Glycal-Type Enecarbamates: Straightforward Access to O- and S-Alpha-Glycoside Mimetics

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1st EuroCarb Young Researcher (ECYR) Workshop

CarboMet Workshop

Mini symposium: Glycobiology at the LUMC and beyond

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Glycal-Type Enecarbamates: Straightforward Access to O- and S-Alpha-Glycoside Mimetics

Elena M. Sánchez-Fernández 1 , Irene Herrera 1 , Cristina Nativi 2 , Abhijit Sau 3 , Carmen Galán 3 , José M García Fernández 4 , Carmen Ortiz Mellet 1

1 University of Seville, Seville, Spain, 2 University of Florence, Florence, Italy, 3 University of Bristol, Bristol, United Kingdom, 4 Instituto de Investigaciones Químicas, CSIC – University of Seville, Seville, Spain

Chemically and conﬁgurationally stable sp²-iminosugar N-, S-, O- and C- pseudo-α-glycosides have shown interesting biological properties as anti-tumor, anti-parasitic and anti-inflammatory agents [1]. The high α-anomeric selectivity achieved in the corresponding glycosylation reactions, using glycosyl fluoride or peracetylated donors, in this family of glycomimetics, is attributed to the presence of the endocyclic sp²-hybridised nitrogen, which results in an unusually strong orbital contribution to the generalized anomeric effect [2]. This peculiar reactivity has further been exploited in the preparation of Tn antigen (GalNAc-α-O-Ser/Thr) mimics as precursors of anti-cancer vaccines [3]. In this case, the incorporation of the acetamido group involved the unsaturated derivative 3a (Figure 1), which can be considered a glycal-enecarbamate hybrid. Given that glycals and enecarbamates have a quite reach chemistry, the use of synthetic intermediates combining the structural features of both classes of compounds to access new families of glycomimetics is very appealing. As a showcase, here we present the efficient synthesis of 2-deoxy-α-glycoside mimics, keeping in mind that this structural unit is present in a wide variety of biologically active natural products [4]. A range of alcohols/thiols have been used as glycosyl acceptors against the pseudoglycals 3a-3c, using different promotors to trigger activation of the C=C bond (boron trifluoride-diethyl ether, ceric ammonium nitrate or thiourea-type organocatalysts). The scope and limitations of the methodology will be discussed.

Figure 1. Retrosynthetic scheme for the stereoselective synthesis of 2-deoxy-α-O-(S)-glycomimetics.

a) E.M. Sánchez-Fernández et al., Chem. Commun. 2010, 46, 5328-5330; b) E.M. Sánchez-Fernández et al., RSC Adv. 2015, 5, 21812-21822; c) E. Schaeffer et al., Eur. J. Med. Chem. 2019, 169, 111-120.

V.M. Díaz Pérez et al., J. Org. Chem. 2000, 65,136-143.

E.M. Sánchez-Fernández et al, Org. Lett. 2016, 18, 3890-3893.

C.S. Bennett et al., Chem. Rev., 2018, 118, 7931-7985.

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