JP5166321B2 - Syn-selective catalytic Mannich-type reaction of sulfonylimidates using alkaline earth metals as catalysts - Google Patents

Description

  The present invention relates to a method for selectively producing a syn isomer of a corresponding amine compound by reacting a sulfonyl imidate compound and an imine compound in a nonpolar solvent in the presence of an alkaline earth metal catalyst.

In the pharmaceutical and agrochemical industries, a large number of compounds have been produced for the development of new active compounds. In recent years, many organic compounds have been produced as element materials such as organic EL elements.
In the production of such organic compounds, development of new synthetic methods for organic compounds has been desired. Nucleophilic reaction is known as one of typical chemical reactions in producing organic compounds and has been used in many industrial fields. In particular, the nucleophilic addition reaction has been developed as a chemical reaction for generating a new C—C bond or C—N bond (see Non-Patent Documents 1 to 8). However, these reactions require a large amount of base of approximately the same amount, and have an electron withdrawing group at a position adjacent to the reaction site in order to ensure the reactivity of the nucleophilic reaction substrate compound. (For example, refer nonpatent literature 9-11).
For this reason, development of a new nucleophilic reagent with a small amount of base and high generality is required.

  On the other hand, alkaline earth metals are abundant on the earth, are inexpensive, do not have great toxicity, and are suitable for commercial use. In particular, alkaline earth metal alkoxides have both the properties of Lewis acids and Bronsted bases, and are considered suitable for addition reactions of enolates with electrophiles. The present inventors have reported an asymmetric Michael reaction using calcium alkoxide or strontium alkoxide and a 1,4-addition reaction of a glycine derivative (see Non-Patent Documents 12 and 13). In addition, the present inventors have reported that an anti-isomer is mainly produced in an addition reaction between a sulfonyl imidate compound and an imine compound using magnesium alkoxide in a polar solvent such as DMF (Non-patent Document 14). And Patent Document 1). However, this method could not make the syn product the main product.

Japanese Patent Application No. 2008-3733

Alcaide, B. et al., Eur. J. Org. Chem., 2002, 1595. List, B., Acc. Chem. Res., 2004, 37, 548. Notz, W., et al., Acc. Chem. Res., 2004, 37, 580. Shibasaki, M., et al., Chem. Commun., 2002, 1989. Shibasaki, M., et al., Chem. Rev., 2002, 102, 2187. Cordova, A., Acc. Chem. Res., 2004, 37, 102. Marques, M., Angew. Chem. Int. Ed., 2006, 45, 348. Shibasaki, M., etal., J. Organomet. Chem., 2006, 691, 2089. Saito, S., et al., J. Am. Chem. Soc., 2006, 128, 8704. Saito, S., et al., Chem. Commun., 2007, 1236. Morimoto, H., et al., J. Am. Chem. Soc., 2007, 129, 9588. M. Agostinho, et al., J. Am. Chem. Soc., 2008, 130, 2430. S. Kobayashi, et al., Org. Lett., 2008, 10, 807. R. Matsubara, et al., J. Am. Chem. Soc., 2008, 130, 1804.

  The present invention provides a method for selectively producing a syn isomer as a main product in an addition reaction between a sulfonyl imidate compound and an imine compound.

In the stereoselective production method, it is desired to establish a method for selectively producing any one of compounds having a desired stereostructure. The present inventors have reported a method for selectively producing an anti-isomer (see Patent Literature 1 and Non-Patent Literature 14), but could not selectively produce a syn-isomer. In addition, since alkaline earth metal catalysts used in the production of anti-forms are cheap and safe, we wanted to develop a method that can selectively produce syn-forms using the same catalyst as much as possible. However, since it was thought that much of the stereoselectivity was dependent on the structure of the catalyst, it was thought that the selective production of the syn form with the same type of catalyst was difficult.
As a result of intensive studies on these points, the present inventors have surprisingly found that a syn form can be selectively produced by changing the polarity of a solvent. The present invention provides a novel syn-selective catalytic Mannich-type reaction.
That is, the present invention provides the following general formula (1)

(In the formula, R ¹ represents an alkyl group which may have a substituent, R ² represents an aryl group having an electron withdrawing group, and R ³ represents an alkyl group which may have a substituent. )
And the following general formula (2)
^{R 5 O-CO-N =} CH-R 4 (2)
(In the formula, R ⁴ represents a hydrocarbon group that may have a substituent or a heterocyclic group that may have a substituent, and R ⁵ represents an alkyl group that may have a substituent.)
In the presence of an alkaline earth metal catalyst in a nonpolar solvent, and the following general formula (3),

(In the formula, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are the same as those shown in the general formulas (1) and (2).)
And a method for selectively producing a syn isomer of an enantiomer thereof.

More specifically, the present invention relates to the following items.
(1) The sulfonyl imidate represented by the general formula (1) and the following general formula (2)
^{R 5 O-CO-N =} CH-R 4 (2)
(In the formula, R ⁴ represents a hydrocarbon group which may have a substituent, and R ⁵ represents an alkyl group which may have a substituent.)
The imine represented by general formula (3) is made to react selectively in the presence of an alkaline-earth metal catalyst in the presence of an alkaline-earth metal catalyst, and the sine body of the amine compound represented by the said General formula (3) is selectively manufactured.
(2) The method according to (1), wherein the reaction is performed in the presence of a ligand having a nitrogen atom.
(3) The ligand is represented by the following formula (4)

Or the following formula (5)

The method as described in said (1) or (2) which is a nitrogen-containing compound represented by these.
(4) The method according to any one of (1) to (3), wherein the nonpolar solvent is THF.
(5) The method according to any one of (1) to (4), wherein R ² in the general formula (1) is a p-nitrophenyl group.
(6) The method according to any one of (1) to (5) above, wherein the alkaline earth metal catalyst is an alkoxy alkaline earth metal or a silazide alkaline earth metal.
(7) The method according to any one of (1) to (6), wherein the alkaline earth metal catalyst is calcium, barium, or strontium.
(8) The amount of the alkaline earth metal catalyst is 0.01 to 20 mol% with respect to the sulfonyl imidate represented by the general formula (1), according to any one of the above (1) to (7) Method.
(9) The method according to any one of (1) to (8), wherein the nucleophilic reaction product is a stereoselective product.
(10) The method according to any one of the above (1) to (9), wherein the syn form is twice or more of the anti form.
(11) Hydrolyzing or reductively hydrolyzing the sulfonyl imidate part of the amine compound represented by the general formula (3) produced by the method according to any one of (1) to (10), and correspondingly A method for producing an ester, amide, or aldehyde.

The present invention provides a method for stereoselectively producing a syn isomer using an inexpensive and highly safe alkaline earth metal catalyst. The method of the present invention can produce a syn form enantioselectively in a high yield under mild reaction conditions.
Further, by hydrolyzing or reductively hydrolyzing the sulfonyl imidate moiety of the syn amine compound represented by the general formula (3) produced by the method of the present invention, the corresponding amino ester, amino acid, or amino Aldehydes and the like can be easily and enantioselectively produced under mild reaction conditions.

As R < ¹ > and R < ³ > of General formula (1) and R < ⁵ > of General formula (2) of this invention, it is C1-C20, Preferably it is C1-C10, C1-C5 Or a linear or branched alkyl group. Examples of such alkyl groups include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, An octyl group, and the like. R ^{1 in the} general formula (1) is preferably a linear or branched alkyl group having 1 to 5 carbon atoms, specifically an i-propyl group. Preferable R ^{3 in the} general formula (1) includes a linear or branched alkyl group having 1 to 5 carbon atoms, and specifically includes a methyl group and an ethyl group. R ^{5 in the} general formula (2) is preferably a linear or branched alkyl group having 1 to 5 carbon atoms, specifically, a t-butyl group.
These alkyl groups may be substituted with various functional groups that do not adversely affect the nucleophilic reaction. Examples of such substituents include hydrocarbon groups such as alkenyl groups, cycloalkyl groups, and aryl groups, halogen atoms such as chlorine atoms, hydroxyl groups, nitro groups, 1 to 4 nitrogen atoms, oxygen atoms, or Heterocyclic group having a 3- to 8-membered ring containing a hetero atom consisting of a sulfur atom, an alkoxy group having 1 to 20 carbon atoms, an alkylcarbonyloxy group having 2 to 21 carbon atoms, and an aryl-carbonyl having 7 to 37 carbon atoms Oxy group, aralkylcarbonyloxy group having 8 to 41 carbon atoms, alkoxycarbonyl group having 2 to 21 carbon atoms, aryloxycarbonyl group having 7 to 37 carbon atoms, aralkyloxycarbonyl group having 8 to 41 carbon atoms, substituted or unsubstituted Examples thereof include, but are not limited to, amino groups and alkylsilyl groups.

The aryl group of R ^{2 in} the general formula (1) of the present invention is a monocyclic, polycyclic, or condensed cyclic group having 6 to 36 carbon atoms, preferably 6 to 18 carbon atoms, or 6 to 12 carbon atoms. A carbocyclic aromatic group is mentioned. Examples of such an aryl group include a phenyl group, a naphthyl group, a biphenyl group, a phenanthryl group, and an anthryl group. A preferable aryl group includes a phenyl group.
The aryl group of R ^{2 in} the general formula (1) is preferably substituted with an electron withdrawing group. Examples of such an electron withdrawing group include a nitro group, a trifluoromethyl group, and a carboxyl group. The substitution position is preferably the ortho position or the para position. Preferred electron withdrawing groups include nitro groups. Examples of the aryl group having a preferable electron withdrawing group for R ² include a p-nitrophenyl group.

Examples of the hydrocarbon group for R ⁴ in the general formula (2) of the present invention include saturated or unsaturated hydrocarbon groups such as an alkyl group, an alkenyl group, a cycloalkyl group, an aryl group, an aralkyl group, and an arylalkenyl group. .
Examples of the alkyl group include linear or branched alkyl groups having 1 to 20 carbon atoms, preferably 1 to 15 carbon atoms and 1 to 10 carbon atoms. Examples of such alkyl groups include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, An octyl group, and the like.
Examples of the alkenyl group include linear or branched alkenyl groups having 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms and 2 to 10 carbon atoms. Examples of such alkenyl groups include vinyl, 1-methyl-vinyl, 2-methyl-vinyl, n-2-propenyl, 1,2-dimethyl-vinyl, 1-methyl-propenyl, Examples include 2-methyl-propenyl group, n-1-butenyl group, n-2-butenyl group, n-3-butenyl group and the like.
Examples of the cycloalkyl group include saturated or unsaturated monocyclic, polycyclic or condensed cyclic alicyclic hydrocarbon groups having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms. Examples of such a cycloalkyl group include a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cyclooctyl group, a bicyclo [1.1.0] butyl group, a tricyclo [2.2.1.0] heptyl group, and a bicyclo group. [3.2.1] Octyl group, bicyclo [2.2.2. Octyl group, adamantyl group (tricyclo [3.3.1.1] decanyl group), bicyclo [4.3.2] undecanyl group, tricyclo [5.3.1.1] dodecanyl group, and the like.

Examples of the aryl group include monocyclic, polycyclic, or condensed cyclic carbocyclic aromatic groups having 6 to 36 carbon atoms, preferably 6 to 18 carbon atoms and 6 to 12 carbon atoms. Examples of such an aryl group include a phenyl group, a naphthyl group, a biphenyl group, a phenanthryl group, and an anthryl group.
As the aralkyl group, a monocyclic, polycyclic or condensed cyclic carbocyclic aromatic group (aryl group) having 6 to 36 carbon atoms, preferably 6 to 18 carbon atoms and 6 to 12 carbon atoms, Examples thereof include aralkyl groups (carbocyclic araliphatic groups) having 7 to 40 carbon atoms, preferably 7 to 20 carbon atoms, and 7 to 15 carbon atoms, to which the above-described alkyl group having 1 to 20 carbon atoms is bonded. Examples of such a group include a benzyl group, a phenethyl group, and an α-naphthyl-methyl group.
The arylalkenyl group is a monocyclic, polycyclic or condensed cyclic carbocyclic aromatic group (aryl group) having 6 to 36 carbon atoms, preferably 6 to 18 carbon atoms and 6 to 12 carbon atoms. And an arylalkenyl group having 8 to 40 carbon atoms, preferably 8 to 20 carbon atoms, and 8 to 15 carbon atoms, to which the above alkenyl group having 2 to 20 carbon atoms is bonded. Examples of such a group include a styryl group, 2-naphthyl-vinyl group and the like. In addition, the hydrocarbon group in the present invention is within the above-described hydrocarbon group within a range that does not adversely affect the nucleophilic reaction. One or two or more carbon atoms may be substituted with a different atom such as a nitrogen atom, an oxygen atom, or a sulfur atom.
As the heterocyclic group in R ⁴ of the general formula (2) of the present invention, a hetero atom composed of 1 to 4, preferably 1 to 3, or 1 to 2 nitrogen atoms, oxygen atoms, or sulfur atoms. Examples thereof include a monocyclic, polycyclic, or condensed cyclic heterocyclic group having a 3- to 8-membered, preferably 5- to 8-membered ring. Examples of such a heterocyclic group include a 2-furyl group, a 2-thienyl group, a 2-pyrrolyl group, a 2-pyridyl group, a 2-indole group, and a benzoimidazolyl group.

  Moreover, the above-mentioned hydrocarbon group and heterocyclic group may be substituted with various functional groups that do not adversely affect the nucleophilic reaction. Examples of such a substituent include, for example, the above-described alkyl group, the above-described alkenyl group, the above-described cycloalkyl group, the above-described aryl group, the above-described aralkyl group, a halogen atom such as a chlorine atom, a hydroxyl group, A nitro group, a heterocyclic group having a 3- to 8-membered ring containing a hetero atom composed of 1 to 4 nitrogen atoms, oxygen atoms or sulfur atoms, an alkoxy group having 1 to 20 carbon atoms, and 2 to 2 carbon atoms 21 alkylcarbonyloxy groups, C7-37 aryl-carbonyloxy groups, C8-41 aralkylcarbonyloxy groups, C2-21 alkoxycarbonyl groups, C7-37 aryloxycarbonyl groups Aralkyloxycarbonyl groups having 8 to 41 carbon atoms, substituted or unsubstituted amino groups, alkylsilyl groups, and the like. That, without being limited thereto.

Preferred examples of the hydrocarbon group or heterocyclic group for R ⁴ in the general formula (2) include an alkyl group, an aryl group, a vinyl group, a furyl group, a thienyl group, and a pyridyl group. A phenyl group, p-fluorophenyl group, m-methylphenyl group, o-methylphenyl group, m-vinylphenyl group, cyclopropyl group, 2-furyl group, 2-thienyl group, 2-pyridyl group and the like can be mentioned.

The method of the present invention is characterized in that an alkaline earth metal compound is used as a catalyst and a nonpolar solvent is used as a solvent.
Examples of the alkaline earth metal of the alkaline earth metal compound used as the catalyst include calcium, magnesium, barium and strontium. Preferred alkaline earth metals include calcium, barium, and strontium.
Alkaline earth metal compounds include, but are not limited to, amidates such as alkoxides and disilazanes. Examples of the alkoxide include linear or branched alkoxy groups having 1 to 20 carbon atoms, preferably 1 to 15 carbon atoms, 1 to 10 carbon atoms, and more preferably 1 to 5 carbon atoms. Examples of such alkoxy groups include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, pentoxy group and the like. Preferred alkoxy groups include i-propoxy groups. As the amidated product, an amidated product of silazane having a Si—N bond can be mentioned. A preferred disilazane is hexamethyldisilazane.
Preferred alkaline earth metal _{compound, Ca (O-i-Pr} ) 2, Ba (O-i-Pr) 2, Sr (O-i-Pr) 2, etc. Sr _{(HMDS) 2} and the like. HMDS represents a hexamethyldisilazide group.
The amount of the alkaline earth metal compound used is not particularly limited, but it is one of the features of the method of the present invention that it is not necessary to use an equal amount as in the conventional method. A preferable addition amount of the alkaline earth metal compound is about 0.01 to 20 mol%, more preferably about 1 to 15 mol% with respect to the sulfonyl imidate represented by the general formula (1).

  As the solvent in the method of the present invention, a polar solvent such as DMF is not preferable, and a nonpolar solvent such as THF (tetrahydrofuran) is preferable. More preferred solvents include ether solvents having an ether bond such as THF, cyclopentyl methyl ether, diethyl ether and the like. Also, DCM (dichloromethane) and halogenated hydrocarbons and hydrocarbons of toluene are not preferable as the solvent in the method of the present invention.

A further preferred embodiment of the present invention includes a method carried out in the presence of a ligand comprising a nitrogen-containing compound. Examples of the nitrogen-containing compound include nitrogen-containing heterocyclic compounds such as benzoxazole, diamines such as ethylenediamine derivatives, and sulfonamide derivatives thereof. Preferred ligands include compounds represented by the above formula (4) and compounds represented by the formula (5). Such a ligand may have asymmetry, but may not have it, but preferred ligands include asymmetric ligands.
Such a ligand includes an equivalent amount to 5 times, preferably an equivalent amount to about 2 times the amount of the alkaline earth metal compound used as a catalyst.
Furthermore, the method of the present invention can be carried out by adding a tertiary amine such as triethylamine.

The process of the present invention can also be carried out in the presence of molecular sieves (preferably 4 angstroms). Preferably, it can be carried out in the presence of 4 angstrom molecular sieve (MS4A).
In the method of the present invention, the imine compound represented by the general formula (2) can be carried out in an equivalent amount with respect to the sulfonyl imidate represented by the general formula (1), preferably 0.8. It can be carried out with ˜2 equivalents and 0.9 to 1.5 equivalents.
The reaction temperature is not particularly limited and can be selected in the range from −45 ° C. to the boiling point of the solvent. A preferable reaction temperature is 0 to room temperature. In many cases, the process of the present invention can be carried out at room temperature. Although reaction time can be selected suitably, about 10-80 hours are mentioned when reaction temperature is low. In the case of a reaction at room temperature, it can be about 10 to 50 hours.
The product produced by the method of the present invention can be appropriately purified by a purification means such as chromatography.

The product of the reaction from the sulfonyl imidate represented by the general formula (1) and the imine compound represented by the general formula (2) has an asymmetric carbon at the β-position of the sulfonyl imidate moiety, and an anti form and a syn form. Exists. The method of the present invention proceeds stereoselectively and can produce a syn form stereoselectively.
It was confirmed by X-ray diffraction that the main product produced by the method of the present invention was a sine.

The product produced by the method of the present invention has a sulfonyl imidate moiety (—C (OR ¹ ) ═NSO ₂ R ² ), and this moiety is decomposed by a known method to produce N-sulfonyl It can be derived into amides, esters, aldehydes and the like.
_{^{-C (OR 1) = NSO 2}} R 2 → -CO-NH-SO 2 R 2
-C (OR ¹ ) = NSO ₂ R ² → -COOR ¹
-C (OR ¹ ) = NSO ₂ R ² → -CHO
In the case of N-sulfonylamide, the product according to the method of the present invention can be produced by hydrolysis in the presence of an acid such as sulfuric acid in a hydrous alcohol (for example, i-Pr alcohol). .
In the case of an ester, the product of the method of the present invention can be produced by hydrolysis in the presence of an acid or a base.
An aldehyde can be produced by reacting in the presence of a reducing agent such as diisobutylaluminum hydride.
The N-sulfonylamide, ester, and aldehyde thus produced have a nitrogen atom or carbon atom introduced by the method of the present invention at the β-position, and can be a β-amino acid derivative, Industrially useful compounds can be easily produced by the method of the present invention. Furthermore, as described above, since the method of the present invention can be performed stereoselectively, a syn isomer can be selectively produced.

EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited at all by these Examples.
¹ H-NMR and ¹³ C-NMR use JEOL JNM-ECX-400, JNM-ECX-500, or JNM-ECX-600 with CDCl ₃ as the solvent (indicated separately when other solvents are used) , Tetramethylsilane (δ = 0, ¹ H-NMR) or CDCl ₃ (δ = 77.0, ¹³ C-NMR) was measured as an internal standard substance.
JASCO FT / IR-610 was used for IR spectrum measurement, and JASCO P-1010 was used for optical rotation measurement. Silica gel 60 (Merck) was used for column chromatography, and Wakogel B-5F was used for preparative thin layer chromatography. All the reactions were carried out under an argon atmosphere, and the solvent used was distilled according to a conventional method.
Moreover, the sulfonyl imidate was synthesize | combined according to the method of the following literature 1-3.
1. Kupfer, R .; Nagel, M .; Wurthwein, E.-U .; Allmann, R. Chem. Ber. 1985, 118, 3089.
2. Matsubara, R .; Berthiol, F .; Kobayashi, SJ Am. Chem. Soc. 2008, 130, 1804.
3. Matsubara, R .; Kobayashi, S. Synthesis 2008, 3009.

  Examples 1 to 10 were performed according to the following reaction formula using various catalysts.

The raw material sulfonyl imidate was produced by the following method.
Production of sulfonyl imidate

Triethylamine (8.3 mL, 59.55 mmol) was added dropwise at room temperature to a solution of imidate hydrochloride A represented by To the resulting suspension was added paranitrobenzenesulfonyl chloride (4.4 g, 19.85 mmol) and dimethylaminopyridine (242.5 mg, 1.985 mmol). After stirring for 40 hours, the reaction solution was poured into water and extracted with methylene chloride. The obtained organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain a crude reaction product. After purification by silica gel chromatography, 6 g of sulfonylimidate was obtained (5.23 g, yield 88%).

In a container containing 4 angstrom molecular sieve (hereinafter referred to as MS4A) (50 mg) and calcium isopropoxide (10 mol%), a solution of imine (0.45 mmol) in THF (0.6 mL) and sulfonyl imidate ( 0.3 mmol) was added. The reaction mixture was stirred at room temperature for 48 hours, and then ethyl acetate (5 mL) was added to dilute the reaction solution. MS4A was filtered off, saturated aqueous ammonium chloride solution (5 mL) was added, the organic layer was separated, the organic layer was dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to obtain a reaction crude product. Diastereoselectivity was determined by ¹ H-NMR of the reaction crude product. The crude product was purified by silica gel chromatography to obtain the product.

  It replaced with the calcium isopropoxide in Example 1, and carried out similarly to Example 1 using strontium isopropoxide.

  It replaced with the calcium isopropoxide in Example 1, and carried out similarly to Example 1 using barium isopropoxide.

Instead of calcium isopropoxide in Example 1, Sr (HMDS) ₂ was used in the same manner as Example 1 using (HMDS = hexamethyldisilazide). The reaction time was 18 hours.

  In the method described in Example 1, the following formula (4)

8.3 mg (0.033 mmol) was added as a ligand, and the same procedure as in Example 1 was performed.

  In Example 2, the same process as in Example 2 was performed, except that the compound represented by the formula (4) was added as a ligand in the same manner as in Example 5.

  In Example 3, the same procedure as in Example 5 was performed, except that the compound represented by the formula (4) was added as a ligand.

  In Example 4, the same process as in Example 4 was carried out, except that the compound represented by formula (4) was added as a ligand in the same manner as in Example 5. The reaction time was 24 hours.

  The reaction was conducted in the same manner as in Example 8 except that the reaction temperature was 0 ° C. and the reaction time was 48 hours.

  The reaction was conducted in the same manner as in Example 8 except that the reaction temperature was −20 ° C. and the reaction time was 72 hours.

  The results of Examples 1 to 10 are summarized in Table 1 below. Each column in Table 1 shows, from the left side, the number of the example, the type of catalyst used, the reaction time (hour), the yield (%), and the ratio of anti-form and syn-form.

From these results, it can be seen that the syn form is selectively produced by the method of the present invention. Moreover, it turns out that the selectivity of a syn isomer improves by adding a ligand (refer Examples 5-8). It can also be seen that even if the reaction temperature is changed, no significant change is observed (see Examples 9 and 10).
In order to show the action of the solvent and the action of the electron withdrawing group in the aryl group in the arylsulfonylamidate, comparative experiments of Comparative Examples 1 to 8 were performed according to the following reaction formula.

Comparative Example 1
In a container containing 4 angstrom molecular sieve (hereinafter referred to as MS4A) (50 mg) and calcium isopropoxide (10 mol%), a solution of imine (0.45 mmol) in DMF (0.6 mL) and sulfonyl imidate ( 0.3 mmol) was added. After the reaction mixture was stirred at room temperature for 17 hours, Et ₂ O (5 mL) was added to dilute the reaction. After MS4A was filtered off, the mother liquor was washed 3 times with water. The obtained organic layer was dried over anhydrous Na ₂ SO ₄ and then concentrated under reduced pressure to obtain a reaction crude product. Diastereoselectivity was determined by ¹ H-NMR of the reaction crude product. The crude product was purified by silica gel chromatography to obtain the product.

Comparative Example 2
It replaced with the calcium isopropoxide in the comparative example 1, and carried out similarly to the comparative example 1 using strontium isopropoxide.

Comparative Example 3
It replaced with the calcium isopropoxide in the comparative example 1, and it carried out similarly to the comparative example 1 using barium isopropoxide.

Comparative Example 4
It replaced with the calcium isopropoxide in the comparative example 1, and performed similarly to the comparative example 1 using magnesium isopropoxide.

Comparative Example 5
It replaced with the calcium isopropoxide in the comparative example 1, and performed similarly to the comparative example 1 using calcium t-butoxide.

Comparative Example 6
It replaced with the calcium isopropoxide in the comparative example 1, and performed similarly to the comparative example 1 using strontium t-butoxide.

Comparative Example 7
It replaced with the calcium isopropoxide in the comparative example 1, and carried out similarly to the comparative example 1 using barium t-butoxide.

Comparative Example 8
Instead of calcium isopropoxide in Comparative Example 1, magnesium t-butoxide was used, and p-nitrobenzenesulfonyl imidate was used instead of 2,5-xylylsulfonyl imidate as the sulfonyl imidate, as in Comparative Example 1. Went to.
These results are shown in Table 2 below.

  Thus, when DMF which is a polar solvent is used as the solvent, or when the substituent of the benzenesulfonyl group is not an electron withdrawing group, the anti product is the main product, not the syn product.

Comparative Example 9
It replaced with the calcium isopropoxide in Example 1, and carried out similarly to Example 1 using DBU (1,8-diazabicyclo [5.4.0] undec-7-ene). The reaction time was 24 hours.
As a result, the yield was 77%, but the ratio of anti-form / sin-form was 74/26, and the anti-form was the main product.
Next, an experiment using various imine compounds according to the following reaction formula was performed using reaction conditions A (Condition A) (comparative example) and reaction conditions B (Condition B) (examples) (however, the entries in Table 3). Except for 10).

(In this formula, R ¹ represents a group shown in the column of R ¹ in Table 3 below, R represents an ethyl group in entry 12 in Table 3, and in other cases represents a methyl group, Ar represents a reaction) (Condition A) (comparative example) indicates a 2,5-xylyl group, and reaction condition B (Condition B) (example) indicates a p-nitrophenyl group.
The results are shown in the column of Reaction Condition B (Condition B) in entry 1 of Table 3 below.

  The target syn-body 3 was produced according to the following reaction formula.

In a container containing MS4A (50 mg) and Sr [HMDS] ₂ (HMDS = hexamethyldisilazide) (12.3 mg, 10 mol%), ligand 4 (8.3 mg, 11 mol%), THF (0.3 mL) was added. ) Was added and stirred for 1 hour. Thereafter, a solution of sulfonylimidate 2 (90.1 mg, 0.3 mmol) and Boc imine 1 (92.3 mg, 0.45 mmol) in THF (0.3 mL) was added, and stirring was continued for 24 hours. Ethyl acetate (5 mL) was added to dilute the reaction solution, and saturated aqueous ammonium chloride solution (5 mL) was added. After an organic layer was obtained by a liquid separation operation, it was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain a reaction crude product. Diastereoselectivity was determined by ¹ HNMR of the reaction crude product (syn: anti = 97: 3). The crude product was purified by silica gel chromatography to give product 3 (148.6 mg, 98% yield).

Isopropyl 3- (tert-butoxycarbonylamino) -2-methyl-N- (4-nitrophenylsulfonyl) -3-phenylpropanimidate (syn):
Mp. 156-157 ° C .; ¹ H NMR (C ₆ D ₆ ) δ =
7.65-7.63 (d, 2H, J = 9.2 Hz), 7.55-7.53 (d, 2H, J = 9.2 Hz),
7.42-7.41 (d, 2H, J = 7.2 Hz), 7.15-7.11 (m, 2H),
7.00-6.98 (t, 1H, J = 7.2 Hz), 5.27-5.22 (t, 1H, J = 10.3 Hz),
4.46-4.42 (m, 1H), 4.22-4.17 (d, 1H, J = 10.3 Hz), 4.16-4.11 (m, 1H),
1.51-1.50 (d, 3H, J = 6.3 Hz), 1.39 (s, 9H),
0.73-0.72 (d, 3H, J = 6.3 Hz), 0.49-0.47 (d, 3H, J = 6.3 Hz);
¹³ C NMR (C ₆ D ₆ ) δ =
176.5, 155.3, 149.8, 147.7, 141.4, 128.9, 128.5, 128.3, 127.6, 123.9,
79.3, 72.6, 56.9, 45.1, 28.4, 20.6, 20.0, 16.2; IR (neat) 3367, 2982,
2942, 1715, 1698, 1582, 1531, 1455, 1349, 1305, 1160, 1081, 1010, 907,
855, 746, 701, 657, 607 cm ^-1 ;
HRMS (DART);
As C ₂₄ H ₃₂ N ₃ O ₇ S, calculated: [M + H] ⁺ 506.1960.
Found: 506.1959.
(98% yield, thin: anti = 93: 7)

The same operation as in Example 11 was performed using imine (R ¹ = p-methoxyphenyl group) instead of imine (R ¹ = phenyl group) in Example 11. The results are shown in the column of Reaction Condition B (Condition B) in entry 2 of Table 3 below.
Isopropyl 3- (tert-butoxycarbonylamino) -3- (4-methoxyphenyl) -2-methyl-N- (4-nitrophenylsulfonyl) propanimidate (syn):
Mp. 164-165 ° C; ₁ H NMR (C ₆ D ₆ ) δ =
7.68-7.66 (d, 2H, J = 9.2 Hz), 7.57-7.56 (d, 2H, J = 9.2 Hz),
7.37-7.35 (d, 2H, J = 8.9 Hz), 6.76-6.74 (d, 2H, J = 8.9 Hz),
5.23-5.18 (t, 1H, J = 10.3 Hz), 4.50-4.45 (m, 1H),
4.30-4.28 (d, 1H, J = 10.3 Hz), 4.18-4.12 (m, 1H), 3.23 (s, 3H),
1.55-1.53 (d, 3H, J = 6.9 Hz), 1.41 (s, 9H),
0.76-0.75 (d, 3H, J = 6.3 Hz), 0.56-0.55 (d, 3H, J = 6.3 Hz);
¹³ C NMR (C ₆ D ₆ ) δ = 176.8, 159.9, 155.6, 150.0, 148.0, 133.6, 129.3,
128.5, 128.4, 128.2, 127.9, 124.1, 114.4, 79.3, 72.6, 56.5, 54.9, 45.4,
28.6, 20.8, 20.4, 16.3; IR (neat) 3370, 3104, 2980, 2936, 2837, 1712,
1698, 1583, 1531, 1513, 1456, 1349, 1304, 1246, 1160, 1092, 1036, 1010,
983, 907, 879, 855, 833, 746 cm ₋₁ ;
HRMS (DART);
Calculated as C ₂₅ H ₃₄ N ₃ O ₈ S: [M + H] ⁺ 536.0206.
Actual value: 536.2042.
(99% yield, thin: anti = 95: 5)

The same operation as in Example 11 was performed using imine (R ¹ = p-fluorophenyl group) instead of imine (R ¹ = phenyl group) in Example 11. The results are shown in the column of Reaction Condition B (Condition B) in entry 3 of Table 3 below.
Isopropyl 3- (tert-butoxycarbonylamino) -3- (4-fluorophenyl) -2-methyl-N- (4-nitrophenylsulfonyl) propanimidate (syn):
Mp. 189-190 ° C .; ₁ H NMR (C ₆ D ₆ ) δ =
7.65-7.63 (d, 2H, J = 8.9 Hz), 7.56-7.53 (d, 2H, J = 8.9 Hz),
7.27-7.24 (m, 2H), 6.81-6.78 (t, 2H, J = 8.6 Hz),
5.17-5.13 (t, 1H, J = 9.8 Hz), 4.43-4.39 (m, 1H),
4.15-4.13 (d, 1H, J = 9.8 Hz), 4.05-3.99 (m ,, 1H),
1.47-1.46 (d, 3H, J = 6.3 Hz), 1.40 (s, 9H),
0.72-0.71 (d, 3H, J = 6.3 Hz), 0.47-0.45 (d, 3H, J = 6.3 Hz);
¹³ C NMR (C ₆ D ₆ ) δ =
176.7, 164.3, 162.3, 155.9, 150.5, 148.2, 137.6, 130.3, 129.1, 128.7,
128.5, 128.2, 124.5, 116.3, 116.1, 80.0, 73.2, 56.7, 45.7, 29.0, 21.1,
20.7, 16.4; IR (neat) 3366, 2981, 2834, 1698, 1599, 1583, 1532, 1510,
1456, 1349, 1302, 1225, 1159, 1091, 1011, 907, 85, 838,
746 cm ₋₁ ;
HRMS (DART);
As C ₂₄ H ₃₁ N ₃ O ₇ SF, calculated value: [M + H] ⁺ 524.1867.
Found: 524.1867.
(87% yield, thin: anti = 92: 8)

The same operation as in Example 11 was performed using imine (R ¹ = m-methylphenyl group) instead of imine (R ¹ = phenyl group) in Example 11. The results are shown in the column of Reaction Condition B (Condition B) in entry 4 of Table 3 below.
Isopropyl 3- (tert-butoxycarbonylamino) -2-methyl-N- (4-nitrophenylsulfonyl) -3-m-tolylpropanimidate (syn):
Mp. 143-144 ° C .; ¹ H NMR (C ₆ D ₆ ) δ =
7.66-7.63 (d, 2H, J = 8.9 Hz), 7.57-7.55 (d, 1H, J = 8.9 Hz),
7.27-7.23 (m, 2H), 7.09-7.06 (t, 1H, J = 7.6 Hz),
6.86-6.85 (d, 1H, J = 7.6 Hz), 5.24-5.20 (t, 1H, J = 10.3 Hz),
4.47-4.42 (m, 1H), 4.31-4.24 (m, 1H), 4.16-4.12 (m, 1H), 2.16 (s, 3H),
1.54-1.53 (d, 3H, J = 6.3 Hz), 1.40 (s, 9H),
0.74-0.73 (d, 3H, J = 6.3 Hz), 0.52-0.51 (d, 3H, J = 6.3 Hz);
¹³ C NMR (C ₆ D ₆ ) δ =
176.8, 155.7, 150.1, 148.2, 141.4, 138.7, 129.1, 128.7, 120.0, 125.5,
124.2, 79.5, 72.8, 52.2, 45.6, 28.8, 21.7, 20.9, 20.4, 16.4;
IR (neat) 3367, 2980, 2935, 1698, 1594, 1583, 1531, 1455, 1349, 1305,
1242, 1159, 1090, 1010, 938, 907, 855, 745, 705, 685 cm ⁻¹ ;
HRMS (DART);
As C ₂₅ H ₃₄ N ₃ O ₇ S, calculated: [M + H] ⁺ 520.2117.
Actual value: 520.2093.
(99% yield, thin: anti = 94: 6)

The same procedure as in Example 11 was performed using imine (R ¹ = o-methylphenyl group) in place of imine (R ¹ = phenyl group) in Example 11. The results are shown in the column of Reaction Condition B (Condition B) in entry 5 of Table 3 below.
Isopropyl 3- (tert-butoxycarbonylamino) -2-methyl-N- (4-nitrophenylsulfonyl) -3-o-tolylpropanimidate (syn):
Mp. 120-121 ° C .; ¹ H NMR (C ₆ D ₆ ) δ =
7.69-7.68 (d, 2H, J = 8.6 Hz), 7.61-7.60 (d, 1H, J = 7.8 Hz),
7.56-7.55 (d, 2H, J = 8.6 Hz), 7.23-7.20 (m, 1H),
6.98-6.95 (t, 1H, J = 7.8 Hz), 6.91-6.90 (d, 1H, J = 7.8 Hz),
5.45-5.41 (t, 1H, J = 10.3 Hz), 4.40-4.35 (m, 1H), 4.25-4.19 (m, 1H),
4.04-4.01 (d, 1H, J = 10.3 Hz), 2.47 (s, 3H),
1.67-1.66 (d, 3H, J = 6.9 Hz), 1.40 (s, 9H),
0.69-0.68 (d, 3H, J = 6.3 Hz), 0.33-0.31 (d, 3H, J = 6.3 Hz);
¹³ C NMR (C ₆ D ₆ ) δ =
176.8, 155.7, 150.0, 148.0, 140.0, 137.1, 131.0, 127.8, 127.1, 126.5,
124.1, 79.3, 72.5, 52.4, 45.3, 28.5, 20.8, 20.1, 19.8, 16.9;
IR (neat) 3369, 2979, 2933, 1714, 1699, 1594, 1583, 1531, 1456, 1349,
1304, 1159, 1089, 1011, 907, 855, 745, 657 cm ⁻¹ ;
HRMS (DART);
As C ₂₅ H ₃₄ N ₃ O ₇ S, calculated: [M + H] ⁺ 520.2117.
Actual value: 520.2099.
Chiral HPLC; Daicel Chiralcel OD-H; hexane / iPrOH = 9/1
flow rate = 0.3 mL / min:
tR = 24.6 min (Minor enantiomer obtained from (R, R) -ligand),
tR = 33.9 min (Major enantiomer obtained from (R, R) -ligand)
(Racemic reaction, 99% yield, syn: anti = 89: 11) (Asymmetric reaction, 85% yield, syn: anti = 83: 17, enantioselectivity of syn form 57% ee)

The same procedure as in Example 11 was performed using imine (R ¹ = m-vinylphenyl group) instead of imine (R ¹ = phenyl group) in Example 11. The results are shown in the column of Reaction Condition B (Condition B) in entry 6 of Table 3 below.
Isopropyl 3- (tert-butoxycarbonylamino) -2-methyl-N- (4-nitrophenylsulfonyl) -3- (3-vinylphenyl) propanimidate (syn):
Mp. 117-118 ° C .; ¹ H NMR (C ₆ D ₆ ) δ =
7.66-7.60 (m, 3H), 7.57-7.52 (m, 2H), 7.32-7.27 (m, 1H),
7.10-7.05 (m, 2H, 6.65 (dd, 1H, J = 10.8, 17.6 Hz),
5.84 (d, 1H, J = 17.6 Hz), 5.23 (t, 1H, J = 10.2 Hz),
5.16 (d, 1H, J = 10.2 Hz), 4.40 (quintet, 1H, J = 6.2 Hz),
4.25-4.10 (m, 2H), 1.55 (d, 3H, J = 6.2 Hz), 1.39 (s, 9H),
0.71 (d, 2H, J = 6.2 Hz), 0.50-0.42 (m, 3H);
¹³ C NMR (C ₆ D ₆ ) δ =
176.6, 155.6, 150.0, 147.9, 141.8, 138.6, 137.2, 129.3, 128.7, 128.5,
127.8, 126.4, 125.8, 124.1, 114. 7, 79.4, 72.7, 57.1, 28.6, 20.8, 20.2,
16.4;
IR (neat) 3734, 3367, 2980, 2938, 1717, 1698, 1594, 1582, 1531, 1455,
1349, 1304, 1159, 1090, 1010, 907, 855, 745, 684 cm ⁻¹ ;
HRMS (DART);
As C ₂₆ H ₃₄ N ₃ O ₇ S, calculated: [M + H] ⁺ 532.2117.
Found: 532.2093.
(90% yield, thin: anti = 93: 7)

The same procedure as in Example 11 was carried out using imine (R ¹ = 2-furyl group) instead of imine (R ¹ = phenyl group) in Example 11. The results are shown in the column of Reaction Condition B (Condition B) in entry 7 of Table 3 below.
Isopropyl 3- (tert-butoxycarbonylamino) -3- (furan-2-yl) -2-methyl-N- (4-nitrophenylsulfonyl) propanimidate (syn):
Mp. 110-111 ° C .; ¹ H NMR (C ₆ D ₆ ) δ =
7.75-7.72 (d, 2H, J = 9.2 Hz), 7.62-7.60 (d, 1H, J = 9.2 Hz),
6.99-6.98 (d, 1H, J = 2.9 Hz), 6.53-6.52 (d, 1H, J = 2.9 Hz),
6.02-6.01 (d, 1H, J = 2.9 Hz), 5.48-5.44 (t, 1H, J = 10.3 Hz),
4.61-4.56 (m, 1H), 4.23-4.21 (d, 2H, J = 10.3 Hz), 4.11-4.05 (m, 1H),
1.49-1.47 (d, 3H, J = 6.9 Hz), 1.40 (s, 9H),
0.76-0.74 (d, 3H, J = 6.3 Hz), 0.65-0.64 (d, 3H, J = 6.3 Hz);
¹³ C NMR (C ₆ D ₆ ) δ =
176.6, 155.6, 154.3, 150.1, 148.0, 142.3, 128.5, 127.9, 124.2, 110.7,
107.3, 100.5, 79.6, 72.9, 50.5, 44.4, 28.6, 20.7, 20.5, 15.7;
IR (neat) 3368, 3107, 2981, 1716, 1597, 1583, 1532, 1455, 1350, 1306,
1238, 1160, 1093, 1011, 945, 908, 884, 856, 746, 685 cm ⁻¹ ;
HRMS (DART);
As C ₂₂ H ₃₀ N ₃ O ₈ S, calculated: [M + H] ⁺ 496.1754.
Found: 496.1776.
(95% yield, thin: anti = 94: 6)

The same operation as in Example 11 was performed using imine (R ¹ = 2-thienyl group) instead of imine (R ¹ = phenyl group) in Example 11. The results are shown in the column of Reaction Condition B (Condition B) in entry 8 of Table 3 below.
Isopropyl 3- (tert-butoxycarbonylamino) -2-methyl-N- (4-nitrophenylsulfonyl) -3- (thiophen-2-yl) propanimidate (syn):
Mp. 126-128 ° C .; ¹ H NMR (C ₆ D ₆ ) δ =
7.71-7.69 (d, 2H, J = 8.6 Hz), 7.58-7.55 (d, 2H, J = 8.6 Hz),
7.32-7.31 (d, 1H, J = 2.3 Hz), 6.73-6.70 (m, 2H),
5.53-5.49 (t, 1H, J = 10.3 Hz), 4.54-4.49 (m, 1H), 4.17-4.08 (m, 2H),
1.50-1.49 (d, 3H, J = 6.9 Hz), 1.39 (s, 9H),
0.74-0.73 (d, 3H, J = 6.3 Hz), 0.58-0.57 (d, 3H, J = 6.3 Hz);
¹³ C NMR (C ₆ D ₆ ) δ =
176.5, 155.4, 150.1, 147.9, 144.7, 127.9, 127.3, 125.1, 124.1, 79.6,
72.9, 51.6, 45.9, 28.6, 20.7, 20.2, 16.3; IR (neat) 3373, 2981, 1714,
1697, 1594, 1582, 1531, 1349, 1306, 1159, 1092, 1010, 908, 855, 745,
657 cm ^-1 ;
HRMS (DART);
As C ₂₂ H ₃₀ N ₃ O ₇ S ₂ , the calculated value: [M + H] ⁺ 512.525.
Actual value: 512.1509.
(99% yield, thin: anti = 93: 7)

The same procedure as in Example 11 was performed using imine (R ¹ = 2-pyridyl group) instead of imine (R ¹ = phenyl group) in Example 11. The results are shown in the column of Reaction Condition B (Condition B) in entry 9 of Table 3 below.
Isopropyl 3- (tert-butoxycarbonylamino) -2-methyl-N- (4-nitrophenylsulfonyl) -3- (pyridin-3-yl) propanimidate (syn):
Mp. 175-177 ° C .; ¹ H NMR (C ₆ D ₆ ) δ =
8.91 (s, 1H), 8.42-8.41 (d, 1H, J = 4.0 Hz), 7.64-7.54 (m, 5H),
6.80 (brs, 1H), 5.19-5.15 (t, 1H, J = 10.3 Hz), 4.41-4.36 (m, 2H),
4.12-4.08 (m, 1H), 1.46-1.44 (d, 3H, J = 6.9 Hz), 1.37 (s, 9H),
0.70-0.68 (d, 3H, J = 6.3 Hz), 0.49-0.48 (d, 3H, J = 6.3 Hz);
¹³ C NMR (CDCl ₃ ) δ =
175.5, 155.0, 149.8, 149.2, 147.1, 135.8, 134.5, 127.9, 127.7, 127.5,
124.0, 123.5, 80.2, 73.3, 54.4, 44.6, 28.2, 20.8, 15.4;
IR (neat) 3364, 3213, 2981, 2928, 1712, 1597, 1583, 1531, 1349, 1305,
1160, 1091, 1010, 906, 855, 746, 715, 684 cm ⁻¹ ;
HRMS (DART);
Calculated as C ₂₃ H ₃₁ N ₄ O ₇ S: [M + H] ⁺ 507.1913.
Actual value: 507.1932.
(70% yield, thin: anti = 94: 6)

The same procedure as in Example 11 was performed using imine (R ¹ = cyclopropyl group) instead of imine (R ¹ = phenyl group) in Example 11. The results are shown in the column of Reaction Condition B (Condition B) in entry 11 of Table 3 below.
Isopropyl 3- (tert-butoxycarbonylamino) -3-cyclopropyl-2-methyl-N- (4-nitrophenylsulfonyl) propanimidate (syn):
Mp. 112-113 ° C .; ¹ H NMR (C ₆ D ₆ ) δ =
7.82-7.80 (d, 2H, J = 8.6 Hz), 7.65-7.62 (d, 2H, J = 8.6 Hz),
4.74-4.66 (m, 1H), 4.05-4.03 (d, 1H, J = 9.8 Hz), 3.84-3.80 (m, 1H),
3.62-3.57 (m, 1H), 1.43 (s, 9H), 1.25-1.24 (d, 3H, J = 6.9 Hz),
0.90-0.89 (d, 3H, J = 6.3), 0.84-0.82 (d, 3H, J = 6.3),
0.51-0.44 (m, 1H), 0.44-0.37 (m, 2H), 0.36-0.32 (m, 1H);
¹³ C NMR (C ₆ D ₆ ) δ =
177.7, 156.3, 150.2, 148.4, 128.8, 128.1, 124.3, 79.1, 73.0, 57.2,
46.6, 28.8, 21.1, 16.5, 15.1, 6.1, 3.2; IR (neat) 3382, 2981, 2933,
1715, 1698, 1582, 1531, 1456, 1349, 1302, 1251, 1159, 1093, 1013, 908,
855, 746, 685 cm ⁻¹ ;
HRMS (DART);
As C ₂₁ H ₃₂ N ₃ O ₇ S, calculated: [M + H] ⁺ 470.1961.
Actual value: 470.1960.
(99% yield, thin: anti = 85: 15)

The same operation as in Example 11 was carried out using imine (R ¹ = cyclohexyl group) instead of imine (R ¹ = phenyl group) in Example 11.
Isopropyl 3- (tert-butoxycarbonylamino) -3-cyclohexyl-2-methyl-N- (4-nitrophenylsulfonyl) propanimidate (syn):
Mp. 191-192 ° C .; ¹ H NMR (C ₆ D ₆ ) δ =
7.78 (d, 2H, J = 8.2 Hz), 7.59 (d, 2H, J = 8.9 Hz),
4.71 (quintet, 1H, J = 6.2 Hz), 4.20-4.27 (m, 1H),
3.94 (d, 1H, J = 11.0 Hz), 3.75-3.80 (m, 1H), 1.95 (d, 1H, J = 12.4 Hz),
1.78 (d, 1H, 13.7 Hz), 1.65-1.75 (m, 1H), 1.55 (d, 1H, J = 13.7 Hz),
1.45 (s, 9H, 1.32-1.40 (m, 1H), 1.26 (d, 3H, J = 6.9 Hz),
1.20-1.30 (m, 1H), 1.10-1.20 (m, 1H), 0.95-1.05 (m, 1H),
0.91 (d, 3H, J = 6.2 Hz), 0.87-0.90 (m, 1H), 0.82 (d, 3H, J = 6.2 Hz), 0.71-0.79 (m, 1H);
¹³ C NMR (C ₆ D ₆ ) δ =
178.2, 156.7, 150.4, 148.4, 129.2, 128.5, 128.3, 124.5, 79.3, 73.0,
59.0, 57.4, 43.2, 42.1, 31.9, 29.1, 27.6, 27.4, 27.2, 27.0, 21.2, 15.1;
IR (neat) 3389, 2977, 2928, 2847, 1715, 1698, 1578, 1531, 1455, 1349,
1301, 1159, 1093, 992, 908, 855, 746, 684, 658 cm ⁻¹ ;
HRMS (DART);
As C ₂₄ H ₃₈ N ₃ O ₇ S, calculated: [M + H] ⁺ 512.430.
Actual value: 512.422.
(82% yield, thin: anti = 84: 16)

It replaced with the sulfonyl imidate (R = methyl group) in Example 11, and carried out similarly to Example 11 using the sulfonyl imidate (R = ethyl group). The results are shown in the column of Reaction Condition B (Condition B) in entry 12 of Table 3 below.
Isopropyl 2-((tert-butoxycarbonylamino) (phenyl) methyl)-N- (4-nitrophenylsulfonyl) butanimidate (syn):
Mp. 156-157 ° C .; ¹ H NMR (C ₆ D ₆ ) δ =
7.60-7.54 (m, 4H), 7.40-7.38 (d, 2H, J = 7.7 Hz),
7.11-7.08 (t 2H, J = 7.7 Hz), 6.99-6.96 (t, 2H, J = 7.7 Hz),
5.34-5.30 (t, 1H, J = 9.7 Hz), 4.52-4.48 (m, 2H), 4.20-4.16 (m, 1H),
1.98 (brs, 1H), 1.78 (brs, 1H), 1.39 (s, 9H),
1.10-1.07 (t, 3H, J = 7.2 Hz), 0.79-0.78 (d, 3H, J = 6.3 Hz),
0.57-0.55 (d, 3H, J = 6.3 Hz);
¹³ C NMR (C ₆ D ₆ ) δ =
174.9, 155.3, 149.8, 147.8, 141.2, 128.8, 128.3, 127.6, 123.9, 79.4,
72.5, 56.2, 51.0, 28.4, 23.6, 20.9, 20.4, 11.4; IR (neat) 3373, 2977,
2938, 1712, 1698, 1597, 1583, 1531, 1456, 1364, 1349, 1305, 1254, 1160,
1088, 1013, 911, 855, 745, 701 cm ₋₁ ;
HRMS (DART);
As C ₂₅ H ₃₄ N ₃ O ₇ S, calculated: [M + H] ⁺ 520.2117.
Actual value: 520.2139.
(85% yield, thin: anti = 95: 5)

The same procedure as in Example 20 was carried out using 2 equivalents instead of 1.5 equivalents of the imine (R ¹ = cyclopropyl group) used in Example 20. The results are shown in the column of Reaction Condition B (Condition B) in entry 13 of Table 3 below.

  A comparative experiment in which the solvent was a polar solvent DMF and the sulfonyl imidate was 2,5-xylylsulfonyl imidate was conducted according to the above reaction formula.

Comparative Example 10
A solution of imine (0.45 mmol) in DMF (0.6 mL) and sulfonyl imidate (0.3 mmol) were added to a container containing MS4A (50 mg) and magnesium t-butoxide (10 mol%). After the reaction mixture was stirred at room temperature for 17 hours, Et ₂ O (5 mL) was added to dilute the reaction. After MS4A was filtered off, the mother liquor was washed 3 times with water. The obtained organic layer was dried over anhydrous Na ₂ SO ₄ and then concentrated under reduced pressure to obtain a reaction crude product. Diastereoselectivity was determined by ¹ H-NMR of the reaction crude product. The crude product was purified by silica gel chromatography to obtain the product.
The results are shown in the column of Reaction Condition A (Condition A) in entry 1 of Table 3 below.

Comparative Example 11
Instead of the imine in Comparative Example 10 ^{(R 1} = phenyl group), it was carried out in the same manner as in Comparative Example 10 using the imine ^(R 1 = p-methoxyphenyl group). The results are shown in the column of Reaction Condition A (Condition A) in entry 2 of Table 3 below.

Comparative Example 12
Instead of the imine in Comparative Example 10 ^{(R 1} = phenyl group), it was carried out in the same manner as in Comparative Example 10 using the imine ^(R 1 = p-fluorophenyl group). The results are shown in the column of Reaction Condition A (Condition A) in entry 3 of Table 3 below.

Comparative Example 13
Instead of the imine in Comparative Example 10 ^{(R 1} = phenyl group), it was carried out in the same manner as in Comparative Example 10 using the imine ^(R 1 = m-methylphenyl group). The results are shown in the column of Reaction Condition A (Condition A) in entry 4 of Table 3 below.

Comparative Example 14
Instead of the imine in Comparative Example 10 ^{(R 1} = phenyl group), it was carried out in the same manner as in Comparative Example 10 using the imine ^(R 1 = o-methylphenyl group). The results are shown in the column of Reaction Condition A (Condition A) in entry 5 of the following Table 3.

Comparative Example 15
Instead of the imine in Comparative Example 10 ^{(R 1} = phenyl group), it was carried out in the same manner as in Comparative Example 10 using the imine ^(R 1 = m-vinylphenyl group). The results are shown in the column of Reaction Condition A (Condition A) in entry 6 of Table 3 below.

Comparative Example 16
It replaced with the imine (R < ¹ > = phenyl group) in the comparative example 10, and performed similarly to the comparative example 10 using the imine (R < ¹ > = 2-furyl group). The results are shown in the column of Reaction Condition A (Condition A) in entry 7 of Table 3 below.

Comparative Example 17
The same procedure as in Comparative Example 10 was performed using imine (R ¹ = 2-thienyl group) instead of imine (R ¹ = phenyl group) in Comparative Example 10. The results are shown in the column of Reaction Condition A (Condition A) in entry 8 of Table 3 below.

Comparative Example 18
The same procedure as in Comparative Example 10 was performed using imine (R ¹ = 2-pyridyl group) instead of imine (R ¹ = phenyl group) in Comparative Example 10. The results are shown in the column of Reaction Condition A (Condition A) in entry 9 of Table 3 below.

Comparative Example 19
The same procedure as in Comparative Example 10 was performed using imine (R ¹ = cyclopropyl group) instead of imine (R ¹ = phenyl group) in Comparative Example 10. The results are shown in the column of reaction condition A (Condition A) in entry 11 of Table 3 below.

Comparative Example 20
It replaced with the sulfonyl imidate (R = methyl group) in the comparative example 10, and performed similarly to the comparative example 10 using the sulfonyl imidate (R = ethyl group). The results are shown in the column of Reaction Condition A (Condition A) in entry 12 of Table 3 below.

Comparative Example 21
The amount of imine (R ¹ = cyclopropyl group) used in Comparative Example 19 was changed to 1.5 equivalents and 2 equivalents. The imine Boc group was replaced with a tosyl group (Ts), and the same procedure as in Comparative Example 19 was performed. It was. The results are shown in the column of Reaction Condition A (Condition A) in entry 13 of Table 3 below.

Comparative Example 22
The same procedure as in Comparative Example 10 was performed, except that the Boc group of imine in Comparative Example 10 was replaced with a tosyl group (Ts). The results are shown in the column of reaction condition A (Condition A) in entry 10 of Table 3 below.
Isopropyl 2-methyl-3- (4-methylphenylsulfonamido)-N- (4-nitrophenylsulfonyl) -3-phenylpropanimidate (syn):
Mp. 159-160 ° C .; ¹ H NMR (C ₆ D ₆ ) δ =
7.99-7.97 (d, 2H, J = 9.2 Hz), 7.63-7.61 (d, 2H, J = 9.2 Hz),
7.38-7.36 (d, 2H, J = 8.0 Hz), 6.88-6.86 (d, 2H, J = 8.6 Hz),
6.79-6.71 (m, 4H), 6.44-6.42 (d, 2H, J = 8.6 Hz), 5.02-4.96 (m, 1H),
4.71-4.67 (t, 1H, J = 10.6 Hz), 4.21-4.15 (m, 1H), 1.74 (s, 3H),
1.46-1.45 (d, 3H, J = 6.3 Hz), 1.02-1.01 (d, 3H, J = 6.3 Hz),
0.89-0.86 (d, 3H, J = 6.3 Hz);
¹³ C NMR (CDCl ₃ ) δ =
177.1, 150.0, 147.0, 142.5, 137.7, 137.4, 128.9, 128.5, 128.0, 127.8,
127.1, 126.6, 124.2, 74.3, 61.7, 46.6, 29.7, 21.3, 21.1, 21.0, 14.7;
IR (neat) 3289, 2983, 2922, 2853, 1594, 1583, 1531, 1456, 1349, 1301,
1160, 1090, 1057, 977, 909, 855, 812, 747, 701 cm ⁻¹ ;
HRMS (DART);
As C ₂₆ H ₃₀ N ₃ O ₇ S ₂ , the calculated value: [M + H] ⁺ 560.1525.
Actual value: 560.1550.
(94% yield, thin: anti = 7: 93)

Comparative Example 23
The same procedure as in Example 11 was performed except that the Boc group of imine in Example 11 was replaced with a tosyl group (Ts). The results are shown in the column of Reaction Condition B (Condition B) in entry 10 of Table 3 below.
The results of Examples 11-22 and Comparative Examples 10-23 are summarized in Table 3 below.

Each column of Table 3 starts from the left, entry number, R ¹ group of imine, yield of reaction condition A (%), ratio of anti isomer / syn isomer of reaction condition A, yield of reaction condition B (%) The ratio of the anti isomer / syn isomer of reaction condition B is shown.
Also from this result, when DMF which is a polar solvent is used as a solvent (see reaction condition A), when there is no electron withdrawing group in the aryl group of arylsulfonylimidate (see reaction condition A), When the alkoxycarbonyl group is not bonded (see entry 10), the anti isomer is the main product, but in the case of the method of the present invention, it can be seen that the syn isomer is the main product.

  According to the following reaction formula, the reaction was carried out using the compound of formula (5) which is an asymmetric ligand.

To a container containing MS4A (50 mg), Sr (OiPr) ₂ (6.2 mg, 10 mol%) and ligand 5 (19.8 mg, 12 mol%), THF (0.8 mL) was added and stirred for 1 hour. Thereafter, paranitrobenzenesulfonylimidate (90.1 mg, 0.3 mmol), Boc imine derived from orthotolualdehyde (98.7 mg, 0.45 mmol), THF (0.2 mL), triethylamine (3.03 mg, 10 mol%) THF (0.05 mL) solution was added and stirring was continued at 20 ° C. for 48 hours. Ethyl acetate (5 mL) was added to dilute the reaction solution, and saturated aqueous ammonium chloride solution (5 mL) was added. After an organic layer was obtained by a liquid separation operation, it was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain a reaction crude product. Diastereoselectivity was determined by ₁ HNMR of the reaction crude product (syn: anti = 83: 17). The crude product was purified by silica gel chromatography to obtain the product (yield 85%, syn: anti = 83: 17). Enantioselectivity was determined to be 57% ee by HPLC.

  The present invention provides a novel method for easily and enantioselectively producing a syn isomer under mild reaction conditions, and the compound produced by the method of the present invention has functional groups such as an imidate group and an amino group. Therefore, it is useful as a novel synthesis method for compounds with a specific three-dimensional structure such as pharmaceuticals, agricultural chemicals and food additives having functional groups, and has industrial applicability. ing.

Claims (11)

The following general formula (1)
(Wherein, R ¹ represents an A alkyl group, R ² represents an aryl group having an electron withdrawing group, R ³ represents an A alkyl group.)
And the following general formula (2)
^{R 5 O-CO-N =} CH-R 4 (2)
(Wherein, R ⁴ represents a heterocyclic group which may have also substituted hydrocarbon group or a substituent having a substituent, R ⁵ is table the A alkyl group, R ⁴ has a substituent Substituents in the case of hydrocarbon groups or heterocyclic groups are alkyl groups, alkenyl groups, cycloalkyl groups, aryl groups, aralkyl groups, halogen atoms, hydroxyl groups, nitro groups, heterocyclic groups, alkoxy groups, alkylcarbonyloxy groups, aryls -Selected from the group consisting of a carbonyloxy group, an aralkylcarbonyloxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group, an amino group, and an alkylsilyl group .
In the presence of an alkaline earth metal catalyst in a nonpolar solvent, and the following general formula (3),
(In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as those shown in the general formulas (1) and (2).)
A method for selectively producing a syn isomer of an amine compound represented by the formula:   The method according to claim 1, wherein the reaction is carried out in the presence of a ligand having a nitrogen atom. The ligand is represented by the following formula (4)
Or the following formula (5)
The method according to claim 1 or 2, which is a nitrogen-containing compound represented by the formula:   The method according to claim 1, wherein the nonpolar solvent is THF. The method according to claim 1, wherein R ² in the general formula (1) is a p-nitrophenyl group.   The method according to claim 1, wherein the alkaline earth metal catalyst is an alkoxy alkaline earth metal or a disilazide alkaline earth metal.   The method according to claim 1, wherein the alkaline earth metal catalyst is calcium, barium, or strontium.   The method according to any one of claims 1 to 7, wherein the amount of the alkaline earth metal catalyst is 0.01 to 20 mol% with respect to the sulfonyl imidate represented by the general formula (1). The method according to claim 1, wherein the amine compound is a stereoselective product.   The method according to any one of claims 1 to 9, wherein the syn form is twice or more of the anti form.   The sulfonyl imidate part of the amine compound represented by the general formula (3) produced by the method according to any one of claims 1 to 10 is hydrolyzed or reductively hydrolyzed to obtain a corresponding ester, amide, or A method for producing aldehydes.