Solution and solid phase synthesis of pyrrolinones and polypyrrolinones

1. 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.

2. 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 a Wang 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 ) o CO 2 H, —(CH 2 ) 0 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.

3. 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;

R 9 corresponds to the side chain of an individual amino acid in a polypeptide;

(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 ) o 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.

4. A process according to claim 1 wherein the oxidant in step (d) is oxalyl chloride, a tertiary amine and dimethylsulfoxide (DMSO).

5. A process according to claim 1 wherein the tertiary amine is diazabicycloundecene or di-iso-propylethyl amine.

6. A process according to claim 1 wherein the crown ether in step (c) is 18-crown-6.

7. A process according to claim 1 wherein the base in step (c) is potassium hexamethyldisilazane.

8. A process according to claim 1 wherein R 6 is a trialkylsilylethoxycarbonyl group.

9. A process according to claim 1 wherein the aldehyde in step (g) is a 3-phenylpropionaldehyde (49) derivative optionally substituted at the 3-position with one or two R 3 substituents

10. A process according to claim 1 wherein the aldehyde in step (g) is 3-phenylpropionaldehyde.

11. A process according to claim 3 wherein the para-hydroxy benzyl alcohol resin is a Wang resin.