Very sterically hindered substrates

One of the first highly efficient Pd-NHC based catalysts for the coupling between aryl chlorides and boronic acids was developed by Nolan and co-workers [100], The catalyst was prepared in situ from a mixture of IPr HCl/PdCdba) or IMes HCl/PdCOAc) and used Cs COj as base. A selection of results obtained using this protocol is shown in Scheme 6.25. These, or very similar, reaction conditions have been applied by other authors and give excellent results for more sterically hindered substrates [101-104]. 

As the steric bulk of the propargylic substituents increased, the preference for the formation of the seven-membered ring increased as well. Formation of a ruthenacyclopentene intermediate with sterically hindered substrates involves a large amount of A(1,3) strain, leading to preferential formation of a 7r-allyl species. This novel cycloisomerization process is very sensitive to alkene substitution the requirement for a m-methyl group was evidenced by the failure of 70 to give... 

The rather complex furylvinylcarbinol derivative 76 shown in Scheme 4.28 was required in enantiopure form as a key intermediate in the synthesis of the natural product cneorin. The carbinol moiety is heavily substituted with sterically demanding groups. Therefore attempts to resolve the furylvinylcarbinol with CALB or lipase PS-II led to very slow reactions. However, the rarely used enzyme Candida antarctica lipase A (CALA), which is known to act on sterically hindered substrates offers an alternative. Thus acylation of the furylvinylcarbinol 76 with 2,2,2-trifluoroethyl butanoate catalyzed by CALA (immobilized on celite with sucrose at pH 7.9) furnished the enantiomerically enriched propanoate of S-76 and R-76 (Scheme 4.28) [90]. Small-scale experiments gave E > 300. 

The Sorghum (S)-oxynitrilase exclusively catalyzes the addition of hydrocyanic acid to aromatic aldehydes with high enantioselectivity, but not to aliphatic aldehydes or ketones [519, 526], In contrast, the Hevea (S)-oxynitrilase was also found to convert aliphatic and a,/ -unsaturated substrates with medium to high selectivity [509, 527]. The stereocomplementary almond (R)-oxynitrilase likewise has a very broad substrate tolerance and accepts both aromatic, aliphatic, and a,/ -unsaturated aldehydes [520, 521, 523, 528, 529] as well as methyl ketones [530] with high enantiomeric excess (Table 9). It is interesting to note that this enzyme will also tolerate sterically hindered substrates such as pivalaldehyde and suitable derivatives 164 which are effective precursors for (R)-pantolactone 165 [531],... 

Nitrogen-based heterocycles can also be prepared through Ni/NHC-catalyzed cyclo addition reactions. For example, Ni/SIPr catalyzed the cycloaddition of diynes with isocyanates under the mildest conditions to date [26]. In particular, excellent yields of pyridones are obtained from diynes and isocyanates at room temperature using only 3 mol % catalyst. As shown in Eq. 8, a variety of diynes were subjected to these optimized conditions. Both aryl and alkyl isocyanates were readily converted to the respective 2-pyridone. Sterically hindered substrates appeared to have very little effect on the reaction, as excellent yields of product were obtained with bulky isocyanates and bulky diynes. 

The single most used lipase for biocatalysis is probably the Candida antarctica B-lipase (CALB) [42]. It is commercialized by Novozymes in liquid formulation as well as in immobilized form under the trade name Novozym 435 (previously SP 435). CALB has high activity on a wide range of substrates (it has some problems with very bulky substrates), often with outstanding selectivities. Formulated as Novozym 435 it is stable up to approx. 90 °C in solvents such as toluene (or solvent-free reaction mixtures). The A-lipase (CALA), currently only commercially available in liquid form, has attractive properties too, including even better thermostability and higher activity on sterically hindered substrates [43]. 

Furthermore, the Tedicyp/fPdClfCjHjljj system efficiently catalyzes the Suzuki coupling of sterically hindered substrates. Very high turnover numbers can be obtained for the coupling of sterically hindered aryl bromides with benzeneboronic acid or for the coupling of bromobenzene with sterically hindered arylboronic acids. Conversely, the formation of tri-ortho-substituted biaryl adducts requires a high catalyst loading (Equation 65) [87]. 

Carbanion-enolates are nucleophiles that react with alkyl halides (or sulfonates) by typical S 2 reactions, Carbanion-enolates are best formed using lithium diisopropylamide (lda), (r-Pr)2N Li, in tetrahydrofuran. This base is very strong and converts all the substrate to the anion. Furthermore, it is too sterically hindered to react with RX. 

Systematic investigations into this reaction have been undertaken and showed that for straight-chain aralkyl hydroperoxides and their cyclic analogues the (R)-alcohol forms, whereas the stereoselection is the opposite for branched hydroperoxides. The reaction could be applied to functionalized hydroperoxides such as a- and (3-hydroperoxy esters or hydroperoxy alcohols with good to excellent diastereo- and enantioselectivities. Up to 99% ees were obtained for small, sterically non-hindered substrates, whereas for tertiary hydroperoxides and for substrates with substituents at the co-position neither good ees nor useful turnover numbers have been reported. HRP reacts very sluggishly also with sterically demanding silyl-substituted allyl hydroperoxides. 

Rh complexes of ferrocene-based ligands are very effective for the hydrogenation of several types of dehydroamino (2,3,29,41,42,44) and itaconic acid derivatives (4,5,28) as well as for enamide 45, enol acetate 26, and a tetrasubstituted C = C-COOH 21. Of particular interest are substrates that have unusual substituents (41,42,44) at the C = C moiety or are more sterically hindered than the usual model compounds (21,42). Table 15.10 lists typical examples with very high ee s and often respectable TONs and TOFs. Several industrial applications have already been reported using Rh-Josiphos and Ru-Josiphos (see Figure 15.7) as well as Rh-Walphos (Scheme 15.8). 

A very recent slick investigation by Majewski and Nowak also supports Collum s theoretical and experimental results. They measured decreases in optical purity of (l )-6, originally in the optically pure form, during the course of deprotonation and provided the rate of the enolization (Sch. 7) [31]. Lithiation of bulky ketone 6 with LDA is first-order in the ketone and 0.5-order in the base. This result is consistent with a spectroscopically invisible dimer-monomer pre-equilibrium of LDA which is also suggested by Collum s results. Fractional order in LDA suggests a pathway involving the monomer of the amide and rate-determining proton transfer. Most notably, a combination of both monomer and dimer pathways is possible, especially for substrates less sterically hindered. 

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