The synthetic versatility of alkoxycarbonyl- and hydroxymethyl-piperazine-2,5-diones
Alkoxycarbonyl- and hydroxymethyl-piperazine-2,5-diones are versatile precursors for the α-functionalisation of piperazine-2,5-diones.
Introduction
The ubiquity of the piperazine-2,5-dione motif in a number of biologically active natural products1 has encouraged research into the development of methods for the selective functionalisation of piperazine-2,5-diones. Although piperazine-2,5-diones are cyclic dipeptides and can formally be synthesized from the condensation of the requisite α-amino acids,2 in practice complex piperazine-2,5-diones are accessed by the functionalisation of readily available piperazine-2,5-dione precursors.3 This approach has the advantage of enabling the assembly of the carbon and heteroatom framework of piperazine-2,5-diones without the need to develop individual strategies for the synthesis of the requisite α-amino acids.
The existing methods for C-functionalisation are limited in scope due to the necessity of using strong bases in cases where the generation of the enolate of the piperazinedione is required.4 Regioselectivity is also a problem with unsymmetrical piperazine-2,5-diones. Other methods for C-functionalisation of piperazinediones include using radical addition chemistry5 and Diels–Alder reactions.6 The former relies on the ability to synthesise suitable radical precursors and/or substrates and is sensitive to polar and steric effects while the latter is more suitable for the synthesis of bicyclic frameworks. Due to the limitations of the aforementioned methodologies, we sought to develop complementary synthetic routes for the C-functionalisation of piperazinediones. In addition we also recognized the need to be able to install heteroatom functionalities on the α-carbon positions of the piperazine-2,5-dione ring as this substitution is present in numerous bioactive piperazine-2,5-diones. These heteroatom functionalised piperazine-2,5-diones can also serve as radical or cationic precursors in subsequent chemical transformations.
Our plan involved the use of an alkoxycarbonyl group as a ‘traceless’ substituent on the piperazine-2,5-dione ring. The choice of the alkoxycarbonyl group was expected to enhance the reactivity of the α-carbon center of the piperazine-2,5-dione ring towards alkylation reactions. In addition, we envisage that the alkoxycarbonyl group can be converted to the carboxy group, which in turn can be ‘deleted’ or manipulated for the installation of carbon and/or heteroatom substituents where desired.
Following on from our previous communication,7 the studies reported herein detail the synthetic utility of alkoxycarbonyl piperazine-2,5-diones in the functionalisation of the piperazine-2,5-dione nucleus. In the course of our studies we also discovered that the readily accessible hydroxymethylpiperazine-2,5-diones complement the chemistry of alkoxycarbonyl derivatives.
Section snippets
Synthesis of alkoxycarbonyl- and carboxy-piperazine-2,5-diones
In order to examine the effects of various substitution patterns on the chemistry of carboxy piperazine-2,5-diones, the acids 1a–c derived from the esters of types 2 and 3, were targeted.
Our initial work was directed towards the synthesis of the target, acid 1a. A three step synthesis of diethyl N-methylaminomalonate (6) was carried out using modification of literature procedures.8, 9, 10 Diethyl malonate was readily converted to diethyl α-bromomalonate 4 in 70% yield using bromine in carbon
Conclusion
Our studies have demonstrated that carboxy- and hydroxymethyl-piperazinediones are complementary precursors for the generation of N-acyliminium ions. The carboxy piperazinediones potentially suffer from problems with premature decarboxylation and lack of solubility in the solvents typically used in these reactions. On the other hand, the carboxy piperazinediones (with the exception of the N-acetylated systems) allow for mild C-alkylation reactions by activating the α-carbon positions of the
General
1H and 13C NMR spectra were recorded on a Varian Gemini II NMR spectrometer at 300 and 75.4 MHz, respectively. CDCl3 was used as the solvent unless otherwise indicated. The chemical shifts (δ) are reported as the shift in ppm from tetramethylsilane (TMS, 0.00 ppm). 1H spectra were appropriately referenced to either the CHCl3 singlet (7.26 ppm), CHD2OD quintet (3.31 ppm), CHD2S(O)CD3 quintet (2.50 ppm), CHD2(CD3)NC(O)D quintet (2.90 ppm) or to TMS. 13C spectra were appropriately referenced to either
Acknowledgements
The authors thank the Australian Research Council (ARC) for support for this project.
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