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Thesis advisor: Amir H. Hoveyda / Chapter 1 Catalytic Enantioselective Addition of Organoaluminum Reagents Catalytic methods involving the enantioselective addition of both commercially available as well as in situ generated organoaluminum reagents are reviewed. An overview of additions to aldehydes, ketones, and imines is provided as well as the difficulties and limitations of such transformations. Furthermore, additions to unsaturation adjacent to a leaving group to form a new stereogenic center are examined. Finally, conjugate addition reactions wherein an organoaluminum reagent is added to an olefin adjacent to a carbonyl or nitro group are discussed. Chapter 2 Synthesis of Quaternary Carbon Stereogenic Centers through Enantioselective Cu-Catalyzed Allylic Substitution with Alkenylaluminum Reagents A method for the formation of 1,4-diene containing quaternary stereogenic centers through catalytic enantioselective allylic substitution is disclosed. The addition of alkyl- and aryl-substituted alkenylaluminum reagents to trisubstituted allylic phosphates is promoted by 0.5–2.5 mol % of a sulfonate-containing bidentate N-heterocyclic carbene–copper complex. Products containing a quaternary stereogenic center as well as a newly formed terminal olefin are obtained in up to 97% yield and 99:1 er with high site selectivity (>98:2 SN2’:SN2). The requisite nucleophiles are generated in situ through hydroalumination of terminal alkynes. The utility of the method is demonstrated through a concise synthesis of natural product bakuchiol. Chapter 3 A Multicomponent Ni-, Zr-, Cu-Catalyzed Strategy for Enantioselective Synthesis of Alkenyl-Substituted Quaternary Carbons Despite the widespread use of conjugate addition in organic synthesis, few reports pertain to the addition of nucleophiles to acyclic systems and none in which the nucleophile is an alkene. Herein, we report the first examples of enantioselective conjugate addition of alkenylmetal reagents to trisubstituted enones to form all-carbon quaternary stereogenic centers. Alkenylaluminum nucleophiles are prepared through a site-selective Ni-catalyzed hydroalumination of terminal alkynes and the requisite E-trisubsituted enones are the products of a regioselective Zr-catalyzed carboalumination/acylation of a terminal alkyne. Products are obtained in up to 97% yield and 99:1 er. A model for enantioselectivity, supported by DFT calculations, is proposed. Chapter 4 Formation of Tertiary Centers through Catalytic Enantioselective Conjugate Addition of Alkenylaluminum Reagents to Acyclic Enones We have developed an enantioselective NHC–Cu catalyzed synthesis of tertiary centers in acyclic systems using in situ generated alkenylaluminum reagents, as current methods typically rely on Rh-catalysis at high temperatures with alkenyl boronic acids in protic solvents. Moreover, most examples include chalcone-derived substrates, which, while more reactive, often preclude further functionalization. With the current method, we are able to couple a variety of alkenyl nucleophiles with α,β-unsaturated ketones. E- or Z-silylalkenylaluminum reagents, derived from hydroalumination of silyl-protected alkynes, lead to products in good yields and high enantioselectivities. Additionally, both the α- and β-alkenylaluminum reagents participate in the reaction. Chapter 5 Development of N-Heterocyclic Carbene–Cu Catalyzed Allylic Substitution of Diboryl Methane to Morita-Baylis-Hillman Derived Allylic Phosphates We have developed a method for the coupling of a geminyl diboron reagent with Morita-Baylis-Hillman derived trisubstituted ester-containing allylic phosphates. With 10 mol % of an in situ generated NHC–Cu complex and 1.5 equivalents of the boron reagent, we are able to form the desired product in high regio- and enantioselectivity with a 2,5-ditert-butyl containing carbene. Simple aryl substituents as well as those containing a halogen or an electron-withdrawing group furnish the desired products in up to 85% yield and 98:2 er. Alkyl-containing substrates are also competent reaction partners, although longer chain aliphatics results in slightly diminished enantioselectivity. We are pursuing the application of this method to the synthesis of α-methylene lactones which can be further functionalized to natural products like tubulin polymerization inhibitor (–)-steganone and glaucoma medication (+)-pilocarpine. / Thesis (PhD) — Boston College, 2016. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

京都大学 / 新制・課程博士 / 博士(理学) / 甲第24438号 / 理博第4937号 / 新制||理||1705(附属図書館) / 京都大学大学院理学研究科化学専攻 / (主査)教授 依光 英樹, 教授 若宮 淳志, 教授 畠山 琢次 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

Thesis advisor: Amir H. Hoveyda / Chapter One: An overview of Cu-catalyzed enantioselective allylic substitutions with organometallic reagents. Chapter Two: Development of Cu-catalyzed enantioselective allylic alkylations of allylic chlorides with Grignard reagents for the formation of all-carbon quaternary stereogenic centers is disclosed. Chapter Three: Development of Cu-catalyzed enantioselective allylic substitutions of allylic phosphates with alkyl, aryl, and heterocyclic aluminum reagents for the formation of quaternary stereogenic centers is discussed. / Thesis (MS) — Boston College, 2010. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Use of a mixed triisobutylaluminum/1,1-diphenylhexyllithium intiator enabled the anionic polymerization of methyl methacrylate at room temperature, resulting in narrow molecular weight distributions and syndiorich structures. Polymerizations were controlled above Al:Li = 2, and control significantly decreased at elevated temperatures above 25 °C. A significant increase in Tg with increasing control of syndiotacticity demonstrated the ability to tailor polymer properties using this technique. Analysis with MALDI-TOF/TOF spectroscopy revealed the dominance of a back-biting side reaction at elevated temperatures. Hydroxy-functional random and block copolymers of n-butyl acrylate (nBA) and 2-hydroxyethyl acrylate were synthesized using nitroxide mediated polymerization. Controlled polymerization was demonstrated, resulting in narrow polydispersities and linear molecular weight vs. conversion plots. In situ FTIR spectroscopy monitored the polymerizations and revealed pseudo first order rate kinetics for random copolymerizations. Protection of the hydroxyl using trimethylsilyl chloride alleviated isolation issues of amphiphilic polymer products. For the first time zwitterion-containing copolymers were electrospun to form nanoscale fibers with diameters as low as 100 nm. Free radical copolymerization of nBA and sulfobetaine methacrylamide produced zwitterionic copolymers with 6-13 mol % betaine. Dynamic mechanical analysis revealed a rubbery plateau and biphasic morphology similar to ionomers. Electrospinning from chloroform/ethanol solutions (80/20 v/v) at 2-7 wt % afforded polymeric fibers at viscosities below 0.02 Pa™s, which is the lowest viscosity observed for fiber formation in our laboratories. We hypothesized that intermolecular interactions rather than chain entanglements dominated the electrospinning process. Solution rheology of zwitterionic copolymers containing 6 and 9 mol % sulfobetaine methacrylate functionality revealed two concentration regimes with a boundary at ~1.5 – 2.0 wt %, regardless of molecular weight. This transition occurred at an order of magnitude lower specific viscosity than the entanglement concentration (Ce) for poly(nBA), and correlated to the onset of fiber formation in electrospinning. Comparison to existing models for polymer solution dynamics showed closest agreement to Rubinstein's theory for associating polymers, in support of our hypothesis that zwitterionic interactions dominate solution dynamics. The effect of ionic liquid (IL) uptake on mechanical properties and morphology of zwitterionic copolymers was explored using 1-ethyl-3-methylimidazolium ethylsulfate (EMIm ES). Dynamic mechanical analysis and impedance spectroscopy revealed a significant change in properties above a critical uptake of ~10 wt % IL. X-ray scattering revealed a significant swelling of the ionic domains at 15 wt % IL, with a 0.3 nm-1 shift in the ionomer peak to lower scattering vector. Results indicated the water-miscible IL preferentially swelled ionic domains of zwitterionic copolymers. / Ph. D.

Frustrierte Lewis-Paare (FLPs) bestehen aus einer Lewis-Säure und -Base, die an der gegenseitigen Neutralisierung gehindert werden und so erfolgreich zur Aktivierung kleiner Moleküle eingesetzt werden konnten. Als Elektronenpaarakzeptoren wurden bislang vorwiegend Borane erforscht. Aluminiumbasierte Systeme, insbesondere intramolekularer Art, sind trotz ihrer ausgeprägten Lewis-Acidität unterrepräsentiert. In der vorliegenden Dissertation wurde untersucht, welche Syntheserouten sich zur Darstellung intramolekularer Phosphor/Aluminium-FLPs mit großer räumlicher Trennung der Lewis-Funktionen eignen und welche Reaktivität diese aufweisen. An einem Xanthenrückgrat mit Diphenylphosphineinheit konnten durch Lithiierung und Metathese Dimesityl- und Bis(pentafluorphenyl)alaneinheiten eingeführt werden und die resultierenden P/Al-FLPs sind in der Lage, Tetrahydrofuran zu öffnen. Das perfluorierte Derivat wies dabei eine zehnfach höhere Geschwindigkeitskonstante der Ringöffnungsreaktion auf. Mittels quantenchemischer Rechnungen konnte dies auf die gesteigerte Lewis-Acidität des Aluminiumzentrums zurückgeführt werden. Durch den Zinn-Aluminium-Austausch eines trimethylstannylierten Xanthenvorläufers mit Methylaluminiumverbindungen konnten P/Al-FLPs aufgebaut werden, die durch ein weiteres Äquivalent des Alanpräkursors stabilisiert werden. Die Verbindungen sind imstande, Kohlenstoffdioxid zu aktivieren, wobei die CO2-Addukte der verschiedenen Derivate mit zunehmender Anzahl elektronegativer Substituenten an den Aluminiumzentren eine zunehmende thermodynamische Stabilisierung erfahren. Die neuartige Syntheseroute konnte auch zur Darstellung eines biphenylengebundenen P/Al-FLPs genutzt werden. In diesem Fall ist das Aluminiumzentrum durch die Wechselwirkung mit dem Phosphandonor ausreichend gesättigt, um die Isolierung der gespannten Verbindungen in monomerer Form zu ermöglichen. Dennoch weist das Alan eine hohe Lewis-Acidität auf und der FLP reagiert mit CO2 und Propadien. / Frustrated Lewis pairs (FLPs) consist of a Lewis acid and base, which are prevented from neutralising each other and in turn could be successfully used to activate small molecules. Boranes have been predominantly explored as electron pair acceptors. In contrast, aluminium-based systems, in particular intramolecular ones, are underrepresented despite their pronounced Lewis acidity. The aim of the present dissertation was to fathom which synthetic route is suitable for the preparation of intramolecular phosphorus/aluminium FLPs with large spatial separation of the Lewis functions and to investigate their reactivity. On a xanthene backbone bearing a diphenylphosphine moiety, dimesityl and bis(pentafluorophenyl)alane units could be introduced by lithiation and metathesis, and the resulting P/Al-FLPs are able to open tetrahydrofuran. The perfluorinated derivative exhibited a tenfold higher rate constant of the ring opening reaction. Using quantum chemical calculations, this could be attributed to the increased Lewis acidity of the aluminium centre. Using a tin-aluminum exchange on a trimethylstannylated xanthene precursor with methylaluminium compounds, P/Al-FLPs could be constructed, which are stabilised by another equivalent of the aluminium precursor. The compounds are capable of activating carbon dioxide, and the CO2 adducts of the various derivatives become increasingly stabilised as the number of electronegative substituents at the aluminium centres increases. The novel synthetic route could also be applied for the synthesis of a P/Al-FLP on the biphenylene linker. In this case, the aluminium centre is sufficiently saturated by an interaction with the phosphane donor to permit the isolation of the strained compounds in monomeric form. Nevertheless, the alane exhibits high Lewis acidity and the FLP reacts with CO2 and propadiene.