Skip to main content
NCBI home page
ACS AuthorChoice logoLink to ACS AuthorChoice
. 2023 Nov 16;145(47):25553–25558. doi: 10.1021/jacs.3c10663

sSPhos: A General Ligand for Enantioselective Arylative Phenol Dearomatization via Electrostatically-Directed Palladium Catalysis

Max Kadarauch 1, David M Whalley 1, Robert J Phipps 1,*
PMCID: PMC10690801  PMID: 37972383

Abstract

graphic file with name ja3c10663_0008.jpg

Arylative phenol dearomatization affords complex, cyclohexanone-based scaffolds from simple starting materials, and asymmetric versions allow access to valuable enantioenriched structures. However, bespoke chiral ligands must typically be identified for each new scaffold variation. We have addressed this limitation by applying the concept of electrostatically-directed palladium catalysis whereby the chiral sulfonated ligand sSPhos engages in electrostatic interactions with a phenolate substrate via its associated alkali metal cation. This approach allows access to highly enantioenriched spirocyclohexadienones, a process originally reported by Buchwald and co-workers in a predominantly racemic manner. In addition, sSPhos is proficient at forming two other distinct scaffolds, which had previously required fundamentally different chiral ligands, as well as a novel oxygen-linked scaffold. We envisage that the broad generality displayed by sSPhos will facilitate the expansion of this important reaction type and highlight the potential of this unusual design principle, which harnesses attractive electrostatic interactions.

Phenol dearomatization is exceptionally useful for building up three-dimensional molecular complexity.1 Although the energetic barriers can be high, the products possess versatile functionality and often a new stereocenter. Dearomatization of phenols is typically more challenging than naphthols, indoles, pyrroles, and the like because of lower electron density. While many methods rely on highly electrophilic reagents, transition metal catalysis has recently expanded the breadth of accessible transformations.2 This has enabled arylative dearomatizations during which a new arene substituent is introduced during the dearomatizing event (early methods for arylative dearomatization relying on stoichiometric lead,3 bismuth,4 and iodine5 arylating reagents possessed various limitations). A pioneering advance was reported by Buchwald and co-workers in 2011 with the palladium-catalyzed intramolecular arylation of phenols, which produced spirocyclohexadienones bearing all-carbon quaternary centers (Figure 1A, upper).6 The scope was explored using an achiral phosphine ligand (L1) but it included two preliminary enantioselective results, one phenol and one naphthol. For the phenol example, L2 allowed 81% ee in the intramolecular dearomatization of 1a (Figure 1A, lower). Since Buchwald’s original report, a number of important developments on palladium-catalyzed arylative phenol dearomatization to form different scaffolds, from the groups of You7 and Tang,8 have been made.9 This includes asymmetric variants using TADDOL-derived chiral phosphoramidites7b and P-chiral biaryl monophosphine ligands,8a respectively. It is evident that success for a new substrate class requires extensive ligand evaluation and tailoring, a feature which hinders more rapid development and widespread use of this important reaction type.10

Figure 1.

Figure 1

Open in a new tab

Previous arylative phenol dearomatization and use of sSPhos as a bifunctional ligand.

We recently reported the use of enantiopure sSPhos as an unexplored chiral, bifunctional phosphine ligand, which can be readily obtained by diastereoselective recrystallization of (rac)-sSPhos as its quinidinium salt (Figure 1B).11 Originally reported by Anderson and Buchwald as a water-soluble ligand for cross-coupling,12 we initially utilized (rac)-sSPhos for control of site selectivity in the cross-coupling of polyhalogenated arenes. Therein, we introduced the concept of electrostatically directed palladium catalysis, whereby an anionic ligand interacts with an anionic substrate via a bridging alkali metal cation through electrostatic interactions (Figure 1C, left).13,14 We subsequently found enantiopure sSPhos to be highly proficient in controlling enantioselectivity in Suzuki–Miyaura couplings to form 2,2′-biphenols, an outcome we tentatively attributed to an organizing network of hydrogen bonds between the ligand sulfonate group and the phenolic hydroxyls on the coupling partners (Figure 1C, right).11 On the basis of these precedents, we hypothesized that enantiopure sSPhos might be an effective ligand for enantiocontrol in the Buchwald arylative dearomatization reaction. Mechanistically, in the presence of a strong base, it is likely that phenolate formation occurs and that the subsequent palladation of this phenolate may be selectivity-determining.7b,15 We envisaged that an attractive electrostatic interaction might occur between the alkali metal cation of the phenolate and the sulfonate group of the ligand, akin to those we invoked in our prior work, thereby providing organization in a chiral environment (Figure 1D). More broadly, we were optimistic that, by exploiting electrostatic interactions with phenolate intermediates, sSPhos might constitute a generally applicable ligand for enantioselective, Pd-catalyzed arylative phenol deromatization across a diverse range of scaffolds.16

We began with conditions similar to those identified in Buchwald’s study6 by using [Pd(cinnamyl)Cl]2 and K2CO3 in dioxane at 110 °C and (R)-sSPhos as the ligand (Table 1, entry 1). Pleasingly, spirocycle 2a was formed in 76% yield with encouraging enantioselectivity. An evaluation of palladium sources (entries 2–4) revealed that Pd2dba3 afforded significant improvement (63% ee), as did switching the base to KOH (entry 5, 84%). Aromatic solvents provided no improvement (entries 6 and 7), but addition of water as a cosolvent increased yield and enantioselectivity in all cases (entries 8–10).17 A PhMe:H2O biphasic mixture proved to be optimal and afforded 2a in 98% yield and 92% ee with the absolute configuration determined by X-ray diffraction (entry 10). Reactivity remained excellent at 90 °C but with no improvement in ee (entry 11). Various group 1 metal hydroxides were tested, which gave very similar enantioselectivity outcomes (entries 12–14).18

Table 1. Reaction Optimization.

graphic file with name ja3c10663_0007.jpg

entry Pd source base solvent yield (%)a ee (%)b
1 [PdCl(cinnamyl)]2 K2CO3 dioxane 76 44
2 [PdCl(allyl)]2 K2CO3 dioxane 48 34
3 Pd(OAc)2 K2CO3 dioxane 13 27
4 Pd2dba3 K2CO3 dioxane 81 63
5 Pd2dba3 KOH dioxane 48 84
6 Pd2dba3 KOH PhCF3 41 83
7 Pd2dba3 KOH PhMe 60 83
8 Pd2dba3 KOH dioxane/H2O (10:1) 66 89
9 Pd2dba3 KOH PhCF3/H2O (10:1) 91 91
10 Pd2dba3 KOH PhMe/H2O (10:1) 99 (98) 92
11c Pd2dba3 KOH PhMe/H2O (10:1) 95 91
12 Pd2dba3 LiOH PhMe/H2O (10:1) 84 95
13 Pd2dba3 NaOH PhMe/H2O (10:1) 98 92
14 Pd2dba3 CsOH PhMe/H2O (10:1) 87 95
Open in a new tab
a

Yields determined by 1H NMR with reference to a dibromomethane internal standard. Value in parentheses refers to isolated yield.

b

ee determined by SFC analysis of the crude reaction mixture, except entry 10.

c

Reaction temperature 90 °C.

We evaluated the scope of the dearomatization and were pleased to find that phenols substituted with methyl and phenyl at the meta position also gave a high ee (Scheme 1, 2b, 2c). Conversion to 2c was low, likely because of hindrance at the forming spirocyclic stereocenter. We were curious as to whether substitution at the phenol ortho position would give good outcomes with the facial differentiation being further from the forming stereocenter. Indeed, high enantioselectivities were maintained for these substrates encompassing phenyl (2d), methoxy (2e), and methyl (2f) substituents. The limits of electronic tolerance on the phenol are displayed by an ortho-fluoro substitution: 2g was obtained in low yield but still remarkably high enantioselectivity given the small size of the differentiating substituent.19 Substitution at two adjacent positions of the phenol ring, including a naphthol, also worked well (2h, 2i), and the tether between the two arenes was extended to afford tetralin derivative 2j. Further extension leading to a seven-membered ring also delivered very high enantioselectivity (2k), although the low yield reflected the present reactivity limit. Substitution of the lower ring gave good outcomes with both electron-poor (2l) and -rich (2m) examples. A substrate bearing both chloride and bromide reacted selectivity at the bromide (2n, 96% ee). A Boc-protected amine was tolerated (2o), as was an ester (2p). A methyl adjacent to the bromide on the lower ring gave a significant ee reduction (2q). Finally, fluorine-containing 2r and 2s were obtained smoothly. When the reaction was scaled to 1 mmol, a small increase in enantioselectivity for 2r was observed (Scheme 1B). This led us to assess a lower 2 mol % loading of Pd (3 mol % sSPhos) at this larger scale with excellent results still obtained for 2l.

Scheme 1. Scope of Arylative Phenol Dearomatization on Substrates Related to 1a.

Scheme 1

Open in a new tab

Yields are isolated; ee values determined by SFC.

48 h reaction time.

Used 3.0 equiv of KOH.

5 mol % Pd2dba3 and 15 mol % (R)-sSPhos for 48 h.

Reaction time of 92 h.

Having demonstrated the effectiveness of sSPhos on Buchwald’s original arylative dearomatization scaffold, we sought to evaluate how generally applicable it might be. We next targeted arylative dearomatization of the para-aminophenol class of substrates reported by You and co-workers racemically in 20147a and enantioselectively in 2020 (Scheme 2).7b These substrates are notable as they map directly onto the skeleton of the Erythrina alkaloids.1b,1d,2b Excellent results could be achieved with only 2.5 mol % Pd to give dearomatized 4a in good yield and excellent enantioselectivity. Usefully, an aryl chloride could also be used as a the starting material. A larger ring in the heterocyclic starting material gave excellent results (4b), and we evaluated several substituents of varying electronic character on the lower ring (4c–4f). Dimethoxy-substituted 4g, upon hydrogenation, leads directly to (−)-3-demethoxyerythratidinone (5), as previously demonstrated by You and co-workers.7

Scheme 2. Enantioselective Arylative Dearomatization of para-Amino Phenols.

Scheme 2

Open in a new tab

To further test the generality of sSPhos, we benchmarked it on a third distinct substrate class, previously reported by Tang and co-workers who elegantly applied it to natural product synthesis (Scheme 3).8a−8c,8e With little modification to the conditions, excellent results could be obtained for chiral phenanthrenone derivatives related to 7a. Several analogues were demonstrated by varying the phenol para substituent (7b), as well as the lower ring substituent (7c–7e).

Scheme 3. Arylative Dearomatization to Give Chiral Phenanthrenone Derivatives.

Scheme 3

Open in a new tab

The substrates so far have generated products possessing all-carbon (Schemes 1 and 3) and α-tertiary amine (Scheme 2) quaternary stereocenters. We questioned whether this might be extended to O-linked substrates to form α-tertiary ethers at the spirocyclic stereocenter. Such motifs have not, to the best of our knowledge, been formed so far using arylative phenoldearomatization, even racemically. The resulting scaffold features in a number of natural products, including members of the urnucratin20 and kadsulignan21 families and parvifloral F.22 Pleasingly, methyl-substituted 9a and methoxy-substituted 9b were obtained in 82% and 83% ee and 9c, which bears a chloride on the lower ring and methyls on the upper, was obtained in 93% ee (Scheme 4). The low to moderate yields are attributed to decomposition of the electron-rich starting material under the reaction conditions. Nevertheless, these results underline the generality of sSPhos as a chiral ligand for arylative phenol dearomatization, in the context of an as-yet-unexplored scaffold.

Scheme 4. Extension to Spiroheterocyclic Scaffolds Incorporating Oxygen.

Scheme 4

Open in a new tab

NaOH (3.0 equiv) used in place of KOH.

We sought to probe the interactions responsible for the effectiveness of sSPhos. The anticipated pKa difference between a phenol and KOH would suggest that the potassium phenolate salt is formed under the reaction conditions, a scenario supported by NMR studies (see the Supporting Information). Phenolate formation would mean it is unlikely that ligand–substrate hydrogen bonding is occurring. We carried out the reaction in anhydrous toluene by comparing the standard phenol with a TMS-protected variant (Scheme 5A). The identical ee values provide further evidence against hydrogen bonding playing a role in selectivity because the latter conditions feature no feasible proton source. Furthermore, use of the preformed potassium phenolate salt as the substrate returned the ee to the exact value (92%) obtained when running the reaction under the optimized conditions with water. We speculate that the presence of water in the optimized conditions assists in rapid potassium phenolate formation, which is crucial for high yield and enantioselectivity. We next sought evidence for the proposed electrostatic interaction involving a bridging metal cation (Figure 1D). During optimization, no significant variation in enantioselectivity had been observed between the various alkali metal cations when they were evaluated in toluene/water (Table 1). However, differences between them were observed in dioxane, which suggests possible involvement in the selectivity-determining step.18 Crucially, replacement of the alkali metal cation with either tetrabutylammonium or tetrabutylphosphonium was found to be detrimental to both yield and ee, thereby suggesting that favorable organization in the enantiodetermining transition state cannot be maintained with these bulky cations (Scheme 5B). Accordingly, reduction of the length of the alkyl chains in tetramethylammonium hydroxide largely restored both metrics.

Scheme 5. Control Experiments to Probe Ligand–Substrate Interactions and Predictive Model.

Scheme 5

Open in a new tab

We further probed the importance of the alkali metal cation by the addition of stoichiometric crown ethers of varying size (Scheme 5C).23 In toluene, almost no effect on ee was observed by the addition of 12-crown-4, as expected, given its small size relative to K+ (entry 2 vs 1).24 However, 15-crown-5 and 18-crown-6 both gave reduced ee, which suggests that binding to the cation disrupts the substrate–ligand organization to some extent (entries 3 and 4). A similar outcome was observed in dioxane (entries 5–8). Finally, we sought to remove the charge from the ligand altogether to rule out the possibility that sSPhos might be exerting enantiocontrol through simple steric repulsion. Accordingly, a neopentyl sulfonate ester derivative of the ligand gave only −6% ee (Scheme 5D). The absolute stereochemistry of the products from Schemes 1,252,7b and 3(8a) could all be reliably determined. In all cases, use of (R)-sSPhos is consistent with arylation occurring from the lower face of the phenol when it is depicted with its substituted side to the left and the unsubstituted to the right (Scheme 5E).

In summary, enantiopure sSPhos, easily obtained via resolution, is an extremely general chiral ligand for the Pd-catalyzed intramolecular arylative dearomatization of phenols. Using Buchwald’s pioneering report, which afforded spirocyclohexadienones bearing all-carbon quaternary centers in a predominatly racemic manner, as a forum for demonstrating its effectiveness, we subsequently extended this to two other substrate classes. We also report several oxygen-linked substrates, which have not to date been explored, that give rise to spiroheterocyclic α-tertiary ethers. These results, combined with our prior work applying sSPhos to asymmetric biphenol synthesis, underscore the remarkable ability of sSPhos to exert enantiocontrol in palladium-catalyzed reactions involving versatile phenolic substrates.

Acknowledgments

We are very grateful to Dr. Andrew Bond (University of Cambridge) for solving and refining the X-ray crystal structure. We thank Dr. Thomas Moss (AstraZeneca) for useful discussions. We are grateful to The Royal Society for a University Research Fellowship (R.J.P., UF130004), the European Research Council under the Horizon 2020 Program (Starting Grant no. 757381), and AstraZeneca for a studentship through the AstraZeneca-Cambridge Ph.D. program (M.K.).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.3c10663.

  • Additional optimization, full experimental details, and characterization data for compounds (PDF)

The authors declare no competing financial interest.

Supplementary Material

ja3c10663_si_001.pdf (17.2MB, pdf)

References

  1. a Pouységu L.; Deffieux D.; Quideau S. Hypervalent iodine-mediated phenol dearomatization in natural product synthesis. Tetrahedron 2010, 66, 2235–2261. 10.1016/j.tet.2009.12.046. [DOI] [Google Scholar]; b Roche S. P.; Porco J. A. Jr Dearomatization Strategies in the Synthesis of Complex Natural Products. Angew. Chem., Int. Ed. 2011, 50, 4068–4093. 10.1002/anie.201006017. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Zhuo C.-X.; Zhang W.; You S.-L. Catalytic Asymmetric Dearomatization Reactions. Angew. Chem., Int. Ed. 2012, 51, 12662–12686. 10.1002/anie.201204822. [DOI] [PubMed] [Google Scholar]; d Ding Q.; Ye Y.; Fan R. Recent Advances in Phenol Dearomatization and Its Application in Complex Syntheses. Synthesis 2012, 45, 1–16. 10.1055/s-0032-1317575. [DOI] [Google Scholar]; e Wu W.-T.; Zhang L.; You S.-L. Catalytic asymmetric dearomatization (CADA) reactions of phenol and aniline derivatives. Chem. Soc. Rev. 2016, 45, 1570–1580. 10.1039/C5CS00356C. [DOI] [PubMed] [Google Scholar]; f Sun W.; Li G.; Hong L.; Wang R. Asymmetric dearomatization of phenols. Org. Biomol. Chem. 2016, 14, 2164–2176. 10.1039/C5OB02526E. [DOI] [PubMed] [Google Scholar]; g Kumar R.; Singh F. V.; Takenaga N.; Dohi T. Asymmetric Direct/Stepwise Dearomatization Reactions Involving Hypervalent Iodine Reagents. Chem. Asian. J. 2022, 17, e202101115 10.1002/asia.202101115. [DOI] [PubMed] [Google Scholar]
  2. a Zheng C.; You S.-L. Catalytic Asymmetric Dearomatization by Transition-Metal Catalysis: A Method for Transformations of Aromatic Compounds. Chem. 2016, 1, 830–857. 10.1016/j.chempr.2016.11.005. [DOI] [Google Scholar]; b Wang Z. Palladium-catalyzed asymmetric dearomative cyclization in natural product synthesis. Org. Biomol. Chem. 2020, 18, 4354–4370. 10.1039/D0OB00818D. [DOI] [PubMed] [Google Scholar]
  3. Morgan J.; Pinhey J. T. Mechanism of arylation of nucleophiles by aryllead triacetates. Part 1. Exclusion of a pathway involving aryl free radicals. J. Chem. Soc., Perkin Trans. 1 1993, 1673–1676. 10.1039/p19930001673. [DOI] [Google Scholar]
  4. a Barton D. H. R.; Blazejewski J.-C.; Charpiot B.; Lester D. J.; Motherwell W. B.; Papoula M. T. B. Comparative arylation reactions with pentaphenylbismuth and with triphenylbismuth carbonate. J. Chem. Soc., Chem. Commun. 1980, 827–829. 10.1039/c39800000827. [DOI] [Google Scholar]; b Barton D. H. R.; Yadav-Bhatnagar N.; Finet J.-P.; Khamsi J.; Motherwell W. B.; Stanforth S. P. The chemistry of pentavalent organobismuth reagents: Part X. Studies on the phenylation and oxidation of phenols. Tetrahedron 1987, 43, 323–332. 10.1016/S0040-4020(01)89960-9. [DOI] [Google Scholar]; c Finet J. P. Arylation reactions with organobismuth reagents. Chem. Rev. 1989, 89, 1487–1501. 10.1021/cr00097a005. [DOI] [Google Scholar]; d Senior A.; Ruffell K.; Ball L. T. meta-Selective C–H arylation of phenols via regiodiversion of electrophilic aromatic substitution. Nat. Chem. 2023, 15, 386–394. 10.1038/s41557-022-01101-0. [DOI] [PubMed] [Google Scholar]
  5. Ozanne-Beaudenon A.; Quideau S. Regioselective Hypervalent-Iodine(III)-Mediated Dearomatizing Phenylation of Phenols through Direct Ligand Coupling. Angew. Chem., Int. Ed. 2005, 44, 7065–7069. 10.1002/anie.200501638. [DOI] [PubMed] [Google Scholar]
  6. Rousseaux S.; García-Fortanet J.; Del Aguila Sanchez M. A.; Buchwald S. L. Palladium(0)-Catalyzed Arylative Dearomatization of Phenols. J. Am. Chem. Soc. 2011, 133, 9282–9285. 10.1021/ja203644q. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. a Xu R.-Q.; Gu Q.; Wu W.-T.; Zhao Z.-A.; You S.-L. Construction of Erythrinane Skeleton via Pd(0)-Catalyzed Intramolecular Dearomatization of para-Aminophenols. J. Am. Chem. Soc. 2014, 136, 15469–15472. 10.1021/ja508645j. [DOI] [PubMed] [Google Scholar]; b Xu R.-Q.; Yang P.; Zheng C.; You S.-L. Pd-Catalyzed Asymmetric Intramolecular Arylative Dearomatization of para-Aminophenols. Chin. J. Chem. 2020, 38, 683–689. 10.1002/cjoc.202000109. [DOI] [Google Scholar]
  8. a Du K.; Guo P.; Chen Y.; Cao Z.; Wang Z.; Tang W. Enantioselective Palladium-Catalyzed Dearomative Cyclization for the Efficient Synthesis of Terpenes and Steroids. Angew. Chem., Int. Ed. 2015, 54, 3033–3037. 10.1002/anie.201411817. [DOI] [PubMed] [Google Scholar]; b Cao Z.; Du K.; Liu J.; Tang W. Synthesis of triptoquinone H and its C-5 epimer via efficient asymmetric dearomative cyclization. Tetrahedron 2016, 72, 1782–1786. 10.1016/j.tet.2016.02.043. [DOI] [Google Scholar]; c Du K.; Yang H.; Guo P.; Feng L.; Xu G.; Zhou Q.; Chung L. W.; Tang W. Efficient syntheses of (−)-crinine and (−)-aspidospermidine, and the formal synthesis of (−)-minfiensine by enantioselective intramolecular dearomative cyclization. Chem. Sci. 2017, 8, 6247–6256. 10.1039/C7SC01859B. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Mu X.; Yu H.; Peng H.; Xiong W.; Wu T.; Tang W. Construction of Various Bridged Polycyclic Skeletons by Palladium-Catalyzed Dearomatization. Angew. Chem., Int. Ed. 2020, 59, 8143–8147. 10.1002/anie.202000953. [DOI] [PubMed] [Google Scholar]; e Sun J.; Chen Y.; Ragab S. S.; Gu W.; Tang Z.; Tang Y.; Tang W. Total Syntheses of Polyhydroxylated Steroids by an Unsaturation-Functionalization Strategy. Angew. Chem., Int. Ed. 2023, 62, e202303639 10.1002/anie.202303639. [DOI] [PubMed] [Google Scholar]
  9. For leading examples of Pd-catalyzed arylative naphthol dearomatization, see;; a Xu R.-Q.; Yang P.; Tu H.-F.; Wang S.-G.; You S.-L. Palladium(0)-Catalyzed Intermolecular Arylative Dearomatization of β-Naphthols. Angew. Chem., Int. Ed. 2016, 55, 15137–15141. 10.1002/anie.201608724. [DOI] [PubMed] [Google Scholar]; b Xu R.-Q.; Gu Q.; You S.-L. Construction of the Benzomesembrine Skeleton: Palladium(0)-Catalyzed Intermolecular Arylative Dearomatization of α-Naphthols and Subsequent Aza-Michael Reaction. Angew. Chem., Int. Ed. 2017, 56, 7252–7256. 10.1002/anie.201703674. [DOI] [PubMed] [Google Scholar]; c Xu R.-Q.; Yang P.; You S.-L. Pd(0)-Catalyzed intramolecular arylative dearomatization of β-naphthols. Chem. Commun. 2017, 53, 7553–7556. 10.1039/C7CC04022A. [DOI] [PubMed] [Google Scholar]; d Zhao G.; Xu G.; Qian C.; Tang W. Efficient Enantioselective Syntheses of (+)-Dalesconol A and B. J. Am. Chem. Soc. 2017, 139, 3360–3363. 10.1021/jacs.7b00783. [DOI] [PubMed] [Google Scholar]
  10. Xu P.-W.; Yu J.-S.; Chen C.; Cao Z.-Y.; Zhou F.; Zhou J. Catalytic Enantioselective Construction of Spiro Quaternary Carbon Stereocenters. ACS Catal. 2019, 9, 1820–1882. 10.1021/acscatal.8b03694. [DOI] [Google Scholar]
  11. Pearce-Higgins R.; Hogenhout L. N.; Docherty P. J.; Whalley D. M.; Chuentragool P.; Lee N.; Lam N. Y. S.; McGuire T. M.; Valette D.; Phipps R. J. An Enantioselective Suzuki–Miyaura Coupling To Form Axially Chiral Biphenols. J. Am. Chem. Soc. 2022, 144, 15026–15032. 10.1021/jacs.2c06529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. a Anderson K. W.; Buchwald S. L. General Catalysts for the Suzuki–Miyaura and Sonogashira Coupling Reactions of Aryl Chlorides and for the Coupling of Challenging Substrate Combinations in Water. Angew. Chem., Int. Ed. 2005, 44, 6173–6177. 10.1002/anie.200502017. [DOI] [PubMed] [Google Scholar]; b Rodriguez J.; Dhanjee H. H.; Buchwald S. L. Amphiphilic Biaryl Monophosphine Ligands by Regioselective Sulfonation. Org. Lett. 2021, 23, 777–780. 10.1021/acs.orglett.0c04001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. a Golding W. A.; Pearce-Higgins R.; Phipps R. J. Site-Selective Cross-Coupling of Remote Chlorides Enabled by Electrostatically Directed Palladium Catalysis. J. Am. Chem. Soc. 2018, 140, 13570–13574. 10.1021/jacs.8b08686. [DOI] [PubMed] [Google Scholar]; b Golding W. A.; Phipps R. J. Electrostatically-directed Pd-catalysis in combination with C–H activation: site-selective coupling of remote chlorides with fluoroarenes and fluoroheteroarenes. Chem. Sci. 2020, 11, 3022–3027. 10.1039/D0SC00105H. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Golding W. A.; Schmitt H. L.; Phipps R. J. Systematic Variation of Ligand and Cation Parameters Enables Site-Selective C–C and C–N Cross-Coupling of Multiply Chlorinated Arenes through Substrate–Ligand Electrostatic Interactions. J. Am. Chem. Soc. 2020, 142, 21891–21898. 10.1021/jacs.0c11056. [DOI] [PubMed] [Google Scholar]
  14. For recent work from the Zhu group applying this concept, see:; a Lou Y.; Wei J.; Li M.; Zhu Y. Distal Ionic Substrate–Catalyst Interactions Enable Long-Range Stereocontrol: Access to Remote Quaternary Stereocenters through a Desymmetrizing Suzuki–Miyaura Reaction. J. Am. Chem. Soc. 2022, 144, 123–129. 10.1021/jacs.1c12345. [DOI] [PMC free article] [PubMed] [Google Scholar]; b On I. K. W.; Hong W.; Zhu Y. Crossing the ortho-hurdle: Ionic stereocontrol enables atroposelective Suzuki-Miyaura coupling. Chem. Catalysis 2023, 3, 100523. 10.1016/j.checat.2023.100523. [DOI] [Google Scholar]; c Wei J.; Gandon V.; Zhu Y. Amino Acid-Derived Ionic Chiral Catalysts Enable Desymmetrizing Cross-Coupling to Remote Acyclic Quaternary Stereocenters. J. Am. Chem. Soc. 2023, 145, 16796–16811. 10.1021/jacs.3c04877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Reductive elimination has also been suggested to be selectivity determining for some substrate types; for example, see ref (8a).
  16. Fanourakis A.; Docherty P. J.; Chuentragool P.; Phipps R. J. Recent Developments in Enantioselective Transition Metal Catalysis Featuring Attractive Noncovalent Interactions between Ligand and Substrate. ACS Catal. 2020, 10, 10672–10714. 10.1021/acscatal.0c02957. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Previous work from Buchwald has used water to assist in the formation of the active Pd(0) catalyst from Pd(OAc)2:; Fors B. P.; Krattiger P.; Strieter E.; Buchwald S. L. Water-Mediated Catalyst Preactivation: An Efficient Protocol for C–N Cross-Coupling Reactions. Org. Lett. 2008, 10, 3505–3508. 10.1021/ol801285g. [DOI] [PMC free article] [PubMed] [Google Scholar]; However, several reports have also found water to have a beneficial effect on reproducibility and enantioselectivity in closely related transformations, even when a Pd(0) precatalyst is used. For examples, see ref (6) and the following:Wu T.; Kang X.; Bai H.; Xiong W.; Xu G.; Tang W. Enantioselective Construction of Spiro Quaternary Carbon Stereocenters via Pd-Catalyzed Intramolecular α-Arylation. Org. Lett. 2020, 22, 4602–4607. 10.1021/acs.orglett.0c01129. [DOI] [PubMed] [Google Scholar]
  18. For further optimization details, see the Supporting Information.
  19. A meta-chloro-substituted phenol gave only traces of product. See the Supporting Information for details of this and several other unsuccessful substrates.
  20. Liu X.-T.; Schwan W. R.; Volk T. J.; Rott M.; Liu M.; Huang P.; Liu Z.; Wang Y.; Zitomer N. C.; Sleger C.; Hartsel S.; Monte A.; Zhang L. Antibacterial Spirobisnaphthalenes from the North American Cup Fungus Urnula craterium. J. Nat. Prod. 2012, 75, 1534–1538. 10.1021/np300221a. [DOI] [PubMed] [Google Scholar]
  21. Liu J.-S.; Li L.; Yu H.-G. Kadsulignan A and B, two novel lignans from Kadsuracoccinea. Can. J. Chem. 1 1989, 67, 682–684. 10.1139/v89-103. [DOI] [Google Scholar]
  22. Wongsa N.; Kanokmedhakul S.; Kanokmedhakul K.; Kongsaeree P.; Prabpai S.; Pyne S. G. Parviflorals A–F, trinorcadalenes and bis-trinorcadalenes from the roots of Decaschistia parviflora. Phytochemistry 2013, 95, 368–374. 10.1016/j.phytochem.2013.07.017. [DOI] [PubMed] [Google Scholar]
  23. We dispensed with the water cosolvent for these experiments to avoid complicating effects arising from potential phase-transfer processes.
  24. Gokel G. W.; Leevy W. M.; Weber M. E. Crown Ethers: Sensors for Ions and Molecular Scaffolds for Materials and Biological Models. Chem. Rev. 2004, 104, 2723–2750. 10.1021/cr020080k. [DOI] [PubMed] [Google Scholar]
  25. Qiao Y.; Bai S.; Wu X.-F.; Yang Y.; Meng H.; Ming J. Rhodium-Catalyzed Desymmetric Arylation of γ,γ-Disubsituted Cyclohexadienones: Asymmetric Synthesis of Chiral All-Carbon Quaternary Centers. Org. Lett. 2022, 24, 1556–1560. 10.1021/acs.orglett.2c00225. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ja3c10663_si_001.pdf (17.2MB, pdf)

Articles from Journal of the American Chemical Society are provided here courtesy of American Chemical Society

RESOURCES