Transition States and Origins of 1,4-Asymmetric Induction in Alkylations of 2,2,6-Trialkylpiperidine Enamines
Identifieur interne : 000113 ( Pmc/Corpus ); précédent : 000112; suivant : 000114Transition States and Origins of 1,4-Asymmetric Induction in Alkylations of 2,2,6-Trialkylpiperidine Enamines
Auteurs : Joann M. Um ; Naeem S. Kaka ; David M. Hodgson ; K. N. HoukSource :
- Chemistry (Weinheim an der Bergstrasse, Germany) [ 0947-6539 ] ; 2010.
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
PubMed: 20411546
PubMed Central: 3049728
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PMC:3049728Le document en format XML
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<author><name sortKey="Kaka, Naeem S" sort="Kaka, Naeem S" uniqKey="Kaka N" first="Naeem S." last="Kaka">Naeem S. Kaka</name>
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<front><div type="abstract" xml:lang="en"><p id="P1">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 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>
</div>
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<journal-id journal-id-type="pubmed-jr-id">21686</journal-id>
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<journal-title>Chemistry (Weinheim an der Bergstrasse, Germany)</journal-title>
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<title-group><article-title>Transition States and Origins of 1,4-Asymmetric Induction in Alkylations of 2,2,6-Trialkylpiperidine Enamines</article-title>
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<contrib-group><contrib contrib-type="author"><name><surname>Um</surname>
<given-names>Joann M.</given-names>
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<xref ref-type="aff" rid="A1">[a]</xref>
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<contrib contrib-type="author"><name><surname>Kaka</surname>
<given-names>Naeem S.</given-names>
<prefix>Dr.</prefix>
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<xref ref-type="aff" rid="A2">[b]</xref>
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<contrib contrib-type="author"><name><surname>Hodgson</surname>
<given-names>David M.</given-names>
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<xref ref-type="corresp" rid="CR2">*</xref>
<xref ref-type="aff" rid="A2">[b]</xref>
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<contrib contrib-type="author"><name><surname>Houk</surname>
<given-names>K. N.</given-names>
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</name>
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<xref ref-type="aff" rid="A1">[a]</xref>
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<aff id="A1"><label>[a]</label>
Department of Chemistry and Biochemistry, UCLA Los Angeles, CA 90095-1569 (USA)</aff>
<aff id="A2"><label>[b]</label>
Department of Chemistry, Chemistry Research Laboratory University of Oxford, Mansfield Road, Oxford, OX1 3TA (UK)</aff>
<author-notes><corresp id="CR1"><label>*</label>
Fax: (+ 1) 310-206-1843 <email>houk@chem.ucla.edu</email>
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<corresp id="CR2"><label>*</label>
Fax: (+ 44) 1865-285002 <email>david.hodgson@chem.ox.ac.uk</email>
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<pub-date pub-type="nihms-submitted"><day>16</day>
<month>2</month>
<year>2011</year>
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<pub-date pub-type="ppub"><day>1</day>
<month>6</month>
<year>2010</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>7</day>
<month>3</month>
<year>2011</year>
</pub-date>
<volume>16</volume>
<issue>21</issue>
<fpage>6310</fpage>
<lpage>6316</lpage>
<permissions><copyright-statement>© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim</copyright-statement>
<copyright-year>2010</copyright-year>
</permissions>
<abstract><p id="P1">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 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>
<kwd-group><kwd>aldehydes</kwd>
<kwd>alkylation</kwd>
<kwd>asymmetric synthesis</kwd>
<kwd>density functional calculations</kwd>
<kwd>transition states</kwd>
</kwd-group>
<contract-num rid="GM1">R01 GM036700-26
||GM</contract-num>
<contract-sponsor id="GM1">National Institute of General Medical Sciences : NIGMS</contract-sponsor>
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