Atroposelective desymmetrization of 2-arylresorcinols via tsuji-trost allylation

ABSTRACT Palladium-catalyzed asymmetric allylic alkylation has proven to be a powerful method for the preparation of a wide variety of chiral molecules. However, the catalytic and

atroposelective allylic alkylation is still rare and challenging, especially for biaryl substrates. Herein, we report the palladium-catalyzed desymmetric and atroposelective allylation, in

which the palladium complex with a chiral phosphoramidite ligand enables desymmetrization of nucleophilic 2-arylresorcinols in a highly enantioselective manner. With the aid of the secondary

kinetic resolution effect, a wide variety of substrates containing a hydroxymethyl group at the bottom aromatic ring are able to provide _O_-allylated products up to 98:2 er. Computational

studies show an accessible quadrant of the allylpalladium complex and provide three plausible transition states with intra- or intermolecular hydrogen bonding. The energetically favorable

transition state is in good agreement with the observed enantioselectivity and suggests that the catalytic reaction would proceed with an intramolecular hydrogen bond. SIMILAR CONTENT BEING

VIEWED BY OTHERS PALLADIUM-CATALYSED BRANCH- AND ENANTIOSELECTIVE ALLYLIC C–H ALKYLATION OF Α-ALKENES Article 30 May 2022 MECHANISTIC STUDY ON THE SIDE ARM EFFECT IN A

PALLADIUM/XU-PHOS-CATALYZED ENANTIOSELECTIVE ALKOXYALKENYLATION OF Γ-HYDROXYALKENES Article Open access 22 November 2023 COPPER-CATALYSED ASYMMETRIC ANNULATION OF YNE-ALLYLIC ESTERS WITH

AMINES TO ACCESS AXIALLY CHIRAL ARYLPYRROLES Article Open access 10 August 2024 INTRODUCTION The development of catalytic and enantioselective syntheses of axially chiral biaryls has been

extensively explored1,2,3,4,5,6,7 because it provides a highly efficient and selective route to access natural products8,9, biologically active compounds10,11,12, and chiral

catalysts13,14,15. Strategies to control a stereogenic axis are generally classified into several categories16,17,18,19,20,21,22,23, such as direct cross-coupling, dynamic kinetic

resolution, ring formation, and desymmetrization (Fig. 1a)24,25,26,27,28,29,30,31. As each strategy inherently possesses its own strengths and weaknesses, they are necessarily complementary

to each other depending on a target molecule. Thus, the diversification of methodologies employing various strategies is highly demanding to expand accessible axially chiral molecules. Among

the strategies, desymmetrization of configurationally stable and symmetric biaryls can provide an alternative and efficient way to approach axially chiral molecules (Fig. 

1b)32,33,34,35,36,37,38,39,40,41,42,43,44. However, compared to other strategies, a limited number of reactions have been reported, which represents the current cutting edge of this type of

reaction33,34,35,36,37,38,39,40,41,42,43,44. Palladium-catalyzed asymmetric allylic alkylation, also known as Tsuji-Trost allylation, is a powerful method to form a C–C bond or C–heteroatom

bond with high enantioselectivities45,46,47,48. In this reaction, a π-allyl-Pd complex with a chiral ligand is formed, in which a nucleophile generally approaches an allyl group in the

opposite direction of the Pd atom (Fig. 1c). In this regard, asymmetric reactions essentially have focused on the control of a stereogenic center that is newly generated on an allyl

group46,47,48, while investigation of the stereogenicity on a nucleophile is relatively underexplored49,50,51,52,53,54,55,56,57,58. When a hard nucleophile is employed, it can be bound to

the palladium center and then transferred to the allyl group (inner-sphere pathway). In this scenario, the orientation and conformation of a prochiral nucleophile should be limited and

affected by the chiral palladium complex49. However, a soft prochiral nucleophile directly attacks to the allyl group from the outside of the catalytic complex (outer-sphere pathway) which

should be challenging to develop new asymmetric methodology50. For these reasons, this type of reactions has restrictively been applied to control the stereogenic axis. For example,

nonbiaryl anilides were initially investigated by dynamic kinetic resolution (Fig. 1d) by Taguchi55 and Curran56 in the early 2000s. Even though the nucleophilic nitrogen atom itself

consists of the stereogenic axis, moderate enantioselectivities were observed. Further efforts have been made by Feng/Du57 and Kitagawa58 to enhance enantioselectivities around the C–N bond.

However, to the best of our knowledge, Pd-catalyzed allylic alkylation of a biaryl substrate has not been developed. Furthermore, this type of reaction has not been explored with

atroposelective desymmetrization despite its long and powerful history. At the outset of our work, we hypothesized that a chiral palladium complex could atroposelectively desymmetrize

symmetric biaryls by distinguishing two prochiral heteroatom nucleophiles. Given the previous literature46,47,48, the major challenge to realize atroposelective allylic alkylation probably

lies in (1) the opposite and remote arrangement of a chiral ligand with prochiral heteroatom nucleophiles and (2) the possible multiple orientations of the prochiral nucleophile when

intermolecularly approaching the allylpalladium complex. To overcome these challenges, we envisioned that a catalytic complex should provide an extensive chiral environment around the

π-allyl-Pd center to limit the orientation of the nucleophile. Furthermore, an additional functional group on the other side of the aromatic ring would be desirable to make favorable

interactions. Herein, we report a highly atroposelective Pd-catalyzed allylation, in which achiral 2-arylresorcinols are desymmetrized by distinguishing two symmetric phenolic hydroxyl

groups (Fig. 1e). RESULTS AND DISCUSSION REACTION OPTIMIZATIONS To test our hypothesis, we designed a substrate, 1A, containing resorcinol at the top and _ortho_-benzylalcohol at the bottom

(Table 1)34. We initially envisioned that the bottom hydroxyl group would form a desirable intra- or intermolecular hydrogen bond for the catalytic and enantioselective reaction. With methyl

cinnamyl carbonate (2A), preliminary chiral ligand screening was performed (Table 1, entries 1–4), in which desired product 3AA was obtained along with disubstituted product 4AA. Among the

tested ligands, phosphoramidite ligand59 (L4) was found to be the most effective at affording 3AA in 44% yield and 91:9 er (Table 1, entry 4 vs. entries 1–3). Based on the results from the

preliminary experiments, we performed a thorough investigation with a series of phosphoramidite ligands (L5–L13), as summarized in Table 1, entries 5–13. Interestingly, when the binaphthyl

group was substituted with a biphenyl group (L5), enantioselectivity was retained to a degree. This result suggested that the point chirality of the catalysts would play an important role in

the observed selectivity. However, further modifications of the ligands did not improve the enantioselectivities (Table 1, entries 6–13), which suggested that all component of L4 would

involve to generate enantioselective environment in good harmony with the allylpalladium complex. We were pleased to find that enantioselectivity was enhanced to 93:7 er, when the reaction

was performed at −20 °C (Table 1, entry 14). When the branched carbonate (2A′) was employed, the enantioselectivity slightly increased to 94:6 er (Table 1, entry 15). After the exhaustive

optimization of various reaction parameters (see Supplementary Table 1−5), we were able to establish the optimized reaction conditions (1.5 equiv of 2A′, 1 mol% of Pd(dba)2, 4 mol% of L4,

THF,−20 °C) to provide the desired product in 49% yield and 97:3 er (Table 1, entry 16). SUBSTRATE SCOPE Next, we explored the substrate scope under the optimized reaction conditions, as

summarized in Fig. 2 and Fig. 3 (for detailed procedures, NMR spectra and HPLC chromatograms, see Supplementary Methods and Supplementary Data 2 and 3). In general, the modifications of

bottom aromatic ring in 2-arylresorcinols are highly tolerable to give the desired products with high atroposelectivity (Fig. 2). The reaction of the substrate (1B) bearing a methyl group

afforded the desired product (3BA) with 95:5 er. The substrate containing 1,3-dioxolane was reacted with 2A′ to provide the allylated product (3CA) with 94:6 er. The introductions of

electron-donating groups such as methyl and methoxy group at the _para_-position of the stereogenic axis were tolerable to afford 3DA with 95:5 er and 3EA with 92:8 er, respectively. When

the reactions were performed with the substrates substituted with electron-withdrawing groups, the desired product were obtained in good enantioselectivity (3FA, 91:9 er; 3GA, 92:8 er; 3HA,

88:12 er), albeit with slightly lower yield. However, the substrates that were substituted at the _para_ position of the hydroxymethyl group showed lower selectivities (3IA, 80:20 er; 3JA,

84:16 er), presumably due to the unfavorable interactions between the substituent and catalytic complex. It was observed that the substitution at the _ortho_ position to the stereogenic axis

was tolerable to give the desired product (3KA) in 94:6 er. Notably, substrates (1L−1P) containing different functional groups instead of the hydroxymethyl group at the bottom aromatic ring

were found to be tolerable to a degree. For example, the substrate containing a methoxymethyl or 2-hydroxyisopropyl group was reacted in the optimized reaction conditions to give the

allylated products (3HA or 3IA) in 88:12 er. Also, the reactions of the substrates with a methyl, isopropyl, or phenyl group provided the desired products with good enantioselectivity (3NA,

methyl-, 83:17 er; 3OA, isopropyl-, 85:15 er; 3PA, phenyl-, 87:13 er). These results suggest that the observed enantioselectivity would originate from repulsive interactions between the

catalytic complex and substrate, and the hydroxyl group in 1A would facilitate the asymmetric transformation. Next, further modifications on the top aromatic ring and allyl carbonate were

performed, which showed high compatibility of our methodology (Fig. 3). When substrates were substituted with a methyl or bromide at the top aromatic ring, they provided 3QA with 98:2 er and

3RA with 91:9 er, respectively. The reaction of 1A with 2B and 2C in which the cinnamyl group was substituted with a methyl or bromide group provided the desired products with 96:4 er.

While thiophene and furan instead of the phenyl group of 2A′ were tolerable to afford 3AD in 96:4 er and 3AE in 91:9 er, the reaction with naphthalene-substituted carbonates (2F) gave lower

enantioselectivity (76:24 er). The nonsubstituted allyl carbonate (2G) was found not to be compatible with our methodology. The absolute configuration of 3EA was determined by X-ray

crystallography (see Supplementary Data 1, Supplementary Fig. 1, and Supplementary Table 6−13). REACTION PROFILE AND SECONDARY KINETIC RESOLUTION EFFECTS Because difunctionalized products

can be formed in desymmetrization, the moderate chemical yields of monofunctionalized products have been observed despite high overall yields38. Furthermore, because the formation of

difunctionalized products is related to secondary kinetic resolution effect, careful investigations are required. To explore this issue more aggressively, the changes in 3AA and 4AA were

examined in the reaction mixture (Fig. 4a). Interestingly, the desired product was quickly formed within 15 min, and the total amount of 3AA was mostly unchanged. Instead, the amount of the

diallylated product (4AA) and enantioselectivity of 3AA increased until 45 min. This result suggests that the substrate (1A) and monosubstituted product (3AA) are allylated at a similar

rate, and favorable secondary kinetic resolution is involved. Indeed, when the racemic mixture of 3AA was reacted with 0.7 equiv of 2A′ under the optimized reaction conditions, the same

atropisomer of 3AA remained at 78:22 er (Fig. 4b). Because the fast initial rate could lead to an uncontrolled reaction in terms of product distribution and selectivity, we tried several

milder reaction conditions, including lower concentrations, catalytic loading, and temperature, to decrease the reaction rate. However, these efforts were found to be unfruitful (see

Supplementary Table 1−5). KINETIC RESOLUTION AND FURTHER TRANSFORMATION Inspired by secondary kinetic resolution effect, we envisioned atroposelective kinetic resolution of mono-substituted

biaryls (Fig. 4c). Two racemic mixtures of 3S and 3AG substituted with a methyl or allyl group, respectively, were reacted with 0.5 equiv of 2A′ under the optimized reaction conditions to

give chiral difunctionalized products with moderate enantioselectivities (4SA, 39% yield, 82:18 er; 4AG′, 33% yield, 76:24 er). In these reactions, the substrates were recovered in

non-racemic, but lower enantioselectivities (3 S, 52% yield, 63:37 er; 3AG, 58% yield, 62:38 er). These results suggest that atroposelective kinetic resolution would be feasible based on

asymmetric Tsuji-Trost reaction. In order to demonstrate the practicality of our method, the monofunctionalized product was further transformed. Even though the hydroxyl group at the bottom

aromatic ring is required to achieve high atroposelectivity in this reaction, this hydroxyl group can be easily transformed to other functionalities which would be additional advantage of

our methodology (Fig. 4d). Because the phenolic OH is highly reactive, selective methylation was initially conducted to provide the methylated product (4SA) in 73% yield and 96:4 er. Then,

the hydroxyl group at the bottom aromatic ring was brominated to afford 5 in 94% yield and 95:5 er, which could be converted to many different functional groups. For example, the bromomethyl

compound was reduced with LiAlH4 to give 6 in 95:5 er and underwent a substitution reaction with NaN3 to furnish 7 without loss of enantioselectivity. We believe that the azide 7 can be

further transformed to a variety of atropisomeric amine compounds. COMPUTATIONAL STUDIES To investigate the configurational stability of the products, we conducted computational calculations

on the rotational barriers of 1A, 3AA, 3KA, and 3NA as shown in Fig. 5a (See Supplementary Table 14−17 in Supplementary Data 4)60. Geometries/frequencies were computed at the

B3LYP/6-31+G(d,p) level of theory, and the single point energies were calculated at the M06-2X/6-311++G(2d,3p) level of theory. In our calculations, the substrate and allylated products were

expected to have a sufficiently high rotational barrier to lock their stereo-configurations at the reaction temperature. In particular, 3KA, which contained another substituent at the

_ortho_ position to the stereogenic axis, showed a much higher rotational barrier (43.8 kcal/mol). To further elucidate the origin of the observed enantioselectivity, we conducted

preliminary computational studies on this transformation (See Supplementary Table 18 in Supplementary Data 4)60. Because of the bulky chiral ligand, the two-layer quantum-mechanical

(QM)/semiempirical (SE) ONIOM model61,62,63 was applied to the palladium complexes. Heteroatoms in ligands, palladium atom, cinnamyl group, and 1A were designated to the QM layer which was

treated with B3LYP/6-31G(d) (C, H, O, N, P)/LANL2DZ (ECP Pd). All carbon and hydrogen atoms in ligands were designated to the SE layer which was treated with PM6 (Fig. 5b). Single-point

energies of these optimized structures were calculated using M06-2X/6-311++G(2d,3p) (C, H, O, N, P)/SDD (ECP Pd) for the QM layer and PM6 for the SE layer with the inclusion of solvation

energy corrections (SMD, tetrahydrofuran). Based on the optimized geometry of the π-allyl palladium complex (AllylPd(L4)(THF)), the steric effects of the ligands were quantitatively assessed

using the steric map produced by the SambVca 2.1 tool64. The results clearly showed an accessible quadrant between the BINOL of L4 and the cinnamyl group (Fig. 5c). With two enantiomers of

anionic 1A, possible transition states (TS1, TS2, and TS3) were obtained (Fig. 5d and Fig. 5e). In our calculations, TS1, which can afford the observed enantiomer, is more energetically

favorable than TS2 by 2.5 kcal/mol. In TS2, the bottom aromatic ring of 2-arylresorcinol pointed to the binaphthyl group in L4, which would make a slight turn clockwise around the Pd-P bond.

We believe that this inevitable turn would cause unfavorable steric interaction (indicated as red lines in Fig. 5d) between the cinnamyl group and the phenyl group of L4. The noncovalent

interaction (NCI) plots also showed this unfavorable interaction in TS2 (See Supplementary Figure 2 in Supplementary Data 4)65. Additionally, these results suggested that the intramolecular

hydrogen bond would stabilize the partially eclipsed conformation of 2-arylresorcinol in TS1 and TS2. This effect would further improve enantioselectivity of 3AA up to 98:2 er, compared to

that of the non-hydroxymethyl substrates such as 3LA, 3NA−3PA. Interestingly, because the _para_ position to the hydroxymethyl group oriented to the ligands in TS1, the substitution at this

position could lead to unfavorable steric repulsion, which was in agreement with the observed result in 3IA and 3JA. Because the hydroxymethyl group could form an intermolecular hydrogen

bond with the BINOL group of L4, the inductive model (TS3) was considered. However, this transition state (TS3) was energetically unfavorable by 5.7 kcal/mol compared to TS1 (Fig. 5e).

CONCLUSION In conclusion, an efficient strategy for the highly atroposelective palladium-catalyzed desymmetrization of 2-arylresorcinols has been established. The chiral palladium complex

with a phosphoramidite ligand smoothly induces the desymmetric allylic _O_-alkylation reaction with excellent enantioselectivities up to 98:2 er. Our calculations reveal that the

hydroxymethyl group at the bottom aromatic ring forms an intramolecular hydrogen bond and facilitates the catalytic reaction. The transition states of this transformation have been obtained

by computational calculations, which have provided insight into the origin of enantioselectivity. Given the importance of catalytic and atroposelective reactions, this unique and efficient

methodology will encourage further efforts in this field. METHODS GENERAL PROCEDURE FOR ATROPOSELECTIVE ALLYLATION In an oven dried reaction tube equipped with a magnetic stirring bar, were

premixed Pd(dba)2 (0.6 mg, 0.001 mmol, 0.01 equiv), L4 (2.2 mg, 0.004 mmol, 0.04 equiv), and THF (0.2 mL). After 10 min, 2 (0.15 mmol, 1.5 equiv) in THF (0.3 mL) was added, and the mixture

was stirred for 10 min. Then, 1 (0.10 mmol, 1 equiv) was added and the vial was sealed with a Teflon cap and further secured with Parafilm MⓇ. The reaction mixture was left to stir for

10–240 h at –20 °C. After that, the crude material was purified by flash column chromatography using an eluent of 9–33% EtOAc/Hx to provide the desired product 3. The enantioselectivity was

determined by chiral HPLC. DATA AVAILABILITY Detailed experimental procedures and characterizations of new compounds are available in Supplementary Information. The X-ray crystallographic

coordinates for structures reported in this Article have been provided as Supplementary Data 1 and deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers

CCDC 701796. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif. 1H and 13C NMR spectra and HPLC

chromatograms can be found in the Supplementary Data 2 and 3, respectively. Computational chemistry details are available in Supplementary Data 4. Reprints and permissions information is

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Multiwfn: A multifunctional wavefunction analyzer. _J. Comput. Chem._ 33, 580–592 (2012). Article  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS This work is supported by the

National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2020R1C1C1006231, 2022R1A4A1018930, and 2022M3E5F2017857). This work is also supported by the

National Supercomputing Center with supercomputing resources including technical support (KSC-2022-CRE-0288). AUTHOR INFORMATION Author notes * These authors contributed equally: Sangji Kim,

Aram Kim. AUTHORS AND AFFILIATIONS * School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea Sangji Kim, Chanhee Lee, Junsoo Moon & Yongseok Kwon * Department of

Chemistry, Sogang University, Seoul, 04107, Republic of Korea Aram Kim, Eun Jeong Hong & Duck-Hyung Lee Authors * Sangji Kim View author publications You can also search for this author

inPubMed Google Scholar * Aram Kim View author publications You can also search for this author inPubMed Google Scholar * Chanhee Lee View author publications You can also search for this

author inPubMed Google Scholar * Junsoo Moon View author publications You can also search for this author inPubMed Google Scholar * Eun Jeong Hong View author publications You can also

search for this author inPubMed Google Scholar * Duck-Hyung Lee View author publications You can also search for this author inPubMed Google Scholar * Yongseok Kwon View author publications

You can also search for this author inPubMed Google Scholar CONTRIBUTIONS S.K., A.K., C.L., J.M., E.J.H., D.-H.L., and Y.K. conceived and designed the experiments. S.K., A.K., and E.J.H.

performed the chemical experiments. S.K., C.L., J.M., and Y.K. performed the computational studies. S.K. and Y.K. wrote the paper. All authors analyzed the results and commented on the

manuscript. CORRESPONDING AUTHOR Correspondence to Yongseok Kwon. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. PEER REVIEW PEER REVIEW INFORMATION

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2-arylresorcinols via Tsuji-Trost allylation. _Commun Chem_ 6, 42 (2023). https://doi.org/10.1038/s42004-023-00839-z Download citation * Received: 14 September 2022 * Accepted: 13 February

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