Challenging Substrates

Until this work, the reactions between the benzyl sulfonium ylide and ketones to give trisubstituted epoxides had not previously been used in asymmetric sulfur ylide-mediated epoxidation. It was found that good selectivities were obtained with cyclic ketones (Entry 6), but lower diastereo- and enantioselectivities resulted with acyclic ketones (Entries 7 and 8), which still remain challenging substrates for sulfur ylide-mediated epoxidation. In addition they showed that aryl-vinyl epoxides could also be synthesized with the aid of a,P-unsaturated sulfonium salts lOa-b (Scheme 1.4). 

The catalytic enantioselective desymmetrization of meso compounds is a powerful tool for the construction of enantiomerically enriched functionalized products." Meso cyclic allylic diol derivatives are challenging substrates for the asymmetric allylic substitution reaction owing to the potential competition of several reaction pathways. In particular, S 2 and 5n2 substitutions can occur, and both with either retention or inversion of the stereochemistry. In the... 

The effieiency of eatalyst Ic was examined in the ring closing metathesis of challenging substrate 3c. Full eonversion of dimethallylamide (3c) was achieved after heating to 80°C for 2.5 h with a catalyst loading of 2.5 mol%. The larger scale run furnished 80% isolated yield of the desired dihydropyrrole 4c. 

Tetrasubstituted alkenes are challenging substrates for enantioselective hydrogenation because of their inherently low reactivity. Crabtree showed that it was possible to hydrogenate unfunctionalized tetrasubstituted alkenes with iridium catalysts [46]. Among the iridium catalysts described in the previous section, several were found to be sufficiently reactive to achieve full conversion with al-kene 77 (Table 30.14). However, the enantioselectivities were significantly lower than with trisubstituted olefins, and higher catalyst loadings were necessary. 

Tetrasubstituted alkenes are among the most challenging substrates for catalytic hydrogenation reactions. Towards this end, Buchwald and co-workers recently reported efficient and highly enantioselective Zr-catalyzed hydrogenations of a range of styrenyl tetrasubstituted alkenes (Scheme 6.41) [123]. Precedents based on efficient polymerization reactions promoted by cationic zirconocenes led these workers to consider similar catalyst species, derived from dimethylzirconocene 107, for this purpose. 

Acyclic Enones as Substrates Compared to cyclic enones, acyclic enones are generally more challenging substrates for the copper-catalyzed asymmetric 1,4-addition reactions. Several ligands have been reported that can achieve high ee when p-aryl acyclic enones are used as substrates in the 1,4-addition of diethyl-zinc (Figure 3.5). ° ... 

Subsequently, List reported that although the method described above was not applicable to the reduction of a,P-unsaturated ketones, use of a chiral amine in conjunction with a chiral anion provided an efficient and effective procedure for the reduction of these challenging substrates [210]. Transfer hydrogenation of a series of cyclic and acyclic a,P-unsaturated ketones with Hantzsch ester 119 could be achieved in the presence of 5 mol% of valine tert-butyl ester phosphonate salt 155 with outstanding levels of enantiomeric control (Scheme 64). A simple mechanistic model explains the sense of asymmetric induction within these transformations aUowing for reliable prediction of the reaction outcome. It should also be noted that matched chirality in the anion and amine is necessary to achieve high levels of asymmetric induction. 

Tab. 10.7 summarizes the results of the application of rhodium-catalyzed allylic etherification to a series of ortho-substituted phenols. The etherification tolerates alkyls, including branched alkanes (entries 1 and 2), aryl substituents (entry 3), heteroatoms (entries 4 and 5), and halogens (entry 6). These results prompted the examination of ortho-disubstituted phenols, which were expected to be more challenging substrates for this type of reaction. Remarkably, the ortho-disubstituted phenols furnished the secondary aryl allyl ethers with similar selectivity (entries 7-12). The ability to employ halogen-bearing ortho-disubstituted phenols should facilitate substitutions that would have proven extremely challenging with conventional cross-coupling protocols. 

The CM of olefins bearing electron-withdrawing functionalities, such as a,/ -unsaturated aldehydes, ketones, amides, and esters, allows for the direct installment of olefin functionality, which can either be retained or utilized as a synthetic handle for further elaboration. The poor nucleophilicity of electron-deficient olefins makes them challenging substrates for olefin CM. As a result, these substrates must generally be paired with more electron-rich crosspartners to proceed. In one of the initial reports in this area, Crowe and Goldberg found that acrylonitrile could participate in CM reactions with various terminal olefins using catalyst 1 (Equation (2))." Acrylonitrile was found not to be active in secondary metathesis isomerization, and no homodimer formation was observed, making it a type III olefin. In addition, as mentioned in Section 11.06.3.2, this reaction represents one of the few examples of Z-selectivity in CM. Subsequent to this report, ruthenium complexes 6 and 7a were also observed to function as competent catalysts for acrylonitrile... 

An understanding of olefin chemoselectivity in CM is also crucial when homologating 1,3-dienes, which represent a particularly challenging substrate class. In 2005, Grubbs and co-workers demonstrated that, by employing either an electronic or steric barrier to reaction, one of the olefins in a conjugated diene could be deactivated relative to the other for CM. For example, in the reaction of ethyl sorbate with 5-hexenyl acetate in the presence of 5 (I0mol%),... 

Cycloheptatriene represents a challenging substrate for cycloaddition. It can react either in a [2 + 4 ]- or [2 + 6]-cycloaddition to yield isomeric endoperoxides 53 and 54, respectively (Scheme 9.8). Moreover, it may give a 1,2-dioxetane (55) in a [2 + 2] process. Norcaradiene, its valence isomer, may also yield a [2 + 4] adduct (56). All four products were detected in the transformation of the nonsubstituted molecule.421,422... 

Another interesting castor oil-derived platform chemical is 10-undecenal, which is at the same time a challenging substrate for olefin metathesis. For the SM of 10-undecenal, Dixneuf et al. modified C3 and C5 by insertion of SnCl2 into one Ru-Cl bond [48]. Modification of C3 led to a binuclear complex, which showed a conversion of 70% at a catalyst loading of 0.33 mol%. On the other hand, both the modified and unmodified C5 gave conversions over 70% with catalyst loadings of 1.25 mol%, but also led to formation of a high amount of by-products. 

Enantiopure propargylic sec-alcohols are valuable synthetic intermediates that can be prepared by a number of efficient asymmetric transformations [131]. KR of the racemic propargylic sec-alcohols is a valuable approach, particularly as subsequent exhaustive hydrogenation of the alkyne provides an indirect approach to enantio-enriched alkyl alkyl sec-alcohols which themselves are challenging substrates for both enzymatic and non-enzymatic KR. 

In the coupling of more challenging substrates, reduction of the aryl halide is frequently observed [21]. Specifically, in the reaction of electron-rich aryl halides or sulfonates, reduced arene is a major by-product. Presumably, this side-product arises when the palladium amide can undergo /1-hydride elimination to generate an imine and a palladium (II) aryl hydride (Scheme 2). Subse-... 

The initial catalyst systems described above were effective with aryl bromides and a relatively narrow array of amines, although these procedures found utility in the preparation of diaminofluorenes [22], poly(aryleneamines) [23], certain iV-aryl-aza-crown ethers [24], N -arylpiperazines [25], and diaminobenzenes [26] (Fig. 1). These original methods often proved reasonably effective in the coupling of cyclic amines. Presumably, cyclic amines are less challenging substrates for the palladium-catalyzed coupling because the cyclic palladium (II) amide intermediates are less prone to /1-H elimination compared to their acyclic counterparts. 

Hydrosilylation/cyclization of hindered polyenes can be efficiently catalyzed by sterically open anra-lanthanocenes, but trimethylsilylcyclopentadienyl derivatives are particular active and allow cyclization of these challenging substrates at room temperature (23) [74],... 

Ligands for Iridium-catalyzed Asymmetric Hydrogenation of Challenging Substrates... 

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