The early years of alkyne metathesis were marked by a somewhat ironic state of affairs: the proposed mechanism was swiftly validated and more than one effective catalyst became available shortly after the discovery of this transformation; surprisingly, however, the impact on synthesis remained very limited for a long period of time. Recent advances, however, suggest that this situation is about to change: the remarkable activity, functional-group tolerance, and reliability of the latest generation of catalysts open the door for highly advanced applications. The resulting (cyclo)alkynes are amenable to numerous postmetathetic transformations, which diversify the product portfolio and bring many different structural motifs into reach. Since the catalysts have also evolved from the glovebox to the benchtop, there should be little barrier left for a wider use of this reaction in organic synthesis.

Alkyne metathesis on the rise.

During the last century, conceptual advances in organometallic chemistry were often rapidly embraced by target oriented synthesis. Feedback provided by such preparative scrutiny has greatly benefitted method development; particularly prominent are examples from the entire cross coupling arena, as well as olefin metathesis.Seen against this backdrop, it is somewhat surprising that the explosive growth of research into π-acid catalysis has not yet yielded a matching number of implementations into the synthesis of structurally complex targets of biological significance. In contrast to the massive output of methodological and mechanistic investigations, few studies illustrate the strategic use of gold, silver, or platinum catalysis in late stages of such multistep endeavors. These elaborate and highly precious compounds demand utmost confidence in the reliability and robustness of the method to be applied.In this Account, we analyze the possible reasons for this imbalance, after a short summary of the concept...

From Understanding to Prediction: Gold- and Platinum-Based π-Acid Catalysis for Target Oriented Synthesis

At last count, nearly 5000 halogenated natural products have been discovered. In approximately half of these compounds, the carbon atom to which the halogen is bound is sp(3) -hybridized; therefore, there are an enormous number of natural products for which stereocontrolled halogenation must be a critical component of any synthesis strategy. In this Review, we critically discuss the methods and strategies used for stereoselective introduction of halogen atoms in the context of natural product synthesis. Using the successes of the past, we also attempt to identify gaps in our synthesis technology that would aid the synthesis of halogenated natural products, as well as existing methods that have not yet seen application in complex molecule synthesis. The chemistry described herein demonstrates yet again how natural products continue to provide the inspiration for critical advances in chemical synthesis.

Stereoselective Halogenation in Natural Product Synthesis

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.

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

Background Transition metal–catalyzed alkene metathesis has revolutionized organic synthesis during the last two decades, even though the commonly used catalysts do not provide kinetic control over the stereochemistry of the newly formed double bonds. It is of utmost importance to fix this shortcoming, because the olefin geometry not only determines the physical and chemical properties of the alkene products but is also innately linked to any biological activities that the olefins may have. Advances Recent progress in catalyst design led to the development of a first set of metal alkylidene complexes of ruthenium, molybdenum, and tungsten that allow a host of inter- and intramolecular alkene metathesis reactions to be performed with good to excellent levels of Z selectivity (see the figure). This marks a considerable advancement over prior art, even though inherently E-selective catalysts remain elusive. In the case of disubstituted olefins, this gap in coverage can be filled by a sequence of alkyne metathesis followed by stereoselective semi-reduction of the resulting acetylene derivatives, which provides highly selective access to either geometrical series. Because the required alkylidyne catalysts have also been greatly improved in terms of activity, functional group tolerance, and user-friendliness, this method constitutes a valuable preparative complement. Advances in catalyst design solve a long-standing stereochemical issue. Alkene metathesis was tremendously successful in the past despite lacking catalyst control over the geometry (E versus Z) of the newly formed double bond. Recently introduced molybdenum (left), tungsten, and ruthenium (center) alkylidenes partly fix this problem as they allow preparation of Z-alkenes with high selectivity. Alternatively, either geometrical series can be accessed by alkyne metathesis followed by semi-reduction, which also benefits from new catalysts (right) of much improved performance. R, generic substituent; TBDPS, tert-butyldiphenylsilyl; Mes, mesityl; Ph, phenyl. Outlook It is expected that the new catalysts will be rapidly embraced by the synthetic community. Because the as-yet limited number of published case studies is very encouraging, it is reasonable to believe that more sophisticated applications to polyfunctionalized and/or industrially relevant targets will follow shortly. Such investigations will allow the selectivity and performance of the stereoselective metathesis catalysts to be scrutinized in great detail. In parallel, growing mechanistic insights into their mode of action will almost certainly be forthcoming that can then be translated into refined ligand design. The resulting feedback loops will likely result in the evolution of ever more selective and practical catalysts, the long-term impact of which on organic synthesis and materials science will surely be profound and lasting.

https://science.sciencemag.org/content/sci/341/6152/1229713.full.pdf

Teaching Metathesis “Simple” Stereochemistry

The spirastrellolides are a small family of exquisitely potent antimitotic agents of marine origin which are reported to exert their function by selective inhibition of the serine/threonine protein phosphatase PP2A (IC50 ca. 1 nm). This activity predestines them as tools for chemical biology and as possible lead structures in the quest for novel therapeutic agents for the treatment of cancer and other metabolic disorders. Although it took more than four years from the initial isolation to the full elucidation of the stereostructure of these compounds, their intricate topology and very limited supply from the natural source aroused considerable interest in the synthetic community even before the molecular architecture had been fully elucidated. These efforts culminated in the first total synthesis of spirastrellolide A methyl ester (2) by Paterson et al., followed by the conquest of the sister compound spirastrellolide F methyl ester (1) by our research group shortly thereafter (Scheme 1). Since only the relative configuration of the four color-coded stereoclusters embedded into the framework of these macrolides but neither

Second-generation total synthesis of spirastrellolide F methyl ester: the alkyne route.

A concise total synthesis of spirastrellolide A methyl ester (1 a, R1=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, R1=Me). Key to success was the masking of the signature Δ15,16-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.

A Total Synthesis of Spirastrellolide A Methyl Ester

The lichen-derived glycoconjugate gobienine A is structurally more complex than most glycolipids isolated from higher plants by virtue of the all-cis substituted γ-lactone substructure embedded into its macrocyclic frame. A concise entry into this very epimerization-prone and hence challenging structural motif is presented, which relies on an enantioselective cyanohydrin formation, an intramolecular Blaise reaction, a palladium-catalyzed alkoxycarbonylation, and a diastereoselective hydrogenation of the tetrasubstituted alkene in the resulting butenolide. This strategy, in combination with ring-closing olefin metathesis for the formation of the macrocyclic perimeter, allowed the proposed structure of gobienine A (1) to be formed in high overall yield. The recorded spectral data show that the structure originally attributed to gobienine A is incorrect and that it is not the epimerization-prone ester site on the butanolide ring that is the locus of misassignment; rather, the discrepancy must be more profound.

Total Synthesis of Nominal Gobienine A

Synthesis of Spirastrellolide F Methyl Ester

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Second-generation total synthesis of spirastrellolide F methyl ester: the alkyne route.

A Total Synthesis of Spirastrellolide A Methyl Ester

Total Synthesis of Nominal Gobienine A

Synthesis of Spirastrellolide F Methyl Ester