Synthesis and chiroptical properties of pseudocolchicine and neocolchicine, novel unnatural regioisomers of colchicine

Abstract

Two novel regioisomers of colchicine 1, pseudocolchicine ((R_a,7S)-N-(1,2,3,11-tetramethoxy-10-oxo-5,6,7,10-tetrahydrobenzo[a]heptalen-7-yl)acetamide 11) and neocolchicine ((R_a,7S)-N-(1,2,3,10-tetramethoxy-11-oxo-5,6,7,11-tetrahydrobenzo[a]heptalen-7-yl)acetamide 13), were obtained from 10-hydroxyneocolchicide 15 by either treatment with CH₂N₂followed by HPLC separation, or treatment with tosyl chloride followed by TLC separation of the resulting tosylates 16 and 17 and their regiospecific methoxylation with Ti(OMe)₄. The observation of similar UV and CD spectra for 11 and 13, and for colchicine 1 and isocolchicine 6, allowed us to come to a far reaching rationalisation of the electronic spectral behaviour of colchicinoids.