Glenn Sammis

The development of mild, selective, efficient, and economical chemical transformations is a foundation of modern synthetic organic chemistry. These chemical processes may be utilized in the syntheses of pharmaceutical compounds, facilitating improved approaches to complex targets. Novel reagents are often created and studied during the development of these more effective protocols. This dissertation explores several synthetic applications of sulfuryl fluoride and thionyl fluoride as reagents in useful chemical processes. Little is known about the synthetic applications of thionyl fluoride, and the work presented herein includes some of the first investigations of this chemical as a reagent in synthetic organic chemistry.Chapter 2 describes the sulfuryl fluoride-mediated transformation of thiols to the corresponding 1,1-dihydrofluoroalkyl sulfide. The primary themes of the work outlined in this chapter include investigations into the chemoselectivity of the title reaction for thiols over other nucleophilic moieties, as well as an expansion of the scope of 1,1-dihydrofluoroalcohols.In Chapter 3, the kinetics of the one-pot sulfuryl fluoride-mediated activation and nucleophilic acyl substitution of carboxylic acids are explored using quantitative 1H and 19F nuclear magnetic resonance spectroscopy. The addition of a tetrabutylammonium halide salt additive as much as doubles the rate of formation of the intermediate acyl fluoride, yet there is no effect on the rate of consumption of this intermediate by the nucleophilic coupling partner. Contributions made to the substrate scope are further outlined in this chapter.Chapter 4 details a comprehensive study of several new synthetic applications of thionyl fluoride in the context of carboxylic acid activation. One-pot, column-free nucleophilic acyl substitutions and one-pot, mild reductions are described in this work. Activated esters, amides, and alcohols are all accessible via the corresponding acyl fluoride intermediate.Chapter 5 explores an expedited one-pot, thionyl-fluoride mediated conversion of sulfinic acids to the corresponding sulfonimidoyl fluoride, utilizing bench-stable and accessible reagents. Sulfonimidoyl fluorides bear both synthetic and pharmaceutical relevance as they enable direct access to other highly desirable sulfur(VI) motifs. This work serves as an advancement over comparable literature protocols as no unstable intermediates need be isolated, and the reaction is conducted in a single reaction vessel.

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Sulfonyl fluorides, alkyl fluorides and acyl fluorides are common functional groups found in numerous industrial products, including in pharmaceuticals, agrochemicals, and functionalized materials. In spite of numerous methods developed, there are still many limitations in the existing protocols to access these fluorinated motifs. This thesis describes my contribution to the development of new synthetic methods to access sulfonyl fluorides, alkyl fluorides, and acyl fluorides using two fluorinated gases, sulfuryl fluoride and thionyl fluoride.Chapter 1 gives a broad introduction to applications of fluorochemicals in pharmaceutical, polymer, and agrochemical industries, which contribute significantly to market share and revenue. Syntheses of fluorochemicals are of great interest in synthetic chemistry using various fluorinating reagents. This chapter details the development and transformations of two gaseous fluorinating reagents, sulfuryl fluoride and thionyl fluoride.Chapter 2 details the development of a novel fluorosulfurylation of Grignard reagents using sulfuryl fluoride. The reaction converts a wide range of alkyl, aryl, and heteroaryl Grignard reagents into the corresponding sulfonyl fluorides in 18-78% yields. A unique advantage of this method over previously reported fluorosulfurylation reactions is that the generated sulfonyl fluorides can be used to access unsymmetrical diaryl sulfones, sulfonate esters, and sulfonamides in a one-pot process.The development of an efficient deoxyfluorination of alcohols using sulfuryl fluoride to synthesize alkyl fluorides is reported in chapter 3. The broad scope including primary and secondary aliphatic alcohols in 46-92% yields demonstrated a good functional group tolerance and net inversion of configuration. A gram-scale synthesis proved the potential synthetic relevance of this methodology. Chapter 4 describes the development of ex situ generation of thionyl fluoride and subsequent demonstration of its use to access amino acid fluorides in 86-98% yields under mild conditions and short reaction time. The method is applicable for sequential reaction, whereby the generated amino acid fluorides can be converted to the corresponding dipeptides in a one-pot, column-free process with retention of optical purity. The broad scope allows for natural and unnatural amino acid substrates with a wide array of protecting groups. The new approach was applied to the sequential liquid phase peptide synthesis and solid phase peptide synthesis.

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This thesis describes my contribution to the development of radical reactions for the synthesis of nitrogen heterocycles and new synthetic methods using sulfuryl fluoride and thionyl fluoride.Chapter 2 contains the development of a novel diastereoselective 6-endo-trig radical cyclization for the synthesis of disubstituted tetrahydrophthalazines from hydrazone. Four of the Boc-hydrazones were useful substrates to form trans-1,4-disubstituted tetrahydrophthalazines in 55-80% yield and up to 90% diastereomeric excess.In Chapter 3, I explain how I develop the first efficient method for SO₂F₂-mediated activation and substitution of aliphatic alcohols. This new method is effective for a wide range of primary alcohols using nitrogen, sulfur-, carbon-, oxygen-based nucleophiles (43-89% yield). Secondary alcohols were also successful substrates using aryl thiols in 49-65% yield and 94-100% enantiomeric excess.Chapter 4 sets forth the development of a more general SO₂F₂-mediated one-pot alcohol activation and substitution method that relies on the alkyl halide intermediates. This method expanded the scope include substitution to nucleophiles that were previously incompatible with one-pot SO₂F₂-mediated alcohol activation and substitution in Chapter 3. Lastly, I describe the development of an efficient sulfamate ester synthesis mediated by SOF₂ in Chapter 5. This new method relies on a key intermediate, either an alkyl fluorosulfite or aminosulfinyl fluoride. Subsequent substitution and oxidation of an alkyl fluorosulfite or aminosulfinyl fluoride affords the corresponding sulfamate ester in 38% to 90% isolated yield. I also applied this method to modify the surface of cellulose nanocrystals (CNCs), affording seven modified CNCs. These modified CNCs are currently undergoing detailed characterization.

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Di- and trifluoromethoxyarenes are industrially relevant motifs found in medicinal compounds, agrochemicals, and materials. However, the number of different strategies available to access these di- and trifluoromethoxy arenes are currently limited. Chapter 2 describes the development of a new fluorodecarboxylation method utilizing xenon difluoride for the synthesis of difluoromethoxyarenes. The reaction occurs rapidly and efficiently with facile purification, affording the desired difluoromethoxyarenes in 34–72% yields.Sulfuryl fluoride is an industrially produced insecticidal fumigant that has been utilized in synthetic chemistry primarily for the synthesis of aryl fluorosulfates. Chapter 3 details a new strategy using sulfuryl fluoride with 1,1-dihydrofluoroalcohols to synthesize 1,1-dihydrofluoroalkylamines. The reaction proceeds through a 1,1-dihydrofluoroalkyl fluorosulfate intermediate, which was demonstrated to be an effective alkylating agent for amines in contrast to previous reports. The method involves a one-pot, single step reaction and was applied to various 1,1-dihydrofluoroalcohols to access a variety of functionalized amines in 42–80% yields. 1,1-Dihydrofluoroalkyl sulfides are commonly synthesized via alkylation of thiols. These methods may require long reaction times or suffer poor selectivity for thiols in the presence of other nucleophiles. Chapter 4 describes the development of a new one-pot thiol 1,1-dihydrofluoroalkylation method using a new class of thiol 1,1-dihydrofluoroalkylating reagents. Bis(trifluoroethyl) sulfate was demonstrated to have excellent reactivity with thiols forming trifluoroethyl sulfides in 58–83% yields, even in the presence of competing amine, hydroxyl, and carboxylic acid functional groups. Additional 1,1-dihydrofluoroalcohols were similarly applied to access longer chain 1,1-dihydrofluoroalkyl sulfides in 70–90% yields. The utilization of sulfuryl fluoride to mediate one-pot transformations from carboxylic acids has been less explored compared to alcohols. Sulfuryl fluoride-mediated carboxylic acid activation has been previously utilized to access acyl fluorides over twelve hours. The long reaction time makes this method unsuitable for further one-pot nucleophilic acyl substitution reactions. Chapter 5 describes an accelerated synthesis of acyl fluorides from carboxylic acids using sulfuryl fluoride and tetrabutylammonium halide salts. Mechanistic investigations revealed that the accelerated reaction predominantly occurs through an acid anhydride intermediate. Acyl fluorides were afforded in 30–80% yields and subsequently utilized in the synthesis of esters, amides, and thioesters in 72–96% yields.

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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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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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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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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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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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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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(–)-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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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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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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