Substrate Scope

The imine structure within the substrate also has a significant influence on asymmetric induction in the salen-Cu(II)-catalyzed enantioselective alkylation 

Entry Substrate RX Catalyst (mol%) Time (days) Yield (%) ee (%) 

Based on a positive non-linear effect observed for the alkylation of alanine and glycine substrates 40 and 20, active species involved in these transformation are predicted to be comprising of more than one salen-Cu(II) complex 39c [32]. Furthermore, enantioselectivity was affected by catalyst concentration, which suggested that a catalytically active dimeric form of the catalyst existed in equilibrium with catalytically inactive oligomeric and monomeric forms of the complex [36]. 

An ion-pair derived from the substrate and solid NaOH forms a cation-assisted dimeric hydrophobic complex with catalyst 39c, and the deprotonated substrate occupies the apical coordination site of one of the Cu(II) ions of the complexes. Alkylation proceeds preferentially on the re-face of the enolate to produce amino acid derivatives with high enantioselectivity. However, amino ester enolates derived from amino acids other than glycine and alanine with R1 side chains are likely to hinder the re-face of enolate, resulting in a diminishing reaction rate and enantioselectivity (Table 7.5). The salen-Cu(II) complex helps to transfer the ion-pair in organic solvents, and at the same time fixes the orientation of the coordinated carbanion in the transition state which, on alkylation, releases the catalyst to continue the cycle. 

Among several chiral cyclic and acyclic diamines, (R,R)-cyclohexane-l,2-diamine-derived salen ligand (which can adopt the gauche conformation) was most effective in providing high enantioselectivity [38]. Further, the introduction of substituents at the 3,4, 5 and 6 positions on the aromatic ring of catalyst 39c was not advantageous, and resulted in low enantioselectivity [32,37,39]. The metal ions from first-row transition metals - particularly copper(II) and cobalt(II) - that could form square-planar complexes, produced catalytically active complexes for the asymmetric alkylation of amino ester enolates [38]. 

ATH of a range of ketimines is almost perfect. Thus the combination of PPh groups and NCHPh groups on the ligand provides an effective ATH catalyst. 

4 Third generation iron catalysts with unsymmetrical [5.5.51-P-NH-N-F ligands 

The previous mechanistic and experimental studies of our second generation catalysts for ATH suggested that one of the imine moieties of complex 67 was reduced to an amido moiety by a hydride from isopropoxide, producing the amido(ene-amido) complex 81. Thus we decided to target this complex using a new synthetic pathway. 

---

The substrate scope is limited, as electron-withdrawing groups (X = p-N02 or p-CF3) on the aromatic substituent are not tolerated. However, this route does provide valuable intermediates to unnatural a-amino phosphonic acid analogues and the sulfimine can readily be oxidized to the corresponding sulfonamide, thereby providing an activated aziridine for further manipulation, or it can easily be removed by treatment with a Grignard reagent. 

The high enantioselectivity and broad substrate scope of the HKR are accompanied by an intriguing mechanistic framework involving cooperative catalysis between different catalyst species. Detailed mechanistic investigation into each of these pathways has produced new insights into cooperative catalysis and has resulted in synthetic improvements in the HKR and other ARO reactions [81],... 

The MT0/H202/pyridine system enjoys a broad substrate scope and has become the method of choice for the epoxidation of di-, tri-, and tetrasubstituted olefins. As an added benefit, it gives high diastereoselectivities for a number of cyclic dienes (Table 12.1). 

In the presence of a catalytic amount (10 %) of PTAB and anhydrous Chloramine-T (1.1 equiv.), a variety of olefins have been readily converted into the corresponding aziridines in acetonitrile at room temperature (Scheme 12.13). This method exhibits broad substrate scope, and the yields are usually high (Table 12.3) [42]. 

Although some methods for reductive etherifications of carbonyl compounds have been reported [152-162], the iron-catalyzed version possesses several advantages (1) fairly short reaction times are needed, (2) not only trimethylsilyl ether but also triethylsilyl and butyldimethylsilyl ethers and alcohols are adaptable, and (3) a broad substrate scope. 

Other reactions not described here are formal [3 -i- 2] cycloadditions of a,p-unsaturated acyl-fluorides with allylsilanes [116], or the desymmetrization of meso epoxides [117]. For many of the reactions shown above, the planar chiral Fe-sandwich complexes are the first catalysts allowing for broad substrate scope in combination with high enantioselectivities and yields. Clearly, these milestones in asymmetric Lewis-base catalysis are stimulating the still ongoing design of improved catalysts. 

Further detailed investigations towards new chiral ruthenium catalysts that could enhance enantioselectivity and expand the substrate scope in asymmetric RCM were reported by Grubbs and co-workers in 2006 [70] (Fig. 3.24). Catalysts 59 and 61, which are close derivatives of 56 incorporating additional substituents on the aryl ring para to the ort/to-isopropyl group, maintained similar enantioselectivity than 56b. However, incorporation of an isopropyl group on the side chain ortho to the ortho-isopropyl group 60 led to an increase in enantioselectivity for a number of substrates. 

The cobalt-catalysed reaction between aryl bromides and Grignard reagents assisted by IMes HCl is also known, however the substrate scope is quit narrow and good yields are only obtained when non-branched long chain alkyl magnesium chlorides are used as coupling reagents [80] (Scheme 6 19)... 

The coupling of thiols with aryl halides has been recently reported using Ni(NHC)2 complexes [171]. After screening different pre-catalysts, compound 28 showed the best behaviour in terms of activity and substrate scope, allowing the coupling of electron rich and poor aryl bromides with aryl or alkyl thiols (Scheme 6.52). 

The oxidative cleavage of alkenes is a common reaction usually achieved by ozonolysis or the use of potassium permanganate. An example of NHC-coordina(ed Ru complex (31) capable of catalysing the oxidative cleavage of alkenes was reported by Peris and co-workers (Table 10.9) [44]. Despite a relatively limited substrate scope, this reaction reveals an intriguing reactivity of ruthenium and will surely see further elaboration. 

This homoenolate methodology has been extended to the use of nitrones 170 as electrophiles [72]. Scheldt and co-workers have shown that enantiomerically enriched y-amino esters 172 can be prepared with excellent levels of stereocontrol from an enal 27 and a nitrone 170 using the NHC derived from triazolium salt 164 (Scheme 12.37). The oxazinone product 171, formally a result of a [3-1-3] cycloaddition, is cleaved to afford the y-amino ester product 172. The reaction shows broad substrate scope, as a range of substituted aryl nitrones containing electron donating and withdrawing substituents are tolerated, while the enal component is tolerant of both alkyl and aryl substituents. 

Although significant progress in the field of asymmetric hydroformylation has been made, it is limited to a rather narrow substrate scope. An alternative approach to a stereoselective hydroformylation might employ substrate control of a chiral alkenic starting material. Of particular use... 

The work described in this chapter illustrates that several approaches can successfully achieve the goal of broadening the substrate scope of aldolases. Whereas these enzymes have been perceived as being useful only in very specific applications due to their strict substrate specificity, it is becoming clear that they can in fact be versatile, practical biocatalysts that can be applied to a wider range of synthetic problems. 

Activated aryl chlorides, which are close in reactivity to unactivated aryl bromides, underwent reaction with the original P(o-tol)3-ligated catalyst.58 Nickel complexes, which catalyze classic C—C bond-forming cross-couplings of aryl chlorides, 9-64 also catalyzed aminations of aryl chlorides under mild conditions.65,66 However, the nickel-catalyzed chemistry generally occurred with lower turnover numbers and with a narrower substrate scope than the most efficient palladium-catalyzed reactions. 

Upon completion of the synthesis of (+)-ll,ll -dideoxyverticillin A (1), it was recognized that there were only a handful of reports of monomeric epitri- or epitetrathiodiketopiperazine syntheses, nearly all of which were accomplished with lack of sulfide chain length control. In the limited cases where selectivity was achieved, the results were highly substrate dependent or the method lacked substrate scope [56],... 

A broad substrate scope for the rhodium-catalyzed asymmetric 1,4-addition has been observed.98 Both arylboronic acids with either electron-donating or electron-withdrawing aryl substituents and alkenylboronic acids can be introduced into acyclic or cyclic enones with high enantioselectivities (Scheme 30). 

Recently, the iron-promoted Barbier-type addition of alkyl halides to aromatic aldehydes has been reported (Equation (26)).326 According to the proposed mechanism, the initial step is the formation of an alkyl radical, which can be reduced to the corresponding carbanion. This carbanion nucleophile can react, while coordinated to the iron pentacarbonyl complex, with the corresponding aldehyde. This stoichiometric method is limited with respect to substrate scope and yield. The same authors have also developed the Reformatsky-type addition of cr-halosub-stituted carbonitriles to aldehydes and ketones in the presence of iron pentacarbonyl.3... 

Subsequent examination of a tethered alkyne-VCP with rhodium(i) resulted in the first metal-catalyzed [5 + 2]-reaction. Excellent yields were obtained with a variety of substrates (Scheme 3) irrespective of the steric and electronic nature of the R1 group. Notably, quaternary centers are accessed in high yield. Since this first report, in-depth studies on catalysts, substrate scope, selectivity, and applications to total synthesis have been carried out. Work in this area has been reviewed.23-26... 

The metal-catalyzed [5 + 2]-cycloaddition reaction of VCPs and 7t-systems provides a new concept for seven-membered ring construction that has been significantly advanced over the last decade in the areas of catalyst development, chemo-, diastereo-, and enantioselectivity, substrate scope, and applications to total synthesis. 

Several phospholane-based ligands have shown a wide substrate scope beyond the standard examples represented in Table 24.2. Both Et-FerroTANE 61 [147] and TangPhos 46 [69 b, 71] have been successfully applied to a diverse range of methyl and ethyl />-aryl-dehydroamino acids containing various aromatic substituents, whilst catASium M 20a [95] has been used for the reduction of numerous yS-alkyl-dehydroamino acid esters. 

These reports announced the rapid development of a large variety of monodentate ligands for rhodium-catalyzed enantioselective hydrogenation. It was shown that the substrate scope for catalysts based on monodentate ligands is most probably at least as big as for their bidentate counterparts. Also, initial doubts about the activity and stability of the monodentate ligand-catalysts have been taken away. Several reports show that substrate catalyst ratios (SCRs) of 103 or higher, essential for industrial application, are possible. In addition, reaction rates are in the studied cases comparable to those reached by catalysts based on state-of-the-art bidentate ligands [16]. 

The promising results obtained with Ir-PHOX complexes prompted an extensive search for related, more selective catalysts with broader substrate scope. 

---