These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
A Bifunctional Iminophosphorane Squaramide Catalyzed Enantioselective Synthesis of Hydroquinazolines via Intramolecular Aza-Michael Addition to α,β-Unsaturated Esters
preprintsubmitted on 18.01.2021, 18:14 and posted on 19.01.2021, 13:06 by Guanglong Su, Connor J. Thomson, Ken Yamazaki, Daniel Rozsar, Kirsten Christensen, Trevor Hamlin, Darren J. Dixon
An efficient synthesis of enantioenriched hydroquinazoline cores via a novel bifunctional iminophosphorane squaramide catalyzed intramolecular aza-Michael addition of urealinked α,β-unsaturated esters is described. The methodology exhibits a high degree of functional group tolerance around the forming hydroquinazoline aryl core and wide structural variance on the nucleophilic N atom of the urea moiety. Excellent yields (up to 99%) and high enantioselectivities (up to 97:3 e.r.) using both aromatic and less acidic aliphatic ureas were realized. The potential industrial applicability of the transformation was demonstrated in a 20 mmol scale-up experiment using an adjusted catalyst loading of 2 mol%. The origin of enantioselectivity and reactivity enhancement provided by the squaramide motif has been uncovered computationally using density functional theory (DFT) calculations, combined activation strain model (ASM) and energy decomposition analysis (EDA).