Chiral aminal-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). 

This reaction can furthermore be applied on chiral aminals, affording a straightforward route to optically pure frawi-2,5-pyrrolidines or chiral alkyl-substituted 1,3-oxazoUdines. This method was used for the en an tio selective synthesis of substituted piperidines . 

The cis relative configuration was accounted for by a chair-like transition state in which the zinc enolate and the olefin moiety are coplanar as described in 127. Using chiral amines as starting materials, pyrrolidines were obtained with complete diastereoselectivity and excellent enantiomeric excess (equation 60)60c,d 63. 

Chiral amines can be prepared by asymmetric hydrogenation, transfer hydrogenation and hydrosilylation of imines. The piperidine 137 with 98% ee was obtained by highly efficient asymmetric hydrogenation of the cyclic imines 136 catalysed by the Ti catalyst 61 [82]. Pyrrolidine 139 with 99% ee was obtained in 34% after 50%... 

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... 

The results from this chiral amine survey indicated that the secondary nitrogen in the pyrrolidine ring and the tertiary nitrogen in the side chain of the catalyst 221 are necessary... 

Chiral Amines with C2 Symmetry, trans-2,5-Dimethylpyrrolidine (1) was the first chiral amine possessing C2 symmetry used as a chiral auxiliary in asymmetric synthesis. Since that time a number of related systems have been developed including the title compound (2) and (4). These amines were developed as C2-symmetric analogs to the commercially available prolinol derivative (5). While proline-derived chiral auxiliaries have been widely used in asymmetric synthesis, the C2-symmetric chiral auxiliaries often give enhanced stereoselectivity when compared directly to the prolinol derivatives. Unfortunately the preparation of the C2-symmetric compounds is more tedious and, at the time of writing, none are commercially available. For example, the standard route to chiral pyrrolidines (2) and (3) involves the resolution of tranf-N-benzylpyrrolidine-2,5-dicarboxylic acid, although other preparations have been... 

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. 

Summary Our research on a-metalated organosilanes currently focuses on (aminomethyl)silanes containii a defined stereogenic center next to the silicon center. A synthetic route based on the preparation of 2-silyl-substituted pyrrolidines was developed. The racemic product could be synthesized by metalation of JV-Boc-pyrrolidine in the presence of TMEDA and conversion with the corresponding chlorosilane, whereas the enantioenriched form was achieved by metalation in the presence of the chiral amine (-)-sparteine. Subsequent metalation and transformation reactions yielded the formation of the corresponding (aminomethyl)(lithiomethyl)silane. 

As part of our studies on a-metalated organosilanes, we use (aminomethyl)(lithiomethyl)silanes of the general type A [1]. Systems of types B and C containing defined stereochemical information could be synthesized starting from either chiral amines or from 5i-chiral silanes. A new structural motif (D) arises if the stereogenic center is adjacent to silicon (preferably as part of a rigid system). The goal of these studies was the synthesis of the enantiomerically pure, lithiated 2-silyl-substituted pyrrolidine E. 

Aminophosphines. - The bis(V-pyrrolidinyl)phosphines (139), prepared conventionally by treatment of the appropriate organodichlorophosphine with an excess of pyrrolidine, have proved to be unusually electron-rich <7-donor ligands when compared to either tris(V-pyrrolidinyl)phosphine, or trialkyl-and triaryl-phosphines. Full details of a route to the polycylic aminophos-phirane systems (140) have now appeared. The bis(aminophosphine) (141) has been prepared and used in the synthesis of macrocyclic metal complexes. Two new chiral aminophosphine systems (142) and (143) have been prepared by transamidation of related aryl bis(dimethylamino)phosphines with a chiral amine. The chiral aminophosphine (144) has been obtained from the reaction of chlorodiphenylphosphine with the methyl ester of alanine. A range of ether-functionalised aminophosphines (145) has also been prepared. 

There are numerous reactions in which enamines and enamine derivatives, such as metalloenamines, are used for the synthesis of enantiomerically pure compounds (EPC synthesis) In principle, such EPC synthesis could involve a chiral amine component of the enamine reacting with an achiral electrophile or an achiral enamine reacting with a chiral electrophile. The cyclohexenamines seem to be the preferred test objects for this kind of reaction enamines of open-chain ketones and aldehydes have been investigated only rarely. Examples are chiral enamines from substituted pyrrolidine 104i -i (R = CHjOMe,CHiOSiMe3,COOMeX = Me,CH20Me),... 

The synthesis of y-butyorolactones was achieved by Kurth et a/. 1.272 a-alkylation and subsequent iodo-lactonisation of Al-acylated chiral amines (Scheme 1.6.35). Pyrrolidine 67 72 was more selective in both alkylation and cyclisation as supported L-prolinol 66.271 Both chiral... 

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 2001, Yamamoto prepared various chiral diamines (pyrrolidine based secondary and tertiary amines) " and screened a range of protic acids to catalyse the aldol reaction. Catalyst la TfOH, had no catalytic activity alone. However, the combination of diamine la and la TfOH catalysed the aldol reaction of ketones with p-nitrobenzaldehyde. The aldol products were obtained with high chemical yields and reasonable to high enantio- and diastereoselectivities (Scheme 9.1). ... 

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... 

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