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 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.
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Scope and definitions
The moniker of total synthesis is less frequently, but nevertheless accurately applied to the synthesis of natural polypeptides and polynucleotides; for instance, the peptide hormones oxytocin and vasopressin were isolated, and their total syntheses first reported, in 1954.
Aims
Although untrue from an historical perspective (see the history of the steroid, cortisone) total synthesis in the modern are has largely been an academic endeavour (in terms of manpower applied to problems), although industrial concerns may pick up particular avenues of total synthesis efforts, and expend considerable resources on particular natural product targets, especially in cases where semi-synthesis can be applied to complex, natural product-derived drugs. Even so, there is 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 in pharmaceutical discovery chemistry, in particular, as well as in process chemistry, in both cases, where 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. This was an important conceptual milestone in chemistry, as it was the first example of a synthesis of a substance known earlier, only as a byproduct of living processes. Wohler obtained urea by treating silver cyanate with ammonium chloride, a simple, one-step synthesis:
AgNCO + NH4Cl → (NH2)2CO + AgClCamphor was a scarce and expensive natural product with a worldwide demand. Haller and Blanc synthesized camphor from camphor acid; however, the precursor, camphoric acid, was of unknown structure. When Finnish chemist Gustav Komppa synthesized camphoric acid from diethyl oxalate and 3,3-dimethylpentanoic acid in 1904, the structure of these precursors allowed chemists at the time 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 this 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, where targets of his included 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, 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 the development of retrosynthetic analysis.
Examples
One classic in total synthesis is quinine total synthesis, which, before its total synthesis, had a history of many partial syntheses that spanned 150 years and included disputes and frustration.