A STEREOCHEMICAL MODEL FOR MERGED 1,2-ASYMMETRIC AND 1,3-ASYMMETRIC INDUCTION IN DIASTEREOSELECTIVE MUKAIYAMA ALDOL ADDITION-REACTIONS AND RELATED PROCESSES

A systematic investigation of the direction and degree of stereoselect ivity in aldol addition reactions is presented involving achiral unsub stituted metal enolate and enolsilane nucleophiles and chiral aldehyde s. The BF3 . OEt(2) mediated Mukaiyama aldol reaction with alpha-unsub stituted, beta-alkoxy aldehydes afforded good levels of 1,3-anti induc tion in the absence of internal aldehyde chelation, The level of 1,3-i nduction was found to be primarily dependent on the electrostatic natu re of the aldehyde beta-substituent. A revised model for 1,3-asymmetri c 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 beta-substituents. A full confor mational analysis, corroborated by semiempirical (AM1) calculations, i s presented to support the proposed model. The merged impact of alpha and beta aldehyde substituents was also systematically investigated, a nd an integrated 1,2- and 1,3-asymmetric induction model is proposed t hat incorporates the salient features of the Felkin-Anh and revised 1, 3-model. In accordance with this integrated model, uniformly high leve ls of Felkin, 1,3-anti diastereofacial selectivity are observed in Muk aiyama aldol reactions with anti substituted alpha-methyl-beta-alkoxy aldehydes, which contain stereocontrol elements that are in a stereore inforcing relationship. In contrast, variable levels of aldehyde facia l induction were observed in the corresponding reactions with syn subs tituted aldehyde substrates, which contain stereocontrol elements in a non-reinforcing relationship. The direction of aldehyde facial induct ion in Mukaiyama aldol additions to the syn substituted aldehydes was found to be primarily dependent on the size of the enolsilane, with th e first known examples of anti-Felkin selective Mukaiyama aldol reacti ons observed under conditions known to preclude chelation for the addi tion of the enolsilane of acetone. We conclude that dominant 1,2-stere oinduction will be found in those reactions proceeding with the reacta nts in an antiperiplanar relationship, favored by sterically encumbere d enolsilane substituents, while dominant 1,3-stereoinduction will be manifest from a synclinal transition state, preferred for less bulky e nolsilane substituents. By inspection, the synclincal transition state may be destabilized by an increase in the steric bulk of the Lewis ac id, and in accordance with this prediction the trityl perchlorate medi ated enolsilane addition resulted in a dramatic reversal of facial sel ectivity relative to the BF3 . OEt(2) mediated reaction. These trends were also documented in the mechanistically related addition of allyls tannanes to anti and syn disubstituted chiral aldehydes.