Privileged Structures as Peptide Backbone Constraints: Polymer-Supported Stereoselective Synthesis of Benzimidazolinopiperazinone Peptides

Abstract

A molecular scaffold comprising a privileged structure was designed and synthesized to serve as a peptide backbone conformational constraint. The synthesis of highly functionalized 2,3,10,10a-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-4(1H)-ones on a solid-phase support was performed via a tandem N-acyl-N-aryliminium ion cyclization-nucleophilic addition reaction. The synthesis proceeded with full stereocontrol of the newly formed stereogenic center. Conventional and microwave-assisted syntheses were compared with respect to efficiency and the optical integrity of the target compounds. Significant epimerization was observed during acylation with (S)- and (R)-2-bromopropionic acids under microwave conditions.

Traceless Solid‐Phase Synthesis of Fused Chiral Macrocycles via Conformational Constraint‐Assisted Cyclic Iminium Formation

“…Subsequently, a sodium dithionite procedure using a phase‐transfer catalyst reduced the nitro group and gave a reactive aniline derivative 3 . Acylation of 3 with α‐bromocarboxylic acids (R 3 ) under microwave conditions (50 °C, 50 W, 1 min for R 3 =H; 86 °C, 50 W, 10 min for R 3 =CH 3 ) yielded an advanced intermediate suitable for diversification. Nucleophilic displacement of the bromine with the protected amino aldehyde at room temperature for 2 h gave resin 5 .…”

“…Polymer-supported amine 1 reacted with different 2-nitrobenzensulfonylc hlorides (2-Nos-Cl's, R 2 )t oy ield resin 2.S ubsequently,asodium dithionite procedure using ap hase-transfer catalyst [43] reduced the nitro group and gave ar eactive aniline derivative 3.A cylation of 3 with a-bromocarboxylic acids (R 3 ) under microwavec onditions (50 8C, 50 W, 1min for R 3 = H; 86 8C, 50 W, 10 minf or R 3 = CH 3 ) [44] yieldeda na dvanced intermediate suitable for diversification. Nucleophilic displacement of the bromine with the protected amino aldehyde at room temperature for 2h gave resin 5.T he last step of the linear precursor 6 involved derivatization of the secondary amine with an aromatic sulfonyl chloride, an aryl fluoride or an aromatic carboxylic acid.…”

Synthesis of Nature‐Inspired Medium‐Sized Fused Heterocycles from Amino Acids

“…The solid‐phase synthesis of these acyclic precursors was performed by using standard solid‐phase chemistry protocols and commercially available building blocks according to our previously reported procedures 34. 36–39…”

“…The reaction conditions for the individual steps of the synthesis have been reported in previous communications. [34,[36][37][38][39]…”

“…The solidphase synthesis of these acyclic precursors wasp erformed by using standards olid-phase chemistry protocolsa nd commercially available buildingb locks according to our previously reported procedures. [34,[36][37][38][39] Briefly,R ink amide [40] was acylated with Fmoc-Ser(tBu)-OH, followed by Fmoc removal and acylationw ith the second amino acid( Fmoc-l-Ala-OH, m = 1, Fmoc-b-Ala-OH, m = 2, and Fmoc-GABA-OH, m = 3). The Fmoc protecting group was removed, and subsequent activationw ith the 4-nitrobenzenesulfonyl (4-Nos) group led to resin-bound sulfonamides, which were subjected to Mitsunobu reactionusing glycolaldehyde dimethyl acetal (n = 1, forl inear precursors 2-3)o r3 ,3-diethoxy-1-propanol (n = 2, for linear precursors 4-6)a st he maskeda ldehydet oo btain the desired linear precursors 2-6{1,1,BB3,1}.…”