JP7244905B2 - Organocatalysts for highly stereoselective asymmetric aldol reactions and their applications - Google Patents

Description

Article 30, Paragraph 2 of the Patent Act applied Posted on March 5, 2018, website address http://www. jsbba. or. jp/MeetingofJSBBA/2018/meeting_of_jsbba_2018. html http://www. jsbba. or. jp/MeetingofJSBBA/2018/MeetingofJSBBA2018. pdf [Publications, etc.] March 16, 2018, Japan Society for Bioscience, Biotechnology, and Agrochemistry, 2018 Annual Meeting Meijo University Tenpaku Campus (1-501 Shiogamaguchi, Tenpaku-ku, Nagoya, Aichi) [Publications, etc.] September 21, 2018 Published in Japan, The 11th Symposium of the Society for Fluorous Science, Proceedings, Page 19, Noguchi Research Institute [Publications] September 21, 2018, The 11th Symposium of the Society for Fluorous Science, Hiroshima City University Satellite Campus (9th floor, Otemachi Peace Building, 4-1-10 Otemachi, Chuo-ku, Hiroshima City, Hiroshima Prefecture)

The present specification relates to an organomolecular catalyst for a highly stereoselective asymmetric aldol reaction using proline and its use.

Since the intermolecular asymmetric aldol reaction using natural proline as a catalyst was reported (Non-Patent Document 1), catalysts using proline have attracted attention as catalysts using chiral elements derived from naturally abundant amino acids. Since then, various organomolecular catalysts have been developed.

For example, it has been reported that high enantioselectivity can be obtained by making the 4-position of proline bulky or by converting the 2-position carboxy group into a sulfonamide group (Non-Patent Documents 2 and 3). In addition, an asymmetric aldol reaction using a proline catalyst in which a perfluoroalkyl group is introduced at the 4-position of proline via oxygen has also been reported (Non-Patent Document 4). A proline catalyst having a ditrifluoromethylbenzenesulfonamide type at the 2-position of the proline catalyst has also been reported (Non-Patent Document 5).

B. List, R. A. Lerner, C. F. Barbas, J. Am. Chem. Soc.2000, 122, 2395-2396. Y. Hayashi, T. Sumiya, J. Takahashi, H. Gotoh, T. Urushima, M. Shoji, Angew. Chem. Int. Ed. 2006, 45, 958-961. A. Berkessel, B. Koch, J. Lex, Adv. Synth. Catal. 2004, 346, 1141-1146. F. Fache, O. Piva, Tetrahedron: Asymmetry 2003, 14, 139-143. M. Kinsella, P. G. Duggan, C. M. Lennon, Tetrahedron: Asymmetry 2011, 22, 1423-1433.

However, none of the previously reported proline catalysts has sufficient enantioselectivity in the aldol reaction.

The present specification provides a proline catalyst capable of achieving high enantioselectivity in an aldol reaction and its utilization.

The present inventors have discovered that by introducing a fluorous tag into the 4-position of the pyrrolidine skeleton of proline and introducing a fluorous tag into the 2-position as well, high enantioselectivity can be achieved in the asymmetric aldol reaction. . This specification provides the following means based on the said knowledge.

（Ｒ¹は、第１のフルオラス基又は炭化水素基を有する第１の置換基を表し、Ｒ²は、第２のフルオラス基を有する第２の置換基を表す。）
［２］前記第１のフルオラス基は、炭素数が４～１６のポリフルオロオロアルキル基である、［１］に記載の有機分子触媒。
［３］前記ポリフルオロアルキル基は、パーフルオロアルキル基である、［２］に記載の有機分子触媒。
［４］前記第１の置換基は、アルキレン基を介して、ピロリジン骨格の４位に導入される前記第１のフルオラス基又は炭化水素基を備えている、［１］～［３］のいずれかに記載の有機分子触媒。
［５］前記第２のフルオラス基は、炭素数１～４のポリフルオロアルキル基である、［１］～［４］のいずれかに記載の有機分子触媒。
［６］前記ポリフルオロアルキル基は、パーフルオロアルキル基である、［５］に記載の有機分子触媒。
［７］前記第２の置換基は、ピロリジン骨格の２位の炭素原子に結合するカルボニル炭素に結合する窒素原子を含むスルホンアミド部分を介して前記第２のフルオラス基を備える、［１］～［６］のいずれかに記載の有機分子触媒。
［８］［１］～［７］のいずれかに記載の有機分子触媒を用いて、α水素を有するカルボニル化合物とケトン又はアルデヒドとのアルドール反応を行ってβ－ヒドロキシ化合物を合成する工程を備える、β－ヒドロキシ化合物製造方法。
［９］前記α水素を有するカルボニル化合物は、ニトロ基を有する、［７］又は［８］に記載の製造方法。 [1] An organic molecular catalyst which is a proline derivative represented by the following formula (1), a proline derivative which is an enantiomer thereof, or a salt thereof.

(R ¹ represents a first substituent having a first fluorous group or a hydrocarbon group, and R ² represents a second substituent having a second fluorous group.)
[2] The organic molecular catalyst according to [1], wherein the first fluorous group is a polyfluorooroalkyl group having 4 to 16 carbon atoms.
[3] The organic molecular catalyst according to [2], wherein the polyfluoroalkyl group is a perfluoroalkyl group.
[4] Any one of [1] to [3], wherein the first substituent comprises the first fluorous group or hydrocarbon group introduced at the 4-position of the pyrrolidine skeleton via an alkylene group. The organic molecular catalyst according to 1.
[5] The organic molecular catalyst according to any one of [1] to [4], wherein the second fluorous group is a polyfluoroalkyl group having 1 to 4 carbon atoms.
[6] The organic molecular catalyst according to [5], wherein the polyfluoroalkyl group is a perfluoroalkyl group.
[7] The second substituent comprises the second fluorous group via a sulfonamide moiety containing a nitrogen atom bonded to the carbonyl carbon bonded to the carbon atom at the 2-position of the pyrrolidine skeleton, [1]- The organic molecular catalyst according to any one of [6].
[8] A step of synthesizing a β-hydroxy compound by performing an aldol reaction between a carbonyl compound having α hydrogen and a ketone or aldehyde using the organic molecular catalyst according to any one of [1] to [7]. , a method for producing a β-hydroxy compound.
[9] The production method according to [7] or [8], wherein the carbonyl compound having α-hydrogen has a nitro group.

The present disclosure relates to organomolecular catalysts for highly stereoselective asymmetric aldol reactions utilizing proline and their use. The present inventors have found that fluorous organocatalysts derived from proline can achieve unprecedentedly high enantioselectivities in asymmetric aldol reactions. Conventionally, catalysts in which a fluorous tag is introduced only at the 4-position or only at the 2-position and aldol reactions using such catalysts have been disclosed, but both have excellent stereoselectivity of reaction products, specifically, enantioselectivity I was unable to achieve sexuality. The present inventors have unexpectedly found that by introducing a fluorous tag into both of these, high enantioselectivity can be obtained.

In addition, the present inventors designed the halogen content of these fluorous tags (for example, the halogen content is about 40% or more and 60% or less), so that recycling is easy. It was also found that a mobile organic molecular catalyst can be obtained. An organic molecular catalyst and an aldol reaction using the catalyst will be described below.

[Organocatalyst]
The organic molecular catalyst (hereinafter simply referred to as the present catalyst) disclosed in the present specification is a proline derivative represented by the following formula (1), an enantiomer thereof, or a salt thereof.

That is, the present catalyst has a first substituent "R ¹ " containing a first fluorous group or, for example, a hydrocarbon group at the 4-position of the pyrrolidine skeleton, and a second substituent having a second fluorous group at the 2-position of the pyrrolidine skeleton. It is an optically active proline derivative or a salt thereof having a substituent "R ² ". The present catalyst uses these two fluorous groups (fluorous tags). For example, the proline derivative represented by formula (1) can be said to be a so-called L-form derivative of proline, and its enantiomer can be said to be a D-form derivative of proline. Although the present catalyst is a proline derivative, it is not meant to be limited to those synthesized from proline.

The first substituent is introduced to the 4-position carbon atom of the pyrrolidine skeleton. The first substituent can comprise a first fluorous group or a hydrocarbon group.

Examples of the first fluorous group include linear or branched polyfluoroalkyl groups. Linear or branched polyfluoroalkyl groups include similar perfluoroalkyl groups. Although such polyfluoroalkyl groups are not particularly limited, they are linear. The polyfluoroalkyl group is preferably a polyfluoroalkyl group having, for example, 3 to 12 carbon atoms, such as 4 to 10 carbon atoms, or such as 6 to 10 carbon atoms. The selection of the number of carbon atoms and the like can be made, for example, based on the fluorine content. Fluorous content has been found to influence high enantioselectivities in aldol reactions. The fluorous content also affects the recyclability of the catalyst. For example, it is preferable to use a fluorous group having a medium fluorous content of about 40% or more and 60% or less as the fluorine content.

The hydrocarbon group is, for example, a linear or branched hydrocarbon group such as an alkyl group, an aryl group, an aralkyl group, and the like. Although such hydrocarbon groups are not particularly limited, they are linear. The hydrocarbon group has, for example, 4 to 18 carbon atoms, 4 to 16 carbon atoms, 6 to 14 carbon atoms, and 6 to 12 carbon atoms. The selection of the number of carbon atoms and the like is not particularly limited, but it is known that bulkiness affects high enantioselectivity, so it can be appropriately selected and used.

The first fluorous group may be directly introduced to the 4-position carbon atom of the pyrrolidine skeleton, or may be introduced via a linking group. As the linking group, for example, a known linking group used for proline asymmetric catalysts such as an alkylene group, an aminoalkylene group, and a benzyl group can be appropriately used. The linking group is not particularly limited, but may be, for example, an alkylene group having 2 to 6 carbon atoms, or, for example, 2 to 4 carbon atoms. When the first fluorous group is a polyfluoroalkyl group that is not a perfluoroalkyl group, the linking group portion includes an alkylene group that is not completely fluorinated. In the case of a hydrocarbon group, it may not be possible to determine from the structure whether it is part of the linking group or part of the hydrocarbon group. In such cases, it shall be included as part of the hydrocarbon group.

Examples of such first fluorous groups include C ₄ F ₉ group, C ₅ F ₁₁ group, C ₆ F ₁₃ group, C ₇ F ₁₅ group, C ₈ F ₁₇ group, C ₉ F ₁₉ group, C ₁₀ F ₂₁ groups, C ₁₁ F ₂₃ groups, C ₁₂ F ₂₅ groups, and the like. _The hydrocarbon _groups include _{C6H13 , C7H15} , _{C8H17 , C9H19 , C10H21 , C11H23} , _{C12H25 ,} C _{13H27 group, C14H29 group, C15H31 group and the} like _.

The second substituent is introduced at the 2-position carbon atom of the pyrrolidine skeleton. Examples of the second fluorous group included in the second substituent include linear or branched polyfluoroalkyl groups. Linear or branched polyfluoroalkyl groups include similar perfluoroalkyl groups. Although such polyfluoroalkyl groups and polyfluoroalkylene groups are not particularly limited, they are linear. The polyfluoroalkyl group has about 1 to 6 carbon atoms, for example, 1 to 4 carbon atoms, for example, 1 to 3 carbon atoms, or for example, 1 to 2 polyfluoro Alkyl groups, also for example trifluoromethyl groups.

The second fluorous group can comprise one or more. For example, it may be provided to replace a hydrogen atom of an aryl or aralkyl group containing a benzene ring. The introduction site of the second fluorous group to the aryl group may be any one of the o-position, m-position and p-position with respect to the linking site of the aryl group to the pyrrolidine skeleton side, or may be two or more. There may be.

The introduction form of the second substituent is not particularly limited. It may be introduced directly or may be introduced via a linking group. As the linking group, for example, a known linking group used for proline asymmetric catalysts such as an alkylene group, an aminoalkylene group, and a benzyl group can be appropriately used. For example, the second fluorous group and the aryl group or aralkyl group having the second fluorous group may be directly introduced to the carbon atom at the 2-position of the pyrrolidine skeleton, but may be linked to the carbon atom at the 2-position of the pyrrolidine skeleton. may be introduced via a carbonyl group sulfonamide moiety (--NHSO ₂ --).

Examples of such a second fluorous group include the following forms. In the following embodiments, a sulfonamide moiety is introduced as a linking group to the carbon atom of the carbonyl group at the 2-position of the pyrrolidine skeleton.

Since the present catalyst has a salt-forming site such as NH in the pyrrolidine skeleton in the proline derivative, it can form a salt with an acid, for example. Examples of the acid include, but are not particularly limited to, carboxylic acid derivatives, sulfuric acid or sulfonic acid derivatives, phosphoric acid derivatives, and hydrochloric acid.

[Method for producing organomolecular catalyst]
Although the production method of the present catalyst is not particularly limited, it can be produced by a known method. For example, after protecting the NH hydrogen atom of hydroxyproline having a hydroxyl group at the 4-position with a benzyloxycarbonyl group or the like, the first fluorous group or hydrocarbon group is introduced at the 4-position. After that, bistrifluoromethylbenzenesulfonamide having a second fluorous group is introduced to the 2-position carbonyl group carbon of the pyrrolidine skeleton of this reaction product.

[Method for Producing β-Hydroxy Compound Comprising Step of Synthesizing β-Hydroxy Compound by Aldol Reaction Using Organic Molecular Catalyst]
The method for producing a β-hydroxy compound disclosed herein uses the present catalyst to synthesize a β-hydroxy compound by performing an aldol reaction with a carbonyl compound having an α hydrogen and a ketone or aldehyde. A process can be provided. According to this method, an optically active β-hydroxy compound can be produced with extremely high enantioselectivity. For example, according to this production method, an optically active anti-β-hydroxy compound can be synthesized with high selectivity.

Moreover, according to the present catalyst, optically active β-hydroxy compounds can be synthesized with high selectivity in water-insoluble solvents such as THF and toluene as well as aqueous media such as water. Further, according to the present catalyst, even if the carbonyl compound is a compound having a nitro group, such as p-nitrobenzaldehyde, an optically active β-hydroxy compound can be synthesized with high selectivity.

The high enantioselectivity of this catalyst is due to the presence of a bulky fluorous group or hydrocarbon group at the 4-position of the pyrrolidine skeleton, and the formation of a stable asymmetric space by the fluorous group at the 2-position of the pyrrolidine skeleton. It is thought that it depends on what is done.

The carbonyl compound having α-hydrogen is not particularly limited, but various aldehydes and ketones can be used. Esters, amides, and the like can also be used as carbonyl compounds having α-hydrogen.

Examples are given below as specific examples in order to more specifically describe the disclosure of the present specification. The following examples are intended to illustrate the disclosure herein and are not intended to dictate its scope.

<Synthesis of catalyst>
In this example, the pyrrolidine skeleton has a fluorous group (C ₈ F ₁₇ group) and a hydrocarbon group (C ₈ H ₁₇ group) at the 4-position, respectively, and a carbonyl group carbon atom at the 2-position via a sulfonamide moiety. proline catalysts (1) and (2) comprising m-bistrifluoromethylbenzene and a pyrrolidine skeleton having a fluorous group (C ₈ F ₁₇ group) at position 4 and a sulfonamide at the carbonyl group carbon atom at position 2 of the pyrrolidine skeleton. A proline catalyst (3) was synthesized with p-trifluoromethylbenzene via a moiety. Separately, as a control, a control proline catalyst (1), which has a hydrocarbon group at the 4-position but has a bismethylbenzene at the carbonyl group carbon atom at the 2-position via a sulfonamide moiety, and a fluorous group at the same A control proline catalyst (2) was synthesized with the 4-position but only with the 2-position carboxy group.

<Synthesis of proline catalyst (1)>
A synthesis scheme of proline catalyst (1) is shown below, and then the methods for synthesizing each compound are described in order. The same applies to other catalysts below.

Synthesis of (2S,4R)-1-((Benzyloxy)carbonyl)-4-hydroxypyrrolidine-2-carboxylic acid This compound was synthesized according to the following formula.

Trans-4-Hydroxy-L-proline (1.64 g 12.6 mmol) and sodium carbonate (3.33 g 31.5 mmol) were dissolved in a mixed solvent of H ₂ O (12 mL) and acetone (2 mL) and stirred for 10 minutes. Over 30 minutes, Cbz-Cl (2.13 mL, 15.12 mmol) was added dropwise to the system in four portions. After that, the mixture was stirred at room temperature for 20.5 hours. After completion of the reaction, the reaction solution was diluted with H ₂ O (30 mL), and then washed with Et ₂ O (15 mL) three times. The aqueous layer was cooled to 0 °C, 6N HCl aq. was added slowly to adjust to pH 1-2, and then extracted with ethyl acetate (25 mL) three times. Further, the mixture was washed twice with saturated brine (20 mL), and the ethyl acetate layer was dehydrated and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:methanol=5:1). (3.27g, 98%)
Colorless oil; ¹ H NMR (270 MHz, CDCl ₃ ); = 18.9 Hz, 2H), 2.46-2.06 (m, 2H).

Synthesis of (2S,4R)-4-(Allyloxy)-1-((benzyloxy)carbonyl)pyrrolidine-2-carboxylic acid

Weigh (2S,4R)-1-((benzyloxy)carbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (2.1 g, 7.9 mmol) into a three-necked flask, replace with nitrogen, and add dry-THF (20 mL). rice field. After cooling the inside of the system to 0°C, sodium hydride (792 mg, 19.8 mmol) was added in three portions, and the mixture was warmed to room temperature and stirred for 15 minutes. After allyl bromide (1.8 mL, 20.6 mmol) was added dropwise into the system, the mixture was stirred under reflux conditions for 41 hours. After completion of the reaction, H ₂ O (17 mL) was added, and the pH of the system was adjusted to 1-2 using 1N HCl aq., followed by extraction with ethyl acetate three times. The organic layer was washed with saturated brine three times, dehydrated and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. NaOH (511 mg, 12.9 mmol), H ₂ O (3 mL) and MeOH (3 mL) were added to the resulting residue and stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was diluted with water and washed with ethyl acetate three times. The aqueous layer was adjusted to pH 1-2 using 1N HCl aq. and extracted three times with ethyl acetate. The organic layer was washed with saturated brine three times, dehydrated and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. (1.66g, 69%)
Colorless oil; ¹ H NMR (270 MHz, CDCl ₃ ); , 4.17 (m, 1H), 3.97-3.96 (m, 2H), 3.75-3.61 (m, 2H), 2.44-2.04 (m, 2H).

(2S,4R)-1-((Benzyloxy)carbonyl)-4-((4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11 Synthesis of ,11-heptadecafluoro-2-iodoundecyl)oxy)pyrrolidine-2-carboxylic acid

After degassing (2S,4R)-4-(allyloxy)-1-((benzyloxy)carbonyl)pyrrolidine-2-carboxylic acid (3.85 g, 13 mmol) at -78 °C under N ₂ atmosphere, _C8F17I (3.43 mL, 13 mmol) was added and the temperature was raised to 80° _C . AIBN (210 mg, 1.3 mmol) was added to the system and stirred for 43 hours. After completion of the reaction, the pH was adjusted to 1-2 using 1N HCl aq., and extracted with ethyl acetate three times. The organic layer was washed with saturated brine three times, dehydrated and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by FSPE (methanol:water=68:32). (4.85g, 43%)
Yellow oil; ¹ H NMR (270 MHz, CDCl ₃ ); , 4.30-4.17 (m, 1H), 3.76-3.54 (m, 4H), 2.99-2.65 (m, 2H), 2.47-2.18 (m, 2H); ¹³ C NMR (125 MHz, CDCl ₃ ); , ^174.79 , 155.98, 154.62, 136.09, 136.09, 128.62, 128.46, 118.37-108.49, 73.76, 67.40 _, 67.40, 58.21-57.65, -34.99 125.96 (2F), -123.35 (2F), -122.56 (2F), -121.74 (4F), -121.41 (2F), -114.29--112.39 (2F), -80.61 (3F); z calcd _{for C24H20O5NF17I 852.0115} , found _: 852.0133.

(2S,4R)-1-((Benzyloxy)carbonyl)-4-((4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11 Synthesis of ,11-heptadecafluoroundecyl)oxy)pyrrolidine-2-carboxylic acid

(2S,4R)-1-((Benzyloxy)carbonyl)-4-((4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11 AIBN (12.6 mg, 0.0766 mmol), hypophosphorous acid (1.44 mL, 7.66 mmol) and sodium bicarbonate (772.8 mg, 9.19 mmol) were added in that order, and the mixture was stirred under reflux for 4 hours. After completion of the reaction, the system was adjusted to pH 1-2 using 1N HCl aq., and extracted three times with ethyl acetate. The organic layer was washed with saturated brine three times, dehydrated and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (dichloromethane:methanol=15:1). (348.7mg, 63%)
Yellow oil; ¹ H NMR (270 MHz, CDCl ₃ ); , 1H), 3.71-3.46 (m, 4H), 2.25-2.08 (m, 4H), 1.85-1.61 (m, 2H).

Synthesis of 3,5-Bis(trifluoromethyl)benzenesulfonamide

3,5-Bis(trifluoromethyl)benzenesulfonyl chloride (2.0 g, 6.4 mmol) was dissolved in H ₂ O (10 mL), 25% aqueous ammonia (2.5 mL, 33.4 mmol) was added, and the mixture was stirred at 100 °C for 2 hours. Stirred for an hour. After concentration under reduced pressure, 1N HCl aq. was added to the resulting crude product, and the resulting precipitate was collected by suction filtration. (1.6g, 85%)
White solid; mp 182-183 °C; ¹ H NMR (270 MHz, CDCl ₃ ); δ 8.39 (s, 2H), 8.09 (s, 1H), 5.00 (s, 2H).

Benzyl(2S,4R)-2-(((3,5-bis(trifluoromethyl)phenyl)sulfonyl)carbamoyl)-4-((4,4,5,5,6,6,7,7,8,8 Synthesis of ,9,9,10,10,11,11,11-heptadecafluoroundecyl)oxy)pyrrolidine-1-carboxylate

( _2S ,4R)-1-((benzyloxy)carbonyl)-4-((4,4,5,5,6,6,7,7,8,8,9,9, 10,10,11,11,11-heptadecafluoroundecyl)oxy)pyrrolidine-2-carboxylic acid (348.8 mg, 0.48 mmol), 3,5-bis(trifluoromethyl)benzenesulfonamide (209.8 mg, 0.72 mmol), DMAP (19.6 mg, 0.12 mmol), and HOBt (110 mg, 0.72 mmol) were dissolved in a mixed solvent of dry-CH ₂ Cl ₂ (10 mL) and dry-DMF (5 mL). After cooling the inside of the system to 0 °C, EDCI (127 mL, 0.72 mmol) was added dropwise and stirred for 10 minutes. Further, the mixture was stirred at room temperature for 32 hours. After completion of the reaction, the system was adjusted to pH 1-2 using 1N HCl aq., and extracted three times with ethyl acetate. The organic layer was washed with saturated brine three times, dehydrated and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane:ethyl acetate=4:1). (400.8 mg, 83%)
Yellow oil; ¹ H NMR (270 MHz, CDCl ₃ ); , 1H), 4.04 (s, 1H), 3.54-3.39 (m, 4H), 2.07-1.76 (m, 4H), 1.25-1.22 (m, 2H); ¹³ C NMR (125 MHz, CDCl ₃ ); 135.49, 132.62-121.46, 118.53-108.00, 68.59, 67.76, 51.64, 27.82, 27.29, 20.91; ¹⁹ F NMR (466 MHz, _CDCl3 ); ), -122.44--122.98 (2F), -121.15--122.35 (6F), -113.92--114.84 (2F), -80.56--80.89 (3F), -62.40--3.58 (6F); ) m/z calcd _{for C32H24O6N2F23S 1001.0988} , found: _{1001.0948 .}

(2S,4R)-N-((3,5-Bis(trifluoromethyl)phenyl)sulfonyl)-4-((4,4,5,5,6,6,7,7,8,8,9,9 Synthesis of ,10,10,11,11,11-heptadecafluoroundecyl)oxy)pyrrolidine-2-carboxamide

Benzyl(2S,4R)-2-(((3,5-bis(trifluoromethyl)phenyl)sulfonyl)carbamoyl)-4-((4,4,5,5,6,6,7,7,8,8 ,9,9,10,10,11,11,11-heptadecafluoroundecyl)oxy)pyrrolidine-1-carboxylate (379.0 mg, 0.38 mmol) was dissolved in MeOH (6 mL) and 5% supported Pd/C (161.76 mg, 0.076 mmol) was added, and the mixture was replaced with H ₂ and stirred at room temperature for 17 hours. Celite filtration was performed using MeOH, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (dichloromethane:methanol=19:1). (286.3mg, 88%)
Yellow solid; mp 103.8-104.9 °C; ¹ H NMR (270 MHz, CDCl ₃ ); 3.62-3.46 (m, 4H), 2.59 (m, 1H), 2.18-2.02 (m, 3H), 1.85-1.71 (m, 2H); ¹³ C NMR (125 MHz, CDCl ₃ ); δ 173.17, 146.40, 131.56-124.56, 77.88, 67.12, 61.10, _50.86 , 35.09, 27.23, 20.36; ¹⁹ F NMR (466 MHz, CDCl3); --123.01 (6F), -115.33 (2F), -82.28 ( _3F ), -64.32 (5F); _HRMS (FAB+ ₎ m/z calcd for _{C24H18O4N2F23S} 867.0620, found: _867.0625 .

<Synthesis of proline catalyst (2)>
A synthesis scheme of proline catalyst (1) is shown below, and then the methods for synthesizing each compound are described in order.

Synthesis of (2S,4R)-1-((Benzyloxy)carbonyl)-4-(undecyloxy)pyrrolidine-2-carboxylic acid

(2S,4R)-1-((benzyloxy)carbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (999.6 mg, 3.8 mmol) was weighed into a three-necked flask, purged with nitrogen, and dry-DMF (10 mL) was added. rice field. After cooling the inside of the system to 0°C, sodium hydride (565.5 mg, 9.4 mmol) was added in two portions, the temperature was raised to room temperature, and the mixture was stirred for 15 minutes. After 1-iodoundecane (2.2 mL, 9.8 mmol) was added dropwise into the system, the mixture was stirred under reflux conditions for 4 days. After completion of the reaction, H ₂ O was added, and the pH of the system was adjusted to 1-2 using 1N HCl aq., followed by extraction with ethyl acetate three times. The organic layer was washed with saturated brine three times, dehydrated and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate:methanol=20:1). (1238.3 mg, 78%)
Yellow Oil; ¹ H NMR (270MHz, CDCl ₃ ) δ = 7.36 (s, 5H), 5.12-5.19 (s, 2H), 4.49-4.55 (s, 1H), 4.06-4.14 (s,1H), 3.57- 3.67 (m, 2H), 3.38-3.43 (m, 2H), 2.05-2.38 (m, 2H), 1.52 (s, 2H), 1.26 (s, 16H), 0.85 (t, J = 7.0Hz, 3H) .

Synthesis of Benzyl (2S,4R)-2-(((3,5-bis(trifluoromethyl)phenyl)sulfonyl)carbamoyl)-4-(undecyloxy)pyrrolidine-1-carboxylate

(2S,4R)-1-((benzyloxy)carbonyl) _-4- (undecyloxy)pyrrolidine-2-carboxylic acid (303.3 mg, 0.72 mmol), 3,5-bis(trifluoromethyl)benzenesulfonamide (313.2 mg, 1.07 mmol), DMAP (29.1 mg, 0.18 mmol), and HOBt (163.1 mg, 1.07 mmol) were dissolved in a mixed solvent of dry-CH ₂ Cl ₂ (10 mL) and dry-DMF (5 mL). rice field. After cooling the inside of the system to 0 °C, EDCI (148 µL, 1.07 mmol) was added dropwise and stirred for 20 minutes. Further, the mixture was stirred at room temperature for 28 hours. After completion of the reaction, the system was adjusted to pH 1-2 using 1N HCl aq., and extracted three times with ethyl acetate. The organic layer was washed with saturated brine three times, dehydrated and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane:ethyl acetate=3:1). (63.9mg, 64%)
Yellow Oil; ¹ H NMR (270MHz, CDCl ₃ ) δ = 8.53 (s,2H), 8.11(s, 1H), 7.34(s, 5H), 5.11-5.22 (s, 2H), 4.37-4.42 (m, 1H), 3.99-4.04 (m, 1H), 3.59-3.64 (m, 2H), 3.29-3.48 (m, 2H), 2.37-2.46 (m, 1H), 2.03-2.17 (m, 1H), 1.46- 1.51 (t, 2H), 1.25 (s, 16H), 0.85 (t, J = 7.0 Hz, 3H).

Synthesis of (2S,4R)-N-((3,5-Bis(trifluoromethyl)phenyl)sulfonyl)-4-(undecyloxy)pyrrolidine-2-carbboxamide

Benzyl (2S,4R)-2-(((3,5-bis(trifluoromethyl)phenyl)sulfonyl)carbamoyl)-4-(undecyloxy)pyrrolidine-1-carboxylate (50.0 mg, 0.07 mmol) in MeOH (600 μL) , 10% supported Pd/C (8.3 mg, 0.007 mmol) was added, replaced with H ₂ , and stirred at room temperature for 22 hours. Celite filtration was performed using MeOH, and the filtrate was concentrated under reduced pressure. (27.6mg, 68%)
Yellow Oil; ¹ H NMR (270MHz, CDCl ₃ ) δ =8.42 (s, 2H), 7.97 (s, 1H), 4.17 (s, 1H), 3.64-3.35 (m, 4H), 3.09 (s, 1H) , 2.68-2.21 (m, 2H), 1.98 (s,2H), 1.53-1.51 (m,2H), 1.25 (s,16H), 0.80 (t, J = 6.5, 3H).

<Synthesis of proline catalyst (3)>
(2S,4R)-1-((Benzyloxy)carbonyl)-4-((4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11 Synthesis of ,11-heptadecafluoroundecyl)oxy)pyrrolidine-2-carboxylic acid

Weigh (2S,4R)-1-((benzyloxy)carbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (506.4 mg, 1.9 mmol) into a three-necked flask, purge with nitrogen, and add dry-DMF (1 mL). rice field. After cooling the inside of the system to 0°C, sodium hydride (333.3 mg, 5.6 mmol) was added in two portions, the temperature was raised to room temperature, and the mixture was stirred for 15 minutes. 1,1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8-heptadecafluoro-11-iodoundecane dissolved in DMF (1 mL) (2.2 mL, 9.8 mmol) was added dropwise and then stirred at room temperature for 90 minutes. After completion of the reaction, H ₂ O was added, and the pH of the system was adjusted to 1-2 using 1N HCl aq., followed by extraction with diethyl ether three times. The organic layer was washed with saturated brine three times, dehydrated and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane:ethyl acetate=3:1). (631.8 mg, 46%)
Yellow oil; ¹ H NMR (270 MHz, CDCl ₃ ); , 1H), 3.71-3.46 (m, 4H), 2.25-2.08 (m, 4H), 1.85-1.61 (m, 2H).

Synthesis of 4-(Trifluoromethyl)benzenesulfonamide

4-(trifluoromethyl)benzenesulfonyl chloride (500 mg, 2.04 mmol) was dissolved in H ₂ O (3.2 mL), 25% aqueous ammonia (785 μL, 20.4 mmol) was added, and the mixture was stirred at 100 °C for 2 hours. . After concentration under reduced pressure, 1N HCl aq. was added to the resulting crude product, and the resulting precipitate was collected by suction filtration. (386.0mg, 84%)
White Solid; mp 166 -170 °C; ¹ H NMR (270MHz, CDCl ₃ ) δ = 8.04-8.07 (d, J = 8.1, 2H), 7.57-7.59 (d, J = 5.4, 2H), 4.93 (s , 2H).

Benzyl (2S,4R)-4-((4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoroundecyl)oxy)- Synthesis of 2-(((4-(trifluoromethyl)phenyl)sulfonyl)carbamoyl)pyrrolidine-1-carboxylate

( _2S , 4R)-1-((benzyloxy)carbonyl)-4-((4,4,5,5,6,6,7,7,8,8,9,9, 10,10,11,11,11-heptadecafluoroundecyl)oxy)pyrrolidine-2-carboxylic acid (93.2 mg, 0.13 mmol), 4-(trifluoromethyl)benzenesulfonamide (27.2 mg, 0.12 mmol), and DMAP (46.1 mg, 0.38 mmol) ) was dissolved in a mixed solvent of ^t BuOH (500 μL) and 1,2-C ₂ H ₄ Cl ₂ (500 μL). EDCI (56 μL, 0.32 mmol) was added dropwise at room temperature and stirred for 28 hours. After completion of the reaction, the system was adjusted to pH 1-2 using 1N HCl aq., and extracted three times with ethyl acetate. The organic layer was washed with saturated brine three times, dehydrated and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane:ethyl acetate=1:3). (56mg, 47%)
Yellow oil: ¹ H NMR (270 MHz, CDCl ₃ ); δ 8.14 (d, J = 7.6 Hz, 2H), 7.76 (d, J = 8.1 Hz, 2H), 7.38 (s, 5H), 5.21 (s, 2H), 4.39 (t, J = 6.5 Hz, 1H), 4.01 (t, J = 4.9 1H), 3.62-3.44 (m, 4H), 2.10-1.81 (m, 4H), 0.88 (t, J = 7.3 Hz, 2H).

(2S,4R)-4-((4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoroundecyl)oxy)-N Synthesis of -((4-(trifluoromethyl)phenyl)sulfonyl)pyrrolidine-2-carboxamide

benzyl (2S,4R)-4-((4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoroundecyl)oxy)- 2-(((4-(trifluoromethyl)phenyl)sulfonyl)carbamoyl)pyrrolidine-1-carboxylate (56 mg, 0.06 mmol) was dissolved in MeOH (1.5 mL) and treated with 5% Pd/C (257.6 mg, 0.12 mmol). was added, replaced with H ₂ , and stirred at 50 °C for 15.5 hours. Celite filtration was performed using MeOH, and the filtrate was concentrated under reduced pressure. (31.9mg, 67%)
Yellow Oil; ¹ H NMR (270MHz, CDCl ₃ ) δ = 8.12-8.05 (m, 2H), 7.80-7.65 (m, 2H), 4.32-4.09 (m, 2H), 3.76-3.80 (m, 1H), 3.48-3.40 (m, 4H), 2.87 (s, 1H), 2.45-2.41 (m, 1H), 2.14-2.05 (m, 3H), 1.83-1.81 (m, 2H).

<Synthesis of control proline catalyst (1)>
The control proline catalyst (1) shown below constructs the sulfonamide site at the 2-position according to Non-Patent Document 3 (Adv. Synth. Catal. 2004, 346, 1141.) and utilizes the usual SN2 reaction. 4-position alkylation was carried out.

<Synthesis of control proline catalyst (2)>
The control proline catalyst (2) shown below was synthesized according to Non-Patent Document 4 (Tetrahedron: Asymmetry 2003, 14, 139.).

In this example, an aldol reaction was carried out using the synthesized proline catalysts (1) to (3).

<Aldol reaction using proline catalyst (1)>
Synthesis of 2-(Hydroxy(4-nitrophenyl)methyl)cyclohexan-1-one

H ₂ O (0.66 mL), cyclohexanone (683.5 μL, 6.6 mmol), and nitrobenzaldehyde (100.3 mg, 0.66 mmol) were added to proline catalyst (1) (5.6 mg, 0.0065 mmol) and stirred at 23 °C for 168 hours. bottom. After completion of the reaction, the residue obtained by concentration under reduced pressure was purified by column chromatography (hexane:ethyl acetate=3:1) (132.7 mg, 81%). The ratio of syn-isomer to anti-isomer was calculated from ¹ H NMR of the crude product (anti-isomer:syn-isomer=100:0). The enantiomeric excess of the anti isomer was calculated by HPLC (Daicel Chiralpak IB + OD-3 column, hex : ⁱ PrOH = 96 : 4, 1.0 mL/min, >99%ee).
white solid; mp 97.7-98.8 °C; ¹ H NMR (270 MHz, CDCl ₃ ); , 1H), 4.13 (d, J = 3.0 Hz, 1H), 2.66-2.31 (m, 3H), 2.16-2.05 (m, 1H), 1.85-1.23 (m, 5H).

Synthesis of 2-(Hydroxy(4-nitrophenyl)methyl)cyclohexan-1-one

THF (0.66 mL), cyclohexanone (683.5 μL, 6.6 mmol), and nitrobenzaldehyde (100.3 mg, 0.66 mmol) were added to proline catalyst (1) (5.6 mg, 0.0065 mmol) and stirred at 23 °C for 96 hours. After completion of the reaction, the residue obtained by concentration under reduced pressure was purified by column chromatography (hexane:ethyl acetate=3:1) (143.9 mg, 87%). The ratio of syn-isomer to anti-isomer was calculated from ¹ H NMR of the crude product (anti-isomer:syn-isomer=100:0). The enantiomeric excess of the anti isomer was calculated by HPLC (Daicel Chiralpak IB + OD-3 column, hex : ⁱ PrOH = 96 : 4, 1.0 mL/min, >99%ee).
white solid; mp 97.7-98.8 °C; ¹ H NMR (270 MHz, CDCl ₃ ); , 1H), 4.13 (d, J = 3.0 Hz, 1H), 2.66-2.31 (m, 3H), 2.16-2.05 (m, 1H), 1.85-1.23 (m, 5H).

Synthesis of 2-(Hydroxy(4-nitrophenyl)methyl)cyclohexan-1-one

Toluene (0.66 mL), cyclohexanone (683.5 μL, 6.6 mmol), and nitrobenzaldehyde (100.1 mg, 0.66 mmol) were added to proline catalyst (1) (5.6 mg, 0.0065 mmol) and stirred at 23 °C for 120 hours. After completion of the reaction, the residue obtained by concentration under reduced pressure was purified by column chromatography (hexane:ethyl acetate=3:1) (152.0 mg, 92%). The production ratio of syn-isomer and anti-isomer was calculated from ¹ H NMR of the crude product (anti-isomer:syn-isomer=97:3). The enantiomeric excess of the anti isomer was calculated by HPLC (Daicel Chiralpak IB + OD-3 column, hex : ⁱ PrOH = 96 : 4, 1.0 mL/min, >99%ee).
white solid; mp 97.7-98.8 °C; ¹ H NMR (270 MHz, CDCl ₃ ); , 1H), 4.13 (d, J = 3.0 Hz, 1H), 2.66-2.31 (m, 3H), 2.16-2.05 (m, 1H), 1.85-1.23 (m, 5H).

Synthesis of 2-(Hydroxy(4-nitrophenyl)methyl)cyclohexan-1-one

Toluene (0.66 mL), cyclohexanone (683.5 μL, 6.6 mmol), and nitrobenzaldehyde (100.7 mg, 0.66 mmol) were added to proline catalyst (1) (56.3 mg, 0.065 mmol) and stirred at 23 °C for 24 hours. After completion of the reaction, the residue obtained by concentration under reduced pressure was purified by column chromatography (hexane:ethyl acetate=3:1) (155.4 mg, 94%). The production ratio of syn-isomer and anti-isomer was calculated from ¹ H NMR of the crude product (anti-isomer:syn-isomer=97:3). The enantiomeric excess of the anti isomer was calculated by HPLC (Daicel Chiralpak IB + OD-3 column, hex : ⁱ PrOH = 96 : 4, 1.0 mL/min, >99%ee).
white solid; mp 97.7-98.8 °C; ¹ H NMR (270 MHz, CDCl ₃ ); , 1H), 4.13 (d, J = 3.0 Hz, 1H), 2.66-2.31 (m, 3H), 2.16-2.05 (m, 1H), 1.85-1.23 (m, 5H).

<Aldol reaction using proline catalyst (2)>
Synthesis of 2-(Hydroxy(4-nitrophenyl)methyl)cyclohexan-1-one

Toluene (180 μL), cyclohexanone (170 μL, 1.7 mmol) and nitrobenzaldehyde (26.1 mg, 0.17 mmol) were added to proline catalyst (2) (9.7 mg, 0.017 mmol) and stirred at room temperature for 24 hours. The residue obtained by concentration under reduced pressure was subjected to ¹ H NMR measurement to calculate the conversion rate and the production ratio of syn isomer and anti isomer (conversion rate = 99%, anti isomer: syn isomer = 100:0). The enantiomeric excess of the anti isomer was calculated by HPLC (Daicel Chiralpak IB + OD-3 column, hex : ⁱ PrOH = 96 : 4, 1.0 mL/min, >99%ee).

Synthesis of 2-(Hydroxy(4-nitrophenyl)methyl)cyclohexan-1-one

Toluene (93 μL), cyclohexanone (96 μL, 0.9 mmol) and nitrobenzaldehyde (14.6 mg, 0.09 mmol) were added to proline catalyst (2) (7.4 mg, 0.009 mmol) and stirred at room temperature for 24 hours. The residue obtained by concentration under reduced pressure was subjected to ¹ H NMR measurement to calculate the conversion rate and syn-to-anti-formation ratio (conversion rate = 67%, anti : syn isomer = 94:6). The enantiomeric excess of the anti isomer was calculated by HPLC (Daicel Chiralpak IB + OD-3 column, hex: ⁱ PrOH = 96:4, 1.0 mL/min, 91%ee).

For the control proline catalysts (1) and (2) as well, the aldol reaction was carried out using the same substrates as in Examples according to Non-Patent Document 3 (Adv. Synth. Catal. 2004, 346, 1141.).

Results for proline catalysts (1)-(3) and control proline catalysts (1)-(2) are shown below.

なお、*は¹Ｈ ＮＭＲによる結果であり、**は、キラルＨＰＬＣ（Daicel Chiralpack
IB+OD-3 カラム、Hex:ｉPrOH=96:4、1.0ml/min）による測定結果である。

In addition, * is the result by ¹ H NMR, ** is chiral HPLC (Daicel Chiralpack
IB+OD-3 column, Hex:iPrOH=96:4, 1.0 ml/min).

As shown in Table 1, the proline catalysts (1) to (3) make it possible to synthesize extremely high optically active anti-β-hydroxy compounds and to obtain high yields at the same time.

Claims (8)

A catalyst for an aldol reaction, which is a proline derivative represented by the following formula (1), a proline derivative that is an enantiomer thereof, or a salt thereof.

(R ¹ represents a first fluorous group or a first substituent having a hydrocarbon group , the first fluorous group is a polyfluoroalkyl group having 4 to 12 carbon atoms, and the first The hydrocarbon group is an alkyl group, aryl group or aralkyl group having 4 to 18 carbon atoms, and R ² has a second fluorous group and a carbonyl group bonded to the 2-position carbon atom of the pyrrolidine skeleton. represents the second substituent having the structure .) 2. The aldol reaction catalyst according to claim 1 , wherein said polyfluoroalkyl group is a perfluoroalkyl group. The aldol reaction catalyst according to claim 1 or 2 , wherein the first substituent comprises the first fluorous group or hydrocarbon group introduced at the 4-position of the pyrrolidine skeleton via an alkylene group. . The aldol reaction catalyst according to any one of claims 1 to 3 , wherein the second fluorous group is a polyfluoroalkyl group having 1 to 4 carbon atoms. 5. The aldol reaction catalyst according to claim 4 , wherein the polyfluoroalkyl group is a perfluoroalkyl group. 6. The aldol reaction catalyst according to any one of claims 1 to 5 , wherein said second substituent comprises said second fluorous group via a sulfonamide moiety containing a nitrogen atom bonded to said carbonyl carbon. A β-hydroxy compound comprising a step of synthesizing a β-hydroxy compound by performing an aldol reaction between a carbonyl compound having α hydrogen and a ketone or aldehyde using the aldol reaction catalyst according to any one of claims 1 to 6 . A method for producing a compound. The production method according to claim 7 , wherein the carbonyl compound having α-hydrogen has a nitro group.