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 pyrrole-imidazole alkaloid family of natural products illustrates the diversity of topographically unique molecules with potent biological activities that can be found in the marine environment. Thus, great interest for this class of compounds has developed leading to new synthetic methodologies and tactics to build these complex secondary metabolites. The overall objectives of this research project include the total synthesis of the phakellins and phakellstatins. First, we revisited the strategy developed in our group for the total synthesis of (+)-dibromophakellstatin and utilized it for the synthesis of its naturally occurring enantiomer and congeners. Second, we proposed and studied a new and more concise approach to the phakellstatins and phakellins based on a key C-H insertion process developed by Du Bois. Attempts to streamline the first synthesis of (+)-dibromophakellstatin proved to be quite challenging. Shortcomings in the reproducibility of some parts of the original strategy precluded us from completing and making more efficient the synthesis of the natural enantiomer (-)-dibromophakellstatin. Fortuitously, our second generation approach though it presented itself as an efficient route to the phakellins and phakellstatins produced the undesired anti diastereomer of the key guanidine intermediate which precluded our study of the pivotal C-H insertion reaction.