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Synlett 2004(14): 2505-2508  
DOI: 10.1055/s-2004-834792
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Chiral γ-Amino-β-hydroxyphosphonate Derivatives from Unsaturated Phosphonates

Takehiro Yamagishi, Keiichi Fujii, Shiroshi Shibuya, Tsutomu Yokomatsu*
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Fax: +81(426)763239; e-Mail: yokomatu@ps.toyaku.ac.jp;
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Publication History

Received 31 July 2004
Publication Date:
20 October 2004 (online)

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Abstract

γ-Amino-β-hydroxyphosphonates, useful intermediates for the synthesis of phosphonic acid analogues of carnitine, were prepared as their protected derivatives in an enantioselective manner from β,γ-unsaturated phosphonates through asymmetric ­dihydroxylation and subsequent regioselective amination via the cyclic sulfates.

Key words

phosphorus - asymmetric synthesis - dihydoxylations - sulfates - regioselectivity

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10

The 1.4 g of AD-mix-α, purchased from Aldrich, was used for conversion of 1.0 mmol of the olefin, which contained 0.2 mol% of K2OsO4·2H2O and 1.0 mol% of chiral ligand (DHQ)2PHAL. However, an additional K2OsO4·2H2O (0.8 mol%) was critical for AD reactions of β,γ-unsaturated phosphonates since the AD reaction of 2b in the absence of the osmium salt resulted in slow reaction rates (20 h at 25 °C) and slight decrease in enantioselectivity (54% yield, 30% ee).

11

Compound 3c: oil; [α]D 26 -2.14 (c 1.03, MeOH). 1H NMR (400 MHz, CDCl3): δ = 7.97 (2 H, d, J = 8.8 Hz), 6.87 (2 H, d, J = 8.8 Hz), 4.38 (2 H, d, J = 5.8 Hz), 4.09 (4 H, q, J = 6.9 Hz), 4.05-4.00 (1 H, m), 3.87-3.85 (1 H, m), 3.82 (3 H, s), 2.22-1.96 (2 H, m), 1.29 (6 H, t, J = 7.0 Hz). 13C NMR (100 MHz, CDCl3): δ = 166.4, 163.5, 131.7, 122.2, 113.6, 72.4 (d, J PC = 14.9 Hz), 66.8 (d, J PC = 4.5 Hz), 65.5, 62.1 (d, J PC = 3.2 Hz), 55.4, 30.1 (d, J PC = 140.0 Hz), 16.3 (d, J PC = 5.9 Hz). 31P NMR (162 MHz, CDCl3): δ = 29.36. IR (neat): 3356, 1713, 1258, 1168 cm-1. ESI-MS: m/z = 399 [MNa+]. HRMS: m/z calcd for C16H25O8NaP [MNa+]: 399.1185. Found: 399.1185.

14

Compound 7b (for a sample of 100% ee): mp 93-95 °C; [α]D 22 -7.92 (c 1.01, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.39-7.32 (10 H, m), 5.12-4.96 (4 H, m), 3.70 (1 H, qd, J = 4.2, 14.9 Hz), 3.59 (1 H, td, J = 5.6, 11.3 Hz), 2.04-1.96 (2 H, m), 1.13 (3 H, d, J = 6.3 Hz). 13C NMR (100 MHz, CDCl3): δ = 136.0 (d, J PC = 5.5 Hz), 135.9 (d, J PC = 5.0 Hz), 128.7, 128.6, 128.6, 128.1, 128.0, 70.7 (d, J PC = 17.4 Hz), 70.4 (d, J PC = 5.6 Hz), 67.6 (d, J PC = 6.4 Hz), 30.5 (d, J PC = 139.6 Hz), 18.9. 31P NMR (162 MHz, CDCl3): δ = 31.91. IR (KBr): 3359, 2968, 1214 cm-1. ESI-MS: m/z = 351 [MH+]. HRMS: m/z calcd for C18H24O5P [MH+]: 351.1361. Found: 351.1352.

17

Compound 12: oil. 1H NMR (400 MHz, CDCl3): δ = 7.37-7.28 (10 H, m), 5.03 (2 H, dd, J = 9.1, 11.8 Hz), 4.95 (2 H, dd, J = 8.2, 11.8 Hz), 4.02-3.87 (1 H, m), 3.15-3.11 (1 H, m), 2.06-1.97 (2 H, m), 1.00 (3 H, d, J = 6.6 Hz), 0.91 (9 H, t, J = 7.9 Hz), 0.58 (6 H, q, J = 7.9 Hz). 13C NMR (100 MHz, CDCl3): δ = 136.2 (d, J PC = 5.4 Hz), 128.5-127.7 (aromatic), 71.6, 67.2 (d, J PC = 6.6 Hz), 67.1 (d, J PC = 6.5 Hz), 51.3 (d, J PC = 7.6 Hz), 30.1 (d, J PC = 138.0 Hz), 17.0, 6.8, 4.9. 31P NMR (162 MHz, CDCl3): δ = 30.81. ESI-MS: m/z = 464 [MH+]. HRMS: m/z calcd for C24H39NO4SiP [MH+]: 464.2386. Found: 464.2382.

18

The chemical structure of 12 was determined after the conversion into γ-amino-β-ketophosphonate 13 through tosylation, desilylation, and oxidation with PDC. In 1H the NMR spectrum (400 MHz, CDCl3) of 13, a signal ascribed to the Me group at the γ-position was observed at δ = 1.18 ppm as a doublet (J = 7.1 Hz) but not as a singlet corresponding to regioisomeric β-amino-γ-ketophosphonate (Scheme [7] ).

Scheme 7