addition as the key synthetic step.12,13 However, only a few
methods of preparing hydroxy-2(1H)-pyridones have been
reported,14 and they typically involve harsh conditions that
preclude the presence of sensitive functional groups.15 We
have recently described a general and flexible entry to a
variety of 3-hydroxy-substituted pyridones.16 The cornerstone
of our synthetic plan is the [3 + 2]-cycloaddition of a
phenylsulfonyl-substituted isomu¨nchnone intermediate (i.e.,
4).17,18 Once the cycloaddition reaction occurs, the resulting
adduct 5 undergoes ready ring opening to give the desired
pyridone 6 (Scheme 1).19 The versatility of the strategy lies
the hydroxyl functionality to a triflate group,20 followed by
a palladium-catalyzed cross-coupling reaction.21 To highlight
the method, the above synthetic strategy was applied to the
angiotensin converting enzyme inhibitor (-)-A58365A (1).
The first total synthesis of A58365A (1) was reported by
Danishefsky and Fang in 198922 and more recently by the
Moeller23 and Clive groups.24 Each of the synthetic routes
utilized involved a fundamentally different strategy. Annu-
lation of a vinylogous urethane with R-methylene glutaric
anhydride was the key reaction employed in Danishefsky’s
synthesis.22 In the Moeller approach, an aniodic amide
oxidation-iminium ion cyclization sequence was employed
for the construction of the bicyclic lactam peptide mimetic.23
Finally, Clive’s method was based on an ene-yne cyclization
involving the addition of tributylstannyl radical to a terminal
alkyne followed by a subsequent 6-endo-trig cyclization onto
a cyclic enamide.24 Our interest in establishing phenylsul-
fonyl-substituted isomu¨nchnones as useful building blocks
for 2-pyridones prompted us to apply the method outlined
in Scheme 1 toward the synthesis of A58365A.
Scheme 1
The four-step conversion of commercially available L-
pyroglutamic acid (7) to the isomu¨nchnone precursor 12 was
carried out using conventional chemistry. Esterification of
7 with methanol in the presence of Dowex ion-exchange resin
gave methyl ester 8 in 98% yield. Treatment of 8 with
(phenylthio)acetyl chloride (9) in benzene afforded methyl
5-oxo-1-(2-phenylthioacetyl)pyrrolidine-2-carboxylate (10)
in 87% yield. Oxidation of 10 with Oxone furnished sulfone
11 (67%) which was converted to diazoimide 12 using
established diazotization procedures25 in 91% yield. Reaction
of 12 with methyl vinyl ketone and a catalytic quantity of
Rh2(OAc)4 in benzene at 80 °C provided the expected
3-hydroxy-2(1H)-pyridone 13 in 86% isolated yield (Scheme
2). Cycloadduct 13 was easily converted to the corresponding
triflate 14 (94%) by treatment with N-phenyltrifluoromethane-
sulfonamide and triethylamine.26 The synthetic potential of
in the fact that by appropriate selection of the diazo precursor
3 and dipolarophile, various groups can be introduced into
the N-1, C-4, C-5, and C-6 positions. Moreover, substituents
can be incorporated into the C-3 position by conversion of
(11) Mynderse, J. S.; Samlaska, S. K.; Fukuda, D. S.; Du Bus, R. H.;
Baker, P. J. J. Antibiot. 1985, 38, 1003. Hunt, A. A.; Mynderse, J. S.;
Samlaska, S. K.; Fukuda, D. S.; Maciak, G. M.; Kirst, H. A.; Occolowitz,
J. L.; Swartendruber, J. K.; Jones, N. D. J. Antibiot. 1988, 41, 771.
O′Connor, S.; Somers, P. J. Antibiot. 1985, 38, 993.
(12) Jones, G. In ComprehensiVe Heterocyclic Chemistry; Katritzky, A.
R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Elmsford, NY,
1996; Vol. 5. Comins, D. L.; Gao, J. Tetrahedron Lett. 1994, 35, 2819.
Sieburth, S. M.; Hiel, G.; Lin, C. H.; Kuan, D. P. J. Org. Chem. 1994, 59,
80. Schmidhauser, J. C.; Khouri, F. F. Tetrahedron Lett. 1993, 34, 6685.
Sieburth, S. M.; Chen, J. L. J. Am. Chem. Soc. 1991, 113, 8163.
(13) Comins, D. L.; Gao, J. Tetrahedron Lett. 1994, 35, 2819. Sieburth,
S. M.; Hiel, G.; Lin, C. H.; Kuan, D. P. J. Org. Chem. 1994, 59, 80.
Schmidhauser, J. C.; Khouri, F. F. Tetrahedron Lett. 1993, 34, 6685.
Sieburth, S. M.; Chen, J. L. J. Am. Chem. Soc. 1991, 113, 8163.
(14) Molenda, J. J.; Jones, M. M.; Johnston, D. S.; Walker, E. M.;
Cannon, D. J. Med. Chem. 1994, 37, 4363.
Scheme 2
(15) Meislich, H. Chemistry of Heterocyclic Compounds; Interscience
Publishers: New York, 1962; Chapter 12, p 509. Tieckelmann, H. Chemistry
of Heterocyclic Compounds; Intersicence Publishers: New York, 1974;
Chapter 12, p 597.
(16) Sheehan, S. M.; Padwa, A. J. Org. Chem. 1997, 62, 438.
(17) Hamaguchi, M.; Ibata, T. Tetrahedron Lett. 1974, 4475. Hamaguchi,
M.; Ibata, T. Chem. Lett. 1975, 499.
(18) Padwa, A.; Marino, J. P., Jr.; 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., Jr.; 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.
(19) Padwa, A. J. Chem. Soc., Chem. Commun. 1998, 1417.
(20) For a review on triflate chemistry, see: Ritter, K. Synthesis 1993,
735.
84
Org. Lett., Vol. 1, No. 1, 1999