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JOCSynopsis Cite This: J. Org. Chem. 2019, 84, 473−485

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Development of and Recent Advances in Pd-Catalyzed Decarboxylative Asymmetric Protonation Cian Kingston,†,‡,§ Jinju James,†,§ and Patrick J. Guiry*,†,‡ Centre for Synthesis and Chemical Biology and ‡Synthesis and Solid State Pharmaceutical Centre, School of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland

J. Org. Chem. 2019.84:473-485. Downloaded from pubs.acs.org by IOWA STATE UNIV on 01/18/19. For personal use only.

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ABSTRACT: Decarboxylative asymmetric protonation (DAP) is a mild and efficient synthetic tool for the catalytic asymmetric formation of tertiary stereocenters adjacent to a carbonyl group. The development of the methodology from the initial racemic report to recent asymmetric examples is summarized. The discovery of an enantiodivergent Pd-catalyzed DAP, in which the choice of the achiral proton source determines the stereochemical outcome, is highlighted. Furthermore, the mechanism of Pd-catalyzed DAP, investigated since the initial report, is also discussed.

1. DEVELOPMENT OF THE ACHIRAL DECARBOXYLATIVE PROTONATION The development of new methods for the asymmetric synthesis of target molecules is a key area of organic chemistry.1 Transition-metal-mediated asymmetric catalysis, wherein the stereoisomeric products are formed in unequal amounts, has many advantages and plays an important role in modern synthetic chemistry.2 Alkylation of β-keto esters, followed by hydrolysis of the ester and decarboxylation, is a convenient method for the regioselective generation of mono- or di-αalkylated ketones.3 In 1985, Tsuji reported the palladiumcatalyzed decarboxylative protonation as a mild alternative to the contemporary (often harsh) conditions to remove the ester moiety. Hydrogenolysis of a variety of cyclic and acyclic allyl β-keto esters 1 using a palladium catalyst and tertiary amine salts of formic acid was carried out in excellent yields of up to 92% (Scheme 1).4 The mild reaction conditions proved tolerant of a variety of functional groups on the α-substituent including acetal, tetrahydropyranyl ethers, and ester substituents. The methodology was subsequently extended to substituted allyl malonates to form the corresponding monocarboxylic acids and esters.5 Similar levels of functional group tolerance were observed, with yields up to 96%. Formic acid has displayed unique properties compared to other hydride donors when it comes to palladium chemistry.4e In the report by Tsuji, the choice of proton source was crucial to form the protonated products 2, as the use of sodium acetate or morpholine instead of ammonium formate led to the formation of α-allyl ketones.4a In a later report, Tsuji also proposed a catalytic cycle wherein oxidative addition of the Pd0 catalyst to the β-keto allyl ester 1 forms an allyl Pd− carboxylate complex 3 (Scheme 1). Tsuji favored Pd-assisted decarboxylation to form a Pd-bound enolate 4, which is protonated by the ammonium formate 5 to generate the desired product 2.6 A second decarboxylation and reductive © 2018 American Chemical Society

elimination regenerates the catalyst and expels propene 8 as a byproduct. However, Shimizu reported a slightly modified reaction mechanism to Tsuji’s initial hypothesis in their work on the synthesis of α-fluoroketones 10 (Scheme 2).7 They favored a mechanism where the formate (produced in situ from formic acid) displaces the carboxylate ligand from the Pd center in 11. The β-keto acid 12 formed by protonation of carboxylate in solution is then proposed to undergo decarboxylation followed by tautomerization of the enol to produce the racemic ketone product 10. In support of their mechanism, they reported that the putative complex 6 was synthesized via anionic ligand exchange of palladium acetate with silver formate. This Pd−allyl formate 6 complex is proposed to undergo decomposition to yield CO2, propene, and the active Pd catalyst.8 The Pd hydride species 7 was not isolated or observed, but this may be due to its transient nature. Tsuji also suggested an alternative mechanism where the decarboxylation and reductive elimination is a concerted process that does not require the formation of a palladium hydride species (Scheme 3).9

2. INITIAL PROGRESS TOWARD DECARBOXYLATIVE ASYMMETRIC PROTONATION (DAP) The first report of an asymmetric variant of decarboxylative protonation was by Muzart in 1992.10 This work was built on their previous experience with asymmetric protonation of simple photochemically derived enols.11 Chiral amino alcohols such as ephedrine 15 were used as the protonating agent to achieve enantioselective protonation of α-substituted allyl enol carbonates 13 or β-keto allyl esters 14. Variable yields and enantioselectivities (up to 50% ee) were obtained depending on the type of substrate used (Scheme 4).10,12 Muzart also Received: September 25, 2018 Published: October 30, 2018 473

DOI: 10.1021/acs.joc.8b02478 J. Org. Chem. 2019, 84, 473−485

JOCSynopsis

The Journal of Organic Chemistry Scheme 1. Racemic Decarboxylative Protonation by Tsuji

Scheme 3. Alternative Concerted Decarboxylation and Reductive Elimination Pathway

demonstrated that similar results could be obtained with catalytic amounts of amino alcohol by using a debenzylation strategy for benzyl enol carbonates.12 Subsequent papers on this topic by Muzart ruled out a kinetic resolution as a reason for the observed enantioselectivity because racemic β-keto allyl ester 14 was recovered when the reaction was carried out to incomplete conversion.13 Initial reports by Muzart described the enantioselective step occurring via a nine-membered ring intermediate 18 formed by polar interactions between the common enol intermediate 17 and ephedrine (Scheme 5A, pathway A).10 Further mechanistic studies led them to propose a mechanism that involved an ammonium enolate 19 (Scheme 5A, pathway B).14 It was suggested that the discrimination between the two faces of the enolate (19a vs 19b), through steric interactions between the bulky groups on ephedrine and the aromatic skeleton of the substrate, gave rise to the moderate enantioselectivities observed (Scheme 5B). The development of the palladium-catalyzed DAP now provided an alternative to existing methods of asymmetric protonation for the formation of α-tertiary stereocenters. This transformation is of particular interest to practitioners of total Scheme 2. Racemic Decarboxylative Protonation of α-Fluoroketones by Shimizu

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JOCSynopsis

The Journal of Organic Chemistry Scheme 4. General Scheme for Amino Alcohol Mediated DAP

Scheme 5. Proposed Pathways in the Amino Alcohol Mediated DAP by Muzart

step, formic acid was used as an achiral proton source to intercept this highly organized Pd−enolate intermediate leading to the formation of tertiary centers with high enantioselectivities of up to 95% ee (Scheme 6B). A variety of chiral ligands were also examined, and it was found that chelating P,N-ligands were most effective. Generally, an excess of formic acid was required to prevent allylated product formation. However, too much formic acid led to a decrease in enantiomeric excess. These factors were also affected by the quantity of molecular sieves (MS) in the reaction, added to sequester any residual water from commercially available formic acid. Large amounts of MS increased the production of allylated product, while small amounts decreased the ee values. In the substrate scope studies, fused aromatic and monocyclic substrates produced moderate to excellent levels of enantioselectivity. A variety of alkyl, benzyl, allyl, and fluoro substituents were tolerated at the α-position. Mechanistically, the authors aligned with Tsuji’s initial proposal, which favored protonation of a Pd−allyl enolate species. Deuterium-labeling studies were inconclusive in determining the fate of the formyl proton or the exact reaction pathway due to low levels of D incorporation (Scheme 6C).

synthesis and medicinal chemistry due to the range of target molecules possessing this structural motif. There are many challenges associated with asymmetric protonation: (a) the requirement to match the pKa of the proton donor and the product to prevent racemization before product isolation; (b) the ability to generate prochiral, sp2-hybridized substrates for protonation; and (c) lack of mechanistic details to assist in reaction development.15 Generally, asymmetric protonation is achieved via a chiral enolate, a chiral Brønsted acid, or a combination of the two. By using β-keto esters for the regioselective alkylation and then their enantioselective removal, the possibility of overalkylation is diminished. However, the application of Muzart’s synthetic approach employing chiral amino alcohols was hampered by somewhat lower enantioselectivities. In Tsuji’s proposed mechanism for the racemic protonation (Scheme 1), a synthetically useful transition-metal enolate 4 is regiospecifically generated upon decarboxylation under neutral conditions.16 In 2006, the Stoltz group realized an opportunity to expand on their previous decarboxylative asymmetric allylic alkylation (DAAA)17 work by intercepting the intermediate enolate associated with the chiral Pd complex 21 with an alternative proton source (Scheme 6A).18 In the enantiodetermining 475


JOCSynopsis

The Journal of Organic Chemistry Scheme 6. DAP Studies Using Formic Acid by Stoltz

Scheme 7. DAP Using Meldrum’s Acid by Stoltz

available Meldrum’s acid 27 was the optimal proton source to provide high levels of enantioselectivity of DAP.20 Meldrum’s acid derivatives were also screened with varying levels of success, but the reactivity, selectivity, and availability of Meldrum’s acid made it the most appropriate choice of proton source for this reaction. As before, a variety of substrates were then tested using these optimized conditions. Unlike the heterogeneous DAP system, in this study there was no issue with competitive formation of the allylated product. The scope of the reaction and enantioselectivities obtained

In 2008, Stoltz reported a homogeneous variant of this Pd-catalyzed DAP reaction eliminating the usage of MS (Scheme 7).19 It should be noted that the terms hetero- and homogeneous only refer to the presence (or absence) of molecular sieves in the reaction and are not a comment on the nature of the reaction mechanism. In this case, Pd2(dba)3 was used as the precatalyst, and (S)-t-Bu-PHOX 24 as the chiral ligand proved most effective. A variety of proton donors were screened, and it was found that proton donors with increased acidity gave increased rates of reaction. Commercially 476


JOCSynopsis

The Journal of Organic Chemistry Scheme 8. Mechanistic Proposal for Homogeneous DAP

were comparable to the results obtained in the heterogeneous system (up to 92% ee). Kinetic studies using 1H NMR spectroscopy revealed a zeroorder decay of the β-keto allyl ester substrate, implying that it reacts quickly to generate an intermediate, which undergoes a slower protonation step.19 This is similar to the results observed in the Stoltz group’s kinetic studies on the DAAA reaction.21 This suggests early stages of both processes are similar, and therefore, a mechanism depicted in Scheme 8 was proposed. The Pd complex coordinates to the allyl group of the β-keto allyl ester 28 leading to oxidative addition followed by decarboxylation to generate the chiral Pd−enolate 33. Proton transfer from Meldrum’s acid 27 occurs in an enantioselective fashion to form the α-tertiary stereocenter in 29. The allyl group is transferred to the mono-deprotonated Meldrum’s acid to form 35. This species undergoes a second proton-transfer step in a subsequent catalytic cycle to generate diallylated Meldrum’s acid 30, which was isolated as the byproduct. Interestingly, the opposite sense of stereoinduction was observed between fused and nonfused cyclic substrates in both formic acid and Meldrum’s acid reactions.19 This led the authors to speculate that the mechanism of DAP may proceed through similar pathways, but the enantioselective step of each was fundamentally different from that of the DAAA, which displayed no such effect.

Scheme 9. Catalytic Asymmetric Synthesis of Isoflavanones by Guiry

3. RECENT DEVELOPMENTS IN DECARBOXYLATIVE ASYMMETRIC PROTONATION Isoflavanones are an important class of plant derived secondary metabolites, which display anticancer and immunosuppressant activity.22 The Guiry group exploited the DAP transformation to enantioselectively produce sterically hindered α-aryl isoflavanones (Scheme 9).23 Remarkably, the DAP protocol was not impeded by use of bulky aryl substituents as observed for

other arylation methodologies. Other arylation methodologies have formed α-aryl ketones with excellent enantioselectivities; however, there were no examples with di-ortho-functionalized arenes to the best of our knowledge.24 Although this DAP transformation has been effective in generating α-tertiary stereocenters for a range of α-alkyl-, benzyl-, and allyl-substituted ketones, Guiry was the first to report the use of this 477


JOCSynopsis

The Journal of Organic Chemistry methodology for the synthesis of sterically hindered α-aryl ketones in order to synthesize natural and non-natural isoflavanones. During optimization, it was found that a decrease in temperature from rt to 0 °C led to an increase in ee but resulted in a slower reaction. This problem was alleviated by changing the (S)-t-Bu-PHOX ligand 24 to the more electrondeficient (S)-(CF3)3-t-Bu-PHOX 36. Interestingly, the optimal temperature proved to be 7 °C, demonstrating the sensitivity of this reaction. The electronic and steric influences of substitution on the aryl ring were investigated. It was found that increasing the electron density of the aryl ring increased the enantioselectivity (up to 92% ee for 38a). Sterics also play an important role as isoflavanones lacking di-ortho-substitution on the aryl ring (38c and 38d) showed dramatically decreased ee values. A stereochemical rationale was proposed to explain the formation of the (S)-enantiomer upon protonation by Meldrum’s acid (Figure 1).

differences between the use of formic acid compared to Meldrum’s acid were apparent, but experimental results were inconclusive about the exact reaction pathway (Scheme 11). Similar levels of deuterium incorporation (46%) were seen as compared to those reported before by Stoltz. To test if the proton source was residual H2O, the DAP was carried out using DCO2D in the presence of 0.5 equiv of D2O. However, a similar level of deuterium incorporation was observed as when using DCO2D alone. Nonetheless, during these studies it was verified that the formyl hydrogen was not incorporated in the product. In 2014, the Guiry group published the catalytic asymmetric synthesis of sterically hindered α-aryl cyclopentanones and cyclohexanones (Scheme 12).27 Careful optimization of a range of factors such as temperature and solvent led to the formation of α-aryl cyclopentanones and cyclohexanones with good yields and moderate to excellent enantioselectivities (up to 92% ee). During the optimization studies, it was observed that increasing the temperature above 50 °C or below 30 °C saw a drop off in ee. It was also noticed that increasing the number of equivalents of Meldrum’s acid 27 had a negative effect on enantioselectivity. The cyclopentanone and cyclohexanone substrates 42 were also investigated to determine if an enantioselective switch, similar to that previously reported for isoflavanones 37, would be observed. Using formic acid as the proton source, it was found that a switch in the absolute configuration was observed in just two of the seven substrates tested (Scheme 12B). Formic acid generally gave low enantioselectivities or racemic products for the cyclopentanone substrates that were employed in the study. Interestingly, formation of the byproduct 44 was reported in Meldrum’s acid reaction conditions if the THF solvent used in the reaction contained peroxide impurities or any dissolved oxygen (Scheme 12C). A plausible mechanism for this would be that a carbon-bound Pd−enolate generated after decarboxylation undergoes a Bayer−Villige-type oxidation to form the ester and β-hydride elimination generates the alkene 44. Guiry also studied the enantiodivergent effect in the DAP of α-aryl-1-indanone substrates (Scheme 13).28 The DAP protocol was developed to generate a series of α-aryl-1-indanones 46 from the corresponding α-aryl-β-keto allyl esters 45 using Meldrum’s acid or formic acid. Switching the achiral proton source, both enantiomers of a series of tertiary α-aryl-1indanones 46 were readily accessed in this excellent example of dual stereocontrol. No enantioselective switch was observed for α-alkyl or α-allyl indanone substrates, indicating the need for sterically hindered α-substituents (α-aryl or α-benzyl) for enantiodivergent outcomes. An alternative catalytic cycle was proposed to explain the enantioselective switch for α-aryl-1indanones (Scheme 14). Taking into account the ability of hard oxo-nucleophiles to coordinate directly to Pd, the Guiry group proposed a pathway where the formate coordinates to the palladium displacing the β-keto acid 48 before decarboxylation. Upon expulsion of propene from 7, the catalyst is regenerated and oxidatively adds to the β-keto acid 48. Decarboxylation of 49 generates a hydridopalladium species 50, which forms the desired product (R)-46 via an intramolecular reductive elimination step. It was postulated that this key difference (intramolecular protonation vs intermolecular protonation) between the formic acid and Meldrum’s acid systems in the enantioselective step might explain the divergent stereochemical outcomes. The use of phenylated substrate 51 enabled easier isolation of byproduct 52, which

Figure 1. Stereochemical rationale for DAP with Meldrum’s acid.

In 2014, the Guiry group went on to utilize this methodology in the first asymmetric synthesis of two naturally occurring 7-hydroxy-substituted isoflavanones, sativanone 40 and 3-O-methylviolanone 41 (Figure 2).25 Surprisingly, it was

Figure 2. Sativanone 40 and 3-O-methylviolanone 41.

also discovered that changing the proton source from Meldrum’s acid to formic acid gave the opposite sense of asymmetric induction (Scheme 10). No such switch in selectivity had been seen by Stoltz in their studies with α-alkyl, allyl, or benzyl substituents.18,19 Enantiodivergent methodology, wherein enantioselectivity is determined by a factor other than the supposed chiral promoter, is an attractive route to both product antipodes, particularly when both enantiomers of the required chiral ligand are not readily available.26 Although levels of enantioselectivity varied with the choice of palladium source and solvent, the absolute configuration of the product was exclusively acid dependent. Based on the mechanistic ambiguity of the DAP, it was speculated the enantiodivergence derived from some unknown change in pathway based on the acid used. This interesting example of dual stereocontrol in a DAP reaction was further probed with deuterium-labeling studies. Mechanistic 478


JOCSynopsis

The Journal of Organic Chemistry Scheme 10. Enantiodivergent Synthesis of Tertiary α-Aryl Isoflavanone

Scheme 11. Investigation of DAP via Deuterium-Labeling Studies

Scheme 12. Synthesis of Tertiary α-Aryl Cyclopentanones and Cyclohexanones

formate instead of formic acid gave the product in 29% yield, further suggesting an alternative, unidentified source for the α-proton in the final product 46. Guiry, Diéguez, Pamies, and Norrby most recently reported the enantioselective synthesis of sterically hindered tertiary α-aryl oxindoles via Pd-catalyzed DAP.29 (CF3)3-t-Bu-PHOX 36, previously successful in similar DAP systems with Meldrum’s acid 27, gave a low 37% ee for the model substrate (54a; Ar = 2,4,6-(MeO)3C6H2). Screening a series of phosphite−N (N = oxazoline or pyridine) ligands found that phosphite−pyridine ligand 53 gave the highest enantioselectivity (49% ee). Optimization of reaction conditions using 53 as the chiral ligand further increased the ee to 70% when the reaction was carried out in methyl tert-butyl ether (MTBE) at room temperature (Scheme 16). Substrate scope studies employing the optimal conditions revealed that di-ortho-substitution with electronrich groups is essential to achieve high levels of enantioselectivity in this system. Substrates possessing aryl groups without di-ortho-substitutions (54b and 54c) gave poor levels enantioselectivity (26−1% ee). Kinetic studies conducted using the model substrate (54a; Ar = 2,4,6-(MeO)3C6H2) indicated that decarboxylation is the rate-determining step. The DAP was probed using a combination of experimental investigation and theoretical calculations to understand the nature of the enantiodetermining step. It was found that the two most stable transition states leading to opposite product enantiomers have very little energy difference (ΔΔGcalc ≈ 1.5 kJ/mol for 54b and 54c vs ΔΔGcalc ≈ 11.4 kJ/mol for 54a), which could explain the low enantioselectivities observed in the substrate scope studies (Figure 3). The screening of three large series of phosphite−N (N = oxazoline and pyridine) ligands and families indicated that the best results were obtained with a readily accessible phosphite−pyridine

revealed 80−90% incorporation of deuterium using DCO2H (Scheme 15A). Unfortunately, 49% deuterium incorporation into the product 45 using HCO2D was still low, given the rigorous drying procedures employed (Scheme 15B). No deuterium incorporation was observed when the reaction was conducted with HCO2H and deuterated molecular sieves. The addition of D2O to the reaction mixture (5 equiv) only showed 8% deuterium incorporation. DAP carried out with sodium 479


JOCSynopsis

The Journal of Organic Chemistry Scheme 13. Enantiodivergent Synthesis of Tertiary α-Aryl-1-indanones

Scheme 14. Alternative Mechanistic Proposal for Heterogenous DAP by Guiry

Recently, Guiry also described the first DAP strategy for lactones and dihydrocoumarins.30 α-Aryl lactones, with arenes possessing di-ortho-substitutions, had not been previously reported via complementary methodologies.24d,31 One of the

ligand library. The introduction of an enantiopure (S)-biaryl phosphite moiety with bulky substituents in the ortho-positions played an essential role in increasing the enantioselectivity of the Pd- catalytic systems. 480


JOCSynopsis

The Journal of Organic Chemistry Scheme 15. Deuterium-Labeling Studies Investigating DAP of α-Aryl-1-indanones

Scheme 16. DAP Studies with Oxindole

more interesting findings was that protonation conditions employing a chiral ligand and an organic proton donor such as Meldrum’s acid or formic acid gave low enantioselectivities (up to 50% ee; (S)-enantiomer). It is also to be noted that no stereoselective switch was observed when using heterogeneous vs homogeneous conditions unlike other substrate classes (isoflavanones, indanones, cyclopentanones). This was quite unexpected and led the authors to examine the DAP using chiral proton sources, influenced by Muzart’s work on selected tetralones and indanones.10−14 A screen of the different chiral proton sources revealed the superiority of (1R,2S)-(−)-ephedrine 15 as the chiral protonating agent for DAP of lactone and dihydrocoumarins. Moreover, the reaction gave high ee’s in the absence of a chiral P,N-ligand (up to 92% ee; (R)-enantiomer).

Figure 3. Most stable calculated TSNU-OCB-re and TSNU-OCB-si transition states for substrates (a) 54b, (b) 54c, and (c) 54a with Meldrum’s acid using ligand 53.

This protonating agent is cheap32 and commercially available in both enantiomeric forms, eliminating the need for an expensive chiral P,N-ligand. The authors note that a limitation of this strategy was the competitive α-allylation, which proceeded faster for aryl groups without ortho-substitutions. However, this could almost entirely be suppressed by carrying 481


JOCSynopsis

The Journal of Organic Chemistry Scheme 17. DAP of δ-Lactone- and Dihydrocoumarin-Derived Substrates

Scheme 18. Catalytic Asymmetric Synthesis of C3-Monosubstituted Carbazolones

out the reaction at low temperatures (−40 °C) in THF without any change in ee. Analyzing the product distribution (decarboxylative allylation vs decarboxylative protonation) led to a mechanistic rationale that highlighted how subtle changes in reaction parameters can lead to selectivity. The stereochemical rationale proposed to account for the sense of stereoinduction observed is illustrated in Scheme 17. The authors suggest that ephedrine has a dual role in the reaction, acting first as the nucleophile toward the cationic η3-[allyl]−Pd complex followed by protonation of the in situ generated

prochiral enolate. The stereochemical outcomes of both δ-lactone- and dihydrocoumarin-derived substrates indicate protonation of the Si face (Scheme 17, pathway 2). The α-aryl substrates (42, 45, 54, and 56) investigated in the DAP by the Guiry group have also been studied in the related decarboxylative asymmetric allylic alkylations, forming α-allyl, α-aryl quaternary stereocenters with excellent enantioselectivities (up to >99% ee).33 The DAP methodology has been used in the formal synthesis of the complex natural product (−)-aspidofractinine 63 482


JOCSynopsis

The Journal of Organic Chemistry (Scheme 18).34 The Shao group examined the Pd-catalyzed DAP of carbazolones 61 to enantioselectively produce C3-monosubstituted carbazolones 62. This is a key structural motif in many natural products and biologically active compounds. A difference between the protonation modes of oxo and organic acids could be noted for the model substrate (61: R = CN), as no protonation was achieved using formic acid, while Meldrum’s acid formed the desired products in high yields and good ee (69% yield, 76% ee). Reaction conditions found through a screening of various reaction parameters revealed that 2-oxocyclopentanecarboxylate 60 was the ideal proton donor for this substrate class, forming the C3-monosubstituted carbazolone 62 in up to 94% yield and 92% ee. Additionally, a variety of functional groups which had not been subjected to the DAP, including cyanide, ester, amine, and azide, were well tolerated in the substrate scope studies.

Pat Guiry. He is currently a postdoctoral fellow in the research group of Professor Phil Baran at The Scripps Research Institute. His research interests include the development and mechanistic investigation of practical synthetic methods.

4. CONCLUSIONS Summarized above is an account of the development, mechanistic understanding, and recent advances in Pd-catalyzed decarboxylative asymmetric protonation. Although the DAP is yet to find widespread synthetic application, its potential as a mild and effective methodology for the asymmetric synthesis of tertiary α-stereocenters has been realized in the first catalytic enantioselective synthesis of isoflavanones and formal synthesis of (−)-aspidofractinine. The mechanism of Pd-catalyzed DAP has been investigated over the last three decades, with recent results pointing toward disparate mechanisms based on the enantioselective nature of the proton source. Notably, a novel enantioselective switch using the same chiral ligand, but different achiral proton sources (Meldrum’s acid vs formic acid), has also been reported. Nonetheless, we believe continued research efforts along with a better mechanistic understanding in this area are necessary to expand the synthetic utility and fully exploit the opportunities that exist in this important transformation.

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Jinju James received her B.Sc. degree in medicinal chemistry and chemical biology from University College Dublin. She received her Ph.D. in Organic Chemistry with Prof. Pat Guiry at University College Dublin (2018). Her research interests include synthetic methodology development and pharmaceutical chemistry.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Pat Guiry was awarded his B.Sc. and Ph.D. degrees from University College Dublin, with Professor Dervilla Donnelly (University College Dublin), Sir Derek Barton (Texas A&M), and Dr. Jean-Pierre Finet (Marseille) as his Ph.D. supervisors. He carried out postdoctoral research in asymmetric catalysis with Dr. John Brown FRS (Oxford University). Returning to University College Dublin in 1993, he was a Visiting Professor at the University of Toronto (2004) and Full Professor of Synthetic Organic Chemistry since 2006.

Patrick J. Guiry: 0000-0002-2612-8569 Author Contributions §

C.K. and J.J. contributed equally to this work.

Notes

The authors declare no competing financial interest. Biographies

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ACKNOWLEDGMENTS C.K. is grateful for the award of a SSPC Ph.D. Scholarship. This publication has emanated from research conducted with the financial support of the Synthesis and Solid State Pharmaceutical Centre (SSPC), funded by Science Foundation Ireland (SFI) under Grant No. 12\RC\2275. J.J. is grateful for the award of an Irish Research Council Enterprise Partnership Scheme Ph.D. Scholarship (EPSPG/2014/110) with Enterprise Partner APC, Ltd. We thank Dr. Kirill Nitikin for his help with artwork of the Cover image and Mr. Alex Doran, who took the original hurling pitch photograph.

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Cian Kingston received his Ph.D. in Organic Chemistry from University College Dublin in 2017 under the supervision of Professor

REFERENCES

(1) (a) Gladysz, J.; Michl, J. Enantioselective Synthesis: Introduction. Chem. Rev. 1992, 92, 739−739. (b) Bolm, C.;

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The Journal of Organic Chemistry Gladysz, J. A. Introduction: Enantioselective Catalysis. Chem. Rev. 2003, 103, 2761−2762. (c) Farina, V.; Reeves, J. T.; Senanayake, C. H.; Song, J. J. Asymmetric Synthesis of Active Pharmaceutical Ingredients. Chem. Rev. 2006, 106, 2734−2793. (2) (a) Trost, B. M.; Crawley, M. L. Asymmetric Transition-MetalCatalyzed Allylic Alkylations: Applications in Total Synthesis. Chem. Rev. 2003, 103, 2921−2944. (b) Bhat, V.; Welin, E. R.; Guo, X.; Stoltz, B. M. Advances in Stereoconvergent Catalysis from 2005 to 2015: Transition-Metal-Mediated Stereoablative Reactions, Dynamic Kinetic Resolutions, and Dynamic Kinetic Asymmetric Transformations. Chem. Rev. 2017, 117, 4528−4561. (c) Feng, J.; Holmes, M.; Krische, M. J. Acyclic Quaternary Carbon Stereocenters via Enantioselective Transition Metal Catalysis. Chem. Rev. 2017, 117, 12564−12580. (d) Newton, C. G.; Wang, S.-G.; Oliveira, C. C.; Cramer, N. Catalytic Enantioselective Transformations Involving C− H Bond Cleavage by Transition-Metal Complexes. Chem. Rev. 2017, 117, 8908−8976. (3) Tsuji, J.; Minami, I. New synthetic reactions of allyl alkyl carbonates, allyl β-keto carboxylates, and allyl vinylic carbonates catalyzed by palladium complexes. Acc. Chem. Res. 1987, 20, 140− 145. (4) (a) Tsuji, J.; Nisar, M.; Shimizu, I. Facile palladium-catalyzed decarboxylation reaction of allylic β-keto esters. J. Org. Chem. 1985, 50, 3416−3417. For reviews on various synthetic methods, including decarboxylative protonation, involving allyl palladium complexes as intermediates, see: (b) Tsuji, J. New general synthetic methods involving π-allylpalladium complexes as intermediates and neutral reaction conditions. Tetrahedron 1986, 42, 4361−4401. (c) Guibé, F. Allylic protecting groups and their use in a complex environment part II: Allylic protecting groups and their removal through catalytic palladium π-allyl methodology. Tetrahedron 1998, 54, 2967−3042. (d) This work was an expansion upon the group’s previous investigations in which formic acid was utilized for the preparation of 1-olefins by the palladium-catalyzed hydrogenolysis of allylic acetates and ethers; see: Tsuji, J.; Yamakawa, T. A convenient method for the preparation of 1-olefins by the palladium catalyzed hydrogenolysis of allylic acetates and allylic phenyl ethers with ammonium formate. Tetrahedron Lett. 1979, 20, 613−616. (e) Tsuji, J.; Shimizu, I.; Minami, I. Regioselective synthesis of 1-olefins by palladium-catalyzed hydrogenolysis of terminal allylic compounds with ammonium formate. Chem. Lett. 1984, 13, 1017−1020. (5) Mandai, T.; Imaji, M.; Takada, H.; Kawata, M.; Nokami, J.; Tsuji, J. Facile transformation of substituted allyl malonates to monocarboxylic acids and esters by the reaction with ammonium formate catalyzed by palladium complexes. J. Org. Chem. 1989, 54, 5395−5397. (6) Tsuji, J.; Mandai, T. Palladium-Catalyzed Hydrogenolysis of Allylic and Propargylic Compounds with Various Hydrides. Synthesis 1996, 1996, 1−24. (7) Shimizu, I.; Ishii, H. Synthesis of α-fluoroketones based on palladium-catalyzed Decarboxylation reactions of allyl β-keto carboxylates. Tetrahedron 1994, 50, 487−495. (8) (a) Hey, H.; Arpe, H.-J. Removal of Allyl groups by Formic Acid Catalyzed by (Triphenylphosphane)palladium. Angew. Chem., Int. Ed. Engl. 1973, 12, 928−929. (b) Oshima, M.; Shimizu, I.; Yamamoto, A.; Ozawa, F. Synthesis and properties of (π-allyl)palladium formates as intermediates in palladium-catalyzed reductive cleavage of allylic acetates and carbonates with formic acid. Organometallics 1991, 10, 1221−1223. (9) Mandai, T.; Matsumoto, T.; Kawada, M.; Tsuji, J. A novel method for stereospecific generation of natural C-17 stereochemistry and either C-20 epimer in steroid side chains by palladium-catalyzed hydrogenolysis of C-17 and C-20 allylic carbonates. Tetrahedron 1994, 50, 475−486. (10) Henin, F.; Muzart, J. Palladium-catalyzed cleavage of prochiral enol carbonates: Enantioselective ketonisation of resulting enols. Tetrahedron: Asymmetry 1992, 3, 1161−1164. (11) Henin, F.; Muzart, J.; Pete, J.; M’boungou-M’passi, A.; Rau, H. Enantioselective Protonation of a Simple Enol: Aminoalcohol-

Catalyzed Ketonization of a Photochemically Produced 2-Methylinden-3-ol. Angew. Chem., Int. Ed. Engl. 1991, 30, 416−418. (12) (a) Aboulhoda, S. J.; Létinois, S.; Wilken, J.; Reiners, I.; Hénin, F.; Martens, J.; Muzart, J. Palladium-mediated enantioselective formation of 2-methyltetral-1-one from the corresponding allyl or benzyl enol carbonate in the presence of enantiopure aminoalcohols. Tetrahedron: Asymmetry 1995, 6, 1865−1868. (b) Muzart, J.; Hénin, F.; Aboulhoda, S. J. Asymmetric protonation of enolic species: dramatic increase in the selectivity with temperature and unexpected Eyring diagram. Tetrahedron: Asymmetry 1997, 8, 381−389. (c) Aboulhoda, S. J.; Reiners, I.; Wilken, J.; Hénin, F.; Martens, J.; Muzart, J. β-Amino tertiary cycloalkanols for the enantioselective protonation of enolic species produced by a palladium-induced cascade reaction. Tetrahedron: Asymmetry 1998, 9, 1847−1850. (d) Roy, O.; Riahi, A.; Hénin, F.; Muzart, J. Catalysed Asymmetric Protonation of Simple Linear Keto-Enolic Species − A Route to Chiral α-Arylpropionic Acids. Eur. J. Org. Chem. 2002, 2002, 3986− 3994. (e) Roy, O.; Loiseau, F.; Riahi, A.; Hénin, F.; Muzart, J. Access to racemic and enantioenriched 3-methyl-4-chromanones: catalysed asymmetric protonation of corresponding enolic species as the key step. Tetrahedron 2003, 59, 9641−9648. (13) Aboulhoda, S. J.; Hénin, F.; Muzart, J.; Thorey, C.; Behnen, W.; Martens, J.; Mehler, T. Production of optically active ketones by a palladium-induced cascade reaction from racemic β-ketoesters. Tetrahedron: Asymmetry 1994, 5, 1321−1326. (14) Muzart, J. Amino alcohol-mediated enantioselective syntheses of α-substituted indanones and tetralones, ammonium enolates as key intermediates. Tetrahedron: Asymmetry 2014, 25, 697−704. (15) (a) Fehr, C. Enantioselective Protonation of Enolates and Enols. Angew. Chem., Int. Ed. Engl. 1996, 35, 2566−2587. (b) Mohr, J. T.; Hong, A. Y.; Stoltz, B. M. Enantioselective protonation. Nat. Chem. 2009, 1, 359−369. (c) Oudeyer, S.; Brière, J.-F.; Levacher, V. Progress in Catalytic Asymmetric Protonation. Eur. J. Org. Chem. 2014, 2014, 6103−6119. (16) For a review on the synthetic application of transition metalcatalyzed decarboxylative enolate formation, see: Tunge, J. A.; Burger, E. C. Transition Metal Catalyzed Decarboxylative Additions of Enolates. Eur. J. Org. Chem. 2005, 2005, 1715−1726. (17) Behenna, D. C.; Stoltz, B. M. The Enantioselective Tsuji Allylation. J. Am. Chem. Soc. 2004, 126, 15044−15045. (18) Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11348−11349. (19) Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Homogeneous Pd-Catalyzed Enantioselective Decarboxylative Protonation. Org. Lett. 2008, 10, 1039−1042. (20) For an investigation into the surprisingly high acidity of Meldrum’s acid, see: Nakamura, S.; Hirao, H.; Ohwada. Rationale for the Acidity of Meldrum’s Acid. Consistent Relation of C−H Acidities to the Properties of Localized Reactive Orbital. J. Org. Chem. 2004, 69, 4309−4316. (21) Behenna, D. C.; Mohr, J. T.; Sherden, N. H.; Marinescu, S. C.; Harned, A. M.; Tani, K.; Seto, M.; Ma, S.; Novák, Z.; Krout, M. R.; McFadden, R. M.; Roizen, J. L.; Enquist, J. A.; White, D. E.; Levine, S. R.; Petrova, K. V.; Iwashita, A.; Virgil, S. C.; Stoltz, B. M. Enantioselective Decarboxylative Alkylation Reactions: Catalyst Development, Substrate Scope, and Mechanistic Studies. Chem. Eur. J. 2011, 17, 14199−14223. (22) (a) McKee, T. C.; Bokesch, H. R.; McCormick, J. L.; Rashid, M. A.; Spielvogel, D.; Gustafson, K. R.; Alavanja, M. M.; Cardellina, J. H.; Boyd, M. R. Isolation and Characterization of New Anti-HIV and Cytotoxic Leads from Plants, Marine, and Microbial Organisms. J. Nat. Prod. 1997, 60, 431−438. (b) Shou, Q.-Y.; Fu, R.-Z.; Tan, Q.; Shen, Z.-W. Geranylated Flavonoids from the Roots of Campylotropis hirtella and Their Immunosuppressive Activities. J. Agric. Food Chem. 2009, 57, 6712−6719. (23) Carroll, M. P.; Muller-Bunz, H.; Guiry, P. J. Enantioselective construction of sterically hindered tertiary α-aryl ketones: a catalytic asymmetric synthesis of isoflavanones. Chem. Commun. 2012, 48, 11142−11144. 484


JOCSynopsis

The Journal of Organic Chemistry (24) For selected examples, see: (a) Cheon, C. H.; Yamamoto, H. A Brønsted Acid Catalyst for the Enantioselective Protonation Reaction. J. Am. Chem. Soc. 2008, 130, 9246−9247 and references cited therein . (b) Liao, X.; Weng, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 195−200. (c) Bigot, A.; Williamson, A. E.; Gaunt, M. J. Enantioselective α-Arylation of N-Acyloxazolidinones with Copper(II)-bisoxazoline Catalysts and Diaryliodonium Salts. J. Am. Chem. Soc. 2011, 133, 13778−13781. (d) Huang, Z.; Liu, Z.; Zhou, J. J. Am. Chem. Soc. 2011, 133, 15882−15885. (e) Kang, B. C.; Nam, D. G.; Hwang, G.-S.; Ryu, D. H. Catalytic Asymmetric Formal Insertion of Aryldiazoalkanes into the C−H Bond of Aldehydes: Synthesis of Enantioenriched Acyclic α-Tertiary Aryl Ketones. Org. Lett. 2015, 17, 4810−4813. (25) Doran, R.; Carroll, M. P.; Akula, R.; Hogan, B. F.; Martins, M.; Fanning, S.; Guiry, P. J. A Stereoselective Switch: Enantiodivergent Approach to the Synthesis of Isoflavanones. Chem. - Eur. J. 2014, 20, 15354−15359. (26) For reviews, see: (a) Zanoni, G.; Castronovo, F.; Franzini, M.; Vidari, G.; Giannini, E. Toggling enantioselective catalysisa promising paradigm in the development of more efficient and versatile enantioselective synthetic methodologies. Chem. Soc. Rev. 2003, 32, 115−129. (b) Bartók, M. Unexpected Inversions in Asymmetric Reactions: Reactions with Chiral Metal Complexes, Chiral Organocatalysts, and Heterogeneous Chiral Catalysts. Chem. Rev. 2010, 110, 1663−1705. (27) Doran, R.; Guiry, P. J. Catalytic Asymmetric Synthesis of Sterically Hindered Tertiary α-Aryl Ketones. J. Org. Chem. 2014, 79, 9112−9124. (28) Kingston, C.; Guiry, P. J. Enantiodivergent Synthesis of Tertiary α-Aryl 1-Indanones: Evidence Toward Disparate Mechanisms in the Palladium-Catalyzed Decarboxylative Asymmetric Protonation. J. Org. Chem. 2017, 82, 3806−3819. (29) Biosca, M.; Jackson, M.; Magre, M.; Pàmies, O.; Norrby, P.-O.; Diéguez, M.; Guiry, P. J. Enantioselective Synthesis of Sterically Hindered Tertiary α-Aryl Oxindoles via Palladium-Catalyzed Decarboxylative Protonation. An Experimental and Theoretical Mechanistic Investigation. Adv. Synth. Catal. 2018, 360, 3124−3137. (30) James, J.; Akula, R.; Guiry, P. J. Pd-Catalyzed Decarboxylative Asymmetric Protonation of Sterically Hindered α-Aryl Lactones and Dihydrocoumarins. Adv. Synth. Catal. 2018, 360, 3138−3149. (31) (a) Emmanuel, M. A.; Greenberg, N. R.; Oblinsky, D. G.; Hyster, T. K. Accessing non-natural reactivity by irradiating nicotinamide-dependent enzymes with light. Nature 2016, 540, 414. (b) Lee, J.-W.; List, B. Deracemization of α-Aryl Hydrocoumarins via Catalytic Asymmetric Protonation of Ketene Dithioacetals. J. Am. Chem. Soc. 2012, 134, 18245−18248. (c) Harvey, J. S.; Simonovich, S. P.; Jamison, C. R.; MacMillan, D. W. C. Enantioselective α-Arylation of Carbonyls via Cu(I)-Bisoxazoline Catalysis. J. J. Am. Chem. Soc. 2011, 133, 13782−13785. (32) Available from Sigma Aldrich, CAS: 299-42-3 €19.35 for 25 g. (33) (a) Akula, R.; Doran, R.; Guiry, P. J. Highly Enantioselective Formation of α-Allyl-α-Arylcyclopentanones via Pd-Catalysed Decarboxylative Asymmetric Allylic Alkylation. Chem. - Eur. J. 2016, 22, 9938−9942. (b) Akula, R.; Guiry, P. J. Enantioselective Synthesis of α-Allyl-α-aryldihydrocoumarins and 3-Isochromanones via Pd-Catalyzed Decarboxylative Asymmetric Allylic Alkylation. Org. Lett. 2016, 18, 5472−5475. (c) Jackson, M.; O’Broin, C. Q.; Muller-Bunz, H.; Guiry, P. J. Enantioselective synthesis of sterically hindered α-allyl-αaryl oxindoles via palladium-catalysed decarboxylative asymmetric allylic alkylation. Org. Biomol. Chem. 2017, 15, 8166−8178. (d) James, J.; Guiry, P. J. Highly Enantioselective Construction of Sterically Hindered α-Allyl-α-Aryl Lactones via Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation. ACS Catal. 2017, 7, 1397− 1402. (34) Zhao, R.; Sun, Z.; Mo, M.; Peng, F.; Shao, Z. Catalytic Asymmetric Assembly of C3-Monosubstituted Chiral Carbazolones and Concise Formal Synthesis of (−)-Aspidofractinine: Application of Enantioselective Pd-Catalyzed Decarboxylative Protonation of Carbazolones. Org. Lett. 2014, 16, 4178−4181. 485


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