Soft enolization conditions are revealed to be markedly better than the typically applied hard enolization protocols for regioselective enoxysilane formation from unsymmetrical 3-substituted cycloalkanones. Five-, six-, and seven-membered cycloalkanones each with 3-methyl, 3-isopropyl, or 3-phenyl substituents were investigated, and in all but one case, regioselectivities were ≥11:1 for enolization away from the substituent. These results are complementary to the regiospecific enoxysilane formation derived from cycloalkenone conjugate addition/enolate silylation.

We describe a total synthesis of the rare isocyanoterpene natural product isoneoamphilectane and two of its unnatural diastereomers. The significantly strained ring system of the reported natural product�along with a hypothesis about a biosynthetic relationship to related family members�inspired us to consider a potential misassignment in the structure's relative configuration. As a result, we initially targeted two less strained, more accessible, stereoisomers of the reported natural product. When these compounds failed to exhibit spectroscopic data that matched those of isoneoamphilectane, we embarked on a synthesis of the originally proposed strained structure via an approach that hinged on a challenging cis-to-trans decalone epimerization. Ultimately, we implemented a novel cyclic sulfite pinacol-type rearrangement to generate the strained ring system. Additional features of this work include the application of a stereocontrolled Mukaiyama−Michael addition of an acyclic silylketene acetal, an unusual intramolecular alkoxide-mediated regioselective elimination, and an HAT-mediated alkene hydroazidation to forge the C−N bond of the tertiary isonitrile. Throughout this work, our synthetic planning was heavily guided by computational analyses to inform on key issues of stereochemical control.