Organocatalytic Diversity-Oriented Asymmetric Synthesis of

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Organocatalytic Diversity-Oriented Asymmetric Synthesis of Structurally and Stereochemically Complex Heterocycles Liang Qiao,† Zhong-Wei Duan,† Xiao-Na Wu,† De-Hai Li,*,†,‡ Qian-Qun Gu,† and Yan-Kai Liu*,†,‡ †

Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, P. R. China ‡ Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, P. R. China S Supporting Information *

ABSTRACT: An asymmetric organocatalytic direct arylation approach to construct arylated quaternary stereogenic centers with a catalyst loading of 1 mol % is reported. The formation of the hemiketal moiety in stabilizing the hydroquinone intermediate proves to be important in leading to hydroquinone products instead of oxidation quinone products obtained in previously reported methods. A series of structurally and stereochemically complex heterocyclic frameworks are obtained, including spiro-, dispiro-, fused, and bridged heterocycles.

T

Scheme 1. Previous Work and Our Designed Michael− Aromatization−Spiroketalization Sequence

he construction of a sterically congested arylated quaternary stereogenic center (AQSC) is a very important, but highly challenging task in the synthesis of biologically active natural and unnatural compounds.1 In this context, transitionmetal-catalyzed direct arylation, in which the aryl halides are generally used as the arylation reagents, provides an efficient solution to this problem.2 However, this method suffers from a number of drawbacks, including the use of air- or moisturesensitive organometallic reagents and costly transition metal catalysts, and these drawbacks may cause severe limitation from a practical point of view. In the past decade, much attention has been focused toward the development of asymmetric organocatalysis under operationally simple and environmentally friendly reaction conditions.3 However, exploring asymmetric organocatalytic direct arylation with general aryl halides as the arylation reagents seems difficult.4 Alternatively, quinones could be potentially used as the arylation reagents in many asymmetric organocatalyzed arylation reactions.5 However, despite the progress that has been achieved in this field, there remains a formidable challenge: the oxidation quinone products, rather than the real arylated hydroquinone products, were finally obtained in all developed approaches (Scheme 1, top),6 when quinones were used as the arylation reagents to construct AQSCs. This oxidation of hydroquinone to quinone may be carried out by molecular oxygen or in a catalytic manner with the quinone starting material.6e Clearly, avoiding the hydroquinone to quinone oxidation problem is the key to the success of organocatalytic direct arylation to construct an AQSC with quinones as the arylation reagents. Acetalization is one of the most fundamental methods for protecting a hydroxy group. Recently, we focused our attention © XXXX American Chemical Society

on the chemistry of chroman-2-ol,7 which contained a hemiacetal moiety. We therefore surmised that the aforementioned oxidation problem of hydroquinone to quinone may be obviated by introduction of a carbonyl group to stabilize the hydroquinone unit through the formation of hemiacetal. Namely, in the designed reaction process (Scheme 1, middle), quinone reacted first with bifunctional substrate I to provide Michael adduct II, followed by proton transfer to give the arylated product III that has a hydroquinone unit. The subsequent intramolecular formation of chroman-2-ol IV between the hydroxy group of the hydroquinone unit and Received: February 2, 2018

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DOI: 10.1021/acs.orglett.8b00377 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

surprise, 3-alkyl-3-aryloxindole 5a was obtained as the only product in high yield with excellent enantioselectivity, while the spirocyclic 5′a, which should be generated from the proposed hemiketal intermediate, was not detected at all by TLC and NMR analysis of the crude reaction mixture. To the best of our knowledge, at least under these conditions, we documented the first organocatalyzed direct arylation of 3-alkyl oxindole, which provides a straightforward route to 3-alkyl-3-aryloxindoles with high enantioselectivity. Unsurprisingly, the reaction exhibited much lower reactivity and selectivity when β-isoquinidine (3b, R = Me) was used as the catalyst, demonstrating the key role of the free OH of 3a in the catalytic process. Furthermore, dehydration of the equilibrium mixture of 4a and 4′a mediated by p-toluenesulfonic acid (p-TSA, 10 mol %) in CH2Cl2 at 25 °C furnished the chiral spirooxindole 6a with high enantioselectivity. When CH2Cl2 was replaced by MeOH, spirooxindole 7a, which contained two tetrasubstituted carbon stereocenters, was afforded as a single diastereomer. Moreover, treatment of 6a with p-TSA in MeOH at 25 °C did not result in the formation of 7a, suggesting that 7a may be formed directly from 4′a under acidic conditions via an in situ generated oxonium ion. To lend further credence to our hypothesis that the ketone carbonyl group is important to avoid the oxidation of hydroquinone to quinone by forming a hemiketal intermediate, 2′a was synthesized by removing the ketone carbonyl group of 2a. The oxidation quinone product 8′a was definitely formed under the standard conditions with good enantioselectivity, along with the arylated product 8a (Scheme 3, a). It should be

carbonyl group is proposed to prevent the oxidation of hydroquinone III to quinone V. It should be noted that this method provides a potentially superior strategy to the preparation of synthetically and biologically important chroman-2-ol derivatives containing two tetrasubstituted carbon stereocenters, one being AQSC. Herein, we present our initial results in this regard. As part of our continued interest in the efficient synthesis of spirooxindoles,8 the easily prepared 3-keto-oxindole derivatives 2 were finally chosen as the bifunctional substrate I to test our hypothesis (Scheme 1, bottom, EWG = electron-withdrawing group), for the following reasons: (1) the 3-keto-oxindole derivatives 2 have never been used in this designed Michael− aromatization−spiroketalization sequence to synthesize chroman-2-ol-containing heterocycles; (2) the high nucleophilicity at the C3 position of 2 could potentially promote the reaction to afford chiral 3-alkyl-3-aryloxindoles and spirooxindoles, both of which are recognized as attractive structures and important synthons because of their prevalence in a large number of natural and unnatural bioactive molecules;9 (3) the functionalized oxindole derivatives containing the hemiketal or hemiacetal moiety may be used as highly versatile functional handles for the facile preparation of biologically useful molecules. With such a design principle in mind, we initiated the optimization study by screening different bifunctional catalysts in the reaction between quinone 1a and 3-keto-oxindole 2a in CH2Cl2 as the solvent (Scheme 2, Boc = tert-butoxycarbonyl; Scheme 2. Selected Optimization Studies

Scheme 3. Control Experiments

noted that the ketone carbonyl group may not be involved in the stereodetermining step since a similar good ee value was obtained for 5a (92%) and 8a (88%), respectively. Delightedly, the proposed key hemiketal intermediate could be further trapped by an ester group (Scheme 3, b). Treatment of 9 with 1a under standard conditions affords the structurally complex dispiro molecule 10 as a single diastereomer in a one-pot procedure. All these results indicated that the ketone carbonyl group in reactant 2 was important to this asymmetric organocatalyzed direct arylation of 3-keto-oxindoles with quinones as the arylation reagents. As shown in Scheme 4, the designed diversity-oriented onepot process was amenable to a series of quinone 1 and 3-ketooxindole 2 with various R1/R2/R3/R4 groups, leading to the production of either nonspirocyclic or spirocyclic oxindole derivatives 5, 6, and 7, respectively. When R2 is an aryl or heteroaryl group, the desired products 5a−g, 6a−g, and 7a−g were obtained in moderate to good yield (50−95%) with good to excellent enantioselectivities (up to 99% ee), regardless of the electronic nature and sites of substituents on the aromatic ring.

DMAP = 4-dimethylaminopyridine; Ac = acetyl).10 We found that, without any precautions to exclude air,6e a low loading of easily prepared β-isocupreidine 3a (β-ICD, 1 mol %) efficiently catalyzed the conjugated addition leading to the potential equilibrium mixture of hydroquinone 4a and hemiketal 4′a. As expected, the oxidation of hydroquinone to quinone, which occurred in previously reported methods under similar conditions, has been completely avoided, and therefore no oxidation quinone product 4aa was observed. Of note is that further acylation were carried out in order to provide stable compounds for a clear and reliable determination. Much to our B

DOI: 10.1021/acs.orglett.8b00377 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 4. Substrate Scope of the Reaction of 1 and 2a

Scheme 5. Substrate Scope of the Diversity-Oriented Process Initiated by the Transformation of 6a

a

See the Supporting Information for more details. For 5a−k, 6a−i, and 7a−k, R1 = OMe, R3 = Boc; for 6j−o, R1 = OMe, R2 = Ph, R4 = H. Isolated yields are given. Enantiomeric excess (ee) determined by chiral HPLC analysis. Troc = 2,2,2-trichloroethoxycarbonyl; Cbz = carbobenzyloxy; Fmoc = 9-fluorenylmethoxycarbonyl.

a

See the Supporting Information for more details. For 12a−g, R3 = Cbz. Isolated yields are given. Enantiomeric excess (ee) determined by chiral HPLC analysis.

Additionally, the reaction showed high efficiency and good tolerance with different substitution patterns of R4 on the oxindole moiety (5h−i, 6h−i, and 7h−i). 2-Naphthyl, and even a methyl group, could be used instead of an aryl group as R2 (5j−k and 7j−k). Moreover, it has been shown that this procedure is applicable to the simple quinone (5l, performed at −55 °C). Furthermore, when switching the N-protecting group (R4, 6j−o) from Boc to benzoyl, cinnamoyl, CO2Me, Troc, Cbz, and Fmoc, we found that Cbz produced enantiopure spirooxindole 6n, while benzoyl- and cinnamoyl-protected products 6j and 6k were formed, respectively, only with moderate enantiocontrol. It should be noted that all products 7a−7k were obtained with two tetrasubstituted carbon stereocenters as a single diastereoisomer. Furthermore, the reaction could be amenable to gram-scale synthesis [7e, 900 mg, 70%, 96% ee (99% ee after recrystallization)]. Next, we studied the possibility to construct more complex molecules by using this protocol (Scheme 5). Treatment of some representative compounds 6 with NaBH4 in MeOH could generate multisubstituted hemiaminal 11, which might be suitable for a more challenging diversity-oriented process. To our delight, the m-chloroperbenzoic acid (m-CPBA) triggered an epoxidation−ring opening reaction sequence of 11 delivering bridged, spirocyclic N,O-aminal 12, which not only contained two tetrasubstituted and four continuous stereocenters but also combined both the biologically important indoline core and chromane core in the molecules. It appeared that both the electronic and steric properties of R1 and R2 had no effect on the outcome of this stepwise sequential process, and in all the examples studied, a good isolated yield and excellent stereoselectivity (single diastereoisomer and up to 99% ee) were attainable (Scheme 5, 12a−g). Moreover, the utility of hemiaminal 11 in the diversity-oriented process could be further demonstrated by approaching 6,5,7,6-fused ring systems. In the presence of BF3·Et2O, hemiaminal 11, regardless of the

substituents of both R1 and R2, could be conveniently transformed into polycyclic compounds 13a−g in good yield, albeit losing all chiral centers. Notably, the Boc group survived these acidic reaction conditions, leading to 12h and 13h both in good yield, although in the case of 12h with slightly decreased enantioselectivity. Unexpectedly, under slightly harsher reaction conditions (conc. HCl at 80 °C) and in the presence of a large excess of 2,2-dimethoxypropane (>15 equiv), the Boc-protected spirocyclic oxindole 6a could be easily converted into structurally complex enantioenriched fused and bridged tetracycle 14a′ with two tetrasubstituted chiral centers, albeit as a relatively less stable compound. Pleasingly, with the methyl protection of the free OH in 6, 14a−f could be obtained as quite stable compounds in good yield with excellent enantioselectivity as a single diastereoisomer, regardless of the properties of both substituents R1 and R2. The absolute configuration of product 7e (CCDC 1813917) as well as the relative configuration of products 12a (CCDC 1813918) and 14a′ (CCDC 1813919) were determined by Xray crystallographic analysis (Scheme 6, the hydrogen atoms are omitted for clarity), and the other products were assigned by analogy. Scheme 6. X-ray Structures of Products 7e, 12a, and 14a′

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DOI: 10.1021/acs.orglett.8b00377 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters *E-mail: [email protected].

As mentioned before, the obtained structurally and stereochemically complex heterocycles combining both indoline and chromane moieties in the molecules may have intriguing biological activities. All the synthesized products were then evaluated for their in vitro cytotoxic activities against five different human cancer cell lines with doxorubicin as the positive control. As expected, we found that compounds 7 exhibited promising activity against several cancer cell lines, such as Hela, K562, A549, and HCT-116 cell lines (Table 1), with IC50 values

ORCID

De-Hai Li: 0000-0002-7191-2002 Yan-Kai Liu: 0000-0002-6559-2348 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the NSFC-Shandong Joint Fund for Marine Science Research Centers (No. U1606403), the Scientific and Technological Innovation Project Financially Supported by Qingdao National Laboratory for Marine Science and Technology (No. 2015ASKJ02-06), and the Fundamental Research Funds for the Central Universities (Nos. 201562031; 201762011).

Table 1. Cytotoxic Activities of Some Obtained Complex Heterocyclic Compounds IC50 (μM)

a

compound

K562

HL-60

HCT-116

Hela

A549

ADMa 7b 7c 7e 7f

0.25 1.38 1.98 4.53 2.89

0.02 9.60 >50 >50 >50

0.20 0.41 0.84 3.31 1.64

0.60 1.27 2.35 7.63 3.78

0.15 2.04 8.96 23.48 12.19

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ADM = doxorubicin (positive control).

ranging from 0.41 to 31.45 μM (see the Surpporting Information); among them, 7b exhibited astonishing activities against all tested cell lines, indicating its potential to be a novel type chemotherapeutic agent. In conclusion, we have reported an asymmetric organocatalytic direct arylation to construct a sterically congested arylated quaternary stereogenic center.11 The salient features of this novel protocol are readily available reagents, a low catalyst loading, operational simplicity, and structurally complex products. The introduction of a ketone carbonyl group to form the hemiketal intermediate is the key to the success of this designed transformation, which could avoid the oxidation of hydroquinone to quinone, thus affording the real arylated hydroquinone products, which has never been realized in the arylation of 3-alkyl oxidoles with quinones as the arylation reagents. This diversity-based strategy provides facile access to synthetically useful complex heterocyclic frameworks, including spiro-, dispiro-, fused, and bridged heterocycles. Additionally, it was shown that several obtained products display potent biological activities. Further applications of this strategy toward the synthesis of complex molecules are currently underway.

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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/acs.orglett.8b00377. Detailed optimization, experimental procedures, spectroscopic data for all new compounds (PDF) Accession Codes

CCDC 1813917−1813919 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 [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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REFERENCES

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. D

DOI: 10.1021/acs.orglett.8b00377 Org. Lett. XXXX, XXX, XXX−XXX