SYNTHETIC METHODS FOR MAKING CARBOXYLIC ACIDS, ESTERS AND LACTONES

1 . A method of making a carboxylic acid compound (24) from an alkene compound (21), wherein the method proceeds through intermediate compounds (22) and (23), which optionally are generated in-situ and not isolated or purified:

wherein the method comprises the following mechanistic steps;

(A) epoxidizing alkene Compound (21), to form epoxide Compound (22);

(B) rearranging epoxide Compound (22) to form aldehyde Compound (23); and

(C) oxidizing aldehyde Compound (23) to form carboxylic acid Compound (24);

wherein R a and R b are each independently selected from 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 selected from H, optionally substituted C 1-6 alkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl;

wherein the method optionally further comprises a step (D) of esterification or lactonization of the carboxylic acid Compound (24) to form the ester or lactone Compound (25):

wherein R d is optionally substituted C 1-12 alkyl, or wherein R d and either R a or R b together form a 5-10-membered heterocyclic ring or a C 5-10 carbocyclic ring.

2 . The method according to claim 1 , which is a method of making a compound (1) from compound (2), or of making compound (6) from compound (7):

the method comprising the step of treating the compound (2) or (7) with an oxidizing agent, and optionally an acid or base, in a suitable solvent (e.g., aqueous solvent), wherein the reaction proceeds in a single vessel without the isolation of any intermediates (e.g., a one-pot reaction);

wherein R is H or a protecting group (e.g., an ether, an ester, or a silyl group), and wherein R a is selected from 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 selected from H, optionally substituted C 1-6 alkyl, optionally substituted aryl, O—R c , and —C(O)—R c , and R c is selected from H, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, and optionally substituted aryl.

3 . The method according to claim 1 , which is a method of making 3,6-dimethylhexahydrobenzofuran-2-one (Compound 1) comprising the steps of:

(A) epoxidizing isopulegol or a derivative thereof (Compound 2), to form epoxide Compound (3);

(B) rearranging epoxide Compound (3) to form aldehyde Compound (4);

(C) oxidizing aldehyde Compound (4) to form carboxylic acid Compound (5); and

(D) ring closing the carboxylic acid Compound (5) to form 3,6-dimethylhexahydrobenzofuran-2-one (Compound 1):

wherein R is H or a protecting group (e.g., an ether protecting group, an ester protecting group, or a silyl ether protecting group).

4 . The method according to claim 2 , wherein R is H.

5 . The method according to claim 2 , wherein R is an ester protecting group, e.g., —C(O)—R 1 , and wherein R 1 is 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 alkoxymethyl (e.g., methoxyethyl or ethoxymethyl), aryl (e.g., phenyl), arylmethyl (e.g., benzyl), aryloxy (e.g., phenoxy), or aryloxymethyl (e.g., phenoxymethyl).

6 . The method according to claim 5 , wherein R is —C(O)—R 1 , and wherein R 1 is methyl, ethyl, propyl, isopropyl, or tert-butyl.

7 . The method according to claim 5 , wherein R is —C(O)—R 1 , and wherein R 1 is methyl.

8 . The method according to claim 3 , wherein the Compound (3) is Compound (3a), Compound (3b) or a mixture thereof:

and/or

wherein the Compound (4) is Compound (4a), Compound (4b) or a mixture thereof:

and/or

wherein the Compound (5) is Compound (5a), Compound (5b) or a mixture thereof:

and/or

wherein the Compound (1) is Compound (1a), Compound (1b) or a mixture thereof:

9 . The method according to claim 3 , wherein the method does not comprise any step using mint lactone (compound (VI) hereinabove) as an intermediate.

10 . The method according to claim 3 , wherein the method does not comprise any step using compound (IV), compound (V), or compound (VIII), as an intermediate:

wherein X is Cl, Br, or I.

11 . The method according to claim 3 , wherein epoxidation step (A) is carried out by treating the compound (2) with a suitable oxidizing agent in a suitable solvent, optionally 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, dimethyl dioxirane (DMDO), tert-butyl hydroperoxide, sodium hypochlorite, sodium tungstate, sodium periodate, iodosyl benzene, pentafluoroiodosyl benzene, cumene hydroperoxide, potassium persulfate, potassium monoperoxysulfate, pyridine N-oxide, 2,6-dichloropyridine N-oxide, or oxygen (e.g., in combination with a transitional metal catalyst, e.g., an iron catalyst), optionally in combination with any secondary reagents (e.g., secondary oxidants, catalysts, complexing agents, directing agents, reducing agent, or chiral auxiliaries).

12 . The method according to claim 3 , wherein the rearrangement step (B) is carried out by treating the compound (3) with a suitable rearrangement catalyst in a suitable solvent, or by heating the compound (3) without catalyst in a suitable solvent (i.e., thermal rearrangement), optionally wherein the rearrangement catalyst is a Lewis acid, a Bronsted acid, a strong base (e.g., LDA, LiTMP, LiHMDS, t-butyl lithium), or a transition metal catalyst or complex (e.g., palladium, ruthenium, rhodium, chromium, iridium, zirconium, manganese, iron, or nickel catalyst or complex);

13 . The method according to claim 12 , wherein the rearrangement catalyst is a solid phase acidic resin (e.g., an acidic polymer resin such as Amberlyst or Nafion-H, or a Montmorillonite, or a Zeolite), e.g., Montmorillonite K10, or Amberlyst H-15.

14 . The method according to claim 3 , wherein oxidation step (C) is carried out by treating the compound (4) with a suitable oxidizing agent in a suitable solvent, optionally wherein in oxidation step (C) the suitable oxidizing agent is one or more of a chromium oxidant (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 with N-hydroxyphthalimide, potassium persulfate, and potassium monoperoxysulfate.

15 . The method according to claim 3 , wherein ring closure step (D) occurs spontaneously during and/or after oxidation step (C).

16 . The method according to claim 3 , wherein ring closure step (D) is carried out by heating the product mixture from step (C).

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

18 . The method according to claim 17 , wherein the reaction comprises the treatment of Compound (2) with an oxidizing agent, and an acid, in a suitable solvent.

19 . The method according to claim 18 , wherein the oxidizing agent is selected from one or more of hydrogen peroxide, a chromium oxidant (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 (mCPB A), trifluoroperacetic acid, periodic acid, magnesium monoperoxyphthalate, dimethyl dioxirane (DMDO), tert-butyl hydroperoxide, sodium hypochlorite, sodium tungstate, sodium periodate, potassium periodate, iodosyl benzene, pentafluoroiodosyl benzene, cumene hydroperoxide, potassium persulfate, potassium monoperoxysulfate, pyridine N-oxide, 2,6-dichloropyridine N-oxide, sodium chlorite, sodium hypochlorite, sodium chlorate, sodium perchlorate, or oxygen (e.g., in combination with a transitional metal catalyst, e.g., an iron catalyst), optionally in combination with any secondary reagents (e.g., secondary oxidants, catalysts, complexing agents, directing agents, reducing agent, or chiral auxiliaries); and wherein the acid is a Bronsted acid, e.g., selected from hydrochloric acid, perchloric acid, sulfuric acid, phosphoric acid, acetic acid, peracetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, trifluoroacetic acid, and nitric acid, or a heteropoly acid (e.g., phosphotungstic acid); and wherein 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 . The method according to claim 19 , wherein the oxidizing agent is hydrogen peroxide, peracetic acid, trifluoroperacetic acid, meta-chloroperoxybenzoic acid, tert-butyl hydroperoxide, or potassium monoperoxysulfate; and wherein the acid is selected from sulfuric acid, phosphoric acid, and nitric acid; and wherein the solvent is acetic acid.

21 . The method according to claim 3 , wherein the method further comprises a Step (E) of treating the Compound (1) with a base to cause enrichment of the Compound (1a) by isomerization of the Compound (1b) to the Compound (1a).

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

23 . The method according to claim 1 , which is a method of making an optionally 3,6-disubstituted hexahydrobenzofuran-2-one (Compound 6) comprising the steps of:

(A) epoxidizing an optionally 5-substituted-2-vinylcyclohexanol, or a derivative thereof (Compound 7), to form epoxide Compound (8);

(B) rearranging epoxide Compound (8) to form aldehyde Compound (9);

(C) oxidizing aldehyde Compound (9) to form carboxylic acid Compound (10); and

(D) ring closing the carboxylic acid Compound (10) to form the Compound (6):

wherein R is H or a protecting group (e.g., an ether, an ester, or a silyl group), and R a is selected from 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 selected from H, optionally substituted C 1-6 alkyl, optionally substituted aryl, O—R c , and —C(O)—R c , and R c is selected from H, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, and optionally substituted aryl.