An Efficient One‐Pot Synthesis of Chiral N‐Protected 3‐Substituted (Diketo)piperazines via Ugi‐4CR/De‐Boc/Cyclization Process

Abstract

A convenient and high yielding method to prepare a vast array of enantiomerically pure 3‐substituted diketopiperazines (3‐DKPs), bearing a benzyl protecting group on nitrogen 1 is reported. The methodology describes a simple one‐pot procedure, starting from readily available N‐protected L‐ or D‐amino acids employing the Ugi‐4CR in pure water, followed by a one‐step Boc‐deprotection and final lactamisation in acetic acid. All disubstituted DKPs were obtained in short times and isolated in excellent yields (84‐94%) by simple precipitation in water and subsequent filtration. The practical utility of this procedure proved efficient for the synthesis of cialis (Tadalafil) analogues.

Structure–Activity Relationship Studies on Oxazolo[3,4-a]pyrazine Derivatives Leading to the Discovery of a Novel Neuropeptide S Receptor Antagonist with Potent In Vivo Activity

“…Enantiomerically pure monosubstituted piperazines 35a–e were prepared starting from commercial chiral amino-esters following previously reported procedures, and the analytical data for intermediates 33–35a–e are in agreement with data from the literature. 19 , 50 A solution of di- tert -butyl dicarbonate (1.1 mmol) in anhydrous THF was added at 0 °C to a solution of compounds 35a–e (1 mmol) in dry THF (10 mL). The reaction mixture was warmed at room temperature and further stirred for 1 h. The solvent was removed in vacuo, and the residue was dissolved in CH 2 Cl 2 (15 mL) and washed with water (3 × 10 mL) and brine (1 × 10 mL).…”

Tadalafil: 15 years' journey in male erectile dysfunction and beyond

“…N-Boc-(L)-or (D)-tryptophan were SCHEME 6 Synthesis of Tadalafil 2 from N-Boc-D-tryptophan used as starting materials, a three-step one-pot reaction was adopted, using the Ugi reaction in water. The Ugi reaction involves the condensation of a carbonyl component, an amine, a carboxylic acid and an isocyanide, to produce α-acylaminoamides, which was followed by a Boc-deprotection, a P-S reaction (with piperonal) and lactamization in acetic acid (Scheme 9) (Jida & Ballet, 2018).…”

One-Pot Diastereoselective Synthesis of Pyrrolopiperazine-2,6-diones by a Ugi/Nucleophilic Substitution/N-Acylation Sequence

“…Regarding pyrrolo-2,5-diketopiperazines, different methodologies based on the Ugi reaction have been described, for instance the Ugi/deprotection/cyclization sequence (UDC), 5 the Ugi four-center three-component reaction (U-4C-3CR), 6 and the Joullié–Ugi/postcondensation sequence. 7 On the other hand, pyrrolo-2,6-diketopiperazines can be prepared through a Ugi five-center four-component reaction (U-5C-4CR) followed by a postcondensation step.…”