Enantioselective metallic nucleophiles

The nucleophilic addition on substituted ketenes is a well-known method to generate a prochiral enolate that can be further protonated by a chiral source of proton. Metallic nucleophiles are used under anhydrous conditions therefore, the optically pure source of proton must be added then (often in a stoichiometric amount) to control the protonation. In the case of a protic nucleophile, an alcohol, a thiol, or an amine, the chiral inductor is usually present at the beginning of the reaction since it also catalyzes the addition of the heteroatomic nucleophile before mediating the enantioselective protonation (Scheme 7.5). The use of a chiral tertiary amine as catalyst generates a zwitterionic intermediate B by nucleophilic addition on ketene A, followed by a rapid diastereoselective protonation of the enolate to acylammonium C, and then the release of the catalyst via its substitution by the nucleophile ends this reaction sequence. 

Enantioselective metal-catalysed allylic substitution reactions have attracted considerable attention, especially over recent years. The metal that has been most widely investigated for allylic substitution reactions is palladium. The mechanism of palladium-catalysed allylic substitution typically involves a double inversion, resulting in overall retention of relative stereochemistry. So, if the stereochemistry of the product is simply based on the stereochemistry of the starting material, how can an asymmetric synthesis be possible The answer lies in the choice of substrate for the enantioselective version of the palladium-catalysed allylic substitution reaction. For example, the substrate (10.40) proceeds via a meso intermediate complex (10.41). Which end of the allyl group the nucleophile adds to dictates which enantiomer of product will be formed, (10.42) or e r-(10.42). 

Shibasaki s heterobimetallic complexes, active in the asymmetric aldol reaction (see Section 7.1) provide the opportunity to activate both the nucleophile and Michael acceptor. Whilst the aluminium lithium bis-BlNOL complex (ALB) (11.28) does not catalyse conjugate addition of a-phosphonate ester (11.29) with cyclopentenone (11.30) by itself, addition of sodium terf-butoxide allows a highly enantioselective reaction to take place. A postulated model for enantioinduction in this process involves simultaneous binding of the metallated nucleophile and acceptor to the catalyst by interaction with a BINAP oxygen and the aluminium centre respectively. Heterobimetallic complexes have also been used to catalyse the addition of a-nitroesters and malonatesto Michael acceptors. 

Under a different manner of cinchona alkaloid activation, azodicarboxylates were utilized as substrates for enantioselective aUylic aminations. The electrophilic addition of nucleophiles to electron-withdrawing aUyUc C-H bonds (21) was feasible via activation by a chiral Bronsted base, DHQ(2PYR) (Scheme 13.6) [15]. This discovery, from Jorgensen s group, highUghts the first enantioselective, metal-free allylic amination using alkyUdene cyanoacetates with dialkyl azodicarboxylates. 

Sulfoximines bearing a chiral sulfur atom have recently emerged as valuable ligands for metal-catalysed asymmetric synthesis.In particular, C2-symmetric bis(sulfoximines), such as those depicted in Scheme 1.51, were applied to the test reaction, achieving enantioselectivities of up to 93% ee. The most selective ligand (R = c-Pent, R = Ph) of the series was also applied to the nucleophilic substitution reaction of l,3-diphenyl-2-propenyl acetate with substituted malonates, such as acetamido-derived diethylmalonate, which provided the corresponding product in 89% yield and 98% ee. 

While the notion that the alkoxides derived from aliphatic alcohols are poor nucleophiles toward 7r-allylmetal complexes has prevailed over the years, much progress made in the recent past has rendered the transition metal-catalyzed allylic alkylation a powerful method for the O-allylation of aliphatic alcohols. In particular, owing to the facility of five- and six-membered ring formation, this process has found extensive utility in the synthesis of tetrahydrofurans (THFs) (Equation (29))150-156 and tetrahydropyrans (THPs).157-159 Of note was the simultaneous formation of two THP rings with high diastereoselectivity via a Pd-catalyzed double allylic etherification using 35 in a bidirectional synthetic approach to halichondrin B (Equation (30)).157 The related ligand 36 was used in the enantioselective cyclization of a Baylis-Hillman adduct with a primary alcohol (Equation (31)).159... 

Scheme 7. The simplest type of enantioselective allylic alkylation which occurs on treatment of an allylic substrate with a metal derivative, together with a stabilized nucleophile (R = H, alkyl or aryl X" = leaving group [M] = metal catalyst Nu" = nucleophile L = coordinating atom).

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