Patent ID: 6667406
Filing Date: 2003-12-23
Classification: C07D

Abstract:
A method for synthesing compounds having an hexahydroisoindole or hexahydroisooxyindole moiety selected from those moieties of the formulae: wherein R1 is a standard natural amino acid side chain other than that derived from glycine; R2 is H, CH3, COOR or CN; R3 is H, alkyl, substituted alkyl, aryl, substituted aryl, butoxycarbonyl (BOC), or carbobenzyloxy (CBz); R4 and R5 are the same or different and are H, benzyl and COOR or R4 and R5 together form an aryl, substituted aryl, cycloalkyl or a heterocyclic ring; R6 and R7 are the same or different and are H, alkyl, halo or alkoxy; R is H, lower alkyl, or benzyl; Y is absent, an oxygen or a CH2 bridging group; P is a solid support resin; and E is COOP; said method comprising:a) preparing a compound comprising a triene moiety selected from those of the formula and stereochemistry: by (i) reacting a protected amino aldehyde (1) with a dialkyl &agr;-phosphonoester (2) to generate a protected amine (3) (ii) removing the protecting group from the amine (3) and alkylating the resulting intermediate to generate (4) and(iii) reacting (4) with an acid halide, anhydride or aldehyde (5) wherein Prot is a standard amino acid protecting group, wherein R6 is lower alkyl, wherein X is a chlorine atom, a bromine atom, R7C(O)â€” wherein R7 is lower alkyl, or H, and wherein W is oxygen or is absent; q is zero; Y is an oxygen, a CH2 bridging group or is hydrogen at each carbon atom; and R1 to R5 and P are as recited above; andb) converting said triene moiety to the corresponding hexahydroisoindole or hexahydroisooxyindole moiety by a Diels Alder cycloaddition reaction at a temperature of between 0 and 110Â° C. and a reaction time of 1 to 64 hours.