Ring-closing metathesis of sulfoximine-substituted N-tethered trienes: modular asymmetric synthesis of medium-ring nitrogen heterocycles

A synthesis of sulfoximine-substituted medium-ring nitrogen heterocycles (MRNHs) having a high degree of substitution has been developed. Its key steps are the modular asymmetric synthesis of sulfoximine-substituted N-tethered trienes and their Ru-catalyzed ring-closing metathesis (RCM) reaction. The highly substituted N-tethered trienes were obtained enantio- and diastereopure through 1) the diastereoselective aminoalkylation of sulfoximine-substituted allyltitanium complexes with N-tert-butylsulfonyliminoester, 2) N-allylation of homoallylic N-sulfonyl amines, 3) allylation, hydroxylalkylation, and formylation of α-lithioalkenylsulfoximines, and 4) allylation of α-formylalkenylsulfoximines. The Ru-catalyzed RCM reaction of the sulfoximine-substituted 1,7,10- and 1,7,12-trienes stereoselectively afforded the corresponding nine-, ten-, and eleven-membered MRNHs in good yields. An interesting difference in reactivity was noted in the case of a sulfoximine-substituted 1,7,10-triene and its corresponding 1,10-diene. While the triene readily underwent a RCM reaction, the diene reacted only in the presence of Ti(OiPr)(4) under formation of the corresponding MRNH. The feasibility of a removal of the sulfoximine auxiliary and the N-sulfonyl protecting group from the MRNHs were demonstrated through reduction and cleavage, respectively, of a nine-membered heterocycle, both of which proceeded readily and gave the corresponding cyclic alkene and amine, respectively.     

Ring-closing metathesis as a basis for the construction of aromatic compounds

The use of metathesis, especially in the context of ring-closing metathesis (RCM) to form five- and six-membered rings, is widespread in organic chemistry today. However, there are surprisingly few examples of the reaction being used to form aromatic compounds. The central place of aromatic compounds in both medicinal chemistry and natural products synthesis, coupled with the efficiency and functional group tolerance of RCM catalysts, means that there is now an interesting opportunity to use RCM for the synthesis of arenes. Although the formation of an aromatic compound was viewed in many early examples as an undesirable degradation product, several rationally designed methods towards the preparation of aromatic compounds by RCM have recently been developed.     

Ring-closing metathesis for the synthesis of heteroaromatics: evaluating routes to pyridines and pyridazines

Ring-closing olefin metathesis (RCM) has been applied to the efficient synthesis of densely and diversely substituted pyridine and pyridazine frameworks. Routes to suitable metathesis precursors have been investigated and the scope of the metathesis step has been probed. The metathesis products function as precursors to the target heteroaromatic structures via elimination of a suitable leaving group, which also facilitates earlier steps by serving as a protecting group at nitrogen. Further functionalisation of the metathesis products is possible both prior to and after aromatisation. The net result is a powerful strategy for the de novo synthesis of highly substituted heteroaromatic scaffolds.     

Ring-closing metathesis of fluoroalkenes toward the synthesis of fluorinated heterocycles containing an oxaza bond

This study reports the ring-closing metathesis reaction of bisolefins, including a reluctant fluoroalkenes, linked with oxaza moiety. The resulting heterocycles were produced in high yields under high diluting conditions disfavoring the homodimerization side reaction of nonfluorinated double bond. The use of a mixture of solvents proved to be a good strategy to obtain the fluorinated heterocycles in fair to excellent yields.     

Ring-closing metathesis in aqueous micellar medium

Underwater exploration: The ring-closing metathesis of N,N-diallyltosylamine (DATs) and diallyldiethyl malonate has been studied in aqueous micellar medium, at room temperature, in the presence of four different gemini cationic surfactants and various ruthenium catalysts. For the first time, the adsorption mechanisms and the reaction steps involved in this heterogeneous catalytic process were elucidated.     

Ring-closing metathesis in glycerol under microwave activation

Glycerol, a biodegradable and virtually non-toxic bio-sourced chemical can be used as an alternative, reusable, sustainable solvent, with so far limited application in the field of green organic chemistry. Herein, the reaction conditions have been screened for the ring-closing metathesis (RCM) of N,N-diallyltosylamine and diethyl diallylmalonate in glycerol, under microwave irradiation and in the presence of the most common commercially available RCM catalysts. The products were isolated in high yield after extraction and the catalyst could be recycled up to two times. Results with simultaneous cooling of the reaction vessel under microwave irradiation are also reported.     

Ring-closing metathesis of α-ester-substituted enol ethers: application to the shortest synthesis of KDO

Ring-closing metathesis reactions of α-ester-substituted enol ethers are described. In the case of unsubstituted terminal olefins, isomerization prior to cyclization was observed as an undesired side reaction, which could not be completely inhibited. Furthermore, this methodology was applied to a formal synthesis of KDO, which now represents the shortest synthetic pathway to KDO and its deoxy analogue. Interestingly, in this route olefin isomerization was not observed, presumably due to the increased steric environment of the double bond. Finally, an efficient two-step conversion to transform an alcohol into an α-alkoxy acrylate is also described.     

Ring-closing metathesis in the synthesis of BC ring-systems of taxol

BC ring-systems of taxol with different or no protecting group for the C1,C2-diol moiety have been efficiently synthesized. The eight-membered B ring is formed by a ring-closing metathesis reaction (RCM) between the C10 and C11 carbon atoms. The influence of the 1,2-diol protecting group on the RCM reaction has been studied in detail.     

Ring-closing metathesis for the synthesis of novel 9- and 10-membered silicon-containing benzo-fused heterocycles

A ring-closing metathesis (RCM) strategy afforded a number of novel 9- and 10-membered benzo-fused compounds containing at least one silicon atom as part of the heterocyclic portion. In this manner, the following compounds containing heterocyclic rings of 9-10 atoms were synthesized: (Z)-2,2-dimethyl-7-[(4-methylphenyl)sulfonyl]-2,3,6,7-tetrahydrobenzo[h][1,7,2]oxazasilonine, (Z)-2,2-dimethyl-3,6-dihydro-2H-benzo[h][1,7,2]dioxasilonine, (Z)-8-isopropoxy-9-methoxy-3,3-dimethyl-1,3,4,7-tetrahydrobenzo[g][1,2]oxasilonine and (Z)-2,2,7,7-tetramethyl-2,3,6,7-tetrahydrobenzo[i][1,8,2,7]dioxadisilecine.     

Ring-closing metathesis in the synthesis of fused sultones

Synthesis of seven-membered sultones fused with different carbo- and heterocycles have been developed using ring closing metathesis as the key operation. The required substrates have been easily synthesized from their commercially available corresponding phenols.     

Ring-closing olefin metathesis on ruthenium carbene complexes: model DFT study of stereochemistry

Ring-closing metathesis (RCM) is the key step in a recently reported synthesis of salicylihalamide and related model compounds. Experimentally, the stereochemistry of the resulting cycloolefin (cis/trans) depends strongly on the substituents that are present in the diene substrate. To gain insight into the factors that govern the observed stereochemistry, density functional theory (DFT) calculations have been carried out for a simplified dichloro(2-propylidene)(imidazole-2-ylidene)ruthenium catalyst I, as well as for the real catalyst II with two mesityl substituents on the imidazole ring. Four model substrates are considered, which are closely related to the systems studied experimentally, and in each case, two pathways A and B are possible since the RCM reaction can be initiated by coordination of either of the two diene double bonds to the metal center. The first metathesis yields a carbene intermediate, which can then undergo a second metathesis by ring closure, metallacycle formation, and metallacycle cleavage to give the final cycloolefin complex. According to the DFT calculations, the stereochemistry is always determined in the second metathesis reaction, but the rate-determining step may be different for different catalysts, substrates, and pathways. The ancillary N-heterocyclic carbene ligand lies in the Ru-Cl-Cl plane in the simplified catalyst I, but is perpendicular to it in the real catalyst II, and this affects the relative energies of the relevant intermediates and transition states. Likewise, the introduction of methyl substituents in the diene substrates influences these relative energies appreciably. Good agreement with the experimentally observed stereochemistry is only found when using the real catalyst II and the largest model substrates in the DFT calculations.     

Ring-closing alkyne metathesis mediated synthesis of cyclic β-turn mimetics

The application of ring-closing alkyne metathesis to synthesise conformationally restricted peptidic β-turn mimics has been investigated. A range of oligopeptides containing either two acetylenic amino acids, or two cysteine residues have been synthesised and subjected to suitable cyclisation conditions. The structures of the cyclic compounds are investigated by 2D NMR analysis.     

Reactions of isocyanatophosphoryl difluoride with π-abundant nitrogen heterocycles and carbonyl compounds

Reactions of electron-rich nitrogen heterocycles with isocyanatophosphoryl difluoride were studied. Novel heteroylaminophosphoryl difluorides were obtained in high yields. N-Phosphorylated imines were synthesized for the first time from carbonyl compounds and phosphorus isocyanates. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 564–566, March, 2006.     

Photochemical Alkene Isomerization for the Synthesis of Polysubstituted Furans and Pyrroles under Neutral Conditions

A photochemical approach to polysubstituted heterocycles using UV-induced alkene isomerization is described. The method allows for the synthesis of disubstituted furans and pyrroles under mild and neutral conditions and also provides access to a class of trisubstituted furans pertinent to natural-product synthesis. The method has broad functional-group tolerance and many richly decorated heterocycles have been prepared incorporating functional groups that are unstable under Brønsted and Lewis acidic conditions.     

Synthesis of phosphorus containing medium ring heterocycles by sequential Claisen rearrangement and ring closing metathesis

An efficient method for the synthesis of novel medium ring phosphorus containing heterocycles starting from phenol derivatives by ruthenium catalyzed ring closing metathesis is described. This work deals with a sequential aromatic Claisen-rearrangement, coupling of an allyl/vinyl phosphonate, and ring closing metathesis reaction. All of these reactions were carried out at ambient temperature to afford the medium-sized phosphorus heterocycles in excellent yields.     

Ring-closing metathesis approach to symmetrical and unsymmetrical cycloakeno[c]fused 2,2′-bipyridine-based cyclophanes

Ring-closing metathesis reactions of symmetrical and unsymmetrical cycloalkeno[c]fused 2,2′-bipyridines, substituted at the α and α′ positions of the pyridine rings with sufficiently long alkenyl ethers, afforded 16-membered cyclophanes, possessing variously annulated 2,2′-bipyridine subunits.     

Systematic synthesis of phthalimide-protected unsaturated hydrazine heterocycles

A four-step route for the synthesis of novel phthalimide-protected hydrazine heterocycles that include a C?C double bond in the cycle was developed. Phthalimide-protected Boc-hydrazine was used as a starting material, which was alkylated with bromoalkenes in mild conditions. Further steps involved Boc-deprotection and second alkylation with bromoalkenes. Finally, the heterocycles were produced by ring-closing metathesis. This route allows access to these versatile building blocks without using electrophilic amination or nitrosylation, therefore, significantly reducing environmental and safety concerns. Phthalimide-protected heterocycles can be derivatized further by modifying the carbon–carbon double bond and by deprotection and subsequent functionalization of the primary amino group. During the current research, various five- to seven-membered hydrazine heterocycles and numerous novel intermediate compounds were synthesized and thoroughly characterized.     

Ring-closing olefin metathesis of 2,2'-divinylbiphenyls: a novel and general approach to phenanthrenes

[reaction: see text] The ring-closing olefin metathesis (RCM) of 2,2'-divinylbiphenyls, using a second-generation RCM ruthenium-based catalyst, leads to differently substituted phenanthrenes in quantitative yield under very mild reaction conditions, independent of both nature and position of the groups present on the biphenyl moiety.