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.
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.
[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.
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.
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