Controlled Microwave Heating as an Enabling Technology: Expedient Synthesis of Protease Inhibitors in Perspective

Abstract

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.

Spatial and Temporal Control of Microwave Triggered Chemiluminescence: A Protein Detection Platform

“…The >95-fold increase in heating rates of aqueous solutions is combined with pronounced cooling of solutions proximal to the conductive metal structures (Supporting Information, Figure S3 and Table S1). Subsequently, this technology potentially offers temperature jumps and rapid cooling rates that exceed denaturation rates of proteins. − In this regard, it is also conceivable that optimized structures can be designed to adequately balance the heating and cooling rates to develop inexpensive monomode reactors for microwave organic synthesis reactions . Furthermore, the extent of heating can be changed by changing the volume of solution or positioning sample distal from the region of maximum electric field enhancements.…”

“…[39][40][41][42] In this regard, it is also conceivable that optimized structures can be designed to adequately balance the heating and cooling rates to develop inexpensive monomode reactors for microwave organic synthesis reactions. 43 Furthermore, the extent of heating can be changed by changing the volume of solution or positioning sample distal from the region of maximum electric…”

Evaluation of a Nonresonant Microwave Applicator for Continuous-Flow Chemistry Applications

“…Since Suzuki and Miyaura first presented the palladium(0)-catalyzed cross-coupling between an organoboro compound and an organic halide (or pseudohalide), , it has become one of the most commonly used methods for C–C bond formation. The benefits of combining this reaction with microwaves are today also well established. , Microwave-assisted Suzuki–Miyaura coupling is commonly used by medicinal chemists and has been used, among other things, to functionalize HIV-1 protease inhibitors. − At a time when robust, chemoselective transformations are in high demand, the importance of this synthesis route makes it a good candidate for evaluation of the CF-MAOS system. Although there are numerous reports on microwave-assisted batch-type Suzuki–Miyaura couplings, and many examples of CF reactions employing classical heating, the number of published papers on MW-assisted Suzuki–Miyaura CF reactions is limited. ,, …”

Microwave-Assisted Ester Formation UsingO-Alkylisoureas: A Convenient Method for the Synthesis of Esters with Inversion of Configuration

“…The formation of esters using solid-supported reagents − and reagents/catalysts that are linked to a soluble-phase label − has been reported. The use of microwave-assisted chemistry has also proven to be useful for the rapid synthesis of esters, including in combination with polymer-assisted solution phase (PASP) chemistry …”