Total synthesis


Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes it from semisynthesis. The target molecules can be natural products, medicinally-important active ingredients, or organic compounds of theoretical interest.
Often, the aim is to discover new route of synthesis for a target molecule for which there already exist known routes. Sometimes, however, no route exists and the chemist wishes to find a viable route for the first time. One important purpose of total synthesis is the discovery of new chemical reactions and new chemical reagents.

Scope and definitions

The term total synthesis is less frequently but still accurately applied to the synthesis of natural polypeptides and polynucleotides. For instance, the peptide hormones oxytocin and vasopressin were isolated and their total syntheses were first reported in 1954.

Aims

Although untrue from a historical perspective, total synthesis in the modern age has largely been an academic endeavour. However, industrial concerns may pick up particular avenues of total synthesis efforts and expend considerable resources on particular natural product targets, especially if semi-synthesis can be applied to complex, natural product-derived drugs. Even so, there is a continuing discussion regarding the value of total synthesis as an academic enterprise, some aspects of which are summarised here.
Total synthesis projects often require a variety of reactions and so efforts to achieve complex total syntheses serve to prepare chemists for pursuits particularly in pharmaceutical discovery chemistry as well as in process chemistry. In both cases, comprehensive knowledge of chemical reactions and a strong and accurate chemical intuition are important qualifications.

History

Friedrich Wöhler discovered that an organic substance, urea, could be produced from inorganic starting materials in 1828. That was an important conceptual milestone in chemistry by being the first example of a synthesis of a substance that had been known only as a byproduct of living processes. Wöhler obtained urea by treating silver cyanate with ammonium chloride, a simple, one-step synthesis:
Camphor was a scarce and expensive natural product with a worldwide demand. Haller and Blanc synthesized it from camphor acid; however, the precursor, camphoric acid, had an unknown structure. When Finnish chemist Gustav Komppa synthesized camphoric acid from diethyl oxalate and 3,3-dimethylpentanoic acid in 1904, the structure of the precursors allowed contemporary chemists to infer the complicated ring structure of camphor. Shortly thereafter, William Perkin published another synthesis of camphor. The work on the total chemical synthesis of camphor allowed Komppa to begin industrial production of the compound, in Tainionkoski, Finland, in 1907.
The American chemist Robert Burns Woodward was a pre-eminent figure in developing total syntheses of complex organic molecules, some of his targets being cholesterol, cortisone, strychnine, lysergic acid, reserpine, chlorophyll, colchicine, vitamin B12, and prostaglandin F-2a.
Vincent du Vigneaud was awarded the 1955 Nobel Prize in Chemistry for the total synthesis of the natural polypeptide oxytocin and vasopressin, which reported in 1954 with the citation "for his work on biochemically important sulphur compounds, especially for the first synthesis of a polypeptide hormone."
Another gifted chemist is Elias James Corey, who won the Nobel Prize in Chemistry in 1990 for lifetime achievement in total synthesis and for the development of retrosynthetic analysis.

Examples

One classic in total synthesis is quinine total synthesis, which, before its total synthesis by Robert Burns Woodward and William von Eggers Doering in 1944, had a history of many partial syntheses that spanned 150 years and included disputes and frustration.