CN110128439B - 一种氧杂螺环化合物及其合成与拆分方法 - Google Patents
一种氧杂螺环化合物及其合成与拆分方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 14
- 150000008628 oxaspiro compounds Chemical class 0.000 title claims abstract description 12
- 238000003786 synthesis reaction Methods 0.000 title abstract description 12
- 230000015572 biosynthetic process Effects 0.000 title abstract description 11
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 38
- 239000013067 intermediate product Substances 0.000 abstract 1
- 238000005457 optimization Methods 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- 239000003446 ligand Substances 0.000 description 37
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 125000003003 spiro group Chemical group 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
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- 239000007787 solid Substances 0.000 description 12
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- 239000002904 solvent Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
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- 125000003118 aryl group Chemical group 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
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- WMPDAIZRQDCGFH-UHFFFAOYSA-N 3-methoxybenzaldehyde Chemical compound COC1=CC=CC(C=O)=C1 WMPDAIZRQDCGFH-UHFFFAOYSA-N 0.000 description 2
- -1 6-nonanediol-modified lithium aluminum hydride Chemical class 0.000 description 2
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- ONIBWKKTOPOVIA-SCSAIBSYSA-N D-Proline Chemical compound OC(=O)[C@H]1CCCN1 ONIBWKKTOPOVIA-SCSAIBSYSA-N 0.000 description 2
- 229930182820 D-proline Natural products 0.000 description 2
- 238000005698 Diels-Alder reaction Methods 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
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- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
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- 229940125782 compound 2 Drugs 0.000 description 2
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
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- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
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- 239000011541 reaction mixture Substances 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- KIUPCUCGVCGPPA-UHFFFAOYSA-N (5-methyl-2-propan-2-ylcyclohexyl) carbonochloridate Chemical compound CC(C)C1CCC(C)CC1OC(Cl)=O KIUPCUCGVCGPPA-UHFFFAOYSA-N 0.000 description 1
- ICPSWZFVWAPUKF-UHFFFAOYSA-N 1,1'-spirobi[fluorene] Chemical compound C1=CC=C2C=C3C4(C=5C(C6=CC=CC=C6C=5)=CC=C4)C=CC=C3C2=C1 ICPSWZFVWAPUKF-UHFFFAOYSA-N 0.000 description 1
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
- VNZVYHRZZXNXSQ-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole 1,2-oxazole Chemical compound C1CC=NO1.C=1C=NOC=1 VNZVYHRZZXNXSQ-UHFFFAOYSA-N 0.000 description 1
- NHFAABIHBNXKDT-UHFFFAOYSA-N 4,5-dihydro-1,3-oxazole;phosphane Chemical compound P.C1CN=CO1 NHFAABIHBNXKDT-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 239000007848 Bronsted acid Substances 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 238000010485 C−C bond formation reaction Methods 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- KUXDQQMEFBFTGX-UHFFFAOYSA-N [N].P Chemical compound [N].P KUXDQQMEFBFTGX-UHFFFAOYSA-N 0.000 description 1
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 1
- 238000005865 alkene metathesis reaction Methods 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
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- 150000001413 amino acids Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 description 1
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
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- 238000007366 cycloisomerization reaction Methods 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
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- 230000009977 dual effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
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- 238000010438 heat treatment Methods 0.000 description 1
- 238000005913 hydroamination reaction Methods 0.000 description 1
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- 238000005669 hydrocyanation reaction Methods 0.000 description 1
- 238000006459 hydrosilylation reaction Methods 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- WLGPHHLNADXABF-UHFFFAOYSA-N methyl 2-hydroxy-2-trimethylsilylacetate Chemical compound COC(=O)C(O)[Si](C)(C)C WLGPHHLNADXABF-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- XVDBWWRIXBMVJV-UHFFFAOYSA-N n-[bis(dimethylamino)phosphanyl]-n-methylmethanamine Chemical compound CN(C)P(N(C)C)N(C)C XVDBWWRIXBMVJV-UHFFFAOYSA-N 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- KZBQRYVHUOPVFW-UHFFFAOYSA-N phosphane;pyridin-2-amine Chemical compound P.NC1=CC=CC=N1 KZBQRYVHUOPVFW-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1845—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing phosphorus
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2213—At least two complexing oxygen atoms present in an at least bidentate or bridging ligand
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/657154—Cyclic esteramides of oxyacids of phosphorus
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- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/60—Reduction reactions, e.g. hydrogenation
- B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
- B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
- B01J2231/645—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of C=C or C-C triple bonds
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Abstract
本发明涉及化学合成技术领域，涉及一类氧杂螺环化合物的合成与拆分，具体提供了一条合成氧杂螺环化合物的方法，并对反应的路线进行了恰当的优化，经过优化后仅需要简单的四步就可以得到螺环二氟中间产物，并且该合成方法在操作上也非常简便，容易进行进一步的放大。此外，其中的氧杂螺环二酚可以通过便宜易得的拆分试剂进行有效的拆分。
Description
技术领域
本发明涉及一种氧杂螺环化合物及其合成与拆分。该化合物可以作为手性配体的骨架结构，在不对称催化领域具有很高的潜在应用价值，属于不对称催化领域。
背景技术
手性螺环配体的催化性能研究始于1992年，Kumar等人将光学纯的cis,cis-螺[4,4]-1,6-壬二醇修饰的氢化铝锂，成功地应用于酮的不对称还原，取得了优秀的对映选择性(最高可达98％ee)。1996年，Keay等人将同样的手性二醇作为手性辅基修饰丙烯酰氯，成功地应用于环戊二烯的不对称Diels-Alder反应中。随后，陈新滋和蒋耀忠等在此骨架基础上设计合成了不同类型的双齿亚磷酸酯配体，并探讨了其在铑催化的不对称氢化和氢甲酰化反应中的应用。其中，在α-脱氢氨基酸及其甲酯的不对称氢化反应中取得了很好的反应活性(反应时间小于10min)和很高的对映选择性(94->99％ee)，这也是螺环骨架的手性配体在不对称催化反应中的首次应用报道。从1999年起，Sasai等人先后设计合成了手性螺环双异噁唑啉配体、双异噁唑配体、异噁唑-异噁唑啉配体、双噁唑啉配体和双吡唑配体，并证明了其在一些Cu(II)及Pd(II)催化的不对称反应中可以取得很好的效果。
1999年，Birman等从丙酮和间甲氧基苯甲醛出发，经过六步反应得到了外消旋的螺二氢茚二酚(SPINOL)。该二酚与氯甲酸薄荷醇酯形成的非对映异构体可以通过柱层析进行分离，从而得到光学纯的螺环二酚。
在此基础上，南开大学的周其林等在2002年报道了更为实用的拆分方法，他们利用氯化苄基辛可宁啶和对映异构体中的一种易形成包结物的特点，通过简单的回流、冷却、结晶、过滤和酸化等步骤就可以得到光学纯的螺二氢茚二酚。随后，他们从螺二氢茚和螺二芴骨架的酚羟基上引入相应取代基团，合成了一系列具有不同结构的单齿磷配体、双齿磷配体、膦-氮配体、膦-噁唑啉配体、双噁唑啉配体以及膦-胺基-吡啶三齿配体等。
与早期的螺环配体相比，由于苯并环的引入，消除了配位基团与螺环相连处的中心手性，使配体变得更为简单易修饰。而且，这样的配体结构更为刚性，从而增强了配体的手性控制能力。因此，周其林等人将该类配体成功应用于不对称氢化、不对称碳-碳键形成以及不对称碳-杂原子键的形成等多种类型的催化反应中，取得令人瞩目的成果。他们的工作也极大地推动了手性螺环配体的发展。
周其林小组基于螺环骨架的手性配体在不对称催化领域取得了巨大的成功，使螺环配体在短短数十年间发展成了一类重要的配体，他们的配体基本上都是基于螺二氢茚骨架之上的，因此具有很强的刚性。但是，和轴手性配体的发展相比，螺环骨架配体不仅是在数目上还是在应用上都显得较为不足，其中很重要的一个原因就是螺环骨架的合成比较困难，修饰也仅限于已有的骨架。因此发展新型的螺环骨架具有深远的意义和非常高的研究价值。合成螺环骨架化合物的难点在于季碳中心的构建，在以往的例子中，季碳中心的构建无一例外的是采用Lewis酸或者Bronsted酸促进的双重Friedel-Craft反应。开发新的构建螺环骨架的方法具有非常高的研究价值和应用价值。
发明内容
在不对称催化领域，催化剂中配体的骨架对于化学反应的活性，区域选择性和立体选择性。在过去的几十年间，螺环骨架配体已经被证明是一种优势骨架配体。本专利提供了一种新型的氧杂螺环骨架化合物的合成和拆分方法。本发明采用了一种新颖的分子内芳香亲核取代反应首次完成了氧杂螺环二酚骨架化合物的合成和拆分。
本发明的主要目的是：
1)提供了一种构建螺环骨架化合物的新方法。
2)提供了一系列具有氧杂螺环骨架的结构新颖的化合物。
3)提供了上述氧杂螺环骨架化合物的合成方法以及拆分方法。
4)为后续的基于氧杂螺环二酚骨架配体的合成打下坚实的基础。
本发明首先提供了一种氧杂螺环化合物，具有以下通式(I)的结构：
通式(I)中：
R1、R2独立为烷基、烷氧基、芳基、芳氧基或者氢原子，R1、R2、R3和R4可成环或不成环；R5、R6独立为烷基、芳基或者氢原子；R7、R8为烷基、苄基或者芳基。
所述氧杂螺环化合物及其相关配体为(±)-氧杂螺环化合物，(+)-氧杂螺环化合物，(-)-氧杂螺环化合物。
本发明另一目的在于提供一种合成前述化合物的方法，通过下面的路线合成得到：
Scheme 1
和
Scheme 2
优选的前述方法，所述手性化合物可以采用便宜易得的脯氨酸作为拆分试剂实现拆分。
本发明另一目的在于提供前述化合物在催化不对称反应中的应用，所述不对称反应包括氢化反应，氢甲酰化反应，硅氢化反应，硼氢化反应，氢羟基化反应，氢氨化反应，氢氰基化反应，异构化甲酰基化反应，氢氨甲基化反应，转移氢化反应，烯丙基化反应，烯烃复分解反应，环异构化反应，Diels-Alder反应，不对称偶联反应，Aldol反应，Michael加成反应，不对称环氧化反应，动力学拆分和[m+n]环化反应。
前述的应用，该化合物与铑的络合物在烯酰胺的不对称氢化中可以得到高达98％的对映选择性。
本发明另一目的在于提供一种催化不对称反应，使用前述化合物作为催化剂，反应路线如下：
本发明相对于现有技术的有益效果包括：
(1)该氧杂螺环化合物具有中心手性，因此有左旋氧杂螺环化合物和右旋氧杂螺环化合物，消旋的氧杂螺环化合物可以通过消旋的氧杂螺环二酚为原料合成得到。
(2)本发明可以作为手性配体用于烯酰胺类底物的不对称氢化中。其与铑的络合物在烯酰胺的不对称氢化中可以得到高达98％的对映选择性。
具体实施方式
下面通过实施例对本发明加以说明，但本发明并不仅限于以下实施例。
实施例1：
化合物6的合成：
1,3-二氟苯(35g,306mmol)溶于150mL无水四氢呋喃中，Ar保护，-78℃条件下，正丁基锂(123mL,2.5M正己烷溶液)逐滴滴入，滴加完毕后，在-78℃下搅拌1h，然后缓慢加入三甲基硅乙醇酸甲酯(24.339g,150mmol)。滴加完毕后，反应升温至-30℃继续搅拌一段时间然后升至室温。反应结束后在低温下加入稀盐酸淬灭反应，同时脱除三甲基硅基。反应混合液用乙醚和二氯甲烷萃取，合并有机相。减压下除去溶剂得到目标产物1，产物1不需要纯化，直接进行下一步反应。
加入化合物1和150mL 26％的硫酸，100℃下回流反应4h。冷却至室温后，用二氯甲烷萃取，有机相用无水硫酸钠干燥。旋转蒸发除去溶剂得到化合物2的粗产物。柱层析纯化后可以得到化合物2的纯品(32.1g,yield＝85％)。
White solid,1H NMR(400MHz,CDCl3,TMS):δ5.30(s,1H,CH),6.72-6.85(m,4H,Ar),7.12-7.20(m,2H,Ar),9.84(pent,1H,J＝2.8Hz,＝CHO).19F NMR(376MHz,CDCl3,TMS)δ-111.59.13C NMR(100MHz,CDCl3,TMS):δ44.0,111.6(m),130.0(m),161.1(dt,J1＝247.9Hz,J2＝4.4Hz,),194.0(t,J＝1.5Hz).HRMS(ESI)calcd.for C15H8F4O[M+H]:269.0584,Found:269.0576.
500mL反应瓶中，加入2(26.8g，100mmol)，氢氧化锂(48g，2000mmol)，多聚甲醛(60g,2000mmol)，置换N2后，加入无水醚类溶剂(四氢呋喃、二甲氧基乙烷等)300mL，加热搅拌，直到反应进行完全。加入稀盐酸淬灭反应，混合液用乙醚和二氯甲烷萃取，合并有机相。减压下除去溶剂得到粗产物3，经过柱层析纯化可以得到化合物3的纯品(7.0g,yield＝90％)。
White solid,1H NMR(400MHz,CDCl3,TMS):δ2.34(br,2H,OH),4.52(s,4H,CH2),6.75-6.79(m,4H,Ar),7.10-7.20(m,2H,Ar).19F NMR(376MHz,CDCl3,TMS)δ-108.82.13C NMR(100MHz,CDCl3,TMS):δ52.3(t,J＝3.6Hz),65.3,112.4(dd,J1＝22.6Hz,J2＝5.4Hz),118.4(t,J＝14.9Hz),128.7(t,J＝11.8Hz),162.3(dd,J1＝246.5Hz,J2＝9.9Hz).HRMS(ESI)calcd.for C15H12O2F4Na[M++Na]:323.0671,Found:323.0666.
500mL反应瓶中，加入3(30g，100mmol)，叔丁醇钾(33.6g，300mmol)，置换Ar后冰浴下加入300mL干燥的四氢呋喃溶液，然后恢复至室温。加热至60°，直到反应进行完全。加入稀盐酸淬灭反应，混合液分别用乙醚和二氯甲烷萃取，合并有机相。减压下除去溶剂得到产物4(25.6g,yield＝99％)。
White solid,1H NMR(400MHz,CDCl3,TMS):δ4.64(d,J＝9.0Hz,2H,CH2),4.79(d,J＝9.0Hz,2H,CH2),6.57-6.61(m,2H,Ar),6.68(d,J＝8.0Hz,2H,Ar),7.15-7.20(m,2H,Ar).19F NMR(376MHz,CDCl3,TMS)δ-115.6(m).13C NMR(125MHz,CDCl3,TMS):δ54.0(m),82.0,106.2(d,J＝3.6Hz),108.5(d,J＝19.9Hz),115.7(d,J＝18.0Hz),131.1(d,J＝9.1Hz),159.5(d,J＝248.3Hz),161.8(d,J＝8.1Hz).HRMS(ESI)calcd.for C15H11O2F2[M++H]:261.0727,Found:261.0722.
500mL反应瓶中，加入4(26g，100mmol)，叔丁醇钾(67.2g，400mmol)，置换Ar后加入苯甲醇(43.2g,400mmol)。最后加入200mL干燥的DMF，加热至100℃，直到反应进行完全。冷却反应体系至室温，加入大量的水后析出白色固体,过滤得到产物5。母液用乙酸乙酯萃取，除去溶剂后可以收集到残留的产物5(43.6g,yield＝100％)。
White solid,1H NMR(500MHz,CDCl3,TMS):δ4.50(d,J＝9.0Hz,2H,CH2),4.78(d,J＝9.0Hz,2H,CH2),4.80(d,J＝12.0Hz,2H,Ar),4.86(d,J＝12.0Hz,2H,Ar),6.39(d,J＝12.0Hz,2H,Ar),6.43(dd,J1＝8.0Hz,J2＝0.5Hz,2H,Ar),6.78-6.80(m,4H,Ar),7.06-7.09(m,8H,Ar).13C NMR(125MHz,CDCl3,TMS):δ54.7,69.1,82.7,103.2,104.6,116.7,126.2,127.2,128.1,130.0,136.8,155.8,161.6.HRMS(ESI)calcd.for C14H8F4ONa[M++H]:437.1753,Found:437.1747.
100mL反应釜中，加入5(43.6g,100mmol),Pd/C(5％,2.0g),然后加入50mL四氢呋喃。在40atm的氢气压力下进行反应24h，反应进行完全。能够以当量的收率拿到目标产物6(25.6g,yield＝100％)。
White solid,1H NMR(500MHz,d6-DMSO,TMS):δ4.50(d,J＝9.0Hz,2H,CH2),4.58(d,J＝9.0Hz,2H,CH2),6.23-6.27(m,4H,Ar),6.92(dd,J1＝8.0Hz,J2＝8.0Hz,2H,Ar),6.78-6.80(m,4H,Ar),7.06-7.09(m,8H,Ar).13C NMR(125MHz,d6-DMSO,TMS):δ54.2,81.4,101.1,108.7,115.6,130.1,155.2,161.7.HRMS(ESI)calcd.for C15H13O4[M+H]+:257.0814,Found:257.0808.
实施例2：
化合物6的拆分：
1000mL反应瓶中，加入rac-6(51.2g,200mmol),D-proline(11.5g,100mmol),然后加入300mL乙酸乙酯。反应混合物在回流条件下搅拌10h。有大量白色固体析出，冷却至室温过滤并收集白色固体A；过滤后的母液在减压条件下出去溶剂，然后再次加入D-proline(11.5g,100mmol)，溶剂改为乙腈，同样在回流条件下搅拌10h，析出大量白色固体，冷却至室温。过滤收集白色不溶物B。母液在减压条件下除去溶剂，接着重复上述拆分过程。将所有收集到的固体A加入到乙酸乙酯和水的混合溶剂中震荡，白色不溶物逐渐溶解消失。将水相用乙酸乙酯萃取1-2遍，合并有机相干燥减压除去溶剂，可以得到(S)-6(ee值在60％到90％之间)，然后在乙酸乙酯中重结晶就可以得到光学纯的(S)-6(ee大于99％)。用同样的方法就可以得到光学纯的(R)-6(ee大于99％)。
实施例3：
氧杂螺环二胺的合成：
N2氛围下，向一个250mL反应瓶中加入(S)-6(7.68g,30mmol)，然后加入150mL干燥的二氯甲烷。室温下搅拌体下加入吡啶(6.0mL,100mmol)。待反应体系澄清后，冷却至零度，然后逐滴加入Tf2O(12.0mL,70mmol)，滴加完毕后升至室温继续搅拌1h。加水淬灭反应。反应体系用稀盐酸洗涤，有机相在减压条件下出去溶剂，经过柱层析就可以得到产物(S)-7(15.6g,yield:99％)
1H NMR(500MHz,CDCl3)δ4.70(d,J＝10.0Hz,2H,CH2),4.87-4.90(m,2H,CH2),6.91-6.93(m,4H,Ar),7.32(dd,J1＝8.5Hz,J2＝8.0Hz,2H,Ar).
N2氛围下，反应管中加入(S)-7(2.60g,4mmol)、Pd(OAc)2、BINAP(504mg,0.8mmol)、BnNH2(5mL,40mmol)、碳酸铯(4.8g,12mmol)和30mL无水甲苯，100℃下反应过夜。冷却至室温后，硅藻土过滤，滤液在减压下出去甲苯。粗产物经过柱层析进行纯化(石油醚：乙酸乙酯＝20:1)可以得到产物(S)-8(1.493g,yield:86％)。
1H NMR(500MHz,CDCl3)δ4.29(s,6H,NH and CH2),4.52(d,J＝9.5Hz,2H,CH2),4.74(d,J＝9.5Hz,2H,CH2),6.22(d,J＝8.0Hz,2H,Ar),6.28(d,J＝8.0Hz,2H,Ar),7.02-7.06(m,6H,Ar),7.20-7.29(m,6H,Ar).
20mL反应瓶中，加入(S)-8(0.868g,2mmol)和10％Pd(OH)2/C(200mg)，然后加入5mL乙酸乙酯和2mL甲醇。40℃条件下，反应在40atm的氢气氛围中进行知道化合物(S)-8反应完全。可以得到产物(S)-9(462mg,yield＝91％)。
1H NMR(400MHz,CDCl3)δ3.68(br,4H,NH2),4.51(d,J＝7.2Hz,2H,CH2),4.70(d,J＝7.2Hz,2H,CH2),6.23(d,J＝6.8Hz,2H,Ar),6.34(d,J＝6.8Hz,2H,Ar),7.04(dd,J1＝J2＝6.4Hz,2H,Ar).
实施例4氧杂螺环单膦配体的合成及其在不对称氢化中的应用
N2氛围下，向25mL封管中加入(R)-6(0.256g,1mmol)和三(二甲氨基)膦(244mg,1.5mmol)，然后加入5mL无水甲苯。120℃条件下，反应8h。冷却至室温后减压除去甲苯，然后柱层析得到目标产物L1(186mg,yield＝67％)。
1H NMR(500MHz,CDCl3)δ2.41(d,J＝9.5Hz,6H,CH3),4.15-4.20(m,2H,CH2),4.63-4.67(m,2H,CH2),6.47-6.49(m,1H,Ar),6.66-6.74(m,3H,Ar),7.13-7.16(m,1H,Ar),7.20-7.23(m,1H,Ar).31PNMR(202MHz,CDCl3)δ125.2.
将烯酰胺底物S1(16mg,0.1mmmol)加入到5mL的氢化小瓶中，然后加入0.5mL的甲苯，底物溶解后加入20μL[RhCODCl]2和L1的二氯甲烷溶液(0.05M,[RhCODCl]2/L1＝1/2.1)，将氢化小瓶放置于10atm的氢气反应釜中室温下搅拌24h。停止反应后通过核磁来确定反应的转化率，通过手性HPLC(ADH,95/5,1.0mL/min)来测定产物P1的ee值。
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本发明的保护范围。
Claims (1)
1.一种合成氧杂螺环化合物的方法，所述化合物具有以下通式(I)的结构：
其特征在于，通式(I)中：
R1、R2、R3、R4、R5、R6独立为氢原子，X、Y同时为F、OBn、OH、OTf、NHBn或NH2；
所述方法是以间二氟苯为原料进行合成，合成路线为：
和
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