New synthetic route to 2-pyridones and its application toward the synthesis of (±)-ipalbidine

Full text of DOI:10.1021/jo961690l

438
J . Org. Chem. 1997, 62, 438-439
Communications
New Syn th etic Rou te to 2-P yr id on es a n d
Its Ap p lica tion tow a r d th e Syn th esis of
(()-Ip a lbid in e†
Sch em e 1
Scott M. Sheehan and Albert Padwa*
Department of Chemistry, Emory University,
Atlanta, Georgia 30322
Received September 4, 1996
Six-membered nitrogen heterocycles comprise the back-
bone of many biologically and structurally interesting
alkaloids.1,2 The 3-hydroxy-2(1H)-pyridone (4) ring sys-
tem is a valuable building block in natural product
synthesis,3 as it can act as a common intermediate for
the preparation of a wide variety of piperidine, pyridine,
quinolizidine, and indolizidine alkaloids.2,4 Only a few
methods of preparing 3-hydroxy-2(1H)-pyridones have
been reported, and they typically involve harsh conditions
that preclude the presence of sensitive functional groups.5
We envisaged a convenient route to these pyridones by
a [3 + 2]-cycloaddition of a phenylsulfonyl-substituted
isomu¨nchnone intermediate6 (i.e., 2) with an alkene,
followed by a subsequent elimination of phenyl sulfinic
acid (Scheme 1).
Sch em e 2
By appropriate selection of the diazo precursor 1 and
the dipolarophile, various groups can be introduced into
the N-1 and C-4, C-5, C-6 positions. Moreover, substit-
uents can be subsequently introduced at C-3 by conver-
sion of the hydroxyl functionality to a triflate group,7
followed by a palladium-catalyzed cross-coupling reac-
tion.8 In this paper, we report on some model studies
leading to the regioselective synthesis of various 3-hy-
droxy-2(1H)-pyridones utilizing this novel cascade pro-
cess. Also presented are the results of the palladium-
mediated transformation of the corresponding triflate to
various pyridone derivatives, as well as an application
of the method to the synthesis of the indolizidine alkaloid
(()-ipalbidine (18).9,10
The preparation of the requisite diazoimide 5 was
accomplished by a diazo transfer reaction11 of 1-[(ben-
zenesulfonyl)acetyl]pyrrolidin-2-one with p-acetamido-
benzenesulfonyl azide and triethylamine. Formation of
the isomu¨nchnone ring was achieved by the reaction of
5 with Rh2(OAc)4 to give a rhodium carbenoid species that
undergoes an intramolecular cyclization onto the neigh-
boring carbonyl oxygen to form the mesoionic dipole
(Scheme 2). Bimolecular trapping of the dipole with
N-phenylmaleimide, methyl acrylate, and vinyl sulfone
proceeded in high yield. The initially formed cycload-
ducts (i.e., 3) were not isolable or observed, as they all
readily underwent ring opening to give the 3-hydroxy-
2(1H)-pyridones 6-8.
Cycloadduct 8 was easily converted to the correspond-
ing triflate 9 by treatment with N-phenyltrifluoromethane-
sulfonamide and triethylamine.12 The synthetic potential
of vinyl triflates has been well established over the last
decade,7 and these compounds have been shown to be
suitable substrates in various types of coupling reactions,
including Stille couplings8 and Heck reactions.13 In
contrast to the numerous examples of cross-coupling
reactions with simple vinyl triflates, there are no ex-
† Dedicated to the memory of Paul Dowd (1936-1996), a valued
friend and exceptional scientist.
(1) Rubiralta, M.; Giralt, E.; Diez, A. Piperidine: Structure, Prepara-
tion, Reactivity, and Synthetic Applications of Piperidine and its
Derivatives; Elsevier: Amsterdam, 1991.
(2) Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W.,
Ed.; J . Wiley and Sons: New York. The Alkaloids, Specialist Periodical
Reports; The Royal Society of Chemistry: London. The Alkaloids;
Brossi, A. Ed.; Academic Press: New York. Natural Products Report;
The Royal Society of Chemistry: London.
(3) Molenda, J . J .; J ones, M. M.; J ohnston, D. S.; Walker, E. M.;
Cannon, D. J . Med. Chem. 1994, 37, 4363.
(4) Elbein, A. D.; Molyneux, R. J . In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1981;
Vol. 5, pp 1-54.
(5) Meislich, H. Chemistry of Heterocyclic Compounds; Interscience
Publishers: New York, 1962; Chapter 12, p 509. Tieckelmann, H.
Chemistry of Heterocyclic Compounds; Interscience Publishers: New
York, 1974; Chapter 12, p 597.
(6) Osterhout, M. H.; Nadler, W. R.; Padwa, A. Synthesis 1994, 123.
Padwa, A.; Marino, J . P., J r.; Osterhout, M. H. J . Org. Chem. 1995,
60, 2704. Padwa, A.; Hertzog, D. L; Nadler, W. R. J . Org. Chem. 1994,
59, 7072. Marino, J . P., J r.; Osterhout, M. H.; Price, A. T.; Semones,
M. A.; Padwa, A. J . Org. Chem. 1994, 59, 5518. Padwa, A.; Hertzog,
D. L.; Nadler, W. R.; Osterhout, M. H.; Price, A. T. J . Org. Chem. 1994,
59, 1418. Hertzog, D. L.; Austin, D. J .; Nadler, W. R.; Padwa, A.
Tetrahedron Lett. 1992, 33, 4731.
(9) Hart, N. K.; J ohns, S. R.; Lamberton, J . A. Aust. J . Chem. 1968,
21, 2579.
(10) Wick, A. E.; Bartlett, P. A.; Dolphin, D. Helv. Chim. Acta 1971,
54, 513.
(11) Regitz, M.; Maas, G. Diazo Compounds: Properties and Syn-
thesis; Academic Press: Orlando, FL, 1986; p 185.
(12) McMurry, J . E.; Scott, W. J . Tetrahedron Lett. 1983, 24, 979.
(13) De Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994,
33, 2379.
(7) For a review on triflate chemistry, see: Ritter, K. Synthesis 1993,
735.
(8) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. Scott,
W. J .; Stille, J . K. J . Am. Chem. Soc. 1986, 108, 3033.
S0022-3263(96)01690-8 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 3, 1997 439
Sch em e 3a
amples of similar reactions with pyridone-derived tri-
flates such as 9. To test the reactivity of this new class
of triflates, we subjected 9 to coupling reactions with
various organometallic reagents.14 Reaction of 9 with
tributylphenyltin in the presence of lithium chloride (3
equiv) and tetrakis(triphenylphosphine)palladium(0) (0.05
equiv) gave the phenyl-substituted pyridone 10 in 86%
yield. A related Stille coupling with vinyltributyltin
afforded pyridone 11 in 78% yield. (Trimethylsilyl)-
acetylene underwent palladium-catalyzed coupling with
triflate 9 to provide acetylene 12 in 91% yield. Conver-
sion of the triflate into the unsubstituted 2-pyridone (R
) H) was achieved via a palladium(0)-catalyzed formate
reduction15 to afford 13 in 92% yield.
a
Reagents: (a) (TfO)2NPh, NEt3; (b) MeOC6H4SnBu3, Pd-
(PPh3)4, LiCl; (c) Ra-Ni, EtOH (65 °C); (d) 48% HBr, reflux; (e)
LiAlH4, AlCl3.
expected 3-hydroxy-2(1H)-pyridone 14 in 51% isolated
yield. Conversion of 14 to the corresponding vinyl triflate
(86%), followed by Stille coupling with tributyl(4-meth-
oxyphenyl)tin,17 gave the aryl-substituted 2-pyridone 15
in 72% yield. Desulfonylation of 15 was effected using
Raney nickel to give 2-pyridone 16 in 90% yield. Heating
a sample of 16 in 48% HBr afforded phenol 17 in 97%
yield. Reduction of 17 with alane (LiAlH4, AlCl3)10 gave
(()-ipalbidine (18) in eight steps in 17% overall yield.
In summary, we have successfully prepared novel
3-hydroxy-2(1H)-pyridones from the [3 + 2]-cycloaddition
reaction of isomu¨nchnone dipoles and studied the pal-
ladium-catalyzed coupling reactions of the corresponding
triflates with various organometallic reagents. This
methodology has proved to be applicable for the synthesis
of the indolizidine alkaloid (()-ipalbidine.
Our interest in establishing 9 as a useful building block
for indolizidine synthesis prompted us to use similar
methodology for the preparation of (()-ipalbidine.10,16
A
short synthesis of this alkaloid was carried out as
depicted in Scheme 3. Reaction of R-diazoimide 5 with
cis-1-(phenylsulfonyl)-1-propene and a catalytic quantity
of Rh(II) acetate in benzene at 80 °C provided the
(14) For
a review on organometallic coupling reactions of enol
triflates, see: Scott, W. J .; McMurry, J . E. Acc. Chem. Res. 1988, 21,
47.
(15) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984, 42,
4821.
Ack n ow led gm en t. We gratefully acknowledge the
National Cancer Institute (CA-26751), DHEW, for gen-
erous support of this work. Use of the high-field NMR
spectrometer used in these studies was made possible
through equipment grants from the NIH and NSF.
(16) For some alternate syntheses of (()-ipalbidine see: Danishef-
sky, S. J .; Vogel, C. J . Org. Chem. 1986, 51, 3916. Iida, H.; Watanabe,
Y.; Kibayashi, C. J . Chem. Soc., Perkin Trans. 1 1985, 261. Cragg, J .
E.; Hedeges, S. H.; Herbert, R. B. Tetrahedron Lett. 1981, 22, 2127.
Howard, A. S.; Gerrans, G. C.; Micael, J . P. J . Org. Chem. 1980, 45,
1713. Hedeges, S. H.; Herbert, R. B. J . Chem. Res., Synop. 1979, 1,
413. Stevens, R. V.; Luh, Y. Tetrahedron Lett. 1977, 979. Govindachari,
T. R.; Sidhaye, A. R.; Viswanathan, N. Tetrahedron 1970, 26, 3829.
(17) Stille, J . K.; Echavarren, A. M.; Williams, R. M.; Hendrix, J .
A. Organic Synthesis; Overman, L. E., Ed.; Wiley and Sons: New York,
1993; Vol. 71, p 97.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the preparation of, as well as spectroscopic data for,
all new compounds (10 pages).
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