The Art and Science of Total Synthesis

The Art and Science of Total Synthesis

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The birth of total synthesis occurred in the nineteenth century. The first conscious total synthesis of a natural product was that of urea (Figure 1) in 1828 by Wöhler. Significantly, this event also marks the beginning of organic synthesis and the first instance in which an inorganic substance (NH4CNO: ammonium cyanate) was converted into an organic substance. The synthesis of acetic acid from elemental carbon by Kolbe in 1845 is the second major achievement in the history of total synthesis. It is historically significant that, in his 1845 publication, Kolbe used the word “synthesis” for the first time to describe the process of assembling a chemical compound from other substances. The total syntheses of alizarin (1869) by Graebe and Liebermann and indigo (1878) by Baeyer spurred the legendary German dye industry and represent landmark accomplishments in thefield. But perhaps, after urea, the most spectacular totalsynthesis of the nineteenth century was that of (.)-glucose(Figure 1) by E. Fischer.This total synthesis is remarkable not only for the complexity of the target, which included, for the first time, stereochemical elements, but also for the considerable stereochemical control that accompanied it. With its oxygen-containing monocyclic structure (pyranose) and five stereogenic centers (four controllable), glucose represented the state-of-the-art in terms of target molecules at the end of the nineteenth century. E. Fischer became the second winner of the Nobel Prize for chemistry (1902), after J. H. van_t Hoff (1901).

As an example for the synthesis of Natural Product as below:

Chlorophyll a (1960)

Chlorophyll a, the green pigment of plants and the essential molecule of photosynthesis, is distinguished from its cousin molecule haemin by the presence of two extra hydrogen atoms (and, therefore, two chiral centers) in one of its pyrrole rings, the presence of the phytyl side chain, and the encapsulation of a magnesium cation rather than an iron cation. Its total synthesis by R. B. Woodward et al. in 1960 represents a beautiful example of bold planning and exquisite execution. This synthesis includes improvements over Fischer’s routes to porphyrin building blocks and, most importantly, a number of clever maneuvers for the installment of the three stereocenters and the extra five-membered ring residing on the periphery of the chlorin system of chlorophyll a. The chemical synthesis of chlorophyll a is a significant advance over Fischer’s total synthesis of haemin] and must have given Woodward the confidence, and prepared the ground, for his daring venture towards vitamin B12 in which he was to be joined by A. Eschenmoser.

The retrosynthesis of chlorophyll a could be explained by following illustration.

Mechanisms are occured throughout this synthesis as bellow:

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Reference:

Nicholaou, et al. 2000. The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century. Angew. Chem. Int. 39, 44 -122.