JPH0229670B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing optically active α-amino aldehydes and peptide aldehydes by oxidizing optically active β-amino alcohols as raw materials. Optically active α-aminoaldehydes are compounds useful as synthetic intermediates for bestatin, pepstatin, amastatin, and the like. On the other hand, among optically active peptide aldehydes, leupeptin, antipain, chymostatin, and elastatinal have been discovered as enzyme inhibitors produced by microorganisms, but these have argininal and phenylalaninal as C-terminal residues, respectively. , contains alaninal. These optically active peptide aldehydes are compatible with various proteases such as plasmin, trypsin, papain,
Strongly inhibits chymotrypsin, esterase, etc. In addition, these enzyme inhibitors have been in the spotlight in recent years as they have been reported to have anti-inflammatory effects, anti-ulcer effects, inhibition of mutation induction, prevention of ascites accumulation, prevention of carcinogenesis and cancer metastasis, and other effects on many diseases. The conventional method for synthesizing α-aminoaldehydes is α-
Reduction method of amino acid derivatives and β derived from α-amino acids
- Can be broadly classified into those made by oxidation of amino alcohols. As a reduction method, sodium amalgam reduction of N-protecting group α-amino acid ester (J.Biol.
Chem., Vol. 217, p. 317, 1955), diisobutylaluminum hydride reduction (Chem.Pharm.Bull.,
23, p. 3081, 1975), N-phthaloyl-α-
Rosenmund reduction of amino acid chlorides (J.Org.
Chem., vol. 18, p. 297, 1953), lithium aluminum hydride reduction of N-protected α-amino acid pyrazolide or 3,5-dimethylpyrazolide (Ann., vol. 640, p. 11, 1961, J. Antibiotics,
Volume 29, page 600, 1976, J.Med.Chem., volume 20, 510
(1977), diisobutylaluminum hydride reduction of N-protected α-amino acid imidazolides (JC
S.Chem.Comm., p. 79, 1979) and catalytic reduction of N-protected α-amino acid mixed acid anhydrides (Chem.
Pharm.Bull., vol. 30, p. 361, 1972), but all of these are obtained as a mixture of raw materials and by-products, and α-aminoaldehydes are unstable to purification methods such as silica gel. As a result of racemization, it has not been possible to obtain α-aminoaldehydes as a single optically pure product. For this reason, the known reduction method requires a two-step operation of protecting and purifying the aldehyde moiety of α-aminoaldehyde and deprotecting it, and also has the drawback of low yield. Also, as an oxidation method, Fitzner-Moffat oxidation of β-amino alcohols (Chem.Pharm.
Bull., vol. 20, p. 361, 1972), chromic acid-pyridine oxidation (J.Org.Chem., vol. 46, p. 4797, 1981)
(2013) are known, but all of these methods only yield mostly racemized α-amino aldehydes. In addition, 3- derived from α-amino acid
Although there are examples of obtaining optically active compounds by glycol oxidative cleavage of amino-1,2-diols using periodic acid, the number of steps from α-amino acids is long and the practicality is poor, and its generality has not been confirmed. No (JCSChem.Comm., p. 875, 1979). As described above, the known methods are unsatisfactory due to drawbacks such as low yields, the need to protect aldehyde groups for purification, and long steps. For this reason, until now, the physical properties of optically pure α-aminoaldehydes are largely unknown. As a result of various studies, the present inventors discovered that sulfur trioxide complex and dimethyl sulfoxide were allowed to act on optically active β-amino alcohols or peptide alcohols in the presence of triethylamine to oxidize the optically active β-amino alcohols or peptide alcohols in a short period of time. The present invention was completed by discovering a new production method for obtaining active α-amino aldehydes or peptide aldehydes as optically pure products. Furthermore, J.
ACS, Vol. 86, p. 5505, 1967, there are reports that alcohols are oxidized to aldehydes, but as in the present invention, optically active β-amino alcohols are converted to optically active α-amino alcohols. No report has yet been found on the production of aldehydes, and by carrying out the method of the present invention, it has become possible to produce excellent optically active α-aminoaldehydes or peptide aldehydes as described below. The method of the present invention can be expressed as a chemical formula as shown below. (In the formula, R ₁ is an amino protecting group, an amino acid residue, a peptide residue, an amino acid residue or a peptide residue with all or part of the functional group protected, R ₂ and R ₄ are a hydrogen atom or an alkyl group, R ₃ is a hydrogen atom, an alkyl group, or an aryl group, and the alkyl group and aryl group may be unsubstituted or substituted.) The amino protecting group for R ₁ is commonly used in peptide synthesis, etc. A tert-butoxycarbonyl group, a carbobenzoxy group, a benzyl group, a tosyl group, etc. can be used. Regarding R ₃ , specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 1-methylpropyl,
Carboxymethyl, 0-benzyloxymethyl,
β-carboxyethyl, β-methylthioethyl,
Benzyl, S-benzylthiomethyl, 4-benzyloxybenzyl, 3,4-dimethoxybenzyl, imidazolylmethyl, 3,4-methylenedioxybenzyl, phenyl, 4-benzyloxyphenyl, N-nitroguanidinopropyl, N 〓―
Boc-aminobutyl, N〓-Boc-aminopropyl, indolylmethyl group, etc. Next, the method of the present invention will be explained. The method for synthesizing β-amino alcohol or peptide alcohol shown by the above formula (1) is as follows:
Although various synthesis methods can be applied, one example is as follows. First, an N-protected amino acid is dissolved in a methanol-benzene mixed solvent, and trimethylsilyldiazomethane is reacted at room temperature. The reaction solvent is distilled off under reduced pressure. After replacing the reaction vessel with argon gas, etc., the tetrahydrofuran/ethanol solvent is added. dissolved in
β-amino alcohol can be easily obtained by adding lithium chloride and sodium borohydride and reacting at room temperature. The product is isolated by distilling off the solvent from the reaction solution, followed by extraction with a solvent such as methylene chloride, washing, drying, and then distilling off the solvent to easily obtain the product as crystals or oil. Obtainable. On the other hand, for peptide alcohol, the methyl ester of the peptide is obtained by a conventional method, and this is added to tetrahydrofuran,
It can be obtained by adding lithium chloride, sodium borohydride and ethanol and reacting under argon gas. The obtained product can be used as it is in the next reaction, but it can be purified by recrystallization in a suitable solvent such as n-hexane, ethyl acetate, methylene chloride, ether/n-hexane, ethyl acetate/n-hexane, etc. Alternatively, it is preferable to purify the product by vacuum distillation or column chromatography and use it in the next reaction. Next, this β-amino alcohol or peptide alcohol and triethylamine are mixed in anhydrous dimethyl sulfoxide and oxidized by adding a solution of a sulfur trioxide complex in anhydrous dimethyl sulfoxide to produce optically active α-amino aldehyde or peptide aldehyde. It is sufficient that the amounts of triethylamine and sulfur trioxide complex used are 2.5 equivalents each, but it is appropriate to use about 3 equivalents. As the sulfur trioxide complex, a complex of sulfur trioxide and pyridine, dioxane, trimethylamine, DMF, or the like can be used.
A reaction time of several minutes to more than ten minutes is sufficient, and the reaction temperature may be room temperature. Anhydrous dimethyl sulfoxide acts as a solvent, but
Benzene, methylene chloride, etc. can also be used if necessary. After the reaction is complete, the reaction mixture is poured into ice water and the product is dissolved in an appropriate solvent such as ether or ethyl acetate-benzene (4:1), washed with an aqueous citric acid solution, water, saturated aqueous sodium bicarbonate, etc., and then dried. When the solvent is distilled off, optically active α-amino aldehydes and peptide aldehydes are obtained as products. The obtained optically active α-amino aldehydes and peptide aldehydes can be used as enzyme inhibitors, etc. without any purification, but crystalline ones can be recrystallized from a suitable solvent. As described above, the method of the present invention provides a new method for producing α-amino aldehyde with high yield and high optical purity using simple operations from β-amino alcohol that can be easily obtained from α-amino acids. The present invention will be explained using examples and examples, but the scope of the present invention is not limited thereby. The abbreviations in this text have the following meanings. Ala: Alanine residue Val: Valine residue Leu: Leucine residue Pro: Proline residue Met: Methionine residue Trp: Tryptophan residue Tyr: Tyrosine residue Lys: Lysine residue Glu: Glutamic acid residue Cys: Cysteine residue Arg: Arginine residue Phe: Phenylalanine residue Gly: Glycine residue Boc: Tertiary butoxycarbonyl group Z: Carbobenzoxy group Bzl: Benzyl group NO ₂ : Nitro group 2.4-DNP: 2,4-dinitrophenyl Hydrazone derivative Py SO ₃ : Sulfur trioxide pyridine complex al: Used with the abbreviation of amino acid residue α
-Represents aminoaldehyde. ol: Used with the abbreviation of amino acid residue β
-Represents amino alcohol. OMe: Methyl ester reference example 1 Synthesis of Boc-L-Lys(Z)-ol Boc-L-Lys(Z)-OH 380 mg (1 mmol)
Add 0.7ml of 2M-trimethylsilyldiazomethane-hexane solution to 20% methanol benzene solution.
Add for 20 minutes and stir at room temperature for 20 minutes. The reaction solution was distilled off under reduced pressure, the reaction vessel was replaced with argon gas, and 85 mg (2 mmol) of lithium chloride, 76 mg (2 mmol) of sodium borohydride, and 9 ml of tetrahydrofuran-ethanol (1:2 volume ratio) were added. Add and stir overnight at room temperature. The reaction solution was distilled off under reduced pressure, 10 ml of 10% citric acid aqueous solution was added, and methylene chloride was added.
Extract with 30 ml three times, and dry the methylene chloride layer with anhydrous sodium sulfate. After evaporation of the solvent, Boc-
L-Lys(Z)-ol is obtained. Yield 358 mg (98
%) This was recrystallized from ether-n-hexane to obtain colorless needle crystals. Melting point: 69-71℃, [α] ²⁰ _D -9.25 (C = 1, methanol) Reference Examples 2-12 Boc-L-Lys (Z) under exactly the same conditions as Reference Example 1
-OH to Boc-L-Ala-OH (Reference Example 2), Boc-
L-Val-OH(3), Boc-L-Leu-OH(4), Boc
-L-Pro-OH(5), Z-L-Pro-OH(6), Boc
-L-Met-OH(7), Z-L-Phe-OH(8), Z-
L-Cys(Bzl)OH(9), Boc-L-Typ-OH(10),
Boc-L-Tyr(Bzl)-OH(11), Boc-L-Arg
Various amino alcohols were synthesized by replacing (NO ₂ )-OH(12).

[Table] Example 1 Synthesis of Z-L-Phe-al Z-L-Phe-ol 570 mg (2 mmol), triethylamine 607 mg (3 mmol), anhydrous dimethyl sulfoxide 6 ml solution under room temperature stirring, Py SO ₃ 955
mg (6 mmol), anhydrous dimethyl sulfoxide 6
ml solution and stirred for 10 minutes, poured the reaction solution into 60 ml of ice water and extracted the aqueous layer three times with 40 ml of ether.
ml twice and dried with anhydrous sodium sulfate. After distilling off the solvent, ZL-Phe-al is obtained as colorless crystals. The yield was 567 mg (100%), and this product was recrystallized from ether-n-hexane to obtain colorless needle crystals. Yield 480mg (85%), melting point: 77-9℃,
[α] ²⁰ _D +44.5 (C = 1, methylene chloride) Examples 2 to 13 Z-L-Phe-ol was prepared under exactly the same conditions as Example 1.
Boc-L-Ala-ol (Example 2), Boc-L-Val-
ol(3), Boc-L-Leu-ol(4), Boc-L-Pro-ol
(5), Z-L-Pro-ol (6), Boc-L-Met-ol (7),
Boc-L-Trp-ol(8), Boc-L-Tyr(Bzl)-
ol(9), Boc-L-Lys(Z)-ol(10), Z-L-Cys
(Bzl)-ol(11), Boc-L-Arg( _NO2 )-ol(12),
Various α-amino aldehydes were synthesized in place of Boc-L-Glu(Bzl)-ol (13).

【table】

Claims (1)

[Claims] 1. General formula (In the formula, R ₁ is an amino protecting group, an amino acid residue, a peptide residue, an amino acid residue or a peptide residue with all or part of the functional group protected, R ₂ and R ₄ are a hydrogen atom or an alkyl group, R ₃ is a hydrogen atom, an alkyl group, or an aryl group, and the alkyl group and the aryl group may be unsubstituted or substituted). A method for producing optically active α-aminoaldehydes represented by the general formula [Formula] (R ₁ , R ₂ , R ₃ , and R ₄ are the same as above), which comprises reacting a sulfur oxide complex.