Stereoselectivity of macrocyclic ring-closing olefin metathesis

[reaction: see text] Macrocyclic ring-closing olefin metathesis using ruthenium catalyst 3 was performed to produce a 14-membered lactone. The E/Z ratio of lactone was high regardless of the R group (auxiliary) or the initial alkene stereochemistry. A kinetic study demonstrates that the high E/Z ratio is due to secondary metathesis reactions that isomerize the product to the thermodynamic E/Z ratio.     

Synthesis of a cryptand with tetrahedral connectivity using multiple ring-closing olefin metathesis

By connecting six terminal olefins sequentially in one molecule under metathesis conditions, three macrocycles were formed efficiently in one pot yielding a novel cryptand with tetrahedral connectivity.     

Formation of macrocycles via ring-closing olefin metathesis

The enhanced metathesis activity of 1,3-dimesityl-4,5-dihydroimidazole-2-ylidene ruthenium carbene catalyst 3 significantly increases the feasibility of synthesizing macrocyclic compounds. Catalyst 3 exhibits sufficient activity in RCM to dimerize alpha,beta-unsaturated ester substrates and afford the corresponding head-to-tail (E,E)-dimeric (and trimeric) macrocycles. The dimerization appears to be under thermodynamic control with the product mixture dependent not only on the electronic and steric nature of the substrate but also on concentration.     

Directed ring-closing metathesis of trienes by silyl substitution

A synthetic strategy for ‘disarming’ a terminal alkene by substitution with a bulky silyl blocking group has been developed. In a series of model studies, sequential selective ring-closing metathesis of trienes followed by selective mono-hydrogenation of the resulting diene is described. The bulky silylated alkene is activated for a subsequent cross-metathesis reaction with a range of diverse alkenes by protodesilylation.     

Construction of carbocyclic ring of indoles using ruthenium-catalyzed ring-closing olefin metathesis

The selective synthesis of substituted indoles was achieved by the ring-closing olefin metathesis (RCM)/elimination sequence or the RCM/tautomerization sequence of functionalized pyrrole precursors. The RCM/elimination sequence was also applied to double ring closure to yield a substituted carbazole.     

Synthesis of diversely functionalized pyrrolizidines and indolizidines using olefin ring-closing metathesis

Various nitrogen-fused tricyclic compounds, having benzoindolizidine and benzopyrrolizidines ring systems were synthesized via ene-ene metathesis using the first and second-generation Grubbs catalyst. The ene-ene metathesis proceeded smoothly in refluxing CH₂Cl₂ with 3.0 mol % of G₁, giving good yields (78-86%) of the benzoindolizidine products 12a,b. The benzopyrrolizidine 6 was prepared after optimization in 64% yield by using 5.0+5.0 mol % of G₂. The resulting olefin moiety of the indolizidine framework is a suitable precursor for polyhydroxy structures via the Sharpless process. The structures of the polyhydroxylated adducts were determined by ¹H NMR spectra and single-crystal X-ray analysis.     

Synthesis of beta-bisabolol by ring-closing olefin metathesis reaction

A ring-closing olefin metathesis is the key step in the synthesis of the beta-bisabolols.     

Oligometallic template strategy for ring-closing olefin metathesis: highly cis- and trans-selective synthesis of a 32-membered macrocyclic tetraoxime

An oligometallic template effect was observed on the cis/trans selectivity of a 32-membered macrocyclic tetraoxime in ring-closing olefin metathesis of an acyclic diallyl derivative H4L; the metathesis of heterotrinuclear complex LZn2M (M=Ca2+, La3+) afforded the cis isomer, whereas uncomplexed H4L gave the trans isomer.     

Synthesis of bridged azabicyclic structures via ring-closing olefin metathesis

A new strategy for the facile synthesis of azabicyclo[m.n.1]alkenes (m = 3-5; n = 3, 2) has been developed that involves the ring-closing metathesis (RCM) reaction of cis-2,6-dialkenyl-N-acyl piperidine derivatives. The requisite 2,6-dialkenylpiperidines may be readily prepared in six steps starting from glutarimide (11) or three steps from 4-methoxypyridine (25). In one example that establishes the practical utility of the procedure, the functionalized 8-azabicyclo[3.2.1]octane 32, which is a potential intermediate for the syntheses of various tropane alkaloids, was prepared. Additionally, a new route for the construction of the bridged tetrahydro-beta-carboline ring system 5 has been developed that features the ring-closing metathesis of the enyne 45 to construct the bridging ring in 46. This concise route to 46 also features a potentially general and useful procedure for the one-step preparation of a terminal alkyne from an ester function. Selective oxidation of the vinyl group in 46 afforded the unsaturated aldehyde 47, which may serve as a useful intermediate in syntheses of several Sarpagine alkaloids.     

New cyclic and macrocyclic silaolefins via ring-closing metathesis of 1,1-bis(silyl)ethene-tethered dienes

Dialkenyl-substituted 1,1-bis(silyl)ethenes of the general formulae (CH₂CH(CH₂)_nMe₂Si)₂CCH₂ and (CH₂CH(CH₂)_nOMe₂Si)₂CCH₂, (where n = 1-3) have been successfully converted into new silacyclic or silamacrocyclic compounds in the presence of ruthenium-benzylidene complex (first generation Grubbs catalyst). The structures of both macrocyclic silaolefins have been confirmed using X-ray diffraction.     

The first examples of ring-closing olefin metathesis of vinyl chlorides

[reaction: see text] Ring-closing metathesis (RCM) of olefinic vinyl chlorides can be effected by using the second generation Grubbs catalyst (10 mol %, PhH, 65 degrees C) to produce a variety of carbocyclic and heterocyclic five-, six-, and seven-membered rings in excellent yields.     

Formal synthesis of optically active ingenol via ring-closing olefin metathesis

The construction of strained carbon skeletons by ring-closing olefin metathesis (RCM) was investigated. With well-designed diene 4, RCM was found to be applicable to the formation of a highly strained inside-outside bicyclo[4.4.1]undecane skeleton of ingenol, a bioactive diterpenoid, and formal total synthesis of optically active ingenol (1) was achieved. The key features of this synthesis are construction of an A-ring by spirocyclization of the ketone with an allylic chloride unit, 26, and ring closure of a B-ring by olefin metathesis. Starting from Funk's keto ester 6, the key intermediate aldehyde 9 in Winkler's total synthesis was synthesized in eight steps in 12.5% overall yield. This strategy of direct cyclization of a strained inside-outside skeleton provided the first easy access to optically active ingenol.     

Synthesis of substituted benzenes and phenols by ring-closing olefin metathesis

New synthetic approaches to substituted aromatic compounds are reported. Ring-closing olefin metathesis (RCM)/dehydration and RCM/tautomerization are the key processes in the synthesis of substituted benzenes 3 and phenols 6, respectively. Readily accessible 1,5,7-trien-4-ols 7, which are the precursors of benzenes, were prepared from beta-halo-alpha,beta-unsaturated aldehydes 11 or beta-halo-alpha,beta-unsaturated esters 19 by utilizing reliable transformations in which cross-coupling with vinylic metal reagents 12 and allylation with allylic metal reagents 13 were employed as carbon-carbon bond forming reactions. RCM of 7, followed by dehydration, afforded a wide variety of substituted benzenes 3. In addition, RCM of 1,5,7-trien-4-ones 9, which were prepared by oxidation of 7, furnished various substituted phenols 6 by automatic tautomerization.     

Highly active chiral ruthenium catalysts for asymmetric ring-closing olefin metathesis

The synthesis of olefin metathesis catalysts containing chiral, monodentate N-heterocyclic carbenes and their application to asymmetric ring-closing metathesis (ARCM) are reported. These catalysts retain the high levels of reactivity found in the related achiral variants (1a and 1b). Using the parent chiral catalysts 2a and 2b and derivatives that contain steric bulk in the meta positions of the N-bound aryl rings (catalysts 3-5), five- through seven-membered rings were formed in up to 92% ee. The addition of sodium iodide to catalysts 2a-4a (to form 2b-4b in situ) caused a dramatic increase in enantioselectivity for many substrates. Catalyst 5a, which gave high enantiomeric excesses for certain substrates without the addition of NaI, could be used in loadings of < or =1 mol %. Mechanistic explanations for the large sodium iodide effect as well as possible mechanistic pathways leading to the observed products are discussed.     

Polycyclic heteroaromatics via hydrazine-catalyzed ring-closing carbonyl–olefin metathesis

The use of hydrazine-catalyzed ring-closing carbonyl–olefin metathesis (RCCOM) to synthesize polycyclic heteroaromatic (PHA) compounds is described. In particular, substrates bearing Lewis basic functionalities such as pyridine rings and amines, which strongly inhibit acid catalyzed RCCOM reactions, are shown to be compatible with this reaction. Using 5 mol% catalyst loadings, a variety of PHA structures can be synthesized from biaryl alkenyl aldehydes, which themselves are readily prepared by cross-coupling.

Hydrazine catalysis enables the ring-closing carbonyl–olefin metathesis (RCCOM) to form polycyclic heteroaromatics, especially those with basic functionality.

Polycyclic heteroaromatic (PHA) structures comprise the core framework of many valuable compounds with a diverse range of applications (Fig. 1A).¹ For example, polycyclic azines (e.g. quinolines) are embedded in many alkaloid natural products, including diplamine² and eupolauramine³ to name just a few. These types of structures are also of interest for their biological activity, such as with the inhibitor of the Src-SH3 protein–protein interaction shown in Fig. 1A.⁴ Many nitrogenous PHAs are also useful as ligands for transition metal catalysis, as exemplified by the widely used ligand 1,10-phenanthroline.⁵ Meanwhile, chalcogenoarenes⁶ such as dinaphthofuran⁷ and benzodithiophene⁸ have attracted high interest for both their medicinal properties⁹ and especially for their potential use as organic light-emitting diodes (OLEDs), organic photovoltaics (OPVs), and organic field-effect transistors (OFETs).¹⁰ These and numerous other examples have inspired the development of a wide variety of strategies to construct PHAs.^1,11–14 Although these approaches are as varied as the structures they target, the wide range of molecular configurations within PHA chemical space and the challenges inherent in exerting control over heteroatom position and global structure make novel syntheses of these structures a topic of continuing interest.Open in a separate windowFig. 1(A) Examples of PHAs. (B) RCCOM strategy for PHA synthesis. (C) Lewis base inhibition for Lewis acid vs. hydrazine catalyzed RCCOM. (D) Hydrazine-catalyzed RCCOM for PHA synthesis.One potentially advantageous strategy for PHA synthesis is the use of ring-closing carbonyl–olefin metathesis¹⁵ (RCCOM) to forge one of the PHA rings, starting from a suitably disposed alkenyl aldehyde precursor 2 that can be easily assembled by cross-coupling (Fig. 1B). In related work, the application of RCCOM to form polycyclic aromatic hydrocarbons (PAHs) was reported by Schindler in 2017.¹⁶ In this case, 5 mol% FeCl₃ catalyzed the metathesis of substrates to form phenanthrenes and related compounds in high yields at room temperature. This method was highly attractive for its efficiency, its use of an earth-abundant metal catalyst, and the production of benign acetone as the only by-product. Nevertheless, one obvious drawback to the use of Lewis acid activation is that the presence of any functionality that is significantly more Lewis basic than the carbonyl group can be expected to strongly inhibit these reactions (Fig. 1C). Such a limitation thus renders this method incompatible with a wide swath of complex molecules, especially PHAs comprised of azine rings. This logic argues for a mechanistically orthogonal RCCOM approach that allows for the synthesis of PHA products with a broader range of ring systems and functional groups.We have developed an alternative approach to catalytic carbonyl–olefin metathesis that makes use of the condensation of 1,2-dialkylhydrazines 5 with aldehydes to form hydrazonium ions 6 as the key catalyst–substrate association step.^17–19 This interaction has a much broader chemoorthogonality profile than Lewis acid–base interactions and should thus be much less prone to substrate inhibition than acid-catalyzed approaches. In this Communication, we demonstrate that hydrazine-catalyzed RCCOM enables the rapid assembly of PHAs bearing basic functionality (Fig. 1D).For our optimization studies, we chose biaryl pyridine aldehyde 7 as the substrate (20 salt 11 was also productive (entry 2), albeit somewhat less so. Notably, iron(iii) chloride generated no conversion at either ambient or elevated temperatures (entries 3 and 4). Trifluoroacetic acid (TFA) was similarly ineffective (entry 5). Meanwhile, a screen of various solvents revealed that, while the transformation could occur in a range of media (entries 6–9), THF was optimal. Finally, by raising the temperature to 90 °C (entry 10) or 100 °C (entry 11), up to 96% NMR yield (85% isolated yield) of adduct 8 could be obtained in the same time period.Optimization studies^a

Synthesis of substituted 1-benzazepin-2-ones via ring-closing olefin metathesis

The 1-benzazepin-2-one ring system is an important structural feature of marketed drugs, clinical candidates, and other bioactive molecules. We have developed a new benzazepinone synthesis that employs ring-closing olefin metathesis as a key step. This route provides efficient access to substituted benzazepinones that are difficult to synthesize via existing procedures.     

Relay ring-closing metathesis (RRCM): a strategy for directing metal movement throughout olefin metathesis sequences

The title concept involves the use of structurally modified RCM substrates that contain extender arms, terminating in a remote reactive alkene. Initiation of an RCM sequence at that reactive alkene is followed by rapid intramolecular relay of the metal center to an initially less reactive alkene in the parent substrate. This permits one to control the relative timing (or direction) of a metathesis sequence. For example, one can reverse the inherent tendency of an unsymmetrical alpha,omega-diene substrate to close, say, left-to-right, to that of right-to-left. Four distinct types of application of the RRCM concept are demonstrated. Among other things, they show the preparation of tetrasubstituted electron-deficient alkenes using G1 [(Cy3P)2(Cl2)Ru=CHPh], complementary control of directionality (endedness), auxiliary benefits (enzyme specificity) from the incorporation of additional steric bulk, the activation of otherwise ineffective substrates for RCM closure, the use of unorthodox alkenes as initiation sites for ring closure, and control of product olefin geometry.     

Synthesis of spirocyclic thiazolidinediones using ring-closing metathesis and one-pot sequential ring-closing/cross metathesis

A novel synthetic route to spirocyclic thiazolidinediones is reported by utilizing ring-closing metathesis (RCM). A selective cross metathesis (CM) of N-allyl azaspiro derivatives with different olefins has been demonstrated to prepare substituted azaspiro-[4.4]nonenediones. The X-ray crystal structure of a spirocyclic thiazolidinedione dimer is described, which has been prepared in two steps from thiazolidinedione using a one-pot sequential ring-closing and self metathesis. Cross metathesis proceeds smoothly with both electron rich and poor olefins. The symmetrical bis-thiazolidinedione spirocyclic system can be used as CM coupling partner with olefins. One-pot sequential RCM-CM has been developed for the synthesis of substituted spirocyclic compounds. The methodology allows a quick access to thia-azaspiro-[4.4]nonene and -[4.5]decene-dione ring systems from readily available starting materials which are not otherwise accessible.