ring-closing methathesis | The Heterocyclist
followed by ring-closing methathesis to access ..
In devising a strategy for the total synthesis of the eudesmanes, we simplified our target to enone 5, which has been utilized in the preparation of structures such as 4, and itself embodies many features present in various family members (cf. 5 and 1, 2) (Figure 2). We envisioned that the stereochemistry of the C(7) substituent could arise by means of the diastereoselective hydrogenation of a substituted cyclohexene (i.e., 6), the stereochemical outcome of which would be controlled by the C(10) quaternary stereocenter. This cyclohexene could be obtainable from a ring-closing methathesis of triolefin 7, which would be derived from an appropriately substituted α-quaternary ketone (i.e., 8). Thus, the key control element in the design of this synthetic strategy is the C(10) quaternary stereocenter, and we therefore sought to develop an efficient and selective means for the preparation of this moiety.
Comparative Ring-Closing Methathesis ..
Macrocyclizations of intermediates 9-(m,n) were conducted on the resin at room temperature in CH2Cl2 using Hoveyda-Grubbs 2nd generation RCM catalyst [(1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium] (). Except for substrates containing short alkenyl side chains (the peptide-peptoid hybrids containing either two residues of 8a or one residue each of 8a and 8b), the open chain precursors were completely consumed in the RCM reaction. The efficiency of ring closure was sequence-dependent, with members from the 2-series giving the highest percentage of expected ring-closed product. Finally, amino terminal acylation with FITC as described above and cleavage of peptides from the resin provided the target macrocyclic peptides 1-(m,n), 2-(m,n), 3-(m,n) and 4-(m,n) (). RCM is known to provide mixtures of alkenyl E/Z geometric isomers during the methathesis reaction. Previously reported examples of RCM macrocyclizations performed on large peptide substrates have highlighted the difficulties of obtaining defined E/Z geometries at the ring-forming alkenyl junction.– Consistent with these prior studies, our current work does not explicitly define the geometries of RCM ring closure, nor does it extrapolate conformations of the resulting macrocycles.