Pyrrolidine catalysts chiral

I, 10mol% chiral pyrrolidine catalyst, NEts, CH2CI2, -40 °C, overnight... 

Modification of the proline structure leads to more efficient chiral pyrrolidine catalysts, showing better selectivity and improved synthetic scope. 

Tetrahydroxanthen-l-ones have been obtained through enantioselective domino oxa-Michael - aldol reactions between salicylaldehydes and cyclohexenones using a chiral pyrrolidine catalyst in the presence of 2-nitrobenzoic acid <07TL2181>. A similar approach using chiral 4-hydroxycyclohexenones and V-methylimidazole as catalyst leads to a diastereomeric mixture of the reduced xanthones (Scheme 40) <07S2175>. Dimeric... 

Recently, Zhao et al. reported the use of 2-trimethylsilanyloxy-methyl-pyrrolidine functionalized chiral dendrimer catalysts (Figure 4.20) for catalytic enantio- and diastereoselective Michael addition of aldehydes to nitrostyrenes (Scheme 4.15)... 

The first asymmetric direct a-iodination of aldehydes has also been described to provide products in moderate to good enan-tioselectivities using an organocatalyst. 3-Methyl-1-butanal was reacted with NIS in the presence of a chiral pyrrolidine catalyst to provide the halogenated product in 78% yield with 89% ee (eq 27). 

The use of o-ribonolactone derived pyrrolidines as chiral catalysts for the addition of diethylzinc to aldehydes is mentioned in Chapter 24 and the synthesis of the pyrrolidine based antibiotic (+)-preussin is covered in Chapter 19. 

Three secondary amine catalysts have been utilized in the a-bromination of aldehydes (Scheme 13.31). J0rgensen reported the use of two different chiral pyrrolidine catalysts that generated the S enantiomer of the product, while Mamoka reported the use of a binaphthyl-based catalyst that generated the R enantiomer of the product [67-69]. Both employed the same bromine source, 4,4-dibromo-2,6-di-tcrt-butyl-cyclohexa-2,5-dienone (inset in Scheme 13.31), and both reduced the aldehyde products in situ to facilitate product isolation and analysis. 

A 1,2,3-triazole-based solid-phase click linker was developed with an aldehyde functionality or a regenerative Michael acceptor (REM) functionality (Figure 11.1). In addition, a chiral pyrrolidine catalyst was grafted to the resin with a 1,2,3-triazole linker, enabling enantioselective Michael addition of ketones to nitroolefins... 

In the same year, Xu et al developed an efficient example of asymmetric cooperative catalysis applied to a domino oxa-Michael-Mannich reaction of salicylaldehydes with cyclohexenones. The proeess was eatalysed by a combination of two chiral catalysts, such as a chiral pyrrolidine and amino acid D-tert-leucine. The authors assumed that there was protonation of the aromatic nitrogen atom of the pyrrolidine catalyst by u-te/t-leucine, which spontaneously led to the corresponding ion-pair assembly (Scheme 2.6). This self-assembled catalyst possessed dual activation centres, enabling the catalysis of the electrophilic and nucleophilic substrates simultaneously. The domino oxa-Michael-Mannich reaction provided a range of versatile chiral tetrahydroxanthenones in high yields and high to excellent enantioselectivities of up to 98% ee, as shown in Scheme 2.6. 

Chiral 1,2,3-triazolium ionic liquid tethered pyrrolidine catalysts built from (S)-proline and its derivatives have been successfully ap>plied in various catalytic reactions (Khan, Shah et al. 2010 Khan, Shah et al. 2010 Maltsev, Kucherenko et al. 2010 Yacob, Shah et al. 2008). The 1,2,3-triazolium ionic liquid-tagged organocatalysts derived from proline and its derivatives are mostly viscous liquids at room temperature and are completely miscible with polar solvents such as methanol, chloroform, acetonitrile, dimethylsulfoxide, dimethylformamide and water. They are insoluble in less-polar solvents such as n-hexane and diethyl ether. In some cases, the ionic liquid sub-unit serves not only as a phase tag for efficient recycling but also as an effective chiral amplifier through polar interactions and steric shielding. 

In Section 31.6 we mentioned the enantioselective reduction of itaconic acid by a number of entrapped chiral organometallic catalysts [25]. A follow-up and major improvement of that study was reported by Volovych et al. [30]. These authors hydrogenated itaconic acid with sol-gel-entrapped Rh complexed with (2S,4S)-l-tert-butoxycarbonyl-4-diphenylphosphino-2-(diphe-nylphosphinomethyl)pyrrolidine catalyst in methanol solutions. The immobilization process was carried out with different sol-gel precursors TMOS, TEOS, triethoxyphenylsilane PhSi(OEt)3/TMOS, and trimethoxy (octyl)silane OcSi(OMe)3/TMOS. The choice of the precursor was found to influence the enantioselectivity and the rate of the reaction. The immobilized catalyst could be recovered and recycled several times under N2 atmosphere. About 90-99% ee was achieved for the hydrogenation of itaconic acid to (S)-(+)-2-methyl succinic acid. 

For the same purpose, various chiral pyrroUdine catalysts such as 50-54 have also been introduced [242-250]. The versatile nature of pyrrolidine catalysts has been recognized by other transformations aldol reaction [251], Mannich-type reaction [252, 253], and oxa-Michael reaction [254]. Among these, Maruoka s work on anti-selective Mannich reactions is noteworthy (Scheme 1.19, compare with Scheme 1.8) [253]. In this case, the remote hydrogen-bonding form 57 derived from catalyst 56 can overcome the steric preference so that the opposite sense of stereochemistry should be observed. 

In 2008, Chi et al. reported a tandem reaction of indoles, a,P-unsaturated aldehydes, and methyl vinyl ketone (MVK) for the synthesis of chiral indole derivatives with two stereogenic centers [ 19]. To avoid the interference of the two secondary amine catalysts and cocatalyst acid, the soluble star polymer-based site isolatbn method was adopted, whereby the supported imidazolidinone catalyst promoted initial Friedel-Crafts alkylation and the supported pyrrolidine derivative promoted the following Michael addition to MVK (Scheme 9.19). Notably, simple combination of these catalysts in one pot didn t mediate the cascade reaction efficiently despite the fact that the MacMillan imidazolidinone and pyrrolidine catalyst can efficiently promote separate Friedel-Crafts reaction and Michael addition, respectively. Moreover, when the pyrrolidine catalyst was replaced by its enantiomer, a diaste-reomer of the product could be obtained with high enantioselectivity. This smdy presented a novel solution to the efficient combination of incompatible substrates and catalysts. 

In 2005, J0rgensen and co-workers introduced 1-benzyl-sulfanyl[ 1,2,4] triazole 416 as an electrophilic sulfur source for the catalytic enantioselective a-sulfenylation of aldehydes (Scheme 46.47). ° The products 418 were obtained in high yields and excellent enantioselectivities, and more importantly, these products obtained by enamine catalysis were not racemized by the action of a chiral pyrrolidine catalyst 417. 

In peptide syntheses, where partial racemization of the chiral a-carbon centers is a serious problem, the application of 1-hydroxy-1 H-benzotriazole ( HBT") and DCC has been very successful in increasing yields and decreasing racemization (W. Kdnig, 1970 G.C. Windridge, 1971 H.R. Bosshard, 1973), l-(Acyloxy)-lif-benzotriazoles or l-acyl-17f-benzo-triazole 3-oxides are formed as reactive intermediates. If carboxylic or phosphoric esters are to be formed from the acids and alcohols using DCC, 4-(pyrrolidin-l -yl)pyridine ( PPY A. Hassner, 1978 K.M. Patel, 1979) and HBT are efficient catalysts even with tert-alkyl, choles-teryl, aryl, and other unreactive alcohols as well as with highly bulky or labile acids. 

Chiral N,N-disubstituted 2-(aminomethyl)pyrrolidines as catalysts for asymmetric acylation of alcohols 99YGK598. 

In 1998, Ruiz et al. reported the synthesis of new chiral dithioether ligands based on a pyrrolidine backbone from (+ )-L-tartaric acid. Their corresponding cationic iridium complexes were further evaluated as catalysts for the asymmetric hydrogenation of prochiral dehydroamino acid derivatives and itaconic acid, providing enantioselectivities of up to 68% ee, as shown in Scheme 8.18. 

An enantioselective variant of the diene cydization reaction has been developed by application of chiral zirconocene derivatives, such as Brintzinger s catalyst (12) [10]. Mori and co-workers demonstrated that substituted dial-lylbenzylamine 25 could be cyclized to pyrrolidines 26 and 27 in a 2 1 ratio using chiral complex 12 in up to 79% yield with up to 95% ee (Eq. 4) [ 17,18]. This reaction was similarly applied to 2-substituted 1,6-dienes, which provided the analogous cyclopentane derivatives in up to 99% ee with similar diastereoselectivities [19]. When cyclic, internal olefins were used, spirocyclic compounds were isolated. The enantioselection in these reactions is thought to derive from either the ate or the transmetallation step. The stereoselectivity of this reaction has been extended to the selective reaction of enantiotopic olefin compounds to form bicyclic products such as 28, in 24% yield and 59% ee after deprotection (Eq. 5) [20]. 

A chiral ethylzinc aminoalkoxide 147, synthesized by the addition of ZnEt2 to (cyclohexene oxide with C02 in almost quantitative yield and with an ee of 49%. This value is somewhat lower than that obtained by the same authors from the in situ generated monomeric form of the catalyst, which furnished product with an ee of 70%.213... 

Racemic 2,5-disubstituted 1-pyrrolines were kinetically resolved effectively by hydrogenation with a chiral titanocene catalyst 26 at 50% conversion, which indicates a large difference in the reaction rate of the enantiomers (Table 21.19, entries 4 and 5), while 2,3- or 2,4-disubstituted 1-pyrrolines showed moderate selectivity in the kinetic resolution (entries 6 and 7) [118]. The enantioselectivity of the major product with cis-configuration was very high for all disubstituted pyrrolidines. The high selectivity obtained with 2,5-disubstituted pyrrolines can be explained by the interaction of the substituent at C5 with the tetrahydroinde-nyl moieties of the catalyst [Eq. (17)]. 

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). 

Nomicotine, an organocatalyst studied by Dickerson and co-workers (Entry 5 [52, 58d], Appendix 7.B), reinforces the important principle that even catalysts from Nature can present problems when it comes to toxicity. The family of nicotinic receptor agonists (Figure 7.9) contains several chiral pyrrolidines and piperidines with the potential to act as asymmetric aldol catalysts. Nomicotine, which can be isolated from plants such as tobacco, or readily synthesized by demethylation of the maj or tobacco alkaloid nicotine, was investigated in some depth as an aldol catalyst by Dickerson and Janda in 2002 [52]. 

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