Thesis advisor: Marc L. Snapper / Chapter 1: Over the past 100 years, ring expansion chemistry with non-stabilized diazoalkanes has grown slowly. While the intrinsic hazards and stigma associated with the use of diazoalkanes has been a serious impediment to more widespread development, a number of groups have made significant advances over the years. This chapter aims to provide a brief historical account of the most significant developments related to diazoalkane- based ring expansion methods. Chapter 2: The construction of stereogenic centers adjacent to ketones remains a challenging synthetic problem for chemists. Deficiencies with regard to reaction scope, efficiency, and generality remain. In contrast to the majority of other methods in the literature, stereoselective insertion of diazoalkanes provides a pathway to directly access enantiomerically enriched α-substituted cycloalkanones. In this chapter, an account of how we developed the first catalytic asymmetric diazoalkane-based ring expansion reactions is presented. Ring expansion of unfunctionalized cycloalkanones with diazoalkanes efficiently affords α-aryl substituted cycloalkanones with high enantiopurity. Additionally, this work led to the synthesis of new chiral bis(oxazoline) ligands and the discovery of a rapid method to assay the concentration of diazoalkane solutions. Chapter 3: Single-carbon ring expansion is a powerful synthetic disconnection, allowing chemists to construct or purchase the lower homologue of a ring system before expanding to the target ring size. Starting from a smaller ring size can often allow access to a broader array of transformations that proceed with greater stereoselection. In our approach to a class of natural products bearing a cis-decalin core, we successfully implemented a catalytic regioselective single-carbon ring expansion reaction in the context of an advanced synthetic intermediate. This chapter describes the experimental details behind the first catalytic single carbon cyclopentanone homologations and how we extended the method to more complex substrates. Chapter 4: Catalytic activation of sp2 hybridized electrophiles by nucleophilic catalysts has been studied extensively and proceeds through a well-defined mechanistic pathway. In constrast, activation of sp3 hybridized electrophiles in a similar fashion with small-molecule organocatalysts remains an elusive endeavor for chemists. This chapter describes prelimi- nary studies towards this lofty goal and how we discovered a new class of imidazole-based catalysts. Thorough mechanistic studies with the newly discovered catalysts ultimately proved that the reactions proceeded through a pathway that does not involve electrophile activation. However, inexpensive and commercially available imidazolium salts were found to catalyze Williamson etherification reactions under mild conditions through a mechanism that involves an unusual imidazolium alkoxide ion-pair. / Thesis (PhD) — Boston College, 2013. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

L’objectif de cette thèse est d’élargir la gamme des composés issus des aziridine-2-carboxylates, obtenues par leur utilisation comme matière première pour la synthèse d’azahétérocycles ciblés diversement substitués, via des réactions d’ouvertures nucléophiles et d’expansions de cycle. La synthèse d’hétérocycles azotés fluorés originaux sera abordée à partir d’aziridines-2-carboxylates trifluorométhylées ainsi que d’aminoalcools et aminoacides trifluorométhylés enantiopures. Les aziridines-2-carboxylates trifluorométhylées dont la synthèse à déjà été décrite dans la littérature conduiront à des hétérocycles fluorés variés selon des réactions d’ouverture et d’agrandissement de cycles faisant intervenir les méthodologies mise au point en série non fluorée par le partenaire Tunisien. Les aminoalcools et aminoacides trifluorométhylés conduiront également à des hétérocycles de type oxazolidinones. Les nouveaux hétérocycles synthétisés trouveront des applications en tant qu’unités pseudo-peptidiques utiles en chimie des peptides. / Our purpose in this thesis is to widen the range of compounds from aziridine-2-carboxylate, which obtained by its use as a feedstock for the synthesis of new hétérocycles through nucleophilic reactions openings and expansions cycle.The synthesis of fluorinated heterocycles will be approached from aziridine-2-carboxylate trifluorométhylées and amino alcohols and amino acids trifluoromethylated enantiopure.Fluorinated aziridines whose synthesis has already been described in the literature will lead to various fluorinated heterocycles according reactions and opening cycles of expansion methodologies involving setting the nonfluorinated series developed by the Tunisian partner.The new synthesized heterocycles find applications as chiral pseudo-peptide units useful in peptide chemistry.

This thesis is concerned with the synthesis and reactions of functionalised 3- liydroxypyridines, in particular 2-aryl- and 2-heteroary 1-3-liydroxypyridines by non- coupling methodology, from furan precursors. Chapter 1 reviews the synthesis and reactions of 3-hydroxypyridines. Chapter 2 describes the synthesis of 2-acylfurans via differing methods, which include acylation of the furan nucleus, Grignard reactions of furaldehydes and, most notably, reaction of lithiofurans with reagents containing a nitrile component. Chapter 3 concerns reaction of acylfurans with ammonia at high pressure and temperature to produce 3-hydroxypyridines. We have found that this ring expansion is able to withstand many differing substituents including bromine. Further development of the pyridine ring system involves reaction of the ring atoms or substituents, including protection of the hydroxy group. This ring expansion was used in the development of a novel azabenzotriazole starting from a simple furan compound, and this is reported in Chapter 4.The methodology described in this thesis is versatile and has allowed access to a range of novel pyridine derivatives in synthetically useful quantities which should be of interest in many areas of organic chemistry.

La préparation d'hétérocycles azotés et/ou oxygénés constitue un domaine majeur de la chimie de synthèse. Les alcoxyamines insaturées sont d'intéressants précurseurs pour accéder à ces hétérocycles car elles contiennent à la fois un atome d'azote et un atome d'oxygène au sein de leur structure. La mise en réaction d'alcoxyamines O-insaturées en condition d'activation de liaison C-H en présence de rhodium(III), non étudiée à ce jour, nous a permis de mettre en évidence une réaction d'oxyamination menant à des hétérocycles oxygénés. Nous décrivons dans ce manuscrit le développement de cette réaction d'oxyamination intramoléculaire d'alcoxyamines O-insaturées N-tosylées, catalysée par des complexes de rhodium(III), permettant d'accéder à des tétrahydrofuranes et tétrahydropyranes aminométhylés, motifs présents au sein de composés d'intérêt biologique. Par ailleurs, nous avons développé une nouvelle méthode d'agrandissement de cycle de pyrrolidines 2-iodométhylées N-tosylées, en présence de sels d'argent, permettant d'accéder à des pipéridines fonctionnalisées en position C3 avec de bonnes sélectivités. / The preparation of nitrogen and/or oxygen containing heterocycles is a very important field of synthetic chemistry. Unsaturated alkoxyamines are interesting precursors for the synthesis of those heterocycles as they contain both nitrogen and oxygen atoms in their structure. The reaction of unsaturated alkoxyamines under C-H activation conditions in the presence of rhodium(III), which has not been studied yet, allowed us to discover an oxyamination reaction leading to oxygenated heterocycles. We describe in this manuscript the development of this rhodium(III)-catalyzed O-unsaturated N-tosylated alkoxyamine intramolecular oxyamination reaction allowing access to aminomethylated tetrahydrofuranes and tetrahydropyranes, which are found in biologically interesting compounds. Otherwise, we have developed a new silver mediated 2-iodomethylated N-tosylated pyrrolidine ring expansion reaction leading to C3-functionalized piperidines with good selectivities.

The synthesis of a novel, cage spiro-oxetane was carried out. Pentacyclo[5.4.0.0^2,6.0^3,10.0^5,9]undecane-8- one (PCUD-8-one) undergoes one-carbon homologation to a mixture of endo- and exo- PCUD-carboxaldehydes which then are converted into 8,8-bis(hydroxymethyl)PCUD. The monotosylate obtained via reaction of 8,8- bis(hydroxymethyl)PCUD with tosyl chloride(1 equivalent) reacts with sodium hydride to afford the corresponding spiro-oxetane via intramolecular Williamson reaction. Six new substituted heptacyclo[6.6.0.0^2,6.0^3,13.0^4,11. 0^5,9.0^10,14]tetradecanes (HCTD) were synthesized. These compounds will be used as substrates in a photoelectron spectroscopic study. The ring-expansion reaction of PCUD-8-one with ethyl diazoacetate in the presence of BF_3:OEt_2 was performed. The major product was converted into an alcohol, and the structure of the 3,5-dinitrobenzoate of this alcohol was elucidated by single crystal x-ray structural analysis.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第20403号 / 工博第4340号 / 新制||工||1673(附属図書館) / 京都大学大学院工学研究科高分子化学専攻 / (主査)教授 澤本 光男, 教授 中條 善樹, 教授 赤木 和夫 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

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Manganese(III) acetate mediated radical cyclisations provide a mild and powerful tool in the construction of complex bicyclic systems. This thesis focuses on the formation of a number of alkenyl substituted [3.3.0]-bicyclic γ-lactones utilising a manganese(III) acetate/copper(II) triflate induced radical cyclisation. The methodology was then applied to a short catalytic and enantioselective synthesis of (+)-aphanamol I and related natural products. Chapter 1 presents a summary of the theories and methodology which will be utilised in this work. In particular, a key focus will revolve around oxidative radical cyclisations and how manganese(III) acetate has become a vital oxidant in such areas. Chapter 2 details a catalytic and asymmetric total synthesis of (+)-aphanamol I. Following an overview of the natural product and its previous total synthesis, a racemic and asymmetric total synthesis is presented which utilises a manganese(III) acetate mediated radical cyclisation and a Claisen ring expansion as key steps. Chapter 3 reports the synthesis and subsequent cyclisation of a wide range of dienyl malonate substrates. Variation of the γ-substituent is first explored, demonstrating the effect that substituent size has on the diastereoselectivity of the cyclisation. Following this, the synthesis of [2.3.0]-,[4.3.0]- and [5.3.0]- bicyclic γ-lactones are investigated. Chapter 4 describes studies towards the total synthesis of a dolabellane natural product. Investigations into substrate synthesis which can be used in a RCM will be presented. Full experimental details and spectral data, with select NMR spectra are also provided.

Esta tese de doutorado está dividida em três partes. Na primeira parte é tratada a expansão de anéis de 1-alquenil-cicloalcanóis promovida por hidróxi(tosilóxi)iodobenzeno (HTIB), com ênfase na síntese de anéis de sete membros. A metodologia se mostrou versátil, possibilitando que diferentes compostos de anéis expandidos pudessem ser obtidos a partir de alcoóis alílicos livres e protegidos. Além disso, foi possível sintetizar uma ceto-lactona de 11 membros a partir da clivagem oxidativa de um dos compostos de anel expandido obtido anteriormente, em bom rendimento num total de quatro etapas. Na segunda parte, está discutida a ciclização de alcoóis homoalílicos promovida por HTIB e iodobenzeno diacetato (DIB) e catalisadas por iodo para obtenção de derivados tetrahidrofurânicos desfavorecidos pelas regras de Baldwin. Foi proposto um mecanismo reacional baseado em intermediários isolados da reação e em precedentes da literatura. Finalmente, na última parte é descrito um estudo do mecanismo de desproporção de DIB e HTIB em acetonitrila por espectrometria de massas de alta resolução por electrospray. Foi mostrado que para o DIB a formação de compostos de I(I) e I(V) passa por intermediários diméricos como [PhI(OH)OIPh]+, [PhI(OAc)OIPh]+, [PhI(OAc)OI(O)Ph]+ e [PhI(O)OAc]+, enquanto que para o HTIB os dímeros [PhI(OH)OIPh]+, [PhIO(OTs)IPh]+ e [PhI(OTs)OI(O)Ph]+, são as principais espécies envolvidas na desproporção. / This thesis is presented in three parts. In the first part, the ring expansion of 1-vinylcycloalkenols promoted by hydroxy(tosyloxy)iodobenzene (HTIB) is discussed. This study focused on the synthesis of seven-membered ring compounds. This reaction is versatile, because different ring expanded molecules could be obtained by slightly changing the reaction conditions. Furthermore, it was possible to synthesize an eleven-membered ring keto-lactone by oxidative cleavage in good yield, achieving a relatively complex structure in four steps. In the second part, the iodine catalysed cyclization of homoallylic alcohols promoted by HTIB and iodobenzene diacetate (DIB) is investigated. This reaction allows to obtain tetrahydrofuran derivatives disfavored by Baldwin\'s rules. A mechanism was proposed based on intermediates isolated from the cyclization and in previous data from literature. Finally, the last part describes the application of high-resolution electrospray mass spectrometry for the elucidation of the disproportionation reaction of DIB and of HTIB in acetonitrile. It is supposed that mechanism of formation of iodine(I) and iodine(V) from DIB involves dimeric intermediates like [[PhI(OH)OIPh]+, [PhI(OAc)OIPh]+, [PhI(OAc)OI(O)Ph]+ and [PhI(O)OAc]+. By the other hand, the main species involved in the disproportionation of HTIB, are the dimers [PhI(OH)OIPh]+, [PhIO(OTs)IPh]+ and [PhI(OTs)OI(O)Ph]+.

Esta tese de doutorado está dividida em três partes. Na primeira parte é tratada a expansão de anéis de 1-alquenil-cicloalcanóis promovida por hidróxi(tosilóxi)iodobenzeno (HTIB), com ênfase na síntese de anéis de sete membros. A metodologia se mostrou versátil, possibilitando que diferentes compostos de anéis expandidos pudessem ser obtidos a partir de alcoóis alílicos livres e protegidos. Além disso, foi possível sintetizar uma ceto-lactona de 11 membros a partir da clivagem oxidativa de um dos compostos de anel expandido obtido anteriormente, em bom rendimento num total de quatro etapas. Na segunda parte, está discutida a ciclização de alcoóis homoalílicos promovida por HTIB e iodobenzeno diacetato (DIB) e catalisadas por iodo para obtenção de derivados tetrahidrofurânicos desfavorecidos pelas regras de Baldwin. Foi proposto um mecanismo reacional baseado em intermediários isolados da reação e em precedentes da literatura. Finalmente, na última parte é descrito um estudo do mecanismo de desproporção de DIB e HTIB em acetonitrila por espectrometria de massas de alta resolução por electrospray. Foi mostrado que para o DIB a formação de compostos de I(I) e I(V) passa por intermediários diméricos como [PhI(OH)OIPh]+, [PhI(OAc)OIPh]+, [PhI(OAc)OI(O)Ph]+ e [PhI(O)OAc]+, enquanto que para o HTIB os dímeros [PhI(OH)OIPh]+, [PhIO(OTs)IPh]+ e [PhI(OTs)OI(O)Ph]+, são as principais espécies envolvidas na desproporção. / This thesis is presented in three parts. In the first part, the ring expansion of 1-vinylcycloalkenols promoted by hydroxy(tosyloxy)iodobenzene (HTIB) is discussed. This study focused on the synthesis of seven-membered ring compounds. This reaction is versatile, because different ring expanded molecules could be obtained by slightly changing the reaction conditions. Furthermore, it was possible to synthesize an eleven-membered ring keto-lactone by oxidative cleavage in good yield, achieving a relatively complex structure in four steps. In the second part, the iodine catalysed cyclization of homoallylic alcohols promoted by HTIB and iodobenzene diacetate (DIB) is investigated. This reaction allows to obtain tetrahydrofuran derivatives disfavored by Baldwin\'s rules. A mechanism was proposed based on intermediates isolated from the cyclization and in previous data from literature. Finally, the last part describes the application of high-resolution electrospray mass spectrometry for the elucidation of the disproportionation reaction of DIB and of HTIB in acetonitrile. It is supposed that mechanism of formation of iodine(I) and iodine(V) from DIB involves dimeric intermediates like [[PhI(OH)OIPh]+, [PhI(OAc)OIPh]+, [PhI(OAc)OI(O)Ph]+ and [PhI(O)OAc]+. By the other hand, the main species involved in the disproportionation of HTIB, are the dimers [PhI(OH)OIPh]+, [PhIO(OTs)IPh]+ and [PhI(OTs)OI(O)Ph]+.