Diazobenzofluorene natural products are a family of structurally complex molecules with a tetracyclic (ABCD) framework bearing a diazo moiety, a functionality rarely found in nature (Scheme 1). Members of this family differ in the levels of functionalization of the cyclohexene moiety (D ring). Kinamycin C (1), [2] which is biosynthetically derived from the epoxide-containing ketoanhydrokinamycin (2), [4] contains a D ring with four contiguous stereocenters. Other epoxykinamycins include FL-120B (3) and the closely related FL-120B' (4). [5] Monomeric diazobenzofluorenes have been shown to exhibit antitumor properties. [2, 6] Numerous studies have suggested that these biological activities may result from damage to DNA mediated by bioreductive pathways, thus leading to loss of the diazo functional group. [6b, 7] This unique family of natural products gained significant attention upon isolation of the dimeric diazobenzofluorenes lomaiviticins A (5) and B (6) by He et al. in 2001. Demonstrated to be DNAdamaging agents, the lomaiviticins were found to display antibiotic acitivity against Gram-positive bacteria and potent cytotoxicity in several cancer cell lines. The C 2 -symmetric lomaiviticins may originate from the C2 À C2' linkage of precursors that closely resemble the monomeric kinamycins.
Since 2006, numerous research groups have reported total syntheses of monomeric diazobenzofluorene natural products [9] as well as studies towards the dimeric lomaiviticins. [10] Recently, Herzon et al. reported a remarkable 11-step synthesis of the lomaiviticin aglycon. Their dimerization approach utilizes an oxidative homocoupling of a silyl enol ether derived from a protected monomer, which resembles 7 (Scheme 2 a). Given the abundance of diazobenzofluorene natural products bearing an epoxide or oxygenated functionality at the C2-position, we believe that a biosynthetic precursor to the lomaiviticins may also be depicted by the proposed monomer 8 (Scheme 2 b). This dimerization process may result from a reductive epoxide-opening event leading to a pivotal carbon-carbon bond formation. In this regard, we report the total synthesis of FL-120B' (4) and development of methods to prepare diazobenzofluorenes with intact epoxides; these methods may also allow future access to the lomaiviticins and related compounds. Scheme 1. Representative diazobenzofluorene natural products.
Scheme 2. Biomimetic approaches to the lomaiviticins.