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Employed as a common chiral starting material, (-1-quinic acid (7) was converted in a concise manner to both enantiomers of the P,y-unsaturated ketone 12. On the one hand, (+)-12 was obtained by stereospecific borohydride reduction of the conjugated ketone intermediate 9, transketalization, and oxidation of the derived homoallylic alcohol using the Dess-Martin periodinane reagent. Alternatively, dehydration of the tertiary alcohol 13 and oxidation of the free hydroxyl group in 14 furnished (-1-12 in good overall yield. Reaction of (+)-12 with dichlorocerium TMS acetylide was followed by Pd (0)-assisted construction of the acyclic enediyne 21. Cyclization of this intermediate on treatment with KHMDS proved efficient, providing the esperamicin intermediate (-)-22 in 60% isolated yield. In an identical fashion -)-12 was converted to the enantiomeric bicyclic enediyne (+)-22. Subsequent liberation of the diol system, and selective oxidation of the allylic alcohol in 25 gave ketone 26. Reaction of this intermediate with Ph2S-NH monohydrate gave aziridine 27 which was readily converted to its carbamate derivative 28 in preparation for aziridine ring opening. Calicheamicin-71' (1) and esperamicin-A1 (2) are amongst the most potent antitumoral agents known, displaying in vitro and in vivo activities at ng/mL levels (IC5,,'s) against a number of tumor systems (B16 melanoma, Moser human carcinoma, HCT-116 carcinoma, and normal and vincristine resistant This activity derives from the capacity of the aglycone component of these two structurally unique "enediyne" @ Abstract published in Advance ACS Abstracts, April 1, 1995. (1) (a) Lee, M. D.; Dunne, T. S.; Siegel, M. M.; Chang, C. C.; Morton, G. 0.; Borders, D. B. J . Am. Chem. Soc. 1987,109, 3464. (b) Lee, M. D.; Dunne, T. S.; Chang, C. C.; Ellestad, G. A.; Siegel, M. M.; Morton, G. 0.; McGahren, W. J.; Borders, D. B. J . Am. Chem. SOC. 1987,109, 3466. (c) Lee, M. D.; Ellestad, G. A.; Borders, D. B. Acc. Chem. Res. 1991,24, 235. (2) (a) Golik, J.; Clardy, J.; Dubay, G.; Groenewold, G.; Kawaguchi, H.; Konishi, M.; Krishnan, B.; Ohkuma, H.; Saitoh, K.; Doyle, T. W. J. Am. Chem. SOC. 1987, 109, 3461. (b) Golik, J.; Dubay, G.; Groenewold, G.; Kawaguchi, H.; Konishi, M.; Krishnan, B.; Ohkuma, H.; Saitoh, K.; Doyle, T. W. J . Am. Chem. SOC. 1987, 109, 3462. (3)(a) Maiese, W. M.; Lechevalier, M. P.; Lechevalier, H. A.; Korshalla, J.; Kuck, N.; Fantini, A.; Wildey, M. J.; Thomas, J.; Greenstein, M. J. Antibiot. 1989,42, 558. (b) Lee, M. D.; Manning, J. K.; Williams, D. R.; Kuck, N. A.; Testa, R. T.; Borders, D. B. J . Antibiot. 1989,42,1070. (c) Konishi, M.; Ohkuma, H.; Saitoh, K.-I.; Kawaguchi, H.; Golik, J.; Dubay, G.; Groenewold, G.; Krishnan, B.; Doyle, T. W. Hangeland, J. J.; Townsend, C. A. J . Am. Chem. SOC. lsgO,ll2,4554. (h) De Voss, J. J.; Townsend, C. A.; Ding, W.-D.; Morton, G. 0.; Ellestad, G. A.; Zein, N.; Tabor, A. B.; Schreiber, S. L. J . Am. Chem. SOC. 1990, 112, 9669. (i) Zein, N.; Poncin, M.; Nilakantan, R.; Ellestad, G. A. Science 1989, 244, 697. 6 ) Zein, N.; M...

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Fiduxosin (1) has been under development at Abbott Laboratories for the treatment of benign prostatic hyperplasia. A convergent strategy required methodologies for preparation of an enantiomerically pure 3,4-cis-disubstituted pyrrolidine and a 2,3,5-trisubstituted thienopyrazine in a regiospecific manner. A [3+2] cycloaddition of an enantiopure azomethine ylide followed by a diastereoselective crystallization was employed to prepare the benzopyranopyrrolidine in high diastereomeric and enantiomeric purity. Conditions for reduction of an O-aryl lactone susceptible to epimerization were developed, and cyclization of the alcohol/phenol to the ether was accomplished in high yield. The thienopyrazine was prepared by condensation of methyl thioglycolate and a regiospecifically prepared 2-bromo-3-cyano-5-phenylpyrazine. Conditions for effective halogen substitutive deamination to prepare regiospecific trisubstituted pyrazines will be described.