A chiral primary amine catalyst with a C2 axisymmetric structure, its preparation method and application

Abstract

The application provides a chiral primary amine catalyst with a C2 axis symmetry structure and a preparation method and application thereof, and belongs to the technical field of organic synthesis and catalysis. The chiral primary amine catalyst comprises a structural general formula I or corresponding enantiomers, diastereoisomers, salts or mixtures thereof of the structural general formula I. The chiral primary amine catalyst with the C2 axis symmetry structure can be used to obtain a target product in an asymmetric Aldol reaction between alpha-branched aldehyde and glyoxylate in a high yield and high enantioselectivity, the catalyst type is enriched, the synthesis process is simple, and the catalyst can be practically applied to industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and catalysis technology, specifically relating to a chiral primary amine catalyst with a C2 axisymmetric structure, its preparation method, and its application. Background Technology

[0002] Chiral primary amine catalysts have proven to be a highly efficient class of organocatalysts, capable of catalyzing Aldol reactions, Mannichi reactions, Michael addition reactions, and others. Among these, the Aldol reaction is an important reaction for forming new carbon-carbon bonds, especially the asymmetric Aldol reaction between isobutyraldehyde and glyoxylate, which can synthesize optically active (R)-2-hydroxy-3,3-dimethyl-3-oxobutyrate, a direct synthetic precursor for vitamin B5 and pantothenic acid lactone, and has significant commercial value.

[0003] Mahrwald's research group has made significant contributions to this field. They discovered that natural amino acids can effectively catalyze the asymmetric Aldol reaction between isobutyraldehyde and ethyl glyoxylate. In particular, L-histidine can yield the target product (R)-2-hydroxy-3,3-dimethyl-3-oxobutyrate with 85% yield and 79% enantioselectivity (ee) under conditions of water and isopropanol as solvents and acetic acid as an additive. Subsequently, optically active (R)-pantolactone can be obtained by reduction. [K. Rohr, R. Mahrwald, Org. Lett. 2012, 14, 2180–2183; M. Markert, U. Scheffler, R. Mahrwald, J. Am. Chem. Soc. 2009, 131, 16642–16643; U. Scheffler, R. Mahrwald, J. Org. Chem. 2012, 7 7, 2310–2330. J. Org. Chem. 2015, 80, 3387–3396].

[0004] In 2020, the Sparr group designed a class of secondary amine ligands using proline and synthesized organometallic complexes by coordinating with metal Ir to catalyze the asymmetric Aldol reaction between α-branched aldehydes and glyoxylates. Hydrogen was then introduced to synthesize (R)-pantolactones and their analogues in a one-pot reaction. Although the process was simple, the reaction yield was low (78%) and the stereoselectivity was not ideal (86% enantioselectivity) [F. Bourgeois, JAMedlock, W. Bonrath, C. Sparr, Org. Lett. 2020, 22, 110–115].

[0005] In 2020, our research group designed and synthesized a series of tetrapeptide primary amine catalysts with β-turn secondary structures for the asymmetric cross-Aldol reaction between α-branched aldehydes and glyoxylates, used to synthesize highly optically active (R)-2-hydroxy-3,3-dimethyl-3-oxobutyrate and its analogues. The application potential of this method was verified in gram-scale reactions, achieving yields as high as 98% and ee values ​​as high as 99%. However, unfortunately, the tetrapeptide catalyst could not be recovered and recycled [Z.-H.Du,B.-X.Tao,M.Yuan,W.-J.Qin,Y.-L.Xu,P.Wang,C.-S.Da,Org.Lett.2020,22,4444-4450]. Subsequently, the inventors supported it on an amino-type resin, achieving catalyst recycling. It is worth noting that after loading the tetrapeptide catalyst, the reaction changed from a homogeneous system to a heterogeneous system. However, this change did not reduce the reaction yield and stereoselectivity [Patent Application No.: 202310824657.9].

[0006] In 2021, the inventors' research group developed a primary amine catalyst with a tertiary leucine skeleton for the asymmetric Aldol reaction between isobutyraldehyde and glyoxylate. With a catalyst dosage of 10 mol% and no additives, the reaction yield reached as high as 91%, and the ee value reached as high as 93%. Subsequently, the reaction was scaled up to 50 mmol, and the yield and ee value were almost unaffected. Subsequently, the obtained (R)-2-hydroxy-3,3-dimethyl-3-oxobutyrate ethyl ester was reduced with NaBH4 to obtain (R)-pantolactone with an ee value of 93%. After recrystallization, the ee value can be increased to 99% [Z.-H.Du,M.Yuan,B.-X.Tao,W.-J.Qin,X.-M.Liang,Y.-Y.Li,H.Lin,L.-C.Zhang,C.-S.Da,Asian J.Org.Chem.2021,10,1167–1162].

[0007] In summary, although some progress has been made in the asymmetric Cross-Aldol reaction between α-branched aldehydes and glyoxylates via asymmetric catalysis, there is still considerable room for further research. For example, the types of catalysts currently reported are relatively limited, and no catalyst method has yet been found that can be practically applied to industrial production. Therefore, developing a class of catalysts that are simple to synthesize and can be used to efficiently catalyze this type of reaction remains an important task in this field. Summary of the Invention

[0008] In view of this, the purpose of this invention is to provide a chiral primary amine catalyst with a C2 axisymmetric structure, its preparation method and application. The chiral primary amine catalyst with a C2 axisymmetric structure obtained by this invention can obtain the target product with high yield and high enantioselectivity in the asymmetric Aldol reaction between α-branched aldehydes and glyoxylates, enriching the types of catalysts, with a simple synthesis process, and can be practically applied to industrial production.

[0009] To achieve the above objectives, the present invention provides the following technical solution:

[0010] This invention provides a chiral primary amine catalyst having a C2 axisymmetric structure, comprising structural formula I or a corresponding enantiomer, diastereomer, salt or mixture thereof;

[0011]

[0012] In Formula I: R is any one of the following C1 to C6 straight-chain alkyl, branched alkyl, cycloalkyl, hydroxyl, hydroxy-substituted alkyl, mercapto-substituted alkyl, methylthio-substituted alkyl, amino-substituted alkyl, guanidinyl-substituted alkyl, aryl, substituted aryl, heteroatom aryl, substituted heteroatom aryl, arylmethyl, and substituted arylmethyl;

[0013] Diamine is any one of 1,2-ethylenediamine, 1,3-propanediamine, 2,2-dimethyl-1,3-propanediamine, 1,4-butanediamine, 1,5-pentanediamine, 3,3-dimethyl-1,5-pentanediamine, 1,6-hexanediamine, 1,7-heptanediamine, 4,4-dimethyl-1,7-heptanediamine, 1,8-octanediamine, 1,9-nonanediamine, 5,5-dimethyl-1,9-nonanediamine, and 1,10-decanediamine.

[0014] More preferably, R is any straight-chain alkyl, branched alkyl, cyclopentyl, cyclohexyl, hydroxyl, hydroxy-substituted alkyl, phenyl, benzyl, or C1-C6 alkyl group. Any one of them.

[0015] Preferably, the general formula I of the structure is as follows:

[0016]

[0017] Preferably, the structural formulas 1-16 are as follows:

[0018]

[0019]

[0020] Secondly, this invention provides a method for preparing the above-mentioned chiral primary amine catalyst, the synthetic route of which is as follows:

[0021] As shown in Equations 2 and 3:

[0022]

[0023] In Formulas 2 and 3, 17 is amino-protected proline, where P is any one of tert-butyloxyformyl, benzyloxyformyl, or fluorenyloxyformyl.

[0024] 18 is any one of 1,2-ethylenediamine, 1,3-propanediamine, 2,2-dimethyl-1,3-propanediamine, 1,4-butanediamine, 1,5-pentanediamine, 3,3-dimethyl-1,5-pentanediamine, 1,6-hexanediamine, 1,7-heptanediamine, 4,4-dimethyl-1,7-heptanediamine, 1,8-octanediamine, 1,9-nonanediamine, 5,5-dimethyl-1,9-nonanediamine, and 1,10-decanediamine;

[0025] 19 is the first intermediate;

[0026] 20 is the second intermediate;

[0027] 21 is an amino acid protected by an amino group, wherein R is any one of the following C1-C6 straight-chain alkyl, branched alkyl, cycloalkyl, hydroxyl, hydroxy-substituted alkyl, mercapto-substituted alkyl, methylthio-substituted alkyl, amino-substituted alkyl, guanidinyl-substituted alkyl, aryl, substituted aryl, heteroatom aryl, substituted heteroatom aryl, arylmethyl, and substituted arylmethyl;

[0028] 1' to 16' are third intermediates;

[0029] 1 to 16 are the target products of structural formulas 1 to 16 as described in claim 2;

[0030] The condensing reagent C1 or condensing reagent C2 can be independently: a combination of carbodiimide and 1-hydroxy-7-azabenzotriazole, a combination of carbodiimide and 1-hydroxybenzotriazole, or a combination of alkoxyformyl chloride R2OCOCl with triethylamine, diethylamine, diisopropylethylamine, morpholine, or N-methylmorpholine; and R2 can be any straight-chain alkyl or branched alkyl group from C1 to C4.

[0031] Solvents S1, S2, S3, and S4 are each independently one or more of dichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, ethyl acetate, N,N-dimethylformamide, acetonitrile, or propionitrile;

[0032] Deprotecting agent D1 and deprotecting agent D2 are each independently any one of methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, trichloroacetic acid, hydrochloric acid, sulfuric acid, piperidine, morpholine, tetrahydropyrrole, dihydropyrrole, pyrrole, diethylamine, dipropylamine, dibutylamine, diisopropylamine, or diisobutylamine.

[0033] More preferably, P is either tert-butyloxyformyl or benzyloxyformyl.

[0034] The condensing reagents C1 and C2 are each independently 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide and a combination of 1-hydroxy-7-azabenzotriazole or 1-hydroxybenzotriazole, or a combination of alkoxyformyl chloride R2OCOCl and triethylamine, diisopropylethylamine, N-methylmorpholine, and R2 is Et or i-Pr or i-Bu.

[0035] The solvents S1, S2, S3, and S4 are each independently any one of dichloromethane, tetrahydrofuran, and N,N-dimethylformamide;

[0036] The deprotecting agent D1 and deprotecting agent D2 are each independently either trifluoroacetic acid or hydrochloric acid.

[0037] More preferably,

[0038] P stands for Boc;

[0039] The condensing reagents C1 and C2 are each independently a combination of EDCI and HOBT;

[0040] The solvents S1, S2, S3 and S4 are independently dichloromethane;

[0041] The deprotecting agent D1 and deprotecting agent D2 are trifluoroacetic acid, which are independent of each other.

[0042] As a preferred option, the specific steps are as follows:

[0043] According to the synthetic route described in Formula 2, amino-protected proline 17, condensing agent C1, and diamine 18 were added to solvent S1 at room temperature for a first stirring reaction to obtain intermediate 19. Then, 19 and deprotecting agent D1 were added to solvent S2 for a second stirring reaction to obtain intermediate product 20.

[0044] Following the synthetic route described in Formula 3, product 20, amino-protected amino acid 21, and condensing agent C2 were added to solvent S3 at room temperature for a third stirring reaction to obtain products 1' to 16'. Then, products 1' to 16' and deprotecting agent D2 were added to solvent S4 for a fourth stirring reaction to obtain the target products 1 to 16.

[0045] Preferably, in the synthetic route described in Formula 2, the molar ratio of diamine 18, proline 17, and condensing agent C1 is 1:(2-5):(2-5);

[0046] The temperature of the first stirring reaction is 0–60℃, and the time is 4–72 h;

[0047] The molar ratio of intermediate 19 to deprotectant D1 is 1:(1-5);

[0048] The second stirring reaction temperature is 0–50℃, and the reaction time is 2–24 h.

[0049] Preferably, in the synthetic route described in Formula 3, the molar ratio of intermediate 20, amino-protected amino acid 21, and condensing agent C2 is 1:(2-5):(2-5);

[0050] The third stirring reaction temperature is 0–60℃, and the reaction time is 4–72 h;

[0051] The molar ratio of intermediates 1' to 16' and deprotectant D2 is 1:(1-5);

[0052] The fourth stirring reaction temperature is 0-50℃, and the reaction time is 2-24h.

[0053] Thirdly, the present invention provides the application of the above-mentioned chiral primary amine catalyst in the asymmetric Aldol reaction of α-branched aldehydes and glyoxylate esters.

[0054] Preferably, the asymmetric Aldol reaction between the α-branched aldehyde and glyoxylate is shown in Formula 4:

[0055]

[0056] In Equation 4: R 1 R 2 Each is independently selected from any one of alkyl, aryl, or arylmethyl; or -R 1 -R 2 - is cyclopentyl or cyclohexyl; R 3 It is any one of alkyl, aryl, or arylmethyl;

[0057] The primary amine catalyst is the chiral primary amine catalyst with a C2 axisymmetric structure obtained above;

[0058] Solvent S5 is any one or more of water, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, ethyl acetate, propyl acetate, toluene, chlorobenzene, bromobenzene, xylene, trimethylbenzene, diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, acetonitrile, propionitrile, methanol, ethanol, propanol, butanol, hexane, and pentane.

[0059] More preferably, the R 1 and R 2 Each is independently selected from methyl, ethyl, propyl, phenyl, or benzyl, R 3 It can be methyl, ethyl, propyl, butyl, or benzyl;

[0060] The primary amine catalyst is any one of 1a to 16d obtained above; more preferably, the primary amine catalyst is 8b and 8c obtained above.

[0061] The solvent S5 is any one or more of dichloromethane, chloroform, dichloroethane, ethyl acetate, tetrahydrofuran, acetonitrile, propionitrile, methanol, and ethanol; more preferably, the solvent S5 is acetonitrile.

[0062] Fourthly, the present invention provides an intermediate compound of the above-described general formula 1, wherein the intermediate compound is the first intermediate, the second intermediate, and the third intermediate described above.

[0063] It contains at least the following beneficial technical effects:

[0064] (1) The chiral primary amine catalyst with C2 axisymmetric structure obtained in this invention can obtain the target product with high yield and high enantioselectivity in the asymmetric Aldol reaction between α-branched aldehyde and glyoxylate. The reaction yield reaches 98% and the enantioselectivity reaches up to 99%, showing good application prospects.

[0065] (2) This invention enriches the types of catalysts, has a simple synthesis process, and can be practically applied to industrial production. Detailed Implementation

[0066] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0067] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Every smaller range between any stated value or intermediate value within a stated range, and any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0068] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0069] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be obvious to those skilled in the art. This application specification and embodiments are merely exemplary.

[0070] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0071] Unless otherwise specified, "room temperature" and "normal temperature" in this invention refer to 25±2℃.

[0072] Unless otherwise specified, all raw materials used in the following embodiments of the present invention are commercially available.

[0073] I. Preparation of chiral primary amine catalysts with C2 axisymmetric structure

[0074] The reaction process for preparing the chiral primary amine catalyst with a C2 axisymmetric structure shown in Formula 1 of this invention is as described in Formulas 2 and 3 above, and the preparation process is more detailed as follows:

[0075] (a) Synthesis of intermediates 19 and 20

[0076] Example 1: Synthesis of intermediate 19b

[0077]

[0078] Boc-L-Pro-OH 17a (9.46 g, 44 mmol), HOBT (5.97 g, 44 mmol), and EDCI (8.4 g, 44 mmol) were added to a 250 mL round-bottom three-necked flask. The flask was sealed and evacuated under nitrogen protection. 50 mL of dry CH2Cl2 was added and the mixture was stirred at 0 °C for 30 min. Then, 1,3-propanediamine 18b (1.7 mL, 20 mmol) and NMM (6.74 mL, 60 mmol) dissolved in CH2Cl2 were added. The mixture was stirred at room temperature for 48 h. The insoluble matter in the reaction system was then removed by filtration. The mixture was washed successively with 1 M NaOH, water, 1 M HCl (aq.), and saturated brine. The mixture was dried over anhydrous MgSO4, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 5:1 as the mobile phase) to obtain a white solid product 19b (9.08 g), with a yield of 97%.

[0079] By replacing Boc-L-Pro-OH 17a with Boc-D-Pro-OH ent-17a, ent-19b can be obtained using the method described above.

[0080] NMR data: 1 H NMR (400MHz, CDCl3-d) δ7.55(s,1H),6.73(s,1H),4.16(brd,2H),3.24(m,8H),2.18-1.50(m,8H),1.70-1.50(m,8H),1.38(s,18H).

[0081] Example 2: Synthesis of intermediate 19c

[0082]

[0083] Boc-L-Pro-OH 17a (9.46 g, 44 mmol), HOBT (5.97 g, 44 mmol), and EDCI (8.4 g, 44 mmol) were added to a 250 mL round-bottom three-necked flask. The flask was sealed and evacuated under nitrogen protection. 50 mL of dry CH2Cl2 was added and the mixture was stirred at 0 °C for 30 min. Then, 2,2-dimethyl-1,3-propanediamine 18c (2.4 mL, 20 mmol) and NMM (6.74 mL, 60 mmol) dissolved in CH2Cl2 were added. The mixture was stirred at room temperature for 48 h. The insoluble matter in the reaction system was then removed by filtration. The mixture was washed successively with 1 M NaOH, water, 1 M HCl (aq.), and saturated brine. The mixture was dried over anhydrous MgSO4, concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 5:1 as the mobile phase) to obtain a white solid product 19b (9.91 g), with a yield of 98%.

[0084] By replacing 17a with Boc-D-Pro-OH ent-17a using the method described above, its enantiomer ent-19c can be obtained.

[0085] NMR data: 1 H NMR (400MHz, CDCl3-d) δ7.40 (s, 1H), 7.18 (s, 1H), 4.13 (d, J = 18.8Hz, 2H), 3.6 0-3.15(m,4H),2.85(brd,4H),2.19-1.67(m,8H),1.33(s,18H),0.75(s,6H).

[0086] Example 3: Synthesis of intermediate 20b

[0087]

[0088] The obtained compound 19b (7.02 g, 15 mmol) was dissolved in dry dichloromethane (15 mL), and then trifluoroacetic acid (15 mL) was slowly added dropwise at 0 °C. After stirring at room temperature for 6 h, the solution was neutralized with 1 M NaOH solution at 0 °C to approximately pH 9.0. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed once with saturated brine, dried over anhydrous MgSO4, and concentrated under reduced pressure to give a yellow oily product 20b (3.66 g), with a yield of 91%. This product was used directly in the next reaction without further purification.

[0089] By following the steps above, replacing 19b with ent-19b, we can obtain its enantiomer ent-20b.

[0090] Example 4: Synthesis of intermediate 20c

[0091]

[0092] The obtained compound 19c (7.44 g, 15 mmol) was dissolved in dry dichloromethane (15 mL), and then trifluoroacetic acid (15 mL) was slowly added dropwise at 0 °C. After stirring at room temperature for 6 h, the solution was neutralized with 1 M NaOH solution at 0 °C to approximately pH 9.0. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed once with saturated brine, dried over anhydrous MgSO4, and concentrated under reduced pressure to give a yellow oily product 20b (4.35 g), with a yield of 98%. This product was used directly in the next reaction without further purification.

[0093] By following the steps above, replacing 19c with ent-19c, we can obtain its enantiomer ent-20c.

[0094] (ii) Synthesis of intermediates 1' to 16'

[0095] Example 5: Synthesis of intermediate 5c'

[0096]

[0097] Boc-D-Val-OH 21a (4.34 g, 20 mmol), HOBT (2.97 g, 22 mmol), and EDCI (4.2 g, 22 mmol) were added to a 100 mL round-bottom three-necked flask. The flask was sealed and evacuated under nitrogen protection. 20 mL of dry CH2Cl2 was added and the mixture was stirred at 0 °C for 30 min. Then, 20c (2.96 g, 10 mmol) and NMM (3.37 mL, 30 mmol) dissolved in CH2Cl2 were added. The mixture was stirred at room temperature for 48 h. The insoluble matter in the reaction system was then removed by filtration. The mixture was washed successively with 1 M NaOH, water, 1 M HCl (aq.), and saturated brine. The mixture was dried over anhydrous MgSO4, concentrated under reduced pressure, and subjected to column chromatography (petroleum ether: ethyl acetate = 5:1 as the mobile phase) to give a white solid product 5c' (6.45 g), with a yield of 93%.

[0098] NMR data: 1 H NMR (400MHz, CDCl3-d) δ7.57(d,J=6.8Hz,2H),5.54(d,J=8.4Hz,2H),4.55(d,J=6.8Hz,2H),4.20(t,J=7.2Hz,2H),3.82(dd,J=9. 2,4.8Hz,2H),3.54-3.50(m,2H),2.95-2.83(m,4H),2.27(s,2H),2.01-1.94(m,8H),1.40(d,J=3.5Hz,18H),0.96-0.81(m,18H). 13 C NMR (101MHz, CDCl3) δ171.8,171.7,156.0,79.4,60.6,57.4,47.2,45.9,36.9,30.7,28.8,28.4,24.7,23.7,19.7,17.7.

[0099] Example 6: Synthesis of intermediate 6c'

[0100]

[0101] Boc-D-Leu-OH 21f (4.62 g, 20 mmol), HOBT (2.97 g, 22 mmol), and EDCI (4.2 g, 22 mmol) were added to a 100 mL round-bottom three-necked flask. The flask was sealed and evacuated under nitrogen protection. 20 mL of dry CH2Cl2 was added and the mixture was stirred at 0 °C for 30 min. Then, 20c (2.96 g, 10 mmol) and NMM (3.37 mL, 30 mmol) dissolved in CH2Cl2 were added. The mixture was stirred at room temperature for 48 h. The insoluble matter in the reaction system was then removed by filtration. The mixture was washed successively with 1 M NaOH, water, 1 M HCl (aq.), and saturated brine. The mixture was dried over anhydrous MgSO4, concentrated under reduced pressure, and subjected to column chromatography (petroleum ether: ethyl acetate = 5:1 as the mobile phase) to give a white solid product 6c' (6.64 g), with a yield of 92%.

[0102] NMR data: 1 H NMR (400MHz, CDCl3-d) δ7.54 (s, 2H), 5.61 (d, J = 6.0Hz, 2H), 4.66-4.48 (m, 2H), 4.44-4.30 (m, 2H), 3.85-3.79 (m, 2H), 3.55-3.4 0(mi,2H),2.98-2.82(m,3H),2.31-2.25(m,2H),2.03-1.95(m,6H),1.73-1.64(m,2H),1.51-1.36(m,22H),0.97-0.8(m,18H). 13 C NMR (101MHz, CDCl3) δ172.5,171.9,156.0,79.6,60.9,50.9,47.0,45.9,41.4,37.0,28.9,28.4,24.7,24.6,23.78,23.48,21.94.

[0103] Example 7: Synthesis of intermediate 8b'

[0104]

[0105] Boc-D-Tle-OH 21h (4.62 g, 20 mmol), HOBT (2.97 g, 22 mmol), and EDCI (4.2 g, 22 mmol) were added to a 100 mL round-bottom three-necked flask. The flask was sealed and evacuated under nitrogen protection. 20 mL of dry CH2Cl2 was added and the mixture was stirred at 0 °C for 30 min. Then, 20b (2.68 g, 10 mmol) dissolved in CH2Cl2 and NMM (3.37 mL, 30 mmol) were added. The mixture was stirred at room temperature for 48 h. The insoluble matter in the reaction system was then removed by filtration. The mixture was washed successively with 1 M NaOH, water, 1 M HCl (aq.), and saturated brine. The mixture was dried over anhydrous MgSO4, concentrated under reduced pressure, and subjected to column chromatography (petroleum ether: ethyl acetate = 5:1 as the mobile phase) to give a white solid product 8b' (6.593 g), with a yield of 94%.

[0106] Example 8: Synthesis of intermediate ent-8b'

[0107]

[0108] Boc-L-Tle-OH ent-21h (4.62 g, 20 mmol), HOBT (2.97 g, 22 mmol), and EDCI (4.2 g, 22 mmol) were added to a 100 mL round-bottom three-necked flask. The flask was sealed and evacuated under nitrogen protection. 20 mL of dry CH2Cl2 was added and the mixture was stirred at 0 °C for 30 min. Then, ent-20b (2.68 g, 10 mmol) and NMM (3.37 mL, 30 mmol) dissolved in CH2Cl2 were added. The mixture was stirred at room temperature for 48 h. The insoluble matter in the reaction system was then removed by filtration. The mixture was washed successively with 1 M NaOH, water, 1 M HCl (aq.), and saturated brine. The mixture was dried over anhydrous MgSO4, concentrated under reduced pressure, and subjected to column chromatography (petroleum ether: ethyl acetate = 5:1 as the mobile phase) to obtain a white solid product ent-8b' (6.385 g), with a yield of 92%.

[0109] NMR data: 1 H NMR (400MHz, CDCl3-d) δ7.61(s,2H),5.33(d,J=8.8Hz,2H),4.42(dd,J=8.4,3.2Hz,2H),4.24(d,J=8.8Hz,2H),3.89-3.83(m,2 H),3.60-3.51(m,4H),3.05-3.0(m,2H),2.24-2.09(m,6H),1.93-1.82(m,4H),1.72-1.66(m,2H),1.42(s,18H),0.95(s,18H). 13C NMR (101MHz, CDCl3) δ171.9,170.9,156.0,79.8,60.4,58.7,48.4,38.0,35.5,29.3,28.4,28.0,26.4,24.8.

[0110] Example 9: Synthesis of intermediate 8c'

[0111]

[0112] Boc-D-Tle-OH 21h (4.62 g, 20 mmol), HOBT (2.97 g, 22 mmol), and EDCI (4.2 g, 22 mmol) were added to a 100 mL round-bottom three-necked flask. The flask was sealed and evacuated under nitrogen protection. 20 mL of dry CH2Cl2 was added and the mixture was stirred at 0 °C for 30 min. Then, 20c (2.96 g, 10 mmol) and NMM (3.37 mL, 30 mmol) dissolved in CH2Cl2 were added. The mixture was stirred at room temperature for 48 h. The insoluble matter in the reaction system was then removed by filtration. The mixture was washed successively with 1 M NaOH, water, 1 M HCl (aq.), and saturated brine. The mixture was dried over anhydrous MgSO4, concentrated under reduced pressure, and subjected to column chromatography (petroleum ether: ethyl acetate = 5:1 as the mobile phase) to give a white solid product 8b' (6.593 g), with a yield of 94%.

[0113] NMR data: 1 H NMR(400MHz, CDCl3-d)δδ7.62(d,J=7.6Hz,2H),5.45(d,J=8.8Hz,2H),4.61-4.47(m,2H),4.30-4.20(m,2H),3.94-3.79(m, 2H),3.66-3.52(m,2H),3.10-2.77(m,4H),2.35-2.17(m,2H),2.11-1.85(m,6H),1.41(s,18H),0.99(s,18H),0.86(s,6H). 13 CNMR (101MHz, CDCl3) δ174.8,172.4,60.3,48.0,46.5,36.9,34.9,29.3,26.4,24.9,24.0.

[0114] (III) Synthesis of chiral primary amine catalysts 1-16 with C2 axisymmetric structure

[0115] Example 10: Synthesis of primary amine catalyst 5c

[0116]

[0117] The obtained compound 5c' (3.47 g, 5 mmol) was dissolved in dry dichloromethane (5 mL), and then trifluoroacetic acid (5 mL) was slowly added dropwise at 0 °C. After stirring at room temperature for 6 h, the solution was neutralized with 1 M NaOH solution at 0 °C to approximately pH 9.0. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed once with saturated brine, dried over anhydrous MgSO4, and concentrated under reduced pressure to give the target product 5c (2.27 g) in 92% yield. Recrystallization from petroleum ether and ethyl acetate yielded a white solid catalyst that could be directly used for catalytic reactions.

[0118] NMR data: 1 H NMR (400MHz, CDCl3-d) δ7.56(t,J=6.4Hz,2H),4.50-4.48(m,2H),3.72-3.67(m,2H),3.51-3.45(m,2H),3.27(d,J=6.4Hz,2H),2.98(dd,J=14.0 ,7.2Hz,2H),2.84(dd,J=13.6,6.0Hz,2H),2.17-2.11(m,2H),2.00-1.88(m,6H),1.84-1.74(m,6H),0.92(dd,J=9.2,6.8Hz,12H),0.82(s,6H). 13 C NMR (101MHz, CDCl3) δ175.5,172.3,60.3,58.7,47.1,46.1,36.8,31.8,29.1,24.8,23.8,20.0,17.6.

[0119] Example 11: Synthesis of primary amine catalyst 6c

[0120]

[0121] The obtained compound 6c' (3.61 g, 5 mmol) was dissolved in dry dichloromethane (5 mL), and then trifluoroacetic acid (5 mL) was slowly added dropwise at 0 °C. After stirring at room temperature for 6 h, the solution was neutralized with 1 M NaOH solution at 0 °C to approximately pH 9.0. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed once with saturated brine, dried over anhydrous MgSO4, and concentrated under reduced pressure to give the target product 5c (2.40 g) in 92% yield. Recrystallization from petroleum ether and ethyl acetate yielded a white solid catalyst that could be directly used for catalytic reactions.

[0122] NMR data: 1H NMR (400MHz, CDCl3-d) δ7.56(t,J=6.4Hz,2H),4.47(d,J=5.6Hz,2H),3.75-3.71(m,2H),3.59(dd,J=8.8,5.2Hz,2H),3.46-3.39(m,2H),2 .97-2.82(m,4H),2.18-2.14(m,6H),1.99-1.95(m,6H),1.84-1.74(m,2H),1.41-1.28(m,4H),0.89(dd,J=6.4,4.0Hz,12H),0.81(s,6H). 13 C NMR (101MHz, CDCl3) δ176.0,172.3,60.6,51.5,46.8,45.8,43.5,36.7,29.1,24.8,24.7,23.7,23.6,21.8.

[0123] Example 12: Synthesis of primary amine catalyst 8b

[0124]

[0125] The obtained compound 8b' (3.61 g, 5 mmol) was dissolved in dry dichloromethane (5 mL), and then trifluoroacetic acid (5 mL) was slowly added dropwise at 0 °C. After stirring at room temperature for 6 h, the solution was neutralized with 1 M NaOH solution at 0 °C to approximately pH 9.0. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed once with saturated brine, dried over anhydrous MgSO4, and concentrated under reduced pressure to give the target product 8b (2.50 g) in 96% yield. Recrystallization from petroleum ether and ethyl acetate yielded a white solid catalyst that could be directly used for catalytic reactions.

[0126] Example 13: Synthesis of primary amine catalyst ent-8b

[0127]

[0128] The obtained compound ent-8b' (3.61 g, 5 mmol) was dissolved in dry dichloromethane (5 mL), and then trifluoroacetic acid (5 mL) was slowly added dropwise at 0 °C. After stirring at room temperature for 6 h, the solution was neutralized with 1 M NaOH solution at 0 °C to approximately pH 9.0. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed once with saturated brine, dried over anhydrous MgSO4, and concentrated under reduced pressure to give the target product ent-8b (2.50 g) in 96% yield. Recrystallization from petroleum ether and ethyl acetate yielded a white solid catalyst that could be directly used for catalytic reactions.

[0129] NMR data:1 H NMR (400MHz, CDCl3-d) δ7.89 (dd, J=8.0, 4.0Hz, 2H), 4.40 (dd, J=8.0, 4.8Hz, 2H), 3.76-3.70 (m, 2H), 3.62-3.51 (m, 4H) ,3.31(s,2H),3.02-2.98(m,2H),2.43(s,4H),2.12-1.91(m,6H),1.85-1.76(m,2H),1.72-1.66(m,2H),0.92(s,18H). 13 C NMR (101MHz, CDCl3) δ173.9,172.3,60.3,60.,48.3,38.20,34.9,29.40,27.5,26.3,25.0.

[0130] Example 14: Synthesis of primary amine catalyst 8c

[0131]

[0132] The obtained compound 8c' (3.61 g, 5 mmol) was dissolved in dry dichloromethane (5 mL), and then trifluoroacetic acid (5 mL) was slowly added dropwise at 0 °C. After stirring at room temperature for 6 h, the solution was neutralized with 1 M NaOH solution at 0 °C to approximately pH 9.0. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed once with saturated brine, dried over anhydrous MgSO4, and concentrated under reduced pressure to give the target product 8c (2.45 g) in 94% yield. Recrystallization from petroleum ether and ethyl acetate yielded a white solid catalyst that could be directly used for catalytic reactions.

[0133] NMR data: 1 H NMR(400MHz, CDCl3-d)δ7.64(t,J=6.4Hz,2H),4.52-4.49(m,2H),3.76-3.71(m,2H),3.58-3.51(m,2H),3.29(s, 2H), 3.06 (dd, J=14.0, 7.6Hz, 2H), 2.82 (dd, J=14.0, 6.0Hz, 2H), 2.14-1.88 (m, 12H), 0.95 (s, 18H), 0.84 (s, 6H). 13 C NMR (101MHz, CDCl3) δ174.9,172.5,60.3,48.0,46.5,36.9,34.9,29.3,26.4,24.9,24.0.

[0134] II. Application of chiral primary amine catalysts with C2 axisymmetric structures in the Aldol reaction

[0135] Example 15: Screening of chiral primary amine catalysts with C2 axisymmetric structure

[0136] The primary amine catalyst (0.025 mmol), α-branched aldehyde (1 mmol), ethyl glyoxylate (0.5 mmol), and 1.0 mL of dry acetonitrile were added to a 5 mL reaction tube. The reaction was carried out at room temperature with magnetic stirring. The reaction was monitored by TLC until the reaction was completed. The product was then purified by column chromatography with petroleum ether and ethyl acetate to obtain pure Aldol reaction product.

[0137] The results of the asymmetric Aldol reaction of isobutyraldehyde with ethyl glyoxylate catalyzed by the six primary amine catalysts 1c, 5c, 6c, 8b, 8c and 14c prepared in this invention are shown in Table 1 below. The results show that 8b exhibits the highest asymmetric catalytic efficiency (Table 1, entry 4).

[0138] Table 1. Asymmetric Aldol reaction between isobutyraldehyde and ethyl glyoxylate catalyzed by chiral primary amine catalysts with C2 axisymmetric structure. a

[0139]

[0140] a The separation yield, ee, was determined by chiral HPLC.

[0141] Example 16: Effect of solvent on the asymmetric Aldol reaction of isobutyraldehyde and ethyl glyoxylate catalyzed by primary amine catalyst 8b.

[0142] The primary amine catalyst 8b (0.025 mmol), isobutyraldehyde (1 mmol), ethyl glyoxylate (0.5 mmol), and 1.0 mL of dry solvent prepared according to the present invention were added to a 5 mL reaction tube. The reaction was carried out at room temperature and under magnetic stirring. The reaction was monitored by TLC until the end of the reaction. The product was then purified by column chromatography with petroleum ether and ethyl acetate to obtain pure Aldol reaction product 24a.

[0143] The effects of various solvents on the reaction yield and ee value are shown in Table 2 below. The results show that acetonitrile has the highest yield and ee value among the screened solvents.

[0144] Table 2. Effect of different solvents on the asymmetric Aldol reaction between isobutyraldehyde and ethyl glyoxylate catalyzed by primary amine catalyst 8b. a

[0145]

[0146]

[0147] a The separation yield, ee, was determined by chiral HPLC.

[0148] Example 17: Observation of the effect of primary amine catalyst dosage on the catalytic efficiency of the asymmetric Aldol reaction.

[0149] Table 3. Effect of catalyst 8b dosage on the Aldol reaction. a

[0150]

[0151] a The separation yield, ee, was determined by chiral HPLC.

[0152] The primary amine catalyst 8b (x mol%) prepared according to this invention, isobutyraldehyde (1 mmol), ethyl glyoxylate (0.5 mmol), and 1.0 mL of dry acetonitrile were added to a 5 mL reaction tube. The reaction was carried out at room temperature with magnetic stirring. The reaction was monitored by TLC until completion. The product was then purified by column chromatography with petroleum ether and ethyl acetate to obtain pure Aldol reaction product. The reaction yield and ee value are shown in Table 3 below. The results show that using 5.0 mol% of 8b as catalyst and acetonitrile as solvent can obtain the optimal asymmetric catalytic effect.

[0153] Example 18: Observation of the substrate adaptability of the asymmetric Aldol reaction between α-branched aldehydes and glyoxylates catalyzed by 8b.

[0154] The primary amine catalyst 8b (5 mol%) prepared according to this invention, α-branched aldehyde (1 mmol), glyoxylate (0.5 mmol), and 1.0 mL of dry acetonitrile were added to a 5 mL reaction tube. The reaction was carried out at room temperature with magnetic stirring. The reaction was monitored by TLC until the end of the reaction. The product was then purified by column chromatography with petroleum ether and ethyl acetate to obtain pure Aldol reaction product. The results are shown in Table 4.

[0155] Table 4. Asymmetric Aldol reaction between α-branched aldehydes and glyoxylates catalyzed by primary amine 8b. a

[0156]

[0157] a The separation yield, dr, and ee values ​​were determined by chiral HPLC.

[0158] Based on the results of the above-mentioned Aldol reaction, the chiral primary amine catalyst with C2 axisymmetric structure described in this invention can obtain the target product 24 with high yield and high enantioselectivity in the asymmetric Aldol reaction between α-branched aldehyde 22 and glyoxylate ester 23. The reaction yield reaches up to 98% and the enantioselectivity reaches up to 96%, showing good application prospects.

[0159] The products 24a to 24k are characterized as follows.

[0160]

[0161] 1H),4.23-4.13(m,2H),3.05(s,1H),1.65-1.58(m,2H),1.40-1.30(m,2H),1.14(s,3H),1.06(s,3H),0.92(t,J=7.2 Hz,3H).

[0162]

[0163]

[0164] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A chiral primary amine catalyst having a C2 axisymmetric structure, characterized in that, Salts containing general formula 1 or general formula 1; In Formula 1: R is any one of C1 to C6 straight-chain alkyl and C1 to C6 branched alkyl; Diamine is any one of 1,3-propanediamine, 2,2-dimethyl-1,3-propanediamine, 1,4-butanediamine, 1,5-pentanediamine, 3,3-dimethyl-1,5-pentanediamine, and 1,6-hexanediamine.

2. The chiral primary amine catalyst according to claim 1, characterized in that, Specifically, general formula 1 is as follows: 。 3. The chiral primary amine catalyst according to claim 2, characterized in that, The specific structure is as follows: 。 4. The method for preparing the chiral primary amine catalyst according to any one of claims 1-3, characterized in that, The synthesis routes are shown in Equations 2 and 3: In Formulas 2 and 3, 17 is amino-protected proline, where P is any one of tert-butyloxyformyl, benzyloxyformyl, or fluorenyloxyformyl. 18 is any one of 1,3-propanediamine, 2,2-dimethyl-1,3-propanediamine, 1,4-butanediamine, 1,5-pentanediamine, 3,3-dimethyl-1,5-pentanediamine, and 1,6-hexanediamine; 19 is the first intermediate; 20 is the second intermediate; 21 is an amino-protected amino acid, wherein R is any one of a C1-C6 straight-chain alkyl group or a C1-C6 branched-chain alkyl group; Formula 1' is a third intermediate; Formula 1 is the chiral primary amine catalyst according to any one of claims 1-3; The condensing reagent C1 is a combination of carbodiimide and 1-hydroxy-7-azabenzotriazole, or a combination of carbodiimide and 1-hydroxybenzotriazole, or a combination of alkoxyformyl chloride R2OCOCl with any one of triethylamine, diethylamine, diisopropylethylamine, morpholine, or N-methylmorpholine; and R2 is a straight-chain alkyl or branched-chain alkyl group from C1 to C4. Solvents S1, S2, S3, and S4 are each independently one or more of dichloromethane, dichloroethane, tetrahydrofuran, 1,4-dioxane, ethyl acetate, N,N-dimethylformamide, acetonitrile, or propionitrile; Deprotecting agent D1 and deprotecting agent D2 are each independently any one of methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, trichloroacetic acid, hydrochloric acid, sulfuric acid, piperidine, morpholine, tetrahydropyrrole, dihydropyrrole, pyrrole, diethylamine, dipropylamine, dibutylamine, diisopropylamine, or diisobutylamine.

5. The preparation method according to claim 4, characterized in that, The specific steps are as follows: According to the synthetic route described in Formula 2, amino-protected proline 17, condensing agent C1, and diamine 18 were added to solvent S1 at room temperature for a first stirring reaction to obtain intermediate 19. Then, 19 and deprotecting agent D1 were added to solvent S2 for a second stirring reaction to obtain intermediate product 20. Following the synthetic route described in Formula 3, product 20, amino-protected amino acid 21, and condensing agent C1 were added to solvent S3 at room temperature for a third stirring reaction to obtain product general formula 1'. Then, product general formula 1' and deprotecting agent D2 were added to solvent S4 for a fourth stirring reaction to obtain the target product general formula 1.

6. The preparation method according to claim 5, characterized in that, In the synthetic route described in Formula 2, the molar ratio of diamine 18, proline 17, and condensing agent C1 is 1:(2~5):(2~5); The first stirring reaction time is 4~72 hours; The molar ratio of intermediate 19 to deprotectant D1 is 1:(1-5); The second stirring reaction temperature is 0~50℃, and the reaction time is 2~24h.

7. The preparation method according to claim 5, characterized in that, In the synthetic route described in Formula 3, the molar ratio of intermediate 20, amino-protected amino acid 21, and condensing reagent C1 is 1:(2~5):(2~5); The third stirring reaction time is 4~72 hours; The molar ratio of intermediate general formula 1' and deprotecting agent D2 is 1:(1~5); The fourth stirring reaction temperature is 0~50℃, and the reaction time is 2~24h.

8. The application of the chiral primary amine catalyst according to any one of claims 1 to 3 in the asymmetric Aldol reaction of α-branched aldehydes with glyoxylates; characterized in that, The process of the asymmetric Aldol reaction between the α-branched aldehyde and glyoxylate is shown in Equation 4: In Equation 4: R 1 R 2 Each is independently selected from any one of alkyl, aryl, or arylmethyl; or -R1-R2- are cyclopentyl or cyclohexyl; R 3 It is any one of alkyl, aryl, or arylmethyl; The primary amine catalyst is the chiral primary amine catalyst with a C2 axisymmetric structure as described in any one of claims 1 to 3; Solvent S5 is any one or more of water, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, ethyl acetate, propyl acetate, toluene, chlorobenzene, bromobenzene, xylene, trimethylbenzene, diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, acetonitrile, propionitrile, methanol, ethanol, propanol, butanol, hexane, and pentane.

9. An intermediate compound of general formula 1 according to claim 1, characterized in that, The intermediate compound is the third intermediate as described in claim 4.

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