ABSTRACT
Development of a practical synthesis of MK-7009, a 20-membered [corrected] macrocycle, is described. A variety of ring-closing strategies were evaluated, including ring-closing metathesis, intermolecular palladium-catalyzed cross-couplings, and macrolactamization. Ring closure via macrolactamization was found to give the highest yields under relatively high reaction concentrations. Optimization of the ring formation step and the synthesis of key intermediates en route to MK-7009 are reported.
Subject(s)
Chemistry Techniques, Synthetic/methods , Indoles/chemistry , Indoles/chemical synthesis , Lactams/chemistry , Macrocyclic Compounds/chemistry , Catalysis , Cyclization , Cyclopropanes , Hydrogenation , Isoindoles , Lactams, Macrocyclic , Leucine/analogs & derivatives , Palladium/chemistry , Proline/analogs & derivatives , SulfonamidesABSTRACT
An efficient asymmetric synthesis of a selective estrogen receptor modulator (SERM) that has a dihydrobenzoxathiin core structure bearing two stereogenic centers is reported. The stereogenic centers were established by an unprecedented chiral sulfoxide-directed stereospecific reduction of an alpha,beta-unsaturated sulfoxide to the saturated sulfide in one step. Studies to elucidate the mechanism for this reduction are reported. Highly efficient Cu(I)-mediated ether formation was used to install the ether side chain, and selective debenzylation conditions were developed to remove the benzyl protecting groups on the phenols.
