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Asymmetric Induction in C‑Alkylation of Tropane-Derived Enamines: Congruence Between Computation and Experiment

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posted on 27.09.2017 by Yifei Li, Kelvin E. Jackson, Andrew Charlton, Ben Le Neve-Foster, Asma Khurshid, Heinrich-K. A. Rudy, Amber L. Thompson, Robert S. Paton, David. M. Hodgson
Quantum chemical studies of C-ethylation of 1-methyl- and 1,4,4-trimethyl-tropane-derived enamines predict good (89:11 er, B3LYP) and high (98:2 er, B3LYP) levels, respectively, of asymmetric induction in the resulting α-alkylated aldehydes. The nonracemic tropanes were synthesized using Mannich cyclization strategies (Robinson-Schöpf and by way of a Davis-type N-sulfinyl amino bisketal, respectively), and ethylation of the derived enamines was found to support the predicted sense and magnitude of asymmetric induction (81:19 er and 95:5 er, respectively). A comparison of several computational methods highlights the robustness of predicted trends in enantioselectivity, enabling theory to guide synthesis.