D. A. Evans The aldol reaction -2 Chem 206 http:/www.courses.fasharvardedu/-chem206/ ■ Assigned Reading Stereoselective Aldol Reactionsw in the Synthesis of Polyketide natural Products, I. Paterson et al. in Modern Carbonyl Chemistry, pp 249-297, J Chemistry 206 Otera, Ed. Wiley VCH, 2000(handout) W.R. Roush, J. Org. Chem. 1991, 56, 4151-4157.(handout Advanced Organic Chemistry Other Useful References Lecture Number 25 Evans, D.A., J V. Nelson, et al. (1982). "Stereoselective Aldol Condensation Top. Stereochem. 13: 1 The aldol reaction-2 Heathcock, C H (1984). The Aldol Addition Reaction. Asymmetric Synthesis Stereodifferentiating Reactions, Part B J D. Morrison. New York, AP. 3: 111 Oppolzer, W.(1987). "Camphor Derivatives as Chiral Auxiliaries in Asymmetric Synthesis. Tetrahedron 43: 1969 Heathcock, C. H (1991). The Aldol Reaction: Acid and General Base Catalysis Comprehensive Organic Synthesis. B M. Trost and L. Fleming. Oxford Pergamon Press. 2: 133 ■&团 Enolates: Felkin Selectivity Heathcock, C. H (1991). The Aldol Reaction: Group I and Group ll Enolate a Double Stereodifferentiating Aldol Reactions Comprehensive Organic Synthesis. B M. Trost and L. Fleming. Oxford The Mukaiyama Aldol Reaction Variant Pergamon Press. 2: 181 Allylmetal Nucleophiles as Enolate Synthons Kim, B M, S. F Williams, et al. (1991). The Aldol Reaction Group Ill Enolates Comprehensive Organic Synthesis. B M. Trost and I Fleming. Oxford Pergamon Press. 2: 239 a Reading Assignment for this Week Franklin, A. S and L. Paterson(1994). "Recent Developments in Asymmetric Aldol meth y. Contemporary Organic Synthesis 1: 317-338 Carey Sundberg: Part A; Chapter 7 Cowden, C J and l. Paterson(1997).". etric aldol reactions using boron Carbanions Other Nucleophilic Carbon Species enolates. Org. React (N.Y. ) 51: 1-200 Carey Sundberg: Part B: Chapter 2 Nelson, S G (1998). Catalyzed enantioselective aldol additions of late Reactions of Carbon Nucleophiles with Carbonyl Compounds enolate equivalents. " Tetrahedron: Asymmetry 9(3): 357-389 Mahrwald, R (1999). "Diastereoselection in Lewis-acid-mediated aldol Matthew d. shair additions. Chem. Rev. 99(5): 1095-1120 November 15. 2002
http://www.courses.fas.harvard.edu/~chem206/ R Me O M O H R R R O Me O M D. A. Evans Chem 206 Matthew D. Shair Friday, November 15, 2002 ■ Reading Assignment for this Week: Carey & Sundberg: Part A; Chapter 7 Carbanions & Other Nucleophilic Carbon Species The Aldol Reaction–2 Carey & Sundberg: Part B; Chapter 2 Reactions of Carbon Nucleophiles with Carbonyl Compounds Chemistry 206 Advanced Organic Chemistry Lecture Number 25 The Aldol Reaction–2 ■ Other Useful References ■ (E) & (Z) Enolates: Felkin Selectivity ■ Double Stereodifferentiating Aldol Reactions ■ The Mukaiyama Aldol Reaction Variant ■ Allylmetal Nucleophiles as Enolate Synthons Evans, D. A., J. V. Nelson, et al. (1982). “Stereoselective Aldol Condensations.” Top. Stereochem. 13: 1. Heathcock, C. H. (1984). The Aldol Addition Reaction. Asymmetric Synthesis. Stereodifferentiating Reactions, Part B. J. D. Morrison. New York, AP. 3: 111. Oppolzer, W. (1987). “Camphor Derivatives as Chiral Auxiliaries in Asymmetric Synthesis.” Tetrahedron 43: 1969. Heathcock, C. H. (1991). The Aldol Reaction: Acid and General Base Catalysis. Comprehensive Organic Synthesis. B. M. Trost and I. Fleming. Oxford, Pergamon Press. 2: 133. Heathcock, C. H. (1991). The Aldol Reaction: Group I and Group II Enolates. Comprehensive Organic Synthesis. B. M. Trost and I. Fleming. Oxford, Pergamon Press. 2: 181. Kim, B. M., S. F. Williams, et al. (1991). The Aldol Reaction: Group III Enolates. Comprehensive Organic Synthesis. B. M. Trost and I. Fleming. Oxford, Pergamon Press. 2: 239. Franklin, A. S. and I. Paterson (1994). “Recent Developments in Asymmetric Aldol Methodology.” Contemporary Organic Synthesis 1: 317-338. Cowden, C. J. and I. Paterson (1997). “Asymmetric aldol reactions using boron enolates.” Org. React. (N.Y.) 51: 1-200. Nelson, S. G. (1998). “Catalyzed enantioselective aldol additions of latent enolate equivalents.” Tetrahedron: Asymmetry 9(3): 357-389. Mahrwald, R. (1999). “Diastereoselection in Lewis-acid-mediated aldol additions.” Chem. Rev. 99(5): 1095-1120. ■ Assigned Reading Stereoselective Aldol Reactionsw in the Synthesis of Polyketide natural Products, I. Paterson et al. in Modern Carbonyl Chemistry, pp 249-297, J. Otera, Ed. Wiley VCH, 2000 (handout) W. R. Roush, J. Org. Chem. 1991, 56, 4151-4157. (handout)
D. A. Evans Carbonyl Addition Reactions:(E)-Enolate Nucleophiles Chem 206 E) Enolates Exhibit Felkin Aldehyde Diastereoface Selection The Non-Reinforcing syn-RCHO is the ng Dependence of the Selectivity of Felkin-controlled Reactions on Nu Size Favored OTMS Felli 19P Felkin/1, 3-syn anti-Felkin/1,3-anti P= PMB P=TBS --M Disfavored 20:2120:21 Anti-Felkin a-substituent dominates for Large Nu t-Bu 96: 04 94: 06 a The illustrated syn-pentane interaction disfavors the ant-Felkin pathway B-substituent dominates for small Nu Me 17: 83 40: 60 Evans, Nelson, Taber, Topics in Stereochemistry 1982, 13, 1-115 W.R. Roush, J. Org. Chem. 1991, 56, 4151-4157 Background Information: The influence of B-OR substituents on RCHO Evans,JAcS1996,118,43224343 0-M Felkin selecton both centers major: minors Felkin reinTon! R=TBs 99: 1(77% yield) R=PMB 93: 7(84% yield) centers major: minors Therefore, one might conclude that reinforcing R=TBS 94: 6 o OR Achiral(E) enolates preferentially add to the Felkin diastereoface cIng non-reinforcing High anti syn diastereoselectivity(97: 3)is observed in all cases Evans etal. JACS 1995. 117. 9073
R 96 : 04 56 : 44 17 : 83 t-Bu i-Pr Me 20 : 21 94 : 06 75 : 25 40 : 60 20 : 21 O MLn Me R H RL O Me Me H O OR Me Me C PO H R Ha H C O–M Hb R Ha H C O–M Me H R O Me H R O OR R C H R L Me Me H H O LnM O C H O MLn O Me H H Me R L R Me H O OR Me Me Nu R OH Me Nu R OH OR R Me OH Me O R L R L O Me OH Me R Me Me OB(Chx)2 Me Me OB(Chx)2 Me Me O H OP Me iPr R OTMS BF3 •OEt2 –78 °C Me H O OR Me Me H O Me Me OR Me R O OH OP Me iPr O Me OR Me OH Me Me Me Me OR Me O Me Me Me OH Me Me R O OH OP Me iPr D. A. Evans Carbonyl Addition Reactions: (E)-Enolate Nucleophiles Chem 206 Evans, Nelson, Taber, Topics in Stereochemistry 1982, 13, 1-115. W. R. Roush, J. Org. Chem. 1991, 56, 4151-4157. ■ The illustrated syn-pentane interaction disfavors the anti-Felkin pathway. (E) Enolates Exhibit Felkin Aldehyde Diastereoface Selection Felkin + + ++ Anti-Felkin Disfavored Favored major : S minors Felkin Achiral (E) enolates preferentially add to the Felkin diastereoface High anti:syn diastereoselectivity (³ 97 : 3) is observed in all cases 99 : 1 93 : 7 (77% yield) (84% yield) R = TBS R = PMB Evans etal. JACS 1995, 117, 9073 major : S minors Felkin 94 : 6 74 : 26 (79% yield) (82% yield) R = TBS R = PMB both centers reinforcing centers non-reinforcing Background Information: The influence of -OR substituents on RCHO Evans, JACS 1996, 118, 4322-4343 Nu Lewis acid Nu Lewis acid a a b b Felkin Selecton 1,3-selection a b stereocenters reinforcing a b stereocenters non-reinforcing Nu: ‡ Nu: ‡ Therefore, one might conclude that: 20 Felkin/1,3-syn 21 anti-Felkin/1,3-anti The Non-Reinforcing syn- RCHO is the most Interesting Dependence of the Selectivity of Felkin-controlled Reactions on Nu Size P = PMB P = TBS 19 6 P = PMB P = TBS -substituent dominates for small Nu -substituent dominates for Large Nu
D. A. Evans Carbonyl Addition Reactions:(4)-Enolate Nucleophiles Chem 206 (Z) Enolates Exhibit Anti-Felkin Aldehyde Diastereoface Selection O OTBS Disfavored R Felkin anti-Felkin(Cram-Chelate) Me h OLi Felkin:anti-Felkin Me D W. Brooks Co-workers TMSO Me27:73 Tetrahedron Lett. 1982, 23, 4991-4994 Me me 9BBN Anti-Felkin The illustrated syn-pentane interaction disfavors the Felkin pathway I The bulky oTBS group disfavors chelation. (see Keck, JACS 1986, 108, 3847) Evans, Nelson, Taber, Topics in Stereochemistry 1982, 13, 1-115 I The boron and lithium enolates display nearly equal levels of anti-Felkin selectivity WR.Rush,og.chem.1991,56,4151-4157 An Early study rationalized results through chelated transition states Titanium enolates exhibit the same trend CH2OBn o H OCH2OBn OPMB OCH2OBn Felkin Anti-Felkin( Cram Chelate) anti-Felkin: Felkin 77: 23(78% 0 H OPMB OPMB Felkin: Anti-Felkin OCH,OBn 17:83 anti-Felkin: Felkin 56: 44(84%) 10:90 am1:87 Evans etal. JACS 1995. 117. 9073 Masamune Acs1982104,5526
O iPr Me OH iPr Me OPMB Me iPr O TiCln O iPr Me OH iPr Me OPMB Me iPr O TiCln R Me O MLn H RL O Me Li O R Me OCH2OBn Me O H R" H Et O Me OCH2OBn OCH2OBn Me O H CHMe2 C6H11 Et Et C6H11 (R) C H O LnM O H Me Me H R L R R C H R L H H Me Me O MLn O Me O OCH2OBn Me OH R R" R R" OH Me O OCH2OBn Me R L O Me OH Me R R Me OH Me O R L H R" O Me O Li CH2OBn H O Me OTBS Me R Me OM OPMB Me O H iPr OPMB Me O H iPr O Me OH Me R Me OTBS TMSO Me OLi Me Me O 9BBN Me PhS Me OH Me O R Me OTBS Favored Disfavored Anti-Felkin + + ++ Felkin (Z) Enolates Exhibit Anti-Felkin Aldehyde Diastereoface Selection The illustrated syn-pentane interaction disfavors the Felkin pathway. Evans, Nelson, Taber, Topics in Stereochemistry 1982, 13, 1-115. W. R. Roush, J. Org. Chem. 1991, 56, 4151-4157. D. W. Brooks & Co-workers Tetrahedron Lett. 1982, 23, 4991-4994. Felkin anti-Felkin (Cram-Chelate) Felkin : anti-Felkin 27 : 73 29 : 71 ■ The bulky OTBS group disfavors chelation. (see Keck, JACS 1986, 108, 3847.) ■ The boron and lithium enolates display nearly equal levels of anti-Felkin selectivity. Titanium enolates exhibit the same trend D. A. Evans Carbonyl Addition Reactions: (Z)-Enolate Nucleophiles Chem 206 Si-face An Early study rationalized results through chelated transition states: Masamune JACS 1982, 104, 5526 Nu: Anti-Felkin (Cram Chelate) 13 : 87 8 : 92 10 : 90 17 : 83 (R") Felkin : Anti-Felkin Felkin anti-Felkin : Felkin 77 : 23 (78%) Evans etal. JACS 1995, 117, 9073 anti-Felkin : Felkin 56 : 44 (84%)
D. A. Evans Double Stereodifferentiating Bond Constructions-1 Chem 206 Double Stereodifferentiating Aldol Bond Constructions Matched reactant pair: Stereo-induction from both partners reinforcing The reference reactions Me Me Stereochemical Control Elements Enolate geometry [aldehyde prod ratio]= 10/1 Product Enolate facial bias Stereochemistry Aldehyde facial bias [enolate prod ratio=10/1 The Issue: Can one reliably take the diastereoselectivites of the individual a The double stereodifferentiating situation: Stereoselectivity? eaction partners and use this information in the illustrated The model reactions. △G(xn) Me OH G The assumption: ( Masamune Heathcock) It is presumed that useful information can be obtained from related achiral enolate& RCHO addition reactions and that the free energy contributions will be additive G+(Rx)~△G+( (enolate)+△G+/RcHo) El AG+(enolate) log[Product ratio]- log [enolate ratio]+ log [aldehyde ratio] Product ratio]-[enolate prod ratio] x [aldehyde prod ratio I Hence, for the case at hand: [Product ratio]-[10]x [10]- 100 Mismatched reactant pair. Stereo-induction from partners nonreinforcing Masamune, Angew. Chem. Int Ed. 1985, 24, 1-76 △AG(Rxn)~△G+( (enolate)-△G+(RcHo)
Me O Me Me OM Me Me O H H O Me Me O Me OH Me Me O H Me OM Me Me OM Me H O Me log [Product ratio] ~ log [enolate ratio] + log [aldehyde ratio] Me OH Me O Me Me OM Me Me O H H O Me Me OM Me Me Me OH Me O Me Me Me OM Me Me O H Me Me OH Me O Me Me O Me OH Me ❊ ❊ ❊ (–) Me O El Me Me OH Nu Me OH Me Me O Me The extrapolation: The model reactions: Can one reliably take the diastereoselectivites of the individual reaction partners and use this information in the illustrated extrapolation: The Issue: ❊ ❊ DDG ‡ (rxn) ❊ Mismatched reactant pair: Stereo-induction from partners nonreinforcing It is presumed that useful information can be obtained from related achiral enolate & RCHO addition reactions and that the free energy contributions will be additive: ■ Hence, for the case at hand: [Product ratio] ~ [10] x [10] ~ 100 ■ The assumption: (Masamune, Heathcock) ■ The double stereodifferentiating situation: Stereoselectivity? The reference reactions: [enolate prod ratio] = 10/1 [aldehyde prod ratio] = 10/1 ❊ [Product ratio] ~ [enolate prod ratio] x [aldehyde prod ratio] DDG ‡ (Rxn) ~ DDG ‡ (enolate) + DDG ‡ (RCHO) ❊ DDG ‡ (rxn) Masamune, Angew. Chem. Int. Ed. 1985, 24, 1-76 DDG ‡ (rxn) = ? DDG ‡ (Rxn) ~ DDG ‡ (enolate) – DDG ‡ (RCHO) Matched reactant pair: Stereo-induction from both partners reinforcing DDG ‡ (enolate) DDG ‡ (aldehyde) El (+) Nu (–) Enolate facial bias Aldehyde facial bias Product Stereochemistry Enolate geometry Stereochemical Control Elements ❊ Double Stereodifferentiating Aldol Bond Constructions ❊ D. A. Evans Double Stereodifferentiating Bond Constructions-1 Chem 206
D A. Evans Double Stereodifferentiating Bond Constructions-2 Chem 206 The Masamune-Heathcock generalizations hold to a point (2)-Titanium Enolates: The reference reactions (E)-Boron Enolates: The reference reactions TBSO SOo o TICl4. EtN-iPT2 B(c-hexh2 R-CHO OTBS O OH OTBS diastereoselection 94: 6 TBSo 0 OH Me Me ( c-hex)2BCL, Et3N MeMe Me M=B(9-BBN) syn: 10: 69 21% anti M=TICl4 syn: 21: 7. diastereoselection 96: 4 Me (E)-Boron Enolates: The matched cases ()-Titanium Enolates: The matched cases Me diastereoselection: anti: others O OTBS Me R=TBS: >99: 1(85% yield) R=PMB:>99:1(84%yed (E)-Boron Enolates: The mismatched cases (]-Titanium Enolates: The mismatched cases TBS R=TBS:52:48(83% diastereoselection 62: 38 (87%) CR=PMB: 81: 19(79% yield) Double Stereodifferentiating Aldol Reactions. The Documentation of" Partially B-center on RCHO can play a significant role in this marginal situation Matched" Aldol Bond Constructions". Evans, D A; Dart, M.J.; Duffy, J. L Rieger,D.L.JAcS1995,117,90739074
O Me Me Me B(c-hex)2 Me OTBS Me Me O OH Me Me Me Me Me Me OM Me O OH Me Me X OPMB Me Me OPMB X Me Me O OH Me Me Me TBSO Me O Me H O Me OTBS Me Me Me Me TBSO Me Me O Me Me OH Me O Me TBSO Me Me Me Me OR Me O H OR R OH Me Me O Me TBSO R Me O Me TBSO Me Me BR2 H O Me OR Me Me Me Me TBSO Me O Me Me OH OR Me Me BR2 O Me Me TBSO Me Me R TBSO Me O Me Me OH R OR Me Me OPMB Me O H TiCln O Me Me TBSO Me Me Me Me OTBS Me O H R TBSO Me O Me Me OH R OTBS TiCln O Me Me TBSO Me Me Me Me OTBS Me O H R TBSO Me O Me Me OH R OTBS R-CHO R-CHO OH Me Me O Me Me TBSO Me Me OTBS R OH Me Me O Me TBSO R OTBS R OH Me Me O Me TBSO R D. A. Evans Double Stereodifferentiating Bond Constructions-2 Chem 206 The Masamune-Heathcock generalizations hold to a point: (E)-Boron Enolates: The reference reactions diastereoselection 94 : 6 diastereoselection 96 : 4 (c-hex)2BCl, Et3N diastereoselection: anti : S others R = PMB: >99 : 1 (84% yield) R = TBS: >99 : 1 (85% yield) (E)-Boron Enolates: The matched cases R = TBS: 52 : 48 (83% yield) R = PMB: 81 : 19 (79% yield) (E)-Boron Enolates: The mismatched cases -center on RCHO can play a significant role in this marginal situation (Z)-Titanium Enolates: The reference reactions TiCl4 , EtN-iPr2 diastereoselection 96 : 4 + + 8% anti 21% anti syn: 21: 71 M = B(9-BBN) M = TiCl4 syn: 10: 69 (Z)-Titanium Enolates: The matched cases (Z)-Titanium Enolates: The mismatched cases diastereoselection 62 : 38 (87%) R = TBS: 87 : 13 (76%) "Double Stereodifferentiating Aldol Reactions. The Documentation of "Partially Matched" Aldol Bond Constructions". Evans, D. A.; Dart, M. J.; Duffy, J. L.; Rieger, D. L. JACS 1995, 117, 9073-9074