A metal-catalyzed enyne-cyclization step for the synthesis of bi- and tricyclic scaffolds amenable to molecular library production

Abstract

A facile metal-catalyzed diversification step for the synthesis of novel bi- and tricyclic scaffolds from enyne substrates is reported in this study. From a single starting material, topologically diverse scaffolds for library synthesis can be generated and decorated in a few steps. The methodology was used to produce a library of 490 compounds within the European Lead Factory (ELF) Consortium.

Reactivity and Synthetic Applications of Multicomponent Petasis Reactions

“…Substituted propargylamines are versatile substrates for the synthesis of diverse heterocycles via a variety of synthetic transformations, such as RCM, ROM, and enyne cyclization reactions. 132,133 The PR of benzylamines, formaldehyde, boronic acid, and propiolic acids constitutes an alternative metal-free approach for the synthesis of functionalized propargylamines through A 3 -coupling of amines, aldehydes, and alkynes. 134 A more recent study reported the synthesis of propargylamines of the same scaffold of 108 – 111 through a four-component reaction of aliphatic amines, formaldehyde, arylboronic acids, and alkynyl carboxylic acids catalyzed by magnetic CuFe 2 O 4 nanoparticles.…”

“…This type of metal-free four-component PR was independently reported by two groups for the synthesis of N -benzyl propargylamines 108 – 111 . , It is noteworthy that two components of formaldehyde are involved in this transformation to form the initial benzyl hemiaminal intermediate 107 , and thus it can also be classified as a five-component reaction (Scheme ). Substituted propargylamines are versatile substrates for the synthesis of diverse heterocycles via a variety of synthetic transformations, such as RCM, ROM, and enyne cyclization reactions. , The PR of benzylamines, formaldehyde, boronic acid, and propiolic acids constitutes an alternative metal-free approach for the synthesis of functionalized propargylamines through A 3 -coupling of amines, aldehydes, and alkynes . A more recent study reported the synthesis of propargylamines of the same scaffold of 108 – 111 through a four-component reaction of aliphatic amines, formaldehyde, arylboronic acids, and alkynyl carboxylic acids catalyzed by magnetic CuFe 2 O 4 nanoparticles …”

Petasis/Diels–Alder/Cyclization Cascade Reactions for the Generation of Scaffolds with Multiple Stereogenic Centers and Orthogonal Handles for Library Production

“…[2b] In comparison of aliphatic and aromatic heterocycles, the former have a better pharmacokinetic profile . The synthesis of libraries containing molecules with several stereocenters and a high percentage of sp 3 carbon atoms from readily accessible building blocks is challenging, and our group has engaged in efforts to develop novel and reliable methods for their synthesis . Some of the libraries have been included in the public compound collection (PCC) of the European Lead Factory (ELF), a private–public European partnership involving pharmaceutical companies, small and medium enterprises (SMEs), and universities that aim towards the discovery of new and innovative leads for drug discovery .…”

Highly Stereoselective Synthesis of a Compound Collection Based on the Bicyclic Scaffolds of Natural Products

“…Finally, a well-established, integrated and efficient workflow was implemented. The collection is a part of JECL and is being evaluated to identify modulators of different therapeutically relevant protein targets in the screening portal of European Lead Factory [ 25 , 26 , 27 , 28 , 30 , 31 , 32 , 33 ].…”

“…The Joint European Compound Library (JECL) is a key component of the European Lead Factory (ELF) [ 20 , 21 ] that holds drug-like and lead-like compounds for ELF’s screening facility [ 22 , 23 , 24 ]. In order to enrich this collection with small molecules rich in sp 3 features, chiral centers as well as drug-like molecular properties, different academic groups and small and medium enterprises (SMEs) are collaborating in library synthesis programs [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. With this perspective and along with our continuing interest in the synthesis of natural product inspired compound collections for biological studies [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ], we report here our synthesis efforts to build a compound library that is represented by six highly sp 3 -rich, novel and distinct hetero- and carbocyclic scaffolds that are found as core-structures in biologically active NPs, as depicted in Figure 1 .…”