Asymmetric Bisprolinamide-Catalyzed Cross-Aldol Reaction of Aldehydes

Abstract

A C ₂-symmetric para-orientation bisprolinamide catalyst has been designed to effectively promote the enantioselective coupling reactions of aldehydes, which delivered the systematic investigation on amine-amide catalysis. Transforming the monoprolinamide 1a into the bisprolinamide 2a improved not only the stereoselectivities but also the reactivities. With this strategy, the functionalized β-hydroxyaldehydes could be furnished in high yields (up to 99%) with good selectivities (up to 8:92 syn/anti and 99% ee) even in the presence of 5 mol% of catalyst 2a. Based on the preliminary experiment and the absolute configuration of cross-aldol adduct, a rational transition state A was proposed to explain the origin of reactivity and selectivity.

Key words

asymmetric catalysis - bisprolinamide - cross-aldol reactions - hydroxyaldehydes - nonlinear effect

References and Notes

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6

Typical Procedure for the Preparation of Bisprolinamides 2a-d:(i) To a solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (678.0 mg, 3.15 mmol) in CH₂Cl₂, dicyclohexylcarbodiimide (DCC; 649.9 mg, 3.15 mmol) and benzotriazol-1-ol (HOBt; 425.6 mg, 3.15 mmol) were added at r.t. under stirring. After 10 min, benzene-1,4-diamine (162.2 mg, 1.5 mmol) was added. The mixture was allowed to be stirred for 10 h and filtered. The filtrate was washed with 1 M KHSO₄, sat. NaHCO₃ and brine and was then dried over anhyd Na₂SO₄ and concentrated.(ii) To the residue in CH₂Cl₂, TFA (3.15 mL) was added and stirring was continued for an hour. Then the solution was concentrated in vacuo to a glutinous phase and H₂O (4 mL) was added. The pH of the mixture was brought into the range of 8-10 by the addition of 2 M NaOH. The aqueous phase was extracted with EtOAc. The EtOAc extracts were pooled, washed with brine, dried over anhyd Na₂SO₄ and evaporated in vacuo. The residue was purified by flash column chromatography using MeOH-EtOAc (1:2) as eluent to afford the bisprolinamide 2a as a white solid (390.1 mg, 86% yield). ¹H NMR (400 MHz, CDCl₃): δ = 9.71 (s, 2 H), 7.56 (s, 4 H), 3.86 (dd, J ₁ = 9.2 Hz, J ₂ = 5.2 Hz, 2 H), 3.06-3.12 (m, 2 H), 2.96-3.02 (m, 2 H), 2.38 (s, 2 H), 2.17-2.26 (m, 2 H), 2.00-2.08 (m, 2 H), 1.80-1.82 (m, 4 H).

7

Typical Procedure for the Catalytic Asymmetric Cross-Aldol Reaction of Aldehydes:To the mixture of bisprolinamide 2a (1.5 mg, 0.005 mmol) and 4-nitrobenzaldehyde (15.1 mg, 0.1 mmol) in NMP (0.2 mL) was added hexanal (24.5 µL, 0.2 mmol) at 0 °C. The mixture was stirred for 30 h and purified by flash column chromatography using EtOAc-PE (1:2) as eluent to afford (2S)-2-[(1R)-hydroxy(4-nitrophenyl)methyl]hexanal (3a; 24.8 mg, 99% yield, 8:92 syn/anti, 99% ee).Typical Procedure for Determining the Enantiomeric Excess of 3a-e (Table 2):To a solution of (2S)-2-[(1R)-hydroxy(4-nitrophenyl)methyl]hexanal (3a; 24.8 mg) in CH₂Cl₂ (1 mL) were added 2,2-dimethyl-1,3-propanediol (10.4 mg, 0.10 mmol), triethyl orthoformate (13.3 µL, 0.08 mmol) and p-toluenesulfonic acid (catalytic amount) in this sequence at r.t. After 2 h of stirring, the reaction was quenched with H₂O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by flash column chromatography on silica gel (PE-EtOAc, 15:1) to afford (1R,2S)-2-(5,5-dimethyl-1,3-dioxan-2-yl)-1-(4-nitrophenyl)hexan-1-ol quantitatively as a colorless oil; [α]_D ²⁵ +9.5 (c = 0.50, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 8.22 (d, J = 8.8 Hz, 2 H), 7.54 (d, J = 8.8 Hz, 2 H), 5.00 (dd, J ₁ = 6.0 Hz, J ₂ = 4.8 Hz, 1 H), 4.47-4.48 (m, 2 H), 3.64-3.71 (m, 2 H), 3.37-3.41 (m, 2 H), 1.97-1.99 (m, 1 H), 1.23-1.26 (m, 9 H), 0.84-0.86 (m, 3 H), 0.75 (m, 3 H). HPLC (Chiralcel OJ-H, hexane-i-PrOH, 96:4; flow rate: 0.5 mL/min, 23 °C, UV: λ = 215 nm): t _R(minor) = 20.665 min, t _R(major) = 22.750 min.