The generation of dihydropyrimidine libraries utilizing Biginelli multicomponent chemistry

With the emergence of high-throughput screening in the pharmaceutical industry over a decade ago, synthetic chemists were faced with the challenge of preparing large collections of molecules to satisfy the demand for new screening compounds. The unique exploratory power of multicomponent reactions such as the Ugi four-component reaction was soon recognized to be extremely valuable to produce compound libraries in a time- and cost effective manner. The present review article summarizes strategies for the construction of libraries through another multicomponent reaction, the Biginelli dihydropyrimidine synthesis. In this three-component condensation dating back to 1893, CH-acidic carbonyl compounds, aldehydes and urea-type building blocks combine to assemble a multifunctionalized dihydropyrimidine scaffold. Due to the interesting pharmacological properties associated with the privileged DHPM structures, the Biginelli reaction and related procedures have received increasing attention in recent years. This review details synthetic advances for the construction of Biginelli libraries via solution phase and solid-phase strategies that are amenable to a high-throughput or combinatorial format.