Bactobolin synthesis

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]. 

Adachi H, Nishimura Y, Takeuchi T (2002) Synthesis and Activities of Bactobolin Derivatives Having New Functionality at C-3. J Antibiot 55 92... 

In a total synthesis of (-)-bactobolin, Garigipati and Weinreb used a dichloromethylcerium reagent. The intermediate product (5) was isolated in 34% yield as a single isomer, as shown in Scheme 7. Di chloromethyllithium alone in this reaction afforded intractable material. 

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 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. 

SES-NSO also reacts with ketones in the presence of Lewis acids and the resulting iV-sulfonylimines can be reduced to the corresponding sulfonamides with NaBH3CN (eq 3). Such a reaction sequence has been employed in a synthesis of the antitumor antibiotic (—)-bactobolin. ... 

In a total synthesis of the antitumor antibiotic (—)-bactobolin (18), the choice of protecting group on the nitrogen was crucial (eq 10). Unlike other protecting groups, the SES group is compatible with a wide variety of transformations and reagents, and is easily removed at the end of the synthesis. 

Munakata, T. Bactobolins, Antitumour Antibiotics from Pseudomonas. Part 2. Synthesis and Microbial Activity of Related Compounds. Yakugaku Zasshi 101, 138 (1981) Chem. Abstr. 95, 42826 (1981). 

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