Chemistry 206 Advanced Organic Chemistry Handout–03A Steric, Electronic, & Conformational Effects in Epoxide–Nucleophile Reactions Matthew D. Shair MondaySeptember 23, 2002 Mick Dart Evans Group Seminar, December, 1993 O R' H Nu HH O R' R' Nu OH Epoxides as ElectrophilesD. A. Evans, M. Dart 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 S N2 reaction. In addition, the carbon atomat which displacement takes place will bear a partial positive charge in the transition-state. "Normal" S N2 behavior is observed under neutral or basic conditions to providenucleophilic 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. δ? δ? δ+ H- N3- RO- RS- RNH2 R2NH NH3 R- Nu = Nu REGIOSELECTIVITY OF EPOXIDE RING OPENING NEUTRAL OR BASIC CONDITIONS: SN2 ? H H Nu H R HO R O H+ R OH + OH R Nu R O HO H H R H Nu R O OH NuR 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_α attack. HI, whose anion is most nucleophilic in the series of acids, provides the highest proportion of normal product as expected. 74HCl, Et2O, ? 26 1882 71 29 4456 REGIOSELECTIVITY OF EPOXIDE RING OPENING ACIDIC CONDITIONS: BORDERLINE SN2 TO SN1 Abnormal ProdNormal Prod HX, H2O 70-85 °C HCl, H2O 45 55 α β α β 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. a73 In the borderline SN2 mechanisms: "Normal Product" "Abnormal Product" "BORDERLINE" SN2 β α δ+ δ? ++ ++ δ? δ+ δ+ δ+ ACIDIC CONDITIONS: BORDERLINE SN2 TO SN1 β α SN1 SN1 Favored electronically Disfavored sterically Disfavored electronically Favored sterically R = alkyl Major product usually Epoxides as ElectrophilesD. A. Evans, M. Dart Chem 206 Me OH O O OHO NHR OHMe OO OEtMe Me F3C OEt O O OEt O O O O NH2 O NH2 HO OEtF3C 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 OArMe OH NHiPr Me OAr OH F3C Me O OH OEt MeF 3C 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 δ+ δ? δ? EWG = Electron Withdrawing Group Attack at C- is discouraged due to destabilization of the transition state by juxtaposition of positive charge. α β EFFECT OF ELECTRONEGATIVE, NONCONJUGATING SUBSTITUENTS Conformational effects are guiding theregioselectivity of reaction 3. 1. 2. 3. δ? δ+ ? Chem 206D. A. Evans, M. Dart Epoxides as Electrophiles 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 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 Ratiosubstituent (X) Lewars, E. G.; In "Comprehensive Heterocyclic Chemistry"; Katritzky,A. R., Ed.; Good pi 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-β being somewhat favored relative to phenoxide. REGIOSELECTIVITY OF EPOXIDE RING OPENINGS EFFECT OF CONJUGATING SUBSTITUENTS Nu- α β 24:76 12:88 06:94HOPh, TsOH 00:100 10:90MeOH, H2SO4 100: 00 70:30 74:26 RatioNucleophile 100: 00 Parker, R. E.; Isaacs, N. C. Chem. Rev. 1959, 59, 737-799. REGIOSELECTIVITY OF EPOXIDE RING OPENINGS EFFECT OF CONJUGATING SUBSTITUENTS Nu- The 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 α-carbon becomes more favorable. α β Chem 206D. A. Evans, M. Dart Epoxides as Electrophiles O X Me MeO Me OPh Ph O MeMeO Me R2NH OH X MeO OH Nu MePh 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 OHH H HO Me H H MeHO 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 NaOMeMeOH MeOH, H2SO4 Nu - (39 to 93 %) Conjugative stabilization by oxygen is responsible for the regioselectivity observedin eq 1. The opposite regioselection observed in eq 2 is surprising. 1 2 REGIOSELECTIVITY OF EPOXIDE RING OPENINGS EFFECT OF CONJUGATING SUBSTITUENTS H -α β X = NO2 38 62Br 84 16 H 74 26 OMe 5 95 H 100 0OMe 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-β than C-α. 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. Chem 206D. A. Evans, M. Dart Epoxides as Electrophiles O Me H Nu OH H H H Me HO Nu H HO O HH O Nu - Nu HO H H O OR O OR OR Nu OH OR OH Nu OR OH Nu OR Nu OH H ORO Nu HO OR O H OR O OR H OR H O ORHO Nu OR HO Nu HO ORNu B C DA DC BA 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 andinductively favored Conformationallyfavored 0 % 100 % 10 % 90 % Inductively favored Nu- Nu- Nu- Nu- Inductive withdrawal of electron density by the C-1ethereal oxygen favors attack at C-3. 1 2 3 1 3 2 NH3 OMe- Basic catalysis Cl- Br- OAc- OMe- Acidic catalysis 10 %90 % only product Nu- Nu- Nu- 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. Chem 206D. A. Evans, M. Dart Epoxides as Electrophiles O CN - O CN OH H CN CN O H OH CN Me O CN O CN- OHMe CN O Me NC - H C O NC - CNMe O Me R HO (CH2)n O CNMe OHMe R HO (CH2)nHO + HO (CH2)n HO+ R O N Me Me MeM R Me Me MeO N M O (CH2)n OH H OR HO O HO R H H OHO R H (CH2)nO OH H H CNR O H H R O H CN H R CN HO H HO CN R H CNR HO R CN HO H BA -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 cyclobutanesand cyclopentanes. Stork's studies exclusively involved cis-epoxides. 5-exo6-endo Nicolaou, JACS 1989, 111, 5330-5334. exo ring closureendo ring closure Developing positive charge can be stabilized through electron donation from an adjacent orbital in A. δ+ δ + 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% 96%60:40 100:0 95% 90%100:0 Epoxides as ElectrophilesD. A. Evans, M. Dart 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 O Me O-MeO H H OMeO O- Me H H O HO R H H OHO R H O HO R OTBSMeO2C H H O O HOR HO R H H H H O O R O OH OH O O H H R HOO O H H H H R HO O OMe Me O HO Me O OMe Br O OTBSO O A B -CH=CH2 -CH=CHCO2Me -CCBr -CH=CHCO2Me -CH=CH2 favored 2 LDA α The olefinic substituent can stabilize positve charge build- up at C- therefore the cyclo- hexane 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% 81%0:100 Yield Product RatioSubstrate (R) 0:100 87% -CH=CHCl (Z) -CH=CHCl (E) Substrate (R) Product Ratio Yield 0:100 86% 95%44:56 76:24 94% 92%33:67 5-exo6-endo (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 Chem 206D. A. Evans, M. Dart Epoxides as Electrophiles O H H H HHO 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 OH 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 AlD3H D D OH DCH2 O D- D- D- AlD3 A LiAlD4 H2O LiAlD4 REDUCTION OF CYCLOBUTENE EPOXIDES POSSIBLE MECHANISMS: a73 1. Initial carbon-carbon bond cleavage a73 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. β 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 Epoxides as ElectrophilesD. A. Evans, M. Dart Chem 206 LiAlH4, THF reflux, 8 hD 2O 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. α β Paquette, L. A.; Youssef, A. A.; Wise, M. L. J. Am. Chem. Soc. 1967, 89, 5246. Red-Al 4:94 1:99 1:99 50:50 20:80 0:100 LiBH4/Ti(OiPr)4 98:2 99:1 87:13 Ph OHO O OHBnO OHOC5H11 O OH Me Me Me O OHR R OH OH OH OHR O OHR OH OHR R OH OH H Al O O R X X O O M H RH R OHO O OHR OH OHR Nu R OH OH Nu H- LiAlH4 Dai, L.; Lou, B; Zhang, Y.; Guo, G. Tetrahedron Lett. 1986, 4343.Sharpless, B. M.; Caron, M. J. Org. Chem. 1985, 50, 1557. No reaction is observed in the absence of Ti(OiPr)4. The reaction is unselective ifthe alcohol is protected. 20-100 : 1 100 : 1 6-9 : 1 14 : 1 100 : 1 100 : 1 R2NH ROH PhSH,PhSNa TMSN3 NH4OBz PhCO2H Nu Ti(OiPr)4 This chelated structure is purported to be responsible for a number of Nu/Ti(OiPr)4 and other Nu/metal regioselective epoxide ring opening reactions. C-3 opening C-2 opening a Sharpless attributes selective C-3 attack to overlap of bond a with an empty d orbital on the metal. Cleavage of this bond also affords a 5-membered chelated ring which is favorable. DIBAL or LiBH4/Ti(OiPr)4 3 2 13 2 1 5-exo REGIOSELECTIVE OPENING OF EPOXYALCOHOLS The reaction is thought to involve initial complexation of the aluminum species to the alcohol followed by internal hydride delivery. Kishi, Y. K.; Finan, J. M. Tetahedron Lett. 1982, 2719. R = CH2CH2OCH3 Epoxides as ElectrophilesD. A. Evans, M. Dart Chem 206 C-2 opening1,3-DiolC-3 opening1,2-Diol 3 2 1 Reduction selectivity C-3 vs C-2 opening 3 2 1 REGIOSELECTIVE OPENING OF EPOXYALCOHOLS Hanson, R. M. Chem. Rev. 1991, 91, 437-475. DIBAL 92:8 Na2AlH2(OR)2 O OHR O O O (RO)3Ti H RH O O R OH OH Nu OH Nu OHR O O R OO - O nC7H15 OHO Me OH OHR OO R OH Me OH Nu OH OHR O - O R OH Nu OH OH Me OHR O O OH OH15C7 O R OH OH Me O OHBu Bu OHOH R O O R2Al H R'H - R' OHO OH Me OHR' R' OH OH Me O Cu O R Me Me AlR3 R- Chong, J. M.; Cyr, D. R.; Mar, E. K. Tetrahedron Lett. 1987, 28, 5009.Roush, W. R.; Adam, M. A.; Peseckis, S. M. Tetrahedron Lett. 1983, 24, 1983. Suzuki, T.; Saimoto, H.; Tomioka, H.; Oshima, K. Tetrahedron Lett. 1982, 23, 3597. REGIOSELECTIVE OPENING OF EPOXYALCOHOLS Reactions with organoaluminum compounds: R' = Bu AlMe3PhCCAlEt 2DIBAL Yields 70-90 % Selectivities for C-3 openings are generally >10:1 3 2 1 Best selectivies are obtained in nonpolarsolvents such as hexane or PhH. Opposite regioselection is observed for cuprates: THF-polar cosolvent For R' = alkyl 84:16 regioselectivity 5-exo3 2 Best selectivities are observed with polar cosolvents. 1 : 17 (84%) Nu Ratio No explanation for the dramatic shift in regioselectivity of the epoxide isomers provided. Cis-epoxyacids unselective. Chong, J. M.; Sharpless, B. M. Tetrahedron Lett. 1985, 26, 4683. 3 2 Cis-epoxyacids exhibit opposite regioselection and are opened at C-3. 3 equiv Me2CuLi Et2O, 0 °C, 3 h Trans-epoxyacids are attacked at C-2. 3 2 Sharpless, K. B.; Chong, J. M. J. Org. Chem. 1985, 50, 1560. 2 3 REGIOSELECTIVE OPENING OF EPOXYACIDS Nu Et2NH-Ti(iOPr)4 PhSH-Ti(iOPr)4 Et2NH >20 : 1 10 : 1 1 : 6 C-3 attack C-2 attack Cuprates and Epoxyacids: 3 equiv Me2CuLi Et2O, 0 °C, 3 h 8 : 1 (91%) 2 3 Chem 206D. A. Evans, M. Dart Epoxides as Electrophiles Me2CuCNLi2