Solid-Phase Synthesis of Multiple Classes of Peptidomimetics from Versatile Resin-Bound Aldehyde Intermediates

A wide variety of highly substituted lactam containing peptidomimetic scaffolds are prepared by
solid-phase synthesis from a single, versatile class of resin-bound aldehyde intermediates (1). These include
monocyclics 3, bicyclics 4, tricyclics 5, and tetracyclics 6. The key intermediate 1 is readily synthesized
from resin-bound natural or unnatural α-amino acids. The synthetic procedures permit the construction of
a large diversity of substitution patterns for ready use in combinatorial chemistry. In every case, the release
of final products from resin is by a cyclitive cleavage process. Since this depends on successful completion
of multiple intermediate synthetic steps, the products are often quite pure, even though previous steps
involve only a filtration workup. The mild conditions for many of these synthetic procedures offer the promise
of using this chemistry in peptide fragment condensations to produce modified peptides, at either the
N-terminus or C-terminus, or as individually assembled peptide segments with a wide variety of
conformationally restricted peptidomimetic linkers at the point of juncture.