Alkenes and Addition Reactions

CRIXIVAN® (Indinavir Sulfate), a critical HIV protease inhibitor developed at Merck, played a vital role in the global fight against HIV/AIDS. Due to the virus’s ability to cross the blood-brain barrier, maintaining effective drug levels throughout the body was a significant challenge. As a result, CRIXIVAN had to be administered in large daily doses—up to 3 grams per person—to ensure adequate therapeutic coverage, including the central nervous system.

Given the high daily dosage and the need to produce CRIXIVAN on a multi-ton scale, the synthesis had to be exceptionally efficient. This requirement led to the implementation of a convergent synthetic strategy, which minimized reaction steps and maximized yield, making large-scale production more feasible. Additionally, cost-effectiveness was a crucial factor, as the drug needed to be affordable for distribution in poorer, resource-limited countries where the HIV/AIDS epidemic was most severe. The synthesis was designed not only to be highly efficient but also economical, ensuring global accessibility and affordability.

The retrosynthesis of CRIXIVAN® revolves around two enantiopure building blocks: an epoxide fragment and (-)-cis-aminoindanol. In this chapter, you will explore the reactions involved in synthesizing the epoxide fragment depicted below, focusing on the formation of the epoxide and its iodohydrin precursor.