Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn

Mixed Li/K amides and enantioselective carbolithiations as effective synthetic tools

Donal O'Shea, Pharmaceutical & Medicinal Chemistry. Keywords: pharmacy, pharmaceutical sciences & chemistry.

We have recently illustrated how mixed Li/K metal TMP amides (LiNK metalation conditions) are uniquely suited for selectively achieving challenging metalations. Specifically, the use of the reagent triad BuLi/KOtBu/TMP(H) to in situ generate a mixed Li/K metal TMP amide has proven to be an efficient and general method to achieve direct vinylic and benzylic metalations with excellent and predictable regioselectivity. The scope of this novel methodology is currently being established and expansion of its synthetic utility for targetted synthesis is in progress. Enantioselective cascade reaction sequences are very powerful synthetic protocols for the assembly of complex organic architectures. The goal is to devise systems in which a facile transformation triggers the conversion of prochiral starting materials to chiral intermediates of high synthetic potential that can subsequently be converted in situ into products of increasing complexity. Our current approach is to exploit a chiral amine controlled enantioselective carbolithiation of ortho-substituted beta-methylstyrenes. The chiral centre, formed in good enantiomeric excess in the carbolithiation step, can be carried through different reaction sequences thereby generating a collection of products. As the chiral centre generated during the carbolithiation step is carried through the subsequent reaction sequences to the final products, selectivity is solely dependent upon achieving an enantioselective alkyllithium addition.

Mentors Donal O'Shea.