Leptofuranin D

The structures of new antitumor antibiotics, leptofuranins A, B, C and D were elucidated to be as shown in Fig. 1 by NMR spectral analysis including a variety of two-dimensional techniques. The leptofuranins are novel leptomycin-related substances containing a tetrahydrofuran ring. Leptofuranins C and D were revealed to be in tautomeric isomerism and their relative stereochemistries were analyzed by NOESY experiments.

A convergent total synthesis of leptofuranin D is described. The linear polyketide C12-C24 segment was assembled through addition of a chiral allenylzinc reagent, derived from mesylate 12, to the chiral aldehyde 11. Directed hydrostannation of the adduct 13 followed by iodinolysis and Sonogashira coupling yielded the enyne 16, which was converted to the methyl-substituted enye 20, through hydrogenolysis of the derived bromide 19. Hydrostannation of the terminal alkyne converted 21 to 22, which was then treated with iodine to afford the vinyl iodide 23. The dihydropyranone precursor 40 was prepared by addition of allenystannane 29 to aldehyde 27. Partial hydrogenation of the derived propargylic alcohol then protection as the TBS ether afforded the (Z)-olefin 34. Further homologation was effected through Witttig condensation of aldehyde 36 with the ylide derived from phosphonium bromide 37. Selective deprotection of the primary TES ether of 38, followed by conversion of alcohol 39 to iodide 40, completed the synthesis of the C1-C11 segment. Suzuki coupling of boronate 41, prepared from iodide 40, with vinyl iodide 23 led to diene 42, with the complete carbon skeleton of leptofuranin D. The synthesis was completed by oxidation of the unprotected alcohol of 42, followed by global desilylation and exposure of the resulting tetrol to MnO(2).

The retinoblastoma protein (pRB) is inactivated in a wide variety of human cancers. In the course of our screening for antitumor antibiotics by using pRB-inactivated cells, an actinomycete identified as Streptomyces tanashiensis was found to produce four new active substances, leptofuranins A, B, C and D. The leptofuranins arrested the growth of normal cells and induced apoptotic cell death against tumor cells and cells transformed with the adenovirus E1A gene.