Addition chiral aminals, pyrrolidine

Scheme 9.17 Chiral aminal-pyrrolidine organocatalyst Ik for Michael additions.

A Knoevenagel condensation/Michael addition sequence has been reported by Barbas III and coworkers (Scheme 2.70) [158] using benzaldehyde, diethyl malonate, and acetone in the presence of the chiral amine (S)-l-(2-pyrrolidinyl-methyl)-pyrrolidine (2-301). As the final product the substituted malonate 2-302 was isolated in 52% yield with 49% ee. 

Highly enantioselective organocatalytic Mannich reactions of aldehydes and ketones have been extensively stndied with chiral secondary amine catalysts. These secondary amines employ chiral prolines, pyrrolidines, and imidazoles to generate a highly active enamine or imininm intermediate species [44], Cinchona alkaloids were previonsly shown to be active catalysts in malonate additions. The conjngate addition of malonates and other 1,3-dicarbonyls to imines, however, is relatively nnexplored. Snbseqnently, Schans et al. [45] employed the nse of Cinchona alkaloids in the conjngate addition of P-ketoesters to iV-acyl aldimines. Highly enantioselective mnltifnnctional secondary amine prodncts were obtained with 10 mol% cinchonine (Scheme 5). 

The stereochemical information on the chiral center formed by the mechanism outlined in Scheme 2.25 is determined by the R -substituent in the chiral amine. Here, two types of interaction are operating, namely electronic and steric. The electronic interaction [2] outlined to the left in Figure 2.5 seems to take place when the R -substituent has an acidic hydrogen atom/proton such as a carboxylic acid or tetrazole in the 2-position of a pyrrolidine ring. The acidic hydrogen atom in these R -substituents interacts with a lone pair in the heteroatom Y of the incoming electrophile. The electrophilic addition of the heteroatom takes thus place... 

Two different chiral auxiliary approaches have been applied to the synthesis of NPS 1407 and it s enantiomer (119) (147). NPS 1407 is an antagonist of the glutamate NMDA receptor that has in vivo activity in neuroprotection and anti-convulsant assays. The J2-en-antiomer was synthesized in four steps from (116)with the chiral center introduced by. a completely stereoselective alkylation of hydra-zone (117). The chiral auxiliary, jS-( )-l-ami-no-2-(methoxylmethyl)pyrrolidine (SAMP), was introduced by condensation with aldehyde (116) and removed by catalytic hydro-genolysis. In the second method, the S-enan-tiomer was formed in a four-step sequence with the chiral center installed by the Michael addition of chiral amine (121) (formed in one step from the readily available a-methylben-zylamine) to benzyl crotonate (120). NPS 1407 (123) was found to be 12 times more potent than it s enantiomer (119)at the NMDA receptor in an in vitro assay. 

Hilmersson and Davidsson studied by means of intensive NMR investigations a mixed 1 1 complex of n-BuLi and the Hthiated methoxyamine 6 (Scheme 1) in diethyl ether at -80°C [68]. A fluxional exchange between tetrameric and dimeric structures of the chiral Hthiated pyrrolidine 14 and -BuLi is apparent in diethyl ether solution [69]. With the Hthiated amine 15, a derivative of 6,75% ee of (S)-l-phenyl-l-pentanol was obtained in n-BuLi additions to PhCHO, using a ratio of 1.0 0.45 0.25 in diethyl ether at -116°C [37]. The N-methyl derivative gave only 2% ee, while the N-isopropyl derivative 16 yielded 82% ee under the same conditions. This demonstrates Ae crucial role of the N-isopropyl substituent in 16. Addition of dimethoxymethane increased the enantioselectivity of 16 to 91% ee of (S)-l-phenyl-l-pentanol. With Hthiated 16, enantioselectivities of up to 98.5% ee were achieved in butylations of aHphatic aldehydes [70]. Hilmersson demonstrated that the mixed Hthium amide/ -BuLi aggregate alkylates aldehydes faster than the pure -BuLi oHgomers, Eq. (2) [71]. 

Nal chiral amines such as DBU, ° (S)-2-[bis(3,5-dimethylphenyl)methyl]pyrrolidine, C2-symmetric (2S,55)-2,5-diphenylpyrrolidine, (-)-quinine, and proline polymer catalysts such as antibody 38C2" and polymer-anchored chiral catalysts and solid base catalysts such as MgO and Mg-Al-O-r-Bu hydrotalcite. Furthermore, the solvent-free Michael addition has been established by application of CeCb 7H20-NaI as catalyst or microwave irradiation of reactants on BiCb or Cdh, EuCb, CeCb 5H20, and alumina surfaces. It is interesting that the thermal treatment or microwave irradiation of 1,5-ketodiesters or 1,5-diketones in DMSO in the presence of NaX (X = Cl, Br, I) results in the retro-Michael addition. ... 

In 2003, Melchiorre and Jprgensen found modest enantioselectivities in the first catalytic version of the direct enantioselective Michael addition of aldehydes to vinyl ketones catalyzed by the chiral amine (5)-2-[bis(3,5-dimethylphenyl)methyl] pyrrolidine (21) (Scheme 2.13) [34]. Further studies on the reaction carried out by different groups led to more efficient catalysts such as diphenylprolinol ethers 22a [35] and 22b [36] and imidazohdinone 23 [37] (Schane 2.13). The highest enantioselectivities reported to date (95-99% ee) have been obtained with catalyst 22b employing significantly lower catalyst loadings (1-5 mol%) than those reported with other organocatalysts (20-30 mol%)[36]. 

The amine-catalysed asymmetric conjugate addition of aldehydes to nitroalkenes is a powerful tool for stereoselective carbon-carbon bond formation, and hence, a large number of chiral amine catalysts have been developed to date. ° In most amine-catalysed reactions, q n-conjugate adducts were obtained as major diastereomers. For instance, the reaction catalysed by a chiral pyrrolidine (5 )-6 gave a sy -conjugate adduct with excellent enantioselectivity (Scheme 17.13). In contrast, the reaction using a biphenyl-based amine catalyst (S)-7 is complementary to most amine-catalysed... 

The first organocatalytic asymmetric Michael addition of unmodified aldehydes with nitroalkenes was reported by Barbas and co-workers [4]. In light of the concept of enamine catalysis, many chiral amines have been screened and (5)-2-(morpho-linomethyl)pyrrolidine 1 (Scheme 5.1) proved to be an effective catalyst to furnish the 7-formyl nitro products in high yields (up to 96%) with moderate enantiose-lectivity (up to 78%). Encouraged by this pioneering research on using chiral secondary... 

The addition of nitroalkanes to chalcones is more attractive since the Michael adducts are useful intermediates for a variety of further elaborated stmctures such as chiral aminocarbonyls, pyrrolidines, y-lactams, and y-amino acids. Thus, many elegant organocatalysts such as cinchona alkaloid-derived chiral tertiary amine thiourea 69 [67] or suqaramide 70 [68] and bisquaternary ammonium salts [69] 71a or 71b have been developed for such a reaction in recent years (Scheme 5.33). In addition, a,(3-unsaturated A -acylpyrroles [70] and 4-oxo-enoates [71] were also applicable in the highly enantioselective conjugated addition with nitroalkanes (Scheme 5.34). 

Readily available chiral amines related to the Betti base [phenyl(2-hydroxy-l-naphthyl)methanamine] catalyse enantioselective addition of diethylzinc to aldehydes in moderate to excellent ee Observed enantioselectivities in addition of diethylzinc to aldehydes catalysed by a series of (5)-proline-derived pyrrolidines have been explained in terms of steric effects. New 2,5-diazabicyclo[2.2.1]heptanes have been applied to enantioselective addition of diethylzinc to benzaldehyde. (S)-2-(3-Methyl-2-pyridyl)-3,5-di-r-butylphenol (76) has been used as an enantioselective catalyst of diethylzinc addition to benzaldehydes. Reaction in toluene shows a significant variation in % ee with temperature, including observation of an inversion temperature with maximum ee. This value varies with the nature of the para-substituent in the aldehyde, and the overall behaviour may be due to a shift in the rate-determining step of the reaction. Other reports of zinc reagents include enantioselective addition of diethylzinc to aldehydes addition of diphenylzinc to aldehydes using a chiral ferrocene-based hydroxyoxazoline catalyst in up to 96% ee and 3-exo-morpholinoisoborneol has been proposed as a more convenient and efficient enantioselective catalyst of alkylzincs than Noyori s original 3-exo-dimethylamino catalyst. ... 

Among several organocatalysts derived from L-proline (1) as a chiral source, pyrrolidine-tertiary amine conjugates constitute a powerful and useful family in asymmetric synthesis [115]. In 1994, Kawara and Taguchi reported pioneering work on the use of such catalysts in asymmetric Michael addition reactions [116]. Since then, several related catalysts have been developed. Figure 1.5 lists representative examples. 

Inspired by the success of intramolecular addition and tautomerization of aldehydes with a pendant alkyne through cooperative catalysis of a secondary amine and an An complex, in 2008, Yang et al. reported a cascade reaction with the combination of a copper complex and an achiral secondary amine catalyst for the synthesis of attractive carbocycles [48]. This chemistry merged a pyrrolidine-promoted Michael addition via iminium ion intermediates and a Cu-catalyzed cycloisomerization protocol (Scheme 9.54). Various ketones and alkyne-tethered active methylene compounds could be converted into densely functionalized cyclopentene derivatives. Although the asymmetric version was not given, the chemistry described here was amenable for the implementation of asymmetric synthesis of such functionalized molecules by a combination of chiral amines and suitable Au complexes. 

As well as the disubstituted C2-symmelrie pyrrolidines E and F, the monosubstituted (f> )-2-(mcthoxymethyl)pyrrolidine G can be used as chiral auxiliary for the diastereoselecti ve addition of organomctallic reagents to a-oxo amides16. As with the phenylglyoxylic acid derivatives derived from amines E and F. methyllithium or methylmagnesium bromide in diethyl ether preferentially attack the (,S)-mms-conformer 11 (R = ( 6H5), leading to predominant formation of the (2 S)-diastercomer by Re-side attack. 

The enantioselectivity of Sn(II) enolate reactions can be controlled by chiral diamine additives. These reagents are particularly effective for silyl thioketene acetals.162 Several diamines derived from proline have been explored and l-methyl-2-(l-piperidinomethyl)pyrrolidine 21 is an example. Even higher enantioselectivity can be achieved by attachment of bicyclic amines to the pyrrolidinomethyl group.163... 

Using l-(2-nitrovinyl)pyrrolidines 108 or 111 as Michael acceptors, the addition of the Reformatsky reagent is followed by amine elimination. A formal vinylic substitution ensues, which can take advantage of the presence of stereocenters in the pyrrolidine moiety, affording new chiral nitroolefins 110151 and 113152, as reported in equations 64 and 65, respectively. In both cases, zinc enolates 109 and 112 are prepared by lithia-tion/transmetallation of the parent ester. 

The use of ketoaminals based on pyrrolidine as chiral auxiliaries has been demonstrated as anotiner entry to optically active a-hydroxycarbonyls. 7 fhe aminals (76 Scheme 6) are readily obtained from a chiral diamine (75) and glyoxal. Addition of Grignard reagents to (76), followed by hydrolysis, provides a chiral a-hychoxy aldehyde (78) with the (5)-contiguration. (Optical purities are measured in die 94—95% range. The chiral diamine can be recovered unchanged from the reaction mixture. 

Addition and cyclization reactions. Chiral propargylic amines are obtained from aUcynylation of imines by catalysis of the silver salt of IB. The enantiomer of phosphate ID also finds use in the addition of indole to a-acetaminostyrenes. One more catalyst for intramolecular hydroamination to form pyrrolidine derivatives is the silylated 3. The... 

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