Studies on the SmI2-promoted pinacol-type cyclization: Synthesis of the hexahydroazepine ring of balanol

The efficiency of the samarium(II) iodide induced pinacol-type coupling for the construction of seven-membered cyclic amino alcohols has been investig ated. With the acyclic carbonylhydrazones 6 and 16, good yields of the hexa hydroazepines 22 and 23 were obtained (56-57%) with high trans-selectivity (= 10:1), which compares well with similar reactions generating the corresp onding five-and six-membered carbocycles (Fallis, A. G.; Sturino, C. F. J. Am. Chem. Sec. 1994, 116, 7447). It is essential for ring formation that th e strongly electron-donating Ligand, herramethylphosphoramide, be present, as in its absense intermolecular pinacol coupling forming the diols 27-30 i s the dominant reaction. Hence, the role for HMPA appears not only to incre ase the rate of electron transfer but also to modulate rate constants for t he subsequent reactions (cyclization and pinacol coupling) of the intermedi ate ketyl. This ring forming reaction has been applied to the construction of the fully functionalized hexahydroazepine ring of the PKC inhibitor, bal anol. Initial attempts to develop an asymmetric version of this reaction in dicate the use of chiral ligands based on the structure of HMPA.