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US 11,505,519 B2Granted
Synthesis of organic acids from α-keto acids
AssigneeFurman University
InventorsGregory Gardner Springsteen, Robert Trent Stubbs
Life of this patent
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Abstract
Methods for syntheses of organic acids from α-keto acids, including methods for syntheses of isotopically enriched organic acids from α-keto acids are disclosed. The isotopically enriched organic acids are useful, for example, in metabolic flux analyses.
Claims25
A method for reducing an α,β-unsaturated bond in an aldol condensation compound, the method comprising
- (1) contacting an aldol nucleophile with an aldehydic electrophile to provide an aldol addition compound;
- (2) dehydrating the aldol addition compound to provide an aldol condensation compound having an α,β-unsaturated bond;
- and
- (3) reducing the α,β-unsaturated bond in the aldol condensation compound by contacting the aldol condensation compound with the aldehydic electrophile;
- wherein the aldol nucleophile is of Formula (A):
- wherein
- R is hydrogen, C1-12alkyl, C2-10heteroalkyl, C6-20aryl, C3-12heteroaryl, C3-10cycloalkyl, C2-10 heterocyclyl, C1-12alkyl-C6-20aryl, C1-12alkyl-C3-12heteroaryl, C1-12alkyl-C3-10cycloalkyl, or C1-12alkyl-C2-10heterocyclyl, wherein alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl are independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof;
- and
- wherein the aldehydic electrophile is of Formula (B):
- wherein
- X is H, COOH or C(═O)OCH2CH3;
- and
- Y is H.
10 more elements
A method for preparing an organic acid, the method comprising
- (1) contacting an α-keto acid with an aldehydic electrophile to provide an aldol addition compound;
- (2) dehydrating the aldol addition compound to provide an aldol condensation compound having an α,β-unsaturated bond;
- (3) reducing the α,β-unsaturated bond in the aldol condensation compound by contacting the aldol condensation compound with the aldehydic electrophile;
- and
- (4) oxidatively decarboxylating the reduced aldol condensation compound to provide the organic acid;
- or
- (5) reducing the keto group in the reduced aldol condensation compound to provide the organic acid;
- or
- (6) subjecting the reduced aldol condensation compound to reductive amination or transamination to provide the organic acid;
- wherein the alpha keto acid is of Formula (A):
- wherein
- R is hydrogen, C1-12alkyl, C2-10heteroalkyl, C6-20aryl, C3-12heteroaryl, C3-10cycloalkyl, C2-10 heterocyclyl, C1-12alkyl-C6-20aryl, C1-12alkyl-C3-12heteroaryl, C1-12 alkyl-C3-10cycloalkyl, or C1-12 alkyl-C2-10heterocyclyl, wherein alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl are independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof;
- and
- wherein the aldehydic electrophile is of Formula (B):
- wherein
- X is H, COOH or C(═O)OCH2CH3;
- and
- Y is H.
15 more elements
A method for conversion of a-keto acids to organic acids thereof, the method comprising
- (1) contacting an alpha keto acid of Formula (A) with an aldehydic electrophile of Formula (B)
- to provide an aldol addition compound of Formula (C)
- (1-1) contacting compound (C) with compound (B) to provide a compound of Formula (J)
- (2) dehydrating the compound of Formula (J) to provide a compound of Formula (K)
- (3) reducing the compound of Formula (K) to provide a compound of Formula (L)
- by contacting the compound of Formula (K) with the aldehydic electrophile;
- (2-1) dehydrating the compound of Formula (L) to provide a compound of Formula (M)
- (3-1) reducing the compound of Formula (M) to obtain a compound of Formula (N)
- by contacting the compound of Formula (M) with the aldehydic electrophile;
- and
- (4) oxidatively decarboxylating the compound of Formula (N) to provide an organic acid of Formula (0)
- wherein
- R is hydrogen, C1-12alkyl, C2-10heteroalkyl, C6-20aryl, C3-12heteroaryl, C3-10cycloalkyl, C2-10 heterocyclyl, C1-12alkyl-C6-20aryl, C1-12alkyl-C3-12heteroaryl, C1-12alkyl-C3-10cycloalkyl, or C1-12 alkyl-C2-10heterocyclyl, wherein alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl are independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof;
- X is selected from the group consisting of H, COOH, and C(═O)OCH2CH3;
- and
- Y is H.
13 more elements
A method of preparing isotoplogue metabolites by reducing an α,β-unsaturated bond in an aldol condensation compound, the method comprising
- (1) contacting an aldol nucleophile with an aldehydic electrophile to provide an aldol addition compound;
- (2) dehydrating the aldol addition compound to provide an aldol condensation compound having an α,β-unsaturated bond;
- and
- (3) reducing the α,β-unsaturated bond in the aldol condensation compound by contacting the aldol condensation compound with the aldehydic electrophile;
- wherein the aldol nucleophile is of Formula (A):
- wherein
- R is hydrogen, C1-12alkyl, C2-10heteroalkyl, C6-20aryl, C3-12heteroaryl, C3-10cycloalkyl, C2-10 heterocyclyl, C1-12alkyl-C6-20aryl, C1-12alkyl-C3-12heteroaryl, C1-12alkyl-C3-10cycloalkyl, or C1-12 alkyl-C2-10heterocyclyl, wherein alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl are independently optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof;
- and
- wherein the aldehydic electrophile is of Formula (B):
- wherein
- X is H, COOH or C(═O)OCH2CH3;
- and
- Y is H.
10 more elements
Dependencies are inferred from the claim text.