TOTAL SYNTHESIS OF A CIS-SYN 2-CARBOMETHOXYPSORALEN FURAN-SIDE THYMIDINE MONOADDUCT

The first total chemical synthesis of a cis-syn furan-side photoproduc t between a psoralen derivative and thymidine is described. The key st ep in the synthesis was an intramolecular [2 + 2] photocycloaddition, which directed the stereochemical course of the reaction to afford a p roduct equivalent to that formed when a psoralen molecule is allowed t o react at a 5/-TpA-3' site in DNA. A model system consisting of a sim ple benzofuranyl acid tethered to the 5' hydroxyl of thymidine showed that it was possible to bias the stereochemical outcome of the photoch emical reaction in favor of the desired cis-syn product. Further refin ement of the model system allowed for the elaboration of a benzofuran- thymidine photoproduct into a cis-syn 2-carbomethoxypsoralen furan-sid e thymidine monoadduct. The stereochemistry of all photoproducts as es tablished by NMR and CD spectroscopy indicated that the cycloadditions occurred on the 3' face of thymine, the equivalent of a psoralen mono adduct in a 5'-TpA-3' site in DNA. Previously, the inability to progra m the sequence context of psoralen-DNA adducts has constrained certain biological studies, such as experiments aimed at deciphering the tran scriptional effects of adducts at TATA sites. This method is a key ste p toward overcoming that problem.