Acetic Anhydride → 5-Methylene-tetrahydro-cyclopenta[c]furan-1,3-dione

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Reaction Steps

Methods for the synthesis of suitable 3-azabicyclo[3.3.0]octane intermediates vary. For instance, Flynn et al., Tetrahedron 53(1): 1-20 (1996), provides two approaches to suitably functionalized 3-azabicyclo[3.3.0]octanes. Such reference is herein incorporated by reference with regard to such synthetic teaching. The first approach involves the palladium-catalyzed [3+2] cycloaddition reaction of 2-trimethylsilylmethyl-2-propen-1-yl acetate with dimethyl maleate. The resulting diester is saponified, treated with acetic anhydride, and pyrolyzed to give the fused cyclic anhydride, tetrahydro-5-methylene-1H-cyclopenta[c]furan-1,3(3aH)-dione. Treatment with ammonia followed by cyclization with acetyl chloride gives the imide, tetrahydro-5-methylene-1H-cyclopenta[c]pyrrole-1,3(2H,2aH)-dione. Reduction with lithium aluminum hydride and protection of the free amine with di-tert-butyl dicarbonate gives 7-methylene-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane. Subsequent transformations, using this methylene compound, are possible. For instance, ozonolysis of 7-methylene-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane will give 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octan-7-one. Alternately, treatment of 7-methylene-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane with borane, followed by aqueous basic hydrogen peroxide, will produce 7-(hydroxymethyl)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane. Oxidation of this alcohol by any number of methods, known to those of skill in the art of organic synthesis, will generate 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane-7-carboxylic acid, a key intermediate for the synthesis of compounds of the present invention.

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