Lessons and revelations from biomimetic syntheses.

Biomimetic synthesis describes the field of organic chemistry that aims to emulate the natural, biosynthetic processes toward natural products. As well as providing insight into how molecules are formed in nature, the benefits of this approach to total synthesis are numerous and extend beyond the gains typical of traditional synthesis. For example, using biosynthetic proposals to design a synthetic route can highlight alternative methods to the desired target. The pursuit of biomimetic syntheses also promotes the development of new reactions to prove or disprove a biosynthetic proposal or to unravel mechanistic implications of a proposed biosynthesis and can lead to the identification of new natural products. Here we look at some recent compelling examples and examine how biomimetic synthesis has led to the discovery of new procedures and principles that would not have been found by other approaches.

Gold-catalysed synthesis of amino acid-derived 2,5-disubstituted oxazoles.

Amino acid-derived propargylic amides are cyclised in a one-pot, Au(III)-catalysed operation to yield 5-bromomethyl oxazoles. These compounds are further elaborated to bis-heterocycles, dipeptide mimics and more.

Structure-activity studies of the pelorusides: new congeners and semi-synthetic analogues.

Two new peloruside congeners (3 and 4) were isolated from wild and aquacultured collections of the New Zealand marine sponge Mycale hentscheli. Small-scale reactions on peloruside A (1) have been performed, which along with the isolation of 3 and 4, give further insight into the bioactive pharmacophore of 1.

Molecular recognition of peloruside A by microtubules. The C24 primary alcohol is essential for biological activity.

Peloruside is a microtubule-stabilizing agent that targets the same site as laulimalide. It binds to microtubules with a 1:1 stoichiometry and with a binding affinity in the low-muM range; thereby reducing the number of microtubular protofilaments in the same way as paclitaxel. Although the binding affinity of the compound is comparable to that of the low-affinity stabilizing agent sarcodictyin, peloruside is more active in inducing microtubule assembly and is more cytotoxic to tumor cells; this suggests that the peloruside site is a more effective site for stabilizing microtubules. Acetylation of the C24 hydroxyl group results in inactive compounds. According to molecular modeling, this substitution at the C24 hydroxyl group presumably disrupts the interaction of the side chain with Arg320 in the putative binding site on alpha-tubulin. The binding epitope of peloruside on microtubules has been studied by using NMR spectroscopic techniques, and is compatible with the same binding site.

Total synthesis of (-)-saliniketals A and B.

A stereocontrolled total synthesis of the orthinine decarboxylase inhibitors saliniketals A and B is described. Key features of the 17-step route include the use of two boron aldol/reduction sequences to control six of the nine stereocenters, an intramolecular Wacker-type cyclization to install the bicyclic acetal core, and a late-stage Stille coupling to append the requisite (2 Z,4 E)-dienamide.