Investigation of methods for seven-membered ring synthesis: A practical synthesis of 4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan-3-carboxylic acid

Several synthetic routes to 4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan- 3-carboxylic acid (1) are described, and the scaleup issues with each route are discussed. Seven-membered ring formation is a key issue with these syn theses, and several strategies are presented, including preparation from cy cloheptane-1,3 dione, ring-expansion routes, Dieckmann cyclization, acetyle ne-furan [4 + 2] cycloaddition, and Friedd-Crafts cyclization. Two of the r outes were scaled in the pilot plant to provide kilogram quantities of the title compound. The first scale-up route is outlined in Scheme 2 and utiliz es a ring-expansion strategy to prepare cycloheptane-1,3-dione from cyclope ntanone, via a [2 + 2] cycloaddition between dichloro-ketene and the silyl enol ether of cyclopentanone. The diketone is converted to the title compou nd by condensation with ethyl bromopyruvate and base, followed by acid hydr olysis. This route was efficient on laboratory scale but encountered proble ms upon wale-up due to a competing fragmentation pathway in the Zn/AcOH-med iated retro-aldol of cyclobutanone 11. The second, more successful scale-up route is described in Scheme 15, and involves Friedel-Crafts acylation of 3-carboethoxyfuran selectively at the 5-position. Reduction, lactonization, and hydrogenolysis provide acid 43, which is cyclized via a second Friedel Crafts reaction to form the seven-membered ketone.