Synthetic studies towards the antimalarial fungal polyketide Codinaeopsin via an intramolecular Diels-Alder reaction and Efficient deprotection of benzyl ethers and aryl acetals using triphenylphosphine hydrobromide

• Main Authors: Mani Ramanathan, 馬瑞門
• Other Authors: Duen-Ren Hou
• Format: Others
• Language: en_US
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/pbp37w

博士 === 國立中央大學 === 化學學系 === 101 === Codinaeopsin (1) a new tryptophan derived polyketide was isolated in 2008 from an endophytic fungus collected in Costa Rica (Fig.1).1 The unique chemical structure of this target includes a densely substituted trans decalin carbocycle which is connected to an indole fragment through an unusual heterocyclic unit. Among the natural products found in this family, Codinaeopsin has the most substituted decalin unit with four methyl and a 1-methyl-propenyl groups attached to it. The unusual α-acyl-γ-hydroxy lactam (modified tetramic acid cores) with oxidized Cα position of tryptophan are often present in natural products from fungal sources. Codinaeopsin is having promising activity against plasmodium falciparum, the causative agent of most lethal form of malaria (IC50=2.33μg/mL) or 4.7μM. The structural complexity, together with the extraordinary biological profile, prompted us to choose this natural product as an ideal synthetic target. The synthetic plan relied on a late stage Lewis acid mediated intramolecular Diels-Alder (IMDA) reaction of E,E,E-triene with a suitable dienophile to yield the appropriately decorated decalin skeleton.The synthetic approach described here shares a number of key features, including rhodium catalyzed hydrogenation of commercially available mesitol, E-selective Horner-Wittig olefination protocol to construct the trisubstituted alkene and one pot TPAP oxidation/Wittig olefination of the sensitive polyene substrate. Syntheses of racemic exo and endo decalin cores of Codinaeopsin are accomplished via intramolecular Diels-Alder reaction under thermal and Lewis acidic conditions. The relative stereochemistry of these IMDA adducts were confirmed by NOE and single crystal X-ray techniques. In chapter 2, Triphenylphosphine hydrobromide is reported to cleave the benzyl ethers derived from 1o, 2o, alkyl and aryl alcohols to the corresponding alcohols and benzyltriphenylphosphonium bromide in good yields. The reaction is optimized both under microwave and conventional heating conditions using stoichiometric amount of triphenylphosphine hydrobromide. The mechanism of this reaction is also discussed. In chapter 3, Triphenylphosphine hydrobromide is reported to deprotect the aryl acetals and ketals to give the corresponding carbonyl compounds and alkyl phosphonium salts under convenient conditions (50 oC, microwave, 5 min. yields up to 90%). The reaction is compatible with acid sensitive functional groups and the mechanism is discussed through the substrates surveyed.