α-Selective Sialylations at −78 °C in Nitrile Solvents with a 1-Adamantanyl Thiosialoside

Abstract

Novel 1-adamantanylthio sialosides were synthesized and coupled to acceptors under NIS/TfOH promotion conditions. These donors showed higher reactivity than the phenylthio sialosides and could be activated by NIS/TfOH in nitrile solvents at −78 °C to afford improved α-sialylations. With the N-acetyl-5-N,4-O-oxazolidinone protected 1-adamantanylthio sialyl donor, high α-selectivities could be achieved in the sialylations of both primary and sterically hindered secondary acceptors, including the important galactose 3-OH acceptors.Oligosaccharides and glycoconjugates incorporating sialic acid residues are ubiquitous in high animals and human beings, and play important roles in a wide variety of biological processes. 1 Over the years considerable efforts have been spent on the development of sialoside donors bearing various leaving groups for efficient installation of α-sialyl linkages, among which 2-sulfide donors of Neu5Ac, ethyl) and S-aryl (phenyl and substituted phenyl) sialosides, have been widely applied. 2 In a previous report, we noted that an N-acetyl-5-N,4-O-oxazolidinone protected 2-phenylthio sialoside donor 1 gave excellent yields and α-selectivities in linking to various primary alkyl and carbohydrate acceptors under the NIS/TfOH in situ activation conditions at −40 °C in dichloromethane (Scheme 1). 3 Importantly, following glycosylation, the oxazolidinone group was readily cleaved under mild conditions leaving the acetamide intact. 3 Similar investigations were also reported by the Takahashi and De Meo groups with N-desacetyl analogs of 1, but harsher conditions were required for cleavage of the oxazolidinone moiety. 4 In an attempt to increase the α-selectivities of the sialylations of 1 with secondary sugar acceptors by means of the nitrile effect, 5 glycosylations promoted by NIS/TfOH were attempted in nitrile solvents at −40 °C. However, no reaction was observed. Noting the work of Oscarson and Lahmann on the reactivity order of various thioglycosides (glucose and galactose), 6,7,8 we turned our attention to the use of more reactive thiosialoside donors, which could possibly be activated in nitrile solvents at low temperature when improved α-selectivities could be anticipated. Here we describe an investigation into the sialylations of 1-adamantanyl thiosialoside donors 2 and 3. The 1-adamantanyl group was chosen because of its greater electron donating properties compared to Oscarson's preferred cyclohexyl group, and the solid (m.p. 99-106°C ) non-volatile nature of 1-adamantanethiol, the precursor for the installation of 1-adamantanylthio leaving group, which reduces the odor problem common to most thiols. 9The penta-acetate derivative 4 10 of neuraminic acid was reacted with 1-adamantanethiol in the presence of BF 3 ·Et 2 O in CH 2 Cl 2 at room temperature to afford 81% of the 1-adamantanyl thiosialoside 5 (Scheme 2). 11 Donor 2 then was derived from 5 in quantitative yield by treatment with i-propenyl acetate catalyzed by CSA at 65 °C (Scheme 2).The preparation of donor 3 started...

New Principles for Glycoside‐Bond Formation

“…[253] 4,5-Oxazolidinone-protected thiosialosides proved to be excellent a-sialylating agents of various acceptors, even in the absence of the acetonitrile effect and neighboring-group participation by an auxiliary. [254] These results again indicate that conformationally constraining protecting groups play a significant role in the stereochemical control of glycosidation.…”

“Active–Latent” Thioglycosyl Donors and Acceptors in Oligosaccharide Syntheses

“…The analogous 5N-acetyl-5N,4O-oxazolidinone protected phenylthio sialoside has also been used previously as a stereocontrolling element from which the oxazolidinone group could be removed under mild basic hydrolysis leading directly to the naturally occurring N-acetyl oligosaccharides [68]. The a-selectivity of the phenylthio sialoside was further improved with the S-adamantanyl analog [69]. In the forthcoming description (Scheme 22), the N-glycolyl analog 96 was chosen because it was adequately armed to be utilized as the first component in a thioglycoside-based iterative one-pot oligosaccharide syntheses (see Sect.…”

“…Glycosidation of acceptor 159 with acceptor 160 with the more potent NIS/TfOH couple afforded protected Scheme 27 Representative cases of one-pot oligosaccharide syntheses [74] "Active-Latent" Thioglycosyl Donors and Acceptors in Oligosaccharide Syntheses 97 trisaccharide 161 which upon standard deprotection gave the target trisaccharide 162 in 53% overall yield. In addition to dispiroketals, acetonide, and benzylidene acetals, conventionally used as "conformational locking" elements for the fine tuning reactivity of thioglycosides [65,68,69,[83][84][85][86] and other types of glycosyl donors, trans-2,3-cyclic carbonates, and analogs have also received consideration (see for instance Scheme 22) above. For instance, it has been demonstrated that trans-2,3-cyclic carbonates deactivated the anomeric center of thioglycosides both electronically and conformationally and that they had lesser reactivities than the corresponding ester-protected thioglycosyl donors [83].…”

C‐5 Modified S‐Benzoxazolyl Sialyl Donors: Towards More Efficient Selective Sialylations

“…[9,10] Similar observations were concomitantly reported by the groups of Takahashi and Crich. [11][12][13][14] To adapt both thioimidoyl and the C-5 modification approaches to chemical sialylation, herein we report a cooperative study of these two concepts. For this purpose we prepared a range of SBox sialyl donors (1b-d, Figure 1) modified at C-5 and performed a comprehensive study of their (2-6)-sialidations with diacetone galactose 5 and thioethyl acceptor 2 under various reaction conditions.…”