Probing chemical space with alkaloid-inspired libraries

Abstract

Screening of small molecule libraries is an important aspect of probe and drug discovery science. Numerous authors have suggested that bioactive natural products are attractive starting points for such libraries, due to their structural complexity and sp3-rich character. Here, we describe the construction of a screening library based on representative members of four families of biologically active alkaloids (Stemonaceae, the structurally related cyclindricine and lepadiformine families, lupin, and Amaryllidaceae). In each case, scaffolds were based on structures of the naturally occurring compounds or a close derivative. Scaffold preparation was pursued following the development of appropriate enabling chemical methods. Diversification provided 686 new compounds suitable for screening. The libraries thus prepared had structural characteristics, including sp3 content, comparable to a basis set of representative natural products and were highly rule-of-five compliant.

Efficient access to sp3-rich tricyclic amine scaffolds through Diels–Alder reactions of azide-containing silyloxydienes

“…6 We have recently described an approach to diverse scaffolds that contain similar structural features to biologically active alkaloid natural products. 7 …”

“…8 This methodology permitted the efficient construction of 5,6,7-tricyclic lactam scaffolds 2 through a Lewis acid-promoted Diels-Alder/Schmidt reaction of azidoenone 1 with a number of silyloxydienes (Scheme 1a). 7b By simply tethering the azide to the diene rather than the dienophile, the structurally similar, but 3-dimensionally rather different, lactams 4 were obtained (Scheme 1b). 7a,9 In the latter Diels–Alder/Schmidt reaction, an excess (2.5 to 3 equiv) of Lewis acid is required for the lactam formation.…”

“…7b By simply tethering the azide to the diene rather than the dienophile, the structurally similar, but 3-dimensionally rather different, lactams 4 were obtained (Scheme 1b). 7a,9 In the latter Diels–Alder/Schmidt reaction, an excess (2.5 to 3 equiv) of Lewis acid is required for the lactam formation. However, by reducing the Lewis acid loading to 1 equiv, the domino reaction can be interrupted so that the Diels–Alder cycloaddition step occurs without subsequent alkyl azide Schmidt reaction (Scheme 1c).…”

Synthesis of novel N-cyclopentenyl-lactams using the Aubé reaction

“…Over the last few decades, this reaction has gained popularity and resulted in the production of a variety of chemical structures and generated new techniques in chemistry [5–10]. Additionally, it was applied to the synthesis of different natural products of biological importance [11–15]. In the Aubé reaction, an intermolecular reaction takes place between an azido alcohol and a ketone to provide lactams through an in situ - generated hemiacetal as a temporary tether.…”

Diversity-oriented synthesis of Lycopodium alkaloids inspired by the hidden functional group pairing pattern

“…As an improvement, Park 25,26 recently initiated a privileged substructure-based DOS strategy to generate skeletal diversity of natural product-like and drug-like molecules with high biological relevance. Although DOS has proven to be a successful strategy for the rapid access to chemical libraries of natural product-like three-dimensional molecular architectures from simple starting materials [27][28][29][30][31][32] , it was rarely applied to natural product total synthesis in parallel with skeletal diversification. Herein, we introduce a novel approach using DOS for the concise construction of both natural products and their analogues possessing diverse, highly complex skeletons in parallel.…”