{"doi":"10.1021/jacs.5c03841","title":"Ruthenium-Catalyzed Enantioselective Alkylation of Sulfenamides: A General Approach for the Synthesis of Drug Relevant <i>S</i>-Methyl and <i>S</i>-Cyclopropyl Sulfoximines","abstract":"Sulfoximines are increasingly utilized in pharmaceuticals and agrochemicals with all sulfoximine clinical candidates incorporating either an S -methyl or an S -cyclopropyl substituent. Here, we report on a general and efficient sequence for the asymmetric synthesis of both of these sulfoximine substitution patterns. The asymmetric synthesis of sulfilimine intermediates by the first Ru-catalyzed enantioselective alkylation of sulfenamides enables the first examples of enantioselective S -alkylation with monosubstituted diazo compounds. The reaction proceeds at ≤1 mol % Ru-catalyst loading, and for tert -butyl diazoacetate, high yields and ≥98:2 er are achieved for an exceedingly broad range of sulfenamides, including with S -(hetero)aryl, -alkenyl, -methyl, -benzyl, -branched alkyl, and - tert -butyl substituents and for sterically and electronically diverse N -acyl groups. Sulfenamides derived from densely functionalized advanced drug intermediates also alkylated with 99:1 er. After oxidation of an N -pivaloyl S - tert -butyl acetate substituted sulfilimine to the corresponding sulfoximine, treatment with trifluoracetic acid in an aprotic solvent resulted in decarboxylation to the S -methyl N -pivaloyl sulfoximine, while aqueous HCl resulted in both decarboxylation and cleavage of the N -acyl group to give the S -methyl NH sulfoximine. Alternatively, sulfoximine alkylation with dibromoethane followed by acid-mediated decarboxylation provided the S -cyclopropyl sulfoximine. The efficient asymmetric synthesis of the preclinical candidate LTGO-33 and the formal asymmetric synthesis of the phase II clinical candidate ART0380 demonstrate the utility of the disclosed approach.","journal":"Journal of the American Chemical Society","year":2025,"id":509254,"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":40,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9512,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1206007,"name":"Na Yeon Kwon","orcid":"0000-0003-2776-4863","position":1,"is_corresponding":false},{"id":896283,"name":"Jonathan A. Ellman","orcid":"0000-0001-9320-5512","position":2,"is_corresponding":false},{"id":914025,"name":"Zachary W. Boyer","orcid":null,"position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-19T02:47:24.513904Z","pmid":"40289728","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":[]}