Synthesis of hydroxylated pyrrolidine and pyrrolizidine compounds from isoxazolidine diols

Authors: Lívia Dikošová 1    Róbert Fischer 1   
1 Institute of Organic Chemistry, Catalysis and Petrochemistry, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, 812 37 Bratislava, Slovak Republic   
Year: 2020
Section: Organic, bioorganic and pharmaceutical chemistry, pharmacology
Abstract No.: 1878
ISBN: 978-80-972360-6-9

Hydroxylated pyrrolidine and pyrrolizidine compounds are a common structural motive amongst the wide range of natural products that exhibit interesting inhibition activities and are considered as possible drug candidates in the treatment of various kinds of illnesses. Our main synthetic target, a pyrrolizidine alkaloid (+)-hyacinthacine C3, was isolated from Scilla socialis and shows a good inhibition activity against C. saccharolyticum ß-glycosidase (IC50 = 25μM) and bovine liver ß-galactosidase (IC50 = 52 μM). [1,2]

This work builds on the ongoing interest of our research group in the synthesis and utilisation of isoxazolidine-4,5-diols. [3] Owing to the hemiacetal character of the anomeric isoxazolidine diols, we were already able to synthesize (-)-hyacinthacine B2, starting from sugar derived nitrone and with 1,3-dipolar cycloaddition and Horner-Wadsworth-Emmons olefination as the key steps. [4]

This report deals with the synthesis of polyhydroxylated pyrrolizidine alkaloid (-)-hyacinthacine C3 and its C-5 isomer starting from a sugar derived five-membered cyclic nitrone that undergoes a syn-stereoselective 1,3-dipolar cycloaddition with vinylene carbonate. The essential step of this synthesis is Wittig olefination of the prepared bicyclic isoxazolidine-2,3-diol with stable P-ylide, which is followed by reduction of the ethyl ester group to build up the primary hydroxymethyl substituent. Next, the reductive cleavage of the weak N-O bond offers a pyrrolidine derivative with an alkenol sidechain that undergoes intramolecular iodocyclisation, leading to a mixture of pyrrolizidines with the configuration of the natural hyacinthacine C3 and its C-5 isomer. The desired products can be obtained by final dehalogenation and deprotection.

We would like to thank gratefully to the Slovak Grant Agencies (VEGA, project no. 1/0552/18 and ASFEU, ITMS project nos. 26240120001, 26240120025).
[1] Imminosugars: from Synthesis to Therapeutic Applications, ed. P. Compain and O. R. Martin, Wiley & Sons, Chichester, 2007.
[2] Kato, A.; Kato, N.; Adachi, I.; Hollinshead, J.; Fleet, G. W. J.; Kuriyama, C.; Ikeda, K.; Asano, N.; Nash, R. J. J. Nat. Prod. 2007, 70, 993.
[3] a) Fischer, R.; Stanko, B.; Prónayová, N. Synlett 2013, 24, 2132; b) Beňadiková, D.; Čurillová, J.; Lacek, T.; Rakovský, E.; Moncol', J.; Doháňošová, J.; Fischer, R. Tetrahedron 2014, 70, 5585; c) Záborský, O.; Malatinský, T.; Marek, J.; Moncol, J.; Fischer, R. Eur. J. Org. Chem. 2016, 23, 3993.
[4] Malatinský, T.; Otočková, B.; Dikošová, L.; Fischer, R. Chemistry Select 2019, 4, 4233.