# US 6,294,374 B1 · Use of catalytic antibodies for synthesizing epothilone

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- Number: US 6,294,374 B1
- Document ID: US6294374B1
- Status: Granted
- Kind: B1
- Application number: 09/415,453
- Filed: 1999-10-08
- Granted: 2001-09-25
- Earliest claimed: 1999-10-08
- Assignees: The Scripps Research Institute
- Inventors: Subhash C. Sinha; Richard A. Lerner; Carlos F. Barbas, III
- Web page: https://patentgrep.com/patent/US6294374B1

## CPC

- C07D 417/06: linked by a carbon chain containing only aliphatic carbon atoms
- A61P 35/00: Antineoplastic agents
- C07D 277/24: Radicals substituted by oxygen atoms
- C07D 277/34: Oxygen atoms
- C07D 277/36: Sulfur atoms
- C07D 493/04: Ortho-condensed systems
- C12N 9/0002: {Antibodies with enzymatic activity, e.g. abzymes}
- C12P 7/26: Ketones
- C12P 17/16: containing two or more hetero rings {(thiamine open chain analogs C12P17/167, i.e. not condensed among themselves or through a common carbocyclic ring system)}
- C12P 17/18: containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin {(e.g. Rifamycin C12P17/189)}
- C12P 41/002: {by oxidation/reduction reactions}
- C07B 2200/07: Optical isomers
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12P: FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE {(brewing of beer C12C; producing vinegar C12J; producing specific peptides or proteins C07K; producing enzymes C12N9/00; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; measuring or testing processes involving enzymes or microorganisms C12Q; measuring or testing processes involving nucleic acid amplification reactions C12Q1/6844; fermentation processes to form a food composition, A21 or A23; compounds in general, see the relevant compound class, e.g. C01, C07)}
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Three monoclonal aldolase antibodies, generated against a β-diketone hapten by reactive immunization, catalyzed rapid and highly enantioselective retro-aldol reactions providing ent-9a-k by kinetic resolution. Compounds 9a, 9g and 9k were resolved in multi-gram quantities using 0.005-0.0004 mol % antibody catalyst. Enantiomerically pure starting materials, 9a-k, are useful synthons for the construction of epothilones A-E (2-6) and their analogs including 13-alkyl derivatives. Previously, the use of compound 9a as a synthon was reported in the preparation of epothilones A-D, 2-5. To further expand this synthon-based strategy, syntheses of epothilone E, 6, 13-methyl epothilone C, 7, and their trans-isomers have been achieved starting from enantiomerically pure thiazole aldols 9g and 9a, respectively, prepared by large-scale antibody catalyzed resolutions.

## Claims

### Claim 1

A process for enantioselectively resolving a racemic mixture of an aldol synthon, the racemic mixture including a first and a second enantiomer of the aldol synthon, said process comprising the following steps:
Step A: Catalyzing a retro-aldol reaction for enantioselectively converting the first enantiomer of the aldol synthon to form an aldehyde product while leaving the second enantiomer of the aldol synthon unmodified, said catalysis employing a catalytic antibody selected from the group consisting of 84G3, 85H6, and 93F3; and then
Step B: Separating the aldehyde product from the unmodified second aldol synthon.

### Claim 2 (depends on 1)

A process according to claim 1 wherein the racemic mixture of the aldol synthon, the aldehyde product, the unmodified second enantiomer of the aldol synthon, and the retro-aldol reaction are all represented as follows:
wherein R1 is a radical selected from the group consisting of Me, CH2OH, SMe, and OMe and R is a radical selected from the group consisting of Me, Et, n-Pr, n-Bu, n-Pentyl, and n-Bu-1-en-4-yl.

### Claim 3

A process for enantioselectively resolving a racemic aldol synthon, the racemic aldol synthon including a first and a second enantiomer, said process comprising the following steps:
Step A: Catalyzing a retro-aldol reaction for enantioselectively converting the first enantiomer of the aldol synthon to form an aldehyde product while leaving the second enantiomer of the aldol synthon unmodified, said catalysis employing a catalytic antibody, the retro-aldol reaction being represented as follows:
wherein A represents the the racemic aldol synthon, B represents the unmodified second enantiomer of the aldol synthon, and C represents the aldehyde product; wherein R1 is a radical selected from the group consisting of Me, CH2OH, SMe, and OMe and R is a radical selected from the group consisting of Me, Et, n-Pr, n-Bu, n-Pentyl, and n-Bu-1-en-4-yl; and then
Step B: Separating the aldehyde product from the unmodified second aldol synthon.