Improved synthetic methods for the preparation of carboxylic acids, esters and lactones

Abstract

The present invention relates to a novel synthetic method for the preparation of 3,6-dimethylhexahydrobenzofuran-2-one, a derivative of mint lactone and an important organoleptic compound useful in the flavor and fragrance industry. Applicant's novel synthetic route is also applicable to other alkene compounds.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is an international application claiming priority to U.S. Provisional Application No. 63 / 293,483, filed December 23, 2021, and U.S. Provisional Application No. 63 / 343,897, filed May 19, 2022, the contents of each of which are incorporated herein by reference in their entireties.

[0002] FIELD OF THEINVENTION The present invention relates to a novel synthetic method for the preparation of 3,6-dimethylhexahydrobenzofuran-2-one, an important organoleptic compound and derivative of mint lactone useful in the flavor and fragrance industry. Applicant's novel synthetic route is also applicable to other alkene compounds. [Background technology]

[0003] background Mint lactone is a natural component of peppermint oil and is used as a precursor to the valuable flavor and fragrance ingredient 3,6-dimethylhexahydrobenzofuran-2-one (also known as Koumalactone®). [ka]

[0004] Many efforts have been made to produce mint lactone and 3,6-dimethylhexahydrobenzofuran-2-one from it in a cost-effective manner. Koch (US 6,512,126) describes the hydrogenation and elimination of hydroxymenthofurolactone (I). [ka]

[0005] Xiong (CN 102,850,309) describes the treatment of 3-methylcyclohexanone (II) with methyl pyruvate in a multi-step synthesis involving sodium borohydride and ferric chloride. [ka]

[0006] Both of these methods are practical but require relatively expensive starting materials and reagents (e.g., Pd / C, NaBH 4 ). Another major drawback of these methods is that they do not produce highly enantioenriched materials. Additional methods have been described, including the use of citronellal (Shishido, et al., Tetrahedron Letters, 33(32), 4589-4592 (1992)) and alkynyl aldehydes (Gao et al., Journal of Organic Chemistry, 74(6), 2592 (2009)), but similarly lack economic feasibility.

[0007] The naturally occurring and commercially available compound isopulegol (III) has been used as a key precursor in the synthesis of mint lactone and 3,6-dimethylhexahydrobenzofuran-2-one. [ka]

[0008] Isopulegol (III) has been used in the past as a starting material for the synthesis of enantiopure mint lactone (Chavan et al., Tetrahedron Letters, 49(29), 6429-6436 (1993)), but this method involves the use of hydroboration and deprotonation with lithium diisopropylamide under low temperature conditions and is considered to share the same drawback of being too expensive to be commercially attractive.

[0009] As a result of these limitations, mintlactone and its derivative 3,6-dimethylhexahydrobenzofuran-2-one, especially in the desired stereochemistry, are extremely expensive to obtain commercially and therefore their use is limited.

[0010] Furthermore, certain isomers of 3,6-dimethylhexahydrobenzofuran-2-one are difficult to obtain using traditional routes. Gaudin, Tetrahedron Letters 56(27), 4769-4776 (2000) and Gaudin, US Patent 5,464,824, describe routes starting from isopulegol that require double bond epoxidation, ring opening with lithium diisopropylamide to give isomeric aryl diols, followed by hydrogenation to form isomeric methane diols, which are then oxidized to form the lactone ring. Other similar routes are disclosed in Chinese Patent Application CN112010826A and US Patent 10,995,080.

[0011] US Patents 10,399,954 and 11,008,299 describe an improved method for producing mint lactone and 3,6-dimethylhexahydrobenzofuran-2-one from isopulegol in a manner that uses inexpensive and commercially available reagents and allows easy access to the desired native stereochemistry. According to this method, isopulegol (III) is treated with ozone to cleave the double bond, followed by reductive quenching with sodium bisulfite to remove the peroxide, yielding 1-(2-hydroxy-4-methyl-cyclohexyl)ethanone (IV). This hydroxyketone (IV) is then treated with aqueous sodium cyanide to produce a cyanohydrin intermediate, which is hydrolyzed in the presence of strong aqueous acid to produce alpha-hydroxylacetone (V). [ka]

[0012] Compound (V) is then treated under known conditions for alcohol elimination to produce enantiopure mint lactone (VI) (e.g., Shishido et al., Tetrahedron Letters, 33(32), 4589-4592 (1992)), followed by hydrogenation to produce enantiopure 3,6-dimethylhexahydrobenzofuran-2-one (VII). [ka]

[0013] However, it has been found that reduction of mint lactone (VI) under basic hydrogenation conditions produces a mixture of isomeric hydrogenation products (IX), (X), (XI) and (XII). [ka]

[0014] Alternatively, compound (V) can be deoxygenated via halogenation (X=Cl, Br, I) to form alpha-halolactone compound (VIII) which can then be reduced to form enantiomerically enriched 3,6-dimethylhexahydrobenzofuran-2-one (VII). For example, compound (V) can be deoxygenated via halogenation (X=Cl, Br, I) to form alpha-halolactone compound (VIII) which can then be reduced to form enantiomerically enriched 3,6-dimethylhexahydrobenzofuran-2-one (VII). 3 , POCl 3 , HCl, Cyanuric chloride, PCl 5 , S.O. 2 Cl 2 , CCl 4 , PBr 3 The intermediate halide can be halogenated using a reagent such as , HBr, HI or any other suitable halogenating agent. The halide intermediate can then be reduced by catalytic hydrogenation in the presence of a catalyst (e.g., Pd, Ru, Ni, Rh, Cu) or by electrolysis or treatment with Zn in a suitable acid such as acetic acid. Importantly, these methods lead to only two isomers of (VII), specifically the diastereomers (IX) and (X). [ka]

[0015] Compounds (IX) and (X), which retain the stereochemistry present in the mint lactone precursor, are highly popular fragrance materials and have extremely strong lactone and coumarin type odors. However, halogenation and hydrogenation are expensive to carry out on an industrial scale, requiring specialized equipment, special safety precautions due to reagent toxicity, or costs associated with environmental protection or hazardous waste cleanup. Summary of the Invention [Problem to be solved by the invention]

[0016] Thus, there remains a need for improved methods for the synthesis of 3,6-dimethylhexahydrobenzofuran-2-one, particularly isomers (IX) and (X), utilizing less hazardous, less expensive and / or less toxic reagents and obtaining the highest yields using the least expensive starting materials. [Means for solving the problem]

[0017] overview The present inventors have discovered a much improved, economically feasible and relatively safe process for the synthesis of carboxylic acids from alkenes without loss of carbon atoms, which involves epoxidation of an alkene, rearrangement of the epoxide to an aldehyde and oxidation of the aldehyde to a carboxylic acid.

[0018] The process is particularly advantageously applied to the synthesis of 3,6-dimethylhexahydrobenzofuran-2-one. The present invention provides a process for the preparation of 3,6-dimethylhexahydrobenzofuran-2-one, which comprises epoxidation of isopulegol or a derivative thereof, rearrangement to an aldehyde, oxidation to a carboxylic acid and internal ring closure to form 3,6-dimethylhexahydrobenzofuran-2-one. The present invention further provides a one-pot process for carrying out the same transformation. The present invention further provides a one-pot process for carrying out the same transformation with other alkene compounds. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Detailed Description Applicant has discovered a much improved, economically feasible, and relatively safe method for the synthesis of 3,6-dimethylhexahydrobenzofuran-2-one, which uses relatively inexpensive and safe reagents compared to prior art methods and provides good yields for high cost-effectiveness.

[0020] In a first aspect, the present invention therefore provides a method for producing a method for treating a cancer cell comprising: (A) epoxidizing isopulegol or a derivative thereof (compound 2) to form an epoxide compound (3); (B) rearrangement of an epoxide compound (3) to form an aldehyde compound (4); (C) oxidizing an aldehyde compound (4) to form a carboxylic acid compound (5); and (D) Ring-closing the carboxylic acid compound (5) to form 3,6-dimethylhexahydrobenzofuran-2-one (compound 1) A method for producing 3,6-dimethylhexahydrobenzofuran-2-one (Compound 1) is provided (Method 1), comprising the steps of: [ka] where R is H or a protecting group, such as an ether, ester or silyl ether protecting group. Importantly, the critical stereochemistry around the cyclohexane ring is preserved during this synthetic methodology.

[0021] In a further embodiment of the first aspect, the present invention provides: 1.1 Method 1, where R is H; 1.2 R is an ester protecting group, e.g., R is -C(O)-R 1 or -S(O) 2 -R 1 where R 1 H, C 1-6 Alkyl (e.g., methyl or ethyl), haloC 1-6 Alkyl (e.g., chloromethyl or trifluoromethyl), C 1-6Alkoxy (e.g., methoxy or ethoxy), C 1-6 Method 1, which is alkoxymethyl (e.g., methoxyethyl or ethoxymethyl), aryl (e.g., phenyl or tolyl), arylmethyl (e.g., benzyl), aryloxy (e.g., phenoxy) or aryloxymethyl (e.g., phenoxymethyl); 1.3 R is -C(O)-R 1 where R 1 is methyl, ethyl, propyl, isopropyl or tert-butyl or R is -S(O) 2 -R 1 where R 1 is methyl, method 1.2; 1.4 R is -C(O)-R 1 where R 1 is methyl, method 1.2; 1.5 R is -C(O)-R 1 where R 1 is chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trichloroethyl, trifluoromethyl, methoxymethyl, phenoxymethyl or benzyl or R is -S(O) 2 -R 1 where R 1 is trifluoromethyl, phenyl or tolyl; 1.6 R is an ether protecting group, e.g., R is unsubstituted C 1-6 Alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl) or substituted C 1-6 Alkyl, e.g. C 1-6 Alkoxy-C 1-6 Alkyl, aryloxy-C 1-6 Alkyl or Aryl-C 1-6 Alkyl (e.g., -CH 2 -O-Me, -CH 2 -O-Et, -CH 2 -S-Me, -CH 2 -O-CH 2 CH 2 - OMe, C.H. 2 -O-CH 2 CCl3 , C.H. 2 -O-CH 2 CH 2 -SiMe 3 , -CH 2 -O-Ph, -CH 2 -O-CH 2 -Ph, -CH 2 -O-CH 2 -(4-Methoxyphenyl), -CH 2 -O-CH 2 -(3,4-dimethoxyphenyl), -CH 2 CH 2 -OEt, -CH 2 CH 2 Si(Me) 3 , -CH 2 CCl 3 , -CH 2 -Ph, -CH 2 -(4-Methoxyphenyl), -CH 2 -(3,4-dimethoxyphenyl), -CH 2 -(2,6-dimethoxyphenyl) or 2-tetrahydropyranyl; 1.7 R is a silyl ether protecting group, e.g., R is -Si(R 2 )(R 3 )(R 4 ), where R 2 , R 3 and R 4 Each independently C 1-6 Alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl, thexyl, benzyl), C 1-6 Method 1, wherein the aryl is selected from alkoxy (e.g., methoxy, ethoxy, tert-butoxy) and aryl (e.g., phenyl); 1.8 Method 1.7, wherein R is selected from trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, di-tert-butylmethylsilyl, tris(trimethylsilyl)silyl, tert-butylmethoxyphenylsilyl, and tert-butoxydiphenylsilyl; 1.9 Compound (3) is a mixture (3a), a compound (3b) or a mixture thereof: [ka] any of methods 1 or 1.1 to 1.8; 1.10 Compound (4) is a mixture (4a), a compound (4b) or a mixture thereof: [ka] any of methods 1 or 1.1 to 1.9; 1.11 Compound (5) is a mixture (5a), a compound (5b) or a mixture thereof: [ka] any of methods 1 or 1.1 to 1.10; 1.12 Compound (1) is a mixture (1a), a compound (1b) or a mixture thereof: [ka] and; Optionally, any of methods 1 or 1.1 to 1.11, wherein compound (1) is enriched in one isomer or the other or the method further comprises a step of purification or separation of the isomers; 1.13 further comprising a step (A') of converting compound (2') (wherein R is H) to compound (2'') (wherein R is not H (e.g., R is a protecting group): [ka] Method 1 or any of 1.1 to 1.12; 1.14 Method 1.13, in which step (A') is the first step in a linear sequence of steps (A) in the method; 1.15 further comprising a step (D') of converting compound (5') (wherein R is not H (e.g., R is a protecting group)) to compound (5'') (wherein R is H): [ka] Method 1 or any of 1.1 to 1.14; 1.16 Method 1.15, wherein step (D') is the penultimate step immediately preceding step (D) in the method; 1.17 Any of Methods 1 or 1.1-1.16, wherein the protecting group R is removed during step (D) (i.e., deprotection step D' is unnecessary); 1.18 Method 1 or any of 1.1 to 1.17, wherein the method does not include any step using mint lactone (compound (VI)) as an intermediate; 1.19 The process comprises the steps of: [ka] (wherein X is Cl, Br or I). Any of methods 1 or 1.1 to 1.18, which does not include any step of using 1.20 Method 1 or any of 1.1-1.19, wherein the method does not yield measurable amounts of either compound (XI) or compound (XII), e.g., as measured by HPLC, GC, MS or NMR; 1.21 Any of methods 1 or 1.1-1.20, wherein the method does not include any synthetic and / or mechanical steps other than steps (A), (B), (C) and / or (D) and optionally (A') and / or (D') from compound (2) or compound (2') to compound (1); 1.22 Any of methods 1 or 1.1-1.21, wherein the epoxidation step (A) is carried out by treatment of compound (2) with a suitable oxidizing agent in a suitable solvent; 1.23 Method 1.22, wherein the suitable oxidizing agent is one or more of hydrogen peroxide, osmium tetroxide, peracetic acid, perchloric acid, perbenzoic acid, meta-chloroperoxybenzoic acid (mCPBA), trifluoroperacetic acid, magnesium monoperoxyphthalate, dimethyldioxirane (DMDO), tert-butyl hydroperoxide, sodium hypochlorite, sodium tungstate, sodium periodate, iodosylbenzene, pentafluoroiodosylbenzene, cumene hydroperoxide, potassium persulfate, potassium peroxymonosulfate, pyridine N-oxide, 2,6-dichloropyridine N-oxide or oxygen (e.g., in combination with a transition metal catalyst, e.g., an iron catalyst), optionally in combination with any secondary reagent (e.g., a secondary oxidizing agent, catalyst, complexing agent, directing agent, reducing agent or chiral auxiliary); 1.24 Process 1.22, in which in the epoxidation step (A), the suitable oxidizing agent is hydrogen peroxide, peracetic acid, meta-chloroperoxybenzoic acid, tert-butyl hydroperoxide, or potassium peroxymonosulfate; 1.25 Method 1.22, in which in the epoxidation step (A), the suitable oxidizing agent is hydrogen peroxide and sodium tungstate, for example hydrogen peroxide (e.g. 30 wt.%, e.g. 1-1.5 equivalents) + sodium tungstate (e.g. sodium tungstate dihydrate, e.g. 0.01-0.10 equivalents) with methyl-tri-n-octylammonium hydrogen sulfate (e.g. 0.01-0.05 equivalents) and phenylphosphonic acid (e.g. 0.01-0.05 equivalents), optionally in an aqueous solvent, optionally at 0-50°C; 1.26 Method 1.22, in which in the epoxidation step (A) the suitable oxidizing agent is m-chloroperoxybenzoic acid; 1.27 Process 1.22, in which in the epoxidation step (A) the suitable oxidizing agent is oxygen gas; 1.28 Method 1.27, in which in the epoxidation step (A), the suitable oxidizing agent is oxygen gas and a transition metal catalyst; 1.29 In the epoxidation step (A), a suitable oxidizing agent is C 2-10 Method 1.27, oxygen gas and iron(III)-tetraphenylporphyrin complex (Fe(III)TPP) in the presence of an aliphatic aldehyde (e.g., isobutyraldehyde); 1.30 Method 1.27, in which in the epoxidation step (A), the suitable oxidizing agent is oxygen gas and N-hydroxyphthalimide; 1.31 Any of methods 1.22 to 1.30, wherein the epoxidation step (A) does not involve the use of ozone; 1.32 In the epoxidation step (A), suitable solvents include hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane), chlorinated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethylene), aromatics (e.g., benzene, toluene, xylene, pyridine), ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether), esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate, any of methods 1.22-1.31, wherein the solvent is selected from the group consisting of butyl acetate, ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone), polar aprotic solvents (e.g., acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide), polar protic solvents (e.g., water, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, glycerol, formic acid, acetic acid, sulfuric acid), acetic anhydride, carbon dioxide (e.g., supercritical carbon dioxide), and carbon disulfide, or a combination thereof; 1.33 Any of methods 1.22 to 1.32, wherein the epoxidation step (A) is carried out using 1.0 to 5.0 equivalents of oxidizing agent, for example, 1.0 to 4.0 equivalents or 1.0 to 3.0 equivalents or 1.0 to 2.0 equivalents or 1.0 to 1.50 equivalents or 1.0 to 1.25 equivalents or 1.0 to 1.15 equivalents or 1.0 to 1.05 equivalents or 1.5 to 2.0 equivalents or 2.0 to 3.0 equivalents; and optionally 0.01 to 1.0 equivalent of any one or more further reagents (for example a secondary oxidizing agent or catalyst or ligand or other agent), for example, 0.01 to 0.5 equivalents, 0.01 to 0.2 equivalents or 0.01 to 0.1 or 0.01 to 0.05 equivalents; 1.34 any of Methods 1.22 to 1.33, wherein the epoxidation step (A) is carried out at a temperature of -100°C to 200°C, for example, -50°C to 150°C or -100°C to 0°C or -100°C to -50°C or -50°C to 0°C or -25°C to 0°C or -25°C to 25°C or 0°C to 200°C or 0°C to 150°C or 0°C to 100°C or 0°C to 50°C or 0°C to 25°C or 25°C to 150°C or 25°C to 100°C or 50°C to 200°C or 50°C to 100°C or 75°C to 200°C or 100°C to 200°C or 150°C to 200°C; 1.35 Any of Methods 1.22-1.34, wherein the epoxidation step (A) is carried out in a batch reactor; 1.36 Any of methods 1.22-1.34, wherein the epoxidation step (A) is carried out in a continuous flow reactor; 1.37 The rearrangement step (B) is carried out by treating compound (3) with a suitable rearrangement catalyst in a suitable solvent or by heating compound (3) in a suitable solvent without a catalyst (i.e., thermal rearrangement), in any of Methods 1 or 1.1-1.36; 1.38. Method 1.37, wherein the rearrangement catalyst is a Lewis acid, a Bronsted acid, a strong base (e.g., LDA, LiTMP, LiHMDS, t-butyllithium) or a transition metal catalyst or complex (e.g., a palladium, ruthenium, rhodium, chromium, iridium, zirconium, manganese, iron or nickel catalyst or complex); 1.39 Process 1.37, wherein the rearrangement catalyst is a solid phase acidic resin (e.g., Amberlyst or Nafion-H or an acidic polymeric resin such as montmorillonite or zeolite), e.g., Montmorillonite K10 or Amberlyst H-15, optionally the catalyst is Montmorillonite K-10, e.g., in a toluene solvent, e.g., at 0-50°C (e.g., about 25°C); 1.40 Process 1.37, wherein the rearrangement catalyst is a Lewis acid selected from, for example, zinc bromide, zinc chloride, magnesium bromide, magnesium bromide-diethyl ether complex, bismuth triflate, boron trifluoride-diethyl ether complex, aluminum triisopropoxide, titanium tetraisopropoxide, titanium tetrachloride, iron trichloride, indium chloride, lithium perchlorate, iridium chloride, iridium bromide, borane-THF complex, chromium tetraphenylporphyrin triflate, dibromobis(triphenylphosphine)nickel complex, methylbis(4-bromo-1,6-di-tert-butylphenoxy)aluminum; 1.41 The process 1.37, wherein the rearrangement catalyst is a Bronsted acid selected from, for example, hydrochloric acid, perchloric acid, sulfuric acid, phosphoric acid, acetic acid, peracetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, trifluoroacetic acid, and nitric acid, or a heteropolyacid (e.g., phosphotungstic acid); 1.42 In the rearrangement step (B), suitable solvents include hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane), chlorinated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethylene), aromatics (e.g., benzene, toluene, xylene, pyridine), ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether), esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate, acetic acid, any of methods 1.37-1.41, wherein the solvent is selected from butyl ketone, ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone), polar aprotic solvents (e.g., acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide), polar protic solvents (e.g., water, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, glycerol, formic acid, acetic acid, sulfuric acid), acetic anhydride, carbon dioxide (e.g., supercritical carbon dioxide), and carbon disulfide, or a combination thereof; 1.43 Any of Methods 1.37 to 1.42, wherein the rearrangement step (B) is carried out using 1.0 to 5.0 equivalents of the rearrangement catalyst, for example, 1.0 to 4.0 equivalents, or 1.0 to 3.0 equivalents, or 1.0 to 2.0 equivalents, or 1.0 to 1.50 equivalents, or 1.0 to 1.25 equivalents, or 1.0 to 1.15 equivalents, or 1.0 to 1.05 equivalents, or 1.5 to 2.0 equivalents, or 2.0 to 3.0 equivalents; or using 0.01 to 1.0 equivalent of the rearrangement catalyst, for example, 0.01 to 0.1 equivalents, 0.1 to 0.5 equivalents, or 0.5 to 1.0 equivalents; 1.44 any of Methods 1.37 to 1.43, wherein the rearrangement step (B) is carried out at a temperature of -100°C to 200°C, for example, -50°C to 150°C or -100°C to 0°C or -100°C to -50°C or -50°C to 0°C or -25°C to 0°C or -25°C to 25°C or 0°C to 200°C or 0°C to 150°C or 0°C to 100°C or 0°C to 50°C or 0°C to 25°C or 25°C to 150°C or 25°C to 100°C or 50°C to 200°C or 50°C to 100°C or 75°C to 200°C or 100°C to 200°C or 150°C to 200°C; 1.45 Any of methods 1.37-1.44, wherein the rearrangement step (B) is carried out in a batch reactor; 1.46 Any of methods 1.37 to 1.45, wherein the rearrangement step (B) is carried out in a continuous flow reactor; 1.47 Any of Methods 1 or 1.1-1.46, wherein the rearrangement step (B) is carried out in the same vessel as the oxidation step (C), e.g., the product of step (B) is not purified or isolated prior to carrying out step (C), or the reagents or reagents and solvent of step (C) are added directly to the reaction mixture of step (B); 1.48 Any of methods 1 or 1.1-1.47, wherein the oxidation step (C) is carried out by treating compound (4) with a suitable oxidizing agent in a suitable solvent; 1.49 Method 1.48, in which in the oxidation step (C), the suitable oxidizing agent is one or more of a chromium oxidizing agent (e.g., chromium trioxide, chromic acid, pyridinium chlorochromate, potassium dichromate, chromium trioxide-pyridine complex, pyridinium dichromate), osmium tetroxide, potassium permanganate, silver oxide, hydrogen peroxide, peracetic acid, perchloric acid, trifluoroperacetic acid, periodic acid, potassium periodate, sodium chlorite, oxygen, and N-hydroxyphthalimide, potassium persulfate, and potassium peroxymonosulfate; 1.50 Method 1.48, in which in the oxidation step (C), the suitable oxidizing agent is a chromium oxidizing agent (e.g., chromium trioxide, chromic acid, pyridinium chlorochromate, potassium dichromate, chromium trioxide-pyridine complex, pyridinium dichromate), optionally the chromium oxidizing agent is, for example, chromium trioxide (i.e., Jones reagent) in an acetone solvent, for example, in aqueous sulfuric acid at 0-50°C (e.g., about 25°C) (e.g., about 1-1.5 equivalents Jones reagent); 1.51 Any of methods 1.48 to 1.50, wherein the oxidation step (C) does not involve the use of ozone; 1.52 In the oxidation step (C), suitable solvents include hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane), chlorinated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethylene), aromatics (e.g., benzene, toluene, xylene, pyridine), ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether), esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate, acetic acid, any of methods 1.48-1.51, wherein the solvent is selected from butyl ketone, ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone), polar aprotic solvents (e.g., acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide), polar protic solvents (e.g., water, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, glycerol, formic acid, acetic acid, sulfuric acid), acetic anhydride, carbon dioxide (e.g., supercritical carbon dioxide), and carbon disulfide, or a combination thereof; 1.53 Any of Methods 1.48 to 1.52, wherein the oxidation step (C) is carried out using 1.0 to 5.0 equivalents of oxidizing agent, 1.0 to 5.0 equivalents of rearrangement catalyst, for example 1.0 to 4.0 equivalents or 1.0 to 3.0 equivalents or 1.0 to 2.0 equivalents or 1.0 to 1.50 equivalents or 1.0 to 1.25 equivalents or 1.0 to 1.15 equivalents or 1.0 to 1.05 equivalents or 1.5 to 2.0 equivalents or 2.0 to 3.0 equivalents; 1.54 any of methods 1.48 to 1.53, wherein the oxidation step (C) is carried out at a temperature of -100°C to 200°C, for example, -50°C to 150°C or -100°C to 0°C or -100°C to -50°C or -50°C to 0°C or -25°C to 0°C or -25°C to 25°C or 0°C to 200°C or 0°C to 150°C or 0°C to 100°C or 0°C to 50°C or 0°C to 25°C or 25°C to 150°C or 25°C to 100°C or 50°C to 200°C or 50°C to 100°C or 75°C to 200°C or 100°C to 200°C or 150°C to 200°C; 1.55 Any of methods 1.48 to 1.54, wherein the oxidation step (C) is carried out in a batch reactor; 1.56 Any of methods 1.48 to 1.54, wherein the oxidation step (C) is carried out in a continuous flow reactor; 1.57 Any of methods 1 or 1.1-1.56, wherein the ring closure step (D) and / or deprotection of the -OR group of compound (5) occurs spontaneously during and / or after the oxidation step (C); 1.58 Any of Methods 1 or 1.1-1.56, wherein the ring closure step (D) and / or deprotection of the -OR group of compound (5) is carried out by heating the product mixture from step (C); 1.59 Any of methods 1 or 1.1-1.56, wherein the ring closure step (D) and / or deprotection of the -OR group of compound (5) is carried out by distillation of the product mixture from step (C); 1.60 Any of Method 1 or 1.1-1.56, wherein the method includes a deprotection step (D') immediately prior to the ring closure step (D) and immediately following the oxidation step (C); 1.61 The deprotection step (D') is carried out by treating compound (5) with aqueous base, aqueous acid, anhydrous base, anhydrous acid or anhydrous fluoride or biphasic acid, biphasic base or biphasic fluoride or other suitable conditions (e.g., sodium azide, mercuric chloride, magnesium bromide, magnesium iodide, DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone, ammonium cerium nitrate, hydrogen over palladium or platinum catalyst) in a suitable solvent, Method 1.60; 1.62 Method 1.61, wherein the base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, ammonium hydroxide, tetrabutyl ammonium hydroxide, ammonia, guanidine, ethylenediamine, ethanolamine, pyridine, lutidine, collidine, triethylamine, diisopropylethylamine, piperidine, morpholine, methylamine, hydrazine, and imidazole; 1.63 Suitable solvents include hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane), chlorinated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethylene), aromatics (e.g., benzene, toluene, xylene, pyridine), ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether), esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate), ketones (e.g., Method 1.62, wherein the solvent is selected from a polar aprotic solvent (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone), a polar aprotic solvent (e.g., acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide), a polar protic solvent (e.g., water, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, glycerol, formic acid, acetic acid, sulfuric acid), acetic anhydride, carbon dioxide (e.g., supercritical carbon dioxide) and carbon disulfide or a combination thereof (including aqueous or anhydrous or biphasic combinations thereof); 1.64 Method 1.61, wherein the acid is selected from hydrochloric acid (e.g., hydrogen chloride), nitric acid, sulfuric acid, phosphoric acid, acetic acid, peracetic acid, formic acid, citric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, perchloric acid, hydrogen fluoride, hydrogen bromide, boron trifluoride-etherate, toluenesulfonic acid, scandium triflate, ytterbium triflate, pyridinium para-toluenesulfonate (PPTS), zinc bromide, zinc chloride, titanium chloride, tin(IV) chloride, bromodimethylborane, boron trichloride, pyridine-HF complex, and solid acidic resins (e.g., Amberlyst H-15; acidic polymers such as silica gel, alumina, montmorillonite K-10, etc.); 1.65 Suitable solvents include hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane), chlorinated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethylene), aromatics (e.g., benzene, toluene, xylene, pyridine), ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether), esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate), ketones (e.g., Method 1.64, wherein the solvent is selected from a polar aprotic solvent (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone), a polar aprotic solvent (e.g., acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide), a polar protic solvent (e.g., water, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, glycerol, formic acid, acetic acid, sulfuric acid), acetic anhydride, carbon dioxide (e.g., supercritical carbon dioxide) and carbon disulfide or combinations thereof (including aqueous or anhydrous or biphasic combinations thereof); 1.66 Method 1.61, wherein the fluoride is selected from hydrogen fluoride (e.g., anhydrous HF, aqueous HF, triethylamine HF complex, pyridine HF complex), TASF (tris(dimethylamino)sulfonium difluorotrimethylsilicate), sodium fluoride, potassium fluoride, cesium fluoride, ammonium fluoride, and tetrabutylammonium fluoride; 1.67 Suitable solvents include hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane), chlorinated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethylene), aromatics (e.g., benzene, toluene, xylene, pyridine), ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether), esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate), ketones (e.g., ethyl acetate, ethyl acetate, butyl acetate), tetrachloroethane, tetrachloroethylene, tetrachloroethane, dichloromethane, tetrachloroethylene, tetrachloroethylene, dichloromethane ... for example, acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone), polar aprotic solvents (e.g., acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoric triamide), polar protic solvents (e.g., water, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, glycerol, formic acid, acetic acid), carbon dioxide (e.g., supercritical carbon dioxide) and carbon disulfide or combinations thereof (including aqueous or anhydrous or biphasic combinations thereof), method 1.66; 1.68 Any of methods 1.60 to 1.67, wherein the deprotection step (D') is carried out using 1.0 to 5.0 equivalents of an acid, base, fluoride or other agent, for example, 1.0 to 4.0 equivalents, or 1.0 to 3.0 equivalents, or 1.0 to 2.0 equivalents, or 1.0 to 1.50 equivalents, or 1.0 to 1.25 equivalents, or 1.0 to 1.15 equivalents, or 1.0 to 1.05 equivalents, or 1.5 to 2.0 equivalents, or 2.0 to 3.0 equivalents; 1.69 Any of Methods 1.60 to 1.68, wherein the deprotection step (D') is carried out at a temperature of -100°C to 200°C, for example, -50°C to 150°C or -100°C to 0°C or -100°C to -50°C or -50°C to 0°C or -25°C to 0°C or -25°C to 25°C or 0°C to 200°C or 0°C to 150°C or 0°C to 100°C or 0°C to 50°C or 0°C to 25°C or 25°C to 150°C or 25°C to 100°C or 50°C to 200°C or 50°C to 100°C or 75°C to 200°C or 100°C to 200°C or 150°C to 200°C; 1.70 Any of methods 1.60-1.69, wherein the deprotection step (D') is carried out in a batch reactor; 1.71 Any of methods 1.60 to 1.70, wherein the deprotection step (D') is carried out in a continuous flow reactor; 1.72 Any of Method 1 or 1.1-1.71, further comprising a protection step (A'); 1.73 The method of method 1.72, wherein the protection step (A') is carried out by treating compound (2) with a suitable protecting agent in a suitable solvent, optionally together with a suitable base; 1.74 The protecting agent is an acyl halide (e.g., acetyl chloride, benzoyl chloride, chloroacetyl chloride, dichloroacetyl chloride, trichloroacetyl chloride, methoxyacetyl chloride, phenoxyacetyl chloride, pivaloyl chloride, benzoyl chloride), an acyl anhydride (e.g., acetic anhydride, chloroacetic anhydride, dichloroacetic anhydride, trichloroacetic anhydride, trifluoroacetic anhydride, methoxyacetyl anhydride, phenoxyacetyl anhydride, pivaloyl anhydride, benzoyl anhydride), an alkyl halide (e.g., methoxymethyl chloride, methoxymethyl bromide, methoxyethyl chloride, methylthiomethyl iodide, benzyloxymethyl chloride, 4-methoxybenzyloxymethyl chloride, 2-methoxyethoxymethyl chloride, 2,2,2-trichloroethoxymethyl chloride, 2-trimethylsilylethoxymethyl chloride, 4-methoxybenzyl chloride, 4-methoxybenzyl bromide, 3,4-dimethoxybenzyl bromide), a silyl Method 1.73, selected from reagents (e.g. chlorides, silanes or triflates of the group trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, di-tert-butylmethylsilyl, tris(trimethylsilyl)silyl, tert-butylmethoxyphenylsilyl and tert-butoxydiphenylsilyl) or other protecting agents (e.g. formic acid, acetic acid, ethyl formate, methyl formate, chloroacetic acid, dihydropyran, 2-hydroxytetrahydropyran, ethyl vinyl ether, trimethylsilylethoxyethene, isobutylene, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, N,N-bis(trifluoromethanesulfonyl)aniline, benzenesulfonyl chloride, toluenesulfonyl chloride); 1.75 The process of 1.73 or 1.74, wherein the suitable base is selected from sodium hydride, potassium hydride, hydroxide bases (e.g., sodium hydroxide, potassium hydroxide), alkoxide bases (e.g., sodium tert-butoxide, potassium tert-butoxide), carbonate bases (e.g., sodium carbonate, potassium carbonate, cesium carbonate), bicarbonate bases (e.g., sodium bicarbonate) and amine bases (e.g., triethylamine, diisopropylethylamine, N-methylmorpholine, DBU, DBN, pyridine, dimethylaminopyridine, imidazole); 1.76 Suitable solvents include hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane), chlorinated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethylene), aromatics (e.g., benzene, toluene, xylene, pyridine), ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether), esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate), ketones (e.g., acetonitrile ... any of methods 1.73-1.75, wherein the solvent is selected from the group consisting of polar aprotic solvents (e.g., acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide), polar protic solvents (e.g., water, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, glycerol, formic acid, acetic acid), carbon dioxide (e.g., supercritical carbon dioxide) and carbon disulfide or a combination thereof, or the solvent is a neat reagent (e.g., pyridine); 1.77 Any of methods 1.73 to 1.76, wherein the protection step (A') is carried out using 1.0 to 5.0 equivalents of the protecting agent, for example, 1.0 to 4.0 equivalents, or 1.0 to 3.0 equivalents, or 1.0 to 2.0 equivalents, or 1.0 to 1.50 equivalents, or 1.0 to 1.25 equivalents, or 1.0 to 1.15 equivalents, or 1.0 to 1.05 equivalents, or 1.5 to 2.0 equivalents, or 2.0 to 3.0 equivalents; 1.78 any of methods 1.73 to 1.77, wherein the protection step (A') is carried out at a temperature of -100°C to 200°C, for example, -50°C to 150°C or -100°C to 0°C or -100°C to -50°C or -50°C to 0°C or -25°C to 0°C or -25°C to 25°C or 0°C to 200°C or 0°C to 150°C or 0°C to 100°C or 0°C to 50°C or 0°C to 25°C or 25°C to 150°C or 25°C to 100°C or 50°C to 200°C or 50°C to 100°C or 75°C to 200°C or 100°C to 200°C or 150°C to 200°C; 1.79 Any of methods 1.73 to 1.78, wherein the protection step (A') is carried out in a batch reactor; 1.80 Any of methods 1.73 to 1.79, wherein the protection step (A') is carried out in a continuous flow reactor; 1.81 Any of Methods 1.1-1.80, wherein intermediates (3), (4), and (5) of steps (A), (B), (C), and (D) are not isolated, e.g., reactant compound (2) is carried forward to product compound (1) in one vessel; 1.82 Method 1.81, in which the reaction comprises treating compound (2) with an oxidizing agent as described above (e.g., an oxidizing agent suitable for step (A) or step (C)) and an acid as described above (e.g., an acid suitable for step (B)) in a suitable solvent; 1.83 Oxidizing agents include hydrogen peroxide, chromium oxidizing agents (e.g., chromium trioxide, chromic acid, pyridinium chlorochromate, potassium dichromate, chromium trioxide-pyridine complex, pyridinium dichromate), osmium tetroxide, potassium permanganate, peracetic acid, perchloric acid, perbenzoic acid, meta-chloroperoxybenzoic acid (mCPBA), trifluoroperacetic acid, periodic acid, magnesium monoperoxyphthalate, dimethyldioxirane (DMDO), optionally in combination with any secondary reagent (e.g., secondary oxidizing agent, catalyst, complexing agent, directing agent, reducing agent or chiral auxiliary). ), tert-butyl hydroperoxide, sodium hypochlorite, sodium tungstate, sodium periodate, potassium periodate, iodosylbenzene, pentafluoroiodosylbenzene, cumene hydroperoxide, potassium persulfate, potassium peroxymonosulfate, pyridine N-oxide, 2,6-dichloropyridine N-oxide, sodium chlorite, sodium hypochlorite, sodium chlorate, sodium perchlorate, or oxygen (e.g., in combination with a transition metal catalyst, e.g., an iron catalyst); 1.84 Method 1.83, in which the oxidizing agent is hydrogen peroxide, peracetic acid, trifluoroperacetic acid, meta-chloroperoxybenzoic acid, tert-butyl hydroperoxide, or potassium peroxymonosulfate; 1.85 Any of methods 1.82-1.84, wherein the reaction is carried out using 1.0 to 5.0 equivalents of oxidizing agent, e.g., 1.0 to 4.0 equivalents or 1.0 to 3.0 equivalents or 1.0 to 2.0 equivalents or 1.5 to 4.0 equivalents or 1.5 to 3.0 equivalents or 1.5 to 2.5 equivalents or 1.5 to 2.0 equivalents or 2.0 to 4.0 equivalents or 2.0 to 3.0 equivalents; and optionally 0.01 to 1.0 equivalent of any one or more further reagents (e.g., secondary oxidizing agents or catalysts or ligands or other agents), e.g., 0.01 to 0.5 equivalents, 0.01 to 0.2 equivalents or 0.01 to 0.1 or 0.01 to 0.05 equivalents; 1.86 Any of methods 1.82 to 1.84, wherein the acid is a Bronsted acid selected from, for example, hydrochloric acid, perchloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, trifluoroacetic acid, and nitric acid, or a heteropolyacid (e.g., phosphotungstic acid); 1.87 Method 1.86, in which the acid is selected from sulfuric acid, phosphoric acid, and nitric acid; 1.88 Any of methods 1.82-1.87, wherein the reaction is carried out using 1.0 to 5.0 equivalents of acid, e.g., 1.0 to 4.0 equivalents or 1.0 to 3.0 equivalents or 1.0 to 2.0 equivalents or 1.5 to 4.0 equivalents or 1.5 to 3.0 equivalents or 1.5 to 2.5 equivalents or 1.5 to 2.0 equivalents or 2.0 to 4.0 equivalents or 2.0 to 3.0 equivalents; 1.89 Reactions are carried out with hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane), chlorinated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethylene), aromatics (e.g., benzene, toluene, xylene, pyridine), ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether), esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate), ketones (e.g., any of Methods 1.82-1.88, wherein the reaction is carried out in a solvent selected from polar aprotic solvents (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone), polar aprotic solvents (e.g., acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide), polar protic solvents (e.g., water, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, glycerol, formic acid, acetic acid, sulfuric acid), acetic anhydride, carbon dioxide (e.g., supercritical carbon dioxide) and carbon disulfide, or a combination thereof; 1.90 Method 1.89, wherein the solvent is acetic acid and / or acetic anhydride, and optionally the reaction further comprises an acetate salt (e.g., sodium or potassium acetate); 1.91 Any of methods 1.81-1.90, wherein the reaction is carried out using a combination of hydrogen peroxide, sulfuric acid, and acetic acid, optionally in an amount of 1.5 to 4 equivalents each (e.g., 2 to 3 equivalents each); 1.92 Any of methods 1.81-1.90, wherein the reaction is carried out using a combination of acetic acid, peracetic acid, and sulfuric acid, optionally in an amount of 1-3 equivalents each (e.g., 1-1.5 equivalents each); 1.93 Any of methods 1.81-1.90, wherein the reaction is carried out using a combination of hydrogen peroxide, acetic acid, peracetic acid and sulfuric acid, optionally with sodium acetate (e.g., 0.05-0.24 equivalents), each at 0.8-5 equivalents (e.g., 1-3 equivalents each); 1.94 Any of methods 1.81-1.90, wherein the reaction is carried out using a combination of hydrogen peroxide, acetic anhydride, acetic acid and sulfuric acid, optionally in an amount of 0.8-5 equivalents each (e.g., 1-3 equivalents each), optionally further comprising a heptane co-solvent; 1.95 Any of Methods 1.81-1.90, wherein the reaction is carried out using a combination of potassium peroxymonosulfate, potassium hydrogen sulfate and potassium sulfate (e.g., Oxone®) in an organic solvent (e.g., acetone / ethyl acetate), optionally using 1-3 equivalents of potassium peroxymonosulfate (e.g., 1-2 equivalents); 1.96 any of methods 1.81-1.95, wherein the reaction is carried out at a temperature between 0°C and 200°C, e.g., between 0°C and 150°C, or between 0°C and 100°C, or between 25°C and 200°C, or between 25°C and 150°C, or between 25°C and 100°C, or between 50°C and 200°C, or between 50°C and 150°C, or between 50°C and 100°C, or between 75°C and 200°C, or between 75°C and 150°C, or between 75°C and 100°C, or between 80°C and 150°C, or between 80°C and 100°C, or between 90°C and 150°C, or between 90°C and 125°C, or between 90°C and 110°C, or between 90°C and 100°C, or between 90°C and 95°C; 1.97 Any of methods 1.81 to 1.96, wherein the reaction is carried out at a temperature of 80°C to 90°C, 20°C to 70°C, 40°C to 90°C, 20°C to 50°C, or 20°C to 30°C; 1.98 Any of methods 1.81-1.97, wherein reaction steps (A), (B), (C) and / or (D) are carried out in a single reaction step in a single vessel, e.g., step (B) spontaneously follows step (A), step (C) spontaneously follows step (B), and step (D) spontaneously follows step (C); 1.99 Any of methods 1.81-1.97, wherein reaction steps (A), (B), (C) and / or (D) are carried out in two reaction steps in one vessel without isolating any intermediates, e.g., at least a second oxidizing agent is added in a second reaction step to initiate step (C), step (B) spontaneously follows step A, and step (D) spontaneously follows step C; 1.100 Any of methods 1.81-1.99, wherein R is H, reactant compound (2) proceeds to product compound (1) in a single vessel, and the reaction is carried out by treating compound (2) with a combination of hydrogen peroxide, sulfuric acid, and acetic acid, optionally in an amount of 1.5-4 equivalents each (e.g., 2-3 equivalents each or 2 equivalents each), optionally at a temperature of 75°C-150°C, or 80°C-100°C, or 90°C-95°C; 1.101 Any of methods 1 or 1.1-1.100, wherein the method further comprises a step (E) of treating compound (1) with a base, resulting in enrichment of compound (1a) by isomerization of compound (1b) to compound (1a); 1.102 Method 1.101, wherein the base is selected from sodium hydride, potassium hydride, hydroxide bases (e.g., sodium hydroxide, potassium hydroxide), alkoxide bases (e.g., sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide), carbonate bases (e.g., sodium carbonate, potassium carbonate, cesium carbonate), bicarbonate bases (e.g., sodium bicarbonate), amide bases (e.g., lithium amide, lithium 2,2,6,6-tetramethylpiperidide (LiTMP), lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide) (LiHMDS)), alkyl lithium bases (e.g., sec-butyl lithium, tert-butyl lithium) and amine bases (e.g., triethylamine, diisopropylethylamine, N-methylmorpholine, DBU, DBN, pyridine, dimethylaminopyridine, imidazole); 1.103 Method 1.102, wherein the base is an alkoxide base (e.g., sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide) or an amide base (e.g., lithium amide, lithium 2,2,6,6-tetramethylpiperidide (LiTMP), lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide) (LiHMDS)); 1.104 Method 1.102, wherein the base is sodium tert-butoxide or potassium tert-butoxide; 1.105 Any of methods 1.101-1.104, wherein step (E) is carried out in a solvent selected from hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane), chlorinated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethylene), aromatics (e.g., benzene, toluene, xylene, pyridine) and ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether); 1.106 Method 1.105, in which step (E) is carried out in a hydrocarbon solvent, e.g., pentane, hexane, heptane, or cyclohexane; 1.107 Any of Methods 1.101 to 1.106, wherein step (E) is carried out at a temperature of -78°C to 200°C, for example, -50°C to 150°C, or -25°C to 100°C, or 0°C to 75°C, or 15°C to 50°C, or 20°C to 30°C, -78°C to 0°C, or -50°C to 0°C, or -25°C to 25°C, or 25°C to 75°C, or 50°C to 100°C, or 75°C to 150°C, or 100°C to 150°C, or 125°C to 200°C, or 150°C to 200°C; 1.108 Any of methods 1.101-1.107, wherein step (E) provides an enrichment of the amount of isomer (1a) of at least 10% by weight of the total weight of compound (1), such as at least 15% or at least 20% or at least 25%; 1.109 Any of methods 1.101-1.108, wherein step (E) provides a product having a ratio of isomer (1a):isomer (1b) of at least 90:10, e.g., at least 92:8, or at least 93:7, or at least 94:6, or at least 95:5; 1.110 Any of Methods 1 or 1.1-1.109, wherein the method further comprises crystallizing the product Compound (1) from a hydrocarbon solvent (e.g., pentane, hexane, heptane, cyclohexane or mixtures thereof) at a temperature below 0° C., e.g., below 25° C., or below 15° C., or below 10° C., or below 5° C., or below 0° C., or below −5° C., or below −10° C., or below −20° C., or below −30° C., or below −40° C., or below −50° C., e.g., as low as −78° C.; 1.111 Method 1.110, wherein the recrystallization step provides a product having a ratio of isomer (1a):isomer (1b) of at least 95:5, e.g., at least 97:3, or at least 98:2, or at least 99:1, or at least 99.5:0.5; 1.112 Any of processes 1.101 to 1.111, wherein the process includes an isomerization step (E) of the product (1), followed by recrystallization; 1.113 Method 1.112, in which the isomerization step (E) and the recrystallization step are carried out as successive steps, such as isomerization followed by recrystallization after each recrystallization, until the desired purity of isomer (1a) is obtained; 1.114 Method 1.113, wherein the successive isomerization and recrystallization steps provide a product having a ratio of isomer (1a):isomer (1b) of at least 95:5, e.g., at least 97:3, or at least 98:2, or at least 99:1, or at least 99.5:0.5; 1.115 Any of Methods 1 or 1.1-1.114, wherein the method does not include the use of any reagents or reactants other than compound (2) and the reagents set forth herein (e.g., acids, bases, oxidants, catalysts, protecting agents, deprotecting agents, solvents), e.g., the method does not include the use of any carbon monoxide, carbonyl equivalents, or enzymes.

[0022] In a further embodiment of method 1, the present invention relates to a compound in which step (B) produces as by-products compounds of formulae XIII, XIV and XV: [ka] In certain embodiments, the present invention provides any of Methods 1 or 1.1-1.115, wherein step (B) provides as a by-product one or more of compounds of formula XIIIa, XIIIb, XIVa, XIVb, and XVa: [ka] The method of any of methods 1 or 1.1 to 1.115 provides one or more of the compounds of formula (I).

[0023] Without being bound by theory, it is believed that the double bond of the compound of formula XIII, XIV, XV, XIIIa, XIIIb, XIVa, XIVb and / or XVa may be formed during step (A) and / or step (B) following method 1, such as by acid catalyzed, base catalyzed or thermal removal of one or more hydroxy groups (-OH) or protected hydroxy groups (-OR) of the compound of formula (2), (3), (3a), (3b), (4), (4a) or (4b). This can be achieved, for example, by the group R being -S(O). 2 -R1 where R 1 is particularly possible when is methyl, trifluoromethyl, phenyl or tolyl. Thus, for example, during steps (A) and (B), the following reaction may occur: [ka] As described above, under the conditions of step (A), the initially formed compound (3) may undergo elimination or formation of an unsaturated epoxide compound (Step A' above), followed by conversion of the unsaturated epoxide compound to an unsaturated aldehyde (Step B'' above) under the conditions of step (B). Alternatively, both of these conversions may occur under the conditions of step B (Step B' followed by Step B'' above). Alternatively, under the conditions of step (B), compound (4) may undergo elimination or formation of an unsaturated epoxide compound (Step B'''' above).

[0024] Optionally, the compounds of formula XIII, XIV, XV, XIIIa, XIIIb, XIVa, XIVb and / or XVa may be isolated (eg by extraction, distillation or chromatographic separation) from the product mixture of step (B).

[0025] In a second aspect, the present invention provides a method for producing a composition comprising: (A) optionally epoxidizing 5-substituted-2-vinylcyclohexanol or a derivative thereof (compound 7) to form an epoxide compound (8); (B) rearrangement of epoxide compound (8) to form aldehyde compound (9); (C) oxidizing an aldehyde compound (9) to form a carboxylic acid compound (10); and (D) Ring-closing the carboxylic acid compound (10) to form compound (6) A method for preparing an optionally 3,6-disubstituted hexahydrobenzofuran-2-one (compound 6) (Method 2), comprising the steps: [ka] where R is H or a protecting group (e.g., an ether, ester, or silyl ether protecting group), and R a is H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted aryl, OR c and -C(O)-R c and R b is H, optionally substituted C 1-6 alkyl, optionally substituted aryl, OR c and -C(O)-R c and R c is H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 It is selected from alkynyl and optionally substituted aryl.

[0026] In a further embodiment of the first aspect, the present invention provides: 2.1 Method 2, where R is H; 2.2 R is an ester protecting group, e.g., -C(O)-R 1 or -S(O) 2 -R 1 where R 1 H, C 1-6 Alkyl (e.g., methyl or ethyl), haloC 1-6 Alkyl (e.g., chloromethyl or trifluoromethyl), C 1-6 Alkoxy (e.g., methoxy or ethoxy), C 1-6 Method 2, wherein the aryl group is alkoxymethyl (e.g., methoxyethyl or ethoxymethyl), aryl (e.g., phenyl or tolyl), arylmethyl (e.g., benzyl), aryloxy (e.g., phenoxy) or aryloxymethyl (e.g., phenoxymethyl); 2.3 R is -C(O)-R 1 where R1 is methyl, ethyl, propyl, isopropyl or tert-butyl or R is -S(O) 2 -R 1 where R 1 is methyl, method 2.2; 2.4 R is -C(O)-R 1 where R 1 is methyl, method 2.2; 2.5 R is -C(O)-R 1 where R 1 is chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trichloroethyl, trifluoromethyl, methoxymethyl, phenoxymethyl or benzyl or R is -S(O) 2 -R 1 where R 1 is trifluoromethyl, phenyl or tolyl; 2.6 R is an ether protecting group, e.g., R is unsubstituted C 1-6 Alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl) or substituted C 1-6 Alkyl, e.g. C 1-6 Alkoxy-C 1-6 Alkyl, aryloxy-C 1-6 Alkyl or Aryl-C 1-6 Alkyl (e.g., -CH 2 -O-Me, -CH 2 -O-Et, -CH 2 -S-Me, -CH 2 -O-CH 2 CH 2 - OMe, C.H. 2 -O-CH 2 CCl 3 , C.H. 2 -O-CH 2 CH 2 -SiMe 3 , -CH 2 -O-Ph, -CH 2 -O-CH 2 -Ph, -CH 2 -O-CH 2 -(4-Methoxyphenyl), -CH 2 -O-CH2 -(3,4-dimethoxyphenyl), -CH 2 CH 2 -OEt, -CH 2 CH 2 Si(Me) 3 , -CH 2 CCl 3 , -CH 2 -Ph, -CH 2 -(4-Methoxyphenyl), -CH 2 -(3,4-dimethoxyphenyl), -CH 2 -(2,6-dimethoxyphenyl) or tetrahydropyranyl; 2.7 R is a silyl ether protecting group (e.g., R is -Si(R 2 )(R 3 )(R 4 ), where R 2 , R 3 and R 4 Each independently C 1-6 Alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl, thexyl, benzyl), C 1-6 Method 2, wherein the aryl is selected from alkoxy (e.g., methoxy, ethoxy, tert-butoxy) and aryl (e.g., phenyl); 2.8 Method 2.7, wherein R is selected from trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, di-tert-butylmethylsilyl, tris(trimethylsilyl)silyl, tert-butylmethoxyphenylsilyl, and tert-butoxydiphenylsilyl; 2.9 Compound (8) is a mixture (8a), a compound (8b) or a mixture thereof: [ka] any of methods 2 or 2.1 to 2.8; 2.10 Compound (9) is a mixture (9a), a compound (9b) or a mixture thereof: [ka] any of methods 2 or 2.1 to 2.9; 2.11 Compound (10) is a mixture (10a), a compound (10b) or a mixture thereof: [ka] any of methods 2 or 2.1 to 2.10; 2.12 Compound (6) is a mixture (6a), a compound (6b) or a mixture thereof: [ka] and; Optionally, any of methods 2 or 2.1 to 2.11, wherein compound (6) is enriched in one isomer or the other or the method further comprises a step of purification or separation of the isomers; 2.13 further comprising a step (A') of converting compound (7') (wherein R is H) to compound (7'') (wherein R is not H (e.g., R is a protecting group): [ka] Method 2 or any of 2.1 to 2.12; 2.14 Method 2.13, in which step (A') is the first step in a linear sequence of steps (A) in the method; 2.15 further comprising a step (D') of converting compound (10') where R is not H (e.g., R is a protecting group) to compound (10'') where R is H: [ka] Method 2 or any of 2.1 to 1.14; 2.16 Method 2.15, wherein step (D') is the penultimate step immediately preceding step (D) in the method; 2.17 Any of Methods 2 or 2.1-2.16, where the protecting group R is removed during step (D) (i.e., deprotection step D' is unnecessary); 2.18 The process comprises producing as an intermediate compound VI' [ka] Any of methods 2 or 2.1 to 2.17, which does not include any step of using 2.19 The process comprises the step of producing as an intermediate compound (IV'), compound (V') or compound (VII'). [ka] (wherein X is Cl, Br or I). Any of methods 2 or 2.1 to 2.18, which does not include any step of using 2.20 Method 2 or any of 2.1-2.19, wherein the method does not yield measurable amounts of either compound (XI) or compound (XII), e.g., as measured by HPLC, GC, MS, or NMR; 2.21 Any of methods 2 or 2.1 to 2.20, wherein the method does not include any synthetic and / or mechanical steps other than steps (A), (B), (C) and / or (D) and optionally (A') and / or (D') in the conversion of compound (7) or compound (7') to compound (6); 2.22 any of methods 2 or 2.1-2.21, in which the epoxidation step (A) is carried out by treating compound (6) with a suitable oxidizing agent in a suitable solvent; 2.23 Method 2.22, wherein the suitable oxidizing agent is one or more of hydrogen peroxide, osmium tetroxide, peracetic acid, perchloric acid, perbenzoic acid, meta-chloroperoxybenzoic acid (mCPBA), trifluoroperacetic acid, magnesium monoperoxyphthalate, dimethyldioxirane (DMDO), tert-butyl hydroperoxide, sodium hypochlorite, sodium tungstate, sodium periodate, iodosylbenzene, pentafluoroiodosylbenzene, cumene hydroperoxide, potassium persulfate, potassium peroxymonosulfate, pyridine N-oxide, 2,6-dichloropyridine N-oxide or oxygen (e.g., in combination with a transition metal catalyst, e.g., an iron catalyst), optionally in combination with any secondary reagent (e.g., a secondary oxidizing agent, catalyst, complexing agent, directing agent, reducing agent or chiral auxiliary); 2.24 Method 2.22, wherein in the epoxidation step (A), the suitable oxidizing agent is hydrogen peroxide, peracetic acid, meta-chloroperoxybenzoic acid, tert-butyl hydroperoxide, or potassium peroxymonosulfate; 2.25 Method 2.22, in which in the epoxidation step (A) the suitable oxidizing agent is hydrogen peroxide and sodium tungstate, e.g. hydrogen peroxide (e.g. 30 wt.%, e.g. 1-1.5 equivalents) + sodium tungstate (e.g. sodium tungstate dihydrate, e.g. 0.01-0.10 equivalents) with methyl-tri-n-octylammonium hydrogen sulfate (e.g. 0.01-0.05 equivalents) and phenylphosphonic acid (e.g. 0.01-0.05 equivalents), optionally in an aqueous solvent, optionally at 0-50°C; 2.26 Method 2.22, in which in the epoxidation step (A) the suitable oxidizing agent is m-chloroperoxybenzoic acid; 2.27 Method 2.22, in which in the epoxidation step (A) the suitable oxidizing agent is oxygen gas; 2.28 Method 2.27, in which in the epoxidation step (A), the suitable oxidizing agent is oxygen gas and a transition metal catalyst; 2.29 In the epoxidation step (A), a suitable oxidizing agent is C 2-10Method 2.27, oxygen gas and iron(III)-tetraphenylporphyrin complex (Fe(III)TPP) in the presence of an aliphatic aldehyde (e.g., isobutyraldehyde); 2.30 Method 2.27, in which in the epoxidation step (A), the suitable oxidizing agent is oxygen gas and N-hydroxyphthalimide; 2.31 Any of methods 2.22 to 2.30, wherein the epoxidation step (A) does not involve the use of ozone; 2.32 In the epoxidation step (A), suitable solvents include hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane), chlorinated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethylene), aromatics (e.g., benzene, toluene, xylene, pyridine), ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether), esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate, any of methods 2.22-2.31, wherein the solvent is selected from the group consisting of butyl acetate, ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone), polar aprotic solvents (e.g., acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide), polar protic solvents (e.g., water, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, glycerol, formic acid, acetic acid, sulfuric acid), acetic anhydride, carbon dioxide (e.g., supercritical carbon dioxide), and carbon disulfide, or a combination thereof; 2.33 Any of methods 2.22-2.32, wherein the epoxidation step (A) is carried out using 1.0 to 5.0 equivalents of oxidizing agent, for example, 1.0 to 4.0 equivalents, or 1.0 to 3.0 equivalents, or 1.0 to 2.0 equivalents, or 1.0 to 1.50 equivalents, or 1.0 to 1.25 equivalents, or 1.0 to 1.15 equivalents, or 1.0 to 1.05 equivalents, or 1.5 to 2.0 equivalents, or 2.0 to 3.0 equivalents; and optionally 0.01 to 1.0 equivalent of any one or more further reagents (for example, secondary oxidizing agents or catalysts or ligands or other agents), for example, 0.01 to 0.5 equivalents, 0.01 to 0.2 equivalents, or 0.01 to 0.1 or 0.01 to 0.05 equivalents; 2.34 any of the methods 2.22 to 2.33, wherein the epoxidation step (A) is carried out at a temperature of -100°C to 200°C, e.g., -50°C to 150°C or -100°C to 0°C or -100°C to -50°C or -50°C to 0°C or -25°C to 0°C or -25°C to 25°C or 0°C to 200°C or 0°C to 150°C or 0°C to 100°C or 0°C to 50°C or 0°C to 25°C or 25°C to 150°C or 25°C to 100°C or 50°C to 200°C or 50°C to 100°C or 75°C to 200°C or 100°C to 200°C or 150°C to 200°C; 2.35 Any of methods 2.22-2.34, wherein the epoxidation step (A) is carried out in a batch reactor; 2.36 Any of methods 2.22-2.34, wherein the epoxidation step (A) is carried out in a continuous flow reactor; 2.37 The rearrangement step (B) is carried out by treating compound (7) with a suitable rearrangement catalyst in a suitable solvent or by heating compound (3) in a suitable solvent without a catalyst (i.e., thermal rearrangement), either in Method 2 or in any of Methods 2.1 to 2.36; 2.38 Method 2.37, wherein the rearrangement catalyst is a Lewis acid, a Bronsted acid, a strong base (e.g., LDA, LiTMP, LiHMDS, t-butyllithium) or a transition metal catalyst or complex (e.g., a palladium, ruthenium, rhodium, chromium, iridium, zirconium, manganese, iron or nickel catalyst or complex); 2.39 Method 2.37, wherein the rearrangement catalyst is a solid phase acidic resin (e.g., Amberlyst or Nafion-H or an acidic polymeric resin such as montmorillonite or zeolite), e.g., Montmorillonite K10 or Amberlyst H-15, and optionally the catalyst is Montmorillonite K-10, e.g., in a toluene solvent, e.g., at 0-50°C (e.g., about 25°C); 2.40 Process 2.37, wherein the rearrangement catalyst is a Lewis acid selected from, for example, zinc bromide, zinc chloride, magnesium bromide, magnesium bromide-diethyl ether complex, bismuth triflate, boron trifluoride-diethyl ether complex, aluminum triisopropoxide, titanium tetraisopropoxide, titanium tetrachloride, iron trichloride, indium chloride, lithium perchlorate, iridium chloride, iridium bromide, borane-THF complex, chromium tetraphenylporphyrin triflate, dibromobis(triphenylphosphine)nickel complex, methylbis(4-bromo-1,6-di-tert-butylphenoxy)aluminum; 2.41 The process 2.37, wherein the rearrangement catalyst is a Bronsted acid selected from, for example, hydrochloric acid, perchloric acid, sulfuric acid, phosphoric acid, acetic acid, peracetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, trifluoroacetic acid, and nitric acid, or a heteropolyacid (e.g., phosphotungstic acid); 2.42 In the rearrangement step (B), suitable solvents include hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane), chlorinated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethylene), aromatics (e.g., benzene, toluene, xylene, pyridine), ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether), esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate, acetic acid, any of methods 2.37-2.41, wherein the solvent is selected from butyl ketone, ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone), polar aprotic solvents (e.g., acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide), polar protic solvents (e.g., water, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, glycerol, formic acid, acetic acid, sulfuric acid), acetic anhydride, carbon dioxide (e.g., supercritical carbon dioxide), and carbon disulfide, or a combination thereof; 2.43 Any of Methods 2.37 to 2.42, wherein the rearrangement step (B) is carried out using 1.0 to 5.0 equivalents of the rearrangement catalyst, for example, 1.0 to 4.0 equivalents, or 1.0 to 3.0 equivalents, or 1.0 to 2.0 equivalents, or 1.0 to 1.50 equivalents, or 1.0 to 1.25 equivalents, or 1.0 to 1.15 equivalents, or 1.0 to 1.05 equivalents, or 1.5 to 2.0 equivalents, or 2.0 to 3.0 equivalents; or using 0.01 to 1.0 equivalent of the rearrangement catalyst, for example, 0.01 to 0.1 equivalents, 0.1 to 0.5 equivalents, or 0.5 to 1.0 equivalents; 2.44 any of Methods 2.37 to 2.43, wherein the rearrangement step (B) is carried out at a temperature of -100°C to 200°C, e.g., -50°C to 150°C or -100°C to 0°C or -100°C to -50°C or -50°C to 0°C or -25°C to 0°C or -25°C to 25°C or 0°C to 200°C or 0°C to 150°C or 0°C to 100°C or 0°C to 50°C or 0°C to 25°C or 25°C to 150°C or 25°C to 100°C or 50°C to 200°C or 50°C to 100°C or 75°C to 200°C or 100°C to 200°C or 150°C to 200°C; 2.45 Any of methods 2.37-2.44, wherein the rearrangement step (B) is carried out in a batch reactor; 2.46 Any of methods 2.37 to 2.45, wherein the rearrangement step (B) is carried out in a continuous flow reactor; 2.47 Any of Methods 2 or 2.1-2.46, wherein the rearrangement step (B) is carried out in the same vessel as the oxidation step (C), e.g., the product of step (B) is not purified or isolated prior to carrying out step (C), or the reagents or reagents and solvent of step (C) are added directly to the reaction mixture of step (B); 2.48 Any of methods 2 or 2.1 to 2.47, wherein the oxidation step (C) is carried out by treating compound (8) with a suitable oxidizing agent in a suitable solvent; 2.49 Method 2.48, in which in the oxidation step (C), the suitable oxidizing agent is one or more of a chromium oxidizing agent (e.g., chromium trioxide, chromic acid, pyridinium chlorochromate, potassium dichromate, chromium trioxide-pyridine complex, pyridinium dichromate), osmium tetroxide, potassium permanganate, silver oxide, hydrogen peroxide, peracetic acid, perchloric acid, trifluoroperacetic acid, periodic acid, potassium periodate, sodium chlorite, oxygen, and N-hydroxyphthalimide, potassium persulfate, and potassium peroxymonosulfate; 2.50 Method 2.48, in which in the oxidation step (C), the suitable oxidizing agent is a chromium oxidizing agent (e.g., chromium trioxide, chromic acid, pyridinium chlorochromate, potassium dichromate, chromium trioxide-pyridine complex, pyridinium dichromate), optionally the chromium oxidizing agent is, for example, chromium trioxide (i.e., Jones reagent) in an acetone solvent, for example, in aqueous sulfuric acid at 0-50°C (e.g., about 25°C) (e.g., about 1-1.5 equivalents Jones reagent); 2.51 Any of methods 2.48 to 2.50, wherein the oxidation step (C) does not involve the use of ozone; 2.52 In the oxidation step (C), suitable solvents include hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane), chlorinated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethylene), aromatics (e.g., benzene, toluene, xylene, pyridine), ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether), esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate, acetic acid, any of methods 2.48-2.51, wherein the solvent is selected from butyl ketone, ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone), polar aprotic solvents (e.g., acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide), polar protic solvents (e.g., water, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, glycerol, formic acid, acetic acid, sulfuric acid), acetic anhydride, carbon dioxide (e.g., supercritical carbon dioxide), and carbon disulfide, or a combination thereof; 2.53 Any of methods 2.48 to 2.52, wherein the oxidation step (C) is carried out using 1.0 to 5.0 equivalents of oxidizing agent, 1.0 to 5.0 equivalents of rearrangement catalyst, for example 1.0 to 4.0 equivalents or 1.0 to 3.0 equivalents or 1.0 to 2.0 equivalents or 1.0 to 1.50 equivalents or 1.0 to 1.25 equivalents or 1.0 to 1.15 equivalents or 1.0 to 1.05 equivalents or 1.5 to 2.0 equivalents or 2.0 to 3.0 equivalents; 2.54 any of methods 2.48 to 2.53, wherein the oxidation step (C) is carried out at a temperature of -100°C to 200°C, for example, -50°C to 150°C or -100°C to 0°C or -100°C to -50°C or -50°C to 0°C or -25°C to 0°C or -25°C to 25°C or 0°C to 200°C or 0°C to 150°C or 0°C to 100°C or 0°C to 50°C or 0°C to 25°C or 25°C to 150°C or 25°C to 100°C or 50°C to 200°C or 50°C to 100°C or 75°C to 200°C or 100°C to 200°C or 150°C to 200°C; 2.55 Any of methods 2.48 to 2.54, wherein the oxidation step (C) is carried out in a batch reactor; 2.56 Any of methods 2.48 to 2.54, wherein the oxidation step (C) is carried out in a continuous flow reactor; 2.57 Any of methods 2 or 2.1 to 2.56, wherein the ring closure step (D) of compound (10) and / or the deprotection of the -OR group occurs spontaneously during and / or after the oxidation step (C); 2.58 Any of methods 2 or 2.1-2.56, wherein the ring closure step (D) of compound (10) and / or the deprotection of the -OR group is carried out by heating the product mixture from step (C); 2.59 Any of methods 2 or 2.1 to 2.56, wherein the ring closure step (D) of compound (10) and / or the deprotection of the -OR group is carried out by distillation of the product mixture from step (C); 2.60 Any of Method 2 or 2.1-2.56, wherein the method includes a deprotection step (D') immediately prior to the ring closure step (D) and immediately following the oxidation step (C); 2.61 The deprotection step (D') is carried out by treating compound (5) with aqueous base, aqueous acid, anhydrous base, anhydrous acid or anhydrous fluoride or biphasic acid, biphasic base or biphasic fluoride or other suitable conditions (e.g., sodium azide, mercuric chloride, magnesium bromide, magnesium iodide, DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone, ammonium cerium nitrate, hydrogen over palladium or platinum catalyst) in a suitable solvent, Method 2.60; 2.62 Method 2.61, wherein the base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, ammonium hydroxide, tetrabutyl ammonium hydroxide, ammonia, guanidine, ethylenediamine, ethanolamine, pyridine, lutidine, collidine, triethylamine, diisopropylethylamine, piperidine, morpholine, methylamine, hydrazine, and imidazole; 2.63 Suitable solvents include hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane), chlorinated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethylene), aromatics (e.g., benzene, toluene, xylene, pyridine), ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether), esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate), ketones (e.g., Method 2.62, wherein the solvent is selected from a polar aprotic solvent (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone), a polar aprotic solvent (e.g., acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide), a polar protic solvent (e.g., water, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, glycerol, formic acid, acetic acid, sulfuric acid), acetic anhydride, carbon dioxide (e.g., supercritical carbon dioxide) and carbon disulfide or combinations thereof (including aqueous or anhydrous or biphasic combinations thereof); 2.64 Method 2.61, wherein the acid is selected from hydrochloric acid (e.g., hydrogen chloride), nitric acid, sulfuric acid, phosphoric acid, acetic acid, peracetic acid, formic acid, citric acid, trifluoroacetic acid, perchloric acid, trifluoromethanesulfonic acid, methanesulfonic acid, hydrogen fluoride, hydrogen bromide, boron trifluoride-etherate, toluenesulfonic acid, scandium triflate, ytterbium triflate, pyridinium para-toluenesulfonate (PPTS), zinc bromide, zinc chloride, titanium chloride, tin(IV) chloride, bromodimethylborane, boron trichloride, pyridine-HF complex, and solid acidic resins (e.g., acidic polymers such as Amberlyst H-15; silica gel, alumina, montmorillonite K-10); 2.65 Suitable solvents include hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane), chlorinated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethylene), aromatics (e.g., benzene, toluene, xylene, pyridine), ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether), esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone), polar aprotic solvents (e.g., acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide), polar protic solvents (e.g., water, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, glycerol, formic acid, acetic acid, sulfuric acid), acetic anhydride, carbon dioxide (e.g., supercritical carbon dioxide) and carbon disulfide or combinations thereof (including aqueous or anhydrous or biphasic combinations thereof), method 2.64; 2.66 Method 2.61, where the fluoride is selected from hydrogen fluoride (e.g., anhydrous HF, aqueous HF, triethylamine HF complex, pyridine HF complex), TASF (tris(dimethylamino)sulfonium difluorotrimethylsilicate), sodium fluoride, potassium fluoride, cesium fluoride, ammonium fluoride, and tetrabutylammonium fluoride; 2.67 Suitable solvents include hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane), chlorinated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethylene), aromatics (e.g., benzene, toluene, xylene, pyridine), ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether), esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate), ketones (e.g., ethyl acetate, ethyl acetate, butyl acetate), tetrachloroethane, tetrachloroethylene, tetrachloroethane, dichloromethane, tetrachloroethylene, tetrachloroethylene, dichloromethane ... for example, acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone), polar aprotic solvents (e.g., acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoric triamide), polar protic solvents (e.g., water, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, glycerol, formic acid, acetic acid), carbon dioxide (e.g., supercritical carbon dioxide) and carbon disulfide or combinations thereof (including aqueous or anhydrous or biphasic combinations thereof), method 2.66; 2.68 Any of methods 2.60 to 2.67, wherein the deprotection step (D') is carried out using 1.0 to 5.0 equivalents of an acid, base, fluoride or other agent, for example, 1.0 to 4.0 equivalents, or 1.0 to 3.0 equivalents, or 1.0 to 2.0 equivalents, or 1.0 to 1.50 equivalents, or 1.0 to 1.25 equivalents, or 1.0 to 1.15 equivalents, or 1.0 to 1.05 equivalents, or 1.5 to 2.0 equivalents, or 2.0 to 3.0 equivalents; 2.69 Any of Methods 2.60 to 2.68, wherein the deprotection step (D') is carried out at a temperature of -100°C to 200°C, for example, -50°C to 150°C or -100°C to 0°C or -100°C to -50°C or -50°C to 0°C or -25°C to 0°C or -25°C to 25°C or 0°C to 200°C or 0°C to 150°C or 0°C to 100°C or 0°C to 50°C or 0°C to 25°C or 25°C to 150°C or 25°C to 100°C or 50°C to 200°C or 50°C to 100°C or 75°C to 200°C or 100°C to 200°C or 150°C to 200°C; 2.70 Any of methods 2.60-2.69, wherein the deprotection step (D') is carried out in a batch reactor; 2.71 Any of methods 2.60 to 2.70, wherein the deprotection step (D') is carried out in a continuous flow reactor; 2.72 Any of Method 2 or 2.1-2.71, further comprising a protection step (A'); 2.73 The process of 2.72, wherein the protection step (A') is carried out by treating compound (7) with a suitable protecting agent in a suitable solvent, optionally together with a suitable base; 2.74 The protecting agent is an acyl halide (e.g., acetyl chloride, benzoyl chloride, chloroacetyl chloride, dichloroacetyl chloride, trichloroacetyl chloride, methoxyacetyl chloride, phenoxyacetyl chloride, pivaloyl chloride, benzoyl chloride), an acyl anhydride (e.g., acetic anhydride, chloroacetic anhydride, dichloroacetic anhydride, trichloroacetic anhydride, trifluoroacetic anhydride, methoxyacetyl anhydride, phenoxyacetyl anhydride, pivaloyl anhydride, benzoyl anhydride), an alkyl halide (e.g., methoxymethyl chloride, methoxymethyl bromide, methoxyethyl chloride, methylthiomethyl iodide, benzyloxymethyl chloride, 4-methoxybenzyloxymethyl chloride, 2-methoxyethoxymethyl chloride, 2,2,2-trichloroethoxymethyl chloride, 2-trimethylsilylethoxymethyl chloride, 4-methoxybenzyl chloride, 4-methoxybenzyl bromide, 3,4-dimethoxybenzyl bromide), a silyl Method 2.73, selected from reagents (e.g. chlorides, silanes or triflates of the group trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, di-tert-butylmethylsilyl, tris(trimethylsilyl)silyl, tert-butylmethoxyphenylsilyl and tert-butoxydiphenylsilyl) or other protecting agents (e.g. formic acid, acetic acid, ethyl formate, methyl formate, chloroacetic acid, dihydropyran, 2-hydroxytetrahydropyran, ethyl vinyl ether, trimethylsilylethoxyethene, isobutylene, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, N,N-bis(trifluoromethanesulfonyl)aniline, benzenesulfonyl chloride, toluenesulfonyl chloride); 2.75 The process of 2.73 or 2.74, wherein the suitable base is selected from sodium hydride, potassium hydride, hydroxide bases (e.g., sodium hydroxide, potassium hydroxide), alkoxide bases (e.g., sodium tert-butoxide, potassium tert-butoxide), carbonate bases (e.g., sodium carbonate, potassium carbonate, cesium carbonate), bicarbonate bases (e.g., sodium bicarbonate) and amine bases (e.g., triethylamine, diisopropylethylamine, N-methylmorpholine, DBU, DBN, pyridine, dimethylaminopyridine, imidazole); 2.76 Suitable solvents include hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane), chlorinated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethylene), aromatics (e.g., benzene, toluene, xylene, pyridine), ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether), esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate), ketones (e.g., acetonitrile ... any of methods 2.73-2.75, wherein the solvent is selected from the group consisting of polar aprotic solvents (e.g., acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoric triamide), polar protic solvents (e.g., water, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, glycerol, formic acid, acetic acid), carbon dioxide (e.g., supercritical carbon dioxide) and carbon disulfide or a combination thereof, or the solvent is a neat reagent (e.g., pyridine); 2.77 Any of methods 2.73 to 2.76, wherein the protection step (A') is carried out using 1.0 to 5.0 equivalents of the protecting agent, for example, 1.0 to 4.0 equivalents, or 1.0 to 3.0 equivalents, or 1.0 to 2.0 equivalents, or 1.0 to 1.50 equivalents, or 1.0 to 1.25 equivalents, or 1.0 to 1.15 equivalents, or 1.0 to 1.05 equivalents, or 1.5 to 2.0 equivalents, or 2.0 to 3.0 equivalents; 2.78 Any of methods 2.73 to 2.77, wherein the protection step (A') is carried out at a temperature of -100°C to 200°C, for example, -50°C to 150°C or -100°C to 0°C or -100°C to -50°C or -50°C to 0°C or -25°C to 0°C or -25°C to 25°C or 0°C to 200°C or 0°C to 150°C or 0°C to 100°C or 0°C to 50°C or 0°C to 25°C or 25°C to 150°C or 25°C to 100°C or 50°C to 200°C or 50°C to 100°C or 75°C to 200°C or 100°C to 200°C or 150°C to 200°C; 2.79 Any of methods 2.73 to 2.78, wherein the protection step (A') is carried out in a batch reactor; 2.80 Any of methods 2.73 to 2.79, wherein the protection step (A') is carried out in a continuous flow reactor; 2.81 R a is H, any of methods 2 or 2.1 to 2.80; 2.82 R a is optionally substituted C 1-6 any of methods 2 or 2.1 to 2.80, wherein the alkyl is alkyl; 2.83 R a any of Method 2 or 2.1-2.80, wherein is optionally substituted aryl; 2.84 R a OR c any of methods 2 or 2.1 to 2.80; 2.85 R a -C(O)-R c any of methods 2 or 2.1 to 2.80; 2.86 R c is H, optionally substituted C 1-6The process of 2.84 or 2.85, wherein the alkyl is selected from alkyl and optionally substituted aryl; 2.87 R c is H and optionally substituted C 1-6 The method of 2.84 or 2.85, wherein the alkyl is selected from the group consisting of aryl, aryl, aryl and alkyl; 2.88 R b is H; any of methods 2 or 2.1 to 2.87; 2.89 R b is optionally substituted C 1-6 any of methods 2 or 2.1 to 2.87, wherein the alkyl is alkyl; 2.90 R b any of Method 2 or 2.1-2.87, wherein is optionally substituted aryl; 2.91 R b OR c and -C(O)-R c Method 2 or any of methods 2.1 to 2.87 selected from the group consisting of: 2.92 R c is H, optionally substituted C 1-6 Method 2.91, wherein the alkyl is selected from alkyl and optionally substituted aryl; 2.93 R c is H and optionally substituted C 1-6 The method of 2.91, wherein the alkyl is selected from the group consisting of alkyl, 2.94 Any of Methods 2.1-2.93, wherein intermediates (8), (9), and (10) of steps (A), (B), (C), and (D) are not isolated, e.g., reactant compound (7) is carried forward to product compound (6) in one vessel; 2.95 Method 2.94, wherein the reaction comprises treating compound (7) with an oxidizing agent as defined above (e.g., an oxidizing agent suitable for step (A) or step (C)) and an acid as defined above (e.g., an acid suitable for step (B)) in a suitable solvent; 2.96 Oxidizing agents include hydrogen peroxide, chromium oxidizing agents (e.g., chromium trioxide, chromic acid, pyridinium chlorochromate, potassium dichromate, chromium trioxide-pyridine complex, pyridinium dichromate), osmium tetroxide, potassium permanganate, peracetic acid, perchloric acid, perbenzoic acid, meta-chloroperoxybenzoic acid (mCPBA), trifluoroperacetic acid, periodic acid, magnesium monoperoxyphthalate, dimethyldioxirane (DMDO), optionally in combination with any secondary reagent (e.g., secondary oxidizing agent, catalyst, complexing agent, directing agent, reducing agent or chiral auxiliary). ), tert-butyl hydroperoxide, sodium hypochlorite, sodium tungstate, sodium periodate, potassium periodate, iodosylbenzene, pentafluoroiodosylbenzene, cumene hydroperoxide, potassium persulfate, potassium peroxymonosulfate, pyridine N-oxide, 2,6-dichloropyridine N-oxide, sodium chlorite, sodium hypochlorite, sodium chlorate, sodium perchlorate, or oxygen (e.g., in combination with a transition metal catalyst, e.g., an iron catalyst); 2.97 Method 2.96, in which the oxidizing agent is hydrogen peroxide, peracetic acid, trifluoroperacetic acid, meta-chloroperoxybenzoic acid, tert-butyl hydroperoxide, or potassium peroxymonosulfate; 2.98 Any of methods 2.95-2.96, wherein the reaction is carried out using 1.0 to 5.0 equivalents of oxidizing agent, e.g., 1.0 to 4.0 equivalents or 1.0 to 3.0 equivalents or 1.0 to 2.0 equivalents or 1.5 to 4.0 equivalents or 1.5 to 3.0 equivalents or 1.5 to 2.5 equivalents or 1.5 to 2.0 equivalents or 2.0 to 4.0 equivalents or 2.0 to 3.0 equivalents; and optionally 0.01 to 1.0 equivalent of any one or more further reagents (e.g., secondary oxidizing agents or catalysts or ligands or other agents), e.g., 0.01 to 0.5 equivalents, 0.01 to 0.2 equivalents or 0.01 to 0.1 or 0.01 to 0.05 equivalents; 2.99 Any of methods 2.95-2.98, wherein the acid is a Bronsted acid selected from, for example, hydrochloric acid, perchloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, trifluoroacetic acid, and nitric acid, or a heteropolyacid (e.g., phosphotungstic acid); 2.100 Method 2.99, wherein the acid is selected from sulfuric acid, phosphoric acid, and nitric acid; 2.101 Any of methods 2.95 to 2.100, wherein the reaction is carried out using 1.0 to 5.0 equivalents of acid, e.g., 1.0 to 4.0 equivalents or 1.0 to 3.0 equivalents or 1.0 to 2.0 equivalents or 1.5 to 4.0 equivalents or 1.5 to 3.0 equivalents or 1.5 to 2.5 equivalents or 1.5 to 2.0 equivalents or 2.0 to 4.0 equivalents or 2.0 to 3.0 equivalents; 2.102 Reactions involving hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane), chlorinated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethylene), aromatics (e.g., benzene, toluene, xylene, pyridine), ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether), esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate), ketones (e.g., any of methods 2.95-2.101, wherein the reaction is carried out in a solvent selected from polar aprotic solvents (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone), polar aprotic solvents (e.g., acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide), polar protic solvents (e.g., water, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, glycerol, formic acid, acetic acid, sulfuric acid), acetic anhydride, carbon dioxide (e.g., supercritical carbon dioxide) and carbon disulfide, or a combination thereof; 2.103 Method 2.102, wherein the solvent is acetic acid and / or acetic anhydride, and optionally the reaction further comprises an acetate salt (e.g., sodium or potassium acetate); 2.104 Any of methods 2.94 to 2.103, wherein the reaction is carried out using a combination of hydrogen peroxide, sulfuric acid, and acetic acid, optionally in an amount of 1.5 to 4 equivalents each (e.g., 2 to 3 equivalents each); 2.105 Any of methods 2.94-2.103, wherein the reaction is carried out using a combination of acetic acid, peracetic acid, and sulfuric acid, optionally in an amount of 1 to 3 equivalents each (e.g., 1 to 1.5 equivalents each); 2.106 Any of methods 2.94-2.103, wherein the reaction is carried out using a combination of hydrogen peroxide, acetic acid, peracetic acid and sulfuric acid, optionally with sodium acetate (e.g., 0.05-0.24 equivalents), each at 0.8-5 equivalents (e.g., 1-3 equivalents each); 2.107 Any of methods 2.94-2.103, wherein the reaction is carried out using a combination of hydrogen peroxide, acetic anhydride, acetic acid and sulfuric acid, optionally in an amount of 0.8-5 equivalents each (e.g., 1-3 equivalents each), optionally further comprising a heptane co-solvent; 2.108 Any of methods 2.94-2.103, wherein the reaction is carried out using a combination of potassium peroxymonosulfate, potassium hydrogen sulfate and potassium sulfate (e.g., Oxone®) in an organic solvent (e.g., acetone / ethyl acetate), optionally using 1-3 equivalents of potassium peroxymonosulfate (e.g., 1-2 equivalents); 2.109 Any of methods 2.94 to 2.108, wherein the reaction is carried out at a temperature between 0°C and 200°C, e.g., between 0°C and 150°C, or between 0°C and 100°C, or between 25°C and 200°C, or between 25°C and 150°C, or between 25°C and 100°C, or between 50°C and 200°C, or between 50°C and 150°C, or between 50°C and 100°C, or between 75°C and 200°C, or between 75°C and 150°C, or between 75°C and 100°C, or between 80°C and 150°C, or between 80°C and 100°C, or between 90°C and 150°C, or between 90°C and 125°C, or between 90°C and 110°C, or between 90°C and 100°C, or between 90°C and 95°C; 2.110 Any of methods 2.94 to 2.108, wherein the reaction is carried out at a temperature of 80°C to 90°C, 20°C to 70°C, 40°C to 90°C, 20°C to 50°C, or 20°C to 30°C; 2.111 Any of methods 2.94 to 2.110, wherein reaction steps (A), (B), (C) and / or (D) are carried out in a single vessel in a single reaction step, e.g., step (B) spontaneously follows step (A), step (C) spontaneously follows step (B), and step (D) spontaneously follows step (C); 2.112 Any of methods 2.94-2.110, wherein reaction steps (A), (B), (C) and / or (D) are carried out in two reaction steps in one vessel without isolating any intermediates, e.g., at least a second oxidizing agent is added in a second reaction step to initiate step (C), step (B) spontaneously follows step A, and step (D) spontaneously follows step C; 2.113 Any of methods 2.94-2.112, wherein R is H, reactant compound (7) proceeds to product compound (6) in a single vessel, and the reaction is carried out by treating compound (7) with a combination of hydrogen peroxide, sulfuric acid, and acetic acid, optionally in an amount of 1.5-4 equivalents each (e.g., 2-3 equivalents each or 2 equivalents each), optionally at a temperature of 75°C to 150°C, or 80°C to 100°C, or 90°C to 95°C; 2.114 Any of methods 2 or 2.1-2.113, wherein the method further comprises step (E) of treating compound (6) with a base, resulting in enrichment of compound (6a) by isomerization of compound (6b) to compound (6a); 2.115 Method 2.114, wherein the base is selected from sodium hydride, potassium hydride, hydroxide bases (e.g., sodium hydroxide, potassium hydroxide), alkoxide bases (e.g., sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide), carbonate bases (e.g., sodium carbonate, potassium carbonate, cesium carbonate), bicarbonate bases (e.g., sodium bicarbonate), amide bases (e.g., lithium amide, lithium 2,2,6,6-tetramethylpiperidide (LiTMP), lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide) (LiHMDS)), alkyl lithium bases (e.g., sec-butyl lithium, tert-butyl lithium) and amine bases (e.g., triethylamine, diisopropylethylamine, N-methylmorpholine, DBU, DBN, pyridine, dimethylaminopyridine, imidazole); 2.116 Method 2.115, where the base is an alkoxide base (e.g., sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide) or an amide base (e.g., lithium amide, lithium 2,2,6,6-tetramethylpiperidide (LiTMP), lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide) (LiHMDS)); 2.117 Method 2.115, wherein the base is sodium tert-butoxide or potassium tert-butoxide; 2.118 Any of methods 2.114-2.117, wherein step (E) is carried out in a solvent selected from hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane), chlorinated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethylene), aromatics (e.g., benzene, toluene, xylene, pyridine), and ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether); 2.119 Method 2.118, wherein step (E) is carried out in a hydrocarbon solvent, such as pentane, hexane, heptane, or cyclohexane; 2.120 Any of methods 2.114 to 2.119, wherein step (E) is carried out at a temperature of -78°C to 200°C, e.g., -50°C to 150°C, or -25°C to 100°C, or 0°C to 75°C, or 15°C to 50°C, or 20°C to 30°C, -78°C to 0°C, or -50°C to 0°C, or -25°C to 25°C, or 25°C to 75°C, or 50°C to 100°C, or 75°C to 150°C, or 100°C to 150°C, or 125°C to 200°C, or 150°C to 200°C; 2.121 Any of methods 2.114-2.120, wherein step (E) provides an enrichment of the amount of isomer (6a) of at least 10% by weight of the total weight of compound (6), such as at least 15% or at least 20% or at least 25%; 2.122 Any of methods 2.114-2.121, wherein step (E) provides a product having a ratio of isomer (6a):isomer (6b) of at least 90:10, e.g., at least 92:8, or at least 93:7, or at least 94:6, or at least 95:5; 2.123 Any of Methods 2 or 2.1-2.122, wherein the method further comprises crystallizing the product compound (6) from a hydrocarbon solvent (e.g., pentane, hexane, heptane, cyclohexane or mixtures thereof) at a temperature below 0° C., e.g., below 25° C., or below 15° C., or below 10° C., or below 5° C., or below 0° C., or below −5° C., or below −10° C., or below −20° C., or below −30° C., or below −40° C., or below −50° C., e.g., as low as −78° C.; 2.124 Method 2.123, wherein the recrystallization step provides a product having a ratio of isomer (1a):isomer (2a) of at least 95:5, e.g., at least 97:3, or at least 98:2, or at least 99:1, or at least 99.5:0.5; 2.125 Any of processes 2.114 to 2.124, wherein the process includes an isomerization step (E) of the product (6), followed by recrystallization; 2.126 Method 2.125, in which the isomerization step (E) and the recrystallization step are carried out as successive steps, such as isomerization followed by recrystallization after each recrystallization, until the desired purity of isomer (6a) is obtained; 2.127 Method 2.126, in which the successive isomerization and recrystallization steps provide a product having a ratio of isomer (6a):isomer (6b) of at least 95:5, e.g., at least 97:3, or at least 98:2, or at least 99:1, or at least 99.5:0.5; 2.128 Any of methods 2 or 2.1-2.127, wherein the method does not include the use of any reagents or reactants other than compound (7) and the reagents depicted herein (e.g., acids, bases, oxidants, catalysts, protecting agents, deprotecting agents, solvents), e.g., the method does not include the use of any carbon monoxide, carbonyl equivalents, or enzymes.

[0027] Method 2 is understood to be a generalization of the more specific Method 1, since compounds (1) to (5) are species of compounds (6) to (10), respectively.

[0028] In a further embodiment of method 2, the present invention relates to a process in which step (B) produces as by-products the compounds of formulae XIII, XIV and XV: [ka] In certain embodiments, the present invention provides any of Methods 2 or 2.1-2.128, wherein step (B) provides one or more of the compounds of formula XVIa, XVIb, XIIa, XIIb, and XVIIIa as by-products: [ka] The method of any of methods 2 or 2.1 to 2.128 provides one or more of the compounds of formula (I).

[0029] Without being bound by theory, it is believed that the double bonds of the compounds of formula XVI, XVII, XVIII, XVIa, XVIb, XVIIa, XVIIb and / or XVIIIa may be formed during step (A) and / or step (B) of method 2 onward, such as by acid catalyzed, base catalyzed or thermal removal of one or more hydroxy groups (-OH) or protected hydroxy groups (-OR) of the compounds of formula (7), (8), (8a), (8b), (9), (9a) or (9b). This can be achieved, for example, by the formation of a double bond between the compound of formula XVI and the compound of formula XVII. 2 -R 1 where R 1 is particularly possible when is methyl, trifluoromethyl, phenyl or tolyl. Thus, for example, during steps (A) and (B), the following reaction may occur: [ka] As described above, under the conditions of step (A), the initially formed compound (8) may undergo elimination or formation of an unsaturated epoxide compound (Step A' above), followed by conversion of the unsaturated epoxide compound to an unsaturated aldehyde (Step B'' above) under the conditions of step (B). Alternatively, both of these conversions may occur under the conditions of step B (Step B' followed by Step B'' above). Alternatively, under the conditions of step (B), compound (9) may undergo elimination or formation of an unsaturated epoxide compound (Step B'''' above).

[0030] If desired, the compounds of formula XVI, XVII, XVIII, XVIa, XVIb, XVIIa, XVIIb and / or XVIIIa may be isolated (eg by extraction, distillation or chromatographic separation) from the product mixture of step (B).

[0031] With respect to "steps" or "synthetic steps", it is understood that the present disclosure describes specific chemical transformations that may optionally be accompanied by various procedural steps known to those skilled in the art, such as stepwise addition of reagents, heating steps, cooling steps, quenching steps, precipitation steps, mixing steps, drying steps, evaporation steps and other purification steps (e.g., aqueous extraction, chromatography, distillation) and analytical steps (e.g., thin layer chromatography, MS, LCMS, NMR, elemental analysis, etc.). In embodiments where the present disclosure of the invention is limited to specific steps, it is understood that such limitations are placed on the synthetic steps performed and not on the procedural steps involved in carrying out the method, unless specifically indicated. The term "reaction steps" refers to the number of procedural steps performed, including the addition of a selection of different reagents.

[0032] In some embodiments, the mechanical steps (A), (B), (C) and (D) can be combined into just two reaction steps. Without being bound by theory, it is believed that this can be achieved because step (B) can occur spontaneously under thermal or acid-catalyzed conditions driven by the reaction conditions of step (A), and similarly, step (D) can occur spontaneously under thermal or acid-catalyzed conditions driven by the reaction conditions of step (C). Thus, a two-step reaction sequence can be used in which an oxidizing agent, optionally an acid and a solvent are added in a first reaction step (e.g., hydrogen peroxide or peracetic acid in sulfuric acid and / or acetic acid and / or acetic anhydride), and after a certain time, a second oxidizing agent, acid and a solvent (e.g., hydrogen peroxide or peracetic acid in sulfuric acid and / or acetic acid and / or acetic anhydride). This two-step sequence can be carried out in two reaction vessels or in one reaction vessel (i.e., the addition of two sets of reagents separated in time). When using a two-step sequence, the reaction mixture of the first step can be added to the reagents and solvent of the second step, or vice versa.

[0033] In a further embodiment of the first and second aspects, it has been unexpectedly found that a one-vessel ("one-pot") procedure can be used to convert compound (2) or (7) to compound (1) or (6), respectively, by treating compound (2) or (7) with an oxidizing agent and an acid or base in a suitable solvent (e.g., an aqueous solvent). Thus, one set of reagents is added and the entire mechanical process is carried out in one "reaction step". In a preferred embodiment, the oxidizing agent is aqueous hydrogen peroxide, the acid is sulfuric acid (e.g., a 60% aqueous solution), and the solvent is acetic acid. Without being bound by theory, it is believed that hydrogen peroxide and acetic acid solvent can be formed in situ from peracetic acid. In another preferred embodiment, the reaction can be carried out using peracetic acid, trifluoromethanesulfonic acid, and acetic acid. In another preferred embodiment, the oxidizing agent is peracetic acid, the acid is sulfuric acid (e.g., a 60% aqueous solution), and the solvent is acetic acid and / or acetic anhydride. In some embodiments, acetate salts, such as sodium acetate or potassium acetate, are added to adjust the acidity of the reaction or provide a buffering effect.

[0034] In the one-pot procedure described herein, it is believed that the reaction proceeds as described above. However, without being bound by theory, it is also believed that the reaction may proceed via other intermediates. For example, in the case of the preparation of compound (1). [ka]

[0035] As described above, under the one-pot reaction conditions described herein (e.g., hydrogen peroxide, sulfuric acid, acetic acid or peracetic acid, trifluoromethanesulfonic acid, acetic acid), the initially formed epoxide (3) can undergo acid-catalyzed polymerization with intermediate (14) to form short oligomers (11), which can be oxidatively depolymerized to form aldehydes (4). Furthermore, the initially formed epoxide (3) can undergo acid-catalyzed self-polymerization to form short oligomers (15), which can also be oxidatively depolymerized to form aldehydes (4). Furthermore, the epoxide (3) can undergo acid-catalyzed intramolecular ring closure to form tertiary alcohols (12), which can rearrange to cyclic hemiacetals (13), which can be reversibly formed by intramolecular condensation of aldehydes (4) or can be directly oxidized to lactone products (1). Additionally, epoxide (3) can undergo acid-catalyzed hydrolysis to form vicinal diol (14), which can undergo acid-catalyzed elimination to form aldehyde (4) (initially as its enol tautomer). Although these individual steps have been shown to be acid-catalyzed, without being bound by theory, it is believed that many of them can also be carried out under base-catalyzed conditions. Thus, without being bound by theory, it is believed that the mechanism occurring in the one-pot procedure can be acid- or base-catalyzed or autocatalyzed in a polar medium (e.g., a medium containing at least one polar solvent, such as water, alcohol, amine, thiol, or other polar protic or polar aprotic solvent).

[0036] The corresponding reactions and intermediates shown in the above scheme are similarly provided for the one-pot conversion of compound (7) to compound (6). Such schemes are essentially the same, except with the compounds and intermediates (6), (7), (8), (9) and (10) as well as the following additional intermediates (16), (17), (18), (19) and (20). [ka]

[0037] In other embodiments, using the conditions and procedures described herein, the present invention also provides a method for preparing compound (1) starting from any one of intermediates (3), (4), (5), (11), (12), (13), (14) or (15) by use of the appropriate reagents and conditions that will be apparent from this disclosure. Similarly, the present invention also provides for preparing compound (6) starting from any one of intermediates (8), (9), (10), (16), (17), (18), (19) or (20).

[0038] Therefore, in a third aspect, the present invention provides a method (Method 3) for preparing compound (1) from compound (2) or compound (6) from compound (7), comprising: [ka] the step of treating compound (2) or (7) with an oxidizing agent and optionally an acid or base in a suitable solvent (e.g., an aqueous solvent), where the reaction proceeds in one vessel without isolating any intermediates (e.g., a one-pot reaction); where R is H or a protecting group (e.g., an ether protecting group, an ester protecting group, or a silyl ether protecting group), and where R a is H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted aryl, OR c and -C(O)-R c and R b is H, optionally substituted C 1-6 alkyl, optionally substituted aryl, OR c and -C(O)-R c and R c is H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6wherein the aryl is selected from alkynyl and optionally substituted aryl.

[0039] In a further embodiment of the third aspect, the present invention provides: 3.1. Method 3, where R is H; 3.2. R is an ester protecting group, e.g., -C(O)-R 1 or -S(O) 2 -R 1 where R 1 H, C 1-6 Alkyl (e.g., methyl or ethyl), haloC 1-6 Alkyl (e.g., chloromethyl or trifluoromethyl), C 1-6 Alkoxy (e.g., methoxy or ethoxy), C 1-6 Method 3, wherein the aryl group is alkoxymethyl (e.g., methoxyethyl or ethoxymethyl), aryl (e.g., phenyl or tolyl), arylmethyl (e.g., benzyl), aryloxy (e.g., phenoxy) or aryloxymethyl (e.g., phenoxymethyl); 3.3. R is -C(O)-R 1 where R 1 is methyl, ethyl, propyl, isopropyl or tert-butyl or R is -S(O) 2 -R 1 where R 1 is methyl, method 3.2; 3.4. R is -C(O)-R 1 where R 1 is methyl, method 3.2; 3.5. R is -C(O)-R 1 where R 1 is chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trichloroethyl, trifluoromethyl, methoxymethyl, phenoxymethyl or benzyl or R is -S(O) 2 -R 1 where R 1 is trifluoromethyl, phenyl or tolyl; 3.6. R is an ether protecting group, e.g., R is unsubstituted C 1-6 Alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl) or substituted C 1-6 Alkyl, e.g. C 1-6 Alkoxy-C 1-6 Alkyl, aryloxy-C 1-6 Alkyl or Aryl-C 1-6 Alkyl (e.g., -CH 2 -O-Me, -CH 2 -O-Et, -CH 2 -S-Me, -CH 2 -O-CH 2 CH 2 - OMe, C.H. 2 -O-CH 2 CCl 3 , C.H. 2 -O-CH 2 CH 2 -SiMe 3 , -CH 2 -O-Ph, -CH 2 -O-CH 2 -Ph, -CH 2 -O-CH 2 -(4-Methoxyphenyl), -CH 2 -O-CH 2 -(3,4-dimethoxyphenyl), -CH 2 CH 2 -OEt, -CH 2 CH 2 Si(Me) 3 , -CH 2 CCl3, -CH 2 -Ph, -CH 2 -(4-Methoxyphenyl), -CH 2 -(3,4-dimethoxyphenyl), -CH 2 -(2,6-dimethoxyphenyl) or tetrahydropyranyl; 3.7. R is a silyl ether protecting group (e.g., R is -Si(R 2 )(R 3 )(R 4 ), where R 2 , R 3 and R 4 Each independently C 1-6Alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl, thexyl, benzyl), C 1-6 Method 3, wherein the aryl is selected from alkoxy (e.g., methoxy, ethoxy, tert-butoxy) and aryl (e.g., phenyl); 3.8. Method 3.5, wherein R is selected from trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, di-tert-butylmethylsilyl, tris(trimethylsilyl)silyl, tert-butylmethoxyphenylsilyl, and tert-butoxydiphenylsilyl; 3.9. Any of Methods 3 or 3.1-3.8, wherein the method comprises an intermediate compound (3), such as compound (3a) or compound (3b), or a mixture thereof, or the method comprises an intermediate compound (8), such as compound (8a) or compound (8b), or a mixture thereof; 3.10. Any of Methods 3 or 3.1-3.9, wherein the method comprises an intermediate compound (4), such as compound (4a) or compound (4b), or a mixture thereof, or the method comprises an intermediate compound (9), such as compound (9a) or compound (9b), or a mixture thereof; 3.11. Any of Methods 3 or 3.1-3.10, wherein the method comprises an intermediate compound (5), such as compound (5a) or compound (5b), or a mixture thereof, or the method comprises an intermediate compound (10), such as compound (10a) or compound (10b), or a mixture thereof; 3.12. Compound (1) is mixture (1a) or compound (1b) or a mixture thereof or compound (6) is mixture (6a) or compound (6b) or a mixture thereof; Optionally, compound (1) or compound (6) is enriched in one isomer or the other and optionally the method further comprises a step of purification or separation of the isomers. Method 3 or any of 3.1 to 3.11; 3.13. Ra is H; 3.14. R a is optionally substituted C 1-6 any of methods 3 or 3.1 to 3.12, wherein the alkyl is alkyl; 3.15. R b any of methods 3 or 3.1 to 3.14, wherein 3.16. R b is optionally substituted C 1-6 any of methods 3 or 3.1 to 3.14, wherein the alkyl is alkyl; 3.17. R a and / or R b is optionally substituted aryl; 3.18. R a and / or R b OR c any of methods 3 or 3.1 to 3.17; 3.19. R a and / or R b -C(O)-R c any of methods 3 or 3.1 to 3.18; 3.20. R c is H, optionally substituted C 1-6 The process of 3.18 or 3.19, wherein R is selected from alkyl and optionally substituted aryl; 3.21. R c is H and optionally substituted C 1-6 The method of 3.18 or 3.19, wherein the alkyl is selected from the group consisting of alkyl, aryl, aryl, aryl and alkyl. 3.22. Oxidizing agents include hydrogen peroxide, chromium oxidizing agents (e.g., chromium trioxide, chromic acid, pyridinium chlorochromate, potassium dichromate, chromium trioxide-pyridine complex, pyridinium dichromate), osmium tetroxide, potassium permanganate, peracetic acid, perchloric acid, perbenzoic acid, meta-chloroperoxybenzoic acid (mCPBA), trifluoroperacetic acid, periodic acid, magnesium monoperoxyphthalate, dimethyldioxirane (DMDO), tert any of Methods 3 or 3.1-3.21, wherein the catalytic active agent is selected from one or more of iodosylbenzene, iodosylbenzene, butyl hydroperoxide, sodium hypochlorite, sodium tungstate, sodium periodate, potassium periodate, iodosylbenzene, pentafluoroiodosylbenzene, cumene hydroperoxide, potassium persulfate, potassium peroxymonosulfate, pyridine N-oxide, 2,6-dichloropyridine N-oxide, sodium chlorite, sodium hypochlorite, sodium chlorate, sodium perchlorate, or oxygen (e.g., in combination with a transition metal catalyst, e.g., an iron catalyst); 3.23. Method 3.22, wherein the oxidizing agent is hydrogen peroxide, peracetic acid, trifluoroperacetic acid, meta-chloroperoxybenzoic acid, tert-butyl hydroperoxide, or potassium peroxymonosulfate; 3.24. Any of methods 3 or 3.1-3.23, wherein the reaction is carried out using 1.0 to 5.0 equivalents of oxidizing agent, e.g., 1.0 to 4.0 equivalents, or 1.0 to 3.0 equivalents, or 1.0 to 2.0 equivalents, or 1.5 to 4.0 equivalents, or 1.5 to 3.0 equivalents, or 1.5 to 2.5 equivalents, or 1.5 to 2.0 equivalents, or 2.0 to 4.0 equivalents, or 2.0 to 3.0 equivalents; and optionally 0.01 to 1.0 equivalent of any one or more additional reagents (e.g., secondary oxidizing agents or catalysts or ligands or other agents), e.g., 0.01 to 0.5 equivalents, 0.01 to 0.2 equivalents, or 0.01 to 0.1 or 0.01 to 0.05 equivalents; 3.25. Any of Methods 3 or 3.1 through 3.24, wherein the reaction involves acid catalysis; 3.26. Method 3.25, wherein the acid is a Bronsted acid selected from, for example, hydrochloric acid, perchloric acid, sulfuric acid, phosphoric acid, acetic acid, peracetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, trifluoroacetic acid, and nitric acid, or a heteropolyacid (e.g., phosphotungstic acid); 3.27. Method 3.26, wherein the acid is selected from sulfuric acid, phosphoric acid, trifluoromethanesulfonic acid, peracetic acid, and nitric acid; 3.28. Any of methods 3.25-3.27, wherein the reaction is carried out using 1.0 to 5.0 equivalents of acid, e.g., 1.0 to 4.0 equivalents or 1.0 to 3.0 equivalents or 1.0 to 2.0 equivalents or 1.5 to 4.0 equivalents or 1.5 to 3.0 equivalents or 1.5 to 2.5 equivalents or 1.5 to 2.0 equivalents or 2.0 to 4.0 equivalents or 2.0 to 3.0 equivalents; 3.29. Any of Methods 3 or 3.1-3.24, wherein the reaction involves base catalysis; 3.30. Method 3.29, wherein the base is an amine base selected from triethylamine, diisopropylethylamine, N-methylpiperidine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, imidazole, N-methylimidazole, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); 3.31. Method 3.30, wherein the base is an inorganic base selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium bicarbonate, and potassium bicarbonate; 3.32. Method 3.30, wherein the base is an amine base selected from triethylamine, diisopropylethylamine, N-methylpiperidine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, imidazole, N-methylimidazole, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); 3.33. Any of methods 3.29-3.32, wherein the reaction is carried out using 1.0 to 5.0 equivalents of base, e.g., 1.0 to 4.0 equivalents or 1.0 to 3.0 equivalents or 1.0 to 2.0 equivalents or 1.5 to 4.0 equivalents or 1.5 to 3.0 equivalents or 1.5 to 2.5 equivalents or 1.5 to 2.0 equivalents or 2.0 to 4.0 equivalents or 2.0 to 3.0 equivalents; 3.34. The reaction is carried out with hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane), chlorinated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethylene), aromatics (e.g., benzene, toluene, xylene, pyridine), ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether), esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate), ketones (e.g., any of Methods 3 or 3.1-3.33, carried out in a solvent selected from polar aprotic solvents (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone), polar aprotic solvents (e.g., acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide), polar protic solvents (e.g., water, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, glycerol, formic acid, acetic acid, sulfuric acid), acetic anhydride, carbon dioxide (e.g., supercritical carbon dioxide) and carbon disulfide, or a combination thereof; 3.35. Method 3.34, wherein the solvent is acetic acid and / or acetic anhydride, and optionally the reaction further comprises an acetate salt (e.g., sodium or potassium acetate); 3.36. Any of Methods 3 or 3.1-3.35, wherein the reaction includes a polar protic solvent (e.g., water, alcohol, amine, or thiol) in any amount (e.g., as a solvent or in a catalytic amount, e.g., less than 0.5 molar equivalents); 3.37. Method 3.36, where the reaction involves water (e.g., an aqueous solvent mixture); 3.38. Method 3.37, where any water present in the reaction is provided by a reagent (e.g., aqueous hydrogen peroxide, aqueous sulfuric acid, etc.); 3.39. Any of Methods 3 or 3.1-3.35, wherein the reaction is non-aqueous (e.g., no water is present) and optionally at least one non-aqueous polar protic solvent (e.g., an alcohol, amine, or thiol) is present; 3.40. Any of Methods 3 or 3.1-3.35, wherein the reaction does not involve a polar protic solvent and / or the reaction is non-aqueous (e.g., water is not present); 3.41. Any of Methods 3 or 3.1-3.40, wherein the reaction is carried out using a combination of hydrogen peroxide, sulfuric acid, and acetic acid, optionally in an amount of 1.5 to 4 equivalents each (e.g., 2 to 3 equivalents each); 3.42. Any of Methods 3 or 3.1-3.40, wherein the reaction is carried out using a combination of peracetic acid (e.g., 2-4 equivalents or about 3 equivalents), trifluoromethanesulfonic acid (e.g., 0.1-2 equivalents or about 0.5 equivalents) and acetic acid (e.g., 2-3 equivalents or about 2.5 equivalents); 3.43. any of methods 3 or 3.1-3.42, wherein the reaction is carried out at a temperature between 0°C and 200°C, e.g., between 0°C and 150°C, or between 0°C and 100°C, or between 0°C and 75°C, or between 0°C and 50°C, or between 0°C and 25°C, or between 25°C and 200°C, or between 25°C and 150°C, or between 25°C and 100°C, or between 25°C and 75°C, or between 25°C and 50°C, or between 50°C and 200°C, or between 50°C and 150°C, or between 50°C and 100°C, or between 75°C and 200°C, or between 75°C and 150°C, or between 75°C and 100°C, or between 80°C and 150°C, or between 80°C and 100°C, or between 90°C and 150°C, or between 90°C and 125°C, or between 90°C and 110°C, or between 90°C and 100°C, or between 90°C and 95°C; 3.44. Any of methods 3 or 3.1-3.43, wherein R is H and reactant compound (2) or (7) proceeds to product compound (1) or (6) in a single vessel, and the reaction is carried out by treating compound (2) or (7) with a combination of hydrogen peroxide, sulfuric acid, and acetic acid, optionally in an amount of 1.5-4 equivalents each (e.g., 2-3 equivalents each or 2 equivalents each), at a temperature of 75° C.-150° C., or 80° C.-100° C., or 90° C.-95° C., or by treating with a combination of peracetic acid (e.g., 2-4 equivalents or about 3 equivalents), trifluoromethanesulfonic acid (e.g., 0.1-2 equivalents or about 0.5 equivalents), and acetic acid (e.g., 2-3 equivalents or about 2.5 equivalents), optionally at a temperature of 25° C.-50° C., or 25° C.-30° C.; 3.45. Any of Methods 3 or 3.1 through 3.44, wherein the method further comprises step (2) of treating compound (1) or (6) with a base to enrich in one or more isomers of compound (1) or (6) by isomerization; 3.46. Method 3.45, wherein the base is selected from sodium hydride, potassium hydride, hydroxide bases (e.g., sodium hydroxide, potassium hydroxide), alkoxide bases (e.g., sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide), carbonate bases (e.g., sodium carbonate, potassium carbonate, cesium carbonate), bicarbonate bases (e.g., sodium bicarbonate), amide bases (e.g., lithium amide, lithium 2,2,6,6-tetramethylpiperidide (LiTMP), lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide) (LiHMDS)), alkyl lithium bases (e.g., sec-butyl lithium, tert-butyl lithium), and amine bases (e.g., triethylamine, diisopropylethylamine, N-methylmorpholine, DBU, DBN, pyridine, dimethylaminopyridine, imidazole); 3.47. Method 3.46, wherein the base is an alkoxide base (e.g., sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide) or an amide base (e.g., lithium amide, lithium 2,2,6,6-tetramethylpiperidide (LiTMP), lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide) (LiHMDS)); 3.48. Method 3.47, wherein the base is sodium tert-butoxide or potassium tert-butoxide; 3.49. Any of Methods 3.45-3.48, wherein step (2) is carried out in a solvent selected from hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane), chlorinated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethylene), aromatics (e.g., benzene, toluene, xylene, pyridine), and ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether); 3.50. The process of 3.49, wherein step (2) is carried out in a hydrocarbon solvent, such as pentane, hexane, heptane, or cyclohexane; 3.51. Any of Methods 3.45 to 3.50, in which step (2) is carried out at a temperature of -78°C to 200°C, for example, -50°C to 150°C, -25°C to 100°C, 0°C to 75°C, 15°C to 50°C, 20°C to 30°C, -78°C to 0°C, -50°C to 0°C, -25°C to 25°C, 25°C to 75°C, 50°C to 100°C, 75°C to 150°C, 100°C to 150°C, 125°C to 200°C, or 150°C to 200°C; 3.52. Any of methods 3.41-3.51, wherein step (2) provides an enrichment of the amount of isomer (1a) or isomer (6a) of at least 10%, e.g., at least 15% or at least 20% or at least 25% of the total weight of compound (1) or (6); 3.53. Any of methods 3.45-3.52, wherein step (2) provides a product having a ratio of isomer (1a):isomer (1b) or isomer (6a):isomer (6b) of at least 90:10, e.g., at least 92:8, or at least 93:7, or at least 94:6, or at least 95:5; 3.54. Any of Methods 3 or 3.1-3.53, wherein the method further comprises crystallizing the product compound (1) or (6) from a hydrocarbon solvent (e.g., pentane, hexane, heptane, cyclohexane or mixtures thereof) at a temperature below 0° C., e.g., below 25° C., or below 15° C., or below 10° C., or below 5° C., or below 0° C., or below −5° C., or below −10° C., or below −20° C., or below −30° C., or below −40° C., or below −50° C., e.g., as low as −78° C.; 3.55. Method 3.54, wherein the recrystallization step provides a product having a ratio of isomer (1a):isomer (1b) or isomer (6a):isomer (6b) of at least 95:5, e.g., at least 97:3, or at least 98:2, or at least 99:1, or at least 99.5:0.5; 3.56. Any of processes 3.45-3.55, wherein the process includes an isomerization step (2) of product (1) or (6), followed by recrystallization; 3.57. Method 3.56, in which the isomerization step (2) and the recrystallization step are carried out as successive steps, such as isomerization followed by recrystallization after each recrystallization, until the desired purity of isomer (1a) or isomer (6a) is obtained; 3.58. The method further comprises converting compound (2') where R is H to compound (2) where R is not H (e.g., R is a protecting group): [ka] or compound (7') (wherein R is H) to compound (7) (wherein R is not H (e.g., R is a protecting group): [ka] any of methods 3 or 3.1 to 3.57, comprising a preliminary synthesis step (protection step) of 3.59. Method 3.58, wherein the protection step immediately precedes the step of treating compound (2) or (7) with an oxidizing agent, acid or base and a suitable aqueous solvent; 3.60. The process of 3.58 or 3.59, wherein the protection step is carried out by treating compound (2') or (7') with a suitable protecting agent in a suitable solvent, optionally with a suitable base; 3.61. The protecting agent is an acyl halide (e.g., acetyl chloride, benzoyl chloride, chloroacetyl chloride, dichloroacetyl chloride, trichloroacetyl chloride, methoxyacetyl chloride, phenoxyacetyl chloride, pivaloyl chloride, benzoyl chloride), an acyl anhydride (e.g., acetic anhydride, chloroacetic anhydride, dichloroacetic anhydride, trichloroacetic anhydride, trifluoroacetic anhydride, methoxyacetyl anhydride, phenoxyacetyl anhydride, pivaloyl anhydride, benzoyl anhydride), an alkyl halide (e.g., methoxymethyl chloride, methoxymethyl bromide, methoxyethyl chloride, methylthiomethyl iodide, benzyloxymethyl chloride, 4-methoxybenzyloxymethyl chloride, 2-methoxyethoxymethyl chloride, 2,2,2-trichloroethoxymethyl chloride, 2-trimethylsilylethoxymethyl chloride, 4-methoxybenzyl chloride, 4-methoxybenzyl bromide, 3,4-dimethoxybenzyl bromide), a silyl Method 3.60, where the reagent (e.g., chlorides, silanes or triflates of the group trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl, di-tert-butylmethylsilyl, tris(trimethylsilyl)silyl, tert-butylmethoxyphenylsilyl and tert-butoxydiphenylsilyl) or other protecting agents (e.g., formic acid, acetic acid, ethyl formate, methyl formate, chloroacetic acid, dihydropyran, 2-hydroxytetrahydropyran, ethyl vinyl ether, trimethylsilylethoxyethene, isobutylene, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, N,N-bis(trifluoromethanesulfonyl)aniline, benzenesulfonyl chloride, toluenesulfonyl chloride); 3.62. The process of 3.60 or 3.61, wherein the suitable base is selected from sodium hydride, potassium hydride, hydroxide bases (e.g., sodium hydroxide, potassium hydroxide), alkoxide bases (e.g., sodium tert-butoxide, potassium tert-butoxide), carbonate bases (e.g., sodium carbonate, potassium carbonate, cesium carbonate), bicarbonate bases (e.g., sodium bicarbonate) and amine bases (e.g., triethylamine, diisopropylethylamine, N-methylmorpholine, DBU, DBN, pyridine, dimethylaminopyridine, imidazole); 3.63. Suitable solvents include hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane), chlorinated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethylene), aromatics (e.g., benzene, toluene, xylene, pyridine), ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether), esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate), ketones (e.g., acetonitrile ... any of methods 3.60-3.62, wherein the solvent is selected from the group consisting of polar aprotic solvents (e.g., acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide), polar protic solvents (e.g., water, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, glycerol, formic acid, acetic acid), carbon dioxide (e.g., supercritical carbon dioxide) and carbon disulfide or a combination thereof, or the solvent is a neat reagent (e.g., pyridine); 3.64. Any of methods 3.60 to 3.63, wherein the protection step is carried out using 1.0 to 5.0 equivalents of protecting agent, e.g., 1.0 to 4.0 equivalents, or 1.0 to 3.0 equivalents, or 1.0 to 2.0 equivalents, or 1.0 to 1.50 equivalents, or 1.0 to 1.25 equivalents, or 1.0 to 1.15 equivalents, or 1.0 to 1.05 equivalents, or 1.5 to 2.0 equivalents, or 2.0 to 3.0 equivalents; 3.65. Any of methods 3.60 to 3.64, wherein the protection step is carried out at a temperature between -100°C and 200°C, e.g., between -50°C and 150°C, or between -100°C and 0°C, or between -100°C and -50°C, or between -50°C and 0°C, or between -25°C and 0°C, or between -25°C and 25°C, or between 0°C and 200°C, or between 0°C and 150°C, or between 0°C and 100°C, or between 0°C and 50°C, or between 0°C and 25°C, or between 25°C and 150°C, or between 25°C and 100°C, or between 50°C and 200°C, or between 50°C and 100°C, or between 75°C and 200°C, or between 100°C and 200°C, or between 150°C and 200°C; 3.66. The method converts intermediate compound (5') where R is not H (e.g., R is a protecting group) to intermediate compound (5'') where R is H: [ka] or converting intermediate compound (10') where R is not H (e.g., R is a protecting group) to intermediate compound (10'') where R is H: [ka] proceeding through a further intermediate step (D') in which the protecting group R is removed spontaneously during the process (i.e., no synthetic deprotection step D' is required), either Method 3 or 3.1-3.65; 3.67. Any of methods 3 or 3.1-3.66, wherein the method does not include any synthetic and / or mechanical steps other than treating compound (2) or compound (7) with an oxidizing agent, acid or base and a suitable solvent or solvents and optionally a protection step, one or more isomerization steps (2) and / or one or more crystallization steps; 3.68. Method 3, or any of 3.1-3.67, wherein the method does not include the use of any reagents or reactants other than Compound (2) or Compound (7) and the reagents depicted herein (e.g., acids, bases, oxidizing agents, catalysts, protecting agents, deprotecting agents, solvents), e.g., the method does not include the use of any carbon monoxide, carbonyl equivalents, or enzymes.

[0040] It will be appreciated that Method 3 is a more specific variant of Methods 1 and 2, since all three methods proceed from the same final starting materials to the same final products and may proceed via the same mechanical steps, but in Method 3 the procedure is simplified by carrying out all steps in a one-pot procedure.

[0041] As used herein, the term "one-pot" refers to a procedure in which all reaction components are present together (apart from the reagents added), no purification steps are performed between reaction steps (e.g., there is no aqueous workup, extraction, filtration, precipitation, chromatography or distillation or any other procedure that removes any components from the reaction mixture), and which may include one reaction step, two reaction steps, or more reaction steps. A one-pot procedure may involve adding all reagents at the beginning of the procedure and allowing the necessary mechanical steps to proceed to completion of the procedure (i.e., a one-reaction step procedure) or a one-pot procedure may involve adding one set of reagents initially and a different set of reagents later, such that it is expected that only some of the mechanical steps will occur after the first reagent is added and the remaining reaction steps will occur after the final reagent is added.

[0042] Thus, the term "one-pot" as used herein refers to the fact that multiple mechanical or reaction steps occur without purification, not necessarily involving only one reaction vessel, although that may be the case. For example, when a "one-pot" procedure involves two reaction steps, it may be necessary to include a second reaction vessel. Thus, in a two reaction step procedure, the reagents of the second reaction step may be added directly to the reaction mixture from the first reaction step. In such a case, only one reaction vessel is required. However, alternatively, the reaction mixture from the first reaction step may be added directly to the reagents of the second reaction step, which are necessarily initially in the second vessel. However, upon completion of this addition, the reaction also involves one vessel that holds all of the reagents, intermediates, reactants and products from all steps, and thus, this is still a "one-pot" procedure.

[0043] The product compounds (1a) and (6a) described herein may be commercially favorable due to their more favorable olfactory effects compared to the isomer compounds (1b) and (6b). Advantageously, method 1+, method 2+ and method 3+ provide improvements over the prior art in that the methods tend to provide an excess of isomers (1a) and (6a) (i.e., racemic products are not usually obtained). In some embodiments of the present invention, the preference for isomers (1a) and (6a) can be further enhanced by subjecting the initial product (1) or (6) to a base-catalyzed isomerization reaction, such as by treating the initial product (1) or (6) with sodium tert-butoxide in a hydrocarbon solvent or similar methods. This substantially increases the amount of isomers (1a) and (6a) produced by the present method.

[0044] In certain embodiments of the present invention, the preference for isomers (1a) and (6a) can be further enhanced by subjecting the initial product to a crystallization procedure that selectively crystallizes isomers (1a) and (6a). For example, initial product (1) or (6) can be crystallized from a hydrocarbon solvent at a temperature below 0° C. If desired, by carrying out method 1 or method 2 or method 3 with a base-catalyzed isomerization step and a crystallization step, product (1) or product (6) can be obtained having 99% or more of isomer (1a) or (6a), respectively.

[0045] In a fourth aspect, the present invention provides compound (1) prepared by any of Methods 1 or 1.1 et seq. or any of Methods 3 or 3.1 et seq. In certain embodiments, compound (1) is isomer (1a) or isomer (1b), or a mixture thereof. [ka] In certain embodiments, compound (1) is enriched in one isomer or the other, hi certain embodiments, the isomers are separated and purified.

[0046] In other embodiments of the fourth aspect, the invention provides compound (6), prepared by any of Methods 2 or 2.1 et seq., or any of Methods 3 or 3.1 et seq.. In certain embodiments, compound (6) is isomer (6a) or isomer (6b), or a mixture thereof. [ka] In some embodiments, compound (6) is enriched in one isomer or the other, hi some embodiments, the isomers are separated and purified.

[0047] In other embodiments of the fourth aspect, the invention provides any one or more of compounds of formula XIII, XIV, XV, XIIIa, XIIIb, XIVa, XIVb and / or XVa, prepared by any of methods 1 or 1.1 et seq., e.g., where the compound is isolated (e.g., separated by extraction, distillation or chromatography) from the product mixture of step (B).

[0048] In other embodiments of the fourth aspect, the invention provides any one or more of compounds of Formula XVI, XVII, XVIII, XVIa, XVIb, XVIIa, XVIIb and / or XVIIIa, prepared by any of Methods 2 or 2.1 et seq., e.g., where the compound is isolated (e.g., separated by extraction, distillation or chromatography) from the product mixture of step (B).

[0049] In a fifth aspect, the present invention provides a method of making a compound of formula XIII, XIV or XV (Method 4), comprising steps (A) and (B) as described in any of Methods 1 or 1.1-1.115, as applicable. In certain embodiments, the method is a method of making a compound of formula XIIIa, XIIIb, XIVa, XIVb and / or XVa.

[0050] In another embodiment of the fifth aspect, the invention provides a method of making a compound of formula XVI, XVII, XVIII (Method 5), comprising steps (A) and (B) as described in any of Methods 2 or 2.1-2.128, as applicable. In certain embodiments, the method is a method of making a compound of formula XVIa, XVIb, XVIIa, XVIIb, and / or XVIIIa.

[0051] In a sixth aspect, the present invention provides a composition comprising a compound of formula XIII, XIV or XV, XIIIa, XIIIb, XIVa, XIVb and / or XVa, or a composition comprising compound (1) produced by any of method 1 or 1.1 or later, or any of method 3 or 3.1 or later, or a composition comprising compound (6) produced by any of method 2 or 2.1 or later, or any of method 3 or 3.1 or later, wherein the compound provides flavor or fragrance to the composition. In some embodiments, the composition is a flavor or fragrance composition, for example, further comprising one or more additional flavor or fragrance agents or additives and at least one solvent or carrier. The composition can be a liquid or solid composition, for example, a soft or waxy solid. The composition can further comprise one or more additives, such as a polymer, a gelling agent, a powdery substrate, a surfactant, an emollient, a plasticizer, a humectant, a swelling agent, or an active agent (e.g., an oral care active or a pharmaceutical active agent) or any other cosmetically acceptable or orally acceptable additive. In certain embodiments, the compound or composition is used to provide a flavor or fragrance to a product, such as a consumer product.

[0052] Suitable solvents for the composition include water, methanol, ethanol, propanol, isopropanol, butanol, 3-methoxy-3-methyl-1-butanol, benzyl alcohol, ethyl carbitol (diethylene glycol monoethyl ether), dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, hexylene glycol, glycerin, ethylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, dipropylene glycol monomethyl ether, isoparaffin, paraffin, limonene, pinene, triethyl citrate, triacetin, benzyl benzoate, isopropyl myristate, triglycerides, liquid waxes, propylene glycol derivatives, ethylene glycol derivatives, other alcohols or ethers or any combination thereof.

[0053] The inventors have also surprisingly discovered that the very convenient one-pot, one or two reaction step procedure provided above for double bond epoxidation, epoxide rearrangement and aldehyde oxidation is a versatile method of converting double bonds to carboxylic acids without loss of a carbon atom (which distinguishes it from direct double ozonolysis or oxidative cleavage). The inventors have thus discovered that this procedure can be used to form a wide variety of carboxylic acids directly from alkenes without proceeding via an oxidative cleavage or hydrolysis reaction.

[0054] Thus, in a seventh aspect, the present invention thus provides a process (Process 7) for the preparation of a carboxylic acid compound (14) from an alkene compound (11), which process proceeds via intermediate compounds (12) and (13), which are optionally produced in situ and not isolated and purified: [ka] wherein the method comprises the mechanical steps of: (A) epoxidizing an alkene compound (21) to form an epoxide compound (22); (B) rearrangement of epoxide compound (22) to form aldehyde compound (23); and (C) oxidizing an aldehyde compound (23) to form a carboxylic acid compound (24); [Here, R a and R b each independently represents H, optionally substituted C 1-30 Alkyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(O)-OR c and -C(O)-R c Selected from R c is H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-10cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl. Optionally, the resulting carboxylic acid can be converted to a carboxylic acid ester or lactone (compound (25)) in a further reaction step carried out in the same one-pot procedure. For example, in certain embodiments, method 7 includes a further step (D) of esterification or lactonization of carboxylic acid compound (24) to form ester or lactone compound (25) as shown below: [ka] Here, R d is an optionally substituted C 1-12 Alkyl or R d and R a or R b are together a 5- to 10-membered heterocyclic ring or C 5-10 Forms a carbocyclic ring.

[0055] In a further embodiment of the seventh aspect, the present invention provides: 7.1. R a or R b is H, method 7; 7.2. R a and / or R b each independently optionally substituted C 1-30 Alkyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(O)-OR c and -C(O)-R c The method of method 7 or 7.1, selected from R a and / or R b each independently optionally substituted C 1-30 Alkyl, e.g., C 1-25 Alkyl or C 1-20 Alkyl or C 1-15 Alkyl or C 1-12 Alkyl or C1-10 Alkyl or C 1-6 Alkyl or C 1-3 alkyl, method 7.2; R a and R b are each independently an optionally substituted C 1-30 Alkyl, e.g., C 1-25 Alkyl or C 1-20 Alkyl or C 1-15 Alkyl or C 1-12 Alkyl or C 1-10 Alkyl or C 1-6 Alkyl or C 1-3 alkyl, method 7.3; R a and / or R b each independently optionally substituted C 3-10 Cycloalkyl, e.g., C 3-8 Cycloalkyl or C 3-6 Cycloalkyl or C 3-5 Cycloalkyl or C 3-4 Method 7.2 or 7.3, wherein the aryl group is cycloalkyl; R a and / or R b The process of 7.2, 7.3 or 7.5, wherein each independently is an optionally substituted heterocycloalkyl, e.g., a 5- or 6-membered heterocycloalkyl, e.g., azetidinyl, aziridinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, oxazepanyl, and the like; R a and / or R b The process of 7.2, 7.3, 7.5 or 7.6, wherein each independently is optionally substituted aryl (e.g., phenyl, naphthyl, phenanthryl, etc.); R a and / or R bis each independently an optionally substituted heteroaryl (e.g., pyridyl, pyrimidinyl, pyrazinyl, thiophenyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, quinolinyl, quinazolinyl, etc.); R a and / or R b each independently represents -C(O)-OR c or -C(O)-R c 7.2, 7.3, 7.5, 7.6, 7.7 or 7.8; 7.10. R c is H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-10 Method 7.9, wherein the aryl group is selected from cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl, as these terms are defined above in any of the embodiments 7.2 to 7.8; 7.11. Any of Methods 7 or 7.1-7.10, wherein the method does not include any synthetic and / or mechanical steps other than steps (A), (B) and (C) in preparing compound (21) to compound (24); 7.12. Any of Methods 7 or 7.1-7.11, wherein the method comprises two reaction steps, in a first reaction step compound (21) is treated with a first oxidizing agent in the presence of a suitable solvent (optionally an acid); and in a second reaction step the crude material from the first reaction step is treated with a second oxidizing agent in the presence of a suitable acid and optionally a suitable solvent, followed by isolating the product compound (24) from the second reaction mixture; and no purification step is performed between the two reaction steps (e.g., the reaction mixture from the first reaction step is added directly to the reagents of the second reaction step or the reagents of the second reaction step are added directly to the reaction mixture from the first reaction step); 7.13. Method 7.12, wherein the epoxidation step (A) and the rearrangement step (B) are carried out in a first reaction step and the oxidation step (C) is carried out in a second reaction step; 7.14. Any of Methods 7 or 7.1-7.11, wherein the method comprises one reaction step in which compound (21) is treated with an oxidizing agent in the presence of a suitable acid and optionally a suitable solvent; followed by isolation of the product compound (24) from the reaction mixture; 7.15. Method 7.14, wherein the epoxidation step (A) and the rearrangement step (B) are carried out in a first reaction step and the oxidation step (C) is carried out in a second reaction step; 7.16. Any of Methods 7.12-7.15, wherein the oxidant, the first oxidant and the second oxidant are each independently selected from hydrogen peroxide, osmium tetroxide, peracetic acid, perchloric acid, perbenzoic acid, meta-chloroperoxybenzoic acid (mCPBA), trifluoroperacetic acid, magnesium monoperoxyphthalate, dimethyldioxirane (DMDO), tert-butyl hydroperoxide, sodium hypochlorite, sodium tungstate, sodium periodate, iodosylbenzene, pentafluoroiodosylbenzene, cumene hydroperoxide, potassium persulfate, potassium peroxymonosulfate, pyridine N-oxide, 2,6-dichloropyridine N-oxide or oxygen (e.g., in combination with a transition metal catalyst, e.g., an iron catalyst), optionally in combination with any secondary reagent (e.g., a secondary oxidant, catalyst, complexing agent, directing agent, reducing agent or chiral auxiliary); 7.17. Method 7.16, wherein the oxidizing agent, the first oxidizing agent, or the second oxidizing agent is independently selected from hydrogen peroxide, peracetic acid, meta-chloroperoxybenzoic acid, tert-butyl hydroperoxide, or potassium peroxymonosulfate; 7.18. Method 7.16, wherein the oxidizing agent is hydrogen peroxide and sodium tungstate, e.g. hydrogen peroxide (e.g. 30 wt.%, e.g. 1-1.5 eq.) + sodium tungstate (e.g. sodium tungstate dihydrate, e.g. 0.01-0.10 eq.) with methyl-tri-n-octylammonium hydrogen sulfate (e.g. 0.01-0.05 eq.) and phenylphosphonic acid (e.g. 0.01-0.05 eq.), optionally in an aqueous solvent, optionally at 0-50°C; 7.19. The method 7.16, wherein the oxidizing agent is m-chloroperoxybenzoic acid; 7.20. The method 7.16, wherein the oxidant is oxygen gas; 7.21. The method 7.16, wherein the oxidant is oxygen gas and a transition metal catalyst; 7.22. The oxidizing agent is C 2-10 Method 7.16, oxygen gas and iron(III)-tetraphenylporphyrin complex (Fe(III)TPP) in the presence of an aliphatic aldehyde (e.g., isobutyraldehyde); 7.23. The method 7.16, wherein the oxidizing agent is oxygen gas and N-hydroxyphthalimide; 7.24. Any of methods 7.16 to 7.23, where the method does not involve the use of ozone; 7.25. Suitable solvents include, independently, hydrocarbons (e.g., pentane, hexane, heptane, cyclohexane), chlorinated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethylene), aromatics (e.g., benzene, toluene, xylene, pyridine), ethers (e.g., diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether), esters (e.g., methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, any of methods 7.16-7.24, wherein the solvent is selected from ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone), polar aprotic solvents (e.g., acetonitrile, dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide), polar protic solvents (e.g., water, methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, glycerol, formic acid, acetic acid, sulfuric acid), acetic anhydride, carbon dioxide (e.g., supercritical carbon dioxide), and carbon disulfide, or a combination thereof; 7.26. Any of methods 7.16-7.25, wherein the reaction comprises the use of 1.0 to 5.0 equivalents of oxidizing agent, e.g., 1.0 to 4.0 equivalents, or 1.0 to 3.0 equivalents, or 1.0 to 2.0 equivalents, or 1.0 to 1.50 equivalents, or 1.0 to 1.25 equivalents, or 1.0 to 1.15 equivalents, or 1.0 to 1.05 equivalents, or 1.5 to 2.0 equivalents, or 2.0 to 3.0 equivalents; and optionally 0.01 to 1.0 equivalent of any one or more additional reagents (e.g., secondary oxidizing agents or catalysts or ligands or other agents), e.g., 0.01 to 0.5 equivalents, 0.01 to 0.2 equivalents, or 0.01 to 0.1 or 0.01 to 0.05 equivalents; 7.27. Any of Methods 7.16-7.26, wherein the acid is a Bronsted acid selected from, for example, hydrochloric acid, perchloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, trifluoroacetic acid, and nitric acid, or a heteropolyacid (e.g., phosphotungstic acid); 7.28. Method 7.27, wherein the acid is selected from acetic acid, sulfuric acid, phosphoric acid, and nitric acid; 7.29. Any of Methods 7.27-7.28, wherein the reaction is carried out using 1.0 to 5.0 equivalents of acid, e.g., 1.0 to 4.0 equivalents or 1.0 to 3.0 equivalents or 1.0 to 2.0 equivalents or 1.5 to 4.0 equivalents or 1.5 to 3.0 equivalents or 1.5 to 2.5 equivalents or 1.5 to 2.0 equivalents or 2.0 to 4.0 equivalents or 2.0 to 3.0 equivalents; 7.30. Any of methods 7.16-7.29, wherein the reacting step or the first reacting step and / or the second reacting step is carried out in a batch reactor; 7.31. Any of methods 7.16-7.29, wherein the reacting step or the first reacting step and / or the second reacting step is carried out in a continuous flow reactor; 7.32. Any of methods 7.16-7.31, wherein the solvent is acetic acid and / or acetic anhydride, and optionally the reaction further comprises an acetate salt (e.g., sodium or potassium acetate); 7.33. Any of methods 7.16-7.31, wherein the reacting step or the first reacting step and / or the second reacting step is carried out using a combination of hydrogen peroxide, sulfuric acid, and acetic acid, optionally in an amount of 1.5 to 4 equivalents each (e.g., 2 to 3 equivalents each); 7.34. Any of Methods 7.16-7.31, wherein the reacting step or the first reacting step and / or the second reacting step is carried out using a combination of acetic acid, peracetic acid, and sulfuric acid, optionally in an amount of 1 to 3 equivalents each (e.g., 1 to 1.5 equivalents each); 7.35. Any of Methods 7.16-7.31, wherein the reacting step or the first reacting step and / or the second reacting step is carried out using a combination of hydrogen peroxide, acetic acid, peracetic acid and sulfuric acid, optionally with sodium acetate (e.g., 0.05-0.24 equivalents), each at 0.8-5 equivalents (e.g., 1-3 equivalents); 7.36. Any of Methods 7.16-7.31, wherein the reacting step or the first reacting step and / or the second reacting step is carried out using a combination of hydrogen peroxide, acetic anhydride, acetic acid and sulfuric acid, optionally in an amount of 0.8 to 5 equivalents each (e.g., 1 to 3 equivalents each), optionally further comprising a heptane co-solvent; 7.37. Any of Methods 7.16-7.31, wherein the reacting step or the first reacting step and / or the second reacting step is carried out using a combination of potassium peroxymonosulfate, potassium hydrogen sulfate and potassium sulfate (e.g., Oxone®) in an organic solvent (e.g., acetone / ethyl acetate), optionally 1-3 equivalents of potassium peroxymonosulfate (e.g., 1-2 equivalents); 7.38. any of methods 7.16-7.31, wherein the reaction step or the first reaction step and / or the second reaction step are independently carried out at a temperature between 0°C and 200°C, e.g., between 0°C and 150°C, or between 0°C and 100°C, or between 25°C and 200°C, or between 25°C and 150°C, or between 25°C and 100°C, or between 50°C and 200°C, or between 50°C and 150°C, or between 50°C and 100°C, or between 75°C and 200°C, or between 75°C and 150°C, or between 75°C and 100°C, or between 80°C and 150°C, or between 80°C and 100°C, or between 90°C and 150°C, or between 90°C and 125°C, or between 90°C and 110°C, or between 90°C and 100°C, or between 90°C and 95°C; 7.39. Any of Methods 7.16-7.31, wherein the reacting step or the first reacting step and / or the second reacting step are independently carried out at a temperature of 80°C to 90°C, 20°C to 70°C, 40°C to 90°C, 20°C to 50°C, or 20°C to 30°C; 7.40. Any of Methods 7 or 7.1 through 7.32, proceeding reactant compound (21) to product compound (24) in a single vessel; 7.41. Any of methods 7 or 7.1-7.40, wherein the method does not involve the use of any reagents or reactants other than compound (21) and the reagents set forth herein (e.g., acids, oxidizing agents, solvents), e.g., the method does not involve the use of any carbon monoxide, carbonyl equivalents, enzymes, ozone, or cyanide reagents; 7.42. The method may further comprise esterifying or lactonizing compound (24) to produce an ester or lactone compound (25), e.g., C 1-12 Any of Methods 7 or 7.1 through 7.41 comprising a step (D) of forming an alkyl ester or a monocyclic or bicyclic lactone, such as a methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, or isodecyl ester.

[0056] Method 7 is understood to be a generalization of the more specific methods 1, 2, and 3, in that compounds (5) and (10) are species of general compound (24) and compound (2), and (7) is a species of general compound (21), and while the different methods proceed through the same mechanical steps (A), (B), and (C), methods 1, 2, and 3 further require mechanical step (D). Method 7 includes the corresponding step (D) as an optional step, which is a step that can be performed on compounds (1) and (6). This leads to the corresponding, more general compound (25).

[0057] In an eighth aspect, the present invention provides compound (24) or compound (25), prepared by any of methods 7 or 7.1 to 7.42.

[0058] In a ninth aspect, the present invention provides a composition comprising compound (24) or compound (25) prepared by any of methods 7 or 7.1-7.42, wherein the compound provides a flavor or fragrance to the composition. The further embodiments described above for the sixth aspect also apply to this ninth aspect.

[0059] In a tenth aspect, the present invention provides a product or composition, e.g., an organoleptic composition, comprising compound (1) prepared by any of Methods 1 or 1.1 or later, or any of Methods 3 or 3.1 or later, or compound (6) prepared by any of Methods 2 or 2.1 or later, or any of Methods 3 or 3.1 or later, or compound (24) or compound (25) prepared by Methods 7 or any of Methods 7.1-7.42. In certain embodiments, compound (1) or compound (6) or compound (24) or compound (25) can be used alone as a fragrance or can be added to fragrance compositions and / or consumer products as an agent to improve the substantivity and / or retention of fragrance preparations and / or as a fixative.

[0060] Suitable solvents for such compositions may include alcohols such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, etc.; lower alkyl esters of lower carboxylic acids such as ethyl acetate; alkanenitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, anisole, etc.; aliphatic hydrocarbons such as pentane, hexane, heptane, octane, cyclohexane, cycloheptane, cyclooctane, etc.; and water. All these solvents can be used alone or in mixtures with each other. Water can also be used as a solvent during the reaction, with or without mixing with the above solvents.

[0061] The invention further provides the use of a compound of formula XIII, XIV or XV, XIIIa, XIIIb, XIVa, XIVb and / or XVa as a flavour or fragrance agent, for example to provide a flavour or fragrance to a composition or product.The invention further provides the use of compound (1) prepared by any of method 1 or 1.1 or later, or any of method 3 or 3.1 or later, or compound (6) prepared by any of method 2 or 2.1 or later, or any of method 3 or 3.1 or later, or compound (24) or compound (25) prepared by method 7 or any of methods 7.1 to 7.42, as a flavour or fragrance agent, for example to provide a flavour or fragrance to a composition or product.

[0062] As used herein, the term "aqueous solvent" refers to a solvent mixture having any amount of water, including trace amounts of water (e.g., when the solvent is miscible with water). The water for "aqueous solvent" may also be provided by an aqueous reagent (e.g., aqueous acid, e.g., sulfuric acid, or aqueous oxidizing agent, e.g., hydrogen peroxide). Without being bound by theory, it is believed that in certain embodiments, water (or other protic solvent) is only required in catalytic amounts for the process described herein to proceed, and thus significant amounts of water may not need to be used in the reaction. In certain embodiments, the reaction may proceed in an autocatalytic manner.

[0063] It will be understood that neither hydrogen peroxide nor peracetic acid (also known as peroxyacetic acid) are pure compounds, but are commonly available as solutions. Hydrogen peroxide is sold as an aqueous solution consisting essentially of 10-70% hydrogen peroxide and the remainder water, with small amounts of other components (e.g., <5% stabilizers or impurities). Peracetic acid is commercially produced by oxidizing dilute acetic acid with hydrogen peroxide. As a result, peracetic acid is commonly sold as a solution of 15% or 32% peracetic acid in an aqueous acetic acid carrier. The solution generally has a small amount of unreacted hydrogen peroxide and possibly stabilizers or other impurities.

[0064] As used herein, the term "fragrance composition" refers to a mixture of fragrance ingredients, optionally including auxiliary substances, dissolved in a suitable solvent or mixed with a powdered substrate to provide a desired odor to the product. Examples of products that may have a fragrance composition include, but are not limited to, perfumes, soaps, insect repellents and insecticides, surfactants, household cleaners, deodorants, air fresheners, pomanders, candles, cosmetics, lotions, pre- and after-shave lotions, talcum powders, hair care products, body deodorants, antiperspirants, and pet litter.

[0065] The term "flavor composition" as used herein means a mixture of flavor ingredients, optionally including auxiliary substances, dissolved in a suitable solvent or mixed with a powdered substrate to provide a desired flavor to the product. Examples of products having flavor compositions include, but are not limited to, dental hygiene products such as mouthwash, toothpaste, floss and breath sprays, orally administered medicines including liquids, tablets or capsules, and foods.

[0066] Fragrance and flavor ingredients and mixtures of fragrance and flavor ingredients which may be used in combination with a compound of formula XIII, XIV or XV, XIIIa, XIIIb, XIVa, XIVb and / or XVa or compound (1) or compound (6) or compound (24) or compound (25) for the preparation of fragrance and flavor compositions include, but are not limited to, natural products including extracts, animal products and essential oils, absolutes, resinous substances, resins and concretes, and synthetic fragrance materials and animal products including, but not limited to, alcohols, aldehydes, ketones, ethers, acids, esters, acetals, phenols, ethers, lactones, furan skeletons, nitriles, acids and hydrocarbons (including both saturated and unsaturated compounds and aliphatic carbocyclic and heterocyclic compounds).

[0067] As used herein, "optionally substituted" means that the indicated functional group is unsubstituted or substituted with one or more groups up to the maximum number allowed by valence principles, where the groups include halo, hydroxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, -O-Si(R x ) 3 , -OR x , -C(O)H, -C(O)-R x , -C(O)-OR x , -C(O)-NH-R x , -C(O)-N-(R x )(R x ), -OC(O)-R x , -NH(R x )-C(O)-R x , -N(R x )(R x )-C(O)-R x ),-NH(R x ), -N(R x )(R xaryl and heteroaryl; 1-6 Alkyl, C 3-6 Each of the cycloalkyl, aryl or heteroaryl is optionally selected from halo, hydroxy, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Haloalkyl, -O-Si(R x ) 3 , -OR x , -C(O)H, -C(O)-R x , -C(O)-OR x , -C(O)-NH-R x , -C(O)-N-(R x )(R x ), -OC(O)-R x , -NH(R x )-C(O)-R x , -N(R x )(R x )-C(O)-R x ),-NH(R x ), -N(R x )(R x ), further substituted with one or more of aryl and heteroaryl; and x are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Selected from cycloalkyl, aryl and heteroaryl. Aryl includes, but is not limited to, optionally substituted phenyl and optionally substituted naphthyl. Heteroaryl includes, but is not limited to, any optionally substituted furan, thiophene, pyrrole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyrimidine, pyridazine, pyrazine, indole, benzofuran, benzoxazole, benzisoxazole, benzothiazole, quinoline, isoquinoline, quinazoline and quinoxaline.

[0068] In method 1 and onwards and method 2 and onwards, the epoxidation step (A) may be carried out using any suitable set of reaction conditions known in the art. Epoxidation is often carried out using a strong oxidant such as mCPBA or a combination of oxygen and a catalyst or a combination of oxidants of various strengths. Commonly used reagents include one or more of hydrogen peroxide, osmium tetroxide, peracetic acid, perchloric acid, perbenzoic acid, meta-chloroperoxybenzoic acid, trifluoroperacetic acid, magnesium monoperoxyphthalate, dimethyldioxirane (DMDO), tert-butyl hydroperoxide, sodium hypochlorite, sodium tungstate or oxygen (e.g., in combination with a transition metal catalyst, e.g., an iron catalyst). In some embodiments, a transition metal doped silica or zeolite catalyst may be used with oxygen and a secondary oxidant, e.g., tert-butyl hydroperoxide, or a co-reagent, e.g., an aliphatic aldehyde. For example, epoxidation can be carried out using catalytic mesoporous SBA-16 silica modified with cobalt, titanium, nickel, iron or manganese according to the procedure of Madadi et al., Applied Cat. B: Environ. 260 (2020) 118049, with oxygen and C. 2-10 This can be carried out by reacting an alkene substrate in the presence of an aliphatic aldehyde (e.g., isobutyraldehyde). In one embodiment, oxygen or peroxides (e.g., hydrogen peroxide) can be reacted with an alkene substrate in the presence of an aliphatic aldehyde (e.g., isobutyraldehyde) via the C 2 O 4 reaction as described in Chinese Patent Publication CN1915983A ("Method for preparing epoxy compounds by oxidizing olefin or cycloolefin through bionic catalytic oxygen"). 2-10In combination with an aliphatic aldehyde (e.g., isobutyraldehyde) and a transition metal porphyrin complex (e.g., tetraphenylporphyrin), it may be used as an oxidizing agent. Other suitable transition metals include titanium, chromium, molybdenum, osmium, and cobalt, while other suitable oxidizing agents include iodosylbenzene, pentafluoroiodosylbenzene, mCPBA, sodium hypochlorite, tert-butyl hydroperoxide, cumene hydroperoxide, potassium persulfate, pyridine N-oxide, and 2,6-dichloropyridine N-oxide. See Amal Salmeen Basaleh, “The Kinetics and Mechanism of the Activation of Metalloporphyrin by Hydrogen Peroxide,” Dissertation (Univ. of Surrey, Guildford, UK, & King Abdulaziz Univ., Jedda, Saudi Arabia) (July 2013). A particularly effective epoxidation method uses hydrogen peroxide and catalytic sodium tungstate, and optionally various additives such as sodium sulfate, methyl-tri-n-octylammonium hydrogen sulfate, and / or phenylphosphonic acid (Noyori oxidation), as described by Hachiya et al., Syn. Lett. 19:2819-22 (2011). A simple mCPBA-mediated epoxidation of isopulegol is described by Zhao et al., Tet. Lett. 45(19):2713-16 (2004).

[0069] In certain embodiments where R is H, the hydroxy group can be used for directed (e.g., asymmetric) epoxidation under mild conditions. For example, epoxidation can be carried out using vanadyl acetylacetonate (VO(acac)) in the presence of tert-butyl hydroperoxide in benzene solvent (or toluene) as described in Gill et al., Chem. Commun. 1743-1744 (1996). 2) can be used. Guidotti et al., Chem. Commun. 1789-1790 (2000) similarly describe the epoxidation of isopulegol using mesoporous titanium MCM-41 complex and tert-butyl hydroperoxide. The use of the simple oxidation system oxone / acetone / sodium bicarbonate is reported by Ferraz et al., Tet. Lett. 41(26):5021-23 (2000).

[0070] In method 1 and onwards and method 2 and onwards, the rearrangement step (B) can be carried out using any suitable set of reaction conditions known in the art, such as the Meinwald rearrangement. In some embodiments, the rearrangement can be carried out thermally without the addition of a reagent. In some embodiments, the rearrangement can be catalyzed by an acid, such as a Bronsted acid, a Lewis acid, or a combination thereof. In some embodiments, the reaction can be catalyzed by a strong base, such as an alkyl lithium or lithium amide base (e.g., sec-butyl lithium, tert-butyl lithium or lithium 2,2,6,6-tetramethylpiperidide (LiTMP), lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide) (LiHMDS)). See, for example, Kumar & Jat, Adv. Synth. Catal., DOI 10.1002 / adsc.201900392 (2019) (disclosing the conversion of epoxides to aldehydes using 1.5 equivalents of LiTMP in THF at room temperature for 12 hours). In some embodiments, the reaction can be catalyzed by transition metal complexes (e.g., palladium, ruthenium, rhodium, chromium, iridium, manganese, iron or nickel catalysts or complexes). Kumar & Jat also describe palladium(0)-catalyzed epoxide rearrangements, such as using Pd(0)-tertiary phosphine complexes (e.g., palladium acetate and triphenylphosphine or tributylphosphine) in solvents such as benzene, toluene and tert-butanol, as well as rearrangements catalyzed by palladium hydride complexes and iridium hydride complexes. Kumar & Jat also describe regioselective and stereoselective rearrangements using transition metal tetraphenylporphyrin complexes, such as chromium(III) tetraphenylporphyrin triflate (e.g., in chlorinated solvents such as dichloroethane) as Lewis acids. Other transition metals such as iron, ruthenium, rhodium or manganese and modified porphyrin structures such as tetratolylporphyrin or tetra(2,4,6-trimethylphenyl)porphyrin complexes can also be used (eg, dichlororuthenium tetra(2,4,6-trimethylphenyl)porphyrin complex).Other methods disclosed in Kumar & Jat use dibromobis(triphenylphosphine)nickel complexes (e.g., in THF solvent at elevated temperature) or methylbis(4-bromo-1,6-di-tert-butylphenoxy)aluminum (e.g., in dichloromethane solvent at room temperature). Humbert et al., Chem. Comm. 50(73):10392-95 (2014) use palladium hydride, ruthenium hydride, zirconium hydride and iridium hydride catalysts, such as [(1,3-bis(di-isopropylphosphino)propane). 3 Pd 2 H 2 ]bistriflate, [(Ph 3 P) 3 RuH(Cl)] (optionally with a bisphosphine ligand, for example, sodium tetrakis-[(3,5 bis(trifluoromethyl)phenyl)borate]), Schwartz's reagent ([(cyclopentadienyl) 2 describes epoxide rearrangements catalyzed by iron(III) perchlorate tetraphenylporphyrin complexes (e.g., in dichloromethane solvent, 1% sulfuric acid in glacial acetic acid, p-toluenesulfonic acid, magnesium bromide diethyl etherate, zinc bromide, zinc chloride, iridium bromide, boron trifluoride, borane catalyzed rearrangements) or the unique cyclometallated iridium(III) hydride complexes disclosed in Humbert (Ir(III) complexed with 1,5-cyclooctadiene, tricyclohexylphosphine, and 8-methylquinoline). Additional methods for epoxide rearrangements are disclosed in Arata & Tanabe, Catal. Rev. Sci. Eng. 25(3):365-320 (1983) (e.g., thermal rearrangements, 1% sulfuric acid in glacial acetic acid, p-toluenesulfonic acid, magnesium bromide diethyl etherate, zinc bromide, zinc chloride, iridium bromide, boron trifluoride, borane catalyzed rearrangements). Takamani et al., Chem. Lett. 1031-32 (1996) describes the use of iron(III) perchlorate tetraphenylporphyrin complexes (e.g., in dichloromethane solvent). Another potential acid catalyst for this rearrangement is phosphotungstic acid (H2SO4), also described in Gusevskaya et al., Chem. Eur. J. 14:6166-72 (2008). 3 P.W. 12 O 40Stork et al., JACS 118(43):10660-61, describes a typical set of conditions for the epoxidation of exocyclic double bonds using mCPBA, followed by the rearrangement of the epoxide to an aldehyde catalyzed by boron trifluoride etherate complex. .

[0071] In a similar study, Jiang et al., Angew. Chem. 120:6740-44 (2008) described a combined method for in situ alkene epoxidation and epoxide to aldehyde rearrangement using ruthenium porphyrin complexes and a final oxidant such as air 2,3-dichloropyridine N-oxide. The intermediate epoxide is not isolated and the aldehyde is provided in good yield. Catalysts include dichlororuthenium tetra(2,4,6-trimethylphenyl)porphyrin, dichlororuthenium tetra(2,6-dichlorophenyl)porphyrin, dioxoruthenium tetra(2,4,6-trimethylphenyl)porphyrin, dioxoruthenium tetra(2,6-dichlorophenyl)porphyrin and dioxoruthenium tetramethyl-tetra(2,6-diphenylphenyl)porphyrin.

[0072] In method 1 onwards and method 2 onwards, the oxidation step (C) may be carried out using any suitable set of reaction conditions known in the art. Typically, the oxidation of the aldehyde to a carboxylic acid is carried out using a strong oxidizing agent, such as a chromium oxidizing agent (e.g., chromium trioxide, chromic acid, pyridinium chlorochromate, potassium dichromate, chromium trioxide-pyridine complex, pyridinium dichromate), osmium tetroxide, potassium permanganate, silver oxide, hydrogen peroxide, peracetic acid, perchloric acid, trifluoroperacetic acid, periodic acid, potassium periodate, sodium chlorite, oxygen and N-hydroxyphthalimide or potassium peroxymonosulfate. Jones's reagent (chromium trioxide in aqueous sulfuric acid) is a particularly effective oxidation system. Chinese patent application CN108315499A also discloses an environmentally friendly oxidation method using an oxygen atmosphere and an N-hydroxyimide catalyst, such as N-hydroxyphthalimide, N-hydroxymaleimide, N-hydroxysuccinimide, N-hydroxyglutarimide N-hydroxy-1,8-naphthalimide or N-hydroxy-benzenedicarboximide (e.g., 0.05-0.15 equivalents in a suitable solvent, such as acetonitrile), optionally in combination with a nitrite agent (e.g., methyl nitrite, ethyl nitrite, propyl nitrite, isopropyl nitrite, butyl nitrite, isoamyl nitrite, tert-butyl nitrite or benzyl nitrite).

[0073] Other suitable transition metal catalyst complexes are described in Piccirilli et al., Catalysts 20:773 (2020).

[0074] In methods 3 onwards and methods 7 onwards, it is contemplated that the methods may be carried out using any oxidizing agent capable of both epoxidation and aldehyde oxidation as described in the preceding paragraphs.

[0075] The oxidant potassium peroxymonosulfate (also known as "MPS", formula KHSO 5 is commonly sold under the trade names Oxone® and Caroat® and contains approximately 2 parts KHSO 5 , Part 1 KHSO 4and Part 1 K 2 SO 4 It is a three-salt mixture consisting of about 47-50% by weight of KHSO 5 It is further understood that the reactive oxygen species KHSO 5 is more stable in this mixture than in the pure form. EXAMPLES

[0076] NMR spectra are recorded using a 500 MHz NMR spectrometer. 1 H-NMR data are reported in δ units, parts per million (ppm) and are calculated using deuterochloroform (CDCl 3 ) is corrected for the signal due to residual chloroform (7.26 ppm). 13 C-NMR data is CDCl 3 The spectra are reported in ppm relative to (77.16 ppm) and are obtained with 1H decoupling. The following abbreviations or combinations thereof have been used to describe the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet, a = apparent.

[0077] GC analysis is performed on an Agilent 6890N gas chromatograph with a Restek-Stabilwax (crossbond Carbowax polyethylene glycol) 30 mm x 0.25 mm x 0.25 νm column (cat. #10623). Injection volume is 1 μL (splitless). Injection temperature is 250° C. Maximum oven temperature is 220° C. with an initial set point of 100° C. and a ramp rate of 20° C. / min. Carrier gas is helium. Flow rate is 1.8 mL / min. Pressure is 22.39 psi. A flame ionization detector at 220° C. is used.

[0078] HPLC is performed using an Agilent HPLC 1100 series and a UV detector.

[0079] Example 1: (1R,2R,5R)-5-methyl-2-(2-methyloxiran-2-yl)cyclohexan-1-ol [ka] In a 100 ml flask, add (-)-isopulegol ((1R,2S,5R)-5-methyl-2-(prop-1-en-2-yl)cyclohexan-1-ol) (10 g, 0.065 mol), sodium tungstate dihydrate (1.28 g, 0.06 equiv.), methyl-tri-n-octylammonium hydrogen sulfate (1.51 g, 0.003 mol, 0.05 equiv.) (Me(n-octyl) 3 NHSO 4 ) and phenylphosphonic acid (0.31 g, 0.0019 mol, 0.03 equiv.) (PhPO 3 H 2 Hydrogen peroxide (30% aqueous, 8.1 mL, 0.071 mol, 1.1 equiv.) is added dropwise over 0.5 h, and the reaction mixture is then stirred at room temperature overnight (20 h). The reaction mixture is diluted with MTBE (40 mL), washed with water, brine, and sodium 2 SO 4 Dry at rt and purify by silica gel flash chromatography (EtOAc / Hexanes: 20-40%) to give the product (9.5 g, 86.2%) as a 1:1 isomeric mixture ((1R,2R,5R)-5-methyl-2-((S)-2-methyloxiran-2-yl)cyclohexan-1-ol and (1R,2R,5R)-5-methyl-2-((R)-2-methyloxiran-2-yl)cyclohexan-1-ol).

[0080] Example 2: (3aS,6R,7aR)-3,6-Dimethylhexahydrobenzofuran-2(3H)-one [ka] To a solution of the product of Example 1 (2.0 g, 0.01118 mol) in toluene (6 ml) is added montmorillonite K10 (0.2 g). The mixture is heated at 75° C. for 30 min and then cooled in an ice-water bath. Acetone (3 ml) is added, followed by Jones reagent (3M chromium trioxide in aqueous sulfuric acid) slowly added over 10 min (3M, 4.7 ml, 0.0147 mol). The mixture is stirred at room temperature for 0.5 h, then quenched by the addition of 2 ml isopropanol and stirred at room temperature for a further 0.5 h. The mixture is then diluted with 15 ml EtOAc and the phases are separated. GC analysis indicates the formation of product in an isomer ratio of 68.6:14 and a crude conversion of 82.6% (net, both isomers). The organic layer is washed with water (2×10 ml), dried (Na 2 SO 4 ) and purify by silica gel flash chromatography (EtOAc / Hexanes: 0-5%) to obtain 0.5 g of product (25% yield) as a 83:17 ratio mixture of 2 isomers, (3S,3aS,6R,7aR)-3,6-dimethylhexahydrobenzofuran-2(3H)-one and (3R,3aS,6R,7aR)-3,6-dimethylhexahydrobenzofuran-2(3H)-one.

[0081] Example 3: H 2 SO 4 / H 2 O 2 / HOAc mediated 3,6-dimethylhexahydrobenzofuran-2(3H)-one [ka] In a 500 ml 4-neck flask equipped with a mechanical stirrer, place 15 ml (0.26 mol, 2 equiv.) of acetic acid and preheat the flask to 90 °C. Sulfuric acid (60% aqueous, 42 g, 0.26 mol, 2 equiv.) and hydrogen peroxide (30% aqueous, 44.2 g, 3 equiv.) are added through two separate dropping funnels. Simultaneously, isopulegol (20 g, 0.13 mol) is added with a syringe pump at a rate of 40 ml / h. The temperature is maintained at 90-95 °C during the addition process. The reaction mixture is further stirred at 95 °C for 2 h, then cooled with cold water and diluted with 100 ml of ice water. The mixture is extracted with EtOAc (3 × 50 ml). The combined EtOAc solution is washed with water (30 ml), saturated sodium carbonate (2 x 50 ml), 10% thiodiglycol solution (30 ml), brine (30 ml), then dried over sodium sulfate and concentrated to dryness under reduced pressure to give an oil. The oil is dissolved in 50 ml hexane and passed through a plug of silica gel (50 g, 40 mm column) and eluted with EtOAc / hexane (8%-12%). The eluent is concentrated to dryness to give the crude product (13.5 g, 62% yield). GC analysis shows a purity of 95.7% and an isomer ratio of 64.8% isomer (1a); 30.9% isomer (1b) (isomer (1a) appears at RT approximately 11.87; isomer (1b) appears at RT approximately 12.49).

[0082] Example 4: Isomerization of 3,6-dimethylhexahydrobenzofuran-2(3H)-one A crude mixture of 3,6-dimethylhexahydrobenzofuran-2(3H)-one with an isomer ratio of 65:34 isomer (1a):isomer (1b) obtained by a procedure similar to Example 3 is dissolved in 70 mL heptane and the mixture is refluxed in a Dean-Stark apparatus to remove water until about 50 mL of heptane is collected. The reaction mixture is then cooled to room temperature and sodium tert-butoxide (0.2 g) is added. The mixture is stirred at room temperature for 18 hours and then further sodium tert-butoxide (0.2 g) is added. The mixture is stirred for another 22 hours and then diluted with water (30 ml) and extracted with methyl tert-butyl ether (MTBE) (30 ml). The MTBE solution is washed with brine (20 ml), dried over sodium sulfate and concentrated to dryness to give 7.0 g oil. GC analysis indicates an isomer ratio of 93.6% isomer (1a):6.4% isomer (1b).

[0083] Example 5: Crystallization of 3,6-dimethylhexahydrobenzofuran-2(3H)-one A crude mixture of 3,6-dimethylhexahydrobenzofuran-2(3H)-one (52 g), containing 90.8% product of isomers (1a) and (1b) in a 94.8:5.2 ratio, is dissolved in 209 g n-hexane with stirring for 10 minutes. The mixture is then placed in a freezer at -10°C for 15 hours. The formation of a white crystalline product is observed. The crystals are separated by filtration and washed with 10 mL of cold n-hexane. The crystals are then transferred to a 50 mL round-bottom flask and heated neat in an oil bath at 50°C. The resulting liquid is dried under high vacuum (approximately 5 Torr) at 50°C for 2 hours with stirring. The liquid is then transferred to a flat surface where it is allowed to solidify. The solid is broken up to form flakes. 29 g of solid flakes are collected. GC analysis indicates the presence of the major isomer at 98.6% (1a).

[0084] Example 6: 3,6-Dimethylhexahydrobenzofuran-2(3H)-one via peracetic acid (one-pot procedure) To 2 g (0.013 mol) of isopulegol, 32% peracetic acid is added dropwise over 10 min at room temperature (approximately 3 ml, 0.039 mol, 3 eq. from a total of 9.3 g). An exothermic phenomenon is observed during the process. The reaction mixture is then stirred at ambient temperature for 1 h. A mixture of triflic acid in acetic acid (1 g TfOH, 0.5 eq.; 2 mL HOAc, 2.7 eq.) is added dropwise. The reaction mixture is stirred at ambient temperature for 2 h. GC analysis shows that the desired lactone is formed with a major isomer content of 48.0% and a minor isomer content of 24.8%. The total product yield by GC is 73%. The reaction can also be carried out by first combining peracetic acid, triflic acid and acetic acid.

[0085] Example 7: 3,6-Dimethylhexahydrobenzofuran-2(3H)-one via peracetic acid (alternative one-pot procedure) In a 500 ml 4-neck flask, place 15 mL of acetic acid (0.26 mol) and preheat the flask to 80 °C. Sulfuric acid (60% aqueous, 64 g, 0.26 mol) and 15% peracetic acid solution (63.6 g, 0.125 mol) (15% peracetic acid, 22% hydrogen peroxide, 16% acetic acid, 46% water; total active oxygen 13.7%) are added through two separate dropping funnels. Simultaneously, isopulegol (30 g, 0.195 mol) is added by syringe pump at a rate of 40 ml / h. The temperature is maintained at 80-85 °C during the addition process. The reaction mixture is further stirred at 80 °C for 1.5 h, then cooled with cold water and diluted with 60 ml of ice water. The mixture is extracted with hexane (3 × 60 ml). The combined hexane solution is diluted with water (30 ml), 20% NaHSO 3 (30 ml), saturated sodium carbonate (100 ml), and brine (30 ml), then the crude solution is passed through a plug of silica gel and eluted with EtOAc / Hexanes (8%-15%). The eluent is concentrated to dryness and dissolved in 80 ml of hexanes. The hexane solution is isomerized with sodium tert-butoxide (0.6 g) and crystallized as described in Examples 4 and 5 to give the product (7.8 g, 24%).

[0086] Example 8: 3,6-Dimethylhexahydrobenzofuran-2(3H)-one via peracetic acid (two-step procedure) Place isopulegol (100 g, 1.297 mol) and sodium acetate (8 g, 0.097 mol) in a 1 L 3-neck flask and cool the mixture in an ice-water bath. Add 32% peracetic acid solution (216 g, 0.908 mol) (32% peracetic acid, 40-50% acetic acid, <8% hydrogen peroxide, remaining water) dropwise over 40 min, then stir the reaction in the water bath for an additional 1 h at approximately 20 °C.

[0087] A 1-L 3-neck flask is charged with 60% sulfuric acid (140 ml) and preheated to 60° C. The mixture from the first reaction step is then added via syringe pump at 5 ml / min. Simultaneously, hydrogen peroxide (30% aqueous, 88 g) is added via syringe pump at 0.6 ml / min. The temperature is maintained at <62° C. during the addition. The reaction mixture is then stirred at 60° C. for an additional hour after hydrogen peroxide addition is complete. The reaction mixture is allowed to cool, diluted with water (100 ml), and extracted with heptane (200 ml, 2×150 ml). The combined heptane solution is diluted with water (100 ml), 10% Na 2 SO 3 , 2N NaOH (50 ml), brine (2×30 ml), then dried (Na 2 SO 4 ), which was distilled under reduced pressure to give the product (61.3 g, GC purity major isomer (1a) 60.1%, minor isomer (1b) 22.5%; GC yield 46%).

[0088] Example 9: 3,6-Dimethylhexahydrobenzofuran-2(3H)-one via hydrogen peroxide (two-step procedure) A 1 L 3-neck flask is charged with isopulegol (200 g, 1.297 mol) and sodium acetate (14 g, 0.169 mol). The flask is preheated to 40 °C, then hydrogen peroxide (30% aqueous, 206 g, 1.816 mol) and acetic anhydride (211 g, 2.08 mol) are added separately via syringe pump at 4 ml / min. During the addition, the temperature is controlled between 40-60 °C. After the addition is complete, the mixture is stirred at 45 °C for 1.5 h, then the reaction mixture is cooled to approximately 15 °C and additional hydrogen peroxide is added (30% aqueous, 206 g, 1.816 mol).

[0089] A 2L Silys reactor is charged with 100g acetic acid and 100ml sulfuric acid (60% aqueous, 3.24mol from 530g total) and the mixture is preheated to 75°C. The reaction mixture from the first reaction step and the remaining sulfuric acid are added separately through the dropping funnel over 85 minutes. The temperature is controlled at 80-88°C during the addition. The reaction mixture is stirred at 80°C for an additional 1.5 hours and then cooled to below 20°C. The reaction mixture is diluted with water (400ml) and extracted with heptane (500ml, 2x250ml). The combined heptane solution is washed with water and diluted with 20% NaHSO. 3 , 2N NaOH, brine, then dried (Na 2 SO 4 ), and the crude solution is passed through a plug of silica gel and eluted with EtOAc / Hexanes (8%-15%). The collected eluents are concentrated to dryness and dissolved in 650 ml of hexanes. To the hexane solution is added sodium tert-butoxide (5 g). The mixture is stirred overnight and then quenched by the addition of water (50 ml). The phases are separated and the organic layer is washed with 0.5 N NaOH, brine and dried (Na 2 SO 4 ). Recrystallize at -20°C as described in Example 5. Wash the resulting crystals with cold hexane to give the product (81 g, 37%).

[0090] Example 10: 3,6-Dimethylhexahydrobenzofuran-2(3H)-one via Hydrogen Peroxide (Two-step procedure using co-solvents) A 500 ml 3-neck flask is charged with isopulegol (50 g, 0.324 mol) and sodium acetate (1.25 g). The flask is preheated to 40 °C in a water bath, then hydrogen peroxide (30% aqueous, 95.2 g total to 50 ml, 0.843 mol) and acetic anhydride (52.9 g, 0.519 mol) are added separately from the dropping funnel over 40 min. The temperature is controlled between 40-60 °C during the addition. The reaction is stirred in the water bath for 1 h. The reaction mixture is then cooled to below 20 °C and the remaining hydrogen peroxide is added.

[0091] To a 1000 mL 3-neck flask, add 10 ml acetic acid and 10 ml sulfuric acid (60% aqueous, from 106 g total, 0.65 mol) and heptane (80 ml). The mixture is heated in a 90° C. heating bath and the reaction mixture from the first reaction step and the remaining sulfuric acid are added separately over 50 minutes. The reaction mixture is gently refluxed during the process. After the addition, the reaction mixture is stirred for an additional hour. The reaction mixture is then allowed to cool, diluted with water (100 ml), the phases are separated and the aqueous layer is extracted with heptane (2×50). The combined heptane solution is diluted with water, 20% NaHSO 3 , 2N NaOH, and brine, dried (Na 2 SO 4 ), then the crude solution is passed through a plug of silica gel and eluted with EtOAc / Hexanes (8%-15%). The eluent is concentrated to dryness. The crude product is dissolved in 250 ml of hexanes, isomerized using sodium tert-butoxide, and recrystallized from hexanes as described in Examples 4 and 5 to give the product (21.2 g, 39%).

[0092] Example 11: 3,6-Dimethylhexahydrobenzofuran-2(3H)-one via Oxone A 2 L 3-neck flask is charged with (-)-isopulegol (26.8 g, 0.174 mol), acetone (160 mL, 2.160 mol), and ethyl acetate (270 mL) and the mixture is vigorously stirred. Aqueous Oxone® (121.0 g, 0.398 mol; in 500 mL water) is added dropwise over 1 h while maintaining the temperature at 20-25 °C. The reaction mixture is then stirred for an additional 7 h. The organic layer is separated, the aqueous layer is extracted with ethyl acetate (300 mL), and the combined organic layers are washed with 20% (w / v) aqueous sodium chloride (250 mL), then with Na 2 SO 4 (50 g). The solution is evaporated to dryness to give a gummy oil (26.0 g, 89.65% crude yield). The crude gummy oil is dissolved in n-hexane (250 mL) and isomerized with sodium tert-butoxide (0.78 g) as described above to give the product (13.0 g, 33% yield; 69.50% isomer (1a) and 4.84% isomer (1b) by GC).

[0093] Example 12: 2-Methyl-hexanoic acid from 2-methyl-1-hexene (one-pot, two-step procedure) To a mixture of 2-methyl-1-hexene (7.1 g, 0.072 mol) and sodium acetate (0.6 g, 0.009 mol) is added hydrogen peroxide (30% aqueous, 11.5 g, 0.101 mol) and acetic anhydride (12.6 g, 0.123 mol) dropwise over 50 minutes via separate addition funnels at 40° C. The reaction is then stirred at room temperature overnight.

[0094] Sulfuric acid (60% aqueous, 12 g) is heated to 70° C. in a separate flask. The reaction mixture from the first step is then added slowly over 30 minutes, and the reaction is then refluxed for 1.5 hours and then cooled to 45° C. Further hydrogen peroxide (30% aqueous, 6.6 g, 0.058 mol) is added dropwise over 30 minutes and the reaction is stirred for 1.5 hours, then cooled, diluted with water (50 ml) and the phases separated. The organic layer is washed with water, 20% NaHSO 3 , washed with brine and dried (Na 2 SO 4 ), to obtain the crude product (4.2 g, GC purity 60%, GC yield 26%).

[0095] The examples provided herein are merely illustrative and are not intended to limit the various aspects and embodiments of the invention described herein.

Claims

1. A process for preparing a carboxylic acid compound (24) from an alkene compound (21) proceeds via intermediate compounds (22) and (23), which are optionally produced in situ and are not isolated or purified: 【Chemistry 1】 Next mechanical process: (A) epoxidizing an alkene compound (21) to form an epoxide compound (22); (B) rearranging the epoxide compound (22) to form the aldehyde compound (23); and (C) oxidizing the aldehyde compound (23) to form the carboxylic acid compound (24); [where R ａ and R ｂ each independently represents H, optionally substituted C １－３０ Alkyl, optionally substituted C ３－１０ cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C(O)—OR ｃ and -C(O)-R ｃ and R ｃ is H, optionally substituted C １－６ Alkyl, optionally substituted C ３－１０ is selected from cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl. Including; If desired, the carboxylic acid compound (24) may be further esterified or lactonized to give an ester or lactone compound (25): 【Chemistry 2】 [where R ｄ is an optionally substituted C １－１２ alkyl or R ｄ and R ａ or R ｂ are taken together to form a 5- to 10-membered heterocyclic ring or C ５－１０ It forms a carbocyclic ring. The method comprises the step (D) of forming

2. A method for producing compound (1) from compound (2) or compound (6) from compound (7), comprising the steps of: 【Transformation 3】 treating compound (2) or (7) with an oxidizing agent and optionally an acid or base in a suitable solvent (e.g., an aqueous solvent), wherein the reaction proceeds in a single vessel without isolating any intermediates (e.g., a one-pot reaction); wherein R is H or a protecting group (e.g., an ether, ester, or silyl group), and wherein R ａ is H, optionally substituted C １－６ Alkyl, optionally substituted C ２－６ alkenyl, optionally substituted C ２－６ alkynyl, optionally substituted aryl, O—R ｃ and -C(O)-R ｃ and R ｂ is H, optionally substituted C １－６ alkyl, optionally substituted aryl, O—R ｃ and -C(O)-R ｃ and R ｃ is H, optionally substituted C １－６ Alkyl, optionally substituted C ２－６ alkenyl, optionally substituted C ２－６ alkynyl and optionally substituted aryl.

10. The method of claim 1.

3. 1. A method for preparing 3,6-dimethylhexahydrobenzofuran-2-one (Compound 1), comprising: (A) epoxidizing isopulegol or a derivative thereof (compound 2) to form an epoxide compound (3); (B) rearranging the epoxide compound (3) to form the aldehyde compound (4); (C) oxidizing the aldehyde compound (4) to form the carboxylic acid compound (5); and (D) Ring closure of carboxylic acid compound (5) to form 3,6-dimethylhexahydrobenzofuran-2-one (compound 1): 【Chemistry 4】 wherein R is H or a protecting group (e.g., an ether protecting group, an ester protecting group, or a silyl ether protecting group).

2. The method of claim 1, comprising:

4. 3. The method of claim 2, wherein R is H.

5. R is an ester protecting group, e.g., —C(O)—R １ where R １ H, C １－６ alkyl (e.g., methyl or ethyl), haloC １－６ alkyl (e.g., chloromethyl or trifluoromethyl), C １－６ Alkoxy (e.g., methoxy or ethoxy), C １－６ 3. The method of claim 2, wherein the aryl group is alkoxymethyl (e.g., methoxyethyl or ethoxymethyl), aryl (e.g., phenyl), arylmethyl (e.g., benzyl), aryloxy (e.g., phenoxy), or aryloxymethyl (e.g., phenoxymethyl).

6. R is -C(O)-R １ where R １ The method of claim 5, wherein is methyl, ethyl, propyl, isopropyl, or tert-butyl.

7. R is -C(O)-R １ where R １ The method of claim 5 wherein is methyl.

8. Compound (3) is a mixture (3a), a compound (3b), or a mixture thereof: 【Transformation 5】 and / or Compound (4) is a mixture (4a), a compound (4b), or a mixture thereof: 【Transformation 6】 and / or Compound (5) is a mixture (5a), a compound (5b), or a mixture thereof: 【Transformation 7】 and / or Compound (1) is a mixture (1a), a compound (1b), or a mixture thereof: 【Transformation 8】 The method according to any one of claims 3 to 7,

9. 8. The method of any one of claims 3 to 7, wherein the method does not include any step using mint lactone (compound (VI) above) as an intermediate.

10. The method comprises reacting as an intermediate compound (IV), compound (V) or compound (VIII): 【Chemistry 9】 wherein X is Cl, Br or I. The method of any one of claims 3 to 7, which does not include any step of using

11. 8. The process of any one of claims 3 to 7, wherein the epoxidation step (A) proceeds by treating compound (2) with a suitable oxidizing agent in a suitable solvent, wherein the suitable oxidizing agent is one or more of hydrogen peroxide, osmium tetroxide, peracetic acid, perchloric acid, perbenzoic acid, meta-chloroperoxybenzoic acid (mCPBA), trifluoroperacetic acid, magnesium monoperoxyphthalate, dimethyldioxirane (DMDO), tert-butyl hydroperoxide, sodium hypochlorite, sodium tungstate, sodium periodate, iodosylbenzene, pentafluoroiodocylbenzene, cumene hydroperoxide, potassium persulfate, potassium peroxymonosulfate, pyridine N-oxide, 2,6-dichloropyridine N-oxide, or oxygen (e.g., in combination with a transition metal catalyst, e.g., an iron catalyst), optionally in combination with any secondary reagent (e.g., a secondary oxidizing agent, catalyst, complexing agent, directing agent, reducing agent, or chiral auxiliary).

12. The process of any one of claims 3 to 7, wherein the rearrangement step (B) is carried out by treating compound (3) with a suitable rearrangement catalyst in a suitable solvent or by heating compound (3) in a suitable solvent without a catalyst (i.e., thermal rearrangement), and the optional rearrangement catalyst is a Lewis acid, a Bronsted acid, a strong base (e.g., LDA, LiTMP, LiHMDS, t-butyllithium), or a transition metal catalyst or complex (e.g., a palladium, ruthenium, rhodium, chromium, iridium, zirconium, manganese, iron, or nickel catalyst or complex).

13. 13. The process of claim 12, wherein the rearrangement catalyst is a solid phase acidic resin (e.g., Amberlyst or Nafion-H or an acidic polymeric resin such as montmorillonite or zeolite), e.g., Montmorillonite K10 or Amberlyst H-15.

14. The process of any one of claims 3 to 7, wherein the oxidation step (C) is carried out by treating compound (4) with a suitable oxidizing agent in a suitable solvent, and optionally, in the oxidation step (C), the suitable oxidizing agent is one or more of a chromium oxidizing agent (e.g., chromium trioxide, chromic acid, pyridinium chlorochromate, potassium dichromate, chromium trioxide-pyridine complex, pyridinium dichromate), osmium tetroxide, potassium permanganate, silver oxide, hydrogen peroxide, peracetic acid, perchloric acid, trifluoroperacetic acid, periodic acid, potassium periodate, sodium chlorite, oxygen and N-hydroxyphthalimide, potassium persulfate, and potassium peroxymonosulfate.

15. 8. The process of any one of claims 3 to 7, wherein the ring closure step (D) occurs spontaneously during and / or after the oxidation step (C).

16. 8. The process of any of claims 3 to 7, wherein the ring-closure step (D) is carried out by heating the product mixture from step (C).

17. 4. The method of claim 3, wherein intermediates (3), (4), and (5) of steps (A), (B), (C), and (D) are not isolated, e.g., reactant compound (2) proceeds to product compound (1) in a single vessel.

18. 18. The process of claim 17, wherein the reaction comprises treating compound (2) with an oxidizing agent and an acid in a suitable solvent.

19. The oxidizing agent may be hydrogen peroxide, optionally in combination with any secondary reagent (e.g., secondary oxidizing agent, catalyst, complexing agent, directing agent, reducing agent, or chiral auxiliary), chromium oxidizing agents (e.g., chromium trioxide, chromic acid, pyridinium chlorochromate, potassium dichromate, chromium trioxide-pyridine complex, pyridinium dichromate), osmium tetroxide, potassium permanganate, peracetic acid, perchloric acid, perbenzoic acid, meta-chloroperoxybenzoic acid (mCPBA), trifluoroperacetic acid, periodic acid, magnesium monoperoxyphthalate, dimethyldioxirane (DMDO), tert-butyl hydroperoxide, sodium hypochlorite, sodium tungstate, sodium periodate, potassium periodate, iodosylbenzene, pentafluoroiodocylbenzene, cumene hydroperoxide, potassium persulfate, or the like.

19. The method of claim 18, wherein the acid is selected from one or more of sodium, potassium peroxymonosulfate, pyridine N-oxide, 2,6-dichloropyridine N-oxide, sodium chlorite, sodium hypochlorite, sodium chlorate, sodium perchlorate, or oxygen (e.g., in combination with a transition metal catalyst, e.g., an iron catalyst); the acid is a Bronsted acid selected from, for example, hydrochloric acid, perchloric acid, sulfuric acid, phosphoric acid, acetic acid, peracetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, trifluoroacetic acid, and nitric acid, or a heteropolyacid (e.g., phosphotungstic acid); and the reaction is carried out in a solvent selected from hydrocarbons, chlorinated hydrocarbons, aromatics, ethers, esters, ketones, polar aprotic solvents, polar protic solvents, carbon dioxide, acetic anhydride, carbon disulfide, or a combination thereof.

20. 20. The method of claim 19, wherein the oxidizing agent is hydrogen peroxide, peracetic acid, trifluoroperacetic acid, meta-chloroperoxybenzoic acid, tert-butyl hydroperoxide, or potassium peroxymonosulfate; the acid is selected from sulfuric acid, phosphoric acid, and nitric acid; and the solvent is acetic acid.

21. 8. The method of any one of claims 3 to 7, further comprising step (E) of treating compound (1) with a base, resulting in enrichment of compound (1a) by isomerization of compound (1b) to compound (1a).

22. 3. The method of claim 2, wherein the oxidizing agent is hydrogen peroxide, peracetic acid, trifluoroperacetic acid, meta-chloroperoxybenzoic acid, tert-butyl hydroperoxide, or potassium peroxymonosulfate; the acid is selected from sulfuric acid, phosphoric acid, trifluoromethanesulfonic acid, and nitric acid; and the solvent is acetic acid.

23. 1. A method for preparing an optionally 3,6-disubstituted hexahydrobenzofuran-2-one (compound 6): (A) optionally epoxidizing 5-substituted-2-vinylcyclohexanol or a derivative thereof (compound 7) to form epoxide compound (8); (B) rearranging the epoxide compound (8) to form the aldehyde compound (9); (C) oxidizing the aldehyde compound (9) to form the carboxylic acid compound (10); and (D) Ring-closing carboxylic acid compound (10) to form compound (6): 【Chemistry 10】 wherein R is H or a protecting group (e.g., an ether, ester, or silyl group), and R ａ is H, optionally substituted C １－６ Alkyl, optionally substituted C ２－６ alkenyl, optionally substituted C ２－６ alkynyl, optionally substituted aryl, O—R ｃ and -C(O)-R ｃ and R ｂ is H, optionally substituted C １－６ alkyl, optionally substituted aryl, O—R ｃ and -C(O)-R ｃ and R ｃ is H, optionally substituted C １－６ Alkyl, optionally substituted C ２－６ alkenyl, optionally substituted C ２－６ alkynyl and optionally substituted aryl. The method of claim 1, comprising the steps of:

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