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. 44-122REVIEWS 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 dicarbox￾ylic 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 syn￾thesis 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 substi￾tuted 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 Wood￾ward 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 cyclization￾decarboxylation 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 cycliza￾tion ± decarboxylation process to fuse the required cyclo￾pentanone 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