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《全合成的科学与艺术》（英文原著）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- vnth

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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] Woodwards 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. Coreys 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 Coreys 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)

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] Storks 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, 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 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 todays 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 pyrroles 2-position, relative to that of the 3-position, led to haemins framework into which the iron cation was implanted in the final step. Among the most remarkable features of Fischers 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 porphyrins 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 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 Robinsons 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 Butenands ketone (4 in Scheme 3). After all, three of equilenins 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]

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