D. A. Evans Double Stereodifferentiating Bond Constructions-1 Chem 206 Double Stereodifferentiating Aldol Bond Constructions Matched reactant pair: Stereo-induction from both partners reinforcing The reference reactions Me Me Stereochemical Control Elements Enolate geometry [aldehyde prod ratio]= 10/1 Product Enolate facial bias Stereochemistry Aldehyde facial bias [enolate prod ratio=10/1 The Issue: Can one reliably take the diastereoselectivites of the individual a The double stereodifferentiating situation: Stereoselectivity? eaction partners and use this information in the illustrated The model reactions. △G(xn) Me OH G The assumption: ( Masamune Heathcock) 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 G+(Rx)~△G+( (enolate)+△G+/RcHo) El AG+(enolate) log[Product ratio]- log [enolate ratio]+ log [aldehyde ratio] Product ratio]-[enolate prod ratio] x [aldehyde prod ratio I Hence, for the case at hand: [Product ratio]-[10]x [10]- 100 Mismatched reactant pair. Stereo-induction from partners nonreinforcing Masamune, Angew. Chem. Int Ed. 1985, 24, 1-76 △AG(Rxn)~△G+( (enolate)-△G+(RcHo)Me O Me Me OM Me Me O H H O Me Me O Me OH Me Me O H Me OM Me Me OM Me H O Me log [Product ratio] ~ log [enolate ratio] + log [aldehyde ratio] Me OH Me O Me Me OM Me Me O H H O Me Me 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 ❊ ❊ ❊ (–) 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: ❊ ❊ DDG ‡ (rxn) ❊ 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: ■ Hence, for the case at hand: [Product ratio] ~ [10] x [10] ~ 100 ■ The assumption: (Masamune, Heathcock) ■ The double stereodifferentiating situation: Stereoselectivity? The reference reactions: [enolate prod ratio] = 10/1 [aldehyde prod ratio] = 10/1 ❊ [Product ratio] ~ [enolate prod ratio] x [aldehyde prod ratio] DDG ‡ (Rxn) ~ DDG ‡ (enolate) + DDG ‡ (RCHO) ❊ DDG ‡ (rxn) Masamune, Angew. Chem. Int. Ed. 1985, 24, 1-76 DDG ‡ (rxn) = ? DDG ‡ (Rxn) ~ DDG ‡ (enolate) – DDG ‡ (RCHO) Matched reactant pair: Stereo-induction from both partners reinforcing DDG ‡ (enolate) DDG ‡ (aldehyde) El (+) Nu (–) Enolate facial bias Aldehyde facial bias Product Stereochemistry Enolate geometry Stereochemical Control Elements ❊ Double Stereodifferentiating Aldol Bond Constructions ❊ D. A. Evans Double Stereodifferentiating Bond Constructions-1 Chem 206