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
A practical, efficient synthesis of 1, a hepatitis C virus RNA replication inhibitor, is described. Starting with the inexpensive diacetone glucose, the 12-step synthesis features a novel stereoselective rearrangement to prepare the key crystalline furanose diol intermediate. This is followed by a highly selective glycosidation to couple the C-2 branched furanose epoxide with deazapurine.
Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/genetics , RNA, Viral/biosynthesis , Antiviral Agents/pharmacology , Chromatography, High Pressure Liquid , Magnetic Resonance SpectroscopyABSTRACT
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.
Subject(s)
Boranes/chemistry , Estrogen Receptor Modulators/chemical synthesis , Safrole/analogs & derivatives , Safrole/chemistry , Magnetic Resonance Spectroscopy , Mass Spectrometry , Oxidation-Reduction , StereoisomerismABSTRACT
The synthesis of a spirobicyclic NK-1 receptor (Substance-P) antagonist 1 antipode is described. Retrosynthetic analysis reveals an allylic halide A bearing the cyclopropoxy-substituted aryl group and a 2-phenyl-3-piperidone B. The stereochemistry in the spirobicyclic system bearing three chiral centers is initially set via a highly diastereoselective zinc-mediated coupling of the allylic bromide 23 to the optically active ketopiperidine 3. The remaining benzylic asymmetric center is set by a diastereoselective hydroboration followed by cyclization to the spirobicyclic system.
