Dual activation, substrate

Dual activation of nucleophile and epoxide has emerged as an important mechanistic principle in asymmetric catalysis [110], and it appears to be particularly important in epoxide ARO reactions. Future work in this area is likely to build on the concept of dual substrate activation in interesting and exciting new ways. 

We reported a catalytic enantioselective cyanosUylation of ketones that produces chiral tetrasubstituted carbons from a wide range of substrate ketones [Eq. (13.31)]. The catalyst is a titanium complex of a D-glucose-derived ligand 47. It was proposed that the reaction proceeds through a dual activation of substrate ketone by the titanium and TMSCN by the phosphine oxide (51), thus producing (l )-ketone cyanohydrins ... 

Corey reported a catalytic enantioselective cyanosilylation of methyl ketones using combination of a chiral oxazaborolidinium and an achiral phosphine oxide, [Eq. (13.23)]. An intermolecular dual activation of a substrate by boron and TMSCN by the achiral phosphine oxide (MePh2PO) is proposed as a transition-state model (54). The same catalyst was also used for cyanosilylation of aldehydes ... 

In 1996, Carreira reported a catalytic enantioselective aUylation of aldehydes using BlNOL-modified Tip4. More recently, Kobayashi reported a catalytic enantioselective aUylation of hydrazono esters in aqueous media using ZnF2-chiral diamine complex, [Eq. (13.36)]. In both reactions, reaction mechanism via dual activation of the substrate by Lewis acid metals and aUylsUanes by fluoride is proposed ... 

Aldehydes and ketones have been alkynylated using indium(III) and Hunig s base (PrjNEt) as catalysts.213 IR and NMR evidence support a dual-activation role for indium it is a Lewis acid for the hard electrophile (carbonyl compound), and has sufficient n -coordination ability for a soft nucleophile such as a terminal alkyne. For the latter substrate, the amine then assists proton abstraction. 

A novel method for enantioselective organocatalytic cyclopropanation has been developed, using a new class of iminium intermediates and based on the concept of directed electrostatic activation (DEA). This novel organocatalytic mechanism exploits dual activation of ylide (153) and enal (152) substrates through the formation of the iminium intermediate (155) and electrostatic activation (156). The resulting (g) trisubstituted cyclopropanes (157) were obtained with high levels of enantio- and diastereo-control.180... 

The specific activities of penicillolysin for clupeine and casein hydrolysates were 3.04 x 10 1 and 5.23 x 10 3 katal/kg protein at pH 7.0, respectively (Table 9) [69], The rate of clupeine hydrolysis was 60-fold greater than that for casein hydrolysis. When zinc is removed, the enzyme is completely inactive, and readdition of zinc restores the dual activities towards clupeine and casein (Table 9). Depending on the casein substrate, the cobalt-penicillolysin (Co-penicillolysin) could be up to ca 1.6 times more active than the native zinc enzyme. On the other hand, in clupeine-hydrolysis, the cobalt enzyme is about 70% as active as the native enzyme. Thus, replacement of the zinc-penicillolysin with cobalt markedly decreases the activity towards clupeins while increases it towards casein. 

Significant levels of syn diastereoselectivities (5 1 to 16 1) were observed for all substrates, with the exception of an ortho-chloro-substituted aryl imine, which provided only 2 1 syn selectivity. The catalyst was viable for a variety of nitroalkanes, and afforded adducts in uniformly high enantioselectivities (92-95% ee). The sense of enantiofacial selectivity in this reaction is identical to that reported for the thiourea-catalyzed Strecker (see Scheme 6.8) and Mannich (see Tables 6.18 and 6.22) reactions, suggesting a commonality in the mode of substrate activation. The asymmetric catalysis is likely to involve hydrogen bonding between the catalyst and the imine or the nitronate, or even dual activation of both substrates. The specific role of the 4 A MS powder in providing more reproducible results remains unclear, as the use of either 3 A or 5 A MS powder was reported to have a detrimental effect on both enantioselectivities and rates of reaction. 

This catalyst was also applicable in the Strecker reaction of ketiinines including quinoline and isoquinoline (Scheme 6.112) [139]. Acid chlorides were combined for use in making iminium cations to enhance the reactivity of this class of poorly electrophihc substrate. Thus the reaction involves dual activation of the acyl quinolium or isoquinolinium ion and MejSiCN by the Lewis acid (Al) and the Lewis base (oxygen atom of phosphor oxide) of 93, respectively. The reaction proceeded with moderate to high enantioselectivity. 

As described in Sections 2.3.1.2 and 2.2.3, Choudary et al. recently revealed nanocrystalline magnesium oxide (NAP-MgO) as a recyclable heterogeneous catalyst [40, 45]. These authors extended the use of this new type of heterogeneous catalyst for the asymmetric Michael reaction of different acyclic enones with nitromethane and 2-nitropropane [69a]. In a Michael reaction of chalcone with nitromethane in THF solvent at -20°C, NAP-MgO/(lR,2R)-(-)-diaminocyclohexane (DAC) was found to be an excellent catalyst system (96% ee, 95% yield) (Scheme 2.32). This Michael reaction proceeds via the dual activation of both substrates (nucleophiles and electrophiles) by NAP-MgO. The Lewis basic site (O /O ) of the NAP-MgO activates the nitroalkanes, while the Lewis acid moiety (Mg /Mg )... 

Concerning the mechanism, the authors suggest a reaction involving the dual activation of donor and acceptor substrate at the amine base site and the neighbouring Bronsted acid site on the SA surface (Scheme 3.39). 

E-ajp-unsaturated ester was employed, while a single diastereoisomer was obtained using the corresponding Z substrate. This reaction design has also been extended to the use of an a,p-unsaturated aldehyde as the initial Michael acceptor, in this case it being necessary to consider the possible dual activation of the Michael donor and acceptor by the catalyst through the formation of the corresponding enamine and iminium intermediates. ... 

Acid and base pairs are known to activate molecules simultaneously and efficiently via dual coordination to promote reactions [1, 2, 43]. Acid and base sites on amorphous SA-supported aminopropyl groups (SA-NEt2), prepared by the treatment of SA with 3-(diethoxyamino)propyltrimethoxysilane, promoted the cyano-ethoxycarbonylation reaction in nonpolar solvents such as toluene and diethyl ether (Scheme 6.17) [121]. A proposed mechanism involves the dual activation of donor and acceptor substrates at the amine base site and the neighboring Bronsted acid site on the SA surface, respectively. 

The catalytic version of this transformation was realized by the group of Sasai. With 5 mol% of the dinuclear vanadium eomplex (S,Sfi -22, the AFC reactions of 2-naphthol with various aryl aldimine substrates proceeded smoothly to afford addition products 21 in 67-82% yields with up to 91% ee. The authors suggested a dual activation model, as depleted in Seheme 6.8. 

Nagasawa and co-workers [108] were the first to introduce chiral thiourea catalyst to the BH reaction. They synthesized a tra 5-(li ,2i )-l,2-diaminocy-clohexane-derived bisthiourea 57 as catalyst to promote the BH reaction of cyclohexanone and aldehydes in the presence of DMAP co-catalyst (Scheme 9.31). The dual activations of both substrates were proposed to account for excellent enantioselectivites (for aliphatic aldehydes) and reactivity enhancement. Later on, chiral bisthiourea 58 was prepared and applied as catalyst under solvent-free conditions [109]. Around at the same time, Raheem and Jacobsen [110] demonstrated that chiral thiourea 59 was an efficient catalyst for the DABCO promoted aza-BH reaction of IV-nosyl imines and methyl acrylate. Chiral Hg-binaphthyl bisthiourea 60 was then prepared by Shi and Liu [111] and used as the co-catalyst of DABCO in the reaction of cyclic enones with aldehydes, providing the products in high enantioselectivities. The application of chiral bisthiourea 61 as catalyst resulted in the formation of S configurational products in good to excellent enantioselectivities (Scheme 9.31) [112]. Moreover, thiourea 62 turned out to be an efficient catalyst in the reaction of cyclohex-2-enone with aldehydes co-catalyzed by triethylamine under solvent-free conditions [113]. 

Both chiral tertiary amine-(thio)ureas 20 [39] and 21 [40] have been able to catalyze the a-amination of 3-ketoesters in excellent yields and high enantioselec-tivity. In these reactions, cyclic 3-ketoesters performed optimum while the acyclic counterparts reacted very slowly, giving very low ee. A transition state model involving dual activation of substrates is supported by DFT calculations [42]. The axially chiral guanidine 22 is another highly active catalyst for a-amination of various cyclic and acyclic 1,3-dicarbonyl compounds. 

Prior to these mechanistic findings by Nolan and coworkers, Hashmi and coworkers found very similar mechanistic principles in their studies of cyclization reactions of 1,5-diynes [31]. In these cyclization reactions, two gold atoms are also needed to dual activate the initial substrate (see Scheme 9.13). Further mechanistic studies also revealed the occurrence of a, in this case even isolable, ew-diarated species, which on their own can serve as catalysts for the studied reactions. These species therefore highlight the importance of organogold compounds. 

The only a-alkyl substrate (R = n-Pr, X = S) reacted with poor yield (15%) and enantioselectivity (11% ee). The unique combination of the catalytic components was specifically chosen to offer a dual activation of the substrate and reagent the formation of the activated nickel-enolate complex was assisted by the presence of the noncoordinating Bronsted base, while the Lewis acidic EtsSiOTf activated NFSI to become a stronger nucleophile, without interfering with the formation of the enolate. C-F bond formation resulted from the reaction between the activated substrate and the activated electrophile, prior to product release. 

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