An Efficient Strategy for the Synthesis of α,α′-cis and trans-Disubstituted Medium Ring Ethers

An asymmetric alkylation-ring-closing metathesis strat-egy was developed for the construction of a,a'-disubstituted medi-um ring ethers. The approach features an asymmetric alkylation of highly functionalized a-alkoxy acyl oxazolidinones followed by ring closure effected by Grubbs' ruthenium catalyst. The relation-ship between diene conformation and the rate of ring-closure was examined. Medium ring ethers are a common structural feature of many ladder ether marine toxins, as well as simpler me-tabolites from Laurencia species. This diverse collection of natural products often contains seven, eight, and nine membered ring ethers. 1 The challenge of efficient con-struction of medium ring ethers has led to the develop-ment of numerous strategies for their synthesis. 2-5 The vast majority of these approaches have focused on the a,a'-cis-disubstitution pattern rather than a,a'-trans-di-substituted medium ring ethers, despite their similar fre-quency of occurrence. trans-Isoprelaurefucin (1), 6 isolau-refucin methyl ether (2), 7 chlorofucin (3), 8 bromofucin (4), 9 isolaureatin (5), 10 and obtusenyne (6), 8 for example, all contain a,a'-trans-disubstituted medium ring ethers (Figure 1). Murai's synthesis of obtusenyne (6) 11 and our own recent syntheses of prelaureatin and laurallene 12 con-stitute the only known syntheses of medium ring ether natural products with the a,a'-trans-disubstitution ar-rangement. The investigation of a versatile, general strat-egy for the synthesis of both a,a'-cis and a,a'-trans-disubstituted medium ring ethers is described here. We recently published a total synthesis of the marine nat-ural product (+)-laurencin (9), in which the key steps were an asymmetric alkylation of the sodium enolate of substi-tuted acyl oxazolidinone 7, followed by ring-closing met-athesis of the resultant diene to give cyclic ether 8 (Scheme 1). 2 Previous work in our laboratory has demon-strated that an asymmetric aldol-ring-closing metathesis strategy for the assembly of medium ring ethers was equally adaptable to both the a,a'-cis and a,a'-trans-di-substituted medium ring ethers. 3,12 The asymmetric alky-lation-ring-closing metathesis approach to cyclic ethers also offered the potential for a similar adaptable strategy