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A brief history of biomimetic total synthesis is reviewed. The molecules covered in this SynPact account include tropinone (Robinson, 1917), usnic acid (Barton, 1956), progesterone (Johnson, 1971), endiandric acids (Nicolaou, 1982), methyl homosecodaphniphyllate (Heathcock, 1988), glabrescol (Corey, 2000), FR182877 (Sorensen, 2002 and Evans, 2002), and intricarene (Pattenden, 2006 and Trauner, 2006). Key biomimetic transformations of the syntheses are highlighted. Our recent biomimetic synthesis of homodimericin A is also discussed. Our study validates the key steps of the biosynthesis proposed by Clardy et al.

The biomimetic epoxide-opening cascades from squalene polyepoxides 4-6 to triterpene polyethers (oxasqualenoids) teurilene (1), glabrescol (2), and omaezakianol (3), respectively, were reproduced in a single event by chemical reaction. These cascades proceeded through the 5-exo tandem cyclization triggered by Brønsted acid-catalyzed hydrolysis of the terminal epoxide, mimicking the direct hydrolysis mechanism of epoxide hydrolases.

The structure of glabrcscol from Spathelia glabrescens Planch has been shown by spcctroscopic methods to be a meso form of 2,23-dihydroxy-2,6,10,15, 19,23-hexamethyl-3,7,11,15,19-penta(oxacyclopentyl)tetracosane.

The structure of glabrescol has been proposed and revised. Could the revised structure have been predicted without the need for total synthesis? Molecular modelling studies showed that the natural product structure proposed for glabrescol was not the most thermodynamically favourable form. When a lithium ion was incorporated, the natural product proved to be the lowest in energy of all symmetric isomers of glabrescol. Further modelling studies have led to the discovery of an asymmetric isomer lower in energy than the natural product when bound to a variety of ions.

The structure of glabrescol has been proposed and revised. Could the revised structure have been predicted without the need for total synthesis? Molecular modelling studies showed that the natural product structure proposed for glabrescol was not the most thermodynamically favourable form. When a lithium ion was incorporated, the natural product proved to be the lowest in energy of all symmetric isomers of glabrescol. Further modelling studies have led to the discovery of an asymmetric isomer lower in energy than the natural product when bound to a variety of ions.

The diastereoselective synthesis of the central 2,5-linked tristetrahydrofuran (trisTHF) 6 of naturally occurring meso polyether, glabrescol (5), has been achieved in a two-directional manner by the vanadium(V)-catalyzed anti oxidative cyclizations of diol 14. The trisTHF podand 6 and its stereoisomeric analogs 7 and 8 exhibited outstanding cation transport abilities for physiologically important Na+ and K+.