Authors: Christopher W. McAtee
Source: Deep Blue (University of Michigan) (article, 2020-01-01)
Field: Chemistry — Organic Chemistry

Development of Lewis-Acid Catalyzed Carbocyclization Reactions; and the Total Synthesis of Herqulines B and C Development of new catalytic methods to assemble carbon-carbon bonds is important in many areas of organic synthesis. These strategies enable the synthesis of biologically active compounds and functionalized materials. In this regard the olefin-olefin metathesis reaction has emerged as a vital carbon-carbon bond forming reaction as demonstrated by the transformation’s broad application in natural product synthesis, pharmaceutical sciences, and organic materials. In comparison. the carbonyl-olefin metathesis (COM) reaction affords entry to similar olefin products. However, while the catalytic COM reaction is less developed in mechanistic understanding and substrate scope than the olefin-olefin metathesis derivative, several attractive qualities have prompted chemists to broaden the synthetic utility of COM. Chapter 1 details the development of a new approach toward polycyclic aromatic compounds (PACs) based on the design principle of iron(III)-catalyzed COM reactions. This protocol is described by its operational simplicity, high functional group compatibility, while relying on FeCl3 as an earth-abundant catalyst. Greater than 40 PACs are synthesized. Isolation and characterization of an aromatic oxetane provides evidence that this carbocyclization proceeds through an oxetane intermediate. Chapter 2 describes an efficient synthesis of cyclopentadienes. Cyclopentadienes (CPs) are important scaffolds in organometallic chemistry and catalysis. This Lewis acid-catalyzed protocol garners 2,3,4-substituted cyclopentadienes incorporating electronically and sterically diverse functionalities, with complete regiocontrol. Our experimental and theoretical investigations provides support for a mechanism that is related to catalytic COM reactions wherein Lewis acid-catalyzed cycloadditions between carbonyl and alkenes garners reactive oxetane intermediates. However in lieu of a [2+2]-cycloreversion, stepwise oxetane fragmentation results in the formation of cyclopentadienes via interrupted carbonyl-olefin metathesis. The scope of this method for cyclopentadiene synthesis is demonstrated in 24 examples and proceeds in up to 85% yield. During our studies related to Lewis acid-catalyzed synthesis of functionalized cyclopentadienes from homoprenylated β-ketoesters (Chapter 2) we observed that sterically congested unsaturated ketones can undergo intramolecular α-tert-alkylation. Chapter 3 details our studies pertaining to the development of an intramolecular α-tert-alkylation reaction of unsaturated β-ketoesters. This approach gives rise to functionalized cyclopentanes and is characterized by its operational simplicity and the use of Sc(OTf)3 as a Lewis acid catalyst. Of interest, cyclopentanes bearing heterocycles, sites for post reaction functionalization and spirocyclic architectures are all accessible. Chapter 4 describes our scalable total synthesis of the secondary metabolite, mycocyclosin. This distorted cyclophane was initially isolated from Mycobacterium tuberculosis in 2009 by Belin and first synthesized by Hutton in 2012. Mycocylosin bears a highly strained 3,3’-dityrosine biaryl system which arises biosynthetically from an intramolecular oxidative dehydrogenative cross-coupling of cyclo(l-Tyr-l-Tyr) (cYY) catalyzed by the P450 enzyme CYP121. Scalable access to mycocyclosin and analogues via a palladium(0)-catalyzed macrocyclization is expected to enable the biological evaluation of these cyclodipeptides as tuberculosis antimicrobials. The herquline alkaloids are characterized by their modest size, yet incredible molecular strain initially isolated by Ōmura in 1979. Comprising of a macrocyclic core, a bridging 1,4-dicarbonyl substructure, and an unsymmetrical, highly Lewis basic piperazine at the base, these alkaloids have sparked the creativity of many synthetic chemists since their isolation nearly 40 years ago. Chapter 5 is a memorable narrative that recounts our synthetic journey in successfully assembling herquline B and C, which closely mirrors their biosynthetic origins. Fraught with unanticipated challenges that ultimately fueled reaction design and ingenuity, our synthetic campaign of the herqulines afforded countless lessons gained which we expect to be instructive to the synthetic community. Lewis acids and bases ; Total synthesis ; Catalysis ; Chemistry ; Stereochemistry ; Organic chemistry Carbohydrate Chemistry and Synthesis