Facile synthesis of cyclic α-perfluoroalkyl-α-aminophosphonates
Introduction
α-Aminophosphonates and the corresponding α-aminophosphonic acids attract persistent attention during several decades due to the high and diverse biological activity determining their practical applications and the permanent search and investigations of novel structures of such type [1]. Some of them are natural products, such as (R)-phosphotyrosine 1 with R = p-CH2C6H4OH which is a key component of two hypotensive tripeptides [2]. Being analogous to amino acids they found applications as antibiotics [2], proteolytic enzyme inhibitors [3], anti-cancer agents [4], and herbicides [5]. α-Aminophosphonates are also of undoubted interest as ligands in homogeneous [6], [7] or organic [8], [9] catalysis.
It is well known that cyclic or heterocyclic rings introduced into the molecular skeleton increase its rigidity and modify electronic effects. Thus many cyclic α-aminophosphonic acids bearing the exocyclic amino group were prepared mostly in racemic series [10], [11], [12], [13], [14]. However, among α-aminophosphonates those containing nitrogen as a ring heteroatom are scarce. Nevertheless, a series of dipeptides which contained phosphonate analogs 2 of proline and piperidine-2-carboxylic acid (homoproline) have been reported as potential therapeutic agents to prevent the rejection of transplanted tissues [15].
In this connection it should be mentioned that synthetic routes to cyclic α-aminophosphonates containing the nitrogen as a ring heteroatom, are limited mostly by addition of hydrophosphoryl compounds to triazine derivatives [16], [17], [18], lactame alkylation using dialkyl phosphite sodium salts [19] or multistep asymmetric synthesis [20] developed for non-substituted 5- and 6-membered compounds, and some procedures developed for aziridine phosphonates [21], [22], [23].
At the same time fluorine introduction in a biomolecule may change the “normal” route of its interaction with a biological target or the direction of binding. That is why fluorine is more and more popular in the construction of new pharmaceutical and biochemical tools. However, in contrast to the rather well developed aminophosphonic and aminophosphinic acids area, only limited representatives of fluorine containing α-aminophosphonates are currently known [24], [25], [26], [27], [28], [29], [30], [31], [32]. The compounds with linear scaffold were obtained in few steps starting from fluorinated acetic acid [25], generated in situ fluorinated aldehydes [26] or fluorinated N-acyl hemiaminals [27] or aluminum iminoderivates obtained in turn by reduction of nitriles with DIBAL [28]. As for cyclic α-CF3-substituted aminophosphonates, till now only unsaturated compounds, namely analogs of dehydropipecolinic and tetrahydroazepin-2-carboxylic acids 3 [32], were obtained via the ring closing metathesis strategy starting from α-CF3-substituted α-amino phosphonates with two alkene chains, 1,7-dienes and 1,8-dienes, obtained in turn by nucleophilic addition of dialkyl phosphites to highly electrophilic imines Cbz-N = C(CF3)P(O)(OR)2 [31].
Section snippets
Results and discussion
It should be mentioned, that the most convenient approach to build phosphonate P–C–N systems comprises a nucleophilic addition of dialkyl phosphites to the C
N double bond of Schiff bases. Depending on the structure and electrophilicity of a Schiff base, dialkyl phosphites are known to add to the CN bond under thermal [33], ultrasonic [34] or microwave [35] initiation, in the presence of strong bases [36] or Lewis acids [35], [37] to give racemic α-aminophosphonates. Using this strategy,
Conclusions
In summary, starting from available fluorinated cyclic imines we elaborated a convenient approach to racemic saturated cyclic α-amino-α-perfluoroalkylphosphonates, which along the free phosphonic acids obtained on their base are of undoubted interest as potent biologically active substances.
General
NMR spectra were recorded with a Bruker Avance-300 (1H, 300.13, 31P, 121.49 and 13C, 75.47 MHz) and Avance 400 (1H, 400.13, 31P, 161.97 and 13C, 100.61 MHz) spectrometers using residual proton signals of deuterated solvent as an internal standard (1H, 13C), CFCl3 (19F) and H3PO4 (31P) as an external standard. The 13C NMR spectra were registered using the JMODECHO mode; the signals for the C atom bearing odd and even numbers of protons have opposite polarities. Melting points are uncorrected.
Acknowledgements
The authors thank the Deutsche Forschungsgemeinschaft (grants Nos. 436 RUS 113/812/0-1; 436 RUS 113/905/0-1) and Russian Foundation of Basic Research (grant 06-03-04003). We are grateful to Dr. Sergey Lyubimov (A.N. Nemeyanov Institute of Organoelement Compounds RAS) for his help in determination of enantiomeric excess.
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