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Synlett 2009(6): 910-912  
DOI: 10.1055/s-0028-1087963
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Practical Phosphorylation Methods for α,α-Disubstituted α-Amino Alcohol Derivatives

Takashi Ohnukib, Takashi Tsujia, Shojiro Miyazakia, Taku Moriguchib, Takahide Nishi*a
a Medicinal Chemistry Research Laboratories I, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
Fax: +81(3)54368563; e-Mail: nishi.takahide.xw@daiichisankyo.co.jp;
b Exploratory Research Laboratories I, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
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Publication History

Received 24 December 2008
Publication Date:
16 March 2009 (online)

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Abstract

We report herein practical phosphorylation methods for α,α-disubstituted α-amino alcohol derivatives which act as S1P1 receptor agonists. A novel direct phosphorylation method for α,α-di­substituted α-amino alcohol derivatives by biotransformation using Circinella muscae, Circinella minor, Circinella mucoroides, and Circinella umbellate was developed. We applied the present method to the synthesis of phosphates of α,α-disubstituted α-amino alcohol derivatives.

Key words

amino alcohols - bioorganic chemistry - biotransfomation - S1P1 receptor agonist - phosphorylation

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Typical Biotransformation Procedure
Circinella muscae was cultivated at 23 ˚C for 2 d in Erlenmeyer flasks containing 80 mL of the medium consisting of 0.1% malt extract, 0.3% corn steep liquor, 1.0% glucose, 0.1% polypepton, 0.1% yeast extract, and 0.1% NaH2PO4 after seed cultivation at 23 ˚C for 2 d. To each of five Erlenmeyer flasks containing the fermentation broth, 0.8 mL of 8 (40 mg, 1.1¥10-4 mol) dissolved in 0.01% aq formic acid (4 mL) was added in order to start the bio-transformation. The reaction was carried out at 23 ˚C for 3 d on a rotary shaker at 210 rpm. The fermentation broth (400 mL) was extracted with an equal volume of acetone with 40 µL of H3PO4, and the mixture was filtered. To the filtrate,
an equal volume of distilled H2O was added, and then the mixture was adsorbed onto a column (40 mL) of DIAION HP-20 packed with 0.1% aq H3PO4. The column was washed with H2O (200 mL) and eluted with 30% and 50% acetone containing 10 mM HCOONH4 (pH 8.0). Both fractions were combined and concentrated in vacuo and lyophilized to give crude powder (67.8 mg). The crude powder was purified by preparative HPLC using a Develosil ODS UG-5 (150 × 20 mm i.d., Nomura Chemical Co., Ltd., Japan) with 30% aq MeCN containing 10 mM HCOONH4 (pH 8.0) as a mobile phase with a flow rate of 10 mL/min. The fractions were concentrated in vacuo and lyophilized to give 10 (34.7 mg, 70% yield) as a colorless powder. IR (KBr): 3429, 2934, 2857, 2717, 2603, 1639, 1557, 1480, 1455, 1378, 1182, 1056, 1041, 946, 915 cm-¹. ¹H NMR (400 MHz, CD3CO2D): δ = 7.25-7.22 (m, 2 H), 7.17-7.11 (m, 3 H), 7.07 (1 H, d, J = 4.4 Hz), 6.04 (1 H, d, J = 4.4 Hz), 4.17 (2 H, d, J = 10.3 Hz), 3.87 (s, 3 H), 2.82-2.71 (m, 4 H), 2.63 (2 H, t, J = 7.3 Hz), 2.20-2.01 (m, 2 H), 1.75-1.63 (m, 4 H), 1.46 (s, 3 H). MS-FAB: m/z = 421 [M - H]-.

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The conversion ratio was determined by the peak-area ratios of alcohol 8 and phosphate 10 using RP-HPLC. The HPLC conditions were follows: mobile phase, 30% aq MeCN containing 10 mM HCOONH4 (pH 4.0); column, Unison UK-C18 (75 × 4.6 mm i.d., Imtakt Corp., Japan); flow rate, 0.8 mL/min; detection, UV 280 nm. Compounds 8 and 10 were eluted at t R = 6.7 and 3.2 min, respectively.