Efficient Stereodivergent Synthesis of cis-(2R,4S)- and trans-(2R,4R)-4-Phosphonomethyl-2-piperidinecarboxylic Acids from the Same Chiral Imine Derived from (R)-Glyceraldehyde

Pablo Etayo; Ramón Badorrey; María D. Díaz-de-Villegas; José A. Gálvez

doi:10.1055/s-2006-950272

LETTER

Efficient Stereodivergent Synthesis of cis-(2R,4S)- and trans-(2R,4R)-4-Phosphonomethyl-2-piperidinecarboxylic Acids from the Same Chiral Imine Derived from (R)-Glyceraldehyde

Pablo Etayo, Ramón Badorrey, María D. Díaz-de-Villegas*, José A. Gálvez*
Departamento de Química Orgánica, Instituto de Ciencia de Materiales de Aragón, Instituto Universitario de Catálisis Homogénea, Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain
Fax: +34(97)6761202; e-Mail: loladiaz@unizar.es; e-Mail: jagl@unizar.es;

Abstract

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Abstract

Two diastereomeric 4-phosphonomethyl-2-piperidinecarboxylic acids have been prepared in ca. 20% overall yield starting from the easily accessible N-[(S)-1-phenylethyl]-(S)-2,3-di-O-benzylglyceraldimine. The key step for the stereodivergent synthesis is the asymmetric reduction of an exocyclic C=C double bond on a highly functionalized chiral intermediate. This intermediate is obtained by Horner-Wadsworth-Emmons (HWE) reaction of a piperidone derived from the cycloadduct obtained in the aza Diels-Alder reaction between N-[(S)-1-phenylethyl]-(S)-2,3-di-O-benzylglyceraldimine and Danishefsky’s diene. In these synthetic routes two new stereogenic centres are created on the piperidine ring with very good or excellent stereoselectivity.

Key words

amino acids - asymmetric synthesis - phosphonates - piperidines - stereoselective reductions

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References

References and Notes

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In the absence of LiCl the HWE olefination reaction using DBU as base did not take place.

( E / Z )-( R )-2-[( S )-1,2-Dibenzyloxyethyl]-4-diethylphos-phonomethylene-1-[(S)-1-phenylethyl]piperidine (5). A 2 M solution of LDA in heptane-THF-ethylbenzene (1.75 mL, 3.5 mmol) was added to a solution of tetraethyl methylenediphosphonate (0.86 g, 3.0 mmol) in anhydrous THF (10 mL) at r.t. under argon and the mixture was stirred for 10 min. A solution of compound 4 (0.44 g, 1.0 mmol) in anhydrous THF (20 mL) was added and the resulting mixture was stirred at r.t. for 23 h (until conversion was complete as monitored by TLC). The reaction was quenched with H₂O (30 mL) and extracted with CH₂Cl₂ (3 × 50 mL). The combined organic extracts were dried over anhydrous MgSO₄, filtered, evaporated under reduced pressure and subsequently chromatographed on silica gel (EtOAc) to yield compound 5 (520 mg, 90%) as an 84:16 mixture of E/Z diastereoisomers, respectively. Data for E diastereoisomer: IR (neat): 1631, 1241 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ = 1.21 (d, J = 6.8 Hz, 3 H), 1.24 (t, J = 7.7 Hz, 3 H), 1.24 (t, J = 7.7 Hz, 3 H), 2.11 (dd, J = 13.4, 8.0 Hz, 1 H), 2.27 (ddd, J = 12.2, 7.3, 3.1 Hz, 1 H), 2.37 (ddd, J = 11.8, 3.3, 3.3 Hz, 1 H), 2.56-2.65 (m, 2 H), 2.70-2.78 (m, 1 H), 2.99-3.05 (m, 1 H), 3.60 (dd, J = 10.6, 6.5 Hz, 1 H), 3.90 (dd, J = 10.6, 1.8 Hz, 1 H), 3.89-3.96 (m, 1 H), 3.98 (q, J = 7.7 Hz, 4 H), 4.06 (q, J = 6.8 Hz, 1 H), 4.49 (d, J = 12.1 Hz, 1 H), 4.54 (d, J = 12.1 Hz, 1 H), 4.62 (d, J = 11.9 Hz, 1 H), 4.74 (d, J = 11.9 Hz, 1 H), 5.30 (d, J = 19.4 Hz, 1 H), 7.15-7.38 (m, 15 H); ¹³C NMR (100 MHz, CDCl₃): δ = 13.2, 16.4 (d, J = 6.5 Hz), 31.0 (d, J = 6.9 Hz), 37.9 (d, J = 23.6 Hz), 44.6, 56.5, 59.0, 61.2 (d, J = 2.1 Hz), 61.2 (d, J = 2.1 Hz), 70.9, 72.7, 73.5, 78.1, 110.1 (d, J = 186.7 Hz), 126.6, 127.4, 127.5, 127.6, 127.7, 127.8, 128.1, 128.3, 128.4, 138.2, 138.8, 144.5, 163.2 (d, J = 6.9 Hz); ³¹P NMR (162 MHz, CDCl₃): δ = 17.9; HRMS (ESI⁺): m/z [M + H⁺] calcd for C₃₄H₄₅NO₅P: 578.3030; found: 578.3034.

Following complete assignment of the ¹H resonances by 2D NMR studies (COSY, HSQC), the E/Z configuration of the exocyclic double bond was unequivocally determined by a series of selective 1D gradient-enhanced nuclear Overhauser enhancement (ge-1D NOESY) experiments. ³ J _C-P values measured in ¹³C NMR spectra provided additional support to the assignment. Diastereomeric ratios were determined by ¹H and ³¹P analyses of the crude reaction mixture.

(2 R ,4 S )-2-[( S )-1,2-Dibenzyloxyethyl]-4-diethylphos-phonomethyl-1-[(S)-1-phenylethyl]piperidine (6). To an E/Z mixture (84:16) of compound 5 (0.58 g, 1 mmol) dissolved in absolute EtOH (18 mL) was added PtO₂ (0.06 g, 0.25 mmol) and the mixture was hydrogenated under an atmosphere of H₂ with shaking at r.t. for 8 h. The reaction mixture was filtered through Celite^® 545 and concentrated in vacuo to afford an 85:15 mixture of 6 and 9, respectively. Purification of the residue by silica gel column chromatog-raphy (EtOAc ® EtOAc-EtOH, 4:1) gave 9 (77 mg, 13%) and 6 (435 mg, 74%) as oils. Data for 6: [α]_D ²⁵ +13.8 (c 1.07, CHCl₃); IR (neat): 1247 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ = 0.80-2.65 (m, 2 H), 1.16 (d, J = 6.8 Hz, 3 H), 1.25 (t, J = 6.3 Hz, 3 H), 1.25 (t, J = 6.0 Hz, 3 H), 1.51-1.73 (m, 4 H), 2.04 (ddd, J = 11.6, 11.6, 1.9 Hz, 1 H), 2.17 (dd, J = 12.6, 2.1 Hz, 1 H), 2.34 (ddd, J = 11.6, 3.0, 3.0 Hz, 1 H), 2.74 (ddd, J = 11.1, 4.0, 2.1 Hz, 1 H), 3.65 (dd, J = 10.6, 7.9 Hz, 1 H), 3.96-4.06 (m, 5 H), 4.07-4.14 (m, 2 H), 4.49 (d, J = 12.2 Hz, 1 H), 4.59 (d, J = 12.2 Hz, 1 H), 4.70 (d, J = 11.9 Hz, 1 H), 4.80 (d, J = 11.9 Hz, 1 H), 7.15-7.41 (m, 15 H); ¹³C NMR (100 MHz, CDCl₃): δ = 6.7, 15.4 (d, J = 6.0 Hz), 29.9 (d, J = 239.3 Hz), 30.7 (d, J = 4.0 Hz), 32.5 (d, J = 12.3 Hz), 33.3 (d, J = 13.6 Hz), 43.8, 52.7, 58.0, 60.2 (d, J = 6.6 Hz), 60.4 (d, J = 6.5 Hz,), 70.4, 71.7, 72.4, 76.6, 125.3, 126.4, 126.5, 126.5, 126.5, 126.7, 126.9, 127.3, 127.4, 137.4, 138.0, 142.6; ³¹P NMR (162 MHz, CDCl₃): δ = 31.4; HRMS (ESI⁺): m/z [M + H⁺] calcd for C₃₄H₄₇NO₅P: 580.3186; found: 580.3192.

(2 R ,4 S )-1- tert -Butoxycarbonyl-4-diethylphosphono-methyl-2-[( S )-1,2-dihydroxyethyl]piperidine (7). Chromatography eluent: (EtOAc ® EtOAc-EtOH, 4:1); yield: 79%; oil, [α]_D ²⁵ +44.4 (c 0.59, CHCl₃); IR (neat): 3404, 1684, 1249 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ = 1.17-1.26 (m, 1 H), 1.31 (t, J = 7.1 Hz, 6 H), 1.42-1.48 (m, 1 H), 1.45 (s, 9 H), 1.65-1.82 (m, 2 H), 1.82-1.89 (m, 1 H), 1.91-2.02 (m, 1 H), 1.98-2.10 (m, 1 H), 3.29-3.38 (m, 1 H), 3.45-3.52 (m, 1 H), 3.53 (dd, J = 11.8, 6.1 Hz, 1 H), 3.58 (dd, J = 11.8, 5.4 Hz, 1 H), 3.66-3.72 (m, 1 H), 3.78-3.85 (m, 1 H), 4.08 (q, J = 7.1 Hz, 4 H); ¹³C NMR (100 MHz, CDCl₃): δ = 16.4 (d, J = 5.9 Hz), 27.7 (d, J = 4.1 Hz), 28.3, 30.8 (d, J = 10.1 Hz), 32.1 (d, J = 12.1 Hz), 32.4 (d, J = 139.8 Hz), 41.5, 56.6, 61.5 (d, J = 6.0 Hz), 63.9, 74.1, 80.7, 158.3; ³¹P NMR (162 MHz, CDCl₃): δ = 30.3; HRMS (ESI⁺): m/z [M + Na⁺] calcd for C₁₇H₃₄NO₇PNa: 418.1965; found: 418.1973.

Representative Procedure for N- and O-Debenzylation: To a solution of the corresponding 2-[(S)-1,2-dibenzyl-oxyethyl]-4-diethylphosphonomethyl-1-[(S)-1-phenyl-ethyl]piperidine (0.44 g, 0.75 mmol) in absolute ethanol (12 mL) were added successively Boc₂O (0.65 g, 3.0 mmol) and Pd(OH)₂/C (20%, 0.22 g) and the mixture was stirred at r.t. under an atmosphere of H₂for 48 h. After completion of the reaction, the mixture was filtered through Celite^® 545 and concentrated in vacuo. The residue was purified by silica gel flash column chromatography.

Representative Procedure for Oxidative Cleavage: NaIO₄ (0.57 g, 2.37 mmol) was added to a stirred solution of the corresponding 1-tert-butoxycarbonyl-4-diethylphosphono-methyl-2-[(S)-1,2-dihydroxyethyl]piperidine (0.25 g, 0.59 mmol) in MeCN-CCl₄-H₂O (2:2:3, 20 mL). After being vigorously stirred for 5 min, anhydrous RuCl₃ (0.006 g, 0.030 mmol) was added to the mixture and stirring was continued for 2 h. The reaction mixture was extracted with CH₂Cl₂(3 × 20 mL) and the combined organic layers were dried over anhydrous MgSO₄ and the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: EtOAc-EtOH, 4:1).

(2 R ,4 S )-1- tert -Butoxycarbonyl-4-diethylphosphono-methylpipecolic Acid (8).Yield 76%; oil, [α]_D ²⁵ +12.5 (c 1.00, CHCl₃); IR (neat) 3600-2300, 1726, 1692, 1247 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ = 1.27 (t, J = 7.0 Hz, 3 H), 1.28 (t, J = 7.1 Hz, 3 H), 1.40 (s, 9 H), 1.54-1.63 (m, 1 H), 1.69-1.77 (m, 1 H), 1.76-1.92 (m, 2 H), 1.91-2.01 (m, 1 H), 2.03-2.19 (m, 2 H), 3.31 (br dd, J = 10.4, 10.4 Hz, 1 H), 3.58-3.67 (m, 1 H), 4.01-4.12 (m, 4 H), 4.35-4.44 (m, 1 H), 8.54-9.00 (br s, 1 H); ¹³C NMR (100 MHz, CDCl₃): δ = 16.2 (d, J = 5.9 Hz), 26.0 (d, J = 4.4 Hz), 28.3, 28.7 (d, J = 173.1 Hz), 29.3 (d, J = 6.9 Hz), 32.2 (d, J = 3.1 Hz), 37.9, 53.0, 61.9 (d, J = 6.7 Hz), 62.0 (d, J = 6.6 Hz), 80.2, 155.8, 174.9; ³¹P NMR (162 MHz, CDCl₃): δ = 31.5; HRMS (ESI⁺): m/z [M + Na⁺] calcd for C₁₆H₃₀NO₇PNa: 402.1652; found: 402.1647.

Representative Procedure for Total Hydrolysis: A mixture of the corresponding 1-tert-butoxycarbonyl-4-diethylphosphonomethylpipecolic acid (0.16 g, 0.4 mmol) and 6 N aq HCl (9 mL) was heated under reflux for 16 h, after which time the mixture was concentrated in vacuo. The resulting residue was dissolved in 70% aq EtOH (3 mL) and propylene oxide (0.4 mL) was added. After stirring for 10 min at r.t. the reaction mixture was washed with CH₂Cl₂(15 mL) and the aqueous layer was evaporated in vacuo. The residue was purified by silica gel flash chromatography (MeCN-H₂O, 4:1® MeCN-H₂O, 1:1) and lyophilized.

(2 R ,4 S )-4-Phosphonomethylpipecolic Acid (1). Yield 69%; white solid, mp = 292-294 °C; [α]_D ²⁵ -3.54 (c 1.00, H₂O); IR (KBr): 3700-2200, 3399, 1732, 1282 cm^-1; ¹H NMR (400 MHz, D₂O): δ = 1.35-1.50 (m, 1 H), 1.42 (ddd, J = 12.9, 12.9, 12.9 Hz, 1 H), 1.64 (ddd, J = 17.6, 14.5, 6.8 Hz, 1 H), 1.69 (ddd, J = 17.6, 14.5, 5.7 Hz, 1 H), 1.96-2.10 (m, 1 H), 2.19 (br d, J = 14.4 Hz, 1 H), 2.44 (br dd, J = 12.9, 1.7 Hz, 1 H), 3.05 (ddd, J = 12.9, 12.9, 2.9 Hz, 1 H), 3.97 (ddd, J = 12.9, 3.7, 1.8 Hz, 1 H), 3.64 (dd, J = 12.9, 3.0 Hz, 1 H); ¹³C NMR (100 MHz, D₂O): δ = 29.0 (d, J = 8.8 Hz), 30.4 (d, J = 3.6 Hz), 34.2 (d, J = 13.0 Hz), 34.3 (d, J = 132.6 Hz), 44.3, 59.2, 174.3; ³¹P NMR (162 MHz, D₂O): δ = 23.2; HRMS (ESI⁺): m/z [M + Na⁺] calcd for C₇H₁₄NO₅PNa: 246.0502; found: 246.0501; Anal. Calcd for C₇H₁₄NO₅P: C, 37.67; H, 6.32; N, 6.28. Found: C, 37.58; H, 6.37; N, 6.23.

<A NAME="RD15606ST-18">18</A> Martin I. Anvelt J. Vares L. Kühn I. Claesson A. Acta Chem. Scand. 1995, 49: 230

<A NAME="RD15606ST-19">19</A> Carey FA. Sundberg RJ. Advanced Organic Chemistry: Structure and Mechanisms, Part A 4th ed.: Springer Science; New York: 2000.

<A NAME="RD15606ST-20">20</A> Badorrey R. Cativiela C. Díaz-de-Villegas MD. Gálvez JA. Tetrahedron 2002, 58: 341

(2 R ,4 R )-2-[( S )-1,2-Dibenzyloxyethyl]-4-diethylphos-phonomethyl-1-[( S )-1-phenylethyl]piperidine (9). A 0.1 M solution of L-Selectride^® in THF (4 mL, 4 mmol) was added drop wise to an E/Z mixture (84:16) of 5 (0.58 g, 1 mmol) dissolved in anhydrous THF (23 mL) at -20 °C under argon and the mixture was stirred for 48 h at -20 °C. The reaction mixture was allowed to warm to 0 °C and then sat. aq NH₄Cl (8.6 mL) was added carefully with stirring. After extraction with Et₂O(3 × 50 mL), the combined organic layers were dried over anhydrous MgSO₄ and the solvent evaporated in vacuo to afford a crude product in which the cis diastereoisomer 6 was not detected. The residue was purified by silica gel flash column chromatography (EtOAc ® EtOAc-EtOH, 4:1) to give 9 (412 mg, 70%) as an oil. [α]_D ²⁵ -20.1 (c 1.51, CHCl₃); IR (neat): 1242 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ = 1.24 (t, J = 7.1 Hz, 6 H), 1.25 (t, J = 6.6 Hz, 3 H), 1.23-1.27 (m, 1 H), 1.49-1.55 (m, 1 H), 1.54-1.70 (m, 4 H), 2.03-2.15 (m, 1 H), 2.50-2.62 (m, 2 H), 3.15-3.21 (m, 1 H), 3.58 (dd, J = 10.7, 5.6 Hz, 1 H), 3.73 (dd, J = 10.7, 2.2 Hz, 1 H), 3.96-4.06 (m, 6 H), 4.47 (d, J = 12.5 Hz, 1 H), 4.50 (d, J = 12.5 Hz, 1 H), 4.61 (d, J = 11.7 Hz, 1 H), 4.76 (d, J = 11.7 Hz, 1 H), 7.11-7.39 (m, 15 H); ¹³C NMR (100 MHz, CDCl₃): δ = 16.4 (d, J = 6.0 Hz), 19.0, 27.0 (d, J = 4.0 Hz), 31.3 (d, J = 7.7 Hz), 31.9 (d, J = 140.2 Hz), 33.0 (d, J = 11.5 Hz), 42.3, 54.1, 59.1, 61.2 (d, J = 6.1 Hz), 61.3 (d, J = 6.0 Hz), 71.5, 72.7, 73.3, 78.2, 126.4, 127.2, 127.3, 127.4, 127.5, 127.7, 128.0, 128.2, 128.3, 138.5, 139.1, 146.9; ³¹P NMR (162 MHz, CDCl₃): δ = 31.8; HRMS (ESI⁺): m/z [M + H⁺] calcd for C₃₄H₄₇NO₅P: 580.3186; found: 580.3174.

(2 R ,4 R )-1- tert -Butoxycarbonyl-4-diethylphosphono-methyl-2-[( S )-1,2-dihydroxyethyl]piperidine (10). Chromatography eluent: EtOAc-EtOH, 4:1; yield 76%; oil, [α]_D ²⁵ +37.9 (c 0.80, CHCl₃); IR (neat): 3414, 1683, 1252 cm^-1; ¹H NMR (400 MHz, CDCl₃): δ = 1.04-1.17 (m, 1 H), 1.26 (t, J = 7.1 Hz, 6 H), 1.28-1.35 (m, 1 H), 1.39 (s, 9 H), 1.48-1.67 (m, 2 H), 1.76 (br d, J = 12.7 Hz, 1 H), 1.91 (br d, J = 12.7 Hz, 1 H), 2.05-2.23 (m, 1 H), 3.03 (br dd, J = 12.6, 12.6 Hz, 1 H), 3.48 (dd, J = 11.1, 4.3 Hz, 1 H), 3.59 (dd, J = 11.1, 2.6 Hz, 1 H), 3.83-3.90 (m, 1 H), 3.88-3.97 (m, 1 H), 4.02 (q, J = 7.1 Hz, 4 H), 4.24-4.32 (m, 1 H); ¹³C NMR (100 MHz, CDCl₃): δ = 16.3 (d, J = 6.0 Hz), 26.6 (d, J = 3.1 Hz), 28.3, 32.7 (d, J = 139.3 Hz), 33.1 (d, J = 12.2 Hz), 34.3 (d, J = 9.9 Hz), 40.7, 50.8, 61.5 (d, J = 1.9 Hz), 61.6 (d, J = 1.9 Hz), 64.0, 72.5, 80.0, 156.5; ³¹P NMR (162 MHz, CDCl₃): δ = 30.9; HRMS (ESI⁺): m/z [M + Na⁺] calcd for C₁₇H₃₄NO₇PNa: 418.1965; found: 418.1976.

(2 R ,4 R )-1- tert -Butoxycarbonyl-4-diethylphosphono-methylpipecolic Acid (11). Yield 73%; oil, [α]_D ²⁵ +13.0 (c 1.09, CHCl₃); IR (neat): 3700-2300, 1732, 1699, 1251 cm^-1; ¹H NMR (mixture of conformers) (400 MHz, CDCl₃): δ = 1.07-1.22 (m, 1 H), 1.31 (t, J = 7.0 Hz, 3 H), 1.31 (t, J = 7.1 Hz, 3 H), 1.32-1.50 (m, 1 H), 1.42 and 1.45 (s, 9 H), 1.60-1.79 (m, 2 H), 1.82-1.95 (m, 2 H), 2.38-2.46 (m, 1 H), 2.98 and 3.07 (ddd, J = 12.9, 12.9, 1.3 Hz and J = 13.0, 13.0, 1.5 Hz, 1 H), 3.94 and 4.00-4.07 (br dd, J = 13.0, 1.3 Hz and m, 1 H), 4.09 (q, J = 7.1 Hz, 4 H), 4.71-4.76 and 4.92-4.96 (m, 1 H); ¹³C NMR (mixture of conformers) (100 MHz, CDCl₃): δ = 16.3 (d, J = 6.1 Hz), 27.6 (d, J = 3.3 Hz) and 27.7 (d, J = 3.4 Hz), 28.2 and 28.3, 32.0 (d, J = 140.0 Hz) and 32.1 (d, J = 139.9 Hz), 32.3 (d, J = 10.9 Hz) and 32.4 (d, J = 9.3 Hz), 34.2 (d, J = 13.0 Hz), 40.5 and 41.5, 53.5 and 54.6, 61.8 (d, J = 6.7 Hz), 61.9 (d, J = 6.5 Hz), 79.9 and 80.1, 155.3 and 155.9, 172.9 and 173.5; ³¹P NMR (mixture of conformers) (162 MHz, CDCl₃): δ = 31.3 and 31.5; HRMS (ESI⁺): m/z [M + Na⁺] calcd for C₁₆H₃₀NO₇PNa: 402.1652; found: 402.1651.

(2 R ,4 R )-4-Phosphonomethylpipecolic Acid (2). Yield 74%; white solid, mp (dec) = 158-160 °C; [α]_D ²⁵ -25.3 (c 0.69, H₂O); IR (KBr): 3780-2200, 3435, 1730, 1262 cm^-1; ¹H NMR (400 MHz, D₂O): δ = 1.56-1.67 (m, 1 H), 1.77 (dd, J = 18.5, 6.7 Hz, 2 H), 1.92 (ddd, J = 13.5, 8.1, 4.7 Hz, 1 H), 1.95-2.04 (m, 1 H), 2.03-2.14 (m, 1 H), 2.26 (ddd, J = 13.5, 6.3, 3.4 Hz, 1 H), 3.28 (dd, J = 13.2, 6.6 Hz, 1 H), 3.33 (dd, J = 13.2, 4.2 Hz, 1 H), 4.06 (dd, J = 6.3, 4.7 Hz, 1 H); ¹³C NMR (100 MHz, D₂O): δ = 26.1 (d, J = 3.1 Hz), 27.8 (d, J = 9.4 Hz), 31.2 (d, J = 11.6 Hz), 31.2 (d, J = 134.3 Hz), 40.5, 53.9, 171.7; ³¹P NMR (162 MHz, D₂O): δ = 24.6; HRMS (ESI⁺): m/z [M + Na⁺] calcd for C₇H₁₄NO₅PNa: 246.0502; found: 246.0494; Anal. Calcd for C₇H₁₄NO₅P: C, 37.67; H, 6.32; N, 6.28. Found: C, 37.56; H, 6.24; N, 6.33.