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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 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.

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 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.

Variable temperature circular dichroism (CD) spectra of the patellamides A (3), B (4) and E (5), isolated from the ascidian (‘sea squirt’) Lissoclinum patella, show that they have very similar thermodynamically preferred macrocyclic ring conformations. In addition, the CD profile of the ‘figure eight like’ conformation 10 in the patellamides has been defined, and CD spectroscopy is shown to provide an insight into the interconversions between the limiting conformations, 9 and 10, in this family of cyclopeptides. The cyclopeptides 3–5 bind both Cu2+ and Zn2+ and CD studies show that as a family, in line with previous studies, they can bind more than one metal ion per molecule. Thus, the first binding domain for the three patellamides shows a binding constant in the range 2 × 104 to 2 × 105, and a second binding site for patellamide B (4) has K = 230 (Cu2+) and K = 16–20 (Zn2+). The CD spectra of the patellamide–metal conjugates can be correlated with the ‘square form’ conformation 9 of the cyclopeptides. This best fit situation vis-a-vis metal chelation, could have important implications regarding the biological activity and modus operandi of the cyclopeptides in vivo.

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.

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 series of N-propenyl substituted N-benzylcarbamoylcobalt(III) salophens, i.e.11, 20 and 30, have been prepared, and have been shown to be useful precursors in a new approach to β-lactams (viz.12-16, 21 and 31), via 4-exo-trig modes of cyclisation of the corresponding intermediate carbamoyl radicals. A new formal synthesis of (±)-thienamycin 1 from the trans-disubstituted azetidin-2-one 31 produced in one step by heating the carbamoylcobalt salophen 30 in toluene, is also described.

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.

A concise synthesis of optically active (–)-zearalenone, which uses a novel 14-endo-trig macrocyclisation from a cinnamyl radical intermediate onto an α,β-enone electrophore as a key feature, is described.

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.

A concise total synthesis of (±)-citreoviral which illustrates a new stereoselective approach to hydroxy-substituted tetrahydrofurans is described. Key features in the synthesis are: (i) elaboration of the Z-unsaturated epoxy ester 10, (ii) acid-catalysed cyclisation of ester 10 to the 4-hydroxyethyl-substituted but-2-enolide 14, (iii) stereoselective vicinal hydroxylation of the butenolide 14 to the diol15, (iv) cyclic ether formation from diol 15 to the bicyclic lactone 8via the benzylidene acetal 9, (v) transesterification of bicycle 8 to the tetrahydrofuran 21 containing three of the four centres in citreoviral in the correct relative configuration. Inversion of the secondary 3-OH group in compound 21, and elaboration of the C-2 side-chain, then completed the synthesis of (±)-citreoviral.

Hydrocobaltation of myrcene (3) by pyridinatocobaloxime leads to a 2:1 mixture of the E- and Z-allylcobaloxime (4a) and (4b) in good yield. When a solution of the cobaloximes (4a) and (4b) in toluene is heated in the presence of tetramethylpiperidine oxide (TEMPO) the hydroxylamines (7a) and (7b) result, which can be converted into geraniol (8a) and nerol (8b) by reduction using zinc in acetic acid. By contrast, in the presence of molecular oxygen, the allylcobaloxime (4) is converted into the allylperoxycobaloxime (15) which on reduction produces (±)-linalool (16). In addition, when the cobaloxime (15) is heated with TEMPO it undergoes cyclisation to the tetrahydrofuran (17), precursor to (+)-linalool oxide (18). Whereas the 1,3-dienes (20)–(24) all failed to undergo hydrocobaltation reactions, both cobaloximes (27) and (28) were easily obtained from 2-methyl-(25) and 2,3-dimethyl-buta-1,3-diene (26), respectively. Using similar chemistry to that described for compound (4), the allylcobaloxime (27) was smoothly converted into the hydroxylamine (29) and into the epoxy-TEMPO derivative (32).

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 phomactin A (1) based on a Cr(II)/Ni(II) macrocyclisation from the aldehyde vinyl iodide 11, leading to 12, followed by elaboration of the epoxyketone 16, which then undergoes spontaneous pyran-hemiacetal formation on deprotection, is described.

Macrocyclic and polycyclic ‘cembranoid’ diterpenes are one of the most widespread groups of natural products that are found in the marine milieu. The macrocyclic cembranoids are linked to each other by a network of oxygenation processes, which often climax with the formation of furano- and furanobutenolide-based macrocyclic cembranoids commonly found in gorgonian and soft corals. These macrocycles are then prone to oxidative rearrangements, photochemical ring contraction, and transannular cyclisations amongst others, leading to a plethora of novel and architecturally attractive marine metabolites. Although there is a dearth of knowledge about the enzymes that trigger some of the steps in their biosynthesis, speculations are rife. In this personal perspective we have examined many of the structural relationships within oxycembranoids and their relatives isolated from corals. This has allowed us to speculate on the likely biosynthetic interrelationships between structurally similar metabolites, and then propose some likely key carbon-to-carbon bond forming reactions that are followed in vivo in linking macrocyclic cembranoids to their polycyclic congeners. Biomimetic synthesis studies, which vindicate some of the biosynthetic speculations, are interweaved in the discussion.

Tubular and cage structures, i.e. 16 and 18, have been synthesised from modified cyclic peptides following selective cyclotrimerisations of L-ornithine and L-glutamic acid thiazole amino acids under high dilution conditions.

An asymmetric synthesis of the furanobutenolide-based macrocyclic diterpene (-)-bipinnatin J (4a) isolated from the gorgonian octocoral Pseudopterogorgonia bipinnata is described. The synthesis is based on elaboration of the chiral lactone-substituted vinyl iodide 26b from (+)-glycidol, followed by an intermolecular Stille coupling reaction with the stannylfurfural 27, leading to 28a, and then an intramolecular Nozaki-Hiyama-Kishi allylation reaction, 28b --> 4a. Treatment of (-)-bipinnatin J (4a) with VO(acac)2-tBuO2H followed by acetylation of the tautomeric hydroxypyranone product 7/8, next gave the acetoxypyrone 30. When the acetoxypyranone 30 was heated in acetonitrile in the presence of DBU, it gave (+)-intricarene 1, which is found in P. kallos, via a novel transannular [5+2] (or 1,3-dipolar) cycloaddition involving the butenolide-oxidopyrylium ion intermediate 31. We believe that this total synthesis of (+)-intricarene 1 mimics its most likely origin in nature via oxidation of (-)-bipinnatin J (4a), presumably involving photochemically generated singlet oxygen or possibly a P450 monooxygenase enzyme system.

A 14-step total synthesis of (+/-)-salinosporamide A (1), a potent inhibitor of the 20S proteasome isolated from the marine bacterium Salinospora tropica, is described. The synthesis is based on a diastereoselective intramolecular aldolisation of a substituted beta-keto amide intermediate, i.e. 13, derived from a beta-keto acid, viz. 21, and an alpha-amino malonate, leading to the pyrrolidinone ring 24 in the natural product. This synthetic approach closely mimics the origin of the pyrrolidinone ring in salinosporamide A in vivo. Another key feature of the total synthesis is a regioselective reduction of the malonate derivative 31 to the key aldehyde intermediate 32, using Super-hydride.

Treatment of the acetylenic bromoamide 42c, derived from the enantiopure alpha-amino alcohol 40, with Bu(3)SnH-AlBN results in an efficient 5-exo dig radical cyclisation to the 4-methylenepyrrolidinone 43/44 (2:1). Cleavage of the alkene bond in 43/44, using O(3)-Me(2)S, next gave the corresponding 4-ketopyrrolidinone 45/46. Alpha-phenylsulfanylation of 45/46, using S-methyl-p-toluenethiosulfonate-Et(3)N, proceeded in a stereoselective manner and led to the methylsulfanyl derivative 48 (ca. 9:1 selectivity). Manipulation of the functionality in 48, using two separate sequences, then led to the substituted pyrrolidinones 49b, 50 and 53 which are advanced intermediates in a previous synthesis of (+)-lactacystin 1. In related studies, the acetylenic bromoamide 28a containing all the carbon atoms in lactacystin was synthesised, but this substrate failed to undergo an anticipated radical cyclisation to the 4-methylenepyrrolidinone 30, analogous to 43/44. Instead, only the product of reduction of 28a, i.e. 28b, was produced, possibly resulting from adventitious intramolecular hydrogen-abstraction processes from the carbon centred radical intermediate 29, i.e. 32 to 33 and/or 31 to 34.

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.

A cascade radical-mediated Diels-Alder reaction with the iododienynone 16b produced the tricyclic ketone 17 (22%). By contrast, treatment of the substituted furans 36 and 47 with Bu(3)SnH-AIBN, instead led to the tetracycles 44 and 58 respectively, rather than the anticipated oestranes, i.e. 38 and 48. In a separate study, attempted cascade radical-mediated cyclisations from the ortho-aryl substituted iododienynones 72 and 73, leading to the ring-D aromatic steroid 7, instead gave the macrocyclic ketone 76 or the novel bridged tricycles 77/82, respectively, depending on whether benzene or heptane was used as solvent in the reactions.

An enantioselective synthesis of rhizoxin D (2), isolated from the plant pathogenic fungus Rhizopus chinensis, is described. The overall strategy is based on elaboration of the δ-lactone-substituted vinyl stannane 7 and the phosphonate-substituted vinyl iodide 9, followed by their coupling to the core 16-membered macrolide 6via a sequential intermolecular Horner–Wadsworth–Emmons olefination, leading to 50, and by an intramolecular Stille reaction. The triene oxazole-containing side chain in rhizoxin D is then introduced using the phosphine oxide 8 in an E-selective Horner–Wittig reaction with the macrolide aldehyde 51b.

Treatment of a variety of substituted vinylcyclopropyl selenyl esters, e.g. 11, with Bu(3)SnH-AIBN in refluxing benzene leads to the corresponding acyl radical intermediates, which undergo rearrangement and intramolecular cyclisations via their ketene alkyl radical equivalents producing cyclohexenones in 50-60% yield. By contrast, treatment of conjugated triene selenyl esters, e.g. 32, with Bu(3)SnH-AIBN produces substituted 2-cyclopentenones via intramolecular cyclisations of their ketene alkyl radical intermediates. Under the same radical-initiating conditions the selenyl esters derived from o-vinylbenzoic acid and o-vinylcinnamic acid undergo intramolecular cyclisations producing 1-indanone and 5,6-dihydrobenzocyclohepten-7-one respectively in 60-70% yields. A tandem radical cyclisation from the alpha,beta,gamma,delta-diene selenyl ester 31 provides an expeditious synthesis of the diquinane 35 in 69% yield.

A concise synthesis of the tricyclic furanochroman unit 3 found in the PAF antagonist phomactin A (1) isolated from the marine fungus Phoma sp., is described. In complementary studies, a variety of synthetic routes towards the bicyclo[9.3.1]pentadecane ring system 4 in phomactin A were explored. These studies culminated in a synthesis of the substituted ring system 79 containing all the carbon atoms and all the necessary oxygen centres for elaboration to phomactin A itself.

The total syntheses of the epoxy cyclic hemiacetal structures 8 and 9, which are isomeric with the structure 6 proposed for the phomactin known as Sch 49028 isolated from the marine fungus Phoma sp. are described. Neither of these structures showed spectroscopic data consistent with those reported for the purported natural product, adding credibility to the proposal that the structure Sch 49028 does not exist in nature and that its NMR spectroscopic data should have been assigned as phomactin A (1).

Regioselective (1,4-) hydrocobaltation of myrcene (1) leads to a 2 : 1 mixture of (E)- and (Z)-allylcobaloximes (2) which can be converted via the corresponding hydroxylamines (5) to geraniol (6a) and nerol (6b); by contrast, in the presence of molecular oxygen, (2) is converted into the peroxyallylcobalt complex (7), a precursor to linalool (8) and to linalool oxide (10).

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.