The art and science of total synthesis at the dawn of the twenty-first century

At the dawn of the twenty-first century, the state of the art and science of total synthesis is as healthy and vigorous as ever. The birth of this exhilarating, multifaceted, and boundless science is marked by Wohler's synthesis of urea in 1828. This milestone event -as trivial as it may seem by today's standards - contributed to a demystification of nature and illuminated the entrance to a path which subsequently led to great heights and countless rich dividends for humankind. Being both a precise science and a fine art, this discipline has been driven by the constant flow of beautiful molecular architectures from nature and serves as the engine that drives the more general field of organic synthesis forward. Organic synthesis is considered, to a large extent, to be responsible for some of the most exciting and important discoveries of the twentieth century in chemistry, biology, and medicine, and continues to fuel the drug discovery and development process with myriad processes and compounds for new biomedical breakthroughs and applications. In this review, we will chronicle the past, evaluate the present, and project to the future of the art and science of total synthesis. The gradual sharpening of this tool is demonstrated by considering its history along the lines of pre-World War II, the Woodward and Corey eras, and the 1990s, and by accounting major accomplish ments along the way. Today, natural product total synthesis is associated with prudent and tasteful selection of challenging and preferably biologically important target molecules; the discovery and invention of new synthetic strategies and technologies; and explorations in chemical biology through molecular design and mechanistic studies. Future strides in the field are likely to be aided by advances in the isolation and characterization of novel molecular targets from nature, the availability of new reagents and synthetic methods, and information and automation technologies. Such advances are destined to bring the power of organic synthesis closer to, or even beyond, the boundaries defined by nature, which, at present, and despite our many advantages, still look so far away.