RESUMO
The kedarcidin chromophore is a formidible target for total synthesis. Herein, we describe a viable synthesis of this highly unstable natural product. This entailed the early introduction and gram-scale synthesis of 2-deoxysugar conjugates of both L-mycarose and L-kedarosamine. Key advances include: (1) stereoselective allenylzinc keto-addition to form an epoxyalkyne; (2) α-selective glycosylations with 2-deoxy thioglycosides (AgPF6/DTBMP) and Schmidt donors (TiCl4); (3) Mitsunobu aryl etherification to install a hindered 1,2-cis-configuration; (4) atropselective and convergent Sonogashira-Shiina cyclization sequence; (5) Ohfune-based amidation protocol for naphthoic acid; (6) Ce(III)-mediated nine-membered enediyne cyclization and ester/mesylate derivatisation; (7) SmI2-based reductive olefination and global HF-deprotection end-game. The longest linear sequence from gram-scale intermediates is 17-steps, and HRMS data of the synthetic natural product was obtained for the first time.
Assuntos
Cicloparafinas/síntese química , Enedi-Inos/síntese química , Naftalenos/síntese química , Antineoplásicos/síntese química , Antineoplásicos/química , Cicloparafinas/química , Enedi-Inos/química , Estrutura Molecular , Naftalenos/químicaAssuntos
Antibióticos Antineoplásicos/síntese química , Cicloparafinas/síntese química , Enedi-Inos/síntese química , Naftalenos/síntese química , Antibióticos Antineoplásicos/química , Ciclização , Cicloparafinas/química , Enedi-Inos/química , Espectroscopia de Ressonância Magnética , Naftalenos/químicaRESUMO
Formation of an epoxide before 9-membered ring cyclization and SmI2 mediated reductive olefination in the presence of the epoxide successfully produced the epoxybicyclo[7.3.0]dodecadienediyne core of the kedarcidin chromophore.