sign in sign up
<<
Home , Adolf Butenandt, Adolf Windaus, Emil Fischer, Georg Wittig, Hans Fischer, Kurt Alder

MILESTONES IN

Ian Grayson A nobel synthesis

IAN GRAYSON Evonik Degussa GmbH, Rodenbacher Chaussee 4, Hanau-Wolfgang, 63457,

he first for chemistry was because it is a scientific challenge, as he awarded in 1901 (to Jacobus van’t Hoff). described in his Nobel lecture: “The synthesis T Up to 2010, the chemistry prize has been of brazilin would have no industrial value; awarded 102 times, to 160 laureates, of whom its biological importance is problematical, only four have been women (1). The most but it is worth while to attempt it for the prominent area for awarding the Nobel Prize sufficient reason that we have no idea how for chemistry has been in organic chemistry, in to accomplish the task” (4). which the Nobel committee includes natural Continuing the list of Nobel Laureates in products, synthesis, catalysis, and polymers. we arrive next at R. B. This amounts to 24 of the prizes. Reading the Woodward. Considered by many the greatest achievements of the earlier organic organic of the 20th century, he who were recipients of the prize, we see that devised syntheses of numerous natural they were drawn to synthesis by the structural Alfred Nobel, 1833-1896 products, including lysergic acid, quinine, analysis and characterisation of natural cortisone and strychnine (Figure 1). 6 compounds. In order to prove the structure conclusively, some In collaboration with Albert Eschenmoser, he achieved the synthesis, even if only a partial synthesis, had to be attempted. It is synthesis of B12, a mammoth task involving nearly 100 impressive to read of some of the structures which were deduced students and post-docs over many years. Not only did he develop using only classical degradation and synthesis reactions, for all this work dates from an age before the everyday application of spectroscopic analysis. Among these early pioneers in the area of natural products, we can mention (1902), (1905), (1910), Richard Willstätter (1915), (1928), (1930), and (1937), (1938), and Leopold Ruzicka Scheme 1. Robinson’s tropinone synthesis. (1939). These chemists deduced the structure and reactions of many classes of natural products, including those that are essential for life, such as the porphyrins, , and . Already early in the 20th century, the importance of synthesis was recognised, both as a definite proof of structure and as a cheaper alternative to extraction. For example, Otto Wallach wrote in 1910: “As soon as chemists have a definite conception of the internal structure of the molecule of an organic compound, they are able to tackle the task of producing these substances by artificial methods, i.e. by synthesis, as we call it” (2). The recognition by the Nobel Prize committee of the importance of synthesis was continued by the award of the 1947 prize to Sir Robert Robinson, for his work on the alkaloids, including morphine and strychnine. Robinson had worked on synthesis for the first half of the 20th century, starting in 1905 in the laboratories of W. H. Perkin, Jr. In his synthesis of tropinone (Scheme 1) he devised both the first tandem reaction, and the first biomimetic synthesis (3). Like many great synthetic chemists, he had a deep understanding of the theoretical basis of the subject, and was responsible for the introduction of the “curly arrow” to describe reaction mechanisms. Robinson gave a clear reason Figure 1. Some natural products synthesised by R.B. Woodward. for performing synthesis – because the molecule exists and

chimica oggi/Chemistry Today - vol. 29 n. 4 July/August 2011 MILESTONES IN CHEMISTRY

chemical synthesis in the last 20-30 years (see the prize awards of 2001, 2005 and 2010). This continues a parallel tradition in the Nobel Prizes for organic chemistry, of honouring the development of new methods in synthesis. Previous prizes in this area had been awarded to (1912), to and (1950), and to Herbert Brown and (1979). Each of these chemists has contributed in different ways in the design of reactions which we now use every day in our own syntheses of pharmaceuticals, agrochemicals and other fine chemical products. Some of these achievements have been described Scheme 2. Corey’s retrosynthetic analysis of longifolene. by Ian Lennon in a previous article in this series celebrating the International Year of Chemistry (9). new procedures during his synthetic work, but his insights into So will there be another Nobel Prize for organic synthesis? the mechanism of the reactions led him, together with Roald Probably not, although future prizes may be awarded for other Hoffmann, to develop the Woodward-Hoffmann rules, describing advances in organic chemistry that are today in their infancy. the conservation of orbital symmetry in pericyclic reactions (5). The Nobel Prize is given “to the person who shall have made the For this work Hoffmann and received the Nobel most important chemical discovery or improvement”, as Nobel Prize in 1981. Woodward missed out on a second Nobel, having wrote in his will. Achieving the synthesis of ever more challenging died in 1979. Woodward’s Nobel lecture differs from that of many molecules with varied biological function, which are constantly of his predecessors. He did not give a retrospective on his life’s being isolated from plants, marine organisms and , work, but used the opportunity to describe a new and previously does not qualify for the Nobel Prize, in the opinion of the Prize unreported synthesis, of Cephalosporin C (6). committee, however breath-taking some of these syntheses Woodward’s work coincided with the introduction of are. Many of these outstanding syntheses are presented in spectroscopic analytical techniques, which made structure published collections to serve as examples for teaching (10), or determination both of natural products and of synthetic in books aimed more at the general chemical reader (11). One compounds much simpler, thing however is clear: the and which has given chemists challenge of synthesis set by the tools to isolate and these pioneers is still drawing synthesise ever more complex chemists to tackle the heights natural substances. of a synthetic challenge, both There was a long wait after in academic and industrial Woodward for the next Nobel Prize laboratories. in synthesis. E.J. Corey received As Georg Wittig put it, in his the prize in 1990, not for the series Nobel lecture delightfully of elegant total syntheses which entitled From Diyls to Ylides to 7 he had accomplished, but for My Idyll: “Chemical research “Development of the theory and mountaineering have much and methodology of organic in common. If the goal or the synthesis”. Corey, like Woodward, Figure 2. Some natural products synthesised by E.J. Corey. summit is to be reached, both was not only fascinated by the initiative and determination “how” of synthesis but also with the “why”. His Nobel Prize recognised as well as perseverance are required. But after the hard work the importance of his development of retrosynthetic analysis as a tool it is a great joy to be at the goal or the peak with its splendid for synthesis. As he said in his Nobel lecture: “In the fall of 1957 I came panorama (12). upon a simple idea which led to an entirely different way of designing a chemical synthesis. In this approach the target structure is subjected to a deconstruction process which corresponds to the reverse of a REFERENCES AND NOTES synthetic reaction, so as to convert that target structure to simpler precursor structures, without any assumptions with regard to starting 1. Details of all the Nobel Prizes, including biographies of the laureates materials. Each of the precursors so generated is then examined in the and the text of the prize lecture, can be found at www.nobelprize. same way, and the process is repeated until simple or commercially org. The chemistry prize lectures have also been reprinted in Angew. Chem. Int. Ed., and in several books, as listed in the references below. available structures result” (7). 2. O. Wallach, Nobel Lectures, Chemistry 1901-1921, Elsevier, Amsterdam, The power of retrosynthetic analysis was demonstrated in pp. 178-194 (1966). Corey’s analysis and subsequent synthesis of longifolene (8). The 3. R. Robinson, J. Chem. Soc., 111, p. 762 (1917). retrosynthetic analysis, breaking the molecule down into simple 4. R. Robinson, Nobel Lectures, Chemistry 1942-1962, Elsevier, precursors as described in his Nobel lecture, is shown in Scheme Amsterdam, pp. 166-185 (1964). 2. This development revolutionised the way chemists thought 5. R.B. Woodward, R. Hoffmann, Angew. Chem., Int. Ed., 8, p. 781 (1969). about designing syntheses, and paved the way for Corey’s 6. R.B. Woodward, Nobel Lectures, Chemistry, 1963-1970, Elsevier, Amsterdam, own syntheses of many more complex molecules, such as pp. 100-121 (1972). maytansine and gibberellic acid (Figure 2). As Corey put it in his 7. E.J. Corey, Nobel Lectures, Chemistry, 1981-1990, World Scientific Nobel lecture: “During the past 20 years systematic retrosynthetic Publishing Co., Singapore, pp. 686-708 (1992). thinking has permeated all areas of carbogenic synthesis. It is 8. E.J. Corey, M. Ohno et al., J. Am. Chem. Soc., 83, p. 1251 (1961). 9. I. Lennon, chimica oggi/Chemistry Today, 29(3), pp. 2-3 (2011). no longer possible to teach the subject of carbogenic synthesis 10. a) I. Fleming, Selected Organic Syntheses, Wiley, London (1973); b) effectively without the extensive use of retrosynthetic concepts K.C. Nicolaou, E.J. Sorensen, Classics in Total Synthesis, Wiley-VCH, and thinking” (7). Weinheim (1996). Corey’s prize was the last to be given for pure organic synthesis. 11. K.C. Nicolaou, T. Montagnon, Molecules that Changed the World, Some subsequent Nobel prizes have been awarded for Wiley-VCH, Weinheim (2008). synthetic method development, all in the more recent area 12. G. Wittig, Nobel Lectures, Chemistry, 1971-1980, World Scientific Publishing of organometallic catalysis, which has entered mainstream Co., Singapore pp. 368-376 (1993).

chimica oggi/Chemistry Today - vol. 29 n. 4 July/August 2011