Catalysis‐Based Total Synthesis of Putative Mandelalide A

A concise synthesis of the putative structure assigned to the highly cytotoxic marine macrolide mandelalide A ( 1 ) is disclosed. Specifically, an iridium‐catalyzed two‐directional Krische allylation and a cobalt‐catalyzed carbonylative epoxide opening served as convenient entry points for the preparation of the major building blocks. The final stages feature the first implementation of terminal‐acetylene metathesis into natural product synthesis, which is remarkable as this class of substrates was beyond reach until very recently; key to success was the use of the highly selective molybdenum alkylidyne complex 42 as the catalyst. Although the constitution and stereochemistry of the synthetic samples are unambiguous, the spectra of 1 as well as of 11‐epi‐ 1 deviate from those of the natural product, which implies a subtle but deep‐seated error in the original structure assignment.     

Concise Total Synthesis of Ivorenolide B

An expeditious route to the potential immunosuppressive lead compound ivorenolide B ( 1 ) is described, which relies on the formation of the distinctive 1,3‐diyne subunit embedded into the 17‐membered framework of this target by ring‐closing alkyne metathesis (RCAM). This key transformation was accomplished with the aid of the molybdenum alkylidyne complex 7 , which turned out to be compatible with the acid sensitive propargylic alcohol substituents as well as the terminal alkyne unit present in the cyclization precursor. As the presence of such functionality had been detrimental for alkyne metathesis until very recently, this example illustrates the excellent application profile of this new catalyst as well as the rapidly increasing scope of the transformation. Its structural outreach can be further increased by subjecting cyclo‐1,3‐diynes to appropriate post‐metathetic transformations, most notably with the help of alkynophilic gold or palladium catalysts. This aspect is illustrated by the conversion of the model compound 4 into various cyclophane products.     

A Mo(VI) alkylidyne complex with polyhedral oligomeric silsesquioxane ligands: homogeneous analogue of a silica-supported alkyne metathesis catalyst

A highly active alkyne metathesis catalyst is realized by replacing the amide ligands of a molybdenum(VI) trisamide alkylidyne complex with silanol groups from incompletely condensed POSS (polyhedral oligomeric silsesquioxane) ligands. This catalyst serves as an effective homogeneous mimic of an amorphous silica-supported catalyst. Reactivities of various catalytic mixtures are reported along with an X-ray structure of the aniline-coordinated amidodisiloxymolybdenum(VI) alkylidyne complex.     

Highly active trialkoxymolybdenum(VI) alkylidyne catalysts synthesized by a reductive recycle strategy

A systematic study of alkyne metathesis catalyzed by trialkoxymolybdenum(VI) alkylidyne complexes is reported, in which substrate functional groups, alkynyl substituents, and catalyst ligands are varied. Sterically hindered trisamidomolybdenum(VI) propylidyne complex 5 was prepared conveniently through a previously communicated reductive recycle strategy. Alcoholysis of 5 with various phenols/alcohols provides a set of active catalysts for alkyne metathesis at room temperature, among which the catalyst with p-nitrophenol as ligand shows the highest catalytic activity and is compatible with a variety of functional groups and solvents. A key finding that enabled the use of highly active molybdenum(VI) catalysts is replacement of the commonly used propynyl substituents on the starting alkyne substrates with butynyl groups. Under reduced pressure using 1,2,4-trichlorobenzene as an involatile solvent, the alkyne metathesis of butynyl substituted compounds proceeds well at 30 degrees C providing high yields (83%-97%) of dimers. Rationalization of the special role played by butynyl substrates is discussed.     

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.     

Chiral and achiral phosphine derivatives of alkylidyne tricobalt carbonyl clusters as catalyst precursors for (asymmetric) inter- and intramolecular Pauson-Khand reactions

Phosphine derivatives of alkylidyne tricobalt carbonyl clusters have been tested as catalysts/catalyst precursors in intermolecular and (asymmetric) intramolecular Pauson-Khand reactions. A number of new phosphine derivatives of the tricobalt alkylidyne clusters [Co3(micro3-CR)(CO)9] (R = H, CO2Et) were prepared and characterised. The clusters [Co3(micro3-CR)(CO)9-x(PR'3)x] (PR'3 = achiral or chiral monodentate phosphine, x = 1-3) and [Co3(micro3-CR)(CO)7)(P-P)] (P-P = chiral diphosphine; 1,1'- and 1,2-structural isomers) were assayed as catalysts for intermolecular and (asymmetric) intramolecular Pauson-Khand reactions. The phosphine-substituted tricobalt clusters proved to be viable catalysts/catalyst precursors that gave moderate to very good product yields (up to approximately 90%), but the enantiomeric excesses were too low for the clusters to be of practical use in the asymmetric reactions.     

A novel hydrophobic copper complex supported on γ‐Fe2O3 as a magnetically heterogeneous catalyst for one‐pot three‐component synthesis of α‐aminophosphonates

A novel hydrophobic copper complex supported on γ‐Fe₂O₃ is synthesized and characterized by different methods such as FT‐IR, XRD, TEM, SEM, TGA, VSM, ICP and CHN analysis. It was used as a magnetically recyclable heterogeneous catalyst for the efficient synthesis of α‐aminophosphonates via a one‐pot three‐component reaction under solvent‐free conditions. The present catalytic system worked extremely well for the synthesis of α‐aminophosphonates even up to five subsequent trails without significant loss of its catalytic activity or copper leaching. The TEM image and FT‐IR spectrum of the catalyst after five times recovery showed that the structure of the catalyst was stable under the reaction conditions with no change being observed. The strong magnetic properties of the reused catalyst were revealed by complete and easy attraction using an external magnet and also by VSM curve. This work represents the first and unique example of a hydrophobic copper complex for catalysis in water generating reactions.     

Optimized synthesis, structural investigations, ligand tuning and synthetic evaluation of silyloxy-based alkyne metathesis catalysts

Nitride- and alkylidyne complexes of molybdenum endowed with triarylsilanolate ligands are excellent (pre)catalysts for alkyne-metathesis reactions of all sorts, since they combine high activity with an outstanding tolerance toward polar and/or sensitive functional groups. Structural and reactivity data suggest that this promising application profile results from a favorable match between the characteristics of the high-valent molybdenum center and the electronic and steric features of the chosen Ar(3) SiO groups. This interplay ensures a well-balanced level of Lewis acidity at the central atom, which is critical for high activity. Moreover, the bulky silanolates, while disfavoring bimolecular decomposition of the operative alkylidyne unit, do not obstruct substrate binding. In addition, Ar(3) SiO groups have the advantage that they are more stable within the coordination sphere of a high-valent molybdenum center than tert-alkoxides, which commonly served as ancillary ligands in previous generations of alkyne metathesis catalysts. From a practical point of view it is important to note that complexes of the general type [(Ar(3) SiO)(3) Mo?X] (X = N, CR; R = aryl, alkyl, Ar = aryl) can be rendered air-stable with the aid of 1,10-phenanthroline, 2,2'-bipyridine or derivatives thereof. Although the resulting adducts are themselves catalytically inert, treatment with Lewis acidic additives such as ZnCl(2) or MnCl(2) removes the stabilizing N-donor ligand and gently releases the catalytically active template into the solution. This procedure gives excellent results in alkyne metathesis starting from air-stable and hence user-friendly precursor complexes. The thermal and hydrolytic stability of representative molybdenum alkylidyne and -nitride complexes of this series was investigated and the structure of several decomposition products elucidated.     

Lewis碱协助的 Lewis酸催化醇脱水合成烯烃及二氢吡喃开环合成2-肉桂基取代1,3-二羰基化合物

醇脱水是合成烯烃的重要方法之一。全球每年约有15%的苯乙烯是通过1-苯乙醇在酸性条件下脱水反应生产。虽然人们对该反应进行了较为深入的研究,但是当使用活性较高的1-苯乙醇衍生物为底物时,由于得到的取代苯乙烯产物具有较高的反应性,在脱水过程中会发生聚合而导致反应选择性降低,因此有必要探索适宜在高活性1-苯基乙醇脱水反应中应用的催化剂体系。
　　本文借助酸碱协同催化方法考察了1-(4-甲氧基苯基)乙醇制备4-甲氧基苯乙烯的反应。发现三苯基磷与 AlCl3构建的 Lewis碱/Lewis酸协同催化体系在硝基甲烷中可以接近定量的收率得到4-甲氧基苯乙烯。 Lewis碱/Lewis酸协同催化体系有效避免了4-甲氧基苯乙烯的二聚现象。底物拓展研究显示该方法具有很好的底物普适性,对多种取代苯乙烯的收率均超过80%。机理研究表明,1-(4-甲氧基苯基)乙醇在酸作用下先生成碳正离子,三苯基磷作为偶极性的电子给体不但能在一定程度上稳定该苄基碳正离子,而且抑制了其与4-甲氧基苯乙烯之间的亲电反应,进而最大化了脱质子生成4-甲氧基苯乙烯的选择性。
　　将Lewis碱协助的 Lewis酸催化提高反应选择性策略用于2-苯基-3,4-二氢吡喃衍生物合成2-肉桂基-1,3-二羰基化合物的开环反应。该类取代二氢吡喃在酸催化剂作用下也可生成苄基碳正离子,但是该中间体易受分子间和分子内亲电反应影响,反应选择性不高。而当使用单质碘/三苯基磷协同催化体系时,2-苯基-3,4-二氢吡喃衍生物能高选择性地实现开环反应,得到反式2-肉桂基-1,3-二羰基化合物。该类1,3-二羰基化合物具有丰富的反应性,是一类重要的合成子。     

Interactions between Catalysts and Amphiphilic Structures and their Implications for a Protocell Model

One of the essential elements of any cell, including primitive ancestors, is a structural component that protects and confines the metabolism and genes while allowing access to essential nutrients. For the targeted protocell model, bilayers of decanoic acid, a single‐chain fatty acid amphiphile, are used as the container. These bilayers interact with a ruthenium–nucleobase complex, the metabolic complex, to convert amphiphile precursors into more amphiphiles. These interactions are dependent on non‐covalent bonding. The initial rate of conversion of an oily precursor molecule into fatty acid was examined as a function of these interactions. It is shown that the precursor molecule associates strongly with decanoic acid structures. This results in a high dependence of conversion rates on the interaction of the catalyst with the self‐assembled structures. The observed rate logically increases when a tight interaction between catalyst complex and container exists. A strong association between the metabolic complex and the container was achieved by bonding a sufficiently long hydrocarbon tail to the complex. Surprisingly, the rate enhancement was nearly as strong when the ruthenium and nucleobase elements of the complex were each given their own hydrocarbon tail and existed as separate molecules, as when the two elements were covalently bonded to each other and the resulting molecule was given a hydrocarbon tail. These results provide insights into the possibilities and constraints of such a reaction system in relation to building the ultimate protocell.     

Green bio‐based synthesis of Fe2O3@SiO2‐IL/Ag hollow spheres and their catalytic utility for ultrasonic‐assisted synthesis of propargylamines and benzo[b]furans

A novel magnetic hybrid system containing nano‐magnetic Fe₂O₃ hollow spheres, silica shell, [pmim]Cl ionic liquid and silver nanoparticles was synthesized and characterized. The silver nanoparticles were prepared via biosynthesis using Achillea millefolium flower as reducing and stabilizing agent. The hybrid system was successfully used as an efficient and reusable catalyst for promoting green ultrasonic‐assisted A³ and KA² coupling reactions as well as benzo[b]furan synthesis. It was found that decoration of the magnetic core with non‐magnetic moieties decreased the maximum saturation magnetization. However, the catalyst was still superparamagnetic and could be simply separated from the reaction mixture using an external magnet. The heterogeneous nature of the catalyst was also confirmed by studying its reusability and stability and the leaching of silver. Use of aqueous media, high yields, short reaction times, broad substrate tolerance and low required amount of catalyst are the merits of this protocol.     

Total syntheses of the actin-binding macrolides latrunculin A, B, C, M, S and 16-epi-latrunculin B

The latrunculins are highly selective actin-binding marine natural products and as such play an important role as probe molecules for chemical biology. A short, concise and largely catalysis-based approach to this family of bioactive macrolides is presented. Specifically, the macrocyclic skeletons of the targets were forged by ring-closing alkyne metathesis (RCAM) or enyne-yne metathesis of suitable diyne or enyne-yne precursors, respectively. This transformation was best achieved with the aid of [(tBu)(Me(2)C(6)H(3))N](3)Mo (37) as precatalyst activated in situ with CH(2)Cl(2), as previously described. This catalyst system is strictly chemoselective for the triple bond and does not affect the olefinic sites of the substrates. Moreover, the molybdenum-based catalyst turned out to be broader in scope than the Schrock alkylidyne complex [(tBuO)(3)W[triple chemical bond]CCMe(3)] (38), which afforded cycloalkyne 35 in good yield but failed in closely related cases. The required metathesis precursors were assembled in a highly convergent fashion from three building blocks derived from acetoacetate, cysteine, and (+)-citronellene. The key fragment coupling can either be performed via a titanium aldol reaction or, preferentially, by a sequence involving a Horner-Wadsworth-Emmons olefination followed by a protonation/cyclization/diastereoselective hydration cascade. Iron-catalyzed C--C-bond formations were used to prepare the basic building blocks in an efficient manner. This synthesis blueprint gave access to latrunculin B (2), its naturally occurring 16-epimer 3, as well as the even more potent actin binder latrunculin A (1) in excellent overall yields. Because of the sensitivity of the 1,3-diene motif of the latter, however, the judicious choice of protecting groups and the proper phasing of their cleavage was decisive for the success of the total synthesis. Since latrunculin A and B had previously been converted into latrunculin S, C and M, respectively, formal total syntheses of these congeners have also been achieved. Finally, a previously unknown acid-catalyzed degradation pathway of these bioactive natural products is described. The cysteine-derived ketone 18, the tetrahydropyranyl segment 31 serving as the common synthesis platform for the preparation of all naturally occurring latrunculins, as well as the somewhat strained cycloalkyne 35 formed by the RCAM reaction en route to 2 were characterized by X-ray crystallography.     

The Triple‐Bond Metathesis of Aryldiazonium Salts: A Prospect for Dinitrogen Cleavage

The {N₂} unit of aryldiazonium salts undergoes unusually facile triple‐bond metathesis on treatment with molybdenum or tungsten alkylidyne ate complexes endowed with triphenylsilanolate ligands. The reaction transforms the alkylidyne unit into a nitrile and the aryldiazonium entity into an imido ligand on the metal center, as unambiguously confirmed by X‐ray structure analysis of two representative examples. A tungsten nitride ate complex is shown to react analogously. Since the bonding situation of an aryldiazonium salt is similar to that of metal complexes with end‐on‐bound dinitrogen, in which {N₂}→M σ donation is dominant and electron back donation minimal, the metathesis described herein is thought to be a conceptually novel strategy toward dinitrogen cleavage devoid of any redox steps and, therefore, orthogonal to the established methods.     

Chelation‐Assisted Nickel‐Catalyzed Oxidative Annulation via Double C−H Activation/Alkyne Insertion Reaction

A nickel/NHC system for regioselective oxidative annulation by double C?H bond activation and concomitant alkyne insertion is described. The catalytic reaction requires a bidentate directing group, such as an 8‐aminoquinoline, embedded in the substrate. Various 5,6,7,8‐tetrasubstituted‐N‐(quinolin‐8‐yl)‐1‐naphthamides can be prepared as well as phenanthrene and benzo[h]quinoline amide derivatives. Diarylalkynes, dialkylalkynes, and arylalkylalkynes can be used in the system. A Ni⁰/Ni^II catalytic cycle is proposed as the main catalytic cycle. The alkyne plays a double role as a two‐component coupling partner and as a hydrogen acceptor.     

Acid‐Acid‐Catalyzed Tandem Reactions Driven by an Additive‐Like Component

Acid‐catalyzed tandem reactions with auto‐tandem catalysis are effective for simplifying organic synthesis. However, some of the reported reactions were established based on the use of well‐designed substrate with complex structure. In some cases, owing to the existence of a big gap between each catalytic cycle, it is hard to bind all the individual reaction steps to be a peaceful sequence. To enrich the diversity and also to strengthen the practical usefulness of the methodology developed by auto‐tandem catalysis, an additive‐like component was added to induce acid‐acid‐catalyzed tandem reaction. During the reaction, the additive‐like component acted either as an activator to increase the reactivity of the starting material or a hided reagent to enable successful transformation of the intermediate. Many novel tandem reactions were established in a one‐pot manner with the aid of this strategy. Importantly, this strategy not only allows the use of simple and commercially available chemicals as substrates, but also possesses multiple merits, such as simplifying operation, lowering waste generation and enhancing synthetic efficiency and atom‐economy. A summarization of the additive‐like component‐induced auto‐tandem catalysis with an acid catalyst was given in this review, in which many acid‐acid‐catalyzed tandem reactions were discussed. The reported additive‐like components were classified as three types: oxidative type, reductive type and neutral type depending on their mechanisms in assisting the establishment of acid‐acid‐catalyzed tandem reactions. Many examples were collected and analyzed from the viewpoints of simplifying the synthesis and manifesting their superior and distinct functionalities of the additives. A perspective of this concept was also given at the end of this review.     

Cross‐Metathesis of Terminal Alkynes

Terminal acetylenes are amongst the most problematic substrates for alkyne metathesis because they tend to undergo rapid polymerization on contact with a metal alkylidyne. The molybdenum complex 3 endowed with triphenylsilanolate ligands, however, is capable of inducing surprisingly effective cross‐metathesis reactions of terminal alkyl acetylenes with propynyl(trimethyl)silane to give products of type R¹?C?CSiMe . This unconventional way of introducing a silyl substituent onto an alkyne terminus complements the conventional tactics of deprotonation/silylation and excels as an orthogonal way of alkyne protecting group chemistry for substrates bearing base‐sensitive functionalities. Moreover, it is shown that even terminal aryl acetylenes can be cross‐metathesized with internal alkyne partners. These unprecedented transformations are compatible with various functional groups. The need to suppress acetylene formation, which seems to be a particularly effective catalyst poison, is also discussed.     

Friedländer condensation of 5‐aminopyrazole‐4‐carbaldehydes with reactive α‐methylene ketones: Synthesis of pyrazolo[3,4‐b]pyridines

A series of 1,3,6‐trisubstituted and 1,3,5,6‐tetrasubstituted pyrazolo[3,4‐b]pyridines 5 has been synthesized by Friedlander condensation of 5‐arninopyrazole‐4‐carbaldehydes 3 with α‐methylene ketones such as acetone (4a) or acetophenones 4b‐f with potassium hydroxide as basic catalyst. Condensation of 5‐aminopyrazole‐4‐carbaldehydes 3 and unsymmetric dialkylketones 6 yielded mixtures of isomeric pyra‐zolo[3,4‐b]pyridine derivatives 7 and 8 . Condensation of 5‐aminopyrazole‐4‐carbaldehydes 3 with CH‐acidic acylacetonitriles 9 and acylacetates 11 with piperidine as basic catalyst yielded pyrazolo[3,4‐b]pyri‐dine‐5‐carbonitriles 10 and pyrazolo[3,4‐b]pyridine‐5‐carboxylates 12 ; with diethyl malonate 13 as CH‐acidic component, pyrazolo[3,4‐b]pyridin‐6‐ones 14 were obtained.     

Polyfunctional Bis‐Lewis‐Acid‐/Bis‐Triazolium Catalysts for Stereoselective 1,4‐Additions of 2‐Oxindoles to Maleimides

Achieving enzyme‐like catalytic activity and stereoselectivity without the typically high substrate specificity of enzymes is a challenge in the development of artificial catalysts for asymmetric synthesis. Polyfunctional catalysts are considered to be a promising tool for achieving excellent catalytic efficiency. A polyfunctional catalyst system was developed, which incorporates two Lewis acidic/Brønsted basic cobalt centers in combination with triazolium moieties that are crucial for high reactivity and excellent stereoselectivity in the direct 1,4‐addition of oxindoles to maleimides. The catalyst is assembled through click chemistry and is readily recyclable through precipitation by making use of its charges. Kinetic studies support a cooperative mode of action. Diastereodivergency is achievable with either Boc‐protected or unprotected maleimide.     

A Mild and Environmentally Benign Synthesis of Tetrahydrobenzo[b]pyrans and Pyrano[c]chromenes Using Pectin as a Green and Biodegradable Catalyst

Pectin was applied as a green and biodegradable catalyst for the one‐pot three‐component synthesis of tetrahydrobenzo[b]pyrans and pyrano[c]chromenes, from the condensation between aromatic aldehydes, malononitrile, and dimedone or 4‐hydroxycumarine at ambient temperature. This protocol has many advantages such as mild conditions, high yields, environmental benignity, simple work‐up procedures, short reaction time, as well as the use of a natural, easily accessible, convenient handling, and inexpensive catalyst. Another advantage of this method is that the products do not require further purification such as column chromatography.     

An Environmentally Benign Process for the Hydrogenation of Ketones with Homogeneous Iron Catalysts

Iron complexes generated in situ catalyze homogeneously the transfer hydrogenation of aliphatic and aromatic ketones by utilizing 2‐propanol as a hydrogen donor in the presence of base. The influence of different reaction parameters on the catalytic activity is investigated in detail by applying a three‐component catalyst system composed of an iron salt, 2,2′:6′,2′′‐terpyridine, and PPh₃. The scope and limitations of the described catalyst is shown in the reduction of 11 different ketones. In most cases, high conversion and excellent chemoselectivity are obtained. Mechanistic studies indicate a monohydride reaction pathway for the homogeneous iron catalyst.