University of Groningen
Glutarimide Alkaloids Through Multicomponent Reaction Chemistry
Konstantinidou, Markella; Kurpiewska, Katarzyna; Kalinowska-Tluscik, Justyna; Dömling,
Alexander
Published in:
European Journal of Organic Chemistry DOI:
10.1002/ejoc.201801276
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Publication date: 2018
Link to publication in University of Groningen/UMCG research database
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Konstantinidou, M., Kurpiewska, K., Kalinowska-Tluscik, J., & Dömling, A. (2018). Glutarimide Alkaloids Through Multicomponent Reaction Chemistry. European Journal of Organic Chemistry, (47), 6714-6719. https://doi.org/10.1002/ejoc.201801276
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Markella Konstantinidou†, Katarzyna Kurpiewska‡,
Justyna Kalinowska-Tłuscik‡ and Alexander
Dömling†*
†Department of Drug Design, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands ‡Faculty of Chemistry, Jagiellonian University, 3 Ingardena Street, 30-060 Krakow, Poland
ABSTRACT: The concise four step synthetic route for glutarimide alkaloids of high biological interest is presented. The scaffold is
accessed via an Ugi four component reaction, hereby introducing two points of variation. This is followed by a hydrolysis, a cy-clization under mild conditions and an amine deprotection. The diastereomers of the cyclized intermediate can be separated, thus leading to optically pure alkaloids. Via this route, four natural products and ten derivatives were synthesized.
The glutarimide moiety (2,6-piperidinedione) is present in a number of natural product scaffolds and is linked to diverse biological activities. In medicinal chemistry, the glutarimide scaffold is present in derivatives with antibiotic,1 antiviral,2,3 anti-inflammatory4 and neuroregenerative properties5, just to name a few. Glutarimide – containing polyketides have shown cell migration inhibitory activity,6 and glutarimide macro-ketones are effective against cancer metastasis.7
Glutarimide alkaloids are an important class of natural products. The scaffold is present in the structure of Julo-crotine, which has shown antiproliferative effects in in vitro tests against the promastigote and amastigote forms of Leish-mania amazonensis.8
The Julocrotine structure was elucidated in 1961 with a se-ries of degradation reactions9 and a report in 1974 showed the synthesis of a lower homologue using harsh conditions.10 In 2011, a six step synthesis starting from L-glutamic acid was described.11 Shortly afterwards, a four-step synthesis was described starting from Cbz-glutamine. 12 In this case, the key amine intermediate was used as the amine component of an Ugi reaction, but with limited diversity. Moreover, a stereose-lective synthesis for Julocrotine and structurally related glu-tarimide alkaloids was reported based on Boc-L-glutamine. 13 (Figure 1)
Figure 1. Comparison of previous works with the current
approach.
All together, the previously reported methodologies are re-stricted to the synthesis of only one alkaloid, not allowing the efficient synthesis of derivatives. However, the establishment
of a convenient synthetic route for structurally related natural products and derivatives is important for the further biological evaluation of this scaffold. Thus, we envisioned an efficient synthetic route with variation points, which was first estab-lished for the natural product Julocrotine. Multi-component reaction (MCR) chemistry allows the effective synthesis of complex scaffolds in a few steps having as starting points easily accessible and diverse building blocks. 14,15,16
Retrosynthetically, the scaffold can be accessed via a 4-component Ugi reaction, followed by an intramolecular cy-clization (scheme 1).
Scheme 1. Retrosynthesis
The aldehyde was synthesized in two steps by applying pre-viously described conditions with slight modifications; 17,18,19 first the opening of γ-butyrolactone towards methyl hydroxybutanoate, and then the oxidation to methyl 4-oxobutanoate (Scheme 2).
Scheme 2. Aldehyde synthesis
We found that the use of pyridinium chlorochromate (PCC) resulted in much higher yields compared to the Swern oxida-tion. Oxidation by Dess-Martin periodinane led to lower yields than PCC and it was more challenging to reproduce the same yields.
Regarding the amine component, the chiral amine (R)-(+)-1-(4-methoxyphenyl)-ethylamine was chosen, in order to play also a protecting role during the intramolecular cyclization. The synthetic route was established as a mild four step synthe-sis; starting from a four-component Ugi reaction, then an ester hydrolysis, and followed by the intramolecular cyclization and the deprotection of the amine component (Scheme 3). From the Ugi reaction, a new chiral center is introduced; thus dia-stereomers are formed (in this case the diastereomeric ratio was 3:2). Interestingly, the diastereomers can be separated easily in the cyclization step with column chromatography. In the last step, the cyclized products were deprotected separate-ly. The initial attempt with hydrogenation and Pd/C was un-successful, but deprotection with refluxing TFA resulted in quantitative yield.
Scheme 3. Synthetic route for Julocrotine.
Conditions: (a) TFE, rt, 48h, 1M (b) LiOH, MeOH – H2O 2:1, rt, 5h (c) (CH3CO)2O, CH3COONa, reflux, 2h, diastereomers separtation by column chromatography, (d) TFA reflux, 24h The main question that remained unanswered from our syn-thetic route, was the assignment of stereochemistry for the final products. In order to determine the stereochemistry, a crystal structure was solved for one of the diastereomers in the cyclization step. This indicated that the isolated product (com-pound 3c-ii) was the (R,R,S) (figure 2). Thus, in order to ob-tain the major diastereomer with the correct stereochemistry, the synthesis was repeated with (S)-(-)-4-methoxy-α-methylbenzylamine. The optical rotations of the final products were the ultimate proof for confirming that the stereochemis-try is maintained in the deprotection step and by using the (S)-(-)-4-methoxy-α-methylbenzylamine the major product was the alkaloid Julocrotine.
Figure 2. Crystal structure of compound 3c-ii.
Furthermore, the same synthetic approach was successfully applied to the synthesis of Crotonimides A, B and C. For these three alkaloids the amino-component was the (S)-(-)-4-methoxy-α-methylbenzylamine, whereas the carboxylic acids were propionic acid for Crotonimide A, isobutyric acid for Crotonimide B and benzoic acid for Crotonimide C (scheme 4).
Scheme 4. Structures of Julocotine and Crotonimides A, B, C.
It is noteworthy that the diasteomeric ratios (S,S) : (R,S) as determined by separation in the cyclization step varied signifi-cantly. More specifically for crotonimides A and B the ratio (S,S) : (R,S) was 4:5 and 3:2, respectively. The greatest differ-ence was observed for crotonimide C with the ratio (S,S) : (R,S) being 1:5, thus the natural product was not the major one.
Next, we went on with the synthesis of a small library of de-rivatives. In the Ugi reaction, there are two points of variation: the carboxylic acid and the isocyanide component. The alde-hyde was kept constant due to its role in the cyclization. To investigate the scope and limitation, 10 derivatives were syn-thesized by using the (R)-(+)-1-(4-methoxyphenyl)-ethylamine and varying either the carboxylic acid or the isocyanide, as shown in the next scheme (scheme 5).
Scheme 5. Structures of derivatives.
The cyclization products were deprotected as racemic or diastereomeric mixtures, although it would have been possible to separate the diastereomers with column chromatography if necessary. The yields for the Ugi reaction varied from 24% to 53%, whereas for the hydrolysis step from 65% to 98% (Table 1). In the cylization step the yields varied significantly from 17% to 94%. Regarding the carboxylic acid variations in the cyclization step, the yields were moderate (benzofuran-2-carboxylic acid 14c (46%), pyridine-2-(benzofuran-2-carboxylic acid 15c (55%), acetic acid 7c (62%), cyclohexane-carboxylic acid 13c 67%), with the exception of meta-bromo-benzoic acid 16c (17%). The isocyanide variation in the same step resulted in moderate yields in the cases of the 3,4-dimethoxy-benzyl-isocyanide 8c (20%) and the 4-methyl-phenyl-3,4-dimethoxy-benzyl-isocyanide 12c (31%). On the contrary, the yields were high in the cases of 4-bromo-benzyl-isocyanide 9c (52%), 4-biphenyl-isocyanide
10c (72%) and 4-cyano-phenyl-isocyanide 11c (94%). The
deprotection of the amine led to high yields in all cases (70-98%).
Table 1. Isolated yields for the derivatives.
Acid Isocyanide Step 1 Step 2 Step 3 Step 4 53% (7a) 98% (7b) 62% (7c) 85% (7d) 52% (8a) 80% (8b) 20% (8c) 75% (8d)
50% (9a) 78% (9b) 52% (9c) 98% (9d) 37% (10a) 90% (10b) 72% (10c) 77% (10d) 40% (11a) 86% (11b) 94% (11c) 70% (11d) 36% (12a) 96% (12b) 31% (12c) 82% (12d) 55% (13a) 82% (13b) 67% (13c) 90% (13d) 24% (14a) 97% (14b) 46% (14c) 89% (14d) 41% (15a) 71% (15b) 55% (15c) 85% (15d) 29% (16a) 65% (16b) 17% (16c) 90% (16d)
It should be noted that although the use of 1-adamantyl-isocyanide resulted in the Ugi and hydrolysis products as expected, in the cyclization step under these conditions only unreacted starting material was obtained, probably due to steric hindrance. Furthermore, the use of the indole moiety, either as carboxylic acid or isocyanide component, resulted into complicated reaction mixtures in the Ugi reactions and products with low purity, which could not be used further. Interestingly, the use of meta-bromo-benzoic acid in the cy-clization step gave only one diastereomer (16c) (as indicated by NMR data), which was deprotected towards an enantiomer with optical rotation of aD = +13.57 (16d). This unexpected result is in good agreement with the data from crotonimide C, where the observed ratio (S,S) : (R,S) was 1:5. Probably due to steric hindrance one diastereomer is significantly favored during the cyclization step of the meta-bromo-benzoic deriva-tive and the other is probably formed in non-isolated traces.
Overall, we have established a straightforward, facile syn-thetic route for glutarimide alkaloids, allowing great diversity in the products, as well as the isolation of optically pure natu-ral products. By our synthetic route, the biological evaluation of the glutarimide alkaloids scaffold for multiple targets will be significantly facilitated in the future.
The Supporting Information is available free of charge on the ACS Publications website.
General experimental procedures; compound characterization data; 1H and 13C spectra of all compounds, SFC, HRMS (ESI), crystal structure (PDF).
* E-mail: a.s.s.domling@rug.nl.
All authors have given approval to the final version of the manu-script.
The authors declare no competing financial interest.
This research has been supported to (AD) by the National Institute of Health (NIH) (2R01GM097082-05), the European Lead Facto-ry (IMI) under grant agreement number 115489, the Qatar Na-tional Research Foundation (NPRP6-065-3-012). Moreover fund-ing was received through ITN “Accelerated Early stage drug dIScovery” (AEGIS, grant agreement No 675555) and, COFUND ALERT (grant agreement No 665250) and KWF Kankerbestrijding grant (grant agreement No 10504). The re-search was carried out with the equipment purchased thanks to the financial support of the European Regional Development Fund in the framework of the Polish Innovation Economy Operational Program (contract no. POIG.02.01.00-12-023/08).
(1) Guo, H.F; Li, Y.H; Zhang, T; Wang, S.Q; Tao, P.Z; Li, Z.R. J. Antibiot 2009, 62(11), 639-642.
(2) Chen, K.X; Nair, L; Vibulbhan, B; Yang, W; Arasappan, A; Bogen, S.L; Venkatraman, S; Bennett, F; Pan, W; Blackman, M.L; Padilla, Al; Prongay, A; Cheng, K.C; Tong, X; Shih, N.Y; Njoroge, F.G. J. Med. Chem. 2009, 52(5), 1370-1379. (3) Ji, X.Y; Zhong, Z.J; Xue, S.T; Meng, S; He, W.Y; Gao, R.M;
Li, Y.H; Li, Z.R. Chem Pharm Bull 2010, 58(11), 1436-1441. (4) Fox, D.J; Reckless, J; Warren, S.G.; Grainger, D.J. J. Med.
Chem. 2002, 45(2), 360-370.
(5) Christner, C.; Wyrwa, R.; Marsch, S; Küllertz, G; Thiericke, R.; Grabley, S.; Schumann, D.; Fischer, G. J. Med. Chem.
1999, 42(18), 3615-3622.
(6) Rajski, S.R; Shen, B. Chembiochem 2010, 24(11), 1951-1954. (7) Chen, L.; Yang, S.; Jakoncic, J.; Zhang, J.J.; Huang, X.Y.
Na-ture 2010, 464(7291), 1062-1066.
(8) Guimarães, L.R.; Rodrigues, A.P.; Marinho, P.S.; Muller A.H.; Guilhon, G.M.; Santos, L.S.; do Nascimento, J.L.; Sil-va, E.O. Parasitol Res. 2010, 107(5), 1075–1081.
(9) Nakano, T.; Djerassi, C.; Corral, R.A.; Orazi, O.O. J. Org. Chem., 1961, 26(4), 1184–1191.
(10) Stuart, K.L.; McNeill, D.; Kuntney, J.P.; Eingendorf, G.; Klein, F.K. Tetrahedron, 1973, 29, 4071-4075.
(11) Silva, L.L.; Joussef, A.C. J. Nat. Prod. 2011, 74(6), 1531-1534.
(12) Neves Filho, R.A.; Westermann, B.; Wessjohann, L.A. Beilstein J. Org. Chem. 2011, 7, 1504-1507.
(13) Teng, B.; Zheng, J.; Huang, H.; Huang P. Chin. J. Chem.
2011, 29, 1312-1318.
(14) Dӧmling, A. Chem. Rev. 2006, 106(1), 17-89
(15) Dӧmling, A.; Wang, W.; Wang, K. Chem. Rev. 2012 112(6), 3083-3135
(16) Zarganis – Tzitzikas, T; Chandgude A.L.; Dӧmling, A. Chem. Res. 2015, 15(5), 981-996
(17) Ohashi, A.; Satake, A.; Kobuke, Y. Bull. Chem. Soc. Jpn.
2004, 77(2), 365-374
(18) Gannett, P.M.; Nagel, D.L.; Reilly, P.J.; Lawson, T.; Sharpe, J.; Toth B. J. Org. Chem. 1988, 53(5), 1064-1071
(19) Gutman, A.L.; Boltanski, A. J. Chem. Soc. Perkin Trans. 1,
