Letter pubs.acs.org/acscatalysis
Enantioselective Dearomative Arylation of Isoquinolines Ming Zhang,‡,§ Wangsheng Sun,‡,§ Gongming Zhu,‡ Guangjun Bao,‡ Bangzhi Zhang,‡ Liang Hong,*,† Min Li,*,† and Rui Wang*,†,‡ †
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, Lanzhou, 730000, China
‡
S Supporting Information *
ABSTRACT: The C1-substituted tetrahydroisoquinolines and 1,2-dihydroisoquinoline constitute an important group and are interesting structural motifs found in many natural products and pharmaceuticals. In this context, a phosphoric-acid-catalyzed enantioselective dearomative arylation of isoquinolines was realized, providing the chiral dihydroisoquinolines with indole substituents at the C1-position in good results (up to >99% yield and 97% ee). The reaction features mild reaction conditions and operational simplicity, which make it an attractive approach to the discovery of biologically interesting α-indolisoquinolines. KEYWORDS: enantioselective, isoquinolines, dearomative arylation, indole, chiral phosphoric acid
I
and used for the treatment of overactive bladder with urge incontinence.4 Owing to this importance, many methods have been developed to construct the chiral C1-substituted hydroisoquinolines, including catalytic enantioselective Reissert-type reaction,5 asymmetric hydrogenation of isoquinolines,6 and enantioselective oxidative cross-dehydrogenative couplings,7 among others. The developed methods focused on the enantioselective alkylation of isoquinolines and tetrahydroisoquinolines, while the asymmetric synthesis of C1-aromatic isoquinolines are by far less well developed. Wanner et al. stereoselectively introduced the aryl group to isoquinolines by using a chiral auxiliary group at the nitrogen atom (Scheme 1a).8 Qiu and Lee reported the synthesis of C1-indol isoquinolines from chiral sulfinimine substrates in multisteps (Scheme 1b).9 Therefore, there is an urgent requirement to develop novel enantioselective arylation of isoquinolines. Recently, the α-indolisoquinolines like IBR2 analogues have been identified as novel small molecule RAD51 inhibitors, which could inhibit the proliferation of triple-negative human breast cancer cells.10 They could also effectively inhibit the NFκB activation by blocking IκBα degradation.11 Further study shows that both enantiomers vary greatly in inhibition activities.12 The traditional methods for the synthesis of αindolisoquinolines include the Ag-catalyzed nucleophilic
soquinolines, found abundantly in the plant kingdom, are the largest family of naturally occurring alkaloids with a wide range of pharmacological activities.1 Among them, the C1substituted tetrahydroisoquinolines and 1,2-dihydroisoquinoline constitute an important group and are interesting structural motifs found in many natural products and pharmaceuticals (Figure 1). For example, Crispine, isolated from the Carduus crispus plant, exhibits a promising cytotoxic activity and antidepressant-like activity.2 Noscapine, a benzylisoquinoline alkaloid from plants of the poppy family, has been used as an antitussive drug and recently discovered as an antiangiogenic drug that induces apoptosis in cancer cells.3 The α-phenylisoquinoline solifenacin is a medicine of the antimuscarinic class
Received: June 15, 2016 Revised: July 8, 2016
Figure 1. Representative examples. © XXXX American Chemical Society
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DOI: 10.1021/acscatal.6b01693 ACS Catal. 2016, 6, 5290−5294
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ACS Catalysis Scheme 1. Routes to Chiral C1-Aromatic Isoquinolines
Table 1. Optimization of the Reaction Conditionsa
entry
cat. 3
1a:2a
solvent
yield (%)b
ee (%)c
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
3a 3b 3c 3d 3e 3f 3f 3f 3f 3f 3f 3f 3f 3f 3f
1:1 1:1 1:1 1:1 1:1 1:1 2:1 3:1 3:1 3:1 3:1 3:1 3:1 3:1 3:1
toluene toluene toluene toluene toluene toluene toluene toluene CH2Cl2 THF Et2O o-xylene m-xylene p-xylene mesitylene
35 48 5 35 24 38 72 84 24 83 54 98 98 98 89
63 92 95 76 90 95 96 96 59 95 93 96 96 97 97
and limited scope of substrates, which hinder its practical application (Scheme 1b). Consequently, the development of a simple, mild, and direct method for the synthesis of αindolisoquinolines, especially in enantioselective version, is the current focus in medicinal organic chemistry. Inspired by the recent enantioselective dearomatization of (iso)quinolines and pyridines,5,14 we became interested in how to catalytically install indoles at the C1 position of isoquinolines. Following our interests in tetrahydroisoquinoline and indole functionalization7d,e,h,15 and the recent advances in chiral anion catalysis,16 we envisioned that an effective chiral induction could be achieved by the interaction of an ion-pair between the ionic isoquinoline substrates and the chiral anion catalyst (Scheme 1c). Herein, we reported a highly enantioselective dearomatization of isoquinoliniums with indoles. We initially explored the dearomatization of isoquinoline 1a in the presence of chiral phosphoric acid catalyst 3a (Table 1). Pleasingly, the reaction proceeded smoothly to afford the dearomatized product 4a in 35% yield and 63% ee. Further screening other phosphoric acids showed that the 3,3′substituents played a significant role on the reaction outcome. Among them, the catalyst 3f gave the best enantioselectivity of 95%, albeit with a slight lower yield of 38%. We then chose 3f in further optimization studies aimed at improving the reaction yield. The amount of substrate isoquinoline 1a had an important impact on the yield. Increasing the amount to 2.0 equiv could significantly improve the yield to 72%, and could be further increased to 84% when 3.0 equiv of 1a was used. Subsequent screening of solvents revealed that the solvents impacted the outcome, and p-xylene was the most ideal for the reaction, affording 4a in 98% yield and 97% ee.17 With the established optimal conditions, we next investigated the substrate scope of the reaction (Scheme 2). In general, a wide range of indoles 2 with different substituents could participate in the reaction smoothly to afford the desired products in moderate to excellent yields (41−99%) and excellent enantioselectivities (93−97%). 4-Methylindole afforded the corresponding product in 45% yield and 96% ee (Scheme 2, 4b). The methyl, methoxy and fluoro group at the C5-, and C6-position gave excellent yields (84−99%) and
a Unless otherwise specified, the reaction was carried out in 0.1 mmol scale in 1 mL of solvent under room temperature within 48 h. b Isolated yield. cDetermined by chiral HPLC on a Chiralcel IA column.
addition of indoles to ortho-alkynylaryl aldimines, basepromoted addition to N-acylisoquinolinium salts, and threecomponent coupling reactions.13 Qiu et al. have tried the enantioselective synthesis by using chiral sulfinimine substrate.8 However, this method needs the use of stoichiometric amount of chiral source and suffers the inefficient multistep synthesis 5291
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ACS Catalysis Scheme 2. Scope of the Reaction
a
Unless otherwise specified, the reaction was carried out in 0.1 mmol scale in 1 mL of p-xylene under room temperature, with the ratio of 1/2/3f = 3.0/1.0/0.1. The ee values were determined by HPLC on a chiral phase (Chiralcel column). bCat. 3b was used. cThe reaction was carried out under 60 °C, and the ee was determined after deprotection of TBS.
enantioselectivities (94−95% ee) (Scheme 2, 4c−4e and 4h− 4j), whereas chloro and bromo substituents led to the lower yields (41−75%) with no difference on the enantioselectivities (94−97% ee) (Scheme 2, 4f,g and 4k,l). In the case of C7substituted indoles, methyl and methoxy substituents showed excellent efficiency (99% yields, 93−95% ee) (Scheme 2, 4m, n), while fluoro substituent reduced the reaction yield (42% yield, 97% ee) (Scheme 2, 4o). Substituted isoquinolines 1 were also tested for the reaction. Isoquinolines with different
Scheme 3. Scope of Other Arylating Reagents
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ACS Catalysis Scheme 4. Transformation of the Products
Scheme 5. Proposed Mechanism
plausible mechanism for this transformation. The intermediate 9 is generated first. Subsequently, with the help of phosphoric acid, intermediate 9 releases a molecule of tBuOH to generate the iminium ion 10, which could be trapped by a nucleophile indole to give the product (Scheme 5). In summary, we have developed a new dearomative arylation method, which represents a simple and direct access to chiral αindoldihydroisoquinolines with excellent enantiomeric purity. The mild reactions and the operational simplicity make this reaction an attractive approach to the discovery of biologically interesting α-indolisoquinolines. Further work will be directed toward the biological evaluation of these synthesized compounds.
substituents led to the corresponding dearomatized products in good yields and enantioselectivities (Scheme 2, 4p−s).18 As a limitation of this catalytic system, the current catalytic system was not suitable for other arylating reagents. We have tried other arenes and heteroarenes like N-benzyl-pyrrole, NTBS-pyrrole, furan, thiophene, and 1,3,5-trimethoxybenzene. Under the employed catalytic conditions, the N-benzyl-pyrrole could afford the corresponding racemic product in 40% yield, but the others showed no reactivity even with longer reaction time or higher reaction temperature (Scheme 3). We also carried out some derivatizations of the products to demonstrate the synthetic utility of this method (Scheme 4). The deprotection of the TBS group could proceed with high efficiency using TBAF to form 5 and 6, respectively. The absolute configuration of 5 was determined to be (S) at the newly formed stereocenter by X-ray analysis.18 Moreover, the double bonds on the 1,2-dihydroisoquinoline moiety of the products could be reduced by Raney nickel under a H2 atm. Additionally, the N−H free α-indoltetrahydro-isoquinoline 8 could be prepared by a two-step reduction/deprotection sequence. To shed more light on the mechanism of this reaction, we prepared the intermediate 9 by mixing isoquinoline and Boc2O,19 and then we exposed the mixture to the standard reaction conditions, which delivered the desired product in 97% ee. Based on this result and previous study,16,20 we proposed a
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.6b01693. Details of experimental procedure, data, HPLC and NMR spectra of all compounds (PDF) Crystallographic data of 5 (CIF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail for L.H.:
[email protected]. 5293
DOI: 10.1021/acscatal.6b01693 ACS Catal. 2016, 6, 5290−5294
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ACS Catalysis *E-mail for M.L.:
[email protected]. *E-mail for R.W.:
[email protected].
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Author Contributions §
These authors contributed equally (M.Z. and W.S.).
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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REFERENCES
We are grateful for the financial support from the NSFC (21432003, 21272102, 21572278, and 21502079) and the Program for Chang-Jiang Scholars and Innovative Research Team in University (IRT_15R27).
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