Synthesis of diketopiperazines
Disclosed herein are methods for synthesizing diketopiperazines with enantiomeric excess by inducing cyclization of an α-keto acid with an acid catalyst.
1. A method of preparing a compound of formula I:
comprising reacting an acid catalyst with a compound of formula II in such a manner so as to produce the compound of formula I with an enantiomeric excess greater than about 50%:
wherein:
R 1 , R 2 , and R 3 are separately selected from the group consisting of hydrogen; halogen; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, alkoxy, acyl, arylalkyl, heteroarylalkyl, alkyloxycarbonyloxy, ester, arylalkoxy, and alkylthio; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: acyloxy, aryloxycarbonyloxy, cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, heteroaryl, heterocycloalkyl, carbonyl, carbonylacyl, amino, aminocarbonyl, amide, aminocarbonyloxy, nitro, azido, phenyl, hydroxyl, arylthio, oxysulfonyl, carboxy, and cyano;
R 4 and R 5 are separately selected from the group consisting of hydrogen; mono -substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 heteroalkyl, C 2-6 aminoalkyl, C 2-6 haloalkyl, C 1-6 alkoxycarbonyl, aryl-C 1-6 -alkyl, and C 2-6 hydroxyalkyl; and mono-substituted, poly-substituted and unsubstituted variants of the following residues: C 3-8 cycloalkyl, —C(O)—C 5-6 aryl substituted with C 1-3 alkyl or halo, C 5-6 aryl, C 5-6 heteroaryl, C 5-6 cycloalkyl, and C 5-6 heterocycloalkyl;
any bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond; and
any carbon-carbon double bond has a configuration selected from the group consisting of cis and trans.
2. The method of claim 1 , wherein the acid catalyst is selected from the group consisting of acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid.
3. The method of claim 1 , wherein the enantiomeric excess is greater than about 80%.
4. The method of claim 1 , wherein the enantiomeric excess is greater than about 90%.
5. The method of claim 1 , wherein R 1 , R 2 , and R 3 are separately selected from the group consisting of hydrogen; halogen; mono-substituted, poly -substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, arylalkyl, and heteroarylalkyl; and mono-substituted, poly -substituted or unsubstituted variants of the following residues: cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycloalkyl.
6. The method of claim 5 , wherein R 1 , R 2 , and R 3 are separately selected from the group consisting of hydrogen; mono-substituted, poly-substituted or unsubstituted, straight or branched chain variants of the following residues: C 1 -C 24 alkyl, arylalkyl, and heteroarylalkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: cycloalkyl, aryl, heteroaryl, and heterocycloalkyl.
7. The method of claim 6 , wherein R 1 , R 2 , and R 3 are separately selected from the group consisting of hydrogen, methyl, methylene, and mono-substituted, poly-substituted or unsubstituted variants of the following residues:
8. The method of claim 7 , wherein the compound of formula I is selected from the group consisting of: