Sequential Nucleophilic Substitution on Halogenated Triazines, Pyrimidines, and Purines:  A Novel Approach to Cyclic Peptidomimetics

Abstract

A novel concept for the synthesis of macrocyclic peptidomimetics which incorporate heteroaromatic units is reported. The method involves sequential SNAr reactions of orthogonally protected amino groups of peptides and other linear oligomers on halogenated heterocycles such as 2,4,6-trichloro[1,3,5]triazine, 2,4,6-trichloropyrimidine, 4,6-dichloro-5-nitropyrimidine, and 2,6,8-trichloro-7-methylpurine. The scope of this novel solid-phase approach was systematically evaluated by means of the SPOT-synthesis methodology on planar cellulose membranes. Besides the question of the accessibility of different ring sizes and the compatibility with protecting groups of commonly used amino acids, the applicability of the technique toward different halogenated heteroaromatics and peptidomimetics was studied. It was found that the procedure is well suited to assemble a wide variety of cyclic peptidomimetics differing in both size (11- to 37-membered rings) and chemical nature of the assembled backbones.

Controlled Microwave Heating in Modern Organic Synthesis

“…[223,224] Apart from traditional cross-linked polystyrene resins a number of different supports and formats have been used in microwave-assisted SPOS. These include tentagel resins, [117,213,214,225] cellulose membranes (SPOT synthesis), [226,227] cellulose beads, [228] and glass surfaces. [229] Janda and co-workers have described the use of JandaJel as the support in the solid-phase synthesis of oxazoles (Scheme 48).…”

Solid-Phase Synthetic Strategies for the Preparation of Purine Derivatives

“…2,6,8-Trichloro-7-methylpurine was used as the ring-closure scaffold to give the cyclic modified peptides of various ring sizes. 43 In Scheme 21, an illustrative example is given for the cyclization of tripeptide Lys-Phe-Ala. Note that the arylation of the polymer-supported peptide 135 with 2,6,8-trichloro-7-methylpurine was not regioselective, and the byproduct of the C 6 substitution was also observed.…”

Six‐Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

“…1,3,5-Triazine-2,4-dithione derivative 256 (VBATDT) is an important dental material [460]. 1,3,5-triazine derivatives are important reagents for the synthesis of peptides [492][493][494][495]. High-loading resins functionalized with 1,3,5-triazine dendrimers can be used as scavenger resins for combinatorial chemistry [496,497].…”