阅读说明：本技术 一种手性2-羟基-1,4-二羰基化合物和泛解酸内酯的合成方法 (Synthesis method of chiral 2-hydroxy-1, 4-dicarbonyl compound and pantoic acid lactone ) 是由 达朝山 杜智宏 陶宝秀 秦文娟 袁梦 白彦兵 林行 张连春 殷杭华 姜伟林 余建 于 2019-04-29 设计创作，主要内容包括：本发明公开由四肽TP或其对映异构体ent-TP为手性催化剂催化脂肪醛与乙醛酸酯或脂肪醛与酰基甲醛一水合物的不对称Aldol反应,合成手性2-羟基-1,4-二羰基化合物,以及合成产物的用途。本发明所述的不对称Aldol反应合成手性2-羟基-1,4-二羰基化合物的方法如式1、2所示。本发明催化脂肪醛与乙醛酸酯或脂肪醛与酰基甲醛一水合物的不对称Aldol反应合成光学活性的2-羟基-1,4-二羰基化合物,据此可以进一步合成光学活性的泛解酸内酯,具有：反应条件温和、易操作、催化剂用量小、可以利用四肽及其对映异构体合成两种构型的2-羟基-1,4-二羰基化合物、产率高的优点。<Image he="408" wi="700" file="DDA0002044425080000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a method for catalyzing fatty aldehyde and glyoxylic ester or ester by using tetrapeptide TP or enantiomer ent-TP thereof as chiral catalystThe asymmetric Aldol reaction of fatty aldehyde and acyl formaldehyde monohydrate to synthesize chiral 2-hydroxy-1, 4-dicarbonyl compound and the application of the synthesized product. The method for synthesizing the chiral 2-hydroxy-1, 4-dicarbonyl compound by the asymmetric Aldol reaction is shown as formulas 1 and 2. The invention catalyzes the asymmetric Aldol reaction of fatty aldehyde and glyoxylate or fatty aldehyde and acyl formaldehyde monohydrate to synthesize the optically active 2-hydroxy-1, 4-dicarbonyl compound, thereby further synthesizing the optically active pantoic acid lactone, and the method has the following advantages: mild reaction conditions, easy operation, small catalyst dosage, capability of synthesizing 2-hydroxy-1, 4-dicarbonyl compounds with two configurations by utilizing tetrapeptide and enantiomers thereof and high yield.)

1. a method for synthesizing chiral 2-hydroxy-1, 4-dicarbonyl compound by catalyzing asymmetric Aldol reaction of fatty aldehyde and glyoxylic ester or fatty aldehyde and acyl formaldehyde monohydrate by using tetrapeptide TP or enantiomer ent-TP thereof as chiral catalyst is characterized in that the chemical reaction formula of the asymmetric catalytic reaction is shown as formula 1 and formula 2:

the synthesis process comprises the following steps: adding fatty aldehyde A, glyoxylate B and tetrapeptide TP shown in formula 1 into a reaction vessel containing a solvent 1, stirring to obtain a product (R) -P with R configuration, adding fatty aldehyde A, glyoxylate B and tetrapeptide ent-TP shown in formula 1 into the reaction vessel containing the solvent 1, stirring to obtain a product (S) -P with S configuration, or adding fatty aldehyde A, acyl formaldehyde monohydrate C and tetrapeptide TP shown in formula 2 into the reaction vessel containing the solvent 1, stirring to obtain a product (R) -Q with R configuration, adding fatty aldehyde A, acyl formaldehyde monohydrate C and tetrapeptide ent-TP shown in formula 2 into the reaction vessel containing the solvent 1, stirring to obtain a product (S) -Q with S configuration, and obtaining the tetrapeptide TP or enantiomer ent-TP thereof with the structure shown in formula 3,

wherein: r₁、R₂Is C₁～C₁₀Any of the straight-chain alkyl, branched-chain alkyl or cyclic alkyl groups of (1), R₃Is C₁～C₄Any of the straight-chain alkyl, branched-chain alkyl or benzyl of (1), R ₄Is any one of aryl, hetero atom aryl, aryl ethyl or aryl vinyl, R₅、R₆Is C₁～C₆The solvent 1 is any one or a mixture of any several of n-hexane, dichloromethane, chloroform, dichloroethane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, ethylene glycol dimethyl ether, dioxane, ethyl acetate, methyl acetate, ethyl formate, methyl tert-butyl ether, acetonitrile, propionitrile, butyronitrile, toluene, xylene, methanol, ethanol, isopropanol or n-butanol.

2. The method for synthesizing the chiral 2-hydroxy-1, 4-dicarbonyl compound according to claim 1, wherein the chiral 2-hydroxy-1, 4-dicarbonyl compound is synthesized by catalyzing asymmetric Aldol reaction of fatty aldehyde and glyoxylic acid ester or fatty aldehyde and acyl formaldehyde monohydrate by using tetrapeptide TP or its enantiomer ent-TP as chiral catalyst, and is characterized in that: r₁＝R₂Is C₁～C₆A straight chain alkyl group of (2), or R₁-R₂Each is any one of cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl, R₃Is C₁～C₄Linear or branched alkyl of R₄Is any one of phenyl, substituted phenyl, naphthyl, heteroatom aryl, anthryl or aryl vinyl, R₅And R ₆Is C₁～C₄And the solvent 1 is any one of dichloromethane, 1, 2-dichloroethane, chloroform, diethyl ether, tetrahydrofuran, ethyl acetate, acetonitrile, toluene, methanol or methyl tert-butyl ether.

3. The method for synthesizing chiral 2-hydroxy-1, 4-dicarbonyl compound according to claim 1, wherein the tetrapeptide TP or its enantiomer ent-TP is used as chiral catalyst to catalyze asymmetric Aldol reaction of fatty aldehyde and glyoxylate or fatty aldehyde and acyl formaldehyde monohydrate, and the used catalyst TP or its enantiomer ent-TP is any one of the compounds shown in formula 4, namely:

4. the product obtained by the catalytic synthesis method is applied to the synthesis of chiral pantoic acid lactone.

5. The use of the synthesis product according to claim 4 for the synthesis of chiral pantoic acid lactone, characterized by the formula 5, i.e.: (R) -P represented by the formula 5 is charged into a reaction vessel containing a reducing agent and a solvent 2

Stirring to obtain (R) -pantolactone, or adding (S) -P shown in formula 5 into a reaction vessel containing reducing agent and solvent 2, and stirring to obtain (S) -pantolactone, wherein R is₄Me or Et, the solvent 2 is any one or more of dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, ethyl acetate, methanol, ethanol and isopropanol, and the reducing agent is any one or more of borane, sodium cyanoborohydride, sodium borohydride acetate, sodium borohydride, lithium borohydride and potassium borohydride.

6. The use of the synthetic product according to claim 5 for the synthesis of chiral pantoic acid lactone, characterized in that the solvent 2 is any one of methanol or ethanol, and the reducing agent is any one of sodium cyanoborohydride, sodium acetate borohydride and sodium borohydride.

Technical Field

The invention relates to a method for synthesizing chiral 2-hydroxy-1, 4-dicarbonyl compound by catalyzing asymmetric Aldol reaction of fatty aldehyde and glyoxylate or fatty aldehyde and acyl formaldehyde monohydrate by a chiral catalyst of tetrapeptide or enantiomer thereof, and application of the synthesized product.

Background

Optically active compounds are ubiquitous in nature and play no alternative role in the life of cells and organisms. Many drugs are optically active compounds, and chirality is an important element of a drug. The chiral catalyst is used to catalyze asymmetric reaction, which is the most economical and green method for synthesizing chiral compounds. Asymmetric catalysis comprises three fields, namely chiral ligand-metal compound catalysts, organic small molecule catalysts and biological enzyme catalytic reaction. Because of green and good economic performance, biological enzyme catalysis is always a hot research field of asymmetric catalysis, but the rapid application of the biological enzyme is limited by factors such as complexity, easy inactivation, specificity and the like of the structure of enzyme protein. The polypeptide is a novel organic catalyst designed and synthesized according to an enzyme catalysis mechanism, has the advantages of simple structure, easy synthesis, wide substrate range, multiple adaptive reaction types, mild reaction conditions, stable structure and the like, is an excellent mimic of natural enzyme, and is a key direction for chemical and biological research.

It has been reported that artificially synthesized short peptides have been widely used in catalysis of many asymmetric reactions such as Aldol, Michael, etc. to synthesize various optically active compounds [ Davie, e.a.c.; mennen, s.m.; xu, y.; miller, s.j.chem.rev.2007,107,5759-5812], in which the most reports are in asymmetric Aldol reactions. The discovery of novel efficient short-peptide catalysts is always a hotspot in the field of chiral compound synthesis.

The optically active 2-hydroxy-3-methyl-3-formylbutyrate generated by the asymmetric Aldol reaction of isobutyraldehyde and glyoxylate is a direct precursor compound for synthesizing optically active pantolactone, and has important application value. The chiral catalysts for catalyzing the asymmetric Aldol reaction reported at present are all focused on the field of natural or unnatural amino acids. The results of this Aldol reaction catalyzed by proline and its derivatives were first reported, but the ee value was only 42% at the highest [ Zhong, g.; fan, J.; barbas, C.F. tetrahedron Lett.2004,45,5681-]. It was found hereafter that non-prolines are also possibleThe ee value of the catalyzed reaction is improved to a certain extent: using 10 mol% catalytic amount of natural histidine as chiral organic catalyst finally obtained 65% ee [ Markert, m.; scheffller, u.; mahrwald, r.j.am.chem.soc.2009,131, 16642-16643]. It was then found that, using 50 mol% of native isoleucine to catalyze the reaction, ee values of up to 77% and yields of 81% were obtained in dimethylsulfoxide solvent [ Rohr, K.; mahrwald, R.org.Lett.2012,14,2180-]. After that, the ee value of the reaction can be increased from 65% to 79% by optimizing the reaction conditions, likewise using 10 mol% of histidine as catalyst, and the conversion of the reaction is 79% [ Heidlindemann, m.; hammel, m.; scheffller, u.; mahrwald, r.; hummel, w.; berkessel, a.; H.J.Org.Chem.2015,80,3387-3396]. As mentioned above, none of these studies have seen ee values exceeding 80%, which is a situation that is far from the synthesis of the highly optically active pantolactone, and the discovery of novel, efficient chiral catalysts for this reaction is urgent and challenging.

Similarly, the asymmetric Aldol reaction of fatty aldehyde and acyl formaldehyde (existing in the form of monohydrate) can also synthesize the 2-hydroxy-1, 4-dicarbonyl compound, the structure is the skeleton component of a plurality of bioactive compounds, a plurality of chiral compounds containing a plurality of organic functional groups can be easily derived, and the method has important significance in the synthesis of complex chiral compounds and medicaments. The method of studying the asymmetric Aldol reaction between fatty aldehydes and acyl formaldehyde monohydrate is not currently reported systematically, but is only scattered in various articles [ Kano, t.; maruoka K.Angew.chem.Int.Ed.2007,46, 1738-1740 ]; [ Kano, T.; maruoka, K.chem.Eur.J.2009,15, 6678-; [ Yan X.; feng, x.m. synlett.2008, 73-76 ], and all use small molecule secondary amine catalysts. Therefore, it is necessary to develop other types of catalysts and methods for catalyzing such reactions.

Disclosure of Invention

The invention provides a method for synthesizing a chiral 2-hydroxy-1, 4-dicarbonyl compound by catalyzing asymmetric Aldol reaction of fatty aldehyde and glyoxylic ester or fatty aldehyde and acyl formaldehyde monohydrate by adopting tetrapeptide or an enantiomer thereof as a chiral catalyst, and further provides a method for synthesizing pantoic acid lactone with high optical activity.

The invention relates to a method for synthesizing a chiral 2-hydroxy-1, 4-dicarbonyl compound by catalyzing asymmetric Aldol reaction of fatty aldehyde and glyoxylate or fatty aldehyde and acyl formaldehyde monohydrate by using tetrapeptide TP or enantiomer ent-TP thereof as a chiral catalyst, which is characterized in that the chemical reaction formulas of the asymmetric catalytic reaction are shown as formulas 1 and 2:

the synthesis process comprises the following steps: adding fatty aldehyde A, glyoxylate B and tetrapeptide TP shown in formula 1 into a reaction vessel containing a solvent 1, stirring to obtain a product (R) -P with R configuration, adding fatty aldehyde A, glyoxylate B and tetrapeptide ent-TP shown in formula 1 into the reaction vessel containing the solvent 1, stirring to obtain a product (S) -P with S configuration, or adding fatty aldehyde A, acyl formaldehyde monohydrate C and tetrapeptide TP shown in formula 2 into the reaction vessel containing the solvent 1, stirring to obtain a product (R) -Q with R configuration, adding fatty aldehyde A, acyl formaldehyde monohydrate C and tetrapeptide ent-TP shown in formula 2 into the reaction vessel containing the solvent 1, stirring to obtain a product (S) -Q with S configuration, and obtaining the tetrapeptide TP or enantiomer ent-TP thereof with the structure shown in formula 3,

Wherein: r₁、R₂Is C₁～C₁₀Any of the straight-chain alkyl, branched-chain alkyl or cyclic alkyl groups of (1), R₃Is C₁～C₄Any of the straight-chain alkyl, branched-chain alkyl or benzyl of (1), R₄Is any one of aryl, hetero atom aryl, aryl ethyl or aryl vinyl, R₅、R₆Is C₁～C₆Any of the straight-chain alkyl group, branched-chain alkyl group, cyclohexyl group, phenyl group and benzyl group of (1), and the solvent 1 is n-hexane or dichloromethaneThe solvent is any one or a mixture of any more of chloroform, dichloroethane, diethyl ether, tetrahydrofuran, methyltetrahydrofuran, ethylene glycol dimethyl ether, dioxane, ethyl acetate, methyl acetate, ethyl formate, methyl tert-butyl ether, acetonitrile, propionitrile, butyronitrile, toluene, xylene, methanol, ethanol, isopropanol or n-butanol.

Preferably, the method for synthesizing the chiral 2-hydroxy-1, 4-dicarbonyl compound by catalyzing the asymmetric Aldol reaction of fatty aldehyde and glyoxylic ester or fatty aldehyde and acyl formaldehyde monohydrate by using tetrapeptide TP or the enantiomer ent-TP thereof as a chiral catalyst comprises the following steps: r₁＝R₂Is C₁～C₆A straight chain alkyl group of (2), or R₁-R₂Each is any one of cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl, R₃Is C₁～C₄Linear or branched alkyl of R ₄Is any one of phenyl, substituted phenyl, naphthyl, heteroatom aryl, anthryl or aryl vinyl, R₅And R₆Is C₁～C₄And the solvent 1 is any one of dichloromethane, 1, 2-dichloroethane, chloroform, diethyl ether, tetrahydrofuran, ethyl acetate, acetonitrile, toluene, methanol or methyl tert-butyl ether.

Preferably, the method for synthesizing the chiral 2-hydroxy-1, 4-dicarbonyl compound by catalyzing the asymmetric Aldol reaction of fatty aldehyde and glyoxylate or fatty aldehyde and acyl formaldehyde monohydrate by using tetrapeptide TP or the enantiomer ent-TP thereof as a chiral catalyst in the invention uses the catalyst TP or the enantiomer ent-TP thereof as any one of the compounds shown in formula 4, namely:

the product obtained by the catalytic synthesis method is applied to the synthesis of chiral pantoic acid lactone.

The application of the synthetic product in synthesizing chiral pantoic acid lactone is shown as a formula 5, namely: adding (R) -P shown in formula 5 into a reaction vessel containing a reducing agent and a solvent 2, and stirring for reaction to obtain (R) -pantoic acid

Or adding (S) -P shown in formula 5 into a reaction vessel containing a reducing agent and a solvent 2, and stirring for reaction to obtain (S) -pantolactone, wherein R is ₄Me or Et, the solvent 2 is any one or more of dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, ethyl acetate, methanol, ethanol and isopropanol, and the reducing agent is any one or more of borane, sodium cyanoborohydride, sodium borohydride acetate, sodium borohydride, lithium borohydride and potassium borohydride.

Preferably, in the application of the synthetic product of the invention in the synthesis of chiral pantoic acid lactone, the solvent 2 is any one of methanol or ethanol, and the reducing agent is any one of sodium cyanoborohydride, sodium acetate borohydride and sodium borohydride.

In the research of asymmetric catalytic Aldol reaction process, the inventor finds that a plurality of tetrapeptide catalysts have excellent asymmetric catalytic action and can catalyze asymmetric Aldol reaction of fatty aldehyde and glyoxylate or fatty aldehyde and acyl formaldehyde monohydrate to synthesize an optically active 2-hydroxy-1, 4-dicarbonyl compound, so that optically active pantoic acid lactone can be further synthesized. The method has the obvious advantages of mild reaction conditions, easy operation, small catalyst dosage, high yield which can reach 99 percent at most, high enantioselectivity which can reach 99 percent ee at most and good application potential, and can synthesize the 2-hydroxy-1, 4-dicarbonyl compounds with two configurations by utilizing tetrapeptide and enantiomers thereof. The partial product synthesized by the method can synthesize the pantolactone with optical activity with high yield and high enantioselectivity, and the ee value reaches 99 percent.

Detailed Description

The present invention is described in further detail below with reference to examples. It should be noted that the following examples are only for illustrating the present invention, and the details of the present invention are not limited to the following examples.