The Cope Rearrangement Lecture Notes D D [3,3] Key Reviews: H. M. L. Davies, Tetrahedron 1993, 49, 5203. D. Enders, M. Knopp, R. Schiffers, Tetrahedron: Asymmetry 1996, 7, 1847. U. Nubbemeyer, Synthesis 2003, 961. [3,3]-Rearrangements: The Claisen and Cope Reactions/Rearrangements O Δ O [Claisen rearrangement] O O [Cope rearrangement] J. Org. Chem. 1976, 41, 3497; J. Org. Chem. 1976, 41, 3512; J. Org. Chem. 1978, 43, 3435. [3,3]-Rearrangements: The Claisen and Cope Reactions/Rearrangements OH OH O [Claisen [Claisen rearrangement] rearrangement] Δ OH O O [Enol-keto [Cope] tauto- merization] J. Org. Chem. 1976, 41, 3497; J. Org. Chem. 1976, 41, 3512; J. Org. Chem. 1978, 43, 3435. [3,3]-Rearrangements: The Claisen and Cope Reactions/Rearrangements OH OH O [Claisen [Claisen rearrangement] rearrangement] Δ OH O O [Enol-keto [Cope] tauto- merization] J. Org. Chem. 1976, 41, 3497; J. Org. Chem. 1976, 41, 3512; J. Org. Chem. 1978, 43, 3435. The Cope Reaction: Initial Discovery EtO2C o NC NC 150 C 4 h EtO2C Bonds Broken Bonds Formed 2 C C 2 C C 1 C C 1 C C Reaction process involves chair-like intermediates in most cases, but is an equilibrium. Special tactical features are required to drive the process towards a single product. A. C. Cope, E. M. Hardy, J. Am. Chem. Soc. 1940, 62, 441. The Cope Reaction: Initial Discovery EtO2C o NC NC 150 C 4 h EtO2C Bonds Broken Bonds Formed 2 C C 2 C C 1 C C 1 C C Reaction process involves chair-like intermediates in most cases, but is an equilibrium. Special tactical features are required to drive the process towards a single product. A. C. Cope, E. M. Hardy, J. Am. Chem. Soc. 1940, 62, 441. The Cope Reaction: Initial Discovery EtO2C o NC NC 150 C 4 h EtO2C Bonds Broken Bonds Formed 2 C C 2 C C 1 C C 1 C C Reaction process involves chair-like intermediates in most cases, but is an equilibrium. Special tactical features are required to drive the process towards a single product. A. C. Cope, E. M. Hardy, J. Am. Chem. Soc. 1940, 62, 441. The Cope Reaction: Ways to Get Single Products 1. Olefin conjugation and increased degree of alkene substitution EtO2C o NC NC 150 C 4 h EtO2C Δ 2. Relief of ring strain Δ A. C. Cope, E. M. Hardy, J. Am. Chem. Soc. 1940, 62, 441. The Cope Reaction: Ways to Get Single Products 1. Olefin conjugation and increased degree of alkene substitution EtO2C o NC NC 150 C 4 h EtO2C Δ 2. Relief of ring strain Δ A. C. Cope, E. M. Hardy, J. Am. Chem. Soc. 1940, 62, 441. The Cope Reaction: Ways to Get Single Products 3. Product isomerization HO HO O This process is known as the oxy-Cope rearrangement D D O O Standard Cope rearrangement Claisen rearrangement 4. Ensuing rearrangements/reactions (can be inter- or intramolecular) O O O [Cope] [Claisen] J. A. Berson, M. Jones, J. Am. Chem. Soc. 1964, 86, 5019. The Cope Reaction: Ways to Get Single Products 3. Product isomerization HO HO O This process is known as the oxy-Cope rearrangement D D O O Standard Cope rearrangement Claisen rearrangement 4. Ensuing rearrangements/reactions (can be inter- or intramolecular) O O O [Cope] [Claisen] J. A. Berson, M. Jones, J. Am. Chem. Soc. 1964, 86, 5019. The Cope Reaction: Ways to Get Single Products 3. Product isomerization HO HO O This process is known as the oxy-Cope rearrangement D D O O Standard Cope rearrangement Claisen rearrangement 4. Ensuing rearrangements/reactions (can be inter- or intramolecular) O O O [Cope] [Claisen] J. A. Berson, M. Jones, J. Am. Chem. Soc. 1964, 86, 5019. The Cope Reaction: Use in Complex Molecule Synthesis o O O 250 C, O PCC xylenes OH (94%) sealed tube, O 22 h O How was this made? (88%) [Cope] OH OH O O O NMe MeN H H HO O morphine morphine T. Hudlicky, C. H. Boros, E. E. Boros, Synthesis 1992, 174. The Cope Reaction: Use in Complex Molecule Synthesis H H Grubb's H H catalyst H H2C CH2 H H H O O benzene, O 80 oC, 10 h [Cope] (74%) O H H H H H H O H O O O (+)-asteriscanolide J. Limanto, M. L. Snapper, J. Am. Chem. Soc. 2000, 122, 8071. The Cope Reaction: Use in Complex Molecule Synthesis CO2Me OAc N2 Rh(OOct)4 + CO2Me hexane, Δ OAc (12 equiv) 140 oC, (49% overall) Kugelrohr distillation [Cope] AcO O O MeO2C how? H H tremulenolide A H. M. L. Davies, B. D. Doan, J. Org. Chem. 1998, 63, 657. The Oxy-Cope Reaction: Perhaps the Most Valuable Version HO 250 oC HO O [slow] KH O 25 oC O O H3O 1010 to 1017 fold rate increase at room temperature Affords an enolate intermediate which can be used directly in further chemistry J. A. Berson, M. Jones, J. Am. Chem. Soc. 1964, 86, 5019. D. A. Evans, A. M. Golob, J. Am. Chem. Soc. 1975, 97, 4765. The Oxy-Cope Reaction: Perhaps the Most Valuable Version HO 250 oC HO O [slow] KH O 25 oC O O H3O 1010 to 1017 fold rate increase at room temperature Affords an enolate intermediate which can be used directly in further chemistry J. A. Berson, M. Jones, J. Am. Chem. Soc. 1964, 86, 5019. D. A. Evans, A. M. Golob, J. Am. Chem. Soc. 1975, 97, 4765. The Oxy-Cope Reaction: Perhaps the Most Valuable Version HO 250 oC HO O [slow] KH O 25 oC O O H3O 1010 to 1017 fold rate increase at room temperature Affords an enolate intermediate which can be used directly in further chemistry J. A. Berson, M. Jones, J. Am. Chem. Soc. 1964, 86, 5019. D. A. Evans, A. M. Golob, J. Am. Chem. Soc. 1975, 97, 4765. Anion Accelerated Oxy-Cope Reaction in Action H H 250 oC OH O OH [slow] H H KH H H o O 25 C H3O O O H H D. A. Evans, A. M. Golob, J. Am. Chem. Soc. 1975, 97, 4765. 4π-Electrocyclic Reactions: Part of a Total Synthesis of Periplanone B O O OH KH, Oxy-Cope rearrangement 18-Crown-6 Me Me Me (75%) Me H Me Me O 175 °C, toluene O O 4π-conrotatory (82%) electrocyclic O O ring opening O 18-crown-6 O O O O + Me Me O Me Me Me Me periplanone B hν Olefin isomerization S. L. Schreiber, C. Santini, J. Am. Chem. Soc. 1984, 106, 4038. For a review, see: Classics in Total Synthesis I, Chapter 21 Ene Reactions in Total Synthesis: Tandem Oxy-Cope/Carbonyl Ene Sequence Me H H H OH O Me OH Me H Me DBU, Me Me toluene H Me HO 220 °C Enol-Keto OTBDPS Oxy-Cope tauto- rearrangement OTBDPS merization OTBDPS OTBDPS TBDPS = t-butyldiphenylsilyl Me H H H OTBDPS TBDPSO Transannular H Me ene reaction Me HO O Me (63%) HO HO OH H O Me Me H H O arteannuin M OTBDPS L. Barriault, D. H. Deon, Org. Lett. 2001, 3, 1925. Anion Accelerated Cope Reaction: Not Just Oxygen! RHN RN -40 oC RN O KH H3O toluene PhS PhS PhS PhS H H -60 oC NBn O KH H3O NHBn NBn THF H H Have intermediate enamine nucleophile which can be used in varied ways D. A. Evans, A. M. Golob, J. Am. Chem. Soc. 1975, 97, 4765. Anion Accelerated Cope Reaction: Not Just Oxygen! RHN RN -40 oC RN O KH H3O toluene PhS PhS PhS PhS H H -60 oC NBn O KH H3O NHBn NBn THF H H Have intermediate enamine nucleophile which can be used in varied ways D. A. Evans, A. M. Golob, J. Am. Chem. Soc. 1975, 97, 4765. Working Backwards: Recognizing Oxy-Cope Products 5 6 O HO 4 HO 1 3 [oxy-Cope] 2 1,5-diene is the critical structural unit of initial product An alkene and carbonyl linked by three carbons is the key unit in final product O OH OH OH [oxy-Cope] Working Backwards: Recognizing Oxy-Cope Products 5 6 O HO 4 HO 1 3 [oxy-Cope] 2 1,5-diene is the critical structural unit of initial product An alkene and carbonyl linked by three carbons is the key unit in final product OH X O OH OH OH OH [oxy-Cope] Working Backwards: Recognizing Oxy-Cope Products 5 6 O HO 4 HO 1 3 [oxy-Cope] 2 1,5-diene is the critical structural unit of initial product An alkene and carbonyl linked by three carbons is the key unit in final product 1 6 OH 1 6 2 X O 2 OH 5 3 3 5 4 4 1,6-diene 1,5-diene OH OH OH [oxy-Cope] Working Backwards: Recognizing Oxy-Cope Products 5 6 O HO 4 HO 1 3 [oxy-Cope] 2 1,5-diene is the critical structural unit of initial product An alkene and carbonyl linked by three carbons is the key unit in final product 1 6 OH 1 6 2 X O 2 OH 5 3 3 5 4 4 1,6-diene 1,5-diene OH OH OH [oxy-Cope] Working Backwards: Recognizing Oxy-Cope Products O O O O A B C D 1. Add a carbonyl at any position which has 3 carbons before either end of the alkene 2. Evaluate each ketone for oxy-Cope viability G.