Halichondrin B: synthesis of the C(1)-C(15) subunit

Area of Science:

• Organic Chemistry
• Synthetic Chemistry
• Natural Product Synthesis

Background:

• Halichondrin B is a marine natural product with significant biological activity.
• The synthesis of complex natural products like halichondrin B presents considerable challenges.
• Access to specific subunits is crucial for further biological evaluation and structural studies.

Purpose of the Study:

• To develop a short and efficient synthesis of the C(1)-C(15) subunit of halichondrin B.
• To establish a reliable route for preparing the polycyclic caged ketal 3 with defined stereochemistry.
• To explore alternative methods for stereochemical control within the synthetic sequence.

Main Methods:

• A 14-step synthesis starting from alpha-D-glucoheptonic acid gamma-lactone.
• Utilizing key reactions such as EtMgBr-promoted pinacol ring expansions and intramolecular Michael additions.
• Employing a one-pot, HF-induced conversion for simultaneous deprotection and cyclization steps.

Main Results:

• Successful synthesis of the C(1)-C(15) subunit (3) containing nine asymmetric centers.
• Demonstration of two similar synthetic routes with key reaction efficiencies.
• Development of alternative protocols for carbinol inversion at C(11).

Conclusions:

• The described synthesis provides an efficient route to a crucial fragment of halichondrin B.
• The methodology highlights the utility of pinacol ring expansions and Michael additions in complex molecule synthesis.
• This work facilitates further research into the chemistry and biology of halichondrin B.