The [3+2] Cycloaddition Reaction Lecture Notes OTBS OPMB O Key Reviews: O Me O Me XX Asymmetric K. V. Gothelf, K. A. Jorgensen, Chem. Rev. 1998, 98, 863. Nitrones P. N. Confalone, Org. React. 1988, 36, 1. Azomethine Ylides I. Coldhaim, R. Hufton, Chem. Rev. 2005, 105, 2765. [3+2] Dipolar Cycloadditions: A Reaction You Have Seen Before B Dipolar A C cycloaddition B A C or E D E D [3+2] reaction Criegee zwitterion O O O O O O O R1 O + Dipolar Dipolar O R2 cycloaddition R1 R2 cycloreversion R1 R2 Me2S R O O O or PPh3 1 O + in situ O R1 R2 reduction R2 [3+2] Dipolar Cycloadditions: General Reaction and Classes of 1,3-Dipoles B Dipolar A C cycloaddition B A C or E D E D [3+2] reaction R1 R2 N R R N O O N N N R3 nitrile oxides nitrones azides R 1 Y N X R R1 O R4 N N R2 R2 R3 azomethine ylides diazoalkanes carbonyl ylides X = electron withdrawing group Y = electron donating group [3+2] Cycloadditions: Understanding Regio- and Diastereoselectivity Regioselectivity EWG EWG N + = N EWG O O EWG = CO2Et, NO2 EDG EDG N + = N O O EDG = OMe, alkyl, Ph EDG [3+2] Cycloadditions: Understanding Regio- and Diastereoselectivity Regioselectivity Note: EWG EWG azides do not follow N + = N EWG this trend O O EWG = CO2Et, NO2 Reactivity: EDG EDG R R + = 1 1 N N > O O R2 R2 EDG = OMe, alkyl, Ph EDG [3+2] Cycloadditions: Understanding Regio- and Diastereoselectivity Regioselectivity Note: EWG EWG azides do not follow N + = N EWG this trend O O EWG = CO2Et, NO2 Reactivity: EDG EDG R R + = 1 1 N N > O O R2 R2 EDG = OMe, alkyl, Ph EDG Diastereoselectivity R2O R O O 1 R2O R O N R1 O 1 R1 O N N O N + OR O O OR2 N OR R1 2 O endo exo O transition state transition state Nitrile Oxides: Synthesis H H HONH2•HCl OH R O R N R NO2 X = Cl, Br, I NaOX R N C O -[HX] X R N O OH R N O R N nitrile oxide nitrile oxide The isocyanate is serving as a dehydrating reagent; can you rationalize a mechanism? Nitrile Oxides: Synthesis H H HONH2•HCl OH R O R N R NO2 X = Cl, Br, I NaOX R N C O -[HX] X R N O OH R N O R N nitrile oxide nitrile oxide The isocyanate is serving as a dehydrating reagent; can you rationalize a mechanism? Nitrile Oxides: Applications in Total Synthesis O OH N N Nitrile oxide N O 1,3-dipolar Me Me aq. NaOCl, cycloaddition Me CH2Cl2, 25 °C (59%) H H OTBDPS OTBDPS OTBDPS Zn, AcOH, (66%) OH 25 °C, 4 h N Me OTES O Me H OTMS N N H H Me MeO2C Me OH MeO OAc N MeO2C H OH OTBDPS OTBDPS Me CO2Me vinblastine T. Fukuyama and co-workers, J. Am. Chem. Soc. 1999, 121, 3791 For a review, see Classics in Total Synthesis II, Chapter 18 Nitrile Oxides: Applications in Total Synthesis MeO C NO MeO2C O 2 2 PhNCO N A Benzene, 25 °C Nitrile oxide Me Me Me Me 1,3-dipolar (89%) cycloaddition A O O O MeO2C N O Me O Me Me Me Me Me Me O Me O O O N A N MeO2C N O MeO C 2 N O Nitrile oxide Me 1,3-dipolar Me Me Me cycloaddition Me Me Me Me R.V. Stevens, J. Am. Chem. Soc. 1975, 97, 5940. Nitrile Oxides: Applications in Total Synthesis Me Me O Me Me O N O O O N N MeO2C N O MeO2C N O Me Me Me Me Me Me Me Me B O Nitrile oxide Me B 1,3-dipolar Me Me cycloaddition Me Me Me Me Me Me Me Me O N N O Me N O N Me N N MeO2C N O Me Me Me Me Me octamethylcorphin Me Me R.V. Stevens, J. Am. Chem. Soc. 1975, 97, 5940. Nitrile Oxides: Applications in Total Synthesis Me Me Me Me Me Me Me Me O O O Me N H , Raney Ni O Me H2N O 2 O MeOH, pH 7 N H2N MeO C 2 N O MeO2C NH2 O Me Me Me Me Me Me Me Me Et N, CHCl , 3 3 Imine formation 25 °C, 24 h Me Me Me Me Me Me Me N N Me O N COMe O N Me N NH N Me Me Me Me Me Me octamethylcorphin Me R.V. Stevens, J. Am. Chem. Soc. 1975, 97, 5940. Nitrile Oxides: Applications in Total Synthesis NO2 -[HOAc] NO2 O2N + + OAc NaS Michael S HS addition PhNCO O HO H O H N O HN NH H N 2 LiAlH N H 4 H Intramolecular S S S H H H nitrile oxide S HO2C 1,3-dipolar cycloaddition biotin P. N. Confalone, J. Am. Chem. Soc. 1980, 102, 1954. Nitrile Oxides: Applications in Total Synthesis Me O Me O N N Cl N C O Et3N, toluene, 80 °C NO N 2 O Intramolecular nitrile oxide (82%) 1,3-dipolar cycloaddition Me O N For reviews: A. Padwa, Angew. Chem. Int. Ed. Engl. 1976, 15, 123 O W. Oppolzer, Angew. Chem. Int. Ed. Engl. 1977, 16, 10. N 19-membered ring [masked aldol product] P. N. Confalone, J. Heterocyclic Chem. 1990, 31. Nitrones: Preparative Methods R R HgO 1 N 2 R1 N R2 + Oxime R1 NH O R OH O 2 oxidation OH nitrone Nitrones: Applications in Total Synthesis CO2Me CO2Me H N + Nitrone N O O OH OH 1,3-dipolar cycloaddition 48 kcal J. Tufariello, Acc. Chem. Res. 1979, 12, 396. Nitrones: Applications in Total Synthesis CO2Me CO2Me H N + Nitrone N O O OH OH 1,3-dipolar cycloaddition 48 kcal 1. MsCl 2. H2, heat OH H 1. cyclize H CO2Me 2. dehydrate OH N 3. LiAlH4 NH supinidine OMs J. Tufariello, Acc. Chem. Res. 1979, 12, 396. Nitrones: Applications in Total Synthesis CO2Me CO2Me N CO Me mCPBA 2 N N O Nitrone O O H 1,3-dipolar H O cycloaddition O O N Oxidative DBU = N Cl ring opening CO2Me CO2Me CO2Me N 1. MsCl, py N OH CO2Me N OH O O O 2. DBU Nitrone MeO2C MeO2C 1,3-dipolar cycloaddition [protection step] J. Tufariello, Acc. Chem. Res. 1979, 12, 396. Nitrones: Applications in Total Synthesis CO2Me O N CO Me xylene, Δ 2 N CO2Me O N [3+2] cycloreversion O MeO2C Nitrone [3+2] (66% overall) cycloaddition CO2Me Me 1. MeI N O CO2Me O Ph 2. H2 N O 3. BzCl H cocaine J. Tufariello, J. Am. Chem. Soc. 1978, 100, 3638. J. Tufariello, J. Am. Chem. Soc. 1979, 101, 2435. Nitrones: Applications in Total Synthesis O O OH OH N HN H H H H NOH•HCl + SnCl4 2 NaBH3CN Me (67%) Me (98% Me overall) Me Diels-Alder H H H reaction H O H O Me Me H H H MeO S F H N N N N CrO O Me O Me 3 Me O Me H H H HO H LiAlH Nitrone 4 [3+2] (94% O H cycloaddition H H H overall) luciduline W. Oppolzer, M. Petrzilka, J. Am. Chem. Soc. 1976, 98, 6722. W. Oppolzer, M. Petrzilka, Helv. Chim. Acta 1978, 61. Nitrones: Applications in Total Synthesis Me CO2Me Me N Me Me O MeO C Me Me Me 2 Me Me Me Me Me 3 steps N O Me Me N O xylene, 140 °C Me Me H Nitrone HO [3+2] H HO H cycloaddition endo product HO MeI, toluene, Me 60 °C; Zn dust, Me Me AcOH Me Me OH Me Me Me Me Me H Me MeI; Me Me Me t-BuOK Me HO N HO Hofmann Me Me degradation H H HO OH HO HO 1α,25-dihydroxyergocalciferol E. G. Baggiolini and co-workers, J. Org. Chem. 1986, 51, 3098. Nitrones: Applications in Total Synthesis CN 1. A, O MgBr O CN O EtO H 2. PCC, CH2Cl2 Olefin cross- (91% overall) metathesis (62%) Me Me Me Me CN N N Cl Me Me Intramolecular Ru H NOH•HCl, NaOAc, Cl 2 nitrone [3+2] O MeOH/MeCN, 50 °C A i-Pr cycloaddition CN CN CN O HO HO N N N 1,3-proton Michael shift addition CN CN CN P. L. Fuchs and co-workers, J. Am. Chem. Soc. 2006, 128, ASAP. D. L. Hughes and co-workers, J. Org. Chem. 2004, 69, 1598. Nitrones: Applications in Total Synthesis CN CN Intramolecular CN O nitrone [3+2] N O cycloaddition N O N (89% overall) NC NC H CN kinetic product toluene, 180 °C Retro [3+2] For original concept, see: sealed tube cycloaddition R. Grigg, J. Chem. Soc., Perkin Trans. 1 1984, 47 CN CN Intramolecular O N nitrone [3+2] N HN O cycloaddition HO (95%) CN thermodynamic CN histrionicotoxin product P. L. Fuchs and co-workers, J. Am. Chem. Soc. 2006, 128, ASAP. D. L. Hughes and co-workers, J. Org. Chem. 2004, 69, 1598. Carbonyl Ylides (Oxidopyryliums): Using Cyclic Systems O O O Base -[ OAc] AcO O AcO O O O H 1,3-Dipolar O 1 2 O O cycloaddition R R R1 O H O 2 R R1 R2 exo adduct In cyclizations of this type, the ENDO isomer places the substituents on the dipolarophile anti to the oxido bridge.