CN111574450A - Novel chiral biphenyl quaternary ammonium salt phase transfer catalyst and preparation method and application thereof - Google Patents
Novel chiral biphenyl quaternary ammonium salt phase transfer catalyst and preparation method and application thereofDownload PDFInfo
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Abstract
Translated fromChinese
Description
Translated fromChinese技术领域technical field
本发明属于合成化学和催化化学技术领域，更具体地，涉及一种手性联苯类季铵盐相转移催化剂及其制备方法和在不对称催化反应中的应用。The invention belongs to the technical field of synthetic chemistry and catalytic chemistry, and more particularly, relates to a chiral biphenyl quaternary ammonium salt phase transfer catalyst, a preparation method thereof, and an application in asymmetric catalytic reaction.
背景技术Background technique
相转移催化(phase-transfer catalysis,PTC)因反应条件温、操作简单、环境友好、可使用水溶液以及易于放大量生产等优势，在学术和工业生产中都得到了规范的应用。不对称相转移催化为手性药物、天然产物手性核心结构、手性精细化学品等手性功能分子的构建提供了方便有效的方法。因此，近年来备受关注。手性相转移催化剂在实现不对称相转移催化中发挥着极其关键的作用。Maruoka课题组开发了手性季铵盐类相转移催化剂(Maruoka Catalyst)，包括：基于手性联萘酚骨架的“螺环型Maruoka相转移催化剂”(Spiro-type Maruoka Catalyst)，基于手性联萘酚骨架的“简化的Maruoka相转移催化剂”(Simplified Maruoka Catalyst)，以及基于手性联苯骨架的“改良的Maruoka相转移催化剂”(Modified Maruoka Catalyst)。该系列相转移催化剂已经成功应用于催化不对称烷基化反应、不对称迈克尔加成反应、不对称曼尼希反应、不对称羟醛缩合反应、不对称达西反应、不对称环氧化反应、不对称史特莱克反应等反应类型。其中，催化不对称烷基化反应已成功应用于开发天然及人造氨基酸及肽，基于联苯骨架的改良Maruoka 相转移催化剂，在不对称烷基化反应中表现出较高的催化活性(0.01-1mol％的催化剂用量)和优异的立体选择性，为α-烷基取代-α-氨基酸的合成提供了使用的方法。光学纯的联苯骨架对于手性联苯类相转移催化剂的开发至关重要。Maruoka 小组早期对联苯类衍生物(6,6'-二甲基-3,3'-二叔丁基-5,5'–二溴-2,2'-联苯酚苯酚) 进行了手性拆分，以(R,R)-二苯基乙二胺为拆分剂，通过与轴手性的联苯酚消旋体进行成盐反应对其进行了化学拆分，拆分后的单一联苯衍生物的ee值>99％，然而，(R,R)-二苯基乙二胺作为拆分剂价格昂贵，使得手性联苯骨架的“改良的 Maruoka相转移催化剂”在工业化生产受限。Phase-transfer catalysis (PTC) has been widely used in both academic and industrial production due to its advantages of mild reaction conditions, simple operation, environmental friendliness, use of aqueous solutions, and ease of large-scale production. Asymmetric phase transfer catalysis provides a convenient and effective method for the construction of chiral functional molecules such as chiral drugs, chiral core structures of natural products, and chiral fine chemicals. Therefore, it has attracted much attention in recent years. Chiral phase transfer catalysts play an extremely critical role in realizing asymmetric phase transfer catalysis. Maruoka's research group has developed chiral quaternary ammonium salt phase transfer catalysts (Maruoka Catalyst), including: "Spiro-type Maruoka Phase Transfer Catalyst" based on chiral binaphthol skeleton, based on chiral A "Simplified Maruoka Catalyst" based on a naphthol skeleton, and a "Modified Maruoka Catalyst" based on a chiral biphenyl skeleton. This series of phase transfer catalysts have been successfully used to catalyze asymmetric alkylation reactions, asymmetric Michael addition reactions, asymmetric Mannich reactions, asymmetric aldol condensation reactions, asymmetric Darcy reactions, and asymmetric epoxidation reactions. , asymmetric Strecker reaction and other reaction types. Among them, the catalytic asymmetric alkylation reaction has been successfully applied to the development of natural and artificial amino acids and peptides. The improved Maruoka phase transfer catalyst based on the biphenyl skeleton showed high catalytic activity in the asymmetric alkylation reaction (0.01- 1 mol% catalyst dosage) and excellent stereoselectivity provide a useful method for the synthesis of α-alkyl-substituted-α-amino acids. Optically pure biphenyl skeletons are crucial for the development of chiral biphenyl-based phase transfer catalysts. The early chiral resolution of biphenyl derivatives (6,6'-dimethyl-3,3'-di-tert-butyl-5,5'-dibromo-2,2'-biphenolphenol) by Maruoka's group (R,R)-diphenylethylenediamine was used as the resolving agent, and the biphenol racemate with axial chirality was subjected to a salt-forming reaction to chemically resolve it. The single biphenyl after the resolution The ee value of the derivative is >99%, however, (R,R)-diphenylethylenediamine is expensive as a resolving agent, which makes the "improved Maruoka phase transfer catalyst" of chiral biphenyl skeleton limited in industrial production .
发明内容SUMMARY OF THE INVENTION
为了克服现有技术的不足和缺陷，本发明提供一种基于廉价易得的(R)-甲氧基苯乙酸为拆分剂构建联苯骨架的化学拆分方法，进而制备一系列手性联苯类季铵盐相转移催化剂。该类催化剂制备工艺简单，总产率较高。该类催化剂催化效率较高和良好的选择性。对于传统有毒过度金属催化来说，基于该类新型催化剂的催化体系，绿色环保，反应条件温和，有利于工业化生产。In order to overcome the deficiencies and defects of the prior art, the present invention provides a chemical splitting method for constructing a biphenyl skeleton based on cheap and easily available (R)-methoxyphenylacetic acid as a splitting agent, and then prepares a series of chiral linkages. Benzene quaternary ammonium salt phase transfer catalyst. The preparation process of this kind of catalyst is simple and the total yield is high. Such catalysts have high catalytic efficiency and good selectivity. For traditional toxic transition metal catalysis, the catalytic system based on this new type of catalyst is green and environmentally friendly, with mild reaction conditions, which is beneficial to industrial production.
本发明的另一目的在于提供上述手性联苯类季铵盐相转移催化剂的制备方法。该方法反应条件温和，操作简单，对环境友好等多个优点，能够高效的合成出手性含联苯骨架季铵盐催化剂。Another object of the present invention is to provide a method for preparing the above-mentioned chiral biphenyl quaternary ammonium salt phase transfer catalyst. The method has the advantages of mild reaction conditions, simple operation, environmental friendliness and the like, and can efficiently synthesize a chiral biphenyl skeleton-containing quaternary ammonium salt catalyst.
本发明的再一目的在于提供上述手性联苯类季铵盐相转移催化剂的不对称反应的催化应用。Another object of the present invention is to provide the catalytic application of the asymmetric reaction of the above-mentioned chiral biphenyl-based quaternary ammonium salt phase transfer catalyst.
上述目的通过以下技术方案予以实现：The above objectives are achieved through the following technical solutions:
一种手性联苯类季铵盐相转移催化剂，所述催化剂包括化合物A和化合物B，所述化合物A的分子结构如式(Ⅰ)所示，所述化合物B的分子结构如式(Ⅱ) 所示：A chiral biphenyl type quaternary ammonium salt phase transfer catalyst, the catalyst comprises a compound A and a compound B, the molecular structure of the compound A is shown in formula (I), and the molecular structure of the compound B is shown in the formula (II) ) as shown:
其中R1是甲氧基和羟基；R2是叔丁基和氢；R3是3,5-双(三氟甲基)苯基和 3,4,5-三氟苯基。wherein R1 is methoxy and hydroxyl; R2 is tert-butyl and hydrogen; R3 is 3,5-bis(trifluoromethyl)phenyl and 3,4,5-trifluorophenyl.
优选地，所述催化剂的分子结构为如下结构式中的一种：Preferably, the molecular structure of the catalyst is one of the following structural formulas:
优选地，包括如下步骤：Preferably, including the following steps:
S1.将5-甲基-2-叔丁基苯酚和四丁基三溴化铵溶于二氯甲烷和甲醇的混合溶剂中，在常温反应1小时，得到4-溴-2-叔丁基-5-甲基苯酚。S1. Dissolve 5-methyl-2-tert-butylphenol and tetrabutylammonium tribromide in a mixed solvent of dichloromethane and methanol, and react at room temperature for 1 hour to obtain 4-bromo-2-tert-butyl -5-Methylphenol.
S2.将4-溴-2-叔丁基-5-甲基苯酚和四甲基乙二胺溶于二氯甲烷中，氯化亚铜为催化剂，在常温条件下反应6小时，得到6,6’-二甲基-3,3’-二叔丁基-5,5’-二溴-2,2’-联苯酚。S2. 4-bromo-2-tert-butyl-5-methylphenol and tetramethylethylenediamine are dissolved in methylene dichloride, and cuprous chloride is a catalyst, and reacts 6 hours under normal temperature conditions to obtain 6, 6'-Dimethyl-3,3'-di-tert-butyl-5,5'-dibromo-2,2'-biphenol.
S3.将6,6’-二甲基-3,3’-二叔丁基-5,5’-二溴-2,2’-联苯酚和氢化钠溶于无水四氢呋喃中，去质子化3小时，往上述体系中逐滴滴加现制的(R)-2-甲氧基苯乙酰氯，继续反应1小时，得到单酯化产物和双酯化产物。S3. Dissolve 6,6'-dimethyl-3,3'-di-tert-butyl-5,5'-dibromo-2,2'-biphenol and sodium hydride in anhydrous tetrahydrofuran and deprotonate After 3 hours, the freshly prepared (R)-2-methoxyphenylacetyl chloride was added dropwise to the above system, and the reaction was continued for 1 hour to obtain a monoesterified product and a double esterified product.
S4.将单酯化产物和者双酯化产物溶于无水四氢呋喃，以四氢铝锂为还原剂，反应1小时，得到手性6,6’-二甲基-3,3’-二叔丁基-5,5’-二溴-2,2’-联苯酚。S4. Dissolve the mono-esterified product and the double-esterified product in anhydrous tetrahydrofuran, use tetrahydroaluminum lithium as the reducing agent, and react for 1 hour to obtain chiral 6,6'-dimethyl-3,3'-dimethy tert-Butyl-5,5'-dibromo-2,2'-biphenol.
S5.手性6,6’-二甲基-3,3’-二叔丁基-5,5’-二溴-2,2’-联苯酚溶于甲苯溶液中，以三氟甲磺酸为氧化剂，得到手性6,6’-二甲基-5,5’-二溴-2,2’-联苯酚。S5.
S6.将上述S4或S5所得产物、四(三苯基膦)钯、碳酸钠和苯硼酸类化合物溶于乙二醇二甲醚(DME)和水的混合体系中，在氩气和95℃条件下反应过夜，得到手性6,6’-二甲基-3,3’-二叔丁基-5,5’-二芳基-2,2’-联苯酚或手性6,6’-二甲基 -5,5’-二芳基-2,2’-联苯酚。S6. Dissolve the product obtained from S4 or S5, tetrakis (triphenylphosphine) palladium, sodium carbonate and phenylboronic acid compounds in a mixed system of ethylene glycol dimethyl ether (DME) and water, under argon and 95° C. Reaction overnight under conditions to obtain chiral 6,6'-dimethyl-3,3'-di-tert-butyl-5,5'-diaryl-2,2'-biphenol or
S7.将手性6,6’-二甲基-3,3’-二叔丁基-5,5’-二芳基-2,2’-联苯酚或手性6,6’-二甲基-5,5’-二芳基-2,2’-联苯酚、碘甲烷和碳酸钾溶于丙酮，回流的条件下反应过夜，得到手性6,6’-二甲基-3,3’-二叔丁基-5,5’-二芳基-2,2’-二甲氧基联苯或手性6,6’- 二甲基-5,5’-二芳基-2,2’-二甲氧基联苯。S7.
S8.将手性6,6’-二甲基-3,3’-二叔丁基-5,5’-二芳基-2,2’-二甲氧基联苯或手性 6,6’-二甲基-5,5’-二芳基-2,2’-二甲氧基联苯、偶氮二异丁腈和N-溴代丁二酰亚胺溶于苯中，在回流条件下反应4小时，得到手性3,3’-二叔丁基-5,5’-二芳基-6,6’- 二溴甲基-2,2’-二甲氧基联苯或5,5’-二芳基-6,6’-二溴甲基-2,2’-二甲氧基联苯。S8.
S9.将手性3,3’-二叔丁基-5,5’-二芳基-6,6’-二溴甲基-2,2’-二甲氧基联苯或5,5’- 二芳基-6,6’-二溴甲基-2,2’-二甲氧基联苯、碳酸钾和正二丁胺溶于乙腈中，在85℃条件下反应过夜，得到手性催化剂化合物A和手性催化剂化合物B，其中R1是甲氧基；R2是叔丁基和氢；R3是3,5-双(三氟甲基)苯基和3,4,5-三氟苯基。S9.
S10.将上述手性甲氧基类催化剂溶于无水二氯甲烷，在-78℃条件下，逐滴滴加1M的三溴化硼，在升至室温反应4小时，得到手性羟基类催化剂，其中 R1是羟基；R2是叔丁基和氢；R3是3,5-双(三氟甲基)苯基和3,4,5-三氟苯基，以本发明实施例为例，以上路径为图2和图3的最后一步，即：由(S)-13合成(S)-15、由(S)-14合成(S)-16、由(R)-23合成(R)-25、由(R)-24合成(R)-26。S10. Dissolve the above-mentioned chiral methoxy-based catalyst in anhydrous dichloromethane, add 1M boron tribromide dropwise at -78°C, and react at room temperature for 4 hours to obtain chiral hydroxy-based catalysts. Catalyst, wherein R1 is hydroxyl; R2 is tert-butyl and hydrogen; R3 is 3,5-bis(trifluoromethyl)phenyl and 3,4,5-trifluorophenyl, according to the embodiment of the present invention For example, the above route is the last step in Figure 2 and Figure 3, namely: synthesis of (S)-15 from (S)-13, synthesis of (S)-16 from (S)-14, synthesis of (R)-23 (R)-25, (R)-26 was synthesized from (R)-24.
优选地，步骤S3所得到单酯化产物和双酯化产物经硅胶柱层析初步分离，再经重结晶可获得立体选择性大于99％，即ee＞99％。Preferably, the mono-esterified product and the double-esterified product obtained in step S3 are preliminarily separated by silica gel column chromatography, and then recrystallized to obtain a stereoselectivity greater than 99%, that is, ee>99%.
优选地，步骤S3中现制的(R)-2-甲氧基苯乙酰氯是由(R)-2-甲氧基苯乙酸和 2M的草酰氯溶于无水二氯甲烷溶液，在N,N-二甲基甲酰胺催化下，氩气保护， 0℃至室温反应6小时制备而成。Preferably, the (R)-2-methoxyphenylacetyl chloride prepared in step S3 is a solution of (R)-2-methoxyphenylacetic acid and 2M oxalyl chloride dissolved in anhydrous dichloromethane solution in N , N-dimethylformamide catalyzed, argon protection, 0 ℃ to room temperature reaction for 6 hours.
优选地，步骤S6所用的苯硼酸类化合物分别是3,5-双(三氟甲基)苯硼酸和 3,4,5-三氟苯硼酸。Preferably, the phenylboronic acid compounds used in step S6 are 3,5-bis(trifluoromethyl)phenylboronic acid and 3,4,5-trifluorophenylboronic acid, respectively.
优选地，步骤S1所述的5-甲基-2-叔丁基苯酚、四丁基三溴化铵、二氯甲烷和甲醇的质量比为1:3:11:4.4。Preferably, the mass ratio of 5-methyl-2-tert-butylphenol, tetrabutylammonium tribromide, dichloromethane and methanol described in step S1 is 1:3:11:4.4.
优选地，步骤S2所述的4-溴-2-叔丁基-5-甲基苯酚、四甲基乙二胺、氯化亚铜和二氯甲烷的质量比为121.5:8.5:5:1.3。Preferably, the mass ratio of 4-bromo-2-tert-butyl-5-methylphenol, tetramethylethylenediamine, cuprous chloride and dichloromethane described in step S2 is 121.5:8.5:5:1.3 .
优选地，步骤S3所述6,6’-二甲基-3,3’-二叔丁基-5,5’-二溴-2,2’-联苯酚、氢化钠、(R)-2-甲氧基苯乙酰氯和无水四氢呋喃的质量比为20:5:3:40。Preferably, in step S3, 6,6'-dimethyl-3,3'-di-tert-butyl-5,5'-dibromo-2,2'-biphenol, sodium hydride, (R)-2 -The mass ratio of methoxyphenylacetyl chloride and anhydrous tetrahydrofuran is 20:5:3:40.
优选地，步骤S4所述单酯化产物、四氢铝锂和无水四氢呋喃的质量比为 0.6:2.1:2；双酯化产物、四氢铝锂和无水四氢呋喃的质量比为1:4:2.3。Preferably, the mass ratio of the monoesterified product, tetrahydroaluminum lithium and anhydrous tetrahydrofuran described in step S4 is 0.6:2.1:2; the mass ratio of the diesterization product, tetrahydroaluminum lithium and anhydrous tetrahydrofuran is 1:4 :2.3.
优选地，步骤S5所述手性6,6’-二甲基-3,3’-二叔丁基-5,5’-二溴-2,2’-联苯酚、三氟甲磺酸和甲苯溶液的质量比为1.4:1:12.9。Preferably, the chiral 6,6'-dimethyl-3,3'-di-tert-butyl-5,5'-dibromo-2,2'-biphenol, trifluoromethanesulfonic acid and The mass ratio of the toluene solution was 1.4:1:12.9.
优选地，步骤S6所述的S4和S5所得产物、四(三苯基膦)钯、碳酸钠、苯硼酸类化合物、乙二醇二甲醚(DME)和水的质量比为(3.1～4.1):1:3.5: (3.7～5.2):28.9:16.7。Preferably, the mass ratio of the products obtained from S4 and S5 described in step S6, tetrakis (triphenylphosphine) palladium, sodium carbonate, phenylboronic acid compounds, ethylene glycol dimethyl ether (DME) and water is (3.1～4.1 ):1:3.5:(3.7～5.2):28.9:16.7.
优选地，步骤S7所述的手性6,6’-二甲基-3,3’-二叔丁基-5,5’-二芳基-2,2’-联苯酚和手性6,6’-二甲基-5,5’-二芳基-2,2’-联苯酚的质量比为1.6:1.2:1.3:1；碘甲烷、碳酸钾和丙酮的质量比为1:2.1:5.2。Preferably, the chiral 6,6'-dimethyl-3,3'-di-tert-butyl-5,5'-diaryl-2,2'-biphenol described in step S7 and the
优选地，步骤S8所述手性6,6’-二甲基-3,3’-二叔丁基-5,5’-二芳基-2,2’-二甲氧基联苯和手性6,6’-二甲基-5,5’-二芳基-2,2’-二甲氧基联苯的质量比为 1.5:1.2:1.3:1；偶氮二异丁腈、N-溴代丁二酰亚胺和苯的质量比为22:1:460。Preferably, the chiral 6,6'-dimethyl-3,3'-di-tert-butyl-5,5'-diaryl-2,2'-dimethoxybiphenyl described in step S8 and chiral The mass ratio of 6,6'-dimethyl-5,5'-diaryl-2,2'-dimethoxybiphenyl is 1.5:1.2:1.3:1; azobisisobutyronitrile, N - The mass ratio of bromosuccinimide and benzene is 22:1:460.
优选地，步骤S9所述手性3,3’-二叔丁基-5,5’-二芳基-6,6’-二溴甲基-2,2’-二甲氧基联苯和5,5’-二芳基-6,6’-二溴甲基-2,2’-二甲氧基联苯的质量比为 1.4:1.2:1.2:1；碳酸钾、正二丁胺和乙腈的质量比为16:1:78。Preferably, the
优选地，步骤S10所述手性甲氧基类催化剂的质量比为1.4:1.1:1.2:1；三溴化硼和无水二氯甲烷的质量比为22:13。Preferably, the mass ratio of the chiral methoxy-based catalyst described in step S10 is 1.4:1.1:1.2:1; the mass ratio of boron tribromide and anhydrous dichloromethane is 22:13.
与现有技术相比，本发明具有以下有益效果：Compared with the prior art, the present invention has the following beneficial effects:
1.本发明的手性联苯类季铵盐相转移催化剂具有高光学纯度，能够有效催化烷基化等多种不对称反应，产率高达97％，对映异构体选择性达93％。1. The chiral biphenyl quaternary ammonium salt phase transfer catalyst of the present invention has high optical purity, can effectively catalyze various asymmetric reactions such as alkylation, the yield is as high as 97%, and the enantiomeric selectivity reaches 93% .
2.本发明的手性联苯类季铵盐相转移催化剂进行构效关系研究发现：(1)2 位和2’位的羟基进行甲基化后，产率变化不大，ee值稍微的提高；(2)3位和3’位的取代基，对反应活性及选择性影响较大。当3位和3’位为H，和小位阻取代基甲氧基时，催化活性及选择性都较高，产率为95～97％，ee值为91～98％。当取代基为3,4,5-三氟苯基取代基时，产率为94％，ee值为86％，反应活性及选择性都有所下降。当3位和3’位引入叔丁基大位阻基团时，催化剂的反应活性及选择性有较大幅度的降低。(3)5位和5’位的取代基对Maruoka相转移催化剂的反应活性和选择性起到非常关键的影响作用。该位置的取代基一方面协助催化剂母体骨架构建手性催化空腔，另一方面对母体骨架的电子分布起到重要的影响。2. The structure-activity relationship of the chiral biphenyl quaternary ammonium salt phase transfer catalyst of the present invention was studied and found that: (1) After the hydroxyl groups at the 2-position and the 2'-position were methylated, the yield did not change much, and the ee value was slightly lower. (2) Substituents at the 3 and 3' positions have a greater impact on the reactivity and selectivity. When the 3-position and the 3'-position are H, and a small sterically hindered substituent methoxy group, the catalytic activity and selectivity are both high, the yield is 95-97%, and the ee value is 91-98%. When the substituent was 3,4,5-trifluorophenyl substituent, the yield was 94%, the ee value was 86%, and the reactivity and selectivity decreased. When tert-butyl sterically hindered groups were introduced into the 3-position and the 3'-position, the reactivity and selectivity of the catalyst were greatly reduced. (3) Substituents at 5 and 5' positions play a key role in the reactivity and selectivity of Maruoka phase transfer catalysts. The substituent at this position assists the catalyst parent framework to construct a chiral catalytic cavity on the one hand, and plays an important role in the electron distribution of the parent framework on the other hand.
3.本发明是以(R)-甲氧基苯乙酸为拆分剂，价格便宜，原料易得。合成反应操作步骤简单，产率高，安全可靠，绿色环保，同时适合多种不同取代基的催化剂合成。这类催化剂有望开发更多新型的不对称催化反应，具有更多的手性催化潜力。3. The present invention uses (R)-methoxyphenylacetic acid as a resolving agent, which is cheap and easy to obtain raw materials. The synthesis reaction has simple operation steps, high yield, safety, reliability, green environmental protection, and is suitable for the synthesis of catalysts with various substituents at the same time. Such catalysts are expected to develop more novel asymmetric catalytic reactions with more chiral catalytic potential.
4.本发明的手性联苯类季铵盐相转移催化剂及不对称催化反应体系的开发，为手性药物和药物中间体合成、手性精细化学品制备、手性材料等手性功能分子的构建，及手性天然产物核心结构合成提供了有效的方法。4. The development of the chiral biphenyl quaternary ammonium salt phase transfer catalyst and the asymmetric catalytic reaction system of the present invention is for the synthesis of chiral drugs and drug intermediates, the preparation of chiral fine chemicals, and chiral functional molecules such as chiral materials. The construction of chiral natural products and the synthesis of core structures of chiral natural products provide an efficient method.
附图说明：Description of drawings:
图1为(R)/(S)-3和(R)/(S)-6联苯类化合物的轴手性的构建流程图。Figure 1 is a flow chart of the construction of the axial chirality of (R)/(S)-3 and (R)/(S)-6 biphenyl compounds.
图2为(S)-13、(S)-14、(S)-15、(S)-16催化剂的合成路线图。Figure 2 is a synthetic route diagram of (S)-13, (S)-14, (S)-15, (S)-16 catalysts.
图3为(R)-23、(R)-24、(R)-25、(R)-26催化剂的合成路线图。Figure 3 is a synthetic route diagram of (R)-23, (R)-24, (R)-25, (R)-26 catalysts.
具体实施方式Detailed ways
下面结合附图说明和具体实施例进一步说明本发明的内容，但不应理解为对本发明的限制。若未特别指明，实施例中所用的技术手段为本领域技术人员所熟知的常规手段。除非特别说明，本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。The content of the present invention is further described below in conjunction with the accompanying drawings and specific embodiments, but should not be construed as a limitation of the present invention. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the technical field.
实施例1 5-甲基-2-叔丁基-4-溴苯酚(2)的制备Example 1 Preparation of 5-methyl-2-tert-butyl-4-bromophenol (2)
室温下,向5-甲基-2-叔丁基苯酚(13.6mL,80.0mmol)的甲醇与二氯甲烷的混合溶液(100mL，体积比为2:3)中，逐滴加入四丁基三溴化铵(38.6g,80.0 mmol)的甲醇与二氯甲烷的混合溶液(80mL，体积比为2:3)，剧烈搅拌反应1h 后，加水淬灭，用乙酸乙酯萃取三次，合并的有机相，经无水硫酸钠干燥，过滤，减压浓缩。得到的粗产品经硅胶柱层析(乙酸乙酯/正己烷,1:40～1:10)分离纯化, 得黄色油状液体目标化合物19.2g，收率99％。At room temperature, to a mixed solution of 5-methyl-2-tert-butylphenol (13.6 mL, 80.0 mmol) in methanol and dichloromethane (100 mL, with a volume ratio of 2:3), tetrabutyltrichloromethane was added dropwise. A mixed solution of ammonium bromide (38.6 g, 80.0 mmol) in methanol and dichloromethane (80 mL, with a volume ratio of 2:3) was stirred vigorously for 1 h, quenched by adding water, extracted three times with ethyl acetate, and the combined organic The phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (ethyl acetate/n-hexane, 1:40-1:10) to obtain 19.2 g of the target compound as a yellow oily liquid with a yield of 99%.
结构测试：1H NMR(400MHz,CDCl3)δ:7.38(s,1H),6.56(s,1H),4.82(s, 1H),2.30(s,3H),1.39(s,9H)；13C NMR(100MHz,CDCl3)δ:153.4,136.3,136.0, 130.9,119.0,115.5,34.5,29.6,22.2.Structural testing:1 H NMR (400 MHz, CDCl3 ) δ: 7.38(s, 1H), 6.56(s, 1H), 4.82(s, 1H), 2.30(s, 3H), 1.39(s, 9H);13 C NMR (100MHz, CDCl3 ) δ: 153.4, 136.3, 136.0, 130.9, 119.0, 115.5, 34.5, 29.6, 22.2.
实施例2 6,6'-二甲基-3,3'-二叔丁基-5,5'–二溴-2,2'-联苯酚(3)的制备Example 2 Preparation of 6,6'-dimethyl-3,3'-di-tert-butyl-5,5'-dibromo-2,2'-biphenol (3)
室温下，化合物2(243.1mg,1.0mmol)、氯化亚铜(9.90mg,0.1mmol)和四甲基乙二胺(22μL,0.15mmol)于二氯甲烷(2mL)中，剧烈搅拌反应过夜后，加水淬灭，体系经二氯甲烷萃取三次，合并后的有机相，用无水硫酸钠干燥，过滤，减压浓缩。得到的粗产品经硅胶柱层析(洗脱剂为正己烷)分离纯化，得白色固体目标物123.5mg，收率51％。Compound 2 (243.1 mg, 1.0 mmol), cuprous chloride (9.90 mg, 0.1 mmol) and tetramethylethylenediamine (22 μL, 0.15 mmol) were dissolved in dichloromethane (2 mL) at room temperature, and the reaction was vigorously stirred overnight Then, water was added to quench, the system was extracted three times with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (eluent is n-hexane) to obtain 123.5 mg of the target product as a white solid with a yield of 51%.
结构测试：1H NMR(400MHz,CDCl3)δ:7.55(s,2H),4.88(s,2H),2.00(s,6H), 1.40(s,18H)；13C NMR(100MHz,CDCl3)δ:151.8,136.8,135.5,132.0,121.8, 116.4,35.0,29.4,19.9.Structural testing:1 H NMR (400MHz, CDCl3 ) δ: 7.55(s, 2H), 4.88(s, 2H), 2.00(s, 6H), 1.40(s, 18H);13 C NMR (100 MHz, CDCl3 ) )δ: 151.8, 136.8, 135.5, 132.0, 121.8, 116.4, 35.0, 29.4, 19.9.
实施例3单酯化产物(R,S)-4和双酯化产物(R,R,R)-5的制备Example 3 Preparation of monoesterified product (R,S)-4 and diesterified product (R,R,R)-5
(R)-2-甲氧基-2-苯基乙酰氯：在两口瓶(250mL)中加入化合物(R)-2-甲氧基-2-苯基乙酸(7.98g,48mmol)，联通氩气，置换气体三次。在0℃条件下，加入无水二氯甲烷(70mL)，再缓慢滴加2M草酰氯(24mL,48mmol)和无水的N,N- 二甲基甲酰胺(800μL)，反应15分钟后，在室温继续反应6h。浓缩，抽干15 分钟得(R)-2-甲氧基-2-苯基乙酰氯。(R)-2-methoxy-2-phenylacetyl chloride: add compound (R)-2-methoxy-2-phenylacetic acid (7.98 g, 48 mmol) to a two-necked flask (250 mL), connect it with argon gas, and replace the gas three times. At 0 °C, anhydrous dichloromethane (70 mL) was added, and then 2M oxalyl chloride (24 mL, 48 mmol) and anhydrous N,N-dimethylformamide (800 μL) were slowly added dropwise. After 15 minutes of reaction, The reaction was continued for 6 h at room temperature. Concentrate and drain for 15 minutes to obtain (R)-2-methoxy-2-phenylacetyl chloride.
在0℃和氩气保护的条件下，向氢化钠(1.44g,36mmol)的干燥四氢呋喃(80 mL)混合液中，缓慢滴入化合物3(5.81g,12mmol)的干燥四氢呋喃(50mL)溶液，滴加完毕后，反应混合物在常温下继续搅拌反应3h。将现制的(R)-2-甲氧基-2- 苯基乙酰氯(8.86g,48mmol)逐滴加入上述反应体系中，剧烈搅拌反应1h，将反应体系缓慢倒入冰水中，二氯甲烷萃取三次，合并后的有机相，用无水硫酸钠干燥，过滤，减压浓缩。得到的粗产品经硅胶柱层析(乙酸乙酯/二氯甲烷/正己烷, 1:1:90～1:1:50)分离纯化,得白色固体目标物(R,S)-4和(R,R,R)-5。A solution of compound 3 (5.81 g, 12 mmol) in dry tetrahydrofuran (50 mL) was slowly added dropwise to a mixture of sodium hydride (1.44 g, 36 mmol) in dry tetrahydrofuran (80 mL) at 0 °C under argon protection, After the dropwise addition was completed, the reaction mixture was stirred at room temperature for 3 h. The prepared (R)-2-methoxy-2-phenylacetyl chloride (8.86g, 48mmol) was added dropwise to the above reaction system, and the reaction was vigorously stirred for 1h. The reaction system was slowly poured into ice water. Extracted with methane three times, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (ethyl acetate/dichloromethane/n-hexane, 1:1:90～1:1:50) to obtain white solid target compounds (R,S)-4 and ( R,R,R)-5.
(R,S)-4：白色固体化合物，3.72g，收率49％，经重结晶(二氯甲烷/正己烷,1:2)后，ee>99％.1H NMR(400MHz,CDCl3)δ:7.60(s,1H),7.41(s,1H),7.33～7.35(m, 3H),7.25～7.23(m,1H),5.05(s,1H),4.17(s,1H),3.02(s,3H),2.01(s,3H),1.94(s, 3H),1.35(s,9H),0.97(s,9H)；13C NMR(100MHz,CDCl3)δ:169.6,151.7,147.7, 142.2,138.0,137.1,134.7,134.0,131.9,131.5,130.7,129.2,128.8,127.8,126.6, 123.4,116.2,82.9,57.6,34.9,34.4,29.6,29.4,20.0,19.8.(R,S)-4: white solid compound, 3.72 g, yield 49%, after recrystallization (dichloromethane/n-hexane, 1:2), ee>99%.1 H NMR (400 MHz, CDCl3 )δ: 7.60(s, 1H), 7.41(s, 1H), 7.33～7.35(m, 3H), 7.25～7.23(m, 1H), 5.05(s, 1H), 4.17(s, 1H), 3.02 (s,3H), 2.01(s,3H), 1.94(s,3H), 1.35(s,9H), 0.97(s,9H);13 C NMR (100 MHz, CDCl3 ) δ: 169.6, 151.7, 147.7 , 142.2,138.0,137.1,134.7,134.0,131.9,131.5,130.7,129.2,128.8,127.8,126.6, 123.4,116.2,82.9,57.6,34.9,34.4,29.6,29.4,20.0,19.8
(R,R,R)-5：白色固体化合物，2.99g，收率30％。经重结晶(二氯甲烷/正己烷,1:3)后，ee>99％.1H NMR(400MHz,CDCl3)δ:7.60(s,2H),7.44～7.34(m, 10H),3.98(s,2H),2.99(s,6H),2.14(s,6H),0.94(s,18H)；13C NMR(100MHz, CDCl3)δ:168.0,146.9,141.6,138.0,135.0,132.3,131.3,129.1,128.6,127.8,123.6, 82.2,58.0,34.2,29.9,20.4。(R,R,R)-5: white solid compound, 2.99 g, yield 30%. After recrystallization (dichloromethane/n-hexane, 1:3), ee>99%.1 H NMR (400 MHz, CDCl3 ) δ: 7.60 (s, 2H), 7.44-7.34 (m, 10H), 3.98 (s,2H), 2.99(s,6H), 2.14(s,6H), 0.94(s,18H);13 C NMR (100 MHz, CDCl3 ) δ: 168.0, 146.9, 141.6, 138.0, 135.0, 132.3, 131.3, 129.1, 128.6, 127.8, 123.6, 82.2, 58.0, 34.2, 29.9, 20.4.
实施例4手性6,6'-二甲基-3,3'-二叔丁基-5,5'-二溴-2,2'-联苯酚(S)-3、(R)-3的制备Example 4
(S)-6,6'-二甲基-3,3'-二叔丁基-5,5'-二溴-2,2'-联苯酚(S)-3:在0℃及氩气保护的条件下，向(R,S)-4(556.5mg,0.88mmol)的无水四氢呋喃(1.8mL)溶液中，缓慢滴加1M四氢铝锂(1.8mL，1.76mmol)，反应1h，将反应体系缓慢倒入冰水混合物中，二氯甲烷萃取三次，合并后的有机相，用无水硫酸钠干燥，过滤，减压浓缩。得到的粗产品经硅胶柱层析(正己烷)分离纯化，得409.3mg白色固体目标物(S)-3，收率96％。1H NMR(400MHz,CDCl3)δ:7.54(s,2H),4.87(s,2H), 1.99(s,6H),1.39(s,18H)；13C NMR(100MHz,CDCl3)δ:151.8,136.8,135.5, 132.0,121.7,116.4,35.0,29.4,19.9.(S)-6,6'-dimethyl-3,3'-di-tert-butyl-5,5'-dibromo-2,2'-biphenol (S)-3: at 0°C under argon Under protected conditions, to a solution of (R,S)-4 (556.5 mg, 0.88 mmol) in anhydrous tetrahydrofuran (1.8 mL), 1M lithium tetrahydroaluminum (1.8 mL, 1.76 mmol) was slowly added dropwise, and the reaction was carried out for 1 h. The reaction system was slowly poured into an ice-water mixture, extracted three times with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (n-hexane) to obtain 409.3 mg of the target product (S)-3 as a white solid with a yield of 96%.1 H NMR (400 MHz, CDCl3 ) δ: 7.54 (s, 2H), 4.87 (s, 2H), 1.99 (s, 6H), 1.39 (s, 18H);13 C NMR (100 MHz, CDCl3 ) δ: 151.8, 136.8, 135.5, 132.0, 121.7, 116.4, 35.0, 29.4, 19.9.
(R)-6,6'-二甲基-3,3'-二叔丁基-5,5'-二溴-2,2'-联苯酚(R)-3:合成步骤与(S)-3 相同，白色固体，669.3mg，产率96％。1H NMR(400MHz,CDCl3)δ:7.54(s,2H), 4.87(s,2H),1.99(s,6H),1.39(s,18H)；13C NMR(100MHz,CDCl3)δ:151.8,136.8, 135.5,132.0,121.7,116.4,35.0,29.4,19.9.(R)-6,6'-Dimethyl-3,3'-di-tert-butyl-5,5'-dibromo-2,2'-biphenol (R)-3: Synthesis steps and (S) -3 Identical, white solid, 669.3 mg, 96% yield.1 H NMR (400 MHz, CDCl3 ) δ: 7.54 (s, 2H), 4.87 (s, 2H), 1.99 (s, 6H), 1.39 (s, 18H);13 C NMR (100 MHz, CDCl3 ) δ: 151.8, 136.8, 135.5, 132.0, 121.7, 116.4, 35.0, 29.4, 19.9.
实施例5手性6,6’-二甲基-5,5’-二溴-2,2’-联苯酚(S)-6、(R)-6的制备Example 5 Preparation of chiral 6,6'-dimethyl-5,5'-dibromo-2,2'-biphenol (S)-6, (R)-6
(S)-6,6'-二甲基-5,5'-二溴-2,2'-联苯酚(S)-6:在0℃及氩气保护的条件下，向(S)-3(377.7mg,0.78mmol)的甲苯(4mL)溶液中缓慢滴加三氟甲磺酸(158.0μL,1.79mmol)，继续搅拌15min，将反应体系倒入冰水混合物中，用二氯甲烷萃取三次，合并后的有机相，用无水硫酸钠干燥，过滤，减压浓缩。得到的粗产品经硅胶柱层析(乙酸乙酯/正己烷,1:10)分离纯化，得272.8mg白色固体目标物(S)-6，收率94％，ee>99％。1H NMR(400MHz,CDCl3)δ:7.54(d,J＝8.4Hz,2H),6.81 (d,J＝8.8Hz,2H),4.76(s,2H),2.07(s,6H)；13C NMR(100MHz,CDCl3)δ:153.1, 138.3,134.3,121.7,116.6,115.3,20.3；HPLC：Diacel Chiralpak AD-H(5μm,4.6 mm×250mm),hexane/EtOH＝20/1(V/V),flow rate＝1.0mL/min,λ＝290nm, retention time:25.1min((S)-enantiomer)and 55.5min((R)-enantiomer).(S)-6,6'-dimethyl-5,5'-dibromo-2,2'-biphenol (S)-6: at 0 °C and under argon protection, to (S)- Trifluoromethanesulfonic acid (158.0 μL, 1.79 mmol) was slowly added dropwise to a solution of 3 (377.7 mg, 0.78 mmol) in toluene (4 mL), stirring was continued for 15 min, the reaction system was poured into an ice-water mixture, and extracted with dichloromethane Three times, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (ethyl acetate/n-hexane, 1:10) to obtain 272.8 mg of target (S)-6 as a white solid, yield 94%, ee>99%.1 H NMR (400 MHz, CDCl3 ) δ: 7.54 (d, J=8.4 Hz, 2H), 6.81 (d, J=8.8 Hz, 2H), 4.76 (s, 2H), 2.07 (s, 6H);13 C NMR (100MHz, CDCl3 )δ: 153.1, 138.3, 134.3, 121.7, 116.6, 115.3, 20.3; HPLC: Diacel Chiralpak AD-H (5 μm, 4.6 mm×250 mm), hexane/EtOH=20/1 (V/ V), flow rate=1.0mL/min, λ=290nm, retention time: 25.1min((S)-enantiomer) and 55.5min((R)-enantiomer).
(R)-6,6'-二甲基-5,5'-二溴-2,2'-联苯酚(R)-6:合成步骤与(S)-6相同，白色固体， 349.7mg，产率94％，ee>99％。1H NMR(400MHz,CDCl3)δ:7.54(d,J＝8.4Hz, 2H),6.81(d,J＝8.8Hz,2H),4.76(s,2H),2.07(s,6H).13C NMR(100MHz,CDCl3) δ:153.1,138.3,134.3,121.7,116.6,115.3,20.3；HPLC：Diacel Chiralpak AD-H(5 μm,4.6mm×250mm),hexane/EtOH＝20/1(V/V),flow rate＝1.0mL/min,λ＝290 nm,retention time:24.6min((S)-enantiomer)and 54.6min((R)-enantiomer).(R)-6,6'-dimethyl-5,5'-dibromo-2,2'-biphenol (R)-6: the same synthetic procedure as (S)-6, white solid, 349.7mg,
实施例6手性6,6’-二甲基-3,3’-二叔丁基-5,5’-二芳基-2,2’-联苯酚(S)-7、(S)-8 和手性6,6’-二甲基-5,5’-二芳基-2,2’-联苯酚(R)-17、(R)-18的制备Example 6
(S)-6,6'-二甲基-3,3'-二叔丁基-5,5'-(3,5-双(三氟甲基)苯基)-2,2'-联苯酚(S)-7：在氩气保护的条件下，将(S)-3(368.0mg,0.76mmol)、3,5-双(三氟甲基)苯硼酸(469.4mg,1.82mmol)、四三苯基膦钯(87.8mg,0.076mmol)和碳酸钠(322.2mg, 3.04mmol)的乙二醇二甲醚(3mL)和水(1.5mL)的混合溶液在90℃下反应过夜。将体系冷却至室温后，缓慢加入饱和氯化铵溶液(10mL)，用二氯甲烷萃取三次，合并后的有机相，用无水硫酸钠干燥，过滤，减压浓缩。得到的粗产品经硅胶柱层析(正己烷为洗脱剂)分离纯化，得553.1mg白色固体目标物(S)-7，收率97％。1H NMR(500MHz,CDCl3)δ:7.87(s,2H),7.80(s,4H),7.24(s,2H),5.19 (s,2H),1.86(s,6H),1.45(s,18H).13C NMR(125MHz,CDCl3)δ:152.8,144.3,135.2,133.4,132.2,131.7(q,JC-F＝33Hz),129.86～129.84(m),129.7,123.5(q,JC-F＝271.1Hz),121.2,120.8～120.7(m),35.0,29.5,17.3。(S)-6,6'-Dimethyl-3,3'-di-tert-butyl-5,5'-(3,5-bis(trifluoromethyl)phenyl)-2,2'-bi Phenol (S)-7: Under argon protection, (S)-3 (368.0 mg, 0.76 mmol), 3,5-bis(trifluoromethyl)phenylboronic acid (469.4 mg, 1.82 mmol), A mixed solution of tetrakistriphenylphosphine palladium (87.8 mg, 0.076 mmol) and sodium carbonate (322.2 mg, 3.04 mmol) in ethylene glycol dimethyl ether (3 mL) and water (1.5 mL) was reacted at 90° C. overnight. After the system was cooled to room temperature, saturated ammonium chloride solution (10 mL) was slowly added, extracted three times with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (n-hexane as the eluent) to obtain 553.1 mg of the target compound (S)-7 as a white solid with a yield of 97%.1 H NMR (500MHz, CDCl3 )δ: 7.87(s, 2H), 7.80(s, 4H), 7.24(s, 2H), 5.19(s, 2H), 1.86(s, 6H), 1.45(s, 18H).13 C NMR (125MHz, CDCl3 )δ: 152.8, 144.3, 135.2, 133.4, 132.2, 131.7 (q, JCF = 33 Hz), 129.86～129.84 (m), 129.7, 123.5 (q, JCF = 271.1Hz), 121.2, 120.8～120.7(m), 35.0, 29.5, 17.3.
(S)-6,6'-二甲基-5,5'-二(3,5-双(三氟甲基)苯基)-2,2'-联苯酚(S)-8：合成步骤与 (S)-7相同，白色固体，632.0mg，产率94％。1H NMR(400MHz,CDCl3)δ:7.88 (s,2H),7.81(s,4H),7.28(d,J＝8.4Hz,2H),7.04(d,J＝8.4Hz,2H),5.17(s,2H), 1.97(s,6H).13CNMR(100MHz,CDCl3)δ:154.1,143.7,136.3,133.0,132.2,131.8 (q,JC-F＝33.1Hz),129.84～129.82(m),123.5(q,JC-F＝271.1Hz),121.0, 121.96～120.90(m),114.1,17.7.(S)-6,6'-Dimethyl-5,5'-bis(3,5-bis(trifluoromethyl)phenyl)-2,2'-biphenol(S)-8: Synthetic Procedure Same as (S)-7, white solid, 632.0 mg, 94% yield.1 H NMR (400 MHz, CDCl3 ) δ: 7.88 (s, 2H), 7.81 (s, 4H), 7.28 (d, J=8.4 Hz, 2H), 7.04 (d, J=8.4 Hz, 2H), 5.17 (s, 2H), 1.97 (s, 6H).13 CNMR (100MHz, CDCl3 ) δ: 154.1, 143.7, 136.3, 133.0, 132.2, 131.8 (q, JCF = 33.1 Hz), 129.84～129.82 (m) ,123.5(q,JCF =271.1Hz),121.0,121.96～120.90(m),114.1,17.7.
(R)-6,6'-二甲基-3,3'-二叔丁基-5,5'-二(3,4,5-三氟苯基)-2,2'-联苯酚(R)-17：合成步骤与(S)-7相同，白色固体，232.7mg，产率93％。1H NMR(400MHz,CDCl3) δ:7.20(s,2H),6.96(dd,J＝8.4,6.4Hz,4H),5.12(s,2H),1.86(s,6H),1.44(s,18H)；13C NMR(100MHz,CDCl3)δ:152.4,150.96(ddd,JC-F＝250,10,4Hz),138.9(dt, JC-F＝250,15Hz),138.2～138.4(m),134.8,133.2,132.3,129.4,121.1,113.9(dd, JC-F＝15.2,5.6Hz),34.9,29.6,17.2.(R)-6,6'-Dimethyl-3,3'-di-tert-butyl-5,5'-bis(3,4,5-trifluorophenyl)-2,2'-biphenol ( R)-17: The same synthetic procedure as (S)-7, white solid, 232.7 mg, 93% yield.1 H NMR (400 MHz, CDCl3 ) δ: 7.20 (s, 2H), 6.96 (dd, J=8.4, 6.4 Hz, 4H), 5.12 (s, 2H), 1.86 (s, 6H), 1.44 (s, 18H);13 C NMR (100MHz, CDCl3 ) δ: 152.4, 150.96 (ddd, JCF =250, 10, 4Hz), 138.9 (dt, JCF =250, 15Hz), 138.2-138.4 (m), 134.8 , 133.2, 132.3, 129.4, 121.1, 113.9 (dd, JCF = 15.2, 5.6Hz), 34.9, 29.6, 17.2.
(R)-6,6'-二甲基-5,5'–二(3,4,5-三氟苯基)-2,2'-联苯酚(R)-18：合成步骤与(S)-7 相同，白色固体，331.0mg，产率95％。1H NMR(400MHz,Acetone)δ:7.86(s,2H), 7.12～7.16(m,6H),6.91(d,J＝8.4Hz,2H),1.96(s,6H).13C NMR(100MHz, Acetone)δ:155.8,151.4(ddd,JC-F＝246,10,4Hz),140.1～140.3(m),139.1(dt,JC-F＝247,15Hz),136.5,132.0,130.8,125.2,114.7(dd,JC-F＝15.3,5.4Hz),114.1,17.9.(R)-6,6'-Dimethyl-5,5'-bis(3,4,5-trifluorophenyl)-2,2'-biphenol(R)-18: Synthesis procedure with (S )-7 same, white solid, 331.0 mg, 95% yield.1 H NMR (400MHz, Acetone)δ: 7.86(s, 2H), 7.12～7.16(m, 6H), 6.91(d, J=8.4Hz, 2H), 1.96(s, 6H).13 C NMR(100MHz) , Acetone)δ:155.8,151.4(ddd,JCF =246,10,4Hz),140.1～140.3(m),139.1(dt,JCF =247,15Hz),136.5,132.0,130.8,125.2,114.7( dd, JCF = 15.3, 5.4 Hz), 114.1, 17.9.
实施例7手性6,6’-二甲基-3,3’-二叔丁基-5,5’-二芳基-2,2’-二甲氧基联苯(S)-9、 (S)-10和手性6,6’-二甲基-5,5’-二芳基-2,2’-二甲氧基联苯(R)-19、(R)-20的制备Example 7
(S)-6,6'-二甲基-3,3'-二叔丁基-5,5'-(3,5-双(三氟甲基)苯基)-2,2'-二甲氧基联苯 (S)-9：向化合物(S)-7(510.4mg,0.68mmol)和碳酸钾(939.7mg,6.8mmol)的丙酮混合液(6.0mL)中缓慢滴加碘甲烷(846μL,13.6mmol)，反应回流过夜.将反应体系冷却至室温后，加水终止反应，用二氯甲烷萃取三次，合并后的有机相，用无水硫酸钠干燥，过滤，减压浓缩.得到的粗产品经硅胶柱层析(乙酸乙酯/正己烷, 1:100)分离纯化，得524.2mg白色固体目标物(S)-9，收率99％。1H NMR(400MHz, CDCl3)δ:7.87(s,2H),7.79(s,4H),7.20(s,2H),3.31(s,6H),1.94(s,9H),1.43(s, 18H)；13C NMR(100MHz,CDCl3)δ:157.9,145.0,141.3,134.6,133.7,132.9,131.6 (q,JC-F＝33.1Hz),129.8～129.7(m),128.0,123.6(q,JC-F＝271.1Hz),120.8～120.7 (m),59.6,35.1,30.8,18.1.(S)-6,6'-Dimethyl-3,3'-di-tert-butyl-5,5'-(3,5-bis(trifluoromethyl)phenyl)-2,2'-di Methoxybiphenyl (S)-9: To a mixture of compound (S)-7 (510.4 mg, 0.68 mmol) and potassium carbonate (939.7 mg, 6.8 mmol) in acetone (6.0 mL) was slowly added dropwise methyl iodide ( 846 μL, 13.6 mmol), the reaction was refluxed overnight. After the reaction system was cooled to room temperature, water was added to terminate the reaction, extracted three times with dichloromethane, and the combined organic phases were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained The crude product was separated and purified by silica gel column chromatography (ethyl acetate/n-hexane, 1:100) to obtain 524.2 mg of the target compound (S)-9 as a white solid with a yield of 99%.1 H NMR (400MHz, CDCl3 )δ: 7.87(s, 2H), 7.79(s, 4H), 7.20(s, 2H), 3.31(s, 6H), 1.94(s, 9H), 1.43(s, 18H);13 C NMR (100 MHz, CDCl3 ) δ: 157.9, 145.0, 141.3, 134.6, 133.7, 132.9, 131.6 (q, JCF = 33.1 Hz), 129.8-129.7 (m), 128.0, 123.6 (q, JCF = 271.1Hz), 120.8～120.7 (m), 59.6, 35.1, 30.8, 18.1.
(S)-6,6'-二甲基-5,5'-二(3,5-双(三氟甲基)苯基)-2,2'-二甲氧基联苯(S)-10：合成步骤与(S)-9相同，白色固体，528.2mg，产率99％.m.p.39～41℃；[α]25D＝+2.8 (c＝0.54,CHCl3)；1H NMR(400MHz,CDCl3)δ:7.76(s,2H),7.74(s,4H),7.16(d, J＝8.4Hz,2H),6.87(d,J＝8.8Hz,2H),3.71(s,6H),1.79(s,6H).13C NMR(100 MHz,CDCl3)δ:157.2,144.5,135.5,132.25,131.5(q,JC-F＝33.1Hz),130.1, 129.96～129.93(m),127.2,123.6(q,JC-F＝216.9Hz),120.6～120.4(m),108.8,56.08, 17.6.(S)-6,6'-Dimethyl-5,5'-bis(3,5-bis(trifluoromethyl)phenyl)-2,2'-dimethoxybiphenyl(S)- 10: The same synthetic procedure as (S)-9, white solid, 528.2 mg, 99% yield. mp 39～41°C; [α]25D=+2.8 (c=0.54, CHCl3 );1 H NMR (400MHz, CDCl3 )δ: 7.76(s, 2H), 7.74(s, 4H), 7.16(d, J=8.4Hz, 2H), 6.87(d, J=8.8Hz, 2H), 3.71(s, 6H), 1.79(s, 6H).13 C NMR (100 MHz, CDCl3 ) δ: 157.2, 144.5, 135.5, 132.25, 131.5 (q, JCF = 33.1 Hz), 130.1, 129.96～129.93 (m), 127.2, 123.6 (q, JCF = 216.9Hz), 120.6～120.4(m), 108.8, 56.08, 17.6.
(R)-6,6'-二甲基-3,3'-二叔丁基-5,5'-二(3,4,5-三氟苯基)-2,2'-二甲氧基联苯 (R)-19：合成步骤与(S)-9相同，白色固体，229.4mg，产率99％。1H NMR(400MHz, CDCl3)δ:7.08(s,2H),6.86(dd,J＝8,6.8Hz,4H),3.17(s,6H),1.85(s,6H),1.31(s, 18H)；13C NMR(100MHz,CDCl3)δ:157.6,151.0(ddd,JC-F＝250,10,4Hz),141.0 (s),138.8～139.0(m),138.9(dt,JC-F＝249,15Hz),134.7,133.7,132.8,127.8,113.8 (dd,JC-F＝15.2,5.5Hz),59.4,35.0,30.8,18.1.(R)-6,6'-Dimethyl-3,3'-di-tert-butyl-5,5'-bis(3,4,5-trifluorophenyl)-2,2'-dimethoxy Biphenyl (R)-19: the same synthetic procedure as (S)-9, white solid, 229.4 mg, 99% yield.1 H NMR (400MHz, CDCl3 )δ: 7.08(s, 2H), 6.86(dd, J=8, 6.8Hz, 4H), 3.17(s, 6H), 1.85(s, 6H), 1.31(s, 18H);13 C NMR (100 MHz, CDCl3 ) δ: 157.6, 151.0 (ddd, JCF =250, 10, 4Hz), 141.0 (s), 138.8-139.0 (m), 138.9 (dt, JCF =249 , 15Hz), 134.7, 133.7, 132.8, 127.8, 113.8 (dd, JCF = 15.2, 5.5Hz), 59.4, 35.0, 30.8, 18.1.
(R)-6,6'-二甲基-5,5'-二(3,4,5-三氟苯基)-2,2'-二甲氧基联苯(R)-20：合成步骤与(S)-9相同，白色固体，386.9mg，产率99％。1H NMR(400MHz,CDCl3)δ:7.18 (d,J＝8.4Hz,2H),6.96(t,J＝7.4Hz,4H),6.89(d,J＝8.4Hz,2H),3.76(s,6H), 1.83(s,6H).13CNMR(100MHz,CDCl3)δ:156.9,150.86(ddd,JC-F＝250,10,4Hz), 138.6(dt,JC-F＝249,15Hz),138.4～138.6(m),135.4,132.4,129.7,127.0,113.9(dd, JC-F＝15.3,5.5Hz),108.5,55.9,17.6.(R)-6,6'-Dimethyl-5,5'-bis(3,4,5-trifluorophenyl)-2,2'-dimethoxybiphenyl (R)-20: Synthesis The same procedure as (S)-9, white solid, 386.9 mg, 99% yield.1 H NMR (400 MHz, CDCl3 ) δ: 7.18 (d, J=8.4 Hz, 2H), 6.96 (t, J=7.4 Hz, 4H), 6.89 (d, J=8.4 Hz, 2H), 3.76 (s , 6H), 1.83 (s, 6H).13 CNMR (100MHz, CDCl3 )δ: 156.9, 150.86 (ddd, JCF =250, 10, 4Hz), 138.6 (dt, JCF =249, 15Hz), 138.4 ~138.6 (m), 135.4, 132.4, 129.7, 127.0, 113.9 (dd, JCF = 15.3, 5.5Hz), 108.5, 55.9, 17.6.
实施例8手性3,3’-二叔丁基-5,5’-二芳基-6,6’-二溴甲基-2,2’-二甲氧基联苯(S)-11、 (S)-12和手性5,5’-二芳基-6,6’-二溴甲基-2,2’-二甲氧基联苯(R)-21、(R)-22的制备Example 8
(S)-3,3'-二叔丁基-5,5'-(3,5-双(三氟甲基)苯基)-6,6'-二溴甲基-2,2'-二甲氧基联苯(S)-11：向化合物(S)-9(420.5mg,0.54mmol)和N-溴代丁二酰亚胺(673.0mg,3.78mmol)的苯(5mL)的混合溶液中加入偶氮二异丁腈(26.6mg,30mol％)，在回流状态下反应4h。将反应体系冷却至室温，加入乙醚稀释、过滤.滤液浓缩后所得的粗产物经硅胶柱层析(乙酸乙酯/正己烷,1:100)分离纯化，得476.9mg 黄色固体目标物，收率94％。1H NMR(400MHz,CDCl3)δ:7.85(s,2H),7.83(s, 2H),7.20(s,2H),4.14(d,J＝10.8Hz,2H),4.00(d,J＝10.4Hz,2H),3.38(s,6H), 1.34(s,18H)；13C NMR(100MHz,CDCl3)δ:157.0,144.9,143.2,136.4,133.5, 131.7(q,JC-F＝33.4Hz),130.8,130.2,129.81～129.78(m),123.5(q,JC-F＝271.1Hz), 121.6～121.5(m),60.0,35.5,30.6,30.1.(S)-3,3'-Di-tert-butyl-5,5'-(3,5-bis(trifluoromethyl)phenyl)-6,6'-dibromomethyl-2,2'- Dimethoxybiphenyl (S)-11: To a mixture of compound (S)-9 (420.5 mg, 0.54 mmol) and N-bromosuccinimide (673.0 mg, 3.78 mmol) in benzene (5 mL) Azobisisobutyronitrile (26.6 mg, 30 mol%) was added to the solution, and the reaction was carried out under reflux for 4 h. The reaction system was cooled to room temperature, diluted with diethyl ether, and filtered. The crude product obtained after the filtrate was concentrated was separated and purified by silica gel column chromatography (ethyl acetate/n-hexane, 1:100) to obtain 476.9 mg of the target yellow solid in a yield of 476.9 mg. 94%.1 H NMR (400 MHz, CDCl3 ) δ: 7.85 (s, 2H), 7.83 (s, 2H), 7.20 (s, 2H), 4.14 (d, J=10.8 Hz, 2H), 4.00 (d, J= 10.4Hz, 2H), 3.38 (s, 6H), 1.34 (s, 18H);13 C NMR (100 MHz, CDCl3 ) δ: 157.0, 144.9, 143.2, 136.4, 133.5, 131.7 (q, JCF =33.4 Hz ), 130.8, 130.2, 129.81～129.78(m), 123.5(q, JCF = 271.1Hz), 121.6～121.5(m), 60.0, 35.5, 30.6, 30.1.
(S)-5,5'-二(3,5-双(三氟甲基)苯基)-6,6'-二溴甲基-2,2'-二甲氧基联苯(S)-12：合成步骤与(S)-11相同,黄色固体,595.5mg，产率96％。1H NMR(400MHz,CDCl3) δ:7.94(s,2H),7.83(s,2H),7.24(d,J＝8.4Hz,2H),7.00(d,J＝8.4Hz,2H),3.94(q, J＝10.4Hz,2H),3.72(s,6H)；13C NMR(100MHz,CDCl3)δ:157.5,142.6,134.7, 133.0,131.7,131.6(q,JC-F＝33.2Hz),129.92～129.90(m),125.8,123.5(q,JC-F＝ 271.2.Hz),121.47～121.4(m),111.5,56.0,30.0.(S)-5,5'-bis(3,5-bis(trifluoromethyl)phenyl)-6,6'-dibromomethyl-2,2'-dimethoxybiphenyl (S) -12: The same synthetic procedure as (S)-11, yellow solid, 595.5 mg, 96% yield.1 H NMR (400 MHz, CDCl3 ) δ: 7.94 (s, 2H), 7.83 (s, 2H), 7.24 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 3.94 (q, J=10.4 Hz, 2H), 3.72 (s, 6H);13 C NMR (100 MHz, CDCl3 ) δ: 157.5, 142.6, 134.7, 133.0, 131.7, 131.6 (q, JCF =33.2 Hz), 129.92～129.90(m), 125.8, 123.5(q, JCF = 271.2.Hz), 121.47～121.4(m), 111.5, 56.0, 30.0.
(R)-3,3'-二叔丁基-5,5'-二(3,4,5-三氟苯基)-6,6'-二溴甲基-2,2'-联苯酚苯酚(R)-21：合成步骤与(S)-11相同，黄色固体,224.3mg，产率78％。1H NMR(400MHz, CDCl3)δ:7.24(s,2H),7.09(dd,J＝8.0,6.4Hz,4H),4.26(d,J＝10.8Hz,2H),4.17 (d,J＝10.4Hz,2H),3.42(s,6H),1.42(s,18H)；13C NMR(100MHz,CDCl3)δ: 156.6,151.0(ddd,JC-F＝249,10,4Hz),144.5,139.4(dt,JC-F＝250,15Hz), 136.9～137.1(m),136.4,133.3,130.7,130.0,113.8(dd,JC-F＝15.4,5.7Hz),59.8, 35.4,30.6,30.3.(R)-3,3'-Di-tert-butyl-5,5'-bis(3,4,5-trifluorophenyl)-6,6'-dibromomethyl-2,2'-biphenol Phenol (R)-21: the same synthetic procedure as (S)-11, yellow solid, 224.3 mg, 78% yield.1 H NMR (400 MHz, CDCl3 ) δ: 7.24 (s, 2H), 7.09 (dd, J=8.0, 6.4 Hz, 4H), 4.26 (d, J=10.8 Hz, 2H), 4.17 (d, J= 10.4Hz, 2H), 3.42 (s, 6H), 1.42 (s, 18H);13 C NMR (100 MHz, CDCl3 ) δ: 156.6, 151.0 (ddd, JCF =249, 10, 4Hz), 144.5, 139.4 (dt, JCF = 250, 15Hz), 136.9 ~ 137.1 (m), 136.4, 133.3, 130.7, 130.0, 113.8 (dd, JCF = 15.4, 5.7Hz), 59.8, 35.4, 30.6, 30.3.
(R)-5,5'-二(3,4,5-三氟苯基)-6,6'-二溴甲基-2,2'-联苯酚苯酚(R)-22：合成步骤与(S)-11相同，黄色固体，194.9mg，产率96％。1H NMR(400MHz,CDCl3)δ:7.17 (d,J＝8.4Hz,2H),7.16(dd,J＝8.4,6.8Hz,4H),7.04(d,J＝8.4Hz,2H),4.08(s, 4H),3.78(s,6H).13C NMR(100MHz,CDCl3)δ:157.16(s),150.8(ddd,JC-F＝249, 10,4Hz),139.3(dt,JC-F＝250,15Hz),136.6～136.4(m),134.5,133.0,131.5,125.7, 114.0(dd,JC-F＝15.4,5.6Hz),111.3,55.9,30.2.(R)-5,5'-bis(3,4,5-trifluorophenyl)-6,6'-dibromomethyl-2,2'-biphenolphenol (R)-22: Synthesis procedure with Same as (S)-11, yellow solid, 194.9 mg, 96% yield.1 H NMR (400 MHz, CDCl3 ) δ: 7.17 (d, J=8.4 Hz, 2H), 7.16 (dd, J=8.4, 6.8 Hz, 4H), 7.04 (d, J=8.4 Hz, 2H), 4.08 (s, 4H), 3.78 (s, 6H).13 C NMR (100 MHz, CDCl3 ) δ: 157.16 (s), 150.8 (ddd, JCF = 249, 10, 4 Hz), 139.3 (dt, JCF = 250, 15Hz), 136.6～136.4(m), 134.5, 133.0, 131.5, 125.7, 114.0(dd, JCF = 15.4, 5.6Hz), 111.3, 55.9, 30.2.
实施例9手性甲氧基类催化剂(S)-13、(S)-14、(R)-23、(R)-24的制备催化剂(S)-13：参照文献方法，室温下，向光学纯的催化剂中间体(S)-11(355.9mg, 0.38mmol)的乙腈(4.0mL)溶液中加入正二丁胺(57.6μL,0.342mmol)和碳酸钾 (655mg,3.8mmol)，在85℃反应过夜。反应结束后，将反应体系冷却至室温，加二氯甲烷稀释，用硅藻土过滤。滤液浓缩后所得的粗产物经硅胶柱层析(甲醇/ 二氯甲烷，1:80～1:20)分离纯化，得245.4mg黄色固体手性季铵盐目标物，收率 66％。1H NMR(400MHz,Acetone)δ:8.48(br s,4H),8.12(s,2H),7.51(s,2H),4.61 (d,J＝14Hz,2H),4.42(d,J＝14Hz,2H),3.36(s,6H),3.28～3.22(m,2H),2.82(td, J＝13.2,4.0Hz,2H),1.50(s,18H),1.30～1.34(m,2H),1.08～1.17(m,2H),0.84～0.89(m,2H),0.61(t,J＝7.2Hz,6H),0.57～0.51(m,2H).13C NMR(100MHz, Acetone)δ:160.0,146.1,143.9,136.4,132.2,131.2,125.5,124.41(q,JC-F＝270.9 Hz),122.6～122.3(m),61.8,59.2,58.2,36.1,30.6,24.9,19.7,13.9.Example 9 Preparation of chiral methoxy-based catalysts (S)-13, (S)-14, (R)-23, (R)-24 Catalyst (S)-13: refer to the literature method, at room temperature, to To a solution of optically pure catalyst intermediate (S)-11 (355.9 mg, 0.38 mmol) in acetonitrile (4.0 mL) was added n-dibutylamine (57.6 μL, 0.342 mmol) and potassium carbonate (655 mg, 3.8 mmol), at 85° C. React overnight. After the reaction was completed, the reaction system was cooled to room temperature, diluted with dichloromethane, and filtered through Celite. The crude product obtained after the filtrate was concentrated was separated and purified by silica gel column chromatography (methanol/dichloromethane, 1:80-1:20) to obtain 245.4 mg of the target chiral quaternary ammonium salt as a yellow solid with a yield of 66%.1 H NMR (400MHz, Acetone) δ: 8.48 (br s, 4H), 8.12 (s, 2H), 7.51 (s, 2H), 4.61 (d, J=14Hz, 2H), 4.42 (d, J=14Hz) ,2H),3.36(s,6H),3.28～3.22(m,2H),2.82(td, J＝13.2,4.0Hz,2H),1.50(s,18H),1.30～1.34(m,2H), 1.08～1.17(m, 2H), 0.84～0.89(m, 2H), 0.61(t, J=7.2Hz, 6H), 0.57～0.51(m, 2H).13 C NMR(100MHz, Acetone)δ:160.0 ,146.1,143.9,136.4,132.2,131.2,125.5,124.41(q,JCF =270.9 Hz),122.6～122.3(m),61.8,59.2,58.2,36.1,30.6,24.9,19.7,13.9.
催化剂(S)-14：合成步骤与催化剂(S)-13相同，黄色固体手性季铵盐，488.1mg，产率82％。1H NMR(400MHz,CDCl3)δ:7.95(s,6H),7.48(d,J＝8.8Hz,2H),7.32 (d,J＝8.8Hz,2H),4.54(d,J＝14Hz,2H),3.94(s,6H),3.90(d,J＝14Hz,2H), 3.14(t,J＝12.8Hz,2H),2.68(td,J＝12.8,4.0Hz,2H),1.04～1.02(m,4H), 0.82～0.76(m,2H),0.58(t,J＝7.2Hz,6H),0.22～0.16(m,2H)；13C NMR(100MHz, CDCl3)δ:157.4,141.4,133.0,132.4,130.0～129.8(m),126.6,124.8,122.7(q,JC-F＝ 271.4Hz),121.5～121.4(m),113.8,57.3,57.2,56.1,24.2,18.9,13.1.Catalyst (S)-14: The synthesis procedure was the same as that of catalyst (S)-13, yellow solid chiral quaternary ammonium salt, 488.1 mg, yield 82%.1 H NMR (400 MHz, CDCl3 ) δ: 7.95 (s, 6H), 7.48 (d, J=8.8 Hz, 2H), 7.32 (d, J=8.8 Hz, 2H), 4.54 (d, J=14 Hz, 2H), 3.94(s, 6H), 3.90(d, J＝14Hz, 2H), 3.14(t, J＝12.8Hz, 2H), 2.68(td, J＝12.8, 4.0Hz, 2H), 1.04～1.02 (m, 4H), 0.82～0.76 (m, 2H), 0.58 (t, J=7.2Hz, 6H), 0.22～0.16 (m, 2H);13 C NMR (100MHz, CDCl3 )δ: 157.4, 141.4 ,133.0,132.4,130.0～129.8(m),126.6,124.8,122.7(q,JCF =271.4Hz),121.5～121.4(m),113.8,57.3,57.2,56.1,24.2,18.9,13.1.
催化剂(R)-23：合成步骤与催化剂(S)-13相同，黄色固体手性季铵盐，189.2mg，产率80％。1H NMR(400MHz,Acetone)δ:7.66(br s,4H),7.46(s,2H),4.81(d,J＝ 14Hz,2H),4.04(d,J＝14Hz,2H),3.27(s,6H),3.23～3.17(m,2H),2.91～2.84(m, 2H),1.47(s,18H),1.30～1.33(m,2H),1.20～1.10(m,2H),0.95～1.04(m,2H),0.71(t, J＝7.2Hz,6H),0.42～0.53(m,2H)；13C NMR(100MHz,Acetone)δ:159.4, 153.3～152.3(m),150.6～150.0(m),145.9,140.1(dt,JC-F＝249,15Hz),137.5～137.3 (m),136.5,132.0,130.5,125.3,117.0～115.1(m),61.4,58.4,57.9,35.9,30.4,25.1, 19.9,13.6.Catalyst (R)-23: the synthesis procedure was the same as that of catalyst (S)-13, yellow solid chiral quaternary ammonium salt, 189.2 mg, yield 80%.1 H NMR (400MHz, Acetone) δ: 7.66 (br s, 4H), 7.46 (s, 2H), 4.81 (d, J=14Hz, 2H), 4.04 (d, J=14Hz, 2H), 3.27 (s ,6H),3.23～3.17(m,2H),2.91～2.84(m,2H),1.47(s,18H),1.30～1.33(m,2H),1.20～1.10(m,2H),0.95～1.04 (m, 2H), 0.71 (t, J=7.2Hz, 6H), 0.42～0.53 (m, 2H);13 C NMR (100MHz, Acetone) δ: 159.4, 153.3～152.3 (m), 150.6～150.0 ( m), 145.9, 140.1 (dt, JCF = 249, 15Hz), 137.5 ~ 137.3 (m), 136.5, 132.0, 130.5, 125.3, 117.0 ~ 115.1 (m), 61.4, 58.4, 57.9, 35.9, 30.4, 25.1 , 19.9, 13.6.
催化剂(R)-24：合成步骤与催化剂(S)-13相同，黄色固体手性季铵盐，337.2mg，产率81％。1H NMR(400MHz,CDCl3)δ:7.41(d,J＝8.8Hz,2H),7.24(d,J＝8.8 Hz,2H),7.17(brs,4H),4.74(d,J＝14Hz,2H),3.89(s,6H),3.64(d,J＝14Hz,2H), 3.18(t,J＝12.8Hz,2H),2.72～2.67(m,2H),1.10～1.09(m,4H),0.99～0.95(m,2H), 0.72(t,J＝6.8Hz,6H),0.29～0.26(m,2H)；13C NMR(100MHz,CDCl3)δ:156.9, 152.2～152.0(m),149.8～149.5(m),139.3(dt,JC-F＝252,15Hz),135.0～134.8(m), 132.5,132.0,126.4,125.1,115.0～113.9(m),113.3,57.2,56.9,55.9,24.3,19.1,13.0.Catalyst (R)-24: the synthesis procedure was the same as that of catalyst (S)-13, yellow solid chiral quaternary ammonium salt, 337.2 mg, yield 81%.1 H NMR (400 MHz, CDCl3 ) δ: 7.41 (d, J=8.8 Hz, 2H), 7.24 (d, J=8.8 Hz, 2H), 7.17 (brs, 4H), 4.74 (d, J=14 Hz, 2H), 3.89(s, 6H), 3.64(d, J=14Hz, 2H), 3.18(t, J=12.8Hz, 2H), 2.72～2.67(m, 2H), 1.10～1.09(m, 4H) , 0.99～0.95 (m, 2H), 0.72 (t, J=6.8Hz, 6H), 0.29～0.26 (m, 2H);13 C NMR (100MHz, CDCl3 )δ: 156.9, 152.2～152.0 (m) ,149.8～149.5(m),139.3(dt,JCF =252,15Hz),135.0～134.8(m),132.5,132.0,126.4,125.1,115.0～113.9(m),113.3,57.2,56.9,55.9, 24.3, 19.1, 13.0.
实施例10手性羟基类催化剂(S)-15、(S)-16、(R)-25、(R)-26的制备Example 10 Preparation of Chiral Hydroxyl Catalysts (S)-15, (S)-16, (R)-25, (R)-26
催化剂(S)-15：在-78℃及氩气保护的条件下，向催化剂(S)-13(118.2mg,0.12mmol)的无水二氯甲烷(1.0mL)溶液中逐滴滴加1M三溴化硼(0.84mL,0.84 mmol)，反应体系升至室温后，在室温下反应4h。将反应体系倒入冰水中，用二氯甲烷萃取三次，合并后的有机相，用无水硫酸钠干燥，过滤，减压浓缩。得到的粗产品经硅胶柱层析(甲醇/二氯甲烷,1:40～1:5)分离纯化，得97.5mg白色固体手性季铵盐，收率81％。1H NMR(400MHz,Acetone-d6)δ:8.35(s,2H),8.22(s, 2H),8.07(s,2H),7.36(s,2H),4.54(d,J＝13.6Hz,2H),3.67(d,J＝13.2Hz,2H), 3.05～2.98(m,2H),2.82(td,J＝13.2,4.4Hz,2H),1.53(s,18H),1.25～1.19(m,2H), 1.11～1.02(m,2H),0.93～0.86(m,2H),0.61(t,J＝7.2Hz,6H),0.47～0.35(m,2H).13C NMR(100MHz,Acetone-d6)δ:159.8,145.3,142.8,131.9～131.7(m),131.5,131.3～131.1(m),130.3,129.7,124.43,124.40(q,JC-F＝270.6Hz),121.5～121.3(m),58.6,57.4,35.9,30.0,24.96,19.7,13.7.Catalyst (S)-15: To a solution of catalyst (S)-13 (118.2 mg, 0.12 mmol) in anhydrous dichloromethane (1.0 mL) was added dropwise 1 M at -78°C under argon protection Boron tribromide (0.84 mL, 0.84 mmol), after the reaction system was warmed to room temperature, the reaction was carried out at room temperature for 4 h. The reaction system was poured into ice water, extracted three times with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (methanol/dichloromethane, 1:40～1:5) to obtain 97.5 mg of white solid chiral quaternary ammonium salt with a yield of 81%.1 H NMR (400MHz, Acetone-d6 )δ: 8.35(s, 2H), 8.22(s, 2H), 8.07(s, 2H), 7.36(s, 2H), 4.54(d, J=13.6Hz, 2H), 3.67(d, J＝13.2Hz, 2H), 3.05～2.98(m, 2H), 2.82(td, J＝13.2, 4.4Hz, 2H), 1.53(s, 18H), 1.25～1.19(m , 2H), 1.11～1.02(m, 2H), 0.93～0.86(m, 2H), 0.61(t, J=7.2Hz, 6H), 0.47～0.35(m, 2H).13 C NMR(100MHz, Acetone -d6 )δ: 159.8, 145.3, 142.8, 131.9 ~ 131.7 (m), 131.5, 131.3 ~ 131.1 (m), 130.3, 129.7, 124.43, 124.40 (q, JCF = 270.6 Hz), 121.5 ~ 121.3 (m ), 58.6, 57.4, 35.9, 30.0, 24.96, 19.7, 13.7.
催化剂(S)-16：合成步骤与催化剂(S)-15相同，黄色固体手性季铵盐，72mg，产率85％。1H NMR(400MHz,MeOD-d4)δ:8.09(s,6H),7.44(d,J＝8.4Hz,2H), 7.29(d,J＝8.8Hz,2H),4.42(d,J＝14Hz,2H),3.73(d,J＝13.6Hz,2H),2.92～2.86 (m,2H),2.62(td,J＝12.8,4.4Hz,2H),1.11～0.92(m,4H),0.85～0.72(m,2H),0.60 (t,J＝7.2Hz,6H),0.24～0.11(m,2H)；13C NMR(100MHz,MeOD-d4)δ:157.0, 143.8,133.9,133.4,131.7,126.7,126.5,124.6(q,JC-F＝270.6Hz),122.7～122.5(m), 119.8,58.2,58.0,25.4,20.1,13.8.Catalyst (S)-16: The synthesis procedure was the same as that of catalyst (S)-15, yellow solid chiral quaternary ammonium salt, 72 mg, yield 85%.1 H NMR (400 MHz, MeOD-d4 ) δ: 8.09 (s, 6H), 7.44 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.8 Hz, 2H), 4.42 (d, J= 14Hz, 2H), 3.73 (d, J＝13.6Hz, 2H), 2.92～2.86 (m, 2H), 2.62 (td, J＝12.8, 4.4Hz, 2H), 1.11～0.92 (m, 4H), 0.85 ～0.72 (m, 2H), 0.60 (t, J=7.2Hz, 6H), 0.24～0.11 (m, 2H);13 C NMR (100 MHz, MeOD-d4 ) δ: 157.0, 143.8, 133.9, 133.4, 131.7, 126.7, 126.5, 124.6 (q, JCF = 270.6 Hz), 122.7～122.5 (m), 119.8, 58.2, 58.0, 25.4, 20.1, 13.8.
催化剂(R)-25：合成步骤与催化剂(S)-15相同，黄色固体手性季铵盐，45.1mg，产率57％。1H NMR(400MHz,Acetone-d6)δ:7.53(br s,2H),7.32(br s,2H),7.25 (s,2H),4.63(d,J＝13.2Hz,2H),3.42(d,J＝13.2Hz,2H),3.02(t,J＝12.4Hz,2H), 2.87(td,J＝12.8,4.4Hz,2H),1.50(s,18H),1.22～1.06(m,6H),0.73(t,J＝7.2Hz, 6H),0.45～0.37(m,2H).13C NMR(100MHz,Acetone-d6)δ:159.9,152.5～151.5(m), 150.0～149.0(m),141.3,138.8～138.6(m),138.6(dt,JC-F＝247.6,15Hz),130.5, 128.7,128.0,123.3,115.2～14.3(m),35.0,29.1,24.3,19.1,12.7.Catalyst (R)-25: the synthesis procedure was the same as that of catalyst (S)-15, yellow solid chiral quaternary ammonium salt, 45.1 mg, yield 57%.1 H NMR (400MHz, Acetone-d6 )δ: 7.53 (br s, 2H), 7.32 (br s, 2H), 7.25 (s, 2H), 4.63 (d, J=13.2Hz, 2H), 3.42 ( d, J＝13.2Hz, 2H), 3.02(t, J＝12.4Hz, 2H), 2.87(td, J＝12.8, 4.4Hz, 2H), 1.50(s, 18H), 1.22～1.06(m, 6H) ), 0.73(t, J=7.2Hz, 6H), 0.45～0.37(m, 2H).13 C NMR (100MHz, Acetone-d6 )δ: 159.9, 152.5～151.5(m), 150.0～149.0(m ), 141.3, 138.8～138.6(m), 138.6(dt, JCF = 247.6, 15Hz), 130.5, 128.7, 128.0, 123.3, 115.2～14.3(m), 35.0, 29.1, 24.3, 19.1, 12.7.
催化剂(R)-26：合成步骤与催化剂(S)-15相同，黄色固体手性季铵盐，34.0mg，产率50％。1H NMR(400MHz,MeOD-d4)δ:7.38(d,J＝8.8Hz,4H),7.22(d,J＝8.8 Hz,4H),4.56(d,J＝13.6Hz,2H),3.54(d,J＝13.6Hz,2H),2.92(t,J＝12.8Hz, 2H),2.67(td,J＝12.8,4.4Hz,2H),1.15～1.03(m,4H),1.01～0.90(m,2H),0.75(t,J ＝7.2Hz,6H),0.25～0.19(m,2H)；13C NMR(100MHz,MeOD-d4)δ:156.6, 153.9～153.4(m),151.4～150.9(m),140.6(dt,JC-F＝250,15Hz),137.8～137.6(m), 133.6,133.2,126.8,126.4,119.5,116.1～115.7(m),57.95,57.9,25.5,20.3,13.6.Catalyst (R)-26: the synthesis procedure was the same as that of catalyst (S)-15, yellow solid chiral quaternary ammonium salt, 34.0 mg, yield 50%.1 H NMR (400 MHz, MeOD-d4 ) δ: 7.38 (d, J=8.8 Hz, 4H), 7.22 (d, J=8.8 Hz, 4H), 4.56 (d, J=13.6 Hz, 2H), 3.54 (d, J＝13.6Hz, 2H), 2.92 (t, J＝12.8Hz, 2H), 2.67 (td, J＝12.8, 4.4Hz, 2H), 1.15～1.03 (m, 4H), 1.01～0.90( m, 2H), 0.75 (t, J=7.2Hz, 6H), 0.25～0.19 (m, 2H);13 C NMR (100MHz, MeOD-d4 )δ: 156.6, 153.9～153.4 (m), 151.4～ 150.9(m), 140.6(dt, JCF = 250, 15Hz), 137.8～137.6(m), 133.6, 133.2, 126.8, 126.4, 119.5, 116.1～115.7(m), 57.95, 57.9, 25.5, 20.3, 13.6 .
应用例Application example
将实施例9和10制得的催化剂运用于以N-(二苯基亚甲基)甘氨酸叔丁酯27为原料的不对称烷基化中，其反应式如下。用chiralpak OD-H柱通过HPLC分析确定产物的对映体构体过量值，如表1中所示。The catalysts prepared in Examples 9 and 10 were used in the asymmetric alkylation of N-(diphenylmethylene)glycine tert-butyl ester 27 as raw material, and the reaction formula was as follows. The enantiomeric excess of the product was determined by HPLC analysis using a chiralpak OD-H column, as shown in Table 1.
表1手性联苯类季铵盐催化剂在不对称烷基化的适应性结果Table 1. Adaptability results of chiral biphenyl quaternary ammonium salt catalysts in asymmetric alkylation
a 内标产率，内标为对硝基苯乙酮。a Yield of internal standard, the internal standard is p-nitroacetophenone.
由表1可知，在0℃的两相溶剂中，改良Maruoka相转移催化剂能够有效的催化N-二苯亚甲基甘氨酸叔丁酯27的苄基化反应，反应收率为70～97％，目标产物的ee值为61～95％。对该系列改良Maruoka相转移催化剂进行构效关系研究发现：(1)2位和2’位的羟基进行甲基化后，产率变化不大，ee值稍微的提高；(2)3位和3’位的取代基，对反应活性及选择性影响较大。当3位和3’位为 H，和小位阻取代基甲氧基时，催化活性及选择性都较高，产率为95～97％，ee 值为91～98％(Entry 2,4,6,8)。当3位和3’位引入叔丁基大位阻基团时，催化剂的反应活性及选择性有较大幅度的降低(Entry 1,3,5,7)。(3)5位和5’位的取代基对Maruoka相转移催化剂的反应活性和选择性起到非常关键的影响作用。该位置的取代基一方面协助催化剂母体骨架构建手性催化空腔，另一方面对母体骨架的电子分布起到重要的影响。基于经典Maruoka催化剂和简化的Maruoka催化剂催化不对称烷基化的研究结果，3,4,5-三氟苯基和3,5-双(三氟甲基)苯基有利于反应的选择性，因此我们在改良Maruoka相转移催化剂的5位和5’位引入3,4,5- 三氟苯基和3,5-双(三氟甲基)苯基。经过结构改造后，含有两类取代基的催化剂都显示出较好的反应活性和选择性(Entry 2,4,6,8),3,4,5-三氟苯基构建的手性空腔有利于非对映选择性的提高。It can be seen from Table 1 that in a two-phase solvent at 0 °C, the improved Maruoka phase transfer catalyst can effectively catalyze the benzylation of N-diphenylmethylene glycine tert-butyl ester 27, and the reaction yield is 70-97%. The ee value of the target product is 61-95%. The structure-activity relationship study of this series of improved Maruoka phase transfer catalysts found that: (1) after methylation of the hydroxyl groups at the 2-position and 2'-position, the yield changed little, and the ee value was slightly increased; (2) the 3-position and The substituent at the 3' position has a great influence on the reactivity and selectivity. When the 3-position and 3'-position are H, and a small sterically hindered substituent methoxy group, the catalytic activity and selectivity are high, the yield is 95-97%, and the ee value is 91-98% (
以下是表1所制备的产物28：The following is the product 28 prepared in Table 1:
在0℃及氩气保护条件下，向N-(二苯基亚甲基)甘氨酸叔丁酯27(90.4mg，0.3mmol)和手性相转移催化剂(0.003mmol)的甲苯(1.5mL)混合液中，逐滴滴加苄溴(109μL，0.9mmol)和50％的KOH水溶液(0.5mL)，并在剧烈搅拌下进行催化反应。反应完成后，将反应混合物倒入水中，用二氯甲烷萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩。得到的粗产品经硅胶柱层析(正己烷/二氯甲烷/ 乙酸乙酯,100:1:1～70:1:1)分离纯化后得到目标化合物N-(二苯基亚甲基)-2-苄基甘氨酸叔丁酯28。HPLC：Diacel Chiralpak OD-H(5μm,4.6mm×250mm), hexane/i-PrOH＝100/1(V/V),flow rate＝0.3mL/min,λ＝254nm,retention time: 21.7min((R)-enantiomer)and 31.0min((S)-enantiomer)；1H NMR(400MHz, CDCl3)δ:7.58～7.56(m,2H),7.38～7.25(m,6H),7.21～7.13(m,3H),7.06～7.04(m, 2H),6.60(d,J＝6.8Hz,2H),4.11(dd,J＝9.2,4.4Hz,1H),3.23(dd,J＝13.6,4.4Hz,1H),3.16(dd,J＝13.2,9.2Hz,1H),1.44(s,9H).13C NMR(100MHz,CDCl3)δ: 171.0,170.4,139.7,138.5,136.5,130.2,130.0,128.9,128.3,128.2,128.2,128.1, 127.8,126.3,81.3,68.1,39.7,28.2。To N-(diphenylmethylene)glycine tert-butyl ester 27 (90.4 mg, 0.3 mmol) and chiral phase transfer catalyst (0.003 mmol) in toluene (1.5 mL) were mixed at 0°C under argon To the solution, benzyl bromide (109 μL, 0.9 mmol) and 50% aqueous KOH (0.5 mL) were added dropwise, and the reaction was catalyzed with vigorous stirring. After the reaction was completed, the reaction mixture was poured into water, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography (n-hexane/dichloromethane/ethyl acetate, 100:1:1～70:1:1) to obtain the target compound N-(diphenylmethylene)- 2-Benzylglycine tert-butyl ester 28. HPLC: Diacel Chiralpak OD-H (5μm, 4.6mm×250mm), hexane/i-PrOH=100/1(V/V), flow rate=0.3mL/min, λ=254nm, retention time: 21.7min(( R)-enantiomer) and 31.0min ((S)-enantiomer);1 H NMR (400MHz, CDCl3 )δ: 7.58～7.56(m, 2H), 7.38～7.25(m, 6H), 7.21～7.13(m ,3H),7.06～7.04(m, 2H),6.60(d,J＝6.8Hz,2H),4.11(dd,J＝9.2,4.4Hz,1H),3.23(dd,J＝13.6,4.4Hz, 1H), 3.16 (dd, J=13.2, 9.2 Hz, 1H), 1.44 (s, 9H).13 C NMR (100 MHz, CDCl3 ) δ: 171.0, 170.4, 139.7, 138.5, 136.5, 130.2, 130.0, 128.9 , 128.3, 128.2, 128.2, 128.1, 127.8, 126.3, 81.3, 68.1, 39.7, 28.2.
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| CN117924173A (en)* | 2024-03-21 | 2024-04-26 | 广东工业大学 | Chiral phase transfer catalysts based on aniline quaternary ammonium salts and their application in asymmetric alkylation of amino acid derivatives |
| CN117924173B (en)* | 2024-03-21 | 2024-07-09 | 广东工业大学 | Chiral phase transfer catalysts based on aniline quaternary ammonium salts and their application in asymmetric alkylation of amino acid derivatives |
| CN120289364A (en)* | 2025-05-08 | 2025-07-11 | 广东工业大学 | N-Alkoxy quaternary ammonium salt chiral catalysts and their applications in hydrogen atom transfer and alkylation reactions |
| CN120289364B (en)* | 2025-05-08 | 2025-10-17 | 广东工业大学 | N-alkoxy quaternary ammonium salt chiral catalyst and application thereof in hydrogen atom transfer and alkylation reaction |
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