Molecular Mechanics Calculations and the Stereochemical Course of Intramolecular Dipolar Cycloadditions of Nitrile Oxides

The intramolecular nitrile oxide cycloaddition of a series of 4-vinyl N-substituted β-lactams has been investigated. The synthesis of the olefinic nitrile oxides involves treating a 4-vinylazetidinone with a dibromoalkane. The resulting bromo lactam was converted to the corresponding nitro compound, which was then treated with a mixture of phenyl isocyanate and triethylamine. The nitrile oxides were not isolated but spontaneously underwent intramolecular cycloaddition to give fused six- and seven-membered ring systems. Two different transition states are possible for the cycloaddition. In the case of the six-membered ring, the reaction proceeds exclusively via a chair transition state leading to a cis cycloadduct. The transition state involved in the formation of the seven-membered ring is much more flexible and can produce the trans cycloadduct as well. MMX calculations of the energy relationships between the cis and trans isomers of the cycloadducts are in good agreement with the experimental results. The ratio of diastereomeric products from the INOC reaction appears to correlate with product stabilities, in accord with a late transition state.