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

Takashi Ohnuki; Takashi Tsuji; Shojiro Miyazaki; Taku Moriguchi; Takahide Nishi

doi:10.1055/s-0028-1087963

LETTER

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

Takashi Ohnuki^b, Takashi Tsuji^a, Shojiro Miyazaki^a, Taku Moriguchi^b, 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

Abstract

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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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References and Notes

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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]^-.

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.