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Selectively N ‐Protected Enantiopure 2,5‐Disubstituted Piperazines: Avoiding the Pitfalls in Solid‐Phase Fukuyama–Mitsunobu Cyclizations
Author(s) -
Ottesen Lars K.,
Olsen Christian A.,
Witt Matthias,
Jaroszewski Jerzy W.,
Franzyk Henrik
Publication year - 2009
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200802044
Subject(s) - enantiopure drug , mitsunobu reaction , phase (matter) , chemistry , stereochemistry , organic chemistry , enantioselective synthesis , catalysis
Robust protocol! A diverse array of piperazine scaffolds was obtained by a robust solid‐phase‐synthesis protocol involving multistep elaboration of a resin‐bound aziridine (see scheme). Microwave‐assisted on‐resin protectinggroup introduction and manipulation as well as intramolecular Fukuyama–Mitsunobu cyclization conditions were key features.An efficient solid‐phase route to ring‐substituted piperazines from O ‐linked resin‐bound ( S )‐aziridine‐2‐methanol is described. Regioselective microwave‐assisted aminolysis followed by intramolecular Fukuyama–Mitsunobu cyclization constitute the key features of the protocol. Simple piperazines and diazepanes were readily obtained without preceding N ‐protection of the acyclic intermediate, whereas attempts to extend this protocol to chiral 2,5‐disubstituted piperazines failed. Modifications encompassing N ‐carbamoylation prior to ring‐closure were therefore investigated. However, standard carbamoylating agents, for example, Fmoc‐Cl and Alloc‐Cl tended to give bis‐protected by‐products. Thus, novel microwave‐assisted solid‐phase N ‐protection procedures were developed for efficient introduction of Fmoc, Boc and Alloc groups. The subsequent cyclization proceeded in moderate to excellent yields depending on the bulk of the side chain and type of N ‐protecting group. This protocol readily provided novel cis‐ and trans‐ 2,5‐disubstituted piperazines displaying a variety of N ‐protecting group patterns after further on‐resin manipulations. Also, unexpected by‐products obtained during these optimization studies were identified and characterized. This includes nosylated ureas arising from an alternative cyclization pathway. Finally, post‐cleavage oxidation gave access to the Fmoc/Boc‐protected α‐amino acid as well as the corresponding aldehyde. The chiral piperazines described in this work will enable construction of combinatorial libraries with a higher chemical diversity compared to those containing simple N , N′ ‐difunctionalized piperazines, often present in drug‐like compounds.