New synthetic applications of trichloromethyl carbinols in synthesis

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dc.contributor Blackstock, Silas C.
dc.contributor Jennings, Michael P.
dc.contributor Shaughnessy, Kevin H.
dc.contributor Zeiler, Thomas A.
dc.contributor.advisor Snowden, Timothy S. Cafiero, Lauren 2017-02-28T22:21:21Z 2017-02-28T22:21:21Z 2009
dc.identifier.other u0015_0000001_0000108
dc.identifier.other Cafiero_alatus_0004D_10134
dc.description Electronic Thesis or Dissertation
dc.description.abstract Trichloromethyl carbinols have been used for over a century to afford α-substituted carboxylic acid derivatives upon treatment with base and an appropriate nucleophile (Jocic reaction). The mechanism involves the formation of an intermediate gem-dichloroepoxide that undergoes regioselective substitution with an added nucleophile. The present work expands the utility of trichloromethyl carbinols as key elements in new synthetic applications. Although the reactivity of aryl, alkyl, and alkenyl trichloromethyl carbinols with various nucleophiles in Jocic-type processes has been explored, the employment of hydride or selenide as a nucleophile source has not been attempted until now. A one-carbon homologation of aldehydes to carboxylic acids via trichloromethyl carbinols is detailed herein. The reaction of aldehydes with trichloromethide followed by treatment with sodium borohydride or sodium phenylseleno(triethyl)borate under basic conditions affords homologated carboxylic acids in high yields. This operationally simple procedure provides a practical, efficient alternative to other homologation protocols. The approach is compatible with sensitive aldehydes including enals and enolizable aldehydes. It also offers convenient access to α-monodeuterated carboxylic acids. The conditions required (base, solvent, temperature) for the reaction to proceed with greatest efficiency have been established. In addition, a new protecting-group for aryl aldehydes has been developed. The tert-butyldimethylsilyloxytrichloromethylmethane (TBSTCM) substituent serves as a readily accessible masking group for aromatic and heteroaromatic aldehydes. This functionality can be installed under mild conditions to afford protected aryl aldehydes in excellent yield. The TBSTCM substituent is compatible with a range of common reagents and offers several strategic advantages over alternative aldehyde protecting groups. The masked aldehydes are conveniently revealed by treatment of the TBSTCM functionality with TBAF in warm DMF. Finally, progress toward the synthesis of (-)-harzialactone A, the antipode of a P388 lymphocytic leukaemia cytotoxin, has commenced. Using our previously established method for the preparation of α,γ-disubstituted butyrolactones from commercially available 4-(trichloromethyl)-2-oxetanone (Wynberg lactone), it is possible to synthesize (-)-harzialactone A in four steps. A concise route to any of the four possible diastereomers of harzialactone from the trichloromethyl β-lactone has been devised. This efficient and expedient protocol offers a useful synthetic alternative to previously reported syntheses of (+)- or (-)-harzialactone.
dc.format.extent 350 p.
dc.format.medium electronic
dc.format.mimetype application/pdf
dc.language English
dc.language.iso en_US
dc.publisher University of Alabama Libraries
dc.relation.ispartof The University of Alabama Electronic Theses and Dissertations
dc.relation.hasversion born digital
dc.rights All rights reserved by the author unless otherwise indicated.
dc.subject.other Chemistry, Organic
dc.title New synthetic applications of trichloromethyl carbinols in synthesis
dc.type thesis
dc.type text University of Alabama. Dept. of Chemistry Chemistry The University of Alabama doctoral Ph.D.

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