Bifunctional ketones, enantioselectivity

The concerted delivery of protons from OH and hydride from RuH found in these Shvo systems is related to the proposed mechanism of hydrogenation of ketones (Scheme 7.15) by a series of ruthenium systems that operate by metal-ligand bifunctional catalysis [86]. A series of Ru complexes reported by Noyori, Ohkuma and coworkers exhibit extraordinary reactivity in the enantioselective hydrogenation of ketones. These systems are described in detail in Chapters 20 and 31, and mechanistic issues of these hydrogenations by ruthenium complexes have been reviewed [87]. 

Trost s group reported direct catalytic enantioselective aldol reaction of unmodified ketones using dinuclear Zn complex 21 [Eq. (13.10)]. This reaction is noteworthy because products from linear aliphatic aldehydes were also obtained in reasonable chemical yields and enantioselectivity, in addition to secondary and tertiary alkyl-substituted aldehydes. Primary alkyl-substituted aldehydes are normally problematic substrates for direct aldol reaction because self-aldol condensation of the aldehydes complicates the reaction. Bifunctional Zn catalysis 22 was proposed, in which one Zn atom acts as a Lewis acid to activate an aldehyde and the other Zn-alkoxide acts as a Bronsted base to generate a Zn-enolate. The... 

Scheme 1. Diastereo- and/or enantioselective aminoalkylation of ketones catalyzed by a chiral bifunctional organocatalyst [8a].

Fig. 3.33 Bifunctional Ru-BINAP(diamine) complexes for enantioselective hydrogenation of simple ketones.

Finally, carbohydrate ligands of enantioselective catalysts have been described for a limited number of reactions. Bis-phosphites of carbohydrates have been reported as ligands of efficient catalysts in enantioselective hydrogenations [182] and hydrocyanations [183], and a bifunctional dihydroglucal-based catalyst was recently found to effect asymmetric cyanosilylations of ketones [184]. Carbohydrate-derived titanocenes have been used in the enantioselective catalysis of reactions of diethyl zinc with carbonyl compounds [113]. Oxazolinones of amino sugars have been shown to be efficient catalysts in enantioselective palladium(0)-catalyzed allylation reactions of C-nucleophiles [185]. 

Table 9. Enantioselective cyanosilylation of ketones using bifunctional catalyst 56...

The Lewis acid-Lewis base bifunctional catalyst 178a, prepared from Ti(Oi-Pr)4 and diol 174 (1 1), realizes highly enantioselective cyanosilylation of a variety of ketones to (R)-cyanohydrin TMS ethers (Scheme 10.241) [645]. The proposed mechanism involves Ti monocyanide complex 178b as the active catalyst this induces reaction of aldehydes with TMSCN by dual activation. Interestingly, the catalyst prepared from Gd(Oi-Pr)3 and 174 (1 2) serves for exclusive formation of (S)-cyanohy-drin TMS ethers [651]. The catalytic activity of the Gd complex is much higher than that of 178a. The results of NMR and ESI-MS analyses indicate that Gd cyanide complex 179 is the active catalyst. It has been proposed that the two Gd cyanide moieties of 179 play different roles - one activates an aldehyde as a Lewis acid and the other reacts with the aldehyde as a cyanide nucleophile. 

Figure 1 The hydride-metal-nitrogen-proton motif in the catalyst attacking a ketone in a bifunctional manner (a) and the source of enantioselectivity in the ADH of ketones catalyzed by trans-RuHJ(R)-binap) (diamine) complexes (b) ...

Additional catalyst development identified the positive effect of 1,2-diamines as additives in the (BlNAP)Ru(OAc)2-catalyzed enantioselective hydrogenations of ketones [24], This discovery ultimately led to the synthesis of a class of (diphosphine) Ru(diamine)X2 (X = H, halide) compounds [25] (Figure 4.1) which have emerged as some of the most active and selective hydrogenation catalysts ever reported [26]. Mechanistic studies by Noyori [14] and Morris [27] have established bifunctional hydrogen transfer to substrate from the cis Ru-H and N-H motifs and identified the importance of ruthenium hydridoamido complexes for the heterolytic splitting of H2. This paradigm allows prediction of the absolute stereochemistry of the chiral alcohols produced from these reachons. 

The addition of cyanide to aldehydes and some ketones has also been achieved in a highly enantioselective manner using a wide variety of catalyst systems including chiral nonracemic Lewis acids, Lewis bases, bifunctional catalysts and even small peptides. 

The bifunctional catalysts developed by Shibasaki and coworkers effective in the asymmetric cyanation of aldehydes and ketones (see Section 6.2) have been applied to good effect in the cyanation of imines. For instance, aluminium BINOL (6.65) catalyses the cyanation of aromatic and a,p-unsaturated N-fluorenylaldimines using TMSCN in good ee, while gadolinium complexes of the glucose-derived ligand (6.71) and derivatives have been used in the enantioselective cyanation of ketimines. ... 

Ligand-metal bifunctional catalysis provides an efficient method for the hydrogenation of various unsaturated organic compounds. Shvo-type [83-85] Ru-H/OH and Noyori-type [3-7] Ru-H/NH catalysts have demonstrated bifimctionality with excellent chemo- and enantioselectivities in transfer hydrogenations and hydrogenations of alkenes, aldehydes, ketones, and imines. Based on the isoelectronic analogy of H-Ru-CO and H-Re-NO units, it was anticipated that rhenium nitrosyl-based bifunctional complexes could exhibit catalytic activities comparable to the ruthenium carbonyl ones (Scheme 29) [86]. 

Tang and coworkers" used bifunctional urea and thiourea-derived orga-nocatalysts (4a,b) for the Michael addition of cyclohexanone to nitro-olefins (Scheme 9.29). Using pyrrolidine-thiourea 4b afforded the desired y-nitroalkanes with high diastereo- and enantioselectivity under solvent-free conditions (up to 99 1 dr, 88-98% ee). Subsequently, Xiao and coworkers screened various bifunctional pyrrolidine-thiourea organocatalysts and identified 4c to be efficient at catalysing the Michael addition of various ketones to nitrostyrenes. Comparable results were observed (up to 99 1 dr and 99% ee) when the reactions were performed in both aqueous media and organic solvents. 

NAP-MgO acts as a bifunctional heterogeneous catalyst for the Claisen-Schmidt condensation (CSC) of benzaldehydes with acetophenones to yield chalcones, followed by asymmetric epoxidation (AE) to afford chiral epoxy ketones in moderate to good yields and impressive enantioselectivities (ee s). NAP-MgO, in combination with the chiral auxiliary (11 ,21 )-(- -)-1,2-diphenyl-1,2-ethylenediamine (DPED), catalyzed the asymmetric Michael addition of malonates to cyclic and acyclic enones. 

A bifunctional iminiumyhydrogen-bonding catalysis has been very recently employed for the first enantioselective organocatalytic conjugate addition of a phosphorous nucleophile (diarylphosphane oxides) to a,ji-unsaturated ketones [370]. The process, which allows efficient additions to cyclic and linear enones as well as the generation of quaternary stereocenters, is catalyzed by quinine-derived thiourea... 

---