Efficient Synthesis of 5-Alkoxy-(3R)-hydroxy-2,3-dihydrospiro[indene-1,4′-piperidines]:
A Novel Scaffold for Renin Inhibitors

Yuji Nakamura; Takaaki Jojima; Chie Suzuki; Shojiro Miyazaki; Takahide Nishi

doi:10.1055/s-0029-1217818

LETTER

Efficient Synthesis of 5-Alkoxy-(3R)-hydroxy-2,3-dihydrospiro[indene-1,4′-piperidines]: A Novel Scaffold for Renin Inhibitors

Yuji Nakamura^a, Takaaki Jojima^b, Chie Suzuki^a, Shojiro Miyazaki^a, 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 Medicinal Chemistry Research Laboratories II, Daiichi Sankyo Co., Ltd., 1-16-13 Kita-kasai, Edogawa-ku, Tokyo 134-8630, Japan

Abstract

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Abstract

We report herein, an efficient synthetic method for the preparation of a 5-alkoxy-(3R)-hydroxy-2,3-dihydrospiro[indene-1,4′-piperidines] scaffold using a regioselective intermolecular reaction and a stereoselective reduction as key steps. Compound 2, based on this scaffold, showed moderate in vitro binding affinity for purified human renin.

Key words

CBS reduction - regioselectivity - spiro-piperidine - stereoselectivity - renin

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References

References and Notes

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Compound 2 was evaluated as a 0.5 fumaric acid salt. The absolute stereochemistry of 2 was determined by an X-ray crystal structure complex with renin (data not shown).

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The ee of 3 was determined by HPLC analysis (CHIRALCEL OJ-H; 4.6 × 250 mm; n-hexane-EtOH, 80:20; 0.5 mL/min), t _R of (S)-isomer = 24.6 min; t _R of
(R)-isomer = 23.0 min.

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Synthesis of spiro-piperidine 5: To a solution of silyl enol ether 4 (1.0 g, 2.30 mmol) in anhydrous THF (4.5 mL), was added LHMDS (1.0 M in THF, 5.8 mL, 5.8 mmol) at -78 ˚C. The mixture was stirred at the same temperature for 30 min, then a solution of N-Boc dichloride 6 (0.67 g, 2.79 mmol) in anhydrous THF (2.3 mL) was added. The mixture was warmed to 0 ˚C and stirred at the same temperature. After 8 h, 1N HCl (9.2 mL, 9.2 mmol) was added and the resulting mixture was stirred for a further 1 h. After extraction of the reaction mixture with EtOAc, the organic extract was washed with H₂O, sat. aq NaHCO₃, and brine then dried over anhydrous Na₂SO₄. The solvent was removed in vacuo, and the residue was purified by silica gel flash column chroma-tography (n-hexane-EtOAc, 2:1) to afford spiro-piperidine 5 (0.58 g, 51% yield) as a colorless oil. ^¹H NMR (500 MHz, CDCl₃): δ = 7.39-7.33 (m, 2 H), 7.26-7.23 (m, 1 H), 7.20 (dd, J = 8.3, 2.4 Hz, 1 H), 7.16 (d, J = 2.4 Hz, 1 H), 6.92 (t, J = 7.6 Hz, 1 H), 6.85 (d, J = 8.3 Hz, 1 H), 4.56 (s, 2 H), 4.22 (br s, 2 H), 4.15-4.10 (m, 2 H), 3.81 (s, 3 H), 3.69 (t, J = 6.1 Hz, 2 H), 2.84 (br s, 2 H), 2.63 (s, 2 H), 2.13-2.08 (m, 2 H), 1.98-1.92 (m, 2 H), 1.50 (s, 9 H), 1.46 (br s, 2 H). MS-FAB: m/z = 496 [M + H]⁺. Synthesis of ( R )-3: To a solution of (S)-2-methyl-CBS-oxazaborolidine (1.0 M in toluene, 43 µL, 0.043 mmol) in anhydrous THF (0.2 mL), a solution of spiro-piperidine 5 (215 mg, 0.43 mmol) in anhydrous THF (0.2 mL) and BH₃˙THF complex (1.0 M in THF, 0.26 mL, 0.26 mmol) were added. The resulting mixture was stirred at r.t. for 30 min, followed by the addition of MeOH and H₂O under ice-cooling. After extraction of the reaction mixture with EtOAc, the organic extract was washed with brine and dried over anhydrous Na₂SO₄. The solvent was then removed in vacuo, and the residue was purified by silica gel flash column chromatography (n-hexane-EtOAc, 1:1) to afford (R)-3 (194 mg, 90% yield) as a colorless oil of optical purity 98% ee. ^¹H NMR (500 MHz, CDCl₃): δ = 7.37-7.35 (m, 1 H), 7.27-7.23 (m, 1 H), 7.08 (d, J = 8.3 Hz, 1 H), 6.96-6.91 (m, 2 H), 6.89-6.83 (m, 2 H), 5.22 (dd, J = 12.2, 6.8 Hz, 1 H), 4.56 (s, 2 H), 4.15-4.03 (m, 4 H), 3.81 (s, 3 H), 3.70 (t, J = 6.1 Hz, 2 H), 2.98-2.88 (m, 2 H), 2.53 (dd, J = 13.4, 7.1 Hz, 1 H), 2.12-2.07 (m, 2 H), 1.93-1.87 (m, 2 H), 1.73 (d, J = 6.8 Hz, 1 H), 1.69 (dd, J = 12.5, 4.2 Hz, 1 H), 1.60 (dd, J = 13.2, 2.0 Hz, 1 H), 1.47 (s, 9 H), 1.37 (br d, J = 13.2 Hz, 1 H). MS-FAB: m/z = 497 [M]⁺.