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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.

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 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.

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 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.

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.

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 .

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 study of the factors affecting the regio- and stereo-selective outcomes of consecutive 6-endo-trig cyclisations of polyene acyl-radical intermediates, leading to decalone, perhydrophenanthrone, and steroid ring constructions, has been carried out. Thus, whereas the E-substituted diene selenyl ester 7 underwent sequential cyclisations in the presence of Bu3SnH-AIBN leading to the trans-decalone 8 exclusively, the corresponding Z- and E-isomers of the methoxycarbonyl-substituted diene 16, under similar conditions, gave rise to a 2∶1 mixture of the trans- and cis-decalones 17a and 17b respectively in 62–73% yield. Cyclisation of the triene selenoate 30 led to a single tricyclic product in 57% yield whose cis,syn,trans relative stereochemistry 32 was established by X-ray diffraction analysis. When solutions of the trienyne selenoates 41a–c in benzene were treated with Bu3SnH–AIBN they each underwent cascades of three 6-endo-trig followed by a 5-exo-dig cyclisation leading to the full steroid ring systems 42, 45, and 47 respectively in 20–40% yields. The stereochemistries of the major steroid diastereoisomers resulting from 41a and 41c were established as trans,anti,trans,anti,cis, e.g.47, following X-ray crystallographic analysis of the corresponding dione 44 produced from 42d and 47 after ozonisation. In each of the cyclisations leading to 42 and 45 varying amounts of other bicyclic products tentatively assigned as 43 and 46 respectively, resulting from a competing radical pathway involving first a 10-endo-trig macrocyclisation of the corresponding acyl radical intermediate onto the C9–C10 olefin in 43/46, followed by a 5-exo-trig cyclisation of the resulting radical intermediate onto the proximal C13–C14 double bond, were produced concurrently. Finally, when the fluoro-alkene selenoate 56 was treated with Bu3SnH–AIBN, a complex mixture of polycyclic products resulted, from which only the indanone 57 could be separated and characterized. The origins of the differing regio- and stereo-selective outcomes in the aforementioned radical cascades are briefly considered.

A range of methods for the synthesis of mono-, bis- and tris-2,4-disubstituted oxazoles were evaluated, which led ultimately to a concise synthesis of the three contiguous oxazole ring system 26 in the ulapualide family of 25-membered macrolides, e.g.1, found in marine organisms. The tris-oxazole macrolide core 30 in ulapualide A (1) was also synthesised based on a macrolactamisation strategy from the two functionalised mono-oxazole precursors 28 and 29, followed by oxazoline 45 and oxazole ring formation, exploiting the methodologies established in the synthesis of linear bis- and tris-oxazoles in the formation of 18 and 26. The tris-oxazole 26 was converted into the corresponding phosphonium salt 5 in readiness for elaboration to ulapualide A (1).

Unsaturated acyl radicals are shown to be useful precursors to α-ketenyl radical intermediates which are then used in the synthesis of aromatic cyclic ketones. The behaviour of cyclopropyl acyl radicals is also described, in particular the 8- endo -trig cyclisation of 3-substituted cyclopropyl acyl radicals to give bicyclo[6.1.0]nonanones, and in the synthesis of cyclic enol lactones.

Separate treatment of the iodotrienedione 19 and the iododienynedione 38 with Bu3SnH–AIBN produces the corresponding taxane ring systems 25 (25–30%) and 56 (50–60%) respectively by way of tandem radical macrocyclisation-radical transannular cyclisations. By contrast the analogous iodopolyenones 61, 63, 65a, 66a, 86a and 87a, together with the corresponding iodoenynones 39a and 59 failed to undergo similar tandem radical reactions, and instead gave products resulting from direct reduction of the carbon–iodine bonds in these substrates. The structures of the taxane analogues 25 and 56 followed from analysis of their NMR spectroscopic data and comparison with similar NMR data for related taxoids described in the literature. The stereochemistry of 56 was secured from an X-ray crystal structure determination of the 1,5-diol 57 produced from reduction of 56 with DIBAL.

A stereoselective synthesis of the 2,6-cis oxane unit, accommodating five contiguous asymmetric centres, found in the novel marine natural product phorboxazole A 1, is described.

Irradiation of a solution of α,β-unsaturated aldehyde 10 in benzene leads to the methylenecyclobutanol 11 by way of a novel intramolecular C–H insertion reaction. The conversion of 10 into 11 has relevance to the possible origin of the cyclobutane ring-based furanocembrane providencin 1 found in gorgonian octocorals.

Treatment of the ω-iodoacetylene 6 with Bu3SnH–AIBN produces the taxane ring system 9 (45–60%) by way of transannular cyclisation from the macrocyclic vinyl radical intermediate 8, whereas the analogous iodoacetylenes 5a, 11 and 13a, together with the iodopolyenones 12a, 14a and 17, failed to give corresponding taxane systems, i.e. 7, 16 and 19 on similar treatment; instead only products resulting from direct reduction of the carbon–iodine bonds in these substrates were obtained.

In a combination of cobalt-mediated cationic and free radical chemistry, treatment of the allyl silane substituted β-hydroxycobaloxime 13 with p TSA led predominantly to the trans -disubstituted cyclopentane 14 , which on irradiation with TEMPO produced 15 . In a similar manner, the cobaloxime 18 was cyclised to 19 in the presence of p TSA which, on irradiation with a sunlamp then underwent radical mediated cyclisation to the substituted indane 20 .

Treatment of the iodo trienone 6 with Bu3SnH–AIBN results in the formation of the angular 5,7,5-ring-fused tricyclic ketone 20 by way of a novel sequential 13-endo-trig macrocyclisation followed by two successive 5-exo-trig transannulation processes, viz 7→8→/18/19→20. The cis-anti-trans stereochemistry of 20 was established from an X-ray crystal structure determination of the corresponding 2,4-dinitrophenylhydrazone. By contrast, treatment of the iodo trienone 21 with Bu3SnH–AIBN, under the same conditions, led to the substituted cyclopropane 33 (instead of the hoped-for tricyclic ketone 22), and only the product 38 of macrocyclisation (without further transannulation to the triquinane 24) was produced when the iodo trienone 23 was treated similarly.

Treatment of the E-α,β-unsaturated selenyl esters 1 and 3a with Bu3SnH-AIBN produces the corresponding cyclohexenones 2 and 7 8 respectively via presumed α-ketene alkyl radical intermediates. In a similar manner the cyclopropyl ester 9 leads to a mixture of 12 and 13, and the 2,7-diene selenyl ester 15 undergoes a novel bi-cyclisation producing the diquinane 17 in 76% yield.

The C20C35 subunit 3 in ulapualide A 1 has been synthesised in enantiomerically pure form using a combination of the Evans aldol reaction, controlled ring opening reactions of chiral epoxides, and Brown's asymmetric allylboration reaction, to set up the eight chiral centres in the key intermediates 4 and 5 . An olefination reaction between 4 and 5 , followed by hydrogenation of 23 , and protection of the resulting alcohol 24 then led to 3 .

The scope for tandem radical mediated macrocyclisation-transannulation processes (Scheme 1) in the elaboration of polycycles is illustrated with the facile syntheses of linear 5,6-, 6,6- and 5,7-ring fused carbobicycles, viz 7, 8, 11, 13 from appropriate iododienone precursors, viz 1, 2, 12 on treatment with Bu 3 SnH-AIBN.

Treatment of appropriately substituted 5,9-diene, 5,9,13-triene and 5,9,13,17-tetraene phenoselenyl esters, e.g. 1a, 9 and 14 , with Bu 3 SnHAIBN is shown to lead to linear and angular six-ring fused polycycles, viz 2, 11 and 15 respectively, via consecutive 6- endo -trig modes of cyclisations starting from the corresponding polyolefin acyl radical intermediates.

The total synthesis of (±)-citreoviral, which co-occurs with citreoviridin, citreoviridinol, and citreodiol in Penicillium citreoviride, is described. The synthesis is based on a biogenetic model, and has as a key feature the elaboration of the dihydroxytetrahydrofuranyl ring portion 10 by an acidcatalysed cyclisation of the central epoxy alcohol intermediate 9 which is derived in ten steps from methyl tiglate.

The 2,6-dioxabicyclo[3.2.1]octane ring systems, viz. systems 24 and 34, present in citreoviridinol and the aurovertins, have been produced in a stereoselective manner by treatment of the corresponding 4-hydroxytetrahydrofuran epoxides 22 and 33, respectively, with toluene-p-sulphonic acid. A number of related epoxy alcohol cyclisations leading to isomeric dioxabicyclooctanes are reported. These studies have led to a greater understanding of the biosynthetic pathway to the citreoviridinols and the aurovertins, and a greater appreciation of the role of epoxide intermediates in the biosynthesis apparatus.

The scope for tandem radical mediated macrocyclisation-transannulation processes (Scheme 1) in the elaboration of polycycles is illustrated with the facile syntheses of linear 5,6-, 6,6- and 5,7-ring fused carbobicycles, viz 7, 8, 11, 13 from appropriate iododienone precursors, viz 1, 2, 12 on treatment with Bu 3 SnH-AIBN.

Treatment of the E-α,β-unsaturated selenyl esters 1 and 3a with Bu3SnH-AIBN produces the corresponding cyclohexenones 2 and 7 8 respectively via presumed α-ketene alkyl radical intermediates. In a similar manner the cyclopropyl ester 9 leads to a mixture of 12 and 13, and the 2,7-diene selenyl ester 15 undergoes a novel bi-cyclisation producing the diquinane 17 in 76% yield.

Treatment of the bicyclo[12.1.0] pentadecatriene casbene 1 with ethanethiol radical (EtSH in C6H6, heat) results in regiospecific 1,4-addition to the vinylcyclopropane ring system, producing the cembrene sulfide 10. In similar reactions chrysanthemyl alcohol 11 and carene 13 lead exclusively to the corresponding sulfides 12 and 14, respectively, whereas irradiation of methyl chrysanthemate 15 with ethanethiol produces a 1 : 1 mixture of the isomeric sulfides 16 and 17. Oxidation of the cembrene sulfide 10, followed by thermolysis of the resulting sulfoxide then produces isocembrene 20, identical with natural material from Pinus sibirica. When a solution of casbene 1 in CCl4 was heated in the presence of NBS and AIBN, it underwent smooth oxidative rearrangement, via 21 and 22, to cembrenene 23, identical with the natural product isolated from the soft coral Sinularia maji.

Treatment of the iodo-trienone (8 b) with tri-n-butyltin hydride in the presence of AIBN is shown to produce the taxane ring system (11) by way of a tandem radical macrocyclisation - radical transannulation sequence, i.e. (8 b) → (9) → (11) (cf. Scheme 1).

A synthesis of the keto-triol formyl enamine moiety ( 3 ) in the marine metabolite halichondramide ( 1 ) is described. The synthesis features judicious applications of the Evans chiral aldol protocol in combination with the controlled ring opening of chiral α-epoxy alcohol precursor molecules to elaborate the units ( 5 ) and ( 6 ). A Wadsworth-Emmons coupling between ( 5 ) and ( 6 ) next provided ( 18 ), which was then elaborated to ( 3 ) via the key intermediates ( 19 ) and ( 21 ).