ABSTRACT
The synthesis of 5-epi-hydroxycornexistin (44), a diastereoisomer of the herbicidal natural product hydroxycornexistin (2) has been completed. Palladium mediated sp(2)-sp(3) coupling of the stannane 25 and the chloride 31 and ring-closing metathesis of the resulting diene 32 has been used to construct the tricyclic lactone 34a, which possesses the nine-membered carbocyclic core found in the natural product, in good yield. The synthesis of 5-epi-hydroxycornexistin (44) has established the feasibility of using a furan as precursor for the cyclic anhydride unit present in the natural product and has demonstrated the viability of other late-stage transformations that will be used to prepare hydroxycornexistin (2).
Subject(s)
Furans/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemical synthesis , Lactones/chemical synthesis , Alkenes/chemistry , Crystallography, X-Ray , Furans/chemistry , Heterocyclic Compounds, 3-Ring/chemistry , Lactones/chemistry , Nitrobenzoates/chemistry , Silicon/chemistry , StereoisomerismABSTRACT
An advanced intermediate in the synthesis of the phytotoxins cornexistin and hydroxycornexistin has been synthesized. Sequential palladium-mediated sp(2)-sp(3) fragment coupling and ring-closing diene metathesis have been used to construct the nine-membered carbocyclic core found in the natural products. [reaction--see text]
Subject(s)
Furans/chemistry , Furans/chemical synthesis , Biological Factors/chemical synthesis , Biological Factors/chemistry , Fungi/chemistry , Herbicides/chemical synthesis , Herbicides/chemistry , Models, Molecular , Molecular Structure , Palladium/chemistryABSTRACT
On the basis of our understanding on the binding interactions of the benzothiophene template within the FIXa active site by X-ray crystallography and molecular modeling studies, we developed our SAR strategy by targeting the 4-position of the template to access the S1 beta and S2-S4 sites. A number of highly selective and potent factor Xa (FXa) and FIXa inhibitors were identified by simple switch of functional groups with conformational changes toward the S2-S4 sites.