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.^[1]

Aims

Although untrue from a historical perspective (see the history of the steroid, cortisone) total synthesis in the modern age 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. {{citation needed|date=August 2015}}

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 + AgCl

Camphor was a scarce and expensive natural product with a worldwide demand.{{when|date=March 2017}}{{according to whom|date=March 2017}} Haller and Blanc synthesized camphor from camphor acid;{{when|date=March 2017}} 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,{{when|date=March 2017}} William Perkin published another synthesis of camphor.{{relevance inline|date=March 2017}} 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.

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 by Robert Burns Woodward and William von Eggers Doering in 1944,^[3] had a history of many partial syntheses that spanned 150 years and included disputes and frustration.

References