CN110092730A - method for preparing α -hydroxy- β -amino acid compound - Google Patents

method for preparing α -hydroxy- β -amino acid compound Download PDF

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CN110092730A
CN110092730A CN201810096500.8A CN201810096500A CN110092730A CN 110092730 A CN110092730 A CN 110092730A CN 201810096500 A CN201810096500 A CN 201810096500A CN 110092730 A CN110092730 A CN 110092730A
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halogen
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CN110092730B (en
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张晓梅
王周玉
蒋珍菊
代兴杰
翁光林
谭平
黄敏
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Xihua University
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Abstract

the invention discloses a method for preparing an optically active N-acyl-alpha-hydroxy- β -amino ester compound shown in a formula II from α -acyloxy- β -enamine ester compound by a one-pot method.

Description

A method of preparing optically active alpha-hydroxyl-beta-aminophenol class compound
Technical field
The present invention relates to a kind of methods for preparing optically active alpha-hydroxyl-beta-aminophenol class compound.
Background technique
Optically active alpha-hydroxyl-beta-aminophenol is a kind of very important structural unit, is widely present in natural products And in drug molecule, wherein foremost have anti-cancer medicine paclitaxel, ubenimex, glycopeptide Dideoxykanamicin A Deng.Therefore, the synthesis of optically active alpha-hydroxyl-beta-aminophenol derivative causes extensive and lasting interest, many for many years More research groups have developed a variety of efficient, highly selective synthetic methods, mainly there is Sharpless asymmetric hydroxylamination and double Hydroxylation reaction, chiral epoxy compound ring-opening reaction, asymmetric nitro Aldol reaction, asymmetric Mannich reaction, 1,3- is even Polar ring addition reaction and other reactions.But optically active Alpha-hydroxy-β-is obtained by the direct asymmetric reduction of enamine The report of amino acid derivativges is also seldom.
2011, inventor, which once designed, synthesized a kind of N- aryl-α-acetoxyl group-β-enamine ester substrate, with hexatomic ring Shape chiral pyridyl benzamide type Lewis-base catalyst is catalyzed the asymmetric hydrosilylation reaction of this kind of substrate, has obtained good Yield, cis-selectivity and enantioselectivity (reaction equation A).
N- aryl-α-acetoxyl group-β-enamine ester asymmetric hydrosilylation reaction of formula A chirality lewis base catalysis
Similar α-acetoxyl group-β-acrylamide ester substrate has also been synthesized with post-tensioning thread Mu Deng, has been catalyzed with chiral phosphine ligand Its asymmetric hydrogenation has been similarly obtained good result.
Although inventor successfully passes through N- aryl-α-acetoxyl group-β-enamine ester of chiral lewis base catalysis not The active alpha-hydroxyl-beta-aminophenol derivative of symmetric hydrogenation Silanization reaction synthesizing optical, but this method there is also it is following not Foot place: 1, reaction substrate synthesis is difficult, and synthetic route is long, condition is harsh, yield is low, and the scope of application is not wide, and α can only Acetoxyl group, acyl group volume it is slightly larger you can't get；It 2, be through when converting paclitaxel lateral chain molecule for reaction product Deacetylation, de- p-methoxyphenyl, benzoylation three-step reaction are crossed, at there are reaction steps long, cumbersome, intermediate product Reason difficulty, inefficient problem (formula B).
The synthesis of formula B paclitaxel lateral chain
Summary of the invention
Based on the above issues, the present invention is intended to provide a kind of one kettle way directly to synthesize such as paclitaxel lateral chain optically active Alpha-hydroxyl-beta-aminophenol class compound, can effectively shorten reaction step, improve reaction efficiency.
Inventor wishes to carry out asymmetric hydrosilylation reaction, obtained alpha-acyloxy-β-by the route of synthesis of formula C After amino ester, then through post-processing under alkaline condition, exchange to obtain N- acyl-alpha-hydroxy-beta-amino ester by intramolecular urethane, this Direct taxol biosynthesis side chain of one kettle way and the like can be realized in sample, can effectively shorten reaction step, improve reaction effect Rate (formula C).
The reaction of formula C alpha-acyloxy-β-enamine ester asymmetric hydrosilylation is imagined
Inventor has found a kind of novel six membered ring shape pyridine carboxamide-sulfonic acid esters lewis base in the course of the research (formula III compound) shows good catalytic activity, very high cis-selectivity and enantioselectivity, utilizes The compound successfully can obtain a series of optically active N- acyl-alpha-hydroxy-beta-amino esters by one pot reaction.
Based on above-mentioned discovery, the present invention provides compounds as follows as alpha-acyloxy-β-enamine ester type compound The purposes of the catalyst in N- acyl-alpha-hydroxy-beta-amino ester compound is prepared by asymmetric hydrosilylation reaction:
Wherein, R4Quantity be 1~5, be selected from H, C1-C6 alkyl or halogenated alkyl, CH3- (CH2) n-O-, nitro, halogen Plain, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C5-C6 heteroaryl, wherein n=0-4；Further, it takes Dai Ji is selected from C1-C6 alkyl or halogenated alkyl, halogen or alkoxy；Further, R4Selected from H, methyl, methoxyl group, trifluoro Methyl, nitro, pyrimidine radicals, halogen, phenyl, benzyloxy；
R5Selected from H, C1-C6 alkyl or halogenated alkyl, CH3- (CH2) n-O-, nitro, halogen, substituted or unsubstituted C6- C10 aryl, substituted or unsubstituted C5-C6 heteroaryl, wherein n=0-4；Further, substituent group is selected from C1-C6 alkyl or halogen Substituted alkyl, halogen or alkoxy；Further, R5Selected from H, methyl, trifluoromethyl, phenyl, 4- aminomethyl phenyl, 4- isopropyl Phenyl, 4- methoxyphenyl, pentafluorophenyl group, naphthalene, 4- nitrobenzophenone, 3,5- 3,5-dimethylphenyl.
Meanwhile on the basis of raw catelyst, the present invention also provides from alpha-acyloxy-β-one pot of enamine ester type compound The method that method prepares N- acyl-alpha-hydroxy-beta-amino ester compound shown in Formula II, reaction equation are as follows:
Wherein, the C of * label is chiral carbon, and R1, R2, R3 are not H；
It is catalyst that formula III compound is used in the reaction:
Wherein, R4Quantity be 1~4, be selected from H, C1-C6 alkyl or halogenated alkyl, CH3- (CH2) n-O-, nitro, halogen Plain, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C5-C6 heteroaryl, wherein n=0-4；Further, it takes Dai Ji is selected from C1-C6 alkyl or halogenated alkyl, halogen or alkoxy；Further, R4Selected from H, methyl, methoxyl group, trifluoro Methyl, nitro, pyrimidine radicals, halogen, phenyl, benzyloxy；
R5Selected from H, C1-C6 alkyl or halogenated alkyl, CH3- (CH2) n-O-, nitro, halogen, substituted or unsubstituted C6- C10 aryl, substituted or unsubstituted C5-C6 heteroaryl, wherein n=0-4；Further, substituent group is selected from C1-C6 alkyl or halogen Substituted alkyl, halogen or alkoxy；Further, R5Selected from H, methyl, trifluoromethyl, phenyl, 4- aminomethyl phenyl, 4- isopropyl Phenyl, 4- methoxyphenyl, pentafluorophenyl group, naphthalene, 4- nitrobenzophenone, 3,5- 3,5-dimethylphenyl.
In the present invention,Indicate that configuration is uncertain.Its configuration includes one of following:
In a specific embodiment of the invention, the catalyzed compound of preparation is comprised the following structure:
It is found in a specific embodiment of the invention, works as R4Selected from trifluoromethyl, nitro or halogen, the halogen is selected from Cl, Br or I, R5When selected from 4- aminomethyl phenyl or 4- methoxyphenyl, preferable catalytic effect can achieve.Such as compound 1b、1e、1g、1i、1c、1d。
It further finds, works as R4Selected from trifluoromethyl, nitro or Cl, R5Selected from 4- aminomethyl phenyl or 4- methoxybenzene When base, preferable catalytic effect can achieve.Such as compound 1b, 1e, 1g, 1i.Certainly, from the point of view of current experiment, 1e and 1i catalytic effect is more excellent.
Wherein, in step 1, the dosage of catalyst is 5~15%mol% of compound of formula I.
Wherein, the reaction temperature in step 1 is controlled at 0 DEG C or less；It is further selected from -40~0 DEG C.
Wherein, reaction dissolvent used in step 1 is selected from CH2Cl2、CHCl3、ClCH2CH2Cl、CCl4, toluene, dimethylbenzene, The combination of one or more of trimethylbenzene, ether, tetrahydrofuran.
Wherein, additive is also used in step 1, the additive is selected from one or more kinds of groups of water, organic acid It closes；Further, the organic acid includes HCOOH, PhCOOH, pentafluoro benzoic acid, p-NO2C6H4COOH、p-ClC6H4COOH、p- CH3C6H4COOH、p-CH3OC6H4COOH, p-tert-butyl benzoic acid, 4- (trifluoromethyl) benzoic acid, o-NO2C6H4COOH, spy penta The combination of one or more of acid, PhCOOH.
Wherein, the additive amount is 0.5-1.5 times of Compound I.
Wherein, alkali described in step 2 is selected from inorganic base；Further, the inorganic base includes potassium carbonate or sodium carbonate.
Wherein, R1 is selected from the heteroaryl of the aryl of substituted or unsubstituted C6~C10, substituted or unsubstituted C5~C6, Hetero atom is selected from one of N, O, S；Further, substituent group is selected from halogen, C1-C6 alkyl, CH3- (CH2) n-O-, wherein N is selected from 0-4 or substituent group collectively forms the naphthenic base or heterocycle of 3-7 member with the atom on the aryl or heteroaryl being connect Alkyl；Further, R1 is selected from phenyl, 4-FC6H4、4-ClC6H4、4-BrC6H4、4-CH3C6H4、4-CH3OC6H4、3- ClC6H4、2-BrC6H4, 3,4- (methylenedioxy) benzyl, 2- naphthalene, 2- thienyl, 2- furyl, benzyl；
R2 is selected from the heteroaryl of the aryl of substituted or unsubstituted C6~C10, substituted or unsubstituted C5~C6, hetero atom Selected from one of N, O, S；Further, substituent group is selected from halogen, C1-C6 alkyl or halogenated alkyl, nitro, CH3- (CH2) N-O-, wherein n is selected from 0-4；Further, R2 is selected from 4-FC6H4、4-ClC6H4、4-BrC6H4、4-NO2C6H4、4- CF3C6H4、4-CH3C6H4、4-CH3OC6H4、4-tBuC6H4、3-CH3OC6H4、2-ClC6H4, 2- naphthalene, 2- thienyl, 2- furans Base；
R3 is selected from C1-C6 alkyl or cycloalkyl；Further, R3 is selected from methyl, isopropyl, cyclohexyl.
The step of previous reaction, is as follows by verbal description:
Reaction mass (such as catalyst, alpha-acyloxy-β-enamine ester type compound, trichlorosilane) is taken to be added to reaction molten It in agent, reacts at a lower temperature, then heats to room temperature, aqueous slkali is added, reacts at room temperature, isolate and purify up to optics Active N- acyl-alpha-hydroxy-beta-amino ester.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific embodiment of form by the following examples remakes further specifically above content of the invention It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention The technology realized all belongs to the scope of the present invention.
Specific embodiment
Raw material, equipment used in the specific embodiment of the invention are known product, are obtained by purchase commercial product.
Embodiment 1
Wherein, Cat is the abbreviation of catalyst provided by the invention
Step: dichloromethane is added in catalyst (0.01mmol) and alpha-acyloxy-β-enamine ester (0.1mmol) and benzoic acid Alkane is cooled to certain temperature, is added trichlorosilane (31ul, 0.3mmol), and mixture reacts 72 hours, then heats to room temperature, Unsaturated carbonate potassium solution is added, is stirred at room temperature 72 hours, is extracted with ethyl acetate three times, merges organic layer sodium sulphate or sulphur Sour magnesium is dry, and solvent is removed in decompression, product by column chromatographic purifying, enantiomeric excess (ee value) and diastereomeric excess (dr value) by Chiral column is analyzed to obtain optically active N- acyl-alpha-hydroxy-beta-amino ester.
Table 1
28 R3=Me 80 >20:1 97
29 R3=i-Pr 98 >20:1 97
30 R3=Cy 99 >20:1 99.7
(2S, 3S) -2- hydroxyl -3- benzamido -3- phenylpropionate: white solid, M.p.:160-161 DEG C, 97%yield, > 99:1dr, 95%ee, HPLC condition: Chiralpak AD-H (n-hexane/isopropyl Alcohol: 60/40,1.0mL/min, tmajor=5.5,10.9) [α]D 20=-38.5 (c1, CHCl3)(lit.[2][α]D 25=-40.3 (c1,CHCl3).1H NMR(300MHz,CDCl3) δ 7.81 (d, J=6.9Hz, 2H), 7.53-7.28 (m, 8H), 7.21 (d, J= 8.6Hz,1H),5.63(dd,J1=8.6Hz, J2=3.5Hz), 4.68 (br s, 1H), 4.20-4.10 (m, 2H), 3.22 (br S, 1H), 1.24 (t, J=7.1Hz, 3H), HRMS (ESI) Calcd for C18H19NO4Na+[M+Na]+336.1206；Found: 336.1209.
(2S, 3S) -2- hydroxyl -3- benzamido -3- p-fluorophenyl ethyl propionate: white is solid Body, m.p.:152-153 DEG C, 89%yield, > 99:1dr, 87%ee, HPLC condition: Chiralpak AD-H (n-hexane/different Propyl alcohol: 60/40,1.0mL/min, t=4.7,9.4) [α]D 20=-38.7 (c 1, CHCl3). 1H NMR(300MHz,CDCl3) δ7.85-7.80(m,2H),7.37-7.30(m,5H),7.14-7.08(m,3H),5.60(dd,J1=8.6Hz, J2=3.5Hz, 1H), 4.69-4.66 (m, 1H), 4.18-4.12 (m, 2H), 3.15 (d, J=6.3Hz, 1H), 1.25 (t, J=7.1Hz, 3H) .13C NMR(75MHz,CDCl3)δ171.7,166.5,165.5,163.2,136.5,129.5,129.4,128.6,128.4, 127.6,115.8,115.5,72.8,62.3,55.5,14.1.RMS(ESI)Calcd forC18H18FNO4Na+[M+Na]+ 354.1112；Found:354.1129.
(2S, 3S) -2- hydroxyl -3- benzamido -3- rubigan ethyl propionate: white is solid Body, m.p.:163-164 DEG C, 90%yield, > 99:1dr, 92%ee, HPLC condition: Chiralpak AD-H (n-hexane/different Propyl alcohol: 60/40,1.0mL/min, t=4.9,5.5,8.5,14.1) [α]D 20=-35.8 (c1, CHCl3).1H NMR (300MHz, DMSO) δ 8.86 (d, J=9.0Hz, 1H), 7.83-7.80 (m, 2H), 7.53-7.43 (m, 5H), 7.38 (d, J= 8.5Hz, 1H), 5.98 (s, 1H), 5.31 (t, J=8.6Hz, 1H), 4.40 (d, J=8.2Hz, 1H), 4.12-3.99 (m, 2H), 1.09 (t, J=7.1Hz, 3H),13C NMR(75MHz,DMSO)δ172.1,165.8,138.8,134.2,132.0,131.5, 130.2,128.3,127.9,127.4,72.8,60.4,54.9,14.1.HRMS(ESI)Calcd forC18H18ClNO4Na+[M+ Na]+370.0817；Found:370.0811.
(2S, 3S) -2- hydroxyl -3- benzamido -3- p-bromophenyl ethyl propionate: white is solid Body, m.p.:160-161 DEG C, 99%yield, > 99:1dr, 98%ee, HPLC condition: Chiralpak AD-H (n-hexane/different Propyl alcohol: 60/40,1.0mL/min, t=5.9,17.3) [α]D 20=-41.6 (c1, CHCl3).1H NMR(300MHz,CDCl3)δ 7.81-7.78(m,2H),7.54-7.41(m,5H),7.27-7.19(m,3H),5.57(dd,J1=8.5Hz, J2=3.6Hz, 1H), 4.67-4.64 (m, 1H), 4.21-4.11 (m, 2H), 3.25 (d, J=5.3Hz, 1H), 1.25 (t, J=7.2Hz, 3H) .13C NMR(75MHz,CDCl3)δ171.5,166.6,135.8,133.8,131.8,131.6,129.4,128.6,127.0, 122.4,62.4,54.9,14.1.HRMS(ESI)Calcd forC18H18BrNO4Na+[M+Na]+414.0311；Found: 414.0320.
(2S, 3S) -2- hydroxyl -3- benzamido -3- p-methylphenyl ethyl propionate: white Solid, m.p.:132-133 DEG C, 96%yield, > 99:1dr, 97%ee, HPLC condition: Chiralpak AD-H (n-hexane/ Isopropanol: 60/40,1.0mL/min, t=5.9,11.6) [α]D 20=-32.8 (c1, CHCl3). 1H NMR(300MHz, CDCl3)δ7.82-7.79(m,2H),7.45-7.40(m,3H),7.26-7.24(m,2H),7.13-7.10(m,3H),5.59 (dd,J1=8.6Hz, J2=3.5Hz, 1H), 4.68 (br s, 1H), 4.63-4.12 (m, 2H), 3.13 (br s, 1H), 2.31 (s,1H),1.29-1.23(m,3H).13C NMR(75MHz,CDCl3)δ171.8,166.6,138.0,134.1,133.5, 131.6,129.2,128.5,127.5,127.0,72.9,62.1,55.2,21.1,14.1.HRMS(ESI)Calcd forC19H21NO4Na+[M+Na]+350.1363；Found:350.1363.
(2S, 3S) -2- hydroxyl -3- benzamido -3- p-methoxyphenyl ethyl propionate: White solid, m.p.:143-144 DEG C, 99%yield, > 99:1dr, 94%ee, HPLC condition: Chiralpak AD-H (just oneself Alkane/isopropanol: 60/40,1.0mL/min, t=6.6,11.9) [α]D 20=-37.1 (c1, CHCl3).1H NMR(300MHz, CHCl3) δ 7.80-7.78 (m, 2H), 7.51-7.37 (m, 3H), 7.29 (d, J=8.7Hz, 2H), 7.22 (d, J=8.5Hz, 1H),5.57(dd,J1=8.5, J2=3.5Hz, 1H), 4.64 (dd, J1=5.7, J2=3.6Hz, 2H), 3.75 (s, 3H), 3.37 (d, J=6.1Hz, 1H), 1.23 (t, J=7.1Hz, 3H),13C NMR(75MHz,CHCl3)δ171.8,166.5, 159.3,134.0,131.6,128.8,128.7,128.4,127.0,113.8,72.9,62.0,55.1,54.8,14.0.HRMS (ESI)Calcd forC19H21NO5Na+[M+Na]+366.1312；Found:366.1319.
(2S, 3S) -2- hydroxyl -3- benzamido -3- (3- chlorphenyl) ethyl propionate: white Solid, m.p.:150-151 DEG C, 98%yield, > 99:1dr, 94%ee, HPLC condition: Chiralpak AD-H (n-hexane/ Isopropanol: 70/30,1.0mL/min, t=10.5,13.8) [α]D 20=-42.1 (c1, CHCl3). 1H NMR(300MHz, CDCl3) δ 7.80 (d, J=2.8Hz, 2H), 7.53-7.42 (m, 4H), 7.38-7.24 (m, 4H), 5.58 (dd, J1=8.1Hz, J2=3.2Hz, 1H), 4.64 (d, J=2.8Hz, 1H), 4.19-4.13 (m, 2H), 3.44 (br s, 1H), 1.25 (t, J= 7.0Hz,3H).13C NMR(75MHz,CDCl3)δ171.4,166.6,138.7,134.3,133.7,131.8,129.7, 128.6,128.4,127.9,127.1,125.9,72.6,62.4,55.0,14.0.HRMS(ESI)HRMS(ESI)Calcd forC18H18ClNO4Na+[M+Na]+370.0817；Found:370.0814.
(2S, 3S) -2- hydroxyl -3- benzamido -3- (2- bromophenyl) ethyl propionate: white is solid Body, m.p.:118-119 DEG C, 91%yield, > 99:1dr, 91%ee, HPLC condition: Chiralpak AD-H (n-hexane/second Alcohol: 70/30,1.0mL/min, t=11.3,18.3) [α]D 20=-35.4 (c1, CHCl3).1H NMR(300MHz,CDCl3)δ 7.83-7.80(m,2H),7.52-7.40(m,5H),7.32-7.29(m,1H),7.24-7.15(m,2H),5.57(dd,J1= 8.6Hz,J2=3.6Hz, 1H), 4.65 (br s, 1H), 4.18 (q, J=7.1Hz, 2H), 3.23 (br s, 1H), 1.28 (t, J =7.1Hz, 3H)13C NMR(75MHz,CDCl3)δ171.4,166.6,139.0,133.8,131.9,131.4,130.9, 130.0,128.6,127.1,126.3,122.5,72.6,62.5,54.9,29.7,14.1.HRMS(ESI)HRMS(ESI) Calcd forC18H18BrNO4Na+[M+Na]+414.0311；Found:414.0317.
(2S, 3S) -2- hydroxyl -3- benzamido -3- (3,4- (methylene-dioxy) benzene Base) ethyl propionate: white solid, m.p.:139-140 DEG C, 94%yield, 93:7dr, 89%ee, HPLC condition: Chiralpak AD-H (n-hexane/isopropanol: 60/40,1.0mL/min, t=6.3,12.1) [α]D 20=-20.1 (c1, CHCl3).1H NMR(300MHz,CHCl3) δ 7.81-7.78 (m, 2H), 7.50-7.39 (m, 3H), 7.18 (d, J=8.3Hz, 1H),6.88-6.84(m,1H),6.83-6.81(m,1H),6.73-6.71(m,1H),5.91(s,2H),5.53-5.49(m, 1H), 4.63 (d, J=3.3Hz, 1H), 4.20-4.10 (m, 2H), 3.29 (br s, 1H), 1.26 (t, J=7.1Hz, 3H),13C NMR(75MHz,CHCl3)δ171.6,166.5,147.6,147.3,133.9,131.6,130.4,128.4,127.0,121.2, 108.0,107.9,101.0,72.8,62.1,55.1,14.0.HRMS(ESI)Calcd forC19H19NO6Na+[M+Na]+ 380.1105；Found:380.1103.
(2S, 3S) -2- hydroxyl -3- benzamido -3- (betanaphthyl) ethyl propionate: white is solid Body, m.p.:177-178 DEG C, 91%yield, > 99:1dr, 89%ee, HPLC condition: Chiralpak AD-H (n-hexane/different Propyl alcohol: 60/40,1.0mL/min, t=7.0,19.1) [α]D 20=-45.3 (c1, CHCl3).1H NMR(300MHz,CHCl3)δ 7.85-7.78(m,7H),7.48-7.36(m,7H), 5.80(dd,J1=8.3Hz, J2=3.2Hz, 1H), 4.13 (q, J= 7.1Hz, 2H), 3.38 (br s, 1H), 1.23 (t, J=7.1Hz, 3H),13C NMR(75MHz,CHCl3)δ171.7,166.7, 134.1,134.0,133.1,133.0,131.7,128.6,128.3,127.9,127.6,127.1,127.0,126.23, 126.16,125.3,73.0,62.2,55.5,14.1.HRMS(ESI)Calcd forC22H21NO4Na+[M+Na]+386.1363； Found:386.1359.
(2S, 3S) -2- hydroxyl -3- benzamido -3- (1- thienyl) ethyl propionate: white Solid, m.p.:160-161 DEG C, 92%yield, 85:15dr, 87%ee, HPLC condition: Chiralpak AD-H (n-hexane/ Ethyl alcohol: 70/30,1.0mL/min, t=12.0,13.9) [α]D 20=-32.6 (c1, CHCl3).1H NMR(300MHz,CHCl3) δ7.80-7.76(anti)(m,1.72H),7.730-7.725(syn)(m,0.30H),7.53-7.48(m,1H),7.45-7.39 (m,2H),7.08-7.03(m,2H),6.99-6.97(syn)(m,0.18H),6.95-6.93(anti)(m,0.95H),4.34- 4.25 (syn) (m, 0.25H), 4.19 (anti) (q, J=7.1Hz, 1.79H), 3.61 (syn) (d, J=4.5Hz, 0.14H), 3.43 (anti) (d, J=5.7Hz, 0.85H), 1.32-1.30 (syn) (m, 0.39H), 1.25 (anti) (t, J=7.1Hz, 3H),13C NMR(75MHz,CHCl3)δ171.4,166.4,138.3,133.8,131.8,128.5,127.1,126.6, 126.5,125.6,72.6,62.4,51.5,14.0.HRMS(ESI)HRMS(ESI)Calcd forC18H18BrNO4Na+[M+Na ]+414.0311；Found:414.0317.
(2S, 3S) -2- hydroxyl -3- benzamido -3- (1- furyl) ethyl propionate: white Color solid, m.p.:160-161 DEG C, 92%yield, > 99:1dr, 82%ee, HPLC condition: Chiralpak AD-H (just oneself Alkane/isopropanol: 60/40,1.0mL/min, t=5.0,6.3) [α]D 20=-36.1 (c1, CHCl3).1H NMR(300MHz, CHCl3) δ 7.45 (s, 1H), 7.41-7.27 (m, 5H), 7.11 (d, J=3.5Hz, 1H), 6.48 (dd, J1=3.3Hz, J2= 1.7Hz,1H),5.57(dd,J1=8.9Hz, J2=3.5Hz, 1H), 4.65 (d, J=3.4Hz, 1H), 4.19-4.06 (m, 2H), 3.26 (s, 1H), 1.23 (t, J=7.1Hz, 3H),13C NMR(75MHz,CHCl3)δ171.6,157.5,147.5,144.1, 136.3,128.4,128.3,127.6,114.7,112.1,72.8,62.2,54.6,14.0.HRMS(ESI)Calcd forC18H18BrNO4Na+[M+Na]+414.0311；Found:414.0317.
(2S, 3S) -2- hydroxyl -3- benzamido -3- benzyl ethyl propionate: white liquid, 87: 13dr, 96%yield, 66:34dr, 80%ee, HPLC condition: Chiralpak AD-H (n-hexane/isopropanol: 60/40, 1.0mL/min, t=5.5,7.2) [α]D 20=-22.8 (c1, CHCl3).1H NMR(300MHz,CHCl3) δ 7.68 (d, J= 7.2Hz, 2H), 7.46-7.42 (m, 1H), 7.36-7.20 (m, 7H), 6.78 (d, J=8.8Hz, 1H), 4.87-4.79 (m, 1H), 4.39 (anti) (d, J=3.2Hz, 0.13H), 4.21 (syn) (d, J=1.7Hz, 0.85H), 4.16-4.08 (m, 2H), 3.11-2.91 (m, 2H), 1.18 (t, J=7.0Hz, 3H),13C NMR(75MHz,CHCl3)δ173.6,167.2,137.3, 134.2,131.4,129.3,128.5,128.4,126.9,126.6,70.2,62.1,53.3,37.7,13.9.HRMS(ESI) Calcd forC19H21NO4Na+[M+Na]+350.1363；Found:350.1352.
(2S, 3S) -2- hydroxyl -3- is to fluorobenzoyl amido -3- phenylpropionate: white solid, M.p.:160-161 DEG C, 91%yield, > 99:1dr, 91%ee, HPLC condition: Chiralpak AD-H (n-hexane/isopropyl Alcohol: 60/40,1.0mL/min, t=5.6,10.6) and [α]D 20=-33.8 (c1, CHCl3).1H NMR(300MHz,CDCl3)δ 7.84-7.79 (m, 2H), 7.37-7.28 (m, 5H), 7.19 (d, J=8.5Hz, 1H), 7.12-7.05 (m, 2H), 5.60 (dd, J1=8.6Hz, J2=3.5Hz, 1H), 4.66 (dd, J1=5.7Hz, J2=3.5Hz, 1H), 4.17-4.09 (m, 2H), 3.27 (d, J=6.1Hz, 1H), 1.24 (t, J=7.1Hz, 3H)13C NMR(75MHz,CHCl3)δ171.7,165.6,164.8(1J =250.5Hz), 136.4,130.17 (4J=3.1Hz), 129.4 (3), J=8.9Hz 128.5,128.3,127.6,115.6 (2J =21.8Hz) .HRMS (ESI) Calcd forC18H18BrNO4Na+[M+Na]+414.0311；Found:414.0317.
(2S, 3S) -2- hydroxyl -3- is to chloro-benzoyl amino -3- phenylpropionate: white solid, M.p.:139-140 DEG C, 88%yield, > 99:1dr, 93%ee, HPLC condition: Chiralpak AD-H (n-hexane/ethyl alcohol: 70/30,1.0mL/min t=15.1,18.4) [α]D 20=-43.0 (c1, CHCl3).1H NMR(300MHz,CDCl3)δ7.74 (d, J=8.5Hz, 2H), 7.40-7.29 (m, 7H), 7.19 (d, J=8.5Hz, 1H), 5.60 (dd, J1=8.5Hz, J2= 3.5Hz, 1H), 4.66 (br s, 1H), 4.19-4.09 (m, 2H), 3.24 (br s, 1H), 1.24 (t, J=7.1Hz, 3H),13C NMR(75MHz,CDCl3)δ171.6,165.6,137.9,136.4,132.4,128.8,128.5,128.4,127.6,72.8, 62.2,55.5,14.0.HRMS(ESI)Calcd forC18H18ClNO4Na+[M+Na]+370.0817；Found:370.0811.
(2S, 3S) -2- hydroxyl -3- is to Bromophenacyl amido -3- phenylpropionate: white solid, M.p.:157-158 DEG C, 94%yield, 99:1dr, 90%ee, HPLC condition: Chiralpak AD-H (n-hexane/isopropanol: 60/40,1.0mL/min t=7.1,21.5) [α]D 20=-51.5 (c1, CHCl3).1H NMR(300MHz,CDCl3)δ7.67 (d, J=8.4Hz, 2H), 7.57-7.54 (m, 2H), 7.34-7.29 (m, 5H), 7.19 (d, J=8.5Hz, 1H), 5.59 (dd, J1=8.6Hz, J2=3.5Hz, 1H), 4.67 (br s, 1H), 4.20-4.11 (m, 2H), 3.21 (br s, 1H), 1.24 (t, J2 =4.0Hz, 3H),13C NMR(75MHz,CDCl3)δ171.6,165.7,136.3,132.9,131.8,128.7,128.5, 128.4,127.6,126.4,72.7,62.2,55.5,14.0.HRMS(ESI)Calcd forC18H18BrNO4Na+[M+Na]+ 414.0311；Found:414.0315.
(2S, 3S) -2- hydroxyl -3- p-nitrophenyl formamido -3- phenylpropionate: white solid, M.p.:157-158 DEG C, 95%yield, > 99:1dr, 91%ee, HPLC condition: Chiralpak AD-H (n-hexane/isopropyl Alcohol: 60/40,1.0mL/min, t=6.8,10.3) [α]D 20=-51.5 (c1, CHCl3).1H NMR(300MHz,CHCl3)δ 8.19 (d, J=8.7Hz, 2H), 7.94-7.91 (m, 2H), 7.53 (d, J=8.5Hz, 1H), 7.36-7.27 (m, 5H), 5.59 (dd,J1=8.5Hz, J2=3.5Hz, 1H), 4.67-4.64 (m, 1H), 4.15-4.08 (m, 2H), 3.51 (d, J=5.9Hz, 1H), 1.21 (t, J=7.2Hz, 3H),13C NMR(75MHz,CHCl3)δ171.4,164.7,149.4,139.5,136.0, 128.5,128.4,128.3,127.5,123.6,72.6,62.2,55.7,13.9.HRMS(ESI)Calcd forC18H18BrNO4Na+[M+Na]+414.0311；Found:414.0315.
(2S, 3S) -2- hydroxyl -3- is to trifluoromethyl benzamide base -3- phenylpropionate: white is solid Body, m.p.:157-158 DEG C, 99%yield, > 99:1dr, 87%ee, HPLC condition: Chiralpak AD-H (n-hexane/different Propyl alcohol: 60/40,1.0mL/min, t=6.9,14.3) [α]D 20=-41.6 (c1, CHCl3).1H NMR(300MHz,CDCl3)δ 7.90 (d, J=8.1Hz, 2H), 7.66 (d, J=8.2Hz, 2H), 7.38-7.29 (m, 6H), 5.61 (dd, J1=8.6Hz, J2= 3.6Hz,1H),4.67(dd,J1=6.2Hz, J2=3.6Hz, 1H), 4.21-4.06 (m, 2H), 3.34 (d, J=6.3Hz, 1H), 1.24 (t, J=7.1Hz, 3H)13C NMR(75MHz,CHCl3)δ171.5,165.4,137.3,136.2,133.3(1J= 32.7Hz),128.5,128.4,127.6,125.5178(2J=11.1Hz), 125.5177 (3), J=3.7Hz 121.7,72.7, 62.3,55.6,14.0.HRMS(ESI)Calcd forC18H18BrNO4Na+[M+Na]+414.0311；Found:414.0315.
(2S, 3S) -2- hydroxyl -3- is to toluyl amido -3- phenylpropionate: white solid, M.p.:154-155 DEG C, 95%yield, > 99:1dr, 94%ee, HPLC condition: Chiralpak AD-H (n-hexane/isopropyl Alcohol: 60/40,1.0mL/min, t=6.0,19.5) [α]D 20=-44.9 (c1, CHCl3).1H NMR(300MHz,CDCl3)δ 7.70 (d, J=8.1Hz, 2H), 7.37-7.27 (m, 6H), 7.21 (d, J=8.0Hz, 2H), 5.61 (dd, J1=8.6Hz, J2= 3.5Hz, 1H), 4.66 (d, J=2.9Hz, 1H), 4.14-4.08 (m, 2H), 3.42 (br s, 1H), 2.38 (s, 1H), 1.22 (t, J=7.1Hz, 3H),13C NMR(75MHz,CDCl3)δ171.7,166.6,142.1,136.7,131.2,129.1, 128.4,128.1,127.6,127.0,72.9,62.1,55.4,21.4,14.0.HRMS(ESI)HRMS(ESI)Calcd forC18H21NO4Na+[M+Na]+350.1363；Found:350.1365.
(2S, 3S) -2- hydroxyl -3- is to methoxy benzamide base -3- phenylpropionate: white is solid Body, m.p.:157-158 DEG C, 86%yield, > 99:1dr, 94%ee, HPLC condition: Chiralpak AD-H (n-hexane/different Propyl alcohol: 60/40,1.0mL/min, t=6.9,25.5) [α]D 20=-41.8 (c1, CHCl3).1H NMR(300MHz,CHCl3)δ 7.80-7.70 (m, 2H), 7.37-7.29 (m, 5H), 7.12 (d, J=8.9Hz, 1H), 5.63-5.59 (m, 1H), 4.67 (d, J =2.8Hz, 1H), 4.20-4.09 (m, 2H), 3.84 (s, 3H), 3.19 (br s, 1H), 1.27-1.24 (m, 3H),13C NMR (75MHz,CHCl3)δ171.8,166.1,162.3,136.7,128.9,128.5,128.2,127.6,126.3,113.7, 72.9,62.2,55.4,14.0.HRMS(ESI)Calcd forC18H21NO4Na+[M+Na]+350.1363；Found: 350.1365.
(2S, 3S) -2- hydroxyl -3- is to t-butylbenzamide base -3- phenylpropionate: white is solid Body, m.p.:136-137 DEG C, 86%yield, 97:3dr, 92%ee, HPLC condition: Chiralpak AD-H (n-hexane/isopropyl Alcohol: 60/40,1.0mL/min, t=7.8,17.8) [α]D 20=-45.6 (c1, CHCl3).1H NMR(300MHz,CDCl3)δ 7.79 (d, J=8.3Hz, 2H), 7.50-7.47 (m, 2H), 7.41-7.34 (m, 5H), 7.24 (d, J=8.6Hz, 1H), 5.66 (dd,J1=8.6Hz, J2=3.5Hz, 1H), 4.71 (d, J=3.4Hz, 1H), 4.24-4.13 (m, 2H), 3.25 (br s, 1H), 1.36 (s, 9H), 1.28 (t, J=7.1Hz, 3H),13C NMR(75MHz,CDCl3)δ171.8,166.5,155.2,136.7, 131.2,128.5,128.3,127.6,126.9,125.5,72.9,62.2,55.4,34.9,31.1,14.1.HRMS(ESI) HRMS(ESI)Calcd forC22H27NO4Na+[M+Na]+392.1832；Found:392.1820.
(2S, 3S) -2- hydroxyl -3- meta-methoxy benzamido -3- phenylpropionate: white is solid Body, m.p.:124-125 DEG C, 99%yield, > 99:1dr, 99%ee, HPLC condition: Chiralpak AD-H (n-hexane/second Alcohol: 70/30,1.0mL/min, t=9.7,14.8) [α]D 20=-31.9 (c1, CHCl3).1H NMR(300MHz,CDCl3)δ 7.38-7.29 (m, 8H), 7.20 (d, J=8.4Hz, 1H), 7.06-7.02 (m, 1H), 5.61 (dd, J1=8.6Hz, J2= 3.5Hz, 1H), 4.68 (br s, 1H), 4.19-4.11 (m, 2H), 3.83 (s, 3H), 3.19 (br s, 1H), 1.24 (t, J= 7.1Hz,3H),13C NMR(75MHz,CDCl3)δ171.7,166.5,159.8,136.5,135.6,129.5,128.5, 128.3,127.6,118.8,117.8,112.6,72.8,62.2,55.5,55.4,14.0.HRMS(ESI)HRMS(ESI) Calcd forC19H21NO5Na+[M+Na]+366.1312；Found:366.1314.
(2S, 3S) -2- hydroxyl -3- m-methyl benzamide base -3- phenylpropionate: white solid, M.p.:144-145 DEG C, 93%yield, > 99:1dr, 93%ee, HPLC condition: Chiralpak AD-H (n-hexane/isopropyl Alcohol: 60/40,1.0mL/min, t=6.2,15.1) [α]D 20=-57.8 (c1, CHCl3).1H NMR(300MHz,CDCl3)δ 7.62-7.59 (m, 2H), 7.35-7.30 (m, 7H), 7.14 (d, J=8.3Hz, 1H), 5.62 (dd, J1=8.7Hz, J2= 3.3Hz, 1H), 4.70-4.67 (m, 1H), 4.20-4.11 (m, 2H), 3.11 (d, J=6.4Hz, 1H), 2.40 (s, 3H), 1.25 (t, J=7.0Hz, 3H),13C NMR(75MHz,CDCl3)δ171.8,166.8,138.5,136.6,134.1,132.4, 128.51,128.46,128.3,127.7,127.6,124.1,72.9,62.2,55.4,21.3,14.1.HRMS(ESI)HRMS (ESI)Calcd forC19H21NO4Na+[M+Na]+350.1363；Found:350.1362.
(2S, 3S) -2- hydroxyl -3- neighbour's chloro-benzoyl amino -3- phenylpropionate: white solid, M.p.:112-113 DEG C, 90%yield, > 99:1dr, 91%ee, HPLC condition: Chiralpak AD-H (n-hexane/isopropyl Alcohol: 60/40,1.0mL/min, t=5.9,7.6) [α]D 20=-21.8 (c1, CHCl3).1H NMR(300MHz,CDCl3)δ 7.68-7.65(m,1H),7.51-7.28(m,9H),5.64(dd,J1=8.6Hz, J2=3.4Hz, 1H), 4.68 (br s, 1H), 4.20-4.09 (m, 2H), 3.14 (d, J=5.8Hz, 1H), 1.26 (t, J=7.1Hz, 3H),13C NMR(75MHz,CDCl3)δ 171.5,165.5,136.1,134.4,131.4, 130.7,130.3,130.2,128.4,128.3,127.7,127.0, 72.8,62.1,55.7,14.0.HRMS(ESI)HRMS(ESI)Calcd forC18H18ClNO4Na+[M+Na]+370.0817； Found:370.0808.
(2S, 3S) -2- hydroxyl -3- betanaphthyl formamido -3- phenylpropionate: white solid, M.p.:169-170 DEG C, 81%yield, > 99:1dr, 98%ee, HPLC condition: Chiralpak AD-H (n-hexane/ethyl alcohol: 70/30,1.0mL/min t=25.5,30.3) [α]D 20=-121.9 (c1, CHCl3).1H NMR(300MHz,CHCl3)δ 8.33(1H,s),7.93-7.85(m,4H),7.59-7.51(m,2H),7.40-7.31(m,6H),5.69(dd,J1=8.5Hz, J2=3.3Hz, 1H), 4.74 (d, J=3.3Hz, 1H), 4.17-4.12 (m, 2H), 3.34 (s, 1H), 1.25 (t, J=7.0Hz, 5H) .7.80-7.70 (m, 2H), 7.37-7.29 (m, 5H), 7.12 (d, J=8.9Hz, 1H), 5.63-5.59 (m, 1H), 4.67 (d, J=2.8Hz, 1H), 4.20-4.09 (m, 2H), 3.84 (s, 3H), 3.19 (br s, 1H), 1.27-1.24 (m, 3H),13C NMR(75MHz,CHCl3)δ171.8,166.7,136.6,134.8,132.5,131.2,128.9,128.5,128.4,128.3, 127.7,127.64,127.58,126.72,123.6,72.9,62.2,55.6,14.0.HRMS(ESI)Calcd forC22H21NO4Na+[M+Na]+386.1363；Found:386.1361.
(2S, 3S) -2- hydroxyl -3- (2- thiophene) formamido -3- phenylpropionate: white is solid Body, m.p.:162-163 DEG C, 98%yield, > 99:1dr, 89%ee, HPLC condition: Chiralpak AD-H (n-hexane/different Propyl alcohol: 60/40,1.0mL/min, t=5.0,8.3) [α]D 20=-27.2 (c1, CHCl3).1H NMR(300MHz,CDCl3)δ 7.57-7.56(m,1H),7.48-7.47(m,1H),7.37-7.28(m,5H),7.09-7.05(m,2H),5.58(dd,J1= 8.6Hz,J2=3.6Hz, 1H), 4.62 (d, J=3.5Hz, 1H), 4.20-4.10 (m, 2H), 3.25 (br s, 1H), 1.23 (t, J=7.1Hz, 3H),13C NMR(75MHz,CDCl3)δ171.7,161.1,138.5,136.4,130.3,128.5,128.4, 128.3,127.6,72.8,62.2,55.4,14.0.HRMS(ESI)HRMS(ESI)Calcd forC16H17NO4SNa+[M+Na]+ 342.0770；Found:342.0760.
(2S, 3S) -2- hydroxyl -3- (2- furans) formamido -3- phenylpropionate: white solid, M.p.:144-145 DEG C, 91%yield, > 99:1dr, 99%ee, HPLC condition: Chiralpak AD-H (n-hexane/ethyl alcohol: 70/30,1.0mL/min t=8.2,10.0) [α]D 20=-57.8 (c1, CHCl3).1H NMR(300MHz,CDCl3)δ7.46- 7.45(m,1H),7.38-7.27(m,6H),7.11(dd,J1=3.5Hz, J2=0.7Hz, 1H), 6.48 (dd, J1=3.5Hz, J2=1.8Hz, 1H), 5.58 (dd, J1=8.9Hz, J2=3.6Hz, 1H), 4.65 (dd, J1=6.3Hz, J2=3.6Hz, 1H), 4.19-4.10 (m, 2H), 3.18 (d, J=6.4Hz, 1H), 1.24 (t, J=7.2Hz, 3H),13C NMR(75MHz,CHCl3)δ 171.6,157.4,147.6,144.1,136.3,128.5,128.3,127.6,114.7,112.2,72.8,62.2,54.6, 14.0.HRMS(ESI)Calcd forC18H16NO5Na+[M+Na]+326.1023；Found:326.1018.
(2S, 3S) -2- hydroxyl -3- benzamido -3- phenylpropionic acid methyl ester: white solid, White solid, m.p.:158-159 DEG C of (lit.[4]m.p.:158-159℃；lit.[5]m.p.:158-159℃；lit.[6]m.p.: 178-181 DEG C), 80%yield, > 99:1dr, 97%ee, HPLC condition: Chiralpak AD-H (n-hexane/ethyl alcohol: 70/ 30,1.0mL/min, t=8.0,11.0) [α]D 20=-23.1 (c1, CHCl3)(lit.[7][α]D 20=-23 (c1, CHCl3)； (lit.[8][α]D 20=-28.8 (c1, CHCl3)；(lit.[4][α]D 20=-23.7 (c1.1, CHCl3)；(lit.[5][α]D 20=+ 8.7(c1.03,MeOH).1H NMR(300MHz,CDCl3)δ7.83-7.79(m,2H),7.43-7.34(m,3H),7.33-7.30 (m, 5H), 7.23 (d, J=8.4Hz, 1H), 5.62 (dd, J1=8.6Hz, J2=8.6Hz, 1H), 4.70 (br s, 1H), 3.71 (s, 3H), 3.24 (d, J=4.3Hz, 3H), the same as literature.[4-8]HRMS(ESI)HRMS(ESI)Calcd forC17H17NO4Na+[M+Na]+322.1050；Found:322.1041.
(2S, 3S) -2- hydroxyl -3- benzamido -3- phenylpropionate: white is solid Body, m.p.:108-109 DEG C, 98%yield, > 99:1dr, 97%ee, HPLC condition: Chiralpak AD-H (n-hexane/different Propyl alcohol: 60/40,1.0mL/min, t=5.0,10.8) [α]D 20=-22.3 (c1, CHCl3).1H NMR(300MHz,CDCl3)δ 7.80-7.79 (m, 2H), 7.52-7.39 (m, 5H), 7.34-7.27 (m, 3H), 7.23 (d, J=3.8Hz, 1H), 5.61 (dd, J1=8.7Hz, J2=3.6Hz, 1H), 4.99-4.91 (m, 1H), 4.65-4.63 (m, 1H), 3.28 (d, J=5.5Hz, 1H), 1.23 (d, J=6.3Hz, 3H), 1.16 (d, J=6.3Hz, 3H),13C NMR(75MHz,CDCl3)δ171.2,166.5, 136.6,134.1,131.6,128.5,128.4,128.2,127.8,127.0,72.8,70.4,55.3,21.7,21.6.HRMS (ESI)HRMS(ESI)Calcd forC19H21NO4Na+[M+Na]+350.1363；Found:350.1377.
(2S, 3S) -2- hydroxyl -3- benzamido -3- phenylpropionic acid cyclohexyl ester: white is solid Body, m.p.:142-143 DEG C, 99%yield, > 99:1dr, 99.7%ee, HPLC condition: Chiralpak AD-H (n-hexane/ Isopropanol: 60/40,1.0mL/min, t=4.6,8.5) [α]D 20=-30.4 (c1, CHCl3).1H NMR(300MHz,CDCl3) δ 7.82-7.80 (m, 2H), 7.43-7.38 (m, 5H), 7.31-7.29 (m, 3H), 7.20 (d, J=8.4Hz, 1H), 5.62 (dd, J1=8.7Hz, J2=3.5Hz, 1H), 4.75-4.66 (m, 2H), 3.19 (br s, 1H), 1.83-1.71 (m, 4H), 1.43- 1.26(m,6H),13C NMR(75MHz,CDCl3)δ171.2,166.5,136.6,134.1,131.6,128.5,128.4, 128.3,127.8,127.1,75.4,72.9,55.3,31.5,31.4,25.1,23.71,23.67.HRMS(ESI)Calcd forC22H25NO4Na+[M+Na]+390.1676；Found:390.1665.
The catalytic effect of 2 different catalysts of embodiment is tested
Step: dichloromethane solution is added in catalyst (0.01mmol) and alpha-acyloxy-β-enamine ester (0.1mmol) In, it is cooled to zero degree, is added trichlorosilane (31ul, 0.3mmol), mixture reacts 72 hours, then heats to room temperature, is added Saturated sodium carbonate solution is stirred at room temperature 72 hours, is extracted with ethyl acetate three times, merges organic layer sodium sulphate or magnesium sulfate Dry, solvent is removed in decompression, and product is by column chromatographic purifying, and enantiomeric excess (ee value) and diastereomeric excess (dr value) are by chirality Column is analyzed to obtain optically active N- acyl-alpha-hydroxy-beta-amino ester.Acquired results are shown in Table 2.
The catalytic effect of 2 different catalysts of table
Number Catalyst Yield (%) Dr value (%) Ee value (%)
1 1a 67 90 40
2 1b 82 94 70
3 1c 81 94 60
4 1d 81 94 56
5 1e 81 94 75
6 1f 82 94 35
7 1g 84 96 71
8 1h 74 90 38
9 1i 81 96 78
According to the result of table 2 as can be seen that the structure of above-mentioned catalyst significantly affects catalytic effect, 9 catalysis Preferable with 1b, 1c, 1d, 1e, 1g, 1i in agent and more preferable with 1b, 1e, 1g, 1i, 1e, 1i are more very.
Influence of 3 different solvents of embodiment to reaction
Step: catalyst (0.01mmol) and alpha-acyloxy-β-enamine ester (0.1mmol) are added (two in different solvents Chloromethanes, chloroform, dichloroethanes, carbon tetrachloride, toluene, ortho-xylene, trimethylbenzene, ether, tetrahydrofuran, acetonitrile etc.), drop Temperature is added trichlorosilane (31ul, 0.3mmol), mixture reacts 72 hours, then heats to room temperature, and saturation is added to zero degree Sodium carbonate liquor is stirred at room temperature 72 hours, is extracted with ethyl acetate three times, merges organic layer sodium sulphate or magnesium sulfate is dry Dry, solvent is removed in decompression, and product is by column chromatographic purifying, and enantiomeric excess (ee value) and diastereomeric excess (dr value) are by chiral column Analysis obtains optically active N- acyl-alpha-hydroxy-beta-amino ester.It the results are shown in Table 3.
Influence of 3 different solvents of table to reaction
Number Solvent Yield (%) Diastereomeric excess (%) Enantiomeric excess (%)
1 CH2Cl2 81 96 78
2 CHCl3 80 80 73
3 ClCH2CH2Cl 80 92 70
4 CCl4 78 90 58
5 Toluene 81 90 56
6 Xylene 73 92 57
7 Mesitylene 61 92 53
8 Ether 67 98 77
9 THF 84 82 28
10 CH3CN 27 92 53
As shown in Table 3, the difference of reaction dissolvent also has a significant impact catalytic effect, in above-mentioned 10 kinds of solvents, with CH2Cl2、CHCl3、ClCH2CH2Cl and ether good catalytic activity, but when use ether, yield is lower；Comprehensively consider, CH2Cl2 Catalytic effect is best.
The influence of 4 different additive of embodiment and post-processing alkali to reaction
Step: by catalyst (0.01mmol) and alpha-acyloxy-β-enamine ester (0.1mmol) and benzoic acid (0.1mmol) Methylene chloride is added, is cooled to zero degree, is added trichlorosilane (31ul, 0.3mmol), mixture reacts 72 hours, then heats up To room temperature, saturated sodium carbonate or solution of potassium carbonate is added, is stirred at room temperature 72 hours, is extracted with ethyl acetate three times, is associated with Machine layer sodium sulphate or magnesium sulfate are dry, and solvent is removed in decompression, and product is by column chromatographic purifying, enantiomeric excess (ee value) and non-right Body excessive (dr value) is reflected to be analyzed to obtain optically active N- acyl-alpha-hydroxy-beta-amino ester by chiral column.
The influence of 4 different additive of table and post-processing alkali to reaction
The above results prove that the addition of additive has certain influence to catalytic effect, the influence especially on yield compared with To be significant, according to upper table as a result, the additive in the present invention further selects HCOOH, PhCOOH, p-NO2C6H4COOH, and with PhCOOH effect is best.
The influence of 5 different temperatures of embodiment and catalyst loadings to reaction
Step: by catalyst (0.01mmol) and alpha-acyloxy-β-enamine ester (0.1mmol) and different additives (water, Formic acid, benzoic acid, pentafluoro benzoic acid, paranitrobenzoic acid, parachlorobenzoic-acid, P-methoxybenzoic acid, p-tert-butyl benzoic acid, To trifluoromethylbenzoic acid, o-nitrobenzoic acid, pivalic acid) methylene chloride is added, it is cooled to zero degree, trichlorosilane is added (31ul, 0.3mmol), mixture react 72 hours, then heat to room temperature, and unsaturated carbonate potassium solution is added, is stirred at room temperature It 72 hours, is extracted with ethyl acetate three times, merges organic layer sodium sulphate or magnesium sulfate is dry, solvent is removed in decompression, and product passes through Column chromatographic purifying, enantiomeric excess (ee value) and diastereomeric excess (dr value) are analyzed to obtain optically active N- acyl by chiral column Base-Alpha-hydroxy-beta-amino ester.
The influence of 5 different temperatures of table and catalyst loadings to reaction
The above results show that catalyst loadings are 10%, and when temperature is spent for -40, catalytic effect is better than other conditions.
The preparation of 6 catalyst of embodiment
It weighs pyridine-2-carboxylic acids (2.2mmol, 1.1eq) to be dissolved under condition of ice bath in 15mL methylene chloride, then successively It weighing EDCI (2.4mmol, 1.2eq), HOBT (2.4mmol, 1.2eq), DIEA (4.0mmol, 2eq) is added into reaction solution, 10-15min is stirred under ice bath, 2- aminocyclohexyl alcohol hydrochloride (2.0mmol, 1.0eq) is eventually adding, warms naturally to room temperature mistake Night reaction；After reaction, revolving removes methylene chloride, is then dissolved with ethyl acetate, saturated sodium bicarbonate solution is added to wash, Organic phase is collected in layering, then ethyl acetate extraction (15mL × 3), merges organic phase, anhydrous magnesium sulfate is dry, silicon after concentration Rubber column gel column purifies to obtain picolinamide cyclohexanol.5mL dichloro will be dissolved under picolinamide cyclohexanol (1mmol, 1eq) ice bath of synthesis It in methane, then sequentially adds triethylamine (3mmol, 3eq), DMAP (0.1mmol, 0.1eq), stirs 0.5h under ice bath, finally It is added to sulfonic acid chloride (2mmol, 2eq) is replaced, warms naturally to ambient temperature overnight reaction；TLC is monitored after the reaction was completed, and revolving removes After solvent, silica gel column purification obtains 1a (55% yield).
1a: white solid, m.p:119-120 DEG C, 60% yield1H NMR(400MHz,CDCl3)δ 8.53 (d, J=4.7Hz, 1H), 8.11 (d, J=7.8Hz, 1H), 7.85 (d, J=1.7Hz, 1H), 7.68 (d, J=8.3Hz, 2H), 7.46-7.43 (m, 1H), 7.04 (d, J=8.1Hz, 2H), 4.59-4.53 (m, 1H), 4.16-4.04 (m, 1H), 2.28 (s,3H),2.17-2.13(m,2H),1.82–1.63(m,3H),1.50–1.26(m,3H).13C NMR(100MHz,CDCl3)δ 163.8,149.7,147.9,144.1,137.2,134.2,129.5,127.5,126.1,122.2,82.8,51.7,32.3, 31.6,31.0,23.9,21.6.[α]D 20=-35.1 (c0.5, CH2Cl2)；HRMS(ESI)Calcd for[C19H22N2O4S+H]+ 375.1373；Found:375.1384.
1b: white solid, m.p:101-102 DEG C, 53% yield1H NMR(300MHz,CDCl3)δ 8.42 (d, J=5.2Hz, 1H), 8.08 (d, J=2.0Hz, 1H), 7.96 (d, J=8.6Hz, 1H), 7.66 (d, J=8.2Hz, 2H), 7.43 (dd, J=5.2,2.2Hz, 1H), 7.07 (d, J=8.2Hz, 1H), 4.59-4.51 (m, 1H), 4.09-3.98 (m, 1H),2.30(s,3H),2.17-2.03 (m,2H),1.81-1.62(m,3H),1.45-1.32(m,3H).13C NMR(75MHz, CDCl3)δ162.6,151.1,148.8,145.6,144.2,134.2,129.4,127.5,126.2,122.8,82.6,52.0, 32.2,31.5,23.9,21.5.[α]D 20=-37.1 (c0.5, CH2Cl2).HRMS(ESI)Calcd for[C19H21ClN2O4S+ Na]+431.0803；Found:431.0801.
1c: white solid, m.p:115-116 DEG C, 60% yield1H NMR(300MHz,CDCl3)δ 8.85 (d, J=5.2Hz, 1H), 8.78 (d, J=2.1Hz, 1H), 8.16-8.14 (m, 1H), 8.07 (d, J=9.1Hz, 1H), 7.69 (d, J=8.2Hz, 2H), 7.14 (d, J=8.3Hz, 2H), 4.62-4.53 (m, 1H), 4.12-4.02 (m, 1H), 2.31 (s,3H),2.20-2.17(m,1H),2.05-2.01(m,1H),1.80-1.61(m,3H),1.46-1.24(m,3H),13C NMR (75MHz,CDCl3)δ161.7,155.0,153.0,150.3,144.4,134.2,129.5,127.4,118.4,115.2, 82.4,52.4,32.0,31.5,23.9,23.8,21.5.[α]D 20=-30.0 (c0.5, CH2Cl2)；HRMS(ESI)Calcd for[C19H21Br N2O4S+H]+453.0478；Found:453.0487.
1d: white solid, m.p:127-128 DEG C, 67% yield1H NMR(300MHz,CDCl3)δ 8.44 (d, J=1.5Hz, 1H), 8.15 (d, J=5.1Hz, 1H), 7.92 (d, J=7.9Hz, 1H), 7.80 (d, J=5.0Hz, 1H), 7.64 (d, J=8.1Hz, 2H), 7.06 (d, J=8.1Hz, 2H), 4.59-4.50 (m, 1H), 4.08-3.96 (m, 1H), 2.30(s,3H),2.14-2.09(m,2H),1.80-1.61(m,3H),1.44-1.25(m,3H),13C NMR(75MHz, CDCl3)δ162.4,149.9,148.1,144.2,135.2,134.2,131.7,129.4,127.4,106.5,82.6,51.9, 32.2,31.5,23.8,21.6.[α]D 20=-29.5 (c0.5, CH2Cl2)；HRMS(ESI)Calcd for[C19H21IN2O4S+H ]+501.0339；Found:501.0356.
1e: white solid, m.p:124-125 DEG C, 65% yield1H NMR(300MHz,CDCl3)δ 8.85 (d, J=5.2Hz, 1H), 8.79 (d, J=2.1Hz, 1H), 8.16 (dd, J=2.2,5.3Hz, 1H), 8.08 (d, J= 8.9Hz, 1H), 7.68 (d, J=8.3Hz, 2H), 7.13 (d, J=8.3Hz, 2H), 4.59-4.54 (m, 1H), 4.14-4.03 (m,1H),2.31(s,3H),2.22-2.17(m,1H),2.06-2.00(m,1H),1.81-1.64(m,2H),1.43-1.25 (m,4H),13C NMR(75MHz,CDCl3)δ161.8,155.1,153.1,150.3,144.4,134.4,129.5,127.5, 118.4,115.2,82.3,52.5,32.0,31.5,23.93,23.86,21.5.[α]D 20=-30.0 (c0.5, CH2Cl2)； HRMS(ESI)Calcd for[C19H21N3O6S+H]+420.1224；Found:420.1239.
1f: white solid, m.p:126-127 DEG C, 63% yield1H NMR(300MHz, CDCl3) δ 8.15 (d, J=2.8Hz, 1H), 8.03 (d, J=8.7Hz, 1H), 7.78 (d, J=8.7Hz, 1H), 7.65 (d, J= 8.2Hz, 2H), 7.28-7.24 (m, 1H), 7.04 (d, J=8.0Hz, 2H), 4.56-4.47 (m, 1H), 4.09-4.00 (m, 1H),3.91(s,3H),2.28(s,3H),2.17-2.11(m,2H),1.79-1.60(m,3H),1.42-1.25(m,3H),13C NMR(75MHz,CDCl3)δ163.7,157.7,144.0,142.5,136.2,134.2,129.4,127.5,123.3,120.0, 82.8,55.7,51.6,32.2,31.6,23.8,21.5.[α]D 20=-44.5 (c0.5, CH2Cl2).；HRMS(ESI)Calcd for[C20H24N2O5S+H]+405.1479；Found:405.1475.
1g: white solid, 45% yield1H NMR(300MHz,CDCl3) δ 8.29 (d, J= 7.7Hz, 1H), 8.04 (t, J=7.9Hz, 1H), 7.88 (d, J=8.7Hz, 1H), 7.84-7.77 (m, 1H), 7.66 (d, J= 8.3Hz, 2H), 7.02 (d, J=8.2Hz, 2H), 4.63-4.55 (m, 1H), 4.18-3.95 (m, 1H), 2.22 (s, 3H), 2.19–2.07(m,2H),1.93–1.63(m,3H),1.54–1.30(m,3H).13C NMR(100MHz,CDCl3)δ162.4, 150.1,144.1,138.9,134.3,129.4,127.5,124.9,122.6,82.7,52.2,32.4,31.5,26.9, 24.0,23.9,21.5.
1h: white solid, m.p:75-76 DEG C, 45% yield1H NMR(300MHz,CDCl3)δ 8.35-8.33 (m, 1H), 8.09 (d, J=9.5Hz, 1H), 7.66 (d, J=8.3Hz, 2H), 7.58-7.55 (m, 1H), 7.30 (dd, J=4.6Hz, 1H), 7.01 (d, J=8.0Hz, 2H), 4.57-4.49 (m, 1H), 4.07-3.96 (m, 1H), 2.66 (s, 3H),2.26(s,3H),2.19-2.04(m,2H),1.80-1.69(m,3H),1.45–1.26(m,3H).13C NMR(100MHz, CDCl3)δ165.3,146.8,145.2,144.0,140.7,135.5,134.3,129.4,127.5,125.6,83.1,51.6, 32.4,31.7,24.0,24.0,21.6,20.6.HRMS(ESI):m/z calcd.for[C20H24N2O4S+H]+389.1457, found389.1530.
1i: white solid, m.p.:63-64 DEG C, 62%yield.1H NMR(300MHz,CDCl3)δ 8.82 (d, J=5.3Hz, 1H), 8.73 (d, J=2.1Hz, 1H), 8.16-8.13 (m, 1H), 8.00 (d, J=8.7Hz, 1H), 7.70 (d, J=11.9Hz, 2H), 6.75-6.70 (m, 2H), 4.60-4.52 (m, 1H), 4.10-3.98 (m, 1H), 3.75 (s, 3H),2.17-2.06(m,2H),1.70-1.24(m,6H),13C NMR(75MHz,CDCl3)δ163.2,161.6,154.9, 152.9,150.2,129.6,128.7,118.3,115.1,114.0,82.4,55.5,52.4,32.2,31.4,23.9.[α]D 20 =-44.5 (c0.5, CH2Cl2), HRMS (ESI) Calcd for [C19H21N3O7S++H]+436.1173；Found:436.1180.

Claims (10)

1. from N- acyl-alpha-hydroxy-beta-amino ester shown in alpha-acyloxy-β-enamine ester type compound one kettle way preparation formula II The method for closing object, it is characterised in that: its reaction equation is as follows:
Wherein, the C of * label is chiral carbon；R1, R2, R3 are not H；
It is catalyst that formula III compound is used in the reaction:
Wherein, R4Quantity be 1~4, be selected from H, C1-C6 alkyl or halogenated alkyl, CH3- (CH2) n-O-, nitro, halogen, substitution Or unsubstituted C6-C10 aryl, substituted or unsubstituted C5-C6 heteroaryl, wherein n=0-4；Further, substituent group is selected from C1-C6 alkyl or halogenated alkyl, halogen or alkoxy；Further, R4Selected from H, methyl, methoxyl group, trifluoromethyl, nitre Base, pyrimidine radicals, halogen, phenyl, benzyloxy；Preferably, R4 be selected from trifluoromethyl, nitro, halogen, the halogen be selected from Cl, Br, I；
R5Selected from H, C1-C6 alkyl or halogenated alkyl, CH3- (CH2) n-O-, nitro, halogen, substituted or unsubstituted C6-C10 virtue Base, substituted or unsubstituted C5-C6 heteroaryl, wherein n=0-4；Further, substituent group is selected from C1-C6 alkyl or alkyl halide Base, halogen or alkoxy；Further, R5Selected from H, methyl, trifluoromethyl, phenyl, 4- aminomethyl phenyl, 4- cumene Base, 4- methoxyphenyl, pentafluorophenyl group, naphthalene, 4- nitrobenzophenone, 3,5- 3,5-dimethylphenyl；Preferably, R5 is selected from 4- methylbenzene Base, 4- methoxyphenyl.
2. according to the method described in claim 1, it is characterized by: the catalyst is selected from such as one of flowering structure:
3. compound according to claim 1 or 2, it is characterised in that: the compound is selected from one of following:
4. according to the method described in claim 1, it is characterized by: trichlorosilane mole dosage is compound of formula I in step 1 1~3 times；The dosage of catalyst is 5~15%mol% of compound of formula I, is further selected from 10%.
5. according to the method described in claim 1, it is characterized by: reaction temperature is controlled at 0 DEG C or less in step 1；Further Selected from -40~0 DEG C, it is further selected from -40 DEG C.
6. according to the method described in claim 1, it is characterized by: reaction dissolvent used in step 1 is selected from CH2Cl2、 CHCl3、ClCH2CH2Cl、CCl4, toluene, dimethylbenzene, trimethylbenzene, ether, one or more of tetrahydrofuran group It closes；Further, the reaction dissolvent is selected from CH2Cl2、CHCl3、ClCH2CH2Cl, ether.
7. according to the method described in claim 1, the additive is selected from it is characterized by: also using additive in step 1 The a combination of one or more of water, organic acid；Further, the organic acid includes HCOOH, PhCOOH, phenyl-pentafluoride first Acid, p-NO2C6H4COOH、p-ClC6H4COOH、p-CH3C6H4COOH、p-CH3OC6H4COOH, p-tert-butyl benzoic acid, 4- (trifluoro Methyl) benzoic acid, o-NO2C6H4The combination of one or more of COOH, pivalic acid, PhCOOH；Further, institute State 0.5-1.5 times that additive amount is compound of formula I.
8. according to the method described in claim 1, it is characterized by: alkali described in step 2 is selected from inorganic base；Further, described Inorganic base includes potassium carbonate or sodium carbonate.
9. according to the method described in claim 1, it is characterized by: R1 is selected from the aryl of substituted or unsubstituted C6~C10, takes The heteroaryl of generation or unsubstituted C5~C6, hetero atom are selected from one of N, O, S；Further, substituent group be selected from halogen, C1-C6 alkyl, CH3- (CH2) n-O-, wherein n is selected from 0-4 or substituent group and the original on the aryl or heteroaryl being connect Son collectively forms the naphthenic base or Heterocyclylalkyl of 3-7 member；Further, R1 is selected from phenyl, 4-FC6H4、4-ClC6H4、4- BrC6H4、4-CH3C6H4、4-CH3OC6H4、3-ClC6H4、2-BrC6H4, 3,4- (methylenedioxy) benzyl, 2- naphthalene, 2- thienyl, 2- Furyl, benzyl；
R2 is selected from the heteroaryl of the aryl of substituted or unsubstituted C6~C10, substituted or unsubstituted C5~C6, and hetero atom is selected from N, one of O, S；Further, substituent group is selected from halogen, C1-C6 alkyl or halogenated alkyl, nitro, CH3- (CH2) n-O-, Wherein, n is selected from 0-4；Further, R2 is selected from 4-FC6H4、4-ClC6H4、4-BrC6H4、4-NO2C6H4、4-CF3C6H4、4- CH3C6H4、4-CH3OC6H4、4-tBuC6H4、3-CH3OC6H4、2-ClC6H4, 2- naphthalene, 2- thienyl, 2- furyl；
R3 is selected from C1-C6 alkyl or cycloalkyl；Further, R3 is selected from methyl, isopropyl, cyclohexyl.
It is made 10. compound as follows is reacted as alpha-acyloxy-β-enamine ester type compound by asymmetric hydrosilylation The purposes of catalyst in standby N- acyl-alpha-hydroxy-beta-amino ester compound:
Wherein, R4Quantity be 1~5, be selected from H, C1-C6 alkyl or halogenated alkyl, CH3- (CH2) n-O-, nitro, halogen, substitution Or unsubstituted C6-C10 aryl, substituted or unsubstituted C5-C6 heteroaryl, wherein n=0-4；Further, substituent group is selected from C1-C6 alkyl or halogenated alkyl, halogen or alkoxy；Further, R4Selected from H, methyl, methoxyl group, trifluoromethyl, nitre Base, pyrimidine radicals, halogen, phenyl, benzyloxy；
R5Selected from H, C1-C6 alkyl or halogenated alkyl, CH3- (CH2) n-O-, nitro, halogen, substituted or unsubstituted C6-C10 virtue Base, substituted or unsubstituted C5-C6 heteroaryl, wherein n=0-4；Further, substituent group is selected from C1-C6 alkyl or alkyl halide Base, halogen or alkoxy；Further, R5Selected from H, methyl, trifluoromethyl, phenyl, 4- aminomethyl phenyl, 4- cumene Base, 4- methoxyphenyl, pentafluorophenyl group, naphthalene, 4- nitrobenzophenone, 3,5- 3,5-dimethylphenyl.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101792361A (en) * 2010-02-25 2010-08-04 西华大学 Reductive amination method of aldehyde
CN103467223A (en) * 2013-09-16 2013-12-25 西华大学 Green conjugated double bond reduction method

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101792361A (en) * 2010-02-25 2010-08-04 西华大学 Reductive amination method of aldehyde
CN103467223A (en) * 2013-09-16 2013-12-25 西华大学 Green conjugated double bond reduction method

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DONG PEI等: "S-Chiral Sulfinamides as Highly Enantioselective Organocatalysts", 《ORGANIC LETTERS》 *
YAN JIANG等: "Highly Diastereoselective and Enantioselective Synthesis of a-Hydroxy b-Amino Acid Derivatives: Lewis Base Catalyzed Hydrosilylation of a-Acetoxy b-Enamino Esters", 《ANGEW.CHEM.INT.ED.》 *
ZHOUYU WANG等: "L-Piperazine-2-carboxylic Acid Derived N-Formamide as a Highly Enantioselective Lewis Basic Catalyst for Hydrosilylation of N-Aryl Imines with an Unprecedented Substrate Profile", 《ORGANIC LETTERS》 *
扈晓艳 等: "A-二芳基甲酮亚胺的不对称催化氢化硅烷化反应研究", 《有机化学》 *

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