CN102531911B - Chiral bicyclics compound and method of asymmetric synthesis thereof - Google Patents
Chiral bicyclics compound and method of asymmetric synthesis thereof Download PDFInfo
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- 0 CC(*)(C1[C@]([C@@]2*)C(C3)=O)[C@]3(*)C1[C@@]2[N+]([O-])=O Chemical compound CC(*)(C1[C@]([C@@]2*)C(C3)=O)[C@]3(*)C1[C@@]2[N+]([O-])=O 0.000 description 1
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Abstract
The invention discloses a kind of chiral bicyclics compound and method of asymmetric synthesis thereof, the structure of described chiral bicyclics compound is such as formula shown in (I).The present invention be with structure such as formula the cyclohexenone derivates shown in (II) and structure such as formula the nitroolefin derivative shown in (III) for substrate, under the co-catalysis of chirality secondary amine catalyst, polyglycol series compound and acid, be obtained by reacting structure such as formula the chiral bicyclics compound shown in (I) in organic solvent.The chiral bicyclics compound of the present invention's synthesis has chirality, can be used as the synthetic intermediate of chipal compounds, has broad application prospects.
Description
(1) technical field
The present invention relates to a kind of chiral bicyclics compound and method of asymmetric synthesis thereof.
(2) background technology
Chirality is natural base attribute, is also one of most important attribute of Living system.As the protein of the large basic substance of life entity three, nucleic acid and polysaccharide, they are nearly all exist with single configuration in life entity.For life entity, the enantiomorph of many chipal compounds has distinct physiologically active, and therefore to have optically active organic compound is the challenge task that chemist faces in synthesis, is also one of the most popular in recent years research topic.Beyond any doubt, the most effective means of chipal compounds are prepared in asymmetric synthesis, and catalysis asymmetric synthesis is optimal method of asymmetric synthesis, it only uses a small amount of chiral catalyst just can obtain a large amount of chiral product, is most effective tool such as exploitation chiral drug, agrochemicals, material and spices etc.Catalysis method of asymmetric synthesis can be divided three classes according to catalyst nature: transition metal-catalyzed, enzyme catalysis and asymmetric organocatalysis.In recent years, metal-free organocatalysis more and more received publicity, and was becoming another focus that chemical field is studied after metal catalyst.Asymmetric organocatalysis is from mimetic enzyme catalysis, the compatible gradually advantage of biocatalysis and chemical catalysis, relative to the organic ligand in transition metal complex, the catalytic activity of organic catalyst is organic compound itself, do not need transition metal and other metal, have more inexpensive, be easy to get, nontoxic, to water and the many merits such as oxygen is relatively stable.Simultaneously owing to there is not transition metal, the reaction product of organic catalyst catalysis does not just need the pollution considering metal, and this provides guarantee to the greenization that medicine, agricultural chemicals etc. synthesize.
Supramolecular chemistry, it is the new chemical branch grown up from beginning of the seventies late 1960s, be one based on non covalent bond, take molecule as the chemistry subject of research object, in molecular recognition, catalysis, information transmission, molecular self-assembling, supramolecular materials, molecular device etc., have many important application.The development of organic catalysis is the catalytic way of analogue enztme, and enzyme can think that it is a kind of organic supermolecular of complexity, so organic supermolecular being applied to the research of catalysis aspect is have scientific value and potential using value.The application of supramolecule in catalysis simultaneously often can significantly improve reactive behavior and reaction preference, and the nowadays application of this respect more and more comes into one's own.2010, what Escuder Research team had used a kind of novelty carrys out 1 of catalysis of pimelinketone and nitroolefin by the supermolecular gel compound of unit molecule self-assembly, 4 additions, it is exactly the object that just can be reached separation by the pH value changing reaction system simply by simple filter operation that this supermolecular catalysis agent has a significant advantage, there is extraordinary using value (Chem.Eur.J.2010,16,8480).In the same year sieve three and Cheng Jin train seminar and dexterously the derivative of supramolecule beta-cyclodextrin and cyclohexanediamine passed through covalent bonds, and the supermolecular catalysis agent of it synthesis is applied in the aldol reaction of aldehyde ketone, achieve good effect, chirality adduct (the J.Am.Chem.Soc.2010 being greater than 99% can be obtained through reaction, 132,7216).These achievements in research have enriched the kind of supermolecular catalysis reaction, but, the research work in this field just just starts, the catalyzer that further exploration is new and reaction type, and then research and develop its application in the fields such as asymmetry organic synthesis, and final obtain the reaction system with good asymmetric induction effect, will be an important emerging research field in Modern Green Chemistry.
The chirality bicyclic alkenes compounds with skeleton 1 is the important chiral reagent of class, it is applied to chirality asymmetry catalysis by the chiral ligand being widely used as rhodium and iridium, excellent chiral induction function (Angew.Chem.Int.Ed.2004,43,3364) is served in part reaction.But the synthetic method of complexity limits the fast development (Angew.Chem.Int.Ed.2008,47,4482) of chirality bicyclic alkenes compounds as chiral ligand.2010, Carnell developed from chirality enol ester through intermediate chirality two ring cyclohexadione compounds 2 and then the simple and easy method (Angew.Chem.Int.Ed.2010,49,2750) synthesizing a class chirality bicyclic alkenes compounds 1.
Therefore, the invention is intended to the advantage design and synthesis one class chipal compounds of development in conjunction with chiral technology and supermolecular catalysis, explore the route of an easy synthesizing chiral compound especially chirality bicyclic alkenes compounds 1.
(3) summary of the invention
First goal of the invention of the present invention is to provide a class chiral bicyclics compound, and described chiral bicyclics compound has chirality, can be used as the synthetic intermediate of chipal compounds (such as chirality bicyclic alkenes compounds).。
Chiral bicyclics compound of the present invention, its structure is such as formula shown in (I):
In formula (I),
R
1, R
2, R
3respective is independently the alkyl of H or C1 ~ C20;
R
4be selected from one of following: H, the alkyl of C1 ~ C20, 2-methoxyl-styrene, 3-methoxyl-styrene, 4-methoxyl-styrene, 2-methyl styrene base, 3-vinyl toluene base, 4-vinyl toluene base, styryl, the fluorine-based styryl of 2-, the fluorine-based styryl of 3-, the fluorine-based styryl of 4-, 2-chloro styryl, 3-chloro styryl, 4-chloro styryl, 2-bromo styryl, 3-bromo styryl, 4-bromo styryl, 2-nitrostyrolene base, 3-nitrostyrolene base, 4-nitrostyrolene base, 2-trifluoromethyl styrene base, 3-trifluoromethyl styrene base, 4-trifluoromethyl styrene base, furyl vinyl, thienyl vinyl, 2-Methoxy-phenylacetylene base, 3-Methoxy-phenylacetylene base, 4-Methoxy-phenylacetylene base, 2-methylbenzene ethynyl, 3-methylbenzene ethynyl, 4-methylbenzene ethynyl, phenylacetylene base, the fluorine-based phenylacetylene base of 2-, the fluorine-based phenylacetylene base of 3-, the fluorine-based phenylacetylene base of 4-, 2-chloro phenylacetylene base, 3-chloro phenylacetylene base, 4-chloro phenylacetylene base, 2-bromo phenylacetylene base, 3-bromo phenylacetylene base, 4-bromo phenylacetylene base, 2-nitrobenzene acetylene base, 3-nitrobenzene acetylene base, 4-nitrobenzene acetylene base, 2-trifluoromethyl phenylacetylene base, 3-trifluoromethyl phenylacetylene base, 4-trifluoromethyl phenylacetylene base, furyl ethynyl, thienylethynyl,
N is 0 ~ 3.
Further, the structure optimization of described chiral bicyclics compound is as follows:
Further, R
1, R
2, R
3independently be preferably hydrogen or methyl separately.
Further, R
4be preferably 2-methoxyl-styrene, 4-methoxyl-styrene, 4-vinyl toluene base, styryl, the fluorine-based styryl of 4-, 3-chloro styryl, 4-chloro styryl, 2-bromo styryl, 4-bromo styryl, 4-trifluoromethyl styrene base or phenylacetylene base.
Further, n is preferably 0 or 1.
Further, R
1, R
2, R
3independently be preferably hydrogen or methyl separately; R
4be preferably 2-methoxyl-styrene, 4-methoxyl-styrene, 4-vinyl toluene base, styryl, the fluorine-based styryl of 4-, 3-chloro styryl, 4-chloro styryl, 2-bromo styryl, 4-bromo styryl, 4-trifluoromethyl styrene base or phenylacetylene base; N is preferably 0 or 1.
Particularly, described chiral bicyclics compound is:
(1) (1S, 4S, 5S, 6R) 6-(2-methoxyl-styrene)-5-nitro two ring [2,2,2] octane-2-ketone,
(2) (1S, 4S, 5S, 6R) 6-(4-methoxyl-styrene)-5-nitro two ring [2,2,2] octane-2-ketone,
(3) (1S, 4S, 5S, 6R) 6-(4-vinyl toluene base)-5-nitro two ring [2,2,2] octane-2-ketone,
(4) (1S, 4S, 5S, 6R) 6-styryl-5-nitro two ring [2,2,2] octane-2-ketone,
(5) (1S, 4S, 5S, 6R) 6-(the fluorine-based styryl of 4-)-5-nitro two ring [2,2,2] octane-2-ketone,
(6) (1S, 4S, 5S, 6R) 6-(3-chloro styryl)-5-nitro two ring [2,2,2] octane-2-ketone,
(7) (1S, 4S, 5S, 6R) 6-(4-chloro styryl)-5-nitro two ring [2,2,2] octane-2-ketone,
(8) (1S, 4S, 5S, 6R) 6-(2-bromo styryl)-5-nitro two ring [2,2,2] octane-2-ketone,
(9) (1S, 4S, 5S, 6R) 6-(4-bromo styryl)-5-nitro two ring [2,2,2] octane-2-ketone,
(10) (1S, 4S, 5S, 6R) 6-(4-trifluoromethyl styrene base)-5-nitro two ring [2,2,2] octane-2-ketone,
(11) (1S, 4S, 5S, 6R) 6-styryl-4-methyl-5-nitro two ring [2,2,2] octane-2-ketone,
(12) (1S, 2R, 3S, 4R) 2-styryl-5,5-dimethyl-3-nitro two ring [2,2,2] octane-7-ketone,
(13) (1S, 4S, 5S, 6R) 6-styryl-5-nitro two ring [2,2,2] heptane-2-ketone,
(14) (1S, 4S, 5S, 6R) 6-phenylacetylene base-5-nitro two ring [2,2,2] octane-2-ketone.
Second goal of the invention of the present invention is to provide a kind of method of simple to operate, reaction conditions is gentle, reaction yield is high, selectivity the is good described chiral bicyclics compound of synthesis.
The technical solution used in the present invention is as follows:
A kind of method of asymmetric synthesis of chiral bicyclics compound, described method be with structure such as formula the cyclohexenone derivates shown in (II) and structure such as formula the nitroolefin derivative shown in (III) for substrate, under the co-catalysis of chirality secondary amine catalyst, polyglycol series compound and acid, be obtained by reacting structure such as formula the chiral bicyclics compound shown in (I) in organic solvent;
In formula (II) or formula (III), R
1, R
2, R
3, R
4, n definition cotype (I);
The structure of described chirality secondary amine catalyst is such as formula shown in (IV):
In the present invention, described polyglycol series compound is one of following: PEG200, PEG400, PEG600, PEG800, PEG1000, PPG200, PPG400, PPG600, PPG800, PPG1000, PPG2000; Preferred polyglycol series compound is PPG1000.
In the present invention, described acid is one of following: HCl, HBr, H
2sO
4, HBF
4, HPF
6, CH
3cOOH, CF
3cOOH, CF
3sO
3h, phenylformic acid, o-fluorobenzoic acid, m-fluorobenzoic acid, parafluorobenzoic acid, toluylic acid, p-methylbenzoic acid, o-Carboxynitrobenzene, M-NITROBENZOIC ACID, p-nitrobenzoic acid, o-trifluoromethyl phenylformic acid, m-trifluoromethylbenzoic acid, to trifluoromethylbenzoic acid, Phenylsulfonic acid, p-methyl benzenesulfonic acid, to Witco 1298 Soft Acid, α-naphthalenesulfonicacid, beta-naphthalenesulfonic-acid, α-naphthaleneacetic acid, oleic acid, stearic acid, dodecyl sulfonic acid, methacrylic acid; Preferred acid is phenylformic acid.
In the present invention, described organic solvent can be one of following: methylene dichloride, chloroform, ether, isopropyl ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, ethyl acetate, toluene, dimethylbenzene, acetonitrile, methyl alcohol, ethanol, Virahol, PEG200, PEG400, PEG600, PPG200, PPG400, PPG600, PPG800; Preferred organic solvent is chloroform.
In the present invention, the mol ratio of described nitroolefin derivative and cyclohexenone derivates is 1: 1 ~ 6, is preferably 1: 3 ~ 5, is more preferably 1: 4.
In the present invention, the mol ratio of described nitroolefin derivative and chirality secondary amine catalyst is 1: 0.05 ~ 0.3, is preferably 1: 0.15 ~ 0.25, is more preferably 1: 0.2.
In the present invention, the mol ratio of described polyglycol series compound and chirality secondary amine catalyst is 1: 2 ~ 5, is preferably 1: 3.
In the present invention, described nitroolefin derivative is 1: 0.05 ~ 0.3 with the mol ratio of acid, is preferably 1: 0.15 ~ 0.25, is preferably 1: 0.2.
In the present invention, the mol ratio of described chirality secondary amine catalyst and organic solvent is 1: 150 ~ 200, is preferably 1: 170.
In the present invention, temperature of reaction is-20 ~ 40 DEG C, and the reaction times is 12 ~ 36h; Further, preferable reaction temperature is 25 DEG C.
Synthetic method of the present invention, after completion of the reaction, can target product be obtained by ordinary method separation and purification, such as, can adopt and carry out separation and purification with the following method: reaction solution is extracted with ethyl acetate, after the de-solvent to the greatest extent of redistillation, column chromatography for separation is purified and is obtained target compound.
Chiral bicyclics compound of the present invention is the important synthetic intermediate of a class, can synthesize a class chirality bicyclic alkenes compounds.Described chiral bicyclics compound just can realize nitro to be converted to carbonyl through simple Nef reaction and synthesize a class chirality two ring dione compounds 2, further reaction can synthesize a class chirality bicyclic alkenes compounds 1 (Angew.Chem.Int.Ed.2010,49,2750).
Compared with prior art, its advantage is in the present invention:
(1) chiral bicyclics compound of the present invention has chirality, can be used as the synthetic intermediate of chipal compounds (such as chirality bicyclic alkenes compounds), has broad application prospects.
(2) synthetic method of the present invention adopts supermolecular catalysis to synthesize this compounds, and show good response characteristic, reaction yield is high, selectivity good; And operation is simple, reaction conditions is gentle.
(4) embodiment
Below in conjunction with specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in this.
Specific embodiments of the invention comprise:
(1S, 4S, 5S, 6R) 6-(2-methoxyl-styrene)-5-nitro two ring [2,2,2] octane-2-ketone;
(1S, 4S, 5S, 6R) 6-(4-methoxyl-styrene)-5-nitro two ring [2,2,2] octane-2-ketone;
(1S, 4S, 5S, 6R) 6-(4-vinyl toluene base)-5-nitro two ring [2,2,2] octane-2-ketone;
(1S, 4S, 5S, 6R) 6-styryl-5-nitro two ring [2,2,2] octane-2-ketone;
(1S, 4S, 5S, 6R) 6-(the fluorine-based styryl of 4-)-5-nitro two ring [2,2,2] octane-2-ketone;
(1S, 4S, 5S, 6R) 6-(3-chloro styryl)-5-nitro two ring [2,2,2] octane-2-ketone;
(1S, 4S, 5S, 6R) 6-(4-chloro styryl)-5-nitro two ring [2,2,2] octane-2-ketone;
(1S, 4S, 5S, 6R) 6-(2-bromo styryl)-5-nitro two ring [2,2,2] octane-2-ketone;
(1S, 4S, 5S, 6R) 6-(4-bromo styryl)-5-nitro two ring [2,2,2] octane-2-ketone;
(1S, 4S, 5S, 6R) 6-(4-trifluoromethyl styrene base)-5-nitro two ring [2,2,2] octane-2-ketone;
(1S, 4S, 5S, 6R) 6-styryl-4-methyl-5-nitro two ring [2,2,2] octane-2-ketone;
(1S, 2R, 3S, 4R) 2-styryl-5,5-dimethyl-3-nitro two ring [2,2,2] octane-7-ketone;
(1S, 4S, 5S, 6R) 6-styryl-5-nitro two ring [2,2,2] heptane-2-ketone;
(1S, 4S, 5S, 6R) 6-phenylacetylene base-5-nitro two ring [2,2,2] octane-2-ketone.
Embodiment 1:(1S, 4S, 5S, 6R) 6-(2-methoxyl-styrene)-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds 2-methoxyl-styrene nitroolefin (0.102g, 0.5mmol), cyclonene (0.192g, 2mmol) with 1mL chloroform, at chirality secondary amine catalyst (IV) (0.02g, 0.1mmol), PPG1000 (0.3g, 0.3mmol) with phenylformic acid (0.012g, the lower 25 DEG C of reaction 36h of co-catalysis 0.1mmol), be extracted with ethyl acetate (3 × 20mL), after the de-solvent to the greatest extent of redistillation, ether-petroleum ether system is used to be eluent (ether volume content is 20%), 100-200 order column layer chromatography silicone rubber is filler, column chromatography for separation is purified and is obtained target compound (0.102g, yield 68%, external form/inner mold (exo/endo) > 20: 1, Ee value is 90%), wherein
1hNMR (500MHz, CDCl
3): δ=7.334-7.309 (m, 1H), 7.234-7.207 (m, 1H), 6.906-6.813 (m, 2H), (6.476-6.444 m, 1H), 6.014-5.944 (m, 1H), 4.622-4.613 (m, 1H), (3.829 s, 3H), 3.750-3.703 (m, 1H), 2.953-2.933 (m, 1H), (2.574-2.563 m, 1H), 2.459-2.352 (m, 2H), 2.159-2.089 (m, 1H), 1.979-1.834 (m, 2H), 1.706-1.623 (m, 1H) ppm,
13cNMR (125MHz, CDCl
3): δ=211.476,156.755,129.134,128.526,127.515,126.890,124.977,120.603,110.869,89.441,55.431,47.258,42.873,42.002,34.224,22.088,18.453ppm,
Embodiment 2:(1S, 4S, 5S, 6R) preparation of 6-(4-methoxyl-styrene)-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds 4-methoxyl-styrene nitroolefin (0.102g, 0.5mmol), cyclonene (0.192g, 2mmol) with 1mL chloroform, at chirality secondary amine catalyst (IV) (0.02g, 0.1mmol), PPG1000 (0.3g, 0.3mmol) with phenylformic acid (0.012g, the lower 25 DEG C of reaction 36h of co-catalysis 0.1mmol), be extracted with ethyl acetate (3 × 20mL), after the de-solvent to the greatest extent of redistillation, ether-petroleum ether system is used to be eluent (ether volume content is 20%), 100-200 order column layer chromatography silicone rubber is filler, column chromatography for separation is purified and is obtained target compound (0.123g, yield 66%, external form/inner mold (exo/endo) > 20: 1, Ee value is 94%), wherein
1hNMR (500MHz, CDCl
3): δ=7.261-7.238 (m, 2H), 6.837-6.820 (m, 2H), 6.462-6.430 (m, 1H), (5.842-5.795 m, 1H), 4.564-4.554 (m, 1H), 3.791 (s, 3H), (3.697-3.671 m, 1H), 2.944-2.926 (m, 1H), 2.556-2.545 (m, 1H), 2.456-2.340 (m, 2H), 2.146-2.208 (m, 1H), 1.959-1.837 (m, 2H), 1.681-1.630 (m, 1H) ppm,
13cNMR (125MHz, CDCl
3): δ=211.465,159.595,131.882,128.757,127.662 (× 2), 125.851,114.039 (× 2), 89.600,55.285,47.093,42.509,41.999,34.143,22.122,18.392ppm.
Embodiment 3:(1S, 4S, 5S, 6R) preparation of 6-(4-vinyl toluene base)-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds 4-vinyl toluene base nitroolefin (0.094g, 0.5mmol), cyclonene (0.192g, 2mmol) with 1mL chloroform, at chirality secondary amine catalyst (IV) (0.02g, 0.1mmol), PPG1000 (0.3g, 0.3mmol) with phenylformic acid (0.012g, the lower 25 DEG C of reaction 36h of co-catalysis 0.1mmol), be extracted with ethyl acetate (3 × 20mL), after the de-solvent to the greatest extent of redistillation, ether-petroleum ether system is used to be eluent (ether volume content is 20%), 100-200 order column layer chromatography silicone rubber is filler, column chromatography for separation is purified and is obtained target compound (0.090g, yield 64%, external form/inner mold (exo/endo) > 20: 1, Ee value is 86%), wherein
1hNMR (500MHz, CDCl
3): δ=7.213-7.197 (d, J=8Hz, 2H), (7.108-7.092 d, J=8Hz, 2H), (6.488-6.456 d, J=16Hz, 1H), (5.933-5.886 m, 1H), 4.566-4.555 (m, 1H), 3.710-3.684 (m, 1H), (2.945-2.928 m, 1H), 2.568-2.551 (m, 1H), 2.455-2.332 (m, 2H), (2.921 s, 3H), 2.146-2.081 (m, 1H), 1.959-1.831 (m, 2H), 1.681-1.629 (m, 1H) ppm,
13cNMR (125MHz, CDCl
3): δ=211.401,137.974,133.205,132.322,129.288 (× 2), 127.017,126.344 (× 2), 89.480,47.003,42.465,41.977,34.133,22.119,21.145,18.387ppm.
Embodiment 4:(1S, 4S, 5S, 6R) preparation of 6-styryl-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds styryl nitroolefin (0.088g, 0.5mmol), cyclonene (0.192g, 2mmol) with 1mL chloroform, at chirality secondary amine catalyst (IV) (0.02g, 0.1mmol), PPG1000 (0.3g, 0.3mmol) with phenylformic acid (0.012g, the lower 25 DEG C of reaction 24h of co-catalysis 0.1mmol), be extracted with ethyl acetate (3 × 20mL), after the de-solvent to the greatest extent of redistillation, ether-petroleum ether system is used to be eluent (ether volume content is 20%), 100-200 order column layer chromatography silicone rubber is filler, column chromatography for separation is purified and is obtained target compound (0.109g, yield 81%, external form/inner mold (exo/endo) > 20: 1, Ee value is 88%), wherein
1hNMR (500MHz, CDCl
3): δ=7.927-7.231 (m, 5H), 6.530-6.499 (d, J=15.5Hz, 1H), 5.996-5.949 (m, 1H), 4.576-4.567 (m, 1H), 3.735-3709 (m, 1H), 2.963-2.945 (m, 1H), 2.586-2.569 (m, 1H), 2.470-2.345 (m, 2H), 2.158-2.093 (m, 1H), 1.973-1.839 (m, 2H), 1.695-1.667 (m, 1H) ppm,
13cNMR (125MHz, CDCl
3): δ=211.403,135.966,132.492,128.622 (× 2), 128.094,128.038,126.457 (× 2), 89.378,46.942,42.454,41.990,34.131,22.103,18.387ppm, GC-MS:m/z91,167,182 (100), 224,271ppm.
Embodiment 5:(1S, 4S, 5S, 6R) preparation of 6-(the fluorine-based styryl of 4-)-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds the fluorine-based styryl nitroolefin of 4-(0.096g, 0.5mmol), cyclonene (0.192g, 2mmol) with 1mL chloroform, at chirality secondary amine catalyst (IV) (0.02g, 0.1mmol), PPG1000 (0.3g, 0.3mmol) with phenylformic acid (0.012g, the lower 25 DEG C of reaction 36h of co-catalysis 0.1mmol), be extracted with ethyl acetate (3 × 20mL), after the de-solvent to the greatest extent of redistillation, ether-petroleum ether system is used to be eluent (ether volume content is 20%), 100-200 order column layer chromatography silicone rubber is filler, column chromatography for separation is purified and is obtained target compound (0.105g, yield 73%, external form/inner mold (exo/endo) > 20: 1, Ee value is 89%), wherein
1hNMR (500MHz, CDCl
3): δ=7.296-7.262 (m, 2H), 7.004-6.969 (m, 2H), 6.492-6.460 (d, J=16Hz, 1H), 5.910-5.863 (m, 1H), (4.558-4.541 m, 1H), 3.713-3.687 (m, 1H), 2.962-2.944 (m, 1H), 2.569-2.553 (m, 1H), 2.469-2.339 (m, 2H), 2.150-2.086 (m, 1H), 1.971-1.842 (m, 2H), 1.697-1.646 (m, 1H) ppm,
13cNMR (125MHz, CDCl
3): δ=211.405,162.664 (d,
1j
c-F=246.375Hz), 132.255,131.409,128.145,128.081,127.912,115.724,115.551,89.412,47.039,42.529,42.063,34.173,22.153,18.439ppm.
Embodiment 6:(1S, 4S, 5S, 6R) preparation of 6-(3-chloro styryl)-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds 3-chloro styryl nitroolefin (0.104g, 0.5mmol), cyclonene (0.192g, 2mmol) with 1mL chloroform, at chirality secondary amine catalyst (IV) (0.02g, 0.1mmol), PPG1000 (0.3g, 0.3mmol) with phenylformic acid (0.012g, the lower 25 DEG C of reaction 24h of co-catalysis 0.1mmol), be extracted with ethyl acetate (3 × 20mL), after the de-solvent to the greatest extent of redistillation, ether-petroleum ether system is used to be eluent (ether volume content is 20%), 100-200 order column layer chromatography silicone rubber is filler, column chromatography for separation is purified and is obtained target compound (0.142g, yield 93%, external form/inner mold (exo/endo) > 20: 1, Ee value is 88%), wherein
1hNMR (500MHz, CDCl
3): δ=7.308 (s, 1H), 7.261-7.165 (m, 3H), 6.474-6.444 (d, J=15Hz, 1H), 6.014-5.967 (m, 1H), (4.550-4.541 m, 1H), 3.729-3.703 (m, 1H), 2.973-2.956 (m, 1H), 2.577-2.560 (m, 1H), 2.476-2.344 (m, 2H), 2.152-2.087 (m, 1H), 1.978-1.842 (m, 2H), 1.705-1.653 (m, 1H) ppm,
13cNMR (125MHz, CDCl
3): δ=211.165,137.847,134.641,131.237,129.833,129.594,128.043,126.356,124.731,89.138,46.829,42.414,41.972,34.069,22.063,18.357ppm.
Embodiment 7:(1S, 4S, 5S, 6R) preparation of 6-(4-chloro styryl)-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds 3-chloro styryl nitroolefin (0.104g, 0.5mmol), cyclonene (0.192g, 2mmol) with 1mL chloroform, at chirality secondary amine catalyst (IV) (0.02g, 0.1mmol), PPG1000 (0.3g, 0.3mmol) with phenylformic acid (0.012g, the lower 25 DEG C of reaction 36h of co-catalysis 0.1mmol), be extracted with ethyl acetate (3 × 20mL), after the de-solvent to the greatest extent of redistillation, ether-petroleum ether system is used to be eluent (ether volume content is 20%), 100-200 order column layer chromatography silicone rubber is filler, column chromatography for separation is purified and is obtained target compound (0.107g, yield 70%, external form/inner mold (exo/endo) > 20: 1, Ee value is 88%), wherein
1hNMR (500MHz, CDCl
3): δ=7.307.276-7.228 (m, 4H), 6.480-6.448 (d, J=16Hz, 1H), 5.974-5.927 (m, 1H), 4.553-4.543 (m, 1H), 3.718-3.692 (m, 1H), 2.964-2.946 (m, 1H), 2.570-2.554 (m, 1H), 2.469-2.338 (m, 2H), 2.147-2.082 (m, 1H), 1.971-1.837 (m, 2H), 1.699-1.647 (m, 1H) ppm,
13cNMR (125MHz, CDCl
3): δ=211.239,134.481,133.773,131.176,128.773 (× 2), 128.723,127.653 (× 2), 89.193,46.865,42.433,41.954,34.059,22.052,18.334ppm.
Embodiment 8:(1S, 4S, 5S, 6R) preparation of 6-(2-bromo styryl)-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds 2-bromo styryl nitroolefin (0.126g, 0.5mmol), cyclonene (0.192g, 2mmol) with 1mL chloroform, at chirality secondary amine catalyst (IV) (0.02g, 0.1mmol), PPG1000 (0.3g, 0.3mmol) with phenylformic acid (0.012g, the lower 25 DEG C of reaction 24h of co-catalysis 0.1mmol), be extracted with ethyl acetate (3 × 20mL), after the de-solvent to the greatest extent of redistillation, ether-petroleum ether system is used to be eluent (ether volume content is 20%), 100-200 order column layer chromatography silicone rubber is filler, column chromatography for separation is purified and is obtained target compound (0.162g, yield 93%, external form/inner mold (exo/endo) > 20: 1, Ee value is 85%), wherein
1hNMR (500MHz, CDCl
3): δ=7.535-7.522 (m, 1H), 7.411-7.396 (m, 1H), 7.263-7.228 (m, 1H), 7.120-7.092 (m, 1H), 6.875-6.844 (d, J=15.5Hz, 1H), 5.938-5.891 (m, 1H), 4.608-4.597 (m, 1H), 3.786-3.759 (m, 1H), 2.982-2.964 (m, 1H), 2.603-2.586 (m, 1H), 2.480-2.359 (m, 2H), 2.164-2.110 (m, 1H), 1.983-1.856 (m, 2H), 1.705-1.643 (m, 1H) ppm,
13cNMR (125MHz, CDCl3): δ=211.148,136.106,133.019,131.579,131.180,129.386,127.568,127.163,123.762,89.035,47.054,42.535,42.039,34.167,22.117,18.459ppm.
Embodiment 9:(1S, 4S, 5S, 6R) preparation of 6-(4-bromo styryl)-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds 4-bromo styryl nitroolefin (0.126g, 0.5mmol), cyclonene (0.192g, 2mmol) with 1mL chloroform, at chirality secondary amine catalyst (IV) (0.02g, 0.1mmol), PPG1000 (0.3g, 0.3mmol) with phenylformic acid (0.012g, the lower 25 DEG C of reaction 24h of co-catalysis 0.1mmol), be extracted with ethyl acetate (3 × 20mL), after the de-solvent to the greatest extent of redistillation, ether-petroleum ether system is used to be eluent (ether volume content is 20%), 100-200 order column layer chromatography silicone rubber is filler, column chromatography for separation is purified and is obtained target compound (0.141g, yield 81%, external form/inner mold (exo/endo) > 20: 1, Ee value is 82%), wherein
1hNMR (500MHz, CDCl
3): δ=7.428-7.411 (d, J=8.5Hz, 2H), (7.186-7.169 d, J=8.5Hz, 2H), (6.466-6.435 d, J=15.5Hz, 1H), (5.991-5.944 m, 1H), 4.553-4.542 (m, 1H), 3.715-3.688 (m, 1H), (2.965-2.948 m, 1H), 2.572-2.555 (m, 1H), 2.470-2.339 (m, 2H), 2.147-2.082 (m, 1H), 1.982-1.838 (m, 2H), 1.700-1.638 (m, 1H) ppm,
13cNMR (125MHz, CDCl
3): δ=211.382,134.985,131.813 (× 2), 131.430,128.901,128.044 (× 2), 122.014,89.228,46.904,42.513,42.033,34.133,22.123,18.411ppm.
Embodiment 10:(1S, 4S, 5S, 6R) preparation of 6-(4-trifluoromethyl styrene base)-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds 4-trifluoromethyl styrene base nitroolefin (0.122g, 0.5mmol), cyclonene (0.192g, 2mmol) with 1mL chloroform, at chirality secondary amine catalyst (IV) (0.02g, 0.1mmol), PPG1000 (0.3g, 0.3mmol) with phenylformic acid (0.012g, the lower 25 DEG C of reaction 36h of co-catalysis 0.1mmol), be extracted with ethyl acetate (3 × 20mL), after the de-solvent to the greatest extent of redistillation, ether-petroleum ether system is used to be eluent (ether volume content is 20%), 100-200 order column layer chromatography silicone rubber is filler, column chromatography for separation is purified and is obtained target compound (0.142g, yield 84%, external form/inner mold (exo/endo) > 20: 1, Ee value is 89%), wherein
1hNMR (500MHz, CDCl
3): δ=7.576-7.559 (d, J=8.5Hz, 2H), (7.436-7.420 d, J=8Hz, 2H), (6.583-6.551 d, J=16Hz, 1H), (6.121-6.074 m, 1H), 4.579-4.568 (m, 1H), 3.774-3.748 (m, 1H), (3.001-2.984 m, 1H), 2.613-2.597 (m, 1H), 2.501-2.366 (m, 2H), 2.176-2.111 (m, 1H), 2.004-1.866 (m, 2H), 1.749-1.680 (m, 1H) ppm,
13cNMR (125MHz, CDCl3): δ=211.161,139.463,131.262,130.753,130.105,126.686 (× 2), 125.634 (× 2), 125.158,89.060,46.790,42.477,41.999,34.084,22.080,18.373ppm.
Embodiment 11:(1S, 4S, 5S, 6R) preparation of 6-styryl-4-methyl-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds styryl nitroolefin (0.088g, 0.5mmol), 2-methyl cyclohexane ketenes (0.22g, 2mmol) with 1mL chloroform, at chirality secondary amine catalyst (IV) (0.02g, 0.1mmol), PPG1000 (0.3g, 0.3mmol) with phenylformic acid (0.012g, the lower 25 DEG C of reaction 36h of co-catalysis 0.1mmol), be extracted with ethyl acetate (3 × 20mL), after the de-solvent to the greatest extent of redistillation, ether-petroleum ether system is used to be eluent (ether volume content is 20%), 100-200 order column layer chromatography silicone rubber is filler, column chromatography for separation is purified and is obtained target compound (0.140g, yield 98%, external form/inner mold (exo/endo) > 30: 1, Ee value is 81%), wherein
1hNMR (500MHz, CDCl
3): 7.312-7.241 (m, 5H), 6.462-6.431 (d, J=15.5Hz, 1H), 5.958-5.911 (m, 1H), 4.483-4.471 (d, J=6Hz, 1H), 3.515-3.487 (m, 1H), (2.573-2.568 m, 1H), 2.305-2.67 (m, 1H), 2.249-2.206 (m, 1H), (2.170-2.117 m, 1H), 2.110-2.067 (m, 1H), 1.990-1.924 (m, 1H), 1.476-1.415 (m, 1H), 1.091 (s, 3H) ppm,
13cNMR (125MHz, CDCl
3): δ=211.200,135.842,132.589,128.599 (× 2), 128.120,127.678,126.466 (× 2), 85.163,49.226,47.240,44.594,37.837,25.007,23.260,22.807ppm.
Embodiment 12:(1S, 2R, 3S, 4R) 2-styryl-5, the preparation of 5-dimethyl-3-nitro two ring [2,2,2] octane-7-ketone
25mL in vitro adds styryl nitroolefin (0.088g, 0.5mmol), 3, 3-dimethyleyelohexane ketenes (0.248g, 2mmol) with 1mL chloroform, at chirality secondary amine catalyst (IV) (0.02g, 0.1mmol), PPG1000 (0.3g, 0.3mmol) with phenylformic acid (0.012g, the lower 25 DEG C of reaction 36h of co-catalysis 0.1mmol), be extracted with ethyl acetate (3 × 20mL), after the de-solvent to the greatest extent of redistillation, ether-petroleum ether system is used to be eluent (ether volume content is 20%), 100-200 order column layer chromatography silicone rubber is filler, column chromatography for separation is purified and is obtained target compound (0.143g, yield 96%, external form/inner mold (exo/endo) > 20: 1, Ee value is 68%), wherein
1hNMR (500MHz, CDCl
3): δ=7.333-7.217 (m, 5H), 6.619-6.587 (d, J=16Hz, 1H), 6.019-5.972 (m, 1H), 4.242-4.227 (m, 1H), (3.836-3.805 m, 1H), 2.923-2.918 (d, J=2.5Hz, 1H), 2.765-2.719 (m, 1H), 2.585-2.575 (m, 1H), (2.208-2.163 m, 1H), 1.915-1.880 (m, 1H), 1.736-1.702 (m, 1H), 1.108 (s, 3H), 1.062 (s, 3H) ppm,
13cNMR (125MHz, CDCl
3): δ=211.588,136.181,132.532,128.637 (× 2), 128.312,128.028,126.484 (× 2), 88.702,49.582,44.196,40.483,40.097,38.976,30.832,30.564,29.470ppm.
Embodiment 13:(1S, 4S, 5S, 6R) preparation of 6-styryl-5-nitro two ring [2,2,2] heptane-2-ketone
25mL in vitro adds styryl nitroolefin (0.088g, 0.5mmol), cyclopentenone (0.164g, 2mmol) with 1mL chloroform, at chirality secondary amine catalyst (IV) (0.02g, 0.1mmol), PPG1000 (0.3g, 0.3mmol) with phenylformic acid (0.012g, the lower 25 DEG C of reaction 36h of co-catalysis 0.1mmol), be extracted with ethyl acetate (3 × 20mL), after the de-solvent to the greatest extent of redistillation, ether-petroleum ether system is used to be eluent (ether volume content is 20%), 100-200 order column layer chromatography silicone rubber is filler, column chromatography for separation is purified and is obtained target compound (0.090g, yield 70%, external form/inner mold (exo/endo) > 20: 1, Ee value is 80%), wherein
1hNMR (500MHz, CDCl
3): δ=7.360-7.261 (m, 5H), 6.595-6.563 (d, J=16Hz, 1H), 6.126-6.079 (m, 1H), 4.914-4.899 (m, 1H), (3.484-3.402 m, 2H), 2.733 (s, 1H), 2.265-2.117 (m, 3H), 1.998-1.950 (m, 1H) ppm,
13cNMR (125MHz, CDCl
3): δ=211.490,136.042,133.022,128.792 (× 2), 128.258,126.466 (× 2), 126.418,91.185,55.679,44.168,41.659,39.083,34.994ppm, GC-MS:m/z91,115,153,168 (100), 210,257ppm.
Embodiment 14:(1S, 4S, 5S, 6R) preparation of 6-phenylacetylene base-5-nitro two ring [2,2,2] octane-2-ketone
25mL in vitro adds phenylacetylene base nitroolefin (0.088g, 0.5mmol), cyclopentenone (0.164g, 2mmol) with 1mL chloroform, at chirality secondary amine catalyst (IV) (0.02g, 0.1mmol), PPG1000 (0.3g, 0.3mmol) with phenylformic acid (0.012g, the lower 25 DEG C of reaction 36h of co-catalysis 0.1mmol), be extracted with ethyl acetate (3 × 20mL), after the de-solvent to the greatest extent of redistillation, ether-petroleum ether system is used to be eluent (ether volume content is 20%), 100-200 order column layer chromatography silicone rubber is filler, column chromatography for separation is purified and is obtained target compound (0.090g, yield 94%, external form/inner mold (exo/endo)=2: 1, Ee
endo=92%, Ee
exo=85%ee), wherein
1hNMR (500MHz, CDCl
3): δ=7.358-7.262 (m, 5H), 4.914-4.908 (d, J=3Hz, 1H), 4.125-4.111 (m, 1H), (2.995-2.976 m, 1H), 2.715-2.697 (m, 1H), 2.560-2.425 (m, 2H), (2.114-2.015 m, 2H), 1.967-1.900 (m, 1H), 1.756-1.692 (m, 1H) ppm,
13cNMR (125MHz, CDCl
3): δ=209.467,131.763 (× 2), 128.652,128.278 (× 2), 121.974,89.193,86.951,84.845,46.966,41.556,34.131,31.725,21.307,18.270ppm.
Claims (9)
1. a structure is such as formula the method for asymmetric synthesis of the chiral bicyclics compound shown in (I), described method be with structure such as formula the cyclohexenone derivates shown in (II) and structure such as formula the nitroolefin derivative shown in (III) for substrate, under the co-catalysis of chirality secondary amine catalyst, polyglycol series compound and acid, be obtained by reacting structure such as formula the chiral bicyclics compound shown in (I) in organic solvent;
In formula (I), formula (II) or formula (III),
R
1, R
2, R
3respective is independently the alkyl of H or C1 ~ C20;
R
4be selected from one of following: H, the alkyl of C1 ~ C20, 2-methoxyl-styrene, 3-methoxyl-styrene, 4-methoxyl-styrene, 2-methyl styrene base, 3-vinyl toluene base, 4-vinyl toluene base, styryl, the fluorine-based styryl of 2-, the fluorine-based styryl of 3-, the fluorine-based styryl of 4-, 2-chloro styryl, 3-chloro styryl, 4-chloro styryl, 2-bromo styryl, 3-bromo styryl, 4-bromo styryl, 2-nitrostyrolene base, 3-nitrostyrolene base, 4-nitrostyrolene base, 2-trifluoromethyl styrene base, 3-trifluoromethyl styrene base, 4-trifluoromethyl styrene base, furyl vinyl, thienyl vinyl, 2-Methoxy-phenylacetylene base, 3-Methoxy-phenylacetylene base, 4-Methoxy-phenylacetylene base, 2-methylbenzene ethynyl, 3-methylbenzene ethynyl, 4-methylbenzene ethynyl, phenylacetylene base, the fluorine-based phenylacetylene base of 2-, the fluorine-based phenylacetylene base of 3-, the fluorine-based phenylacetylene base of 4-, 2-chloro phenylacetylene base, 3-chloro phenylacetylene base, 4-chloro phenylacetylene base, 2-bromo phenylacetylene base, 3-bromo phenylacetylene base, 4-bromo phenylacetylene base, 2-nitrobenzene acetylene base, 3-nitrobenzene acetylene base, 4-nitrobenzene acetylene base, 2-trifluoromethyl phenylacetylene base, 3-trifluoromethyl phenylacetylene base, 4-trifluoromethyl phenylacetylene base, furyl ethynyl, thienylethynyl,
N is 0 ~ 3;
The structure of described chirality secondary amine catalyst is such as formula shown in (IV):
2. the method for asymmetric synthesis of chiral bicyclics compound as claimed in claim 1, is characterized in that: the structure of described chiral bicyclics compound is as follows:
3. the method for asymmetric synthesis of chiral bicyclics compound as claimed in claim 1 or 2, is characterized in that: R
1, R
2, R
3respective is independently hydrogen or methyl; R
4for 2-methoxyl-styrene, 4-methoxyl-styrene, 4-vinyl toluene base, styryl, the fluorine-based styryl of 4-, 3-chloro styryl, 4-chloro styryl, 2-bromo styryl, 4-bromo styryl, 4-trifluoromethyl styrene base or phenylacetylene base; N is 0 or 1.
4. the method for asymmetric synthesis of chiral bicyclics compound as claimed in claim 1, is characterized in that: described polyglycol series compound is one of following: PEG200, PEG400, PEG600, PEG800, PEG1000, PPG200, PPG400, PPG600, PPG800, PPG1000, PPG2000.
5. the method for asymmetric synthesis of chiral bicyclics compound as claimed in claim 1, is characterized in that: described acid is one of following: HCl, HBr, H
2sO
4, HBF
4, HPF
6, CH
3cOOH, CF
3cOOH, CF
3sO
3h, phenylformic acid, o-fluorobenzoic acid, m-fluorobenzoic acid, parafluorobenzoic acid, toluylic acid, p-methylbenzoic acid, o-Carboxynitrobenzene, M-NITROBENZOIC ACID, p-nitrobenzoic acid, o-trifluoromethyl phenylformic acid, m-trifluoromethylbenzoic acid, to trifluoromethylbenzoic acid, Phenylsulfonic acid, p-methyl benzenesulfonic acid, to Witco 1298 Soft Acid, α-naphthalenesulfonicacid, beta-naphthalenesulfonic-acid, α-naphthaleneacetic acid, oleic acid, stearic acid, dodecyl sulfonic acid, methacrylic acid.
6. the method for asymmetric synthesis of chiral bicyclics compound as claimed in claim 1, it is characterized in that: described organic solvent is one of following: methylene dichloride, chloroform, ether, isopropyl ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, ethyl acetate, toluene, dimethylbenzene, acetonitrile, methyl alcohol, ethanol, Virahol, PEG200, PEG400, PEG600, PPG200, PPG400, PPG600, PPG800.
7. the method for asymmetric synthesis of chiral bicyclics compound as claimed in claim 1, it is characterized in that: the mol ratio of described nitroolefin derivative and cyclohexenone derivates, chirality secondary amine catalyst, acid is 1:1 ~ 6:0.3 ~ 0.05:0.3 ~ 0.05, the mol ratio of described polyglycol series compound and chirality secondary amine catalyst is 1:2 ~ 5, and the mol ratio of described chirality secondary amine catalyst and organic solvent is 1:150 ~ 200.
8. the method for asymmetric synthesis of chiral bicyclics compound as claimed in claim 1, it is characterized in that: temperature of reaction is-20 ~ 40 DEG C, the reaction times is 12 ~ 36h.
9. the method for asymmetric synthesis of chiral bicyclics compound as claimed in claim 1, it is characterized in that: described organic solvent is chloroform, described polyglycol series compound is PPG1000, described acid is phenylformic acid, described nitroolefin derivative is 1:4:0.2:0.2 with the ratio of the amount of substance of cyclohexenone derivates, chirality secondary amine catalyst, acid, the mol ratio of described polyglycol series compound and chirality secondary amine catalyst is 1:3, and the mol ratio of described chirality secondary amine catalyst and organic solvent is 1:170; Temperature of reaction is 25 DEG C, and the reaction times is 12 ~ 36h.
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| CN101525291A (en) * | 2009-04-03 | 2009-09-09 | 浙江工业大学 | Green asymmetric synthesis method of chiral bicyclics compound |
| CN101597286A (en) * | 2008-06-04 | 2009-12-09 | 中国科学院大连化学物理研究所 | A kind of organic catalyst and preparation thereof that contains primary amine, tertiary amine and urea or thiocarbamide |
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| CN101525291A (en) * | 2009-04-03 | 2009-09-09 | 浙江工业大学 | Green asymmetric synthesis method of chiral bicyclics compound |
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