Ring-dosing metathesis

A different approach toward cyclic peptides has been presented by Leatherbarrow and coworkers, employing ring-dosing metathesis (RCM) on a solid support [50], The authors reported on the synthesis of conformationally strained cyclic peptides of the Bowman-Birk inhibitor type, which are naturally occurring serine protease... 

For a recent report on the mechanism of the Ru-catalyzed ring-dosing metathesis, see Dias EL, Nguyen ST, Grubbs RH (1997) J Am Chem Soc. 119 3887... 

These alkylation processes become particularly attractive when used in conjunction with powerful catalytic ring-dosing metathesis protocols [11]. The requisite starting materials can be readily prepared catalytically and in high yields. The examples shown in Scheme 6.3 demonstrate that synthesis of the heterocyclic alkene and subsequent alkylation can be carried out in a single vessel to afford unsaturated alcohols and amides in good yields and with >99% ee (GLC analysis) [12],... 

Initial efforts in the ring-dosing metathesis approach were attempted with substrates 34 and 35. However, after employing a variety of catalysts and experimental conditions, no cydized systems (36 or 37) were obtained. Other substrates were prepared to further probe this unexpected failure however, no observable reaction was realized. Model systems later suggested that die dense functionality between C3 and C8 was the culprit for lack of macrocycle formation. Eventually a second generation Cl2-03 RCM (not shown here) approach was developed [26] which yielded mixtures of C12-C13 Z/E isomers that were used in early SAR studies. [26b] However, since the separation of products was so difficult, we did not seriously pursue this route for total synthesis. 

The ruthenium indenylidene IX catalyzed the ring dosing metathesis of a homoallyl ether diene to give a bicydic compound, which is an intermediate for the synthesis of different marine natural products (Equation 8.10) [63]. 

Seven-membered Rings and Their Benzo-fused Systems 2.3.3.1 Azepines by Ugi-4CR and Ring-dosing Metathesis... 

Banfi and co-workers applied the tandem Ugi reaction/ring-dosing metathesis to the synthesis of unsaturated nine-membered lactams as potential reverse-turn inducers. Reaction of allyl-substituted racemic isocyanoacetates with preformed imines and carboxylic acids gave adducts 195 that were treated with Grubbs first-generation catalyst to give nine-membered lactams 196 (Scheme 2.70) [102],... 

With respect to this, Ellman and coworkers [16], Zhu and coworkers [17], Amusch and Pieters [18], and Liskamp and coworkers [19] have prepared (monocyclic) mimics of the D-E part of the cavity of these antibiotics via an intramolecular nucleophilic aromatic substitution [16-18] or a Sonogashira-based macrocyclization [19] (Figure 1.4). Recently, a bicydic mimic of the C-D-E cavity, which was prepared by a Stille reaction followed by tandem ring-dosing metathesis (9, Figure 1.4), was described by liskamp and coworkers [20]. Considerable challenges lie ahead for the synthetic chemist in order to develop practical syntheses of mimics of vancomydn capable of binding not only D-Ala-D-Ala, but also cell wall parts of resistant bacteria, i.e. D-Ala-D-lactate. 

Ring-dosing metathesis and asymmetric dihydroxiyation synthesis of iminoaiditois... 

Blechert has used a water compatible support for a metathesis catalyst [57]. The support swells with water and allows ring-dosing metathesis to be carried out in aqueous media. The commercially available PEGA-NH2 (Structure 20) resin was functionalized and connected to a phosphine free metathesis catalyst to prepare heterogeneous complex 21. 

Olefin Metathesis Ru-catalyzed ring-dosing metathesis (RCM)... 

Scheme 10 Synthesis of benzofurans using ring-dosing metathesis of enol ethers.

Scheme 11 Synthesis of benzofurans using an isomerization/ring-dosing metathesis strategy.

The C2-symmetric trienes 7 and 9 readily derived from D-marmitol underwent a symmetrical cleavage via a domino process featuring two ring-dosing metathesis (RCM) events to afford the enantiopure lactones 8 and 10, respectively (Scheme 2.2) [4]. While the second-generation Grubbs catalyst 2 led to an effident conversion of the p,Y-unsaturated diester 9, the more reactive phosphine-ffee catalyst 4 was required for a dean transformation of the a,fi-unsaturated diester 7. 

Hruby et al. used the rearrangement of cinnamyl ester 125g (entry 8) as a key step in their synthesis of conformationally constrained reverse turn dipeptide mimetics [67]. Piscopio et al. applied the rearrangement of crotyl esters in combination with an N-aUylation and subsequent ring dosing metathesis towards the synthesis of pipecoli-nic acid derivatives A [68], while Morimoto et al. used the rearrangement products for the synthesis of cyclopropyl amino adds B (Scheme 5.2.38) [69]. 

Several examples of sequential isomerization/ring-dosing metathesis for the preparation of heterocycles have also been performed by using two successive catalytic reactions catalyzed by two different ruthenium catalysts, but the second catalyst was introduced after completion of the first catalytic reaction. The isomerization was usually catalyzed by RuHCl(CO)(PPh3)3 [48], or RuCl2(= CHPh)(PCy3)(bis(mesityl)imidazolylidene) in the presence of trimethylsilyl vinyl ether [49], whereas a classical metathesis catalyst was subsequently introduced for the cyclization [48,49]. 

Fu GC, Nguyen ST, Grubbs RH. Catalytic ring-dosing metathesis of functionalized dienes by a ruthenium carbene complex. Jdm Chem Soc. 1993 115(21) 9856—9857. 

Kirkland TA, Gmbbs RH. Effects of Olefin Substimtion on the Ring-dosing Metathesis of Dienes. J Org Chem. 1997 62(21) 7310—7318. 

Linderman RJ, Siedlecki J, O Neil SA, Sun H. Conformational Bias by a Removable Substituent. Synthesis of Eight-Membered Cychc Ethers via Ring-dosing Metathesis. 

Farina V, Shu C, Zeng X, et al. Second-Generation Process for the HCV Protease Inhibitor BILN 2061 A Greener Approach to Ru-Catalyzed Ring-dosing Metathesis. 

Ring-dosing metathesis (RCM) using Grubbs and Schrock catalysts... 

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