Ring dosing reaction

Unlike what is typically observed with Ru-catalyzed ring-dosing metatheses (ref. 5a,b), the products of reactions reported herein are isomers of the starting materials the Ru-catalyzed reactions thus constitute a rearrangement... 

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. 

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. 

Reference to Scheme 1 reveals that there are six possible patterns for formation of pyrrole rings in reactions which dose two bonds. These can be further subdivided into the [4 + 1] processes (IIab, IIac and IIbe) and the [3 + 2] processes (Ilac, Had and IIbd). In this section we will consider first the [4+1] processes and then the [3 + 2] processes. 

Beside this ring dosing, a second reaction takes place in the experiment made above. The sulphuric acid saponifies the primarily formed acid-ester, with the elimination of carbonic add ... 

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]. 

The Nicolaou strategy is based on RCM [14] as the final ring dosing step in order to establish the 16-membered macrolide. The linear subunit of C1-C12 was obtained by an intermolecular aldol reaction, in which an a-chiral aldehyde was coupled with an achiral enolate, yielding the desired aldol product as a 2 3 ratio of diastereomers 8 and 9. 

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