D. A. Evans. M. Dart Epoxides as Electrophiles Chem 206 STORK'S EPOXYNITRILE CYCLIZATIONS CIS VS TRANS GEOMETRY IN EPOXYNITRILE CYCLIZATIONS 6-endo-tet cis-epaxide gives cyclobutanes exclusively NaNH2, THF (75%) 5-endo-tet Ratio of 5: 4 membered ring formation Trans-epoxides afford mitures of cyclobutanes Geometrical constraints for ring closure with epoxides are relaxed M 7228 involved cis-epo relative to normal ring forming reactions.( Consider the Walsl model or bent-bonding in the epoxide ring 65:35 88 Lellemand, J Y: Onanga, M. Tetrahedron lett. 1975, ACTIVATION OF 6-ENDO OVER 5-EXO EPOXIDE OPENINGS 55h 7%) 5-exo-tet Stork. G : Cama L D. Coulson. D.R. J. Am. chem. Soc. 1974. 96 5268 to25°c Stork. G: Cohen. J F. J Am. Chem. Soc. 1974. 96 5270 Product Ratio Yield △ 4-exo-tet 1H Analysis of transition-state requirements show that proper -cH2 CH2CO2Me 0:100 alignment for C-O bond cleavage is more easily attained in a Nicolaou JACS 1989.111.5330-5334.CH=CHCO2Me 4-exo rather than a 5-endo ring closure 100095% 100:0 90% KHMDS PhH 125h,(70%) Proposed Transition-State: R=H, Me HO (cHl + Hd (cH,ln- HO (cH2) The effective steric hindrance of the positive charge can be stabilzed larger than the alkyl substituent. hrough electron donation from an adjacen r orbital in A. endo ning closure exo ning closureO CN - O CN OH H CN CN O H OH CN Me O CN O CN - Me OH CN O Me NC - H C O NC - Me CN O Me R HO (CH2 )n O CN Me Me OH R H O (CH2 ) HO n + HO (CH2 )n H O+ R O N Me Me Me M R Me Me O Me N M O (CH2 )n OH H R O HO O HO R H H O HO R H (CH2 ) O n OH H H R CN O H H R O H CN H R CN HO H HO CN R H R CN HO R CN HO H A B -CH2CH2CO2Me -CH=CHCO2Me -CH=CH2 -CH=CBr2 cis-epoxide gives cyclobutanes exclusively R 5:4 Yield % Me 72:28 90 Bu 62:38 88 C5H11 65:35 88 Ratio of 5:4 membered ring formation NaNH2 , THF 4 h, 40 °C NaNH2 , THF 4 h, 40 °C CIS VS TRANS GEOMETRY IN EPOXYNITRILE CYCLIZATIONS Lellemand, J. Y.; Onanga, M. Tetrahedron lett. 1975, 585. Trans-epoxides afford mixtures of cyclobutanes and cyclopentanes. Stork's studies exclusively involved cis-epoxides. 5-exo 6-endo Nicolaou, JACS 1989, 111, 5330-5334. endo ring closure exo ring closure Developing positive charge can be stabilized through electron donation from an adjacent orbital in A. d + d + 0.1 equiv CSA CH2Cl2, -40 to 25 °C b a ACTIVATION OF 6-ENDO OVER 5-EXO EPOXIDE OPENINGS Substrate Product Ratio Yield 0:100 94% 60:40 96% 100:0 95% 100:0 90% D. A. Evans, M. Dart Epoxides as Electrophiles Chem 206 Stork, G.; Cama, L. D.; Coulson, D. R. J. Am. Chem. Soc. 1974, 96, 5268. Stork, G.; Cohen, J. F. J. Am. Chem. Soc. 1974, 96, 5270. Geometrical constraints for ring closure with epoxides are relaxed relative to normal ring forming reactions. (Consider the Walsh model or bent-bonding in the epoxide ring). "6-endo-tet" "5-endo-tet" 5-exo-tet 5.5 h (77 %) (75 %) 2 h (70 %) 2. tBuOH 1. KNH2 , NH3 glyme, 7 min STORK'S EPOXYNITRILE CYCLIZATIONS ‡ ‡ ‡ 4-exo-tet Analysis of transition-state requirements show that proper alignment for C-O bond cleavage is more easily attained in a 4-exo rather than a 5-endo ring closure. KHMDS, PhH 1.25 h, (70 %) Proposed Transition-State: favored The effective steric hindrance of the metal salt of the cyano anion is larger than the alkyl substituent. R = H, Me