Development of olefin cross metathesis on solid support and its application to the synthesis of biologically promising compounds

SEBASTIÁN A. TESTERO; ANDRES A. POEYLAUT-PALENA; ERNESTO G. MATA

Itapema (Brasil)

Congreso; 12th Brazilian Meeting in Organic Chemistry; 2007

Sociedad Brasilera de Química

Cross-metathesis (CM) represents an interesting alternative to more traditional C-C bond forming reactions. Nevertheless, application of alkene cross-metathesis in synthesis is far behind its ring-closing counterpart, mainly due to the difficulty of avoiding unwanted homodimeric products.1 Consequently, the immobilization of one of the olefins during CM will have a series of potential advantages [(i) site isolation can limit the homodimerization of the resin-bound olefin and (ii) non-immobilized olefin homodimer can be easily eliminated by simple filtration] (Scheme 1). However, very few examples of this approach have been reported. During our research on the application of solid-phase methodologies to biologically promising compounds,2 we became interested in using solid-phase CM as the key step for the development of libraries with high molecular diversity. We have prepared immobilized olefins as models for the CM using different olefin partners in the presence of ruthenium carbene complexes, such as 2nd generation Grubbs and Hoveyda-Grubbs precatalysts. In our study, we have demonstrate that solid-phase CM is strongly dependent of the degree of homodimerization of the non-immobilized olefin and the reactivity of such homodimer. We have also noticed the effect of microwave heating, giving higher CM yields and reduced reaction time. As in homogeneous phase, the Hoveyda-Grubbs precatalyst was better for α,β-unsaturated carbonyl compounds. The solid-phase CM has been applied to the synthesis of β-lactam analogues of cholesterol absorption inhibitors. Thus, different polymer-bound 3-vinyl-β-lactams (1) were synthesized in four steps from Fmoc-protected p-aminophenol, according to a protocol developed by us. We have found that these vinyl-β-lactams react smoothly with different olefins in the presence of 2nd generation Grubbs precatalyst (2) to give 3-(aryl)alkenyl-β-lactams (3) (Scheme 2).3 The simple experimental procedure did not require any air exclusion precautions and low catalyst loading (5 mol %) was used in order to reduce ruthenium-contaminated products. The whole solid-phase synthetic sequence proceeded efficiently giving good overall isolated yields and the desired β-lactams were obtained with excellent 3,4-trans selectivity and complete E selectivity at the C-3 side chain. To the best of our knowledge, this is the first application of solid-supported cross metathesis to the development of complex biologically interesting molecules. We have established guidelines for the solid-supported olefin cross metathesis using ruthenium carbene complexes. That information has been applied to the generation of a library of cholesterol absorption inhibitor analogues.