Synthesis of L-sugars from 4-deoxypentenosides.

Article abstract of DOI:10.1021/ol026175q

[reaction: see text] 4-Deoxypentenosides, which are readily derived from D-sugars, resemble glycals in structure and reactivity and can undergo stereoselective epoxidation and S(N)2 nucleophilic addition to produce L-sugars in pyranosidic form.

Full text of DOI:10.1021/ol026175q

ORGANIC
LETTERS
2002
Vol. 4, No. 13
2281-2283
Synthesis of L-Sugars from
4-Deoxypentenosides
Fabien P. Boulineau and Alexander Wei*
Department of Chemistry, Purdue UniVersity, 1393 Brown Building,
West Lafayette, Indiana 47907-1393
alexwei@purdue.edu
Received May 11, 2002
ABSTRACT
4-Deoxypentenosides, which are readily derived from D-sugars, resemble glycals in structure and reactivity and can undergo stereoselective
epoxidation and SN2 nucleophilic addition to produce L-sugars in pyranosidic form.
L-Sugars, designated as such by the configuration of the
stereogenic carbon most remote from the aldehydo/keto
functionality,1 have been a subject of enduring scientific
interest. L-Sugars in their pyranosidic forms are important
constituents of antibiotics2 and clinically useful agents such
as heparin;3 they have also demonstrated potential as
noncaloric sweeteners4 and selectively toxic insecticides.5
Numerous synthetic approaches toward L-pyranosides have
been reported, including de novo syntheses,6 homologation
of shorter-chain sugars,7 and epimerization of readily avail-
able D-sugars.8 Most strategies involving the latter employ
an acyclic intermediate to establish the C5 stereocenter,
which often leads to a mixture of products upon cyclization.
Several groups have reported epimerization of the critical
stereocenter without opening the pyranose ring,9 but overall,
an efficient synthetic route to L-pyranosides has been lacking.
Here we introduce a direct and potentially general ap-
proach to L-pyranosides via 4-deoxypentenosides (4,5-
unsaturated pentopyranosides). These unsaturated sugars bear
a strong resemblance to glycals, a widely used intermediate
in the synthesis of oligosaccharides10 and a variety of natural
products.11 Indeed, the methodology reported herein suggests
that 4-deoxypentenosides and glycals have similar reactivity
profiles: both can be stereoselectively epoxidized by dimethyl-
dioxirane (DMDO) and can react with carbon nucleophiles
with inversion of configuration. We demonstrate this with a
stereoselective, two-step synthesis of L-altropyranoside de-
rivatives bearing a diverse range of functional groups at C5.
(1) McNaught, A. D. Pur. Appl. Chem. 1996, 68, 1919-2008.
(2) Collins, P. M. Dictionary of Carbohydrates; Chapman and Hall:
London, 1987.
(3) HeparinsChemical and Biological Properties; Clinical Applications;
Lane, D. A., Lindahl, U., Eds.; Edward Arnold: London, 1989.
(4) (a) Shallenberger, R. S.; Acree, T. E.; Lee, C. Y. Nature 1969, 221,
555-56. (b) Levin, G. V. U.S. Patent 4,262,032, 1981.
(5) (a) Levin, G. V.; Zehner, L. R. U.S. Patent 5,166,193, 1992. (b)
Anzeveno, P. B.; Green, F. R., III. In Synthesis and Chemistry of
Agrochemicals, VI; Baker, D. R., Fenyes, J. G., Lahm, G. P., Selby, T. P.,
Stevenson, T. M., Eds.; ACS Symposium Series 800; American Chemical
Society: Washington, DC, 2002; pp 262-76.
(6) Examples of de novo syntheses: (a) Ko, S. Y.; Lee, A. W. M.;
Masamune, S.; Reed, L. A.; Sharpless, K. B.; Walker, F. J. Science 1983,
220, 949-51. (b) Bednarski, M.; Danishefsky, S. J. Am. Chem. Soc. 1986,
108, 7060-67. (c) Takeuchi, M.; Taniguchi, T.; Ogasawara, K. Synthesis
1999, 341-46.
(7) Examples of homologation: (a) Sowden, J. C.; Fischer, H. O. J. Am.
Chem. Soc. 1945, 67, 1713-15. (b) Kuhn, R.; Klesse, P. Chem. Ber. 1958,
91, 1989-91. (c) Dondoni, A.; Marra, A.; Massi, A. J. Org. Chem. 1997,
62, 6261-67. (d) Takahashi, S.; Kuzuhara, H. J. Chem. Soc. Perk. Trans.
1 1997, 607-12. (e) Lubineau, A.; Gavard, O.; Alais, J.; Bonnaffe´, D.
Tetrahedron Lett. 2000, 41, 307-11.
(8) Examples of C5 epimerization: (a) Blanc-Muesser, M.; Defaye, J.
Synthesis 1977, 568-69. (b) Jacquinet, J.-C.; Petitou, M.; Duchaussoy, P.;
Lederman, I.; Choay, J.; Torri, G.; Sinay¨, P. Carbohydr. Res. 1984, 130,
221-41. (c) Ojeda, R.; de Paz, J. L.; Mart´ın-Lomas, M.; Lassaletta, J. M.
Synlett 1999, 8, 1316-18. (d) Takahashi, H.; Hitomi, Y.; Iwai, Y.; Ikegami,
S. J. Am. Chem. Soc. 2000, 122, 2995-3000.
(9) (a) Pegram, J. J.; Anderson, C. B. Carbohydr. Res. 1988, 184, 276-
78. (b) Rochepeau-Jobron, L.; Jacquinet, J.-C. Carbohydr. Res. 1997, 303,
395-406. (c) Bazin, H. G.; Wolff, M. W.; Linhardt, R. J. J. Org. Chem.
1999, 64, 144-52.
(10) (a) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989,
111, 6661-66. (b) Seeberger, P. H.; Bilodeau, M. T.; Danishefsky, S. J.
Aldrichimica Acta 1997, 30, 75-92.
(11) Selected examples: (a) Aicher, T. D.; Buszek, K. R.; Fang, F. G.;
Forsyth, C. J.; Jung, S. H.; Kishi, Y.; Scola, P. M. Tetrahedron Lett. 1992,
33, 1549-52. (b) Hayward, M. M.; Roth, R. M.; Duffy, K. J.; Dalko, P. I.;
Stevens, K. L.; Guo, J.; Kishi, Y. Angew. Chem., Int. Ed. 1998, 37, 192-
96. (c) Evans, D. A.; Trotter, B. W.; Coˆte´, B. Tetrahedron Lett. 1998, 39,
1709-12. (d) Rainier, J. D.; Allwein, S. P. J. Org. Chem. 1998, 63, 5310-
11.
10.1021/ol026175q CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/05/2002

Scheme 1a
Table 3. Nucleophilic Ring-Opening of â-Epoxide 2
a Reaction conditions: (a) (i) TEMPO (5 mol %), KBr (10 mol
%), n-Bu4NBr (5 mol %), NaOCl, NaHCO3, CH2Cl2/H2O, 0 °C;
(ii) N,N-dimethylformamide dineopentyl acetal (5 equiv), toluene,
120 °C (70% overall yield). (b) 0.1 M DMDO in acetone, CH2Cl2,
-55 °C (quantitative yield).
4-Deoxypentenoside 1 was prepared from the correspond-
ing methyl R-D-glucoside in 70% yield by a two-step
oxidation-decarboxylative elimination, modified from a
procedure reported by Zemlicka and co-workers (see Scheme
1).12 Several methods for epoxidation were investigated;
however, the sensitivity of the resulting 4,5-epoxypyranosides
to acidic hydrolysis precluded purification by silica chro-
matography, placing considerable limitations on the choice
of reagents and reaction media (see Table 1 for selected
Table 1. Selected Epoxidation Conditions for
4-Deoxypentenoside 1
conditiona
â:R selectivity
MMPP, NaHCO3, CH2Cl2, rt
NR
2:1
5:1
5:1
10:1
m-CPBA, NaHCO3, CH2Cl2/H2O, 0 °C
CF3C(OO)Me/trifluoroacetone, CH2Cl2, -78 °C
DMDO/acetone, CH2Cl2, -20 °C (4 h)
DMDO/acetone, CH2Cl2, -55 °C (48 h)
a MMPP ) magnesium monoperoxyphthalate; m-CPBA ) m-chlorop-
eroxybenzoic acid; DMDO ) 2,2-dimethyldioxirane.
conditions). Nevertheless, we observed that epoxidation of
1 with DMDO at -55 °C proceeded quantitatively with â:R
1
selectivities of approximately 10:1, as determined by H
NMR spectroscopy (300 MHz, C6D6) and the ensuing
product ratios (see below). Epoxidation stereoselectivity was
strongly affected by the transannular substituents, which can
influence both the pentenoside ring conformation and the
local steric environment; for example, epimerization at C1
or C2 resulted in high selectivity for the R face (see Table
2).13
Table 2. Substituent Effects on 4-Deoxypentenoside
Epoxidation
configuration
â:R selectivity
R-methyl gluco (1)
R-isopropyl gluco
â-isopropyl gluco
R-methyl manno
10:1a
8:1a
a Reaction conditions: (A) 3.5 equiv of Nu, 1.5 equiv of CuI, THF, -10
°C. (B) 3.5 equiv of Nu, 0.1 equiv of CuI, THF, -10 °C. (C) 10-20 equiv
of Nu in aq DMF, rt. (D) 9.0 equiv of Nu in THF, 0°C. (E) 5.0 equiv of Nu
in Et2O, rt. b Mixture of diastereomers ) 10:1 L-altro/D-gluco. c Isolated
yield.
1:5b
>1:20b
a DMDO (0.1 M) in acetone/CH2Cl2, -55 °C. b DMDO (0.1 M) in
acetone/CH2Cl2, 0 °C.
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Org. Lett., Vol. 4, No. 13, 2002

Epoxypyranoside 2 was evaluated for its reactivity under
SN2 conditions with a broad set of nucleophiles. â-Epoxide
ring-opening was observed to proceed in many cases with
complete regioselectivity and inversion of stereochemistry
at C5, producing the corresponding L-altro derivatives as the
major products (see Table 3).14,15 In particular, Cu(I)-assisted
Grignard additions proceeded with both high yields and
stereocontrol.16 Similar nucleophiles have been reported to
react with R-epoxyglycals and related intermediates with
inversion of configuration at C1.11b-d,17 Heteroatomic nu-
cleophiles were also observed to add in an SN2 fashion,
yielding novel 1,5-bisacetals. It should be noted that several
of the products in Table 3 can be readily converted to genuine
L-hexopyranosides; for example, a Tamao-Fleming oxida-
tion18 on dimethylphenylsilane 3e yields L-altropyranoside
4 in 75% yield (see Scheme 2).
Scheme 2
be used to install both natural and unnatural substituents at
C5; (ii) it is an efficient method for introducing isotopic
labels and can be used to prepare 6-[13C]-hexopyranosides;19
and (iii) it provides direct access to protected L-pyranosides
with fixed anomeric configurations and may be adapted
directly toward the construction of 1,4-linked saccharides
such as the glycosaminoglycans. We anticipate that 4-deoxy-
pentenosides will also be useful as synthetic intermediates
toward higher-order or exotic sugars and other complex
tetrahydropyrans.11
The 4-deoxypentenoside route toward L-sugars offers some
distinct advantages over other synthetic methods: (i) it can
(12) Philips, K. D.; Zemlicka, J.; Horwitz, J. P. Carbohydr. Res. 1973,
30, 281-86.
(13) Transannular stereoelectronic effects on reactions involving tet-
rahydropyran ring systems have been noted previously: Romero, J. A. C.;
Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2000, 122, 168-69 and
references therein.
Acknowledgment. The authors gratefully acknowledge
support from the American Cancer Society (IRG-58-006-
41), the American Chemical Society Petroleum Research
Fund (36069-AC1), and the American Heart Association
Midwest Affiliates (30399Z).
(14) The product of entry i is formally a 5S-[2H]-L-arabinoside. It should
be mentioned that additions to the minor R-epoxide isomer also proceeded
with inversion at C5 to yield the corresponding D-gluco derivatives.
(15) Stereochemistry was assigned on the basis of 1H NMR coupling
constants of both the major and minor stereoisomers, supplemented by
nuclear Overhauser effect experiments (see Supporting Information).
(16) Erdik, E. Tetrahedron 1984, 40, 641-57. We have observed that
Grignard additions without Cu(I) did not add exclusively by the SN2
pathway.
Supporting Information Available: Experimental pro-
cedures for the synthesis of compounds 1-4, plus selected
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(17) (a) Bellosta, V.; Czernecki, S. J. Chem. Soc., Chem. Commun. 1989,
199-200. (b) Bellosta, V.; Czernecki, S. Carbohydr. Res. 1993, 244, 275-
84. (c) Best, W. M.; Ferro, V.; Harle, J.; Stick, R. V.; Tilbrook, D. M. G.
Aust. J. Chem. 1997, 50, 463-72. (d) Chiappe, C.; Crotti, P.; Menichetti,
E.; Pineschi, M. Tetrahedron: Asymmetry 1998, 9, 4079-88.
(18) Fleming, I.; Sanderson, P. E. J. Tetrahedron Lett. 1987, 28, 4229-
32.
OL026175Q
(19) King-Morris, M. J.; Bondo, P. B.; Mrowca, R. A.; Serianni, A. S.
Carbohydr. Res. 1988, 175, 49-58.
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