Total Synthesis of Halistatins 1 and 2

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Medicinal Chemistry

Background:

• Halistatins are complex natural products with potential anticancer properties.
• Previous synthetic efforts have been limited by challenges in constructing the core structure.

Purpose of the Study:

• To achieve the first total synthesis of halistatins 1 and 2.
• To develop novel synthetic methodologies using chromium-mediated coupling reactions.
• To investigate the stereochemical control in key bond-forming steps and spiroketalization.

Main Methods:

• Utilized stoichiometric Ni/Cr-mediated coupling for α-quaternary aldehyde and vinyl iodide coupling (C11/C12 bond).
• Employed catalytic, asymmetric Co/Cr-mediated iodoallylation for stereoselective C17-C19 fragment incorporation.
• Applied asymmetric Ni/Cr-mediated coupling for C19/C20 bond formation.
• Investigated solvent effects on [5,5]-spiroketalization stereoselectivity using p-toluenesulfonic acid (PTSA).

Main Results:

• Successfully synthesized halistatins 1 and 2.
• Achieved efficient C11/C12, C17/C19, and C19/C20 bond formations using various Cr-mediated couplings.
• Demonstrated that solvent composition critically influences spiroketalization stereoselectivity, with a 1:1 methanol-water mixture yielding >20:1 selectivity for the natural series.
• Showed that PTSA in 1:1 methanol-water can isomerize C38-epi-halichondrins to natural halichondrins.

Conclusions:

• The developed synthetic strategy provides a viable route to halistatins and related analogs.
• The study highlights the importance of solvent selection in controlling stereochemistry during complex molecule synthesis.
• The findings offer insights into the synthesis and potential epimerization of halichondrin-based compounds.