http://www.courses.fas.harvard.edu/~chem206/ R OTMS H Rβ O OP BF3?OEt2 Me H iPr O OPMB Me iPr OH OPMB R O Me H iPr O OPMB Me iPr OH OPMB R O R OTMS BF 3?OEt2 Rβ OH OP R O iPr OH OPMB R O Me Chem 206Sarah Siska, C. A. Morales Matthew D. Shair Monday, November 4, 2002 a73 Reading Assignment for this Week: Carey & Sundberg: Part A; Chapter 8Reactions of Carbonyl Compounds Models for Carbonyl Addition Chemistry 206 Advanced Organic Chemistry Lecture Number 20 The Evolution of Models for Carbonyl Addition a73 Useful Reviews (1) 1,3-Anti Construct a model for the addition process in eq 1 using the principles learned thus far in the course. Felkin 96 : 4 4 : 96 R = t-Bu R = Me R = Me, t-Bu ≥ 97 : 3 (2) (3) a73 A problem Aldehydes 1 & 2 contain 2 stereocenters, each of which may influence the course of the addition process. For 1, the reaction is Felkin selective for all enolsilanes; however, for 2, this is not the case. Explain. For the answer see: Evans, JACS 1996, 118, 4322. (pdf) 1 2 Fischer Cram Cornforth Felkin Anh/Eisenstein Cieplak Tomoda a73 1,2-Asymmetric Induction Models a73 1,3-Asymmetric Induction Models a73 Merged 1,2- and 1,3-Asymmetric Induction a73 Unpredicted, highly selective carbonyl additions Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191-1223 Gung, B. W. Tetrahedron 1996, 52, 5263-5301 Ager, D. J.; East, M. B. Tetrahedron 1992, 48, 2803-2894 Reetz, M. T. Angew. Chem. Int. Ed. Engl. 1984, 23, 556-569 Morrison, J. D.; Mosher, H. S. Asymmetric Organic Reactions; Prentice Hall Inc.: 1971 Wipf, P.; Kim, Y. J. Am. Chem. Soc. 1994, 116, 11678-11688, ref. 1-5, 7 Chem 206Sarah Siska, C. A. Morales Models for Carbonyl Addition Introduction R RS RM RL O H RL RM O H RM/L O X R RS RM RL HO Nu Nu RL OH RM Nu RM/L OH X Nu RL OH RM Nu RM/L OH X R RS RM RL Nu OH RL/X RS RM OR M Felkin product = commonly accepted term for the major carbonyl addition product predicted by the Felkin-Anh model; also predicted by Cram and Karabatsos for steric cases, Cornforth for α-heteroatom (non-chelating) cases Nu: Felkin-Anh model Felkin products anti-Felkin products a73 Examples: also Cram-chelate product Nu–M Nu–M Nu–M + + + a73 Definition of Terms glucose* CHO OHH HHO HHO CH2OH CO2, H2CO H OH OHH HHO HHO CH2OH COOH OHH HHO HHO CH2OH HO H COOH chlorophyll* Fischer, E. Ber. 1894, 27, 3189Freudenberg, K. Adv. in Carbohydrate Chem. 1966, 21, 1 chlorophyll* Fischer, and the Dawn of Asymmetric Induction Fischer, E. Ber. 1890, 23, 2611Fischer, E. Ber. 1894, 27, 3189 Assimilation in nature: propagation of asymmetry from one chiral molecule to another "To my knowledge these observations furnish the first definitive evidence that further synthesis with asymmetric systems proceeds in an asymmetric manner." L-arabinose 1) HCN 2) hydrolysis L-mannonic acid L-gluconic acid + ~3 : 1 not isolated initially, but later found in mother liquor -Emil Fischer, 1894 Chem 206Sarah Siska, C. A. Morales Cram's Rule R O M R O M O R RS RM RL RL RM RS RL RM RS R RS RM RL HO Nu R RS RM RL Nu OH RL RM RS R OH Nu Don Cram: 1952 Nu: Nu-M Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc. 1952, 74, 5828 predicted(Felkin product) (anti-Felkin product) Cram acyclic model torsional effects not considered Nu: activated carbonyl considered to be largest group steric repulsion between R L and R not discussed Features and Liabilities Cram's Rule: "In reactions of the following type, that diastereomer will predominate which would be formed by the approach of the entering group from the least hindered side of the double bond when the rotational conformation of the C–C bond is such that the double bond is flanked by the two least bulky groups attached to the adjacent asymmetric center." + 90° trajectoryof nucleophile Nu-M = RMgX, LAH RL = Ph RM = Me, Et RS = H R = H, Ph, Me, Et Basis for Model selectivities ranging from 2:1 to >4:1, favoring Felkin product HNH Me Ph O MgBr NH H MgBr Ph O MgBr O Ph Me NH3Cl Me MePh OHp-tolyl NH3Cl MePh p-tolylHO NH3Cl Nu: a73 Bottom Line Cram's acyclic model is a convenient mnemonic that predicts Felkin products in α-alkyl or aryl aldehydes or ketones. p-CH3C6H4MgBr Nu: Among the 27 cited reactions whose stereoselection is "predicted" by Cram's acyclic rule: Ranking of steric bulk of α-substituents is somewhat arbitrary: Me > NH3Cl due to the amino group's formation of a non-rigid "more adaptable" ion pair major(anti-Felkin) minor(Felkin) yield not reported Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc. 1952, 74, 5828 one proposed transition state: in the end, a suggestion of a chelate . . . Curtin, D. Y.; Pollak, P. I. J. Am. Chem. Soc. 1951, 73, 992 ? Low or unreported yields may result in misleading selectivities? Model based on qualitative assessment of steric bulk + a73 Possible Pitfalls Chem 206Sarah Siska, C. A. Morales Cornforth-1 Don Cram: 1959 R O M XRS RM/L R O M O Ph Ph MeX O Ph OR M Me Ph CH3MgI CH3Li A major Ph Ph MeX OHR' X OHOMe RL RM RS Ph Ph MeX R'HO B minor Nu: Methyl has greater effective bulk than OH; Cram cites "A-values" of Winstein, who compares the relative tendency of groups to occupy the equatorial position on a cyclohexane ring. CH3 > OSO2C6H4CH3-p > OCOCH3 > OH The acyclic model would predict the opposite product in the case of an α-heteroatom -- a new model is needed! Cram acyclic model Cram chelate model Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81, 2748 "The open-chain model applies to systems which contain only groups attached to asymmetric carbon of the starting material which are incapable of complexing with organometallic reagents." Nu: + ? expects groups OH, OR, OAc, NR2, NHAc to chelate 1) R'-M 2) H3O+ A : BR'-M Winstein, S.; Holmes, N. J. J. Am. Chem. Soc. 1955, 77, 5562 nucleophile approaches from the back face Nu: 11.5 : 19 : 1 yield of A (%) 2050 R O M R O M X O R Cl RS RL RL RS X RL RS R Cl RS RL R'HO R Cl RS RL OHR' X RL RS R OH Nu Cornforth: 1959 Nu: Cornforth model Cornforth, J. W.; Cornforth, R. H.; Mathew, K. K. J. Chem. Soc. 1959, 112 1) R'-M Et2O, -70 °C2) AcOH ? argument based on importance of polarization in transition state, and evidence of selectivity in α-chlorocyclohexanone additions ? ". . . where the dipoles are antiparallel, the polarization of the carbonyl group would be easiest," thereby lowering transition state energy ? a modification of Cram's rule for electronegative, non-chelating α-substituents X + predicted(Felkin) as in Cram acyclic model, torsional effects not considered Nu: activated carbonyl considered to be largest group Features 90° trajectoryof nucleophile net dipole of molecule minimized (anti-Felkin) Additions to -Chloro Carbonyls RL O Ph O O RS RM O R Cl RS RL Cl O R O M RL RS R(M) H Ph O MH R(M) H O MH Ph Nu: Nu: O Cl O R Cl RLRS O H Et Cl n-Bu Et O n-Bu Et Cl OH X n-Bu Et Cl OH n-Bu Et O Ph R O H R Mei-Pr PhNu R OH A PhNu R OH PhNu R OH PhNu R OH B Karabatsos: 1967 Karabatsos, G. J. J. Am. Chem. Soc. 1967, 89, 1367 Nu-M Karabatsos model Given Cram's acyclic model, Karabatsos is surprised by the following selectivities: + ? it appears that i-Pr is effectively smaller than Me, if Ph = RL Karabatsos' explanation: Cram transition states are incorrect ? ratios depend not on Nu a163 H and Nu a163 RM, but instead on RM a163 O vs. RL a163 O major minor H° Me a163 O – Ph a163 Oi-Pr a163 O – Ph a163 O Compared Interaction 0.6 kcal/mol0.2 kcal/mol A : B 2–4 : 11–2 : 1 2nd-best conformerCornforth, J. W.; Cornforth, R. H.; Mathew, K. K. J. Chem. Soc. 1959, 112 Prelog, V. Bull. Soc. Chim. Fr. 1956, 987Bellamy, L. J.; Thomas, L. C.; Williams, R. L. J. Chem. Soc. 1956, 3704 Bellamy, L. J.; Williams, R. L. ibid. 1957, 4294 Nu: Cornforth model Chem 206Sarah Siska, C. A. Morales Cornforth-2 7 (Felkin) 3 (anti-Felkin) aq. NaOH 1) n-BuMgBr 2) AcOH + aq. NaOH (±) (±) (±) :68% Cornforth: Rationalization and Evidence Corey, E. J. J. Am. Chem. Soc. 1953, 75, 2301Corey, E. J.; Burke, H. J. ibid. 1955, 77, 5418 Support and Contradiction for Dipole Minimization Chlorohydrin Synthesis (note: methylpyruvate does not adopt this conformation) These were known products. O MR RS RL O MR RM RS RM O H M RM RSRL RS RL OR N H Z RM RSRL ≈ O H RL RM RM RLNu RM OH RLNu RM OH RL O R RL Me RL RS RM OR M LiAlH4 RL RS RM OR M R RL Me OH R RL Me OH A B R MeEt i-Prt-Bu RL RS RMNu R OH Felkin: 1968 Chérest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 18, 2199 Felkin model ? "reactant-like" transition state ? assumption of torsional strain in partially formed or broken bonds: first fully staggered acyclic model ? substituents minimized around R; leads to inconsistency in aldehyde substrates a169 see DAE Chem 206 Lecture Notes (2000), 18-08 ? polar effect: maximize separation between incoming anionic nucleophile and electronegative α-substituent (RS, RM, or RL) Nu: larger RL ≈ better selectivity substituents minimized around ketone R 90° trajectory of nucleophile RL = Cy RL = Ph A / B 1.62.0 4.11.6 2.83.2 5.049 torsional strain accounted for; leads to fully staggered product + Features larger nucleophile ≈ better selectivity Reduction of -Methyl Ketones Chem 206Sarah Siska, C. A. Morales Felkin-1 Karabatsos model Nu: Nu: Karabatsos, G. J. J. Am. Chem. Soc. 1967, 89, 1367 ? energy difference (??H°) between interactions of RM a163 O and RL a163 O determines product ratio ? reactant-like transition state ? model based on most stable ground-state conformation ? energy differences between major and minor conformations are <1 kcal/mol Nu-M + major(Felkin) minor(anti-Felkin) Rationalizations most stable ground state conformer a) ?H°(imine N a163 R) ≈ ?H°(carbonyl O a163 R) b) imine geometry ≈ complexed C=O geometry ?H°(imine N a163 R) ≈ ?H°(complexed C=O O a163 R) Z = alkyl, OR, NR2 Nu: RL RS RM ROM RM RL RS ROM (CH2)4 (CH2)4OMe H Nu: Nu: O Cyt-Bu Me O Me LAH LiAlH4 Me t-Bu Cy OH 1.6 Me OH t-Bu Cy Me OH 1 Me OH H OMe RL RS RM Me Me Me O Felkin: Accounting for Less Selective Reactions 1) The t-butyl ketone case ? cannot adopt Felkin-type conformation; still considered as a reactant-like transition state ? selectivity based on competition between torsional strain and steric strain possible when R M is relatively small torsional strain(large Nu:)steric strain(small Nu:) + : Chem 206Sarah Siska, C. A. Morales Felkin-2 major Nu: ? with α-branching, in any staggered conformation, syn-pentane is impossible to avoid 2) Transition states for minor products (does not consider conformers with RL next to R) 3) 2-methylcyclohexanone possible for small nucleophiles + Chérest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 18, 2199; 2205 RL RS RM HOM RL RS RM HOM RL RS RM OH M Nu: Nu: Nu: X RS RM/L OR M OX RM/LRS H M Anh, N. T.; Eisenstein, O. Nouv. J. Chim. 1977, 1, 61 Bürgi, H. B.; Dunitz, J. D.; Shefter, E. J. Am. Chem. Soc. 1973, 95, 5065Bürgi, H. B.; Dunitz, J. D.; Lehn, J. M.; Wipff, G. Tetrahedron 1974, 30, 1563 Weaknesses in Felkin's Argument Nu: ? main repulsion to minimize between Nu and electronegative group X -- no justification given 1) Polar effect 2) Breakdown for aldehydes wrong prediction Anh's Solutions 1) Antiperiplanar effect ? best acceptor σ* orbital aligned parallel to pi and pi* orbitals of carbonyl; stabilization of incoming anion piC=O a163 σ*C-X nNu a163 σ*C-X ? without ketone R, important steric interaction removed: would predict RM to be next to H rather than carbonyl 2) Non-perpendicular attack ? incorporation of the Bürgi-Dunitz trajectory favored disfavored Nu Chem 206Sarah Siska, C. A. Morales Ciekplak Model Et H Me OH Li H– Cl H Me OH Li H– RS RL RS RL OR RM O MR RM θ = 107° Nu: X H Me OH Li H– ORR M Anh's Calculated Transition State Energies Anh, N. T.; Eisenstein, O. Tetrahedron Lett. 1976, 155 Anh, N. T.; Eisenstein, O. Nouv. J. Chim. 1977, 1, 61 Anh, N. T. Top. Curr. Chem. 1980, 88, 146 1.5 ? θ θ = 90°, 100°, 110° rotate C–C bond by 30° increments 1.63 ? 2-methylbutanal(Felkin-Anh model) 2-chloropropanal(Felkin-Anh polar model) The model: Lowest energy transition states: STO-3G ab initio method (low level) (interpolated using a quadratic curve) Karabatsos model Nu: 95 – 105° Non-perpendicular attack most stable ground state conformer a range of angles for optimum overlap >2.7 kcal/mol EFelkin model EG1 G1 C Nu C Nuσ? H XD HRM/L O M Nu C XD C XD C XA C XA XD RS RM/L OR M σ (Houk disputes the ordering of C–H, C–C) CieplakFelkin Anh σ σ? σ? σ Cieplak, A. S. J. Am. Chem. Soc. 1981,103, 4540; Cieplak, A. S.; Tait, B. D.; Johnson, C. R. J. Am. Chem. Soc. 1989, 111, 8447 Cieplak Model for Carbonyl Addition - DAE Cieplak model Nu: ? similar to Anh-Eisenstein modification of the Felkin model: stabilization of nucleophile via antiperiplanar C–XD bond ? assumes an electron-poor transition state: aligns best donor C–XD anti to incoming nucleophile to stabilize σ* of forming bond ? a model generated to explain unexpected selectivities ? importance of torsional effects (Felkin, Anh, Houk, Paddon-Row) disputed σC–Xd a163 σ*C---Nu C–H > C–C > C–N > C–O better donor "Structures are stabilized by stabilizing their highest energy filled states. This is one of the fundamendal assumptions in frontier molecular orbital theory. The Cieplak hypothesis is nonsense." "Just because a hypothesis correlates a set of observations doesn't make that hypothesis correct." Chem 206Sarah Siska, C. A. Morales Correlating Theory with Experiment-Peter Wipf-1 Me OMe O O O Me OTMS O Me OBz O O O O O O O O O Me OH O ' (58%) ' (39%) ' (42%) R' OR O R' ORHO Me R' ORMe HO MeMgBrTHF -78 °C + 4,4-Disubstituted Cyclohexadienones: Experimental Data 7.9 : 1 (26%) 4.8 : 1 (81%) 8.6 : 1 (32%) 5.5 : 1 (53%) 17.7 : 1 (93%) KEY: : (yield) 8.2 : 1 (85%) 32 : 1 (79%) 11 : 1 (29%) ~4 ? ("vinylogous Felkin-Anh") CF2CF3 OMe O R' OR O M O Me OMe O Me OMe Nuβ α β α Nu CF2CF3 OMeHO Me CF2CF3 OMeMe HO Nu-M solvent + 1 5 : Wipf Seeking an Explanation "vinylogous Anh-Eisenstein" model "vinylogous Cieplak" model ? stabilizing σ* of the incipient bond ? predicts α attack, but no qualitative correlation between ratio of isomers and σ energy of donor C–C bonds LUMO of enone has phase inversion due to double bond between carbonyl and donor/acceptor orbital Stereoelectronic effect? Chelate shielding of the β face is not likely, since 1,4-addition, when it does occur, is β-selective. Electrostatic effect? Substrate with inverted dipole exhibits good β selectivity! Neither vinylogous Felkin nor vinylogous Cieplak sufficiently explains or predicts selectivity. ? stabilizing HOMO of nucleophile? predicts β attack -- wrong product! Wipf, P.; Kim, Y. J. Am. Chem. Soc. 1994, 116, 11678 Wipf, P.; Jung, J-K. Chem. Rev. 1999, 99, 1469 -3 -2 -1 0 1 2 3 4 -3 -2 -1 0 1 2 3 4 calc. dipole moment [Debye] ln Chem 206Sarah Siska, C. A. Morales Correlating Theory with Experiment-Peter Wipf-2 O O O O O Me OMe O CF2CF3 OMe O OO Me OMe O O [ ' (42%)] 32 : 1 (79%) 8.6 : 1 (32%) 4.8 : 1 (81%) Quantitative Correlation Between Facial Selectivity and Dipole Moment Qualitative Assessment ? calculated dipole moments of five representative dienones using SPARTAN ? linear correlation between perpendicular vector of dipole moment and natural log of facial selectivity ? validity of ground-state dipole moment: complexed carbonyl should affect dipoles of all dienone substrates in same manner ? approach of nucleophile toward positive end of dipole favored Dipole Moment Calculations CO2Me O CO2Me O EWG O OH CO2Me CO2Me HO Nu O O O R R CO2Me CO2Me Nu OH anti δ+ Nu: δ– syn anti δ+ Nu: δ– δ– syn Nu δ– δ+ δ– δ– δ+ δ+ δ+ synanti O X NaBH4 Nu-M NaBH4 MeLi A X HHO C D X OHH B p-PhNO2 F CO2Me CF3 SiMe3 OH X An Electrostatic Take on Some Controversial Cases synanti Cheung, et al. J. Am. Chem. Soc. 1986, 108, 1598 A : B + 66 : 3462 : 38 61 : 3959 : 41 45 : 5543 : 57 favorable electrostatic interaction hydroxyl may create too much lone-pair repulsion (Felkin-Anh) Adcock, W.; Cotton, J.; Trout, N. A. J. Org. Chem. 1994, 59, 1867 (Felkin-Anh) + Nu-M 70>90 3010 : :: favorable electrostatic interaction Mehta, G.; Khan, F. A. J. Am. Chem. S, 1990, 112, 6140 Paddon-Row, M. N.; Wu, Y-D.; Houk, K. N. J. Am. Chem. Soc. 1992, 114, 10638 Ganguly, B.; Chandrasekhar, J.; Khan, F. A.; Mehta, G. J. Org. Chem. 1993, 58, 1734 Chem 206Sarah Siska, C. A. Morales Houk & Heathcock X O X ONu δ+ δ– δ– δ+ Nu δ+ δ–δ–δ + O X NaBH4 MeOH X X H OH A X OH H B Houk: Axial Effect axial attack equatorial attack Heq OH eq OAceq Br eq Clax OH ax OAcax Cl ax F 60 : 4061 : 39 71 : 2966 : 34 71 : 2985 : 15 83 : 1788 : 12 87 : 13 A : B Wu, Y-D.; Tucker, J. A.; Houk, K. N. J. Am. Chem. Soc. 1991, 113, 5018Paddon-Row, M. N.; Wu, Y-D.; Houk, K. N. J. Am. Chem. Soc. 1992, 114, 10638 Rationalization: repulsive a remote electrostatic effect preferred + attractive R MeO H OH M OMe H R OH M Nu: Nu: O H R OMe OLi t-Bu A R OMe t-Bu O OH R OMe t-Bu O OH B R MeEt i-PrPh t-Bu Felkin-Anh polar model + Felkin anti-Felkin THF, -78 °C A : B Lodge, E. P.; Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 3353 58 : 4276 : 24 92 : 0883 : 17 93 : 07 electrostatic model ? Would expect some erosion of selectivity as size of R increases -- observe just the opposite! ? As R is anti to incoming nucleophile, increasing size of R should not erode selectivity? As R gets larger, conformation may be more "locked" in the above conformer "Quite simply, we believe our data show that the Anh-Eisenstein hypothesis is only partly correct." steric effect on Nu: is underemphasized steric effect on Nu: is overemphasized In both models, the stereoelectronic or electrostatic control element is not consistently dominant! Both the size and the electronic properties of the α-substituents must be considered. Heathcock: -Alkoxy Lithium Aldol Chem 206Sarah Siska, C. A. Morales 1,2-Induction H R OP PO H R H O M H O M H O P HR O M R PO H OH Nu M electrostatic modelFelkin-Anh model ? best acceptor σ* orbital aligned parallel to pi and pi* orbitals of carbonyl: hyperconjugative stabilization ? leads directly to staggered conformation, Felkin product Nu: Nu: Are Felkin-selective reactions of α-heteroatom aldehydes going through the Felkin-Anh transition state? ? assumes a covalent transition state in which FMO stabilization dominates ? leads directly to staggered conformation, Felkin product ? dipoles of carbonyl and α-C-O are minimized, with increasing stabilization as pyramidalization occurs at the reactive center ? assumes a more ionic transition state in which coulombic interactions dominate ? larger pi* coefficient on C of oxocarbenium species may enable a wider range of angles for nucleophilic trajectory piC=O a163 σ*C-OP RL RS RM OH M XRS RM/L R O MX RM RL RS RM OR M X RS RM/L OR M XD RS RM/L OR M RM/L X RS OR M RL RL RS RM RS R O MR O M RS RL O MR Nu: Nu:Nu: Nu: Nu: Nu: Nu: Nu: Nu: PDAS Felkin model (1968)steric, torsional Cornforth model (1959)electrostatic Models Proposed for 1,2-Asymmetric Induction Cram acyclic model (1952)steric Cram rigid model (1959)chelation Karabatsos model (1967)ground-state, steric Felkin-Anh model (1977)steric, torsional, Bürgi-Dunitz Felkin-Anh polar model (1977)electronic, torsional, Bürgi-Dunitz Cieplak model (1981)electronic, torsional, Bürgi-Dunitz electrostatic model (2001)electrostatic, torsional, Bürgi-DunitzTomoda EFOE model (1997) ground-state, steric, electronic H Me Me O H Rβ OBn Me SiMe3 n-Bu2Zn Me SiMe3 SiMe3 SiMe3 R' TiLn O O H Rβ BnHH H n-Bu n-Bu Me Me Me R A OH R' Rβ OBn n-Bu TiLn O O H Rβ BnHH H B R' OBnOH Rβ RS O R RL RSRM RM O R X RMRS H O R M RM RSX O TiLnO H Nu H Rβ Bn R RL RSRMOHH R X RMRSNuHO H H OR M RS R L RM R RL RSRMHO H R X RMRSNu OH Nu: 1,3-Asymmetric Induction: Open-Chain Models Brienne, M-J.; Ouannès, C.; Jacques, J. Bull. Soc. Chim. Fr. 1968, 3, 1036 RL Jacques steric model Nu: Nu: + major minor LAH 3-D depiction of Jacques model ? rationalization similar to Felkin: minimization of R a163 β-R steric interactions + major minor NuMgX Cram polar model ? an adaptation of the Cram steric model, with the key feature being dipole minimization of electronegative substituent X and carbonyl Leitereg, T. J.; Cram, D. J. J. Am. Chem. Soc. 1968, 90, 4011, 4019 RMgX, RLi, and R2CuLi fail to give high chelation selectivities for β-alkoxy aldehydes. 1,3-anti Chem 206Sarah Siska, C. A. Morales 1,3-Induction-1 Reetz: Chelation in -Alkoxy Aldehydes Reetz proposes possible transmetallation event of nucleophile: internal delivery. Reagent TiCl4 CH2Cl2 -78 °C Reagent yields ≥90% R' A : B + 95 : 05 95 : 05 90 : 10 95 : 5 99 : 01 Nu: ? leads to a chair-like intermediate Cram-Reetz chelate model 1,3-syn Reetz, M. T.; Jung, A. J. Am. Chem. Soc. 1983, 105, 4833 (hydrocarbon R groups) Chem 206Sarah Siska, C. A. Morales 1,3-Induction-2 OSiMe3 i-Pr O H R X BF3?OEt2 -78 °C H H OR M X R β H X OPMB OTBS OPMB OTBS OAc Cl Me A 1,3-anti R X i-Pr O OH i-Pr i-Pr CH2CH2Ph CH2CH2Ph CH2CH2Ph CH2CH2Ph C(Me2)CHCH2 R O i-Pr R OH X B 1,3-syn 1,3-Asymmetric Induction: Open-Chain Models Nu: Evans polar model A : B Evans: Mukaiyama Aldols yield (%) 92 : 08 80 : 2081 : 19 73 : 27 43 : 57 83 : 1758 : 42 91 8487 90 79 8488 ? staggered to avoid torsional strain ? dipoles of Cβ–X and carbonyl minimized ? non-perpendicular nucleophile trajectory Evans, D. A.; Duffy, J. L.; Dart, M. J. Tetrahedron Lett. 1994, 35, 8537Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc. 1996, 116, 4322 See also: Bonini, C.; Esposito, V.; D'Auria, M.; Righi, G. Tetrahedron 1997, 53, 13419 ++ H Rα OR M X R β H O H i-Pr OP Me OSiMe3 R R t-Bui-Pr Me A OH Nu i-Pr OP Me B OH Nu i-Pr OP Me Evans Merged Model for 1,2- and 1,3-Asymmetric Induction Nu: Evans merged model ? for non-chelating conditions ? a merger of the Felkin-Anh (1,2) model and the Evans polar (1,3) model ? minimized dipole moment ? non-perpendicular trajectory ? RL anti to incoming nucleophile ? predicts 1,2-Felkin control and 1,3-anti Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G.; Livingston, A. B. J. Am. Chem. Soc. 1995, 117, 6619 Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc. 1996, 118, 4322 P = PMB P = TBS yield (%)A : B A : B 99 : 0198 : 02 97 : 03 9498 86 99 : 0195 : 05 71 : 29 9388 92 yield (%) The stereoreinforcing case (Felkin and 1,3-anti induction coincide) + Felkin anti-Felkin BF3?OEt2 CH2Cl2 -78 °C Chem 206Sarah Siska, C. A. Morales Merged Models O H i-Pr OPMB Me OSiMe3 R H Rα OR M X R β H R t-Bui-Pr Me C OH Nu i-Pr OPMB Me D OH Nu i-Pr OPMB Me Me H OH M PMBOi-PrH The non-stereoreinforcing case: Felkin control opposes 1,3-stereocontrol + Felkin anti-Felkin C : DCH 2Cl2 C : Dtolueneyield (%) yield (%) 96 : 0456 : 44 17 : 83 8998 82 88 : 1232 : 68 06 : 94 7586 92 Nu: Evans merged model ? with a small nucleophile, β-stereocenter becomes the dominant control element ? 1,3-induction is enhanced in nonpolar media Evans Merged Model for 1,2- and 1,3-Asymmetric Induction Nu: non-stereoreinforcingtransition state BF3?OEt2 solvent -78 °C H Rα OP H H HPO R β PO H Rα H O M H O M H O M Nu:Nu: Nu: OR O H Rβ OP1 OP2O H Rβ OP2 OP1 Nu Rα OP OH Nu OH Rβ OP Integration of α- and β-Alkoxy Aldehyde Models in Non-chelating Systems Which is stereoreinforcing, anti or syn? "Felkin" product predicted electrostatic modelFelkin-Anh model Evans model For β-alkoxy aldehydes: For α-alkoxy aldehydes: 1,3-anti product predicted non-chelating Lewis acid ? under non-chelating conditions, 1,3-anti selectivity is observed Evans, D. A.; Duffy, J. L.; Dart, M. J. Tetrahedron Lett. 1994, 35, 8537-8540 ? no systematic electronic + steric study has been done How does the α-alkoxy substituent affect the conformation of the β-stereocenter? For α,β-bisalkoxy aldehydes: non-chelating Lewis acid Chem 206Sarah Siska, C. A. Morales Examples SS Me Me OTBDPS S S Me Me O H OP P MOMTBS TBDPS RL PO H HO S S Me Me OH PO SS Me Me OTBDPS Me OH PO SS Me Smith: Rapamycin t-BuLi, 10% HMPA/THF-78 °C + Aanti-Felkin BFelkin A : B yield (%) Smith, A. B., III; Condon, S. M.; McCauley, J. A.; Leazer, J. L., Jr.; Leahy, J. W.; Maleczka, R. E., Jr. J. Am. Chem. Soc. 1997, 119, 947 2 : 15 : 1 >20 : 1 3275 60 Nu: suggested as reactive conformer OTBS S OTBS S BnO O H OTBS TBSO O O OBn O H BF3?Et2O CH2Cl2, -78 °C 20 h BF3?Et2O CH2Cl2, -78 °C O SBnO OH OTBS TBSO O S OH O O BnO Kobayashi: Monosaccharide Derivatives on the Solid Phase ds >98 : 2 anti-Felkin 1,3-syn Kobayashi, S.; Wakabayashi, T.; Yasuda, M. J. Org. Chem. 1998, 63, 4868 after cleavage from resin, 61% over 4 steps, the third of which is the aldol ds 95 : 5 after cleavage from resin, 61% over 4 steps, the third of which is the aldol 1,3-anti Felkin Chem 206Sarah Siska, C. A. Morales Conclusions a73 Judging by the Smith and Kobayashi results, as well as many others, it remains a challenge to predict the stereochemical outcome of addition to α- and β-heteroatom-substituted carbonyl compounds. It may be that more than one model is operational in a single system. a73 While the Felkin-Anh model has withstood the test of time for hydrocarbon α-substituents, the numerous exceptions to the electronic model have sparked a flurry of new explanations, beginning with Cieplak in 1981. The debate continues, between steric, torsional, electronic, and electrostatic effects. a73 Nucleophilic additions to α-heteroatom-substituted carbonyl compounds are highly sensitive to solvent, nature and size of nucleophile, nature and size of protecting group, and size of other α-substituent.