A multitasking C-silylation strategy using the readily available compound 26 as a surrogate for cinnamic acid represents the key design element of a total synthesis of all known members of the ipomoeassin family of resin glyosides. This protecting group maneuver allows the unsaturated acids decorating the glucose subunit of the targets to be attached at an early phase of the synthesis, prevents their participation in the ruthenium-catalyzed ring-closing metathesis (RCM) used to form the macrocyclic ring, and protects them against reduction during the hydrogenation of the resulting cycloalkene over Wilkinson's catalyst. As the C-silyl group can be concomitantly removed with the O-TBS substituent using tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF) in acetonitrile, no separate protecting group manipulations were necessary in the final stages, thus contributing to a favorable overall "economy of steps". In addition to the naturally occurring ipomoeassins, a small set of synthetic analogues has also been prepared by "diverted total synthesis". The cytotoxicity of these compounds was assayed with two different cancer cell lines. The recorded data confirm previous findings that the acylation- and oxygenation pattern of these amphiphilic glycoconjugates is highly correlated with their biological activity profile. Ipomoeassin F turned out to be the most promising member of the series, showing IC(50) values in the low nanomolar range.

A productive total synthesis of both enantiomers of berkelic acid (1) is outlined that takes the structure revision of this bioactive fungal metabolite previously proposed by our group into account. The successful route relies on a fully optimized triple-deprotection/1,4-addition/spiroacetalization cascade reaction sequence, which delivers the tetracyclic core 32 of the target as a single isomer in excellent yield. The required cyclization precursor 31 is assembled from the polysubstituted benzaldehyde derivative 20 and methyl ketone 25 by an aldol condensation, in which the acetyl residue in 20 transforms from a passive protecting group into an active participant. Access to fragment 25 takes advantage of the Collum-Godenschwager variant of the ester enolate Claisen rearrangement, which clearly surpasses the classical Ireland-Claisen procedure in terms of diastereoselectivity. Although it is possible to elaborate 32 into the target without any additional manipulations of protecting groups, a short detour consisting in the conversion of the phenolic -OH into the corresponding TBS-ether is beneficial. It tempers the sensitivity of the compound toward oxidation and hence improves the efficiency and reliability of the final stages. Orthogonal ester groups for the benzoate and the aliphatic carboxylate terminus of the side chain secure an efficient liberation of free berkelic acid in the final step of the route.

Orevactaene and epipyrone A were previously thought to comprise the same polyunsaturated tail but notably different C-glycosylated 4-hydroxy-2-pyrone head groups. Total synthesis now shows that the signature bicyclic framework assigned to orevactaene is a chimera; the compound is almost certainly identical with epipyrone A, whose previously unknown stereochemistry has also been established during this study. Key to success was the ready formation of the bicyclic core of putative orevactaene by a sequence of two alkyne cycloisomerization reactions using tungsten and gold catalysis. Equally important was the flexibility in the assembly process gained by the use of heterobimetallic polyunsaturated modules whose termini could be selectively and consecutively addressed in a practical one-pot cross-coupling sequence.

The first total synthesis of the potent antibiotic disciformycin B( 2)i sd escribed, which is exceptionally isomerization-prone and transforms into disciformycinA (1)e ven undern otably mild conditions. To outweigh this bias, the approach to 2 hingedo nt he use of as ilyl residue at C4 to lock the critical double bond in place and hence insure the integrity of the synthetic intermediates en route to 2.This tactic was instrumental for the preparation of the buildingb locks and formation of the macrocyclic ring via ring closing alkyne metathesis (RCAM). To make the end game successful, however,i tp rovedn ecessary to cleave the C-silyl protecting group off;i tw as at this stage that the exceptional sensitivity of the target becamef ully apparent.The ever-faster emergenceo fr esistantp athogenic bacteria renders the visionofaplanetliberated from infectious diseases by effective broad-spectrum antibiotics increasingly unlikely. [1] Therefore the search for new activep rinciples with different modes of action is warranted, if not even vital in the longer run. [2,3] It is against this backdropt hat the recent reports on the myxobacterialm etabolites of the disciformycina nd gulmirecin families must be seen (Figure 1). [4][5][6][7] These compounds exhibit considerable activity against Gram-positiveb acteria, including several methicillin-or vancomycin-resistant Staphyllococcus aureus strains;m ost notably,t hey seem to address an as yet unknown biological targeta nd hence likelyp rovide new opportunities in the quest for antibiotics devoid of cross-resistance with approved drugs.The constitution and stereostructure of these remarkable polyketides were determined by two independentg roups, each of which masterfullyc omplemented the spectroscopica rgumentsb ya na nalysis of the encoding gene cluster. [4,5] One of these studies suggestedt hat disciformycin B( 2,F igure 1) represents the primary product of biosynthesis;i nterestingly, 2 also proved considerably more active than its sibling 1 in an assay comprising eight different bacterial strains. [4] Yet, preliminary evidence suggests that 2 is fragile and subject to irreversible double bond migration, which is likelyd riven by the highers tabilityo ft he trisubstituted enoate in 1 compared to the disubstituted enonemotif in the parent compound 2.Intrigued by the biologicalp romisea nd the synthetic challenge forecastb yt hese reports, [4,5] we embarked into ap rogram aiming at ac hemical investigation of this familyo fn ew lead compounds. To tal synthesis is the first step to be taken in order to assess the ingrained metastabilityo f2 in more detail and scout possible remedies.A tthe same time, it is desirable to identify promising sites for late-stage modification to be addressed in then ext phase of the project. [8] The actualc onquest of disciformycin Aa nd Bo utlined below meets many of these goals;m ost notably,i tr evealed some remarkable chemical caprices of these target compounds,w hich will guide our ongoing efforts at establishing am ore scalabler ou...

A concise total synthesis of spirastrellolide A methyl ester (1 a, R(1) =Me) as the parent compound of a series of highly cytotoxic marine macrolides is disclosed, which exploits and expands the flexibility of a synthesis plan previously developed by our group en route to the sister compound spirastrellolide F methyl ester (6 a, R(1) =Me). Key to success was the masking of the signature Δ(15,16) -bond of 1 a as a C16-carbonyl group until after the stereogenic center at C24 had been properly set by a highly selective hydrogenation of the C24 exo-methylene precursor 66. Conformational control over the macrocyclic frame allowed the proper stereochemical course to be dialed into this reduction process. The elaboration of the C16 ketone to the C15-C16 double bond was accomplished by a chemoselective alkenyl triflate formation followed by a palladium-catalyzed hydride delivery. The role of the ketone at C16 as a strategic design element is also evident up-stream of the key intermediate 66, the assembly of which hinged upon the addition of the polyfunctionalized dithiane 37 to the similarly elaborate aldehyde fragment 46. Other crucial steps of the total synthesis were an alkyl-Suzuki coupling and a Yamaguchi lactonization that allowed the Northern and the Southern sector of the target to be stitched together and the macrocyclic perimeter to be forged. The lateral chain comprising the remote C46 stereocenter was finally attached to the core region by a modified Julia-Kocienski olefination. The preparation of the individual building blocks led to some methodological spin-offs, amongst which the improved procedure for the N-O-bond cleavage of isoxazolines by zero-valent molybdenum and the ozonolysis of a double bond in the presence of other oxidation-prone functionality are most noteworthy. Preliminary biological data suggest that the entire carbon framework, that is the macrocyclic core plus the lateral chain, might be necessary for high cytotoxicity.