Continuous Flow Inter- and Intramolecular Macrolactonization under High Dilution Conditions

Abstract

An efficient continuous flow process for the macrolactonization of seco acids and diacids using diols in the presence of Mukaiyama reagent (N-methyl-2-chloropyridinium iodide) has been developed for medium to large sized macrocyclic lactones. In comparison with other methods, the continuous flow process provided good to high yield in a short reaction time. By using this methodology, a wide range of macrocyclic lactones (11 compounds), dilactones (15 compounds), and tetralactone derivatives (2 compounds) with various ring sizes (12–26 atoms in the core) were synthesized in just 35 min of residence time. Advantageously, macrolactonization under the flow process is very elegant to handle the high dilution of reactants with a defined perfluoroalkoxy alkanes (PFA) tube reactor volume (7 mL).

Synthesis of Macrolactams from Macrolactones Using Ru-/Ir-Catalytic System under Neutral Conditions

“…Construction of amide bonds can be done by the coupling of carboxylic acids and amines using various coupling reagents, oxidative amidation of alcohol and amines, organocatalysis and metal catalysis, etc. Subsequently, macrolactams can be achieved using a ring expansion process, imine formations for ring closure, coupling of amines with acids, esters, and the use of the Mukaiyama salt for ring closure . Despite traditional approaches for macrolactams, fewer catalytic methods such as Sn-catalyzed double activation strategy (Figure A) and Cu-catalyzed intramolecular coupling of phenol and aryl halide to synthesize vancomycin (Figure B) are described.…”