Ring System Distortion Reactions for Complex Small Molecule Synthesis
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Solution Overview
Problem
Current drug discovery methods face challenges in creating small molecules with high structural and stereochemical complexity, as existing compound screening collections are predominantly composed of planar molecules with limited structural or stereochemical complexity, making it difficult to modulate complex biological targets effectively.
Innovation Solution
A novel strategy involving ring system distortion reactions is applied to natural products to systematically convert them into structurally complex compounds with diverse molecular architectures, increasing the number of stereogenic centers and molecular weight, thereby creating a high-throughput screening library with enhanced biological potential.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If traditional high-throughput screening libraries are constructed using simple planar molecules, then the screening process is efficient and compounds are easy to synthesize, but the structural complexity and stereochemical diversity are insufficient to effectively modulate complex biological targets
Solution Approach 1:
Instead of building complex molecules step-by-step from simple precursors (traditional approach), the patent inverts the approach by starting with simple planar molecules and applying ring closure reactions to generate complex three-dimensional structures. This inversion allows efficient synthesis while achieving high structural complexity, as the ring closure step consolidates multiple bonds into a single transformation.
Solution Approach 2:
The patent systematically varies key molecular parameters including the number of ring systems (2-5 rings), molecular weight (300-1000 Da), and stereochemical complexity (1-5 stereocenters) to create diverse libraries. By controlling these parameters through selective ring closure reactions, the method generates structurally complex molecules that can effectively modulate complex biological targets while maintaining synthetic efficiency.
2Reliability
If compounds with high structural complexity and multiple stereogenic centers are synthesized, then affinity and specificity for biological targets improve, but the difficulty of building such complexity in large collections increases
Solution Approach 1:
The patent segments the molecule building process into distinct modular steps: starting with simple planar cores, applying ring closure reactions to create ring systems, and introducing stereogenic centers through controlled reactions. This segmentation allows systematic generation of complexity while maintaining control over the synthesis process, making it feasible to create large collections of complex molecules.
Solution Approach 2:
The patent performs preliminary actions by establishing simple planar molecular cores first, then systematically applying ring closure reactions to build complexity. This preliminary structuring ensures that the foundation is stable and well-defined before adding complex features, making the overall process more controllable and reproducible for large-scale library generation.
3Device complexity
If natural products are used as starting materials for diversity-oriented synthesis, then structural complexity and stereochemical richness are preserved, but the need to rapidly convert them to diverse chemotypes with distinct architectures increases
Solution Approach 1:
The patent extracts the stereochemical complexity and structural richness from natural products and separates it from the need for complex synthesis. By using ring closure reactions that preserve stereocenters while generating diverse ring system architectures, the method maintains the valuable stereochemical information from natural products while rapidly generating diverse chemotypes suitable for drug discovery.
Data Source
AI summary
The invention provides a novel, general, and facile strategy for the creation of small molecules with high structural and stereochemical complexity. Aspects of the methods include ring system distortion reactions that are systematically applied to rapidly convert readily available natural products to structurally complex compounds with diverse molecular architectures. Through evaluation of chemical properties including fraction of sp3 carbons, ClogP, and the number of stereogenic centers, these compounds are shown to be significantly more complex and diverse than those in standard screening collections. This approach is demonstrated with natural products (gibberellic acid, adrenosterone, and quinine) from three different structural classes, and methods are described for the application of this strategy to any suitable natural product.