Asymmetric arylation, 3-ketoesters

A series of Ru(ii) compounds associated with modified BINAP ligands (Scheme 14) dissolved in [G8GiIm]BF4/ methanol have been used as recyclable biphasic catalytic systems for the asymmetric hydrogenation of / -aryl ketoesters. " ... 

Hu A, Ngo H, Lin WB. Rematkahle 4,4 -Substituent effects on binap highly enantioselective Ru catalysts for asymmetric hydrogenation of (l-aryl ketoesters and their immobilization in room-temperature ionic liquids. Angew Chem hit Ed 2004 43 2501-4. 

Chiral transition-metal complexes have also been featured in the following reports " of asymmetric carbonyl reductions hydrogenation of / -aryl- -ketoesters 0 using H2 and iridium-bearing spiro pyridine-aminophosphine ligand rhodium in a theoretical study of catalysis involving amino acid-derived ligands and in... 

The potential application of this catalytic system was illustrated by Takemoto in the application to a tandem conjugate addition towards the asymmetric synthesis of (-)-epibatidine, a biologically active natural product [100, 101], The authors designed an enantioselective double Michael addition of an unsaturated functionalized P-ketoester to a p-aryl nitro-olefm. The asymmetric synthesis of the 4-nitro-cyclohexanones was achieved in both high diastereoselectivity and enantioselectivity, with the natural product precursor synthesized in 90% yield and 87.5 12.5 er (Scheme 49). The target (-)-epibatidine was subsequently achieved in six steps. 

Under similar conditions, the same authors were able to control two stereogenic centers in an asymmetric vinylogous Mannich reaction. Indeed, treatment of imines derived from aryl a-ketoesters with siloxyfuran under related conditions gave functionalized y-butenolides with high diastereo- and enantioselectivities (Scheme 10.21 ).40... 

In 2007, Jorgensen and coworkers reported an asymmetric a-arylation of [1-ketoester 101 under homogeneous condition using (—)-quinine as organocatalyst (Scheme 6.30) [58]. They demonstrated that the reaction of [hkctoesters 101 with 1,4-quinone 102 could be a good strategy of enantioselective a-arylation for aromatic... 

The catalyst lr-(R)-28a also showed good performance in the asymmetric hydrogenation of P-aryl p-ketoesters with excellent enantioselecfivity (up to 99.8% ee) and extremely high TONs (as high as 1 230 000) under mild reaction conditions (Scheme 17) [68]. 

During recent years, asymmetric catalysis by small organic molecules has received much attention [140]. Because these reactions proceed through intermediates that are inherently less reactive, the Friedel-Crafts reactions of electron-rich (hetero)aryls generally seem to be well suited. For instance, Deng described the use of readily accessible cinchona-derived ligand 178 to perform highly enantioselective indole additions to a-ketoesters and even simple aldehydes (Scheme 8.49) [141]. Bisindole adducts, the major side products in many Lewis acid-catalyzed reactions, were formed to only a minor extent. 

The nickel-iminophosphine-catalysed 4- -2-cycloaddition of enones with allenes formed highly substituted dihydropyrans. The enantioselective amine-catalysed 4-I-2-cycloaddition of allenoates with oxo-dienes produced polysubstituted dihydropyrans in high yields and with high enantioselectivities. Novel enam-ine/metal Lewis acid bifunctional catalysis has been used in the asymmetric inverse-electron-demand hetero-Diels—Alder reactions of cyclic ketones with Q ,j9-unsaturated a-ketoesters. The 4- -2-cycloaddition of acylketenes (80) with 2-unsubstituted and 2-monosubstituted 3-aryl-2//-azirines (81) produced 1 1 (82) or 2 1 (83) adducts, being derivatives of 5-oxa-l-azabicyclo[4.1.0]hept-3-ene or 5,7-dioxa-l-azabicyclo[4.4.1]undeca-3,8-diene. The formation of the monoadducts proceeds via a stepwise non-pericyclic mechanism (Scheme 25). A-heterocyclic carbene-catalysed 4- -2-cycloaddition of ketenes with 1-azadienes yielded optically active 3,4-dihydropyrimidin-2-ones (93% ee) ... 

Figure 15.16 summarizes a series of optically active alcohols and amines reported (in a review by Blacker at Avecia ) to be produced by the CATHy catalysts. These include the types of products described for the different classes of hydrogenations described in the previous sections. These products include those from the reduction of alkyl aryl ketones, a-ketoesters, aliphatic ketones, a,(3-unsaturated ketones, cyclic ketones, and a-hydroxy ketones. In addition, transfer hydrogenation allows for the asymmetric formation of amines by the reduction of N-diphenylphosphinylimines. These transfer hydrogenations... 

Asymmetric a-functionalization of carbonyl compounds with iodine(lll) reagents is discussed in Chap. 639 and in a recent review [178], and is only briefly covered here. Asymmetric a-arylations with chiral diaryliodonium salts have proven to be difficult to achieve, both because of complicated synthetic routes to chiral, unsymmetric salts with suitable dummy groups, and because of the modest enantioselectivities observed in the arylations [188, 189]. Ochiai and coworkers reported the only successful example to date, where 1,1 -binaphthyl-derived iodonium salts gave chemo- and enantioselective arylation of p-ketoesters in up to 53% ee (see Scheme 7 in Chap. X) [190]. 

Stereoselective carbon-carbon bond formations with hypervalent iodine reagents are also prominently described in the literature. Direct asynunetric a-arylation reactions are not easy to perform. Ochiai et al. synthesized chiral diaryliodonium salts such as [l,l -binaphthalen]-2-yl(phenyl)iodonium tetrafluoroborate derivatives 21 via a BFs-catalyzed tin-X -iodane exchange reaction and developed the direct asymmetric a-phenylation of enolate anions derived from cyclic p-ketoesters (Scheme 7) [37]. A beautiful example of direct asymmetric a-arylation of cyclohexanones in the course of a natural product synthesis was presented through the desymmetrization of 4-substituted cyclohexanones using Simpkin s base, followed by coupling with diaryliodonium salts [38]. Other binaphthyl iodonium salts related to 21 have also been reported [39]. 

Chiral 1,5-diols (153) have been efficiently accessed by iridium-catalysed asymmetric hydrogenation of 6-aryl-5-ketoesters (152). A gas chromatographic study indicates 0 initial ketone reduction, to the hydroxyl-ester. Loss of ethanol gives a 5-lactone intermediate, which is reductively reopened this sequence is confirmed by generation of (153) when an authentic sample of the lactone is treated under the same conditions. 

The asymmetric hydrogenation of 5-aryl-5-ketoesters is efficiently catalysed by (78) (Ar = 3,5-Bu 2C6H3) under H2 in presence of EtOH and Bu OK to give chiral 1,5-diol products with excellent enantioselectivity and turnover numbers (TONs) as high as 10 ... 

The asymmetric reaction of nitromethane with aldehydes as well as activated ketones (e.g., trifluoroacetophenone and a-ketoesters) is possible with various chiral metallic complexes or organocatalysts under atmospheric pressure with good yield and enantioselectivity. However, the Henry reaction of aryl alkyl ketones still remains problematic and challenging. Matsumoto s group also tested the very difficult reaction of acetophenone and nitromethane with quinidine. No product was observed under Ibar and only traces at 7 kbar, but application of 10 kbar resulted in a significant improvement in yield (31%) -unfortunately, no enantioselectivity was detected (Scheme 21.3). 

A powerful application of this technology has been demonstrated by the conversion of racemic p-ketoesters to a single stereoisomer via asymmetric reduction combined with dynamic kinetic resolution. Cationic ruthenium complexes were employed in the conversion of 28 to 29, a key intermediate in the synthesis of carbapenem antibiotics (Scheme 14.10). Increased steric bulk on the aryl groups was required to give high diastereoselectivity as well as enantioselectivity, and this process was used for industrial production on a scale of 100 metric tonnes per year. 

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