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The synthesis, physicochemical properties, and biological activities of a series of novel spiro cyclopropyl compounds, modeled on the potent antitumor antibiotic CC-1065 (1), are described. Many of these synthetic analogues are significantly more effective than 1 against murine tumors. In particular, compound 27 exhibits high activity and potency. Structure-activity analysis supports a molecular mechanism for biological action involving hydrophobic interaction of the drug with DNA and acid-catalyzed alkylation of DNA.

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CC-1065, a novel antitumor antibiotic,' has drawn significant synthetic attention2 due to its unusual structure and potent biological properties. Interest in this area waned to some extent with the discovery of dealyed deaths3 caused by CC-1065 but has been reignited by the recent disclosure of highly potent and active analogues which do not produce this unusual t~x i c i t y .~ Most of the synthetic efforts have been directed at the synthesis of either the left hand segment (Le., CPI) or a t PDE-I and its dimer. W a r p e h~s k i~~ describes a method for the coupling of the on 3-$tyN" OMe CPI OMS CC-1065 no4 n -fNnz H o o d d $ OMe : N n z H On on OMe OMe PDE.1 PDE-I dimer two portions, suitable for analogues but not for the preparation of CC-1065 itself.5 We report here coupling of CPI and its derivatives with a variety of acids including PDE-I dimer.6 This provides the first synthesis of CC-1065 as well as its enantiomer' (1) (a) Chidester, C. G.; Krueger, W. C.; Mizsak, S. A,; Duchamp, D. J.; Martin, D. G. J. Am. Chem. SOC. 1981, 103, 7629. (b) Martin, D. G.; Biles, C.; Gerpheide, S. A,; Hanka, L. J.; Krueger, W. C.; McGovren, J. P.; Mizsak, S. A,; Neil, G. L.; Stewart, J. C.; Visser, J. Scheme I" c 2 R cp' b / 3 0 +' c PDE:, dimer 5 % a (a) LDA, THF-HMPA, -78 OC; (b) RCOCl (from RCOOH and (COCI,) or RCOOH, EDC, and hydroxybenzotriazol. Scheme 11" BZlO HO 3 o+-R 9 "(a) REDAL, THF-toluene or glyme 85 OC; (b) EDC, RCOOH; (c) MsCI, pyridine; (d) H,, Pd/C or TMSCI, NaI, CH3CN; (e) EtpN-THF or EtOAc; (f) LiC1, DMF, 80-100 'C; (g) NH,OHCO, Pd/C, MeOH; (h) Et,N, H,O, CH3CN-I:1:1; (i) HCI, EtOAc.and allows rapid and efficient preparation of a wide range of CC-1065 analogues.Conceptually, the ideal approach to CC-1065 and its analogues is the direct coupling of CPI to PDE-I dimer or other acids. We felt that it might be possible to prepare specifically the anion of the vinylogous amide of CPI without deprotonating the pyrrole nitrogen (Scheme I).In the event, treatment of CPI with LDA in THF containing HMPA at -78 O C followed by the addition of an acid chloride such as hexanoyl chloride or indole-2-carboxylic acid chloride resulted in the direct formation of 3a and 3b, respectively, in 40-60% yield^.^,^ (7) Natural CC-1065 and its congeners all possess the spirocyclopropyl ring down as shown in this paper. The enantiomeric (= ent) series (not shown) differs only in that the spirocyclopropyl ring of the CPI moiety protrudes above the plane. Both enantiomers of CPI derivative 4 are available (ref 4a).(8) The conditions of this reaction are quite critical. Using different bases such as NaH or KH or conducting the reaction in THF in the absence of HMPA resulted in much lower yields.