Homodiphenylprolinol Methyl Ether as a Highly Efficient Catalyst for Asymmetric Michael Addition of Ketones to Nitroalkenes

Abstract

A series of novel homoprolinol analogues and ethers were developed and evaluated in direct Michael addition of ketones to nitroalkenes. Excellent yields (up to 99%), diastereoselectivities (up to 98% dr) and enantioselectivities (up to 98% ee) were achieved in the presence of 5 mol% homodiphenylprolinol methyl ether as catalyst and 5 mol% o-methylbenzoic acid as the additive at room temperature.

Key words

homodiphenylprolinol methyl ether - organocatalyst - asymmetric Michael addition - ketone - nitroolefin

References and Notes

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11

The Synthesis and Characterization of the Catalyst 3k.
Compound 8a (see Supporting Information; 24.8 g, 62 mmol) was dissolved in MeI (2 mL) and THF (10 mL), NaH (310 mmol) was added slowly to the stirred mixture over a course of 30 min at 0 ˚C under N₂. The reaction mixture was then stirred overnight and quenched with H₂O. Excess MeI was removed under reduced pressure in a well-ventilated hood. The residue was dissolved in EtOAc and partitioned between EtOAc and H₂O. The organic layers were collected, washed with brine, dried over with MgSO₄, filtered, and concentrated to give colorless oil. The oil was eluted through a SiO₂ column by EtOAc-hexane gave pure 9a with yield 70%.
The resulting 9a was dissolved in MeOH (6 mL) and Pd/C (20% in weight) was added. The mixture was stirred overnight at r.t. under H₂ atmosphere (1.013 bar). Then, the mixture was filtered through Celite and the solvent evaporated under reduced pressure to afford the crude product, which was further purified by flash column chromatography on SiO₂ (CH₂Cl₂-MeOH = 90:10) to afford the title compounds 3k (Scheme 2). White solid, mp 86-87 ˚C, [α]_D ^²5 +27.0 (c 1.0, CHCl₃). ^¹H NMR (300 MHz, CDCl₃): δ = 1.17-1.23 (m, 1 H), 1.50-1.71 (m, 3 H), 1.90 (s, 1 H), 2.46-2.52 (dd, J = 14.2, 4.7 Hz, 1 H), 2.56-2.68 (m,
2 H), 2.76-2.82 (m, 1 H), 2.87-2.94 (m, 1 H), 3.06 (s, 3 H), 7.17-7.36 (m, 10 H) ppm. ^¹³C NMR (75.5 MHz, CDCl₃): δ = 23.8, 32.1, 40.9, 45.7, 50.5, 54.5, 82.3, 126.5, 126.7, 126.8, 127.0, 127.8, 127.9, 145.3, 145.5 ppm. IR (KBr):
ν = 3416, 3363, 3022, 2958, 2826, 1618, 1599, 1491, 1444, 1400, 1189, 1155, 1122, 1065, 916, 849, 752, 698, 621, 594 cm^{- ¹}. HRMS (TOF): m/z calcd for C₁₉H₂₄NO [M + H]⁺: 282.1858; found: 282.1832.

Scheme 2

12

The trimethyl silyl ether showed good catalytic reactivity and slightly decreased diastereoselectivity (up to 97:3) and enantioselectivity (up to 93% ee) compared to 3k. Unfortunately, it was unstable and easily decomposed into alcohol.

13

When benzoic acid was used as cocatalyst, the same good results were obtained at r.t. (99% yield, 96% ee and 92% dr after 24 h). But, when the reaction proceeded at 0 ˚C, benzoic acid has shown slightly lower reactivity (58% yield) than o-methylbenzoic acid (63% yield) with the same stereoselectivities (99% ee, 98% dr) after 48 h.

14

Typical Procedure for the Direct Asymmetric Michael Addition of Ketones to Nitroolefins
To a stirred solution of catalyst (0.05 equiv) in hexane (0.5 mL) and ketone (3 equiv) at r.t. was added o-methylbenzoic acid (0.05 equiv) and, after 5 min, nitroolefin (1 equiv) was added. The reaction mixture was stirred at r.t. for the appropriate time. The solvent was evaporated and the residue was chromatography on SiO₂ column (hexane-EtOAc = 10:1) to afford the desired product. The ee of the product was determined by chiral HPLC analysis (Daicel Chiralpak AS-H or AD-H) to compare with their corresponding racemic peaks.