2,5-Disubstituted Pyrrolidines as Chiral Auxiliaries in Radical Reactions: A Theoretical Approach

• Published in: European Journal of Organic Chemistry Vol. 2010; no. 25; pp. 4841 - 4850
• Main Authors: Georgieva, Miglena K., Duarte, Filipe J. S., Bakalova, Snezhana M., Santos, A. Gil
• Format: Book Review Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01-09-2010; WILEY‐VCH Verlag; Wiley-VCH
• Subjects: Ab initio calculations; Chemistry; Chiral auxiliaries; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Lewis acid catalysis; Organic chemistry; Preparations and properties; Radical reactions; Transition states; Molecular structure; Nitrogen heterocycle; Ab initio method; Molecular interaction; Chiral compound; Selectivity; Lewis acid catalysis; Free radical reaction; Pyrrolidine derivatives; Transition states; Ester; Chiral auxiliary; Alkene; Radical reactions; Steric effect; Ab initio calculations; Chiral auxiliaries; Acrylic acid derivatives; Lewis acid; Prediction; Theoretical study; Acid catalysis; Diastereoselectivity; Transition state; Density functional method; Carboxamide; Conjugated compound; Ethylenic compound
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.201000479

The radical addition to amides derived from chiral 2,5‐disubstituted pyrrolidines has been theoretically studied by the use of density functional methods and the results compared with known experimental data. The results agree quite well with those obtained experimentally and allow the full rationalization of the factors influencing the diastereoselectivity. Steric effects are the main factors determining the selectivity, but electronic interactions can also be very important when the attacking alkene is α,β‐conjugated, as in acrylic esters or acrylamides. Additions at the α‐ and β‐positions of the amide chain in the auxiliary are subject to different rules, with the former usually yielding high diastereoselectivities both experimentally and theoretically, whereas the latter is theoretically predicted to occur with low selectivity. We fully rationalize these two opposite behaviours and suggest several ways to circumvent this limitation, thus strongly increasing the interest of this type of structure as chiral auxiliaries in radical reactions.
Radical additions to amides with stereocontrol by C2‐symmetric chiral auxiliaries have been studied by theoretical methods, and the factors that affect the selectivity of the additions at the α and β‐positions have been clarified. Rationalized structural modifications as well as the use of achiral Lewis acids are proposed to maximize the selectivity of addition.