D.A. Evans Design of Soft Enolization Systems Chem 206 Strategy Lithium enolates Choose Lewis Acid( LA) which can reversibly associate with amine base(B Roush Masamune Tet. Lett. 1984. 25. 2183-2186 B Horner-Wadsworth-Emmons Reaction This system has the potential to enolize carbonyl functional groups LiCL, 1.2 equiv ∠LA Base, 1.0equiv (Eto)2P B-H CHO. 1 e0 R CH2-H 1.2 equ Mecn pKa 19.2(DMSO), K counterion Base Dbu 5 min. 99%>50: 1 E: Z pKa 12.2(Diglyme), Li counterion Base= diPea, 7h, 97%, >50: 1 E Z Isefullewis Acid airs Complexation -OT =-OSO2 CF3 MgBr2 NEt3 Re NHCbz CHo using DIPEg NHCbz O Li-X Nr3 Reversible Sn(oTi)2+ NR3 Reversible(Et3N, EtNi-Pr2) 24 h. rt R2B-OTf NR3 Reversible(Et3N, EtNi-Pr2) 85%+ 10% recovered aldehyde R2BCI NR3 Reversible(Et3N, EtNi-PT2 Conventional methods of deprotonation (NaH)resulted in epimerization PhBCl2+ NR3 Reversible(Et3N, EtNi-Pr2 (Overman JACS 1978, 5179) TICl4 NR3 Irreversible(Et3N, EtNi-Pr2) i-PrOTiCl3 Nr Reversible(Et3N, EtNi-Pr2 Rathke, Nowak J. Org. Chem. 1985, 50, 2624-2626 i-Pro)2TiCl2 NR3 Reversible(Et3N, EtNi-Pr2 (Et3N, EtNi-Pr2) MgBr2, 1.2 equiv All of the above systems will enolize simple ketones to some extent EtN, 1.1 equiv OEt THF. rt R= i-Pr, 40% yield 100% enolization for B Sn. ti partial enolization for Li, MgChoose Lewis Acid (LA) which can reversibly associate with amine base (B:). This system has the potential to enolize carbonyl functional groups: R CH2–H O LA O LA R CH2 Useful Lewis Acid Pairs All of the above systems will enolize simple ketones to some extent. O + R CH3 LA B B: B: LA B Me N Me B–H O OEt (EtO)2P O O OEt (EtO)2P O NHCbz CHO Me R CH3 O O RS CH3 PhO CH3 O O EtO CH3 R2N CH3 O Me NHCbz OEt O R OEt O OEt O Me Me Lithium Enolates Rathke, Nowak J. Org. Chem. 1985, 50, 2624-2626. MgBr2, 1.2 equiv Et3N, 1.1 equiv 1 equiv R= i-Pr, 40% yield R= n-C6H13, 100% yield Conventional methods of deprotonation (NaH) resulted in epimerization (Overman JACS 1978, 5179). 85% + 10% recovered aldehyde Above conditions using DIPEA 24 h, rt Base = DBU, 5 min, 99%, >50:1 E:Z Base = DIPEA, 7 h, 97%, >50:1 E:Z Horner-Wadsworth-Emmons Reaction. 1.2 equiv LiCl, 1.2 equiv Base, 1.0 equiv i-PrCHO, 1 equiv MeCN rt pKa 19.2 (DMSO), K+ counterion pKa 12.2 (Diglyme), Li+ counterion D.A. Evans Design of Soft Enolization Systems Chem 206 Strategy LA + (–) (+) + LA + + (+) (–) (+) Complexation MgBr2 + NEt3 Reversible Li–X + NR3 Reversible Sn(OTf)2 + NR3 Reversible (Et3N, EtNi-Pr2) -OTf = - OSO2CF3 R2B-OTf + NR3 Reversible (Et3N, EtNi-Pr2) R2BCl + NR3 Reversible (Et3N, EtNi-Pr2 ) PhBCl2 + NR3 Reversible (Et3N, EtNi-Pr2) TiCl4 + NR3 Irreversible (Et3N, EtNi-Pr2 ) i-PrOTiCl3 + NR3 Reversible (Et3N, EtNi-Pr2) (i-PrO)2TiCl2 + NR3 Reversible (Et3N, EtNi-Pr2) (i-PrO)3TiCl + NR3 Reversible (Et3N, EtNi-Pr2) 100% enolization for B, Sn, Ti partial enolization for Li, Mg RCHO, 1 equiv THF, rt Roush & Masamune, Tet. Lett. 1984, 25, 2183-2186