Diversity‐Oriented Synthesis

O’Connell, Kieron M. G.; Galloway, Warren R. J. D.; Ibbeson, Brett M.; Isidro‐Llobet, Albert; and, Cornelius J. O'Connor; Spring, David R.

doi:10.1002/9781118141649.ch4

Cited by 3 publications

(2 citation statements)

References 90 publications

(147 reference statements)

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“…Typically, such libraries were comprised of flat, sp 2 rich and structurally similar compounds. [2][3][4] As a result, there has been a drive in recent years to develop robust methodologies that allow for the rapid generation of compounds possessing more complex and diverse sp 3 -rich architectures.…”

Section: Historymentioning

confidence: 99%

“…Natural products represent a highly diverse and structurally innovative compound class. They possess significant sp 3 character, chirality, diverse core scaffolds, differing ratios of hetero to non-hetero atoms and, computationally, occupy a larger fraction of chemical space than typical combinatorial libraries. [5][6][7][8] As such, natural products play a crucial role in the discovery of drugs.…”

Section: Natural Productsmentioning

confidence: 99%

See 1 more Smart Citation

A novel complexity-to-diversity strategy for the diversity-oriented synthesis of structurally diverse and complex macrocycles from quinine

Ciardiello

Stewart

Sore

et al. 2017

Bioorganic & Medicinal Chemistry

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Recent years have witnessed a global decline in the productivity and advancement of the pharmaceutical industry. A major contributing factor to this is the downturn in drug discovery successes. This can be attributed to the lack of structural (particularly scaffold) diversity and structural complexity exhibited by current small molecule screening collections. Macrocycles have been shown to exhibit a diverse range of biological properties, with over 100 natural product-derived examples currently marketed as FDA-approved drugs. Despite this, synthetic macrocycles are widely considered to be a poorly explored structural class within drug discovery, which can be attributed to their synthetic intractability. Herein we describe a novel complexity-to-diversity strategy for the diversity-oriented synthesis of novel, structurally complex and diverse macrocyclic scaffolds from natural product starting materials. This approach exploits the inherent structural (including functional) and stereochemical complexity of natural products in order to rapidly generate diversity and complexity. Readily-accessible natural product-derived intermediates serve as structural templates which can be divergently functionalized with different building blocks to generate a diverse range of acyclic precursors. Subsequent macrocyclisation then furnishes compounds that are each based around a distinct molecular scaffold. Thus, high levels of library scaffold diversity can be rapidly achieved. In this proof-of-concept study, the natural product quinine was used as the foundation for library synthesis, and six novel structurally diverse, highly complex and functionalized macrocycles were generated.

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Section: Historymentioning

confidence: 99%