Proline-Catalyzed Enantioselective Michael Additions of Ketones to Nitrostyrene

Abstract

Proline-catalyzed Michael additions of ketones to nitrostyrene were examined to obtain optically active g-nitro ketones. The catalytic asymmetric 1,4-additions afforded the desired g-nitro ketones in medium to excellent yields and up to 97% de of the syndiastereomers and 76% ee.Key words: asymmetric synthesis, asymmetric catalysis, Michael additions, nitro ketones, nitroalkenesIn recent years, we have been studying various asymmetric Michael additions with nitroalkenes taking advantage of their low tendency for 1,2-addition and the anion-stabilizing effect of the nitro group. 2 In the case of ketones, the Michael adducts to nitroalkenes are useful as precursors to other functionalities that can be derived from the venerable nitro group. 3 Therefore, we have recently described an efficient asymmetric synthesis of a,b-disubstituted g-nitro ketones via a-t-butyldimethylsilyl ketones. 2f,g Although, our reliable methodology leads to the products in good overall yields with excellent diastereo-and enantiomeric excesses, a catalytic variant is of interest.In addition, the enantioselective stoichiometric Michael additions between ketone lithium enolates to nitroalkenes by chiral amines and chiral lithium amides, 4a,b and between silyl enol ethers derived from ketones to nitroalkenes mediated by chiral Lewis acids have been reported. 4c However, very few catalytic asymmetric Michael additions of ketones to nitroalkenes, 5-7 excepting the use of active methylene compounds have been reported. Based on the pioneering work of Yamada et al. 8a and Eder, Sauer, Wiechert, Hajos and Parrish, 8b,c proline-catalyzed versions of enamine-related reactions have been studied recently. 7,9 In addition, Michael additions of proline derived enamines to conjugated nitroalkenes have been described by Seebach et al. 10

Asymmetric Conjugate Addition of Ketones to β‐Nitrostyrenes by Means of 1,2‐Amino‐Alcohol‐Derived Prolinamides as Bifunctional Catalysts.

“…Compounds 27aa, [7] 27ba, [11] 27ca, [8b] 27da, [8a] have been previously described and spectroscopic data were in agreement with published. See supporting information for HPLC separation conditions.…”

“…[7] In contrast, α-methyl-L-proline (28), a very efficient organocatalyst for the intramolecular α-alkylation of aldehydes, [38] was not effective in the 1,4-addition after long reaction periods ( (30) has been presented as a valid alternative to proline and proline derivatives in different asymmetric organocatalytic processes due to its high solubility in organic solvents. [39] However, the catalytic activity of 30 in the conjugate addition of 3-pentanone to nitrostyrene in MeOH resulted very low affording 27aa in a 58% conversion and 38%…”

“…A related study by Enders showed a strong solvent effect in the reaction since in MeOH the enantioselectivity could be increased to 76% for the major syn diastereomer in the reaction between 3-pentanone and trans-β-nitrostyrene employing a 20 mol% of Lproline as catalyst. [7] Since these preliminary studies, very effective catalytic systems (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] have been developed for the asymmetric Michael reaction of ketones with nitroalkenes being the process generally syn-selective (Scheme 1). Best improvements to this reaction have been mostly achieved using pyrrolidine-based catalytic derivatives.…”

“…Furthermore, catalyst 15 and the fluorous sulfonamide 19 can be easily recycled by precipitation and fluorous solid-phase extraction, respectively, and reused without significant loss of activity and stereoselectivity. [7] up to 76% ee 2 [8] up to 81% ee 3 [9] up to 99% ee [18] up to 86% ee 13 [19] up to 91% ee [25] …”

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“…The re-discovery of organocatalysis 7 started with proline (cf. Yamada, Wiechert, and Hajos in 1969, 1971, and 1974) and one of the reactions studied first in 2001 was the Michael addition of ketones to nitrostyrene (List, Barbas, Enders 8 ), a type of reaction dear to the Enders group. 9 While other organocatalysts, such as chiral carbenes, squaramides, and Brønsted acids, were also used by Dieter in previous and subsequent investigations, the most prominent catalysts employed in his recent publications are proline-derived pyrrolidines, especially those of the HayashiJørgensen-type (S)-or (R)-2-[Arl 2 (R 3 SiO)C]-pyrrolidines.…”