{"doi":"10.17615/8dae-pd10","title":"An Efficient Strategy for the Synthesis of α,α′-cis and trans-Disubstituted Medium Ring Ethers","abstract":"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.","journal":"Carolina Digital Repository (University of North Carolina at Chapel Hill)","year":2021,"id":230259,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9549,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":328001,"name":"Kyle A. Emmitte","orcid":"0000-0002-6643-3947","position":1,"is_corresponding":false},{"id":600708,"name":"Michael T. Crimmins","orcid":"0000-0003-0313-6010","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:55:05.844766Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}