Total Synthesis and Structural Confirmation of Malayamycin A: A Novel Bicyclic C-Nucleoside from Streptomyces malaysiensis

Article abstract of DOI:10.1021/ol030095k

(Equation presented) The stereocontrolled synthesis of malayamycin A, a novel naturally occurring bicyclic C-nucleoside of the perhydrofuropyran type, is described.

Full text of DOI:10.1021/ol030095k

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4277-4280
Total Synthesis and Structural
Confirmation of Malayamycin A:
A Novel Bicyclic C-Nucleoside from
Streptomyces malaysiensis
Stephen Hanessian,* Ste´phane Marcotte, Roger Machaalani, and Guobin Huang
Department of Chemistry, UniVersite´ de Montre´al, P.O. Box 6128, Station Centre-Ville,
Montre´al, Quebec H3C 3J7, Canada
stephen.hanessian@umontreal.ca
Received August 4, 2003
ABSTRACT
The stereocontrolled synthesis of malayamycin A, a novel naturally occurring bicyclic C-nucleoside of the perhydrofuropyran type, is described.
Nucleosides have a rich legacy in the realm of carbohydrate-
based natural products, particularly as potent antitumor,
antiviral, and antibiotic agents.1 Their structures transcend
the traditional N-glycosyl-linked purines and pyrimidines
which are the cornerstones of the chemistry and biology of
DNA and RNA. Nature has also provided C-nucleosides as
anomerically stable variants with impressive biological
properties.2 Among this class are a small group of bicyclic
C-nucleosides in which the glycosyl portion can be related
“rationally designed” ribosomal inhibitors also harbors a
bicyclic sugar mimic.
We now wish to report on the total synthesis, structural
identity, and stereochemical confirmation of malayamycin
A 1, a novel member of the antifungal family of bicyclic
C-nucleosides (Figure 1).
Malayamycin was isolated from the soil organism Strep-
tomyces malaysiensis by a group at the Syngenta Crop
Protection laboratories in Jealott’s Hill, U.K.9 Its structure
was determined by detailed NMR studies and by degradative
work. Natural malayamycin A was found to be unstable
4
to a perhydrofuropyran motif.3 Ezomycin B2 (Figure 1) is
a representative example of such natural products with
reported antifungal activity. This group also comprises
bicyclic N-nucleosides such as ezomycin A1 and A2,5 and
the octosyl acids.6,7 Quantamycin,8 one of the earliest
(5) (a) Sakata, K.; Sakurai, A.; Tamura, S. Agric. Biol. Chem. 1973, 37,
697. (b) Sakata, K.; Sakurai, A.; Tamura, S. Agric. Biol. Chem. 1975, 39,
885, 3141.
(1) For pertinent recent reviews, see: (a) Ichikawa, S.; Kato, K. Curr.
Med. Chem. 2001, 8, 3895. (b) Knapp, S. Chem. ReV. 1995, 95, 1859. (c)
Isono, K. Pharm. Ther. 1991, 52, 269. (d) Isono, K.; J. Antibiotics 1988,
41, 1711 and earlier references therein.
(2) For pertinent examples, see: Chaudhuri, N. C.; Reu, R. X.-F.; Kool,
E. T. Synlett 1997, 341.
(3) (a) Hanessian, S.; Liak, T. J.; Dixit, D. M. Carbohydr. Res. 1981,
88, C14-C19. (b) Hanessian, S.; Dixit, D. M.; Liak, T. J. Pure Appl. Chem.
1981, 53, 129.
(6) Isono, K.; Crain, P. F.; McCloskey, J. A. J. Am. Chem. Soc. 1975,
97, 943.
(7) For the total synthesis of octosyl acid A, see: (a) Danishefsky, S.;
Hungate, R. J. Am. Chem. Soc. 1986, 108, 2486. (b) Hanessian, S.; Kloss,
J.; Sugawara, T. J. Am. Chem. Soc. 1986, 108, 2758.
(8) Hanessian, S.; Sato, K.; Liak, T. J.; Danh, N.; Dixit, D. M.; Cheney,
B. V. J. Am. Chem. Soc. 1984, 106, 6114.
(9) Benner, J. P.; Boehlendorf, B. G. H.; Kipps, M. R.; Lambert, N. E.
P.; Luck, R.; Molleyres, L.-P.; Neff, S.; Schuez, T. C.; Stanley, P. D. WO
03/062242, CAN 139: 132519.
(4) Sakata, K.; Sakurai, A.; Tamura, S. Tetrahedron Lett. 1975, 3191.
10.1021/ol030095k CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/15/2003

The felicitous inclusion of the Grubbs olefin metathesis
reaction14 in our present-day repertoire of versatile methods
for carbocyclization compelled us to adopt it in our plan for
the synthesis of malayamycin A. Thus, the main challenge
became one of peripheral manipulation of a diol in â-
pseudouridine, installation of the vinyl and allyl ether
appendages, and testing the Grubbs metathesis reaction to
produce the strained trans-fused bicyclic motif. The judicious
choice of reagents and timing of reactions from the unsatur-
ated bicyclic motif would eventually lead to the intended
target.
D-Ribonolactone 2 was converted to the corresponding 2,3-
O-isopropylidene-5-(2-methoxy-2-methyl) ether 3 in excel-
lent yield (Scheme 1). Treatment with 2,4-dimethoxy-5-
lithiopyrimidine led to a mixture of anomeric hemiacetals,
which was reduced with L-Selectride in the presence of ZnCl2
to afford diol 5 with high stereoselectivity.11 Under the
conditions of the Mitsunobu reaction,15 diol 5 underwent a
site-selective oxycyclization to give the protected â-pseudo-
uridine derivative 6 in 91% yield. Cleavage of the acetals,
and selective etherification at C3′/C5′ as the disiloxane
derivative followed by treatment with p-methoxybenzyl
bromide led to 7 in excellent yield. Mild selective cleavage
of the disiloxane exposed the free primary alcohol, which
was oxidized to the aldehyde and further converted to the
olefin 9. Allylation under standard conditions afforded 10,
which was subjected to a Grubbs metathesis reaction14 to
give the bicyclic tetrahydrofuropyran derivative 11 in 89%
yield.16 Treatment of 11 with NBS in aq THF17 gave the
bromohydrin 12, which when treated with aqueous NaOH
gave the epoxide 13 in good overall yield. Regioselective
opening of the epoxide ring with NaN3 led to the trans azido
alcohol 14 as the major product (5:1) as ascertained by
detailed NMR studies.
Figure 1.
under strongly acidic (pH <1) or basic conditions (pH >12),
but could otherwise be easily handled at neutral pH.
The perhydrofuropyran motif in malayamycin A distin-
guishes itself from the structurally related ezomycins and
octosyl acids by the absence of a carboxyl group, and the
presence of a cis-vicinal amino alcohol in the “D-ribo-
perhydropyran” portion. Clearly, the main challenges in
planning the synthesis of malayamycin A consist of the
5-pyrimidinyl â-C-glycosidic bond, the trans-fused bicyclic
perhydrofuropyran motif, and securing the relative as well
as absolute configuration of stereogenic centers. Although
the commercially available â-pseudouridine could be utilized
as a starting material, its high cost10 compelled us to seek
an alternative synthesis that was amenable to scale-up.11
Previously, our construction of the trans-fused perhydrofu-
ropyran motif in quantamycin8 and octosyl acid A6,7 relied
on an intramolecular oxycyclization of a thionium inter-
mediate3b,12 and oxymercuration13 of an olefin, respectively.
Oxidation of the alcohol to give 15 and NMR analysis
confirmed the position of the azide group. Treatment of the
(12) A related method was used in the synthesis of the octosyl nucleoside
portion of ezomycin A1: Knapp, S.; Shih, W.-C.; Jaramillo, C.; Trilles, R.
V.; Nandan, J. R. J. Org. Chem. 1994, 59, 948.
(13) Hill, C. L.; Whitesides, G. M. J. Am. Chem. Soc. 1974, 96, 820.
(14) (a) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100. For pertinent reviews, see: (b) Grubbs, R.; Chang, S. Tetrahedron
1998, 54, 4413. (c) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1998,
371. Fu¨rstner, A.; Picquet, M.; Bruneau, C.; Dixneuf, H. H. Chem. Commun.
1998, 1315. Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997,
36, 2036.
(15) (a) Guianvarc’h, D.; Fourrey, J.-L.; Tran Huu Dau, M.-E.; Gue´rineau,
V.; Benhida, R. J. Org. Chem. 2002, 67, 3724. For reviews, see: (b)
Mitsunobu, O. Synthesis 1981, 1. (c) Hughes, D. C. Org. React. 1992, 42,
335.
(16) For the synthesis of related bicyclic fused compounds, see: (a) Ravn,
J.; Nielsen, P. J. Chem. Soc., Perkin Trans. 1 2001, 985. (b) Oh, J.; Lee, C.
R.; Chun, K. H. Tetrahedron Lett. 2001, 42, 4879. (c) Leeuwenburgh, M.
A.; Kulker, C.; Dugnster, H. I.; Overkleeft, H. S.; van der Marel, G. A.;
van Boom, J. Tetrahedron 1999, 55, 8253. (d) Leeuwenburgh, M. A.;
Overkleeft, H. S.; van der Marel, G. A.; van Boom, J. Synlett 1997, 1263.
(e) Nicolaou, K. C.; Postema, H. D.; Claiborne, C. I. J. Am. Chem. Soc.
1996, 118, 1565. (f) Clark, J. S.; Kettle, J. G. Tetrahedron Lett. 1997, 38,
127. (g) Oishi, T.; Nagumo, Y.; Hirama, M. Chem. Commun. 1998, 1041.
(h) Delgado, M.; Martin, J. D. Tetrahedron Lett. 1997, 38, 6299. (i) Peris,
E.; Cave´, A.; Estornell, E.; Zafra,-Polo, M. C.; Frigade`re, B.; Cortes, D.;
Bermejo´, A. Tetrahedron 2002, 58, 1335.
(10) (a) Grohar, P. J.; Chow, C. S. Tetrahedron Lett. 1999, 40, 2049.
(b) Brown, D. M.; Ogden, R. C. J. Chem. Soc., Perkin Trans. 1 1981, 723
and references therein. For the synthesis of unnatural C-linked nucleosides,
see: (c) Matulic-Adamic, J. M.; Beigelman, L.; Portmann, S.; Egli, M.;
Usman, N. J. Org. Chem. 1996, 61, 3909. (d) Matulic-Adamic, J. M.;
Beigelman, L. Tetrahedron Lett. 1997, 38, 1669. (e) Schweitzer, B. A.;
Kool, E. T. J. Org. Chem. 1994, 59, 7238. (f) Hildebrand, S.; Leumann, C.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1968. (g) Parsch, J.; Engels, J. W.
HelV. Chim. Acta 2000, 83, 1791.
(17) (a) Bannard, R. A. B.; Casselman, A. A.; Hawkins, L. R. Can. J.
Chem. 1965, 43, 2398. (b) Bannard, R. A. B.; Casselman, A. A.; Langstaff,
E. J.; Moir, R. Y. Can. J. Chem. 1968, 46, 35.
(11) Hanessian, S.; Machaalani, R. Tetrahedron Lett. In press.
4278
Org. Lett., Vol. 5, No. 23, 2003

Scheme 1a
a Reagents and conditions: (a) 2,2-dimethoxypropane, Na2SO4, PPTS, 94%; (b) 2,4-dimethoxy-5-iodopyrimidine, t-BuLi, 75%; (c)
L-Selectride, ZnCl2, DCM, 86%; (d) DIAD, Ph3P, THF, 91%; (e) 70% AcOH, 85%; (f) 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane, pyridine,
89%; (g) NaH, PMBBr, DMF/THF, 84%; (h) 1 N HCl, Dioxane, 88%; (i) DMSO, (COCl)2, i-Pr2NEt, DCM; (j) Ph3PCH3Br, NaHMDS,
THF (36%, 2 steps); (k) allyl bromide, NaH, DMF, 93%; (l) Cl2RuCHPh(PCy3)2, DCM, reflux (89%); (m) NBS, H2O, THF; (n) NaOH,
THF; (o) NaN3, methoxyethanol (5:1, 41%, 3 steps for 14); (p) Dess-Martin periodinane, DCM; (q) NaBH4, MeOH; (r) NaH, Mel, DMF
(93%, 3 steps); (s) DDQ, H2O, DCM (84%); (t) PivCl, DMAP, NEt3, pyridine; (u) TMSCl, Nal, acetonitrile (42%, 2 steps); (v) PMe3, H2O,
THF; (w) trichloroacetylisocyanate, DCM; (x) MeNH2, MeOH, H2O (60%, 3 steps).
ketone with NaBH4 and O-methylation gave 16 in excellent
overall yield. Unfortunately, the PMB group was not
compatible with the conditions of removal of the methoxy
groups in the pyrimidine (NaI/TMSCl).18 Thus, treatment of
16 with DDQ19 followed by pivaloylation afforded the
protected alcohol 17. The methoxy groups were smoothly
cleaved with NaI/TMSCl to the corresponding pyrimidinedi-
one derivative 18. Reduction of the azide group under
Staudinger conditions,20 followed by treatment of the result-
ing amine with trichloroacetyl isocyanate12,21 gave the
corresponding trichloroacetyl urea derivative. Finally, treat-
ment with aqueous methylamine, followed by silica gel
chromatography gave pure malayamycin A (1), which was
found to be identical with the natural product in all respects
(1H, 13C NMR, [R]D, HPLC, and plant fungicidal activity).
The regioselective formation of 14 is worthy of comment.
When the tetrahydrofuropyran intermediate 11 was treated
with m-CPBA and the resulting epoxide 19 opened with
NaN3, the main product was the wrong regioisomeric azido
(18) (a) Kundu, N. G.; Das, B.; Spears, C. P.; Majundar, A.; Kang, S. J.
Med. Chem. 1990, 33, 1975. (b) Silverman, R. B.; Radat, R. E.; Hacker, N.
P. J. Org. Chem. 1979, 44, 4920.
(19) Horitai, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron Lett. 1986, 42, 3021.
(20) (a) Vaultier, M.; Knouz, N.; Carrie, R. Tetrahedron Lett. 1983, 24,
263. (b) Staudinger, H.; Meyer, J. HelV. Chim. Acta 1919, 2, 635.
(21) Hecker, S.; Minich, M. L.; Lackey, K. J. Org. Chem. 1990, 55,
4904.
Org. Lett., Vol. 5, No. 23, 2003
4279

R-epibromonium ion 21 gives the trans-diaxial bromohydrin,
which upon treatment with base leads to the â-epoxide 13.
A second trans-diaxial opening with azide ion affords the
desired azido alcohol 14 as the major product.
Scheme 2
The total synthesis of malayamycin A by a highly
stereocontrolled route confirms the structure and absolute
configuration proposed by NMR studies.9 Further studies on
the design and synthesis of analogues, congeners, and
especially the N-nucleoside analogue of malayamycin A will
be reported in due course.
Acknowledgment. We thank Syngenta Crop Protection
for generous financial assistance through the NSERC Me-
dicinal Chemistry Chair Program, and Dr. Patrick Crowley,
Syngenta, Jealott’s Hill, U.K. for stimulating discussions.
We also thank Julien Pierron (UHP-Nancy I) for technical
assistance.
Supporting Information Available: Selected experi-
mental procedures, H and 13C NMR spectra, compound
characterizations. This material is available free of charge
via the Internet at http://pubs.acs.org.
1
alcohol 20 (Scheme 2). This stereochemical result could arise
from epoxidation of 11 from the least-hindered endo-face
of the bicyclic motif, followed by a trans-diaxial ring opening
with azide ion. On the other hand, solvolytic opening of the
OL030095K
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Org. Lett., Vol. 5, No. 23, 2003