9-Diazofluorene

Huisgen et al. (1960, 1977 b) found that (i )-4-chlorobenzenediazocyanide reacts with 9-diazofluorene to give the azomethine imine 6.38 in 93 % yield (Scheme 6-28). Huisgen et al. interpret this reaction in terms of the electrophilicity of the diazocyanide at its a-nitrogen atom (not 0 ) and the nucleophilic character of 9-diazofluorene, as shown in the bipolar mesomeric structure 6.37. 

Final resolution of these problems, particularly the complications from multiple matrix sites, came from investigations using spectroscopic methods with higher time resolution, viz. laser flash photolysis. Short laser pulse irradiation of diazofluorene (36) in cold organic glasses produced the corresponding fluorenylidene (37), which could be detected by UV/VIS spectroscopy. Now, in contrast to the results from EPR spectroscopy, single exponential decays of the carbene could be observed in matrices... 

Laser flash irradiation of diazofluorene in perdeuterated matrices, in contrast, gave severely nonexponential decay of the carbene spectra. Analyses of the products formed in the low-temperature matrices showed that, as with the EPR studies, the carbene was not undergoing D-abstraction. LFP of the diazo compound 36 in CFCl3-CF2BrCF2Br glasses gave linear first-order decays, and linear Arrhenius plots, which were attributed to classical Cl and Br abstractions. 

Recently, [2+3] cycloaddition reaction of 2-acetyl-[l,2,3]diazaphosphole (6) with 9-diazofluorenes (96) has been reported [105, 106], From the reaction in cyclohexane at rt, bicyclic phosphirane 97 was obtained as a result of the loss of nitrogen from the initial cycloadduct (Scheme 30). The cycloadduct, 3-spiro substituted 3H-[l,2,4]diazaphospholo-fused [l,2,3]diazaphosphole (98) could be isolated in good yield at room temperature in one case (R=/Bu) its stability was assigned to the presence of bulky fert-butyl group at 7-position. Use of polar solvent like dichloromethane led to the cyclic trimeric compound 99 (Scheme 30). 

Scheme 30 [3+2] Cycloaddition of 2-acetyl-[l,2,3]diazaphosphole with 9-diazofluorene...

Porco s synthesis of ( )-kinamycin C (3) constituted the first reported route to any of the diazofluorene antitumor antibiotics. This synthesis invokes several powerful transformations, including a modified Baylis-Hillman reaction, a catalyst-controlled asymmetric nucleophilic epoxidation, and a regioselective epoxide opening to establish the D-ring of the kinamycins. The tetracyclic skeleton was constructed by an... 

Our retrosynthesis of (—)-kinamycin F (6) is shown in Scheme 3.20 [45]. It was envisioned that (—)-kinamycin F (6) could be prepared from the protected diazofluorene 114 by conversion of the ketone function of 114 to a trans-], 2-diol, followed by deprotection of the acetonide and methoxymethyl ether protecting groups. The diazofluorene 114 was envisioned to arise from diazo transfer to the hydroxyfulvene 115. The cyclopentadiene substructure of 115 was deconstructed by a two-step annulation sequence, to provide the bromoquinone 116 and the p-trimethylsilylmethyl unsaturated ketone 117. The latter two intermediates were prepared from juglone (118) and the silyl ether 119, respectively. 

To complete the synthesis of the diazofluorene, the cyclization product 126 is treated with diisopropylethylamine and triflyl azide [50], to afford the diazofluorene 127 in 81 % yield. Under these conditions, the hydroxyfulvene is likely deprotonated to generate a cyclopentadienyl anion. Attack of this anion on the trifyl azide reagent... 

With an effective strategy for construction of the diazofluorene established, we set out to prepare the coupling partners required for synthesis of (—)-kinamycin F (6). The synthesis of the enone 117 began with meta-cresol (128, Scheme 3.23). Silylation formed the silyl ether 119 in nearly quantitative yield. Birch reduction of the silyl ether 119 formed the cyclohexadiene derivative 129 in excellent yield. Asymmetric dihydroxylation [52] of 129 occurred regioselectively to afford the... 

Our studies of ( )-kinamycin F (6) motivated the development of a three-step sequence for synthesis of the diazofluorene function, comprising fluoride-mediated coupling, palladium-mediated cyclization, and diazo transfer. Our synthesis also features the strategic use of substrate bias to establish the trans- 1,2-diol of the target. 

In the reaction of diazofluorene with PTAD the dipolar intermediate (87) is isolable.136 Collapse to a five-membered ring is prevented by the steric constraints of the cyclic system, and although three-membered ring formation is possible, dimerization is the only process observed on heating. However, the dipole reacts with a variety of dipolarophiles (a=b, PhN=CO, Me02CC CC02Me, etc.) to give the expected adducts as shown in Scheme 11. 

The presence of 9-diazofluorene groups in kinamycin antitumor natural products would lead one to think of an active role for the diazo group. The hypothesis may be substantiated by the fact that one of the precursors in kinamycin biosynthesis, kinafluorenone 10 [44], which lacks the diazo moiety, shows no antibiotic activity against B. subtilis ATCC 6633, known to be very sensitive to the kinamycins. However, prekinamycin (9) [49], which is similar to kinafluorenone but retains the diazo group, shows activity to-... 

The cation 18 did not show any DNA cleavage, due probably to its inherent stability (18 would be more stable than a benzyl cation [66], relatively stable ions that do not alkylate the heterocyclic bases in DNA). The 9-diazofluorene 19 would not undergo reduction like the corresponding diazonium salts (17) because of the presence of a negative charge on the fluorenyl carbon. 

The isolation of diazobenzo[fr ]fluorenes as stable antitumor natural products raises several questions about their mode of action. The inability to cleave DNA by diazotization of 9-aminofluorene may imply that if the diazo functionality is involved in the mode of interaction of kinamycins with DNA, its conversion to diazonium and the ensuing reduction may seem to be of negligible importance. An additional possibility, which will be discussed later, is that 9-diazofluorene may not be the ideal model for these natural products. In exploring DNA cleavage as a possible route to the kinamycins role as a stable antitumor agent, which may supplement their speculative and as yet unconfirmed role as alkylating molecules [67], this early model seemed to suggest that the well-established activation of diazonium may not be relevant. 

For the generation of DNA-cleaving moieties from 9-diazofluorenes two other mechanisms, which may not be relevant under physiological conditions, can be envisioned ... 

The synthesis of 9-diazofluorene 19 is easily accomplished from commercially available 9-fluorenonehydrazone (HgO, Et20 followed by KOH in EtOH yield = 98%) [72], Diazo compounds on photolytic decomposition tend to generate carbenes [73,74], Fluorenylidene, generated by the photolysis of 9-diazofluorene adds to olefins with negligible amounts of hydrogen abstraction [75,76]. Copper and its salts, however, have been shown to lead to... 

The role of different ring systems present in kinamycin has also been investigated. The /3-naphthylphenyldiazomethane (29), readily available from /3-naphthylphenylketonc [81] 28, also showed DNA cleavage under conditions identical to 9-diazofluorene (Fig. 23). Additionally, consistent with results with 9-diazoniumfluorene, no DNA cleavage was observed upon treatment of /3-naphthylphenyldiazomclhane with buffered acid. 

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