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. 2024 Apr 23;2(5):208–220. doi: 10.1021/prechem.4c00008

Catalytic Asymmetric Diastereodivergent Synthesis of 2-Alkenylindoles Bearing both Axial and Central Chirality

Shuang Yang †, Jia-Bo Huang ‡, Da-Hua Wang §, Ning-Yi Wang †, Yu-Yu Chen †, Xin-Yan Ke ‡, Hao Chen †, Shao-Fei Ni ‡,*, Yu-Chen Zhang †,*, Feng Shi †,∥,*
PMCID: PMC11504580  PMID: 39474410

Abstract

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The catalytic asymmetric diastereodivergent synthesis of axially chiral 2-alkenylindoles was established via chiral phosphoric acid-catalyzed addition reactions of C3-unsubstituted 2-alkenylindoles with o-hydroxybenzyl alcohols under different reaction conditions. Using this strategy, two series of 2-alkenylindoles bearing both axial and central chirality were synthesized in a diastereodivergent fashion with moderate to high yields and good stereoselectivities (up to 99% yield, 95:5 er, >95:5 dr). Moreover, theoretical calculations were performed on the key transition states leading to different stereoisomers, which provided an in-depth understanding of the origin of the observed stereoselectivity and diastereodivergence of the products under different reaction conditions. More importantly, these 2-alkenylindoles were utilized in asymmetric catalysis as chiral organocatalysts and in medicinal chemistry for evaluation of their cytotoxicity, which demonstrated their potential applications. This study has not only established the catalytic atroposelective synthesis of axially chiral 2-alkenylindoles, but also provided an efficient strategy for catalytic asymmetric diastereodivergent construction of indole-based scaffolds bearing both axial and central chirality.

Keywords: 2-Alkenylindole, Axial chirality, Central chirality, Diastereodivergent synthesis, Chiral phosphoric acid

Introduction

Chiral compounds bearing multiple stereogenic centers are widely found in pharmaceuticals and materials.1,2 The absolute and relative configurations of these compounds have an impact on their physiological or pharmacological properties.3,4 Therefore, developing efficient strategies to access all stereoisomers of chiral compounds bearing multiple stereocenters is crucial.

Catalytic asymmetric diastereodivergent reactions have recently been recognized as a class of powerful methods for synthesizing each stereoisomer of chiral compounds using the same set of starting materials by slightly modulating the reaction conditions.5−10 Thus, developing catalytic asymmetric diastereodivergent reactions has attracted intensive attention from the scientific community.11−28 Among them, catalytic asymmetric diastereodivergent reactions for the synthesis of chiral compounds bearing multiple central chirality have been well-developed (Scheme 1a).17−28 However, in stark contrast, catalytic asymmetric diastereodivergent reactions for the synthesis of chiral compounds bearing both axial and central chirality remain largely unexplored (Scheme 1b)29,30 in spite of the importance of atropisomers bearing multiple chiral elements.31 The challenges in realizing such diastereodivergent reactions mainly include: 1) simultaneously controlling the axial chirality and central chirality to achieve excellent diastereoselectivity and enantioselectivity; 2) finding suitable reaction conditions for diastereodivergent generation of two chiral elements. Therefore, it is highly desired to develop efficient strategies toward settling these challenges and realize catalytic asymmetric diastereodivergent reactions for the synthesis of chiral compounds bearing both axial and central chirality.

Scheme 1. Profile of Catalytic Asymmetric Diastereodivergent Reactions.

Scheme 1

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Axially chiral indole-based scaffolds, a class of unique axially chiral skeletons,31−45 are widely found in natural products,46−48 pharmaceutically relevant molecules,49−51 and chiral catalysts.52−55 Therefore, catalytic asymmetric construction of axially chiral indole-based scaffolds has become an emerging field.56,57 As shown in Scheme 2a, various elegant strategies have been developed for the enantioselective construction of axially chiral (hetero)arylindoles, such as five-six-membered axially chiral arylindoles49,58−103 and five-five-membered axially chiral (hetero)arylindoles.51,52,104−116 However, in sharp contrast, axially chiral alkenylindoles, more challenging axially chiral indole-based scaffolds,50,117−123 remain rarely studied except for a few examples on the synthesis of axially chiral 3-alkenylindoles117 and N-alkenylindoles118−123 (Scheme 2b). Despite this progress, catalytic atroposelective synthesis of axially chiral 2-alkenylindoles is still unknown due to the much lower rotational barrier of this class of molecules. Therefore, how to overcome the very weak configurational stability of axially chiral 2-alkenylindoles and to develop efficient strategies for constructing such skeletons in a catalytic asymmetric manner remain challenging.

Scheme 2. Profile of Catalytic Atroposelective Construction of Axially Chiral Indole-Based Scaffolds.

Scheme 2

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To overcome the challenges in developing catalytic asymmetric diastereodivergent reactions for the synthesis of chiral compounds bearing both axial and central chirality, and to construct axially chiral 2-alkenylindole skeletons, we proposed the concept of our strategy as designing new platform molecules for diastereodivergent synthesis of 2-alkenylindoles bearing both axial and central chirality. As shown in Scheme 3a, C3-unsubstituted 2-alkenylindoles were designed as indole-based platform molecules. The structural features of C3-unsubstituted 2-alkenylindoles mainly include: (1) the unsubstituted C3-position of the indole ring could not only act as a nucleophilic site, but also make the indole ring and the alkenyl group be able to rotate freely around the axis and result in rapid racemization; (2) the bulky cyclohexyl group and the N-substituent could serve as steric groups to generate rotational restriction for the products and increase the configurational stability of the products; (3) this kind of C3-unsubstituted 2-alkenylindoles could be easily synthesized from the corresponding 2-indolylmethanols124−126 via dehydration. These structural features enable C3-unsubstituted 2-alkenylindoles to undergo catalytic asymmetric diastereodivergent addition reactions with bulky electrophiles bearing a prochiral center under different reaction conditions, thus leading to the generation of two series of 2-alkenylindoles bearing both axial and central chirality in a diastereodivergent manner. Although this strategy seems feasible, there are still some challenging issues to be solved, such as finding suitable bulky electrophiles bearing a prochiral center and selecting suitable chiral catalysts to control the reactivity and the stereoselectivity.

Scheme 3. Our Strategy for Catalytic Asymmetric Diastereodivergent Synthesis of 2-Alkenylindoles Bearing Both Axial and Central Chirality.

Scheme 3

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To address these issues, based on our long-lasting efforts in chiral indole chemistry,127−130 we designed a chiral phosphoric acid (CPA)-catalyzed asymmetric diastereodivergent addition reaction of C3-unsubstituted 2-alkenylindoles 1 with o-hydroxybenzyl alcohols 2 (Scheme 3b). In this design, the selection of o-hydroxybenzyl alcohols as suitable bulky electrophiles bearing prochiral center is based on that o-hydroxybenzyl alcohols can be converted into highly reactive o-quinone methides (o-QMs) in the presence of Brønsted acids and generate a new chiral center by the addition reaction.131−133 CPA was selected as a suitable chiral catalyst due to its ability to activate o-hydroxybenzyl alcohols, thus simultaneously controlling both the axial chirality and central chirality of products 3 and 4.134−141 Therefore, the significance of this study lies in that it will not only establish the first catalytic atroposelective synthesis of axially chiral 2-alkenylindoles, but also provide a new strategy for diastereodivergent construction of indole-based scaffolds bearing both axial and central chirality. Moreover, the in-depth investigations on the reaction pathways and potential applications of the products will be carried out.

Results and Discussion

To verify the feasibility of our design, the reaction of C3-unsubstituted 2-alkenylindole 1a with o-hydroxybenzyl alcohol 2a was conducted (Scheme 4). As anticipated, this addition reaction occurred under the catalysis of CPA (R)-5a in 1,2-dichloroethane (DCE) at 20 °C and delivered axially chiral 2-alkenylindoles 3aa and 4aa in high total yields albeit with low enantioselectivity and moderate diastereoselectivity (80% yield, 3aa: 53:47 er, 4aa: 64:36 er, 18:82 dr). To realize asymmetric diastereodivergent addition reaction, various reaction parameters such as catalysts, solvents, additives, reagents ratio, reaction temperature, and catalyst loading were screened (see the Supporting Information for details). Finally, product 3aa was obtained as the major diastereomer in a moderate yield of 52% with a high enantioselectivity of 92:8 er and an excellent diastereoselectivity of 95:5 dr under the optimal conditions A (1a:2a = 3:1, 20 mol % (S)-7a, DCE, 36 h, 3 Å MS, 0 °C). On the other hand, product 4aa could be obtained as the major diastereomer in an excellent yield of 99% with a high enantioselectivity of 93:7 er and a good diastereoselectivity of 92:8 dr under the optimal conditions B (1a:2a = 2:1, 10 mol % (S)-7b, p-xylene, 12 h, 4 Å MS, 20 °C).

Scheme 4. Catalysts and Model Reaction Employed for Condition Optimization.

Scheme 4

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After establishing the optimal reaction conditions, we investigated the substrate scope of this catalytic asymmetric diastereodivergent addition reaction. First, the substrate scope for atroposelective synthesis of 2-alkenylindoles 3 as the major diastereomers bearing both axial and central chirality was examined under optimal conditions A. As shown in Table 1, a series of o-hydroxybenzyl alcohols 2a–2k bearing various R2/R3 groups were successfully employed to generate chiral 2-alkenylindoles 3ab–3ak in moderate to good yields (up to 88%) with high enantioselectivities (up to 93:7 er) and diastereoselectivities (up to 95:5 dr). For C3-unsubstituted 2-alkenylindoles 1, substrates 1b–1d with different R groups on the C5-position of the indole ring were suitable reactants for this addition reaction to produce chiral 2-alkenylindoles 3ba–3da in moderate yields (up to 55%) with good enantioselectivities (up to 92:8 er) and diastereoselectivities (up to 91:9 dr). Besides, N-benzyl substituted 2-alkenylindole 1e could participate in the reaction to afford chiral 2-alkenylindole 3ei in a moderate yield (44%) with a high enantioselectivity (91:9 er) and a moderate diastereoselectivity (75:25 dr).

Table 1. Substrate Scope for Atroposelective Synthesis of Chiral 2-Alkenylindoles 3a.

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a

Reaction conditions: 1 (0.3 mmol), 2 (0.1 mmol), (S)-7a (20 mol %), 3 Å MS (100 mg), DCE (2 mL), 0 °C for 36 h. Isolated yields were provided, the er value was determined by HPLC and the dr value (3:4) was determined by 1H NMR. The absolute configuration of 3aa was determined as (Ra,S) via single-crystal X-ray diffraction analysis (see the Supporting Information for details).142

b

4 mL of DCE was used.

c

1 mL of DCE was used.

d

Catalyzed by 30 mol % (S)-7a for 48 h.

e

Using 5 Å MS (100 mg) as additives.

f

Catalyzed by 20 mol % (S)-5i.

To investigate the generality of this strategy for atroposelective synthesis of chiral 2-alkenylindoles 4 as the major diastereomers bearing both axial and central chirality, a wide scope of C3-unsubstituted 2-alkenylindoles 1 with different R/R1 groups and o-hydroxybenzyl alcohols 2 bearing various R2/R3 groups were employed as substrates under optimal conditions B. As shown in Table 2, a variety of 2-alkenylindoles 4 bearing axial and central chirality were synthesized in good yields (up to 99%) with high enantioselectivities (up to 95:5 er) and moderate to excellent diastereoselectivities (up to >95:5 dr).

Table 2. Substrate Scope for Atroposelective Synthesis of Chiral 2-Alkenylindoles 4a.

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a

Reaction conditions: 1 (0.2 mmol), 2 (0.1 mmol), (S)-7b (10 mol %), 4 Å MS (100 mg), p-xylene (4 mL), 20 °C for 12 h. Isolated yields were provided, the er value was determined by HPLC and the dr value (4:3) was determined by 1H NMR. The structure of rac-4ak was confirmed by single-crystal X-ray diffraction analysis,142 and the absolute configuration of 4ak was determined to be (Ra, R) by comparison with a known chiral compound (see the Supporting Information for details).

b

Catalyzed by 10 mol % (S)-7c.

c

Catalyzed by 10 mol % (S)-7c at −30 °C in mesitylene for 24 h.

d

Catalyzed by 10 mol % (R)-6b.

e

Catalyzed by 20 mol % (R)-6b at 0 °C in mesitylene for 24 h, 1g:2a = 3:1.

Notably, cyclopentyl- and isopropyl-substituted 2-alkenylindoles 1f–1g successfully participated in this catalytic asymmetric diastereodivergent addition reaction to deliver axially chiral 2-alkenylindoles 3fa–3ga and 4fa–4ga, respectively, in acceptable yields with good to excellent enantioselectivities and diastereoselectivities.

Subsequently, we evaluated the stereodivergence of this catalytic asymmetric addition reaction. As shown in Scheme 5a, the addition reactions of 1a and 2a under conditions A or B in the presence of CPA 7a or 7b with different absolute configurations were carried out, which delivered four stereoisomers of 2-alkenylindoles 3aa and 4aa bearing both axial and central chirality in moderate to good yields with high enantioselectivities and diastereoselectivities, respectively. In addition, we investigated the configurational stability and rotational barriers of axially chiral 2-alkenylindoles 3aa and 4aa (Scheme 5b). Products 3aa and 4aa were stirred in i-PrOH at 100 °C for 5 h and recovered in high yields with retained enantioselectivities and diastereoselectivities. These results indicated that products 3aa and 4aa have high configurational stability. The rotational barriers of products 3aa and 4aa were theoretically calculated as 39.5 and 46.3 kcal mol–1, respectively, which were in accordance with the experimentally observed high configurational stability of these products.

Scheme 5. Demonstration of the Stereodivergence and Study on the Configurational Stability.

Scheme 5

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To demonstrate the utility of the reaction, we performed the synthesis of products 3aa and 4aa on 1 mmol scale (Scheme 6a). Compared with the small-scale reactions, these 1 mmol scale reactions smoothly afforded products 3aa and 4aa in similar yields with maintained high enantioselectivities and diastereoselectivities. Moreover, we further investigated the utility of this new class of 2-alkenylindoles bearing both axial and central chirality (Scheme 6b). For instance, product 4aa was transformed into the corresponding chiral phosphine ligand 9 bearing multiple chiral elements via a two-step reaction. The preliminary application of chiral ligand 9 was verified in a palladium-catalyzed enantioselective allylic alkylation reaction, which afforded chiral product 13 in a high yield of 92% with a good enantioselectivity of 87:13 er. Therefore, this result demonstrated the promising applications of this kind of 2-alkenylindole skeletons bearing both axial and central chirality in asymmetric catalysis.

Scheme 6. Synthesis (1 mmol Scale) and Application of Axially Chiral 2-Alkenylindoles in Asymmetric Catalysis.

Scheme 6

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To find the possible bioactivities of this class of chiral 2-alkenylindoles, a preliminary evaluation on the cytotoxicity of some selected products 3 and 4 was carried out (see the Supporting Information for details). As shown in Figure 1a, several products 3 and 4 exhibited some extent of cytotoxicity against HepG2 cancer cells, and the IC50 values were ranging from 20.0 to 50.4 μg/mL. Besides, the cytotoxicity of some selected products 3 and 4 against PC-3 cancer cells was also investigated (Figure 1b). Among them, product 3ac exhibited potent cytotoxicity against PC-3 cancer cells with a very low IC50 value of 16.7 μg/mL. These results indicated that this class of chiral 2-alkenylindoles might find their potential applications in medicinal chemistry.

Figure 1.

Figure 1

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Chiral 2-alkenylindoles 3 and 4 with promising anticancer activity

To elucidate the possible activation mode, we conducted some control experiments (Scheme 7a). When methyl-protected o-hydroxybenzyl alcohol 2n was allowed to react with C3-unsubstituted 2-alkenylindole 1a under standard conditions A and B, no reaction occurred. This indicated that the OH group in o-hydroxybenzyl alcohols played a crucial role in controlling the reactivity, possibly by forming hydrogen-bonding interactions with CPA. Based on the control experiments, we proposed a possible reaction pathway for this catalytic asymmetric diastereodivergent reaction. As shown in Scheme 7b, (Ra)-1a and (Sa)-1a were two enantiomers of racemic C3-unsubstituted 2-alkenylindole 1a, and the rotational barrier of 1a was calculated as 21.4 kcal mol–1, which verified our proposal that (Ra)-1a and (Sa)-1a could rapidly transform to each other, resulting in rapid racemization for the dynamic kinetic resolution (DKR) process. Under the activation of (S)-7a via hydrogen-bonding interaction (conditions A), a fast nucleophilic addition between (Ra)-1a and o-quinone methide (o-QM) (generated via dehydration of o-hydroxybenzyl alcohol 2a) occurred to give product (Ra,S)-3aa. When using (S)-7b as the catalyst (conditions B), diastereomer (Ra,R)-4aa was obtained, thus realizing the diastereodivergence process and the generation of two types of 2-alkenylindoles bearing both axial and central chirality. On the other hand, in the presence of CPA (S)-7a or (S)-7b, the nucleophilic addition of (Sa)-1a with o-QM was very slow and (Sa)-1a continuously transformed into (Ra)-1a via rapid racemization, resulting in the DKR process.

Scheme 7. Control Experiments and Proposed Reaction Pathway.

Scheme 7

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To explain the observed high enantioselectivity of products 3, 4 and the diastereodivergence of this addition reaction under different reaction conditions, we performed density functional theory (DFT) calculations on the key transition states leading to four possible stereoisomers in the catalytic asymmetric diastereodivergent reactions between 1a and 2a under the catalysis of different CPAs (S)-7a and (S)-7b, respectively (Figure 2). As shown in Figure 2a, the Gibbs free energy barrier of transition state (Ra,S)-TS1, leading to the formation of major product (Ra,S)-3aa, was calculated as 19.4 kcal·mol–1, which was the lowest energy barrier among the transition states leading to four possible stereoisomers under the catalysis of CPA (S)-7a (see Figure S4 in the Supporting Information for details). Notably, the C=O group in o-QM could form hydrogen-bonding interactions with CPA in (Ra,S)-TS1, demonstrating that the OH group in o-hydroxybenzyl alcohol 2a played a crucial role in controlling the reactivity, which was consistent with the control experiments.

Figure 2.

Figure 2

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Key transition states to explain the enantioselectivity and diastereodivergence of the products.

To explain the observed absolute configuration and good enantioselectivity of product (Ra,S)-3aa, we compared the key transition states (Ra,S)-TS1 and (Sa,R)-TS1, which ultimately led to the formation of two enantiomers of 3aa. The energy difference between (Ra,S)-TS1 and (Sa,R)-TS1 was calculated as 1.7 kcal mol–1, which was in accordance with the observed er value (92:8). Moreover, the origin of the energy difference leading to the observed enantioselectivity of 3aa was studied by energy decomposition analysis and noncovalent interaction (NCI) plots (see Figures S5 and S6 in the Supporting Information for details). Energy decomposition analysis indicated that the energy difference between (Ra,S)-TS1 and (Sa,R)-TS1 could be mainly attributed to the difference of distortion energies of the substrates and the catalyst. Structure analysis in Figure 2a indicated that the planar carbon center of C3-unsubstituted 2-alkenylindole 1a (∠C5C6C7H8 = 179.2°) and o-QM (∠C1C2H4C3 = 180.0°) as well as the angle in o-QM (∠C1C2C3 = 127.7°) were ready to distort to pyramidal structures during the nucleophilic addition. The dihedral angles of these two carbon centers in (Ra,S)-TS1 (∠C5C6C7H8 = 157.1° and ∠C1C2H4C3 = 156.2°) and the angle of o-QM (∠C1C2C3 = 127.6°) were bigger than those in (Sa,R)-TS1 (∠C5C6C7H8 = 152.9°, ∠C1C2H4C3 = 145.1°, ∠C1C2C3 = 122.2°), indicating more structural distortions in (Sa,R)-TS1 than those in (Ra,S)-TS1. Besides, the hydrogen bond between the oxygen atom and the hydrogen atom of CPA (S)-7a in (Ra,S)-TS1 (b1 = 1.416 Å) was considerably shorter than that in (Sa,R)-TS1 (b1 = 1.449 Å), further indicating the bigger structural distortion in (Sa,R)-TS1. These results well explain the observed absolute configuration and good enantioselectivity of the major enantiomer of product 3aa. Moreover, the energy barrier of (Ra,S)-TS1 was much lower than those of (Ra,R)-TS1 and (Sa,S)-TS1, which corresponded to the formation of minor diastereomers (Ra,R)-4aa and (Sa,S)-4aa. So, these calculation results also explained the observed high diastereoselectivity of 3aa in the presence of CPA (S)-7a.

In addition, Figure 2b shows the calculated transition states leading to four possible stereoisomers under the catalysis of CPA (S)-7b. Obviously, the energy barrier of (Ra,R)-TS2 leading to the formation of major product (Ra,R)-4aa was lower (19.3 kcal·mol–1) than those of other three transition states (see Figure S7 in the Supporting Information for details). The energy difference between the transition states (Ra,R)-TS2 and (Sa,S)-TS2, leading to the generation of two enantiomers of 4aa, was 2.2 kcal·mol–1, which well explained the observed absolute configuration of major enantiomer (Ra,R)-4aa and its good enantioselectivity of 93:7 er. Similarly, the origin of the energy difference leading to the observed enantioselectivity of 4aa was also investigated by energy decomposition analysis (see Figure S8 in the Supporting Information for details). Energy decomposition analysis indicated that the energy difference between (Ra,R)-TS2 and (Sa,S)-TS2 mainly comes from the difference of interaction energies between the substrates and CPA (S)-7b. As shown in Figure 2b, three C–H···O (b3 = 2.209 Å, b4 = 2.321 Å, b5 = 2.540 Å) and four C–H···π interactions (b6 = 2.920 Å, b7 = 2.853 Å, b8 = 2.755 Å, b9 = 3.128 Å) between the substrates [(Ra)-1a and o-QM] and CPA (S)-7b were observed in (Ra,R)-TS2. In contrast, only one C–H···O (b3 = 2.513 Å) and two C–H···π interactions (b4 = 2.530 Å, b5 = 2.427 Å) were observed in (Sa,S)-TS2, indicating that the interactions between the substrates and CPA (S)-7b in (Sa,S)-TS2 were weaker than those in (Ra,R)-TS2. These noncovalent interactions could also be visualized from the NCI plots (see Figure S9 in the Supporting Information for details). These results well explained the observed absolute configuration and good enantioselectivity of the major product (Ra,R)-4aa. Evidently, under the catalysis of CPA (S)-7b, the energy barrier of (Ra,R)-TS2 was much lower than those of (Ra,S)-TS2 and (Sa,R)-TS2 corresponding to the generation of minor diastereomers (Ra,S)-3aa and (Sa,R)-3aa, which explained the observed high diastereoselectivity of 4aa in the presence of CPA (S)-7b. Therefore, the theoretical calculations provided an in-depth understanding of the origin of the observed stereoselectivity and diastereodivergence of the products under different reaction conditions.

Conclusions

In summary, we have established the first catalytic asymmetric diastereodivergent synthesis of 2-alkenylindoles bearing both axial chirality and central chirality via CPA-catalyzed addition reactions of C3-unsubstituted 2-alkenylindoles with o-hydroxybenzyl alcohols. Using this approach, two series of 2-alkenylindoles bearing multiple chiral elements were synthesized in a diastereodivergent fashion with moderate to high yields and excellent stereoselectivities. Moreover, such 2-alkenylindoles bearing both axial and central chirality could be converted into new chiral ligand, and several 2-alkenylindole products displayed potent anticancer activities, which demonstrated their promising applications in asymmetric catalysis and medicinal chemistry. Besides, theoretical calculations have been performed on the key transition states leading to different stereoisomers, which provided an in-depth understanding of this catalytic asymmetric diastereodivergent reaction. Therefore, this work has not only established the first catalytic atroposelective synthesis of axially chiral 2-alkenylindoles with potential applications, but also provided a new strategy for diastereodivergent construction of indole-based scaffolds bearing both axial and central chirality, thus offering an efficient tactic toward settling the challenges in developing catalytic asymmetric diastereodivergent reactions for the synthesis of chiral compounds bearing both axial and central chirality.

Acknowledgments

We are grateful for financial support from NSFC (22125104 and 22101103), Project for Excellent Scientific and Technological Innovation Team of Jiangsu Province, the open research fund of Songshan Lake Materials Laboratory (2023SLABFN16) and the STU Scientific Research Foundation for Talents (NTF20022). We are grateful for Prof. Shu Zhang for her help in biological evaluation.

Data Availability Statement

The data underlying this study are available in the published article and its online Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/prechem.4c00008.

  • Experimental procedures, spectroscopic data for all new compounds, theoretical calculations (PDF)

  • X-ray crystallographic data for 3aa (CIF)

  • X-ray crystallographic data for rac-4ak (CIF)

Accession Codes

CCDC 2326447 (3aa) and CCDC 2326448 (rac-4ak) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.

Author Contributions

S.Y., J.-B.H., and D.-H.W. contributed equally to the work.

The authors declare no competing financial interest.

Supplementary Material

pc4c00008_si_001.pdf (17.6MB, pdf)
pc4c00008_si_002.cif (1.1MB, cif)
pc4c00008_si_003.cif (2.2MB, cif)

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Associated Data

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

Supplementary Materials

pc4c00008_si_001.pdf (17.6MB, pdf)
pc4c00008_si_002.cif (1.1MB, cif)
pc4c00008_si_003.cif (2.2MB, cif)

Data Availability Statement

The data underlying this study are available in the published article and its online Supporting Information.

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