JP4277068B2 - Process for producing homoallylamine compounds - Google Patents

Description

The present invention relates to a process for producing homoallylamine compounds using ammonia, and more particularly, a high chemical selection by a three-component reaction consisting of an aldehyde compound , ammonia and allylboronic acid or allylboronate. The present invention relates to a method for producing a homoallylamine compound with high selectivity and stereoselectivity.

Ammonia is a primary product of nitrogen fixation and a nitrogen source for many nitrogenous natural products. For example, L-glutamic acid is biosynthesized by reductive amination reaction between α-ketoglutamic acid and ammonia by NADPH. In addition, the amino groups of many other α-amino acids are formed from L-glutamic acid by a transamination reaction. Ammonia is also important as one of inexpensive and versatile nitrogen sources in chemical processes.
Nucleophilic addition of ammonia to a carbon atom of a carbon-X single bond or multiple bond (X represents a halogen atom, a hetero atom or a carbon atom) enables introduction of a nitrogen atom into an organic molecule. In particular, the three-component reaction consisting of a carbonyl compound, ammonia (or a nitrogen nucleophile such as an amine) and a carbon nucleophile simultaneously forms a nitrogen-carbon bond and a carbon-carbon bond between the carbonyl carbon and the nucleophile. Useful for. These reactions are called α-aminoalkylation reactions of carbonyl compounds, and various techniques have been reported depending on the nucleophile used. Recently, Petasis et al. Developed a novel method for synthesizing allylamine compounds or benzylamine compounds from hydroxy- or carboxy-aldehydes, amines, and vinylboronic acids or arylboronic acids (Non-patent Documents 1, 2, and Patent Document 1).

J. Am. Chem. Soc. 1997, 119, 445-446 J. Am. Chem. Soc. 1998, 120, 11798-11799 U.S. Patent No. 6,232,467

  However, there are few known methods using ammonia (or ammonium salt) for the α-aminoalkylation reaction. This is because the product primary amine further reacts with a carbon-X bond (X is the same as above) to produce a higher amine. Therefore, in most reactions, primary amine or secondary amine is used instead of ammonia. Nevertheless, ammonia is considered a promising raw material candidate because it can directly produce primary amines by a process with high atomic efficiency.

(式中、Ｒ^１〜Ｒ^４は下記で定義され、Ｍはホウ素等の原子を表し、Ｌは配位子を表し、ｎは配位子の数を表す。)
In order to solve such problems, the inventors considered the possibility of immobilizing ammonia in an organic molecule through a carbon-carbon bond forming reaction, and used an allylating agent as a carbon nucleophile to form an aldehyde. The α-aminoallylation reaction (α-aminoallylation) of the compounds was examined (Scheme 1). As a result, it has been found that a homoallyl primary amine can be obtained with high chemical selectivity and stereoselectivity by a three-component reaction comprising an aldehyde compound , ammonia and allylboronate, and the present invention has been completed.

(Wherein R ^{1 to} R ⁴ are defined below, M represents an atom such as boron, L represents a ligand, and n represents the number of ligands.)

（式中、Ｒ^１は、アルキル基、アルケニル基、アリール基、脂環式炭化水素基、複素環基、アルコキシカルボニル基又はカルボキシル基を表し（但し、アルキル基、アルケニル基、アリール基、脂環式炭化水素基、及び複素環基は置換基を有していてもよく、この置換基はアルキル基、ハロゲン原子、アリール基、水酸基、メルカプト基またはアミノ基である。）、Ｒ^２は水素原子を表す。）で表されるアルデヒド化合物又はアルドース型の糖類、下式（化２）

（式中、Ｒ^３及びＲ^４は、それぞれ同じであっても異なってもよく、水素原子、アルキル基又はアリール基を表し、Ｒ^５及びＲ^６は、それぞれ同じであっても異なってもよく、水素原子、アルキル基又はアリール基を表し、Ｒ^５及びＲ^６はこれらが結合するＯ−Ｂ−Ｏと一緒に環状構造を形成してもよい。）で表されるアリルボロン酸又はアリルボロネート、及びアンモニア（ＮＨ_３）を反応させることから成るホモアリルアミン化合物を製造する方法である。
That is, the present invention is the following formula in the liquid phase (Chemical Formula 1)

(Wherein R ¹ represents an alkyl group, an alkenyl group, an aryl group, an alicyclic hydrocarbon group, a heterocyclic group, an alkoxycarbonyl group or a carboxyl group (provided that an alkyl group, an alkenyl group, an aryl group, an alicyclic ring). wherein the hydrocarbon group, and the heterocyclic group rather it may also have a substituent, this substituent is an alkyl group, a halogen atom, an aryl group, a hydroxyl group, a mercapto group or an amino group.), R ² is hydrogen An aldehyde compound or an aldose type saccharide represented by the following formula (Formula 2):

(In the formula, 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 ⁵ and R ⁶ may be the same or different, respectively. Represents a hydrogen atom, an alkyl group or an aryl group, and R ⁵ and R ⁶ may form a cyclic structure together with O—B—O to which they are bonded .) And a process for producing a homoallylamine compound comprising reacting ammonia (NH ₃ ).

（式中、Ｒ^１及びＲ^３は前記と同様に定義される。）で表されるアンチ(anti)体ホモアリルアミン化合物である。 Further, the present invention provides a homopolymer produced by the above method using E-form allylboronic acid or allylboronate in which R ² is a hydrogen atom, R ⁴ is a hydrogen atom, and R ³ is other than a hydrogen atom. An allylamine compound having the following formula (Formula 3)

(Wherein R ¹ and R ³ are defined in the same manner as described above).

（式中、Ｒ^１及びＲ^４は前記と同様に定義される。）で表されるシン(syn)体ホモアリルアミン化合物である。 Furthermore, the present invention provides a homoallylamine compound produced by the above method using Z-form allylboronic acid or allylboronate wherein R ² is a hydrogen atom, R ³ is a hydrogen atom and other than R ⁴ hydrogen atom. And the following formula (Formula 4)

(Wherein R ¹ and R ⁴ are defined in the same manner as described above), and a syn-form homoallylamine compound.

The inventors have found that an efficient method for fixing ammonia can be achieved by a three-component reaction in which an aldehyde compound and allylboronate are reacted with ammonia. As a result, homoallyl primary amines were obtained with high yield and chemical and stereoselectivity, and by utilizing this reaction, a simple and stereoselective synthesis method of alloisoleucine was achieved.
By using a saccharide such as a monosaccharide or oligosaccharide as the aldehyde compound , an amino polyol having an allyl group at the terminal can be synthesized.
The product, an aminoallylated polyol, can be expected to have interesting biological activity, and can be derived into various sugar analogs by converting allyl groups to other functional groups. Furthermore, it can also be used as a raw material for immobilizing oligosaccharides on a polymer carrier or the like via an allyl group.

式中、Ｒ^１は、アルキル基、アルケニル基、アリール基、脂環式炭化水素基、複素環基、アルコキシカルボニル基又はカルボキシル基を表し、Ｒ^２は水素原子を表す。これらアルキル基、アルケニル基、アリール基、脂環式炭化水素基、複素環基は置換基を有していてもよく、このような置換基としてアルキル基、ハロゲン原子、アリール基、水酸基、メルカプト基、アミノ基等が挙げられる。更に、カルボキシル基はエステル化されていてもよい（即ち、アルコキシカルボニル基）。アリール基としては、フェニル基やナフチル基、好ましくはフェニル基が挙げられる。脂環式炭化水素基としてシクロへキシル基が好ましく挙げられる。複素環基として、含窒素複素環基が挙げられ、含窒素複素環基としては２−、３−、４−、５−又は６−ピリジン基、２−、４−又は５−ピリミジン基、２−、３−、４−又は５−ピラジン基等が挙げられる。
糖類は、アルドース型の（即ち、アルデヒド基を有する）糖類であり、好ましくは単糖又はオリゴ糖である。
The present invention is a method for producing a homoallylamine compound by reacting an aldehyde compound, allylboronic acid or allylboronate, and ammonia (NH ₃ ) in a liquid phase.
In the method of the present invention, an aldehyde compound represented by the following formula (Formula 1) or an aldose type saccharide is used as the aldehyde compound.

In the formula, R ¹ represents A alkyl group, an alkenyl group, an aryl group, an alicyclic hydrocarbon group, a heterocyclic group, an alkoxycarbonyl group or a carboxyl group, R ² represents a hydrogen atom. These alkyl group, alkenyl group, aryl group, alicyclic hydrocarbon group, and heterocyclic group may have a substituent, such as an alkyl group, a halogen atom, an aryl group, a hydroxyl group, a mercapto group. And amino groups. Furthermore, the carboxyl group may be esterified (ie, an alkoxycarbonyl group). Examples of the aryl group include a phenyl group and a naphthyl group, preferably a phenyl group. Preferred examples of the alicyclic hydrocarbon group include a cyclohexyl group. Examples of the heterocyclic group include a nitrogen-containing heterocyclic group, and examples of the nitrogen-containing heterocyclic group include a 2-, 3-, 4-, 5- or 6-pyridine group, a 2-, 4- or 5-pyrimidine group, 2 -, 3-, 4- or 5-pyrazine group and the like can be mentioned.
Saccharide, the aldose type (i.e., to have a aldehyde group) saccharide, preferably a monosaccharide or oligosaccharide.

Ｒ^３及びＲ^４は、それぞれ同じであっても異なってもよく、水素原子、アルキル基又はアリール基であり、好ましくはアルキル基が挙げられる。Ｒ^３及びＲ^４の少なくとも一方は水素原子ではないことがより好ましい。 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 ³ and R ⁴ may be the same or different and are a hydrogen atom, an alkyl group or an aryl group, preferably an alkyl group. More preferably, at least one of R ³ and R ⁴ is not a hydrogen atom.

アリルボロネートとしては、アルコール全般から誘導されるボロン酸エステルが好ましく、光学活性アルコール由来のものでもよい。


R ⁵ and R ⁶ may be the same or different and each is a hydrogen atom, an alkyl group or an aryl group, and R ⁵ and R ⁶ form a cyclic structure together with O—B—O to which they are bonded. It may be formed . For example, both R ⁵ and R ⁶ may be an arylene 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 general organic solvent such as water, alcohol, ether, nitrile, or ester can be used as the solvent. Among these solvents, water or alcohol is particularly preferable.
Further, as an ammonia (NH _3), liquid ammonia, solvent and dissolved ammonia water (1% to 25%) or ammonia gas may be used. When using liquid ammonia as ammonia, it is preferable to use alcohol as the solvent, and when using ammonia water as ammonia, it is preferable to use a water-containing organic solvent or an aqueous solution containing no organic solvent as the solvent.
The concentration of each component in the solvent is preferably 0.01 to 5 mol / l.
The temperature of this reaction is preferably −78 to 100 ° C.
This reaction time is about several minutes to several hours.
In addition to the above components, known additives such as catalysts and surfactants may be added to this reaction system as appropriate.
As the surfactant, various substances such as anionic and cationic can be used. Among these, anionic surfactants are preferable, and among them, alkylbenzenesulfonic acid or a salt thereof is particularly preferable.
The product homoallylamine compound can be recovered using general purification methods such as extraction, column chromatography, distillation, recrystallization and the like.

（式中、Ｒ^１〜Ｒ^４は上記と同様に定義される。）
本発明では、特にＲ^３及びＲ^４の一方が水素原子であり他方が水素原子以外である場合、Ｅ体（Ｒ^４が、例えば、水素原子である。）のアリルボロン酸又はアリルボロネートからアンチ体のホモアリルアミン化合物が、Ｚ体（Ｒ^３が、例えば、水素原子である。）のアリルボロン酸又はアリルボロネートからシン体のホモアリルアミン化合物が立体選択的に生成する。
このようにして製造したホモアリルアミン化合物は、医薬中間体等の用途に用いることができる。

以下、実施例にて本発明を例証するが本発明を限定することを意図するものではない。 The homoallylamine compound which is the product of the present invention can be represented by the following formula (Formula 7).

(Wherein R ^{1 to} R ⁴ are defined in the same manner as described above.)
In the present invention, in particular, when one of R ³ and R ⁴ is a hydrogen atom and the other is other than a hydrogen atom, the isomer is converted from an allyl boronic acid or allyl boronate of E-form (R ⁴ is, for example, a hydrogen atom) The homoallylamine compound of the form is stereoselectively formed from the allylboronic acid or allylboronate of the Z form (R ³ is, for example, a hydrogen atom).
The homoallylamine compound thus produced 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, the product was purified by silica gel chromatography using silica gel 60 (Merk) or Wakogel B-5F. Ethanol was distilled using sodium and stored with 3Å MS. Distilled water was used for the aqueous reaction. Other solvents were purified by standard methods.
In this example, the following compounds were used. Aldehyde compounds 1a and 1d-k were purified by distillation before use. Aldehyde compounds 1b and 1c were purified by recrystallization from ethanol water and ethanol, respectively. Glyoxylic acid monohydrate (1 l) was purchased from Tokyo Chemical Industry and used without purification. Allylboronate 2 and (E)-and (Z) -crotylboronate 5 are described in the literature (Tetrahedron Lett. 1985, 26, 3427; (a) J. Am. Chem. Soc. 1986, 108, 3422, (b ) Liebigs Ann. Chem. 1989, 883.) Liquid ammonia (99.999%, Nippon Oxygen Co., Ltd.) and aqueous ammonia (28.0-30.0% by weight, Wako Pure Chemical Industries, Ltd.) were used without purification. For hydrogenation, palladium on carbon (5% by weight, PH-type, wet, Kawaken Fine Chemical Co., Ltd.) was used. Other compounds were purified by standard methods.

  Prior to the examples, several allyl metals (boron, silicon, tin) were evaluated in the reaction of benzaldehyde (1a) with ammonia. As a result, allylboronate and allylboronate were effective. It turned out to be an agent.

Examples 1-40
According to the above results, in this example, ammonia, aldehyde compound 1 and allyl boronate 2 were reacted in four ways (methods A to D) as shown in the following formula. As a result, amine 3 and alcohol 4 are produced.

Method A: Ammonia gas was introduced into a two-necked flask with a septum cooled to −78 ° C. under an argon atmosphere to obtain liquid ammonia (about 0.5 ml). Ethanol (0.5 ml) was added thereto, aldehyde compound 1 (0.5 mmol) was added, and the mixture was washed with ethanol (0.5 ml). When the aldehyde compound is 1b and 1c (solid), the aldehyde compound is put in the flask before adding liquid ammonia (about 0.5 ml) and ethanol (0.5 ml). The mixture was heated to −10 ° C. and stirred at this temperature for 2 hours. During this time, excess ammonia vaporizes in the reaction vessel. Next, allyl boronate 2 (0.6 mmol) dissolved in ethanol was added dropwise to the solution. As a result, a colorless precipitate was obtained. The mixture was stirred at −10 ° C. for 3 hours and at room temperature for 1 hour. Next, the septum was removed to vaporize most of the ammonia, and 1N HCl was added to the solution to make it acidic (about pH 1). The mixture was washed with diethyl ether, alkalized with 6N aqueous NaOH (about pH 10), and extracted with dichloromethane. The dichloromethane layer was dried over anhydrous Na ₂ CO ₃ , filtered and concentrated under reduced pressure to give almost pure amine 3. The crude product (amine 3) was purified by silica gel chromatography (hexane / isopropylamine = 10/1). On the other hand, alcohol 4 is contained in the ether extraction layer. The extract was dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The yield of alcohol 4 was determined by ¹ HNMR analysis using 1,2,4,5-tetramethylbenzene as an internal standard.

Method B: Aldehyde compound 1 (0.5 mmol) is stirred in 28-30 wt% aqueous ammonia (about 20 equivalents, about 0.74 ml) and ethanol (1 ml) at room temperature for 2 hours. To this solution was added allylboronate 2 (0.6 mmol) and the mixture was stirred at room temperature for 3 hours and worked up in the same manner as in Method A for 1a.
In the case of glyoxylic acid (1 l), the reaction mixture is concentrated under reduced pressure, and the residue is poured into a cation exchange resin column (DOWEX 50W-X2, 50-100mesh, H ⁺ form; about 7 g (wet)) with water. Passed through. After washing with a sufficient amount of water, the product was eluted with 0.2N aqueous ammonia. The fraction was detected by silica gel thin layer chromatography using a 0.1% by weight ninhydrin acetone / water (80/20 volume ratio) solution, and the fraction containing 3 l of the product was collected and concentrated to dryness.

Method C: Allylboronate 2 (0.6 mmol) dissolved in ethanol (0.5 ml) was added to liquid ammonia (ca. 0.5 ml) at −78 ° C. and washed with ethanol (0.5 ml). Addition of allyl boronate 2 gave a colorless precipitate. After stirring at room temperature for 30 minutes, aldehyde compound 1 (0.5 mmol) was added to this suspension and washed with ethanol (0.5 ml). This mixture was stirred at room temperature for 2 hours, and then the same operation as in Method A was performed.

  In this example, the effects of the solvents (ethanol, 2-propanol, t-butanol, acetonitrile, and 1,4-dioxane) were not significantly different, so the environmental load was small and the solubility of ammonia was high. Therefore, ethanol was used. Although allyl boronate can be variously substituted, 2-allyl-4,4,5,5-tetramethyl [1,3,2] dioxaborolane (2) having high stability was used. Excess ammonia (saturated in ethanol) is very important to obtain high chemical selectivity (amine 3 / alcohol 4 ratio) (Table 1, Example 1, Method A). Although the chemical selectivity is slightly inferior, aqueous ammonia (28-30 wt%, about 20 equivalents) can be used instead of liquid ammonia (Table 1, Example 2, Method B).

ｂ：単離収率
ｃ：この収率は、1,2,4,5-テトラメチルベンゼンを内部標準として^１ＨＮＭＲ分析により決定した。
ｎｄ：検出されなかった。
ｄ：アルデヒド化合物（１ｉ）は、２ａのアンモニア／エタノール溶液に２時間かけてゆっくり添加した。
ｅ：syn/anti = 73/27 Table 1 shows the results obtained using various aldehyde compounds shown in Table 1.

b: Isolated yield c: This yield was determined by ¹ HNMR analysis using 1,2,4,5-tetramethylbenzene as an internal standard.
nd: not detected.
d: The aldehyde compound (1i) was slowly added to the ammonia / ethanol solution of 2a over 2 hours.
e: syn / anti = 73/27

  Next, Method A was used to examine the substrate effects of this reaction. Benzaldehyde derivatives having electron-withdrawing and electron-donating substituents (Example 3-6) and heteroaromatic aldehydes (Examples 7 and 8) produced homoallylamine 3 in high yield. Cinnamic aldehyde showed high 1,2 addition selectivity (Example 9). Aliphatic aldehydes produced homoallylamine with high selectivity (Example 10-12) simply by changing the addition order of the reactants (Method C). Interestingly, these enolizable aldehydes were not complicated by side reactions derived from enamine formation.

  On the other hand, glyoxylic acid is an interesting substrate because it directly produces α-amino acid derivatives. By using Method B, α-aminoallylation reaction proceeded smoothly and α-allylglycine was quantitatively produced (Example 13). By using aqueous ammonia, glyoxylic acid was effectively dissolved in the reaction solution. The product 3l is quantitatively converted to norvaline by hydrogenation using Pd / C.

  The reaction mechanism is not yet clear, but there are two possibilities. One is a mechanism in which an N-unsubstituted imine is formed from an aldehyde compound and ammonia and is allylated by allyl boronate. The other is a mechanism in which a novel aminoallylating agent is formed from allylboronate and ammonia in the system. The effective use of excess ammonia (Method A and Method B) is believed to favor the equilibrium of aldehyde compounds and ammonia to imine and promote the former mechanism. On the other hand, the fact that it was effective to previously mix allylboronate and ammonia (Method C) is considered to promote the latter mechanism.

  In the control experiment, amine 3 and alcohol 4 did not change under the reaction conditions, so there is no possibility of interconversion between amine 3 and alcohol 4. On the other hand, there is a possibility that the product 3 reacts with the aldehyde compound 1 to form N-alkylimine and is subsequently allylated with allyl boronate, but such a process does not exist in this reaction. In fact, when the amount of ammonia was reduced, it was observed that N-alkylimines were formed from 1a and 3a, indicating that under these conditions, N-alkylimines are inactive against allylboronate. It shows that there is. To further clarify this point, we tried reacting 1a, isopropylamine or benzylamine (5 equivalents) and 2 in ethanol, but no allylated product was produced, instead the corresponding imine was produced. Observed. This indicates that ammonia is important as a reactant in the present α-aminoallylation reaction.

Method D: In this method, aqueous ammonia was used as ammonia (NH ₃ ), and the reaction was performed in an aqueous solution. First, the influence of the surfactant was examined, and then the influence of the aldehyde compound was examined.
After stirring a mixture of allyl boronate 2 (0.6 mmol), the surfactant shown in Table 2 (0.05 mmol) and 25% aqueous ammonia (1 ml) at room temperature for 30 minutes, aldehyde compound ( 1i: Ph (CH ₂ ) ₂ CHO) (0.5 mmol) was added. After vigorously stirring for 2 hours at room temperature, the reaction mixture was acidified with 3N hydrochloric acid and extracted with dichloromethane. The organic layer was concentrated and then produced by silica gel chromatography to obtain an alcohol form (4). On the other hand, the aqueous layer after extraction was alkalized with 6N NaOH, extracted with dichloromethane, and dried over anhydrous Na ₂ SO ₄ . After evaporating the solvent under reduced pressure, the amine compound (3) was obtained by producing by silica gel chromatography.

ａ：1,2,4,5-テトラメチルベンゼンを内部標準としたＮＭＲ分析による収率
ｂ：ドデシルベンゼンスルホン酸
ｃ：ドデシル硫酸ナトリウム
ｄ：ドデシルベンゼンスルホン酸ナトリウム
ｅ：臭化セチルトリメチルアンモニウム

a: Yield by NMR analysis using 1,2,4,5-tetramethylbenzene as an internal standard b: dodecylbenzenesulfonate c: sodium dodecylsulfate d: sodium dodecylbenzenesulfonate e: cetyltrimethylammonium bromide

ａ：単離収率
ｂ：1,2,4,5-テトラメチルベンゼンを内部標準としたＮＭＲ分析による収率 Next, the same reaction was performed using DBSA (dodecylbenzenesulfonic acid) and the aldehyde compound 1 shown in Table 3 as surfactants. The results are shown in Table 3.

a: Isolated yield b: Yield by NMR analysis using 1,2,4,5-tetramethylbenzene as internal standard

Example 41
In this example, the reaction of benzaldehyde (1a) with (Z)-or (E) -crotylboronate 5 (α-aminocrotylation; α-amino2-butenylation) was investigated. (Scheme 2) The reaction was performed according to Method C above.

  (Z)-or (E) -Crotylboronate 5 (0.75 mmol) dissolved in ethanol (0.5 ml) was added to liquid ammonia (about 0.5 ml) at -78 ° C. and ethanol (0.5 ml) was added. ). The addition of crotylboronate 5 gave a colorless precipitate. After stirring at room temperature for 30 minutes, 1,4-dioxane solution (0.5 ml) of aldehyde 1a (0.5 mmol) or aldehyde 1b (0.5 mmol) was added to this suspension, and ethanol (0. 5 ml) or 1,4-dioxane (0.5 ml). This mixture was stirred at room temperature for 2 hours, and then the same operation as in Method A was performed.

  As a result, high γ-addition selectivity and stereospecificity were observed. That is, (Z) -crotylboronate (2-butenylboronate) 5 produced a syn-adduct 6 and (E) -crotylboronate 5 produced an anti-adduct 6. It should be noted that the stereochemistry in these cases is similar to that of aldehydes, unlike the general N-substituted imine crotylation reaction.

Example 42
The α-aminocrotylation reaction can be used for a simple one-pot synthesis of alloisoleucine, one of the unusual α-amino acids found in certain peptide antibiotics (Scheme 3). When (Z) -crotylboronate 5 is allowed to act on glyoxylic acid in ethanol / liquid ammonia (Method C), an aminocrotylated product is formed. When ammonia is removed with an aspirator and hydrogenation is performed using Pd / C, alloisoleucine is produced with high yield and high selectivity.

  (Z) -Crotylboronate 5 (137.5 mg, 0.75 mmol) dissolved in ethanol (0.5 ml) was added to liquid ammonia (about 0.5 ml) at −78 ° C. and ethanol (0.5 ml) was added. Washed in with. After stirring at −10 ° C. for 30 minutes, an aqueous solution (0.5 ml) of glyoxylic acid (1 l) (46.5 mg, 0.5 mmol) was added to the suspension and washed with ethanol (0.5 ml). The mixture was stirred at −10 ° C. for 3 hours. Next, most of the ammonia was removed with an aspirator. Pd / C (5 wt%, wet, 15.2 mg) was added and the mixture was stirred for 12 hours at room temperature under a hydrogen atmosphere using a balloon (about 1 atm). The mixture was filtered through celite and concentrated under reduced pressure. The residue was purified by ion exchange resin chromatography to obtain alloisoleucine (60 mg, 91%).

Example 43
In this example, the reaction of 2-pyridinecarboxaldehyde (1f) with (Z)-or (E) -crotylboronate 5 was investigated (Scheme 4). The reaction was performed according to Method D above.

25% aqueous ammonia (1 ml) was added to an aqueous solution in which (Z)-or (E) -crotylboronate 5 (0.6 mmol) and DBSA (0.05 mmol) were dissolved at room temperature. The addition of crotylboronate 5 gave a colorless precipitate. After stirring at room temperature for 30 minutes, aldehyde 1f (0.5 mmol) was added to the suspension. This mixture was stirred at room temperature for 2 hours, and then the same operation as in Method D was performed.
As a result, the reaction proceeded with high stereoselectivity, and an aminoallylated product was obtained in high yield. That is, (Z) -crotylboronate 5 produced syn-adduct 6f in a yield of 87%, and (E) -crotylboronate 5 produced an anti-adduct 6f in a yield of 90%.

Ｄ−グルコース（１、０．５ミリモル）を２５％アンモニア水（１．０ｍｌ）に溶解し、室温で３０分間攪拌した。アリルボロネート（２、０．７５ミリモル）を加え、さらに６時間攪拌した後、水とエーテルを加えた。水相を減圧濃縮後、残渣を上記方法Ｂと同様に陽イオン交換樹脂によるカラムクロマトグラフィーで生成しアミノアリル化化合物（３）を収率９３％、ｓｙｎ／ａｎｔｉ＝９３／７で得た。 Example 44
In this example, the reaction between saccharides and allyl boronate was examined.

D-glucose (1, 0.5 mmol) was dissolved in 25% aqueous ammonia (1.0 ml) and stirred at room temperature for 30 minutes. Allyl boronate (2, 0.75 mmol) was added and stirred for a further 6 hours before adding water and ether. After concentrating the aqueous phase under reduced pressure, the residue was produced by column chromatography using a cation exchange resin in the same manner as in Method B above, and the aminoallylated compound (3) was obtained in a yield of 93% and syn / anti = 93/7.

Claims (8)

In the liquid phase:

(Wherein R ¹ represents an alkyl group, an alkenyl group, an aryl group, an alicyclic hydrocarbon group, a heterocyclic group, an alkoxycarbonyl group or a carboxyl group (provided that an alkyl group, an alkenyl group, an aryl group, an alicyclic ring). wherein the hydrocarbon group, and the heterocyclic group rather it may also have a substituent, this substituent is an alkyl group, a halogen atom, an aryl group, a hydroxyl group, a mercapto group or an amino group.), R ² is hydrogen An aldehyde compound or an aldose type saccharide represented by the following formula (Formula 2):

(In the formula, 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 ⁵ and R ⁶ may be the same or different, respectively. Represents a hydrogen atom, an alkyl group or an aryl group, and R ⁵ and R ⁶ may form a cyclic structure together with O—B—O to which they are bonded .) And a process for producing a homoallylamine compound comprising reacting ammonia (NH ₃ ).
The method according to claim 1, wherein liquid ammonia is used as the ammonia (NH ₃ ) and the reaction is performed in alcohol. The method according to claim 1, wherein ammonia water is used as the ammonia (NH ₃ ) and the reaction is performed in a water-containing organic solvent. The method according to claim 1, wherein ammonia water is used as the ammonia (NH ₃ ) and the reaction is performed in an aqueous solution not containing an organic solvent. The method according to claim 4, wherein a surfactant is added to the reaction system. R ⁴ is a method according to any one of claims 1 to 5 with Ariruboron acid or boronate of the E isomer is other than and R ³ is a hydrogen atom and a hydrogen atom, manufacturing homo The allylamine compound has the following formula (Formula 3)

(In the formula, R ¹ and R ^3. Which is as defined above) The method is anti (anti) body Homoallylic amine compound represented by the. R ³ is A method according to any one of claims 1 to 5 with Ariruboron acid or boronate of the Z-form is other than and R ⁴ is a hydrogen atom and a hydrogen atom, manufacturing homo The allylamine compound has the following formula (Formula 4)

(Wherein, R ¹ and R ^4. Which is as defined above) The method is a thin (syn) body Homoallylic amine compound represented by the. Glyoxylic acid, formula

(Wherein R ³ represents a hydrogen atom, R ⁴ represents a methyl group, R ⁵ and R ⁶ may be the same or different, and each represents a hydrogen atom, an alkyl group or an aryl group; ⁵ and R ⁶ may form a cyclic structure together with O—B—O to which they are bonded .) (Z) -crotylboronate represented by the following formula and ammonia (NH ₃ )

(Wherein R ¹ represents —COOH and R ⁴ represents a methyl group). A method for producing alloisoleucine comprising the steps of producing a homoallylamine compound represented by the formula: and hydrogenating the homoallylamine compound.