Synthesis of disubstituted tetrahydroisoquinolines by means of metal-catalyzed pictet-spengler reaction Luana Grmusa and Daniel A. Cruz Instituto de Productos Naturales y Agrobiología, CSIC, España Tetrahydroisoqinolines are quite of interest due to their wide range of biological activities, such as antitumor and antimicrobial activity as well as due to their modulation of sodium and potassium channels which leads to antiepileptic and analgesic effects. 1,2 Likewise, as such or in their oxidized form, they are part of more complex structures and with different biological activities, such as the Saframycins family, safracins, and even the ecteinascidine 743 complex (Yondelis ®). 3 There are several methods to obtain the tetrahydroisoquinolines, being the Pictet-Spengler reaction one of the most effective. It usually consists of the intramolecular condensation of an amine that reacts with aldehydes in the presence of strong mineral acids. 4 In our case, we have focused on the synthesis of disubstituted tetrahydroisoquinolines in the alpha position of the nitrogen group which appears in a multitude of natural products, as we have previously described. 3
Scheme 1 .- Outcome for the metal-catalyzed Pictet-Spengler reaction. In our research group, we have developed a straightforward metal-catalyzed methodology that allows the preparation of a wide range of potentially biologically active disubstituted tetrahydroisoquinolines in a short pathway and with good yields. Acknowledgments: This research was supported by the Ministerio de Ciencia e Innovación (MCIN), la Agencia Estatal de Investigación (AEI), and Fondo Europeo de Desarrollo Regional (FEDER). Grant PID2021-126747NB-I00 funded by MCIN/AEI/ 10.13039/501100011033 and by “ERDF A way of making Europe.” References 1. Scott, J. D., & Williams, R. M. (2002). Chemistry and biology of the tetrahydroisoquinoline antitumor antibiotics. Chemical Reviews , 102 (5), 1669–1730. 2. Glas, C., Wirawan, R., & Bracher, F. (2021). A Short Approach to N -Aryl-1,2,3,4-tetrahydroisoquinolines from N -(2-Bromobenzyl)anilines via a Reductive Amination/Palladium-Catalyzed Ethoxyvinylation/Reductive N -Alkylation Sequence. Synthesis (Germany) , 53 (11), 1943–1954. 3. Saito, N., Harada, S., Yamashita, M., Saito, T., Yamaguchib, K., & Kuboa, A. (1995). Synthesis of Saframycins. XI. Synthetic Studies toward a Total Synthesis of Safracin A (Vol. 51, Issue 30). 4. Fishlock, D., & Williams, R. M. (2008). Synthetic studies on Et-743. Assembly of the pentacyclic core and a formal total synthesis. Journal of Organic Chemistry , 73 (24), 9594–9600. 5. Larsson, R., Blanco, N., Johansson, M., & Sterner, O. (2012). Synthesis of C-1 indol-3-yl substituted tetrahydroisoquinoline derivatives via a Pictet-Spengler approach. Tetrahedron Letters , 53 (37), 4966–4970.
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