Search

Biosynthesis of (1R,4aS,7S,7aR)-nepetalactol (1) and (4aS,7S,7aR)-nepetalactone (2) in plants involves iridoid synthase (ISY), an atypical reductive cyclase that catalyses the reduction of 8-oxogeranial into the reactive enol of (S)-8-oxocitronellal, and cyclization of this enol intermediate, either non-enzymatically or by a nepetalactol-related short chain dehydrogenase enzyme (NEPS) that yields the nepetalactols. In this study, we investigated the biosynthesis in vivo of 1 and 2 in the pea aphid, Acyrthosiphon pisum, using a library of isotopically-labelled monoterpenoids as molecular probes. Topical application of deuterium-labelled probes synthesized from geraniol and nerol resulted in production of 2 H4 -lactol 1 and 2 H4 -lactone 2. However, deuterium incorporation was not evident using labelled probes synthesized from (S)-citronellol. These results suggest that iridoid biosynthesis in animals, specifically aphids, may follow a broadly similar route to that characterised for plants.

A heterocyclic, sp(3)-rich chemical scaffold was synthesised in just 6 steps via a highly regio- and diastereo-selective tandem nitrone formation/intramolecular nitrone-alkene [3+2] cycloaddition reaction. A library of 543 lead-like compounds based on the scaffold core has been produced.

In order to address the current downturn in the drug discovery pipeline, initiatives are being undertaken to synthesise screening libraries of sp3-rich, low molecular weight compounds. As part of the European Lead Factory initiative, the synthesis and derivatisation of a simple hexahydrooxazolo[5,4-c]pyridin-2(1H)-one bicyclic carbamate has been achieved. The synthetic route employed involved a telescoped hetero-Diels-Alder/[2,3]-sigmatropic rearrangement/cyclisation sequence to deliver the desired core scaffold containing two points for further diversification. When applied, this synthesis was found to be robust and scalable which allowed the production of a 155 compound library.

A stable, simple to synthesise and versatile chiral alde- hyde building-block has been developed, its reactivity in Wittig, Horner-Wadsworth-Emmons and Grignard reactions investigated, and its use is demonstrated in a highly efficient synthesis of an in- termediate in Dixon's synthesis of nakadomarin A.

Syntheses of the potent neurotoxins and biochemical probes anatoxin-a and homoanatoxin and several analogues by a combined two-directional synthesis―tandem reaction strategy are presented. Key steps include an oxidative desymmetrisation and a tandem Michael―intramolecular Mannich cyclisation.

The application of a tandem condensation/cyclisation/[3+2]-cycloaddition/elimination reaction gives an sp(3)-rich tricyclic pyrazoline scaffold with two ethyl esters in a single step from a simple linear starting material. The successive hydrolysis and cyclisation (with Boc anhydride) of these 3-dimensional architectures, generates unprecedented 16-membered macrocyclic bisanhydrides (characterised by XRD). Selective amidations could then be achieved by ring opening with a primary amine followed by HATU-promoted amide coupling to yield an sp(3)-rich natural product-like library.

A tandem oxime formation/Michael addition/1,4-prototopic shift/[3+2]-cycloaddition of an acyclic symmetrical precursor results in a tricyclic isooxazolidine which then undergoes a further fragmentation/lactamisation cascade to generate a non-symmetrical tricyclic a-ketolactam as a single diastereomer.

A synthesis of the spirocyclic core structure of halichlorine, an inhibitor of the induced expression of VCAM-1 and the pinnaic acids, inhibitors of PLA 2 , is presented. A two-directional strategy is employed, in conjunction with a tandem oxime formation/Michael addition/cycloaddition to form the key azaspirocyclic skeleton in a very direct manner.

© 2014 The Royal Society of Chemistry. The first total synthesis of myrmicine ant alkaloid 5-epi-cis-275B′ (4) is presented. A tandem cyclisation established the entire core of the structure in a single transformation as well as the required 2,5-anti stereochemistry. Two-directional synthesis was used to furnish the cyclisation precursor 2, as in each of the subsequent steps towards the natural product. The first electrophysiology studies for 4 (against nicotinic acetylcholine receptors) were also conducted, finding modest inhibition of current.

A 6-step synthesis of the potent anthelmintic SB-201561 is described. The key stage of the synthesis is a novel Beckmann type oxime fragmentation to give a lactone, followed by a 2-step reassembly of the spirolcetal moiety.

A tandem bromonium ion-promoted cyclization of two pendant hydroxyl groups onto a central furan core provides a highly direct route to both the [5,5,5]- and the [6,5,6]-trioxadispiroketal ring systems.

The TiCl4-mediated reaction of ketones (I) and (IV) with primary amines involves an enamine formation/Michael addition/aza-Michael addition sequence to give diastereomeric mixtures of azabicycles.

Stereoselective synthesis of 2,3-di- and 2,2′,3-tri-substituted aziridines in good yields and excellent diastereoselectivities are achieved through aza-Darzens reactions of a range of tert-butanesulfinyl aldimines and ketimines with ethyl bromoacetate.

A two-directional synthesis strategy and a tandem deprotection/double intramolecular Michael addition provides a very direct route to the 4,6-disubstituted quinolizidine 4.

The formal synthesis of (±)-histrionicotoxin and (±)-histrionicotoxin 235A using a two-directional strategy has been accomplished. The key feature of the synthesis is a tandem oxime formation/Michael addition/nitrone cycloaddition sequence, which form the azaspiro[5.5]undecane skeleton in two operations from an acyclic symmetrical precursor.

Two-directional ring-opening cross-metathesis of a range of cyclic alkenes with a variety of electron deficient alkenes has been accomplished; it was found that the process is quite general and gives complete selectivity for the E,E-dienes, making this a very useful and high-yielding protocol for two-directional chain synthesis.

Two-directional cross-metathesis of a range of alpha,omega dienes with a variety of electron deficient alkenes has been accomplished. It was found that the process is quite general and gives complete selectivity for the E,E-dienes, making this a very useful and high yielding protocol for two-directional chain elongation.

Two new tandem reactions for the synthesis of 3,5-disubstituted pyrrolizidines and the first total synthesis of alkaloid cis-223B (in 7 steps and 43% overall yield), involving a double cross metathesis and double Michael addition as key steps, are presented.

Total syntheses of the potent neurotoxins, environmental hazards, and biochemical probes anatoxin-a and homoanatoxin have been achieved from a common intermediate using a combined two-directional synthesis-tandem reaction strategy which includes key advances in oxidative desymmetrisation, tandem Michael-intramolecular Mannich cyclisations and a new method for deprotection of N-tosyl anatoxin-a.

Covering: up to June 2006 This article brings together for the first time reviews of all the synthetic attempts towards the spirocyclic histrionicotoxin alkaloids published since the discovery of the group in 1971. This covers 5 total syntheses of the fully unsaturated parent alkaloidHTX-283A, 7 total syntheses of perhydrohistrionicotoxin, 15 total syntheses of other members of this alkaloid family, 25 formal syntheses, and 19 partial syntheses involving the successful formation of the core azaspirocyclic structure but lacking advancement towards the target structure.

A tandem azide formation/intramolecular cycloaddition/triazoline fragmentation/Michael addition, which results in a non-symmetrical quinolizidine from an acyclic symmetrical precursor, is presented.

Two-directional total stereoselective syntheses of (+/-)-hippodamine and (+/-)-epi-hippodamine, utilising a tandem deprotection/intramolecular double Michael addition sequence as the key step, are presented.

An entirely two-directional synthesis of (+/-)-perhydrohistrionicotoxin is presented, utilizing a tandem oxime formation/Michael addition/[3 + 2] cycloaddition as the key step. This approach also constitutes formal syntheses of (+/-)-histrionicotoxin and (+/-)-histrionicotoxin 235A.

The formal synthesis of (±)-histrionicotoxin and (±)-histrionicotoxin 235A using a two-directional strategy has been accomplished. The key feature of the synthesis is a tandem oxime formation/Michael addition/nitrone cycloaddition sequence, which form the azaspiro[5.5]undecane skeleton in two operations from an acyclic symmetrical precursor.

The synthesis of (+/-)-histrionicotoxin has been achieved in just nine steps using a two-directional synthesis strategy. Key reactions include a two-directional cross-metathesis, a tandem oxime formation/Michael addition/1,4-prototopic shift/[3 + 2]-cycloaddition cascade, a selective Z,Z-bisenyne formation, and a one-pot N-O and bischloroacetylene reduction.

Total syntheses of alkaloid cis-223B and xenovenine are reported in 3 and 4 steps respectively using a two-directional synthesis/triple reductive amination strategy, and their neurotoxic properties assessed.

A two-directional synthesis strategy and a tandem deprotection/double intramolecular Michael addition provides a very direct route to the 4,6-disubstituted quinolizidine 4.

Tying the knot! The marriage of two-directional synthesis and tandem reactions allows access to twelve skeletally diverse scaffolds in just fifteen reactions. Two-directional synthesis yields a symmetrical linear “rope-like” keto-dienoate which is then subjected to twelve separate tandem reactions to “tie the rope in knots” thus creating twelve diverse natural product-like scaffolds containing useful functionality for further elaboration.

Total syntheses of the potent neurotoxins, environmental hazards, and biochemical probes anatoxin-a and homoanatoxin have been achieved from a common intermediate using a combined two-directional synthesis-tandem reaction strategy which includes key advances in oxidative desymmetrisation, tandem Michael-intramolecular Mannich cyclisations and a new method for deprotection of N-tosyl anatoxin-a.

BackgroundHippodamine is a volatile defence alkaloid isolated from ladybird beetles which holds potential as an agrochemical agent and was the subject of a synthesis by our group in 2005.ResultsTwo enhancements to our previous syntheses of (±)-hippodamine and (±)-epi-hippodamine are presented which are able to shorten the syntheses by up to two steps.ConclusionsKey advances include a two-directional homologation by cross metathesis and a new tandem reductive amination / double intramolecular Michael addition which generates 6 new bonds, 2 stereogenic centres and two rings, giving a single diastereomer in 74% yield.