Product Manager：Nick Wilde

Introduction

Currently, chemists are becoming increasingly interested in spirocyclic building block molecules containing quaternary rings. Aladdin Scientific offers a range of spiral building block products, including various types of spiral [3.3] heptanes1 and spiral [3.4] octanes2-3. These building blocks can be used to synthesize spirocyclic compounds, creatively utilizing three-dimensional space, not only to obtain innovative skeletons in medicinal chemistry, but also to explore unexplored areas in chemical space. In addition, these blocks can be used to functionalize drug like compounds to improve their physicochemical properties and provide unprecedented useful 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 offer three-dimensional accessibility via a single module, characterized by their dense and rigid substructures that produce clearly defined spatial exit vectors, or the dimensionality of substituents. Our company provides a diverse range of spirocyclic building blocks with various exit vectors, enabling the exploration and modification of chemical space to cater to your synthetic requirements in medicinal chemistry.4

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

Advantages

• Enhanced aqueous solubility,
• Potentially heightened metabolic stability,
• Diversification of building blocks at numerous branching points,
• Clearly defined exit vectors facilitate access to and assessment of chemical space,
• Functional modification of pharmacophores.

?Representative Applications

Starting Molecules

We provide appropriate starting materials (M134506、I165344、M177398) for the synthesis of spirocyclic building blocks. For instance, Carreira and colleagues demonstrated the preparation of oxa-azaspiro[3.4]octanes using a conjugated ester as the starting material.2

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

Building Blocks

The development of angular azaspiro[3.3]heptanes represents a significant improvement over earlier linear azaspiro[3.3]heptanes. By introducing two heteroatoms, these structures provide additional exit vectors for substituents, enabling a more effective exploration and population of three-dimensional chemical space.1

To broaden the three-dimensional chemical space available to medicinal chemists, Carreira and colleagues developed novel thia-azaspiro[3.4]octane (B167022) and oxa-azaspiro[3.4]octane (B486617、T486591、B467123、A486590、B167199、B167201) building blocks. The inclusion of a sulfur or oxygen heteroatom within the spirocyclic framework enables the efficient synthesis of "drug-like" thia- or oxa-azaspirocyclic systems, offering enhanced versatility for drug discovery.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

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