Synthesis of chromene based natural products

The primary aim of this project was to develop total syntheses of natural products kamalachalcone A and rottlerin, as their syntheses have never been reported. These two targets are structurally related, and thus the complete syntheses of these molecules would help explain their biosynthesis and key bond formations in nature. Novel chromene analogues with fused ring systems were synthesized by developing a method to generate ortho-quinone methide precursors, which could be reacted with various electron-rich alkenes to form fused heterocyclic rings. The results showed that electron-rich alkenes such as vinyl ether and styrene derivatives favour the cycloaddition reaction whereas electron poor alkenes do not undergo this reaction. The results also showed that electron-rich arenes could also furnish biarylmethane compounds, a potential strategy towards the synthesis of rottlerin. To explore the properties of ortho-quinone methides further, novel fluorinated dependensin analogues were synthesized by the FeCl3-catalyzed dimerization reaction of the corresponding fluorinated flavenes. The results suggested that the dimerization reaction of flavenes is controlled electronically, with electronegative fluorine substituents appearing to deactivate the overall nucelophilicity of flavenes, thus leading to lower yields of the dimeric products. Dimerization reactions were only successful with flavene scaffolds containing two or fewer fluorine substituents. By understanding the properties of ortho-quinone methides, kamalachalcone A was synthesized for the first time via the acid-catalyzed dimerization of red compound. The use of FeCl3 offered the best yield with short reaction time. The structurally similar compound, rottlerin, was synthesized by reacting 5-hydroxychromene with Eschenmoser’s salt to provide N,N-dimethylaminomethyl chromene as an ortho-quinone methide precursor, which upon heating with acetophenone, provided rottlerin. By understanding the formation of the side product rottlerone during the deprotection of MOM-protected chromene, the overall synthesis was re-designed and a new five-step gram scale synthesis of rottlerin was developed. Upon keeping rottlerin in DMSO, the chalcone moiety of rottlerin underwent cyclization leading to the formation of another natural product called isorottlerin, and this is the first report of the ability of rottlerin to undergo such a change