P-23 海洋産環状デプシペプチド・ハリペプチン類の全合成研究(ポスター発表の部)
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Halipeptins A (1) and B (2) are novel 16-membered cyclic depsipeptide isolated from the marine sponge Haliclona sp. by Gomez-Paloma and co-workers in 2001. Halipeptin A (1) is known to show strong anti-inflammatory activity in vivo. In addition to their potent biological activities, their intriguing structures containing (2S,3S)-N-methyl-5-hydroxyisoleucine (N-MeOHIle), methylthiazoline unit and novel highly substituted decanoic acid derivatives called HTMMD/HTMHD prompted us to initiate efforts directed towards the total synthesis. Among these fragments, we synthesized N-MeOHIle via installation of a double bond to bicyclic lactam (3) using N-tert-butyl phenylsulfinimidoyl chloride (4), highly exo-selective Michael reaction with lithium dimethylcuprate, Ru-catalyzed oxidation, and subsequent deprotection as the key steps. (3S,4R,7S)-HTMMD was retrosynthetically divided into the C1-C5 and the C6-C10 fragments. The former was synthesized via asymmetric Aldol reaction using chiral oxazaborolidinone reagent (17) and the latter was synthesized via proline-catalyzed α-oxidation. The both fragments were coupled by Julia reaction to give the (3S,4R,7S)-HTMMD (32) in 63% to which the introduction of (S)-alanine residue was attained by the acid chloride method using AgCN. The methylthiazoline core could be constructed by the method using triphenylphosphine oxide and triflic anhydride. The condensation of the highly hindered methylthiazoline (46) and N-MeOHIle residue (47) smoothly proceeded with BMTB reagent in 94% yield. The final coupling of the two subunits was achieved by the acid chloride method. Deprotection and macrocyclization of 52 toward the total synthesis of halipeptin A (1) is actively underway.
- 2005-09-15
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