Enantioselective synthesis of (R)-tolterodine using lithiation/borylation–protodeboronation methodology
The synthesis of the pharmaceutical (R)-tolterodine is reported using lithiation/borylation–protodeboronation of a homoallyl carbamate as the key step. This step was tested with two permutations: an electron-neutral aryl Li-carbamate reacting with an electron-rich boronic ester and an electron-rich...
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| Veröffentlicht in: | Canadian journal of chemistry 2012-11, Vol.90 (11), p.965-974 |
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| container_title | Canadian journal of chemistry |
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| creator | Roesner, Stefan Aggarwal, Varinder K |
| description | The synthesis of the pharmaceutical (R)-tolterodine is reported using lithiation/borylation–protodeboronation of a homoallyl carbamate as the key step. This step was tested with two permutations: an electron-neutral aryl Li-carbamate reacting with an electron-rich boronic ester and an electron-rich aryl Li-carbamate reacting with an electron-neutral boronic ester. It was found that the latter arrangement was considerably better than the former. Further improvements were achieved using magnesium bromide in methanol leading to a process that gave high yield and high enantioselectivity in the lithiation/borylation reaction. The key step was used in an efficient synthesis of (R)-tolterodine in a total of eight steps in a 30% overall yield and 90% ee. |
| doi_str_mv | 10.1139/v2012-069 |
| format | Article |
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This step was tested with two permutations: an electron-neutral aryl Li-carbamate reacting with an electron-rich boronic ester and an electron-rich aryl Li-carbamate reacting with an electron-neutral boronic ester. It was found that the latter arrangement was considerably better than the former. Further improvements were achieved using magnesium bromide in methanol leading to a process that gave high yield and high enantioselectivity in the lithiation/borylation reaction. The key step was used in an efficient synthesis of (R)-tolterodine in a total of eight steps in a 30% overall yield and 90% ee.</description><identifier>ISSN: 0008-4042</identifier><identifier>EISSN: 1480-3291</identifier><identifier>DOI: 10.1139/v2012-069</identifier><identifier>PMID: 23750041</identifier><identifier>CODEN: CJCHAG</identifier><language>eng</language><publisher>Canada: NRC Research Press</publisher><subject>Aromatic compounds ; asymmetric synthesis ; boronic esters ; Chemical properties ; Chemical reactions ; Chemical synthesis ; Chemistry ; Composition ; Electrons ; Enantiomers ; esters boroniques ; gem-diarylalkyl ; gem-diarylalkyle ; Identification and classification ; lithiation/borylation reaction ; Lithium ; Magnesium ; Magnesium bromides ; Muscarinic antagonists ; Organic compounds ; Permutations ; Pharmaceutical chemistry ; Pharmaceuticals ; Production processes ; réaction de lithiation/borylation ; Synthesis ; synthèse asymétrique ; tolterodine ; toltérodine</subject><ispartof>Canadian journal of chemistry, 2012-11, Vol.90 (11), p.965-974</ispartof><rights>COPYRIGHT 2012 NRC Research Press</rights><rights>Copyright National Research Council of Canada Nov 2012</rights><rights>2012 Published by NRC Research Press</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c734t-b1fbe9e18cebac4596b81c31bcc2fbf116153450dbc9e462db55e957acdabdc23</citedby><cites>FETCH-LOGICAL-c734t-b1fbe9e18cebac4596b81c31bcc2fbf116153450dbc9e462db55e957acdabdc23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,782,786,887,27933,27934</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23750041$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Roesner, Stefan</creatorcontrib><creatorcontrib>Aggarwal, Varinder K</creatorcontrib><title>Enantioselective synthesis of (R)-tolterodine using lithiation/borylation–protodeboronation methodology</title><title>Canadian journal of chemistry</title><addtitle>Can J Chem</addtitle><description>The synthesis of the pharmaceutical (R)-tolterodine is reported using lithiation/borylation–protodeboronation of a homoallyl carbamate as the key step. This step was tested with two permutations: an electron-neutral aryl Li-carbamate reacting with an electron-rich boronic ester and an electron-rich aryl Li-carbamate reacting with an electron-neutral boronic ester. It was found that the latter arrangement was considerably better than the former. Further improvements were achieved using magnesium bromide in methanol leading to a process that gave high yield and high enantioselectivity in the lithiation/borylation reaction. The key step was used in an efficient synthesis of (R)-tolterodine in a total of eight steps in a 30% overall yield and 90% ee.</description><subject>Aromatic compounds</subject><subject>asymmetric synthesis</subject><subject>boronic esters</subject><subject>Chemical properties</subject><subject>Chemical reactions</subject><subject>Chemical synthesis</subject><subject>Chemistry</subject><subject>Composition</subject><subject>Electrons</subject><subject>Enantiomers</subject><subject>esters boroniques</subject><subject>gem-diarylalkyl</subject><subject>gem-diarylalkyle</subject><subject>Identification and classification</subject><subject>lithiation/borylation reaction</subject><subject>Lithium</subject><subject>Magnesium</subject><subject>Magnesium bromides</subject><subject>Muscarinic antagonists</subject><subject>Organic compounds</subject><subject>Permutations</subject><subject>Pharmaceutical chemistry</subject><subject>Pharmaceuticals</subject><subject>Production processes</subject><subject>réaction de lithiation/borylation</subject><subject>Synthesis</subject><subject>synthèse asymétrique</subject><subject>tolterodine</subject><subject>toltérodine</subject><issn>0008-4042</issn><issn>1480-3291</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><recordid>eNqV0l1r1TAYB_AiijtOL_wCUvRmA7vlpW-5EcaYOhgKU69Dkj5tM9rkLEkPnju_g9_QT2LO2Zw7UgbSi7RPfvk3IU-SvMToCGPKjlcEYZKhkj1KFjivUUYJw4-TBUKoznKUk73kmfdX8bNCpHia7BFaFQjleJHoMyNM0NbDACroFaR-bUIPXvvUtunB5WEW7BDA2UYbSCevTZcOOvRaxFXmWFq3Hravv378XDobbAOxZs22lo4QetvYwXbr58mTVgweXtyO-8m392dfTz9mF58_nJ-eXGSqonnIJG4lMMC1AilUXrBS1lhRLJUirWwxLnFB8wI1UjHIS9LIogBWVEI1QjaK0P3k3U3ucpIjNApMcGLgS6dH4dbcCs13Z4zueWdXnJYVYcUm4OA2wNnrCXzgo_YKhkEYsJPnuCZlUWFU1ZG--Yde2cmZeDxOckLrPGbShxQmUdGqxOyv6sQAXJvWxt2pza_5CcW0YiWtN5vLZlQHBuJRrIFWx_KOfz3j1VJf8_voaAbFp4FRq9nUw50F0QT4Hjoxec_Pv1z-h_00a5Wz3jto764NI75pdb5tdR5bPdpX9-_5Tv7p7Qje3gDjlAMPwqn-gbzfhvQG5A</recordid><startdate>20121101</startdate><enddate>20121101</enddate><creator>Roesner, Stefan</creator><creator>Aggarwal, Varinder K</creator><general>NRC Research Press</general><general>Canadian Science Publishing NRC Research Press</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>ISN</scope><scope>ISR</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20121101</creationdate><title>Enantioselective synthesis of (R)-tolterodine using lithiation/borylation–protodeboronation methodology</title><author>Roesner, Stefan ; Aggarwal, Varinder K</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c734t-b1fbe9e18cebac4596b81c31bcc2fbf116153450dbc9e462db55e957acdabdc23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Aromatic compounds</topic><topic>asymmetric synthesis</topic><topic>boronic esters</topic><topic>Chemical properties</topic><topic>Chemical reactions</topic><topic>Chemical synthesis</topic><topic>Chemistry</topic><topic>Composition</topic><topic>Electrons</topic><topic>Enantiomers</topic><topic>esters boroniques</topic><topic>gem-diarylalkyl</topic><topic>gem-diarylalkyle</topic><topic>Identification and classification</topic><topic>lithiation/borylation reaction</topic><topic>Lithium</topic><topic>Magnesium</topic><topic>Magnesium bromides</topic><topic>Muscarinic antagonists</topic><topic>Organic compounds</topic><topic>Permutations</topic><topic>Pharmaceutical chemistry</topic><topic>Pharmaceuticals</topic><topic>Production processes</topic><topic>réaction de lithiation/borylation</topic><topic>Synthesis</topic><topic>synthèse asymétrique</topic><topic>tolterodine</topic><topic>toltérodine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Roesner, Stefan</creatorcontrib><creatorcontrib>Aggarwal, Varinder K</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Canadian journal of chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Roesner, Stefan</au><au>Aggarwal, Varinder K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Enantioselective synthesis of (R)-tolterodine using lithiation/borylation–protodeboronation methodology</atitle><jtitle>Canadian journal of chemistry</jtitle><addtitle>Can J Chem</addtitle><date>2012-11-01</date><risdate>2012</risdate><volume>90</volume><issue>11</issue><spage>965</spage><epage>974</epage><pages>965-974</pages><issn>0008-4042</issn><eissn>1480-3291</eissn><coden>CJCHAG</coden><abstract>The synthesis of the pharmaceutical (R)-tolterodine is reported using lithiation/borylation–protodeboronation of a homoallyl carbamate as the key step. This step was tested with two permutations: an electron-neutral aryl Li-carbamate reacting with an electron-rich boronic ester and an electron-rich aryl Li-carbamate reacting with an electron-neutral boronic ester. It was found that the latter arrangement was considerably better than the former. Further improvements were achieved using magnesium bromide in methanol leading to a process that gave high yield and high enantioselectivity in the lithiation/borylation reaction. The key step was used in an efficient synthesis of (R)-tolterodine in a total of eight steps in a 30% overall yield and 90% ee.</abstract><cop>Canada</cop><pub>NRC Research Press</pub><pmid>23750041</pmid><doi>10.1139/v2012-069</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Aromatic compounds asymmetric synthesis boronic esters Chemical properties Chemical reactions Chemical synthesis Chemistry Composition Electrons Enantiomers esters boroniques gem-diarylalkyl gem-diarylalkyle Identification and classification lithiation/borylation reaction Lithium Magnesium Magnesium bromides Muscarinic antagonists Organic compounds Permutations Pharmaceutical chemistry Pharmaceuticals Production processes réaction de lithiation/borylation Synthesis synthèse asymétrique tolterodine toltérodine |
| title | Enantioselective synthesis of (R)-tolterodine using lithiation/borylation–protodeboronation methodology |
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