D.A. Evans Acyclic Conformational Analysis-2 Chem 206 Problems of the Day: (To be discussed) http://www.courses.fas.harvard.edu/-chem206/ Can you predict the stereochemical outcome of this reaction? OTs OTS Chemistry 206 LINR Advanced Organic Chemistry n-C4Hg n-C4H9 982 Lecture Number 5 ■ Relevant enolate conformations Acyclic Conformational Analysis-2 n-CAHg Conformations of Simple Olefinic Substrates Introduction to Allylic Strain (CH2)4OTS TSO(H2C)4 Introduction to Allylic Strain-2: Amides and enolates SoLi Me-LC-CmOR Bu\ / CH2lS H OLi A1 Reading Assignment for week critical conformations A. Carey& Sundberg: Part A; Chapters 2&3 R. W. Hoffmann. Chem. Rev. 1989. 89. 1841-1860 Allylic 1-3-Strain as a Controlling Element in Stereoselective Transformations TSO(2C)4 R. W. Hoffmann, Angew. Chem. Int. Ed. Engl. 2000, 39, 2054-2070 CH2)lOTs Conformation Design of Open-Chain Compounds A2 B2 F. Weinhold, Angew. Science 2001, 411, 539-541 'A New Twist on Molecular Shape Frida EtOC.E Carl a. morales September 27, 2002 minor n-C4Hg
http://www.courses.fas.harvard.edu/~chem206/ EtO Me O n-C4H9 OTs H EtO Me OLi n-C4H9 OTs H C Bu H (CH2 )4OTs C OLi OR C Me H Bu TsO(H2C)4 C OLi OR Me C H Bu (CH2)4OTs C OLi OR Me C H Bu (CH2)4OTs C OLi OR Me C H Bu (CH2)4OTs C OLi OR C Me TsO(H2C)4 H Bu C OLi OR Me H n-C4H9 EtO2C Me H n-C4H9 O Me EtO A1 B1 C1 A2 B2 C2 LiNR2 D. A. Evans Chem 206 Carl A. Morales Friday, September 27, 2002 Chemistry 206 Advanced Organic Chemistry Lecture Number 5 Acyclic Conformational Analysis-2 ■ Conformations of Simple Olefinic Substrates ■ Introduction to Allylic Strain ■ Introduction to Allylic Strain-2: Amides and Enolates ■ Reading Assignment for week Acyclic Conformational Analysis-2 A. Carey & Sundberg: Part A; Chapters 2 & 3 R. W. Hoffmann, Chem. Rev. 1989, 89, 1841-1860 Allylic 1-3-Strain as a Controlling Element in Stereoselective Transformations R. W. Hoffmann, Angew. Chem. Int. Ed. Engl. 2000, 39, 2054-2070 Conformation Design of Open-Chain Compounds F. Weinhold, Angew. Science 2001, 411, 539-541 "A New Twist on Molecular Shape" 98:2 Can you predict the stereochemical outcome of this reaction? ■ Problems of the Day: (To be discussed) 2 1 critical conformations 1 + 2 ■ Relevant enolate conformations major minor
D.A. Evans Useful Destabilizing Interactions to Remember Chem 206 Hierarchy of Vicinal Eclipsing Interactions It may be concluded that in-plane 1, 3(Mee Me) interactions are Ca +4 kcal/mol while 1, 2 (Me+Me) interactions are destablizing by ca +3 kcal/mol X—Y8Ekca|mol-1 H-H +10 H H-Me +14 Me-Me +3.1 Estimates of In-Plane 1.2 1, 3-Dimethyl Eclipsing Interactions 7.6
~ 3.1 ~ 3.7 ~3.9 ~ 7.6 Estimates of In-Plane 1,2 & 1,3-Dimethyl Eclipsing Interactions Me Me Me Me Me Me Me Me Hierarchy of Vicinal Eclipsing Interactions d E kcal mol -1 +1.0 +1.4 +3.1 C C X Y H H H H X Y H H H Me Me Me Useful Destabilizing Interactions to Remember It may be concluded that in-plane 1,3(Me«Me) interactions are Ca +4 kcal/mol while 1,2(Me«Me) interactions are destabliizing by Ca +3 kcal/mol. minimized structure D. A. Evans Chem 206
D. A. Evans Stabilized Eclipsed Conformations in Simple Olefins Chem 206 Simple olefins exhibit unusal conformational a The Propylene Barrier 人 staggered properties relative to their saturated counterparts Butane versus 1-Butene +20 kcal/mol eclipsed conformation conformation a Acetaldehyde exhibits a similar conformational bias angered RCH2 conformation The low-energy conformation in each of above cases is eclispec △G°=-083 kcal mol1 Propane versus The Torsional Energy Profile d=50 ①=180 H New destabilizing effect emulsive interaction between .33 I-C-X&o-C-H 1.32 kcal +049 kcal =120 =0 Conforms to ab initio (3-21G)values H Wiberg, K B; Martin, E.J. Am. Chem. Soc. 1985, 107, 5035 K Wiberg,JACS1985.107,5035-5041 K. Houk,JAcS1987,109,6591-6600
D. A. Evans Stabilized Eclipsed Conformations in Simple Olefins Chem 206 Butane versus 1-Butene eclipsed conformation staggered conformation D G° = +4 kcal mol-1 Me C H C H H Me H Me H H H H Me eclipsed conformation staggered conformation D G° = –0.8.3 kcal mol-1 Me C C H H CH2 CH2 H H Me +1.33 kcal +1.32 kcal +0.49 kcal F = 180 F = 120 F = 50 F = 0 F = 0 F = 180 The Torsional Energy Profile Conforms to ab initio (3-21G) values: Wiberg, K. B.; Martin, E. J. Am. Chem. Soc. 1985, 107, 5035. H C H C H H H H C H C H H H H C H C H H H Me Me H H C C H H H Me Me Simple olefins exhibit unusal conformational properties relative to their saturated counterparts ■ The Propylene Barrier C H CH2 H H H C H CH2 H eclipsed conformation staggered conformation +2.0 kcal/mol ■ Acetaldehyde exhibits a similar conformational bias O H H H H O Me H H H O H Me H H O Me Me H H The low-energy conformation in each of above cases is eclisped H Me H H H H 109° H CH2 H H H 120° Propane versus Propene Hybridilzation change opens up the C–C–C bond angle K. Wiberg, JACS 1985, 107, 5035-5041 X C H H H H repulsive interaction between p–C–X & s–C–H X C H H H K. Houk, JACS 1987, 109, 6591-6600 New destabilizing effect H H
Evans, Duffy Ripin Conformational Barriers to Rotation: Olefin A-1, 2 Interactions Chem 206 1-butene 2-propen-1-o/ 2 180 Co Deg) ΦDeg) The Torsional Energy Profile The Torsional Energy Profile Φ=50 =180H Φ=12 2.00 +133 kcal ①=0 +1.32 kcal 1.18 kcal +0.49 kcal Φ=120 +0. 37 kcal Conforms to ab initio( 3-21G)values iberg, K B; Martin, E.J. Am. Chem. Soc. 1985, 107, 5035
0 1 2 3 4 5 -180 -90 0 90 180 0 1 2 3 4 5 -180 -90 0 90 180 C H C H H OH H H C H C H H Me H H C C H H H Me H H Me H H C C H H H Me H H C H C H H Me H H C H C H H HO H H C C H H H OH H H C H C H H HO H H C C H H H OH H H C C H H H F F F = 0 F = 180 F = 0 F = 60 F = 120 F = 180 +1.18 kcal +0.37 kcal +2.00 kcal +1.33 kcal +1.32 kcal +0.49 kcal F = 180 F = 120 F = 50 F = 0 F = 0 F = 180 E (kcal/mol) The Torsional Energy Profile The Torsional Energy Profile Evans, Duffy, & Ripin Conformational Barriers to Rotation: Olefin A-1,2 Interactions Chem 206 (Deg) E (kcal/mol) 1-butene 2-propen-1-ol Conforms to ab initio (3-21G) values: Wiberg, K. B.; Martin, E. J. Am. Chem. Soc. 1985, 107, 5035. (Deg)
Evans, Duffy, Ripin Conformational Barriers to Rotation Olefin A-1, 2 Interactions-2 Chem 206 2-methyl-1-butene 2-methyl-2-propen-1-0/ 2 ,4 ΦqDeg) The Torsional Energy Profile The Torsional Energy Profile ①=180 d: 60 =120 ①=110 +2.68 +2.01 Φ=0 +1. 39 kcal +1.16 kcal 0.21 kcal +0.06 kcal Φ=180
0 1 2 3 4 5 -180 -90 0 90 180 0 1 2 3 4 5 -180 -90 0 90 180 Evans, Duffy, & Ripin Conformational Barriers to Rotation: Olefin A-1,2 Interactions-2 Chem 206 (Deg) 2-methyl-1-butene E (kcal/mol) +2.68 kcal +1.39 kcal +0.06 kcal F = 180 F = 110 F = 50 F = 0 F = 0 F = 180 The Torsional Energy Profile (Deg) 2-methyl-2-propen-1-ol E (kcal/mol) The Torsional Energy Profile F = 0 F = 180 F = 0 F = 60 F = 120 F = 180 +0.21 kcal +1.16 kcal +2.01 kcal H C H C Me H H H C H C Me H H H C H Me H H C C Me H H C Me H H Me Me H H C C Me H H Me Me H C H C Me H H OH OH HO H C H H C Me H OH HO H H C C Me H H H H C C Me H H H H C C Me H H F F
Evans, Duffy, Ripin Conformational Barriers to Rotation: Olefin A-1, 3 Interactions Chem 206 2r-2-pentene (Z-2-buten-1-o/ § 0--s 180 -90 ΦqDeg) 180 ΦpDeg) 90 The Torsional Energy Profile The Torsional Energy Profile Φ=0 Φ=180 +3. 88 kcal Φ=180 Φ=90 +144 kcal Φ=120 kcal +0.52 alues calculated using MM2 (molecular mechanics)force fields via the Macromodel multiconformation search Review Hoffman. R. W. Chem. Rev. 1989. 89. 1841
0 1 2 3 4 5 -180 -90 0 90 180 0 1 2 3 4 5 -180 -90 0 90 180 Values calculated using MM2 (molecular mechanics) force fields via the Macromodel multiconformation search. Review: Hoffman, R. W. Chem. Rev. 1989, 89, 1841. (Z)-2-pentene (Z)-2-buten-1-ol (Deg) (Deg) Evans, Duffy, & Ripin Conformational Barriers to Rotation: Olefin A-1,3 Interactions Chem 206 E (kcal/mol) E (kcal/mol) +0.86 kcal +1.44 kcal F = 180 F = 120 F = 0 F = 0 F = 180 The Torsional Energy Profile The Torsional Energy Profile F = 0 F = 180 F = 0 F = 90 F = 180 +3.88 kcal +0.52 kcal H C Me C H H H H C Me Me H H C C H Me H H C Me C H H H OH C H H H HO OH H H C C H Me H OH Me H C Me C H H H Me Me H H C C H Me H H H C C H Me H F F
Evans, Duffy, Ripin Conformational Barriers to Rotation: Olefin A-1, 3 Interactions-2 Chem 206 (2p-2-hydroxy-3-pentene Rotate clockwise 4.6 kcal/mol u 0.3-0.4 kcal/mol Me Lowest energy conformer -90 ΦDeg) The Torsional Energy Profile Φ=0 M大=140 Φ=110 68 A(1, 3)interaction 4.0 kcal/mol 23R1 +0.34 +0. 40 kcal 0=180: A(1, 2)interaction 2.7 kcal/mol(MM2)
0 1 2 3 4 5 -180 -90 0 90 180 60 ° 2.7 kcal/mol Lowest energy conformer 30 ° +0.66 +4.68 +0.34 +0.40 kcal F = -80 F = 0 F = 80 E (kcal/mol) +2.72 F = 150 F = 110 F = -140 F = 0 F = 180 The Torsional Energy Profile Evans, Duffy, & Ripin Conformational Barriers to Rotation: Olefin A-1,3 Interactions-2 Chem 206 (Z)-2-hydroxy-3-pentene Rotate clockwise (Deg) 30 ° Lowest energy conformer 100 ° 100 ° 4.6 kcal/mol 0.3-0.4 kcal/mol H C Me C H H OH Me H C Me C H H HO H C Me H C Me C H HO H Me C H H HO Me Me OH H C C H Me H Me H Me OH C C H Me H H C Me C H H HO Me Me OH OH Me H Me C C H Me H H Me H C Me C H Me H OH C H Me C H OH H HO Me C C H Me H OH Me Me H Me H C C H C HO Me OH H Me C Me H H A(1,3) interaction 4.0 kcal/mol A(1,2) interaction 2.7 kcal/mol (MM2) 3 2 1 R small R3 X Y R2 R1 R * large F
D. A. Evans Discodermolide Chem 206 Me me 16 OH M Me OH Me Me OH immunosuppressive activity tent microtubule-stabilizing agent (antitumor activity similar to that of taxol) The epimers at C16 and C 17 have no or almost no biological activity The conformation about C16 and C17 is critical to discodermolide 's biological activity S L. Schreiber et al. JAcS 1996. 118. 11061
D. A. Evans Chem 206 O Me Me OH Me O HO Me OH Me Me O Me OH Me O NH2 H 16 17 hinge - immunosuppressive activity - potent microtubule-stabilizing agent (antitumor activity similar to that of taxol) The conformation about C16 and C17 is critical to discodermolide's biological activity. Discodermolide The epimers at C16 and C17 have no or almost no biological activity. S. L. Schreiber et al. JACS 1996, 118, 11061
D A. Evans Conformational Analysis -Discodermolide X-ray 1 Chem 206
D. A. Evans Conformational Analysis - Discodermolide X-ray 1 Chem 206 O Me Me OH Me O HO Me OH Me Me O Me OH Me O NH2 H
D A. Evans Conformational Analysis-Discodermolide X-ray 2 Chem 206 16
D. A. Evans Conformational Analysis - Discodermolide X-ray 2 Chem 206 O Me Me OH Me O HO Me OH Me Me O Me OH Me O NH2 H 16 16
