Bifunctional (Thio)urea–Phosphine Organocatalysts Derived from d-Glucose and α-Amino Acids and Their Application to the Enantio­selective Morita–Baylis–Hillman Reaction

Abstract

Novel (thio)urea–tertiary phosphines were developed for use as bifunctional organocatalysts readily available from naturally occurring molecules: saccharides and amino acids. The efficiency of the organocatalysts was demonstrated in the asymmetric Morita–Baylis–Hillman (MBH) reaction of aromatic aldehydes with acrylates. The MBH products were obtained in good yields (up to 85%) and with high enantioselectivities (up to 87% ee).

Key words

organocatalysis - Morita–Baylis–Hillman reactions - phosphines - amino acids - asymmetric catalysis

• References and Notes


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• 23 N-[({(1S)-1-[(Diphenylphosphino)methyl]-2-methylpropyl}-amino)carbonothioyl]-2,3,4,6-tetra-O-methyl-β-d-glucopyranosylamine (5c); Typical Procedure for the Synthesis of the Thiourea CatalystsIsothiocyanate 3a (1.16 g, 4.20 mmol) was dissolved in dry CH₂Cl₂ (10 mL) under argon in a dry Schlenk flask. A solution of aminophosphine 2c (1.14 g, 4.20 mmol) in dry CH₂Cl₂ (10 mL) was slowly added from a syringe, and the mixture was stirred at r.t. for 5 h. The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography [silica gel, hexane–EtOAc (4:1 to 1:1)] to give a colorless viscous oil that was freeze-dried to give a white solid; yield: 1.65 g (72%); [α]_D ²⁵ −26.1 (c 0.35, CHCl₃). IR (KBr): 507, 698, 740, 937, 985, 1030, 1096, 1165, 1186, 1251, 1308, 1347, 1368, 1389, 1431, 1455, 1479, 1541, 1550, 1616, 1739, 1814, 1885, 1960, 2833, 2902, 2929, 2953, 3052, 3072, 3306 cm⁻¹. ¹H NMR (600 MHz, CDCl₃): δ_H = 7.55–7.49 (m, 2 H), 7.48–7.41 (m, 2 H), 7.37–7.27 (m, 6 H), 7.14 (br s, 1 H), 6.24 (br s, 1 H), 4.46 (br s, 1 H), 4.38 (br s, 1 H), 3.63 (s, 3 H), 3.60 (s, 3 H), 3.58 (dd, J = 14.3, 3.7 Hz, 1 H), 3.50 (s, 3 H), 3.48 (dd, J = 10.5, 5.5 Hz, 1 H), 3.33 (ddd, J = 9.7, 5.2, 1.9 Hz, 1 H), 3.26 (s, 3 H), 3.23–3.11 (m, 3 H), 2.39–2.26 (m, 2 H), 2.16 (dq, J = 13.3, 6.8 Hz, 1 H), 0.89 (d, J = 6.9 Hz, 3 H), 0.87 (d, J = 6.8 Hz, 3 H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ_C = 183.7 (s), 138.5 (d, J = 15.6 Hz), 138.3 (d, J = 12.0 Hz), 133.0 (s), 132.9 (s), 128.6 (s), 128.5–128.3 (m), 87.1 (s), 84.1 (s), 81.9 (s), 79.5 (s), 76.4 (s), 70.9 (s), 60.8 (s), 60.7 (s), 60.5 (s), 59.0 (s), 58.0 (d, J = 14.0 Hz), 31.4 (d, J = 6.5 Hz), 31.2 (d, J = 13.6 Hz), 18.6 (s), 17.5 (s). ³¹P{¹H} NMR (121 MHz, CDCl₃): δ_P −24.4. HRMS (ESI-TOF­): m/z [M + H]⁺ calcd for C₂₈H₄₂N₂O₅PS: 549.2546; found: 549.2546.
• 24 N-[({(1S)-1-[(Diphenylphosphino)methyl]-2-methylpropyl}-amino)carbonyl]-2,3,4,6-tetra-O-methyl-β-d-glucopyranosylamine (6a); Typical Procedure for the Synthesis of the Urea CatalystsAmine 4a (100.0 mg, 0.43 mmol) and triphosgene (126.2 mg, 0.43 mmol) were added to a mixture of CH₂Cl₂ (3 mL) and sat. aq NaHCO₃ (1 mL), and the mixture was stirred at r.t. for 2 h. The resulting mixture was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were dried (MgSO₄) and concentrated, and the residue was dissolved in CH₂Cl₂ (1 mL). A solution of aminophosphine 2c (86.8 mg, 0.32 mmol) in CH₂Cl₂ (1 mL) was added dropwise, and the mixture was stirred at r.t. for 18 h. The resulting mixture was concentrated, and the residue was purified by flash column chromatography [silica gel, hexane–EtOAc (1:1)]. The product was crystallized (CHCl₃) to give a white glacial solid; yield: 124.0 mg (79%); mp 137–138 °C; [α]_D ²⁵ +22.6 (c 0.27, CHCl₃). IR (KBr, acetone): 510, 701, 740, 934, 952, 988, 1027, 1069, 1099, 1144, 1165, 1186, 1242, 1263, 1308, 1368, 1389, 1416, 1437, 1464, 1482, 1565, 1640, 1811, 1888, 1957, 2830, 2893, 2905, 2932, 2956, 3046, 3072, 3309 cm⁻¹. ¹H NMR (600 MHz, CDCl₃): δ_H = 7.47 (tt, J = 5.1, 2.0 Hz, 2 H), 7.41 (tt, J = 6.0, 2.3 Hz, 2 H), 7.36–7.27 (m, 6 H), 4.98 (d, J = 6.9 Hz, 1 H), 4.82 (d, J = 7.0 Hz, 1 H), 4.61 (t, J = 8.0 Hz, 1 H), 3.75 (br s, 1 H), 3.64 (s, 3 H), 3.60 (dd, J = 10.4, 2.0 Hz, 1 H), 3.54 (s, 3 H), 3.53–3.50 (m, 1 H), 3.52 (s, 3 H), 3.31 (s, 3 H), 3.24 (t, J = 8.9 Hz, 1 H), 3.21–3.15 (m, 1 H), 2.98 (t, J = 8.9 Hz, 1 H), 2.23 (d, J = 7.2 Hz, 2 H), 2.02–1.94 (m, 1 H), 0.85 (d, J = 1.1 Hz, 3 H), 0.84 (d, J = 1.2 Hz, 3 H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ_C = 157.0 (s), 138.7 (d, J = 12.5 Hz), 132.9 (d, J = 19.3 Hz), 132.8 (d, J = 19.1 Hz), 128.7–128.4 (m), 87.1 (s), 82.7 (s), 82.0 (s), 79.4 (s), 75.8 (s), 70.9 (s), 60.7 (s), 60.4 (s), 60.2 (s), 59.1 (s), 52.9 (d, J = 14.2 Hz), 32.2 (s), 32.05 (d, J = 7.8 Hz), 18.9 (s), 17.3 (s). ³¹P{¹H} NMR (121 MHz, CDCl₃): δ_P = −23.7. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₂₈H₄₂N₂O₆P: 533.2775; found: 533.2776.
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• 26 Methyl 2-[(R)-Hydroxy(4-nitrophenyl)methyl]acrylate (12a); Typical Procedure for the Asymmetric MBH ReactionAcrylate 11a (43.0 mg, 0.50 mmol) was added to a solution of organocatalyst 5c (5.5 mg, 0.01 mmol) in t-BuOMe (1 mL) at r.t., and the solution was stirred for 15 min. Aldehyde 10a (15.1 mg, 0.10 mmol) was added, and mixture was stirred at 25 °C for 1 d (Table 3). The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography [silica gel, hexane–EtOAc (4:1)] to give a yellow solid; yield: 18.1 mg (76%); [α]_D ²⁵ −57.3 (c 0.52, MeOH, 86% ee). ¹H NMR (600 MHz, CDCl₃): δ_H = 8.22 (d, J = 8.7 Hz, 2 H), 7.59 (d, J = 8.6 Hz, 2 H), 6.41 (s, 1 H), 5.89 (s, 1 H), 5.64 (d, J = 6.1 Hz, 1 H), 3.76 (s, 3 H), 3.34 (d, J = 6.3 Hz, 1 H). ¹³C{¹H} NMR (151 MHz, CDCl₃): δ_C = 166.4, 148.5, 147.5, 140.9, 127.3, 123.6, 72.8, 52.2. MS (EI-TOF): m/z = 237.1 [M]^+•. HPLC (ChiralPak IC column, heptane–i-PrOH (80:20), flow rate: 1.0 mL/min, λ = 220 nm): t_R  = 6.69 min (minor), 8.04 min (major).
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