Trapping of carbolithiation-derived tertiary benzylic α-lithio piperidines with carbon electrophiles: Controlling the formation of α-amino quaternary and vicinal stereocenters

Abstract

The interception of carbolithiation-derived tertiary benzylic α-lithio piperidines with carbon electrophiles, under HMPA-mediated conditions, has led to the diastereoselective synthesis of vicinally functionalized piperidines bearing α-amino quaternary stereocenters.

Regio- and stereoselective intermolecular carbolithiation reactions

“…When, aer introduction of the alkyllithium at À78 C, the reaction mixture was warmed at À30 C in the presence of hexamethylphosphoramide (HMPA), the desired vicinally functionalized piperidines 121 were obtained in higher yields with respect to the additive-free conditions. 58 In fact, without additive, the attack on the Boc-group by strongly nucleophilic alkyllithiums is competitive with b-alkylation. Moreover, piperidine-derived tertiary benzylic organolithiums, generated by carbolithiation of a-aryl piperidine enecarbamates, can be successfully trapped, under HMPA-mediated conditions, with several carbon electrophiles, (Scheme 42).…”

“…Moreover, piperidine-derived tertiary benzylic organolithiums, generated by carbolithiation of a-aryl piperidine enecarbamates, can be successfully trapped, under HMPA-mediated conditions, with several carbon electrophiles, (Scheme 42). 58 Such carbolithiation/trapping process allowed to obtain, in diastereoselective manner, vicinally functionalized piperidines bearing a-amino quaternary stereocenters with up to three contiguous stereocenters.…”

Leveraging the 1,3-azadiene-anhydride reaction for the synthesis of functionalized piperidines bearing up to five contiguous stereocenters

“…In particular, polysubstituted piperidines and 2-oxopiperidines are increasingly attractive fragments for potential drug discovery since the strategic placement of substituents about this three-dimensional scaffold is ideally suited for structure–activity relationship studies. 3 Although the synthesis of functionalized piperidines remains daunting, 4 recent advances 5 are starting to bring these once elusive building blocks into the mainstream. However, most of these advances are predicated on taking an existing piperidine scaffold and installing substituents by functionalization ( e.g.…”

Gold(I)-Catalyzed Enantioselective Annulations between Allenes and Alkene-Tethered Oxime Ethers: A Straight Entry to Highly Substituted Piperidines and aza-Bridged Medium-Sized Carbocycles

“…5 These drawbacks are even more pronounced in the case of piperidines containing highly substituted carbon stereocenters adjacent to their nitrogen atom. 6 The piperidine scaffold is also embedded in the skeleton of many polycyclic natural products exhibiting complex structures. 7 Especially relevant because of their biological and medical significance are those which feature tropane-like aza-bridged skeletons ( Figure 1).…”