Perophoramidine 1 is a halogenated natural product which contains two contiguous quaternary centres within its structure. In this thesis, approaches towards the synthesis of perophoramidine are described. In particular, the synthesis of the tetracyclic core structure and the formation of the quaternary centres have been examined. In Chapter 1, the natural product perophoramidine 1 is introduced and its isolation, structure and biological activity is discussed. The structurally related communesin family of natural products are also introduced before the literature published on both the biosynthesis and laboratory synthesis of perophoramidine 1, is reviewed. Finally the Westwood group's approach towards the synthesis of perophoramidine 1 is introduced with a summary of non-halogenated model system investigations previously carried out within the group being provided. Chapter 2 describes studies towards the synthesis of an appropriately halogenated indolo[2,3-b]quinoline core structure of perophoramidine 1. This then allowed methodology previously developed within the group on model system substrates to be applied to the formation of the first of the two quaternary centres required for the synthesis of perophoramidine 1. Chapter 3 describes the attempted formation of the second quaternary centre using an ester alkylation approach. After initial studies failed to generate the desired quaternary centre, non-halogenated model system studies were carried out in an attempt to develop an alternative approach. In Chapter 4, model system studies were continued with cyclic ether compounds investigated as potential intermediates towards the synthesis of perophoramidine 1. The results obtained in this chapter provided a novel route to the formation of the second quaternary centre and led to a redesigned approach towards perophoramidine 1 being developed. In Chapter 5, this redesigned approach was applied to the halogenated intermediates synthesised in Chapter 1. This led to the formation of the first halogenated intermediate synthesised within the group which contained the two contiguous quaternary centres required for the synthesis of perophoramidine 1.

This thesis describes the synthesis of novel analogs of the unique opioid receptor modulator mitragynine along with pharmacological and behavioral studies of a subset of its novel analogs. In Chapter 1, a general overview of opioid receptors and the importance of the mu opioid receptor (MOR) for the treatment of pain is provided. The rise of the opioid epidemic is discussed which brings into attention the need to develop safer opioid therapeutics for the treatment of pain. In this regard the Mitragyna indole alkaloids, isolated from kratom leaves are of great interest as they are considered to be “atypical” opioid ligands and represent novel molecular scaffolds for the development of safer opioid receptor modulators. The introductory chapter includes a brief description of the pharmacological profile of mitragynine as a prelude to the work that follows – examining unexplored positions on the alkaloid by devising new methodology and synthetic routes to synthesize novel analogs to study its structure-activity relationship (SAR) at the opioid receptors. Chapter 2 describes the development of a new synthetic method for selective functionalization of the unexplored C11 position of the MG scaffold (C6 position in indole numbering). The method takes advantage of an indole-ethylene glycol adduct as a key intermediate which can undergo subsequent iridium-catalyzed borylation at the desired position. This late-stage C(sp2)-H functionalization approach provides a practical route to novel C11-analogs of mitragynine and related scaffolds starting from the natural product, thus allowing a systematic SAR exploration of the C11 position. Chapter 3 directly builds on Chapter 2, summarizing the neuropharmacological and behavioral studies on the C11 analogs of 7-hydroxymitragynine (7OH) and mitragynine ethylene glycol (MG-EG). Through these studies we discover that the C11 position represents a key locant for fine-tuning opioid receptor signaling efficacy. We also discuss that the parent 7-hydroxymitragynine (7OH), a low efficacy agonist, is transformed to an even lower efficacy agonist by introducing a fluorine substituent at the C11 position (11-F-7OH). This is demonstrated in vitro at both mouse and human mu opioid receptors (mMOR/hMOR) and in vivo in mouse analgesia tests. Low efficacy opioid agonists are of high interest as candidates for generating safer opioid therapeutics with mitigated side effects. Thus, this section concludes with the identification 11-F-7OH as lead compound for future investigation. Chapter 4 describes our attempts towards the functionalization of another unexplored and vital position for the activity of mitragynine at the mu opioid receptor (MOR) – the ethyl group at the C20 position. This chapter illustrates our extensive efforts towards the late-stage functionalization of the ethyl group in the C20 position of mitragynine via directed C(sp3)-H activation. Various strategies including using the mitragynine ethylene glycol (MG-EG) as a bidentate ligand or manipulating the acrylate ester group on mitragynine as a directing group are discussed in the chapter. Also described are all the screened reaction conditions using palladium catalysts and various ligands starting from pyridine-based to mono-protected amino acid-based ligands. The outcomes and hypotheses for the failures of each strategy employed are also presented in the chapter. Chapter 5 describes our efforts towards the de novo synthesis of the C20 analogs, as an alternative strategy to the failed late-stage functionalization from Chapter 4. We present a strategy to synthesize the C20 analogs through a diversification strategy from a common intermediate. We further discuss the results of our efforts towards the formal synthesis of this common intermediate. The chapter concludes with a discussion of an alternate strategy for the synthesis of the C20 analogs.

This thesis describes investigations directed towards developing a novel synthetic route to the natural products perophoramidine and the communesins, with particular emphasis placed on the formation of the two vicinal all-carbon quaternary centres contained in these molecules. Chapter 1 introduces perophoramidine and the communesin group of natural products and explains how they are related to the calycanthaceous alkaloids. The isolation of perophoramidine and the communesins is outlined and their biosynthesis is discussed. Specific structural features of these natural products are highlighted before established synthetic strategies are reviewed. Chapter 1 concludes by proposing a novel synthetic route for the synthesis of perophoramidine and the communesins that involves a Claisen rearrangement in the indolo[2,3-b]quinoline system as a key step. Chapter 2 describes model studies on the proposed Claisen rearrangement in an attempt to form a quaternary centre in the indolo[2,3-b]quinoline system. These initial studies did not result in the generation of the desired quaternary centre. However, a detailed understanding of the reactions that occur leads to the design of a new model substrate. Chapter 3 describes studies on the revised model system that result in the formation of the desired quaternary centre using a Claisen rearrangement. The differences between the two systems are discussed before an investigation into the scope of the rearrangement is described. Chapter 3 concludes by describing an investigation into a protecting group strategy that would by required with this synthetic route. Chapter 4 describes investigations into the formation of the second vicinal quaternary centre using a model system. The synthetic routes investigated lead to two separate methods for the formation of the desired quaternary centre. Chapter 5 describes investigations into the effect a C-10 substituent has on the Claisen rearrangement. Additionally, an asymmetric version of the Claisen rearrangement is examined. Chapter 5 culminates in the preparation of an intermediate relevant to an asymmetric synthesis of the communesins.

Graduation date: 1995

The oxidation of simple benzene derivatives by a mutant of Pseudomonas putida, called 39-D, produces cis-arenediols (1). The diols are enantiomerically pure and can be used as synthons for the preparation of a variety of interesting compounds because of their stereochemistry and the special array of functional groups. See: Figure 1 cis -Toluenedio] (2) served as a chiral intermediate in an efficient synthesis of enone (3). which has been used to attain prostaglandin Fra and Neplanocin A. The same diol (2) was transformed into both enantiomers of a terpene synthon (4). See: Figures 2, 3, 4 Oxidative functionalization of cis-chlorobenzenediol (5) afforded intermediates suitable for transformation into L-erythrose (6), conduritol C (7), dihydroconduritol C (8) and aminoconduntol F-4 (9). See: Figures 5, 6, 7, 8 The application of this versatile synthetic protocol culminated in an approach to kifunensine (10), an important glycosidase inhibitor, which was approached according to the following retrosynthetic analysis: See: Figures 10, 11, 12, 5, 14, 13 A detailed study of the nucleophilic opening of epoxide 13 was carried out in order to better understand the parameters of the diastereoselective functionalization of arenediols. Details are provided for the oxidative functionalization of chlorobenzenediol (5), the key compound in all of the projects discussed. / Ph. D.

Abstract not available

Irradiation of a tryptamine linked through its side-chain nitrogen to an alkylidene malonate residue results in an intramolecular [2 + 2] cycloaddition to the indole 2,3-double bond. The resultant cyclobutane undergoes spontaneous retro-Mannich fission to produce a spiro[indoline-3,3-pyrrolenine] with relative configuration defined by the orientation of substituents in the transient cyclobutane. The novel tandem intramolecular photocycloaddition- retro-Mannich (TIPCARM) sequence leads to a spiropyrrolidine which is poised to undergo a second retro-Mannich fragmentation [TIPCA(RM)₂] that expels the malonate unit present in the photo substrate and generates transiently an indolenine. The indolenine undergoes rearrangement to a β-carboline which can undergo further rearrangement under oxidizing conditions to an oxindole. Three oxindole natural products, coerulescine, horsfiline and elacomine, were synthesized using this strategy. The TIPCARM strategy was extended to an approach that would encompass the Vinca alkaloids vindorosine and minovine. In this case, the TIPCARM sequence was followed by an intramolecular cyclization that provided tetracyclic ketone 5.86 containing rings A, B, C and D of vindorosine. A tetracyclic intermediate was synthesized which could also provided access to the Vinca alkaloid minovine. / Graduation date: 2012

The thesis entitled “Enantiospecific total synthesis of indole alkaloids eburnamonine, aspidospermidine, quebrachamine, henrycinols A and B and synthesis of azepino[4,5-b]indolones” is divided into three chapters. In the first chapter, a unified strategy for the enantiospecific total synthesis of monoterpene indole alkaloids (+)-eburnamonine (1), (–)-aspidospermidine (2) and (–)-quebrachamine (3) is described. The chiral pool synthesis commenced with (S)-ethyl lactate 4, which was elaborated to the allylic alcohol 5. Johnson-Claisen orthoester rearrangement of the allylic alcohol 5 furnished the key chiral building block 6 possessing a quaternary stereogenic center. Pictet-Spengler cyclization of tryptamine with the corresponding aldehydes obtained by appropriate functionalization of the chiral building block 6 and ring closing metathesis were the key reactions employed en route the total synthesis of the indole alkaloids 1–3 (Scheme 1). Scheme 1. Unified strategy for the synthesis of monoterpene indole alkaloids (+)-eburnamonine (1), (–)-aspidospermidine (2) and (–)-quebrachamine (3). The second chapter of the thesis pertains to the synthesis of azepino[4,5-b]indolones 7 via Brønsted acid mediated intramolecular cyclization of unsaturated tryptamides 8. Various ,-unsaturated acids 9 derived from different -hydroxy esters 10, were converted to the corresponding unsaturated tryptamides 8 and subjected to the optimized reaction conditions. The results of the study indicated that -substituted unsaturated secondary tryptamides derived from (S)-ethyl lactate were the most effective in undergoing an intramolecular cyclization to furnish the corresponding azepino[4,5-b]indolones 7, possessing a quaternary stereogenic center in good yields. The presence of an alkenyl moiety in the quaternary center allowed the functionalization of these compounds and was subsequently employed to access the ABCD core 11 of tronocarpine and the tetracyclic cores 12 of some iboga alkaloids. The loss of chirality in the formation of the azepino[4,5-b]indolones indicated that the reaction proceeds predominantly by an SN1 pathway. During the course of the study an interesting formation of an azonino[5,4-b]indolone 13 by a competing SN1 pathway and a tetracyclic azepino[4,5-b]indolone 14 via a cascade cyclization were noticed (Scheme 2). Scheme 2. Synthesis of azepino[4,5-b]indolones 7 possessing a quaternary stereogenic center. The first total synthesis of two new indole alkaloids, henrycinols A (15) and B (16) which were isolated from the plant Melodinus henryi CRAIB is described in the third chapter of the thesis. The key reaction in the synthetic sequence is the Pictet-Spengler cyclization of L-tryptophan methyl ester 17a and the aldehyde 18 derived from D-tartaric acid which leads to the installation of all the stereogenic centers present in the natural products. Interestingly, a switch in the diastereoselectivity of the reaction was observed by varying the substituent on the amine in L-tryptophan methyl ester 17. When L-tryptophan methyl ester 17b possessing an N-allyl substitution was employed, the desired 1,3-trans tetrahydro--carboline 19b could be obtained in good yields, which was subsequently elaborated to the natural products 15 and 16 (Scheme 3). Scheme 3. Total synthesis of henrycinols A (15) and B (16).

SIRT1 and SIRT2 are two NAD⁺-dependent deacetylases which negatively modulate the activity of p53, a protein which is involved in cell cycle arrest, senescence and apoptosis following genotoxic stress. Part I of the thesis describes the exploration of the chemical space around a reported unselective and modest inhibitor of SIRT1 and SIRT2 with the aim of improving the selectivity and potency of the inhibitor against the two isoforms. Particular emphasis is placed upon understanding the mode of binding of the novel analogues within the active site of the enzymes. Chapter 1 reviews the physiological roles of class III NAD⁺-dependent deacetylases, also known as sirtuins. In particular, the application of SIRT1 and SIRT2 inhibitors as potential anticancer agents is described. Amongst these, only cambinol and the tenovins showed in vivo activity in a mouse xenograft model. Previously only one analogue of cambinol had been reported in the literature. Chapter 2 describes the development of a small collection of novel cambinol analogues (First Generation Studies). The role played by different substituents at the phenyl group and at the N-1 of the thiouracil core is discussed. Along with the synthesis and structure activity relationship (SAR) associated with the core structure, in-cell experiments intended to confirm the activity of the most active compounds are reported. Chapter 3 provides a rationalisation for the SAR discussed in Chapter 2. Based on computational molecular modelling studies (GOLD), the activity of the most potent and selective SIRT2 inhibitors is explained. Two series of novel cambinol analogues were designed (Second and Third Generation Analogues) in order to assess further the proposed binding mode. Chapter 4 focuses on the development of the “Second Generation” analogues, characterised by the presence of lipophilic substituents at the sulfur atom and at the N-3 position of the thiouracil core. The synthesis, biological evaluation and SAR are discussed in detail. Chapter 5 reports the development of the “Third Generation” analogues, characterised by either a benzyl group or para-alkoxy-substituted benzyl group at the N-1 position of cambinol. Once again, the synthesis, biological evaluation and SAR data are presented. An improved understanding of the mode of binding of the novel compounds is proposed based on molecular dynamics (MD) studies. Indole-based alkaloids, such as Vincristine and Vinblastine, are well known for their anticancer activity. Recently, the anticancer activity of members of the calycanthaceous family of alkaloids has been discovered. Part II of the thesis focuses on model studies aimed at developing the total synthesis of one of these compounds, perophoramidine. Chapter 7 provides an overview of the calycanthaceous alkaloid family of natural products, including their biological properties. The structural features of perophoramidine, along with the previously reported synthetic studies are outlined. Chapter 8 describes the synthesis of an advanced intermediate in the total synthesis of dehaloperophoramidine, a structural analogue of perophoramidine Problems encountered, optimisation studies and the synthesis of a re-designed intermediate are also reported in this chapter.