Michael addition prolines

Thus the product in such cases can exist as two pairs of enantiomers. In a di-astereoselective process, one of the two pairs is formed exclusively or predominantly as a racemic mixture. Many such examples have been reported. In many of these cases, both the enolate and substrate can exist as (Z) or (E) isomers. With enolates derived from ketones or carboxylic esters, (E) enolates gave the syn pair of enantiomers (p. 146), while (Z) enolates gave the anti pair. Addition of chiral additives to the reaction, such as proline derivatives, or (—)-sparteine lead to product formation with good-to-excellent asynunetric induction. Ultrasound has also been used to promote asymmetric Michael reactions. Intramolecular versions of Michael addition are well known. ... 

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... 

Hydroxamic acids constitute an important class of siderophores, which play a major role in iron solubilization and transport. Some of them are important as therapeutic agents. The Michael addition of nitroacetyl proline esters to allyl acrylate followed by Pd(0)-catalyzed intramolecular allyl transfer and subsequent reduction of the nitro group yields a novel class of cyclic hydroxamic acids related to pyroglutamic acid (Scheme 5.9).85... 

A very interesting organocatalyzed one-pot Michael addition/aldol condensation/Darzens condensation has been reported for the asymmetric synthesis of epoxy-ketones <06JA5475>. An initial asymmetric Michael condensation between 16 and 17 is catalyzed by proline derivative 18. Intermediate 19 then undergoes an aldol condensation followed by a stereoselective Darzens condensation to provide epoxy-ketone 20 in moderate yield and with surprisingly good enantiomeric excess. 

Several examples exist of the application of chiral natural N-compounds in base-catalyzed reactions. Thus, L-proline and cinchona alkaloids have been applied [35] in enantioselective aldol condensations and Michael addition. Techniques are available to heterogenize natural N-bases, such as ephedrine, by covalent binding to mesoporous ordered silica materials [36]. 

Michael additions using proline (2) as the organocatalyst have proven disappointing in terms of enantiocontrol, ° ° ° stimulating the search for a more selective enamine catalyst system. In this context, imidazolidinones (initially... 

Barbas, one of the pioneers of enamine catalysis, has incorporated iminium ion intermediates in complex heterodomino reactions. One particularly revealing example that uses the complementary activity of both iminium ion and enamine intermediates is shown in Fig. 12 [188]. Within this intricate catalytic cycle the catalyst, L-proline (58), is actively involved in accelerating two iminium ion catalysed transformations a Knoevenagel condensation and a retro-Michael/Michael addition sequence, resulting in epimerisation. 

On the basis of encouraging work in the development of L-proline-DMSO and L-proline-ionic liquid systems for practical asymmetric aldol reactions, an aldolase antibody 38C2 was evaluated in the ionic liquid [BMIM]PF6 as a reusable aldolase-ionic liquid catalytic system for the aldol synthesis of oc-chloro- 3-hydroxy compounds (288). The biocatalytic process was followed by chemical catalysis using Et3N in the ionic liquid [BMIM]TfO at room temperature, which transformed the oc-chloro-(3-hydroxy compounds to the optically active (70% ee) oc, (3-epoxy carbonyl compounds. The aldolase antibody 38C2-ionic liquid system was also shown to be reusable for Michael additions and the reaction of fluoromethylated imines. 

Mukaiyama et al. 200) synthesized optically active 3-substituted succinialdehyde acid esters (204) via a Michael-addition. The methyl ester of fumaraldehydic acid was converted into the corresponding aminal (203) by treatment with the (S)-proline-derived chiral diamine (99). The Michael-addition of Grignard reagent to the aminal, followed by hydrolysis produced stereoselectivily 3-substituted succinaldehydic acid ester (204) in good yield. 

Instead of introducing the (S)-proline-derived chiral auxiliary (206), its enantiomer in the Michael-addition, the authors obtained the enantiomeric product (208 ) having opposite optical rotation compared to (208). 

Mukaiyama-Michael addition of a chiral ketene acetal to nonprochiral vinyl ketones gives products of 72-75% ee.145 A chirally modified glycine derivative (Schiff-base) adds to vinylic phosphorus compounds to yield, after hydrolysis, products with 54-85% ee.146 Another chiral glycine equivalent was used for the preparation of homochiral proline derivatives via diastereoselective addition to a,3-unsatu-rated aldehydes and ketones.147-148... 

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... 

The synthesis starts with the preparation of diethyl (2-cyanoethyl)malonate (Expt 5.161) by the Michael addition of diethyl malonate to acrylonitrile. Hydrogenation over Raney nickel converts the cyanoethyl compound to the corresponding primary amine (41) which is converted into proline (isolated initially as the hydrochloride) by the reaction sequence shown. Liberation of the free amino acid from its salt is achieved in this case by treatment with triethyl-amine (cf. serine, Expt 5.183). 

A series of diaryl-2-pyrrolidinemethanols have been tested as catalysts for the enan-tioselective Michael addition of malonate esters to nitroalkenes.30 Bis-(3,5-dimethyl-phenyl)[(S)-pyrrolidin-2-yl]methanol (6), easily prepared from L-proline, has been found the most efficient bifunctional organocatalyst, providing up to 56% ee. 

The catalytic application of L-proline in the asymmetric Michael addition of unmodified aldehydes or ketones with nitroalkenes in ionic liquids has been studied. The ... 

The organocatalytic asymmetric Michael addition of 2,2-dimethyl-l,3-dioxan-5-one (143) to various nitroalkenes (144), using a number of proline-based catalysts, afforded... 

The MacMillan catalysts (42, 45), the Jorgensen catalyst (51), and proline itself can promote Michael additions by iminium ion formation with the acceptor enal or enone (A, Scheme 4.22). Secondary amines can also activate a carbonyl donor by enamine formation (Scheme 4.22, B) [36, 37]. 

N-terminal L-proline, again in DMSO as solvent [40], In this study the maximum ee in the addition of acetone to trans-2-nitrostyrene was 31%. Alexakis and Andrey successfully employed the bis-pyrrolidine 52 as catalyst for the addition of aldehydes and ketones to trans-fi-nitrostyrene [41], whereas Barbas and Betancort [42] were able to perform the Michael addition of unprotected aldehydes to nitroolefins using the pyrrolidine derivative 53 as catalyst (Scheme 4.24). 

This reaction is particularly suitable for the preparation of the Wieland-Miescher ketone 96, a very useful building block for construction of a broad variety of biologically active compounds such as steroids, terpenoids, and taxol. On the basis of the proline-catalyzed approach described above Barbas et al. recently reported an optimized procedure for formation of the chiral Wieland-Miescher ketone, 96 [105]. It has been shown that this synthesis (which comprises three reactions) can be performed as a one-pot synthesis. The desired product is obtained in 49% yield with enantioselectivity of 76% ee (Scheme 6.43). Here L-proline functions as an efficient catalyst for all three reaction steps (Michael-addition, cydiza-tion, dehydration). It is also worth noting that although many other amino adds and derivatives thereof were tested as potential alternative catalysts, L-proline had the best catalytic properties for synthesis of 96. This result emphasizes the superior catalytic properties of proline reported after previous comparative studies by the Hajos group [100, 101]. 

Organocatalyst (56), a pyrrolidine sulfonamide derived from L-proline, catalyses the direct Michael addition of aldehydes to nitrostyrene with high ee and de, apparently exploiting its bifunctional (acid-base) nature.220 ... 

Org. Lett. 1999, 1, 157 d) Baylis-Hillman reaction Y. Iwabuchi, M. Nakatani, N. Yokoyama, S. Hatakeyama, J. Am. Chem. Soc. 1999, 121, 10219 e) Michael-Addition using alkali metal salts of proline M. Yamaguchi, T. Shiraishi, M. Hirama,... 

The three-component reaction of indole (2) with sugar hydroxyaldehyde 281 and Meldrum s acid 282, with a catalytic amount of D,L-proline, afforded the 3-substitution product 283 as a single isomer [203]. The substituent possesses the czs-fused furo [ 3,2- b ] pyranonc skeleton. The proline catalyzes the Knoevenagel condensation of the sugar aldehyde 281 and Meldrum s acid 282 to provide the alkylidene derivative 284 of Meldrum s acid. Then a diastereo-selective Michael addition of indole and an intramolecular cyclization of this adduct 285 with evolution of carbon dioxide and elimination of acetone furnish the furopyranone in one-pot (Scheme 62). 

Prolines.1 The complex 2 undergoes base-catalyzed (CH,ONa) Michael addition to a,p-enals and -enones. Reaction of 2 with acrolein furnishes a dihydro-pyrrole-2-carboxylic acid which is reduced to (S)-proline. 

Enders D, Seki A (2002) Proline-catalyzed enantioselective Michael additions of ketones to nitrostyrene. Synlett 2002 26-28 Enders D, Vrettou M (2006) Asymmetric synthesis of (+)-polyoxamic acid via an efficient organocatalytic Mannich reaction as the key step. Synthesis 13 2155-2158... 

List B, Lerner RA, Barbas CF 3rd (2000) Proline-catalyzed direct asymmetric aldol reactions. J Am Chem Soc 122 2395-2396 List B, Pojarliev P, Martin HJ (2001) Efficient proline-catalyzed Michael additions of unmodified ketones to nitro olefins. Org Lett 3 2423-2425 List B, Pojarliev P, Biller WT, Martin HJ (2002) The proline-catalyzed direct asymmetric three-component Mannich reaction scope, optimization, and application to the highly enantioselective synthesis of 1,2-amino alcohols. J Am Chem Soc 124 827-833... 

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