Synthetic Studies on the Incorporation of N-Acetylallosamine in Hyaluronic Acid-Inspired Thiodisaccharides.

Alejandro E Cristófalo,María Laura Uhrig

doi:10.3390/molecules26010180

Abstract

Two approaches for the synthesis of the thiodisaccharide β-S-GlcA(1→3)β-S-AllNAc are described here. The target disaccharide was a C-3 epimer and thio-analogue of the hyaluronic acid repetitive unit, tuned with a thiopropargyl anomeric group for further click conjugation. Thus, we analysed and tested two convenient sequences, combining the two key steps required to introduce the thioglycosidic bonds and consequently reach the target molecule: the SN2 substitution of a good leaving group (triflate) present at C-3 of a GlcNAc derivative and the introduction of the anomeric thiopropargyl substituent. The use of a 2-azido precursor showed to be a convenient substrate for the SN2 step. Nevertheless, further protecting group manipulation and the introduction of the thiopropargyl anomeric residue were then required. This approach showed to provide access to a variety of thiodisaccharide derivatives as interesting building blocks for the construction of neoglycoconjugates.

Highlights

There is a large amount of evidence that the construction of thioglycosidic linkages remains a convenient strategy for the development of sugar-based stable enzyme inhibitors and lectin ligands [1,2,3,4]
The H-5 signal appeared at 4.84 ppm, remarkably deshielded with respect to the same signal of the the α-S-GlcA-(1→4)-α-Glc thiodisaccharide (δ 5.79 ppm, J1′,2′ = 5.4 Hz) [9]
We studied two distinct sequences involving the two key steps required for the introduction of both structural features of this thiodisaccharide, namely, the anomeric thiopropargylation of the GlcNAc residue and the (1→3) thioglycosidic bond formation

Summary

Introduction

There is a large amount of evidence that the construction of thioglycosidic linkages remains a convenient strategy for the development of sugar-based stable enzyme inhibitors and lectin ligands [1,2,3,4]. Considering the relevant role of carbohydrates in a myriad of normal and aberrant physiological processes, the resulting sugar derivatives can be envisaged as potential tools for the development of carbohydrate-based therapies. Even classical methods involving SN2-mechanisms deserve further exploration, as they have shown to be both high-yielding and stereoselective processes [5,6,7,8]. Improved conditions by using specific solvent mixtures or additives broaden the possibilities for the access to more complex novel structures, which can be considered analogues of natural compounds [8,9]. The complexity of sugars in terms of their stereochemical diversity, can be seen as a major advantage for the study of these processes, and deserves further exploration and exploitation. Considering this background, and encouraged by our latest findi3nogf 1r2elated to the unexpected affinity of AllNAc for WGA [10], we were prone to investigate differen syntChoentiscidaepripnrgotahcihsebsactokgwraourdnsd,naenwd agllsyocoenmcoimureatgicedstbryucotuurrelastecsot nfisntdruincgterdelafrteodmtothis non tchleasusCniceoaxnlpsesidcutegerdainragbfftuihniilisdtybinaogcfkAbgllrlooNcuAkn.cdM,foaornrdWeoaGvlsAeor[,e1nt0ac]ko, iuwnregagwienedtroebycporoonunsreidlateotreaisnttvifioennstdioginuagtrerwedloiafrftekrdeontnot the syn sttyhhneetsuhinesteioxcpfaetpchpteerdohaaycfhafilenusirttyoonwoafanArdlmlsNinmAewcetfiogcrlytWchoiGmoAdimi[s1ea0tci]cc,hwsaterruiwdcteeur,erβeps-rSco-onGnelsctorAui(cn1tve→des3tf)irgβoa-mSte-tGdhilfscfNenroAenc-t [8], and csalyalsnsosthicetahtliecsuatgphapirorobgaulycilhcdeoisnsygtolbawltoiaocrkdn.sMmneoewrtehogovldyerc,odtmeakvimienlegotpicnetdsotrcubocyntusiurdesesrtcaootinoosntbrotuaucirtnewdcoflrirkcokmoanbtthlheies Nsnyo-nan-c-etylhex taocsaoahlysllnssaseanoaosamtsimhltsitoihechnigoeasneeiflotsehdutstohhiuedsofeirgeogtithavrhhglyirealyivcytoahbiaocvdlyustoueiyiaisvrsslllyoduaae[lnticr2sanioaco9tg[innh]no2,aan9bmmwnr]lio,emidmctwhreikemeeot.eptβhdieocro-MtSderidcttp-eohGtvhordihoeelreilodcrotvoeAvidphesetila(eeswor1cd,arp→coectbhecaddytha3kwria)iusiβnrbdtosiigy-dentSd,oeci-u,intβAosβst-sbtolS-yilttSn-NanocG-citGonAhtlonclecsbcAcstlAytii(adcpn1(kie1rnat→ar→ehpbape3cptl3l)teairiβo)iorcβcNn-ekaS-a-dacS-aophbG-cuGflepeleorsctlrrycNotwNNlofhaAou-Aecoarcrxhcbktoe[eth[8ast8oseya]i]nn,rlm,thoaactteinnhhnlxoiddee-cbktacionntjhue adgneaartilivoogantoi.uvessth[2io9]d,iwsaeccrheparoirdteheβr-eS-tGwlocAd(is1t→in3c)tβs-ySn-AthlelNticAacppreopacahreds tfoorobfutaritnhethr eclaicnkalcoognojusgthaitoiodnis. accharide β-S-GlcA(1→3)β-S-AllNAc prepared for further click conjugation

Results and Discussion

H-5 H-1 H-6ax H-2

Conclusions