1,3-cyclohexanedione derivatives and 1,3-cyclopentanedione derivatives as buffering molecules in non-aqueous solutions

Abstract

To provide compounds having buffering function in non-aqueous solutions.SOLUTION: Provided is use of a 1,3-dione compound represented by Formula I or Formula II (wherein R1 to R5 each represent a hydrogen atom or a substituent, and any two of R1 to R5 may form a ring) as a regulator of structural change of a compound caused by an acid or base in a non-aqueous solution containing an organic solvent.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to 1,3 - cyclohexanedione derivatives and 1,3 - cyclopentanedione derivatives having a buffering function in a non - aqueous solution, and the use of the buffering function of these molecules in a non - aqueous solution for controlling chemical events by adjusting conditions.

Background Art

[0002] In order to control chemical reactions in an aqueous solution or to maintain conditions suitable for the storage of biological samples such as enzyme - catalyzed reactions and enzymes and antibodies, the use of a buffer is a common means (Non - Patent Document 1).

[0003] However, in order to maintain conditions suitable for a chemical reaction, molecules having a buffering function in a non - aqueous solution have not generally been used. To remove a specific molecule in a non - aqueous solution to maintain desired conditions, scavengers have been used (Non - Patent Documents 2 and 3). However, general scavenger molecules do not have a buffering function, and it is not possible to remove a base using a scavenger that removes an acid, and vice versa.

Prior Art Documents

Non - Patent Documents

[0004]

Non - Patent Document 1

Non - Patent Document 2

Non-Patent Document 3

Summary of the Invention

[0005] The present invention relates to 1,3-cyclohexanedione derivatives or 1,3-cyclopentanedione derivatives having a buffering function in a non-aqueous solution. These may be conjugated to a solid support.

[0006] One aspect of the present invention is a method for buffering a non-aqueous solution comprising adding a buffering molecule to the non-aqueous solution, wherein the non-aqueous solution contains an organic solvent, the buffering molecule is a 1,3-cyclohexanedione derivative or a 1,3-cyclopentanedione derivative, and the buffering molecule may be conjugated to a solid support.

[0007] In certain embodiments, the 1,3-cyclohexanedione derivative has the structure represented by Formula I:

Chemical formula

[0008] In certain embodiments, the 1,3 - cyclopentanedione derivative has the structure represented by Formula II:

Chemical formula

[0009] In certain embodiments, the substituent is alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, or acyl, which may be substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, nitro, cyano, halogen, hydroxy, acyl, carboxyl, carboxamide, carboxylic acid ester, haloalkyl, haloalkoxy, aryl, heterocycloalkyl, and heteroaryl.

[0010] In certain embodiments, the buffering molecule is conjugated to a solid support. The solid support can be a particle, a container, or a device.

[0011] In certain embodiments, the organic solvent is selected from the group consisting of aliphatic compounds, aromatic compounds, alcohols, esters, ethers, ketones, nitriles, and halogenated hydrocarbons.

[0012] In certain embodiments, the method further includes storing a chemical compound in a non - aqueous solution. In such embodiments, an acid or a base may cause isomerization, racemization, or decomposition of the chemical compound, and the buffering molecule suppresses such isomerization, racemization, or decomposition.

[0013] In certain embodiments, the method further comprises adding at least one reactant to the non-aqueous solution and conducting a chemical reaction with the reactant. In such embodiments, the chemical reaction can produce a product different from the product of the reaction conducted without using a buffering molecule.

[0014] Another aspect of the present invention is a method for controlling the structural change of a compound in a non-aqueous solution, wherein the structural change of the compound can be caused by an acid or a base, and the method comprises preparing a non-aqueous solution containing the compound and a buffering molecule represented by Formula I or Formula II. The method includes a method for suppressing the structural change of a compound in a non-aqueous solution and a method for converting a compound into a product having another structure. The latter method includes converting a compound having another structure by reacting two or more molecules of the compound with each other or by reacting the compound with an organic solvent.

[0015] According to another aspect of the present invention, the non-aqueous solution is a 1,3-cyclohexanedione derivative or a 1,3-cyclopentanedione derivative and contains a buffering molecule which may be conjugated to a solid support. The non-aqueous solution may contain a compound whose structural change can be caused by an acid or a base.

[0016] Another aspect of the present invention is an article comprising a solid support and a buffering molecule conjugated to the solid support, wherein the buffering molecule is a 1,3-cyclohexanedione derivative or a 1,3-cyclopentanedione derivative.

Advantages of the Invention

[0017] To suppress decomposition, isomerization, and racemization, the cause (i.e., whether it is an acid or a base, or what kind of acid or base) should usually be understood, and the measures should be different according to the cause. When using this buffer molecule, it is not necessary to consider whether decomposition, isomerization, and / or racemization are caused by a base or an acid, or what kind of acid or base causes decomposition, isomerization, and / or racemization. For example, simply adding a buffer molecule or a buffer molecule conjugated to a solid support to the storage solution of the target molecule can suppress decomposition, isomerization, and / or racemization caused by either an acid or a base. Furthermore, simply adding a buffer molecule or a buffer molecule conjugated to a solid support to a chemical reaction mixture can also change the reaction product.

Brief Description of the Drawings

[0018]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Modes for Carrying Out the Invention

[0019] Certain embodiments of the present invention are described below. Although the embodiments of the present invention are described in this specification, the description is merely illustrative. Further modifications of the present invention disclosed in this specification will be conceived by those skilled in the art in each technical field, and all such modifications are considered to be within the scope of the present invention defined by the appended claims. The documents cited in this specification are incorporated herein by reference as supplementary references.

[0020] The following are the definitions of the terms used in this specification.

[0021] "Alkyl", by itself or as part of another substituent, refers to a saturated hydrocarbon group. "Alkyl" can be a straight-chain or branched-chain group having the number of carbon atoms specified, if any (i.e., C 1~8 means from 1 to 8 carbon atoms). "Cycloalkyl" is an alkyl group that is cyclic. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, and sec-butyl. Examples of cycloalkyl groups include cyclohexyl, cyclopentyl, (cyclohexyl)methyl, cyclopropylmethyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane. An alkyl group can be substituted or unsubstituted, unless otherwise indicated. Examples of substituted alkyls include haloalkyl, perhaloalkyl, thioalkyl, aminoalkyl. In some embodiments, alkyl can be intervened or linked by oxygen, sulfur, or nitrogen.

[0022] "Aryl" refers to an aromatic hydrocarbon group having a single ring (monocyclic) or multiple rings (such as bicyclic) that may be fused together or linked by covalent bonds. An aryl group having 6 to 10 carbon atoms is preferred, where the number of carbon atoms can be specified, for example, by C 6~10 . Examples of aryl groups include phenyl and naphthalen-1-yl, naphthalen-2-yl, biphenyl. An aryl group can be substituted or unsubstituted, unless otherwise indicated.

[0023] "Heterocycloalkyl" refers to a saturated or unsaturated non-aromatic ring containing at least one heteroatom (typically 1 to 5 heteroatoms) selected from nitrogen, oxygen, sulfur, or silicon. The heterocyclyl ring can be monocyclic or bicyclic. Preferably, these groups contain 0 to 5 nitrogen atoms, 0 to 2 sulfur atoms, and 0 to 2 oxygen atoms. More preferably, these groups contain 0 to 3 nitrogen atoms, 0 to 1 sulfur atom, and 0 to 1 oxygen atom. Examples of heterocycloalkyl groups include pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-dioxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, and the like.

[0024] "Heteroaryl" refers to an aromatic group containing at least one heteroatom, where the heteroaryl group can be monocyclic or bicyclic. Examples include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzofuranyl, benzothienyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, or thienyl.

[0025] One aspect of the present invention is a method for buffering a non-aqueous solution, which includes adding a buffering molecule to the non-aqueous solution, wherein the non-aqueous solution contains an organic solvent, the buffering molecule is a 1,3-cyclohexanedione derivative or a 1,3-cyclopentanedione derivative, and the buffering molecule may be conjugated to a solid support.

[0026] In certain embodiments, the 1,3-cyclohexanedione derivative has the structure represented by Formula I:

Chemical formula

[0027] In Formula I of such embodiments, R 1 ~R 5 may each independently be hydrogen or a substituent, and any two of R 1 ~R 5 may form a ring. The substituent may be conjugated to a solid support such as resin beads.

[0028] In certain embodiments, the 1,3-cyclopentanedione derivative has the structure represented by Formula II:

Chemical formula

[0029] In Formula II of such embodiments, R 1 ~R 3 may each independently be hydrogen or a substituent, and any two of R 1 ~R 3 may form a ring. The substituent may be conjugated to a solid support such as resin beads.

[0030] In certain embodiments, the substituent is alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, or acyl, which may be substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, nitro, cyano, halogen, hydroxy, acyl, carboxyl, carboxamide, carboxylic acid ester, haloalkyl, haloalkoxy, aryl, heterocycloalkyl, and heteroaryl. In some embodiments, the above substituents may be unsubstituted.

[0031] In particular, the substituents R 1 ~R 5 in formula I, and the substituents R 1 ~R 3 in formula II may each independently be C 1~18 alkyl, C 3~18 cycloalkyl, aryl, C 3~18 heterocycloalkyl, or heteroaryl, which may be substituted with one or more substituents selected from the group consisting of C 1~18 alkyl, C 2~18 alkenyl, C 2~18 alkynyl, C 1~18 alkoxy, nitro, cyano, halogen, hydroxy, carboxy, carboxamide, carboxylic acid ester, haloalkyl, halo-C 1~18 -alkoxy, aryl, C 3~18 -heterocycloalkyl, and / or heteroaryl.

[0032] In some embodiments, the alkyl may be C 1~5 alkyl, C 1~8 alkyl, or C 1~10 alkyl, the cycloalkyl may be C 3~6 cycloalkyl, C 3~8 cycloalkyl, or C 3~10 cycloalkyl, the heterocycloalkyl may be C 3~8 heterocycloalkyl, C 3~10 heterocycloalkyl, or C 3~12It may be a heterocycloalkyl, and aryl is C 6~8 aryl, C 6~10 aryl, or C 6~12 It may be aryl, and heteroaryl is C 5~8 heteroaryl, C 5~10 heteroaryl, or C 5~12 It may be heteroaryl.

[0033] Preferably, the buffer molecule is

Chemical formula

[0034] In certain embodiments, the buffer molecule is conjugated to a solid support.

[0035] When a solid support is linked to a 1,3 - cyclohexanedione derivative having a structure represented by formula I, the position where the solid support is linked can be any one of R 1 ~R 5 For example, the solid support is linked to R 1 as exemplified below:

[0036]

Chemical formula

[0037] When a solid support is linked to a 1,3 - cyclopentanedione derivative having a structure represented by formula II, the position where the solid support is linked can be any one of R 1 ~R 3 can be any one of them.

[0038] The linkage between the solid support and the buffer molecule can be a covalent bond. The solid support may be made of any suitable material known in the art. For example, the solid support may be made of a resin such as silicone resin, polystyrene resin, acrylic resin, etc.

[0039] The solid support may be linked directly or via a linker to the buffer molecule. The linker is R in formula I 1 ~R 5 Any one of, and R in the above formula II 1 ~R 3 May be connected to any one of. In certain embodiments, the substituent R in formula I 1 ~R 5 At least one of may be a linker. In certain embodiments, the substituent R in formula II 1 ~R 3 At least one of may be a linker. The linker can be any suitable linker known in the art. The linker may be as simple as a covalent bond (e.g., a carbon-carbon bond, a disulfide bond, a carbon-heteroatom bond, an ether, an amide, an ester, a bond formed by click chemistry (such as a C-C triple bond and an azide, etc.)), or the linker may be a polymeric linker (e.g., polyethylene, polyethylene glycol, polyamide, polyester, etc.) or a ring formed by click chemistry (such as a C-C triple bond and an azide, etc.), a Diels-Alder reaction, a hetero-Diels-Alder reaction, and a cascade reaction (such as an aldol-aldol reaction, an aldol-Michael reaction, an aldol-Henry reaction, and other reactions). For example, an alkenyl resin, an amine-functionalized resin, a benzhydrylamine (BHA) resin, a Br-functionalized resin, a chloromethyl resin, a CHO-functionalized resin, a Cl-functionalized resin, an F-functionalized resin, a CO2H-functionalized resin, etc. may be linked to the buffer molecule. In one embodiment, 4-benzyloxybenzaldehyde resin may be linked to the buffer molecule.

[0040] The solid support can be a particle, a container, or a device. In one embodiment, the buffering molecule may be conjugated to the inner wall of the container to which the non-aqueous solution is added. In another embodiment, the buffering molecule may be conjugated to a particle, and such particles may be suspended in the non-aqueous solution. Alternatively, the buffering molecule may be conjugated to the surface of the device used in the non-aqueous solution.

[0041] The solid support can be made in a conventional manner using conventional compounds. Also, the solid support can be obtained from commercial sources. The solid support can be conjugated to the buffering molecule by methods known in the art.

[0042] The organic solvent can be appropriately selected by those skilled in the art from any organic solvent known in the art according to the requirements and purposes. Suitably, the organic solvent is neither acidic nor basic. In certain embodiments, the organic solvent is selected from the group consisting of aliphatic compounds, aromatic compounds, alcohols, esters, ethers, ketones, nitriles, and halogenated hydrocarbons. For example, the organic solvent is selected from the group consisting of hexane, octane, cyclohexane, pentane, benzene, toluene, xylene, methanol, ethanol, propanol, butanol, 1,4-dioxane, tetrahydrofuran, butyl methyl ether, diethyl ether, dibutyl ether, acetone, 2-butanone, 3-pentanone, ethyl acetate, acetonitrile, dichloromethane, chloroform, monohalogenated benzene, dihalogenated benzene, trihalogenated benzene, and polyhalogenated benzene, trifluoromethylbenzene, 1,1,2,2-tetrachloroethane, CDCl3, toluene-d8, CD3CN, acetone-d6, THF-d8, CD3OD, furan, thiophene, and benzofuran. The non-aqueous solution can contain two or more organic solvents.

[0043] The non-aqueous solution may contain trace amounts of water as an impurity. In certain embodiments, the non-aqueous solution is water-free or substantially water-free. The non-aqueous solution may contain water molecules as co-products or intermediates of chemical reactions.

[0044] In certain embodiments, the method further comprises storing a chemical compound in a non-aqueous solution containing a buffering molecule. In such embodiments, an acid or a base may cause isomerization, racemization, or decomposition of the chemical compound, and the buffering molecule may suppress such isomerization, racemization, or decomposition. In this embodiment, even if the non-aqueous solution contains an acid or a base, preferably no more than 1%, more preferably no more than 0.5%, and most preferably 0% of the compound being stored is isomerized, racemized, or decomposed by the acid or the base. In a non-aqueous solution containing a buffering molecule, the progress of the decomposition, racemization, or isomerization of the chemical compound that occurs in the presence of an acid or a base and in the absence of a buffering molecule may be reduced to a maximum of 30%, a maximum of 20%, a maximum of 10%, a maximum of 5%, a maximum of 1%, a maximum of 0.5%, preferably 0%.

[0045] Using a buffering molecule, a chemical compound can be stored over a certain period of time without being isomerized, racemized, or decomposed by an acid or a base. Thus, a method of storing a chemical compound in a non-aqueous solution containing a buffering molecule can be implemented. The chemical compound to be stored can be added to the non-aqueous solution containing the buffering molecule.

[0046] To suppress the decomposition, isomerization, and racemization of a chemical compound by a buffering molecule, it is not necessary to consider whether the decomposition, isomerization, and / or racemization is caused by a base or an acid, or what types of acids or bases cause the decomposition, isomerization, and / or racemization.

[0047] The chemical compound to be stored can be any compound known in the art. For example, the chemical compound to be stored can be one from alcohols, aldols, aldehydes, ketones, esters, amides, N-protected aminoaldehydes, Mannich reaction products, N-protected amino acids, N-protected amino acid esters, N-protected peptides, N-protected amino acid derivatives, β-hydroxy-α-amino acid derivatives, and functionalized N-protected amino acid derivatives.

[0048] In one embodiment, the compound to be stored is an organic solvent. In this embodiment, the buffer molecule can suppress the isomerization, racemization, or decomposition of the solvent.

[0049] The chemical compound can be stored in a non-aqueous solution for any length of time. For example, the chemical compound can be stored for at least 10 minutes, 1 hour, 6 hours, 12 hours, 72 hours, or 1 month, or 1 year. The compound can be stored for several days, or several months, or several years, or several decades. The temperature at which the compound is stored can be appropriately selected by those skilled in the art according to requirements and purposes. For example, the temperature can be from minus 100 degrees Celsius (-100 °C) to 70 degrees Celsius (70 °C), for example, room temperature or a temperature higher than that, for example, 60 °C.

[0050] The chemical compound to be stored can be included in any appropriate amount in a non-aqueous solution or as a suspension. For example, the amount of the chemical compound to be stored can be 1.0×10 -6 M to 10 M, for example, 1.0×10 -6 M, 1.0×10 -5 M, 1.0×10 -4 M, 1.0×10 -3 M, 1.0×10 -2 M, 1.0×10 -1 M, 0.5 M, 1.0 M, 2.0 M, and 10 M.

[0051] Buffer molecules can have the function of suppressing the decomposition, isomerization, or racemization of stored chemical compounds for various acids and bases. The acid can be any organic acid or inorganic acid. The acid can cause the decomposition, isomerization, or racemization of a specific compound in an organic solvent. For example, the organic acid can be a carboxylic acid or a sulfonic acid, and the inorganic acid can be hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, or boric acid. In particular, the acid can be trifluoromethanesulfonic acid, CH3COOH, phosphoric acid, CH3SO3H, p-toluenesulfonic acid, or sulfuric acid. The base can be any organic base or inorganic base. The base can cause the isomerization, racemization, or decomposition of a specific compound in an organic solvent. For example, the base can be an alkoxide, an amine, an amidine, or a nitrogen-containing heterocyclic compound. In particular, the base can be 1,8-diazabicyclo[5.4.0]undec-7-ene, Et3N, i-Pr2NEt, quinidine, NaOMe, KO t Bu, or 1,1,3,3-tetramethylguanidine.

[0052] In certain embodiments, the method further includes adding at least one reactant to a non-aqueous solution and performing a chemical reaction (or chemical transformation) with the reactant. For example, two or more reactants can be added to the non-aqueous solution. In such embodiments, this chemical reaction can produce a product different from the product of the same reaction performed without using buffer molecules.

[0053] The chemical reaction carried out by this method can be appropriately selected by those skilled in the art from any chemical reaction carried out in an organic solvent. In some embodiments, the chemical reaction is carried out in the presence of an acid or a base. For example, the reaction is a reaction catalyzed by an acid or a reaction catalyzed by a base.

[0054] When the above chemical reaction is carried out, the non-aqueous solution may contain an acid or a base. The acid can be any organic acid or inorganic acid. For example, the organic acid can be a carboxylic acid or a sulfonic acid, and the inorganic acid can be hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, or boric acid. In particular, the acid can be trifluoromethanesulfonic acid, CH3COOH, phosphoric acid, CH3SO3H, p-toluenesulfonic acid, or sulfuric acid. The base can be any organic base or inorganic base. For example, the base can be an alkoxide, an amine, an amidine, or a nitrogen-containing heterocyclic compound. In particular, the base can be 1,8-diazabicyclo[5.4.0]undec-7-ene, Et3N, i-Pr2NEt, quinine, NaOMe, KO t Bu, or 1,1,3,3-tetramethylguanidine.

[0055] As shown in the examples, simply adding a buffering molecule to the reaction mixture can completely change the reaction pathway. Preferably, the buffering molecule does not react with the reactant(s) to form a reaction product(s) derived from the buffering molecule and the reactant(s). In other words, the buffering molecule does not form part of the reaction product. For example, the chemical reaction can be a protection reaction, a deprotection reaction, a bond-forming reaction (e.g., aldol reaction, Michael reaction, and Mannich reaction), an addition reaction, an elimination reaction, a substitution reaction, an organic redox reaction, or a rearrangement reaction. In the chemical composition, the acid or base can be included in any suitable amount.

[0056] The non-aqueous solution can contain buffer molecules in any suitable amount. For example, when the non-aqueous solution contains a chemical compound or reactant to be stored, the amount of buffer molecules can be at least 0.01 molar equivalent, 0.05 molar equivalent, 0.1 molar equivalent, 0.2 molar equivalent, 0.3 molar equivalent, 0.4 molar equivalent, 0.5 molar equivalent, 0.8 molar equivalent, 1.0 molar equivalent, 2.0 molar equivalents, or 3.0 molar equivalents relative to the chemical compound or the reactant. The amount of buffer molecules can be, for example, from 0.01 molar equivalent to 4.0 molar equivalents, from 0.1 molar equivalent to 3.0 molar equivalents, or from 0.5 molar equivalent to 2.0 molar equivalents. The buffer molecules can be added to the non-aqueous solution in a conventional manner using conventional equipment at room temperature and room pressure. When the reactant is subjected to a chemical reaction, an acid or a base can be included in any suitable amount. For example, the amount of acid or base can be from 0.01 molar equivalent to 5.0 molar equivalents relative to the reactant, for example, 0.05 molar equivalent, 0.1 molar equivalent, 0.2 molar equivalent, 0.3 molar equivalent, 0.4 molar equivalent, 0.5 molar equivalent, 0.8 molar equivalent, or 1.0 molar equivalent relative to the reactant.

[0057] According to another aspect of the present invention, the non-aqueous solution is an organic solvent and a buffer molecule which is a 1,3-cyclohexanedione derivative or a 1,3-cyclopentanedione derivative and which may be conjugated to a solid support. The organic solvent, buffer molecule, and solid support can be selected from those described above. Using this solution, the chemical compound therein can be stored as described above, or the chemical conversion therein can be controlled.

[0058] According to another aspect of the present invention, an article for buffering a non-aqueous solution includes a solid support and a buffer molecule which is a 1,3-cyclohexanedione derivative or a 1,3-cyclopentanedione derivative conjugated to the solid support. The buffer molecule and the solid support can be selected from those described above. Using this article, the chemical compound in the non-aqueous solution can be stored as described above, or the chemical conversion in the non-aqueous solution can be controlled.

[0059] Another aspect of the present invention is a 1,3 - cyclohexanedione derivative or a 1,3 - cyclopentanedione derivative that buffers a non - aqueous solution. The 1,3 - cyclohexanedione derivative or 1,3 - cyclopentanedione derivative can be selected from those described above.

Examples

[0060] The following examples are intended to illustrate the present invention and are not intended to limit the scope of the appended claims.

[0061] Materials and Methods for Examples 1 - 4 Synthesis of Substituted Cyclohexane - 1,3 - dione and Related Compound 1 Synthesis of Compound 1c Compound 1c was synthesized as previously reported by X. Wu, Z. Chen, Y.-B. Bai, V.M. Dong, Journal of the American Chemical Society (J. Am. Chem. Soc.) 2016, Vol. 138, p. 12013.

[0062] Synthesis of Compound 1d Compound 1d was synthesized as previously reported by C. Kong, N. Jana, C. Jones, T.G. Driver, Journal of the American Chemical Society (J. Am. Chem. Soc.) 2016, Vol. 138, p. 13271.

[0063] Synthesis of Compound 1f Compound 1f was synthesized by a modified method of the method previously reported by X. Wu, Z. Chen, Y.-B. Bai, V. M. Dong, Journal of the American Chemical Society (J. Am. Chem. Soc.) 2016, Vol. 138, p. 12013. To a solution of cyclohexane-1,3-dione (200 mg, 1.78 mmol) and NaOH (71.3 mg, 13 mmol) in H2O (20 mL), 2-iodopropane (267 μL, 2.67 mmol) was added at room temperature (25 °C), and the mixture was heated at 100 °C for 5 h. After cooling to room temperature, the resulting solid was collected by filtration. The solid was washed with H2O and hexane, dissolved in EtOAc-hexane, and purified by flash column chromatography (hexane / EtOAc = 3:1) to give compound 1f (189.8 mg, 69%) as a colorless solid.

[0064] Synthesis of Compound 1j Compound 1j was synthesized by a modified method of the method previously reported by X. Wu, Z. Chen, Y.-B. Bai, V. M. Dong, Journal of the American Chemical Society (J. Am. Chem. Soc.) 2016, Vol. 138, p. 12013. To a solution of cyclohexane-1,3-dione (200 mg, 1.78 mmol) and NaOH (71.3 mg, 13 mmol) in H2O (20 mL), iodocyclohexane (345 μL, 2.67 mmol) was added at room temperature (25 °C), and the mixture was heated at 100 °C for 5 h. After cooling to room temperature, the resulting solid was collected by filtration. The solid was washed with H2O and hexane, and purified by flash column chromatography (hexane / EtOAc = 2:1) to give compound 1j (183.6 mg, 53%) as a colorless solid.

[0065] Synthesis of Compound 1k To a solution of cyclohexane-1,3-dione (200 mg, 1.78 mmol) and triphenylchloromethane (497.6 mg, 1.78 mmol) in CH2Cl2 (10 mL), Et3N (373 μL, 2.67 mmol) was added at room temperature (25 °C), and the solution was stirred at the same temperature for 12 h. The mixture was washed with H2O, dried over Na2SO4, concentrated, and purified by flash column chromatography (hexane / EtOAc = 5:1) to afford compound 1k (391.6 mg, 62%) as a colorless solid.

[0066] Synthesis of 1b conjugated to resin [Chemical formula]

[0067] The method reported for the synthesis of 2-benzyl-1,3-cyclohexanedione from benzaldehyde and 1,3-cyclohexanedione was used (Y. Wu, I. Arenas, L. M. Broomfield, E. Martin, A. Shafir, Chem. Eur. J. 2015, Vol. 21, p. 18779). A mixture of 4-benzyloxybenzaldehyde resin (Chem-Impex International, Wang resin, a polystyrene resin cross-linked with divinylbenzene, 100 mesh - 200 mesh, 2.5 mmol / g - 3.0 mmol / g, 1.00 g), 1,3-cyclohexanedione (841 mg, 7.50 mmol), diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (Hünig's ester, 1.90 g, 7.50 mmol), and L-proline (57.6 mg, 0.50 mmol) in CH2Cl2 (40 mL) was stirred at 70 °C for 3 days. After cooling to room temperature, the mixture was filtered and the beads were washed sequentially with CH2Cl2, acetone, H2O, acetone, and CH2Cl2 (the beads were stirred in each washing solvent for at least 5 minutes and filtered). This washing cycle was repeated 8 times. For each cycle, the filtrate of the CH2Cl2 phase was collected, concentrated, 1 and analyzed by 1H NMR. In the 7th and 8th washing cycles, it was confirmed by NMR analysis that no compound was contained in the filtrate. The beads were dried under reduced pressure for 3 days to obtain compound 1b conjugated to the resin. To use compound 1b conjugated to this resin, the loading of 1,3-cyclohexanedione on the beads was estimated to be 2.0 mmol / g from the expected complete conversion (2.5 mmol / 1.24 g).

[0068] Evaluation of the effect of compound 1a on the isomerization from compound 2 to compound 3 (Tables 1 - 9 below) Item 1 in Table 1: Compound 2 (12.7 mg, 0.0286 mmol) was dissolved in CDCl3 (1.0 mL) in an NMR tube at room temperature (25 °C), and the solution was capped and held at the same temperature for 5 minutes. The solution was gently shaken, 1 and analyzed by 1H NMR to determine the ratio of Compound 2 to Compound 3.

[0069] The procedures for the other items in Table 1 and the items in Tables 2 - 9 were the same as those for Item 1 in Table 1, except for the modifications shown in the tables.

[0070] Evaluation of the effect of compounds in the isomerization from Compound 2 to Compound 3 (Figures 1 and 2) Procedures for the tests on DBU - catalyzed isomerization in Figures 1 and 2 To a mixture of Compound 2 (12.7 mg, 0.0286 mmol, 1.0 equiv) and the compound to be tested (0.0286 mmol, 1.0 equiv) in CDCl3 (1.0 mL) in an NMR tube, DBU (0.67 M in CDCl3, 0.43 μL, 2.9×10 -4 mmol, 0.01 equiv) was added at room temperature (25 °C), and the mixture was capped and held at the same temperature for 5 minutes. The mixture was gently shaken, 1 and analyzed by 1H NMR to determine the ratio of Compound 2 to Compound 3. When Compound 1a was used, the reaction mixture was a homogeneous and clear solution. Compound 1b was less soluble in CDCl3 than Compound 1a, and the reaction mixture with Compound 1b showed an insoluble precipitate (i.e., Compound 1b was partially soluble and partially precipitated in the reaction mixture). Depending on the compound to be tested, the reaction mixture was either a clear solution or showed an insoluble precipitate. NMR analysis was performed as described regardless of the solubility of the compound to be tested in the reaction mixture.

[0071] Procedures for the tests on TfOH - catalyzed isomerization in Figures 1 and 2 To a mixture of compound 2 (12.7 mg, 0.0286 mmol, 1.0 equiv) and the compound to be tested (0.0286 mmol, 1.0 equiv) in CDCl3 (1.0 mL) in an NMR tube, TfOH (1.1 M in CD3CN, 2.53 μL, 0.00286 mmol, 0.1 equiv) was added at room temperature (25 °C), and the mixture was capped and held at 60 °C for 1.0 h using an oil bath. After cooling to room temperature, the solution was gently shaken and 1 analyzed by 1H NMR to determine the ratio of compound 2 to compound 3. Depending on the compound to be tested, the reaction mixture was either a clear solution or showed an insoluble precipitate.

[0072] Evaluation of the effects of compound 1b and related compounds on the isomerization and decomposition of compound 4 (Scheme a in Figure 3) (a) Procedure for Scheme a(i) in Figure 3 Scheme a(i) in Figure 3 in the absence of a buffering molecule To a solution of compound (S)-4 (100% ee, 41.1 mg, 0.20 mmol, 1.0 equiv) in CD3CN (3.5 mL) in a glass vial, DBU (3.0 μL, 0.020 mmol, 0.1 equiv) was added at room temperature (25 °C), and the solution was capped and stirred at the same temperature. At each of the indicated time points, a portion of the solution was transferred to an NMR tube and 1 analyzed by 1H NMR. NMR analysis indicated the formation of compound 5, and the ratio of compound 4 to compound 5 was 1 determined by 1H NMR analysis. Immediately after the NMR analysis, the portion of the reaction mixture that had been analyzed by NMR was purified directly by preparative TLC (hexane / EtOAc = 1:1) to recover compound 4, which was analyzed by HPLC to determine the enantiomeric purity. HPLC (Daicel Chiralpak IC-3, hexane / 2-PrOH = 70:30, 0.5 mL / min, λ = 254 nm): t R (major enantiomer, (S)-4) = 38.3 min, t R (minor enantiomer, (R)-4) = 33.6 min.

[0073] Scheme a(i) in Figure 3 in the presence of compound 1b To a solution of compound (S)-4 (100% ee, 41.1 mg, 0.20 mmol, 1.0 equiv) and compound 1b (25.3 mg, 0.20 mmol, 1.0 equiv) in CD3CN (3.5 mL) in a glass vial, DBU (3.0 μL, 0.020 mmol, 0.1 equiv) was added at room temperature (25 °C), and the resulting solution was capped and stirred at the same temperature. At each of the indicated time points, a portion of the solution was transferred to an NMR tube and 1 analyzed by 1H NMR. NMR analysis showed that compound 4 remained unchanged and that the formation of compound 5 was not observed. Immediately after the NMR analysis, the portion of the reaction mixture that had been analyzed by NMR was purified directly by preparative TLC (hexane / EtOAc = 1:1) to recover compound 4, which was analyzed by HPLC to determine the enantiomeric purity. The HPLC conditions used were the same as those described in Scheme a(i) of Figure 3 in the absence of buffer molecules.

[0074] Scheme a(i) of Figure 3 in the presence of compound 1b conjugated to the resin To a solution of compound (S)-4 (100% ee, 41.1 mg, 0.20 mmol, 1.0 equiv) and 1b conjugated to the resin (2.0 mmol / g, 99.2 mg, 0.20 mmol, 1.0 equiv) in CD3CN (3.5 mL) in a glass vial, DBU (3.0 μL, 0.020 mmol, 0.1 equiv) was added at room temperature (25 °C), and the resulting solution was capped and stirred at the same temperature. At each of the indicated time points, a portion of the solution was transferred to an NMR tube and 1 analyzed by 1H NMR. NMR analysis showed that compound 4 remained unchanged and that the formation of compound 5 was not observed. Immediately after the NMR analysis, the portion of the reaction mixture that had been analyzed by NMR was purified directly by preparative TLC (hexane / EtOAc = 1:1) to recover compound 4, which was analyzed by HPLC to determine the enantiomeric purity. The HPLC conditions used were the same as those described in Scheme a(i) of Figure 3 in the absence of buffer molecules.

[0075] The procedures for the tests in Tables 10 to 13 were the same as those in the procedure of Figure 3, except that changes were made as shown in the tables.

[0076] (b) Procedure for the test in Scheme a(ii) of Figure 3 Scheme a(ii) of Figure 3 in the absence of buffer molecules To a solution of compound (S)-4 (100% ee, 41.1 mg, 0.20 mmol, 1.0 equiv) in CD3CN (3.5 mL) in a glass vial, TfOH (1.8 μL, 0.020 mmol, 0.1 equiv) was added at room temperature (25 °C), and the solution was capped and stirred at the same temperature. At the indicated reaction time (72 h), a portion of the solution was transferred to an NMR tube 1 and analyzed by 1H NMR. The formation of compound 6 was indicated by NMR analysis, and the ratio of compound 4 to compound 6 was 1 determined by 1H NMR analysis. Immediately after the NMR analysis, the portion of the reaction mixture that had been analyzed by NMR was purified directly by preparative TLC (hexane / EtOAc = 1:1) to recover compound 4, which was analyzed by HPLC to determine the enantiomeric purity. The HPLC conditions used were the same as those described in the procedure for Scheme a(i) of Figure 3. Also, compound 6 was isolated from the reaction mixture by flash column chromatography (hexane / EtOAc = 2:1), and its structure was confirmed.

[0077] Scheme a(ii) of Figure 3 in the presence of compound 1b To a solution of compound (S)-4 (100% ee, 41.1 mg, 0.20 mmol, 1.0 equiv) and compound 1b (25.3 mg, 0.20 mmol, 1.0 equiv) in CD3CN (3.5 mL) in a glass vial, TfOH (1.8 μL, 0.020 mmol, 0.1 equiv) was added at room temperature (25 °C), and the solution was capped and stirred at the same temperature. At the indicated reaction time (72 h), a portion of the solution was transferred to an NMR tube 1It was analyzed by \(^1\)H NMR. NMR analysis showed that Compound 4 was almost unchanged and the formation of Compound 6 was less than 1% of Compound 4. Immediately after the NMR analysis, a portion of the reaction mixture that had been analyzed by NMR was directly purified by preparative TLC (hexane / EtOAc = 1:1) to recover Compound 4, which was then analyzed by HPLC to determine the enantiomeric purity. The HPLC conditions used were the same as those described in the procedure for Scheme a(i) of Figure 3.

[0078] Scheme a(ii) of Figure 3 in the case where Compound 1b conjugated to the resin is present To a solution of Compound (S)-4 (100% ee, 41.1 mg, 0.20 mmol, 1.0 equiv) and Compound 1b conjugated to the resin (2.0 mmol / g, 99.2 mg, 0.20 mmol, 1.0 equiv) in CD3CN (3.5 mL) in a glass vial, TfOH (1.8 μL, 0.020 mmol, 0.1 equiv) was added at room temperature (25 °C), and the solution was capped and stirred at the same temperature. At the indicated reaction time point (72 h), a portion of the solution was transferred to an NMR tube, 1 It was analyzed by \(^1\)H NMR. NMR analysis showed that Compound 4 was almost unchanged and the formation of Compound 6 was less than 1% of Compound 4. Immediately after the NMR analysis, a portion of the reaction mixture that had been analyzed by NMR was directly purified by preparative TLC (hexane / EtOAc = 1:1) to recover Compound 4, which was then analyzed by HPLC to determine the enantiomeric purity. The HPLC conditions used were the same as those described in the procedure for Scheme a(i) of Figure 3.

[0079] Additional results for Scheme a(ii) of Figure 3 in CDCl3 To a mixture of Compound (S)-4 (100% ee, 5.9 mg, 0.028 mmol, 1.0 equiv) and Compound 1b (3.6 mg, 0.028 mmol, 1.0 equiv) in CDCl3 (0.5 mL) in a glass vial, TfOH (1.1 M in CD3CN, 2.5 μL, 2.8×10 -3(0.1 equivalent) was added at room temperature (25 °C), and the resulting mixture was stirred at the same temperature for 72 hours with the cap closed. Compound 1b was partially soluble and partially precipitated in the reaction mixture. A portion of the solution was transferred to an NMR tube and 1 analyzed by ¹H NMR. The ratio of compound 4 to compound 6 was 1 determined by ¹H NMR analysis to be 4:6 = 98:2, and the enantiomeric purity of compound 4 was determined to be 99.3% ee by HPLC analysis as described in the procedure for Scheme a(i) of Figure 3. In the same reaction but without the addition of compound 1b, the reaction mixture turned black after 1 hour, and 1 according to ¹H NMR analysis, this included the formation of a complex mixture.

[0080] Evaluation of the effect of compound 1b and related compounds on the isomerization and decomposition of compound 7 (Scheme b in Figure 3) (a) Procedure for Scheme b(i) in Figure 3 Scheme b(i) in Figure 3 in the absence of a buffering molecule To a solution of compound (R)-7 (100% ee, 20.0 mg, 0.0823 mmol, 1.0 equivalent) in CDCl₃ (0.5 mL) in a glass vial, DBU (1.3 μL, 0.0082 mmol, 0.1 equivalent) was added at room temperature (25 °C), and the solution was stirred at the same temperature with the cap closed. At the indicated reaction time (12 hours), a portion of the solution was transferred to an NMR tube and 1 analyzed by ¹H NMR. ¹H NMR analysis showed the formation of compound 8 and compound 9, and the ratio of compound 7 to compound 8 and compound 9 was 1 determined by ¹H NMR analysis. 1 ¹H NMR analysis also showed that the α-position of the ketone of 7 was partially deuterated. Immediately after the NMR analysis, the portion of the reaction mixture that had been NMR-analyzed was purified directly by preparative TLC (hexane / EtOAc = 5:1) to recover compound 7, which was analyzed by HPLC to determine the enantiomeric purity. HPLC (Daicel Chiralpak AS-H, hexane / 2-PrOH = 90:10, 0.5 mL / min, λ = 220 nm): t R(Main enantiomer, (R)-7) = 28.3 minutes, t R (Minor enantiomer, (S)-7) = 34.1 minutes. Also, compounds 8 and 9 were isolated from the reaction by flash column chromatography (hexane / EtOAc = 5:1) and their structures were confirmed.

[0081] Scheme b(i) of Figure 3 in the presence of compound 1b To a mixture of compound (R)-7 (100% ee, 20.0 mg, 0.0823 mmol, 1.0 equiv) and compound 1b (10.4 mg, 0.0823 mmol, 1.0 equiv) in CDCl3 (0.5 mL) in a glass vial, DBU (1.3 μL, 0.0082 mmol, 0.1 equiv) was added at room temperature (25 °C), and the resulting mixture was capped and stirred at the same temperature. Compound 1b was partially soluble and partially precipitated in the reaction mixture. At the indicated reaction time (12 h), a portion of the solution was transferred to an NMR tube and 1 analyzed by 1H NMR. NMR analysis showed that compound 7 remained unchanged. Immediately after the NMR analysis, the portion of the reaction mixture that had been NMR-analyzed was purified directly by preparative TLC (hexane / EtOAc = 5:1) to recover compound 7, and this was analyzed by HPLC to determine the enantiomeric purity.

[0082] Scheme b(i) of Figure 3 in the presence of compound 1k To a solution of compound (R)-7 (100% ee, 20.0 mg, 0.0823 mmol, 1.0 equiv) and compound 1k (29.2 mg, 0.0823 mmol, 1.0 equiv) in CDCl3 (0.5 mL) in a glass vial, DBU (1.3 μL, 0.0082 mmol, 0.1 equiv) was added at room temperature (25 °C), and the resulting mixture was capped and stirred at the same temperature. At the indicated reaction time (12 h), a portion of the solution was transferred to an NMR tube and 1Analysis was performed by \(^1H\) NMR. NMR analysis showed that Compound 7 remained unchanged. Immediately after the NMR analysis, a portion of the reaction mixture that had been analyzed by NMR was directly purified by preparative TLC (hexane / EtOAc = 5:1) to recover Compound 7, which was then analyzed by HPLC to determine the enantiomeric purity.

[0083] (b) Procedure for Scheme b(ii) in Figure 3 Scheme b(ii) in Figure 3 in the absence of a buffering molecule To a solution of Compound (R)-7 (100% ee, 20.0 mg, 0.0823 mmol, 1.0 equiv) in CDCl3 (0.5 mL) in a glass vial, TfOH (0.73 μL, 0.0082 mmol, 0.1 equiv) was added at room temperature (25 °C), and the solution was capped and stirred at the same temperature. At the indicated reaction time point (6 h), a portion of the solution was transferred to an NMR tube, 1 and analyzed by \(^1H\) NMR. NMR analysis showed the formation of Compound 8 and Compound 9, and the ratio of Compound 7 to Compound 8 and Compound 9 was 1 determined by \(^1H\) NMR analysis. Immediately after the NMR analysis, a portion of the reaction mixture that had been analyzed by NMR was directly purified by preparative TLC (hexane / EtOAc = 5:1) to recover Compound 7, which was then analyzed by HPLC to determine the enantiomeric purity. Also, Compound 9 was isolated from the reaction mixture and its structure was confirmed.

[0084] Scheme b(ii) in Figure 3 in the presence of Compound 1b To a mixture of Compound (R)-7 (100% ee, 20.0 mg, 0.0823 mmol, 1.0 equiv) and Compound 1b (10.4 mg, 0.0823 mmol, 1.0 equiv) in CDCl3 (0.5 mL) in a glass vial, TfOH (0.73 μL, 0.0082 mmol, 0.1 equiv) was added at room temperature (25 °C), and the resulting mixture was capped and stirred at the same temperature. Compound 1b was partially soluble and partially precipitated in the reaction mixture. At the indicated reaction time point (6 h), a portion of the solution was transferred to an NMR tube, 1Analysis was performed by \(^1H\) NMR. NMR analysis showed that compound 7 remained unchanged. Immediately after the NMR analysis, a portion of the reaction mixture that had been analyzed by NMR was directly purified by preparative TLC (hexane / EtOAc = 5:1) to recover compound 7, which was then analyzed by HPLC to determine the enantiomeric purity of compound 7.

[0085] Scheme b(ii) of Figure 3 in the presence of compound 1k To a solution of compound (R)-7 (100% ee, 20.0 mg, 0.0823 mmol, 1.0 equiv) and compound 1k (29.2 mg, 0.0823 mmol, 1.0 equiv) in CDCl3 (0.5 mL) in a glass vial, TfOH (0.73 μL, 0.0082 mmol, 0.1 equiv) was added at room temperature (25 °C), and the solution was capped and stirred at the same temperature. At the indicated reaction time (6 h), a portion of the solution was transferred to an NMR tube, 1 Analysis was performed by \(^1H\) NMR. NMR analysis showed that compound 7 remained unchanged. Immediately after the NMR analysis, a portion of the reaction mixture that had been analyzed by NMR was directly purified by preparative TLC (hexane / EtOAc = 5:1) to recover compound 7, which was then analyzed by HPLC to determine the enantiomeric purity of compound 7.

[0086] Evaluation of the effect of compound 1b on the isomerization of compound 10 (Scheme c of Figure 3) (a) Procedure for Scheme c of Figure 3 Scheme c of Figure 3 in the absence of a buffering molecule To a solution of compound (±)-10 / 11 (10:11 = 86:14, 23.9 mg, 0.0815 mmol, 1.0 equiv) in CDCl3 (1.0 mL) in a glass vial, DBU (1.2 μL, 0.0081 mmol, 0.1 equiv) was added at room temperature (25 °C), and the solution was capped and stirred at the same temperature. At the indicated reaction time (10 h), a portion of the solution was transferred to an NMR tube, 1 Analysis was performed by \(^1H\) NMR. NMR analysis showed that the ratio of 10 / 11 changed from the ratio before the addition of DBU, and the ratio of compound 10 to compound 11 was 1Determined by \(^1\)H NMR analysis.

[0087] Scheme c of Figure 3 in the presence of compound 1b To a mixture of compound (±)-10 / 11 (10:11 = 86:14, 23.9 mg, 0.0815 mmol, 1.0 equiv) and compound 1b (10.3 mg, 0.0815 mmol, 1.0 equiv) in CDCl3 (1.0 mL) in a glass vial, DBU (1.2 μL, 0.0081 mmol, 0.1 equiv) was added at room temperature (25 °C), and the resulting mixture was capped and stirred at the same temperature. Compound 1b was partially soluble and partially precipitated in the reaction mixture. At the indicated reaction time (10 h), a portion of the solution was transferred to an NMR tube and 1 analyzed by \(^1\)H NMR. NMR analysis showed that the ratio of 10 / 11 remained unchanged.

[0088] Evaluation of the effect of compound 1b on the isomerization and decomposition of compound 12 (Scheme d of Figure 3) (a) Procedure for Scheme d of Figure 3 Scheme d(i) of Figure 3 in the absence of a buffering molecule To a solution of L-threonine derivative 12 (100 mg, 0.29 mmol, 1.0 equiv) in CDCl3 (5.0 mL) in a glass vial, DBU (4.4 μL, 0.029 mmol, 0.1 equiv) was added at room temperature (25 °C), and the solution was capped and stirred at the same temperature for 1.0 h. A portion of the solution was transferred to an NMR tube and 1 analyzed by \(^1\)H NMR. NMR analysis showed the formation of compound 13, 1 and the ratio of 12 / 13 was determined to be 85:15 by \(^1\)H NMR analysis. Immediately after the NMR analysis, the solution was purified by flash chromatography (hexane / EtOAc = 3:1) to isolate compound 12 and compound 13. The recovered compound 12 was 1 analyzed by \(^1\)H NMR, and the purity of compound 12 exceeded 95%. 1 \(^1\)H NMR suggested that the impurity (less than 5% of compound 12) was a diastereomer of compound 12 (this impurity had the same R as compound 12f had a value). The presence of impurities was also indicated by HPLC analysis, which was probably a diastereomer of compound 12. HPLC (Daicel Chiralpak IC-3, hexane / 2-PrOH = 90:10, 0.5 mL / min, λ = 254 nm): t R (12) = 57.6 min, t R (impurity, probably a diastereomer of compound 12) = 53.9 min.

[0089] Scheme d(i) of Figure 3 in the presence of compound 1b To a mixture of L-threonine derivative 12 (100 mg, 0.29 mmol, 1.0 equiv) and compound 1b (36.8 mg, 0.29 mmol, 1.0 equiv) in CDCl3 (5.0 mL) in a glass vial, DBU (4.4 μL, 0.029 mmol, 0.1 equiv) was added at room temperature (25 °C), and the resulting mixture was capped and stirred at the same temperature for 1.0 h. Compound 1b was partially soluble and partially precipitated in the reaction mixture. A portion of the solution was transferred to an NMR tube and 1 analyzed by 1H NMR. NMR analysis showed that compound 12 remained unchanged. Immediately after the NMR analysis, the solution was purified by flash column chromatography (hexane / EtOAc = 3:1) to isolate compound 12. The recovered compound 12 was 1 analyzed by 1H NMR, and it was shown that the recovered compound 12 was pure and there was no sign of the presence of a diastereomer of compound 12 or other impurities together with the recovered compound 12. HPLC analysis also confirmed the purity of the recovered compound 12.

[0090] Scheme d(ii) of Figure 3 in the absence of a buffering molecule To a solution of L-threonine derivative 12 (100 mg, 0.29 mmol, 1.0 equiv) in CDCl3 (5.0 mL) in a glass vial, TfOH (2.6 μL, 0.029 mmol, 0.1 equiv) was added at room temperature (25 °C), and the solution was capped and stirred at the same temperature for 12 h. A portion of the solution was transferred to an NMR tube and 1It was analyzed by \(^1\)H NMR. The formation of benzyl alcohol was shown by NMR analysis, and the ratio of compound 12 / benzyl alcohol was 1 determined by \(^1\)H NMR analysis. Immediately after the NMR analysis, the solution was purified by flash chromatography (hexane / EtOAc = 3:1) to isolate compound 12 and benzyl alcohol. The structure of the isolated benzyl alcohol was 1 confirmed by \(^1\)H NMR analysis and 13 \(^{13}\)C NMR analysis. When the recovered compound 12 was 1 analyzed by \(^1\)H NMR, it was confirmed that there was no sign of the existence of diastereomers of compound 12.

[0091] Scheme d(ii) of Figure 3 in the case where compound 1b is present To a mixture of L-threonine derivative 12 (100 mg, 0.29 mmol, 1.0 equiv) and compound 1b (36.8 mg, 0.29 mmol, 1.0 equiv) in CDCl\(_3\) (5.0 mL) in a glass vial, TfOH (2.6 μL, 0.029 mmol, 0.1 equiv) was added at room temperature (25 °C), and the resulting mixture was capped and stirred at the same temperature for 12 h. Compound 1b was partially soluble and partially precipitated in the reaction mixture. A portion of the solution was transferred to an NMR tube and 1 analyzed by \(^1\)H NMR. NMR analysis showed that compound 12 was unchanged (formation of benzyl alcohol was not detected). After the NMR analysis, the solution was purified by flash column chromatography (hexane / EtOAc = 3:1) to isolate compound 12. The recovered compound 12 was 1 analyzed by \(^1\)H NMR and HPLC to confirm its purity.

[0092] Chemical transformation: Evaluation of the effect of compound 1b in the protection of hydroxy groups (Figure 4) (a) Procedure for the scheme in Figure 4 Reaction of compound 14 in Figure 4 in the absence of a buffering molecule A solution of (±)-14 (74.2 mg, 0.286 mmol, 1.0 equiv) and TMSCN (trimethylsilyl cyanide) (53.8 μL, 0.43 mmol, 1.5 equiv) in CHCl3 (1.0 mL) was added with DBU (4.3 μL, 0.029 mmol, 0.1 equiv) at room temperature (25 °C), and the resulting mixture was stirred at 60 °C for 1 h. After cooling to room temperature, the reaction mixture was purified by flash column chromatography (hexane / EtOAc = 5:1) to give compound 15 (27.6 mg, 29%), compound 16 (35.7 mg, 29%, as a mixture of diastereomers, dr ≈ 10:1 by TLC analysis), and compound 17 (34.9 mg, 34%). The major diastereomer of compound 16 was further purified by flash column chromatography (hexane / EtOAc = 5:1).

[0093] Reaction of compound 14 in Figure 4 in the presence of compound 1b A solution of (R)-14 (74.3 mg, 0.286 mmol, 1.0 equiv), TMSCN (53.8 μL, 0.43 mmol, 1.5 equiv), and compound 1b (36.2 mg, 0.286 mmol, 1.0 equiv) in CHCl3 (1.0 mL) was added with DBU (4.3 μL, 0.029 mmol, 0.1 equiv) at room temperature (25 °C), and the resulting mixture was stirred at 60 °C for 1.5 h. After cooling to room temperature, the reaction mixture was purified by flash column chromatography (hexane / EtOAc = 5:1) to give compound 15 (91.2 mg, 96%, 100% ee).

[0094] Chemical transformation: Evaluation of the effect of compound 1b in the addition reactions of furan and thiophene (Figure 5) (a) Procedure for the scheme in Figure 5 Reaction of compound 18 with furan in CDCl3 for Scheme a in Figure 5 in the absence of a buffering molecule To a solution of compound 18 (100 mg, 0.286 mmol, 1.0 equiv) and furan (62.5 μL, 0.860 mmol, 3.0 equiv) in CDCl3 (1.0 mL), TfOH (2.5 μL, 0.029 mmol, 0.1 equiv) was added at room temperature (25 °C), and the mixture was stirred at 60 °C for 1.0 h. After cooling to room temperature, the reaction mixture was 1 Analyzed by 1H NMR, the formation of compound 19 was indicated (100% NMR yield).

[0095] Reaction of compound 18 with furan under neat conditions of Scheme a in Figure 5 in the absence of a buffering molecule To a solution of compound 18 (100 mg, 0.286 mmol, 1.0 equiv) in furan (1.0 mL, 13.7 mmol, 48 equiv), TfOH (2.5 μL, 0.029 mmol, 0.1 equiv) was added at room temperature (25 °C), and the mixture was stirred at 60 °C for 1.0 h. TLC analysis of the reaction mixture indicated the formation of more than seven products different from compound 20 or compound 21.

[0096] Reaction of 18 with furan of Scheme a in Figure 5 in the presence of compound 1b To a solution of compound 18 (100 mg, 0.286 mmol, 1.0 equiv) and compound 1b (36.2 mg, 0.286 mmol, 1.0 equiv) in furan (1.0 mL, 13.7 mmol, 48 equiv), TfOH (2.5 μL, 0.029 mmol, 0.1 equiv) was added at room temperature (25 °C), and the mixture was stirred at 60 °C for 1.0 h. After cooling to room temperature, 1 The ratio of 20 / 21 was determined by 1H NMR analysis, and the reaction mixture was purified by flash column chromatography (hexane / EtOAc = 5:1) to obtain compounds 20 and 21 (112 mg in total, 98%, 20:21 = 35:65). Compounds 20 and 21 were further purified by flash column chromatography (hexane / EtOAc = 5:1) to isolate them from each other.

[0097] Reaction of compound 18 with furan without using TfOH of Scheme a in Figure 5 in the presence of compound 1b A solution of compound 18 (100 mg, 0.286 mmol, 1.0 eq) and compound 1b (36.2 mg, 0.286 mmol, 1.0 eq) in furan (1.0 mL, 13.7 mmol, 48 eq) was stirred at 60 °C for 24 h. TLC analysis of the reaction mixture showed that starting material 18 remained unchanged (i.e., no reaction).

[0098] Reaction of compound 22 with furan in Scheme b of Figure 5 in the presence of compound 1b To a solution of compound 22 (109.6 mg, 0.286 mmol, 1.0 eq) and compound 1b (36.2 mg, 0.286 mmol, 1.0 eq) in furan (1.0 mL, 13.7 mmol, 48 eq) was added TfOH (2.5 μL, 0.029 mmol, 0.1 eq) at room temperature (25 °C), and the mixture was stirred at 60 °C for 1.0 h. After cooling to room temperature, 1 The ratio of 23 / 24 was determined by 1H NMR analysis, and the reaction mixture was purified by flash column chromatography (hexane / EtOAc = 5:1) to give compounds 23 and 24 (118.9 mg in total, 96%, 23:24 = 55:45).

[0099] Reaction of compound 14 with furan in Scheme c of Figure 5 in the presence of compound 1b To a solution of compound 14 (74.2 mg, 0.286 mmol, 1.0 eq) and compound 1b (36.2 mg, 0.286 mmol, 1.0 eq) in furan (1.0 mL, 13.7 mmol, 48 eq) was added TfOH (2.5 μL, 0.029 mmol, 0.1 eq) at room temperature (25 °C), and the mixture was stirred at 60 °C for 1.0 h. After cooling to room temperature, the reaction mixture was 1 analyzed by 1H NMR and purified by flash column chromatography (hexane / EtOAc = 5:1) to give compound 25 (81.4 mg, 92%).

[0100] Reaction of compound 18 with thiophene in Scheme d of Figure 5 in the presence of compound 1b A solution of compound 18 (100 mg, 0.286 mmol, 1.0 equiv) and compound 1b (36.2 mg, 0.286 mmol, 1.0 equiv) in thiophene (1.0 mL, 12.5 mmol, 44 equiv) was added with TfOH (2.5 μL, 0.029 mmol, 0.1 equiv) at room temperature (25 °C), and the mixture was stirred at 60 °C for 1.0 h. After cooling to room temperature, the reaction mixture was 1 analyzed by 1H NMR and purified by flash column chromatography (hexane / EtOAc = 5:1) to afford compound 26 (104.6 mg, 88%).

[0101] Reaction of compound 18 with benzofuran in Scheme d of Figure 5 in the presence of compound 1b A solution of compound 18 (100 mg, 0.286 mmol, 1.0 equiv) and compound 1b (36.2 mg, 0.286 mmol, 1.0 equiv) in benzofuran (1.0 mL, 9.1 mmol, 32 equiv) was added with TfOH (2.5 μL, 0.029 mmol, 0.1 equiv) at room temperature (25 °C), and the mixture was stirred at 60 °C for 5.0 h. After cooling to room temperature, the reaction mixture was purified by flash column chromatography (hexane / EtOAc = 3:1) to afford compound 27 (60.1 mg, 45%).

[0102] Chemical transformation: Evaluation of the effect of compound 1b in the dimerization of isatin aldol derivatives (Figure 6) (a) Procedure for the scheme in Figure 6 Reaction of compound 18 in the presence of TfOH in Scheme a of Figure 6 in the absence of a buffering molecule To a solution of compound 18 (100 mg, 0.286 mmol, 1.0 equiv) in CHCl3 (2.0 mL) was added TfOH (2.5 μL, 0.029 mmol, 0.1 equiv) at room temperature (25 °C), and the solution was stirred at 60 °C for 1 h. After cooling to room temperature, a portion of the reaction mixture was diluted with CDCl3 and analyzed by TLC and 1 1H NMR, which showed the formation of compound 19 (100% NMR yield).

[0103] Reaction of Compound 18 in the Presence of TfOH in Scheme a of Figure 6 in the Presence of Compound 1b To a mixture of Compound 18 (100 mg, 0.286 mmol, 1.0 equiv) and Compound 1b (36.2 mg, 0.286 mmol, 1.0 equiv) in CHCl3 (2.0 mL) was added TfOH (2.5 μL, 0.029 mmol, 0.1 equiv) at room temperature (25 °C), and the mixture was stirred at 60 °C for 12 h. After cooling to room temperature, the reaction mixture was purified by flash column chromatography (hexane / EtOAc = 7:1) to afford Compound 28 (61.7 mg, 65%, single diastereomer (>95% purity)). Compound 28 was crystallized from MeOH and CH2Cl2 - hexane, respectively. The relative stereochemistry of Compound 28 was determined by X-ray crystallographic analysis. The carbon-carbon double bond of Compound 28 was partially isomerized from E to Z during storage.

[0104] Reaction of Compound 19 in the Presence of TfOH in the Control Reaction of Scheme a of Figure 6 in the Presence of Compound 1b To a solution of Compound 19 (25.0 mg, 0.071 mmol, 1.0 equiv) and Compound 1b (9.0 mg, 0.071 mmol, 1.0 equiv) in CHCl3 (0.5 mL) was added TfOH (0.63 μL, 0.007 mmol, 0.1 equiv) at room temperature (25 °C), and the solution was stirred at 60 °C for 12 h. After cooling to room temperature, the reaction mixture was diluted with CDCl3, 1 Analysis by 1H NMR showed that Compound 19 remained unchanged (i.e., no reaction).

[0105] Reaction of Compound 29 in the Presence of TfOH in Scheme b of Figure 6 in the Presence of Compound 1b To a solution of compound 29 (112.1 mg, 0.286 mmol, 1.0 equiv) and compound 1b (36.2 mg, 0.286 mmol, 1.0 equiv) in CHCl3 (2.0 mL) was added TfOH (2.5 μL, 0.029 mmol, 0.1 equiv) at room temperature (25 °C), and the solution was stirred at 60 °C for 12 h. After cooling to room temperature, the reaction mixture was purified by flash column chromatography (hexane / EtOAc = 7:1) to afford compound 32 (75.9 mg, 71%).

[0106] Reaction of compound 30 in the presence of TfOH in Scheme b of Figure 6 in the presence of compound 1b To a solution of compound 30 (100.1 mg, 0.286 mmol, 1.0 equiv) and compound 1b (36.2 mg, 0.286 mmol, 1.0 equiv) in CHCl3 (2.0 mL) was added TfOH (2.5 μL, 0.029 mmol, 0.1 equiv) at room temperature (25 °C), and the solution was stirred at 60 °C for 12 h. After cooling to room temperature, the reaction mixture was purified by flash column chromatography (hexane / EtOAc = 7:1) to afford compound 33 (63.6 mg, 67%).

[0107] Reaction of compound 31 in the presence of TfOH in Scheme b of Figure 6 in the presence of compound 1b To a solution of compound 31 (95.9 mg, 0.286 mmol, 1.0 equiv) and compound 1b (36.2 mg, 0.286 mmol, 1.0 equiv) in CHCl3 (2.0 mL) was added TfOH (2.5 μL, 0.029 mmol, 0.1 equiv) at room temperature (25 °C), and the solution was stirred at 60 °C for 12 h. After cooling to room temperature, the reaction mixture was purified by flash column chromatography (hexane / EtOAc = 7:1) to afford compound 34 (55.3 mg, 61%).

[0108] [Example 1] Evaluation of the inhibition of 1,3 - cyclohexanedione on acid - catalyzed isomerization and base - catalyzed isomerization in organic solvents To test the buffering function of 1,3 - cyclohexanedione to neutralize both acids and bases in a non - aqueous solution, first, 1,3 - cyclohexanedione (1a):

Chemical formula

[0109]

Table 1

[0110] Compound 2 is a synthetic intermediate useful in the formation of spirooxyindole polycycles and is readily isomerized to Compound 3 under acidic or basic conditions (J.-R. Huang, M. Sohail, T. Taniguchi, K. Monde, F. Tanaka, Angew. Chem. Int. Ed. 2017, Vol. 56, p. 5853; Angew. Chem. 2017, Vol. 129, p. 5947, M. Sohail, F. Tanaka, Communications Chem. 2019, Vol. 2, p. 73, doi:10.1038 / s42004-019-0177-5). The ratio of Compound 2 to Compound 3 can be readily determined as described in J.-R. Huang, M. Sohail, T. Taniguchi, K. Monde, F. Tanaka, Angew. Chem. Int. Ed. 2017, Vol. 56, p. 5853; Angew. Chem. 2017, Vol. 129, p. 5947.

[0111] Regarding the isomerization of Compound 2 catalyzed by DBU, the ratio of Compound 2 to Compound 3 was 24:76 five minutes after the addition of DBU (Item 2 in Table 1). In the presence of Compound 1a (1.0 equivalent relative to Compound 2), Compound 2 remained unchanged, i.e., it was not isomerized by the addition of DBU (Item 3 in Table 1). In the presence of Compound 1a, the formation of Compound 3 was less than 1% even after three days. Similarly, in the presence of Compound 1a, Compound 2 was not isomerized to Compound 3 by the addition of TfOH (Item 8 in Table 1). Since Compound 1a blocked both the isomerization of Compound 2 catalyzed by DBU and the isomerization of Compound 2 catalyzed by TfOH, it indicates that Compound 1a neutralized both the base and the acid. Acetic acid only suppressed the isomerization catalyzed by the base (Items 4 and 9 in Table 1), and benzylamine only suppressed the isomerization catalyzed by the acid (Items 5 and 10 in Table 1). That is, acetic acid neutralized only the base, and benzylamine neutralized only the acid. Therefore, the effect of Compound 1a on both the base and the acid in the organic solvent (Items 3 and 8 in Table 1) was demonstrated. These results suggest that Compound 1a has a buffering function in non-aqueous solutions.

[0112] Next, as shown in Table 2, by evaluating the effect of Compound 1a on the isomerization reaction of Compound 2 to Compound 3 catalyzed by various bases and acids, the ability of Compound 1a to neutralize various bases and acids in the organic solvent was analyzed.

[0113]

Table 2

[0114] The degree of base-catalyzed isomerization and acid-catalyzed isomerization varies depending on the base or acid, but Compound 1a completely or almost completely suppressed the isomerization of Compound 2 catalyzed by various bases such as potassium tert-butoxide and 1,1,3,3-tetramethylguanidine, as well as the isomerization of Compound 2 catalyzed by various acids such as methanesulfonic acid and p-toluenesulfonic acid. That is, the buffering function of Compound 1a was observed against various bases and acids in a non-aqueous solution.

[0115] The inhibitory function of Compound 1a on the isomerization of Compound 2 to Compound 3, or the range of the buffering function of Compound 1a, was also investigated in various solvents as shown in Tables 3 and 4.

[0116]

Table 3

[0117]

Table 4

[0118] In all the solvents tested, isomerization of Compound 2 to Compound 3 by DBU or TfOH was observed to some extent in the absence of Compound 1a. In the presence of Compound 1a, isomerization of Compound 2 was not detected in chloroform or toluene. In acetonitrile, acetone, 2-propanol, 1,4-dioxane, and tetrahydrofuran (THF), in the presence of Compound 1a, isomerization of Compound 2 to Compound 3 was almost completely suppressed (less than 5%). In dimethyl sulfoxide (DMSO), isomerization was partially inhibited by Compound 1a. In polar solvents, the pKa values of the base, acid, and Compound 1a change from those in non-polar solvents, which may affect the neutralization function of Compound 1a, or hydrogen bonds are formed between the solvent molecules and Compound 1a, which may suppress the interaction between Compound 1a and the base or acid. In such cases, a decrease in the buffering function of Compound 1a is brought about. The buffering function of Compound 1a did not function in some polar solvents, but Compound 1a buffered various organic solvents including 2-propanol.

[0119] As shown in Tables 5 and 6, Compound 1a also inhibited acid-catalyzed and base-catalyzed isomerizations of Compound 2 to Compound 3 over a wide range of concentrations.

[0120]

Table 5

[0121]

Table 6

[0122] When the isomerization reaction of Compound 2 to Compound 3 catalyzed by DBU and the isomerization reaction of Compound 2 to Compound 3 catalyzed by TfOH in CDCl3 were analyzed over various concentrations of Compound 2 in the presence of 1 equivalent of Compound 1a, in the range of 0.003 M to 0.14 M, the isomerization was suppressed to less than 1%.

[0123] Furthermore, even when Compound 1a was present in less than 1 equivalent relative to Compound 2, the buffering function of 1a was observed as shown in Tables 7 and 8.

[0124]

Table 7

[0125]

Table 8

[0126] Furthermore, the buffering function of Compound 1a was maintained in solution for more than 3 days even at 60 °C in the presence of TfOH, as shown in Table 9.

[0127]

Table 9

[0128] Compound 1a has a buffering function over a wide range of conditions in non-aqueous solutions.

[0129] [Example 2] Identification of Other Molecules Exhibiting a Buffering Function in Non-Aqueous Solutions Next, the effects of 1,3 - cyclohexanedione derivatives and related molecules on the isomerization reaction of compound 2 to compound 3 catalyzed by DBU and the isomerization reaction of compound 2 to compound 3 catalyzed by TfOH were evaluated (Figures 1 and 2). In the absence of the 1,3 - cyclohexanedione derivative, the 2:3 ratio was 24:76 for the reaction with DBU and 29:71 for the reaction with TfOH (Table 1). Since 1,3 - cyclohexanedione derivatives 1b - 1e completely inhibited the isomerization of compound 2 as in the case of compound 1a, it is shown that monosubstitution with a methyl group, benzyl group, or phenyl group at the 2 - position of 1,3 - cyclohexanedione, as well as methyl substitution at the 4 - and 6 - positions of 1,3 - cyclohexanedione, does not affect the buffering function (Figure 1). In the presence of the 1,3 - cyclohexanedione derivative having an isopropyl group at the 2 - position (compound 1f), the isomerization of compound 2 was less than 1%. 1,3 - cyclohexanedione derivatives having a mono - or disubstitution at the 5 - position (compounds 1g - 1i) also inhibited the isomerization to the same extent as compound 1f. For 1,3 - cyclohexanedione having a cyclohexyl group or a triphenylmethyl group, which are bulkier substituents than the isopropyl group at the 2 - position (compounds 1j and 1k, respectively), the effect of inhibiting isomerization decreased slightly compared to compound 1f. 1,3 - cyclohexanedione conjugated to resin beads (1b conjugated to the resin) also inhibited the isomerization.

[0130] In the isomerization reaction of compound 2 catalyzed by DBU and the isomerization reaction of compound 2 catalyzed by TfOH, 1,3 - cyclopentanedione (1l) and 2 - acetyl - 1,3 - cyclohexanedione (1m) also had some buffering functions. On the other hand, 1,2 - cyclohexanedione (1n), 1,4 - cyclohexanedione (1o), and 2,2 - dimethyl - 1,3 - cyclohexanedione (1p) did not have a buffering function to suppress isomerization. The acyclic molecule 2,4 - pentanedione (1q) also did not inhibit the isomerization.

[0131] These results indicate that compounds 1a - 1e are preferred buffer molecules among the tested compounds. Compounds 1f, 1j, and 1k may also be suitable for various applications that require a buffering function. Similarly, 1,3 - cyclohexanedione attached to resin beads (compound 1b conjugated to the resin) may also be suitable for various applications that provide a buffering function.

[0132] The same test was also conducted for compounds S1a - S1ee (Figure 2). A solution of compound 2 (2:3 >99.5:0.5, 1.0 equivalent) and compounds S1a - S1ee (1.0 equivalent) in CDCl₃ was stirred at room temperature (25 °C) for 5 minutes in the presence of DBU (0.01 equivalent) or at 60 °C for 1 hour in the presence of TfOH (0.1 equivalent). The 2:3 ratio was determined by 1 ¹H NMR analysis, and the reaction with DBU is shown in the upper row and the reaction with TfOH is shown in the lower row. S1k is a cis / trans mixture. During the isomerization reaction of compound 2, the formation of cyclohexane - 1,3 - dione (in the case of compounds S1o - S1w) or 2 - methyl - 1,3 - cyclohexanedione (in the case of compounds S1x and S1y) was observed (monitored by TLC), and the 2:3 ratio was affected by the generated dione. Compound S1cc is identical to 1b conjugated to the resin in Figure 1. Molecules used as buffers in aqueous solutions such as 2 - [bis(2 - hydroxy)amino]ethanesulfonic acid (BES) also did not inhibit isomerization (Figure 2).

[0133] [Example 3] Effect of 1,3 - cyclohexanedione derivatives on inhibiting acid - catalyzed and base - catalyzed isomerization and decomposition Next, compound 1 was evaluated in the isomerization and decomposition reactions of the aldol product or β-hydroxy ketone (Scheme a and Scheme b in Figure 3). Aldol 4 is readily racemized under basic conditions (A.V. Malkov, M.K. Kabeshov, M. Bella, O. Kysllka, D.A. Malyshev, K. Pluhackova, P. Kocovsky, Org. Lett. 2007, Vol. 9, p. 5473, N. Duangdee, W. Harnying, G. Rulli, J.-M. Neudorfl, H. Groger, A. Berkessel, J. Am. Chem. Soc. 2012, Vol. 134, p. 11196), and the retro-aldol reaction of aldol 4 is also induced by basic conditions to produce compound 5 (Scheme a(i) in Figure 3). When 2-methyl-1,3-cyclohexanedione (1b) was added to the solution of aldol 4, the racemization and retro-aldol reaction of aldol 4 catalyzed by the base were blocked (Scheme a(i) in Figure 3). This was tested at various time points (Table 10) using various compounds (Table 11), various solvents (Table 12), and various amounts of compound 1b (Table 13).

[0134]

Table 10

[0135]

Table 11

[0136]

Table 12

[0137]

Table 13

[0138] As described above, 1b supported on resin also completely inhibited racemization and decomposition. When 2-pyridinecarboxylic acid, N,N-dimethylglycine, or glycine was added instead of compound 1a, racemization could not be suppressed (Table 11). Aldol 4 was also racemized under acidic conditions, and the acidic conditions brought about the formation of the elimination product 6 (L.J. Macpherson, A.E. Dubin, M.J. Evans, F. Marr, P.G. Schultz, B.F. Cravatt, A. Patapoutian, Nature 2007, Vol. 445, p. 541) (Scheme a(ii) in Figure 3). Compound 1b also suppressed the acid-catalyzed racemization reaction and elimination reaction of aldol 4 (Scheme a(ii) in Figure 3).

[0139] Similarly, 1,3-cyclohexanedione derivatives 1b and 1k also completely inhibited the racemization of β-hydroxy ketone 7 and the decomposition of β-hydroxy ketone 7 to produce compounds 8 and 9 (Scheme b in Figure 3).

[0140] The isomerization of the Mannich reaction product or amino aldehyde derivative 10 to 11 in the presence of DBU was also suppressed by the addition of compound 1b (Scheme c in Figure 3). The decomposition reaction of the β-hydroxy-α-amino acid derivative or protected threonine derivative 12, which brought about dehydration to form compound 13 and hydrolysis to produce benzyl alcohol, was also inhibited by compound 1b (Scheme d in Figure 3).

[0141] [Example 4] Effect of 1,3-cyclohexanedione derivatives on changing and controlling chemical conversions 2-Methyl-1,3-cyclohexanedione (1b) was tested for its function to change the products of chemical conversion (Figs. 4, 5, and 6). To protect the hydroxy group of aldol 14, aldol 14 was treated with TMSCN at 60 °C in the presence of DBU as a base, and products 15, 16, and 17 were obtained. The selective formation of 15 in high yield was not achieved without compound 1b (Fig. 4). When the same reaction was carried out with the addition of compound 1b, product 15 was obtained in high yield, and the enantiomeric purity of the starting material was retained in the product (Fig. 4). In the absence of compound 1b, the cyanide anion generated from TMSCN reacted with aldol 14 to give products 16 and 17. In the presence of compound 1b, the cyanide anion is protonated, thus suppressing its action as a nucleophile.

[0142] Furthermore, compound 18 was used instead of the above compound 14. For the reaction of compound 18 in the absence of a buffering molecule, DBU (4.3 μL, 0.029 mmol, 0.1 equivalent) was added to a solution of (±)-18 (100 mg, 0.286 mmol, 1.0 equivalent) and TMSCN (53.8 μL, 0.43 mmol, 1.5 equivalents) in CHCl3 (1.0 mL) at room temperature (25 °C), and the mixture was stirred at 60 °C for 1 hour. After cooling to room temperature, the mixture was purified by flash column chromatography (hexane / EtOAc = 5:1) to obtain compound 35 (32.5 mg, 27%), compound 36 (44.7 mg, 30%, dr = 1:1), and compound 37 (51.6 mg, 40%). For the reaction of compound 18 in the presence of compound 1b, DBU (4.3 μL, 0.029 mmol, 0.1 equivalent) was added to a mixture of (R)-18 (100 mg, 0.286 mmol, 1.0 equivalent), TMSCN (53.8 μL, 0.43 mmol, 1.5 equivalents), and compound 1b (36.2 mg, 0.286 mmol, 1.0 equivalent) in CHCl3 (1.0 mL) at room temperature (25 °C), and the mixture was stirred at 60 °C for 1.5 hours. After cooling to room temperature, the reaction mixture was purified by flash column chromatography (hexane / EtOAc = 5:1) to obtain compound 35 (118.2 mg, 98%, 96% ee).

[0143] [Chemical formula]

[0144] The reaction of β-hydroxy enone derivative 18 with furan was also changed by the addition of compound 1b (Scheme a in Figure 5). Under acidic conditions, compound 18 was easily converted to oxa-Michael cyclization product 19 in the absence of compound 1b. Under neat conditions for the reaction of compound 18 with furan using TfOH as a catalyst and without using compound 1b, the formation of a complex mixture containing more than seven new spots in TLC analysis was brought about. None of these were product 20 or product 21. In contrast, under the same neat conditions but in the presence of compound 1b, the addition products 20 (keto form) and 21 (enol form) with furan added were obtained (Scheme a in Figure 5). Similarly, the reaction of β-hydroxy enone derivative 22 with furan catalyzed by TfOH in the presence of compound 1b gave the corresponding addition products 23 and 24 (Scheme b in Figure 5), and the reaction of aldol 14 under these conditions gave product 25 (Scheme c in Figure 5). The reaction of β-hydroxy enone derivative 18 with thiophene or benzofuran catalyzed by TfOH in the presence of compound 1b gave the corresponding addition products 26 and 27, respectively (Scheme d in Figure 5).

[0145] Furthermore, as a control reaction, the reaction of compound 38 with furan was carried out in the presence of compound 1b. Specifically, to a solution of compound 38 (47.4 mg, 0.143 mmol, 1.0 equivalent) and compound 1b (18.1 mg, 0.143 mmol, 1.0 equivalent) in furan (0.5 mL, 6.9 mmol, 48 equivalents), TfOH (1.3 μL, 0.014 mmol, 0.1 equivalent) was added at room temperature (25 °C), and the mixture was stirred at 60 °C. When the reaction mixture was analyzed by TLC and 1 1H NMR, it was shown that 38 remained unchanged (i.e., no reaction) over 12 hours, as shown below.

[0146] [Chemical formula]

[0147] Furthermore, by using the buffering function of Compound 1b, the synthesis of complex spirooxindole derivatives became possible (Figure 6). Spirooxindoles with a fused ring system have attracted interest for the development of pharmaceuticals and related molecules (J.-R. Huang, M. Sohail, T. Taniguchi, K. Monde, F. Tanaka, Angew. Chem. Int. Ed. 2017, Vol. 56, p. 5853; Angew. Chem. 2017, Vol. 129, p. 5947, M. Sohail, F. Tanaka, Communications Chem. 2019, Vol. 2, p. 73, doi:10.1038 / s42004-019-0177-5, D. Enders, Angew. Chem. Int. Ed. 2017, Vol. 56, p. 8516; Angew. Chem. 2017, Vol. 129, p. 8636, Z. Zhou, Z.-X. Wang, Y.-C. Zhou, W. Xiao, Q. Ouyang, W. Du, Y.-C. Chen, Nat. Chem. 2017, Vol. 9, p. 590, K. Jiang, Z.-J. Jia, X. Yin, L. Wu, Y.-C. Chen, Org. Lett. 2010, Vol. 12, p. 2766, L.-L. Zhang, J.-W. Zhang, S.-H. Xiang, Z. Guo, B. Tan, Org. Lett. 2018, Vol. 20, p. 6022).However, the concise construction of functionalized fused ring systems remains a challenge (B.M. Bocknack, L.-C. Wang, M.J. Krische, Proc. Natl. Acad. Sci. USA, 2004, Vol. 101, p. 5421). Under acidic conditions containing TfOH, compound 18 was converted to oxacyclization product 19 in the absence of compound 1b (Scheme a in Figure 6). When the same reaction was carried out with the addition of compound 1b, dimerization of compound 18 occurred, resulting in the formation of spiroxyindole octahydropentalene derivative 28 (Scheme a in Figure 6). The relative stereochemistry of compound 28 was determined by X-ray crystal structure analysis. Treatment of spiroxyindole tetrahydropyran 19 (i.e., with TfOH and compound 1b) under the conditions used for the formation of compound 28 did not result in the formation of compound 28. Treatment of compound 18 with only compound 1b without TfOH also did not result in the formation of compound 19 or compound 28. Weaker acids such as acetic acid and trifluoroacetic acid also did not catalyze the formation of compound 28 from compound 18. These results suggest that the use of compound 1b in the reaction catalyzed by TfOH adjusts the reaction conditions such that compound 28 is formed, i.e., compound 1b lowers the acidity of the reaction environment catalyzed by TfOH, enabling the formation of the enolate required for the C-C bond formation leading to the formation of compound 28 from 18. Similarly, the reactions of compounds 29 - 31 catalyzed by TfOH in the presence of compound 1b gave compounds 32 - 34, respectively (Scheme b in Figure 6). The buffering function of compound 1b enabled the synthesis of complex spiroxyindole octahydropentalene.

Claims

1. Formula I: 【Chemistry 1】 (In the formula, R １ ~R ５ are each hydrogen or a substituent, R １ ~R ５ any two groups may form a ring) or Formula II: 【Chemistry 2】 (In the formula, R １ ~R ３ are each hydrogen or a substituent, R １ ~R ３ any two groups may form a ring) as a buffer molecule in a non-aqueous solution containing an organic solvent.

2. A method for controlling a structural change of a compound in a non-aqueous solution, comprising the steps of: The structural change of the compound can be induced by an acid or a base, The method comprises reacting the compound of formula I: 【Chemistry 3】 (In the formula, R １ ~R ５ are each hydrogen or a substituent, R １ ~R ５ any two groups may form a ring) or Formula II: 【Chemistry 4】 (In the formula, R １ ~R ３ are each hydrogen or a substituent, R １ ~R ３ and a buffer molecule represented by the formula:

3. The method according to claim 2 , which is a method for suppressing a structural change of the compound in the non-aqueous solution.

4. 4. The method of claim 3, wherein said compound can be caused to isomerize by an acid or a base, and said method is a method of suppressing isomerization of said compound in said non-aqueous solution.

5. 4. The method of claim 3, wherein decomposition of said compound can be caused by an acid or a base, and said method inhibits decomposition of said compound in said non-aqueous solution.

6. 3. The method of claim 2, wherein the compound is converted into a product having a different structure.

7. The method of claim 6 , wherein the product is produced by reacting two or more molecules of the compound with each other.

8. A compound whose structural change can be induced by an acid or a base; Formula I: 【Chemistry 5】 (In the formula, R １ ~R ５ are each hydrogen or a substituent, R １ ~R ５ any two groups may form a ring) or Formula II: 【Chemistry 6】 (In the formula, R １ ~R ３ are each hydrogen or a substituent, R １ ~R ３ any two groups may form a ring; and A non-aqueous solution comprising:

9. A solid support; Conjugated to said solid support is a compound of formula I: 【Chemistry 7】 (In the formula, R １ ~R ５ are each hydrogen or a substituent, R １ ~R ５ any two groups may form a ring) or Formula II: 【Chemistry 8】 (In the formula, R １ ~R ３ are each hydrogen or a substituent, R １ ~R ３ any two groups may form a ring; and Items including.

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