Palladium-catalyzed allylic substitution enantioselective

Vasse, J.-L., Stranne, R., Zalubovskis, R., Gayet, C. and Moberg, C. (2003) Influence of steric symmetry and electronic dissymmetry on the enantioselectivity in palladium-catalyzed allylic substitutions. /. Org. Chem., 68, 3258-3270. 

In order to permit complete conversion to one product enantiomer under the influence of a chiral catalyst, substrates for palladium-catalyzed allylic substitution either have to possess a meso structure (equation 1) or else give rise to complexes with 7t-allyl ligands as depicted in equations 2 and 3. Whereas oxidative addition of the substrate to the palladium(O) species constitutes the enantioselective step for meso compounds (equation 1), nucleophilic attack determines the absolute configuration of the product for reactive intermediates with a meso tt-allyl ligand (equation 2) or a zr-allyl unit that undergoes rapid epimerization by the n-a-n mechanism10-59 relative to substitution (equation 3). 

Tridentate salen ligands (10) derived from 1 have given excellent results in the enantiocontrol of the hetero Diels-Alder addition reaction of dienes with aldehydes (eq 7) and in the asymmetric additions of TMS-azide to mc5o-epoxide and trimethylsilyl cyanide to benzaldehyde (up to 85% ee). Phosphino-oxazolines derived from 1 have been employed for the asymmetric control of palladium-catalyzed allylic substitution reactions products of 70-90% ee were obtained. Photolysis of crystalline adducts of enantiomerically pure 1 with prochiral alcohols results in asymmetric inductions of up to 79% in a rare example of a solid-state enantioselective reaction. ... 

Allylic Substitution Use of 2-[(45)-4-( 1,1 -dimethylethyl)-4,5-dihydro-2-oxazolyl]-6-methylpyridine(l) for enantioselective palladium-catalyzed allylic substitution has been reported. 

Helmchen, G. Enantioselective palladium-catalyzed allylic substitutions with asymmetric chiral ligands. J. Organomet. Chem. 1999, 576, 203-214. 

In the absence of nucleophiles, the intermediate allyl complexes are stable and can be isolated. This is an attractive, quite unique feature of palladium-catalyzed allylic substitutions, because in most catalytic processes it is difficult to isolate or even merely detect intermediates of the catalytic cycle. The vast amount of data on the structure and reactivity of (allyl)palladium complexes that is available, has led to valuable insights into the mechanism of allylic substitutions and the origin of enantioselection in reactions with chiral catalysts (see Sect. 7). 

Activated methylene compounds such as dimethyl malonate have found substantial utility in palladium catalyzed allylic substitution reactions. Accordingly, the Krapcho decarboxylation is often used in conjunction with these reactions. As an example, the first total synthesis of enantiomerically pure (-)-wine lactone has utilized the sequence of reactions.27 First, the allylic substitution reaction of 2-cyclohexen-l-yl acetate (49) with alkali sodium dimethylmalonate yielded 51 with high enantioselectivity, as a result of the use of chiral phosphine ligand 50. The malonate was then subjected to Krapcho decarbomethoxylation using NaCl, H2O, and DMSO at 160 °C to yield 52. This reaction has been used similarly following the allylic substitution reaction with other malonate derivatives.28-30... 

Enantioselective Palladium-Catalyzed Allylic Substitutions with Asymmetric Chiral Ligands. 

Thanks to the fundamental studies of Tsuji, Trost, and others, palladium-catalyzed allylic substitution has become a versatile, widely used process in organic synthesis [40]. The search for efficient enantioselective catalysts for this class of reactions is an important goal of current research in this field [41]. It has been shown that chiral phosphine ligands can induce substantial enantiomeric excesses in Pd-catalyzed reactions of racemic or achiral allylic substrates with nucleophiles [42]. Recently, promising results have also been obtained with chiral bidentate nitrogen ligands [43]. We have found that palladium complexes of neutral aza-semicorrin or methylene-bis(oxazoline) ligands are effective catalysts for the enantioselective allylic alkylation of l,3-diphenyl-2-propenyl acetate or related substrates with dimethyl malonate (Schemes 18 [25,30] and 19 [44]). 

The asymmetric aUylic substitution has become a popular method for the synthesis of enantiomeric ally pure molecules [82-84]. The palladium-catalyzed allylic substitution of acetate in rac-1,3-diphenylprop-2-enyl acetate with dimethylmalonate is a benchmark reaction for chiral ligands (Scheme 5.16). Ligands 7 yielded good catalytic activities and high enantioselectivities (e.e. up to 93%, see Table 5.1) [64], proving amongst the most efficient P,S ligands for this reaction [51-54]. 

AUylic substitution catalyzed by copper is a transformation that is related to ally-lie substitutions catalyzed by other transition metals discussed previously in this chapter, but several features of copper-catalyzed allylations make them worth differentiating. First, copper-catalyzed allylic substitutions are conducted with different types of nucleophiles tiian most allylic substitutions catalyzed by other metals. Second, the regioselectivity of the copper-catalyzed reactions is typically different from that of reactions catalyzed by complexes of other metals, particularly of reactions catalyzed by complexes of palladium. Thus, this last section of tiie chapter describes studies on allylic substitution catalyzed by copper, witii an emphasis on enantioselective examples. 

A procedure for the highly enantioselective synthesis of chiral chromenes and tetrahydroquinolines was achieved in 2012 by Feringa and co-workers. By combining asymmetric copper-catalyzed allylic substitution with Grignard reagents and an efficient palladium-catalyzed intramolecular Heck... 

Scheme 5.26 Enantioselective palladium-catalyzed allylic alkylation of fluoro-substituted silyl enol ethers 80.

Asymmetric synthesis of tricyclic nitro ergoline synthon (up to 70% ee) is accomplished by intramolecular cyclization of nitro compound Pd(0)-catalyzed complexes with classical C2 symmetry diphosphanes.94 Palladium complexes of 4,5-dihydrooxazoles are better chiral ligands to promote asymmetric allylic alkylation than classical catalysts. For example, allylic substitution with nitromethane gives enantioselectivity exceeding 99% ee (Eq. 5.62).95 Phosphi-noxazolines can induce very high enatioselectivity in other transition metal-catalyzed reactions.96 Diastereo- and enantioselective allylation of substituted nitroalkanes has also been reported.9513... 

The formation of chromane derivatives has also been realised in the palladium catalyzed intramolecular nucleophilic substitution of allyl carbonates (Tsuji-Trost reaction). In most cases the reaction is accompanied by the formation of a new centre of chirality. Using Trost s chiral ligand the ring closure was carried out in an enantioselective manner. The asymmetric allylation of the phenol derivative shown in 4.20. was achieved both in good yield and with excellent selectivity.23... 

A tandem palladium-catalyzed reaction can effect a similar transformation to produce 2-vinyl-substituted heterocyclic systems as in Eq. 8E.11. By varying the amino acid moiety of the ligand, 83% ee could be obtained from the use of the glycine-derived ligand 129 [161]. A maximum enantioselectivity of 65% ee has been recorded for this type of reaction in an earlier study with BINAP as ligand [ 162]. Because both ( )- and (Z)-isomers gave the same enantioselectivity, attack on the rapidly interconverting 7t-allyl intermediates seems to determine the selectivity. Modest enantioselectivities have been reported for the related asymmetric preparation of 2-vinylpiperazine and 1,4-benzodioxane derivatives [163,164],... 

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