Total synthesis of (-)-agelastatin A via photochemical transformation of pyridinium salt and enzymatic kinetic resolution of aziridine João R. Vale 1,2 , Milene Fortunato 1 , Filipa Siopa 1 , and Carlos A. M. Afonso 1 1 University of Lisbon, Portugal, 2 Tampere University, Finland Agelastatin alkaloids have attracted scientific interest since the isolation of (-)-agelastatin A (AglA) from the sponge Agelas dendromorpha by Pietra et al . in 1993. 1 AglA showed remarkable cytotoxicity against a variety of tumour cells 2 and strong inhibition of osteopontin-mediated neoplastic transformation and metastasis. 3 Additionally, it displays high brine shrimp toxicity and insecticidal properties. 4 Since large quantities of AglA are unreasonable to obtain via natural sources, its total synthesis is highly desirable and some have been developed. 5 Asymmetric synthesis is challenging and requires laborious steps and protecting groups to construct the four contiguous nitrogen-bound stereocenters of the cyclopentane C-ring. We have developed a strategy (Scheme 1) that involves the early-stage photochemical transformation of pyridinium salts (I) to bicyclic vinyl aziridines (II) that originate, in one step, the AglA's C-ring with the desired functionality and relative configuration. The presence of a secondary alcohol on the cyclic core allowed enzymatic kinetic resolution in high ee (>98%). Both mentioned transformations were performed under flow conditions to increase the efficiency and scale of the processes. Then, a sequence of nitrogen-carbon bond forming reactions culminated in the total synthesis of (-)-agelastatin A in only 12 steps with 4% overall yield, with the use of a single protective group.
Scheme 1: Retrosynthetic analysis of (-)-agelastatin A. The authors acknowledge Fundação para a Ciência e Tecnologia (FCT)(UIDB/04138/2020, UIDP/04138/2020, SFRH/BD/120119/2016)for financial support. The project leading to this application has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 951996. References 1. M. D’Ambrosio, A. Guerriero, C. Debitus, O. Ribes, J. Pusset, S. Leroy and F. Pietra, J. Chem. Soc. Chem. Commun. , 1993 , 1305–1306. 2. M. D’Ambrosio, A. Guerriero, M. Ripamonti, C. Debitus, J. Waikedre and F. Pietra, Helv. Chim. Acta , 1996 , 79 , 727–735. 3. C. K. Mason, S. McFarlane, P. G. Johnston, P. Crowe, P. J. Erwin, M. M. Domostoj, F. C. Campbell, S. Manaviazar, K. J. Hale and M. El-Tanani, Mol. Caner Ther. , 2008 , 7 , 548–558.
4. T. W. Hong, D. R. Jimenez and T. F. Molinski, J. Nat. Prod. , 1998 , 61 , 158–161. 5. S. W. M. Crossley and R. A. Shenvi, Chem. Rev. , 2015 , 115 , 9465–9531.
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