Pergamon Tetrahedron Letters 40 (1999) 1475-1478 TETRAHEDRON LETTERS New Submonomers for Poly N-Substituted Glycines (Peptoids) Tetsuo Uno, Eric Beausoleil, Richard A. Goldsmith, Barry H. Levine and Ronald N. Zuckermann** Chiton Technologies. Chiron Corporation. 4560 Horton Street, Emeryville. CA 94608-2916 Received lO November 1998; revised 17 December 1998; accepted 18 December 1998 Abstract: Five protected submonomers for peptoid synthesis were prepared, including N~-BOC-tryptamine, O-t-butyl tyramine, PMC-guanidino-propylamine, 6-amino-6-deoxy- D-galactopyranose diacetonide, and 5-amino-2,2-dimethyl-l,3-dioxane. The first three mimic natural aminoacid sidechains i.e. tryptophan, tyrosine, and arginine, while the last two provide hydrophilic sidechains. These submonomers were successfully used for preparation of oligo-peptoids by the submonomer synthesis method. © 1999 Elsevier Science Ltd. All rights reserved. Poly N-substituted glycines (peptoids) are a novel class of sequence-specific heteropolymers that were originally developed for drug discovery.' Recently, peptoids have been shown to form stable helical secondary structures 2", mediate the delivery of DNA to cells2b and increase the potency of ligands for SH3 domains 2~. Peptoids are synthesized by the solid-phase submonomer method 3. Thus, N-substituted glycine monomers are constructed on the growing chain of a resin-bound peptoid by repeating a two step cycle of (a) bromoacetylation of the N-terminal secondary amine, and Co) subsequent SN2 displacement of the bromide by a desired primary amine (submonomer) (Scheme 1). The coupling efficiency of these two steps have been optimized to such a degree that peptoids as long as 36 residues 2a'2b can be synthesized routinely. In order to introduce many interesting reactive or polar functionalities into peptoids, suitably protected amine submonomers need to be prepared. Table 1 shows the protected amines prepared in this study. Table 1 These submonomers include important amines such as Sidechaina) tryptamine, tyramine and guanidinoalkylamines that mimic natural amino acid sidechains (1, 2, 3). In addition, f"~j_NH submonomers with varing degrees of hydrophilicity were also prepared (4, 5). For these monomers, we chose protecting "/--'"a'~ groups that can be removed during the cleavage of the peptoid ~1, OH from resins with 95% [v/v] TFA in water. Furthermore, by- NH products of these protecting groups are volatile for easy -,/~, NJ~ NH2 removal from the crude product except for the by-products of H the guanidine protecting group# .),,,,~ Oy OH HO "Y " OH To avoid side reaction of the indole system during peptoid OH synthesis, we chose the t-BOC group for indole nitrogen protection. Nin-t-BOC-tryptamine was prepared in three steps (Figure 1). The amino group of tryptamine was first protected with trifluoroacetic an_hydridein pyridine/CH2Cl2 at room *ron_zuckermann@cc.chiron.com Submonomer o H2N~ ~0" (yBu 1 H2N~ 2 (YBu NH 02 I- 12 1"~ l~ II "1 H H .~_~ 3 O*~g "O 4 4-° "•oHOH H2N ~ O a)/ indicates the bond attached to the backbone N. 0040-4039/99/$ - see front matter © 1999 Elsevier Science Ltd. All fights reserved. PH: S0040-4039(98)02696-3