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
D. A. Evans Introduction to Complex Aldol Bond Constructions Chem 206 Synthesis of Polyketide chains The Lonomycin Synthesis: An example of polypropionate assembage Evans, Ratz, Huff, Sheppard JACS 1995, 117, 3448 Given a polyprpionate chain of Iterating Me& OH substitutents select a disconnection point subunits of comparable complexity by adding C=o as illustrated R Meme m MeMeMeMeMe Me OMe OHOH HO 1 Focusing on the=O FG, there are 2 1st-order aldol disconnections highlighted. Lets proceed forward with BH3 Transform: See Lecture No 8 T1B. Carry out the disconnection to Me Me subunits 2K and 2A CrC11 Assemblage a center important Both centers important 1. NaBH(OAc)3 2.(MeO)CMe 2, H For substituted enolate and enolsilane- based processes, there are at least three identifiable stereochemical determinants that influence reaction diastereoselectivity (eq 1). Two of these determinants are associated with the local chirality of the individual reaction partners. For example, enolate(enolsilane)chirality infiuences the (85%)Diastereoselection absolute stereochemistry of the forming methyl-bearing stereocenter, and in a similar H fashion, aldehyde chirality controls the absolute stereochemical outcome of the incipient hydroxyl-bearing stereocenter. The third determinant, the pericyclic OH reactions of metal enolates(M= BR 2, T 3, Li, etc. ) but is absent in the Lewis acid catalyzed( Mukaiyama)enolsilanes aldol variants that proceed via open transition Matched aldol addition Me Sn(otn o al Determinants M= BR2 M= siR3 Et3N Xp 1 enolate facial bias vv aldehyde facial bias Anti-Felkin Adduct Diastereoselection >95: 5 (86%) pericyclic transition state The Sn(oTi)2 aldol reaction of A: seethis lecture+ JACS, 1990, 112, 866
M R1 O Me Me R1 O Me Me OH R2 Me H R2 O Me H OMe O Me O Me O HO Me OH Me OH Me O N Me O O Me O Bn OMe Me O Me O HO Me OH Me OH Me O N Me O O Me O Bn a a' a a' 11 11 Me O O XP Me O Me Me Me Me O O XP Me OH Me Me OH Me XP O O Me O O Me Me Me Me HO O O Me OMe Me Me OMe Me OH Me O O O Me Me O O Me OMe Me OMe Me Me OH H H H H O O O Me Me Me Me Me Sn(OTf)2 Sn(OTf)2 Et3N Et3N Me O H A A H R O Me OR Me 2A R R OR O Me Me OR Me Me OH Me OR Me R R OH OH Me Me OR Me Me OH Me OH Me R OR O Me Me OR Me Me 2K T1A T1B R R OH O Me Me OR Me Me OR Me OR Me Synthesis of Polyketide chains D. A. Evans Introduction to Complex Aldol Bond Constructions Chem 206 Given a polyprpionate chain of alternating Me & OH substitutents, select a disconnection point sectioning the fragments into subunits of comparable complexity by adding C=O as illustrated. Focusing on the =O FG, there are 2 1st-order aldol disconnections highlighted. Let's proceed forward with T1B. Carry out the dissconnection to subunits 2K and 2A. a b a' b' aldol a b a' b' a center important b center ignore Both centers important ✔ ✔ ✔ ✘ ✔ ✔ (1) Stereochemical Determinants M = BR2 M = SiR3 enolate facial bias aldehyde facial bias pericyclic transition state For substituted enolate and enolsilane-based processes, there are at least three identifiable stereochemical determinants that influence reaction diastereoselectivity (eq 1). Two of these determinants are associated with the local chirality of the individual reaction partners. For example, enolate (enolsilane) chirality influences the absolute stereochemistry of the forming methyl-bearing stereocenter, and in a similar fashion, aldehyde chirality controls the absolute stereochemical outcome of the incipient hydroxyl-bearing stereocenter. The third determinant, the pericyclic transition state, imposes a relative stereochemical relationship between the developing stereocenters. This important control element is present in the aldol reactions of metal enolates (M = BR 2 , TiX 3 , Li, etc.), but is absent in the Lewis acid catalyzed (Mukaiyama) enolsilanes aldol variants that proceed via open transition states. The Lonomycin Synthesis: An example of polypropionate assembage Evans, Ratz, Huff, Sheppard JACS 1995, 117, 3448 C1–C11 Assemblage 1 3 5 7 9 Swern 86% LiBH4 , EtOH 1. NaBH(OAc)3 2. (MeO)2CMe2 , H+ (85%) Diastereoselection 95 : 5 5 5 9 5 9 5 9 7 7 9 1 3 5 7 9 BH3 Transform: See Lecture No. 8 93% 1 3 1 5 9 Anti-Felkin Adduct Diastereoselection >95 : 5 (86%) The Sn(OTf)2 aldol reaction of A: seethis lecture + JACS, 1990, 112, 866 JACS, 1990, 112, 866 Stereochemically Matched aldol addition
D. A. Evans Introduction to Complex Aldol Bond Constructions Chem 206 he Altohyrtin Synthesis: An example of polypropionate assembage Model studies OB(C-Hexh2 3°C Diastereoselection 97. 3 Background H Evans, Trotter, Coleman, Cote, Dias, Rajapakse, Tetrahedron 1999, 55, 8671-8726 Meo R=PMB69:31 iPr Aldol o OTBS M The Aldol Fragment Coupling Me oTBs B(cHexh2 Tro OTBS each fragment were ev 人 Model studies Meo a OTBS Diastereoselection 90: 10(70%) OTBS 2. 1 mixture of diastereomers
O O MeO O H O O HO H O Me AcO H OH O O OH Me Me H OAc Me OH H OH O H OH Me HO H X H H H H H H H H O Me TBSO O O Me Et Me OB(c-Hex)2 O O TESO H OTBS Me TESO Me H O H O O MeO H OTBS H TrO H Me O M O O TESO H OTBS TESO Me O O MeO H OTBS H TrO H O Me OH Me H O O MeO H OTBS H TrO H Me O B(c-Hex)2 Me Me H O O O MeO H OTBS H TrO H O Me Me Me OH Me H O OR iPr iPr OB(Chx)2 Me iPr BR2 O O O MeO H OTBS H TrO H O Me B(cHex)2 O O TESO H OTBS TESO Me O O MeO H OTBS H TrO H O Me OH Me H iPr OH iPr O OR Me O Me OR Me OH iPr iPr OH Me TBSO O O Et Me Me O O O TESO H OTBS Me TESO Me H O H D. A. Evans Introduction to Complex Aldol Bond Constructions Chem 206 The Altohyrtin Synthesis: An example of polypropionate assembage Evans, Trotter, Coleman, Côté, Dias, Rajapakse, Tetrahedron 1999, 55, 8671-8726. Aldol ? Reaction The stereochemical determinants from each fragment were evaluated pentane, -78 °C 2:1 mixture of diastereomers Diastereoselection 97:3 -78 °C 14 Model Studies major : S others R = TBS R = PMB 99 : 1 93 : 7 R = PMB 69:31 Background Model Studies Diastereoselection 90:10 (70%) The Aldol Fragment Coupling
D. A. Evans Introduction to Complex Aldol Bond Constructions Chem 206 Bafilomycin A, Synthesis: An example of polypropionate assembage Evans. Calter. Tetrahedron Lett. 1993. 34. 6871 Enolization Conditions: PhBCl2, APT NEt, CH2Cl, -78C MeMe oMe Critical Aldol Disconnection diastereoselection Me. >99:1 Critical Aldol Disconnection OMe Me TMSOI Aldehyde Fragment: Target contains syn aldol retro with anti-Felkin relationship at 1&2 Enolate Fragment: Can the needed enolate facial bias be built into the reaction?? diastereoselection >95 Aldol Model Studies Enolization Conditions: PhBCl2, A-Pr2NEt, CH2Ch, -78oC MeMe oMe OTBSOTES O OTBSOTES tBu tBu Me2 CHCHO TMSOII The Critical observation Me2 CHCHO le diastereoselection Bafilomycin Al
Bafilomycin A1 Me O Me O Me O Si tBu tBu Me Me O Me O Me O Si tBu tBu Me O O Me OMe Me OMe Me TMSO Me OH Me Me Me O Me O Me O Si tBu tBu Si tBu tBu O O Me O Me Me Me OH Me Me Me TBSO O O Me OMe Me OMe Me HO Me OH OH Me OH Me Me Me Me O O O Me OMe Me OMe Me TMSO Me H O Me Me Me H TBSO Me O Me Me O Me O Me O Si tBu tBu O OTBS Me OTES Me Me Me Me Me OR Me OR Me O O O Me OMe Me OMe Me HO Me OR OH Me OH Me Me Me Me O Me2CHCHO Me2CHCHO O O Me OMe Me OMe Me RO Me H O Me O O Me O Me Me Si tBu Me Me OH Me tBu O OTBS Me OTES Me Me Me Me OH Me D. A. Evans Introduction to Complex Aldol Bond Constructions Chem 206 Bafilomycin A1 Synthesis: An example of polypropionate assembage Critical Aldol Disconnection Enolization Conditions: PhBCl2 , i-Pr2NEt, CH2Cl2 , -78oC. diastereoselection >99:1 diastereoselection 62:38 9 diastereoselection >99:1 Aldol Model Studies The Critical Observation Enolization Conditions: PhBCl2 , i-Pr2NEt, CH2Cl2 , -78oC. diastereoselection >95:5 60% Critical Aldol Disconnection Required: Syn aldol addition Aldehyde Fragment: Target contains syn aldol retron wilth anti-Felkin relationship at 1 & 2 Enolate Fragment: Can the needed enolate facial bias be built into the reaction?? 1 2 Evans, Calter, Tetrahedron Lett. 1993, 34, 6871 94% Bafilomycin A1 HF.pyridine, THF, 25oC
D.A. Evans The Mukayama Aldol Reaction -1 Chem 206 Type I Aldol Reaction: Metal Aldol Process Recent Review This reaction may be run with either a stoichiometric or cat amount of base R. Mahrwald. Diatereoselection in Lewis Acid Mediated Aldo/ Additions chem.Rev.1999,99,1095-1120 S G. Nelson, Catalyzed enantioselective aldol additions of latent Mukaiyama Aldol Reaction, E Carreira In Comprehensive H-B-M Asymmetric Catalysis, Jacobsen, E.N. Pfaltz, A and Yamamoto, H Editors; Springer Verlag: Heidelberg, 1999; Vol lI, 998-1059 o OH Reaction Mechanism: "Closed"versus "Open"Transition States Catalytic Version: Slow step in the catalytic variant is protonation of The Mukaiyama aldol reaction proceeds through an"open"transition the intermediate metal aldolate state. The two illustrated competing Ts orientations do not differ significantly in energy. For most reactions in this family there is not a Type ll Aldol Reaction: Mukaiyama Aldol Process good understanding of reactans-pair orientation. There is a prevalent This reaction may be run with either a stoichiometric or catalytic amount view that the anti-periplanar TS is favored on the basis of electrostatic of lewis acid The minimalist mechanism MX= Lewis acid R TMso R1 ⑥M!sow TMS-X Metal aldolate Ts anti-peniplanar TS synclinal Ts oM Other events are also taking place Silyl transfer is not Carreira Tet. Lett 1994. 35. 4323 necessarily intramolecular
O M O M M M H R2 H R2 X R2 O O R1 M H–B–M H R2 O X R2 O OH R1 X R2 O O R1 TMS M X R2 O O R1 TMS R OTMS C C R R R TMSO C C R R O C O M H L L R2 X Me H X R2 O O R1 M TMS–X X B–M H R2 O M X O R1 M H R2 O X O R1 X O R1 TMS D. A. Evans The Mukayama Aldol Reaction-1 Chem 206 Type I Aldol Reaction: Metal Aldol Process This reaction may be run with either a stoichiometric or catalytic amount of base. Type II Aldol Reaction: Mukaiyama Aldol Process This reaction may be run with either a stoichiometric or catalytic amount of Lewis acid. Catalytic Version: Slow step in the catalytic variant is protonation of the intermediate metal aldolate Recent Reviews R. Mahrwald, Diatereoselection in Lewis Acid Mediated Aldol Additions, Chem. Rev. 1999, 99, 1095-1120 S. G. Nelson, Catalyzed enantioselective aldol additions of latent enolate equivalents Tetrahedron: Asymmetry 1998, 9, 357-389. Mukaiyama Aldol Reaction, E. Carreira In Comprehensive Asymmetric Catalysis, Jacobsen, E. N.; Pfaltz, A.; and Yamamoto, H. Editors; Springer Verlag: Heidelberg, 1999; Vol III, 998-1059. Reaction Mechanism: "Closed" versus "Open" Transition States anti-periplanar TS "Open" synclinal TS "Open" Metal aldolate TS "Closed" The Mukaiyama aldol reaction proceeds through an "open" transition state. The two illustrated competing TS orientations do not differ significantly in energy. For most reactions in this family there is not a good understanding of reactans-pair orientation. There is a prevalent view that the anti-periplanar TS is favored on the basis of electrostatic effects. The minimalist mechanism: MX = Lewis acid Other events are also taking place: Carreira Tet. Lett 1994, 35, 4323 slow slow Silyl transfer is not necessarily intramolecular
D. A. Evans The Mukayama Aldol Reaction-2 Chem 206 Denmark has designed a nice substrate to distinguish between Syn-Anti Aldol Diastereoselection synclinal and anntiperiplanat transition states Denmark, J. Org. Chem. 1994, 59, 707-709 Heathcock: J. Org. Chem 1986, 51, 3027 OTMS O OTMS BF3°Et2 o OTMS 丰 synclinal HcHO OTMS BF3 0Et2 o OTMS O OTMS CHO OTMS OTMS BF3. oEt2 M antiperiplanar AP# AP The effectice size of the enol substituents are probably dominant Lewis Acid syn anti The transition state? Me3C OTMS These reactions "exhibit little simple diastereoselection except in special 18:82 cases. .Heathcock SnCa BF3OEt2 29:71 7822 conclusion there is a modestpreference for the antiperiplanar Ts
O XM O MX H H H O M Ph Me CHO OTMS O TMS H Me HO O Me Me OTMS Me Me Me Me OTMS PhCHO BF3•OEt2 BF3•OEt2 Me HO O O TMS H S ‡ S AP‡ AP TiCl4 21:79 SnCl4 18:82 BF3•OEt2 29:71 TrClO4 27:73 SnCl2 78:22 Me3C OTMS Me BF3•OEt2 R O Me Ph OTMS R O Me Ph OTMS R O Me Ph OTMS Me3C OTMS C C H Me R O Me Ph OTMS R O Me Ph OTMS D. A. Evans The Mukayama Aldol Reaction-2 Chem 206 synclinal antiperiplanar ‡ ‡ Denmark has designed a nice substrate to distinguish between synclinal and anntiperiplanat transition states: Denmark, J. Org. Chem. 1994, 59, 707-709 Lewis Acid syn:anti conclusion: there is a modestpreference for the antiperiplanar TS Syn-Anti Aldol Diastereoselection 56:44 56:44 These reactions "exhibit little simple diastereoselection except in special cases."....Heathcock Heathcock: J. Org. Chem 1986, 51, 3027 >95:5 The transition state? The effectice size of the enol substituents are probably dominant
