Synthesis of — -Kinamycin

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 

In the next step of the sequence, the authors sought to introduce a hydroxy-methylene substituent at the unsubstituted 7-position of the enone. This bond construction can be carried out by conducting a Baylis-Hillman reaction with formaldehyde. In this instance, the authors used a modification of the Baylis-Hillman reaction which involves the use of a Lewis acid to activate the enone [26]. Under these conditions, the enone 42 is treated with excess paraformaldehyde in the presence of triethylphosphine (1 equiv), lanthanum triflate (5 mol%), and triethanolamine (50 mol%). It is proposed that the lanthanum triflate forms a complex with the triethanolamine. This complex is able to activate the enone toward 1,4-addition of the nucleophilic catalysts (here, triethylphosphine). In the absence of triethanolamine, the Lewis acid catalyst undergoes nonproductive complexation with the nucleophilic catalyst, leading to diminution of catalysis. Under these conditions, the hydroxymethylene derivative 37 was formed in 70 % yield. In the next step of the sequence, the authors sought to conduct a stereoselective epoxidation of the allylic 

These epoxide-opening conditions were originally developed by Sharpless and coworkers for the regiocontrolled opening of 2,3-epoxy alcohols [30]. It has been proposed that ligand exchange of the substrate with isopropoxide forms a covalently bound substrate-titanium complex (Chart 3.3). Nucleophilic attack on this complex at the 3-position is favored over attack at the 2-position. In the case of 49, 

Chart 3.3 Proposed substrate-reagent assembly for the regioselective titanium-mediated opening of epoxyalcohols 

The methoxymethyl ether protecting groups of 33 were then cleaved using triphenylphosphine and carbon tetrabromide. The resulting hydroquinone function was oxidized by palladium on carbon under an atmosphere of air to afford the quinone 52 (70 %). A two-step procedure was implemented to install the diazo function. First, the ketone function of 52 was condensed with N,N -bis( tert-butyldimethylsilyl)hydrazine in the presence of scandium triflate, which formed the Af-tert-butyldimethylsilyl hydrazone 53. The hydrazone (53) was then oxidized using difluoroiodobenzene to afford kinamycin C (3) in 35 % yield. 

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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... 

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... 

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... 

Scheme 5.4.17 Stille coupling in the synthesis of kinamycin C (MOM methoxymethyl)...

Scheme 26 Porco s synthesis of kinamycin C featuring the Myers methodology...

The replacement of copper by other metals in the Ullmann reaction usually results in milder and more efficient pathways. The common use of Pd in conjunction with copper in the Ullmann coupling can be seen in many examples. Nicolaou et al. utilized such modifications in their total synthesis of kinamycins C, F, and J. Bromide 9 underwent coupling with iodide 10 to give aldehyde 11 in a satisfactory 83% yield. 

Ishikawa s synthesis of ( )-0-methylkinamycin C (54) represents a distinct approach to the kinamycins that hinges on a key Diels-Alder reaction to establish the tetracyclic skeleton of the natural products. Additional key steps in the sequence include a substrate-directed dihydroxylation, substrate-directed reduction, and spontaneous epimerization of an a-hydroxyketone intermediate. 

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. 

Scheme 20.52 Synthesis of the benzo[f>]fluorene core of the kinamycins.

The enantioselective total synthesis of the diazobenzofiuorene antibiotic (-)-kinamycin C (91) via the coupling of bromoenone 88 with naphthylstannane 89, has been reported by Porco and coworkers... 

Intramolecular or partially intramolecular cycloaddition reactions are extremely useful tools in the synthesis of polycyclic molecules, since they can allow the construction of several rings in a single step. Preliminary studies indicate that this general principle also holds for partially intramolecular versions of the palladium-catalyzed cocycloaddition of arynes and alkynes. For example, benzo[fc]fluorenones 144a-d, which constitute the polycyclic skeleton of the kinamycin family of antitumour antibiotics, can be obtained by [2+2+2] cy-... 

Methods for the synthesis of tetracyclic benzocarbazoles and benzo-b-carbazoloquinone have become relevant to alkaloidal synthesis due to the progress in the chemistry of the kinamycin group antibiotics. 

Porco s 2006 approach to (-)-kinamycin C utilized the Myers s procedures in the final stages of the synthesis, both for A -TBS-hydrazone installation as well as oxidative unveiling of the stabilized diazoalkane [166] (Scheme 26). An alternate strategy reported by the Nicoloau group involved merging advanced intermediate 62 with tosylhydrazine under acidic conditions [167]. Subsequent oxidation by CAN furnished kinamycin C after desilylation (7). Further manipulation of the acetoxy functions allowed for flexible access to kinamycins F and J by this route. In more recent work, Herzon and coworkers accomplished diazotization within the... 

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