Phosphoramidite ligand with carbazole structure, and preparation method and application thereof

Abstract

The application discloses a phosphoramidite ligand with a carbazole structure and a preparation method and application thereof. The structural formula of the phosphoramidite ligand is shown in the following formula: wherein R1 or R3 is independently selected from hydrogen or a phenyl group, and R2 is selected from hydrogen or a methyl group. The carbazole structure is introduced into the SPHENOL type phosphoramidite ligand, compared with a traditional imino stilbene structure, the carbazole structure makes the N-terminal modification of the phosphoramidite ligand simpler and easier, different substituents are added on different positions of the carbazole structure, and a series of different SPHENOL type phosphoramidite ligands can be derived, which is a new attempt to enrich the SPHENOL type phosphoramidite ligand. The phosphoramidite ligand has a regulating effect on the formation of chirality in a catalytic reaction, and sometimes shows different performance from traditional phosphoramidite in the chiral regulation, has unique advantages, and therefore, on the basis of the traditional phosphoramidite ligand, the application range of the ligand is expanded.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of asymmetric reaction, and particularly relates to a phosphoramidite ligand with a carbazole structure and a preparation method and application thereof. BACKGROUND

[0002] Phosphoramidite Phosphoramidites are currently recognized as a very versatile and readily available class of good chiral ligands suitable for the field of asymmetric catalysis. Their modular structure enables the creation of a library of ligands and facilitates fine-tuning for specific catalytic reactions. Their molecular structure is characterized by the presence of a coordinatable P-N bond in the molecule, which can coordinate with many metals to form chiral species, thereby catalyzing the occurrence of asymmetric reactions. They have a wide range of applications and can induce the generation of various chiral environments. In addition, with the continuous development of the field, their monodentate nature is also essential in the use of mixed ligand combination catalysis.

[0003] Since 1996, when Feringa et al. (Angew. Chem., Int. Ed. 1996, 35, 2374.) developed the first chiral phosphoramidite ligand (which is an axially chiral monodentate phosphorus ligand derived from BINOL with C2 symmetry), 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 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 skeleton. Its rigid conformation and chemical robustness are key features that endow this structure and its variants with great importance in asymmetric catalysis. The application of its skeleton 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 exhibit better catalytic activity, while SPINOL-based catalysts generally exhibit better asymmetric induction ability. Therefore, when synergy cannot be achieved in these two features, a dilemma will be encountered.

[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 integrate the advantages of BINOL and SPINOL skeletons, and its application has not been fully developed, so the SPHENOL skeleton can be introduced into the phosphoramidite.

[0007] So far, the molecular skeleton of the 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 ligand with the fourth skeleton (i.e. the SPHENOL bisphenol skeleton) has a larger development space. However, most of the modifications of the SPHENOL spiro phosphoramidite ligand currently still remain in the chiral control end of the bisphenol, and the modification of the N end of the aromatic ring has not involved the modification of the heterocyclic aromatic hydrocarbon. SUMMARY

[0010] The purpose of the present application is to provide a phosphoramidite ligand with a carbazole structure and its preparation method and application, enrich and develop the phosphoramidite ligand library, and provide a new catalytic means for asymmetric reactions.

[0011] To achieve the above-mentioned purpose of the application, the technical solutions of the present application are as follows:

[0012] A phosphoramidite ligand with a carbazole structure, the structural formula of the phosphoramidite ligand is shown as 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 application introduces a carbazole structure into the SPHENOL type phosphoramidite ligand. Compared with the traditional imino stilbene structure, the carbazole structure makes the modification of the N end of the phosphoramidite ligand more simple and easy, and a series of different SPHENOL type phosphoramidite ligands can be derived by adding different substituents on different positions of the carbazole structure, which is a new attempt to enrich the SPHENOL type phosphoramidite ligand.

[0016] The phosphoramidite ligand of the present application also has a regulating effect on the formation of chirality in catalytic reactions, and sometimes shows different performance from traditional phosphoramidite in chiral regulation, has its unique advantages, and therefore expands the application range of the ligand on the basis of traditional phosphoramidite ligand.

[0017] As preferred, the structure of the phosphoramidite ligand with the carbazole structure is shown in formula (II) or (III):

[0018]

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

[0020] Both of the phosphoramidite ligands show good chiral control in asymmetric azido-ynol [3+2] cycloaddition reaction, indole ynamine and o-benzyloxybenzene borate [4+2] cyclization reaction, and ynamine [2+2+2] cycloaddition reaction.

[0021] The application also provides a preparation method of the phosphoramidite ligand with the carbazole structure, which comprises: under an inert atmosphere, using a carbazolyl heterocyclic compound, a phosphorus donor and a SPHENOL bisphenol skeleton as raw materials, and synthesizing the phosphoramidite ligand with the 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, uniformly mixing in an ice bath to obtain solution A;

[0024] Preferably, the base comprises triethylamine, the phosphorus donor comprises phosphorus trichloride, and the solvent comprises ultradry grade dichloromethane or tetrahydrofuran;

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

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

[0027] Preferably, the structure of the carbazolyl heterocyclic compound is shown in formula (IV) or (V):

[0028]

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

[0030] (3) under inert atmosphere, adding SPHENOL bisphenol skeleton into solution B, and then reacting for 3-15 min in ice bath, and then reacting for 4-5 h at room temperature, to obtain the phosphoramidite ligand.

[0031] The application further provides application of the phosphoramidite ligand with the carbazole structure in catalyzing an asymmetric azido-internal alkyne [3+2] cycloaddition reaction.

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

[0033] Experiments show that in the rhodium-catalyzed asymmetric azido-internal alkyne [3+2] cycloaddition reaction, the participation of Phos C makes the yield of the target product reach 38 % and the ee value reach 47 %; and the participation of Phos D makes the yield of the target product reach 60 % and the ee value reach 53 %.

[0034] The application further provides application of the phosphoramidite ligand with the carbazole structure in catalyzing a [4+2] cyclization reaction of an indolyl ynamine and o-benzylcyano phenylboronic acid ester.

[0035] Preferably, the content of the phosphoramidite ligand in the [4+2] cyclization reaction of the indolyl ynamine and o-benzylcyano phenylboronic acid ester is 10 mol %.

[0036] Experiments show that in the rhodium-catalyzed [4+2] cyclization reaction of the indolyl ynamine and o-benzylcyano phenylboronic acid ester, the participation of Phos C makes the yield of the target product reach 55 % and the ee value reach 45 %; and the participation of Phos D makes the yield of the target product reach 54 % and the ee value reach 44 %.

[0037] The application further provides application of the phosphoramidite ligand with the carbazole structure in catalyzing a ynamine [2+2+2] cycloaddition reaction.

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

[0039] Experiments show that in the rhodium-catalyzed asymmetric azido-internal 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 %; and the participation of Phos D makes the yield of the target product reach 54 % and the ee value reach 55 %.

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

[0041] (1) The application introduces a carbazole structure into the SPHENOL type phosphoramidite ligand, compared with the traditional imino stilbene structure, the carbazole structure makes the N-terminal modification of the phosphoramidite ligand simpler and easier, and adding different substituents on different positions of the carbazole structure can derive a series of different SPHENOL type phosphoramidite ligands, which is a new attempt to enrich the SPHENOL type phosphoramidite ligands.

[0042] (2) The phosphoramidite ligand of the application also has a regulating effect on the formation of chirality in a catalytic reaction, and sometimes shows different performance from traditional phosphoramidite in chirality regulation, has its unique advantages, and therefore expands the application range of the ligand on the basis of traditional phosphoramidite ligand.

[0043] (3) The two phosphoramidite ligands Phos C and Phos D provided by the application show good chirality regulation effect in asymmetric azide-internal alkyne [3+2] cycloaddition reaction, [4+2] cyclization reaction of indole alkyne amine and o-benzyl cyanobenzenboronic acid and [2+2+2] cycloaddition reaction of alkyne amine. In the rhodium-catalyzed asymmetric azide-internal alkyne [3+2] cycloaddition reaction, the participation of Phos D makes the yield of the target product reach 60%, and the ee value reaches 53%; in the rhodium-catalyzed [4+2] cyclization reaction of indole alkyne amine and o-benzyl cyanobenzenboronic acid, the participation of Phos C makes the yield of the target product reach 55%, and the ee value reaches 45%; in the rhodium-catalyzed asymmetric azide-internal alkyne [3+2] cycloaddition reaction, the participation of Phos C makes the yield of the target product reach 61%, and the ee value reaches 52%; the participation of Phos D makes the yield of the target product reach 54%, and the ee value reaches 55%. BRIEF DESCRIPTION OF DRAWINGS

[0044] Figure 1 The synthesis route map of the phosphoramidite ligand Phos C with a carbazole structure of the application is shown in the figure;

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

[0046] Figure 2 The nuclear magnetic resonance analysis spectrum of the phosphoramidite ligand Phos C with a carbazole structure of the application is shown in the figure;

[0047] Figure 3 The synthesis route map of the phosphoramidite ligand Phos D with a carbazole structure of the application is shown in the figure;

[0048] Figure 4 The nuclear magnetic resonance analysis spectrum of the phosphoramidite ligand Phos D with a carbazole structure of the application is shown in the figure;

[0049] Figure 5 Reaction scheme of rhodium-catalyzed asymmetric azide-internal alkyne [3+2]cycloaddition reaction;

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

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

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

[0053] Figure 7 Reaction scheme of rhodium-catalyzed [4+2]cyclization reaction of indole yne amine and o-benzyl cyanobenzenborate;

[0054] Wherein, THF represents tetrahydrofuran;

[0055] Figure 8 Reaction scheme of iridium-catalyzed yne amine [2+2+2]cycloaddition reaction;

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

[0057] The technical solutions of the present application will be further described in detail below in combination with the drawings and specific embodiments.

[0058] Synthesis of phosphoramidite ligand Phos C with carbazole structure in Example 1

[0059] The phosphoramidite ligand Phos C with carbazole structure in this embodiment has a structural formula as shown in formula (II):

[0060]

[0061] The synthesis route of the phosphoramidite ligand Phos C with carbazole structure is shown in the following formula (I): Figure 1 and specifically includes the following steps:

[0062] (1) Mix the base, solvent and phosphorus donor, mix in the ice bath to obtain solution A;

[0063] Specifically, take a sealed tube, several syringes, first put into the oven, fill the balloon, take ice standby, set the stirring heater temperature to 45℃; when the sealed tube is very hot, take it out, immediately screw on the lid, do not need to be completely sealed, then use the vacuum pump to extract, wait for cooling, adjust the double-pipe nitrogen, after the sealed tube cools down, fill and discharge nitrogen three or four times, then let the sealed tube be in a nitrogen atmosphere; take the baked syringe and needle tube, first empty the air and nitrogen three times, extract triethylamine (8 equivalents); under the nitrogen atmosphere, carefully open the sealed tube lid, inject triethylamine into it, the same operation takes dichloromethane (super dry) (0.25M), then place the sealed tube in an ice water bath, the same method takes phosphorus trichloride (1.5 equivalents), then cover the lid, turn off the nitrogen, place in the ice bath and stir for 15 min to obtain solution A;

[0064] (2) Under the inert atmosphere, add the carbazolyl heterocyclic compound to solution A, mix in the ice bath, and then stir at 25-55℃ overnight to obtain solution B;

[0065] Specifically, weigh the carbazole (1.5 equivalents) and add it to solution A under the nitrogen atmosphere, place in the ice bath for 3 min, and then stir at 45℃ overnight to obtain solution B;

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

[0067]

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

[0069] Specifically, under the nitrogen atmosphere, weigh the SPHENOL bisphenol (1 equivalent) and add it, react in the ice bath for 5 min, then continue to react at room temperature for 4-5 h after taking it out, and the reaction is basically complete; after the reaction is complete, add silica gel powder, spin dry, and then pass through the column with the eluent petroleum ether: ethyl acetate = 50-20:1 to obtain the phosphoramidite ligand Phos C.

[0070] The obtained phosphoramidite ligand Phos C is analyzed by nuclear magnetic resonance and high-resolution mass spectrometry (as shown in Figure 2 The analysis results are as follows:

[0071] 1H NMR (400 MHz, CDC13) δ 7.91 (d, J = 6.8 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 8.2 Hz, 1H), 7.51 - 7.44 (m, 2H), 7.41 (d, J = 7.2 Hz, 1H), 7.36 (d, J = 5.8 Hz, 2H), 7.32 (d, J = 7.4 Hz, 2H), 7.28 (d, J = 2.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 1H), 6.97 - 6.89 (m, 1H), 6.72 (d, J = 8.8 Hz, 1H), 6.49 (d, J = 8.8 Hz, 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) calcd for C 38 H 28 NNaO2P[M + Na] + : 584.1750, found: 584.1752.

[0074] Synthesis of Phosphoramidite Ligand Phos D with a Carbazole Structure

[0075] This example is a phosphoramidite ligand Phos D with a carbazole structure, whose structural formula is shown in formula (III):

[0076]

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

[0078]

[0079] The obtained phosphoramidite ligand Phos C was subjected to nuclear magnetic and high resolution mass spectrum analysis (as shown in Figure 4 ), and the analysis results are as follows:

[0080] 1H NMR (400 MHz, CDC13) δ 8.25 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.81-7.74 (m, 3H), 7.65 (d, J = 8.0 Hz, 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 = 8.8 Hz, 1H), 6.61 (d, J = 7.2 Hz, 2H), 6.33 (d, J = 8.8 Hz, 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) calcd for C 49 H 34 NNaO2P [M + Na] + : 722.2219, found: 722.2218.

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

[0084] The reaction route of rhodium-catalyzed asymmetric azide-internal alkyne [3+2]cycloaddition reaction is shown in Figure 5 , and the amount of each raw material is shown in Figure 5 .

[0085] Before adding 1a and 2a into the reaction system, the catalyst and the ligand were mixed and stirred for 40 min. In this example, different ligands were added into the reaction system, and under different ligands and corresponding reaction conditions, the yield (determined by 1H NMR using 1,3,5-trimethoxybenzene as an internal standard) and ee value (determined by chiral high performance liquid chromatography) of the target product (3a) are shown in Figure 6 .

[0086] As can be seen from Figure 6 , L3 is Phos C, and L8 is Phos D.

[0087] From the condition screening of the substrate, it is found that the phosphoramidite ligands Phos C and Phos D of the application can be successfully applied in 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 phosphoramidite ligand with carbazole structure in [4+2] cyclization reaction of indolyl ynamine and o-benzyloxy cyanobenzene

[0089] The reaction route of the rhodium-catalyzed [4+2] cyclization reaction of indolyl ynamine and o-benzyloxy cyanobenzene is shown in Figure 7 , and the amount of each raw material is shown in Figure 7 .

[0090] It is found through experiments that in the rhodium-catalyzed [4+2] cyclization reaction of indolyl ynamine and o-benzyloxy cyanobenzene, the participation of Phos C makes the yield of the target product reach 55% and the ee value reach 45%; the participation of Phos D makes the yield of the target product reach 54% and the ee value reach 44%.

[0091] Example 5: Application of phosphoramidite ligand with carbazole structure in ynamine [2+2+2] cycloaddition reaction

[0092] The reaction route of the iridium-catalyzed ynamine [2+2+2] cycloaddition reaction is shown in Figure 8 , and the amount of each raw material is shown in Figure 8 .

[0093] It is found through experiments that in the iridium-catalyzed ynamine [2+2+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%.

Claims

1. A phosphoramidite ligand having a carbazole structure, characterized in that: The structural formula is shown in formula (I): （Ⅰ）； In formula (I), R1 or R3 is independently selected from hydrogen or phenyl, and R2 is selected from hydrogen or methyl.

2. The phosphoramidite ligand having a carbazole structure according to claim 1, wherein The structural formula is shown in formula (II): （Ⅱ）。 3. The phosphoramidite ligand having a carbazole structure according to claim 1, wherein The structural formula is shown in formula (III): （Ⅲ）。 4. The method for preparing a phosphoramidite ligand having a carbazole structure according to any one of claims 1 to 3, wherein: include: Under an inert atmosphere, the phosphoramidite ligand having a carbazole structure is synthesized by a nucleophilic substitution reaction using a carbazole heterocyclic compound, a phosphorus donor and a SPHENOL bisphenol skeleton as raw materials; The phosphorus donor is selected from phosphorus trichloride.

5. The preparation method according to claim 4, wherein The following steps are involved: (1) Mix the base, solvent, and phosphorus donor and mix them in an ice bath to obtain solution A; (2) Under an inert atmosphere, add a carbazole-based heterocyclic compound to solution A, mix well in an ice bath, and stir 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, wherein In step (1), the base is selected from triethylamine, and the solvent is selected from ultra-dry 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, wherein In step (2), the structural formula of the carbazole-based heterocyclic compound is shown in formula (IV) or (V): （Ⅳ） ； （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 according to 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 according to 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 according to any one of claims 1 to 3 in catalyzing the [2+2+2] cycloaddition reaction of alkynamines.

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