Synthetic design for combinatorial chemistry. Solution and polymer-supported synthesis of polycyclic lactams by intramolecular cyclization of azomethine ylides

The rapidly expanding field of combinatorial chemistry has stimulated the development of new methods and synthetic strategies for assembly of compound libraries. We propose four criteria that are desirable for synthetic routes to such libraries: (1) the sequence involves a small number of steps; (2) no more than one variable is introduced in any step; (3) starting materials are readily obtained with a diverse selection of substituents, and (4) cyclic, nonoligomeric structures represent the most interesting targets. Guided by these criteria, we have explored an intramolecular version of the azomethine ylide cycloaddition reaction which utilizes readily available amino acids, aldehydes, and 2 degrees amines as inputs. We prepared a number of cycloadducts in solution to optimize conditions and examine the scope of the process and to identify a synthetic strategy that would be amenable to solid-phase synthesis of these compounds. Transfer of the sequence to solid phase was demonstrated by the synthesis of a number of representative compounds, indicating that the chemistry is suitable for construction of a combinatorial library.