Boron in My Mind: A Comprehensive Review of the Evolution of the Diverse Syntheses of 4-Borono-l-Phenylalanine, the Leading Agent for Boron Neutron Capture Therapy.

Boron Neutron Capture Therapy (BNCT) leverages the nuclear reaction between boron-10 and thermal neutrons to selectively destroy cancer cells while minimizing damage to surrounding healthy tissues. This therapy has found use in treating glioblastoma, which as a brain cancer, is difficult to treat using conventional radiotherapy, surgery, and chemotherapy due to location and the risk of brain damage. However, to work, the cells must contain 10B. 4-Borono-l-phenylalanine (l-BPA) is the most frequently used boron delivery agent in this therapy. Surprisingly, despite its seemingly simple structure, there is no consensus approach to making it-the synthesis of l-BPA has been approached through multiple routes, reflecting the challenges in producing high-purity, isotopically enriched material. When a new site is looking to make this essential material, it can be challenging to determine the best route for the situation as there is no critical analysis comparing and discussing the relative merits of the approaches. Herein, we comprehensively and critically examine and compare the reported methods, from both the academic and patent literature, used to synthesize l-BPA. The review also highlights the limitations of each method regarding scalability, cost-effectiveness, and safety, especially considering the high cost of isotopically enriched 10B.