Actinobolin, synthesis

However, these refinements came too late to be of use to Kozikowski and coworkers in their actinobolin synthesis, since they had already settled on doing the reaction at 220 °C, where the proportion of C4 was greatest [40]. 

The first and, at the time of this writing, only synthesis of bactobolin that has been achieved comes from the laboratory of Weinreb and co-workers. The strategy pursued made successful use of an advanced intermediate from their actinobolin synthesis (Sect. 1.6). However, this achievement was decidedly nontrivial. In their actinobolin studies (Scheme 18), a key process had been the intramolecular 0- and C-acylation E7 - E8 - E9 but it transpired that an analogous protocol could not be pursued here. 

Intramolecular C-acylation.1 In a synthesis of (+ )-actinobolin 4, an antibiotic from S. griseovirides, the final carbon atom was introduced by O-acylation... 

Scheme 12.38. Synthesis of actinobolin using a three-component conjugate addition/aldol condensation, by Chida and co-workers [135] TBS = t-butyldimethylsilyl, Bn = benzyl, PMB = p-methoxybenzyl.

Ttoo groups employed the p-methylbenzylsulfonyl group299 for the synthesis of the antibiotic Actinobolin.300 301 In the synthesis by Weinreb and co-workers [Scheme 8.125],300 deprotection of a single amino function took place on treatment of a p-methylbenzylsulfonamide with neat anhydrous HF in the presence of anisole. A more convenient procedure employs 70% HF in pyridine containing 2 equivalents of anisole34 2 to accomplish the deprotection of a mesitylene-sulfonamide.303... 

Easily prepared from glycols, enones have been investigated as dienophiles. They react with butadiene under Lewis acid catalysis to form chiral cyclohexenes used in the synthesis of compactin analogs [353]. Levoglucosenone has been used in a Diels-Alder reaction with acetoxy-butadiene to construct a part of the indole alkaloid reserpine [354], and in synthetic studies toward tetrodotoxin [355]. Analogs of the anthracycline rhodomycinone have been similarly prepared [356]. [4 + 2]-Cycloaddition of the same enone with silyloxydiene allowed the creation of the fused ring system present in actinobolin [357]. 

Recently the Ferrier-II rearrangement was used as a key step in the synthesis of unnatural (-) actinobolin. The 5,6-unsaturated compound 72 was prepared by a base-induced elimination of HI from the 6-deoxy-6-iodo-derivative 71 (O Scheme 31) [69]. 

A consequence of the retrosynthetic plan (Scheme 7) was that a contra-thermodynamic y-lactam 5-lactone conversion would have to be carried out at some stage of the synthesis. This challenging undertaking necessitated that the C-8/COOMe group be altered and in the interest of efficiency, this became an opportune stage for installation of a synthon for the carbonyl group required at that site in actinobolin. This synthon took the form of the phenylselenomethyl residue shown in B5c, a convenient precursor for an exocyclic methylene via selenoxide elimination, and thence a carbonyl group via ozonolysis. 

In the studies of Danishefsky and co-workers, the initial objective was a synthesis of bactobolin in chiral racemic form [10a]. However, because of insurmountable hurdles encountered in the course of the synthesis, the plan was re-tooled, and the synthesis of racemic N-acetyldesalanyl actinobolin was achieved [10b]. 

In the retrosynthetic plan (Scheme 14), the key step was based on the crucial supposition that the truns-fused bicyclic hemiacetal Dill would undergo a reversible ring tautomerization with the monocyclic system DII, the skeletal and functionalization of which are well correlated with both actinobolin 1 and bactobolin 2 (vide infra). Further retrosynthesis of Dill led to unsaturated hemiacetal DIV which is reminiscent of a 2,3-unsaturated pyranose (i.e., a pseudo glycal) [46], and thence to lactone DV. The construction of the unsaturated bicyclic lactone therefore constituted the first plateau of this synthesis. 

The synthesis of actinobolin reported by Weinreb [11] and co-workers is the most concise of the five approaches (see Sects. 1.3-1.7) thus far reported. This noteworthy achievement is attributable to their use of the topographical features of [3.3.1] bicyclic molecules for providing stereocontrol in two critical areas (a) in the reduction of the imine EIII Eli (Scheme 17) and (b) for the exclusive... 

Rahman and Fraser-Reid used a sugar-based approach for their synthesis of actinobolin [12], and hence an optically active product was assured. Therefore the challenge, as with the use of L-threonine in Sects. 1.3 and 1.4, was to make the most efficient use of the chiron [27]. In this context, efficiency can be equated with stereoselectivity, and as such, it is the direct outcome of synthetic design. 

One source of difficulty came from the fact that, based on their experience with actinobolin, the p-methylbenzyl sulfonyl group was used for amine protection (see Scheme 18). However, this lead to complications at late stages of the attempted bactobolin synthesis. Substantial re-tooling was therefore required and after a protracted search, it was discovered that the [P-] (trimethylsilyl)-ethyl] sulfonyl group would be suitable [77]. 

Three-Component Coupling Reaction Synthesis of (-)- and (+)-Actinoboline... 

The enantiomer of 72 (ent-72) was synthesized from the same starting material 106 fScheme 12.37). Benzylation of a hydroxy group in 106 followed by acetal hydrolysis afforded 140, which was converted into 5-enop)Tanoside 141 by the conventional method. The Ferrier carbocyclization of 141 generated 142 as a diastereomeric mixture in 83% yield. Protection of the hydroxy group in 142 as a THP ether and subsequent reduction of the ketone carbonyl gave 143. 0-Mesylation of 143 followed by acidic work-up afforded 144. Swern oxidation of 144 was accompanied by the p-elimination of the OMs group to furnish ent-72 in 93% yield. Cyclohexenone ent-72 could be used for the synthesis of natural enantiomer of actinoboline. 

The antibiotics enomycin and phenomycin have been found to inhibit protein synthesis by specific interaction with ribosomes of the 80 S type but not of the 70 S typeOn the other hand, bottromycin and bernin-amycin are only active with the 70 S ribosomes . and actinobolin with both O c,... 

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