Atroposelective Total Synthesis of Darobactin A

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Synthetic Biology

Background:

• Darobactin A is a novel antibiotic featuring a complex, strained macrocyclic structure.
• The development of efficient synthetic routes is crucial for accessing and studying novel antibiotics.
• Existing methods for synthesizing complex macrocycles can be lengthy and inefficient.

Purpose of the Study:

• To disclose a concise and modular synthesis of the novel antibiotic darobactin A.
• To establish a method for constructing the strained macrocyclic core of darobactin A.
• To incorporate medicinal chemistry considerations for potential drug development.

Main Methods:

• Utilized sequential macrocyclization strategies.
• Employed two atroposelective Larock-based macrocyclizations.
• Incorporated C-H activation and decarboxylative cross-coupling for building blocks.

Main Results:

• Successfully forged the strained macrocyclic ring system of darobactin A.
• Achieved exquisite regioselectivity in a key macrocyclization step with an unprotected alkyne.
• Prepared unnatural amino acid building blocks in enantiopure form efficiently.

Conclusions:

• The developed synthesis provides a viable and modular route to darobactin A.
• The strategy allows for late-stage appendage of key molecular portions, aiding medicinal chemistry efforts.
• This work facilitates further investigation and potential development of darobactin A as an antibiotic.