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While several methods have been developed for synthesis of <jats:italic>trans<\/jats:italic>\u2010CF<jats:sub>3<\/jats:sub>\u2010CPAs, stereoselective production of corresponding <jats:italic>cis<\/jats:italic>\u2010diastereomers remains a formidable challenge. We report a biocatalyst for diastereo\u2010 and enantio\u2010selective synthesis of <jats:italic>cis<\/jats:italic>\u2010CF<jats:sub>3<\/jats:sub>\u2010CPAs with activity on a variety of alkenes. We found that an engineered protoglobin from <jats:italic>Aeropyrnum pernix<\/jats:italic> (<jats:italic>Ape<\/jats:italic>Pgb) can catalyze this unusual reaction at preparative scale with low\u2010to\u2010excellent yield (6\u201355\u2009%) and enantioselectivity (17\u201399\u2009% ee), depending on the substrate. Computational studies revealed that the steric environment in the active site of the protoglobin forced iron\u2010carbenoid and substrates to adopt a pro\u2010<jats:italic>cis<\/jats:italic> near\u2010attack conformation. This work demonstrates the capability of enzyme catalysts to tackle challenging chemistry problems and provides a powerful means to expand the structural diversity of CF<jats:sub>3<\/jats:sub>\u2010CPAs for drug discovery.<\/jats:p>","DOI":"10.1002\/anie.202208936","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T14:00:21Z","timestamp":1671458421000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Protoglobin\u2010Catalyzed Formation of <i>cis<\/i>\u2010Trifluoromethyl\u2010Substituted Cyclopropanes by Carbene Transfer"],"prefix":"10.1002","volume":"62","author":[{"given":"Lucas","family":"Schaus","sequence":"first","affiliation":[{"name":"Division of Chemistry and Chemical Engineering California Institute of Technology  1200 E California Blvd. Pasadena CA 91125 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9344-4414","authenticated-orcid":false,"given":"Anuvab","family":"Das","sequence":"additional","affiliation":[{"name":"Division of Chemistry and Chemical Engineering California Institute of Technology  1200 E California Blvd. Pasadena CA 91125 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9665-8197","authenticated-orcid":false,"given":"Anders M.","family":"Knight","sequence":"additional","affiliation":[{"name":"Division of Chemistry and Chemical Engineering California Institute of Technology  1200 E California Blvd. Pasadena CA 91125 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0105-4337","authenticated-orcid":false,"given":"Gonzalo","family":"Jimenez\u2010Os\u00e9s","sequence":"additional","affiliation":[{"name":"Center for Cooperative Research in Biosciences (CIC bioGUNE) Basque Research and Technology Alliance (BRTA)  Bizkaia Technology Park, Building 800 48160 Derio Spain"},{"name":"Ikerbasque, Basque Foundation for Science  48013 Bilbao Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8387-5261","authenticated-orcid":false,"given":"K. 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