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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.

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.

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.

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.

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 .

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).

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.

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.

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

A synthetic approach towards the cytotoxic polyene polyol macrolide amphidinolide B (1), based on elaboration of the C1C13 carboxylic acid 4 and the C14C25 alcohol 3 units, their esterification to the iodostannyl ester 2, and an intramolecular Stille sp2–sp2 coupling reaction, is described. In spite of adequate precedent and model experiments, circumstances conspired and the aforementioned coupling reaction was not realised in this case.

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.

Treatment of the butenyl-substituted allenecyclopropanes 5 and 12 with tris - (trimethylsilyl)silane (TTMSS)–AIBN results in facile radical cyclisations into the cyclopropane-carbon centres of the allene moieties, followed by cyclopropane ring-opening and allene isomerisation, leading to the bicyclic 1,3-dienes 10 and 13 , respectively. By contrast, treatment of the pentenyl-substituted allenecyclopropane 15a and the iodoethane 18 with TTMSS–AIBN, led to the alkylsilane 16 , and the enyne 21 , respectively. Desilylation of 10 and 13 gave the corresponding bicyclic hydrocarbons.

A total synthesis of the novel reverse prenyl substituted cyclic peptide mollamide, isolated from the ascidian Didemnum molle, is described.

Ab initio calculations at the RHF/6-31G* and MP2/6- 31G*//RHF/6-31G* levels of theory are performed for 2-methyl-4-carboxamido-oxazoles and -thiazoles, including rotational profiles for the ring-carboxamide bond, which showed the expected conjugation and hydrogen bonding effects. On the basis of these data, newly optimised stretch, bend and torsional parameters for the AMBER* force field are derived, along with CHELPG-fitted partial atomic charges.

A convergent and stereoselective synthesis of the C31C46 side chain unit in the marine natural product phorboxazole A, which accommodates five asymmetric centres, three carbon-to-carbon double bonds and an oxane-hemiacetal unit, is described.

A total synthesis of (+)-curacin A 1 which features a facile and selective thioacylation of the polyene amino-alcohol 2 with the benzotriazole-derived cyclopropyl thioamide 3, leading to 15, as a key step is described.

A cascade of three consecutive 6-endo-trig radical cyclisations from the polyene acyl radical intermediate 12 derived from the selenoate 11 is used to construct the trans,anti,trans,anti,cis-tetracyclic keto lactone 20 in one step. Manipulation of the ketone function in 20 to the corresponding gem-dimethyl substituted carbon then completed a concise synthesis of the marine metabolite spongian-16-one 1.

Treatment of the enamide selenoesters 8 and 14 with Bu3SnH–AIBN is shown to lead to the nitrogen tricycle 9 (63%) and the D-homo-12-azasteroid 16 (45%) respectively, by way of serial stereoselective 6-endo-trig radical cyclisations.

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 polyene iodide 3, containing a vinylcyclopropane electrophore, with tris-(trimethylsilyl)silane (TTMSS)-AIBN gave 6 and 7 (2:1, 65%) resulting from a radical cascade 13-endo macrocyclisation followed by successive 6-exol5-exo transannular cyclisations. In a similar manner, the iodo vinylcyclopropane 12a underwent triple cyclisation to a mixture of diastereoisomers of the oestrone analogue 14 (∼ 16%), but the vinylcyclopropyl ester 9a gave only the product 11 of macrocyclisation on treatment with TTMSS-AIBN.

Treatment of the undeca-1,4,8-triene hydrocarbon humulene 1 with ethanethiol radicals results in a facile radical-mediated transannulation producing the sulfide 7 in 50% yield. The structure of 7 follows from its conversion into the bicyclo[6.3.0]undeca-4,9-diene 9 and from an X-ray crystal determination on the di-epoxide 10 derived from 9.

A concise synthesis of the 19-membered bis -lactone core 2b present in pateamine 1 using chiral pool starting materials and featuring an intramolecular Stille coupling reaction as a key stratagem, is described.

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.

A concise synthesis of the tricyclic furanochroman unit 2 found in the unusual PAF antagonist phomactin A 1 is described. The synthesis is based on elaboration of the novel dihydrofuran enol ether 3 as key intermediate via the iodopyran 6 or the dihydrofuran 20. Treatment of 3 with dimethyldioxirane in acetone-water then gave the furanochroman 2.

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.

A total synthesis of lissoclinamide 5, and some of its stereoisomers, shows that its stereostructure should be revised to 13.

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 iodotrienone 1 with Bu3SnH-AIBN results in the formation of the angular 5,7,5-ring fused tricycle 6, by way of a novel sequential 13-endo-trig macrocyclisation followed by two successive 5-exo-trig transannulation processes.

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.

Novel thiazole- and oxazole-containing modified cyclopeptide C3-symmetric cages have been synthesised utilising a trimeric linker to control the assembly and cyclooligomerisation of heterocyclic amino acids.

A total synthesis of the novel antifungal substance myxothiazol 1 isolated from the myxobacterium Myxococcus fulvus is described. The synthesis is based on elaboration of the S-E,E -diene thioamide 1 5 and the 2 R S , 3 S R amide aldehyde 2 5 as key intermediates, followed by conversion of 1 5 into the bis -thiazole 1 9 and a final Wittig coupling reaction between 2 5 and the salt 2 0 c leading to 7 S ,18 S R , 19 R S myxothiazol.

Treatment of the N-formyl derivative of the thiazolidine adduct derived from (R-cysteine methyl ester hydrochloride and pivalaldehyde, with LDA-DMPU at −90°C, followed by reaction with iodomethane produces the corresponding methylated thiazolidine containing the methyl and t-butyl groups virtually exclusively anti- to one another. Hydrolysis in the presence of 5M HCl then affords (R-2-methylcysteine hydrochloride in excellent yield and enantiomeric purity. A range of other 2-alkyl substituted cysteines of excellent optical purity are prepared by this modification of Seebach's “self-reproduction of chirality” protocol.

Treament of the bicyclic dienol (8) with iodosylbenzene diacetate-iodine is shown to lead to the 7,5,-tricycle (11, 81%) by way of a cascade ra

A concise total synthesis of the thiazoline-thiazole containing metabolite didehydromirabazole A 1 is described. The synthesis uses the unusual amino acid (R)-2-methylcysteine 20 in sequential cyclocondensations with imino ethers as key steps, viz22→32 and 37→38.

The acyclic carotenoids phytoene and phytofluene, which are precursors of 9-cis-β-carotene produced by the alga Dunaliella bardawil, have been separated and characterised. Spectroscopic data, and comparison with synthetic model compounds and corresponding carotenoids found in the fruits of the Tangerine tomato Lycopersicon esculentum var., establish that the pigments have the stereochemistries 15-cis-6 and 9-cis-11 respectively. The data suggest that phytoene 6 is the clear branch point for the formation of 9-cis-β-carotene 2 in D. bardawil. In addition, spectroscopic data for β-carotene isolated from D. bardawil showed that it was isomerically pure 9-cis-β-carotene 2.

Arylmethyl- and allyl-carbonylcobalt salophen complexes, e.g.(7), (8), (9), and (22), readily undergo carbon-to-cobalt-bond homolysis and in situ decarbonylation, producing new alkyl radical centres which can be intercepted with oxygen-, nitrogen-, halogen-, sulphur-, and selenium-containing radical-trapping agents leading to functionalised noralkanes. The sequence constitutes a useful, and in some cases more flexible, variant of the classical Hunsdiecker reaction, and amounts to a cobalt equivalent of the Barton radical decarboxylation reaction of carboxylic acids via their corresponding thiohydroxamic esters. In a similar manner, irradiation of the oxy-substituted acylcobalt salen reagents (25) and (26) in the presence of tetramethylpiperidine oxide produces the products (14) and (27), respectively, resulting from homolysis–decarboxylation and alkyl-radical trapping. In the absence of radical-trapping agents, irradiation of (7c) produces (18), and irradiation of (29) leads to the but-2-enolide (32).

Alkyl radicals generated by photolytic homolysis of cobalt salophen reagents, e.g.(6) and (15), are shown to add to activated carbon-to-carbon double bonds, i.e. ethyl acrylate, methyl vinyl ketone, acrylonitrile, and styrene, producing preparatively useful yields of new alkene products, viz.(9), (10), (12) and (14)[from (6)], and (16)[from (15)]. The reactions proceed via radical (Michael) additions, followed by ‘dehydrocobaltation’ from the presumed organocobalt intermediates (2)(Scheme 4). By use of this chemistry, in combination with the Schrauzer ‘hydrocobaltation’ reaction of alkenes, a new method for the cross-coupling reactions between two alkenes, leading to new functionalised alkenes, e.g.(24), (25), (26), (27), (28), and (29), is developed [Equation (2)].