biosynthesis of tenellin 3, bassianin 4, and ilicicolin H 5 has
been studied in some detail,6-8 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 pyrido-
macrolidin 2 has not yet been elucidated. However, it is
possible to propose a biomimetic formation of pyrido-
macrolidin 2 from pyridovericin 1 (which was coisolated with
2 from the same fungus) via a number of steps (Scheme 1),
Scheme 2. Retrosynthetic Analysis of Pyridovericin 1
Scheme 1. Proposed Biosynthesis of Pyridomacrolidin 2
would be synthesized via selective palladium-catalyzed
monocoupling between boronic acid 13 and dibromide 14.
The convergent synthesis began with commercially avail-
able 2,4-dihydroxypyridine 15, which was selectively di-
brominated at the C3 and C5 positions16 and then bis-O-
methylated17 to give pyridine 16 in good yield (Scheme 3).
Scheme 3a
namely, (i) oxidation of pyridovericin 1 to hydroxamic acid
6, (ii) further oxidation to the novel acyl nitrone intermediate
7, (iii) 1,3-dipolar cycloaddition9 with cephalosporolide B
8, and (iv) re-aromatization to form pyridomacrolidin 2.
Cephalosporolide B 8 is itself a natural product, isolated
independently from the fungus Cephalosporium aphidicola,10
although it has not yet been isolated from B. bassiana.
Chemically, this class of compounds has elicited a
significant amount of interest as demonstrated by the
significant synthetic work already published.11-15
Herein, we describe our progress toward the biomimetic
synthesis of pyridomacrolidin 2 by reporting a convergent
and efficient synthesis of pyridovericin 1 from cheap and
readily available starting materials.
a (a) Br2, 47% HBr; (b) MeI, Ag2CO3, DCM; (c) BnBr, TBAI,
NaH, THF; (d) (i) nBuLi, B(OiPr)3, THF; (ii) sat. NH4Cl; (e)
Pd(PPh3)4, Na2CO3, 4:1 toluene:ethanol.
We envisaged that the core structure of pyridovericin 1
could be constructed via addition of lithiated pyridine 10 to
aldehyde 11, giving precursor 9 after oxidation (Scheme 2).
The organolithium 10 would be generated via metal-halogen
exchange from the corresponding bromide 12, which in turn
Synthesis of the required boronic acid coupling partner
began with 4-bromophenol 17, which was readily protected
under standard conditions18 to generate the corresponding
benzyl ether in good yield. Metal-halogen exchange fol-
lowed by treatment with boron triisopropoxide19 proceeded
cleanly to afford, after hydrolysis, the desired boronic acid
18.
Next, it was found that reaction of 16 and 18 under Suzuki-
type conditions20 afforded a separable mixture of mono- and
bis-coupled adducts 19-21, in which the major product was
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(9) Padwa, A. 1,3-Diploar Cycloaddition Chemistry; Wiley-Inter-
science: New York, 1984.
(10) Ackland, M. J.; Hanson, J. R.; Hitchcock, P. R.; Ratcliff, A. H. J.
Chem. Soc., Perkin Trans. 1 1985, 843.
(11) Williams, D. R.; Lowder, P. D.; Gu, Y. G. Tetrahedron Lett. 1997,
38, 327.
(16) Den Hertog, H. J. Recl. TraV. Chim. Pays-Bas. 1945, 64, 85.
(17) Loppinet-Serani, A.; Charbonnier, F.; Rolando, C.; Huc, I. J. Chem.
Soc., Perkin Trans. 2 1998, 937.
(12) Buck, J.; Madeley, J. P.; Adeley, J. P.; Pattenden, G. J. Chem. Soc.,
Perkin Trans. 1 1992, 67.
(18) Kanai, K.; Sakamoto, I.; Ogawa, S.; Suami, T. Bull. Chem. Soc.
Jpn. 1987, 60, 1529.
(19) Piettre, S. R.; Andre, C.; Chanal, M. C.; Ducep, J. B.; Lesur, B.;
Piriou, F.; Raboisson, P.; Rondeau, J. M.; Schelcher, C.; Zimmermann, P.;
Ganzhorn, A. J. J. Med. Chem. 1997, 40, 4208.
(20) Badone, D.; Baroni, M.; Cardamone, R.; Ielmini, A.; Guzzi, U. J.
Org. Chem. 1997, 62, 7170.
(13) Rigby, J. H.; Qabar, M. J. Org. Chem. 1989, 54, 5853.
(14) Williams, D. R.; Sit, S. Y. J. Org. Chem. 1982, 47, 2846.
(15) Zhang, Q. S.; Curran, D. P. Abstracts of Papers, 222nd National
Meeting of the American Chemical Society, Chicago, IL; American
Chemical Society: Washington, DC, Aug. 26-30, 2001; ORGN-519.
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Org. Lett., Vol. 4, No. 13, 2002