Synthesis ring-closing metathesis

The last decade has witnessed the growing use of olehn metathesis in organic synthesis.Ring closing metathesis RCM, Eq. (6)] and ring opening metathesis [ROM, Eq. (7)1 as well as a combination of these transformations have resulted in providing opportunities to build molecules of interest and importance. 

Scheme 3. New directions in organic synthesis ring-closing metathesis as a key step in Nicolaou s total synthesis of coleophomones C and B (46 and 47).

Gurjar and co-workers prepared several novel carbohydrate-based spirocycles and a spirocyclic proline derivative for applications in peptide, nucleoside, and carbohydrate synthesis. Ring-closing metathesis of carbohydrate diene precursor 78 furnished the corresponding spirocycle 80 in 88% yield using a catalytic amount of 3 in dichloromethane. Reaction of proline derivative 79 under similar conditions gave the corresponding spirocyclic peptide 81 in 96% yield. 

Synthesis of azasugars and alkaloids via ring-closing metathesis 99EJ0959. 

Kishi s synthesis 290 ring closing metathesis 302 ring expansion 65, 98... 

The diene core does not necessarily need to remain intact, but can rather be cleaved to enable further functionalization. Taking advantage of the diastereomeric s vitch , such a strategy was implemented together with a ring closing metathesis step in the total synthesis of undecenolides like cladospolide [258,259]. 

With a-monosubstituted ylides the oxidation results in the formation of alkenes (by subsequent Wittig reaction on the intermediate aldehyde). A recent example of such synthesis is found in the preparation of all-(Z)-cyclododecate-traene by oxidation of the appropriate bis-ylide [33]. It must be pointed out that an approach of the same macrocycle based on ring closing metathesis was found ineffective. 

A nice application of this reaction for the synthesis of cyclic a-sulfanylphos-phonates 63 has been reported [42]. It involves a Rh(II)-catalyzed [2,3]-sigmatropic rearrangement and a ring-closing metathesis of the resulting a-(S-allyl) y,d-unsaturated phosphonates 62 (Scheme 16). However, the last step occurs with a low yield (19%) when R = H. 

A systematic investigation of the ring-closing metathesis of 138 in the synthesis of a range of fourteen-membered ring lactams 139 and lactones has been reported by Weiler. The geometry of the resulting double bond was determined, the position of the olefin was broadly varied. The ratios obtained were compared to that derived from molecular mechanics calculations, Eq. (15), Table 4 [34]. 

Negishi E, Tan Z (2005) Diastereoselective, Enantioselective, and Regioselective Carbo-alumination Reactions Catalyzed by Zirconocene Derivatives. 8 139-176 Netherton M, Fu GC (2005)Pa]ladium-catalyzed Cross-Coupling Reactions of Unactivated Alkyl Electrophiles with Organometallic Compounds. 14 85-108 Nicolaou KC, King NP, He Y (1998) Ring-Closing Metathesis in the Synthesis of EpothUones and Polyether Natmal Products. 1 73-104 Nishiyama H (2004) Cyclopropanation with Ruthenium Catalysts. 11 81-92 Noels A, Demonceau A, Delaude L (2004) Ruthenium Promoted Catalysed Radical Processes toward Fine Chemistry. 11 155-171... 

A highly convergent route for the synthesis of BILN 2061 has also been reported [112]. The synthesis is based on the assembly of four key fragments with an overall yield of 10-15% as shown in Scheme 2.1. The crucial step is a ring closing metathesis of an acyclic precursor. 

Ring-closing metathesis has been successfully used in the synthesis of [3.5.0], [4.5.0], and [5.5.0] ring systems <2001TL8231>. The ruthenium complex 160 was employed on both symmetrical and unsymmetrical substrates with equal success, as outlined in Equation (15). Compounds 161-164 were synthesized in this fashion. 

A practical synthesis of the bicyclic dienyl sultam 246 has been reported <06JOC6573>. The key step of the ring-closing metathesis (RCM) represented by conversion of 243 to 244 has to be implemented prior to the sultam formation (244 to 245). Bicyclic sultam is converted to dienyl sultam 246 in two steps. 

The application of olefin metathesis to the synthesis of piperidines continues to be widely employed. The use of ring closing metathesis (RCM) in the synthesis of fluorovinyl-containing a,P-unsaturated lactams 148 and cyclic amino acid derivatives 149 is shown below. A key improvement in these reactions is the addition of the Grubbs 2nd generation catalyst (G2) in small portions during the reaction to compensate for catalyst decomposition that occurs at elevated reaction temperatures <06EJOl 166>. 

As part of the development of an efficient synthetic strategy for the synthesis of the little known 3,5- and 3,6-disubstituted tetrahydro-li/-azepines, ring-closing metathesis of the diene 31 to 32 in high yield was reported <06JOM5406>. 

The synthesis of the /V-protected 7-methylazepine derivative 34 was achieved in 89% yield by a ring-closing metathesis reaction on 33 mediated by Grubbs I ruthenium catalyst. This azepine was an important precursor for the preparation, via epoxidation of the double bond, of a number of 7-methylazepanone derivatives for evaluation as cathepsin K inhibitors <06JMC1597>. 

The concept of performing microwave synthesis in room temperature ionic liquids (RTIL) as reaction media has been applied to several different organic transformations (Scheme 4.18), such as 1,3-dipolar cycloaddition reactions [54], catalytic transfer hydrogenations [55], ring-closing metathesis [56], the conversion of alcohols to alkyl halides [57, 58], and several others [59-61],... 

A further application of ring-closing metathesis in seven-membered heterocyclic ring formation is in the synthesis of the trans-fused oxpane systems. This process involved tandem RCM/allylstannane-aldehyde cyclizations and interaction of the process provides access to trans-fused polyoxepanes <00S883>. 

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