Patent ID: 7772159

Claim:
A solid-phase process for preparing an optical isomer of a polypyrrolinone comprising the steps: (a) linking an optical isomer of carboxylic acid that contains a latent aldehyde to a solid support wherein the latent aldehyde is converted to an aldehyde (41); wherein: R 6 is an amino protecting group, R 8 is 3-methyl-1-but-2-enyl, 2,2-dimethoxyethyl, 2-hydroxyethyl, and is para-hydroxy benzyl alcohol resin; (b) reacting an α-amino-α-substituted-1,4-dioxo compound (41), optionally with an alkoxycarbonyl protecting group, with an optical isomer of 2-substituted-2-aminovalerolactone (7), trimethylorthoformate, optionally in the presence of a solvent, to produce imine (40) wherein: R 6 is an amino protecting group; R 7 is a carboxyl linked to a solid support; (c) cyclizing (40) by forming metalloimine carbanion with base, optionally in the presence of a crown ether, to form a pyrrolinone (41) (d) oxidizing the —CH 2 CH 2 OH group to the corresponding aldehyde; (e) repeating steps (b)-(d) m times to produce polypyrrolinone (42) (f) terminating the synthesis using a substituted α amino acid ester in place of the valerolactone (7) in step (b) to yield (43) (g) Cleaving the polypyrrolinone from the resin by removing the protecting group R 6 in (43), and exposing the resulted free NH 2 moiety to a plurality of treatments with an aldehyde, trimethylorthoformate, optionally in the presence of a solvent, to produce the corresponding imine; and, (h) cyclizing the imine by forming the metalloimine carbanion with base, optionally in the presence of a crown ether, to produce the (i) the polypyrrolinone having the formula (38) wherein: R is independently selected from a group consisting of a straight C 1 -C 6 alkyl, a branched C 3 -C 7 alkyl, C 3 -C 7 cycloalkyl, a straight C 1 -C 6 alkenyl, a branched C 3 -C 7 alkenyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 thioalkyl, C 1 -C 4 methylthioalkyl, —(CH 2 ) o N(R 5 ) 2 , —(CH 2 ) 0 CO 2 H, —(CH 2 ) o CON(R 5 ) 2 , heteroaryl, phenyl optionally substituted with one to three hydroxyl, C 1 -C 8 alkoxy, halo, nitro, or cyano groups, and benzyl optionally substituted with one to three hydroxyl, C 1 -C 8 alkoxy, halo, nitro or cyano groups; R 1 is hydrogen, hydroxyl, C 1 -C 8 alkoxy, amino or alkoxycarbonyl-protected amino; R 2 is R, carboxyl, a carbonyl linked to a solid support or alkoxycarbonyl; R 3 is R or hydrogen; R 4 is R or (46) R 5 is hydrogen or C 1 -C 8 alkyl; n is 0 to 3; o is 1 to 4; wherein the stereochemical configuration, R or S, is preserved at each chiral center of the starting material through the ultimate product.