A Reverse Approach to the Total Synthesis of Halichondrin B.

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Medicinal Chemistry

Background:

• Halichondrin B is a complex natural product with significant therapeutic potential.
• Traditional synthesis strategies for halichondrin B involve sequential C-C bond formation followed by C-O bond formation.
• Developing efficient and convergent synthetic routes remains a key challenge.

Purpose of the Study:

• To introduce a novel synthetic strategy for halichondrin B.
• To reverse the classical order of C-O and C-C bond formation in the synthesis.
• To explore new opportunities for synthesizing halichondrin and eribulin family compounds.

Main Methods:

• Utilized the Nicholas reaction to generate linear ether precursors.
• Employed a convergent synthesis approach involving the coupling of key fragments (I, MN, EFG, A).
• Key steps included C-O bond formation prior to C-C bond formation, followed by macrolactonization.

Main Results:

• Successfully synthesized defined fragments I, MN, EFG, and A.
• Assembled these fragments into advanced intermediates IJKLMN and EFGHIJKLMN.
• Completed the total synthesis of halichondrin B via a short and convergent pathway.

Conclusions:

• The reversed strategy of C-O bond formation before C-C bond formation is effective for halichondrin B synthesis.
• This novel approach offers a more efficient and flexible route to halichondrin and eribulin analogs.
• The developed methodology opens new avenues for accessing complex polycyclic compounds.