FORMATION OF CHIRAL 4-CHROMANONES USING CHIRAL PYRROLIDINES IN THE PRESENCE OF ACIDS

摘要

The present invention relates to a synthesis of chromanones or chromanes in a stereospecific matter in view of the 2-position in the chromanone or chromane ring. It has been found that this synthesis is particularly possible in the presence of a chiral compound of a specific type and of at least one Bransted acid or in the presence a specific chiral compound having a Bransted acid functional group in the molecule.

主权项

1. Process for the manufacturing of a compound of formula (I)comprising the step of reacting a compound of formula (II-A) and a compound of formula (II-B) or a ketal thereof in the presence of an organic solvent and either
of at least one chiral compound of formula (II-C) and of at least one Brønsted acid having a pKa of between 5 and 10.5, measured at 25° C. in DMSO; or of at least one chiral compound of formula (II-C-A) having a pKa of between 5 and 10.5, measured at 25° C. in DMSO, or an internal salt thereof wherein R1, R3 and R4 are independently from each other hydrogen or methyl groups; R2 and R2′ represents hydrogen or a phenol protection group; R5 represents either a linear or branched completely saturated C6-25-alkyl group or a linear or branched C6-25-alkyl group comprising at least one carbon-carbon double bond; Y1 represents either CH2Y2 or wherein R6 represents a linear or branched C1-12-alkyl group which optionally further comprises at least one aromatic group and/or C═O and/or NH and/or NH2 group; Y2 represents either OH or OR7 or NHR7 or NHCOOR7 or wherein R7 represents either
a linear or branched C1-12-alkyl group which optionally further comprises at least one aromatic group and/or C═O and/or NH and/or NH2 group oran aryl group or a substituted aryl group or a heteroaryl group or a substituted heteroaryl group and A represents a substituent carrying a Brønsted acid functional group and the dotted line(s) represents the bond(s) by which the corresponding substituent is bound to the rest of formula (II-C); and wherein * represents the chiral centre of the chiral isomer of formula (I).