Methods for the synthesis of olefins and derivatives

Abstract

The invention provides a method of producing acrylic acid. The method includes contacting fumaric acid with a sufficient amount of ethylene in the presence of a cross-metathesis transformation catalyst to produce about two moles of acrylic acid per mole of fumaric acid. Also provided is an acrylate ester. The method includes contacting fumarate diester with a sufficient amount of ethylene in the presence of a cross-metathesis transformation catalyst to produce about two moles of acrylate ester per mole of fumarate diester. An integrated process for process for producing acrylic acid or acrylate ester is provided which couples bioproduction of fumaric acid with metathesis transformation. An acrylic acid and an acrylate ester production also is provided.

1 .- 72 . (canceled) 
     
     
         73 . A non-naturally microbial organism comprising a set of metabolic modifications obligatorily coupling fumaric acid production to growth of the non-naturally microbial organism, the set of metabolic modifications comprising disruption of at least one gene encoding an enzyme catalyzing reactions selected from the group consisting of:
 (1) Fumarase (FUM), Phosphogluconate dehydrogenase (PGDH), Formyltetrahydrofolate hydrolase (FTHFD) and   (2) Fumarase (FUM), Phosphogluconate dehydrogenase (PGDH), Serine hydroxymethyl transferase (GHMT2) or an ortholog thereof, which confer stable growth-coupled production of fumaric acid.   
     
     
         74 . The non-naturally occurring microbial organism of  claim 73 , wherein the reactions encoding the metabolic modifications further comprises disruption of at least one gene selected from a set encoding enzyme reactions selected from the group consisting of reactions:
 (1) Fumarase (FUM), Phosphogluconate dehydrogenase (PGDH), Formyltetrahydrofolate hydrolase (FTHFD), Acetate kinase (ACKr)   (2) Fumarase (FUM), Phosphogluconate dehydrogenase (PGDH), Formyltetrahydrofolate hydrolase (FTHFD), Glutamate dehydrogenase (GLUDy);   (3) Fumarase (FUM), Phosphogluconate dehydrogenase (PGDH), Formyltetrahydrofolate hydrolase (FTHFD), Transhydrogenase (THD2); and   (4) Fumarase (FUM), Formyltetrahydrofolate hydrolase (FTHFD), Transhydrogenase (THD2), Acetate kinase (ACKr), Phosphoglyceromutase (PGM), Phosphogluconal acotonase (PGL).   
     
     
         75 . The non-naturally occurring microbial organism of  claim 74 , wherein the disruption comprises a deletion of at least one gene within the reaction set. 
     
     
         76 . A process comprising:
 culturing by fermentation a non-naturally occurring microbial organism that produces fumaric acid in a sufficient amount of nutrients and media;   wherein said non-naturally occurring microbial organism comprises a set of metabolic modifications comprising disruption of at least one gene encoding an enzyme catalyzing reactions selected from the group consisting of:   (1) Fumarase (FUM), Phosphogluconate dehydrogenase (PGDH), Formyltetrahydrofolate hydrolase (FTHFD) and   (2) Fumarase (FUM), Phosphogluconate dehydrogenase (PGDH), Serine hydroxymethyl transferase (GHMT2) or an ortholog thereof, which confer stable growth-coupled production of fumaric acid;   or an ortholog thereof, which confer stable growth-coupled production of fumaric acid; and   
     
     
         77 . The process of  claim 76 , further comprises esterifying the fumaric acid to fumarate dialkyl ester. 
     
     
         78 . The process of  claim 76 , wherein the esterifying comprises contacting the fumaric acid with an alcohol at a 1:2 molar ratio under condensation reaction conditions sufficient to produce fumarate dialkyl ester and water at a 1:2 molar ratio. 
     
     
         79 . The process of  claim 76 , further comprising an esterification catalyst. 
     
     
         80 . The process of  claim 79 , wherein the esterification catalyst comprises sulfuric acid (H 2 SO 4 ) or p-toluene sulfonic acid. 
     
     
         81 . The process of  claim 78 , wherein the alcohol is a butyl alcohol. 
     
     
         82 . The process of  claim 81 , wherein the fumarate dialkyl ester is dibutyl fumarate. 
     
     
         83 . The process of  claim 76 , wherein the nutrients and media comprise at least one carbon substrate selected from glucose, xylose, arabinose, galactose, mannose or fructose. 
     
     
         84 . The process of  claim 76 , further comprising a metathesis catalyst comprising a ruthenium catalyst comprising an N-heterocyclic carbene ligand. 
     
     
         85 . The process of  claim 84 , wherein the metathesis ruthenium catalyst bearing an N-hetrocyclic carbine ligand is selected from the group consisting of
 [1,3 bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro[(2-(1-methyleth-oxy)phenyl)methylene]ruthenium;   [1,3-bis(2-methylphenyl)-2-imidazolidinylidene]dichloro(benzylidene) (tricyclohexylphosphine)ruthenium(II);   [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(3-methyl-2-butenylidene)(tricyclohexylphosphine)ruthenium(II); and   [1,3-bis-(2,4,6 trimethylphenyl)-2-imidazolidinylidene]dichloro(phenylmethylene)(tricyclo-hexylphosphine) ruthenium.   
     
     
         86 . The process of  claim 76 , wherein the metathesis transformation catalyst is a ruthenium catalyst and the rhuthenium catalyst comprises Cl 2 (PCy 3 ) 2 Ru═CHPh or the phosphine-free carbene ruthenium catalyst [1,3-bis(2,6-dimethylphenyl)4,5-dihydroimidazol-2-ylidene](C 5 H 5 N) 2 (Cl) 2 Ru═CHPh. 
     
     
         87 . A process comprising:
 (a) culturing by fermentation in a sufficient amount of nutrients and media a non-naturally occurring microbial organism that produces fumaric acid; and   (b) performing a chemical modification comprising metathesis with ethylene to convert fumaric acid to acrylic acid.   
     
     
         88 . The process of  claim 87  further comprising:
 (a) contacting the acrylic acid with a sufficient amount of a disubstitued alkene in the presence of an olefin metathesis transformation catalyst to produce a second, different olefin. 
 
     
     
         89 . The process of  claim 87 , wherein the non-naturally occurring microbial organism comprises comprises a set of metabolic modifications comprising disruption of at least one gene encoding an enzyme catalyzing reactions selected from the group consisting of:
 (1) Fumarase (FUM), Phosphogluconate dehydrogenase (PGDH), Formyltetrahydrofolate hydrolase (FTHFD) and   (2) Fumarase (FUM), Phosphogluconate dehydrogenase (PGDH), Serine hydroxymethyl transferase (GHMT2) or an ortholog thereof, which confer stable growth-coupled production of fumaric acid;   or an ortholog thereof, which confer stable growth-coupled production of fumaric acid.   
     
     
         90 . The process of  claim 87 , wherein the non-naturally occurring microbial organism is  Escherichia coli.    
     
     
         91 . The process of  claim 87 , wherein the olefin metathesis transformation catalyst comprises a ruthenium catalyst comprises an N-heterocyclic carbene ligand. 
     
     
         92 . The process of  claim 87 , wherein the olefin metathesis transformation catalyst comprisies [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro[[2-(1-methoxy)phenyl]methylene], [1,3-Bis(2-methylphenyl)-2-imidazolidene]dichloro(benzylidene) (tricyclohexylphosphine) ruthenium (II), ruthenium, dichloro(phenylmethylene)bis(tricyclohexylphospine), [1,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(3-methyl-2-butenylidene)(tricyclohexylphosphine) ruthenium (II), and ruthenium, [1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(phenylmethylene)(tricyclohexylphosphine).