Hoveyda catalyst

A different task was pursued by the CM of CsA with various maleates 339 [ 148]. The CM demanded in this case the highly active Hoveyda catalyst D, that exhibits potency not reached by the phosphine-containing catalysts C and E. Under the conditions given in Scheme 65, metathesis with maleates 339 led (E)-selectively to the a,/J-unsaturated ester derivatives 340 in high yield. Compounds 340 still demonstrated activity comparable to that of CsA and are thus potential soft drugs via esterase-mediated biotransformation to the corresponding inactive carboxylic acids 341. 

Figure 16.13. Schrock-Hoveyda catalyst for asymmetric metathesis...

The use of the second-generation Grubbs catalyst or the Grubbs-Hoveyda catalyst (cat. Gr. H.) (Scheme 37) enables the synthesis of benzo-fused lactams 148 (09TA1154), 149 (05JOC5519), and a-amino-a, -unsaturated lactam 150a (08TL5141). 

Grubbs, Grubbs-Herrmann, Grubbs-Hoveyda Catalysts). 141... 

Fig.1 Well-defined metathesis initiators. Schrock catalyst (A, R = Me, Ph, R = CMes, CMe(CF3)2), Grubbs-catalyst (B), Grubbs-Herrmann catalyst (C), Grubbs-Hoveyda catalyst (D, R " = H, NO2)...

Finally, a monolith-supported version of the Grubbs-Hoveyda catalyst was prepared in an analogous approach using a perfluoroglutaric anhydride-derived ligand (Scheme 19). When used in continuous flow experiments, TOFs of 0.1 s were observed, and TONs were > 500 [ 127,128]. 

This strategy has already been found useful in natural product synthesis. In the course of a synthesis of V-ATPase inhibitor oximidine HI, John Porco of Boston University has described (Angew. Chem. Ini. Ed. 2004,43, 3601) the cyclization of 7 to 8. In the absence of the pententyl director, the initial complexation of the Ru catalyst was with the 1,3-diene, leading to allylidene complex and so effectively killing the catalyst. In this case, the Hoveyda catalyst 8 provided a cleaner product than G2 did. 

Epimerization of vinylcyclopropanes by Grubbs I-type ruthenium catalysts (28) has been explored.33 The reaction can also be effected by the Grubbs-Hoveyda catalyst (29) provided that an additional phosphine is added. Mechanistic studies (experimental and theoretical) suggest that the epimerization goes through a ruthenacyclopentene intermediate (30). 

The simpler architecture is the 1,1 -biphenyl scaffold, likewise introduced by Hoveyda and coworkers [19]. The synthesis of the imidazolium salt starts with a chiral diamine and a substituted, achiral biphenyl [82-84], Subsequent introduction of a Mes substituent on the remaining primary amino end and ring closure reaction yields the chiral saturated imidazolium salt after hydrolysation of the methoxy group to liberate the phenolic hydroxy group (see Figure 4.22). Reaction with silver(I) oxide and carbene transfer to a Grubbs (Hoveyda) catalyst sets up the ruthenium catalyst complex. 

We start with studies that aim to overcome solubility problems when a typical metathesis reaction is transferred into water. The first way to introduce water is to use a solvent pair capable of rendering the reaction mixture homogeneous. For example, after an optimization study, the Hoveyda catalyst 68 was found to promote the RCM of various dienes in aqueous DME and acetone solutions. Under these homogeneous conditions, substrates with various substituents underwent RCM to form five-, six- and seven-membered cyclic products. 

General aspects and new metathesis catalysts. For alkene metathesis Grubbs I (1) and Grubbs II (2, 3) complexes, and the Grubbs-Hoveyda catalyst (4A) and Grela catalyst (4B) remain the workhorses. 

For cross metathesis of alkenes, it is found that in the preparation of disubstituted alkenes with one or more aUyhc substituents Grubbs-Hoveyda catalysts possessing iV-(o-tolyl) groups in the azolecarbene unit are more efficient than those with the iV-mesityl groups. But for the formation of trisubstituted alkenes the Al-mesityl catalysts are superior due to discrimination between productive and nonproductive reaction pathways. 

In this regard, the Hoveyda catalyst 71 was next examined. To our great delight, it afforded the desired cyclopentene 68 in an excellent 92% yield after overnight heating in toluene at 110 °C (Entry 4). Importantly, the reaction could be successfully performed, without any special precautions, in non-distilled commercial solvent in a reaction vessel that was open to the air. 

---