Tuning the Stereoelectronic Properties of 1-Sulfanylhex-1-enitols for the Sequential Stereoselective Synthesis of 2-Deoxy-2-iodo-β-d-allopyranosides

Abstract

The preparation of challenging 2-deoxy-2-iodo-β-D-allo precursors of 2-deoxy-β-D-ribo-hexopyranosyl units and other analogues is reported using a robust olefination-cyclization-glycosylation sequence. Here, we particularly focus on tuning the stereoelectronic properties of the alkenyl sulfides intermediates in order to improve the diastereoselectivity of the cyclization step and, hence, the efficiency of the overall transformation. Phosphine oxides with the general formula Ph2P(O)CH2SR (R = t-Bu, Cy, p-MeOPh, 2,6-di-ClPh, and 2,6-di-MePh) were easily synthesized and subsequently used in the olefination reaction with 2,3,5-tri-O-benzyl-D-ribose and -D-arabinose. The corresponding sugar-derived alkenyl sulfides were submitted to a 6-endo [I(+)]-induced cyclization, and the resulting 2-deoxy-2-iodohexopyranosyl-1-thioglycosides were used as glycosyl donors for the stereoselective synthesis of 2-deoxy-2-iodohexopyranosyl glycosides. Among the different S-groups studied, t-Bu derivative was the best performer for the synthesis of cholesteryl 2-deoxy-2-iodomannopyranosides, whereas for the synthesis of 2-deoxy-2-iodoallopyranosides none of the derivatives here studied proved superior to the phenyl analogue previously described. Glycosylation of cholesterol with different d-allo and d-manno derivatives produced 2-deoxy-2-iodoglycosides with stereoselectivities in the same order in each case, reinforcing the involvement of an oxocarbenium ion as the common intermediate of this crucial glycosylation step.

Methods for 2-Deoxyglycoside Synthesis

“…In this manner, the diastereoselectivity of the cyclization step was improved and thus the methodology could be expanded to the preparation of challenging 2-deoxy-2-iodo-β- d -alloglycosides as precursors of 2-deoxy-β- d -ribohexopyranosides. 311 …”

Stereoselective Synthesis of α‐Linked 2‐Deoxy Glycosides Enabled by Visible‐Light‐Mediated Reductive Deiodination

“…further demonstrated that the iodo‐substituent at the C‐2 position well controlled the stereochemistry of the newly formed glycosidic bond 11. This character was further illustrated in the glycosylation of 2‐deoxy‐2‐halo‐glycosyl trifluoroacetimidtaes,8a trichloroacetimidates,12a–c thioethers,12d,e and fluorides,12f,g which provided the corresponding 2‐deoxy‐2‐halo‐glycosides, and after reductive removal, the 2‐deoxy‐glycosides with high stereroselectivity. Meanwhile, the use of oxidative coupling of glycals in the preferential synthesis of 2‐deoxy‐2‐halo‐α‐glycosides was developed by Lemieux,13a Tatsuta,13b Thiem,13c,d Kessler,13e and Danishefsky,13f respectively.…”

Efficient Preparation of 2‐SAc‐Glycosyl Donors and Investigation of Their Application in the Synthesis of 2‐Deoxyglycosides

“…However, it is a big challenge to control the anomeric stereochemistry due to the lack of C‐2 oxygen during glycosylation of 2‐deoxyglycosyl donors [1l] . One type of strategy is to use glycosyl donors with temporary protecting groups at the C‐2 position to control the stereoselectivity of glycosidic bonds during glycosylation [1l–n,2] . Among them, the use of glycosyl donors containing C‐2 thioacetate (SAc) in glycosylation for exclusive α/β‐stereoselectivity, followed by desulfurization to obtain 2‐deoxyglycosides, has been fully demonstrated [2] .…”