Simultaneous Separation and Assignment of Absolute Configuration of γ-Amino-β-Hydroxyphosphonates by NMR Using (S)-Methoxyphenylacetic Acid (MPA)

Angelina González-Morales, Mario Fernández-Zertuche, and Mario Ordóñez*

Centro de Investigaciones Químicas. Universidad Autónoma del Estado de Morelos, Av. Universidad No. 1001. 62210 Cuernavaca, Morelos, México. E-mail: palacios@ciq.uaem.mx

Recibido el 28 de agosto del 2004.
Aceptado el 20 de octubre de 2004.

Abstract

γ-(N,N-disubstituted)amino-β-hydroxypropylphosphonates are important intermediates in the preparation of enantiomerically pure γ-amino-β-hydroxypropylphosphonic acid (GABOB^P), an analogue of γ-amino-β-hydroxybutyric acid (GABOB), which acts in a variety of clinical conditions including schizophrenia, epilepsy, and other character-based disorders including severe convulsions. The synthesis of γ-amino-β-hydroxypropylphosphonic acid (GABOB^P) enantiomerically pure is now an area of great interest, and for this reason, a variety of synthetic routes have been developed.

Key words: γ-amino-β-hydroxypropylphosphonic acid (GABOB^P), assignment of absolute configuration, (S)-methoxyphenylacetic acid (MPA).

Resumen

Los γ-amino-β-hidroxipropilfosfonatos N,N-disubstituidos son importantes intermediarios en la preparación de ácidos γ-amino-β-hidroxipropilfosfónicos enantioméricamente puros (GABOB^P), análogos del ácido γ-amino-β-hidroxibutírico (GABOB), el cual se utiliza en una gran variedad de tratamientos clínicos incluyendo esquizofrenia, epilepsia, y en otras enfermedades incluyendo convulsiones severas. La síntesis de ácidos γ-amino-β-hidroxipropilfosfónicos enantioméricamente puros es ahora una de las áreas de gran interés, motivo por el cual varias rutas de síntesis han sido desarrolladas en los dos últimos años.

Palabras clave: ácido γ-amino-β-hidroxipropilfosfónico (GABOB^P), asignación de la configuración absoluta, ácido (S)-metoxifenilacético (MPA).

Dedicated to the memory of Dr. Raymundo Cruz Almanza

Introduction

The synthesis of both enantiomers of a chiral compound is a very important task in asymmetry synthesis. To attain this goal, traditional methods require the use of either antipode of chiral material to obtain stereoisomers with opposite configurations, where the determination of the optical purity and absolute configuration is a must.

Several analytical instrumental methods exist for the determination of absolute configuration. The most known are X-ray crystallography, followed by chiroptical methods (e.g. circular dichroism (CD) [1], optical rotatory dispersion (ORD), or specific optical rotation) [2]; however, their use is not devoid of some inconveniences and limitations related sometimes to the instrument, such as the specificity of the method used which requires a special training for its use, and in other cases the sample, which in the case of X-ray diffraction requires a monocrystal of good quality. Other methods include specific rotation [3], infrared vibrational [4], and vibrational Raman optical activity [5].

Recently, different approaches to the problem of determining absolute configuration have emerged, based on NMR spectroscopy. These techniques are very appealing, because of the undoubted advantages, which include: (1) the instrument is available in most laboratories; (2) an in-depth understanding of the fundamentals of the method is not necessary to apply this method; (3) a small amount of sample is needed, and this can be recovered; and (4) because the analysis is conducted in solution, it is applicable to both solid and liquid samples. Consequently, in recent years there has been a marked increase in the number of papers describing the use of NMR for the assignment of the absolute configuration of organic compounds [6]. Thus, the determination of the absolute configuration by NMR involves the transformation of the chiral substrate to two different species (e.g. diastereomers). In the classical approach developed by Dale and Mosher [7], this transformation can be carried out; (a) by reaction of the compound of unknown configuration with the two enantiomeric forms of a chiral derivatizing agent (CDA), generally an arylmethoxyacetic acid derivative, such as methoxytrifluoromethylphenylacetic acid (Mosher's reagent) or methoxyphenylacetic acid (MPA), (Figure 1); and (b) by reaction of the substrate in both configurations (racemic mixture) with only one enantiomer of the chiral derivatizing agent (CDA), producing two diastereomeric derivatives. The different orientation of the aromatic shielding cone effect in the diastereomeric derivatives leads to a selective shielding or deshielding of the R₁ or R₂ substituents at the asymmetric center [8]. Thus, the spatial relationship between R₁/R₂ and the aryl ring is correlated to the observed chemical shift change. In the Figure 1, the R₁ substituent of the (R,R) diastereomer is at higher field than the R₂ substituent. Inversely, R₂ in the (S,R) derivative shifts more upfield relative to R₁. Consequently the absolute configuration of the alcohol would be established. Although the nuclei used in NMR experiments include ²H, ¹³C, ³¹P, ²⁹Si, ¹H NMR remains to be the most popular method.

Between the most important chiral derivatizing compounds used for the resolution and assignment of the absolute configuration of secondary alcohols and amines found in the literature include the methoxytrifluoromethylphenylacetic acid (MTPA), methoxyphenylacetic acid (MPA), 9-anthrylmethoxyacetic acid (9-AMA), and Boc-phenylglycine (BPG).

In this paper we show that (S)-methoxyphenylacetic acid [(S)-MPA] is a reliable reagent for the simultaneous separation and determination of the absolute configuration of γ-(N,N-disubtituted)amino-β-hydroxypropylphosphonates, which are important intermediaries for the synthesis of enantiomerically pure γ-amino-β-hydroxypropylphosphonic acid GABOB^P 2 [9], an analogue of (R)-γ-amino-β-hydroxybutyric acid (L-GABOB) 1 [10].

The mixtures of γ-(N,N-disubstituted)amino-β-hydroxypropylphosphonates 3a-e [11] were treated with (S)-methoxyphenylacetic acid [(S)-MPA] in the presence of DCC and DMAP in dichloromethane as solvent at room temperature, to obtain the corresponding mandelates 4 and 5. The mixtures of diastereomers 4a-e and 5a-e were cleanly separated on column chromatography affording in all cases the diastereomer 4a-e as the less polar compound, and the diastereomer 5a-e as the more polar compound. Table 1 summarizes the results obtained.

According to the model developed by Trost [12], it is assumed that the representative conformer in terms of NMR is the one in which the methoxy, carbonyl, and C(1')H groups are situated in the same plane, as observed in the extended Newman projection (Figure 2). In this manner, we expected that in the diastereomers 4a-e, the phenyl group shields the methylene and methyl protons of the CH₂P(O)(OMe)₂ moiety, whereas in the diastereomers 5a-e, the shielding goes over the methylene protons and the protons of the R₁ and R₂ substituents on the CH₂NR₁R₂ fragment.

The comparison of selected chemical shifts in ¹H and ³¹P NMR revealed some significant differences between diastereomers 4a-e and 5a-e. (Figures 3 and 4).

In the analysis of some selected chemical shifts in the ¹H and ³¹P NMR spectra for mandelates 4a-e and 5a-e, we found that in effect, the protons of the CH₂P(O)(OMe)₂ fragment in diastereomers 4a-e are at higher field than those in diastereomers 5a-e (Figures 3 and 4). On the other hand, the protons in the CH₂NR₁R₂ fragments in diastereomers 5a-e are at higher field than those in diasteromers 5a-e. Additionally, the ³¹P NMR chemical shifts for the 4a-e diastereomer appear at a higher field than the 5a-e methylmandelates. This can be explained by the spatial relationship between CH₂P(O)(OMe)₂/CH₂NR₁R₂ fragments and the phenyl group of (S)-methoxyphenylacetic acid (MPA). Further confirmation was given by single crystal X-ray analysis of dimethyl 3-[(S,S)-N-N-bis(α-methylbenzylamino)]-(2R)-hydroxypropylphosphonate (R,S,S)-3d diastereomerically pure[11], obtained after hydrolysis of mandelate (R,S,S,S)-5d with lithium hydroxide.

In conclusion, the (S)-methoxyphenylacetic acid (MPA) method for determining the absolute configuration of chiral compounds, is applicable to γ-(N,N-disubstituted)amino-β-hydroxypropylphosphonates. The spatial relationship between CH₂P(O)(OMe)₂/CH₂NR₁R₂ fragments and the phenyl group in the acid moiety is reflected in the chemical shift differences Δδ through the anisotropic time-weighted shielding effect of the phenyl ring.

Experimental

Optical rotations were taken at 20 °C on a Perkin-Elmer 241 polarimeter in an 1 dm tube; concentrations are given in g/100 mL. For flash chromatography, silica gel 60 (230-400 mesh ASTM, Merck) was used. ¹H NMR spectra were recorded on a Varian (400 MHz) and ¹³C NMR on AMX-500 (100 MHz). The spectra were recorded in D₂O or CDCl₃ solution, using TMS as internal reference. Microanalyses were registered on an Elemental VARIO EL III.

Flasks, stirrings bars, and hypodermic needles used for the generation of organometallic compounds were dried for ca. 12 h at 120 ° C and allowed to cool to room temperature in a dessicator over anhydrous calcium sulphate. Anhydrous solvents (ethers) were obtained by distillation from benzophenone ketyl.

Preparation of the mandelates 4a and 5a. The preparation of (S,S)-4a and (R,S)-5a have been described by Ordóñez et al [9a].

Preparation of mandelates 4b and 5b. The reaction was carried out starting from β-hydroxypropylphosphonate 3b (545 mg, 1.44 mmol), (S)-O-methylmandelic acid (384 mg, 2.3 mmol), 1,3-dicyclohexylcarbodiimide (477 mg, 2.3 mmol), dimethylaminopyridine (27 mg, 0.2 mmol) in dry dichloromethane (20 mL). The crude product was purified by column chromatography using ethyl acetate:hexane (13:9) to afford 270 mg (35%) of diastereomer (S,S,S)-4b (less polar) and 460 mg (61%) of diastereomer (R,S,S)-5b (more polar), both as colorless oils.

Diastereomer (S,S,S)-4b. [α]_D = -25.7 (c = 4.5 CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 1.36 (d, J = 6.8 Hz, 3H, CH₃CH), 1.59 (ddd, J = 16.8, 16.8, 8 Hz, 1H, CH₂P), 2.02 (ddd, J = 19.2, 16.0, 4.4 Hz, 1H, CH₂P), 2.47 (dd, J = 13.2, 6.4 Hz, 1H, CH₂N), 2.72 (ddd, J = 13.2, 6.0, 3.6 Hz, 1H, CH₂N), 3.34 (d, J = 11.0 Hz, 3H, (CH₃O)₂P), 3.39 (s, 3H, CHOCH₃), 3.47 (d, J = 11.0 Hz, 3H, (CH₃O)₂P), 3.57 (d, J = 13.6 Hz, 1H, CH₂Ph), 3.62 (d, J = 13.6 Hz, 1H, CH₂Ph), 3.93 (q, J = 6.8 Hz, 1H, CHCH₃), 4.66 (s, 1H, CHOCH₃), 5.13-5.24 (m, CHOCO), 7.20-7.48 (m, 15H, H_arom). ¹³C NMR (100 MHz, CDCl₃) δ, 13.5 (CH₃CH), 27.5 (d, J = 141.2 Hz, CH₂P(O)), 52.2 (d, J = 6.8 Hz, (CH₃O)₂P), 53.0 (d, J = 11.3 Hz, (CHCH₂N), 55.3 (CH₂Ph), 57.3 (CH₃CH), 57.7 (CHOCH₃), 68.8 (d, J = 3 Hz, CH₂N), 82.5 (CHOCH₃), 126.9 (C_arom), 127.3 (C_arom), 128.0 (C_arom), 128.2 (C_arom), 128.5 (C_arom), 128.7 (C_arom), 128.9 (C_arom), 135.9 (C_arom), 139.6 (C_arom), 142.2 (C_arom), 169.8 (C=O). ³¹P NMR (200 MHz, CDCl₃) δ 30.82.

Diastereomer (R,S,S)-5b. [α]_D = -11.7 (c = 6.5 CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 1.24 (d, J = 6.8 Hz, 3H, CH₃CHPh), 2.00 (ddd, J = 18.8, 9.2, 9.2 Hz, 2H, CH₂P), 2.39 (ddd, J = 14.0, 5.6, 2.8 Hz, 1H, CH₂N), 2.56 (dd, J = 13.6, 6.0 Hz, 1H, CH₂N), 3.23 (d, J = 13.6 Hz, 1H, CH₂Ph), 3.38 (s, 3H, CHOCH₃), 3.45 (d, J = 13.6 Hz, 1H, CH₂Ph), 3.62 (d, J = 11.0 Hz, 3H, (CH₃O)₂P), 3.63 (d, J = 11.0 Hz, 3H, (CH₃O)₂P), 3.74 (q, J = 6.8 Hz, 1H, CHCH₃), 4.72 (s, 1H, CHOCH₃), 5.15-5.26 (m, CHOCO), 7.18-7.48 (m, 15H, H_arom). ¹³C NMR (100 MHz, CDCl₃) δ 15.2 (CH₃CH), 27.7 (d, J = 141.2 Hz, CH₂P(O)), 52.3 (d, J = 6.1 Hz, (CH₃O)₂P), 52.5 (d, J = 6.8 Hz, (CH₃O)₂P), 53.0 (d, J = 12.9 Hz, (CHCH₂N), 55.1 (CH₂Ph), 57.4 (CH₃CH), 58.3 (CHOCH₃), 68.9 (d, J = 4.5 Hz, (CH₂N), 82.4 (CHOCH₃), 126.8 (C_arom), 126.8 (C_arom), 127.3 (C_arom), 127.9 (C_arom), 128.1 (C_arom), 128.5 (C_arom), 128.6 (C_arom), 128.7 (C_arom), 135.9 (C_arom), 139.6 (C_arom), 141.7 (C_arom), 169.7 (C=O). ³¹P NMR (200 MHz, CDCl₃) δ 31.32.

Preparation of mandelates 4c and 5c. The reaction was carried out starting from β-hydroxypropylphosphonate 3c (1.07 g, 2.84 mmol), (S)-O-methylmandelic acid (753 mg, 4.5 mmol), 1,3-dicyclohexylcarbodiimide (935 mg, 4.54 mmol), dimethylaminopyridine (52 mg, 0.43 mmol) in dry dichloromethane (50 mL). The crude product was purified by column chromatography using ethyl acetate:hexane (13:9) to afford 740 mg (50%) of diastereomer (S,R,S)-4c (less polar) and 500 mg (33%) of diastereomer (R,R,S)-5c (more polar), both as colorless oils.

Diastereomer (S,R,S)-4c. [α]_D = +57.3 (c = 4.5, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 1.40 (d, J = 7.0 Hz, 3H, CH₃CHPh), 1.78 (ddd, J = 17.6, 16.0, 7.2 Hz, 1H, CH₂P), 2.05 (ddd, J = 18.4, 15.6, 5.2 Hz, 1H, CH₂P), 2.54 (ddd, J = 13.2, 6.4, 2.9 Hz, 1H, CH₂N), 2.73 (dd, J = 13.6, 5.6 Hz, 1H, CH₂N), 3.39 (d, J = 10.8 Hz, 3H, (CH₃O)₂P), 3.40 (s, 3H, CHOCH₃), 3.49 (d, J = 13.6 Hz, 1H, CH₂Ph), 3.53 (d, J = 10.8 Hz, 3H, (CH₃O)₂P), 3.65 (d, J = 13.6 Hz, 1H, CH₂Ph), 3.90 (q, J = 7.0 Hz, 1H, CHCH₃), 4.58 (s, 1H, CHOCH₃), 5.16-5.26 (m, CHOCO), 7.24-7.36 (m, 15H, H_arom). ¹³C NMR (100 MHz, CDCl₃) δ 15.0 (CH₃CH), 27.7 (d, J = 141.2 Hz, CH₂P(O)), 52.2 (d, J = 6.1 Hz, (CH₃O)₂P), 52.3 (d, J = 6.1 Hz, (CH₃O)₂P), 53.3 (d, J = 10.6 Hz, (CHCH₂N), 55.4 (CH₂Ph), 57.4 (CH₃CH), 58.1 (CHOCH₃), 68.8 (d, J = 3.1 Hz, (CH₂N), 82.4 (CHOCH₃), 126.9 (C_arom), 127.3 (C_arom), 128.0 (C_arom), 128.1 (C_arom), 128.3 (C_arom), 128.5 (C_arom), 128.6 (C_arom), 128.9 (C_arom), 135.9 (C_arom), 139.7 (C_arom), 142.0 (C_arom), 169.8 (C=O). ³¹P NMR (200 MHz, CDCl₃) δ 30.57.

Diastereomer (R,R,S)-5c. [α]_D = +21.7 (c = 5.6, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 1.19 (d, J = 6.8 Hz, 3H, CH₃CHPh), 1.73 (ddd, J = 16.4, 16.4, 8.4 Hz, 1H, CH₂P), 2.07 (ddd, J = 19.6, 16.0, 4.02 Hz, 1H, CH₂P), 2.31 (dd, J = 13.6, 6.4, Hz, 1H, CH₂N), 2.61 (ddd, J = 13.6, 6.0, 3.2 Hz, 1H, CH₂N), 3.41 (s, 3H, CHOCH₃), 3.43 (d, J = 14.0 Hz, 1H, CH₂Ph), 3.48 (d, J = 13.6 Hz, 1H, CH₂Ph), 3.61 (d, J = 11.0 Hz, 3H, (CH₃O)₂P), 3.63 (d, J = 11.0 Hz, 3H, (CH₃O)₂P), 3.75 (q, J = 6.8 Hz, 1H, CHCH₃), 4.74 (s, 1H, CHOCH₃), 5.14-5.26 (m, CHOCO), 7.18-7.48 (m, 15H, H_arom). ¹³C NMR (100 MHz, CDCl₃) δ 13.8 (CH₃CH), 27.9 (d, J = 141.9 Hz, CH₂P(O)), 52.4 (d, J = 6.8 Hz, (CH₃O)₂P), 52.7 (d, J = 6.8 Hz, (CH₃O)₂P), 52.8 (d, J = 12.2 Hz, CHCH₂N), 55.4 (CH₂Ph), 57.5 (CH₃CH), 57.6 (CHOCH₃), 68.7 (d, J = 4.6 Hz, (CH₂N), 82.7 (CHOCH₃), 126.9 (C_arom), 127.0 (C_arom), 127.5 (C_arom), 128.1 (C_arom), 128.1 (C_arom), 128.3 (C_arom), 128.7 (C_arom), 128.8 (C_arom), 128.9 (C_arom), 136.0 (C_arom), 139.7 (C_arom), 142.2 (C_arom), 170.0 (C=O). ³¹P NMR (200 MHz, CDCl₃) δ 30.99.

Preparation of mandelates 4d and 5d. The reaction was carried out starting from β-hydroxypropylphosphonate 3d (450 mg, 1.15 mmol), (S)-O-methylmandelic acid (306 mg, 1.84 mmol), 1,3-dicyclohexylcarbodiimide (380 mg, 1.84 mmol), dimethylaminopyridine (21 mg, 0.17 mmol) in dry dichloromethane (20 mL). The crude product was purified by column chromatography using ethyl acetate:hexane (13:9) to afford 83 mg (13%) of diastereomer (S,S,S,S)-4d (less polar) and 403 mg (65%) of diastereomer (R,S,S,S)-5d (more polar), both as colorless oils.

Diastereomer (S,S,S,S)-4d. [α]_D = -20.9 (c = 3.5, CHCl₃). ¹H NMR (400 MHz, CDCl₃) δ 1.39 (d, J = 7.2 Hz, 6H, CH₃CHPh), 1.82 (ddd, J = 18.8, 16.0, 4.4 Hz, 2H, CH₂P), 2.53 (dd, J = 14.4, 6.8 Hz, 1H, CH₂N), 2.91 (ddd, J = 14.4, 6.8, 3.6 Hz, 1H, CH₂N), 3.33 (d, J = 10.8 Hz, 3H, (CH₃O)₂P), 3.43 (s, 3H, CH₃OCH), 3.46 (d, J = 10.8 Hz, 3H, (CH₃O)₂P), 3.95 (q, J = 6.8 Hz, 2H, CHCH₃), 4.73 (s, 1H, CHOCH₃), 5.00 (m, 1H, CHOCO), 7.20-7.48 (m, 15H, H_arom). ¹³C NMR (100 MHz, CDCl₃) δ 18.3 (CH₃CH), 27.4 (d, J = 141.1 Hz, CH₂PO), 49.9 (d, J = 12.2 Hz, (CHCH₂N), 52.3 (d, J = 5.3 Hz, (CH₃O)₂P), 52.3 (d, J = 6.1 Hz, (CH₃O)₂P), 57.6 (CHCH₃), 58.3 (CHCH₂P), 70.2 (d, J = 3.1 Hz, (CH₂N), 82.7 (CHOCH₃), 126.9 (C_arom), 127.0 (C_arom), 127.5 (C_arom), 127.5 (C_arom), 127.9 (C_arom), 128.0 (C_arom), 128.3 (C_arom), 128.6 (C_arom), 128.7 (C_arom), 128.8 (C_arom), 136.1 (C_arom), 144.0 (C_arom), 170.0 (C=O). ³¹P NMR (200 MHz, CDCl₃) δ 30.91.

Preparation of mandelates 4e and 5e. The reaction was carried out starting from β-hydroxypropylphosphonate 3e (530 mg, 1.35 mmol), (S)-O-methylmandelic acid (360 mg, 2.17 mmol), 1,3-dicyclohexylcarbodiimide (447 mg, 2.17 mmol), dimethylaminopyridine (25 mg, 0.20 mmol) in dry dichloromethane (30 mL). The crude product was purified by column chromatography using ethyl acetate:hexane (13:9) to afford 489 mg (67%) of diastereomer (S,R,R,S)-4e (less polar) and 154 mg (21%) of diastereomer (R,R,R,S)-5e (more polar), both as colorless oils.

Diastereomer (S,R,R,S)-4e. [α]_D = +23.5 (c = 2.9, CH₃Cl). ¹H NMR (400 MHz, CDCl₃) δ 1.38 (d, J = 6.8 Hz, 6H, CH₃CHPh), 1.82 (ddd, J = 23.6, 15.6, 7.6 Hz, 1H, CH₂P), 2.27 (ddd, J = 19.2, 16.0, 4.8 Hz, 1H, CH₂P), 2.61 (ddd, J = 14.4, 9.6, 3.2 Hz, 1H, CH₂N), 2.89 (dd, J = 14.4, 6.4 Hz, 1H, CH₂N), 3.37 (s, 3H, CH₃OCH), 3.39 (d, J = 11.6 Hz, 3H, (CH₃O)₂P), 3.56 (d, J = 11.6 Hz, 3H, (CH₃O)₂P), 3.91 (q, J = 6.8 Hz, 2H, CHCH₃), 4.51 (s, 1H, CHOCH₃), 5.08-5.17 (m, 1H, CHOCO), 7.21-7.36 (m, 15H, H_arom). ¹³C NMR (100 MHz, CDCl₃) δ 19.2 (CH₃CH), 27.5 (d, J = 141.2 Hz, CH₂PO), 49.3 (d, J = 10.6 Hz, (CHCH₂N), 52.2 (d, J = 6.1 Hz, (CH₃O)₂P), 52.4 (d, J = 6.8 Hz, (CH₃O)₂P), 57.3 (CHCH₃), 58.5 (CHCH₂P), 70.2 (d, J = 3.0 Hz, CH₂N), 82.3 (CHOCH₃), 126.8 (C_arom), 127.3 (C_arom), 127.8 (C_arom), 127.9 (C_arom), 128.2 (C_arom), 128.4 (C_arom), 128.5 (C_arom), 128.6 (C_arom), 135.9 (C_arom), 143.9 (C_arom), 169.9 (C=O). ³¹P NMR (200 MHz, CDCl₃) δ 31.09.

Diastereomer (R,R,R,S)-5e. [α]_D = +18.1 (c = 3.3, CH₃Cl). ¹H NMR (400 MHz, CDCl₃) δ 1.22 (d, J = 6.8 Hz, 6H, CH₃CHPh), 1.44 (ddd, J = 25.2, 16.0, 8.8 Hz, 1H, CH₂P), 1.88 (ddd, J = 19.2, 15.6, 3.6 Hz, 1H, CH₂P), 2.36 (dd, J = 14.4, 7.2 Hz, 1H, CH₂N), 2.71 (ddd, J = 14.4, 6.4, 3.6 Hz, 1H, CH₂N), 3.42 (s, 3H, CH₃OCH), 3.60 (d, J = 10.8 Hz, 3H, (CH₃O)₂P), 3.61 (d, J = 10.8 Hz, 3H, (CH₃O)₂P), 3.82 (q, J = 6.8 Hz, 2H, CHCH₃), 4.74 (s, 1H, CHOCH₃), 4.92-5.03 (m, 1H, CHOCO), 7.10-7.45 (m, 15H, H_arom). ¹³C NMR (100 MHz, CDCl₃) δ 18.0 (CH₃CH), 27.6 (d, J = 141.9 Hz, CH₂P(O)), 49.8 (d, J = 12.9 Hz, CHCH₂N), 52.4 (d, J = 6.1 Hz, (CH₃O)₂P), 52.7 (d, J = 6.1 Hz, (CH₃O)₂P), 57.6 (CH₃CH), 58.3 (CHCH₂P), 69.8 (d, J = 4.6 Hz, CH₂N), 82.7 (CHOCH₃), 126.9 (C_arom), 127.4 (C_arom), 127.7 (C_arom), 1278 (C_arom), 128.0 (C_arom), 128.2 (C_arom), 128.3 (C_arom), 128.7 (C_arom), 128.9 (C_arom), 136.2 (C_arom), 144.1 (C_arom), 170.1 (C=O). ³¹P NMR (200 MHz, CDCl₃) δ 31.39.

Acknowledgments

We wish to thank CONACYT of Mexico, for financial support via grant 41657-Q for this work. One of us, AGM, also wishes to thank CONACYT for a Graduate Scholarship.

References

1. (a) Berova, N.; Nakanishi, K.; Woody, R. W. Circular Dichroism: Principles and Applications; Wiley-VCH Publishers: New York, 2000.         [ Links ] (b) Lightner, D.; Gurst, J. E. Organic Conformational Analysis and Stereochemistry from Circular Dichroism Spectroscopy; Wiley-VCH Publishers: New York, 2000.         [ Links ]

2. (a) Charney, E. Molecular Basis of Optical Activity: Optical Rotatory Dispersion and Circular Dichroism; Krieger Pub Co. 1985.         [ Links ] (b) Cooley, J. H.; Williams, R. V. J. Chem. Ed. 1997, 74, 585-586.         [ Links ]

3. Polavarapu, P. L. Chirality 2002, 14, 768-781.         [ Links ]

4. Wang, F.; Wang, Y.; Polavarapu, P. L.; Li, T.; Drabowics, J.; Pietrusiewcs, K. M.; Zygo, K. J. Org. Chem. 2002, 67, 6539-6541.         [ Links ]

5. Constante, J.; Hecht, L.; Polavarapu, P. L.; Collet, A.; Barron, L. D. Angew. Chem. Int. Ed. Engl. 1997, 36, 885-887.         [ Links ]

6. (a) Seco, J. M.; Quiñoá, E.; Riguera, R. Chem. Rev. 2004, 104, 17-117 and references herein.         [ Links ] (b) Seco, J. M.; Tseng, L.-H.; Godejohann, M.; Quiñoá, E.; Riguera, R. Tetrahedron:Asymmetry 2002, 13, 2149-2153.         [ Links ] (c) Seco, J. M.; Quiñoá, E.; Riguera, R. Tetrahedron: Asymmetry 2001, 12, 2915-2925.         [ Links ] (d) Latypov, S. K.; Seco, J. M.; Quiñoá, E.; Riguera, R. J. Org. Chem. 1996, 61, 8569-8577.         [ Links ]

7. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512-519.         [ Links ]

8. Lewis, R. A.; Korpium, O.; Mislow, K. J. Am. Chem. Soc. 1968, 90, 4847-4853.         [ Links ]

9. (a) Ordóñez, M.; González-Morales, A.; Ruiz, C.; De la Cruz-Cordero, R.; Fernández-Zertuche, M.Tetrahedron: Asymmetry 2003, 14, 1775-1779.         [ Links ] (b) Yuan, C.; Wang, K.; Li, J.; Li, Z. Phosphorus, Sulfur Silicon and Relat. Elem. 2002, 177, 2391-2397.         [ Links ] (c) Yuan, C.; Wang, K.; Li, J.; Li, Z. Heteroatom Chem. 2002, 13, 153-156.         [ Links ] (d) Wroblewsky, A. E.; Halajewska-Wosik, A. Tetrahedron: Asymmetry 2003, 14, 3359-3363.         [ Links ] (e) Very recently, enzymatic synthesis of (S)-phosphogabob was reported: Wang, K.; Zhang, Y.; Yuan, C. Org. Biomol. Chem. 2003, 1, 3564-3569.         [ Links ]

10. Jain, R. P.; Williams, R. M. Tetrahedron 2001, 57, 6505-6509 and references herein.         [ Links ]

11. The γ-(N,N-disubstituted)amino-β-hydroxyphosphonates 3a-e were prepared by reduction of the corresponding γ-(N,N-disubstituted)amino-β-ketophosphonates. Ordóñez, M.; González-Morales, A.; Salazar-Fernández, H. Tetrahedron:Asymmetry 2004, 15, 2719-2725.         [ Links ]

12 (a) Trost, B. M.; Belletire, J. L; Godleski, S.; McDougal, P. G.; Balkovec, J. M. J. Org. Chem. 1986, 51, 2370-2374.         [ Links ] (b) Trost, B. M.; Bunt, R. C.; Pulley, S. R. J. Org. Chem. 1994, 59, 4202-4205.         [ Links ]