Improved Synthesis of Sulfur-Containing Glycosides by Suppressing Thioacetyl Migration

Abstract

Complex mixtures were often observed when we attempted to synthesize 4-thio-and 2,4-dithio-glycoside derivatives by double parallel and double serial inversion, thus leading to no or low yields of target products. The reason was later found to be that many unexpected side products were produced when a nucleophile substituted the leaving group on the substrate containing the thioacetate group. We hypothesized that thioacetyl migration is prone to occur due to the labile thioacetate group even under weak basic conditions caused by the nucleophile, leading to this result. Therefore, we managed to inhibit the generation of thiol groups from thioacetate groups by the addition of an appropriate amount of conjugate acid/anhydride, successfully improving the synthesis of 4-thio-and 2,4-dithio-glycoside derivatives. The target products which were previously difficult to synthesize, were herein obtained in relatively high yields. Finally, 4-deoxy-and 2,4-dideoxy-glycoside derivatives were efficiently synthesized through the removal of thioacetate groups under UV light, starting from 4-thio-and 2,4-dithio-glycoside derivatives.

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

“…Using 30 as the starting material, methyl 2‐SAc β‐glucoside 4 was synthesized in 90 % yield through the substitution of KSAc, and 1‐OAc, 2‐SAc β‐glucosyl donor 31 was efficiently obtained in a 82 % yield from 4 (Scheme 4). The synthesis of methyl 2‐SAc galactoside 32 from methyl 3,6‐di‐OAc mannoside through double serial inversion failed due to the similar inversion reactivity at 2‐ and 4‐postions for the triflate intermediate of methyl 3,6‐di‐OAc mannoside in our previous report [2c] . Therefore, we synthesized methyl 3,4,6‐tri‐OBz β‐taloside 33 (63 % yield for two steps) from methyl β‐galactoside 1 according to the literature [8a] .…”

“…Our next goal was to synthesize 1‐OAc, 2‐SAc taloside donor 36 from methyl 2‐SAc taloside 6 (Scheme 5b). However, 6 was obtained in only 11 % yield from methyl 3,6‐di‐OAc glucoside 35 through a double serial inversion strategy, likely due to the steric hindrance of the formed axial 4‐OAc [2c] . Therefore, we adjusted the double serial inversion strategy, in which the 4‐position was inversed by nitrite to the axial 4‐OH for the triflate intermediate of 35 , followed by inversion of the 2‐OTf by KSAc.…”

“…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] . A method of efficient ultraviolet light‐induced desulfurization developed by us makes the advantage of thioacetate as a temporary guiding group for the synthesis of 2‐deoxyglycosides more obvious [2b,c,3] . However, a big challenge for this strategy is how to efficiently obtain 2‐SAc glycosyl donors.…”

“…However, a big challenge for this strategy is how to efficiently obtain 2‐SAc glycosyl donors. So far, the only reported 2‐SAc donors are 1,3,4,6‐tetra‐ O ‐acetyl‐2‐ S ‐acetyl‐β‐glucose and 1,3,4,6‐tetra‐ O ‐acetyl‐2‐ S ‐acetyl‐α‐mannose, [2b,c] and the reported methods to obtain them are very inefficient. For obtaining 1,3,4,6‐tetra‐ O ‐acetyl‐2‐ S ‐acetyl‐glucose, a method starting from 1,6‐anhydro glucose [4] and another method starting from mannose (Scheme 1a) [2a] required at least 6 steps with very low total yields.…”

Visible-Light-Promoted Desulfurization to Synthesize Deoxyglycosides

“…This method has particular advantages in terms of safety since the use of conventional Raney nickel or Pd-catalyzed hydrogenation means is avoided. We thus further applied this method to the synthesis of 2-deoxyglycosides with exclusive α/β-stereoselectivity − using C-2 thioacetate (SAc) as the temporary guiding group in glycosylation. The 2-SAc glycosyl donors can be efficiently prepared starting from free methyl glycosides by combining selective protection strategies and thioacetate-involved substitution strategies. − However, this desulfurization has to be performed in a dedicated photochemical reactor, and, in some cases, the high-energy UV light can induce the formation of undesired byproducts.…”