Anisomycin synthesis

The reactions depicted in Scheme 39 were already conducted in view of a potential use in the synthesis of pyrrolidinols and piperidinols. The structural feature of a 2-arylmethyl-3-hydroxysubstitution is not only found in preussin but also in anisomycin (152) [87] or in the piperidine alkaloid FR 901483 (153) [88] (Fig. 5). 

We have extended our work on a new synthesis of the antiprotozoal antibiotic anisomycin to the necine bases of the pyrrolizidine alkaloids, in particular retronecine and crotanecine. The key intermediate, (2R,3S,4R)-2-(alkoxy-carbonylmethyl)-3,4—isopropylidenedioxypyrrolidine, has been prepared by three distinct routes from D-ribose and g-erythrose, using reactions of high stereoselectivity. 

We were first attracted to chiral pyrrolidines by the possibility of applying methods used in C-nucleoside synthesis (1) to the synthesis of the antiprotozoal antibiotic anisomycin (p from D-ribose (2). 

Scheme 2 illustrates a synthesis of the benzyloxycarbonyl derivative (H) of the ester (9a) using chemistry analogous to that for anisomycin (Scheme 1). In the formation of the D-allo-triol (.12),...

The triflate of (39) has been converted into the pyrrolidine (4 directly by treatment with ammonia. The 6-configuration, inappropriate for a synthesis of anisomycin, was expected, assuming that displacement of the triflate group is the first stage in the reaction. We have so far been unable to rearrange the 6-isomer (45) into the required a-series. This work is being continued. 

Alice et al studied the turnover kinetics of Listeria OTonocytogenex-secreted p60 protein (a murein hydrolase) by host cell cytosolic proteasomes. J774 cells, seeded in flasks and incubated overnight in culture medium, were infected with log-phase cultures of E. monocytogenes for 30 min, washed, and incubated in culture medium for 3 h, with gentamicin (50 tg/ml) added after the first 30 min to inhibit extracellular bacterial growth. Cells then were washed and placed in methionine-free medium with spectinomycin, gentamicin, the eukaryotic protein synthesis inhibitors [cycloheximide (50 tg/mL) and anisomycin (30 tg/ml),] and 25 dVI calpain inhibitor I. After 30 min, [ S]methionine was added, and the cells were pulse-labeled for periods of 20 to 60 min. Cells... 

SCHEME 35. Richardson s total synthesis of (—)-anisomycin with Ram Bhatt, John Moffatt, and Julian Verheyden (and others) at Syntex in 1975. 

Another impressive example is the synthesis of ( + )-anisomycin, the unnatural enantiomer, in 88-90% ee and 22% overall yield, the key step being an asymmetric alkylation of 2,5-dihydro-1//-pyrrole44. ... 

J. G. Moffat Chiral synthesis of the antibiotics anisomycin and pentenomycin A. S. Perlin Aspects of the chemistry of glycosides... 

Frey U, Krug M, Reymann KG, Matthies H (1988) Anisomycin, an inhibitor of protein synthesis, blocks late phases of LTP phenomena in the hippocampal CA1 region in vitro. Brain Res 452 57-65... 

Pyrroline is a desirable starting material for alkylation of heterocycles. 1-(Methoxycarbonyl)-3-pyrroline2 has been used to prepare 2,5-dialkylated pyrrolines,3 which resulted in the synthesis of the Pharaoh ant trail pheromone43 and gephyrotoxin 2 2 3.4b Alkylation of 3-pyrrolines has also led to the synthesis of 12-azaprostaglandins.5 The submitters have used a formamidine derived from 3-pyrroline to provide access to 2-substituted pyrrolines and pyrrolidines,6 which has led to the synthesis of the unnatural (+)-anisomycin.7... 

The ready availability of both enantiomers of (1) has greatly enhanced its value as a synthetic intermediate. The pheromone (S)-(—)-ipsenol (2), prepared in 16% overall yield in four steps from (/ )-( ), is just one of many examples of this utility. In practice, either isomer can sometimes be used by adjusting the order of addition of the groups at C-1 and C-3. The synthesis of (—)-anisomycin (3) illustrates this point. ... 

Although the Birch reduction (alkali metals in liquid NH3) of the pyrrole ring is apparently unknown (c/. equation 8), the partial reduction of pyrroles to 2,5-dihydropyrroles using Zn/HCl has been of considerable utility. For example, pyrrole gives 2,5-dihydropynole as the major product upon treatment with Zn dust/20% aq. HCl (equation 9), and Lemal and McGregor observed that 2,5-dimethylpyrrole gives a mixture of trans- (78%) and c/5-2,5-dimethyl-2,5-dihydropyrrole (22%) under similar conditions (47% yield). In one of these studies, Hudson and Robertson demonstrated that 2,5-dihydropyrrole is not reduced to pyrrolidine under these reaction conditions. Using these same conditions, Schumacher and Hall reported the reduction of 2-benzylpyrrole to the 2,5-dihydro derivative (67%) in a synthesis of the antibiotic anisomycin. ... 

Illustrative of the chemistry of the aminyl radical is a synthesis of the A -methyl derivative of the antibiotic (—)-anisomycin (73) [20]. It was obtained by treating (E )-5-alkenylamine 71 with -butyllithium at —78°C, followed by anodic oxidation at a constant current (17.5mA/cm") in a 100 1 mixture of tetrahydrofuran (THE) and hexamethyl-phosphor-ous-triamide (HMPA) containing 0.25 M lithium perchlorate at — 10°C. A 5-exo,trig cycli-zation of the metalated aminyl radical afforded pyrrolidine 72 as a single isomer in a 53% yield. A routine series of transformations converted 72 to the target structure 73. 

Actidione and Anisomycin. These two anti-fungal antibiotics were tested, not because they were antibiotics, but because of their known inhibitory effects on biological systems such as those involved in protein synthesis. Both were found to be active 21) but were never pursued beyond the initial screening stages because of high cost and particularly their animal toxicity, especially to the mucosa. 

The asymmetric alkylation of A -pyrroline has been used in the synthesis of anisomycin in 90% ee using a formamidine chiral auxiliary, as shown in Scheme 22. ... 

The synthesis of the antibiotic anisomycin (160) provides another example of the efficient alkylation of a thioamide with an a-bromoarylacetate. Thiolactam (154) was alkylated with a-bromo ester (155) followed by sulfide contraction to generate the vinylogous carbamate (156) in good yield (Scheme 33). In contrast, initial attempts to condense the imidate of the dimethoxylactam (161) with various aryl components (162) met with failure that was attributed to the steric hindrance created by the alkoxy groups (Scheme 34). The vinylogous carbamate (156) was converted to the acid, which decarboxylated to the enamine (157). Reduction yielded a 70 30 mixture of pyrrolidines (158) and (159) and the latter was converted to anisomycin. 

Synthesis from o-galactose (-)-Anisomycin (1) has been synthesized" from D-galactose by conversion firstly to ethyl 2,3-di-0-benzyl-(3-D-galactofuranoside... 

Synthesis from i-arabinose (-)-Anisomycin (1) was prepared from 2,3,5-tri-O-benzyl-(3-L-arabinofuranose (9) (Scheme 2). Compound 9 was treated with benzylamine... 

Synthesis from a-mannitol An enantioconvergent synthesis of (-)-anisomycin... 

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