The Art and Science of Total Synthesis REVIEWS The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century** K. C. Nicolaou,* Dionisios Vourloumis, Nicolas Winssinger, and Phil S. Baran Dedicated to Professor E. J. Corey for his outstanding contributions to organic synthesis At the dawn of the twenty-first cen- of the most exciting and important covery and invention of new synthetic tury, the state of the art and science of discoveries of the twentieth century in strategies and technologies; and explo- total synthesis is as healthy and vigor- chemistry, biology, and medicine, and rations in chemical biology through ous as ever. The birth of this exhilarat- continues to fuel the drug discovery molecular design and mechanistic ing, multifaceted, and boundless sci- and development process with myriad studies. Future strides in the field are ence is marked by Wöhlers synthesis processes and compounds for new likely to be aided by advances in the of urea in 1828. This milestone eventÐ biomedical breakthroughs and appli- isolation and characterization of novel as trivial as it may seem by todays cations. In this review, we will chroni- molecular targets from nature, the standardsÐcontributed to a ªdemysti- cle the past, evaluate the present, and availability of new reagents and syn- fication of natureº and illuminated the project to the future of the art and thetic methods, and information and entrance to a path which subsequently science of total synthesis. The gradual automation technologies. Such advan- led to great heights and countless rich sharpening of this tool is demonstrated ces are destined to bring the power of dividends for humankind. Being both a by considering its history along the organic synthesis closer to, or even precise science and a fine art, this lines of pre-World War II, the Wood- beyond, the boundaries defined by discipline has been driven by the con- ward and Corey eras, and the 1990s, nature, which, at present, and despite stant flow of beautiful molecular archi- and by accounting major accomplish- our many advantages, still look so far tectures from nature and serves as the ments along the way. Today, natural away. engine that drives the more general product total synthesis is associated field of organic synthesis forward. with prudent and tasteful selection of Keywords: drug research ´ natural Organic synthesis is considered, to a challenging and preferably biologically products ´ synthetic methods ´ total large extent, to be responsible for some important target molecules; the dis- synthesis 1. Prologue more or less useful, are constantly discovered and investi- gated. For the determination of the structure, the architecture ªYour Majesty, Your Royal Highnesses, Ladies and Gentle- of the molecule, we have today very powerful tools, often men. borrowed from Physical Chemistry. The organic chemists of In our days, the chemistry of natural products attracts a very the year 1900 would have been greatly amazed if they had lively interest. New substances, more or less complicated, heard of the methods now at hand. However, one cannot say that the work is easier; the steadily improving methods make [*] K. C. Nicolaou, D. Vourloumis, N. Winssinger, P. S. Baran it possible to attack more and more difficult problems and the Department of Chemistry ability of Nature to build up complicated substances has, as it and The Skaggs Institute for Chemical Biology The Scripps Research Institute seems, no limits. 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA) In the course of the investigation of a complicated and substance, the investigator is sooner or later confronted by Department of Chemistry and Biochemistry the problem of synthesis, of the preparation of the substance University of California, San Diego by chemical methods. He can have various motives. Perhaps 9500 Gilman Drive, La Jolla, CA 92093 (USA) Fax: (1) 858-784-2469 he wants to check the correctness of the structure he has E-mail: [email protected] found. Perhaps he wants to improve our knowledge of the [**] A list of abbreviations can be found at the end of the article. reactions and the chemical properties of the molecule. If the Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000 1433-7851/00/3901-0045 $ 17.50+.50/0 45 REVIEWS K. C. Nicolaou et al. substance is of practical importance, he may hope that the The synthesis of a complicated molecule is, however, a very synthetic compound will be less expensive or more easily difficult task; every group, every atom must be placed accessible than the natural product. It can also be desirable to in its proper position and this should be taken in its most modify some details in the molecular structure. An antibiotic literal sense. It is sometimes said that organic synthesis substance of medical importance is often first isolated from a is at the same time an exact science and a fine art. Here microorganism, perhaps a mould or a germ. There ought to nature is the uncontested master, but I dare say that exist a number of related compounds with similar effects; they the prize-winner of this year, Professor Woodward, is a good may be more or less potent, some may perhaps have second.º[1] undesirable secondary effects. It is by no means, or even With these elegant words Professor A. Fredga, a member of probable, that the compound produced by the microorgan- the Nobel Prize Committee for Chemistry of the Royal ismÐmost likely as a weapon in the struggle for existenceÐis Swedish Academy of Sciences, proceeded to introduce R. B. the very best from the medicinal point of view. If it is possible Woodward at the Nobel ceremonies in 1965, the year in which to synthesize the compound, it will also be possible to modify Woodward received the prize for the art of organic synthesis. the details of the structure and to find the most effective Twenty-five years later Professor S. Gronowitz, then a mem- remedies. ber of the Nobel Prize Committee for Chemistry, concluded K. C. Nicolaou D. Vourloumis N. Winssinger P. S. Baran K.C. Nicolaou, born in Cyprus and educated in England and the US, is currently Chairman of the Department of Chemistry at The Scripps Research Institute, La Jolla, California, where he holds the Darlene Shiley Chair in Chemistry and the Aline W. and L. S. Skaggs Professorship in Chemical Biology as well as Professor of Chemistry at the University of California, San Diego. His impact on chemistry, biology, and medicine flows from his works in organic synthesis described in nearly 500 publications and 70 patents as well as his dedication to chemical education, as evidenced by his training of over 250 graduate students and postdoctoral fellows. His recent book titled ªClassics in Total Synthesisº,[3] which he co- authored with Erik J. Sorensen, is used around the world as a teaching tool and source of inspiration for students and practitioners of organic synthesis. Dionisios Vourloumis, born in 1966 in Athens, Greece, received his B.Sc. degree from the University of Athens and his Ph.D. from West Virginia University under the direction of Professor P. A. Magriotis, in 1994, working on the synthesis of novel enediyne antibiotics. He joined Professor K. C. Nicolaous group in 1996, and was involved in the total synthesis of epothilones A and B, eleutherobin, sarcodictyins A and B, and analogues thereof. He joined Glaxo Wellcome in early 1999 and is currently working with the Combichem Technology Team in Research Triangle Park, North Carolina. Nicolas Winssinger was born in Belgium in 1970. He received his B.Sc. degree in chemistry from Tufts University after conducting research in the laboratory of Professor M. DAlarcao. Before joining The Scripps Research Institute as a graduate student in chemistry in 1995, he worked for two years under the direction of Dr. M. P. Pavia at Sphinx Pharmaceuticals in the area of molecular diversity focusing on combinatorial chemistry. At Scripps, he joined the laboratory of Professor K. C. Nicolaou, where he has been working on methodologies for solid-phase chemistry and combinatorial synthesis. His research interests include natural products synthesis, molecular diversity, molecular evolution, and their application to chemical biology. Phil S. Baran was born in Denville, New Jersey in 1977. He received his B.Sc. degree in chemistry from New York University while conducting research under the guidance of Professors D. I. Schuster and S. R. Wilson, exploring new realms in fullerene science. Upon entering The Scripps Research Institute in 1997 as a graduate student in chemistry, he joined the laboratory of Professor K. C. Nicolaou where he embarked on the total synthesis of the CP molecules. His primary research interest involves natural product synthesis as an enabling endeavor for the discovery of new fundamental processes and concepts in chemistry and their application to chemical biology. 46 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Natural Products Synthesis REVIEWS his introduction of E. J. Corey, the 1990 Nobel prize winner, mentioned. The labeling of these eras is arbitraryÐnot with the following words: withstanding the tremendous impact Woodward and Corey ª...Corey has thus been awarded with the Prize for three had in shaping the discipline of total synthesis during their intimately connected contributions, which form a whole. time. As in any review of this kind, omissions are inevitable Through retrosynthetic analysis and introduction of new and we apologize profusely, and in advance, to those synthetic reactions, he has succeeded in preparing biologically whose brilliant works were omitted as a result of space important natural products, previously thought impossible to limitations. achieve. Coreys contributions have turned the art of synthesis into a science...º[2] This description and praise for total synthesis resonates today with equal validity and appeal; most likely, it will be 2.