New synthetic applications of trichloromethyl carbinols in synthesis

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University of Alabama Libraries

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.

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Organic chemistry