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Current research predominantly focuses on centrally chiral unnatural \u03b1\u2010amino acids, while \u03b1\u2010amino acids featuring other chirality types are yet to be disclosed. We therefore sought to expand the chemical space of \u03b1\u2010amino acids by introducing the concept of axially chiral \u03b1\u2010amino acid. Here, we rationally design a prochiral \u03b1\u2010amino acid substrate derived from a spiro[3.3]heptane scaffold, an emerging Fsp\n                    <jats:sup>3<\/jats:sup>\n                    \u2010enriched isostere in medicinal chemistry, and subsequent catalytic asymmetric synthesis of axially chiral \u03b1\u2010amino acids is realized via a reductive amination enabled by chiral phosphoric acid catalysis. A wide array of spiro[3.3]heptane\u2010based axially chiral \u03b1\u2010amino acids are obtained in generally high yields and enantioselectivities, and are readily incorporated into complex peptides by both solution\u2010phase and solid\u2010phase peptide synthesis. As conformationally constrained\n                    <jats:sc>\n                      <jats:italic>L<\/jats:italic>\n                    <\/jats:sc>\n                    \u2010lysine mimetics, these amino acids can enhance inhibitory activities against PD\u20101\/PD\u2010L1 and improve physicochemical properties. Experimental and computational studies elucidate the reaction mechanism, the origin of enantioselectivity, and the structural basis for the improved biological activities. This work expands the accessible chemical space of \u03b1\u2010amino acids and establishes valuable building blocks for complex peptide synthesis.\n                  <\/jats:p>","DOI":"10.1002\/anie.7366839","type":"journal-article","created":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T07:03:39Z","timestamp":1792134219000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Catalytic Asymmetric Synthesis of Spiro[3.3]heptane\u2010Based Axially Chiral \u03b1\u2010Amino Acids"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4441-1963","authenticated-orcid":false,"given":"Yu\u2010Ping","family":"Tang","sequence":"first","affiliation":[{"name":"Chongqing Key Laboratory of Natural Product Synthesis and Drug Research School of Pharmaceutical Sciences Chongqing University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Chen","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Natural Product Synthesis and Drug Research School of Pharmaceutical Sciences Chongqing University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingqin","family":"Huang","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Natural Product Synthesis and Drug Research School of Pharmaceutical Sciences Chongqing University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu\u2010Cheng","family":"Lei","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Natural Product Synthesis and Drug Research School of Pharmaceutical Sciences Chongqing University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4225-7408","authenticated-orcid":false,"given":"Lei","family":"Dai","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Natural Product Synthesis and Drug Research School of Pharmaceutical Sciences Chongqing University  Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,16]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01795749"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb\u20102006\u20107\u20101\u2010102"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1717100115"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021\u20109258(18)64093\u20101"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022\u20102836(80)90308\u20103"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.4.1110"},{"key":"e_1_2_8_8_1","volume-title":"Amino Acids, Peptides and Proteins in Organic Chemistry","author":"Hughes A. 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