Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Phenanthridine-Fused Tetracyclic Ring System: Metal-Free Diastereoselective Modular Construction of Highly Constrained Polyheterocycles via Post-Ugi Tandem Modifications Karandeep Singh,†,‡ Bhanwar Kumar Malviya,† Pradeep K. Jaiswal,§ Ved Prakash Verma,∥ Swapandeep Singh Chimni,‡ and Siddharth Sharma*,† †
Department Department § Department ∥ Department
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‡
of of of of
Chemistry, Mohanlal Sukhadia University, Udaipur 313001, India Chemistry, Guru Nanak Dev University, Amritsar 143005, India Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, United States Chemistry, Banasthali University, Newai-Jodhpuriya Road, Vanasthali 304022, India
S Supporting Information *
ABSTRACT: A metal-free diastereo-/regioselective modular synthetic approach for the synthesis of highly constrained tetrahydroquinoline-fused tetracyclic heterocycles from easily available substrates has been developed. This two-step strategy utilizes an Ugi four-component reaction, followed by the intramolecular spirocarbocyclization and iodination reactions in a single operation. The transformation is mild and operationally simple, which provides architecturally complex polycyclic heterocycles with high diastereoselectivity. Furthermore, the preliminary cytotoxicity screening of selected compounds displayed promising anticancer activity against human cancer cell lines.
F
environmentally benign conditions is a real challenge and is in great demand. Over the years, the metal-free rapid construction of natural products mimicking novel complex molecular scaffolds having functional diversity has fascinated synthetic organic chemists.3 In this context, the development of diversity-oriented syntheses (DOSs)4,5 has given streamlined access to diverse molecular frameworks that can be difficult to prepare using classical organic synthesis. This approach has unfolded the hidden chemical space within the molecules along with maximum stereochemical diversity just by tethering the suitable functional groups. Multicomponent reactions (MCRs) have enormous capabilities to increase the molecular complexity as well as the diversity in organic molecules.6,7 Among the variants of MCRs,8 isocyanide-based multicomponent reactions (IMCRs) such as the four-component Ugi reaction9 have gained extreme popularity because of their ability to perform tandem reactions to construct complex polycyclic heterocycles.10 Recently, Van der Eycken’s group has reported several important contributions to the construction of complex heterocyclic scaffolds using post-Ugi modifications. For
used phenanthridines and tetrahydroquinolines containing constrained scaffolds are present in various alkaloids (Figure 1).1,2 These alkaloids exhibit a broad spectrum of
Figure 1. Representative erythrina and lycorine classes of alkaloids having tetrahydroquinoline- and phenanthridine-fused complex bioactive polycyclic heterocycles.
activities such as antimitotic, antineoplastic, and antiviral activities and insect antifeedant activities. Additionally, they inhibit the cell-division process in higher plants, the in vivo growth of a murine transplantable tumor, and the DNA synthesis in murine cells.1,2 Because of their vast biological importance, the development of new synthetic strategies to enhance the chemical space from a simple substrate under © XXXX American Chemical Society
Received: July 7, 2019
A
DOI: 10.1021/acs.orglett.9b02340 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters example, in 2017, Van der Eycken et catalyzed domino cyclization of the synthesis of fused aza-spiro tetracyclic tization of phenol and its derivatives
Previously, the Ugi adducts have been reported for the electrophilic ipso cyclization cascade to construct complex spirocyclic compounds via ortho- and para-activated amines. In principle, relatively unknown electrophilic ipso cyclization using the unactivated amine component is a challenging task because unlike previous works, the Ugi adduct might form a less stable carbocation intermediate (Figure 2). We speculated
al. reported the goldUgi adduct for the scaffolds by dearoma(Scheme 1a).11 Very
Scheme 1. Some Previous and Present Reports for the Synthesis of Fused Polyheterocycles via Dearomative PostUgi Modifications
Figure 2. Plausible mechanism for the synthesis of 6 via domino cyclization and ORTEP diagram of 6a with 30% probability factor.
that Ugi adducts (derived from the unactivated amine component) in the presence of a strong electrophile (I+) may undergo ipso cyclization via a less stable spirocyclic carbocation intermediate, along with immediate trapping by an intramolecular nucleophile, which can afford the novel ring annulations with high structural complexity. With this purpose in mind, we commenced our investigation by synthesizing Ugi adduct 5a, as a model substrate, from the four component Ugi reaction using unsubstituted aniline (1a), 2,5-dimethoxybenzaldehyde (2a), 3-phenylpropiolic acid (3a), and tert-butyl isocyanide (4a) in methanol at room temperature. Next, the model substrate 5a was reacted with molecular iodine in 1,2dichloroethane (DCE) at room temperature for 12 h. To our delight, the desired cyclized product 6a was isolated in 34% yield (Table 1, entry 1). Furthermore, switching to the other solvents likes MeCN and dichloromethane (DCM) under similar conditions did not improve the yield (Table 1, entries 2 and 3). Surprisingly, the use of iodine monochloride in DCE yielded the desired product 6a exclusively in 84% yield (Table 1, entry 4). Among the various electrophiles, such as I2, ICl, NIS, and IBr (Table 1, entries 1, 4, 6, and 7), in DCE solvent, iodine monochloride (ICl) furnished 6a in the best yield at room temperature for 12 h (Table 1, entry 4). Notably, switching the solvent from DCE to MeCN further reduced the yield of 6a (Table 1, entry 5). Additionally, the temperature and reaction time were also investigated to get the improved yield of 6a. Increasing the temperature to 80 °C decreased the yield to 58% (Table 1, entry 8), whereas increasing or decreasing the reaction time could not improve the yield of 6a (Table 1, entries 9 and 10). Furthermore, varying the electrophile amount loading could not increase the yield of
recently, the same group reported the gold-catalyzed post-Ugi cyclization reaction to synthesize a diverse polyheterocyclic framework using the dearomatization/ipso-cyclization/Michael sequence (Scheme 1b).12 In addition, an elegant metal-free acid-catalyzed intramolecular ipsocyclization approach via a post-Ugi reaction cascade has also been disclosed by Srivastava’s group for the construction of fused tricyclic-alkaloid-mimicking skeletons (Scheme 1c).13 Overall, the common strategy of the aforementioned methods is two tandem cyclizations from the Ugi adduct to generate complexity in a single step. However, these protocols utilize either expensive gold catalysts or toxic acid catalysts, and at the same time, preactivated amines or aldehydes in the Ugi adduct are a prerequisite for the ipso cyclization to achieve the complexity.11−14 Herein we report a conceptually different metal-free modular approach for the synthesis of novel polyheterocycles using a post-Ugi intramolecular carbocyclization/iodination reaction cascade (Scheme 1d). The key feature of this developed strategy is the two domino cyclizations, followed by two C−C bond formations along with iodination in a single step with high distereoselectivity. B
DOI: 10.1021/acs.orglett.9b02340 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization Study for the Synthesis of 6a from Ugi Adduct 5aa,b
entry no.
solvent
electrophile
1 2 3 4 5 6 7 8 9 10 11 12 13d
DCE CH3CN DCM DCE CH3CN DCE DCE DCE DCE DCE DCE DCE DCE
I2 (2.5 equiv) I2 (2.5 equiv) I2 (2.5 equiv) ICl (2.5 equiv) ICl (2.5 equiv) NIS (2.5 equiv) IBr (2.5 equiv) ICl (2.5 equiv) ICl (2.5 equiv) ICl (2.5 equiv) ICl (2.0 equiv) ICl (3.0 equiv) ICl (2.5 equiv)
temp time (h) rt rt rt rt rt rt rt 80 rt rt rt rt rt
12 12 12 12 12 12 12 12 20 8 12 12 12
Scheme 2. Substrate Scope of the Cascade Dearomative Spirocarbocyclization/Iodination Processa,b
yield of 6a (%)b,c 34 20 28 84 51 0 39 58 75 57 70 80 68
a Reaction conditions: All reactions were performed with 5a (0.1 mmol) in a screw-cap culture vial with solvent (3.0 mL). b Diastereomeric ratio of 6a in crude product is >20:1 in all reactions based on the 1H NMR analysis. cIsolated yields. dReaction stopped at dearomatization when the iodocylization of 4-methoxy aniline-derived Ugi reaction product 5aa was performed in place of aniline. (See the Supporting Information for details.)
6a (Table 1, entries 11 and 12). Thus ICl was found to be the best source of electrophile, which afforded 6a in 84% yield after 12 h at room temperature in DCE solvent (Table 1, entry 4). The desired product 6a was fully characterized by its spectroscopic analysis, such as NMR and HRMS, and was further confirmed by X-ray crystallography (Figure 2). To explore the substrate scope and the generality of the present methodology, a variety of Ugi adducts 5a−q were synthesized from readily available starting substrates using several substituents on the isonitriles, propiolic acids, amines, and aldehydes. The Ugi adduct 5a−q isolated in 67−91% yield was further subjected to optimized reaction conditions, and, interestingly, the reaction was well amenable with substituted phenyl propiolic acids (Scheme 2, 6a−f, yield = 64−87%). The electronic factors of the substituent present on the phenyl propiolic acid also influenced this transformation to some extent. An electron-donating substituent tethered on the phenyl propiolic acid yielded the requisite products in better yield (6c, 6e,f, 6g−i, 6m,n) in comparison with the fluorinesubstituted propiolic acid adducts, which afforded relatively moderate yield (6d and 6l).Ugi adducts derived from 3,4,5trimethoxy and 2,5-dimethoxy aldehyde combined with the different isocyanides, that is, 1,1,3,3-tetramethylbutyl isocyanide and ethyl isocyanoacetate (EtOOC−CH2−NC), under the standard optimized reaction conditions (entry 6g−i) led to the required product in good yield (71−76%). Moreover, functionalized aldehyde, phenyl propiolic acid, and cyclohexylisocyanide-derived Ugi adduct 5j−n furnished the cyclized product 6j−n in moderate to good yield (58−77%). It is
a
Reaction conditions: All reactions were performed with 5a−a′ (0.1 mmol) and ICl (2.5 equiv) in DCE (3.0 mL) at room temperature for 12 h in a screw-cap culture vial. bDiastereomeric ratios of 6a−q in crude products are >20:1 based on the 1H NMR analysis. cIsolated yields.
noteworthy to mention that the aliphatic acids having Ugi adduct 5o,p also furnished the desired product in good yield (entry 6o,p). As far as the substitution on amine is concerned, the 3-methyl-substituted aniline-derived Ugi adduct afforded the cyclization for the synthesis of 6q in 86% yield. Furthermore, several aliphatic as well as aromatic substituted isocyanides such as 1,1,3,3-tetramethylbutyl, ethyl isocyanoacetate, Cy (cyclohexyl), n-pentyl, and 2,6-dimethyl phenylderived Ugi adducts were also examined under our optimized reaction conditions and furnished the desired cyclized products 6r−a′ in moderate to good yield (Scheme 2; yield = 52−83%). Among the aliphatic isocyanides, only n-pentyl isonitrileC
DOI: 10.1021/acs.orglett.9b02340 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Table 2. IC50 Values (in μM) of Some Selected Analogues in Human Cancer Cell Linesa
derived Ugi adduct gave the minimum yield (Scheme 2, 6u, yield = 52%). Furthermore, the aromatic isonitrile-based (i.e., 2,6-dimethylphenyl isocyanide) Ugi adduct resulted in the desired cyclized product (6v and 6z) in moderate yield (62 and 56%, Scheme 2), which may be due to the possible steric hindrance of two methyl groups tethered on the phenyl ring. Moreover, the scalability of the developed methodology was also demonstrated by performing a gram-scale synthesis of 6a, which was obtained in 78% yield. A plausible mechanism of the domino cyclization from 5 to the desired 6, is depicted in Figure 2. In the first step, an iodonium (I+) ion induced the π activation of the alkyne moiety of the Ugi adduct 5 to generate the intermediate II. Next, the ipso nucleophilic attack of the aniline to the activated triple bond is switched on in a 5-endo-dig manner, affording the regioselective spirocyclic carbocation intermediate III. Subsequently, the immediate trapping of the carbocation by the intramolecular nucleophile underwent the Friedel−Crafts type cyclization to access the complex cyclized desired product 6. To further explore the reactivity of complex iodocylization products 6b and 6i, Suzuki coupling and Sonogashira coupling were performed using Pd catalysts (Figure 3). As expected, the desired products 7a and 7b were found in 63 and 72% yield, respectively.
no.
compounds
A549 (lung cancer)
1 2 3 4
6f 6n 6i doxorubicin
>15 >15 >15 NT
MCF-7 (breast cancer)
PC-3 (prostate cancer)
± ± ± ±
>15 >15 11.58 ± 0.26 NT
2.41 4.44 8.36 0.68
0.67 0.18 0.42 0.23
a
50% inhibitory concentration after 48 h of drug treatment. NT = not tested.
with a good substrate scope and excellent regio- and diastereoselectivity. Furthermore, the identification of the promising preliminary cytotoxic potential of selected compounds emphasized the practicality of this methodology. The extensive pharmaceutical potential of these molecules is currently under investigation and will be reported in due course.
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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.9b02340. Experimental procedures and compound characterization data, including the 1H/13C NMR spectra (PDF) Accession Codes
CCDC 1898047 contains 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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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected];
[email protected].
Figure 3. Suzuki and Sonogashira coupling reactions on 6b and 6i, respectively.
ORCID
Ved Prakash Verma: 0000-0003-2142-2459 Siddharth Sharma: 0000-0003-2759-4155
Because of the potential cytotoxic activity of this class of complex polyheterocycles,15a−c it was anticipated that the analogues would display cytotoxicity. Thus the selected synthesized compounds were evaluated for their cytotoxic activity against three human cancer cell lines, that is, A549 (lung cancer), MCF-7 (breast cancer), and PC-3 (prostate cancer), using an azolium-based colorimetric cytotoxicity assay (MTT assay).16 Trimethoxy-substituted compounds 6f, 6n, and 6i exhibited >50% cytotoxicity at 10 μM concentration (Table 2). These compounds were further selected to evaluate concentration-dependent responses and displayed promising antiproliferative activity against MCF-7 (breast cancer) cell lines, with IC50 values ranging from 2.41 ± 0.67 to 8.36 ± 0.42 μM (Table 2). The promising anticancer activity of these compounds further opens a new way to get a novel drug lead in cancer treatment. In conclusion, we have reported the first example of a cascade ipso cyclization of nonactivated amines for the synthesis of a polycyclic phenanthridine-fused constrained heterocyclic scaffold via post-Ugi cyclization. A variety of phenanthridine-fused heterocyclic scaffolds could be prepared
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by a UGC start-up research grant from UGC-New Delhi and a DST INSPIRE Faculty research grant (IFA-13 CH-113) to S.S. Work was partially supported by the DST-SERB grant no. DST-YSS/2015/001838 to V.P.V.
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REFERENCES
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