JP4320443B2 - Method for producing allylglycine or an analog thereof - Google Patents

Description

  The present invention relates to a method for producing allyl glycine or an analog thereof, and preferably relates to a method for producing allyl glycine or an analog thereof with high chemical selectivity and stereoselectivity.

Allylglycine and its analogs often have pharmacological actions such as enzyme inhibitory activity themselves (Non-Patent Document 1), and various non-natural amino acids and natural products by chemical conversion of double bond moieties. This compound group is also useful as a synthetic intermediate (Non-Patent Documents 2 to 5).
As a method for producing optically active allylglycine and its analogs, a direct synthesis method by an asymmetric allylation reaction has been tried (Non-Patent Documents 6 to 8), but it has not yet been industrialized in terms of cost. The problem remains.
On the other hand, an allylation reaction of a carbonyl compound using an allylboron compound, an α-aminoallylation reaction of a carbonyl compound using both an allylboron compound and ammonia have been reported (Non-Patent Documents 9 and 10). The latter document also describes a method for stereoselective production of isoleucines by a three-component reaction of glyoxylic acid, ammonia and crotylboronate.

Kunz, D. A .: Ribbons, D. w .; Chapman, P. J. J. Bacteriol 148, 72 (1981). Schneider, H .; Sigmund, G .; Schricker, B .; Trirring, K .; Berner, H. J. Org. Chem. 58, 683 (1993). Hutton, C. A .; White, J. M. Tetrahedron Lett. 38, 1643 (1997). Baldwin, J. E .; Bradley, M .; Turner, N. J .; Adlington, R. M .; Pitt, A. R .; Sheriden, H, Tetrahedron 47, 8203 (1991). Kurokawa, N .; Ohfune, Y. Tetrahedron, 28, 6195 (1993). Hamon, D. P. G .; Massy-Westropp, M .; Razzino, P. Tetrahedron, 14, 4183 (1995). Hamada, T .; Manabe, K .; Kobayashi, S. Angew. Chem. Int. Ed. 42. 3927 (2003). Williams, R. M. "Synthesis of Optically Active α-Amino Acids (Organic Chemistry Series, J. E. Baldwin, Series Editor), Pergamon Press, 410, 1989 Sugiura, M .; Hirano, K .; Kobayashi, S. J. Am. Chem. Soc. 126, 7182 (2004). U.S. Patent No. 6232467

However, in the case of the above-described conventional techniques, there are problems that a protecting group is necessary and that the starting material is a compound having a complicated structure.
Therefore, the present invention is a one-step allylation reaction using a compound having a simple structure as a raw material without using a protecting group. Allylglycine or the like thereof is preferably obtained in a high yield and preferably high diastereoselectivity. And a method for producing isoleucine or alloisoleucine.

  In order to solve such a problem, the present inventors use hydroxyglycine as a starting material, and nucleophilic reaction of a predetermined allylboronic acid (or allylboronate) to the unprotected allylglycine ( Or an analog thereof) and the present invention has been completed.

That is, the present invention is the following formula in an alcohol (Formula 1)
And the following formula (Formula 2)
(Wherein R ¹ , R ² , R ³ , and R ⁴ may be the same or different and each represents a hydrogen atom, an alkyl group, or an aryl group, and R ² and R ⁴ are bonded to B. A ring may be formed together with a carbon atom, and R ⁵ and R ⁶ may be the same or different and each represents a hydrogen atom, an alkyl group or an aryl group, and R ⁵ and R ⁶ are a method of producing allyl glycine or analogues thereof comprising B and together reacting Ariruboron acid or boronate represented by may also be.) to form a ring.

It is preferred to add the amine or alkali inorganic salt reaction system.

The present invention, in the above method, as the Ariruboron acid or boronate (E) - crotyl boronate ^{(R 1} is a methyl group; ^R 2, ^{R 3} and R ⁴ are hydrogen atoms.) Using (Formula 3)
(Wherein R ¹ and R ⁴ are defined in the same manner as described above), the step of producing an anti-allyl allylic glycine analog, and hydrogenating the anti-allyl glycine analog A process for producing isoleucine.

Furthermore, the present invention uses (Z) -crotyl boronate (R ² is a methyl group ; R ¹ , R ³ and R ⁴ are hydrogen atoms) as the allyl boronic acid or allyl boronate in the method . (Formula 4)
(Wherein R ² and R ⁴ are defined in the same manner as described above), a step of producing a syn allylic glycine analog represented by hydrogenation of the syn allylic glycine analog A method for producing alloisoleucine.

  According to a preferred embodiment of the present invention, for example, in the case of crotylation reaction, the syn / anti selectivity of the product can be controlled by the geometric isomerism of the raw material crotylboronate.

  According to the present invention, for example, allyl glycine or an analog thereof useful as a raw material or a synthetic intermediate of a pharmaceutical or its lead compound is a one-step reaction using a compound having a simple structure as a raw material without using a protecting group. It can be obtained in high yield, preferably with high stereoselectivity.

The present invention relates to a method for producing allyl glycine or an analog thereof by reacting hydroxyglycine with allylboronic acid or allylboronate in a liquid phase, an allylglycine analog produced by this method, and isoleucine or alloisoleucine. It is a manufacturing method.
Hydroxyglycine used in the method of the present invention is represented by the following formula (Formula 1).
Hydroxyglycine is an ammonia adduct of glyoxylic acid, obtained as an amphoteric ion near the isoelectric point (pH = about 6), and easily decomposes into glyoxylic acid in an acidic aqueous solution stronger than pH 6. Hydroxyglycine as zwitterion is described in, for example, Reference 11 (Hoefnagel, A .; van Bekkum, H .; Peters, JAJ Org. Chem, 57, 3916 (1992)).
Further, iminoacetic acid, which is the actual reactive species in this reaction of hydroxyglycine, is represented by the following formula (Formula 5).

The allylboronic acid used in the method of the present invention (in the following formula (Chemical Formula 2), R ⁵ and R ⁶ both represent a hydrogen atom), or allylboronate is represented by the following formula (Chemical Formula 2). In the method of the present invention, allyl boronate is preferably used.
R ¹ , R ² , R ³ and R ⁴ may be the same or different and each represents a hydrogen atom, an alkyl group or an aryl group, preferably an alkyl group, and R ² and R ⁴ are cyclic May be made.

R ⁵ and R ⁶ may be the same or different, and are a hydrogen atom, an alkyl group, or an aryl group, and R ⁵ and R ⁶ may both be cyclic. For example, both R ⁵ and R ⁶ may be an arylene group or an alkylidene group as shown in the following formula (Formula 6).
As the allyl boronate, boronic acid esters derived from all alcohols are preferable, and those derived from optically active alcohols may be used.

  In the method of the present invention, a protic solvent can be suitably used as the solvent. As the protic solvent, alcohol is generally preferable, and lower alcohols such as methanol, ethanol and propanol are particularly preferable, and methanol is more preferable. However, water is not preferable because hydroxyglycine is partially hydrolyzed to glyoxylic acid, resulting in a decrease in yield.

The concentration of each component in the solvent is preferably 0.01 to 5 mol / l.
The temperature of this reaction is preferably 20-60 ° C. The room temperature to about 40 ° C. is more preferable because the reaction can be performed under mild conditions. If the temperature becomes too high, hydroxyglycine may be decomposed.
This reaction time is about several minutes to several hours (or several tens of hours).

  In the present invention, a basic substance is preferably added. The addition of a basic substance greatly improves the yield of the target substance. This is considered to be because the conversion of the starting material hydroxyglycine to the reactive active species iminoacetic acid is promoted by the basic substance and the rearrangement reaction of the product is suppressed. Examples of basic substances include amines and alkali inorganic salts. In particular, tertiary amines are preferable, and triethylamine is particularly preferable. The addition amount of amines can be 10-300 mol% with respect to hydroxyglycine, for example.

  As a purification method of the product, allylglycine or its analog, it can be recovered by using a general purification method such as ion exchange, extraction, column chromatography, recrystallization and the like.

The product of the present invention, allylglycine or its analog, can be represented by the following formula (Formula 7).
(Wherein R ¹ , R ² , R ³ and R ⁴ are defined in the same manner as described above.)
In the present invention, particularly when R ^{3 of} allyl boronic acid and one of R ¹ or R ² is a hydrogen atom and the other is other than a hydrogen atom, allyl boronic acid or allyl of E form (R ¹ and R ³ are hydrogen atoms) An anti-allyl glycine analog is formed from boronate, and a allylic glycine analog of Z form (R ² and R ³ is a hydrogen atom) or an allyl boronate of a Z form (R ² and R ³ are hydrogen atoms) is generated in a stereoselective manner. Allyl glycine or its analog produced in this manner can be used for pharmaceutical intermediates and the like.

  The following examples illustrate the invention but are not intended to limit the invention.

  In this example, hydroxyglycine 1 was synthesized according to the above document 11. Allyl boronates 3a to 3f were synthesized according to the following documents 12 to 15.

Reference 12: Roush, WR; Walts, AE Tetrahedron Lett. 26, 3427 (1985).
Reference 13: Roush, WR; Adam, MA; Walts, AE; Harris, DJJ Am. Chem. Soc. 108, 3422 (1986).
Reference 14: Hoffmann, W .; Ladner, W .; Ditrich, K. Liebigs Ann. Chem. 1989, 883.
Reference 15: Murata, M .; Watanabe, S .; Masuda, Y. Tetrahedron Lett. 41, 5877 (2000).

In addition, in this Example, other compounds were used after being purified as necessary.

<Example 1>
Reaction of hydroxyglycine (1) with allylboronate (3a) Allylboronate 3a with stirring in hydroxyglycine 1 (45.5 mg, 0.5 mmol) suspended in dry methanol (2 ml) under argon atmosphere (0.6 mmol) was added at room temperature. After a predetermined time, water was added for dilution, and the solution was added together with water into a column tube filled with a cation exchange resin (DOWEX 50W-X2, 50-100 mesh, H ⁺ type, about 5 g). The resin was thoroughly washed with distilled water and then eluted with 1.0 M aqueous ammonia. From the eluate, fractions positive for the ninhydrin reaction were collected and concentrated to obtain allylglycine 4a. In addition, as a by-product, α-hydroxy acid 5a in which glyoxylic acid is allylated, which is a hydrolyzate of hydroxyglycine 1, may be generated.

Table 1 shows the results of Example 1.

In Table 1, the subscript a indicates the isolation yield. The subscript b indicates the yield determined by ¹ H-NMR analysis of the crude product based on the isolated yield of allylglycine 4a. The subscript c is an average value of two tests. nd indicates that it was not detected. The subscript d includes experimental errors in the integration of the ¹ H-NMR spectrum.

In ethanol and methanol, allyl glycine was obtained in a moderate yield, and the production of α-hydroxy acid 5a was slight (Experimental Examples 1 and 2).
In methanol, the yield was improved even when the reaction temperature was increased or the reaction time was extended (Experimental Examples 3 and 4).
Further, the yield was significantly improved by adding a catalytic amount (20 mol%, 0.1 mmol in the solvent) of triethylamine (Experimental Example 5). In this case, α-hydroxy acid 5a was not produced at all. The acceleration effect of the reaction with triethylamine is considered to be because the conversion of hydroxyglycine 1 to iminoacetic acid 2 was promoted by the base.
On the other hand, in an aqueous solvent, glyoxylic acid, which is a hydrolyzate of hydroxyglycine 1, was allylated, and α-hydroxy acid 5a became the main product (Comparative Example 1). Further, almost allyl glycine 4a was hardly obtained in the aprotic solvent (Comparative Examples 2 to 4).

<Example 2>
Reaction when triethylamine was added The reaction was performed using various allylboronates 3 (3b to 3f) under the reaction conditions of Experimental Example 5 in Table 1.

Table 2 shows the results of Example 2.

In Table 2, the subscript a indicates the total yield of the products 4, 4 ′ (symbol 4 is a γ-adduct, 4 ′ is an α-adduct). The subscript b indicates a value determined by ¹ HNMR analysis. The subscript c indicates that 1 equivalent of triethylamine was added. The subscript d indicates that 2 equivalents of triethylamine was added. The subscript e indicates that the reaction time was 6 hours.

When methallyl boronate was used, the target product was obtained in 81% yield by using 1 equivalent of triethylamine (Experimental Example 6).
In the crotylation reaction, a syn-form γ-adduct is obtained as a main product from the Z-form crotylboronate (the product syn-4c in Experimental Example 7), and an E-form crotylboronate. An anti-γ-adduct was obtained as the main product from the nate (product anti-4c of Experimental Example 8). However, in all cases, α-adduct was slightly produced (product 4c ′ of Experimental Examples 7 and 8).
When cinnamyl boronate and cyclohexyl boronate were used, the product was obtained in high yield and highly stereoselectively (Experimental Examples 9 and 10). In the case of Experimental Example 9, it was possible to suppress the formation of the α-adduct (product 4d ′) by adding 1 equivalent of triethylamine.
When propenyl boronate having two substituents at the γ-position was used, the product was obtained in high yield by adding 2 equivalents of triethylamine (Experimental Example 11). In this case, a mixture of γ adduct: α adduct = 85: 15 was obtained.

  In Example 2, when the reaction mixture was heated after the reaction and before the purification operation, the ratio of the α-adduct increased. On the other hand, the production of α-adducts could be suppressed by subjecting the solution after the reaction to direct ion exchange treatment (ion exchange resin: DOWEX 50W-X2). Moreover, the addition of triethylamine was confirmed not only to accelerate the reaction but also to suppress the formation of α-adduct and to improve the yield of the target γ-adduct.

(Analytical value of the aminoallylation product of Example 2)
Analytical values of the compounds in Table 2 are shown. The parentheses in the following product names correspond to the symbols of the compounds in Table 2. Mp represents the melting point. . ¹ H- ¹³ C NMR spectra were measured in D ₂ O using JEOL measuring equipment (JEOL ECX-400, ECX-600) and 1,4-Dioxane was used as the internal standard (? 3.75 ppm for ¹ H NMR,? 67.19 ppm for ¹³ C NMR). High resolution ionization mass spectrometry (HR-ESIMS) was performed with a mass spectrometer (BRUKER DALTONICS BioTOF II mass spectrometer).

2-Aminopent-4-enoic acid (4a)
: According to Non-Patent Document 9 above.
2-Amino-4-methylpent-4-enoic acid (4b)
: Mp = 228-231 ° C. ¹ H NMR (400 MHz) δ: 5.00 (s, 1H), 4.90 (s, 1H), 3.85 (dd, J = 9.6, 4.6 Hz, 1H), 2.68 (dd, . J = 14.7, 4.6 Hz, 1H), 2.50 (dd, J = 14.7, 9.6 Hz, 1H), 1.77 (s, 3H) 13 C NMR (100 MHz) δ: 175.2, 140.7, 116.0, 53.2, 39.7, 21.3.HR-ESIMS calcd for C ₆ H ₁₂ NO ₂ (M + H ⁺ ) 130.0863, found 130.0867.
syn-2-Amino-3-methylpent-4-enoic acid (syn-4c)
: Mp = 224-227 ° C. ¹ H NMR (400 MHz) δ: 5.84 (ddd, J = 17.9, 10.1, 6.4 Hz, 1H), 5.26 (d, J = 10.1 Hz, 1H), 5.25 (d, J = 17.9 Hz, 1H), 3.76 (d, J = 4.1 Hz, 1H), 2.94-2.82 (m, 1H), 1.10 (d, J = 6.9 Hz, 3H). ¹³ C NMR (100 MHz) δ: 174.0, 138.2, 118.2, 59.0, 38.4, 13.6. HR-ESIMS calcd for C ₆ H ₁₂ NO ₂ (M + H ⁺ ) 130.0863, found 130.0866.
anti-2-Amino-3-methylpent-4-enoic acid (anti-4c)
: Mp = 220-223 ° C. ¹ H NMR (400 MHz) δ: 5.75 (ddd, J = 17.4, 10.1, 7.3 Hz, 1H), 5.25 (d, J = 17.4 Hz, 1H), 5.24 (d, J = 10.1 Hz, 1H), 3.61 (d, J = 5.5 Hz, 1H), 2.87-2.74 (m, 1H), 1.16 (d, J = 7.3 Hz, 3H). ¹³ C NMR (100 MHz) δ: 174.4, 137.3, 118.8, 59.8, 39.1, 16.0.HR-ESIMS calcd for C ₆ H ₁₂ NO ₂ (M + H ⁺ ) 130.0863, found 130.0862.
2-Aminohex-4-enoic acid (4c ')
: ¹ H NMR (400 MHz) (E-isomer) δ: 5.74 (dqt, J = 15.1, 6.4, 1.4 Hz, 1H), 5.38 (dtq, J = 15.1, 7.3, 1.8 Hz, 1H), 3.83 (dd , J = 6.7, 5.3 Hz, 1H), 2.67-2.49 (m, 2H), 1.67 (d, J = 6.4 Hz, 3H). (Z-isomer, a representative signal) δ: 1.63 (d, J = 6.9 Hz, 3H).
anti-2-Amino-3-phenylpent-4-enoic acid (4d) and (E) -2-Amino-5-phenylpent-4-enoic acid (4d ') (4d / 4d' = 93: 7)
: Mp = 172-176 ° C. ¹ H NMR (400 MHz) δ: 7.52-7.28 (m, 5.00H), 6.65 (d, J = 15.6 Hz, 0.07H), 6.29-6.14 (m, 1.00H) , 5.36 (d, J = 17.4 Hz, 0.93H), 5.34 (d, J = 10.1 Hz, 0.93H), 3.98 (d, J = 7.8 Hz, 0.93H), 3.91-3.83 (m, 1.00H), ^{2.89-2.71 (m, 0.14H) 13 C} NMR (150 MHz) 4d:. δ:. 173.6, 139.2, 135.3, 129.8, 128.54, 128.47, 120.6, 60.0, 51.8 4d '(distinguishable signals): δ: 174.7, 137.2, 129.5, 127.0, 123.6, 54.9, 34.7.HR-ESIMS calcd for C ₁₁ H ₁₄ NO ₂ (M + H ⁺ ) 192.1019, found 192.1021.
syn-Aminocyclohex-2-enyl-acetic acid (4e):
Mp = 233-236 ° C. ¹ H NMR (400 MHz) δ: 6.07-5.96 (m, 1H), 5.54 (d, J = 10.1 Hz, 1H), 3.78 (d, J = 4.1 Hz, 1H), 2.94-2.80 (m, 1H), 2.08-1.90 (m, 2H), 1.85-1.74 (m, 1H), 1.72-1.61 (m, 1H), 1.60-1.46 (m, 1H), 1.40-1.25 (m , 1H). ¹³ C NMR (100 MHz) δ: 174.4, 133.7, 126.1, 58.9, 37.1, 24.8, 23.2, 21.6.HR-ESIMS calcd for C ₈ H ₁₄ NO ₂ (M + H ⁺ ) 156.1019, found 156.1015 .
2-Amino-3,3-dimethylpent-4-enoic acid (4f):
Mp = 212-216 ° C. ¹ H NMR (400 MHz) δ: 5.86 (dd, J = 17.4, 11.0 Hz, 1H), 5.24 (d, J = 11.0 Hz, 1H), 5.21 (d, J = 17.4 Hz, 1H), 3.52 (s, 1H), 1.21 (s, 3H), 1.14 (s, 3H). ¹³ C NMR (100 MHz) δ: 173.4, 143.0, 116.0, 62.9, 38.8, 25.0, 22.0.HR -ESIMS calcd for C ₇ H ₁₄ NO ₂ (M + H ⁺ ) 144.1019, found 144.1020 (checked as a 83:17 mixture of 4f and 4f ').
2-Amino-5-methylhex-4-enoic acid (4f '):
Mp = 198-202 ° C. ¹ H NMR (400 MHz) δ: 5.10 (t, J = 7.8 Hz, 1H), 3.74 (t, J = 6.0 Hz, 1H), 2.68-2.50 (m, 2H), 1.74 (s, 3H), 1.65 (s, 3H). ¹³ C NMR (100 MHz) δ: 175.1, 139.6, 116.7, 55.3, 29.7, 25.7, 17.7. HR-ESIMS calcd for C ₇ H ₁₄ NO ₂ (M + H ⁺ ) 144.1019, found 144.1021.

<Example 3>
Production of Alloisoleucine and Isoleucine Hydrogenation reaction was allowed to proceed by directly adding palladium activated carbon to the products of Experimental Examples 10 and 11 in Table 2 without introducing isolation and introducing hydrogen gas.

  In Experimental Example 10 (Z-form crotylboronate as a starting material), alloisoleucine (97% syn) was obtained in a yield of 70%. In Experimental Example 11 (using E-form crotylboronate as a raw material), isoleucine (95% anti) was obtained in a yield of 82%.

Claims (4)

The following formula in alcohol (Chemical Formula 1)
And the following formula (Formula 2)
(Wherein R ¹ , R ² , R ³ , and R ⁴ may be the same or different and each represents a hydrogen atom, an alkyl group, or an aryl group, and R ² and R ⁴ are bonded to B. A ring may be formed together with a carbon atom, and R ⁵ and R ⁶ may be the same or different and each represents a hydrogen atom, an alkyl group or an aryl group, and R ⁵ and R ⁶ are method for producing allyl glycine or analogues thereof comprising B and together reacting Ariruboron acid or boronate represented by may also be.) to form a ring. The method according to claim 1 , wherein an amine or an alkali inorganic salt is added to the reaction system. 3. The method according to claim 1, wherein (E) -crotylboronate (R ¹ is a methyl group ; R ² , R ^3, and R ⁴ are hydrogen atoms) as the allylboronic acid or allylboronate. Use the following formula (Formula 3)
(Wherein R ¹ and R ⁴ are defined in the same manner as described above), the step of producing an anti-allyl allylic glycine analog, and hydrogenating the anti-allyl glycine analog A process for producing isoleucine comprising the step of: 3. The method according to claim 1, wherein (Z) -crotylboronate (R ² is a methyl group ; R ¹ , R ^3, and R ⁴ are hydrogen atoms) as the allylboronic acid or allylboronate. Using the following formula (Formula 4)
(Wherein R ² and R ⁴ are defined in the same manner as described above), a step of producing a syn allylic glycine analog represented by hydrogenation of the syn allylic glycine analog A method for producing alloisoleucine comprising the step of: