D. A. Evans The aldol reaction -1 Chem 206 http:/www.courses.fas.harvardedu/-chem206/ ■ Assigned Reading Stereoselective Aldol Reactions in the Synthesis of Polyketic Products, I. Paterson et al. in Modern Carbonyl Chemistry, pp 249-297, J Chemistry 206 Otera, Ed. Wiley VCH, 2000 CCB Library Ager, D.J., L. Prakash, et al. (1997). "Chiral oxazolidinones in asymmetric Advanced Organic Chemistry synthesis. Aldrichimica Acta 30(1): 3-12 Other Useful References Lecture Number 24 Evans, D.A., J V. Nelson, et al. (1982). "Stereoselective Aldol Condensations The aldol reaction-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: 13 I Polyketide Biosynthesis Historical Perspective on the Aldol Reaction Heathcock, C. H(1991). The Aldol Reaction: Group I and Group lI Enolates Comprehensive Organic Synthesis. B M. Trost and L. Fleming. Oxford Aldol Diastereoselectivity Pergamon Press. 2: 181 nolate Diastereoface Selectivity Kim, B M, S. F Williams, et al. (1991). The Aldol Reaction: Group Ill Enolates Absolute control in the aldol process Comprehensive Organic Synthesis. B M. Trost and L. 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 Car anaes tner nrgc epah ic: capers Cowden, C J. and l. Paterson(1997). " Asymmetric aldol reactions using boron plates. o Carey& Sundberg: Part B: Chapter 2 Nelson, S.G.(1998). Catalyzed enantioselective aldol additions of latent Reactions of Carbon Nucleophiles with Carbonyl Compounds enolate equivalents. Tetrahedron: Asymmet Mahrwald, R.(1999). " Diastereoselection in Lewis-acid-mediated aldol Matthew d. shair Wednesday, additions. Chem. Rev. 99(5): 1095-1120 November 13 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 Wednesday, November 13, 2002 ■ Reading Assignment for this Week: Carey & Sundberg: Part A; Chapter 7 Carbanions & Other Nucleophilic Carbon Species The Aldol Reaction–1 Carey & Sundberg: Part B; Chapter 2 Reactions of Carbon Nucleophiles with Carbonyl Compounds Chemistry 206 Advanced Organic Chemistry Lecture Number 24 The Aldol Reaction–1 ■ Other Useful References ■ Polyketide Biosynthesis ■ Historical Perspective on the Aldol Reaction ■ Aldol Diastereoselectivity ■ Enolate Diastereoface Selectivity ■ 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 ■ Assigned Reading
D. A. Evans The Aldol Reaction: Polypropionate Biosynthesis Chem 206 Nature, it seems, is an organic chemist having some predilection Polypropionate Biosynthesis: The Elementary Steps for the aldol and related cond OH O J W. Conforth Reduction Me That Outpost of Empire, Australia Produces some Curious Mammalia NMe The Kangaroo Rat and Aurthur birch. inter alia OHOH O Acylation Me Erythromycin A, R=OH R Erythromycin, R=H R Retro-biosynthesis OH O Erythromycin Seco Acid The 7 Propionate Subunits Et NMe2 The Acylation Ev Decarboxylation -Acylation could either be stepwise(Option A)or concerted Meo The stepwise Option SR Erythromycin Seco Acid The overall acylation stereospecific Recent overview. Staunton, Angew. Chem. Int. Edit. 1991, 30, 1302-1306 ee Lecture 23: page 23-08 for first laboratory example
O Me O Me Et O O Me OH O Me Me Me R OH O OH Me Me MeO O Me OH NMe2 H H O HO Me SR O O Me OH R SR O R SR R SR O Me O R O Me O Me OH SR H H NMe2 OH Me O MeO Me O Me OH O O HO OH Me Me Me OH Me O Et O Me O Me OH Me O Me Et O O Me OH OH Me Me Me HO OH H H Me Me Me OH OH Me O Et O Me O Me Me OH OH OH Me OH Me O Me Me OH Me OH Me O O Me OH Me OH Me Me O Me OH Me OH OH Me OH OH O OH OH O OH O SR Me HO O C O SR H Me O O – O C O C Me H C SR O – C O RS Me R SR OH Me O SR OH Me OH Me O R O Me O R SR "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 = OH Erythromycin 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 ✻ ✻ ✻ ✻ ✻ – CO2 Acylation Reduction 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
D. A. Evans Polypropionate Biosynthesis: A Laboratory Simulation Chem 206 Polypropionate Polyacetate Biosynthesis Develop a Laboratory Simulation Latter Stages of Lonomycin Biosynthesis OMe Me MeMeMeMeMeMe Me Erythrolide B The 7 Propionate Subunits HO2C Polypropionate Biosynthesis: The Elementary Steps 义人 MeMeMeMe Me Me me Cane. C Acylation 人 Reduction R Sn(oTf)2 EtN(Pr2 The Laboratory Mimic. 95:5(685%yed) Dipropionyl Synthon ee Lecture 23; page 23-08 Me ome with M. Ennis JACS 1984. 106. 1154 937(86%yed with Ratz, Huff, Sheppard, JACS 1995, 117, 3448
O N Me O O Me O Bn N O Me O O Me O Bn O HO Me SR O O Me OH R SR O R SR OR Me O Me Et O O Me OH OR Me Me 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 Me Me 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 Me Me OMe Me OMe Me O O HO2C O Me OMe Me Me OMe Me OH Me O O Me Me O O Me OMe Me OMe Me Me OH H H H OH O Me Me O Me O OMe Me Me O Me OMe O HO2C O Me OMe Me Me OMe Me OH Me H XC O Me O Me R H O O O Me OMe R–CHO TiCl4 N O O Me O Bn OH Me R O O Me Me O O Bn O N O Me O D. A. Evans Polypropionate Biosynthesis: A Laboratory Simulation Chem 206 ✻ ✻ ✻ ✻ ✻ – CO2 Acylation Reduction 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
D A. Evans The Aldol Reaction: Early Contributions Chem 206 General Reviews of the aldol literature DuBois 1965-67: Rough correlation between enolate stucture product stereochemistry for alkali and alkaline earth enolates Mukaiyama in Organic Reactions, 1982; Vol 28, pp 203-331 o OH o OH 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 (E)Enolate anti diastereomers oup i& ll metal enolates: Heath Group Ill metal enolates: Masamune 17,pp239 o OH Transition metal enolates: Paterson: Chapter 1.9, pp 30 Control relative stereochemical relationships (Z) Enolate syn diastereomers Zimmerman 1957: Zimmerman-Traxler Model for(4) Enolates Proposed chair-like geometry for the Ivanov Reaction X OM OMaX 丰 HcHO - MgBr MgBr R2 R2 OH O R2CHO Me H syn: anti anti diastereomer M=Li >98: 2 Heathcock 1977 Zimmerman recognized that diastereoselection should be a function of the X=CE3 1 M=MgBr >95: 5 DuBois 1972 relative sizes of the substituents on the carbonyl component. He also speculated on the role that the metal center might play in controlling The onby flaw in the study was that he failed to determine whether the aldol M=AlEt2 50: 50 House 1971 dducts were stable to the reaction condition Zimmerman J. Am. Chem. Soc 1956, 79, 1920 Stereocontrol optimal for " large"X; the reaction is not general
Rough correlation between enolate stucture & product stereochemistry for alkali and alkaline earth enolates DuBois 1965-67: Stereocontrol optimal for "large" X; the reaction is not general. OMgBr OMgBr Ph O MgBr O H 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 Me X O M O M i-PrMgBr PhCHO H3O + R2CHO H R O O H R C H Me X H M L L O O R2 O C O M H 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 D. A. Evans The Aldol Reaction: Early Contributions Chem 206 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 aldol adducts 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 M = Li 48 : 52 M = Li > 98 : 2 M = MgBr > 95 : 5 M = Li 80 : 20 M = AlEt2 50 : 50 Heathcock 1977 DuBois 1972 House 1971
D. A. Evans The Aldol reaction Boron enolates Chem 206 Why Boron? Are(E)enolates intrinsically less diastereoselective? M-0→B0MC→BC Design TS where control can come 1.9-2.2A 1.4-1.5A 2.0-2.2A 1.5-1.6A Now that there are good methods for preparing(E) enolates Dialkylboron chlorides(Brown) exclusively from metal center it appears that both enolate geometries are nearly equivalent /ACS. 1989, 111, 3441-3442 0 OH R2CHO Acs.1989,11,3441-3442 Jorg.chem.199358,147-153 Me Chx2BCI HcHO favored syn diastereomer 99% 95% anti RaCHO 9-BBN-CI OB-9-BBN anti diastereomer 98% syn X= CMe3 M=U >98: 2 Heathcock 1977 It appears that there is not a great difference in aldol diastereoselectivity DuBois 1972 M=BBu2 >97: 3 DuBois 1972 Dissection of the Aldol problem: Selection of one enantioface X= C6H5 M=Li 80:20 0 Evans. Masamune. 1979-81 X=Et 80:20 =BBu2>97 HR 48:52 House1971 M=BBu2 33: 67(ether) r diastereomers M=BCy(thex) 6: 94(CH 2C12)I Evans/masamune, 1979-81 Control attack on the two enolate enantiofaces E(+) M=B(Cyp)2 <5: 95(pentane 0-+M Evans et al.JAcs1979,101,61206123;JACS1981,103,3099-3111 Masamune,Tet.Lett1979,1665,2225,229,3937 Relevant stereochemical inform E(+) ould be included in either X
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 Me Ph OB-9-BBN O X Me R OH OH R Me X O O M Me H X 9-BBN-Cl Et3N Et2O H R O O Ph Me O Me X El O Me X M O M X Me M–C B–C R2 OH X O Me Me O X OH R2 M–O B–O O C O B H L L R2 X Me H C H Me X H B L L O O R2 O M O M (t)BuS Me R2CHO R2CHO Me X O BL2 D. A. Evans The Aldol Reaction: Boron Enolates Chem 206 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 M = Li 48 : 52 M = Li > 98 : 2 M = MgBr > 95 : 5 M = Li 80 : 20 M = AlEt2 50 : 50 Heathcock 1977 DuBois 1972 House 1971 disfavored M = BBu2 > 97 : 3 DuBois 1972 M = BBu2 > 97 : 3 M = BBu2 > 97 : 3 X = Et M = Li 80 : 20 Yamamoto 1977 M = BBu2 33 : 67 (ether) M = BBu 17 : 83 (pentane) 2 M = BCy(thex) 6 : 94 (CH2Cl2 ) M = B(Cyp)2 <5 : 95 (pentane) 1.9-2.2 Å 1.4-1.5 Å 2.0-2.2 Å 1.5-1.6 Å 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 anti diastereomers 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
D. A. Evans The Aldol reaction Boron Imide enolates Chem 206 The Alpha substituent, X, plays pivotal role in aldol diastereoselection Imide Enolates: The problem of enolate face selectivity OR Me2CHCHO Br-CH2R Bu2B-OTf Et3N How can we rationalize these data X=SMe Model for Asymmetric Induction(unpublished) CHO favored Chelate organization precluded, therefore face selectivity uncertain RCHO The aldol reaction selects for the opposite enolate diastereoface △AG(273K)~26kca H 6 J.Am.Chem.Soc1981,103,212-2129 disfavored product diastereomer: The destabilizing interaction?
O B O R N O R Me O L L B L L O Me O N R O R O O O N Me O R R O N Me O O Li Br-CH2R R Me R O N O O O B O O R N O X R R R H Me2CHCHO O N Me R O O BL2 O BL2 O R Me O N O O N R O R Me OH H O R B R R N O Me O R O O B O O O N Me R R R R H R O N Me O 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 N R O R O O O B O R O N R Me O L L RCHO Bu2B-OTf Et3N R N O H O Me H R O B L L O H O B O L L H R H Me N O O H R O O N R O R X OH OH X N R O O O R disfavored product diastereomer: The destabilizing interaction? disfavored favored Model for Asymmetric Induction (unpublished) DDG ‡ (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
D A. Evans The Aldol reaction Imide Transformations Chem 206 Imide Hydrolysis Trans-esterification OMe Imides may suffer attack at either of the two C=O functions(eq 1, eq 2) OMe N3 TH(OBn4 RO OF-4949 Synthe sis) JACS1989, 111, 1063 Product distribution a function of attacking nucleophile(Tet. Lett. 1987, 28, 6141) Trans-thioesterification. Exo: Endo Substrate ubstrate Reagent Exo: Endo LOH06:89 9094% PhH2C LiOOH 96: 04 Damon, Tet. Lett.1990,31,28492852 OTIPS OTIPS OMe OTES OTES HF 25'C N3 BohN. X=SEt X=H OTBS 5% Pd/CaCO/Pbo (OF-4949 Synthesis)JACS 1989, 111, 1063 1993,115,44974513 RCOSR-RCHO Fukuyama, J Am. Chem. Soc 1990, 112, 7050-7051 Transamination to Weinreb Amides (see Handout 23A) Me Me(oMe)NHMe OMe o-Protect M. Bilodeau, unpublished results complete hydroytic selectivity possibl for recent examples see, J. Am. Chem. Soc 1992, 114, 9434-9453
O N O O Bn R El O Bn N O Me O Me MeO N O Me O O Bn O N O OBn OMe O O NH NH2 O BocHN 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 PhH2C O O Me Bn Me O Me O MeO OH HN O O Bn N3 O BocHN O NH2 NH O O OMe O OBn OH LiOH LiOOH HN O O Bn RCOSR R Bn O N O Me OH O 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 N Me O O O Me Ph MeO OMe 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 OMe O 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:Endo Ratio 06 : 89 96 : 04 0 : 100 76 : 16 Exo:Endo Ratio Reagent Substrate 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
D. A. Evans The Aldol Reaction: Syn Aldol Rxns of Chiral Ethyl Ketones Chem 206 General Reaction for Syn Aldols: M=B, Ti n-Bu2BOTf RCHO M=B Ti R-CH TBSO TBSo Me TBS= SIMe2 Bu The Transition States 973 R Masamune. JACS 1981. 103.15 Me RCHO L\ 982 BnOCH2 CH2 96: 4 Me2CH RL Me L2BOTf Me PT2NEt RCHO Me me Diastereoselection Evans,JAcS1991,113,1047 This system does not give a completely 63:37-84:16 clean(Z) enolate Examples 17-85:15 ()-lpc Bu2BOTf BuMe2Si PInET BuM Paterson, McClure, Tet. Lett. 1987. 28, 1229. (++-lpc 91: 9-94: 6 Enders aclEE 1988 27. 581 Diastereoselection 96-98% TBSo O OH MeMe Me Me? CHCHO TBSQ O TBSo O OH TBS Evans,JAcS1991,113,1047 Diastereoselection: 99: 1(81%) Evans, JACS 1991. 113. 104 Diastereoselection: 95: 5 (80-90%)
RM H RL C H R H Me O O M L L O M O C H Me H R RM H RL L L ‡ ‡ O M RL RM Me O Me RM RL M O Me RM RL M R-CHO Me OH R R L RM O RL R RM Me O OH O OH RM Me R RL Me R 1 O Me TBSO TBSO O Me R3N RCHO n-Bu2BOTf tBuMe2Si Me O Me Me O tBuMe2Si R Me OH TBSO Me O Me Me Me Me Me Me O Me TBSO TBSO O Me OH Me Me Me O TBSO Me2CHCHO TiCl4 EtNiPr2 TiCl4 EtNiPr2 Me2CHCHO RCHO RCHO Me2CHCHO TiCl4 EtNiPr2 R OH Me R O TBSO TBSO Me O R 1 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 Evans, JACS 1991, 113, 1047. Diastereoselection: 95:5 (80-90%) 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 Paterson, McClure, Tet.Lett. 1987, 28, 1229. (+)-Ipc 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 Diastereoselection Evans, 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 = SiMe2 tBu Diastereoselection M = B, Ti
D. A. Evans The Aldol Reaction: Anti Aldol Rxns of Chiral Ethyl Ketones Chem 206 Examples or:∑ others General Reaction R-CHO.R TBS ( Chx)2BCI TBSQ Syn Aldols syn-anti diastereomer General Reaction R-CHO TBS O CI TBSo 0 OH Anti Aldols 964(75%) Me MeMeMe Me The Transition States However, the preceding precedent does not extend to these systems RCHO 00 PrCHO Me me diastereoselection 84: 16 D.A. Evans, H. P Ng, J.S. Clark, D. L. Rieger Tetrahedron, 1992, 48, 2127-2142. disfavored An analogous case o OH Evans,JAcs1991,113,1047 (Chx)2BCl Bno Bno r Bno RCHO (E)Enolate Facial Bias MeMe Me Me Meme RCHO RIS diastereoselection 95: 5 disfavored I Patterson, J M. Goodman. M. Isaka Tetrahedron Lett. 1989. 30. 7121-7124 anti-anti diastereomer RCHO favored syn-anti diastereomer These enolates do not comply with steric analysis: electronic effects? Tetrahedron,1992,48,2127-2142
H RL RM C H R Me H O O M L L O M O C H H Me R RL RM H L L ‡ ‡ O M RL RM Me O RM Me RL M O M RL RM Me R-CHO R-CHO O RM R L R OH Me Me OH R R L RM O O OH RM Me R RL Me Me O Me TBSO Me Me Me O Me TBSO Me O N Me O O O Me Bn RL R RM Me O O OH RM Me RL M C C C H RL Me Me O H M OH R RL O Me Me Me Me O RL R OH RL O Me Me BnO O Me Me Bn Me O O O Me O N RCHO RCHO RCHO BnO O Me Me 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 Me Me 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%) Diastereoselection major : S others (Chx)2BCl Et3N iPrCHO iPrCHO (Chx)2BCl Et3N General 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)2BCl Et3N diastereoselection 95:5 An analogous case: These enolates do not comply with steric analysis: ® electronic effects? Tetrahedron, 1992, 48, 2127-2142
D. A. Evans The Aldol Reaction: Metal-Centered Chirality Chem 206 Masamune. Sato, Kim Wollmann J. Am. Chem. Soc. 1986. 108. 8279-828 disfavored SCEt3 (95%ee) favored DIPEA SETs SCEt30°c,1h ScEt RCHO Yield, antisyn ee%(corrected) n-PrCHO 91 i-PrCHO 85 t-BuCHO 32:1 33:1 Chem 3D RCHO SCEt3 RCHO Yield, ee %(corrected Analogous Carbonyl Allylation n-PrCHO Masamune, Sato, Kim, Wollmann J. Org. Chem. 1987, 52, 4831 t-BuCHO 8753 HcHO favored See analogous study by Reetz Reetz Tetrahedron lett. 1986. 4721 Rcho Me enantioselection: 95-97%
O SCEt3 Me TfO–B Me Me O BR*2 Me SCEt3 O SCEt3 BR*2 n-PrCHO i-PrCHO t-BuCHO c-C6H11CHO PhCHO n-PrCHO i-PrCHO t-BuCHO c-C6H11CHO PhCHO RCHO RCHO O SCEt3 Me BR*2 HO R SCEt3 O O R SCEt3 HO Me Cl–B Ph Ph Me B Me Me B O H Me O H R S R Me Me O B O Me Me S Me H H R R HO Me R HO Me R SCEt3 O O R SCEt3 Me HO R Me HO Reetz Tetrahedron Lett. 1986, 4721 See analogous study by Reetz disfavored D. A. Evans The Aldol Reaction: Metal-Centered Chirality Chem 206 Yield, % 82 81 71 95 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 33:1 30:1 30:1 32:1 33:1 Yield, % 91 85 95 82 (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