Bactobolin

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

The fused azetidine derivative of bactobolin 477 has been prepared <1998JAN184>. The azatricycle 186 has been synthesized by an intramolecular nucleophilic cyclization (see Section 2.04.7.1) <20020L1259>. 

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. 

Weinreb has reported the total syndieses of (+)-actinobolin and (-)-bactobolin from common intermediate (21). Both the reductive cleavage and Grignard addition proceeded in high overall yield (equation 11). ... 

A closer examination of the rather sparse literature that exists on SES group removal very quickly revealed that Ward and coworkers had experienced similar problems during their attempted removal of a SES group from a primary amine in their synthetic studies on bactobolin. In that instance, a range of fluoride sources were examined unsuccessfully, including TBAF in THF at reflux, and CsF in DMF at 95 °C. 

A much greater impact came from the isolation of bactobolin from Pseudomonas, whose structure was assigned as 2 on the basis of spectroscopic comparisons with actinobolin [5]. Bactobolin showed activity against leukemias [6], as well as enhanced antitumor activity, as compared with actinobolin [7]. 

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. 

---