Chemistry 206 Advanced organic chemistry Handout-03A Steric. electronic Conformational Effects in Epoxide- Nucleophile Reactions Mick dart Evans group seminar, december, 1993 Matthew d shair Mond September 23, 2002
Chemistry 206 Advanced Organic Chemistry Handout–03A Steric, Electronic, & Conformational Effects in Epoxide–Nucleophile Reactions Matthew D. Shair Monday September 23, 2002 Mick Dart Evans Group Seminar, December, 1993
D. A. Evans. M. Dart Epoxides as electrophiles Chem 206 STERIC ELECTRON/C AND CONFORMATIONAL EFFECTS IN EPOXIDE/NUCLEOPHILE REACTIONS REGIOSELECTIVITY OF EPOXIDE RING OPENING NEUTRAL OR BASIC CONDIT/ONS: SN2 arkerRE. Isaacs, N. c. Chem. rev. 1959. 59. 737-799. Rosowsky, A. In The Chemistry of Heterocyclic Compounds Weissberger, A, Ed; Interscience: New York, 1964: Vol 19, Part 1, p 1. H SN2 Transition-State Buchanon, J. G: Sable, H. Z. In Selective Organic Transformations: Thyagarajan, B S Ed. Wiley: New York, 1972: VoL. 2, p 1 Berti, G. In Topics in Stereochemistry, Allinger, N. L. Eliel, E L, Eds. Interscience Publishers: New York, 973: Vol. 7, p93 rnha R=various alkyl, aryl, or vinyl substituents Rao,A.S:Paknikar,SK;Kirtane,JG.Tetrahedron1983,39,2323 R2NH Sharpless, B K, Behrens, C. H. Katsuki, T Lee, A. W. M; Martin, V.S.; Takatani, M Viti, S. M: Walker, F. J; Woodward, S.S. Pure Appl. Chem. 1983, 55, 589-604 Behrens, C H;, Sharpless, B. K. Aldrichimica Acta 1983, 16, 67-80 Due to ring strain, bond breaking is more advanced than bond making in the transition-state relative to a normal SN2 reaction. In addition, the carbon atom Gorzynski Smith, J. Synthesis 1984, 629-656 at which displacement takes place will bear a partial positive charge in the ewars,E.G. In Comprehensive Heterocyclic Chemistry, Katritzky, A.R., Ed; transition-state Normal" SN2 behavior is observed under neutral or basic conditions to provide Rossiter, B E. In Assymetric Synthesis; Morison, J D, Ed. Academic: New York, Ris alkyl or a group having no marked inductive or conjugative effects 1985: Vol 5, Chapter 7. Hanson, R. M. Chem Rev. 1991, 91, 437-475 Exceptions: Hydrogenation in the presence of Raney-nickel proceeds with Also see: Larock, R. C. Comprehensive Organic Transformations, p 505-526 opposite regioselection Parker,RE:Isaacs,NC.Chem.Rev.1959,59,737-799
O R' H Nu H H O R' R' Nu OH D. A. Evans, M. Dart Epoxides as Electrophiles Chem 206 Parker, R. E.; Isaacs, N. C. Chem. Rev. 1959, 59, 737-799. Rosowsky, A. In The Chemistry of Heterocyclic Compounds; Weissberger, A., Ed.; Interscience: New York,1964: Vol 19, Part 1, p 1. Buchanon, J. G.; Sable, H. Z. In Selective Organic Transformations; Thyagarajan, B. S., Ed.; Wiley: New York,1972: Vol. 2, p 1. Berti, G. In Topics in Stereochemistry; Allinger, N. L. ; Eliel, E. L., Eds.; Interscience Publishers: New York, 973: Vol. 7, p 93. Rao, A. S.; Paknikar, S. K.; Kirtane, J. G. Tetrahedron 1983, 39, 2323. Sharpless, B. K.; Behrens, C. H.; Katsuki, T.; Lee, A. W. M.; Martin, V. S.; Takatani, M.; Viti, S. M.; Walker, F. J.; Woodward, S. S. Pure Appl. Chem. 1983, 55, 589-604. Behrens, C. H.; Sharpless, B. K. Aldrichimica Acta 1983, 16, 67-80. Gorzynski Smith, J.; Synthesis 1984, 629-656. Lewars, E. G. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Ed.; Pergamon Press: New York,1984: Vol. 7, p 100. Weissberger, A.; Taylor, E.C. In The Chemistry of Heterocyclic Compounds; Hassner A., Ed.; Wiley: New York, 1985: Vol. 42, Part 3, p 1. Rossiter, B. E. In Assymetric Synthesis; Morrison, J. D., Ed.; Academic: New York, 1985; Vol. 5, Chapter 7. Hanson, R. M. Chem Rev. 1991, 91, 437-475. Also see: Larock, R. C. Comprehensive Organic Transformations, p 505-526. STERIC, ELECTRONIC, AND CONFORMATIONAL EFFECTS IN EPOXIDE / NUCLEOPHILE REACTIONS Reviews Parker, R. E.; Isaacs, N. C. Chem. Rev. 1959, 59, 737-799. R = various alkyl, aryl, or vinyl substituents SN2 Transition-State Due to ring strain, bond breaking is more advanced than bond making in the transition-state relative to a normal SN2 reaction. In addition, the carbon atom at which displacement takes place will bear a partial positive charge in the transition-state. "Normal" SN2 behavior is observed under neutral or basic conditions to provide nucleophilic attack at the least substituted carbon with inversion. R' is alkyl or a group having no marked inductive or conjugative effects. Exceptions: Hydrogenation in the presence of Raney-nickel proceeds with opposite regioselection. d - d - d + H - N3 - RORSRNH2 R2NH NH3 R - Nu = Nu REGIOSELECTIVITY OF EPOXIDE RING OPENING NEUTRAL OR BASIC CONDITIONS: SN2 ‡
D. A Evans. M. Dart Epoxides as Electrophiles Chem 206 GJOSELECTIVITY OF EPOXIDE RING OPENING ACIDIC CONDITIONS: BORDERLINE SN2 TO SN1 REGIOSELECTIVITY OF EPOXIDE RING OPENING ACIDIC CONDITIONS: BORDERLINE SN2 TO SN1 №u 70-85℃Me Normal prod Abnormal prod 56 HC,Et2O,△74 Disfavored sterically More"abnormal" is formed in H2o than in Et2o which is expected since the "Normal Product reaction proceeds through a polar transition state Major product usually Favored sterically The electron donating inductive effect of an extra methyl substituent slightly a In the borderline SN2 mechanisms overrides the additional steric effect thereby enhancing C-a attack HI, whose anion is most nucleophilic in the series of acids, provides the highest Nucleophilic attack occurs on the conjugate acid of the epoxide proportion of normal product as expected The transiton state is more polar and c-o bond cleavage is more advanced than in SN2 reactions Buchanon, J G: Sable, H. Z. In"Selective Organic Transformations Thyagarajan, B. S, Ed. Wiley: New York, 1972: VoL. 2, p 1 Epoxides which exhibit normal SN2 behavior under basic or neutral conditions give mixtures under acidic conditions Stewart, C A: VanderWerf, C. A. J Am. Chem. Soc. 1954, 76, 1259 Swain. C. G: Scott. C. B. J. Am. Chem. Soc. 1953. 75. 141 Steric factors are important although less so than observed in SN2 reactions The positive charge build up is stabilized by electron releasing groups
H H Nu H R H O R O H + R OH + OH R Nu R O H O H H R H Nu R O OH Nu R Nu R OH Me O OH X Me X Me OH O Me Me Me Cl OH Me Me OH Me Cl HI HBr HCl HX B A More "abnormal" is formed in H2O than in Et2O which is expected since the reaction proceeds through a polar transirtion state. The electron donating inductive effect of an extra methyl substituent slightly overrides the additional steric effect thereby enhancing C_a attack. HI, whose anion is most nucleophilic in the series of acids, provides the highest proportion of normal product as expected. HCl, Et2O, D 74 26 82 18 71 29 56 44 REGIOSELECTIVITY OF EPOXIDE RING OPENING ACIDIC CONDITIONS: BORDERLINE SN2 TO SN1 Normal Prod Abnormal Prod HX, H2O 70-85 °C HCl, H2O 45 55 a b a b Buchanon, J. G.; Sable, H. Z. In "Selective Organic Transformations"; Thyagarajan, B. S., Ed.; Wiley: New York, 1972: Vol. 2, p 1. Stewart, C. A.; VanderWerf, C. A. J. Am. Chem. Soc. 1954, 76, 1259. Swain, C. G.; Scott, C. B. J. Am. Chem. Soc. 1953, 75, 141. REGIOSELECTIVITY OF EPOXIDE RING OPENING Nucleophilic attack occurs on the conjugate acid of the epoxide. The transiton state is more polar and C_O bond cleavage is more advanced than in SN2 reactions. Epoxides which exhibit normal SN2 behavior under basic or neutral conditions give mixtures under acidic conditions. Steric factors are important although less so than observed in SN2 reactions. The positive charge build up is stabilized by electron releasing groups. ■ In the borderline SN2 mechanisms: "Normal Product" "Abnormal Product" "BORDERLINE" SN2 b a d + d - ++ ++ d - d + d + d + ACIDIC CONDITIONS: BORDERLINE SN2 TO SN1 b a SN1 SN1 Favored electronically Disfavored sterically Disfavored electronically Favored sterically R = alkyl Major product usually D. A. Evans, M. Dart Epoxides as Electrophiles Chem 206
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uKm159152
Me 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
D.A. Evans, M. Dart Epoxides as Electrophiles Chem 206 REGIOSELECTIVITY OF EPOXIDE RING OPENINGS REGIOSELECTIVITY OF EPOXIDE RING OPENINGS EFFECT OF CONJUGATING SUBSTITUENTS EFFECT OF CONJUGATING SUBSTITUENTS ubstituent(X) Rati 100:00 36:64 70:30 7624 MeOH, H2SO4 10:90 -OMe NaoMe -H 30:70 Nadph 24:76 Good I donors(OMe)can stabilize the incipient carbocation to offset steric HOPh, TSOH 06: 94 effects Methoxide, which is more nucleophilic than phenoxide, has increased The reaction of styrene oxide with nucleophiles is a balance between sensitivity to sterics and exibits more SN2 behavior with attack at C-B being somewhat favored relative to phenoxide Resonance stabilization favors attack at the a-carbon Steric effects direct attack to the B-carbon Lewars, E.G.: In"Comprehensive Heterocyclic Chemistry": Katritzky, A.R. Ed Under acidic conditions attack at the a-carbon becomes more favorable Olefinic and acetylenic substituents behave similarly Parker.RE. Isaacs. N c. Chem. Rev. 1959. 59. 737-799
O OH Nu Nu OH O X Nu OH X OH Nu X NaOMe -H NaOPh -OMe -H -NO2 NaOPh HOPh NaN3 MeONa PhLi LiBH4 LiAlH4 30:70 Nu 100:0 76:24 36:64 substituent (X) Ratio Lewars, E. G.; In "Comprehensive Heterocyclic Chemistry"; Katritzky, A. R., Ed.; Good p donors (OMe) can stabilize the incipient carbocation to offset steric effects. Methoxide, which is more nucleophilic than phenoxide, has increased sensitivity to sterics and exibits more SN2 behavior with attack at C-b being somewhat favored relative to phenoxide. REGIOSELECTIVITY OF EPOXIDE RING OPENINGS EFFECT OF CONJUGATING SUBSTITUENTS Nua b 24:76 12:88 HOPh, TsOH 06:94 00:100 MeOH, H2SO4 10:90 100: 00 70:30 74:26 Nucleophile Ratio 100: 00 Parker, R. E.; Isaacs, N. C. Chem. Rev. 1959, 59, 737-799. REGIOSELECTIVITY OF EPOXIDE RING OPENINGS EFFECT OF CONJUGATING SUBSTITUENTS NuThe reaction of styrene oxide with nucleophiles is a balance between resonance and steric effects: Resonance stabilization favors attack at the -carbon. Steric effects direct attack to the -carbon. Olefinic and acetylenic substituents behave similarly. Under acidic conditions attack at the a-carbon becomes more favorable. a b D. A. Evans, M. Dart Epoxides as Electrophiles Chem 206
D. A. Evans. M. Dart Epoxides as Electrophiles Chem 206 REGIOSELECTIVITY OF EPOXIDE RING OPENINGS CONFORMATIONAL EFFECTS IN EPOXIDE RING OPENINGS EFFECT OF CONJUGATING SUBSTITUENTS FURST-PLATTNER RULE H2S04, acetone e only product no cis diol observed Henbest, H B, Smith, M; Thomas, A. J. Chem. Soc. 1958, 3293 Rickborn, B; Murphy, D K J. Org. Chem. 1969, 34, 3209 H= LAIH H= LiAlH4 with Xs AlCl Anomalous result with the p-NO2 derivative: a prion one would expect more attack at C-B than C-a. Fuchs. R: VanderWerf. C. A. J. Am. chem. Soc. 1954.76. 1631-1634 Morand. P Can arker, R. E. Isaacs, N S. Chem. Rev. 1959, 59. 737-799 F=< LiAIHg Furst, A, Plattner, P. A. He/v. Chim. Acta 1949, 32, 275 Alt, G H: Barton D H R. J. Chem. Soc. 1954. 4284 (39t93%) The major product in the reactions of rigid cyclohexene epoxides is ble for the regioselectivity observed derived from diaxial ning opening 1. The ole, H. Z. In"Selective Organic Transformations": Thyagarajan, d. T.H. J. Am. Chem Stevens. C. C. H. J. Org. Chem 01
O X Me MeO Me O Ph Ph O Me MeO Me R2NH OH X MeO OH Nu Ph Me Me Ph NR2 O Me Me OH X O Me Me H H H Me HO X HO X Me H HX HX O Me H H Me O H H OH Me Me OH LiAlH4 LiAlH4 Me Me OH OH H H HO Me H H Me HO CONFORMATIONAL EFFECTS IN EPOXIDE RING OPENINGS FÜRST-PLATTNER RULE Aq H2SO4 , acetone (90 %) only product no cis diol observed Fürst, A.; Plattner, P. A. Helv. Chim. Acta 1949, 32, 275. Alt, G. H.; Barton, D. H. R. J. Chem. Soc. 1954, 4284. Henbest, H. B; Smith, M.; Thomas, A. J. Chem. Soc. 1958, 3293. Rickborn, B.; Murphy, D. K. J. Org. Chem. 1969, 34, 3209. The major product in the reactions of rigid cyclohexene epoxides is derived from diaxial ring opening. Buchanon, J. G.; Sable, H. Z. In "Selective Organic Transformations"; Thyagarajan, B. S., Ed.; Wiley: New York, 1972: Vol. 2, p 1. Stevens, C. L.; Coffield, T. H. J. Am. Chem. Soc. 1958, 80, 1919. Stevens, C. L.; Chang, C. H. J. Org. Chem. 1962, 27, 4392. LiAlH4 NaOMe MeOH MeOH, H2SO4 Nu - (39 to 93 %) Conjugative stabilization by oxygen is responsible for the regioselectivity observed in eq 1. The opposite regioselection observed in eq 2 is surprising. 1 2 REGIOSELECTIVITY OF EPOXIDE RING OPENINGS EFFECT OF CONJUGATING SUBSTITUENTS H - a b X = NO2 38 62 Br 84 16 H 74 26 OMe 5 95 H 100 0 OMe 80 20 H 2-10 90-98 H - = LiBH4 H - = LiAlH4 H - = LiAlH4 with xs AlCl3 Anomalous result with the p-NO2 derivative; a priori one would expect more attack at C-b than C-a. Fuchs, R.; VanderWerf, C. A. J. Am. Chem. Soc. 1954, 76, 1631-1634. Kayser, M. M.; Morand, P. Can. J. Chem. 1980, 58, 302-306. Parker, R. E.; Isaacs, N. S. Chem. Rev. 1959, 59, 737-799. D. A. Evans, M. Dart Epoxides as Electrophiles Chem 206
D. A Evans. M. Dart Epoxides as Electrophiles Chem 206 CONFORMATIONAL EFFECTS IN EPOXIDE RING OPENINGS INDUCT/VE STERIC AND CONFORMATIONAL FURST-PLATTNER RULE EFFECTS IN EPOXIDE RING OPENINGS Acidic catalysis only product Basic catalysis Consider a rigid cyclohexene oxide system OMe Inductive withdrawal of electron density by the C-1ethereal oxygen favors attack at C-3 Conformationally and A100% D 10% Conformationally inductively favor on thes e mple model, the transition-state leading to 1 involves diaxial opening epoxide ring and is chainlike B0% However, formation of diequatorial isomer 2 requires a boat-(or skew)like Inductively favored ransition-state. Therefore, according to the Furst-Plattner rule, diaxial opening of the epoxide ring to afford the diaxial product 1 is preferred annard. R.A. B. Casselman. A.A.. Hawkins. L.R. Can. J. chem. 1965. 43 2398 Bannard, R. A. B; Casselman, A. A Langstaff, E J; Moir, R. Y. Can J. Chem. 1968, 46, 35. Buchanon, J. G. Sable, H Z. In" Selective Organic Transformations Thyagarajan, B S, Ed. Wiley: New York, 1972: Vol 2, p 1
O Me H Nu OH H H H Me HO Nu H O H H O H O Nu - Nu HO H H O OR O OR OR Nu OH OR OH Nu OR OH Nu OR Nu OH H O OR Nu HO OR O H OR O OR H OR H O OR HO Nu OR HO Nu HO OR Nu B C A D C D B A INDUCTIVE, STERIC, AND CONFORMATIONAL EFFECTS IN EPOXIDE RING OPENINGS Bannard, R. A. B.; Casselman, A. A.; Hawkins, L. R. Can. J. Chem. 1965, 43, 2398. Bannard, R. A. B.; Casselman, A. A.; Langstaff, E. J.; Moir, R. Y. Can. J. Chem. 1968, 46, 35. Conformationally and inductively favored Conformationally favored 0 % 100 % 10 % 90 % Inductively favored NuNuNuNuInductive withdrawal of electron density by the C-1ethereal oxygen favors attack at C-3. 1 2 3 1 3 2 NH3 OMeBasic catalysis ClBrOAcOMeAcidic catalysis 90 % 10 % only product NuNuNu- 1 2 In this simple model, the transition-state leading to 1 involves diaxial opening of the epoxide ring and is chairlike. However, formation of diequatorial isomer 2 requires a boat- (or skew) like transition-state. Therefore, according to the Fürst-Plattner rule, diaxial opening of the epoxide ring to afford the diaxial product 1 is preferred. Consider a rigid cyclohexene oxide system: CONFORMATIONAL EFFECTS IN EPOXIDE RING OPENINGS FÜRST-PLATTNER RULE Buchanon, J. G.; Sable, H. Z. In "Selective Organic Transformations"; Thyagarajan, B. S., Ed.; Wiley: New York, 1972: Vol 2, p 1. D. A. Evans, M. Dart Epoxides as Electrophiles Chem 206
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 closure
O 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
D. A. Evans. M. Dart Epoxides as electrophiles Chem 206 ACTIVATION OF 6-ENDO OVER 5-EXO EPOXIDE OPENINGS ALL YLIC EPOXIDE CYCLIZATION CIS-EPOXIDES OMe 0. 1 equiv CSA cH2C2,+40 t025°c 6-endo exo The olefinic substituent stabilize positve charge -CH=cHco, Me 86% up at C-a therefore the hexane is formed ￡CH=CHCI(E 762494% -CHCHCI 2 3367 -ccBr 87% The cis-epoxide stereochemistry disfavors highly selective 6-endo ring closure. This Stork claims that the axial orientation of the enolate has severe 1.3-diaxial interactions ay be due to failure of these substrates to attain a planar arrangement necessary for resembling those of a tert-butyl group. Therefore transition-state B, with the enolate in maximum orbital overlap and stabilization of the transition-state an equatorial position, is prefered and accounts for the stereoselectivity observed in the reactio OTBS 0.1 equv CSA 2LDA (92100% ."Tort 43%) 0. 1 equiv CSA Product Ratio Yield 0:100 Stork, G. Kobayashi, Y, Suzuki, T; Zhao, K. JACS 1990, 112, 1661-1663. 24:76 Stork, G: Zhoa, K. JACS 1990, 112, 5875-5876
O Me O MeO - H H OMe O O - Me H H O HO R H H O HO R H O HO R MeO2C OTBS H H O O R HO HO R H H H H O O R O O H OH O O H H R O HO O H H H H R HO O OMe Me O HO Me O OMe Br O O OTBS O A B -CH=CH2 -CH=CHCO2Me -CCBr -CH=CHCO2Me -CH=CH2 favored 2 LDA a The olefinic substituent can stabilize positve charge buildup at C- therefore the cyclohexane is formed. ALLYLIC EPOXIDE CYCLIZATION Stork claims that the axial orientation of the enolate has severe 1,3-diaxial interactions resembling those of a tert-butyl group. Therefore transition-state B, with the enolate in an equatorial position, is preferred and accounts for the stereoselectivity observed in the reaction. -78 °C to rt (43 %) Stork, G.; Kobayashi, Y.; Suzuki, T.; Zhao, K. JACS 1990, 112, 1661-1663. Stork, G.; Zhoa, K. JACS 1990, 112, 5875-5876. 24:76 86% 0:100 81% Substrate (R) Product Ratio Yield 0:100 87% -CH=CHCl (Z) -CH=CHCl (E) Substrate (R) Product Ratio Yield 0:100 86% 44:56 95% 76:24 94% 33:67 92% 6-endo 5-exo (92-100 %) 0.1 equiv CSA CH2Cl2 , -40 to 25 °C 0.1 equiv CSA CH2Cl2 , -40 to 25 °C The cis-epoxide stereochemistry disfavors highly selective 6-endo ring closure. This may be due to failure of these substrates to attain a planar arrangement necessary for maximum orbital overlap and stabilization of the transition-state. CIS-EPOXIDES 0.1 equiv CSA CH2Cl2 , -40 to 25 °C ACTIVATION OF 6-ENDO OVER 5-EXO EPOXIDE OPENINGS D. A. Evans, M. Dart Epoxides as Electrophiles Chem 206
D. A. Evans. M. Dart Epoxides as Electrophiles Chem 206 REDUCTION OF CYCLOBUTENE EPOXIDES REDUCTION OF CYCLOBUTENE EPOXIDES POSSIBLE MECHANISMS 1. Initial carbon-carbon bond cleavage (90-95% LIA/H, THF H0 D DCH 60:40 Only 2 of the 4 possible alcohols were forme therefore only attack at C-P is observed. atio is 46: 54 in ether 2. Initial carbon-oxygen bond cleavage Deuterium labelling studies LAID D then H2O LiAlDA THF flux Rat05248 Products are stable to the reaction conditions, therefore mechanism 2 may be disfavored. However the cyclobutane anions may not be identical under both sets of reaction conditions. The relative position of the aluminum species may have an THF influential role. The proximity of the aluminum (immediately after hydride delivery to t he backside of the B-C may be necessary for c-c bond cleavage b Paquette, L. A; Youssef, A A; Wise, M. L J Am. Chem. Soc. 1967, 89, 5246 No product from fragmentation pathway b is observed, which one would expect to be competitive with (or favored over) reaction a. Paquette concludes that the anomalous reduction of cyclobutene epoxides proceeds by initial C-O bond
O H H H H HO Me HO H H O O HO O H H HO Me O O O H H H H O D H HO H O DCH2 OH D H H O O H HO O H H OD DCH2 O H H O D H H O - O O H H O H H D O H H - D H H O O H H - D H D O H O H - H - O DCH2 OH D H H O O O H H D HO H H H H O D H O H - O O H AlD3 H D D OH DCH2 O D - D - D- AlD3 A LiAlD4 H2O LiAlD4 REDUCTION OF CYCLOBUTENE EPOXIDES POSSIBLE MECHANISMS: ■ 1. Initial carbon-carbon bond cleavage ■ 2. Initial carbon-oxygen bond cleavage D - then H2O quench Products are stable to the reaction conditions, therefore mechanism 2 may be disfavored. However the cyclobutane anions may not be identical under both sets of reaction conditions. The relative position of the aluminum species may have an influential role. The proximity of the aluminum (immediately after hydride delivery) to t he backside of the -C may be necessary for C-C bond cleavage. b No product from fragmentation pathway b is observed, which one would expect to be competitive with (or favored over) reaction a. Paquette concludes that the anomalous reduction of cyclobutene epoxides proceeds by initial C-O bond cleavage (mechanism 2). a b D. A. Evans, M. Dart Epoxides as Electrophiles Chem 206 LiAlH4, THF reflux, 8 h D2O quench Ratio 55:45 Ratio 52:48 H2O quench LiAlD4, THF reflux, 8 h Deuterium labelling studies: ratio is 46:54 in ether 60:40 64:36 (100 %) (90-95 %) LiAlH4, THF reflux, 8 h LiAlH4, THF reflux, 2 d REDUCTION OF CYCLOBUTENE EPOXIDES Only 2 of the 4 possible alcohols were formed, therefore only attack at C- is observed. a b Paquette, L. A.; Youssef, A. A.; Wise, M. L. J. Am. Chem. Soc. 1967, 89, 5246