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Synlett 2006(17): 2799-2803  
DOI: 10.1055/s-2006-950272
LETTER
© Georg Thieme Verlag Stuttgart · New York

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;
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Received 1 June 2006
Publication Date:
09 October 2006 (online)

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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

8

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

9

( 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.

10

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.

11

(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.

12

(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.

13

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 H2 for 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.

14

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).

15

(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.

16

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.

17

(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.

21

(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.

22

(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.

23

(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.

24

(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.