Asymmetric nucleophilic allylic substitution

Chiral pyridine-based ligands were, among various Ar,AT-coordinating ligands, more efficient associated to palladium for asymmetric nucleophilic allylic substitution. Asymmetric molybdenum-catalyzed alkylations, especially of non-symmetric allylic derivatives as substrates, have been very efficiently performed with bis(pyridylamide) ligands. 

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. 

Keywords N,N-Containing ligands Asymmetric catalysis Cyclopropanation Diels-Alder reaction Nucleophilic allylic substitution... 

Schulz E (2005) Use of JV,JV-Coordinaling Ligands in Catalytic Asymmetric C-C Bond Formations Example of Cyclopropanation, Diels-Alder Reaction, Nucleophilic Allylic Substitution. 15 93-148... 

Four reviews on allylic substitution reactions have been published. The first deals with the enantioselective allylic substitutions by carbon nucleophiles, in the presence of both palladium and non-palladium catalysts. The second reviews stere- 0 oselective allylic substitution reactions forming asymmetric C-C, C-N, and C-O bonds. The third review covers new developments in metal-catalysed asymmetric 0 allylic substitution reactions with heteroatom-centred nucleophiles. Several applications of this new methodology are included. Finally, the catalytic 5 2 and 5 2 reactions of allylic alcohols, most of which occur with a very high ee, have been reviewed. ... 

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%). 

Although Helmchen et al. showed that asymmetric iridium-catalyzed allylic substitution could be achieved, the scope of the reactions catalyzed by iridium complexes of the PHOX ligands was limited. Thus, they evaluated reactions catalyzed by complexes generated from [lr(COD)Cl]2 and the dimethylamine-derived phosphoramidite monophos (Scheme 8) [45,51]. Although selectivity for the branched isomer from addition of malonate nucleophiles to allylic acetates was excellent, the highest enantiomeric excess obtained was 86%. This enantiomeric excess was obtained from a reaction of racemic branched allylic acetate. The enantiomeric excess was lower when linear allylic acetates were used. This system catalyzed addition of the hthium salts of A-benzyl sulfonamides to aUylic acetates, but the product of the reaction between this reagent and an alkyl-substituted linear aUylic acetate was formed with an enantiomeric excess of 13%. 

Asymmetric allylic substitutions are widely applied in organic synthesis, using various metal complexes, chiral ligands, nucleophiles and allyl systems [39]. Although Pd is often the metal of choice, this is not the case for monosubstituted allylic substrates, where most Pd catalysts predominantly produce the achiral linear product. In contrast. Mo, W and Ir catalysts preferentially give rise to the desired branched products and, in recent years, a number of very effective Ir catalysts for various substrates have been developed [40]. Since, to the best of our... 

Monoalkylation of a-isocyano esters by using tert-butyl isocyano acetate (R = fBu) has been reported by Schollkopf [28, 33]. Besides successful examples using primary halides, 2-iodopropane has been reported to produce the a-alkylated product (1) as well by this method (KOfBu in THF). In the years 1987-1991, Ito reported several methods for the monoalkylation of isocyano esters, including the Michael reaction under TBAF catalysis as described earlier [31], Claisen rearrangements [34], and asymmetric Pd-catalyzed allylation [35]. Finally, Zhu recently reported the first example of the introduction of an aromatic substituent by means of a nucleophilic aromatic substitution (Cs0H-H20, MeCN, 0°C) in the synthesis of methyl ot-isocyano p-nitrophenylacetate [36]. 

Whereas Pd-catalyzed asymmetric allylic substitution reactions, with carbon as well as with heteronucleophiles, are widespread in stereoselective catalysis, it seems unusual that sulfur nucleophiles are less commonly used. Therefore we tested our ligands in such a reaction. We employed ligands 2 and 3 successfully in the reaction of racemic 3-methoxycarbonyloxyhept-4-ene with lithium t-butylsulfinate in the presence of 1.5 mol% of Pd2dba3 and 4.5 mol% of the ligands. In all cases full conversion was achieved, but with marked differences in the product selectivities (Scheme 1.4.9, Table 1.4.7). 

Transition metal (such as Pd, Ir, Mo and W)-catalyzed asymmetric allylic substitutions with various nucleophiles are widely employed in organic synthesis and played an important role in the area of asymmetric C-C bond formation. Trost, Helmchen, Pfaltz and others have focused primarily on the direct allylation of malonates by prochiral electrophiles ... 

Reactions with Sulfur Nucleophiles. The use of sulfur nucleophiles in palladium-catalyzed allylic substitution reactions is less well documented than that of carbon, nitrogen and oxygen nucleophiles. The asymmetric synthesis of allylic sulfones utilizing a catalytic phase transfer system has been used to produce (35)-(phenylsulfonyl)cyclohex-l-ene on a 45 g scale (eq 10). In many cases, it has been reported that allylic carbonates are more reactive than allylic acetates in asymmetric allylic substitution... 

Two types of palladium-catalyzed asymmetric reaction have been reported. One is the allylation of nucleophiles in which a new chiral carbon center is created in the nucleophile and the other is the allylic substitution reaction in which it is created in the allylic substrate (Scheme 2-24). Chiral ferrocenylbisphosphines designed and modified on the side chain have been successfully used for both of the two types of asymmetric reaction [5 c, d]. 

In the allylic substitution of racemic 2-propenyl acetates or related substrates with the same substituents at 1 and 3 positions, the jt-allylpalladium intermediate containing a meso type 7r-allyl group is formed from both enantiomers of the allylic substrate. Two jt-allyl carbons at the 1- and 3-positions are diastereotopic on coordination of a chiral phosphine ligand to palladium. The asymmetric induction arises from preferential attack by the nucleophile on either of the two diastereotopic TT-allyl carbon atoms (Scheme 2-28). 

The resulting derivatives were applied with success in the standard asymmetric allylic alkylation (up to 97 % ee) [134, 136] or in transformations involving either specific allylic substrates (2-cycloalkenyl derivatives, up to >99% ee) [135, 137], unsymmetrical substrates (monosubstituted allyl acetate, up to 83% ee) [140], or especial nucleophiles (nitroalkanes [141], iminoesters [138 a], or diketones [139, 140, 142]). Such ligands were also effective in the formation of quaternary chiral carbon through allylic substitution (eq. (6)) [138, 143], deracemiza-tion of vinyl epoxides (up to 99% ee) [144], or alkylation of ketone enolates [138 b], and deracemization of allylic derivatives [145]. 

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