CN113979975A - Chiral phosphoric acid catalyzed aryl allyl tertiary alcohol kinetic resolution method - Google Patents
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Abstract
The invention discloses a dynamic resolution method of aryl allyl tertiary alcohol catalyzed by chiral phosphoric acid, which is carried out in a solvent and an additiveIn the presence of the chiral phosphoric acid catalyst shown in the formula II, the allyl tertiary alcohol compound shown in the formula I is subjected to kinetic resolution to generate an aryl allyl tertiary alcohol compound shown in the formula III and a dihydroisobenzofuran compound shown in the formula IV, wherein the aryl allyl tertiary alcohol compound and the dihydroisobenzofuran compound respectively contain a chiral center, and the reaction formula is as follows:
Description
Technical Field
The invention relates to a chiral phosphoric acid catalyzed aryl allyl tertiary alcohol kinetic resolution method.
Background
At present, the acquisition of chiral diaryl tertiary alcohol structures relies to a large extent on transition metal catalyzed asymmetric addition reactions [ Collados J.F.; solatron r., haruyunyan s.r.; maci < B.ACS Cat.2016, 6(3) < 1952- > 1970 ]. Asymmetric dihydroxylation with olefins [ Heravi m.m.; zadsirjan v.; esfandyari m.; lashaki T.B. tetrahedron Asymmetry 2017,28(8): 987-; aggarwal v.k.chem Eur J2011: 9-15. ], and epoxide opening [ Jacobsen e.n.; kakiuchi f.; konsler R.G.; larrow j.f.; tokunaga M.tetrahedron Lett.1997,38(5): 773-; takatsu k.; hayashi T.chem.Commun.2010,46(36): 6822-6827.).
Although the construction of chiral tertiary alcohols by transition metal catalyzed asymmetric addition of organoborons to carbonyl compounds is simple and efficient, it is necessary to catalyze them by transition metals, which results in many side reactions and wastes of metalates. Compared with the method of utilizing the kinetic resolution to construct the chiral tertiary alcohol structure, the method has the advantages of high catalytic efficiency, simple operation and the like and has a wide industrial application prospect. Thus, catalytic kinetic resolution of tertiary alcohols becomes an excellent alternative for the construction of chiral tertiary alcohols. However, tertiary alcohols are sterically hindered, thereby reducing reactivity. Therefore, it is necessary to develop a suitable chiral catalyst to distinguish the three non-hydrogen substituents at the stereocenter.
However, to date, there have been few reports of obtaining chiral tertiary alcohols by non-enzymatic kinetic resolution, and List and Yang have now implemented tertiary alcohols using chiral phosphoric acid catalysts
I.；Müller S.；List B.J.Am.Chem.Soc.2010,132(49):17370–17373.]And aminoallyl alcohol [ Rajkumar s.; he S.; yang X.Angew.chem.Int.Ed.2019,58(30): 10315-10319.]The kinetic resolution of (2). The chiral phosphoric acid catalyzed tertiary alcohol kinetic resolution generally adopts a phosphoric acid catalyst with larger steric hindrance, and List adopts a pocket type chiral phosphoric acid catalyst to realize the kinetic resolution of tertiary alcohol, and has wide substrate range and high resolution efficiency. The Yang subject group adopts a chiral phosphoric acid catalyst substituted by 3,3' -cyclohexyl to realize the high-efficiency kinetic resolution of the tertiary 2-alkoxy carboxyl amino allyl alcohol, and the chiral amino alcohol obtained by derivatizing the resolution product has great scientific research significance. In addition, the Oestreich group achieved kinetic resolution of tertiary propargyl alcohol by transition metal catalysis [ Seliger J.; dong X.; oestreich M.Angew.chem.2019,131(7): 1991-.]The Zhao topic group is based on the synergistic effect of oxidizing NHC catalysts with lewis acid additives [ Lu s; poh S.B.; siau w.y.; ZHao Y.Angew.chem.2013,125(6): 1775-1778.]The dynamic resolution of tertiary alcohol is realized, and a Smith topic group is obtained by using an isothiourea catalyst [ Greenhalgh M.D.; smith s.m.; walden d.m.; taylor j.e.; brice Z.; robinson e.r.t.; fallan c.; cores d.b.; slawin A.M.Z.; richardson h.c.; grove m.a., Cheong p.h.y.; smith A.D.Angew.chem.2018,130(12): 3254-3260.]The chiral Lewis base catalyzed acylation kinetic resolution of the heterocyclic ring substituted tertiary alcohol is realized. Miller and his colleagues used pentapeptide catalyst [ Jarvo E.R.；Evans C.A.；Copeland G.T.；Miller S.J.J.Org.Chem.2001,66(16):5522–5527.]The method realizes the kinetic high-efficiency resolution of various alkyl substituted tertiary alcohols.
Recently, Smith achieved acyl kinetic resolution of acyclic tertiary alcohols with very high enantioselectivity using newly developed isoselenourea catalysts based on previous work [ Qu s; smith s.m.; laina Mart v.; neyyappadat r.m.; greenhalgh m.d.; smith A.D.Angew.chem.Int.Ed.2020,59(38): 16572-16578 ]. By using the adjacent carbonyl substituents as recognition motifs for the acylation catalyst, 25 α -hydroxy ester derivatives were obtained, with the highest selection factor (s factor) of 200.
Meanwhile, the chiral dihydroisobenzofuran skeleton has strong biological activity and exists in a plurality of natural products and drug molecules, and the polysubstituted dihydroisobenzofuran and derivatives thereof are more important medical and organic synthesis intermediates, for example, after the antidepressant citalopram taking the dihydroisobenzofuran as a matrix is introduced into chirality, the drug effect is greatly improved, so that the stereoselectivity for constructing the skeleton is valued by pharmaceutical chemists.
The construction of the dihydroisobenzofuran skeleton, which is currently mainly synthesized under the catalysis of transition metal palladium, has recently become increasingly important in the synthesis of heterocycles, since it is particularly attractive in the process of cyclization of acyclic substrates with nucleophilic and hydrophilic functions. They can regioselectively provide heterocycles having desired substitution patterns under substantially neutral conditions. In 2003, the Pittelli group reported palladium-catalyzed cycloisomerization of 2-alkynyl benzyl alcohols under neutral conditions to synthesize (Z) -1-alkylene-1, 3-dihydroisobenzofurans [ gabrile b.; salerno g.fazio a.; pittelli r. tetrahedron 2003,59(33): 6251-; zhang r.; cai j.; chen j.q.; ji M. Chin. chem. Lett.2014,25(4): 549-. In this novel synthetic route, o-aroylbenzaldehydes, which are key intermediates, can be successfully obtained by oxidation of the aroyl group of salicylaldehyde with lead tetraacetate. The novel process exhibits high functional group tolerance and yields a variety of substituted 1, 3-dihydroisobenzofurans in high yields. However, chiral resolution is dominant in the acquisition of chiral dihydroisobenzofuran skeleton, and in 2007, the Mathad task group resolved by using diastereoisomeric salts of (-) -di-p-methylbenzoyltartaric acid (DPTTA) [ Elati c.r.; kolla n.; vankawala p.j.; gangula s.; chalamala s.; sundaram v.; bhattacharya, a.; vurimidi h.; mathad V.T.Org.Process Res.Dev.2007,11(2): 289-292. ] realizes the dynamic resolution of racemic dihydroisobenzofuran skeleton compounds to successfully prepare chiral dihydroisobenzofuran compounds, and the research on the catalytic asymmetric synthesis of the chiral dihydroisobenzofuran compounds is less reported. In 2016, the highly enantioselective arylboroxine addition reaction to simple aryl ketones was first achieved with Rh catalysts by the thomson project group, providing a series of chiral diarylalkyl carbinols with excellent ee values and yields [ Huang l.; zhu j.; jiao g.; wang Z.; yu X.; deng w.p.; tang W., Angew.chem.int.Ed.2016,55(14): 4527-. Meanwhile, the method realizes asymmetric synthesis of the chiral dihydroisobenzofuran skeleton.
In conclusion, the research of the literatures finds that the construction mode of chiral tertiary alcohol still mainly uses transition metal catalyzed asymmetric addition reaction of organic boron and aldehyde ketone, the application range of the reaction is greatly limited by the intervention of the transition metal, and the chiral tertiary alcohol structural compound is obtained by dynamic resolution catalyzed by organic small molecules, so that great difficulties and challenges exist at present: (1) most research has focused on secondary alcohols, while tertiary alcohols have difficulty in chiral kinetic resolution reactions due to the presence of three more sterically hindered groups. (2) Nucleophilic substitution reactions of tertiary alcohols typically proceed as single molecule nucleophilic substitution reactions, with highly substituted carbon centers tending to form more stable carbenium ions or ion pair intermediates, resulting in partial or total loss of stereochemical integrity. And the construction of the chiral dihydroisobenzofuran skeleton mainly adopts chiral resolution, and the catalytic asymmetric synthesis research reports on the chiral dihydroisobenzofuran skeleton are less.
Therefore, the invention aims to solve the technical problem of developing an asymmetric catalytic system by utilizing small organic molecules, and preparing the chiral diaryl tertiary alcohol through dynamic resolution with high efficiency and high enantioselectivity and simultaneously synthesizing the dihydroisobenzofuran containing the tetra-substituted carbon chiral center.
Disclosure of Invention
The invention aims to provide a chiral phosphoric acid catalyzed aryl allyl tertiary alcohol dynamic resolution method aiming at the defects of the prior art, and develops an organic small molecule catalyzed aryl allyl tertiary alcohol dynamic resolution method.
The method for dynamically splitting the aryl allyl tertiary alcohol catalyzed by chiral phosphoric acid is characterized in that the aryl allyl tertiary alcohol compound shown in the formula I is subjected to dynamic splitting reaction in the presence of an organic solvent and an additive under the catalytic action of a chiral phosphoric acid catalyst shown in the formula II to generate an aryl allyl tertiary alcohol compound shown in the formula III and containing a chiral center and a dihydroisobenzofuran compound shown in the formula IV, wherein the reaction formulas are as follows:
R1selected from one of the following: C6-C20 aryl, C4-C8 heteroaryl having 1-3 heteroatoms selected from N, S and O; wherein in R1, the C6-C20 aryl is preferably C6-C14 aryl, and the C4-C8 heteroaryl having 1-3 heteroatoms selected from N, S and O is preferably C4-C8 heteroaryl containing an oxygen heteroatom, a sulfur heteroatom or a nitrogen heteroatom4～C8A heteroaryl group;
r2 is selected from one of the following: C3-C8 cycloalkyl, C6-C14 aryl, C4-C8 heteroaryl having 1-3 heteroatoms selected from N, S and O; wherein in R2, the C3-C8 naphthenic base is preferably C3-C6 naphthenic base; the aryl of C6-C14 is preferably C6-C10 aryl; the C4-C8 heteroaryl with 1-3 heteroatoms selected from N, S and O is preferably C4-C8 heteroaryl containing one oxygen or sulfur or nitrogen heteroatom;
r3 is selected from one of the following: C1-C6 alkyl or substituted alkyl, halogen; wherein in R3, the C1-C6 alkyl or substituted alkyl is preferably C1-C5 alkyl or substituted alkyl, and the halogen is preferably Cl or Br;
ar is selected from one of the following: 2, 4-isopropyl-6-anthracenylbenzene, 2,4, 6-neopentylphenyl, 2,4, 6-tricyclohexylphenyl and 2,4, 6-tricyclopentylphenyl, preferably 2,4, 6-tricyclohexylphenyl;
x is selected from one of the following: hydrogen, nitro, C1-C10 alkyl, tert-butyl diphenyl silicon base and triisopropyl silicon base, preferably triisopropyl silicon base.
The method for dynamically splitting the aromatic allyl tertiary alcohol catalyzed by the chiral phosphoric acid is characterized in that in R1, C6-C14 aryl is phenyl, p-fluorophenyl, methoxyphenyl, trimethoxyphenyl, methylphenyl, biphenyl, naphthyl, phenanthryl or anthryl, and C4-C8 heteroaryl containing one oxygen heteroatom, sulfur heteroatom or nitrogen heteroatom is thiophene; in the R2, the C3-C6 naphthenic base is cyclohexyl, the C6-C10 aryl is methylphenyl, fluorophenyl, methoxyphenyl or naphthyl, and the C4-C8 heteroaryl containing one oxygen atom, sulfur atom or nitrogen heteroatom is substituted pyrrole, thiophene or benzofuran; the C1-C5 alkyl or substituted alkyl in the R3 is methyl, methoxy or trifluoromethyl.
The method for dynamically resolving the aromatic allyl tertiary alcohol catalyzed by the chiral phosphoric acid is characterized in that the aromatic allyl alcohol compound shown in the formula I is selected from one of the following compounds:
the method for dynamically splitting the aromatic allyl tertiary alcohol catalyzed by the chiral phosphoric acid is characterized in that the reaction temperature is-30-10 ℃, and preferably-10-0 ℃; the organic solvent is at least one of dichloromethane, toluene, 1, 2-dichloroethane, carbon tetrachloride, tetrahydrofuran, acetonitrile, trifluorotoluene, chloroform and n-hexane, preferably chloroform.
The method for dynamically resolving allyl tertiary alcohol catalyzed by chiral phosphoric acid is characterized in that the mass ratio of a catalyst to a compound shown in a formula I is 10-20: 100, preferably 15: 100; the ratio of the amount of the substance of the compound represented by the formula I to the volume of the organic solvent is 0.025-0.5: 1, preferably 0.2:1, the amount of the substance is in mmol, and the volume is in mL.
The method for dynamically splitting the aromatic allyl tertiary alcohol catalyzed by the chiral phosphoric acid is characterized in that the additive is a molecular sieve with the type of the molecular sieve
Molecular sieve,
Molecular sieves or
Molecular sieves, preferably
A molecular sieve; the ratio of the mass of the molecular sieve to the mass of the compound shown in the formula I is 1-2.0: 1, preferably 1.6:1, the unit of the mass is g, and the unit of the mass is mmol.
The dynamic resolution method of the aryl allyl tertiary alcohol compound catalyzed by chiral phosphoric acid is characterized in that the chiral phosphoric acid catalyst shown in the formula II is selected from one of the following:
compared with the prior art, the invention has the following innovation points:
(1) compared with the method for obtaining the chiral aromatic allyl tertiary alcohol through the asymmetric addition reaction of the organic boron and the aldehyde ketone catalyzed by the transition metal, the method for preparing the chiral aromatic allyl tertiary alcohol through the asymmetric addition reaction of the organic boron and the aldehyde ketone catalyzed by the transition metal utilizes the chiral phosphoric acid as the catalyst and the molecular sieve as the additive, can realize the preparation of the aryl allyl tertiary alcohol and the dihydroisobenzofuran with high enantioselectivity through the kinetic resolution, avoids the use of the transition metal, and has the advantages of simple and mild reaction conditions and wide application range.
(2) The invention carries out kinetic resolution on racemic aromatic allyl tertiary alcohol by utilizing a chiral phosphoric acid catalyst, has less side reaction, and the chiral aromatic allyl tertiary alcohol structure as one of the products is an organic synthesis intermediate with higher value in organic synthesis; the other polysubstituted chiral dihydroisobenzofuran compound obtained by the reaction and the more important intermediate for medicine and organic synthesis.
(3) The method only generates water in the side reaction, has extremely high atom economy, is simple and convenient to prepare the substrate diaryl tertiary alcohol, has good industrial application prospect, and overcomes the difficulties that chiral kinetic resolution reaction of the tertiary alcohol is difficult to occur due to three groups with larger steric hindrance, nucleophilic substitution reaction of the tertiary alcohol is usually carried out by monomolecular nucleophilic substitution reaction, and highly substituted carbon centers tend to form more stable carbocation or ion pair intermediates, which can cause partial or complete loss of stereochemical integrity.
(4) The invention reports a method for synthesizing chiral aromatic allyl tertiary alcohol and dihydroisobenzofuran with high enantioselectivity, the reaction steps are simple and convenient, the chiral aromatic allyl tertiary alcohol and dihydroisobenzofuran can be obtained by only one-step reaction, the substrate application range is wide, the reaction conditions are simple, the number of byproducts is small, and the obtained two products with high optical activity can be further converted into various drug intermediates and various natural products. In conclusion, the invention has great advantages in atom economy, step economy, greenness, diversity-oriented synthesis and the like.
(5) Compared with the patent of the prior application of the laboratory on chiral phosphoric acid catalysis of allyl alcohol, the invention mainly changes the substituent group at the 6,6 'position in the existing catalyst system in the laboratory, introduces a brand-new TBDPS substituent, changes the rigidity of the catalyst by introducing different substituent groups at the 6,6' position, and influences the activity of the catalyst by adjusting the rigidity. In our substrate structure, multiple aryl groups are distributed on both sides of the reaction site, and greater steric hindrance results in lower activity of the reaction itself. Therefore, the chiral phosphoric acid derived from the modified binaphthol skeleton, which is a catalyst with higher activity, can help to promote the forward direction of the reaction, and simultaneously better control the enantioselectivity of the product, and the electronic effect and the steric effect act on the control of the stereoselectivity.
(6) Compared with the patent of chiral phosphoric acid catalysis allyl alcohol previously applied in the laboratory, the aryl benzyl alcohol compound with good functional group compatibility and stable property is adopted as the resolution substrate, compared with the alkyl primary alcohol compound which is previously applied and used as the substrate, the steric hindrance is larger, the resolution difficulty is higher, the chiral dihydroisobenzofuran medicine parent nucleus is successfully constructed by adopting different substrates and utilizing the chiral phosphoric acid catalysis, the technical problem of synthesizing the chiral dihydroisobenzofuran structure is solved, the method for preparing various chiral dihydroisobenzofurans with high yield and high enantioselectivity is provided, and the application prospect and the social value are better.
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
An analytical instrument: melting points were determined using a Buchi B-540 capillary melting point apparatus. Including 1H NMR, and the like, in the sample,13C NMR，19NMR data including F NMR spectra were recorded on a Bruker 400MHz or 600MHz instrument. All of13The C NMR spectra are all broadband proton decoupled.1Chemical shifts are reported in ppm by H NMR relative to the residual signal of the solvent.19F NMR used perfluorobenzene as an internal standard. Using ESI as ion source, in Agilent6210 High Resolution Mass (HRMS) was recorded on TOF LC/MS. Optical rotation was measured using an AUTOPOLV automatic polarimeter. The enantiomeric excess value (ee%) was determined by HPLC analysis using Agilent 1100 equipped with Daicel Chiralpak IA, IC, IE, IF, IG chromatography columns.
In the catalyst of the present invention, the catalysts (R) -L1 and (R) -L3 to (R) -L5 except the chiral phosphoric acid catalyst (R) -L2 are prior art, and are described in reference documents [1-6 ]:
document [1 ]: rauniyar V., Lacknera.D., Hamilton G.L., Toste F.D., et al asymmetry electronic fluorescence use an Anionic Phase-Transfer Catalyst [ J ] Science 2011,334(6063): 1681-.
Document [2 ]: kuroday, Harada S., Oonishi A, Kiyama H, Yamaokay, Yamada K, Takasu K, et al Use of a Catalytic, crystalline leave Group for Asymmetric Substitutions at Sp3-Hybridized carbohydrates, Kinetic Resolution of β -Amino Alcohols by p methoxy benzene hydrolysis [ J ]. Angew.Chem.Int.Ed.2016, (55) (42) 13137-13141.
Document [3 ]: narute S, Pappo D, et al Iron phosphor catalyst assisted asymmetry Cross-dehydrogenation Coupling of 2-naphthaols with β -Ketolestizers [ J ] org. Lett.2017,19(11) 2917-.
Document [4 ]: harada S., Kuwano S., Yamaoka, Y., Yamada K., Takasu K., et al, Kinetic Resolution of second alcohol catalysis by means of a Chiral Phosphoric acid [ J ]. Angew.chem.int.Ed.2013,52(39): 10227. 10230.
Document [5 ]: knipe P.C., Smith M.D., et al endogenous selective One-Point Synthesis of hydroquinones via BINOL-Derived Lewis Acid Catalysis [ J ] Org Biomol Chem 2014,12(28): 5094-.
Document [6 ]: cheng X, Goddard R, Buth G, List B, et al Direct catalysis asymmetry Three, Kabachnik-Fields Reaction [ J ]. Angew. chem. int. Ed.2008,47(27): 5079-.
Example (b):
the chiral phosphoric acid catalyst (R) -L2 was prepared as follows:
the reaction flask containing binaphthol in the R configuration (52.3mmol,1.0equiv) and anhydrous dichloromethane (100mL) was cooled to-78 deg.C, followed by dropwise addition of liquid bromine (6.7mL,130.8mmol,2.5equiv) to the reaction vessel over 45 minutes. After the liquid bromine was added completely, the reaction solution was slowly warmed to ambient temperature and then stirred for another 12 hours. The reaction was monitored by TLC and after completion of the reaction, Na was added dropwise in an ice bath at a concentration of 10% by mass2SO3Aqueous solution (20mL) to quench. After stirring for 20 min, the layers were separated and the aqueous layer was extracted with dichloromethane (3X 20 mL). The combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (n-hexane/ethyl acetate 10/1, v/v) to give the isolated product as a light yellow foam in 83% yield (25.1g,42.2 mmol).
To a suspension containing sodium hydride (60% w/w dispersed in mineral oil, 6.8g,168.8mmol,5.0equiv) and anhydrous tetrahydrofuran (100mL) was added portionwise (R) -6,6' -dibromo- [1,1' -binaphthyl ] -2,2' -diol (33.8mmol,1.0equiv) at 0 ℃. The resulting mixture was stirred at 0 ℃ for 30 minutes (forming a grey slurry) and then at room temperature for an additional 1 hour (the slurry redissolved). The temperature was then lowered to 0 ℃ and bromomethyl ether (6.9mL,84.4mmol,2.5equiv) was added dropwise via syringe. The resulting mixture was stirred at room temperature for 6 hours. After completion of the reaction, the mixture was quenched with saturated aqueous ammonium chloride (20mL) and extracted with dichloromethane (3X 20 mL). The crude product was purified by flash chromatography on silica gel (n-hexane/ethyl acetate 50/1, v/v) to give the isolated product as white crystals in 68% yield (12.1g,22.7 mmol).
To a solution of (R) -6,6' -bromo-2, 2' -bis (methoxymethoxy) -1,1' -binaphthyl (7.7g,14.5mmol) in anhydrous tetrahydrofuran (80mL) at-78 deg.C was added n-BuLi (2.4M solution in hexane, 15.4mL,36.9mmol,2.55equiv) dropwise. After stirring for 60 minutes, freshly distilled TBDPSOTf (16.9g,43.6mmol,2.6equiv) was added dropwise over 20 minutes. After addition was complete, the reaction was removed from the cooling bath, warmed to ambient temperature and stirred for an additional 2 hours. The reaction mixture was then poured into a saturated aqueous solution of sodium bicarbonate (50mL) and then diluted with additional water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (3X 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (n-hexane → n-hexane/ether 95/5, v/v) to give the product as a white solid in 55% yield (6.9g,8.0 mmol).
To a solution of (R) -6,6' -tert-butyldiphenyl-2, 2' -bis (methoxymethoxy) -1,1' -binaphthyl (4.0g,4.7mmol,1.0equiv) in anhydrous tetrahydrofuran (80mL) at-78 ℃, n-BuLi (2.4M solution in hexane, 15.4mL,8.1mmol,4.1equiv) was added dropwise. After stirring the mixture at-78 ℃ for 30 minutes, gradually increasing the temperature to 0 ℃ and stirring at this temperature for a further 2 hours, a fine light brown precipitate can be observed. After a period of time, the reaction mixture was cooled to-78 ℃ and solid iodine (5.0g,19.7mmol,4.2equiv) was added in portions, then the reaction was allowed to warm slowly to ambient temperature and stirred overnight. The reaction was monitored by TLC and, after completion of the reaction, Na was added dropwise at a concentration of 10% by mass2S2O3Aqueous solution (20mL) to quench the reaction. The layers were separated and the aqueous layer was extracted with ether (3X 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (n-hexane/ether 99/1, v/v) to give the product as a foamy white solid in isolated yield68% (3.5g,3.2 mmol).
Preparation of Grignard reagents: activated magnesium turnings (2.0g,82.5mmol,5.0equiv) were suspended in anhydrous tetrahydrofuran (5mL) and 1, 2-dibromoethane (0.5mL) was added. After the addition was complete, the reaction mixture was heated to reflux with a hot air gun and a suspension of 1-bromo-2, 4, 6-tricyclohexylbenzene (7.32g,16.5mmol,1.0equiv) in anhydrous tetrahydrofuran (25mL) was added slowly to the mixture at that temperature. The resulting solution was heated to reflux for 6 hours until only a small amount of magnesium metal had not reacted.
At ambient temperature, adding Ni (Ph)3P)2Cl2(303.0mg,0.48mmol,0.1equiv) and the product of the previous step (2.7g,2.5mmol,1.0 equiv) were dissolved in anhydrous tetrahydrofuran (20mL) and stirred well and the solution was observed to appear as a gray suspension. The prepared grignard reagent was then slowly added dropwise into the gray suspension and the solution in the reaction flask was observed to gradually change from a gray suspension to a brownish red solution. After the addition was complete, the temperature was raised to 40 ℃ and stirred at this temperature for 24 hours. The reaction was monitored by TLC and after completion of the reaction, the mixture was poured into saturated aqueous ammonium chloride solution. The aqueous layer was then extracted with dichloromethane (3 × 50mL) and the combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (n-hexane → n-hexane/dichloromethane 9/1, v/v). The product was obtained as a white foam, giving a yield of 63% in both steps (1.5g,1.0 mmol).
The MOM ether prepared in the previous step (1.5g,1.0mmol,1.0equiv) was dissolved in anhydrous 1, 4-dioxane (25.0mL) and concentrated aqueous hydrochloric acid (32% w/w,5.0mL) was added. The reaction mixture was heated at 70 ℃ for 6 hours. The reaction was monitored by TLC and after completion of the reaction, the solvent was evaporated in vacuo and the residue was dissolved in dichloromethane. Washed with saturated aqueous sodium bicarbonate (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (n-hexane → n-hexane/dichloromethane 9/1, v/v). The product was obtained as a white foam in 64% yield (0.9g,0.64 mmol).
(R) -3,3 '-bis (2,4, 6-tricyclohexylphenyl) -6,6' -bis (tert-butyldiphenylsilane) - [1,1 '-binaphthyl ] -2,2' -diol (0.9g,0.6mmol,1.0equiv) was dissolved in anhydrous pyridine (5.0mL) and heated to 90 ℃. At this temperature, freshly distilled phosphorus oxychloride (149.0 μ L,1.6mmol,2.5equiv) was added dropwise over 1 minute. After the resulting mixture was stirred at 100 ℃ for 12 hours, water (5.0mL) was slowly added, followed by continued heating for 12 hours. The reaction was monitored by TLC and after completion of the reaction, the reaction mixture was cooled to ambient temperature and poured into 6M aqueous HCl (50 mL). The reaction mixture was extracted with dichloromethane (3 × 50mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (n-hexane → n-hexane/dichloromethane 5/1, v/v).
Acidification and recrystallization: the resulting purified white foamy solid was dissolved in 20mL of dichloromethane, followed by addition of 6M aqueous HCl (20mL) and stirring at room temperature for 2 hours. After stirring was complete, the reaction mixture was extracted with dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude phosphoric acid obtained by concentration was recrystallized from methylene chloride/acetonitrile to obtain the final product L2 as a white solid with a yield of 55% (0.5g,0.4 mmol).
Example 1: synthesis of products III-1 and IV-1
The experimental steps are as follows: in N2Under the protection, the reaction system is sealed inAnhydrous and anaerobic treatment is carried out, the temperature is adjusted to be 0 ℃, and I-1(0.1mmol, 1.0equiv), chiral binaphthol catalyst (R) -L1(0.015mmol, 0.15equiv) and additive are added into a 10mL reaction bottle in sequence
A reaction was carried out using a molecular sieve (160mg) and chloroform (0.5mL) as a solvent. After the reaction was monitored by HPLC analysis until the reaction was completed, the reaction system was filtered through celite and concentrated, and the resulting concentrated crude product was separated and purified by column chromatography using petroleum/ethyl acetate 5/1(v/v) as an eluent to give the objective compound III-1 as a white foamy solid in a yield of 47% and an ee value of 92%. [ alpha ] to]D 20＝–17.28(c 1.0,CHCl3)1H NMR(600MHz,DMSO-d6)δ7.56(d,J＝7.6Hz,1H),7.45(dd,J＝7.8,1.8Hz,3H),7.35–7.28(m,7H),7.28–7.20(m,3H),6.94(d,J＝15.8Hz,1H),6.45(d,J＝15.8Hz,1H),6.32(s,1H),5.08(t,J＝5.4Hz,1H),4.47(dd,J＝14.4,5.2Hz,1H),4.12(dd,J＝14.4,4.8Hz,1H).13C NMR(151MHz,DMSO-d6)δ146.4,143.5,141.1137.0,136.6,128.7,128.1,127.8,127.4,127.3,127.2,126.8,126.5,126.4,126.1,125.9,78.7,60.9.HRMS(ESI)m/z calcd.for C22H20NaO2[M+Na]+:339.1463；found 339.1356.
The objective compound IV-1 was a colorless oily liquid, yield 48%, ee value 86%. [ alpha ] to]D 20＝+11.3(c1.0,CHCl3)。1H NMR(400MHz,DMSO-d6)δ7.56–7.41(m,9H),7.40–7.18(m,5H),6.96(d,J＝16.0Hz,1H),6.61(d,J＝16.0Hz,1H),5.21(d,J＝1.6Hz,2H).13C NMR(101MHz,DMSO-d6)δ144.3,143.5,138.3,136.2,132.7,128.6,1283,127.2,127.6,127.6,127.5,127.3,126.6,125.8,122.8,121.4,90.3,71.3.HRMS(ESI)m/z calcd.for C22H19O[M+H]+:299.1358；found 299.1366.
Comparative example 1: synthesis of products III-1 and IV-1
The same procedures as in example 1 were repeated except for replacing the chiral binaphthol catalyst (R) -L1 in example 1 with an equimolar amount of chiral binaphthol catalyst (R) -L2 to finally obtain the corresponding compounds III-1 and IV-1.
The target compound III-1 is a white foamy solid, the yield is 42 percent, and the ee value is 55 percent;
the objective compound IV-1 was a colorless oily liquid, yield 40%, ee value 82%.
Comparative example 2: synthesis of products III-1 and IV-1
The same procedures as in example 1 were repeated except for replacing the chiral binaphthol catalyst (R) -L1 in example 1 with an equimolar amount of chiral binaphthol catalyst (R) -L3 to finally obtain the corresponding compounds III-1 and IV-1.
The target compound III-1 is a white foamy solid, the yield is 45 percent, and the ee value is 95 percent;
the objective compound IV-1 was a colorless oily liquid, yield 51%, ee value 64%.
Example 2: synthesis of products III-2 and IV-2
The compound shown in the formula I-1 in the example 1 is replaced by the compound shown in the formula I-2 with the same molar amount, and the rest of the operation steps are the same as the example 1, so that the corresponding compounds III-2 and IV-2 are finally obtained.
Product III-2 was obtained as a white foamy solid in 42% yield with an ee value of 93%. [ alpha ] to]D 20＝–5.29(c1.0,CHCl3)。1H NMR(400MHz,DMSO-d6)δ7.55(d,J＝7.0Hz,1H),7.42(dd,J＝12.4,4.4Hz,3H),7.36–7.27(m,3H),7.27–7.15(m,4H),6.91(d,J＝16.0Hz,1H),6.87(d,J＝8.8Hz,2H),6.39(d,J＝16.0Hz,1H),6.20(s,1H),5.05(t,J＝5.4Hz,1H),4.46(dd,J＝14.4,5.4Hz,1H),4.16(dd,J＝14.4,5.2Hz,1H),3.73(s,3H).13C NMR(101MHz,DMSO-d6)δ157.8,143.6,141.1,138.3,137.2,136.7,128.6,128.0,127.4,127.4,127.2,127.1,126.6,126.4,125.9,113.2,79.2,78.4,61.0,55.0,40.2,39.9,39.7,39.5,39.3,39.1,38.9.HRMS(ESI)m/z calcd.for C23H22NaO3[M+Na]+:369.1461；found 369.1464.
The product IV-2 is obtained as a colorless oily liquid in 52% yield and with an ee value of 72%. [ alpha ] to]D 20＝+17.30(c1.0,CHCl3)。1H NMR(400MHz,DMSO-d6)δ7.51–7.43(m,2H),7.42–7.33(m,3H),7.37–7.26(m,4H),7.27–7.18(m,1H),6.95–6.87(m,1H),6.59(d,J＝16.0Hz,1H),5.16(d,J＝2.1Hz,2H),3.72(s,3H).13C NMR(101MHz,DMSO-d6)δ158.5,143.8,138.4,136.3,136.2,132.9,128.6,127.7,127.6,127.5,127.4,127.3,126.6,122.8,121.5,113.6,90.1,71.1,55.1.HRMS(ESI)m/z calcd.for C23H22O3[M+H]+:329.1536；found 329.1548.
Example 3: synthesis of products III-3 and IV-3
The compound shown in the formula I-1 in the example 1 is replaced by the compound shown in the formula I-3 with the same molar amount, and the rest of the operation steps are the same as the example 1, so that the corresponding compounds III-3 and IV-3 are finally obtained.
Product III-3 was obtained as a white foamy solid in 30% yield and with an ee value of 70%. [ alpha ] to]D 20＝–7.19(c1.0,CHCl3)。1H NMR(400MHz,DMSO-d6)δ7.55(d,J＝7.4Hz,1H),7.44(dd,J＝7.6,1.2Hz,1H),7.39–7.28(m,7H),7.29–7.18(m,2H),7.13(d,J＝8.0Hz,2H),6.86(d,J＝16.0Hz,1H),6.38(d,J＝16.0Hz,1H),6.28(s,1H),5.06(t,J＝5.4Hz,1H),4.46(dd,J＝14.4,5.4Hz,1H),4.11(dd,J＝14.4,5.2Hz,1H),2.28(s,3H).13C NMR(101MHz,DMSO-d6)δ146.5,143.6,141.1,136.7,136.0,133.8,129.2,128.0,127.8,127.3,127.2,126.7,126.5,126.4,126.2,125.9,78.7,60.9,20.8.HRMS(ESI)m/z calcd.for C23H22NaO2[M+Na]+:353.1620；found 353.1512.
The product IV-3 is obtained as a colorless oily liquid in 61% yield and with an ee value of 32%. [ alpha ] to]D 20＝+25.63(c1.0,CHCl3)。1H NMR(400MHz,DMSO-d6)δ7.55–7.48(m,2H),7.48–7.41(m,1H),7.40–7.22(m,8H),7.12(d,J＝8.0Hz,2H),6.89(d,J＝15.8Hz,1H),6.55(d,J＝15.8Hz,1H),5.20(d,J＝2.1Hz,2H),2.26(s,3H).13C NMR(101MHz,DMSO-d6)δ144.4,143.7,138.3,137.0,133.5,131.7,129.2,128.3,127.7,127.5,127.5,127.3,126.6,125.8,122.8,121.5,90.3,71.3,20.8.HRMS(ESI)m/z calcd.for C23H21O[M+H]+:313.1514；found 313.1524.
Example 4: synthesis of products III-4 and IV-4
The compound shown in the formula I-1 in the example 1 is replaced by the compound shown in the formula I-4 with the same molar amount, and the rest of the operation steps are the same as the example 1, so that the corresponding compounds III-4 and IV-4 are finally obtained.
Product III-4 was obtained as a yellow foamy solid in 43% yield and with an ee value of 96%. [ alpha ] to]D 20＝–34.31(c1.0,CHCl3)。1H NMR(400MHz,DMSO-d6)δ7.56(d,J＝7.4Hz,1H),7.54–7.48(m,2H),7.45(dd,J＝7.4,1.2Hz,1H),7.35–7.27(m,5H),7.24(ddd,J＝11.0,8.2,3.0Hz,2H),7.14(t,J＝9.0Hz,2H),6.90(d,J＝16.0Hz,1H),6.45(d,J＝16.0Hz,1H),6.32(s,1H),5.09(t,J＝5.4Hz,1H),4.46(dd,J＝14.4,5.2Hz,1H),4.11(dd,J＝14.4,5.0Hz,1H)；13C NMR(101MHz,DMSO-d6)δ162.7,160.3,146.4,143.5,141.0,137.0,136.0,133.2,133.2,128.4,128.3,128.1,127.9,127.3,127.2,126.5,126.1,126.0,125.6,115.5,115.3,78.7,61.0.HRMS(ESI)m/z calcd.for C23H19F1NaO2[M+Na]+:357.1261；found 311.1254.
The product IV-4 is obtained as a colorless oily liquid in 53% yield with an ee value of 75%. [ alpha ] to]D 20＝+17.90(c1.0,CHCl3)。1H NMR(400MHz,DMSO-d6)δ7.57–7.47(m,4H),7.44(dd,J＝6.2,2.6Hz,1H),7.40–7.22(m,8H),6.92(d,J＝15.8Hz,1H),6.61(d,J＝15.8Hz,1H),5.20(d,J＝1.8Hz,2H).13C NMR(101MHz,DMSO-d6)δ162.8,160.4,144.2,143.4,138.3,132.8,132.8,132.6,132.6,128.5,128.5,128.4,128.4,128.2,127.6,127.4,127.2,126.4,125.8,122.7,121.3,115.4,115.2,90.2,71.2.HRMS(ESI)m/z calcd.for C22H18FO[M+H]+:317.1336；found 317.1332.
Example 5: synthesis of products III-5 and IV-5
The compound shown in the formula I-1 in the example 1 is replaced by the compound shown in the formula I-5 with the same molar amount, and the rest of the operation steps are the same as the example 1, so that the corresponding compounds III-5 and IV-5 are finally obtained.
Product III-5 was obtained as a white foamy solid in 42% yield with an ee value of 90%. [ alpha ] to]D 20＝–2.21(c1.0,CHCl3)。1H NMR(400MHz,DMSO-d6)δ7.57(dd,J＝7.6,1.6Hz,1H),7.40(dd,J＝6.2,1.6Hz,2H),7.37–7.20(m,7H),7.07(dd,J＝3.6,1.2Hz,1H),7.03–6.97(m,1H),6.65(d,J＝15.8Hz,1H),6.53(d,J＝15.8Hz,1H),6.34(s,1H),5.07(t,J＝5.4Hz,1H),4.46(dd,J＝14.6,5.6Hz,1H),4.09(dd,J＝14.6,5.2Hz,1H)；13C NMR(101MHz,DMSO-d6)δ146.0,143.2,141.5,141.1,136.5,128.0,127.9,127.8,127.3,127.1,126.6,126.2,126.1,125.9,124.9,120.7,78.5,60.9；HRMS(ESI)m/z calcd.for C20H18NaO2S[M+Na]+:345.0920,found 345.0929.
The product IV-5 is obtained as a colorless oily liquid in 51% yield and 70% ee. [ alpha ] to]D 20＝+5.33(c 1.0,CHCl3)。1H NMR(400MHz,DMSO-d6)δ7.54–7.46(m,2H),7.46–7.41(m,2H),7.38–7.30(m,5H),7.30–7.24(m,1H),7.12(dd,J＝3.6,1.2Hz,1H),6.99(dd,J＝5.2,3.6Hz,1H),6.75(d,J＝15.6Hz,1H),6.62(d,J＝15.6Hz,1H),5.19(s,2H).13C NMR(101MHz,DMSO-d6)δ144.0,143.2,141.1,138.4,132.0,128.4,127.9,127.6,127.4,126.9,125.8,125.4,122.8,121.6,121.5,90.0,71.3；HRMS(ESI)m/z calcd.for C20H17OS[M+H]+:305.0994,found 305.0989.
Example 6: synthesis of products III-6 and IV-6
The compound shown in the formula I-1 in the example 1 is replaced by the compound shown in the formula I-6 with the same molar amount, and the rest of the operation steps are the same as the example 1, so that the corresponding compounds III-6 and IV-6 are finally obtained.
Product III-6 was obtained as a white foamy solid in 45% yield and with an ee value of 87%. [ alpha ] to]D 20＝–56.48(c1.0,CHCl3)。1H NMR(400MHz,DMSO-d6)δ7.87(d,J＝9.4Hz,4H),7.77(dd,J＝8.6,1.8Hz,1H),7.59(dd,J＝7.6,1.6Hz,1H),7.55–7.43(m,3H),7.34(td,J＝8.4,6.6Hz,5H),7.31–7.20(m,2H),7.11(d,J＝16.0Hz,1H),6.62(d,J＝16.0Hz,1H),6.42(s,1H),5.14(t,J＝5.4Hz,1H),4.52(dd,J＝14.5,5.4Hz,1H),4.14(dd,J＝14.6,5.2Hz,1H).；13C NMR(101MHz,DMSO-d6)δ146.4,143.5,141.2,137.7,134.2,133.3,132.5,128.2,128.0,128.0,127.9,127.6,127.4,127.3,126.9,126.6,126.4,126.3,126.0,126.0,123.9,78.9,60.9.；HRMS(ESI)m/z calcd.for C26H22NaO2[M+Na]+:389.1512,found 389.1518.
The product IV-6 is obtained as a colorless oily liquid in 48% yield and with an ee value of 85%. [ alpha ] to]D 20＝+22.18(c1.0,CHCl3)。1H NMR(400MHz,DMSO-d6)δ7.90–7.81(m,4H),7.77(dd,J＝8.7,1.7Hz,1H),7.61–7.53(m,2H),7.53–7.41(m,3H),7.41–7.29(m,5H),7.32–7.23(m,1H),7.13(d,J＝15.8Hz,1H),6.78(d,J＝15.8Hz,1H),5.24(s,2H).13C NMR(101MHz,DMSO-d6)δ144.3,143.6,138.4,133.8,133.4,133.2,132.6,128.4,128.1,127.9,127.8,127.7,127.6,127.6,127.4,126.5,126.4,126.0,125.9,123.9,122.9,121.5,90.4,71.4；HRMS(ESI)m/z calcd.for C26H21O[M+H]+:349.1586,found 349.1580.
Example 7: synthesis of products III-7 and IV-7
The compound shown in the formula I-1 in the example 1 is replaced by the compound shown in the formula I-7 with the same molar amount, and the rest of the operation steps are the same as the example 1, so that the corresponding compounds III-7 and IV-7 are finally obtained.
Product III-7 was obtained as a white foamy solid in 45% yield and with an ee value of 91%. [ alpha ] to]D 20＝–50.21(c1.0,CHCl3)。1H NMR(400MHz,DMSO-d6)δ8.04–7.95(m,1H),7.93(dd,J＝7.0,2.4Hz,1H),7.85(d,J＝8.2Hz,1H),7.74(d,J＝7.0Hz,1H),7.61(dd,J＝7.6,1.6Hz,1H),7.59–7.46(m,4H),7.43–7.30(m,5H),7.30–7.17(m,3H),6.95(d,J＝15.6Hz,1H),6.47(s,1H),5.09(t,J＝5.4Hz,1H),4.57(dd,J＝14.6,5.4Hz,1H),4.17(dd,J＝14.6,5.4Hz,1H).13C NMR(101MHz,DMSO-d6)δ146.4,143.4,141.3,140.1,134.0,133.3,130.7,128.5,128.0,127.9,127.7,127.3,127.3,126.6,126.3,126.2,126.0,125.9,125.8,123.7,123.6,123.2,79.0,60.9；HRMS(ESI)m/z calcd.for C26H22NaO2[M+Na]+:389.1512；found 389.1522.
The product IV-7 was obtained as a colorless oily liquid in 49% yield and 87% ee. [ alpha ] to]D 20＝+46.35(c1.0,CHCl3)。1H NMR(400MHz,DMSO-d6)δ8.08–7.81(m,3H),7.79–7.19(m,14H),6.97(d,J＝15.6Hz,1H),5.30(s,2H).13C NMR(101MHz,DMSO-d6)δ144.2,143.5,138.4,135.7,133.4,133.2,130.5,128.5,128.3,127.9,127.8,127.5,127.4,126.4,125.9,125.7,124.3,123.8,123.1,122.8,121.5,90.5,71.4；HRMS(ESI)m/z calcd.for C26H21O[M+H]+:349.1586,found 349.1593.
Example 8: synthesis of products III-8 and IV-8
The compound shown in the formula I-1 in the example 1 is replaced by the compound shown in the formula I-8 with the same molar amount, and the rest of the operation steps are the same as the example 1, so that the corresponding compounds III-8 and IV-8 are finally obtained.
Product III-8 was obtained as a white foamy solid in 47% yield and with an ee value of 89%. [ alpha ] to]D 20＝–17.97(c1.0,CHCl3)。1HNMR(600MHz,DMSO-d6)δ8.51(s,1H),8.13(dd,J＝8.8,1.6Hz,2H),8.07(d,J＝8.4Hz,2H),7.66(d,J＝7.6Hz,1H),7.56(d,J＝7.8Hz,1H),7.52–7.42(m,6H),7.43–7.38(m,2H),7.35(t,J＝7.6Hz,1H),7.33–7.25(m,2H),7.19(d,J＝16.0Hz,1H),6.65(dd,J＝16.0,1.2Hz,2H),5.08(td,J＝5.4,1.2Hz,1H),4.66(dd,J＝14.6,5.6Hz,1H),4.21(dd,J＝14.6,5.4Hz,1H).13C NMR(151MHz,DMSO-d6)δ146.2,145.1,143.0,141.4,132.2,130.9,129.0,128.6,128.1,127.9,127.3,127.2,126.6,126.1,126.0,125.9,125.6,125.4,125.3,122.9,79.3,60.9；HRMS(ESI)m/z calcd.for C30H24NaO2[M+Na]+:439.1776；found439.1669.
The product IV-8 is obtained as a colorless oily liquid in 48% yield and with an ee value of 92%. [ alpha ] to]D 20＝+2.68(c 1.0,CHCl3)。1H NMR(600MHz,DMSO-d6)δ8.51(s,1H),8.13–8.00(m,4H),7.71–7.64(m,2H),7.61–7.55(m,1H),7.52–7.40(m,8H),7.41–7.35(m,2H),7.35–7.27(m,2H),6.64(d,J＝16.2Hz,1H),5.42(d,J＝12.8Hz,1H),5.34(d,J＝12.8Hz,1H).13C NMR(151MHz,DMSO-d6)δ143.9,143.3,141.0,138.5,131.4,130.9,128.8,128.6,128.4,127.9,127.6,127.4,126.2,125.9,125.8,125.3,125.1,124.0,122.8,121.6,90.6,71.5；HRMS(ESI)m/z calcd.for C30H23O[M+H]+:399.1743,found 399.1733.
Example 9: synthesis of products III-9 and IV-9
The compound shown in the formula I-1 in the example 1 is replaced by the compound shown in the formula I-9 with the same molar amount, and the rest of the operation steps are the same as the example 1, so that the corresponding compounds III-9 and IV-9 are finally obtained.
Product III-9 was obtained as a white foamy solid in 47% yield and with an ee value of 96%. [ alpha ] to]D 20＝–13.26(c1.0,CHCl3)。1H NMR(400MHz,DMSO-d6)δ8.93–8.75(m,1H),8.12–7.98(m,2H),7.83–7.52(m,3H),7.48–7.24(m,5H),7.04(d,J＝15.6Hz,1H),6.53(s,1H),5.10(t,J＝5.4Hz,1H),4.59(dd,J＝14.6,5.6Hz,1H),4.19(dd,J＝14.6,5.2Hz,1H)；13C NMR(101MHz,DMSO-d6)δ146.5,143.4,141.3,140.4,132.9,131.3,130.1,129.9,129.5,128.6,128.0,127.9,127.4,127.3,127.0,126.8,126.7,126.6,126.2,126.0,124.2,124.1,124.0,123.5,122.7,79.0,60.9；HRMS(ESI)m/z Calcd for C30H24NaO2[M+Na]+:439.1669,Found 439.1683.
The product IV-9 is obtained as a colorless oily liquid in 49% yield and with an ee value of 95%. [ alpha ] to]D 20＝+22.27(c1.0,CHCl3)。1H NMR(400MHz,DMSO-d6)δ8.93–8.72(m,2H),8.11–7.95(m,3H),7.86–7.59(m,6H),7.57–7.52(m,1H),7.49–7.24(m,7H),7.05(d,J＝15.4Hz,1H),5.52–5.13(m,2H).13C NMR(101MHz,DMSO-d6)δ144.2,143.5,138.4,136.2,132.4,131.2,129.9,129.5,128.6,128.4,127.8,127.6,127.4,127.1,127.0,126.8,126.8,125.9,124.9,124.4,124.0,123.5,122.8,122.7,121.5,90.5,71.5；HRMS(ESI)m/z calcd.for C26H21O[M+H]+:399.1671,found 399.1682.
Example 10: synthesis of products III-10 and IV-10
The compound shown in the formula I-1 in the example 1 is replaced by the compound shown in the formula I-10 with the same molar amount, and the rest of the operation steps are the same as the example 1, so that the corresponding compounds III-10 and IV-10 are finally obtained.
Product III-10 was obtained as a yellow foamy solid in 47% yield with an ee value of 94%. [ alpha ] to]D 20＝–14.55(c1.0,CHCl3)。1H NMR(400MHz,DMSO-d6)δ7.56(dd,J＝7.6,1.6Hz,1H),7.45(dd,J＝7.6,1.6Hz,1H),7.32(d,J＝4.4Hz,5H),7.29–7.20(m,2H),6.92(d,J＝15.8Hz,1H),6.76(s,2H),6.39(d,J＝15.8Hz,1H),6.29(s,1H),5.09(t,J＝5.4Hz,1H),4.46(dd,J＝14.4,5.4Hz,1H),4.13(dd,J＝14.4,5.2Hz,1H),3.79(s,6H),3.64(s,3H)；13C NMR(101MHz,DMSO-d6)δ153.0,146.5,143.6,141.1,137.1,136.3,132.4,128.1,127.9,127.5,127.2,127.0,126.5,126.2,125.9,103.8,78.8,61.1,60.0,55.9；HRMS(ESI)m/z Calcd for C25H26NaO5[M+Na]+:429.1672,Found429.1682.
The product IV-10 is obtained as a colorless oily liquid in 48% yield and with an ee value of 91%. [ alpha ] to]D 20＝+8.14(c1.0,CHCl3)。1H NMR(400MHz,DMSO-d6)δ7.54–7.46(m,2H),7.46–7.39(m,1H),7.39–7.31(m,5H),7.27(t,J＝7.4Hz,1H),6.91(d,J＝15.8Hz,1H),6.78(s,2H),6.52(d,J＝15.8Hz,1H),5.19(s,2H),3.77(s,6H),3.63(s,3H).13C NMR(101MHz,DMSO-d6)δ153.0,144.2,143.5,138.5,137.2,132.1,131.9,128.2,128.1,127.7,127.5,127.3,125.9,122.9,121.4,104.0,90.4,71.2,60.0,55.9；HRMS(ESI)m/z calcd.for C25H24NaO4[M+Na]+:411.1567,found 411.1587.
Examples 11 to 21
The invention has wide substrate practicability, and according to the reaction conditions in the example 1, a plurality of substrates can participate in the reaction, and the aromatic allyl tertiary alcohol and the dihydroisobenzofuran compounds containing a chiral center can be obtained with high yield and high stereoselectivity.
EXAMPLES 11-21 example 1 was repeated except that "the compound of formula I-1 in example 1 was replaced with an equimolar amount of the tertiary aryl allyl alcohol compound of formula I", and the remaining procedure was as in example 1 to finally obtain the corresponding tertiary aryl allyl alcohol compound of formula III containing one chiral center and the corresponding dihydroisobenzofurans compound of formula IV containing one chiral center according to the following reaction schemes:
in the reaction formula, the substituent R in the structural formulas of formula III and formula IV1、R2、R3Are the same as in the structural formula I. Wherein, the molecular structural formulas of the aryl allyl tertiary alcohol compounds used in examples 11 to 21 are respectively shown as I-11 to I-21, and the reaction results are shown in Table 1.
TABLE 1
Finally, it should also be noted that the above list is only a specific implementation example of the present invention. It is obvious that the invention is not limited to the above embodiment examples, but that many variations are possible. All modifications which may be suggested to one skilled in the art and guided by the teachings herein provided should be within the scope of the invention.
Claims (7)
1. A method for dynamically splitting aryl allyl tertiary alcohol catalyzed by chiral phosphoric acid is characterized in that chiral phosphoric acid is used as a catalyst, and aryl allyl tertiary alcohol compounds shown as a formula I are subjected to dynamic splitting reaction in the presence of an organic solvent and an additive under the catalysis of a chiral phosphoric acid catalyst shown as a formula II to generate aryl allyl tertiary alcohol compounds shown as a formula III and dihydroisobenzofuran compounds shown as a formula IV, wherein the aryl allyl tertiary alcohol compounds contain a chiral center, and the reaction formulas are as follows:
R1selected from one of the following: C6-C20 arylA C4-C8 heteroaryl group having 1-3 heteroatoms selected from N, S and O; wherein in R1, the C6-C20 aryl is preferably C6-C14 aryl, and the C4-C8 heteroaryl with 1-3 heteroatoms selected from N, S and O is preferably C4-C8 heteroaryl containing one oxygen heteroatom, sulfur heteroatom or nitrogen heteroatom;
r2 is selected from one of the following: C3-C8 cycloalkyl, C6-C14 aryl, C4-C8 heteroaryl having 1-3 heteroatoms selected from N, S and O; wherein in R2, the C3-C8 naphthenic base is preferably C3-C6 naphthenic base; the aryl of C6-C14 is preferably C6-C10 aryl; the C4-C8 heteroaryl with 1-3 heteroatoms selected from N, S and O is preferably C4-C8 heteroaryl containing one oxygen or sulfur or nitrogen heteroatom;
r3 is selected from one of the following: C1-C6 alkyl or substituted alkyl, halogen; wherein in R3, the C1-C6 alkyl or substituted alkyl is preferably C1-C5 alkyl or substituted alkyl, and the halogen is preferably Cl or Br;
ar is selected from one of the following: 2, 4-isopropyl-6-anthracenylbenzene, 2,4, 6-neopentylphenyl, 2,4, 6-tricyclohexylphenyl and 2,4, 6-tricyclopentylphenyl, preferably 2,4, 6-tricyclohexylphenyl;
x is selected from one of the following: hydrogen, nitro, C1-C10 alkyl, tert-butyl diphenyl silicon base and triisopropyl silicon base, preferably triisopropyl silicon base.
2. The method for kinetic resolution of tertiary aromatic allyl alcohol catalyzed by chiral phosphoric acid as claimed in claim 1, wherein in R1, the C6-C14 aryl group is phenyl, p-fluorophenyl, methoxyphenyl, trimethoxyphenyl, methylphenyl, biphenyl, naphthyl, phenanthryl or anthryl, the C4-C8 heteroaryl group containing a hetero oxygen atom, sulfur atom or nitrogen atom is thiophene; in the R2, the C3-C6 naphthenic base is cyclohexyl, the C6-C10 aryl is methylphenyl, fluorophenyl, methoxyphenyl or naphthyl, and the C4-C8 heteroaryl containing one oxygen atom, sulfur atom or nitrogen heteroatom is substituted pyrrole, thiophene or benzofuran; the C1-C5 alkyl or substituted alkyl in the R3 is methyl, methoxy or trifluoromethyl.
3. The method for the kinetic resolution of tertiary aromatic allyl alcohol catalyzed by chiral phosphoric acid according to claim 1, wherein the tertiary aryl allyl alcohol compound represented by formula I is selected from one of the following compounds:
4. the method for the kinetic resolution of tertiary aromatic allyl alcohol catalyzed by chiral phosphoric acid according to claim 1, wherein the reaction temperature is-30 ℃ to 10 ℃, preferably-10 ℃ to 0 ℃; the organic solvent is at least one of dichloromethane, toluene, 1, 2-dichloroethane, carbon tetrachloride, tetrahydrofuran, acetonitrile, trifluorotoluene, chloroform and n-hexane, preferably chloroform.
5. The method for kinetic resolution of allyl tertiary alcohol catalyzed by chiral phosphoric acid according to claim 1, wherein the mass ratio of the catalyst to the compound of formula I is 10-20: 100, preferably 15: 100; the ratio of the amount of the substance of the compound represented by the formula I to the volume of the organic solvent is 0.025-0.5: 1, preferably 0.2:1, the amount of the substance is in mmol, and the volume is in mL.
6. The method for kinetic resolution of tertiary aromatic allyl alcohol catalyzed by chiral phosphoric acid as claimed in claim 1, wherein the additive is molecular sieve type
Molecular sieve,
Molecular sieves or
Molecular sieves, preferably
A molecular sieve; the ratio of the mass of the molecular sieve to the mass of the compound shown in the formula I is 1-2.0: 1, preferably 1.6:1, the unit of the mass is g, and the unit of the mass is mmol.
7. The method of claim 1, wherein the chiral phosphoric acid-catalyzed aryl allyl tertiary alcohol compound is selected from one of the following chiral phosphoric acid catalysts represented by formula II:
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