Synthetic Approaches to the Anticancer Agent Streptonigrin
McElroy, William Thomas
MetadataShow full item record
Pd-catalyzed coupling reactions have a central place in synthetic chemistry. In particular, studies from the DeShong laboratory have demonstrated that aryltrialkoxysilanes, in the presence of Pd(0) and fluoride, are capable of aryl group transfer to a range of aryl halides and triflates and allylic benzoates. The cross-coupling reaction represents an ideal opportunity to construct the tetracyclic core of the anticancer agent streptonigrin. This strategy is highly convergent and readily amenable to the synthesis of analogues, and as such would constitute an improvement over previous total syntheses of this natural product. A series of 4-bromopyridines (streptonigrin C ring precursors) were prepared, and their couplings with various arylsiloxanes (streptonigrin D ring precursors) examined. The coupling reaction generally tolerated the preparation of sterically demanding biaryls. The coupling of the 3-nitro-4-bromopyridine derivative was problematic, as dehalogenation was found to compete with arylation. The use of nitro group surrogates and a variety of catalyst systems offered no improvement. These results indicated the coupling reaction is highly sensitive to the electronic environment of bromopyridine. The analogous biaryl coupling reaction employing an organoboron species was more effective and allowed for additional streptonigrin CD analogues to be prepared. This reaction was found to be highly sensitive to the reaction conditions. A fully functionalized C ring precursor (prepared in 10 synthetic operations) underwent Suzuki coupling with a fully functionalized D ring precursor (prepared in 3 steps) to give an adduct possessing the streptonigrin CD skeleton. This species was elaborated to a precursor suitable for appendage to the AB ring component. A streptonigrin A ring derivative has been prepared in 6 steps from resorcinol. The functionalities present in this species are compatible with several possible strategies to prepare the ABCD framework of the natural product. Results of a model study indicate that the coupling of an A ring aryl siloxane with the CD fragment (possessing a three-carbon fragment in the form of an allylic benzoate) is viable approach to the natural product. Further studies are warranted to evaluate the requisite annulation to prepare the B ring.