Transition States and Origins of 1,4‐Asymmetric Induction in Alkylations of 2,2,6‐Trialkylpiperidine Enamines
Identifieur interne : 001724 ( Istex/Corpus ); précédent : 001723; suivant : 001725Transition States and Origins of 1,4‐Asymmetric Induction in Alkylations of 2,2,6‐Trialkylpiperidine Enamines
Auteurs : Joann Um ; Naeem Kaka ; David Hodgson ; K. HoukSource :
- Chemistry – A European Journal [ 0947-6539 ] ; 2010-06-01.
English descriptors
- KwdEn :
- Aldehyde, Alkene, Alkylation, Alkylations, Allyl, Allyl bromide, Angew, Asymmetric induction, Axial, Axial methyl, Axial methyl group, Bromide, Chem, Conformation, Conformer, Enamine, Enantiomeric ratios, Equatorial, Equatorial position, Ethyl iodide, Gmbh, Good agreement, Hodgson, Intermolecular nucleophilic substitution, Isopropyl, Isopropyl enamine, Isopropyl group, Kgaa, Lone interaction, Lone pair, Methyl, Methyl enamine, Model enamines, Olefinic protons, Phys, Piperidine, Piperidine ring, Preferential attack, Relative enthalpies, Transition state, Transition states, Transition structures, Unfavorable interaction, Verlag, Verlag gmbh, Weinheim, Weinheim chem.
- Teeft :
- Aldehyde, Alkene, Alkylation, Alkylations, Allyl, Allyl bromide, Angew, Asymmetric induction, Axial, Axial methyl, Axial methyl group, Bromide, Chem, Conformation, Conformer, Enamine, Enantiomeric ratios, Equatorial, Equatorial position, Ethyl iodide, Gmbh, Good agreement, Hodgson, Intermolecular nucleophilic substitution, Isopropyl, Isopropyl enamine, Isopropyl group, Kgaa, Lone interaction, Lone pair, Methyl, Methyl enamine, Model enamines, Olefinic protons, Phys, Piperidine, Piperidine ring, Preferential attack, Relative enthalpies, Transition state, Transition states, Transition structures, Unfavorable interaction, Verlag, Verlag gmbh, Weinheim, Weinheim chem.
Abstract
The asymmetric C‐alkylation of chiral enamines derived from terminal epoxides and lithium 2,2,6‐trialkylpiperidides has previously been shown to provide α‐alkylated aldehydes by intermolecular nucleophilic substitution in good levels of asymmetric induction. We now report a computational study of the origins of asymmetric induction in these reactions. Computational modeling with density functional theory (B3LYP/6‐31G(d)) agrees closely with the experimental observations. This stereoselectivity is attributed to a preferential conformation of the enamine and the piperidine ring that places the C‐6 alkyl substituent in an axial position due to A1, 3 strain. Preferential attack occurs away from the axial group, for steric reasons. The effects of changing the C‐6 substituent from methyl to isopropyl were studied, and twist transition states were found to contribute significantly in the latter alkylations.
Url:
DOI: 10.1002/chem.201000046
Links to Exploration step
ISTEX:035F03995891F79B507BD6081B3B87643B691835Le document en format XML
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We now report a computational study of the origins of asymmetric induction in these reactions. Computational modeling with density functional theory (B3LYP/6‐31G(d)) agrees closely with the experimental observations. This stereoselectivity is attributed to a preferential conformation of the enamine and the piperidine ring that places the C‐6 alkyl substituent in an axial position due to A1, 3 strain. Preferential attack occurs away from the axial group, for steric reasons. The effects of changing the C‐6 substituent from methyl to isopropyl were studied, and twist transition states were found to contribute significantly in the latter alkylations.</div></front></TEI><istex><corpusName>wiley</corpusName><keywords><teeft><json:string>enamine</json:string><json:string>chem</json:string><json:string>isopropyl</json:string><json:string>alkylation</json:string><json:string>methyl enamine</json:string><json:string>allyl</json:string><json:string>ethyl iodide</json:string><json:string>isopropyl enamine</json:string><json:string>conformer</json:string><json:string>bromide</json:string><json:string>aldehyde</json:string><json:string>phys</json:string><json:string>allyl bromide</json:string><json:string>transition states</json:string><json:string>methyl</json:string><json:string>alkene</json:string><json:string>angew</json:string><json:string>alkylations</json:string><json:string>weinheim</json:string><json:string>asymmetric induction</json:string><json:string>verlag</json:string><json:string>gmbh</json:string><json:string>verlag gmbh</json:string><json:string>kgaa</json:string><json:string>hodgson</json:string><json:string>piperidine</json:string><json:string>unfavorable interaction</json:string><json:string>transition structures</json:string><json:string>isopropyl group</json:string><json:string>lone pair</json:string><json:string>axial</json:string><json:string>weinheim chem</json:string><json:string>preferential attack</json:string><json:string>axial methyl group</json:string><json:string>olefinic protons</json:string><json:string>relative enthalpies</json:string><json:string>conformation</json:string><json:string>equatorial</json:string><json:string>intermolecular nucleophilic substitution</json:string><json:string>enantiomeric ratios</json:string><json:string>axial methyl</json:string><json:string>model enamines</json:string><json:string>good agreement</json:string><json:string>piperidine ring</json:string><json:string>transition state</json:string><json:string>equatorial position</json:string><json:string>lone interaction</json:string></teeft></keywords><author><json:item><name>Joann M. Um</name><affiliations><json:string>Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA 90095‐1569 (USA), Fax: (+1) 310‐206‐1843</json:string></affiliations></json:item><json:item><name>Naeem S. Kaka Dr.</name><affiliations><json:string>Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA (UK), Fax: (+44) 1865‐285002</json:string></affiliations></json:item><json:item><name>David M. Hodgson Prof.</name><affiliations><json:string>Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA (UK), Fax: (+44) 1865‐285002</json:string><json:string>E-mail: david.hodgson@chem.ox.ac.uk</json:string></affiliations></json:item><json:item><name>K. N. Houk Prof.</name><affiliations><json:string>Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA 90095‐1569 (USA), Fax: (+1) 310‐206‐1843</json:string><json:string>E-mail: houk@chem.ucla.edu</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>aldehydes</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>alkylation</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>asymmetric synthesis</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>density functional calculations</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>transition states</value></json:item></subject><articleId><json:string>CHEM201000046</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><abstract>The asymmetric C‐alkylation of chiral enamines derived from terminal epoxides and lithium 2,2,6‐trialkylpiperidides has previously been shown to provide α‐alkylated aldehydes by intermolecular nucleophilic substitution in good levels of asymmetric induction. We now report a computational study of the origins of asymmetric induction in these reactions. Computational modeling with density functional theory (B3LYP/6‐31G(d)) agrees closely with the experimental observations. This stereoselectivity is attributed to a preferential conformation of the enamine and the piperidine ring that places the C‐6 alkyl substituent in an axial position due to A1, 3 strain. Preferential attack occurs away from the axial group, for steric reasons. The effects of changing the C‐6 substituent from methyl to isopropyl were studied, and twist transition states were found to contribute significantly in the latter alkylations.</abstract><qualityIndicators><score>5.774</score><pdfVersion>1.3</pdfVersion><pdfPageSize>595.276 x 841.89 pts (A4)</pdfPageSize><refBibsNative>true</refBibsNative><abstractCharCount>913</abstractCharCount><pdfWordCount>4274</pdfWordCount><pdfCharCount>24182</pdfCharCount><pdfPageCount>7</pdfPageCount><abstractWordCount>125</abstractWordCount></qualityIndicators><title>Transition States and Origins of 1,4‐Asymmetric Induction in Alkylations of 2,2,6‐Trialkylpiperidine Enamines</title><genre><json:string>article</json:string></genre><host><title>Chemistry – A European Journal</title><language><json:string>unknown</json:string></language><doi><json:string>10.1002/(ISSN)1521-3765</json:string></doi><issn><json:string>0947-6539</json:string></issn><eissn><json:string>1521-3765</json:string></eissn><publisherId><json:string>CHEM</json:string></publisherId><volume>16</volume><issue>21</issue><pages><first>6310</first><last>6316</last><total>7</total></pages><genre><json:string>journal</json:string></genre><subject><json:item><value>Full Paper</value></json:item></subject></host><categories><wos><json:string>science</json:string><json:string>chemistry, multidisciplinary</json:string></wos><scienceMetrix><json:string>natural sciences</json:string><json:string>chemistry</json:string><json:string>general chemistry</json:string></scienceMetrix><inist><json:string>sciences appliquees, technologies et medecines</json:string><json:string>sciences biologiques et medicales</json:string><json:string>sciences biologiques fondamentales et appliquees. psychologie</json:string><json:string>biophysique des tissus, organes et organismes</json:string></inist></categories><publicationDate>2010</publicationDate><copyrightDate>2010</copyrightDate><doi><json:string>10.1002/chem.201000046</json:string></doi><id>035F03995891F79B507BD6081B3B87643B691835</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/035F03995891F79B507BD6081B3B87643B691835/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/document/035F03995891F79B507BD6081B3B87643B691835/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/035F03995891F79B507BD6081B3B87643B691835/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Transition States and Origins of 1,4‐Asymmetric Induction in Alkylations of 2,2,6‐Trialkylpiperidine Enamines</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>WILEY‐VCH Verlag</publisher><pubPlace>Weinheim</pubPlace><availability><licence>Copyright © 2010 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim</licence></availability><date type="published" when="2010-06-01"></date></publicationStmt><notesStmt><note type="content-type" subtype="article" source="article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-6N5SZHKN-D">article</note><note type="publication-type" subtype="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note></notesStmt><sourceDesc><biblStruct type="article"><analytic><title level="a" type="main" xml:lang="en">Transition States and Origins of 1,4‐Asymmetric Induction in Alkylations of 2,2,6‐Trialkylpiperidine Enamines</title><author xml:id="author-0000"><persName><forename type="first">Joann M.</forename><surname>Um</surname></persName><affiliation>Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA 90095‐1569 (USA), Fax: (+1) 310‐206‐1843<address><country key="US"></country></address></affiliation></author><author xml:id="author-0001"><persName><forename type="first">Naeem S.</forename><surname>Kaka</surname><roleName type="degree">Dr.</roleName></persName><affiliation>Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA (UK), Fax: (+44) 1865‐285002<address><country key="GB"></country></address></affiliation></author><author xml:id="author-0002"><persName><forename type="first">David M.</forename><surname>Hodgson</surname><roleName type="degree">Prof.</roleName></persName><email>david.hodgson@chem.ox.ac.uk</email><affiliation>Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA (UK), Fax: (+44) 1865‐285002<address><country key="GB"></country></address></affiliation></author><author xml:id="author-0003"><persName><forename type="first">K. N.</forename><surname>Houk</surname><roleName type="degree">Prof.</roleName></persName><email>houk@chem.ucla.edu</email><affiliation>Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA 90095‐1569 (USA), Fax: (+1) 310‐206‐1843<address><country key="US"></country></address></affiliation></author><idno type="istex">035F03995891F79B507BD6081B3B87643B691835</idno><idno type="ark">ark:/67375/WNG-BK3KB5BX-P</idno><idno type="DOI">10.1002/chem.201000046</idno><idno type="unit">CHEM201000046</idno><idno type="toTypesetVersion">file:CHEM.CHEM201000046.pdf</idno></analytic><monogr><title level="j" type="main">Chemistry – A European Journal</title><idno type="pISSN">0947-6539</idno><idno type="eISSN">1521-3765</idno><idno type="book-DOI">10.1002/(ISSN)1521-3765</idno><idno type="book-part-DOI">10.1002/chem.v16:21</idno><idno type="product">CHEM</idno><imprint><biblScope unit="vol">16</biblScope><biblScope unit="issue">21</biblScope><biblScope unit="page" from="6310">6310</biblScope><biblScope unit="page" to="6316">6316</biblScope><biblScope unit="page-count">7</biblScope><publisher>WILEY‐VCH Verlag</publisher><pubPlace>Weinheim</pubPlace><date type="published" when="2010-06-01"></date></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><abstract xml:lang="en" style="main"><head>Abstract</head><p>The asymmetric <hi rend="italic">C</hi>‐alkylation of chiral enamines derived from terminal epoxides and lithium 2,2,6‐trialkylpiperidides has previously been shown to provide α‐alkylated aldehydes by intermolecular nucleophilic substitution in good levels of asymmetric induction. We now report a computational study of the origins of asymmetric induction in these reactions. Computational modeling with density functional theory (B3LYP/6‐31G(d)) agrees closely with the experimental observations. This stereoselectivity is attributed to a preferential conformation of the enamine and the piperidine ring that places the C‐6 alkyl substituent in an axial position due to A<hi rend="superscript">1, 3</hi> strain. Preferential attack occurs away from the axial group, for steric reasons. The effects of changing the C‐6 substituent from methyl to isopropyl were studied, and twist transition states were found to contribute significantly in the latter alkylations.</p></abstract><abstract xml:lang="en" style="graphical"><p><hi rend="bold">The origins</hi> of asymmetric induction in the intermolecular alkylation reaction of piperidine‐based enamines (see scheme) were investigated and described by using density functional theory.<figure type="box"><media mimeType="image" url="urn:x-wiley:09476539:media:CHEM201000046:content"></media><media mimeType="image/gif" url="" rendition="webLoRes"></media><media mimeType="image/gif" url="" rendition="webOriginal"></media><media mimeType="image/gif" url="" rendition="webHiRes"></media></figure></p></abstract><textClass><keywords xml:lang="en"><term xml:id="kwd1">aldehydes</term><term xml:id="kwd2">alkylation</term><term xml:id="kwd3">asymmetric synthesis</term><term xml:id="kwd4">density functional calculations</term><term xml:id="kwd5">transition states</term></keywords><keywords rend="articleCategory"><term>Full Paper</term></keywords><keywords rend="tocHeading1"><term>Full Papers</term></keywords><keywords rend="tocHeading2"><term>Asymmetric Induction</term></keywords></textClass><langUsage><language ident="en"></language></langUsage></profileDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/035F03995891F79B507BD6081B3B87643B691835/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>WILEY‐VCH Verlag</publisherName><publisherLoc>Weinheim</publisherLoc></publisherInfo><doi registered="yes">10.1002/(ISSN)1521-3765</doi><issn type="print">0947-6539</issn><issn type="electronic">1521-3765</issn><idGroup><id type="product" value="CHEM"></id></idGroup><titleGroup><title type="main" xml:lang="en">Chemistry – A European Journal</title><title type="short">Chemistry – A European Journal</title></titleGroup></publicationMeta><publicationMeta level="part" position="210"><doi origin="wiley" registered="yes">10.1002/chem.v16:21</doi><numberingGroup><numbering type="journalVolume" number="16">16</numbering><numbering type="journalIssue">21</numbering></numberingGroup><coverDate startDate="2010-06-01">June 1, 2010</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="26" status="forIssue"><doi origin="wiley" registered="yes">10.1002/chem.201000046</doi><idGroup><id type="unit" value="CHEM201000046"></id></idGroup><countGroup><count type="pageTotal" number="7"></count></countGroup><titleGroup><title type="articleCategory">Full Paper</title><title type="tocHeading1">Full Papers</title><title type="tocHeading2">Asymmetric Induction</title></titleGroup><copyright ownership="publisher">Copyright © 2010 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim</copyright><eventGroup><event type="manuscriptReceived" date="2010-01-08"></event><event type="firstOnline" date="2010-04-21"></event><event type="publishedOnlineFinalForm" date="2010-05-25"></event><event type="publishedOnlineAcceptedOrEarlyUnpaginated" date="2010-04-21"></event><event type="xmlConverted" agent="Converter:JWSART34_TO_WML3G version:2.3.25 mode:FullText source:FullText result:FullText" date="2010-10-27"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-01-09"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-15"></event></eventGroup><numberingGroup><numbering type="pageFirst">6310</numbering><numbering type="pageLast">6316</numbering></numberingGroup><objectNameGroup><objectName elementName="figure">Scheme</objectName></objectNameGroup><linkGroup><link type="toTypesetVersion" href="file:CHEM.CHEM201000046.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="20"></count><count type="tableTotal" number="1"></count><count type="referenceTotal" number="63"></count></countGroup><titleGroup><title type="main" xml:lang="en">Transition States and Origins of 1,4‐Asymmetric Induction in Alkylations of 2,2,6‐Trialkylpiperidine Enamines</title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#aa"><personName><givenNames>Joann M.</givenNames><familyName>Um</familyName></personName></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#ab"><personName><givenNames>Naeem S.</givenNames><familyName>Kaka</familyName><degrees>Dr.</degrees></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#ab"><personName><givenNames>David M.</givenNames><familyName>Hodgson</familyName><degrees>Prof.</degrees></personName><contactDetails><email>david.hodgson@chem.ox.ac.uk</email></contactDetails></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#aa"><personName><givenNames>K. N.</givenNames><familyName>Houk</familyName><degrees>Prof.</degrees></personName><contactDetails><email>houk@chem.ucla.edu</email></contactDetails></creator></creators><affiliationGroup><affiliation xml:id="aa" countryCode="US" type="organization"><unparsedAffiliation>Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA 90095‐1569 (USA), Fax: (+1) 310‐206‐1843</unparsedAffiliation></affiliation><affiliation xml:id="ab" countryCode="GB" type="organization"><unparsedAffiliation>Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA (UK), Fax: (+44) 1865‐285002</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en" type="author"><keyword xml:id="kwd1">aldehydes</keyword><keyword xml:id="kwd2">alkylation</keyword><keyword xml:id="kwd3">asymmetric synthesis</keyword><keyword xml:id="kwd4">density functional calculations</keyword><keyword xml:id="kwd5">transition states</keyword></keywordGroup><fundingInfo><fundingAgency>National Institute of General Medical Sciences</fundingAgency></fundingInfo><fundingInfo><fundingAgency>National Institutes of Health</fundingAgency><fundingNumber>GM 36700</fundingNumber></fundingInfo><fundingInfo><fundingAgency>Engineering and Physical Sciences Research Council</fundingAgency></fundingInfo><supportingInformation><p>Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer‐reviewed, but not copy‐edited or typeset. They are made available as submitted by the authors.
</p><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:09476539:media:chem201000046:chem_201000046_sm_miscellaneous_information"></mediaResource><caption>miscellaneous_information</caption></supportingInfoItem></supportingInformation><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>The asymmetric <i>C</i>‐alkylation of chiral enamines derived from terminal epoxides and lithium 2,2,6‐trialkylpiperidides has previously been shown to provide α‐alkylated aldehydes by intermolecular nucleophilic substitution in good levels of asymmetric induction. We now report a computational study of the origins of asymmetric induction in these reactions. Computational modeling with density functional theory (B3LYP/6‐31G(d)) agrees closely with the experimental observations. This stereoselectivity is attributed to a preferential conformation of the enamine and the piperidine ring that places the C‐6 alkyl substituent in an axial position due to A<sup>1, 3</sup> strain. Preferential attack occurs away from the axial group, for steric reasons. The effects of changing the C‐6 substituent from methyl to isopropyl were studied, and twist transition states were found to contribute significantly in the latter alkylations.</p></abstract><abstract type="graphical" xml:lang="en"><p><b>The origins</b> of asymmetric induction in the intermolecular alkylation reaction of piperidine‐based enamines (see scheme) were investigated and described by using density functional theory.<blockFixed type="graphic"><mediaResourceGroup><mediaResource alt="image" eRights="yes" copyright="WILEY-VCH" href="urn:x-wiley:09476539:media:CHEM201000046:content"></mediaResource><mediaResource alt="thumbnail image" rendition="webLoRes" mimeType="image/gif" href=""></mediaResource><mediaResource alt="original image" rendition="webOriginal" mimeType="image/gif" href=""></mediaResource><mediaResource alt="magnified image" rendition="webHiRes" mimeType="image/gif" href=""></mediaResource></mediaResourceGroup></blockFixed></p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Transition States and Origins of 1,4‐Asymmetric Induction in Alkylations of 2,2,6‐Trialkylpiperidine Enamines</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Transition States and Origins of 1,4‐Asymmetric Induction in Alkylations of 2,2,6‐Trialkylpiperidine Enamines</title></titleInfo><name type="personal"><namePart type="given">Joann M.</namePart><namePart type="family">Um</namePart><affiliation>Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA 90095‐1569 (USA), Fax: (+1) 310‐206‐1843</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Naeem S.</namePart><namePart type="family">Kaka</namePart><namePart type="termsOfAddress">Dr.</namePart><affiliation>Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA (UK), Fax: (+44) 1865‐285002</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">David M.</namePart><namePart type="family">Hodgson</namePart><namePart type="termsOfAddress">Prof.</namePart><affiliation>E-mail: david.hodgson@chem.ox.ac.uk</affiliation><affiliation>Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA (UK), Fax: (+44) 1865‐285002</affiliation><affiliation>E-mail: david.hodgson@chem.ox.ac.uk</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">K. N.</namePart><namePart type="family">Houk</namePart><namePart type="termsOfAddress">Prof.</namePart><affiliation>E-mail: houk@chem.ucla.edu</affiliation><affiliation>Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA 90095‐1569 (USA), Fax: (+1) 310‐206‐1843</affiliation><affiliation>E-mail: houk@chem.ucla.edu</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-6N5SZHKN-D">article</genre><originInfo><publisher>WILEY‐VCH Verlag</publisher><place><placeTerm type="text">Weinheim</placeTerm></place><dateIssued encoding="w3cdtf">2010-06-01</dateIssued><dateCaptured encoding="w3cdtf">2010-01-08</dateCaptured><copyrightDate encoding="w3cdtf">2010</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><extent unit="figures">20</extent><extent unit="tables">1</extent><extent unit="references">63</extent></physicalDescription><abstract lang="en">The asymmetric C‐alkylation of chiral enamines derived from terminal epoxides and lithium 2,2,6‐trialkylpiperidides has previously been shown to provide α‐alkylated aldehydes by intermolecular nucleophilic substitution in good levels of asymmetric induction. We now report a computational study of the origins of asymmetric induction in these reactions. Computational modeling with density functional theory (B3LYP/6‐31G(d)) agrees closely with the experimental observations. This stereoselectivity is attributed to a preferential conformation of the enamine and the piperidine ring that places the C‐6 alkyl substituent in an axial position due to A1, 3 strain. Preferential attack occurs away from the axial group, for steric reasons. The effects of changing the C‐6 substituent from methyl to isopropyl were studied, and twist transition states were found to contribute significantly in the latter alkylations.</abstract><abstract>The origins of asymmetric induction in the intermolecular alkylation reaction of piperidine‐based enamines (see scheme) were investigated and described by using density functional theory.</abstract><note type="funding">National Institute of General Medical Sciences</note><note type="funding">National Institutes of Health - No. GM 36700; </note><note type="funding">Engineering and Physical Sciences Research Council</note><subject lang="en"><genre>keywords</genre><topic>aldehydes</topic><topic>alkylation</topic><topic>asymmetric synthesis</topic><topic>density functional calculations</topic><topic>transition states</topic></subject><relatedItem type="host"><titleInfo><title>Chemistry – A European Journal</title></titleInfo><titleInfo type="abbreviated"><title>Chemistry – A European Journal</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><note type="content"> Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer‐reviewed, but not copy‐edited or typeset. 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