KR20240070838A - Chiral 1,2-amino tertiary alcohols and methods for their synthesis - Google Patents

Abstract

The present invention relates to a chiral 1,2-amino tertiary alcohol with high enantioselectiveness and a method for synthesizing the same. The method for synthesizing chiral 1,2-amino tertiary alcohol according to an embodiment of the present invention is a chiral boron Lewis acid. (Chiral boron Lewis acid) It may include reacting α-silyl amine and aryl methyl ketone by irradiating visible light in the presence of a catalyst and a photosensitizer.

Description

Chiral 1,2-amino tertiary alcohols and methods for their synthesis}

The present invention relates to chiral 1,2-amino tertiary alcohols with high enantioselective properties and methods for their synthesis.

1,2-amino alcohol compounds are important skeletons that are easily found in many bioactive molecules existing in nature, and the development of efficient methods to synthesize this structure is very important. To synthesize 1,2-amino secondary alcohol, one of these important frameworks, an asymmetric addition reaction of an α-amino alkyl radical and an aldehyde compound using visible light was developed.

However, asymmetric photoreactions with ketones rather than aldehydes are known to be more difficult to apply to reactions using visible light because the reduction potential of ketone compounds is generally higher than that of aldehydes. In fact, the previously reported method of synthesizing 1,2-amino tertiary alcohol using visible light cannot be applied to general ketones with low reactivity and has the limitation of being applied only to ketone compounds with activating functional groups, so it may be applied more universally. Development of a synthetic method is necessary.

One object of the present invention is to provide a method for synthesizing chiral 1,2-amino tertiary alcohol with high optical selectivity using visible light with excellent yield.

Another object of the present invention is to provide a chiral 1,2-amino tertiary alcohol exhibiting high enantioselectivity.

The method for synthesizing chiral 1,2-amino tertiary alcohol according to an embodiment of the present invention is to synthesize α-silyl amine by irradiating visible light in the presence of a chiral boron Lewis acid catalyst and a photosensitizer. It includes the step of reacting (α-Silyl amine) with aryl methyl ketone.

In one embodiment, the chiral boron Lewis acid catalyst is characterized in that it is a compound represented by the following formula (1).

[Formula 1]

In Formula 1, Ar ^a represents a phenyl group or a 3,5-dimethylphenyl group, and Ar ^b represents a phenyl group or a 3-fluorophenyl group.

In one embodiment, the aryl methyl ketone is represented by the following formula (2).

[Formula 2]

In Formula 2, Ar ¹ represents a substituted or unsubstituted phenyl group or naphthyl group, and Me represents a methyl group.

In one embodiment, the aryl methyl ketone is represented by the following Chemical Formula 2-1 or the following Chemical Formula 2-2.

[Formula 2-1]

In Formula 2-1, R ₁ represents -Cl, -F, -Br, -CF ₃ , an acetoxy group, or a methyl group, and Me represents a methyl group.

[Formula 2-2]

In Formula 2-2, Me represents a methyl group.

In one embodiment, the α-silyl amine forms an α-amino alkyl radical by irradiation with visible light, and the α-amino alkyl radical is a chiral boron Lewis acid. It is characterized in that it reacts with the aryl methyl ketone under a (chiral boron Lewis acid) catalyst.

In one embodiment, the α-silyl amine is represented by the following formula (3).

[Formula 3]

In Formula 3, Ar ² represents a substituted or unsubstituted phenyl group, and TMS represents a trimethylsilyl group.

In one embodiment, in Formula 3, Ar ² is a p-bromophenyl group or a p-tolyl group.

In one embodiment, the catalyst may be included at a concentration of 20 mol% or 40 mol%, and the photosensitizer may be included at a concentration of 0.5 mol% to 1.0 mol%.

In one embodiment, the reaction step may be performed at room temperature under visible light irradiation with a wavelength of 425 nm or 461 nm.

In one embodiment, a step of deprotecting a protecting group present in the synthesized product may be further included after the reaction step.

In one embodiment, the chiral 1,2-amino tertiary alcohol is represented by the following formula (4).

[Formula 4]

In Formula 4, Ar ¹ represents a substituted or unsubstituted phenyl group or naphthyl group, and Ar ² represents a substituted or unsubstituted phenyl group.

In one embodiment, the chiral 1,2-amino tertiary alcohol may be represented by any of the following compounds.

In the above formula, Me refers to a methyl group and Ph refers to a phenyl group.

Meanwhile, the chiral 1,2-amino tertiary alcohol according to another embodiment of the present invention has a structure represented by the following formula (4) and exhibits enantioselective properties.

[Formula 4]

In Formula 4, Ar ¹ represents a substituted or unsubstituted phenyl group or naphthyl group, and Ar ² represents a substituted or unsubstituted phenyl group.

In one embodiment, the chiral 1,2-amino tertiary alcohol may be represented by any one of the following compounds.

In the above formula, Me refers to a methyl group and Ph refers to a phenyl group.

According to the present invention, chiral 1,2-amino tertiary alcohol can be synthesized with excellent yield and high stereoselectivity.

In addition, in the present invention, the α-amino alkyl radical generated by irradiating visible light to α-Silyl amine is converted into aryl methyl ketone with various functional groups under a chiral boron Lewis acid catalyst. A chiral 1,2-amino tertiary alcohol with excellent optical activity can be synthesized in high yield through an over-addition reaction.

Figure 1 shows a schematic diagram of a method for synthesizing chiral 1,2-amino tertiary alcohol according to one embodiment of the present invention.
Figure 2 is a diagram showing the synthesis mechanism of chiral 1,2-amino tertiary alcohol according to an embodiment of the present invention.
Various embodiments are now described with reference to the drawings, wherein like reference numerals are used to indicate like elements throughout the drawings. In this specification, for purposes of explanation, various descriptions are presented to provide a better understanding of the invention. However, it will be clear that these embodiments may be practiced without these specific descriptions. In other instances, well-known structures and devices are presented in block diagram form to facilitate describing the embodiments.

Hereinafter, embodiments of the present invention will be described in detail with reference to the attached drawings. Since the present invention can be subject to various changes and have various forms, specific embodiments will be illustrated in the drawings and described in detail in the text. However, this is not intended to limit the present invention to a specific disclosed form, and should be understood to include all changes, equivalents, and substitutes included in the spirit and technical scope of the present invention. While describing each drawing, similar reference numerals are used for similar components.

The terms used in this application are only used to describe specific embodiments and are not intended to limit the present invention. Singular expressions include plural expressions unless the context clearly dictates otherwise. In this application, terms such as “comprise” or “have” are intended to designate the presence of features, steps, operations, components, parts, or combinations thereof described in the specification, but are not intended to indicate the presence of one or more other features or steps. , it should be understood that it does not exclude in advance the possibility of the existence or addition of operations, components, parts, or combinations thereof.

Figure 1 shows a schematic diagram of a method for synthesizing chiral 1,2-amino tertiary alcohol according to one embodiment of the present invention.

Referring to Figure 1, the method for synthesizing chiral 1,2-amino tertiary alcohol according to an embodiment of the present invention uses visible light in the presence of a chiral boron Lewis acid catalyst and a photosensitizer. It includes the step of reacting α-Silyl amine and Aryl methyl ketone by irradiation.

In one embodiment, the chiral boron Lewis acid catalyst may be a compound represented by the following Chemical Formula 1, and one activated by triflic acid (TfO) may be used.

[Formula 1]

In Formula 1, Ar ^a represents a phenyl group or a 3,5-dimethylphenyl group, and Ar ^b represents a phenyl group or a 3-fluorophenyl group.

In one embodiment, the catalyst may be used at a concentration of 15 to 40 mol% or 20 to 40 mol%, most preferably 20 mol% or 40 mol%. However, the concentration is not limited to the above-mentioned range and may vary.

In one embodiment, the aryl methyl ketone may be represented by the following formula (2).

[Formula 2]

In Formula 2, Ar ¹ represents a substituted or unsubstituted phenyl group or naphthyl group, and Me represents a methyl group.

More specifically, the aryl methyl ketone may be represented by Formula 2-1 or Formula 2-2.

[Formula 2-1]

In Formula 2-1, R ₁ represents -Cl, -F, -Br, -CF ₃ , an acetoxy group, or a methyl group, and Me represents a methyl group.

[Formula 2-2]

In Formula 2-2, Me represents a methyl group.

Meanwhile, in the reaction step of the present invention, α-silyl amine forms an α-amino alkyl radical by irradiation with visible light, and the α-amino alkyl radical is formed by the chiral It can react with the aryl methyl ketone under a boron Lewis acid catalyst.

In one embodiment, the α-Silyl amine may be represented by the following formula (3).

[Formula 3]

In Formula 3, Ar ² represents a substituted or unsubstituted phenyl group, and TMS represents a trimethylsilyl group. More specifically, in Formula 3, Ar ² may be a p-bromophenyl group or a p-tolyl group.

In one embodiment, the photosensitizer is a material that is excited by visible light irradiation and reduced by receiving one electron from α-Silyl amine, for example, Ir(dFppy) ₃ (dFppy = 2-(4,6-difluorophenyl)pyridyl) can be used, but is not particularly limited.

Meanwhile, in the reaction step of the present invention, the catalyst may be included at a concentration of 15 to 40 mol%, or 20 to 40 mol%, and the photosensitizer may be included at a concentration of 0.5 mol% to 1.0 mol%. Preferably, the catalyst may be included at a concentration of 20 mol% or 40 mol%, and the photosensitizer may be included at a concentration of 1.0 mol%. However, the concentration is not limited to the above-mentioned range and may vary.

Additionally, the reaction step may be performed at room temperature under visible light irradiation with a wavelength of 380 to 500 nm. As an example, the reaction step may be performed at room temperature under visible light irradiation with a wavelength of 425 nm or 461 nm.

In one embodiment, a step of deprotecting a protecting group present in the synthesized product may be further included after the reaction step. For example, a protecting group such as a silyl group may be present in the product synthesized after the reaction step, and the protecting group can be deprotected by removing it using a tetrabutylammonium fluoride (TBAF) solution.

In one embodiment, the chiral 1,2-amino tertiary alcohol synthesized including the reaction step may be represented by the following formula (4).

[Formula 4]

In Formula 4, Ar ¹ represents a substituted or unsubstituted phenyl group or naphthyl group, and Ar ² represents a substituted or unsubstituted phenyl group.

More specifically, the chiral 1,2-amino tertiary alcohol may be represented by any of the following compounds.

In the above formula, Me refers to a methyl group and Ph refers to a phenyl group.

Meanwhile, the chiral 1,2-amino tertiary alcohol according to another embodiment of the present invention has the structure represented by Chemical Formula 4 and exhibits enantioselective properties.

More specifically, the chiral 1,2-amino tertiary alcohol may be represented by any one of compounds 5a to 5u.

Hereinafter, the synthesis mechanism of chiral 1,2-amino tertiary alcohol according to an embodiment of the present invention will be described with reference to FIG. 2.

Referring to Figure 2, first, photosensitizer 4 becomes 4*, an excited state by light, and is reduced while receiving one electron from α -silyl amine. Afterwards, the activated α -amino alkyl radical 9 causes a radical addition reaction with the ketone compound 1a coordinated with the chiral boron Lewis acid catalyst 3b, forming radical intermediate 11.

Intermediate 12 is then formed by receiving one electron from another α -silyl amine 2a, and the desired material can be obtained by removing the trimethylsilyl group (TMS) protecting group of 12 with TBAF (tetrabutylammonium fluoride).

Hereinafter, the content of the present invention will be further explained through specific examples.

[Scheme 1]

In Example 1, as shown in Scheme 1, to synthesize 1,2-amino tertiary alcohol 5a, acetophenone 1a (0.25 mmol) and N-phenyl-N were used in the presence of three types of catalysts (3a - 3c) representing the above structures. An enantioselective radical addition reaction was performed using (trimethylsilyl)methylaniline 2a (0.30 mmol).

Specifically, the reaction was performed under visible light in the presence of 20 mol % concentration of catalyst 3 (3a - 3c) and 1.0 mol % concentration of photosensitizer 4 activated with triflic acid in dichloromethane (DCM) (1.25 mL). The investigation was carried out at 35°C until all reactants were consumed, and the desired product was obtained by removing the silyl group protecting group using a 1M tetrabutylammonium fluoride (TBAF) solution.

Meanwhile, in the present invention, additional reactions were performed by changing reaction conditions such as the type of light source, type of catalyst, and presence or absence of a photosensitizer, and the results are shown in Table 1 below. The yield was determined by measurement after separation and ee was determined by chiral HPLC.

(In Table 1, ^d means that the reaction is carried out at 35°C for 12 hours, ^e means that the reaction is carried out without a photosensitizer, and ^f means that the reaction does not occur.)

Looking at Table 1 above, it can be seen that the reactivity and yield of entry 2, which irradiated visible light using blue LEDs (425 and 461 nm), were improved compared to entry 1, which used a 23 W compact fluorescent light bulb (CFL) as the light source.

Meanwhile, looking at entries 2 - 4, in various catalyst structures, catalyst 3b with 3,5-dimethylphenyl and phenyl substituents showed high yield and reactivity results. Catalyst 3c provided 1,2-amino tertiary alcohol 5a with high enantioselectivity, but the yield was lower than that of catalyst 3b.

Additionally, looking at entries 5 - 6, when the reaction was performed without a catalyst or photosensitizer (entry 6), the catalytic reaction did not proceed well. Additionally, looking at entry 7, no reaction occurred even when the reaction was performed without visible light irradiation.

Through these results, it was confirmed that the reaction did not proceed well in the absence of any one of the chiral boron Lewis acid catalyst, photosensitizer, and light.

[Scheme 2]

In Example 2, after optimizing the reaction conditions in the same way as entry 3 of Example 1, aryl methyl ketone 1 (0.25 mmol) with various functional groups was used as a reactant as shown in Scheme 2, and α-silyl amine 2a (0.30 mmol) The reaction was performed. The products and synthesis yields according to the above reaction are as follows.

The reaction results show that, in addition to acetophenone, various ketone compounds with ortho-, meta- or para-substituted aromatic groups can produce optically active 1,2-amino tertiary alcohols 5a-5k in excellent yields with high enantioselectivity. The generated results can be confirmed, and it can be confirmed that the reaction proceeds without problems even if the amount of the 5a compound is increased up to 1 mmol (5a ^c ).

Specifically, ketone compounds with an electron withdrawing group showed high yield and stereoselectivity (5b-5h), and even with an electron donating group, good yield and stereoselectivity were shown. 1,2-amino tertiary alcohol could be synthesized (5i-5k).

Previously, electron-donating substituents were not good in the reaction of ketones, resulting in low reactivity and optical selectivity, but in the present invention, the reaction concentration of aryl methyl ketone 1 was increased (0.5 mL DCM, 0.5 mol% photosensitizer) during the synthesis of 5j and 5k. Reactivity was increased, which made it possible to synthesize 1,2-amino tertiary alcohol with good yield and stereoselectivity (5j-5k).

Meanwhile, it was confirmed that 1,2-amino tertiary alcohol (5I) having a 2-naphthyl group was formed in good yield with high optical selectivity.

[Scheme 3]

In Example 3, various α-silylamines (α-silylamine) 1 (0.25 mmol) and various aryl methyl ketones (0.30 or 0.5 mmol) were used as shown in Scheme 3 above, under the same conditions as Example 2. The reaction proceeded. As a result, chiral 1,2-amino tertiary alcohol (5m-5u) with high optical selectivity could be synthesized in high yield. Here, the synthesis of products 5m, 5q, and 5s is the result of the reaction using 0.5 mL DCM solvent and 0.5 mol% photosensitizer in Scheme 3, and 40 mol% catalyst was used in the synthesis of product 5s.

The synthesized product is a chiral 1,2-amino tertiary alcohol.

The reaction results show that chiral 1,2-amino tertiary alcohol 5m-5p was produced using para-bromophenyl-substituted silyl amine, which uses Suzuki-Miyaura coupling or Buchwald-Hartwig coupling to introduce various functional groups. It can be a useful substrate for coupling reactions such as minhwa.

In addition, the results of synthesizing 1,2-amino tertiary alcohol with a carbazole functional group, known as a potential bioactive compound, with high yield and enantioselectivity (5q-5t) can be confirmed.

Specifically, comparing the synthesized materials, when the ortho-substituted ketone reacts with α-silyl amine, the product is synthesized in lower yield than the para-substituted ketone (5p, 5s-5t vs 5m -5o, 5q-5r), which is due to high steric hindrance.

Meanwhile, the para-tolyl-substituted silyl amine was reacted by changing to 3a, a highly active catalyst, and the chiral product 5u was produced in high yield with high optical selectivity.

An experiment was conducted to confirm the mechanism of the enantioselective radical addition reaction.

[Scheme 4]

First, to confirm the radical pathway mechanism, a radical trapping experiment was performed by adding 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) as a radical scavenger (Scheme 4A) . As a result, when 1 equivalent of TEMPO was added, the enantioselective radical addition reaction was completely inhibited, confirming that this reaction passed through a radical intermediate, and radical by-products were confirmed through mass spectrometry and nuclear magnetic resonance analysis.

Next, to confirm the expected formation of ketyl radicals in the radical-radical coupling mechanism, a radical clock experiment was performed using cyclopropyl methyl ketone 6 (Scheme 4B).

As a result of the reaction, only addition product 7 material was produced in 8% yield, confirming that this reaction went through an addition reaction route, and no coupling product with an open ring was found. Therefore, it was confirmed that the present invention proceeds through a radical addition route rather than a coupling route. Afterwards, the quantum yield was measured and it was confirmed that the reaction was a radical chain reaction through the high quantum yield value of 307.

The description of the presented embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be apparent to those skilled in the art, and the general principles defined herein may be applied to other embodiments without departing from the scope of the invention. Thus, the present invention is not limited to the embodiments presented herein, but is to be construed in the broadest scope consistent with the principles and novel features presented herein.

Claims (14)

Including the step of reacting α-Silyl amine and Aryl methyl ketone by irradiating visible light in the presence of a chiral boron Lewis acid catalyst and a photosensitizer. doing,
Methods for the synthesis of chiral 1,2-amino tertiary alcohols.
According to paragraph 1,
A method for synthesizing chiral 1,2-amino tertiary alcohol, wherein the chiral boron Lewis acid catalyst is a compound represented by the following formula (1):
[Formula 1]

In Formula 1,
Ar ^a represents a phenyl group or a 3,5-dimethylphenyl group, and Ar ^b represents a phenyl group or a 3-fluorophenyl group.
According to paragraph 1,
A method for synthesizing chiral 1,2-amino tertiary alcohol, wherein the aryl methyl ketone is represented by the following formula (2):
[Formula 2]

In Formula 2,
Ar ¹ represents a substituted or unsubstituted phenyl group or naphthyl group, and Me represents a methyl group.
According to paragraph 3,
The aryl methyl ketone is characterized in that the aryl methyl ketone is represented by the following formula 2-1 or the following formula 2-2. Method for synthesizing chiral 1,2-amino tertiary alcohol:
[Formula 2-1]

In Formula 2-1,
R ₁ represents -Cl, -F, -Br, -CF ₃ , an acetoxy group or a methyl group, and Me represents a methyl group.
[Formula 2-2]

In Formula 2-2, Me represents a methyl group.
According to paragraph 1,
The α-Silyl amine forms an α-Amino alkyl radical upon irradiation with visible light, and the α-amino alkyl radical forms a chiral boron Lewis acid. Characterized by reacting with the aryl methyl ketone under a catalyst,
Methods for the synthesis of chiral 1,2-amino tertiary alcohols.
According to paragraph 1,
Method for synthesizing chiral 1,2-amino tertiary alcohol, wherein the α-Silyl amine is represented by the following formula (3):
[Formula 3]

In Formula 3 above,
Ar ² represents a substituted or unsubstituted phenyl group, and TMS represents a trimethylsilyl group.
According to clause 6,
In Formula 3, Ar ² is a p-bromophenyl group or a p-tolyl group.
Methods for the synthesis of chiral 1,2-amino tertiary alcohols.
According to paragraph 1,
The catalyst is contained at a concentration of 20 mol% or 40 mol%, and the photosensitizer is contained at a concentration of 0.5 mol% to 1.0 mol%,
Methods for the synthesis of chiral 1,2-amino tertiary alcohols.
According to paragraph 1,
The reaction step is performed at room temperature under visible light irradiation with a wavelength of 425 nm or 461 nm.
Methods for the synthesis of chiral 1,2-amino tertiary alcohols.
According to paragraph 1,
Characterized in that it further comprises a step of deprotecting a protecting group present in the synthesized product after the reaction step.
Methods for the synthesis of chiral 1,2-amino tertiary alcohols.
According to paragraph 1,
Method for synthesizing chiral 1,2-amino tertiary alcohol, characterized in that the chiral 1,2-amino tertiary alcohol is represented by the following formula (4):
[Formula 4]

In Formula 4 above,
Ar ¹ represents a substituted or unsubstituted phenyl group or naphthyl group, and Ar ² represents a substituted or unsubstituted phenyl group.
According to clause 11,
A method for synthesizing chiral 1,2-amino tertiary alcohol, wherein the chiral 1,2-amino tertiary alcohol is represented by any one of the following compounds.







In the above formula, Me refers to a methyl group and Ph refers to a phenyl group.
A chiral 1,2-amino tertiary alcohol having a structure represented by the following formula (4) and exhibiting enantioselective properties:
[Formula 4]

In Formula 4 above,
Ar ¹ represents a substituted or unsubstituted phenyl group or naphthyl group, and Ar ² represents a substituted or unsubstituted phenyl group.
According to clause 13,
A chiral 1,2-amino tertiary alcohol represented by any of the following compounds.







In the above formula, Me refers to a methyl group and Ph refers to a phenyl group.