Enantioselective halocyclization of polyprenoids induced by nucleophilic phosphoramidites

Polycyclic bio-active natural products that contain halogen atoms have been isolated from a number of different marine organisms(1). The biosynthesis of these natural products appears to be initiated by an electrophilic halogenation reaction at a carbon - carbon double bond(2-4) via a mechanism that is similar to a proton-induced olefin polycyclization(5-8). Enzymes such as haloperoxidases generate an electrophilic halonium ion ( or its equivalent), which reacts with the terminal carbon - carbon double bond of the polyprenoid, enantioselectively inducing a cyclization reaction that produces a halogenated polycyclic terpenoid. Use of an enantioselective halocyclization reaction is one possible way to chemically synthesize these halogenated cyclic terpenoids; although several brominated cyclic terpenoids have been synthesized via a diastereoselective halocyclization reaction that uses stoichiometric quantities of a brominating reagent(9-12), the enantioselective halocyclization of isoprenoids induced by a chiral promoter has not yet been reported. Here we report the enantioselective halocyclization of simple polyprenoids using a nucleophilic promoter. Achiral nucleophilic phosphorus compounds are able to promote the diastereoselective halocyclization reaction to give a halogenated cyclic product in excellent yields. Moreover, chiral phosphoramidites promote the enantioselective halocyclization of simple polyprenoids with N-iodosuccinimide to give iodinated cyclic products in up to 99% enantiomeric excess and diastereomeric excess. To the best of our knowledge, this is the first successful example of the enantioselective halopolycyclization of polyprenoids.