Symmetrical 1,3-Disubstituted Substrates

For this type of substrates, starting from a racemic mixture, achiral complexes are formed which can yield enantiomerically enriched compounds via enantiodiscrimination of the allylic termini (compare type C).

Scheme 5.12: General scheme for symmetrical 1,3-disubstituted substrates.

Due to its stringent demand on the ligand scaffold, the asymmetric allylic alkylation with meso-intermediates is considered to be a common benchmark.^[153] Accordingly, different catalytic systems have been developed which can be categorized into three different methods for achieving enantiodiscrimination. The corresponding most prominent ligands for each of the three mechanisms are depicted in Figure 5.3.

Figure 5.3: Ligand systems used for the three different approaches: (I) Bis(diphenylphosphino)ferrocenyl ligand, (II) Phosphine oxazoline (PHOX) ligands, (III) Trost ligand.

The three approaches can be summed up as follows:

(I) Attachment of a group to the ligand scaffold, which can interact with the incoming nucleophile, leading to a regioselective attack. This concept of secondary interaction was introduced by Hayashi^[154] and subsequently applied by other groups.^[155]

(II) Electronic discrimination of the two allylic termini, due to the trans-effect. This can be achieved by the use of heterodonor, bidentate ligands (mainly P,N-ligands). The electronic asymmetry becomes evident in bond lengths for the solid state structures, as well as by the chemical shift for the terminal carbon atoms, observed in the ¹³C-NMR spectrum. It was even tried to correlate the observed enantioselectivities with the different electrophilicity, evidenced by the separation of the two chemical shifts.^[156]

Further, the ligand scaffold must sterically disfavor one rotameric isomer over the other.

Helmchen, Pfaltz and Williams^[157] did remarkable pioneering work in this field.

(III) Due to steric discrimination within a chiral pocket created by a C2-symmetrical ligand, certain trajectories or intermediates are disfavored. By increasing the bite angle (L-Pd-L) of the ligand, for instance by a larger chelating ring, a smaller and more selective chiral cavity is generated by the shielding substituents. Major contributions were made by Trost and co-workers.^[134f]

Next, the implications of the fluxional behavior will be introduced on the basis of the endo/exo isomerization (Scheme 5.13). Although, for C2-symmetric binding sites (approach III), these isomers are irrelevant, the same kinetic scheme can be applied for syn/anti isomers.

Scheme 5.13: Exo-endo exchange in a C1-symmetric binding site and its impact on the nucleophilic attack.

As a result of the exo/endo exchange, the opposite enantiomer is obtained after nucleophilic attack at the same termini relative to the ligand (pathway a and c, respectively b and d). As this phenomenon can have a critical impact on the net stereoselectivity, the distributions, as well as the rate constants for the interconversion, have to be considered.

In most but not all cases, equilibration is faster than the nucleophilic attack, thus, the Curtin-Hammett principle^[158] applies (Figure 5.4).^[152] If this is not the case, the stereochemistry of the product would be determined by the formation rates of the different isomers (A and B) from the starting material.

Scheme 5.14: Curtin-Hammett kinetic scheme with respect to Scheme 5.13, preequilibrium between A and B, A reacts irreversibly to C with rate constant k2,a, B reacts irreversibly to D with rate constant k2,b.

According to the Curtin-Hammett principle, the rate of nucleophilic addition to any allylic termini results from the product of the Boltzmann population of the corresponding conformer (ground state) and the intrinsic reactivity of the allylic carbon atom (transition state). Thus, three scenarios can arise. First, if the major isomer possesses the highest reactivity, the selectivities deviate positively from the observed distribution. Second, if both isomers react with a similar rate, the selectivity resembles the ground state distribution (ΔΔG^‡ = ΔG). Third, in case that the minor isomer possesses a higher reactivity, the selectivities are smaller than expected with respect to the A:B ratio.

Figure 5.4: Energy profile for Curtin-Hammett principle: Preequilibrium between A and B fast, compared to the irreversible reactions to C and D; selectivities determined by ΔΔG^‡; here, minor isomer A more reactive than B.

As only investigations of the ground state (allyl palladium(II) or less frequently olefin palladium(0) complexes) are accessible, the Hammond-Leffer postulate^[159] has been often adopted, in order to derive information on the transition state.

Figure 5.5: Hammond-Leffer postulate, R = reactant, P = product, TS = transition state;

a) exergonic reaction / early TS, b) medium TS, c) endergonic reaction, late TS; note that for the intermediate (roughly thermoneutral) case b) the postulate is less suitable.

The Hammond postulate states, that for an exergonic reaction the geometry of the transition state should be more similar to the starting material, as their difference in energy should be smaller (early transition state, Figure 5.5,a)). In contrast, for an endergonic reaction the geometry of the transition state is expected to be more product-like (late transition state, Figure 5.5, c)).

Thus, for an early transition state, predictions of the enantiodiscrimination can be made on grounds of the relative abundances and reactivities of the diastereomeric (η³-allyl)-palladium complexes.^[160] Further, it would follow, that the obtained enantiomeric excess should only be sensitive to the chiral ligand used and relatively insensitive to the type of the nucleophile.

Although, earlier investigations^[142,161] supported an early transition state, recent studies, both experimental and theoretical, suggest a mechanism via a more “olefin-like” late transition state.[136b,162] Accordingly, a sterically controlled rotation of the allyl ligand takes places during the nucleophilic attack. In order to reduce the steric constraints between ligand and allyl group, the most stable trigonal planar olefin complex is formed. This preferential rotational concept allows the explanation of the observed selectivities, for allylic termini which differ only slightly in their steric and electronic properties and can also be adopted for the prior oxidative addition event.^[163] Evidence for this model might be found in the solid state structures, by the observed twist of the allyl group towards a more

product-like state or unequal bond distances between the allylic carbon atoms.^[164,165] On the other hand, it might be illustrated by a more olefinic chemical shift for one allylic termini.^[155]

Experimental structural data of the relevant (η²-olefin)palladium(0) complexes is rather scarce and often limited to olefins bearing electron-withdrawing groups.^[166] Nonetheless, structural information of olefinic complexes can also be derived in solution by advanced NMR experiments.^[167] Later theoretical studies on the transition state stressed the importance of the bite angle of the ligand, the nature of the donor atoms, as well as the nature and orientation of the allylic substituents.^[165]

Nevertheless, examination of the easily accessible allyl isomer distribution is frequently part of any mechanistic consideration for the asymmetric allylic substitution, as many geometric features of these intermediates are expected to be preserved in the transition state.^[152]