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Covering: up to May 2018The verticillene family of 6,12-membered ring-fused diterpenes are found in plants, liverworts, corals and insects. Carbocations derived from verticillene hydrocarbons are central intermediates in the biosynthesis of the taxane and the phomactin families of polycyclic natural products. This perspective delineates these unique biosynthetic interrelationships, which are reinforced by recent biomimetic synthesis investigations, alongside quantum chemical calculations and targeted engineering studies of the taxadiene synthase (TXS) cascade.

DFT calculations on the carbocation intermediates that connect the biosynthetic pathways leading to the sand fly pheromone sobralene and taxadiene have been made. Establishment of the conformation of the macrocyclic carbocation intermediate required to produce the (

A new sex-aggregation pheromone, sobralene, produced by the sand fly Lutzomyia longipalpis from Sorbral (Ceara State, Brazil) is shown to have the novel 6,12-membered ring-fused diterpene structure 3. It is proposed that sobralene is a likely shunt metabolite of the taxadiene synthase-catalysed cyclisation of geranygeranyl diphosphate.

The sex-aggregation pheromone sobralene produced by the sandfly Lutzomyia longipalpis is isomerised to verticillenes in the presence of mild acid, thereby providing credence to the proposal that sobralene is a likely shunt metabolite of the taxadiene synthase cascade.

Graphical abstract, Highlights • Established the structure of a diterpenoid sex-aggregation pheromone (sobralene). • Sobralene has a novel bicyclic ring, related to the verticillenes. • Propose sobralene has its origins as a shunt metabolite of taxadiene synthase., A new sex-aggregation pheromone, sobralene, produced by the sand fly Lutzomyia longipalpis from Sobral (Ceará State, Brazil) is shown to have the novel 6,12-membered ring-fused diterpene structure 3. It is proposed that sobralene is a likely shunt metabolite of the taxadiene synthase-catalysed cyclisation of geranygeranyl diphosphate.

In studies towards a biomimetic synthesis of plumarellide 1, acid-catalysed rearrangement of the furanobutenolide-based acetonide 10b led to the ring system 15b in plumarellide together with the cycloheptene-based ring system 11 found in rameswaralide 4, in a combined yield of 60%. RCM of the ω-dienes 30a and 30b led to the macrocycles 38a and 38b, respectively with the Z-configuration. Treatment of the vinyl bromide/vinyl stannanes 32a and 47 under Stille conditions failed to give the macrocycles 31a and 48, respectively. Reactions of the macrocycles 38a and 38b with TFA containing water produced the 5,6,7-tricyclic compounds 56a and 56b, respectively in >90% yield, instead of the plumarellide-based ring system 52. A summary and perspective on possible pathways from the C-13 acetoxy furanocembranoid 66 and from the C13–C14 unsaturated enol ether/cyclic hemiketal 9/59 to plumarellide 1 in vivo is given.

DFT calculations probing potential (4 + 2) and (4 + 3) cycloaddition pathways leading to the polycyclic ring systems found in the coral secondary metabolites plumarellide, mandapamate and rameswaralide are described. Formation of plumarellide and mandapamate via stepwise intramolecular cycloaddition of a furanoxonium ion onto a 1,3-diene is shown to be viable. The calculations also predict the outcome of related cyclisations involving model systems.

Treatment of the furanbutenolide 18a with trifluoroacetic acid in dichloromethane results in hydrolysis and rearrangement leading to the cycloheptene ring-containing system 19a found in rameswaralide ( 5 ). Similar treatment of the diastereoisomeric furanbutenolide 17 produces the cyclohexene ring-containing system 23 present in plumarellide ( 1 ), together with the C-7 epimer 24 of 19a . The acid-catalysed conversions 18a → 19a and 17 → 23 are rationalised implicating [6+4] and [4+2] cycloaddition pathways and/or two-step carbocation cyclisation sequences.

Moulds are able to cause spoilage in preserved foods through degradation of the preservatives using the Pad-decarboxylation system. This causes, for example, decarboxylation of the preservative sorbic acid to 1,3-pentadiene, a volatile compound with a kerosene-like odour. Neither the natural role of this system nor the range of potential substrates has yet been reported. The Pad-decarboxylation system, encoded by a gene cluster in germinating spores of the mould Aspergillus niger, involves activity by two decarboxylases, PadA1 and OhbA1, and a regulator, SdrA, acting pleiotropically on sorbic acid and cinnamic acid. The structural features of compounds important for the induction of Pad-decarboxylation at both transcriptional and functionality levels were investigated by rtPCR and GCMS. Sorbic and cinnamic acids served as transcriptional inducers but ferulic, coumaric and hexanoic acids did not. 2,3,4,5,6-Pentafluorocinnamic acid was a substrate for the enzyme but had no inducer function; it was used to distinguish induction and competence for decarboxylation in combination with the analogue chemicals. The structural requirements for the substrates of the Pad-decarboxylation system were probed using a variety of sorbic and cinnamic acid analogues. High decarboxylation activity, ~ 100% conversion of 1 mM substrates, required a mono-carboxylic acid with an alkenyl double bond in the trans (E)-configuration at position C2, further unsaturation at C4, and an overall molecular length between 6.5 A and 9 A. Polar groups on the phenyl ring of cinnamic acid abolished activity (no conversion). Furthermore, several compounds were shown to block Pad-decarboxylation. These compounds, primarily aldehyde analogues of active substrates, may serve to reduce food spoilage by moulds such as A. niger. The possible ecological role of Pad-decarboxylation of spore self-inhibitors is unlikely and the most probable role for Pad-decarboxylation is to remove cinnamic acid-type inhibitors from plant material and allow uninhibited germination and growth of mould spores.

Treatment of a solution of the macrocyclic norcembranoid 7 with lithium hexamethyldisilazide in THF at −78 °C to 0 °C, leads to the polycyclic norcembranoids ineleganolide 1 and sinulochmodin C ( 2 ) (65%), which are found in the corals Sinularia inelegans and Sinularia lochmodes , respectively. The conversions are believed to be biomimetic, and occur by successive transannular Michael reactions in 7 . Under different temperature conditions the novel polycycle 30 is the main product, alongside small quantities of 1 and 2 . The polycycle 30 is possibly produced from ineleganolide 1 , following a reverse oxy-Michael reaction and two successive aldol reactions. The significance of the synthesis of ineleganolide 1 , sinulochmodin C ( 2 ) and the structure 30 from 5-episinuleptolide 7 , to the likely biosynthesis of the related norcembranoids scabrolide A ( 3 ), scabrolide B ( 4 ) and horiolide 31 found in Sinularia sp. is discussed.

Irradiation of natural rubifolide ( 1 ) and bipinnatin J ( 2 ) for short periods of time using a 400 W sunlamp results in photochemical Z - to E -isomerisations to their corresponding E -isomers 10 and 16 , respectively, neither of which has yet been discovered in Nature. Prolonged irradiation of rubifolide ( 1 ) produces the ring-contracted compound kallolide B ( 11a ), and photooxidation of E -rubifolide ( 10 ) leads to epilophodione ( 12 ); both 11a and 12 are found in corals. The photoisomerisation studies provide an insight into the most likely origins of more complex cembranoids, for example, 4 , 5 , 18 and 19 from the archetypal cembranoids 1 , 2 , and 3 in vivo. The studies also suggest a likely route to the unusually rearranged cembranoid sarcofuranocembrenolide B ( 23 ) via a cascade of photo-initiated radical cyclisations and rearrangements from the biradical intermediate 24 produced from cembranoid 22 .

A concise synthesis of the macrocyclic vinylbutenolide 19 is described, based on a facile RCM reaction of the substrates 16/18. Treatment of 19 with TFA containing water led to the 5,6,7-tricyclic compound 27, in a single step, in >90% yield, rather than to the alternative ring system 23 found in plumarellide (1). A rationale for the formation of 27 is presented, involving initial acid-catalysed hydrolysis of the furanmethanol intermediate 20 to the furanoxonium ion 21, which is next hydrolysed to the enol ether cyclic hemiketal 22. The intermediate 22 undergoes rapid tautomerisation and isomerisation producing enedione 24, which then takes part in a transannular Diels–Alder cyclisation to 26. Dehydration of 26 finally produces the tricyclic compound 27.

A new approach to the synthesis of oxygenated furanocembranoids, exemplified by danielid 3, is described. The approach features an intermolecular Knoevenagel-type condensation together with an intramolecular aldolisation to elaborate the furan and the lactone rings, respectively, in the initial target compound 14. Efforts to isomerise the C13–C14 double bond, or to introduce an alkene bond at C11–C12 in 14, leading to structures 3 and 8, respectively, are described.

Irradiation of a solution of synthetic Z-deoxypukalide 10 in acetonitrile (Pyrex; 400 W Hg lamp) resulted in isomerisation, leading to E-deoxypukalide 12, which was isolated recently from the octocoral Leptogorgia spp. Further irradiation of 12, or prolonged irradiation of 10, then gave the ring-contracted product, deoxypseudopterolide 1 (>90%) found in octocorals of the genera Pseudopterogorgia and Leptogorgia. The contraction of the 14-membered rings in 10 and 12 to the 12-membered ring as 1, occurs by way of photochemical [1,3]-sigmatropic rearrangement.

Oxidations of the 2-alkenylfurans 8a and 8b , using peroxy reagents, lead to the dienedione 9 and the furan epoxide 10 , respectively. Treatment of the epoxide 10 with p -TSA in MeOH produces the enol ether cyclic ketal 12 , which is rapidly isomerised to the furanmethanol ether 15 , isolated in 80% yield. By contrast, when the propanol-substituted furan epoxide 23 was kept in CDCl 3 containing traces of HCl for 2 h, a 3:2 mixture of Z - and E -isomers of the enol ether spiro ketals 25a and 25b was produced in >92% yield; after 24 h this mixture of isomers underwent dehydration leading to the corresponding enol ether triene 26 (70%). When a solution of the dienedione 9 in H 2 O–THF containing p -TSA was stirred at 25 °C for 20 h, the tertiary alcohol 27 was produced which, after a further 20 h was converted into the furan vicinal diol 29 . Likewise, when the ‘cembranoid’ dienedione 31 was treated with p -TSA–H 2 O, the hydroxymethyl-substituted furanobutenolide 33 was produced in 40% yield. It is probable that the enol ether cyclic hemiketals 28 and 32 / 34 , which are related to 12 and 25 , and also to the naturally occurring cembranoids 1 and 2 found in corals, are transient intermediates in the conversions leading to 29 and 33 from 9 and 31 , respectively.

A concise synthesis of the polycycle 27 , which incorporates the 5,5,7-tricyclic ring core of rameswaralide 1 , using a biogenetically inspired acid-catalysed [4+3]-cycloaddition approach starting from the furanobutenolide 26 is described, namely, 26→28 / 29→27 . Under thermal conditions, the same furanobutenolide 26 gives the alternative polycyclic compound 35 , resulting from a [4+2]-cycloaddition involving the furan as dienophile.

Concise syntheses of the substituted enynediones 28a, 33b and 36 starting from the cyclohexenealdehyde 18, corresponding to ring A in the taxanes, and the vinylstannane 24, are described. Treatment of 36 with Bu3SnH–AIBN did not lead to the oxy-substituted taxadiene 37 expected from a tandem radical macrocyclisation–radical transannulation sequence; instead, a mixture of unidentified products resulted. When the PMB ether 33b corresponding to the alcohol 36 was treated with Bu3SnH–AIBN under similar conditions, p-anisaldehyde was isolated, as a major by-product, but no evidence for the formation of a taxadiene could be observed. In contrast, the iododienynedione 41, i.e., deoxy 36, underwent a tandem radical macrocyclisation–transannulation sequence, when treated with Bu3SnH–AIBN, leading to the tetraoxy-bis-nortaxadiene 42 in 44% yield. Attempts to synthesise the alcohol 28b from the silyl ether 28a en route to the iodide 28c instead gave the substituted tetrahydrofuran 29 via an intramolecular oxy-Michael reaction.

Treatment of α-bromosilyl ether 27 derived from the substituted cyclopentenol 26 and (bromomethyl)chlorodimethylsilane, with 1,1′-azobis(cyclohexanecarbonitrile) in n-heptane at 100 °C, in the presence of allyltri-n-butylstannane leads to the silicon heterocycle 28 by way of a stereocontrolled tandem radical cyclisation (to 11)–trapping process. Oxidative cleavage of the carbon–silicon bond in 28, using H2O2–KF in THF–MeOH, next led to the corresponding cyclopentane diol 29a, which was then elaborated to the β-hydroxy ester 30b using five steps. Oxidation of 30b using Moffatt conditions, followed by methylation of the resulting enol ester 32a gave the fully functionalised cyclopentene ring in the antitumoural antibiotic substance viridenomycin 1 isolated from Streptomyces viridochromogenes and Streptomyces gannmycicus.

A 5- exo -dig radical cyclisation of the bromoamide 34 derived from the enantiopure α-ethynyl substituted amino alcohol 31 led to a 2:1 mixture of β-C3 and α-C3 methyl epimers of the pyrrolidinone 35a – 36a in a combined yield of 73%. Treatment of the homoallylic alcohol 35b , derived from 35a , with OsO 4 –TMEDA, gave a single diastereoisomer of the pyrrolidinone triol 37 , resulting from selective dihydroxylation from the β-face, i.e. syn to the CH 2 OH group of 35b . The pyrrolidinone triol 37 is a potential common precursor, cf. 9 , to the spiro β-lactone pyrrolidinone 8 and the γ-lactone pyrrolidinone 10 ring systems in oxazolomycin A ( 1 ) and neooxazolomycin 2 , respectively. Sequential protection of the 1,2-diol functionality in 37 as the acetonide 39 , and the primary alcohol group in 39 as the SEM ether 41a , followed by methylation of the nitrogen centre in 41a , using NaH–MeI, then gave the selectively protected pyrrolidinone 42 .

By the use of x-ray structures and flexible docking, we have developed the first in silico ligand-based view of the structural determinants of the binding of small molecule mimics of gelsolin, natural products bound to actin. Our technique highlights those residues on the actin binding site forming important hydrophobic and hydrogen-bonding interactions with the ligands. Significantly, through the flexible docking of toxin fragments, we have also identified potential residues on the actin binding site that have yet to be exploited. Guided by these observations, we have demonstrated that kabiramide C can be modified to produce a structure with a predicted binding energy increased by 20% while the molecular mass is reduced by 20%, clearly indicating the potential for future elaboration of structures targeting this important component of the cytoskeleton.

Several marine macrolide toxins act as potent and specific actin-severing molecules. Recent elucidation of their stereochemistries and modes of interaction with actin has allowed the syntheses of bioactive analogues. Here we used synthetic analogues in a structure-function analysis of ulapualide A, a trisoxazole-based macrolide. Ulapualide A harboured potent actin-depolymerising activity both in cells and in vitro. Its synthetic diastereoisomer was three orders of magnitude less active than the natural toxin and synthetic macrolide fragments lacked actin-capping/ severing activity altogether. Modulation of serum response factor (SRF)-dependent gene expression, as described for other actin-binding toxins, was also examined. Specific changes in response to ulapualide A were not observed, primarily due to its profound effects on cytoskeletal integrity and cell adhesion. Several synthetic fragments of ulapualide A also had no effect on SRF-dependent gene expression. However, inhibition was observed with a molecule corresponding to the extended aliphatic side chain of halichondramide, a structurally related macrolide. These findings indicate that side-chain derivatives of trisoxazole-based macrolides may serve to uncouple gene-regulatory events from actin dynamics.

A synthetic approach to ring-D aromatic steroids, viz. 5, based on a cascade of radical-mediated cyclisations from the orthoaryl-substituted iododienynones 12 and 13, instead led to the macrocyclic ketone 16 or to the novel, bridged tricycle 17, respectively, as the major products.

Novel N -methylated valine-thiazole cyclic octa- and dodecapeptides are produced by cyclooligomerisation of a N -methylated- l -valine thiazole amino acid HCl in the presence of pentafluorophenyl diphenylphosphinate (FDPP).

Basil Charles Leicester Weedon, ‘Prof’ to his chemistry colleagues but ‘Jimmy’ to his friends and family, died on 10 October 2003. He had two distinct careers, the first as Professor of Organic Chemistry at Queen Mary College, London, over the period 1960–76, and the second as Vice-Chancellor of Nottingham University from 1976 to 1988.

Treatment of solutions of the furfuryl alcohol 6 in dichloromethane–methanol with buta-1,3-diene or cyclohexa-1,3-diene or with cyclopentadiene in the presence of trifluoroacetic acid leads to the corresponding substituted furyl tetrahydrofurans, 8 , 12 and 15 respectively, rather than to the products 10 , 13 and 16 anticipated from intermolecular (4+3)-type cycloaddition reactions. These outcomes provide indirect experimental support for a stepwise carbonium ion pathway operating in (4+3)-cycloaddition reactions between furanoxonium ions and 1,3-dienes. Alongside other results, the outcomes also highlight a limitation to (4+3) cycloadditions in cycloheptene ring synthesis when the precursors contain hydroxyl groups capable of intercepting any carbonium ion intermediates leading to O-heterocyclic by-products.

A conceptually new total synthesis of oestrone, based on a novel cascade of radical cyclisations from the iodo aryl vinylcyclopropane 2 , via 10 , 15 , 16 and 17 , leading to the intermediate trans , anti , trans -oestradiol derivative 11 in one step, is described. Oxidation of 11 , followed by demethylation of the resulting aryl methyl ether 18 then gives (±)-oestrone 1 .

A diastereoselective 5-exo-dig radical cyclisation of the bromoamide 7 produced from the enantiopure α-ethynyl substituted amino alcohol 5 led to the pyrrolidinone 8 (2:1 α:β epimers) in 70% yield. Oxidative cleavage of the alkene bond in 8, followed by a stereoselective α-methylsulfanylation of the resulting 4-keto derivative 9, next led to the methylsulfanyl derivative 10. Finally, the pyrrolidinone derivative 10 was converted into the key intermediate 12 used previously in an enantioselective synthesis of (+)-lactacystin.

Novel proline–thiazole based cyclopeptides were produced by cyclooligomerisation of an L-proline thiazole amino acid HCl in the presence of pentafluorophenyl diphenylphosphinate (FDPP) or diphenyl phosphorazidate (DPPA).

The synthesis of a range of thiazole containing cyclic peptides using cyclooligomerisation reactions of amino acid substituted thiazole monomers and by macrolactamisation procedures is reported. The synthetic approaches lead to high yields of novel 18- and 24-membered ring analogues of the naturally occurring Lissoclinum families of cyclic peptides found in marine organisms and algae.

A concise synthesis of the oxygen substituted ring A compound 2 found in Taxol® 1a and Taxotere® 1b starting from 2,2-dimethylcyclohexane-1,3-dione and proceeding via the key intermediates 8 and 11 , is described. The absolute configuration of 2 was established from an X-ray crystal structure determination of a 4-bromophenylbenzoate derivative, viz. 15 .

Full details of a total synthesis of the doubly prenylated cyclic peptide trunkamide A of marine origin, and also its C45 epimer, are described.

Full details of a total synthesis of the novel reverse prenyl substituted cyclic peptide mollamide, isolated from the ascidian Didemnum molle, are described.

A convergent total synthesis of phorboxazole A (1a), from the C(3–19), C(20–27) and C(33–46) fragments 5, 4 and 91, respectively, concentrating on stereocontrolled formation of the bonds at C(2–3), C(19–20) and C(27–28), is described. Although a coupling reaction between a macrolide ketone and the side chain substituted sulfone, at C(27–28) was not successful, a Wadsworth–Emmons olefination involving the oxane methyl ketone 4 and an oxazole produced the oxane 90 which was next coupled to 91 leading to the C(20–46) unit 100. A further coupling of 100 to 71c at C(19–20) then led to 105, ultimately, and the synthesis was completed by a macrocyclisation reaction from 105, at the C(2–3) alkene bond, followed by deprotection of 106.

A concise total synthesis of (+)-curacin A, a potent antimitotic agent isolated from the cyanobacterium Lyngbya majuscula, is described. The synthesis features a new strategy to the 2-cyclopropyl-4-alkenyl substituted thiazoline unit in the natural product involving facile and selective thioacylation of the amino-alcohol 10 with the benzotriazole derived thioamide 11, leading to 28, as a key step. Cyclodehydration of 28 using Burgess' reagent then completed the synthesis of curacin A 1.

A chronological summary of the contributions made by researchers in Nottingham, UK, to developing the scope for the intramolecular Stille reaction in target natural product syntheses, e.g. leinamycin, the virginiamycins, macrolactin A, rhizoxin, the amphidinolides, lophotoxin, and pateamine, is described.

A new and convergent synthesis of the antitumour macrolide rhizoxin D 2 is described. The synthesis features a Wadsworth–Emmons olefination and a facile intramolecular Stille reaction to elaborate the 16-membered macrocyclic core 5 from the vinyl iodide 3 and the vinyl stannane 4 as key steps.

Substituted furfuryl alcohols are extraordinarily versatile starting materials in synthesis. They are precursors to furanoxonium ion intermediates which are implicated in the Piancatelli reaction (leading to 2-cyclopentenones) and in the synthesis of novel dihydrofuran-based exo enol ether/cyclic ketal natural products. They are also intermediates in a recently discovered (4+3) cycloaddition reaction with 1,3-dienes leading to furan ring-fused cycloheptenes. Here we provide a perspective on recent developments in these areas of synthesis, alongside recent applications of the Achmatowicz reaction and [5+2] cycloaddition reactions of the resulting oxidopyrylium ions.

A new approach to ring A aromatic steroids, based on cascade 13- endo - trig/dig macrocyclisations followed by sequential 5- exo-trig and 6- exo-trig transannulations, exemplified in the syntheses of the cis,anti,trans tetracycle 9 and the trans,syn tetracycle 13 from the ortho -substituted aryl polyen(yne) precursors, 8 and 12 respectively, is described.

A total synthesis of the doubly prenylated cyclic peptide trunkamide A of marine origin, and also its C45 epimer, is described.

Leslie Crombie was born in York on 10 June 1923, the second eldest, and only boy, of Walter Crombie and Gladys (née Clarkson). On his father's side his great-grandfather had kept a tobacconist shop in York and his grandfather, George, had founded a prosperous legal practice in the City of York. On his mother's side, Leslie's great–grandfather originated from London and settled in York after helping to build the York Railway Station. Leslie's father qualified as a solicitor and practised law in his grandfather George's office. However, he disliked the profession and, after his marriage and the death of his father, Walter passed over the practice to his brother Norman and took the lease of a hotel in the Isle of Wight. Unfortunately, the hotel did not prosper and was given up after a few years, and the family, which included Leslie's three sisters, Ivy, June and Molly, moved to Portsmouth. Although Leslie's father had a small allowance from his brother Norman and the legal practice in York, and he had various small intermittent incomes from teaching, the family was desperately poor during the 1930s. Leslie received little encouragement from his parents, but he passed the 11+ examination and entered Portsmouth Northern Grammar School in 1934, where he was awarded a very respectable School Certificate when he was 16 years old. However, it was now 1939 and World War II was about to start, and his school was evacuated to Winchester. With poor living conditions and little facilities for study, the young Leslie was determined to take a job and study part-time. He was appointed in 1940 as an assistant in the analytical laboratory of Timothy Whites and Taylor at their head office in Portsmouth under the supervision of Ron Gillham, who greatly influenced his further career; he was paid 13 shillings and 6 pence (in decimal terms, 67½pence) per week. In the evenings, Leslie studied at Portsmouth Municipal College for a London University Intermediate BSc. Alas, after a heavy bombing raid in January 1941, Timothy Whites and Taylor's laboratories were removed from the map, along with a great deal of the centre of Portsmouth—but fortunately not the MunicipalCollege.

In a quite remarkable regio- and stereoselective manner, each of the (all-E)-polyene selenoates 5a – c is shown to undergo cascade radical-mediated polycyclisations via consecutive 6-endo-trig reactions, leading to the corresponding all-trans, anti, tri-, penta- and heptacycles, i.e., 20, 23, and 25, in good yields. The configurations of these `steroid-like' polycycles followed from detailed examination and correlation of chemical shift data in their 13C-NMR spectra.