A bifunctional iminophosphorane squaramide catalyzed enantioselective synthesis of hydroquinazolines via intramolecular aza-Michael reaction to α,β-unsaturated esters.

Guanglong Su,Connor J. Thomson,Darren J. Dixon,Ken Yamazaki,Trevor A. Hamlin,Kirsten E. Christensen,Daniel Rozsar

doi:10.1039/d1sc00856k

Abstract

An efficient synthesis of enantioenriched hydroquinazoline cores via a novel bifunctional iminophosphorane squaramide catalyzed intramolecular aza-Michael reaction of urea-linked 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 er) 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 with the activation strain model (ASM) and energy decomposition analysis (EDA).

Highlights

Heterocyclic organic compounds containing a hydroquinazoline core are commonplace amongst various natural products and potent drug substances used in the clinic.[1]
Much effort has been directed towards the synthesis of hydroquinazoline compounds,[5] highly enantioselective catalytic methods are still relatively uncommon, especially for unbiased/unactivated systems (Scheme 1)
Scheme 4 (A) Lowest energy TS structure for the formation of (R)-product and (B) lowest energy TS structure for the formation of (S)-product of the bifunctional iminophosphorane (BIMP) squaramide-catalyzed intramolecular aza-Michael reaction computed at conductor-like screening model (COSMO)(toluene)-zeroth-order regular approximation (ZORA)-M06-2X/TZ2P//COSMO(toluene)ZORA-BLYP-D3(BJ)/DZP

Summary

Introduction

Heterocyclic organic compounds containing a hydroquinazoline core are commonplace amongst various natural products and potent drug substances used in the clinic.[1]. A pyridine-based substrate (1i) was found to be well-tolerated affording the desired product in excellent yield and enantioselectivity under the standard reaction conditions. Substrates possessing single iodine, bromine and uorine atoms at various ring positions as well as a 3,5dichloro example, performed typically well providing the desired hydroquinazoline core in excellent yield and good er (1j to 1p).

Results

Conclusion