Stereochemistry ring-closing metathesis

The enyne cross metathesis was first developed in 1997 [170,171]. Compared to CM it benefits from its inherent cross-selectivity and in theory it is atom economical, though in reality the aUcene cross-partner is usually added in excess. The inabihty to control product stereochemistry of ECM reactions is the main weakness of the method. ECM reactions are often directly combined with other transformations like cyclopropanation [172], Diels-Alder reactions [173], cychsations [174] or ring closing metathesis [175]. 

Recent studies by Grubbs on the effect of stereochemistry on synthesis of macrocyclic peptides (disubstituted alkenes) by ring closing metathesis were not disclosed at the time of our planning. See (a) Ref. 6a. (b) Miller SJ, Blackwell H, Grubbs RH (1996) J Am Chem Soc 118 9606... 

Ring-closing metathesis of diene 318 with a Grubbs second-generation catalyst gave 2,5-dihydropyrrole 319 (Equation 56). The absolute stereochemistry was assigned based on single crystal X-ray diffraction analysis... 

Scheme 8.19 Ring closing metathesis stereochemistry depending on the catalyst nature.

Large-ring products can be accessed readily by ring-closing metathesis. If more than one alkene is present in the substrate then the less-hindered, typically mono-substituted, alkene reacts preferentially. For example, the anticancer epothilone compounds can be prepared by using metathesis as the key ring-forming step. Treatment of the substrate 95 with the catalyst 84 resulted in the formation of both the desired Z-alkene 96 and the E-alkene 97 (2.115). Control of alkene stereochemistry in macrocycle formation is often difficult unless a conformational constraint... 

Diels-Alder reactions to construct the cis-decalin system. Metathesis of triene 214 in the presence of 5 mol % of 4 in toluene gave the corresponding cw-decalin system 215 in quantitative yields. The authors reported on the ring-closing metathesis of several additional trienes differing only in the stereochemistry of the groups with similar success. 

Important classes of olefin metathesis reactions include cross metathesis (CM), ring-closing metathesis (RCM), " acyclic diene metathesis polymerization (ADMET), and ringopening olefin metathesis polymerization (ROMP). > This chapter focuses on the last class of metathesis reactions, ROMP, and in particular on the stereochemistry of the resulting macromolecular products. 

Castoldi, D., Caggiano, L., Panigada, L., Sharon, O., Costa, A.M., and Gennari, C. (2006) A formal total synthesis of eleutherobin using the ring-closing metathesis (RCM) reaction of a densely functionalized diene as the key step investigation of the unusual kinetically controlled RCM stereochemistry. Chem. Ear. J., 12, 51-62. 

A major drawback of alkene metathesis is lack of control over the stereochemistry of the newly formed double bond. For unstrained systems, E/Z ratios are virtually unpredictable. Alkyne metathesis, on the other hand, can always be combined with subsequent Lindlar hydrogenation, thereby giving access to stereochemically pure 2-olefins. In 1998, Ftirstner and Seidel were the first to report a ring-closing alkyne metathesis [7]. Under high-dilution conditions (0.02 m) and reduced pressure (20 mbar, removal of 2-butyne, solvent 1,2,4-trichlorobenzene (b.p. 214 °C)) the Schrock catalyst was applied to assemble macrocydic... 

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