Progress Toward the Asymmetric Total Synthesis of Variecolin and Gas-Phase Studies of the Twisted Amide 2-Quinuclidone

Citation

Krout, Michael Raymond (2010) Progress Toward the Asymmetric Total Synthesis of Variecolin and Gas-Phase Studies of the Twisted Amide 2-Quinuclidone. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z9765C9X. https://resolver.caltech.edu/CaltechTHESIS:05282010-090825123

Abstract

Biologically active natural products and pharmaceuticals often present intriguing structural features that can challenge the state of the art in catalysis and synthetic methodology for their preparation. The identification of unique targets thus stimulates the development of new strategies and methods for chemical synthesis. The complex architecture representative of the variecolin family of sesterterpenes has inspired our pursuit of new tactics that has enabled the expansion of methods from our laboratory.

First, progress toward the asymmetric total synthesis of variecolin is discussed. Our convergent synthetic approach bisects the target into two complex fragments to address the main structural challenges. A microwave-promoted tandem Wolff/Cope rearrangement of vinyl cyclobutyl diazocarbonyls has been developed that provides access to functionalized, fused eight-membered rings and is used to construct the central B ring of variecolin. In addition, the utility of our Pd-catalyzed enantioselective alkylation method is extended to a new vinylogous ester substrate class to produce a quaternary ketone in excellent yield with high selectivity that is an exceptional substrate for an efficient ring contraction to the cyclopentene D ring system. The successful asymmetric preparation of our two devised fragments has facilitated initial studies toward their coupling and completion of variecolin.

Second, a preliminary examination of the substrate scope for the asymmetric alkylation of the vinylogous β-ketoester substrate class is described. Derivatives that perturb substrate electronics display enhanced reactivity and selectivity, generating products with excellent selectivities and expanding the potential of this versatile class of substrates. Furthermore, their utility is underscored as the key enantioselective transformation en route to the synthesis of the sesquiterpenoid (+)-carissone.

Finally, gas-phase studies of the twisted amide 2-quinuclidone are described. Proton affinity experiments have quantified its high basicity, which is comparable to a tertiary amine. A gas-phase synthesis of 2-quinuclidione via elimination of water and subsequent fragmentation further highlight the unusual characteristics of extremely twisted amides.

Thesis Files