Strategies to synthesize the natural product maoecrystal V have been investigated. The initial strategy involved a tandem Michael-aldol reaction to form the [2.2.2] bicyclic core of maoecrystal V. This proposed route was not successful. A modified route to maoecrystal V, inspired by studies on the aldol ring closure reactions, enabled the synthesis of a complex intermediate that allowed for the formation of the core structure. Further elaboration of this key intermediate afforded the methodology to form four of the five rings in maoecrystal V. Additionally, this key intermediate allowed for further modifications that can potentially be an entry point toward an enantioselective synthesis of maoecrystal V that intersects with the initial synthesis of the racemic compound.

Apoptolidin 1.1 was isolated in 1997 by Hayakawa and co-workers from a soil bacterium Nocardiopsis sp. during screening for specific apoptosis inducers. The primary biological test revealed that this polyketide macrolide induced apoptosis in cells transformed with the adenovirus type E1A oncognene, but not normal cells. This dissertation describes the latest studies in understanding of apoptolidin’s biological activity mechanism and previous contributions towards its total synthesis. Synthesizing apoptolidinone 1.26 by an intra-molecular Horner-Wadsworth-Emmons approach featuring a Suzuki coupling, cross metathesis and two diastereoselective aldol reactions is discussed. 15 mg apoptolidinone is prepared via our previously developed intramolecular Suzuking coupling approach. Ammocidin 3.1, which was found to induce apoptosis in Ba/F3-v12 cells in an IL- 3 free medium, is a specific apoptosis inducer discovered by Hayakawa and co-workers in 2001 from Saccharothrix sp. AJ9571. A strategy featuring Suzuki coupling, cross metathesis, Yamaguchi macrolactonization and three asymmetric aldol reactions was applied to the total synthesis of ammocidinone 3.6, the aglycone of ammocidin. The preparation of the key building blocks was discussed in the following chapter: aldehyde 3.8 (C14-C19) was synthesized via Sharpless asymmetric epoxidation; ethyl ketone 3.9’ (C20-C28) was prepared via Kobayashi and Crimmins’s asymmetric aldol methodologies; aldehyde 3.14 (C7-C13) was generated by Brown crotylation and cross metathesis.

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Several novel multicomponent assembly processes have been developed for the preparation of a diverse array of complex heterocyclic systems from relatively simple starting materials. These studies resulted in the discovery of a new quinazolone forming reaction, which was applied to the one-step synthesis of the quinazolinocarboline alkaloid rutaecarpine. Biological screening of these complex heterocycles culminated in the identification of a potent sigma-2 receptor ligand. A novel N-acyliminium ion mediated cascade reaction was employed for the concise synthesis of (±)-actinophyllic acid. The completion of the synthesis relied on the development of a reaction sequence that avoided a potentially detrimental fragmentation process. Furthermore, several anti-cancer compounds were identified through a diverted total synthesis approach. / text

Thesis advisor: Amir H. Hoveyda / A general method for the catalytic enantioselective addition of silylallenes to phosphinoyl aldimines has been developed. Reactions are promoted in the presence of 5.0 mol% of an N–heterocyclic carbene–copper complex and a silyl-protected propargyl boron reagent. The reaction is efficient, requiring only 10 minutes, highly group selective, enantioselective and products can be further functionalized. Utility is highlighted in the total synthesis of marine alkaloid (S)-(–)-cyclooroidin using our product as a key intermediate in the total synthesis. The catalytic enantioselective addition of a 1,3-butadiene has been developed using a homoallenylboron reagent. These transformations are promoted by a C1-symmetric N–heterocyclic carbene–copper complex within 4 hours. Products can be obtained with gamma selectivity to afford the diene containing product. Efforts have been expanded towards the application of our product as a key intermediate towards the total synthesis of (+)-homochelidonine. Key transformations include a highly selective 1,2-protoboration of the 1,3-diene product followed by a Pd-catalyzed intramolecular sp2-sp3 Suzuki cross coupling. The development of a general catalytic enantioselective method for the propargyl addition to trifluoroketones has been studied. Reactions are complete within 15 minutes, broadly applied to alkyl-, alkenyl, alkynyl, aryl, and heteroaryl-substituted trifluoroketones, highly enantioselective and group selective. Key findings include use of an aminophenol containing an electron-withdrawing to improve reactivity and enantioselectivities. The method can be carried out on gram scale and has been applied to a substrate which can be elaborated towards glucocorticoid agonist BI 653048. / Thesis (PhD) — Boston College, 2017. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Allylboration reactions have been thoroughly utilized in organic chemistry since it was discovered that they could add in a nucleophilic fashion to aldehydes and ketones in 1964. Modification of allylboronates and the substrates that they can react with has been the focus of many research groups over the past three decades. Recent works have made use of catalysis to promote the addition of allylboronates that are generally otherwise unreactive toward various electrophiles. Chapter 2 will discuss the discovery that Brnsted acids can catalyze the addition of unreactive 2-alkoxycarbonyl allylboronates to aldehydes and that the diastereoselectivity of the reaction is determined by the electronic nature of the aldehyde. Ketones and imines are much less reactive than aldehydes towards allylboronates due to steric and electronic factors. As a result, new conditions are often required to promote the allylboration reaction of ketones and imines. Chapter 3 will briefly discuss the challenges that ketones present as substrates for allylboration reactions and show my attempts at achieving this transformation. Chapter 4 will describe imines and their associated challenges as substrates for allylboration reactions. However, once harnessed, these substrates provide easy access to -methylene -lactones when a 2-alkoxycarbonyl allylboronate is used as the allylating reagent. The modification of important or interesting molecules by making major or minor changes to a common core structure is the basis of diversity-oriented synthesis of combinatorial libraries. -Alkylidene -lactones and -alkylidene -lactams are biologically interesting compounds present in numerous natural products. Chapter 5 will discuss how the title compounds were modified by various metal-catalyzed coupling reactions to provide a diversity-oriented combinatorial library of -lactones and -lactams. Since -lactones are prevalent in many natural products, the application of 2-alkoxycarbonyl allylboronates to a target-oriented synthesis was intriguing. Unlike diversity-oriented synthesis, target oriented synthesis aims at synthesizing a single compound through any number of controlled steps, arriving at one specific product that is obtained as a pure isomer. Access to highly complex -lactones is often tedious, however, Chapter 6 will discuss how a simple, one-step allylboration reaction of a complex aldehyde with a 2-alkoxycarbonyl allylboronate can lead to a highly substituted -lactone. This -lactone can be further modified and transformed into chinensiolide B, a biologically active natural product isolated from a plant found in various locations in China.

To address the issue of unnecessary functional group transformations in synthesis, the direct functionalization of carbon-hydrogen (C―H) bonds presents itself as an efficient and atom economical process. In particular, palladium(II)-catalyzed oxidative functionalization of arene C–H bonds were investigated to yield intermolecular and intramolecular arylations. Kinetic studies and characterization of bimetallic palladium(II) complexes led to the discovery of two other palladium(II)-catalyzed processes: arene hydroxylation and selective chlorination of anilides. Realizing the potential of biocatalysis and of transition-metal catalysis, we marriaged these two fundamentally different methods to access complex molecules in rapid and step economical ways and chose popular synthetic target, 6-deoxyerythronolide B to showcase the efficiency of these stereoselective reactions. To form the 14-membered lactone, we employed a transition-metal catalyzed ring-closing metathesis. Two different fragments were assembled via traditional and reliable aldols, oxidations and reductions, crotylations and protective group chemistry.

To address the issue of unnecessary functional group transformations in synthesis, the direct functionalization of carbon-hydrogen (C―H) bonds presents itself as an efficient and atom economical process. In particular, palladium(II)-catalyzed oxidative functionalization of arene C–H bonds were investigated to yield intermolecular and intramolecular arylations. Kinetic studies and characterization of bimetallic palladium(II) complexes led to the discovery of two other palladium(II)-catalyzed processes: arene hydroxylation and selective chlorination of anilides. Realizing the potential of biocatalysis and of transition-metal catalysis, we marriaged these two fundamentally different methods to access complex molecules in rapid and step economical ways and chose popular synthetic target, 6-deoxyerythronolide B to showcase the efficiency of these stereoselective reactions. To form the 14-membered lactone, we employed a transition-metal catalyzed ring-closing metathesis. Two different fragments were assembled via traditional and reliable aldols, oxidations and reductions, crotylations and protective group chemistry.

Marine natural products biogenetically derived from the pyrrole-imidazole oroidin (i) display fascinating structural diversity and exhibit a wide range of significant biological activities. Hence, they have attracted great interest from the synthetic community leading to the development of new synthetic methodologies and providing an admirable set of strategies and tactics to assemble the most complex representatives of this class of alkaloids. In this work, a synthesis of the potent antitumor dibromophakellstatin (ii) was devised featuring a highly diastereoselective acylation of the C2-symmetric prolyl-prolyl anhydride (iii), an intramolecular Mitsunobu reaction installing the C6 aminal and a tandem Hofmann rearrangement/cyclization that delivered the targeted imidazolidinone of the phakellstatins. Both enantiomers of phakellstatin were prepared starting from either D- or L- proline. Building on several findings made in the course of the synthesis of phakellstatin, namely the differential reactivity of the aminal centers (C6 and C9) and the formation of an oxidized phakellstatin, a second generation approach towards these deceitfully simple alkaloids was initiated. The second generation synthetic strategy towards phakellstatin (iv) and phakellin (v) utilizes a novel variation of Du Bois' C-H insertion involving a urea or a guanidine. This approach appears more amenable to the annulation of the phakellin substructure for the final stages of the synthesis of the potent immunosuppressant palau'amine (vi).

The marine diterpene (–)-stolonidiol (1) has been shown to upregulate neuronal levels of acetylcholine. The mechanism through which a small molecule can impart this allosteric-like effect is currently unknown. A laboratory preparation of the natural product was undertaken in order to produce matieral for biological testing and elucidation of the unknown mechanism of action. During the course of this study, a tandem enyne-Suzuki reaction was investigated to form both rings of the fused bi-cyclic structure 26 in a single operation, but was met with undesired diastereoselectivity in the first cyclization step. The directing effect was found to be general on 1,6-homopropargyl enynes. Further efforts toward the molecule focused on an enantioselective formation of the cyclopentane core through an extension of a copper-mediated silylcyclization of epoxyalkyne 71. Using this intermediate two routes involving acrylate as a lynchpin to close the large ring were investigated. Additionally, a route designed to employ an intramolecular Knoevenagel condensation was explored to generate this ring system. / text