Polypropionates represent a large family of natural products and several strategies have been developed for their synthesis. The aldol reaction is one of the most important tools for the construction of polypropionate natural products. The Ward group has developed an approach to polypropionate natural products based on sequential aldol reactions of thiopyran building blocks. The Thiopyran Route to Polypropionates (TR2P) involves the stepwise aldol reactions of 15 and 16 to rapidly access stereochemically complex tetrapropionate and hexapropionate synthons in a few steps. The current work describes the effort to prepare enantioenriched 17-AA and/or 17-SA through chiral transition metal based Lewis acids (176) and chiral organocatalysts (48, 179) with chelating Lewis acids. The preparation of non-Felkin tetrapropionate and hexapropionate synthons through the use of a weak base in conjunction with a Lewis acid was developed.

Polypropionates represent a large family of natural products and several strategies have been developed for their synthesis. The aldol reaction is one of the most important tools for the construction of polypropionate natural products. The Ward group has developed an approach to polypropionate natural products based on sequential aldol reactions of thiopyran building blocks. The Thiopyran Route to Polypropionates (TR2P) involves the stepwise aldol reactions of 15 and 16 to rapidly access stereochemically complex tetrapropionate and hexapropionate synthons in a few steps. The current work describes the effort to prepare enantioenriched 17-AA and/or 17-SA through chiral transition metal based Lewis acids (176) and chiral organocatalysts (48, 179) with chelating Lewis acids. The preparation of non-Felkin tetrapropionate and hexapropionate synthons through the use of a weak base in conjunction with a Lewis acid was developed.

Thesis advisor: Amir Hoveyda / Chapter 1: A review of recent iron catalyzed cross coupling advances. Abstract: Herein, advances in iron catalyzed cross coupling from 2010-2015 are thoroughly reviewed. Newly developed protocols and the mechanistic work that has been conducted to gain understanding of these systems are discussed. Specific emphasis is placed on the techniques used for mechanistic investigations. Chapter 2: Cross coupling applications of pyridyl(diimine) iron complexes. Abstract: Versatile and redox noninnocent pyridyl(diimine) iron complexes were explored for catalytic ability in iron catalyzed cross coupling reactions. These complexes were found active for the coupling of benzyl halides and aryl Grignard reagents, producing moderate yields. Although active for the coupling of cyclohexyl chloride and aryl Grignard reagents, the catalytic ability of these complexes was not general for alkyl halides, and the majority of substrates readily underwent β- hydride elimination. Mechanistic studies indicated the role of PDIFe(I)Ph and PDIFe(0)(N2)2 as offcycle species. Additionally, these complexes were employed for the Suzuki-type coupling of alkyl halides with 1,1-bis(boronates), leading to the conclusion that the processes were instead base catalyzed. Chapter 3: Electronic structure analysis and catalytic applications of carbeno(diamidine) iron complexes. Abstract: Iron(II) pincer complexes carbeno(diamidine) iron dibromide [(CDA)FeBr2] and bis(N-heterocyclic carbene)pyridine iron dibromide [(CNC)FeBr2] were examined by magnetic circular dichroism and density functional theory studies to invesitgate the effect that NHC moieties have on electronic structure and bonding in tridentate pincer ligands. The increased Fe-C bonding and pincer-donating abilities that result from NHC incorporation have a direct impact on spin state and observed ligand fields. Additionally, the position of the NHC moiety on the tridentate ligand and the overall geometry of the molecule were found to effect the net donor ability of the pincers and the strength of the iron-pincer interactions. Three new variations of the CDA ligand were developed and evaluated for catalytic ability in olefin hydrogenation and atom transfer radical polymerization reactions. While iron CDA complexes were found to be mediocre catalysts for both transformations, a cobalt CDA dimer complex was developed that showed promising catalytic activity for olefin hydrogenation. Chapter 4: The direct functionalization of lactide. Abstract: In an effort to provide cyclic diesters that could generate useful and biodegradable polymers, the direct functionalization of lactide was pursued. Lactide undergoes ring opening under a wide range of conditions, and thus traditional methods used for the functionalization of lactones could not be employed here. Typical routes for the formation of cyclic diesters involve multi-step syntheses and low yielding cyclization reactions. Herein, C-H activation and soft enolization have been identified as promising avenues toward the direct functionalization of lactide. Palladium catalyzed C-H activation was not amenable for lactide, however, soft enolization techniques led to low yields of the desired functionalized product. / Thesis (MS) — Boston College, 2017. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

<p>Carbon–carbon bond-forming reactions comprise the most important class of synthetic transformations. The development of improved and simplified approaches to these reactions will make important and useful contributions not only to the field of synthetic organic chemistry, but also to the many other areas of science that rely on it. Enolate based carbon–carbon bond formation is fundamental to synthetic organic chemistry and has provided the foundation for advancement to its present state. Herein, an important aspect of enolate chemistry is explored: the development of direct methods for carbon–carbon bond formation based on soft enolization of thioesters. Both metal-mediated and organocatalytic approaches to soft enolization are described.</p><p>MgBr₂·OEt₂-promoted soft enolization conditions were developed and successfully applied to the aldol addition and Mannich reactions, resulting in a mild and efficient direct reaction that is inexpensive and can be used under atmospheric conditions. A conjugate addition approach to chemoselective deprotonation was also explored and applied to the aldol. In addition, the first organocatalytic Mannich reaction based on proximity-accelerated intramolecular soft enolization of thioesters was developed. Given the advantages of soft enolization, including the inherent operational simplicity, and the accessibility of thioesters, we expect these methods to meet with wide application.</p> / Dissertation

<p>Three methodology studies and two total synthesis endeavors are presented. First, a study of Lewis acid and hydrogen bond mediated soft enolization of thioesters and their addition to imines in the Mannich reaction is reported. MgBr2*OEt2 and Hunig's base are used in concert with bulky thioesters and aromatic aldehydes to generate syn-b-aminothioesters with moderate diastereoselectivity and yield. Next, a biomimetic organocatalytic Mannich reaction is presented using a chiral cinchona alkaloid to effect the enantioselective addition of an imines to thioesters with high yield and diastereoselectivity and enantioselectivities up to 88:12.</p><p>The direct addition of enolizable aldehydes to a-iodo thioesters to produce b-hydroxy thioesters enabled by reductive soft enolization is reported. The transformation is operationally simple and efficient and has the unusual feature of giving high syn-selectivity, which is the opposite of that produced in the aldol addition with (thio)esters under conventional conditions. This method is tolerant to aldehydes and imines that contain acidic a-protons, as well as electrophiles containing other acidic protons and base-sensitive functional groups.</p><p>The development of a strategy for the asymmetric synthesis of a large portion of the polycyclic polyprenylated acyl phloroglucinols via N-amino cyclic carbamate hydrazones, and its application to the first asymmetric total synthesis of both (+)- and (-)-clusianone is discussed. The clusianones are synthesized with an er of 99:1 and their anti-HIV activity is found to be 1.53 and 1.13 &#61549;M, respectively. A library of clusianone-like compounds is synthesized and their biological activity has been probed.</p><p>Finally, efforts towards the total synthesis of brasilicardin A are reported. An appropriate model system was synthesized, and conditions were established using a pinene-based aldol reaction to synthesize the b-methoxy-a-amino ester side chain of the molecule. Next, efforts toward the synthesis of the anti-syn-anti- perhydro-phenanthrene core are discussed.</p> / Dissertation