New synthetic applications for ring-closing metathesis and cross-metathesis employing well-defined ruthenium alkylidenes

Citation

Blackwell, Helen Elizabeth (1999) New synthetic applications for ring-closing metathesis and cross-metathesis employing well-defined ruthenium alkylidenes. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/XBZ4-CV61. https://resolver.caltech.edu/CaltechETD:etd-09262005-133922

Abstract

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The development of well-defined ruthenium alkylidene [...] (1) has revolutionized the application of the olefin metathesis reaction in organic synthesis. This thesis describes: (1) the application of ring-closing metathesis (RCM) to the synthesis of constrained cyclic peptides, (2) the conformational analyses of these peptide architectures, and (3) the development of new selective cross-metathesis (CM) methodology employing alkylidene 1.

Chapter 2 describes the initial application of RCM to the synthesis of cyclic amino acids and peptide [...]. Introduction of olefin functionality into peptidic structures proved straightforward, and treatment with ruthenium alkylidene 1 generated cyclic amino acids and dipeptides in excellent yields. Tetrapeptide diene analogs of naturally-occurring disulfide [...] proved to be robust substrates for RCM, and the macrocyclic olefin products could be prepared either in solution or on solid support.

Chapter 3 describes the application of RCM to the synthesis of macrocyclic hexapeptide [Beta]-sheets. The acyclic hexapeptide diene frameworks were modeled after hexapeptide disulfides reported to adopt [Beta]-sheet conformations. Treatment with ruthenium alkylidene 1, however, afforded only low yields of the desired 20-membered macrocycles: conformational analyses suggested that the hexapeptides adopted a helical rather than [Beta]-sheet conformation in the apolar solvents in which RCM was performed. These peptide systems were redesigned in Chapter 4 so that macrocyclization was favored when the peptides adopted a helical conformation. A series of macrocyclic heptapeptides were prepared in high yield via RCM which were shown to adopt [...]-helical conformations both in solution and in the solid state.

Chapter 5 describes new CM methodology involving the coupling of terminal olefins with symmetrically disubstituted olefins to generate heterodimeric cross-products in excellent yields and with high trans selectivity. CM was employed in an initial self-metathesis step to synthesize a variety of disubstituted olefins with diverse functionality, which were then further processed in the CM with terminal olefins. Finally, a new CM application was introduced involving the metathesis of acrolein acetal derivatives with terminal olefins to generate [...] aldehydes.

Thesis Files