Method for late introduction of the (8R) hydroxyl group carbapenem β-lactam antibiotic synthesis

Patent metadata

Field	Value
Publication number	US-9458479-B2
Application number	US-201514860103-A
Country	US
Kind code	B2
Filing date	Sep 21, 2015
Priority date	Dec 11, 2009
Publication date	Oct 4, 2016
Grant date	Oct 4, 2016

Abstract

The presently disclosed subject matter demonstrates that ThnG and ThnQ enzymes encoded by the thienamycin gene cluster in Streptomyces cattleya oxidize the C-2 and C-6 moieties of carbapenems, respectively. ThnQ stereospecifically hydroxylates PS-5 giving N-acetyl thienamycin. ThnG catalyzes sequential desaturation and sulfoxidation of PS-5, giving PS-7 and its sulfoxide. The ThnG and ThnQ enzymes are relatively substrate selective, but give rise to the oxidative diversity of carbapenems produced by S. cattleya , and orthologues likely function similarly in allied streptomyces.

First claim

That which is claimed:

1. A process for preparing a carbapenem of Formula (II):

the process comprising contacting or incubating a carbapenem substrate of Formula (IIa):

with a ThnG enzyme under reaction conditions to produce the carbapenem of Formula (II);
wherein:
R 1 is H;
R 4 is selected from the group consisting of, —NH-glycyl, —NH-beta-alanyl, —NHC(═O)CH 2 CH 2 CH 2 NH 2 , —NH-pantethienic acid amide, an acyl group comprising C 1 -C 10 substituted or unsubstituted linear or branched alkyl, which can further comprise one or more 3-6 member cycloalkyl rings; and
R 3 is H.

2. The process of claim 1 , wherein R 4 is selected from the group consisting of 2-hydroxyacetyl, 2-methoxyacetyl, 3-hydroxypropionyl, 4-hydroxybutanoyl, and 3,4-dihydroxybutanoyl.

3. The process of claim 1 , wherein the carbapenem of Formula (II) is:

4. A process for preparing a carbapenem of Formula (III):

the process comprising contacting or incubating a carbapenem substrate of Formula (IIIa):

with a ThnG enzyme under reaction conditions to produce a carbapenem of Formula (IIIb):

then contacting or incubating the carbapenem of Formula (IIIb) with a ThnG enzyme under reaction conditions to produce a carbapenem of Formula (III);
wherein:
R 1 is H;
R 4 is selected from the group consisting of —NH-glycyl, —NH-beta-alanyl, —NHC(═O)CH 2 CH 2 CH 2 NH 2 , —NH-pantethenic acid amide, an acyl group comprising C 1 -C 10 substituted or unsubstituted linear or branched alkyl, which can further comprise one or more 3-6 member cycloalkyl rings; and
R 3 is H.

5. The process of claim 4 , wherein R 4 is selected from the group consisting of 2-hydroxyacetyl, 2-methoxyacetyl, 3-hydroxypropionyl, 4-hydroxybutanoyl, and 3,4-dihydroxybutanoyl.

6. The process of claim 4 , wherein the carbapenem of Formula (III) is:

Assignees

• Univ Johns Hopkins

Inventors

• Townsend Craig Arthur
• Bodner Micah Jeffrey
• Phelan Ryan Martin
• Freeman Michael Francis

Classifications

• C07D477/20

  Sulfur atoms · CPC title

• C12P17/184 Primary

  containing a beta-lactam ring, e.g. thienamycin · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• C12P17/10 Primary

  Nitrogen as only ring hetero atom · CPC title