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THE SYNTHESIS OF CARBOCYCLES AND HETEROCYCLES BY CLAISEN REARRANGEMENT MEDIATED RING CONTRACTION OF MACROCYCLIC LACTONES
Abstract
A general method for the preparation of hetero- and carbocycles by four-atom-ring contractions of macrolides has been developed, and is described in this dissertation. The n -membered macrocyclic lactones 16, readily available from the corresponding hydroxy acids 15, can be contracted to n -4 membered carbocycles 33 by Claisen rearrangement of the intermediate ketene acetals. Preferential formation of cis -2-alkenylcycloalkanecarboxylic acids 33 is observed for n = 1-4, while cis - and trans -isomers are produced for n = 7.$$\vbox{\vskip72pt}$$==>>> Cyclopropane rings may be efficiently prepared by this approach, as illustrated by the synthesis of cis -chrysanthemic acid (44a) form lactone 25c, shown below.$$\vbox{\vskip108pt}$$==>>> This methodology may be applied to heterocycle synthesis provided the heteroatom is judiciously placed within the macrocyclic lactone. Accordingly, lactone 73 contracts to the piperidine 75 in high yield. Homologation of 75 by the Wolff rearrangement reaction afforded N-benzoylmeroquinene methyl ester (45), an important degradation product and key synthetic intermediate of the Cinchona alkaloids, most notably, quinine.$$\vbox{\vskip144pt}$$==>>> In contrast, lactone 106 affords the pyrrolidine 108b in low yield as a result of $\beta$-elimination of the carbamate nitrogen during ketene acetal formation and subsequent Claisen rearrangement. This approach was directed toward the total synthesis of the neurologically active alkaloid $\alpha$-kainic acid (77), as shown below.$$\vbox{\vskip144pt}$$==>>>
Subject Area
Organic chemistry
Recommended Citation
MUNGER, JOHN DUNCAN, "THE SYNTHESIS OF CARBOCYCLES AND HETEROCYCLES BY CLAISEN REARRANGEMENT MEDIATED RING CONTRACTION OF MACROCYCLIC LACTONES" (1987). ETD collection for University of Nebraska-Lincoln. AAI8800008.
https://digitalcommons.unl.edu/dissertations/AAI8800008