Synthesis of 7-methoxy-3′,4′,5′,6′-tetrahydrospiro[isobenzofuran-1(3H),2′-pyran]-3-one and 5,7-dimethoxy-3′,4′,5′,6′-tetrahydrospiro[isobenzofuran-1(3H),2′-pyran]-3-one

The synthesis of novel aryl spiroketals, which contain a, similar substitution pattern to that present in the antifungal agents the papulacandins, is described. Thus, spiroketal (7) was obtained from acid-catalysed cyclization of the keto alcohol (13), and spiroketal (8) was obtained from acid-catalysed cyclization of keto alcohols (12) and (19). Keto alcohols (12), (13) and (19) in turn were prepared by ortho-directed lithiation of amides (10), (11) and oxazoline (17) respectively, followed by reaction with delta-valerolactone. Substitution of the aromatic ring occurred at the sterically hindered position ortho to both the methoxy and ortho-directing metalation group. In an alternative approach to the synthesis of the desired spiroketals, two palladium(0)-catalysed coupling strategies were examined. The Stille coupling between the aryl stannane (24) and iodoglucal (25) resulted in a low yield of the aryl C-glycoside (21). Likewise, a low yield for the same coupled product (21) was achieved by a Suzuki coupling between the arylboronic acid (26) and iodoglucal (25).