Atroposelective [4+1] annulation for the synthesis of isotopic isoindolinones bearing both central and axial chirality

Abstract

Isotopically chiral molecules have drawn much attention due to their practical applications in drug discovery. However, existing studies in this area are mainly limited to centrally chiral molecules and H/D exchange. Herein, we report a chiral phosphoric acid-catalyzed atroposelective [4+1] annulation of ketoaldehydes and 1H-indol-1-amines. By means of this strategy, a series of D- and ¹⁸O-labeled atropisomers featuring both central and axial chiralities are synthesized with high enantioselectivities and diastereoselectivities and good to excellent isotopic incorporation. Experimental and density functional theory studies suggest that the reaction involves a sequential condensation, cyclization and isomerization cascade, in which the second step is the enantio-determining process.

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Introduction

The isotope labeling strategy has been widely used in many fields such as quantitative proteomics, organic reaction mechanisms, and new drug discovery.¹ In this context, deuterium (D), as a nonradioactive isotope of hydrogen, was intentionally introduced into bioactive molecules since D-incorporation may not only improve the pharmacokinetic (PK) profile but also provide a solution when bioactive molecules face metabolism-mediated toxicity, drug interactions and low bioactivation.² In 2017, the U.S. Food and Drug Administration (FDA) granted marketing approval for the first deuterated drug molecule deutetrabenazine, which is used to treat chorea associated with Huntington's disease and tardive dyskinesia (Fig. 1a, left).³ In addition, deucravacitinib, a tyrosine kinase 2 (TYK2) inhibitor approved for the treatment of psoriasis, represents another example of a deuterated FDA-approved drug in 2022 (Fig. 1a, right).⁴ Therefore, much attention has been paid to synthesizing deuterated bioactive molecules.⁵ Despite these advances, the synthesis of optically active isotopic molecules is mainly limited to H/D exchange based on either centrally or axially chiral compounds.⁶ The efficient construction of deuterated molecules featuring multiple chiral elements is far more challenging and yet to be explored. More importantly, beyond the H/D exchange,⁷ the incorporation of other nonradioactive isotope (e.g.¹⁸O) into chiral molecules bearing multiple chiral elements is still undeveloped, despite the fact that these kinds of molecules may also have superior comprehensive performance compared to non-isotopic molecules.

Fig. 1 State of the art for the synthesis of isotopically chiral molecules. (a) Representative deuterated drugs. (b) Hypothesis of water involvement in chiral molecule formation. (c) Atroposelective [4+1] annulation for the synthesis of isotopic isoindolinones bearing both central and axial chirality.

Isotopic water (D₂O and H₂¹⁸O) is one of the most desirable reagents for the synthesis of isotopically chiral molecules. In this regard, water-involved reactions offer an efficient approach for introducing D or ¹⁸O without the need for tedious synthetic procedures of isotopic starting materials. However, the asymmetric introduction of isotopes (D and ¹⁸O) by using isotopic water is still in its early stages.⁸ To this end, we envision the strategy of asymmetric water-nucleophilic attack that could be used for the construction of chiral molecules featuring multiple chiral elements. As shown in Fig. 1b, by using compound I as the substrate, we posited that H₂O as the nucleophile could be introduced into compound I to initiate asymmetric cyclization via chiral phosphoric acid (CPA) catalysis. This may cause the carbonyl moiety to first convert to the corresponding hydroxyl group, which affords the chiral intermediate II. The sequential elimination of one molecule of water would then give intermediate III, thus achieving the deletion of the carbonyl group of I. It should be noted that, if the X group is bulky enough, the axially chiral intermediate II can be afforded. Finally, the intramolecular isomerization would occur to generate the isoindolinones IV bearing both axial and central chirality, which accomplishes carbonyl relocation. More importantly, since H₂O is a key reactant of the reaction, the isotopically chiral IV may be easily afforded by simply adding D₂O or H₂¹⁸O into the reaction system.

Inspired by the reports on practical synthesis of isoindolinones,⁹ we propose that the reaction of acetaldehyde 1 with 1H-indol-1-amine 2 by CPA catalysis could generate intermediate (V), featuring the active N-amine moiety¹⁰ with the release of one molecule of H₂O (Fig. 1c). Herein, extra isotopic D₂O could be added to the reaction system to replace the H₂O and then react with V. On the other hand, due to the keto–enol tautomerism of V (or 1), D-incorporation at the benzylic site would also be expected. Similarly, the ¹⁸O-labeled products could also be afforded by subjecting H₂¹⁸O to the reaction mixture. In this regard, isotopically chiral isoindolinones bearing both carbon central and N–N axial chirality^11,12 would be produced that may possess potential applications in medicinal chemistry.¹³

Results and discussion

We commenced our study by investigating the CPA-catalyzed reaction of 2-acetylbenzaldehyde 1a with 2-(phenylsulfonyl)-1H-indol-1-amine 2a, envisioning that the molecular H₂O released during the amine generation would participate in the asymmetric annulation to 3a (Table 1). Gratifyingly, the reaction proceeded smoothly at 35 °C in toluene by CPA1 catalysis, affording 3a in 73% enantiomeric excess (ee) with 89% yield, albeit with a low diastereomeric ratio (dr) of 3 : 1 (Table 1, entry 1). We then screened a variety of CPA catalysts for the reaction and identified CPA4 as the optimal catalyst that gave 3a in 94% ee and 91% yield with a dr of over 20 : 1 (entries 2–7). The absolute configuration of 3a was determined to be (P, S) by single-crystal X-ray analysis. The use of other solvents such as CH₂Cl₂, CHCl₃, CCl₄, chlorobenzene or EtOAc gave no better results than toluene (entries 8–12). A lower concentration of the reaction mixture resulted in comparable ee of 3a but with a relatively lower yield of 68% and 17 : 1 dr (entry 13). Moreover, as shown in entries 14–16, decreasing the reaction temperature and catalyst loading both led to 3a with lower ee (77–91%). When the SO₂Ph group was replaced with the H group, 68% ee of isoindolinone 3a was obtained. In order to examine the axial configurational stability of 3a, a density functional theory (DFT) study was performed. As a result, the rotational barrier of 3a around the N–N axis in toluene at room temperature is 31.5 kcal mol⁻¹, suggesting the high configurational stability of the N–N moiety of 3a.

Table 1 Optimized conditions for the reaction^a

Entry	Catalyst	Solvent	ee (%)	Yield (%)	dr
a Reaction conditions: 1a (0.2 mmol), 2a (0.1 mmol), CPA catalyst (10 mol%), solvent (1.0 mL), 35 °C and 24 h. Isolated yield, ee values were determined by high performance liquid chromatography (HPLC), and dr values were determined by ^1H-NMR analysis of the crude reaction mixture. b Toluene (2.0 mL). c The reaction was carried out at 25 °C. d 5 mol% of CPA4 was used. e PhSO2 group was replaced with H.
1	CPA1	Toluene	73	89	3 : 1
2	CPA2	Toluene	27	71	4 : 1
3	CPA3	Toluene	−75	76	12 : 1
4	CPA4	Toluene	94	91	>20 : 1
5	CPA5	Toluene	94	91	17 : 1
6	CPA6	Toluene	−51	88	15 : 1
7	CPA7	Toluene	5	80	11 : 1
8	CPA4	CH2Cl2	91	91	>20 : 1
9	CPA4	CHCl3	90	90	>20 : 1
10	CPA4	CCl4	71	91	20 : 1
11	CPA4	Cl-Ph	80	88	18 : 1
12	CPA4	EtOAc	80	44	10 : 1
13^b	CPA4	Toluene	93	68	17 : 1
14^c	CPA4	Toluene	91	80	15 : 1
15^d	CPA4	Toluene	83	66	16 : 1
16^e	CPA4	Toluene	68	36	—

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With the optimal conditions in hand, the scope of the reaction was investigated. As shown in Table 2, the reaction proceeded smoothly when substrates 2 with substituents at the C3 or C4 position, affording 3b–3e in 62–80% yields and 86–94% ee with >20 : 1 dr in all cases. Substrates 2 bearing electron withdrawing and donating groups at the C5 position were compatible with the reaction, providing the desired products (3f–3k) in good to excellent yields and high enantioselectivities (92–96% ee), with excellent to high levels of diastereomeric control (10 : 1 to >20 : 1 dr). However, relatively lower ee and dr were obtained when substrates 2 possessing C6 substituents (3l and 3m) were used. On the other hand, the phenylsulfonyl group could be verified by other groups including Ts, Fs and different ester groups, delivering products 3n–3r in high ee and excellent to high dr. Moreover, the reaction also occurred when 2-(trifluoromethyl)-1H-benzo[d]imidazole was used as the substrate, leading to 3s in 42% yield and 82% ee, but only with 2 : 1 dr. Finally, different ketoaldehydes 1 were examined for the reaction. To our delight, isoindolinones (3t–3a′) were readily isolated in high ee (88–98%) with 10 : 1 to 20 : 1 dr, but only 37% yield and 60% ee of 3b′ were obtained when 2-acetyl-6-chlorobenzaldehyde was used as the substrate. Notably, long-chain ketones also tolerated the reaction, delivering 3c′ and 3d′ in 94% ee and 92% ee with 18 : 1 and 14 : 1 dr, respectively. However, no desired product 3e′ was generated when 2-benzoylbenzaldehyde was used for the reaction under the optimal conditions.

Table 2 Substrate scope^a

a Reaction conditions: 1a (0.2 mmol), 2a (0.1 mmol), CPA4 (10 mol%), toluene (1.0 mL), 35 °C and 24 h. Isolated yield, ee values were determined by HPLC, and dr values were determined by ¹H-NMR analysis of the crude reaction mixture. Ts = tosyl and Fs = p-fluorobenzenesulfonyl. b Reaction conditions: 1a (0.2 mmol), 2a (0.1 mmol), CPA catalyst (10 mol%), solvent: chlorobenzene (1.0 mL), −10 °C and 12 h.

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Having established the strategy for the synthesis of chiral isoindolinones 3, we next explored the potential isotopic incorporation of 3 by adding D₂O or H¹⁸O into the reaction mixture. As shown in Table 3, the use of D₂O led to D-incorporation at two different sites, affording D-labeled isoindolinones 4 featuring both central and axial chirality. Substrates 2 bearing substituents with electron-neutral, -withdrawing and -donating groups at the C3, C4 or C5 position were well tolerated to produce the corresponding products in high yields with good to high dr (4a–4e). In addition, ketoaldehydes 1 bearing different groups at the phenyl ring were tolerated under the reaction conditions, affording 4f–4h in good yield, high ee and excellent dr. It should be noted that, in all cases, the isoindolinones 4 were obtained with high D-incorporation at the methyl group (89–91%) and moderate D-incorporation at the benzylic position (63–70%). The moderate D-incorporation at the benzylic position may be attributed to the fact that the H/D exchange of keto–enol tautomerism of 1 would generate extra H₂O rebounded into the reaction system, thus decreasing the D-incorporation at the benzylic position. On the other hand, replacing the Me with the C₇H₁₅ group gave 4i in high ee and dr with moderate D-incorporation.

Table 3 Substrate scope of D-labeled isoindolinones^a

a Reaction conditions: 1a (0.2 mmol), 2a (0.1 mmol), CPA4 (10 mol%), toluene (1.0 mL), D₂O (50 μL), 35 °C and 24 h. Isolated yield and ee values were determined by HPLC. The dr values and D-incorporation were determined by ¹H-NMR analysis of the crude reaction mixture.

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Subsequently, reactions of representative ketoaldehydes 1 and 2-(phenylsulfonyl)-1H-indol-1-amines 2 with H₂¹⁸O were studied (Table 4). As a result, substituents attached at different positions of the indolyl ring were well-accommodated, affording ¹⁸O-labeled isoindolinones 5a–5e in high ee and dr with an excellent level of ¹⁸O incorporation (70–86%). The 82–91% ¹⁸O incorporation of 5 was also obtained in good yield, high ee and good to high dr (5f–5i). It should be noted that this reaction represents a very rare example of the synthesis of ¹⁸O-labeled atropisomers bearing both central and axial chirality.

Table 4 Substrate scope of ¹⁸O-labeled isoindolinones^a

a Reaction conditions: 1a (0.2 mmol), 2a (0.1 mmol), CPA4 (10 mol%), toluene (1.0 mL), H₂¹⁸O (50 μL), 35 °C and 24 h. Isolated yield, ee values were determined by HPLC, and dr values were determined by ¹H-NMR analysis of the crude reaction mixture. The ¹⁸O-incorporation was determined by high-resolution mass spectrometry (HRMS).

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To gain some insight into the details of the reaction, we performed a series of experiments to probe the mechanism. As shown in Fig. 2a, we probed the reaction intermediates by performing the reaction of 1a with 2a at low temperature. As a result, compound Int0 was readily afforded and isolated in E-configuration under either CPA4 or ent-CPA4 catalysis. The configuration of Int0 was unambiguously determined by single crystal X-ray diffraction analysis. Moreover, CPA4 catalyzed the reaction of Int0 with H₂O converted to (P, S)-3a in 71% yield with 93% ee. The use of ent-CPA4 for the reaction led to (M, R)-3a in 90% ee with >20 : 1 dr. It should be noted that lower yield and ee would be obtained when the reactions proceeded in the absence of extra H₂O in the system. All these results indicated that Int0 is the key intermediate of the annulation, and the enantioselectivity and diastereoselectivity are derived from the transformation of Int0 with H₂O to 3a.

Fig. 2 Mechanistic studies. (a) Control experiments. (b) Deuterium- and ¹⁸O-labeling experiments. (c) Proposed reaction pathway. (d) Enantio-determining-step investigation.

To probe the isotope introduction step of the reaction, we then performed D- and ¹⁸O-labeling experiments (Fig. 2b). The reaction of D-1a with 2a resulted in 3a in 90% yield and 94% ee, but with no D-incorporation observed in 3a. In addition, the reaction of Int0 with D₂O or H₂¹⁸O yielded 4a or 5a with excellent D- or ¹⁸O-incorporation, respectively. These results suggested that H₂O participated in the reaction and is responsible for the isotope introduction of isoindolinones. Finally, we explored the origin of enantioselectivity. Based on these results, we proposed that the reaction may proceed via concerted or stepwise annulation (Fig. 2c). However, currently, the isolation of this intermediate ii or iii has failed. Nevertheless, we explored the reaction of 1a with 9H-carbazol-9-amine 6 since achiral iii-6a would be generated in this case (Fig. 2d). As a result, compound 7 was obtained in 77% yield but only with 7% ee. This result indicated that the generated axial chirality is a key factor for the efficient synthesis of isoindolinones 3 in high ee. Thus, the origin of enantioselectivity for the reaction of 1 and 2 is mainly attributed to the axially chiral generation, derived from the chiral intermediate ii (Fig. 2c). Our calculation suggested that the rotational barrier of ii at room temperature is 30.7 kcal mol⁻¹, indicating that the axial chirality is generated in this step. Furthermore, the high diastereoselectivity is attributed to the stereospecific intramolecular isomerization induced by axial information rather than the chiral induction catalyzed by CPA.

DFT studies were then performed to gain deep insight into the reaction mechanism. We first examined whether the annulation of Int0 and H₂O occurred stepwise or concertedly to afford the intermediate ii (Fig. 2c). The energy profiles of the stepwise process are shown in Fig. 3, and the coordination of Int0 with CPA4 was selected as the reference point. With H₂O participating in the reaction, the dual H-bonding effect was generated with an energy barrier of 16.0 kcal mol⁻¹ (Int0 + H₂O). The Re-face attack of the amine by water formed Int1_Rvia transition state TS1_Re with an energy barrier of 24.5 kcal mol⁻¹, whereas the Si-face attack formed Int6_Svia transition state TS6_Si with a higher energy barrier of 28.4 kcal mol⁻¹. Thus, Int1_R is the more favorable intermediate, which undergoes sequential N-nucleophilic addition to the carbonyl group. In this case, four intermediates Int2–5 may be generated accordingly, with Int3_1S-Sa-3R was superior to others because of the relatively lower energy barrier of TS3_1Re-Sa-3R (24.3 kcal mol⁻¹).

Fig. 3 DFT studies of stepwise annulation. Free energy diagrams of the chiral phosphoric acid-catalyzed stepwise mechanism in asymmetric annulation. Gibbs free energy obtained at the M06-2X/def2-TZVPP(SMD, Toluene)//M06-2X/def2-SVP level. The meaning of the corner mark in the structure name: Re: the rectus face; Si: the sinister face; Ra: the (potential) R-configuration for the N–N axis; Sa: the (potential) S-configuration for the N–N axis; R: the R-configuration for the central chirality; S: the S-configuration for the central chirality.

Alternatively, if concerted annulation occurred, only four pathways might be experienced via transition states TS11_1Re-Ra-3Re, TS12_1Si-Ra-3Si, TS17_1Re-Sa-3Re or TS18_1Si-Sa-3Si (Fig. 4). This is mainly because the bulky indole moiety existing in Int0 induced exclusive suprafacial activation by CPA4. In this regard, the annulation that proceeded viaTS18_1Si-Sa-3Si has an overcome energy barrier of 30.5 kcal mol⁻¹, a finding that is not possible. On the other hand, although Int3_1S-Sa-3R could be easily afforded viaTS3_1Re-Sa-3R, the sequential dehydration step has an extremely high energy barrier of 38.8 kcal mol⁻¹viaTS19_1S-Sa-3R, which is not possible either. This result also ruled out the only possible stepwise pathway that occurred from Int3_1S-Sa-3R (Fig. 3, blue line). In contrast, our calculation revealed that Int2_1S-Ra-3R and Int8_1R-Ra-3S are more favorable intermediates, which are generated viaTS11_1Re-Ra-3Re and TS12_1Si-Ra-3Si with energy barriers of 23.4 and 24.3 kcal mol⁻¹, respectively. However, the dehydration from Int2_1S-Ra-3R required overcoming a relatively higher energy barrier than that of Int8_1R-Ra-3S. Therefore, the reaction preferred to undergo dehydration viaTS14_1R-Ra-3S to afford Int11_P. The intramolecular isomerization then occurred viaTS15_P-Re to afford (P, S)-3a with an energy barrier of 26.9 kcal mol⁻¹. This result is consistent with our experimental observation that isoindolinone 3a was obtained in preferential (P, S) configuration.

Fig. 4 DFT studies of concerted annulation. Free energy diagrams of the chiral phosphoric acid-catalyzed concerted mechanism for asymmetric annulation, and the investigation of enantioselectivity. M and P were used to replace the R and S configurations of axial chirality, respectively. The structures of Int2, Int3, Int7 and Int8 are shown in Fig. 3.

Finally, synthetic transformations of isoindolinones 3a were performed (Fig. 5). First, the large-scale experiment of 3a was carried out, which afforded 3a in 80% yield with 95% ee. Interestingly, treatment of 3a with LiAlH₄ resulted in semi-reduction, affording centrally chiral product 8 in 95% ee with > 20 : 1 dr. When the reduction was performed with diisobutylaluminium hydride (DIBAL-H) in THF, complete reduction of the carbonyl moiety was observed, producing compound 9 in 85% yield with 90% ee. Additionally, the bromo group was easily introduced via the bromination of 3a with NBS, affording 10 in 76% yield with 91% ee. The stereospecific addition of 3a could be achieved by using MeMgCl, which furnished 11 in 53% yield with 95% ee and >20 : 1 dr.

Fig. 5 Synthetic transformations.

Conclusions

In conclusion, we have reported the atroposelective [4+1] annulation of ketoaldehydes with 1H-indol-1-amines for the synthesis of centrally and axially chiral isoindolinones bearing N–N axes. By subjecting D₂O or H₂¹⁸O to the reaction system, a series of isotopically chiral isoindolinones could be easily obtained with D- or ¹⁸O-incorporation in good to excellent levels, respectively. Control experiments and DFT studies indicated that the reaction proceeded through condensation to E-imine intermediates, followed by nucleophilic addition-driven CPA-catalyzed enantioselective cyclization and isomerization. We anticipate that the strategy herein could inspire more studies on the synthesis of isotopically chiral molecules with multiple chiral elements.

Data availability

The data supporting this article have been included as part of the ESI.†

Author contributions

H. Y. conceived and designed the experiment. G. J., Z. L.-H. and Z. H.-F. performed experiments and collected the data. G. J. provided the DFT calculations. H. Y. wrote the manuscript with the revision of all authors.

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgements

We gratefully acknowledge the financial support from the National Natural Science Foundation of China (22201131) and the Natural Science Foundation of Jiangsu Province (BK20220137).

Notes and references

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13. (a) J. E. Smyth, N. M. Butler and P. A. Keller, Nat. Prod. Rep., 2015, 32, 1562–1583; (b) S. R. LaPlante, L. D. Fader, K. R. Fandrick, D. R. Fandrick, O. Hucke, R. Kemper, S. P. F. Miller and P. J. Edwards, J. Med. Chem., 2011, 54, 7005–7022; (c) M. Basilaia, M. H. Chen, J. Secka and J. L. Gustafson, Acc. Chem. Res., 2022, 55, 2904–2919.

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Footnote

† Electronic supplementary information (ESI) available: Experimental details and characterization data for all new compounds, computational methods, and Cartesian coordinates. CCDC 2359270, 2354174, 2362138, and 2393057. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d5sc00594a

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