Resolution of Racemic α-Hydroxyphosphonates: Bi(OTf)3-Catalyzed Stereoselective Esterification of α-Hydroxyphosphonates with (+)-Dibenzoyl-l-tartaric Anhydride.

A practical and efficient method has been developed for the preparation of optically active α-hydroxyphosphonates through resolution of the racemates. Treatment of racemic diethyl 1-hydroxy-1-phenylmethylphosphonate (1) with (+)-dibenzoyl-L-tartaric anhydride gave two diastereomeric esters 2 and 3 in the presence of bismuth triflate (15 mol %) in an 86:14 ratio. The two diastereomeric esters were separated by simple column chromatography, and the structure for the major diastereomer was determined by X-ray crystallographic analysis. Simple hydrolysis of the isolated major diastereomer in the usual manner afforded (R)-O,O-diethyl-1-[hydroxyl(phenyl)methyl] phosphonate 1. The advantages of the present method are that the operation is simple and easy to handle, along with rapid and good yield preparations of both enantiomers of the racemic α-phosphonates 1. Diastereoselective reactions of various racemic α-hydroxyphosphonates with d-Bz-L-TA in the presence of Bi(OTf)3 are also described.

Introduction

α-Substituted phosphonates have received considerable attention in medicinal and organic chemistry.[1−5] Among α-substituted phosphonates, α-hydroxyphosphonates and their acids are considered as structural analogues of α-hydroxycarboxy acids that possess potential biological activities applicable to inhibitors against EPSPS synthase, autotoxin inhibitors, and enzyme inhibitors toward rennin and HIV protease.[6−8] Moreover, α-hydroxyphosphonates are a convenient precursor for the synthesis of other biologically significant α-substituted phosphonates such as α-aminophosphonates. It is not surprising that the biological activity is often dependent on the absolute configuration of the α-position of the phosphoryl compounds.[9−11] Therefore, the preparation of α-hydroxyphosphonates in the enantiomerically pure form can be an attractive research area in view of medicinal chemistry.

Various synthetic methods have been described for the synthesis of racemic α-hydroxyphosphonates.[12−18] Beside these works, many researchers are challenging to obtain the enantiomerically pure forms by using various methods including asymmetric dihydroxylation of vinylphosphonates and hydrophosphonylation of aldehydes with asymmetric catalysts. To obtain optically active α-hydroxyphosphonates from the racemates, many works report the kinetic resolution of racemic α-hydroxyphosphonates by lipase-catalyzed acyl transfer reaction or hydrolysis reaction of their acyl counterpart.[19−21] However, the resolution of racemic α-hydoxyphosphonates with chemical resolving agents is rarely examined. In this context, we have pursued to find efficient resolving agents for racemic α-hydroxyphosphonates.[22−25]

l-Tartaric anhydride (L-TA) and O,O′-dibenzoyl-l-tartaric anhydride (d-Bz-L-TA) have been employed as efficient chiral resolving agents for the separation of racemic alcohols and amines (Figure ).[26] In the resolution with these resolving agents, the racemic alcohols and amines are usually converted to a diastereomeric mixture of the half-esters derived from d-Bz-L-TA, which are readily separated by column chromatography. There is only one literature note discussing the application of d-Bz-L-TA as a chiral resolving agent for the separation of racemic aminophosphonates.[27] As part of our efforts to develop facile and practical methods for the separation of racemic phosphonic and phosphinic acid derivatives,[31−33] we have recently developed a novel method for the preparation of (R)- and (S)-pyrrolidine-2-phosphonic acids through resolution of (±)-diethyl pyrrolidine-2-phosphonate by the formation of diastereomeric amides with d-Bz-L-TA.[34] In our continuous research program directed to the preparation of optically active α-substituted phosphonates, now, we have focused on the method applicable to the resolution of α-hydroxyphosphonates. Herein, we report on the preparation of optically active α-hydroxyphosphonates through Lewis acid-catalyzed stereoselective acylation of racemic diethyl 1-hydroxy-1-phenylmethylphosphonate (rac-1) with d-Bz-L-TA.

Figure 1

Structures of α-hydroxyphosphonates, L-TA, and d-Bz-L-TA.

Results and Discussions

Racemic diethyl 1-hydroxy-1-phenylmethylphosphonate (rac-1) was prepared in a quantitative yield according to an earlier reported method by our laboratory (Scheme ).[35]d-Bz-L-TA was prepared via the thermal heating of a mixture of l-tartaric acid and benzoyl chloride (3 equiv) according to the method reported by Bell.[26]

Scheme 1

Preparation of rac-1 and d-Bz-L-TA

Reaction of d-Bz-L-TA and rac-1 was examined to give the diastereomeric mixtures of 2 and 3 under the various conditions. The diastereomeric ratios were determined by 31P NMR analysis of the reaction mixture. The results and experimental data for screening conditions are listed in Table . Upon treatment of rac-1 (1.0 equiv) with d-Bz-L-TA (1.0 equiv) in CH2Cl2 (5 mL) at room temperature for 24 h without catalyst, no reaction occurred to give 2 and 3 (entry 1). However, in the presence of DMAP (10 mol %),[36] the reaction proceeded at room temperature in CH2Cl2 for 24 h to give a mixture of 2 and 3 in a low yield (36%). Under this reaction, the individual enantiomer was acylated with d-Bz-L-TA in an approximately similar rate to give 2 and 3 in the ratio of 51:49 (entry 2).

Table 1

Optimization of the Reaction between rac-1 and d-Bz-L-TA under Various Conditions

entry	catalyst	solvent (5 mL)	cat (mol %)	T (°C)	time (h)	yield (%)a	ratio of 2/3b
1		CH2Cl2		rt	24
2	DMAP	CH2Cl2	10	rt	24	36	51:49
3	FeCl3	CH2Cl2	15	rt	24
4	ZnCl2	CH2Cl2	15	rt	24
5	AlCl3	CH2Cl2	15	rt	24	15	50:50
6	BiCl3	CH2Cl2	15	rt	24	7	51:49
7	Sc(OTf)3	CH2Cl2	15	rt	24
8	Bi(OTf)3	CH2Cl2	15	rt	24	58	83:17
9	Bi(OTf)3	CH2Cl2	15	rt	8	58	83:17
10	Bi(OTf)3	CH2Cl2	15	rt	6	51	86:14
11	Bi(OTf)3	CH2Cl2	15	rt	3	43	84:16
12	Bi(OTf)3	CH2Cl2	10	rt	8	54	81:19
13	Bi(OTf)3	CH2Cl2	5	rt	8	26	85:15
14	Bi(OTf)3	CH2Cl2	15	rt	1	26	86:14
15	Bi(OTf)3	CH2Cl2	15	–40	24	37	86:14
16	Bi(OTf)3	dioxane	15	rt	6	51	80:20
17	Bi(OTf)3	THF	15	rt	6	70	53:47
18	Bi(OTf)3	toluene	15	rt	6	32	78:22
19	Bi(OTf)3	MeOH	15	rt	24
20	Bi(OTf)3	CH3CN	15	rt	24	trace
21	Bi(OTf)3	CH3CN	15	rt	8	40	83:17c

31P NMR yield (a blank sample including 1:1 of rac-1 and diastereomeric compound 2 was used).

Diastereomeric ratio was calculated by 31P NMR.

0.5 equiv of anhydride.

We anticipate that if the acylation of the individual enantiomer with d-Bz-L-TA significantly differs in their reaction rates, the kinetic resolution of rac-1 would be feasible. Keeping this in mind, acylation of rac-1 with 1 equiv of d-Bz-L-TA was studied in the presence of various Lewis acids.[33−41]

In these experiments, no reaction was observed when FeCl3 and ZnCl2 were used as catalysts (entries 3 and 4). Upon using AlCl3 and BiCl3, equal amounts of the half esters 2 and 3 were obtained in low yields after 24 h (entries 5 and 6). No catalytic activities were observed with Sc(OTf)3 (entry 7). In an effort to find good catalytic systems, we are interested in using bismuth triflate (Bi(OTf)3), which is a nontoxic and eco-friendly Lewis acid catalyst that has been reported for many organic transformations.[28,29] It has also been shown that Bi(OTf)3 is one of the most efficient catalysts for the large scale acylation of alcohols.[30] Interestingly, when the reaction was conducted with Bi(OTf)3 (0.15 equiv) in CH2Cl2 for 24 h, the mixture of 2 and 3 was obtained in 58% yield in a ratio of 83:17 (entry 8). In this reaction, a large amount of (S)-diethyl 1-hydroxy-1-phenylmethylphosphonate ((S)-1) remained unreacted and isolated. The enantiomeric excess (ee) of (S)-1 obtained from this reaction was determined by HPLC analysis to be 83% (Chiralpak OD-H column).

To improve the diastereomeric ratio of 2 and 3, the effects of the amount of Bi(OTf)3, the reaction times and temperatures, and solvents were investigated (entries 8–20). The results showed that decreasing the reaction time resulted in only a slight loss in the diastereoselectivity, along with decreasing the reaction yields (entries 8–11). Decreasing amounts of the catalyst gave a marked decrease in the yield of the mixture of 2 and 3, without a significant loss in the diastereomeric ratios (entries 9 and 12–13). The reaction temperature strongly affects the yield but not the diastereoselectivity. When the reaction was carried out at −40 °C for 24 h, the reaction yield was decreased to 37% with no remarkable change in stereoselection (entry 8 vs 15). The results for the reactions conducted in various solvents showed that there was no reaction when methanol and CH3CN were used as polar protic and nonprotic solvents (entries 19 and 20), while using dioxane and toluene, the half esters 2 and 3 were obtained in modest yields in moderate selectivity (entries 16 and 18). It is worthy to note that the acylation of rac-1 proceeds to give an equal amount of individual diastereoisomer in a moderate yield when the reaction was conducted in THF at room temperature (entry 17). When the reaction was conducted with 0.5 equiv of anhydride, the mixture of 2 and 3 was obtained in 40% yield with a good diastereoselection of 83:17 (entry 21).

The diastereomeric esters 2 and 3, obtained by the optimal reaction conditions (entry 10), and enantioenriched (S)-1 were readily separated by column chromatography. Stereochemistry of the major diastereomer 2 was determined by X-ray crystallographic analysis. The crystal structure of 2 is illustrated in Figure . At this stage, the analysis clearly shows that the major diastereoisomer 2 is derived from (R)-1 by preferential reaction with d-Bz-L-TA under the same conditions. The enantiomeric excess of unreacted (S)-1 was determined by HPLC analysis using a chiral column (Chiralpak OD-H column).

Figure 2

ORTEP drawing of compound 2 with Flack parameter: −0.06 (4).

To constitute the resolution of racemic α-hydroxyphosphonates 1, finally, hydrolysis of 2 and 3 in an ammonia medium (25%) at room temperature for 2 h was carried out to yield (R)-1 and (S)-1 in quantitative yields, respectively. The specific rotations of (R)-1 and (S)-1, prepared by our present method, were determined to be [α]D20 + 24.5 (c 0.5, CHCl3) and [α]D20 −21.7(c 0.8, CHCl3), respectively. These data are in good agreement correspond to reported data by Nesterov and Kolodiazhnyi (Scheme ).[42]

Scheme 2

Separation of Enantiomers of Compound 1 with d-Bz-L-TA

To survey the origins of the diastereoselectivity, interaction of the rac-1 and d-Bz-L-TA with Bi(OTf)3 was studied by NMR experiments. In these experiments, the chemical shift change of signals of 1H, 13C, and 31P corresponding to rac-1 and d-Bz-L-TA was investigated in the presence or absence of Bi(OTf)3 (Table ). The 31P NMR experiment with rac-1 shows that the phosphorus atom resonated in downfield in the presence of Bi(OTf)3, as compared with that in the absence of Bi(OTf)3. On the other hand, the 13C NMR analysis for interaction between d-Bz-L-TA and Bi(OTf)3 showed that chemical shift corresponding to the C=O group of the anhydrous moiety shifts to downfield in the presence of Bi(OTf)3. 1H NMR analysis of the mixture of rac-1 and Bi(OTf)3 showed the broad signal corresponding to the OH group shifts to downfield (Δδ = 0.62). On the basis of these results, possible transition states for the Bi(OTf)3-catalyzed stereoselective esterification of rac-1 with d-Bz-L-TA are envisaged as shown in Scheme . In this mechanism, Bi(OTf)3 has a borderline role and would coordinate not only to the ester moiety (C=O) of d-Bz-L-TA but also to the P=O and OH groups of rac-1, leading to dually activated transition states (TS-A and TS-B), in which the activated substrates would make two reaction sites (carbonyl and hydroxyl sites) close. Subsequent acylation takes place readily through the nucleophilic addition of the hydroxyl group of rac-1 to the bismuth-coordinated anhydride to yield the compounds 2 and 3, respectively. On the basis of the Felkin-Anh model, it seems that the TS-B produced from (R)-1 would more favorable than TS-A produced from (S)-1 due to highly steric hindrance of the phenyl groups of (S)-1 and d-Bz-L-TA (Scheme ).

Table 2

NMR Data for the Interaction of the Compound 1 and Anhydride with Bi(OTf)3

sample	δ C=O	δ P	δ OH	Δδa
anhydride	165.52
anhydride + Bi(OTf)3	169.17			3.65
compound 1		21.46	4.45 (broad)
compound 1 + Bi(OTf)3		23.05	5.07 (sharp)	1.56 (0.62)b

Δδ = δ (mixture) – δ (pure).

Δδ in parentheses is the shift for the OH group.

Scheme 3

Possible Transition States for Diastereoselective Acylation of Compounds 1 with 2

In order to establish the generality of the present method, diastereoselective reactions of various racemic α-hydroxyphosphonates 4 with d-Bz-L-TA in the presence of Bi(OTf)3 were examined, and the obtained results are summarized in Table . The diastereoselective reaction of α-hydroxyphosphonates bearing aromatic ring with para-methoxy and para-nitro substituents gave a mixture of the corresponding 5 and 6 in a ratio of 89:11. This protocol was also applied to α-hydroxyphosphonates bearing styryl- and naphthyl groups. The reaction of the compounds 4c and 4d with d-Bz-L-TA in the presence of Bi(OTf)3 gave the corresponding 5 and 6 in a ratio of 87:13 and 88:12 in moderate yields, respectively. α-Hydroxyphosphonate with the nonaromatic substituent 4e also gave the corresponding 5 in 15% yield in the presence of Bi(OTf)3 for 24 h.

Table 3

Diastereoselective Reaction of Compound 4 with d-Bz-L-TA in the Presence of Bi(OTf)3a

Data in parenthesis is: (conversion %, ratio of 5:6) determined by 31P NMR.

Reaction carried out for 24 h.

The diastereoselective reaction of a quaternary α-hydroxyphosphonate 7 with d-Bz-L-TA in the presence of Bi(OTf)3 failed to give the corresponding diastereoisomers of 8 and 9 (Scheme ). Surprisingly, the 31P NMR of the reaction mixture showed two peaks for the compound 7 due to the combination of compound 7 with d-Bz-L-TA in the presence of Bi(OTf)3 in TS (Figure S33 in the Supporting Information).

Scheme 4

Diastereoselective Reaction of Compound 7 with d-Bz-L-TA in the Presence of Bi(OTf)3

We have shown both enantiomers of diethyl 1-hydroxy-1-phenylmethylphosphonate (rac-1) can be accessed by resolution of the racemic mixture with (+)-dibenzoyl-l-tartaric anhydride (d-Bz-L-TA). In this study, we found that Bi(OTf)3-catalyzed acylation of rac-1 with d-Bz-L-TA was preferable to react with the R-enantiomer, as compared with the S-enantiomer in their reaction rates. This phenomenon was applicable as a novel method for kinetic resolution of rac-1 to give diastereomerically pure 2 and enantioenriched (S)-1. We have also studied the diastereoselective reaction of various racemic α-hydroxyphosphonates with d-Bz-L-TA in the presence of Bi(OTf)3. The features of the present method open up new ways for both enantiomers of 1-hydroxyphosphonate derivatives.

Experimental Section

General Procedure

All melting points are uncorrected. NMR spectra were obtained on a 400 NMR spectrometer (1H NMR: 400 MHz, 13C NMR: 100 MHz, and 31P NMR: 162 MHz). Optical rotations were obtained with a path length of 0.1 dm using the 589.3 nm D-line. Solutions were prepared using spectroscopic-grade solvents, and concentrations (c) were quoted in g/100 mL. Analytical TLC was carried out with plates precoated with silica gel 60 F254 (0.25 mm thick). Column chromatography was performed either with silica gel 60 (70–230 mesh) in common glass columns. All solvents were distilled before use. Enantiomeric excess analysis was carried out using a Chiralpak OD-H column.

X-ray crystal data of the ester compound 2 were collected by a SMART APEX II diffractometer. The structure was solved by a direct method using SHLEXS-97 (Scheldrik, 1997) and refined with a full matrix laser-square method. Molecular formula = C29H29O11P, MW = 584.51, monoclinic, space group = C2, a = 23.4329 (13) Å, b = 11.9702 (7) Å, c = 22.3049 (12) Å, V = 6006.7 (6) Å3, T = 90 K, Z = 4, Dx = 1.306 Mg/m3, (Mo Kα) = 0.71073 Å, and R = 0.020 over independent reflections. Crystallographic data (excluding structure factors) for the X-ray crystal structure analysis reported in this article were deposited in the Cambridge Crystallographic Data Center (CCDC) as supplementary publication no. CCDC 1571255. Copies of these data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K. [Fax: +44(0)-1223-336033 or E-mail: deposit@ccdc.cam.ac.uk].

Diethyl 1-Hydroxy-1-phenylmethylphosphonate (rac-1)

This compound was obtained according to the method reported in our report.[35] Diethyl phosphite (5.65 mL, 40 mmol) was added to a stirred mixture of benzaldehyde (4.16 mL, 40 mmol) and MgO (2 g) at ambient temperature. The resultant mixture was mixed thoroughly with a mortar and pestle for 1 h. The mixture was suspended in CH2Cl2 (100 mL) and the filtrate was evaporated. The pure product of rac-1 was obtained by recrystallization in CH2Cl2/n-hexane in 90% yield. White crystal, mp (n-hexane/CH2Cl2) = 76 °C.

1H NMR (CDCl3, 400 MHz) δ 1.24 (3H, t, J = 7.1 Hz), 1.29 (3H, t, J = 7.1 Hz), 3.95–4.15 (4H, m), 4.45 (s, broad, 1H), 5.05 (d, J = 10.9 Hz, 1H), 7.28–7.55 (5H, m). 13C NMR (CDCl3, 101 MHz): δ 164 (d, JPC = 4.0 Hz), 16.4 (d, JPC = 4.1 Hz), 63.1 (d, JPC = 7.3 Hz), 63.4 (d, JPC = 7.0 Hz), 70.8 (d, JPC = 158.8 Hz), 127.1 (d, JPC = 5.8 Hz), 128.1 (d, JPC = 3.1 Hz), 128.3 (d, JPC = 2.4 Hz), 136.7 (d, JPC = 1.9 Hz). 31P NMR (CDCl3/H3PO4): δ 21.48 ppm.

Preparation of O,O′-Dibenzoyl-l-tartaric anhydride (d-Bz-L-TA)

d-Bz-L-TA was prepared according to the literature reported method by Bell[26] with a modification. A mixture of l-(+)-tartaric acid (4.3 g, 28.7 mmol) and benzoyl chloride (7.2 mL, 115 mmol) were heated at 130 °C for 15 h. The mixture was cooled to room temperature, and during cooling, a light brown solid was formed. The solid was washed with cold ether (100 mL) to give pure d-Bz-L-TA in 87% yield after recrystallization from toluene. White crystal: mp 196–198 °C [Lit.[43] mp 195–199 °C], 1H NMR (CDCl3, 400 MHz): δ 6.02 (s, 2H), 7.54 (t, J = 7.8 Hz, 4H), 7.70 (t, J = 7.5 Hz, 2H), 8.12 (d, J = 7.1 Hz, 4H); 13C NMR (CDCl3, 101 MHz): δ 165.5, 163.5, 134.7, 130.4, 128.8, 127.2, 72.9.

Bi(OTf)3-Catalyzed Esterification of rac-1 with d-Bz-L-TA for the Preparation of Esters of 2 and 3

Compound rac-1 (1.22 g, 5 mmol) and Bi(OTf)3 (0.49 g, 15 mol %) were dissolved in CH2Cl2 (5 mL). A solution of d-Bz-L-TA (0.85 g, 2.5 mmol) in CH2Cl2 (5 mL) was added dropwise into the reaction mixture. The mixture was stirred at room temperature for 6 h. The solvent was removed in vacuo and the residue was passed through a short column (silica-gel) using EtOAc-MeOH (100:0 to 95:5 v/v) as an eluent to give a crude mixture of 2 and 3 as a white solid and an unreacted compound 1 ((S)-1). The individual diastereomers 2 and 3 were subsequently separated by silica-gel chromatography using a mixture of EtOAc–MeOH (100:0 to 95:5 v/v) as an eluent. Well-separated fractions were collected and evaporated. Physical data for 2 and 3 are described below.

(2R,3R)-2,3-Bis(benzoyloxy)-4-[(R)-(diethoxyphosphoryl)(phenyl)methyl]-4-oxobutanoic Acid (2)

Colorless crystal, mp = 134–136 °C; 1H NMR (CDCl3, 400 MHz): δ =1.06 (t, J = 6.9 Hz, 3H), 1.21 (t, J = 6.9 Hz, 3H), 3.68–3.84 (m, 1H), 3.89–4.04 (m, 1H), 4.05–4.21 (m, 2H), 6.07 (d, J = 13.5 Hz, 1H), 6.39 (d, J = 2.5 Hz, 1H), 6.45 (d, J = 2.5 Hz, 1H), 6.90 (t, J = 7.2 Hz, 1H), 6.98 (t, J = 7.4 Hz, 2H), 7.29 (d, J = 6.2 Hz, 2H), 7.35 (t, J = 7.7 Hz, 2H), 7.48 (t, J = 7.7 Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.86 (d, J = 7.3 Hz, 2H), 8.18 (d, J = 7.3 Hz, 2H). 13C NMR (101 MHz, CDCl3): δ 16.0 (d, J = 6 Hz), 16.3 (d, J = 5 Hz), 64.7 (d, J = 7 Hz), 64.7 (d, J = 7 Hz), 71.4 (d, J = 19 Hz), 127.8 (d, J = 6 Hz), 128.2 128.5, 128.7, 128.8, 128.9, 130.0, 130.0, 130.3, 131.7, 133.2, 133.7, 164.7 (d, J = 11 Hz), 164.9, 165.1, 167.1. 31P NMR (CDCl3/H3PO4): δ 17.84 ppm. [ ∝ ]D20 +20.05 (c 3.7, CHCl3). Anal. Calcd for C29H29O11P: C, 59.57; H, 5.00. Found: C, 59.5; H, 4.9.

(2R,3R)-2,3-Bis(benzoyloxy)-4-[(S)-(diethoxyphosphoryl)(phenyl)methyl]-4-oxobutanoic Acid (3)

Colorless crystal, mp = 125–127 °C; 1H NMR (CDCl3, 400 MHz): 1.01 (t, J = 6.8 Hz, 3H), 1.09 (t, J = 6.8 Hz, 3H), 3.8–3.9 (m, 2H), 3.9–4.01 (m, 2H), 5.91 (d, J = 4. Hz, 1H), 6.15 (d, J = 3.9 Hz, 1H), 6.20 (d, J = 13.4 Hz, 1H), 7.2–7.37 (m, 7H), 7.4–7.5 (m, 4H), 8.04 (t, J = 7.9 Hz, 4H). 13C NMR (101 MHz, CDCl3): δ 16.0 (d, J = 6 Hz), 16.2 (d, J = 5 Hz), 63.5 (d, J = 7 Hz), 63.9 (d, J = 5 Hz), 72.8 (d, J = 6 Hz), 127.5, 127.5, 128.2, 128.3, 128.5, 129.0, 129.7, 130.1, 133.0, 133.1, 133.3, 165.6, 166.4, 166.8 (d, J = 9 Hz), 171.0. 31P NMR (CDCl3/H3PO4): δ 16.23 ppm. [ ∝ ]D20 −28.5 (c 2.1, CHCl3). Anal. Calcd for C29H29O11P: C, 59.57; H, 5.00. Found: C, 59.5; H, 4.8.

(R)-Diethyl 1-Hydroxy-1-phenylmethylphosphonate (R)-1

A solution of ester 2 (0.584 g, 1 mmol) in ethanol (7 mL) containing aqueous ammonia (25%, 6 mL) was left at room temperature for 2 h. The volatiles were removed in vacuo and the residue was passed through a short column (silica-gel) using EtOAc as an eluent to give (R)-1 (0.205 g) in 84% yield.[44] [ ∝ ]D20 +24.52 (c 0.5, CHCl3) (Lit.[42] [α]D20 +28.3 (c 2.1, CHCl3).

(S)-Diethyl 1-Hydroxy-1-phenylmethylphosphonate (S)-1

This compound was obtained from ester 3 as a white solid in a quantitative yield in an analogous manner for the preparation of (R)-1. [α]D20 −21.7 (c 0. 8, CHCl3) (Lit.[42] [α]D20 −15.4 (c 2.6, CHCl3).

Diethyl 1-Hydroxyphosphonates (4 and 7)

The compounds were obtained according to the method reported in our report.[35] Diethyl phosphite (5.65 mL, 40 mmol) was added to a stirred mixture of aldehyde or acetophenone (40 mmol) and MgO (2 g) at ambient temperature (60 °C in the case of acetophenone). The resultant mixture was stirred for 1–12 h (depends on the nature of the carbonyl compound). The mixture was suspended in CH2Cl2 (100 mL) and the filtrate was evaporated. The pure products of 4 and 7 were obtained by recrystallization in CH2Cl2/n-hexane.

Diethyl 1-Hydroxy-1-(4-nitrophenylmethyl)phosphonate (4a)

Pale yellow crystal, mp (n-hexane/CH2Cl2) = 86–87 °C; 1H NMR (CDCl3, 400 MHz) δ 1.30 (m, 6H), 4.03–4.22 (m, 4H), 5.21 (d, J = 12.3 Hz, 1H), 5.37 (s, 1H), 7.65–7.75 (m, 2H), 8.25 (d, J = 8.6 Hz, 2H). 13C NMR (CDCl3, 101 MHz) δ 16.3–16.5 (m), 63.3 (d, JPC = 7.6 Hz), 64.0 (d, JPC = 7.1 Hz), 70.0 (d, JPC = 158.5 Hz), 123.3 (d, JPC = 2.6 Hz), 127.7 (d, JPC = 5.2 Hz), 144.3, 147.5 (d, JPC = 3.7 Hz); 31P NMR (CDCl3/H3PO4) δ 19.74 ppm.

Diethyl 1-Hydroxy-1-(4-methoxyphenylmethyl)phosphonate (4b)

White crystal, mp (n-hexane/CH2Cl2) = 120–122 °C; 1H NMR (CDCl3, 400 MHz) δ 1.30 (t, J = 7.1 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H), 3.65 (s, broad, 1H),1.99–2.12 (m, 2H), 2.71–2.82 (m, 1H), 2.94–3.04 (m, 1H), 3.62 (s, broad, 1H), 3.84 (s, 3H), 3.93–4.04 (m, 1H), 4.04 (m, 3H), 4.98 (d, J = 10.0 Hz, 1H), 6.92 (d, J = 8.5 Hz, 2H), 7.44 (dd, J = 8.6, 1.8 Hz, 2H). 13C NMR (CDCl3, 101 MHz) δ 16.3–16.5 (m), 55.28, 63.0 (d, J = 7.2 Hz), 63.2 (d, J = 7.0 Hz), 70.4 (d, J = 160.7 Hz), 113.8 (d, J = 2.2 Hz), 128.4–124.6 (m), 159.5 (d, J = 2.9 Hz); 31P NMR (CDCl3/H3PO4) δ 25.18 ppm.

Diethyl 1-Hydroxy-1-(1-naphthylmethyl)phosphonate (4c)

White crystal, mp (n-hexane/CH2Cl2) = 115–116 °C; 1H NMR (CDCl3, 400 MHz) δ 1.08 (t, J = 7.0 Hz, 3H). 1.23 (t, J = 7.0 Hz, 3H), 3.75–3.90 (m, 1H), 3.93–4.17 (m, 3H), 4.34 (s, 1H), 5.90 (dd, J = 11.3, 4.2 Hz, 1H), 7.50–7.55 (m, 3H), 7.81–7.96 (m, 3H), 8.12 (d, J = 8.1 Hz, 1H). 13C NMR (CDCl3, 101 MHz) δ 16.2 (d, J = 5.6 Hz), 16.3 (d, J = 5.8 Hz), 63 (d, J = 7.4 Hz), 63.4 (d, J = 7.1 Hz), 67.2 (d, J = 160.8 Hz), 123.7, 125.3 (d, J = 3.4 Hz), 125.5 (d, J = 6.1 Hz), 125.6, 126.0, 128.6, 128.7, 130.8 (d, J = 6.0 Hz), 132.9 (d, J = 1.6 Hz), 133.5 (d, J = 1.7 Hz); 31P NMR (CDCl3/H3PO4) δ 21.70 ppm.

Diethyl 1-Hydroxy-1-(3-phenylallyl)phosphonate (4d)

Pale yellow crystal, mp (n-hexane/CH2Cl2) = 105–106 °C; 1H NMR (CDCl3, 400 MHz,) δ 1.37 (m, 6H), 4.23 (m, 4H), 4.71 (dd, J = 12.9, 6.2 Hz, 1H), 6.30–6.41 (m, 1H), 6.82 (dd, J = 15.9, 4.5 Hz, 1H), 7.24–7.48 (m, 5H). 13C NMR (CDCl3, 101 MHz) δ 16.5, 16.7, 63.1 (d, JPC = 7.3 Hz), 63.2 (d, JPC = 7.1 Hz), 69.5 (d, JPC = 160.7 Hz), 123.7 (d, JPC = 4.6 Hz), 126.6 (d, JPC = 1.6 Hz), 128.6, 127.9, 132.4 (d, JPC = 13.0 Hz), 136.3 (d, JPC = 2.8 Hz); 31P NMR (CDCl3/H3PO4) δ 21.51 ppm.

Diethyl 1-Hydroxy-1-(3-phenylpropyl)phosphonate (4e)

Colorless oil; 1H NMR (CDCl3, 400 MHz) δ 1.28–1.40 (m, 6H), 1.99–2.12 (m, 2H), 2.71–2.82 (m, 1H), 2.94–3.05 (m, 1H), 3.79 (s, broad, 1H), 3.85–3.93 (m, 1H), 4.11–4.25 (m, 4H), 7.19–7.36 (m, 5H); 13C NMR (CDCl3, 101 MHz) δ 16.5 (d, J = 3.8 Hz). 16.5 (d, J = 3.8 Hz), 31.7 (d, J = 14.1 Hz), 33 (d, J = 1.5 Hz), 62.5 (d, J = 7.1 Hz), 62.7 (d, J = 7.1 Hz), 66.8 (d, J = 160.9 Hz), 125.9, 128.4, 128.6, 141.3; 31P NMR (CDCl3/H3PO4) δ 25.18 ppm.

Diethyl 1-Hydroxy-1-phenylethylphosphonate (7)

White crystal, mp (n-hexane/CH2Cl2) = 75–77 °C; 1H NMR (CDCl3,400 MHz) δ 1.22 (t, J = 7.1 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.86 (d, J = 15.4 Hz, 3H), 3.84–4.06 (m, 2H), 4.06–4.16 (m, 2H), 7.27–7.43 (m, 3H),7.64 (d, J = 7.7 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 16.3–16.4 (m), 26.0 (d, JPC = 3.6 Hz), 61.8 (d, JPC = 5.5 Hz), 63.2–63.4 (m), 73.56 (d, JPC = 158.8 Hz), 125.9 (d, JPC = 4.2 Hz), 127.4 (d, JPC = 2.4 Hz), 128.0, 140.9; 31P NMR (CDCl3/H3PO4) δ 23.93 ppm.