Combretastatin synthesis

Brown T, Holt H Jr, Lee M (2006) Synthesis of Biologically Active Heterocyclic StUbene and Chalcone Analogs of Combretastatin. 2 1-51... 

The aforementioned section described the synthesis of a wide range of biologically important heterocyclic derivatives of combretastatin. The next part of this chapter will focus on the synthesis of heterocyclic chalcone derivatives. 

The synthesis of biologically important heterocyclic stilbene and chalcone derivatives of combretastatins has been discussed. Combretastatins have been shown to be inhibitors of tubulin polymerization. In many cases the compounds described in this chapter were included because of an interesting synthesis or structure, although limited biological data were found. It is the author s opinion that a great number of the compounds contained within this review are worthy of further investigation as potential tubulin binders. 

Pettit GR, Temple C, Narayanan VL, Varma R, Simpson MJ, Boyd MR, Rener GA, Bansal N. (1995) Antineoplastic agents 322. Synthesis of combretastatin A-4 prodrugs. Anticancer Drug Des 10 299-309. 

Bui VP, Hudlicky T, Hansen TV, Stenstrom Y (2002) Direct Biooxidation of Arenes to Corresponding Catechols with E. coll JM109 (pDTG602). Application to Synthesis of Combretastatins A-l and B-l. Tetrahedron Lett 43 2839... 

E. coli JM109(pDTG602). Application to synthesis of combretastatins A-1 and B-1. Tetrahedron Letters, 43, 2839-2841. 

The combretastatins are a group of antimitotic agents isolated from the bark of the South African tree Combretum caffrum. A novel and highly stereoselective total synthesis of both the c/s and trans isomers of combretastatin A-4 was developed by J.A. Hadfield and co-workers.The (Z)-stereoisomer was prepared using the Perkin reaction as the key step in which 3,4,5-trimethoxyphenylacetic acid and 3-hydroxy-4-methoxbenzaldehyde was heated with triethylamine and acetic anhydride at reflux for several hours. The a,p-unsaturated acid was isolated in good yield after acidification and had the expected ( ) stereochemistry. Decarboxylation of this acid was effected by heating it with copper powder in quinoline to afford the natural product (Z)-combretastatin A-4. 

A different approach consists of a two-steps stereoselective synthesis of Combretastatin A-4, based on the Perkin condensation of 3,4,5-trimethoxy phenyl acetic acid and 3-hydroxy-4-methoxy benzaldehyde, followed by decarboxylation of the cirmamic acid intermediate using copper and quinoline [11] (Schema 4). 

Stilbenophanes. During a research directed at the synthesis and evaluation of new cytotoxic agents based on natural products, several macrocyclic derivatives of combretastatin A-4 and related compounds were investigated. Fig. (5) [22]. These compounds are poly oxygenated stilbenophanes macrocyclized through a polymethylene(polyether) chain sharing in part the structure of crownophanes. 

Scheme 7. Synthesis of combretastatin A-4 using the palladium-catalyzed Suzuki cross-coupling...

The synthesis of many combretastatin analogues (e.g., 18a, 18b, and 18c) clearly illustrates the power of a relatively simple natural product structure to spawn a prolific output of medicinal and combinatorial chem-... 

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