Rubidium prolinate

Hanessian described the facile addition of cyclic and acyclic nitroalkanes to cyclic a,P-unsaturated ketones using L-proline 58 as the catalyst (3-7 mol%) in the presence of 2,5-dimethylpiperazine [100], The reactions proceeded efficiently at room temperature and consistently provided adduct 59 with increased levels of enantioselectivity when compared with the rubidium prolinate method disclosed by Yamaguchi [29] (Scheme 24). The presence of trace amounts of water in the reaction was found to be essential, suggesting a hydrolytic step is involved in the catalytic... 

D ee achieved by Yamaguchi et al. using rubidium prolinate as catalyst (refs. 25,26). 

Unsaturated acetals undergo a similar process when NiClj and a chiral phosphine 58 are added." The reaction of enones with diethylzinc is catalyzed by CuCOTf) which is coordinated to 59. Rubidium prolinate acts both as a base and chirality elicitor in reactions involving nitroalkanes, and an azacrown ether constructed out of sugar also induces the... 

Scheme 3.16 The Michael reaction of malonates and enones catalyzed by rubidium prolinate and proline-derived tetraalkylammonium salt 52.

Yamaguchi and coworkers reported in the early 1990s the use of alkali metal salts of proline (e.g., rubidium prolinate) for the conjugate addition of malo-nates to enals with promising results [8]. Soon after, Taguchi and coworker developed a similar reaction using (2-pyrroUdyl)(alkyl)ammonium hydroxide as catalyst [9]. 

Yamaguchi and coworkers have found that proline rubidium salts catalyze the asymmetric Michael addition of nitroalkanes to prochiral acceptors. When (25)-L-prolines are used, acyclic ( )-enones give (S)-adducts. Cyclic (Z)-enones give (R)-adducts predominantly (Eq. 4.139).203 Recently, Hanessianhas reported that L-proline (3 7% mol equiv) and 2,5-dimethylpiperazine are more effective to induce catalytic asymmetric conjugate addition of nitroalkanes to cycloal-kanones.204... 

In a series of reports between 1991 and 1997 Yamaguchi showed that rubidium salts of L-proline (9) catalysed the conjugate addition of both nitroalkanes [29, 30] andmalonates [31-33] to prochiral a,p-unsaturated carbonyl compounds in up to 88% ee (Scheme 1). Rationalisation of the selectivities observed involved initial formation of an iminium ion between the secondary amine of the catalyst and the a,p-unsaturated carbonyl substrate. Subsequent deprotonation of the nucleophile by the carboxylate and selective delivery using ion pair... 

Another interesting example was reported by Yamaguchi et al. by using a simple L-proline rubidium salt 27 (Scheme 8D. 15) [32], A reversible iminium salt formation, involving the amine moiety of the catalyst and the carbonyl group of an enone, was proposed as the key intermediate. 

Chiral crown ether phosphine-palladium complexes have been used to catalyse the alkylation of carbanions derived from a-nitro ketones and a-nitro esters,63 and proline rubidium salts have been used to catalyse asymmetric Michael addition of nitroalkanes to prochiral acceptors 64 80% enantioselectivity can be achieved in each case. 

A rubidium salt of proline (5-10 mol%) has been reported to catalyse the asymmetric Michael addition of nitroalkanes to prochiral acceptors. When L-proline was used, acyclic (I )-enones produced (.S )-adducts. whereas cyclic (Z)-enones gave (R )-adducts.88... 

Cheap and readily available L-proline has been used numerous times for the intermediate and reversible generation of chiral iminium ions from a,/ -unsaturated carbonyl compounds. For example, Yamaguchi et al. reported in 1993 that the rubidium salt of L-proline catalyzes the addition of di-iso-propyl malonate to the acyclic Michael acceptors 40a-c (Scheme 4.13), with enantiomeric excesses as high as 77% [22], With 2-cycloheptenone and 2-cyclohexenone as substrates ca 90% yield and ee of 59% and 49% were obtained. Later the enantioselectivity of this process was increased to a maximum of 88% ee in the addition of di-tert-butyl malonate to the E-pentenone 40a in the presence of 20 mol% Rb-L-prolinate and 20 mol% CsF [23], Taguchi and Kawara employed the L-proline-derived ammonium salts 41a and... 

The rubidium salt of L-proline 3 catalyzed the asymmetric Michael reaction of malonate and nltroalkane with enones. High enantiomeric excesses were realized... 

In order to broaden the scope of the amine-catalyzed Michael addition, Yamaguchi examined the system of amine and alkali metal salt [2]. Although amine did not promote the addition of malonate to enones, the LiCl04-Et3N catalyst turned out to be effective. Optically active amines, however, gave racemic adducts. As an extension, the (S)-proline rubidium salt, (S)-21, was developed, which possessed a cation and an amine moiety in the same molecule [2, 22]. The catalyst (S)-21 in chloroform promoted the asymmetric addition of malonate to a wide range of enones and enals as exemplified by the reaction of... 

Under an argon atmosphere, a mixture of 1.30 mL diisopropyl malonate (6.72 mmol), 0.50 mL 2-cycloheptenone (4.48 mmol), and 46 mg L-proline rubidium salt (0.22 mmol) in 5 mL chloroform was stirred for 59 h at 25°C. The reaction was quenched with 2 M HCl, and organic materials were extracted twice with EtOAc. The combined extracts were washed with brine, dried over Na2S04, filtered, concentrated, and flash chromatographed over silica gel to give 1.21 g diisopropyl (7 )-(+)-(3-oxocycloheptyl)malonate, in a yield of 91%, and 59% e.e. 

The scope of the reaction was later enlarged to malonates as nucleophiles employing L-proline rubidium salt [156,188] and L-proUne-derived ammonium salts [211], which turned to be efficient catalysts for the asymmetric addition of malonates to cyclic and acyclic enones with enantioselectivities of up to 88% ee. 

In the 1990s, Yamaguchi and Taguchi used proline derivatives (or lithium or rubidium salts of proline) as catalysts for the enantioselective Michael reactions of enals and suggested iminium ion activation as the catalytic principle [22]. 

Yamaguchi s pioneering report on asymmetric Michael addition of nitromethane to cyclic ketones catalyzed by proline rubidium salt [58], Hanessian and Pham [59] developed the first organocatalytic system for such a reaction where proline and trans-2,5 -dimethy Ipiperazine 64 additive were used as the catalyst. Later on, with the same additive, improved selectivities were obtained when using pyrrolidine-tetrazole 61 [60] and tra i-4,5-methano-L-proline 62 [61] as the organocatalyst. In 2008, multifunctional primary amine 63 [62] was also proved to be effective catalyst for such a reaction (Scheme 5.31). 

Later, they revisited their prototypical catalyst system. After a series of screening of the metal (Li, Na, K, Rb, Cs, Mg, Ca, Sr, Ba), sodium and potassium L-prolinate were found more effective than the lithium salt. Rubidium and cesium salts enhanced the stereoselectivity. Increasing the size of the ester group of the malonate resulted in a higher... 

A typical procedure for the Michael addition catalyzed by metal prolinate According to the literature, under an argon atmosphere, to a mixture of di(tert-butyl) malonate (0.88 mL, 4.5 mmol), 2-cyclohexen-l-one (0.25 mL, 2.5 mmol) in CHCI3 (2mL), L-proline rubidium salt (100 mg, 0.50 mmol), and CsF (70 mg, 0.50 mmol) were added, and the mixture was stirred vigorously at room temperature for 48 hours. The reaction was then treated with 2-M HCl and was extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (Na2S04), filtered, concentrated, and fiash chromatographed over silica gel, giving the (i )-(+)-adduct (658 mg, 84%) with 65% ee. 

In 1993, Yamaguchi reported an important milestone in the use of chiral amines as catalysts for enantioselective conjugate addition reactions (Equation 22) [114, 115]. The rubidium salt of proline (120) proved particularly ef ficient by comparison to proline or to its other metal salts. In the course of studies aimed at optimizing the process, beneficial effects were observed in the presence of CsF as an additive. This procedure led to the production of Michael adduct 121 from enone 118 in 88% ee [115]. 

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