Peptoid macrocycles

Rapid Synthesis of Peptoid Macrocycles by Multi Component Reactions. . 163... 

Keywords Cyclopeptides Depsipeptides Peptoids Macrocycles Diketopiper-azines Benzodiazepines Ugi-reaction Polycyclic compounds Orthogonal reactivity Sequential reactions Iteration Bifunctional building blocks Medium sized rings Beta-turn motif... 

Macrocyclic lactones [840-850], lactams [842,851], carbamates [852], pyridi-nium salts [853], ethers [811,854-858], peptoids [859-864], and calixarenes [865] can also be prepared by RCM. As in other macrocyclizations, yields can usually be improved by lowering the concentration of the reactants. 

A similar type of compounds, without the nitro group, was achieved by Wessjohann and coworkers (Scheme 15) [79]. Their approach also uses the Ugi reaction to build the linear peptoid intermediates, but a nucleophilic substitution is employed for the ring closure, which is a difficult task with a strained phenolate. A small library of macrocycles with general formula 15a was prepared, including also some 15-membered ansa-cycles (not shown). 

The cyclic pentapeptoid skeleton 23a was assembled after three consecutive U-4CRs, two of them to prepare the linear precursor b and the final one for the ring closure. The approach has been shown to be straightforward and opens the possibility for a combinatorial strategy toward a wide range of cyclic oligopeptoids. This was the first report where the peptoid backbone and the macrocycle closure were performed by consecutively employing MCRs. 

Because thioether formation is a rapid, irreversible reaction, it has been widely used for the macrocyclization of peptides or peptoids on supports (Entries 1-4, Table 8.5 [62]). For this purpose, either S-protected cysteine or S-protected co-aminomercap-tans are linked to a support and then elongated by standard solid-phase peptide/pep-toid chemistry. When a suitable length has been reached, the terminal amine is acy-... 

Using steroid as supporting scaffold, the reaction of diamine 67, diisocyanide 68 (both being derived from lithocholic acid), acetic acid and formaldehyde afforded the macrocycle 69a in 58% yield as a mixture of head-to-tail and head-to head cyclic dimers ((1), Scheme 20 for the sake of clarity, only the head-to-tail regioi-somer was shown) [96-98]. On the other hand, the reaction of diacid 70, diisocyanide 68, isopropylamine and formaldehyde afforded the steroid-peptoid conjugate... 

Taillefumier et al. were the first to report on cyclic j8-peptoids and described macrocycles comprised of A-propargyl-j8-alanine oligomers 44. " The cyclic tetramer was... 

Holub JM, Jang HJ, Kirshenbaum K (2007) Fit to be tied conformation-directed macrocyclization of peptoid foldamers. Org Lett 9(17) 3275-3278... 

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