Computational study of the syn,anti-selective aldol additions of lithiated bis-lactim ether to 1,3-dioxolane-4-carboxaldehydes

Abstract Ab initio (RHF/6-31G*) and two-layer hybrid ab initio:semi-empirical (ONIOM) calculations were carried out to investigate the syn , anti -selective aldol additions of lithiated Schollkopf′s bis-lactim ether to 1,3-dioxolane-4-carboxaldehydes. Initial lithium–carbonyl coordination to form a disolvated complex with 4.6–8.4 kcal/mol exothermicity is followed by the rate-determining reorganization to the aldolate products through six-membered chair-like transition structures. The experimental stereoselectivities of the aldol additions have been adequately reproduced. According to the calculations, the most stable transition structures are characterized by a non-Anh conformation of the aldehyde moiety. In addition, the β-methyl substituent of the aldehyde, trans to the carbonyl group, is found to increase the energy barrier of the competitive pathways, thus reinforcing the syn , anti -stereoselection of the aldol process.

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