{"doi":"10.1021/jacs.3c04870","title":"Enantio- and Diastereoenriched Enzymatic Synthesis of 1,2,3-Polysubstituted Cyclopropanes from (<i>Z</i>/<i>E</i>)-Trisubstituted Enol Acetates","abstract":"In nature and synthetic chemistry, stereoselective [2 + 1] cyclopropanation is the most prevalent strategy for the synthesis of chiral cyclopropanes, a class of key pharmacophores in pharmaceuticals and bioactive natural products. One of the most extensively studied reactions in the organic chemist’s arsenal, stereoselective [2 + 1] cyclopropanation, largely relies on the use of stereodefined olefins, which can require elaborate laboratory synthesis or tedious separation to ensure high stereoselectivity. Here, we report engineered hemoproteins derived from a bacterial cytochrome P450 that catalyze the synthesis of chiral 1,2,3-polysubstituted cyclopropanes, regardless of the stereopurity of the olefin substrates used. Cytochrome P450 BM3 variant P411-INC-5185 exclusively converts ( Z )-enol acetates to enantio- and diastereoenriched cyclopropanes and in the model reaction delivers a leftover ( E )-enol acetate with 98% stereopurity, using whole Escherichia coli cells. P411-INC-5185 was further engineered with a single mutation to enable the biotransformation of ( E )-enol acetates to α-branched ketones with high levels of enantioselectivity while simultaneously catalyzing the cyclopropanation of ( Z )-enol acetates with excellent activities and selectivities. We conducted docking studies and molecular dynamics simulations to understand how active-site residues distinguish between the substrate isomers and enable the enzyme to perform these distinct transformations with such high selectivities. Computational studies suggest the observed enantio- and diastereoselectivities are achieved through a stepwise pathway. These biotransformations streamline the synthesis of chiral 1,2,3-polysubstituted cyclopropanes from readily available mixtures of ( Z / E )-olefins, adding a new dimension to classical cyclopropanation methods.","journal":"Journal of the American Chemical Society","year":2023,"id":331538,"datarank":0.5050943744979712,"base_score":3.367295829986474,"endowment":3.367295829986474,"self_citation_contribution":0.5050943744979712,"citation_network_contribution":0.0,"self_endowment_contribution":0.5050943744979712,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":28,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9497,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1056890,"name":"Daniel J. Wackelin","orcid":null,"position":1,"is_corresponding":false},{"id":363424,"name":"Cooper S. Jamieson","orcid":"0000-0002-6076-6230","position":2,"is_corresponding":false},{"id":1056511,"name":"Torben Rogge","orcid":"0000-0002-4519-4596","position":3,"is_corresponding":false},{"id":651911,"name":"Shilong Gao","orcid":"0000-0003-2808-6283","position":4,"is_corresponding":false},{"id":298858,"name":"Anuvab Das","orcid":"0000-0002-9344-4414","position":5,"is_corresponding":false},{"id":783726,"name":"Doris Mia Taylor","orcid":"0000-0001-6854-7844","position":6,"is_corresponding":false},{"id":292448,"name":"K. N. Houk","orcid":"0000-0002-8387-5261","position":7,"is_corresponding":false},{"id":272467,"name":"Frances H. Arnold","orcid":"0000-0002-4027-364X","position":8,"is_corresponding":false},{"id":997451,"name":"Runze Mao","orcid":"0000-0003-4678-7251","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:09:19.317824Z","pmid":"37433085","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":[]}