Synthesis of 2-phosphonopyrroles via a one-pot RCM/oxidation sequence

A four-step synthesis of 2-phosphonopyrroles is presented starting from suitable aldehydes. The key step in the synthesis involves a one-pot ring-closing metathesis/oxidation sequence of a functionalized alpha-aminoalkenyl phosphonate. Notwithstanding the presence of a nucleophilic nitrogen atom and high substitution patterns in the substrate, the results of the RCM reaction are excellent using mild reaction conditions. Furthermore, a synergism is observed between the RCM catalyst and the oxidizing agent, causing higher oxidation rates and allowing reaction for substrates that normally fail to ring close under standard RCM conditions.     

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.     

General route from simple methyl, alkyl, and cycloalkyl arenes to polycyclic cyclopentenyl aryl derivatives. The CpFe(+) group as an activator and tag

[reaction: see text] The CpFe(+) group activates the perallylation of the benzylic groups of arenes using KOH and allylbromide under ambient conditions. This reaction can be followed by ruthenium-catalyzed RCM metathesis using Grubbs' catalyst at room temperature to give polycyclic aromatic derivatives in high yields, and these products are easily separated from the catalyst by extraction using ether. Alternatively, the RCM metathesis can be best carried out in ionic liquids at 80 degrees C, and extraction using ether is then facile.     

A tandem enyne/ring closing metathesis approach to the synthesis of novel angularly fused dioxa-triquinanes

Triquinanes and their oxygenated congeners, oxa- and dioxa-triquinanes, exhibit versatile biological activities in conjunction with synthetically challenging molecular architecture. Owing to these properties, several new strategies have been developed to accomplish the synthesis of these sesquiterpenes. Among the new strategies, cascade radical cyclization strategy has been broadly explored and well studied. Herein, we report our efforts in detail for the synthesis of dioxa-triquinanes using a domino enyne/RCM strategy as the key step. Carbohydrate based synthesis not only allows the use of inexpensive and optically pure starting materials, but also the furanose derivatives, which already possess one of the requisite dihydro-furan moieties in the desired dioxa-triquinane. The other two five-membered rings were constructed simultaneously by the cascade enyne/RCM reaction using the Grubbs' second-generation catalyst. During the course of our synthesis it was observed that the acetonide protection hinders the RCM reaction, after the initial enyne metathesis reaction. The reaction underwent smoothly under argon atmosphere, whilst use of ethylene atmosphere was found to hinder the formation of the tandem enyne/RCM product. The effect of substitution on the key reaction is described here.     

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.     

Microwave-assisted ring-closing metathesis of diallylamines: a rapid synthesis of pyrrole and pyrroline derivatives

The ring-closing metathesis (RCM) reactions of diallylamines occurred under controlled microwave irradiation. In addition to the high reaction rate, the key features of the reaction are that it can be carried out without deactivation of the substrates and without the use of Lewis acids.     

Synthetic studies toward macrocidins: an RCM approach for the construction of the central cyclic core

The central macrocyclic core of the macrocidins was constructed using RCM as the key reaction. A preliminary investigation dealing with the key reactions, that is, the Dieckmann cyclization and the RCM, revealed that RCM of the β-ketoamide is better than RCM of the corresponding acyltetramic acid.     

Olefin metathesis: remote substituents governing the stereoselectivity of 11-membered-ring formation

[reaction: see text] Stereospecific RCM reaction of 7 (R1 = Me) results in the formation of (Z)-11-membered macrocycle 9c. Cascade RCM/ROM/RCM transformation of 7 (R1 = H) affords the thermodynamically more stable spirocycle product 12.     

RCM of tripeptide dienes containing a chiral vinylcyclopropane moiety: impact of different Ru-based catalysts on the stereochemical integrity of the macrocyclic products

[structures: see text] Tripeptide dienes containing an (1R,2S)-vinyl aminocyclopropylcarboxylate residue were cyclized to beta-strand scaffolds under ring-closing metathesis (RCM). Conformational factors, ligand effects, and reaction conditions were evaluated. A protocol was developed for the efficient synthesis of 15-membered ring peptides in high diastereomeric purity. These peptides are key synthetic precursors to antiviral agents that target the hepatitis C virus and represent the first class of clinically validated pharmaceutical agents that are synthesized in large scale using RCM.     

Kinetically controlled ring-closing metathesis: synthesis of a potential scaffold for 12-membered salicylic macrolides

For the synthesis of a 12-membered salicylic macrolide scaffold, ring-closing metathesis (RCM) of a omega-diene compound was planned. The stereochemical outcome of the RCM reaction changed depending on the type of Ru catalyst that was used; a "first-generation" Grubbs catalyst produced exclusively the E isomer and "second-generation" catalysts provided a mixture of the E and Z isomers under kinetic control (not thermodynamic control). Considerations for the E/Z selectivity are described.     

关环转换反应在天然产物合成中的应用

关环转换反应是形成碳碳双键的重要反应之一,即双烯化合物在金属碳烯催化下关环得到环烯类化合物。本文概述了关环转换反应所用催化剂体系及其在天然产物合成中的应用,内容涉及到碳环及含氧、含氮杂环天然产物的合成。     

Total synthesis of macrosphelides A, B, and E: first application of ring-closing metathesis for macrosphelide synthesis

A new synthetic route for macrosphelides A, B, and E based on ring-closing metathesis (RCM) was established. The substrates for RCM could be synthesized starting from commercially available chiral materials, methyl (S)-lactate and methyl (S)- or (R)-3-hydroxybutyrate, in good overall yields. In the investigation of the key RCM step, it was found that the steric factor around the reaction site significantly affected the reaction rate of macrocyclization. A detailed account regarding this synthetic study is described herein.     

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.     

Synthetic study of manzamine B: synthesis of the tricyclic central core by an asymmetric Diels-Alder and RCM strategy

Tricyclic core of manzamine B was successfully synthesized through asymmetric Diels-Alder reaction and RCM strategy. Cr-salen-F complex was found to be the most effective catalyst in DA reaction of aminodienes with heterocyclic dienophiles to give up to 97% ee. In the construction of 11-membered ring by RCM, first-Grubbs cat. gave better stereoselectivity.     

Synthesis of heterocyclic and carbocyclic fluoro-olefins by ring-closing metathesis

[reaction: see text] Ring-closing metathesis (RCM) of vinyl fluoride-containing dienes in the presence of ruthenium alkylidene carbene complex 11 proceeded efficiently to give six- and seven-membered cyclic vinyl fluorides. The RCM reaction was used to prepare amine- and sulfamide-linked cyclo-olefins, as well as carbocyclic systems, from a simple commercial fluoro-olefin.     

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 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.     

Macrocyclization by ring-closing metathesis in the total synthesis of natural products: reaction conditions and limitations

The construction of macrocycles by ring-closing metathesis (RCM) is often used as the key step in the synthesis of natural products containing large rings. This reaction is attractive because of its high functional group compatibility and the possibility for further transformations. The finding of suitable reaction conditions is critical for the success of the synthesis. In this Minireview we summarize the efforts of many research groups to develop efficient RCM reactions on their way towards the total synthesis of natural macrocyclic products. Their findings should help in future synthesis to reduce the time-consuming phase of the optimization of the reaction conditions.     

New strategy for the total synthesis of macrosphelides a and B based on ring-closing metathesis

[reaction: see text] A new total synthesis of macrosphelides A and B using ring-closing metathesis (RCM) as a macrocyclization step is described. The substrate of the RCM could be synthesized from readily available chiral materials, methyl (S)-(+)-3-hydroxybutyrate and methyl (S)-(-)-lactate, with a high efficiency. The RCM proceeded in the presence of Grubbs' Ru-complex, providing a new effective synthetic route to these natural products.     

Asymmetric synthesis of fluorinated amino macrolactones through ring-closing metathesis

The synthesis of new chiral fluorinated amino and azamacrolactones of types 1 and 2 is described. A ring-closing metathesis (RCM) reaction constitutes the key step in this methodology, which uses fluorinated amino alcohols 7 as starting materials. The influence of the CF2 group, which is located in the alpha-position relative to the carbon bearing the amino group, on the efficiency of the RCM reaction is noteworthy. This method allows for the preparation of the desired fluorinated macrolactones in excellent yields.