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. 2019 Jul 11;10:3062. doi: 10.1038/s41467-019-10878-7

NHC-catalyzed atropoenantioselective synthesis of axially chiral biaryl amino alcohols via a cooperative strategy

Gongming Yang 1, Donghui Guo 1, Di Meng 1, Jian Wang 1,✉
PMCID: PMC6624290  PMID: 31296847

Abstract

Axially chiral biaryl amino-alcohols play a pivotal role in organic synthesis and drug discovery. However, only a very few enantioselective methods have been reported to synthesize chiral biaryl amino-alcohols. Therefore, the rapid enantioselective construction of optically active biaryl amino-alcohols still remains a formidable challenge. Here we report an N-heterocyclic carbene (NHC)-catalyzed atropoenantioselective acylation of biphenols triggered by a cooperative strategy consisting of desymmetrization followed by kinetic resolution. This protocol features broad substrate scope and good functional group tolerance, and allows for a rapid construction of axially chiral biaryl amino-alcohols in good to high yields and with excellent enantioselectivities. Furthermore, the structurally diverse axially chiral biaryl amino-alcohol derivatives provide multiple possibilities for chemists to develop catalysts or ligands for different chemical transformations.

Subject terms: Asymmetric catalysis, Organocatalysis, Stereochemistry, Synthetic chemistry methodology

Axially chiral biaryl amino-alcohols play a pivotal role in organic synthesis and drug discovery. Here, the authors report a cooperative strategy consisting of desymmetrization followed by kinetic resolution to deliver non-classical NOBIN derivatives in high yields and enantioselectivity via NHC catalysis.

Introduction

Axially chiral biaryls1–3 have widely applied in many areas, including material science4,5 and drug discovery6. In addition, chiral biaryls have often played as ligands7 or catalysts8 in the development of enantioselective catalytic transformations. During the past two decades, BINOL and BINAM have proven to be representative examples in this category9–14. Afterward, NOBIN (Fig. 1) gradually grows up to the next privileged scaffold15 with numerous important applications, due to its perfect enantio-control and prominent bioactivity (Fig. 1, (R)-Streptonigrin, an antitumor agent).

Fig. 1.

Fig. 1

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Representative molecules and synthetic protocols. a Two representative axially chiral molecules. b Asymmetric kinetic resolution of achiral biaryl amino alcohols. c Our synthetic proposal via a NHC-catalyzed atroposelective synthesis of axially chiral biaryl amino-alcohols via a cascade strategy of desymmetrization followed by kinetic resolution

In sharp contrast to the asymmetric preparation of BINOL or BINAM16–19, to date, only a very few enantioselective methods have been reported to synthesize NOBIN-type biaryl amino alcohols20–23. In 1992, Kocovsky24 and coworkers reported the asymmetric synthesis of NOBIN via oxidative of 2-naphthol with 2-naphylamine. However, the use of large excess amount of chiral auxiliary and required multistep crystallization sometimes restrict its further application. To face this issue, Tan’s group25 uncovered a phosphoric acid-catalyzed cross-coupling of 2-naphthylamines with iminoquinones, affording chiral biaryl amino alcohols in a concise and catalytic pattern. Shortly after, optical resolution rapidly developed into the next attractive method to isolate NOBIN enantiomers by leveraging the power of diastereoisomeric chiral salt formation, but was confined to unstable reproducibility in practical26,27. Getting the NOBIN derivatives through a direct transformation from chiral raw materials (e.g., BINOL28 or BINAM29) has also become an interesting way. Regrettably, this protocol is mostly applied to construct chiral binaphthyl-type amino-alcohols. Recently, kinetic resolution is recognized as an impresive technology to produce such biaryl structures. For example, the groups of Maruoka30 and Zhao31 reported a phase-transfer- or N-heterocyclic carbene-catalyzed asymmetric kinetic resolution to prepare enantioenriched chiral biaryl amino alcohols, independently (Fig. 1). However, no more than 50% theoretical yields inevitably affect the application of this approach. Overall, rapid synthesis of axially chiral biaryl amino-alcohols in a highly atropoenantioselective fashion is still in its infancy

Our group is interested in exploring carbene catalysis for the rapid assembling of axially chiral molecules. To date, we have successfully reported the N-heterocyclic carbene-catalyzed atropoenantioselective [3 + 3] annulation and kinetic resolution of anilides, affording valuable chiral α-pyrone-aryls and isoindolinones, respectively32,33. Despite aforementioned achievements, the unsolved challenges and the continuously growing demands of atropoenantiomers still drive us to develop more efficient and revolutionary protocols. We herein report a carbene-catalyzed34–41 atroposelective synthesis of axially chiral biaryl amino-alcohols via a cascade strategy of desymmetrization followed by kinetic resolution42 (Fig. 1). First, this approach can deliver nonclassical NOBIN derivatives (e.g., biphenyl- or phenyl-naphthyl-type amino-alcohols) in a high chemical yield. From the aspect of structural diversity, non-classical NOBIN-type derivatives will offer more possibilities for the exploration of new chiral catalysts or ligands. Second, in contrast to an independent desymmetrization or kinetic resolution method, the cooperation of desymmetrization43–48 with kinetic resolution49–53 has certain superiority in the control of enantioselectivity.

Results

Reaction optimization

We commenced our study by using biphenols (1a–c) as the model prochiral substrates, aldehyde (2a) as acylation reagent54–62 and DQ as oxidant63,64. Key results of reaction optimization are briefly summarized in Table 1. Building upon the indanol-derived triazolium scaffold, precatalysts with N-2,4,6-(Cl)3C6H265, or N-C6F566, substituents (Table 1, C2 and C3), derived from α-amino acids, were tested but exhibited low conversions and enantioselectivities (Table 1, entries 4 and 5). Interestingly, precatalyst C1 with N-2,4,6-(Me)3C6H2 (N-Mes)67 substituent provided 3a in 63% with 85% ee (Table 1, entry 1). If substrate 1b or 1c replaced 1a (R = NO2 or NH2; More information about changing R groups, see Supplementary Table 2), low ee and yield were observed (Table 1, entries 2 and 3). To our delight, further improved enantioselectivities were achieved with the N-2,4,6-(iPr)3C6H2 substituted catalyst C4 or C568 (Table 1, entries 6 and 7). Notably, the triazolium catalyst C5, which bears a strong electron-withdrawing group (NO2) at the remote aryl position, afforded 95% ee and 80% yield (Table 1, entry 7). We then chose catalyst C5, substrate 1a and 2a for further optimization. After extensive screening of solvents, bases and catalyst loading, an ideal result was obtained by using 10 mol% of C5 as catalyst, DCM as the solvent, and K2CO3 as the base (Table 1, entry 15). Meanwhile, nuclear magnetic resonance (NMR) spectrum confirmed that the main byproduct of this reaction was a bisadduct in which two hydroxyl groups were both acylated (see Supplementary Note 4).

Table 1.

Optimization of the reaction conditionsa

graphic file with name 41467_2019_10878_Figa_HTML.gif
Entry NHC cat. Solvent Base Yield (%)b ee (%)c
1 C1 THF K2CO3 63 85
2d C1 THF K2CO3 71 50
3e C1 THF K2CO3 15 □−
4 C2 THF K2CO3 23 23
5 C3 THF K2CO3 < 5 □−
6 C4 THF K2CO3 74 90
7 C5 THF K2CO3 80 95
8 C5 toluene K2CO3 90 96
9 C5 MeCN K2CO3 78 84
10 C5 MTBE K2CO3 80 98
11 C5 DCM K2CO3 95 96
12 C5 DCM Cs2CO3 85 92
13 C5 DCM Et3N 76 97
14f C5 DCM K2CO3 78 93
15g C5 DCM K2CO3 92 99
16h C5 DCM K2CO3 87 96
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aConditions: 1a (0.1 mmol), 2a (0.15 mmol), catalyst (10 mol %), base (0.12 mmol) and DQ (0.1 mmol), solvent (1.0 mL), room temperature, Ar, 2 h

bIsolated yields after flash column chromatography

cEnantiomeric ratio (ee) determined via chiral-phase HPLC analysis

d1b replaced 1a

e1c replaced 1a

f2a (0.12 mmol), 15 h

gDQ (0.12 mmol), 12 h

hC5 (5 mol %), DQ (0.12 mmol), 24 h.

Substrate scope

Having the optimal condition in hand, we turned our attention to the generality of aldehydes. As indicated in Fig. 2, a diverse set of aliphatic aldehydes underwent acylating reactions, affording their corresponding products in high yields with high to excellent ee values (Figs. 2 and 3b–i). Unambiguously, the steric effect of aldehydes has identified to be a critical factor for achieving high enantioselectivity. Aliphatic aldehydes bearing a steric bulky chain afforded a higher ee value (Figs. 2 and 3a, b, f, g). When aromatic aldehydes were used as substrates, reactions are generally messy, probably caused by the competitive benzoin reaction.

Fig. 2.

Fig. 2

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Scope of aldehydes. Reaction conditions: a mixture of 1a (0.10 mmol), 2 (0.15 mmol), K2CO3 (0.12 mmol), and DQ (0.12 mmol) in CH2Cl2 (1.0 mL) was stirred at room temperature under N2 for 12–24 h

Fig. 3.

Fig. 3

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Scope of biaryl biphenols. Reaction conditions: a mixture of 4a–4o (0.10 mmol), 2a (0.15 mmol), K2CO3 (0.12 mmol), and DQ (0.12 mmol) in CH2Cl2 (1.0 mL) was stirred at room temperature under N2 for 12–24 h. bent-cat. C5 was used

Encouraged by success with aliphatic aldehydes, we then planed to investigate the reactivity of biaryl-type biphenol substrates. N-Cbz protected compounds 4a–j having electron-donating groups (Me, MeO) and/or electron-withdrawing groups (Cl, CN) on the lower ring (Fig. 3, phenyl ring B) generated the coresponding products in high yields (85–94%) with excellent enantioselectivities (96– >99% ee). Cyclohexane ring fused biphenyl substrate also performed well as expected (Fig. 3, 4l, 91% yield and 96% ee). Pleasingly, the indole-based biaryl substrate also proceeded smoothly to afford product 4m with a promising ee value. Gratifyingly, the phenyl-naphthalenyl-type biaryl substrate was also tolerated to deliver the anticipated structure 4n with excellent enantioselectivity (Fig. 3, 99% ee). Incidentally, enantiomeric products can be achieved entirely through the enantiomer catalyst and similar reaction conditions (Fig. 3, 4o).

Mechanistic studies

To verify the mechanism, two control experiments were conducted. As indicated in Fig. 1a, 4), ent-3a was obtained in 49% yield with 93% ee in the presence of DQ (0.6 equiv). On the basis of these data, we can conclude that desymmetrization is a key contributor for enantio-control (Vfast/Vslow = 28:1)69. Meanwhile, we also wonder whether the second acylation is a kinetic resolution process, eventually resulting in an improved enantioselectivity. To approve this hypothesis, the control experiment of (±)-3a with 2a was designed and carried out, generating ent-3a in 47% yield with 76% ee (Fig. 1a, 4). This experiment result suggests that the conversion of 1a to major enantiomer 3a is much faster than the process between 1a and minor enantiomer (Vfast/Vslow = 5:1)69.

Fig. 4.

Fig. 4

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Postulated mechanistic pathways. a The control experiments (Eqs. (1) and (2)) show that the desymmetrization process is the main contributor to the observed ee of the product and the second acylation is a effective KR process that could improve the ee of (−)-3a. b The postulated mechanistic pathway to generate product (−)-3a

Synthetic transformations and applications

We anticipated that the biaryl amino-alcohol 7 (Fig. 5), prepared from 4n via a N-Cbz protected intermediate 6, could be directly utilized as a chiral catalyst in asymmetric alkylation reaction. As highlighted in Fig. 6, compound 7 successfully catalyzed the asymmetric alkylation of Ni-complex 8 with alkyl bromide 9–11 to generate complex 12–14 with promising er values. After a subsequent deprotection, 12–14 could efficiently transfer to valuable chiral α-amino acids70. To further expand synthetic utility, we conducted a Ru-catalyzed asymmetric reduction of ketone 18 by using chiral biaryl amino-alcohol derivatives 15–17 as ligands (for preparation of 15–17, see Supplementary Note 5). As indicated in Fig. 6, ligands 15–17 led to the corresponding product 19 in suggestable er values. In addition, a gram-scale synthesis (3.4 mmol) carried out under standard conditions afforded optically pure 3a in a pleasant result (Fig. 7, 89% yield, 99% ee). The absolute configuration of derivative 6 was determined by X-ray single crystal analysis (See Supplementary Fig. 1), and other structures were assigned by analogy.

Fig. 5.

Fig. 5

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Synthetic transformations. Reaction conditions: (1) 4n, TMSCHN2, CHCl3:MeOH/5:1, r.t., 24 h. (2) NaOMe, MeOH, r.t., 1.0 h. (3) Pd/C, H2, MeOH, r.t., 3.0 h

Fig. 6.

Fig. 6

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Synthetic applications. a Use of 7 as a chiral catalyst. b Utility of 15–17 as chiral ligands

Fig. 7.

Fig. 7

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Gram-scale synthesis. Reaction conditions: a mixture of 1a (3.4 mmol, 1.19 g), 2a (5.1 mmol, 0.55 mL), in CH2Cl2 (34.0 mL) was stirred at room temperature for 15 h

Discussion

In conclusion, we have developed an atropoenantioselective NHC-catalyzed acylation for the preparation of axially chiral biaryl amino-alcohols. The cascade strategy of desymmetrization followed by kinetic resolution could efficiently deliver axially chiral biaryl amino-alcohols with high to excellent ee values (up to >99% ee). Further studies on the exploration of other substrates and applications are ongoing projects in our laboratory.

Methods

Synthesis of racemic ¾

In a glovebox, a flame-dried Schlenk reaction tube equipped with a magnetic stir bar, were added racemic NHC precatalyst C13 (0.01 mmol,), K2CO3 (16.6 mg, 0.12 mmol), oxidant DQ (49.0 mg, 0.12 mmol), 1 (0.10 mmol), 2 (0.15 mmol), and freshly distilled CH2Cl2 (1.0 mL). The reaction mixture was stirred at room temperature for 12 h. The mixture was then filtered through a pad of Celite washed with CH2Cl2. After solvent was evaporated, the residue was purified by flash column chromatography to afford the racemic product 3/4.

Synthesis of ¾

In a glovebox, a flame-dried Schlenk reaction tube equipped with a magnetic stir bar, were added NHC precatalyst C5 (0.01 mmol,), K2CO3 (16.6 mg, 0.12 mmol), oxidant DQ (49.0 mg, 0.12 mmol), 1 (0.10 mmol), 2 (0.15 mmol), and freshly distilled CH2Cl2 (1.0 mL). The reaction mixture was stirred at room temperature until the starting material 1 was completely consumed (12–24 h). The mixture was then filtered through a pad of Celite washed with CH2Cl2. After solvent was evaporated, the residue was purified by flash column chromatography to afford the desired product 3/4.

Supplementary information

Supplementary Information (8.8MB, pdf)
Peer Review File (262.7KB, pdf)

Acknowledgements

Generous financial support for this work is provided by: the National Natural Science Foundation of China (Nos. 21672121 and 21871160), the “Thousand Plan” Youth Program of China, the Tsinghua University, the Bayer Investigator fellow, the Fellowshio of Tsinghua-Peking Centre for Life Sciences (CLS).

Author contributions

G.M.Y. conducted the main experiments; D.H.G. and D.M. prepared the several starting materials, including substrates. J.W. conceptualized and directed the project, and drafted the paper with the assistance from co-authors. All authors contributed to the discussions.

Data availability

For 1H, 13C NMR and high-performance liquid chromatography spectra of compounds in this paper, see Supplementary Figs. 1–187. For details of the synthetic procedures, see Supplementary Notes. The supplementary crystallographic data for this paper could be obtained free of charge from The Cambridge Crystallographic Data Centre (6: CCDC 1880233) via www.ccdc.cam.ac.uk/data_request/cif.

Competing interests

The authors declare no competing interests.

Footnotes

Peer review information: Nature Communications thanks Yong Huang and other anonymous reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information accompanies this paper at 10.1038/s41467-019-10878-7.

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Associated Data

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

Supplementary Materials

Supplementary Information (8.8MB, pdf)
Peer Review File (262.7KB, pdf)

Data Availability Statement

For 1H, 13C NMR and high-performance liquid chromatography spectra of compounds in this paper, see Supplementary Figs. 1–187. For details of the synthetic procedures, see Supplementary Notes. The supplementary crystallographic data for this paper could be obtained free of charge from The Cambridge Crystallographic Data Centre (6: CCDC 1880233) via www.ccdc.cam.ac.uk/data_request/cif.

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