Enantioselective reduction of ketophosphonates using adducts of chiral natural acids with sodium borohydride

A method for asymmetric reduction of α-and β − ketophosphonates using chiral complexes prepared from sodium borohydride and natural aminoacids or tartaric acids was developed. Reduction of α − or β − ketophosphonates by these reagents led to formation of chiral ( S )- or ( R )- hydroxyphosphonates. Reduction of chiral di-(1 R ,2 S ,5 R )-menthylketophosphonates by the chiral complexes NaBH 4 /( R,R )-proline or NaBH 4 /( R,R )-tartaric acid due to the double matched asymmetric induction resulted in increased stereoselectivity of the reaction and led to the formation of hydroxyphosphonates up to 90% ee or higher. Dimenthyl 2-hydroxy-3-chloropropylphosphonate was utilized as a chiron for the preparation of a number of biologically active compounds in multigram quantity.


Introduction
2][3] They possess antibacterial, antiviral, antibiotic, pesticidal, anticancer, and enzyme inhibitor properties. 1,23][4] The previously employed methods provide access to many α-hydroxyphosphonates, but the use of chiral auxiliaries and/or catalysts is required to improve the stereoselectivity of these methods.A possible method for the stereoselective introduction of the hydroxyl group is a stereoselective reduction of prochiral keto compounds.
The asymmetric reduction of ketophosphonates has been studied earlier.It included reduction with borane or catecholborane in the presence of chiral oxazaborolydine catalysts, 6 reduction with chiral chlorodiisopynacampheylboranes 7 and enantioselective hydrogenation in the presence of chiral BINAP-ruthenium(II) catalyst 8 (BINAP = 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl).However all these methods require application of expensive reagents and specific reaction conditions which often are too complicated to be reproduced.
The asymmetric reduction can occur under the control of chiral auxiliaries, which are included in the ketophosphonate, under the control of asymmetric catalysts, or chiral reagents.The reduction of diethyl α−ketophosphonates 9 with borane in the presence of chiral β−butyloxazoborolidines as a catalyst yielded (S)-or (R)-diethyl 1-hydroxyalkylphosphonates in good yields and moderate enantiomeric excesses (53-83% ee). 10 Acylphosphonic and bisacylphosphonic acid sodium salts were directly reduced by sodium borohydride to the corresponding hydroxyphosphonates and dihydroxy-alkanebisphosphonates. 11The reduction of [(N-p-toluenesulfonyl) amino]-β−ketophosphonates 12 with different borohydrides gave [(N-ptoluenesulfonyl)amino]-β−hydroxyphosphonates in good chemical yields and moderate diastereoselectivity.Only the zinc borohydride reduction of ketophophonates resulted in the formation of hydroxy-aminophosphonates with good diastereoselectivity. 13 For these reasons, in continuation of our studies on application of available natural compounds as the reagents in asymmetric synthesis, [14][15][16] we attempted to find simple procedures for the reduction of the ketophosphonates with chiral reagents prepared on the basis of sodium borohydride and the chiral natural acids such as tartaric acid or aminoacid proline.

Scheme 2
The best results in improving of stereoselectivity of ketophosphonate reduction were attained with chiral complex of sodium borohydride with natural amino acid -L-proline (NaBH4-Pro) (Scheme 3).At the same time P-alanine and L-leucine showed moderate stereoselectivity (See Table 1).For the preparation of this reducing reagent, an equimolar amount of L-proline was added to sodium borohydride suspended in THF, and the mixture was stirred at room temperature for several hours. 18.
The ketophosphonates 3a-c were then added to NaBH4-Pro, resulting in the formation of (S)-hydroxyphosphonate with a stereoselectivity in the range from 52% to 79% de purity (Method a).Compounds (S)-3a-c were crystallized from hexane and isolated in approximately 100% optical purity (Scheme 4) The chiral menthyl groups of 3a-c were cleaved off under mild conditions by a modified procedure of Morita et al. 19 The reaction of the dimenthyl αhydroxyphosphonates 3a-c with trimethylsilyl chloride and NaI in acetonitrile led to bis(trimethysilyl)-α-hydroxyphosphonates, which were finally hydrolyzed in amixture of water/ethanol to afford the optically active α-hydroxyphosphonic acids 5a-c.The treatment of αhydroxyphosphonates 3a-c with hydrochloric acid in water/dioxane solution also gave the corresponding free optically active phosphonic acids 5a-c in good yields.Owing to the steric hindrance of the esters 1a-c, it was necessary to use longer reaction times and higher temperatures ketophosphonates with sodium borohydride (Scheme 4).

Scheme 4
Compounds 3 and 5 were identified by 1 H, 13 C, and 31 P NMR spectroscopy and liquid chromatography.Dimenthyl α-hydroxyphosphonates are easily crystallizable compounds, which are obtained in a stereochemically pure state.

31
P NMR spectra of compounds 3a-c show signals for the two diastereomers, with δP values in the area of 21.0-21.5 ppm, The downfield signal belongs to the (R)-diastereomer and the upfield signal to the (S)-diastereomer of α-hydroxyphosphonates 3. 1 H NMR spectra of compounds 3a-c revealed that the signals belong to the protons of the menthyl group, aromatic protons of appropriate multiplicity and intensity, a broad signal due to the OH group at δH =3.7 ppm, and a CH doublet at δ H = 4.9 ppm. 1 H and 13 C NMR spectra of compounds 3a-c indicate that the molecules are asymmetric, because the signals of the two menthyl groups bonded to phosphorus are magnetically nonequivalent.The configuration of (R)-(+)-αhydroxybenzylphosphonic acid 5a was confirmed by comparing its optical rotation with literature data. 20he reduction of dimenthyl ketophosphonates with NaBH4 led preferably to the formation of (R)-α-hydroxyphosphonates, whereas the reduction with NaBH4-Pro furnishes (S)hydroxyphosphonates.
The preferential formation of (R)-diastereomers observed in the reduction of αketophosphonates 1 with NaBH4 in ethanol can be anticipated to some extent by examining their molecular models.The molecular structures of α-ketophosphonate 1a and α-hydroxyphosphonate 3b indicate the high asymmetry of the molecules owing to a propeller-like arrangement of the menthyl groups around the phosphorus atom.Thus, one can make the reasonable assumption that the attack of the reducing agent on the carbonyl group will take place preferentially from the side leading to the (R)-configuration rather than from the opposite side, which is shielded by the menthyl group (Figure 1, left).This corresponds to an approach to the more exposed face of the αketophosphonate.The selectivity of the reduction with NaBH4-Pro depends upon the geometry of the complex formed by coordination of the carbonyl oxygen to the boron atom and of the carboxylic sodium to the oxygen of the P-O group.The reaction cycle inside the favored intermediate complex is shown in Fig. 1, right.It is evident that in this case the attack of the chiral reducing agent on the carbonyl group will take place preferentially from the side leading to the (S)-configuration rather than the opposite Re side.In summary, the described asymmetric reduction of dimenthyl α-ketophosphonates provides an easy route to both stereoisomers of optically active α-hydroxyphosphonic acids in good yield and in enantiomeric excess.We succeeded in the further improvement of the stereoselectivity of ketophosphonate hydroborination when used chiral complex of sodium borohydride with natural (R,R)-(+)-tartaric acids. 21,22This reducing reagent was prepared by mixing sodium borohydride with tartaric acids in 1:1 ratio in THF followed by refluxing the mixture.After removing the solvent the adduct could be isolated as a colorless fine crystalline substance with high melting point (>250 o C).The compound is very hygroscopic and reacts with water.It contains coordinatively bonded THF (0.5 equv.) as confirmed by 1 H NMR spectrum which contains a multiplet at 1.7 ppm (CH2C), a multiplet at 3.7 ppm (CH2O) and a multiplet at 4.5 ppm (CHOH).Detailed study of structure is restricted due to its low solubility in ordinary organic solvents.Note that compounds obtained by treatment of sodium borohydride with achiral carboxylic acids (acetic or trifluoroacetic) to which structure of Na[BH(OAc)3] or Na[BH2(OAc)2] (depending on the initial reagent ratio) is assigned are well known and are used as reducing reagents in organic synthesis (Scheme 5). 23

Scheme 6
The higher stereoselectivity of reduction in the case of dimenthyl arylketophosphonates we explain by the effect of double asymmetric induction, 24 because here the asymmetric inductions due to menthyl groups supplementes that of tartaric acid.At the same time, reduction of dimenthyl ketophosphonates with the sodium borohydride (S,S)-tartaric acid reagent resulted in lower stereoselectivity.For example, reduction of dimenthyl 1-oxobenzylphosphonate yielded corresponding hydroxyphosphonate with 45% de.It is obviously that asymmetric inductions due to (1R,2S,5R)-menthyl groups and (R,R)-tartaric acids are compatible and therefore are summated and increase the total stereoselectivity.On the other hand, asymmetric inductions of (1R,2S,5R)-menthyl groups and (S,S)-tartaric acid act in opposite directions and diminish resulting stereoselectivity.The reduction of chiral di(1R,2S,5R)-dimenthyl ketophosphonate 2b with the chiral complex (R,R)-TA/NaBH4 proceeded under control of double stereoselectivity to yield the (S)-β-hydroxyphosphonate 4b with 96% de that was considerably higher than the single stereoselectivity when the achiral diethyl 2-keto-3-chloropropylphosphonate 2a was reduced with (R,R)-TA/NaBH4 with 80% ee (Table 2).Insofar as reduction of ketophosphonates with the complex NaBH4/(R,R)-tartaric acid affords (S)-hydroxyphosphonates, it is very probable that P=O group is involved to the transition state leading to formation of hydroxyphosphonates as it shown in Figure 2, and promotes stereofacial attack of carbonyl group by hydride ion from the Si side.Diethyl α− and β−hydroxyphosphonates were purified by column chromatography.Dimenthyl α− and β−hydroxyphosphonates were obtained enantiomericaly pure after crystallization from acetonitrile (Table 2).
Several methods were used for elucidation optical purity of the synthesized compounds.The diastereoisomeric ratio of hydroxyphosphonate dimenthyl esters was registered by 31 P-{ 1 H} NMR spectroscopy directly.In the case of homochiral diethyl hydroxyphosphonates the optical purity was determined after derivatization with di-(1R,2S,5R)-menthyl chlorophosphite resulted in formation of diastereomers of the derivatives with a significant difference in chemical shifts P in 31 P NMR spectra, which provided accurate integration of signals and correct measuring of their diastereomeric ratio. 21or determination of optical purity of diethyl hydroxyphosphonates we found convenient to use natural cinchonidine as a chiral solvating reagent.In this case the signals of the hydroxyphosphonate (R)-and (S)-enantiomers in 31 P-{ 1 H}NMR spectra were separated up to zero line and could be easily measured by integration. 32,33The absolute configuration of dimenthyl hydroxyphosphonates was determined by the method of chemical extrapolation.6][27][28][29][30][31][32] For example, the hydrolysis of dimenthyl 2-hydroxy-3chloropropylphosphonate 4b with conc.hydrochloric acid in dioxane afforded the enantiopure (S)-2-Hydroxy-3-chloropropylphosphonic acid (S)-6b with high yield.
Stereoisomers of dimenthyl 2-hydroxy-3-chloropropylphosphonate 4b and 2-hydroxy-3chloropropylphosphonic acid 6b of high optical purity represent useful chiral synthetic building blocks (chirons) for the synthesis of enantiomerically pure β−hydroxyphosphonates.6]22  The treatment of (S)-4a,b with K2CO3 in acetonitrile-DMF in the presence of potassium iodide led quantitatively to the formation of epoxide (R)-9a with 99% de.The reaction of epoxide 9a with sodium azide in the presence of ammonium chloride in methanol afforded the (R)-2-hydroxy-3-azidopropylphosphonate 10a in very high yield (Scheme 8).The epoxides 9a,b were converted consequently into azides 10a,b and aziridine 12.
The diethyl (2R)-2,3-epoxypropylphosphonate (R)-9a,b reacted readily with sodium azide in the presence of ammonium chloride in methanol to afford dialkyl (2R)-2-hydroxy-3azidopropylphosphonates 10a,b.The reaction of azidophosphonates 10a,b with triphenylphosphine at room temperature led at first to the formation of intermediate products 11a,b, bearing pentacoordinated phosphorus, which were registered by 31 P NMR spectra.Thus, the 31 P NMR spectrum of the product 11a reveals two signals: P −55.1 (pentacoordinated phosphorus) and +26.9 ppm (tetracoordinated phosphorus) of equal intensity according to the structure of this compound.Then, upong heating, 11a converts into triphenylphosphine oxide (P 30.2 ppm) and aziridinophosphonate 12a (P 29 ppm), which were isolated in good yields.The diethyl (2S)-aziridine-2-yl-propylphosphonate (S)-12a was purified by distillation under vacuum and isolated in pure state as colorless liquid The dimenthyl aziridine-2-yl-propylphosphonate 12 b was also prepared, however this product contained ~20% of by-products, which we were not able to separate by column chromatography to obtain this compound in pure state.We are continuing this work with aim to prepare pure 12 b.
The enantiomeric purity of diethyl β−hydroxy-−chloropropylphosphonates 4a was analyzed using cinchonidine as a chiral solvated reagent, 33 and dimenthylchlorophosphite as a chiral derivatizing reagent. 21The 1 H NMR spectra of β-hydroxyphosphonates are of special interest.They disclose signals of diastereotopic protons in PCH2 and CH2X groups as doublet doublets due to spin-spin coupling with phosphorus atom, proton of CHOH group (vicinal constant 3 JHH), and due to mutual coupling 2 JHH.The NMR spectra allows to perform conformational analysis of the obtained compounds.2-Hydroxy-3-chloropropylphosphonate 4a probably exist mainly as trans-conformers at the C 1 -C 2 bond, as follows from the values of vicinal constants 3 J HP = 18 Hz and geminal constants 3 JHH and 3 JHH equal to 15-18 Hz and 6.3-8.0Hz, respectively.In the molecules of β-hydroxyphosphonates probably there is an intramolecular hydrogen bond between hydrogen atom of CH-OH group and P=O group, in consistence with the downfield shift of the signal of hydroxyl proton to 4.7-5 ppm.Stability of the trans-conformers probably is higher due to formation six-membered ring with conformation approaching chair form.In the phosphocarnitine molecule this intramolecular hydrogen bond is probably especially strong, as follows from even greater downfield shift of the signal of OH proton, to 5-5.1 ppm, because in this case it involves negatively charged oxygen atom in P=O-group.

Experimental Section
General.Melting points are uncorrected.NMR spectra were registered on a Varian VXR-300 instrument at 300 ( 1 H) and 126.16 ( 31 P) MHz with internal TMS ( 1 H) and external 85% H3PO4 in D2O ( 31 P).Optical rotation angles were measured on a Polax-2L polarimeter (Japan) and on a Perkin-Elmer Model 241 spectropolarimeter Column chromatography was performed with Merck 60 silica gel.All experiments were performed in inert atmosphere (Ar).For the reaction anhydrous solvents were used: THF was freshly distilled over sodium in the presence of benzophenone, methylene chloride was distilled over P4O10.The Fluka tartaric acids, sodium borohydride and menthol were used.Tartaric acids and sodium borohydride priory to use were kept for 2 h in a vacuum at 30 o C.

Reduction of ketophosphonates (1a−c) with NaBH4-Pro by Method a
To a suspension of sodium borohydride (0.045 g, 1.19 mmol) in 8 mL of THF, L-proline (0.137 g, 1.19 mmol) was added.The mixture was stirred at room temperature for 6 to 12 h.Ketophosphonate 1a (0.368 g, 0.795 mmol) was then added, and the mixture was stirred for further 24 h at room temperature.The solvent was evaporated and 10 mL of water/ethyl acetate (1:1) mixture was added to the residue.The organic layer was separated and the aqueous layer was extracted with ethyl acetate.The extract was washed with 1N HCl, then with sodium carbonate solution, again with water, and finally dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure to give the crystalline solid.

Reduction of ketophosphonates (1a−f, 2a-c) with NaBH4-TA by Method b
To a suspension of sodium borohydride (0.36 g, 10 mmol) in 35 ml of THF was added (R,R)-(+)-tartaric acid (1.5 g, 10 mmol), then the reaction mixture was refluxed for 4 h.After that a solution of ketophosphonate (2.5 mmol) in 10 ml of the THF was added at −30 o C and the reaction mixture was stirred at this temperature for 24 h.Then to the reaction mixture was added 15 ml of ethyl acetate and 35 ml of 1 N hydrochloric acid dropwise.The organic layer was separated, the aqueous phase was saturated with NaCl and extracted two times with ethyl acetate.The organic extracts were washed with a saturated solution of Na2CO3 and dried with Na2SO4.The solvent was removed under vacuum, the residue was crystallized from acetonitrile.

(S)-1-Phenyl(1-hydroxyl)methylphosphonic acid (S)-(5a).
To a solution of hydroxyphosphonate 3a (1.15 g, 2.5 mmol) in 50 ml of dioxane was placed in a flask, and 25 ml of 6 N. hydrochloric acid was added.The reaction mixture was left for 3 days at 80°C.The course of reaction was monitored by 31 P NMR spectroscopy.When the reaction was completed, the solvent was evaporated, the residue was dissolved in ethanol and the excess of cyclohexylamine (~1.5 ml) was added, the dicyclohexylammonium salt was filtered off.Yield: 50%, colorless solid, mp 226 °C.[α]D 20 −14.0 (c 1, MeOH-water 1:1) corresponds to the (S)configuration of 5a. 15,25)-1-Phenyl-1-hydroxymethylphosphonic acid (R)-(5a) (Method a).A solution of hydroxymethylphosphonate 3a (1 g, 2 mmol) in 50 mL of dioxane was placed in a flask and 25 mL of 6N hydrochloric acid was added.The reaction mixture was then left for 3 days at 80 o C. The hydrolysis was monitored by 31 P NMR spectroscopy.When the reaction was complete, the solvent was evaporated under reduced pressure, the residue was dissolved in ethanol, followed by the excess addition of cyclohexylamine (∼1.5 ml).The precipitate of the dicyclohexylammonium salt was collected by filtration.

Table 1 .
Asymmetric reduction of ketophosphonates to hydroxyphosphonates