Prochiral nucleophiles, nucleophilic substitution

It should be noted that Trost s DPPBA-derived ligand 21 possesses considerable utility in many other situations of allylic substitution, for example with substrates which are cyclic or which possess enantiotopic leaving groups, or with prochiral nucleophiles.1171... 

The scope of reactions catalyzed by metalacychc iridium-phosphoramidite complexes is remarkably broad, but reactions with some substrates, such as allylic alcohols, prochiral nucleophiles, branched allylic esters, and highly substituted allylic esters, that would form synthetically valuable products or would lead to simpler symthesis of reactants occur with low yields and selectivities. In addition, iridium-catalyzed allylic substitution reactions are sensitive to air and water and must be conducted with dry solvents under an inert atmosphere. Several advances have helped to overcome some, but not aU of these challenges. 

Besides the transition-metal-catalyzed asymmetric addition reactions to prochiral olefins, the substitution reaction of a carbon nucleophile to allylic esters has been investigated using a variety of chiral transition-metal catalysts. Using the aforementioned sugar diphosphites... 

In addition to coupling reactions that occur with aryl and vinyl nucleophiles and electrophiles, coupling reactions that occur with sp -hybridized nucleophiles or electrophiles have been developed. These reactions include those that form tertiary and quaternary stereocenters from racemic or prochiral nucleophiles, as shown in Equation 19.4. Substitution reactions at propargylic and benzylic electropliiles have also been reported, and several groups have reported in recent years progress in metal-catalyzed substitutions of alkyl electrophiles, including enantioselective substitutions of aliphatic organic halides. 

A final approach to enantioselective allylic substitution is the reaction of prochiral nucleophiles with allylic esters. In this case, the stereocenter is not generated on the allyl unit it is generated at the nucleophilic carbon. This chemistry has been conducted with cyanoesters and related unsymmetrical stabilized carbon nucleophiles, including azlactones, which are a protected form of ammo acids. This generation of a stereocenter in the nucleophile is thought to be particularly challenging because the position at which the stereocenter is formed is further from the metal than it is in reactions that form a stereocenter at the allyl group. 

The use of a prochiral nucleophile in allylic substitution reactions provides an additional opportunity for asymmetric indnction. Allyl acetate itself can be used as the electrophilic partner and the new stereogenic center is positioned further away from the allyl group (Scheme 28). 

The azalactone 152 has been used as a prochiral nucleophile in a similar process providing the substitution product 153 and 154 upon reaction with either cyclohexenyl acetate 92 or the gem-diacetate... 

Several approaches have been described for the preparation of optically active sulfoxides [5-7]. The three main routes to obtain these compounds are as follows (i) the asymmetric sulfoxidation of prochiral sulfides, (ii) nucleophilic substitution using a chiral sulfur precursor, and (iii) the kinetic resolution of racemic sulfoxides. The first of tiiese methods involves the use of various oxidants and catalysts and has been the most extensively employed. There are many examples in the scientific literature and reviews are available on this approach. In recent years, much attention has been focused on the synthesis of organic sulfoxides by emplo5dng conditions compatible with the green chemistry procedures [8-10]. For this reason, mild oxidants such as molecular oxygen or hydrogen peroxide are considered in combination with novel catalysts in order to develop a mild and environmentally friendly process. 

The protocol of the allylic alkylation, which proceeds most likely via a c-allyl-Fe-intermediate, could be further improved by replacing the phosphine ligand with an M-heterocyclic carbene (NHC) (Scheme 21) [66]. The addition of a ferf-butyl-substituted NHC ligand 86 allowed for full conversion in the exact stoichiometric reaction between allyl carbonate and pronucleophile. Various C-nucleophiles were allylated in good to excellent regioselectivities conserving the 71 bond geometry of enantiomerically enriched ( )- and (Z)-carbonates 87. Even chirality and prochirality transfer was observed (Scheme 21) [67]. 

Trost and his co-workers succeeded in the allylic alkylation of prochiral carbon-centered nucleophiles in the presence of Trost s ligand 118 and obtained the corresponding allylated compounds with an excellent enantioselec-tivity. A variety of prochiral carbon-centered nucleophiles such as / -keto esters, a-substituted ketones, and 3-aryl oxindoles are available for this asymmetric reaction (Scheme jg) Il3,ll3a-ll3g Q jjg recently, highly enantioselective allylation of acyclic ketones such as acetophenone derivatives has been reported by Hou and his co-workers, Trost and and Stoltz and Behenna - (Scheme 18-1). On the other hand, Ito and Kuwano... 

An interesting use of the nickel-catalyzed allylic alkylation has prochiral allylic ketals as substrate (Scheme 8E.47) [206]. In contrast to the previous kinetic-resolution process, the enantioselectivity achieved in the ionization step is directly reflected in the stereochemical outcome of the reaction. Thus, the commonly observed variation of the enantioselectivity with respect to the structure of the nucleophile is avoided in this type of reaction. Depending on the method of isolation, the regio- and enantioselective substitution gives an asymmetric Michael adduct or an enol ether in quite good enantioselectivity to provide further synthetic flexibility. 

Nucleophiles such as enolates or substituted allylmetal compounds are known to react with prochiral aldehydes and ketones to form mixtures of threo or erythro adducts. In case of aldehydes, high degrees of diastereoselection have been achieved 48 91,108). In the following three Sections, reactions of titanium and zirconium enolates as well as allyl derivatives are presented. 

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 ... 

Michael Addition. Titanium imide enolates are excellent nucleophiles in Michael reactions. Michael acceptors such as ethyl vinyl ketone, Methyl Acrylate, Acrylonitrile, and f-butyl acrylate react with excellent diastereoselection (eq 21 ). - Enolate chirality transfer is predicted by inspection of the chelated (Z)-enolate. For the less reactive unsaturated esters and nitriles, enolates generated from TiCl3(0-j-Pr) afford superior yields, albeit with slightly lower selectivities. The scope of the reaction fails to encompass p-substituted, a,p-unsaturated ketones which demonstrate essentially no induction at the prochiral center. Furthermore, substimted unsamrated esters do not act as competent Michael acceptors at all under these conditions. 

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. 

Oxygen nucleophiles have not frequently been used as terminators in cascade car-bometallation reactions. The intramolecular carbopalladation starting with an iodo- or trifluoromethylsulfonyloxyalkenyl-substituted derivative in the presence of tetrabutylam-monium acetate led to a suitable precursor of the sesquiterpene (-)-A (i )-capneUene. In this case, desymmetrization of the prochiral precursor was achieved using (5)-BINAP as the ligand on the palladium catalyst (Scheme 32). ... 

In 2009, Breit et al. [109d] have extended the enamine strategy to unactivated allyl alcohols as substrates for the allyhc substitution (Scheme 12.47). When (d/l)-proline is used as the amine component, the carboxylic acid moiety in situ activates the allylic alcohol for abstraction of water and formation of a tt-allylpalladium complex. Subsequent nucleophilic attack of the enamine leads to the a-allylated ketones or aldehydes. Interestingly, the use of enantiopure prohne has no effect on the stereochemical outcome of the reaction with prochiral substrates. 

An enantioselective method in which a chiral catalyst is responsible of a desymmetrizing nucleophilic aromatic substitution through discrimination in the displacement of an enantiotopic leaving group has been reported very recently in the heterocyclic series. Under PTC conditions, the chiral counterion 113 (10% mol) directs the substitution of prochiral dichloropyrimidine 112 by PhSKby a tandem desymmetrization/kinetic resolution mechanism, leading to the chiral product 114 (Scheme 8.23) [87]. 

Synthesis of a chiral compormd from an achiral compound requires a prochiral substrate that is selectively transformed into one of the possible stereoisomers. Important prochiral substrates are, for example, alkenes with two different substituents at one of the two C-atoms forming the double bond. Electrophilic addition of a substitutent different from the three existing ones (the two different ones above and the double bond) creates a fourth different substituent and, thus, an asymmetric carbon atom. Another class of important prochiral substrates is carbonyl compounds, which form asymmetric compounds in nucleophilic addition reactions. As exemplified in Scheme 2.2.13, prochiral compounds are characterized by a plane of symmetry that divides the molecule into two enantiotopic halves that behave like mirror images. The side from which the fourth substituent is introduced determines which enantiomer is formed. In cases where the prochiral molecule already contains a center of chirality, the plane of symmetry in the prochiral molecules creates two diastereotopic halves. By introducing the additional substituent diasterom-ers are formed. 

---