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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

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.

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.