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, 44-122Natural 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 devia￾tion 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]