In organic chemistry, a total synthesis is, in principle, the complete chemical synthesis of complex organic molecules from simpler pieces, usually without the aid of biological processes. In practice, these simpler pieces are commercially available in bulk and semi-bulk quantities, and are often petrochemical precursors. Sometimes bulk natural products (e.g. sugars) are used as starting materials and it is assumed that these have been or can be synthesised from their constituent elements. The target molecules can be natural products (biomolecules), medicinally important active ingredients, or organic compounds of theoretical interest in chemistry or biology. A new route for synthesis is developed in the course of the investigation, and the route may be the first one to be developed for the substance.
The first demonstration of organic total synthesis was Friedrich Wöhler's synthesis of urea in 1828, which demonstrated that organic molecules can be produced from inorganic precursors, and the first commercialized total synthesis was Gustaf Komppa's synthesis and industrial production of camphor in 1903. Early efforts focused on building chemicals which were extracted from biological sources, and using them to verify their biological activities—in this fashion, total synthesis was associated with disproving the existence of a vital force. As the sophistication of biology and chemistry became more understood, the primary purpose for total synthesis changed, although some total synthesis continues to be a tool for biological verification, for example if a compound contains ambiguous stereochemistry or to create analogs ("chemical mutations") to directly assess or improve the mechanism of biological activity.
Today, total synthesis is often justified as a playground for the development of new chemical reactions and routes, and highlights the sophistication of modern synthetic organic chemistry. Sometimes total synthesis inspires the development of novel mechanisms, catalysts, or techniques. Finally since a total synthesis project will often span a variety of reactions, it serves to prepare chemists for pursuits in process chemistry, where encyclopedic knowledge of chemical reactions and a strong and accurate sense of chemical intuition are necessary.
A formal synthesis describes not the synthesis of the desired end product but the synthesis of a compound that is already known from the literature to be a precursor to that desired end product. If it is known from the literature that B can be converted to C then a novel route from compound A to compound B is a formal proof that A can also give access to C.
Classical examples are the total syntheses of cholesterol, cortisone, strychnine, lysergic acid, reserpine, chlorophyll, colchicine, vitamin B12 and prostaglandin F-2a by the Nobel Prize winner Robert Burns Woodward between 1945 and 1976. Another classic is quinine total synthesis that has a history spanning 150 years. In some cases the structures of the molecules assigned by spectroscopic methods have been shown to be wrong, when synthesised.
Elias James Corey won the Nobel Prize in Chemistry in 1990 for lifetime achievement in total synthesis and the development of retrosynthetic analysis. In 2005 the group of Corey published an aflatoxin total synthesis and in 2006 an oseltamivir total synthesis.
- K. C. Nicolaou, D. Vourloumis, N. Winssinger and P. S. Baran (2000). "The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century" (reprint). Angewandte Chemie International Edition 39 (1): 44–122. doi:10.1002/(SICI)1521-3773(20000103)39:1<44::AID-ANIE44>3.0.CO;2-L. PMID 10649349.
- Nicolaou, K. C.; Sorensen, E. J. (1996). Classics in Total Synthesis: Targets, Strategies, Methods. Wiley. ISBN 978-3-527-29231-8.
- Nicolaou, K. C.; Snyder, S. A. (2003). Classics in Total Synthesis II: More Targets, Strategies, Methods. Wiley. ISBN 978-3-527-30684-8.