The Selective Aldol Reaction O O OH O R3 1 2 1 R R X R X R2 R4 4 R3 R Alan B. Northrup MacMillan Group Meeting September 18, 2002 A Brief Recent General Review: Palomo, C.; Oiarbide, M.; García, J. M. "The Aldol Addition Reaction: An Old Transformation at Constant Rebirth" Chem. Eur. J. 2002, 8, 36. Review Focusing on Enzymatic and other Catalytic Aldols: Machajewski, T. D.; Wong, C.- H. "The Catalytic Asymmetric Aldol Reaction" Angew. Chem. Int. Ed. 2000, 39, 1352. Classic Reviews Evans, D. A.; Nelson, J. V.; Taber, T. R. "Stereoselective Aldol Condensations," in Topics in Stereochemistry, New York, 1982; Vol. 13, p. 2. Mukaiyama, T. "The Directed Aldol Reaction," in Organic Reactions, New York, 1982; Vol. 28, p 203. Heathcock, C. H. Asymmetric Synthesis; Morrion, J. D., Ed.; Academic Press: New York, 1984; Vol. 3, part B, p 111. Aldol Reaction Time-Line OTMS O OH OTMS O OH O OH O H 20 mol% cat 2 NaOH TiCl4 Ph Me H rt EtS RCHO EtS R Me H PhCHO 50% yield Me Me 82%, 3:1 syn:anti ! 93:7 dr Aldol Reaction ! 91% ee Discovered Independently Mukaiyama Publishes Mukaiyama Describes By Charles Adolphe Wurtz in Germany "New Aldol Type Reaction" A Catalytic, Enantioselective and Aleksandr Borodin in Russia in Chem. Lett. Aldol Reaction 1957 1981 1997 1864 1973 1990 Zimmerman Proposed Evans Oxazolidone Shibasaki Claims Closed Chair-Like TS Chiral Auxiliary Aldol the First non-Enzymatic Led to Zimmerman-Traxler Models Described Enantioselective X Catalytic Direct Aldol H OBR2 M OH O O N O R X O LLB O OH R R' O R' O Ph Me RCHO Ph R (Z)-Enolate syn - Aldol X PhCHO up to 94% ee H OH O M O R' O R X O OH R R' N Ph (E)-Enolate anti - Aldol O Me O 88%, > 500 : 1 1 Racemic Aldol Technology OTMS O OH OTMS O OH O OH O H 20 mol% cat 2 NaOH TiCl4 Ph Me H rt EtS RCHO EtS R Me H PhCHO 50% yield Me Me 82%, 3:1 syn:anti ! 93:7 dr Aldol Reaction ! 91% ee Discovered Independently Mukaiyama Publishes Mukaiyama Describes By Charles Adolphe Wurtz in Germany "New Aldol Type Reaction" A Catalytic, Enantioselective and Aleksandr Borodin in Russia in Chem. Lett. Aldol Reaction 1957 1981 1997 1864 1973 1990 Zimmerman Proposed Evans Oxazolidone Kobayashi Claims Closed Chair-Like TS Chiral Auxiliary Aldol the First non-Enzymatic Led to Zimmerman-Traxler Models Described Enantioselective X Catalytic Direct Aldol H OBR2 M OH O O N O R X O LLB O OH R R' O R' O Ph Me RCHO Ph R (Z)-Enolate syn - Aldol X PhCHO up to 94% ee H OH O M O R' O R X O OH R R' N Ph (E)-Enolate anti - Aldol O Me O 88%, > 500 : 1 Enolate Geometry Correlates with Product Diastereoselectivity Under Kinetic Control ! The anti - Aldol Stereochemistry is Thermodynamically Favored: OLi OH O OH O PhCHO Subsequent cross-over experiments implicate aldol-retro-aldol equilibration Ph Ph OH OLi 25 ºC, 3d Ph OH rather than epimerization Ph Ph 8% 92% Mulzer, et al. Tet. Lett., 1977, 4651. ! Zimmerman Proposed a Chair Transition State for Kinetic Selectivity of the Ivanov Reaction: OMgBr OMgBr OMgBr PhCHO H H OH O Ph MgBr MgBr O O OMgBr - 78 ºC Ph O O Ph OH Ph Ph Ph Ph diequatorial favored 3:1 anti:syn should lead to anti-aldol Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920. ! Model Holds for a Variety of Enolates Both E and Z X OH O H OM M OH O PhCHO O Me X R' X O R X R Me R' R' M X Z:E anti:syn (Z)-Enolate syn - Aldol X Li i-Pr >98:2 90:10 H OH O Li Mesityl 5:95 8:92 M O B >97:3 R' i-Pr >99:1 O R X B St-Bu 5:95 5:95 R R' Mg t-Bu >99:1 >97:3 (E)-Enolate anti - Aldol 2 Selective Enolization Can Be Achieved ! Kinteic vs. Thermodynamic Acidity: OLi OLi O OLi OLi Me Me LDA Me Ph3CLi Me Me – 78 ºC ! 99% 1% 10% 90% For other examples, see Evans 206 Kinetic Acidity ! Structure of Carbonyl Compound Can Influence Ratio of Enolates Formed under Kinetic Control: These result can be rationalized with the Ireland model: OLi O LDA OLi R Me Me O R THF R R H Me Li (E) Me R H (E)-enolate (Z)-enolate O N R R Me O R E : Z R Me H Li (Z) OR, SR 95 : 5 R N H Et 77: 23 R t-Bu 0 : 100 NR2 0 : 100 Ireland et al. J. Am. Chem. Soc., 1976, 98, 2868 Ireland, J. Org. Chem. 1991, 56, 650 ! Solvent Can Impact Enolate Ratios: R Solvent E : Z OMe THF 95 : 5 Difference due to Enolate Equilibration OMe THF/HMPA 16 : 84 The Mukaiyama Aldol Reaction ! Mukaiyama's Report of a New Aldol-Type Process: O OTMS O OH H • Broad Range of Ketone Nucleophiles 1.02 eq TiCl • Range of Aldehyde + Ketone Electrophiles LDA, TMSCl 4 Ph • 50-93% yield 1.0 eq PhCHO • 1:1 to 3:1 syn:anti – 78 ºC, CH Cl • Open Transition State 1.0 eq 2 2 • Use of SKA or thio-SKA can increase the dr aq. TsOH workup Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011 Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974, 96, 7503 ! Reaction is syn-Selective Regardless of Enolsilane Geometry OTMS O OH OTMS O OH TiCl4 TiCl4 Me PhCHO PhCHO EtO – 78 ºC EtO Ph EtO – 78 ºC EtO Ph Me Me Me 3:1 syn:anti 2:1 syn:anti ! Attractive Prospects for Catalysis...More on this Later R3Si O OMLn silyl transfer O OSiR3 R + ML n X catalyst turnover R n ML X A OSiR3 O Path R X H ML n R Si LnM Path 3 O OSiR OMLn O 3 B R R X H X metal readily transmetalation dissociates from product 3 Chiral Auxiliary Technology OTMS O OH OTMS O OH O OH O H 20 mol% cat 2 NaOH TiCl4 Ph Me H rt EtS RCHO EtS R Me H PhCHO 50% yield Me Me 82%, 3:1 syn:anti ! 93:7 dr Aldol Reaction ! 91% ee Discovered Independently Mukaiyama Publishes Mukaiyama Describes By Charles Adolphe Wurtz in Germany "New Aldol Type Reaction" A Catalytic, Enantioselective and Aleksandr Borodin in Russia in Chem. Lett. Aldol Reaction 1957 1981 1997 1864 1973 1990 Zimmerman Proposed Evans Oxazolidone Kobayashi Claims Closed Chair-Like TS Chiral Auxiliary Aldol the First non-Enzymatic Led to Zimmerman-Traxler Models Described Enantioselective X Catalytic Direct Aldol H OBR2 M OH O O N O R X O LLB O OH R R' O R' O Ph Me RCHO Ph R (Z)-Enolate syn - Aldol X PhCHO up to 94% ee H OH O M O R' O R X O OH R R' N Ph (E)-Enolate anti - Aldol O Me O 88%, > 500 : 1 The Evans Aldol Reaction ! Chelate Organization Allowed for Highly Diastereoselective Alkylations of Imide Enolates Li O O O O O O LDA R'–Br Me Me R' O N O N O N R'–Br must be Re-face reactive, R' " i-Pr Me R R R ! 99 : 1 dr all cases Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982, 104, 1737 ! Chelate Organization Precluded in Aldol Process Bu Bu H O O OH B O O O R Re-face O N R Me O N Me Bu Bu B R O O R RCHO free rotation Me O N Bu Bu H R R O OH B R O O R Si-face N R Me N O Me O O O ! Will this Reaction be Selective Given Lack of Chelate Control? 4 The Evans Aldol Reaction ! Surprisingly, This Reaction is Highly Enolate Face-Selective: Bu Bu Bu Bu B B O O i-Pr O OH O O Me O OH RCHO RCHO Me Me Ph O N N R O N N R O Me O Me i-Pr O Ph Me O Evans, D. A.; Bartroli, J.; Shih, T. L. ! Reaction is Highly Diastereoselective in all propionate cases (141 : 1 to > 500 : 1) J. Am. Chem. Soc. 1981, 103, 2127 ! Reaction is Tolerant of a Broad Range of Aldehydes; R = Alkyl, Aryl, hindered, unhindered ! Acetyl-done provides poor selectivity—1 : 1 for the two diastereomers; Acetate aldol product via desulfurization ! One of the most reliable and predictable reactions in organic synthesis; industrially useful ! Possible Model for Asymmetric Induction: O BR2 O O OH O O H O R Si-face i-Pr N disfavored Me B O N R O N R O R dipole maximized O Me i-Pr i-Pr Me O O i-Pr BR2 N R i-Pr O OH i-Pr O Re-face H B favored Me O N R N R dipole minimized O O O R Me Me O O ! Model does not account for the impact of the acyl-done !-substituent on diastereoselectivity. Perhaps a boat TS should be considered for smaller acyl donors as a competitive pathway Heathcock's Modification to the Evans Aldol ! Chelated S-imides give Re-face attack and Non-Chelated Imides give Si-Face Attack Li Bu Bu H O O O O B R'–Br R O OH Me R' R O O R' O N O N Si-face Re-face Me N R' Me N O Me R R O ! 99 : 1 dr all cases O O "Evans" syn ! Based on that Observation, Heathcock Developed a "non-Evans" syn or anti Aldol: J.