D. A Evans. M. Dart Epoxides as Electrophiles Chem 206 EFFECT OF ELECTRONEGAT/VE NONCONJUGATING SUBSTITUENTS REGIOSELECTIVITY OF EPOXIDE RING OPENINGS Me EPOXIDES ADJACENT TO CARBONYLS (NH2) oMe Conformational effects are guiding the regioselectivity o Steric effects do ations(Furst-Plattner rule portant. However and substituent EWG=Electron Withdrawing Group Other nucleophiles such as amines, various hydrides, and malonate anions show Attack at C-a is discouraged due to destabilization the same regioselectivity of the transition state by juxtaposition of positive charge IPrNH2 R=Hor Bn NHR aq PINH2 The opposite selectivity observed in this case is due to stabilization of the developing positive charge at C-2 by the carboxylate anion. The reaction proceeds with inversion of stereochemistry at this center Liwschitz. Y: Rabinsohn. Y: Perera. d. J chem. soc. 1962. 1116 Parker, R. E, Isaacs, N. C. Chem. Rev. 1959, 59, 737-799 配uKm159152Me OH O O HO O NHR Me OH O O Me OEt Me F3C OEt O O OEt O O O O NH2 O NH2 HO F OEt 3C Me OEt NH2 OH O Me H2N OH O OEt NH2 O H2N OH O R' R' H Nu EWG OH OMe NH2 O Me OAr Me OAr O O OMe OMe O OMe OH OMe OMe OH OMe O Me NHiPr Me OAr OH NHiPr Me OAr OH F3C Me O OH OEt Me F3C NaOMe NaOMe NH3 (NH2 ) RNH2 NH3 Parker, R. E.; Isaacs, N. C. Chem. Rev. 1959, 59, 737-799. Lemieux, R. U.; Kullnig, R. K.; Moir, R. Y. J. Am. Chem. Soc. 1958, 80, 2237. Steric effects dominate regioselectivity, especially in acyclic systems in which conformational considerations (Fürst-Plattner rule) may not be as important. However, in many systems sterics on each side of the epoxide may be similar and substituent electronic effects emerge as the important factors in determining regioselection. EtOH, H2SO4 aq iPrNH2 aq iPrNH2 or NH3 d + d - d - EWG = Electron Withdrawing Group Attack at C- is discouraged due to destabilization of the transition state by juxtaposition of positive charge. a b EFFECT OF ELECTRONEGATIVE, NONCONJUGATING SUBSTITUENTS Conformational effects are guiding the regioselectivity of reaction 3. 1. 2. 3. d - d + ‡ D. A. Evans, M. Dart Epoxides as Electrophiles Chem 206 EPOXIDES ADJACENT TO CARBONYLS Other nucleophiles such as amines,various hydrides, and malonate anions show the same regioselectivity. REGIOSELECTIVITY OF EPOXIDE RING OPENINGS Liwschitz, Y.; Rabinsohn, Y.; Perera, D. J. Chem. Soc. 1962, 1116. R = H or Bn The opposite selectivity observed in this case is due to stabilization of the developing positive charge at C-2 by the carboxylate anion. The reaction proceeds with inversion of stereochemistry at this center. Parker, R. E.; Isaacs, N. C. Chem. Rev. 1959, 59, 737-799. 2 3