Ring-closing Alkyne Metathesis Research Articles

Total Synthesis of the Guangnanmycin A Alcohol

AbstractGuangnanmycin A is a recently discovered congener of the well‐known antitumor drug lead leinamycin; its macrolactam ring, however, is even more strained than that of the parent compound. The first synthetic foray towards this challenging target is reported, which relies on molybdenum‐catalyzed macrocyclization by ring closing alkyne metathesis (RCAM) followed by ruthenium‐catalyzed redox isomerization of the propargyl alcohol thus formed; the resulting enone enabled the introduction of the yet missing exo‐methylene group by a modified Peterson olefination. The signature disulfide moiety of guangnanmycin A was installed by strain‐driven thia‐Michael addition followed by conversion of the thioether thus formed into an unsymmetric disulfide with the aid of (methylthio)dimethylsulfonium tetrafluoroborate and MeSSMe. While this sequence furnished racemic guangnanmycin A alcohol in good overall yield, the final oxidation to the corresponding acid failed, most likely because of the exceptional sensitivity of the strained scaffold.

Total Synthesis of the Guangnanmycin A Alcohol.

Guangnanmycin A is a recently discovered congener of the well-known antitumor drug lead leinamycin; its macrolactam ring, however, is even more strained than that of the parent compound. The first synthetic foray towards this challenging target is reported, which relies on molybdenum-catalyzed macrocyclization by ring closing alkyne metathesis (RCAM) followed by ruthenium-catalyzed redox isomerization of the propargyl alcohol thus formed; the resulting enone enabled the introduction of the yet missing exo-methylene group by a modified Peterson olefination. The signature disulfide moiety of guangnanmycin A was installed by strain-driven thia-Michael addition followed by conversion of the thioether thus formed into an unsymmetric disulfide with the aid of (methylthio)dimethylsulfonium tetrafluoroborate and MeSSMe. While this sequence furnished racemic guangnanmycin A alcohol in good overall yield, the final oxidation to the corresponding acid failed, most likely because of the exceptional sensitivity of the strained scaffold.

Total Synthesis of the Allenic Macrolide (+)-Archangiumide.

Archangiumide is the first known macrolide natural product comprising an endocyclic allene. For the ring strain that this linear substructure might entail, it was planned to unveil the allene at a very late stage of the projected total synthesis; in actual fact, this was achieved as the last step of the longest linear sequence by using an otherwise globally deprotected substrate. This unconventional timing was made possible by a gold catalyzed rearrangement of a macrocyclic propargyl benzyl ether derivative that uses a -PMB group as latent hydride source to unveil the signature cycloallene; the protecting group therefore gains a strategic role beyond its mere safeguarding function. Although the gold catalyzed reaction per se is stereoablative, the macrocyclic frame of the target was found to impose high selectivity and a stereoconvergent character on the transformation. The required substrate was formed by ring closing alkyne metathesis (RCAM) with the aid of a new air-stable molybdenum alkylidyne catalyst.

Total Synthesis of Njaoamine C by Concurrent Macrocycle Formation.

In conceptual terms, the first total synthesis of the cytotoxic marine natural product njaoamine C differs from all known approaches toward related alkaloids of the manzamine superfamily in that both macrocyclic rings enveloping the diazatricyclic core are concomitantly formed; this goal was reached by double ring closing alkyne metathesis (dRCAM). The success of this maneuver does not merely reflect a favorable preorientation of the four alkyne chains that need to be concatenated in the proper pairwise manner but is also the outcome of dynamic covalent chemistry involving error correction by the chosen "canopy" molybdenum alkylidyne catalyst. The end game downstream of dRCAM capitalizes on the striking chemoselectivity of palladium-catalyzed hydrostannation, which selects for (hetero)arylalkynes even in the presence of sterically much more accessible dialkylalkynes or alkenes; for this preference, the method complements the classical repertoire of hydrometalation and semireduction reactions.

Synthesis of Berkeleylactone A by Ring‐Closing Alkyne Metathesis

AbstractA new route to the macrolactone antibiotic berkeleylactone A was developed. As a key step, a ring‐closing alkyne metathesis (RCAM) of an ester substrate featuring 1‐propynyl termini was used. The carboxylic part of the substrate was easily assembled using alkyne chemistry, like carboxylation of a diyne followed by isomerization of the ynoate section to a dienoate and dihydroxylation of the 4,5‐double bond. The synthesis of the alcohol part of the ester started with opening of (R)‐propylene oxide with an acetylide and was followed by two triple bond migrations. After successful RCAM which formed the C8−C9 bond, the triple bond was selectively hydrogenated to the corresponding alkene before the 4,5‐diol was oxidized to the 5‐hydroxy‐4‐oxo derivative. At this stage, the thioether was formed and the 8,9‐double bond reduced. We also prepared the 8,9‐didehydro analog of berkeleylactone A. However, it turned out that its antimicrobial activity was slightly reduced.

Total Synthesis of the Tetracyclic Pyridinium Alkaloid epi-Tetradehydrohalicyclamine B.

The first total synthesis of a tetracyclic marine pyridinium alkaloid hinged on recent advances in chemoselectivity management: While many classical methods failed to afford the perceptively simple pyridine-containing core of the target, nickel/iridium photoredox dual catalysis allowed the critical C-C bond to be formed in good yield. Likewise, ring closing alkyne metathesis (RCAM) worked well in the presence of the unhindered pyridine despite the innately Lewis acidic Mo(+6) center of the alkylidyne catalyst. Finally, an iridium catalyzed hydrosilylation was uniquely effective in reducing a tertiary amide without compromising an adjacent pyridine and the lateral double bonds; this transformation is largely without precedent. The second strained macrocycle enveloping the core was closed by intramolecular N-alkylation with formation of the pyridinium unit; the reaction proceeded site- and chemoselectively in the presence of an a priori more basic tertiary amine.

Total Synthesis of the Tetracyclic Pyridinium Alkaloid epi‐Tetradehydrohalicyclamine B

AbstractThe first total synthesis of a tetracyclic marine pyridinium alkaloid hinged on recent advances in chemoselectivity management: While many classical methods failed to afford the perceptively simple pyridine‐containing core of the target, nickel/iridium photoredox dual catalysis allowed the critical C−C bond to be formed in good yield. Likewise, ring closing alkyne metathesis (RCAM) worked well in the presence of the unhindered pyridine despite the innately Lewis acidic Mo(+6) center of the alkylidyne catalyst. Finally, an iridium catalyzed hydrosilylation was uniquely effective in reducing a tertiary amide without compromising an adjacent pyridine and the lateral double bonds; this transformation is largely without precedent. The second strained macrocycle enveloping the core was closed by intramolecular N‐alkylation with formation of the pyridinium unit; the reaction proceeded site‐ and chemoselectively in the presence of an a priori more basic tertiary amine.

Alkyne Metathesis with d2 Re(V) Alkylidyne Complexes Supported by Phosphino-Phenolates: Ligand Effect on Catalytic Activity and Applications in Ring-Closing Alkyne Metathesis.

A family of d2 Re(V) alkylidyne complexes bearing two decorated phosphino-phenolates (POs) and a labile pyridine ligand were prepared that can efficiently promote alkyne metathesis reactions in toluene. The relative activity of these complexes varies with the PO ligands. Complexes with an electron-rich metal center have a higher activity. Ligand exchange experiments suggest that the pyridine ligands of the Re(V) alkylidynes with more electron-donating PO ligands are more labile and are more easily released to generate catalytically active species. However, complexes with electron-withdrawing PO ligands are more air-stable than those with electron-donating PO ligands. These Re(V) alkylidyne catalysts can promote the homometathesis of functionalized internal alkyl- and aryl-alkynes, as well as ring-closing alkyne metathesis (RCAM) of methyl-capped diynes, forming macrocycles with a ring size ≥12 efficiently for concentrations ≤5 mM. These reactions represent the first examples of RCAM mediated by non-d0 alkylidyne complexes. The Re(V) alkylidyne catalysts tolerate a wide range of functional groups including ethers, esters, ketones, aldehydes, alcohols, phenols, amines, amides, and heterocycles. Moreover, the catalytic RCAM reactions promoted by robust Re(V) alkylidyne catalysts could also proceed normally in wet toluene.

A Unified Approach to Polycyclic Alkaloids of the Ingenamine Estate: Total Syntheses of Keramaphidin B, Ingenamine, and Nominal Njaoamine I.

Many polycyclic marine alkaloids are thought to derive from partly reduced macrocyclic alkylpyridine derivatives via a transannular Diels–Alder reaction that forms their common etheno-bridged diaza-decaline core (“Baldwin–Whitehead hypothesis”). Rather than trying to emulate this biosynthesis pathway, a route to these natural products following purely chemical logic was pursued. Specifically, a Michael/Michael addition cascade provided rapid access to this conspicuous tricyclic scaffold and allowed different handles to be introduced at the bridgehead quarternary center. This flexibility opened opportunities for the formation of the enveloping medium-sized and macrocyclic rings. Ring closing alkyne metathesis (RCAM) proved most reliable and became a recurrent theme en route to keramaphidin B, ingenamine, xestocyclamine A, and nominal njaoamine I (the structure of which had to be corrected in the aftermath of the synthesis). Best results were obtained with molybdenum alkylidyne catalysts endowed with (tripodal) silanolate ligands, which proved fully operative in the presence of tertiary amines, quinoline, and other Lewis basic sites. RCAM was successfully interlinked with macrolactamization, an intricate hydroboration/protonation/alkyl-Suzuki coupling sequence, or ring closing olefin metathesis (RCM) for the closure of the second lateral ring; the use of RCM for the formation of an 11-membered cycle is particularly noteworthy. Equally rare are RCM reactions that leave a pre-existing triple bond untouched, as the standard ruthenium catalysts are usually indiscriminative vis-à-vis the different π-bonds. Of arguably highest significance, however, is the use of two consecutive or even concurrent RCAM reactions en route to nominal njaoamine I as the arguably most complex of the chosen targets.

Ring-Closing Metathesis Approaches towards the Total Synthesis of Rhizoxins.

Efforts are described towards the total synthesis of the bacterial macrolide rhizoxin F, which is a potent tubulin assembly and cancer cell growth inhibitor. A significant amount of work was expanded on the construction of the rhizoxin core macrocycle by ring-closing olefin metathesis (RCM) between C(9) and C(10), either directly or by using relay substrates, but in no case was ring-closure achieved. Macrocycle formation was possible by ring-closing alkyne metathesis (RCAM) at the C(9)/C(10) site. The requisite diyne was obtained from advanced intermediates that had been prepared as part of the synthesis of the RCM substrates. While the direct conversion of the triple bond formed in the ring-closing step into the C(9)-C(10) E double bond of the rhizoxin macrocycle proved to be elusive, the corresponding Z isomer was accessible with high selectivity by reductive decomplexation of the biscobalt hexacarbonyl complex of the triple bond with ethylpiperidinium hypophosphite. Radical-induced double bond isomerization, full elaboration of the C(15) side chain, and directed epoxidation of the C(11)-C(12) double bond completed the total synthesis of rhizoxin F.

Formation of alkyne-bridged ferrocenophanes using ring-closing alkyne metathesis on 1,1'-diacetylenic ferrocenes.

Novel alkyne-bridged ferrocenophanes [fc{CO2(CH2)nC≡}2] (2a: n = 2; 2b: n = 3) were synthesized from the corresponding terminal diacetylenic ferrocenes [fc{CO2(CH2)nC≡CH}2] (1a: n = 2; 1b: n = 3) through ring-closing alkyne metathesis (RCAM) utilizing the highly effective molybdenum catalyst [MesC≡Mo{OC(CF3)2CH3}3] (MoF6; Mes = 2,4,6-trimethylphenyl). The metathesis reaction occurs in short time with high yields whilst giving full conversion of the terminal alkynes. Furthermore, the solvent-dependant reactivity of 2a towards Ag(SbF6) is investigated, leading to oxidation and formation of the ferrocenium hexafluoroantimonate 4 in dichloromethane, whereas the silver(I) coordination polymer 5 was isolated from THF solution.

Molecular Ansa-Basket: Synthesis of Inherently Chiral All-Carbon [12](1,6)Pyrenophane.

The synthesis of inherently chiral all-carbon C2-symmetric [12](1,6)pyrenophane 1 is reported. The cyclophane 1 was obtained via a ring-closing alkyne metathesis reaction using Mortreux's catalyst molybdenum hexacarbonyl and 2-fluorophenol as a phenol additive. The M and P enantiomers of the all-carbon pyrenophane 1 were demonstrated to be very stable in their enantiopure form even upon prolonged heating at 200 °C. [12](1,6)Pyrenophane-6-yne 1 was fully characterized by high-resolution mass spectrometry, nuclear magnetic resonance, UV-vis, and measured and calculated electronic circular dichroism spectroscopy.

Total Synthesis of (-)-Sinulariadiolide. A Transannular Approach.

The constrained tricyclic skeleton of the nor-cembranoid sinulariadiolide (1) with a nine-membered nexus was obtained by a cascade of transannular Michael reaction, carbonate elimination, butenolide formation, and spontaneous oxa-Michael addition of MeOH. The required macrocyclic precursor was prepared by ring-closing alkyne metathesis followed by trans-hydrostannation/carbonylation.

Well-Defined Alkyne Metathesis Catalysts: Developments and Recent Applications.

Although alkyne metathesis has been known for 50 years, rapid progress in this field has mostly occurred during the last two decades. In this article, the development of several highly efficient and thoroughly studied alkyne metathesis catalysts is reviewed, which includes novel well-defined, in situ formed and heterogeneous systems. Various alkyne metathesis methodologies, including alkyne cross-metathesis (ACM), ring-closing alkyne metathesis (RCAM), cyclooligomerization, acyclic diyne metathesis polymerization (ADIMET), and ring-opening alkyne metathesis polymerization (ROAMP), are presented, and their application in natural product synthesis, materials science as well as supramolecular and polymer chemistry is discussed. Recent progress in the metathesis of diynes is also summarized, which gave rise to new methods such as ring-closing diyne metathesis (RCDM) and diyne cross-metathesis (DYCM).

Synthesis and Molecular Editing of Callyspongiolide, Part 1: The Alkyne Metathesis/trans-Reduction Strategy.

A path-scouting investigation into the highly cytotoxic marine macrolide callyspongiolide is reported that capitalizes on the selective formation of the C10-C11 alkene site. While the closure of the macrocycle by ring closing alkyne metathesis (RCAM) with the aid of a molybdenum alkylidyne complex was high yielding, the envisaged semi-reduction of the cycloalkyne to the corresponding E-alkene proved challenging. The reasons are likely steric in origin, in that the methyl branches on either side of the alkyne seem to prevent effective coordination of the substrate to the ruthenium catalyst, which must carry a bulky Cp* ligand to ensure high trans-selectivity. This notion is supported by the preparation of a callyspongiolide analogue, in which the two methyl groups in question are excised; its formation by RCAM followed by trans-hydrostannation/proto-destannation was straightforward. In parallel work the formation of the fully functional building block 54 showed that the presence of an unprotected -OH group allows even hindered substrates to be processed: the protic group adjacent to the triple bond engages with a chloride ligand on the ruthenium catalyst in hydrogen bonding and hence assists in substrate binding. Moreover, the preparation of an alkynylogous callyspongiolide analogue is described.

Total Synthesis of Callyspongiolide, Part 2: The Ynoate Metathesis/cis-Reduction Strategy.

The macrocyclic core of the cytotoxic marine natural product callyspongiolide (1) was forged by ring-closing alkyne metathesis (RCAM) of an ynoate precursor using a molybdenum alkylidyne complex endowed with triarylsilanolate ligands as the catalyst. This result is remarkable in view of the failed attempts documented in the literature at converting electron deficient alkynes with the aid of more classical catalysts. The subsequent Z-selective semi-reduction of the resulting cycloalkyne by hydrogenation over nickel boride required careful optimization in order to minimize overreduction and competing dehalogenation of the compound's alkenyl iodide terminus as needed for final attachment of the side chain of 1 by Sonogashira coupling. The required cyclization precursor itself was prepared via Kocienski olefination.

Efficient catalytic alkyne metathesis with a fluoroalkoxy-supported ditungsten(III) complex.

The molybdenum and tungsten complexes M2(OR)6 (Mo2F6, M = Mo, R = C(CF3)2Me; W2F3, M = W, R = OC(CF3)Me2) were synthesized as bimetallic congeners of the highly active alkyne metathesis catalysts [MesC≡M{OC(CF3)nMe3−n}] (MoF6, M = Mo, n = 2; WF3, M = W, n = 1; Mes = 2,4,6-trimethylphenyl). The corresponding benzylidyne complex [PhC≡W{OC(CF3)Me2}] (WPhF3) was prepared by cleaving the W≡W bond in W2F3 with 1-phenyl-1-propyne. The catalytic alkyne metathesis activity of these metal complexes was determined in the self-metathesis, ring-closing alkyne metathesis and cross-metathesis of internal and terminal alkynes, revealing an almost equally high metathesis activity for the bimetallic tungsten complex W2F3 and the alkylidyne complex WPhF3. In contrast, Mo2F6 displayed no significant activity in alkyne metathesis.

A "Motif-Oriented" Total Synthesis of Nannocystin Ax. Preparation and Biological Assessment of Analogues.

The highly cytotoxic cyclodepsipeptides of the nannocystin family are known to bind to the eukaryotic translation elongation factor 1α (EF-1α). Analysis of the docking pose, as proposed by a previous in silico study, suggested that the trisubstituted alkene moiety and the neighboring methyl ether form a domain that might be closely correlated with biological activity. This hypothesis sponsored a synthetic campaign which was designed to be "motif-oriented": specifically, a sequence of ring closing alkyne metathesis (RCAM) followed by hydroxy-directed trans-hydrostannation of the resulting cycloalkyne was conceived, which allowed this potentially anchoring substructure to be systematically addressed at a late stage. This inherently flexible approach opened access to nannocystin Ax (1) itself as well as to 10 non-natural analogues. While the biological data confirmed the remarkable potency of this class of compounds and showed that the domain in question is indeed an innate part of the pharmacophore, the specific structure/activity relationships can only partly be reconciled with the original in silico docking study; therefore, we conclude that this model needs to be carefully revisited.

Total Synthesis of Disciformycin A and B: Unusually Exigent Targets of Biological Significance.

The first total synthesis of the potent antibiotic disciformycin B (2) is described, which is exceptionally isomerization-prone and transforms into disciformycin A (1) even under notably mild conditions. To outweigh this bias, the approach to 2 hinged on the use of a silyl 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 building blocks and formation of the macrocyclic ring via ring closing alkyne metathesis (RCAM). To make the end game successful, however, it proved necessary to cleave the C-silyl protecting group off; it was at this stage that the exceptional sensitivity of the target became fully apparent.

Tuning the Catalytic Alkyne Metathesis Activity of Molybdenum and Tungsten 2,4,6-Trimethylbenzylidyne Complexes with Fluoroalkoxide Ligands OC(CF3)nMe3–n (n = 0–3)

The molybdenum and tungsten 2,4,6-trimethylbenzylidyne complexes [MesC≡M{OC(CF3)nMe3–n}3] (M = Mo: MoF0, n = 0; MoF3, n = 1; MoF6, n = 2; MoF9, n = 3; M = W: WF3, n = 1; Mes = 2,4,6-trimethylphenyl) were prepared by the reaction of the tribromides [MesC≡MBr3(dme)] (dme = 1,2-dimethoxyethane) with the corresponding potassium alkoxides KOC(CF3)nMe3–n. The molecular structures of all complexes were established by X-ray diffraction analysis. The catalytic activity of the resulting alkylidyne complexes in the homometathesis and ring-closing alkyne metathesis of internal and terminal alkynes was studied, revealing a strong dependency on the fluorine content of the alkoxide ligand. The different catalytic performances were rationalized by DFT calculations involving the metathesis model reaction of 2-butyne. Because the calculations predict the stabilization of metallacyclobutadiene (MCBD) intermediates by increasing the degree of fluorination, MoF9 was treated with 3-hexyne to afford the MCBD complex [(C3Et3)Mo{...