http://www.courses.fas.harvard.edu/~chem206/ R Me O M O H R R R O Me OM Chem 206D. A. Evans Matthew D. Shair Friday, November 15, 2002 a73 Reading Assignment for this Week: Carey & Sundberg: Part A; Chapter 7Carbanions & Other Nucleophilic Carbon Species The Aldol Reaction–2 Carey & Sundberg: Part B; Chapter 2Reactions of Carbon Nucleophiles with Carbonyl Compounds Chemistry 206 Advanced Organic Chemistry Lecture Number 25 The Aldol Reaction–2 a73 Other Useful References a73 (E) & (Z) Enolates: Felkin Selectivity a73 Double Stereodifferentiating Aldol Reactions a73 The Mukaiyama Aldol Reaction Variant a73 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. a73 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) R 96 : 04 56 : 44 17 : 83 t-Bui-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 HPO R Ha C O–MH Hb R Ha C O–MH Me H R O Me H R ORO R C H R L Me Me H H O LnM O C H O MLn OMe H H Me R L R Me H O OR Me Me Nu R OH Me Nu R OROH R Me OH Me O R L R L O Me OH Me R MeMe 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 MeMe Me OR Me O MeMeMe OH Me Me R O OH OP Me iPr Carbonyl Addition Reactions: (E)-Enolate NucleophilesD. A. Evans Chem 206 Evans, Nelson, Taber, Topics in Stereochemistry 1982, 13, 1-115. W. R. Roush, J. Org. Chem. 1991, 56, 4151-4157. a73 The illustrated syn-pentane interaction disfavors the anti-Felkin pathway. (E) Enolates Exhibit Felkin Aldehyde Diastereoface Selection Felkin ++ ++ Anti-Felkin Disfavored Favored Felkinmajor : Σ minors Achiral (E) enolates preferentially add to the Felkin diastereoface High anti:syn diastereoselectivity (≥ 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 : Σ minors Felkin 94 : 6 74 : 26 (79% yield) (82% yield) R = TBS R = PMB both centersreinforcing centersnon-reinforcing Background Information: The influence of -OR substituents on RCHO Evans, JACS 1996, 118, 4322-4343 Nu Lewisacid Nu Lewisacid α α ββ Felkin Selecton 1,3-selection α β stereocentersreinforcing α β stereocentersnon-reinforcing Nu: ? Nu: ? Therefore, one might conclude that: 20Felkin/1,3-syn 21anti-Felkin/1,3-anti The Non-Reinforcing syn- RCHO is the most InterestingDependence of the Selectivity of Felkin-controlled Reactions on Nu Size P = PMB P = TBS 196 P = PMBP = TBS -substituent dominates for small Nu -substituent dominates for Large Nu O iPr Me OH iPr Me OPMB MeiPr O TiCln O iPr Me OH iPr Me OPMB MeiPr O TiCln R Me O MLn H RL O Me LiO R Me OCH2OBn Me O H R" EtH O Me OCH2OBn OCH2OBn Me O H CHMe2C6H11 Et Et C6H11 (R) C H OLnM O H MeMe H R L R R C H R L H H Me Me O MLnO Me O OCH2OBn Me OH R"R R R" OH Me OCH2OBnO Me R L O Me OH Me R R Me OH Me O R L R"H O Me OLi CH2OBn H O Me OTBS Me R Me OM OPMB Me O iPrH OPMB Me O iPrH O Me OH Me R Me OTBS TMSO Me OLi MeMe O 9BBN MePhS Me OH Me O MeR 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. anti-Felkin (Cram-Chelate)Felkin Felkin : anti-Felkin 27 : 73 29 : 71 a73 The bulky OTBS group disfavors chelation. (see Keck, JACS 1986, 108, 3847.) a73 The boron and lithium enolates display nearly equal levels of anti-Felkin selectivity. Titanium enolates exhibit the same trend Chem 206D. A. Evans Carbonyl Addition Reactions: (Z)-Enolate Nucleophiles 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 Felkin : Anti-Felkin(R") Felkin anti-Felkin : Felkin 77 : 23 (78%) Evans etal. JACS 1995, 117, 9073 anti-Felkin : Felkin 56 : 44 (84%) Me O Me Me OM Me Me O H H O Me Me O Me OH Me Me O HMe OM Me Me OM Me H O Me log [aldehyde ratio] log [enolate ratio] log [Product ratio] ~ + Me OH Me O Me Me OM Me Me O H H O MeMe 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 a69 a69a69 (–) 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: a69a69??G? (rxn) a69 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: a73 Hence, for the case at hand: [Product ratio] ~ [10] x [10] ~ 100 a73 The assumption: (Masamune, Heathcock) a73 The double stereodifferentiating situation: Stereoselectivity? The reference reactions: [enolate prod ratio] = 10/1 [aldehyde prod ratio] = 10/1 a69 [Product ratio] ~ [enolate prod ratio] x [aldehyde prod ratio] ??G? (Rxn) ~ ??G? (enolate) + ??G? (RCHO) a69 ??G? (rxn) Masamune, Angew. Chem. Int. Ed. 1985, 24, 1-76 ??G? (rxn) = ? ??G? (Rxn) ~ ??G? (enolate) – ??G? (RCHO) Matched reactant pair: Stereo-induction from both partners reinforcing ??G? (enolate) ??G? (aldehyde) El (+) Nu (–) Enolate facial bias Aldehyde facial bias Product Stereochemistry Enolate geometry Stereochemical Control Elements a69 Double Stereodifferentiating Aldol Bond Constructions a69 Chem 206D. A. Evans Double Stereodifferentiating Bond Constructions-1 O MeMe Me B(c-hex)2 Me OTBS Me Me O OH Me Me Me Me Me Me OM Me OHO Me MeX 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 MeMe 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 MeMe OH OR Me Me BR2O Me Me TBSO Me Me R TBSO Me O MeMe OH R OR Me Me OPMB Me O H TiClnO Me Me TBSO Me Me Me Me OTBS Me O H R TBSO Me O MeMe OH R OTBS TiClnO Me Me TBSO Me Me Me Me OTBS Me O H R TBSO Me O MeMe 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 Double Stereodifferentiating Bond Constructions-2D. A. Evans 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 : Σ 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. M R1 O Me Me R1 O Me Me OH R2 Me H R2 O Me H OOMe Me O Me O HO Me OH Me OH Me NO Me O O Me O Bn OMe Me O Me O HO Me OH Me OH Me NO Me O O Me O Bn α α' α α' 11 11 Me OO XP Me O Me MeMe Me OO XP Me OH Me Me OH Me XP O O Me O O Me Me MeMe OHO O Me OMeMe Me OMe Me OHMe O O O Me Me O O OMeMe Me OMe Me Me OH HHH H O O O Me Me Me MeMe Sn(OTf)2 Sn(OTf)2 Et3N Et3N Me O H A A H R O Me OR Me 2A R R OR O MeMe OR Me Me OH Me OR Me R R OH OH MeMe OR Me Me OH Me OH Me R OR O MeMe OR Me Me 2K T1BT1A R R OH O MeMe OR Me Me OR Me OR Me Synthesis of Polyketide chains Chem 206D. A. Evans Introduction to Complex Aldol Bond Constructions 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. αβ α' β' aldol αβ α' β' α center important β center ignore Both centers important a20 a20 a24a20 a20 a20 (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 theindividual 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 pericyclictransition 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 transitionstates. 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%) Diastereoselection95 : 5 5 5 9 95 5 9 77 9 1 3 5 7 9 BH3 Transform: See Lecture No. 8 93% 1 3 51 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 OO MeO O H O O HOH O Me AcO H OH O O OHMe 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 OTESO H OTBS Me TESO Me H O H OO MeO HOTBSHTrO H Me O M O OTESO H OTBS TESO Me OO MeO HOTBSHTrO H O Me OH Me H OO MeO HOTBSHTrO H Me O B(c-Hex) 2 Me Me H O OO MeO HOTBSHTrO H O Me Me Me OH Me H O OR iPr iPr OB(Chx)2 Me iPr BR2O OO MeO HOTBSHTrO H O Me B(cHex)2 O OTESO H OTBS TESO Me OO MeO HOTBSHTrO H O Me OH Me H iPr OH iPr O OR Me O Me OR Me OH iPriPr OH Me TBSO O O MeEt Me O O OTESO H OTBS Me TESO Me H O H Chem 206D. A. Evans Introduction to Complex Aldol Bond Constructions The Altohyrtin Synthesis: An example of polypropionate assembage Evans, Trotter, Coleman, C?té, 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 : Σ others R = TBS R = PMB 99 : 1 93 : 7 R = PMB 69:31 Background Model Studies Diastereoselection 90:10 (70%) The Aldol Fragment Coupling Bafilomycin A1 Me O Me O Me O Si tButBu Me Me O Me O Me O Si tButBu Me O O OMeMe OMeMe Me TMSO Me OH Me Me Me O Me O Me O Si tButBu Si tButBu O O Me O Me Me Me OH Me Me Me TBSO O O OMeMe OMeMe Me HO Me OHOH MeOH Me Me Me Me O O O OMeMe OMeMe Me TMSO Me H O Me Me Me H TBSO Me O Me Me O Me O Me O Si tButBu O OTBS Me OTES Me Me Me Me Me OR Me OR Me O O O OMeMe OMeMe Me HO Me OROH MeOH Me Me Me Me O Me2CHCHO Me2CHCHO O O OMeMe OMeMe Me RO Me H O Me O O Me O Me Me Si tBu Me Me OH Me tBu O OTBS Me OTES Me MeMe Me OH Me Chem 206D. A. Evans Introduction to Complex Aldol Bond Constructions 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 >95:560% 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. 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 MTMS X R2 O O R1 TMS R OTMSC C RR R TMSO C C R RO C O MH 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 Chem 206The Mukayama Aldol Reaction-1D. A. Evans 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 O XM O MX H H H O M Ph Me CHO OTMS OTMS H Me OHO Me Me OTMS Me Me Me Me OTMS PhCHO BF3?OEt2 BF3?OEt2 Me OHO OTMS H SS? 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 OTMSC C MeH R O Me Ph OTMS R O Me Ph OTMS Chem 206The Mukayama Aldol Reaction-2D. A. Evans 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. OTMS Me Me Me OTMS Me Me Me RH O Me OTBS RH O Me OTBS RH O Me OTBS BF3?OEt2 BF3?OEt2 BF3?OEt2 R O Me OH R Me OTBS R O Me OH R Me OTBS R O Me OH R Me OTBS R O Me OH R Me OTBS Me R O OH R Me OTBS R O Me OH R Me OTBS Me Me OTMS R TBSO MeMe OTMS R TBSO RH O Me OTBS CC C H Me RL Me HO TMS Me R O OH R Me OTBS R O Me OH R Me OTBS RH O Me OTBS BF3?OEt2 MeMe OTMS R TBSO RH O Me OTBS Me O Me OH R TBSO R Me O Me OH R TBSO R R Me O Me OH Me OTBS R TBSO R Me O Me OH Me OTBS R TBSO Me O Me OH R TBSO R Me O Me OH R TBSO R Chem 206The Mukayama Aldol Reaction-3D. A. Evans Merged Syn-Anti & Felkin Diastereoselection Evans: JACS 1995, 117, 9598 Felkin : anti-Felkin 99 : 1 Felkin : anti-Felkin > 99 : 1 95 : 5 (95%) 70 : 30 (89%) R = iPr 87 : 13 (68%) 91 : 9 (75%) Felkin : anti-Felkin > 99 : 1 Felkin : anti-Felkin 87 : 13 R = iPr Conclusions: Moderate to Good syn diastereoselectlion Excellent Felkin diastereoselectlion Conclusions: Moderate to Good syn diastereoselectlion Excellent Felkin diastereoselectlion R = iPr Enolsilane Face Selectivity 90 : 10 95 : 5 (80%) iPrCHO iPrCHO 59 : 41 (82%) Enolsilane Face Selectivity 95 : 5 Enolslane Face Selection favored A(1-3) control is good for the (E) enolsilane R = iPr 98 : 2 (83%) 98 : 2 (72%) Double Stereodifferentiating Syn Aldol Rxns with Enolsilanes Me MeMe MsN O B Me MeMe O Ph O B R BR R BR R Me BR R Me RCHO RCHO RCHO EtCHO R OH R OH Me R OH Me Me OH R Et OH BnN BnN O B O O O O O BiPrO2C iPrO2C O O BiPrO2C iPrO2C Me O O B MeiPrO2C iPrO2C O O B SiMe2(OChex)iPrO2C iPrO2C H O H O H O Chex OH OH Chex OH Me Chex OH Me Chex OH Chex OH Chex OH (OChex)Me2Si 93% Yield72% ee W. Roush, Tetrahedron Lett. 1990, 31, 7563-7566. H2O2, KF, KHCO3 a73 The General Reactions a73 A Reagent for the Generation of Anti-1,2-Diols W. Roush, J. Am. Chem. Soc. 1988, 110, 3979-3982. Yield = 40%ee = 97% W. Roush, J. Am. Chem. Soc. 1985, 107, 8186-8190.Tetrahedron Lett. 1988, 29, 5579-5582. Yield = 90%ee = 83% Yield = 100%ee = 91% Yield = 72%ee = 87% a73 The Tartrate-derived Allylboronic Esters M. Reetz Chem. Ind. (London) 1988, 663-664. R. Hoffman Tetrahedron Lett. 1979, 4653-4656.ACIEE, 1978, 17, 768-769. R = Me: Yield = 93%ee = 60-70% R = H: Yield = 92%ee = 65% 1) CH3CHO 2) N(CH2CH2OH)3 Chem 206Allyl and Crotylmetal Species–1 : BoronD. A. Evans, D. M. Barnes a73 General Reviews of Allyl Metal Reagents:Comprehensive Organic Synthesis, 1991;Vol. 2. a73 The Hoffman Chiral Allylboronic Esters Yield = 92%ee = 92% Ph Me OH O B O O CH2C iPrO2C iPrO2C H2C C CHB(OH)2 N N BPh Ph Ts Ts N N BPh Ph Ts Ts H O H O Ph Me O OB C CH2 HO R OH R OH HO Me OH Chex OH H2C C O BO Ph Me OH Me B Me H Me B Me R1 R2 Me B Me B Me Me Me B Me Me Me CH3CHO CH3CHO MeH O Me H2N OH Me OH Me OH R1R2 Me OHH Me Me OH Me Me Me OH Me 70% 76% H. C. Brown, J. Am. Chem. Soc. 1983, 105, 2092-2093.J. Org. Chem. 1991, 56, 401-404. J. Org. Chem. 1992, 57, 6614. > 99% ee a73 The Brown IPC Controller a73 The Corey Stein Controller D. A. Evans, D. M. Barnes Chem 206 a73 The Masamune Borolane 96:497% ee 96:493% ee S. Masamune, J. Org. Chem. 1987, 52, 4831-4832. 98% ee 98% ee E. J. Corey, J. Am. Chem. Soc. 1989, 111, 5495-5496.J. Am. Chem. Soc. 1990, 112, 878-879. a73 Allenylboronic Esters: Tartrate-derived Controllers and Internal Delivery Yield = 56%ee = 92% 95% Yield>99:1H. Yamamoto, J. Am. Chem. Soc. 1982, 104, 7667-7669Tetrahedron Lett. 1986, 27, 1175-1178. R1 = Me, R2 = H: ee = 90% R1 = H, R2 = Me: ee = 90% R1 = H, R2 = OMe: ee = 90% H. C. Brown, J. Am. Chem. Soc. 1988, 110, 1535-1538.See also: Tetrahedron Lett. 1990, 31, 455-458. 1) THF, RT 2) CH3CHO 3) H. C. Brown, J. Chem. Soc., Perkin Trans. 1, 1991, 2633. + ee = 94% Allyl and Crotylmetal Species–2 : Boron TiR*O R*O Me B Me Me BO Me MeH Me H R H B O H Me H R Me MeH O O HO O O O Me Me MeMe H H HO Me R Me OH HO Me R R Me HO R Me HO O O B R Me Cl Me Me Me O O B Chex Chex Me Me Ti O O O O PhPh Ph Ph O B O O Ph H Cl H MeMe R Me Me PhCHO PhCHO PhCHO Ph Cl OH R Ph OH Me Me Ph OH O B O O Ph H H Me Chex Chex Me Duthaler Chem. Rev. 1992, 92, 807 The favored transition states R. Hoffman, Chem. Ber. 1986, 119, 2013-2024.Chem. Ber. 1988, 121, 1501-1507. ACIEE, 1986, 25, 1028-1030. 68% Yield99% ee R = H: 92% eeR = Me: 98% ee Chiral -Substituted Allyl Metal Reagents: Boron M. Riediker, R. Duthaler, ACIEE, 1989, 28, 494-495. In Organic Synthesis via Organometallics, 1991, 285-309.J. Am. Chem. Soc. 1992, 114, 2321-2336. R*OH = ee = 85 - 94%RCHOR = alkyl, aryl An Enantioselective Allyltitanium Reagent Allyl and Crotylmetal Species–3D. A. Evans, D. M. Barnes Chem 206 The Allylboron Reagents Add to Carbonyl Compounds via a Zimmerman-Traxler Transition State Another Enantioselective Allyltitanium Reagent R. Duthaler, J. Am. Chem. Soc. 1992, 114, 2321-2336. 95% ee favored + RCHO anti:syn, 96:4 favored enantioselection: 95-97% disfavored Masamune, Sato, Kim, Wollmann J. Org. Chem. 1987, 52, 4831 Me SiMe3 Me SnBu3 COOH iPrO OiPr O OH COOH O O Ti Cl Cl n-C7H15 OH Ph Me OH Me OHOH OH OH SnBu3 H O O O Ti OiPr OiPr O O Ti O O R OH Pb: S. Torii, Chem. Lett. 1986, 1461-1462.Mo: J. Faller, Tetrahedron Lett. 1991, 32, 1271-1274. Cr: Y. Kishi, Tetrahedron Lett. 1982, 23, 2343-2346. P. Knochel, J. Org. Chem. 1992, 57, 6384-6386. Sb: Y. Butsugan, Tetrahedron Lett. 1987, 28, 3707-3708. Mn: T. Hiyama, Organometallics, 1982, 1, 1249-1251.Zn: T. Shono, Chem. Lett. 1990, 449-452. Ba: H. Yamamoto, J. Am. Chem. Soc. 1991, 113, 8955-8956. a73 Many Other Metals Have Been Employed in the Allylation Reaction ... Allyl and Crotylmetal Species–4: Catalytic SystemsD. A. Evans, D. M. Barnes a73 Three Catalytic Asymmetric Allylations of Aldehydes are Known + BH3-THF BLn* E/Z = 61/39 + PhCHO 20 mol % BLn* H. Yamamoto, Synlett 1991, 561-562. n-C7H15CHO + 81% yield97.4% ee 63% yield90% ee E. Tagliavini, A. Umani-Ronchi J. Am. Chem. Soc. 1993, 115, 7001-7002. G. Keck J. Am. Chem. Soc. 1993, 115, 8467-8468. 20 mol % Ti(OiPr)4, 4? sieves Ti(OiPr)4, 4? sieves CF3COOH or TfOH 1 2 1 or 2 (10 mol %), RCHO R Ph Chex Catalyst 12 12 12 Yield (%) 8898 6695 4278 ee (%) 9592 9492 8977 Chem 206