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The structure of glycyl-l-glutamyl-l-phosphoseryl-l-leucine, (C16H29N4O11P)2·3H2O is reported. The dimeric structure is characterized by an unusual absence of head-to-tail chains in connection with an extended intermolecular hydrogen bonding network. Two of the three H2O molecules included in the network are disordered. The protonation constants of the tetrapeptide were determined as log K1 = 1.50, log K2 = 3.63, log K3 = 4.32, log K4 = 6.08 and log K5 = 8.65 by potentiometric pH titration. The dimeric structure of glycyl-l-glutamyl-l-phosphoseryl-l-leucine, (C16H29N4O11P)2·3H2O is characterized by the unusual absence of head-to-tail chains in connection with an extended intermolecular hydrogen bonding network.

Peptidomimetic-based macrocycles typically have improved pharmacokinetic properties over those observed with peptide analogs. Described are the syntheses of 13 peptidomimetic derivatives that are based on active sansalvamide A structures, where these analogs incorporate heterocycles (triazoles, oxazoles, thiazoles, or pseudoprolines) along the macrocyclic backbone. The syntheses of these derivatives employ several approaches that can be applied to convert a macrocyclic peptide into its peptidomimetic counterpart. These approaches include peptide modifications to generate the alkyne and azide for click chemistry, a serine conversion into an oxazole, a Hantzsch reaction to generate the thiazole, and protected threonine to generate the pseudoproline derivatives. Furthermore, we show that two different peptidomimetic moieties, triazoles, and thiazoles, can be incorporated into the macrocyclic backbone without reducing cytotoxicity: triazole and thiazole.

Cyclic tetrapeptides have generated great interest because of their broad-ranging biological properties. In order to synthesize these highly strained 12-membered cyclic compounds, a cyclization strategy using pseudoprolines as removable turn inducers has been developed. The pseudoproline derivatives induce a cisoid amide bond in the linear peptide backbone which facilitates cyclization. After cyclization, the turn inducers can be readily removed to afford cyclic tetrapeptides containing serine or threonine residues.

The first synthesis of the naturally occurring cyclic peptide axinellin A has been achieved. Cyclization and subsequent deprotection of linear precursors containing either a t-butyl protected Thr residue or a Thr(ΨMe,Mepro) derivative gave a cyclic peptide, identical in all respects to the naturally occurring material, with the exception that the synthetic peptide does not exhibit the cytotoxic activity reported for the natural product.

[Structure: see text] A formal total synthesis of diisocyanoadociane, a marine diterpenoid with potent antimalarial properties, has been completed. The synthesis begins with a phenanthrenoid precursor that is transformed into a pyrene-derived intermediate by means of an intramolecular Michael reaction. Nitrogen functionality is introduced via a double Curtius reaction.

Publisher Summary This chapter discusses the total synthesis of the marine diterpenoid, diisocyanoadociane. A fascinating variety of approximately 80 diterpenes possessing isonitrile and related functions has been isolated from marine sponges. Three of these compounds are acyclic while the bulk of the remainder are based on one of four novel cyclic skeletons, namely kalihinane (- preamphilectane), amphilectane, cycloamphilectane, and isocycloamphilectane. Wells and coworkers isolated diisocyanoadociane as well as six other isonitriles from a marine sponge belonging to the genus Amphimedon. Subsequently, a further 12 related compounds were isolated from the marine sponge Cymbastela hooperi. Investigation of the biological activity of these compounds revealed significant antiplasmodial activity when tested in vitro against two clones of the malaria parasite Plasmodium falciparum. The activity of the compounds towards the mammalian KB cell line was also tested in order to calculate an experimental selectivity index, which indicated whether the observed antiplasmodial activity was a specific or general toxic effect. Results show that diisocyanoadociane displays antiplasmodial potency and selectivity that rivals the in vitro results obtained with some clinically-used antimalarial drugs. The combination of biological activity with the unusual perhydropyrene based structure makes diisocyanoadociane an enticing target for synthetic chemists and an elegant enantioselective synthesis based on sequential. In the final stages of their synthesis, however, the isonitrile groups were introduced without diastereochemical control.

The synthesis of alkaloid GB 13 (4), isolated from the North Australian rain forest tree Galbulimima belgraveana is described. Birch reductive alkylation of 2,5-dimethoxybenzoic acid by 3-methoxybenzyl bromide, followed by an acid-catalyzed cyclization was used to synthesize the [3.3.1]bicyclononane 12. Ring contraction performed on the diazoketone 19 followed by a Diels–Alder reaction generated a pentacyclic intermediate 34 with a carbon skeleton closely resembling the target alkaloid. The surplus nitrile substituent, required for activation and regioselectivity in the Diels–Alder reaction, was removed by treatment with lithium and liquid ammonia. Birch reduction of the aromatic ring could be performed at the same time to give diene 38 and thence enone 41, which was cleaved by means of an Eschenmoser fragmentation. The piperidine ring found in the natural product was formed by reductive cyclization of bis-oxime 49 derived from the alkynyl ketone 48 and the resulting material further elaborated to GB 13.