THE TOTAL SYNTHESIS OF - -ARISUGACIN

Richard P. Hsung f and Kevin P. Cole Department of Chemistry University of Minnesota Minneapolis, Minnesota 55455 

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Arisugacin not only demonstrates impressive potency in inhibiting AChE with an IC50 value of 1 nM, but more importantly, it is highly selective for AChE since 18 flM is required to inhibit butyrylcholinesterase [BuChE], In contrast, tacrine and other inhibitors are less selective for AChE. In the case of tacrine, it is actually more selective for BuChE with an IC50 value of 12 nM, thereby raising concerns about its potential in liver damage.13 

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Also see Hsung, R. P. Cole, K. P. (2004) The total synthesis of (—)-arisugacin A. In Harmata, M. (Ed.) Strategies and Tactics in Organic Synthesis, Vol. 4, Elsevier Science, Pergamon Press Oxford, England, pp. 41-70. 

The retrosynthetic analysis of arisugacin is shown in Scheme 12.2. It is clear to us that this formal [3+3] cycloaddition method could be invaluable to achieve a practical total synthesis of arisugacin A 6 or other family members and their analogs [20]. Specifically, the reaction of a,(3-unsaturated iminium salts 13 with 6-aryl-4-hydroxy-2-pyrones 14 should provide a facile access to the advanced pentacyclic intermediate 12. 

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