Asymmetric Aldol-Ring-Closing Metathesis Strategy for the Enantioselective Construction of Six- to Nine-Membered Oxygen Heterocycles.

The ring closing metathesis reaction has rapidly become an important transformation in organic synthesis.1 Examples of many ring sizes with a variety of functional appendages2 have been constructed by this powerful method, largely because of the advent of the functionally tolerant ruthenium3 and molybdenum4 carbene complexes. Even kinetically and thermodynamically disfavored eight-membered rings have been prepared by ringclosing metathesis. However, virtually all5 successful eight-membered ring closures have required the incorporation of cyclic conformational constraints6 or rigid acyclic conformational control elements to avoid formation of dimers or oligomers.7 It is noteworthy that cyclic constrained dienes underwent more efficient ringclosing metathesis to form eight-membered rings when the two olefinic chains were positioned trans on the cyclic constraint than when they were cis.7 Grubbs6a has attributed this effect to a greater difference in energy between the diene and the cyclic olefin in the cissubstituted substrate. We reasoned that dienes with an appropriate acyclic conformational bias might allow eight (or nine)-membered ring formation and avoid the additional strain imposed by a fused ring attached to the newly formed cyclic olefin. We recently reported an asymmetric aldol-ring-closing metathesis strategy for the enantioselective synthesis of the carbocyclic fragment of the nucleoside analogue 1592U89.8 In view of the importance of enantioselective approaches to cyclic ethers of all sizes, particularly eightand nine-membered ring metabolites that are abundant in marine algae,9 an extension of the aldol-metathesis strategy to oxygen heterocycles seemed in order. We report here an efficient, general strategy for the asymmetric synthesis of sixto nine-membered cyclic ethers.10