阅读说明：本技术 一种手性四醇类糖醇化合物的不对称合成方法 (Asymmetric synthesis method of chiral tetraol sugar alcohol compound ) 是由 宋静远 王百贵 于 2020-06-24 设计创作，主要内容包括：1,2,3,4-四醇(C4糖醇)是一种具有四个连续相邻的手性羟基的化合物,具有极高的应用价值。本发明提供一种制备手性1,2,3,4-四醇类化合物的方法。所述方法是在有机溶剂中,通过二茂铁类型PNN类、PNO类三齿配体的铱配合物催化剂和碱的作用,将化合物I和氢气进行不对称催化氢化反应,通过动态动力学机制能够快速、高效地构建含有连续四个手性中心的1,2,3,4-四醇类化合物,具有很高的原子经济性。本发明方法制备所得的产物对映选择性非常高,dr值最高可达>99:<1,立体选择性,ee值最高超过了99.9％。本发明所用底物易于制备,且反应条件温和,后处理操作方便简洁,即可以高收率、高对映选择性地得到目标化合物,底物适用范围广泛。(The 1,2,3, 4-tetrol (C4 sugar alcohol) is a compound with four consecutive adjacent chiral hydroxyl groups and has extremely high application value. The invention provides a method for preparing chiral 1,2,3, 4-tetrol compounds. The method is characterized in that in an organic solvent, under the action of an iridium complex catalyst of ferrocene type PNN and PNO tridentate ligands and alkali, a compound I and hydrogen are subjected to asymmetric catalytic hydrogenation reaction, and a 1,2,3, 4-tetraol compound containing four continuous chiral centers can be quickly and efficiently constructed through a dynamic kinetic mechanism, so that the method has high atom economy. The product prepared by the method has very high enantioselectivity, the dr value can reach more than 99 to <1, and the stereoselectivity and the ee value are more than 99.9% at most. The substrate used in the invention is easy to prepare, the reaction condition is mild, the post-treatment operation is convenient and simple, the target compound can be obtained with high yield and high enantioselectivity, and the substrate has wide application range.)

1. A process for the asymmetric synthesis of 1,2,3, 4-tetraol (C4 sugar alcohol) compounds containing four consecutive chiral centers. In an organic solvent, under the action of an asymmetric hydrogenation catalyst and a base, carrying out asymmetric catalytic hydrogenation on the compound I and hydrogen to prepare the compound shown in the formula II.

Characterized in that R is¹,R²Is an alkyl substituent or an aryl substituent.

When R is¹＝R²When the compound is a phenyl group, 4-methylphenyl group, 4-methoxyphenyl group, 4-cyclohexylphenyl group, 4-n-butylphenyl group, 4-fluorophenyl group, 2-methylphenyl group, 2-methoxyphenyl group, 2-fluorophenyl group, 3-methylphenyl group, 3-methoxyphenyl group, 1-naphthyl group, 1-furyl group, 1-thienyl group.

When R is¹≠R²When R is¹When it is phenyl, R²Is 4-methylphenyl, 4-methoxyphenyl, 4-isobutylphenyl, 4-chlorophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-methylphenyl, 3-methoxyphenyl, 1-naphthyl, 1-furyl, 1-thienyl, methyl.

2. The process according to claim 1, wherein the base is one or more of sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium acetate, sodium carbonate, potassium carbonate, and cesium carbonate.

3. The process according to claim 1, wherein said iridium PNN-type catalyst containing a ferrocene-type tridentate ligand is f-amphox, f-amphamide or a derivative thereof.

4. The process according to claim 1, wherein the ferrocene type tridentate ligand iridium PNO catalyst is provided with a PNO ligand of f-amphol, f-alpha or a derivative thereof.

5. The method of claim 1, wherein the organic solvent is one or more of methanol, ethanol, isopropanol, dichloromethane, tetrahydrofuran, toluene, and 1, 2-dichloroethane.

6. The method according to claims 1 to 5, wherein the amount of the asymmetric hydrogenation catalyst is 1:200 to 1000 in terms of a molar ratio of the catalyst to the compound I.

7. The method according to claims 1-6, wherein the amount of the base is 1:20 to 1:100 in terms of the molar ratio of the base to the compound I.

Technical Field

The invention belongs to the field of organic synthesis methodology, and relates to an asymmetric synthesis method for synthesizing chiral tetrol sugar compounds by asymmetric hydrogenation and dynamic dynamics.

Background

The carbohydrate is an organic compound containing multiple hydroxyl groups, which is abundant in nature and involved in many biological processes. At present, carbohydrate compounds are only available from natural sources, and this densely oxidized framework has important application values for many disciplines. Therefore, sugar alcohols having a biomimetic effect of sugars and an effect of containing an oxygen-functionalized chiral synthon are increasingly being the subject of research for developing new drugs and functional materials. Therefore, it is very important to develop a simple synthetic method for constructing these sugar alcohol compounds.

In general, sugar alcohols have the following characteristics: steric diversity (configuration of hydroxyl groups), substituent diversity, and length diversity of hydroxyl chains. However, the polyhydroxylated structures have poor solubility in organic solvents, poor thermal stability and a limited range of functionalization. Thus, sugar alcohols are relatively difficult to obtain, which prevents the use of sugar alcohols in further synthetic chemistry, also losing a comprehensive assessment of their structure-activity relationship necessary in drug design.

1,2,3, 4-tetraol (C4 sugar alcohol) is a compound having four consecutive adjacent chiral hydroxyl groups, and is widely present in medicines, agricultural chemicals, daily chemicals, and organic materials. The conventional methods for the synthesis of 1,2,3, 4-tetraol backbones are mainly Sharpless dihydroxylation of conjugated dienes, dihydroxylation and reduction of 1, 2-dioxopyrimidines, deoxygenation of carbohydrates, metabolic activation, nucleophilic addition or reduction, and derivatization from tartaric acid. However, these methods are often multi-step, time and labor intensive, and inefficient.

Disclosure of Invention

The invention provides a method for constructing a 1,2,3, 4-tetraol (C4 sugar alcohol) compound containing four continuous chiral centers by asymmetrically hydrogenating a racemate substrate cis-2, 3-dihydroxy-1, 4-diketone compound. A method for constructing a chiral 1,2,3, 4-tetraol (C4 sugar alcohol) compound rapidly and efficiently by using a dynamic kinetic method under the conditions of a chiral catalyst, hydrogen pressure and alkali. The method has the advantages of mild conditions, simple operation, wide substrate application range and high product application value, and obtains the target compound with high yield, high enantioselectivity and high stereoselectivity.

The invention provides a method for synthesizing a chiral 1,2,3, 4-tetraol (C4 sugar alcohol) compound, which has the following reaction equation:

in the formula R¹,R²Is an alkyl substituent or an aryl substituent. When R is¹＝R²When the compound is a phenyl group, 4-methylphenyl group, 4-methoxyphenyl group, 4-cyclohexylphenyl group, 4-n-butylphenyl group, 4-fluorophenyl group, 2-methylphenyl group, 2-methoxyphenyl group, 2-fluorophenyl group, 3-methylphenyl group, 3-methoxyphenyl group, 1-naphthyl group, 1-furyl group, 1-thienyl group. When R is¹≠R²When R is¹When it is phenyl, R²Is 4-methylphenyl, 4-methoxyphenyl, 4-isobutylphenyl, 4-chlorophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-methylphenyl, 3-methoxyphenyl, 1-naphthyl, 1-furyl, 1-thienyl, methyl.

The invention provides a preparation method of a compound shown in a formula II, wherein the asymmetric hydrogenation catalyst comprises but is not limited to a ferrocene type tridentate ligand catalyst. The ferrocene type tridentate ligand catalyst can be iridium PNN type or iridium PNO type. Wherein, in the iridium PNN catalyst, the PNN ligand can be f-amphox, f-amphetamine or derivatives thereof. In the iridium PNO catalyst, the PNO ligand can be f-amphol, f-alpha or derivatives thereof.

The iridium PNN catalyst or the iridium PNO catalyst is prepared by in-situ complexing the PNN ligand or the PNO ligand and a transition metal Ir complex precursor in an organic solvent. Wherein said transition metal Ir complex precursor comprises: [ Ir (COD) Cl ]2, Ir (COD) X, [ Ir (COE) Cl ]2, Ir (COD) X, [ Ir (NBD)2Cl ]2, [ Ir (NBD)2] X. Wherein X is a counter anion.

The iridium PNN catalyst has the following structure

In some embodiments, the amount of the asymmetric hydrogenation catalyst may be the amount conventionally used for asymmetric hydrogenation reactions; the preferable reaction dosage of the invention can be 1: 200-1000 in terms of molar ratio of the catalyst to the compound I.

The invention provides a preparation method of a compound shown in formula II, wherein the organic solvent is an organic solvent used for asymmetric hydrogenation catalytic reaction, such as one or more of methanol, ethanol, isopropanol, dichloromethane, tetrahydrofuran, toluene and 1, 2-dichloroethane, preferably one or more of dichloromethane, 1, 2-dichloroethane and toluene.

In the preparation method of the compound of the formula II, the alkali can be one or more of sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium acetate, sodium carbonate, potassium carbonate and cesium carbonate.

In some embodiments, in the process for preparing the compound of formula II, the amount of base employed may be a catalytic amount used in conventional reactions; the preferable reaction dosage in the invention is 1:100 to 1:1000 in terms of the molar ratio of the base to the compound I.

The invention provides a preparation method of a compound shown in a formula II, wherein the pressure of asymmetric hydrogenation reaction is the conventional pressure of asymmetric hydrogenation reaction. The pressure of hydrogen is preferably 20 to 80atm, more preferably 60 to 80 atm.

According to the preparation method of the compound of the formula II, the temperature of the asymmetric hydrogenation reaction is the common temperature of catalytic hydrogenation reaction in the field, preferably 20-80 ℃, and more preferably 25-30 ℃.

Compared with the prior art, the preparation method of the compound of the formula II has the advantages that the synthesized stereoselectivity and yield can be greatly improved, the highest ee value of the stereoselectivity is more than 99.9%, and the enantioselectivity dr is more than 99: <1 >. Therefore, the invention provides a method for obtaining the series of 1,2,3, 4-tetrol (C4 sugar alcohol) compounds with high efficiency, high yield, high enantioselectivity and high stereoselectivity.

Detailed Description

In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.

The technical means for structure confirmation are all common technical means known to the technicians in the field, such as nuclear magnetic resonance technology and high-resolution mass spectrometry. The chiral optical property confirmation technical means are all common technical means known to the technical personnel in the field, such as high performance liquid chromatography and optical rotation photometry.