Enantioselective total synthesis of (-)-candelalides A, B and C: potential Kv1.3 blocking immunosuppressive agents.
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 gamma-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.
Oguchi
Takamasa
T
Laboratory of Synthetic Medicinal Chemistry, Department of Chemical Pharmaceutical Science, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, 981-8558, Japan.
Watanabe
Kazuhiro
K
Ohkubo
Kôichi
K
Abe
Hideki
H
Katoh
Tadashi
T
D001688:Biological Products / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004224:Diterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001688:Biological Products; D004224:Diterpenes; D007166:Immunosuppressive Agents; D051664:Kv1.3 Potassium Channel; D011753:Pyrones; C431986:candelalide A; C431985:candelalide B; C431984:candelalide C