哈佛大学：《高等有机化学》（英文版）Lecture 7 Other Reading Material

D.A. Evans Conformational Analysis: Part-4 Chem 206 Other Reading Material http://www.courses.fasharvardedu/-chem206/ The Curtin-Hammett Principle Chemistry 206 J I. Seeman, J. Chem. Ed. 1986, 63, 42-48 Advanced Organic Chemistry J 1. Seeman Chem Rev. 1983. 83. 83-134 Leading References Eiel,p.647-655 Lecture Number 7 Carey& Sundberg, Part A, CH 4, pp 187-250 Conformational Analysis-4 a Problems of the Day:(To be discussed) Conformational Analysis of C6 >Cg Rings continued Predict the stereochemical outcome of this reaction. The Transition State torsional effects diastereoselection is 99: 1 Curtin-Hammett Principle mCPBA a Reading Assignment for week Eliel& Wilen, Stereochemistry of Carbon Compounds Chapter 11 (on reserve in CCB library Martinelli et al. Tett. Lett. 1989. 30. 3935 A. Carey Sundberg: Part A; Chapter 4 Study Descrption of Reaction Mechanisms Rationalizethe stereochemical outcome of this reaction K.Houk, Science.1986,231,1108-1117 Theory& Modeling of Stereoselective Organic Reactions(Handout) I COmE LiNE eo、coMe J I Seeman, chem Ed. 1986. 63. 42-48 The Curtin-Hammett Principle( Handout Matthew d shair October 2. 2002 Ladner, et al. Angew. Chemie, Int. Ed 1982, 21, 449-450

http://www.courses.fas.harvard.edu/~chem206/ J. I. Seeman, J. Chem. Ed. 1986, 63, 42-48 The Curtin-Hammett Principle (Handout) O Me O Me Me CO2Me N Ph O H LiNR2 Me-I N Ph O O H O Me O Me Me CO2Me Me D. A. Evans Chem 206 Matthew D. Shair Wednesday, October 2, 2002 ■ Reading Assignment for week A. Carey & Sundberg: Part A; Chapter 4 "Study & Descrption of Reaction Mechanisms" Conformational Analysis: Part–4 Chemistry 206 Advanced Organic Chemistry Lecture Number 7 Conformational Analysis-4 ■ Problems of the Day: (To be discussed) K. Houk, Science. 1986, 231, 1108-1117 Theory & Modeling of Stereoselective Organic Reactions (Handout) ■ Conformational Analysis of C6 ® C8 Rings continued ■ Transition State Torsional Effects ■ Curtin–Hammett Principle Leading References: The Curtin-Hammett Principle J. I. Seeman, J. Chem. Ed. 1986, 63, 42-48. J. I. Seeman, Chem Rev. 1983, 83, 83-134. Eliel, pp. 647-655 Carey & Sundberg,Part A, CH 4, pp 187-250 ■ Other Reading Material mCPBA Martinelli, et.al. Tett. Lett. 1989, 30, 3935 Predict the stereochemical outcome of this reaction. The diastereoselection is 99:1 Rationalizethe stereochemical outcome of this reaction. Ladner, et.al. Angew. Chemie, Int. Ed 1982, 21, 449-450 Eliel & Wilen, Stereochemistry of Carbon Compounds" Chapter 11 (on reserve in CCB library) diastereoselection is 8:1

D.A. Evans Ground state Torsional effects Chem 206 Torsional Effects Relevant Orbital Interactions: Torsional Strain: the resistance to rotation about a bond Torsional energy: the energy required to obtain rotation about a bond Torsional Angle: also known as dihedral angle Torsional steering: Stereoselectivity originating from transition stat torsional energy considerations GC-H& T electrons are C-H's properly aligned for T* overlap AG =+3 kcal mol destabilizing Dorigo, A E Pratt, D W; Houk, K N. JACS 1987, 109, 6591-6600 Conformational Preferences: Acetaldehyde Torsional Strain(Pitzer Strain): Ethane The eclipsed conformation(conformation A)is preferred Polarization of the carbonyl decreases the 4 electron destabilizing Houk. JACS 5,59805988 +2.0 kcal/mol eclipsed Conformational Preferences conformation 1-Butene(X= CH2); Propanal (X=O) Wiberg K B. Martin, E.J. Amer. Chem. Soc. 1985, 107, 5035-5041 A M H X+Me B See Lecture 5 for previous discussion Conformation A is preferred. There is little steric repulsion between the

Torsional Angle: also known as dihedral angle H H H H H O H Me X H H C C H H H H C C H H H H H H C C H H H C C H H H H H O H H H H H H X H H H Me H H B A B C H H H CH2 CH2 H A B A H C H H H D. A. Evans Ground State Torsional Effects Chem 206 Torsional Strain: the resistance to rotation about a bond Torsional energy: the energy required to obtain rotation about a bond Torsional steering: Stereoselectivity originating from transition state torsional energy considerations DG = +3 kcal mol-1 Torsional Strain (Pitzer Strain): Ethane staggered eclipsed Relevant Orbital Interactions: Dorigo, A. E.; Pratt, D. W.; Houk, K. N. JACS 1987, 109, 6591-6600. Wiberg K. B.; Martin, E. J. Amer. Chem. Soc. 1985, 107, 5035-5041. s C–H's properly aligned for p* overlap hence better delocalization s C–H & p electrons are destabilizing Conformational Preferences: Acetaldehyde The eclipsed conformation (conformation A) is preferred. Polarization of the carbonyl decreases the 4 electron destabilizing Rotational barrier: 1.14 kcal/mol Houk, JACS 1983, 105, 5980-5988. Conformational Preferences 1-Butene (X = CH2); Propanal (X = O) Conformation A is preferred. There is little steric repulsion between the methyl and the X-group in conformation A. Torsional Effects eclipsed conformation staggered conformation +2.0 kcal/mol See Lecture 5 for previous discussion

D.A. Evans Transition State Torsional Effects According to Houk Chem 206 Houk: Torsional effects in transition states are more important than in ground states H Transition states H H-radical and H-anion: antiperiplanar o*C-R orbital stabilized the ts H illustrated for Nu additio H2C=C-+H H2C R C-RL C-RL 0°30°60°90°120 +16 Forming bond Same trends are observed for H+ addition Forming bond Houk, Science1981,231,1108-1117 "The Theory and Modeling of Stereoselective Organic Reactions 2 Carmol Transition state a*C-RL 53 N 0°30°60°90°120 Houk,JACS1981,103,2438 Ground state F*C-RL Houk,JACs1982,104,7162 RL

D. A. Evans Transition State Torsional Effects According to Houk Chem 206 H2C C H* H2C C H* H2C C H* 60° 90° 0° 120° 30° 60° 90° 120° 2 Kcalmol-1 +4.7 0 0 H 0 H H +1.6 H H H 0° H 30° H H +5.3 +2.4 no H* Transition states Houk, JACS 1981, 103, 2438 Houk: "Torsional effects in transition states are more important than in ground states" C Nu C RL H-radical and H-anion: antiperiplanar s*C–R orbital stabilized the TS illustrated for Nu addition Houk, Science 1981, 231, 1108-1117 "The Theory and Modeling of Stereoselective Organic Reactions" Same trends are observed for H+ addition sC-Nu s*C-RL sC-Nu homo s*C-RL lumo Forming bond Forming bond Houk, JACS 1982, 104, 7162 H H H C C H H H RL H H Nu sC-Nu s*C-RL Transition state C R H RL H H Nu sC-Nu s*C-RL Ground state H - H • H +

D.A. Evans Transition State Torsional Effects: Olefin Additions Chem 206 Olefin Addition Reactions: Case one Olefin Addition Reactions: Case two How do we account for the high exo selectivities in addition How do we account for the high selectilvities in the oxidation of ctions to norbornene? the indicated olefin? exo Highly exo selective for electrophilic, Oso nucleophilic and cycloaddition reactions mCPBA Rate enhancement due to strain ndo 98:2 diastereoselectivity diastereoselectivity The Controversy over origin of high exoselectivities Steric effects Nitrogen protecting group does not affect selectivities Least nuclear motion A Orbital distortion Schleyer: torsional steering Favored Schleyer, P. R.J. Amer. Chem. Soc. 1967, 89, 701 Martinelli et al. Tett. Lett. 1989. 30. 3935 Addition from exo face avoids eclipsing A &B hydrogens Addition from indicated olefin face avoids eclipsing a&BHs tter hy perconjugative stabilization of transition state) (better hyperconjugative stabilization of transition state Martinelli has carried out further studies on related structures

Steric effects Least nuclear motion Orbital distortion Nitrogen protecting group does not affect selectivities H H N Ph O OH OH H OsO4 N Ph O H A B A N Ph O O H B D. A. Evans Transition State Torsional Effects: Olefin Additions Chem 206 ■ Olefin Addition Reactions: Case one How do we account for the high exo selectivities in addition reactions to norbornene? exo endo Highly exo selective for electrophilic, nucleophilic and cycloaddition reactions The Controversy over origin of high exoselectivities Schleyer: torsional steering Rate enhancement due to strain Schleyer, P. R. J. Amer. Chem. Soc. 1967, 89, 701. Addition from exo face avoids eclipsing A & B hydrogens (better hyperconjugative stabilization of transition state) 98 : 2 diastereoselectivity 99 : 1 diastereoselectivity Martinelli, et.al. Tett. Lett. 1989, 30, 3935 mCPBA ■ Olefin Addition Reactions: Case two Favored Addition from indicated olefin face avoids eclipsing A & B H's (better hyperconjugative stabilization of transition state) How do we account for the high selectilvities in the oxidation of the indicated olefin? Martinelli has carried out further studies on related structures

D. A. Evans Transition State Torsional Effects: Olefin Additions Chem 206 Martinelli. Torsional steering important in selectivity mCPBA 99: 1 diastereoselectivity mCPBA 50: 50 diastereoselectivity Authors propose that diastereoselection controlled by TS torsional effects Martinelli& Houk, J. Org. Chem. 1994, 59, 2204

63° 62° 74° 40° major Me O H Me O O H D. A. Evans Transition State Torsional Effects: Olefin Additions Chem 206 Martinelli: Torsional steering important in selectivity 99 : 1 diastereoselectivity 50 : 50 diastereoselectivity 99 : 1 diastereoselectivity Martinelli & Houk, J. Org. Chem. 1994, 59, 2204. mCPBA mCPBA mCPBA 89° major Authors propose that diastereoselection controlled by TS torsional effects

D. A. Evans Cyclohexanone Addition Reactions: Hydride Reduction Chem 206 Stereoselective Reductions: Cyclic Systems Nu: Attack Trajectories for Cyclohexanone Torsional Argument) Me3C Axial Diastereomer This approach favo 102030 500070 Nu. DIBAL-H 72: 28 L-Selectride 8: 92 The steric hindrance encountered by Nu-attack from the axial C=o face by the axial NaBH4 79: 21 K-Selectride 3: 97 ring substituents(hydrogens in this case)at the 3-positions is more severe than the steric hinderance encountered from Nu-attack from the equatorial C=o face LiAlH(O+-Bu)3 92: 8 -CHaMe 3 Observation: Increasingly bulky hydride reagents prefer to attack from H the equatorial C=o face The most stereoselective Reductions o 0-C-C-H dihedral: +63.0° H COH 0-C-C-H dihedral o 0-C-C-He dihedral KBH(S-Bu)3 Li in NH3 The Issues associated with the reduction process Steric Effects: Attack across equatorial c=o face sterically more favorabl Me3C- Torsional Effects: However, attack across the axial face of the c=o group avoids evelopment of eclipsing i ions in the transition sta Ganem, Tet. Let 1981, 22, 3447 R=Bn LiBH(s-Bu)3 03: 97 Hutchins, JOC 1983, 48, 3412 R=Ph LiBH(s-Bu)3 01: 99 For small "hydride reagents such as LiAlH4, torsional effects Prediction are felt to be dominant and this explains the predisposition for je"hydride reagents such as H-BRa, steric effects Predicti

Nu: Nu: H Me3C O [H] H Me3C H OH M + H B C H Me CH2Me H Me3C OH H HA H Me3C O H Me3C H OH H Me3C OH H H NHR Me3C H NHR H Me3C H NPh Me3C H LiBH(s-Bu)3 (R) [H] KBH(s-Bu)3 LiBH(s-Bu)3 [H] HA private communication Hutchins, JOC 1983, 48, 3412 R = Ph 01 :99 R = Bn 03 :97 Al/Hg/MeOH Ganem, Tet. Let 1981, 22, 3447 D. A. Evans Cyclohexanone Addition Reactions: Hydride Reduction Chem 206 – 3 DIBAL-H 72:28 L-Selectride 8:92 NaBH K-Selectride 3:97 4 79:21 LiAlH(Ot-Bu)3 92:8 LiAlH4 93:7 0 10 20 30 40 50 60 70 80 90 100 % Axial Diastereomer Increasingly bulky hydride reagents prefer to attack from the equatorial C=O face. Observation: Stereoselective Reductions: Cyclic Systems The most stereoselective Reductions Reagent Ratio 03 :97 Li in NH3 99 :01 ~90 :10 Reagent Ratio The steric hindrance encountered by Nu-attack from the axial C=O face by the axial ring substituents (hydrogens in this case) at the 3-positions is more severe than the steric hinderance encountered from Nu-attack from the equatorial C=O face. Attack Trajectories for Cyclohexanone H (Torsional Argument) E This approach favored sterically HE O–C–C–He dihedral: +63.0 ° Axial Attack Equatorial Attack O–C–C–He dihedral: +4.0 ° O–C–C–He dihedral: –56.0 ° H: – H: – Attack across equatorial C=O face sterically more favorable. However, attack across the axial face of the C=O group avoids development of eclipsing interactions in the transition state. (Note the dihedral angle sign changes between reactants & products shown above). These "torsional effects" favor axial attack. Steric Effects: Torsional Effects: For "small" hydride reagents such as LiAlH4, torsional effects are felt to be dominant and this explains the predisposition for axial attack. Prediction Prediction For "large" hydride reagents such as H–BR4 , steric effects now are dominant and this explains the predisposition for equatorial attack. The Issues Associated with the Reduction Process 3

K. A Beaver, D. A. Evans Conformational Analysis and Reactivity: Curtin-Hammett Principle Chem 206 eading References: J. L Seeman, J. Chem. Ed 1986, 63, 42-48 Case 1: Kinetic Quench J I Seeman. Chem Rev. 1983. 83. 83-134 >>kA, kB: If the rates of rea rate of conversion, a and b cannot eq irse of the reaction, and the product distribution initia How does the conformation of a molecule effect its [PA (Alo Consider the following example Do the two different conformers react at the same rate or different rates? The situation In this case, the product distribution depends solely on the initial ratio of the two conformers Consider two interconverting conformers, A and B, each of which can undergo a reaction resulting in two different products, PA and PB hindrance PA B PB AG=-30 kcal/mol We'll consider two limiting cases Me-Br (1)The rate of reaction is faster than the rate of conformational interconversion (2 )The rate of reaction is slower than the rate of conformational interconversion major product minor product reactants are not in equilibrium during the course of the reaction and complex mathmatical solutions are necessary. See Seeman, Chem. Rev. 1983, 83-144 for While enolate conformers can be equilibrated at higher temperatures, the products of analytical solutions alkylation at C always reflect the initial ratio of enloate isomers Padwa. JACS 1997 4565

J. I. Seeman, Chem Rev. 1983, 83, 83-134. J. I. Seeman, J. Chem. Ed. 1986, 63, 42-48. N Me N Me PA [PA] [PB] [B]o [A]o A B PB (1) kB k1 kA k2 PA O N Me Me H A Me–Br N O Me Me Me H B Me O N Me H N O Me Me H Me PB Me–Br K. A. Beaver, D. A. Evans Conformational Analysis and Reactivity: Curtin-Hammett Principle Chem 206 Leading References: How does the conformation of a molecule effect its reactivity? Consider the following example: Do the two different conformers react at the same rate, or different rates? What factors determine the product distribution? major minor Consider two interconverting conformers, A and B, each of which can undergo a reaction resulting in two different products, PA and PB. The situation: See also Eliel, pp. 647-655 13 Me–I 13 Me–I DG° DGAB ‡ DG1 ‡ DG2 ‡ Rxn. Coord. Energy k1 , k2 >> kA, kB: If the rates of reaction are faster than the rate of interconversion, A and B cannot equilibrate during the course of the reaction, and the product distribution (PB/PA) will reflect the initial composition. = In this case, the product distribution depends solely on the initial ratio of the two conformers. major product minor product less stable more stable Padwa, JACS 1997 4565 DG = -3.0 kcal/mol (ab initio calculations) Case 1: "Kinetic Quench" We'll consider two limiting cases: (1) The rate of reaction is faster than the rate of conformational interconversion (2) The rate of reaction is slower than the rate of conformational interconversion -78°C While enolate conformers can be equilibrated at higher temperatures, the products of alkylation at -78° C always reflect the initial ratio of enloate isomers. If the rates of conformationall interconversion and reaction are comparable, the reactants are not in equilibrium during the course of the reaction and complex mathmatical solutions are necessary. See Seeman, Chem. Rev. 1983, 83 - 144 for analytical solutions. steric hindrance

K A Beaver. D.A. Evans Curtin-Hammett: Limiting Cases Chem 206 Case 2. Curtin-Hammett Conditons k1, k, < kA, kB: If the rates of reaction are much slower than the rate of To relate this quantity to AG values, recall that AG =-RT In Keg or Keg interconversion, (AGAB is small relative to AG, and AG2), then the ratio of e aRT, k, =e G tRT, and k2 =e" GRT. Substituting this into the above A to B is constant throughout the course of the reaction Combining terms 问“e,dm=ore . AAG/RT Curtin-Hammett Principle: The product composition is not solely dependent on relative proportions of the conformational isomers in the substrate; it is controlled by the difference in standard Gibbs energies of the respective transition states major Rxn Coord minor The Derivation Within these limits, we can envision three scenarios Using the rate equations PA/ KiA and d=kalB] we can write If both conformers react at the same rate, the product distribution will be the same as the ratio of conformers at equilibrium d(PBl k2[B d(Pal (2) If the major conformer is also the faster reacting conformer, the product from the major conformer should prevail, and will not reflect the Ince A and B are in equlIbrium, we ca3ne丙 equilibrium distribution If the minor conformer is the faster reacting conformer, the product apPAl Integrating, we get Pel k2 ratio will depend on all three variables in eq(2), and the observed product distribution will not reflect the equilibrium distribution PAl k This derivation implies that you could potentially isolate a product and b are in uilibrium we mus which is derived from a conformer that you cant even observe in the of the conformers as well as the equilib ground state! ing the product

PB (2) (3) Using the rate equations = (4) [PB] [PA] A B k2 [B] [B] [A] [PB] [PA] [PB] [PA] PA kB k1 kA k2 d[PA] d[PB] = k1[A] d[PB] d[PA] k1[A] = k2 [B] or Since A and B are in equilibrium, we can substitute Keq = k1 = k2 Keq e -DG 2 /RT e -DG 1 /RT (e-DG°/RT) e -DG 2 /RTe -DG°/RTe DG 1 = /RT e -(DG2 + DG°-DG1 = )/RT or e = -DDG/RT A B PB [PB] [PA] PA K. A. Beaver, D. A. Evans Curtin - Hammett: Limiting Cases Chem 206 k1, k2 << kA, kB: If the rates of reaction are much slower than the rate of interconversion, (DGAB ‡ is small relative to DG1 ‡ and DG2 ‡ ), then the ratio of A to B is constant throughout the course of the reaction. DG° DDG ‡ DG1 ‡ DG2 ‡ Rxn. Coord. Energy major minor d[PA] dt = k1[A] and d[PB] dt = k2[B] we can write: d[PB] d[PA] k1 = k2 Keq k1 = k2 Keq Integrating, we get To relate this quantity to DG values, recall that DG o = -RT ln Keq or Keq = e -DG°/RT, k1 = e-DG 1 ‡/RT, and k2 = e-DG 2 ‡/RT. Substituting this into the above equation: Where DDG ‡ = DG2 ‡+DG°-DG1 ‡ The Derivation: Curtin - Hammett Principle: The product composition is not solely dependent on relative proportions of the conformational isomers in the substrate; it is controlled by the difference in standard Gibbs energies of the respective transition states. When A and B are in rapid equilibrium, we must consider the rates of reaction of the conformers as well as the equilibrium constant when analyzing the product ratio. (1) Case 2: Curtin-Hammett Conditons Within these limits, we can envision three scenarios: • If the major conformer is also the faster reacting conformer, the product from the major conformer should prevail, and will not reflect the equilibrium distribution. • If both conformers react at the same rate, the product distribution will be the same as the ratio of conformers at equilibrium. • If the minor conformer is the faster reacting conformer, the product ratio will depend on all three variables in eq (2), and the observed product distribution will not reflect the equilibrium distribution. This derivation implies that you could potentially isolate a product which is derived from a conformer that you can't even observe in the ground state! Combining terms: DGAB ‡ slow slow fast

K.A. Beaver D. A. Evans Some Curtin-Hammett Examples Chem 206 Tropane alky lation is a well-known example Enantioselective lithiat less stable more stable S-BuLi (1-Sparteine faster"Me- Because sparteine is ()-Sparteine ave different minor product The less stable conformer reacts much faster than the more stable onformer, resulting in an unexpected major product Joc1974319 faster owe Oxidation of piperidines -. P2N、∠O less stable Me Me,c 只 Me more stable 82-87% slower:k1 H202 aste 0 her, reaction in the absence of ( -sparte minor produci Ratio: 5: 95 major product enantioselectivity is the same over the course of the reaction. If they were not uilibrating the enantioselectivity should be higher at lower conversions When the equilibrium constant is known, the Curtin-Hammett derivation This is a case of Dynamic Kinetic Resolution: Two enantiomeric alkyl be used to calculate the relative rates of reaction of the two lithium complexes are equilibrating during the course of a reaction with an conformers. Substituting the above data into[PBVPal= k2K/k,, the ratio Beak. Acc. Chem. Res. 1996. 552 Note that in this case, the more stable conformer is also the faster reacting conformer Tet1972573 Tet1977915

N Me H Me3C O – Me3C H Me N N Me H Me3C N Me N Me N Me 13Me N Me 13Me + + + i-Pr2N O Me H i-Pr2N O Me Li•sparteine s-BuLi Me3C H Me N O – i-Pr2N O Me Cl H2O2 i-Pr2N O Me Li i-Pr2N O Me i-Pr2N O Me Li•sparteine N N K. A. Beaver, D. A. Evans Some Curtin-Hammett Examples Chem 206 k1 k2 Keq = 10.5 Ratio: 5 : 95 + less stable more stable slower faster minor product major product Oxidation of piperidines: major product minor product 13 Me–I 13 Me–I slower faster less stable more stable Tropane alkylation is a well-known example. When the equilibrium constant is known, the Curtin-Hammett derivation can be used to calculate the relative rates of reaction of the two conformers. Substituting the above data into [PB]/[PA] = k2K/k1, the ratio k2/k1 ~ 2. Note that in this case, the more stable conformer is also the faster reacting conformer! The less stable conformer reacts much faster than the more stable conformer, resulting in an unexpected major product! JOC 1974 319 Tet. 1972 573 Tet. 1977 915 (-)-Sparteine slower faster 82 - 87% ee This is a case of Dynamic Kinetic Resolution: Two enantiomeric alkyl lithium complexes are equilibrating during the course of a reaction with an electrophile. Beak, Acc. Chem. Res, 1996, 552 Enantioselective Lithiation: (-)-Sparteine Enantioselectivities are the same, regardless of whether or not the starting material is chiral, even at low temperatures. Further, reaction in the absence of (-)-sparteine results in racemic product. Note that the two alkyllithium complexes MUST be in equilibrium, as the enantioselectivity is the same over the course of the reaction. If they were not equilibrating, the enantioselectivity should be higher at lower conversions. Because sparteine is chiral, these two complexes are diastereomeric and have different properties

K.A. Beaver. D. A. Evans Mechanism of Asymmetric Hydrogenation Chem 206 The asymmetric hydrogenation of prochiral olefins catalyzed by Rhodium is an important catalytic process [LRh coordination Meo2C、NHAc minor Enantioselectivities are generally very high when the ligand is a chelating diphosphine (ee's are given for S, S-CHIRAPHOS When a chiral ligand is used, there are two diastereomeric complexes which hydrogenfaster slower may be formed addition Moc minor comple. major complex (NMR, X-Ray) H2 migration +s migration MeO2C R observed product Observations 2 is the only diasteromer observed for the catalyst-substrate complex Ray crystallography) in the absence of hydrogen - L2RhS2 elimination The enantioselectivity is strongly dependant on the pressure of H2, and degrades rapidly at higher hydrogen pressures The observed enantiomer is exclusively derived from the minor complex 2 Meo2C、NHAc MeO2C、NHAc These observations may be explained using the Curtin-Hammett Principl 95% Ipem, Science, 217, 1982, 401

Rh O P H P H Ph HN Me CO2Me Rh O H P P H Ph NH Me MeO2C Rh O P P Ph NH Me MeO2C Rh S H P P O Me NH CO2Me CH2Ph Rh O P P Ph HN Me CO2Me S R S Rh O P P Ph NH Me MeO2C S Rh O P P Ph HN Me CO2Me Ph MeO2C NHAc R Ph MeO2C NHAc Ph MeO2C NHAc R Rh S H P P O Me HN MeO2C PhH2C Ph MeO2C NHAc > 95% ee 2 Ph MeO2C NHAc H2 H2 Ph MeO2C NHAc S,S Rh S P S P Ph MeO2C NHAc K. A. Beaver, D. A. Evans Mechanism of Asymmetric Hydrogenation Chem 206 The asymmetric hydrogenation of prochiral olefins catalyzed by Rhodium is an important catalytic process. [L2Rh]+ > 95% ee Enantioselectivities are generally very high when the ligand is a chelating diphosphine. (ee's are given for S,S-CHIRAPHOS) coordination coordination hydrogen addition hydrogen addition migration reductive elimination reductive elimination migration -L -L2RhS2 2RhS2 Observations: • Complex 2 is the only diasteromer observed for the catalyst-substrate complex (1HNMR, X-Ray crystallography) in the absence of hydrogen • The enantioselectivity is strongly dependant on the pressure of H2 , and degrades rapidly at higher hydrogen pressures • The observed enantiomer is exclusively derived from the minor complex 2 These observations may be explained using the Curtin - Hammett Principle Halpern, Science, 217, 1982, 401 When a chiral ligand is used, there are two diastereomeric complexes which may be formed: observed product major complex 1 * * faster slower (NMR, X-Ray) + S + S minor complex minor major fast slow