A Au(I)-Catalyzed N-Acyl Iminium Ion Cyclization Cascade

Abstract

A one-pot Au(I)-catalyzed reaction cascade to multi-ring heterocyclic products from alkynoic acids and primary amines is reported. The gold catalyst initially primes the alkynoic acid, via cyclization to an enol lactone, to react with a primary amine tethered to an electron rich heteroaromatic system. Then, via postulated Lewis acid assisted acidity, the Au(I) catalyst activates the amido ketone intermediate to undergo an N-acyl iminium ion cyclization. The reaction sequence is simple to perform, efficient, and broad in its scope to a diverse range of complex heterocyclic products.

A conceptual framework for analysing and planning synthetic approaches to diverse lead-like scaffolds

“…Synthetic approaches are classified according to the number of new bonds formed to each of the building blocks in the conversion into molecular scaffolds; new bonds between 40 functional groups within a building block are counted only once. Illustrative examples of three approaches to molecular scaffolds are shown in Scheme 1.…”

“…26 This article focuses, therefore, on 35 illustrative approaches that have emerged that allow (or have potential to allow) control over the scaffold of lead-like small molecules; it is not a comprehensive review of these approaches. The approaches are organised according to the conceptual framework that we have developed to classify, capture and extend 40 approaches to the synthesis of diverse molecular scaffolds.…”

“…41 Initially, the aldehyde 87 and the nitro compound 89 were Examples of scaffolds that may be prepared using a related two-component process exploiting cyclic imines. 40 The power of approaches to small molecule scaffolds further increases with the connectivity of the building blocks used. A synthesis of substituted oxabispidine scaffolds (Scheme 16) exploits two tri-connective building blocks -an aminesubstituted epoxide (e.g.…”

“…Around half of the known compounds are based on just 0.25% of known molecular exploration is also reflected in small molecule screening collections: 6,9 consequently, the biological properties of small molecules have not been annotated systematically, with huge emphasis on a small number of synthetically accessible scaffolds. To what extent, then, are our collective views about the biological 40 relevance of chemical space skewed by our uneven exploration by synthesis?…”

“…40 Initially, Au-catalysed cyclisation of alkynyl carboxylic acids (e.g. 79) gave cyclic enol ethers (e.g.…”