Stereoselective Synthesis of β-Amino-α-hydroxy(allyl)phosphinates and an Application to the Synthesis of a Building Block for Phosphinyl Peptides

Abstract

Hydrophosphinylation of N,N-dibenzyl-α-amino aldehydes with ethyl allylphosphinate in the presence of (S)-ALB afforded anti-β-amino-α-hydroxy(allyl)phosphinates in high diastereoselectivity. The hydrophosphinylation product was transformed to a potentially useful transition state mimic for hydrolysis of dipeptides.

phosphorus - amino aldehyde - β-amino-α-hydroxy(allyl)phosphinates - hydrophosphinylation - diastereoselectivity

References

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<A NAME="RU02902ST-10">10</A>

Genaral Procedure for the Hydrophosphinylation of 3a-c in the Presence of ( S )-ALB. To a solution of ethyl allylphosphinate (804 mg, 6.0 mmol) in THF (4 mL) was added 0.1 M THF solution of (S)-ALB (8 mL, 0.8 mmol), prepared from (S)-BINOL (458 mg, 1.6 mmol) and LiAlH₄ (30.4 mg, 0.8 mmol) in situ, and a solution of 2a-c (4.0 mmol) in THF (8 mL) at 0 °C under stirring. After being stirred for 12 h at the same temperature, the mixture was diluted with H₂O and extracted with CHCl₃. The combined extracts were washed with brine and dried over MgSO₄. Removal of solvent gave a residue, which was chromatographed on silica gel (hexane-EtOAc = 2:1) to give syn-3a-c and anti-3a-c.
syn-3a. This compound was obtained as a mixture of diastereomers arising from the chirality of the phosphorus atom in a ratio of 1:1.6. Mp 87-89 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.42-7.20 (15 H, m), 5.91-5.79 (0.5 H, m), 5.58-5.46 (0.5 H, m), 5.28-5.21 (1 H, m), 4.93-4.88 (1 H, m), 4.16-4.12 (2 H, m), 3.84-3.59 (3 H, m), 3.53-3.43 (2 H, m), 3.04-2.94 (1 H, m), 2.82-2.60 (1 H, m), 2.44-2.34 (0.5 H, m), 2.25-2.16 (0.5 H, m), 1.34 (3 H, t, J = 7.0 Hz); ³¹P NMR (162 MHz, CDCl₃) δ 52.35, 50.21; IR (KBr) 3215, 1046 cm^-1; EIMS m/z 464 (MH⁺). Anal. calcd for C₂₈H₃₄NO₃P: C, 72.55; H, 7.39. Found: C, 72.44; H, 7.25.
anti-3a. This compound was obtained as a mixture of diastereomers arising from the chirality of the phosphorus atom in a ratio of 1:1.1. Mp 168-170 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.27-7.06 (15 H, m), 5.87-5.71 (1 H, m), 5.29-5.05 (2 H, m), 4.15-3.92 (3 H, m), 3.87 (2 H, d, J = 14.1 Hz), 3.59 (2 H, d, J = 14.1 Hz), 3.49-3.38 (1 H, m), 3.18-3.07 (2 H, m), 2.78-2.50 (2 H, m), 1.20 (3 H, t, J = 7.0 Hz), 1.18 (3 H, t, J = 7.0 Hz); ³¹P NMR (162 MHz, CDCl₃) δ 49.18, 49.05; IR (KBr) 3259, 1033 cm^-1; EIMS m/z 464 (MH⁺). Anal. calcd for C₂₈H₃₄NO₃P: C, 72.55; H, 7.39. Found: C, 72.30; H, 7.35.
syn-3b. This compound was obtained as a mixture of diastereomers arising from the chirality of the phosphorus atom in a ratio of 1:1. Oil; ¹H NMR (400 MHz, CDCl₃) δ 7.33-7.28 (10 H, m), 5.88-5.77 (0.5 H, m), 5.58-5.46 (0.5 H, m), 5.25-4.86 (2 H, m), 4.13-4.05 (2 H, m), 3.88 (2 H, d, J = 13.1 Hz), 3.59 (2 H, d, J = 13.1 Hz), 3.53-3.46 (1 H, m), 3.28-3.14 (1 H, m), 2.77-2.56 (1 H, m), 2.39-2.11 (1 H, m), 2.11-2.04 (1 H, m), 1.83-1.67 (2 H, m), 1.31 (3 H, t, J = 7.0 Hz), 1.04-0.99 (6 H, m); ³¹P NMR (162 MHz, CDCl₃) δ 51.75, 50.22; IR(neat) 3262, 1036 cm^-1; EIMS m/z 430 (MH⁺). High resolution MS calcd for C₂₅H₃₇NO₃P (MH⁺): 430.2511. Found: 430.2488.
anti-3b. This compound was obtained as a mixture of diastereomers arising from the chirality of the phosphorus atom in a ratio of 1:1.1. Mp 141-143 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.35-7.20 (10 H, m), 5.91-5.76 (1 H, m), 5.30-5.15 (2 H, m), 4.22-3.91 (3 H, m), 3.88 (1 H, d, J = 13.6 Hz), 3.85 (1 H, d, J = 13.6 Hz), 3.53 (1 H, d, J = 13.6 Hz), 3.52 (1 H, d, J = 3.6 Hz), 3.22-3.11 (1 H, m), 2.82-2.39 (2 H, m), 1.80-1.70 (1 H, m), 1.40-1.29 (2 H, m), 1.24 (1.5 H, t, J = 7.0 Hz), 1.20 (1.5 H, t, J = 7.0 Hz), 0.91 (3 H, d, J = 6.7 Hz), 0.58 (1.5 H, d, J = 6.5 Hz), 0.55 (1.5 H, d, J = 6.5 Hz); ³¹P NMR (162 MHz, CDCl₃) δ 50.05, 49.44; IR (KBr) 3278, 1033 cm^-1; EIMS m/z 430 (MH⁺). Anal. calcd for C₂₅H₃₆NO₃P: C, 69.91; H, 8.45. Found: C, 69.77; H, 8.28.

<A NAME="RU02902ST-11">11</A>

For improving the syn-diastereoselectivity, we also examined hydrophosphinylation of 2b using other types of binaphthol-modified heterobimetallic complexes [(R)-LPB [21] and (R)-GaLB [22] ]. However, the syn-selectivity was not observed. The (R)-LPB catalyzed reaction showed moderate anti-selectivity (syn-3b:anti-3b = 22:78). A poor anti-selectivity (syn-3b:anti-3b = 44:51) was observed with (R)-GaLB.

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<A NAME="RU02902ST-15">15</A> The ¹H NMR spectroscopic analysis has been successfully applied to determine the relative stereochemistry of 5-phosphonyloxazolidin-2-one, see: Yokomatsu T. Yamagishi T. Shibuya S. Tetrahedron: Asymmetry  1993,  4:  1401 ; see also ref. 2

<A NAME="RU02902ST-16">16</A>

X-Ray crystal data of anti-3c-A were collected by a Mac-Science DIP Image plate diffractometer. The structure was solved by a direct method using SIR-97 [23] and refined with a full matrix least-squares method. [24] Molecular formula = C₂₂H₃₀NO₃P, M _r = 387.46, orthorhombic, space group = P2₁2₁2₁, a = 8.454(5), b = 11.111(2), c = 23.484(10) Å, V = 2205.9(2) ų, T = 296 K, Z = 4, D _x = 1.167 Mg m^-3, (Mo-Kα) = 0.71073 Å, µ = 0.145 mm^-1, R = 0.050 over 2591 independent reflections.

<A NAME="RU02902ST-17">17</A>

Crystallographic data (excluding structure factors) for the X-ray crystal structure analysis reported in this paper have been deposited with the Cambridge Crystallographic Data Center (CCDC) as supplementary publication No. CCDC 187211. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:[phone] or e-mail: [e-mail]].

<A NAME="RU02902ST-18">18</A> For a review on asymmetric dihydroxylation, see: Kolb HC. VanNieuwenhze MS. Sharpless KB. Chem. Rev.  1994,  94:  2483 

<A NAME="RU02902ST-19">19</A>

The PDC oxidation of 9 in DMF, followed by esterificaton afforded 10 in 7% yield.

<A NAME="RU02902ST-20">20</A>

11. Amorphous; [α]_D ²⁶ = -7.21 (c 0.67, MeOH); ¹H NMR (400 MHz, CD₃OD) δ 4.17 (1 H, dd, J = 5.3, 5.3 Hz), 3.73 (3 H, s), 3.69-3.54 (1 H, m), 3.23-3.00 (2 H, m), 1.87-1.59 (3 H, m), 1.00 (3 H, d, J = 5.9 Hz), 0.97 (3 H, d, J = 6.2 Hz); ³¹P NMR (162 MHz, CD₃OD) δ 41.91; ¹³C NMR (100 MHz, CD₃OD) δ 168.4, 68.9 (d, J _PC = 119.5 Hz), 59.1, 53.0, 38.8, 36.0 (d, J _PC = 81.7 Hz), 25.9, 23.5, 21.8; IR(neat) 3314, 2956, 1729, 1115 cm^-1; FABMS m/z 254 (MH⁺). High resolution MS calcd for C₉H₂₁NO₅P (MH⁺): 254.1157. Found: 254.1164.

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<A NAME="RU02902ST-24">24</A> Sheldrick GM. SHELXL97, Program for the Refinement of Crystal Structures   University of Göttingen; Germany: 1997.