Tetrahedron Letters,Vo1.25,No.25,?q 2649-2652,1984 0040-4039/84 $3.00 + .OO Printed in Great Britain 01984 Peraamon Press Ltd. zyxwvutsrqp LIMITATIONS AND FACTORS AFFECTING THE LACTAM REDUCTION APPROACH TO THE SYNTHESIS OF ANTHRAMYCIN ANALOGS David E. Thurston*, Pravin T.P. Kaumaya, and Laurence H. Hurley College of Pharmacy, University of Texas at Austin Austin, Texas 78712 Abstract: The limitations and factors affecting the hydride reduction of pyrrolo[l,4]benzo- diazepine-5,10-diones to anthramycin-type analogs have been explored. Anthramycin, sibiromycin, tomaymycin and the neot;ramycins belong to the pyrrolo[l,4] benzodiazepine(P[1,4]B)group of antitumor antibiotics. Previous Jnvestigations have provided information on the precise manner in ;hich these drugs biid to DNA and on the probable features responsible for their cardiotoxicity. We have suggested4 a rational approach to the development of clinically useful drugs in this series, and have embarked upon investigations designed to provide versatile synthetic methodologies which should allow us to5test our SAR predictions. Two synthetically useful methods have been published, that lead to compounds possessing a carbinolamine moiety i or its chemical equivalent) contained within a P[1,4]B ring system. Catalytic reductive cycliza;iyn of a nitro aldehyde has provided a total synthesis of tomaymycin and we have also investigated ’ the applicability of this approach to other analogs. The second method which is the subject of ;his paper, involves hydride reduction of a P[1,4]B-5,10-dione (dilactam), a technique utilized by Leimgruber and co-workers for the total synthesis of anthramycin. The results presented here provide insights into the limitations of this approach. The final step of the synthesis of anthramycin methyl ether (AME)(3) involves reduction of the dilactam (1) with sodium borohydride (SBH) in methanol at 5'C (or lithium aluminium hydride in THF at -6O'C) to afford the intermediate carbinolamine (Z), which is then treated with methanolic HCl to hydrolyze the phenyloxazoline ring and form the carbinolamine methyl e;hf; (3). To investigate the generality of this procedure we first prepared ’ dilactams 4a and 4b which failed to reduce with SBH under similar conditions. This was attributed to initial reaction of the hydride reducing agent with the amidic N-10 proton (and the C-g hydroxyl proton in the case of 4b) followed by precipitation of an insoluble complex that is not further reduced. 2649