Phosphoramidite ligand with carbazole structure as well as preparation method and application of phosphoramidite ligand

Abstract

The invention discloses a phosphoramidite ligand with a carbazole structure as well as a preparation method and application of the phosphoramidite ligand. The structural formula of the phosphoramidite ligand is # imgabs0, in the formula, R1 or R3 is independently selected from hydrogen or phenyl, and R2 is selected from hydrogen or methyl. A carbazole structure is introduced into the SPHENOL type phosphoramidite ligand, compared with a traditional iminostilbene structure, the carbazole structure enables N-terminal modification of the phosphoramidite ligand to be simpler and easier to obtain, a series of different SPHENOL type phosphoramidite ligands can be derived by adding different substituent groups at different positions of the carbazole structure, and the phosphoramidite ligand has the advantages that the structure is simple and easy to obtain; and a new attempt is provided for enriching the SPHENOL type phosphoramidite ligand. The phosphoramidite ligand disclosed by the invention also has a regulation effect on formation of chirality in a catalytic reaction, sometimes shows performance different from that of traditional phosphoramidite in chiral regulation, and has unique advantages, so that the application range of the ligand is expanded on the basis of the traditional phosphoramidite ligand.

Description

Technical Field

[0001] The invention belongs to the technical field of asymmetric reactions, and in particular relates to a phosphoramidite ligand with a carbazole structure, a preparation method and an application thereof. Background Art

[0002] Phosphoramidite It is currently recognized as a very versatile and easily available class of good chiral ligands suitable for asymmetric catalysis. Their modular structure can create a ligand library and help fine-tune specific catalytic reactions. Its molecular structure is characterized by the presence of a coordinating PN bond in the molecule, which can coordinate with many metals to form chiral species, thereby catalyzing asymmetric reactions. It has a wide range of applications and can induce the generation of a variety of chiral environments; and, as the field continues to develop, its monodentate properties are also essential in the combined catalysis using mixed ligands.

[0003] Since Feringa et al. (Angew. Chem., Int. Ed. 1996, 35, 2374.) developed the first chiral phosphoramidite ligand (the ligand is an axially chiral monodentate phosphorus ligand with C2 symmetry derived from BINOL) in 1996, a large number of phosphoramidite ligands derived from the BINOL skeleton have been developed and applied.

[0004] Recently, due to the pioneering contributions of Zhou Qilin et al. and Birman et al. (Tetrahedron: Asymmetry. 1999, 10, 125-131; Tetrahedron: Asymmetry. 2002, 13, 1363-1366; Acc. Chem. Res. 2008, 41, 581-593; Acc. Chem. Res. 2012, 45, 1365-1377.), SPINOL has become another superior chiral framework. Its rigid conformation and chemical robustness are the outstanding features that endow this structure and its variants with crucial asymmetric catalysis. The application of its framework in phosphoramidites has also been effectively developed.

[0005] Although both BINOL and SPINOL are versatile, their properties and catalytic behaviors, including their phosphoramidite derivatives, are sometimes complementary. For example, BINOL-based catalysts sometimes show better catalytic activity, while SPINOL-based catalysts usually show better asymmetric induction ability. Therefore, a dilemma is encountered when synergy cannot be achieved in these two features.

[0006] Recently, Sun Jianwei et al. developed a new structure SPHENOL (J.Am.Chem.Soc.2021,143,12445-12449.), which is a new skeleton that is expected to combine the advantages of both BINOL and SPINOL skeletons. Its application has not been fully developed, so the SPHENOL skeleton can be introduced into phosphoramidite.

[0007] So far, the molecular skeleton of phosphoramidite ligand has undergone changes from BINOL, SPINOL, TADDOL to today's SPHENOL:

[0008]

[0009] Compared with the first three well-developed phosphoramidite skeletons, the phosphoramidite ligands with the fourth skeleton (i.e., SPHENOL bisphenol skeleton) still have a large room for development. However, most of the current modifications of SPHENOL spirocyclic phosphoramidite ligands are still limited to the chiral control end of bisphenol, while the modification of the aromatic ring at the N-terminus has not yet involved the modification of heterocyclic aromatic hydrocarbons. Summary of the invention

[0010] The invention aims to provide a phosphoramidite ligand with a carbazole structure and a preparation method and application thereof, enrich and develop the phosphoramidite ligand library, and provide a new catalytic means for asymmetric reactions.

[0011] To achieve the above-mentioned object of the invention, the technical solution of the present invention is as follows:

[0012] A phosphoramidite ligand having a carbazole structure, wherein the phosphoramidite ligand has a structural formula as shown in formula (I):

[0013]

[0014] In formula (I), R1 or R3 is independently selected from hydrogen or phenyl, and R2 is selected from hydrogen or methyl.

[0015] The present invention introduces a carbazole structure into a SPHENOL type phosphoramidite ligand. Compared with a traditional iminostilbene structure, the carbazole structure makes the N-terminal modification of the phosphoramidite ligand simpler and easier to obtain. A series of different SPHENOL type phosphoramidite ligands can be derived by adding different substituents at different positions of the carbazole structure, which is a new attempt to enrich the SPHENOL type phosphoramidite ligands.

[0016] The phosphoramidite ligand of the present invention also has a regulating effect on the formation of chirality in catalytic reactions, and sometimes exhibits different performance from traditional phosphoramidites in chirality regulation, and has its unique advantages. Therefore, on the basis of traditional phosphoramidite ligands, the scope of application of the ligand is expanded.

[0017] Preferably, the structural formula of the phosphoramidite ligand having a carbazole structure is as shown in formula (II) or (III):

[0018]

[0019] The phosphoramidite ligand shown in formula (II) is named Phos C, and the phosphoramidite ligand shown in formula (III) is named Phos D.

[0020] These two phosphoramidite ligands exhibited good chiral regulation in the asymmetric azide-alkyne [3+2] cycloaddition reaction, the [4+2] cyclization reaction of indole alkynamine and o-benzene cyanophenyl borate, and the [2+2+2] cycloaddition reaction of alkynamine.

[0021] The present invention also provides a method for preparing the above-mentioned phosphoramidite ligand with a carbazole structure, which comprises: in an inert atmosphere, using a carbazole heterocyclic compound, a phosphorus donor and a SPHENOL bisphenol skeleton as raw materials, and synthesizing the phosphoramidite ligand with a carbazole structure through a nucleophilic substitution reaction.

[0022] Specifically, the preparation method comprises the following steps:

[0023] (1) mixing a base, a solvent and a phosphorus donor, and mixing them in an ice bath to obtain a solution A;

[0024] Preferably, the base comprises triethylamine, the phosphorus donor comprises phosphorus trichloride, and the solvent comprises ultra-dry methylene chloride or tetrahydrofuran;

[0025] The equivalent ratio of triethylamine to SPHENOL bisphenol skeleton is (6-10):1, more preferably 8:1; the equivalent ratio of phosphorus trichloride to SPHENOL bisphenol skeleton is (1-2.5):1, more preferably 1.5:1;

[0026] (2) under an inert atmosphere, adding a carbazole-based heterocyclic compound to solution A, mixing in an ice bath, and stirring at 25-55° C. overnight to obtain solution B;

[0027] Wherein, the structural formula of the carbazole heterocyclic compound is as shown in formula (IV) or (V):

[0028]

[0029] The equivalent ratio of the carbazole heterocyclic compound to the SPHENOL bisphenol skeleton is (1-3):1; more preferably 1.5:1;

[0030] (3) Under an inert atmosphere, add the SPHENOL bisphenol skeleton to solution B, first react in an ice bath for 3-15 minutes, and then react at room temperature for 4-5 hours to obtain the phosphoramidite ligand.

[0031] The present invention also provides the use of the phosphoramidite ligand having a carbazole structure in catalyzing an asymmetric azide-internal alkyne [3+2] cycloaddition reaction.

[0032] Preferably, in the asymmetric azide-internal alkyne [3+2] cycloaddition reaction system, the content of the phosphoramidite ligand is 5 mol%.

[0033] The experiment found that in the rhodium-catalyzed asymmetric azide-alkyne [3+2] cycloaddition reaction, the participation of Phos C made the yield of the target product reach 38% and the ee value reached 47%; the participation of Phos D made the yield of the target product reach 60% and the ee value reached 53%.

[0034] The present invention also provides the use of the phosphoramidite ligand having a carbazole structure in catalyzing the [4+2] cyclization reaction of indole alkynamine and o-benzylcyanophenyl borate.

[0035] Preferably, in the [4+2] cyclization reaction system of indole alkynamine and o-benzylcyanophenyl borate, the content of the phosphoramidite ligand is 10 mol%.

[0036] The experiment found that in the rhodium-catalyzed [4+2] cyclization reaction of indole acetylamine and o-benzene cyanophenyl borate, the participation of Phos C made the yield of the target product reach 55% and the ee value reached 45%; the participation of Phos D made the yield of the target product reach 54% and the ee value reached 44%.

[0037] The present invention also provides the use of the phosphoramidite ligand having a carbazole structure in catalyzing the [2+2+2] cycloaddition reaction of alkynamines.

[0038] Preferably, in the asymmetric azide-internal alkyne [3+2] cycloaddition reaction system, the content of the phosphoramidite ligand is 5 mol%.

[0039] The experiment found that in the rhodium-catalyzed asymmetric azide-alkyne [3+2] cycloaddition reaction, the participation of Phos C made the yield of the target product reach 61% and the ee value reached 52%; the participation of Phos D made the yield of the target product reach 54% and the ee value reached 55%.

[0040] Compared with the prior art, the technical effects of the present invention are embodied in:

[0041] (1) The present invention introduces a carbazole structure into a SPHENOL-type phosphoramidite ligand. Compared with the traditional imidostilbene structure, the carbazole structure makes the N-terminal modification of the phosphoramidite ligand simpler and easier to obtain. By adding different substituents at different positions of the carbazole structure, a series of different SPHENOL-type phosphoramidite ligands can be derived, which is a new attempt to enrich the SPHENOL-type phosphoramidite ligands.

[0042] (2) The phosphoramidite ligand of the present invention also has a regulatory effect on the formation of chirality in catalytic reactions. In chirality regulation, it sometimes exhibits different performance from traditional phosphoramidites and has its own unique advantages. Therefore, on the basis of traditional phosphoramidite ligands, the scope of application of this ligand is expanded.

[0043] (3) The two phosphoramidite ligands Phos C and Phos D provided by the present invention show relatively good chiral regulation effects in the asymmetric azide-internal alkyne [3+2] cycloaddition reaction, the [4+2] cyclization reaction of indole acetylamine and o-benzene cyanophenyl borate, and the [2+2+2] cycloaddition reaction of acetylamine. Among them, in the rhodium-catalyzed asymmetric azide-alkyne [3+2] cycloaddition reaction, the participation of Phos D makes the yield of the target product reach 60% and the ee value reach 53%; in the rhodium-catalyzed [4+2] cyclization reaction of indole acetylamine and o-benzene cyanophenyl borate, the participation of Phos C makes the yield of the target product reach 55% and the ee value reach 45%; in the rhodium-catalyzed asymmetric azide-alkyne [3+2] cycloaddition reaction, the participation of Phos C makes the yield of the target product reach 61% and the ee value reach 52%; the participation of Phos D makes the yield of the target product reach 54% and the ee value reach 55%. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 The synthetic route of the phosphoramidite ligand Phos C having a carbazole structure of the present invention;

[0045] Wherein, equiv means equivalent, PCl3 means phosphorus trichloride, NRt3 means triethylamine, DCM(dry) means dichloromethane (ultra-dry), rt means room temperature, and yield means yield; the same below;

[0046] Figure 2 is the nuclear magnetic analysis spectrum of the phosphoramidite ligand Phos C having a carbazole structure of the present invention;

[0047] Figure 3 The synthetic route of the phosphoramidite ligand Phos D having a carbazole structure of the present invention;

[0048] Figure 4 is the nuclear magnetic analysis spectrum of the phosphoramidite ligand Phos D having a carbazole structure of the present invention;

[0049] Figure 5 The reaction scheme for the rhodium-catalyzed asymmetric azide-internal alkyne [3+2] cycloaddition reaction;

[0050] Wherein, [Rh(COD)Cl]2 represents COD rhodium chloride dimer, Ligand represents ligand, and reactioncondition represents reaction conditions; the same below;

[0051] Figure 6 The results of ligand screening for rhodium-catalyzed asymmetric azide-alkyne [3+2] cycloaddition reaction;

[0052] Wherein, entry indicates the number, catalyst indicates the catalyst, and ee(%) indicates the enantiomeric excess (percentage);

[0053] Figure 7 The reaction scheme for the rhodium-catalyzed [4+2] cyclization of indole acetylamines and o-benzylcyanophenylboronic acid esters is shown;

[0054] Wherein, THF represents tetrahydrofuran;

[0055] Figure 8 The reaction scheme for the iridium-catalyzed [2+2+2] cycloaddition of alkynylamines;

[0056] Wherein, [Ir(COD)Cl]2 represents COD iridium chloride dimer, Zn(OTf)2 represents zinc trifluoromethanesulfonate, toluene represents toluene, and RT represents room temperature. DETAILED DESCRIPTION

[0057] The technical solution of the present invention is further described in detail below in conjunction with the accompanying drawings and specific implementation methods.

[0058] Example 1 Synthesis of Phosphoramidite Ligand Phos C with Carbazole Structure

[0059] This embodiment provides a phosphoramidite ligand Phos C having a carbazole structure, and its structural formula is shown in formula (II):

[0060]

[0061] The synthetic route of the phosphoramidite ligand Phos C having a carbazole structure is as follows: Figure 1 As shown, the specific steps include:

[0062] (1) mixing a base, a solvent and a phosphorus donor, and mixing them in an ice bath to obtain a solution A;

[0063] Specifically, take a sealed tube and several syringes, put them in an oven first, inflate the balloon, take out ice for later use, and set the temperature of the stirring heater to 45°C; take out the sealed tube when it is very hot, screw on the lid immediately, it does not need to be completely sealed, then use a vacuum pump to pump, wait for cooling, adjust the double-row nitrogen, after the sealed tube is cooled, fill and discharge nitrogen three or four times, and then let the sealed tube be in a nitrogen atmosphere; take the baked syringes and needles, first exhaust the air and pump out nitrogen three times, and extract triethylamine (8 equivalents); in a nitrogen atmosphere, carefully open the sealed tube lid and inject triethylamine, and take dichloromethane (ultra-dry) (0.25M) in the same operation, and then put the sealed tube in an ice water bath, and take phosphorus trichloride (1.5 equivalents) in the same way, and then cover the lid, turn off the nitrogen, and stir in an ice bath for 15 minutes to obtain solution A;

[0064] (2) under an inert atmosphere, adding a carbazole-based heterocyclic compound to solution A, mixing in an ice bath, and stirring at 25-55° C. overnight to obtain solution B;

[0065] Specifically, carbazole (1.5 equivalents) was weighed, added to solution A under a nitrogen atmosphere, placed in an ice bath for 3 minutes, and then stirred at 45° C. overnight to obtain solution B;

[0066] The structural formula of the carbazole heterocyclic compound is shown in formula (IV):

[0067]

[0068] (3) Under an inert atmosphere, add the SPHENOL bisphenol skeleton to solution B, first react in an ice bath for 3-15 minutes, and then react at room temperature for 4-5 hours to obtain the phosphoramidite ligand of this example;

[0069] Specifically, under a nitrogen atmosphere, SPHENOL bisphenol (1 equivalent) was weighed and added, and the mixture was reacted in an ice bath for 5 minutes. After the mixture was taken out and reacted at room temperature for 4 to 5 hours, the reaction was basically completed. After the reaction was completed, silica gel powder was added, and the mixture was spin-dried and passed through a column with an eluent of petroleum ether: ethyl acetate = 50 to 20:1 to obtain the phosphoramidite ligand Phos C.

[0070] The obtained phosphoramidite ligand Phos C was analyzed by NMR and high-resolution mass spectrometry (such as Figure 2 The analysis results are as follows:

[0071] 1H NMR (400MHz, CDCl3) δ7.91(d,J=6.8Hz,1H),7.83(d,J=8.4Hz,2H),7.79(d,J=8.2Hz,1H),7.51-7.44(m,2H),7.41(d,J=7.2Hz,1H),7.36(d,J=5.8 Hz,2H),7.32(d,J=7.4Hz,2H),7.28(d,J=2.8Hz,2H),7.05(d,J=8.8Hz,1 H),6.97-6.89(m,1H),6.72(d,J=8.8Hz,1H),6.49(d,J=8.8Hz,1H),6.43-

[0072] 6.36(m,1H),3.63-3.44(m,2H),3.31-3.07(m,2H),3.02-2.97(m,3H),2.59-2.42(m,2H),2.33-2.17(m,2H).

[0073] HRMS (ESI, m / z) calculation for C 38 H 28 NNaO2P[M+Na] + :584.1750,found:584.1752.

[0074] Example 2 Synthesis of Phosphoramidite Ligand Phos D Having Carbazole Structure

[0075] This embodiment provides a phosphoramidite ligand Phos D having a carbazole structure, and its structural formula is shown in formula (III):

[0076]

[0077] The synthetic route of the phosphoramidite ligand Phos D having a carbazole structure is as follows: Figure 3 As shown, the preparation method is basically the same as that of Example 1, except that the carbazole heterocyclic compound used in step (2) is as shown in formula (V):

[0078]

[0079] The obtained phosphoramidite ligand Phos C was analyzed by NMR and high-resolution mass spectrometry (such as Figure 4 The analysis results are as follows:

[0080] 1H NMR (400MHz, CDCl3) δ8.25(s,1H),8.09(d,J=8.0Hz,1H),7.91(d,J=8.0Hz,1H),7.86(d,J=8 .8Hz,1H),7.81-7.74(m,3H),7.65(d,J=8.0Hz,1H),7.55-7.44(m,3H),7.43-7.37(m,2H),7. 37-7.31(m,2H),7.24-7.18(m,4H),7.17-7.07(m,3H),6.99(d,J=8.8Hz,1H),6.61(d,J=7.2H z,2H),6.33(d,J=8.8Hz,1H),3.59-3.37(m,2H),3.19-3.01(m,2H),2.57-2.39(m,2H),2.29-

[0081] 2.14 (m, 2H).

[0082] HRMS (ESI, m / z) calculation for C 49 H 34 NNaO2P[M+Na] + :722.2219,found:722.2218.

[0083] Example 3 Application of phosphoramidite ligands with carbazole structure in asymmetric azide-internal alkyne [3+2] cycloaddition reaction

[0084] The reaction scheme for the rhodium-catalyzed asymmetric azide-alkyne [3+2] cycloaddition is shown in Figure 5 , the amount of each raw material has been Figure 5 Shown in.

[0085] Before adding 1a and 2a to the reaction system, the catalyst and the ligand were mixed and stirred for 40 minutes. In this example, different ligands were added to the reaction system. Under different ligands and corresponding reaction conditions, the yield (measured by 1H NMR with 1,3,5-trimethoxybenzene as internal standard) and ee value (measured by chiral high performance liquid chromatography) of the target product (3a) were as follows: Figure 6 shown.

[0086] Depend on Figure 6 It can be seen that L3 is Phos C and L8 is Phos D.

[0087] From the screening of substrate conditions, it can be found that the phosphoramidite ligands Phos C and Phos D of the present invention can be successfully applied to the rhodium-catalyzed asymmetric azide-internal alkyne [3+2] cycloaddition reaction. Among them, the participation of Phos C makes the yield of the target product reach 38% and the ee value reach 47%; the participation of Phos D makes the yield of the target product reach 60% and the ee value reach 53%.

[0088] Example 4 Application of a phosphoramidite ligand having a carbazole structure in the [4+2] cyclization reaction of indole alkynamine and o-benzylcyanophenylboronic acid ester

[0089] The reaction scheme for the rhodium-catalyzed [4+2] cyclization of indole acetylamines and o-benzyl cyanophenyl borate is shown in Figure 7 The amount of each raw material is already in Figure 7 Shown in.

[0090] The experiment found that in the rhodium-catalyzed [4+2] cyclization reaction of indole acetylamine and o-benzene cyanophenyl borate, the participation of Phos C made the yield of the target product reach 55% and the ee value reached 45%; the participation of Phos D made the yield of the target product reach 54% and the ee value reached 44%.

[0091] Example 5 Application of phosphoramidite ligands with carbazole structure in alkynylamine [2+2+2] cycloaddition reaction

[0092] The reaction scheme for the iridium-catalyzed [2+2+2] cycloaddition of alkynylamines is shown in Figure 8 The amount of each raw material is already in Figure 8 Shown in.

[0093] The experiment found that in the iridium-catalyzed [2+2+2] cycloaddition reaction of alkynylamine, the participation of Phos C made the yield of the target product reach 61% and the ee value reached 52%; the participation of Phos D made the yield of the target product reach 54% and the ee value reached 55%.

Claims

1. A phosphoramidite ligand having a carbazole structure, It is characterized in that The structural formula is shown in formula (I): In formula (I), R 1 or R 3 are independently selected from hydrogen or phenyl, R 2 is selected from hydrogen or methyl.

2. The phosphoramidite ligand having a carbazole structure as claimed in claim 1, It is characterized in that The structural formula is shown in formula (II):

3. The phosphoramidite ligand having a carbazole structure as claimed in claim 1, It is characterized in that The structural formula is shown in formula (III):

4. A method for preparing a phosphoramidite ligand having a carbazole structure according to any one of claims 1 to 3, It is characterized in that include: In an inert atmosphere, the phosphoramidite ligand having a carbazole structure is synthesized by using a carbazole heterocyclic compound, a phosphorus donor and a SPHENOL bisphenol skeleton as raw materials through a nucleophilic substitution reaction.

5. The preparation method according to claim 4, It is characterized in that The following steps are involved: (1) mixing a base, a solvent and a phosphorus donor, and mixing them in an ice bath to obtain a solution A; (2) under an inert atmosphere, adding a carbazole-based heterocyclic compound to solution A, mixing in an ice bath, and stirring at 25-55° C. overnight to obtain solution B; (3) Under an inert atmosphere, add the SPHENOL bisphenol skeleton to solution B, first react in an ice bath for 3-15 minutes, and then react at room temperature for 4-5 hours to obtain the phosphoramidite ligand.

6. The preparation method according to claim 5, It is characterized in that In step (1), the base comprises triethylamine, the phosphorus donor comprises phosphorus trichloride, and the solvent comprises ultra-dry grade dichloromethane or tetrahydrofuran; The equivalent ratio of triethylamine to SPHENOL bisphenol skeleton is (6-10):1; the equivalent ratio of phosphorus trichloride to SPHENOL bisphenol skeleton is (1-2.5):

1.

7. The preparation method according to claim 5, It is characterized in that In step (2), the structural formula of the carbazole heterocyclic compound is as shown in formula (IV) or (V): The equivalent ratio of the carbazole heterocyclic compound to the SPHENOL bisphenol skeleton is (1-3):

1.

8. Use of the phosphoramidite ligand having a carbazole structure as claimed in any one of claims 1 to 3 in catalyzing an asymmetric azide-internal alkyne [3+2] cycloaddition reaction.

9. Use of the phosphoramidite ligand having a carbazole structure as claimed in any one of claims 1 to 3 in catalyzing the [4+2] cyclization reaction of indole alkynamine and o-benzylcyanophenyl borate.

10. Use of the phosphoramidite ligand having a carbazole structure as claimed in any one of claims 1 to 3 in catalyzing the [2+2+2] cycloaddition reaction of alkynamines.

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