An operationally simple, fast and green synthesis of novel γ-hydroxyphosphonate and phosphine oxide derivatives

ABSTRACT A green and versatile method for the preparation of γ-hydroxyphosphonate and phosphine oxide derivatives in 5 min, is accomplished through the reduction of γ-phosphonylketones with sodium borohydride supported on alumina, at room temperature, under solvent free conditions. GRAPHICAL ABSTRACT


Introduction
An increasing interest has been paid for several years to the synthesis of hydroxyphosphonates due to their promising pharmacological activities. Much of these activities has been attributed to the physical and structural similarity of hydroxyphosphonates and phosphonic acids to the biologically important natural hydroxycarboxylic acids, in which a carboxylic group is replaced by phosphonic or related functionality (1). Such structural similarity enables hydroxyphosphonates to inhibit, by mimetic effect, enzymes involved in hydroxycarboxylic acid metabolism and thus affects a variety of physiological processes (2). For instance, αhydroxyphosphonates, which are structural analogs of α-hydroxyacids, are an important class of compounds in medicinal chemistry with potential biological effects as inhibitors of human renin (3) and HIV protease (4). Some are also medicinally important as antitumor (5), antibacterial (6), antiviral (7) and antioxidant (8) agents.
Although αand β-hydroxyphosphonates are well described in the literature, their γ-hydroxyphosphonate homologues did not receive sufficient attention despite their structural resemblance to γ-hydroxybutyric acid (GHB), wich is a naturally occurring neurotransmitter and a psychoactive drug used in a medical setting as a general anesthetic and as a treatment for cataplexy, narcolepsy and alcoholism (13)(14)(15). It is a precursor to GABA, glutamate, and glycine in certain brain areas, and it is an agonist at the GHB and GABA B receptors (16,17).
There is only a limited number of synthetic approaches to γ-hydroxyphosphonates. This includes (i) the BF 3 .OEt 2 -or TiCl 4 -catalyzed nucleophilic ring opening reaction of epoxides by methanephosphonates (18)(19)(20) and (ii) the oxazaborolidine-catalyzed catecholborane reduction of γ-ketophosphonates (21,22). However, in spite of their potential utility, these procedures suffer from one or the other drawbacks such as the use of expensive catalysts and hydride reducing agents, where specialized handling techniques and tedious work-up are necessary, as well as long reaction time, use of solvent and lack of generality. Therefore, the development of a simple, mild, eco-benign and low cost protocol is still desirable to obtain a wider variety of γ-hydroxyphosphonates for biological screening.
In recent years, NaBH 4 supported on inorganic solid supports especially alumina, has been reported in literature (23) as an efficient and eco-benign reagent for the reduction of aldehydes and ketones. With this in mind, and in the continuation of our interest to develop efficient protocols for the synthesis of biologically active phosphonates (24)(25)(26)(27), we report herein an operationally simple, green and fast methodology for the synthesis of γ-hydroxyphosphonates and phosphine oxides, in excellent yields, through the reduction of γ-phosphonylketones with NaBH 4 supported on alumina, at room temperature, under solvent-free conditions, within few minutes.

Results and discussion
In order to establish the optimum reaction conditions for the formation of the target compounds, we used γ-ketophosphonate 1a as model substrate. The reduction of 1a was initially carried out with one hydride equivalent of LiAlH 4 in anhydrous THF. Unfortunately, the expected γ-hydroxyphosphonate 2a was not obtained ( Table 1, entry 1). Although the starting materials were completely consumed, the 31 P NMR analysis of the reaction mixture showed complete dephosphonylation due to C-P bond cleaving (24,25,28). When the reaction was conducted with 1 equiv of NaBH 4 in EtOH at room temperature, the desired product 2a was isolated in only 30% yield (Table 1, entry 2). Further improvement of the yield to 65% was observed when using 3 equiv of NaBH 4 , under the same reaction conditions (Table 1, entry 3). It was gratifying to observe that performing the reduction with NaBH 4 (3 equiv) supported on alumina (12 equiv), in the presence of few drops of MeOH (5 drops for 1 mmol 1a), at room temperature, under solvent-free conditions, afforded the desired product 2a in 90% yield, within 5 min (Table 1, entry 4).
With optimized reaction conditions in hand, we next studied the scope of this methodology. A variety of structurally diverse γ-phosphonylketones were investigated and a series of γ-hydroxyphosphonates and phosphine oxides of type 2 were afforded in high to excellent yields ( Table 2). Pure products can be isolated by simple extraction without the need for chromatography or recrystallization.
Compounds 2a-g, presenting two stereocenters, were obtained as a mixture of two unseparable  diastereoisomers, as evidenced by their NMR spectral data. The relative proportions of these diastereoisomers were estimated from the 31 P NMR spectra where a singlet for each one was found (Table 2).

Conclusion
We have successfully developed an efficient, green and fast methodology for the synthesis of γ-hydroxyphosphonates and phosphine oxides, through the reduction of γ-phosphonylketones with NaBH 4 supported on alumina, in the presence of few drops of MeOH, at room temperature, under solvent-free conditions. This synthetic strategy offers significant advantages such as high to excellent yields, short reaction time, versatile substituents, mild reaction conditions, easy work-up and environmental safety, what make this protocol more amenable for high throughput library synthesis. These compounds are potential agonists at the GHB and GABA B receptors. This aspect is currently under study in our laboratory and will be reported in due course.

General informations
Commercially available analytical grade reagents were used without further purification.
General procedure for the synthesis of γhydroxyphosphonates and phosphine oxides 2 A round-bottomed flask equipped with a magnetic stir bar was charged with Al 2 O 3 (12 mmol) and NaBH 4 (3 mmol). The mixture was stirred for 30 min at 25°C, under nitrogen atmosphere. The γ-ketophosphonate or phosphine oxide (1 mmol) and five drops of MeOH were added to this mixture and stirring was continued for 5 min (reactions were monitored by TLC). The reaction mixture was poured into ether (15 mL) and then filtred. The filtrate was washed with water (2 × 5 mL). The organic phase was dried over Na 2 SO 4 and concentrated under vacuum to afford the pure products in 85-93% isolated yields.