Indolizinones as synthetic scaffolds: fundamental reactivity and the relay of stereochemical information

Abstract

Indolizinones are under-explored N-heterocycles that react with exquisite chemo- and stereoselectivity. An exploration of the fundamental reactivity of these azabicycles demonstrates the potential to relay stereochemical information from the ring-fusion to newly formed stereocenters on the bicyclic core. The indolizinone diene undergoes selective hydrogenation and readily participates in Diels–Alder cycloadditions as well as ene reactions. The vinylogous amide embedded in the five-membered ring is resistant to reaction when the diene is in place. However, removal of the diene allows for diastereoselective hydrogenation of, and 1,4-additions to, the vinylogous amide. These fundamental reactions with indolizinones have provided a structurally diverse array of products that hold promise in the context of natural product synthesis.

Transition-Metal-Free BF3-Mediated Regioselective Direct Alkylation and Arylation of Functionalized Pyridines Using Grignard or Organozinc Reagents

“…Pyridines are an important class of N -heterocycles including many bioactive compounds and functional materials . The direct functionalization of these heterocyclic scaffolds has been achieved by numerous methods, including C–H activation, radical reaction, and directed metalation .…”

Catalytic, Asymmetric Indolizidinone Aza-Quaternary Stereocenter Synthesis: Expedient Synthesis of the Cylindricine Alkaloid Core

“…Due to their interesting architecture and biological activity many methods to synthesize these tricyclic alkaloids have been developed. Most of these syntheses are racemic or use chiral starting materials and take advantage of an aza-Michael addition (single or double) to form the functionalized piperidine core. Shibasaki (5 steps, 82% ee ) and Zhang (10 steps, 87% ee ) have reported catalytic asymmetric approaches to the cylindricines.…”

Chichibabin-Type Direct Alkylation of Pyridyl Alcohols with Alkyl Lithium Reagents

“…For example, during investigations on the reactivity of indolizinones, 13 we required efficient access to an alkylated variant of pyridyl alcohol 1 (Figure 2). After extensively investigating various methods for the introduction of a butyl group at C(6) of 1 , it was determined that only the direct, Chichibabin-type reaction with n -BuLi furnished the desired product.…”

“…An attractive option to achieve the direct alkylation of pyridyl alcohols would be to employ an alkylative variant of the Chichibabin reaction, which has been previously used in the direct alkylation of pyridines. 7 For example, during investigations on the reactivity of indolizinones, 13 we required efficient access to an alkylated variant of pyridyl alcohol 1 (Figure 2). After extensively investigating various methods for the introduction of a butyl group at C( 6) of 1, it was determined that only the direct, Chichibabin-type reaction with n-BuLi furnished the desired product.…”

“…Supporting Information Available. Experimental details and copies of 1 H and 13 C spectra for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.…”