1,3-Aliphatic diol compounds and their derivatives

Abstract

The present disclosure relates to the field of specialty chemicals. Specifically, the present disclosure provides novel 1,3-fatty diol compounds of formula (II) and (IV) and their derivatives, specifically glycosides, which can be used, for example, in the production of personal care products, surfactants, detergents, polymers, pigments, coatings, and as emulsifiers, emollients and thickeners in cosmetics and foods, as industrial solvents and plasticizers, etc.

Description

[0001] This application is a divisional application of the Chinese patent application with application number 201780063821.1 (PCT / US / 2017 / 051664), application date September 14, 2017, and invention name “1,3-fatty diol compounds and their derivatives”. Technical Field

[0002] The present disclosure relates generally to the field of specialty chemicals useful as components in industrial reagents and processes, such as in the production of detergents and surfactants, as emulsifiers, emollients and thickeners in cosmetics and foods, as industrial solvents and plasticizers, and the like.

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of U.S. Provisional Application No. 62 / 394,537, filed September 14, 2016, which is incorporated herein by reference in its entirety. Background Art

[0005] Fatty alcohols, especially fatty diols (or aliphatic diols), are amphiphilic molecules with a variety of commercial and industrial uses. For example, fatty alcohols can be used as emollients and thickeners in cosmetics and foods, as well as industrial solvents, plasticizers, lubricants, emulsifiers, polymer building blocks, etc. (see, e.g., H. Maag (1984) Journal of the American Oil Chemists' Society 61(2): 259–267). Particularly useful are 1,3-fatty diols.

[0006] 1,3-Fatty diols can be used as lubricants, as linking molecules between other molecules, for example, in polymer production. 1,3-Fatty diols can also be used as surfactants and as precursors of surfactants, for example, 1,3-Fatty diols can be used to prepare "Gemini" surfactants, in which the alcohol moieties are chemically modified (e.g., ethoxylated, glycosylated, sulfated, etc.). Gemini surfactants or Gemini-type surfactants exhibit superior properties compared to those of similar conventional surfactants (see, for example, Gemini Surfactants: Synthesis, Interfacial and Solution-Phase Behavior, and Applications, Vol. 117, Zana, R.; Xia, J. ed.; Marcel Dekker: New York, 2004).

[0007] The 3-hydroxyl moiety of 1,3-aliphatic diols forms a chiral center at the third carbon (C-3), which makes 1,3-aliphatic diols useful as synthons for the production of chiral important compounds such as pharmaceuticals, nutraceuticals, pesticides, herbicides, flavors, fragrances, solvents, bioactive compounds, etc.

[0008] In addition to the functionality of the hydroxyl group, changes in the carbon chain structure of 1,3-fatty diols provide molecules with other chemical properties and / or potentially new properties that can be used to solve old problems in an improved way and / or that can find entirely new uses. For example, unsaturated fatty diols have additional functional groups in the form of double bonds that can be used for chemical reactions.

[0009] Unsaturated fatty alcohols and fatty diols are particularly valuable because the presence of the double bond imparts a number of advantageous properties to the molecule. For example, unsaturated fatty diols have lower melting points, higher water solubility, and offer the possibility of introducing functional groups into the C=C double bond compared to their saturated counterparts (Egan, R. et al., (1984) Journal of the American Society of Oil Chemists, Vol. 61 (2): 324-329). Unsaturated fatty alcohols are therefore important intermediates for a large number of products in the chemical industry (see, for example, U. Ploog et al., Soaps, Oils and Waxes (Seifen- -Fette-Wachse)》109,225(1983)).

[0010] Unlike saturated fatty diols which are easily produced from petroleum precursors using, for example, the Prince reaction (see, e.g., E. Arundale, LA Mikeska Chem. Rev.; 1952; 51(3); 505-555), unsaturated fatty diols are significantly more difficult to produce using petrochemical materials and processes.

[0011] Typically, unsaturated fatty alcohols are produced by subjecting a mixture of fatty acid methyl esters derived from oils (e.g., sunflower oil, palm oil, palm kernel oil, and coconut oil) to high pressure hydrogenation in the presence of a chromium- and / or zinc-containing mixed oxide catalyst (see, e.g., Ullmann's Encyclopedia of Industrial Chemistry, 7th ed., Vol. 14: 117. John Wiley and Sons, Inc. 2011). Zinc chromite-type catalysts promote selective hydrogenation of carbonyl groups rather than C=C double bonds (see, e.g., Adkins and Sauer, (1937) Journal of the American Chemical Society, Vol. 59(1): 1-3).

[0012] Unfortunately, because unsaturated fatty alcohols and unsaturated fatty diols can only be produced from a limited variety of natural oils, the supply of raw materials can be unstable and variable. In addition, the reliance on natural oils and their inherent structures for fatty diol production limits the diversity of chemical structures that can be produced.

[0013] Clearly, then, since 1,3-fatty diols, and especially unsaturated 1,3-fatty diols, are such useful molecules, there is a need in the art for new 1,3-fatty diols.

[0014] Fortunately, as will be appreciated from the detailed description below, the present disclosure provides this and other needs. Summary of the invention

[0015] One aspect of the present disclosure provides a 12-carbon, unbranched, unsaturated aliphatic diol having a single Δ5 double bond and having a hydroxyl group at carbon number 1 (C-1) and a hydroxyl group at carbon number 3 (C-3), wherein a chiral center is present at C-3, and wherein the aliphatic diol has a general chemical formula according to Formula II.

[0016]

[0017] In one exemplary embodiment, the double bond is in the (Z) configuration. In another exemplary embodiment, the double bond is in the (E) configuration. In one exemplary embodiment, the chiral center at C-3 has the R configuration. In one exemplary embodiment, the chiral center at C-3 has the S configuration. In another exemplary embodiment, the double bond is in the (Z) configuration and the chiral center at C-3 has the R configuration.

[0018] One aspect of the present disclosure provides a 14-carbon, unbranched, unsaturated fatty diol having a single Δ7 double bond and having a hydroxyl group at carbon number 1 (C-1) and a hydroxyl group at carbon number 3 (C-3), wherein a chiral center is present at C-3, and wherein the fatty diol has a general chemical formula according to Formula III.

[0019]

[0020] In one exemplary embodiment, the double bond is in the (Z) configuration. In another exemplary embodiment, the double bond is in the (E) configuration. In one exemplary embodiment, the chiral center at C-3 has the R configuration. In one exemplary embodiment, the chiral center at C-3 has the S configuration. In another exemplary embodiment, the double bond is in the (Z) configuration and the chiral center at C-3 has the R configuration.

[0021] One aspect of the present disclosure provides a 16-carbon, unbranched, unsaturated aliphatic diol having a single Δ9 double bond and having a hydroxyl group at carbon number 1 (C-1) and having a hydroxyl group at carbon number 3 (C-3), wherein a chiral center is present at C-3, and wherein the aliphatic diol has a chemical formula according to Formula IV

[0022]

[0023] In one exemplary embodiment, the double bond is in the (Z) configuration. In another exemplary embodiment, the double bond is in the (E) configuration. In one exemplary embodiment, the chiral center at C-3 has the R configuration. In one exemplary embodiment, the chiral center at C-3 has the S configuration. In another exemplary embodiment, the double bond is in the (Z) configuration and the chiral center at C-3 has the R configuration.

[0024] One aspect of the present disclosure provides a 1,3-aliphatic diol derivative having a chemical formula according to Formula V.

[0025]

[0026] wherein n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, and wherein R 1 and R 2 Each is independently selected from the group consisting of: H, a monosaccharide bound at the anomeric carbon of a monosaccharide, a disaccharide bound at the anomeric carbon of a disaccharide, a trisaccharide bound at the anomeric carbon, and a polysaccharide bound at the anomeric carbon. 1 and R 2 Both are not H. In another exemplary embodiment, R 1 and R 2 Neither is H. In another exemplary embodiment, the monosaccharide is selected from pentoses and hexoses. In another exemplary embodiment, the hexose is selected from allose, altrose, glucose, mannose, gulose, idose, galactose, or talose. In another exemplary embodiment, the disaccharides, trisaccharides, and polysaccharides comprise a sugar selected from pentoses, hexoses, or mixtures of any two or more thereof. In another exemplary embodiment, the hexose is selected from allose, altrose, glucose, mannose, gulose, idose, galactose, talose, or mixtures of any two or more thereof. In another exemplary embodiment, R 1 and R 2 are different monosaccharides. In another exemplary embodiment, R 1 and R 2are the same monosaccharide. In another exemplary embodiment, the monosaccharide, disaccharide, trisaccharide and polysaccharide comprise a hexose selected from allose, altrose, glucose, mannose, gulose, idose, galactose, talose or a mixture of any two or more thereof. In another exemplary embodiment, the monosaccharide, disaccharide, trisaccharide or polysaccharide comprises a sugar selected from furanose, pyranose or a mixture of any two or more thereof.

[0027] One aspect of the present disclosure provides a 1,3-aliphatic diol derivative having a chemical formula according to Formula VI.

[0028]

[0029] wherein m is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 18, and wherein R 3 and R 4 Each is independently selected from the group consisting of: H, a monosaccharide bound at the anomeric carbon of a monosaccharide, a disaccharide bound at the anomeric carbon of a disaccharide, a trisaccharide bound at the anomeric carbon, and a polysaccharide bound at the anomeric carbon. 3 and R 4 Both are not H. In another exemplary embodiment, R 3 and R 4 Neither is H. In another exemplary embodiment, the monosaccharide is selected from pentoses and hexoses. In another exemplary embodiment, the hexose is selected from allose, altrose, glucose, mannose, gulose, idose, galactose, or talose. In another exemplary embodiment, the disaccharides, trisaccharides, and polysaccharides comprise a sugar selected from pentoses, hexoses, or mixtures of any two or more thereof. In another exemplary embodiment, the hexose is selected from allose, altrose, glucose, mannose, gulose, idose, galactose, talose, or mixtures of any two or more thereof. In another exemplary embodiment, R 3 and R 4 are different monosaccharides. In another exemplary embodiment, R 3 and R 4 are the same monosaccharide. In another exemplary embodiment, the monosaccharide, disaccharide, trisaccharide and polysaccharide comprise a hexose selected from allose, altrose, glucose, mannose, gulose, idose, galactose, talose or a mixture of any two or more thereof. In another exemplary embodiment, the monosaccharide, disaccharide, trisaccharide or polysaccharide comprises a sugar selected from furanose, pyranose or a mixture of any two or more thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1A Schematic illustration of the fragment ions formed by the fragmentation of 1,3-dodecanediol trimethylsilyl ether. Figure 1B The experimental mass spectrum fragmentation pattern of 1,3-dodecanediol trimethylsilyl ether is shown. Note the distinctive ions of 331 (MW-15), 229, and 219 of the saturated diol adduct.

[0031] Figure 2A Schematic diagrams illustrate the fragment ions formed by the fragmentation of 5-dodecene-1,3-diol trimethylsilyl ether. In the schematic diagrams of the fragment ions, the double bond is shown as (E). However, the mixture is both (Z) and (E). In fact, due to the unique fatty acid metabolism, fermentation mainly produces 5-(Z)-dodecene-1,3-diol. Figure 2B The experimental mass spectrum fragmentation pattern of 5-dodecene-1,3-diol trimethylsilyl ether is shown. Note the distinctive ions of 329 (MW-15), 227, and 219 of the unsaturated diol adduct. DETAILED DESCRIPTION

[0032] definition

[0033] As used herein and in the appended claims, singular articles such as "a" and "an" and "the" and similar referents in the context of describing elements are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0034] As used herein, "about" is understood by those of ordinary skill in the art and may vary to some extent depending on the context in which it is used. If the use of the term "about" is unclear to one of ordinary skill in the art after considering the context in which the term is used, then "about" will mean up to plus or minus 10% of the particular item.

[0035] As will be appreciated by those skilled in the art, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof for any and all purposes. In addition, as will be appreciated by those skilled in the art, ranges include each individual member. Thus, for example, a group having 1-3 atoms refers to a group having 1, 2, or 3 atoms. Similarly, a group having 1-5 atoms refers to a group having 1, 2, 3, 4, or 5 atoms, and the like.

[0036] Unless otherwise defined, the technical and scientific terms used herein have the same meaning as those of ordinary skill in the art generally understood. Specifically, the disclosure utilizes conventional techniques in recombinant genetics, organic chemistry, fermentation and biochemistry. The basic texts of the common terms in public molecular biology and genetics include, for example, Lackie, "Dictionary of Cell and Molecular Biology", Elsevier Publishing Company (Elsevier) (5th edition 2013). The basic texts of the general methods and terms in public biochemistry include, for example, "Lehninger Principles of Biochemistry" 6th edition, David L.Nelson and Michael M.Cox edited, WH Freeman Publishing Company (WHFreeman) (2012). The basic texts of the general methods and terms in public fermentation include, for example, "Principles of Fermentation Technology", 3rd edition, Peter F Stanbury, Allan Whitaker and Stephen J Hall. Butterworth-Heinemann Publishing Company (Butterworth-Heinemann) (2016). Basic texts disclosing general methods and terminology in organic chemistry include, for example, Favre, Henri A. and Powell, Warren H. Nomenclature of Organic Chemistry. IUPAC Recommendations and Preferred Name 2013. Cambridge, UK: The Royal Society of Chemistry, 2013; Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques, edited by Stephane Caron, John Wiley & Sons (2011); Organic Chemistry, 9th ed. - Francis Carey and Robert Giuliano, McGraw Hill (2013).

[0037] Those skilled in the art will appreciate that the compounds of the present technology may exhibit tautomerism, conformational isomerism, geometric isomerism and / or stereoisomerism. Since the chemical formula diagrams in the specification and claims may represent only one of the possible tautomeric, conformational, stereochemical or geometric isomeric forms, it should be understood that the present technology encompasses any tautomeric, conformational, stereochemical and / or geometric isomeric forms of the compounds having one or more utilities described herein, as well as mixtures of the multiple different forms.

[0038] "Tautomer" refers to isomeric forms of compounds that are balanced with each other. The presence and concentration of isomeric forms will depend on the environment in which the compound is located and may be different, depending on, for example, whether the compound is solid or in an organic or aqueous solution. For example, in an aqueous solution, quinazolinone may exhibit the following isomeric forms, which are referred to as tautomers of each other:

[0039]

[0040] As another example, guanidine can exhibit the following isomeric forms, also known as tautomers of each other, in protic organic solutions:

[0041]

[0042] Due to the limitations of the structural formulae representing compounds, it is to be understood that all formulae of compounds described herein represent all tautomeric forms of the compounds and are within the scope of the present technology.

[0043] Unless a specific stereochemistry is explicitly indicated, stereoisomers (also referred to as optical isomers) of a compound include all chiral, diastereomeric, and racemic forms of the structure. Thus, compounds used in the present technology include optical isomers enriched or resolved at any or all asymmetric atoms, as shown in the figures. Both racemic and diastereomeric mixtures, as well as individual optical isomers, can be separated or synthesized to be substantially free of their enantiomeric or diastereomeric partners, and these stereoisomers are within the scope of the present technology.

[0044] Geometric isomers can be represented by symbols representing bonds, which can be single bonds, double bonds or triple bonds as described herein. A variety of geometric isomers and mixtures thereof obtained by arranging substituents around carbon-carbon double bonds are provided herein. Substituents around carbon-carbon double bonds are named as in "Z" or "E" configurations, wherein the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both "E" and "Z" isomers.

[0045] Substituents around a carbon-carbon double bond may alternatively be referred to as "cis" or "trans," where "cis" represents substituents on the same side of the double bond and "trans" represents substituents on opposite sides of the double bond. The term "cis" represents substituents on the same side of the ring plane, and the term "trans" represents substituents on opposite sides of the ring plane. Mixtures of compounds in which substituents are placed on both the same and opposite sides of the ring plane are designated "cis / trans."

[0046] In certain embodiments, the pharmaceutically acceptable forms thereof are isomers. "Isomers" are different compounds with the same molecular formula. "Stereoisomers" are isomers that differ only in the arrangement of atoms in space. As used herein, the term "isomer" includes any and all geometric isomers and stereoisomers. For example, "isomers" include cis- and trans-isomers, E- and Z-isomers, R- and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, racemic mixtures thereof, and other mixtures thereof, which fall within the scope of the present disclosure.

[0047] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A mixture of a pair of enantiomers in any proportion may be referred to as a "racemic" mixture. If appropriate, the term "(+-)" is used to name a racemic mixture. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by R or S. The resolved compound whose absolute configuration is unknown may be named (+) or (-), depending on the direction in which it rotates plane polarized light (right-handed or left-handed) at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers, and enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- according to absolute stereochemistry may be produced therefrom. The chemical entities, pharmaceutical compositions and methods of the invention are intended to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)-isomers may be prepared, for example, using chiral synthons or chiral reagents, or may be resolved using conventional techniques. The optical activity of the compounds may be analyzed by any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of dominance of one stereoisomer over another may be determined.

[0048] As used herein, the term "fatty diol" or "fatty diol" refers to an aliphatic diol having a carbon chain length of at least 5 carbons, which contains two hydroxyl (-OH) groups covalently bound to the carbon chain. In an exemplary embodiment, the "fatty diol" is a "1,3-fatty diol". As used herein, the expression "1,3-fatty diol" refers to an aliphatic diol having a carbon chain length of at least 8 carbons, wherein the alcohol portion is located at the first carbon (C-1) and the third carbon (C-3). "1,3-fatty diol" can be saturated or unsaturated. Therefore, generally as used herein, the expression "1,3-fatty diol" refers to a molecule having a structural formula as shown in Formula IA or Formula IB.

[0049]

[0050] In Formula IA, m is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 18, and the C-3 carbon can be the (R) or / and (S) enantiomer.

[0051]

[0052] In Formula IB, n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, the double bond can be in (Z) or (E) configuration, and the C-3 carbon can be (R) or / and (S) enantiomers. In an exemplary embodiment, the 1,3 fatty diol is 5-dodecene-1,3-diol. In other exemplary embodiments, the 1,3 fatty diol is 9-hexadecene-1,3-diol.

[0053] As used herein, the term "5-dodecene-1,3-diol" or equivalently "1,3-dodec-5-ene diol" or equivalently "5-dodecene-1,3-diol" or equivalently "dodec-5-ene-1,3-diol" refers to a novel 12-carbon, unbranched, unsaturated 1,3-diol having a double bond between carbons 5 and 6 (i.e., a Δ5 double bond, which can be in the (Z) or (E) configuration) and a hydroxyl group at carbon 1 (C-1) and a hydroxyl group at carbon 3 (C-3), wherein there is a chiral center at C-3 and the C-3 carbon can be the (R) or / and (S) enantiomer. Such molecules have the general structure shown in Formula II.

[0054]

[0055] As used herein, the term "7-tetradecene-1,3-diol" or equivalently "1,3-tetradecene-7-enediol" or equivalently "7-tetradecene-1,3-diol" or equivalently "tetradecene-7-ene-1,3-diol" refers to a novel 14-carbon, unbranched, unsaturated 1,3-diol having a double bond between carbons 7 and 8 (i.e., a Δ7 double bond, which can be in the (Z) or (E) configuration), and having a hydroxyl group at carbon 1 (C-1) and a hydroxyl group at carbon 3 (C-3), wherein there is a chiral center at C-3 and the C-3 carbon can be the (R) or / and (S) enantiomer.

[0056] Such molecules have the general structure shown in Formula III.

[0057]

[0058] As used herein, the term "9-hexadecene-1,3-diol" or equivalently "1,3-hexadecene-9-ene diol" or equivalently "9-hexadecene-1,3-diol" or equivalently "hexadecene-9-ene-1,3-diol" refers to a novel 16-carbon, unbranched, unsaturated 1,3-diol having a double bond between carbons 9 and 10 (i.e., a Δ9 double bond, which can be in the (Z) or (E) configuration), and having a hydroxyl group at carbon 1 (C-1) and a hydroxyl group at carbon 3 (C-3), wherein there is a chiral center at C-3 and the C-3 carbon can be the (R) or / and (S) enantiomer.

[0059] Such molecules have the general structure shown in Formula IV.

[0060]

[0061] As used herein, the term "polyol" refers to a compound having more than one hydroxyl group, typically a fatty alcohol. Thus, as referred to herein, a polyol may have two hydroxyl groups, three hydroxyl groups, four hydroxyl groups, etc. In general, a "polyol" having two hydroxyl groups is referred to herein as a "diol," a "polyol" having three hydroxyl groups is referred to herein as a "triol," a "polyol" having four hydroxyl groups is referred to herein as a "tetraol," and so on.

[0062] The expressions "hydroxyl", "hydroxyl group", "alcohol group" are used interchangeably herein and refer to a chemical functional group containing an oxygen atom covalently bonded to one hydrogen atom (-OH).

[0063] The term "enzyme classification (EC) number" refers to a number that designates a specific polypeptide sequence or enzyme. EC numbers classify enzymes according to the reaction they catalyze. EC numbers are established by the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology (IUBMB), and a description of these numbers is available on the IUBMB Enzyme Nomenclature website on the World Wide Web.

[0064] As used herein, the term "isolated" with respect to a product (eg, 5-dodecene-1,3-diol) refers to the product separated from cellular components, cell culture medium, or chemical or synthetic precursors.

[0065] As used herein, the terms "purification", "purified" or "purification" mean removing or separating a molecule from its environment by, for example, separation or partitioning. A "substantially purified" molecule is at least about 60% free (e.g., at least about 65% free, at least about 70% free, at least about 75% free, at least about 80% free, at least about 85% free, at least about 90% free, at least about 95% free, at least about 97% free, at least about 98% free, at least about 99% free) of other components to which it is bound. As used herein, these terms also refer to the removal of contaminants from a sample. For example, removal of contaminants can result in an increase in the percentage of fatty diols in a sample. For example, when 1,3-diol is produced in a recombinant host cell, 1,3-diol can be purified by removing host cell proteins. After purification, the percentage of 1,3-diol in the sample increases. The terms "purification", "purified" and "purification" are relative terms and do not require absolute purity. Thus, for example, when 1,3-diol is produced in a recombinant host cell, purified 1,3-diol is 1,3-diol that is substantially separated from other cellular components (eg, nucleic acids, polypeptides, lipids, carbohydrates or other hydrocarbons).

[0066] I. 1,3-Aliphatic diol compounds and their derivatives

[0067] A. General Methods

[0068] The present disclosure utilizes the conventional techniques in the field of recombinant genetics. The basic texts of the general methods and terms in public molecular biology and genetics include, for example, Sambrook et al., "Molecular Cloning, a Laboratory Manual", Cold Spring Harbor Press, 4th edition (Cold Spring Harbor, New York 2012); "Current Protocols in Molecular Biology" Vol. 1-3, John Wiley & Sons Publishing Company (1994-1998). The present disclosure also utilizes the conventional techniques in the field of biochemistry. The basic texts of the general methods and terms in public biochemistry include, for example, "Leininger's Principles of Biochemistry" 6th edition, David L. Nelson and Michael M. Cox, editors, WH Freeman Publishing Company (2012). The present disclosure also utilizes the conventional techniques in industrial fermentation. Basic texts disclosing the general methods and terms in fermentation include, for example, "Principles of Fermentation Technology", 3rd edition, Peter F. Stanbury, Allan Whitaker and Stephen J. Hall. Butterworth-Heinemann Publishing Company (2016); "Fermentation Microbiology and Biotechnology", 2nd edition, EMT El-Mansi, CFA Bryce, Arnold L. Demain and AR Allman, eds., CRC Press (CRC Press) (2007). The present disclosure also utilizes conventional techniques in the field of organic chemistry. Basic texts disclosing common methods and terminology in organic chemistry include, for example, Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques, edited by Stephane Caron, John Wiley & Sons (2011); The Synthetic Organic Chemist's Companion, Michael C. Pirrung, John Wiley & Sons (2007); Organic Chemistry, 9th Edition - Francis Carey and Robert Giuliano, McGraw-Hill (2013).

[0069] B.1,3-Aliphatic diols and their derivatives

[0070] As mentioned above, 1,3-aliphatic diols are particularly useful molecules. In addition to providing two hydroxyl functional groups for reaction to form derivatives, the 3-hydroxyl moiety of the 1,3-aliphatic diol forms a chiral center at the third carbon (C-3), which makes the 1,3-aliphatic diol useful as a synthon for the production of chirally important compounds, such as pharmaceuticals, nutraceuticals, pesticides, herbicides, flavors, fragrances, solvents, biologically active compounds, etc.

[0071] In addition to the functionality of the hydroxyl group, changes in the carbon chain structure of 1,3-fatty diols provide molecules with additional chemical properties and / or potentially new properties that can be used to solve old problems in an improved way and / or that can find entirely new uses. For example, unsaturated fatty alcohols have additional functional groups in the form of double bonds that can be used for chemical reactions.

[0072] Unsaturated fatty alcohols are particularly valuable because the presence of the double bond imparts a number of advantageous properties to the molecule. For example, unsaturated fatty alcohols have lower melting points, higher water solubility, and offer the possibility of introducing functional groups into the C=C double bond compared to their saturated counterparts (Egan, R. et al., (1984) Journal of the American Society of Oil Chemists, Vol. 61 (2): 324-329). Unsaturated fatty alcohols are therefore important intermediates for a large number of products in the chemical industry (see, e.g., U. Ploog et al., Soaps, Oils, and Waxes 109, 225 (1983)).

[0073] In an exemplary embodiment, the present disclosure provides novel unsaturated, unbranched 1,3-fatty diols. In an exemplary embodiment, the novel unsaturated, unbranched 1,3-fatty diols have the systematic names: 5-dodecene-1,3-diol or dodecan-5-ene-1,3-diol. In some exemplary embodiments, the double bond is in the (Z) configuration. In other exemplary embodiments, the double bond of 5-dodecene-1,3-diol is in the (E) configuration. 5-Dodecene-1,3-diol has a general structural formula II.

[0074]

[0075] In Formula II, the chiral C-3 carbon can be either the (R) enantiomer or the (S) enantiomer.

[0076] In another exemplary embodiment, the novel unsaturated, unbranched 1,3-fatty diol has the systematic name: 7-hexadecene-1,3-diol or hexadecene-7-ene-1,3-diol. In some exemplary embodiments, the double bond is in the (Z) configuration. In other exemplary embodiments, the double bond is in the (E) configuration. 7-hexadecene-1,3-diol has the general structural formula (III).

[0077]

[0078] In Formula III, the chiral C-3 carbon can be either the (R) enantiomer or the (S) enantiomer.

[0079] In another exemplary embodiment, the novel unsaturated, unbranched 1,3-fatty diol has the systematic name: 9-hexadecene-1,3-diol or hexadecene-9-ene-1,3-diol. In some exemplary embodiments, the double bond is in the (Z) configuration. In other exemplary embodiments, the double bond is in the (E) configuration. 9-hexadecene-1,3-diol has the general structural formula (IV).

[0080]

[0081] In Formula IV, the chiral C-3 carbon can be either the (R) enantiomer or the (S) enantiomer.

[0082] 1. Physical properties of 1,3-aliphatic diols

[0083] All 1,3-fatty diols disclosed herein contain two alcohol groups and a chiral center located at the C-3 carbon. In addition, the unsaturated 1,3-fatty diols disclosed herein (e.g., 5-dodecene-1,3-diol) also contain double bonds. Therefore, the 1,3-fatty diols disclosed herein can undergo a wide variety of chemical reactions to form a wide variety of molecules. Therefore, in addition to the value of any 1,3-fatty diols disclosed herein themselves, such as as surfactants. In exemplary embodiments, the 1,3-fatty diols disclosed herein (e.g., 5-dodecene-1,3-diol) are used as building blocks for an unlimited number of unique and useful derivative molecules.

[0084] a. Double bond

[0085] The unsaturated 1,3-fatty diols disclosed herein (e.g., 5-dodecene-1,3-diol) contain double bonds. Depending on how the 1,3-fatty diol is produced and / or processed (see below), the double bond can be (Z) or (E). Thus, the unsaturated 1,3-fatty diols disclosed herein (e.g., 5-dodecene-1,3-diol) can participate in chemical reactions involving double bonds, including, for example, polymerization, alkylation, metathesis, and the like. Chemical reactions utilizing carbon-carbon double bonds are known in the art (see, for example, Practical Synthetic Organic Chemistry: Reactions, Principles, and Techniques, Stephane Caron, ed. (supra)).

[0086] Therefore, in exemplary embodiments, the carbon-carbon double bonds of the unsaturated 1,3-fatty diols disclosed herein (e.g., 5-dodecene-1,3-diol, 9-hexadecene-1,3-diol, etc.) participate in addition reactions. Exemplary addition reactions include, for example, halogenation, hydrogenation, hydration, epoxidation, free radical polymerization, hydroxylation, etc. Therefore, in some exemplary embodiments, the carbon-carbon double bonds of the unsaturated 1,3-fatty diols disclosed herein (e.g., 5-dodecene-1,3-diol, 9-hexadecene-1,3-diol, etc.) participate in hydrogenation reactions, thereby forming corresponding alkanes. In other exemplary embodiments, the carbon-carbon double bonds of the unsaturated 1,3-fatty diols disclosed herein (e.g., 5-dodecene-1,3-diol, 9-hexadecene-1,3-diol, etc.) participate in hydration reactions to add water at both ends of the double bonds, thereby producing polyols.

[0087] In other exemplary embodiments, the carbon-carbon double bonds of the unsaturated 1,3-fatty diols disclosed herein (eg, 5-dodecene-1,3-diol, 9-hexadecene-1,3-diol, etc.) participate in polymerization reactions to produce polymers with high industrial value, such as unique plastics.

[0088] b. Hydroxyl

[0089] All 1,3-aliphatic diols disclosed herein (eg, 5-dodecene-1,3-diol, 9-hexadecene-1,3-diol, etc.) contain two hydroxyl functional groups available for chemical reactions.

[0090] As is well known in the art, the chemical properties of diols are roughly the same as those of alcohols (see, e.g., Organic Chemistry, 9th edition, Francis Carey and Robert Giuliano (2013) supra). Therefore, due to the polar nature of the -OH bond, the 1,3-aliphatic diols disclosed herein (e.g., 5-dodecene-1,3-diol, 9-hexadecene-1,3-diol, etc.) are prone to hydrogen bonding with other 1,3-aliphatic diol molecules or other hydrogen bonding systems (e.g., water). Therefore, 1,3-aliphatic diols generally have relatively high melting and boiling points and relatively high solubility in aqueous media compared to similar alkanes.

[0091] The hydroxyl functional group can participate in a wide variety of chemical reactions featuring the hydroxyl group. Thus, in one exemplary embodiment, the hydroxyl functional group of the 1,3-aliphatic diols disclosed herein (e.g., 5-dodecene-1,3-diol, 9-hexadecene-1,3-diol, etc.) participates in a nucleophilic substitution reaction, wherein the hydroxyl group acts as a leaving group, or wherein -OH or -O- functions as a nucleophile, e.g., via halide substitution.

[0092] In other exemplary embodiments, the hydroxyl functional groups of the 1,3-aliphatic diols disclosed herein (e.g., 5-dodecene-1,3-diol, 9-hexadecene-1,3-diol, etc.) participate in nucleophilic addition reactions, wherein the hydroxyl groups act as nucleophiles, thereby forming acetals with aldehydes or ketones. Exemplary nucleophilic addition reactions include, for example, glycosylation reactions, which are discussed in more detail below.

[0093] In other exemplary embodiments, the hydroxyl functional groups of the 1,3-fatty diols disclosed herein (e.g., 5-dodecene-1,3-diol, 9-hexadecene-1,3-diol, etc.) participate in nucleophilic acyl substitution reactions, wherein the hydroxyl groups act as nucleophiles to form esters with carboxylic acids and carboxylic acid derivatives, such as nucleophilic acyl substitution of 5-dodecene-1,3-diol with fatty acids to form, for example, fatty esters.

[0094] In other exemplary embodiments, the hydroxyl functionality of the 1,3-aliphatic diols disclosed herein (eg, 5-dodecene-1,3-diol, 9-hexadecene-1,3-diol, etc.) participates in an elimination reaction wherein the hydroxyl group is removed as water and a carbon double bond (olefin) is formed.

[0095] In other exemplary embodiments, the hydroxyl functional group of the 1,3-fatty diols disclosed herein (e.g., 5-dodecene-1,3-diol, 9-hexadecene-1,3-diol, etc.) participates in an oxidation reaction, wherein the hydroxyl group is converted to a carbonyl group (C=O), thereby producing a carbonyl compound. In the oxidation reaction, the resulting carbonyl compound may be an aldehyde, a ketone, or a carboxylic acid, depending on the oxidant used (see, e.g., Organic Chemistry, 9th Edition, Francis Carey and Robert Giuliano (2013) supra).

[0096] Thus, the multiple hydroxyl functional groups of the 1,3-fatty diols disclosed herein (e.g., 5-dodecene-1,3-diol, 9-hexadecene-1,3-diol, etc.) allow the disclosed 1,3-fatty diols to undergo a wide variety of reactions. This in turn provides the possibility of a variety of derivatives with unique and useful properties. Some exemplary hydroxyl derivatives of the 1,3-fatty diols disclosed herein (e.g., 5-dodecene-1,3-diol, 9-hexadecene-1,3-diol, etc.) are discussed below.

[0097] c. Chirality

[0098] Chiral molecules (e.g., 1,3-aliphatic diols, such as 5-dodecene-1,3-diol, which have a chiral center located at the C-3 carbon) are building blocks for the synthesis of compounds (e.g., drugs, nutraceuticals, etc.) that are affected by stereochemistry. Since most isomers of chiral drugs exhibit significant differences in biological activity (e.g., pharmacology, toxicology, pharmacokinetics, biorecognition, metabolism, etc.), chirality is an important property to be considered, for example, in drug design. In fact, choosing the appropriate enantiomer can have a significant impact on the biological properties of the molecule.

[0099] 2. Nonionic surfactants

[0100] In some exemplary embodiments, the hydroxyl functional groups of the 1,3-aliphatic diols disclosed herein (eg, 5-dodecene-1,3-diol, 9-hexadecene-1,3-diol, etc.) are used to prepare nonionic surfactants.

[0101] i. Glycosylated derivatives

[0102] In an exemplary embodiment, the hydroxyl moiety of a 1,3-fatty diol (e.g., 5-dodecene-1,3-diol) disclosed herein can be used to react with a sugar to provide an alkyl polyglycoside. Alkyl polyglycosides are a class of nonionic surfactants derived from sugars and fatty alcohols and are well known in the art (see, e.g., Alkyl Polyglycosides: Technology, Properties, Applications, Karlheinz Hill; Wolfgang von Rybinski; Gerhard Stoll, ed. Wiley (2008); Novel Surfactants: Preparation Applications And Biodegradability, Surfactant Science Series, Vol. 114, 2nd ed., Krister Holmberg, ed., Marcel Dekker: New York and Basel, Switzerland. 2003). Thus, in exemplary embodiments, a 1,3-fatty diol as disclosed herein (eg, 5-dodecene-1,3-diol) is reacted with, for example, xylose, galactose, mannose, glucose, etc. to form alkyl polyglycosides having new useful properties.

[0103] When derived from glucose, the alkyl polyglycoside is referred to as an alkyl polyglucoside. Thus, in an exemplary embodiment, a 1,3-fatty diol as disclosed herein (e.g., 5-dodecene-1,3-diol, 9-hexadecene-1,3-diol, etc.) is reacted with glucose to form an alkyl polyglucoside. Alkyl polyglucosides are known in the art (see, e.g., "Nonionic Surfactants: Alkyl Polyglucosides". Surfactant Science Series. Vol. 91, Dieter Balzer and Harald Lüders, ed. Marcel Decker Publishing Company: New York and Basel, Switzerland. 2000; Rather and Mishra: "β-Glycosidase: An alternative enzyme based method for synthesis of alkyl-glycosides". Sustainable Chemical Processes 20131:7).

[0104] Alkyl polyglycosides can be prepared by any method known in the art. Exemplary methods suitable for preparing glycosylated molecules as disclosed herein include, for example, U.S. Pat. No. 5,449,763, U.S. Pat. No. 3,547,828, U.S. Pat. No. 3,839,318; K., Tietze, L. "Synthesis of alkyl polyglycosides: Effect of catalyst-type on reaction rate and product composition" "Eur. J. Lipid Sci. Tech." (1998) 100, 38-41; Rybinski, W., Hill, K. "Alkyl Polyglycosides-Properties and Applications of a new Class of Surfactants" "Angew. Chem. Int. Ed." (1998) 37(10), 1328-1345; "Handbook of Chemical Glycosylation: Advances in Stereoselectivity and Therapeutic Relevance" Relevance” edited by AV Demchenko, John Wiley & Sons, April 9, 2008; Luley-Goedl, C. et al., Carbohydrate Research (2010) 345, 1736-1740; Rather, MY, Mishra, S. (2013) supra; Ojha, S. et al. “Synthesis of hexyl α-glucoside and α-polyglucosdies by a novel Microbacterium isolate” Appl. Microbiol. Biotechnol. (2013) 97, 5293-5301; Wooten, J. “Glycosylation of Amino Acids and Efficient Synthesis of Glycosphingolipids” Glycosphingolipids” Thesis, Georgia State University, 2015).

[0105] Thus, in exemplary embodiments, the present disclosure provides alkyl polyglycosides having the general formula according to Formula V and / or Formula VI.

[0106]

[0107] In Formula (V), n is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, the double bond can be in the (Z) or (E) configuration, and the C-3 carbon can be the (R) or (S) enantiomer.

[0108] In addition, in formula (V), R 1 and R 2 Each is independently H, a monosaccharide bound at the anomeric carbon of a monosaccharide, a disaccharide bound at the anomeric carbon of a disaccharide, a trisaccharide bound at the anomeric carbon, or a polysaccharide bound at the anomeric carbon. In an exemplary embodiment, R 1 and R 2 They cannot be H at the same time. In other exemplary embodiments, R 1 and R 2 Neither is H.

[0109] In exemplary embodiments, the monosaccharide is selected from pentoses and hexoses. In some exemplary embodiments, the hexose is selected from allose, altrose, glucose, mannose, gulose, idose, galactose, or talose. In other exemplary embodiments, the disaccharide, trisaccharide, and / or polysaccharide comprises a sugar selected from pentoses, hexoses, or mixtures of any two or more thereof. In some exemplary embodiments, the hexose is selected from allose, altrose, glucose, mannose, gulose, idose, galactose, talose, or mixtures of any two or more thereof. In some exemplary embodiments, R 1 and R 2 are different monosaccharides. In other exemplary embodiments, R 1 and R 2 It's the same monosaccharide.

[0110] In an exemplary embodiment, the monosaccharide, disaccharide, trisaccharide and / or polysaccharide comprises a hexose selected from allose, altrose, glucose, mannose, gulose, idose, galactose, talose or a mixture of any two or more thereof. In other exemplary embodiments, the monosaccharide, disaccharide, trisaccharide or polysaccharide comprises a sugar selected from furanose, pyranose or a mixture of any two or more thereof.

[0111]

[0112] In Formula (VI), m is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 18, and the C-3 carbon may be the (R) or (S) enantiomer.

[0113] In addition, in formula (VI), R 3 and R 4 Each is independently H, a monosaccharide bound at the anomeric carbon of a monosaccharide, a disaccharide bound at the anomeric carbon of a disaccharide, a trisaccharide bound at the anomeric carbon, or a polysaccharide bound at the anomeric carbon. In an exemplary embodiment, R 3 and R 4 They cannot be H at the same time. In other exemplary embodiments, R 3 and R 4 Neither is H.

[0114] In exemplary embodiments, the monosaccharide is selected from pentoses and hexoses. In other exemplary embodiments, the disaccharide, trisaccharide and / or polysaccharide comprises a sugar selected from pentoses, hexoses or a mixture of any two or more thereof. In some exemplary embodiments, R 3 and R 4 are different monosaccharides. In other exemplary embodiments, R 3 and R 4 It's the same monosaccharide.

[0115] In an exemplary embodiment, the monosaccharide, disaccharide, trisaccharide and / or polysaccharide comprises a sugar selected from the group consisting of allose, altrose, glucose, mannose, gulose, idose, galactose, talose or a mixture of any two or more thereof. In other exemplary embodiments, the monosaccharide, disaccharide, trisaccharide or polysaccharide comprises a sugar selected from the group consisting of furanose, pyranose or a mixture of any two or more thereof.

[0116] The term "anomeric carbon" as applied herein to any compound of the present technology is well understood by those skilled in the art, where examples of anomeric carbons attached to sugars are illustrated below by glucosylation variants:

[0117]

[0118] The anomeric carbon of a sugar (here, a monosaccharide) is indicated by an open arrow. Similarly, glucose disaccharides include those illustrated in the following two schematic diagrams:

[0119] Diagram 1: α(1→4) disaccharide (α-maltose) with α-glycosidic bond to non-sugar chain

[0120]

[0121] Scheme 2: α(1→6) disaccharide (α-isomaltose) with α-glycosidic bond to non-sugar chain

[0122]

[0123] As illustrated in schematic diagrams 1 and 2, in the case where R is indicated 1 When referring to "bound to the anomeric carbon of the disaccharide maltose or isomaltose", this is understood to refer to the anomeric carbon of a free disaccharide having a free hydroxyl group that is susceptible to forming the bond with, for example, a compound of formula IA, IB, II, III, IV, as indicated by the hollow arrows above, rather than the anomeric carbon involved in the intersaccharide linkage (hereinafter, "glycosidic linkage") of disaccharides, trisaccharides and polysaccharides, as indicated by the dotted arrows. This applies to the meaning of "bound to the anomeric carbon" with reference to trisaccharides and polysaccharides. Therefore, in any embodiment herein, in R 1 , R 2 , R 3 and / or R 4 When it is a monosaccharide, disaccharide, trisaccharide and / or polysaccharide, R 1 , R 2 , R 3 and / or R 4 The binding may be via an α-glycosidic bond or a β-glycosidic bond. In addition, the disaccharide, trisaccharide and / or polysaccharide may be a saccharide comprising an α-glycosidic bond linkage, a β-glycosidic bond linkage or (for trisaccharides and / or polysaccharides) a mixture thereof.

[0124] In exemplary embodiments, the monosaccharide is selected from pentoses and hexoses. In other exemplary embodiments, the disaccharide, trisaccharide and / or polysaccharide comprises a sugar selected from pentoses, hexoses or mixtures thereof. In some exemplary embodiments, R 3 and R 4 are different monosaccharides. In other exemplary embodiments, R 3 and R 4 It's the same monosaccharide.

[0125] In an exemplary embodiment, the monosaccharide, disaccharide, trisaccharide and / or polysaccharide comprises a sugar selected from the group consisting of allose, altrose, glucose, mannose, gulose, idose, galactose, talose or a mixture of any two or more thereof. In other exemplary embodiments, the monosaccharide, disaccharide, trisaccharide or polysaccharide comprises a sugar selected from the group consisting of furanose, pyranose or a mixture thereof.

[0126] Thus, in any embodiment herein, the monosaccharide, disaccharide, trisaccharide or polysaccharide may comprise a pentose, a hexose or (in R 1 and R 2 or R 3 and R 4 The monosaccharides, disaccharides, trisaccharides or polysaccharides of any embodiment herein may include allose, altrose, glucose, mannose, gulose, idose, galactose, talose or (in R 1 and R 2 or R3 and R 4 For different monosaccharides and / or for any one or more disaccharides, trisaccharides or polysaccharides) any mixture of two or more thereof. In addition, in any embodiment herein, the monosaccharide, disaccharide, trisaccharide or polysaccharide may contain furanose, pyranose or (in R 1 and R 2 or R 3 and R 4 For different monosaccharides and / or for any one or more disaccharides, trisaccharides or polysaccharides) any mixture of two or more thereof. In any embodiment herein,

[0127] R 1 , R 2 , R 3 and R 4 can be independently H or Where R 5 Each occurrence is independently H or r is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, and s is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. In any embodiments herein, R 1 , R 2 , R 3 , R 4 and R 5 can each independently include allose, altrose, glucose, mannose, gulose, idose, galactose, talose or (in R 1 , R 2 , R 3 , R 4 and R 5 Any two or more of the above are different monosaccharides and / or any one or more disaccharides, trisaccharides or polysaccharides) are mixtures of any two or more thereof. 1 , R 2 , R 3 , R 4 and / or R 5 When R is a monosaccharide, disaccharide, trisaccharide and / or polysaccharide as indicated above, 1 , R 2 , R 3 , R 4 and / or R 5 The binding may be via an α-glycosidic bond or a β-glycosidic bond. 1 , R 2 , R 3 , R 4 and / or R 5The disaccharide, trisaccharide and / or polysaccharide may be a saccharide comprising α-glycosidic linkages, β-glycosidic linkages, or (for trisaccharides and / or polysaccharides) a mixture of any two or more thereof.

[0128] a. Compositions containing alkyl polyglucoside

[0129] Alkyl polyglycosides are particularly useful molecules that can be advantageously incorporated into a variety of industrial reagents and processes. Indeed, alkyl polyglycosides can be used, for example, as emulsifiers, emollients and thickeners in cosmetics and foods, in agricultural formulations (e.g. in pesticide formulations) for delivering active ingredients to targets (e.g. waxy surfaces of leaves), in the oil and gas industry as industrial solvents to improve oil recovery, as plasticizers, as surfactants and detergents and in the production of surfactants and detergents, etc.

[0130] Alkyl polyglycoside surfactants are particularly valuable because they have advantages over other surfactants with respect to dermatological properties, compatibility with standard products, and favorable environmental characteristics. Therefore, they are widely used in a variety of household and industrial applications, such as in medicines for dissolving hydrophobic drugs in aqueous media, as components of emulsions or surfactant self-assembly vehicles for oral and transdermal drug delivery, as plasticizers in semisolid delivery systems, as agents to improve drug absorption and penetration, etc. Therefore, in exemplary embodiments, alkyl polyglycosides are incorporated into personal care products as, for example, biological ingredients that are less irritating to the skin than other surfactants and solubilizers with reduced toxicological characteristics.

[0131] Thus, in exemplary embodiments, personal care compositions are provided comprising a compound as disclosed herein and a cosmetically acceptable carrier.

[0132] Personal care products are known in the art, see, for example, Surfactants in Personal Care Products and Decorative Cosmetics, 3rd edition, Linda D. Rhein, Mitchell Schlossman, Anthony O'Lenick, P. Somasundaran, ed. CRC Press (2006). In an exemplary embodiment, the personal care product is a skin care composition. Skin care compositions are known in the art, see, for example, Cosmetic Formulation of Skin Care Products, Zoe Diana Draelos, Lauren A. Thaman, ed. CRC Press (2005).

[0133] In an exemplary embodiment, the cosmetically acceptable carrier in the personal care composition is selected from the group consisting of water, emollients, fatty acids, fatty alcohols, thickeners, and combinations thereof.

[0134] In one exemplary embodiment, the personal care composition comprises water at a concentration between about 40 weight percent (wt%) to about 96 wt%.

[0135] In another exemplary embodiment, the personal care composition comprises an emollient selected from the group consisting of silicone oils, natural or synthetic esters, hydrocarbons, alcohols, fatty acids, and combinations thereof. In some exemplary embodiments, the emollient is present in a concentration between about 0.1% to about 60% by weight of the personal care composition. In other exemplary embodiments, the emollient is present in a concentration between about 30% to about 50% by weight.

[0136] In another exemplary embodiment, the personal care composition comprises a silicone oil. Silicone oils can be divided into volatile and non-volatile categories. As used herein, the term "volatile" refers to materials that have a measurable vapor pressure at ambient temperature. Volatile silicone oils are preferably selected from cyclic polydimethylsiloxanes (cyclomethicone) or linear polydimethylsiloxanes containing 3, 4, 5, 6, 7, 8 or 9 silicon atoms, preferably 5 to 6 silicon atoms. Non-volatile silicone oils include polyalkyl siloxanes, polyalkylaryl siloxanes and polyether siloxane copolymers. Non-volatile polyalkyl siloxanes that can be used herein include, for example, polydimethylsiloxanes having a viscosity of about 5x10-6m at 25°C. 2 / s to about 0.1m 2 / s, preferably about 1x10-5m at 25°C 2 / s to about 4x10-4m 2 / s. Other classes of non-volatile silicones are emulsifying and non-emulsifying silicone elastomers, such as dimethicone / vinyl dimethicone crosspolymer (available as Dow Corning 9040, General Electric SFE 839, and Shin-Etsu KSG-18). Silicone waxes (e.g., Silwax WS-L, dimethicone copolyol laurate) may also be included in any embodiment of the personal care compositions described herein.

[0137] In another exemplary embodiment, the personal care composition comprises an ester emollient. In another exemplary embodiment, the ester emollient is an alkyl ester of a saturated fatty acid having 10 to 24 carbon atoms. In an exemplary embodiment, the alkyl ester is a member selected from the group consisting of behenyl neopentanoate, isononyl isononanoate, isopropyl myristate, and octyl stearate.

[0138] In another exemplary embodiment, the personal care composition comprises an ether-ester of an ethoxylated saturated fatty alcohol (eg, a fatty acid ester).

[0139] In another exemplary embodiment, the personal care composition comprises polyol esters, such as ethylene glycol mono- and di-fatty acid esters, diethylene glycol mono- and di-fatty acid esters, polyethylene glycol (200-6000) mono- and di-fatty acid esters, propylene glycol mono- and di-fatty acid esters, polypropylene glycol 2000 monostearate, ethoxylated propylene glycol monostearate, glyceryl mono- and di-fatty acid esters, polyglycerol polyfatty esters, ethoxylated monostearate glyceryl, 1,3-butylene glycol monostearate, 1,3-butylene glycol distearate, polyoxyethylene polyol fatty acid esters, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters are satisfactory polyol esters. In another exemplary embodiment, the polyol ester is selected from the group consisting of pentaerythritol, trimethylolpropane, and neopentyl glycol esters of C1-C30 alcohols.

[0140] In another exemplary embodiment, the personal care composition comprises wax esters, such as beeswax, spermaceti, and tribehenin wax.

[0141] In another exemplary embodiment, the personal care composition comprises sugar esters of fatty acids, such as sucrose polybehenate and sucrose polycottonate.

[0142] In some exemplary embodiments, the personal care composition comprises a natural ester emollient. Natural ester emollients are mainly based on mono-, di- and tri-glycerides. Representative examples include sunflower seed oil, coconut oil, cottonseed oil, borage oil, borage seed oil, primrose oil, castor oil and hydrogenated castor oil, rice bran oil, soybean oil, olive oil, safflower oil, shea butter, jojoba oil and any two or more compositions thereof. Animal-derived emollients include, for example, lanolin oil and lanolin derivatives. In an exemplary embodiment, the amount of natural esters is present in a concentration in the range of about 0.1% by weight to about 20% by weight of the personal care composition.

[0143] In some exemplary embodiments, the personal care composition comprises a hydrocarbon. Suitable cosmetically acceptable hydrocarbon carriers include, for example, petrolatum, mineral oil, C8-C30 normal alkanes, C8-C30 normal alkenes, C11-C13 isoparaffins, polybutenes, and especially isohexadecane (available as Permethyl 101A from Presperse Inc.).

[0144] In some exemplary embodiments, the personal care composition comprises a fatty acid. Generally, a fatty acid having 6 to 30 carbon atoms is provided as a cosmetically acceptable carrier. In some exemplary embodiments, a fatty acid having 10 to 30 carbon atoms is provided as a cosmetically acceptable carrier. In other exemplary embodiments, a fatty acid having 8 to 24 carbon atoms is provided as a cosmetically acceptable carrier. In other exemplary embodiments, a fatty acid having 6 to 24 carbon atoms is provided as a cosmetically acceptable carrier.

[0145] Some exemplary 1-30 carbon fatty acids include nonanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, hydroxystearic acid and behenic acid and mixtures of any two or more thereof. Fatty alcohols having 10 to 30 carbon atoms are another useful class of cosmetically acceptable carriers. Illustrative examples of this class are stearyl alcohol, lauryl alcohol, myristyl alcohol, oleyl alcohol, cetyl alcohol and mixtures of any two or more thereof.

[0146] In some exemplary embodiments, the personal care composition comprises a thickener. Exemplary thickeners include cross-linked acrylates (e.g., Carbopol ), hydrophobically modified acrylates (e.g., Carbopol ), polyacrylamide (e.g., Sepigel ), acryloyl methyl propane sulfonic acid / salt polymers and copolymers (e.g., Aristoflex and ), cellulose derivatives, natural gums and any two or more thereof. Useful cellulose derivatives are especially sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, hydroxymethyl cellulose and any two or more thereof. Natural gums include, but are not limited to, guar gum, xanthan gum, sclerotium gum, carrageenan, pectin and any two or more thereof. Inorganic substances can also be used as thickeners, in particular clays (such as bentonite and hectorite), fumed silica, talc, calcium carbonate and silicates (such as magnesium aluminum silicate ) and any combination of two or more of these organic substances. Any combination of two or more thickeners can also be used in the personal care compositions of the present technology. The amount of the thickener can be in the range of about 0.0001 wt % to about 10 wt %, preferably about 0.001 wt % to about 1 wt %, and optimally about 0.01 wt % to about 0.5 wt % of the personal care composition.

[0147] In some exemplary embodiments, the personal care composition includes a wetting agent. In an exemplary embodiment, a polyol-type wetting agent is used as an acceptable carrier for cosmetics. Exemplary polyols include, for example, glycerol, polyalkylene glycols (more preferably alkylene polyols and derivatives thereof, including propylene glycol, dipropylene glycol, polypropylene glycol, polyethylene glycol and derivatives thereof), sorbitol, hydroxypropyl sorbitol, hexylene glycol, 1,3-butylene glycol, isopentyl glycol, 1,2,6-hexanetriol, ethoxylated glycerol, propoxylated glycerol and mixtures thereof. In an exemplary embodiment, the amount of the wetting agent is present in a concentration between about 0.5% by weight and about 50% by weight of the personal care composition. In an exemplary embodiment, the amount of the wetting agent present in the personal care composition is between about 0.5% by weight and about 50% by weight. In some exemplary embodiments, when a wetting agent is included, it is included in an amount between about 1% by weight and 15% by weight of the personal care composition.

[0148] In some exemplary embodiments, a skin moisturizing agent is included as an acceptable carrier for cosmetics. Therefore, in exemplary embodiments, hyaluronic acid and / or its precursor N-acetylglucosamine are included as an acceptable carrier for cosmetics. In some exemplary embodiments, N-acetylglucosamine is derived from shark cartilage or shiitake mushrooms, and can be purchased from Maypro Industries, Inc. (New York). In other exemplary embodiments, a skin moisturizing agent is included as an acceptable carrier for cosmetics, which is hydroxypropyl tri (C1-C3 alkyl) ammonium salt. In some exemplary embodiments, hydroxypropyl tri (C1-C3 alkyl) ammonium salt is obtained by a synthetic procedure, for example, obtained by the hydrolysis of chlorohydroxypropyl tri (C1-C3 alkyl) ammonium salt. In other exemplary embodiments, especially when used in combination with the ammonium salts mentioned above, the moisturizing agent includes, for example, substituted ureas, such as hydroxymethyl urea, hydroxyethyl urea, hydroxypropyl urea; bis(hydroxymethyl) urea; bis(hydroxyethyl) urea; bis(hydroxypropyl) urea; N,N'-dimethylol urea; N,N'-di-hydroxyethyl urea; N,N'-di-hydroxypropyl urea; N,N,N'-tri-hydroxyethyl urea; tetra(hydroxymethyl) urea; tetra(hydroxyethyl) urea; tetra(hydroxypropyl urea; N-methyl-N'-hydroxyethyl urea; N-ethyl-N'-hydroxyethyl urea; N-hydroxypropyl-N'-hydroxyethyl urea, N,N'-dimethyl-N-hydroxyethyl urea.

[0149] In another exemplary embodiment, the personal care composition comprises a pH between about 4 and about 8. In some exemplary embodiments, the pH of the personal care composition is about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, or any range including any two of these values ​​and between them. In an exemplary embodiment, the pH of the personal care composition is between about 5 and about 7. In other exemplary embodiments, the pH of the personal care composition is between about 5 and about 6.

[0150] In another exemplary embodiment, the personal care composition comprises an inorganic sunscreen. In an exemplary embodiment, the amount of the inorganic sunscreen is present in a concentration between about 0.1% to about 10% by weight of the personal care composition. Inorganic sunscreens are well known in the art and include, but are not limited to, zinc oxide, iron oxide, silicon dioxide (e.g., fumed silica), and titanium dioxide.

[0151] In some exemplary embodiments, the personal care composition comprises a cosmetic benefit ingredient. Exemplary cosmetic benefit ingredients include, but are not limited to, skin whitening ingredients, retinoids, herbal extracts, antifungal agents, resveratrol, alpha-lipoic acid, ellagic acid, kinetin, retinyl trimethylsilane, ceramides, ceramide-like substances, colorants, sunscreens, abrasives, and combinations thereof.

[0152] ii. Ethoxylated derivatives

[0153] In an exemplary embodiment, the hydroxyl moiety of 5-dodecene-1,3-diol can be used for ethoxylation to prepare novel alcohol ethoxylates, ethoxysulfates, propoxylates and butoxylates, fatty alcohol polyglycol ethers, etc. Alcohol ethoxylates are known in the art (see, e.g., U.S. Pat. No. 4,223,163; Surfactants, Elvers, Barbara et al., Ullmann Encyclopedia of Industrial Chemistry. Weinheim, GER: Wiley-VCH).

[0154] Fatty alcohol ethoxylates are the first nonionic surfactants produced on an industrial scale. They are widely used in cosmetics and other commercial products such as detergents, cleaning agents, etc.

[0155] 3. Polyurethane

[0156] In some exemplary embodiments, the hydroxyl functional groups of 5-dodecene-1,3-diol are used to prepare the polyurethane.

[0157] The double bond of 5-dodecene-1,3-diol serves as the epoxidation site, as shown, for example, in Formula VII

[0158]

[0159] As is known in the art, standard epoxidation chemistry involves heat between 30°C-80°C, using hydrogen peroxide and a catalyst from the Jacobsen catalyst or TS-1 zeolite catalyst class.

[0160] In an exemplary embodiment, the alcohol group of 5-dodecene-1,3-diol is prevented from reacting itself at the epoxide ring by protecting group chemistry (e.g., acetyl), as is known in the art (see, e.g., Practical Synthetic Organic Chemistry, Stephane Caron, ed. (2011) supra; Organic Chemistry, 9th ed., Carey and Giuliano (2013) supra) and as shown, for example, in Formula VIII

[0161]

[0162] In an exemplary embodiment, the epoxide ring on the derivatized 5-dodecene-1,3-diol is opened with water using methods known in the art, thereby producing a tetraol as shown, for example, in Formula IX.

[0163]

[0164] In other exemplary embodiments, the epoxide ring is opened using a hydrogen reactant using methods known in the art, thereby producing a triol, such as shown in Formula X

[0165]

[0166] In an exemplary embodiment, the use of hydrogen for selective ring opening of dodecan-1,3,6-triol is preferred. Epoxide chemistry is large and widely used, and other diols, alcohols and functionalized moieties can react at this site (Y. Li et al., Bio-based Polyols and Polyurethanes, Springer Briefs, Green Chemistry for Sustainability, DOI 10.1007 / 978-3-319-21539-6_2).

[0167] In other exemplary embodiments, the alcohol group on 5-dodecene-1,3-diol is used to perform ring opening at the epoxy group using a one-step "one-pot" reaction as known in the art (see, e.g., Monteavaro LL et al., Journal of the American Society of Oil Chemists 82:365-371, 2005) to produce a structure such as that shown in Formula XI.

[0168]

[0169] Ring opening at the epoxy group using the alcohol group on 5-dodecene-1,3-diol provides a branched polyol having a higher viscosity than the original 5-dodecene-1,3-diol. The high viscosity polyol is useful in applications such as: oil exploration and production, pigments and coatings, and personal care.

[0170] In other exemplary embodiments, reacting dodecan-1,3,6-triol of Formula X with an epoxide of Formula VII provides a branched polyol of Formula XII.

[0171]

[0172] In an exemplary embodiment, the polyol produced from 5-dodecene-1,3-diol is further derivatized, for example by copolymerization with ethylene oxide, thereby providing a polyether polyol. The resulting polyether polyol can be used as such in a variety of applications, for example as a building block for polyurethanes.

[0173] In an exemplary embodiment, 5-dodecene-1,3-diol, related triols or tetraols, or related branched or other polyols produced using 5-dodecene-1,3-diol as disclosed herein, can be subjected to standard chemistry with an isocyanate compound to form a polyurethane. These reactions can be promoted by UV light or by catalysts (e.g., dibutyltin dilaurate or bismuth octanoate) by methods known in the art (see, e.g., Y. Li et al., Bio-based Polyols and Polyurethanes, Springer Briefs, Sustainable Green Chemistry, DOI 10.1007 / 978-3-319-21539-6_2). A variety of different isocyanates (from linear to aromatic) can be used; and the techniques used to prepare the polymers may or may not pass through a prepolymer phase, such as preparing diols, triols or polyols with isocyanate groups (see, e.g., U.S. Pat. No. 4,532,316).

[0174] In an exemplary embodiment, a carbamate is used as an intermediate for the synthesis of isocyanates and direct conversion with a diol to prepare a non-isocyanate polyurethane (NIPU; see, e.g., Maisonneuve, L. et al. (2015) Chem. Rev. 115: 12407-12439). Non-isocyanate polyurethanes are particularly useful to the world because they allow the performance and properties of polyurethanes used in a variety of applications from building materials to medical devices to be produced without the use of carcinogenic isocyanates. This allows for safer working conditions for producers, commodity users, and even everyday consumers who are exposed when using polyurethane products such as coatings and adhesives. Thus, the use of 5-dodecene-1,3-diol in the preparation of NIPU allows for the creation of new carbonate structures having improved reactivity relative to 1,2-diol (1,3-diol to 6-membered rings relative to 1,2-diol to 5-membered rings), as well as the crosslinking or rearrangement flexibility afforded by the double bond, thereby providing new non-isocyanate polyurethane products.

[0175] To prepare NIPU, 5-dodecene-1,3-diol can be used as a diol, or converted to a polyol as discussed above, and used in reactions with a wide variety of carbamates (see, e.g., Rokocki, G et al., Polym. Adv. Technol. 26, 707-761, 2015). The 1,3-diol rearrangement in 5-dodecene-1,3-diol has an advantage over 1,2-diol in that the alcohol reaction center is less sterically hindered.

[0176] The hydroxyl moiety of 5-dodecene-1,3-diol can be used to react with dimethyl carbonate or carbon dioxide to prepare a 6-membered cyclic carbonate ring, which is subsequently reacted with a primary amine to provide a novel "non-isocyanate" polyurethane (NIPU). If the carbonate is double-terminated, that is, if the carbonate is first reacted with itself in a crosslinking or metathesis reaction to obtain two ends to continue for the polymer chain, then the carbonate can be used for further reaction to NIPU; this can be done before or after the formation of the carbonate structure. Therefore, the branched polyol in Formula XII can also be converted into a 2-carbonate polymer building block, such as Formula XIII.

[0177]

[0178] Exemplary catalysts that can be used to produce carbonate derivatives from 5-dodecene-1,3-diol or tetraols produced from 5-dodecene-1,3-diol include, for example, 1,5,7-triazabicyclo[4.4.0]dec-5-ene with dimethyl carbonate (Mutlu et al., Green Chem., 2012);2 In the presence of various imidazolium or thiazolium carbene catalysts at atmospheric pressure (Bobbink et al., Chem. Commun., 2016); and in the presence of CO 2 CeO in the presence 2 With 2-cyanopyridine (Honda et al., ACS Catal., 2014).

[0179] 6-membered cyclic carbonates derived from 1,3-diol moieties, such as those produced from 5-dodecene-1,3-diol, have 30x the reactivity relative to 5-membered cyclic carbonates derived from 1,2-diol moieties and are therefore more preferred in use (Maisonneuve et al., Chemical Reviews, 2015, supra).

[0180] In an exemplary embodiment, self-metathesis to form a "two-terminal" structure employs a metathesis catalyst known in the art, such as a first or second generation Grubbs catalyst, a specific example being bis(tricyclohexylphosphine)dichlorobenzylideneruthenium(II), [(PCy3)2Cl2]Ru=CHPh (see, e.g., International Application No. PCT / US95 / 09655).

[0181] The metathesis reaction is driven under vacuum to draw off the internal olefin byproducts. In some exemplary embodiments, the metathesis reaction is performed prior to carbonate formation, i.e., diol to tetraol, see Formula XIV. Formula XIV as a polyol has applications as discussed above.

[0182]

[0183] Alternatively, carbonates can be first generated from diols and then metathesized to dual-terminal carbonates. That is, a 6-membered cyclic carbonate molecule generated from 5-dodecene-1,3-diol then metathesizes to a molecule having two 6-membered cyclic carbonates, thereby providing a molecule of formula XV. The metathesis reaction can produce a mixture of cis and trans double bonds.

[0184]

[0185] In some exemplary embodiments, 5-dodecene-1,3-diol or a related 6-membered cyclic carbonate is first reacted in ethylene metathesis to form the terminal olefin counterpart, as shown below.

[0186]

[0187] Subsequently, Formula XVI and Formula XVII each metathesize upon themselves to provide di-terminal compounds of Formula XIV and XV, respectively.

[0188] Further reactions of Formula XV can be carried out across the double bond to increase rigidity, explore the increase in the glass transition temperature (Tg) of the subsequent polymer, or add pendant groups. In an exemplary embodiment, Formula XV is reacted with butadiene and a Lewis acid in a standard Diels-Alder reaction to provide Formula XVIII.

[0189]

[0190] 4. Polyester

[0191] As discussed above, the 1,3-diol structure has less steric hindrance than, for example, a 1,2-diol of similar chain length, facilitating polymer formation.

[0192] The chemistry used to form polyesters has been studied for more than 100 years and is well known in the art. Exemplary chemistries include, but are not limited to, reactions catalyzed by heat and acid; lipase-catalyzed polycondensation; using scandium triflate as a catalyst, etc. (see, e.g., Díaz, A. et al., Macromolecules 2005, 38, 1048-1050).

[0193] In an exemplary embodiment, 5-dodecene-1,3-diol is reacted with a diacid (eg, adipic acid) to form a "bushes-branched" polyester, such as the molecule shown below as Formula XIX, where n is an integer from 1-1000.

[0194]

[0195] The "bushy branching" character of the polyester structure will provide lower crystallinity and improved performance in micelle formation in surfactants, as well as providing hydrophobicity in other polymer applications, compared to polyesters produced, for example, with α-ω diols (1,2-diols).

[0196] The structure of 5-dodecene-1,3-diol functions to affect crystallinity (e.g., promote lower crystallinity) and glass transition temperature (Tg); polymer phase interactions; extrusion properties; and solubility and surface interactions with water, solvents, and complex formulations. Thus, in exemplary embodiments, 5-dodecene-1,3-diol is used as an additive to increase hydrophobicity and produce a plasticizer effect. Thus, in exemplary embodiments, 5-dodecene-1,3-diol is used at a concentration between about 0.001% and about 45% of the diol or polyol species to affect the structure of known polyesters. Thus, in exemplary embodiments, 5-dodecene-1,3-diol is incorporated into polybutyrate (copolyester of adipic acid, 1,4-butanediol, and dimethyl terephthalate) at a percentage lower than the primary monomer to provide, for example, a molecule shown below as formula XX, wherein m and n are each independently an integer from 1 to 1000.

[0197]

[0198] II. Preparation of (Z)-5-dodecene-1,3-diol

[0199] a. General pathways for biosynthesis

[0200] 5-Dodecene-1,3-diol can be prepared by any method known in the art. As mentioned above, unsaturated fatty alcohols are difficult to produce from petroleum. In contrast, unsaturated fatty alcohols are usually produced by processing non-petroleum sources (e.g., fats and oils of plant and animal origin) (see, for example, EF Hill et al. (1954) "Industrial and Engineering Chemistry (Ind. Eng. Chem.)", 46 (9): 1917-1921). Such processes are cumbersome, can cause pollution and generally only produce a limited variety of unsaturated fatty alcohol products.

[0201] Fortunately, however, biological methods can be used to directly produce 5-dodecene-1,3-diol. Thus, in an exemplary embodiment, 5-dodecene-1,3-diol is prepared using a biological method as disclosed, for example, in WO 2016 / 011430 A1 and as disclosed in detail in Example 1 below.

[0202] In brief, the preparation of 5-dodecene-1,3-diol can be carried out in a recombinant host cell (e.g., a bacterial cell modified to produce 1,3-diol) by utilizing nucleic acids and their corresponding polypeptides having enzyme functions to modify the enzyme pathway for producing the desired compound (e.g., 5-dodecene-1,3-diol) in vivo. The enzyme polypeptides are identified below by enzyme accession numbers (EC numbers).

[0203] WO 2016 / 011430 A1 discloses an enzyme pathway modified to produce 1,3-diol. An exemplary pathway for producing 5-dodecene-1,3-diol utilizes a 3'hydroxyacyl carrier protein (ACP) (e.g., acyl-ACP or 3-hydroxyacyl-ACP) carrying an acyl intermediate, which is converted to 1,3-diol with the aid of 3'hydroxy fatty acids (3'-OH FA) and 3'hydroxy fatty aldehydes (3'-OH fatty aldehydes) as intermediates. Without being bound by theory, it is believed that a simple carbon source such as glucose is first converted to 3'hydroxyacyl-ACP by a microorganism (e.g., Escherichia, Bacillus, Lactobacillus, etc.). Therefore, in one embodiment, the acyl-ACP or 3'hydroxyacyl-ACP that starts the modified enzyme pathway is produced by the natural pathway of the microorganism. In an exemplary embodiment, 3'hydroxy acyl-ACP is converted to an intermediate (e.g., 3'-OHFA) by an enzyme having thioesterase (TE) activity (EC 3.1.2.- or EC 3.1.2.14 or EC 3.1.1.5). Subsequently, the intermediate 3'-OH FA is converted to another intermediate (e.g., 3'OH aldehyde) by an enzyme having carboxylic acid reductase (CAR) activity (EC1.2.99.6). Subsequently, an enzyme having alcohol dehydrogenase (ADH) or aldehyde reductase (AR) activity (EC1.1.1.1 or EC1.1.1.2) converts the 3'OH aldehyde to 1,3-diol.

[0204] In other embodiments, 3'-hydroxy acyl-ACP is converted into an intermediate (e.g., 3'-OH fatty aldehyde) by an enzyme having acyl-ACP reductase (AAR, EC1.2.1.42) activity. The production of fatty alcohols and / or fatty aldehydes by AAR can be enhanced by heterologous expression of a gene called accABCD, which encodes acetyl-CoA carboxylase. Subsequently, an enzyme (EC1.1.1.1 or EC1.1.1.2) having alcohol dehydrogenase (ADH) or aldehyde reductase (AR) activity can convert 3'-OH aldehydes into fatty diols, such as 1,3-diols. Therefore, the present disclosure provides recombinant microorganisms that can effectively and selectively produce 1,3-fatty diols, such as 5-dodecene-1,3-diol in vivo. It should be noted that most cells naturally produce enzymes that can reduce aldehydes because they are cytotoxic. Therefore, the production of fatty alcohols and diols may not require heterologous expression of AR and ADH, but it can improve the efficiency of producing fatty diols.

[0205] Thus, saturated and unsaturated 1,3-fatty diols are produced using the methods disclosed herein. Exemplary 1,3-fatty diols include, for example, C 5 1,3 fatty diols (e.g., 1,3-pentanediol); C6 1,3 fatty diols (e.g., 1,3-hexanediol); C 7 1,3 aliphatic diols (e.g., 1,3-heptanediol); C 8 1,3 fatty diols (e.g., 1,3-octanediol); C 9 1,3 fatty diols (e.g., 1,3-nonanediol); C 10 1,3 fatty diols (e.g., 1,3-decanediol); C 11 1,3 fatty diols (e.g., 1,3-undecanediol); C 12 1,3 fatty diols (e.g., 1,3-dodecanediol, 5-dodecene-1,3-diol); C 13 1,3 fatty diols (e.g., 1,3-tridecanediol); C 14 1,3 fatty diols (e.g., 1,3-tetradecanediol, 7-tetradecene-1,3-diol); C 15 1,3 fatty diols (e.g., 1,3-pentadecanediol); C 16 1,3 fatty diols (e.g., 1,3-hexadecanediol, 9-hexadecene-1,3-diol); C 17 1,3 fatty diols (e.g., 1,3-heptadecanediol); C 18 1,3 fatty diols (e.g., 1,3-octadecanediol, 11-octadecene-1,3-diol); C 19 1,3 fatty diols (e.g., 1,3-nonadecanediol); etc. Although even-chain 1,3-fatty diols are primarily disclosed herein, odd-chain 1,3-fatty diols are also found, such as those having 7-21 carbons, and more preferably 5-19 carbons.

[0206] Generally, in exemplary embodiments, the unsaturated 1,3-fatty diols produced using microorganisms as disclosed above carry double bonds in the (Z) configuration. However, as will be discussed below, the methods can be used to rearrange the (Z) double bonds of unsaturated 1,3-fatty diols (e.g., the double bonds of (Z)-5-dodecene-1,3-diol) so that double bonds in the (E) configuration are produced.

[0207] For further guidance on the biosynthesis of 1,3-fatty diols, one of ordinary skill in the art may refer to, for example, Examples 1-3 below and / or International Patent Application Publication No. WO 2016 / 011430 A1.

[0208] b. Chirality of 5-dodecene-1,3-diol

[0209] The 3-hydroxyl functional group of the 1,3-aliphatic diols (e.g., 5-dodecene-1,3-diol) disclosed herein forms a stereogenic center at C-3, providing a chiral point to the molecule. As described above, chirality can be a useful molecular attribute in defining molecular applications, including, for example, polymer properties, biological activity, medicinal potential, etc.

[0210] The stereoisomers of 1,3-fatty diols produced by microorganisms depend on the selectivity of the fatty acid biosynthetic pathway (FAS) in which they are produced. By manipulating which FAS enzymes are responsible for the synthesis of 1,3-fatty diols (e.g., 5-dodecene-1,3-diol), the chirality of the resulting 1,3-fatty diols can be controlled.

[0211] For example, in an exemplary embodiment, native E. coli FAS is used to produce the (R) enantiomer of an unsaturated 1,3-fatty diol (e.g., 5-dodecene-1,3-diol). In this embodiment, the chiral center of the unsaturated 1,3-fatty diol is generated by the activity of 3-ketoacyl-ACP reductase, which is an enzyme encoded by the FabG gene in E. coli. The activity of 3-ketoacyl-ACP reductase produces (R)-3-hydroxyacyl ACP, which can then enter the modified enzyme pathway discussed above in Section II a.

[0212] In other exemplary embodiments, the β-oxidation pathway is used to produce the (S) enantiomer of an unsaturated 1,3-fatty diol (e.g., 5-dodecene-1,3-diol). In this embodiment, the (S) enantiomer of an unsaturated 1,3-fatty diol is prepared by causing the accumulation of (S)-3-hydroxyacyl CoA, which is an intermediate in the degradation of fatty acids via the β-oxidation pathway. Excess (S)-3-hydroxy-acyl CoA is then converted to the (S) enantiomer of an unsaturated 1,3-fatty diol by the action of a fatty alcohol-forming polypeptide.

[0213] Thus, in an exemplary embodiment, to prepare the (S) enantiomer of an unsaturated 1,3-fatty diol (e.g., 5-dodecene-1,3-diol), the available free fatty acid is first converted to acyl-CoA by acyl-CoA synthase, which is catalyzed by FadD in E. coli (and homologs in other microorganisms). The resulting acyl-CoA is then oxidized to trans-2-enoyl-CoA by fatty acyl-CoA dehydrogenase, which is catalyzed by FadE in E. coli (and homologs in other microorganisms). The resulting trans-2-enoyl-CoA is then hydrated to (S)-3-hydroxy-acyl-CoA by 2-trans-enoyl-CoA hydratase / (S)-3-hydroxy-acyl-CoA dehydratase, which is catalyzed by FadB in E. coli (and homologs in other microorganisms).

[0214] In the wild-type β-oxidation pathway, (S)-3-hydroxy-acyl-CoA is then further oxidized to 3-keto-acyl-CoA by 3-keto-acyl-CoA dehydrogenase, which is also catalyzed by FadB in E. coli (and homologs in other microorganisms). The resulting 3-keto-acyl-CoA is thiolyzed to acyl-CoA and acetyl-CoA by 3-ketoacyl-CoA thiolase, which is catalyzed by FadA in E. coli (and homologs in other microorganisms).

[0215] In an exemplary embodiment, the accumulation of (S)-3-hydroxy-acyl-CoA is caused by selectively blocking the dehydrogenase activity of 3-keto-acyl-CoA dehydrogenase (FadB) to prevent (S)-3-hydroxy-acyl-CoA from being oxidized to 3-keto-acyl-CoA. In an exemplary embodiment, the selective blocking of the (S)-3-hydroxy-acyl-CoA dehydrogenase activity of FadB is achieved by mutation of histidine 450 in the FadB gene of Escherichia coli (see, e.g., He XY and Yang SY (1996) Biochemistry 35(29):9625-9630). The (S)-3-hydroxy-acyl-CoA accumulated in the cell is then converted to the (S) enantiomer of an unsaturated 1,3-fatty diol (e.g., (S)-5-dodecene-1,3-diol) by the action of a fatty alcohol forming polypeptide (e.g., such as those disclosed in WO 2016 / 011430 A1).

[0216] The determination / confirmation of the enantiomeric configuration obtained is realized by any method known in the art, for example, by non-chromatographic techniques such as polarimetry, by nuclear magnetic resonance, isotope dilution, calorimetry and enzyme technology. These techniques require pure samples, and are not related to the separation of enantiomers. The quantitative (it does not need pure samples) and separation of enantiomers can be carried out simultaneously by chiral chromatography, such as using gas chromatography (GC) or high performance liquid chromatography (HPLC) of chiral columns (see, for example, " Stereochemistry of Organic Compounds ", Ernest L.Elil and Sanuel H.Wilen, 1994, John Wiley and Sons Publishing Company). The chiral purity of the product can be identified using chiral chromatography, such as chiral HPLC or LC / MS (see, for example, U.S. Patent Application Publication No. US2008 / 0248539A1 and No. US2013 / 0052699A1).

[0217] c. Fermentation and production of 1,3-fatty diols

[0218] As used herein, fermentation refers broadly to the conversion of organic materials into target substances by recombinant host cells. For example, this includes the conversion of carbon sources by recombinant host cells into fatty acid derivatives (e.g., 1,3-fatty diols) by recombinant host cell cultures in a medium comprising a carbon source. Conditions that allow the production of target substances (e.g., 1,3-fatty diols, such as 5-dodecene-1,3-diol) are any conditions that allow host cells to produce desired products (e.g., 1,3-fatty diol compositions). Suitable conditions include, for example, typical fermentation conditions, for example, see Principles of Fermentation Technology, 3rd edition (2016) supra; Fermentation Microorganisms and Biotechnology, 2nd edition, (2007) supra.

[0219] Fermentation conditions may include multiple parameters, including but not limited to temperature range, pH level, aeration level, feed rate and medium composition. Each of these conditions allows host cell growth individually and in combination. Fermentation may be aerobic, anaerobic or its variation (e.g., microaerobic). Exemplary culture medium includes fermentation liquid (liquid) or gel (solid). Typically, culture medium includes a carbon source (e.g., a simple carbon source derived from renewable raw materials) that can be directly metabolized by the host cell. In addition, enzymes can be used in the culture medium to promote the activation of the carbon source (e.g., starch or cellulose depolymerization is fermentable sugar) and subsequent metabolism.

[0220] For small-scale production, host cells engineered to produce 1,3-fatty diols can be grown, for example, in batches of about 100 μL, 200 μL, 300 μL, 400 μL, 500 μL, 1 mL, 5 mL, 10 mL, 15 mL, 25 mL, 50 mL, 75 mL, 100 mL, 500 mL, 1 L, 2 L, 5 L, or 10 L; fermented; and induced to express a desired polynucleotide sequence, such as a polynucleotide encoding a polypeptide having a particular enzymatic activity (e.g., thioesterase (TE), carboxylic acid reductase (CAR), alcohol dehydrogenase (ADH), fatty acyl-CoA / ACP reductase (FAR), acyl-CoA reductase (ACR), acyl-CoA carboxylase (ACC), and / or acyl-ACP / CoA reductase (AAR) enzyme activity). For large-scale production, the modified host cells can be grown in cultures having about 10L, 100L, 1000L, 10,000L, 100,000L, 1,000,000L or larger volume batches; fermented; and induced to express any desired polynucleotide sequence. The 1,3-fatty diol compositions described herein can be found in the extracellular environment of the recombinant host cell culture and can be easily separated from the culture. Fatty acid derivatives (e.g., 1,3-fatty diols, e.g., 5-dodecene-1,3-diol) and / or fatty alcohols can be secreted by the recombinant host cells, transported to the extracellular environment or passively transferred to the extracellular environment of the recombinant host cell culture. The 1,3-fatty diol compositions can be separated from the recombinant host cell culture using conventional methods known in the art (see, e.g., Example 2 below).

[0221] Exemplary microorganisms suitable for use as production host cells include, for example, bacteria, cyanobacteria, yeast, algae, or filamentous fungi, etc. In order to produce 1,3-fatty diols, the production host cell (or equivalently, the host cell) is modified to contain a modified fatty acid biosynthetic pathway relative to an unmodified or native host cell, such as discussed above in Section II.a. and modified as disclosed in WO 2016 / 011430 A1. The production host modified to contain a modified fatty acid biosynthetic pathway can efficiently convert glucose or other renewable raw materials into fatty acid derivatives, including fatty alcohols and 1,3-fatty diols, such as 5-dodecene-1,3-diol. Protocols and procedures for high density fermentation to produce various compounds have been established (see, e.g., U.S. Pat. Nos. 8,372,610; 8,323,924; 8,313,934; 8,283,143; 8,268,599; 8,183,028; 8,110,670; 8,110,093; and 8,097,439).

[0222] In some exemplary embodiments, host cells are cultured in a medium (e.g., fermentation medium) containing a carbon source (e.g., a simple carbon source) at an initial concentration of about 20 g / L to about 900 g / L. In other embodiments, the medium contains a carbon source at an initial concentration of about 2 g / L to about 10 g / L; about 10 g / L to about 20 g / L; about 20 g / L to about 30 g / L; about 30 g / L to about 40 g / L; or about 40 g / L to about 50 g / L. In some embodiments, the level of available carbon source in the medium can be monitored during the fermentation process. In some embodiments, the method further includes adding a supplemental carbon source to the medium when the level of the initial carbon source in the medium is less than about 0.5 g / L.

[0223] In some exemplary embodiments, when the carbon source level in the culture medium is lower than about 0.4g / L, lower than about 0.3g / L, lower than about 0.2g / L or lower than about 0.1g / L, the supplementary carbon source is added to the culture medium. In some embodiments, the supplementary carbon source is added to maintain the carbon source level for about 1g / L to about 25g / L. In some embodiments, the supplementary carbon source is added to maintain the carbon source level for about 2g / L or higher (e.g., about 2g / L or higher, about 3g / L or higher, about 4g / L or higher). In certain embodiments, the supplementary carbon source is added to maintain the carbon source level for about 5g / L or lower (e.g., about 5g / L or lower, about 4g / L or lower, about 3g / L or lower). In some embodiments, the supplementary carbon source is added to maintain the carbon source level for about 2g / L to about 5g / L, about 5g / L to about 10g / L or about 10g / L to about 25g / L.

[0224] In an exemplary embodiment, the fermentation carbon source is derived from a renewable raw material. In some embodiments, the carbon source is glucose. In other embodiments, the carbon source is glycerol. Other possible carbon sources include, but are not limited to, fructose, mannose, galactose, xylose, arabinose, starch, cellulose, pectin, xylan, sucrose, maltose, cellobiose and turanose; cellulosic materials and variants, such as hemicellulose, methylcellulose and sodium carboxymethylcellulose; saturated or unsaturated fatty acids, succinates, lactates and acetates; alcohols, such as ethanol, methanol and glycerol, or mixtures thereof. In one embodiment, the carbon source is derived from corn, sugar cane, sorghum, sugar beet, switch grass, silage, straw, wood, pulp, sewage, garbage, cellulosic municipal waste, flue gas, synthesis gas or carbon dioxide. Simple carbon sources can also be products of photosynthesis, such as glucose or sucrose. In one embodiment, the carbon source is derived from waste products, such as glycerol, flue gas, or synthesis gas; or from the reforming of organic materials (such as biomass); or from natural gas or methane, or from the reforming of these materials to synthesis gas; or from carbon dioxide fixed by photosynthesis, for example, 1,3 diols can be grown photosynthetically and use CO2 The recombinant cyanobacteria of carbon source is produced. In certain embodiments, the carbon source is derived from biomass. An exemplary source of biomass is plant matter or vegetation, such as corn, sugar cane or switchgrass. Another exemplary source of biomass is metabolic waste products, such as animal matter (e.g., cow dung). Other exemplary sources of biomass include algae and other marine plants. Biomass also includes waste products from industry, agriculture, forestry and family, including but not limited to fermentation waste, silage, straw, timber, sewage, rubbish, cellulosic urban waste, urban solid waste and food residues.

[0225] In some exemplary embodiments, 1,3-fatty diol (e.g., 5-dodecene-1,3-diol) is produced at a concentration of about 0.5 g / L to about 40 g / L. In some embodiments, 1,3-fatty diol is produced at a concentration of about 1 g / L or more (e.g., about 1 g / L or more, about 10 g / L or more, about 20 g / L or more, about 50 g / L or more, about 100 g / L or more). In some embodiments, 1,3-fatty diol is produced at a concentration of about 1 g / L to about 170 g / L, about 1 g / L to about 10 g / L, about 40 g / L to about 170 g / L, about 100 g / L to about 170 g / L, about 10 g / L to about 100 g / L, about 1 g / L to about 40 g / L, about 40 g / L to about 100 g / L, or about 1 g / L to about 100 g / L.

[0226] In other exemplary embodiments, the 1,3-fatty diol is produced at a titer of about 25 mg / L, about 50 mg / L, about 75 mg / L, about 100 mg / L, about 125 mg / L, about 150 mg / L, about 175 mg / L, about 200 mg / L, about 225 mg / L, about 250 mg / L, about 275 mg / L, about 300 mg / L, about 325 mg / L, about 350 mg / L, about 375 mg / L, about 400 mg / L, about 425 mg / L, about 450 mg / L, about 475 mg / L, about 500 mg / L, about 525 mg / L, about 55 0mg / L, about 575mg / L, about 600mg / L, about 625mg / L, about 650mg / L, about 675mg / L, about 700mg / L, about 725mg / L, about 750mg / L, about 775mg / L, about 800mg / L, about 825mg / L, about 850mg / L, about 875mg / L, about 900mg / L, about 925mg / L, about 950mg / L, about 975mg / L, about 1000mg / L, about 1050mg / L, about 1075mg / L, about 1100mg / L, about 1125mg / L, about 1150mg / L, about 1175 mg / L, about 1200 mg / L, about 1225 mg / L, about 1250 mg / L, about 1275 mg / L, about 1300 mg / L, about 1325 mg / L, about 1350 mg / L, about 1375 mg / L, about 1400 mg / L, about 1425 mg / L, about 1450 mg / L, about 1475 mg / L, about 1500 mg / L, about 1525 mg / L, about 1550 mg / L, about 1575 mg / L, about 1600 mg / L, about 1625 mg / L, about 1650 mg / L, about 1675 mg / L, about 1700 g / L, about 1725 mg / L, about 1750 mg / L, about 1775 mg / L, about 1800 mg / L, about 1825 mg / L, about 1850 mg / L, about 1875 mg / L, about 1900 mg / L, about 1925 mg / L, about 1950 mg / L, about 1975 mg / L, about 2000 mg / L (2 g / L), 3 g / L, 5 g / L, 10 g / L, 20 g / L, 30 g / L, 40 g / L, 50 g / L, 60 g / L, 70 g / L, 80 g / L, 90 g / L, 100 g / L, or a range bounded by any two of the foregoing values. In other embodiments, the 1,3-fatty diol (e.g., 1,3-diol) is produced at a titer of greater than 100 g / L, greater than 200 g / L, greater than 300 g / L, or higher, such as 500 g / L, 700 g / L, 1000 g / L, 1200 g / L, 1500 g / L, or 2000 g / L.The preferred titer of 1,3-fatty diols (e.g., 1,3-diols) produced by recombinant host cells according to the disclosed methods is 5 g / L to 200 g / L, 10 g / L to 150 g / L, 20 g / L to 120 g / L, and 30 g / L to 100 g / L, 100 g / L to 150 g / L, and 120 g / L to 180 g / L. In one embodiment, the titer of 1,3-fatty diols (e.g., 1,3-diols) produced by recombinant host cells according to the disclosed methods is about 1 g / L to about 250 g / L, and more specifically 90 g / L to about 120 g / L. The titer may relate to a specific 1,3-diol produced by a given recombinant host cell culture or a combination of 1,3-diols of different chain lengths or different functions, such as a mixture of saturated and unsaturated 1,3-fatty diols.

[0227] In other exemplary embodiments, the host cell engineered to produce 1,3-fatty diols (e.g., 5-dodecene-1,3-diol) according to the methods of the present disclosure has a yield of at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, or at least 30%, or at least 40%, or a range bounded by any two of the foregoing values. In other embodiments, 1,3-fatty diols (e.g., 5-dodecene-1,3-diol) are produced at a yield of greater than 30%, 40%, 50%, 60%, 70%, 80%, 90% or more. Alternatively or additionally, the yield is about 30% or less, about 27% or less, about 25% or less, or about 22% or less. Thus, the yield can be bounded by any two of the above endpoints. For example, the yield of 1,3-fatty diols (e.g., 1,3-diols) produced by recombinant host cells according to the disclosed methods may be 5% to 15%, 10% to 25%, 10% to 22%, 15% to 27%, 18% to 22%, 20% to 28%, or 20% to 30%. In specific embodiments, the yield of 1,3-fatty diols (e.g., 1,3-diols) produced by recombinant host cells is about 10% to about 40%. In another specific embodiment, the yield of 1,3-fatty diols (e.g., 1,3-diol) produced by recombinant host cells is about 25% to about 30%. The yield can be related to a specific 1,3-fatty diol (e.g., 5-dodecene-1,3-diol) or a combination of 1,3-diols produced by a given recombinant host cell culture. In addition, the yield also depends on the raw materials used.

[0228] In some exemplary embodiments, the productivity of a host cell modified to produce 1,3-fatty diols (e.g., 5-dodecene-1,3-diol) according to the methods of the present disclosure is at least 100 mg / L / hour, at least 200 mg / L / hour, at least 300 mg / L / hour, at least 400 mg / L / hour, at least 500 mg / L / hour, at least 600 mg / L / hour, at least 700 mg / L / hour, at least 800 mg / L / hour, at least 900 mg / L / hour, at least 1000 mg / L / hour, at least 1 ...1200 mg / L / hour, at least 1400 mg / L / hour, at least 1500 mg / L / hour, at least 1600 mg / L / hour, at least 1700 mg / L / hour, at least 1800 mg / L / hour, at least 1900 mg / L / hour, at least 2000 mg / L / hour, at least 2100 mg / L / hour, at least 2200 mg / L / hour, at least 2300 mg / L / hour, at least 2400 mg / L / hour In some embodiments, the productivity of 1,3-diol produced by recombinant host cells according to the disclosed methods may be from 500 mg / L / hour to 2500 mg / L / hour, or from 700 mg / L / hour to 2000 mg / L / hour. In an exemplary embodiment, the productivity is about 0.7 mg / L / hour to about 3 g / L / hour.As used herein, productivity relates to a particular 1,3-fatty diol (eg, 5-dodecene-1,3-diol) produced by a given recombinant host cell culture.

[0229] In some exemplary embodiments, the host cells used for the fermentation procedures discussed herein (above) are mammalian cells, plant cells, insect cells, yeast cells, fungal cells, filamentous fungal cells, algal cells, cyanobacterial cells, and bacterial cells. In particular embodiments, the host cells are selected from the following genera: Escherichia, Bacillus, Pseudomonas, Lactobacillus, Rhodococcus, Synechococcus, Synechoystis, Pseudomonas, Aspergillus, Trichoderma, Neurospora, Fusarium, Humicola, Rhizomucor, Kluyveromyces, Pichia, Mucor, Myceliophtora, Penicillium, Phanerochaete, Pleurotus, Trametes, Chrysosporium, Saccharomyces, Stenotrophamonas, Schizosaccharomyces, Yarrowia or Streptomyces. In other exemplary embodiments, the host cell is a Bacillus lentus cell, a Bacillus brevis cell, a Bacillus stearothermophilus cell, a Bacillus licheniformis cell, a Bacillus alkalophilus cell, a Bacillus coagulans cell, a Bacillus circulans cell, a Bacillus pumilis cell, a Bacillus thuringiensis cell, a Bacillus clausii cell, a Bacillus megaterium cell, a Bacillus subtilis cell, or a Bacillus amyloliquefaciens cell.In other exemplary embodiments, the host cell is a Pseudomonas putida cell. In certain embodiments, the host cell is Synechococcus PCC7002, Synechococcus elongatus PCC 7942, Synechococcus PCC 6803, Synechococcus elongatus PCC6301, Prochlorococcus marinus CCMP1986 (MED4), Anabaena variabilis ATCC29413, Nostocpunctiforme ATCC29133 (PCC73102), Gloeobacter violaceus ATCC 29082 (PCC7421), Nostoc ATCC 27893 (PCC7120), Cyanothece PCC7425 (29141), Cyanothece ATCC 51442 or Synechococcus ATCC 27264 (PCC7002). In other exemplary embodiments, the host cell is a Trichoderma koningii cell, a Trichoderma viride cell, a Trichoderma reesei cell, a Trichoderma longibrachiatum cell, an Aspergillus awamori cell, an Aspergillus fumigates cell, an Aspergillus foetidus cell, an Aspergillus nidulans cell, an Aspergillus niger cell, an Aspergillus oryzae cell, a Humicola insolens cell, a Humicola lanuginose cell, a Rhodococcus opacus cell, a Rhizomucor miehei cell, or a Mucor miehei cell. michei cells. In other exemplary embodiments, the host cell is an Actinomycetes cell. In other exemplary embodiments, the host cell is a Streptomyces lividans cell or a Streptomyces murinus cell. In other embodiments, the host cell is a Saccharomyces cerevisiae cell.

[0230] In other exemplary embodiments, the host cell is a cell from a eukaryotic plant, algae, cyanobacterium, green sulfur bacteria, green non-sulfur bacteria, purple sulfur bacteria, purple non-sulfur bacteria, extremophiles, yeast, fungi, engineered organisms thereof, or synthetic organisms. In some exemplary embodiments, the host cell is a cell from Arabidopsis thaliana, Panicum virgatums, Miscanthus giganteus, Zea mays, botryococcuse braunii, Chalamydomonas reinhardtii, Dunaliela salina, Thermosynechococcus elongatus, Synechococcus elongatus, Synechococcus sp., Synechocystis sp., Chlorobium tepidum, Chloroflexus auranticus, Chromatium vinosum, Rhodospirillum rubrum, Rhodobacter capsulatus, Rhodopseudomonas palustris, In some other exemplary embodiments, the host cell is from Pichia pastoris, Saccharomyces cerevisiae, Yarrowia lipolytica, Schizosaccharomyces pombe, Pseudomonas fluorescens, Pseudomonas putida, or Zymomonas mobilis. In other exemplary embodiments, the host cell is a cell from Synechococcus sp. PCC 7002, Synechococcus sp. PCC 7942, or Synechocystis sp. PCC 6803. In some exemplary embodiments, the host cell is a CHO cell, a COS cell, a VERO cell, a BHK cell, a HeLa cell, a Cv1 cell, a MDCK cell, a 293 cell, a 3T3 cell or a PC12 cell. In some exemplary embodiments, the host cell is an Escherichia coli cell.In some exemplary embodiments, the E. coli cell is a strain B, strain C, strain K, or strain W E. coli cell.

[0231] d. Double decomposition

[0232] As discussed above, the double bonds of unsaturated 1,3-fatty diols (eg, 5-dodecene-1,3-diol) produced by recombinant host cells engineered to produce 1,3-fatty diols are primarily in the (Z) configuration.

[0233] U.S. Patent No. 9,163,267 teaches a method for producing olefins by contacting a composition comprising at least one ω-7-olefinic fatty acid or derivative thereof with a cross-metathesis catalyst under conditions that allow for cross-metathesis conversion, wherein the at least one ω-7-olefinic fatty acid or derivative thereof is produced in a genetically engineered microorganism. Thus, in an exemplary embodiment, the (E) isomer of an unsaturated (Z)-1,3-fatty diol, such as the (E) isomer of 5-dodecene-1,3-diol, is prepared using a modified microorganism as disclosed above, using, for example, a method disclosed in U.S. Patent No. 9,163,267. As is well known in the art, in cross-metathesis reactions, (Z)-(E) selectivity is generally biased toward the formation of the (E) isomer (see, e.g., Naeimeh Bahri-Laleh et al., (2011) Beilstein J. Org. Chem. 7:40–45).

[0234] III. Compositions and formulations of 1,3-fatty diols

[0235] Bioproducts (e.g., compositions comprising 5-dodecene-1,3-diol produced using engineered microorganisms as discussed above in Sections II a-II d) are produced from renewable sources (e.g., from a simple carbon source derived from a renewable feedstock) and are therefore novel compositions of matter. These novel bioproducts can be identified based on dual carbon isotope fingerprinting or 14 C dating distinguishes from organic compounds derived from petrochemical carbon. In addition, the specific origin of biogenic carbon (e.g., glucose versus glycerol) can be determined by double carbon isotope fingerprinting by methods known in the art (see, e.g., U.S. Pat. No. 7,169,588, WO 2016 / 011430 A1, etc.).

[0236] The following examples are provided to illustrate but not to limit the present invention.

[0237] Specific implementation plan

[0238] Example 1:

[0239] The following example illustrates the production of 5-dodecene-1,3-diol by fermentation. 5-Dodecene-1,3-diol is produced by fermentation using an E. coli strain engineered to produce fatty alcohols and 1,3 diols. These 1,3-fatty diols are then refined from the resulting fermentation broth.

[0240] Strain stNH1282 is a derivative of strain MG1655, which was modified as disclosed, for example, in WO 2016 / 011430 A1 to attenuate the activity of FadE (involved in fatty acid degradation) and engineered to overexpress thioesterases specific for C12 chain length (e.g., FatB1), EntD (phosphopantetheinyl transferase), CarB (carboxylic acid reductase), and AlrA-ADP1 (alcohol dehydrogenase). The strain stNH1282 was inoculated from 1 mL of glycerol freezer stock into LB medium (100 mL) containing spectinomycin (115 mg / L) and shaken at 32°C for 6-8 hours until the culture OD reached 3-6.

[0241] Two seed bioreactors were prepared with 4 liters of seed medium 2 (Table I) and subsequently inoculated with this LB culture at 1.0% (v / v) and cultured using the following bioreactor parameters: pH = 6.9 with addition of NH 4 OH, airflow = 0.5 v / v / m (dissolved oxygen) DO = 30% saturation, and temperature = 33° C. The bioreactors were run overnight (approximately 16 hours) until the glucose was exhausted and the culture optical density (OD) was between 20 and 30 absorbance units (AU).

[0242] Table I .Bioreactor seed culture medium composition.

[0243] Components concentration <![CDATA[(NH 4 ) 2 SO 4 (g / L)]]> 0.5 <![CDATA[KH 2 PO 4 (g / L)]]> 2 TM4 solution (ml / L) – Table III. 2.5 <![CDATA[CaCl 2 -2H 2 O(mg / L)]]> 140 Ferric citrate mg / L 80 NaCl(g / L) 1 <![CDATA[MgSO 4 -7H 2 O(g / L)]]> 0.5 Microvitamin solution (ml / L) – Table IV. 0.625 Thiamine (mg / L) 0.1 Add after sterilization Glucose (g / L) 40 Spec 1 Inoculum (ml / L) 10

[0244] First, a 700 liter (L) production bioreactor was batched with 250 L production medium (Table II) and inoculated with a 7.5 L seed bioreactor (3% volume / volume (v / v)). The following bioreactor parameters were used to cultivate this bioreactor: pH = 6.9 and NH 4 OH, air flow = 0.5 volume / volume / minute (v / v / m), DO = 15% saturation (with 1 bar back pressure), and temperature = 33°C.

[0245] At OD greater than 10AU, the culture was induced by bringing the medium to 0.5mM IPTG. After the initial glucose in the tank was depleted, a glucose solution (62% weight / weight (w / w)) was fed to the bioreactor at a rate of 10 g / L (initial volume) / hour for 1 hour. A subsequent glucose feed of 1 hour was started after glucose depletion, which was triggered by a rise in dissolved oxygen in the tank. This continued throughout the fermentation. The automated addition of Xiameter (Dow Corning) to control any foaming. The run was terminated after 72 hours and the culture broth was collected by centrifugation.

[0246] Table II. Generate bioreactor medium composition.

[0247] Components concentration <![CDATA[(NH 4 ) 2 SO 4 (g / L)]]> 0.5 <![CDATA[KH 2 PO 4 (g / L)]]> 2 TM4 solution (ml / L) – Table III. 2.5 <![CDATA[CaCl 2 -2H 2 O(mg / L)]]> 140 Ferric citrate mg / L 80 NaCl(g / L) 1 <![CDATA[MgSO 4 -7H 2 O(g / L)]]> 2.2 Microvitamin solution (ml / L) – Table IV. 0.625 Thiamine (mg / L) 0.1 Add after sterilization Glucose (g / L) 10 Inoculum (ml / L) 32

[0248] Table III. Microvitamin solution.

[0249] Components concentration <![CDATA[ZnCl 2 ]]> 4g / L <![CDATA[CaCl 2 ·2H 2 Or]]> 8g / L <h2 style=";text-align:left;direction:ltr"><![CDATA[Na <h2 style=";text-align:left;direction:ltr"> 2 <h2 style=";text-align:left;direction:ltr"> MoO<h2 style=";text-align:left;direction:ltr"> 4 <h2 style=";text-align:left;direction:ltr"> 2H<h2 style=";text-align:left;direction:ltr"> 2 <h2 style=";text-align:left;direction:ltr"> O]]><h2 style=";text-align:left;direction:ltr"> 8g / L <![CDATA[CuSO 4 ·5H 2 Oh]]> 7.6g / L <![CDATA[H 3 BO 3 ]]> 2.0g / L HCl(conc.) 8mL / L

[0250] Table IV. Microvitamin solution.

[0251] Components concentration Riboflavin 0.06g / L Pantothenic acid 5.4g / L niacin 6g / L Pyridoxine 1.4g / L Biotin 0.06g / L Folic acid 0.01g / L

[0252] Example 2:

[0253] The following example illustrates the refining of 1,3 diols from a centrifuged fermentation broth.

[0254] The fermentation product described in Example 1 above is a mixture of three phases, i.e., an organic phase rich in fatty alcohols and 1,3 diols, an aqueous phase containing a spent fermentation medium, and a solid phase containing Escherichia coli biomass. After centrifugation, the lighter organic phase is collected. Then this material is deacidified by alkali refining and moisture drying. Then the obtained deacidified oil is fractionated by distillation, and the fractions rich in 5-dodecane-1,3-diols and 5-dodecene-1,3 diols are collected and pooled. The composition of fatty alcohols and 1,3 diols in the enriched collection is determined by gas chromatography and mass spectrometry, as described in Example 3 below, and is shown in Table V. The mass spectrum of 5-dodecane-1,3 diols and 5-dodecene-1,3 diols (which are the main components) is shown in Figures 1 and 2, respectively.

[0255] Table V - Analytical evidence for the fraction enriched in 1,3-diol.

[0256]

[0257] Example 3:

[0258] The following examples illustrate exemplary methods for analytical evaluation of fatty alcohols and 1,3 diols using gas chromatography (GC) and mass spectrometry (MS).

[0259] A sample (e.g., the 1,3 diol-enriched fraction described in Example 2 above) was reacted with a 1:1 mixture of (N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) + (1% trimethylchlorosilane (TMCS)): toluene to form silyl ethers of alcohols. Hydrocarbons, methyl esters, and aldehydes were not derivatized. The sample was then analyzed by a rapid temperature ramp method using a narrow bore column. The GC program calculated the weight percentages of the sample components by comparing the response factors of the sample to those of the standard using methyl tridecanoate as an internal standard. The results of the oil analysis of the 1,3 diol-enriched fraction of Example 2 are shown in Table V. Each compound eluting from the GC was identified by its retention time and mass spectrum. The mass spectrum of 1,3-diol and a schematic diagram showing possible silyl ether-derived ions are shown in Figures 1 and 2.

[0260] Example 4:

[0261] The following example illustrates the synthesis of (S)-2-[2-(benzyloxy)ethyl]oxirane, which can be used to prepare 5-dodecene-1,3-diol via the chemical synthesis route disclosed below in Example 5. This is a prophetic example.

[0262]

[0263] (S)-2-[2-(Benzyloxy)ethyl]oxirane will be prepared by literature procedures (see, e.g., Cink, RD; Forsyth, CJ. J. Org. Chem 1995, 60, 8122). Briefly, NaH (63 mg, 2.6 mmol) will be added to a magnetically stirred solution of S-4-(benzyloxy)butane-1,2-diol (207 mg, 1.05 mmol, CAS No. 69985-32-6) in THF (10.6 mL) at 0°C. The resulting mixture will be allowed to warm to room temperature and stirred for 1 hour, then cooled to 0°C, after which N-toluenesulfonyl imidazole (237 mg, 1.07 mmol) will be added in three equal portions over 20 minutes. The mixture will be allowed to warm to room temperature and stirred for 45 minutes, then cooled to 0°C. Saturated NH 4 Cl and Et 2 O aqueous solution (65 mL), with H 2 The separated organic phase was washed with 25 mL of O and brine (25 mL), then with Et 2 The combined aqueous layers were extracted with 4% CO (2x25 mL) and then dried (Na 2 SO 4) The combined organic layers were filtered and concentrated by rotary evaporation. Chromatography (silica gel; hexane / EtOAc 5:1) of the expected residue afforded the desired product.

[0264] Example 5:

[0265] The following example illustrates a method for producing (R,Z)-dodec-5-ene-1,3-diol (ie, (R,Z)-5-dodecene-1,3-diol) using synthetic chemistry. This is a prophetic example.

[0266]

[0267] To a -78 °C solution of oct-1-yne (1.8 eq) in THF (0.5 M) was added 2.5 M n-butyllithium (1.81 eq) in hexanes and the resulting solution was stirred for 15 min before being added to a solution of (S)-2-[2-(benzyloxy)ethyl]oxirane (1 eq) in THF (0.2 M) at -78 °C. BF was then added dropwise 3 ·OEt 2 (2 eq.) and the resulting mixture was stirred at -78 °C until completion. If necessary, the temperature was slowly raised to -30 °C. Saturated NH 4 Cl and Et 2 O aqueous solution, followed by H 2 O and then washed the separated organic phase with brine and then with Et 2 The combined aqueous layers were extracted with 0.5% ethanol and then dried (Na 2 SO 4 ) The combined organic layers were filtered and concentrated by rotary evaporation. Subsequent chromatography (silica gel; hexanes / EtOAc) of the residue provided (R)-1-(benzyloxy)dodec-5-yn-3-ol.

[0268] (R)-1-(benzyloxy) dodecan-5-yn-3-ol was then taken up in hexane in a flask to produce a 0.2 M mixture, to which was added 20 wt % of freshly prepared Lindlar catalyst (see Lindlar, H.; Dubuis, R. "Org. Synth." 1966, 46, 89, and using freshly precipitated calcium carbonate) or 5% palladium on calcium carbonate (10 wt % relative to (R)-1-(benzyloxy) dodecan-5-yn-3-ol), followed by freshly distilled quinolone (10 wt % relative to (R)-1-(benzyloxy) dodecan-5-yn-3-ol). The flask was rinsed three times with hydrogen, and the mixture was then heated under H 2 Stir and pass H 2After indicating that the reaction is complete (e.g., after 1 equivalent of H is consumed), 2 The suspension was filtered through a pad of silica gel, which was thereafter washed with diethyl ether. This organic layer was concentrated and purified by chromatography (silica gel; hexane / EtOAc), and it is expected to provide (R,Z)-1-(benzyloxy)dodec-5-ene-3-ol. [Note: It is well known that the benzyl protecting group can usually be retained in the Lindela hydrogenation reaction. However, insofar as the conditions provide a certain degree of debenzylation to provide (R,Z)-dodec-5-ene-1,3-diol, this can be obtained by a chromatographic step].

[0269] In CH 2 Cl 2 (R,Z)-1-(Benzyloxy)dodec-5-en-3-ol was taken up in a 2M solution and stirred at 0°C. To this solution was added 1.3 equivalents of neat trimethylsilyl iodide via a dry syringe. The progress of the reaction was monitored by TLC. Upon completion, the reaction was quenched by the slow addition of 4 equivalents of MeOH. Saturated NH 4 Cl and Et 2 O aqueous solution, with H 2 The separated organic phase was washed with O and brine, and then with Et 2 The combined aqueous layers were extracted with 4% CO (2x25 mL) and then dried (Na 2 SO 4 ) The combined organic layers were filtered and concentrated by rotary evaporation. The residue was then chromatographed (silica gel; hexanes / EtOAc) to provide (R,Z)-dodec-5-ene-1,3-diol.

[0270] Alternatively, the secondary alcohol of (R,Z)-1-(benzyloxy)dodecan-5-en-3-ol can be protected by a tert-butyldimethylsilyl ("TBS") group prior to benzyl cleavage, and the TBS group subsequently removed after debenzylation. Thus, (R,Z)-1-(benzyloxy)dodecan-5-en-3-ol (1 equivalent) was reacted with CH 2 Cl 2 2,6-lutidine (1.3 eq.) was added to a 0.1 M solution in 1% ethanol and the mixture was then cooled to 0°C, after which tert-butyldimethylsilyl trifluoromethanesulfonate (1.1 eq.) was added dropwise with stirring. The solution was allowed to stir at 0°C until completion as monitored by thin layer chromatography. Saturated NH 4 Cl and Et 2 O aqueous solution, followed by H 2 O and then washed the separated organic phase with brine and then with Et 2 The combined aqueous layers were extracted with 0.5% ethanol and then dried (Na 2 SO 4) The combined organic layers were filtered and concentrated by rotary evaporation. The residue was then chromatographed (silica gel; hexanes / EtOAc) to provide (R,Z)-((1-(benzyloxy)dodec-5-en-3-yl)oxy)(tert-butyl)dimethylsilane.

[0271] In CH 2 Cl 2 (R,Z)-((1-(benzyloxy)dodec-5-en-3-yl)oxy)(tert-butyl)dimethylsilane was taken up in a 2.0 M solution and stirred at 0°C. To this solution was added 1.3 equivalents of neat trimethylsilyl iodide via a dry syringe. The progress of the reaction was monitored by thin layer chromatography. Upon completion, the reaction was quenched by the slow addition of 4 equivalents of MeOH. Saturated NH 4 Cl and Et 2 O aqueous solution, with H 2 The separated organic phase was washed with O and brine, and then with Et 2 The combined aqueous layers were extracted with 4% CO (2x25 mL) and then dried (Na 2 SO 4 ) The combined organic layers were filtered and concentrated by rotary evaporation. The residue was then chromatographed (silica gel; hexanes / EtOAc) to provide (R,Z)-3-((tert-butyldimethylsilyl)oxy)dodec-5-en-1-ol.

[0272] To a stirred 2.0 M solution of (R,Z)-3-((tert-butyldimethylsilyl)oxy)dodec-5-en-1-ol in THF was added tetrabutylammonium fluoride (1.0 M in THF; 1.2 eq.) at 0 °C, after which the mixture was allowed to slowly warm to room temperature and the reaction was allowed to proceed to completion (monitored by thin layer chromatography). Upon completion, saturated NH 4 Cl and Et 2 O aqueous solution, followed by H 2 O and then washed the separated organic phase with brine and then with Et 2 The combined aqueous layers were extracted with 0.5% ethanol and then dried (Na 2 SO 4 ) The combined organic layers were filtered and concentrated by rotary evaporation. The residue was then chromatographed (silica gel; hexanes / EtOAc) to provide (R,Z)-dodec-5-ene-1,3-diol.

[0273] Example 6:

[0274] The following example illustrates an exemplary chemical synthesis method for preparing (R,Z)-tetradeca-7-ene-1,3-diol. This is a prophetic example.

[0275]

[0276] 1-Bromodec-3-yne is available from commercial sources or can be obtained by reacting oct-1-yne with ethylene oxide in BF 3 ·OEt 2 1-bromodecan-3-yne) is reacted in the presence of 2-hydroxy-1- 4-nitropropene (see Example 5 above) to produce dec-3-yn-1-ol, which is then converted to 1-bromodecan-3-yne, for example, by reaction with thionyl bromide, as described in U.S. Pat. No. 9,353,090. Specifically, dec-3-yn-1-ol (1 equivalent) is reacted in CH 2 Cl 2 To a stirred solution in 4% ethyl acetate (0.2 M) was added freshly distilled dimethylformamide (0.5 eq.) followed by thionyl bromide (1.3 eq.). The mixture was stirred continuously and allowed to warm slowly to 20°C. After the reaction was complete (e.g., as indicated by thin layer chromatography and / or gas chromatography), Et 2 O and subsequently saturated NH 4 Cl aqueous solution, H 2 The separated organic phase was washed with O and brine, and then with Et 2 The combined aqueous layers were extracted with 0.5% ethanol and then dried (Na 2 SO 4 ) The combined organic layers were filtered and concentrated by rotary evaporation. The residue was then chromatographed (silica gel; petroleum ether / Et 2 O) to provide 1-bromodecan-3-yne.

[0277] To a 0.1 M room temperature solution of (S)-2-[2-(benzyloxy)ethyl]oxirane in THF was added CuCN (0.5 eq), after which the mixture was stirred for 5 minutes and then cooled to -40°C. To this stirred solution was added 3.3 eq of freshly prepared dec-3-yn-1-ylmagnesium bromide (1.0 M; prepared from 1-bromodecan-3-yne) in THF at -20°C. The resulting mixture was maintained at -40°C for approximately 1 hour, then warmed to 0°C over 75 minutes. After the reaction was complete, saturated NH 4 Cl and Et 2 O aqueous solution, with H 2 The separated organic phase was washed with O and brine, and then with Et 2 The combined aqueous layers were extracted with 0.5% ethanol and then dried (Na 2 SO 4 ) The combined organic layers were filtered and concentrated by rotary evaporation. The residue was then chromatographed (silica gel; hexanes / EtOAc) to provide (R)-1-(benzyloxy)tetradeca-7-yn-3-ol.

[0278] (R)-1-(benzyloxy)tetradec-7-yn-3-ol was then taken up in hexane in a flask to produce a 0.2 M mixture, to which was added 20 wt % of freshly prepared Lindlar catalyst (see Lindlar, H.; Dubuis, R. Organic Synthesis 1966, 46, 89, and using freshly precipitated calcium carbonate) or 10 wt % of palladium on 5% calcium carbonate (relative to (R)-1-(benzyloxy)tetradec-7-yn-3-ol), followed by the addition of freshly distilled quinolone (10 wt % relative to (R)-1-(benzyloxy)tetradec-7-yn-3-ol). [Note: Solubility can be increased by using EtOAc as a co-solvent or in place of hexane]. The flask was rinsed three times with hydrogen, and the mixture was then heated in H 2 Stir and pass H 2 After indicating that the reaction is complete (e.g., after 1 equivalent of H is consumed), 2 The suspension was filtered through a pad of silica gel, which was then washed with diethyl ether. The organic layer was concentrated and purified by chromatography (silica gel; hexane / EtOAc) and is expected to provide (R, Z)-1-(benzyloxy)tetradecene-7-ene-3-ol. [Note: It is well known that the benzyl protecting group is usually retained in the Lindela hydrogenation reaction. However, insofar as the conditions provide a certain degree of debenzylation to provide (R, Z)-tetradecene-7-ene-1,3-diol, this can be separated by a chromatographic step].

[0279] In CH 2 Cl 2 (R,Z)-1-(Benzyloxy)tetradec-7-en-3-ol was taken up in 4% paraformaldehyde to give a 2M solution which was stirred at 0°C. To this solution was added 1.5 equivalents of Et 3 N, followed by the addition of 2.3 equivalents of neat trimethylsilyl iodide. The reaction progress was monitored by TLC. Upon completion, the reaction was quenched by the slow addition of 4 equivalents of MeOH. NaHSO was then added 4 aqueous solution (1.0 M), the mixture was stirred for 15 min, after which Et 2 O. Then H 2 The separated organic phase was washed with O and brine, and then with Et 2 The combined aqueous layers were extracted with 4% CO (2x25 mL) and then dried (Na 2 SO 4 ) The combined organic layers were filtered and concentrated by rotary evaporation. The residue was then chromatographed (silica gel; hexanes / EtOAc) to provide (R,Z)-tetradeca-7-ene-1,3-diol.

[0280] Alternatively, the secondary alcohol of (R,Z)-1-(benzyloxy)tetradeca-7-en-3-ol can be protected with TBS, followed by deprotection of the benzyl group, and finally deprotection of TBS by the alternative procedure disclosed in Example 5 above.

[0281] Example 7:

[0282] The following example illustrates an exemplary chemical synthesis method for preparing (R,Z)-tridec-6-ene-1,3-diol. This is a prophetic example.

[0283]

[0284] 1-Bromonon-2-yne (CAS No. 5921-74-4) used to form non-2-yn-1-ylmagnesium bromide is available from commercial sources.

[0285] To a 0.1 M room temperature solution of (S)-2-[2-(benzyloxy)ethyl]oxirane in THF was added CuCN (0.5 eq), after which the mixture was stirred for 5 minutes and then cooled to -40°C. To this stirred solution was added 3.3 eq of freshly prepared non-2-yn-1-ylmagnesium bromide (1.0 M; prepared from 1-bromonon-2-yne) in THF at -20°C. The resulting mixture was maintained at -40°C for approximately 1 hour, then warmed to 0°C over 75 minutes. After the reaction was complete, saturated NH 4 Cl and Et 2 O aqueous solution, with H 2 The separated organic phase was washed with O and brine, and then with Et 2 The combined aqueous layers were extracted with 0.5% ethanol and then dried (Na 2 SO 4 ) The combined organic layers were filtered and concentrated by rotary evaporation. The residue was then chromatographed (silica gel; hexanes / EtOAc) to provide (R)-1-(benzyloxy)tridec-6-yn-3-ol.

[0286] (R)-1-(benzyloxy)tridec-6-yn-3-ol was then taken up in hexane in a flask to produce a 0.2 M mixture, to which was added 20 wt % of freshly prepared Lindlar catalyst (see Lindlar, H.; Dubuis, R. Organic Synthesis 1966, 46, 89, and using freshly precipitated calcium carbonate) or 5% palladium on calcium carbonate (10 wt % relative to (R)-1-(benzyloxy)tridec-6-yn-3-ol), followed by freshly distilled quinolone (10 wt % relative to (R)-1-(benzyloxy)tridec-6-yn-3-ol). [Note: Solubility can be increased by using EtOAc as a co-solvent or in place of hexane]. The flask was rinsed three times with hydrogen, and the mixture was then heated in H 2 Stir and pass H 2 After indicating that the reaction is complete (e.g., after 1 equivalent of H is consumed), 2 The suspension was filtered through a pad of silica gel, which was then washed with diethyl ether. The organic layer was concentrated and purified by chromatography (silica gel; hexane / EtOAc) and is expected to provide (R, Z)-1-(benzyloxy)tridec-6-ene-3-ol. [Note: It is well known that the benzyl protecting group is usually retained in the Lindela hydrogenation reaction. However, insofar as the conditions provide a degree of debenzylation to provide (R, Z)-tridec-6-ene-1,3-diol, this can be separated by a chromatographic step].

[0287] In CH 2 Cl 2 (R,Z)-1-(Benzyloxy)tridec-6-en-3-ol was taken up in 4% paraformaldehyde to give a 2M solution and stirred at 0°C. To this solution was added 1.5 equivalents of Et 3 N, followed by the addition of 2.3 equivalents of neat trimethylsilyl iodide. The reaction progress was monitored by TLC. Upon completion, the reaction was quenched by the slow addition of 4 equivalents of MeOH. NaHSO was then added 4 aqueous solution (1.0 M), the mixture was stirred for 15 min, after which Et 2 O. Then H 2 The separated organic phase was washed with O and brine, and then with Et 2 The combined aqueous layers were extracted with 4% CO (2x25 mL) and then dried (Na 2 SO 4 ) The combined organic layers were filtered and concentrated by rotary evaporation. The residue was then chromatographed (silica gel; hexanes / EtOAc) to provide (R,Z)-trideca-6-ene-1,3-diol.

[0288] Alternatively, the secondary alcohol of (R,Z)-1-(benzyloxy)tride-6-en-3-ol can be protected with TBS, followed by deprotection of the benzyl group, and finally deprotection of TBS by the alternative procedure disclosed in Example 5 above.

[0289] Example 8:

[0290] The following example illustrates the chemical synthesis of (R,E)-dodec-5-ene-1,3-diol. This is a prophetic example.

[0291]

[0292] To a 0.1 M room temperature solution of (S)-2-[2-(benzyloxy)ethyl]oxirane in THF was added CuCN (0.5 eq), after which the mixture was stirred for 5 minutes and then cooled to -40°C. To this stirred solution was added 3.3 eq of a freshly prepared -20°C solution of (E)-oct-1-en-1-ylmagnesium bromide in THF (1.0 M). The resulting mixture was maintained at -40°C for approximately 1 hour, then warmed to 0°C over 75 minutes. After the reaction was complete, saturated NH 4 Cl and Et 2 O aqueous solution, with H 2 The separated organic phase was washed with O and brine, and then with Et 2 The combined aqueous layers were extracted with 0.5% ethanol and then dried (Na 2 SO 4 ) The combined organic layers were filtered and concentrated by rotary evaporation. The residue was then chromatographed (silica gel; hexanes / EtOAc) to provide (R,E)-1-(benzyloxy)dodec-5-en-3-ol.

[0293] In CH 2 Cl 2 (R,E)-1-(Benzyloxy)dodec-5-en-3-ol was taken up in 4% paraformaldehyde to give a 2M solution and stirred at 0°C. To this solution was added 1.5 equivalents of Et 3 N, followed by the addition of 2.3 equivalents of neat trimethylsilyl iodide. The reaction progress was monitored by TLC. Upon completion, the reaction was quenched by the slow addition of 4 equivalents of MeOH. NaHSO was then added 4 aqueous solution (1.0 M), the mixture was stirred for 15 min, after which Et 2 O. Then H 2 The separated organic phase was washed with O and brine, and then with Et 2 The combined aqueous layers were extracted with 4% CO (2x25 mL) and then dried (Na 2 SO 4) The combined organic layers were filtered and concentrated by rotary evaporation. The residue was then chromatographed (silica gel; hexanes / EtOAc) to provide (R,E)-dodec-5-ene-1,3-diol.

[0294] Alternatively, the secondary alcohol of (R,E)-1-(benzyloxy)dodec-5-en-3-ol can be protected with TBS, followed by deprotection of the benzyl group, and finally deprotection of TBS by the alternative procedure described in Example 2.

[0295] Example 9.

[0296] The following example illustrates the chemical synthesis of (R)-dodecane-1,3-diol. This is a prophetic example.

[0297] A flask was charged with (R)-1-(benzyloxy)dodec-5-yn-3-ol (1 eq.), Pd / C (0.01 eq. based on Pd content), and degassed EtOAc to form a 0.1 M solution based on (R)-1-(benzyloxy)dodec-5-yn-3-ol. The flask was flushed three times with hydrogen, and the mixture was then heated under H 2 The mixture was stirred at 40 °C and monitored by gas chromatography and / or NMR. After completion, the suspension was filtered through a pad of silica gel and the pad was washed with diethyl ether. The organic layer was concentrated and purified by chromatography (silica gel; hexane / EtOAc) and is expected to provide (R)-dodecane-1,3-diol.

[0298] Example 10. Exemplary two-step synthesis of glycosylated (R,Z)-dodec-5-ene-1,3-diol.

[0299] The following example illustrates an exemplary two-step synthesis of glycosylated (R,Z)-dodec-5-ene-1,3-diol. This is a prophetic example.

[0300] The synthesis of glycosylated (R,Z)-dodec-5-ene-1,3-diol can also be achieved by a two-step method similar to that described in El-Sukkary et al., "Synthesis and Characterization of some Alkyl Polyglycosides Surfactants," J. Surfact Deterg, 2008, 11, 129-137. Briefly, to prepare glycosylated (R,Z)-dodec-5-ene-1,3-diol using the process disclosed in the El-Sukkary reference, glucose is first reacted with butanol in the presence of p-toluenesulfonic acid to form butyl polyglucoside. The now more organophilic butyl polyglucoside is then reacted with a long chain alcohol at elevated temperature and vacuum to remove the butanol, thereby forming the desired alkyl polyglucoside. The reported yields for this procedure are 35-45%. In a modified form of the invention, a sugar (e.g., glucose) is reacted with butanol in the presence of p-toluenesulfonic acid to form a butyl sugar, which is then reacted with (R,Z)-dodec-5-ene-1,3-diol to provide glycosylated (R,Z)-dodec-5-ene-1,3-diol. When glucose is used as the sugar, mono- and / or di-glucosylated (R,Z)-dodec-5-ene-1,3-diol can be achieved based on the choice of conditions. The product yield is measured and determined by 1 The products were characterized by H-NMR, FTIR and LC-MS.

[0301] Example 11:

[0302] The following example illustrates an exemplary one-step process for preparing (R,Z)-dodec-5-ene-1,3-diol. This is a prophetic example.

[0303] As described in the El-Sukkary reference, the direct synthesis of glycosylated long chain aliphatic hydrocarbon alcohols is limited by the immiscibility of the starting reagents (e.g., water soluble glucose and organic soluble 1-octanol). This solubility problem can be alleviated by increasing the solubility of compounds of Formula IA, IB, II, III and / or IV, and thereby allowing a one-step synthesis of compounds of Formula V and / or VI.

[0304] In an exemplary embodiment, comparing the water solubility of compounds is accomplished by comparing their corresponding log P values. As will be appreciated by those skilled in the art, log P is the logarithm of the ratio of the concentration of a compound in n-octanol to water, as illustrated in Equation 1.

[0305] log P = log([compound] 正辛醇 / ([Compound]水 ) Equation 1

[0306] Thus, compounds with higher log P are more lipophilic and less soluble in water; compounds with lower log P values ​​are less lipophilic and more soluble in water. As illustrated by the calculated log P values ​​of (R,Z)-dodec-5-ene-1,3-diol, (Z)-dodec-5-ene-1-ol, and dodecan-1-ol, (R,Z)-dodec-5-ene-1,3-diol is one order of magnitude more soluble in water than (Z)-dodec-5-ene-1-ol, and is almost two orders of magnitude more soluble in water than dodecan-1-ol.

[0307]

[0308] The synthesis of glycosylated compounds of Formula V and / or VI by a one-step reaction will be carried out at an initial glucose scale of 25 g (about 240 mL total reaction volume). The molar ratio of aliphatic diol (e.g., one or more compounds of Formula IA, IB, II and / or III) to glucose is set to 6:1 and the reaction temperature is set to about 120°C. Varying the reaction conditions to produce different glycosylated products of Formula V and / or VI will include varying the p-toluenesulfonic acid catalyst concentration and the reaction time. The product yields will be measured and analyzed by 1 The products were characterized by H-NMR, FTIR and LC-MS.

[0309] It is obvious to those skilled in the art that various modifications and changes may be made to the above aspects and embodiments without departing from the spirit and scope of the present disclosure. Such modifications and changes are therefore within the scope of the present disclosure.

Claims

1. A compound having a structure represented by formula (V): Its stereoisomers, or pharmaceutically acceptable salts thereof, wherein: n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14; R 1 and R 2 independently selected from H, a monosaccharide, a disaccharide, a trisaccharide, and a polysaccharide, wherein each of said monosaccharide, disaccharide, trisaccharide or polysaccharide is bound at the anomeric carbon; The double bond is in the (Z) or (E) configuration; There is a chiral center at C-3; and The chiral center at C-3 has the R configuration or the S configuration.

2. The compound according to claim 1, wherein: n is 3; R 1 and R 2 is H; The compound is a 14-carbon, unbranched, unsaturated aliphatic diol having a single Δ7 double bond and a hydroxyl group at carbon number 1 (C-1) and a hydroxyl group at carbon number 3 (C-3); and The compound has a structure shown in formula (III): (III) 3. The compound according to claim 2, wherein: The double bond is in the (Z) configuration and wherein the chiral center at said C-3 has the R configuration.

4. The compound according to claim 1, wherein: n is 1; R 1 and R 2 is H, and the compound is an unsaturated 1,3-fatty diol; The alcohol group of the unsaturated 1,3-fatty diol is protected with an acetyl group; and The 1,3-fatty diol having an acetylated alcohol group has a structure shown in formula (VIII): (VIII) 5. The compound according to claim 1, wherein: R 1 , R 2 , or R 1 and R 2 The two are monosaccharides, disaccharides, trisaccharides or polysaccharides; The monosaccharide is selected from pentoses or hexoses; and The disaccharide, trisaccharide or polysaccharide comprises a sugar selected from pentoses, hexoses, or a mixture of any two or more thereof.

6. The compound according to claim 5, wherein: The monosaccharide, disaccharide, trisaccharide or polysaccharide is bound at the anomeric carbon via an α-glycosidic bond or a β-glycosidic bond.

7. The compound according to claim 5, wherein: The double bond is in the (Z) configuration and wherein the chiral center at said C-3 has the R configuration.

8. The compound according to claim 5, wherein: The monosaccharide, disaccharide, trisaccharide or polysaccharide comprises allose, altrose, glucose, mannose, gulose, idose, galactose, talose, furanose, pyranose, or a mixture of any two or more thereof.

9. The compound according to claim 5, wherein: R 1 and R 2 are different monosaccharides, or R 1 and R 2 It's the same monosaccharide.

10. The compound according to claim 5, wherein: R 1 It's glucose.

11. The compound according to claim 5, wherein: R 1 It is maltose or isomaltose.

12. The compound according to claim 5, which is an alkyl polyglycoside.

13. The compound according to claim 5, which is an alkyl polyglucoside.

14. A composition comprising the compound of any one of claims 1-13, wherein the composition is a personal care product, a food, or an agricultural formulation.

15. An alkyl polyglycoside composition comprising: (i) Compound represented by formula (V) in n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14; R 1 and R 2 independently selected from H, a monosaccharide, a disaccharide, a trisaccharide, and a polysaccharide, wherein each of said monosaccharide, disaccharide, trisaccharide or polysaccharide is bound at the anomeric carbon; R 1 and R 2 One or both of them are not H; The double bond is in the (Z) or (E) configuration; There is a chiral center at C-3; and The chiral center at C-3 has the R configuration or the S configuration; and (ii) Compound represented by formula (VI) (VI) in m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18; R 3 and R 4 independently selected from H, a monosaccharide, a disaccharide, a trisaccharide, and a polysaccharide, wherein each of said monosaccharide, disaccharide, trisaccharide or polysaccharide is bound at the anomeric carbon; R 3 and R 4 One or both of them are not H; There is a chiral center at C-3; and The chiral center at C-3 has the R configuration or the S configuration.

16. The composition of claim 15, wherein the composition is a personal care product, a food, or an agricultural formulation.

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