# Short Scalable Route to Bis-morpholine Spiroacetals and Oxazepane Analogues: Useful 3D-Scaffolds for Compound Library Assembly

## TL;DR

This paper presents a scalable method to synthesize complex molecular scaffolds useful for drug discovery.

## Contribution

A novel four-step synthesis of sp3-rich spiroacetal scaffolds with morpholine rings is introduced.

## Key findings

- The method allows high-yield synthesis of spiroacetal scaffolds on a large scale.
- The approach enables substitution of morpholine rings with oxazepanes to generate diverse analogues.
- The resulting compounds occupy a drug-like chemical space but are structurally novel.

## Abstract

sp3-Rich molecular scaffolds incorporating
nitrogen
heterocycles represent important starting points for assembling compound
screening libraries and drug discovery. Herein, we report a four-step
synthesis of a conformationally well-defined sp3-rich scaffold
incorporating two morpholine rings embedded within a spiroacetal framework.
The synthesis involves the intermediacy of a 2-chloromethyl-substituted
morpholine, accessed from epichlorohydrin and readily available β-aminoalcohols.
Base-mediated dehydrochlorination affords an exocyclic enol ether,
from which the second morpholine ring is constructed in two steps.
Scaffold synthesis is high-yielding and can be performed on a large
scale. The methodology allows ready substitution of one–or
both– of the morpholine rings for 1,4-oxazepanes and the generation
of 6,7- and 7,7-spiroacetal analogues, which are virtually unexplored
in drug discovery. Substituted 6,6-systems can be prepared and, in
some instances, undergo acid-mediated anomerization to deliver the
scaffolds in high diastereoselectivity. The two amine functionalities
embedded in the 6,6- and 6,7-spiroacetal scaffolds were sequentially
functionalized to provide a diverse physical compound library. These
library compounds occupy a similar chemical space to small-molecule
drugs that have been approved for clinical application by the Food
and Drug Administration yet are structurally dissimilar and may therefore
act upon novel targets, representing attractive starting materials
for drug discovery.