http://www.courses.fas.harvard.edu/~chem206/ O N Me Cl Me O TiCl4 Me O OH O Me O N O Me Me OOH OTMSMe Me Chem 206D. A. Evans Matthew D. Shair Wednesday, October 23, 2002 a73 Reading Assignment for week: Carey & Sundberg: Part A; Chapter 11Concerted Pericyclic Reactions Cycloaddition Reactions: Part–1 Chemistry 206 Advanced Organic Chemistry Lecture Number 15 Cycloaddition Reactions-1 a73 Introduction to Cycloaddition Reactions a73 [2+2] Cycloaddition Reactions a73 The Diels-Alder Reaction a73 Other Reading Material: Fleming: Chapter 4Thermal Pericyclic Reactions a73 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, 9726Carey & Sundberg: Part B; Chapter 6 Cycloadditions, Unimolecular RearrangementsThermal 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 a68 a68 Kurth, JOC 1985, 50, 1840 Predict the stereochemical outcome of this reaction Et O Et Et OEt NMe2Me N Me OMe C3H5 R ON Me Me BF4- + + + OH Me C OEt OEt OEt EtO OEtMe O OH OEt O O OEt Me S Me OH Me EtO2C Me O MeMe Me OHC Me Et2N OMe O O Me H NMe 2Et OH Et Me CO2Me OH Me Me OH Me Me NMe2Me O Me Me O Me OH Me Me Me OMeMe OMeEt2N Me OLi CMe2(OBn) O N Me Me OLiMe N Et OMe CMe2(OBn) O Me Me Me Me Me O Me Me Me CHOMe Me Me Me OMe Me OEt H3PO4 ? CH3C(OEt)3 CH3C(NMe2)(OMe)2 CH2=C(OMe)(NEt2) Et2O EtOH NaOEt CO2MeMe O Me2N Me O NEt2 NEt2 O NMe2Me EtO OEt Et Me NMe2 O H a73 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 diastereomerWelch, JACS 1987, 109, 6716 Stevenson, Tet. Let. 1991, 32, 4199 diastereoselection 6:1Predict the major diastereomer a73 Compare the two variants: 92% (E:Z = 98:2) 98% (E:Z = 86:14) 60% 138oC 98oC Hg(OAc)2, EVE CH3CH2CO2H (cat) a73 Lead paper: Johnson, Faulkner, Peterson, JACS 1970, 92, 741 Johnson Orthoester Claisen Johnson & Eschenmoser Claisen RearrangementsD. A. Evans Chem 206 a73 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 = 99:1Faulkner and Peterson Xylene, 140oC, 14h 70% Me R2 R1 OTBS O O OTBS R1R2 Me O O R1R2 Me O Et OEt N R R H H R Li OMe N R R H Me R Li OH a56 a56 a56O O Me O OTMS R O Me Hc Hb Ha C OR HbHc R O – OLi R Me R Me OLi OH O O Me Me OH OH Me Me MeMe MeMe O RO OR Me Me O O MeH OTBSH R1H O R2 R2 H OR1 OTBSH Me H MeMe OO MeMe OMe Me O O R2 R1 OTBS OMe Me O OTBS R1R2 OTBSOTBS Me OMe O O Me MeMe 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% a73 Reviews Pereira, Aldrichimica Acta 1993, 26, 17-29 (Ireland-Claisen) Ireland, Aldrichimica Acta 1988, 21, 59-69 (Claisen-related) Chem 206D. A. Evans Ireland Enolate Claisen Rearrangement a73 Enolization: Amide Bases LM–NR2 ? (E) Geometry (Z) Geometry The Ireland Model (JACS 1976, 98, 2868) Narula, Tetrahedron Lett. 1981, 22, 4119more recent study: Ireland, JOC 1991, 56, 650 Substituted enolates afford an additional stereocenter LDA, TBSCl LDA, TBSClDMPU a56 (E) (Z) (E):(Z)conditions LDA, TBSCl LDA, TBSClDMPU 94:6 7:93 key study: Ireland, JOC 1991, 56, 650 and earlier cited papers Stereoelectronic Requirements: The α-C-H bond must be able to overlap with pi? C–O – Ha+ base pi? C–O Paterson, Tet Lett 1991, 32, 7601 LDA, TMSClEt 3N 20-60 °C 1,2 syn aldol relation permuted into1,5 syn relationship via Claisen rearrangement 63% yield (diastereoselection 86%) Double Claisen Rearrangements are also possible ? ? favored disfavored control kinetic thermo X CC CC CC CC 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 Cycloaddition Reactions-1 Chem 206D. A. Evans Why does maleic anhydride react easily with 1,3-butadiene, but not with ethylene? So what are the "rules"? [4+2] [2+2] pi* pi concerted a54 bonding bonding + energy a54 + light a54 pi pi* newHOMO light a73 Consider [2 + 2] cycloaddition: Photochemical activation [ pi2s + pi2s] bonding a73 Consider [2 + 2] cycloaddition: Thermal activation [ pi2s + pi2s] The frontier orbitals of the reacting species must have the proper symmetries heat a73 The related reaction of 2 ethylenes is nonconcerted: [2 + 2] cycloaddition LUMO ?? a73 We also know that the photochemical variant is concerted a73 Nomenclature pi2s pi2a Using this nomenclature, the Diels-Alder reaction is a pi4s + pi2s cycloaddition pi2s pi2s antibonding [ pi2s + pi2s] "forbidden" pi2api2s [ pi2s + pi2a] "allowed" bonding bonding antarafacialsuprafacial [pi2s + pi2a] TL 1967, 4357, 4723.must be antarafical for indicated stereochem [2+2] Cycloaddition - Examples hν [pi2s + pi2s] hν [pi2s + pi2s] Quadricyclane Prismane-Der. Dauben, Tet. 1961, 15, 197. Sch?fer, AC 1967, 79, 54. Dewarbenzene-Derivative H2C C O Ph2C C O H C O O ZnBr2 Zn O O ? O Ph Br O Ph Br O OO H ORR' O OR R' R' R ORR' R' RO (CH3CO)2O R X O R' C O R R' ? H2C C O AcOH OH R O OAr C O R-ArO H2O C O R R' N ORR' Z Y XO R R' X Y Y X O R' R O R' OR1 R2 R3 C OR1 R2 R3or ? R R' O N2 or ? C O R R' R O H ? -CH2CH2 C O R H HOMO O H H O ? R3N RCH2CO2Ar O ORR' Cycloaddition Reactions-2 Chem 206D. A. Evans 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 hν hν [pi2spi2a] LUMO FMO Analysis X Cl Cl Cl Cl H R H R C C O R' H C O Me X RH H R C R' H O Me X O X Br Br Br X Me O OR' R R O C H H O C Me Me O C Me Me OCMeMe Me Me Me Me Me Me C Me Me C HMe MeH O OO H HH H B OMe Me Me Me OMeMe Me MeA A C Me Me C MeH MeH O OMeMe Me MeB O H H O O H H H H O O Cycloaddition Reactions-3 Chem 206D. A. Evans [2+2]: Stepwise Versus Concerted ? Ketenes add stereoselectively to Z alkenes ? Z olefins are much more reactive than E least hinderedbond 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 ? ?+ + + _ + _ + 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. O MeO CMe3 CO2H O R2 R1 O O R2N O O O O R2 R1 O Me2S CH2COCl H NEt3 S O O O R1 Nu OH R2 O R2 R1 R2N CO2H R' O CMe3 H O H O R Cl C O HR O Cl N O Ph O Et3N N SH NBn ArH C O HR Et3N N SH NR RH N S HR –O H N S HR –O H N Bn Ar O HHNO Ph O N S O HHR N R R O HHR N S O HHR N S O HHR N Bn Ar O HHNO Ph O Cycloaddition Reactions-4 Chem 206D. A. Evans The Staudinger Reaction In this process, the illustrated ketene, generated in situ from an acid chloride,undergoes reaction with the indicated substrates to form β -lactams in a stereoselective process. When the azo-methine (RN=CHR) geometry in thereactant is (Z) the product stereochemistry is trans (eq 1). In a complementary fashion, the (E) imine affords the cis-substituted product (eq 2). While thistransformatlion could be viewed as a [2s+2a] cycloaddition, it is felt that this reaction is stepwise. (1) (2) a73 The stepwise mechanism + (1) conrotatoryclosure + conrotatoryclosure 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 _+ ? 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, ? 2. NBu3, toluene, ? JOC 1982, 47, 3470. 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 MeOMe MeOMeO NMe2 O O O O MeEt H O H HHH H H Me H H H H OH Me MeH O H OOMe O R Me O OHO HO Et H O Me O O O Me H Me H Me HH Me H H HO OHH H H Ph CO2HH 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, 3694Clive, JACS 1988, 110, 6914 Kozikowski, JOC 1987, 52, 3541 Mevinolin: R = Me Compactin: R = H (Synthesis) Evans, JACS, 1993, 115, 4497 Lepicidin a73 Representative natural products displaying the Diels-Alder retron: + ?a73 The Reaction: Natural Products Synthesis Through Pericyclic ReactionsDesimoni, 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 SynthesisBoger, 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 SurveySauer, Angew. Chem. Int. Ed., 1980, 19, 779-807 DA Reactions Part II: The Reaction MechanismSauer, Angew. Chem. Int. Ed., 1967, 6, 16-33 DA Reactions Part I: New Preparative AspectsSauer, Angew. Chem. Int. Ed., 1966, 5, 211-230 Silyloxydienes in Organic SynthesisDanishefsky, Acct. Chem. Res., 1981, 14, 400-406 DA Reactions of AzadienesBoger, Tetrahedron, 1983, 39, 2869-2939 Preparation & DA Reactions of Heterosubstituted 1, 3-DienesPetrzilka, Synthesis, 1981, 753-786 Retro-DA Strategy in Natural Products SynthesisIchihara, Synthesis, 1987, 207-222 Intramolecular [4 +2] & [3 + 2] Cycloadditions in Organic SynthesisOppolzer, Angew. Chem. Int. Ed., 1977, 16, 10-23 The Intramolecular DA Rxn: recent advances and synthetic applicationsFallis, Can. J. Chem., 1984, 62, 183-234 Synthetic Aspects of D-A Cycloadditions with HeterodienophilesWeinreb, Tetrahedron, 1982, 38, 3087-3128 The Diels-Alder Reaction Chem 206D. A. Evans, C. A. Morales Longithorone A (Synthesis)Sorensen, JACS, 2002, 124, 4552 Evans, ACIE 2002, 41, 1787 FR182877 Additional Reading: Lowry & Richardson, Chapter 10, theory of Pericyclic Rxns pp 839-900 a73 Note that the termini only match at one end for theHOMO-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 reactionsare called "symmetry-forbidden". LUMO-pi 3 HOMO-pi2 Does the possibility for the followingconcerted dimerization exist? The Other Dimerization Possibility for Butadiene a73 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: a73 Primary orbital overlap leads directly to the formation of new chemical bonds. LUMO-pi3 HOMO-pi2 Frontier MO Explanation for the Endo Rule If the symmetries of the frontier MO's of reacting partners are "properly matched" thereaction 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-pi3 HOMO-pi2LUMO-pi3 HOMO-pi2 En erg y 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 ? a73 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 ? Diels-Alder Reaction-Orbital Symmetry ConsiderationsD. A. Evans Chem 206 H HH H H H H H CC C C C C C C C CCC CC C C C CCC CC C C C C C C C C C C ? Me Me HOMO3 HOMO2 HOMO1 O HH 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 Rate Acceleration?E (LUMO3-HOMO1) < ?E (LUMO2-HOMO1) + LUMO1 + E LUMO3 LUMO2 Dienophile E(LUMO1) - E(HOMO2) or E(LUMO2) - E(HOMO1) a73 The closer the two orbitals are in energy, the better they interacta73 As ?E decreases for the relevant ground state FMOs, rxn rates increase LUMO1 LUMO2 Diene The Critical Energy Difference: ene rgy Chem 206D. A. Evans Diels-Alder Reaction: The Transition Structure rel rate = 10+5rel rate = 1 exptl ?H ? = 14.0 kcal/mol ?S? = -38.3 eu?S? = -32.1 eu ?H? = 22.5 kcal/mol a73 Bond formation is not synchronus with substituted dienophiles (Jorgensen) 2.325 ?2.091 ?2.193 ? 2.193 ? Houk, Jorgensen, JACS 1989, 111, 9172 Jorgensen, JACS 1993, 115, 2936-2942leading references: a73 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 ReactionsHouk Angew. chem. Int. Ed. 1992, 31, 682-708 ? + a73 Diene Reactivity as measured against Maleic anhydride Sauer, Angew. Chem. Int. Ed., 1980, 19, 779-807 log k = 4.96 log k = 1.83log k = 2.12log k = 2.19log k = 2.36 a73 Lewis Acid Catalysis of the reaction is possible: Yates & Eaton, JACS 1960, 82, 4436 Me R CO2Me COX COX CO2Me H COX Me COX R CO2Me H Me COX R COX PhS AcO RO RO COMe COX CO2Me O2N MgBr2 CO2Me NO2 RO RO NO2 CO2Me PhS COMe AcO R3SnH RO COX –NO2– NO2 O O O2N H MeMe R3SnH RO NO2 CO2Me RO CO2Me CO2MeRO COXRO Me H H O AcO PhS COMe base Here is an interesting problem in reaction design disfavoredfavored a73 Orientation of Reacting Partners Diels-Alder Reaction: RegiochemistryD. A. Evans Chem 206 toluene, 120 °C 59 : 41 96 : 04C6H6, SnCl4, 25 °C 100 : 00 @ 75 °C favored disfavored for R = CO2HX = OH 4.5 : 01 @ 100 °C Lewis acid catalysis improves orientation favored disfavored C6H6, SnCl4, 25 °C 95 : 05 80 : 20CH2Cl2, 0 °C Lewis acid catalysis improves endo diastereoselection DA Reactions Part II: The Reaction Mechanism, Sauer, Angew. Chem. Int. Ed., 1967, 6, 16-33 In general, 1-substituted dienes are more regioselective than their 2-substituted counterparts: Sauer, Angew. Chem. Int. Ed., 1967, 6, 16-33 favored disfavored However, what if you need the disfavored product? disfavored favored Ni(Raney) Trost, JACS 1980, 102, 3554 By employing a removable substituent, it is possible to access the normallydisfavored product diastereomer Danishefsky, JACS 1978, 100, 2918: The NO2 FG completely dominates directivity It then can be removed by elimination or by reductionOno, Tet. 1985, 4013 83% 86% mixture of ring-fusionisomers Ono, Chem. Commun. 1982, 33-34 4.1 Intermolecular Diels-Alder Reactions, W. Oppolzer, See page 347 Comprehensive Organic Synthesis, Vol. 5, Trost, Ed. 1991 O O MeO Me Me Me O O O Me F3B O OOH RO Me MeOSnCl 4 OMe O Me OMe Me OMe Me MgI2 BF3?OEt2 Me MeO O O H Me Me H O O MeO Me MeH O O MeO Me BF3?OEt2 (-20 °) RO OH O O OMe Me Me OMe O OOH RO MeH O O MeO Me X CH2OMe Me OR Me CNCl O O N–Ph O O N–Ph Cu(BF4)2 CN Cl MeOCH2 H Me Me ORH PhN O O Ph–N X O O H H –OH –OMe N–Ph O OMe ORMe H H O O X Ph–N Me Me H OR NPh O O Cl CN H CH2OMe Me OR Me O O N–Ph 25-50 °C Corey, JACS 1969, 91, 5675 Ratio: 90 : 10 0 °C Instructive Issues of Regiocontrol with Quinone Dienophiles Chem 206D. A. Evans Diels-Alder Reaction: Regiochemistry Orientation of Reacting Partnerscontrolled by Lewis acid structure Conditions Ratio thermal (100 °) SnCl4 (-20 °) 50 : 50 <5 : 95 80 : 20 δ+ selection 80 : 20 selection >95 :5 δ+ Reusch JOC 1980, 45, 5013 0.5 equiv 0.4 equiv selection >95 :5 selection >95 :5 Kelly Tet. Let. 1978, 4311 Similar results provided by Stoodley Chem. Comm. 1982, 929 83 : 17 >97 : 3 36 : 64 Ratio –Me X = Overman, JACS 1988, 110, 4625 25-50 °C Franck, Tet. Lett. 1985, 26, 3187 Franck, JACS 1988,110, 3257 R = Me: Ratio; 83 : 17 R = Me3Si: Ratio; 88 : 12 better than Comments on the Transition State a73 Avoid Eclipsing allylic substituents a73 better donor (Me) anti to forming bond a73 avoid gauche OR interaction Diels-Alder Reactions with Chiral Dienes