Continuous Flow Inter- and Intramolecular Macrolactonization under High Dilution Conditions

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).