Enzyme and Gold Catalysis: A New Enantioselective Entry into Functionalized 4-Hydroxy-2-pyrrolines

Abstract

A new route toward functionalized pyrrolines starting from acetylenic aldehydes was developed. Key steps involved a ­hydroxynitrile lyase catalyzed asymmetric hydrocyanation of acetylenic aldehydes and a gold-catalyzed cyclization of substituted acetylene-containing amino alcohols.

Key words

gold catalysis - cyanohydrins - hydroxynitrile lyases - pyrrolines - pyrrolidines

• References and Notes


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• 16 Representative Procedures (R)-2-[(tert-Butyldimethylsilyl)oxy]-4-phenylbut-3-ynenitrile (9) A solution of 3-phenyl-2-propynal (8, 2.42 g, 15.4 mmol) in MTBE (15 mL) was added to a cooled (0 °C) solution of KCN (10.0 g, 154 mmol, 10.0 equiv) in citrate buffer (15 mL, pH 5.0). After addition of a lysate of (R)-HNL¹⁷ (4 mL) the reaction mixture was stirred at 0 °C for 4 h and quenched with 5 M HCl (10 mL). The precipitated enzyme was filtered over a glass funnel filled with cotton. The filtrate was extracted with CH₂Cl₂ (3 × 50 mL), and the organic layers were combined, dried (Na₂SO₄), and concentrated in vacuo. The residue was dissolved in dry CH₂Cl₂ (150 mL) at 0 °C, and TBSCl (2.79 g, 1.2 equiv) and imidazole (2.10 g, 2.0 equiv) were added. After stirring overnight at r.t., the mixture was quenched with sat. aq NH₄Cl the aqueous layer was extracted with CH₂Cl₂ (3 × 40 mL). The organic layers were combined, dried (Na₂SO₄), and concentrated in vacuo. Purification by column chromatography (EtOAc–heptane, 0:1 to 1.5:8.5) afforded 9 (3.60 g, 86% yield) as a yellow oil. R_f = 0.69 (EtOAc–heptane, 1:3). [α]_D ²⁰ –7.2 (c 1.33, CH₂Cl₂); 95% ee [Chiralpak AD-H column: HPLC eluent hexane–i-PrOH (85:15), flow 1.0 mL/min]; t _R1 = 6.12 min (S); t _R1 = 7.01 min (R). IR (ATR): 2958, 2928, 2855, 2228, 2202, 1489, 1256, 1091, 836, 780, 759, 694 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.49–7.46 (m, 2 H), 7.42–7.33 (m, 3 H), 5.50 (s, 1 H), 0.95 (s, 9 H), 0.28 (s, 3 H), 0.26 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 132.0, 129.7, 128.6, 121.0, 116.5, 87.1, 81.9, 52.7, 25.6, 18.3, –4.6. HRMS (EI): m/z calcd for C₁₆H₂₁NOSi: 271.1392; found: 271.1394. (1S,2R)-2-[(tert-Butyldimethylsilyl)oxy]-1,4-diphenyl-but-3-yn-1-amine (22) To a solution of 9 (1.00 g, 3.68 mmol) in dry Et₂O (37 mL) was added dropwise PhMgBr (3.68 mL of a 3.0 M solution in Et₂O, 3.0 equiv) at 0 °C. After 5 min the reaction mixture was stirred at r.t. for 2 h. Then dry MeOH (15 mL) was added, and the reaction mixture was cooled to –78 °C followed by dropwise addition of a solution of freshly prepared Zn(BH₄)₂ in THF–Et₂O (1:1) in 30 min, and the reaction mixture was stirred overnight. The mixture was quenched with sat. aq NaHCO₃ (20 mL) and the product extracted with EtOAc (3 × 20 mL). The organic layers were combined, dried (Na₂SO₄) and concentrated in vacuo. Purification by column chromatography (EtOAc–heptane, 0:1 to 3:7) afforded 22 (742 mg, 58% yield) as a yellow oil [inseparable mixture of diastereoisomers (1:8)]. Major diastereoisomer: R_f = 0.34 (EtOAc–heptane, 1:3). [α]_D ²⁰ –12.4 (c 1.71, CH₂Cl₂). IR (ATR): 3031, 2957, 2922, 2850, 1666, 1593, 1493, 1359, 1251, 1091, 836, 788, 758, 702 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.44–7.27 (m, 10 H), 4.61 (d, J = 5.9 Hz, 1 H), 4.10 (d, J = 5.9 Hz, 1 H), 1.99 (br s, 2 H), 0.85 (s, 9 H), 0.04 (s, 3 H), –0.01 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 141.5 131.7, 128.5, 128.4, 128.2, 127.7, 127.6, 122.9, 88.6, 86.4, 69.9, 61.5, 29.9, 25.9, –4.6, –5.1. ESI-HRMS: m/z calcd for C₂₂H₃₀NOSi [M + H]⁺: 352.2097; found: 352.2086. (4R,5S)-N-tert-Butoxycarbonyl-2,5-diphenyl-4-hydroxy-2-pyrroline (38) To a solution of 30 (50.0 mg, 0.11 mmol) in dry THF (2 mL) was added dropwise TBAF (110 μL, 1.1 equiv) at 0 °C. The reaction mixture was warmed to r.t. and stirred for 1 h. It was quenched with sat. aq NH₄Cl (10 mL), diluted with CH₂Cl₂ (10 mL), and extracted with CH₂Cl₂ (3 × 10 mL). The organic layers were combined, dried (Na₂SO₄), and concentrated in vacuo. The resulting colorless oil was dissolved in dry THF (2 mL) and NaAuCl₄·2H₂O (4.4 mg, 0.1 equiv) was added at r.t. The reaction temperature was increased to 50 °C, and the mixture was stirred for 6 h. After cooling to r.t., Et₃N (10 μL, 5.0 equiv) was added, and the solvent was removed in vacuo. Purification by column chromatography [EtOAc–heptane–1% Et₃N (v/v), 0:1 to 1:3] afforded 38 (30 mg, 87% yield) as a yellowish oil. R_f = 0.17 [EtOAc–heptane–1% Et₃N (v/v), 1:3]. [α]_D ²⁰ +22.4 (c 0.71, CH₂Cl₂). IR (ATR): 3408, 2980, 2924, 1698, 1636, 1367, 1166, 1018, 752, 697 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.52–7.48 (m, 2 H), 7.42–7.36 (m, 7 H), 7.32–7.26 (m, 1 H), 5.34 (dd, J = 0.4, 3.3 Hz, 1 H), 5.10 (d, J = 1.2 Hz, 1 H), 4.35 (dd, J = 1.2, 3.3 Hz, 1 H), 1.15 (s, 9 H). ¹³C NMR (75 MHz, CDCl₃): δ = 154.4, 149.6, 142.5, 135.3, 129.8, 129.5, 128.9, 128.5, 126.3, 112.2, 82.1, 79.5, 74.2, 60.2, 28.1. ESI-HRMS: m/z calcd for C₂₁H₂₄NO₃ [M + H]⁺: 338.1756; found: 338.1769.
• 17 The gene encoding for (S)-HNL, originating from the rubber tree Hevea brasiliensis, was cloned and efficiently expressed in the yeast strain Pichia pastoris as an intracellular protein; the enzyme preparation was obtained by homogenization (French press) of the cells, removal of insolubles by filtration, and subsequent concentration of the clear filtrate using ultrafiltration/diafiltration.¹⁸ The wild-type gene encoding for (R)-HNL, originating from bitter almonds (Prunus amygdalus), was cloned and efficiently expressed in the yeast strain Pichia pastoris. The enzyme was secreted from the cells and was obtained from cell-free supernatant by concentration using ultrafiltration/diafiltration.¹⁹ The crude lysates (cell-free extracts) containing (R)-HNL and (S)-HNL were kindly provided by DSM Innovative Synthesis (Geleen, the Netherlands).
• 18 Hasslacher M, Schall M, Hayn M, Bona R, Rumbold K, Luckl J, Griengl H, Kohlwin SD, Schwab H. Protein Expression Purif. 1997; 11: 61
• 19 Glieder A, Weis R, Skranc W, Poechlauer P, Dreveny I, Majer S, Wubbolts M, Schwab H, Gruber K. Angew. Chem. Int. Ed. 2003; 42: 4815