Enantioselective allylic substitutions substrates

S ]2 -selective reactions between primary allylic substrates and otganocoppet reagents testiU in the creation of new Chirality in previously aChital molecules, and it is tempting to try to take advantage of this for the development of enantioselective allylic substitution reactions. 

Allyl derivatives 11 with identical substituents at Cl and C3 are an important class of substrates for enantioselective allylic substitution (Scheme 10). Starting from either enantiomer (11 or ent-ll) the same allyl-palladium complex 12 is formed. Therefore, the first part of the catalytic cycle leading to this intermediate usually is irrelevant for the stereoselectivity of the overall reaction [31]. The two termini of the free allyl system are enantiotopic. If the catalyst is chiral, they become diasterotopic in the allyl-metal complex and, therefore, may exhibit different reactivities toward nucleophiles. Under the influence of a suitable chiral ligand attached to palladium, nucleophilic attack can be rendered regioselective leading preferentially either to product 13 or its enantiomer ent-l3. 

Substrates derived from meso-cycloalkenediols such as 41 are a highly versatile starting materials for enantioselective allylic substitutions [15]. Regioselective displacement of one of the enantiotopic leaving groups by the chiral catalyst leads to a chiral allyl intermediate 42 which is attacked regioselectively at the ster-ically less hindered position to afford product 43 (Scheme 17). Products of this type can be converted to variety of useful compounds by a second allylic substitution reaction. 

Substrates which do not proceed via symmetrical allyl intermediates such as (10.41) can also be subject to enantioselective allylic substitution reactions in some circumstances. Substrates which can equilibrate through a tt—ct—tt mechanism provide one option, however, the intermediate tt-allyl group must contain two identical groups at one terminus for racemisation/epimerisation to occur. Thus the racemic compound (10.57) has been used with bidentate phosphines and... 

Even oxygen nucleophiles have been introduced with good enantioselectivity using both palladium- and iridium-based catalysts. The conditions of the reaction need to be sufficiently mild that the product does not become a substrate for the allylic substitution, since this will ultimately lead to racemisation. Pivalate ( BuC02 ) and phenols have been used as nucleophiles, in the presence of palladium catalysts, with good results, while linear allylic carbonates are converted into chiral branched products with high ee using phenolates, aUcoxides and also hydroxylamines with iridium complexes. Sulfur nucleophiles have also been used in enantioselective allylic substitution reactions. ... 

Many non-carbon nucleophiles have been successfully used in Pd-catalysed enantioselective allylic substitutions. With P-stereogenic ligands, there are reports mainly of allylic aminations and sulfonylations, with formation of C N and C-S bonds respectively. Not surprisingly, the benchmark substrate is 11 for both reactions. 

Enantioselective allylic substitution can also be achieved by selective cleavage of one of two enantiotopic leaving groups. Hiis selectivity can occur within a cyclic substrate, as shown in Equation D of Scheme 20.10. Enantioselective allylic substitutions can also occur by replacement of one of two enantiotopic leaving groups on the same carbon, as shown for the acetal structure in Equation E of Scheme 20.10. 

Butadiene monoepoxide 166 has been used as a substrate for enantioselective allylic substitution reactions. The reaction with phthalimide has been performed with excellent regiocontrol and excellent enantiocontrol. The best results were obtained with a variant 168 of the standard ligand (Scheme 36). ° " ... 

When a racemic allylic substrate is employed in an enantioselective substitution reaction, one of the two substrate enantiomers may react more quickly than the other. This effect is a kinetic resolution and has been noted reasonably often in enantioselective allylic substitution reactions. Several studies on kinetic resolution have been reported, - and a few highlight reactions are noted in Scheme 45. These include recovery of unreacted cy-clohexenyl acetate 92, as well as the tetraacetate 225. Kinetic resolution has also been observed in allylic snbstitution using a snlfinate nucleophile (Li02STlu) with allyl acetate... 

It may be concluded from die different examples sliown here tiiat die enantio-selective copper-catalyzed allylic substitution reaction needs ftirdier improvemetiL High enantioselectivities can be obtained if diirality is present in tiie leaving group of die substrate, but widi external diiral ligands, enantioselectivities in excess of 9096 ee have only been obtained in one system, limited to die introduction of die sterically hindered neopeatyl group. 

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... 

In order to rationalize the factors determining the enantioselectivity of the hydrosilylation of the para-substituted styrenes, we have calculated the relative thermodynamic stabilities of all the intermediates of the catalytic cycle that are precursors of the two enantiomeric products as a function of the para-substituted substrates. Since, the 5 configuration product was formed in 64% ee from styrene, whereas 4-(dimethylamino)styrene afforded the R product with 64% ee [6], we have performed all calculations with these two different substrates. We shall demonstrate, in fact, that the relative thermodynamic stabilities of the fi3-allylic complexes are decisive for both the regio and the stereoselectivity. 

As previously discussed, activation of the iridium-phosphoramidite catalyst before addition of the reagents allows less basic nitrogen nucleophiles to be used in iridium-catalyzed allylic substitution reactions [70, 88]. Arylamines, which do not react with allylic carbonates in the presence of the combination of LI and [Ir(COD)Cl]2 as catalyst, form allylic amination products in excellent yields and selectivities when catalyzed by complex la generated in sim (Scheme 15). The scope of the reactions of aromatic amines is broad. Electron-rich and electron-neutral aromatic amines react with allylic carbonates to form allylic amines in high yields and excellent regio- and enantioselectivities as do hindered orlAo-substituted aromatic amines. Electron-poor aromatic amines require higher catalyst loadings, and the products from reactions of these substrates are formed with lower yields and selectivities. 

No examples have been reported of enantioselective, iridium-catalyzed allylic substitutions of linear allylic esters to generate 1,1-disubstituted or 2-substituted 7i-allyl intermediates. Takeuchi published reactions in which the proposed allylir-idium intermediates are 1,1- or 1,3-disubstituted, but these substrates have not been shown to undergo reactions catalyzed by chiral iridium complexes. No reactions of 1,2-disubstituted substrates have been published (Scheme 34). 

Table 17) with two substituents in position C3 the oxygen transfer by the chiral hydroperoxides occurred from the same enantioface of the double bond, while epoxidation of the (ii)-phenyl-substituted substrates 142c,g,i resulted in the formation of the opposite epoxide enantiomer in excess. In 2000 Hamann and coworkers reported a new saturated protected carbohydrate hydroperoxide 69b , which showed high asymmetric induction in the vanadium-catalyzed epoxidation reaction of 3-methyl-2-buten-l-ol. The ee of 90% obtained was a milestone in the field of stereoselective oxygen transfer with optically active hydroperoxides. Unfortunately, the tertiary allylic alcohol 2-methyl-3-buten-2-ol was epoxidized with low enantioselectivity (ee 18%) with the same catalytic system . 

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