).
(1) Sears, P.; Wong, C.-H. Proc. Natl. Acad. U.S.A. 1996, 93, 12086-
12093.
Scheme 2
(2) Witczak, Z. J. Curr. Med. Chem. 1995, 1, 392-405.
(3) Lemieux, R. U.; Du, M.-H.; Spohr, U. J. Am. Chem. Soc. 1994, 116,
9803-9804.
(4) Postema, M. H. D. C-Glycoside Synthesis; CRC Press: Boca Raton,
1995; Levy, D.; Tang, C. The Synthesis of C-Glycosides; Elsevier/Pergamon:
Oxford, 1995.
(5) Ravishankar, R.; Surolia, A.; Vijayan, M.; Lim, S.; Kishi, Y. J. Am.
Chem. Soc. 1998, 120, 11297-11203.
(6) Martin-Lomas, M.; Imberty, A.; Can˜ada, F. J.; Jimenez-Barbero, J. J.
Am. Chem. Soc. 1998, 120, 1309-1318.
(7) 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, 4501-4502.
Mortell, K. H.; Weatherman, R. V.; Kiessling, L. L. J. Am. Chem. Soc. 1996,
118, 2297-2298.
Compound 7 was obtained on large scale in four straightforward
operations from commercially available D-lyxose.19 Acetonation
of D-lyxose provided the known derivative 420 which was
converted to the silyl ether 5. The reaction of 5 with (diacetoxy-
iodo)-benzene (DIB)/I2 according to the Suarez procedure, led
to the acetate 6 in high yield.21 Treatment of 6 with thiophenol
and boron trifluoride etherate at low temperature, followed by
basic hydrolysis of the crude product gave 7 in 90% from 6.
The plan for C-glycoside synthesis requires the esterification
of 7, the glycone segment, with an acid 8 which corresponds to
(8) Hirschmann, R.; Hynes, J., Jr.; Cichy-Knight, M. A.; van Rijn, R. D.;
Sprengeler, P. A.; Spoors, P. G.; Shakespeare, W. C.; Pientranico-Cole, S.;
Barbosa, J.; Liu, J.; Yao, W.; Rohrer, S.; Smith, A. B., III. J. Med. Chem.
1998, 41, 1382-1391.
(9) Recent examples of less complex C-glycosides, see: Ben, R. N.;
Orellana, A.; Arya, P. J. Org. Chem. 1998, 63, 4817-4820. Dondoni, A.;
Marra, A.; Massi, A. Tetrahedron 1998, 54, 2827-2832. Griffin, F. K.;
Murphy, P. V.; Paterson, D. E.; Taylor, R. J. K. Tetrahedron Lett. 1998, 39,
8179-82. Belica, P. S.; Franck, R. W. Tetrahedron Lett. 1998, 39, 8225-
8228. Evans, D. A.; Trotter, B. W.; Coˆte´, B. Tetrahedron Lett. 1998, 39, 1709-
1712. Spencer, R. P.; Schwartz, J. J. Org. Chem. 1997, 62, 4204-4205.
Johnson, C. R.; Johns, B. A. Synth. Lett. 1998, 1406-1408.
(10) For “true” C-glycosides only the intersaccharide oxygen of the
O-saccharide is replaced by a methylene. These should be distinguished from
analogues which have longer or substituted intersaccharide linkers and
modified aglycon segments, and are less synthetically challenging. In general,
existing approaches to C-glycosides are more easily easily applied to the latter
than the former.
(15) De novo approaches: Wang, Y.; Babirad, S. A.; Kishi, Y. J. Org.
Chem. 1992, 57, 468-481 and refs 16 and 17.
(16) Sutherlin, D. P.; Armstrong, R. W. J. Org. Chem. 1997, 62, 5267-
5283.
(17) Danishefsky, S. J.; Pearson, W. H.; Harvey, D. F.; Maring, C. J.;
Springer, J. P. J. Am. Chem. Soc. 1985, 107, 1256-1268. Jacques, F.;
Dupeyroux, H.; Joly, J.-P.; Chapleur; Y. Tetrahedron Lett. 1997, 38, 73-76.
(18) Shan, W.; Wilson, P.; Liang, W.; Mootoo, D. R. J. Org. Chem. 1994,
59, 7986-7992.
(19) D-Lyxose may be also obtained in one step, from calcium D-
galactonate: Methods in Carbohydrate Chemistry; Whistler, R. L., Wolfrom,
M. L., Eds.; Academic Press: London, 1962; Vol. 1, pp 77-78.
(20) Levene, P. A.; Tipson, R. S. J. Biol. Chem. 1936, 115, 731-747.
(21) De Armas, P.; Francisco, C. G.; Suarez, E. Angew. Chem., Int. Ed.
Engl. 1992, 31, 772-774.
(11) Glycosyl nucleophiles: Beau, J.-M.; Gallagher, T. Top. Curr. Chem.
1997, 187, 1-54.
(12) Glycal nucleophiles: Eisele, T.; Ishida, M.; Hummel, G.; Schmidt,
R. Liebigs Ann. 1995, 2113-2121.
(13) C1 radicals: Rubinstenn, G.; Mallet, J.-M.; Sinay¨, P. Tetrahedon Lett.
1998, 39, 3697-3700.
(14) C1 electrophiles: Rouzad, D.; Sinay¨, P. J. Chem. Soc., Chem. Commun.
1983, 1353-1354. Preuss, R.; Schmidt, R. R. J. Carbohydr. Chem. 1991, 10,
887-900.
10.1021/ja9843270 CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/07/1999

Communications to the Editor
J. Am. Chem. Soc., Vol. 121, No. 20, 1999 4919
Table 1*
Scheme 3
the aglycon. Olefination of the ester 9 to an enol ether 10, followed
by activation of the thioacetal in 10, should lead to the C1-
substituted glycal 11. Finally hydroboration of 11 would provide
a â-C-galactoside 12 (Scheme 3).
The protocol was applied to 7 and the acids 8a-e. Compounds
8b-e were prepared by standard procedures on known precur-
sors.22 Esterifications were promoted by DCC with DMAP as
catalyst and performed in dry benzene.23 The enol ethers were
prepared by the Tebbe reaction on the esters.24 Treatment of the
enol ether with methyl triflate and 2,6-di-tert-butyl-4-methylpy-
ridine (DTBMP) in anhydrous dichloromethane led to a single
endo-glycal product in all cases except for the reaction of 11c,
which gave a small amount of the exo-glycal. This was smoothly
converted to the endo isomer on heating in benzene. C-glycoside
12e illustrates that the protocol may be extended to aglycon
components which contain amino groups. Notably, the sulfonyl-
protecting group is compatible with the conditions of the Tebbe
and the key cyclization reaction. In general the esterification-
Tebbe sequence and the cyclization step each occurred in
approximately 70-80% (see Table 1). Hydroboration of the
glycals with BH3‚Me2S, provided in each case the â-C-galactoside,
as a single product in high yield. The galacto configuration of
the C-glycoside was confirmed by 1HNMR analysis of the
hydroboration products or their acetate derivatives. The coupling
constants for 12a are representative and in agreement with those
expected for the 3,4-O-isopropylidene galacto residue (J1,2 ) 9.9,
J2,3 ) 7.2, J3,4 ) 4.5, and J4,5 ) 2.2 Hz).25
*(i) 7, DCC, DMAP, PhH; (ii) Tebbe; (iii) MeOTf, DTBMP, CH2Cl2;
(iv) BH3‚DMS then Na2O2 a1.2-1.5 equiv of acid used, yield based
b
on 7. Reaction quenched at ca. 80% completion, based on recovered
starting material. cIncludes the product obtained from isomerization of
the exo-glycal isomer (10%).
Scheme 4
provided a single THP 14,30 in which the isopropenyl substituent
was trans to the cis-isopropylidenedioxy residue (Scheme 4). The
stereochemical result is identical to that observed for the more
substituted oxo-carbenium ion precursor 1, and remains to be
further investigated.
In summary a highly general synthesis of Gal-â-C-galactosides
has been described. Noteworthy aspects are the highly convergent
design, the easy availability and stability of the glycone synthon,
and the applicability to a variety of complex aglycon segments.
Glyconic analogues of these structures would be obtainable by
using diastereomers of 7 which are available from the correspond-
ing furanoses. It should be also possible to use 1-thio-1,2-O-
isopropylidenes as synthons for highly oxygenated cyclohexanes
and carbasugars. These directions are currently being pursued.
C-glycosides 12a-e are analogues of, or model compounds
for, important â-galactosides such as those contained in the blood
group antigens, tumor-associated antigens, receptors for patho-
genic bacteria, and glycolipids.26,27 In particular, O-glycolipids
related to 12a and the O-saccharide of 12b have recently attracted
attention as selectin ligands.28,29
To illustrate the synthesis of other THP motifs, the thioacetal
7 was converted to 13 by alkylation with 1-bromo-2-methyl-2-
butene. Treatment of 13 with IDCP in anhydrous dichloromethane
(22) For precursors to 8b-e, see: Hosomi, A.; Sakata, Y.; Sakurai, H.
Tetrahedron Lett. 1984, 25, 2383-2386 (8b); Wilson, P.; Jammalamadaka,
V.; Mootoo, D. R. J. Carbohydr. Chem. 1994, 13, 841-849 (8c); ref 15,
(8d); Reinhardt, G.; J. App. Biochem. 1980, 2, 495-509 (8e).
(23) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17, 522-
523.
(24) 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.
(25) Barili, P. L.; Catelani, G.; D’Andrea, F.; Mastrorilli, E. J. Carbohydr.
Chem. 1997, 16, 1001-10. See Supporting Information.
Acknowledgment. This investigation was supported by NIH grants
RR 03037 (RCMI) and GM 57865.
Supporting Information Available: Synthetic procedures and physi-
cal data for compounds 7, 8b-e, 9a, 9b, 9d, 9e, 10a-d, 11a-e, 12a-e,
and 14 (PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
(26) Feizi, T. Nature 1985, 314, 53-57. Varki, A. Glycobiology 1993, 3,
97-130. Bremer, E. G.; Levery, S. B.; Sonnino, S. B.; Ghidoni, R.; Canevari,
S.; Kannagi, R.; Hakomori, S. J. Biol. Chem. 1984, 259, 14773-14777. Boren,
T.; Falk, P.; Rock, K. A.; Larson, G. Normack, S. Science 1993, 262, 1892-
1895. Van Echten, G.; Sandhoff, K. J. Biol. Chem. 1993, 268, 5341-5344.
(27) Marino-Albernas, J. R.; Bittman, R.; Peters, A.; Mayhew, E. J. Med.
Chem. 1996, 39, 3241-3247.
JA9843270
(29) Hiruma, K.; Kajimoto, T.; Weitz-Schmidt, G.; Ollmann, I.; Wong,
C.-H. J. Am. Chem. Soc. 1996, 118, 9265-9270.
(30) For 14: J1,2 ) 4.4, 11.4; J2,3 ) 11.0; J3,4 ) 5.2; and J4,5 ) 2.6 Hz.
(28) Tanahashi, E.; Murase, K.; Shibuga, M.; Igarashi, Y.; Ishida, H.;
Hasegawa, A.; Kiso, M. J. Carbohydrate. Chem. 1997, 16, 831-858.