Bisprolinediamides with the Binaphthyl Backbone as Organocatalysts for the Direct Asymmetric Aldol Reaction

Abstract

A series of l-prolineamides derived from various aromatic diamines including 1,1′-binaphthyl-2,2′-diamine, were prepared in good yields. They were evaluated as catalysts for the direct asymmetric aldol reaction. The presence of the binaphthyl and proline moieties in one molecule has beneficial effects on the stereo­chemical outcome of the reaction of acetone with a model aldehyde. Furthermore, it was shown that dioxane as the solvent significantly improved both yield and enantioselectivity, reaching 89% and 86%, respectively.

Key words

organocatalysis - aldol reaction - asymmetric synthesis - binaphtyl - proline

References and Notes

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21

Compounds of Type 4; Typical Procedure
To a solution of N-Boc protected proline 1 (4.3 g, 20.0 mmol) in anhyd THF (50 mL), Et₃N (2.8 mL, 20.1 mmol) was added and the mixture was cooled to 0 °C, then ethyl chloroformate (2.5 mL, 20 mmol) was added dropwise over 15 min. The reaction temperature was maintained at 0 °C for 30 min, then a THF (10 mL) solution of racemic 1,1′-bi-naphthyl-2,2′-diamine (2.84 g, 10 mmol) was added drop-wise over 15 min at 0 °C. The reaction mixture was stirred overnight and then refluxed for 4 h. Finally, after cooling to r.t., the white precipitate (Et₃N·HCl) was removed by filtration, and the filtrate was concentrated in vacuo. Then the residue was purified by column chromatography (n-hexane-EtOAc, ca 4:1) to give two diastereomeric products 3e (2.41 g, 3.6 mmol) and 3f (2.46 g, 3.7 mmol) in 73% overall yield. To a solution of diamide 3e (0.75 g, 1.1 mmol) in CH₂Cl₂ (3 mL), excess TFA (1.5 mL), and Et₃SiCl (1.5 mL) was added and the resulting mixture was stirred for 2 h at r.t. The solvent was removed and the pH of the residue was adjusted to <7 by the addition of an aq sat. solution of NaHCO₃, the product was extracted with CH₂Cl₂, and dried over MgSO₄. Removal of the solvent resulted in pure 4e (0.45 g, 0.94 mmol, 85%).
4e Mp 203-208 °C (dec.); [α]_D ²⁵ -142.8 (c 0.94, CH₂Cl₂). ¹H NMR (200 MHz, CDCl₃): δ = 9.70 (1 H, s), 8.82 (2 H, AB/2, J = 9.0 Hz), 8.04 (2 H, AB/2, J = 9.0 Hz), 7.44-7.15 (6 H, m), 3.62 (2 H, dd, J = 9.3, 4.4 Hz), 2.40 (2 H, ddd, J = 9.6, 6.6, 7.8 Hz), 1.96 (4 H, m), 1.57 (2 H, br s), 1.45 (2 H, ddd, J = 6.6, 9.8, 4.8 Hz), 1.35-1.17 (2 H, m), 0.98-0.77 (2 H, m). ¹³C NMR (50 MHz, CDCl₃): δ = 174.0, 135.2, 132.5, 130.9, 129.6, 128.2, 126.9, 125.0, 124.9, 119.7, 119.2, 60.6, 46.2, 30.7, 25.4. HRMS (ESI): m/z calcd for C₃₀H₃₁N₄O₂: 479.2442; found: 479.2458.

22

Compounds of Type 5; Typical Procedure
To a solution of N-Boc protected proline 1 (0.43 g, 2 mmol) in anhyd THF (5 mL), Et₃N (0.24 mL, 2 mmol) was added and the mixture was cooled to 0 °C with stirring, then ethyl chloroformate (0.18 mL, 1.5 mmol) was added dropwise over 15 min. After the addition the reaction temperature was maintained at 0 °C for 30 min. Then a THF solution (1 mL) of (R)-1,1′-binaphthyl-2,2′-diamine (0.57 g, 2 mmol) was added dropwise over 5 min at 0 °C. The reaction was stirred overnight at r.t. and the white precipitate (Et₃N·HCl) formed was removed by filtration. The filtrate was concentrated in vacuo, and the residue was purified by column chromatog-raphy (n-hexane-EtOAc, ca. 4:1) to yield (S)-tert-butyl 2-[(R)-1-(2-aminonaphthalen-1-yl)naphthalene-2-yl-carbamoyl]pyrrolidine-1-carboxylate (0.42 g, 0.87 mmol, 44%).
To a solution of (S)-tert-butyl 2-[(R)-1-(2-aminonaphthalen-1-yl)naphthalene-2-yl-carbamoyl]pyrrolidine-1-carboxylate (175 mg, 0.36 mmol) in anhyd THF (5 mL), Et₃N (50 µL, 0.36 mmol) was added and the resulting mixture was cooled to 0 °C. Then benzoyl chloride (45µL, 0.36 mmol) was added dropwise, the mixture was stirred for 2 h, and the white precipitate (Et₃N·HCl) was removed by filtration. The filtrate was concentrated in vacuo and then the residue was purified by column chromatography (n-hexane-EtOAc, 7:3) to give (S)-tert-butyl 2-[(R)-1-(2-benzamido)naphthalene-1-yl]naphthalene-2-yl-carbamoylpyrrolidine-1-carboxylate (198 mg, 0.34 mmol) in 94% yield.
To a solution of (S)-tert-butyl 2-[(R)-1-(2-benzamido)naph-thalene-1-yl]naphthalene-2-yl-carbamoyl-pyrrolidine-1-carboxylate (198 mg, 0.34 mmol) in CH₂Cl₂ (680 µL), excess TFA (340 µL), and Et₃SiCl (45 µL) was added. The resulting mixture was stirred for 2 h at r.t. The volatile compounds were removed and the pH of the residue was adjusted to <7 by the addition of a sat. aq solution of NaHCO₃, the product was extracted with CH₂Cl₂, and dried over MgSO₄. The solvent was removed to give pure 5b (160 mg, 0.33 mmol, 97%). Mp 80-82 °C; [α]_D ²⁵ +10.9 (c 0.80, CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ = 9.70 (1 H, s), 8.80 (1 H, AB/2, J = 9.0 Hz), 8.55 (1 H, AB/2, J = 9.0 Hz), 8.09 (1 H, AB/2, J = 9.1 Hz), 8.08 (1 H, AB/2, J = 9.1 Hz), 7.95 (2 H, dd, J = 3.8, 8.1 Hz), 7.86 (1 H, br s), 7.68-7.11 (11 H, m), 3.58 (1 H, dd, J = 4.4, 9.4 Hz), 2.57 (1 H, dt, J = 9.9, 7.2 Hz), 1.90-1.82 (1 H, m), 1.59 (1 H, ddt, J = 12.5, 7.2, 4.9 Hz), 1.44-1.36 (1 H, m), 1.26 (1 H, s), 1.15 (1 H, dq, J = 20.0, 7.3 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 174.1, 165.4, 135.2, 135.0, 134.4, 132.6, 132.5, 131.7, 131.2, 131.1, 130.2, 130.0, 128.6, 128.3, 128.2, 127.5, 127.1, 126.7, 125.6, 125.23, 125.19, 125.1, 121.2, 120.8, 60.6, 46.6, 30.5, 25.6. HRMS (ESI): m/z calcd for C₃₂H₂₈N₃O₂: 486.2176; found: 486.2171.
Aldol Reaction; General Procedure
To a stirred solution of a catalyst (0.1 mmol) in dioxane (4 mL) at 0 °C, acetone (1 mL) (or other ketones) and an aldehyde 6 (1 mmol) were added under air in a closed system. The reaction mixture was stirred at 4 °C for 68 h. Then the reaction mixture was diluted with EtOAc and washed with a sat. aq solution of NH₄Cl. The organic layer was separated and dried over Na₂SO₄. Column chromatography (silica gel, hexanes-EtOAc) gave pure aldol 7.