Completion of total synthesis

Completion of total synthesis of retigeranic acid by Corey... 

Fig. 37), the late-stage enantioselective alkene RCM required the closure reaction onto one of two sterically hindered vinyl groups at a congested quaternary carbon in the presence of a potentially problematic tertiary amine moiety. Through an extensive screen of chiral catalysts, gratifyingly, the desired tetracycle (142) was obtained in 84% yield and 96% ee, which allowed the completion of total synthesis of (+)-quebrachamine (139). 

An intramolecular palladium(o)-catalyzed cross-coupling of an aryl iodide with a trans vinylstannane is the penultimate maneuver in the Stille-Hegedus total synthesis of (S)-zearalenone (142) (see Scheme 38).59 In the event, exposure of compound 140 to Pd(PPh3)4 catalyst on a 20% cross-linked polystyrene support in refluxing toluene brings about the desired macrocyclization, affording the 14-membered macrolide 141 in 54% yield. Acid-induced hydrolysis of the two methoxyethoxymethyl (MEM) ethers completes the total synthesis of 142. 

Only two operations remain. Reaction of the enolic form of aldehyde 162 with Eschenmoser s reagent (H2C=NMe2+I-)62 in the presence of triethylamine provides the desired enal after a simple / -elimination. Finally, cleavage of the remaining tcrt-butyldi-methylsilyl ether with HF pyridine completes the total synthesis of (+)-brevetoxin B (1). 

Tropinone is another classic compound in the history of total synthesis. The celebrated plans of Willstatter and Robinson are shown in Schemes 4.20 and 4.21 and Figure 4.63 shows a synthesis map for different ways this compoimd has been made. The synthesis tree for the three-component Robinson plan is shown in Figure 4.64. Calcium carbonate and hydrochloric acid are added as inputs to complete the balanced chemical equation since these are involved in a neutralization reaction. It is clear from the results summarized in Table 4.30 that the Robinson plan is the clear front-rimner because the synthesis is achieved in a single step even though the reaction yield is modest. Any further improvements to this method would be directed to improving this parameter. 

Ley and Baxendale have shown that it is possible to complete a total synthesis by using a number of flow devices in series, which contained immobihzed reagents (14). Use of a number of CCSs in series would allow cascade catalysis in which the catalytic systems have been separated (Figure 4.2). This is quite attractive in view of the fact that often each catalyst needs highly specific operating conditions, such as temperature and pH. 

Richter utilized a reductive amination in their synthesis of the natural product (+)-hapalindole Q [294], Employing 10 equivalents of sodium cyanoborohydride and 40 equivalents of ammonium acetate in a methanol/THF mixture (150 °C, 2 min), the primary amine was obtained as a 6 1 mixture of diastereomers. Transformation to the isothiocyanate completed the total synthesis of (+)-hapalindole Q (Scheme 6.150). 

Banwell, Steglich and Kashman [62,63] have combined their expertise to complete a total synthesis of halitulin and this is described in Scheme 29. 

Grieco in the total synthesis of (—)-epothilone B 134 used a rhodium-catalyzed hydroboration as a key step in the synthesis of the macrocyclic ring (Figure 15).141 Completion of the synthesis of the C(3)-C(12) fragment was carried out using a rhodium-catalyzed hydroboration as the key step. 

Using a similar C12,C 13 disconnection approach, Schinzer et al. also achieved a total synthesis of epothilone A (4) [16]. The key step involved a highly selective aldol reaction between ketone 27 and aldehyde 10 to afford exclusively alcohol 28 with the correct C6,C7 stereochemistry (Scheme 6). Further elaboration led to triene 29, which underwent RCM using ruthenium initiator 3 in dichloromethane at 25°C, to afford macrocyles 30 in high yield (94%). Although no selectivity was observed (Z E=1 1), deprotection and epoxidation of the desired Z-isomer (30a) completed the total synthesis [16]. 

As depicted in Scheme 21, subjection of 86 with 20 mol% of freshly prepared 2 after 4 h at 22 °C indeed afforded 87 in 92% yield after silica gel chromatography (>98% Z). Stereocontrolled hydrogenation of the trisubstituted olefin (72% yield) and removal of the acetate and trifluroacetate groups, effected by subjection of the hydrogenated adduct with hydrazine in MeOH, delivered Sch 38516 (1) in 96% yield to complete the total synthesis. 

Finally, this chapter discusses the synthesis of two taxol components bac-catin III, the polycyclic part of taxol and the side chain of taxol. Although several groups have completed the total synthesis of taxol, work on taxol synthesis is still far from over. Chemists working in the area of asymmetric synthesis will find challenge and opportunity in Section 7.5 of this chapter. 

The final stage is to introduce the C-13 hydroxyl group via PCC oxidation of 187 and subsequent reduction of the carbonyl group, and this completes the total synthesis of baccatin III (Scheme 7-58). The synthesized compound is identical to a natural sample of baccatin III in all respects, including optical rotation. 

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