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We would like to acknowledge EPSRC for PhD funding through the Doctoral Training Schemes and the EPSRC National Mass Spectrometry Service Centre, Swansea for mass spectrometric analysis. The bioactive alkaloid natural product perophoramidine and the related family of compounds known as the communesins have inspired the synthesis community for more than a decade. Many of the elegant approaches have required the synthesis of complex intermediates that have not always reacted in the expected manner. In this study we describe a series of cyclic ether-containing precursors that were prepared during our synthetic studies towards these natural products. Attempts to open the cyclic ether ring and trap the resulting stabilised carbocation with a carbon nucleophile ultimately led to the preparation of a diallyl-substituted all carbon quaternary centre. Subsequent attempts to differentiate between the two allyl groups resulted in a relatively clean transformation to an unexpected compound. Extensive structural characterisation, including small molecule X-ray crystallography, showed that a dearomatisation reaction had occurred. Postprint

Chapter one discusses previous synthetic efforts toward the communesin alkaloids and perophoramidine. The chapter highlights not only new methods developed toward the communesin scaffold, but also the total syntheses of racemic and enantioenriched communesin alkaloids and perophoramidine. Chapters two, three, and four highlight our explorations of the interrupted Fischer indolization reaction. Chapter two details the development of our method to access the fused indoline scaffold, particularly the furoindoline and pyrrolidinoindoline motifs. Furthermore, this chapter discusses the formal synthesis of physovenine, the total synthesis of debromoflustramine B,and the synthesis of the communesin scaffold, as well as methods to access enantioenriched furoindolines. Chapter three discusses how the interrupted Fischer indolization reaction was used to prepare the alzheimer's therapeutic candidate (+)-phenserine (a.k.a. Posiphen), in enantioenriched form. Finally, chapter four highlights the use of the interrupted Fischer indolization in a complex setting, with studies toward the communesin alkaloids andperophoramidine.

A new concise methodology was developed for the synthesis of the two vicinal quaternary centers of the natural product perophoramidine. Key steps involved the Morita–Baylis–Hillman reaction, reductive cyclization and allylic alkylation. Moreover, most conditions are simple and convenient with good yields.

This thesis describes our efforts towards the total synthesis of natural products and the development of a newmethodology to afford a synthetically important scaffold.Chapter 2 outlines our efforts towards the total synthesis of a marine natural product, perophoramidine as wellas our completed synthesis of dehaloperophoramidine. The focus of the studies was to develop an efficient andconcise strategy to afford the natural products. We aimed at utilising the inherent structure and symmetry of thenatural product to encourage domino processes and gain access to the key features. The vicinal quaternarystereocenters were installed by employing Overman’s diastereoselective dialkylation protocol. Two new dominoprocesses were discovered. The first domino process led to the formation of the ortho-amide and carefulinvestigation of its reactivity led to the discovery of the second domino process which ultimately delivereddehaloperophoramidine. The synthesis was completed in eight steps starting from isoindigo.Chapter 3 describes our efforts towards the total synthesis of strictamine. The key features of strictamine thatneed to be addressed when pursuing the synthesis are: (i) the quaternary stereocenter, (ii) the centralcyclohexane moiety (D ring) with four stereocenters, and (iii) the cage-like methanoquinolizidine core. We aimedat accessing these key features through intramolecular Heck reaction to access the central D ring with parts ofthe substitution pattern already present and the quaternary stereocenter. For the methanoquinolizidine core, weplanned to adopt our previously described domino carbopalladation/carbonylation protocol. The synthesis is inan advanced state with two additional functionalisation left in order to access the target compound. Described inthis chapter is our effort to access the core structure of strictamine with all the rings installed.The third part of this thesis deals with the development of a new methodology to access indoline scaffolds thatfeature an all-carbon quaternary stereocenter. We were able to synthesise allyl anilines through the regio- andstereoselective ring-opening of vinyl aziridines with 2-iodoaniline. The final indoline scaffold was furnished byintramolecular Heck reaction with concomitant formation of the quaternary stereocenter.

The first copper-catalyzed intermolecular asymmetric propargylic dearomatization/annulation cascade sequence of indoles via a copper-allenylidene amphiphilic intermediate has been achieved. This protocol provides a direct asymmetric synthetic method for the preparation of tetrahydro-5H-indolo[2,3-b]quinolines, the core structure of indole alkaloids communesins A-H and perophoramidine. This method features excellent yields, high diastereoselectivity (up to >19:1 d.r.) and enantioselectivity (up to 94 % ee), mild conditions and wide substrate scope.

An efficient, unified, and stereodivergent approach toward communesin F and perophoramidine was examined. The C(3) all-carbon quaternary center of an oxindole was smoothly constructed by base-promoted indolone-malonate alkylation chemistry. The complementary relative stereochemistry of the crucial vicinal quaternary centers found in communesin F and perophoramidine was selectively installed by substrate-controlled decarboxylative allylic alkylations.

An intramolecular SmI2-mediated reductive cyclization of carbodiimides and unsaturated lactams was applied to functionalized substrates bearing tetrasubstituted olefins. The reaction afforded arylated spiro-2-iminoindolines in high yield. Although the stereochemistry of the product was different from the desired one, the optimized palladium-catalyzed aryl amidination realized the isomerization and C–N bond formation in a single step and resulted in efficient construction of pentacyclic core of perophoramidine synthetically equivalent to the Rainier's intermediate.

This account describes our efforts toward developing a stereodivergent entry to perophoramidine and the communesin alkaloids. The original approach toward our simplified model substrates relied on a palladium-catalyzed carbopalladation–carbonylation of a tetrasubstituted olefin to install the vicinal all-carbon quaternary stereocenters present in the target molecules, the olefin's stereochemistry thus dictating the relative stereochemistry of the quaternary stereocenters. Although the carbonylation–carbopalladation sequence worked well for trisubstituted olefins, only premature esterification was observed when using tetrasubstituted alkene substrates. Our second approach made use of the latent symmetry embedded in our target molecules. A Diels–Alder reaction or SmI2-mediated bis-alkylation of isoindigo was to be used to access the communesin and perophoramidine scaffolds, respectively. We found that due to unfavorable thermodynamics, it was not possible to reach the communesin scaffold. However, two new complexity-generating, cascade reactions were encountered en route to the synthesis of dehaloperophoramidine, resulting in a short and efficient synthesis.

The communesin alkaloids are a diverse family of Penicillium-derived alkaloids. Their caged-polycyclic structure and intriguing biological profiles have made these natural products attractive targets for total synthesis. Similarly, the ascidian-derived alkaloid, perophoramidine, is structurally related to the communesins and has also become a popular target for total synthesis. This review serves to summarize the many elegant approaches that have been developed to access the communesin alkaloids and perophoramidine. Likewise, strategies to access the communesin ring system are reviewed.

Expedient synthetic approaches to the highly functionalized polycyclic alkaloids communesin F and perophoramidine are described using a unified approach featuring a key decarboxylative allylic alkylation to access a crucial and highly congested 3,3-disubstituted oxindole. Described are two distinct, stereoselective alkylations that produce structures in divergent diastereomeric series possessing the critical vicinal all-carbon quaternary centers needed for each synthesis. Synthetic studies toward these challenging core structures have revealed a number of unanticipated modes of reactivity inherent to these complex alkaloid scaffolds. Finally, a previously unknown mild and efficient deprotection protocol for the o-nitrobenzyl group is disclosed – this serendipitous discovery permitted a concise endgame for the formal syntheses of both communesin F and perophoramidine. In addition, the atroposelective synthesis of PINAP ligands has been accomplished via a palladium-catalyzed C–P coupling process through dynamic kinetic resolution. These catalytic conditions allow access to a wide variety of alkoxy- and benzyloxy-substituted PINAP ligands in high enantiomeric excess. An efficient and exceptionally mild intramolecular nickel-catalyzed carbon–oxygen bond-forming reaction between vinyl halides and primary, secondary, and tertiary alcohols has been achieved. This operationally simple method allows direct access to cyclic vinyl ethers in high yields in a single step. Finally, synthetic studies toward polycyclic ineleganolide are described. The entire fragmented carbon framework has been constructed from this work. Highly (Z)-selective olefination was achieved by the method by the Ando group.

The communesin alkaloids are a diverse family of Penicillium-derived alkaloids. Their caged-polycyclic structure and intriguing biological profiles have made these natural products attractive targets for total synthesis. Similarly, the ascidian-derived alkaloid, perophoramidine, is structurally related to the communesins and has also become a popular target for total synthesis. This review serves to summarize the many elegant approaches that have been developed to access the communesin alkaloids and perophoramidine. Likewise, strategies to access the communesin ring system are reviewed.

The asymmetric key step of the new protocol is the molybdenum-catalyzed allylic alkylation of the oxindole (II) to give (III) with high enantioselectivity.

which contains vicinal quaternary centers, was established with the help of extensive 2DNMR experiments and was later validated by the total synthesis developed by Fuchs and Funk. Preliminary biological data indicated that perophoramidine is cytotoxic to HMT 116 colon carcinoma cells and is able to induce apoptosis by poly(adenosine-5’-diphosphateribose)polymerase (PARP) cleavage. Our interest in the synthetic chemistry of 2-thioindoles, combined with the novel structural features of perophoramidine and its preliminary biological data, induced us to initiate a program to target its synthesis. Described herein are our preliminary results in this area and the synthesis of ( )dehaloperophoramidine. We considered several synthetic routes to the perophoramidine skeleton, but ultimately settled upon the approach illustrated in Scheme 2. We envisioned that the intramolecular coupling between the 3-position of a 2-thioindole with a pendant electrophile would serve to generate one of the perophoramidine spiro-fused rings; the resulting thioimidate

Expedient synthetic approaches to the highly functionalized polycyclic alkaloids communesin F and perophoramidine are described using a unified approach featuring a key decarboxylative allylic alkylation to access a crucial and highly congested 3,3-disubstituted oxindole. Described are two distinct, stereoselective alkylations that produce structures in divergent diastereomeric series possessing the critical vicinal all-carbon quaternary centers needed for each synthesis. Synthetic studies toward these challenging core structures have revealed a number of unanticipated modes of reactivity inherent to these complex alkaloid scaffolds. Additionally, several novel and interesting intermediates en route to the target natural products, such as an intriguing propellane hexacyclic oxindole encountered in the communesin F sequence, are disclosed. Indeed, such unanticipated structures may prove to be convenient strategic intermediates in future syntheses.

Highly congested vicinal all-carbon quaternary stereocenters were generated via catalytic asymmetric alkylation reaction of 3-bromooxindoles with 3-substituted indoles. These catalytic reactions proceeded in excellent yields with a broad scope on either reaction partner, and with outstanding diastereo- and enantiocontrol. The newly developed method led to the total synthesis of (+)-perophoramidine in a highly efficient manner.

A concise approach toward the total synthesis of the communesin alkaloids and perophoramidine is reported. The strategy relies on the use of the interrupted Fischer indolization to build the tetracyclic indoline core of the natural products. Studies to probe the scope and limitations of this plan are presented. Although the methodology does not tolerate a C8-allyl substituent en route to the challenging vicinal quaternary stereocenters, variation at C7 and on the C ring is permitted.

Chemical investigation of the Philippine ascidian Perophora namei has resulted in the isolation of a novel polycyclic alkaloid, perophoramidine (1). The structure of 1 was determined by the interpretation of 1D/2D NMR and MS data. Dehalogenation of perophoramidine (1) by ammonium formate catalyzed transfer hydrogenation confirmed the type and number of halogen atoms present in 1.

The communesin/nomofungin/perophoramidine story is an impressive example of how biogenetic considerations can lead to the correction of structural misassignments and inspire synthetic chemists with new, fruitful ideas. Intensive studies by a number of research groups culminated in the total synthesis of perophoramidine by the Funk research group in 2004. In 2007, Qin and co-workers completed the first total synthesis of a communesin.

The communesin/nomofungin/perophoramidine story is an impressive example of how biogenetic considerations can lead to the correction of structural misassignments and inspire synthetic chemists with new, fruitful ideas. Intensive studies by a number of research groups culminated in the total synthesis of perophoramidine by the Funk research group in 2004. In 2007, Qin and co-workers completed the first total synthesis of a communesin.

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.

The development of an approach to the alkaloid communesin B (2) is presented. The approach is based on considerations of a possible biosynthetic sequence involving an oxidative coupling of tryptamine with a derivative of the ergot alkaloid aurantioclavine. Structure revision is also suggested for the recently isolated microfilament disrupting alkaloid nomofungin.

The first total synthesis of racemic perophoramidine is described. The key step features the highly stereoselective introduction of the vicinial quaternary centers via base-promoted carbon−carbon bond formation between a 3-alkylindole and a 3-bromo-3-alkylindolin-2-one. This transformation presumably proceeds through a conjugate addition or Diels−Alder cycloaddition of the 3-alkylindole with a 3-alkylindol-2-one intermediate.