Spirocyclic Building Blocks for Scaffold Assembly

Introduction

Spirocyclic modules containing four-membered rings are currently of growing interest to discovery chemists. We are pleased to offer a suite of spirocyclic building blocks in collaboration with Professor Dr. Erick Carreira and SpiroChem that includes assorted spiro[3.3]heptanes¹ and spiro[3.4]octanes.^2-3 Using these building blocks affords the synthesis of spirocycles that creatively exploit three dimensions, providing access to not only innovative sets of scaffolds in medicinal chemistry but also underexplored regions in chemical space. In addition, the building blocks can be used to functionalize drug-like compounds to improve physicochemical properties and represent a useful collection of unprecedented inputs for fragment-based libraries.^1-4

Figure 1. To access three-dimensional space, chemists traditionally must combine multiple “flat” chemical components (e.g., biaryl molecules)

The spirocyclic building blocks provide three-dimensional access through only one module. Their dense and rigid substructures create spatially well-defined exit vectors, or the dimensionality of the substituents. Through the variety of spirocyclic building blocks with different exit vectors offered by our company, chemical space permeation can be surveyed and altered for your synthetic needs in medicinal chemistry.⁴

Figure 2. Chemical space permeation can be surveyed and altered for your synthetic needs in medicinal chemistry.

Advantages

• Increased aqueous solubility
• Potentially increased metabolic stability
• Diversification of building blocks possible on many branching points
• Defined exit vectors enable access to and evaluation of chemical space
• Functionalization of pharmacophores

Representative Applications

Starting Molecules

We offer suitable starting materials (792578, 792586, 793868) for synthesis of spirocyclic building blocks. In one example highlighted below, Carreira and co-workers prepared oxa-azaspiro[3.4]octanes from the starting conjugated ester.²

Figure 3. Carreira and co-workers prepared oxa-azaspiro[3,4]octanes from the starting conjugated e

Building Blocks

Available angular azaspiro[3.3]heptanes (797499, 797529) are an advancement from earlier linear azaspiro[3.3]heptanes. By incorporating two heteroatoms, the number of exit vectors for substituents is increased for better population of three-dimensional chemical space.¹

To further expand the three-dimensional landscape for medicinal chemists, Carreira and co-workers constructed novel thia-azaspiro[3.4]octane (797154, 797588, 797626, 797561) and oxa-azaspiro[3.4]octane (795895, 797413, 797421, 797448, 797456, 797464, 797472, 797596) building blocks. The presence of a sulfur or oxygen heteroatom in the spirocycle facilitates preparation of “drug-like” thia- or oxa-azaspirocyclic systems.^2-3

Figure 4. The presence of a sulfur or oxygen heteroatom in the spirocycle facilitates preparation of “drug-like” thia- or oxa-azaspirocyclic systems.

References

1. Burkhard JA, Guérot C, Knust H, Carreira EM. 2012. Expanding the Azaspiro[3.3]heptane Family: Synthesis of Novel Highly Functionalized Building Blocks. Org. Lett.. 14(1):66-69. https://doi.org/10.1021/ol2028459

2. Li DB, Rogers-Evans M, Carreira EM. 2013. Construction of Multifunctional Modules for Drug Discovery: Synthesis of Novel Thia/Oxa-Azaspiro[3.4]octanes. Org. Lett.. 15(18):4766-4769. https://doi.org/10.1021/ol402127b

3. Li DB, Rogers-Evans M, Carreira EM. 2011. Synthesis of Novel Azaspiro[3.4]octanes as Multifunctional Modules in Drug Discovery. Org. Lett.. 13(22):6134-6136. https://doi.org/10.1021/ol2025313

4. Carreira EM, Fessard TC. 2014. Four-Membered Ring-Containing Spirocycles: Synthetic Strategies and Opportunities. Chem. Rev.. 114(16):8257-8322. https://doi.org/10.1021/cr500127b