Amination reactions enantioselective organocatalytic

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). 

Scheme 2.29 The application of organocatalytic enantioselective a-amination reaction of 3-(4-bromophenyl)-2-methylpropanal 8 for the total synthesis of the optically active cell-adhesion inhibitor BIRT-377 [7b].

Catalytic enantioselective Mannich reactions provide one of the most versatile approaches for the synthesis of optically active chiral amines. Recently, several organocatalytic protocols have been developed using the parent cinchona alkaloids or their derivatives. 

In 2008, Zhang, Ying, and co-workers reported an organocatalytic p-amination reaction of a,p-unsaturated aldehydes with nitrosobenzene catalyzed by an NHC. Specifically, the addition of NHC to a,p-unsaturated aldehyde generates a homoenolate intermediate that reacts with nitrosobenzene to afford Af-phenylisoxazolidin-5-ones, followed by an acid-catalyzed esterification and Bamberger-type rearrangement to produce Af-PMP-protected p-amino esters. A preliminary study on the enantioselective reaction of... 

In the late 1990s, several research groups worked on the development of chiral DMAP analogs. The works of Fu [23], Vedejs [24], and Fuji [25] led to the synthesis of powerful catalysts and the development of enantioselective organocatalytic reactions such as Steghch rearrangements, kinetic resolutions of secondary alcohols, kinetic resolution of amines, and so on (Scheme 1.8). 

New sulfur-containing spirocyclic scaffords were synthesized by two different enantioselective organocatalytic cascade reactions (13EJ07979). In the first synthesis, benzothiophene-2-one and an enal react in the presence of a secondary amine catalyst via a Michael-Aldol sequence to yield spiro-cyclo-hexenecarbaldehydes with excellent selectivities [20 1 diastereomeric ratios (dr) up to 20 1]. In the second reaction, the double Michael addition of ben-zothiophene-2-one to aromatic dieneones with primary amine catalysts yields the corresponding spiro-cyclohexanones with slighdy lower dr values. 

Indole-fused pyran-4-ones are prepared in one-pot two-step synthesis. In the first there is the acylation of 1-substituted 3-acetyl-lH-indol-2-ols with acid chlorides using triethylamine as base, in dichloromethane at room temperature. The second consists in the 4ff-pyran-4-one ring formation firom the in situ-obtained 3-acetyl-2-acyloxy-lF/-indole derivatives (13S1235).A highly diastereo- and enantioselective organocatalytic formal hDA reaction of enones with isatins occurs in the presence of amine 34, acid 35, and thiourea 36 to produce spirooxindole tetrahydro-4ff-pyran-4-ones (Scheme 59) (13CEJ6213). 

The same approach was used by Benagha s group for the enantioselective organocatalytic reduction of P-trifluoromethyl nitroaUcenes 73, with the aim of achieving chiral yS-trifluoromethyl amines 75 (Scheme 28) [161]. The authors also performed the organocatalyzed reduction of a-substituted-p-trifluoromethyl nitroalkenes, although with poorer results. The stereochemical result of the reaction and the behavior of thiourea catalyst 74 were discussed based on computational studies and DFT transition-state analysis. 

Scheme 6.47 The enantioselective organocatalytic Petasis reaction among salicylaldehydes, amines, and organoboronic acids described by Yuan and coworkers [66].

The first report of an enantioselective organocatalytic Mukaiyama-Michael reaction involves the use of an amine catalyst during the 1,4-addition of TMSOF to the electron deficient olefin ( )-but-2-enal. The cafalyst is employed as its dinitroben-zoic acid (DNBA) salt (eq 35). Several other substituted TMSOFs are used in this reaction with similar levels of success. A formal enantioselective synthesis of (+)-compactin incorporates this method. ... 

In 2009, Chen and coworkers reported a highly enantioselective organocatalytic inverse electron demand HDAR reaction of o-benzoquinone diimides and aliphatic aldehydes catalyzed by a,a-diphenylprolinol (9-TMS ether 269 as a chiral secondary amine (Scheme 2.40) (Li et al. 2009b). 

Another important reaction by which to form C-C bonds is the nitroalkane Michael addition. The first attempt to obtain a nitroalkane enantioselective addition to enones was reported by Yamaguchi in 1994, using as a catalyst rubinate salts of proline. The first truly enantioselective organocatalytic addition of nitroalkanes to enones was developed by Hanessian using proline as catalyst in the presence of an amine additive. The reaction affords good yields and enantioselectivities when cyclic enones were used (up to 93% ee) however, the addition to chalcones renders the products in lower enantioselectivities (up to 68% ee) [90]. 

List gave the first examples of the proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines (Scheme 14) [35], This was the first organocatalytic asymmetric Mannich reaction. These reactions do not require enolate equivalents or preformed imine equivalent. Both a-substituted and a-unsubstituted aldehydes gave the corresponding p-amino ketones 40 in good to excellent yield and with enantiomeric excesses up to 91%. The aldol addition and condensation products were observed as side products in this reaction. The application of their reaction to the highly enantioselective synthesis of 1,2-amino alcohols was also presented [36]. A plausible mechanism of the proline-catalyzed three-component Mannich reaction is shown in Fig. 2. The ketone reacts with proline to give an enamine 41. In a second pre-equilib-... 

Asymmetric addition of ketenes to aldehydes is a highly attractive synthetic access to yfi-lactones with perfect atom economy [134, 135]. This reaction can be catalyzed efficiently by using chiral amines as organocatalysts. As early as 1967 Borr-mann et al. described an organocatalytic asymmetric ketene addition to aldehydes [136] chiral tertiary amines, in particular (—)-N,N-dimethyl-a-phenylethylamine or (—)-brucine, were used as catalysts [136]. The resulting lactones were obtained with modest enantioselectivity of up to 44% ee. 

In this chapter, we will outline the application of organocatalysis for the enantio-selective a-heteroatom functionalization of mainly aldehydes and ketones. Attention will be focused on enantioselective animation-, oxygenation-, fluorination-, chlorination-, bromination-, and sulfenylation reactions catalyzed by chiral amines. The scope, potential and application of these organocatalytic asymmetric reactions will be presented as the optically active products obtained are of significant importance, for example in the life-science industries. 

Barbas and colleagues have applied the organocatalytic direct amination of aldehydes in a series of reports [7]. By combining acetone, various aldehydes, dibenzyl azodicarboxylate and i-proline as the catalyst, a one-pot synthesis of functionalized /Tamino alcohols was achieved [7a]. The scope of the reaction was found to be quite general for various aldehydes, and the optically active / -amino alcohols were obtained in high yields with low diastereoselective control. However, excellent enantioselectivity of especially the anti-adduct was obtained. 

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