J. zyxwvutsr Org. Chem. zyxwvu 1994,59,451-454 451 Synthesis of the Antifungal Agent Neoenactin A and Its N-Deshydroxy Derivative Ihab S. Darwish and Marvin J. Miller' Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana zyx 46556 Receiued September 17, 199P The first total and unequivocal syntheses of neoenactin A (1, NE A) as well as its N-deshydroxy analog 2 are described. The two key steps in the syntheseswere the oxidative cleavageof an appropriate olefin 8a to yield the desired keto acid 9 and the Michael addition of serinehydroxamates zyx 11 or 12 to the appropriate vinyl ketone 10. Biological activity of 1 and 2 against Escherichia coli and several fungi has been investigated. Introduction Neoenactins (NEs) are a new family of L-serinehydrox- amic acid-based antifungal agents produced by Strep- tomyces roseoviridis.' The potency of these compounds against a wide variety of fungi has been demonstrated.lb Thus far, several congeners of NEs have been isolated, and all of them are almost equally active against many organisms.2 Our synthetic efforts were therefore focused on the main component of NEs, neoenactin A (NE A, l), and analogs. We have already reported3 the synthesis of norneoenactin A (31, an analog of NE A, and herein we describe the first total syntheses of NE A (1) zyxwvut as well as N-deshydroxyneoenactin A (2). 00 HOi 1, Nmnactln A (NE A), nd, X=OH 2, EI'-Deshydroxy-neoenactln A, n=S, X=H 3, NomeOenaCtln A, n.5, X=OH Results and Discussion To synthesize neoenactin A, we wanted to develop a flexible convergent approach which should provide NE A (1) in addition to a number of analogs. On the basis of our earlier work? Michael addition of the hydroxamate nitrogen of serinehydroxamates 11 or 12 to vinyl ketone 10 should, upon further manipulation, provide the target molecule 1. In our successful attempt to synthesize norneoenactin A (3)? we have reported the synthesis of 7-oxotridecanoic acid (61, which was obtained by basic hydrolysis of 2-heptanoylcyclohexanone (4a, Scheme 1). Unfortunately, 8-oxotetradecanoicacid (9) could not be obtained by basic hydrolysis of 2-heptanoylcycloheptanone (4b).4 Interest- ingly, simple variation from cyclohexanone 4a to cyclo- heptanone 4b drastically alters the regioselectivity of nucleophilic attack on these diones. This is attributed to the decreased activity of the ring carbonyl group caused by a shielding effect due to ring puckering. Thus, base * Abstract published in zyxwvutsrqpon Advance ACS Abstracts, January 1, 1994. (1) Leadingreferences: (a) Yamamoto, K.; Shiinoki, Y.; Furukawa, J.; Nakamura, S. Chem. Pharm. Bull. 1991, 39, 1436. (b) Okada, H.; Yamamoto, K.; Tsutano, S.; Inouye, Y.; Nakamura, S.; Furukawa, J. zyxwvutsrq J. Antibiot. 1989, 42, 276. (2) Roy, S. K.; Inouye, Y.; Nakamura, S. J. Antibiot. 1987, 40, 266. (3) Darwish, I. &;Patel, C.; Miller, M. J. J. Og. Chem. 1993,58,6072. (4) Kawamura, K.; Gagosian, R. B. J. Chromatogr. 1988, 438, 299. 0022-3263/94/1959-0451$04.50/0 Scheme 1 5 pTsOH 6 i t hydrolysis of 2-heptanoylcycloheptanone (4b) provides cycloheptanone and hexanoic acid as the main products. A literature search revealed three reports for the synthesis of keto acid 9, the direct precursor of vinyl ketone 10. In the first: the acid chloride of suberic acid monomethyl ester was treated with 1-hexylcadmium chloride to give the methyl ester of 9 which upon base hydrolysis afforded 9 in 63 % overall yield. Although the starting suberic acid monoethyl ester is commercially available, its use would not have allowed flexibility for the eventual preparation of analogs. The other two references were not readily available.6 Alternatively, it should be possible to obtain 8-oxotet- radecanoic acid (9) from 7-oxotridecanoic acid (5) em- ploying one of two approaches. First, conversion of ketone 53 to ketal 6, homologation utilizing the Arndt-Eistert protocol, and acid hydrolysis should provide keto acid 9. Conversion of the keto group in 5 to olefin 7, homologation, and oxidative cleavage of the double bond is yet another route that could provide the desired keto acid9. However, initial difficulties in isolating or purifying the ketal acid 6, in addition to the numerous steps required to protect, homologate, and deprotect the ketone in 5, led us to seek an alternative, more flexible route to neoenactin A (1) and analogs. (5) Aragozzini,F.;Manachini,P. L.;Craveri,R.;Rindone,B.;Scolestico, C.Tetrahedron 1972,28, 6493. (6) (a) Breusch, F. L.; Kirkal, A. Fette, Seifen, Ahstrichmittel 1963, 65,995. (b) Faqqua, S. A. Ph.D.The&, Universityof Wisconeinat Madieon 1957. 0 1994 American Chemical Society