A Stereochemical Model for Merged 1,2- and 1,3-Asymmetric Induction in Diastereoselective Mukaiyama Aldol Addition Reactions and Related Processes

Abstract

A systematic investigation of the direction and degree of stereoselectivity in aldol addition reactions is presented involving achiral unsubstituted metal enolate and enolsilane nucleophiles and chiral aldehydes. The BF3·OEt2 mediated Mukaiyama aldol reaction with α-unsubstituted, β-alkoxy aldehydes afforded good levels of 1,3-anti induction in the absence of internal aldehyde chelation. The level of 1,3-induction was found to be primarily dependent on the electrostatic nature of the aldehyde β-substituent. A revised model for 1,3-asymmetric induction is presented to account for these results based primarily on minimization of internal electrostatic and steric repulsion between the aldehyde carbonyl moiety and the β-substituents. A full conformational analysis, corroborated by semiempirical (AM1) calculations, is presented to support the proposed model. The merged impact of α and β aldehyde substituents was also systematically investigated, and an integrated 1,2- and 1,3-asymmetric induction model is proposed that incorporates the salient features of the Felkin−Anh and revised 1,3-model. In accordance with this integrated model, uniformly high levels of Felkin, 1,3-anti diastereofacial selectivity are observed in Mukaiyama aldol reactions with anti substituted α-methyl-β-alkoxy aldehydes, which contain stereocontrol elements that are in a stereoreinforcing relationship. In contrast, variable levels of aldehyde facial induction were observed in the corresponding reactions with syn substituted aldehyde substrates, which contain stereocontrol elements in a non-reinforcing relationship. The direction of aldehyde facial induction in Mukaiyama aldol additions to the syn substituted aldehydes was found to be primarily dependent on the size of the enolsilane, with the first known examples of anti-Felkin selective Mukaiyama aldol reactions observed under conditions known to preclude chelation for the addition of the enolsilane of acetone. We conclude that dominant 1,2-stereoinduction will be found in those reactions proceeding with the reactants in an antiperiplanar relationship, favored by sterically encumbered enolsilane substituents, while dominant 1,3-stereoinduction will be manifest from a synclinal transition state, preferred for less bulky enolsilane substituents. By inspection, the synclinal transition state may be destabilized by an increase in the steric bulk of the Lewis acid, and in accordance with this prediction the trityl perchlorate mediated enolsilane addition resulted in a dramatic reversal of facial selectivity relative to the BF3·OEt2 mediated reaction. These trends were also documented in the mechanistically related addition of allylstannanes to anti and syn disubstituted chiral aldehydes.