Kinetic Resolution of Amino Acids by Phosphine Oxide Catalyzed Enantioselective Esterification

Kinetic Resolution of Amino Acids by Phosphine Oxide Catalyzed Enantioselective Esterification | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Kinetic Resolution of Amino Acids by Phosphine Oxide Catalyzed Enantioselective Esterification Ji-Wei Ren This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6496592/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract The first highly efficient kinetic resolution (KR) of racemic amino acids with L -pyroglutaminol as an esterification reagent was reported through a novel phosphine oxide organocatalyst catalyzed under mild conditions, which provides a wide range of chiral esters and recovered amino acids with excellent stereoselectivities (s > 1057). The catalyst demonstrated excellent stereocontrol and catalytic activity, which presumably benefited from an intimate double H-bonding interaction between the pyroglutaminol core and the catalyst. Chiral amino acids find applications as versatile building blocks in the synthesis of functional molecules, as a source of chiral information in asymmetric synthesis and as tools to expand and explore the function of native biological machinery. 1 – 8 Therefore, chiral amino acids represent a class of valuable and indispensable compounds whose stereoselective synthesis is a major objective within synthetic chemists and synthetic biologists. 9 – 10 To the best of our knowledge, an array of effective synthetic strategies for the construction of chiral amino acids have been developed, such as asymmetric hydrogenation and nucleophilic addition of imines 11 – 18 , enantioselective carbene insertion into N-H bonds of amines or amides 19 – 23 , stereoselective photobiocatalytic cross-coupling 24 – 27 , and stereocontrolled 1,3-nitrogen migration of carboxylic acids 28 . However, identifying a highly enantioselective chiral catalyst for a specific reaction is not always an easy task. An alternative well-established strategy relies on the catalytic KR of a racemic mixture (Fig. 1a). 29 – 31 The KR stands out as one of the most practical and straightforward strategies for obtaining enantioenriched molecules and recovering the starting materials, effectively allowing for access to both enantiomers from a single enantiomer of catalyst. Numerous highly efficient catalytic KR processes have been developed that reliably deliver enantiopure compounds, including chiral alcohols 32 – 36 , monohydrosilanes 37 , organoperoxides 38 , alkynes 39 – 40 , sulfonyl ketones 41 , amines 42 , imines 43 , sulfoximines 44 – 45 , aldehydes 46 , phosphindane oxides 47 – 48 , and heterocyclic compounds 49 – 52 . Despite this significant progress in the field, the catalytic KR of amino acids remains a challenging task and has been rarely explored. 53 – 57 Physical sciences/Chemistry/Catalysis/Organocatalysis Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology Full Text Additional Declarations There is NO Competing Interest. The authors declare no competing financial interest. Supplementary Files supportinformation.pdf Kinetic Resolution of Amino Acids by Phosphine Oxide Catalyzed Enantioselective Esterification Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6496592","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":452470668,"identity":"8871696c-78b8-4294-89af-3c39982468d2","order_by":0,"name":"Ji-Wei Ren","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5UlEQVRIiWNgGAWjYJACgwQGBh429uYDBz4Y2MgRr4WP51jiwRkFacbEWyUnkWN8mOfD4USCKs3bew8UPGyzkWGTyDE4bGPAnMDAfvjoBnxaZM6cSzBIbEvjYeN5VnA4x4Atj4EnLe0GPi0SQMMNErcdBno/eQNQC08xgwSPGX4t8m9AWv7zsDEkGBy2MJBIbCCoRYIHpOUADxtHisFhBiCbsBYekMP+JQP9cizhYI9BgjEbQb+wnzEz/HHGzl6+vfnwhx9//svxsx8+hlcLELAZoHIJKAcB5gdEKBoFo2AUjIKRDADY/Ec5oVyUpgAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-5796-4976","institution":"Taishan University","correspondingAuthor":true,"prefix":"","firstName":"Ji-Wei","middleName":"","lastName":"Ren","suffix":""}],"badges":[],"createdAt":"2025-04-21 13:45:30","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6496592/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6496592/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82124436,"identity":"67734519-f7e6-42e1-a0c2-550eb6b28921","added_by":"auto","created_at":"2025-05-07 03:38:33","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1360966,"visible":true,"origin":"","legend":"Article File","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6496592/v1_covered_916a06f2-3d01-414b-9bdc-852c6384f24b.pdf"},{"id":82118288,"identity":"76ac5854-7db4-45f1-ba75-871c75a9255d","added_by":"auto","created_at":"2025-05-07 03:06:32","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":18311198,"visible":true,"origin":"","legend":"Kinetic Resolution of Amino Acids by Phosphine Oxide Catalyzed Enantioselective Esterification","description":"","filename":"supportinformation.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6496592/v1/277e5ce5fe03ac23ae7228d7.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.\nThe authors declare no competing financial interest.","formattedTitle":"Kinetic Resolution of Amino Acids by Phosphine Oxide Catalyzed Enantioselective Esterification","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6496592/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6496592/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe first highly efficient kinetic resolution (KR) of racemic amino acids with \u003cem\u003eL\u003c/em\u003e-pyroglutaminol as an esterification reagent was reported through a novel phosphine oxide organocatalyst catalyzed under mild conditions, which provides a wide range of chiral esters and recovered amino acids with excellent stereoselectivities (s\u0026thinsp;\u0026gt;\u0026thinsp;1057). The catalyst demonstrated excellent stereocontrol and catalytic activity, which presumably benefited from an intimate double H-bonding interaction between the pyroglutaminol core and the catalyst.\u003c/p\u003e \u003cp\u003eChiral amino acids find applications as versatile building blocks in the synthesis of functional molecules, as a source of chiral information in asymmetric synthesis and as tools to expand and explore the function of native biological machinery.\u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5 CR6 CR7\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Therefore, chiral amino acids represent a class of valuable and indispensable compounds whose stereoselective synthesis is a major objective within synthetic chemists and synthetic biologists.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e To the best of our knowledge, an array of effective synthetic strategies for the construction of chiral amino acids have been developed, such as asymmetric hydrogenation and nucleophilic addition of imines\u003csup\u003e\u003cspan additionalcitationids=\"CR12 CR13 CR14 CR15 CR16 CR17\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e, enantioselective carbene insertion into N-H bonds of amines or amides\u003csup\u003e\u003cspan additionalcitationids=\"CR20 CR21 CR22\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e, stereoselective photobiocatalytic cross-coupling\u003csup\u003e\u003cspan additionalcitationids=\"CR25 CR26\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e, and stereocontrolled 1,3-nitrogen migration of carboxylic acids\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. However, identifying a highly enantioselective chiral catalyst for a specific reaction is not always an easy task. An alternative well-established strategy relies on the catalytic KR of a racemic mixture (Fig.\u0026nbsp;1a).\u003csup\u003e\u003cspan additionalcitationids=\"CR30\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e The KR stands out as one of the most practical and straightforward strategies for obtaining enantioenriched molecules and recovering the starting materials, effectively allowing for access to both enantiomers from a single enantiomer of catalyst. Numerous highly efficient catalytic KR processes have been developed that reliably deliver enantiopure compounds, including chiral alcohols\u003csup\u003e\u003cspan additionalcitationids=\"CR33 CR34 CR35\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e, monohydrosilanes\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e, organoperoxides\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e, alkynes\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e, sulfonyl ketones\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e, amines\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e, imines\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e, sulfoximines\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e, aldehydes\u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e, phosphindane oxides\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e, and heterocyclic compounds\u003csup\u003e\u003cspan additionalcitationids=\"CR50 CR51\" citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e. Despite this significant progress in the field, the catalytic KR of amino acids remains a challenging task and has been rarely explored.\u003csup\u003e\u003cspan additionalcitationids=\"CR54 CR55 CR56\" citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e","manuscriptTitle":"Kinetic Resolution of Amino Acids by Phosphine Oxide Catalyzed Enantioselective Esterification","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-07 03:06:27","doi":"10.21203/rs.3.rs-6496592/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"500176f1-b4ef-4dd2-a0a7-b85b18b69fe0","owner":[],"postedDate":"May 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":48116847,"name":"Physical sciences/Chemistry/Catalysis/Organocatalysis"},{"id":48116848,"name":"Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology"}],"tags":[],"updatedAt":"2026-03-24T15:17:02+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-07 03:06:27","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6496592","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6496592","identity":"rs-6496592","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}