A Short and Scalable Route to Orthogonally O-Protected 2-Deoxystreptamine

Abstract

A seven-step synthesis of orthogonally O-protected 2-deoxy-streptamine has been developed from readily available neomycin, with an overall yield of 28%. Key chemical transformations include a chemoselective glycosidic bond hydrolysis and two regioselective protective group manipulations involving acetylation and deacetylation. The synthetic route is amenable to scale-up for the production of multigram quantities of enantiopure and orthogonally O-protected 2-deoxystreptamine, a versatile scaffold for the generation of libraries of RNA-targeting ligands.

Synthesis of Glycosidic (β-1′′→6, 3′ and 4′) Site Isomers of Neomycin B and Their Effect on RNA and DNA Triplex Stability

“…The 5-OH group of neamine ( 7 ) is less nucleophilic than the 6-, 3′- and 4′-OH groups. For this reason, selective triacetylation of N -protected neamines (e.g., 5 from 7 ) may be readily carried out as described previously in several studies [19,20]. On using a smaller excess of acetic anhydride, diacetylated neamines ( 8 – 10 ) may also be obtained, albeit the yield and ratio of the products ( 8 , 9 , 10 , 5 and monoacetylated neamines) are more sensitive to reaction conditions (temperature, reaction time, and the addition rate and excess of acetic anhydride).…”

“…2,5,3′,4′-Tetra-O-acetyl-2′,6′-diazido-1-phenylthio-α/β-neobiosamine ( 4 ). Peracetylated neomycin azide ( 3 , 5.8 g, 5.6 mmol, synthesized according to the literature [18,20]) and PhSH (0.64 mL, 6.2 mmol) were dissolved in dry dichloromethane (50 mL). The mixture was cooled down to 0 °C, and BF 3 ·Et 2 O (2.1 mL, 17 mmol) was slowly added under nitrogen.…”

2-Deoxystreptamine Conjugates by Truncation–Derivatization of Neomycin

“…It was hypothesized that 2-deoxystreptamine is a crucial scaffold to build aminoglycoside libraries and that the all-equatorial substitution pattern is highly favorable to position other pharmacophores in the proper orientation. Although a large number of synthetic routes to 2-deoxystreptamine have been developed over the years [44], including contributions from our own lab [45,46,47,48], we realized that the most straightforward and cheapest route to 2-deoxystreptamine commences from natural neomycin. Apart from that, we surmised that partial degradation of neomycin would leave the ribofuranoside as a suitable substituent at the 5-position of 2-deoxystreptamine, as in structure 2 (Scheme 1).…”

Short and Efficient Synthesis of Alkyne‐Modified Amino Glycoside Building Blocks

“…Although the neamine and the 2-DOS moiety can be readily obtained by acidolysis of neomycin B on a multigram scale, [33,34] derivatization essentially includes regio-and enantio-controlled arrangement of protecting groups. As an example, the esterase-mediated racemic resolution of peracetylated 2-DOS diazide is a common route to the enantiopure protected 2-DOS building block.…”

“…Flash chromatography was performed on silica gel 60 from Merck and octadecyl-modified silica gel (end-capped) from Machery & Nagel. 1 Neamine (6) [34] and compounds 7a, [34] 7b, [37] 8b, [37] and 12 [41] were synthesized as described previously. The conjugates 2A2 and 2B2 have been described before.…”