The Synthesis of 5,5-Disubstituted Piperidinones via a Reductive Amination–Lactamization Sequence: The Formal Synthesis of (±)-Quebrachamine

Abstract

A preliminary investigation into the prospect of a common synthetic intermediate for the synthesis of a variety of indole alkaloids has led to a synthesis of substituted piperidinones and the corresponding piperidines. These common natural product cores are accessed via a reductive amination–lactamization sequence of dimethyl 3-ethyl-3-formylpimelate. The synthetic utility of this initial study has been displayed in the formal synthesis of (±)-quebrachamine.

Key words

natural product - alkaloid - quebrachamine - heterocycles - piperidine

• References and Notes


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• 14 General Experimental Procedure for the Synthesis of Piperidinones 3a–i Compound 2 (1 equiv) and primary amine (1 equiv) were dissolved in MeOH. Sc(OTf)₃ (0.025 equiv) was then added, and the mixture was stirred for 1–2 h, followed by the addition of NaBH₄ (1.25 equiv). Upon completion by TLC analysis H₂O was added to the reaction mixture and extracted 3 times with EtOAc. The organic layer was dried, and the solvent was removed. The residue was purified by flash chromatography (EtOAc–hexanes) to yield the desired piperidinones 3a–i. Piperidinone 3c Yellow oil, 76% yield (346 mg, 0.93 mmol). R_f = 0.27, EtOAc. ¹H NMR (600 MHz, CDCl₃): δ = 3.76 (dd, J = 5.9, 5.9 Hz, 2 H), 3.67 (s, 3 H), 3.49–3.40 (m, 2 H), 3.18 (AB system, 2 H), 2.35 (dd, J = 7.0, 7.0 Hz, 2 H), 2.25–2.22 (m, 2 H), 1.75–1.66 (m, 2 H), 1.63–1.55 (m, 2 H), 1.44–1.38 (m, 1 H), 1.36–1.30 (m, 1 H), 0.89 (s, 9 H), 0.84 (t, J = 7.3 Hz, 3 H), 0.05 (s, 6 H). ¹³C NMR (150 MHz, CDCl₃): δ = 173.8, 169.6, 61.6, 58.9, 51.7, 50.5, 34.5, 29.7, 28.9, 28.5, 28.3, 26.9, 25.8, 18.1, 7.4, –5.5. IR (thin film): 2930, 2858, 1740, 1646, 1493, 1470, 1436, 1363, 1256, 1105, 1054, 1006, 921, 837, 778 cm^–1. HRMS: m/z calcd for C₁₉H₃₇NO₄Si [M + 1]: 372.2565; found: 372.2565. Piperidinone 3e Orange oil, 81% yield (202 mg, 0.67 mmol). R_f = 0.28, EtOAc. ¹H NMR (600 MHz, CDCl₃): δ = 7.32–7.30 (m, 2 H), 7.27–7.24 (m, 3 H), 4.57 (AB system, 2 H), 3.65 (s, 3 H), 2.91 (AB system, 2 H), 2.46 (dd, J = 7.0, 1.2 Hz, 2 H), 2.18–2.12 (m, 1 H), 2.04–1.98 (m, 1 H), 1.63–1.59 (m, 4 H), 1.33–1.22 (m, 2 H), 0.71 (t, J = 7.6 Hz, 3 H). ¹³C NMR (150 MHz, CDCl₃): δ = 173.7, 169.5, 137.1, 128.6, 128.3, 127.5, 55.4, 51.7, 50.3, 34.3, 30.0, 28.9, 28.5, 28.2, 26.5, 7.2. IR (thin film): 3454, 3056, 3062, 3029, 2948, 1736, 1647, 1494, 1454, 1363, 1229, 1069, 1002, 854, 703 cm^–1. HRMS: m/z calcd for C₁₈H₂₅NO₃ [M]: 303.1834; found: 303.1825. General Experimental Procedure for the Synthesis of 5-(3-Hydroxypropyl)piperidin-2-one 4a–c Procedure 1 Piperidinone (1 equiv) was dissolved in MeOH, followed by the addition of NaBH₄ (5 equiv). The mixture was heated to reflux for 10 min and then cooled to r.t. Then additional NaBH₄ (5 equiv) was added followed by a 10 min reflux period, this process was continued until a total of 40 equiv NaBH₄ was added. Upon complete addition of NaBH₄, H₂O was slowly added to the reaction mixture and extracted 3 times with EtOAc. The organic layer was dried, and the solvent was removed. The residue was purified by flash chromatography (EtOAc–hexanes) to yield the desired piperidinones 4a–c. Procedure 2 Dimethyl 3-ethyl-3-formylpimelate (1 equiv) and primary amine (1 equiv) were dissolved in MeOH. Sc(OTf)₃ (0.025 equiv) was then added, and the mixture was stirred for 1–2 h, followed by the addition of NaBH₄ (5 equiv). The mixture was heated to reflux for 10 min and then cooled to r.t. Then additional NaBH₄ (5 equiv) was added followed by a 10 min reflux period, this process was continued until a total of 40 equiv NaBH₄ was added. Upon complete addition of NaBH₄, H₂O was slowly added to the reaction mixture and extracted 3 times with EtOAc. The organic layer was dried and the solvent was removed. The residue was purified by flash chromatography (EtOAc–hexanes) to yield the desired piperidinones 4a–c. 5-(3-Hydroxypropyl)piperidin-2-one 4a Thick yellow oil, 99% yield (630 mg, 1.81 mmol). R_f = 0.14, EtOAc. ¹H NMR (600 MHz, CDCl₃): δ = 3.71 (dd, J = 5.3, 5.3 Hz, 2 H), 3.56 (dd, J = 5.9, 5.9 Hz, 2 H), 3.46–3.42 (m, 1 H), 3.37–3.33 (m, 1 H), 3.14 (AB system, 2 H), 2.47 (br s, 1 H), 2.29 (dd, J = 7.0, 7.0 Hz, 2 H), 1.55 (dd, J = 7.0, 7.0 Hz, 2 H), 1.46–1.34 (m, 4), 1.33–1.26 (m, 2 H), 0.84 (s, 9 H), 0.79 (t, J = 7.6 Hz, 3 H), 0.00 (s, 6 H). ¹³C NMR (150 MHz, CDCl₃): δ = 170.1, 62.9, 61.4, 59.3, 50.5, 34.5, 30.0, 29.8, 28.5, 27.1, 26.2, 25.8, 18.1, 7.4, –5.5. IR (thin film): 2930, 2858, 1626, 1497, 1464, 1418, 1362, 1255, 1101, 1058, 837, 778 cm^–1. HRMS: m/z calcd for C₁₈H₃₇NO₃Si [M + 1]: 344.2622; found: 344.2615. 5-(3-Hydroxypropyl)piperidin-2-one 4c Dark yellow oil, 100% yield (1459 mg, 5.30 mmol). R_f = 0.14, EtOAc; ¹H NMR (600 MHz, CDCl₃): δ = 7.32–7.30 (m, 2 H), 7.27–7.24 (m, 3 H), 4.55 (AB system, 2 H), 3.51 (dd, J = 5.9, 5.9 Hz, 2 H), 2.92 (AB system, 2 H), 2.43 (dd, J = 7.0, 7.0 Hz, 2 H), 1.62 (m, 3 H), 1.43–1.35 (m, 1 H), 1.34–1.16 (m, 5 H), 0.71 (t, J = 7.0 Hz, 3 H). ¹³C NMR (150 MHz, CDCl₃): δ = 169.8, 137.3, 128.5, 128.3, 127.4, 63.1, 55.7, 50.3, 34.3, 30.2, 29.9, 28.5, 26.9, 26.2, 7.3. IR (thin film): 3395, 2939, 2866, 1620, 1496, 1454, 1419, 1363, 1308, 1229, 1067, 1028, 703 cm^–1. HRMS: m/z calcd for ­C₁₇H₂₅NO₂ [M]: 275.1885; found: 275.1880. General Experimental Procedure for the Synthesis of Piperidines 5a,b Piperidinone (1 equiv) was dissolved in THF followed by the addition of Red-Al^® (65% by weight; 4 equiv). Upon completion by TLC analysis H₂O was added to the reaction mixture and extracted 3 times with EtOAc. The organic layer was dried and the solvent was removed. The residue was purified by flash chromatography (EtOAc–hexanes) to yield the desired product 5a,b. Piperidine 5a Orange oil, 72% yield (160 mg, 0.49 mmol). R_f = 0.11, EtOAc. ¹H NMR (600 MHz, CDCl₃): δ = 3.71 (dd, J = 6.5, 6.5 Hz, 2 H), 3.61 (ddd, J = 6.5, 6.5, 2.3 Hz, 2 H), 2.51–2.39 (m, 3 H), 2.31–2.19 (m, 2 H), 2.08–2.04 (m, 1 H), 1.61–1.50 (m, 2 H), 1.49–1.37 (m, 3 H), 1.36–1.25 (m, 4 H), 1.20–1.16 (m, 1 H), 0.88 (s, 9 H), 0.77 (t, J = 7.0 Hz, 3 H), 0.05 (s, 6 H). ¹³C NMR (150 MHz, CDCl₃): δ = 63.8, 63.6, 61.3, 61.2, 55.4, 35.3, 33.6, 28.3, 25.9, 21.9, 18.3, 7.3, 5.3 (missing 2 carbons, presumably due to overlap). IR (thin film): 2933, 2857, 1463, 1255, 1103, 1068, 836, 776 cm^–1. HRMS: m/z calcd for C₁₈H₃₉NO₂Si [M]: 329.2750; found: 329.2754.