Semisynthetic routes to organic compounds
View Patent ↗The present disclosure relates to chemo-enzymatic processes for the preparation of lactones (including, e.g., macrolactones, γ-lactones, and δ-lactones) and/or macrocyclic ketones, which are compounds of industrial value, for example, for use as fragrance ingredients. The chemo-enzymatic processes combine the in vivo microbial production of fatty acid derivatives and the subsequent ex vivo synthetic transformation of the fatty acid derivatives to provide the lactones and macrocyclic ketones.
1. A chemo-enzymatic process for producing Z-9 cyclohexadecenolide having the chemical structure:
the process comprising:
(i) culturing a recombinant microorganism in the presence of a carbon-based feedstock, wherein
the recombinant microorganism is a bacterium, cyanobacterium, yeast, or filamentous fungus,
the recombinant microorganism is genetically engineered to overexpress or to exogenously express an ω-hydroxylase or oxygenase of E.C. 1.14.15.3 compared to a native host cell, and
the recombinant microorganism produces an unsaturated ω-hydroxy fatty acid derivative that is ω-hydroxy-cis-9-hexadecenoic acid having the chemical structure:
and
(ii) contacting the ω-hydroxy-cis-9-hexadecenoic acid ex vivo with a reagent under conditions sufficient to produce the Z-9 cyclohexadecenolide, wherein the contacting comprises dehydration, lactonization, or a combination thereof.
2. The chemo-enzymatic process of claim 1 , wherein the recombinant microorganism is further engineered to overexpress or exogenously express a thioesterase.
3. The chemo-enzymatic process of claim 1 , wherein the recombinant microorganism is further engineered to overexpress a desaturase (EC 1.14.19).
4. The chemo-enzymatic process of claim 1 , wherein the recombinant microorganism is a recombinant Escherichia coli ( E. coli ).
5. The chemo-enzymatic process of claim 1 , further comprising isolating the ω-hydroxy-cis-9-hexadecenoic acid prior to the contacting.
6. The chemo-enzymatic process of claim 1 , wherein the ω-hydroxy -cis-9-hexadecenoic acid is secreted from the recombinant microorganism and the contacting is performed without isolating the ω-hydroxy-cis-9-hexadecenoic acid.
7. The chemo-enzymatic process of claim 1 , wherein the carbon-based feedstock comprises a simple carbon source.
8. The chemo-enzymatic process of claim 1 , wherein the carbon-based feedstock is renewable.
9. The chemo-enzymatic process of claim 1 , wherein the reagent comprises a Lewis acid.
10. The chemo-enzymatic process of claim 9 , wherein the Lewis acid is an organostannane transesterification catalyst, a copper salt, a zinc salt, a silver triflate, or a zeolite.
11. The chemo-enzymatic process of claim 1 , wherein the reagent comprises a protic acid.
12. The chemo-enzymatic process of claim 11 , wherein the protic acid is hydrochloric acid, sulfuric acid, phosphoric acid, or a recoverable resin acid.
13. The chemo-enzymatic process of claim 1 , wherein the Z-9 cyclohexadecenolide is a fragrance ingredient.
14. The chemo-enzymatic process of claim 1 , wherein the reagent comprises a peptide coupling agent.
15. A chemo-enzymatic process for producing a fragrance or perfume comprising Z-9 cyclohexadecenolide having the chemical structure:
the process comprising:
(i) culturing a recombinant microorganism in the presence of a carbon-based feedstock, wherein
the recombinant microorganism is a bacterium, cyanobacterium, yeast, or filamentous fungus,
the recombinant microorganism is genetically engineered to overexpress or to exogenously express an ω-hydroxylase or oxygenase of E.C. 1.14.15.3 compared to a native host cell, and
the recombinant microorganism produces an unsaturated ω-hydroxy fatty acid derivative that is ω-hydroxy-cis-9-hexadecenoic acid having the chemical structure:
(ii) contacting the ω-hydroxy-cis-9-hexadecenoic acid ex vivo with a reagent under conditions sufficient to produce the Z-9 cyclohexadecenolide, wherein the contacting comprises dehydration, lactonization, or a combination thereof; and
wherein the Z-9 cyclohexadecenolide is used to produce the fragrance or perfume.
16. A fragrance or perfume produced by the chemo-enzymatic process of claim 15 .