Domino Transformations of Ene/Yne Tethered Salicylaldehyde Derivatives: Pluripotent Platforms for the Construction of High sp³ Content and Privileged Architectures

Abstract

Diversity‐oriented synthesis (DOS) has become a powerful synthetic tool that facilitates the construction of nature‐inspired and privileged chemical space, particularly for sp3‐rich non‐flat scaffolds, which are needed for phenotypic screening campaigns. These diverse compound collections led to the discovery of novel chemotypes that can modulate the protein function in underrepresented biological space. In this context, starting material‐driven DOS is one of the most important tools used to build diverse compound libraries with rich stereochemical and scaffold diversity. To this end, ene/yne tethered salicylaldehyde derivatives have emerged as a pluripotent chemical platform, the products of which led to the construction of a privileged chemical space with significant biological activities. In this review, various domino transformations employing o‐alkene/alkyne tethered aryl aldehyde/ketone platforms are described and discussed, with emphasis on the period from 2011 to date.

Unusual Reactivities of ortho-Hydroxy-β-nitrostyrene

“…Salicylaldehyde condenses with carbonyl or nitro compounds to afford conjugate systems possessing a hydroxy group at the ortho -position. Since these compounds are often used as a substrate for various purposes in organic syntheses [ 19 , 20 , 21 ], the insights obtained here will provide useful information to researchers using such compounds.…”

“…These unusual reactivities prompted us to study the influence of the ortho -hydroxy group. Since compounds derived from salicylaldehyde are widely used in organic synthesis [ 19 , 20 , 21 ], information on specific properties caused by the ortho -hydroxy group will be useful for many researchers.…”

Salicylaldehydes Derived from 5-Chloromethyl-2-hydroxybenzaldehyde – Synthesis and Reactions

“…1 Alkene-or alkyne-tethered salicylaldehyde derivatives (such as Oallylsalicylaldehyde or O -propargylsalicylaldehyde) can generate diverse compound libraries with rich stereochemical and scaffold diversity that include benzopyranes, chromenoquinolines, various other chromene-fused heterocycles, benzoxazepines and macrocycles. 2,3 Upon cyclocondensation with α-haloketones under the conditions of the Rap-Stoermer reaction, salicylaldehydes produce 2-acylbenzofurans, 4,5 while this particular reaction was shown to be amenable to an ultrasound-assisted approach that improves the yields of the target benzofurans. 6 Also, several synthetic variants for the preparation of 1,2benzisoxazoles from oximes of ortho-hydroxybenzaldehydes using para-toluenesulfonyl chloride in the presence of an amine in acetonitrile, 7 trifluoromethanesulfonic anhydride in dichloromethane, 8 or a triphenylphosphine-2,3-dichloro-5,6-dicyano-1,4-benzoquinone system 9 have been reported.…”

Divergent Strategy for Diastereocontrolled Synthesis of Small- and Medium-Ring Architectures

“…During the studies of efficient one-pot methodologies yielding privileged, biologically significant substructures, we encountered serendipitous discovery of cascades that led to the synthesis of diverse small- and medium-sized ring collections. , The first cascade was discovered while attempting the synthesis of compound 8 (Scheme ). This synthetic plan was inspired by Boger’s powerful intramolecular [4 + 2]/[3 + 2]-cycloaddition cascade of 1,3,4-oxadiazoles, leading to vindorosine, vinblastine, and vincristine .…”