Practical Synthesis of Macrobicyclic Thiolincosamines

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Synthetic Chemistry

Background:

• Antibiotic resistance necessitates the development of novel therapeutic agents.
• Thiolincosamine fragments are crucial components of complex, biologically active molecules.
• Efficient synthetic routes are required for antibiotic candidates like BT-33 and cresomycin.

Purpose of the Study:

• To present scalable synthetic strategies for the northern macrobicyclic thiolincosamine fragments.
• To detail a key diastereoselective transformation for constructing these complex fragments.
• To enable the synthesis of antibiotic candidates BT-33 and cresomycin.

Main Methods:

• Development of scalable synthetic routes.
• Utilizing a zinc-promoted Barbier-type propargylation protocol.
• Employing a highly diastereoselective addition of an allenylzinc nucleophile to an Ellman sulfinimine intermediate.

Main Results:

• Successful scalable syntheses of thiolincosamine fragments were achieved.
• The key transformation demonstrated high diastereoselectivity.
• The protocol proceeded with dynamic kinetic resolution.
• Efficient synthesis utilized only 1.2 equiv of propargyl bromide precursors.

Conclusions:

• The presented synthetic methods provide scalable access to key fragments of complex antibiotics.
• The developed Barbier-type propargylation protocol is effective for diastereoselective synthesis.
• This work facilitates further development of antibiotic candidates BT-33 and cresomycin.