Editor's Choice

Professor Margaret Brimble from the University of Auckland, New Zealand, chooses her favourite works published in OBC during 2007:

My selection of articles is from the 2007 issues of the journals and reflects my interest in natural products synthesis. The following five articles (in chronological order) attracted my attention.

 

My first paper by John Mann and colleagues from Queen's University Belfast in Ireland reports an elegant synthesis of the tricyclic skeleton of the acetylcholine esterase inhibitor huperzine A that is in clinical trials as a potential treatment for Alzheimer's disease. The use of a regioselective intramolecular Heck reaction under microwave conditions to effect formation of a key strategic bond was of particular interest. 

My second paper by Chris Moody and colleagues at the University of Nottingham reports the concise synthesis and biological evaluation of simplified analogues of the Hsp90 molecular chaperone inhibitor, geldanamycin. As Moody states this paper demonstrates that "de novo synthesis of simpler derivatives of complex natural products is a realistic proposition." The synthetic strategy combines use of Grubbs' ring closing metathesis to assemble the macrocycle with a Claisen rearrangement (under microwave conditions) to afford a ring-expanded ansa-lactam.

My next paper by Steve Ley and co-workers at Cambridge reports the synthesis of unnatural analogues of the potent sarco/endoplasmic reticulum Ca²⁺ ATPase (SERCA) inhibitor thapsigargin. The natural product thapsigargin is a densely oxygenated guianolide that has already succumbed to total synthesis by the Ley group. In this paper rational modifications are made to the lactone region demonstrating the utility of total synthesis in the preparation of analogues of an important natural product that is in short supply - its natural source Thapsia cannot be cultivated. 

My fourth paper by Lew Mander et al. at the Australian National University reports a concise synthesis of the tropone moiety of the structurally rigid and congested diterpene tropone harringtoniolide. Harringtonolide exhibits both anti-neoplastic and antiviral properties.   The tropone moiety is innovatively assembled via arene cyclopropanation with Diels-Alder cycloaddition providing a means to install the lactone ring that also facilitates incorporation of the bridge methyl substituent. 

My final selection is a paper by Amos B. Smith III et al. at the University of Pennsylvania who report the synthesis of simplified analogues of the anticancer agent (+)-discodermolide. This marine natural product is potent stabilizer of microtubules with a similar mechanism of action to the anticancer agents paclitaxel and the epothilones. The large quantity of discodermolide required for the phase I trials could only be obtained by total synthesis. The search for simpler analogues of discodermolide that are more synthetically accessible, is therefore a challenge of considerable commercial importance. Smith et al. demonstrate that by replacing the C1-C-7 fragment of the discodermolide with a simple coumarin moiety, compounds with equivalent potency to the natural product can be obtained.