Atropisomeric transition state analogs

Transition state mimicry is one of the most powerful concepts in enzyme inh ibitor design and has led to the development of catalytic antibodies. Trans ition state analogs are compounds with a fixed shape that resemble the geom etry and charge distribution of the transition state of a given reaction. S tabilization of a transition state like conformation is most often achieved by incorporating a ring system into the analog. We show herein that atropi somerism can be used as a new principle for enforcing a transition state li ke conformation. Atropisomerism relates to the existence of stereoisomers o f structurally constrained molecules due to a frozen rotation about a singl e bond, as for example in binaphthol. The 1-aminomethylnaphthalene derivati ve 1 exhibits atropisomerism due to a frozen rotation about the C(1)-C(meth ylene) single bond, which holds the dihedral angle theta[C(2)-C(1)-C(methyl ene)-N] close to 90 degrees. Compound 1 mimics the transition state for hyd ride transfer between 1,4-dihydroquinolines 4 and acetone.