Biology‐Oriented Synthesis of Stereochemically Diverse Natural‐Product‐Derived Compound Collections by Iterative Allylations on a Solid Support

Abstract

A strategy aiming at the introduction of stereocenters into polymer-bound natural-product-derived and -inspired compound collections is presented. Treatment of immobilized aldehydes with Brown's pinene-derived allylboranes results in the stereoselective formation of homoallylic alcohols with up to 89 % ee (ee=enantiomeric excess). Subsequent iterative ozonolysis-allylation sequences with up to three allylations on a solid support give access to 1,3-polyols with different relative configurations. Esterification with acryloyl chloride and final ring-closing metathesis yields alpha,beta-unsaturated delta-lactones with multiply oxygenated side chains, a substructure found in a group of natural products with a broad range of biological activity. The flexibility of the approach is exemplified by the parallel synthesis of all eight diastereomers of cryptocarya diacetate on a solid support. The individual isomers are obtained in overall yields of 40-60 % over 10 steps and with 63-85 % diastereoselectivity for the major isomer.

Scaffold Diversity Synthesis and Its Application in Probe and Drug Discovery

“…Adrenosterone (2), as teroid hormone produced in the adrenal cortex of mammals,c ontains five contiguous stereogenic centers.F our of the carbocyclic rings of 2 are functionalized with an enone or ketone.These key functional groups provide synthetic handles to transform 2 into as et of diverse frameworks in few synthesis steps.Byexploiting ringexpansion processes,n amely aS chmidt reaction and aB V oxidation, and selective ring-opening reactions,f ive distinct and complex scaffolds (11)(12)(13)(14)(15)w ith functional groups for further modifications were generated (Scheme 1c).…”

“…[8] Meanwhile, biology-oriented synthesis (BIOS), ac oncept developed by the Waldmann group,emerged as an interesting but arguably more challenging concept that aimed on the one hand to identify natural product (NP) based common ligands for functionally diverse proteins embodying similar ligand-binding sites [9] and on the other hand to explore compound collections based on biologically prevalidated scaffolds [10] in chemical biology and medicinal chemistry. [11] Theq uality of compound libraries thus began to gain attention. [12] Thefocus of synthetic chemists moved to the diversity and complexity of the core structures or scaffolds present within acompound collection.…”

Principles, implementation, and application of biology-oriented synthesis (BIOS)

“…Screening of a BIOS-derived a,b-unsaturated d-lactone compound collection in two cell based screens yielded small molecule modulators of cell cycle progression and of viral entry via the secretory pathway (Leßmann et al, 2007). Extensive screening and synthesis efforts also resulted in highly selective phosphatase inhibitors with enhanced properties (Bialy and Waldmann, 2004;Umarye et al, 2007).…”

Biology-inspired synthesis of compound libraries

“…A merging of these two approaches into one concept, i.e., BIOS, leads to synergistic effects, providing, for example, an approach to simplify structures of known inhibitors while retaining their basic biological activity [27,37,40,51]. The scaffold tree approach arranges scaffolds of natural products in a tree-like structure with the inner segments of the tree representing less complex scaffolds.…”