Progress Towards the Synthesis and Biological Evaluation of  Truncated Spirastrellolide A

Jagadeesh Nagendra Manda, Barry B. Butler Jr, and Aaron Aponick*

University of Florida

Natural products and their derivatives have been continuously evolving as novel lead compounds in drug discovery. Design and synthesis of structurally simplified analogues of natural products which could retain their biological activity is always of great interest. Spirastrellolide A was isolated by the Anderson group in 2003 from the Caribbean marine sponge Spirastrella coccinea. Due to its novel antimitotic potency (IC50 = 100 ng/mL) and selective inhibition of protein phosphatase 2A (IC50 = 1 nM), it is considered as a potential lead compound for the development of an anti-cancer agent. In order to examine the structure and activity studies of truncated spirastrellolide A analogues, a convergent synthesis was designed involving two key intermediates including a tetrahydropyran and a [6,6]-spiroketal. Two gold-catalyzed cyclization methods developed in our group were employed in the synthesis, namely 1) Gold-catalyzed dehydrative cyclization of monoallylic diols for the synthesis of the tetrahydropyran, and 2) Regioselective gold-catalyzed spiroketalization for the efficient generation of the [6,6]-spiroketal. Our proposed pharmacophore model, synthetic strategy, and progress towards the synthesis of truncated Spirastrellolide A analogues will be presented.