Kinamycin

FIGURE 7.23 Prototype diazobenzo[6]fluorene-based natural products kinamycin A and prekinamycin. Compounds prepared for this study are shown in the inset. 

Figure 7.23 shows the prototype diazobenzo[Z ]fluorene-based natural products kinamycin A and prekinamycin. The kinamycin A-D family were first isolated from Streptomyces murayamaensis, but the structures were incorrectly characterized as having a cyanobenzo[Z ]carbazole ring. Since the initial discovery of the kinamycins, many new analogues have been discovered from natural sources.88-92... 

Marco-Contelles, J. Molina, M. T. Naturally occurring diazo compounds the kinamycins. Curr. Org. Chem. 2003, 7, 1433-1442. 

Hasinoff, B. B. Wu, X. Yalowich, J. C. Goodfellow, V. Laufer, R. S. Adedayo, O. Dmitrienko, G. I. Kinamycins A and C, bacterial metabolites that contain an unusual diazo group, as potential new anticancer agents antiproliferative and cell cycle effects. Anti-Cancer Drugs 2006, 17, 825-837. 

Cone, M. C. Seaton, R J. Halley, K. A. Gould, S. J. New products related to kinamycin from Streptomyces murayamaensis. I. Taxonomy, production, isolation and biological properties. J. Antibiot. 1989, 42, 179-188. 

The structure elucidation of the kinamycins was a formidable challenge, and the information presented below draws from the work of several research groups over a period of more than 20 years. As will be shown, the originally proposed structure of the kinamycins contained a cyanamide rather than a diazo function. Subsequent synthetic and biosynthetic studies led to replacement of the cyanamide with a diazo function. The structural elucidation was challenging, in part, because of the high degree of unsaturation of the kinamycins, which limits the utility of H and 2D NMR analysis. In addition, because these structures were unprecedented, there were no clear benchmarks for comparison at the time. The pathway from isolation to determination of the correct structure is described below. 

Subsequent biosynthetic and synthetic studies, however, provided data that were inconsistent with the (V-cyanocarbazole function. Gould synthesized 15(V2-kinamycin... 

Chart 3.2 13 Originally proposed structure for kinamycin C 14 structure an /V-cyanoindo-loquinone synthesized by Dmitrienko and coworkers 15 originally proposed structure for the metabolite prekinamycin... 

The matter was settled in 1994 in back-to-back communications by Gould [12] and Dmitrienko [13]. Gould showed that treatment of natural prekinamycin with dirhodium tetraacetate in methanol yielded the fluorene 16 (Scheme 3.1). The vinyl proton formed in this reaction (H-l) provided a critical spectroscopic handle and allowed unambiguous determination of the carbocyclic structure, excluding the presence of an indole heterocycle. In parallel, his research group obtained a high-quality crystal structure of a kinamycin derivative. The refined data set was shown to best accommodate a diazo rather than cyanamide (or isonitrile) function. 

Feldman and Eastman have suggested that the kinamycins may by reductively activated to form reactive vinyl radical (25) and orf/to-quinone methide (26) intermediates (Scheme 3.2c) [16]. The authors provided convincing evidence that the alkenyl radical 25 is generated when the model substrate dimethyl prekinamycin (24) is exposed to reducing conditions (tri-n-butyltin hydride, AIBN). Products that may arise from addition of this radical (25) to aromatic solvents (benzene, anisole, and benzonitrile) were isolated. The ort/io-quinone methide 26 was also formed,... 

Gould and coworkers have extensively studied the biosyntheses of the kinamycins, and this work was recently reviewed [5a]. Feeding studies established that the carbo-cyclic skeletons of the kinamycins are constructed from 10 equivalents of 5-acetyl coenzyme A, and the pathway shown in Scheme 3.4 was proposed. The pathway begins with formation of the natural product dehydrorabelomycin (29). A novel ring contraction then occurs to form the cyclopentadienone 30. Feeding studies with /V-15-ammonium sulfate established that the diazo functional group is then installed... 

Prior to our work in this area, three groups reported syntheses of various kinamycins. These are presented in chronological order below. A large number of synthetic studies toward the lomaiviticins have been reported, although these are not discussed here [23]. 

Porco and Lei reported the first synthesis of (—)-kinamycin C (3) [24]. Their route constitutes the first completed pathway to any of the kinamycins and provides several powerful insights into the strategies that are viable for construction of... 

Porco s route to (—)-kinamycin C (3) began with 2,5-dihydroxybenzaldehyde (38), which was elaborated to the enone 35 by the sequence shown in Scheme 3.6. Regioselective bromination [25] followed by methylation and reduction of the aldehyde function afforded the primary alcohol 39. The alcohol 39 was dearomatized by treatment with bis(acetoxy)iodobenzene, to afford the quinone monoketal 41. Transketalization with 1,3-propanediol followed by silylation of the primary alcohol generated the silyl ether 42 in 72 % yield over three steps. 

Porco s pathway to complete the synthesis of (- )-kinamycin C (3) is shown in Scheme 3.8. The arylstannane 34 and the a-bromoenone 35 were efficiently coupled by a Stille reaction using tris(dibenzylideneacetone)dipalladium and triphenylarsine... 

---