Synthetic studies towards the core structure of Huperzine A

Abstract

The current study focused on utilising a radical cyclisation reaction of phenylselenide intermediates as the key bond-forming step in an attempt to develop a flexible, convergent, and efficient synthetic route to the core structure ofhup-A (1). In order to probe the synthetic utility of the key bond-forming step, simplified model systems were prepared. From the synthesis of these model systems it was shown that 3-pyridinyl radicals can undergo 5-exo-trig radical cyclisation in excellent yields to give hexahydroindenopyridinol (103). 2-Pyridylmethyl radicals have been shown to have utility in synthesis, undergoing 5-exo-trig radical cyclisation to efficiently give hexahydroindenopyridinol (118). Furthermore, pyridylmethyl radicals have been shown to undergo 6-exo-trig cyclisation under standard conditions in moderate yield. The mode of cyclisation of such radicals has been used to access efficiently the bicyclo[3.3.1]nonane (92) which has the same framework as hup-A. The 6-exo-trig of cyclisation has been shown to be dependant on the bulk of substituents on the cyclohexene ring, with yields increasing with the increasing size of the substituent, hi addition, a novel approach to the radical precursors by direct selenation of 2- methylpyridines has also been developed using a deprotonation/ Selenylation sequence providing access to highly functionalised compounds. The effect of a conjugated carbonyl group on the radical cyclisation reaction was also investigated and resulted in the synthesis of model compound (135). Werein is reported the first crystal structure of a bicyclo[3.3.1]nonane related to hup-A (1) compound. Attention then turned to the synthesis of more highly functionalised derivatives by the addition of 3-pyridyl and 2-pyridylmethyl Organometallics to quinols. Despite numerous attempts and revision of the synthetic strategies employed, this reaction sequence was not successful in generating any bicyclononanes. An alternative synthetic strategy utilising Diels-Alder methodology to build the ring system was successful in generating radical cyclisation precursor (200); subsequent radical cyclisation of this compound yielded target compound (221) from a 6-exo-trig mode.