Unconventional Macrocyclizations in Natural Product Synthesis

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• Macrocyclic compounds are significant therapeutic candidates in drug discovery.
• Their pharmacological activity relies on restricted 3D orientation, leading to high-affinity binding.
• Efficient synthetic access to macrocycles is crucial but challenging due to entropic penalties and oligomerization.

Purpose of the Study:

• To highlight unconventional macrocyclization strategies beyond common methods.
• To showcase versatile transformations for synthesizing natural products and analogues.
• To provide an outlook on advanced synthetic approaches for macrocyclic drug candidates.

Main Methods:

• Focus on a selection of unconventional macrocyclization examples.
• Review of synthetic strategies beyond ring-closing metathesis, macrolactonization, and macrolactamization.
• Application of these methods to the synthesis of natural products or analogues.

Main Results:

• Demonstration of efficient macrocyclization via unconventional routes.
• Successful synthesis of complex natural products and analogues.
• Expansion of the synthetic toolbox for macrocycle construction.

Conclusions:

• Unconventional macrocyclizations offer efficient alternatives for synthesizing therapeutic macrocycles.
• These methods overcome limitations of traditional approaches, enabling access to novel drug candidates.
• The presented strategies are valuable for advancing drug discovery and natural product synthesis.