This work is mainly composed of two parts. The first part talks about synthesis and reactivity studies of metallacyclobutenes (MCB) and 4-cobalt-cyclopentadienes derived therefrom, which includes chapter 1, 2, 3, and 4. The second part talks about ruthenium-mediated/catalyzed cyclizations of conjugated tri- molecules, which includes chapter 5, 6, 7, and 8.

Chapter 1 is a review of historical development of metallacyclobutenes and 4-cyclopentadienes with numerous literature-reported representative examples. Chapte 2 talks about preparation of new cobaltocyclobutenes, reversible thermolysis of MCB to dicobalt propendiyl complex, formation of 4-diene complexes from MCB, photochemical isomerization of MCB, and the reactivities of MCB/cobalt-alkyne complexes towards dizaoacetamide. Chapter 3 presents syntheses of 4-cyclopentadienes and vinylmetallacyclobutene complexes, as well as further reactivity study of 4-cyclopentadienes to produce highly functionalized cobaltocenium cations and arenes. Chapter 4 introduces a Brønsted acids triggered demetallation of 4-cyclopentadiene to give fulvenol, cyclopentenone, and cyclopentadienes as products.

Chapter 5 talks about an air-stable ruthenium-naphthalene complex Cp*Ru(Nap)PF6 as trigger of “Cp*Ru+” under photochemical conditions to cycloaromatize enediyne in the presence of 1,4-cyclohexandiene at ambient temperature. Chapter 6 describes a chemoseletive ruthenium-mediated cycloaromatization of dienynes with phenyl goup. A noval ruthenium-catalyzed cyclization mode was also discovered on a chlorine and methyl incorporated dienyne, whose regioselectivity is controlled by the size of a nearby fused ring. Chapter 7 is a clean-up work of an unprecedented cycloaromatization mode of enediynes. Both vinyl chloride intermediates and arene products were resynthesized from a modified method with higher yields, and products were furtherly purified and fully characterized. Mechanistic studies were carried out via deuterium labelling experiments. Chapter 8 introduces ruthenium-mediated/catalyzed conjugated trienes. The reactions of Cp*Ru(NCMe)3PF6 with trienes at ambient temperature give 6-arene complex with excellent yields. VT NMR experiments allows the observation and isolation of variable metal-triene intermediates at low temperature. Furthermore, the first example of metal-complexation catalyzed 6 electrocyclization of conjugated trienes was discovered.

The work contained within this thesis represents contributions to our understanding of ruthenium-mediated cycloaromatization reactions of trienes and novel cycloaromatization reactions of nitrogen-containing enediynes. Previous work done in the O’Connor lab demonstrated room temperature cyclizations of enediynes and dienynes via proposed hexahapto metal coordination. Preliminary calculations suggest that η6-metal complexation to the π system lowers the activation energy for cyclization. The mechanistic hypothesis for this transformation involves η6-metal complexation to the triene system, followed by a 6π electrocyclization.

The first η6-acyclic conjugated triene ruthenium complex was successfully synthesized by the reaction of [CpRu(NCMe)3]PF6 with an (E,E) diphenyl-substituted 1,2-divinylcyclopentene derivative. The presence of phenyl substituents is thought to inhibit the metal-mediated disrotatory ring closure of the triene due to steric congestion. This complex was further characterized by exploring electronic effects of para-substituted phenyl substituents on the overall geometry. More specifically, electronic effects were examined by hexahapto metal complexation to 1,2-bis((E)-4-(trifluoromethyl)styryl)cyclopentene and 1,2-bis((E)-4-methoxystyryl)cyclopentene. The more electron-deficient η6-triene ruthenium complex adopted an s-cis/s-cis conformation, as determined by X-ray crystallographic analysis. The more electron-rich η6-triene ruthenium complex adopted both s-cis/s-cis and s-cis/s-trans conformations in a 3:1 ratio. Additional analysis of this ratio by cold-probe variable temperature 1H NMR spectroscopy confirms that the two isomers exists in equilibrium at room temperature. The relative stabilities of these diastereomeric complexes were examined by a time course migration study where the migration of ruthenium from (η5-cyclopentadienyl)(η6-1,2-bis((E)-4-(trifluoromethyl)styryl)cyclopentene) ruthenium(II) hexafluorophosphate to 2-bis((E)-4-methoxystyryl)cyclopentene was monitored by 1H NMR spectroscopy. Based on the final ratio of isomers, it was estimated that the more electron-rich ruthenium complex is > -4.0 kcal/mol more stable than the electron-deficient η6-triene ruthenium complex.

Finally, a recently discovered thermal cyclization of enediynes was extended to include pyridine-based enediynes. Thermolysis of 2-(1-pentynyl)-3-(1-propynyl)pyridine in CDX3 (X = Br, I) and 1,4-cyclohexadiene led to the regioselective formation of 5-halo-6-methyl-7-propylquinoline derivatives. Halogen connectivity was established via HMBC and NOE NMR spectroscopic analysis. The cyclization is proposed to involve a key diene intermediate, (E)-3-(1-halo-1-propenyl)-2-(1-pentynyl)pyridine, which may form by one or both of the following mechanisms. The first mechanism involves addition of HX to the alkyne (X = Br, I). The hydrogen halide is proposed to form in situ from the reaction of 1,4-cyclohexadiene with CDX3 (X = Br, I) to form HX, CDHX2, and benzene. In the second mechanism, the diene intermediate is proposed to form through free radical addition of a hydrogen atom from the cyclohexadienyl radical to an alkyne to give a dienyne radical, followed by abstraction of a halogen atom from CDX3 to produce the halo-dienyne intermediate. This key dienyne intermediate is then proposed to undergo a Hopf-type cyclization to yield the halogenated aromatic product.

Since the discovery of ferrocene in 1951 and subsequent structure elucidation in the following years, a wealth of literature is available on ferrocene functionalization. The remarkable stability of ferrocene under aqueous and aerobic conditions along with its low cost and high availability has led to widespread popularity for usage in anticancer research.

Our research has explored the cytotoxicity of ferrocenyl anticancer agents with and without drug delivery carriers and possible mechanism of action within the tumor cells. We investigated selective generation of cytotoxic iron overload in tumor cells by synthesizing benzoyl-ferrocene and ferrocenyl chalcone derivatives. Photolysis of these two complexes lead to formation of free iron(II) in situ, which can react endogenously to form reactive oxygen species (ROS), such as hydroxyl radicals. This iron(II) would then be oxidized to iron(III) which could also react with endogenous ROS such as superoxide to reduce back to iron(II), resulting in catalytic generation of iron(II) which lends itself to unwanted, detrimental reactions within the cell. We propose a new method to photodynamic therapy (PDT) using generation of iron(II) in situ. We proposed that the generation of free iron(II) intracellular through this PDT method could induce ferroptosis and is actively pursuing experiments to determine if it is the case. We have also explored using porous silicon nanoparticles as a drug delivery carrier to ensure a higher iron payload delivery into cells, for greater cytotoxicity.

This work started with a thorough review on current study in activating conjugate alkene or alkyne system with metal complexes. The insightful research on various metal coordinated η6, η4 and η2 complexes provided us with concrete references in resolving metal mediated electrocyclizations. With these studies we proposed many interesting hypotheses and investigated and produced novel research results.In chapter 2, we continued investigating the Cp*Ru+L3 triggered electrocyclization. We successfully isolated and characterized the first Cp*Ru(η6 -dienyne) complex, which was believed to be the crucial intermediate during the electrocyclization. Further study was carried out with a focus on phenyl substituted dienyne substrates. We confirmed the coordination priority and resolved an isomerization within its mechanism. We then ameliorated the ruthenium complex with a naphthalene ligand to achieve a control on the para-diradical formation with photon activation. Lastly, we presented an interesting and unexpected result when replacing the Ruthenium metal center with Iridium in reacting with dienyne substrate. In chapter 3, we report a chromium complex mediator, Cr(CO)3(η6-naphthalene), that mediates the traditional thermal dienyne cyclization at ambient temperature. Successful cycloaromatizations were observed to proceed to moderate yield in coordination. Further mechanistic study was undertaken by monitoring v(CO) stretching via infrared (IR) spectroscopy. A speculative Cr(CO)3(η6-dienyne) intermediate was observed using 2D-IR spectroscopic analysis and coanalysis. In chapter 4, we report a newly discovered alkene reduction reaction mediated by tris(acetonitrile)tricarbonylchromium in acetone. While attempting to effect chromium-mediated thermal cycloaromatization of dienynes, we discovered that, in a homogeneous tris(acetonitrile)tricarbonylchromium-acetone solution system, a highly selective reduction of a less hindered terminal alkene can be achieved without the source of hydrogen. A further mechanistic study has confirmed that hydrogen was provided by the solvent, acetone. Therefore, we present an attempt to elucidate its mechanism. In chapter 5 reports the use of a soluble Lewis acid complex, [Zn(cyclam)]2+ (cyclam = 1,4,8,11-tetraazacyclotetradecane) as a co-catalyst coupled with Mn(Mesbpy)(CO)3Br (Mesbpy = 6,6’-dimesityl-2,2’-bipyridine) for the electrochemical reduction of CO2 to CO. Utilization of the soluble chelated Lewis acid avoids the use of sacrificial additives and prevents the formation of insoluble products such as MgCO3 or ZnCO3 that change the thermodynamics of the CO2 reduction. The use of soluble Lewis acids greatly improves catalysis compared to previously reported systems that used sacrificial anodes.

ABSTRACT OF THE THESIS

Ruthenium-Catalyzed Cyclization/Cycloaromatization of Conjugated Trienes

by

Li-An Wang

Master of Science in Chemistry

University of California San Diego, 2019

Professor Joseph M. O’Connor, Chair

The work describes mechanistic studies on ruthenium-accelerated cyclization/cycloaromatization of trienes. In the beginning, thermal and photochemical reactions of trienes were conducted in order to compare the temperatures and reaction times to those for ruthenium-accelerated analogues. According to the Woodward-Hoffmann rules, cyclization of trienes to cyclohexadienes should proceed in a disrotatory fashion. In the literature, Chaudret and co-workers published that [Cp*Ru(OMe)]2/HOTf could lead to cycloaromatization of (E)-1,3,5-hexatriene, while the mechanism for this reaction was not discussed. And based on previous work from the O’Connor lab, the authors demonstrated that [Cp*Ru(NCMe)3]PF6 mediated the cyclization of conjugated enediynes and dienynes at room temperature, possibly via the formation of hexahapto intermediates, η6-enediyne and η6-dienyne, respectively. Consequently, we proposed that [CpRu(NCMe)3]PF6 would trigger the cycloaromatization of trienes at room temperature via η6-(acyclic triene) metal intermediates, followed by elimination of two hydrogen atoms to generate an arene product.

In the reactions of trienes with [CpRu(NCMe)3]PF6, η4- and η6-acyclic metal complexes were clearly identified by 1H NMR spectroscopy and X-ray crystallography. Subsequently, the isolated η6-acyclic metal complex was heated at 50 ˚C to give 6,7-dimethyl-1,2,3,4-tetrahydronaphthalene. Thus, the hexahapto metal complex was implicated in acceleration of the cyclization. Moreover, the reaction of 1-((E)-prop-1-en-1-yl)-2-((Z)-prop-1-en-1-yl)cyclohex-1-ene with [CpRu(NCMe)3]PF6 sufficiently illustrated that 6π electrocyclization of trienes proceeds in a disrotatory fashion. An agostic interaction was also observed by 1H NMR spectroscopy in a η4-cyclohexadiene ruthenium intermediate, followed by a [1,5]-hydride shift. Most surprisingly, a truly catalytic reaction was found in the reactions of (Z)-1-(2-methylprop-1-en-1-yl)-2-(prop-1-en-1-yl)cyclohex-1-ene and (E)-1-(2-methylprop-1-en-1-yl)-2-(prop-1-en-1-yl)cyclohex-1-ene with [CpRu(NCMe)3]PF6 since the appearance of a free cyclohexadiene derivative was observed and excess triene was consumed. Based on the results of these experiments, several reasonable mechanisms for ruthenium-mediated cyclization of trienes were proposed.

Chapter 1. Historical Development of Stable Metallacyclobutenes

Fred Tebbe and co-workers synthesized the first stable metallacyclobutene complexes in the late 1970’s by treatment of an intermediate titanium methylene species – later popularized as the “Tebbe reagent” – with acetylenes. Robert Grubbs at Caltech further studied this system, using it to detail a degenerate metathesis reaction and to isolate a metallacyclobutane complex – which was implicated in the emerging field of alkene metathesis. Further development of stable metallacyclobutene complexes is explored chronologically, particularly with regard to systems developed by Thorn, Bianchini, Hughes, O’Connor, Casey, Wojcicki, and Chen.

Chapter 2. Reactivity of Stable Metallacyclobutenes and Vinylcarbenes with Alkenes

Cobalt-metallacyclobutene complex (η⁵-C₅H₅)(PPh₃)Co[κ²-(C,C)-C(SO₂Ph)=C(TMS)CH(CO₂Et)] is allowed to react with a variety of acyclic and cyclic alkenes to generate stable η⁴-1,4-pentadienes (9-12) and κ²-metallacyclohexenes (13-14), respectively. The reaction is thought to occur through a vinylcarbene intermediate such as 15-17, and a model complex of an oxametallabenzene containing an internal vinylcarbene moiety is calculated (18). Complex 13-exo reacts with trimethylphosphine to decomplex the ester carbonyl, generating a PMe₃ complex, 20-exo. Oxidative demetallation of complexes 9-ZZ and 9-ZE is effected with iodine to generate organic pentadienes 21-22. Iron vinylcarbene complex (CO)₃Fe(η³-C(OMe)C(CO₂Me)=CH(CO₂Me) (25a) is synthesized, and its reactivity with maleic anhydride and maleimide is found to generate dinuclear iron complex 30, and new organic species 31 and 32. Compounds 31-32 are formulated as the [4 + 2]-cycloaddition product of an intermediate furan or α-pyrone.

Chapter 3. Reactivity of Stable Metallacyclobutenes with C-Nitroso Reagents

Cobaltacyclobutene complex (η⁵-C₅H₅)(PPh₃)Co[κ²-(C,C)-C(SO₂Ph)=C(TMS)CH(CO₂Et)] is found to react with C-nitroso reagents to afford bicyclic [κ²-(C,O)-η¹-(N)-hydroxylamido complexes 5-9. Complexes 5-9 contain a [3.1.0] fused-ring framework, with the 3-membered oxametallaziridine moiety formed in either a cis or trans relationship to the ethyl ester. Formation of products 5-9 is proposed to occur through a [4 + 2]-cycloaddition mechanism from an oxametallabenzene, with stereo-selection via rapid epimerization of nitrogen from the post-cyclization intermediate.

Chapter 4. The Isolation of a Large Cyclopentadienylcobaltsulfide Cluster – Synthesis and

Crystal Structure of Octahedral closo-[(η⁵-C₅H₅)Co]₅S

The metallacyclobutene complex (η⁵-C₅H₅)(PPh₃)Co[κ²-(C,C)-C(SO₂Ph)=C(TMS)CH(CO₂Et)] reacts with added (η⁵-C₅H₅)Co(PPh₃)₂ to give the cluster compound closo-[(η⁵-C₅H₅)Co]₅S (1), the largest (η⁵-C₅H₅)Co cluster known.

This work describes mechanistic studies into a ruthenium-mediated cycloaromatization of dienynes. The results of deuterium labeling experiments are consistent with a mechanism that proceeds via a 6-electrocyclization to form an 4-isobenzene adduct followed by a metal-mediated [1,5]-hydride shift. The cycloaromatization of dienynes with substituents in the E-position of the distal alkene is proposed to give arene product via a process involving two sequential [1,2]-hydride shifts. Dienynes bearing phenyl substituents in either the E or Z-position of the distal alkene or acetylenic position were shown to cycloaromatize.

The ruthenium-mediated cycloaromatization of acyclic trienes was accomplished in excellent yields. Observation and characterization of an 6-triene ruthenium complex were accomplished. Deuterium labeling experiments led to a mechanistic proposal involving 6-complexation of ruthenium to the triene followed by disrotatory electrocyclic ring closure. The deprotonation of the 4-1,3-cyclohexadiene intermediate is proposed to generate a cyclohexadienyl ligand, which aromatizes via a ruthenium-assisted protolytic cleavage of a C-H or C-C bond.

In continuation of catalytic metal-triggered cyclization of enediynes under photolytic conditions, the effects of sterics and electronics in Cp-ligated iron and ruthenium were investigated with the 1,2,3,4-tetramethyl-5-trifluoromethylcyclopentadienyl (Cp‡) ligand. A series of Cp‡-ligated iron and ruthenium complexes were prepared. Attempts to generate [Cp‡Fe(6-benzene)]PF6 led to activation of all three C-F bonds and the formation of a new (diphenylmethyl)tetramethylcyclopentadienyl ligand. The cyclization of an enediyne bearing a propargylic stereocenter was shown to have similar stereoselectivity for Cp- and Cp‡-ligated ruthenium (1:1), as compared to Cp* (8:2). The photochemical release of naphthalene from ruthenium in the presence of enediynes or dienynes was observed to give cycloaromatized products in excellent yields.

Finally, a recently discovered thermal cyclization of enediynes was extended to include incorporation of chloride or bromide from chloroform or bromoform, respectively. The haloform was demonstrated to react with 1,4-cyclohexadiene to generate hydrogen halide in situ, which then added across an alkyne to produce a cis, cis-dienyne. The chloro and bromo dienyne intermediates were independently prepared and shown to undergo the cyclization. The cyclization is proposed to involve a cascade of pericyclic reactions initiated by either a [1,7]-hydride shift or 6-electrocyclization leading to arene products with different substitution patterns. When iodoform was used, the iodo dienyne was observed at lower temperatures, but the product of a formal Bergman cyclization was the only product observed at higher temperatures. Fluoroform was observed to have no effect on the rate or product of the enediyne cyclization, presumably due to high bond strengths in fluoroform.

The discovery of ferrocene in 1951 and subsequent structure elucidation essentially founded the field of modern organometallic chemistry. The remarkable stability of the sandwich complex’s iron-carbon bonds and ease of derivatization have made the archetypal metallocene ubiquitous across an array of scientific disciplines. Coupled with the wealth of literature available on ferrocene functionalization and the complex’s stability in aqueous and aerobic media, it is no wonder ferrocene has gained widespread popularity among anti-cancer researchers in particular.

Our research has explored two avenues of cytotoxicity for ferrocene-based antitumor agents. First, we wished to explore selective generation of cytotoxic metals in tumor cells. To this end, we describe the preparation of a series of ferrocene derivatives that are photosensitive and undergo successive ring--slips to form cyclopentadienes and inorganic iron(II) when exposed to visible light. We proposed the photochemically generated iron(II) would form reactive oxygen species in situ by reaction with endogenous hydrogen peroxide, forming the highly toxic hydroxyl radical via the Haber Weiss Cycle. The synthesis, characterization, photochemical properties, and biological activity of the synthesized antitumor agents were examined in detail. Second we wished to take advantage of the unique photochemical properties of benzoylferrocene to selectively deliver cytotoxic enediyne ligands to tumor cells. We proposed that once the organoferrous enediynes were localized within the cell, irradiation with visible light would trigger enediyne cycloaromatization. The reactive para-benzyne diradical could abstract hydrogen atoms from DNA in a similar manner to that of the enediyne antibiotics. To this end we describe the preparation of I, which was expected to cyclize intramolecularly to form para-benzyne. Then we describe the synthesis and characterization of ferrous enediynes II-IV, which are extremely light sensitive upon irradiation. The biological activity of selected ferrous enediynes in both the light and dark is also provided and discussed.

Cisplatin, the first successful metallotherapy, has been utilized over the past four decades as chemotherapy treatment of a wide range of tumors. However, due to persistent side-effects and a buildup of platinum resistance in cancer cells, alternative metallotherapies have been sought after. Ferrocene is a promising scaffold alternative due to advantages such as cost, biologically stability, and iron is a biologically relevant metal. Ferrocene compound Ferroquine, has been successful clinically as an anti-malarial compound, currently going through the third phase of clinical trial.

We have synthesized para-substituted benzoyferrocene derivatives that photochemically release free iron(II). Through the group of derivatives, we have optimized highly specific photodynamic therapy (PDT) compounds that induce no cytotoxicity in the dark but do after irradiation. It is hypothesized that the observed cytotoxicity is due to the release of iron(II), which catalyzes the Fenton reaction, leading to the formation of toxic reactive oxygen species (ROS) in the cell. Through a series of in vitro experiments, we have reported that photolysis in cells incubated with 1,1`-bis(4-n-pentylbenzoyl)ferrocene leads to a dose-dependent increase in lipid peroxidation, suggesting ferroptosis as a mechanism of cell death. Additionally, we found that ferroptosis GPx4, SOD1, and VDAC are overexpressed after irradiation. Overall this work reports ferrocene derivatives function as highly specific PDT anti-cancer agents.