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

Abstract

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 δ-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).