WO2025199154A1 - Synthesis of e pheromones - Google Patents

Abstract

Improved methods for preparing lepidopteran insect pheromones and structurally related compounds. In one aspect, the invention provides a method for synthesizing a fatty olefin drivative. Methods include use of linear C3-C12 olefin with a delta 9-unsaturated fatty acid alkyl ester in the presence of a Z-selective metathesis catalyst. Alternative methods include contacting jojoba oil or oleic alcohols with a metathesis catalyst.

Description

SYNTHESIS OF E PHEROMONES

PRIORITY CLAIM

This application claims the benefit of the filing date of United States Provisional Patent

Application Serial Number 63/566,891 , filed March 18, 2024 for “SYNTHESIS OF E PHEROMONES” which are incorporated herein in its entirety.

TECHNICAL FIELD

The present invention relates to methods for synthesizing a fatty olefin derivative.

DESCRIPTION OF THE ART

Insect infestation is a primary cause of crop loss throughout the United States. A wide variety of chemical pesticides has been relied upon in the past to control insect pests. However, environmental concerns as well as consumer safety concerns have led to the de-regi strati on of many pesticides and a reluctance to use others on agricultural products which are ultimately consumed as food. As a consequence, there is a desire for the development of alternative biological control agents.

Pheromones are chemicals which are secreted outside the body of insects can be classified according to the type of behavioral reaction they induce. Pheromone classes include aggregation pheromones, sexual pheromones, trail pheromones, and alarm pheromones. Sex pheromones, for example, are typically secreted by insects to attract partners for mating.

When pheromones are dispersed on leaves of a crop plant, or in an orchard environment in small quantities over a continuous period of time, pheromone levels reach thresholds that can modify insect behavior. Maintenance of pheromone levels at or above such thresholds can impact insect reproductive processes and reduce mating. Use of pheromones in conjunction with conventional insecticides can therefore reduce the quantity of insecticide required for effective control and can specifically target pest insects while preserving beneficial insect populations. These advantages can reduce risks to humans and the environment and lower overall insect control costs.

Despite these advantages, pheromones are not widely used today because of the high cost of active ingredient (Al). Even though thousands of insect pheromones have been identified, less than about twenty insect pests worldwide are currently controlled using pheromone strategies, and only 0.05% of global agricultural land employs pheromones. Lepidopteran pheromones, which are naturally occurring compounds, or identical or substantially similar synthetic compounds, are designated by an unbranched aliphatic chain (between 9 and 18 carbons) ending in an alcohol, aldehyde, or acetate functional group and containing up to 3 double bonds in the aliphatic backbone. Improved methods for preparing lepidopteran insect pheromones and structurally related compounds are needed. The present invention meets this and other needs.

DETAILED DESCRIPTION AND EXAMPLES

In one aspect, the invention provides a method for synthesizing a fatty olefin derivative. The method includes: a) contacting an olefin according to Formula I with a metathesis reaction partner according to Formula lib

(Ubl in the presence of a metathesis catalyst under conditions sufficient to form a metathesis product according to Formula Illb:

(Ulb) b) converting the metathesis product to the fatty olefin derivative. Each R¹ is independently selected from H, Ci-i8 alkyl, and C2-18 alkenyl; R^2b is C1-8 alkyl; subscript y is an integer ranging from 0 to 17; and subscript z is an integer ranging from 0 to 17; and c) contacting the fatty olefin derivative with a second metathesis catalyst.

In certain embodiments, the metathesis catalyst is a tungsten catalyst or a molybdenum catalyst. In various embodiments, the fatty olefin derivative is a pheromone. Pheromone compositions and methods of using them are also described. Steps a) and b) above are described in U.S. Patent Nos: 9,776,179; 10,596,562; and 1 1,779,911, the contents of which are hereby incorporated by reference in their entirety for all purposes.

In another aspect, the invention provides a method for synthesizing a fatty olefin derivative. The method includes: a) contacting an olefin according to Formula Iwith a metathesis reaction partner according to Formula lib in the presence of a metathesis catalyst under conditions sufficient to form a metathesis product according to Formula Illb; b) converting the metathesis product to the fatty olefin derivative. Each R1 is independently selected from H, Cl-18 alkyl, and C2-18 alkenyl; R2b is Cl-8 alkyl; subscript y is an integer ranging from 0 to 17; and subscript z is an integer ranging from 0 to 17; and c) contacting the fatty olefin derivative with a second metathesis catalyst..

In certain embodiments, the metathesis catalyst is a tungsten catalyst or a molybdenum catalyst. In various embodiments, the fatty olefin derivative is a pheromone. Pheromone compositions and methods of using them are also described. Pheromone compositions and methods of using them are also described. Steps a) and b) above are described in U.S. Patent No: 11,077,433, the contents of which are hereby incorporated by reference in their entirety for all purposes.

Using M72 (C627) catalyst, Z8-12Ac was converted to E8-12Ac with E:Z ratio of 85:15 with 1 ppm catalyst loading (mole ppm per double bond), as shown:

Double bond migration was minimized to N.D. (not detected) with low catalyst loading and low temperature. Isomerization to Z/E8-1 lAc and Z/E8-13Ac was reduced to N.D. with purification of M72 catalyst. E/Z8-12Ac product was produced with high purity (E+Z isomer overall purity: >98.5%), and a E:Z ratio of 85: 15. The yield of produced E/Z8-12Ac product was 88% when 3 equivalents of 4-octene was used.

Experimental results are summarized in Table 1 through Table 5 below. E:Z ratio of 85: 15 was achieved, with an overall (E+Z)8-12Ac purity of >97.8% (starting material Z+E8- 12Ac purity: 97.1%). In Stage 3, the overall (E+Z)8-12Ac purity of >98.5% was achieved using >98.5% purity (Z+E)8-12Ac as a starting material. Low temperatures (0° to 10 °C) and low catalyst loadings (<50 ppm) were necessary to minimize the double bond migration byproducts (E/Z9-12Ac and E/Z7-12Ac) to <0.1%, F as shown in Table 1. Hydroperoxides kill the catalyst stoichiometrically and leads to the need of high catalyst loadings and increased chances of impurity formation; the purified 4-octene via alumina treatment gave better results at low catalyst loading (12.5 ppm).

Using high purity Z8-12Ac and 4-octene, the catalyst loading (mol ppm/all double bonds) was reduced from 200 ppm to 1 ppm (screened catalyst loadings were 200 ppm, 100 ppm, 50 ppm, 25 ppm, 12.5 ppm and 1 ppm) and same results were obtained: at 1 ppm catalyst loading, 1 h at 0 °C, 96% Z8-12Ac was converted to 84% E8-12Ac and 15% Z8-12Ac. The presence of 1.3% 8-9Ac in Z8-12Ac did not inhibit/change the catalyst reactivity -- at 1 ppm catalyst loading, the desired 85: 15 E/Z ratio was achieved. The presence of 4-octene (3 equiv. to Z8-12Ac) successfully reduced the unwanted self-metathesis byproduct (diacetate). Without 4- octene, the yield of (E+Z)8-12Ac was only 45%; with 3 equiv. of 4-octene, the yield of (E+Z)8- 12Ac was increased to 88%. After the reaction reached equilibrium within 1 h, the reaction mixture was left to 4 h (without quenching) to check if new impurities grew in — no new impurities were observed, and no increase was observed for double bond migrated byproducts.

Table 1. Initial screening result of metathesis reaction with Soneas Z8-12Ac containing 0.1% 8-9Ac and Z4-octene from Fisher

Table 2. Catalyst loading screening result of metathesis reaction with Z8-12Ac containing 1.3% 8-9 Ac and 4-octene from Soneas

Table 3. Reaction time screening result of metathesis reaction

In an alternative embodiment, instead of using Z8-12Ac as starting material, the chemistry can also work using the following materials and steps:

1 Pot, 2 Step Route into Faise Codhng Moth (E8-12AC)

¹ UltraCat is a CAAC (Cycfc Alkyl Amino Carbene) catalyst

² US Patent 6,215,019 Pederson and Grubbs, Use vacuum, te E5-lQAc procedure

The present invention further relates to an improved method for synthesizing pheromones using jojoba and oleic alcohols as starting materials. This method employs advanced metathesis reactions to efficiently produce fatty olefin derivatives that serve as key intermediates in pheromone synthesis, as described and shown below.

Step 1: Metathesis Reaction to Form a Metathesis Product

The synthesis begins with contacting an olefin of Formula I with a metathesis reaction partner of Formula lib in the presence of a metathesis catalyst under controlled reaction conditions. This reaction yields a metathesis product of Formula Illb. The olefin substrates are derived from natural sources, specifically jojoba oil and oleic alcohols, which provide the necessary hydrocarbon chains.

Each R1 is independently selected from hydrogen (H), Cl-18 alkyl, or C2-18 alkenyl groups, while R2b is a Cl -8 alkyl group. The values for subscripts y and z are integers ranging from 0 to 17, ensuring the generation of diverse metathesis products suitable for subsequent conversion. The metathesis reaction is catalyzed by tungsten or molybdenum-based catalysts, which enhance the efficiency and selectivity of the reaction, yielding high-purity products with minimal side reactions.

Step 2: Conversion to Fatty Olefin Derivative

Once the metathesis product is formed, it undergoes a series of transformations to convert it into a fatty olefin derivative. This conversion may include selective hydrogenation, isomerization, or oxidation-reduction steps, depending on the desired end-product characteristics. The precise reaction conditions, including temperature, pressure, and solvent selection, are optimized to maximize yield and minimize by-products.

Step 3: Secondary Metathesis for Final Pheromone Formation

In the final step, the fatty olefin derivative is subjected to a second metathesis reaction using another tungsten or molybdenum catalyst. This step tailors the molecular structure to produce the final pheromone compound with high specificity. The method enables the production of pheromones with well-defined functional groups, essential for their biological activity.

Utilizing jojoba oil and oleic alcohols provides a renewable and environmentally friendly approach to pheromone synthesis. High Selectivity and Yield: The use of tungsten or molybdenum catalysts ensures high reaction efficiency and minimal by-product formation, thus creating high selectivity and yield. The resulting pheromones can be applied in pest control, agriculture, and other industries requiring specific semiochemicals. The method is designed for industrial scalability, allowing for large-scale production of pheromone compounds with consistent quality. The invention also encompasses various pheromone compositions derived from this method and their applications in different industries. The processes described herein are further detailed in U.S. Patent Nos. 9,776,179; 10,596,562; 11,779,911; and 11,077,433, all of which are incorporated by reference in their entirety for all applicable purposes.

Yet another embodiment relates to the synthesis of El l-14Ac, where a jojoba acetate composition is utilized as the precursor. The jojoba acetate composition comprises:

. ~6% Z9-18Ac

. 55% Z11-20 Ac

. -34% Z 13-22 Ac ~5% >Z15-24Ac

The synthesis process involves selective transesterification and subsequent catalytic isomerization to achieve the desired E-isomer, as shown below. The jojoba acetates undergo selective cleavage via enzymatic or chemical hydrolysis to yield their respective alcohols. The alcohol fraction, primarily composed of Z11-20OH, is then subjected to controlled oxidation to yield Z1 l-20Ac. This intermediate is then selectively isomerized under catalytic conditions favoring the E-isomer formation, producing El l-14Ac with a high degree of purity.

An alternative embodiment relates to the synthesis of The synthesis of El l-16Ac begins with jojoba oil as the raw material. The process follows a stepwise transformation, as described and shown below:

Step 1 - Jojoba Oil to Jojoba Alcohols: Jojoba oil undergoes hydrolysis or transesterification to yield the corresponding jojoba alcohols.

Step 2 - Jojoba Alcohols to Jojoba Acetates: The alcohols are acetylated using acetic anhydride or an alternative acetylation reagent to produce jojoba acetates.

Step 3 - Introduction of Z5-Decene: The addition of Z5-decene enables chain modification through cross-metathesis or another selective reaction method. Step 4 - Cross-metathesis: Jojoba acetates undergo an olefin cross-metathesis reaction with (Z)5-decene to yield El 1 -16Ac and other metathesis co-products, which are separated by fractional distillation

Step 5 - Isomerization to Ell-16Ac: The resultant intermediate undergoes catalytic isomerization under conditions that favor the E-isomer, achieving an E:Z ratio of approximately 85: 15.

In a particular embodiment, a stabilizing agent may also be added.

This process ensures a high-yield conversion of jojoba-derived precursors into El l-16Ac, providing a scalable and efficient synthetic pathway for pheromone applications and other specialty chemical uses.

Claims

1. A method for synthesizing a fatty olefin derivative, the method comprising: a) contacting a linear C3-C12 olefin with a A⁹ -unsaturated fatty acid alkyl ester in the presence of a Z-selective metathesis catalyst to form a Cn-C2o(Z)-9-unsaturated fatty acid alkyl ester; b) converting the Cn-C2o(Z)-9-unsaturated fatty acid alkyl ester to the fatty olefin derivative; wherein the fatty olefin derivative is selected from the group consisting of a Cu-C2o(Z)-⁹ -fatty alcohol, an acetate ester of a Cn-C2o(Z)-9-fatty alcohol, and a Cn-C2o(Z)-9-alkenal; and c) contacting the fatty olefin derivative with a second metathesis catalyst.

2. A method for synthesizing a fatty olefin derivative according to Formula VIb:

VIb the method comprising: a) reducing an alkyl ester according to Formula lib ilb to form an alkenol according to Formula VIII b) acylating the alkenol to form an acylated alkenol according to Formula IX c) contacting the acylated alkenol with an olefin according to Formula I i in the presence of a metathesis catalyst having the formula:

under conditions sufficient to form the fatty olefin derivative; wherein:

R¹ is selected from the group consisting of H, Cuis alkyl, and C2-18 alkenyl;

R^2b is Ci-8 alkyl,

R^2c is Ci-e acyl, subscript y is an integer ranging from 0 to 17; and subscript z is an integer ranging from 0 to 17; and d) contacting the fatty olefin derivative with a second metathesis catalyst.

3. A method for synthesizing a compound according to Formula VIb:

(Vlb; the method comprising: a) acylating an alkenol according to Formula VIII

(VlII) to form an acylated alkenol according to Formula IX b) contacting the acylated alkenol with an olefin according to Formula I in the presence of a metathesis catalyst having a structure according to Formula 2a thereby forming the compound of Formula VIb; wherein:

R¹ is selected from the group consisting of H, Cuis alkyl, and C2-18 alkenyl;

R^2c is Ci-e acyl, subscript y is an integer ranging from 0 to 17; subscript z is an integer ranging from 0 to 17;

M is Mo or W;

R^3ais aryl, heteroaryl, alkyl, or cycloalkyl, each of which is optionally substituted;

R^7ais pyrrolyl, imidazolyl, indolyl, pyrazolyl, azaindolyl, or indazolyl, each of which is optionally substituted;

R^8ais optionally substituted aryl;

R^5ais a hydrogen atom, alkyl, or alkoxy;

R^4b is a hydrogen atom, — O — (C1-6 alkyl), — CH2 — O — (C1-6 alkyl), heteroalkoxy, or — N(Ci- 6 alkyl)2; and

R^4C and R^4d are independently a hydrogen atom, C1-6 alkyl, C1-6 alkoxy, a halogen atom, — NO2, an amide, or a sulfonamide; and c) contacting the fatty olefin derivative with a second metathesis catalyst.

4. A method for synthesizing a fatty olefin derivative, the method comprising: a) contacting an olefin according to Formula I wherein

R’ is Ci -is alkyl, and subscript z is an integer ranging from 0 to 17, with a metathesis reaction partner according to Formula lib wherein

R¹ is selected from the group consisting of H, Ci-18 alkyl, and C2-18 alkenyl,

R^2b is C1-8 alkyl, and subscript y is an integer ranging from 0 to 17, in the presence of a Z-selective metathesis catalyst to form a metathesis product according to Formula IIIc: b) converting the metathesis product to the fatty olefin derivative; wherein the fatty olefin derivative is selected from the group consisting of an unsaturated fatty alcohol, an unsaturated fatty alcohol acetate, an unsaturated fatty aldehyde, and an unsaturated fatty acid ester; and wherein:

(i) the Z-selective metathesis catalyst has a structure according to Formula 2:

(2) wherein:

M is Mo or W;

R^3ais selected from the group consisting of aryl, heteroaryl, alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl, each of which is optionally substituted;

R^4aand R^5aare independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted heteroalkyl, optionally substituted heteroalkenyl, optionally substituted aryl, and optionally substituted heteroaryl;

R^7ais selected from the group consisting of alkyl, alkoxy, heteroalkyl, aryl, aryloxy, heteroaryl, silylalkyl, and silyloxy, each of which is optionally substituted; and

R^6ais R^8a — X — , wherein

X is O or S and lea is optionally substituted aryl; or X is O and R^8a is SiR^9aR^10aR^{l la} or CR^12aR^13aR^14a, wherein R^9a, R^10a, R^lla, R^12a, R^13a, and R^14a are independently selected from the group consisting of optionally substituted alkyl and optionally substituted phenyl; or

R^6a and R^7a are linked together and are bonded to M via oxygen; or (ii) the Z-selective metathesis catalyst is selected from the group consisting of

c) contacting the fatty olefin derivative with a second metathesis catalyst.

5. A method for synthesizing a fatty olefin derivative, the method comprising: a) contacting jojoba oil or oleic alcohols with a metathesis catalyst under conditions sufficient to form an unsaturated fatty olefin derivative; b) converting the unsaturated fatty olefin derivative to a composition suitable for pheromone synthesis; c) isolating the resultant product with a purity greater than 98.5%; and d) minimizing unwanted byproducts, including double bond migration byproducts, to below 0.1%.

6. A method for isomerizing Z8-12Ac to E8-12Ac, the method comprising: a) contacting Z8-12Ac with ruthenium catalyst at a catalyst loading of 1 ppm (mole ppm per double bond); b) maintaining the reaction temperature between 0°C and 10°C to minimize double bond migration; c) introducing 4-octene in an appropriate molar ratio relative to Z8-12Ac; and d) allowing the reaction to proceed to achieve an E:Z ratio of approximately 85: 15.

7. The method according to claim 6, further comprising isolating an E/Z8-12Ac product with an overall isomer purity of greater than 98.5%.

8. The method according to claim 6, further comprising minimizing the formation of double bond migration byproducts, including E/Z9-12Ac and E/Z7-12Ac, to below 0.1%.

9. A method for converting Z-isomers to E-isomers of unsaturated fatty acid derivatives, the method comprising: a) contacting a Z-isomer of an unsaturated fatty acid derivative with a metathesis catalyst under controlled reaction conditions; b) maintaining reaction temperatures between 0°C and 10°C to minimize byproduct formation; c) utilizing a molar equivalent of an olefinic co-reactant to enhance the isomerization efficiency; and d) achieving an E:Z isomer ratio of at least 85:15.

10. The method according to claim 9, further comprising isolating the resultant E-isomer with a purity of greater than 98.5%.

11. The method according to claim 9, further comprising minimizing the formation of double bond migration byproducts to below 0.1%.