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This study reports the challenging direct asymmetric alkylation of cyclic ketones with dehydroalanine derivatives via a conjugate addition reaction for the synthesis of enantiopure ketone\u2010based \u03b1\u2010unnatural amino acids. The key to success was the design of a bifunctional primary amine\u2010thiourea catalyst that combines H\u2010bond\u2010directing activation and enamine catalysis. The simultaneous dual activation of the two relatively unreactive partners, confirmed by mass spectrometry studies, results in high reactivity while securing high levels of stereocontrol. A broad substrate scope is accompanied by versatile downstream chemical modifications. The mild reaction conditions and consistently excellent enantioselectivities (&gt;95\u2009%\u2005ee in most cases) render this protocol highly practical for the rapid construction of valuable noncanonical enantiopure \u03b1\u2010amino\u2010acid building blocks.<\/jats:p>","DOI":"10.1002\/chem.202201994","type":"journal-article","created":{"date-parts":[[2022,8,2]],"date-time":"2022-08-02T15:32:45Z","timestamp":1659454365000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Asymmetric Alkylation of Cyclic Ketones with Dehydroalanine via H\u2010Bond\u2010Directing Enamine Catalysis: Straightforward Access to Enantiopure Unnatural \u03b1\u2010Amino Acids"],"prefix":"10.1002","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0218-8505","authenticated-orcid":false,"given":"Michele","family":"Retini","sequence":"first","affiliation":[{"name":"Department of Biomolecular Sciences University of Urbino Carlo Bo  Piazza Rinascimento 6 61029 Urbino PU Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2063-4230","authenticated-orcid":false,"given":"Silvia","family":"Bartolucci","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences University of Urbino Carlo Bo  Piazza Rinascimento 6 61029 Urbino PU Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0400-7771","authenticated-orcid":false,"given":"Francesca","family":"Bartoccini","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences University of Urbino Carlo Bo  Piazza Rinascimento 6 61029 Urbino PU Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0418-7143","authenticated-orcid":false,"given":"Giovanni","family":"Piersanti","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences University of Urbino Carlo Bo  Piazza Rinascimento 6 61029 Urbino PU Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,8,18]]},"reference":[{"key":"e_1_2_8_1_1","unstructured":"\u00a0"},{"key":"e_1_2_8_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-331-8"},{"key":"e_1_2_8_3_2","volume-title":"Amino Acids, Peptides and Proteins in Organic Chemistry","author":"Hughes A. 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