Di(1R,2S,5R)-menthyl 2-Hydroxy-3-chloropropylphosphonate as a Useful Chiral Synthon for the Preparation of Enantiomerically Pure Phosphonic Acids

Abstract

Stereochemically pure di(1R,2S,5R)-menthyl (S)- and (R)-2-hydroxy-3-chloropropylphosphonates were synthesized by reaction of di(1R,2S,5R)-menthyl ketophosphonate with chiral complexes prepared from sodium borohydride and (R,R)-(+)-tartaric acid or with (S,S)-(-)-tartaric acid. Dimenthyl 2-hydroxy-3-chloropropylphosphonate was utilized as a chiron for the preparation of biologically active products.

Key words

asymmetric synthesis - reductions - double stereoselectivity - phosphono-GABOB - phosphono-carnitine

References and Notes

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• 5c Asymmetric Synthesis   Vol. 2:  Morrison JD. Academic Press; New York: 1983.  Chap. 2 and 3.
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9

Synthesis of Dimenthyl 2-Hydroxy-3-chloropropylphos-phonates ( 1a)Compound ( S )-1a
(R,R)-Tartaric acid (5.35 g, 19.56 mmol) was added to a suspension of NaBH₄ (1.35 g, 19.56 mmol) in abs. THF (195 mL) and then the reaction mixture was refluxed with stirring for 4 h. The reaction mixture was cooled to -30 °C, a solution of 4.0 g of 7a [19] in THF (15 mL) was added and the mixture was left overnight at -30 °C with stirring. Then EtOAc (50 mL) and 1 N HCl (40 mL) were added consecutively to the mixture, the organic and the aqueous layers were separated, and the latter was extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with sat. aq Na₂CO₃ and dried (Na₂SO₄). The solvent was removed under reduced pressure and the residue was purified by crystallization in MeCN to give (S)-1a as a colorless solid (2.4 g, 60%). Mp 86.2 °C; [α]_D ²⁰ -97.2 (c 3, CHCl₃). IR (film): 1256 (P=O), 3200 (OH) cm^-1. ¹H NMR (400 MHz, C₆D₆): δ = 0.71 (d, J = 6.9 Hz, 3 H, CH₃), 0.76 (d, J = 6.9 Hz, 3 H, CH₃), 0.81-0.84 (m, 12 H, CH₃), 0.88-2.18 (m, 17 H, CH₂ and CH), 1.53 [m, 1 H, CH(CH₃)₂], 1.73 (m, 1 H, CH^aP), 1.97 (m, 1 H, CH^bP), 1.96 [m, 1 H, CH(CH₃)₂], 3.29 (dd, J = 10.8, 6.7 Hz, 1 H, CH^aCl), 3.43 (ddd, J = 10.8, 4.7, 2.8 Hz, 1 H, CH^bCl), 3.90-4.10 (m, 2 H, OCH), 4.15 (m, 1 H, CHOH), 4.44 (br, 1 H, OH). ¹³C NMR (100.6 MHz, CDCl₃): δ = 16.13, 16.37, 21.34, 21.41, 22.24, 22.25, 23.40, 23.43, 26.00, 26.12, 31.98, 32.01, 32.64 (d, J = 141.2 Hz, CH₂P), 34.49, 34.49, 43.62, 44.13, 49.07 (d, J = 6.5 Hz, CH), 49.08 (d, J = 6.5 Hz, CH), 49.36 (d, J = 18.2 Hz, CH₂Cl), 67.29 (d, J = 3.6 Hz, CHOH), 78.33 (d, J = 7.5 Hz, OCH), 78.36 (d, J = 7.5 Hz, OCH). ³¹P NMR (161.96 MHz, CDCl₃): δ = 28.81. Anal. Calcd for C₂₃H₄₄ClO₄P: C, 61.25; H, 9.83; P, 6.87. Found: C, 61.28; H, 9.86; P, 6.88.
Compound ( R )-1a Colorless solid, mp 76.5 °C(hexane); [α]_D ²⁰ -64.3 (c 2, CHCl₃). IR (film): 1256 (P=O), 3200 (OH) cm^-1. ¹H NMR (400 MHz, C₆D₆): δ = 0.72 (d, J = 6.9 Hz, 3 H, CH₃), 0.73 (d, J = 6.9 Hz, 3 H, CH₃), 0.81-0.84 (m, 12 H, CH₃), 0.88-2.18 (m, 17 H, CH₂ and CH), 1.53 [m, 1 H, CH(CH₃)₂], 1.71 (ddd, J = 15.7, 15.5, 9.1 Hz, 1 H, CH^aP), 1.97 (m, 1 H, CH^bP), 1.96 [m, 1 H, CH(CH₃)₂], 3.29 (dd, J = 10.8, 7.4 Hz, 1 H, CH^aCl), 3.43 (ddd, J = 10.8, 4.4, 3.4 Hz, 1 H, CH^bCl), 3.90-4.05 (m, 2 H, OCH), 3.95 (m, 1 H, CHOH), 4.25 (br, 1 H, OH). ¹³C NMR (100.6 MHz, CDCl₃): δ = 16.13, 16.36, 21.34, 21.41, 22.24, 22.25, 23.40, 23.41, 26.00, 26.12, 31.98, 32.01, 32.61 (d, J = 141.2 Hz, CH₂P), 34.49, 34.49, 43.62, 44.13, 49.07 (d, J = 6.5 Hz, CH), 49.08 (d, J = 6.5 Hz, CH), 49.36 (d, J = 18.2 Hz, CH₂Cl), 67.29 (d, J = 3.6 Hz, CHOH), 78.34 (d, J = 7.5 Hz, OCH), 78.37 (d, J = 7.5 Hz, OCH). ³¹P NMR (161.96 MHz, CDCl₃): δ = 28.7. Anal. Calcd for C₂₃H₄₄ClO₄P: C, 61.25; H, 9.83; P, 6.87. Found: C, 61.25; H, 9.88; P, 6.85.
Synthesis of Compound ( S )-1b
To a solution of dimenthyl hydroxyphosphonate (S)- 1a (4.5 g, 9.97 mmol) in dioxane (270 mL) was added concd HCl (80 mL) and the reaction mixture was left for 3 d at 85 °C. Then the solvent was removed under reduced pressure, to the residue was added H₂O (50 mL) and the mixture was washed with toluene (3 × 15 mL). Afterwards H₂O was removed in vacuo, the residue was dissolved in EtOH, and treated with activated charcoal. The solvent was evaporated to give (S)-1b as a colorless oil (1.63 g, 93.5%). The spectroscopically pure product was used without further purification. ¹H NMR (300 MHz, C₆D₆): δ = 1.6-1.9 (m, 2 H, PCH₂), 3.2-3.4 (m, 2 H, CH₂Cl), 4.8 (m, 1 H, CHO), 4.9 (br, OH). ³¹P NMR (121.4 MHz, CDCl₃): δ = 25.5.²⁰ Compound ( R )-1b Colorless oil; yield 90%. ¹H NMR (300 MHz, C₆D₆): δ = 1.6-1.9 (m, 2 H, PCH₂), 3.2-3.4 (m, 2 H, CH₂Cl), 4.8 (m, 1 H, CHOH). ³¹P NMR (121.4 MHz, CDCl₃): δ = 25.5.

12

Phosphono-carnitine ( R )-(+)-6
A solution of 30% trimethylamine (80 mL) was added to a solution of (S)-1b (1.74 g, 10 mmol) in H₂O. The mixture was left for 48 h at 40 °C, the solvent was evaporated under reduced pressure and the residue was chromatographed on silica gel (MeOH-H₂O, 1:1) to give (R)-6 (2g, 80%) as a white solid; yield 80%; mp >250 °C (decomp.); [α]_D ²⁰ +26 (c 1, H₂O). ¹H NMR (400 MHz, CD₃OD): δ = 1.80 (ddd, J = 18, 14.7, 6.6 Hz, 1 H, PC^aH), 1.89 (ddd, J = 17.7, 14.8, 6.9 Hz, 1 H, PC^bH), 3.20 [s, 9 H, (CH₃)₃N], 3.40 (dd, J = 13.8, 9.8 Hz, 1 H, CH^aN), 3.60 (dd, J = 13.8, 1.2 Hz, 1 H, CH^bN), 4.50 (m, 1 H, CHOH). ¹³C NMR (100.6 MHz, D₂O): δ = 35.55 (d, J = 131.7 Hz, CH₂P), 54.91, 54.94, 54.98, 63.65, 71.57. ³¹P NMR (161.96 MHz, D₂O): δ = 18.1.
Phosphono-carnitine ( S )-(-)-6 White solid; yield 80%; mp >250 °C (decomp.); [α]_D ²⁰ -26.0 (c 1, H₂O). The NMR spectroscopy data are identical to (R)-(+)-6.

13

Compound ( R )-2a To a stirred solution of (S)-(-)-1a (4.5 g, 10 mmol) in a 10:3.5 mixture of MeCN-DMF (100 mL) were added K₂CO₃ (3.0 g) and KI (0.3 g). The mixture was refluxed for 8 h, filtered off, and the filtrate was evaporated to give (R)-2a (4.05 g, 98%) as a colorless oil; [α]_D ²⁰ -62.4 (c 7.0, CHCl₃). ¹H NMR (400 MHz, C₆D₆): δ = 0.80 (d, J = 7 Hz, 3 H, CH₃), 0.88 (d, J = 7 Hz, 3 H, CH₃), 0.89 (d, J = 7 Hz, 3 H, CH₃), 0.90 (d, J = 7 Hz, 3 H, CH₃), 0.91 (d, J = 7 Hz, 3 H, CH₃), 0.80-1.65 (m, 16 H CH₂C), 2.15-2.05 (m, 5 H, PCH₂, CH₂, and CH), 2.40 (dd, J = 5.1, 2.1 Hz, 1 H, CH^aO), 3.0 (dd, J = 5.1, 4.0 Hz, 1 H, CH^bO), 3.00 (m 1 H, CHO), 4.24 (m, 2 H, CHOP). ³¹P NMR (121.4 MHz, CDCl₃): δ = 25.3.
Compound ( R )-3a Colorless solid; yield 70%; mp 73 °C; [α]_D ²⁰ -45.92 (c 4.57, CHCl₃). ¹H NMR (300 MHz, C₆D₆): δ = 0.73 (d, J = 7.0 Hz, 3 H, CH₃), 0.80 d (3H, J = 7.0 Hz, CH₃), 0.87 (d, J = 7.0 Hz, 3 H, CH₃), 0.90 (d, J = 7.0 Hz, 3 H, CH₃), 0.91 (d, J = 7.0 Hz, 3 H, CH₃), 0.92 (d, J = 7.0 Hz, 3 H, CH₃), 0.96-2.25 (m, 19 H, CH₂C, CH, and CH^aP), 1.82 (ddd, J = 18.3, 15.1, 3.4 Hz, 1 H, CH^bP), 2.48 (m, 2 H, CH₂N), 3.55 (s, 4 H, CH₂Ph), 3.60 (m, 1 H, OH), 3.90-4.00 (m, 3 H, OCH and CHOH), 7.10-7.30 (m, 10 H, 2 C₆H₅). ³¹P NMR (121.4 MHz, CDCl₃): δ = 30.0.
Compound ( R )-3b Colorless solid; yield 3.1 g (85%). ¹H NMR (300 MHz, CD₃OD): δ = 1.73 (ddd, J _HP = 32.4 Hz, J _HH = 17.4 Hz, J _HH = 8.1 Hz, CH^aP), 1.93 (ddd, J = 34.5, 14.7, 4.5 Hz, 1 H, CH^bP), 2.96 (dd, J = 13.2, 9.3 Hz, 1 H, CH^aN), 3.20 (dd, J = 13.2, 9.3 Hz, CH^bN), 4.08-4.21 (m, 1 H, CHOH), 7.52-7.54 (m, 10 H, C₆H₅). ³¹P NMR (121.4 MHz, H₂O): δ = 26.5.
Compound ( R )-4a Colorless solid; yield 70%; mp 93 °C; [α]_D ²⁰ -63.9 (c 1.17, CHCl₃). ¹H NMR (300 MHz, C₆D₆): δ = 0.75-1.63 (m, 13 H, 8 CH₂ and 5 CH) 0.80 (d, J = 7.0 Hz, 3 H, CH₃), 0.81 (d, J = 7.0 Hz, 3 H, CH₃), 0.90 (d, J = 7.0 Hz, 3 H, CH₃), 0.91 (d, J = 7.0 Hz, 3 H, CH₃), 0.92 (d, J = 7.0 Hz, 3 H, CH₃), 0.93 (d, J = 7.0 Hz, 3 H, CH₃), 1.79 (m, 1 H, C^αH₂P), 1.85 (m, 1 H, C^βH₂P), 2.02-2.49 [m, 10 H, CH₂N, O(CH₂CH₂)₂N, 2 CH₂, and CH], 3.54 [m, 4 H, O(CH₂CH₂)₂N], 3.59 (br, 1 H, OH), 3.96 (m, 1 H, CHOH), 4.10 (m, 2 H, 2 CHOH). ³¹P NMR (121.4 MHz, CDCl₃): δ = 30.0.
Compound ( R )-5a
Colorless oil; yield 96%; [α]_D ²⁰ -74.2 (c 2.5, CHCl₃). IR (film): ν_max = 2120 (N₃), 1200 (P=O) cm^-1. ¹H NMR (300 MHz, C₆D₆): δ = 0.79 (d, J = 7 Hz, 3 H, CH₃), 0.81 (d, J = 7 Hz, 3 H, CH₃), 0.91 (d, J = 7 Hz, 3 H, CH₃), 0.92 (d, J = 7 Hz, 3 H, CH₃), 0.93 (d, J = 7 Hz, 3 H, CH₃), 0.94 (d, J = 7 Hz, 3 H, CH₃), 1.00-2.00 (m, 16 H, CH₂C), 1.80 (m, 2 H, PCH), 3.15 (m, 2 H, CH₂N), 4.05 (m, 2 H, CHO), 4.14 (m, 2 H, CHOH and OH). ³¹P NMR (121.4 MHz, CDCl₃): δ = 27.4.

18

Phosphono-GABOB ( R )-(+)-4c A solution of (R)-3b (1.85 g, 5 mmol) in MeOH (210 mL) was hydrogenated over 10% Pd/C (1.75 g) for 20 h at r.t. The mixture was filtered off and concentrated under reduced pressure, washed with acetone, and dried in vacuo. The residue was purified by ion-exchange chromatography to give a colorless hygroscopic solid (0.69 g, 90%); [α]_D ²⁰ +10.2 (c 1, H₂O). ¹H NMR (400 MHz, D₂O): δ = 1.78 (ddd, J = 31.2, 15.0, 6.3 Hz, CH^aP), 1.86 (ddd, J = 32.1, 14.7, 6.3 Hz, CH^bP), 2.99 (dd, J = 13.5, 8.5 Hz, CH^aN), 3.27 (dd, J = 13.1, 3.4 Hz, CH^bN), 4.14 (m, 1 H, CHOH). ¹³C NMR (100.6 MHz, D₂O): δ = 37.01 (d, J = 128.3 Hz, CH₂P), 48.13 (d, J = 9.0 Hz, CH₂N), 67.41. ³¹P NMR (161.96 MHz, D₂O): δ = 18.1.

19

Di(1 R ,2 S ,5 R )-menthyl 2-keto-3-chloropropylphos-phonate ( 7a)
Yield 70%; mp 65.5-65.6 °C; [α]_D ²⁰ -78.0 (c 1, CHCl₃). IR (film): 1256 (P=O), 1725 (C=O) cm^-1. ¹H NMR (300 MHz, C₆D₆): δ = 0.79 (d, J = 7 Hz, 3 H, CH₃), 0.81 (d, J = 7 Hz, 3 H, CH₃), 0.89 (d, J = 7 Hz, 3 H, CH₃), 0.90 (d, J = 7 Hz, 3 H, CH₃) 0.91 (d, J = 7 Hz, 3 H, CH₃), 0.93 (d, J = 7 Hz, 3 H, CH₃), 0.90-2.10 (m, 16 H, CH₂ and CH), 1.52 [m, 1 H, CH(CH₃)₂], 1.94 [m, 1 H, CH(CH₃)₂], 3.04 (d, J = 23.5 Hz, 2 H, PCH₂), 4.04 (s, 2 H, CH₂Cl), 4.07 (m, 2 H, 2 OCH). ¹³C NMR (100.6 MHz, CDCl₃): δ = 15.64, 15.81, 20.93, 20.99, 21.85, 22.88, 22.95, 25.53, 25.65, 31.58, 31.66, 33.98, 41.58 (d, J = 128.6 Hz, CH₂P), 42.90, 43.54, 48.49 (d, J = 9.3 Hz, CH), 48.51 (d, J = 9.3 Hz, CH), 48.53 (d, J = 19.3 Hz, CH₂Cl), 78.62 (d, J = 7.5 Hz, OCH), 78.90 (d, J = 7.5 Hz, OCH), 193.10 [d, J = 6.1 Hz, C(O)]. ³¹P NMR (121.4 MHz, CDCl₃): δ = 16.7.

20

All new compounds gave satisfactory analytical data in C, H, P (or N).