Proofreading experimentally assigned stereochemistry through Q2MM predictions in Pd-catalyzed allylic aminations

Identifier:  imarina:9242238

Handle: https://hdl.handle.net/20.500.11797/imarina9242238

Authors:  Wahlers, J; Margalef, J; Hansen, E; Bayesteh, A; Helquist, P; Diéguez, M; Pàmies, O; Wiest, O; Norrby, PO

Abstract:
The palladium-catalyzed enantioselective allylic substitution by carbon or nitrogen nucleophiles is a key transformation that is particularly useful for the synthesis of bioactive compounds. Unfortunately, the selection of a suitable ligand/substrate combination often requires significant screening effort. Here, we show that a transition state force field (TSFF) derived by the quantum-guided molecular mechanics (Q2MM) method can be used to rapidly screen ligand/substrate combinations. Testing of this method on 77 literature reactions revealed several cases where the computationally predicted major enantiomer differed from the one reported. Interestingly, experimental follow-up led to a reassignment of the experimentally observed configuration. This result demonstrates the power of mechanistically based methods to predict and, where necessary, correct the stereochemical outcome. © 2021, The Author(s).