Studies toward the synthesis and structural elucidation of chamuvarinin

Polyketides--Synthesis;Plant metabolites;Natural products--Synthesis

Vanga, Raghava Reddy ; Florence, Gordon John ; Florence, Gordon John

University:University of St Andrews

Department:Chemistry (School of)

关键词: Polyketides--Synthesis;    Plant metabolites;    Natural products--Synthesis;   

Others  :  https://research-repository.st-andrews.ac.uk/bitstream/handle/10023/953/RaghavaVangaPhDThesis.pdf?sequence=3&isAllowed=y

来源: DR-NTU

【 摘 要 】

Chamuvarinin (22) is a unique annoanceaeous acetogenin isolated from the roots ofSenegalese medicinal plant Uvaria chamae by Laurens and co-workers in 2004. Itdisplays highly potent cytotoxicity towards the cervical cancer cell lines (KB 3-1, IC₅₀=0.8 nM). Structurally, chamuvarinin is the first reported acetogenin to contain anadjacently linked bis-THF-THP ring system spanning the C15-C28 carbon backbone.However, initial efforts to assign the relative and absolute configuration within thisstereochemical array, on the basis of ¹H and ¹³C NMR analysis, provided only partialinformation pertaining to the relative configuration of C15-C19 region. As aconsequence, 32 diastereomeric structural possibilities exist for the highly unusualstructure of chamuvarinin; an unrealistic target for total synthesis. The synthesis of thecentral core tricyclic (BCD) intermediate represents the most challenging aspect in theentire synthesis, which in turn will aid ultimate structural proof.At the outset of the project the stereochemical configuration of C15-C28 (BCD) ofchamuvarinin was uncertain and a library approach was proposed to enable structureelucidation (Scheme A-1). Chapter 2 and Chapter 3 detail the synthesis of possiblediastereomers of the C9-C21 (51) and C22-C34 fragments (52). Chapter 4 details theintial strategy to couple the key diastereomeric fragments in a series of model studies.Chapter 5 describes the successful coupling strategy via an revised synthetic approach toreach the advanced C9-C34 intermediate 251 (Scheme A-2).