Enantioselective Total Synthesis of (−)‐Candelalides A, B and C: Potential Kv1.3 Blocking Immunosuppressive Agents

Abstract

Abstract Potential immunosuppressive agents : Candelalides A, B and C (see figure), novel blockers of the voltage‐gated potassium channel Kv1.3, have been efficiently synthesized for the first time in a convergent and unified manner starting from (+)‐5‐methyl‐Wieland–Miescher ketone. The method explored has potential for preparing various types of candelalide analogues for the structure–activity relationship studies. magnified image Novel Kv1.3 blocking immunosuppressants, (−)‐candelalides A, B and C, were efficiently synthesized for the first time in a convergent and unified manner starting from (+)‐5‐methyl‐Wieland–Miescher ketone. The synthetic method involved the following key steps: i) a strategic [2,3]‐Wittig rearrangement of a stannylmethyl ether to install the stereogenic center at C9 and the exo ‐methylene function at C8 present in the decalin portion; ii) a straightforward coupling of a trans ‐decalin portion (BC ring) and a γ‐pyrone moiety through the C16C3′ bond to assemble the requisite carbon framework; and iii) a construction of a characteristic di or tetrahydropyran ring (A ring) by internal nucleophilic ring closure of a hydroxy aldehyde or a hydroxy epoxide. The present total synthesis has fully established the absolute configuration of these natural products.