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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 total synthesis establishes the structure and stereochemistry of the novel heterocycle-based cyclopeptide cyclodidemnamide isolated from the “sea squirt” Didemnum molle as 1b , not 1a .

Total synthesis demonstrates that the structures and stereochemistries of the cyclopeptides raocyclamide A and B isolated from a cyanobacterium should be altered to those shown in formulae 13 and 14 respectively.

Vanadium(V) oxytrinitrate is an easy to handle reagent which can be used to nitrate a range of substituted aromatic compounds in dichloromethane at room temperature, leading to >99% yields of nitration products in most cases.

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 2 , is described.

The scope for a range of sp 2 -sp 2 coupling protocols to elaborate the phenyl-indole, indole-oxazole, oxazole-oxazole, and quaternary carbon units in the marine natural product diazonamide A 1 are described, leading to the synthesis of the benzofuran oxazoles 11a and 18 , the benzofuran/biphenyl/indole 16 , and the indole- bis -oxazole, 25 .

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 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.

The total synthesis of lissoclinamide 4 and lissoclinamide 5, which are novel oxazoline/thiazole/thiazoline-based cyclopeptides isolated from the ascidian (“sea squirt”) Lissoclinum patella, are described. The synthesis of the bis-thiazole based lissoclinamide 5 necessitated the development of practical solutions to the elaboration of enantiomerically pure valine and phenylalanine substituted thiazoles. To overcome the problems associated with the configurational lability of enantiopure amino acid substituted thiazolines, the thiazoline-based cyclopeptide lissoclinamide 4 was synthesised using a novel strategy whereby both the oxazoline and the thiazoline rings in the natural product were formed simultaneously in a “one-pot” double cyclodehydration sequence from an appropriate thioamide/amide cyclopeptide precursor. Based on our synthetic work the stereochemistries 2 and 1 published for natural lissoclinamide 4 and lissoclinamide 5 were re-assigned to 16 and 15 respectively.

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

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.

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

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

The vicinal bis- and tris- epoxides (14) and (20), together with their diastereoisomeric partners are conveniently produced when the corresponding polyenes (12) and (13) are treated with dimethyldioxirane. In a similar manner, treatment of (25) with dimethyldioxirane leads to the stereoisomer (26) of (14). Acid-catalysed, biomimetic, cyclisations of the vicinal bis-epoxides (14), (20) and (26) then leads to the corresponding dihydroxytetrahydrofuran products, including the stereoisomer (27) used in a synthesis of (±)-citreoviral (1).

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

This presentation summarises the progress maded in the constructing models for the biological activities of the ulapualides,lissoclinamides and leinamycin

Cobalt mediated tandem radical cyclisations, viz ( 1 ), → ( 3 ), ) 5 ) → ( 7 ), ( 10 ) → ( 13 ), can be carried out in sequence with isolation of intermediate organocobalt reagents, i.e ( 2 ), ( 6 ), ( 11 ), or alternatively in a ‘one-pot’ operation. In the presence of reactive radical trapping agents (e.g. 3 O 2 , TEMPO) the intermediate organocobalt reagents undergo functional group exchange, [e.g. ( 11 ) → ( 15 ) and ( 14 ) respectively], whereas in the presence of less reactive styrene, a cascade of cobalt group transfer-radical trapping-tandem radical cyclisation - dehydrocobaltation reactions result allowing, for example, the five step ‘one-pot’ synthesis of ( 12 ) from ( 10 ) in 20% overall yield.

A concise synthesis of the furan-containing macrocyclic (cembranoid) ring system 8 (10-isopropenyl-3,7,1 13-trimethyl-15-oxabicyclo[10.2.1] pentadeca-2,6,12,14-tetraene) found in lophotoxin (1) and other members of this family of irreversible nicotinic receptor antagonists, is described. The synthesis features a 14-endo trig cyclisation from an unsaturated acyl radical intermediate incor porating a terminal conjugated enone moiety, viz 10, leading to the macrocycle (5E,9E)-13-isopropenyl-2,6,10-trimethylcyclotetradeca-5,9-diene-2,4-dione (9), followed by acid-catalysed furan ring formation from the resulting 1,4-dione system in 9 (Scheme 1)

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.

A new approach to the synthesis of the angular triquinane (±)-pentalenene, based on sequential 5- exo -trig and 5- exo -dig radical cyclisations involving ketene intermediates produced from an α,β-unsaturated acyl radical precursor, is described.

A total synthesis of the novel sesquiterpene anthecularin 1, isolated from Greek Anthemis auriculata, based on an intramolecular [5+2] (1,3-dipolar) cycloaddition involving the oxidopyrylium ion 12 derived from the furanmethanol 9, is described.

A synthesis of the 1,3-dioxo-1,2-dithiolabne residue ( 2 ) found in the antitumour antibiotic substance leinamycin ( 1 ) is described which features: (i) elaboration of the thiolactone ( 5 ), followed by (ii) ring opening to the thioacid ( 9 ) using H 2 S-Et 3 N and (iii) ring closure of ( 9 ) to ( 4 ) in the presence of aq. FeCl 3 , and finally (iv) oxidation (Scheme 1). 30071991

Treatment of the unsaturated decanols (7), (9) and (16) with iodosylbenzene diacetate-iodine leads to the formation of intermediate allyloxy radicals viz (1) which undergo fragmentation followed by transannular cyclisation of the resulting carbon centered radicals (2) leading to the bicyclo [5.3.0]decanones [(3), “hydroazulenones”] (Scheme 1). When the iodomethylhydroazulenones (3) (R′=I) are treated with Bu3SnH-AIBN under high dilution, they undergo ring expansion to the isomeric bicyclo[6.3.0]undecanones (4).

A new synthesis of (±)-thienamycin (1), based on elaboration of the key intermediate (12) in one step by heating a solution of the carbamoylcobalt salophen (11) in toluene, 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.

A convergent, complementary, synthetic approach to the contiguously linked tris-oxazole units 10, 11 and 12 in telomestatin (1) and YM-216391 (2) is described. The route involves coupling reactions between oxazole 4-carboxylic acids, viz 16a, 16c, 16d and oxazole 2-substituted methylamines, viz 16b, 16e, 17, leading to the amides 18 and 21, followed by cyclodehydrations to the corresponding bis-oxazole oxazolines, e.g. 19, and oxidations of the latter using well-established protocols. The tris-oxazoles 11 and 12 were next converted stepwise into the hexa-oxazole bis-macrolactams 33. Although the bis-macrolactams 33 (cf. 28) could be converted into the corresponding oxazoline-hexa-oxazoles 34 and to the enamides 35, neither of these intermediates could be elaborated to the hepta-oxazole 30en route to telomestatin 1. Likewise, neither the hexa-oxazole 47 or application of an intramolecular Hantzsch oxazole ring-forming reaction from 44b allowed access to the advanced polyoxazole-macrolactam intermediates 48 and 30a, respectively, towards telomestatin. Combination of the tris-oxazole based methylamine 70 with the dipeptide carboxylic acid 71 derived from D-valine and L-isoleucine, leads to the corresponding amide which, in two straightforward steps, is converted into the -amino acid 78. Macrolactamisation of 78, using HATU, next produces the cyclopeptide 79 which is then elaborated to the thiazole and oxazole based cyclopeptide YM-216391 (2). The synthetic cyclopeptide 2 is shown to be the enantiomer of the natural product isolated from Streptomyces nobilis.

A new, second generation, total synthesis of ulapualide A (1), whose stereochemistry was recently determined from X-ray analysis of its complex with the protein actin, is described. The synthesis is designed and based on some speculation of the biosynthetic origin of the contiguous tris-oxazole unit in ulapualide A, alongside that of the related co-metabolites that contain only two oxazole rings, e.g. 6 and 7. The mono-oxazole carboxylic acid 67b and the mono-oxazole secondary 55b alcohol which, together, contain all of the 10 asymmetric centres in the natural metabolite, were first elaborated using a combination of contemporary asymmetric synthesis protocols. Esterification of 67b with 55b under Yamaguchi conditions gave the ester 77 which was then converted into the omega-amino acid 18a following simultaneous deprotection of the t-butyl ester and the N-Boc protecting groups. Macrolactamisation of 18a, using HATU, now gave the key intermediate macrolactam 17, containing two of the three oxazole rings in ulapualide A (1). A number of procedures were used to introduce the third oxazole ring in ulapualide A from 17, including: a) cyclodehydration to the oxazoline 78a followed by oxidation using nickel peroxide leading to 76; b) dehydration to the enamide 79, followed by conversion into the methoxyoxazoline 78b, via 80, and elimination of methanol from 78b using camphorsulfonic acid. The tris-oxazole macrolide 76 was next converted into the aldehyde 82b in four straightforward steps, which was then reacted with N-methylformamide, leading to the E-alkenylformamide 83. Removal of the TBDPS protection at C3 in 83 finally gave (-)-ulapualide A, whose 1H and 13C NMR spectroscopic data were indistinguishable from those obtained for naturally derived material. It is likely that the tris-oxazole unit in ulapualide A (1) is derived in nature from a cascade of cyclodehydrations from an acylated tris-serine precursor, e.g.9, followed by oxidation of the resulting tris-oxazoline intermediate, i.e.10. It is also plausible to speculate that the biosynthesis of metabolites related to ulapualide A, e.g. the bis-oxazole 6 and the imide 7, involve cyclisations of just two of the serine units in 9. These speculations were given some credence by carrying out pertinent interconversions involving the bis-oxazole amide 24, the enamide 25, the imide 26, the oxazoline 27 and the tris-oxazole 30 as model compounds. An alternative strategy to the tris-oxazole macrolide intermediate 76 was also examined, involving preliminary synthesis of the aldehyde 73, containing a shortened (C25-C34) side chain from 67b and 47b. A Wadsworth-Emmons olefination reaction between 73 and the phosphonate ester 74 led smoothly to the E-alkene 75, but we were not able to reduce selectively the conjugated enone group in 75 to 76 without simultaneous reduction of the oxazole alkene bond, using a variety of reagents and reaction conditions.

A total synthesis of the all- cis cyclopentanetetrol moiety (19) present in funiculosin (1), featuring the Claisen-Ireland rearrangement (8) → (9), iodolactonisation (9) → (10 a ), and the intramolecular oxygen nucleophile displacement (14) → (16), as key steps, is described.