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1、Lecture:Transition Metal Catalyzed Complexity Generating Reactions 2Metathesis,OutlineOverview of olefin metathesisOlefin metathesisRing closing metathesisRing opening metathesisCross metathesisEnyne metathesisDiyne metathesis,ReferenceACIEE.,2000,39,3012ACIEE.,1997,36,2036JCS.PT1,1998,371Tetrahedro
2、n.1998,54,4413Acc.Chem.Res.1995,28,446,更多资源,Organo-transition Metal Chemistry,Chemistry involves intermediates containing transition metal-carbon bonds,Olefin Metathesis,Olefin Metathesis:metal-catalyzed exchange of olefins.,Metal-carbene Complex,Olefin metathesis catalysts tend to be between Schroc
3、kand Fischer carbenes,Representative Catalysts,Development of well-defined metal-carbene complexes as pre-catalysts,Developments in Catalyst,Sigma-donating N-heterocyclic carbene ligands increase general reactivity and thermal stabilityArduengo A.et al Acc.Chem.Res.1999,32,913,Attaching Privileged c
4、hiral ligandPossible bench top use Hoveyda.A.H.et al Angew.Chem.Int.Ed.2001,40,1452,Still useful for some substratesAir and moisture sensitive(glove box)J.Org.Chem.1998,63,8626,Mechanistic Model of the Metathesis Reaction,Consists of a sequence of reversible formal 2+2 cycloaddition/cycloreversion p
5、rocesses.,Grubbs.R.H.et al J.Am.Chem.Soc.1975,97,3265,Categories of Metathesis Events,RCM(Ring-closing metathesis)A B CROM(Ring-opening metathesis)C B ACM(Cross metathesis)A B DROMP(Ring-opening metathesis polymerization)C B E,Engineering the Direction of the Equilibrium for Ring Closing Metathesis,
6、Ethylene gas generally decreases RCM rateLower concentration can prevent polymerization and cross metathesisHigher temperature usually promotes RCM process(S gain),Detailed Mechanistic Model of RCM,Dissociative pathway dominates,Grubbs.R.H.et al J.Am.Chem.Soc.1997,119,3887,Factors Affecting RCM,Subs
7、titution effects on metal carbene and olefin exchange(sterics and electronics),Grubbs.R.H.et al.Organometallics 1998,17,2484,RCM is one of the most useful strategies for ring closure but it cannot be used to make three or four membered rings due to ring strain and the reversibility of the process,Ma
8、ier.M.E.et al.Angew.Chem.Int.Ed.2000,39,2073,Substitution Effects on RCM:A Comparison of Catalysts,Chemtracts(Org.Chem)2000,88,RCM:An Invaluable Tool for Generation of Cyclic Structures in TOS,Remarkable functional group tolerance,Danishesky.S.J.et al J.Am.Chem.Soc.1997,119,10073,Martin.S.F.et al J.
9、Am.Chem.Soc.1999,121,866Furstner.A.et al J.Org.Chem.1996,61,8746Hoveyda.A.H et al J.Am.Chem.Soc.1995,117,2943,Clark.J.et al Angew.Chem.Int.Ed.2000,39,372,Double RCM 1,Diastereoselective two-directional RCM,About“Two-directional chain synthesis in TOS”Schreiber.S.L.et al Acc.Chem.Res.1994,27,9,Double
10、 RCM 2,Wallace.D.J.et al Tet.Lett.2000,41,2027Harrity.J.P.et al Tet.Lett.1999,40,3247,Differentiation of diastereotopic olefins,ROM/Double RCM 1,A powerful topology-altering reaction.,Schreiber.S.L.et al,Org.Lett.2000,2,709,Shair M.D.et al,unpublished,ROM/Double RCM or RCM,Schreiber.S.L.et al unpubl
11、ished,One stereocenter dictates mode of cyclization,ROM/RCM 2,Unstrained cyclic olefin(cyclopentane,cyclohexane).Ethylene gas prevents polymerization.Subtle differences in substrates frequently alter the equilibrium.,Blechert.S.et al Chem.Comm.2000,1501,ROM/Double RCM 3,Burke.S.D.et al J.Org.Chem.19
12、98 63 8826,Difference in reactivity of two catalysts,RCM:Macrocycle Synthesis,Furstner.A.et al,Synthesis 1997 792,En Masse Generation of Macrocycles Using Conformational Analysis,Schreiber.S.L.et al J.Am.Chem.Soc.1999,121,10648.,Expanded six-membered ring leads to higher effective molarity between t
13、wo reactive terminiMinimization of Syn-pentane interaction and A1,3 strain,En Masse Generation of Macrocycles Using Conformational Analysis,Schreiber S.L.et al unpublished,Preference for E-olefin formation due to the conformational bias.,Cross Metathesis 1,In general,lack of control of homo-and hete
14、ro-dimerizationEmployment of an excess of the disubstituted olefin counterpart(preformed homo-dimer)relative to terminal olefin leads to selective formation of hetero-dimer.,Grubbs.R.H.et al.J.Am.Chem.Soc.2000,122,58,Cross Metathesis 2,Grubbs.R.H.et al.J.Am.Chem.Soc.2000,122,3783,Smith III.A.B.et al
15、 J.Am.Chem.Soc.2000,122,4984AlsoFurstner.A.et al Org.Lett.2001,3,449,CM/Macro-RCM 1,Target product is much lower in energy than other possible productsRemarkable robustness of metal carbene speciesExploitation of reversible nature of cross-metathesis process,CM-RCM 2Convergence of Intermediates to P
16、roducts,Smith III.A.B.et al J.Am.Chem.Soc.2000,122,4984,Enyne Metathesis,Mechanism:Yne-ene type or Ene-yne type,Enyne-RCM gives Type I or Type II diene formation,Grubbs.R.H.et al J.Am.Chem.Soc.1994,116,10802,Tandem Dienyne RCM 1,Tandem Dienyne RCM 2,Boyer.F.D.et al Org.Lett.2001,3,3095,Mori.M.et al
17、Org.Lett.2001,3,1161,ROM/RCM on Enyne Substrate,Without ethylene gas,the reaction does not proceed,Enyne-CM/RCM/DA,Diver.S.et al Tet.Lett.2001,42,171,E/Z selectivity of CM determines RCM,Macro-Enyne-RCM 1 Type II Diene Formation,Shair.M.D.et al,unpublished,Macro-Enyne-RCM 2 Transannular Diels-Alder
18、Reaction,Shair.M.D.et al,unpublished,更多资源,Diyne Metathesis,Alkyne RCM in combination with Lindlar partial hydrogenation is a selective way to generate macrocyclic(Z)-olefins,Catalyst(Schrock alkylidyne complex),Diyne Macro-RCM,Furstner.A.et al J.Am.Chem.Soc.1999,121.11108,Tandem AA and RO-RCM,Bleche
19、rt.S.et al.J.Am.Chem.Soc.2000,122,9584,Sequential Pd-catalyzed asymmetric allylic alkylation followed by ROM/RCM,RCM-Heck Reaction,Stepwise,Sequential,Cascade process,Grigg.R.et al Tet.Lett.1998,39,4139,Tandem Heck-RCM,Sequential Process:Removal of CO and protonation of the amine allows metathesis to proceed,Grigg.R.et al Tet.Lett.1999,40,3021,Combination of Enyne-RCM with Intermolecular Diels-Alder Reaction,Heerding.D.A.et al,Tet.Lett.1998,39,6815,A 4,320 member split-pool library was synthesized,
