Katalyse und Totalsynthese: eine persönliche Zwischenbilanz

Lactones are known to react with the reagent generated in situ from CCl4 and PPh3 in a Wittig-type fashion to give gem-dichloro-olefin derivatives. Such compounds are now shown to undergo reductive alkylation on treatment with organolithium reagents RLi to furnish acetylene derivatives bearing the substituent R at their termini (R=Me, n-, sec-, tert-alkyl, silyl); the reaction can be catalyzed with either Cu(acac)2 or Fe(acac)3 /1,2-diaminobenzene. Two alkynol derivatives prepared in this way from readily accessible lactone precursors served as the key building blocks for the total syntheses of the cytotoxic marine macrolides tulearin A (1) and C (2). The assembly of these fragile targets hinged upon ring closing alkyne metathesis (RCAM) followed by a formal trans-reduction of the resulting cycloalkynes via trans-hydrosilylation/protodesilylation.

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“…First forays in this direction have recently been reported by our laboratory, which are currently subject to intense scrutiny. [67][68][69][70] …”

Section: Resultsmentioning

confidence: 99%

A New Method for the Preparation of Non‐Terminal Alkynes: Application to the Total Syntheses of Tulearin A and C

Lehr

Schulthoff

Ueda

et al. 2014

Chemistry A European J

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“…From a somewhat larger perspective, this study therefore also helps illustrate the tremendous opportunities that π‐acid catalysis provides for heterocyclic chemistry and natural product synthesis 35. Together with the selective triple‐bond metathesis event as the other key step en route to 1 , it adds a new entry into a now rapidly growing list of examples featuring the strategic advantages of contemporary (catalytic) alkyne chemistry, to which our group is strongly committed 36…”

Section: Methodsmentioning

confidence: 99%

Total Synthesis of an Exceptional Brominated 4‐Pyrone Derivative of Algal Origin: An Exercise in Gold Catalysis and Alkyne Metathesis

Hoffmeister

Fukuda

Pototschnig

et al. 2015

Chemistry A European J

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A concise approach to the algal metabolite 1 is described, which also determines the previously unknown stereostructure of this natural product. Compound 1 is distinguished by a rare brominated 4-pyrone nucleus linked as a ketene–acetal to a polyunsaturated macrocyclic scaffold comprising an extra homoallylic bromide entity. The synthesis of 1 is based on the elaboration and selective functionalization of the linear precursor 23 endowed with no less than six different sites of unsaturation including the highly enolized oxo-alkanoate function. Key to success was the formation of the 2-alkoxy-4-pyrone ring by a novel gold-catalyzed transformation which engages only the acetylenic β-ketoester substructure of 23 but leaves all other π-bonds untouched. The synthesis was completed by a ring-closing alkyne metathesis to forge the signature cycloalkyne motif of 1 followed by selective bromination of the ketene–acetal site in the resulting product 27 without touching the skipped diene–yne substructure resident within the macrocyclic tether

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“…21 Moreover, it becomes increasingly clear that ample synergy can be drawn from these orthogonal ways of making and/or manipulating triple bonds, when properly synchronized 17. 79 This strategic dividend rendered our syntheses of 1 and 4 very competitive, not least in terms of an auspicious step count and a generous material supply. Ongoing work in this laboratory intends to further leverage the merits of catalytic alkyne chemistry.…”

Section: Resultsmentioning

confidence: 99%

Concise Total Syntheses of Amphidinolides C and F

Valot

Mailhol

Regens

et al. 2014

Chemistry A European J

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The marine natural products amphidinolide C (1) and F (4) differ in their side chains but share a common macrolide core with a signature 1,4-diketone substructure. This particular motif inspired a synthesis plan predicating a late-stage formation of this non-consonant ("umpoled") pattern by a platinum-catalyzed transannular hydroalkoxylation of a cycloalkyne precursor. This key intermediate was assembled from three building blocks (29, 41 and 47 (or 65)) by Yamaguchi esterification, Stille cross-coupling and a macrocyclization by ring-closing alkyne metathesis (RCAM). This approach illustrates the exquisite alkynophilicity of the catalysts chosen for the RCAM and alkyne hydroalkoxylation steps, which activate triple bonds with remarkable ease but left up to five other π-systems in the respective substrates intact. Interestingly, the inverse chemoselectivity pattern was exploited for the preparation of the tetrahydrofuran building blocks 47 and 65 carrying the different side chains of the two target macrolides. These fragments derive from a common aldehyde precursor 46 formed by an exquisitely alkene-selective cobalt-catalyzed oxidative cyclization of the diunsaturated alcohol 44, which left an adjacent acetylene group untouched. The northern sector 29 was prepared by a two-directional Marshall propargylation strategy, whereas the highly adorned acid subunit 41 derives from D-glutamic acid by an intramolecular oxa-Michael addition and a proline-mediated hydroxyacetone aldol reaction as the key steps; the necessary Me3 Sn-group on the terminus of 41 for use in the Stille coupling was installed via enol triflate 39, which was obtained by selective deprotonation/triflation of the ketone site of the precursor 38 without competing enolization of the ester also present in this particular substrate.

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Katalyse und Totalsynthese: eine persönliche Zwischenbilanz

Cited by 38 publications

References 213 publications

A New Method for the Preparation of Non‐Terminal Alkynes: Application to the Total Syntheses of Tulearin A and C

A New Method for the Preparation of Non‐Terminal Alkynes: Application to the Total Syntheses of Tulearin A and C

Total Synthesis of an Exceptional Brominated 4‐Pyrone Derivative of Algal Origin: An Exercise in Gold Catalysis and Alkyne Metathesis

Concise Total Syntheses of Amphidinolides C and F

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