Recent advances in the total syntheses of oxazole-containing natural products

Amino acids, the building blocks of proteins, also serve as precursors to a wide range of other naturally occurring substances including alkaloids, antibiotics, and, the subject of this Review, heterocyclic peptides. Simple α-amino acids are converted into complex arrays of heteroaromatic rings that display interesting and potent biological activity. The thiopeptide antibiotics, with their complex molecular architectures, are wonderful examples. In this Review we show how organic chemists have developed innovative methods for the synthesis of the heterocyclic ring systems, including routes inspired by the likely biosynthetic processes, and successfully assembled such building blocks into the final target molecule by application of orthogonal protecting groups and coupling methodologies.

From amino acids to heteroaromatics--thiopeptide antibiotics, nature's heterocyclic peptides.

Thiopeptides, or thiazolyl peptides, are a relatively new family of antibiotics that already counts with more than one hundred different entities. Although they are mainly isolated from soil bacteria, during the last decade, new members have been isolated from marine samples. Far from being limited to their innate antibacterial activity, thiopeptides have been found to possess a wide range of biological properties, including anticancer, antiplasmodial, immunosuppressive, etc. In spite of their ribosomal origin, these highly posttranslationally processed peptides have posed a fascinating synthetic challenge, prompting the development of various methodologies and strategies. Regardless of their limited solubility, intensive investigations are bringing thiopeptide derivatives closer to the clinic, where they are likely to show their veritable therapeutic potential.

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Thiopeptide Antibiotics: Retrospective and Recent Advances

The ocean contains a host of macroscopic life in a great microbial soup. Unlike the terrestrial environment, an aqueous environment provides perpetual propinquity and blurs spatial distinctions. Marine organisms are under a persistent threat of infection by resident pathogenic microbes including bacteria, and in response they have engineered complex organic compounds with antibacterial activity from a diverse set of biological precursors. The diluting effect of the ocean drives the construction of potent molecules that are stable to harsh salty conditions. Members of each class of metabolite—ribosomal and non-ribosomal peptides, alkaloids, polyketides, and terpenes—have been shown to exhibit antibacterial activity. The sophistication and diversity of these metabolites points to the ingenuity and flexibility of biosynthetic processes in Nature. Compared with their terrestrial counterparts, antibacterial marine natural products have received much less attention. Thus, a concerted effort to discover new antibacterials from marine sources has the potential to contribute significantly to the treatment of the ever increasing drug-resistant infectious diseases.

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Antibacterials from the sea.

The genome of the model plant Arabidopsis thaliana encodes 13 oxidosqualene cyclases, 9 of which have been characterized by heterologous expression in yeast. Here we describe another cyclase, baruol synthase (BARS1), which makes baruol (90%) and 22 minor products (0.02−3% each). This represents as many triterpenes as have been reported for all other Arabidopsis cyclases combined. By accessing an extraordinary repertoire of mechanistic pathways, BARS1 makes numerous skeletal types and deprotonates the carbocation intermediates at 14 different sites around rings A, B, C, D, and E. This undercurrent of structural and mechanistic diversity in a superficially accurate enzyme is incompatible with prevailing concepts of triterpene biosynthesis, which posit tight control over the mechanistic pathway through cation−π interactions, with a single proton acceptor in a hydrophobic active site. Our findings suggest that mechanistic diversity is the default for triterpene biosynthesis and that product accuracy results f...

An oxidosqualene cyclase makes numerous products by diverse mechanisms: a challenge to prevailing concepts of triterpene biosynthesis.

The structure of the antibiotic micrococcin P has been determined by 13C n.m.r. spectroscopy.

Total structure of the polythiazole-containing antibiotic micrococcin P. A 13C nuclear magnetic resonance study

Further examination of the hexane extract of the root bark of Simarouba amara (Simaroubaceae) has led to the isolation of two side chain oxygenated Δ7-tirucallol-type triterpenes in addition to the already reported compounds 4 and 5. One has been found to be identical with the known melianone 8 and the second is a new compound and has been shown to be 21,20-anhydromelianone 11. The 13C-NMR spectra of nine Δ7-tirucallol derivatives have been analysed and the data obtained have been applied to the confirmation of the structure of the new substance 11.

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21,20‐Anhydromelianone and Melianone from Simarouba amara (Simaroubaceae); Carbon‐13 NMR Spectral Analysis of Δ7‐Tirucallol‐Type Triterpenes

A stereospecific synthesis of evalose, a constituent of orthosomycin antibiotics

Synthesis of nagolose, a component of the antitumor antibiotic nogalamycin

Synthesis of labilose a component of the antibiotic labilomycin and structural revision of flambamycin by high resolution high field 13C N.M.R. spectroscopy

Rosa Rabanal

Papers

Total structure of the polythiazole-containing antibiotic micrococcin P. A 13C nuclear magnetic resonance study

21,20‐Anhydromelianone and Melianone from Simarouba amara (Simaroubaceae); Carbon‐13 NMR Spectral Analysis of Δ7‐Tirucallol‐Type Triterpenes

A stereospecific synthesis of evalose, a constituent of orthosomycin antibiotics

Synthesis of nagolose, a component of the antitumor antibiotic nogalamycin

Synthesis of labilose a component of the antibiotic labilomycin and structural revision of flambamycin by high resolution high field 13C N.M.R. spectroscopy