Glenn Sammis


Relevant Degree Programs


Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - May 2021)
Studies on one-pot sulfuryl fluoride-mediated transformations of aliphatic alcohols (2021)

This thesis describes my contributions to the development of new synthetic methods that employ fluorinated reagents and/or access fluorinated motifs.In Chapter 2, investigations on di- and trifluoromethoxylation of heterocyclic and bioactive molecules is presented. α,α-Difluoroaryloxyacetic acids were employed as precursors to two pharmaceutically relevant motifs, tri- and difluoromethoxyarenes. The syntheses of the former were found to be challenging due to poor solubility or degradation of the starting material. The latter, on the other hand, were successfully accessed through a thermal acid-mediated protodecarboxylation. Chapter 3 details the development of a novel method to access N-trifluoroethylamines. Sulfuryl fluoride, a commodity chemical produced industrially on a large scale, was used to activate trifluoroethanol, and the resulting product, trifluoroethyl fluorosulfate, was found to trifluoroethylate amines. The initial studies focused on a two-step trifluoroethanol activation-substitution process. With the aid of kinetic data, we were later able to successfully combine two steps into an operationally simpler one-pot protocol. Using this one-pot approach we demonstrated trifluoroethylation of a range of primary and secondary amines in moderate to good yields (31-72%).Chapter 4 describes the development of a general one-pot method of SO2F2-mediated aliphatic alcohol substitution. During preliminary optimization studies, we found the choice of base to be an important factor. DBU proved to be uniquely effective, potentially due to its involvement in the activation of sulfuryl fluoride. The one-pot substitution was demonstrated for a range of alcohols with nitrogen-, sulfur-, and carbon-based nucleophiles (12-95% yields) under mild conditions in only 10 minutes. One of the reactions was also successfully performed on a gram-scale, and the product purification was achieved without chromatography. In Chapter 5, the development of a novel primary alcohol deoxygenation method is described. During preliminary investigations, we found that primary alcohols could be readily converted to the corresponding alkyl iodides through the one-pot activation with sulfuryl fluoride followed by nucleophilic substitution. The alkyl iodides could then be dehalogenated under radical conditions. Using this two-step process, we demonstrated deoxygenation of several primary alcohols in moderate to excellent yields (38-95%). Importantly, this approach tolerated several functional groups which are typically reduced by other common deoxygenation methods.

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Studies on radical reactions for the syntheses of pharmaceutically relevant organic motifs (2019)

Organic synthesis plays a significant role in the pharmaceutical industry, particularly in providing a large array of pharmaceutically active molecules for drug discovery. In spite of numerous methods developed, there are still many limitations in the existing synthetic methodologies for pharmarceutically important organic motifs. Two such motifs are organofluorine derivatives and nitrogen heterocycles. This thesis focuses on my research on the development of new and efficient methodologies for the syntheses of these two motifs.Chapter 2 describes the development of a new radical fluorodecarboxylation method using xenon difluoride. This method can efficiently convert 2-aryl-2-fluoroacetic acids with different substitutents to difluoromethyl aryl ethers in good to excellent yields (53-80%). Chapter 3 details studies on the mechanism of fluorine transfer in radical fluorinations by N-F reagents, including Selectfluor and N-fluorobenzenesulfonimide (NFSI). Two strategies, carbocation rearrangement and carbocation trapping, were applied to identify the possible carbocation intermediates during the fluorinations of alkyl radicals. The results of our studies are consistent with a fluorine atom transfer pathway between alkyl radicals and either Selectfluor or NFSI. Mechanistic studies into silver-catalyzed radical fluorination method indicated the formation of carbocations, presumably via a single electron transfer pathway between alkyl radicals and the silver catalyst. The carbocation formation was supported by the detection of the products from carbocation rearrangement as well as carbocation trapping by nucleophiles. Chapter 4 describes the development of a novel 6-endo-trig radical cyclization onto hydrazones for the regio-controlled and stereoselective syntheses of tetrahydrophthalazines. Two synthetic protocols using this radical cyclization were developed, including one-pot or stepwise processes, to access substituted tetrahydrophthalazines. These protocols showed good efficiency and robustness, and were able to afford high yields (50-98%) of the desired products with excellent functional group tolerance. This radical cyclization is also the first method to achieve excellent trans-diastereoselectivity in the syntheses of 1,4-disubstituted tetrahydrophthalazines.Chapter 5 describes the applications of the 6-endo-trig radical cyclization for the syntheses of other nitrogen-containing motifs, such as tetrahydroazaphthalazines, tetrahydropyradizines, dihydrophthalazines, aromatic phthalazines, and pyrazolo phthalazine diones. Additionally, we have developed a Pt-catalyzed hydrogenation for the cleavage of N-N bonds of the tetrahydrophthalazines, as a new route to 1,4-diamines.

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Radical Methods for the Synthesis of Fluoroalkanes and Fluoromethyl Aryl Ethers and Copper-Catalyzed Three-Component Carboetherification of Alkenes (2016)

Fluorinated molecules have become popular compounds among pharmaceuticals. The introduction of fluorine atoms on bioactive compounds has indeed the potential to improve their biophysical properties. Given the utility of fluorinated substituents on pharmaceuticals, fluorine chemistry has become an area of intensive research. Despite the progress made in selective fluorination, however, radical fluorination has been limited notably due to the paucity of atomic fluorine sources. In this thesis, the uncovering of new atomic fluorine sources and the development of new radical fluorination methods will be described. Chapter 1 presents the importance of fluorinated molecules and the currently available fluorinating agents. A discussion on radical fluorination is presented that includes the most recent advances in the field. In Chapter 2, the exploratory work on the ability of electrophilic N—F fluorinating agents to transfer fluorine to alkyl radicals is detailed. Peresters were chosen as radical precursors and reacted with traditionally electrophilic fluorine sources, NFSI and Selectfluor®. Under those conditions, various fluoroalkanes could be synthesized in good yields.A radical fluorination method subsequently developed using Selectfluor® is described in Chapter 3. The ability of phenoxyacetic acid derivatives to undergo fluorodecarboxylation under UV-light excitation using Selectfluor® was demonstrated. The methodology was successfully applied to the synthesis of mono- and difluoromethyl aryl ethers in 40 to 86% yields. Chapter 4 details the application of the photofluorodecarboxylation to the synthesis of trifluoromethyl aryl ethers. It was found that the wavelength required for the substrate’s excitation led to the decomposition of the desired products. A method using benzophenone as a photosentizer was developed allowing the use of another wavelength to promote the reaction, which proved to be substrate dependent. The use of a faster fluorine transfer agent, XeF2, allowed the synthesis of trifluoromethoxy arenes in good yields. A copper catalyzed difunctionalization of alkenes, developed in collaboration with Prof. Jieping Zhu, is presented in Chapter 5. This reaction allows the direct introduction of alkyl nitriles via C—H activation. A C—O bond and a C—C bond were created in a single step. A wide range of α substituted styrenes were difunctionalized in yields up to 82%.

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Fluorination of Alkyl Radicals Using Electrophilic N-F Reagents and Investigation on the Intramolecular Chemoselectivity of Alkoxy Radicals (2015)

The selective fluorination of organic molecules has become increasingly important for the pharmaceutical and agrochemical industries, given that the presence of this atom enhances the lipophilicity and bioavailability of molecules. Despite the extensive research in fluorine chemistry, there is a paucity of selective and safe sources of fluorine for radical reactions. I hereby present the investigation of N−F reagents as efficient fluorine atom transfer agents to alkyl radicals. Although most of the research presented in this work focuses on fluorination methodologies, a study on the intramolecular chemoselectivity of alkoxy radicals is also discussed.Chapter 2 describes the exploratory work into the feasibility of transferring a fluorine atom to alkyl radicals from electrophilic sources of fluorine. Diacyl peroxides and t-butylperesters were homolyzed to generate alkyl radicals in the presence of different N−F fluorine sources. Primary, secondary, and tertiary fluoroalkanes were successfully synthesized under the reaction conditions. This methodology was successfully applied to the fluorination of a cholic acid derivative.In Chapter 3, photoredox catalysis was explored as an alternative method to generate alkyl radicals in the context of radical fluorination. Trisbipyridylruthenium (II) and visible light were utilized to promote the decarboxylative fluorination of phenoxyacetic acid derivatives. Electronwithdrawing groups on the aryl ring favoured the transformation, while electron-donating groups provided undesired products. An estrone derivative was successfully fluorinated with our visible-light mediated methodology. Additionally, transient absorption spectroscopy studies in collaboration with the Wolf group at the University of British Columbia, along with cyclic voltammetry experiments performed in collaboration with the Bizzotto group at the same institution, provided evidence to support an oxidative mechanism of the photocatalytic cycle.Chapter 4 describes a study to assess the chemoselectivity of alkoxy radical cyclizations onto silyl enol ethers, when other radical pathways can occur. Cyclization of intramolecular competition substrates showed that 5-exo cyclization of alkoxy radicals onto silyl enol ethers were preferred over 5-exo cyclizations onto terminal, disubstituted and trisubstituted alkenes, as well as 1,5-hydrogen atom transfer reactions and β-fragmentations. Silyl enol ethers as alkoxy radical acceptors strongly favour 6-exo cyclization over 1,5-hydrogen atom transfer from an allylic position.

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Development of heteroatom radical based synthetic strategies (2014)

This thesis presents investigations of carbo- and heterocycle formation using radical relay cyclization reactions initiated by alkoxy radicals, cyclic imine formation using substoichiometric stannane and photodeoxygenation reactions involving benzotriazole-borane complexes. Chapter 1 describes our investigations and development of radical relay cyclizationreactions initiated by alkoxy radicals that provided carbo- and heterocyclic compounds.Pairing N-alkoxyphthalimides as alkoxy radical precursors with the slow addition of radicalinitiator provided a wide range of carbocycles. Incorporation of functionality into thelinear backbone provided substituted heterocyclic compounds in excellent yield.Chapter 2 describes the cyclization of aminyl radicals onto silyl enol ethers. The rateacceleration imparted by the silyl enol ether allowed for high yielding pyrrolidineformation. Investigations focused on an unexpected cyclic imine product that wasobserved in our previous studies. We sought to both optimize our conditions to providethis imine in the highest possible yield, and investigated the mechanism by which thisimine product may be formed. Chapter 3 describes the development of a photodeoxygenation reaction usingbenzotriazole-borane complexes. The coordination of a benzotriazole ligand withcommercially available borane-tetrahydrofuran provides the benzotriazole-boranecomplex as a bench stable white powder. DFT calculations suggested these benzotriazoleboranecomplexes could behave a radical chain deoxygenation reaction. Irradiation of avariety of xanthates provided the deoxygenated products in excellent yield. Furthermore,our work suggests that the benzotriazole ligand may be catalytic in these deoxygenationreactions.

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Radical fluorination methods for the synthesis of aryl mono-, di-, and tri- fluoromethyl esthers (2014)

New reagents for selective radical fluorine transfer have been identified and utilized to develop two novel photochemical reactions to access fluorinated methoxy arenes. I have discovered that SelectfluorTM can be employed as a radical fluorinating agent, leading to the development of a photochemical methodology (in aqueous alkaline SelectfluorTM solutions containing 2-aryloxyacetic acids) for the synthesis of aryl fluoromethyl, difluoromethyl, and trifluoromethyl ethers. In the second reaction developed, acetone N-fluorobenzensulfonimide solutions containing 2-aryloxyacetic acids will promote a different, milder, photosensitized decarboxylative fluorination reaction capable of delivering more electron rich aryl fluoromethyl ethers, and aryl difluoromethyl ethers. Density Functional Theory calculations support the assertion that radical intermediates are involved in fluorination. Alkoxyl radical reactions have also been investigated. I have found that the rate of alkoxyl 5-exo cyclization onto a silyl enol ether is only marginally faster than cyclization onto a trisubstituted alkene. The assumption that secondary and primary alkoxyl radicals display similar cyclization behaviour was proven unsound, and primary alkoxyl 5-exo cyclization onto a simple terminal alkene is likely faster than published rates. Alkoxyl radical 1, 5-hydrogen atom transfer was studied in the context of a radical relay cyclization methodology. I have demonstrated that primary, secondary and tertiary alkoxyl radicals may be successfully employed in the relay cyclization of 5 (5-exo), and 6 (6-endo) membered carbocyclic rings.

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Towards a Total Synthesis of (-)-Amphidinolide K: Development of New Radical Cascade Methods (2014)

(–)-Amphidinolide K, a novel 19-membered macrolide isolated by Kobayashi and coworkers, possesses cytotoxic activity against L1210 and KB cells in vitro. I have utilized our radical relay cyclization methodology to access the tetrahydrofuran ring in high diastereoselectivity from a readily accessible precursor. N-alkoxyphthalimides, when subjected to radical conditions, are able to generate oxygen radicals, which may undergo a 1,5-hydrogen atom transfer, and subsequently cyclize onto a nearby radical acceptor. I also extended this radical methodology towards the synthesis of a number of 5-membered carbo- and heterocycles.The 1,3-dimethyl stereocenters of our target natural product were accessed by utilizing the inherent C₂ symmetry of a simple diol precursor. Several methods to rapidly access a diene fragment of our target have been explored. A tandem ring-closing metathesis/cycloreversion strategy was originally sought, with a number of approaches towards the synthesis of the requisite sulfur-containing precursors. While this strategy was ultimately unsuccessful, it was the model inspiration for a tandem one-electron/pericyclic cascade approach. Commencing with simple alkyl aldehydes, we are now about to effect the synthesis of substituted 1,3-butadienes in a single step with high yields and diastereoselectivities.Details of this work and progress towards the total synthesis of (–)-amphidinolide K will be discussed herein.

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Construction of carbo- and oxacycles using radical relay cyclizations initiated by alkoxy radicals (2013)

An investigation of a versatile radical relay cyclization methodology for the rapid construction of carbo- and heterocycles from simple linear precursors has been presented in this thesis. This thesis mainly focuses on 1,5-hydrogen atom translocation and subsequent cyclization reactions (radical relay cyclization reactions). In Chapter 1, an up-to-date literature review of this concept (radical relay cyclization) is presented including 1,5-hydrogen translocation reactions initiated by carbon radicals as well as oxygen and nitrogen radicals. In Chapter 2, the formation of cyclopentane and cyclohexane derivatives utilizing radical relay cyclization reactions initiated by alkoxy radicals has been described. The diastereoselectivity of final carbocycles is discussed. In Chapter 3, the formation of 1,2-disubstituted tetrahydrofuran and tetrahydropyran derivatives utilizing radical relay cyclization reactions has been described. With the incorporation of an oxygen atom into the precursors, the diastereoselectivity has been increased dramatically compared to carbon analogs. In Chapter 4, the formation of 2,3,5-trisubstituted tetrahydrofuran derivatives utilizing radical relay cyclization reactions has been described. With the strategic incorporation of an oxygen atom into cyclization precursors, 1,5-hydrogen atom translocation and subsequent cyclization reactions are able to compete over direct cyclization reactions and β-fragmentation reactions through the dative control. Furthermore, the incorporation of an oxygen atom into precursors enables 1,6-hydrogen atom translocation reactions to outcompete 1,5-hydrogen atom translocation reactions. In Chapter 5, the application of this radical relay cyclization methodology for the synthesis of the tetrahydrofuran fragment within (–)-amphidinolide K has been demonstrated. The final fragment in (–)-amphidinolide K can be achieved in 60% yield with a >95:5 ratio of cis to trans isomers.

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New synthetic methods using single-electron processes (2012)

This thesis presents investigations of alkoxy and aminyl radical cyclizations onto silyl enol ethers, as well as the development of a new photoinduced electron transfer-promoted redox fragmentation of N-alkoxyphthalimides.We investigated alkoxy radical cyclizations onto silyl enol ethers as a method for the synthesis of alpha-oxygenated oxacycles. Cyclizations to form tetrahydrofurans displayed a high degree of chemoselectivity relative to competing 1,5-hydrogen atom transfer, fragmentation and cyclization pathways. The rate acceleration imparted by the silyl enol ether allowed for a highly chemoselective 6-exo cyclization, a difficult mode of alkoxy radical reactivity to access due to competing 1,5-hydrogen atom transfers.We next examined the applications of silyl enol ether acceptors for aminyl radical cyclizations and the factors that lead to high diastereoselectivity in these cyclizations. This methodology allows for the synthesis of the 2-hydroxymethylpyrrolidine core found in many polyhydroxylated alkaloid natural products. In the course of our synthesis of the alkaloid CYB-3, we found that the cyclization diastereoselectivity was dependent on a complex combination of sterics and olefin geometry. Alkyl- and aryl-substituted substrates cyclized with high selectivity regardless of olefin geometry or substitution pattern. When electronegative substituents were introduced alpha to the silyl enol ether, only Z-silyl enol ethers provided high cyclization diastereoselectivities.Finally, we report a new fragmentation reaction of N-alkoxyphthalimides mediated by visible light and a Ru(bpy)₃²⁺ photocatalyst. Our mechanistic data support a unique concerted intramolecular fragmentation process, initiated by a single electron transfer to the phthalimide from either the metal catalyst or directly from a tertiary amine additive. The redox fragmentation reaction was applied to aryl, allyl and lactol derivatives. We found that the reaction could be carried out under catalyst-free conditions, but the yields of many substrates were improved in the presence of Ru(bpy)₃²⁺. The redox fragmentation of N-alkoxyphthalimides was applied to the mild and selective redox fragmentation of sensitive nitrogen-containing heterocycles.

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Master's Student Supervision (2010 - 2020)
A new radical trifluoromethoxylation strategy and investigation on the fluorination of boronic acids using electrophilic N-F reagents (2016)

Fluorine-containing motifs are important components in pharmaceuticals and agrochemicals. Upon incorporation of fluorinated moieties, many small molecules show enhanced bioavailability, lipophilicity and metabolic stability. Despite their industrial importance, many fluorinated motifs remain a significant synthetic challenge. This thesis describes the investigation and development of new radical fluorination methods for the synthesis of two important, and synthetically challenging fluorinated motifs: trifluoromethoxyarenes and aryl fluorides. Chapter 1 provides a literature survey on the importance of fluorinated small molecules and outlines current methods to synthesize them. The chapter begins with a historic overview of fluorinated pharmaceuticals. Common fluorination reagents are then summarized, including anionic, cationic, and radical sources of fluorine. The chapter concludes with a brief survey of the application of ¹⁸F-fluorinated molecules in Positron Emission Tomography (PET). Chapter 2 outlines work towards the development of a radical fluorodecarboxylation methodology for the synthesis of trifluoromethoxy ethers. The chapter begins with a review of synthetic methodologies to access trifluoromethoxylated molecules that have been developed over the last few decades. Next, a novel methodology based on a radical fluorodecarboxylation method will be presented along with substrate scope studies. XeF₂ was used both to induce decarboxylation and as atomic fluorine source. The reaction afforded good yields for electron-rich substrates, whereas electron-deficient substrates and naphthol derivatives produced lower yields. Chapter 3 outlines work for the fluorination of aryl boronic acid and boronated derivatives using Selectfluor®. The chapter starts with a brief overview of known methodologies in fluorination of boronic acid derivatives. Studies towards synthesizing aryl fluorides from a number of boronic acid and boronate ester derivatives will then be described. Preliminary results of this transition metal-free method showed that the reaction is substrate dependent, and the general product yields were low.

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