Stress relief: Exercising Lewis acid catalysis for donor-acceptor cyclopropane ring-opening annulations, a basis for new reaction methodologies

Cavitt, Marchello Alfonzo

Title:

Stress relief: Exercising Lewis acid catalysis for donor-acceptor cyclopropane ring-opening annulations, a basis for new reaction methodologies

dc.contributor.advisor	France, Stefan
dc.contributor.author	Cavitt, Marchello Alfonzo
dc.contributor.committeeMember	Liotta, Charles
dc.contributor.committeeMember	Schuster, Gary
dc.contributor.committeeMember	Fahrni, Christoph
dc.contributor.committeeMember	Jones, Christopher
dc.contributor.committeeMember	Gelbaum , Leslie
dc.contributor.department	Chemistry and Biochemistry
dc.date.accessioned	2016-01-07T17:38:47Z
dc.date.available	2016-01-07T17:38:47Z
dc.date.created	2015-12
dc.date.issued	2015-11-16
dc.date.submitted	December 2015
dc.date.updated	2016-01-07T17:38:47Z
dc.description.abstract	Nature’s biodiversity is complex and filled with beauty and wonder which are all observable on the macroscopic scale. This exquisiteness of nature’s intricacies are mirrored on the molecular level such that substances, large or small, are assembled to serve as signaling molecules, protective agents, and fundamental composites of higher-order frameworks for the operation and survival of life. Over the years, chemists have isolated and synthesized these molecules, known as natural products, to understand and evaluate their functions in biology and potential for medicinal applications. Although bioactive natural products demonstrate medicinal promise, poor pharmacological effects require further derivatization because semisynthesis is not sufficient to refine adverse pharmacokinetics. For some active molecules, isolation results in poor yields. In addition to small quantity isolation, many natural products, reflecting the immense complexity of biology itself, pose difficult synthetic challenges to organic chemists because of skeletal heterogeneity, stereochemical complexity, and substitution divergence. As a result of these synthetic obstacles to natural product utilization, improvements are needed in current chemical approaches, and new innovative methodologies for synthesis and chemical space exploration are necessary. Pharmaceutically relevant frameworks, natural products, and synthetic biologically active molecules are comprised of polycarbocyclic and heterocyclic scaffolds. Traditionally, cycloadditions, transannular transformations, and annulation reactions serve as powerful methods for polycyclic formation. In order to assemble diverse polycycles, donor-acceptor cyclopropanes are useful, versatile synthetic equivalents for C-C bond formations. By taking advantage of the strain within these unique, polarized systems, differing molecular architectures can be accessed directly to perform contemporary organic synthesis. Moreover, the donor-acceptor cyclopropanes initially utilized in these studies provided a fundamental basis for new methods to synthesize other relevant scaffolds. Unique, efficient, Lewis acid-catalyzed intramolecular cyclization strategies for the construction of functionalized polycycles using Friedel-Crafts-type alkylation sequences are presented to expand the reaction repertoire of the molecular architect. Generally, products were formed from commercially-available starting materials in high yields with broad scope. The methodologies were demonstrated to be modular, operationally simple, and amenable to different substitution patterns and functional groups to afford tetrahydroindolizines, heteroaromatic cyclohexenones, hydropyrido[1,2-a]indoles, pyrrolo[1,2-a]indoles, pyrrolo[3,2,1-ij]quinolines, pyrrolizines, and tetrahydrobenzo[ij]quinolizines. To demonstrate the utility of the methodologies devised, progress toward, (±)-rhazinicine, a natural product, is discussed. This dissertation is organized into six chapters: (1) an introduction, paradoxical stress and molecular strain’s utility in synthesis; (2) annulation reactions for the formation of heteroaromatic cyclohexenones; (3) hydropyrido[1,2-a]indole formation via an In(III)-catalyzed cyclopropane ring-opening/Friedel-Crafts alkylation sequence; (4) tetrahydroindolizine formation and progress toward the total synthesis of (±)-rhazinicine (5) pyrrolo[1,2-a]indole synthesis using a Michael-type Friedel-Crafts cyclization approach; and (6) a versatile protocol for the intramolecular formation of functionalized pyrrolo[3,2,1-ij]quinolines.
dc.description.degree	Ph.D.
dc.format.mimetype	application/pdf
dc.identifier.uri	http://hdl.handle.net/1853/54448
dc.language.iso	en_US
dc.publisher	Georgia Institute of Technology
dc.subject	Cyclopropane
dc.subject	Organic chemistry
dc.subject	Methodology development
dc.subject	Lewis acid
dc.subject	Catalysis
dc.subject	Heteroaromatics
dc.title	Stress relief: Exercising Lewis acid catalysis for donor-acceptor cyclopropane ring-opening annulations, a basis for new reaction methodologies
dc.type	Text
dc.type.genre	Dissertation
dspace.entity.type	Publication
local.contributor.advisor	France, Stefan
local.contributor.corporatename	School of Chemistry and Biochemistry
local.contributor.corporatename	College of Sciences
relation.isAdvisorOfPublication	60127d9c-be17-4aa7-bd28-c94458c4a043
relation.isOrgUnitOfPublication	f1725b93-3ab8-4c47-a4c3-3596c03d6f1e
relation.isOrgUnitOfPublication	85042be6-2d68-4e07-b384-e1f908fae48a
thesis.degree.level	Doctoral