JPH11147890A - Solid phase-supported optically active phosphine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an asymmetric synthetic catalyst ligand applicable to a high-speed synthesis with a combinatorial chemistry or an automatic synthesizer. SOLUTION: This solid phase-supported optically active phosphine is represented by formula (I) or (I') [XNH denotes the terminal of a terminal amino group resin (XNH2 ); A denotes an L- or a D-amino acid which may be protected; (n) denotes an integer of 1-5] and is capable of providing a palladium-phosphine complex by reaction thereof with various palladium catalysts and useful for various kinds of asymmetric synthetic reactions. Furthermore, solid phase-supported optically active phosphine is supported on the solid phase and thereby applicable to a high-speed synthesis with a combinatorial chemistry or an automatic synthesizer.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a solid-supported optically active phosphine which is important in organic synthesis. The compound of the present invention gives a palladium-phosphine complex by reacting with various palladium catalysts, and is useful for many asymmetric synthesis reactions.Since it is supported on a solid phase, it can be applied to combinatorial chemistry and high-speed synthesis using automatic synthesis equipment. it can.

[0002]

BACKGROUND OF THE INVENTION Palladium-phosphine complexes are widely used as catalysts for various organic conversion reactions. Recently, the importance of high-speed organic synthesis has been increasing as seen in combinatorial chemistry and the like.However, conventional palladium-phosphine complexes cannot be easily removed from the reaction system because they are dissolved in a solvent. There were problems such as necessity of column purification.

[0003]

The present inventors have developed a number of palladium-phosphine complexes useful in organic synthesis, particularly in asymmetric synthesis. Among them, 2-diphenylphosphino- having a feature that the structure is rigid and a monodentate ligand
Palladium-phosphine complexes using 2'-methoxy-1,1'-binaphthyl are particularly useful as having unprecedented reactivity and selectivity (Bull. Chem. Soc. Jp.
n., 68, 718 (1995) Acta Chemical Scandinavica, 50, 259
(1996) J. Am. Chem. Soc., 116, 775 (1994) J. Synth. Org. Che.
m., Jpn, 52,900 (1994). This time, as a result of further study,
The inventors have invented a solid-phase-supported optically active phosphine, which is a compound of the present invention, which gives a palladium-phosphine complex that can be easily removed from the reaction system and can be used in both an organic solvent and an aqueous medium. The compound of the present invention can be used for the reactions described in the above-mentioned literatures by forming a solid-phased palladium-phosphine complex with various palladium compounds.

Hereinafter, the present invention will be described in detail. The solid-supported optically active phosphine of the present invention has the formula (I) or (I ′)

[0005]

Embedded image

Wherein XNH- represents the terminal of the terminal amino group resin (XNH ₂ ), A represents an L- or D-amino acid which may be protected, and n is an integer of 1 to 5. Is a solid supported optically active phosphine represented by the following formula:

Here, examples of the terminal amino group resin include polystyrene resin, PEG-polystyrene resin, PGA resin and the like, and PEG-polystyrene resin is preferably used.

Further, n represents an integer of 1 to 5, and preferably 1 to 3.

As amino acids, L- or D-alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, serine,
Threonine, cysteine, tryptophan, glutamine, asparagine, tyrosine, lysine, histidine, aspartic acid, glutamic acid, but preferably L- or D-alanine, valine, leucine, isoleucine, proline, phenylalanine, serine, threonine, tyrosine Is mentioned.

[0010] The amino acid may have a protected residue, and examples of the protecting group include the following.

Examples of the hydroxyl-protecting group include silyl groups such as trimethylsilyl group, t-butyldimethylsilyl group and t-butyldiphenylsilyl group, and substituted methyl groups represented by methoxymethyl group, triphenylmethyl group and diphenylmethyl group. , 1-ethoxyethyl group, substituted ethyl group represented by allyl group, benzyl group, p-methoxybenzyl group, p-phenylbenzyl group, substituted benzyl group represented by p-chlorobenzyl group, t-butyl group Representative examples include an alkyl group, an acetyl group, and a phenoxymethylcarbonyl group.

The protective group for the thiol group includes a substituted methyl group represented by a methoxymethyl group, a triphenylmethyl group and a diphenylmethyl group, a substituted ethyl group represented by a 1-ethoxyethyl group, a substituted ethyl group represented by an allyl group, a benzyl group, substituted benzyl group represented by p-methoxybenzyl group, p-phenylbenzyl group, p-chlorobenzyl group, acetamidomethyl group, trimethylacetamidomethyl group, 3-nitro-2-pyridylsulfenyl group, carbomethoxysulfenyl group A methylphenylcarbamoylsulfenyl group, a benzyloxymethyl group, a ferrocenylmethyl group,
Examples include a 2-ferrocenylpropan-2-yl group, a 9-fluorenylmethyl group, and a dimethylphosphinothioyl group.

The protecting groups for the phenolic hydroxyl group include benzyl, p-methoxybenzyl, p-phenylbenzyl, substituted benzyl represented by p-chlorobenzyl, methoxymethyl, triphenylmethyl, diphenylmethyl. Examples include a substituted methyl group represented by a group, an alkyl group represented by a t-butyl group, an acetyl group, and a benzoyl group.

Examples of carboxyl-protecting groups include alkyl groups such as methyl, ethyl and t-butyl, benzyl, p-nitrobenzyl, p-chlorobenzyl, p-methoxybenzyl, Examples include a benzyl group typified by an o-cyanobenzyl group and the like, a 4-picolyl group, a mesitylenemethyl group, a phthalimidomethyl group, and a benzyloxymethyl group.

As the amino-protecting group, a benzyl group,
p-methoxybenzyl group, p-phenylbenzyl group, p
Substituted benzyl group represented by -chlorobenzyl group, benzyloxycarbonyl group, 2-chlorobenzyloxycarbonyl group, benzyloxycarbonyl group represented by 2,4-dichlorobenzyloxycarbonyl group, t-butyloxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, isonicotinyloxycarbonyl group, 2- (methylsulfonyl) ethoxycarbonyl group, tolylmethylsulfonyl group, formyl group, trifluoroacetyl group, triphenylmethyl group, p-toluenesulfonyl And the like.

Examples of the protective group for the guanidino group include a sulfonyl group represented by a mesitylene-2-sulfonyl group, a p-methoxybenzenesulfonyl group, a p-toluenesulfonyl group, and a triphenylmethyl group.

Examples of the protecting group for the imidazole group include benzyl, p-methoxybenzyl, p-phenylbenzyl, substituted benzyl represented by p-chlorobenzyl, benzyloxycarbonyl, and 2-chlorobenzyloxycarbonyl. Benzyloxycarbonyl group represented by 2,4-dichlorobenzyloxycarbonyl group, t-butyloxycarbonyl group, mesitylene-2-
Examples include a sulfonyl group, a p-methoxybenzenesulfonyl group, a sulfonyl group represented by a p-toluenesulfonyl group, a benzyloxymethyl group, a t-butyloxymethyl group, and the like.

Examples of the protecting group for the indole nucleus include a formyl group, a benzyloxycarbonyl group and a t-butyloxycarbonyl group.

The protecting group for the amide group is a xanthyl group,
Examples thereof include a 2,4-dimethoxybenzyl group and a diphenylmethyl group.

[0020]

BEST MODE FOR CARRYING OUT THE INVENTION

The preferred compounds used in the present invention include the following compounds. (1) Terminal amino group resin is PEG-polystyrene resin, n = 1 to 3, amino acid A is L- or D-alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, serine,
Threonine, cysteine, tryptophan, glutamine, asparagine, tyrosine, lysine, histidine, aspartic acid, an amino acid selected from glutamic acid,
A solid supported optically active phosphine composed of a combination of: (2) The terminal amino group resin is a PEG-polystyrene resin, n = 1 to 3, and the amino acid A is selected from L- or D-alanine, valine, leucine, isoleucine, proline, phenylalanine, serine, threonine, and tyrosine. A solid supported optically active phosphine composed of a combination of amino acids. (3) Terminal amino group resin is PEG-polystyrene resin, n = 1, amino acid A is L- or D-alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, serine, threonine, cysteine, tryptophan A solid-supported optically active phosphine composed of a combination of amino acids selected from glutamine, asparagine, tyrosine, lysine, histidine, aspartic acid, and glutamic acid. (4) a terminal amino group resin is a PEG-polystyrene resin, n = 1, and an amino acid A is an amino acid selected from L- or D-alanine, valine, leucine, isoleucine, proline, phenylalanine, serine, threonine, tyrosine, A solid supported optically active phosphine composed of a combination of:

The method for producing the compound of the present invention will be described below.

[0023]

Embedded image

(R)-(+)-2- (diphenylphosphinyl) -2'-
Compound 1 is synthesized by condensation of hydroxybinaphthyl and halide X (CH ₂ ) _n CO ₂ R ¹ in the presence of a base. Here, X represents a halogen atom, and is selected from chlorine, bromine and iodine, and preferably bromine and iodine. The amount used is 0.
It is 5 to 20 equivalents, preferably 1 to 10 equivalents. n represents an integer of 1 to 5. As the base, either an inorganic base or an organic base may be used, but potassium carbonate and sodium carbonate are preferably used. The amount used is 0.5 to 10 equivalents, preferably 1 equivalent to halide.
It is equivalent to 5 equivalents. As R ¹ , a C _1-6 alkyl group such as a methyl group and an ethyl group, a benzyl group and the like are used, and a methyl group, an ethyl group and the like are preferably selected.

Further, compound 1 is converted to compound 2 under reducing conditions, and then compound 3 is obtained by hydrolysis. Here, various conditions are used as the reduction conditions, and a reduction method using trichlorosilane is preferably selected.

As the hydrolysis conditions, ordinary ester hydrolysis conditions may be used, but preferably hydrolysis conditions using alkali hydroxide or alkali carbonate are selected.

Similarly, compound 4 can be synthesized using (S)-(-)-2- (diphenylphosphinyl) -2'-hydroxybinaphthyl as a starting material.

[0028]

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On the other hand, a protected amino acid 6 and A (NHY) are converted into a compound 7 by condensation reaction with the terminal amino group resin 5. Here, the amino acid amino protecting group Y includes a benzyloxycarbonyl group, a substituted benzyloxycarbonyl group, an alkyloxycarbonyl group, a t-butyloxycarbonyl group, a t-amyloxycarbonyl group, an isobornyloxycarbonyl group, a diphenylphosphinyl Group, diphenylphosphinothioyl group, dimethylphosphinothioyl group, triphenylmethyl group, o-nitrophenylsulfenyl group, 2- (p-biphenyl) isopropyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group (Fmoc), 4-isopropyloxycarbonyloxybenzyloxycarbonyl group, 5-
Benzisoxazolylmethyloxycarbonyl group, 2
-(Trifluoromethyl) -6-chromonylmethyleneoxycarbonyl group, 3,5-dinitro-4-pyridone group, phthaloyl group, formyl group, acetoacetyl group and the like.

Examples of the condensation reaction include a peptide bond reaction. 1) Acid chloride method (including F and CN) 2) Asymmetric anhydride method Mixed acid anhydride method, phosphoric anhydride method, arsenic anhydride method Product method, intramolecular anhydride method 3) symmetric anhydride method Mixed acid anhydride disproportionation method, carbodiimide method, ethoxyacetylene method, inamine method, acylisourea method 4) Active N-acyl compound method carbonylimidazole method, etc. 5) Active ester method Alkyl, phenyl, S-alkyl, S-phenyl ester active method, N-hydroxylamine active ester method,
6) Azide method using substituted hydrazide and diphenylphosphoryl azide 7) Trialkylphosphine-tetrahalogenated carbon method 8) Acyloxyphosphonium method 9) Triphenylphosphorous acid-imidazole method No.

Preferably, the carbodiimide method, particularly 1-
A method using a water-soluble carbodiimide such as (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI) is selected. At this time, N-hydroxybenzotriazole (HOBt) may coexist.

The amino group-protecting group is deprotected by a reaction according to each protecting group to give compound 8, A (NH ₂ ).

Examples of the deprotection method include a catalytic reduction method, a liquid sodium method, a hydrogen bromide method, a trifluoroacetic acid method, a dilute hydrochloric acid method, a hydrogen fluoride method, a tris (trifluoroacetic acid) boron method, and a boron tribromide method. Hydrogen fluoride-pyridine method, trifluoromethanesulfonic acid method, trimethylsilyltrifluoromethanesulfonate method, trimethylsilyl bromide method,
Examples thereof include a tetrafluoroboric acid method and a base condition method.

The compound 9 of the present invention can be obtained by condensing it with the above-mentioned separately synthesized compound 3. or,
If the partner to be condensed is compound 4, compound 10 of the present invention and compound 10 can be obtained.

Here, the condensation reaction may be selected from those described above, and is preferably a carbodiimide method,
In particular, a method using a water-soluble carbodiimide such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI) is selected. At this time, N-hydroxybenzotriazole (HOBt) may coexist.

[0036]

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

Reference Example 1 Synthesis of Compound 13

Embedded image (R)-(-)-2- (diphenylphosphinyl) -2'-hydroxybinaphthyl ((R) -1) (470 mg, 1 mmol) and potassium carbonate (690 m
g, 5 mmol) was replaced with nitrogen and acetone (7 mL) was added. Ethyl bromoacetate was added to this suspension and refluxed. After about 12 hours, the reaction solution was diluted with diethyl ether and filtered through celite. The filtrate was concentrated under reduced pressure, and this was subjected to column chromatography (silica gel; n-hexane / ethyl acetate = 1).
/ 1 → ethyl acetate) to give Compound 11 almost quantitatively.

Compound 11: ^l H NMR δ 1.13 (t, J = 7.3 Hz, 3H), 4.09 (dq, J = 1.9 and
7.3 Hz, 2H), 4.45 (dd, J = 9.3 and 16.6 Hz, 2H), 6.77-7.
^{98 (m, 22H); 31} P NMRδ25.1 (s),

Under a nitrogen stream, triethylamine (6.8 mL) was added to a 25 mL toluene solution of compound 11 (1 mmol). After adding Cl ₃ SiH (10 mmol, 1.3 mL) dropwise thereto in an ice bath,
Refluxed for hours. After completion of the reaction, the reaction solution was returned to room temperature, diluted with diethyl ether, added with about 1 mL of a saturated sodium hydrogen carbonate solution, and filtered through celite. The filtrate was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; n-hexane / ethyl acetate = 1/1) to give Compound 12 at 77%.
In a yield of

Compound 12: ^l H NMR δ 0.83 (m, 2H), 1.23 (m, 7H), 1.90 (m, 2H), 3.7
4 (m, 2H), 4.07 (q, J = 7.3 Hz, 2H), 6.91-7.97 (m, 22
H); ³¹ P NMRδ-12.93 (s)

Compound 12 (0.66 mmol) was placed in a nitrogen stream at 8.5 m
L Dissolve in methanol, 1.7m 40% potassium hydroxide aqueous solution
L was added and refluxed. After about 4 hours, the reaction solution was adjusted to about pH 2 using concentrated hydrochloric acid in an ice bath, diluted with a small amount of water and extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate, filtered, and filtrated. Was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel; ethyl acetate) to obtain Compound 13 in a 99% yield.

Compound 13: ¹ H NMR δ 4.29 (d, J = 16.1 Hz, 1 H), 4.47 (d, J = 16.1 Hz, 1
H), 6.92-7.97 (m, 22H); ³¹ P NMR δ-11.43 (s)

Reference Example 2 Synthesis of Compound 16

[0044]

Embedded image

(S)-(+)-2- (diphenylphosphinyl) -2'-
Hydroxybinaphthyl (470 mg, 1 mmol) and potassium carbonate (6
90 mg (5 mmol) was replaced with nitrogen, and acetone (7 mL) was added.
Ethyl bromoacetate was added to this suspension and refluxed. About 1
After 2 hours, the reaction solution was diluted with diethyl ether and filtered through celite. The filtrate was concentrated under reduced pressure, and purified by column chromatography (silica gel; n-hexane / ethyl acetate = 1/1 → ethyl acetate) to obtain Compound 14 almost quantitatively.

Compound 14: ^l H NMR δ 1.13 (t, J = 7.3 Hz, 3H), 4.09 (dq, J = 1.9 and
7.3 Hz, 2H), 4.45 (dd, J = 9.3 and 16.6 Hz, 2H), 6.77-7.
^{98 (m, 22H); 31} P NMRδ25.1 (s)

Under a nitrogen stream, triethylamine (6.8 mL) was added to a 25 mL toluene solution of compound 14 (1 mmol). After adding Cl ₃ SiH (10 mmol, 1.3 mL) dropwise in an ice bath, about 1
Refluxed for 2 hours. After completion of the reaction, the reaction solution was returned to room temperature, diluted with diethyl ether, added with about 1 mL of a saturated sodium hydrogen carbonate solution, and filtered through Celite. The filtrate was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; n-hexane / ethyl acetate = 1/1) to obtain Compound 15 in a 77% yield. Was.

Compound 15: ^l H NMR δ 0.83 (m, 2H), 1.23 (m, 7H), 1.90 (m, 2H), 3.7
4 (m, 2H), 4.07 (q, J = 7.3 Hz, 2H), 6.91-7.97 (m, 22
H); ³¹ P NMR δ-12.93 (s) Compound 15 (0.66 mmol) was dissolved in 8.5 mL of methanol under a nitrogen stream, and 1.7 mL of a 40% aqueous potassium hydroxide solution was added thereto, followed by refluxing. After about 4 hours, the reaction solution was adjusted to about pH 2 using concentrated hydrochloric acid in an ice bath, diluted with a small amount of water and extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate, filtered, and filtrated. Was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel; ethyl acetate) to obtain Compound 16 at a yield of 99%. Compound 16: ¹ H NMR δ 4.29 (d, J = 16.1 Hz, 1 H), 4.47 (d, J = 16.1 Hz, 1
H), 6.92-7.97 (m, 22H); ³¹ P NMR δ-11.43 (s)

Reference Example 3 Synthesis of Compound 19

[0050]

Embedded image

(R)-(-)-2- (diphenylphosphinyl) -2'-
Hydroxybinaphthyl (470 mg, 1 mmol) and potassium carbonate (6
90 mg (5 mmol) was replaced with nitrogen, and acetone (7 mL) was added.
Ethyl bromobutyrate (5 mmol) was added to this suspension and refluxed. After about 12 hours, the reaction solution was diluted with diethyl ether and filtered through celite. The filtrate was concentrated under reduced pressure, and this was subjected to column chromatography (silica gel; n-hexane /
(Ethyl acetate = 1/1 → ethyl acetate) to give Compound 17 almost quantitatively.

Compound 17: ^l H NMR δ 1.18 (t, J = 7.3 Hz, 3H), 1.74 (m, 2H), 1.86
(m, 2H), 3.83 (m, lH), 3.94 (m, 1H), 4.00 (m, 2H), 6.
85-7.96 (m, 22H); ^3I P NMR δ 27.1 (s).

Under a nitrogen stream, triethylamine (6.8 mL) was added to a 25 mL toluene solution of compound 17 (1 mmol). After adding Cl ₃ SiH (10 mmol, 1.3 mL) dropwise thereto in an ice bath,
Refluxed for hours. After completion of the reaction, the reaction solution was returned to room temperature, diluted with diethyl ether, added with about 1 mL of a saturated sodium hydrogen carbonate solution, and filtered through Celite. The filtrate was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; n-hexane / ethyl acetate = 1/1) to obtain Compound 18 in a 88% yield. Was.

Compound 18: ¹ H NMR δ 1.17 (m, 3H), 1.56 (m, 2H), 1.79 (m, 2H), 3.7
7 (m, 2H), 3.99 (m, 2H), 6.90-7.97 (m, 22H); ³¹ P NMR
δ-14.55 (s)

Compound 18 (0.66 mmol) was placed in a nitrogen stream at 8.5 m
L Dissolve in methanol, 1.7m 40% potassium hydroxide aqueous solution
L was added and refluxed. After about 4 hours, the reaction solution was adjusted to about pH 2 using concentrated hydrochloric acid in an ice bath, diluted with a small amount of water, and extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; ethyl acetate) to obtain Compound 19 at a yield of 94%.

Compound 19: ^I H NMR δ 1.57 (m, 2H), 1.79 (m, 2H), 3.78 (m, 2H), 6.9
2-7.97 (m, 22H); ³¹ P NMR δ-14.62 (s)

Reference Example 4 Synthesis of Compound 22

[0058]

Embedded image

(R)-(-)-2- (diphenylphosphinyl) -2'-
Hydroxybinaphthyl (470 mg, 1 mmol) and potassium carbonate (6
90 mg (5 mmol) was replaced with nitrogen, and acetone (7 mL) was added.
Ethyl 6-bromohexanoate (5 mmol) was added to the suspension, and the mixture was refluxed. After about 12 hours, the reaction solution was diluted with diethyl ether and filtered through celite. The filtrate is concentrated under reduced pressure,
This was purified by column chromatography (silica gel; n-hexane / ethyl acetate = 1/1 → ethyl acetate) to obtain Compound 20 almost quantitatively.

Compound 20: ¹ H NMR δ 0.86 (m, 2H), 1.25 (m, 5H), 1.44 (m, 2H), 1.9
2 (m, 2H), 3.73 (m, 1H), 3.88 (m, 1H), 4.07 (q, J = 7.3H
z, 2H), 6.88-7.97 (m, 22H); ³¹ P NMR δ 29,4 (s).

Under a nitrogen stream, triethylamine (6.8 mL) was added to a 25 mL toluene solution of the compound 20 (1 mmol). After adding Cl ₃ SiH (10 mmol, 1.3 mL) dropwise thereto in an ice bath,
Refluxed for hours. After completion of the reaction, the reaction solution was returned to room temperature, diluted with diethyl ether, added with about 1 mL of a saturated sodium hydrogen carbonate solution, and filtered through Celite. The filtrate was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; n-hexane / ethyl acetate = 1/1) to obtain Compound 21 in a 67% yield. Was.

Compound 21: ¹ H NMR δ 0.83 (m, 2H), 1.23 (m, 2H), 1.90 (dt, J = 7.3 a)
nd 10.8Hz, 2H), 3.75 (m, 2H), 4.07 (dd, J = 6.8 and 1
4.1Hz, 2H), 6.90-7.97 (m , 22H); 31 P NMRδ-14.55 (s)

Compound 21 (0.66 mmol) was added to a 8.5 m
L Dissolve in methanol, 1.7m 40% potassium hydroxide aqueous solution
L was added and refluxed. After about 4 hours, the reaction solution was adjusted to about pH 2 using concentrated hydrochloric acid in an ice bath, diluted with a small amount of water, and extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; ethyl acetate) to obtain Compound 22 at a yield of 83%.

Compound 22: ¹ H NMR δ 0.82 (m, 2H), 1.23 (m, 4H), 1.92 (m, 2H), 3.7
3 (m, 2H), 6.77-7.99 (m, 22H); ³¹ P NMR δ-12.93 (s).

Example 1 Synthesis of Compound 23

[0066]

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The washed Tenta G in the Merrifield vessel
el S NH ₂ (0.025mmol amino acid residue conversion, 200mg) and Fmoc
-L-valine (0.05 mmol), EDCI.HCl (0.075 mmol, 14 m
g) and HOBt (0.075 mmol, 10 mg) in dimethylformamide (4 m
In L), the mixture was shaken at room temperature. After 2 hours, the completion of the reaction was confirmed by Kaiser Test, the reaction solution was filtered off, the beads were washed with dimethylformamide, and treated with a 20% piperidine / dimethylformamide solution (5 mL, 5 min × 3 times) to obtain an Fm.
After washing with dimethylformamide,
Compound 13 (0.05 mmol, 26 mg), EDCI.HCl (0.075 mmo1,1
4 mg) and a solution of HOBt (0.075 mmol, 10 mg) in 4 mL of dimethylformamide were added and shaken. Nine hours later, after confirming that the Kaiser Test was negative, the reaction solution was separated by filtration and washed with dimethylformamide and dichloromethane. Compound 23 is obtained by drying the obtained solid support under reduced pressure.

Example 2 Synthesis of Compound 24

[0069]

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The cleaned Tenta G in the Merrifield vessel
el S NH ₂ (0.025mmol amino acid residue conversion, 200mg) and Fmoc
-D-valine (0.05 mmol), EDCI.HCl (0.075 mmol, 14 m
g) and HOBt (0.075 mmol, 10 mg) in dimethylformamide (4 m
In L), the mixture was shaken at room temperature. Two hours later, the completion of the reaction was confirmed by the Kaiser Test, the reaction solution was filtered off, the beads were washed with dimethylformamide, and treated with a 20% piperidine / dimethylformamide solution (5 mL, 5 min × 3 times) to obtain an Fm.
After washing with dimethylformamide,
Compound 13 (0.05 mmol, 26 mg), EDCI.HCl (0.075 mmo1,1
4 mg) and a solution of HOBt (0.075 mmol, 10 mg) in 4 mL of dimethylformamide were added and shaken. Nine hours later, after confirming that the Kaiser Test was negative, the reaction solution was separated by filtration and washed with dimethylformamide and dichloromethane. Compound 24 is obtained by drying the obtained solid support under reduced pressure.

Example 3 Synthesis of Compound 25

[0072]

Embedded image

In the Merrifield vessel, the cleaned Tenta G
el S NH ₂ (0.025mmol amino acid residue conversion, 200mg) and Fmoc
-L-valine (0.05 mmol), EDCI.HCl (0.075 mmol, 14 m
g), HOBt (0.075 mmol, 10 mg) in dimethylformamide (4 m
In L), the mixture was shaken at room temperature. Two hours later, the completion of the reaction was confirmed by the Kaiser Test, the reaction solution was filtered off, the beads were washed with dimethylformamide, and treated with a 20% piperidine / dimethylformamide solution (5 mL, 5 min × 3 times) to obtain an Fm.
After washing with dimethylformamide,
Compound 16 (0.05 mmol, 26 mg), EDCI.HCl (0.075 mmol 1,1
4 mg) and a solution of HOBt (0.075 mmol, 10 mg) in 4 mL of dimethylformamide were added and shaken. Nine hours later, after confirming that the Kaiser Test was negative, the reaction solution was separated by filtration and washed with dimethylformamide and dichloromethane. Compound 25 is obtained by drying the obtained solid support under reduced pressure.

Example 4 Synthesis of Compound 26

[0075]

Embedded image

In the Merrifield vessel, the cleaned Tenta G
el S NH ₂ (0.025mmol amino acid residue conversion, 200mg) and Fmo
c-D-valine (0.05 mmol), EDCI.HCl (0.075 mmol, 14 m
g) and HOBt (0.075 mmol, 10 mg) in dimethylformamide (4 m
In L), the mixture was shaken at room temperature. Two hours later, the completion of the reaction was confirmed by the Kaiser Test, the reaction solution was filtered off, the beads were washed with dimethylformamide, and treated with a 20% piperidine / dimethylformamide solution (5 mL, 5 min × 3 times) to obtain an Fm.
After washing with dimethylformamide,
Compound 16 (0.05 mmol, 26 mg), EDCI.HCl (0.075 mmol 1,1
4 mg) and a solution of HOBt (0.075 mmol, 10 mg) in 4 mL of dimethylformamide were added and shaken. Nine hours later, after confirming that the Kaiser Test was negative, the reaction solution was separated by filtration and washed with dimethylformamide and dichloromethane. Compound 27 is obtained by drying the obtained solid support under reduced pressure.

Example 5 Synthesis of Compound 28

[0078]

Embedded image

In the Merrifield vessel, the cleaned Tenta G
el S NH ₂ (0.025mmol amino acid residue conversion, 200mg) and Fmoc
-L-proline (0.05 mmol), EDCI.HCl (0.075 mmol, 14 m
g) and HOBt (0.075 mmol, 10 mg) in dimethylformamide (4 m
In L), the mixture was shaken at room temperature. Two hours later, the completion of the reaction was confirmed by the Kaiser Test, the reaction solution was filtered off, the beads were washed with dimethylformamide, and treated with a 20% piperidine / dimethylformamide solution (5 mL, 5 min × 3 times) to obtain an Fm.
After washing with dimethylformamide,
Compound 13 (0.05 mmol, 26 mg), EDCI.HCl (0.075 mmo1,1
4 mg) and a solution of HOBt (0.075 mmol, 10 mg) in 4 mL of dimethylformamide were added and shaken. Nine hours later, after confirming that the Kaiser Test was negative, the reaction solution was separated by filtration and washed with dimethylformamide and dichloromethane. Compound 27 is obtained by drying the obtained solid support under reduced pressure.

[0080]

Example 6 Synthesis of Compound 28

[0082]

Embedded image

In the Merrifield vessel, the cleaned Tenta G
el S NH ₂ (0.025 mmol in terms of amino acid residues and Fmoc-D-proline (0.05 mmol), EDCI · HCl (0.075 mmol, 14 mg), HOBt
(0.075 mmol, 10 mg) was shaken in dimethylformamide (4 mL) at room temperature. After 2 hours, the completion of the reaction was confirmed by the Kaiser Test, the reaction solution was filtered off, the beads were washed with dimethylformamide, and treated with a 20% piperidine / dimethylformamide solution (5 mL, 5 min × 3 times) to obtain an Fmoc After washing with dimethylformamide, Compound 1 was removed.
3 (0.05 mmol, 26 mg), EDCI.HCl (0.075 mmol 1, 14 mg), HO
A solution of Bt (0.075 mmol, 10 mg) in 4 mL of dimethylformamide was added and shaken. Nine hours later, after confirming that the Kaiser Test was negative, the reaction solution was separated by filtration and washed with dimethylformamide and dichloromethane. Compound 28 is obtained by drying the obtained solid support under reduced pressure.

Example 7 Synthesis of Compound 29

[0085]

Embedded image

In the Merrifield vessel, the cleaned Tenta G
el S NH ₂ (0.025mmol amino acid residue conversion, 200mg) and Fmoc
-L-proline (0.05 mmol), EDCI.HCl (0.075 mmol, 14 m
g) and HOBt (0.075 mmol, 10 mg) in dimethylformamide (4 m
In L), the mixture was shaken at room temperature. Two hours later, the completion of the reaction was confirmed by the Kaiser Test, the reaction solution was filtered off, the beads were washed with dimethylformamide, and treated with a 20% piperidine / dimethylformamide solution (5 mL, 5 min × 3 times) to obtain an Fm.
After washing with dimethylformamide,
Compound 16 (0.05 mmol, 26 mg), EDCI.HCl (0.075 mmol 1,1
4 mg) and a solution of HOBt (0.075 mmol, 10 mg) in 4 mL of dimethylformamide were added and shaken. Nine hours later, after confirming that the Kaiser Test was negative, the reaction solution was separated by filtration and washed with dimethylformamide and dichloromethane. Compound 29 is obtained by drying the obtained solid support under reduced pressure.

Example 8 Synthesis of Compound 30

Embedded image In the Merrifield vessel, washed Tenta Gel S NH ₂ (0.0
25 mmol amino acid residue equivalent, 200 mg), Fmoc-D-proline (0.05 mmol), EDCI.HCl (0.075 mmol, 14 mg), HOBt (0.0
(75 mmol, 10 mg) was shaken in dimethylformamide (4 mL) at room temperature. After 2 hours, confirm the completion of the reaction by Kaiser Test, filter the reaction solution, wash the beads with dimethylformamide, and add a 20% piperidine / dimethylformamide solution.
(5 mL, 5 min × 3 times) to remove the Fmoc group.After washing with dimethylformamide, Compound 16
(0.05mmol, 26mg), EDCI ・ HCl (0.075mmo1, 14mg), HOBt
(0.075 mmol, 10 mg) in 4 mL of dimethylformamide was added and shaken. Nine hours later, after confirming that the Kaiser Test was negative, the reaction solution was separated by filtration and washed with dimethylformamide and dichloromethane. Compound 30 is obtained by drying the obtained solid support under reduced pressure.

[0088]

Example 9 Synthesis of Compound 31

[0089]

Embedded image

In the Merrifield vessel, the cleaned Tenta G
el S NH ₂ (0.025mmol amino acid residue conversion, 200mg) and Fmoc
-L- serine ^{(O t Bu) (0.05mmol)} , EDCI · HCl (0.075mmo
l, 14 mg) and HOBt (0.075 mmol, 10 mg) were shaken in dimethylformamide (4 mL) at room temperature. Two hours later, Kaiser Tes
After confirming the completion of the reaction at t, the reaction solution was filtered off, the beads were washed with dimethylformamide, and treated with a 20% piperidine / dimethylformamide solution (5 mL, 5 min × 3 times) to remove the Fmoc group. After washing with dimethylformamide, Compound 13 (0.05 mmol, 26 mg), EDCI.HCl (0.07
5 mmo1, 14 mg) and a solution of HOBt (0.075 mmol, 10 mg) in 4 mL of dimethylformamide were added and shaken. 9 hours later, Kaiser
After confirming that the test was negative, the reaction solution was separated by filtration and washed with dimethylformamide and dichloromethane. The resulting solid support is dried under reduced pressure to obtain Compound 31.

Example 10 Synthesis of Compound 32

[0092]

Embedded image

In the Merrifield vessel, the cleaned Tenta G
el S NH ₂ (0.025mmol amino acid residue conversion, 200mg) and Fmoc
-D- serine ^{(O t Bu) (0.05mmol)} , EDCI · HCl (0.075mmo
l, 14 mg) and HOBt (0.075 mmol, 10 mg) were shaken in dimethylformamide (4 mL) at room temperature. Two hours later, Kaiser Tes
After confirming the completion of the reaction at t, the reaction solution was filtered off, the beads were washed with dimethylformamide, and treated with a 20% piperidine / dimethylformamide solution (5 mL, 5 min × 3 times) to remove the Fmoc group. After washing this with dimethylformamide, compound 13 (0.05 mmol, 26 mg), EDCI.HCl (0.07
5 mmo1, 14 mg) and a solution of HOBt (0.075 mmol, 10 mg) in 4 mL of dimethylformamide were added and shaken. 9 hours later, Kaiser
After confirming that the test was negative, the reaction solution was separated by filtration and washed with dimethylformamide and dichloromethane. The resulting solid support is dried under reduced pressure to obtain Compound 32.

Example 11 Synthesis of Compound 33

[0095]

Embedded image

In the Merrifield vessel, the cleaned Tenta G
el S NH ₂ (0.025mmol amino acid residue conversion, 200mg) and Fmoc
-L- serine ^{(O t Bu) (0.05mmol)} , EDCI · HCl (0.075mmo
l, 14 mg) and HOBt (0.075 mmol, 10 mg) were shaken in dimethylformamide (4 mL) at room temperature. Two hours later, Kaiser Tes
After confirming the completion of the reaction at t, the reaction solution was filtered off, the beads were washed with dimethylformamide, and treated with a 20% piperidine / dimethylformamide solution (5 mL, 5 min × 3 times) to remove the Fmoc group. After washing with dimethylformamide, compound 16 (0.05 mmol, 26 mg), EDCI.HCl (0.07
5 mmo1, 14 mg) and a solution of HOBt (0.075 mmol, 10 mg) in 4 mL of dimethylformamide were added and shaken. 9 hours later, Kaiser
After confirming that the test was negative, the reaction solution was separated by filtration and washed with dimethylformamide and dichloromethane. The obtained solid support is dried under reduced pressure to obtain compound 33.

Example 12 Synthesis of Compound 34

[0098]

Embedded image

In the Merrifield vessel, the cleaned Tenta G
el S NH ₂ (0.025mmol amino acid residue conversion, 200mg) and Fmoc
-D- serine ^{(O t Bu) (0.05mmol)} , EDCI · HCl (0.075mmo
l, 14 mg) and HOBt (0.075 mmol, 10 mg) were shaken in dimethylformamide (4 mL) at room temperature. Two hours later, Kaiser Tes
After confirming the completion of the reaction at t, the reaction solution was filtered off, the beads were washed with dimethylformamide, and treated with a 20% piperidine / dimethylformamide solution (5 mL, 5 min × 3 times) to remove the Fmoc group. After washing with dimethylformamide, compound 16 (0.05 mmol, 26 mg), EDCI.HCl (0.07
5 mmo1, 14 mg) and a solution of HOBt (0.075 mmol, 10 mg) in 4 mL of dimethylformamide were added and shaken. 9 hours later, Kaiser
After confirming that the test was negative, the reaction solution was separated by filtration and washed with dimethylformamide and dichloromethane. The resulting solid support is dried under reduced pressure to obtain Compound 34.

Example 13 Compound 35 was synthesized in Example 1 using Compound 19 instead of Compound 13.

[0101]

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Embodiment 14

[0103]

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In Example 2, compound 1 was used instead of compound 13.
Compound 36 was synthesized by using Compound 9.

Embodiment 13

[0106]

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In Example 5, compound 1 was used instead of compound 13.
Compound 37 was synthesized by using Compound 9. Example 14

[0108]

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In Example 6, compound 1 was used instead of compound 13.
Compound 38 was synthesized by using Compound 9.

Embodiment 15

[0111]

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In Example 9, compound 1 was used instead of compound 13.
Compound 40 was synthesized by using Compound 9.

Embodiment 16

[0114]

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Compound 40 was synthesized in Example 10 by using Compound 19 instead of Compound 13.

Embodiment 17

[0117]

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In Example 1, compound 2 was used instead of compound 13.
Compound 41 was synthesized by using Compound 2.

Embodiment 18

[0120]

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In Example 2, compound 2 was used instead of compound 13.
Compound 42 was synthesized by using Compound 2.

Embodiment 19

[0123]

Embedded image

In Example 5, compound 2 was used instead of compound 13.
Compound 43 was synthesized by using Compound 2.

Embodiment 20

[0126]

Embedded image

In Example 6, compound 2 was used instead of compound 13.
Compound 44 was synthesized by using Compound 2.

Embodiment 21

[0129]

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In Example 9, compound 2 was used instead of compound 13.
Compound 45 was synthesized by using Compound 2.

Embodiment 22

[0132]

Embedded image

Compound 46 was synthesized in Example 10 by using Compound 22 instead of Compound 13.

Reference Example 5 Representative Reaction Example: Allyl Substitution Reaction

[0135]

Embedded image

Compound 23 synthesized in Example 1 was added to [π-C ₃ H
₅ PdCl] ₂ (0.014 mmol, 5.0 mg) in 4 mL of dichloromethane was added, shaken for 5 minutes, washed with dichloromethane,
A catalyst is prepared by drying under reduced pressure. Catalyst (0.010mm) in polypropylene syringe for reaction (with filter)
(ol palladium conversion) was replaced with nitrogen, and 1.5 mL of a 1.5 M aqueous potassium carbonate solution was added. To this were added 1,3-diphenyl-3-acetoxy-1-propene (0.5 mmol, 125 mg) and 3-methyl-2,4-pentanedione (0.75 mmol, 85 mg), and the mixture was shaken at room temperature. After 12 hours, the aqueous layer (reaction solution) was removed, the bead catalyst was washed with chloroform, the bead wash was dried over sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel; n). -Hexane / ethyl acetate = 10/1) to obtain Compound 47, which is an allyl-substituted product, in a yield of 49% and an optical isomer excess of 78%.

Compound 47: ¹ H NMR δ 1.50 (s, 3H), 1.94 (s, 3H), 2.17 (s, 3H), 4.69
(d, J = 8.8, 1H), 6.39 (dd, J = 8.8 and 16.1, 1H), 6.46
(d, J = 15.6, 1H), 7.21-7.32 (m, 10H).

The results obtained by the same operation are shown below.

Ligand Yield Asymmetric Yield Compound 23 49% 78% ee Compound 24 75% 81% ee Compound 25 75% 81% ee Compound 26 48% 79% ee Compound 27 42% 62% ee Compound 28 71 % 61% ee Compound 29 70% 62% ee Compound 30 43% 63% ee Compound 31 52% 77% ee Compound 32 81% 82% ee Compound 33 80% 81% ee Compound 34 54% 76% ee

[0140]

The present invention relates to a solid-supported optically active catalyst which is important for organic synthesis, particularly for asymmetric synthesis. Since the compound of the present invention can be easily removed from the reaction system by being supported on a solid phase, it can be applied to combinatorial chemistry and high-speed synthesis using an automatic synthesizer.

Claims (5)

[Claims] 1. Formula (I) or (I ′) (Wherein, XNH- represents a terminal of a terminal amino group resin (XNH ₂ ), and A represents L- or D- which may be protected.
Represents an amino acid, and n represents an integer of 1 to 5). 2. A terminal amino group resin is PEG-polystyrene resin, n = 1 to 3, amino acid A is L- or D-alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, serine, threonine. The solid-supported optically active phosphine according to claim 1, comprising a combination of an amino acid selected from cysteine, tryptophan, glutamine, asparagine, tyrosine, lysine, histidine, aspartic acid, and glutamic acid. 3. The amino acid A is L- or D-alanine,
The solid-supported optically active phosphine according to claim 2, which is an amino acid selected from valine, leucine, isoleucine, proline, phenylalanine, serine, threonine, and tyrosine. 4. The solid-supported optically active phosphine according to claim 2, wherein n = 1. 5. The solid-supported optically active phosphine according to claim 3, wherein n = 1.