Synthesis of the ezomycin nucleoside disaccharide.

Article abstract of DOI:10.1021/ol005696f

[equation--see text] A protected ezomycin octosyl nucleoside was glycosylated at O-6' with a protected ezoaminuroic acid donor to afford, following several functional group modifications, the title compound 1 ( identical with 4-desamino-4-oxoezomycin A(2)).

Full text of DOI:10.1021/ol005696f

ORGANIC
LETTERS
2000
Vol. 2, No. 10
1391-1393
Synthesis of the Ezomycin Nucleoside
Disaccharide
Spencer Knapp* and Vijay K. Gore
Department of Chemistry, RutgerssThe State UniVersity of New Jersey,
610 Taylor Road, Piscataway, New Jersey 08854-8087
knapp@rutchem.rutgers.edu
Received February 19, 2000
ABSTRACT
A protected ezomycin octosyl nucleoside was glycosylated at O-6′ with a protected ezoaminuroic acid donor to afford, following several
functional group modifications, the title compound 1 (≡ 4-desamino-4-oxoezomycin A2).
The ezomycins are a class of fermentation-derived complex
nucleoside antibiotics1 whose structures were elucidated in
the 1970s.2,3 They feature an unusual combination of parts:
an octosyl nucleoside, a [1′′f6′]-â-glycosylating 3-amino-
3,4-dideoxy-D-glucuronic acid (“ezoaminuroic acid”), and an
N-linked pseudopeptide (L-cystathionine).
Three ezomycins containing the L-cystathionine compo-
nent, A1, B1, and C1 (the anomer of B1 at C-1′), are active
against certain species of phytopathogenic fungi such as
Sclerotinia and Botritus, whereas those lacking this pseudo-
peptide (e. g., A2 and B2) are inactive. Some members (B,
C, and D series) bear a C-5 glycosylated pseudo-uracil rather
than the more usual N-1 linked pyrimidine nucleoside bases.
A number of synthetic routes to the ezoaminuroic acid
portion have appeared,4,5 and several groups have synthesized
octosyl nucleosides that resemble the ezomycin component.6,7
A method for glycosylating a model octose at C-6′ was
reported from our lab in 1994.5 In this paper we describe
the first synthesis of the ezomycin nucleoside disaccharide
1 (≡ 4-desamino-4-oxoezomycin A2).
Although we had previously developed a satisfactory route
to the ezoaminuroic acid donor 6,5 the requirement of excess
donor for the nucleoside glycosylation, and the difficulties
associated with large-scale preparation of the Cerny epoxide
precursor, prompted us to develop the shorter alternative
route shown in Scheme 1. Selective hydrolysis8 of 3-azido-
3-deoxy-1,2:5,6-di-O-isopropylidene-R-D-glucofuranose 2,9
(6) Kim, K. S.; Szarek, W. A. Can. J. Chem. 1981, 59, 878-887. Bovin,
N. V.; Zurabyan, S. E.; Khorlin, A. Y. Carbohydr. Res. 1981, 98, 25-35.
Hanessian, S.; Dixit, D.; Liak, T. Pure Appl. Chem. 1981, 53, 129-148.
Kim, K. S.; Szarek, W. A. Carbohydr. Res. 1982, 100, 169-176.
Danishefsky, S.; Hungate, R. J. Am. Chem. Soc. 1986, 108, 2486-2489.
Hanessian, S.; Kloss, J.; Sugawara, T. J. Am. Chem. Soc. 1986, 108, 2758-
2759. Sakanaka, O.; Ohmuri, T.; Kozaki, S.; Suami, S. Bull. Chem. Soc.
Jpn. 1987, 60, 1057-1062. Danishefsky, S. J.; Hungate, R.; Schulte, G. J.
Am. Chem. Soc. 1988, 110, 7434-7440. Maier, S.; Preuss, R.; Schmidt, R.
R. Liebigs Ann. Chem. 1990, 483-489. Haraguchi, K.; Hosoe, M.; Tanaka,
H.; Tsuruoka, S.; Kanmuri, K.; Miyasaka, T. Tetrahedron Lett. 1998, 39,
5517-5520. See also refs 1 and 5 and references therein.
(7) Knapp, S. Shieh, W.-C.; Jaramillo, C.; Trilles, R. V.; Nandan, S. R.
J. Org. Chem. 1994, 59, 946-948.
(8) Redlich, H.; Roy, W. Liebigs Ann. Chem. 1981, 1223-1233.
(9) Meyer zu Reckendorf, W. Chem. Ber. 1968, 101, 3802-3807.
Stevens, J. D. Methods Carbohydr. Chem. 1972, 6, 123.
(1) Recent reviews: Knapp, S. Chem. ReV. 1995, 95, 1859-1876. Isono,
K. Pharmacol. Ther. 1991, 52, 269-286.
(2) Isolation and biological activity: Sakata, K.; Sakurai, A.; Tamura,
S. Agric. Biol. Chem. 1974, 38, 1883-1890. Sakata, K.; Sakurai, A.;
Tamura, S. Agric. Biol. Chem. 1977, 41, 2027-2032 and references therein.
(3) Structures: Sakata, K.; Sakurai, A.; Tamura, S. Agric. Biol. Chem.
1975, 39, 885-892. Sakata, K.; Sakurai, A.; Tamura, S. Agric. Biol. Chem.
1977, 41, 2033-2039 and references therein.
(4) Mieczkowski, J.; Zamojski, A. Bull. Acad. Pol. Sci. 1975, 23, 581-
583. Ogawa, T.; Akatsu, M.; Matsui, M. Carbohydr. Res. 1975, 44, C22-
24. Knapp, S.; Levorse, A. T.; Potenza, J. A. J. Org. Chem. 1988, 53, 4773-
4779.
(5) Knapp, S.; Jaramillo, C.; Freeman, B. J. Org. Chem. 1994, 59, 4800-
4804.
10.1021/ol005696f CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/18/2000

solvent benzene,13 and then exchange of pivaloate for
phenylthio at C-1 furnished the donor 6, identical to that
prepared previously.5
The octosyl nucleoside acceptor 10 was constructed from
thioglycoside donor 77 by N-1 glycosylation of O,O′-bis-
(trimethylsilyl)uracil under conditions previously developed
for this purpose (Scheme 2).7,13,14 The resulting nucleoside
8 was accompanied by varying amounts of the 5-iodinated
product 9.14 A more efficient overall glycosylation was
obtained by driving the reaction further toward 9 with
additional N-iodosuccinimide, and 9 proved to be superior
in subsequent transformations anyway. The uracil was
efficiently N-3-protected by using benzyloxymethyl chloride
and BEMP,15 and then the benzylidene was cleaved with
HCl under reducing conditions16 to give the required acceptor
10 possessing a free C-6′ hydroxyl.
Glycosylation of 10 with no less than 3.6 equiv of donor
6 gave the nucleoside disaccharide 11 in excellent yield
considering the complexity and multisite Lewis basicity17
of the acceptor. A series of highly selective functional group
transformations was then carried out to convert 11 to the
target ezomycin nucleoside disaccharide 1. Clean hydro-
genolysis of the C-5 iodide was followed by selective
hydrogenolysis of the azido to amino18 and then protection
of the amino as its N-benzoylcarbamoyl derivative 12.
Hydrogenolysis of the three benzyl protecting groups exposed
primary hydroxyls at C-8′ and C-6′′. These were oxidized
under Widlanski conditions19 to afford dicarboxylic acid 13
(for complete conversion, a followup treatment with sodium
chlorite was required). Ammonolysis in methanol solution
removed the four acyl protecting groups (indicated by dashed
arrows) and provided 1 directly. The nucleoside disaccharide
was purified by HPLC and characterized by HRMS and
and then selective benzylation at O-6 by way of the 5,6-O-
stannyleneacetal,10 afforded the mono-benzyl ether 3. Hy-
drolysis of the second isopropylidene ketal and reformulation
of the resulting triol as the pyranose 1,2-ketal 4 was followed
by reduction of the azide and protection of the amino as its
trifluoroacetyl derivative. Radical deoxygenation11 at C-4 led
to the pyranose 5. Attempted deoxygenation prior to the
reduction of the azido function was unsuccessful owing to
the reactivity of azido under the reducing conditions.12
Hydrolysis of 5 to the diol, O-pivaloylation in the nonpolar
1
COSY-assisted H NMR analysis, which confirmed the
full deprotection and the close similarity of 1 to ezomycin
A2.
Scheme 1
1392
Org. Lett., Vol. 2, No. 10, 2000

Scheme 2
We envision modifying this synthetic route to include
Acknowledgment. We thank Hoffmann-La Roche for
financial support, Silvano DeBernardo and Theodore Lam-
bros for helpful suggestions for the synthesis of 6 and the
purification of 1, respectively, and Gino Sasso, Vance Bell,
Richard Szypula, and Theresa Burchfield of the Physical
Chemistry Department at Hoffmann-La Roche for obtaining
NMR and mass spectra.
conversion of the pyrimidine base from uracil to cytosine
and site-selective attachment of the cystathionine to afford
ezomycin A1.
(10) Veyrieres, A.; Thieffry, A.; David, S. J. Chem. Soc., Perkin Trans.
1 1981, 1796-1801.
(11) Barton, D. H. R.; Ferreira, J. A.; Jaszberenyi, J. C. Prep. Carbohydr.
Chem. 1997, 151-172.
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterization for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) For example, see: Benati, L.; Nanni, D.; Sangiorgi, C.; Spagnolo,
P. J. Org. Chem. 1999, 64, 7836-7841.
(13) Knapp, S.; Nandan, S. R. J. Org. Chem. 1994, 59, 281-283.
(14) Knapp, S.; Shieh, W.-C. Tetrahedron Lett. 1991, 32, 3627-
3630.
(15) Schwesinger, R.; Schlemper, H. Angew. Chem., Int. Ed. Engl. 1987,
26, 1167-1169.
OL005696F
(16) Garegg, P. J.; Hultberg, J.; Wallin, S. Carbohydr. Res. 1982, 108,
97-101.
(18) Corey, E. J.; Nicolaou, K. C.; Balanson, R. D.; Machida, Y. Synthesis
1975, 590-591.
(19) Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64, 293-295.
(17) Knapp, S.; Gore, V. K. J. Org. Chem. 1996, 61, 6744-6747 and
references therein.
Org. Lett., Vol. 2, No. 10, 2000
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