JP4913077B2 - Process for producing optically active homoallyl hydrazino esters - Google Patents

Description

  In the present invention, an α-hydrazonoester and an allylborane derivative are reacted in the presence of a catalyst obtained by mixing a zinc compound and a chiral diamine ligand in a mixed solvent of water and an organic solvent. And a process for producing the corresponding optically active homoallyl hydrazino esters.

An optically active homoallylamine derivative is an important compound as a synthetic intermediate for natural products and physiologically active substances because it can convert the double bond in various ways. The optically active homoallylamine derivative is usually synthesized by an asymmetric allylation reaction on imines, and among them, the catalytic asymmetric allylation reaction to α-iminoester can directly synthesize an optically active α-amino acid derivative. This is one of the highly anticipated methods.
However, several catalytic asymmetric allylation reactions to imines containing an α-imino ester have been reported so far, most of which are reactions under strict anhydrous conditions (Non-Patent Documents 1 to 3). 10), and examples of highly selective asymmetric allylation reactions under mild conditions such as in water or a mixed solvent of water and an organic solvent are limited.
Yamamoto et al. Have reported a highly selective allylation reaction of imine in the presence of water using a palladium catalyst, but there are no studies using α-iminoesters as substrates and allyltin derivatives used. There is room for improvement in the fact that there is a strong harmfulness to the skin (see Non-Patent Document 11).

  In addition, the present inventors have reported an asymmetric allylation reaction of α-hydrazonoester in a mixed solvent of water and an organic solvent using an allylsilane derivative in the presence of an optically active zinc catalyst (Patent Document 1 and Non-Patent Document 1). (See Patent Document 12). This method is effective as a method for synthesizing optically active α-amino acid derivatives because the hydrazino ester obtained can be converted to an amino ester by cleaving its nitrogen-nitrogen bond (Non-patent Document 12). However, there remains room for improvement in the selectivity of the reaction itself. On the other hand, Cook et al. Have reported the asymmetric allylation of acylhydrazone, but this is a reaction in an organic solvent and requires an excessive amount of indium (Non-patent Document 13).

JP 2004-262873 A H. Nakamura, K. Nakamura, Y. Yamamoto, J. Am. Chem. Soc. 1998, 120, 4242-4243. D. Ferraris, T. Dudding, B. Young, W. J. Drury III, T. Lectka, J. Org. Chem. 1999, 64, 2168-2169. K. Nakamura, H. Nakamura, Y. Yamamoto, J. Org. Chem. 1999, 64, 2614-2615. X. Fang, M. Johannsen, S. Yao, N. Gathergood, R. G. Hazell, K. A. Jφrgensen, J. Org. Chem. 1999, 64, 4844-4849. T. Gastner, H. Ishitani, R. Akiyama, S. Kobayashi, Angew. Chem. Int. Ed. 2001, 40, 1896-1898. D. Ferraris, B. Young, C. Cox, T. Dudding, W. J. Drury III, L. Ryzhkov, A. E. Taggi, T. Lectka, J. Am. Chem. Soc. 2002, 124, 67-77. R. A. Fernandes, Y. Yamamoto, J. Org. Chem. 2004, 69, 735-738. G. R. Cook, R. Kargbo, B. Maity, Org. Lett. 2005, 7, 2767-2770. R. Wada, T. Shibuguchi, S. Makino, K. Oisaki, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2006, 128, 7687-7691. K. L. Tan, E. N. Jacobsen, Angew. Chem. Int. Ed. 2007, 46, 1315-1317 R. A. Fernandes, A. Stimac, Y. Yamamoto, J. Am. Chem. Soc. 2003, 125, 14133-14139. T. Hamada, K. Manabe, S. Kobayashi, Angew. Chem. Int. Ed. 2003, 42, 3927-3930. R. Kargbo, Y. Takahashi, S. Bhor, G. R. Cook, G. C. Lloyd-Jones, I. R. Shepperson, J. Am. Chem. Soc. 2007, 129, 3846-3847

  In the catalytic asymmetric allylation reaction for α-hydrazonoester using an allylborane derivative in a mixed solvent of water and an organic solvent, the present invention is capable of optically active homoallyl with higher yield and higher stereoselectivity. A method for producing a hydrazino ester is provided.

  The present inventors have studied a method for producing an optically active homoallyl hydrazino ester with higher yield and higher stereoselectivity. Conventional methods using allylsilane derivatives are less toxic than allyltin derivatives and are excellent methods, but yields and stereoselectivity are not always sufficient, and further improvements have been demanded. The inventors of the present invention have studied various allylating agents and are allylating agents having characteristics that are more reactive than allylsilane derivatives. The inventors have found that it has excellent characteristics, and have completed an invention about a highly enantioselective catalytic asymmetric allylation reaction of hydrazone using an allylborane derivative in a mixed solvent of an organic solvent and water.

That is, the present invention reacts an α-hydrazonoester with an allylborane derivative in the presence of a catalyst obtained by mixing a zinc compound and a chiral diamine ligand in a mixed solvent of water and an organic solvent. And a process for producing the corresponding optically active homoallyl hydrazino esters.
The present invention also relates to a method for producing the corresponding amino ester by cleaving the nitrogen-nitrogen bond of the optically active homoallyl hydrazino ester produced by the above-described method.

The present invention will be described in more detail as follows.
(1) In the presence of a catalyst obtained by mixing a zinc compound and a chiral diamine ligand in a mixed solvent of water and an organic solvent, an α-hydrazonoester and an allylborane derivative are reacted, A process for producing the corresponding optically active homoallyl hydrazino esters.
(2) A chiral diamine ligand is represented by the following general formula (1),

(In the formula, each R ¹ independently represents a hydrocarbon group which may have a substituent, or two R ¹ groups together to form a 5- to 10-membered ring together with adjacent carbon atoms. And R ² represents an aromatic hydrocarbon group which may have a substituent.)
The method as described in said (1) which is a diamine derivative represented by these.
(3) The method according to (2), wherein R ¹ in the general formula (1) is an aryl group which may have a substituent.
(4) α-hydrazono ester is represented by the following general formula (2),

(In the formula, R ³ and R ⁴ each independently represent a hydrocarbon group which may have a substituent.)
The method according to any one of (1) to (3) above, which is an α-hydrazonoester represented by the formula:
(5) The method according to (4), wherein R ³ in the general formula (2) is an alkyl group having 1 to 30 carbon atoms, and R ⁴ is an aryl group which may have a substituent.
(6) An allylborane derivative is represented by the following general formula (3):

(In the formula, R ⁵ and R ⁶ each independently represent a hydrogen atom or a hydrocarbon group which may have a substituent, and R ⁷ , R ⁸ and R ⁹ each independently represent a hydrogen atom. Or an optionally substituted aliphatic hydrocarbon group, R ¹⁰ represents a hydrogen atom, an optionally substituted aliphatic hydrocarbon group, a halogen group, an optionally protected hydroxyl group, An amino group which may be protected or a mercapto group which may be protected is shown.)
The method in any one of said (1)-(5) which is an allyl borane derivative represented by these.
(7) R ⁵ and R ⁶ in the general formula (3) are alkyl groups having 1 to 30 carbon atoms, R ⁷ , R ⁸ , and R ⁹ are hydrogen atoms, R ¹⁰ is a hydrogen atom, carbon The method as described in said (6) which is a C1-C30 alkyl group, a halogen group, the hydroxyl group which may be protected, or the amino group which may be protected.
(8) The method according to any one of (1) to (7), wherein the zinc compound is a zinc salt or zinc oxide.
(9) Zinc salt is ZnX ₂ (wherein X is an anion comprising a halogen atom, alkyl sulfonate ion, aryl sulfonate ion, perfluoroalkyl sulfonate ion, alkyl sulfate ion, aryl sulfate ion, perfluoroalkyl) (Showing sulfate ion, nitrate ion, perchlorate ion, acetate ion, or hydroxide ion).
(10) The optically active homoallyl hydrazino ester is represented by the following general formula (4):

(In the formula, R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ are the same as described above, and the * mark indicates an asymmetric carbon atom.)
The method in any one of said (1)-(9) which is optically active homoallyl hydrazino ester represented by these, or this isomer.
(11) A method for producing a corresponding amino ester by cleaving a nitrogen-nitrogen bond of the optically active homoallyl hydrazino ester produced by any one of the methods (1) to (10).
(12) The method according to (11) above, wherein the breaking of the nitrogen-nitrogen bond is reductive cleavage.

Below, the aspect of this invention is demonstrated in detail.
The α-hydrazono ester of the present invention includes those in which the α-position of carboxylic acid esters is hydrazoned, and preferably the other nitrogen atom of hydrazone is acylated. Preferred α-hydrazonoesters include α-hydrazonoesters represented by the general formula (2).
The “hydrocarbon group” of the group R ³ and the group R ⁴ in the α-hydrazono ester represented by the general formula (2) of the present invention has 1 to 30 carbon atoms, preferably 1 to 20 carbon atoms, A linear or branched alkyl group having 1 to 10 carbon atoms; a linear or branched alkenyl group having 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms and 2 to 10 carbon atoms; 15, preferably a saturated or unsaturated monocyclic, polycyclic or condensed cyclic alicyclic hydrocarbon group having 3 to 10 carbon atoms; 6 to 36 carbon atoms, preferably 6 to 18 carbon atoms, 6-12 monocyclic, polycyclic, or fused-ring carbocyclic aromatic groups; 6-36 carbon atoms, preferably 6-18 carbon atoms, 6-12 carbon atoms monocyclic, polycyclic The above-mentioned alkyl group having 1 to 20 carbon atoms is bonded to the carbocyclic aromatic group (aryl group) of the formula or condensed ring, and the carbon number is 7 Arylalkyl groups (carbocyclic araliphatic groups) having 7 to 20 carbon atoms, preferably 7 to 20 carbon atoms and 7 to 15 carbon atoms. Examples of such alkyl groups include, for example, methyl group, ethyl Group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, octyl group, etc., and examples of the alicyclic hydrocarbon group For example, cyclopropyl group, cyclopentyl group, cyclohexyl group, cyclooctyl group, bicyclo [1.1.0] butyl group, tricyclo [2.2.1.0] heptyl group, bicyclo [3.2.1] octyl The group bicyclo [2.2.2. Octyl group, adamantyl group (tricyclo [3.3.1.1] decanyl group), bicyclo [4.3.2] undecanyl group, tricyclo [5.3.1.1] dodecanyl group, and the like. Examples of the carbocyclic aromatic group include a phenyl group, a naphthyl group, a biphenyl group, a phenanthryl group, and an anthryl group. Examples of the arylalkyl group (carbocyclic araliphatic group) include a benzyl group. , A phenethyl group, an α-naphthyl-methyl group, and the like. Preferred hydrocarbon groups include linear or branched alkyl groups having 1 to 10 carbon atoms, monocyclic, polycyclic or condensed cyclic aryl groups having 6 to 12 carbon atoms, or 7 carbon atoms. To 15 arylalkyl groups, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, phenyl group, naphthyl group, benzyl group and the like. These groups may have a substituent as appropriate.
Particularly preferred group R ³ includes a linear or branched alkyl group having 1 to 10 carbon atoms, or an arylalkyl group having 7 to 15 carbon atoms, and group R ⁴ includes an alkyl group such as a methyl group. Monocyclic or polycyclic having 6 to 12 carbon atoms which may be substituted with a substituent such as an alkoxy group such as a methoxy group, a halogen atom such as a chlorine atom, a dialkylamino group such as a hydroxyl group, a nitro group or a dimethylamino group And an aryl group of the formula or condensed cyclic. Further preferred groups R ⁴ include phenyl group, p-dimethylaminophenyl group, p-methoxyphenyl group, p-nitrophenyl group, p-hydroxyphenyl group and the like.

Examples of the allylborane derivative of the present invention include a borane compound in which a boron atom is bonded to an allyl position in a carbon-carbon double bond. As a preferable allylborane derivative, an allylborane derivative represented by the above general formula (3) is used. Can be mentioned.
Examples of the “hydrocarbon group” of R ⁵ and R ⁶ in the allylborane derivative represented by the general formula (3) of the present invention include the above-described hydrocarbon groups, and these hydrocarbon groups are substituted with the above-described substituents. May be. Preferred groups of R ⁵ and R ⁶ in the allylborane derivative represented by the general formula (3) are linear or branched having 1 to 30 carbon atoms, preferably 1 to 20 carbon atoms and 1 to 10 carbon atoms. Alkyl groups such as a methyl group and an ethyl group. These R ⁵ and R ⁶ may be the same or different.
The “aliphatic hydrocarbon group” of R ⁷ , R ⁸ , R ⁹ and R ^{10 in} the allylborane derivative represented by the general formula (3) of the present invention has 1 to 30 carbon atoms, preferably 1 to 1 carbon atoms. 20, a linear or branched alkyl group having 1 to 10 carbon atoms; a linear or branched alkenyl group having 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, and 2 to 10 carbon atoms; Examples include saturated or unsaturated monocyclic, polycyclic or condensed cyclic alicyclic hydrocarbon groups having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, preferably 1 to 10 carbon atoms. Or a linear or branched alkyl group. Preferred examples of R ⁷ , R ⁸ and R ⁹ include a hydrogen atom, and R ¹⁰ represents a hydrogen atom or a straight chain having 1 to 30 carbon atoms, preferably 1 to 20 carbon atoms and 1 to 10 carbon atoms. A branched alkyl group can be mentioned.

In addition, examples of the halogen group of R ^{10 in} the allylborane derivative represented by the general formula (3) of the present invention include a chlorine atom, a bromine atom, an iodine atom, and a fluorine atom.
In the allylborane derivative represented by the general formula (3) of the present invention, the hydroxyl group, amino group, or mercapto group of R ¹⁰ may be protected with an appropriate protecting group as necessary. In the chemical reaction in the method of the invention, it is a group that can be chemically modified so as not to participate in the reaction, and after the reaction, the functional group can be easily eliminated by hydrolysis or hydrogenolysis Any group can be used as long as it can be reconstituted, and examples thereof include a protective group for a hydroxyl group, an amino group, or a mercapto group used in peptide synthesis. More specifically, as such a protecting group, for example, a straight chain or branched chain having 1 to 30 carbon atoms such as a methyl group or an ethyl group, preferably 1 to 20 carbon atoms, or 1 to 10 carbon atoms. An aralkyl group having 7 to 30 carbon atoms such as a benzyl group, preferably 7 to 20 carbon atoms, and 7 to 12 carbon atoms; 1 to 30 carbon atoms such as a t-butylcarbonyl group, preferably 1 to 1 carbon atom. 20, an alkylacyl group composed of a linear or branched alkyl group having 1 to 10 carbon atoms; for example, 6 to 36 carbon atoms such as a phenylcarbonyl group, preferably 6 to 18 carbon atoms, 6 to 12 carbon atoms An arylcarbonyl group consisting of a monocyclic, polycyclic or condensed cyclic aryl group; an aralkyl group having 7 to 30 carbon atoms, such as a benzylcarbonyl group, preferably 7 to 20 carbon atoms and 7 to 12 carbon atoms Aral consisting of An alkyloxycarbonyl group consisting of a linear or branched alkyl group having 1 to 30 carbon atoms, preferably 1 to 20 carbon atoms and 1 to 10 carbon atoms, such as a t-butoxycarbonyl group; Examples thereof include an aralkyloxycarbonyl group composed of an aralkyl group having 7 to 30 carbon atoms, preferably 7 to 20 carbon atoms and 7 to 12 carbon atoms, such as a benzyloxycarbonyl group. In addition, these alkyl groups, aryl groups, and aralkyl groups may be appropriately substituted with a halogen group such as a fluorine atom. Preferred “optionally protected hydroxyl group” for R ¹⁰ includes an aralkyloxy group having 7 to 30 carbon atoms, preferably 7 to 20 carbon atoms and 7 to 12 carbon atoms, more specifically a benzyloxy group. Can be mentioned.

The chiral diamine ligand used in the method of the present invention includes a chiral compound having two saturated nitrogen atoms. Preferred chiral diamine ligands include chiral diamine ligands represented by the general formula (1).
Examples of the “hydrocarbon group” of the group R ¹ in the diamine derivative represented by the general formula (1) of the present invention include the same hydrocarbon groups as those described above. For example, a linear or branched alkyl group having 1 to 30 carbon atoms, preferably 1 to 20 carbon atoms and 3 to 20 carbon atoms; 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, 3 carbon atoms -15 linear or branched alkenyl groups; saturated or unsaturated monocyclic, polycyclic or condensed alicyclic hydrocarbons having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms Group: C6-C36, preferably C6-C18, C6-C12 monocyclic, polycyclic or condensed cyclic carbocyclic aromatic group; C6-C36, preferably The above-described alkyl group having 1 to 20 carbon atoms is bonded to a monocyclic, polycyclic or condensed cyclic carbocyclic aromatic group (aryl group) having 6 to 18 carbon atoms or 6 to 12 carbon atoms. An arylalkyl group (carbocyclic araliphatic group) having 7 to 40 carbon atoms, preferably 7 to 20 carbon atoms and 7 to 15 carbon atoms. And the like.
Moreover, these hydrocarbon groups may be substituted with the above-described substituents. Preferable R ¹ is a monocyclic, polycyclic or condensed cyclic aryl group having 6 to 36 carbon atoms, preferably 6 to 18 carbon atoms and 6 to 12 carbon atoms, such as a phenyl group or a naphthyl group. Is mentioned. These aryl groups may have a substituent as described above.
In the group R ¹ of the diamine derivative represented by the general formula (1) of the present invention, “R ¹ together with the adjacent carbon atom together with the monocyclic, polycyclic or condensed cyclic 5 to 10 member In the case of forming a ring, the two R ¹ groups bonded to adjacent carbon atoms are combined to form a straight chain having 1 to 8, preferably 3 to 8, and 3 to 6 carbon atoms. Examples include those that form a chain or branched alkylene group and form a 5- to 10-membered aliphatic cyclic group with two adjacent carbon atoms. may be, but preferably include saturated ring. as the thus yet another ring the ring formed or may be connected to or fused. preferred examples, R ¹ each other In some cases, they together form a cyclohexane ring with adjacent carbon atoms. I can get lost.

The “aromatic hydrocarbon group” of the group R ² in the diamine derivative represented by the general formula (1) of the present invention is a C6-C36, preferably C6-C18, C6-C12 single unit. A cyclic, polycyclic, or condensed cyclic aromatic hydrocarbon group (aryl group) may be mentioned. More specifically, a phenyl group, a naphthyl group, etc. are mentioned. These aromatic hydrocarbon groups (aryl groups) may have a substituent as described above. Preferred substituents include alkyl groups having 1 to 6 carbon atoms such as methyl groups, alkoxy groups having 1 to 6 carbon atoms such as methoxy groups, halogen atoms such as chlorine atoms, carbons such as hydroxyl groups, nitro groups, and dimethylamino groups. Examples thereof include dialkylamino groups of 1 to 6.
Among these, more preferable examples of the diamine containing an asymmetric carbon atom include the following.

(In formula, R shows a C1-C20 linear or branched alkyl group each independently, or a C6-C36 aryl group which may have a substituent.)
The diamine diamine derivative or cyclohexyl diamine derivative represented by these is mentioned. The aryl group in the above formula may have one or more substituents, and examples of such substituents include methyl group, ethyl group, i-propyl group, and t-butyl group. A linear or branched alkyl group having 1 to 10 carbon atoms; a linear or branched alkoxy group having 1 to 10 carbon atoms such as a methoxy group or an ethoxy group; a chlorine atom, a fluorine atom, a bromine atom, etc. And the like. More preferred aryl groups include unsubstituted phenyl groups, halogen-substituted phenyl groups such as p-bromophenyl groups, and alkyl-substituted phenyl groups such as 3,5-xylyl groups. Particularly preferred examples of the aryl group include a p-bromophenyl group, a phenyl group, and a 3,5-xylyl group.
The chiral diamine ligands of the present invention are known, for example, Hamada, T .; Manabe, K .; Kobayashi, S. Angew. Chem. Int. Ed. 2003, 42, 3927-3930. Or can be produced according to this method.

The zinc compound may be selected from various compounds such as zinc salt, zinc oxide, zinc hydroxide, zinc complex salt, organometallic compound, etc. Among them, zinc oxide or salt with organic acid or inorganic acid, or this A complex with a salt or an organic complex is preferable. Preferred zinc salts include salts with acids, such as perfluoroalkylsulfonic acid, perchloric acid, sulfuric acid, and the like, and complexes and organic complexes thereof.
ZnX ₂
(Wherein X is an anion comprising a halogen atom, alkyl sulfonate ion, aryl sulfonate ion, perfluoroalkyl sulfonate ion, alkyl sulfate ion, aryl sulfate ion, perfluoroalkyl sulfate ion trifluoromethane sulfonate ion, nitric acid. Ion, perchlorate ion, acetate ion, or hydroxide ion.)
The zinc salt represented by these is mentioned. Examples of the alkyl group in the aforementioned alkyl sulfonate ion, perfluoroalkyl sulfonate ion, alkyl sulfate ion, and perfluoroalkyl sulfate ion include the alkyl groups described above. Preferred alkyl groups include alkyl groups having 1 to 10 carbon atoms, preferably 1 to 5 carbon atoms. Examples of the aryl group in the aryl sulfonate ion and aryl sulfate ion described above include the aryl groups described above. The aryl group is preferably an alkyl group having 1 to 5 carbon atoms such as a methyl group or an ethyl group, or an optionally substituted substituent such as an alkoxy group having 1 to 5 carbon atoms such as a methoxy group or an ethoxy group. ˜12 aryl groups.
Examples of the zinc compound in the present invention include zinc oxide, zinc hydroxide, zinc chloride, zinc fluoride, zinc nitrate, zinc perchlorate, zinc trifluoromethanesulfonate, and zinc acetate. Preferred zinc compounds include zinc fluoride and zinc hydroxide.
The zinc compound in the method of the present invention may be prepared by mixing a zinc compound as described above and a chiral diamine ligand in advance to prepare a complex, which may be used as a catalyst or in a reaction system. A zinc compound and a chiral diamine ligand may be mixed and used. About the use ratio as a catalyst, a zinc compound and a chiral diamine ligand are used substantially in an equivalent amount, Preferably it is used in the quantity that a ligand becomes a little excess. Moreover, it can be set as the ratio of about 0.1-50 mol% normally with respect to (alpha) -hydrazonoester, Preferably about 0.5-20 mol%.

The method of the present invention can be carried out in a mixed solvent of water and an organic solvent. As an organic solvent, it is preferable to carry out in a homogeneous system as an organic solvent compatible with water. Examples of such an organic solvent include acetone, acetonitrile, tetrahydrofuran (THF), dioxane, methanol, ethanol, ethylene glycol, and the like, and preferably a water-acetone solvent and a water-THF solvent. In addition, hydrocarbon solvents such as toluene, xylene, mesitylene, hexane, decane as organic solvents; halogenated hydrocarbon solvents such as methylene chloride, dichloroethane, chlorobenzene, dichlorobenzene, bromobenzene, carbon tetrachloride: butanol, octanol, etc. It is also possible to use a water-insoluble or insoluble organic solvent such as a higher alcohol solvent. In this case, the solvent system is a phase-separated two-phase system, but since the reaction can be carried out by using a phase transfer catalyst or the like, such a solvent system is also an example of a preferable solvent system in the method of the present invention. can do.
The reaction temperature can be appropriately selected within the range of preferably −20 ° C. to the boiling point of the solvent and about −20 ° C. to 40 ° C. The atmosphere can be air or an inert atmosphere such as argon gas.
By using the catalyst of the present invention as described above, one enantiomer of the optically active homoallyl hydrazino ester is stereoselectively formed, and at the carbon atom at the α-position of the raw α-hydrazono ester ( Either one of R) or (S) is preferentially generated. In this specification, the excess of either the (R) isomer or the (S) isomer at this position is expressed as an enantiomeric excess (ee) (%). This enantiomeric excess is ((R) − (S)) / ((R) + (S)) × 100 or ((S) − (R)) / ((R) + (S)) × 100 Is calculated as

Representative examples of the optically active homoallyl hydrazino esters produced by the method of the present invention include esters represented by the general formula (4) described above, depending on the reaction conditions in the method of the present invention. This isomer may be the product. As an isomer, as shown in the general formula (4), an allyl group does not react from the boron side, but a carbon in which R ⁷ and R ⁸ on the opposite side to the boron side are bonded by so-called allyl transition occurs. What reacted from the atom side is mentioned.
The optically active homoallyl hydrazino esters produced by the method of the present invention are those in which a nitrogen atom having a specific configuration is bonded to the α-position of the ester group, and the nitrogen-nitrogen bond of the hydrazino group is reduced. Therefore, optically active α-amino acids can be produced from optically active homoallyl hydrazino esters obtained by the method of the present invention.
Accordingly, the present invention provides a method for producing the corresponding optically active α-amino-α-allyl ester compound by reducing the optically active homoallyl hydrazino ester produced by the method of the present invention. . Further, the optically active homoallyl hydrazino esters produced by the method of the present invention can be compounds having a carbon atom having a specific configuration at the β-position.

The present invention is a method capable of performing a catalytic asymmetric allylation reaction on α-hydrazonoester using an allylborane derivative in a mixed solvent of water and an organic solvent with high yield and high stereoselectivity. According to the method of the present invention, a high-purity product can be efficiently produced, and there are few by-products and the separation of the product is easy. Therefore, the present invention provides an industrially excellent method with few problems to the environment due to the organic solvent.
The optically active homoallyl hydrazino esters produced by the method of the present invention can be derived into corresponding optically active amino acid derivatives by cleaving the nitrogen-nitrogen bond, and various optically active α-amino acid derivatives. Is useful as a method for producing optically active pharmaceuticals and foods, and intermediates thereof.

  EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited at all by these Examples.

  According to the following reaction formula, hydrazonoester (1) and allylborane derivative (2) are reacted in the presence of asymmetric ligand (3) to give optically active homoallylhydrazinoester (4). Manufactured.

  Zinc fluoride hydrate (2.1 mg, 0.020 mmol) and asymmetric ligand (3) (Hamada, T .; Manabe, K .; Kobayashi, S. Angew. Chem. Int. Ed. 2003, 42 , 3927-3930.) (10.8 mg, 0.024 mmol) was dissolved by sequentially adding pure water (3 mL) and acetone (5 mL) to obtain the hydrazonoester (1) (49.9 mg, 0.200 mmol). And then ice-cooled. To this was added allylboron reagent (2) (45 mL, 0.240 mmol) and stirred (9 hours), then the reaction was terminated with saturated aqueous sodium hydrogen carbonate (1 mL), and the aqueous layer was extracted with dichloromethane (10 mL × 3). The obtained organic layer was concentrated under reduced pressure and subjected to preparative thin layer chromatography (developing solvent; n-hexane / ethyl acetate = 4/1) to obtain the desired allylated product (4) (57.2 mg, 0.196 mmol, After obtaining a yield of 98%, HPLC analysis was performed.

Methyl 2- [N '-(p-dimethylaminobenzoyl) hydrazino] -4-pentenoate (4).
¹ H-NMR (CDCl ₃ ) δ:
2.43-2.51 (m, 1H), 2.59-2.65 (m, 1H), 3.01 (s, 6H), 3.75 (s, 3H),
3.85 (m, 1H), 5.09 (brs, 1H), 5.18 (d, 1H, J = 10.4 Hz),
5.22 (d, 1H, J = 20.4 Hz), 5.89 (ddt, 1H, J = 20.4, 10.4, 5.0 Hz),
6.65 (d, 2H, J = 8.0 Hz), 7.64 (d, 2H, J = 8.4 Hz), 7.84 (brs, 1H);
¹³ C-NMR (CDCl ₃ ) δ:
35.2, 40.0, 52.0, 62.3, 111.0, 118.7, 118.9 128.4, 133.0, 152.7,
167.2, 173.1;
HPLC (Daicel Chiralcel OD, hexane / i-PrOH = 4/1,
(Flow rate = 1.0 mL / min)
tR = 13.0 minutes (R),
tR = 17.9 minutes (S).

The corresponding ethyl 2- (N'-) was used in the same manner as in Example 1 except that 2- (N'-benzoylhydrazono) -ethyl acetate (1a) was used in place of the hydrazonoester (1). Benzoylhydrazino) -4-pentenoate (4a) was prepared.
[Α] _D ²¹ +34.8 (c 0.83, CHCl ₃ , 74% ee);
IR (neat) 3289, 3070, 2979, 1735, 1650, 1530, 1464, 1303, 1201,
694 cm ^-1 ;
¹ H-NMR (CDCl ₃ ) δ:
1.26 (t, 3H, J = 7.2 Hz), 2.39-2.54 (m, 1H), 2.55-2.69 (m, 1H),
3.85 (dd, 1H, J = 7.6, 5.2 Hz), 4.20 (t, 2H, J = 7.1 Hz),
4.93 (brs, 1H), 5.10-5.24 (m, 2H),
5.87 (ddt, 1H, J = 16.8, 12.5, 5.0 Hz), 7.37-7.55 (m, 3H),
7.73-7.81 (m, 2H), 8.46 (brs, 1H);
¹³ C-NMR (CDCl ₃ ) δ:
14.1, 35.1, 61.0, 62.0, 118.7, 126.9, 128.5, 131.7, 132.5, 132.8,
167.0, 172.5;
As HRMS (ESI-TOF) C ₁₄ H ₁₉ N ₂ O ₃ ([M + H] ⁺ ):
Calculated value 263.1396,
Measured value 263. 1383;
HPLC (Daicel Chiralcel OD, hexane / i-PrOH = 9/1,
(Flow rate = 1.0 mL / min)
tR = 10.1 minutes (R),
tR = 13.8 minutes (S).

The corresponding benzyl 2- (N′-) was used in the same manner as in Example 1 except that 2- (N′-benzoylhydrazono) -benzyl acetate (1b) was used in place of the hydrazono ester (1). Benzoylhydrazino) -4-pentenoate (4b) was prepared.
¹ H-NMR (CDCl ₃ ) δ:
2.44-2.51 (m, 1H), 2.61-2.67 (m, 1H), 3.90 (m, 1H), 5.12 (brs, 1H),
5.13-5.28 (m, 4H), 5.85 (m, 1H), 7.34-7.54 (m, 8H),
7.67 (d, 2H, J = 7.2 Hz), 8.12 (brs, 1H);
¹³ C-NMR (CDCl ₃ ) δ:
35.1, 62.1, 66.8, 119.0, 126.9, 128.3, 128.4, 128.6, 131.9, 132.4,
132.7, 135.4, 166.9, 172.4;
HPLC (Daicel Chiralcel OD, hexane / i-PrOH = 9/1,
Flow rate = 1.0 mL / min)
tR = 15.9 minutes (R),
tR = 20.3 minutes (S).

The corresponding methyl 2- (N′-) was used in the same manner as in Example 1 except that 2- (N′-benzoylhydrazono) -methyl acetate (1c) was used in place of the hydrazonoester (1). Benzoylhydrazino) -4-pentenoate (4c) was prepared.
¹ H-NMR (CDCl ₃ ) δ:
2.43-2.51 (m, 1H), 2.61-2.65 (m, 1H), 3.75 (s, 3H),
3.87 (t, 1H, J = 5.2 Hz), 5.12 (brs, 1H), 5.18 (d, 1H, J = 10.0 Hz),
5.21 (d, 1H, J = 16.8 Hz), 5.89 (ddt, 1H, J = 16.8, 10.0, 5.0 Hz),
7.28-7.54 (m, 3H), 7.74-7.75 (m, 2H), 8.25 (brs, 1H);
¹³ C-NMR (CDCl ₃ ) δ:
35.1, 52.0, 62.1, 118.9, 126.9, 128.5, 131.8, 132.4, 132.7, 167.1,
173.1;
HPLC (Daicel Chiralcel OD, hexane / i-PrOH = 9/1,
Flow rate = 1.0 mL / min)
tR = 12.1 minutes (R),
tR = 16.5 minutes (S).

2- [N ′-(p-nitrobenzoyl) hydrazono] -ethyl acetate (1d) was used instead of the hydrazono ester (1) in the same manner as in Example 1, except that the corresponding ethyl 2- [N ′-(p-nitrobenzoyl) hydrazino] -4-pentenoate (4d) was prepared.
¹ H-NMR (CDCl ₃ ) δ:
1.29 (t, 3H, J = 7.2 Hz), 2.40-2.54 (m, 1H), 2.57-2.70 (m, 1H),
3.86 (ddd, 1H, J = 7.6, 4.7, 2.9 Hz), 4.12-4.31 (m, 2H),
5.12-5.25 (m, 2H), 5.17 (brs, 1H), 5.77-5.93 (m, 1H),
7.94-8.00 (m, 2H), 8.24-8.31 (m, 2H), 8.73 (brd, 1H, J = 5.3 Hz);
¹³ C-NMR (CDCl ₃ ) δ:
14.1, 35.1, 61.3, 61.9, 119.0, 123.7, 128.3, 132.5, 138.1, 149.7,
164.9, 172.7;
HPLC (Daicel Chiralcel OD, hexane / i-PrOH = 4/1,
Flow rate = 1.0 mL / min)
tR = 11.3 minutes (R),
tR = 15.4 minutes (S).

2- [N ′-(p-methoxybenzoyl) hydrazono] -ethyl acetate (1e) was used in place of the hydrazonoester (1) in the same manner as in Example 1, except that the corresponding ethyl 2- [N ′-(p-methoxybenzoylhydrazino] -4-pentenoate (4e) was prepared.
[Α] _D ²⁴ +23.5 (c 1.11, CHCl ₃ , 81% ee);
IR (neat) 3288, 2983, 1734, 1642, 1606, 1510, 1463, 1297, 1260, 1190,
1030, 815 cm ⁻¹ ;
¹ H-NMR (CDCl ₃ ) δ:
1.27 (t, 3H, J = 7.2 Hz), 2.43-2.52 (m, 1H), 2.57-2.66 (m, 1H),
3.79-3.88 (m, 1H), 3.84 (s, 3H), 4.14-4.28 (m, 2H), 5.12 (brs, 1H),
5.17 (d, 1H, J = 10.4 Hz), 5.21 (d, 1H, J = 17.1 Hz),
5.82-5.93 (m, 1H), 6.91 (d, 2H, J = 8.8 Hz), 7.73 (d, 2H, J = 8.8 Hz),
8.16 (brs, 1H);
¹³ C-NMR (CDCl ₃ ) δ:
14.1, 35.2, 55.3, 61.0, 62.1, 113.8, 118.7, 124.7, 128.7, 132.9,
162.4, 166.6, 172.6;
HRMS _(EI) as _{C 15 H 20 N 2 O 4} : Calculated 292.1423,
Measured value 292.1443;
HPLC (Daicel Chiralcel OD, hexane / i-PrOH = 4/1,
Flow rate = 1.0 mL / min)
tR = 8.0 minutes (R),
tR = 10.8 minutes (S).

2- [N ′-(p-hydroxybenzoyl) hydrazono] -ethyl acetate (1f) was used in place of the hydrazonoester (1) in the same manner as in Example 1, except that the corresponding ethyl 2- [N ′-(p-hydroxybenzoylhydrazino] -4-pentenoate (4f) was prepared.
mp: 94-99 ° C;
[Α] _D ²⁸ +30.4 (c 1.17, CHCl ₃ , 84% ee);
IR (KBr) 3172, 1737, 1637, 1603, 1441, 1287, 1245, 1203, 1169 cm ⁻¹ ;
¹ H-NMR (CDCl ₃ ) δ:
1.25 (t, 3H, J = 7.2 Hz), 2.37-2.68 (m, 2H),
3.82 (dd, 1H, J = 6.1, 6.1 Hz), 4.10-4.29 (m, 2H), 5.07-5.23 (m, 2H),
5.70-5.93 (m, 1H), 6.87 (d, 2H, J = 8.6 Hz), 7.60 (d, 2H, J = 8.6 Hz),
8.33 (brs, 1H);
¹³ C-NMR (CDCl ₃ ) δ:
14.1, 35.1, 61.3, 62.2, 115.7, 119.0, 123.3, 129.0, 132.6, 160.5,
167.6, 173.0;
As HRMS (ESI-TOF) C ₁₄ H ₁₉ N ₂ O ₄ ([M + H] ⁺ ):
Calculated value 279.1345,
Measured value 279.1361;
HPLC (Daicel Chiralcel OD, hexane / i-PrOH = 4/1,
Flow rate = 0.4mL / min)
tR = 20.2 minutes (R),
tR = 23.3 minutes (S).

The corresponding ethyl 2 was used in the same manner as in Example 1 except that 2- [N ′-(p-dimethylaminobenzoyl) hydrazono] -ethyl acetate (1 g) was used instead of the hydrazono ester (1). -[N '-(p-dimethylaminobenzoylhydrazino] -4-pentenoate (4 g) was prepared.
[Α] _D ²⁷ +3.76 (c 1.67, CHCl ₃ , 84% ee);
IR (neat) 3291, 2979, 2910, 1735, 1605, 1525, 1449, 1371, 1303,
1202 cm ⁻¹ ;
¹ H-NMR (CDCl ₃ ) δ:
1.27 (t, 3H, J = 7.1 Hz), 2.42-2.53 (m, 1H), 2.57-2.67 (m, 1H),
3.01 (s, 6H), 3.83 (dd, 1H, J = 7.8, 5.0 Hz), 4.00 (brs, 1H),
4.14-4.28 (m, 2H), 5.13-5.25 (m, 2H), 5.83-5.95 (m, 1H),
6.65 (d, 2H, J = 9.0 Hz), 7.64 (d, 2H, J = 9.0 Hz), 7.89 (s, 1H);
¹³ C-NMR (CDCl ₃ ) δ:
14.2, 35.2, 40.0, 60.9, 62.2, 111.0, 118.6, 119.1, 128.4, 133.1,
152.7, 167.1, 172.6;
As HRMS (ESI-TOF) C ₁₆ H ₂₄ N ₃ O ₃ ([M + H] ⁺ ):
Calculated value 306.1818,
Measured value 306.1818;
HPLC (Daicel Chiralcel OD, hexane / i-PrOH = 4/1,
Flow rate = 1.0 mL / min)
tR = 9.7 minutes (R),
tR = 12.9 minutes (S).

In the following examples, zinc fluoride (ZnF ₂ ) hydrate and zinc hydroxide (Zn (OH) ₂ ) were purchased from Aldrich Corp. and Soekawa Riken Corp., respectively. Water purified using MILLIPORE Gradient A10 was used, and acetone was purchased from Kanto Chemical Co., Inc. The chiral ligand (3), which is a chiral diamine, is produced according to the method described in the literature (Hamada, T .; Manabe, K .; Kobayashi, S. Angew. Chem. Int. Ed. 2003, 42, 3927). did.

(1) ZnF ₂ A solution of ZnF ₂ hydrate (319.0mg) was added to water (300 mL), and stirred for 5 minutes. Ultrasonic irradiation was performed for 10 minutes, and the solution was filtered through Kiriyama filter paper (No. 4 and No. 5B). The concentration of the solution was determined by ICP analysis. The solution was stored at 4 ° C.
(2)
The ZnF ₂ solution (0.159 mM, 1.86 mL, 0.015 mmol) prepared in (1) above was diluted with water (0.36 mL), and the chiral diamine (3) (16.2 mg, 0.036 mmol) and acetone (3.75 mL) was added and stirred for 30 minutes. The hydrazonoester (1) (75.0 mg, 0.30 mmol) used in Example 1 was added and stirred at 0 ° C. for 20 minutes, and the allyl boronate (2) used in Example 1 (69 μL, 0. 36 mmol) was added. After 36 hours, the reaction was stopped by adding a saturated aqueous sodium hydrogencarbonate solution, extracted four times with methylene chloride (CH ₂ Cl ₂ ), and the organic layers were combined and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by preparative thin layer chromatography (silica gel, hexane / ethyl acetate = 1/4) and methyl 2- [N ′-(p-dimethylaminobenzoyl) hydrazino] -4-pentenoate. (4) was obtained quantitatively. The enantiomeric excess (ee) of the product was determined by HPLC analysis (90% ee).

¹ H-NMR (CDCl ₃ ) δ:
2.43-2.51 (m, 1H), 2.59-2.65 (m, 1H), 3.01 (s, 6H), 3.75 (s, 3H),
3.85 (m, 1H), 5.09 (brs, 1H), 5.18 (d, 1H, J = 10.4 Hz),
5.22 (d, 1H, J = 20.4 Hz), 5.89 (ddt, 1H, J = 20.4, 10.4, 5.0 Hz),
6.65 (d, 2H, J = 8.0 Hz), 7.64 (d, 2H, J = 8.4 Hz), 7.84 (brs, 1H).
¹³ C-NMR (CDCl ₃ ) δ:
35.2, 40.0, 52.0, 62.3, 111.0, 118.7, 118.9 128.4, 133.0, 152.7,
167.2, 173.1.
IR (neat) 3734, 3648, 3283, 2951, 1738, 1608, 1520, 1437, 1363,
1300, 1219, 921, 828, 772 cm ^-1 .
[Α] _D ²³ +6.50 (c1.44, CHCl ₃ , 90% ee).
HRMS: Calculated as C ₁₅ H ₂₂ N ₃ O ₃ : [M + H] ⁺ 292.156,
Actual value: 292.1650.
HPLC (Daicel Chiralcel OD, hexane / i-PrOH = 4/1,
(Flow rate = 1.0 mL / min)
t _R = 13.0 minutes (R),
t _R = 17.9 min (S).

Instead of allyl boronate (2) in Example 9, 1-methyl-allyl boronate (2a) was used, except that corresponding (2R, 3R) -methyl 2- [N ′-(p-dimethylaminobenzoyl) hydrazino] -3-methyl-4-pentenoate (4i) was prepared. Yield: quantitative. Thin / anti ratio: less than 1% / greater than 99%. ee: 88%.
¹ H-NMR (CDCl ₃ ) δ:
1.15 (d, 3H, J = 6.8), 2.64 (td, 1H, J = 14.8, 7.1 Hz)), 3.05 (s, 6H),
3.68 (m, 1H), 3.76 (s, 3H), 5.10 (brs, 1H), 5.14 (dd, 1H, J = 6.9, 1.3 Hz), 5.17 (dd, 1H, J = 12.6, 1.3 Hz), 5.86 (ddd, 1H, J = 17.9, 9.6, 7.6 Hz),
6.64 (d, 2H, J = 8.9 Hz), 7.62 (d, 2H, J = 8.9 Hz),
7.69 (d, 1H, J = 5.5 Hz).
¹³ C-NMR (CDCl ³ ) δ:
16.9, 39.9, 40.0, 51.8, 67.7, 111.0, 116.5, 118.9, 128.3, 139.1,
152.7, 167.4, 173.0.
IR (neat) 3283, 2952, 1737, 1608, 1520, 1444, 1363, 1298, 1204,
1162, 1063, 946, 827, 768 cm ⁻¹ .
^{_{[Α] D 23 -2.20 (c1.27}} , CHCl 3, 88% ee).
HRMS: Calculated as C ₁₆ H ₂₄ N ₃ O ₃ : [M + H] ⁺ 306.1812,
Actual value: 306.1814.
HPLC (Daicel Chiralcel OD-H, hexane / i-PrOH = 19/1
(Flow rate = 0.5 mL / min)
t _R = 66.3 min (2R, 3R),
t _R = 77.8 min (2S, 3S).

(2R, 3R) -Methyl 2- in the same manner as in Example 9 except that 1-ethyl-allylboronate (2b) was used instead of allylboronate (2) in Example 9. [N ′-(p-dimethylaminobenzoyl) hydrazino] -3-ethyl-4-pentenoate (4j) was prepared. Yield: 98%. Thin / anti ratio: less than 1% / greater than 99%. ee: 87%.
¹ H-NMR (CDCl ₃ ) δ:
0.95 (t, 3H, J = 7.2 Hz), 1.42-1.49 (m, 1H), 1.58-1.65 (m, 1H),
2.43-2.38 (m, 1H), 3.02 (s, 6H), 3.76 (s, 3H), 5.10 (brs, 1H, J = 2.7 Hz), 5.15 (dd, 1H, J = 16.8, 1.9 Hz), 5.22 (dd, 1H, J = 12.6, 1.9 Hz),
5.75 (dt, 1H, J = 18.8, 8.6 Hz), 6.65 (d, 2H, J = 8.9 Hz), 7.59 (brs, 1H), 7.61 (d, 2H, J = 9.0 Hz).
¹³ C-NMR (CDCl ₃ ) δ:
11.6, 24.1, 40.1, 47.7, 51.9, 66.7, 111.0, 118.4, 118.9, 128.3, 137.3,
152.7, 167.3, 173.3.
IR (neat) 3303, 2969, 1737, 1637, 1608, 1520, 1460, 1362, 1205,
772 cm ⁻¹ .
[Α] _D ²² +20.3 (c 0.66, CHCl ₃ , 87% ee).
HRMS: Calculated as C ₁₇ H ₂₅ N ₃ NaO ₃ : [M + H] ⁺ 342.1788,
Actual value: 342.1787.
HPLC (Daicel Chiralcel OJ-H, hexane / i-PrOH = 9/1,
(Flow rate = 0.5 mL / min)
t _R = 42.3 minutes (2R, 3R),
t _R = 59.1 min (2S, 3S).

(2R, 3R) -Methyl 2- in the same manner as in Example 9 except that 1-butyl-allylboronate (2c) was used instead of allylboronate (2) in Example 9. [N ′-(p-dimethylaminobenzoyl) hydrazino] -3-butyl-4-pentenoate (4k) was prepared. Yield: 88%. Thin / anti ratio: less than 1% / greater than 99%. ee: 87%.
¹ H-NMR (CDCl ₃ ) δ:
0.89 (t, 3H, J = 6.9 Hz), 1.24-1.38 (m, 2H), 1.40-1.46 (m, 1H),
1.50-1.56 (m, 1H), 2.45-2.50 (m, 1H), 3.01 (s, 6H), 3.74 (brs, 1H),
3.76 (s, 3H), 5.12 (brs, 1H), 5.12 (dd, 1H, J = 18.0, 1.4 Hz),
5.18 (dd, 1H, J = 10.2, 1.4 Hz), 5.75 (dt, 1H, J = 19.0, 8.6 Hz),
6.65 (d, 2H, J = 8.9 Hz), 7.62 (d, 2H, J = 8.9 Hz), 7.71 (brs, 1H).
¹³ C-NMR (CDCl ₃ ) δ:
13.9, 22.4, 29.2, 30.6, 40.0, 46.0, 51.9, 67.0, 111.0, 118.1, 119.0,
128.3, 137.7, 152.7, 167.3, 173.2.
IR (neat) 3852, 3648, 3299, 2928, 1736, 1608, 1507, 1457, 1362,
1299, 1205 cm ⁻¹ .
[Α] _D ²¹ +13.1 (c 1.06, CHCl ₃ , 87% ee).
HRMS: Calculated as [C ₁₉ H ₃₀ N ₃ O ₃ : [M + H] ⁺ 348.2282,
Found: 348.2278.
HPLC (Daicel Chiralcel OD-H, hexane / i-PrOH = 9/1,
(Flow rate = 0.5 mL / min)
t _R = 42.6 minutes (2R, 3R),
t _R = 54.9 min (2S, 3S).

Corresponding in the same manner as in Example 9 except that 1- (3-methylbutyl) -allylboronate (2d) was used instead of allylboronate (2) in Example 9 (2R, 3R) -Methyl 2- [N '-(p-dimethylaminobenzoyl) hydrazino] -3- (3-methylbutyl) -4-pentenoate (4l) was prepared. Yield: 76%. Thin / anti ratio: less than 1% / greater than 99%. ee: 87%.
¹ H-NMR (CDCl ₃ ) δ:
0.87 (t, 6H, J = 6.2 Hz), 1.29-1.13 (m, 2H), 1.37-1.49 (m, 1H),
1.50-1.59 (m, 2H), 2.41-2.49 (m, 1H), 3.01 (s, 6H), 3.74 (brs, 1H),
3.76 (s, 3H), 5.13 (brs, 1H), 5.13 (dd, 1H, J = 17.2, 1.7 Hz),
5.19 (dd, 1H, J = 10.8, 1.7 Hz), 5.75 (dt, 1H, J = 18.8, 8.5 Hz),
6.65 (d, 2H, J = 9.2 Hz), 7.64 (d, brs, 3H, J = 9.2 Hz).
¹³ C-NMR (CDCl ₃ ) δ:
22.3, 22.8, 27.8, 28.8, 36.2, 40.0, 46.2, 51.9, 67.1, 111.0, 118.2,
119.0, 128.3, 137.7, 152.7, 167.3, 173.2.
IR (neat) 3865, 3750, 3278, 2938, 1740, 1648, 1612, 1516, 1462,
1364, 1305, 1209 cm ⁻¹ .
[Α] _D ²¹ +3.00 (c 0.71, CHCl ₃ , 87% ee).
_HRMS: as _{C 20 H 32 N 3 O 3} , ^{Calcd: [M + H] + 362.2438} ,
Actual value: 362.2427.
HPLC (Daicel Chiralcel OD-H, hexane / i-PrOH = 9/1,
Flow rate = 1.0 mL / min)
t _R = 16.9 minutes (2R, 3R),
t _R = 23.2 minutes (2S, 3S).

  Instead of allyl boronate (2) in Example 9, 1-benzyloxy-allyl boronate (2a) was used, and instead of chiral diamine (3), the following formula

(2S, 3S) -methyl 2- [N ′-(p-dimethylamino) is prepared in the same manner as in Example 9 except that the chiral diamine (3a) represented by Benzoyl) hydrazino] -3-benzyloxy-4-pentenoate (4m) was prepared. Yield: 65%. Thin / anti ratio: less than 1% / greater than 99%. ee: 82%.
¹ H-NMR (CDCl ₃ ) δ:
2.99 (s, 6H), 3.73 (s, 3H), 4.11 (dd, 1H, J = 2.8, 4.0 Hz),
4.24 (dd, 1H, J = 4.0, 7.6 Hz), 4.56 (d, 1H, J = 12.0),
4.64 (d, 1H, J = 12.0), 5.37-5.31 (m, 2H), 5.46 (brm, 1H),
5.98 (ddd, 1H, J = 8.0, 10.0, 17.0), 6.61 (d, 2H, J = 8.8 Hz),
7.35-7.26 (m, 5H), 7.59 (d, 2H, J = 8.8 Hz), 7.78 (brd, 1H, J = 6.4 Hz).
¹³ C-NMR (CDCl ₃ ) δ:
40.0, 52.0, 66.1, 70.4, 79.8, 110.0, 119.0, 120.0, 127.5, 127.7, 128.3,
128.3, 134.2, 137.7, 152.6, 166.9, 171.0.
IR (KBr): 3298, 3257, 3024, 2887, 1739, 1610, 1523, 1346, 1323,
1207, 1159, 1092, 984, 829, 739, 698, 617 cm ⁻¹ .
[Α] _D ²² -0.32 (c 0.53, CHCl ₃ , 82% ee).
HRMS: Calculated as: C ₂₂ H ₂₇ N ₃ O ₄ : [M ⁺ + Na] 420.1894
Found: 420.1888.
HPLC (Daicel Chiralcel OJ-H, hexane / EtOH = 4/1,
Flow rate = 1.0 mL / min)
t _R = 20.6 minutes (2S, 3S),
t _R = 27.0 min (2R, 3R).

Catalytic asymmetric allylation with Zn (OH) ₂ :
Zn (OH) ₂ (3.0 mg, 0.030 mmol) was added to water (3.5 mL) and stirred for 10 minutes. Chiral diamine (3) (32.7 mg, 0.072 mmol) and acetone (7.5 mL) were added and stirred for 10 minutes. The hydrazono ester (1) (149.7 mg, 0.60 mmol) was added, and the mixture was stirred at 0 ° C. for 15 minutes, and allyl boronate (2) (92 μL, 0.36 mmol) was added. After 36 hours, the reaction was stopped by adding a saturated aqueous sodium hydrogencarbonate solution, extracted four times with methylene chloride (CH ₂ Cl ₂ ), and the organic layers were combined and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by preparative thin layer chromatography (silica gel, hexane / ethyl acetate = 1/4) and methyl 2- [N ′-(p-dimethylaminobenzoyl) hydrazino] -4-pentenoate. (4) was obtained at 80%. The enantiomeric excess (ee) of the product was determined by HPLC analysis (85% ee).

Methyl (S) -2- [N- (benzyloxycarbonyl) amino] -4-pentenoate (6) [literature (Abbott, SD; Lane-Bell, P .; Sidhu, KPS; Vederas, JCJ Am. Chem. Soc 1994, 116, 6513.)] Methyl 2- [N ′-(p-dimethylaminobenzoyl) hydrazino] -4-pentenoate (4) was converted to benzyloxycarbonyl chloride in the presence of sodium bicarbonate. After treatment with (Cbz-Cl) (yield: 81%), treatment with samarium iodide (SmI ₂ ) (yield: 75%) gave the title product.
¹ H-NMR (CDCl ₃ ) δ:
2.47-2.61 (m, 2H), 3.76 (s, 3H), 4.46 (dd, 1H, J = 13.5, 5.7 Hz),
5.13 (m, 4H), 5.31 (m, 1H), 5.68 (td, 1H, J = 17.2, 7.5 Hz),
7.30-7.36 (m, 5H).
¹³ C-NMR (CDCl ₃ ) δ:
36.7, 52.3, 53.2, 67.0, 119.4, 128.1, 128.2, 128.5, 131.9, 136.2,
155.7, 172.1.
IR (neat) 3861, 3743, 3358, 2948, 1724, 1645, 1516, 1467, 1342,
1216, 1049 cm ^-1 .
^{_{[Α] D 20 -13.7 (c0.18}} , CHCl 3).

(2R, 3R) -methyl 2- [N- (benzyloxycarbonyl) amino] -3-methyl-4-pentenoate (7) [literature (Kazmaier, U .; Mues, H .; Krebs, A. Chem. Eur J. 2002, 8, 1850.)]] (2R, 3R) -methyl 2- [N ′-(p-dimethylaminobenzoyl) hydrazino] -3-methyl-4 prepared in Example 10 - pentenoate (4i), in the presence of sodium bicarbonate was treated with benzyloxycarbonyl chloride (yield: 75%) after and then treated with samarium iodide (SmI ₂₎ (yield: 95%), The title product was obtained.
¹ H-NMR (CDCl ₃ , main rotamer) δ:
1.03 (d, 3H, J = 6.9 Hz), 2.71 (m, 1H), 3.67 (s, 3H),
4.29 (dd, 1H, J = 4.6 Hz), 4.99-5.10 (m, 4H), 5.11 (d, 1H, J = 8.2 Hz),
5.56-5.52 (m, 1H), 7.25-7.29 (m, 5H); (selected signals)
0.85 (t, 3H, J = 7.2 Hz), 2.60-2.70 (m, 1H), 3.59 (s, 3H),
4.40 (dd, 1H, J = 4.6 Hz), 5.42-5.48 (m, 1H).
¹³ C-NMR (CDCl ₃ , main rotamer) δ:
16.0, 40.0, 52.2, 58.2, 67.1, 117.0, 128.1, 128.2, 128.5, 136.2,
137.5, 156.2, 172.0; (selected signals) 11.7, 23.5, 48.0, 56.9,
118.4, 136.2.
IR (neat) 3750, 3344, 2960, 1724, 1517, 1449, 1347, 1267, 1216,
1096, 1055, 1017, 931, 771, 701 cm ^-1 .
[Α] _D ²¹ -8.2 (c 0.32, CHCl ₃ ).

(2S, 3S) -methyl 2- [N- (tert-butoxycarbonyl) amino] -3-hydroxy-4-pentanoate (8) [literature (Kandula, SRV; Kumar, P. Tetrahedron: Asym. 2005, 16, 3268; delle Monache, Monache, G .; Giovanni, MCD; Misiti, D .; Zappia, G. Tetrahedron: Asym. 1997, 8, 231.)]] The compound prepared in Example 14 (2S, 3S ) -Methyl 2- [N '-(p-dimethylaminobenzoyl) hydrazino] -3-benzyloxy-4-pentenoate (4m) was treated with benzyloxycarbonyl chloride in the presence of sodium bicarbonate (yield: 90%) followed by treatment with samarium iodide (SmI ₂ ) (yield: 71%) followed by catalytic reduction with Pd / C in the presence of tert-butoxycarbonyl anhydride (Boc ₂ O) ( (Yield: 71%) and the title product was obtained.
¹ H-NMR (CDCl ₃ ) δ:
1.00 (t, 3H, J = 7.2 Hz), 1.45 (s, 9H), 1.51 (m, 2H), 2.83 (br, 1H),
3.78 (s, 3H), 3.81 (br, 1H), 4.39 (br, 1H), 5.48 (br, 1H).
¹³ C-NMR (CDCl ₃ ) δ:
10.2, 26.4, 28.3, 52.4, 58.0, 74.5, 80.4, 155.9, 171.3.
IR (neat) 3435, 2977, 1714, 1505, 1165, 734 cm ⁻¹ .
HRMS: Calculated as: C ₁₁ H ₂₂ NO ₅ : [M ⁺ + H] 248.1492,
Found: 248.1497.
[Α] _D ²² = −15.1 (c1.6, CHCl ₃ ).

The present invention provides an industrially excellent method for producing optically active homoallyl hydrazino esters with high yield and high stereoselectivity.
The optically active homoallyl hydrazino esters produced by the method of the present invention can be derived into corresponding optically active amino acid derivatives by cleaving the nitrogen-nitrogen bond, and various optically active α-amino acid derivatives. Is useful as a method for producing optically active pharmaceuticals, foods, and the like and intermediates thereof, and the present invention has industrial applicability.

Claims (8)

In a mixed solvent of water and an organic solvent, a zinc compound and the following general formula (1),

(In the formula , each R ¹ independently represents a hydrocarbon group which may have a substituent, or two R ¹ groups together to form a 5- to 10-membered ring together with adjacent carbon atoms. And R ² represents an aromatic hydrocarbon group which may have a substituent.)
In the presence of a catalyst obtained by mixing with a chiral diamine ligand represented by the following general formula (2),

(In the formula, R ³ and R ⁴ each independently represent a hydrocarbon group which may have a substituent.)
Α-hydrazonoester represented by the following general formula (3),

(In the formula, R ⁵ and R ⁶ each independently represent a hydrogen atom or a hydrocarbon group which may have a substituent, and R ⁷ , R ⁸ and R ⁹ each independently represent a hydrogen atom. Or an optionally substituted aliphatic hydrocarbon group, R ¹⁰ represents a hydrogen atom, an optionally substituted aliphatic hydrocarbon group, a halogen group, an optionally protected hydroxyl group, An amino group which may be protected or a mercapto group which may be protected is shown.)
Is reacted with an allylborane derivative represented by the following general formula (4),

(In the formula, R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ , and R ¹⁰ are the same as described above , and the * mark indicates an asymmetric carbon atom.)
The optically active homoallyl hydrazino ester represented by these , or the method of manufacturing this isomer . The method according to claim 1 , wherein R ¹ in the general formula (1) is an aryl group which may have a substituent. The method according to claim 1 or 2 , wherein R ³ in the general formula (2) is an alkyl group having 1 to 30 carbon atoms, and R ⁴ is an aryl group which may have a substituent. R ⁵ and R ⁶ in the general formula (3) are alkyl groups having 1 to 30 carbon atoms, R ⁷ , R ⁸ , and R ⁹ are hydrogen atoms, R ¹⁰ is a hydrogen atom, and 1 to C carbon atoms. The method according to any one of claims 1 to 3, which is 30 alkyl groups, a halogen group, an optionally protected hydroxyl group, or an optionally protected amino group. The method according to any one of claims 1 to 4 , wherein the zinc compound is a zinc salt or zinc oxide. The zinc salt is ZnX ₂ (wherein X is an anion comprising a halogen atom, an alkyl sulfonate ion, an aryl sulfonate ion, a perfluoroalkyl sulfonate ion, an alkyl sulfate ion, an aryl sulfate ion, a perfluoroalkyl sulfate ion, It represents nitrate ion, perchlorate ion, acetate ion, or hydroxide ion.) The method according to claim 5 . A method for producing a corresponding amino ester by cleaving a nitrogen-nitrogen bond of the optically active homoallyl hydrazino ester produced by the method according to any one of claims 1 to 6 . The method according to claim 7 , wherein the breaking of the nitrogen-nitrogen bond is a reductive cleavage.