D. A. Evans Cycloaddition Reactions: Part-1 Chem 206 Other Reading material http://www.courses.fas.harvardedu/-chem206/ [2+2] Cycloaddition Reactions Tidwell, T. T. Ketenes, John Wiley and Sons, 1995 Chemistry 206 Ghosez, L; Marchand-Brynaert, J. Comprehensive Organic Synthesis, Vol 5, Pergamon, 1991, p. 85-122 Advanced Organic Chemistry The Diels-Alder Cycloaddition Reactions Diels-Alder Reactions". Evans. D. A: Johnson J. s In Lecture number 15 Comprehensive Asymmetric Catalysis, Jacobsen, E N; Pfaltz, A and yamamoto, h ed oringer Verlag: Heidelberg, 1999: Vol ll.1178-1235(pdf Cycloaddition Reactions-1 ■ Problems of the Day I Introduction to Cycloaddition Reactions Propose a mechanism for this transformation I(2+2] Cycloaddition Reactions The Diels- Alder reaction EtN(Pr)2 Reading Assignment for week Carey Sundberg: Part A; Chapter 11 Concerted Pericyclic Reactions MacMillan, JACS 1999. 121 9726 Carey Sundberg: Part B; Chapter 6 Cycloadditions, Unimolecular Rearrangements Thermal eliminations Predict the stereochemical outcome of this reaction Fleming: Chapter 4 2 LDA, TMSCI oH O Thermal Pericyclic Reactions Wednesday Matthew d. shair October 23 2002 Kut,JOc1985,50,1840
http://www.courses.fas.harvard.edu/~chem206/ O N Me Cl Me O TiCl4 Me O OH O Me O N O Me Me OH O Me OTMS Me D. A. Evans Chem 206 Matthew D. Shair Wednesday, October 23, 2002 ■ Reading Assignment for week: Carey & Sundberg: Part A; Chapter 11 Concerted Pericyclic Reactions Cycloaddition Reactions: Part–1 Chemistry 206 Advanced Organic Chemistry Lecture Number 15 Cycloaddition Reactions-1 ■ Introduction to Cycloaddition Reactions ■ [2+2] Cycloaddition Reactions ■ The Diels-Alder Reaction ■ Other Reading Material: Fleming: Chapter 4 Thermal Pericyclic Reactions ■ Problems of the Day: [2+2] Cycloaddiltion Reactions The Diels-Alder Cycloaddition Reactions EtN(iPr)2 Propose a mechanism for this transformation MacMillan, JACS 1999, 121, 9726 Carey & Sundberg: Part B; Chapter 6 Cycloadditions, Unimolecular Rearrangements Thermal Eliminations Tidwell, T. T. Ketenes, John Wiley and Sons, 1995. Ghosez, L.; Marchand-Brynaert, J. Comprehensive Organic Synthesis, Vol. 5, Pergamon, 1991, p. 85-122. "Diels-Alder Reactions". Evans, D. A.; Johnson J. S. In Comprehensive Asymmetric Catalysis, Jacobsen, E. N.; Pfaltz, A.; and Yamamoto, H. Editors; Springer Verlag: Heidelberg, 1999; Vol III, 1178-1235 (pdf) 2 LDA, TMSCl ❉ ❉ Kurth, JOC 1985, 50, 1840 Predict the stereochemical outcome of this reaction
D A. Evans Johnson Eschenmoser Claisen Rearrangements Chem 206 Johnson Orthoester Claisen Eschenmoser- Claisen Lead paper. Johnson, Faulkner, Peterson, JACS 1970, 92, 741 Eschenmoser. A. Helv. Chem. Acta 1964. 47 2425: He/v. Chim Acta 1969. 52. 1030 EtCo2H(cat) Me-C-oEt Eto oEt Et2N OMe I Compare the two variants CH3CH2 H(cat) Eto2C CH3C(NMe2)(OMe)2 38°c M 60% Hg(OAc)2.EVE High yield, E:Z= 99:1 98°c CH2=C(OMe)NEI2) Me2N OHC 98%(EZ=86:14) Xylene,140°C,14h The Saucy Marbet Alternative a Synthesis of Amide Acetals NMe, EtOH Me NMe2 94% 125°C C3H5 diastereoselection 6. 1 oEt Me evenson Tet Let. 1991. 32 4199 OL Saucy, Marbet, He/v. Chim. Acta 1967, 50, 2091, 2095 Me2(oBn) CMez(oBn Welch, JACS 1987
Et O Et Et OEt Me NMe2 N Me OMe C3H5 R N O Me Me BF4 - + + + OH Me C OEt OEt OEt EtO OEt Me O OH OEt O O OEt Me S Me OH Me EtO2C Me O Me Me Me OHC Me Et2N OMe O O Me H NMe2 Et OH Et Me CO2Me OH Me Me OH Me Me Me NMe2 O Me Me O Me OH Me Me Me Me OMe Et2N OMe Me OLi CMe2(OBn) O N Me Me Me OLi N Et OMe CMe2 (OBn) O Me Me Me Me Me O Me Me Me CHO Me Me Me Me OMe Me OEt H3PO4 D CH3C(OEt)3 CH3C(NMe2)(OMe)2 CH2=C(OMe)(NEt2) Et2O EtOH NaOEt CO2Me Me O Me2N Me O NEt2 NEt2 O Me NMe2 EtO OEt Et Me NMe2 O H ■ Reactions to ponder: 60% 94% 125oC 125oC H3PO4 or TsOH The Saucy Marbet Alternative Saucy, Marbet, Helv. Chim. Acta 1967, 50, 2091,2095 EtCO2H (cat) + Predict the major diastereomer Welch, JACS 1987, 109, 6716 Stevenson, Tet. Let. 1991, 32, 4199 diastereoselection 6:1 Predict the major diastereomer ■ Compare the two variants: 92% (E:Z = 98:2) 98% (E:Z = 86:14) 60% 138oC 98oC Hg(OAc)2 , EVE CH3CH2CO2H (cat) ■ Lead paper: Johnson, Faulkner, Peterson, JACS 1970, 92, 741 Johnson Orthoester Claisen D. A. Evans Johnson & Eschenmoser Claisen Rearrangements Chem 206 ■ Synthesis of Amide Acetals Eschenmoser-Claisen Eschenmoser, A. Helv. Chem. Acta 1964, 47, 2425; Helv. Chim.Acta 1969, 52, 1030. Xylene, 150oC Xylene, 110oC High yield, E:Z = 99:1 Faulkner and Peterson Xylene, 140oC, 14h 70%
D. A. Evans reland Enolate Claisen Rearrangement Chem 206 Ireland-Enolate Claisen Substituted enolates afford an additional stereocenter a Reviews Pereira. Aldrichimica Acta 1993. 26.17-29 Ireland. Aldrichimica Acta 1988. 21 59-69 Ireland, R. E: Mueller, R. H: Willard, A. K.J. Am. Chem. Soc. 1976. 98, 2868 OTBS OTBS conditions(E)-( z control 12(320c)=35h LDA. TBSCI LDA, TBSCI 94: 6 kinetic 7 93 thermo Enolization: Amide bases R2 Stereoelectronic Requirements: The a-CH bond must be able to erlap withπ*C-O OTB key study: Ireland, JOC 1991, 56, 650 and earlier cited papers 兀*C-0 Hc\hb R Double Claisen Rearrangements are also possible Paterson, Tet Lett 1991, 32, 7601 avored 日 LDA TMSC LM-Nr, disfavored 1,2 1, 5 syn relationship via The Ireland model 976,98,286 a、(地地了8y 981.22,4119 more recent study. 0c1991,56,650
Me R2 R1 OTBS O O OTBS R2 R1 Me O O R2 R1 Me O Et OEt N R R H H R Li O Me N R R H Me R Li O H ✽ ✽ ✽ O O Me O OTMS R O Me Hc Hb Ha R C O Hc Hb R O – OLi R Me R Me OLi OH O O Me Me OH OH Me Me Me Me Me Me O RO OR Me Me O O Me H OTBS H H R1 O R2 R2 H O R1 H OTBS Me H Me Me O O Me Me O Me Me O O R2 R1 OTBS O Me Me O OTBS R2 R1 OTBS OTBS Me O Me O O Me Me Me Me Ireland-Enolate Claisen Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868 LDA Me3SiCl t1/2 (32oC) = 3.5 h 66% ■ Reviews Pereira, Aldrichimica Acta 1993, 26, 17-29 (Ireland-Claisen) Ireland, Aldrichimica Acta 1988, 21, 59-69 (Claisen-related) D. A. Evans Ireland Enolate Claisen Rearrangement Chem 206 ■ Enolization: Amide Bases LM–NR2 ‡ (E) Geometry (Z) Geometry The Ireland Model (JACS 1976, 98, 2868) Narula, Tetrahedron Lett. 1981, 22, 4119 more recent study: Ireland, JOC 1991, 56, 650 Substituted enolates afford an additional stereocenter LDA, TBSCl LDA, TBSCl DMPU ✽ (E) (Z) conditions (E):(Z) LDA, TBSCl LDA, TBSCl DMPU 94:6 7:93 key study: Ireland, JOC 1991, 56, 650 and earlier cited papers Stereoelectronic Requirements: The a-C-H bond must be able to overlap with p* C–O – Ha + base p* C–O Paterson, Tet Lett 1991, 32, 7601 LDA, TMSCl Et3N 20-60 °C 1,2 syn aldol relation permuted into 1,5 syn relationship via Claisen rearrangement 63% yield (diastereoselection 86%) Double Claisen Rearrangements are also possible ‡ ‡ favored disfavored control kinetic thermo
D. A. Evans Cycloaddition Reactions-1 Chem 206 Why does maleic anhydride react easily with 1, 3-butadiene, but not with ■ Consider2+2] cycloaddition: Photochemical activation[π2s+π2s] ethylene? So what are the rules"? dThe related reaction of 2 ethylenes is nonconcerted: [2+ 2] cycloaddition HOMO 区一叹 a We also know that the photochemical variant is concerted The frontier orbitals of the reacting species must have the proper symmetries [2+2] Cycloaddition-Examples Nomenclature uprafacial Dy Quadricyclane Dauben, Tet. 1961, 15, 197 Using this nomenclature the Diels-Alder reaction is a T4s+ I2S ■ Consider2+2 I cycloaddition: Thermal activation【π2s+π2S] Schafer, AC 1967. 79. 54 Dewarbenzene-Derivative Prismane-Der akan抛 bonding t2 bonding [π2S+π2a" allowed π2s+π2]" forbidden must be antarafical for indicated stereochem L1967.4357.4723
X C C C C C C C C C C C C C C C C C C C C C C C C C C C C O O O O O O X Y Y X C C H Me Me Me Me Me Me Me Me Me Me Me Me HOMO X Y O O O D. A. Evans Cycloaddition Reactions-1 Chem 206 Why does maleic anhydride react easily with 1,3-butadiene, but not with ethylene? So what are the "rules"? [4+2] [2+2] p* p concerted ✻ bonding bonding + energy ✻ + light ✻ p p* new HOMO light ■ Consider [2 + 2] cycloaddition: Photochemical activation [ p2s + p2s] bonding ■ Consider [2 + 2] cycloaddition: Thermal activation [ p2s + p2s] The frontier orbitals of the reacting species must have the proper symmetries heat ■ The related reaction of 2 ethylenes is nonconcerted: [2 + 2] cycloaddition LUMO · · ■ We also know that the photochemical variant is concerted ■ Nomenclature p2s p2a Using this nomenclature, the Diels-Alder reaction is a p4s + p2s cycloaddition p2s p2s antibonding [ p2s + p2s] "forbidden" p2s p2a [ p2s + p2a] "allowed" bonding bonding suprafacial antarafacial [p 2 s + p 2 a] must be antarafical for indicated stereochem TL 1967, 4357, 4723. [2+2] Cycloaddition - Examples hn [p 2 s + p 2 s ] hn [p 2 s + p 2 s ] Quadricyclane Prismane-Der. Dauben, Tet. 1961, 15, 197. Schäfer, AC 1967, 79, 54. Dewarbenzene-Derivative
D. A. Evans Cycloaddition Reactions-2 Chem 206 Summary of Ketene Cycloadditions 人 c=0 Br Zn PhC=C=O R cH2c CH2 C=0 FMO Analysis Ketene Preparation HOMO sc=o Staudinger Reaction(very gener X=CL Ts AcO. DCC. etc.. (CH3 CO)20 H2C=C=0 ACOH RCH2CO2Ar -,O C=0
H2C C O Ph2C C O H C O O ZnBr2 Zn O O D O Ph Br O Ph Br O O O H O R R' O O R R' R' R O R R' R' R O (CH3CO)2O R X O R' C O R R' D H2C C O AcOH OH R O OAr C O R -ArO H2O C O R R' N O R R' Z Y O X R R' X Y Y X O R' R O R' R O 1 R 2 R 3 C O R 1 R 2 R 3 or D R R' O N2 or D C O R R' R O H D -CH2CH2 C O R H HOMO O H H O D R3N RCH2CO2Ar O O R R' D. A. Evans Cycloaddition Reactions-2 Chem 206 Ketene Preparation Staudinger Reaction (very general) X = Cl, Ts, AcO, DCC, etc... + _ _ _ _ _ _ or Alkene Imine R = -CH=CH2 1,3-Dipole Carbonyl Summary of Ketene Cycloadditions 550 °C hn hn [p 2 sp 2 a ] LUMO FMO Analysis
D. A. Evans Cycloaddition Reactions-3 [2+2]: Stepwise Versus Concerted Ketene-Alkene[2+2 H R 一兮 least hindered Stepwise Concerted Very large polar effects E olefins yield a mixture of cis and trans Ketenes add stereoselectively to Z for support stepw than e Calculations(Wang and Houk show a highly synchronus transition state in the gas phase All stereochemical outcomes can be tionalized assuming a stepwise mechanism Frey, H M. Isaacs, NJ J. Chem soc.B,1970,830832 Solvent Effects Ketenes Aldehydes Afford p-Lactones ab initio calulations endolexo path A 38 kcal/mol cl hexane 4.3/1 Br hexane 0.71/1 Cl Et3N 2.2/1 Br Et3N 16/1 Br CH3CN 0. 14/1 CI CH3C 0.59/1 Solvent effects implicate a zwitterionic intermediate Brady, et al, JACS 1970, 92, 146-148 Pons. J. -M. et. al JAcs1997,119,333
X Cl Cl Cl Cl H R H R C C O R' H C O Me X H R H R C R' H O Me X O X Br Br Br X Me O R' O R R O C H H O C Me Me O C Me Me C O Me Me Me Me Me Me Me Me C Me Me C Me H H Me O O O H H H H B O Me Me Me Me O Me Me Me Me A A C Me Me C H Me H Me O O Me Me Me Me B O H H O O H H H H O O D. A. Evans Cycloaddition Reactions-3 Chem 206 [2+2]: Stepwise Versus Concerted • Ketenes add stereoselectively to Z alkenes • Z olefins are much more reactive than E least hindered bond rotation • Very large polar effects • E olefins yield a mixture of cis and trans products • Solvent effects observed, but it could merely be a ground state effect • KIE seen for many reactions support stepwise mechanism • Calculations (Wang and Houk) show a highly asynchronus transition state in the gas phase reaction • All stereochemical outcomes can be rationalized assuming a stepwise mechanism Stepwise Concerted Solvent Effects + + endo exo Solvent hexane Et3N CHCl3 CH3CN endo / exo 4.3 / 1 2.2 / 1 1.6 / 1 0.59 / 1 Solvent hexane Et3N CH3CN endo / exo 0.71 / 1 0.28 / 1 0.14 / 1 • Solvent effects implicate a zwitterionic intermediate Brady,et. al, JACS 1970, 92, 146-148. Ketene-Alkene [2+2] + Fast 1 : 2 D D + + + _ + _ + Frey, H. M.; Isaacs, N. J. J. Chem Soc. B, 1970, 830-832. + 38 kcal/mol 32 kcal/mol Ketenes + Aldehydes Afford -Lactones path A path B ab initio Calulations Pons, J. -M.; et. al. JACS 1997, 119, 3333
D.A. Evans Cycloaddition Reactions-4 Chem 206 Transformations of B-Lactones The Staudinger Reaction In this process, the ilustrated ketene, generated in situ from an acid chloride, △orBF3 stereoselective process. When the azo-methine(RN=CHR) geomety n theo undergoes reaction with the indicated substrates to form B -lactams in reactant is(z) the product stereochemistry is trans(eq 1). In fashion, the(E) imine affords the cis-substituted product (eq 2). While RLi(2eq) O2H Arnold. L D: Drover. j. C j : Vedras J C. J. Am Chem.Soc.1987.107.4649 a The stepwise mechanism or acid Nu= OH2, ROH, R2NH Application in Natural Product Synthesis: Ginkolide B Ther are two contortaory modes. Meo J. Corey JACS 1988, 110, 649 If you control the conrotatory mod you control the absolute stereochemistry of the reaction ①“的 CMes Et3N 2.NBu3, toluene,△ D2H Evans, SogrenTet. Lett. 1985, 26, 3783, 3787 diastereoselection >95: 5 ns, Tet. Lett:1988,29,5065 Joc1982,47,3470. ition/fragmentation strategies for the synthesis of natural and unnatural products. Winkler, J D; Bowen, C ta,F.chem.Re1995,95,203 eoselective intermolecular[2+2H-photocycloaddition reactions and their application in synthesis T. Synthesis 1998, 68
O MeO CMe3 CO2H O R 2 R 1 O O R2N O O O O R 2 R 1 O Me2S CH2COCl H NEt3 S O O O R 1 Nu OH R 2 O R 2 R 1 R2N CO2H R' O CMe3 H O H O R Cl C O R H O Cl N O Ph O Et3N N S H N Bn H Ar C O R H Et3N N S H N R H R N S H R –O H N S H R –O H N Bn Ar O H H N O Ph O N S O H H R N R R O H H R N S O H H R N S O H H R N Bn Ar O H H N O Ph O D. A. Evans Cycloaddition Reactions-4 Chem 206 The Staudinger Reaction In this process, the illustrated ketene, generated in situ from an acid chloride, undergoes reaction with the indicated substrates to form b -lactams in a stereoselective process. When the azo-methine (RN=CHR) geometry in the reactant is (Z) the product stereochemistry is trans (eq 1). In a complementary fashion, the (E) imine affords the cis-substituted product (eq 2). While this transformatlion could be viewed as a [2s+2a] cycloaddition, it is felt that this reaction is stepwise. (1) (2) ■ The stepwise mechanism + (1) conrotatory closure + conrotatory closure enantiomers Ther are two contortaory modes. If you control the conrotatory mode, you control the absolute stereochemistry of the reaction: See also Evans, Williams, Tet. Lett. 1988, 29, 5065. Evans, SjogrenTet. Lett. 1985, 26, 3783, 3787. diastereoselection > 95:5 80-90% yields "[2+2] photocycloaddition/fragmentation strategies for the synthesis of natural and unnatural products.", Winkler, J. D.; Bowen, C. M.; Liotta, F. Chem. Rev. 1995, 95, 2003. "Stereoselective intermolecular [2+2]-photocycloaddition reactions and their application in synthesis.", Bach, T. Synthesis 1998, 683. Transformations of -Lactones _ + D or BF3 -CO2 base or acid Nu = OH2, ROH, R2NH CuCN R'Li (2eq) Arnold, L. D.; Drover, J. C. J.; Vederas, J. C. J. Am. Chem. Soc. 1987, 107, 4649. Application in Natural Product Synthesis: Ginkolide B, E. J. CoreyJACS 1988, 110, 649. 1. (COCl)2 , PhH, D 2. NBu3 , toluene, D JOC 1982, 47, 3470
D. A. Evans. C. A. Morales The Diels-Alder reaction Chem 206 Articles and monographs of Significance ■ The reaction: Comprehensive Organic Synthesis, Vol. 5, Trost, Ed. 1991 4.1 Intermolecular Diels-Alder Reactions, W. Oppolzer 4.2 Heterodienophile Additions to Dienes, S M. Weinreb 4.3 Heterodiene Additions, D. L. Boger 4.4 Intramolecular Diels-Alder Reactions, W. R Roush 4.5 Retrogade Diels-Alder Reactions, R W. Sweger, A. W. Czarnik a Representative natural products displaying the Diels-Alder retro ular Diels-Alder Reactions, Org Rxns, Vol 32, 1984 These natural products could well have incorporated the DA nxn into their Asymmetric Cycloaddition Reactions(Inter-& Intramolecular DA rxns) Asymmetric Synthesis, Vol 3 Morison, J. D, Academic Press, 1984 Hetero Diels-Alder Me L and Weinreb. S N. Academic Press. 1987 Natural Products Synthesis Through Pencyclic Reactions Desimoni, Tacconi, Barco, Polini, ACS Monograph 180, 1983, Chapter 5 Asymmetric Diels-Alder Reactions with Chiral Enoates as Dienophiles Mevinolin:R= Me odem Synthetic Methods 1986, Scheffold, Ed. Springer-Verlag Intramolecular Diels-Alder and Alder Ene Rxns, D F. Taber, Springer-Verlag, 1984 (Biosynthesis)JACS 1985, 107, 3694 clve,JAcS1988,110,6914 Kozikowski. JOC 1987. 52 3541 Weinreb, Tetrahedron, 1982. 38. 3087-3128 Hepcidin The Intramolecular DA RXn. recent advances and synthetic applications Fallis. Can J. Chem. 1984. 62. 183-234 Intramolecular /4+2 &3+ 2 Cycloadditions in Organic Synthesis Meo H Oppolzer, Angew. Chem. Int Ed, 1977, 16, 10-23 ns,JAcs,1993,115,4497 Preparation DA Reactions of Heterosubstituted 1, 3-Dienes Petrzilka, Synthesis, 1981, 753-786 DA Reactions of azadienes Boger, Tetrahedron, 1983, 39, 2869-2939 Silyloxydienes in Organic Synthesis Danishefsky, Acct. Chem. Res, 1981, 14, 400-406 FR182877 presen JACS. 2002. 124. 4552 Sauer, Angew. Chem. Int 5,211-4 Evans,ACE2002,41,1787 DA Reactions part /: The reaction mechanism auer, Angew. Chem. Int Ed, 1967, 6, 16-33 ongithorone A mechanistic Aspects of Diels-Alder Reactions: A Cntical Survey auer, Angew. Chem. Int Ed. 1980, 19, 779-80 Endiandric Acid B hair,JAcS,2002,124,773 Retro-DA Strategy in Natural Products Synthesis hihara, Synthesis, 1987, 207-222
4.1 Intermolecular Diels-Alder Reactions, W. Oppolzer 4.2 Heterodienophile Additions to Dienes, S. M. Weinreb 4.3 Heterodiene Additions, D. L. Boger 4.4 Intramolecular Diels-Alder Reactions, W. R. Roush 4.5 Retrogade Diels-Alder Reactions, R. W. Sweger, A. W. Czarnik Comprehensive Organic Synthesis, Vol. 5, Trost, Ed. 1991 O H O Me OMe MeO MeO NMe2 O O O O Me Et H O H H H H H H Me H H H H O H Me Me H O H O O Me O R Me O HO O H O Et H O Me O O O Me H Me H Me H H Me H H HO H OH H H Ph CO2H H H H H These natural products could well have incorporated the DA rxn into their biosynthesis. Endiandric Acid B (Syntheses) Nicolaou, JACS 1982, 104, 5555 (Synthesis) Shair, JACS, 2002, 124, 773 (Biosynthesis) JACS 1985, 107, 3694 Clive, JACS 1988, 110, 6914 Kozikowski, JOC 1987, 52, 3541 Mevinolin: R = Me Compactin: R = H (Synthesis) Evans, JACS, 1993, 115, 4497 Lepicidin ■ Representative natural products displaying the Diels-Alder retron: + ‡ ■ The Reaction: Natural Products Synthesis Through Pericyclic Reactions Desimoni, Tacconi, Barco, Polini, ACS Monograph 180, 1983, Chapter 5, Articles and monographs of Significance Asymmetric Diels-Alder Reactions with Chiral Enoates as Dienophiles Modern Synthetic Methods 1986, Scheffold, Ed. Springer-Verlag, Asymmetric Cycloaddition Reactions (Inter- & Intramolecular DA rxns) Asymmetric Synthesis, Vol. 3 Morrison, J. D., Academic Press, 1984 Hetero Diels-Alder Methodology in Organic Synthesis Boger, D.L. and Weinreb, S.N., Academic Press, 1987 Intramolecular Diels-Alder Reactions, Org Rxns, Vol. 32, 1984 Intramolecular Diels-Alder and Alder Ene Rxns, D. F. Taber, Springer-Verlag, 1984 Mechanistic Aspects of Diels-Alder Reactions: A Critical Survey Sauer, Angew. Chem. Int. Ed., 1980, 19, 779-807 DA Reactions Part II: The Reaction Mechanism Sauer, Angew. Chem. Int. Ed., 1967, 6, 16-33 DA Reactions Part I: New Preparative Aspects Sauer, Angew. Chem. Int. Ed., 1966, 5, 211-230 Silyloxydienes in Organic Synthesis Danishefsky, Acct. Chem. Res., 1981, 14, 400-406 DA Reactions of Azadienes Boger, Tetrahedron, 1983, 39, 2869-2939 Preparation & DA Reactions of Heterosubstituted 1, 3-Dienes Petrzilka, Synthesis, 1981, 753-786 Retro-DA Strategy in Natural Products Synthesis Ichihara, Synthesis, 1987, 207-222 Intramolecular [4 +2] & [3 + 2] Cycloadditions in Organic Synthesis Oppolzer, Angew. Chem. Int. Ed., 1977, 16, 10-23 The Intramolecular DA Rxn: recent advances and synthetic applications Fallis, Can. J. Chem., 1984, 62, 183-234 Synthetic Aspects of D-A Cycloadditions with Heterodienophiles Weinreb, Tetrahedron, 1982, 38, 3087-3128 D. A. Evans, C. A. Morales The Diels-Alder Reaction Chem 206 Longithorone A (Synthesis) Sorensen, JACS, 2002, 124, 4552 Evans, ACIE 2002, 41, 1787 FR182877
D. A. Evans Diels-Alder Reaction-Orbital Symmetry Considerations Chem 206 The Alder Endo rule The following observation illustrates an example of the Orbital Symmetry Considerations for Diels Alder Reaction Alder rule which will be defined below If the reaction is referred to as"symmetry-allowed". The Diels-Alder is such a case As illustrated. the homo and lumo of both the diene and dien which in this case are the same, will constructively overlap as indicated in formation of both sigma bonds disfavored HoM-π LUMO-π Endo product Observation: The endo Diels-Alder adduct is formed faster even though the exo product is more stable. There is thus some special stabilization in the transition state leading to the endo product which is lacking the exo transition state HOMo-π a Primary orbital overlap leads directly to the formation of new chemical bonds Frontier MO Explanation for the Endo Rule LUMO-Tt3 a Secondary(transient )orbital overlap can also occcur in the stabilization of certain transition state geometries. Such a transient stabilizing interaction can occur in the endo, but not exo, transition state a Of the two possible transition states, the one having the "greatest accumulation of interacting double bonds will be preferred"(the Alder Endo Rule econdary orbital overlap is noted below The Other Dimerization Possibility for Butadiene orbital over ○■ Note that the termini only match at one end for the HOMO-T HOMO-L retry This does not mean that the rea only that the reaction will not be Such reactions are called Exo Ts t Endo ts t Additional Reading: Lowry Richardson
Additional Reading: Lowry & Richardson, Chapter 10, theory of Pericyclic Rxns pp 839-900 ■ Note that the termini only match at one end for the HOMO-LUMO pairing. Hence we say that the symmetry requirements for the reaction in question are not met. This does not mean that the reaction will not occur, only that the reaction will not be concerted. Such reactions are called "symmetry-forbidden". LUMO-p3 HOMO-p2 Does the possibility for the following concerted dimerization exist? The Other Dimerization Possibility for Butadiene ■ Secondary (transient) orbital overlap can also occcur in the stabilization of certain transition state geometries. Such a transient stabilizing interaction can occur in the endo, but not exo, transition state: ■ Primary orbital overlap leads directly to the formation of new chemical bonds. LUMO-p3 HOMO-p2 Frontier MO Explanation for the Endo Rule If the symmetries of the frontier MO's of reacting partners are "properly matched" the reaction is referred to as "symmetry-allowed". The Diels-Alder reaction is such a case. As illustrated, 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. Orbital Symmetry Considerations for Diels Alder Reaction LUMO-p3 LUMO-p3 HOMO-p2 HOMO-p2 Energy Secondary orbital overlap disfavored favored The Alder Endo Rule The following observation illustrates an example of the Alder Rule which will be defined below. + "Endo product" "Exo product" Observation: The endo Diels-Alder adduct is formed faster even though the exo product is more stable. There is thus some special stabilization in the transition state leading to the endo product which is lacking the exo transition state. 2 Exo TS ‡ Endo TS ‡ ■ Of the two possible transition states, the one having the "greatest accumulation of interacting double bonds will be preferred" (the Alder Endo Rule). Secondary orbital overlap is noted below. Exo TS ‡ Endo TS ‡ D. A. Evans Diels-Alder Reaction-Orbital Symmetry Considerations Chem 206 H H H H H H H H C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C C D
D. A. Evans Diels-Alder Reaction: The Transition Structure Chem 206 Transition State Modelling is Coming of Age a Lewis Acid Catalysis of the reaction is possible: Yates Eaton JAcs1960,82,4436 LUMO, LUMOz The Critical Energy a The lengths of the forming C-c bonds are Ca. 1.5 times the normal bond E(LUMO1)-E(HOMO2 distance. This factor comes out of the ab initio work of Jorgensen& Houk + leading references Jorgensen, JACS 1993, 115, 2936-2942 Houk, Jorgensen, JACS 1989, 111, 9172 4#a E(LUMO2 )-E(HOMO1 Transition Structures of Hydrocarbon Pericyclic Reactions Houk Angew. chem. Int. Ed. 1992, 31, 682-708 a Bond formation is not synchronus with substituted dienophiles (Jorgensen) i AS AE decreases for the relevant ground state FMOS, ran rates increase 2193A 2193A 2.091A 2325A UMO LUMO △s+=-321eu s+=383 rel rate 1 rel rate= 10*5 44 a Diene Reactivity as measured against Maleic anhydride HOMO AE(LUMO3-HOMO1)AE(LUMO2-HOMO1)= Rate Acceleration log k=4.96 log k= 2.36 log k=2.19 log k=2.12 log k=1.83 Lewis acid catalysis not only dramatically increases rates by ca 10* Sauer,Angew.Chem. Int Ed,1980,19,779-807/it also improves reaction regiochemistry endo diastereoselectivity
Me Me HOMO3 HOMO2 HOMO1 O H H O HOMO2 HOMO1 Lewis acid catalysis not only dramatically increases rates by ca 10+6 it also improves reaction regiochemistry & endo diastereoselectivity Ethylene & Butadiene Vs Butadiene & Acrolein DE (LUMO3 -HOMO1 ) < DE (LUMO2 -HOMO1 ) Rate Acceleration + LUMO1 + E LUMO3 LUMO2 Dienophile E(LUMO1 ) - E(HOMO2 ) or E(LUMO2) - E(HOMO1) ■ The closer the two orbitals are in energy, the better they interact ■ As DE decreases for the relevant ground state FMOs, rxn rates increase LUMO1 LUMO2 Diene The Critical Energy Difference: energy D. A. Evans Diels-Alder Reaction: The Transition Structure Chem 206 rel rate = 10+5 rel rate = 1 exptl DH ‡ = 14.0 kcal/mol DS ‡ DS = -38.3 eu ‡ = -32.1 eu DH ‡ = 22.5 kcal/mol ■ Bond formation is not synchronus with substituted dienophiles (Jorgensen) 2.091 Å 2.325 Å 2.193 Å 2.193 Å Houk, Jorgensen, JACS 1989, 111, 9172 Jorgensen, JACS 1993, 115, 2936-2942 leading references: ■ The lengths of the forming C–C bonds are Ca. 1.5 times the normal bond distance. This factor comes out of the ab initio work of Jorgensen & Houk Transition State Modelling is Coming of Age Transition Structures of Hydrocarbon Pericyclic Reactions Houk Angew. chem. Int. Ed. 1992, 31, 682-708 ‡ + ■ Diene Reactivity as measured against Maleic anhydride Sauer, Angew. Chem. Int. Ed., 1980, 19, 779-807 log k = 4.96 log k = 2.36 log k = 2.19 log k = 2.12 log k = 1.83 ■ Lewis Acid Catalysis of the reaction is possible: Yates & Eaton, JACS 1960, 82, 4436