In 2011 our laboratory disclosed the first report of an asymmetric palladium-catalyzed conjugate addition to generate all-carbon quaternary stereocenters.⁴¹ Our studies revealed that chiral pyridineoxazoline (PyOx) ligands (L4-L9) complexed to Pd(OCOCF₃)₂ were particularly adept in providing the conjugate addition products in high yield. Other chiral ligands such as bisoxazoline (L1), pyridinebisoxazoline (L2), and (-)-spartine (L3) did not give rise to catalytically active palladium complexes. The palladium catalyst derived from t-BuPyOx (L7) provided the highest levels of enantioselectivity, whereas ligands derived from phenylalanine (L4), leucine (L5), or valine (L6) provided significantly lower levels of enantioselectivity. Finally, electronic rich (L8), and electron poor (L9) t-BuPyOx derivatives were both inferior to the unsubstituted variant (Table 1). While t-BuPyOx can be synthesized in one step from methyl picolinimidate and tert-leucinol, the two-step procedure outlined in the original Organic Syntheses article was more efficient to produce larger quantities of t-BuPyOx in our hands.

Our initial report details the addition of a wide variety of boronic acids including electron rich (product 3), electron poor (products 4 and 5), and boronic acids containing potentially reactive functional groups such as ketones (product 5). Notably, electron rich boronic acids tend to exhibit lower levels of enantioselectivity. With respect to the enone component, the reaction of five-, six-, and seven-membered rings were well tolerated (products 6, 7, and 8 respectively). Moreover, substrates with increased sterich indrance about the enone react smoothly under the standard reaction conditions to generate highly congested all-carbon quaternary centers (products 9 and 10). After our initial report, Stanley and coworkers disclosed a similar study that details the conjugate addition of arylboronic acids to β-aryl α,β-unsaturated ketones to yield enantioenriched bis-benzylic quaternary stereocenters.⁴²

Despite the broad substrate scope and efficiency of the process, attempts to scale up the reaction with gram quantities of 1 were initially unsuccessful (Scheme 1A, Eq. 1). To this end, we set out to study the mechanism computationally in collaboration with Ken Houk's group at UCLA and devise an improved set of reaction conditions to address the problem of scalability.⁴³ An important feature of our proposed mechanism is the enantiodetermining carbopalladation to provide the palladium(II) enolate (IV), which must then be protonated to close the catalytic cycle (Scheme 1B). We initially hypothesized that the boronic acid could act as a proton source to turn over the catalytic cycle; however, the lack of scalability of the reaction caused us to reconsider this hypothesis. We posited that addition of an external proton source would be beneficial for the reaction. To our delight, addition of 5 equivalents of water to the previously employed reaction conditions allowed for facile scale-up of this process with no change in yield or enantioselectivity (Scheme 1A, Eq. 2).

We then turned our attention to the addition of metal salts containing weakly coordinating counter ions (PF₆^-, SbF₆^-, BF₄^-, etc) in an effort to improve the activity of the palladium catalyst. This would allow for lower catalyst loadings and lower reaction temperatures. We hypothesize that weakly coordinating anions could undergo a salt metathesis with the palladium(II) trifluoroacetate, resulting in a more reactive, cationic palladium(II) species. In line with our hypothesis, addition of NaCl (Table 3, entry 1) inhibited reactivity, presumably due to the strongly coordinating nature of chloride anion. Conversely, when sodium salts bearing weakly coordinating counterions were employed, enhanced reactivity was observed (Table 3, entries 2-4); however, the enantioselectivity of the process was diminished. Enantioselectivity could be restored at the expense of the reaction rate when tetrabutylammonium salts were employed (Table 3, entries 5-6). Sodium tetraphenylborate (Table 3, entry 7) failed to promote the desired reactivity due to concomitant formation of biphenyl, presumably via an oxidative coupling of the tetraphenylborate nucleophile. Finally, ammonium salts were effective in providing an optimal balance of reactivity and enantioselectivity (Table 3, entries 8-9), with the hexafluorophosphate anion yielding the best result (Table 3, entry 9).

The combination of 5 equivalents of water, and NH₄PF₆ allowed for the reaction to be conducted at lower temperatures, and with lower catalyst loadings to provide product 2 in essentially the same yield and enantioselectivity as the standard reaction conditions (Scheme 2A). Moreover, the addition of water, and NH₄PF₆ allows for more efficient reaction of substrates that proved difficult under the initial set of conditions (Scheme 2B).

Subsequent efforts from our group have led to the expansion of this method to include chromenones as electrophiles, providing access to tertiary stereocenter containing flavanones (Scheme 3A).⁴⁴ Unfortunately, even the improved conditions outlined above were unable to promote the reaction of C(2)-substituted chromenones. Interestingly, Stanley and coworkers reported the reaction of C(2)-substituted chromenones with a palladium(II)-phenanthroline complex in the presence of aqueous Na(OCOCF₃); however, these reaction conditions generate a racemic mixture of the products bearing tetrasubstituted stereocenters.⁴⁵ Subsequent investigation of different ligand scaffolds in collaboration with Sukwon Hong's group of GIST, revealed that pyridine-dihydroisoquinoline (PyDHIQ) ligands, and an oxygen atmosphere allowed for smooth reaction of C(2)-substituted chromenone electrophiles with excellent levels of enantioselectivity (Scheme 3B).⁴⁶ Finally, we became interested in the reaction of 3-acyl cyclohexenones, a challenging substrate class due to the possibility of the formation of constitutional isomers. Employing palladium(II) trifluoroacetate and (S)-t-BuPyOx allows for selective formation of compound 20, which bears a quaternary stereocenter at the exclusion of forming a tertiary center via addition to the other end of the olefin (Scheme 3C).⁴⁷

The robust nature and scalability of this reaction has led to its use in the synthesis natural products and active pharmaceutical ingredients. In 2019, AbbVie reported the synthesis of ABBV-2222 (24), which is a preclinical candidate for the treatment of cystic fibrosis.⁴⁸ Synthesis of ABBV-2222 was accomplished via a key conjugate addition of boronic acid 22 to chromenone 21 to produce 13 grams of conjugate addition adduct 23 with excellent enantioselectivity, in a single pass. Enantioenriched flavanone 23 could then be carried forward through 5 more steps to generate >130 g of the active pharmaceutical ingredient 24 (Scheme 4).⁴⁹

Additionally, our group has utilized a palladium-catalyzed conjugate addition to accomplish a formal synthesis of (+)-dichroanone and (+)-taiwaniaquinone H.⁵⁰ Plotting the enantiomeric ratio versus the Hammett (σ_P) value for a variety of arylboronic acids revealed a strong positive linear correlation. This suggests that the difference in the diastereomeric transition states in the enantiodetermining step is larger with more electron withdrawing para substituents on the arylboronic acid. To this end, para-halogenated boronic acid 25 was selected to undergo conjugate addition with enone 1 to provide enantioenriched β-quaternary ketone 26 in excellent yield and enantioselectivity. This material was then advanced to intermediate 27, which is a known intermediate in the synthesis of (+)-dichroanone and (+)-taiwaniaquinone H.⁵¹

More recently, Wood and coworkers utilized an enantioselective palladium-catalyzed conjugate addition toward the total synthesis of (-)-caesalpinflavans A and B in 2019.⁵² Addition of phenyl boronic acid to chromenone 30 allowed for enantioselective synthesis of flavanone 31. A divergent approach from this key intermediate can then grant access to (-)-caesalpinflavans A and B (Scheme 6). This strategy highlights the mild nature of boronic acid nucleophiles, which allowed for the use of 30 in its unprotected form.

In summary, the asymmetric palladium-catalyzed conjugate addition of arylboronic acids to β,β-disubstituted α,β-unsaturated carbonyl compounds has emerged as a useful strategy for the construction of enantioenriched quaternary centers. The t-BuPyOx ligand required for the catalytically active cationic palladium(II) complex is easily synthesized in two steps from commercially available starting materials, as outlined in the original article. Furthermore, this process is advantageous due to the use of commercially available boronic acid nucleophiles, which are mild and easily handled on the benchtop. Finally, the reaction is easily scaled and extremely tolerant to air and water. The aforementioned attributes make this strategy attractive for the facile construction of enantioenriched building blocks toward the synthesis of complex molecules.