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 Wednesday, November 13, 2002 a73 Reading Assignment for this Week: Carey & Sundberg: Part A; Chapter 7Carbanions & Other Nucleophilic Carbon Species The Aldol Reaction–1 Carey & Sundberg: Part B; Chapter 2Reactions of Carbon Nucleophiles with Carbonyl Compounds Chemistry 206 Advanced Organic Chemistry Lecture Number 24 The Aldol Reaction–1 a73 Other Useful References a73 Polyketide Biosynthesis a73 Historical Perspective on the Aldol Reaction a73 Aldol Diastereoselectivity a73 Enolate Diastereoface Selectivity a73 Absolute Control in the Aldol Process 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. 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 CCB Library Ager, D. J., I. Prakash, et al. (1997). “Chiral oxazolidinones in asymmetric synthesis.” Aldrichimica Acta 30(1): 3-12 a73 Assigned Reading O Me O MeOEt O MeOH O MeMe Me R OH O OH Me MeMeO O Me OH NMe2H H O HO Me SR O O Me OH SRR O R SR R SR O Me O R O Me O Me OH SR H H NMe2OH Me O MeO Me O Me OH O O OHHOMe Me Me OH Me O OEt Me O Me OH Me O MeOEt O MeOH OH MeMe MeHO OH HHMe Me Me OH OH Me O OEt Me O Me OHMe OH OH Me OH Me O Me Me OH Me OH Me O O Me OH Me OH MeMe O Me OH Me OH OHMe OOHOHOOHOH OH O SR Me HO O C OSRH Me O O – C OO CMeH C SR O – C ORSMe R SR OH Me O SR OH Me OH Me O R O Me O SRR "Nature, it seems, is an organic chemist having some predilection for the aldol and related condensations." J. W. Cornforth D. A. Evans The Aldol Reaction: Polypropionate Biosynthesis Chem 206 Erythromycin Seco Acid Retro-biosynthesis Erythromycin A, R = OHErythromycin B, R = H The overall acylation is stereospecific The Acylation Event The stepwise Option Decarboxylation-Acylation could either be stepwise (Option A) or concerted (Option B). Erythromycin Seco Acid a54a54a54a54 a54– CO2 ReductionAcylation Polypropionate Biosynthesis: The Elementary Steps Reduction The 7 Propionate Subunits Acylation – CO2 Recent overview: Staunton, Angew. Chem. Int. Edit. 1991, 30, 1302-1306 See Lecture 23; page 23-08 for first laboratory example "That Outpost of Empire, Australia Produces some Curious Mammalia The Kangaroo Rat The Blood-sucking Bat and Aurthur J. Birch, inter alia." erythronolide aglycon NO Me O O Me O Bn N O Me OO Me O Bn O HO Me SR O O Me OH SRR O R SR OR Me O MeOEt O MeOH OR MeMe Me H OH R SR O Me O R O Me O Me OH SR Me OH OH Me OH Me O Me Me HO OH Me OH Me O O Me OH Me OH MeMe O Me OH Me OH OH Me R SR OH Me O SR OH Me OH Me O R Sn(OTf)2 HO2C OMe Me O Me Me OH Me OH Me OMe O Me Me MeMe OMe Me OMe Me O OHO2C O Me OMeMe Me OMe Me OHMe O O Me Me O O OMeMe Me OMe Me Me OH HHH OH O Me Me O Me O OMe Me Me O Me OMe OHO2C O Me OMeMe Me OMe Me OHMe H XC O Me O MeHR O OO Me OMe R–CHO TiCl4 N O MeO O Bn OH Me R O O Me Me OOBn O N O Me O D. A. Evans Polypropionate Biosynthesis: A Laboratory Simulation Chem 206 a54a54a54a54 a54– CO2 ReductionAcylation Polypropionate Biosynthesis: The Elementary Steps Acylation – CO2 Erythrolide B The 7 Propionate Subunits Polypropionate & Polyacetate Biosynthesis: Develop a Laboratory Simulation ? The Laboratory Mimic: Aldol(–) Cane, Celmer, Westley JACS 1983, 105, 3594 Reduction Latter Stages of Lonomycin Biosynthesis 95:5 (85% yield) EtN(iPr)2 93:7 (86% yield) EtN(iPr)2 with Ratz, Huff, & Sheppard, JACS 1995, 117, 3448 See Lecture 23; page 23-08: with M. Ennis JACS 1984, 106, 1154. Dipropionyl Synthon Rough correlation between enolate stucture & product stereochemistry for alkali and alkaline earth enolatesDuBois 1965-67: Stereocontrol optimal for "large" X; the reaction is not general. OMgBr OMgBr Ph O MgBrOH Ph OMgX Ph H H Ph OMgX H O Ph MgBr O O Me X M O M X Me R2CHO Ph OH O O OH Ph Ph OH OH Ph Ph OH O MeX O M O M i-PrMgBr PhCHO H3O+ R2CHO H R O O RH CH Me X H M L L O O R2 OC O MH L L R2 X Me H O X Me R OH OH R Me X O Me O X OH R2 R2 OH X O Me OH R Me X O O X Me R OH Mukaiyama in Organic Reactions, 1982; Vol 28, pp 203-331 Chem 206The Aldol Reaction: Early ContributionsD. A. Evans General Reviews of the Aldol Literature: Evans in Topics in Stereochemistry, 1982; Vol 13, pp 1-115 Heathcock in Asymmetric Synthesis, 1984; Vol 3, pp 111-212 Comprehensive Organic Synthesis, 1991; Vol 2 Group I & II metal enolates: Heathcock; Chapter 1.6, pp 181 Group III metal enolates: Masamune; Chapter 1.7, pp 239 Transition metal enolates: Paterson; Chapter 1.9, pp 301 (Z) Enolate (E) Enolate anti diastereomers Control relative stereochemical relationships syn diastereomers Zimmerman 1957: Proposed chair-like geometry for the Ivanov Reaction ratio, 75:25 ? ? Zimmerman recognized that diastereoselection should be a function of the relative sizes of the substituents on the carbonyl component. He also speculated on the role that the metal center might play in controlling the process. The only flaw in the study was that he failed to determine whether the aldoladducts were stable to the reaction conditions. Zimmerman, J. Am. Chem. Soc 1956, 79, 1920 anti diastereomer favored ? syn diastereomer ? Zimmerman-Traxler Model for (Z) Enolates syn:anti X = C6H5 X = CMe3 48 : 52M = Li M = Li > 98 : 2 > 95 : 5M = MgBr 80 : 20M = Li M = AlEt2 50 : 50 Heathcock 1977 DuBois 1972 House 1971 Ph O Me Ph OH OH Ph Me O Ph El X Me O PhCHO PhCHO OH R Me X O O X Me R OH OBChx2 Ph Me MePh OB-9-BBN O X Me R OH OH R Me X O MO MeH X 9-BBN-Cl Et3N Et2O H R O O Ph Me O MeX El O MeX M O M X Me B–CM–C R2 OH X O Me Me O X OH R2 B–OM–O OC O BH L L R2 X Me H CH Me X H B L L O O R2 O M O M (t)BuS Me R2CHO R2CHO MeX O BL2 Chem 206The Aldol Reaction: Boron EnolatesD. A. Evans Evans et al. JACS 1979, 101, 6120-6123; JACS 1981, 103, 3099-3111 anti diastereomer favored ? syn diastereomer? Why Boron? syn:anti X = C6H5 X = CMe3 48 : 52M = Li M = Li > 98 : 2 > 95 : 5M = MgBr 80 : 20M = Li M = AlEt2 50 : 50 Heathcock 1977 DuBois 1972 House 1971 disfavored DuBois 1972M = BBu2 > 97 : 3 M = BBu2 > 97 : 3 > 97 : 3M = BBu2 M = Li 80 : 20X = Et Yamamoto 1977 M = BBu2 33 : 67 (ether) 17 : 83 (pentane)M = BBu2 M = BCy(thex) 6 : 94 (CH2Cl2) <5 : 95 (pentane)M = B(Cyp)2 1.9-2.2 ? 1.4-1.5 ? 1.5-1.6 ?2.0-2.2 ?To tighten up the transition state.Design TS where control can come exclusively from metal center Masamune, Tet. Lett 1979, 1665, 2225, 2229, 3937 Are (E) enolates intrinsically less diastereoselective? Now that there are good methods for preparing (E) enolates,it appears that both enolate geometries are nearly equivalent.Dialkylboron chlorides (Brown)JACS. 1989, 111, 3441-3442. J. Org. Chem. 1992, 57, 499-504. J. Org. Chem. 1992, 57, 2716-2721. J. Org. Chem. 1992, 57, 3767-3772. J. Org. Chem. 1993, 58, 147-153. Chx2BCl JACS. 1989, 111, 3441-3442. ~99% (E) 95% anti ~99% (Z) 98% syn DIPEA Et2O It appears that there is not a great difference in aldol diastereoselectivity Dissection of the Aldol Problem: Selection of one enantioface antidiastereomers syn diastereomers Relevant stereochemical information could be included in either X or M Control attack on the two enolate enantiofaces El(+) El(+) Evans, Masamune, 1979-81 Evans/masamune, 1979-81 O B O R N O R Me O L L B LL O Me RO N O R O O NO Me O R R O N MeO O Li Br-CH 2R R MeR NO O O O B O O R N O X R R R H Me2CHCHO O N Me OR O BL2 O BL2O R MeNOO O N R O R Me OH H ROB RR N O Me O R O O B OO NO Me R R R R H R O N MeO O B R R O N O O R Me R OH O B O O R N O Me R R R H OH Me RN O R O O O BO R NO R Me O L L RCHO Bu2B-OTf Et3N R N O H O Me H R O B L L O H O BO L L H R H Me N O O H R O O N R O R X OH OH X RN OO O R disfavored product diastereomer: The destabilizing interaction? disfavored favored Model for Asymmetric Induction (unpublished) ??G? (273 K) ~ 2.6 kcal mol -1 How can we rationalize these data ? The Alpha substituent, X, plays pivotal role in aldol diastereoselection + Substituent Ratio > 300 : 1 60 : 1 1 : 1 X = Me X = SMe X = H Result discovered but not predicted diastereoselection > 98% The aldol reaction selects for the opposite enolate diastereoface LDA Face selectivity predicated on chelate organization RCHO Chelate organization precluded, therefore face selectivity uncertain Imide Enolates: The problem of enolate face selectivity J. Am. Chem. Soc 1981, 103, 212-2129 D. A. Evans The Aldol Reaction: Boron Imide Enolates Chem 206 O N O O Bn R El O Bn N O OMe Me MeO N O Me O O Bn O N O OBn OMe O O NH NH2 OBocHN O N3 Bn O O LiO2H LiOH LiOOH LiOOH OR' O R El El R O N Bn O–C(O)OR'H N O OPhH2C O BnMe Me O Me O OHMeO HN O O Bn N3 O BocHN O NH2 NH O O OMe OBnO OH LiOH LiOOH HN O O Bn RCOSR R Bn O N O Me OOH N H H H H H OTBS Et Me O O OTIPS OTES O O O Bn O O OMe N3 O OCMe3 N O Bn O RCHO Me3Al Me(OMe)NHMe NMe O O O Me Ph OMeMeO LiSEt Ti(OBn)4 OH N O Me OMe Me R X H H H H H OTBS Et Me O O OTIPS OTES O Bn-SLi O O OMe N3 O OCMe3 OBn MeO OMeO Me SBn R Me O R OP Et3SiH HOH/THF M. Bilodeau, unpublished results complete hydroytic selectivity possible for recent examples see, J. Am. Chem. Soc 1992, 114, 9434-9453 R–metal O-Protect THF, 0 °C 90-94% Damon, Tet. Lett. 1990, 31, 2849-2852 Trans-thioesterification: Trans-esterification (OF-4949 Synthesis) JACS 1989, 111, 1063 Transamination to Weinreb Amides (see Handout 23A) (OF-4949 Synthesis) JACS1989, 111, 1063 90-93% yield 89% yield Fukuyama, J. Am. Chem. Soc 1990, 112, 7050-7051 X = H X = SEt (Lepicidin Synthesis) J. Am. Chem. Soc 1993, 115, 4497-4513 97% THF, 25 °C 96% *5% Pd/CaCO3/PbO Substrate Reagent Exo:EndoRatio 06 : 89 96 : 04 0 : 100 76 : 16 Exo:EndoRatioReagentSubstrate Product distribution a function of attacking nucleophile (Tet. Lett. 1987, 28, 6141) pKa 20 Imides may suffer attack at either of the two C=O functions (eq 1, eq 2) endocyclic * * (2) (1)R'O – * exocyclic R'O– Imide Hydrolysis D. A. Evans The Aldol Reaction: Imide Transformations Chem 206 RMH RL C H R H Me O OM L L O M O C H Me H R RMH RL L L ? ? O M RL RM Me O Me RM RL M O Me RM RL M R-CHO Me OH RR L RM O RL R RM Me OHO O OH MeRM RRL MeR1 O Me TBSO TBSO O Me R3NRCHO n-Bu2BOTf tBuMe2Si Me O Me Me O tBuMe2Si R Me OH TBSO Me O MeMe Me Me Me Me O Me TBSO TBSO O Me OH Me Me Me O TBSO Me2CHCHO TiCl4EtNiPr 2 TiCl4EtNiPr 2 Me2CHCHO RCHO RCHO Me2CHCHO TiCl4EtNiPr 2 R OH Me R O TBSO TBSO Me O R1 R Me OH Ph Et BnOCH2CH2 Me2CH OH Me O Me TBSO Me Me Me Me Me Me Me Me TBSO Me O Me OH Diastereoselection: 95:5 (80-90%)Evans, JACS 1991, 113, 1047. This system does not give a completely clean (Z) enolate 63:37 - 84:16 83:17 - 85:15 72:28 91:9 - 94:6 Bu 9-BBN (-)-Ipc (+)-IpcPaterson, McClure, Tet.Lett. 1987, 28, 1229. L2BOTf iPr2NEt Enders ACIEE 1988, 27, 581. Diastereoselection = 96-98% Bu2BOTf, iPr2NEt Examples: General Reaction for Syn Aldols: M = B, Ti D. A. Evans The Aldol Reaction: Syn Aldol Rxns of Chiral Ethyl Ketones Chem 206 L DiastereoselectionEvans, JACS 1991, 113, 1047. RCHO disfavored favored RCHO The Transition States: Evans, JACS 1991, 113, 1047. Diastereoselection: 99:1 (81%) Masamune, JACS 1981, 103, 1566. 97:3 98:2 96:4 >99:<1 TBS = SiMe2tBu Diastereoselection M = B, Ti H RL R M C H R Me H O OM L L O M O C H H Me R RLRM H L L ? ? O M RL RM Me O MeRM RL M O M RL RM Me R-CHO R-CHO O RM R L R OH Me Me OH RR L RM O O OH MeRM RRL Me Me O Me TBSO Me Me Me O Me TBSO Me NO Me O O O MeBn RL R RM Me OHOO MeRM RL M CC CHRL Me Me HO M OH RRL O MeMe Me Me O RL R OH RL O MeMe BnO O MeMe Bn Me OOO Me NO RCHO RCHO RCHO BnO O MeMe R OH Me Me O BnO Me Me O Me TBSO Me Me OH Me Me Me O Me TBSO Me Me OH Me Xq R O O Me Me OH BnO O MeMe R OH Xq R O O Me OH Me D. A. Evans The Aldol Reaction: Anti Aldol Rxns of Chiral Ethyl Ketones Chem 206 General Reaction for Syn Aldols: Examples: 96:4 (75%) 94:6 (90%) Diastereoselectionmajor : Σ others (Chx)2BCl Et3N iPrCHO iPrCHO (Chx)2BCl Et3NGeneral Reaction for Anti Aldols: Evans, JACS 1991, 113, 1047. RCHO disfavored favored RCHO The Transition States: syn-anti diastereomer anti-anti diastereomer favored ? (E) Enolate Facial Bias disfavored ? syn-anti diastereomer D. A. Evans, H. P. Ng, J. S. Clark, D. L. Rieger Tetrahedron, 1992, 48, 2127-2142. (Chx)2BCl Et3N iPrCHO diastereoselection 84:16 However, the preceding precedent does not extend to these systems: I. Patterson, J. M. Goodman, M. Isaka Tetrahedron Lett. 1989, 30, 7121-7124. (Chx)2BClEt 3N diastereoselection 95:5 An analogous case: These enolates do not comply with steric analysis: → electronic effects? Tetrahedron, 1992, 48, 2127-2142. O SCEt3Me TfO–B Me Me O BR*2 Me SCEt3 O SCEt3 BR*2 n-PrCHO i-PrCHOt-BuCHO c-C6H11CHO PhCHO n-PrCHO i-PrCHOt-BuCHO c-C6H11CHO PhCHO RCHO RCHO O SCEt3 Me BR*2 HO R SCEt3 O O SCEt3R HO Me Cl–B Ph Ph Me B Me Me B O H OMe H R S R Me Me O BO Me Me S Me H H R R HO Me R HO Me R SCEt3 O O SCEt3R Me HO R Me HO Reetz Tetrahedron Lett. 1986, 4721 See analogous study by Reetz disfavored Chem 206The Aldol Reaction: Metal-Centered ChiralityD. A. Evans Yield, % 8281 7195 78 ee % (corrected) 87 (91)87 (92) 94 (98)86 (90) 88 (92) + RCHO -78 °C 3 → 10 h ee % (corrected) 93 (98)95 (99) 96 (99.9)93 (98) 96 (99.8) anti/syn 33:130:1 30:132:1 33:1 Yield, % 9185 9582 (71) 3 → 36 h -78 °C+ RCHO (95 % ee) DIPEA Masamune, Sato, Kim, Wollmann J. Am. Chem. Soc. 1986, 108, 8279-8281. 0 °C, 1 h favored Masamune, Sato, Kim, Wollmann J. Org. Chem. 1987, 52, 4831 Analogous Carbonyl Allylation favored + RCHO syn:anti, 96:4 enantioselection: 95-97% Chem 3D MeCH2- Me2CH- (R) (R) Me2CH- (R) Br Me (X) (X) (R) 94 : 6Ph- Yield Ratiosyn:anti 86 % 91 % 68 % 98 : 2 >98 : 2 % ee 97 95 >98 83 91 % ee 82 % 84 % Yield Ph- Br 91 96 % ee 2 : 98 65 % 86 % chex- Ratiosyn:anti Yield Ph- 2 : 98 Me 2 : 98Ph- Yield Ratiosyn:anti chex- 93 % 82 %6 : 94 % ee 94 75 O SCEt3 B Me R R N B N SS O O O OBr CF3 F3C CF3 CF3Ph Ph RCHO O tBuO Me O MePhS R R S RH RH Me BOO PhS Me O B *R2 Me tBuO O B *R2 HO Me R SCEt3 O Me Me O X OtBu O O SPhMe RCHO RCHO RCHO O OtBuR X HO R OH SPh O O Me OH Me R Chem 206The Aldol Reaction: Metal-Centered ChiralityD. A. Evans, D. H. Ripin favored Masamune-Reetz Analogy: a73 Metal-Based Chiral Auxilliary: 1 References: (Corey) JACS. 1989,111, 5494 (Corey) JACS. 1990,112, 4977 (Corey) TL. 1991,32, 2857(Corey) TL. 1993,34, 1737. 1, Triethylamine a73 Enolization: 1, Hunig's Base Either enolate geometry possible with proper choice of base, solvent, and substrate. A mechanistic proposal for enolization control is presented in paper (Corey) JACS. 1989,111, 5494 enolization a73 Chiral Acetate Aldol Reaction JACS 1989,111, 5494. a73 Chiral Anti Aldol Reaction: JACS 1990,112, 4977; TL 1991,32, 2857. a73 Chiral Syn Aldol Reaction JACS 1989,111, 5494. Does this reagent perform in accord with the Masamune-Reetz analogy?Note: The sulfonamide nitrogens are pseudo-tetrahedral enolization enolization PhCH3 / Hexane -78?C CH2Cl2 -78?C Me3SiO O Me Me O tBuMe2SiO O M RL RO Me O Me RO RL M Me2CHCHO TiCl4EtNiPr 2 R-CHO R-CHO OH Me Ph O Me3SiO tBuMe2SiO O Me OH Me Me O RO R L R OH Me Me OH RR L RO O NO Me O O O Bn Me RCHO RCHO RCHO TiCl4i-Pr 2NEt Sn(OTf)2Et 3N O Li O RL O Me Ph HH R O Li O L Me L R RL BnO O MeMe Sn(OTf)2 Et3N RCHO RCHO RCHO PhCHO PhCHO BnO O MeMe R OH Me R OO OH Xq Me Me Xq OHO O R Me OH R Me Me O BnO Me R OO OH Xq Me BnO O MeMe R OH Tetrahedron Lett. 1988, 29, 585-588 Tetrahedron Lett. 1992, 33, 4233-4236 Tetrahedron Lett. 1989, 30, 7121-7124 anti-anti anti-syn syn-syn (+)(IPC)2-OTf i-Pr2NEt (Chx)2BClEt 3N JACS, 1990, 112, 866; Tetrahedron, 1992, 48, 2127-2142. (Chx)2BClEt 3N syn-syn anti-syn anti-anti Complimentary aldol reactions may be obtained by changing metal as well as enolate geometry Thorton, Tet. Let. 1990, 31, 6001 Chelation possible for R = Bn, TMSbut marginal for TBS LDA ? LDA Nonchelate Reaction Diastereoselection: 90:10 Masamune, JACS 1981, 103, 1566 (boron enolate) Diastereoselection: 99:1 Evans, JACS 1991, 113, 1047 (titanium enolate) D. A. Evans The Aldol Reaction: Chelate vs Steric Control Chem 206 Reference Rxn Chelate-OrganizedVariant chiral reagent needed Paterson & co-workers