Efforts towards the total synthesis of 20-deoxyapoptolidinone and 'chimeric' analogues

Isolated in 1997 from the bacteria, Nocardiopsis sp., apoptolidin was discovered to be remarkably selective in killing cells transformed by the adenovirus E1A oncogene while leaving normal cells unharmed. Apoptolidin's particularly interesting mode of action has been proposed to involve inhibition of the F1F0-ATP synthase found in the inner-membrane of the mitochondria. Polyketide derived, apoptolidin, consists of a 20-membered macrolide, highly-substituted pyran, and carbohydrate appendages. Because of this structural complexity and cytotoxicity, apoptolidin has garner considerable interest in the scientific community resulting in several total syntheses, SAR work, and further isolations of compounds in the apoptolidin family.;While working towards the total synthesis of apoptolidinone (apoptolidin's aglycone core), several research groups discovered at physiological pH and temperature, apoptolidin isomerizes to the 21-membered macrolide, isoapoptolidin. Isoapoptolidin was found to be considerably less active than apoptolidin calling into question previous assay data. Attempts were made to block this acyl-migration, but led to a loss in activity.;Our efforts have been focused on synthesizing the 20-deoxy analogue of apoptolidinone eliminating the acyl-migration without adversely affecting the structural conformation of 20-deoxyapoptolidinone. Because of its complexity, 20-deoxyapoptolidinone was partitioned into three smaller fragments.;Fragment A was rapidly synthesized through repetitive thionyl chloride rearrangements demonstrating its utility as an alternative to the classic Wittig and Horner-Wadsworth-Emmons protocol widely used. Fragment B in its various forms was synthesized from commercially available (L)-malic acid utilizing the purchased stereochemistry to influence the addition of several new stereocenters. Fragment C consisting of several propionate units was constructed via repetitive oxazolidinonethione based aldol condensations achieving the fragment in an efficient and timely manner. Once constructed the three fragments are coupled together through a Mukaiyama aldol, Stille coupling and Yamaguchi macrolactonization yielding the desired 20-deoxyapoptolidinone. Upon completion, the synthesis of 20-deoxyapoptolidinone will provide the framework for future "chimeric" analogues. These "chimeric" analogues will consist of 20-deoxyapoptolidin's macrolide with the pyran portions of concanamycin and bafilomycin in an effort to achieve cross affinity for F0F1- and V-type ATPase.