Synthesis of the CD-ring of the anticancer agent streptonigrin: studies of aryl–aryl coupling methodologies

• Published in: Tetrahedron Vol. 62; no. 29; pp. 6945 - 6954
• Main Authors: McElroy, William T., DeShong, Philip
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 17.07.2006; Elsevier
• Subjects: Chemistry; Chemistry, Organic; Cross-coupling; Organosiloxanes; Palladium-catalyzed; Physical Sciences; Science & Technology; Streptonigrin; Palladium-catalyzed; Cross-coupling; Organosiloxanes; Streptonigrin; SYSTEM; METALATION; ACID; REAGENTS; ANALOGS; streptonigrin; HYPERVALENT SILOXANE DERIVATIVES; organosiloxanes; DIRECTED ORTHOMETALATION; palladium-catalyzed; CONNECTION; cross-coupling; STILLE; CONVERGENT SYNTHESIS
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2006.04.074

A series of functionalized 4-bromopyridines, representing the C-ring of the anticancer agent streptonigrin have been prepared and their abilities to undergo Pd-catalyzed cross-coupling with streptonigrin D-ring siloxanes were evaluated. The coupling reaction was generally tolerant to the preparation of hindered CD biaryls; however, the electronic effects of both partners play a pivotal role in the success of the coupling process. Analogs of the CD biaryl were prepared by coupling of aryl siloxane derivatives (D-ring component) with highly functionalized 4-bromopyridines (C-ring); however, the CD biaryl of the natural product could not be prepared in high yield by siloxane coupling due to the facile formation of reduced pyridine under the coupling conditions. Alternatively, the fully functionalized CD biaryl of streptonigrin was prepared using a Suzuki coupling of appropriately functionalized C-ring bromide and D-ring aryl boronic acid. The described approach is highly convergent and readily amenable to the synthesis of analogs. [Display omitted]