JP2004091417A - Hydrolysis method and thioacetalization method for thioester compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new hydrolysis method for a thioester compound which realizes hydrolysis using an acid catalyst even in the absence of an organic solvent, while enabling the catalyst to be easily recovered and reused as the catalyst, and to provide a new reaction method using the same acid catalyst. <P>SOLUTION: The thioester compound having a partial structure expressed by -CO-S- is hydrolyzed in an aqueous medium in the presence of an acid catalyst supported with an organic polymer, giving a carboxylic acid compound and a thiol compound. <P>COPYRIGHT: (C)2004,JPO

Description

【００１３】
（ｎ，ｍは、各々、１または２以上の数を示し、Ｒ^１およびＲ^２は、各々、同一または別異に、置換基を有していてもよい炭化水素基または複素環基を示す）
で表わすことができる。そして、ここでの炭化水素基としては、この出願の発明の反応を阻害することのないものであれば、飽和または不飽和の、脂肪族あるいは脂環式の炭化水素基、単環または多環の芳香族炭化水素基のうちから選択された各種のものであってよい。また複素環基についても同様であって、異項原子として酸素や窒素等を有する単環または多環の各種のものであってよい。これらに置換してもよい置換基も反応を阻害しない限り任意のものであってよい。各種の炭化水素基やアルコキシ基、ニトロ基、シアノ基、ハロゲン原子等から適宜に選択されたものであってよい。
【００１４】
加水分解反応によって、たとえば式（１）（２）で表わされるチオエステル化合物からは、カルボン酸化合物：Ｒ^１ＣＯＯＨ，チオール化合物：Ｒ^２ＳＨが生成されることになる。
【００１５】
この加水分解反応には、この出願の発明では水性媒体が使用される。より好適には、有機溶媒による環境負荷のない水が媒体として使用される。ただ、所望によっては、水を主とする有機溶媒、たとえばジオキサン、ＴＨＦ管との混合物であってよい。しかしながら、水のみを媒体とすることで高い反応性で加水分解を実現し、しかも触媒の回収・再利用を可能とすることがこの出願の発明の本質的で重要な特徴である。加水分解のための触媒としては、前記のとおり、有機ポリマーに支持した酸触媒を使用する。この場合の有機ポリマーとしては、酸成分を支持もしくは担持することができ、反応時に劣化や変質することのない各種のものであってよい。一般には、媒体の水による膨潤がないが、極めて少ない疎水性の大きいものが好ましい。
【００１６】
このような有機ポリマーの好適なものとしては、市販品として入手しやすく、また合成も比較的容易なポリスチレン系ポリマー、たとえばジビニルベンゼン架橋ポリスチレン等が挙げられる。この出願の発明の触媒は、このようなポリマーに酸成分を担持させるか、もしくはポリマーの合成時に酸成分が存在するようにして調製することができる。
【００１７】
触媒の酸成分としては、スルホン酸基、硫酸基、あるいは過塩素酸基等が好適なものとして考慮される。
【００１８】
加水分解反応においては、以上の有機ポリマー支持酸触媒は、反応基質のチオエステル化合物に対して３０モル％以下、一般により好適には５〜１５モル％の割合で存在させ、還流温度までの温度範囲において反応を実施することが考慮される。
【００１９】
加水分解反応は、前記のとおりのカルボン酸化合物とチオール化合物の製造法として価値があるだけでなく、カルボキシル基およびチオール基の脱保護基のための方法としても重要である。
【００２０】
また、この出願の発明においては、加水分解反応だけでなく、ベンジルアルコール化合物を反応系に存在させることによるチオエーテル化方法を実現すること、そして、アルデヒド化合物を反応系に存在させることによるチオアセタール化方法を実現することもできる。
【００２１】
チオエーテル化反応においては、次式（３）
【００２２】
【化２】

【００２３】
（式中のＲ^３，Ｒ^４およびＲ^５は、各々、水素原子または置換基を有していてもよい炭化水素基もしくは複素環基を示し、Ｒ^３，Ｒ^４およびＲ^５のうちの少くとも一つは置換基を有していてもよいフェニル基を示す。）で表わされるベンジルアルコール化合物を存在させる。これによって、チオエステル化合物との反応で、たとえばＲ^２−Ｓ−ＣＲ^３Ｒ^４Ｒ^５で表わされるチオエーテル化合物が合成される。この反応は、Ｒ^２−ＳＨチオール化合物の観点からすると、チオール基（ＳＨ）の保護基をＲ^１ＣＯ−のカルボニル基から−ＣＲ^３Ｒ^４Ｒ^５に交換することを意味している。つまりトランスプロテクション方法が実現されることになる。
【００２４】
同様にチオアセタール化反応方法においては、次式（４）
【００２５】
【化３】

【００２６】
（Ｒ^６は、置換基を有していてもよい炭化水素基もしくは複素環基を示す。）
で表わされるアルデヒド化合物を反応系に存在させる。これによって、たとえばＲ^３−Ｃ（ＳＲ^２）_２が生成させることになる。この場合、チオエステル化合物が、−ＣＯ−Ｓ−Ｒ^２−Ｓ−ＣＯ−のジチオエステルであれば、環状の化合物が生成されることになる。
【００２７】
反応基質としての前記のベンジルアルコール化合物やアルデヒド化合物は、一般的に、チオエステル化合物に対してモル比として０．１〜１０の広い範囲において選択することができ、前記の加水分解とほぼ同様の条件を適宜に採用することができる。
【００２８】
なお、前記のＲ^３〜Ｒ^６については、Ｒ^１およびＲ^２と同様の範囲のものとして考慮することができる。
【００２９】
そこで以下に実施例を示し、さらに詳しく説明する。もちろん、以下の例によって発明が限定されることはない。
【００３０】
【実施例】
＜実施例１＞
（ポリマー支持体スルホン酸（ＰＳ−ＳＯ_３Ｈ）の作製）
ポリスチレン（１０．０６ｇ、１％ＤＶＢ　架橋済み、２００−４００メッシュ）のジクロロメタン（１５０ｍＬ）懸濁液に対し、クロロスルホン酸（０．３７ｍＬ）のジクロロメタン（２０ｍＬ）溶液を０℃で徐々に添加し、全体を６時間振とうした。ＴＨＦ／水（５／１、６０ｍＬ）を加え室温下に１時間振とう後一夜静置し、この樹脂をガラスフィルター上に採取し、水、水／ＴＨＦ、ＴＨＦおよびジクロロメタンでゆすぎ、減圧乾燥してポリマー支持体スルホン酸（ＰＳ−ＳＯ_３Ｈ）を得た。元素分析の結果（実測値：Ｓ、１．４８％）スルホン酸含量は０．４６２ｍｍｏｌ／ｇと推定された。
＜実施例２＞
（水中におけるチオエステルのＰＳ−ＳＯ_３Ｈ触媒による加水分解）
脱気水（６ｍＬ）中で、ドデシルチオ酢酸エステル（１．０ｍｍｏｌ）と実施例１において調製したポリマー支持体触媒（ＰＳ−ＳＯ_３Ｈ、チオエステルに対し１０ｍｏｌ％）の混合液を、環流条件下で２４時間攪拌した。反応混液を室温まで冷却後、ポリマーをガラスフィルターでろ過し、水およびエーテルで洗浄した。有機層をＮａ_２ＳＯ_４上で乾燥し蒸発させた。ドデカンチオールが本質的に純粋な形で得られた。回収したＰＳ−ＳＯ_３Ｈは減圧下で乾燥後、数回再利用しても活性の消失はみられなかった。
【００３１】
その結果を比較例とともに、次の表１のエントリーＮｏ．８に示した。
【００３２】
比較例としては、ドデシルチオール金酸塩の加水分解をモデル反応として、種々のプレーンステッド酸類の触媒活性を検討した。予想された通り、触媒の非存在下（エントリーＮｏ．１）、あるいは数種のプレーンステッド酸の（エントリーＮｏ．６）で、２４時間の水還流条件下、３Ｎ硫酸（触媒量は９００ｍｏｌ％）あるいは６Ｎ塩酸（触媒量は３６００ｍｏｌ％）（エントリーＮｏ．５および６）中でも、加水分解反応は全く進行しなかった。また、いつかの水中有機反応に有効であるｐ−ドデシルベンゼンスルホン酸のような表面活性剤型プレーンステッド酸もまた不活性であった（エントリーＮｏ．７）。一方、極めて興味あることに、実施例としての、１％ＤＶＢ架橋ポリスチレン（２００−４００メッシュ）をスルホン化して調製した疎水性のポリスチレン支持体スルホン酸（ＰＳ−ＳＯ_３Ｈ、０．４６２ｍｍｏｌ／ｇ）がこの加水分解に有効であった（エントリーＮｏ．８）。
【００３３】
【表１】

【００３４】
＜実施例３＞
実施例２と同様にして、ＰＳ−ＳＯ_３Ｈにより触媒されるチオエステルの水中における加水分解の基質についての検討を行なった。この反応はスムースに進行し、高い、あるいは極めて高い収率で、各種チオエステルに対応するチオールまたはカルボン酸を与えた。表２はその結果を示したものである。反応時間が長いものの、加水分解の触媒にはほんの２ｍｏｌ％だけのＰＳ−ＳＯ_３Ｈで充分であった（エントリーＮｏ．７）。塩基性条件下ではジスルフィドの生成がしばしばみられるが、エントリーＮｏ．７に示した基質の加水分解を空気雰囲気下で行なった場合でさえもこれが全く認められなかったことは特筆に価する。
【００３５】
【表２】

【００３６】
そのうえ、次のとおり、ＰＳ−ＳＯ_３Ｈは回収および再利用が可能であった。これらの結果は、このチオエステルの加水分解がチオールあるいはカルボン酸を脱保護する一般的で有用な方法を提供することを実証するものである。
【００３７】
【表３】

【００３８】
＜実施例４＞
塩基性条件下でチオエステルの加水分解を行なう場合に、しばしばラセミ化が認められるが、これは重大な問題である。一方、表４に示したとおり、ＰＳ−ＳＯ_３Ｈにより触媒される光学活性チオエステル、エチル（Ｒ）−（−）−２−フェニル−チオプロピオネートの加水分解は、水還流条件下で進行し、鏡像体過剰率のごくわずかな損失がみられただけであった。したがって、これはチオエステルの酸触媒加水分解の利点のひとつである。
【００３９】
【表４】

【００４０】
＜実施例５＞
（水中におけるチオールのＰＳ−ＳＯ_３Ｈ触媒によるトランスプロテクション）脱気水（１．５ｍＬ）中で、ベンジルチオ酢酸エステル（０．２５ｍｍｏｌ）、トリフェニルメタノール（０．２５ｍｍｏｌ）およびポリマー支持体触媒（ＰＳ−ＳＯ_３Ｈ、チオエステルに対し１０ｍｏｌ％）の混合液を、還流条件下で２４時間攪拌した。反応混液に飽和ＮａＨＣＯ_３水溶液を加えて冷却し、室温まで冷却後、かん水で冷却した。ポリマーをろ過し、水および酢酸エチルで洗滌した。有機層をＮａ_２ＳＯ_４上で乾燥し蒸発させた。この混合物をシリカゲルの分取ＴＬＣにより精製し、ドデシルトリフェニルメチルスルフィド（８０ｍｇ、８８％）を得た。
【００４１】
この結果を表５のエントリーＮｏ．４として示した。
【００４２】
同様に表５に示したように、ベンジル型アルコールの存在下でチオエステルの加水分解を行なうことにより、水中でチオールのトランスプロテクションが実現できた。反応はスムースに進行し、高収率でチオエステルからチオエーテルを生成した。興味深いことには、この反応条件下で逆のタイプの反応（加水分解と脱水反応）が同一容器内でおこる。この系は、中間体であるチオールを分離せずにチオエステルをチオエーテルに変換できる効果的な方法を提供する。
【００４３】
【表５】

【００４４】
＜実施例６＞
（水中におけるジチオエステルを用いたベンズアルデヒドのＰＳ−ＳＯ_３Ｈ触媒によるジチオアセタール化）
表６に示した反応式に従って、脱気水（１．５ｍＬ）中で、ベンズアルデヒド（０．２５ｍｍｏｌ）、ジチオエステル（０．２７６ｍｍｏｌ）、およびポリマー支持体触媒（ＰＳ−ＳＯ_３Ｈ、チオエステルに対し１０ｍｏｌ％）の混合液を、還流条件下で２４時間攪拌した。ポリマーをろ過し、室温に冷却後、水およびジクロロメタンで洗浄した。有機層をＮａ_２ＳＯ_４上で乾燥し蒸発させた。この混合物をシリカゲルの分取ＴＬＣにより精製し、２−フェニル−１，３−ジチアン（４８ｍｇ、９８％）を得た。
【００４５】
このことから、不快臭のあるジチオールの替わりにほとんど無臭のジチオエステルを、カルボニル化合物のジチオアセタール化に直接使用することができることがわかる。発明者の知る限り、これはジチオエステルを用いるジチオアセタール化の最初の事例である。
【００４６】
【表６】

【００４７】
【発明の効果】
以上詳しく説明したとおり、この出願の発明によって、従来の問題点を解消し、有機溶媒の共存なしでもチオエステル化合物の酸触媒加水分解反応を実現し、しかも、触媒としての回収、再利用をも容易に可能とすることのできる、チオエステル化合物の新しい加水分解反応方法と、これに用いる酸触媒による新しい反応方法をも提供することができる。[0001]
TECHNICAL FIELD OF THE INVENTION
The invention of this application relates to a hydrolysis reaction of a thioester compound and a thioacetalization reaction method.
[0002]
[Prior Art and Problems of the Invention]
Thioester: Since the structure of —CO—S— is widely used as a structure of a protecting group for a thiol group or a carboxyl group, it is useful in a synthesis reaction, and at the same time, a thioester compound provides a physiologically active substance. As a biologically important compound. Conventionally, hydrolysis of such a thioester compound to a thiol or carboxylic acid is generally performed under basic conditions. However, the problem with this method is that oxidation of thiol to disulfide is apt to occur, and more than equimolar amount of reagent is required. Therefore, an acid-catalyzed hydrolysis of a thioester compound has been developed as an important alternative, but the activation energy of the acid-catalyzed hydrolysis is high, and the use of an excessive amount of a strong acid such as 6N hydrochloric acid is necessary ( Synthesis, 1999, 270; J. Med. Chem., 1999, 42, 95; Chem. Ber., 1989, 122, 553, etc.), and this method is rarely used. Furthermore, it is very difficult to achieve acid-catalyzed hydrolysis of water-insoluble thioesters without the presence of an organic solvent.
[0003]
Water is an easily available, economical, safe and environmentally friendly solvent, so organic reactions in water without any harmful organic solvents have been a major concern in recent years and have enabled organic conversion in water For this purpose, various catalysts have been developed. However, in many cases, the manifestation of the activity as a catalyst and the recovery and reuse of the catalyst have been issues.
[0004]
Therefore, the invention of this application solves the conventional problems as described above, realizes an acid-catalyzed hydrolysis reaction of a thioester compound without the coexistence of an organic solvent, and easily recovers and reuses the catalyst. It is an object of the present invention to provide a new hydrolysis reaction method of a thioester compound and a new reaction method using an acid catalyst used for the method.
[0005]
[Means for Solving the Problems]
The invention of this application solves the above-mentioned problems. First, a thioester compound having a partial structure represented by -CO-S- is prepared by adding a thioester compound in an aqueous medium to an organic polymer in the presence of an acid catalyst. The present invention also provides a method for hydrolyzing a thioester compound, which comprises hydrolyzing a carboxylic acid compound and a thiol compound.
[0006]
Secondly, the invention of this application is characterized in that a carboxylic acid compound and / or a thiol compound are obtained from a thioester compound by the above-mentioned method. Thirdly, there is provided a method for removing a protecting group, which comprises removing a protecting group for a carboxyl group of a carboxylic acid compound or a thiol group of a thiol compound by the above method.
[0007]
Fourth, the invention of this application is to react a thioester compound having a partial structure represented by -CO-S with a benzyl alcohol compound in an aqueous medium in the presence of an acidic catalyst supported by an organic polymer. Fifth, a method for producing a thioether compound, characterized in that a thioether compound is obtained by this method, and sixth, a method for producing a thioether compound, Provided is a method for transprotecting a thiol compound, which comprises converting a protecting group from a carbonyl group to a benzyl group.
[0008]
Seventh, the invention of this application is directed to reacting a thioester compound having a partial structure represented by -CO-S- with an aldehyde compound in an aqueous medium in the presence of an acid catalyst supported on an organic polymer. Eighthly, a method for producing a thioacetal compound is provided. The eighth method provides a method for producing a thioacetal compound by obtaining a thioacetal compound.
[0009]
Furthermore, ninthly, the invention of this application is characterized in that the aqueous medium is water, and tenthly, the acid catalyst comprises a sulfonic acid group, a sulfate group, or a peroxide group. Any method characterized by having a chloric acid group is provided.
[0010]
BEST MODE FOR CARRYING OUT THE INVENTION
The invention of this application has the features as described above, and embodiments thereof will be described below.
[0011]
First, the thioester compound targeted by the invention of the present application will be described. This compound has one or more thioester group structures of -CO-S- as a part of its molecular structure. . This thioester compound has, for example, the following formula (1) or (2)
[0012]
Embedded image

[0013]
(N and m each represent 1 or 2 or more, and R ¹ and R ² each independently or independently represent a hydrocarbon group or a heterocyclic group which may have a substituent. )
Can be represented by As the hydrocarbon group here, a saturated or unsaturated, aliphatic or alicyclic hydrocarbon group, monocyclic or polycyclic, as long as it does not inhibit the reaction of the invention of this application, And various types selected from the aromatic hydrocarbon groups described above. The same applies to the heterocyclic group, which may be various monocyclic or polycyclic compounds having oxygen, nitrogen, or the like as a hetero atom. The substituents which may be substituted on these may be arbitrary as long as they do not inhibit the reaction. It may be appropriately selected from various hydrocarbon groups, alkoxy groups, nitro groups, cyano groups, halogen atoms and the like.
[0014]
By the hydrolysis reaction, for example, a carboxylic acid compound: R ¹ COOH and a thiol compound: R ² SH are produced from the thioester compounds represented by the formulas (1) and (2).
[0015]
For the hydrolysis reaction, an aqueous medium is used in the invention of this application. More preferably, water having no environmental load due to the organic solvent is used as the medium. However, if desired, an organic solvent mainly composed of water, for example, a mixture with dioxane and a THF tube may be used. However, the essential and important feature of the invention of the present application is that hydrolysis is realized with high reactivity by using only water as a medium, and that the catalyst can be recovered and reused. As described above, an acid catalyst supported on an organic polymer is used as a catalyst for hydrolysis. In this case, various organic polymers that can support or support an acid component and do not deteriorate or deteriorate during the reaction may be used. In general, a medium that does not swell with water in the medium but has a very small hydrophobicity is preferable.
[0016]
Preferable examples of such an organic polymer include a polystyrene-based polymer which is easily available as a commercial product and is relatively easy to synthesize, such as divinylbenzene-crosslinked polystyrene. The catalyst of the invention of this application can be prepared by supporting an acid component on such a polymer or by allowing the acid component to be present during the synthesis of the polymer.
[0017]
As the acid component of the catalyst, a sulfonic acid group, a sulfuric acid group, a perchloric acid group, or the like is considered to be suitable.
[0018]
In the hydrolysis reaction, the organic polymer-supported acid catalyst is present in an amount of 30 mol% or less, generally more preferably 5 to 15 mol%, based on the thioester compound as a reaction substrate. It is contemplated to carry out the reaction at.
[0019]
The hydrolysis reaction is not only valuable as a method for producing a carboxylic acid compound and a thiol compound as described above, but also important as a method for deprotecting a carboxyl group and a thiol group.
[0020]
Further, in the invention of this application, not only a hydrolysis reaction but also a thioetherification method by causing a benzyl alcohol compound to be present in a reaction system, and a thioacetalization method by causing an aldehyde compound to be present in a reaction system. A method can also be implemented.
[0021]
In the thioetherification reaction, the following formula (3)
[0022]
Embedded image

[0023]
(R ³ , R ⁴ and R ⁵ in the formula each represent a hydrogen atom or a hydrocarbon group or a heterocyclic group which may have a substituent, and a small number of R ³ , R ⁴ and R ⁵ And at least one of them represents a phenyl group which may have a substituent.). Thus, a thioether compound represented by, for example, R ² —S—CR ³ R ⁴ R ⁵ is synthesized by the reaction with the thioester compound. This reaction means that the protecting group of the thiol group (SH) is exchanged from the carbonyl group of R ¹ CO— to —CR ³ R ⁴ R ⁵ from the viewpoint of the R ² —SH thiol compound. That is, a trans-protection method is realized.
[0024]
Similarly, in the thioacetalization reaction method, the following formula (4)
[0025]
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[0026]
(R ⁶ represents a hydrocarbon group or a heterocyclic group which may have a substituent.)
Is present in the reaction system. Thus, for example, ^R 3 -C ^(SR ₂₎ 2 is thereby generated. In this case, thioester compounds, if ^{-CO-S-R 2 -S-} CO- dithio ester, so that the cyclic compounds are produced.
[0027]
The above-mentioned benzyl alcohol compound or aldehyde compound as a reaction substrate can be generally selected in a wide range of 0.1 to 10 as a molar ratio with respect to the thioester compound, under substantially the same conditions as in the above-mentioned hydrolysis. Can be appropriately adopted.
[0028]
Note that R ^{3 to} R ⁶ can be considered as having the same range as R ¹ and R ² .
[0029]
Therefore, an embodiment will be shown below and will be described in more detail. Of course, the invention is not limited by the following examples.
[0030]
【Example】
<Example 1>
(Preparation of polymer support sulfonic acid (PS-SO ₃ H))
To a suspension of polystyrene (10.06 g, 1% DVB cross-linked, 200-400 mesh) in dichloromethane (150 mL), a solution of chlorosulfonic acid (0.37 mL) in dichloromethane (20 mL) was slowly added at 0 ° C. The whole was shaken for 6 hours. THF / water (5/1, 60 mL) was added, shaken at room temperature for 1 hour, and allowed to stand overnight. The resin was collected on a glass filter, rinsed with water, water / THF, THF and dichloromethane, and dried under reduced pressure. Te polymer support sulfonate _(PS-SO 3 H) was obtained. As a result of elemental analysis (actual value: S, 1.48%), the sulfonic acid content was estimated to be 0.462 mmol / g.
<Example 2>
(Hydrolysis by PS-SO ₃ H catalyst thioester in water)
A mixture of dodecyl thioacetate (1.0 mmol) and the polymer support catalyst prepared in Example 1 (PS-SO ₃ H, 10 mol% based on thioester) in degassed water (6 mL) was refluxed under reflux conditions. Stirred for 24 hours. After cooling the reaction mixture to room temperature, the polymer was filtered through a glass filter and washed with water and ether. The organic layer was evaporated and dried over _Na 2 SO _4. Dodecanethiol was obtained in essentially pure form. After drying the recovered PS-SO 3 _H under reduced pressure, loss of activity be reused several times was observed.
[0031]
The results are shown in Table 1 below along with the comparative examples. 8 is shown.
[0032]
As a comparative example, the catalytic activity of various plainstead acids was examined using the hydrolysis of dodecylthiol aurate as a model reaction. As expected, 3N sulfuric acid (catalyst amount is 900 mol%) in the absence of a catalyst (entry No. 1) or in the presence of several plainstead acids (entry No. 6) under water reflux for 24 hours. Alternatively, even in 6N hydrochloric acid (catalyst amount: 3600 mol%) (entries Nos. 5 and 6), the hydrolysis reaction did not proceed at all. Also, surfactant-type plainstead acids, such as p-dodecylbenzenesulfonic acid, which are effective in some organic reactions in water, were also inactive (entry No. 7). On the other hand, that there very interesting, as an embodiment, 1% DVB crosslinked polystyrene (200-400 mesh) was prepared by sulfonating hydrophobic polystyrene support sulfonate _{(PS-SO 3 H, 0.462mmol} / g ) Was effective for this hydrolysis (entry No. 8).
[0033]
[Table 1]

[0034]
<Example 3>
In the same manner as in Example 2, was performed discussion of substrate hydrolysis in water of thioester catalyzed by PS-SO 3 _H. The reaction proceeded smoothly and gave thiols or carboxylic acids corresponding to various thioesters in high or very high yield. Table 2 shows the results. Although the reaction time is long, the catalyst of hydrolysis was sufficient just 2 mol% only of PS-SO ₃ H (entry No.7). Disulfide formation is often seen under basic conditions, but as described in entry no. It is noteworthy that this was not observed at all even when the hydrolysis of the substrate shown in 7 was carried out in an air atmosphere.
[0035]
[Table 2]

[0036]
Moreover, the following, PS-SO ₃ H was possible to recover and reuse. These results demonstrate that hydrolysis of the thioester provides a general and useful method for deprotecting thiols or carboxylic acids.
[0037]
[Table 3]

[0038]
<Example 4>
Racemization is often observed when hydrolyzing thioesters under basic conditions, which is a serious problem. On the other hand, as shown in Table 4, the hydrolysis of the optically active thioester, ethyl (R)-(-)-2-phenyl-thiopropionate, catalyzed by PS-SO ₃ H proceeds under water reflux conditions. However, only a slight loss of enantiomeric excess was observed. Therefore, this is one of the advantages of acid-catalyzed hydrolysis of the thioester.
[0039]
[Table 4]

[0040]
<Example 5>
In degassed water (1.5 mL) (trans Protection by PS-SO ₃ H catalyst thiol in water), benzylthio acetate (0.25 mmol), triphenyl methanol (0.25 mmol) and polymer support catalysts (PS -SO ₃ H, a mixture of 10 mol%) relative thioester, and stirred for 24 hours under reflux. A saturated aqueous solution of NaHCO ₃ was added to the reaction mixture, and the mixture was cooled, cooled to room temperature, and then cooled with brine. The polymer was filtered and washed with water and ethyl acetate. The organic layer was evaporated and dried over _Na 2 SO _4. This mixture was purified by preparative TLC on silica gel to give dodecyltriphenylmethyl sulfide (80 mg, 88%).
[0041]
The results are shown in Table 5, entry no. 4 is shown.
[0042]
Similarly, as shown in Table 5, by performing hydrolysis of the thioester in the presence of the benzyl alcohol, transprotection of the thiol was achieved in water. The reaction proceeded smoothly, producing thioether from thioester in high yield. Interestingly, under these reaction conditions, the opposite types of reactions (hydrolysis and dehydration) occur in the same vessel. This system provides an efficient way to convert thioesters to thioethers without separating the intermediate thiol.
[0043]
[Table 5]

[0044]
<Example 6>
(Dithio acetalization by benzaldehyde PS-SO ₃ H catalyst with dithio ester in water)
According to the reaction formula shown in Table 6, in degassed water (1.5 mL), benzaldehyde (0.25 mmol), dithio ester (0.276 mmol), and the polymeric support catalyst _(PS-SO 3 H, with respect to the thioester (10 mol%) was stirred under reflux conditions for 24 hours. The polymer was filtered, cooled to room temperature, and washed with water and dichloromethane. The organic layer was evaporated and dried over _Na 2 SO _4. This mixture was purified by preparative TLC on silica gel to give 2-phenyl-1,3-dithiane (48 mg, 98%).
[0045]
From this, it can be seen that almost odorless dithioester can be directly used for dithioacetalization of a carbonyl compound instead of dithiol having an unpleasant odor. To the inventor's knowledge, this is the first case of dithioacetalization using a dithioester.
[0046]
[Table 6]

[0047]
【The invention's effect】
As described in detail above, the invention of this application solves the conventional problems, realizes an acid-catalyzed hydrolysis reaction of a thioester compound without the coexistence of an organic solvent, and also facilitates recovery and reuse as a catalyst. It is also possible to provide a novel hydrolysis reaction method of a thioester compound and a new reaction method using an acid catalyst used for the method.

Claims (10)

A thioester compound characterized by hydrolyzing a thioester compound having a partial structure represented by -CO-S- into a carboxylic acid compound and a thiol compound in an aqueous medium in the presence of an acid catalyst supported by an organic polymer. Hydrolysis reaction method. A method for producing a carboxylic acid compound and a thiol compound, comprising obtaining a carboxylic acid compound and / or a thiol compound from a thioester compound by the method of claim 1. 2. A method for removing a protecting group, comprising removing a protecting group for a carboxyl group of a carboxylic acid compound or a thiol group of a thiol compound by the method of claim 1. A thioetherification reaction method comprising reacting a thioester compound having a partial structure represented by -CO-S with a benzyl alcohol compound in an aqueous medium in the presence of an acidic catalyst supported on an organic polymer. A method for producing a thioether compound, comprising obtaining a thioether compound by the method according to claim 4. 5. A transprotection method for a thiol compound, comprising converting the thiol-protecting group of the thiol compound from a carbonyl group to a benzyl group by the method of claim 4. A thioacetalization method comprising reacting a thioester compound having a partial structure represented by -CO-S- with an aldehyde compound in an aqueous medium in the presence of an acid catalyst supported on an organic polymer. A method for producing a thioacetal compound, comprising obtaining a thioacetal compound by the method according to claim 7. 9. The method according to claim 1, wherein the aqueous medium is water. The method according to any one of claims 1 to 9, wherein the acid catalyst has a sulfonic acid group, a sulfuric acid group, or a perchloric acid group.