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

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: (1) through stepwise changes in
the size of the nitrogen-bearing ring; (2) through the oxidation state
of the carbon-centered point of diversification; (3) through the relative
stereochemical orientation of the two diversification sites in those
members that are stereogenic; and (4) 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.