Synthesis of syn-γ-Amino-β-hydroxyphosphonates by Reduction of β-Ketophosphonates Derived from L-Proline and L-Serine

The reduction of γ-N-benzylamino-β-ketophosphonates 6 and 10, readily available from L-proline and L-serine, respectively, can be carried out in high diastereoselectivity with catecholborane (CB) in THF at -78 °C to produce the syn-γ-N-benzylamino-β-hydroxyphosphonates 11 and 13 as a single detectable diastereoisomer, under non-chelation or Felkin-Anh model control.

Recently, we reported the synthesis of phosphostatine and phosphoepistatine [48,49] via a high diastereoselective reduction of γ-amino-β-ketophosphonates readily obtained from L-amino acids [50][51][52]. In order to establish a general methodology for the synthesis of syn-γ-amino-βhydroxyphosphonates derived from L-amino acids, in this paper we would like to report the synthesis of γ-amino-β-ketophosphonates 6 and 10 derived from L-proline and L-serine, respectively, and their highly diastereoselective reduction.

Results and Discussion
In our initial study, the synthesis of (S)-N-benzyl-O-benzylpyrrolidine-2-carboxylate (5) was carried out by treatment of L-proline with benzyl bromide and K 2 CO 3 in refluxing ethanol [50], however under this conditions a disappointing poor yield was obtained. For that reason, we decided to examine the methodology developed by Overman and co-workers [53] as a potentially more efficient and practical route to compound 5. Thus, treatment of L-proline with benzyl bromide and NaHCO 3 in N,Ndimethylformamide (DMF) at 100 ºC provided the corresponding N-benzyl O-benzyl proline 5 in 83% yield. Nevertheless, with the O-benzyl ester 5 in our hands, we focused our attention on the transformation to β-ketophosphonate 6. Thus, reaction of 5 with three equivalents of the lithium salt of dimethyl methylphosphonate at -78 ºC in THF afforded the corresponding N-benzylamino-βketophosphonate 6 in 80% yield (Scheme 1).

Scheme 1.
Preparation of β-ketophosphonate 6. On the other hand, the reaction of hydrochloride salt of methyl ester of L-serine 7 readily obtained from commercial source or by treatment of L-serine with thionyl chloride in refluxing methanol, with benzyl bromide in the presence of K 2 CO 3 in acetonitrile at room temperature gave the N,N-dibenzyl ester 8 in 92% yield. Subsequent treatment with tert-butyldimethylsilyl chloride (TBSCl) in the presence of triethylamine and catalytic amounts of 4-N,N-dimethylaminopyridine (DMAP) in dichloromethane produced the full protected L-serine 9 in 97% yield [54]. O-protection in 8 with TBSCl and imidazole in DMF proceed in poor yield. Finally, reaction of 9 with the lithium salt of dimethyl methylphosphonate at -78 ºC in THF provided the corresponding γ-N,N-dibenzylamino-βketophosphonate 10 in 81% yield (Scheme 2). Having efficiently prepared the β-ketophosphonates 6 and 10, we turned our attention to the diastereoselective reduction of the carbonyl groups to obtain the corresponding γ-N-dibenzylaminoand γ-N,N-dibenzylamino-β-hydroxyphosphonates syn-11 and syn-13, respectively. For this propose we choose NaBH 4 , LiBH 4 , DIBAL-H and catecholborane (CB) as the reducing agents, according to our previous results. Diastereoisomeric excess of the reduction of the β-ketophosphonates 6 and 10 were determined by means of 31 P-NMR. In fact, the signals for the diastereoisomers syn were more shielded than for the diastereoisomers anti. Conditions, yields and diastereoisomeric ratio are summarized in Tables 1 and 2. O + a Determined after purification; b syn:anti ratios have been determined on the crude products using 31 P-NMR.
The formation of the γ-amino-β-hydroxyphosphonates syn-11 and syn-13 as major diastereoisomer in the reduction of the β-ketophosphonates 6 and 10, respectively, with catecholborane, we propose that the reduction might took place under non-chelation or Felkin-Anh model control [55][56][57][58], and that the bulkiness of the N-benzylaminoand N,N-dibenzylaminogroups in the β-ketophosphonates 6 and 10, are sufficient to simultaneously limit the rotamer populations around the hinge bounds adjacent to the carbonyl group blocking the re face of carbonyl group and, thereby allowing the addition of hydride to take in a diastereoselective manner by the si face ( Figure 1).

General Procedures
Optical rotations were taken on a Perkin-Elmer 241 polarimeter in a 1 dm tube; concentrations are given in g/100 mL. For flash chromatography, silica gel 60 (230-400 mesh ASTM, Merck) are used. 1 H-NMR spectra were recorded on a Varian INOVA 400 (at 400 MHz), 13 C-(100 MHz) and 31 P-NMR on a Varian Mercury 200 instrument. HRMS spectra were recorded on a JEOL JMS-700 instrument. Flasks, stirring bars, and hypodermic needles used for the generation of organometallic compounds were dried for ca. 12 h at 120 ºC and allowed to cool in a desiccator over anhydrous calcium sulfate. Anhydrous solvents (ethers) were obtained by distillation from benzophenone ketyl. The preparation and spectroscopic data for the compounds (S)-N-benzyl-O-benzylpyrrolidine-2-carboxylate (5) [53], (S)-methyl-2-(dibenzylamino)-3-hydroxypropanoate (8) [59] and (S)-methyl-3-(tert-butyldimethylsilyloxy)-2-(dibenzylamino) propanoate (9) [59], have all been described in the cited literature. (6). A solution of dimethyl methylphosphonate (830 mg, 6.8 mmol) in anhydrous THF (50 mL), was cooled at -78 ºC before the slow addition of n-BuLi 2.35 M in hexanes (2.9 mL, 6.9 mmol). The resulting solution was stirred at -50 ºC for 1.5 h and then cooled at -78 ºC, followed by the addition of a solution of benzyl ester 5 (500 mg, 1.7 mmol) in anhydrous THF (50 mL). The reaction mixture was stirred at -78 ºC for 4 h before the addition of a saturated solution of NH 4 Cl. The solvent was evaporated under reduced pressure, the residue was dissolved in water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered and evaporated under reduced pressure. The crude product was purified by column chromatography using hexane-ethyl acetate (50:50) as eluent to afford the desired product (420 mg, 80% yield) as a viscous oil.  Dimethyl-4-(tert-butyldimethylsilyloxy)-3-N,N-(dibenzylamino)-2-oxobutylphosphonate (10). A solution of dimethyl methylphosphonate (3.30 g, 26.6 mmol) in anhydrous THF (125 mL), was cooled at -78 ºC before the slowly addition of n-BuLi 2.15 M in hexanes (12.7 mL, 27.3 mmol). The resulting solution was stirred at -50 ºC for 1.5 h and then cooled at -78 ºC followed by the addition of a solution of benzyl ester 9 (2.75 g, 6.7 mmol) in anhydrous THF (125 mL). The reaction mixture was stirred at -78 ºC for 4 h before the addition of a saturated solution of NH 4 Cl. The solvent was evaporated under reduced pressure, the residue was dissolved in water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered and evaporated under reduced pressure. The crude product was purified by column chromatography using hexane-ethyl acetate (50:50) as eluent to give the desired product (2.7 g, 81% yield) as a viscous oil.

Conclusions
In conclusion, we have found that the reduction of N,N-disubstituted-γ-amino-β-ketophosphonates readily obtained from the appropriate L-amino acids, with catecholborane (CB) afforded the syn-γamino-β-hydroxyphosphonates as principal diastereoisomers, which could be used as template compounds for the synthesis of molecules with biological and chemical interest.