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ChemInform Abstract: Application of Catalytic Z-Selective Olefin Metathesis in Natural Product Synthesis
Abstract
Over the last few years, a number of olefin metathesis catalysts have been disclosed that enable the synthesis of energetically disfavoured Z-alkenes. The application of this method to the synthesis of complex natural products has driven the development of new catalysts and furthered the understanding of their behaviour and reactivity. This digest discusses the progress made and highlights the benefits of this chemistry over more traditional protocols.
Squamostolide belongs to acetogenins, a class of polyoxygenated compounds, typified by a fatty long chain, with a terminal γ‐lactone subunit. These compounds, isolated from tropical plants, have various biological activities such as antimalarial, antibiotic or antitumor. For each of two approaches according to M.J. Wu and K.J. Quinn, bond disconnections are carried out along the carbon chain linking the two butyrolactones. The first is based on a Sonogashira coupling between a terminal alkyne and a vinyl iodide catalyzed by palladium (0). For the second, a tandem process of cyclization and cross‐coupling by metathesis allows both the formation of one of the lactone units and the formation of the carbon chain linking them. In order to reduce the steps of a synthesis, the combination of different metathesis reactions through cascade or domino processes allows access to complex structures.
Rational design of second-generation ruthenium olefin metathesis catalysts with desired initiation rates can be enabled by a computational model that depends on a single thermodynamic parameter. Using a computational model with no assumption about the specific initiation mechanism, the initiation kinetics of a spectrum of second-generation ruthenium olefin metathesis catalysts bearing modified chelating ortho-alkoxy benzylidenes were predicted in this work. Experimental tests of the validity of the computational model were achieved by the synthesis of a series of ruthenium olefin metathesis catalysts and investigation of initiation rates by UV/Vis kinetics, NMR spectroscopy, and structural characterization by X-ray crystallography. Included in this series of catalysts were thirteen catalysts bearing alkoxy groups with varied steric bulk on the chelating benzylidene, ranging from ethoxy to dicyclohexylmethoxy groups. The experimentally observed initiation kinetics of the synthesized catalysts were in good accordance with computational predictions. Notably, the fast initiation rate of the dicyclohexylmethoxy catalyst was successfully predicted by the model, and this complex is believed to be among the fastest initiating Hoveyda–Grubbs-type catalysts reported to date. The compatibility of the predictive model with other catalyst families, including those bearing alternative NHC ligands or disubstituted alkoxy benzylidenes, was also examined.
In this article, a new ruthenium carbene catalyst containing a N-heterocyclic carbene, a pyridine-appended benzylidene carbene, and a 1,2-dicarbadodecab- orane(12)-1,2-dithiolate ligand was synthesized. The ruthenium complex is very stable in air or in solution owing to the large steric hindrance and strong coordination effect of the ligands. The ruthenium complex is almost inert for olefin metathesis reactions. When combined with a Lewis acid or a p-toluene sulfonic acid, the ruthenium complex could catalyze the cross metathesis reactions of terminal alkenes and (Z)-but-2-ene-1,4-diol to give high yields of desired products. The E-products were obtained predominantly in these reactions. Similar to other ruthenium-based catalysts, this new ruthenium complex can tolerate many different functional groups.
This is a review of papers published in the year 2015 that focus on the synthesis, reactivity, or properties of compounds containing a carbon-transition metal double or triple bond. Highlights for the year 2015 include: (1) significant advances in the design of new precursors to carbene complex intermediates that serve as safer alternatives to potentially hazardous diazo compounds, (2) continued vast employment of olefin metathesis for the synthesis of complex small molecules and polymers, including many examples of Z-selective reactions, (3) design of novel transformations employing metallacumulene intermediates, (4) preparation of novel aromatic ring systems incorporating transition elements, and (5) uses of alkyne metathesis for preparation of highly functionalized macrocyclic compounds and novel polymeric materials.
Ring-closing metathesis (RCM) is one of the most widely applied methods for the synthesis of a range of ring systems. Highlighting seminal examples from literature, this chapter, on the synthesis of aromatic heterocycles using RCM, discusses contributions from the Donohoe group. This chapter is divided into various sections based on the type of aromatic heterocycle synthesized. Application of the developed methodologies toward the synthesis of natural products is also elaborated.
Olefin metathesis catalysts provide access to molecules that are indispensable to physicians and researchers in the life sciences. A persisting problem, however, is the dearth of chemical transformations that directly generate acyclic Z allylic alcohols, including products that contain a hindered neighbouring substituent or reactive functional units such as a phenol, an aldehyde, or a carboxylic acid. Here we present an electronically modified ruthenium-disulfide catalyst that is effective in generating such high-value compounds by cross-metathesis. The ruthenium complex is prepared from a commercially available precursor and an easily generated air-stable zinc catechothiolate. Transformations typically proceed with 5.0 mole per cent of the complex and an inexpensive reaction partner in 4-8 hours under ambient conditions; products are obtained in up to 80 per cent yield and 98:2 Z:E diastereoselectivity. The use of this catalyst is demonstrated in the synthesis of the naturally occurring anti-tumour agent neopeltolide and in a single-step stereoselective gram-scale conversion of a renewable feedstock (oleic acid) to an anti-fungal agent. In this conversion, the new catalyst promotes cross-metathesis more efficiently than the commonly used dichloro-ruthenium complexes, indicating that its utility may extend beyond Z-selective processes.
Many natural products contain a C = C double bond through which various other derivatives can be prepared; the stereochemical identity of the alkene can be critical to the biological activities of such molecules. Catalytic ring-closing metathesis (RCM) is a widely used method for the synthesis of large unsaturated rings; however, cyclizations often proceed without control of alkene stereochemistry. This shortcoming is particularly costly when the cyclization reaction is performed after a long sequence of other chemical transformations. Here we outline a reliable, practical and general approach for the efficient and highly stereoselective synthesis of macrocyclic alkenes by catalytic RCM; transformations deliver up to 97% of the Z isomer owing to control induced by a tungsten-based alkylidene. Utility is demonstrated through the stereoselective preparation of epothilone C (refs 3-5) and nakadomarin A (ref. 6), the previously reported syntheses of which have been marred by late-stage, non-selective RCM. The tungsten alkylidene can be manipulated in air, delivering the products in useful yields with high stereoselectivity. As a result of efficient RCM and re-incorporation of side products into the catalytic cycle with minimal alkene isomerization, desired cyclizations proceed in preference to alternative pathways, even under relatively high substrate concentration.
Alkenes are found in many biologically active molecules, and there are a large number of chemical transformations in which alkenes act as the reactants or products (or both) of the reaction. Many alkenes exist as either the E or the higher-energy Z stereoisomer. Catalytic procedures for the stereoselective formation of alkenes are valuable, yet methods enabling the synthesis of 1,2-disubstituted Z alkenes are scarce. Here we report catalytic Z-selective cross-metathesis reactions of terminal enol ethers, which have not been reported previously, and of allylic amides, used until now only in E-selective processes. The corresponding disubstituted alkenes are formed in up to >98% Z selectivity and 97% yield. These transformations, promoted by catalysts that contain the highly abundant and inexpensive metal molybdenum, are amenable to gram-scale operations. Use of reduced pressure is introduced as a simple and effective strategy for achieving high stereoselectivity. The utility of this method is demonstrated by its use in syntheses of an anti-oxidant plasmalogen phospholipid, found in electrically active tissues and implicated in Alzheimer's disease, and the potent immunostimulant KRN7000.
This is a complete examination of the theory and methods of modern olefin metathesis, one of the most widely used chemical reactions in research and industry. Provides basic information for non-specialists, while also explaining the latest trends and advancements in the field to experts. Discusses the various types of metathesis reactions, including CM, RCM, enyne metathesis, ROMP, and tandem processes, as well as their common applications. Outlines the tools of the trade-from the important classes of active metal complexes to optimal reaction conditions-and suggests practical solutions for common reaction problems. Includes tables with structures of commercial catalysts, and recommendations for commercial catalyst suppliers.
Olefin cross metathesis is a particularly powerful transformation that has been exploited extensively for the formation of complex products. Until recently, however, constructing Z-olefins using this methodology was not possible. With the discovery and development of three families of ruthenium-based Z-selective catalysts, the formation of Z-olefins using metathesis is now not only possible but becoming increasingly prevalent in the literature. In particular, ruthenium complexes containing cyclometalated NHC architectures developed in our group have been shown to catalyze various cross metathesis reactions with high activity and, in most cases, near perfect selectivity for the Z-isomer. The types of cross metathesis reactions investigated thus far are presented here and explored in depth.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
A convergent
diastereo- and enantioselective total synthesis of
anticancer and antifungal macrocyclic natural product disorazole C1 is reported. The central feature of the successful route
is the application of catalytic Z-selective cross-metathesis
(CM). Specifically, we illustrate that catalyst-controlled stereoselective
CM can be performed to afford structurally complex Z-alkenyl–B(pin) as well as Z-alkenyl iodide
compounds reliably, efficiently, and with high selectivity (pin =
pinacolato). The resulting intermediates are then joined in a single-step
operation through catalytic inter- and intramolecular cross-coupling
to furnish the desired 30-membered ring macrocycle containing the
critical (Z,Z,E)-triene moieties.
Molybdenum-, tungsten-, and ruthenium-based complexes that control the stereochemical outcome of olefin metathesis reactions have been recently introduced. However, the complementary nature of these systems through their combined use in multistep complex molecule synthesis has not been illustrated. A concise diastereo- and enantioselective route that furnishes the anti-proliferative natural product neopeltolide is now disclosed. Catalytic transformations are employed to address every stereochemical issue. Among the featured processes are an enantioselective ring-opening/cross-metathesis promoted by a Mo monoaryloxide pyrrolide (MAP) complex and a macrocyclic ring-closing metathesis that affords a trisubstituted alkene and is catalyzed by a Mo bis(aryloxide) species. Furthermore, Z-selective cross-metathesis reactions, facilitated by Mo and Ru complexes, have been employed in the stereoselective synthesis of the acyclic dienyl moiety of the target molecule.
DFT calculations have predicted a new, highly Z-selective ruthenium-based olefin metathesis catalyst that is considerably more robust than the recently reported (SIMes)(Cl)(RS)RuCH(o-OiPrC6H4) (, SIMes = 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene, R = 2,4,6-triphenylbenzene) [J. Am. Chem. Soc., 2013, 135, 3331]. Replacing the chloride of by an isocyanate ligand to give was predicted to increase the stability of the complex considerably, at the same time moderately improving the Z-selectivity. Compound is easily prepared in a two-step synthesis starting from the Hoveyda-Grubbs second-generation catalyst . In agreement with the calculations, the isocyanate-substituted appears to be somewhat more Z-selective than the chloride analogue . More importantly, can be used in air, with unpurified and non-degassed substrates and solvents, and in the presence of acids. These are traits that are unprecedented among highly Z-selective olefin metathesis catalysts and also very promising with respect to applications of the new catalyst.
There have been numerous significant advances in catalytic olefin metathesis (OM) during the past two decades. Such progress has transformed this important set of reactions to strategically pivotal processes that generate stereochemical identity while delivering molecules that cannot be easily prepared by alternative routes. In this Perspective, an analysis of the origin of the inception of bidentate benzylidene ligands for Ru-based OM catalysts is first presented. This is followed by an overview of the intellectual basis that culminated in the development of Mo-based diolates and stereogenic-at-Ru complexes for enantioselective OM. The principles accrued from the study of the latter Ru carbenes and Mo alkylidenes and utilized in the design of stereogenic-at-Mo, -W, and -Ru species applicable to enantioselective and Z-selective OM are then discussed. The influence of the recently introduced catalytic OM protocols on the design of synthesis routes leading to complex organic molecules is probed. The impact of a better understanding of the mechanistic nuances of OM toward the discovery of stereoselective catalysts is reviewed as well.
The olefin cross-metathesis
reaction allows rapid access to 1,5-dicarbonyl
intermediates which, upon treatment with a primary or secondary amine,
allow the synthesis of a range of multisubstituted carbocyclic aryl
amines. This de novo arene synthesis yields nonclassical substitution
patterns in a regioselective and predictable approach that is compatible
with several functional groups.
A set of protocols for catalytic enantioselective allylic substitution (EAS) reactions that allow for additions of alkenyl units to readily accessible allylic electrophiles is disclosed. Transformations afford 1,4-dienes that contain a tertiary carbon stereogenic site and are promoted by 1.0-5.0 mol % of a copper complex of an N-heterocyclic carbene (NHC). Aryl- as well as alkyl-substituted electrophiles bearing a di- or trisubstituted alkene may be employed. Reactions can involve a variety of robust alkenyl-(pinacolatoboron) [alkenyl-B(pin)] compounds that can be either purchased or prepared by various efficient, site-, and/or stereoselective catalytic reactions, such as cross-metathesis or proto-boryl additions to terminal alkynes. Vinyl-, E-, or Z-disubstituted alkenyl-, 1,1-disubstituted alkenyl-, acyclic, or heterocyclic trisubstituted alkenyl groups may be added in up to >98% yield, >98:2 SN2':SN2, and 99:1 enantiomeric ratio (er). NHC-Cu-catalyzed EAS with alkenyl-B(pin) reagents containing a conjugated carboxylic ester or aldehyde group proceed to provide the desired 1,4-diene products in good yield and with high enantioselectivity despite the presence of a sensitive stereogenic tertiary carbon center that could be considered prone to epimerization. In most instances, the alternative approach of utilizing an alkenylmetal reagent (e.g., an Al-based species) represents an incompatible option. The utility of the approach is illustrated through applications to enantioselective synthesis of natural products such as santolina alcohol, semburin, nyasol, heliespirone A, and heliannuol E.
The total synthesis of (±)-streptonigrin, a potent tetracyclic aminoquinoline-5,8-dione antitumor antibiotic that reached phase II clinical trials in the 1970s, is described. Two routes to construct a key pentasubstituted pyridine fragment are depicted, both relying on ring-closing metathesis but differing in the substitution and complexity of the precursor to cyclization. Both routes are short and high yielding, with the second-generation approach ultimately furnishing (±)-streptonigrin in 14 linear steps and 11% overall yield from inexpensive ethyl glyoxalate. This synthesis will allow for the design and creation of druglike late-stage natural product analogues to address pharmacological limitations. Furthermore, assessment of a number of chiral ligands in a challenging asymmetric Suzuki-Miyaura cross-coupling reaction has enabled enantioenriched (up to 42% ee) synthetic streptonigrin intermediates to be prepared for the first time.
The stereoselective formation of carbon–carbon double bonds is a longstanding topic in organic chemistry. Since the early 90s, catalytic olefin metathesis has emerged as a synthetic tool of choice for the creation of carbon–carbon double bonds, and its use is now widespread. However, except for the synthesis of small cycles, the reversible character of olefin metathesis usually results in the formation of the thermodynamic E product, and more generally in mixtures of E and Z products. This issue has been addressed in different ways; these are reviewed herein. Synthetic protocols, which aim at the selective synthesis of Z olefins, for example, sequential alkyne metathesis/cis-hydrogenation, and the use of removable silyl groups, are summarized. Tailor-made molybdenum, tungsten and ruthenium catalysts, which allow for very high stereoselectivity, are also reviewed. The advances achieved with these methods and catalysts are illustrated by the synthesis of various natural products or their precursors.
The asymmetric total synthesis of the anti-proliferative macrolide (+)-neopeltolide has been completed. The stereochemically defined trisubstituted tetrahydropyran ring was constructed via a catalytic hetero-Diels-Alder reaction creating two new chiral centers in a highly diastereoselective manner. The other key features of this synthesis included Brown's asymmetric allylation to install the requisite C-11 and C-13 stereocenters. The synthesis of the oxazole side chain consisted of a hydrozirconation of an alkynyl stannane to establish the Z stereochemistry, followed by a palladium catalyzed cross coupling to introduce the desired Z olefin in the oxazole side chain.
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.
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.
Magnificent seven: The chlorosulfolipid mytilipin A was synthesized in racemic form in seven steps and in enantioenriched form in eight steps. Key transformations include a highly diastereoselective bromoallylation of a sensitive α,β-dichloroaldehyde, a kinetic resolution of a vinyl epoxide, a convergent and highly Z-selective alkene cross-metathesis, and a chemoselective and diastereoselective dichlorination of a complex diene.
Rationally designed Ru-based catalysts for efficient Z-selective olefin metathesis are featured. The new complexes contain a dithiolate ligand and can be accessed in a single step from commercially available precursors in 68-82% yield. High efficiency and exceptional Z selectivity (93:7 to >98:2 Z:E) were achieved in ring-opening metathesis polymerization (ROMP) and ring-opening/cross-metathesis (ROCM) processes; the transformations typically proceed at 22 °C and are operationally simple to perform. Complete conversion was observed with catalyst loadings as low as 0.002 mol %, and turnover numbers of up to 43 000 were achieved without rigorous substrate purification or deoxygenation protocols. X-ray data and density functional theory computations provide support for key design features and shed light on mechanistic attributes.
Get me a Z (olefin): Efficient catalytic cross-metathesis reactions that afford Z-disubstituted allylic silyl or benzyl ethers are reported (see scheme, MAP=monoalkoxide pyrrolide). The approach, in combination with catalytic cross-coupling, provides a general entry to otherwise difficult-to-access alkyne-containing Z olefins.
We describe herein a concise synthesis of (+)-neopeltolide, a marine macrolide natural product that elicits a highly potent antiproliferative activity against several human cancer cell lines. Our synthesis exploited the powerful bond-forming ability and high functional group compatibility of olefin metathesis and esterification reactions to minimize manipulations of oxygen functionalities and to maximize synthetic convergency. Our findings include a chemoselective olefin cross-metathesis reaction directed by H-bonding, and a ring-closing metathesis conducted under non-high dilution conditions. Moreover, we developed a 16-member stereoisomer library of 8,9-dehydroneopeltolide to systematically explore the stereostructure-activity relationships. Assessment of the antiproliferative activity of the stereoisomers against A549 human lung adenocarcinoma, MCF-7 human breast adenocarcinoma, HT-1080 human fibrosarcoma, and P388 murine leukemia cell lines has revealed marked differences in potency between the stereoisomers. This study provides comprehensive insights into the structure-activity relationship of this important antiproliferative agent, leading to the identification of the pharmacophoric structural elements and the development of truncated analogues with nanomolar potency.
The first examples of catalytic cross-metathesis (CM) reactions that furnish Z-(pinacolato)allylboron and Z-(pinacolato)alkenylboron compounds are disclosed. Products are generated with high Z selectivity by the use of a W-based monoaryloxide pyrrolide (MAP) complex (up to 91% yield and >98:2 Z:E). The more sterically demanding Z-alkenylboron species are obtained in the presence of Mo-based MAP complexes in up to 93% yield and 97% Z selectivity. Z-selective CM with 1,3-dienes and aryl olefins are reported for the first time. The utility of the approach, in combination with catalytic cross coupling, is demonstrated by a concise and stereoselective synthesis of anticancer agent combretastatin A-4.
A one-step substitution of a single chloride anion of the Grubbs-Hoveyda second-generation catalyst by a 2,4,6-triphenylbenzenethiolate ligand results in an active and remarkably Z-selective olefin metathesis catalyst, reaching 96 % in metathesis homocoupling of terminal olefins. High turnover numbers, in homocoupling of 1-octene up to 2000, are obtained along with sustained appreciable Z-selectivity (> 85 %). Apart from the Z-selectivity, many properties of the new catalyst, such as robustness toward oxygen and water as well as tendency to isomerize substrates and react with internal olefin products, resemble those of the parent Grubbs-Hoveyda catalyst.
The first broadly applicable set of protocols for efficient Z-selective formation of macrocyclic disubstituted alkenes through catalytic ring-closing metathesis (RCM) is described. Cyclizations are performed with 1.2-7.5 mol % of a Mo- or W-based monoaryloxide pyrrolide (MAP) complex at 22 °C and proceed to complete conversion typically within two hours. Utility is demonstrated by synthesis of representative macrocyclic alkenes, such as natural products yuzu lactone (13-membered ring: 73 % Z) epilachnene (15-membered ring: 91 % Z), ambrettolide (17-membered ring: 91 % Z), an advanced precursor to epothilones C and A (16-membered ring: up to 97 % Z), and nakadomarin A (15-membered ring: up to 97 % Z). We show that catalytic Z-selective cyclizations can be performed efficiently on gram-scale with complex molecule starting materials and catalysts that can be handled in air. We elucidate several critical principles of the catalytic protocol: 1) The complementary nature of the Mo catalysts, which deliver high activity but can be more prone towards engendering post-RCM stereoisomerization, versus W variants, which furnish lower activity but are less inclined to cause loss of kinetic Z selectivity. 2) Reaction time is critical to retaining kinetic Z selectivity not only with MAP species but with the widely used Mo bis(hexafluoro-tert-butoxide) complex as well. 3) Polycyclic structures can be accessed without significant isomerization at the existing Z alkenes within the molecule.
Olefin metathesis catalysts for controlling the formation of trisubstituted macrocyclic Z alkenes have been developed. The most effective complexes are Mo alkylidenes with a pentafluorophenylimido group and two large aryloxide ligands. The macrocyclic lactone precursor to anticancer agents epothilones B and D is obtained in 73 % yield and 91 % Z selectivity in less than 6 hours at room temperature.
The first report of Z-selective macrocyclizations using a ruthenium-based metathesis catalyst is described. Selectivity for Z-macrocycles is consistently high for a diverse set of substrates with a variety of functional groups and ring sizes. The same catalyst was also employed for the Z-selective ethenolysis of a mixture of E and Z macrocycles, providing the pure E-isomer. Notably, only an atmospheric pressure of ethylene was required. These methodologies were successfully applied to the construction of several olfactory macrocycles, as well as the formal total synthesis of the cytotoxic alkaloid motuporamine C.
The use of insect sex pheromones to limit specifically targeted pest populations has gained increasing popularity as a viable, safe, and environmentally friendly alternative to insecticides. While broad-spectrum insecticides are toxic compounds that have been shown to adversely affect human health,[1] extensive studies have shown that insect pheromones are nontoxic and safe for human consumption at the levels used in pest control practices.[2] Female sex pheromones are mainly employed in pest control in a process termed mating disruption. This involves dispersing pheromones over a large area, overloading the sensory organs of male insects and preventing them from locating and mating with females who are releasing a much smaller amount of the same pheromone blends; this strategy has proven to reduce specific insect populations dramatically.[3] To date, the United States Environmental Protection Agency (EPA) has approved approximately twenty lepidopteran female sex pheromones as active ingredients for pest control.[2]
The phosphine-free “second-generation” Blechert/Hoveyda−Grubbs catalyst Ru(C(H)C6H4-o-O-i-Pr)(H2IMes)Cl2 (H2IMes = 4,5-dihydro-1,3-dimesitylimidazol-2-ylidene) and Piers catalyst [Ru(CHPCy3)(H2IMes)Cl2]BF4 (Cy = cyclo-C6H11) for olefin metathesis effected cross-metathesis (CM) of vinyl chloride and 1,2-dichloroethene with several unhindered terminal and internal alkenes in up to 95% yield (5 mol % catalyst). In most cases, 1,2-dichloroethene was more successful than vinyl chloride. Ring-opening CM of cyclooctene provided greater yields than CM: with vinyl chloride, 93% yield; with 1,2-dichloroethene, >95%. Other common Ru-based catalysts failed to effect CM under similar conditions, but instead underwent rapid decomposition. The dimeric ruthenium-monochloromethylidene complex [Ru(CHCl)(H2IMes)Cl(μ-Cl)]2 was isolated as a thermally unstable intermediate. CM reactions with 1,2-dibromoethene afforded 22% CM product in the best case; halide exchange with the catalyst was significant. CM reactions involving vinyl fluoride typically led to <3 turnovers, but the dimeric intermediate [Ru(CHF)(H2IMes)Cl(μ-Cl)]2 was sufficiently long-lived to be characterized by single-crystal X-ray diffraction. Ring-opening CM of cyclooctene with vinyl fluoride (55% yield) was more favorable than CM.
A novel manzamine-related alkaloid consisting of unprecedented 8/5/5/5/15/6 ring system, nakadomarin A (1), has been isolated from an Okinawan marine sponge Amphimedon sp., and the unique structure containing a furan ring was elucidated on the basis of the spectroscopic data. The relative stereochemistry was deduced from the NOE data and proton couplings, and a plausible biogenetic path of 1 through ircinal A was proposed.
Convergent, stereocontrolled total syntheses of the microtubule-stabilizing macrolides epothilones A (2) and B (3) have been achieved. Four distinct ring-forming strategies were pursued (see Scheme 1). Of these four, three were reduced to practice. In one approach, the action of a base on a substance possessing an acetate ester and a nonenolizable aldehyde brought about a remarkably effective macroaldolization see (89 → 90 + 91; 99 → 100 + 101), simultaneously creating the C2−C3 bond and the hydroxyl-bearing stereocenter at C-3. Alternatively, the 16-membered macrolide of the epothilones could be fashioned through a C12−C13 ring-closing olefin metathesis (e.g. see 111 → 90 + 117; 122 → 105 + 123) and through macrolactonization of the appropriate hydroxy acid (e.g. see 88 → 93). The application of a stereospecific B-alkyl Suzuki coupling strategy permitted the establishment of a cis C12−C13 olefin, thus setting the stage for an eventual site- and diastereoselective epoxidation reaction (see 96 → 2; 106 → 3). The development of a novel cyclopropane solvolysis strategy for incorporating the geminal methyl groups of the epothilones (see 39 → 40 → 41), and the use of Lewis acid catalyzed diene−aldehyde cyclocondensation (LACDAC) (see 35 + 36 → 37) and asymmetric allylation (see 10 → 76) methodology are also noteworthy.
The olefin metathesis approach to epothilone A (1) and several analogues (39−41, 42−44, 51−57, 58−60, 64−65, and 67−69) is described. Key building blocks 6−8 were constructed in optically active form and were coupled and elaborated to olefin metathesis precursor 4 via an aldol reaction and an esterification coupling. Olefin metathesis of compound 4, under the catalytic influence of RuCl2(CHPh)(PCy3)2, furnished cis- and trans-cyclic olefins 3 and 48. Epoxidation of 49 gave epothilone A (1) and several analogues, whereas epoxidation of 50 resulted in additional epothilones. Similar elaboration of isomeric as well as simpler intermediates resulted in yet another series of epothilone analogues and model systems.
Twenty-nine disorazoles A–H (1–29) were isolated by solvent partitions and chromatographic separations from Sorangium cellulosum, strain So ce12, the producer of the sorangicin antibiotics. The disorazoles proved to be highly cytotoxic and active against fungi. The structures of the main component disorazole A1 (1) and 28 variants were elucidated by 2D-NMR and mass spectroscopy. The disorazoles are macrocyclic dilactones of two 2-pentadecyloxazol-4-carboxylic acids, which are modified in their carbon chain by variation of the position and configuration of double bonds and oxygen substituents like epoxide, hydroxyl, or methyl ether groups. In addition to these, three disorazoles are ring-enlarged by lactonization to a more distant hydroxyl group. By feeding of 13C-enriched precursors the biosynthetic origin of the carbons in disorazole A (1) was investigated. C-2 of the oxazole and the attached pentadecyl chain arise from acetate. The geminal methyl groups and the methoxyl group are derived from the methyl group of methionine.
Olefin metathesis opens up new industrial routes to important petrochemicals, oleochemicals, polymers and specialty chemicals. The most important applications of olefin metathesis in the field of petrochemicals are the olefins conversion technology (OCT) process (originally the Phillips triolefin process) and the Shell higher olefins process (SHOP). In particular, naphtha steam crackers with an integrated metathesis unit are an interesting alternative for producing propene via the OCT process, as a high global demand for propene outpaces supply from conventional sources. In the polymer field, ring-opening metathesis polymerisation (ROMP) of cycloalkenes is an attractive process for making polymers possessing special properties. Several industrial processes involving ROMP have been developed and brought into practice, such as the ROMP of cyclooctene, norbornene and dicyclopentadiene, leading to useful polymers. Metathesis of natural fats and oils and their derivatives offers possibilities for future developments in the oleochemical industry, providing a contribution to a sustainable chemical industry. Moreover, in the light of the new metal–carbene metathesis catalysts, in particular the functional-group-tolerant well-defined ruthenium-based catalysts, it is to be expected that in the fine chemistry the metathesis reaction will soon find its way as a tool for the synthesis of agrochemicals, insect pheromones, fragrances, pharmaceutical intermediates, etc.
Molybdenum or tungsten monoaryloxide pyrrolide (MAP) complexes that contain OHIPT as the aryloxide (hexaisopropylterphenoxide) are effective catalysts for homocoupling of simple (E)-1,3-dienes to give (E,Z,E)-trienes in high yield and with high Z selectivities. A vinylalkylidene MAP species was shown to have the expected syn structure in an X-ray study. MAP catalysts that contain OHMT (hexamethylterphenoxide) are relatively inefficient.
Zelectivity!! A new generation of olefin metathesis catalysts have made it possible to obtain Z-configured olefins selectivity. This highlight records the latest developments in this field, with applications, implications and examples.
Temporary silicon-tethered ring-closing metathesis represents an important cross-coupling strategy for the formation of medium-sized silacycles. These intermediates are valuable synthons in organic synthesis due to their propensity to undergo a facile refunctionalization through protodesilylation, oxidation, silane-group transfer or transmetallation. A particularly attractive utility of this methodology is an application in the synthesis of biologically important natural products. The purpose of this review article is to highlight the recent progress in methodology development and its strategic application toward the target-directed synthesis.
A compound isolated from root tissue extracts of Daucus carota L. showed antifungal activity towards Mycocentrospora acerina and Cladosporium cladosporioides. It was identified with the aid of u.v. and infrared spectroscopy, nuclear magnetic resonance and mass spectrometry as cis-heptadeca-1,9-diene-4,6-diyne-3,8-diol with the trivial name of falcarindiol. A concentration gradient in carrot roots varying from 93 μg/g fresh wt in periderm and pericyclic parenchyma to 2 μg/g in xylem parenchyma was demostrated. The ED50 for inhibition of germination of chlamydospores of M. acerina was 31·8 μg/ml. The rôle of this compound in disease resistance is discussed.
The mechanism and origins of Z-selectivity in olefin metathesis with chelated Ru catalysts were explored using density functional theory. The olefin approaches from the "side" position of the chelated Ru catalysts, in contrast to reactions with previous unchelated Ru catalysts that favor the bottom-bound pathway. Steric repulsions between the substituents on the olefin and the N-substituent on the N-heterocyclic carbene ligand lead to highly selective formation of the Z product.
The olefin metathesis reaction has underpinned spectacular achievements in organic synthesis in recent years. Arguably, metathesis has now become the foremost choice for a carbon-carbon double bond disconnection. Despite this general utility, de novo routes to heteroaromatic compounds using the cross-metathesis (CM) reaction have only recently emerged as an efficient strategy. This approach allows a convergent union of simple, functionalised, three- to four-carbon olefinic core building blocks, to generate furans, pyrroles and pyridines with a high degree of control of substitution pattern in the product.
Several new C-H-activated ruthenium catalysts for Z-selective olefin metathesis have been synthesized. Both the carboxylate ligand and the aryl group of the N-heterocyclic carbene have been altered and the resulting catalysts evaluated using a range of metathesis reactions. Substitution of bidentate with monodentate X-type ligands led to a severe attenuation of metathesis activity and selectivity, while minor differences were observed between bidentate ligands within the same family (e.g., carboxylates). The use of nitrato-type ligands in place of carboxylates afforded a significant improvement in metathesis activity and selectivity. With these catalysts, turnover numbers approaching 1000 were possible for a variety of cross-metathesis reactions, including the synthesis of industrially relevant products.
A concise formal synthesis of (+)-neopeltolide (1) has been accomplished. The synthesis demonstrated high atom efficiency employing only one step of functional group protection. Key steps involved iridium-catalyzed double asymmetric carbonyl allylation, palladium-catalyzed intramolecular alkoxycarbonylation, ruthenium-catalyzed olefin isomerization, and ring-closing metathesis.
The synthesis of the potent antitumor agent (±)-streptonigrin has been achieved in 14 linear steps and 11% overall yield from ethyl glyoxalate. The synthesis features a challenging ring-closing metathesis reaction, followed by elimination and aromatization, to furnish a key pentasubstituted pyridine fragment.
We present the first productive ring-closing metathesis reaction that leads to the construction of cyclic alkenyl bromides. Efficient catalysis employing commercially available Grubbs II catalyst is possible through appropriate modification of the starting bromoalkene moiety.
Dendritic cells (DCs) are important for regulating the immune response. We report an herbal medicine compound called falcarindiol that affects DC function. Ethanol extracts of 99 crude drugs that are the main components of 210 traditional Japanese medicines (Kampo medicine) approved by the Ministry of Health, Labor and Welfare in Japan were prepared and screened using the murine epidermal-derived Langerhans cell line XS106. Notopterygii Rhizoma strongly suppressed major histocompatibility complex (MHC) class II expression in XS106 cells. Activity-guided fractionation led to the isolation and identification of falcarindiol as a principal active compound in Notopterygii Rhizoma. Falcarindiol (1-5 microM) dose-dependently suppressed MHC II expression in XS106 cells. Fresh-isolated bone marrow-derived DCs were examined for the production of MHC II, CD80, CD86, interleukin (IL)-12p70, and IL-10. Treatment of bone marrow-derived DCs with 5 muM falcarindiol significantly inhibited lipopolysaccharide-induced phenotype activation and cytokine secretion and inhibited MHC II expression by CD40 ligation, but not phorbol 12-myristate 13-acetate + ionomycin or IL-12. Falcarindiol inhibited DC maturation by blocking the canonical pathway of nuclear factor-kappaB and phosphorylated p38. Topical application of 0.002 and 0.01% falcarindiol before sensitization dose-dependently suppressed delayed-type hypersensitivity to ovalbumin (p < 0.01). Falcarindiol induces immunosuppressive effects in vitro and in vivo and might be a novel therapy for autoimmune or allergic diseases.
Bioassay-guided fractionation of a chloroformic extract obtained from Crithmum maritimum leaves led to the chemical isolation of falcarindiol, a polyacetylene widely distributed within the Apiaceae family. Structure of this compound was confirmed by NMR and activity was tracked using a screening microplate bioassay. Falcarindiol strongly inhibited the growth of Micrococcus luteus and Bacillus cereus, with a minimum inhibitory concentration (MIC) value of 50 microg ml(-1). Moreover, this compound showed cytotoxicity against IEC-6 cells with an IC50 value of 20 microM after 48 h of exposition. These results suggest that Crithmum maritimum could be potentially used in food manufactures and cosmetology as preservative agents and biopesticides, or in medicine as new antibiotics, confirming the interest in studying halophytic species as sources of bioactive compounds.
Mo and W MonoAryloxide-Pyrrolide (MAP) olefin metathesis catalysts can couple terminal olefins to give as high as >98% Z-products in moderate to high yields with as little as 0.2% catalyst. Results are reported for 1-hexene, 1-octene, allylbenzene, allyltrimethylsilane, methyl-10-undecenoate, methyl-9-decenoate, allylB(pinacolate), allylOBenzyl, allylNHTosyl, and allylNHPh. It is proposed that high Z-selectivity is achieved because a large aryloxide only allows metallacyclobutanes to form that contain adjacent cis substituents and because isomerization of Z-product to E-product can be slow in that same steric environment.
A short and highly stereoselective synthesis of (-)-nakadomarin A has been developed using combinations of catalyst-controlled bond formations, one-pot multistep procedures, and powerful route-shortening reaction cascades. Several unprecedented chemical transformations were developed, including a highly Z-selective, eight-membered-ring-forming intramolecular Julia-Kocienski reaction, a highly diastereoselective intramolecular furan/iminium ion cyclization, and a sulfonic acid-controlled Z-selective macrocyclic ring-closing metathesis. In conjunction with a diastereoselective nitro olefin Michael addition under bifunctional organocatalysis and a nitro-Mannich/lactamization cascade, these transformations allowed the construction of this architecturally complex natural product in significant quantities in 12 steps (longest linear sequence) from commercially available starting materials.
The importance of ring-closing metathesis (RCM) in the synthesis of aromatic compounds are reported. RCM has been applied to many aromatic and heteroaromatic substrates, often providing unique access to substrates otherwise synthetically challenging to assemble by classical synthetic approaches. Yoshida and Imamoto have demonstrated the power of utilizing RCM, aromatization strategies for the synthesis of substituted benzene systems. The same group also modified their methodology to afford substituted benzene by invoking a dehydration to facilitate aromatization after metathesis. Yoshida, Narui, and Imamoto also utilized an RCM-aromatization approach for the synthesis of substituted phenolic compounds. It is expected that this review will stimulate researchers to reevaluate the structures of aromatic compounds classes not traditionally considered amenable to synthesis by a RCM approach.
The molybdenum-based monoaryloxide monopyrrolide (MAP) species, Mo(NAd)(CHCMe(2)Ph)(C(4)H(4)N)(HIPTO) (2a), which contains "small" imido (Ad = 1-adamantyl) and "large" aryloxide (HIPTO = O-2,6(2,4,6-i-Pr(3)C(6)H(2))C(6)H(3)) ligands, catalyzes Z-selective metathesis reactions as a consequence of intermediate metallacyclobutane species not being able to have an (anti) substituent pointing toward the HIPTO group. Ring-opening metathesis polymerization (ROMP) of dicarbomethoxynorbornadiene (DCMNBD) with 2% 2a in toluene leads to >99% cis and >99% syndiotactic poly(DCMNBD), while ROMP of cyclooctene and 1,5-cyclooctadiene (300 equiv) with initiator 2a leads to poly(cyclooctene) and poly(cyclooctadiene) that have cis contents of >99%; all are previously unknown microstructures. Z-Selectivity is also observed in the metathesis of cis-4-octene and cis-3-hexene by initiator 2a to give cis-3-heptene.
Protein compatible . Olefin metathesis has emerged as a viable strategy for site‐selective protein modification. This minireview traces its development from early peptide models and metathesis in water to its ultimate application to protein substrates. Prospects in chemistry and biology are also discussed. magnified image
For a reaction to be generally useful for protein modification, it must be site‐selective and efficient under conditions compatible with proteins: aqueous media, low to ambient temperature, and at or near neutral pH. To engineer a reaction that satisfies these conditions is not a simple task. Olefin metathesis is one of most useful reactions for carbon–carbon bond formation, but does it fit these requirements? This minireview is an account of the development of olefin metathesis for protein modification. Highlighted below are examples of olefin metathesis in peptidic systems and in aqueous media that laid the groundwork for successful metathesis on protein substrates. Also discussed are the opportunities in protein engineering for the genetic introduction of amino acids suitable for metathesis and the related challenges in chemistry and biology.
The first highly Z- and enantioselective class of ring-opening/cross-metathesis reactions is presented. Transformations are promoted in the presence of <2 mol % of chiral stereogenic-at-Mo monoaryloxide complexes bearing an adamantylimido ligand that are prepared and used in situ. Reactions involve meso oxabicyclic substrates and afford the desired pyrans in 50-85% yield and up to >98:<2 enantiomer ratio. Importantly, the desired chiral pyrans thus obtained bear a Z olefin either exclusively (>98:<2 Z/E) or predominantly (>or=87:13 Z/E).
Chemical biology relies on effective synthetic chemistry for building molecules to probe and modulate biological function. Olefin metathesis in organic solvents is a valuable addition to this armamentarium, and developments during the previous decade are enabling metathesis in aqueous solvents for the manipulation of biomolecules. Functional group-tolerant ruthenium metathesis catalysts modified with charged moieties or hydrophilic polymers are soluble and active in water, enabling ring-opening metathesis polymerization, cross metathesis, and ring-closing metathesis. Alternatively, conventional hydrophobic ruthenium complexes catalyze a similar array of metathesis reactions in mixtures of water and organic solvents. This strategy has enabled cross metathesis on the surface of a protein. Continuing developments in catalyst design and methodology will popularize the bioorthogonal reactivity of metathesis.