The facile preparation of primary and secondary amines via an improved Fukuyama–Mitsunobu procedure. Application to the synthesis of a lung-targeted gene delivery agent

Abstract

An efficient modification of the Fukuyama-Mitsunobu procedure has been developed whereby primary or secondary amines can be synthesized from alkyl alcohols and the corresponding nosyl-protected/activated amine. Most importantly, the use of the DTBAD and diphenylpyridinylphosphine, as Mitsunobu reagents, generates reaction by-products that can be easily removed, providing a remarkably clean product mixture. This improved technique was implemented in the synthesis of a complex lipopeptide designed to target alpha9beta1-integrin proteins predominant on upper airway epithelial cells.

N-Alkylation Reactions and Indirect Formation of Amino Functionalities in Solid-Phase Synthesis

“…264 On the other hand, di-tert-butyl azodicarboxylate (DTBAD) and diphenylpyridinylphosphine gave acceptable yields (40-50%) with secondary alcohols in solution. 266 Since these reagents presumably resemble DEAD and PPh 3 with respect to their reactivity, these findings are in good agreement with our recent results of screening for reagent combinations capable of coupling secondary alcohols on solid phase. 267 DEAD-PPh 3 and DEAD-PEt 3 proved to be efficient for the alkylation of sulfonamide-activated resin-bound diamines, and the DEAD-PPh 3 combination was superior for the alkylation of resin-bound N-nosylglycine.…”

Direct Synthesis of Allyl Amines with 2‐Nitrosulfonamide Derivatives via the Tsuji‐Trost Reaction

“…To avoid such limitations, we optimized the conditions for the Tsuji‐Trost coupling reaction and obtained a method that allowed to obtain a wide range of allyl amine derivatives in good to excellent yields using commercially available ligands and stable palladium complex. In order to achieve this, we chose the 2‐nitrosulfonyl group (nosyl) as it is a dual protective and activating group efficiently cleavable in mild conditions and compatible with allylsulfonamide motifs [38,39] . In addition, 2‐nitrosulfonamide derivatives are stable intermediates that are obtained upon 2‐nitrosulfonylchloride treatment of amines.…”

“…In order to achieve this, we chose the 2‐nitrosulfonyl group (nosyl) as it is a dual protective and activating group efficiently cleavable in mild conditions and compatible with allylsulfonamide motifs. [ 38 , 39 ] In addition, 2‐nitrosulfonamide derivatives are stable intermediates that are obtained upon 2‐nitrosulfonylchloride treatment of amines.…”

Towards Safe Nanoparticle Technologies for Nucleic Acid Therapeutics

“…Over the past few years we have examined a number of possible peptide and carbohydrate systems as potential targeting agents for nucleic acid delivery [33][34][35][36][37][38][39][40][41][42][43] but our most convincing, novel system to date uses the C-terminal fragments of tetanus toxin (TH C ), botulinum toxin (BH C ), or the truncated C-terminal domain of TH C that are all GT1b-ganglioside specific ligands for the ligandmediated transfection of neuronal cells) 44 . These ligands were incorporated into pDNA-ABCD nanoparti- Figure 6 -Formulation of synthetic, self-assembly ABCD nanoparticles Top: Pre-modification Post-modification strategy implies that ABC nanoparticles are prepared directly (step i) with a low mol% incorporation of stealth/biocompatibility polymer lipid.…”