http://www.courses.fas.harvard.edu/~chem206/ EtO Me O n-C4H9 OTs H EtO Me OLi n-C4H9 OTs H C HBu (CH2)4OTs C OLiORMeC H Bu TsO(H2C)4 C OLi ORMe C H Bu (CH2)4OTs C OLiORMe C H Bu (CH2)4OTs C OLiORMe C H Bu (CH2)4OTs C OLiORMeC TsO(H2C)4 H Bu C OLiORMe Hn-C4H9 EtO2C Me Hn-C4H9 O Me EtO A1 B1 C1 A2 B2 C2 LiNR2 Chem 206D. A. Evans Carl A. Morales Friday, September 27, 2002 Chemistry 206 Advanced Organic Chemistry Lecture Number 5 Acyclic Conformational Analysis-2 a73 Conformations of Simple Olefinic Substrates a73 Introduction to Allylic Strain a73 Introduction to Allylic Strain-2: Amides and Enolates a73 Reading Assignment for week Acyclic Conformational Analysis-2 A. Carey & Sundberg: Part A; Chapters 2 & 3 R. W. Hoffmann, Chem. Rev. 1989, 89, 1841-1860Allylic 1-3-Strain as a Controlling Element in Stereoselective Transformations R. W. Hoffmann, Angew. Chem. Int. Ed. Engl. 2000, 39, 2054-2070Conformation 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? a73 Problems of the Day: (To be discussed) 2 1 critical conformations 1 2+ a73 Relevant enolate conformations major minor ~ 3.1 ~ 3.7 ~3.9 ~ 7.6 Estimates of In-Plane 1,2 &1,3-Dimethyl Eclipsing Interactions Me Me MeMe Me MeMeMe Hierarchy of Vicinal Eclipsing Interactions δ E kcal mol -1+1.0 +1.4+3.1C C X Y HH H H X Y H HH 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 Chem 206D. A. Evans Stabilized Eclipsed Conformations in Simple OlefinsD. A. Evans Chem 206 Butane versus 1-Butene eclipsed conformationstaggered conformation ? G° = +4 kcal mol-1 MeC H C H H MeH Me H HH H Me eclipsed conformationstaggered conformation ? G° = –0.8.3 kcal mol-1 Me CC H H CH2CH2 HH Me +1.33kcal +1.32 kcal +0.49 kcal Φ = 180 Φ = 120 Φ = 50 Φ = 0 Φ = 180Φ = 0 The Torsional Energy Profile Conforms to ab initio (3-21G) values:Wiberg, K. B.; Martin, E. J. Am. Chem. Soc. 1985, 107, 5035. H CH C H H HH C H C H H H H CH C HH H Me Me HH C HCHH Me Me Simple olefins exhibit unusal conformational properties relative to their saturated counterparts a73 The Propylene Barrier C H CH2 H H H CH CH2 Heclipsed conformation staggered conformation +2.0 kcal/mol a73 Acetaldehyde exhibits a similar conformational bias O HHH H O MeHH H O HMeH H O MeMeH H The low-energy conformation in each of above cases is eclisped H Me H H HH 109° H CH 2 H HH 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 pi–C–X & σ–C–H X C H H H K. Houk, JACS 1987, 109, 6591-6600 New destabilizing effect H H 0 1 2 3 4 5 -180 -90 0 90 180 0 1 2 3 4 5 -180 -90 0 90 180 CH C HH OH H H CH C HH Me H H C HCHH Me H H Me H H C HC H H Me H H CH C HH Me H H CH C HH HO H H C HCHH OH H HC H C H H HO H H C HCHH OH H H C HCHH ΦΦ Φ = 180Φ = 0 Φ = 0 Φ = 60 Φ = 120 Φ = 180 +1.18 kcal +0.37 kcal +2.00kcal +1.33kcal +1.32 kcal +0.49 kcal Φ = 180 Φ = 120 Φ = 50 Φ = 0 Φ = 180Φ = 0 E (kca l/mol) The Torsional Energy ProfileThe Torsional Energy Profile Chem 206Evans, Duffy, & Ripin Conformational Barriers to Rotation: Olefin A-1,2 Interactions (Deg) E (kca l/mol) 2-propen-1-ol1-butene Conforms to ab initio (3-21G) values:Wiberg, K. B.; Martin, E. J. Am. Chem. Soc. 1985, 107, 5035. (Deg) 0 1 2 3 4 5 -180 -90 0 90 180 0 1 2 3 4 5 -180 -90 0 90 180 Chem 206Evans, Duffy, & Ripin Conformational Barriers to Rotation: Olefin A-1,2 Interactions-2 (Deg) 2-methyl-1-butene E (kca l/mol ) +2.68kcal +1.39 kcal +0.06 kcal Φ = 180 Φ = 110 Φ = 50 Φ = 0 Φ = 180Φ = 0 The Torsional Energy Profile (Deg) 2-methyl-2-propen-1-ol E (kca l/mol ) The Torsional Energy Profile Φ = 0 Φ = 180 Φ = 0 Φ = 60 Φ = 120 Φ = 180 +0.21 kcal +1.16 kcal +2.01kcal H CH C Me H H H CH C MeH H H CH Me H H C MeCHH C MeH H Me Me HH C MeCHH Me Me H CH C Me HH OH OH HO H CH HC MeH OH HO H HC MeC HH HH C MeCHH H H C MeCH H Φ Φ 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 fieldsvia the Macromodel multiconformation search. Review: Hoffman, R. W. Chem. Rev. 1989, 89, 1841. (Z)-2-buten-1-ol(Z)-2-pentene (Deg) (Deg) Chem 206Evans, Duffy, & Ripin Conformational Barriers to Rotation: Olefin A-1,3 Interactions E (kca l/mol ) E (kca l/mol ) +0.86kcal +1.44 kcal Φ = 180 Φ = 120 Φ = 0 Φ = 180Φ = 0 The Torsional Energy ProfileThe Torsional Energy Profile Φ = 0 Φ = 180 Φ = 0 Φ = 90 Φ = 180+3.88 kcal +0.52kcal H CMe C H H H H CMe Me H H C HCMeH H CMe C HHH OH C HH H HO OH HH C HCMeH OH Me H CMe C HH H Me Me H HC HC MeH H H C HCMe H Φ Φ 0 1 2 3 4 5 -180 -90 0 90 180 60 ° 2.7 kcal/mol Lowest energy conformer 30 ° +0.66 +4.68 +0.40 kcal+0.34 Φ = -80 Φ = 0 Φ = 80 E (kca l/mol) +2.72 Φ = 150 Φ = 110 Φ = -140 Φ = 180Φ = 0 The Torsional Energy Profile Chem 206Evans, Duffy, & Ripin Conformational Barriers to Rotation: Olefin A-1,3 Interactions-2 (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 CMe C HH OH Me H CMe C HHHO H CMe H CMe C H HHO Me C H H HO Me Me OHH C HC MeH Me HMe OH C HCMeH H CMe C HH HO Me Me OH MeOH H Me C HCMeH H Me H C Me C HMe H OH CHMe CH OH H HO Me C HCMeH OH MeMe H Me H C CH CHO Me OH H Me C MeH H A(1,3) interaction 4.0 kcal/mol A(1,2) interaction 2.7 kcal/mol (MM2) 3 2 1R small R3 X YR2 R1 R large* Φ D. A. Evans Chem 206 O Me Me OH Me O HO Me OH Me Me O Me OH Me O NH2H 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. Conformational Analysis - Discodermolide X-ray 1D. A. Evans Chem 206 O Me Me OH Me O HO Me OH Me Me O Me OH Me O NH2H Conformational Analysis - Discodermolide X-ray 2D. A. Evans Chem 206 O Me Me OH Me O HO Me OH Me Me O Me OH Me O NH2H 16 16 R C R1 N O R3 R1 Me Me N CO Me Me N HO CO RH R large Y R1 X R2 R3 R small NC O R H R R R3 N C–O R1 R+ N C R R–O + HCR O N R MeCRO N HHMe NC O R Me H Me H N MeMe Ph O O O N R O H H H HO N R C N R –O R R R + C R N O R R R C H Me H O N LL C MeH H O N LL C HMe H O N L L C H H Me O N L L Me N L OM L H N L OM LMe HN O HHOCO PhPh OH O N N H H O R H O HN R H O HN C O R HCO2H ? ? base base (Z)-Enolate disfavored favored (E)-Enolate As a result, amides afford (Z) enolates under all conditions A(1,3) interaction between the C2 & amide substituents will strongly influence the torsion angle between C1 & C2. 1 221 DisfavoredFavored Favored forR = CORFavored for R = H, alkyl The selection of amide protecting group may be done with the knowledge that altered conformational preferences may result: Allylic Strain & Amide ConformationD. A. Evans Chem 206 a54 a54 D. Hart, JACS 1980, 102, 397 diastereoselection >95% a73 Problem: Predict the stereochemical outcome of this cyclization. published X-ray structure of this amide shows chairdiaxial conformation Quick, J. Org. Chem. 1978, 43, 2705 ChowCan. J. Chem. 1968, 46, 2821 strongly favored a73 conformations of cyclic amides strongly favored A(1,3) interactions between the "allylic substituent" and the R1 moiety will strongly influence the torsion angle between N & C1. 1 12 3Consider the resonance structures of an amide: Disfavored Favored A(1,3) identify HOMO-LUMO pair O N RRC R Me H O N RRC H R Me MO O N OMe BnBn Me O N O O Bn Me O N O O El C HMe H O N L L C HMe El O N L L C H Me El O N L L C H MeEl O N L L A CB Bn Me O N O O CH2OHO Me N Me N O Me Me OH O HO Me SR O O R SR R SR O Me O R SR OH Me O N O OO Me O Me O N O O Me Li Et Cl O Allylic Strain & Amide ConformationD. A. Evans Chem 206 El(+) JACS. 1982,104, 1737. LDA or NaNTMS2 enolization selectivity >100:1 A(1,3) Strain and Chiral Enolate Design ? favoredenolization geometry a73 In the enolate alkylation process product epimerization is a serious problem. Allylic strain suppresses product enolization through the intervention of allylic strain While conformers B and C meet the stereoelectronic requirement for enolization, they are much higher in energy than conformer A. Further, as deprotonation is initiated, A(1,3) destabilization contributes significantly to reducing the kinetic acidity of the system These allylic strain attributes are an integral part of the design criteria of chiral amide and imide-based enolate systems Evans JACS 1982,104, 1737.EvansTetr Lett. 1977, 29, 2495 Myers JACS 1997, 119, 6496 Polypropionate Biosynthesis: The Acylation Event Acylation Reduction – CO2 First laboratory analogue of the acylation event Diastereoselection ~ 97 : 3 favored X-ray structure with M. Ennis JACS 1984, 106, 1154. Why does'nt the acylation product rapidy epimerize at the exocyclic stereocenter?? a70 Allylic Strain & Enolate Diastereoface SelectionD. A. Evans Chem 206 Y. Yamaguchi & Co-workers, Tetrahedron Letters 1985, 26,1723. R = Me: > 15 :1R = H: one isomerTHF -78 °C diastereoselection 90:10 at C3one isomer at C 271% yield I. Fleming & Co-workers, Chem. Commun. 1986, 1198. Me–CHO Me–IPh(MeS)2C–Li86% diastereoselection 99:1 K. Koga & Co-workers, Tetrahedron Letters 1985, 26, 3031. T. Mukaiyama & Co-workers, Chem. Letters 1986, 637 diastereoselection >95% 91-95% Y. Yamamoto & Co-workers, Chem. Commun. 1984, 904. major diastereomer opposite to that shown40:60 80:2087:13R = CHMe 2 R = EtR = Me R-substituent diastereoselection I. Fleming & Co-workers, Chem. Commun. 1985, 318. R = Ph: diastereoselection 97:3R = Me: diastereoselection 99:1 I. Fleming & Co-workers, Chem. Commun. 1984, 28. D. Kim & Co-workers, Tetrahedron Lett. 1986, 27, 943. diastereoselection 98:2 G. Stork & Co-workers, Tetrahedron Lett. 1987, 28, 2088. "one isomer" 95% yield "one isomer" T. Money & Co-workers, Chem. Commun. 1986, 288. diastereoselection 89:11 RMe3Si OMe Ph O N OMPh OMeMe3Si R N Me O S NBoc N SBnBn SBoc S OMe OHR H OMe OMeMeSMeS Me Me3Si MeS OBn Ph O OPh OBnMe3Si Me H O OMeMe OH H H CO2Et CO2-t-Bu OLi O-t-BuCO2Et I R R CO2Me MeRO 2C O O H H O ORO 2C Me CO2Me EtO Me O n-C4H9 OTs H Hn-C4H9 O Me EtO Br H EtO H CH2 EtO O CO2Me MeTBSOCH 2H CH2 H TBSOCH2 Me CO2Me Me n-C4H9 H MeO n-C4H9 H MePhMe2Si OEt R OOMR OEtPhMe2Si KOt-Bu LiNR2 R–CHOSn(OTf)2 NH4Cl MeI LiNR2 LiNR2 LiNR2MeI LiNR2MeI