WO2013024720A1 - PEPTIDE CATALYST AND ALDEHYDE ASYMMETRIC α－AMINATION USING SAME - Google Patents

Abstract

　This catalyst is composed of a peptide and a carrier, said peptide containing an amino acid represented by formula (SAA)-(AA)-(AA2) or (SAA1)-(SAA)- (AA)- (AA2) at the N-terminus thereof. (In the formula, SAA, SAA1 independently represent an amino acid having a secondary amino group; AA represents a α,α－disubstituted amino acid; SAA2 represents one or two natural or non natural amino acids.) and the C-terminus thereof being bonded to the carrier and immobilized. In the presence of the peptide catalyst, an aldhehyde is reacted with a diazodicarboxylate derivative.

Description

Peptide catalyst and asymmetric α-amination of aldehydes using the same

The present invention relates to a peptide catalyst and a method for asymmetric amination of an α-position of an aldehyde using the peptide catalyst.

Peptides have attracted attention for their functions and physiological activities, and have been the subject of various studies. In recent years, the activity as a reaction catalyst in precision organic synthesis has attracted attention, and many reactions have been developed (Non-patent Document 1). In particular, peptide catalysts whose N-terminal is a proline derivative have been studied in various ways because they can be used for asymmetric functionalization of the α-position of the carbonyl group, such as an asymmetric aldol reaction. However, it is difficult to predict a suitable sequence for each reaction and substrate (Non-patent Documents 2 and 3).

On the other hand, among the reactions in which the α-position of the carbonyl group is asymmetrically functionalized, the product of the asymmetric α-amination reaction of the aldehyde is useful as an intermediate for pharmaceuticals, agricultural chemicals, etc. In spite of this important reaction, no reaction example using a peptide catalyst has been reported.

The object of the present invention is to develop a peptide catalyst capable of proceeding with a highly stereoselective asymmetric α-amination reaction of an aldehyde.

As a result of intensive studies, the present inventors include a sequence in which an amino acid having a secondary amino group and an α, α-disubstituted amino acid and one or two amino acids are bonded at the N-terminus, and the C-terminus is bonded to a carrier. The present inventors have found that the above problem can be solved by reacting an aldehyde with a diazodicarboxylate derivative in the presence of a peptide catalyst immobilized thereon.

That is, the present invention comprises a peptide and a carrier, and the peptide is represented by the following formula (1):
(SAA)-(AA)-(AA2) (1)
(Wherein SAA represents an amino acid having a secondary amino group, AA represents an α, α-disubstituted amino acid, and AA2 represents one or two natural or non-natural amino acids). The present invention relates to an immobilized peptide catalyst having an amino acid sequence at the N-terminus and having the C-terminus bound to a carrier and immobilized and having 27 or less amino acid residues.

The present invention comprises a peptide and a carrier, and the peptide is represented by the formula (1) or the following formula (2):
(SAA1)-(SAA)-(AA)-(AA2) (2)
(In the formula, SAA and SAA1 each independently represent an amino acid having a secondary amino group. AA represents an α, α-disubstituted amino acid. AA2 represents one or two natural or non-natural amino acids. )) In the presence of a peptide catalyst containing the amino acid represented by the following formula (3):

(Wherein R ¹ and R ² are each independently a substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 12 carbon atoms, and a substituted group having 6 to 18 carbon atoms. Or an unsubstituted aryl group or hydrogen.) And an aldehyde represented by the following formula (4):

(Wherein R ³ is a substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 12 carbon atoms, a substituted or unsubstituted aryl group having 6 to 18 carbon atoms, or And a diazodicarboxylate derivative represented by the following formula (5):

(Wherein R ¹ , R ² and R ³ are the same as above, * represents an asymmetric carbon).

By using the peptide catalyst according to the present invention, an asymmetric α-amination reaction of an aldehyde useful as a method for synthesizing intermediates for pharmaceuticals and agricultural chemicals can be advanced with high stereoselectivity.

Hereinafter, the present invention will be described in detail.
The amino acid having an asymmetric point described in the present application may be an L-isomer or a D-isomer unless otherwise specified. Moreover, the mixture of a compatible body may be sufficient. When the L-form and D-form are specified, the optical purity of the optically active amino acid is preferably 80% ee or more, more preferably 90% ee or more, and most preferably 95% ee or more. .

In the present application, the amino acid side chain having a functional group may be substituted with a protecting group or the like. For example, in the case of L-serine in which the side chain hydroxyl group is protected with a t-butyl group, “L-Ser (tBu)”, and in the case of L-serine in which the side chain hydroxyl group is protected with an acetyl group, “ In the case of “L-Ser (Ac)” and L-asparagine in which the side chain amide group is protected with a trityl group, it is expressed as “L-Asp (Trt)”.
The immobilized peptide catalyst according to the present invention comprises a peptide and a carrier, and the peptide is represented by the following formula (1):
(SAA)-(AA)-(AA2) (1)
Or the following formula (2):
(SAA1)-(SAA)-(AA)-(AA2) (2)
Is contained at the N-terminus, and the C-terminus is immobilized by binding to a carrier. More preferably, it is an immobilized peptide represented by the formula (1).

In the above formulas (1) and (2), the N-terminal amino acid may be in the N-free form or may form a salt with the acid.

Examples of the acid include organic acids such as trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and benzoic acid, and inorganic acids such as hydrochloric acid and sulfuric acid. Among them, an organic acid is preferable, trifluoroacetic acid, methanesulfonic acid, and benzoic acid are more preferable, and trifluoroacetic acid is most preferable.

In the above formulas (1) and (2), SAA represents an amino acid having a secondary amino group. Examples of amino acids having a secondary amino group include proline (Pro), 3-hydroxyproline (3-Hyp), 3-hydroxyproline derivatives, azetidine-2-carboxylic acid, and the like. The 3Hyp derivative is not particularly limited, and examples thereof include protected O-TBDMS (Ot-butyldimethylsilyl-3-hydroxyproline). Among these, Pro is preferable because it is inexpensive and easily available.

In the above formula (2), SAA1 represents an amino acid having a secondary amino group. Examples of the amino acid having a secondary amino group include those described above. Among them, Pro is preferable because it can be obtained relatively inexpensively.

In the above formulas (1) and (2), AA represents an α, α-disubstituted amino acid. In this α, α-disubstituted amino acid, the substituent bonded to the α-position carbon is preferably an alkyl group or a cyclic alkylene group. The total number of carbon atoms of the two substituents may be preferably 10 or less, more preferably about 5 or less. Examples of α, α-disubstituted amino acids include the following formula (6):

Α-aminoisobutyric acid (Aib) represented by the following formula (7):

Α-aminocyclohexanecarboxylic acid (Ach) represented by Of these, Aib is preferred.

In the formulas (1) and (2), AA2 represents 1 or 2 natural amino acids or non-natural amino acids. A natural amino acid represents an amino acid constituting a protein, and when the amino acid has an asymmetric point, its absolute structure may be L-form or D-form. For example, natural amino acids having hydrophobic side chains such as Gly, Ala, Val, Leu, Ile, Met, Trp, Phe, Pro, and uncharged polar groups such as Ser, Thr, Cys, Tyr, Asn, Gln Examples include natural amino acids having a chain, natural amino acids having a positive charge such as Lys, His, and Arg in the side chain, and natural amino acids having a negative charge such as Asp and Glu in the side chain.

Examples of non-natural amino acids include amino acids other than the above-mentioned natural amino acids. When an amino acid has an asymmetric point, its absolute structure may be L-form or D-form. For example, Aib, Ach, the following formula (8):

Ala (1-Pyn), β-alanine, phenylglycine, 2-aminobenzoic acid, 3-aminobenzoic acid and the like represented by

AA2 is preferably a natural amino acid having a hydrophobic side chain, a natural amino acid having an uncharged polar group in the side chain, Aib, Ach, Ala (1-Pyn), or a combination thereof, and more preferably Is a natural amino acid having a hydrophobic side chain, a natural amino acid having an uncharged polar group, or a combination thereof, more preferably Ala, Val, Ile, Trp, Phe, Ser, or a combination thereof And most preferably Ala, Trp, Phe, Ser, or a combination thereof. As a combination of two amino acids, Ser-Ser, Trp-Trp, or Ser-Trp is preferable.

In the above formulas (1) and (2), AA2 and the carrier may be directly bonded, or a further amino acid may be present between AA2 and the carrier.

In the above formula (1), the number of amino acid residues present between AA2 and the carrier is not particularly limited. The total number of amino acid residues constituting the peptide is preferably 27 or less, more preferably 10 or less, and most preferably 4 or less. Accordingly, the amino acid residue present between AA2 and the carrier is preferably 0 to 24 residues, more preferably 0 to 7 residues, still more preferably 0 or 1, and most preferably 0. It is.

In the formula (1), when an amino acid is present between AA2 and the carrier, the amino acid present is not particularly limited, and may be a natural amino acid or a non-natural amino acid. Also good. Examples of natural amino acids include those described above. Examples of non-natural amino acids include those described above. Of these, natural amino acids are preferable because they are inexpensive and easily available.

In the above formula (2), the number of amino acid residues present between AA2 and the carrier is not particularly limited. The total number of amino acid residues constituting the peptide is preferably 50 or less, and more preferably 40 or less. Accordingly, the number of amino acid residues present between AA2 and the carrier is preferably 0 to 46 residues, more preferably 0 to 36 residues, and most preferably 4 to 36 residues composed of the same amino acid. It is a group.

In the formula (2), when an amino acid is present between AA2 and the carrier, the existing amino acid is not particularly limited, and may be a natural amino acid or a non-natural amino acid. Also good. Examples of natural amino acids include those described above. Examples of non-natural amino acids include those described above. Of these, natural amino acids are preferable because they are inexpensive and easily available. Furthermore, polyamino acids composed of the same amino acids are preferred, and among them, polyamino acids known to form α-helices are preferred, and polyleucine is most preferred.

Since the immobilized peptide catalyst can achieve a high enantioselectivity of 80% ee or higher,
L-Pro-D-Pro-Aib-L-Trp-L-Trp- (L-Leu) _{6 to} 35-(carrier),

D-Pro-Aib-L-Ser-L-Ser- (carrier),
L-Pro-Aib-L-Ser-L-Ser- (carrier) (SEQ ID NO: 1),

D-Pro-Aib-L-Ser-L-Trp- (carrier),
L-Pro-Aib-L-Ser-L-Trp- (carrier) (SEQ ID NO: 2),

D-Pro-Aib-L-Ala- (carrier),
L-Pro-Aib-L-Ala- (carrier),
D-Pro-Aib-D-Ala- (carrier),
L-Pro-Aib-D-Ala- (support),

D-Pro-Aib-L-Phe- (carrier),
L-Pro-Aib-L-Phe- (carrier),
D-Pro-Aib-D-Phe- (carrier),
L-Pro-Aib-D-Phe- (carrier),

D-Pro-Aib-L-Trp- (carrier),
L-Pro-Aib-L-Trp- (carrier),
D-Pro-Aib-D-Trp- (carrier),
L-Pro-Aib-D-Trp- (carrier),
Is preferred.

In the immobilized peptide catalyst, the carrier is made of a resin having an amine as a functional group. By condensing the amine and the C-terminal carboxyl group of the peptide, the peptide is immobilized on the carrier.

The resin having an amine functional group is not particularly limited. For example, aminomethylpolystyrene (aminomethylresin), Tentagel (on a low-crosslinked polystyrene carrier, polyethylene (-O- is bonded to the ethylene moiety). (Including polyoxyethylene formed) graft-bonded resin, manufactured by Rapp Polymere, registered trademark) -NH ₂ resin, PEGA (polyethylene glycol-polyacrylamide copolymer) -NH ₂ resin (aminoPEGA resin), Examples include MBHA (4-methylbenzhydrylamine) resin, rinkamide resin (4- (2 ′, 4′-dimethoxyphenyl-Fmoc-aminomethyl) -phenoxyresin), rinkamide MBHA resin, and the like. Among these, aminomethyl polystyrene (aminomethyl resin) and Tentagel (registered trademark) -NH ₂ resin are preferable because they are easily available and inexpensive.
Preferred carriers include, for example, a resin having a polystyrene main chain and an amino group, particularly preferably a resin having a cross-linked polystyrene main chain and an amino group and a polyoxyalkylene chain (for example, a polyoxyethylene chain) in the side chain. May be included.

The amount of the amine functional group introduced into the carrier (loading capacity) is not particularly limited, but is preferably 0.1 to 3.0 mmol / g, more preferably 0.2 to 2.0 mmol / g.

The average particle size of the carrier is not particularly limited, but is preferably 10 to 500 mesh, and more preferably 20 to 300 mesh.
The carrier may be cross-linked or not cross-linked. When a crosslinked carrier is used, the reagent used for crosslinking and the amount of crosslinking are not particularly limited.

The immobilized peptide catalyst according to the present invention can be synthesized by an ordinary solid phase synthesis method. For example, Tentagel-NH ₂ resin, 9-fluorenylmethyloxycarbonyl (hereinafter Fmoc) -amino acid, HOBt (hydroxybenzotriazole), HBTU (1- [bis (dimethylamino) methylene] -1H-benzotriazolium A DMF solution consisting of -3-oxide hexafluorophosphate) and DIEA (diisopropylethylamine) is stirred for several tens of minutes at room temperature, then filtered, and the residue is washed with DMF. An extended Fmoc-protected amino acid resin can be synthesized. Subsequently, a 20% (vol / vol) piperidine / DMF solution is added, stirred for several tens of minutes, filtered, and the residue is washed with DMF to obtain an N-free amino acid resin. An immobilized peptide catalyst can be synthesized by performing these operations using any Fmoc amino acid and finally deprotecting the side chain protecting group as necessary.

In the presence of the peptide catalyst, the following formula (3):

And an aldehyde represented by the following formula (4):

By reacting the diazodicarboxylate derivative represented by the following formula (5):

The α-aminoaldehyde derivative represented by can be produced with high selectivity.

In the above formula (3), R ¹ and R ² are each independently a substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 12 carbon atoms, or a carbon number of 6 Represents -18 substituted or unsubstituted aryl groups, or hydrogen. The substituted alkyl group may be an alkyl group substituted with an unsaturated hydrocarbon group, that is, an alkenyl group, an alkynyl group, or the like, and may further have another substituent. Examples of the substituted or unsubstituted alkyl group having 1 to 15 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, Examples thereof include an n-octadecanoyl group, a 4-pentenyl group, and a 4-pentynyl group. Examples of the substituted or unsubstituted aralkyl group having 7 to 12 carbon atoms include benzyl group, p-chlorobenzyl group, o-chlorobenzyl group, m-chlorobenzyl group, 3,5-dichlorobenzyl group, and p-bromobenzyl. Group, o-bromobenzyl group, m-bromobenzyl group, p-nitrobenzyl group, p-methoxyphenyl group, p-trifluoromethylbenzyl, 3,5-bis (trifluoromethyl) benzyl group and the like. Examples of the substituted or unsubstituted aryl group having 6 to 18 carbon atoms include phenyl group, p-chlorophenyl group, o-chlorophenyl group, m-chlorophenyl group, p-bromophenyl group, 3,5-dichlorophenyl group, o- Examples include bromophenyl group, m-bromophenyl group, p-nitrophenyl group, p-methoxyphenyl group, p-trifluoromethylphenyl group, 3,5-bis (trifluoromethyl) phenyl and the like.
The upper limit of the carbon number of the alkyl group represented by R ¹ and R ² is preferably 12 or less, more preferably 10 or less. The upper limit of the carbon number of the aralkyl group is preferably 10 or less, more preferably 8 or less. The upper limit of the carbon number of the aryl group is preferably 10 or less, more preferably 8 or less.

Since the product has an asymmetric point, it is preferable that R ¹ and R ² are different substituents, and it is more preferable that either R ¹ or R ² is hydrogen.

In the formula (4), R ³ represents a substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 12 carbon atoms, or a substituted or unsubstituted aryl group having 6 to 18 carbon atoms. Represents a group or hydrogen. Examples of the substituted or unsubstituted alkyl group having 1 to 15 carbon atoms include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, n-pentyl group, n -Octadecyl group and the like. Examples of the substituted or unsubstituted aralkyl group having 7 to 12 carbon atoms include benzyl group, p-nitrobenzyl group, p-trifluoromethylbenzyl group, p-methoxybenzyl group, 1-naphthyl group and 2-naphthyl group. Is mentioned. Examples of the substituted or unsubstituted aryl group having 6 to 18 carbon atoms include a phenyl group, a p-nitrophenyl group, a p-trifluoromethylphenyl group, and a p-methoxyphenyl group. Among them, an ethyl group, an isopropyl group, a t-butyl group, and a benzyl group are preferable, and an isopropyl group, a t-butyl group, and a benzyl group are more preferable because they are easily available and can be handled relatively safely. Most preferred are isopropyl group and benzyl group.
The upper limit of the carbon number of the alkyl group represented by R ³ is preferably 12 or less, more preferably 10 or less. The upper limit of the carbon number of the aralkyl group is preferably 10 or less, more preferably 8 or less. The upper limit of the carbon number of the aryl group is preferably 10 or less, more preferably 8 or less.

In the formula (5), R ¹ , R ² and R ³ are the same as described above.

In the above formula (5), * represents an asymmetric point. Its absolute configuration may be (S) -isomer or (R) -isomer. (5) having each absolute configuration can be selectively obtained by completely inverting the absolute configuration of the amino acid residues of the catalyst or changing the amino acid sequence.

The amount of the immobilized peptide catalyst used for the reaction is not particularly limited, but may be 0.1 to 100 mol%, preferably 0.1 to 20 mol%, relative to the azodicarboxylate derivative (4). More preferably, it is 0.1 to 10 mol%.

The amount of aldehyde (3) used in the reaction is not particularly limited, but it may be used in an amount of 1.0 to 5.0 equivalents relative to the azodicarboxylate derivative (4), preferably 1.0 to 3.0 equivalents, more preferably 1.0 to 2.0 equivalents.

The solvent to be used is not particularly limited, and examples thereof include aprotic polar solvents such as N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone, and hexamethylphosphoric triamide; hexamethylbenzene, Hydrocarbon solvents such as toluene, n-hexane, cyclohexane; ether solvents such as diethyl ether, tetrahydrofuran (THF), diisopropyl ether, methyl tert-butyl ether, dimethoxyethane; chlorobenzene, methylene chloride, chloroform, 1,1,1 -Halogen solvents such as trichloroethane; ester solvents such as ethyl acetate and butyl acetate; nitrile solvents such as acetonitrile and butyronitrile; methanol, ethanol, isopropanol, n-propanol, butano Le, alcohol solvents octanol and the like; and water. These may be used alone or in combination of two or more. Of these, hydrocarbon solvents, halogen solvents, nitrile solvents, ester solvents, alcohol solvents, and water are preferable, and toluene, dichloromethane, acetonitrile, ethyl acetate, isopropyl acetate, methanol, and water are more preferable. Most preferred are dichloromethane, acetonitrile, ethyl acetate, methanol and water.

The reaction temperature is usually in the range of −30 to 120 ° C., preferably −20 to 60 ° C. More preferably, it is −20 to 40 ° C.

After completion of the reaction, the filtrate may be concentrated after separating the immobilized peptide catalyst from the reaction solution by filtration to obtain a crude product from the reaction solution. By filtering the reaction solution in this way, the catalyst can be easily separated.

The separated catalyst may be washed with an organic solvent or the like. The separated immobilized peptide catalyst can be reused. For example, the separated catalyst may be used for the reaction as it is, or the separated catalyst may be dried under reduced pressure and then used for the reaction.

The obtained reaction liquid may be processed according to a general post-treatment method. For example, the extraction operation is performed using a general extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane and the like. The target compound is obtained by distilling off the reaction solvent and the extraction solvent from the resulting extract by an operation such as heating under reduced pressure. Furthermore, after the reaction solvent is distilled off or the solvent is replaced by an operation such as heating under reduced pressure, the same operation as described above may be performed.

The target product thus obtained is almost pure, but purification may be carried out by a general method such as crystallization purification, fractional distillation, column chromatography, etc. to further increase the purity.

The α-aminoaldehyde derivative that can be obtained in this way may be unstable or difficult to analyze the product. Therefore, the α-aminoaldehyde derivative may be obtained after converting the aldehyde functional group to a functional group such as alcohol or carboxylic acid. May be. For example, it can be obtained as a carboxylic acid derivative by reducing with sodium borohydride and oxidizing with sodium chlorite (NaClO ₂ ) as an alcohol derivative.

In the above formula (1), in particular, the immobilized peptide catalyst having 27 or less amino acid residues is a novel peptide catalyst that has been found to have high selectivity in the asymmetric α-amination reaction of aldehydes. Not only can the reaction solution be easily separated from the reaction system by filtering the reaction solution, but also it can be easily synthesized by an industrially established solid-phase synthesis method, which is preferable. *

This application claims the benefit of priority based on Japanese Patent Application No. 2011-177167 filed on August 12, 2011. The entire content of the specification of Japanese Patent Application No. 2011-177167 filed on August 12, 2011 is incorporated herein by reference.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Example 1 Tentagel (registered trademark (hereinafter, the same)) in a synthetic disposable desalting column (trade name PD-10, manufactured by GE Healthcare ) of D-Pro-Aib-L-Ser-L-Ser-Tentagel ) S-NH ₂ (purchased from Aldrich) (loading capacity 0.26 mol / kg, 300 mg) was added and washed with dichloromethane (5 mL × 2) and DMF (5 mL × 2). Fmoc-L-Ser (tBu) -OH (89.7 mg, 0.23 mmol), HOBt (31.6 mg, 0.23 mmol), HBTU (88.7 mg, 0.23 mmol), DIEA (82 μL, 0.47 mmol) A DMF (5 mL) solution consisting of was added and allowed to react for 30 minutes with occasional shaking. The reaction solution was separated by filtration, and the residue (Fmoc-L-Ser (tBu) -Tentagel) was washed with DMF (5 mL × 5 times). Subsequently, 20% (vol / vol) piperidine / DMF solution (5 mL) was added and allowed to react for 30 minutes with occasional shaking. The reaction solution was separated by filtration, and the residue was washed with DMF (5 mL × 5 times) to obtain L-Ser (tBu) -Tentagel. A series of the same operations are sequentially performed using Fmoc-L-Ser (tBu) -OH, Fmoc-Aib-OH, and Fmoc-D-Pro-OH, and D-Pro-Aib-L-Ser (tBu) -L- Ser (tBu) -Tentagel was obtained. The obtained peptide was dried under reduced pressure (20 ° C./1 mmHg, 1 h), and water (3 drops with a dropper) and trifluoroacetic acid (5 mL) were added. The reaction was allowed to proceed for 60 minutes with occasional shaking. The reaction solution was separated by filtration, and the residue was dichloromethane (5 mL × 5 times), DMF (5 mL × 5 times), triethylamine (5 mL × 5 times), DMF (5 mL × 5 times), dichloromethane (5 mL × 5 times). Washed with The obtained residue was dried under reduced pressure (20 ° C./1 mmHg, 15 h) to obtain the title peptide.

Example 2 Synthesis of L-Pro-Aib-L-Ser-L-Ser-Tentagel According to the method described in Example 1, Tenogel S-NH ₂ was converted to Fmoc-L-Ser (tBu) -OH, Fmoc- L-Ser (tBu) -OH, Fmoc-Aib-OH, and Fmoc-L-Pro-OH were sequentially condensed. The same deprotection operation as in Example 1 was performed to obtain the title compound.

Example 3 Synthesis of D-Pro-Aib-L-Ser-L-Trp-Tentagel According to the method described in Example 1, Tentagel S-NH ₂ was converted to Fmoc-L-Trp-OH, Fmoc-L-Ser. (TBu) -OH, Fmoc-Aib-OH and Fmoc-D-Pro-OH were sequentially condensed. The same deprotection operation as in Example 1 was performed to obtain the title compound.

Example 4 Synthesis of D-Pro-Aib-L-Ser-L-Ser-aminomethylpolystyrene According to the method described in Example 1, aminomethylpolystyrene (loading capacity 1.5 mol / kg) was substituted for Tentagel-NH _2. ) Was used to synthesize the title compound.

(Example 5) Tentagel S-NH ₂ (loading capacity 0.26 mol / kg) in a disposable desalting column (trade name PD-10, manufactured by GE Healthcare ) of D-Pro-Aib-L-Phe-Tentagel , 100 mg), and washed with dichloromethane (1 mL × 2 times) and DMF (1 mL × 2 times). DMF consisting of Fmoc-L-Phe-OH (30.2 mg, 0.078 mmol), HOBt (10.5 mg, 0.078 mmol), HBTU (29.6 mg, 0.078 mmol), DIEA (27 μL, 0.156 mmol) (1 mL) solution was added and allowed to react for 30 minutes with occasional shaking. The reaction solution was separated by filtration, and the residue (Fmoc-L-Phe-Tentagel) was washed with DMF (5 mL × 5 times). Subsequently, 20% (vol / vol) piperidine / DMF solution (1 mL) was added and allowed to react for 30 minutes with occasional shaking. The reaction solution was separated by filtration, and the residue was washed with DMF (1 mL × 5 times) to obtain L-Phe-Tentagel. A series of the same operations were sequentially performed using Fmoc-Aib-OH and Fmoc-D-Pro-OH to obtain D-Pro-Aib-L-Phe-Tentagel. The obtained peptide was washed with dichloromethane (1 mL × 5 times). The obtained residue was dried under reduced pressure (20 ° C./1 mmHg, 15 h) to obtain the title peptide.

Example 6 Synthesis of D-Pro-Aib-L-Ala-Tentagel According to the method described in Example 5, Tentagel S-NH ₂ was mixed with Fmoc-L-Ala-OH, Fmoc-Aib-OH, Fmoc-D. -Pro-OH was sequentially condensed to give the title compound.

Example 7 Synthesis of TFA / D-Pro-Aib-L-Ser-L-Ser-Tentagel D-Pro-Aib-L-Ser-L-Ser-Tentagel (100 mg) obtained in Example 1 is disposable Weighed in a desalting column (trade name PD-10, manufactured by GE Healthcare), and trifluoroacetic acid (0.5 mL) was added at room temperature. The reaction was separated after 10 minutes of reaction with occasional shaking. The residue was washed successively with dichloromethane (1 mL × 3), DMF (1 mL × 3), and dichloromethane (1 mL × 3). The obtained resin was dried under reduced pressure (20 ° C./1 mmHg, 15 h) to obtain the title peptide in which N-terminal D-Pro formed a salt with trifluoroacetic acid.

Example 8 Synthesis of (S) -2- [N, N′-di (isopropyloxycarbonyl) hydrazino] -3-phenylpropan-1-ol Peptide catalyst D-Pro-Aib- obtained in Example 1 Acetonitrile (600 μL) was added to L-Ser-L-Ser-Tentagel (21.6 mg, 5.06 × 10 ⁻³ mmol) and cooled in an ice bath. At the same temperature, 3-phenylpropanal (13.4 μL, 0.1 mmol) and diisopropyl diazodicarboxylate (1.9 mol / L-toluene solution, 26.2 μL, 0.05 mmol) were added. After stirring at the same temperature for 6 hours, the catalyst was separated by a filtration operation to obtain a reaction solution. The separated catalyst was washed with acetonitrile (1 mL), and the washing solution and the reaction solution were combined and concentrated. The separated catalyst was recovered as it was and reused as appropriate for the same reaction. The concentrate was diluted in THF (1 mL) and sodium borohydride (appropriate amount) was added at room temperature. After stirring at the same temperature for 1 hour, water (3 mL) was added, and extraction was performed with dichloromethane (15 mL × 1 + 5 mL × 1). The extract was dried using magnesium sulfate and then concentrated. The obtained crude product was purified by preparative TLC (silica gel, ethyl acetate: hexane = 3: 7) to obtain the title compound (15.2 mg, yield: 90%). As a result of optical purity analysis using HPLC, it was 94% ee.
¹ H-NMR (400 MHz, CDCl ₃ ) σ0.92-1.41 (12H, m), 2.81-2.48 (2H, m), 3.57 (2H, s), 4.02-5 .11 (4H, m), 6.65 (1H, d), 7.06-7.35 (5H, m)
Column: Chiralcel OD-H (250 × 4.6 mm), eluent: isopropanol: hexane = 5: 95, flow rate: 0.5 mL / min, detector; UV 220 nm, column temperature: 25 ° C., retention time: 15.2 min (S-isomer), 18.4 min (R-isomer)
The chiral cell OD-H is a product name of Daicel Corporation (hereinafter the same).

Example 9 Synthesis of (S) -2- [N, N′-di (isopropyloxycarbonyl) hydrazino] -3-phenylpropan-1-ol According to the method described in Example 8, dichloromethane was replaced with dichloromethane. The title compound was obtained in the same manner as above (yield 94%, 83% ee (S-form)).

Example 10 Synthesis of (S) -2- [N, N′-di (isopropyloxycarbonyl) hydrazino] -3-phenylpropan-1-ol According to the method described in Example 8, ethyl acetate was changed to acetonitrile. Was used for the same reaction to obtain the title compound (yield 100%, 84% ee (S-form)).

Example 11 Synthesis of (R) -2- [N, N′-di (isopropyloxycarbonyl) hydrazino] -3-phenylpropan-1-ol According to the method described in Example 8, described in Example 2. The same reaction was carried out using the peptide catalyst L-Pro-Aib-L-Ser-L-Ser-Tentagel obtained by the above method to obtain the title compound (yield 86%, 89% ee (R-isomer)) ).

Example 12 Synthesis of (S) -2- [N, N′-di (isopropyloxycarbonyl) hydrazino] -3-phenylpropan-1-ol According to the method described in Example 8, described in Example 3. The same reaction was carried out using the peptide catalyst D-Pro-Aib-L-Ser-L-Trp-Tentagel obtained by the above method to obtain the title compound (yield 70%, 86% ee (S-form)) ).

Example 13 Synthesis of (S) -2- [N, N′-di (isopropyloxycarbonyl) hydrazino] -3-phenylpropan-1-ol According to the method described in Example 8, described in Example 4. Using the peptide catalyst D-Pro-Aib-L-Ser-L-Ser-aminomethyl polystyrene obtained by the above method, the same reaction was carried out using dichloromethane instead of acetonitrile to obtain the title compound (yield 100). %, 91% ee (S-form)).

Example 14 Synthesis of (S) -2- [N, N′-di (isopropyloxycarbonyl) hydrazino] -3-phenylpropan-1-ol According to the method described in Example 8, described in Example 5. Using the peptide catalyst D-Pro-Aib-L-Phe-Tentagel obtained by the above method, the same reaction was carried out to obtain the title compound (yield 99%, 89% ee (S-form)).

Example 15 Synthesis of (S) -2- [N, N′-di (isopropyloxycarbonyl) hydrazino] -3-phenylpropan-1-ol According to the method described in Example 8, described in Example 6. The same reaction was carried out using the peptide catalyst D-Pro-Aib-L-Ala-Tentagel obtained by the above method to obtain the title compound (yield 100%, 88% ee (S-form)).

Example 16 Synthesis of (S) -2- [N, N′-di (isopropyloxycarbonyl) hydrazino] -3-phenylpropan-1-ol According to the method described in Example 8, described in Example 7. The same reaction was performed using the peptide catalyst TFA • D-Pro-Aib-L-Ser-L-Ser-Tentagel obtained by the above method to obtain the title compound (yield 99%, 88% ee (S- body)).

Example 17 Synthesis of (S) -2- [N, N′-di (isopropyloxycarbonyl) hydrazino] -3-phenylpropan-1-ol Org. Lett. L-Pro-D-Pro-Aib-L-Trp-L-Trp- (L-Leu) ₃₃ -Tentagel (20.3 mg, 2.53 × 10 ⁻³ ) produced by the method described in 2008, 10, 2035 mmol) was added water (210 μL), MeOH (90 μL), 3-phenylpropanal (6.7 μL, 0.05 mmol), and cooled to −12 ° C. using a low temperature bath. Diisopropyl diazodicarboxylate (1.9 mol / L-toluene solution, 13.1 μL, 0.025 mmol) was added at the same temperature. After stirring at the same temperature for 6 hours, the catalyst was separated by a filtration operation to obtain a reaction solution. The separated catalyst was washed with acetonitrile (1 mL), and the washing solution and the reaction solution were combined and concentrated. The separated catalyst was recovered as it was and reused as appropriate for the same reaction. The concentrate was diluted in THF (1 mL) and sodium borohydride (appropriate amount) was added at room temperature. After stirring at the same temperature for 1 hour, water (3 mL) was added, and extraction was performed with dichloromethane (15 mL × 1 + 5 mL × 1). The extract was dried using magnesium sulfate and then concentrated. The obtained crude product was purified by preparative TLC (silica gel, ethyl acetate: hexane = 3: 7) to obtain the title compound (6.9 mg, yield: 82%). As a result of optical purity analysis using HPLC, it was 85% ee.

Example 18 Synthesis of (S) -2- [N, N′-di (benzyloxycarbonyl) hydrazino] -3-methylbutan-1-ol Peptide catalyst D-Pro-Aib-L obtained in Example 1 To Ser-L-Ser-Tentagel (31.4 mg, 7.29 × 10 ⁻³ mmol) was added acetonitrile (860 μL). At room temperature (26 ° C.), 3-methylbutanal (isovaleraldehyde) (15.7 μL, 0.15 mmol) and dibenzyldiazodicarboxylate (90 wt% content, 26.1 mg, 0.08 mmol) were added. After stirring at the same temperature for 6 hours, the catalyst was separated by a filtration operation to obtain a reaction solution. The separated catalyst was washed with acetonitrile (1 mL), and the washing solution and the reaction solution were combined and concentrated. The separated catalyst was recovered as it was and reused as appropriate for the same reaction. The concentrate was diluted in THF (1 mL) and sodium borohydride (appropriate amount) was added at room temperature. After stirring at the same temperature for 6 hours, water (3 mL) was added, and extraction was performed with dichloromethane (15 mL × 1 + 5 mL × 1). The extract was dried using magnesium sulfate and then concentrated. The obtained crude product was purified by preparative TLC (silica gel, ethyl acetate: hexane = 3: 7) to obtain the title compound (26.5 mg, yield: 90%). As a result of optical purity analysis using HPLC, it was 94% ee.
¹ H-NMR (400 MHz, CDCl ₃ ) σ0.76-0.94 (6H, m), 1.55-1.70 (1H, m), 3.40-3.45 (1H, m), 3 .63-3.79 (1H, m), 3.88-4.45 (2H, m), 5.04-5.26 (4H, m), 6.85 (1H, s), 7.20 -7.40 (10H, m)
Column: Chiralcel OD-H (250 × 4.6 mm), eluent: isopropanol: hexane = 5: 95, flow rate: 1.0 mL / min, detector; UV 220 nm, column temperature; 25 ° C., retention time: 24.0 min (R-isomer), 29.8 min (S-isomer)

Example 19 Synthesis of (S) -2- [N, N′-di (benzyloxycarbonyl) hydrazino] -hexane-1-ol In accordance with the method described in Example 18, instead of 3-methylbutanal The same reaction was carried out using hexanal to obtain the title compound (yield 100%, 96% ee (S-form)).
¹ H-NMR (400 MHz, CDCl ₃ ) σ0.80-0.90 (3H, m), 1.04-1.30 (6H, m), 3.35-3.55 (2H, m), 4 .10-4.45 (2H, m), 5.02-5.30 (4H, m), 6.80 (1H, s), 7.20-7.40 (10H, m)
Column: Chiralcel OJ-H (250 × 4.6 mm), eluent: isopropanol: hexane = 10: 90, flow rate: 1.0 mL / min, detector; UV 220 nm, column temperature; 25 ° C., retention time: 15.0 min (R-isomer), 17.6 min (S-isomer)
The chiral cell OJ-H is a product name of Daicel Corporation.

Example 20 Synthesis of (S) -2- [N, N′-di (benzyloxycarbonyl) hydrazino] -3-phenylpropan-1-ol According to the method described in Example 18, 3-methylbutanal Instead, the same reaction was carried out using 3-phenylpropanal to obtain the title compound (yield 100%, 90% ee (S-form)).
¹ H-NMR (400 MHz, CDCl ₃ ) σ2.50-2.70 (2H, m), 3.52-3.65 (2H, m), 3.96-4.91 (2H, m), 4 .92-5.25 (4H, m), 6.63 (1H, d), 7.10-7.40 (15H, m)
Column: Chiralpak AS (250 × 4.6 mm), eluent: isopropanol: hexane = 10: 90, flow rate: 1.0 mL / min, detector; UV 210 nm, column temperature; 25 ° C., retention time; 20.6 min ( S-form), 45.3 min (R-form)
The chiral pack AS is a product name of Daicel Corporation.

(Example 21) Reuse experiment 1 of catalyst
According to the method described in Example 8, the same reaction was performed using the catalyst recovered in Example 16, and (S) -2- [N, N′-di (isopropyloxycarbonyl) hydrazino] -3-phenylpropane- 1-ol (yield 100%, 86% ee (S-form)) was obtained.

(Example 22) Catalyst reuse experiment 2
According to the method described in Example 8, a similar reaction was performed using the catalyst recovered in Example 21, and (S) -2- [N, N′-di (isopropyloxycarbonyl) hydrazino] -3-phenylpropane- 1-ol (yield 88%, 87% ee (S-form)) was obtained.

(Example 23) Catalyst reuse experiment 3
According to the method described in Example 8, a similar reaction was performed using the catalyst recovered in Example 22, and (S) -2- [N, N′-di (isopropyloxycarbonyl) hydrazino] -3-phenylpropane- 1-ol (yield 90%, 91% ee (S-form)) was obtained.

(Example 24) Catalyst reuse experiment 4
According to the method described in Example 8, the same reaction was carried out using the catalyst recovered in Example 23 to obtain (S) -2- [N, N′-di (isopropyloxycarbonyl) hydrazino] -3-phenylpropane- 1-ol (yield 100%, 90% ee (S-form)) was obtained.

(Example 25) Catalyst reuse experiment 5
According to the method described in Example 8, the same reaction was performed using the catalyst recovered in Example 24, and (S) -2- [N, N′-di (isopropyloxycarbonyl) hydrazino] -3-phenylpropane- 1-ol (yield 98%, 92% ee (S-form)) was obtained.

(Example 26) Catalyst reuse experiment 6
According to the method described in Example 8, the same reaction was performed using the catalyst recovered in Example 25, and (S) -2- [N, N′-di (isopropyloxycarbonyl) hydrazino] -3-phenylpropane- 1-ol (99% yield, 92% ee (S-form)) was obtained.

(Example 27) Catalyst reuse experiment 7
According to the method described in Example 8, a similar reaction was performed using the catalyst recovered in Example 26, and (S) -2- [N, N′-di (isopropyloxycarbonyl) hydrazino] -3-phenylpropane- 1-ol (yield 84%, 92% ee (S-form)) was obtained.

Example 28 Catalyst Reuse Experiment 8
According to the method described in Example 8, the same reaction was performed using the catalyst recovered in Example 27, and (S) -2- [N, N′-di (isopropyloxycarbonyl) hydrazino] -3-phenylpropane- 1-ol (yield 92%, 91% ee (S-form)) was obtained.

(Comparative Example 1) Synthesis of D-Pro-L-Ala-L-Phe-Tentagel According to the method described in Example 5, Tentagel S-NH ₂ was converted to Fmoc-L-Phe-OH, Fmoc-L-Ala-OH. , Fmoc-D-Pro-OH were sequentially condensed to give the title compound.

(Comparative Example 2) Synthesis of D-Pro-L-Phe-L-Phe-Tentagel According to the method described in Example 5, Tentagel S-NH ₂ was mixed with Fmoc-L-Phe-OH, Fmoc-L-Phe-OH. , Fmoc-D-Pro-OH were sequentially condensed to give the title compound.

(Comparative Example 3) Synthesis of D-Pro-L-Trp-L-Phe-Tentagel According to the method described in Example 5, Tentagel S-NH ₂ was mixed with Fmoc-L-Phe-OH, Fmoc-L-Trp-OH. , Fmoc-D-Pro-OH were sequentially condensed to give the title compound.

(Comparative Example 4) Synthesis of D-Pro-L-Tyr (tBu) -L-Phe-Tentagel According to the method described in Example 5, Tentagel S-NH ₂ was mixed with Fmoc-L-Phe-OH, Fmoc-L- Tyr (tBu) -OH and Fmoc-D-Pro-OH were sequentially condensed to obtain the title compound.

Comparative Example 5 Synthesis of (S) -2- [N, N′-di (isopropyloxycarbonyl) hydrazino] -3-phenylpropan-1-ol According to the method described in Example 8, described in Comparative Example 1. The same reaction was carried out using the peptide catalyst D-Pro-L-Ala-L-Phe-Tentagel obtained by the above method to obtain the title compound (yield 17%, 63% ee (S-form)).

Comparative Example 6 Synthesis of (S) -2- [N, N′-di (isopropyloxycarbonyl) hydrazino] -3-phenylpropan-1-ol According to the method described in Example 8, described in Comparative Example 2. The same reaction was performed using the peptide catalyst D-Pro-L-Phe-L-Phe-Tentagel obtained by the above method to obtain the title compound (yield 25%, 57% ee (S-form)).

Comparative Example 7 Synthesis of (S) -2- [N, N′-di (isopropyloxycarbonyl) hydrazino] -3-phenylpropan-1-ol According to the method described in Example 8, described in Comparative Example 3. The same reaction was carried out using the peptide catalyst D-Pro-L-Trp-L-Phe-Tentagel obtained by the above method to obtain the title compound (yield 36%, 52% ee (S-form)).

Comparative Example 8 Synthesis of (S) -2- [N, N′-di (isopropyloxycarbonyl) hydrazino] -3-phenylpropan-1-ol According to the method described in Example 8, described in Comparative Example 4. Using the peptide catalyst D-Pro-L-Tyr (tBu) -L-Phe-Tentagel obtained by the above method, the same reaction was carried out to obtain the title compound (yield 32%, 53% ee (S-form) )).

(Comparative Example 9) Synthesis of D-Pro-Aib-Tentagel According to the method described in Example 5, Fmoc-Aib-OH and Fmoc-D-Pro-OH were sequentially condensed to Tentagel S-NH ₂ to give the title compound. Obtained.

(Comparative Example 10) Synthesis of D-Pro-Tentagel According to the method described in Example 5, Fmoc-D-Pro-OH was sequentially condensed with Tentagel S-NH ₂ to obtain the title compound.

Comparative Example 11 Synthesis of (S) -2- [N, N′-di (isopropyloxycarbonyl) hydrazino] -3-phenylpropan-1-ol According to the method described in Example 8, described in Comparative Example 9. The same reaction was carried out using the peptide catalyst D-Pro-Aib-Tentagel obtained by the above method to obtain the title compound (yield 92%, 72% ee (S-form)).

Comparative Example 12 Synthesis of (S) -2- [N, N′-di (isopropyloxycarbonyl) hydrazino] -3-phenylpropan-1-ol According to the method described in Example 8, described in Comparative Example 10. The same reaction was carried out using the peptide catalyst D-Pro-Tentagel obtained by the above method to obtain the title compound (yield 93%, 61% ee (S-form)).

The present invention is useful for asymmetric amination of the α-position of an aldehyde. Aldehydes asymmetrically aminated at the α-position are useful as intermediates for pharmaceuticals, agricultural chemicals and the like.

Claims (15)

1. It consists of a peptide and a carrier, and the peptide is represented by the following formula (1):
   (SAA)-(AA)-(AA2) (1)
   Or the following formula (2):
   (SAA1)-(SAA)-(AA)-(AA2) (2)
   (Wherein SAA and SAA1 each independently represent an amino acid having a secondary amino group. AA represents an α, α-disubstituted amino acid. AA2 represents one or two natural or non-natural amino acids. In the presence of a peptide catalyst in which the C-terminus is bound to a carrier and immobilized, in the presence of the amino acid represented by formula (3):
   

   

   Wherein R ¹ and R ² are each independently a substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 12 carbon atoms, or a substitution having 6 to 18 carbon atoms. Or an unsubstituted aryl group or hydrogen.) And an aldehyde represented by the following formula (4):
   

   

   (Wherein R ³ is a substituted or unsubstituted alkyl group having 1 to 15 carbon atoms, a substituted or unsubstituted aralkyl group having 7 to 12 carbon atoms, a substituted or unsubstituted aryl group having 6 to 18 carbon atoms, or And a diazodicarboxylate derivative represented by the following formula (5):
   

   

   (Wherein R ¹ , R ² and R ³ are the same as above, * represents an asymmetric carbon).
2. The production method according to claim 1, wherein SAA1 is proline.
3. The method according to claim 1 or 2, wherein SAA is proline.
4. The production method according to any one of claims 1 to 3, wherein AA is α-aminoisobutyric acid.
5. The production method according to any one of claims 1 to 4, wherein the carrier is a resin having an amino group in which polyethylene is graft-bonded on a low cross-linked polystyrene carrier or aminomethyl polystyrene.
6. The production method according to any one of claims 1 to 5, wherein AA2 is a natural amino acid.
7. The production method according to claim 6, wherein AA2 is a natural amino acid having a hydrophobic side chain or a natural amino acid having an uncharged polar group.
8. The production method according to any one of claims 1 to 7, wherein either R ¹ or R ² is hydrogen.
9. The production method according to any one of claims 1 to 8, wherein the peptide catalyst has a peptide represented by the formula (1).
10. Following formula (1):
    (SAA)-(AA)-(AA2) (1)
    (Wherein SAA represents an amino acid having a secondary amino group, AA represents an α, α-disubstituted amino acid, and AA2 represents one or two natural or non-natural amino acids). An immobilized peptide catalyst having an amino acid sequence at the N-terminus and having a C-terminus bound to a carrier and immobilized, wherein the number of amino acid residues is 27 or less.
11. The immobilized peptide catalyst according to claim 10, wherein AA is α-aminoisobutyric acid.
12. The immobilized peptide catalyst according to claim 10 or 11, wherein the carrier is a resin or aminomethylpolystyrene having an amino group in which polyethylene is graft-bonded on a low cross-linked polystyrene carrier.
13. The immobilized peptide catalyst according to any one of claims 10 to 12, wherein AA2 is directly bonded to the carrier.
14. The immobilized peptide catalyst according to any one of claims 10 to 13, wherein AA2 is a natural amino acid.
15. The process according to claim 14, wherein AA2 is a natural amino acid having a hydrophobic side chain or a natural amino acid having an uncharged polar group.