An unusual oxidative cyclization: Studies towards the biomimetic synthesis of pyridomacrolidin

Article abstract of DOI:10.1021/ol034736n

(Matrix presented) An unusual oxidative cyclization of a N-hydroxy pyridone 9 with Z-2-cyclodecenone 11 has been achieved, thus demonstrating a possible biomimetic route to pyridomacrolidin 2.

Full text of DOI:10.1021/ol034736n

ORGANIC
LETTERS
2003
Vol. 5, No. 13
2351-2354
An Unusual Oxidative Cyclization:
Studies towards the Biomimetic
Synthesis of Pyridomacrolidin
,†
Nageswara Rao Irlapati,† Jack E. Baldwin,* Robert M. Adlington,† and
Gareth J. Pritchard‡
Dyson Perrins Laboratory, Department of Chemistry, Oxford UniVersity,
South Parks Road, Oxford OX1 3QY, United Kingdom, and Department of Chemistry,
Loughborough UniVersity, Loughborough, Leicester LE11 3TU, United Kingdom
Andrew Cowley
Chemical Crystallography, Oxford UniVersity, South Parks Road,
Oxford OX1 3QR, United Kingdom
jack.baldwin@chem.ox.ac.uk
Received May 2, 2003
ABSTRACT
An unusual oxidative cyclization of a N-hydroxy pyridone 9 with Z-2-cyclodecenone 11 has been achieved, thus demonstrating a possible
biomimetic route to pyridomacrolidin 2.
Pyridovericin 1 and pyridomacrolidin 2 are novel metabolites
isolated in 1998 by Nakagawa and co-workers from the
entomopathogenic fungus BeauVeria bassiana (Figure 1).1
Both pyridovericin 1 and pyridomacrolidin 2 contain a
common p-hydroxyphenyl pyridone unit that is also present
in the related fungal metabolites tenellin 3,2 bassianin 4,3
and ilicicolin 5.4 Chemically, this class of compounds has
elicited a significant amount of interest as demonstrated by
synthetic work already published.5,6
The biological activity of both pyridovericin 1 and
pyridomacrolidin 2 has been shown to include the inhibition
† Oxford University.
‡ Loughborough University.
(1) (a) Takahashi, S.; Kakinuma, N.; Uchida, K.; Hashimoto, R.;
Yanagishima, T.; Nakagawa, A. J. Antibiot. 1998, 51, 596. (b) Takahashi,
S.; Kakinuma, N.; Uchida, K.; Hashimoto, R.; Yanagishima, T.; Nakagawa,
A. J. Antibiot. 1998, 51, 1051.
(2) ElBayouni, S. H.; Brewer, D.; Vining, L. C. Can. J. Bot. 1968, 46,
441.
(3) Wat, C.-K.; McInnes, A. G.; Smith, D. G.; Wright, J. C. L.; Vining,
L. C. Can. J. Chem. 1977, 55, 4090.
Figure 1. Pyridovericin 1, pyridomacrolidin 2, and related
metabolites.
(4) Matsumoto, M.; Minato, H. Tetrahedron Lett. 1976, 17, 3827.
10.1021/ol034736n CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/06/2003

such reactions have not been demonstrated from a nitrone
(such as 7) derived from the oxidation of a 5-(4-hydroxy-
phenyl)-N-hydroxy-2-pyridone (such as 6). Since, as ex-
pected, our attempts to oxidatively generate and trap
unsubstituted quinonoid species similar to 7 were unsuc-
cessful, probably due to competing additions to this highly
electron deficient system as well as solubility problems, we
chose to block the phenolic ortho-positions by sterically
hindering groups. Thus we prepared 9 and studied its
oxidative cycloaddition with Z-2-cyclodecenone 1114 (Scheme
2).
Scheme 1. Proposed Biosynthesis of Pyridomacrolidin 2
Scheme 2
of protein tyrosine kinase (PTK) activity at concentrations
of 100 µg/mL.1 PTK inhibitors are of potential use as
therapeutic agents against a variety of proliferative and
inflammatory diseases.7 In common with several compounds
found to inhibit PTK’s, pyridovericin 1 and pyridomacrolidin
2 contain a p-hydroxy phenyl moiety, which presumably
mimics tyrosine.
The combination of structural novelty and complexity
coupled with promising biological activity prompted us to
design a biomimetic synthesis of pyridomacrolidin 2. The
biosynthesis of tenellin 3, bassianin 4, and ilicicolin 5 has
been studied in some detail,8-10 and it was shown that they
are derived from a polyketide chain and an aromatic amino
acid. While the biosynthesis of pyridovericin 1 presumably
follows a similar pathway, the biosynthesis of pyridomacro-
lidin 2 has not yet been elucidated. However, it is possible
to propose a biomimetic formation of pyridomacrolidin 2
from pyridovericin 1 (which was co-isolated with pyrido-
macrolidin from the same fungus) via a number of steps,
namely (i) oxidation of pyridovericin 1 to hydroxamic acid
6, (ii) further oxidation to the novel acyl nitrone intermediate
7, (iii) 1,3-dipolar cycloaddition11 with cephalosporolide B
8, and (iv) re-aromatization to form pyridomacrolidin 2
(Scheme 1). Cephalosporlide B is itself a natural product,
isolated independently from the fungus Cephalosporium
aphidicola,12 although it has not yet been isolated from B.
bassiana.
A retrosynthetic analysis reduced the target compound 9
to a Suzuki cross-coupling between boronic acid 13 and
bromide 14 followed by deprotection (Scheme 3). The
Scheme 3. Retrosynthetic Scheme
Although the 1,3-dipolar cycloadditions of nitrones with
enones is well documented,13 to the best of our knowledge,
bromide 14 itself should be available following modification
of methodology developed by Williams et al.5d
Thus, a requisite hydroxamic acid derivative 19 was
initially prepared in excellent overall yield as illustrated in
Scheme 4. First, the enamine 1615 was prepared by passing
dimethylamine gas into an ice-cooled solution of methyl
propiolate 15 in diethyl ether, which on subsequent reflux
(5) (a) Williams, D. R.; Lowder, P. D.; Gu, Y. G. Tetrahedron Lett.
1977, 38, 327. (b) Buck, J.; Madeley, J. P.; Adeley, J. P.; Pattenden, G. J.
Chem. Soc., Perkin Trans. 1 1992, 67. (c) Rigby, J. H.; Qabar, M. J. Org.
Chem. 1989, 54, 5853. (d) Williams, D. R.; Sit, S. Y. J. Org. Chem. 1982,
47, 2846. (e) Zhang, Q. S.; Curran, D. P. Abstracts of Papers, 222nd
National Meeting of the American Chemical Society, Chicago, IL, Aug.
26-30, 2001; American Chemical Society: Washington, DC, 2001; ORGN-
519.
(6) Baldwin, J. E.; Adlington, R. M.; Aurelia, C.; Nageswara Rao, I.;
Marquez, R.; Pritchard, G. J. Org. Lett. 2002, 4, 2125.
(7) Levitzki, A.; Gazit, A. Science 1995, 267, 1782
(8) McInnes, A. G.; Smith, D. G.; Wat, C.-K.; Vining, L. C.; Wright, J.
L. C. J. Chem. Commun. 1974, 281.
(9) Tanable, M.; Urano, S. Tetrahedron 1983, 39, 3569.
(10) Leete, E.; Kowanko, N.; Newmark, R. A.; Vining, L. C.; McInnes,
A. G.; Wright, J. L. C. Tetrahedron Lett. 1975, 16, 4103.
(11) Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; Wiley-Inter-
science: New York, 1984.
(13) See for example: (a) Iwasa, S.; Tsushima, S.; Shimada, T.;
Nishiyama, H. Tetrahedron Lett. 2001, 42, 6715. (b) Fourets, O.; Cauliez,
P.; Simonet, J. Tetrahedron Lett. 1998, 39, 565. (c) Gothelf, K. V.;
Jorgensen, K. A. J. Org. Chem. 1994, 59, 5687. (d) Joucla, M.; Tonnard,
F.; Gree, D.; Hamelin, J. J. Chem. Res. (S) 1978, 240. (e) Joucla, M.;
Hamelin, J.; Carrie, R. Bull. Chem. Soc. Fr. 1973, 11, 3116. (f) Padwa, A.
1,3-Dipolar Cycloaddition Chemistry; Wiley-Interscience: New York, 1984,
Chapters 1, 9, and 12.
(14) Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y.-L. J. Am.
Chem. Soc. 2002, 124, 2245.
(12) Ackland, M. J.; Hanson, J. R.; Hitchcock, P. R.; Ratcliff, A. H. J.
Chem. Soc., Perkin Trans. 1 1985, 843.
(15) Kurtz, A. N.; Billups, W. E.; Greenlee, R. B.; Hamil, H. F.; Pace,
W. T. J. Org. Chem. 1965, 30, 3141.
2352
Org. Lett., Vol. 5, No. 13, 2003

Scheme 4a
Scheme 5a
a Reagents and conditions: (a) (CH3)2NH, Et2O, rt, 1 h; (b)
H2NOBn, xylene, reflux, 24 h; (c) NaCNBH3,EtOH‚HCl, rt, 12 h;
(d) diketene, DMAP, Et3N, THF 0 °C, 30 min.
in xylene with O-benzylhydroxylamine containing a catalytic
amount of camphor sulfonic acid gave 1716 in excellent yield.
Oxime 17 was then reduced with sodium cyanoborohydride
in ethanolic aqueous HCl. Acylation of the resulting amine
18 with diketene, conducted in anhydrous THF containing
triethylamine and a catalytic amount of 4-(dimethylamino)-
pyridine, afforded the amide 19 (Scheme 4).
Ester hydrolysis of the amide 19 in a 1:1 mixture of THF
and water was achieved with lithium hydroxide in quantita-
tive yield. The resultant crude carboxylic acid, 20, was treated
with 1,1′-carbonyldiimidazole in THF, which after intramo-
lecular cyclization following addition of sodium hydride
yielded the 5,6-dihydro pyridone 21 in very good yield.
Unlike the Williams chemistry precedent5d attempted oxida-
tion of pyridone 21 with several oxidants (MnO2, DDQ,
p-chloranil, Pd/C, H2SO4, PhSeCl/LDA then H2O2) met with
failure. After considerable experimentation oxidation was
achieved with lead tetraacetate17 in 25% yield to provide
pyridone 22, which on bromination18 afforded the crucial
Suzuki coupling partner 14 in good yield.
The phenyl boronic acid 13 required for the Suzuki
coupling was prepared by the transmetalation of the com-
mercially available 4-bromo-2,6-di-tert-butyl phenol 23 with
tert-butyllithium and quenching of the organo lithium species
with triisopropyl borate, followed by acid hydrolysis. Cou-
pling of the bromide 14 and boronic acid 13 was carried out
under standard Suzuki conditions19 to yield the N-protected
pyridone 24. Deprotection of the benzyl group with 10%
palladium on carbon/hydrogen furnished the N-hydroxy
pyridone 9 in excellent yield (Scheme 5).
a Reagents and conditions: (a) LiOH, THF + H2O, rt, 2 h; (b)
CDI, THF, NaH, rt, 12 h; (c) Pb(OAc)4, benzene, 70 °C, 24 h; (d)
Br2, DCM, reflux, 12 h; (e) t-BuLi, B(OCH(CH3)2)3, THF, rt, 12
h; (f) Pd(Ph3)4, Na2CO3, 4:1 toluene:ethanol, reflux, 12 h; (g) 10%
Pd/C, dioxane, H2, rt, 1 h.
Next, oxidation of the hydroxamic acid 9 in the presence
of Z-2-cyclodecenone 11 with iodobenzene diacetate in
dichloromethane at reflux temperature was attempted. En-
couragingly, the unstable nitrone formed by the oxidation
of hydroxamic acid 9 underwent [3+2] cycloaddition with
enone 11 smoothly to give the cyclized products phenol 12
and quinone methide 27 in 60% combined yield (Scheme
7).
The structures of the cyclized products 12 and 27 were
established by extensive NMR studies and confirmed by
single-crystal crystallography. It is clear from the crystal
structures (Figure 2) that the nitrogen in quinone methide
27 is pyramidal whereas in phenol 12 it is planar.
Various attempts to equilibrate the two cyclized products
in the presence of trifluoroacetic acid or Hunig’s base in
Scheme 6a
When oxidation of the benzyl-protected pyridone 24 was
carried out with iodobenzene diacetate in methanol there was
obtained the cyclohexadienone 25 in moderate yield.20
Likewise oxidation of hydroxamic acid 9 in methanol gave
a similar cyclohexadienone 26 in moderate yield (Scheme
6).
(16) Macchia, M.; Menchini, E.; Nencetti, S.; Orlandini, E.; Rossello,
A.; Belfore, M. S. II Farmaco 1996, 51, 255.
(17) Daniel, L.; Jean-Charles, L.; Max, R. Tetrahedron Lett. 1985, 26,
1295.
(18) Japanese Patent 5-78324, 1993.
(19) Badone, D.; Baroni, M.; Cardamone, R.; Ielmini, A.; Guzzi, U. J.
Org. Chem. 1997, 62, 7170.
(20) Pelter, A.; Elgendy, S. Tetrahedron Lett. 1988, 29, 677.
a Reagents and conditions: (a) PhI(OAc)2, MeOH, 40 °C, 20 h.
Org. Lett., Vol. 5, No. 13, 2003
2353

Scheme 7a
Scheme 8
a Reagents and conditions: (a) PhI(OAc)2, 2-cyclodecenone 11,
DCM, reflux, 24 h, 60%.
tert-butyl alcohol were unsuccessful; quinone methide 27 was
found to be stable under these conditions.
The formation of these compounds can be rationalized by
the addition of nitrone 10 to the alkene 11 via [3+2]
cycloaddition to obtain a mixture of endo (28) and exo (27)
quinone methide adducts. Under the reaction conditions the
endo product 28 selectively underwent further aromatization
to provide phenol 12. It is noticeable that the X-ray structures
of 12 and exo 27 indicate that these molecules exist in
different tautomeric structures in the pyridone-like core
(Scheme 8). Whether endo 28 was formed with the same
tautomeric structure as phenol 12, thus permitting fascile
aromatization, or that these differences result from crystal
packing is unknown at this time.
In conclusion an unusual oxidative cyclization of N-
hydroxy pyridone 9 with Z-2-cyclodecenone 11 has been
achieved, thus demonstrating a possible biomimetic route
to pyridomacrolidin 2. The beneficial effect of the tert-butyl
groups in this process is notable. It may well be that in an
enzyme-mediated oxidation that the enzyme structure pro-
vides a similar protective effect on the proposed key
intermediate 7.
Acknowledgment. N.R.I. is indebted to Dr. Reddy’s
Research Foundation (DRF), Hyderabad, India for their
support and financial assistance.
Supporting Information Available: Experimental pro-
cedure and spectral data for compounds 12 and 27. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 2. Crystal structures of phenol 12 and quinone 27.
OL034736N
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Org. Lett., Vol. 5, No. 13, 2003