哈佛大学：《高等有机化学》（英文版）Lecture 18 Carbonyl and Azomethine Electrophiles

D. A. Evans Carbonyl and Azomethine Electrophiles-1 Chem 206 Additional Reading Material Provided http://ww.courses.fasharvardedu/-chem206/ Additions to 5-&6-Membered oxocarbenium ions Chemistry 206 Woerpel etaL. JACS 1999, 121, 12208 Woerpel etal. JACS 2000. 122, 168 Advanced Organic Chemistry "Theoretical Interpretation of 1, 2-Asymmetric Induction. The Importance of Antiperiplanarity", N. T. Anh, O Eisenstein Lecture number 18 Nouv j chem1977,1,61-70 Carbonyl and Azomethine Electrophiles-1 Relevant Dunitz Articles Geometrical Reaction Coordinates. Il. Nucleophilic Addition to Reactivity Trends a Carbonyl Group", JACS 1973, 95, 5065 C=X Stereoelectronic Effects Carbonyl Addition: Theoretical Models Stereochemistry of Reaction Paths at Carbonyl Centers Tetrahedron 1974. 30. 1563 The Felkin-Anh-Eisenstein model for c=o Addition Diastereoselective Ketone reduction From Crystal Statics to Chemical Dynamics", Accounts Chem Research1983,16,153 a Reading Assignment for this Week Stereochemistry of Reaction Paths as Determined from Crystal Carey& Sundberg: Part A; Chapter 8 Structure Data. A Relationship Between Structure and Energy Reactions of Carbonyl Compounds Burgi, H.-B. Angew Chem., Int Ed. Engl. 1975, 14, 460 Carey Sundberg: Part B; Chapter 2 Reactions of Carbon Nucleophiles with Carbonyl Compounds rey Sundberg: Part B; Chapter 5 Reduction of Carbonyl Other Functional Groups ednesday Matthew d shair October 30. 2002

D. A. Evans Chem 206 Matthew D. Shair Wednesday, October 30, 2002 http://www.courses.fas.harvard.edu/~chem206/ ■ Reading Assignment for this Week: Carey & Sundberg: Part A; Chapter 8 Reactions of Carbonyl Compounds Carbonyl and Azomethine Electrophiles-1 Additional Reading Material Provided Chemistry 206 Advanced Organic Chemistry Lecture Number 18 Carbonyl and Azomethine Electrophiles-1 R C R O R C R O R R C R N R R C R N R R ■ Reactivity Trends ■ C=X Stereoelectronic Effects ■ Carbonyl Addition: Theoretical Models ■ The Felkin-Anh-Eisenstein Model for C=O Addition ■ Diastereoselective Ketone Reduction Carey & Sundberg: Part B; Chapter 2 Reactions of Carbon Nucleophiles with Carbonyl Compounds Carey & Sundberg: Part B; Chapter 5 Reduction of Carbonyl & Other Functional Groups ■ Relevant Dunitz Articles "Geometrical Reaction Coordinates. II. Nucleophilic Addition to a Carbonyl Group", JACS 1973, 95, 5065. "Stereochemistry of Reaction Paths at Carbonyl Centers", Tetrahedron 1974, 30, 1563 "From Crystal Statics to Chemical Dynamics", Accounts Chem. Research 1983, 16, 153. "Stereochemistry of Reaction Paths as Determined from Crystal Structure Data. A Relationship Between Structure and Energy.", Burgi, H.-B. Angew. Chem., Int. Ed. Engl. 1975, 14, 460. Additions to 5- & 6-Membered oxocarbenium Ions: Woerpel etal. JACS 1999, 121, 12208. Woerpel etal. JACS 2000, 122, 168. "Theoretical Interpretation of 1,2-Asymmetric Induction. The Importance of Antiperiplanarity", N. T. Anh, O. Eisenstein Nouv. J. Chem. 1977, 1, 61-70

D. A. Evans C=X Electrophiles: Carbonyls, Imines Their Conjugate Acids Chem 206 The Set of Functional Groups Stereoelectronic Considerations for c=o Addition LUMO iS I*C-O: HOMO Provided by Nu: π*C-0 Aldimine minIum These functional groups are among the most versatile sources of electrophilic carbon 兀*C-0 in both synthesis and biosynthesis. The ensuing discussion is aimed at providing a more advanced discussion of this topic. ■C= X Polarization +0 HOMO Dunitz-Burgi trajectory Partial Charge: As the familiar polar resonance structure above indicates, the carbonyl carbon supports a partial positive charge due to the polarization of the sigma and pi system by the more electronegative heteroatom. The partial charges for this g NuC family of functional groups derived from molecular orbital calculations (ab initio, -Nu 3-21(G) HF)are illustrated below R C=0 6+0.33 6+0.51 8+0.54 6+0.61{R=H a What about C=X VS C=X-R(+)? a Proton Activation of C=X Functional groups 6+0.61 The electrophilic potential of the C=o FG may be greatly increased by either Lewis acid coordination of by protonation. The magnitide of this increase in reactivity is-10*6 Among the weakest Bronsted acids that may be used for C=O activation(ketalization) The LUMo coefficient on carbon for B will be considerably larger than for A.Does is pyridinium ion(pKa=5). Hence, the Keq below, while quite low, is still functional this mean that there is a lower constraint on the approach angle for the attacking H nucleophile? There is no experimental proof for this question; however, it is wort Keq -10 pka=5 a What was the basis for the Dunitz-Burgi analysis

C O R R Nu C R R O C R R X C R R X R ~107 ° d – d – R C R O R C R N R R C R O R C R O R R C R O R C R N R R R C R N R R + C R O – R C R O R C R O H H–A A – R C R O R C R O H N H N R C R O R R C R N R R C=X Electrophiles: Carbonyls, Imines & Their Conjugate Acids A B D. A. Evans Chem 206 Oxocarbenium ion Iminium ion Aldimine Ketimine (Imine) Aldehyde Ketone These functional groups are among the most versatile sources of electrophilic carbon in both synthesis and biosynthesis. The ensuing discussion is aimed at providing a more advanced discussion of this topic. ■ C=X Polarization Partial Charge: As the familiar polar resonance structure above indicates, the carbonyl carbon supports a partial positive charge due to the polarization of the sigma and pi system by the more electronegative heteroatom. The partial charges for this family of functional groups derived from molecular orbital calclulations (ab initio, 3-21(G)*, HF) are illustrated below: d + 0.51 d + 0.61 (R = H) d + 0.63 (R = Me) d + 0.33 d + 0.54 electrophilic reactivity ■ Proton Activation of C=X Functional groups d + 0.51 d + 0.61 + The electrophilic potential of the C=O FG may be greatly increased by either Lewis acid coordination of by protonation. The magnitide of this increase in reactivity is ~ 10+6 . Among the weakest Bronsted acids that may be used for C=O actilvation (ketalization) is pyridinium ion (pKa = 5). Hence, the Keq below, while quite low, is still functional. + pka = 5 pka = -6 Keq ~ 10-11 The forming bond s Nu–C Stereoelectronic Considerations for C=O Addition p C–O p* C–O HOMO (Nu) LUMO LUMO is p* C–O; HOMO Provided by Nu: p* C–O Dunitz-Burgi trajectory ■ What was the basis for the Dunitz-Burgi analysis? ■ What about C=X vs C=X-R(+)? The LUMO coefficient on carbon for B will be considerably larger than for A. Does this mean that there is a lower constraint on the approach angle for the attacking nucleophile? There is no experimental proof for this question; however, it is worthy of consideration ■ The Set of Functional Groups:

D A. Evans The Dunitz-Burgi Trajectory for C=O Addition Chem 206 Relevant Dunitz Articles Geometrical Reaction Coordinates. Il. Nucleophilic Addition to a Carbonyl Group", JACS 1973, 95, 5065. Stereochemistry of Reaction Paths at Carbonyl Centers", Tetrahedron 1974, 30, 1563 From Crystal Statics to Chemical Dynamics", Accounts Chem. Research 1983, Stereochemistry of Reaction Paths as Determined from Crystal Structure Data. A Relationship Between Structure and Energy Burgi, H.B. Angew. Chem., Int Ed EngL1975.14,460 a Dunitz Method of Analysis A series of organic structures containing both C=O and Nu FGs disposed in a eometry for mutual interaction were designed. These structures positioned the In this structure(A), at 2.56A the C=0 is starting to pyramidalize interacting FGs an increasingly closer distances. The X-ray structures of these structures were determined to ascertain the direction of c=o distortion the two families of structures that were evaluated are shown below Cyclic amine es. Medium-ring ketones of various ring sizes were analyzed for the interaction of amine an C=O FGs. One example is shown below Nu------ c-o Dunitz. Helv. Chem. Acta 1978. 61. 2783 229A Analysis of distortion of C=o in this basis of value should be taken as A(shown) Birmbaum JACS 1974. 966165

H3C CH3 Me2N O Me MeO O Me B C O N O Me R R D. A. Evans The Dunitz-Burgi Trajectory for C=O Addition Chem 206 ■ Relevant Dunitz Articles "Geometrical Reaction Coordinates. II. Nucleophilic Addition to a Carbonyl Group", JACS 1973, 95, 5065. "Stereochemistry of Reaction Paths at Carbonyl Centers", Tetrahedron 1974, 30, 1563 "From Crystal Statics to Chemical Dynamics", Accounts Chem. Research 1983, 16, 153. "Stereochemistry of Reaction Paths as Determined from Crystal Structure Data. A Relationship Between Structure and Energy.", Burgi, H.-B. Angew. Chem., Int. Ed. Engl. 1975, 14, 460. ■ Dunitz Method of Analysis A series of organic structures containing both C=O and Nu FG's disposed in a geometry for mutual interaction were designed. These structures positioned the interacting FGs an increasingly closer distances. The X-ray structures of these structures were determined to ascertain the direction of C=O distortion. The two families of structures that were evaluated are shown below. Nu 1,8-Disubstituted Naphthalenes. Substituents located at these positions are strongly interacting as illustrated by the MM2 minimized di-methyl-naphthalene structure shown below. 2.56Å In this structure (A), at 2.56Å the C=O is starting to pyramidalize A (shown) 2.29Å Sekirkine Birnbaum JACS 1974, 96 6165 Dunitz, Helv. Chem. Acta 1978, 61, 2783 Analysis of distortion of C=O in this and related structures formed the basis of the 107° attack angle. This value should be taken as approximate. Cyclic aminoketones. Medium-ring ketones of various ring sizes were analyzed for the interaction of amine an C=O FGs. One example is shown below

D. A. Evans Stereoelectronic Effects in the Addition to iminium and oxo-carbenium ions Chem 206 ■ Pivotal articles R.V. Stevens in L An early example from Eliel; JACS 1969, 91, 536 ategies and tactics in Organic synthesis", vol. 1 Salts:a Powerful Heuristic Principle for the Stereorationale Design of Alkaloid Synthesis OMe PhMgBr H Eliel etal. JACS 1969. 91 Kishi etal. JACS 1982. 104. 4976-8 dioxolenium ion ans:cs95:5(95% a The Proposal for Oxo-carbenium lons(Eliel, Kishi) Eliel was the first to attibute stereoelectronic factors to the addition of nucleophiles to yclic oXo-carbenium ions Path A I Kishi Examples: JACS 1982, 104, 4976-8 conformations Me3 Bno BF, oEt PMBOO stereoselection 10: 1 a The Proposal for Iminium lons(Stevens OBn Et3Si-H BF3°Et2 O CH2OBn Path a Chair-aixal attack on oxo-carbenium ion occurs for both carbon and hydride nucleophiles d Iminium lons( Stevens)cited reference It was proposed that chair-axial addition would be preferred as a consequence of the only one stereoisomer tervention of a transition state anomeric effect(Path A). Attack through Path B would necessitate the generation of the twist-boat kinetic product conformation thus PrMgl destabilizing attack from the equatorial diastereoface. While Stevens espoused this concept for iminium ions in the late 70s, his untimely death at the age of 42 significantly CAH

C N H H R R C O H H R N Nu H R R N Nu H H R R O Nu H R O Nu H H R N H Nu H R R O H Nu H R O O H Me H Me OMe H O CH2OBn OBn OBn BnO OH C4H9 N Me O CH2OBn OBn OBn BnO PMBO PhMgBr NaCNBH3 BF3•OEt2 Et3Si–H BF3 •OEt2 SiMe3 O O H Me H Me H C4H9 N n-PrMgBr C4H9 N n-Pr C4H9 N Me O CH2OBn OBn OBn BnO H O CH2OBn OBn OBn BnO H O O H Me H Me Ph H D. A. Evans Stereoelectronic Effects in the Addition to Iminium and Oxo-carbenium Ions Chem 206 ■ Pivotal Articles R. V. Stevens in "Strategies and Tactics in Organic Synthesis", Vol. 1. On the Stereochemistry of Nucleophilic Additions to Tetrahydropyridinium Salts: a Powerful Heuristic Principle for the Stereorationale Design of Alkaloid Synthesis.; Lindberg, T., Ed.; Academic Press, 1984; Eliel etal. , JACS 1969, 91, 536 Kishi etal. , JACS 1982, 104, 4976-8 ■ The Proposal for Oxo-carbenium Ions (Eliel, Kishi) + Nu Nu kinetic product conformations It was proposed that chair-axial addition would be preferred as a consequence of the intervention of a transition state anomeric effect (Path A). Attack through Path B would necessitate the generation of the twist-boat kinetic product conformation thus destabilizing attack from the equatorial diastereoface. While Stevens espoused this concept for iminium ions in the late 70's, his untimely death at the age of 42 significantly delayed his cited publication. Path A Path B + Nu Nu kinetic product conformations Path A Path B ■ The Proposal for Iminium Ions (Stevens) ■ An early example from Eliel; JACS 1969, 91, 536 trans : cis 95:5 (95%) dioxolenium ion Eliel was the first to attibute stereoelectronic factors to the addition of nucleophiles to cyclic oxo-carbenium ions. ■ Kishi Examples; JACS 1982, 104, 4976-8 stereoselection 10:1 (55%) stereoselection 10:1 (55%) Chair-aixal attack on oxo-carbenium ion occurs for both carbon and hydride nucleophiles ■ Iminium Ions (Stevens) cited reference only one stereoisomer

D. A. Evans Stereoelectronic Effects in the Addition to Iminium and oxo-carbenium lons Chem 206 5-Membered oxocarbenium lons: Woerpel etal. JACS 1999, 121, 12208 BF3.OEt2 Me0 SiMe3 trans: c is 99: 1(69%) 一 SiMe cis trans 89: 11(75%) BFr. oEt Bno These cases provide dramatic evidence for the importance of electrostatic effects in C=( controlling face selectivity 6-Membered oxocarbenium lons: Woerpel etaL. JACS 2000, 122, 168 cis trans 83: 17(84%) Controling ta ce selectdcaty atc evidence for the importance of ectrostatcefect in BF3OEt Are the preceding addition reactions somehow related to the apparently OSiR SiMe cis: trans 94: 6(74%) R3SIO Eto2C oc1991,56,387 trans cis 99:1(75%) C↓ This analysis presumes that only pseudo-chai transition states need be considere Allyl OSiR3 OSiR 3 oerpel's model states that axial attack from the most stable chair former predicts the major product. exclusive adduct Tet. Lett.1988,29,6593

O BnO OAc O Me OAc O OAc BnO O OAc Me BF3•OEt2 BF3•OEt2 SnBr4 SnBr4 O BnO O C OBn H H O C H Me H O Me SiMe3 SiMe3 O BnO O Me O H Me Allyl H O OBn H Allyl H O BnO OAc O Me OAc O OAc OBn R3SiO EtO BF3 •OEt2 BF3 •OEt2 BF3•OEt2 OSiR3 O O OSiR3 C O H BnO H C O H H Me C O H BnO H AlCl3 HgI2 BnO O H Allyl H Cl Cl N N H2C SiMe3 SiMe3 OSiR3 OSiR3 EtO2C O OSiR3 H H Cl N Cl N H H O Allyl H H Me O Allyl H BnO H O Allyl H BnO H D. A. Evans Stereoelectronic Effects in the Addition to Iminium and Oxo-carbenium Ions Chem 206 5-Membered oxocarbenium Ions: Woerpel etal. JACS 1999, 121, 12208. stereoselection 99:1 stereoselection >95:5 These cases provide dramatic evidence for the importance of electrostatic effects in controlling face selecticity. 6-Membered oxocarbenium Ions: Woerpel etal. JACS 2000, 122, 168. cis:trans 94:6 (74%) trans:cis 99:1 (75%) Are the preceding addition reactions somehow related to the apparently contrasteric reactions shown below?? trans:cis 99:1 (69%) cis:trans 89:11(75%) cis:trans 83:17(84%) These cases provide dramatic evidence for the importance of electrostatic effects in controlling face selecticity. Tet. Lett. 1988, 29, 6593 JOC 1991, 56, 387 >94 : 6 93 : 7 exclusive adduct Woerpel's model states that axial attack from the most stable chair conformer predicts the major product. This analysis presumes that only pseudo-chair transition states need be considered

D A. Evans Diastereoselective Oxocarbenium lon Additions in the Phorboxazole synthesis Chem 206 Phorboxazole b B: The C-22 Reduction Evans. Fitch Smith Cee JACS 2000. 122. 10033 Et3 SiH Me H Stereochemical analogies Kishi et al.: JACS 1982. 104. 4976-8 A: The C-11 Reduction TIPSO TIPSO C: The C-9 C-C Bond construction EnoCH TIPSO Diastereoselection CH2 89:11

H Me O H O H TIPSO H R CH2 H O OHO H TIPSO H R CH2 H O R TIPSO H 4 22 20 H Me 4 9 9 H Me O Me R H H N Me O Me H OTPS RO2C O Me OH H N Me O Me H OTPS H R H R Me Br HSi O H H O O N O Me H H H HO H CH2 Me O MeO OH H N O H H O O H HO H R 46 38 33 19 1 9 13 9 13 9 13 13 Et3SiH O H BnOCH2 H O O O H R Me H H RO H Me R Me OTMS O Me O H BnOCH2 H O O BF3•OEt2 C Et3SiH Me OTMS TMSOTf B O OAc H BnOCH2 H O O C C Et3SiH A B BF3•OEt2 Et3SiH A D. A. Evans Diastereoselective Oxocarbenium Ion Additions in the Phorboxazole Synthesis Chem 206 >95:5 Diastereoselection ‡ Phorboxazole B Evans, Fitch, Smith, Cee, JACS 2000, 122, 10033 91% > 95:5 Diastereoselection 89% Diastereoselection 89:11 A: The C-11 Reduction B: The C-22 Reduction C: The C-9 C–C Bond Construction Stereochemical analogies: Kishi et. al.: JACS 1982, 104, 4976-8

D. A. Evans Carbonyl Addition Reactions: Transition State Geometry Chem 206 4- vs 6-Membered Transition Structures for c=o Addition Do these results relate to "real"reactions? Yes! O-ZI-R C=O +R-Z0-R H2C=0 n HOH H2C(OH)2 +(n-1)HOH Observation: catalytic amounts of znl 2 dramatically catalyze ddition process H 0 Zn- The bimetallic transition state +422 4- Versus 6-Center Transition states for Boron 4-Centered B-Me R2c=0 H2c=o +1 HOH +2 HOH disfavored: rxn does not proceed) Schowen J. Am. Chem. Soc. 105, 31, (198 6-Centered verall Process CH-C R2C=0 fast H-0 2H-0-H 6-Centered Transiton structure T2 determined to be -40 kcal/mol more stable than OBL2 transition structure T1

■ 4- vs 6-Membered Transition Structures for C=O Addition T1 O H C H H O H C O H H O H H H O H C O H H H O H C H O H O O H H H H O H H O H C O H H H T2 C H H OH OH B L L H B L L R R B L Me L C R' H O R2C=O R2C=O R2C=O R Zn R O Zn C H R R Zn I I R B L L CH2 C O H2C CH R R B L L CH2 C O H C R R R R B L C R R O Me L O Zn–R C H R R' Me C OBL2 R R C R R OBL2 H C OBL2 R R H2C R R ‡ The bimetallic transition state Observation: catalytic amounts of ZnI2 dramatically catalyze addition process. slow + ■ Do these results relate to "real" reactions? Yes! Overall Process: Transiton structure T2 determined to be ~40 kcal/mol more stable than transition structure T1 . fast 2 ‡ ■ 4– Versus 6–Center Transition States for Boron ‡ disfavored : rxn does not proceed!) favored 4-Centered 6–Centered 6–Centered favored Schowen J. Am. Chem. Soc. 105, 31, (1983). H2C=O + n HOH H2C(–OH)2 + (n-1) HOH +6.7 H2C=O + 2 HOH H2C=O + 1 HOH +42.2 + HOH Consider carbonyl hydration: D. A. Evans Carbonyl Addition Reactions: Transition State Geometry Chem 206

D. A. Evans Carbonyl Addition Reactions: Transition State Geometry Chem 206 Carbonyl Addition: 4- Versus 6-Center Transition States for Aluminum ■ Grignard Reagents ■4- Centered Al-M R2c=0 OIL The molecularity and transition structure for this reaction have not been carefully elucidated. The fact that the grignard reagent is not a single species in solution greatly complicates the kinetic analysis disfavored rel. Rate 1 Monometallic(Mononuclear) Mechanism. 6-Centered 0+ Mg-R2 R2C' favored rel. Rate =1.000 R2-Mgr Bimetallic Transition states a Bimetallic(Binuclear) Mechanism: The more probable situation Br fast M 4-Centered 6-Centered boat 6-Centered Chair RR solvent(S) break bridge R2 Mg Mg O-MgR BicyclIC TS The 6-membere Ashby JOC 1977, 42, 425 try for transferring the R2 ligand from the metal to the C=O is far less strai

C O R R R2 Mg Br Al L Me L Al L C R R O Me L Me C OAlL2 R R Al L Me L O Al C R R Me Al L L Me L Me C R R OAlL2 Me Al L C R R Al Me O L Me L Me Al O Me L Me Al L C Me R R L Al O Me L Al Me L C Me L R R Al O Me L Al Me C L Me L R R O Al L R C R Al Me L Me L Me Mg S R2 Br S C R R O O Mg Br C R R R2 S Mg S Br C O R R R2 R2 Mg Br S Mg R2 S Br C O R R C R R O R2 Mg Br S Mg R2 Br Mg S Mg Br O Br R2 S R2 C R R R2C=O R2C=O +S Mg S Br C O R R R2 C R R O R2 MgBr Br Mg Mg O Br R2 S R2 C R R O MgBr C R2 R R C R R O R2 MgR2 D. A. Evans Carbonyl Addition Reactions: Transition State Geometry Chem 206 ‡ disfavored ■ 4–Centered Carbonyl Addition: 4– Versus 6–Center Transition States for Aluminum ■ 6–Centered ‡ favored 2 rel. Rate = 1 rel. Rate = 1,000 ■ Bimetallic Transition States 4-Centered 6-Centered Boat 6-Centered Chair Bicyclic TS Ashby JOC 1977, 42, 425 + solvent (S) The 6-membered geometry for transferring the R2 ligand from the metal to the C=O is far less strained. The molecularity and transition structure for this reaction have not been carefully elucidated. The fact that the Grignard reagent is not a single species in solution greatly complicates the kinetic analysis. + MgBr2 ■ Bimetallic (Binuclear) Mechanism: The more probable situation. ‡ slow + + fast + slow fast ‡ + – – + solvent (S) + + + ■ Grignard Reagents: ■ Monometallic (Mononuclear) Mechanism: break bridge

D. A. Evans Evolution of a model for c=o Addition Chem 206 a Product Development& Steric Approach Control Dauben JACS 1956.78 2579 Assumptions in Felkin Model Transition states are all reactant -like rather than product-like Me3C oH Me c Torsional strain considerations are dominant Staggered TS conformations preferre a The principal steric interactions are between Nu&R eomer一 o predicted to be ofcR+ destabilizing DIBAL-H 72: 28 L-Selectride 8: 92 R. favored TS NaBH479:21 K-Selectride 3: 97 LiAIH(Ot-Bu)3 92: 8 The flaw in the Felkin model: A problem with aldehydes!! LiAIH4 93.7 predicted to be Observation: Increasingly bulky hydride reagents prefer to attack from the destabilizing O favored Ts Assumption: Hindered reagents react through more highly developed transition states than unhindered reagents wrong pred Carbonyl Addition: Evolution of Acyclic Models Stereoelectronic Effec The homo-LUMo interaction dictates the ring reaction gec C-0 M LUMO favored disfavored R HOMO M attack angle greater than 90 estimates place it in the 100-110range Cram arabatsos JACS1952,745828Jcs1967,89,13677L1968,2199 Burgi, Dunitz, Acc. Chem. Res. 1983, 16, 153-161

Observation: Increasingly bulky hydride reagents prefer to attack from the equatorial C=O face. Hindered reagents react through more highly developed transition states than unhindered reagents Assumption: H Me3C O R L O R M H [H] C O R R L H R M H R L Nu R M R OH C R O R L H Me3C H OH R M R OH R M Nu R L M + H R C O H B C H Me CH2Me R L H Me3C OH H R M H H H C O R C O R L R L C O R R Nu R M R M H H O C R R L O C H R L R M R M HOMO Burgi, Dunitz, Acc. Chem. Res. 1983, 16, 153-161 attack angle greater than 90 °; estimates place it in the 100-110 ° range Nu: The Dunitz-Bürgi Angle ~107 ° Stereoelectronic Effect: The HOMO-LUMO interaction dictates the following reaction geometry: d – p C–O d – p* C–O LUMO wrong prediction ✓ destabilizing interaction predicted to be favored TS Nu: destabilizing interaction predicted to be favored TS Nu: Nu: The flaw in the Felkin model: A problem with aldehydes!! Nu: Carbonyl Addition: Evolution of Acyclic Models Nu: favored disfavored Karabatsos JACS 1967, 89, 1367 Nu: Nu: Cram JACS 1952, 74, 5828 Nu: Felkin TL. 1968, 2199-2208 % Axial Diastereomer 0 10 20 30 40 50 60 70 80 90 100 LiAlH4 93:7 LiAlH(Ot-Bu)3 92:8 NaBH4 79:21 K-Selectride 3:97 DIBAL-H 72:28 L-Selectride 8:92 3 – ■ Product Development & Steric Approach Control: Dauben, JACS 1956, 78, 2579 ■ The principal steric interactions are between Nu & R. ■ Torsional strain considerations are dominant. Staggered TS conformations preferred ■ Transition states are all reactant-like rather than product-like. D. A. Evans Evolution of a Model for C=O Addition Chem 206 Assumptions in Felkin Model:

D.A. Evans The felkin-Anh eisenstein model Chem 206 The flaw in the Felkin model: A problem with aldehydes!! "The tendency for the staggering of partially formed R vicinal bonds is greater than for fully formed bonds predicted to be HC0←m0长CH favored TS Lets begin with ground state effects: Ethane Rotational Barrier Anh Eisenstein Noveau J. Chim. 1977.. 61-70 Anh Topics in Curent Chemistry. 1980, No 88, 146-162 △G=+3kcal RL One explanation for the rotational barrier in ethane is that better overlap is achieved in the staggered conformation than in the eclipsed conformation Felkin M In the staggered conformation there are 3 anti-periplanar C-H Bonds favored R Ha0c LUMO C anti-Fe kin M HOMO H disfavored In the eclipsed conformation there are 3 syn-periplanar C-H Bonds New Additions to Felkin Model HH Dunitz-Burgi C=O-Nu orientation applied to Felkin model Q LUMO a The antiperiplanar effect C-C 型/性 Hyperconjugative interactions between C-Rl which will lower T"C=O will stablize the transition state gument one might conclude that Theoretical Support for Staggered Transition states a The staggered conformer has a better orbital match between bonding Houk,AcS1982,104,71626 and antibonding states uk, Science1986.231.1108-17 a The staggered conformer can form more delocalized molecular orbital

H H C H C H C C H H C HO H Nu C Nu H OH R L R L R M R M R L O R M H H H C O R L R M H H H C O O C H R L R L R M R M H O C H R L R M Y C C C C X H Following this argument one might conclude that: ■ The staggered conformer has a better orbital match between bonding and antibonding states. ■ The staggered conformer can form more delocalized molecular orbitals. s C–H s* C–H In the eclipsed conformation there are 3 syn-periplanar C–H Bonds s* C–H LUMO s C–H HOMO s* C–H s C–H H In the staggered conformation there are 3 anti-periplanar C–H Bonds s C–H HOMO s* C–H LUMO D G =+3 kcal mol -1 Lets begin with ground state effects: Ethane Rotational Barrier D. A. Evans The Felkin-Anh Eisenstein Model Chem 206 wrong prediction destabilizing interaction predicted to be favored TS Nu: Nu: The flaw in the Felkin model: A problem with aldehydes!! Anh & Eisenstein Noveau J. Chim. 1977, 1, 61-70 Anh Topics in Current Chemistry. 1980, No 88, 146-162 anti-Felkin Nu: Nu: Nu: Felkin ‡ ‡ Nu: favored disfavored ■ The antiperiplanar effect: Hyperconjugative interactions between C-RL which will lower p*C=O will stablize the transition state. ■ Dunitz-Bürgi C=O–Nu orientation applied to Felkin model. New Additions to Felkin Model: Theoretical Support for Staggered Transition states Houk, JACS 1982, 104, 7162-6 Houk, Science 1986, 231, 1108-17 "The tendency for the staggering of partially formed vicinal bonds is greater than for fully formed bonds" One explanation for the rotational barrier in ethane is that better overlap is achieved in the staggered conformation than in the eclipsed conformation. Houk: