The Art and science of Total Synthesis 。 “ Diels-Adet WS ANGEWANDTE GH气M CWILEY-VCH
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 exhil continues to fuel the drug discovery molecular design and mechanistic ing, multifaceted, and boundless and development process with myriad studies. Future strides in the field are ence is marked by Wohler's synthesis processes and compounds for new likely to be aided by advances in the of urea in 1828. This milestone event- 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 standards-contributed to a"demysti- cle the past, evaluate the present, and availability of new reagents and syn fication of nature"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 Il, 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: research natural Organic synthesis is considered, to a challenging and preferably biologically products hetic 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 "Your 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 year 1900 ely 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 IK. C Nicolaou, D. Vourloumis, N. winssinger, P.S. Baran it possible to attack more and more difficult problems and and The Skaggs Institute for Chemical Biology ability of Nature to build up complicated substances has, as it The Scripps Research Institute seems no limits. 50 North Torrey Pines Road, La Jolla, CA 92037(USA) y. In the course of the investigation of a complicated Ibstance, the investigator is sooner or later confronted by Department of C and Biochemistry San Diego the problem of synthesis, of the preparation of the substance 9500 Gilman D olla, CA 92093 (USA) by chemical methods. He can have various motives. Perhaps Fax:(+1)858-78 he wants to check the correctness of the structure he has 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 O WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000 1433-7851/00N3901-0045 S 17.50+.500
1. Prologue ªYour Majesty, Your Royal Highnesses, Ladies and Gentlemen. In our days, the chemistry of natural products attracts a very lively interest. New substances, more or less complicated, more or less useful, are constantly discovered and investigated. For the determination of the structure, the architecture of the molecule, we have today very powerful tools, often borrowed from Physical Chemistry. The organic chemists of the year 1900 would have been greatly amazed if they had heard of the methods now at hand. However, one cannot say that the work is easier; the steadily improving methods make it possible to attack more and more difficult problems and the ability of Nature to build up complicated substances has, as it seems, no limits. In the course of the investigation of a complicated substance, the investigator is sooner or later confronted by the problem of synthesis, of the preparation of the substance by chemical methods. He can have various motives. Perhaps he wants to check the correctness of the structure he has found. Perhaps he wants to improve our knowledge of the reactions and the chemical properties of the molecule. If the 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 century, the state of the art and science of total synthesis is as healthy and vigorous as ever. The birth of this exhilarating, multifaceted, and boundless science is marked by Wöhler s synthesis of urea in 1828. This milestone eventÐ as trivial as it may seem by today s standardsÐcontributed to a ªdemystification of natureº and illuminated the entrance to a path which subsequently led to great heights and countless rich dividends for humankind. Being both a precise science and a fine art, this discipline has been driven by the constant flow of beautiful molecular architectures from nature and serves as the engine that drives the more general field of organic synthesis forward. Organic synthesis is considered, to a large extent, to be responsible for some of the most exciting and important discoveries of the twentieth century in chemistry, biology, and medicine, and continues to fuel the drug discovery and development process with myriad processes and compounds for new biomedical breakthroughs and applications. In this review, we will chronicle the past, evaluate the present, and project to the future of the art and science of total synthesis. The gradual sharpening of this tool is demonstrated by considering its history along the lines of pre-World War II, the Woodward and Corey eras, and the 1990s, and by accounting major accomplishments along the way. Today, natural product total synthesis is associated with prudent and tasteful selection of challenging and preferably biologically important target molecules; the discovery and invention of new synthetic strategies and technologies; and explorations in chemical biology through molecular design and mechanistic studies. Future strides in the field are likely to be aided by advances in the isolation and characterization of novel molecular targets from nature, the availability of new reagents and synthetic methods, and information and automation technologies. Such advances are destined to bring the power of organic synthesis closer to, or even beyond, the boundaries defined by nature, which, at present, and despite our many advantages, still look so far away. Keywords: drug research ´ natural products ´ synthetic methods ´ total synthesis [*] K. C. Nicolaou, D. Vourloumis, N. Winssinger, P. S. Baran Department of Chemistry and The Skaggs Institute for Chemical Biology The Scripps Research Institute 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA) and Department of Chemistry and Biochemistry University of California, San Diego 9500 Gilman Drive, La Jolla, CA 92093 (USA) Fax: (1) 858-784-2469 E-mail: kcn@scripps.edu [**] A list of abbreviations can be found at the end of the article. REVIEWS 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 comp will be le difficult task: every group, every atom must be place 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. "ll 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 ism--most likely as a weapon in the struggle for existence--is Swedish Academy of Sciences, proceeded to introduce R. 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- ber of the Nobel Prize Committee for Chemistry, concluded K. C. Nicolaou D. Vourloumis 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 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"Classics in Total Synthesis /which he co- authored with Erik J. Sorensen, is used around the world as a teaching tool and source of inspiration for students and 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. Nicolaou's 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. D'Alarcao. 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 197. 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 llerene 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 Angew. Chem. Int. Ed. 2000. 39. 44-122
REVIEWS K. C. Nicolaou et al. substance is of practical importance, he may hope that the synthetic compound will be less expensive or more easily accessible than the natural product. It can also be desirable to modify some details in the molecular structure. An antibiotic substance of medical importance is often first isolated from a microorganism, perhaps a mould or a germ. There ought to exist a number of related compounds with similar effects; they may be more or less potent, some may perhaps have undesirable secondary effects. It is by no means, or even probable, that the compound produced by the microorganismÐmost likely as a weapon in the struggle for existenceÐis the very best from the medicinal point of view. If it is possible to synthesize the compound, it will also be possible to modify the details of the structure and to find the most effective remedies. The synthesis of a complicated molecule is, however, a very difficult task; every group, every atom must be placed in its proper position and this should be taken in its most literal sense. It is sometimes said that organic synthesis is at the same time an exact science and a fine art. Here nature is the uncontested master, but I dare say that the prize-winner of this year, Professor Woodward, is a good second.º[1] With these elegant words Professor A. Fredga, a member of the Nobel Prize Committee for Chemistry of the Royal Swedish Academy of Sciences, proceeded to introduce R. B. Woodward at the Nobel ceremonies in 1965, the year in which Woodward received the prize for the art of organic synthesis. Twenty-five years later Professor S. Gronowitz, then a member of the Nobel Prize Committee for Chemistry, concluded 46 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 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 coauthored 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. Nicolaou s 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. D Alarcao. 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. K. C. Nicolaou D. Vourloumis N. Winssinger P. S. Baran
Natural Products Synthesis REVIEWS his introduction of E J. Corey, the 1990 Nobel prize winner, mentioned. The labeling of these eras is arbitrary--not with the following word tremendous 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 inevitabl 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."12I This description and praise for total synthesis resonates oday with equal validity and appeal; most likely, it will be 2. Total Synthesis in the Nineteenth Century valid for some time to come. Indeed, unlike many one-time discoveries or inventions, the endeavor of total synthesis 3-olis The birth of total synthesis occurred in the nineteenth in a constant state of effervescence and flux. It has been on the century. The first conscious total synthesis of a natural product move and center stage throughout the twentieth century and was that of urea(Figure 1)in 1828 by Wohler Is Significantly continues to provide fertile ground for new discoveries and this event also marks the beginning of organic synthesis and nventions. Its central role and importance within chemistry will undoubtedly ensure its present preeminence into the future. The practice of total synthesis demands the following virtues from, and cultivates the best in, those who practice it ingenuity, artistic taste, experimental skill, persistence, and acetic acid glucose character. In turn, the practitioner is often rewarded with discoveries and inventions that impact, in major ways, not [ohler, 1828/8) only other areas of chemistry but most significantly material Figure 1. Selected nineteenth century landmark total syntheses of natural science, biology, and medicine. The harvest of chemical ynthesis touches upon our everyday lives in myriad ways medicines, high-tech materials for computers, communication the first instance in which an inorganic substance and transportation equipment, nutritional products, vitamins, (NH CNO: ammonium cyanate) was converted into an or- cosmetics, plastics, clothing, and tools for biology and ganic substance. The synthesis of acetic acid from elemental carbon by Kolbe in 1845 is the second major achievement in di. But why is it that total synthesis has such a lasting value as a the history of total synthesis. It is historically significant that, discipline within chemistry There must be several reasons for in his 1845 publication, Kolbe used the word"synthesis"for this phenomenon. To be sure, its dual nature as a precise the first time to describe the 1 of assembling a chemical science and a fine art provides excitement and rewards of rare compound from other substances. The total syntheses of heights. Most significantly, the discipline is continually being alizarin(1869) by Graebe and Liebermann/lol and indigo challenged by new structural types isolated from nature's( 1878) by Baeyerlll spurred the legendary German dye cemingly unlimited library of molecular architectures. Hap- industry and represent landmark accomplishments in the pily, the practice of total synthesis is being enriched constantly field. But perhaps, after urea, the most spectacular total by new tools such as new reagents and catalysts as well as synthesis of the nineteenth century was that of (+)-glucose analytical instrumentation for the rapid purification and(Figure 1)by E. Fischer. 2I This total synthesis is remarkable characterization of compound not only for the complexity of the target, which included, for Thus, the original goal of total synthesis during the first part the first time, stereochemical elements, but also for the of the twentieth century to confirm the structure of a natural considerable stereochemical control that accompanied product has been replaced slowly but surely with objectives With its oxygen-containing monocyclic structure(pyranose) related more to the exploration and discovery of new and five stereogenic centers(four controllable), glucose chemistry along the pathway to the target molecule. More represented the state-of-the-art in terms of target molecules recently, issues of biology have become extremely important at the end of the nineteenth century. E. Fischer became the components of programs in total synthesis. It is now clear that second winner of the Nobel Prize for chemistry(1902), after as we enter the twenty-first century both exploration and J. H. van't Hoff(1901 ). 31 discovery of new chemistry and chemical biology will be facilitated by developments in total synthesis. In this article, and following a short historical perspective of otal synthesis in the nineteenth century, we will attempt to 3. Total Synthesis in the Twentieth Century review the art and science of total synthesis during the twentieth century. This period can be divided into the pre The twentieth century has been an age of enormous World War II Era, the Woodward Era, the Corey Era, and the scientific advancement and technological progress. To be 1990s. There are clearly overlaps in the last three eras and sure, we now stand at the highest point of human accomplish- many more practitioners deserve credit for contributing to the ment in science and technology, and the twenty-first century evolution of the science during these periods than are promises to be even more revealing and rewarding. Advances Angew. Chem. Int Ed 2000, 39, 44-122
Natural Products Synthesis REVIEWS his introduction of E. J. Corey, the 1990 Nobel prize winner, with the following words: ª...Corey has thus been awarded with the Prize for three intimately connected contributions, which form a whole. Through retrosynthetic analysis and introduction of new synthetic reactions, he has succeeded in preparing biologically important natural products, previously thought impossible to achieve. Corey s 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 valid for some time to come. Indeed, unlike many one-time discoveries or inventions, the endeavor of total synthesis[3±6] is in a constant state of effervescence and flux. It has been on the move and center stage throughout the twentieth century and continues to provide fertile ground for new discoveries and inventions. Its central role and importance within chemistry will undoubtedly ensure its present preeminence into the future. The practice of total synthesis demands the following virtues from, and cultivates the best in, those who practice it: ingenuity, artistic taste, experimental skill, persistence, and character. In turn, the practitioner is often rewarded with discoveries and inventions that impact, in major ways, not only other areas of chemistry, but most significantly material science, biology, and medicine. The harvest of chemical synthesis touches upon our everyday lives in myriad ways: medicines, high-tech materials for computers, communication and transportation equipment, nutritional products, vitamins, cosmetics, plastics, clothing, and tools for biology and physics. [7] But why is it that total synthesis has such a lasting value as a discipline within chemistry? There must be several reasons for this phenomenon. To be sure, its dual nature as a precise science and a fine art provides excitement and rewards of rare heights. Most significantly, the discipline is continually being challenged by new structural types isolated from nature s seemingly unlimited library of molecular architectures. Happily, the practice of total synthesis is being enriched constantly by new tools such as new reagents and catalysts as well as analytical instrumentation for the rapid purification and characterization of compounds. Thus, the original goal of total synthesis during the first part of the twentieth century to confirm the structure of a natural product has been replaced slowly but surely with objectives related more to the exploration and discovery of new chemistry along the pathway to the target molecule. More recently, issues of biology have become extremely important components of programs in total synthesis. It is now clear that as we enter the twenty-first century both exploration and discovery of new chemistry and chemical biology will be facilitated by developments in total synthesis. In this article, and following a short historical perspective of total synthesis in the nineteenth century, we will attempt to review the art and science of total synthesis during the twentieth century. This period can be divided into the preWorld War II Era, the Woodward Era, the Corey Era, and the 1990s. There are clearly overlaps in the last three eras and many more practitioners deserve credit for contributing to the evolution of the science during these periods than are mentioned. The labeling of these eras is arbitraryÐnot withstanding the tremendous impact Woodward and Corey had in shaping the discipline of total synthesis during their time. As in any review of this kind, omissions are inevitable and we apologize profusely, and in advance, to those whose brilliant works were omitted as a result of space limitations. 2. Total Synthesis in the Nineteenth Century 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.[8] Significantly, this event also marks the beginning of organic synthesis and O NH2 NH2 O Me OH O OH HO HO OH OH urea [Wöhler, 1828][8] acetic acid [Kolbe, 1845][9] glucose [Fischer, 1890][12] Figure 1. Selected nineteenth century landmark total syntheses of natural products. 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[9] is the second major achievement in the history of total synthesis. It is historically significant that, in his 1845 publication, Kolbe used the word ªsynthesisº 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[10] and indigo (1878) by Baeyer[11] spurred the legendary German dye industry and represent landmark accomplishments in the field. But perhaps, after urea, the most spectacular total synthesis of the nineteenth century was that of ()-glucose (Figure 1) by E. Fischer.[12] 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). [13] 3. Total Synthesis in the Twentieth Century The twentieth century has been an age of enormous scientific advancement and technological progress. To be sure, we now stand at the highest point of human accomplishment in science and technology, and the twenty-first century promises to be even more revealing and rewarding. Advances Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 47
REVIEWS K. C. Nicolaou et al in medicine, computer science, communication, and trans portation have dramatically changed the way we live and the way we interact with the world around us. An enormous lount of wealth has been created and opportunities for new enterprises abound. It is clear that at the heart of this a-terpineol technological revolution has been science, and one cannot Komppa, 1903/15 deny that basic research has provided the foundation for this to occur Chemistry has played a central and decisive role in shaping Me- the twentieth century. Oil, for example, has reached potential only after chemistry allowed its analysis, fractiona tion, and transformation into myriad of useful products such as kerosene and other fuels. Synthetic organic chemistry is perhaps the most expressive branch of the science of Ho c haemin co,H pyridoxine hydrochlorlde chemistry in view of its creative power and unlimited scope. To appreciate its impact on modern humanity one only has to Figure 2. Selected landmark total syntheses of natural products from 1901 to1939 look around and recognize that this science is a pillar behind pharmaceuticals, high-tech materials, polymers, fertilizers, pesticides, cosmetics, and clothing. 7I The engine that drives forward and sharpens our ability to create such molecules 3. 2. The Woodward Era through chemical synthesis(from which we can pick and choose the most appropriate for each application)is total In 1937 and at the age of 20 R B. Woodward became an synthesis. In its quest to construct the most complex and assistant professor in the Department of Chemistry at challenging of nature's products, this endeavor--perhaps Harvard University where he remained for the rest of his more that any other-becomes the prime driving force for life. Since that time, total synthesis and organic chemistry the advancement of the art and science of organic synthesis. would never be the same. a quantum leap forward was about Thus, its value as a research discipline extends beyond to be taken, and total synthesis would be elevated to a providing a test for the state-of-the-art. It offers the oppor- powerful science and a fine art. Woodward's climactic tunity to discover and invent new science in chemistry and contributions to total synthesis included the conquest of some related disciplines, as well as to train, in a most rigorous way, of the most fearsome molecular architectures of the time. One young practitioners whose expertise may feed many periph- after another, diverse structures of unprecedented complexity eral areas of science and technology. 16) succumbed to synthesis in the face of his ingenuity and resourcefulness. The following structures(some are shown in Figure 3)are amongst his most spectacular synthetic achieve ments: quinine(1944), 2I patulin(1950). 231 cholesterol and 3.1 The pre World War ll era cortisone(1951), 24 lanosterol( 1954), /25 lysergic acid (1954). /261 strychnine(1954), z7 reserpine(1958), 28I chlorophyll a(1960), 129) The syntheses of the nineteenth century were relatively colchicine (1965), 26 cephalosporin C(1966), 50 prostaglan simple and, with a few exceptions, were directed towards din F2a( 1973), 311 vitamin B12(with A. Eschenmoser)(1973), 32 benzenoid compounds. The starting materials for these target and erythromycin A(1981) 3 Some of these accomplishments molecules were other benzenoid compounds, chosen for their will be briefly presented in Section 3.5 resemblance to the targeted substance and the ease by which Woodward brought his towering intellect to bear on these the synthetic chemist could connect them by simple function- daunting problems of the 1940s, 1950s, and 1960s with alization chemistry. The twentieth century was destined to distinctive style and unprecedented glamour. His spectacular bring dramatic advances in the field of total synthesis. The successes were often accompanied by appropriate media pre-World War II Era began with impressive strides and with coverage and his lectures and seminars remained legendary increasing molecular complexity and sophistication in strat- for their intellectual content, precise delivery, and mesmeriz egy design. Some of the most notable examples of total ing style, not to mention their colorful nature and length! synthesis of this era are a-terpineol(Perkin, 1904), 4) What distinguished him from his predecessors was not just his camphor(Komppa, 1903; Perkin, 1904), 5 tropinone(Rob- powerful intellect, but the mechanistic rationale and stereo- inson, 1917: Willstatter, 1901), 16-17 haemin(H. Fischer, chemical control he brought to the field. If Robinson 1929), 8I pyridoxine hydrochloride(Folkers, 1939), 19-20 and introduced the curved arrow to organic chemistry(on paper) equilenin(Bachmann, 1939)211( Figure 2). Particularly im- Woodward elevated it to the sharp tool that it became for pressive were Robinsons one-step synthesis of tropinone teaching and mechanistic understanding, and used it 1917)161 from succindialdehyde, methylamine, and acetone explain his science and predict the outcome of chemical dicarboxylic acid and H. Fischer's synthesis of haemin s reactions. He was not only a General but, most importantly, a (1929). These total syntheses are among those which will be generalist and could generalize observations into useful highlighted below. Both men went on to win a Nobel Prize for theories. He was master not only of the art of total synthesis, Chemistry(Fischer, 1929; Robinson, 1947). 31 but also of structure determination an endeavor he cherished Angew. Chem. Int. Ed. 2000. 39. 44-122
REVIEWS K. C. Nicolaou et al. in medicine, computer science, communication, and transportation have dramatically changed the way we live and the way we interact with the world around us. An enormous amount of wealth has been created and opportunities for new enterprises abound. It is clear that at the heart of this technological revolution has been science, and one cannot deny that basic research has provided the foundation for this to occur. Chemistry has played a central and decisive role in shaping the twentieth century. Oil, for example, has reached its potential only after chemistry allowed its analysis, fractionation, and transformation into myriad of useful products such as kerosene and other fuels. Synthetic organic chemistry is perhaps the most expressive branch of the science of chemistry in view of its creative power and unlimited scope. To appreciate its impact on modern humanity one only has to look around and recognize that this science is a pillar behind pharmaceuticals, high-tech materials, polymers, fertilizers, pesticides, cosmetics, and clothing.[7] The engine that drives forward and sharpens our ability to create such molecules through chemical synthesis (from which we can pick and choose the most appropriate for each application) is total synthesis. In its quest to construct the most complex and challenging of nature s products, this endeavorÐperhaps more that any otherÐbecomes the prime driving force for the advancement of the art and science of organic synthesis. Thus, its value as a research discipline extends beyond providing a test for the state-of-the-art. It offers the opportunity to discover and invent new science in chemistry and related disciplines, as well as to train, in a most rigorous way, young practitioners whose expertise may feed many peripheral areas of science and technology. [6] 3.1. The Pre-World War II Era The syntheses of the nineteenth century were relatively simple and, with a few exceptions, were directed towards benzenoid compounds. The starting materials for these target molecules were other benzenoid compounds, chosen for their resemblance to the targeted substance and the ease by which the synthetic chemist could connect them by simple functionalization chemistry. The twentieth century was destined to bring dramatic advances in the field of total synthesis. The pre-World War II Era began with impressive strides and with increasing molecular complexity and sophistication in strategy design. Some of the most notable examples of total synthesis of this era are a-terpineol (Perkin, 1904),[14] camphor (Komppa, 1903; Perkin, 1904),[15] tropinone (Robinson, 1917; Willstätter, 1901),[16±17] haemin (H. Fischer, 1929),[18] pyridoxine hydrochloride (Folkers, 1939),[19±20] and equilenin (Bachmann, 1939)[21] (Figure 2). Particularly impressive were Robinson s one-step synthesis of tropinone (1917)[16] from succindialdehyde, methylamine, and acetone dicarboxylic acid and H. Fischer s synthesis of haemin[18] (1929). These total syntheses are among those which will be highlighted below. Both men went on to win a Nobel Prize for Chemistry (Fischer, 1929; Robinson, 1947).[13] Figure 2. Selected landmark total syntheses of natural products from 1901 to 1939. 3.2. The Woodward Era In 1937 and at the age of 20 R. B. Woodward became an assistant professor in the Department of Chemistry at Harvard University where he remained for the rest of his life. Since that time, total synthesis and organic chemistry would never be the same. A quantum leap forward was about to be taken, and total synthesis would be elevated to a powerful science and a fine art. Woodward s climactic contributions to total synthesis included the conquest of some of the most fearsome molecular architectures of the time. One after another, diverse structures of unprecedented complexity succumbed to synthesis in the face of his ingenuity and resourcefulness. The following structures (some are shown in Figure 3) are amongst his most spectacular synthetic achievements: quinine (1944), [22] patulin (1950), [23] cholesterol and cortisone (1951), [24] lanosterol (1954), [25] lysergic acid (1954),[26] strychnine (1954), [27] reserpine (1958), [28] chlorophyll a (1960), [29] colchicine (1965), [286] cephalosporin C (1966), [30] prostaglandin F2a (1973), [31] vitamin B12 (with A. Eschenmoser) (1973),[32] and erythromycin A (1981). [33] Some of these accomplishments will be briefly presented in Section 3.5. Woodward brought his towering intellect to bear on these daunting problems of the 1940s, 1950s, and 1960s with distinctive style and unprecedented glamour. His spectacular successes were often accompanied by appropriate media coverage and his lectures and seminars remained legendary for their intellectual content, precise delivery, and mesmerizing style, not to mention their colorful nature and length! What distinguished him from his predecessors was not just his powerful intellect, but the mechanistic rationale and stereochemical control he brought to the field. If Robinson introduced the curved arrow to organic chemistry (on paper), Woodward elevated it to the sharp tool that it became for teaching and mechanistic understanding, and used it to explain his science and predict the outcome of chemical reactions. He was not only a General but, most importantly, a generalist and could generalize observations into useful theories. He was master not only of the art of total synthesis, but also of structure determination, an endeavor he cherished 48 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122
Natural Products Synthesis REVIEWS cortisone( ychnine(1954) 271 M reserpine(1958) 28 6-demethyl-6-deoxytetracycline(1962)285 cephalosporin C(1966)30 isolongistrobine(1973) 2871 penems(1978) 2901 vitamin B12(1973)/32 HOOo with A Eschenmoser illudalic acid(1977)/289 illudinine(1977)/ 289 illudacetalic acid (1977)/289 erythromycin A(1981)33 Figure 3. Selected syntheses by the Woodward Group(1944-1981). throughout his career. He clearly influenced the careers of not Urbana-Champaign. His dynamism and brilliance were to only his students, but also of his peers and colleagues, for make him the natural recipient of the total synthesis baton Blo nple, J. wilkinson(sandwich structure of ferrocene), K. from R.B. Woodward, even though the two men overlapped Block(steroid biosynthesis), R. Hoffmann(Woodward and for two decades at Harvard. Corey's pursuit of total synthesis Hoffmann rules), all of whom won the Nobel Prize for was marked by two distinctive elements, retrosynthetic analysis and the development of new synthetic methods lis brilliant use of rings to install and control stereo- an integral part of the endeavor, even though Woodward hemical centers and to unravel functionality by rupturing (consciously or unconsciously) must have been engaged in them is an unmistakable feature of his syntheses. This theme such practices. It was Corey's 1961 synthesis of longifolene/ 34 ppears in his first total synthesis, that of quinine, 12 and that marked the official introduction of the principles of appears over and over again as in the total synthesis of retrosynthetic analysis 4I He practiced and spread this concept reserpine, /28 vitamin B2, B32 and, remarkably, in his last throughout the world of total synthesis, which became a much ynthesis, that of erythromycin. 33 Woodwards mark was that more rational and systematic endeavor. Students could now of an artist, treating each target individually with total be taught the"logic"of chemical synthesis I by learning how mastery as he moved from one structural type to another. to analyze complex target molecules and devise possibl He exercised an amazing intuition in devising strategies synthetic strategies for their construction. New synthetic toward his targets, magically connecting them to suitable methods are often incorporated into the synthetic schemes starting materials through elegant, almost balletlike, maneu- towards the target and the exercise of the total synthesis becomes an opportunity for the invention and discovery of However, the avalanche of new natural products appearing new chemistry. Combining his systematic and brilliant ap- on the scene as a consequence of the advent and development proaches to total synthesis with the new tools of organic of new analytical techniques demanded a new and more synthesis and analytical chemistry, Corey synthesized hun systematic approach to strategy design. A new school of dreds of natural and designed products within the thirty year thought was appearing on the horizon which promised to take period stretching between 1960 and 1990 (Figure 4)the year the field of total synthesis, and that of organic synthesis in of his Nobel Prize general, to its next level of sophistication Corey brought a highly organized and systematic approach to the field of total synthesis by identifying unsolved and important structural types and pursuing them until they fell. 3.3. The Corey Era The benefits and spin-offs from his endeavors were even more impressive: the theory of retrosynthetic analysis, new syn In 1959 and at the age of 31 E J. Corey arrived at Harvard thetic methods, asymmetric synthesis, mechanistic proposals, as a full professor of chemistry from the University of Illinois, and important contributions to biology and medicine. Some of Angew. Chem. Int Ed 2000, 39, 44-122
Natural Products Synthesis REVIEWS throughout his career. He clearly influenced the careers of not only his students, but also of his peers and colleagues, for example, J. Wilkinson (sandwich structure of ferrocene), K. Block (steroid biosynthesis), R. Hoffmann (Woodward and Hoffmann rules), all of whom won the Nobel Prize for chemistry. [13] His brilliant use of rings to install and control stereochemical centers and to unravel functionality by rupturing them is an unmistakable feature of his syntheses. This theme appears in his first total synthesis, that of quinine, [22] and appears over and over again as in the total synthesis of reserpine, [28] vitamin B12 , [3, 32] and, remarkably, in his last synthesis, that of erythromycin. [33] Woodward s mark was that of an artist, treating each target individually with total mastery as he moved from one structural type to another. He exercised an amazing intuition in devising strategies toward his targets, magically connecting them to suitable starting materials through elegant, almost balletlike, maneuvers. However, the avalanche of new natural products appearing on the scene as a consequence of the advent and development of new analytical techniques demanded a new and more systematic approach to strategy design. A new school of thought was appearing on the horizon which promised to take the field of total synthesis, and that of organic synthesis in general, to its next level of sophistication. 3.3. The Corey Era In 1959 and at the age of 31 E. J. Corey arrived at Harvard as a full professor of chemistry from the University of Illinois, Urbana-Champaign. His dynamism and brilliance were to make him the natural recipient of the total synthesis baton from R. B. Woodward, even though the two men overlapped for two decades at Harvard. Corey s pursuit of total synthesis was marked by two distinctive elements, retrosynthetic analysis and the development of new synthetic methods as an integral part of the endeavor, even though Woodward (consciously or unconsciously) must have been engaged in such practices. It was Corey s 1961 synthesis of longifolene[34] that marked the official introduction of the principles of retrosynthetic analysis. [4] He practiced and spread this concept throughout the world of total synthesis, which became a much more rational and systematic endeavor. Students could now be taught the ªlogicº of chemical synthesis[4] by learning how to analyze complex target molecules and devise possible synthetic strategies for their construction. New synthetic methods are often incorporated into the synthetic schemes towards the target and the exercise of the total synthesis becomes an opportunity for the invention and discovery of new chemistry. Combining his systematic and brilliant approaches to total synthesis with the new tools of organic synthesis and analytical chemistry, Corey synthesized hundreds of natural and designed products within the thirty year period stretching between 1960 and 1990 (Figure 4)Ðthe year of his Nobel Prize. Corey brought a highly organized and systematic approach to the field of total synthesis by identifying unsolved and important structural types and pursuing them until they fell. The benefits and spin-offs from his endeavors were even more impressive: the theory of retrosynthetic analysis, new synthetic methods, asymmetric synthesis, mechanistic proposals, and important contributions to biology and medicine. Some of Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 49 N H N H H H MeO2C H OMe O O MeO OMe OMe H N N N N Me Me H2N H2N H2N Me Me NH2 Me H H H H Me Me H O O O NH2 O O Co CN Me NH O O P O Me O O O OH HO H N N Me Me H H H NH2 O H Me Me Me HO Me H Me O OH Me O Me O Me O Me HO Me OH O Me Me O Me OMe MeOH O HO NMe2 Me NMe H CO2H HO HO CO2H H OH OH OH O OH O NH2 NMe2 H OHO N O O H H H H N N S H H3N N O OAc CO2H H H CO2 O MeO O NHAc MeO MeO OMe O Me Me O O OH OH H H H N N N N Mg MeO O 2C O O HN H O H H OHC O HO N S O CO2H R' H N H O R O N N Me N O OH O O O OH N MeO HO N H H N O O OMe CO2H OH OHC HO O OMe MeO OMe HO O reserpine (1958)[28] vitamin B12 (1973)[32] [with A. Eschenmoser] marasmic acid (1976)[288] lanosterol (1954)[25] penems (1978)[290] erythromycin A (1981)[33] lysergic acid (1954)[26] PGF2α (1973)[31] 6-demethyl-6-deoxytetracycline (1962)[285] strychnine (1954)[27] cephalosporin C (1966)[30] colchicine (1965)[286] isolongistrobine (1973)[287] patulin (1950)[23] quinine (1944)[22] cortisone (1951)[24] chlorophyll a (1960)[29] illudinine (1977)[289] illudalic acid (1977)[289] illudacetalic acid (1977)[289] Figure 3. Selected syntheses by the Woodward Group (1944 ± 1981)
REVIEWS K. C. Nicolaou et al +h-porantherine(1974)30 miroestrol(1993) 342) forskolin(1988) oleanolic acid (1993)3391 venustatriol 20(S)-camptothecin(1975)/306) Me (*r-vermiculine(1975)/307) 0(+} elemene(195345 poral(1963)2931 Me hybridalactone(1984)323 Me dolabellane(1996)345 O:H bongkrekic acid (1 7, 20-diisocyanoadociane(1987/329) nAm ∠Co2H saframycin A(1999)349 leukotriene Ca lactacystin(1992)3 aplasmomycin(1982)3211 +)-atractyligenin(1987). HOC ene(197330 HO2 C H Me gibberellic acid (1978)/312 gracilis B(1995)3441 dihydrocostunollde(1963) 294. HOC cHo (*Fumagillin(1972)302) CCO,H lipoxin A(1986)328 332 CO:H Cco, H M picrotoxinin(1979)(314] Me dk-sirenin (1969) glycinoeclepin A(1990) (*)-perhydrohistrionicotoxin(1975)3051 thromboxane B2(1977)/3091 Figure 4. Selected syntheses by the Corey Group(1961-1999) Angew. Chem. Int. Ed. 2000. 39. 44-122
REVIEWS K. C. Nicolaou et al. 50 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Figure 4. Selected syntheses by the Corey Group (1961 ± 1999)
Natural Products Synthesis REVIEWS his most notable accomplishments in the field are highlighted unprecedented challenges and opportunities. To be sure, the final decade of the twentieth centu The period of 1950-1990 was an era during which total exciting and rewarding period in the history of total synthesis synthesis underwent explosive growth as evidenced by on of the primary chemical literature. In addition to the Woodward and Corey schools, a number of other groups 3. 4. The 1990s era contributed notably to this rich period for total synthesis -51 The climactic productivity of the 1980s in total synthesis second half of the twentieth century a number of great boded well for the future of the science, and the seeds were synthetic chemists made significant contributions to the field. already sown for continued breakthroughs and a new as natural products became opportunities to initiate and focus explosion of the field. Entirely new types of structures were ajor research programs and served as ports of entry for on the minds of synthetic chemists, challenging and presenting adventures and rewarding voyages. them with new opportunities. These luring architectures Among these great chemists are G. Stork, A Eschenmoser included the enediynes such as calicheamicin and dynemicin, nd Sir D. H.R. Barton, whose sweeping contributions began the polyether neurotoxins exemplified by brevetoxins A and with the Woodward era and spanned over half a century. The B, the immunosuppressants cyclosporin, FK506, rapamycin, Stork-Eschenmoser hypothesis 51 for the stereospecific nd sanglifehrin A, taxol and other tubulin binding agents. course of biomimetic-cation cyclizations, such as the con- such as the epothilones eleutherobin and the sarcodictyins version of squalene into steroidal structures, stimulated much ecteinascidin, the manzamines, the glycopeptide antibiotics nthetic work(for example, the total synthesis of progester- such as vancomycin, the CP molecules, and everninomicin one by w.S. Johnson, 1971). 36 Stork s elegant total syntheses 13,384-1(see Section 3.5) (for example, steroids, prostaglandins, tetracyclins)57-39Idec Most significantly, total synthesis assumed a more serious orate beautifully the chemical literature and his useful role in biology and medicine. The more aggressive incorpo- methodologies(for example, enamine chemistry, anionic ring ration of this new dimension to the enterprise was aided and closures, radical chemistry, tethering devices)40-43I have found encouraged by combinatorial chemistry and the new chal- important and widespread use in many laboratories and lenges posed by discoveries in genomics. Thus, new fields of industrial settings. Similarly, Eschenmoser's beautiful total syntheses (for thetic chemists taking advantage of the novel molecular example, colchicine, corrins, vitamin BI2, designed nucleic architectures and biological action of certain natural products. acids) 4-7I are often accompanied by profound mechanistic Besides culminating in the total synthesis of the targeted insights and synthetic designs of such admirable clarity and natural products, some of these new programs expanded into deep thought. His exquisite total synthesis of vitamin B, the development of new synthetic methods as in the past, but (with Woodward), in particular, is an extraordinary achieve- also into the areas of chemical biology, solid phase chemistry. ment and will always remain a classic sl in the annals of and combinatorial synthesis Synthetic chemists were moving organic synthesis. The work of D. H.R. Barton, 48 starting deeper into biology, particularly as they recognized the with his contributions to conformational analysis and bio- timeliness of using their powerful tools to probe biological both in total synthesis and synthetic methodology, was tional genomics. Biologists, in turn, realized the tremendous synthesis as we know it today. Among his most significant and adopted it, primarily through interdisciplinary collabo- contributions are the barton reaction. which involves the rations with synthetic chemists. A new philosophy for total photocleavage of nitrite esters I and its application to the synthesis as an important component of chemical biology synthesis of aldosterone-21-acetate, I ol and his deoxygenation began to take hold, and natural products continued to be in reactions and related radical chemistry, [SIl which has found the center of it all. In the next section we briefly discuss a numerous applications in organic and natural product synthesis. number of selected total syntheses of the twentieth century It seemed for a moment in 1990. that the efforts of the synthetic chemists had conquerred most of the known structural types of secondary metabolites: prostaglandins, 3.5. Selected Examples of Total Syntheses eroids, p-lactams, macrolides, polyene macrolides, The chemical literature of the twentieth century is adorned ers,alkaloids, porphyrinoids, endiandric acids, palitoxin with beautiful total syntheses of natural products. B-1 We have carboxyclic acid, and gingkolide; all fell as a result of the chosen to highlight a few here as illustrative examples of awesome power of total synthesis Tempted by the lure of structural types and synthetic strategie other unexplored and promising fields, some researchers even thought that total synthesis was dead, and declared it so. They Tropinone(917) were wrong. To the astute eye, a number of challenging and beautiful architectures remained standing, daring the syn Perhaps the first example of a strikingly beautiful total thetic chemists of the time and inviting them to a feast of synthesis is that of the alkaloid (+)-tropinone(1 in Scheme 1) discovery and invention. Furthermore, several new structures reported as early as 1917 by Sir R. Robinson. 5. 16 In this n to be discovered from nature that offered elegant synthesis--called biomimetic because of its resem- Angew. Chem. Int Ed 2000, 39, 44-122
Natural Products Synthesis REVIEWS his most notable accomplishments in the field are highlighted in Section 3.5. The period of 1950 ± 1990 was an era during which total synthesis underwent explosive growth as evidenced by inspection of the primary chemical literature. In addition to the Woodward and Corey schools, a number of other groups contributed notably to this rich period for total synthesis[3±5] and some continue to do so today. Indeed, throughout the second half of the twentieth century a number of great synthetic chemists made significant contributions to the field, as natural products became opportunities to initiate and focus major research programs and served as ports of entry for adventures and rewarding voyages. Among these great chemists are G. Stork, A. Eschenmoser, and Sir D. H. R. Barton, whose sweeping contributions began with the Woodward era and spanned over half a century. The Stork ± Eschenmoser hypothesis[35] for the stereospecific course of biomimetic ± cation cyclizations, such as the conversion of squalene into steroidal structures, stimulated much synthetic work (for example, the total synthesis of progesterone by W. S. Johnson, 1971).[36] Stork s elegant total syntheses (for example, steroids, prostaglandins, tetracyclins)[37±39] decorate beautifully the chemical literature and his useful methodologies (for example, enamine chemistry, anionic ring closures, radical chemistry, tethering devices)[40±43] have found important and widespread use in many laboratories and industrial settings. Similarly, Eschenmoser s beautiful total syntheses (for example, colchicine, corrins, vitamin B12 , designed nucleic acids)[44±47] are often accompanied by profound mechanistic insights and synthetic designs of such admirable clarity and deep thought. His exquisite total synthesis of vitamin B12 (with Woodward), in particular, is an extraordinary achievement and will always remain a classic[3] in the annals of organic synthesis. The work of D. H. R. Barton,[48] starting with his contributions to conformational analysis and biogenetic theory and continuing with brilliant contributions both in total synthesis and synthetic methodology, was instrumental in shaping the art and science of natural products synthesis as we know it today. Among his most significant contributions are the Barton reaction, which involves the photocleavage of nitrite esters[49] and its application to the synthesis of aldosterone-21-acetate, [50] and his deoxygenation reactions and related radical chemistry, [51] which has found numerous applications in organic and natural product synthesis. It seemed for a moment, in 1990, that the efforts of the synthetic chemists had conquerred most of the known structural types of secondary metabolites: prostaglandins, steroids, b-lactams, macrolides, polyene macrolides, polyethers, alkaloids, porphyrinoids, endiandric acids, palitoxin carboxyclic acid, and gingkolide; all fell as a result of the awesome power of total synthesis. Tempted by the lure of other unexplored and promising fields, some researchers even thought that total synthesis was dead, and declared it so. They were wrong. To the astute eye, a number of challenging and beautiful architectures remained standing, daring the synthetic chemists of the time and inviting them to a feast of discovery and invention. Furthermore, several new structures were soon to be discovered from nature that offered unprecedented challenges and opportunities. To be sure, the final decade of the twentieth century proved to be a most exciting and rewarding period in the history of total synthesis. 3.4. The 1990s Era The climactic productivity of the 1980s in total synthesis boded well for the future of the science, and the seeds were already sown for continued breakthroughs and a new explosion of the field. Entirely new types of structures were on the minds of synthetic chemists, challenging and presenting them with new opportunities. These luring architectures included the enediynes such as calicheamicin and dynemicin, the polyether neurotoxins exemplified by brevetoxins A and B, the immunosuppressants cyclosporin, FK506, rapamycin, and sanglifehrin A, taxol and other tubulin binding agents, such as the epothilones eleutherobin and the sarcodictyins, ecteinascidin, the manzamines, the glycopeptide antibiotics such as vancomycin, the CP molecules, and everninomicin 13,384-1 (see Section 3.5). Most significantly, total synthesis assumed a more serious role in biology and medicine. The more aggressive incorporation of this new dimension to the enterprise was aided and encouraged by combinatorial chemistry and the new challenges posed by discoveries in genomics. Thus, new fields of investigation in chemical biology were established by synthetic chemists taking advantage of the novel molecular architectures and biological action of certain natural products. Besides culminating in the total synthesis of the targeted natural products, some of these new programs expanded into the development of new synthetic methods as in the past, but also into the areas of chemical biology, solid phase chemistry, and combinatorial synthesis. Synthetic chemists were moving deeper into biology, particularly as they recognized the timeliness of using their powerful tools to probe biological phenomena and make contributions to chemical and functional genomics. Biologists, in turn, realized the tremendous benefits that chemical synthesis could bring to their science and adopted it, primarily through interdisciplinary collaborations with synthetic chemists. A new philosophy for total synthesis as an important component of chemical biology began to take hold, and natural products continued to be in the center of it all. In the next section we briefly discuss a number of selected total syntheses of the twentieth century. 3.5. Selected Examples of Total Syntheses The chemical literature of the twentieth century is adorned with beautiful total syntheses of natural products. [3±5] We have chosen to highlight a few here as illustrative examples of structural types and synthetic strategies. Tropinone (1917) Perhaps the first example of a strikingly beautiful total synthesis is that of the alkaloid ()-tropinone (1 in Scheme 1) reported as early as 1917 by Sir R. Robinson. [5, 16] In this elegant synthesisÐcalled biomimetic because of its resemAngew. Chem. Int. Ed. 2000, 39, 44 ± 122 51
REVIEWS K. C. Nicolaou et al prior to elimination of the latter functionalities. In contrast to the rather brutal reagents and conditions used in this porphyrin's synthesis, the tools of the "trade"when Wood HzNMe */o ward faced chlorophyll a, approximately thirty years later, Mannich reaction CoH were much sharper and selective Equilenin(1939) H20= The first sex hormone to be constructed in the laboratory by total synthesis was equilenin (1 in Scheme 3). The total Intermolecular Mannich reaction) of o, synthesis of this first steroidal structure was accomplished in 4: Butenandt's ketone cheme 1. a) Strategic bond disconnections and retrosynthetic analysis of (*)-tropinone and b)total synthesis( Robinson, 1917). COH blance to the way nature synthesizes tropinone-Robinson CO-H utilized a tandem sequence in which one molecule of succindialdehyde, methylamine, and either acetone dicarbox Arndt-Eistert reaction ylic acid (or dicarboxylate)react together to afford the natural ubstance in a simple one-pot procedure. Two consecutive b) Mannich reactions are involved in this synthesis, the first in an inter- and the second one in an intramolecular fashion In a way, the total synthesis of (+)-tropinone by Robinson was quite ahead of its time both in terms of elegance and logic TRefon n a. BrancHzc With this synthesis robinson introduced aesthetics into total b SoCI. py synthesis, and art became part of the endeavor. It was left, C KOH, MeOH however. to R. B. woodward to elevate it to the artistic status cO.e cOH that it achieved in the 1950s and to E J. Corey to make it into A(39% overally the precise science that it became in the following decades. Me [Amdt-Eistert a CH2N2 (B4 Haemin(1929) cOoMe Co Me Haemin(1 in Scheme 2), the red pigment of blood and the carrier of oxygen within the human body, belongs to the porphyrin class of compounds. Both its structure and total COmE He synthesis were established by H. Fischer. 5, 18 This combined 1: equine program of structural determination through chemical syn- Scheme 3. a)Strategic bond disconnections and retrosynthetic analysis of thesis is exemplary of the early days of total synthesis. Such equilenin and b)total synthesis(Bachmann et al., 1939) practices were particularly useful for structural elucidation in the absence of todays physical methods such as NMr 1939 by Bachmann and his group at the University of spectroscopy, mass spectrometry, and X-ray crystallography. Michigan /21 52) This synthesis featured relatively simple In the case of haemin, the molecule was degraded into smaller chemistry as characteristically pointed out by the authors fragments, which chemical synthesis confirmed to be substi- "The reactions which were used are fairly obvious ones. "121 tuted pyrroles. The assembly of the pieces by exploiting the Specifically, the sequence involves enolate-type chemistry,a reater nucleophilicity of pyrrole's 2-position, relative to that Reformatsky reaction, a sodium amalgam reduction,an of the 3-position, led to haemin,s framework into which the Arndt-Eistert homologation, and a Dieckmann cycliza iron cation was implanted in the final step. Among the most tion-decarboxylation process to fuse the required cyclo- remarkable features of Fischer's total synthesis of haemin are pentanone ring onto the pre-existing tricyclic system of the the fusion of the two dipyrrole components in succinic acid at starting material. As the last pre-World War II synthesis of 180-190C to form the cyclic porphyrin skeleton in a single note, this example was destined to mark the end of an era: A tep by two c-C bond-forming reactions, and the unusual way new epoch was about to begin in the 1940s with R. in which the carbonyl groups were reduced to hydroxyl groups Woodward and his school of chemistry at the helm. Angew. Chem. Int. Ed. 2000. 39. 44-122
REVIEWS K. C. Nicolaou et al. N O Me NMe O CHO CHO CO2H CO2H O CHO O CHO N Me O2C CO2 O NMe OH NMe O N O Me HO CO2H CO2H N O Me CO2H CO2H N O Me CO2H CO2H N O Me H H H H HCl -2 CO2 1 a) Mannich reaction Mannich reaction H2NMe 2 H2NMe b) H2O H2O 1: tropinone + + 3 4 2: succin-dialdehyde 5 6 7 10 9 8 [intermolecular Mannich reaction] [intramolecular Mannich reaction] + - H Scheme 1. a) Strategic bond disconnecions and retrosynthetic analysis of ()-tropinone and b) total synthesis (Robinson, 1917).[16] blance to the way nature synthesizes tropinoneÐRobinson utilized a tandem sequence in which one molecule of succindialdehyde, methylamine, and either acetone dicarboxylic acid (or dicarboxylate) react together to afford the natural substance in a simple one-pot procedure. Two consecutive Mannich reactions are involved in this synthesis, the first one in an inter- and the second one in an intramolecular fashion. In a way, the total synthesis of ()-tropinone by Robinson was quite ahead of its time both in terms of elegance and logic. With this synthesis Robinson introduced aesthetics into total synthesis, and art became part of the endeavor. It was left, however, to R. B. Woodward to elevate it to the artistic status that it achieved in the 1950s and to E. J. Corey to make it into the precise science that it became in the following decades. Haemin (1929) Haemin (1 in Scheme 2), the red pigment of blood and the carrier of oxygen within the human body, belongs to the porphyrin class of compounds. Both its structure and total synthesis were established by H. Fischer.[5, 18] This combined program of structural determination through chemical synthesis is exemplary of the early days of total synthesis. Such practices were particularly useful for structural elucidation in the absence of today s physical methods such as NMR spectroscopy, mass spectrometry, and X-ray crystallography. In the case of haemin, the molecule was degraded into smaller fragments, which chemical synthesis confirmed to be substituted pyrroles. The assembly of the pieces by exploiting the greater nucleophilicity of pyrrole s 2-position, relative to that of the 3-position, led to haemin s framework into which the iron cation was implanted in the final step. Among the most remarkable features of Fischer s total synthesis of haemin are the fusion of the two dipyrrole components in succinic acid at 180 ± 190 8C to form the cyclic porphyrin skeleton in a single step by two CÿC bond-forming reactions, and the unusual way in which the carbonyl groups were reduced to hydroxyl groups prior to elimination of the latter functionalities. In contrast to the rather brutal reagents and conditions used in this porphyrin s synthesis, the tools of the ªtradeº when Woodward faced chlorophyll a, approximately thirty years later, were much sharper and selective. Equilenin (1939) The first sex hormone to be constructed in the laboratory by total synthesis was equilenin (1 in Scheme 3). The total synthesis of this first steroidal structure was accomplished in HO Me O H HO Me H CO2Me CO2Me HO Me H CO2H CO2H MeO O MeO O MeO O MeO O CO2Me CO2Me Me MeO CO2H Me CO2H MeO CO2H Me CO2H H MeO CO2Me Me H HO Me O H O Cl MeO CO2Me Me H O MeO CO2Me Me H CO2Me Arndt-Eistert reaction a. CH2N2 b. NaOH c. SOCl2 Reformatsky reaction a. CH2N2 b. Ag2O, MeOH [-N2] 1: equilenin 4: Butenandt's ketone Dieckmann cyclization a. (CO2Me)2, MeONa b. 180 °C, glass MeI, MeONa a. BrZnCH2CO2Me b. SOCl2, py c. KOH, MeOH d. Na-Hg a) b) a. MeONa b. HCl, AcOH 1: equilenin [Arndt-Eistert reaction] [Dieckmann cyclizationdecarboxylation sequence] (90%) (92%) [Reformatsky reaction] [dehydration] [saponification] (39% overall) (84% overall) (92%) 2 3 4 5 6 8 3a 7 9 10 : Scheme 3. a) Strategic bond disconnections and retrosynthetic analysis of equilenin and b) total synthesis (Bachmann et al., 1939).[21] 1939 by Bachmann and his group at the University of Michigan.[21, 52] This synthesis featured relatively simple chemistry as characteristically pointed out by the authors: ªThe reactions which were used are fairly obvious ones...º[21] Specifically, the sequence involves enolate-type chemistry, a Reformatsky reaction, a sodium amalgam reduction, an Arndt ± Eistert homologation, and a Dieckmann cyclization ± decarboxylation process to fuse the required cyclopentanone ring onto the pre-existing tricyclic system of the starting material. As the last pre-World War II synthesis of note, this example was destined to mark the end of an era; A new epoch was about to begin in the 1940s with R. B. Woodward and his school of chemistry at the helm. 52 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122
Natural Products Synthesis REVIEWS CO-H 1: haemin Co H HO-C Eto2c Me aHSO (H)、如m可 COEt CO E COEt H20. dE CO2Et EIc CO,Et COH HO-C COEl ⊙coe CO-H e NH HN Ifusion in succinic acid] COH 3 COH CO:H Ac,O, AICI3 o KOH, EtoH, A [Friedef-Crafts acylation reduction/ 1: haemin Scheme 2. a)Strategic bond disconnections and retrosynthetic analysis of haemin and b) total synthesis(Fisher, 1929). I Before we close this era of total synthesis and enter into a cyclohexane system in order to accomplish his goal. The issue new one, the following considerations might be instructive in of stereochemistry of the two stereocenters was probably left attempting to understand the way of thinking of the pre-World open to chance in contrast to the rational approaches towards War II chemists as opposed to those who followed them. The such matters of the later periods. Connecting the chosen rather straightforward synthesis of equilenin is representative starting material 4 with the target molecule 1 was apparently of the total syntheses of pre-World War II era-with the obvious to Bachmann, who explicitly stated the known nature exception of Robinsons unique tropinone synthesis. In of the reactions he used to accomplish the synthesis. contemplating a strategy towards equilenin, Bachmann must Since the motivations for total synthesis were strongly tied have considered several possible starting materials before to the proof of structure, one needed a high degree of recognizing the resemblance of his target molecule to confidence that the proposed transformations did indeed lead Butenand's ketone (4 in Scheme 3). After all, three of to the proposed structure. Furthermore, the limited arsenal of quilenin's rings are present in 4 and all he needed to do chemical transformations did not entice much creative devia was fuse the extra ring and introduce a methyl group onto the tion from the most straightforward course. This high degree of Angew. Chem. Int Ed 2000, 39, 44-122
Natural Products Synthesis REVIEWS Before we close this era of total synthesis and enter into a new one, the following considerations might be instructive in atempting to understand the way of thinking of the pre-World War II chemists as opposed to those who followed them. The rather straightforward synthesis of equilenin is representative of the total syntheses of pre-World War II eraÐwith the exception of Robinson s unique tropinone synthesis. In contemplating a strategy towards equilenin, Bachmann must have considered several possible starting materials before recognizing the resemblance of his target molecule to Butenand s ketone (4 in Scheme 3). After all, three of equilenin s rings are present in 4 and all he needed to do was fuse the extra ring and introduce a methyl group onto the cyclohexane system in order to accomplish his goal. The issue of stereochemistry of the two stereocenters was probably left open to chance in contrast to the rational approaches towards such matters of the later periods. Connecting the chosen starting material 4 with the target molecule 1 was apparently obvious to Bachmann, who explicitly stated the known nature of the reactions he used to accomplish the synthesis. Since the motivations for total synthesis were strongly tied to the proof of structure, one needed a high degree of confidence that the proposed transformations did indeed lead to the proposed structure. Furthermore, the limited arsenal of chemical transformations did not entice much creative deviation from the most straightforward course. This high degree of Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 53 N N Me Me N N Me Me HO2C CO2H Fe NH HN Me Me Me N H Me Me N H Me OHC Me N H Me CO2H Me CO2Et N H Me Me N H Me O Me NH HN Me Me Me Me HO H H NH HN Me Me Me Me HO H NH HN Me Me Me Me N H EtO2C Me CO2Et Me N H Me CO2Et Me N H Me CO2Et OHC Me N H Me CO2Et Me HO2C N H Me CO2Et Me HO2C N H Me CO2Et Me HO2C N H CO2Et Me HO2C H N H CO2Et Me HO2C Br Br N H CO2Et Me HO2C Br H N H CO2Et Me HO2C Br N H CO2Et Me HO2C N H CO2Et Me HO2C HO NH HN Me Me Me CO2H CO2H NH HN Me Me HO2C CO2H Br Br N N Me Me N N Me Me HO2C CO2H Fe NH HN Me Me CO2H CO2H N H CO2Et Me HO2C HO N H CO2Et Me NH HN Me Me CO2H HO2C EtO2C CO2Et O H NH HN Me Me CO2H CO2H CO2H HO2C Br Br NH HN Me Me HO2C CO2H HO2C Br O O H Br Br NH HN Me Me Me NH HN Me Me NH HN Me Me CO2H HO2C Me Br Br NH HN Me Me NH HN Me Me CO2H HO2C Br NH HN Me Me NH HN Me Me HO2C CO2H H H H H N HN Me O O Me NH N Me Me HO2C CO2H N HN Me Me NH N Me Me HO2C N HN Me OH HO Me NH N Me Me O2C CO2 CO2H HO2C NH HN Me Me Me H HBr, Br2 2 3 4 5 6 4 5 7 9 11 12 13 15 8 2 14 18 6 16 22 21 20 1: haemin a) b) H 17 19 H Br δ+ δ- H2O HBr a. H2SO4 b. ∆ HCO2H HCl piperidine H [Knoevenagel] Na/Hg 28 22 23 25 2 29 27 3 30 31 24 26 32 b. Fe Cl 3 a. Fe3 b. Ac2O, AlCl3 c. H δ+ δ- – [CO2] [oxidation] [fusion in succinic acid] [Friedel-Crafts acylation] KOH,EtOH, ∆ [reduction] 1: haemin [dehydration] a. ∆/H 10 Scheme 2. a) Strategic bond disconnections and retrosynthetic analysis of haemin and b) total synthesis (Fisher, 1929).[18]
