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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 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).

A total synthesis of ulapualide A (1), whose relative stereochemistry was assigned on the basis of an earlier molecular mechanics study of its hypothetical metal chelated complex 9, is described. The synthesis is based on: i, elaboration of the double functionalised tris-oxazole 11; ii, synthesis and installation of the top side chain 16 (C-26–C-41) via a stereoselective Wittig reaction, leading to 17; iii, conversion of 17 into 73a and attachment of the C-1–C-9 portion 18; iv, macrocyclisation of 19 by an intramolecular Wadsworth–Emmons olefination leading to the macrolide 20; v, incorporation of the C-9 methyl group (to 80) and, finally vi, manipulation of the side chain functionality in 80 and introduction of the terminal formyl enamine residue. The synthetic ulapualide A showed NMR spectroscopic data which were almost identical to those described for the natural product, and did not separate from the natural material in HPLC analysis. Small differences in the 13C NMR spectroscopic data however lead us to conclude that the stereochemistry of the synthetic ulapualide differs from that in the natural product at one or more of the stereogenic centres along the C-28–C-33 portion of the side chain.

A total synthesis of the proposed structure 1 for the oxazoline/thiazoline-based cyclopeptide cyclodidemnamide, isolated from the sea squirt Didemnum molle, is described. The synthesis features a novel double cyclodehydration, sequential formation of chiral thiazoline and oxazoline rings in a preformed cyclopeptide intermediate, as a key stratagem. The NMR spectroscopic data for synthetic 1 and natural cyclodidemnamide did not correlate. The configuration of the natural product was re-assigned as 15, the C-15-(R)-Val epimer, which was confirmed by total synthesis.

A cascade of seven radical-mediated 6-endo-trig cyclisations from the all-E-heptaene selenoate ester 1 results in the production of the all-trans, anti heptacycle 2 together with the isolation of the all-trans, anti tetracycle 15.

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.

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.

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.

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.

A concise synthesis of the yellow pigment benzylthiocrellidone 1, based on a Michael addition–elimination of dimedone 2 to the ketene thioacetal 7 derived from dimedone, benzyl bromide and carbon disulfide, is described. The synthetic pigment had an X-ray crystal structure identical to that measured for the natural product.

The scope for tandem radical mediated macrocyclisation–transannulation processes in the elaboration of ring-fused carbocycles has been examined. Thus, a range of E-iodo dienones viz. 21, 30b, 40, 42 and 44 were first prepared using synthetic sequences based on sound literature precedent. Treatment of the iodo dienone 21 with Bu3SnH–AIBN led to a 3 : 2 mixture of trans-and cis-isomers of 1-decalone, 35 and 36, respectively, in a combined yield of 72%, whereas the positional isomer 30b of 21 underwent 10-endo macrocyclisation and transannulation to a 1 : 1 mixture of trans-1-decalone 35 and cis-octahydroazulen-1-one 39 (combined yield 68%), resulting from competitive 6-exo/5-exo transannular cyclisation from the intermediate cyclodecenone radical 38.In further investigations of the scope for sequential radical macrocyclisation–transannulations in the synthesis of bicyclic systems, the iodo dienone 40 was found to undergo regioselective cyclisation to the cis-tetralone 41(50%), whereas the iodo dienone 42 produced only (Z)-cyclooct-3-enone 54 and none of the expected bicyclo[3.3.0] octanone 43 on treatment with Bu3SnH–AIBN. Only the 4-cyclo-pentylcyclohexanone 61, and none of the hoped for 7,6-bicyclic ketone 45, was produced from radical cyclisation of the iodo dienone 44.The differing reaction pathways followed by the iodo dienones 21, 30b, 40 and 42 have been rationalised in terms of the conformational preferences of the macrocyclic α-keto radical intermediates, e.g. 32, 38 and 52 involved in the various cyclisations supported by some preliminary MM2 studies and calculations.

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.

A range of substituted Se-phenyl 5,9-dieneselenoates, viz. 15a, 25, 26, 27, 42 and 52, have been synthesised and their reactions with Bu3SnH–AIBN investigated. The diene esters 15a, 42 and 52 are shown to lead to decalone and to perhydrophenanthrone derivatives, viz. 19, 43 and 53, respectively, via consecutive 6-endo trig modes of cyclisations starting from the corresponding 5,9-diene acyl radical intermediates. By contrast, the 5,9-dienoates 25 and 27 lacking alkyl substitution at C-9 instead underwent cyclisation to the indanones 36 and 37, respectively, and the 6-methyl substituted analogue 26 produced only the cyclopentanone 38 on treatment with Bu3SnH–AIBN.

Treatment of appropriately substituted Se-phenyl 5,9,13-triene- and 5,9,13,17-tetraene-selenoates, i.e 9b,33,40,47a and 47b, with Bu3SnH–AIBN is found to lead to angular six-ring fused polycycles, viz. 20, 34, 50, 53 and 54 respectively, via consecutive 6-endo-trig modes of cyclisations, starting from the corresponding polyene acyl radical intermediates. The structures and stereochemistries of the polycyclic products were determined largely from detailed analysis and correlation of 13C NMR spectroscopic data. The trans-anti-trans stereochemistry of the tricyclic ketone 50 was established from X-ray analysis of a solid solution of a 1 : 1 mixture of ring C methyl epimers of the corresponding 2,4-dinitrophenylhydrazone derivative.

Cobalt(I)-mediated mono- and bi-cyclisations of halo-polyenes are compared and contrasted with corresponding reactions using the Heck reaction. The procedures are found to complement one another, with each having advantages and disadvantages, in the cases studied. Thus, treatment of the vinyl iodide 1 under Heck conditions led to the novel 1,3-diene 3 in 93% yield, whereas reaction between 1 and cobalt(I) salophen resulted in the formation of the organocobalt complex 4 (∼50%) as black crystals. Subsequent irradiation of 4 then led to the 6,5-ring fused bicycle 5 in 85% yield. In similar fashion, a Heck reaction with the analogous vinyl iodide 8 produced the product 9 of 6-ring cyclisation followed by β-hydride elimination, whereas the corresponding cobalt-mediated reaction with 8 led to the new organocobalt 10 albeit in only low yield (∼20%). In reactions akin to those studied by Overman et al., Heck reaction with the dienyl aryl iodide 14 was shown to lead to a mixture of the bicycle 16 and the tricycle 17 in a 1:1 ratio. By contrast treatment of 14 with cobalt(I) salophen produced largely the tetralin 18. The iodo-diene 33 gave rise to the spirocycle 35 under Heck reaction conditions, and the related spirocycle 42 was produced from the bromo-acetal 40 via 41, using cobalt(I) mediated reactions.

A total synthesis of the virginiamycin 14,15-anhydropristinamycin IIB 16 has been achieved from chiral, non-racemic starting materials, and using a route which features an intramolecular Stille coupling reaction, viz. 14→15, as the key stratagem. The virginiamycin 16 was identical with an authentic sample produced from a Streptomyces fermentation process.

Carbamoylcobalt(III) salophen compounds, such as 4, are sources of carbamoyl radicals under either thermal or photolytic conditions. Generation of N,N-dimethylcarbamoyl radicals, e.g.5, in the presence of trapping agents such as diphenyl disulfide or 2,2,6,6-tetramethylpiperidin-1-yloxy radical 7 afforded the expected amido derivatives, e.g.6 and 8, respectively. These radicals 5 also underwent oxidative intermolecular addition to styrene; the thermal process gave the E-cinnamide 10 exclusively, whereas under photochemical conditions a 1:1 mixture of E- and Z-cinnamides, 10 and 11, respectively, was obtained. A series of N-alkenyl-N-alkylcarbamoylcobalt(III) salophens have also been prepared (i.e.14, 33 and 43), and are shown to be suitable precursors for the synthesis of β-,γ- and δ-lactams through the 4-, 5- or 6-exo-trig-modes of cyclisation of the corresponding intermediate carbamoyl radicals. The products of these cyclisations, N-alkyl-3-lactamidomethyl radical (i.e.16, 34 or 46) are trapped by the cobalt(II) salophen to give the corresponding alkylcobalt(III) salophens (e.g.16→17). Although these alkylcobalt salophens appeared to be stable at temperatures ⩽40 °C, under the thermolytic conditions for radical generation that were usually employed (110 °C) dehydrocobaltation occurred, and the unsaturated lactam was formed. Results concerning the introduction of side-chain oxygen functionality at the product radical centre in tandem with the carbamoyl radical cyclisation are also presented. Computer-generated molecular modelling calculations supporting the novel 4-exo-trig-cyclisation of 15 are discussed.

A total synthesis of pukeleimide A 5, a member of a rare family of naturally occurring 5-ylidenepyrrol-2(5H)-ones produced by the marine blue alga Lyngbya majuscula, is described. The synthesis is based on elaboration of the ylidenepyrrolone 11a from the maleimide 13a by a regioand stereo-selective Wittig reaction with ethoxycarbonylmethylene(triphenyl)phosphorane, followed by conversion of 11a into the amide 25, and oxidation of 25 with selenium dioxide.

A series of maleimides 5 have been prepared by reaction of the appropriate maleic anhydrides with either ammonium acetate or methylammonium acetate in boiling acetic acid. The maleimides underwent Wittig-type reactions with stabilised phosphoranes, under moderately forcing conditions, to give 5-ylidenepyrrol-2(5H)-ones 6. The ease of the reaction and the regiochemistry of the addition to unsymmetrical maleimides depended upon the nature of the 3-substituent and on the presence or absence of an N-alkyl substituent. Thus, 3- methoxymaleim ides reacted exclusively at C-2; the presence of an N-methyl substituent required the use of more forcing reaction conditions, but did not alter the preference for C-2 attack. With 3-methylmaleimides, however, the slight preference for reaction at C-2 in 5c was overturned by the presence of an N-methyl substituent as in 5d. The related reactions of unstabilised phosphoranes or phosphine oxides usually only afforded intractable gums, and with Julia-type reagents only starting materials were recovered. However, the lithium enolate of methyl trimethylsilylacetate (or other Peterson-type reagents) underwent successful addition to N-methylmaleimides at –78 °C; the 5-ylidenepyrrolone product distributions were similar to those obtained with the stabilised phosphoranes. Variation of the 5-alkylidene side-chain was achieved through the reactions of N-methylmaleimides with alkyl Grignard reagents by dehydrating-the first-formed 5-alkyl-5-hydroxypyrtolone. 4-Methoxy-1-methylpyrrol-2(5H)-one could be deprotonated exclusively at the 5-position under kinetic control (i.e. BuLi, THF, –78 °C), and the anion then quenched with a variety of electrophilic agents to give 5-substituted pyrrolones. These derivatives proved amenable to dehydration or dehydrogenation, as appropriate, to afford the corresponding 5-alkylidenepyrrolones.

A stereoselective [2,3]-sigmatropic (Wittig) rearrangement of prop-2-ynyl 2-silyl allyl ethers 22 leading to E-vinyl silanes, e.g.23 is described. Stereospecific protiodesilylation of 23, via26, next produces the Z-alkene 27. sp-sp and sp-sp2 Coupling reactions between the acetylenic alcohol 5 produced from 27, and 3-bromoprop-2-ynol or 3-bromoprop-2-enol THP ether, then leads to the key intermediates 3 and 31 in leukotriene B41 synthesis.

A total synthesis of the all-cis cyclopentanetetraol moiety 2,3,4,5-tetrahydroxycyclopentane-1-acetonitrile, present in the antiviral substance funiculosin produced by Penicillium funiculosum, is described. Conversion of the known cyclopent-4-ene-1,2,3-triol into the 1-[1-(t-butyldimethylsiloxy)vinyl] 2,3-methylene trisether, followed by Claisen–lreland rearrangement in xylene at 190 °C, first provided the key intermediate all-cis-4,5-(methylenedioxy)cyclopent-2-ene-1-acetic acid. Iodolactonisation of this acid then led to the iodo lactone 4β-iodohexahydrofuro[2′,3′:4,3]cyclopenta [d][1,3]dioxolan-6-one, which on direct nucleophilic displacement using potassium superoxide in the presence of 18-crown-6 produced the corresponding 4β-hydroxy lactone by an SN1 mechanism probably via the C-4 radical intermediate. The structure and stereochemistry of the hydroxy lactone were determined by X-ray analysis of its t-butyldimethylsilyl ether.The above iodo lactone was converted into the iodohydrin-acetonitrile 2α-hydroxy-3β-iodo-4α,5α-(methylenedioxy)cyclopentane-1α-acetonitrile in three steps, which was then treated with methyl (chloroformyl)acetate to give the corresponding mixed malonate diester. Treatment of this diester with sodium hydride resulted in smooth, intramolecular oxygen nucleophile displacement leading to the all-cis ketene acetal methyl [7-(cyanomethyl)-3b,6a,7,7a-tetrahydro-3aH-cyclopenta [1,2-d;3,4-d′]-di [1,3]dioxol-2-ylidene]acetate in 92% yield, hydrolysis of which produced a mixture of positional isomers of all-cis-2-(cyanomethyl)-5-hydroxy-3,4-(methylenedioxy)cyclopentyl methyl malonate, which was then saponified to give the all-cis cyclopentane-substituted 2,3-dihydroxy-4,5-(methylenedioxy) cyclopentane-1-acetonitrile. The full structure and stereochemistry of this acetonitrile followed from X-ray analysis. The synthesis of (±)-all-cis-2,3,4,5-tetrahydroxycyclopentane-1-acetonitrile was then completed following treatment of the 4,5-methylenedioxy compound with ozone, leading to the 4-formate (and its 5-isomer), and saponification.

A range of alternative radical macrocyclisation approaches to cembranoids have been evaluated. Radical macrocyclisations involving the allylic radicals 11 generated from the corresponding allylic iodides, 15b and 20b, in the presence of Bu3SnH–AIBN, are shown to lead to 14-membered trienones, viz10, via selective 14-endo-trig processes. Both 10a and 10b can then be elaborated to the natural marine cembranoids 8(mukulol) and 9 respectively, by straightforward functional group interconversions.Concise syntheses of the α,ω-dial 28, the terminal acetylenic aldehyde 27 and the allylic iodide enal 37 were developed, but neither was found to undergo radical mediated cyclisation to the corresponding 14-membered carbocycles 29, 30 and 38 respectively. Instead, only the products of reduction, e.g.39, or intermolecular pinacolisation, e.g.34 were produced.

A number of complementary synthetic approaches to the β-thiolactone intermediate 9 for elaboration to the novel 1,3-dioxo-1,2-dithiolane moiety 6 found in the antitumour antibiotic substance leinamycin 1 are described.Thus, deprotection of the benzylthio ether produced from 3-methylbut-2-enoic acid and toluene-α-thiol, leads to the mercapto acid 12 which on cyclisation produces the thiolactone 13. α-Methylation of the thiolactone 13, followed by α-oxygenation then gives rise to the substituted β-thiolactone 9. The β-thiolactone 9 is also produced when: (i) the sodium glycidate 17 is stirred with sodium sulfide leading to 18, followed by thiolactonisation; (ii) thioacetone is treated with the ketene derived from 2-acetoxypropanoyl chloride; and (iii) by irradiation of 3-methyl-2-trimethylsilyloxybut-2-ene 22 with thiophosgene leading to 23, followed by hydrolysis.The β-thiolactone 9 is then converted in three steps into the 1,3-dioxo-1,2-dithiolane 6 by: (i) ring opening to the thioic acid 15, using hydrogen sulfide–triethylamine; (ii) ring closure of 15 to 8 in the presence of aqueous ferric chloride; and finally (iii) oxidation using dimethyldioxirane.Treatment of the ethyl glycidate 19 with disodium disulfide in hot ethanol for 3 days provides the 1,2-dithiolane 8 directly, but in low yields (11–15%).When the aforementioned reaction sequences are translated to the glycidate 24, derived from 4-methylcyclohex-3-enone and α-chloropropanoic acid, the syntheses of the key intermediates 25, 27 and 26en route to the spiro-fused 1,3-dioxo-1,2-dithiolane 7 and leinamycin 1(see Scheme 1) were secured.

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.

A synthesis of the grevillin group of pyrandione pigments e.g.3, 23 and 24 present in fungi is described. The synthesis, which is based on a biogenetic model, uses bis-benzylacyloins 9 and their corresponding oxalate derivatives as key intermediates (Scheme 3). Treatment of the grevillins 25–c with sodium ethoxide in ethanol effects their quantitative isomerisation into the corresponding terphenylquinone pigments 4a–c. Perkin-type condensations between the terphenylquinones 4 and arylacetic acids in the presence of sodium acetate–acetic anhydride then produces the xylerythrin pigments 29a–e, whereas rearrangements of 4 in the presence of dimethyl sulphoxide leads to pulvinic acid derivatives, e.g.31, 32 and 5. These synthetic studies interrelate the biosynthetic origins of the pigment types 3, 4, 5 and 8 together with the related pulvinone 6 and furanone 7 fungal pigments.

A number of complementary biomimetic approaches to the tetrahydrofuranyl portion of the dienal 13, which was used in a synthesis of preaurovertin, are described. Epoxidation of the trienoate 31 produces largely the β-epoxide 32, which on treatment with aqueous trifluoroacetic acid undergoes deacetalisation and concomitant cyclisation leading to compound 34. After conversion of 34 into dienal 13, a Wittig reaction with the ylide derived from the phosphonium salt 37 produces preaurovertin.Preaurovertin is a putative biogenetic precursor of aurovertin found in Calcarisporium arbuscula. Citreoviridin produced by Penicillium citreoviride relates to preaurovertin, and the citreoviridinols are related structurally to aurovertin. In addition, aurovertin is related biogenetically to asteltoxin found in Aspergillus stellatus. These structural and biosynthetic interrelationships are considered alongside the synthetic work.

A total synthesis of all-E-citreomontanin, produced by Pencillium pedemontanum and believed to be the putative precursor of citreoviridin and citreoviridinol, involving successive epoxidations of its terminal triene portion, is described. Elaboration of the pyrone 9a to the phosphonium salt 13b was smoothly accomplished via the key pyrone aldehyde intermediates 10 and 12. The all-E-trienal 7 required for Wittig coupling with compound 13b was readily produced from the aldehyde 14 by use of two successive stereoselective Wittig olefination reactions involving the stabilised phosphorane 15; i.e., 14+15→16, and 17+15→18. A Wittig coupling reaction between the ylide 8 derived from 13b and the trienal 7 then produced the all-E-polyene 1, as an orange solid, which was identical with citreomontanin isolated from P. pedemontanum.

Conversion of arabinose 10 to the protected ketone 13 followed by Wittig condensation to 14, acidcatalysed cyclisation (to lactone 16), dehydration and deprotection provides a brief synthesis of the mycotoxic substance patulin 1, which is produced by Penicillium and Aspergillus spp. In a similar manner, the biogenetic precursor to patulin, neopatulin 8, is synthesized from lyxose 25via the key intermediates 24, 28 and 30.

Reactions between substituted maleic anhydrides, viz. 1, and sodium dimethyl phosphite in refluxing benzene are shown to lead to the corresponding furan-2(5H)-one phosphonates 2 and 8. Wadsworth–Emmons olefination reactions involving 2 and heteroarylaldehydes and arylbenzoyl formates 14 then provides a new synthesis of heterocyclic analogues of pulvinones, i.e.10–13, and of permethylated pulvinic acids, e.g.16–17 which are found in higher fungi.

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)].

Reactions between the CoI species derived from cobalt (III) salen (11) or cobalt(II) salophen (12) and (O-allyl) or (O-but-3-enyl) iodophenols lead to isolatable cobalt complexes, viz.(16) and (27), which can be converted into substituted benzofurans, i.e.(17) and (23), and benzopyrans, i.e.(28) and (34); similarly, interaction between compound (36) and CoI salen led in one step to 1,3-dimethyl-indole (37). Radical cyclisation of the acetal (38a) in the presence of CoI cobaloxime [from (10)] leads to the cis-ring-fused alkyl cobalt complex (42), which can be converted in a preparative manner into lactone (44) following 1,2-elimination [to (43)] and hydrolysis/oxidation, and into lactone (53) following insertion of molecular oxygen [to (50)], reduction [to (51)] and hydrolysis/oxidation.

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).

Acylcobalt salophen reagents (6) are conveniently synthesised from carboxylic acid chlorides following treatment with the sodium derivative (5) produced from reduction of cobalt(II) salophen with sodium amalgam in tetrahydrofuran at room temperature. The acylcobalt salophens (6) undergo homolytic cleavage in the presence of light from a conventional 300 W sunlamp to give acyl radicals (24) which then undergo additions to activated carbon-to-carbon double bonds, leading to enones, viz.(26)[following dehydrocobaltation from presumed organocobalt intermediates (25)], or saturated ketones, viz.(34)[following H-quenching of intermediates (25)]. Intramolecular cyclisations of the acylcobalt salophens (42a) and (42b) lead to the ylidenecyclopentanones (43) and (45), respectively.

A synthesis of the spirobenzoquinonefuran unit, i.e.(10), present in stypoldione, a novel marine toxin found in the brown alga Stypopodium zonale which shows pronounced narcotic and hyperactive effects upon reef-dwelling fish, is described. The synthesis uses a strategy, viz(17)→(18)→(19)→(11)→(10), which has close similarities to the probable biogenesis of this portion of the natural product (scheme 1). The advanced precursors (30) and (36) for projected syntheses of deoxystypoldione (33) and stypodiol (3) respectively were also prepared, but neither substrate underwent polyene cyclization to the required pentacyclic molecules.

Irradiations of the alkylcobalt salophen complexes (14), (21), (22), and (23) in the presence of radical-trapping agents, e.g. molecular oxygen, tetramethylpiperidine oxide, nitrogen monoxide, diphenyl disulphide, diphenyl diselenide, methanesulphonyl chloride, bromotrichloromethane, or iodine, leads to oxgen-[e.g., (18), (19), and (25)], nitrogen-[e.g., (27) and (28)], sulphur/selenium-[e.g., (30) and (31)] or halogen-(34) functionalised products. When these radical-trapping methodologies are combined with cobalt-mediated radical cyclisation reactions (Scheme 2) a powerful synthetic procedure, i.e. radical carbon-to-carbon bond formation with simultaneous functionalisation of the product radical centre, becomes available.

The constitutions of unsymmetrically substituted aspulvinone pigments from Aspergillus terreus are re-examined by a combination of X-ray crystallographic and spectroscopic analysis. The crystal structure of aspulvinone (18a) is determined by X-ray diffraction from diffractometer data by direct methods. Crystals are triclinic, space group P, with Z= 2 in a unit cell of dimensions : a= 9.546 ± 0.005, b= 11.019 ± 0.005, c= 13.437 ± 0.006 A, α= 102.94 ± 0.05, β= 113.73 ± 0.05. γ= 91.39 ± 0.15°. The structure was refined by least squares to R 0.054 for 2 106 independent reflections. Comparative spectroscopic data establish constitutions (18b) and (18d) for the structurally related metabolites.The present data, combined with synthetic studies, have led to the revision of structures assigned to all ‘unsymmetrically’ substituted aspulvinones found in A. terreus. The biosynthesis of this new class of natural products is considered.

Thermolysis of 2-(2,2-dimethylcyclopropyl)cyclopent-2-enone (2) and 2-cyclopropylcyclohex-2-enone (6) is shown to produce 2-(3-methylbut-2-enylidene)cyclopentanone (10) and 2-propylphenol (14), respectively, via homo[1,5]sigmatropic H-migration and isomerisation. Heating 2-cyclopropylcyclopent-2-enone (8) under a variety of conditions led only to decomposition; no products [e.g.(11)] resulting from vinylcyclopropane–cyclopentene rearrangement were detected.

Irradiation of 3-acetoxy-2-pent-4-enylcyclohex-2-enone (12) leads to the tricyclic adduct (18), in high yield (>95%), which on hydrolytic cleavage in ethanolic potassium hydroxide gives rise to bicyclo[6.3.0]-undecane-2,6-dione (20).In contrast, irradiation of the isomeric enol acetate, 3-acetoxy-4-pent-4-enylcyclohex-2-enone (17) led to the two photoadducts (25) and (26) resulting from intramolecular photocycloaddition, and to the trione (24) produced via photo-Fries rearrangement of (17); the formation of (25) and (26) followed from the structures (29) and (27) produced after saponification-retroaldolisation of mixtures containing (25) and (26). Irradiation of the 6-pentenyl substituted enol ester (16) gave rise to only the photo-Fries rearrangement product (24).Irradiation of 1-acetoxy-2-pent-4-enoylcyclopentene(39) led (93%) to a 2:3 mixture of the photoadducts (41) and (42) whose structures followed from X-ray measurements. The corresponding cyclohexene (45), instead produced the product (46) of photo-Fries rearrangement on irradiation. Hydrolytic cleavage of (41) in KOH–EtOH leads to the bicyclo[5.3.0]decanone (47), whereas similar treatment of (42) instead gave directly the aldol (49) by way of the transient retro-aldol intermediate (48).

The application of 2-methoxy-3-n-pentylmaleic anhydride (8) in the synthesis of methyl O-methylmulticolanate (9) and its geometrical isomer is described. Comparison of 1H and 13C n.m.r. data with those of the dimethyl derivative of natural multicolanic acid (1a) from Penicillium multicolor establishes an E-geometry for (1a), and for the related multicolic (1b) and multicolosic acids (1c). The alternative bis-butenolide formulation (11) is entertained for the ylidenetetronic acids.

Rearrangement of the 4-ylidenebutenolides (4) and (5), with sodium methoxide in methanol, leads to the cyclopent-2-ene-1,4-diones (6), which when heated with sodium chloride in dimethyl sulphoxide give the 1,4-diones (7). The latter can be reduced using zinc in acetic acid, to the dihydrorethrolones (8). In a similar manner, rearrangement of (10) produces (11a) which can be demethoxycarbonylated to (11b), an intermediate used previously in a synthesis of natural jasmololone (8; R = EtCH:CH).

The application of 2-aryl O-methyltetronic acids (7) and (20) to the total synthesis of permethylated derivatives of pulvinic acid pigments found in Lepraria flava and Gomphidius glutinosus is described. Metallation of the tetronic acid (7), followed by treatment with methyl benzoylformate and dehydration of the intermediate carbinol led to O-methyl pinastric acid (9), identical with the O-methyl derivative of natural pinastric acid from L. flava. In a similar manner the tetronic acid (11) and methyl 4-methoxybenzoylformate gave O-methylisopinastric acid (12), and condensation between (20) and methyl 4-methoxybenzoylformate led to permethylated gomphidic acid (21). Comparison of 1H n.m.r. shift data for (21) with those reported for gomphidic acid from G. glutinosus established structure (2b) for the natural metabolite.

Condensation reactions between ethylidenetetronic acid (6) and aryl aldehydes in the presence of weak bases, lead to the 2 : 1 adducts (8); with 3,4-dimethoxybenzaldehyde the 1 : 1 adduct (10) is produced concurrently. Reaction between (6) and acetone initially leads to a similar 2 : 1 adduct i.e. (12), but on further heating in acetone this adduct disporportionates giving the novel dihydropyran (13). The structure of (13) was solved by single crystal X-ray determination. Comparison of spectral data, and synthesis show that the structure of the analogous compound ‘ramigenic acid’ isolated from Penicillium charlesii should be reassigned as shown in formula (17b).

A total synthesis of the iridoid lactone (±)-allamcin (3) found in Allamanda neriifolia is described. Starting from the readily available bicyclo[3.3.0]octenone (10), the synthesis uses a strategy based on: (i) elaboration of the key acetoxy-aldehyde intermediate (9) through epoxidative rearrangement of the enol acetate (71) derived from (10)via the unsaturated aldehyde (57), (ii) fusion of the β-oxy-γ-butyrolactone ring system on to (9) using the dianion (20) derived from 2-phenylthiobutanoic acid, (iii) chemo-selective vic-bishydroxylation of the ring B carbon-to-carbon double bond in (75), using osmium tetraoxide, leading to (76), (iv)in situ oxidation and elimination of phenylsulphenic acid from (76) producing the (E)-ethylidenefuranone (78), and (v) oxidative-cleavage and cyclisation from the 1,2-diol (78) in the presence of sodium metaperiodate. Allamcin was also produced when the allylic transposed intermediate (84) derived from compound (83)(MeOH–K2CO3) was treated with periodic acid. Since allamcin has previously been converted into plumericin (4) and allamandin (5), the synthesis of compound (3) also constitutes formal syntheses of (±)-(4) and (±)-(5).

Irradiation of 1:1 mixtures of enol acetates derived from 4-prop-2-enylcyclopentane-1,3-diones [i.e.(9), (23), (27), (32a), (32b)], leads to 6-acetoxytricyclo[3.2.1.03,6]octan-2-ones [i.e.(12), (24), (28), (33a), (33b)] in high yield (>70%). The adducts result from regioselective intramolecular [2 + 2] cycloaddition in the 5-prop-2-enyl enol acetate isomers [e.g.(10)], suggesting that equilibration between the isomeric enol acetates [e.g.(10) and (11)] is rapid during the irradiations. Fragmentation of the 6-acetoxytricyclo[3.2.1.03,6]octan-2-ones, either directly [e.g.(12)→(16); KOH–EtOH] or via the corresponding acetoxy-mesylates [e.g.(24)→(25)→(26)] provides a facile route to a range of substituted bicyclo[3.2.1]octane ring systems.Irradiation of the isomerically pure enol acetates (39), containing a methyl substituent at C-2, by contrast produce largely (ratio 3:2) 3-acetoxytricyclo[3.2.1.03,6]octan-7-one adducts (43) resulting from the alternative mode of intramolecular cycloaddition in the enol acetate (see Scheme 1); these adducts are also elaborated to bicyclo[3.2.1]octenones [e.g.(45)].

Oxidation of 3-acetyl-1 -propyl-5,6,7,8-tetrahydro-2-naphthol (6) with lead(IV) acetate or lead(IV) benzoate is shown to produce almost entirely the o-quinol esters, (8) and (20), respectively. By contrast, electrochemical oxidation of (6) in acetic acid at a platinum anode leads largely to the corresponding p-quinol acetate (7) in addition to (8), and also to other products [(10) and (11)]. Structure (8) was assigned unambiguously from a two-dimensional homonuclear shift-correlated 13C spectrum obtained by using a symmetrised INADEQUATE program, and an X-ray crystal structure determination was carried out on the benzoate (20). Treatment of the o-quinol acetate (8) with acetic anhydride containing sulphuric acid leads to the diacetate (9a), whereas dissolution of the p-quinol acetate (7) in dichloromethane containing ethanolic sulphuric acid produces the phenol (12). Saponification of either (12) or (9a) gives the 2′,6′-dihydroxyacetophenone (9b), a useful precursor to proxicromil (2).

(Z)-3,7-Dimethylocta-2,6-dienyltriphenylphosphonium bromide (4) has been prepared, and its condensations with formaldehyde and citral have been shown to proceed with retention of configuration about the α-double bond in the salt. Reaction between compound (4) and (Z)-citral gives a mixture of (6Z,8Z,10Z)-(15) and (6Z,8E,10Z)-(14) pentaenes showing retention or configuration about both Z-bonds in the starting materials. In a similar manner, compound (4) and (E)-citral or the (E)-phosphonium salt (5) and (Z)-citral give the pentaenes (11) and (12), whereas compound (5) and (E)-citral lead to a mixture of (6E,8E,10E)-(9) and (6E,8Z,10E)-(10) pentaenes. Mixtures of (9) and (10) and of (14) and (15) were also obtained, from (E)- and (Z)-citral respectively, by reductive coupling with titanium trichloride–lithium aluminium hydride. The isomeric pentaenes (9)–(12), (14), and (15) have been separated and characterised. 13 C N.m.r. data for the isomers of the pentaene (9), the C20 analogue of phytoene, are presented and discussed. The stereochemistry of a new isomer of phytoene from Rhodospirillum rubrum is re-examined by using comparative 13C n.m.r. data.