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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 on the carbocation intermediates that connect the biosynthetic pathways leading to the sand fly pheromone sobralene and taxadiene have been made. Establishment of the conformation of the macrocyclic carbocation intermediate required to produce the (

A new sex-aggregation pheromone, sobralene, produced by the sand fly Lutzomyia longipalpis from Sorbral (Ceara State, Brazil) is shown to have the novel 6,12-membered ring-fused diterpene structure 3. It is proposed that sobralene is a likely shunt metabolite of the taxadiene synthase-catalysed cyclisation of geranygeranyl diphosphate.

The sex-aggregation pheromone sobralene produced by the sandfly Lutzomyia longipalpis is isomerised to verticillenes in the presence of mild acid, thereby providing credence to the proposal that sobralene is a likely shunt metabolite of the taxadiene synthase cascade.

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.

Treatment of the furanbutenolide 18a with trifluoroacetic acid in dichloromethane results in hydrolysis and rearrangement leading to the cycloheptene ring-containing system 19a found in rameswaralide ( 5 ). Similar treatment of the diastereoisomeric furanbutenolide 17 produces the cyclohexene ring-containing system 23 present in plumarellide ( 1 ), together with the C-7 epimer 24 of 19a . The acid-catalysed conversions 18a → 19a and 17 → 23 are rationalised implicating [6+4] and [4+2] cycloaddition pathways and/or two-step carbocation cyclisation sequences.

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.

Irradiation of natural rubifolide ( 1 ) and bipinnatin J ( 2 ) for short periods of time using a 400 W sunlamp results in photochemical Z - to E -isomerisations to their corresponding E -isomers 10 and 16 , respectively, neither of which has yet been discovered in Nature. Prolonged irradiation of rubifolide ( 1 ) produces the ring-contracted compound kallolide B ( 11a ), and photooxidation of E -rubifolide ( 10 ) leads to epilophodione ( 12 ); both 11a and 12 are found in corals. The photoisomerisation studies provide an insight into the most likely origins of more complex cembranoids, for example, 4 , 5 , 18 and 19 from the archetypal cembranoids 1 , 2 , and 3 in vivo. The studies also suggest a likely route to the unusually rearranged cembranoid sarcofuranocembrenolide B ( 23 ) via a cascade of photo-initiated radical cyclisations and rearrangements from the biradical intermediate 24 produced from cembranoid 22 .

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.

Irradiation of a solution of synthetic Z-deoxypukalide 10 in acetonitrile (Pyrex; 400 W Hg lamp) resulted in isomerisation, leading to E-deoxypukalide 12, which was isolated recently from the octocoral Leptogorgia spp. Further irradiation of 12, or prolonged irradiation of 10, then gave the ring-contracted product, deoxypseudopterolide 1 (>90%) found in octocorals of the genera Pseudopterogorgia and Leptogorgia. The contraction of the 14-membered rings in 10 and 12 to the 12-membered ring as 1, occurs by way of photochemical [1,3]-sigmatropic rearrangement.

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.

Concise syntheses of the substituted enynediones 28a, 33b and 36 starting from the cyclohexenealdehyde 18, corresponding to ring A in the taxanes, and the vinylstannane 24, are described. Treatment of 36 with Bu3SnH–AIBN did not lead to the oxy-substituted taxadiene 37 expected from a tandem radical macrocyclisation–radical transannulation sequence; instead, a mixture of unidentified products resulted. When the PMB ether 33b corresponding to the alcohol 36 was treated with Bu3SnH–AIBN under similar conditions, p-anisaldehyde was isolated, as a major by-product, but no evidence for the formation of a taxadiene could be observed. In contrast, the iododienynedione 41, i.e., deoxy 36, underwent a tandem radical macrocyclisation–transannulation sequence, when treated with Bu3SnH–AIBN, leading to the tetraoxy-bis-nortaxadiene 42 in 44% yield. Attempts to synthesise the alcohol 28b from the silyl ether 28a en route to the iodide 28c instead gave the substituted tetrahydrofuran 29 via an intramolecular oxy-Michael reaction.

Treatment of α-bromosilyl ether 27 derived from the substituted cyclopentenol 26 and (bromomethyl)chlorodimethylsilane, with 1,1′-azobis(cyclohexanecarbonitrile) in n-heptane at 100 °C, in the presence of allyltri-n-butylstannane leads to the silicon heterocycle 28 by way of a stereocontrolled tandem radical cyclisation (to 11)–trapping process. Oxidative cleavage of the carbon–silicon bond in 28, using H2O2–KF in THF–MeOH, next led to the corresponding cyclopentane diol 29a, which was then elaborated to the β-hydroxy ester 30b using five steps. Oxidation of 30b using Moffatt conditions, followed by methylation of the resulting enol ester 32a gave the fully functionalised cyclopentene ring in the antitumoural antibiotic substance viridenomycin 1 isolated from Streptomyces viridochromogenes and Streptomyces gannmycicus.

A 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 .

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).

Treatment of solutions of the furfuryl alcohol 6 in dichloromethane–methanol with buta-1,3-diene or cyclohexa-1,3-diene or with cyclopentadiene in the presence of trifluoroacetic acid leads to the corresponding substituted furyl tetrahydrofurans, 8 , 12 and 15 respectively, rather than to the products 10 , 13 and 16 anticipated from intermolecular (4+3)-type cycloaddition reactions. These outcomes provide indirect experimental support for a stepwise carbonium ion pathway operating in (4+3)-cycloaddition reactions between furanoxonium ions and 1,3-dienes. Alongside other results, the outcomes also highlight a limitation to (4+3) cycloadditions in cycloheptene ring synthesis when the precursors contain hydroxyl groups capable of intercepting any carbonium ion intermediates leading to O-heterocyclic by-products.

A conceptually new total synthesis of oestrone, based on a novel cascade of radical cyclisations from the iodo aryl vinylcyclopropane 2 , via 10 , 15 , 16 and 17 , leading to the intermediate trans , anti , trans -oestradiol derivative 11 in one step, is described. Oxidation of 11 , followed by demethylation of the resulting aryl methyl ether 18 then gives (±)-oestrone 1 .

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.

A concise synthesis of the oxygen substituted ring A compound 2 found in Taxol® 1a and Taxotere® 1b starting from 2,2-dimethylcyclohexane-1,3-dione and proceeding via the key intermediates 8 and 11 , is described. The absolute configuration of 2 was established from an X-ray crystal structure determination of a 4-bromophenylbenzoate derivative, viz. 15 .

Full details of a total synthesis of the doubly prenylated cyclic peptide trunkamide A of marine origin, and also its C45 epimer, 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.

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.

A new and convergent synthesis of the antitumour macrolide rhizoxin D 2 is described. The synthesis features a Wadsworth–Emmons olefination and a facile intramolecular Stille reaction to elaborate the 16-membered macrocyclic core 5 from the vinyl iodide 3 and the vinyl stannane 4 as key steps.

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 new approach to ring A aromatic steroids, based on cascade 13- endo - trig/dig macrocyclisations followed by sequential 5- exo-trig and 6- exo-trig transannulations, exemplified in the syntheses of the cis,anti,trans tetracycle 9 and the trans,syn tetracycle 13 from the ortho -substituted aryl polyen(yne) precursors, 8 and 12 respectively, is described.

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

In a quite remarkable regio- and stereoselective manner, each of the (all-E)-polyene selenoates 5a – c is shown to undergo cascade radical-mediated polycyclisations via consecutive 6-endo-trig reactions, leading to the corresponding all-trans, anti, tri-, penta- and heptacycles, i.e., 20, 23, and 25, in good yields. The configurations of these `steroid-like' polycycles followed from detailed examination and correlation of chemical shift data in their 13C-NMR spectra.

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 concise and convergent synthesis of the polyene thiazole-containing 19-membered bis-lactone ()-pateamine 1 is described. The synthesis features both the intra- and intermolecular Stille sp 2 – sp 2 coupling reactions to elaborate the E,Z -diene macrolide core and the side-chain all- E polyene portion of the natural product, and highlights the scope for enantiopure sulfinimine intermediates in the synthesis of chiral β - amino ester moieties in complex structures.

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.

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.

The Stille cross-coupling reaction between a vinylcyclopropylstannaneand iodobenzene or phenol triflate provides an expedious route to1,2-phenylvinylcyclopropanes. However, similar coupling reactionsusing ORTHO-substituted aromatic substratesalso lead to butylaromatic products, resulting from competitivesp 3 -sp 2 -sp 2  couplingreactions.

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.

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 .

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

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.

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.