Total Synthesis of Darobactin A

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Synthetic Biology

Background:

• Darobactin A is a recently discovered antibiotic with selective activity against Gram-negative bacteria.
• The complex structure of darobactin A presents a significant challenge for chemical synthesis.
• Targeting Gram-negative bacteria is crucial due to rising antibiotic resistance.

Purpose of the Study:

• To achieve the total synthesis of darobactin A.
• To develop scalable synthetic routes for key building blocks, including non-canonical amino acids.
• To explore and optimize cyclization strategies for constructing the bismacrocyclic core.

Main Methods:

• Convergent synthesis strategy.
• Development of scalable routes for three non-canonical amino acids.
• Sequential, halogen-selective Larock indole syntheses for bismacrocycle closure.

Main Results:

• Successful total synthesis of darobactin A accomplished.
• Longest linear sequence of 16 steps achieved from d-Garner's aldehyde and l-serine.
• The order of sequential cyclizations was critical for forming the correct atropisomer.

Conclusions:

• The total synthesis of darobactin A is feasible using a convergent approach.
• The developed methods provide access to a promising new antibiotic scaffold.
• This work validates the utility of sequential Larock indole syntheses in complex molecule construction.