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]. 

So far only a few examples of the uses of organosilicon compounds in cross-couplings have been published. Noteworthy is the smooth reaction with a sterically hindered substrate (87).295 The synthesis of the alkaloid nitidine included a cross-coupling step using an alkenylsilane (88),296 while the syntheses of some antitumor agents involved the alkenylation of unprotected iodouracyls using alkenyl-silicon species.297... 

Commercially available Pd(PtBu3)2 is a unique, air-stable 14e Pd° complex, an excellent catalyst for cross-coupling reactions of aryl chlorides. The ability of P Bu3 to stabilize such a coordin-atively unsaturated, extremely reactive, and yet easily manageable form of Pd° is one of the most amazing and fruitful recent findings in Pd-based catalysis. The cross-coupling of arylzinc reagents with aryl or vinyl chlorides can be readily accomplished with as little as 0.03% of this catalyst. Both electron-rich and sterically hindered substrates are welcome in this protocol.404... 

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. 

Due to the suppression of racemization and the ability to couple sterically hindered substrates, this methodology has been utilized in solid-phase peptide synthesis. In particular, 9-fluorenyl-methoxycarbonyl-protected amino acid fluorides have been used with this protocol.110 1,3... 

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],... 

While the reaction is generally thought to proceed through a nucleophilic addition mechanism, sterically hindered substrates may react according to mi SET (single electron transfer) mechanism ... 

Silver ion catalysis fails with sterically hindered substrates, pointing to the requisite formation of a substrate complex with the ion. In these cases, photochemical excitation is the method of choice. 

Many copper-containing organometallic compounds add to a,/3-unsaturated ketones in smooth 1,4-additions (for the term 1,4-addition see Figure 10.31). The most important ones are Gilman cuprates (Figure 10.43, left). For sterically hindered substrates, their rate of addition can be increased by adding Me3SiCI to the reactants. 

The catalyst precursor complex [ Rh(COD) Diop] BF4 has been used for the screening of five substrates containing prochiral C=C double bond (COD = 1,5-cyclooctadiene) [266]. These were methylacetamidoacrylate (SI), Z-a-methylacetamidocinnamate (S2), dimethylitaconate (S3), methone (S4) and rac-a-pinene (S5) (see Figure 4.56). Activated C=C bonds such as those in the two acetamido derivatives were more reactive. The most reactive molecule is the less sterically hindered substrate methylacetamidoacrylate. Reaction was less pronounced for unsubstituted and sterically hindered substrates such as methone. The reduction of C=0 bond in a-pinene is more difficult. These results are in agreement with the general trends reported for asymmetric hydrogenations. 

From kinetic studies it was shown that nucleophilic substitutions involving sterically hindered substrates, such as bromoadamantane proceed through single electron transfer261. 

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. 

We elected to first prepare a 1,6-linked-C-disaccharide 12) since it possessed two linking atoms and was a less sterically hindered substrate than the corresponding 1,4-, 1,3-, or 1,2-Iinked derivatives. 

Pseudomonas fluorescens esterase MS growth/ pH-indicator active double mutant acting on sterically hindered substrate 22, 24, 26... 

ArMgBr —> ArOH. The reagent converts an arylmagnesium bromide or an aryl-lithium into an ate complex (a), which rearranges to b. Phenols are obtained on acid-catalyzed hydrolysis of b. Yields are usually higher from Grignard reagents they are poor with sterically hindered substrates. 

The reaction fails when highly sterically hindered substrates are used. From t-butanol and 1-phenylcyclohexane-l-carboxylic acid or 2,4,6-trimethylbenzoic acid, respectively, only the dianhydrides of the carboxylic acids are obtained. Better yields of the thiolesters are obtained by first reacting the carboxylic acid with 1-hydroxybenzotriazole in the presence of DCC, followed by reaction with the thioalcohol. A number of sugar esters are obtained in a similar manner. The use of DCC in the polycondensation of aliphatic dicar-boxylic acids and diols is also reported. These polyester are biodegradable surface active compounds. ... 

A separation step may not always be necessary when measuring low molecular weight haptens by EIA. In some cases, antibody binding to the enzyme-labeled hapten causes complete inhibition of enzyme activity. This may occur when antibody binding either sterically hinders substrate access to the active site of the enzyme or induces enzyme conformational changes. Whatever the cause, a more convenient homogeneous EIA system can result. - ... 

Proazaphosphatrane ligands in combination with Pd2(dba)3 also generate highly active catalysts for Buchwald-Hartwig amination of aryl chlorides, e.g. (132) from (130) and (131). The PAP ligand with R = Bu was particularly effective and the catalyst performed extremely well with sterically hindered substrates. ... 

DMAP is often used as catalyst in amidations and esterifications, especially for sterically hindered substrates. 

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