Enantio‐ and Diastereoselective Michael Addition Reactions of Unmodified Aldehydes and Ketones with Nitroolefins Catalyzed by a Pyrrolidine Sulfonamide

Abstract

Chiral (S)-pyrrolidine trifluoromethanesulfonamide has been shown to serve as an effective catalyst for direct Michael addition reactions of aldehydes and ketones with nitroolefins. A wide range of aldehydes and ketones as Michael donors and nitroolefins as acceptors participate in the process, which proceeds with high levels of enantioselectivity (up to 99 % ee) and diastereoselectivity (up to 50:1 d.r.). The methodology has been employed successfully in an efficient synthesis of the potent H(3) agonist Sch 50917. In addition, a practical three-step procedure for the preparation of (S)-pyrrolidine trifluoromethanesulfonamide has been developed. The high levels of stereochemical control attending Michael addition reactions catalyzed by this pyrrolidine sulfonamide, have been investigated by using ab initio and density functional methods. Transition state structures for the rate-limiting C--C bond-forming step, corresponding to re- and si-face addition to the reactive conformation of the key enamine intermediates have been calculated. Analysis of these structures indicates that hydrogen bonding plays an important role in catalysis and that the energy barrier for si-face attack in reactions of aldehydes to form 2R,3S products is lower than that for the re-face attack leading to 2S,3R products. In contrast, the energy barrier for re-face addition is lower than that for si-face addition in reactions of ketones. The computational results, which are in good agreement with the experimental observations, are discussed in the context of the stereochemical course of these Michael addition reactions.

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

“…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 (2-20) [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 up to 91% ee 5 [11] up to 68% ee 6 [12] up to 92% ee 7 [13] up to 94% ee 8 [14] up to 87% ee 9 [15] up to 98% ee 10 [16] up to 98% ee 11 [17] up to 91% ee 14 [20] up to 98% ee 15 [21] up to 99% ee 16 [22] up to 90% ee 17 [23] up to 99% ee 18 [24] up to 99% ee 20 [26] up to 97% ee 19 [25] up to 95% ee …”

A Novel Bifunctional Sulfonamide Primary Amine‐Catalyzed Enantioselective Conjugate Addition of Ketones to Nitroolefins

“…The absolute stereoconfiguration of the product 3a was determiend based on the comparision of the optical rotation of its known counterpart. [11] [a] Isolated yield. [b] Determined by chiral HPLC analysis (Chiralpak AS-H).…”

Highly Efficient Ion‐Tagged Catalyst for the Enantioselective Michael Addition of Aldehydes to Nitroalkenes

“…[2][3][4][5] In particular, O-TMS-protected diphenylprolinol (1; TMS= trimethylsilyl), [6] pyrrolidinesulA C H T U N G T R E N N U N G fon-A C H T U N G T R E N N U N G amide 2 (Tf = trifluoromethanesulfonyl) [7] and trans-4-hydroxyprolylamide 3 [8] ( Figure 1) act as effective organocatalysts for this class of reactions, affording almost complete enantioselectivities.…”