Imine Amidation Catalyzed by a Chiral VAPOL Calcium Phosphate

Abstract

Over the last 16 years, chiral phosphoric acids (CPAs) have been shown to be excellent asymmetric catalysts, very effectively used in constructing chiral molecules with high enantiocontrol. In 2010, Ishihara et al. discovered that chiral metal phosphate complexes (or salts) could be found in substantial quantities, as contaminates, in some reported CPA-catalyzed reactions (Angew. Chem., Int. Ed.20104938233826). These metal phosphates were shown to actually catalyze the reactions in addition to CPAs. In this work, we have investigated in depth a reaction first reported to be catalyzed by CPAs based on a vaulted bis-phenanthrol (VAPOL) backbone. We have found that VAPOL metal phosphates were, in fact, superior catalysts for this reaction. Upon optimization, a wide substrate scope, low catalyst loading, and mild conditions could provide intermolecular imine amidation reactions producing chiral N,N′-aminal products in high yields and with excellent ee values (up to >99% yield, >99% ee).

Progress on the Synthesis and Applications of Aminals: Scaffolds for Molecular Diversity

“…They proceeded with the facile mono deprotection of formamide derivative (22a) to prepare the N-Boc imidazoline (22g) under mild hydrolysis conditions (KOH, MeOH, 94%). Although the conversion of 22g into the corresponding vicinal diamine (24) proved to be unsuccessful by acid or base mediated hydrolysis, the electrochemical oxidation of 22g yielded the amidine (23), which was successfully converted into the 1,2-diamine (24) in excellent yield (Scheme 4b). Similarly, Keyserlingk and Martens 17 reported a metal-free alternative for the synthesis 1,2-diamines based on the hydrolysis of aminals.…”

“…Despite successfully describing a sophisticated one-pot double asymmetric cascade reaction for the synthesis of aminals 42 and chlorinated oxindoles 43 , limited advancements were achieved in terms of expanding the scope or enhancing the enantioselectivity of the latter. Additionally, Antilla 23 expanded the application of chiral VAPOL calcium phosphate to his earlier asymmetric addition of sulfonamides (Scheme 7b ). Notably, the calcium-phosphate complexes exhibited superior performance compared to their protic counterparts.…”

Chiral organophosphates as ligands in asymmetric metal catalysis

“…Catalyst-substrate-complex: Antilla´s group successfully applied Ca-bisphosphate catalysts for various reactions, e.g. for the synthesis of chlorinated oxindoles and geminal diamines 34 , for the amidation of imines 35 , as well as for the amination of benzofuranones 36 and -keto esters 37 (not shown in detail).…”

Diastereo-divergent synthesis of chiral hindered ethers via a synergistic calcium(II)/gold(I) catalyzed cascade hydration/1,4-addition reaction

“…1d). Specifically, we have discovered that chiral BINOL-derived calcium phosphate catalysts [70][71][72][73][74][75][76][77][78][79][80] serve as efficient Lewis acids for the generation and activation of o-QMs. By carefully selecting a suitable chiral Au(I) complex in combination with the chiral calcium phosphate catalyst, we have achieved stereodivergent cascade reactions, providing access to all four stereoisomers of the products (Fig.…”