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Enantioselective Total Synthesis of (−)‐Candelalides A, B and C: Potential Kv1.3 Blocking Immunosuppressive Agents
Author(s) -
Oguchi Takamasa,
Watanabe Kazuhiro,
Ohkubo Kôichi,
Abe Hideki,
Katoh Tadashi
Publication year - 2009
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200802122
Subject(s) - stereocenter , stereochemistry , total synthesis , chemistry , moiety , tetrahydropyran , decalin , ring (chemistry) , enantioselective synthesis , epoxide , convergent synthesis , organic chemistry , catalysis
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.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 C16C3′ 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.