Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/22106
Title: Synthetic studies towards total synthesis of bielschowskysin
Authors: GOVINDAN SUBRAMANIAN
Keywords: bielschowskysin, synthesis, right fragment, left fragment, diterpene, macrolide
Issue Date: 16-Aug-2010
Citation: GOVINDAN SUBRAMANIAN (2010-08-16). Synthetic studies towards total synthesis of bielschowskysin. ScholarBank@NUS Repository.
Abstract: This thesis presents the synthetic studies towards the natural product bielschowskysin. Bielschowskysin, a new diterpene isolated from the Caribbean gorgonian octocoral Pseudopterogorgia kallos, possesses a fascinating tricyclic [5-4-9] ring architecture, unprecedented in the realms of natural products. This diterpene exhibits antiplasmodial activity against several drug-resistant strains of the malaria-causing protozoan parasite, Plasmodium falciparum, at IC50 of 10 ?g/mL. Our initial studies based on the biomimetic inspired model study to fuse the tricyclic core of bielschowskysin. From malic acid, the allene appended butenolide was prepared in 13 steps and [2+2] cycloaddition was carried out under the UV lamps to form the tricyclic core of bielschowskysin. After making the tricyclic core, retrosynthetic analysis of key intermediate leads to left and right fragment. Left fragment, seleno-lactone was prepared in 15 steps from R-glyceraldehyde. SAE and LAH reduction was employed to fix the quartenary chiral centre. In order to form the lactone, Wittig homologation with methyl (triphenylphosphoranylidene) acetate followed by hydrogenation and TBAF mediated cyclisation was performed. Regarding right fragment, our initial approaches were unsuccessful due to scalability and decomposition. Thus tartaric acid was converted into 5-membered unsaturated lactone in 7 steps. Michael addition of diethyl malonate and decarboxylation was key step to generate the C1 chiral centre. Homologation with acetylene unit, protection and aldehyde formation will then complete the synthesis of right fragment. But in our hands, we were able to complete the synthesis at the aldehyde stage and last step, the final protecting group at the lactol needs to be revised. Meanwhile, right fragment was successfully prepared from D-glucose. Thus, C1 chiral centre was constructed via hydrogenation of the trans-unsaturated ester followed by homologation and aldehyde formation with DIBAL-H. Initially, we relied on the Baylis-Hillman reaction to couple the two fragments. But in our hands, we were able to achieve the product in lesser yields. Finally, we were able to couple the two fragments using Pattenden?s alkylation methods. The future plans will be the protection of the alcohol, deprotection of the silyl group followed by oxidation would afford the precursor for macrocyclisation. At this stage, NHK protocol would be useful to form the macrocyclic propargylic alcohol. The one step procedure of Myer?s stereospecific allene synthesis and the resultant allene butenolide would be subjected for novel [2+2] cycloaddition to form the cyclobutane ring. Remaining steps would be the cationic cyclisation with the Lewis acid and adjustment of the protecting groups to achieve the total synthesis of bielschowskysin.
URI: http://scholarbank.nus.edu.sg/handle/10635/22106
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