Concise Synthesis of (2S,3R)-3-Hydroxy-2-phenylpiperidine: An Advanced Key Intermediate of Human Non-Peptide NK-1 Receptor Antagonists

Abstract

The rapid, high-yielding synthesis of (2S,3R)-3-hydroxy-2-phenylpiperidine, a known advanced key intermediate of some non-peptide human NK-1 receptor antagonists such as (+)-CP-99,994, (+)-CP-122,721 and (+)-LP-733,060, is reported. This synthesis involves the stereoselective addition of racemic 3-(methoxymethoxy)allenylzinc bromide to enantiopure (R _S,E)-N-2-benzylidene-2-methylpropane-2-sulfinamide and a ring-closing metathesis reaction as the key steps. Following this procedure, (2S,3R)-3-hydroxy-2-phenylpiperidine is obtained in seven steps in 56.2% overall yield.

Key words

metathesis - piperidines - ring-closure - stereoselective synthesis - zinc

References and Notes

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24

Procedure for the formation of 5: Under a nitrogen atmosphere, to a stirred solution of 3-[(methoxymethoxy)-prop-1-ynyl]trimethylsilane (8.40 mL, 48.00 mmol) and TMEDA (0.66 mL, 4.80 mmol) in anhydrous Et₂O (400 mL) at -80 ˚C, was added dropwise s-BuLi (1.3 M in cyclo-hexane-hexane, 92:8, 36.90 mL, 48.00 mmol). The resulting clear orange mixture was stirred for 1 h at -80 ˚C and then a solution of ZnBr₂ (1 M in Et₂O, 48.00 mL, 48.00 mmol) was added. The resulting white slurry of allenylzinc (±)-3 was stirred at -80 ˚C for an additional 20 min before imine 4 (2.51 g, 12.00 mmol) in anhydrous Et₂O (48 mL) was added dropwise. The mixture was stirred for 1 h at -80 ˚C, then HCl (1 M, 200 mL) was added and the mixture was warmed to room temperature. The layers were separated and the aqueous phase was extracted with Et₂O (3 × 200 mL). The combined organic layers were washed with sat. NaHCO₃ (60 mL), water (2 × 120 mL) and brine (120 mL), dried over MgSO₄ and concentrated in vacuo. The residual oil was purified by flash chromatography on silica gel (EtOAc-cyclohexane, 20→50%) to produce the desired compound 5 (4.32 g, 94%) as a pale-yellow solid. The physical and spectroscopic data of 5 were in good agreement with those previously reported for its antipode.^²¹h

25

Procedure for the formation of 8: Under an argon atmosphere, to a stirred solution of 7 (1.12 g, 3.20 mmol) in anhydrous CH₂Cl₂ (1 L), was added Grubbs II catalyst (109 mg, 0.128 mmol). After 20 h stirring at 40 ˚C, additional Grubbs II catalyst (109 mg, 0.128 mmol) was added. The mixture was stirred for an additional 20 h and then cooled to room temperature. Removal of the solvent in vacuo gave a dark oil, which was purified by flash chromatography on silica gel (EtOAc-cyclohexane, 30→50%) to yield 8 (984 mg, 95%) as a brown oil; [α] _d ^²0 +13.4 (c 1.11, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 7.43-7.26 (m, 5 H), 6.11-6.02 (m, 2 H), 4.78 (AB system, J = 7.0 Hz, 1 H), 4.74 (AB system, J = 7.0 Hz, 1 H), 4.62 (d, J = 3.3 Hz, 1 H), 4.51-4.47 (m, 1 H), 3.77-3.60 (m, 2 H), 3.36 (s, 3 H), 1.18 (s, 9 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 137.7, 129.4, 129.3, 128.4, 128.2, 127.8, 125.3, 95.0, 71.3, 63.8, 59.3, 55.51, 55.50, 40.1, 23.2. IR (ATR diamond): 3033, 2948, 2887, 1657, 1601, 1028, 699 cm^-¹. HRMS (ESI): m/z [M + H⁺] calcd for C₁₇H₂₆NO₃S: 324.1628; found: 326.1620.

26

Procedure for the formation of 9: To a solution of 8 (1.35 g, 4.18 mmol) in absolute MeOH (100 mL), Raney Ni (5 spatulas) was added. The flask was flushed with H₂ (3×). After 16 h stirring at room temperature under 1 atm of H₂, the reaction mixture was filtered through a short pad of flash silica gel (EtOAc-cyclohexane, 30%). The solvents were removed and the residue was filtered through a short pad of flash silica gel eluting with EtOAc. Removal of the solvent gave 9 (1.23 g, 91%) as a colorless viscous oil; [α] _d ^²0 +105.3 (c 0.82, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 7.46 (d, J = 8.0 Hz, 2 H), 7.40 (t, J = 8.0 Hz, 2 H), 7.31-7.26 (m, 1 H), 4.63 (AB system, J = 6.8 Hz, 1 H), 4.57 (AB system, J = 6.8 Hz, 1 H), 4.39 (d, J = 5.0 Hz, 1 H), 4.14-4.09 (m, 1 H), 3.43 (ddd, J = 13.1, 9.4, 3.5 Hz, 1 H), 3.31-3.22 (m, 1 H), 3.27 (s, 3 H), 2.02-1.91 (m, 1 H), 1.86-1.77 (m, 1 H), 1.76-1.65 (m, 1 H), 1.61-1.51 (m, 1 H), 1.18 (s, 9 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 138.1, 128.6, 128.1, 127.3, 94.6, 74.6, 64.6, 59.6, 55.4, 41.1, 27.2, 23.4, 21.3. IR (ATR diamond): 3059, 3028, 2927, 2862, 1601, 1032, 914 cm^-¹. HRMS (ESI): m/z [M + H⁺] calcd for C₁₇H₂₈NO₃S: 326.1784; found: 326.1768.