Pyrrolidines chiral catalysts

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

These studies were expanded by Yang and coworkers [48], who uses fluorinated chiral pyrrolidine as catalysts, such that the epoxidation of l-phenylcydohexene was achieved with an enantioselectivity of up to 61% ee (Scheme 7.14). 

Scheme 2.38 Chiral pyrrolidine-derived catalysts for Michael-type addition of ketones to activated olefins.

We examined optically active pyrrolidine derivatives as efficient chiral catalysts in the asymmetric 1,4-addition of thiols to a,j3-unsaturated ketones. Thus, benzenethiol in the presence of 1 mol% of a chiral diamino alcohol, 3a-f, as catalyst was added to 2-cyclohexen-l-one in toluene at —20 °C. The results are listed in Table IS . 

All the examples reported consist of chiral pyrrolidines containing a pyridinium 26 or methylimidazolium side chain 27, 28. Catalyst 26 when added directly to a mixture of a broad range of Michael acceptors and donors in the absence of water gives the expected products in yields (up to 100%), diaster-eoselectivities (synlanti up to >99 1) and enantioselectivities (ee up to 99%) that are affected by the structure of the counter-ion. These chiral catalyst are easily recovered and reused. ... 

Despite the fact that piperidines seem to yield less selective reactions than pyrrolidines, they have been successfully used as substrates for the synthesis of ///reo-methy]phenidate (Ritalin) and analogs (Scheme 35) [108-110], For the synthesis of Ritalin itself, A-Boc-piperidine 146 was treated with methyl phenyl-diazoacetate 99 and a chiral catalyst. Davies and coworkers found that bridged prolinate Rh2(.S -biDOSP)4 (27) provided the desired product in 86% ee, although in moderate diastereoselectivity, providing threo-147 in 52% yield [109]. Winkler obtained the same product in a maximum of 69% ee (recrystallized to 95%), but with 94% de using carboxamidate Rh2(5R-MEPY)4 (5R-28b) in 44% yield, 26% after recrystallization [108],... 

Propargylic alcohok The highly enantioselective aldol reaction of Mukaiyama can also be used to obtain optically active propargylic alcohols by reaction of acetylenic aldehydes with a silyl enol ether. The most effective chiral catalyst is obtained by a combination of tin(II) triflate with a diamine derived from (S)-proline, (S)-l-methyl-2-[N-naphthylamino)methyl]pyrrolidine (1). Thus the reaction of an acetylenic aldehyde... 

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. 

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, the groups headed by Hayashi [80], Barbas [81], and Cordova [82] simultaneously extended the scope of this asymmetric MCR using aldehyde donors in the presence of chiral pyrrolidine-based catalysts for the so-called enantioselective cross-Mannich reaction (Scheme 16.39). This efficient combination of two different aldehydes has led to a highly stereoselective synthesis of 3-amino aldehydes and y-amino alcohols. Recently, chiral ionic liquids have been efficiently used as catalysts for similar asymmetric Mannich reactions [83]. 

A more efficient approach to control the stereochemical outcome for the Robinson annulation can be through the use of chiral catalysts such as in the case of the enantioselective Hajos-Wiechert variation introduced earlier. There are other chiral agents other than the popular (S)-proline-mediated annulation reaction that are used for these transformations—for example the use of (Bronsted acid such as trifluoroacetic (TFA). This new catalyst for the Robinson annulation was reported in 2007 by Endo et. al., where the Bronsted acid, contrary to Hajos-Wiechert reaction, gives the (i )-isomer of the Wieland-Miescher ketone 44 in a moderate yield of 47% and 75% ee. 

Nitroalkanes are a particularly useful source of stabilised carbanions for the asymmetric addition to electron-poor alkenes. This type of nucleophiles has been added to cyclic and acyclic a,p-unsaturated enones in the presence of a novel class of organocatalysts, such as chiral a-aminophosphonates.This study revealed that the hydrate salt of a pyrrolidine-based catalyst bearing a phosphonate group, depicted in Scheme 1.14, was found to be the best catalytic species, providing, in the presence of tra i-2,5-dimethylpiperazine as an additive, moderate to good results for a range of substrates, as summarised in Scheme 1.14. 

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. 

There is significant interest in controlling the absolute stereochemistry of ring opening in epoxide/C02 copolymerization. Cyciohexene oxide, a meso molecule, is an ideal substrate for desymmetrization using chiral catalysts. In 1999, Nozaki et al7 reported that a 1 1 mixture of ZnEt2 and (S)-diphenyl (pyrrolidine-2-yl)methanol (11) (Scheme 13) was active for stereoselective cyciohexene oxide/C02 copolymerization at 40 °C and 30 atm. CO2 (Scheme 14). The resultant polycarbonate contained 100% carbonate linkages, had an Ain of... 

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. 

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... 

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