Synthesis of a Family of Spirocyclic Scaffolds: Building Blocks for the Exploration of Chemical Space

Abstract

This report describes the preparation of a series of 17 novel racemic spirocyclic scaffolds that are intended for the creation of compound libraries by parallel synthesis for biological screening. Each scaffold features two points of orthogonal diversification. The scaffolds are related to each other in four ways: Through stepwise changes in the size of the nitrogen bearing ring.Through the oxidation state of the carbon centered point of diversification.Through the relative stereochemical orientation of the two diversification sites in those members that are stereogenic.Through the provision of both saturated and unsaturated versions of the furan ring in the scaffold series derived from 3-piperidone. The scaffolds provide incremental changes in the relative orientation of the diversity components that would be introduced onto them. The scaffolds feature high sp3 carbon content which is essential for the three dimensional exploration of chemical space. This characteristic is particularly evident in those members of this family that bear two stereocenters, i.e. the two series derived from 3-piperidone and 3-pyrrolidinone. In the series derived from 3-piperidone we were able to “split the difference” between the two diastereomers by preparation of their corresponding unsaturated version.

Charting Biologically Relevant Spirocyclic Compound Space

“…Although separation of the isomers using traditional silica column chroma-tography was not possible, both compounds 8 and 9 could be separatedb yu sing supercritical fluid chromatography.T he structure and relative stereochemistry of major isomer 9 was confirmed by X-ray crystallography ( Figure 5) [25] and the stereochemistry of both isomersw as established by 2D NMR experiments.I nc ontrastt op reviously reported diastereoselectivities of the Prins cascade cyclization of diol 7 [17] the diastereomeric ratio found for cycloadducts 8 and 9 was 1:3. After separation the synthesis was continuedw ith the major diastereomer (9) and the N-tosyl protectiveg roup was removed. Subsequently, the morpholine amine was readily functionalized.…”

“…Albeit chemically challenging, several synthesis schemes have been introduced to generate spirocyclic building blocks and derivatives . With their saturated fused ring systems, spirocyclic compounds are characterized by distinct three‐dimensionality, which provides an avenue to depart from aromatic molecular “flatlands”, the extensive exploration of which has hampered medicinal chemistry efforts over the past years . Thus, it is hoped that chemical saturation, distinct three‐dimensionality, and stereochemical richness might yield new chemical entities that can be effectively evolved into drug leads.…”

“…Albeit chemically challenging, several synthesis schemes have been introduced to generate spirocyclic building blocks and derivatives. [7,8] With their saturated fused ring systems,s pirocyclic compounds are characterized by distinct three-dimensionality, which provides an avenuet od epart from aromatic molecular "flatlands", [9] the Figure 1. Classificationo fs pirocyclic compounds.…”

“…(b) From the left to the right, the 'ringcombination (RC)-scaffold (SC)-compound (CPD)' hierarchyi si llustrated for an exemplary spirocyclic compoundw ith extensive exploration of which has hampered medicinal chemistry efforts over the past years. [9] Thus, it is hoped that chemicals aturation,d istinct three-dimensionality,a nd stereochemicalr ichness might yield new chemical entities that can be effectively evolved into drug leads. To gether with improved synthetic accessibility,t his conjecture might explain the increasingi nterest in spirocyclic compounds (and other natural products)i nm edicinal chemistry.…”

Extending accessible chemical space for the identification of novel leads

“…Preferential use of such compounds is thought to hamper further progress in lead discovery [8]. The generation of natural product-derived compounds is not limited to metabolites that are easily accessible synthetically, but currently also focuses on chemical entities of high complexity such as spirocyclic [9] and macrocyclic compounds [10] (Figure 1), which are especially considered for notoriously difficult small molecule targets or (assumed) undruggable targets [11]. Moreover, reactions from biosynthetic pathways have also been adapted for combinatorial exploration [12].…”