Controlled microwave heating as an enabling technology: Expedient synthesis of protease inhibitors in perspective

Since the early days of organic chemistry, oil baths, hot plates, metal blocks, and isomantles have been the heating devices of choice for driving chemical reactions. Over the last years, microwave heating has evolved as a well-demonstrated alternative to classic heating with the potential to emerge as the preferred heating method in organic synthesis. In this perspective, we will illustrate that microwave heating has an edge over conventional heating also in medicinal and high-throughput chemistry applications, enabling both an expanded reaction range and the diminishing of reaction times from many hours or days down to minutes. By focusing on the development of protease inhibitors, we present a series of successful lead optimizations starting from complex core structures and using controlled microwave heating as the energy source. In short, hundreds of protease inhibitors have been quickly synthesized under microwave irradiation since the start of our high-speed program back in 1998.