Thesis advisor: Amir H. Hoveyda / Chapter 1. Catalytic SN2”-Selective and Enantioselective Substitution Reactions. The first broadly applicable strategy for SN2”-selective and enantioselective catalytic allylic substitution will be presented. It will be shown that transformations can be promoted by 5.0 mol% of a sulfonate-containing NHC–Cu complex (NHC = N-heterocyclic carbene), and may be carried out by the use of a commercially available allenyl–B(pin) (pin = pinacolato) or a readily accessible silyl protected propargyl–B(pin). Products bearing a 1,3 diene, a silyl allenyl or a propargyl moiety were obtained in high efficiency and selectivities. Also provided is insight regarding several of the unique mechanistic attributes of the catalytic process, obtained on the basis of kinetic isotope effect measurements and DFT studies. These investigations indicated that cationic π-allyl–Cu complexes are the likely intermediates, clarifying the role of the s-cis and s-trans conformers of the intermediate organocopper species and their impact on E:Z selectivity and enantioselectivity. It will also be shown we were able to highlight the utility of the approach by chemoselective functionalization of various product types, through which the propargyl, allenyl, or 1,3-dienyl sites within the products can be converted catalytically and chemoselectively to several synthetically useful derivatives. Chapter 2. NHC–Copper–Hydride-Catalyzed Enantioselective Processes with Allenyl Boronates and its Application in Natural Product Synthesis. Here, the development of a catalytic process that delivers otherwise difficult-to-access organoboron compound will be detailed. These processes involve the combination of a hydride, an allenyl–B(pin) and an allylic phosphate. As will be discussed, two unique selectivity problems were solved: avoiding rapid Cu–H reduction of an allylic phosphate, while promoting its addition to an allenylboronate as opposed to the commonly observed Cu–B exchange. We were able to underscore the considerable utility of the approach by applications to preparation of the linear fragment of pumiliotoxin B (myotonic, cardiotonic) and the first enantioselective synthesis of netamine C (anti-tumor), which also served to confirm its stereochemical identity. Chapter 3. Catalytic Enantioselective Prenyl Conjugate Addition Reactions. In this final section, studies leading to the development of the first class of catalytic enantioselective strategies for prenyl conjugate additions will be detailed. At the core of these investigations was finding ways to overcome two problems. One challenge originated from the fact that highly activated allylmetal species often deliver product with low enantioselectivity. The other was that regioselectivity was difficult to control owing to a strong preference for γ-selective additions. As will be described, we were able to address these difficulties by the use of a hydroxy NHC-copper complex and 3,3-dimethyl allyl–B(pin) as a reagent. In the end, we were able to use acyclic as well as cyclic enoates as substrates. The results of DFT studies that provide insight regarding varying selectivity profiles with different chiral ligands will be discussed as well. / Thesis (PhD) — Boston College, 2020. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

The first successful synthesis and isolation of a boronic acid was reported in 1860 by Frankland in the pursuit of novel organometallic compounds. For more than a century, further studies of boronic acids were sparsely published. Suzuki and Miyaura jumpstarted the field in 1979 with an innovative carbon-carbon bond forming reaction employing an organoboronic acid and a carbon halide under palladium catalysis. Indeed, the Nobel Prize in Chemistry was awarded to Professor Akira Suzuki, along with Professors Richard Heck and Ei-ichi Negishi, in 2010 for their important contributions in palladium-catalyzed cross-coupling chemistry. Over the last 30 years, reports on organoboron compounds have increased exponentially. This dissertation describes the author's contributions to the development of preparative methods for organoboronic acid derivatives using transition metal-catalyzed reactions of diboron reagents. A unique "mixed" diboron reagent was developed (PDIPA diboron) that contains sp2- and sp3-hybridized boron atoms, unambiguously confirmed by X-ray crystallography. PDIPA diboron is sufficiently activated internally through a dative-bonding amine to selectively transfer the sp2-hybridized boron regioselectively, in the presence of copper, to electron deficient alkenes including α,β-unsaturated ketones, esters, amides, aldehydes, and nitriles to provide the corresponding boratohomoenolates. A unique β,β-diboration of an α,β-acetylenic ketone was also discovered. The scope of PDIPA diboron reactions was then expanded to a set of substrates with a more complex structural backbone. Allenoates are α,β,γ-unsaturated esters with orthogonal pi systems, which pose several possible difficulties with the regioselectivity of addition, not to mention known isomerizations catalyzed by copper. However, we successfully installed the boron moiety regioselectively on the β-carbon of a variety of allenoates, providing a vinyl boronic ester, and also observed exclusive formation of the (Z)-isomer from racemic starting materials. The resulting vinyl boronic ester was then shown to be an excellent Suzuki-Miyaura cross-coupling partner, affording a diastereopure, trisubstituted alkene in quantitative yield. Commercially available bis(pinacolato)diboron has shown remarkable stability towards hydrolysis and autoxidation. Using this reagent, we developed a copper- and amine-catalyzed boration protocol performed entirely in water and open to air. Using only 1 mol% copper, extraordinary activity was observed. UV-Vis, 11B NMR, and solvent kinetic isotope experiments were employed to gain insight into the mechanism, which showed the possibility of autocatalysis. Attempts to control stereoselectivity were not successful, although these results were rationalized by a dynamic catalyst structure. / Ph. D.

The versatility of organoboron compounds has been demonstrated by their use as synthetic intermediates and more recently in therapeutic applications since the FDA approval of Velcade©. As a result, transition metal-catalyzed protocols to incorporate boron reagents into unsaturated compounds have been extensively researched. While an abundance of literature protocols have been reported, the majority utilize harsh reaction conditions in combination with expensive reagents. This dissertation discloses the author’s contributions to the development of efficient, cost-effective, and operationally simple transition metal-catalyzed borylation protocols with alkynes and diboron reagents. An open-to-air copper(II)-catalyzed aqueous borylation protocol of alkynoates and a symmetrical diboron reagent is reported. Conjugate addition of the boryl-copper species to the electrophilic β-carbon provided β-boryl-α,β-unsaturated esters in moderate to excellent yields. Exclusive (Z)-stereochemistry was confirmed by nOe experiments. The resulting vinyl boronate esters are useful cross-coupling partners. The scope of the aqueous β-borylation protocol was extended to the unsymmetrical diboron reagent, pinB-Bdan. This alternative protecting group has emerged as an orthogonal protecting group and alters the reactivity of the boron moiety. Activation of the pinacol moiety to form the Lewis acid-base adduct allowed for the chemoselective transfer of the 1,8- diaminonapthalene moiety to the β-carbon. An alternative novel synthesis of vinyl, allyl diboronate esters from propargylic alcohols has also been described. Formation of a leaving group in-situ with a palladium- and coppercatalyzed protocol can lead to several competing reaction pathways and the formation of multiple products. Fortunately, the resulting vinyl, allyl diboronate esters were stereoselectively synthesized in moderate GC yields despite significate decomposition during purification, as confirmed by stability studies. The terminal diboration of allenes was previously the only reported method for the synthesis of vinyl, allyl diboronate esters. / Ph. D.

Organoboron compounds have shown a wide variety of applications in both organic synthesis and the pharmaceutical field in the past decades. Transition metal-catalyzed boration of unsaturated compounds has been studied extensively as an efficient method to install C-B bonds. Most of the previous examples employed symmetrical diboron reagents such as B₂(pin)₂ (pin = pinacolate) and B₂(cat)₂ (cat = catecholate). There are, however, limited examples of boration using unsymmetrical diboron reagents. This dissertation discloses two transition metal-catalyzed borations of unsaturated compounds with unsymmetrical diboron compounds. A Cu-catalyzed β-boration of electrophilic allenoates with a novel sp²-sp³ hybridized diboron reagent (PDIPA) is described. This unsymmetrical diboron reagent is preactivated and allows the boration to go smoothly under mild reaction conditions. The reaction provides β-borylated β,γ- unsaturated esters with exclusive (Z)-double bond geometry. These borylated products are useful intermediates for subsequent Suzuki-Miyaura cross-coupling reaction. In order to install two C-B bonds in one reaction, a Pt-catalyzed diboration of allenes with a differentially protected diboron reagent (PDAN) is presented. This unsymmetrical diboron reagent is prepared from the sp²-sp³ hybridized diboron compound, and it reacts with a series of 1,1- disubstituted allenes chemo- and regioselectively. Steric control ensures that both boryl moieties add to the terminal double bond, and the pinacol boronate preferentially attaches to the sp-hybridized carbon. The bis-boronyl products can be further converted to other functional groups as well as cross-coupling reactions. A collaborative project with Department of Physics and Department of Chemical Engineering is also discussed. In this project, a series of 𝑜-nitrobenzyl ligands containing a disulfide group as the anchor to gold surfaces are synthesized. The 𝑜-nitrobenzyl group uncages an amine upon photoexcitation. Attempts to make a water soluble analog failed, however, the mixture of methanol and water as the solvent was sufficient to attach them on gold surfaces. / Ph. D.

Our research seeks new methods for functionalizing organic small molecules using organoboronic derivatives as a versatile handle for late-stage manipulations. Metal-catalyzed formation of new carbon-boron bonds and their subsequent transformations are highlighted. Among the myriad of unsaturated substrates for conducting borylation reactions, allenes have received minimal attention. These substrates are uniquely advantageous given that diboration results in the formation of both allylic and vinylic boronates. Orthogonal reactivity of the sp2 and the sp3 C-B bonds can allow for chemoselective transformations. However, oxidation of the carbon-boron bond is one example in which the conditions are unselective. To address this shortcoming, a platinum catalyst was developed for the diboration of 1,1-diaryl allenes with a differentially protected diboron reagent, pinB-Bdan. The reaction proceeds regioselectively in high yields to furnish olefins bearing a vinylic Bpin and an allylic Bdan moiety. The subsequent chemoselective transformation of each boron center was demonstrated. Methods for preparing 1,8-diaminonaphthalene protected vinylboronates conjugated to carbonyl groups are severely limited. A simple and efficient protocol was developed for carrying out an environmentally friendly copper(II)-catalyzed beta-borylation of alkynoates and alkynamides in water and open-to-air. Following the discriminative activation of the more Lewis acidic pinacol protected boron center in pinB-Bdan, a regio-, stereo- and chemoselective beta-borylation of acetylenic substrates delivers (Z)-beta-boryl enoates and primary, secondary, and tertiary enamides under very mild conditions. As an inexpensive and earth abundant metal, catalysts based on copper are highly desirable. An international collaborative project to develop a copper-catalyzed cross-coupling reaction of beta-boryl carbonyl compounds was explored. Preliminary results found these substrates to be either unstable towards or unreactive under the reactions conditions screened. / Ph. D.

<p>Multifunctional enzymes have alternative functions or activities, known as “moonlighting” or “promiscuous”, which are often hidden behind a native enzyme activity and therefore only visible under special environmental conditions. In this thesis, the active-site of Pseudozyma (formerly Candida) antarctica lipase B was explored for a promiscuous conjugate addition activity. Pseudozyma antarctica lipase B is a lipase industrially used for hydrolysis or transacylation reactions. This enzyme contains a catalytic triad, Ser105-His224-Asp187, where a nucleophilic attack from Ser105 on carboxylic acid/ester substrates cause the formation of an acyl enzyme. For conjugate addition activity in Pseudozyma antarctica lipase B, replacement of Ser105 was assumed necessary to prevent competing hemiacetal formation. However, experiments revealed conjugate addition activity in both wild-type enzyme and the Ser105Ala variant. Enzyme-catalyzed conjugate additions were performed by adding sec-amine, thiols or 1,3-dicarbonyl compounds to various α,β-unsaturated carbonyl compounds in both water or organic solvent. The reactions followed Michaelis-Menten kinetics and the native ping pong bi bi reaction mechanism of Pseudozyma antarctica lipase B for hydrolysis/transacylation was rerouted to a novel ordered bi uni reaction mechanism for conjugate addition (Paper I, II, III). The lipase hydrolysis activity was suppressed more than 1000 times by the replacement of the nucleophilic Ser105 to Ala (Paper III).</p>

This thesis is concerned with the asymmetric conjugate addition reactions of a range of chiral nucloeophiles. Chapter 1 introduces the conjugate addition reaction as a valuable carbon-carbon and carbon-heteroatom bond forming reaction in organic chemistry, and explores the asymmet- ric conjugate addition of a range of chiral and achiral carbon and nitrogen nucleophiles to a range of acceptors. Chapter 2 explores the use of the N-benzyl-N-(α-methylbenzyl)amino group as a chi- ral auxiliary, by employing the attempted conjugate additions of both N-benzyl-N-(α- methylbenzyl)hydrazine and N -benzyl-N -(α-methylbenzyl)hydroxylamine as chiral ammo- nia and water equivalents respectively. Chapter 3 describes the asymmetric and stereoselective preparation of a range of 4,4- disubstituted isoxazolidin-5-ones from the conjugate addition of lithium (S)-N-tert-butyl- dimethylsilyloxy-N -(α-methylbenzyl)amide. The isoxazolidin-5-ones are then globally de- protected via hydrogenolysis, giving rise to the corresponding β^2,2,3-amino acids. Chapter 4 focuses on the development of a protocol to effect the conjugate addition of a chiral aniline equivalent. The scope of the reaction is delineated by varying both the nu- cleophile and the α,β-unsaturated ester. Finally, cyclisation of the β-N-arylamino esters to the corresponding tetrahydroquinolines is explored, and an application to the synthesis of the natural product (−)-angustureine is presented. Chapter 5 contains full experimental procedures and characterisation data for all com- pounds synthesised in Chapters 2, 3 and 4.

<p>Medium-sized cyclic ethers are challenging synthetic targets due to enthalpic and entropic barriers. Methods for the stereoselective synthesis of &#945;,&#945;&#900;-disubstituted medium-sized cyclic ethers began to appear with the discovery of naturally-occurring, ladder-shaped polycyclic ethers, such as brevetoxin B, and monocyclic ethers, such as (+)-laurencin. Despite the progress made in this field, limitations remain including competing formation of smaller ring sizes and scarcity of catalytic methods. Our aim has been to develop stereoselective syntheses for 7- and 8-membered cyclic ethers which have potential for application in natural product synthesis. The C-O bond disconnection was selected for the methods described within because cyclization and stereoinduction could be achieved simultaneously. In the case of 7-membered cyclic ethers, an organocatalytic oxa-conjugate addition reaction promoted by the gem-disubstituent (Thorpe&#8722;Ingold) effect has been developed to stereoselectively provide &#945;,&#945;&#8242;-trans-oxepanes. A gold(I)-catalyzed alkoxylation reaction has also allowed access to &#945;,&#945;&#8242;-cis-oxocenes. This method has been probed for feasibility in the stereoselective synthesis of (+)-intricenyne, an 8-membered cyclic ether belonging to the C15 nonterpenoid acetogenin natural product class. These methods have the potential to become general and efficient routes to highly functionalized oxepanes and oxocenes.</p> / Dissertation

Thesis advisor: Amir H. Hoveyda / Chapter 1 Enantioselective Conjugate Additions of Carbon Nucleophiles to Activated Olefins: Preparation of Enantioenriched Compounds Containing All-Carbon Quaternary Stereogenic Centers. Methods for enantioselective conjugate addition of nucleophiles to activated olefins generating products containing all-carbon quaternary stereogenic centers are critically reviewed. Enantioselective conjugate addition has been shown to be a powerful and concise approach to construct carbon-carbon bonds to prepare compounds containing sterically hindered stereogenic centers and has seen great advances in the past several years. Owing to the difficult nature of additions to relatively unreactive conjugate acceptors, compared to additions generating tertiary stereogenic centers, and construction of a sterically-hindered bond, in many cases, new and active catalysts had to be developed. The review discusses the areas where significant advances have been made as well as current limitations and future outlook. Chapter 2 Development of New and Active Catalysts for Cu-Catalyzed Enantioselective Conjugate Addition of Alkyl- and Arylzinc Reagent. Through development of new chiral catalysts, we have found an active and enantiodiscriminating bidentate, sulfonate-containing NHC-Cu catalyst that effects enantioselective conjugate addition of alkyl- and arylzinc reagents on notoriously difficult trisubstituted cyclic enones. Products are prepared with high levels of selectivity and participate in a variety of further functionalizations. The enantioselective additions are efficient and practical, not requiring rigorously anhydrous or oxygen-free conditions. Chapter 3 Cu-Catalyzed Enantioselective Conjugate Addition of Alkyl- and Arylaluminum Reagents to Trisubstituted Enones. Outlined in this chapter is the first effective solution for Cu-catalyzed enantioselective addition of alkyl and aryl nucleophiles to trisubstituted cyclopentenones generating products bearing a &beta;-all-carbon quaternary stereogenic center. Products are obtained in up to 97% yield and 99:1 er, only requiring 5 mol % of an in situ generated Cu-NHC catalyst. The methodology was highlighted as one of the key steps in the total synthesis of clavirolide C. Not only five-membered rings, but six- and seven-membered rings serve as proficient partners in the enantioselective process. Moreover, in cases for the enantioselective aryl addition, in situ prepared Me₂AlAr can be used without purification, filtration, or isolation, only requiring the corresponding aryl halides. The additions have also been extended to trisubstituted unsaturated lactones and chromones. Chapter 4 Cu-Catalyzed Enantioselective Conjugate Addition of Vinylaluminum Reagents to Cyclic Trisubstituted Enones. An enantioselective protocol for the formation of &beta;,&beta;-disubstituted cyclic ketones containing a synthetically versatile vinylsilane is disclosed. Enantioselective conjugate addition of in situ prepared silyl-substituted vinylaluminum reagents to &beta;,&beta;-unsaturated ketones promoted by 5 mol % of chiral Cu-NHC complexes delivers desired products with high efficiency (up to 95% yield after purification) and enantioselectivities (up to >98:<2 er). Several functionalizations utilizing the vinylsilanes, vicinal to an all-carbon quaternary stereogenic center, are shown, including an oxidative rearrangement, vinyl iodide formation and protodesilylation, accessing products not previously attainable. Furthermore, the enantioselective protocol is demonstrated as the key transformation in the total synthesis of riccardiphenol B. / Thesis (PhD) — Boston College, 2011. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Polypropionate marine natural products have emerged as a class of compounds that display a high degree of structural diversity. Specifically, metabolites such as that reported as tridachiahydropyrone (7), isolated from sacoglossan molluscs, display novel ring systems. The introductory chapter gives some background on tridachione marine natural products and outlines the isolation of metabolites from several species of sacoglossan mollusc. Chapter One also gives examples of the utility of the tandem conjugate addition-Dieckmann condensation approach being applied to the synthesis of these compounds. Chapter Two describes the development of the tandem conjugate addition-Dieckmann condensation and subsequent trans methylation approach to cyclohexenone rings. The synthetic strategy utilised chiral, functionalised cyclohexenone rings as synthons in the formation of bicyclic ring systems, so development of the carbocyclic ring formation was of vital importance to the overall strategy. Examples are given which confirm the viability of the proposed synthetic route to cyclohexenones such as 91, 92 and 104 from the reaction of [alpha,beta]-unsaturated carbonyl compounds 39 and 59 with dialkyl and dialkenyl Gilman cuprates. Chapter Three describes the incorporation of chiral cyclohexenone 117 into the bicyclic framework of model compound 105, analogous to the marine natural product reported as tridachiahydropyrone (7). The chapter explores the use of cyclohexenone precursor 43 that contained the total carbon framework of the bicyclic core of the desired pyrone. Once again, a tandem conjugate addition-cyclisation reaction was employed using a dialkyl Gilman cuprate, followed by trans methylation to give the requisite cyclohexenone synthon 117. A novel Eaton’s reagent-promoted intramolecular cyclisation of acid 122 to pyrone 123 was then effected. Subsequent O-methylation afforded [alpha]-methoxy-[beta]-methyl-[gamma]-pyrone 105 as a single enantiomer, which had the identical core structure to the natural product. The structure, including relative stereochemistry of 105, was confirmed by single crystal X-ray analysis. Chapter Four builds on the previous two chapters and describes the conjugate addition-cyclisation with a higher order Gilman cuprate derived from vinyl bromide 44, which would deliver the vinyl side-chain required for the synthesis of reported natural product 7. The same acyclic precursor 43 as used in Chapter Three was cyclised and methylated to yield yet another cyclohexenone synthon 41. A single crystal X-ray analysis of related alcohol 162 confirmed the relative stereochemistry and structure. Another novel P2O5-mediated intramolecular cyclisation was achieved to give pyrone 168 and O-methylation provided a compound with the reported structure of natural product 7 as a single enantiomer. The structure of synthetic 7 was established unequivocally through extensive NMR studies. Comparisons of spectral data confirmed that natural tridachiahydropyrone was not the same as synthetic compound 7, so revision of the assigned natural product structure is warranted. Several other analogues were also synthesised using this methodology, highlighting the versatility of the method under development.