A Stereoselective Synthesis of the ACE Inhibitor Trandolapril

Abstract

A conceptually novel and stereoselective synthesis of the enantiopure octahydroindole building block and its conversion into the ACE inhibitor trandolapril was achieved. Key steps include the α-allylation of a protected l-pyroglutamic acid derivative, a highly diastereoselective Hosomi–Sakurai reaction and a Ru-catalyzed ring-closing metathesis of a 4,5-diallylated proline. This way, the synthesis of trandolapril was efficiently achieved in 25% overall yield (12 steps).

Key words

proline derivatives - ACE inhibitors - diastereoselective alkylation - Hosomi–Sakurai reaction - Ru catalysis - ring-closing metathesis

• References and Notes

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• 20 Detailed experimental procedures and characterization data are given in the Supporting Information. Synthesis of Di-tert-butyl-(2S,4R)-4,5-diallylpyrrolidine-1,2-dicarboxylate (8) To a solution of 0.55 g (1.61 mmol, 1.0 equiv) of methoxyproline (12) in 13 ml CH₂Cl₂ were added 0.64 ml (4.03 mmol, 2.5 equiv) of allyl-TMS at –78 °C. Afterwards, 0.85 ml (3.22 mmol, 2 equiv) of BF₃·OEt₂ (48%) were added dropwise over 5 min. After 2 h of stirring at –78 °C, the reaction mixture was quenched with 5 ml of a saturated solution of NaHCO₃ and the aqueous layer extracted three times with 30 ml of MTBE. The combined organic layers were washed two times with a saturated solution of sodium chloride, dried over MgSO₄, filtered, and evaporated to dryness. After chromatographic separation of the diastereomeric mixture (17:1 ‘cis/trans’) and purification on silica (EtOAc/CyHex = 1:4) 0.42 g (1.19 mmol, 74%) of the diallylated proline 8 was obtained as a colorless oil. ¹H NMR (300 MHz, CDCl₃, mixture of rotamers): δ = 5.76–5.50 (m, 2 H, H-10/13), 4.99–4.85 (m, 4 H, H-11/14), 4.10–3.93 (m, 1 H, H-2), 3.58–3.42 (m, 1 H, H-5), 2.56–2.40 (m, 1 H, H-4), 2.19–1.72 (m, 6 H, H-3/9/12), 1.34;1.31 (2 × s, 18 H, H-8) ppm. ¹³C NMR (75 MHz, CDCl₃, mixture of rotamers): δ = 172.2, 172.0 (C-6), 154.1, 153.7 (C-15), 136.4, 135.7, 135.4 (C-10/13), 116.8, 116.7 (C-11/14), 80.6 (C-7), 79.6, 79.5 (C-16), 62.9 (C-2), 59.4, 58.9 (C-5), 41.3, 40.2 (C-4), 38.8 (C-12), 38.1, 37.8 (C-9), 33.3, 32.4 (C-3), 28.3, 27.9 (C-8/17) ppm. HRMS (ESI): m/z = [M + Na]⁺calcd: 374.2302; found: 374.2301. Synthesis of Di-tert-butyl-(2S,3aR,7aS)-2,3,3a,4,7,7a-hexa-hydro-1H-indole-1,2-dicarboxylate (7) To a solution of 0.40 g (1.14 mmol, 1.00 equiv) of diallylproline 8 in 35 ml CH₂Cl₂ was added 0.05 g (0.06 mmol, 0.05 equiv) Grubbs II catalyst and 0.02 g (0.09 mmol, 0.08 equiv) CuI at room temperature. After stirring for 2.5 h, the solution was evaporated under reduced pressure to dryness. After chromatographic purification on silica (CyHex/EtOAc = 4:1) the hexahydroindole 7 (0.35 g, 1.08 mmol, 95%) was obtained as colorless oil. ¹H NMR (300 MHz, CDCl₃): δ = 5.72–5.62 (m, 2 H, H-7/8), 4.37–4.11 (m, 1 H, H-2), 3.25–3.04 (m, 1 H, H-5), 2.32–1.65 (m, 7 H, H-3/4/6/9), 1.46 (s, 18 H, H-12/15) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 172.2 (C-10), 154.3 (C-13), 126.4, 126.1 (C-7/8), 80.8 (C-11), 79.6 (C-14), 61.0 (C-2), 60.2 (C-5), 40.0 (C-4), 34.5 (C-9), 32.7 (C-6), 30.4 (C-3), 28.4, 28.0 (C-12/15) ppm. HRMS (ESI): m/z = [M + Na]⁺calcd: 346.1989; found: 346.1987.