Toluene Dioxygenase-Mediated cis-Dihydroxylation of Aromatics in Enantioselective Synthesis. Asymmetric Total Syntheses of Pancratistatin and 7-Deoxypancratistatin, Promising Antitumor Agents 1 Tomas Hudlicky,* Xinrong Tian, Kurt Ko 1 nigsberger, Rakesh Maurya, Jacques Rouden, and Boreas Fan † Contribution from the Department of Chemistry, UniVersity of Florida, GainesVille, Florida 32611-7200 ReceiVed February 23, 1996 X Abstract: Whole-cell biooxidation of bromobenzene with Pseudomonas putida 39D or the recombinant Escherichia coli JM109 (pDTG601) yields (1S,2S)-3-bromocyclohexa-3,5-diene-1,2-diol (9a), which is protected as the acetonide and converted to vinylaziridines 7, 15a, 63, and 64. Our route to (+)-pancratistatin features the coupling of a higher order cyanocuprate (derived by ortho-metalation from N,N-dimethyl-2-[(tert-butyldimethylsilyl)oxy]-3,4-(methyl- enedioxy)benzamide) with aziridine 7 to generate 28, which contains the carbon framework of the title alkaloid. Functional group manipulations resulted in the preparation of epoxydiol 50, which was transformed in a unique fashion and under mild conditions (H 2 O/PhCO 2 Na) to (+)-pancratistatin, thus completing a concise synthesis of (+)-pancratistatin in 14 steps from bromobenzene (2% overall yield). To improve this first generation attempt, a new route was devised utilizing carbomethoxyaziridine 64 and its coupling to the cuprate of 3,4-(methylenedioxy)- bromobenzene. The adduct was converted to (+)-7-deoxypancratistatin in a total of 11 steps from bromobenzene (3% overall yield), and the basis for further improvement toward a practical synthesis of pancratistatin-type alkaloids was formulated. Introduction The medicinal value of oil from the daffodil Narciclasus poeticus L. in the treatment of illnesses related to cancer was already known to physician Hippocrates of Cos 2 in ancient Grecian times, but it was not until 1877 that the first member of the Amaryllidaceae family of alkaloids, lycorine (1, Figure 1), was isolated from Narcissus pseudonarcissus. 3 Since that time, more than 100 structurally diverse alkaloids have been isolated from various Amaryllidaceae species. In 1958, lycorine was shown to possess antitumor acivity. 4 Lycoricidine (2) and narciclasine (3) were discovered in 1968 in the bulbs of Lycoris radiate. 5 Sixteen years later, another highly oxygenated phenanthridone alkaloid was extracted from Pancratium litto- rale. 6 The compound was named pancratistatin (4); 7 it subse- quently attracted considerable attention because of its spectrum of antineoplastic activities. 6c Although pancratistatin’s mech- anism of action remains to be elucidated, that of narciclasine has been studied, and it is believed that the compound disrupts protein biosynthesis in eukaryotes. 8 Both lycoricidine and † Undergraduate Research Participant, Summer 1993. X Abstract published in AdVance ACS Abstracts, October 1, 1996. (1) Preliminary accounts of this work, performed fully (a) or in part (b) at Virginia Polytechnic Institute and State University, have been published. (a) Tian, X.; Hudlicky, T.; Ko ¨nigsberger, K. J. Am. Chem. Soc. 1995, 117, 3643. (b) Tian, X.; Maurya, R.; Ko ¨nigsberger, K.; Hudlicky, T. Synlett 1995, 1125. (2) Hartwell, J. L. Lloydia 1967, 30, 379. (3) Cook, J. W.; Loudon, J. D. In The Alkaloids; Manske, R. H. F., Holmes, H. L., Eds.; Academic Press: New York, 1952; Vol. 2, Chapter 11, p 331. (4) Fitzgerald, R.; Hartwell, J. L.; Leiter, J. J. Natl. Cancer Inst. 1958, 20, 763. (5) Okamoto, T.; Torii, Y.; Isogai, Y. Chem. Pharm. Bull. 1968, 16, 1860. (6) (a) Pettit, G. R.; Gaddamidi, V.; Cragg, G. M.; Herald, D. L.; Sagawa, Y. J. Chem. Soc., Chem. Commun. 1984, 1693. (b) Pettit, G. R.; Gaddamidi, V.; Cragg, G. M. J. Nat. Prod. 1984, 47, 1018. (c) Pettit, G. R.; Gaddamidi, V.; Herald, D. L.; Singh, S. B.; Cragg, G. M.; Schmidt, J. M.; Boettner, F. E.; Williams, M.; Sagawa, Y. J. Nat. Prod. 1986, 49, 995. (7) The word pancratistatin should more appropriately be spelled pancratistatinum in correct “chemical” Latin. It implies an “all-powerful breaker or stopper” of some activity, in this case cell division. The derivation is of some interest here. The name of the plant translates literally as “all- powerful from the shore of a lake” and is a Latin rendition of a Greek word pankration, which means “victory by any and all means”. It refers to an ancient wrestling contest which was frequently fought to the death or unconditional surrender of one of the opponents. Barred from this match was only the use of biting or gougingsall else was allowed. The root of the word pankration in Greek implies power or strength (kratos) and in Latin hurdles or obstacles. We thank Dr. Thomas MacAdoo (Virginia Tech) for this interesting elucidation. (8) (a) Carrasco, L.; Fresno, M.; Vazquez, D. FEBS Lett. 1975, 52, 236. (b) Jimenez, A.; Sanchez, L.; Vazquez, D. FEBS Lett. 1975, 55, 53. (c) Jimenez, A.; Santos, A.; Alonso, G.; Vasquez, D. Biochim. Biophys. Acta 1976, 425, 342. (d) Mondon, A.; Krohn, K. Chem. Ber. 1975, 108, 445. Figure 1. 10752 J. Am. Chem. Soc. 1996, 118, 10752-10765 S0002-7863(96)00596-3 CCC: $12.00 © 1996 American Chemical Society