WO2010055376A1

WO2010055376A1 - Chiral amine-(sulphur) urea double functional catalyst and synthesis method and use thereof

Info

Publication number: WO2010055376A1
Application number: PCT/IB2009/006808
Authority: WO
Inventors: 陈芬儿; 熊非; 王苏西; 陈旭翔; 赵磊; 陈文学
Original assignee: 帝斯曼知识产权资产管理有限公司; 复旦大学
Priority date: 2008-09-12
Filing date: 2009-09-11
Publication date: 2010-05-20
Also published as: CN101362100A

Abstract

A chiral amino- (thio) carbamide dual function tructural formulas (S, R) or (R, S) wherein R¹ is hydrogen, a nitro group, alkylsulfonyl group, alkylsulfinyl group, cyano group, halogen or C₁-C₄ alkoxy group; R² and R³ are hydrogen, C₁-C₆ straight chain or branched alkyl groups, C₃-C₈ cycloalkyl groups, C₂-C₆ alkenyl groups, C₂-C₆ alkynyl groups, aralkyl groups or aralkenyl groups; R⁴ is a C₁-C₄ alkylsilyl group, arylsilyl group, aralkylsilyl group, C₁-C₆alkyl group, substituted alkyl group, aralkyl group, C₂-C₆ alkenyl group or C₂-C₆ alkynyl group; R⁵ is a C₃-C₈ cycloalkyl group, C₁-C₆ alkylsulfinyl group, heterocyclic group, aryl group or R⁶ or/and R⁷-substituted aryl group, where the said R⁶ or R⁷ substituent is a perfluoro C₁-C₄ alkyl group, C₁-C₄ alkoxy group, halogen, nitro group, alkyl-acyl group, alkylsulfonyl or alkylsulfinyl group; and X is sulfur or oxygen.

Description

Chiral amine-(thio)urea bifunctional catalyst and its synthesis method and application

The invention belongs to the field of organic chemistry, and particularly relates to a novel chiral amine-(thio)urea bifunctional catalyst and a synthesis method thereof and application thereof in asymmetric catalytic reaction. Background technique

Since the Jacobsen group reported for the first time the chiral thiourea-catalyzed asymmetric Strecker reaction, U. Am. Chem. Soc. 2000, 122, 2395), chiral (thio)urea derivatives with their high catalytic activity and extensive The advantages of the scope of application have attracted great interest from chemists in recent years. The chiral (thio)urea has a weak Bnpnsted acidity, and the transition state of the reaction can be stabilized by hydrogen bonding, thereby promoting the progress of the reaction. In 2003, the Takemoto group introduced a Lewis basic group in a chiral (thio)urea molecule to develop a chiral tertiary amine-(thio)urea bifunctional catalyst 1 derived from cyclohexanediamine (Am. Chem. Soc. 2003, 125, 12672), the catalyst can simultaneously activate nucleophilic and electrophilic reagents for more efficient stereo control, and exhibits many organic reactions such as asymmetric annich reaction, Michael addition, and Baylis-Hillman reaction. Efficient chiral induction. Since then, people have developed similar catalysts derived from chiral cinchona and chiral binaphthene 2 and 3 Org. Lett. 2005, 7, 1967; Org. Lett. 2005, 7, 4293 ), both have achieved very Good catalytic effect.

Chiral amine-(thio)urea bifunctional catalysts have been increasingly used for asymmetric anti-

1

Confirmation However, so far, the reported catalysts are still very limited, and some catalysts are cumbersome to synthesize, harsh in reaction conditions, high in cost, and difficult to apply in industry. Therefore, a kind of low-cost, easy-to-synthesize and high-efficiency development is developed. The novel chiral amine-(thio)urea bifunctional catalyst is the core of current research in this field. Summary of the invention

The technical problem to be solved by the present invention is to provide a novel chiral amine-(thio)urea bifunctional catalyst, which has the characteristics of low cost and high efficiency.

Another technical problem to be solved by the present invention is to provide a method for synthesizing the above chiral amine-(thio)urea bifunctional catalyst.

A further technical problem to be solved by the present invention is to provide the use of the above chiral amine-(thio)urea bifunctional catalyst in an asymmetric reaction.

The technical solution adopted by the present invention to solve the above technical problems is: A chiral amine-(thio)urea bifunctional catalyst, the catalyst has the following structural formula:

(S, R) (R, S) wherein R ¹ is hydrogen, nitro, alkylsulfonyl, alkylsulfinyl, cyano, halogen or a decyloxy group of CC ₄ ;

R ² , R ³ are hydrogen, d-C ₆ linear or branched fluorenyl, C ₃ -C ₈ cyclodecyl, QC ₆ alkenyl, C ₂ ~ alkynyl, aralkyl or aralkenyl;

Is a C alkylsilyl group, an arylsilyl group, an arylsilyl group, an alkyl group, an alkyl group, an aralkyl group, a C ₂ -C ₆ alkenyl group or a C ₂ -C ₆ alkynyl group;

R ⁵ is C ₃ -C ₈ cyclodecyl, CH ₆ fluorenylsulfinyl, heterocyclic, aryl or An aromatic group substituted with R ⁶ 3⁄4 / and R ⁷ wherein the R ⁶ or R ⁷ substituent is a perfluoro d-C ₄ 'alkyl group, a d a Q alkoxy group, a halogen, a nitro group, an alkane a acyl group, a decylsulfonyl group or a fluorenylsulfinyl group;

X is sulfur or oxygen.

The chiral amine-(thio)urea bifunctional catalyst of the present invention typically includes a compound of the following structural formula, but is not limited thereto.

(S. (S, R)-V (s, R)-vi For the synthesis of the above chiral amine-(thio)urea bifunctional catalyst, the steps are as follows:

(1) Using threo-aminopropanediol or ^/^-1 as a chiral source, the threo-compound-2 or (i, JiJ-2) is obtained by Leuckart-Wallach reaction. The reaction formula is:

OH OH

Wherein R ¹ is hydrogen, nitro, alkylsulfonyl, alkylsulfinyl, cyano, halogen or C,~C ₄ decyloxy:

R ² , ³ are hydrogen, CH: ₆ straight or branched alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, arylsulfonyl or aralene a base, wherein R ² and R ^{3 are the} same or different;

(2) Protecting the thiol of the threo compound -2 or (3⁄4/? 2 terminal) to give the threo compound S, S 3 or ^, ^-3, the reaction formula is:

Wherein R ⁴ is C C ₄ fluorenyl silicon, aryl silicon, aralkyl silicon, (: alkyl, substituted alkyl, aralkyl, C 2 -c ₆ alkenyl or CH : ₆ alkynyl;

(3) The hydroxy configuration of the threo compound 3⁄4S 3 or (R,H)-3 is reversed by the Mitsunobu reaction to obtain a erythro compound ruler -4 or (3⁄4 4 , the reaction formula is:

(4) The hydroxy group of the erythric compound ^, -4 or -4 is protected with a methylsulfonyl group, and with: S _N 2 nucleophilic substitution reaction of sodium nitride gives an azide compound f5, i^-5 or (3⁄4 -5, the reaction formula is:

(5) The azide compound 5 or 3⁄4 -5 is reduced with triphenylphosphine to obtain a diamine compound (S, R)-6 or (R, S)-6, and the reaction formula is:

(6) The diamine compound fS, -6 or ^ <S 6 is reacted with an equimolar ratio of iso(thio):ester to give a chiral amine-(thio)urea catalyst having a configuration of or 73⁄4;

Wherein R ⁵ is an _8- cycloalkyl group, a d-C ₆ alkylsulfinyl group, a heterocyclic group, an aryl group or an R ⁶ 3⁄4K- and R ⁷ -substituted aryl group, wherein the or R ⁷ substituent is a perfluorod to C4 alkyl group, c, ~c ₄ alkoxy group, halogen, nitro group, alkyl acyl group, decyl sulfonyl group or alkyl sulfinyl group;

X is sulfur or oxygen.

Based on the above scheme, in the step (3), based on the molar amount of the threo compound 3 or -3 at room temperature and inert gas, the S-type compound, -3 or (3⁄4 -3 and 1.5~) 2.5 times the molar amount of benzoic acid, 1 to 2 times the molar amount of diisopropyl azodicarboxylate and 1.5-2.5 times the molar amount of triphenylphosphine in the solvent Mitsunobu reaction, the reaction time is 5 to 10 hours, minus After removing the solvent by pressure, potassium carbonate and methanol were added to obtain a erythric compound S 4 or (S, i^4).

Specifically, the molar amount of benzoic acid may be 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1,

2.2, 2.3, 2.4 or 2.5 times;

The molar amount of diisopropyl azodicarboxylate may be 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2 times;

The molar amount of triphenylphosphine may be 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2,

2.3, 2.4 or 2.5 times;

The reaction time can be 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or 10 hours.

In the basestone of the above scheme, in step (4), at room temperature and under the protection of an inert gas, based on the molar amount of erythric acid compound-4, the erythric compound "foot-4 or ^ and 2 to 3 times A molar amount of triethylamine, 2-3 times the molar amount of methanesulfonyl chloride and catalysis The amount of 4-dimethylaminopyridine is reacted in a solvent to form a mesylate in 0 to 12 hours, and the mesylate is reacted in a solvent with 1.5 to 2.5 times the molar amount of sodium azide for 10 to 12 hours. Azide compound ί5; 5 or (3⁄4 -5.

Specifically, the molar amount of triethylamine may be 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6,

2.7, 2.8, 2.9 or; 3 times:

The molar amount of methanesulfonyl chloride can be 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7,

2.8, 2.9 or 3 times;

The reaction may form a mesylate at a time of 10, 10.5, 11, 11.5 or 12 hours: the molar amount of sodium azide may be 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2,

2.3, 2.4 or 2.5 times, the reaction time can be 10, 10.5, 11, 11.5 or 12 hours.

The inert gas described in the present invention is generally nitrogen gas, and may be argon gas or helium gas. Based on the above scheme, in step (5), at 50~60'C, based on the molar amount of azide (S, R)-5, the azide compound f3⁄4 ? 5 or fK, S 5 and

The 1-2 times molar amount of triphenylphosphine is reacted in a solvent for 10 to 12 hours to form a reduction product diamine compound J > -6 or -6.

Specifically, the molar amount of triphenylphosphine may be 1, 1.1, 1.2, 1.3, 1.4, 1.5,

1.6, 1.7, 1.8, 1.9 or 2 times, ·

The reaction time can be 10, 10.5, 11, 11.5 or 12 hours.

Based on the above scheme, in the step (6), the diamine compound -6 or

Based on the molar amount of -6, the diamine compound, -6 or -6 is reacted with 1 to 1.5 times the molar amount of the aryl iso(thio) cyanate for 4 to 10 hours to obtain a configuration of ^, or ^? , a chiral amine-(thio)urea catalyst.

Specifically, the molar amount of the aryl iso(thio) cyanate may be 1, 1.1, 1.2,

1.3, 1.4 1.5 times;

The reaction time can be 4, 5, 6, 7, 8, 9 or 10 hours. A series of chiral amine-thiourea (urea) compounds were synthesized by a six-step reaction such as Leuckart-Wallach reaction, (silicon) alkylation protection and Mitsunobu reaction using inexpensive threo aminopropanediol as a chiral source.

The following is a detailed description of the chiral amine-(thio)urea catalyst prepared by the configuration of the threo aminopropanediol as a chiral source, and the preparation process can be expressed by the following reaction formula:

Among them, step (1) and step (2) can be carried out according to literature reports Org. Lett 2002, 4, 3451; Angew. Chem. Int. Ed. 2003, 43, 216).

Step (3): under the protection of nitrogen at room temperature, using tetrahydrofuran as solvent, the sodium-based amino alcohol (S, S)-3 is first mixed with 2-fold molar amount of benzoic acid, 1.5 times molar amount of diisopropyl azodicarboxylate. The ester (DIAD) and the 2-fold molar amount of triphenylphosphine are subjected to a Mitsunobu reaction for a reaction time of 5 to 10 hours. The solvent is removed under reduced pressure, and then the red form is obtained by methanolysis with 2 times the molar amount of potassium carbonate. Amino alcohol (5>4.

Step (4): under the protection of nitrogen at room temperature, using methylene chloride as solvent, amino alcohol (5 -4 with 2.5 times molar amount of triethylamine, 2.5 times molar amount of methanesulfonyl chloride and catalytic amount of 4- The dimethylaminopyridine (DMAP) was reacted for 12 hours to form the corresponding mesylate. Then the above crude product was reacted with 2 times the molar amount of sodium azide at room temperature in DMF. In hours, azide 0S, i?)-5 is obtained.

Step (5): At 60 ° C, a mixture of tetrahydrofuran and water is used as a solvent, wherein the volume ratio of tetrahydrofuran to water is 4:1, azide (&)-5 and 1.5 times molar amount of triphenyl The phosphine reaction was carried out for 12 hours to form the reduced product diamine C3⁄4i?)-6.

Step (6): Nitrogen protection at room temperature, using dichloromethane as solvent, diamine compound 05^6 and 1.1 times molar ratio of aryl iso(thio) cyanate for 4 to 10 hours to obtain a chiral amine of configuration - (thio)urea catalyst.

(The chiral amine-(thio)urea catalyst of the R 5 configuration was prepared in the same manner as above using a threo-aminopropylene glycol as a chiral source.

For the application of the above chiral amine-(thio)urea bifunctional catalyst, in the asymmetric reaction, the asymmetric reaction is Mannich reaction, Michael reaction, Aldol reaction, Baylis-Hillman reaction, Michael-Aldol series reaction And desymmetrization reaction with cyclic anhydride.

Based on the above scheme, the molar ratio of the chiral amine-(thio)urea bifunctional catalyst to the catalytic target is 0.05 to 0.1:1.

Specifically, it can be 0.05, 0.06, 0.07, 0.08, 0.09, 0.1: 1.

Advantageous Effects of the Invention - Compared with the prior art, the present invention provides a novel structure of chiral amine-(thio)urea bifunctional catalysts which are simply reacted by an extremely inexpensive chiral source. It is prepared and exhibits high chiral induction ability in many asymmetric reactions. It is a kind of chiral (thio)urea catalyst with research potential and industrial value. detailed description

The present invention is further described below in conjunction with specific embodiments, but the scope of protection of the present invention is not limited thereto. A method for synthesizing a chiral amine-(thio)urea bifunctional catalyst comprises the following steps:

(I) Using a compound of the formula I as a chiral source, a (p-nitrophenyl)-2-dimethylamino-1,3-propanediol is obtained by a Leuckart-Wallach reaction, and the specific steps can be carried out according to literature reports ( Org. Lett. 2002, 4, 3451; Angew. Chem. Int. Ed. 2003, 43, 216).

The reaction formula is:

(S, S)-1 I (S, S)-2 I

(2) The hydroxyl group at the end of the compound ^^-2 is protected by silylation under the action of imidazole to obtain a threo compound (α<5,25)-1-(4-nitrophenyl)-2-dimethyl Amino-3-tert-butyldimethylsiloxy-1-propanol, the specific steps can be carried out according to methods reported in the literature (C. Lett. 2002, 4, 3451; Angew. Chem. Int. Ed. 2003, 43, 216) ₀

The reaction formula is:

(S, S)-2 I (S' ^s )" ^{3 1}

(3) The hydroxyl structure of the cyclic compound 5 25 -1-(4-nitrophenyl)-2-dimethylamino-3-tert-butyldimethylsiloxy-1-propanol by Mitsunobu reaction The type is inverted to obtain the erythric compound (1R, 25 1-(4-nitrophenyl)-2-dimethylamino-3-tert-butyldimethylsilyloxy-1-propanol. The specific steps are as follows: Under a nitrogen atmosphere, add 5.31 g (15 mmol) (lS, 2 -1-(4-nitrophenyl)-2-dimethylamino tert-butyldimethylsiloxane in a 100 mL dry three-necked flask. 1-propanol, 7.86 g (30 mmol) triphenylphosphine, 3.66 g (30 mmol) benzoic acid and 50 mL of tetrahydrofuran, cooled to 0 X, stirred for 10 min, then 4,55 g (22.5 mmol) diisopropyl azodicarboxylate was added dropwise. After the dropwise addition, the temperature was raised to room temperature and stirring was continued for 10 h. The reaction mixture was concentrated under reduced pressure. After the reaction was stopped, the solvent was evaporated to dryness, and water and dichloromethane (30 mL) were evaporated, and the organic phase was separated, and the aqueous phase was extracted several times with methylene chloride. The organic phase was combined and dried over anhydrous sodium sulfate. This was chromatographed on silica gel eluting elut elut elut [ a ] _D ²³ = -15.3 (c 1.0, CHC1 ₃ ): 'Η NMR (400 MHZ, CDC1 ₃ ) 6 8.15 (d, /= 8.8 Hz, 2H), 7.56 (d, J= 8.8 Hz, 2H) , 4.59 (d, J= 9.6 Hz, 1H), 3.63-3.60 (dd, J= 11 Hz, 3.2 Hz, 1H), 3.46-3.42 (dd, J= 11 Hz, 4.4 Hz, 1H), 2.45 (m , 7H), 0.83 (s, 9H), -0.07 (s, 6H); ¹³ C NMR (75 MHz, CDCI3) δ 150.2, 147.3, 128.0, 123.2, 71.3, 69.0, 57.1, 41.6, 25.6, 17.8, - 5.9 ppm; IR (neat) 3344, 2954, 2931, 2858, 1606, 1525, 1471, 1349, 1257, 1114, 1039, 946, 839, 777, 699; ESI-MS: 355 [M+H] ⁺

The reaction formula is:

(s, s z I (R, S I

(4) The hydroxyl group of the erythric compound (l?,2S)-l-(4-nitrophenyl)-2-dimethylamino-3-tert-butyldimethylsiloxy-1-propanol Protected with a methanesulfonyl group and subjected to S _N 2 nucleophilic substitution reaction with sodium azide to obtain an azide compound ( 5; 2 ΜΛ ^ dimethyl-1-(4-nitrophenyl 1 - azide-3) -tert-butyldimethylsilyloxy-2-propylamine, the specific steps are: 3.54 g (10 mmol) (7 ?, S l-(4-nitrobenzene) in a 100 mL dry three-necked flask under nitrogen protection Benzyl-2-methylamino-3-tert-butyl dimethyloxypropanol, 2.52 g (25 匪ol) triethylamine, 20 mg 4-dimethylaminopyridine (DMAP) and 50 mL Methyl chloride, cooled to 0 'C, then 2.87 g (25 mmol) of methanesulfonyl chloride was added dropwise, and the temperature was raised to room temperature. Stir for 12 h. After the completion of the reaction, 100 mL of a saturated aqueous solution of sodium hydrogencarbonate was added, and the organic phase was separated. The aqueous phase was extracted with dichloromethane. This crude product was dissolved in 20 mL of dimethylformamide, and 1.30 g (20 mmol) of sodium azide was added and stirred at room temperature for 12 h. After the end of the reaction, 100 mL of methylene chloride was added, and the organic phase was washed with water (5×50 mL). The yield was 65%.

[ a ] _D ²⁵ = 75.9 (c 1.5, CHC1 ₃ ); 'Η MR(400 MHZ, CDC1 ₃ ) δ 8.22 (d, J = 8.8 Hz, 2H), 7.53 (d, J- 8.8 Hz, 2H), 4.87 (d, J= 8.8 Hz, 1H), 3.74-3.71 (dd, J = 11 Hz, 3.2 Hz, 1H), 3.27-3.23 (dd, J= 11 Hz, 4.4 Hz, 1H), 2.77 (m, 1H), 2.47 (s, 6H), 0.88 (s, 9H), -0.02 (s, 6H); ¹³ C NMR (75 MHz, CDC1 ₃ ) δ 146.6, 145.0, 127.7, 122.6, 67.9, 63.0, 57.1, 41.1, 24.8, 17.0, -6.8; IR (neat) 2958, 2929, 2859, 2103, 1727, 1600, 1525, 1464, 1348, 1274, 1121, 1073, 1040, 837, 778, 743, 666, 462; ESI -MS: 380 [M+H] ⁺ reaction formula:

(R. S;-4 I (S, R)-5 I

(5) Azide compound, i? 5 or 3⁄4 -5 is reduced with triphenylphosphine to give the diamine compound C lS _f 2R -N ² , ^-dimethyl small (4-nitrophenyl) -3- tert-Butyldimethylsilyl-1,2-propanediamine, the specific steps are: 1.89 g (5 mmol) (1 & 2/ ^ _ dimethyl small ( ₄ _ nitro) in a 100 mL three-necked flask Phenyl) _1-azido-3-tert-butyldimethylsilyloxy-2-propylamine, 1.97 g (7.5 mmol) of triphenylphosphine, 40 mL of tetrahydrofuran and 10 mL of water, warmed to 60 ° C, After stirring for 12 h, tetrahydrofuran was removed under reduced pressure, and 50 mL of dichloromethane was added, and the organic phase was washed with water, dried over anhydrous sodium sulfate, and evaporated. Yield 95% [ a ] _D ²⁵ = -9.6 (c 1.6, CHC1 ₃ ); Ή NMR (400 MHz, CDC1 ₃ ) « 8.14 (d, J= 8.8 Hz, 2H), 7.59 (d, J- 8.8 Hz, 2H), 4.17 (d, 7= 10 Hz, IH ), 3.58-3.54 (dd, 7=11 Hz, 3.2 Hz, IH), 3.25-3.21 (dd, = 11 Hz, 4.4 Hz, IH), 2.52 (m, IH), 2.44 (s, 6H), 0.83 (s, 9H), -0.11 (s, 6H); ^{, 3} C MR (75 MHz, CDC1 ₃ ) δ 151.3, 146.1, 127.8, 122.3, 69.3, 56.8, 52.9, 40.8, 24.8, 16.9, -6.8; IR (neat) 3379, 3294, 2958, 2894, 2791, 1668, 1603, 1523, 1470, 1347, 1255, 1109, 1043, 938, 838, 777, 701; ESI-MS: 354.2 [M+H] ⁺ .

The reaction formula is:

(S, RJ-5 I (S, R)-6 I

(6) Diamine compound ( & 2 - ² , N ² -dimethyl small (4-nitrophenyl)-3-tert-butyldimethylsilyl-1,2-propanediamine and equimolar ratio Reaction of iso(thio)cyanate to give 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1& 2Λ)-1-(4-nitrophenyl) >2-di Methylamino-3-tert-butyldimethylsilyloxy-propyl) urea catalyst, the specific steps are: 353 mg (lmmol) (7 & dimethyl-1) in a 25 mL three-necked flask under nitrogen protection - nitrophenyl)-3-tert-butyldimethylsilyl-1,2-propanediamine and 10 mL of dichloromethane, then 298 mg (l.lmmol) 3,5-di (three) The fluoromethyl)phenyl isothiocyanate was stirred at room temperature for 5 h. After the reaction was completed, the solvent was evaporated evaporated evaporated. Yield 95% Mp73~75'C; [i] _D ²⁵ = -110 (c 1.0, CHCI3); 'Η NMR (400 MHz, CDC1 ₃ ) δ 8.15 (d, ·/= 8.8 Hz, 2H), 7.70 (s, 3H), 7.49 (d, J = 8.8 Hz, 2H), 5.21 (d, J = 10.4 Hz, IH), 3.78-3.74 (dd, J = 11.2 Hz, 2Hz, IH), 3.33-3.29 (dd, 7 = 11.2 Hz, 4.4 Hz, IH), 2.65 (m, IH), 2.36(s, 6ίί), 0.89(s, 9H ), -0.02(s, 6H); ^I3 C NMR (75 MHz, CDClj) δ 179.4, 146.0, 137.8, 132.1, 131.8, 127.8, 125.8, 123.1, 122.5, 120.4, 67,9, 55.8, 55.5, 40.3, 24.7, 17.0, -6.8; IR (KBr) 3418, 3236, 2932, 2859, 1607, 1523, 1471, 1348, 1278, 1177, 1136, 1109, 938, 849, 838 , 777, 701: 682, 418; ESI-MS: 625 [M+H] ⁺

The reaction formula is:

Application example 1

The chiral amine-thiourea (urea) bifunctional catalyst prepared by the above synthesis method is used in the asymmetric Mannich reaction:

Under a nitrogen atmosphere, add 77 mg (0.5 mmol) of cis-hexahydrophthalic anhydride, 16 mg (0.025 mmol) of catalyst (^)-I and 40 mL of methyl succinyl ether in a 100 mL reaction flask. Then, 80 mg (2.5 mol) of methanol was added dropwise and stirred at room temperature for 24 h. After the reaction was completed, the solvent was removed under reduced pressure, and then 5 mL of dichloromethane and 5 mL of saturated sodium carbonate were added, and the mixture was stirred for 5 min, the organic phase was discarded, and the aqueous phase was adjusted to pH 1-2 with 2N hydrochloric acid. The mixture was extracted several times, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the desired product as a half ester of 87 mg (yield 94%, ee value 95%).

The reaction formula is:

Application example 2

Chiral amine-thiourea (urea) bifunctional catalyst prepared by the above synthesis method Application of I in asymmetric Mannich reaction:

Under a nitrogen atmosphere, add 103 mg (0.5 mmol) of tert-butyl N-benzylidenecarbamate, 31 mg (0.05 mmol) of catalyst I and 20 mL of dichloromethane to a 50 mL reaction flask, and cool to -40 'C, 188 mg (2.5 mmol) of nitroethane was added dropwise, and stirring was continued for 48 h. After the reaction was completed, the solvent was removed under reduced pressure and purified by silica gel column chromatography to afford product 134 mg (yield 96%, ee value 93) %, dr value 87/13).

The reaction formula is -

Of course, it can also be applied in the asymmetric reaction described as Michael reaction, Aldol reaction, Baylis-Hillman reaction, Michael-Aldol series reaction and desymmetrization reaction of cyclic anhydride.

Claims

1. A chiral amine-(thio)urea bifunctional catalyst having the following structural formula:

(S, F (RS) wherein R' is hydrogen, nitro, decylsulfonyl, alkylsulfinyl, cyano, halogen or alkoxy of d~C ₄ ;

R ² , R ³ are hydrogen, ^Q straight or branched alkyl, Q cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, arylfluorenyl or aralkenyl;

! ^ is alkylsilyl, arylsilyl, aralkylsilyl, d~C ₆ fluorenyl, substituted alkyl, aralkyl, C ₂ -C ₆ alkenyl or C ₂ ~C alkynyl ;

R ⁵ is a C ₃ -C ₈ cycloalkyl group, a d-C ₆ alkylsulfinyl group, a heterocyclic group, an aryl group or an R ⁶ S 3⁄4/ and R ⁷ substituted aryl group, wherein the R ⁶ or R ^The substituent ⁷ is a perfluoro CH: ₄ alkyl group, a C _{4 4} decyloxy group, a halogen, a nitro group, an alkyl acyl group, an alkylsulfonyl group or a decylsulfinyl group;

X is sulfur or oxygen.

A method for synthesizing a chiral amine-(thio)urea bifunctional catalyst according to claim 1, which comprises the steps of:

(1) The threo compound ^ -2 or -2 is obtained by the Leuckart-Wallach reaction with threo-aminopropylene glycol -1 or as a chiral source. The reaction formula is:

Wherein R ¹ is hydrogen, nitro, alkylsulfonyl, alkylsulfinyl, cyano, halogen or alkoxy;

R ² , R ³ are hydrogen, C, up to ₆ straight or branched fluorenyl, C-C ₈ cyclodecyl, C ₂ -C ₆ alkenyl, C ₂ to ₆ alkynyl, aralkyl or An alkenyl group, wherein R ² and R ^{3 are the} same or different;

(2) Protecting the thiol of the S-type compound (S, S 2 or 3⁄4 2 to give a threo compound (3⁄4 -3 or (R, ^-3), the reaction formula is:

Wherein R ⁴ is CH ₄ fluorenyl silicon, aryl silicon, aralkylsilyl, C ₆ alkyl, substituted alkyl, aralkyl, C ₂ -C ₆ alkenyl or C ₂ ~C ₆ Alkynyl group

(3) The base structure of the cyclic compound (5, S-3 or (Κ, /ζ)-3 is inverted by Mitsunobu reaction to obtain a erythric compound, -4 or ^-4, and the reaction formula is:

(R, «)-3 (s, m-

(4) The erythric compound, -4 or /4, of the hydroxy group is protected with a methylsulfonyl group, and then subjected to S _N 2 nucleophilic substitution reaction with sodium azide to obtain an azide compound fS, /? 5 (R, S) -5, the reaction formula is:

(5) azide compound or ruler -5 is reduced with triphenylphosphine to obtain a diamine compound (S, R)-6 or -6;

(6) Diamine compound? 6 or fK, -6 is reacted with an equimolar ratio of iso(thio)cyanate to obtain a chiral amine-lip catalyzed by a formula of:

Wherein R ⁵ is 0: ₃ ~ < ₈ cycloalkyl, Cr^e fluorenylsulfinyl, heterocyclic, aryl or R ⁶ or/and R ⁷ substituted aryl, wherein The R ⁶ or R ⁷ substituent is perfluoro c, a c ₄ alkyl group, c, a ^ alkoxy group, a halogen, a nitro group, an alkyl acyl group, an alkyl sulfonyl group or an alkyl sulfinyl group;

X is sulfur or oxygen.

3. The method for synthesizing a chiral amine-(thio)urea bifunctional catalyst according to claim 2, wherein: in step (3), at room temperature and under inert gas protection, the erythric compound threo compound fS ^ 3 or the molar amount is based on the formula, the sodium compound 3⁄4 -3 or ^?, 3 and 1.5 to 2.5 times the molar amount of benzoic acid, 1 to 2 times the molar amount of diisopropyl azodicarboxylate and 1.5-2.5 A molar amount of triphenylphosphine is subjected to a Mitsunobu reaction in a solvent for a reaction time of 5 to 10 hours. After removing the solvent under reduced pressure, potassium carbonate and methanol are added to obtain a erythro compound 4 or, -4.

The method for synthesizing a chiral amine-(thio)urea bifunctional catalyst according to claim 2, wherein: in step (4), at room temperature and under inert gas, the erythric compound ^, -4 Or a molar amount of ^-4, erythric acid compound-4 or 4 and 2-3 times the molar amount of lanethylamine, 2 to 3 times the molar amount of formazan chlorin and a catalytic amount of 4-dimethylamino Pyridine is reacted in a solvent for 10 to 12 hours to form a mesylate. The mesylate is in a solvent. Reaction with 1.5 to 2.5 times the molar amount of sodium azide 1 (^12 hours, to obtain an azide compound (S, R)-S hetero-SJ-5 o

The method for synthesizing a chiral amine-(thio)urea bifunctional catalyst according to claim 2, wherein in the step (5), at 5 (60'C, an azide compound? 5 or ^- Based on the molar amount of 5, the azide compound fS, J? 5 or (K, S 5 and 1 to 2 times the molar amount of triphenylphosphine in the solvent for 10 to 12 hours to form a reduction product diamine compound ^ ^- 6 or (RS) -6.

The method for synthesizing a chiral amine-(thio)urea bifunctional catalyst according to claim 2, wherein: in the step (6), based on the molar amount of the diamine compound or -6, the diamine Compound, -6 or 3⁄4 -6 with 1 to 1.5 times the molar amount of aryl

The (thio)cyanate is reacted for 4 to 10 hours to obtain a chiral amine-(thio)urea catalyst having a configuration or a ruler.

7. The use of the chiral amine-(thio)urea bifunctional catalyst of claim 1 for use in an asymmetric reaction wherein the asymmetric reaction is a Mannich reaction, a Michael reaction, an Aldol reaction, and a Baylis-Hillman reaction. , Michael-Aldol series reaction and desymmetrization of cyclic anhydride.

8. The use of a chiral amine-(thio)urea bifunctional catalyst according to claim 7, characterized in that the molar ratio of the chiral amine-(thio)urea bifunctional catalyst to the catalytic object is from 0.05 to 0.1:1 .