Pd Asymmetric Allylic Alkylation (AAA). A Powerful Synthetic Tool.

Abstract

Chiral compounds have many applications. None are more important than those related to biological targets. The chiral nature of biological receptors make chiral ligands common objectives as pharmaceuticals and agrichemicals. Thus, developing efficient synthetic methods to such compounds represents an important challenge. In spite of great advances, resolution methods still frequently represent the most economical method for commercial production in spite of the fact that the theoretical yield of the single desired enantiomer cannot exceed 50% unless the opposite enantiomer can be converted to the desired one. Using starting materials from the chiral pool also constitutes a common strategy. More recently, attention has shifted to inducing chirality into achiral precursors. Two tacts have been explored. In one, chiral auxiliaries, normally emanating from the chiral pool, are covalently attached to prochiral substrates.1) The advantage of this approach is the high degree of success in transmitting chiral information in this more controlled strategy. However, it suffers from numerous drawbacks. First, it requires stoichiometric amounts of the chiral auxiliary which ultimately is not part of the final product. It also requires additional steps to add and subsequently remove the chiral auxiliary. Clearly, the conceptually most attractive strategy is employing asymmetric catalytic reactions. 2)Some of these have achieved great success. Two of the most successful have been asymmetric catalytic hydrogenation and asymmetric catalytic oxidation of alkenes, notably epoxidation. These two reactions, in addition to virtually every other asymmetric catalytic reaction, share a common feature-the enantiodiscriminating event involves recognizing the enantiotopic faces of a prochiral p-unsaturation such as a carbonyl group or a double bond. Furthermore, each of these reactions also involve formation of just one bond type-a C-H bond in the case of hydrogenation and a C-O bond in the case of oxidation.Catalytic asymmetric allylic alkylation differs from virtually all other catalytic processes in two important ways. In the first, there are many enantiodiscriminating mechanisms, not just one. As shown in Fig. 1, there are at least five such mechanisms. As in most other catalytic asymmetric reactions, differentiating the enantiotopic faces of a p-unsaturation is one mechanism (Fig. 1, A). A second mechanism is differentiating enantiopic leaving groups (Fig. 1, B). Mechanism C involves differentiating enantiotopic termini of a pallylmetal intermediate. Since this intermediate derives from a chiral racemic precursor in which the chirality of the substrate is lost, this deracemization constitutes a dynamic kinetic asymmetric transformation (DYKAT). Mechanism D is a varient of mechanism A wherein the p-allylmetal intermediates interconvert faster than they are attacked by a nucleophile and asymmetric induction derives from differential rates of reaction of the two diastereomeric intermediates. This mechanism allows employment of either an ...

The Reaction Mechanism of the Enantioselective Tsuji Allylation: Inner-Sphere and Outer-Sphere Pathways, Internal Rearrangements, and Asymmetric C–C Bond Formation

“…5 The 2-allyl-2-alkyl cyclohexanone products formed are distinct from the vast majority of asymmetric allylic alkylation products. In contrast to previous works that utilized prochiral electrophiles, 4,9,12,14–16,18,19,31–35 we demonstrated enantioselective Tsuji allylation using non-prochiral electrophiles and prochiral ketone enolate nucleophiles. This permits the formation of quaternary centers from ketone enolates that have two similarly acidic sites alpha to the ketone.…”

“…The resulting Pd II π-allyl complex then reacts with the in situ generated enolate forming α-allylated ketone 2 . Before our work, the majority of asymmetric enolate allylations focused on reactions of prochiral allyl fragments with malonate nucleophiles, 11–13 or on prochiral ketones that had a single α-site or whose α-sites had large differences in acidity (e.g., Trost 12,14–17 ). Related to our work, Helmchen 18 and Pfaltz 4 also used malonates with similar catalyst ligands as we employed.…”

Mechanistically Driven Development of Iridium Catalysts for Asymmetric Allylic Substitution

“…Catalytic allylic substitution (eq 1) was one of the first examples of organometallic catalysts applied to organic synthesis 1–3. For decades, the development of catalysts for these reactions focused on palladium complexes 2–4.…”

Origins of Enantioselectivity during Allylic Substitution Reactions Catalyzed by Metallacyclic Iridium Complexes

“…21 In either case, the enantioselectivity is based on a high stereoselectivity for oxidative addition, and this mode of enantioselection is different from that proposed to control enantioselectivity with palladium complexes that undergo facile η 3 -η 1 -η 3 interconversions. 32–33 …”