WO2015115650A1 - 光学活性カルボン酸エステルの製造方法 - Google Patents
光学活性カルボン酸エステルの製造方法 Download PDFInfo
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- WO2015115650A1 WO2015115650A1 PCT/JP2015/052882 JP2015052882W WO2015115650A1 WO 2015115650 A1 WO2015115650 A1 WO 2015115650A1 JP 2015052882 W JP2015052882 W JP 2015052882W WO 2015115650 A1 WO2015115650 A1 WO 2015115650A1
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- carboxylic acid
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- optically active
- acid ester
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- 0 CC*(CC)*(C(C)NC)[Au](C)CC Chemical compound CC*(CC)*(C(C)NC)[Au](C)CC 0.000 description 5
- HWJMXFOOQWFOCE-UHFFFAOYSA-N C1N(c(cccc2)c2S2)C2=NC1 Chemical compound C1N(c(cccc2)c2S2)C2=NC1 HWJMXFOOQWFOCE-UHFFFAOYSA-N 0.000 description 1
- AZVFODUSJMQLJH-QNGWXLTQSA-N CC(C)(C)OC([n]1c(cccc2)c2c(C[C@@H](C(OC(c2c(cccc3)c3ccc2)c2cccc3c2cccc3)=O)[n]2cccc2)c1)=O Chemical compound CC(C)(C)OC([n]1c(cccc2)c2c(C[C@@H](C(OC(c2c(cccc3)c3ccc2)c2cccc3c2cccc3)=O)[n]2cccc2)c1)=O AZVFODUSJMQLJH-QNGWXLTQSA-N 0.000 description 1
- DLMOQVVMTIUKEQ-UHFFFAOYSA-N CCC/N=C1/SCCN1 Chemical compound CCC/N=C1/SCCN1 DLMOQVVMTIUKEQ-UHFFFAOYSA-N 0.000 description 1
- GOVXKUCVZUROAN-UHFFFAOYSA-N CCc1c[nH]c2ccccc12 Chemical compound CCc1c[nH]c2ccccc12 GOVXKUCVZUROAN-UHFFFAOYSA-N 0.000 description 1
- LSSMJCLWXQTWGJ-UXQKWJTISA-N C[C@@H](C(OC(C1=CC=CC2C=CC=CC12)c1cccc2c1cccc2)=O)[n]1c2ccccc2cc1 Chemical compound C[C@@H](C(OC(C1=CC=CC2C=CC=CC12)c1cccc2c1cccc2)=O)[n]1c2ccccc2cc1 LSSMJCLWXQTWGJ-UXQKWJTISA-N 0.000 description 1
- NDEYFVPMJVFFQG-NRFANRHFSA-N C[C@@H](C(OC(c1c(cccc2)c2ccc1)c1cccc2c1cccc2)=O)[n](ccc1c2)c1ccc2Cl Chemical compound C[C@@H](C(OC(c1c(cccc2)c2ccc1)c1cccc2c1cccc2)=O)[n](ccc1c2)c1ccc2Cl NDEYFVPMJVFFQG-NRFANRHFSA-N 0.000 description 1
- QRKARMOHVSRMKT-YFKPBYRVSA-N C[C@@H]1N=C2SCCN2C1 Chemical compound C[C@@H]1N=C2SCCN2C1 QRKARMOHVSRMKT-YFKPBYRVSA-N 0.000 description 1
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N Cc1cnc[nH]1 Chemical compound Cc1cnc[nH]1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 1
- JJBQFKXGJDAIQK-JMAPEOGHSA-N O=C([C@H](Cc(nc1)c[n]1[Tl])[n]1cccc1)OC(c1c(cccc2)c2ccc1)c1c(cccc2)c2ccc1 Chemical compound O=C([C@H](Cc(nc1)c[n]1[Tl])[n]1cccc1)OC(c1c(cccc2)c2ccc1)c1c(cccc2)c2ccc1 JJBQFKXGJDAIQK-JMAPEOGHSA-N 0.000 description 1
- FDAAVANEOUCASO-BHVANESWSA-N O=C([C@H](Cc1cccc2c1cccc2)[n]1cccc1)OC(c1c(cccc2)c2ccc1)c1c(cccc2)c2ccc1 Chemical compound O=C([C@H](Cc1cccc2c1cccc2)[n]1cccc1)OC(c1c(cccc2)c2ccc1)c1c(cccc2)c2ccc1 FDAAVANEOUCASO-BHVANESWSA-N 0.000 description 1
- XUSGBSQBGZWTIT-ZDUSSCGKSA-N OC[C@H](Cc1c[nH]c2ccccc12)[n]1cccc1 Chemical compound OC[C@H](Cc1c[nH]c2ccccc12)[n]1cccc1 XUSGBSQBGZWTIT-ZDUSSCGKSA-N 0.000 description 1
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- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
- C07D207/327—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
- C07D207/416—2,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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- C07D209/04—Indoles; Hydrogenated indoles
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- C07D209/04—Indoles; Hydrogenated indoles
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
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- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Definitions
- the present invention relates to a method for producing an optically active carboxylic acid ester using dynamic kinetic optical resolution.
- Optically active carboxylic acid esters are used in various fields as pharmaceuticals, bioactive substance intermediates, natural product synthesis intermediates, and the like.
- Patent Document 1 a method for producing an optically active carboxylic acid ester by reacting a racemic carboxylic acid and an alcohol in the presence of benzoic anhydride or a derivative thereof using tetramisol or benzotetramisole as a catalyst. Has been proposed.
- Patent Document 2 proposes a method for producing an optically active carboxylic acid ester using dynamic kinetic optical resolution. According to the method of Patent Document 2, one enantiomer of a racemic carboxylic acid is selectively esterified to produce an optically active carboxylic acid ester, and the optically active carboxylic acid that is the other enantiomer is racemized to be esterified. By increasing the amount of carboxylic acid produced, an optically active carboxylic acid ester can be produced with a high yield of more than 50%.
- ⁇ -amino acids are regarded as fundamental compounds in the natural sciences related to living organisms, and a method for producing optically active ⁇ -amino acids and their derivatives in high yield is desired.
- the present invention has been made in view of such problems, and by using dynamic kinetic optical resolution, an optically active carboxylic acid ester having an ⁇ -nitrogen substituent can be obtained in high yield and high enantioselectivity.
- the object is to provide a method of manufacturing.
- the inventors of the present invention have made extensive studies to solve the above problems. As a result, it was found that an optically active carboxylic acid ester can be produced with high yield and high enantioselectivity by using a racemic carboxylic acid having a nitrogen-containing heteroaromatic group as an ⁇ -nitrogen substituent. Further, it has been found that 1H-pyrrol-1-yl group among nitrogen-containing heteroaromatic ring groups can be used as a protecting group for amino group.
- the present invention is based on such knowledge, and more specifically is as follows.
- a method for producing an optically active carboxylic acid ester by dynamic kinetic optical resolution The following formula (a): [In the formula (a), R a1 represents a nitrogen-containing heteroaromatic group bonded to an asymmetric carbon via a nitrogen atom constituting the ring, and R a2 represents an organic group. ]
- R c represents a phenyl group, a naphthyl group, an anthryl group, or a phenanthryl group which may have a substituent
- n represents an integer of 1 to 5.
- R c represents a phenyl group, a naphthyl group, an anthryl group, or a phenanthryl group which may have a substituent
- n represents an integer of 1 to 5.
- R c represents a phenyl group, a naphthyl group, an anthryl group, or a phenanthryl group which may have a substituent
- n represents an integer of 1 to 5.
- the asymmetric catalyst is represented by the following formulas (d) to (g): [In the formulas (d) to (g), X represents the following substituent. And R represents a hydroxyl-protecting group. ]
- the manufacturing method of the optically active carboxylic acid ester of the said (1) description represented by either.
- the base is represented by the following formula (i): [In the formula (i), [In the formula (i), R 1 , R 2 and R 3 each independently represents an alkyl group having 1 to 8 carbon atoms. ]
- the manufacturing method of the optically active carboxylic acid ester as described in said (5) represented by.
- the method further comprises the step of converting the amino group of the racemic ⁇ -amino acid represented by formula (1) to the 1H-pyrrol-1-yl group to obtain the racemic carboxylic acid represented by the formula (a).
- the manufacturing method of the optically active carboxylic acid ester in any one.
- Racemic carboxylic acid The racemic carboxylic acid used in the production method according to the present invention is represented by the following formula (a).
- R a1 represents a nitrogen-containing heteroaromatic group bonded to an asymmetric carbon via a nitrogen atom constituting the ring.
- Nitrogen-containing heteroaromatic groups include 1H-pyrrol-1-yl group, 1H-indol-1-yl group, 1H-benzo [d] imidazol-1-yl group, 9H-carbazol-9-yl group, 1H -Imidazol-1-yl group, 1H-pyrazol-1-yl group, 1H-cyclopenta [b] pyridin-1-yl group, 2H-isoindol-2-yl group, 1H-indazol-1-yl group, 7H -Purin-7-yl group, 10H-phenoxazin-10-yl group, 10H-phenothiazin-10-yl group, 3H-3-benzazepin-3-yl group and the like.
- the nitrogen-containing heteroaromatic ring group may have an arbitrary substituent such as an alkyl group, an aryl group, an alkoxy group, an alkylcarbonyl group, a cyano group, or a halogen atom on the ring, but is preferably unsubstituted.
- an alkyl group such as an alkyl group, an aryl group, an alkoxy group, an alkylcarbonyl group, a cyano group, or a halogen atom on the ring
- nitrogen-containing heteroaromatic groups a 1H-pyrrol-1-yl group, a 1H-indol-1-yl group are more preferable, and a 1H-pyrrol-1-yl group is particularly preferable.
- R a2 represents an organic group.
- the organic group include an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an alkoxyalkyl group, an alkoxyalkenyl group, an alkoxyalkynyl group, an arylalkyl group, an arylalkenyl group, an arylalkynyl group, a heteroarylalkyl group, Examples include heteroarylalkenyl groups, heteroarylalkynyl groups, alkylaryl groups, alkylheteroaryl groups, alkoxyaryl groups, alkoxyheteroaryl groups, etc.
- These groups are groups other than organic groups such as halogen atoms, phenyl, naphthyl Or a heteroaryl group such as thiophene, imidazole or indole.
- groups having no branching at the ⁇ -position are preferable to groups having a branching at the ⁇ -position such as an isopropyl group and a phenyl group.
- the 1H-pyrrol-1-yl group can be used as an amino-protecting group.
- an amino group is converted to a 1H-pyrrol-1-yl group by a Clausson-Curse synthesis method in which a racemic ⁇ -amino acid represented by the following formula (h) and 2,5-dialkoxytetrahydrofuran are refluxed.
- Racemic carboxylic acids represented by the above formula (a) can be obtained (see, for example, K. Kashima et al., J. Chem. Res. Miniprint, 1988, 601-645).
- R a2 has the same meaning as formula (a) above.
- the 1H-pyrrol-1-yl group can be converted to an amino group by, for example, ozonolysis (K. Kashima et al. , J. Chem. Soc. Perkin Trans. 1, 1989, 1041-1046, etc.).
- R b represents a phenyl group, naphthyl group, anthryl group, or phenanthryl group which may have a substituent.
- substituent for R b include an alkyl group, an alkoxy group, an aryl group, and a halogen atom.
- Rb is particularly preferably a 2-tolyl group, 1-naphthyl group, or 9-phenanthryl group.
- R c represents a phenyl group, naphthyl group, anthryl group, or phenanthryl group which may have a substituent, and is preferably a naphthyl group.
- substituent for R c include an alkyl group, an alkoxy group, an aryl group, and a halogen atom.
- R c When a plurality of R c are present, they may be the same or different.
- phenol derivatives those in which the 2,6-positions of phenol are substituted with a naphthyl group are preferable.
- the acid anhydride used in the production method according to the present invention acts as a dehydration condensation agent.
- the acid anhydride include benzoic acid, benzoic acid in which an electron donating group such as an alkyl group, an alkoxy group, an amino group, and an alkoxyalkyl group is bonded to a phenyl group, or a polysubstituted carboxylic acid in which the ⁇ -position is a quaternary carbon.
- benzoic acid 1 to 3 substituted benzoic acid, pivalic acid, 2-methyl-2-phenylpropionic acid, or 2,2-diphenylpropion bonded with benzoic acid, an alkyl group having 1 to 3 carbon atoms or an alkoxy group. What is obtained from an acid is more preferable.
- the asymmetric catalyst used in the production method according to the present invention is not particularly limited, but those represented by the following formulas (d) to (g) are preferable.
- R is a hydroxyl-protecting group, and examples thereof include an alkyl group, an acyl group, and a silyl group.
- a catalyst represented by the above formula (d) or (e), wherein X is a phenyl group is referred to as tetramisole
- the above formula (f) Alternatively, the catalyst represented by (g) and X is a phenyl group is referred to as benzotetramisole.
- These catalysts can be obtained as commercial products, or can be synthesized using amino acids having a substituent represented by X as a side chain.
- the polar solvent used in the production method according to the present invention has a dipole moment of 3.5 or more.
- Such polar solvents include N, N-dimethylacetamide, N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone, dimethyl sulfoxide, nitrobenzene, pyridazine, benzonitrile, pro Examples include pionitrile.
- An optically active carboxylic acid ester is produced by adding a racemic carboxylic acid, an alcohol or phenol derivative, an acid anhydride, and an asymmetric catalyst in a polar solvent, but adding a base in the reaction system.
- a base an organic base having no nucleophilicity is preferable, and the following formula (i):
- R 1 , R 2 and R 3 independently represent an alkyl group having 1 to 8 carbon atoms.
- the amine represented by is more preferable.
- R 1 , R 2 and R 3 are not particularly limited as long as they are alkyl groups having 1 to 8 carbon atoms, but at least one of R 1 , R 2 and R 3 is preferably a methyl group.
- Examples of the amine represented by the above formula (i) include trimethylamine, triethylamine, diisopropylethylamine, dimethylethylamine, dimethylisopropylamine, diethylmethylamine, diisopropylmethylamine and the like.
- the order of addition of the base into the polar solvent is arbitrary, but it is preferable to sequentially add the organic base and the asymmetric catalyst into a solution containing the racemic carboxylic acid, alcohol or phenol derivative, and acid anhydride.
- the amount of each addition is not particularly limited, but the alcohol or phenol derivative is used in an amount equal to or more than that of the racemic carboxylic acid because all the racemic carboxylic acid is consumed and converted to an optically active carboxylic acid ester. It is preferable to use 1.0 to 1.5 equivalents.
- the acid anhydride is necessary to form an acid anhydride and a mixed acid anhydride to be an intermediate for enantioselective advancement of esterification, and is preferably used in an equivalent amount or more with respect to the racemic carboxylic acid. It is more preferable to use 1.0 to 5.0 equivalents.
- the base has a function of neutralizing an acid derived from an acid anhydride generated as the reaction proceeds and a function of promoting racemization of a mixed acid anhydride activated by an asymmetric catalyst.
- the reaction proceeds without the addition of a base, in order to promote racemization and increase the yield and enantiomeric excess of the target optically active carboxylic acid ester, It is preferable to add 2 to 4.8 equivalents.
- the asymmetric catalyst is necessary for enantioselective advancement of esterification, and is preferably used in an amount of 0.1 to 10 mol% based on the racemic carboxylic acid.
- the reaction temperature is preferably ⁇ 23 to 30 ° C., and the reaction time is preferably 10 minutes to 72 hours.
- Np naphthyl Piv 2 O: pivalic anhydride
- Me methyl Et: ethyl n-Pr: normal propyl i-Pr: isopropyl n-Bu: normal butyl i-Bu: isobutyl n-Hex: normal hexyl
- Ac acetyl Ph: phenyl
- Bn benzyl Tr: trityl
- Ms methanesulfonyl Boc: tert-butoxycarbonyl
- DMF dimethylformamide
- DMA dimethylacetamide
- optically active ester (2) and unreacted optically active carboxylic acid were separated by silica gel thin layer chromatography to obtain respective compounds.
- the enantiomeric excess (ee) was determined by HPLC analysis using a chiral column.
- racemic carboxylic acids having Boc-protected amino groups, electron-withdrawing imide groups, and amide groups as ⁇ -nitrogen substituents are not sufficiently reactive, and the yield is 50%. It was the following (entries 1-6).
- nitrogen-containing groups such as 1H-pyrrol-1-yl group, 1H-indol-1-yl group, 1H-benzo [d] imidazol-1-yl group, and 9H-carbazol-9-yl group as ⁇ -nitrogen substituents
- the reaction proceeded with high enantioselectivity, and the yield of the corresponding optically active carboxylic acid ester exceeded 50% (entries 7 to 10). That is, it was clear that dynamic kinetic optical resolution was progressing.
- the yield and enantioselectivity were particularly good when they had a 1H-pyrrol-1-yl group and a 1H-indol-1-yl group.
- the physical properties of the obtained optically active carboxylic acid ester are as follows.
- the enantiomeric excess of compound 2g is determined after reducing compound 2g with LiAlH 4 , acylating with p-nitrobenzoic acid chloride, and converting to the corresponding p-nitrobenzoic acid ester 2g ′. It was.
- reaction solvent As shown in the above reaction formula, the effect of the reaction solvent was examined in kinetic optical resolution by asymmetric esterification with racemic carboxylic acid (1 g) as a substrate and di (1-naphthyl) methanol.
- the reaction conditions were as described above except that the amounts of dimethylethylamine, pivalic anhydride and di (1-naphthyl) methanol used as the base were as shown in the above reaction formula, and the reaction solvent was as shown in Table 2 below. Similar to Example 1.
- the theoretical upper limit of the E value in the dynamic kinetic resolution is 200, and the E value of 200 indicates that an optically pure target product can be obtained in a yield of 100% from a racemic substrate.
- reaction proceeds with good efficiency in any combination of a base selected from diisopropylethylamine, triethylamine, diethylmethylamine or dimethylethylamine and a reaction solvent selected from dimethylformamide or dimethylacetamide. 115.9 to 180.2.
- optically active carboxylic acid ester could be obtained with a high yield and a high enantiomeric excess when using any of the substrates (entries 1 to 19).
- the physical properties of the obtained optically active carboxylic acid ester are as follows.
- the enantiomeric excess of compound 2t is determined after reduction of compound 2t using LiAlH 4 , acylation using p-nitrobenzoic acid chloride, and conversion to the corresponding p-nitrobenzoic acid ester 2t ′. It was.
- the enantiomeric excess of compound 2gg is determined after reduction of compound 2gg using LiAlH 4 and acylation using p-nitrobenzoic acid chloride to convert to 2gg ′ of the corresponding p-nitrobenzoic acid ester. It was.
- the ester exchange reaction was first performed to obtain the soluble carboxylic acid methyl ester 3s in a yield of 89%.
- the di (1-naphthyl) methyl ester residue was isolated as di (1-naphthyl) methyl methyl ether in 91% yield (Formula 1).
- the carboxylic acid methyl ester 3s was then ozonolyzed and Boc protected to give N-Boc-phenylalanine methyl ester 4s in 70% yield while maintaining a high enantiomeric excess (Formula 2, 87% ee ).
- the crude product was separated by silica gel thin layer chromatography (developing solvent: toluene), and pale yellow oily carboxylic acid methyl ester 3s (89.6 mg, yield 89%, 87% ee) and colorless solid di (1 -Naphthyl) methyl methyl ether (120 mg, 91% yield) was obtained.
- 1,4-dioxane (4.0 M, 7.46 mL, 29.8 mmol) containing hydrochloric acid was added to the mixture at 0 ° C., and the mixture was stirred at room temperature for 6 hours.
- the solution was dried under reduced pressure, and the residue was suspended in THF (5 mL).
- saturated aqueous sodium hydrogen carbonate solution (5 mL) and di (tert-butyl) dicarbonate (325 mg, 1.49 mmol) were added to the mixture at 0 ° C.
- the reaction was stirred at room temperature for 60 hours and then diluted with water. Next, the mixture was extracted with ethyl acetate, and the organic layer was separated.
- optically active alcohol 5s was obtained in a yield of 89%, and at the same time, di (1-naphthyl) methanol was recovered in a yield of 96% (formula 4 ).
- the corresponding trifluoromethanesulfonate 6s is alkylated using a potassium salt of di (tert-butyl) malonate to carry out 2-carbon elongation conversion of optically active alcohol 5s, and dicarboxylic acid tert-butyl diester 7s is converted to optically active alcohol.
- the yield was 91% from 5 s (Formula 5).
- the dicarboxylic acid tert-butyl diester 7s is then decarboxylated and intramolecular Friedel-Crafts acylated to give the 6,7-dihydroindolizin-8 (5H) -one derivative 8s, which is hydrogenated using palladium on carbon.
- Indolizidine derivative 9s was obtained as a single diastereomer. Note that the enantiomeric excess of the intermediate and product 9s was maintained during the series of conversions. Details of each reaction are as follows.
- the mixture was filtered through a short celite pad with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain a crude product.
- the residue was diluted with 1M hydrochloric acid (3 mL) and washed with ethyl acetate.
- the aqueous layer was basified using an aqueous sodium hydroxide solution (4.2 M, 2 mL), and then extracted with chloroform, and the organic layer was separated.
- the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product.
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Abstract
Description
下記式(a):
で表されるラセミのカルボン酸と、下記式(b):
で表されるアルコール又は下記式(c):
で表されるフェノール誘導体とを、酸無水物及び不斉触媒の存在下、双極子モーメント3.5以上の極性溶媒中で反応させ、上記ラセミのカルボン酸のうち一方のエナンチオマーを選択的にエステル化するとともに、他方のエナンチオマーをラセミ化する工程を含む、光学活性カルボン酸エステルの製造方法。
のいずれかで表される、上記(1)記載の光学活性カルボン酸エステルの製造方法。
で表されるラセミのα-アミノ酸のアミノ基を1H-ピロール-1-イル基に変換し、上記式(a)で表されるラセミのカルボン酸を得る工程をさらに含む、上記(1)~(8)いずれかに記載の光学活性カルボン酸エステルの製造方法。
本発明に係る製造方法で用いられる酸無水物は、脱水縮合剤として作用する。酸無水物としては、安息香酸、フェニル基にアルキル基、アルコキシ基、アミノ基、アルコキシアルキル基等の電子供与性基が結合した安息香酸、又はα位が4級炭素である多置換カルボン酸から得られるものが好ましく、安息香酸、炭素数1~3のアルキル基又はアルコキシ基が結合した1~3置換の安息香酸、ピバル酸、2-メチルー2-フェニルプロピオン酸、又は2,2-ジフェニルプロピオン酸から得られるものがより好ましい。
本発明に係る製造方法で用いられる極性溶媒は、双極子モーメントが3.5以上である。このような極性溶媒としては、N,N-ジメチルアセトアミド、N,N-ジメチルホルムアミド、1,3-ジメチル-2-イミダゾリジノン、N-メチルピロリドン、ジメチルスルホキシド、ニトロベンゼン、ピリダジン、ベンゾニトリル、プロピオニトリル等が挙げられる。双極子モーメントが3.5以上の極性溶媒を用いることによって、エステル化対象ではない光学活性カルボン酸のラセミ化が起こりやすくなる。
光学活性カルボン酸エステルの製造は、極性溶媒中に、ラセミのカルボン酸、アルコール又はフェノール誘導体、酸無水物、及び不斉触媒を添加することによって行われるが、反応系内に塩基を添加することが好ましい。この塩基としては、求核性を有さない有機塩基が好ましく、下記式(i):
で表されるアミンがより好ましい。R1、R2及びR3としては、炭素数1~8のアルキル基であれば特に制限されないが、R1、R2及びR3のうち少なくとも1つがメチル基であることが好ましい。
酸無水物は、ラセミのカルボン酸と混合酸無水物をつくり、エナンチオ選択的にエステル化を進行させる中間体となるために必要であり、ラセミのカルボン酸に対して当量以上用いることが好ましく、1.0~5.0当量用いることがより好ましい。
塩基は、反応進行に伴って生成する酸無水物由来の酸を中和する働きと、不斉触媒によって活性化される混合酸無水物のラセミ化を促進する働きとがある。塩基を添加しなくても反応は進行するが、ラセミ化を促進し、目的とする光学活性カルボン酸エステルの収率及び鏡像体過剰率を高くするためには、ラセミのカルボン酸に対し、1.2~4.8当量添加することが好ましい。
不斉触媒は、エナンチオ選択的にエステル化を進行させるために必要であり、ラセミのカルボン酸に対し、0.1~10モル%用いることが好ましい。
反応温度は-23~30℃が好ましく、反応時間は10分間~72時間が好ましい。
なお、実施例において、以下の略号を用いることがある。
Np:ナフチル
Piv2O:ピバル酸無水物
Me:メチル
Et:エチル
n-Pr:ノルマルプロピル
i-Pr:イソプロピル
n-Bu:ノルマルブチル
i-Bu:イソブチル
n-Hex:ノルマルヘキシル
Ac:アセチル
Ph:フェニル
Bn:ベンジル
Tr:トリチル
Ms:メタンスルホニル
Boc:ターシャリーブトキシカルボニル
DMF:ジメチルホルムアミド
DMA:ジメチルアセトアミド
tR:保持時間
得られた光学活性カルボン酸エステルの物性は以下のとおりである。
HPLC(CHIRALPAK IA-3,i-PrOH/ヘキサン=1/4,flow rate=0.75mL/min):tR=17.9min(54.9%),tR=24.4min(45.1%);
1H NMR(CDCl3):δ
8.42(s,1H,1’-H),
8.03-7.75(m,6H,Ar),
7.57-7.27(m,8H,Ar),
5.09(d,J=7.2Hz,1H,NH),
4.46(td,J=7.2,7.2Hz,1H,2-H),
1.40(s,9H,t-Bu),
1.38(d,J=7.2Hz,3H,3-CH3);
13C NMR(CDCl3):δ172.6(1),155.0(Boc),134.4,134.2,133.81,133.79,131.0,130.9,129.18,129.16,128.9,128.8,126.74,126.68,125.9,125.9,125.8,125.23,125.20,123.4,123.2,123.2,79.8(t-Bu),71.9(1’),49.5(2),28.3(t-Bu),18.7(3);
HR MS:calcd for C29H29NO4Na(M+Na+) 478.1989,found 478.1970.
HPLC(CHIRALPAK ID,i-PrOH/hexane=1/9,flow rate=0.75mL/min):tR=43.0min(25.6%),tR=51.9min(74.4%).
HPLC(CHIRALPAK AD-H,i-PrOH/hexane=1/19,flow rate=0.75mL/min):tR=19.3min(66.1%),tR=21.8min(33.9%);
1H NMR(CDCl3):δ
8.40(s,1H,1’-H),
7.96-7.67(m,6H,Ar),
7.49-7.37(m,5H,Ar),
7.27-7.23(m,1H,Ar),
7.16-7.04(m,3H,Ar),
6.99-6.93(m,2H,Ar),
6.72-6.66(m,1H,Ar),
5.37(q,J=7.6Hz,1H,2-H),
1.66(d,J=7.6Hz,3H,3-CH3),
1.25(s,3H,CH3),
1.10(s,3H,CH3);
13C NMR(CDCl3):δ180.7,169.6(1),140.0,135.6,134.4,134.0,133.8,133.6,130.84,130.79,129.1,129.0,128.9,128.7,127.3,126.64,126.60,126.1,125.8,125.6,125.5,125.2,124.9,123.3,123.1,122.4,122.3,109.7,72.3(1’),48.7,43.7,24.4(Me),24.0(Me),14.1(3);
HR MS:calcd for C34H29NO3Na(M+Na+) 522.2040,found 522.2029.
HPLC(CHIRALCEL OD-H,i-PrOH/hexane=1/9,flow rate=0.75mL/min):tR=23.2min(91.9%),tR=30.7min(8.1%);
1H NMR(CDCl3):δ
8.45(s,1H,1’-H),
8.01-7.70(m,6H,Ar),
7.53-7.34(m,7H,Ar),
7.26-7.20(m,2H,Ar),
7.09(t,J=8.0Hz,1H,Ar),
6.92(t,J=7.6Hz,1H,Ar),
6.51(d,J=8.0Hz,1H,Ar),
5.35(q,J=7.2Hz,1H,2-H),
1.68(d,J=7.2Hz,3H,3-CH3);
13 NMR(CDCl3):δ182.3,168.9(1),157.7,148.9,137.8,133.9,133.8,133.7,130.84,130.81,129.40,129.40,129.37,129.0,128.9,126.7,126.7,126.5,125.9,125.8,125.8,125.3,125.2,125.0,123.6,123.3,123.2,117.6,111.5,73.4(1’),49.2(2),14.2(3);
HR MS:calcd for C32H23NO4Na(M+Na+) 508.1519,found 508.1526.
HPLC(CHIRALPAK IC-3,i-PrOH/hexane=1/19,flow rate=0.75mL/min):tR=46.3min(7.1%),tR=50.7min(92.9%);
1H NMR(CDCl3):δ
8.46(s,1H,1’-H),
8.01-7.71(m,6H,Ar),
7.54-7.33(m,6H,Ar),
7.27-7.09(m,3H,Ar),
7.01(ddd,J=8.0,7.6,1.2Hz,1H,Ar),
6.87(ddd,J=8.0,7.6,0.8Hz,1H,Ar),
6.73(dd,J=7.6,1.2Hz,1H,Ar),
5.24(q,J=7.6Hz,1H,2-H),
1.75(d,J=7.6Hz,3H,3-CH3);
13C NMR(CDCl3):δ168.7(1),154.0,142.5,133.95,133.89,133.8,133.7,130.9,130.8,129.4,129.3,129.2,129.0,128.9,126.8,126.7,126.1,126.0,125.88,125.86,125.2,125.1,123.6,123.2,123.1,122.5,110.1,109.9,73.0(1’),51.7(2),14.9(3);
HR MS:calcd for C31H23NO4Na(M+Na+) 496.1519,found 496.1496.
HPLC(CHIRALPAK AS-H,i-PrOH/hexane=1/9,flow rate=0.75mL/min):tR=31.2min(11.9%),tR=43.2min(88.1%);
1H NMR(CDCl3):δ
8.39(s,1H,1’-H),
8.09-7.78(m,6H,Ar),
7.56-7.29(m,8H,Ar),
5.04(q,J=7.2Hz,1H,2-H),
3.36-3.16(m,2H,3’-CH2),
2.38-2.20(m,2H,5’-CH2),
1.93-1.67(m,2H,4’-CH2),
1.42(d,J=7.2Hz,3H,3-CH3);
13C NMR(CDCl3):δ175.2,170.8(1),134.4,134.3,133.8,133.8,131.0,130.9,129.2,129.1,128.9,128.9,126.8,126.6,126.2,125.9,125.8,125.7,125.3,125.2,123.27,123.25,72.0(1’),49.5,43.4,30.7,18.0,14.7(3);
HR MS:calcd for C28H25NO3Na(M+Na+) 446.1727, found 446.1706.
1H NMR(CDCl3):δ
8.39(s,1H,1’-H),
8.05-7.72(m,6H,Ar),
7.54-7.28(m,6H,Ar),
7.15(d,J=7.2Hz,1H,Ar),
7.03(d,J=7.2Hz,1H,Ar),
6.73(t,J=2.0Hz,2H,pyrrole),
6.21(t,J=2.0Hz,2H,pyrrole),
4.86(q,J=7.2Hz,1H,2-H),
1.73(d,J=7.2Hz,3H,3-CH3);
13C NMR(CDCl3):δ170.2(1),134.2,134.0,133.8,133.7,131.0,130.8,129.2,129.1,128.9,128.8,126.8,126.7,126.1,125.9,125.8,125.5,125.3,125.3,123.2,123.1,119.8(pyrrole),108.8(pyrrole),71.9(1’),57.1(2),17.8(3);
HR MS:calcd for C28H23NO2Na(M+Na+) 428.1621, found 428.1603.
なお、化合物2gの鏡像体過剰率は、LiAlH4を用いて化合物2gを還元し、p-ニトロ安息香酸クロライドを用いてアシル化して、対応するp-ニトロ安息香酸エステル2g’に変換した後に求めた。
HPLC(CHIRALPAK AD-H,i-PrOH/hexane=1/19,flow rate=0.75mL/min):tR=19.6min(92.8%),tR=22.0min(7.2%);
1H NMR(CDCl3):δ
8.32-8.22(m,2H,Ar),
8.18-8.06(m,2H,Ar),
6.77(t,J=2.0Hz,2H,pyrrole),
6.18(t,J=2.0Hz,2H,pyrrole),
4.59-4.40(m,3H,2-H,1-CH2),
1.61(d,J=6.4Hz,3H,3-CH3);
13C NMR(CDCl3):δ164.2,150.6,135.0,130.7,123.6,118.8(pyrrole),108.4(pyrrole),69.1(1),53.5(2),17.7(3);
HR MS:calcd for C14H14N2O4Na(M+Na+) 297.0846, found 297.0844.
1H NMR(CDCl3):δ
8.37(s,1H,1’-H),
7.93-7.72(m,6H,Ar),
7.67-7.60(m,1H,Ar),
7.50-7.33(m,4H,Ar),
7.26-7.00(m,7H,Ar),
6.98-6.88(m,1H,Ar),
6.52(d,J=3.2Hz,1H,Ar),
5.22(q,J=7.2Hz,1H,2-H),
1.81(d,J=7.2Hz,3H,3-CH3);
13C NMR(CDCl3):δ170.5(1),136.2,134.0,133.9,133.73,133.72,130.90,130.87,129.1,129.1,128.9,128.84,128.76,126.69,126.66,125.9,125.84,125.84,125.81,125.2,125.1,125.0,123.2,123.1,121.8,121.0,120.0,109.4,102.5,72.1(1’),53.9(2),17.0(3);
HR MS:calcd for C32H25NO2Na(M+Na+) 478.1778,found 478.1774.
なお、化合物2hの鏡像体過剰率は、LiAlH4を用いて化合物2hを還元し、対応するアルコール2h’に変換した後に求めた。
HPLC(CHIRALCEL OJ-H,i-PrOH/hexane=1/9,flow rate=0.75mL/min):tR=28.4min(4.7%),tR=33.5min(95.3%);
1H NMR(CDCl3):δ
7.64(d,J=8.4Hz,1H,Ar),
7.41(d,J=8.4Hz,1H,Ar),
7.30-7.17(m,2H,Ar),
7.11(ddd,J=8.0,7.6,0.8Hz,1H,Ar),
6.57(d,J=0.8Hz,1H,Ar),
4.67(tdd,J=6.8,6.4,5.2Hz,1H,2-H),
3.90(dd,J=11.6,6.4Hz,1H,1-CH2),
3.87(dd,J=11.6,5.2Hz,1H,1-CH2),
1.56(d,J=6.8Hz,3H,3-CH3),
1.48(br m,1H,OH);
13C NMR(CDCl3):δ136.2,128.6,124.2,121.5,121.0,119.6,109.5,102.0,66.4(1),53.1(2),16.9(3);
HR MS:calcd for C11H14NO(M+H+) 175.1070,found 175.1062.
HPLC(CHIRALPAK ID,i-PrOH/hexane=2/3,flow rate=0.5mL/min):tR=29.6min(11.3%),tR=35.9min(88.7%);
1H NMR(CDCl3):δ
8.41(s,1H,1’-H),
7.97(s,1H,benzimidazole-2’),
7.92-7.72(m,7H,Ar),
7.51-7.32(m,4H,Ar),
7.30-7.07(m,6H,Ar),
6.98(d,J=7.2Hz,1H,Ar),
5.18(q,J=7.2Hz,1H,2-H),
1.87(d,J=7.2Hz,3H,3-CH3);
13C NMR(CDCl3):δ169.3(1),143.7,141.2,141.2,133.78,133.76,133.7,133.5,133.4,130.82,130.80,129.34,129.31,128.9,128.9,126.7,125.93,125.93,125.91,125.8,125.10,125.07,123.1,123.0,122.9,122.5,120.5,109.9,72.8(1’),53.8(2),17.0(3);
HR MS:calcd for C31H25N2O2(M+H+) 457.1911,found 457.1911.
1H NMR(CDCl3):δ
8.48(s,1H,1’-H),
8.21-8.02(m,3H,Ar),
7.92-7.70(m,4H,Ar),
7.64(d,J=8.0Hz,1H,Ar),
7.56-7.45(m,2H,Ar),
7.41-7.06(m,10H,Ar),
6.91(t,J=7.8Hz,1H,Ar),
6.75(d,J=6.8Hz,1H,Ar),
5.47(q,J=7.2Hz,1H,2-H),
1.84(d,J=7.2Hz,3H,3-CH3);
13C NMR(CDCl3):δ170.2(1),139.6,134.4,133.9,133.8,133.6,131.1,130.6,129.3,129.0,128.73,128.67,126.9,126.6,126.4,125.9,125.7,125.6,125.5,125.2,124.9,123.5,123.3,123.2,120.2,119.4,109.6,72.3(1’),52.4(2),15.4(3);
HR MS:calcd for C36H27NO2Na(M+Na+) 528.1934,found 528.1942.
なお、化合物2jの鏡像体過剰率は、LiAlH4を用いて化合物2jを還元し、対応するアルコール2j’に変換した後に求めた。
HPLC(CHIRALCEL OD-H,i-PrOH/hexane=1/9,flow rate=1.0mL/min):tR=24.2min(18.0%),tR=35.0min(82.0%);
1H NMR(CDCl3):δ
8.09(d,J=7.6Hz,2H,Ar),
7.55-7.37(m,4H,Ar),
7.27-7.17(m,2H,Ar),
4.89(dtd,J=9.2,7.6,4.8Hz,1H,2-H),
4.26(dd,J=11.2,9.2Hz,1H,1-CH2),
3.91(dd,J=11.2,4.8Hz,1H,1-CH2),
1.64(d,J=7.6Hz,3H,3-CH3),
1.79-1.38(br m,1H,OH);
13C NMR(CDCl3):δ139.9,125.6,123.5,120.3,119.1,110.0,64.5(1),53.4(2),15.1(3);
HR MS:calcd for C15H15NONa(M+Na+) 248.1046,found 248.1052.
表中、E値は光学分割の効率を示す指標であり、E(%)=収率(%)×ee(%)×2÷100で定義される。動的速度論的光学分割におけるE値の理論的な上限値は200であり、E値が200であることは、ラセミ体の基質から光学的に純粋な目的物が100%の収率で得られたことを意味する。
得られた光学活性カルボン酸エステルの物性は以下のとおりである。
HPLC(CHIRALPAK AD-H,i-PrOH/hexane=1/9,flow rate=1.0mL/min):tR=13.4min(96.9%),tR=22.5min(3.1%);
1H NMR(CDCl3):δ
8.37(s,1H,1’-H),
8.02(d,J=5.6Hz,1H,Ar),
7.98-7.73(m,5H,Ar),
7.58-7.18(m,8H,Ar),
7.09-7.00(m,1H,Ar),
6.98-6.89(m,1H,Ar),
6.26-6.09(br m,2H,pyrrole,2-H),
2.28(s,3H,Ac-CH3),
1.66(d,J=7.2Hz,3H,3-CH3);
13C NMR(CDCl3):δ188.5(Ac),170.8(1),134.6,134.2,133.9,133.8,131.1,130.9,130.6,129.2,129.0,128.8,128.7,127.0,126.7,126.6,126.2,125.9,125.84,125.75,125.2,125.2,123.7,123.4,120.5,108.7,72.3(1’),55.7(2),27.1(Ac),17.7(3);
HR MS:calcd for C30H25NO3Na(M+Na+) 470.1727,found 470.1726.
HPLC(CHIRALPAK IC-3,i-PrOH/hexane=1/19,flow rate=0.75mL/min):tR=18.6min(5.9%),tR=21.5min(94.1%);
1H NMR(CDCl3):δ
8.41(s,1H,1’-H),
8.05-7.78(m,6H,Ar),
7.56-7.30(m,8H,Ar),
6.94(dd,J=2.8,1.6Hz,1H,pyrrole),
6.79(dd,J=4.0,1.6Hz,1H,pyrrole),
6.18(dd,J=4.0,2.8Hz,1H,pyrrole),
5.18(q,J=7.2Hz,1H,2-H),
1.77(d,J=7.2Hz,3H,3-CH3);
13C NMR(CDCl3):δ169.2(1),133.9,133.84,133.76,133.6,131.0,130.8,129.5,129.3,129.0,128.9,126.9,126.9,126.2,126.0,125.9,125.7,125.24,125.20,124.5,123.1,123.0,120.4,113.3,110.2,104.4,73.0(1’),56.0(2),18.0(3);
HR MS:calcd for C29H22N2O2Na(M+Na+) 453.1573,found 453.1571.
1H NMR(CDCl3):δ
8.33(s,1H,1’-H),
7.94-7.87(m,1H,Ar),
7.83-7.66(m,5H,Ar),
7.44-7.05(m,12H,Ar),
6.97(d,J=7.2Hz,1H,Ar),
6.91(dd,J=2.4,2.0Hz,1H,pyrrole),
6.65(dd,J=2.8,2.4Hz,1H,pyrrole),
6.42(dd,J=2.8,2.0Hz,1H,pyrrole),
4.75(q,J=7.2Hz,1H,2-H),
1.66(d,J=7.2Hz,3H,3-CH3);
13C NMR(CDCl3):δ170.0(1),135.7,134.1,134.0,133.8,133.7,131.0,130.8,129.3,129.1,128.9,128.8,128.5,128.5,126.8,126.7,126.2,125.9,125.8,125.6,125.50,125.47,125.3,125.1,123.13,123.10,120.9,116.5,107.0,72.1(1’),57.3(2),17.7(3);
HR MS:calcd for C34H27NO2Na(M+Na+) 504.1934,found 504.1948.
なお、化合物2mの鏡像体過剰率は、LiAlH4を用いて化合物2mを還元し、対応するアルコール2m’に変換した後に求めた。
HPLC(CHIRALPAK AD-H,i-PrOH/hexane=1/9,flow rate=0.75mL/min):tR=10.0min(91.0%),tR=11.5min(9.0%);
1H NMR(C6D6):δ
7.64-7.53(m,2H,Ar),
7.34-7.21(m,2H,Ar),
7.14-7.06(m,1H,Ar),
6.80(dd,J=2.2,1.8Hz,1H,pyrrole),
6.57(dd,J=2.6,1.8Hz,1H,pyrrole),
6.42(dd,J=2.6,2.2Hz,1H,pyrrole),
3.56-3.41(m,1H,2-H),
3.23-3.08(m,2H,1-CH2),
1.16-1.00(br m,1H,OH),
0.93(d,J=6.9Hz,3H,3-CH3);
13C NMR(C6D6):δ136.8,129.0,128.7,125.6,125.4,120.1,115.9,106.7,67.2(1),57.2(2),17.1(3);
HR MS:calcd for C13H15NONa(M+Na+) 224.1046,found 224.1040.
HPLC(CHIRALPAK IC-3,i-PrOH/hexane=3/7,flow rate=0.4mL/min):tR=36.9min(12.6%),tR=46.4min(87.4%);
1H NMR(CDCl3):δ
8.41(s,1H,1’-H),
7.99-7.76(m,6H,Ar),
7.55-7.26(m,6H,Ar),
7.26-7.17(m,2H,Ar),
7.09(d,J=7.2Hz,1H,Ar),
6.66(dd,J=2.8,2.4Hz,1H,pyrrole),
6.61(dd,J=2.8,1.6Hz,1H,pyrrole),
4.81(q,J=7.2Hz,1H,2-H),
2.31(s,3H,Ac-CH3),
1.73(d,J=7.2Hz,3H,3-CH3);
13C NMR(CDCl3):δ193.3(Ac),169.3(1),133.77,133.76,133.73,133.67,130.9,130.8,129.4,129.3,129.0,128.9,126.84,126.76,126.4,126.0,126.0,125.9,125.5,125.2,125.1,124.8,122.94,122.93,121.6,109.4,72.5(1’),57.6(2),27.0(Ac),17.8(3);
HR MS:calcd for C30H25NO3Na(M+Na+) 470.1727,found 470.1707.
HPLC(CHIRALCEL OD-H,i-PrOH/hexane=1/4,flow rate=0.75mL/min):tR=9.6min(7.5%),tR=16.2min(92.5%);
1H NMR(CDCl3):δ
8.35(s,1H,1’-H),
7.93-7.72(m,6H,Ar),
7.57(d,J=1.6Hz,1H,Ar),
7.49-7.31(m,4H,Ar),
7.28-7.14(m,3H,Ar),
7.07-6.91(m,4H,Ar),
6.44(d,J=3.2Hz,1H,indole-3’-H),
5.14(q,J=7.2Hz,1H,2-H),
1.80(d,J=7.2Hz,3H,3-CH3);
13C NMR(CDCl3):δ170.1(1),134.6,133.9,133.84,133.78,130.91,130.87,129.8,129.24,129.22,128.90,128.89,126.71,126.69,126.4,125.93,125.89,125.89,125.8,125.8,125.7,125.11,125.07,123.13,123.06,122.1,120.4,110.4,102.2,72.4(1’),54.2(2),16.9(3);
HR MS:calcd for C32H24ClNO2Na(M+Na+) 512.1388,found 512.1371.
HPLC(CHIRALCEL OD-H,i-PrOH/hexane=1/4,flow rate=0.75mL/min):tR=12.4min(9.8%),tR=30.8min(90.2%);
1H NMR(CDCl3):δ
8.36(s,1H,1’-H),
7.94-7.69(m,6H,Ar),
7.50-7.30(m,4H,Ar),
7.27-6.93(m,7H,Ar),
6.74(dd,J=9.2,2.8Hz,1H,indole-6’-H),
6.44(d,J=3.2Hz,1H,indole-3’-H),
5.14(q,J=7.2Hz,1H,2-H),
3.84(s,3H,indole-5’-OCH3),
1.79(d,J=7.2Hz,3H,3-CH3);
13C NMR(CDCl3):δ170.5(1),154.4,134.1,134.0,133.8,133.7,131.6,130.93,130.91,129.2,129.1,129.1,128.9,128.8,126.68,126.66,125.9,125.8,125.8,125.8,125.6,125.15,125.11,123.18,123.16,112.0,110.1,102.9,102.1,72.2(1’),55.9(5’-OCH3),54.1(2),16.9(3);
HR MS:calcd for C33H27NO3Na(M+Na+) 508.1883,found 508.1872.
HPLC(CHIRALCEL OD-H,i-PrOH/hexane=3/7,flow rate=0.75mL/min):tR=12.0min(92.1%),tR=18.8min(7.9%);
1H NMR(CDCl3):δ
8.41(d,J=8.0Hz,1H,indole-2’’-H),
8.39(s,1H,1’-H),
7.92-7.74(m,7H,Ar),
7.52-7.33(m,4H,Ar),
7.33-7.13(m,5H,Ar),
7.09(d,J=7.2Hz,1H,Ar),
7.02(d,J=7.2Hz,1H,Ar),
5.25(q,J=7.2Hz,1H,2-H),
2.38(s,3H,Ac-CH3),
1.87(d,J=7.2Hz,3H,3-CH3);
13C NMR(CDCl3):δ193.1(Ac),169.5(1),136.8,133.8,133.8,133.6,133.5,132.1,130.83,130.78,129.4,129.3,128.9,128.9,126.79,126.76,126.2,125.98,125.96,125.96,125.8,125.11,125.09,123.6,123.0,123.0,123.0,122.8,118.0,109.5,72.9(1’),54.2(2),27.5(Ac),17.1(3);
HR MS:calcd for C34H27NO3Na(M+Na+) 520.1883,found 520.1864.
得られた光学活性カルボン酸エステルの物性は以下のとおりである。
HPLC(CHIRALPAK OD-H×2,i-PrOH/hexane=1/9,flow rate=0.5mL/min):tR=26.4min(1.9%),tR=28.1min(98.1%)
その他の機器データは、試験例1のものと一致した。
HPLC(CHIRALPAK OD-H×2,i-PrOH/hexane=1/9,flow rate=0.5mL/min):tR=22.4min(87.6%),tR=24.21min(12.4%);
1H NMR(CDCl3):δ
8.40(s,1H,1’-H),
8.04-7.71(m,6H,Ar),
7.53-7.00(m,8H,Ar),
6.76-6.63(m,2H,pyrrole),
6.26-6.14(m,2H,pyrrole),
4.46(dd,J=9.2,6.6Hz,1H,2-H),
2.26-1.92(m,2H,3-CH2),
0.84(t,J=7.2Hz,3H,4-CH3);
13C NMR(CDCl3):δ169.7(1),134.3,134.1,133.8,133.7,131.0,130.9,129.2,129.0,128.9,128.8,126.7,126.6,126.0,125.9,125.8,125.6,125.2,125.2,123.2,123.1,120.0(pyrrole),108.7(pyrrole),71.9(1’),63.6(2),25.5(3),10.3(4);
HR MS:calcd for C29H25NO2Na(M+Na+) 442.1778,found 442.1757.
1H NMR(CDCl3):δ
8.33(s,1H,1’-H),
7.98-7.64(m,6H,Ar),
7.56-7.11(m,9H,Ar),
7.10-6.90(m,4H,Ar),
6.71(t,J=2.0Hz,2H,pyrrole),
6.18(t,J=2.0Hz,2H,pyrrole),
4.89(dd,J=8.0,7.6Hz,1H,2-H),
3.49(dd,J=14.0,8.0Hz,1H,3-CH2),
3.26(dd,J=14.0,7.6Hz,1H,3-CH2);
13C NMR(CDCl3):δ169.1(1),136.1,134.0,133.9,133.79,133.76,131.0,130.9,129.2,129.03,128.99,128.9,128.8,128.6,127.0,126.8,126.7,126.1,125.9,125.8,125.5,125.29,125.26,123.2,123.1,120.1(pyrrole),109.0(pyrrole),72.3(1’),63.5(2),38.6(3);
HR MS:calcd for C34H27NO2Na(M+Na+) 504.1934,found 504.1911.
なお、化合物2sの鏡像体過剰率は、LiAlH4を用いて化合物2sを還元し、対応するアルコール2s’に変換した後に求めた。
HPLC(CHIRALPAK AD-H,i-PrOH/hexane=1/50,flow rate=0.75mL/min):tR=26.1min(93.5%),tR=48.2min(6.5%);
1H NMR(CDCl3):δ
7.34-7.13(m,3H,Ar),
7.08-6.94(m,2H,Ar),
6.70(t,J=2.0Hz,2H,pyrrole),
6.17(t,J=2.0Hz,2H,pyrrole),
4.20(tt,J=7.6,6.0Hz,1H,2-H),
3.83(dd,J=6.4,6.0Hz,2H,1-CH2),
3.06(d,J=7.6Hz,2H,3-CH2),
1.47(t,J=6.4Hz,1H,OH);
13C NMR(CDCl3):δ137.5,128.8,128.5,126.6,119.2(pyrrole),108.4(pyrrole),65.3,63.5,38.5(3);
HR MS:calcd for C13H15NONa(M+Na+) 224.1046,found 224.1044.
1H NMR(CDCl3):δ
8.39(s,1H,1’-H),
8.03-7.74(m,6H,Ar),
7.57-7.24(m,6H,Ar),
7.14(d,J=7.2Hz,1H,Ar),
7.04(d,J=7.2Hz,1H,Ar),
6.71(t,J=2.0Hz,2H,pyrrole),
6.19(t,J=2.0Hz,2H,pyrrole),
4.66(dd,J=9.2,6.4Hz,1H,2-H),
2.21-1.93(m,2H,3-CH2),
1.32-1.18(m,2H,4-CH2),
0.85(t,J=7.2Hz,3H,5-CH3);
13C NMR(CDCl3):δ169.9(1),134.3,134.1,133.83,133.78,131.0,130.9,129.2,129.0,128.9,128.8,126.7,126.6,126.1,125.9,125.8,125.6,125.3,125.3,123.2,123.2,120.0(pyrrole),108.7(pyrrole),71.9(1’),61.8(2),34.0(3),19.0(4),13.4(5);
HR MS:calcd for C30H27NO2Na(M+Na+) 456.1934,found 456.1932.
なお、化合物2tの鏡像体過剰率は、LiAlH4を用いて化合物2tを還元し、p-ニトロ安息香酸クロライドを用いてアシル化して、対応するp-ニトロ安息香酸エステル2t’に変換した後に求めた。
HPLC(CHIRALCEL OD-H,i-PrOH/hexane=1/50,flow rate=1.0mL/min):tR=15.7min(13.2%),tR=18.8min(86.8%);
1H NMR(CDCl3):δ
8.27(d,J=8.8Hz,2H,Ar),
8.09(d,J=8.8Hz,2H,Ar),
6.73(t,J=2.0Hz,2H,pyrrole),
6.18(t,J=2.0Hz,2H,pyrrole),
4.57(dd,J=11.2,4.4Hz,1H,1-CH2),
4.48(dd,J=11.2,8.0Hz,1H,1-CH2),
4.35-4.22(m,1H,2-H),
1.96-1.75(m,2H,3-CH2),
1.39-1.25(m,2H,4-CH2),
0.94(t,J=7.2Hz,3H,5-CH3);
13C NMR(CDCl3):δ164.4,150.4,130.7,123.6,119.1(pyrrole),108.4(pyrrole),68.3(1),58.3(2),34.0(3),19.1(4),13.7(5);
HR MS:calcd for C16H18N2O4Na(M+Na+) 325.1159,found 325.1164.
1H NMR(CDCl3):δ
8.35(s,1H,1’-H),
7.96-7.64(m,7H,Ar),
7.57-7.12(m,9H,Ar),
7.11-7.03(m,1H,Ar),
6.99-6.88(m,2H,Ar),
6.80-6.70(m,2H,pyrrole),
6.49(d,J=2.0Hz,1H,indole-2’’),
6.24-6.12(m,2H,pyrrole),
4.99(t,J=7.6Hz,1H,2-H),
3.68(dd,J=14.8,7.6Hz,1H,3-CH2),
3.39(dd,J=14.8,7.6Hz,1H,3-CH2);
13C NMR(CDCl3):δ169.6(1),135.9,134.0,133.9,133.7,133.7,130.9,130.8,129.1,129.0,128.81,128.77,126.9,126.7,126.7,126.0,125.84,125.79,125.6,125.2,125.2,123.21,123.18,123.0,122.1,120.1(pyrrole),119.6,118.2,111.1,109.9,108.8,72.1(1’),62.4(2),28.3(3);
HR MS:calcd for C36H28N2O2Na(M+Na+) 543.2043,found 543.2018.
なお、化合物2uの鏡像体過剰率は、LiAlH4を用いて化合物2uを還元し、対応するアルコール2u’に変換した後に求めた。
HPLC(CHIRALPAK AD-H,i-PrOH/hexane=1/9,flow rate=0.75mL/min):tR=26.1min(91.8%),tR=36.0min(8.2%);
1H NMR(DMSO-d6):δ
10.73(s,1H,indole-1’),
7.48(d,J=7.5Hz,1H,indole),
7.30(d,J=7.5Hz,1H,indole),
7.04(dd,J=7.5,7.5Hz,1H,indole),
6.96(dd,J=7.5,7.5Hz,1H,indole),
6.83-6.71(m,3H,indole,pyrrole),
6.01-5.85(m,2H,pyrrole),
4.90(t,J=5.5Hz,1H,OH),
4.21(ddt,J=8.5,6.5,5.5Hz,1H,2-H),
3.66(dd,J=5.5,5.5Hz,2H,1-CH2),
3.25(dd,J=14.5,6.5Hz,1H,3-H),
3.03(dd,J=14.5,8.5Hz,1H,3-H);
13C NMR(DMSO-d6):δ135.9,127.3,123.1,120.8,119.4,118.2,118.1,111.3,110.7,106.9,64.3(1),62.0(2),27.8(3);
HR MS:calcd for C15H16N2ONa(M+Na+) 263.1155,found 263.1156.
HPLC(CHIRALPAK IA-3,i-PrOH/hexane=1/9,flow rate=0.5mL/min):tR=12.2min(5.6%),tR=14.5min(94.4%);
1H NMR(CDCl3):δ
8.35(s,1H,1’-H),
7.90-7.68(m,6H,Ar),
7.86(d,J=7.2Hz,1H,indole-7’),
7.50-7.14(m,9H,Ar),
7.01(s,1H,indole-2’),
6.95(d,J=6.8Hz,1H,Ar),
6.91(d,J=7.2Hz,1H,Ar),
6.77(t,J=2.0Hz,2H,pyrrole),
6.21(t,J=2.0Hz,2H,pyrrole),
5.02(t,J=7.6Hz,1H,2-H),
3.63(dd,J=14.8,7.6Hz,1H,3-CH2),
3.33(dd,J=14.8,7.6Hz,1H,3-CH2),
1.61(s,9H,t-Bu);
13C NMR(CDCl3):δ169.2(1),149.4(Boc),135.3,133.9,133.8,133.69,133.67,130.9,130.8,129.8,129.2,129.0,128.84,128.75,126.7,126.6,125.94,125.85,125.8,125.5,125.2,125.1,124.5,124.2,123.1,123.0,122.6,120.0(pyrrole),118.5,115.3,114.7,109.1(pyrrole),83.5(t-Bu),72.3(1’),61.7(2),28.12(t-Bu),28.07(3);
HR MS:calcd for C41H36N2O4Na(M+Na+) 643.2567,found 643.2551.
HPLC(CHIRALPAK IA-3,i-PrOH/hexane=2/8,flow rate=0.75mL/min):tR=30.3min(5.8%),tR=32.9min(94.2%);
1H NMR(CDCl3):δ
8.35(s,1H,1’-H),
7.93-7.74(m,5H,Ar),
7.70(d,J=8.4Hz,1H,Ar),
7.54-7.18(m,6H,Ar),
7.12-6.98(m,5H,Ar),
6.95(d,J=7.2Hz,1H,Ar),
6.69(t,J=2.0Hz,2H,pyrrole),
6.18(t,J=2.0Hz,2H,pyrrole),
4.84(dd,J=8.0,7.6Hz,1H,2-H),
3.48(dd,J=14.0,7.6Hz,1H,3-CH2),
3.24(dd,J=14.0,8.0Hz,1H,3-CH2),
3.04(s,3H,Ms);
13C NMR(CDCl3):δ168.8(1),148.1,135.5,133.8,133.73,133.67,130.9,130.7,130.6,130.6,129.3,129.0,128.9,128.8,126.8,126.7,126.1,125.9,125.8,125.3,125.2,123.1,122.9,122.0,122.0,120.0(pyrrole),109.2(pyrrole),72.3(1’),63.1(2),37.8(Ms),37.2(Ms);
HR MS:calcd for C35H29NO5SNa(M+Na+) 598.1659,found 598.1663.
HPLC(CHIRALPAK ID,i-PrOH/hexane=2/8,flow rate=0.75mL/min):tR=29.9min(8.5%),tR=32.6min(91.5%);
1H NMR(CDCl3):δ
8.39(s,1H,1’-H),
8.02-7.66(m,6H,Ar),
7.55-7.39(m,3H,Ar),
7.37-7.20(m,4H,Ar),
7.09(d,J=6.8Hz,1H,Ar),
7.03-6.85(m,3H,Ar),
6.65(t,J=2.0Hz,2H,pyrrole),
6.16(t,J=2.0Hz,2H,pyrrole),
4.83(dd,J=9.2,6.4Hz,1H,2-H),
3.44(dd,J=14.0,6.4Hz,1H,3-CH2),
3.27(dd,J=14.0,9.2Hz,1H,3-CH2),
3.15(s,3H,Ms),3.05(s,3H,Ms);
13C NMR(CDCl3):δ168.5(1),140.8,139.9,137.1,133.78,133.76,133.7,133.6,130.9,130.6,129.4,129.1,129.0,128.81,128.77,128.77,127.0,126.7,126.3,126.0,125.8,125.2,125.2,124.3,124.2,123.0,122.8,120.1(pyrrole),109.4(pyrrole),72.4(1’),62.7(2),38.4(Ms),38.3(Ms),37.8(3);
HR MS:calcd for C36H31NO8S2Na(M+Na+) 692.1383,found 692.1412.
1H NMR(CDCl3):δ
8.41(s,1H,1’-H),
7.97-7.80(m,6H,Ar),
7.50-7.11(m,13H,Ar),
6.75(t,J=2.1Hz,2H,pyrrole),
6.18(t,J=2.1Hz,2H,pyrrole),
4.94(t,J=6.0Hz,1H,2-H),
4.42(d,J=12.0Hz,2H,Bn),
4.06(dd,J=9.8,6.0Hz,1H,3-CH2),
3.96(dd,J=9.8,6.0Hz,1H,3-CH2).
なお、化合物2yの鏡像体過剰率は、LiAlH4を用いて化合物2yを還元し、p-ニトロ安息香酸クロライドを用いてアシル化して、対応するp-ニトロ安息香酸エステル2y’に変換した後に求めた。
(S)-3-(benzyloxy)-2-(1H-pyrrol-1-yl)propyl 4-nitrobenzoate(2y’)
HPLC(CHIRALPAK AD-H,i-PrOH/hexane=1/9,flow rate=0.7mL/min):tR=22.7min(82.1%),tR=24.3min(17.9%);
1H NMR(CDCl3):δ
8.25(d,J=8.8Hz,2H,Ar),
8.06(d,J=8.8Hz,2H,Ar),
8.04-7.26(m,5H,Ar),
6.78(t,J=2.0Hz,2H,pyrrole),
6.18(t,J=2.0Hz,2H,pyrrole),
4,74(dd,J=11.2,4.8Hz,1H,1-CH2),
4.69(dd,J=11.2,7.6Hz,1H,1-CH2),
4.54(d,J=12.0Hz,2H,Bn)
4.57-4.50(m,1H,2-H),
3.88(dd,J=9.8,6.0Hz,1H,3-CH2),
3.85(dd,J=9.8,5.2Hz,1H,3-CH2),
13C NMR(CDCl3):δ164.2(1’),150.6,137.4,135.0,130.7,128.5,127.9,127.7,123.6,119.8(pyrrole),108.7(pyrrole),73.5(Bn),69.8(3),65.6(2),57.9(1);
IR(KBr):3109,3062,3031,2916,2862,1959,1728,1527,1350,1273,1103,725cm-1.
HPLC(CHIRALPAK AD-H,i-PrOH/hexane=1/99,flow rate=0.5mL/min):tR=28.8min(7.4%),tR=30.2min(92.6%);
1H NMR(CDCl3):δ
8.43(s,1H,1’-H),
8.02-7.23(m,6H,Ar),
7.55-7.07(m,8H,Ar),
6.76(t,J=2.2Hz,2H,pyrrole),
6.24(t,J=2.2Hz,2H,pyrrole),
5.66(ddt,J=17.0,10.0,6.8Hz,1H,4-H),
5.09(ddd,J=17.0,2.6,1.6Hz,1H,5-CH2),
5.05(ddd,J=10.0,2.6,1.2,1H,5-CH2),
2.98-2.76(m,2H,3-CH2);
13C NMR(CDCl3):δ169.2(1),134.1,133.9,133.8,133.7,132.1,131.0,130.8,129.3,129.0,128.9,128.8,126.8,126.6,126.2,125.9,125.8,125.5,125.26,125.25,123.22,123.17,120.0(pyrrole),118.9,108.9(pyrrole),72.1(1’),61.7(2),36.2(3);
HR MS:calcd for C30H25NO2Na(M+Na+) 454.1778,found 454.1789.
IR(KBr):3062,3016,2931,1743,1550,1389,1164,941,756cm-1.
HPLC(CHIRALPAK OD-H×2,i-PrOH/hexane=1/9,flow rate=0.5mL/min):tR=19.5min(95.5%),tR=23.5min(4.5%);
1H NMR(CDCl3):δ
8.38(s,1H,1’-H),
8.03-7.70(m,6H,Ar),
7.53-7.20(m,6H,Ar),
7.11(d,J=7.2Hz,1H,Ar),
7.01(d,J=7.2Hz,1H,Ar),
6.71(t,J=2.0Hz,2H,pyrrole),
6.18(t,J=2.0Hz,2H,pyrrole),
4.22(d,J=10.4Hz,1H,2-H),
2.95-2.36(m,1H,3-H),
0.97(d,J=6.4Hz,3H,4-CH3)
0.75(d,J=6.4Hz,3H,4-CH3);
13C NMR(CDCl3):δ169.4(1),134.2,134.0,133.81,133.76,131.0,130.9,129.2,129.0,128.9,128.8,126.7,126.6,126.1,125.9,125.8,125.5,125.2,125.2,123.22,123.18,120.3(pyrrole),108.6(pyrrole),71.9(1’),69.1(2),30.9(3),19.5(4),18.5(4);
HR MS:calcd for C30H27NO2Na(M+Na+) 456.1934,found 456.1932;
IR(KBr):3061,2967,2873,1740,1599,1509,1486,1180,783,735cm-1.
Mp:149-152℃(CHCl3/hexane)
Di(1-naphthyl)methyl (S)-2-(1H-pyrrole-1-yl)hexanoate(2bb)[表6中、エントリー5;収率定量的、79%ee]
HPLC(CHIRALPAK AD-H,i-PrOH/hexane=2/98,flow rate=0.5mL/min):tR=20.1min(10.3%),tR=21.7min(89.7%);
1H NMR(CDCl3):δ
8.38(s,1H,1’-H),
7.97-7.79(m,6H,Ar),
7.50-7.03(m,8H,Ar),
6.71(t,J=2.1Hz,2H,pyrrole),
6.19(t,J=2.1Hz,2H,pyrrole),
4.64(dd,J=9.2,6.6Hz,1H,2-H),
2.14(ddt,J=20.4,9.2,3.2Hz,1H,3-CH2),
2.00(ddt,J=20.4,6.6,3.2Hz,1H,3-CH2),
1.31-1.15(m,4H,3-CH2,4-CH2),
0.80(t,J=7.0Hz,3H,6-CH3);
13C NMR(CDCl3):δ169.9(1),134.3,134.1,133.82,133.76,131.0,130.9,129.2,129.1,128.9,128.8,126.7,126.6,126.1,125.9,125.8,125.6,125.3,123.2,120.0(pyrrole),108.7(pyrrole),71.9(1’),62.1(2),31.8(3),27.9(4),22.1(5),13.7(6);
HR MS:calcd for C31H29NO2Na(M+Na+) 470.2091,found 470.2103;
IR(KBr):3052,2958,2929,2862,1745,1599,1510,1488,1162,796,721cm-1.
Mp:108-109℃(CH2Cl2/hexane)
1H NMR(CDCl3):δ
8.37(s,1H,1’-H),
7.97-7.80(m,6H,Ar),
7.51-7.01(m,8H,Ar),
6.71(t,J=2.2Hz,2H,pyrrole),
6.19(t,J=2.2Hz,2H,pyrrole),
4.75(dd,J=8.8,6.8Hz,1H,2-H),
1.97(ddd,J=12.0,8.8,3.8Hz,1H,3-CH2),
1.95(ddd,J=12.0,6.8,3.8Hz,1H,3-CH2),
1.47(qqt,J=6.4,6.4,3.8Hz,1H,4-H),
0.86(d,J=6.4Hz,6H,5-CH3);
13C NMR(CDCl3):δ170.0(1),134.2,134.1,133.81,133.76,131.0,130.9,129.2,129.0,128.9,128.8,126.7,126.6,126.1,125.9,125.8,125.6,125.3,123.1,120.1(pyrrole),108.7(pyrrole),71.9(1’),60.3(2),40.9(3),24.6(4),22.6(5),21.8(5);
HR MS:calcd for C31H30NO2(M+H+) 448.2271,found 448.2270;
IR(KBr):3057,2957,2931,1749,1597,1509,1173,961,774,723cm-1;
Mp:133-135℃(CH2Cl2/hexane)
なお、化合物2ccの鏡像体過剰率は、LiAlH4を用いて化合物2ccを還元し、p-ニトロ安息香酸クロライドを用いてアシル化して、対応するp-ニトロ安息香酸エステル2cc’に変換した後に求めた。
HPLC(CHIRALPAK OD-H,i-PrOH/hexane=1/9,flow rate=0.5mL/min):tR=16.5min(13.2%),tR=18.2min(86.8%);
1H NMR(CDCl3):δ
8.26(d,J=8.8Hz,2H,Ar),
8.08(d,J=8.8Hz,2H,Ar),
8.01-7.20(m,7H,Ar),
6.73(t,J=2.2Hz,2H,pyrrole),
6.17(t,J=2.2Hz,2H,pyrrole),
4.55(dd,J=11.2,4.4Hz,1H,1-CH2),
4.45(dd,J=11.2,8.4Hz,1H,1-CH2),
4.41-4.34(m,1H,2-H),
1.91(dd,J=10.2,4.8Hz,1H,3-CH2),
1.88(dd,J=10.2,4.8Hz,1H,3-CH2),
1.64-1.46(m,2H,3-CH2,4-H),
0.95(d,J=6.4Hz,3H,5-CH3),
0.92(d,J=6.4Hz,3H,5-CH3);
13C NMR(CDCl3):δ164.3(1’),150.7,135.2,130.7,123.6,119.1(pyrrole),108.4(pyrrole),68.6(1),56.6(2),40.7(3),24.5(4),23.0(5),21.8(5);
HR MS:calcd for C17H21N2O4(M+H+) 317.1496,found 317.1502;
IR(KBr):3108,3074,2955,2933,2869,1729,1520,1270,1119,719cm-1.
HPLC(CHIRALPAK AD-H,i-PrOH/hexane=1/9,flow rate=0.7mL/min):tR=7.8min(10.5%),tR=8.2min(89.5%);
1H NMR(CDCl3):δ
8.38(s,1H,1’-H),
7.97-7.80(m,6H,Ar),
7.52-7.04(m,8H,Ar),
6.71(t,J=2.0Hz,2H,pyrrole),
6.19(t,J=2.0Hz,2H,pyrrole),
4.64(dd,J=8.8,6.8Hz,1H,2-H),
2.13(ddt,J=14.0,8.8,5.2Hz,1H,3-CH2),
2.00(ddt,J=14.0,6.8,5.2Hz,1H,3-CH2),
1.23-1.15(m,8H,4-CH2,5-CH2,6-CH2,7-CH2),
0.83(t,J=7.0Hz,3H,8-CH3);
13C NMR(CDCl3):δ169.9(1),134.3,134.1,133.81,133.76,131.0,130.9,129.2,129.1,128.9,128.8,126.7,126.6,126.1,125.9,125.8,125.6,125.3,123.2,120.0(pyrrole),108.7(pyrrole),71.9(1’),62.1(2),32.1(3),31.5(4),28.7(5),25.7(6),22.4(7),13.98(8);
HR MS:calcd for C33H33NO2Na(M+Na+) 498.2404,found 498.2421;
IR(KBr):3052,2954,2926,2856,1737,1598,1509,1159,1092,796,719cm-1;
Mp:96-97℃(CH2Cl2/hexane)
HPLC(CHIRALPAK AD-H,i-PrOH/hexane=2/98,flow rate=0.5mL/min):tR=31.5min(2.9%),tR=43.3min(97.1%);
1H NMR(CDCl3):δ
8.40(s,1H,1’-H),
8.03-7.73(m,6H,Ar),
7.52-7.01(m,8H,Ar),
6.72(t,J=2.1Hz,2H,pyrrole),
6.20(t,J=2.1Hz,2H,pyrrole),
4.87(t,J=7.6Hz,1H,2-H),
3.04(ddd,J=16.8,7.6,2.6Hz,1H,3-CH2),
2.90(ddd,J=16.8,7.6,2.6Hz,1H,3-CH2),
1.96((t,J=2.6Hz,1H,5-H);
13C NMR(CDCl3):δ168.1(1),133.91,133.86,133.7,131.8,131.4,130.9,130.8,129.1,129.0,128.9,128.8,127.9,127.5,126.74,126.69,126.4,125.99,125.9,125.8,125.64,125.56,125.4,125.3,125.2,123.2,123.1,122.8,120.1(pyrrole),109.0(pyrrole),72.3(1’),62.4(2),35.8(3);
HR MS:calcd for C30H24NO2Na(M+Na+) 430.1802,found 430.1817;
IR(KBr):3054,3010,2958,1738,1598,1510,1273,1157,944,777,731cm-1.
1H NMR(CDCl3):δ
8.40(s,1H,1’-H),
8.00-7.87(m,6H,Ar),
7.85-7.00(m,13H,Ar),
6.71(t,J=2.1Hz,2H,pyrrole),
6.22(t,J=2.1Hz,2H,pyrrole),
4.61(dd,J=9.2,6.0Hz,1H,2-H),
2.60-2.29(m,4H,3-CH2,4-CH2);
13C NMR(CDCl3):δ169.6(1),140.0,134.2,134.0,133.84,133.76,131.0,130.8,129.3,129.04,128.96,128.8,128.5,126.8,126.7,126.3,126.2,125.9,125.8,125.5,125.3,123.18,123.16,120.1(pyrrole),108.9(pyrrole),71.98(1’),60.98(2),33.4(3),31.6(4);
HR MS:calcd for C35H29NO2Na(M+Na+) 518.2091,found 518.2077;
IR(KBr):3052,3025,2956,2925,2858,1737,1626,1490,1285,1174,794,728cm-1;
Mp:114-115℃(CH2Cl2/hexane)
なお、化合物2ffの鏡像体過剰率は、LiAlH4を用いて化合物2ffを還元し、p-ニトロ安息香酸クロライドを用いてアシル化して、対応するp-ニトロ安息香酸エステル2ff’に変換した後に求めた。
HPLC(CHIRALPAK AD-H,i-PrOH/hexane=1/9,flow rate=0.5mL/min):tR=21.9min(82.5%),tR=27.9min(17.5%);
1H NMR(CDCl3):δ
8.26(d,J=8.8Hz,2H,Ar),
8.07(d,J=8.8Hz,2H,Ar),
7.32-7.13(m,5H,Ar),
6.75(t,J=2.2Hz,2H,pyrrole),
6.22(t,J=2.2Hz,2H,pyrrole),
4.54(dd,J=11.6,5.2Hz,1H,1-CH2),
4.49(dd,J=11.6,7.4Hz,1H,1-CH2),
4.24(dddd,J=10.4,7.4,5.0,4.8Hz,1H,2-H),
2.68-2.48(m,2H,4-CH2)
2.28-2.16(m,2H,3-CH2);
13C NMR(CDCl3):δ164.2(1’),150.6,140.4,135.0,130.7,128.6,128.5,126.3,123.6,119.1(pyrrole),108.7(pyrrole),68.2(1),57.5(2),33.4(3),31.7(4);
IR(KBr):3109,3062,3024,2931,2862,1952,1728,1527,1273,1103,717cm-1
1H NMR(CDCl3):δ
8.34(s,1H,1’-H),
7.92-7.70(m,9H,Ar),
7.47-6.92(m,12H,Ar),
6.74(t,J=2.0Hz,2H,pyrrole),
6.19(t,J=2.0Hz,2H,pyrrole),
5.09(dd,J=7.8,6.8Hz,1H,2-H),
4.02(dd,J=14.4,7.8Hz,1H,3-CH2),
3.66(dd,J=14.4,6.8Hz,1H,3-CH2);
13C NMR(CDCl3):δ169.2(1),133.91,133.86,133.7,131.8,131.4,130.9,130.8,129.1,129.0,128.9,128.8,127.9,127.5,126.74,126.69,126.4,125.99,125.9,125.8,125.64,125.56,125.4,125.3,125.2,123.2,123.1,122.8,120.1(pyrrole),109.0(pyrrole),72.3(1’),62.4(2),35.8(3);
IR(KBr):3054,3010,2958,1738,1598,1510,1273,1157,944,777,731cm-1.
なお、化合物2ggの鏡像体過剰率は、LiAlH4を用いて化合物2ggを還元し、p-ニトロ安息香酸クロライドを用いてアシル化して、対応するp-ニトロ安息香酸エステル2gg’に変換した後に求めた。
HPLC(CHIRALPAK AD-H,i-PrOH/hexane=1/9,flow rate=0.5mL/min):tR=33.6min(92.9%),tR=36.8min(7.1%);
1H NMR(CDCl3):δ
8.24(d,J=8.8Hz,2H,Ar),
8.03(d,J=8.8Hz,2H,Ar),
8.01-7.20(m,7H,Ar),
6.77(t,J=2.0Hz,2H,pyrrole),
6.18(t,J=2.0Hz,2H,pyrrole),
4.77-4.70(m,1H,2-H),
4.64(dd,J=11.2,6.4Hz,1H,1-CH2),
4.60(dd,J=11.2,5.2Hz,1H,1-CH2),
3.70(dd,J=14.0,7.6Hz,1H,3-CH2),
3.66(dd,J=14.0,6.8Hz,1H,3-CH2);
13C NMR(CDCl3):δ164.1(1’),150.6,134.9,134.0,132.7,131.5,130.7,129.2,127.99,127.5,126.5,125.8,125.5,123.6,122.9,119.2(pyrrole),108.7(pyrrole),67.4(1),58.8(2),36.6(3);
IR(KBr):3109,3055,3008,2954,1952,1728,1527,1273,1095,725cm-1
HPLC(CHIRALPAK AD-H,i-PrOH/hexane=1/9,flow rate=0.5mL/min):tR=15.1min(2.2%),tR=22.3min(97.8%);
1H NMR(CDCl3):δ
8.36(s,1H,1’-H),
7.94-7.27(m,12H,Ar),
7.12(dd,J=5.4,1.2Hz,1H,thiophen),
7.03(d,J=7.2Hz,1H,Ar),
6.93(d,J=7.2Hz,1H,Ar),
6.84(dd,J=5.4,3.2Hz,1H,thiophen),
6.72(t,J=2.0Hz,2H,pyrrole),
6.64(d,J=3.2Hz,1H,thiophen),
6.21(t,J=2.0Hz,2H,pyrrole),
4.89(t,J=7.6Hz,1H,2-H),
3.74(dd,J=14.8,7.6Hz,1H,3-CH2),
3.46(dd,J=14.8,7.6Hz,1H,3-CH2);
13C NMR(CDCl3):δ168.8(1),137.7,133.9,133.80,133.79,133.72,131.0,130.8,129.3,129.0,128.9,128.8,126.92,126.86,126.6,126.5,126.3,125.9,125.8,125.3,124.6,123.2,123.1,120.1(pyrrole),109.2(pyrrole),72.4(1’),63.3(2),32.7(3);
HR MS:calcd for C32H25NO2SNa(M+Na+) 510.1498,found 510.1505;
IR(KBr):3056.1741,1598,1509,1263,1167,955,778,727cm-1;
Mp:120-121℃(CH2Cl2/hexane).
HPLC(CHIRALPAK AD-H,i-PrOH/hexane=3/7,flow rate=0.75mL/min):tR=22.6min(17.3%),tR=23.7min(82.7%);
1H NMR(CDCl3):δ
8.41(s,1H,1’-H),
7.99(d,J=8.4Hz,1H,Ar),
7.88-7.74(m,5H,Ar),
7.49-7.17(m,17H,Ar),
7.05(d,J=7.2Hz,1H,Ar),
7.00-6.92(m,6H,Ar),
6.63(t,J=2.0Hz,2H,pyrrole),
6.22(s,1H,imidazole),
6.11(t,J=2.0Hz,2H,pyrrole),
5.13(dd,J=10.0,5.6Hz,1H,2-H),
3.41(dd,J=14.8,5.6Hz,1H,3-CH2),
3.19(d,J=14.8,10.0Hz,1H,3-CH2);
13C NMR(CDCl3):δ169.3(1),149.4,142.2,138.1,135.5,134.1,134.0,133.7,133.6,130.9,130.8,129.6,129.1,128.9,128.7,127.8,126.7,126.5,126.1,125.8,125.6,125.5,125.2,125.1,123.1,123.0,120.0(pyrrole),119.9,108.4(pyrrole),106.4,75.0(Tr),71.8(1’),61.7(2),31.8(3);
HR MS:calcd for C50H39N3O2(M+H+) 714.3115,found 714.3104;
IR(KBr):3053,2923,1741,1598,1510,1486,1158,797,782,773,750,718cm-1;
Mp:191-194℃(AcOEt/hexane)
カルボン酸ジ(1-ナフチル)メチルエステル2sは難溶性であるため、まずエステル交換反応を行い、可溶性のカルボン酸メチルエステル3sを収率89%で得た。ジ(1-ナフチル)メチルエステル残基は、ジ(1-ナフチル)メチルメチルエーテルとして収率91%で単離された(式1)。次いで、カルボン酸メチルエステル3sをオゾン分解してからBoc保護し、高い鏡像体過剰率を維持したままでN-Boc-フェニルアラニンメチルエステル4sを収率70%で得た(式2、87%ee)。さらに、ジ(1-ナフチル)メチルメチルエーテルを加水分解して、ジ(1-ナフチル)メタノールを収率92%で回収した(式3)。
なお、ジ(1-ナフチル)メタノールの回収に関して、Birmanの報告ではカルボン酸ジ(1-ナフチル)メチルエステルをLiAlH4で還元して対応するアルコールを得ているが(X.Yang, V.B.Birman, Angew. Chem. Int. Ed., 2011,50, 5553-5555)、上記の方法では基質のカルボニル基が保持されるという利点がある。
各反応の詳細は以下のとおりである。
カルボン酸ジ(1-ナフチル)メチルエステル2s(211mg,0.439mmol)をメタノール(13.2mL)及びジクロロメタン(13.2mL)に溶解した溶液中に、1,4-ジオキサン(4.0M,4.39mL,17.6mmol)を0℃で加えた。反応液を室温で24時間撹拌した後、クロロホルムで抽出し、有機層を分取した。有機層を硫酸ナトリウムで乾燥した後、濾過、減圧濃縮して粗生成物を得た。粗生成物をシリカゲル薄層クロマトグラフィ(展開溶媒:トルエン)により分離し、淡黄色油状のカルボン酸メチルエステル3s(89.6mg,収率89%,87%ee)と、無色固体状のジ(1-ナフチル)メチルメチルエーテル(120mg,収率91%)を得た。
HPLC(CHIRALPAK AD-H,i-PrOH/hexane=1/49,flow rate=0.75mL/min):tR=25.4min(93.6%),tR=37.6min(6.4%);
[α]D 26 -50.6(c 1.09,CHCl3);
IR(neat):3030,2952,2852,1745,1488,1169,726cm-1;
1H NMR(CDCl3):δ
7.29-7.19(m,3H,Ar),
7.07-6.98(m,2H,Ar),
6.71(t,2H,J=2.8Hz,pyrrole),
6.14(t,2H,J=2.8Hz,pyrrole),
4.75(dd,J=11.6,8.8Hz,1H,2-H),
3.70(s,3H,OCH3),
3.42(dd,J=18.4,8.8Hz,1H,3-CH2),
3.25(dd,J=18.4,11.6Hz,1H,3-CH2);
13C NMR(CDCl3):δ170.6(1),136.3,128.8,128.5,127.0,120.1(pyrrole),108.7(pyrrole),63.5(2),52.5(OCH3),39.5(3);
HR MS:calcd for C14H15NO2Na(M+Na+) 252.0995,found 252.1000.
Mp:139-141℃(AcOEt/hexane);
IR(KBr):2981,2880,1595,1508,1155,1092,815,790,777cm-1;
1H NMR(CDCl3):δ
8.10-7.98(m,2H,Ar),
7.93-7.87(m,2H,Ar),
7.85-7.78(m,2H,Ar),
7.53-7.35(m,8H,Ar),
6.72(s,1H,1-H),
3.62(s,3H,OCH3);
13C NMR(CDCl3):δ136.0,134.0,131.8,128.8,128.6,126.3,125.8,125.6,125.4,123.7,79.4(1),57.9(OCH3);
HR MS:calcd for C22H18ONa(M+Na+) 321.1250,found 321.1249.
カルボン酸メチルエステル3s(85.6mg,0.373mmol)をメタノール(15mL)に溶解した溶液を-78℃で2時間、オゾン処理した。反応液中にアルゴンガスを1分間バブリングした後、チオ尿素(34.1mg,0.448mmol)をメタノール(4mL)中に溶解した溶液を-78℃で添加した。次いで、反応液を-78℃で30分間、0℃で1時間撹拌し、セライト濾過した。濾液を減圧乾燥し、残渣をメタノール(7.46mL)に溶解した。
次いで、その混合液中に、塩酸を含有する1,4-ジオキサン(4.0M,7.46mL,29.8mmol)を0℃で加え、室温で6時間撹拌した。その液を減圧乾燥し、残渣をTHF(5mL)に懸濁させた。
次いで、その混合液中に飽和炭酸水素ナトリウム水溶液(5mL)及びジ(tert-ブチル)ジカーボネート(325mg,1.49mmol)を0℃で添加した。反応液を室温で60時間撹拌した後、水で希釈した。次いで、混合液を酢酸エチルで抽出し、有機層を分取した。有機層を硫酸ナトリウムで乾燥した後、濾過、減圧濃縮して粗生成物を得た。粗生成物をシリカゲル薄層クロマトグラフィ(展開溶媒:酢酸エチル/ヘキサン=6/14)により分離し、無色油状のN-Boc-フェニルアラニンメチルエステル4s(72.9mg,収率70%,87%ee)を得た。
HPLC(CHIRALPAK IB-3,i-PrOH/hexane=1/49,flow rate=0.75mL/min):tR=12.3min(6.6%),tR=14.4min(93.4%);
[α]D 25 +39.5(c 1.13,CHCl3).
なお、特定旋光度を含め、分光分析データは文献値と一致していた。
ジ(1-ナフチル)メチルメチルエーテル(119mg,0.399mmol)を1,4-ジオキサン(6.4mL)に溶解した溶液中に、スルホン酸水溶液(2M,3.2mL,6.4mmol)を室温で加えた。反応液を80℃で4時間加熱した後、室温で水を添加した。次いで、混合液を酢酸エチルで抽出し、有機層を分取した。有機層を硫酸ナトリウムで乾燥した後、濾過、減圧濃縮して粗生成物を得た。粗生成物をシリカゲル薄層クロマトグラフィ(展開溶媒:酢酸エチル/ヘキサン=1/3)により分離し、無色固体状のジ(1-ナフチル)メタノール(105mg,収率92%)を得た。なお、ジ(1-ナフチル)メタノールの分光分析データは文献値と一致していた。
カルボン酸ジ(1-ナフチル)メチルエステル2sを還元することにより、光学活性アルコール5sが収率89%で得られ、同時にジ(1-ナフチル)メタノールが収率96%で回収された(式4)。次いで、ジ(tert-ブチル)マロネートのカリウム塩を用いて対応するトリフルオロメタンスルホナート6sをアルキル化して、光学活性アルコール5sの2炭素伸長変換を行い、ジカルボン酸tert-ブチルジエステル7sを光学活性アルコール5sから収率91%で得た(式5)。次いで、ジカルボン酸tert-ブチルジエステル7sを脱炭酸及び分子内フリーデル-クラフツアシル化して6,7-ジヒドロインドリジン-8(5H)-オン誘導体8sを得、これをパラジウム炭素を用いて水素化し、単一のジアステレオマーとしてインドリジジン誘導体9sを得た。なお、中間体及び生成物9sの鏡像体過剰率は一連の変換中も維持された。
各反応の詳細は以下のとおりである。
カルボン酸ジ(1-ナフチル)メチルエステル2s(87%ee,196mg,0.407mmol)をテトラヒドロフラン(THF)(8.1mL)に溶解した溶液中に、LiAlO4(46.3mg,1.22mmol)を0℃で加えた。反応液を室温で3時間撹拌した後、水(60μL)及び水酸化ナトリウム水溶液(4.2M,60μL)を0℃で加えた。混合液を酢酸エチルとともに短セライトパッドで濾過し、濾液を減圧濃縮して粗生成物を得た。粗生成物をシリカゲル薄層クロマトグラフィ(展開溶媒:酢酸エチル/ヘキサン=9/11)により分離し、無色油状の光学活性アルコール5s(73.0mg,収率89%,88%ee)を得るとともに、ジ(1-ナフチル)メタノール(111mg,収率96%)を回収した。
HPLC(CHIRALPAK AD-H,i-PrOH/hexane=1/49,flow rate=0.75mL/min):tR=25.4min(93.9%),tR=37.4min(6.1%);
[α]D 27 -85.3(c 1.05,CHCl3);
IR(neat):3467,3028,2943,2877,1604,1493,725,702,636cm-1;
1H NMR(CDCl3):δ
7.34-7.13(m,3H,Ar),
7.08-6.94(m,2H,Ar),
6.70(t,J=2.0Hz,2H,pyrrole),
6.17(t,J=2.0Hz,2H,pyrrole),
4.20(tt,J=7.6,6.0Hz,1H,2-H),
3.83(dd,J=6.4,6.0Hz,2H,1-CH2),
3.06(d,J=7.6Hz,2H,3-CH2),
1.47(t,J=6.4Hz,1H,OH);
13C NMR(CDCl3):δ137.5,128.8,128.5,126.6,119.2(pyrrole),108.4(pyrrole),65.3,63.5,38.5(3);
HR MS:calcd for C13H15NONa(M+Na+) 224.1046,found 224.1044.
ジ(tert-ブチル)マロネート(2.76mL,12.4mL)をテトラヒドロフラン(THF)(22.4mL)に溶解した溶液中に、水素化カリウム(499mg,12.4mL)をTHF(6.2mL)に懸濁した液を0℃で滴下した。反応液を室温で18時間撹拌した後、ヘキサン(40mL)を加えた。その後、沈殿を濾別し、乾燥することにより、目的の化合物を無色固体として得た(2.57g,収率82%)。この化合物は、精製することなく以降の実験に使用した。
Mp:139-141℃(THF/hexane);
1H NMR(DMSO-d6):δ
1.41(s,1H,2-H),
1.27(s,18H,t-Bu).
光学活性アルコール5s(70.8mg,0.352mmol)及び2,6-ルチジン(81.1μL,0.704mmol)をジクロロメタン(4mL)に溶解した溶液中に、トリフルオロメタンスルホン酸無水物(70.9μL,0.422mmol)をジクロロメタン(4mL)に溶解した液を-30℃でゆっくりと加えた。反応液を-30℃で25分間撹拌した後、0.5Mの塩酸(6mL)を加えた。混合液をクロロホルムで抽出し、有機層を分取した。有機層を硫酸ナトリウムで乾燥した後、濾過、減圧濃縮して、トリフルオロメタンスルホナート6sの粗生成物を得た。この粗生成物は、精製することなく以降の実験に使用した。
HPLC(CHIRALPAK IA-3,i-PrOH/hexane=1/200,flow rate=0.75mL/min):tR=9.5min(93.6%),tR=11.9min(6.4%);
[α]D 27 -23.5(c 1.05,CHCl3);
IR(neat):2978,2935,1728,1489,1142,849,725cm-1;
1H NMR(C6D6):δ
7.06-6.94(m,3H,Ar),
6.79-6.74(m,2H,Ar),
6.48(t,J=2.0Hz,2H,pyrrole),
6.23(t,J=2.0Hz,2H,pyrrole),
4.16(dddd,J=11.6,8.6,6.0,4.0Hz,1H,2’-H),
3.07(dd,J=10.8,4.0Hz,1H,2-H),
2.74(dd,J=14.0,8.6Hz,1H,3’-CH2),
2.66(dd,J=14.0,6.0Hz,1H,3’-CH2),
2.50(ddd,J=14.4,10.8,4.0Hz,1H,1’-CH2),
2.32(ddd,J=14.4,11.6,4.0Hz,1H,1’-CH2),
1.29(s,9H,t-Bu),
1.28(s,9H,t-Bu);
13C NMR(C6D6):δ168.6(CO2t-Bu),168.5(CO2t-Bu),138.4,129.1,128.5,126.6,119.0(pyrrole),108.8(pyrrole),81.1(t-Bu),81.0(t-Bu),60.0(2’),50.8(2),43.6(3’),35.4(1’),27.8(t-Bu),27.7(t-Bu);
HR MS:calcd for C24H33NO4Na(M+Na+) 422.2302,found 422.2303.
ジカルボン酸tert-ブチルジエステル7s(121mg,0.303mmol)を1,4-ジオキサン(1.82mL)に溶解した溶液中に、12Mの塩酸(1.21mL)を加えた。反応液を0℃で3時間、室温で65時間撹拌した後、水を加えた。混合液を酢酸エチルで抽出し、有機層を分取した。有機層を硫酸ナトリウムで乾燥した後、濾過、減圧濃縮して粗生成物を得た。粗生成物をシリカゲル薄層クロマトグラフィ(展開溶媒:酢酸エチル/ヘキサン=1/1)により分離し、淡黄色油状の6,7-ジヒドロインドリジン-8(5H)-オン誘導体8s(58.8mg,収率86%,87%ee)を得た。
HPLC(CHIRALPAK IB-3,i-PrOH/hexane=1/9,flow rate=0.75mL/min):tR=24.5min(6.4%),tR=27.2min(93.6%);
[α]D 27 -86.2(c 1.02,CHCl3);
IR(neat):3024,2947,1658,1527,1496,748,702cm-1;
1H NMR(C6D6):δ
7.37-7.22(m,3H,Ar),
7.15-7.07(m,2H,Ar),
7.05(dd,J=4.0,2.0Hz,1H,pyrrole),
6.63(dd,J=2.4,2.0Hz,1H,pyrrole),
6.19(dd,J=4.0,2.4Hz,1H,pyrrole),
4.50-4.33(dddd,J=10.4,9.6,7.6,7.2Hz,1H,5-H),
3.22(dd,J=13.6,7.2Hz,1H,CH2Ph),
3.00(dd,J=13.6,7.6Hz,1H,CH2Ph),
2.73(ddd,J=18.0,11.2,5.2Hz,1H,7-CH2),
2.52(ddd,J=18.0,5.2,4.8Hz,1H,7-CH2),
2.32(dddd,J=11.2,10.8,9.6,4.8Hz,1H,6-CH2),
2.13(dddd,J=10.8,10.4,5.2,5.2Hz,1H,6-CH2);
13C NMR(C6D6):δ186.8,136.9,130.0,129.1,128.8,127.1,125.4,114.5,110.1,56.1(5),41.2(7),32.8(CH2Ph),27.4(6);
HR MS:calcd for C15H15NONa(M+Na+) 248.1078,found 248.1086.
6,7-ジヒドロインドリジン-8(5H)-オン誘導体8s(59.6mg,0.246mmol)及び硫酸(10μL)をメタノール(5.3mL)に溶解した溶液中に、パラジウム炭素(10%担持,50質量%,450mg,0.211mmol)を加えた。3atmの水素雰囲気下、混合液を室温で4日間撹拌した後、アルゴン置換した。混合液を短セライトパッドで濾過し、濾液を減圧濃縮した。残渣を1Mの塩酸(3mL)で希釈し、酢酸エチルで洗浄した。水酸化ナトリウム水溶液(4.2M,2mL)を用いて水層を塩基化した後、クロロホルムで抽出し、有機層を分取した。有機層を硫酸ナトリウムで乾燥した後、濾過、減圧濃縮して粗生成物を得た。粗生成物をシリカゲル薄層クロマトグラフィ(展開溶媒:28%アンモニア水/メタノール/クロロホルム=2/3/95)により分離し、無色油状のインドリジジン誘導体9s(31.1mg,収率53%,88%ee)を得た。
HPLC(CHIRALCEL OJ-H ×2,diethylamine/i-PrOH/hexane=0.2/1/100,flow rate=0.5mL/min):tR=16.7min(93.9%),tR=27.2min(6.1%);
[α]D 24 +66.4(c 1.01,CHCl3);
IR(neat):3024,2931,2862,1604,1496,1126,748cm-1;
1H NMR(C6D6):δ
7.25-7.04(m,5H,Ar),
3.26(ddd,J=8.8,8.8,2.2Hz,1H,3-CH2),
3.07(dd,J=13.0,4.0Hz,1H,CH2Ph),
2.48(dd,J=13.0,9.6Hz,1H,CH2Ph),
2.15(dddd,J=13.2,9.6,4.0,2.4Hz,1H,5-CH2),
1.94(ddd,J=8.8,8.8,8.8Hz,1H,3-CH2),
1.80-1.33(m,8H,1-CH2,2-CH2,6-CH2,8-CH2,8a-H),
1.27-0.96(m,3H,6-CH2,7-CH2);
13C NMR(C6D6):δ140.2,129.9,128.4,126.1,65.2,65.0,52.0,42.1,31.4,31.3,31.2,25.0,21.0;
HR MS:calcd for C15H22N(M+H+) 216.1747,found 216.1744.
Claims (10)
- 動的速度論的光学分割による光学活性カルボン酸エステルの製造方法であって、
下記式(a):
で表されるラセミのカルボン酸と、下記式(b):
で表されるアルコール又は下記式(c):
で表されるフェノール誘導体とを、酸無水物及び不斉触媒の存在下、双極子モーメント3.5以上の極性溶媒中で反応させ、前記ラセミのカルボン酸のうち一方のエナンチオマーを選択的にエステル化するとともに、他方のエナンチオマーをラセミ化する工程を含む、光学活性カルボン酸エステルの製造方法。 - 前記式(a)中のRa1が1H-ピロール-1-イル基である、請求項1又は2記載の光学活性カルボン酸エステルの製造方法。
- 双極子モーメント3.5以上の極性溶媒が、ジメチルアセトアミド、ジメチルホルムアミド、1,3-ジメチル-2-イミダゾリジノン、N-メチルピロリドン又はジメチルスルホキシドである、請求項1~3いずれか1項に記載の光学活性カルボン酸エステルの製造方法。
- 前記工程を塩基の存在下に行う、請求項1~4いずれか1項に記載の光学活性カルボン酸エステルの製造方法。
- 前記R1、R2及びR3の少なくとも1つがメチル基である、請求項6に記載の光学活性カルボン酸エステルの製造方法。
- 前記塩基が、ジイソプロピルエチルアミン、トリエチルアミン、ジメチルエチルアミン、ジメチルイソプロピルアミン、ジエチルメチルアミン又はジイソプロピルメチルアミンである、請求項6に記載の光学活性カルボン酸エステルの製造方法。
- 動的速度論的光学分割により得られた光学活性カルボン酸エステルの1H-ピロール-1-イル基をアミノ基に変換する工程をさらに含む、請求項1~9いずれか1項に記載の光学活性カルボン酸エステルの製造方法。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008140074A1 (ja) * | 2007-05-14 | 2008-11-20 | Tokyo University Of Science Educational Foundation Administrative Organization | 光学活性カルボン酸エステルを製造する方法 |
WO2009113428A1 (ja) | 2008-03-11 | 2009-09-17 | 学校法人東京理科大学 | 光学活性エステルの製造方法及び光学活性カルボン酸の製造方法 |
WO2012169575A1 (ja) | 2011-06-10 | 2012-12-13 | 学校法人東京理科大学 | 光学活性カルボン酸エステルの製造方法 |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008140074A1 (ja) * | 2007-05-14 | 2008-11-20 | Tokyo University Of Science Educational Foundation Administrative Organization | 光学活性カルボン酸エステルを製造する方法 |
WO2009113428A1 (ja) | 2008-03-11 | 2009-09-17 | 学校法人東京理科大学 | 光学活性エステルの製造方法及び光学活性カルボン酸の製造方法 |
WO2012169575A1 (ja) | 2011-06-10 | 2012-12-13 | 学校法人東京理科大学 | 光学活性カルボン酸エステルの製造方法 |
Non-Patent Citations (7)
Title |
---|
ATSUSHI TENGEJI ET AL.: "Racemic Amino San Hogotai no Doteki Sokudoron-teki Kogaku Bunkatsu ni yoru Kogaku Kassei Amino San no Gosei", CSJ: THE CHEMICAL SOCIETY OF JAPAN DAI 94 SHUNKI NENKAI (2014) KOEN YOKOSHU IV, 12 March 2014 (2014-03-12), pages 1358 * |
K. KASHIMA ET AL., J. CHEM. RES. MINIPRINT, 1988, pages 601 - 645 |
K. KASHIMA ET AL., J. CHEM. SOC. PERKIN TRANS., vol. 1, 1989, pages 1041 - 1046 |
KEN'YA NAKATA ET AL.: "Racemic-2-Amino-2-Aryl Sakusan-rui no Seiteki Oyobi Doteki Sokudoron Kogaku Bunkatsu Hanno no Kaihatsu", CSJ: THE CHEMICAL SOCIETY OF JAPAN DAI 93 SHUNKI NENKAI (2013) KOEN YOKOSHU IV, 8 March 2013 (2013-03-08), pages 1371 * |
TAKAYOSHI NAKAHARA ET AL.: "Racemic Amino San Hogotai no Doteki Sokudoron Kogaku Bunkatsu ni yoru Kogaku Kassei Amino San no Gosei", DAI 106 KAI SYMPOSIUM ON ORGANIC SYSTHESIS, 27 October 2014 (2014-10-27), JAPAN YOSHISHU, pages 74 - 75 * |
X. YANG; V. B. BIRMAN, ANGEW. CHEM. INT. ED., vol. 50, 2011, pages 5553 - 5555 |
YANG,X. ET AL.: "Kinetic Resolution of alpha- Substituted Alkanoic Acids Promoted by Homobenzotetramisole", CHEMISTRY - A EUROPEAN JOURNAL, vol. 17, no. 40, 2011, pages 11296 - 11304, XP055163057 * |
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Publication number | Publication date |
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EP3098217A1 (en) | 2016-11-30 |
US9796640B2 (en) | 2017-10-24 |
JPWO2015115650A1 (ja) | 2017-03-23 |
EP3098217A4 (en) | 2016-11-30 |
JP6498614B2 (ja) | 2019-04-10 |
US20170008820A1 (en) | 2017-01-12 |
EP3098217B1 (en) | 2018-04-25 |
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