Development of a convergent entry to the diazofluorene antitumor antibiotics: enantioselective synthesis of kinamycin F.
We describe a 12-step enantioselective synthetic route to the complex anticancer antimicrobial agent kinamycin F (3). Key to the success of the route was the development of a three-step sequence for construction of the diazonapthoquinone (diazofluorene, blue in structure 3) function of the natural product. This sequence comprises fluoride-mediated coupling of a beta-(trimethylsilylmethyl)-cyclohexenone and halonapthoquinone, palladium-mediated cyclization to construct the tetracyclic scaffold of the natural product, and mild diazo-transfer to a complex cyclopentadiene to introduce the diazo function. Ortho-quinone methide intermediates, formed by reduction and loss of dinitrogen from 3, have been postulated to form in vivo, and our approach provides a straightforward synthetic pathway to such compounds.
Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA.
Christina M
CM
Woo
Liang
L
Lu
Shivajirao L
SL
Gholap
Devin R
DR
Smith
Seth B
SB
Herzon
D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis*; D011809:Quinones / Q000138:chemical synthesis; D013237:Stereoisomerism; D000095602:Angucyclines and Angucyclinones
D000903:Antibiotics, Antineoplastic; D011809:Quinones; C059021:kinamycin F; D000095602:Angucyclines and Angucyclinones