Studies Toward the Synthesis of (-)-Zampanolide: Preparation of N-Acyl Hemiaminal Model Systems Dawn M. Troast and John A. Porco, Jr.* Department of Chemistry and Center for Streamlined Synthesis, Metcalf Center for Science and Engineering, Boston UniVersity, 590 Commonwealth AVenue, Boston, Massachusetts 02215 porco@chem.bu.edu Received January 15, 2002 ABSTRACT Synthesis of N-acyl hemiaminal model systems related to the side chain of the antitumor natural product zampanolide is reported. Key steps involve oxidative decarboxylation of N-acyl-r-amino acid intermediates, followed by ytterbium triflate mediated solvolysis. Evidence for stabilization of the N-acyl hemiaminal moiety in model compounds by an intramolecular hydrogen-bonding network is described. The unique 20-membered macrolide (-)-zampanolide (1) was isolated in 1996 by Tanaka and Higa from the sponge Fasciospongia rimosa, collected near Okinawa, Japan. 1 This structurally interesting molecule has a high degree of unsaturation and an unusual N-acyl hemiaminal side chain. 2 In addition to its unique structure, zampanolide displays potent cytotoxic activity (1-5 ng/mL) against a number of tumor cell lines. Recently, Smith et al. reported the total synthesis and tentative stereochemical assignment of the antipode (+)-zampanolide in which the C(20) stereogenic center associated with the N-acyl hemiaminal was epimerized in a deprotection step, illustrating the lability of this functionality. 3 We have initiated studies on zampanolide as a synthetic target and have focused our initial efforts on the synthesis of the unusual and unstable N-acyl hemiaminal side chain. In this Letter, we report the synthesis of N-acyl hemiaminal model compounds related to zampanolide, as (1) (a) Tanaka, J.-i.; Higa, T. Tetrahedron Lett. 1996, 37, 5535-5538. (b) Higa, T.; Tanaka, J.-i.; Garcia Gravalos., D. PCT Int. Appl. WO 9710242 A1, 1997. For a related natural product (dactylolide) lacking the N-acyl hemiaminal side chain, see: (c) Cutignano, A.; Bruno, I.; Bifulco, G.; Casapullo, A.; Debitus, C.; Gomez-Paloma, L.; Riccio, R. Eur. J. Org. Chem. 2001, 775-778. (2) For examples of N-acyl hemiaminal-containing natural products, see: (a) Echinocandin B: Benz, F.; Knuesel, F.; Nuesch, J.; Treichler, H.; Voser, W.; Nyfeler, R.; Keller-Schierlein, W. HelV. Chim. Acta 1974, 57, 2459-2477. (b) Spergualin: Umezawa, H.; Kondo, S.; Iinuma, H.; Kunimoto, S.; Ikeda, Y.; Iwasawa, H.; Ikeda, D.; Takeuchi, T. J. Antibiot. 1981, 34, 1622-1624. For N-acyl aminal natural products, see: (c) Mycalamides: Perry, N. B.; Blunt, J. W.; Munro, M. H. G.; Pannell, L. K. J. Am. Chem. Soc. 1988, 110, 4850-4851. (d) Pederin: Matsumoto, T.; Yanagiya, M.; Maeno, S.; Yasuda, S. Tetrahedron Lett. 1968, 6297-6300. (e) Tallysomycins (glycosylcarbinolamide): Konishi, M.; Saito, K.; Numata, K.; Tsuno, T.; Asama, K.; Tsukiura, H. Naito, T.; Kawaguchi, H. J. Antibiot. 1977, 30, 789-805. (3) Smith, A. B., III; Safanov, I. G.; Corbett, R. M. J. Am. Chem. Soc. 2001, 123, 12426-12427. ORGANIC LETTERS 2002 Vol. 4, No. 6 991-994 10.1021/ol025558l CCC: $22.00 © 2002 American Chemical Society Published on Web 03/01/2002