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

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

References and Notes

• 1 Evans BE. Rittle KE. Bock MG. DiPardo RM. Freidinger RM. Whitter WL. Lundell GF. Veber DF. Anderson PS. Chang RSL. Lotti VJ. Cerino DJ. Chen TB. Kling PJ. Kunkel KA. Springer JP. Hirshfield J. J. Med. Chem.  1988,  31:  2235 
• 2 Mason JS. Morize I. Menard PR. Cheney DL. Hulme C. Labaudiniere RF. J. Med. Chem.  1999,  42:  3251 
• 3a Vieira E. Binggeli A. Breu V. Bur D. Fischli W. Güller R. Hirth G. Märki HP. Müller M. Oefner C. Scalone M. Stadler H. Wilhelm M. Wostl W. Bioorg. Med. Chem. Lett.  1999,  9:  1397 
• 3b Güller R. Binggeli A. Breu V. Bur D. Fischli W. Hirth G. Jenny C. Kansy M. Montavon F. Müller M. Oefner C. Stadler H. Vieira E. Wilhelm M. Wostl W. Märki HP. Bioorg. Med. Chem. Lett.  1999,  9:  1403 
• 3c Cody WL. Holsworth DD. Powell NA. Jalaie M. Zhang E. Wang W. Samas B. Bryant J. Ostroski R. Ryan MJ. Edmunds JJ. Bioorg. Med. Chem.  2005,  13:  59 
• 5a Efange SMN. Khare AB. Foulon C. Akella SK. Parsons SM. J. Med. Chem.  1994,  37:  2574 
• 5b Limanto J. Shultz CS. Dorner B. Desmond RA. Devine PN. Krska SW. J. Org. Chem.  2008,  73:  1639 
• 6 Corey EJ. Bakshi RK. Shibata S. J. Am. Chem. Soc.  1987,  109:  5551 
• 8 Brown HC. Chandrasekharan J. Ramachandran PV. J. Am. Chem. Soc.  1988,  110:  1539 

4

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).

7

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.

9

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]⁺.