Celogentin C and theonellamide F are a class of natural products that have potential antimitotic behavior. They both contain interesting bicyclic structures with unusual linkages within a central moiety. Celogentin C's highly functionalized tryptophan moiety has two unusual linkages, a β-substituted Leu connection to the C6 of the indole structure that makes up the left-hand ring, and a τ-N connection of the imidazole to the C2 of the indole constructing the right-hand ring. This right-hand ring connection was solved via a novel oxidative coupling procedure developed in our group and the left-hand ring was initially constructed via a radical conjugated addition of an isopropyl group. Due to stereoselective concerns, our group explored hydrogen bond donors as potential catalyst candidates. Unfortunately, there were challenges in limiting the background reaction and obtaining reproducible results. We then designed an alternative route to solve this left-hand ring connection which would have utilized MacMillan asymmetric hydrogenation and α-chlorination procedures. Further work towards a second generation synthesis of the β-Leu-(C6)Trp connection was halted with the publication of two formal syntheses of celogentin C. Theonellamide F contains a τ-L-histidino-D-alanine (τ-HAL) bridging unit that separates the left-and right-hand rings. Previous efforts in the synthesis of this natural product were hindered due to an inefficient regioselective synthesis of τ-HAL. Our proposed synthesis of τ-HAL began with commercially available L- and D-Ser methyl esters which were then chemically transformed and coupled to one another to create a bis-amino subunit. Further preparations afforded us with an important cyclic intermediate which should readily lead to the first regioselective synthesis of a τ-HAL.

Theonellamide is a bicyclic peptide isolated from a marine sponge, which shows interesting biological activity. It contains several unnatural amino acids, among which are (2S,3R)-3-hydroxyasparagine (L-erythro-β-hydroxyasparagine) (β-OHAsn) and τ-L-histindino-D-alanine (τ-HAL). Although there were previous synthetic efforts toward each of these unnatural amino acids, the efforts were not ideal due to expensive starting material, time-consuming steps, and poor regioselectivity. The presented work demonstrates an inexpensive, enantioselective synthesis of β-OHAsn, which can be completed in a matter of weeks, as well as several attempts at a novel regiospecific approach toward τ-HAL, including work on a model study.