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, 44-122Natural 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. 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 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 natures seemingly unlimited library of molecular architectures. Hap￾pily, 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 pre￾World 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 or￾ganic 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. vant 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 accomplish￾ment 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