A convergent strategy for the synthesis of beta-carba-galacto-disaccharides.

Article abstract of DOI:10.1021/ol0156906

[reaction in text] A convergent strategy for the synthesis of beta-carba-galacto-disaccharides is illustrated by the preparation of 1 and 4, from a central "glycone" component 22, and the corresponding "aglycone" segments, monosaccharide alcohols, 23a or

Full text of DOI:10.1021/ol0156906

ORGANIC
LETTERS
2001
Vol. 3, No. 9
1323-1325
A Convergent Strategy for the Synthesis
of â-Carba-galacto-disaccharides
Xuhong Cheng, Noshena Khan, Govindaraj Kumaran, and David R. Mootoo*
Department of Chemistry, Hunter College/CUNY, 695 Park AVenue,
New York, New York 10021
dmootoo@shiVa.hunter.cuny.edu
Received February 9, 2001
ABSTRACT
A convergent strategy for the synthesis of â-carba-galacto-disaccharides is illustrated by the preparation of 1 and 4, from a central “glycone”
component 22, and the corresponding “aglycone” segments, monosaccharide alcohols, 23a or 23b. The key step is the formation of the
carbasugar ring via an oxocarbenium ion−enol ether cyclization
Glycomimetic molecules have attracted considerable interest
as biochemical probes and potential therapeutic agents.1
Analogues that have limited structural modifications relative
to the native carbohydrate are of relevance to the systematic
dissection of mechanistic pathways.2 The notion that the
oxygens of the acetal linkages are generally intimately
involved in carbohydrate-receptor interactions has led to
interest in acetal analogues. Structures in which the endo-
cyclic or the exocyclic oxygen of the acetal linkage is
replaced by a methylene residue are especially common.3-5
These carba and C-glycosides (e.g., 1 and 2, respectively,
Figure 1) are expected to exhibit steric and conformational
features similar to those of the parent O-glycoside 3 but
would be stable to chemical and enzymic hydrolysis.6
C-glycoside/carbasugar analogue pairs of a given O-
glycoside could be valuable for the evaluation of the relative
importance of the individual acetal oxygens in carbohydrate
mechanisms.7 We have been interested in the synthesis of
disaccharide mimetics because of their potential to provide
information regarding substrate specificity.8 A number of
(1) (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 1645-1680. (b) Sears, P.; Wong, C.-
H. Angew. Chem., Int. Ed. 1999, 38, 2300-2324. Sears, P.; Wong, C.-H.
Proc. Natl. Acad. Sci.U.S.A. 1996, 93, 12086-93. (c) Carbohydrates in
Drug Design; Witczak, Z. J., Nieforth, K. A., Eds.; Marcel Dekker: New
York, 1997. (d) Carbohydrate Mimics: Concepts and Methods; Chapleur,
Y., Ed.; Wiley-VCH: New York, 1998. (e) Dwek, R. A. Chem. ReV. 1996,
96, 683-720.
(2) (a) Lemieux, R. U.; Du, M.-H.; Spohr, U. J. Am. Chem. Soc. 1994,
116, 9803-9804. (b) Bundle, D. R.; Alibe´s, R.; Nilar, S.; Otter, A.; Warwas,
M.; Zhang, P. J. Am. Chem. Soc. 1998, 120, 5317-5318.
(3) Carbasugars: (a) Sollogoub, M.; Pearce, A. J.; He´rault, A.; Sina¨y,
P. Tetrahedron: Asymmetry 2000, 11, 283-294. (b) Ogawa, S.; Hirai, K.;
Odagiri, T.; Matsunaga, N.; Yamazaki, T.; Nakajima, A. Eur. J. Org. Chem.
1998, 1099-1109. (c) Ogawa, S. In Carbohydrates in Drug Design;
Witczak, Z. J., Nieforth, K. A., Eds.; Marcel Dekker: New York, 1997; pp
433-469. Carbohydrate Mimics: Concepts and Methods; Chapleur, Y.,
Ed.; Wiley-VCH: New York, 1998; pp 87-106. (d) Suami, T.; Ogawa, S.
AdV. Carbohydr. Chem. Biochem. 1990, 48, 22-90.
(4) C-Glycosides: (a) Smoliakova, I. P. Curr. Org. Chem. 2000, 4, 589-
608. (b) Du, Y.; Linhardt, R. J.; Vlahov, J. R. Tetrahedron 1998, 54, 9913-
9959. (c) Togo, H.; He, W.; Waki, Y.; Yokoyama, M. Synlett 1998, 700-
717. (d) Postema, M. H. D. C-Glycoside Synthesis; CRC Press: Boca Raton,
1995. (e) Levy, D.; Tang, C. The Synthesis of C-Glycosides; Elsevier/
Pergamon: Oxford, 1995.
Figure 1. Acetal analogues of disaccharides.
10.1021/ol0156906 CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/05/2001

convergent methodologies have been developed for the
synthesis of C-disaccharides.4 By comparison the synthesis
of carba-disaccharides are not as well explored. The most
common strategy utilizes the coupling of an epoxysugar or
epoxycyclitol with an alcohol partner.3b-d,9 However syn-
theses of the epoxide components are not trivial, coupling
yields are low when secondary alcohols are used, and the
overall procedures are lengthy.
analogues of a sialyl Lewis X mimetic and methyl lactoside,
respectively.11
Scheme 1
We have shown that 1-thio-1,2-O-isopropylidene acetals
(TIAs, e.g., 13) provide a convergent entry to C-galacto-
disaccharides.10 Thus esterification of TIA alcohol 13 and a
saccharide acid 15, followed by Tebbe olefination of the
resulting ester, provides an enol ether 11. An oxo-carbenium
ion-alkene cyclization on 11 leads to the C1-substituted
glycal 9, which is converted to the â-C-galactoside 7. We
envisaged synthesis of the corresponding carba analogue 8
by juxtaposing the location of the alcohol and acid residues
in the C-glycoside precursors. Accordingly, TIA acid 14 and
saccharide alcohol 16 may be transformed in two steps to
the enol ether 12. Notwithstanding the position of the olefin
in the cyclization product, the enol ether 10 would be
expected to give under conditions of hydroboration-oxida-
tion, the â-carbo-galactoside 8. Herein is described the
application of this methodology to the synthesis of 1 and 4,
(5) C-Carbasugars have also been described: Cossy, J.; Ranaivosata, J.-
L.; Bellosta, V.; Ancerewicz, J.; Ferritto, R.; Vogel, P. J. Org. Chem. 1995,
60, 8351-8359.
(6) (a) Montero, E.; Garc´ıa-Herrero; Asensio, J. L.; Hirai, K.; Ogawa,
S.; Santoyo-Gonza´lez, Can˜ada, F. J.; Jime´nez-Barbero, J. Eur. J. Org. Chem.
2000, 1945-1952. Asensio, J. L.; Espinosa, J. F.; Dietrich, H.; Can˜ada, F.
J.; Schmidt, R. R.; Martin-Lomas, M.; Andre´, S.; Gabius, H.-J.; Jime´nez-
Barbero, J. J. Am. Chem. Soc. 1999, 121, 8995-9000. (b) Ravi-shankar,
R.; Surolia, A.; Vijayan, M.; Lim, S.; Kishi, Y. J. Am. Chem. Soc. 1998,
120, 11297-11303.
(7) For examples of biological activity of carbasugars: Ogawa, S. In
Carbohydrates in Drug Design; Witczak, Z. J., Nieforth, K. A., Eds.; Marcel
Dekker: New York, 1997; pp 433-469. Carbohydrate Mimics: Concepts
and Methods; Chapleur, Y., Ed.; Wiley-VCH: New York, 1998; pp 87-
106. For examples of biological activity of C-glycosides: (a) Link, J. T.;
Sorensen, B. K. Tetrahedron Lett. 2000, 41, 9213-9217. (b) Xin, Y.-C.;
Zhang, Y.-M.; Mallet, J.-M.; Glaudemans, C. P. J.; Sina¨y, P. Eur. J. Org.
Chem. 1999, 471-476 (c) Mortell, K. H.; Weatherman, R. V.; Kiessling,
L. L. J. Am. Chem. Soc. 1996, 118, 2297-2298. (d) Wei, A.; Boy, K. M.;
Kishi, Y. J. Am. Chem. Soc. 1995, 117, 9432-9436.
(8) (a) Heightman, T. D.; Vasella, A. T. Angew. Chem., Int. Ed. 1999,
38, 750-770. (b) van den Broek, L. A. G. M.; Vermaas, D. J.; Heskamp,
B. M.; van Boeckel, C. A. A.; Tan, M. C. A. A.; Bolscher, J. G. M.; Ploegh,
H. L.; van Kemenade, F. J.; De Goede, R. E. Y.; Miedema, F. Recl. TraV.
Chim. Pays-Bas 1993, 112, 82-94.
(9) An elegant entry to carba-disaccharides from the rearrangement of
O-disaccharide precursors has recently been described: Sollogoub, M.;
Pearce, A. J.; He´rault, A.; Sina¨y, P. Tetrahedron: Asymmetry 2000, 11,
283-294.
(10) Cheng, X.; Khan, N.; Mootoo, D. R. J. Org. Chem. 2000, 65, 2544-
2547. Khan, N.; Cheng, X.; Mootoo, D. R. J. Am. Chem. Soc. 1999, 121,
4918-4919.
The TIA-acid 22 corresponding to the glycone component
was obtained from the C-branched pyranoside 18, which has
been previously prepared in four steps from D-lyxose 17 by
Keck and co-workers.12 Sodium ammonia reduction of the
benzyl ether in 18 provided the lactol 19. Treatment of 19
with diiodosobenzene diacetate (DIB) according to the Suarez
methodology for fragmentation of anomeric alkoxy radicals
led to a mixture of 1,2-O-isopropylidene acetates 20 in 96%
yield.13 It was important that this reaction be carried out under
high dilution conditions. Lower yields of products resulting
from an intramolecular iodoetherification reaction of the
alkene appeared to be significant when the reaction was
carried out at high concentrations.14 Acetal exchange on 20
with thiophenol, followed by basic hydrolysis of the crude
product and benzylation of the resulting alcohol, provided
21 as an approximately 4:1 mixture of acetals in 70% overall
yield from 20.15 Ozonolysis of 21 and NaClO2 oxidation16
of the derived aldehyde led to a mixture of TIA acids 22.
(11) For activity of O-glycoside analogue of 1, see: Hiruma, K.;
Kajimoto, T.; Weitz-Schmidt, G.; Ollmann, I.; Wong, C.-H. J. Am. Chem.
Soc 1996, 118, 9265-9270. For C-glycoside analogue of 1, see: Cheng,
X.; Khan, N.; Mootoo, D. R. J. Org. Chem. 2000, 65, 2544-2547. Khan,
N.; Cheng, X.; Mootoo, D. R. J. Am. Chem. Soc. 1999, 121, 4918-4919.
For conformational studies on 4, see: Montero, E.; Garc´ıa-Herrero; Asensio,
J. L.; Hirai, K.; Ogawa, S.; Santoyo-Gonza´lez, Can˜ada, F. J.; Jime´nez-
Barbero, J. Eur. J. Org. Chem. 2000, 1945-1952. Asensio, J. L.; Espinosa,
J. F.; Dietrich, H.; Can˜ada, F. J.; Schmidt, R. R.; Martin-Lomas, M.; Andre´,
S.; Gabius, H.-J.; Jime´nez-Barbero, J. J. Am. Chem. Soc. 1999, 121, 8995-
9000.
(14) Wilson, P.; Shan, W.; Mootoo, D. R. J. Carbohydr. Chem. 1994,
13, 133-140.
(15) The TIA mixture 21 was inseparable by chromatography and used
without separation in the next step. The subsequent acid 22 and the ester
and enol ether derivatives of 22 showed similar mixture ratios. That the
origin of the mixture was at the acetal carbon was confirmed by the
formation of a single glycal product in the subsequent oxocarbenium ion
cyclizations.
(12) Keck, G. E.; Kachensky, D. F.; Enholm, E. J. J. Org. Chem. 1985,
50, 4317-4325. Keck, G. E.; Enholm, E. J.; Yates, J. B.; Wiley, M. R.
Tetrahedron 1985, 41, 4079-4094.
(13) De Armas, P.; Francisco, C. G.; Suarez, E. Angew. Chem., Int. Ed.
Engl. 1992, 31, 772-774.
(16) No appreciable oxidation of the thioether was detected. For related
selective oxidation of hydroxy-thioethers, see: (a) Smith, A. B., III; Wan,
Z. J. Org. Chem. 2000, 65, 3738-3753. (b) Crimmins, M. T.; Al-awar, R.
S.; Vallin, I. M.; Hollis, W. G., Jr.; O’Mahony, R.; Lever, J. G.; Bankaitis-
Davis, D. M. J. Am. Chem. Soc. 1996, 118, 7513-7528.
1324
Org. Lett., Vol. 3, No. 9, 2001

Scheme 2a
Scheme 3a
a (i) Na, NH3, THF; (ii) DIB, I2, cyclohexane (0.04 M); (iii)
PhSH, BF3‚OEt2, -78 °C then NaOMe, MeOH; (iv) NaH, BnBr,
Bu4NI, DMF; (v) O3, MeOH/CH2Cl2, -78 °C then Ph3P; (vi)
NaClO2, CH3CN, 2-methyl-2-butene.
a (i) DCC, DMAP, PhH; (ii) Tebbe; (iii) MeOTf, DTBMP,
CH2Cl2 (iv) BH3‚Me2S then Na2O2; (v) MeOH, HCl; (vi) Pd/C
EtOH, HCOOH 1, 4 (both 72% over two steps).
DCC-mediated esterification17 of the known manno and
gluco alcohol components 23a18 and 23b19 with 1.2 equiv
of acid 22 led to esters 24a and 24b in approximately 80%
yield in both cases. Ester mixture 24b was found to be a
single R-anomer with respect to the mannose linkage, as
determined from the H-H and C-H coupling constants
(JH1,H2 ) 2, JC1H1 ) 175 Hz).15,20 Tebbe olefination21 of 24a
and 24b gave the corresponding enol ethers 25a and 25b in
80% and 86% yields, respectively. The enol ethers were
stable to purification on silica gel.
Activation of 25a and 25b with methyl triflate in the
presence of 2,6-di-tert-butyl-4-methylpyridine (DTBMP) led
to the cyclic enol ethers 26a and 26b in yields of 64% and
75%, respectively. In neither case was any of the regioso-
meric alkene product detected. Treatment of 26a and 26b
with BH3‚Me2S provided the carbadisaccharides 27a and 27b
in respective yields of 72% and 78%. The observed J values
for the acetate derivatives of 27a and 27b (J1,2 ) 10.0 and
10.5, J2,3 ) 8.0 and 8.5, J3,4 ) 4.0 and 3.5, J4,5 ) 4.0 and
3.5 Hz, respectively) were in close agreement with those for
related 3,4-O-isopropylidene-â-O-galactosides.22 In addition,
for the manno acetate derivative NOEs between H5 and H1
and H5 and H3 were clearly discernible. The deprotected
carbadisaccharides 1 and 4 were obtained in good yield from
27a and 27b over two straightforward operations involving
hydrolysis of the acetonide and hydrogenolysis of the benzyl
ethers.
The alcohol component 16 for the carbadisaccharide
methodology is the identical compound that would normally
be used as the glycosyl acceptor in the synthesis of the parent
â-O-galactoside and is also the precursor for the acid
aglycone component 15 in our earlier synthesis of â-C-
galactosides (Scheme 2). The TIA methodology therefore
provides a general protocol for conversion of a given glycosyl
acceptor 16 to either its â-C-galactoside 8 or â-carbagalac-
toside 7. In both the C-glycoside and carbasugar synthesis
the key “glycone”-“aglycone” coupling step is an esterifi-
cation reaction. The reliability of this segment coupling
reaction should allow for the general synthesis of â-galacto
mimetics with a high degree of complexity in the aglycone
segment.
Acknowledgment. We thank the National Institutes of
Health (NIH), General Medical Sciences (GM 57865), for
their support of this research. Research Centers in Minority
Institutions award RR-03037 from the National Center for
Research Resources of the NIH, which supports the infra-
structure (and instrumentation) of the Chemistry Department
at Hunter, is also acknowledged. The contents are solely the
responsibility of the authors and do not necessarily represent
the official views of the NCRR/NIH.
(17) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17,
522-523.
(18) Decoster, E.; Lacombe, J.-M.; Strebler, J.-L.; Ferrari, B.; Pavia, A.
A. J. Carbohydr. Chem. 1983, 2, 329.
(19) Garegg, P. J.; Hultberg, H.; Wallin, S. Carbohydr. Res. 1982, 108,
97-101.
(20) (a) Bock, K.; Pedersen, C. J. Chem. Soc,. Perkin Trans. 2 1974,
293-297. (b) Singh, G.; Vankayalapati, H. Tetrahedron: Asymmetry 2000,
11, 125-138. (c) Li, Z.-J.; Huang, H.-Q.; Cai, M.-S. J. Carbohydr. Chem.
1996, 15, 501-506.
(21) 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.
(22) For example, see: Barili, P. L.; Catelani, G.; D’Andrea, F.;
Mastrorilli, E. J. Carbohydr. Chem. 1997, 16, 1001-1010.
Supporting Information Available: 1H and 13C NMR
and HRMS data for 1, 4, 22, 27a, and 27b. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0156906
Org. Lett., Vol. 3, No. 9, 2001
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