Preparation of Protected Alpha-Keto Beta-Amino Esters and Amides

A method for preparing a p-sulfinamide α-keto amide of Formula (S,Ss)-IV or (R,Rs)-IV:

• wherein:
• R1 is alkyl or aryl;
• R2 is alkyl, cycloalkyl, (cycloalkyl)alkyl, alkenyl, aryl, or heterocycloalkyl bonded to the carbon atom C* at a ring carbon atom;
• and
• R4 is hydrogen, alkyl, cycloalkyl, or aryl;
• Comprising the step of:
• mixing the compound of Formula (S,Ss)-I or (R,Rs)-I:
• with an amine of the formula R4NH2 to give a product of Formula (S,Ss)-IV or (R,Rs)-IV, wherein R1, R2, and R4 are as defined above, and R3 in the compound of Formula (S,Ss)-I or (R,Rs)-I is alkyl or aryl.

A method for preparing a n-sulfonamide α-keto amide of Formula (S,Ss)-IV or (R,Rs)-IV:

• wherein:
• R1 is alkyl or aryl;
• R2 is alkyl, cycloalkyl, (cycloalkyl)alkyl, alkenyl, aryl, or heterocycloalkyl bonded to the carbon atom C* at a ring carbon atom;
• and
• R4 is hydrogen, alkyl, cycloalkyl, or aryl;
• Comprising the steps of:
• a) mixing the compound of Formula (S,Ss)-I or (R,Rs)-I:
• wherein R3 is alkyl or aryl, with an aqueous base solution optionally in the presence of a co-solvent;
• b) neutralizing the solution to provide a carboxylic acid of Formula (S,Ss)-V or (R,Rs)-V:
• and
• c) mixing the carboxylic acid of Formula (S,Ss)-V or (R,Rs)-V with an amine R4NH2, wherein R4 is as defined above, to provide a product of Formula (S,Ss)-IV or (R,Rs)-V.

A method for preparing a n-sulfonamide α-keto amide of Formula (S,Ss)-IV or (R,Rs)-IV,

• wherein:
• R1 is alkyl or aryl;
• R2 is alkyl, cycloalkyl, (cycloalkyl)alkyl, alkenyl, aryl, or heterocycloalkyl bonded to the carbon atom C* at a ring carbon atom;
• and
• R4 is hydrogen, alkyl, cycloalkyl, or aryl;
• comprising the steps of:
• a) mixing a sulfinimine of Formula (Ss)-II or (Rs)-II:
• with a dithiolane carboxylate ester of Formula III:
• in the presence of a base of sufficient strength to deprotonate the dithiolane hydrogen of Formula III, wherein R1 and R2 in Formula II and R3 in Formula III are as defined above, to give a β-sulfonamide α-keto ester of Formula (S,Ss)-I or (R,Rs)-I:
• and
• b) mixing the compound of Formula (S,Ss)-I or (R,Rs)-I with an amine of the formula R4NH2 to give a product of Formula (S,Ss)-IV or (R,Rs)-IV:
• wherein R1, R2, and R4 are as defined above, and R3 in the compound of Formula (S,Ss)-I or (R,Rs)-I is alkyl or aryl;
• or
• mixing the compound of Formula (S,Ss)-I or (R,Rs)-I with an aqueous base solution optionally in the presence of a co-solvent;
• neutralizing the solution to provide a carboxylic acid of Formula (S,Ss)-V or (R,Rs)-V;
• and mixing
• the carboxylic acid of Formula (S,Ss)-V or (R,Rs)-V with an amine R4NH2, wherein R4 is as defined above, to provide a product of Formula (S,Ss)-IV or (R,Rs)-IV.

A process for coupling an amide of Formula (S,Ss)-IV or (R,Rs)-IV to a peptide containing a carboxylic acid terminus (HOOC-Pep.)

• wherein:
• the α-keto group is protected as a 1,3-dithiolane derivative;
• R1 is alkyl or aryl;
• R2 is alkyl, cycloalkyl, (cycloalkyl)alkyl, alkenyl, aryl, or heterocycloalkyl bonded to the carbon atom C* at a ring carbon atom;
• and
• R4 is hydrogen, alkyl, cycloalkyl, or aryl,
• Comprising the steps of:
• a) mixing a solution of the amide (S,Ss)-IV or (R,Rs)-IV with a mineral acid to provide a compound of Formula (S)-VI or (R)-VI:
• wherein R1 is as defined above;
• b) mixing the compound of Formula (S)-VI or (R)-VI with the carboxylic acid terminus of the peptide optionally in the presence of a coupling agent to give a compound of Formula (S)-VII or (R)-VII:
• and
• c) removing the 1,3-dithiolane protecting group in the compound of Formula (S)-VII or (R)-VII in the presence of an oxidant to provide a peptide of Formula (S)-VIII or (R)-VIII:
• containing a β-amino α-keto amide functionality.

A compound of Formula I, Formula IV, or Formula VI:

• wherein:
• each of R1 and R3 independently is alkyl or aryl;
• R2 is alkyl, cycloalkyl, (cycloalkyl)alkyl, alkenyl, aryl, or heterocycloalkyl;
• and
• R4 is hydrogen, alkyl, cycloalkyl, or aryl.