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, 44-122Natural 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 con￾version of squalene into steroidal structures, stimulated much synthetic work (for example, the total synthesis of progester￾one by W. S. Johnson, 1971).[36] Storks elegant total syntheses (for example, steroids, prostaglandins, tetracyclins)[37±39] dec￾orate 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, Eschenmosers 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 achieve￾ment 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 bio￾genetic 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, polyeth￾ers, 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 syn￾thetic 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 incorpo￾ration of this new dimension to the enterprise was aided and encouraged by combinatorial chemistry and the new chal￾lenges posed by discoveries in genomics. Thus, new fields of investigation in chemical biology were established by syn￾thetic 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 func￾tional genomics. Biologists, in turn, realized the tremendous benefits that chemical synthesis could bring to their science and adopted it, primarily through interdisciplinary collabo￾rations 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 resem￾Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 51