1、State Key Lab of Organometallic Chem, SIOC, China,有机合成反应,张兆国金属有机化学国家重点实验室,电话： 64163300 X 3435 (办公室) E-mail: 地址： 3# 435,State Key Lab of Organometallic Chem, SIOC, China,Cycloaddition Reactions-1,Diels-Alder Reaction2003-10-13,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction,Di
2、els, O.; Alder, K. Justus Liebigs Ann.Chem. 1928, 460, 98-122.,The discovery of the Diels-Alder reaction in 1928, a reaction for which the namesakes would receive the Nobel Prize in Chemistry in 1950: Diels the professor, Alder the student. Angew. Chem. Int. Ed. 2002, 41, 1668.,Diels-Alder Reaction,
3、State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction,Definition The 1,4-addition of the double bond of a dienophile to a conjugated diene to generate a six-membered ring, such that up to four new stereocenters may be created simultaneously. The 4+2-cycloaddition usually occurs with
4、 high regio- and stereoselectivity.,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction,Diels, O.; Alder, K. Justus Liebigs Ann.Chem. 1928, 460, 98-122.,Diels, O.; Blom, J. H.; Koll, W. Justus Liebigs Ann.Chem. 1925, 443, 242.,State Key Lab of Organometallic Chem, SIOC, China,Diel
5、s-Alder Reaction,Synthetic Application,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction,Synthetic Application,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction,Stereochemistry,1. With respect to the dienophile, the addition is stereospecifically syn, with v
6、ery few exceptions.,2. With respect to 1,4-disubatituted dienes,fewer cases have been investigated, but here too the reaction is stereospecific. Thus, trans, trans-1,4-diphenylbutadiene gives cis-1,4-diphenylcyclohexene.,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction,Stereoch
7、emistry,3. The diene must be in cisoid conformation. If it is frozen into the transoid conformation, the reaction does not take place. The diene either must be frozen into cisoid conformation or must be able to achieve it during the reaction.,4. When the diene is cyclic, there two possible ways in w
8、hich addition can occur if the dienophile is not symmetrical. The larger side of the dienophile is not symmetrical. The larger side of the dienophile may be under the ring (endo addition), or it may be the smaller side (exo addition). Most of the time, the addition is predominately endo.,State Key L
9、ab of Organometallic Chem, SIOC, China,Diels-Alder Reaction,Stereochemistry,5. When an usymmetrical diene adds to an unsymmetrical dienophile, there two possible products (not counting stereoisomers).,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction,Reaction rate-determining fa
10、ctors,Electron-donating groups in the diene accelerate the reaction EWG in the diene retard the reaction EDG in the dienophile increase the reaction rate EWG in the dienophile decrease the reaction rate,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction,Reaction rate-determining
11、factors,Diene Reactivity as measured against Maleic anhydride,Sauer, Angew. Chem. Int. Ed., 1980, 19, 779-807,Lewis Acid catalysis of the reaction is possible Although Diels-Alder reaction usually needs no catalysts, Lewis acids catalyze the reaction and influence the endo/exo selectivity. Addition
12、of Lewis acids sometimes increase the reaction rate dramatically and/or alter the reaction selectivity. (Yates & Eaton, JACS 1960, 82, 4436),State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction,Orbital symmetry considerations for D-A reaction,If the symmetries of the frontier MOs o
13、f reacting partners are “properly matched“ the reaction is referred to as “symmetry-allowed“. The Diels-Alder reaction is such a case. The HOMO and LUMO of both the diene and dienophile, which in this case are the same, will constructively overlap as indicated in formation of both sigma bonds. Prima
14、ry orbital overlap leads directly to the formation of new chemical bonds.,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction,The Alder Endo Rule: Why endo-selective,Of the two possible transition states, the one having the “greatest accumulation of interacting double bonds will b
15、e preferred“ (the Alder Endo Rule).,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction,The Alder Endo Rule: Why endo-selective,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction,Frontier MO Explanation for the Endo Rule,Secondary (transient) orbital overlap ca
16、n also occur in the stabilization of certain transition state geometries. Such a transient stabilizing interaction can occur in the endo, but not exo.,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction,The closer the two orbitals are in energy, the better they interact As DE decr
17、eases for the relevant ground state FMOs, rxn rates increase,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction-Role of Lewis acid,Role of Lewis acids-Rate enhancement and regioselectivity control,Lewis acid c
18、atalysis not only dramatically increases rates by ca 106 it also improves reaction regiochemistry,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction-Role of Lewis acid,Role of Lewis acids-Endoselectivity improvement,Lewis acid catalysis improves endo diastereoselection D-A Reacti
19、on Mechanism, Sauer, Angew. Chem. Int. Ed., 1967, 6, 16-33,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction- Regioselectivity control,Regioselectivity control: Removable group in dienes (EDG),State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction- Regioselectivi
20、ty control,Regioselectivity control: Removable group in dienophiles (EWG),By employing a removable substituent, it is possible to access the normally disfavored product diastereoisomer Danishefsky, JACS 1978, 100, 2918: The NO2 FG completely dominates directivity,State Key Lab of Organometallic Chem
21、, SIOC, China,Diels-Alder Reaction-,Diels-Alder Reaction- Regioselectivity control,Homework-1,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction-case study,Lewis acid tuned regioselectivity -A model,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction-,Diels-Ald
22、er Reaction-case study,Lewis acid tuned regioselectivity -explanation,Similar results provided by Stoodley, Chem. Comm. 1982, 929,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction-,Diels-Alder Reaction-case study,Lewis acid tuned regioselectivity -a second model,Similar results
23、provided by Kelly Tet. Let. 1978, 4311,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction-,Diels-Alder Reaction-case study,Diels-Alder Reactions with Chiral Dienes,Comprehensive Organic Synthesis, Vol. 5, Trost, Ed. 1991 4.1 Intermolecular Diels-Alder Reactions, W. Oppolzer, See
24、page 347,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction-,Diels-Alder Reaction-case study,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction-,Diels-Alder Reaction-Lewis acid catalysis,Lewis Acid Carbonyl Complexes,The eta-1 complexes are well studied,State
25、Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction-,Diels-Alder Reaction-Lewis acid catalysis,Calculated Muliken Charges on Carbonyl Carbon (PM3),State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction-,Diels-Alder Reaction-case study,Diels-Alder Reaction-Lewis acid cata
26、lysis,Well-defined Lewis acid-C=O Complexes,Aldehydes: LA oriented anti to R moiety,Esters: Lewis acid oriented anti to RO moiety,Oxygen-lone pairs* CO interactions strongly stabilize the (Z) ester conformation. Such stabilization should be expected to increase in LA-substrate complex.,State Key Lab
27、 of Organometallic Chem, SIOC, China,Diels-Alder Reaction-,Diels-Alder Reaction-case study,Diels-Alder Reaction-Lewis acid catalysis,Well-defined Lewis acid-C=O Complexes,Amides: Lewis acid oriented anti to R2N moiety,Chelating Esters & Amides: Lewis acid can be bidentate coordinated,This situation
28、is sometimes hard to predict,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction-,Diels-Alder Reaction-case study,Diels-Alder Reaction-Lewis acid catalysis,Representative 1 Complexes & their X-ray Structuctures,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction
29、-,Diels-Alder Reaction-case study,Diels-Alder Reaction-Lewis acid catalysis,Representative h1titanium complexes with organic compounds,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction-,Diels-Alder Reaction-case study,Diels-Alder Reaction-Lewis acid catalysis,Representative h1ti
30、tanium complexes with organic compounds,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction-,Diels-Alder Reaction-case study,Diels-Alder Reaction-Lewis acid catalysis,Chem 3D Model For the explanation of stereochemistry,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder
31、 Reaction-,Diels-Alder Reaction-case study,Diels-Alder Reaction-Lewis acid catalysis,Explanation to Regio- and stereoselectivity for Non-Chelate Ester-Type Chiral Auxiliaries,Oppolzer ACIEE 1984, 23, 876.,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction-,Diels-Alder Reaction-ca
32、se study,Ester-Type Chiral Auxiliaries: Chelating Dienophiles,Helmchen Tetrahedron Lett. 1984, 25, 2191. ACIEE 1985, 24, 112. Tetrahedron Lett. 1985, 26, 3095.,Diels-Alder Reaction-Lewis acid catalysis,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction-,Diels-Alder Reaction-case
33、study,Chelating Imide-type Chiral Auxiliaries,Diels-Alder Reaction-Lewis acid catalysis,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction-,Diels-Alder Reaction-case study,Binding Mode Dictates Diastereoselectivity,Diels-Alder Reaction-Lewis acid catalysis,State Key Lab of Organo
34、metallic Chem, SIOC, China,Diels-Alder Reaction-,Diels-Alder Reaction-case study,Diels-Alder Reaction-Lewis acid catalysis,A Case for P-Stacking,Angew Chem, Int Ed. 1987, 26, 1184,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction-,Diels-Alder Reaction-case study,Diels-Alder Reac
35、tion-Lewis acid catalysis,A Case for P-Stacking,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction-,Diels-Alder Reaction-case study,Diels-Alder Reaction-Lewis acid catalysis,A Case for P-Stacking,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction-,Diels-Alder
36、Reaction-Asymmetric catalysis,Cu(box) and Cu(pybox) catalyst-substrate complexes implicated in enantioselective reactions,“Chiral Bis(oxazoline) Copper (II) Complexes: Versatile Catalysts for Enantioselective Cycloaddition, Adol,Michael and Carbonyl Ene Reactions“. Johnson, Evans, Acc. Chem. Res. 20
37、00, 33, 325-335.,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction-,Diels-Alder Reaction-case study,Diels-Alder Reaction-Asymmetric catalysis,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction-,Diels-Alder Reaction-case study,Diels-Alder Reaction-Asymmetric c
38、atalysis,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction-,Diels-Alder Reaction-Reading materials,The Diels-Alder Cycloaddition Reactions “Diels-Alder Reactions“. Evans, D. A.; Johnson J. S. In Comprehensive Asymmetric Catalysis, Jacobsen, E. N.; Pfaltz, A.; and Yamamoto, H. Ed
39、itors; Springer Verlag: Heidelberg, 1999; Vol III, 1178-1235“Chiral Bis(oxazoline) Copper (II) Complexes: Versatile Catalystsf or Enantioselective Cycloaddition, Adol, Michael and Carbonyl Ene Reactions“. Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325-335.“New Strategies for Organic Cata
40、lysis: The first Highly Selective Organocatalytic Diels-alder Reaction“, MacMillan, JACS, 2000, 122, 4243.“New Strategies for Organic Catalysis: The first Enantioselective Organocatalytic 1,3-Dipolar Cycloaddition“, MacMillan, JACS, 2000, 122, 4243.“” Ding, JACS, 2003, 125, 11,State Key Lab of Organometallic Chem, SIOC, China,Diels-Alder Reaction-,Diels-Alder Reaction-Home Work,Rationalize the sense of asymmetric induction for this Diels-Alder Reaction reported by MacMillan, JACS, 2000, 122, 4243.,Design a reasonable route to make the following compound,
