Enantioselective Allylic Substitution

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. 

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. 

Helquist et al. [129] have reported molecular mechanics calculations to predict the suitability of a number of chiral-substituted phenanthrolines and their corresponding palladium-complexes for use in asymmetric nucleophilic substitutions of allylic acetates. Good correlation was obtained with experimental results, the highest levels of asymmetric induction being predicted and obtained with a readily available 2-(2-bornyl)-phenanthroline ligand (90 in Scheme 50). Kocovsky et al. [130] prepared a series of chiral bipyridines, also derived from monoterpene (namely pinocarvone or myrtenal). They synthesized and characterized corresponding Mo complexes, which were found to be moderately enantioselective in allylic substitution (up to 22%). 

Asymmetric nucleophilic allylic substitution has rarely been studied in its heterogeneous version, probably because of the difficulties encoimtered in properly stabilizing and recycling Pd(0) species. Nevertheless, some promising examples have been pubhshed. Lemaire et al. [143] studied the activity and enantioselectivity of various chiral C2-diamines for the asymmetric Pd-catalyzed transformation of various allyl acetates. The structures tested are represented in Scheme 58. 

Since Pd complexes are well-known catalysts for enantioselective allylic substitution reactions, here the catalytic behaviour of palladium NPs for this reaction is examined (Scheme 1). One example involving a chiral phosphite with a carbohydrate backbone, able to coordinate firmly at the surface of NPs together with oxygen atoms capable to interact weakly with this surface, is presented. In particular. 

Since carbohydrates constitute an inexpensive and highly modular chiral source for preparing chiral ligands," Claver et al. have reported the use of a series of thioether-phosphite" and thioether-phosphinite furanoside ligands" in the test palladium-catalysed allylic substitution reaction. In the first type of ligand, a systematic variation of the donor group attached to the carbon atom C5 indicated that the presence of a bulky phosphite functionality had a positive effect on the enantioselectivity. Indeed, the enantioselectivity was controlled mainly by the phosphite moiety. This was confirmed by the use of a ligand... 

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... 

A review8 with more than 186 references discusses the synthesis of Rh and Pd complexes with optically active P,N-bidentate ligands and their applications in homogeneous asymmetric catalysis. The effect of the nature of the P,N-bidentate compounds on the structure of the metal complexes and on enantioselectivity in catalysis was examined. Allylic substitution, cross-coup-ling, hydroboration and hydrosilylation catalyzed by Rh or Pd complexes with optically active P,N-bidentate ligands are considered. 

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... 

It is noteworthy that ZnEt2 has been used as a base in enantioselective allylic substitutions. A remarkable increase in ee was observed when ZnEt2 was used instead of KH, NaH, LiH, LDA, or BuLi in the Pd-catalyzed alkylations of allylic acetates by enolates of malonic esters and related compounds.403 In contrast, application of ZnEt2 was not as very effective as in similar iridium-catalyzed allylic alkylations.404... 

The synthesis of lycorane (13) by Mori and Shiba-saki121 is breathtaking for its use of three consecutive Pd catalyzed C-C bond forming reactions. Thus, Pd-catalyzed asymmetric allylic substitution of a benzoate in meso 7 in the presence of the chiral bisphos-phine 8 leads to the regioselective formation of 10 in 40 % ee It is easy to overlook this low level of enantioselectivity when we are faced with the subsequent elegant Pd-catalyzed reactions Pd-catalyzed intramolecular animation is followed by a Pd-catalyzed Heck coupling to afford 12, which is then readily converted to the target molecule... 

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