Thesis advisor: Kian L. Tan / Scaffolding ligand, 14, was designed to direct the hydroformylation of 1,2 disubstituted alkenes, such that the aldehyde forms at the carbon distally from the directing group. The ligand has the ability to form reversible covalent bonds with the substrate and bind to the metal to achieve high conversion, regio- and diastereoselectivity of homoallylic alcohol products. / Thesis (MS) — Boston College, 2013. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

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Thesis advisor: Amir H. Hoveyda / Homoallylic alcohols and amines are commonly used building blocks for synthesis of biologically active molecules, yet a survey of the methods for their synthesis reveals a plague of limitations. Notably, the use of toxic reagents (Cr-, Mn-, and Sn-containing), precious metal catalysts (Ir- and In-based), non-ambient reaction temperatures (–78 to 140 °C), and extended reaction times (up to 240 hours), limit application on larger scale. The protection/deprotection sequences required to install directing/activating groups for reaction efficiency and enantioselectivity not only add synthetic steps but the conditions required for removal of such entities are not amenable to more complex and sensitive molecules. The development of catalytic enantioselective methods for addition of allyl moieties to readily available substrates including halomethyl ketones, trifluoromethyl-substituted ketimines, and nitriles have been developed. In the first two cases, an aminophenol-based boryl catalyst is utilized for enantioselective additions of allyl moieties through transition states controlled by either electrostatic attraction between a C–X bond and the catalyst’s ammonium moiety or minimization of steric and dipolar repulsion. In the latter, multicomponent additions to nitriles have been developed for synthesis of cyclic amines. In all cases, application is demonstrated through synthesis of otherwise difficult-to-access derivatives or biologically active molecules. / Thesis (PhD) — Boston College, 2020. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Amir H. Hoveyda / A previously developed catalytic system which can catalyze a variety of efficient and enantioselective allyl additions has been expanded to include regio-, diastereo-, Z-, and enantioselective crotyl addition reactions. As discussed in Chapter 1, we were able to carry out efficient crotyl additions to N-phosphinoyl imines by discovering a sufficiently Lewis acidic co-catalyst, zinc(II) methoxide. This finding enabled us to vastly improve reaction efficiency, in addition to enabling a 1,3-borotropic shift during the course of the reaction, turning a previously α selective transformation into a γ-selective one. These findings allowed us to develop a catalytic, enantioselective crotyl addition to N-phosphinoyl imines utilizing the commercially available Z-crotyl–B(pin). When the reaction conditions elucidated for crotyl additions to imines were utilized on a more electrophilic substrate, such as trifluoromethyl ketones, an entirely different finding was observed (Chapter 2). We found that if direct addition is more facile than 1,3-borotropic shift the transformation will again be α-selective, furnishing a linear product, rather than the typically observed, branched crotyl addition product. This finding allowed us to establish the first broadly applicable, efficient, regio-, Z-, and enantioselective crotyl addition to trifluoromethyl ketones. We then highlighted the utility of these products by using this method in tandem with Z-selective olefin metathesis, affording complex, enantioenriched, trifluoromethyl-containing homoallylic alcohols. During the course of these studies, and through density functional theory computations, we learned that Z- and E-crotyl–B(pin) react through distinct transition states to form the same Z-olefin-containing product with varying levels of enantioselectivity. These findings led us to the results reported in Chapter 3, the first examples of enantioselective aminophenol-promoted allyl additions to aldehydes. We were able to utilize Z-CF3-allyl–B(pin) and Z-Cl-allyl–B(pin) (both accessed through catalytic olefin metathesis) in Z- and enantioselective additions to aldehydes, affording products which cannot be accessed readily through previously reported methods. We quickly realized the potential of Z-chloro-substituted homoallylic alcohols for the synthesis of Z-homoallylic alcohols, to demonstrate this potential, we carried out the total synthesis of mycothiazole, which we accomplished in seven steps from commercially available materials and 17% overall yield, a marked improvement over the previous synthetic strategy. / Thesis (PhD) — Boston College, 2018. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

The stereochemical course of the Pd–catalyzed Suzuki-Miyaura cross-coupling of α-substituted, enantioenriched allylic boronic esters with phenyl iodide has been examined. The secondary boronic esters were prepared in both racemic and enantioenriched forms via borylationof a lithiated carbenoid with a geometrically defined vinyl boronic ester. The geometric purities were determined to be >99% and the enantiomeric excesses of stereodefined secondary boronic esters were found to exceed 98:2. In total, 8 allylic boronic esters were successfully cross-coupled, providing arylated products with high regioselectivities (>90:10) and complete enantiospecificities (>99%). The cross-coupling of a sterically and electronically unbiased, deuterated substrate confirmed that fully equilibrated π-allylic intermediates are not involved. Additionally, correlating the absolute configurations of the allylic boronic ester and the cross-coupling product allowed us to confirm that the transmetalation step of the reaction proceeded through a closed transition state via a syn-SE’ mechanism, which further suggests the importance of the distinct Pd-O-B bond linkage. Further, the cross-coupling of vinyl iodides to secondary boronic esters was investigated. / Thesis (Master, Chemistry) -- Queen's University, 2013-11-12 19:05:19.488

Alginates are (1and4) linked linear copolysaccharides composed of B-D-mannuronic acid (M) and its C-5 epimer, a-L-guluronic acid (G). Several strategies to synthesize organically modified alginate derivatives have been reported, but almost all chemistries are performed in either aqueous or aqueous-organic media. The ability to react alginates homogeneously in organic solvents would open up access to a wide range of new chemistries and derivatives. However, past attempts have been restricted by the absence of methods for alginate dissolution in organic media. We therefore report a strategy to solubilize tetrabutylammonium (TBA) salts of alginic acid in polar aprotic solvents containing tetrabutylammonium fluoride (TBAF). Acylation of TBA-alginate was performed in DMSO/TBAF to get products with DSacetyl up to ~ 1.0. We further report that by using appropriate solvent conditions, placement of acyl groups can be controlled to achieve either random or M-selective substitution. Alginate acetates synthesized in an M-selective fashion were used to study the ability of these derivatives to form Ca-crosslinked hydrogels. Detailed structure-property analyses were performed to identify acetylation reaction conditions and product properties that may be ideal for hydrogel formation. Furthermore, alginate esters were synthesized via modification of carboxylate groups on the backbone. These derivatives dissolved in polar aprotic solvents without the need to add TBAF. A proof of concept study showed their utility in the solubility enhancement of the poorly water soluble flavonoid naringenin. / Ph. D.

The addition of allyl magnesium and allyl indium reagents to a key TBS protected norbornenyl building block, synthesised in 6-steps from commercially available 1,1-dimethoxy-2,3,4,5-tetrachlorocyclo-pentadiene, has been achieved providing the syn addition products with high diastereoselectivity. The subsequent exposure of the addition products to metathesis conditions, in the presence of ethylene, then provided cis fused [3.0.3]-carbocycles with very high regioselectivity, via a Ring Rearrangement Metathesis (RRM) transformation. The high level of regioselectivity is due to the rearrangement of the metathesis intermediates to give the more thermodynamically stable product This work has been expanded to include [2.2.2]-bicycles, addition of allyl magnesium and indium reagents to a key bicyclo[2.2.2]oct-5-en-2-one has been achieved, giving both diastereoisomers, separable by chromatography. The subsequent exposure of the addition products to optimised metathesis conditions, then provided cis fused [3.3.1] carbocycles with very high regioselectivity, via a RRM transformation. It was found that two possible cyclisation pathways occur under our reaction conditions; pathway (a) will yield a cis-fused [4.0.3]-carbocycle while pathway (b) will deliver the observed [3.3.1]-carbocycle.

The electron rich and aromatic character of the indole group allows for a wide range of oxidative and substitution reactions, creating a versatile platform for generating structurally diverse molecules. This thesis explores enzyme and synthetic chemistries that act upon indoles and related molecules. Chapter 1 describes the results of in vivo studies of RebC, an enzyme that plays a pivotal role in the biosynthesis of the indolocarbazole alkaloid rebeccamycin. A homologous enzyme, StaC, exists in the biosynthetic pathway for staurosporine, a related indolocarbazole. Structural differences between the RebC and StaC active sites were hypothesized to play a pivotal role in determining the oxidation state in the corresponding natural products. Sequence alignment of RebC and StaC with homologous enzymes from related indolocarbazole biosynthetic pathways revealed six non-conserved residues in the active site. Three RebC variants were generated by replacement of all six, four, or two specific residues with their StaC counterparts. It was demonstrated that only two substitutions, F216V and R239N, are required to convert the specificity of RebC to that of StaC. Analysis of the structure of the RebC bound to a putative reaction intermediate supports the importance of F216 and R239 in catalysis. Based on these results, contrasting mechanisms for RebC and StaC are proposed to account for their differing specificities. Chapter 2 describes a synthetic approach to primarily heterocyclic analogues of lycogarubin C. Suzuki coupling of appropriately functionalized 3,4-dibromopyrrole or 3,4-bis(trifluoromethanesulfonyl)pyrrole was effective for numerous π-excessive five-membered heterocyclic-3-boronic acids. The optimized conditions were less effective for cross-couplings involving heteroaromatic-2-boronic acids, π-deficient heteroaromatic boronic acids, and heteroaromatic boropinacolate esters. Oxidative cyclization of the 3,4-bis(thiophen-3-yl)pyrrole and 3,4-bis(benzothiophen-3-yl)pyrrole to give analogues of the corresponding indolocarbazoles was demonstrated. Chapter 3 describes preliminary results on the development of regioselective C-5 and C-7 indole metalation tactics of indole-6-carboxamides, in order to provide new functionalized indoles. The use of an indole C-2 silicon protection strategy in combination with a sterically bulky C-6 N,N-di-isopropyl carboxamide directed metalation group overcame undesired side reactions observed with the analogous N,N-diethyl indole-6-carboxamide, affording the C-5 and C-7 substituted products in 40% and 13% yields, respectively. / Thesis (Ph.D, Chemistry) -- Queen's University, 2013-02-13 11:14:49.599

Thesis advisor: Shih-Yuan Liu / Described herein are three projects that derive from in-depth studies of the distinct electronic structure of monocyclic 1,2-dihydro-1,2-azaborine (heretofore referred to as simply 1,2-azaborine). In the first chapter, the first comprehensive review of the late-stage functionalization methods available for 1,2-azaborines as well as their bicyclic and polycyclic (BN-PAH) counterparts is presented. In the second chapter, the development of a general method for both C4 and C5 functionalization based on the building block approach is described. The distinct electronic structure of 1,2-azaborine enables the chemical separation and further functionalization of C4 and C5 borylated isomers. In the second part, the C4, C5, and C6 isomers of BN-styrene analogues were prepared using the newly developed azaborine building blocks. The corresponding polymers were synthesized and extensively characterized in order to compare the effects of the BN-bond positioning relative to the polymer chain. In the fourth and final chapter, 1,2-azaborine-containing phosphine ligands featuring a P-B bond are synthesized. A comparative electronic structure analysis is performed between the BN-phosphine ligands and their direct all-carbon counterparts. / Thesis (PhD) — Boston College, 2019. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.