Exploring the Chemistry and Applications of Thio-, Seleno-, and Tellurosugars

Academic Edi o s: F ancesca Ca dona
and Maca ena Ma ínez-Bailén
Recei ed: 1 Ma ch 2025
Re ised: 28 Ap il 2025
Accep ed: 28 Ap il 2025
Published: 5 May 2025
Ci a ion: Ma ínez-Pascual, R.;
Vale a-Za agoza, M.; Fe nández-
Bolaños, J.G.; López, Ó. Explo ing he
Chemis y and Applica ions o Thio-,
Seleno-, and Tellu osuga s. Molecules
2025,30, 2053. h ps://doi.o g/
10.3390/molecules30092053
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Licensee MDPI, Basel, Swi ze land.
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licenses/by/4.0/).
Re iew
Explo ing he Chemis y and Applica ions o Thio-, Seleno-,
and Tellu osuga s
Roxana Ma ínez-Pascual 1, Ma io Vale a-Za agoza 1, José G. Fe nández-Bolaños 2and Ósca López 2,*
1Cen o de In es igaciones Cien í icas, Ins i u o de Química Aplicada, Uni e sidad del Papaloapan, Ci cui o
Cen al 200, Col. Pa que Indus ial, Tux epec 68301, Oaxaca, Mexico; [email p o ec ed] (R.M.-P.);
[email p o ec ed] (M.V.-Z.)
2Depa amen o de Química O gánica, Facul ad de Química, Uni e sidad de Se illa, Apa ado 1203,
E-41071 Se ille, Spain; [email p o ec ed]
*Co espondence: [email p o ec ed]
Abs ac : Gi en he c ucial oles o ca bohyd a es in ene gy supply, biochemical p ocesses,
signaling e en s and he pa hogenesis o se e al diseases, he de elopmen o ca bohyd a e
analogues, called glycomime ics, is a key esea ch a ea in Glycobiology, Pha macology, and
Medicinal Chemis y. Among he many s uc u al ans o ma ions explo ed, he eplace-
men o endo- and exocyclic oxygen a oms by ca bon (ca basuga s) o he e oa oms, such
as ni ogen (aza- and iminosuga s), phospho ous (phosphasuga s), sul u ( hiosuga s),
selenium (selenosuga s) o ellu ium ( ellu osuga s) ha e ga ne ed signi ican a en ion.
These isos e ic subs i u ions can modula e he ca bohyd a e bioa ailabili y, s abili y, and
bioac i i y, while in oducing new p ope ies, such as edox ac i i y, in e ac ions wi h
pa hological lec ins and enzymes, o cy o oxic e ec s. In his manusc ip we ha e ocused
on h ee majo amilies o glycomime ics: hio-, seleno-, and ellu osuga s. We p o ide a
comp ehensi e e iew o he mos ele an syn he ic pa hways leading o subs i u ions
p ima ily a he endocyclic and glycosidic posi ions. The scope includes me al-ca alyzed
eac ions, o ganoca alysis, elec o- and pho ochemical ans o ma ions, ee- adical p o-
cesses, and au oma ed syn heses. Addi ionally, mechanis ic insigh s, s e eoselec i i y, and
biological p ope ies a e also discussed. The s uc u al di e si y and p omising bioac i i ies
o hese glycomime ics unde sco e hei signi icance in his esea ch a ea.
Keywo ds: glycomime ics; hiosuga s; selenosuga s; ellu osuga s; hioglycosides;
selenoglycosides
1. In oduc ion
Ca bohyd a es a e ubiqui ous biomolecules wi h essen ial biological unc ions ac oss
all domains o li e. Beyond se ing as a p ima y ene gy sou ce and s o age o m, hey play
c ucial s uc u al oles (e.g., cellulose, chi in), and ac as key building blocks in anabolic
pa hways, including nucleic acids biosyn hesis [
1
]. Complex ca bohyd a es (glycans) [
1
]
a e also in eg al componen s o glycoconjuga es such as glycolipids and glycop o eins,
which a e embedded in cell memb anes and pa icipa e in c i ical signaling e en s, bo h
endogenous and pa hogen-media ed.
Mo eo e , ca bohyd a es se e as empla es o he de elopmen o no el he apeu-
ics [
1
] a ge ing me abolic diso de s [
2
], cance (e.g., ca bohyd a e-based accines) [
3
],
in ec ious diseases [4], and d ug deli e y sys ems, including nanoca ie s [5].
Gi en hei immense biological signi icance, ca bohyd a e analogues, e e ed o as
glycomime ics, ha e eme ged as a p omising esea ch a ea, o e ing deepe insigh s in o
Molecules 2025,30, 2053 h ps://doi.o g/10.3390/molecules30092053
Molecules 2025,30, 2053 2 o 54
ca bohyd a e in e ac ions, modula ing bioac i i y, and e en in oducing no el p ope ies.
Among he as a ay o syn he ic modi ica ions applicable o ca bohyd a e s uc u es,
bioisos e ic eplacemen s o oxygen and ca bon a oms dese e a en ion. The subs i u ion
o he endocyclic oxygen, o he anome ic ca bon wi h ca bon (ca basuga s) [
6
], ni ogen
(iminosuga s) [
7
], phospho ous (phosphasuga s) [
8
], sul u ( hiosuga s) [
9
], selenium
(selenosuga s) [
10
] and ellu ium ( ellu osuga s) [
11
] (Figu e 1) has led o he de elopmen
o an a senal o compounds ha ha e expanded he on ie s o Glycobiology esea ch, and
cons i u e some o he mos ele an glycomime ics.
Molecules 2025, 30, x FOR PEER REVIEW 2 o 58
Gi en hei immense biological signi icance, ca bohyd a e analogues, e e ed o as
glycomime ics, ha e eme ged as a p omising esea ch a ea, offe ing deepe insigh s in o
ca bohyd a e in e ac ions, modula ing bioac i i y, and e en in oducing no el p ope ies.
Among he as a ay o syn he ic modi ica ions applicable o ca bohyd a e s uc u es,
bioisos e ic eplacemen s o oxygen and ca bon a oms dese e a en ion. The subs i u ion
o he endocyclic oxygen, o he anome ic ca bon wi h ca bon (ca basuga s) [6], ni ogen
(iminosuga s) [7], phospho ous (phosphasuga s) [8], sul u ( hiosuga s) [9], selenium (se-
lenosuga s) [10] and ellu ium ( ellu osuga s) [11] (Figu e 1) has led o he de elopmen
o an a senal o compounds ha ha e expanded he on ie s o Glycobiology esea ch,
and cons i u e some o he mos ele an glycomime ics.
Figu e 1. Gene al s uc u e o ele an glycomime ics.
In his e iew, we will discuss ecen ad ances in he de elopmen o chalcogen-con-
aining glycomime ics and hei implica ion in Glycoscience.
2. S-Con aining Ca bohyd a es
Thiosuga s ep esen a as amily o glycoconjuga es in which ei he a hyd oxyl
g oup o he endocyclic oxygen is eplaced by sul u . This isos e ic subs i u ion induces
signi ican con o ma ional and physico-chemical changes in he suga mimic. Due o i s
bigge a omic adius, sul u o ms longe C‒S bonds compa ed o oxygen, esul ing in
smalle dihed al angles [12]. Addi ionally, sul u has smalle elec onega i i y and a mo e
hyd ophobic cha ac e , while no exhibi ing hyd ogen bonding accep ance capaci y, which
a ec s wa e solubili y [13]; he s onge sul u -π in e ac ions be ween hiosuga s and lec-
ins compa ed o oxygen can be use ul in he design o e ec i e d ugs [14]. Many hiosuga s
exhibi subs an ially imp o ed hyd oly ic o enzyma ic s abili y compa ed o hei oxygen-
con aining coun e pa s, which is undoub edly ad an ageous o he design o new d ugs
[9]. The e a e some examples ound in na u e, like 5- hio-D-mannose, hioglycosides (e.g.,
glucosinola es) and 1,4- hioanhyd osuga s (e.g., ko alanol, salacinol, Figu e 2) [15].
Figu e 2. S uc u e o salacinol and ko alanol.
Figu e 1. Gene al s uc u e o ele an glycomime ics.
In his e iew, we will discuss ecen ad ances in he de elopmen o chalcogen-
con aining glycomime ics and hei implica ion in Glycoscience.
2. S-Con aining Ca bohyd a es
Thiosuga s ep esen a as amily o glycoconjuga es in which ei he a hyd oxyl
g oup o he endocyclic oxygen is eplaced by sul u . This isos e ic subs i u ion induces
signi ican con o ma ional and physico-chemical changes in he suga mimic. Due o
i s bigge a omic adius, sul u o ms longe C–S bonds compa ed o oxygen, esul ing
in smalle dihed al angles [
12
]. Addi ionally, sul u has smalle elec onega i i y and a
mo e hyd ophobic cha ac e , while no exhibi ing hyd ogen bonding accep ance capaci y,
which a ec s wa e solubili y [
13
]; he s onge sul u -
π
in e ac ions be ween hiosuga s
and lec ins compa ed o oxygen can be use ul in he design o e ec i e d ugs [
14
]. Many
hiosuga s exhibi subs an ially imp o ed hyd oly ic o enzyma ic s abili y compa ed
o hei oxygen-con aining coun e pa s, which is undoub edly ad an ageous o he
design o new d ugs [
9
]. The e a e some examples ound in na u e, like 5- hio-D-mannose,
hioglycosides (e.g., glucosinola es) and 1,4- hioanhyd osuga s (e.g., ko alanol, salacinol,
Figu e 2) [15].
Molecules 2025, 30, x FOR PEER REVIEW 2 o 58
Gi en hei immense biological signi icance, ca bohyd a e analogues, e e ed o as
glycomime ics, ha e eme ged as a p omising esea ch a ea, offe ing deepe insigh s in o
ca bohyd a e in e ac ions, modula ing bioac i i y, and e en in oducing no el p ope ies.
Among he as a ay o syn he ic modi ica ions applicable o ca bohyd a e s uc u es,
bioisos e ic eplacemen s o oxygen and ca bon a oms dese e a en ion. The subs i u ion
o he endocyclic oxygen, o he anome ic ca bon wi h ca bon (ca basuga s) [6], ni ogen
(iminosuga s) [7], phospho ous (phosphasuga s) [8], sul u ( hiosuga s) [9], selenium (se-
lenosuga s) [10] and ellu ium ( ellu osuga s) [11] (Figu e 1) has led o he de elopmen
o an a senal o compounds ha ha e expanded he on ie s o Glycobiology esea ch,
and cons i u e some o he mos ele an glycomime ics.
Figu e 1. Gene al s uc u e o ele an glycomime ics.
In his e iew, we will discuss ecen ad ances in he de elopmen o chalcogen-con-
aining glycomime ics and hei implica ion in Glycoscience.
2. S-Con aining Ca bohyd a es
Thiosuga s ep esen a as amily o glycoconjuga es in which ei he a hyd oxyl
g oup o he endocyclic oxygen is eplaced by sul u . This isos e ic subs i u ion induces
signi ican con o ma ional and physico-chemical changes in he suga mimic. Due o i s
bigge a omic adius, sul u o ms longe C‒S bonds compa ed o oxygen, esul ing in
smalle dihed al angles [12]. Addi ionally, sul u has smalle elec onega i i y and a mo e
hyd ophobic cha ac e , while no exhibi ing hyd ogen bonding accep ance capaci y, which
a ec s wa e solubili y [13]; he s onge sul u -π in e ac ions be ween hiosuga s and lec-
ins compa ed o oxygen can be use ul in he design o e ec i e d ugs [14]. Many hiosuga s
exhibi subs an ially imp o ed hyd oly ic o enzyma ic s abili y compa ed o hei oxygen-
con aining coun e pa s, which is undoub edly ad an ageous o he design o new d ugs
[9]. The e a e some examples ound in na u e, like 5- hio-D-mannose, hioglycosides (e.g.,
glucosinola es) and 1,4- hioanhyd osuga s (e.g., ko alanol, salacinol, Figu e 2) [15].
Figu e 2. S uc u e o salacinol and ko alanol.
Figu e 2. S uc u e o salacinol and ko alanol.
2.1. 4′- and 5′-Thiosuga s
Classical syn he ic app oaches o in oducing a sul u a om in o a ing o gi e hio-
suga s ha e been ecen ly e iewed [
16
]; one o he mos success ul app oaches in ol es
Molecules 2025,30, 2053 3 o 54
he in oduc ion o a lea ing g oup a he app op ia e posi ion o he suga , and eac ion
wi h a sul u -con aining nucleophile. He ein, ecen syn heses o hiosuga s wi h p ac ical
in e es will be e iewed.
Ueda and co-wo ke s epo ed [
17
] he p epa a ion o he suc ose analogues (+)-
5- hiosuc ose (5) and (+)-5- hioisosuc ose (6) as po en ial swee ene s and glycosidase
inhibi o s. The key s ep o he syn hesis was a s e eoselec i e glycosyla ion eac ion
be ween a D-psicose o a D- uc ose dono , espec i ely, and a 5- hio-D-glucose de i a i e
(1and 3)
as accep o s (Scheme 1). Due o he s ong anome ic e ec induced by
1and 3,
hey
ac ed as
α
-di ec ing glycosyl accep o s. Un o una ely, none o he compounds displayed
app eciable ac i i y as swee ene s o inhibi o s [17].
Molecules 2025, 30, x FOR PEER REVIEW 3 o 58
2.1. 4′- and 5′-Thiosuga s
Classical syn he ic app oaches o in oducing a sul u a om in o a ing o gi e hio-
suga s ha e been ecen ly e iewed [16]; one o he mos success ul app oaches in ol es
he in oduc ion o a lea ing g oup a he app op ia e posi ion o he suga , and eac ion
wi h a sul u -con aining nucleophile. He ein, ecen syn heses o hiosuga s wi h p ac ical
in e es will be e iewed.
Ueda and co-wo ke s epo ed [17] he p epa a ion o he suc ose analogues (+)-5-
hiosuc ose (5) and (+)-5- hioisosuc ose (6) as po en ial swee ene s and glycosidase inhib-
i o s. The key s ep o he syn hesis was a s e eoselec i e glycosyla ion eac ion be ween a
D-psicose o a D- uc ose dono , espec i ely, and a 5- hio-D-glucose de i a i e (1 and 3)
as accep o s (Scheme 1). Due o he s ong anome ic effec induced by 1 and 3, hey ac ed
as α-di ec ing glycosyl accep o s. Un o una ely, none o he compounds displayed ap-
p eciable ac i i y as swee ene s o inhibi o s [17].
Scheme 1. Re osyn he ic analysis o he p epa a ion o (+)-5- hiososuc ose (5) and (+)-5- hioisosu-
c ose (6).
Díaz-Fe nández and Pino-González epo ed [18] a simple app oach o he syn hesis
o he hiomonosaccha ide 10 om D-mannose. The syn hesis in ol ed he use o di-O-
isop opylidene D-mannose 7, which was ans o med in o he dias e eome ic E/Z mix u e
o oxime 8 using hyd oxylamine hyd ochlo ide unde basic condi ions. The hyd oxyl
g oups o 8 we e subsequen ly mesyla ed o p oduce compound 9. Finally, he mesyla e
g oup unde wen an SN2 subs i u ion eac ion wi h Na2S, ollowed by in amolecula cy-
cliza ion on he ni ile g oup, yielding he hiosuga 10 (Scheme 2).
Scheme 1. Re osyn he ic analysis o he p epa a ion o (+)-5- hiososuc ose (5) and (+)-5-
hioisosuc ose (6).
Díaz-Fe nández and Pino-González epo ed [
18
] a simple app oach o he syn hesis
o he hiomonosaccha ide 10 om D-mannose. The syn hesis in ol ed he use o di-O-
isop opylidene D-mannose 7, which was ans o med in o he dias e eome ic E/Zmix u e
o oxime 8using hyd oxylamine hyd ochlo ide unde basic condi ions. The hyd oxyl
g oups o 8we e subsequen ly mesyla ed o p oduce compound 9. Finally, he mesyla e
g oup unde wen an S
N
2 subs i u ion eac ion wi h Na
2
S, ollowed by in amolecula
cycliza ion on he ni ile g oup, yielding he hiosuga 10 (Scheme 2).
Molecules 2025, 30, x FOR PEER REVIEW 4 o 58
Scheme 2. Syn hesis o hiomonosaccha ide 10. Reagen s and condi ions: (a) NH2OH·HCl,
NaHCO3; (b) MsCl, 0 °C→ . .; (c) Na2S·9H2O, DMF
Liu and cowo ke s explo ed [19] he p epa a ion o S-linked u ona es (12–15) using
a hiola ion eac ion (PhSH, BnSH) unde alkaline and adical-media ed condi ions on
Δ4,5-unsa u a ed me hyl u ona e 11 (Scheme 3). The eac ion demons a ed o be inefficien
unde adical condi ions, which was a ibu ed o he elec on-wi hd awing effec o he
es e moie y loca ed on C-5, al hough i p oceeded wi h good egio- and s e eoselec i i y
a C-4 and C-5 posi ions. Unde basic condi ions, good s e eoselec i i y was ob ained a
C-4, bu , con e sely, poo s e eoselec i i y a C-5, en a i ely due o a e o hiol-Michael
eac ion. A emp s o ob ain a S-linked pseudodisaccha ide ailed as, unexpec edly, when
13 was ea ed wi h a Lewis acid (AlCl3) o emo e he benzyl g oup, he hio u anoside
16 was ob ained se endipi ously (Scheme 3).
Scheme 3. Syn hesis o S-linked u ona e de i a i es and o ma ion o he hio u onoside 16. Rea-
gen s and condi ions: (a) PhSH, BnSH; (b) BnSH, he mal/pho o-ini i a o ; c) AlCl3, oluene, 48 h.
A amily o hiosuga s ha has gained conside able a en ion is he sul onium-con-
aining ca bohyd a es, as hey a e analogues o he na u ally occu ing ko alanol and sa-
lacinol (Figu e 2), bo h isola ed om Salacia e icula a ex ac s, and known o be po en
inhibi o s o in es inal glycosidases [20]. These sul onium glycomime ics a e he e o e
p omising candida es o he ea men o diabe es [21].
In his con ex , Takashima e al. hypo hesized [22] ha he inco po a ion o a hyd o-
phobic moie y in o he side chain o salacinol could enhance i s inhibi o y ac i i y agains
glycosidases h ough a o able an de Waals in e ac ions. To es his hypo hesis, de i -
a i es 19‒24 we e p epa ed (Scheme 4), he alkyla ion o O-p o ec ed hiosuga 17 using
cyclic sul a es 18 being he key s ep. The inal compounds we e e alua ed as inhibi o s o
a mal ase, suc ose and isomal ase, as well as human mal ase. While no clea effec s o
he hyd oca bon esidue we e obse ed on mal ase o isomal ase inhibi ion, suc ose inhi-
bi ion displayed a leng h-dependen inhibi o y ac i i y, wi h longe appendages yielding
he mos po en compounds (IC50 = 0.15‒0.73 µM o 19–22, 1.4 and 0.38 µM o 23 and 24).
This esul ed in an up o en- old inc ease in ac i i y compa ed o pa en salacinol [22].
Scheme 2. Syn hesis o hiomonosaccha ide 10. Reagen s and condi ions: (a) NH
2
OH
·
HCl, NaHCO
3
;
(b) MsCl, 0 ◦C→ . .; (c) Na2S·9H2O, DMF.
Liu and cowo ke s explo ed [
19
] he p epa a ion o S-linked u ona es (12–15) using
a hiola ion eac ion (PhSH, BnSH) unde alkaline and adical-media ed condi ions on
Molecules 2025,30, 2053 4 o 54
∆4,5
-unsa u a ed me hyl u ona e 11 (Scheme 3). The eac ion demons a ed o be ine icien
unde adical condi ions, which was a ibu ed o he elec on-wi hd awing e ec o he
es e moie y loca ed on C-5, al hough i p oceeded wi h good egio- and s e eoselec i i y
a C-4 and C-5 posi ions. Unde basic condi ions, good s e eoselec i i y was ob ained a
C-4, bu , con e sely, poo s e eoselec i i y a C-5, en a i ely due o a e o hiol-Michael
eac ion. A emp s o ob ain a S-linked pseudodisaccha ide ailed as, unexpec edly, when
13 was ea ed wi h a Lewis acid (AlCl
3
) o emo e he benzyl g oup, he hio u anoside
16 was ob ained se endipi ously (Scheme 3).
Molecules 2025, 30, x FOR PEER REVIEW 4 o 58
Scheme 2. Syn hesis o hiomonosaccha ide 10. Reagen s and condi ions: (a) NH2OH·HCl,
NaHCO3; (b) MsCl, 0 °C→ . .; (c) Na2S·9H2O, DMF
Liu and cowo ke s explo ed [19] he p epa a ion o S-linked u ona es (12–15) using
a hiola ion eac ion (PhSH, BnSH) unde alkaline and adical-media ed condi ions on
Δ4,5-unsa u a ed me hyl u ona e 11 (Scheme 3). The eac ion demons a ed o be inefficien
unde adical condi ions, which was a ibu ed o he elec on-wi hd awing effec o he
es e moie y loca ed on C-5, al hough i p oceeded wi h good egio- and s e eoselec i i y
a C-4 and C-5 posi ions. Unde basic condi ions, good s e eoselec i i y was ob ained a
C-4, bu , con e sely, poo s e eoselec i i y a C-5, en a i ely due o a e o hiol-Michael
eac ion. A emp s o ob ain a S-linked pseudodisaccha ide ailed as, unexpec edly, when
13 was ea ed wi h a Lewis acid (AlCl3) o emo e he benzyl g oup, he hio u anoside
16 was ob ained se endipi ously (Scheme 3).
Scheme 3. Syn hesis o S-linked u ona e de i a i es and o ma ion o he hio u onoside 16. Rea-
gen s and condi ions: (a) PhSH, BnSH; (b) BnSH, he mal/pho o-ini i a o ; c) AlCl3, oluene, 48 h.
A amily o hiosuga s ha has gained conside able a en ion is he sul onium-con-
aining ca bohyd a es, as hey a e analogues o he na u ally occu ing ko alanol and sa-
lacinol (Figu e 2), bo h isola ed om Salacia e icula a ex ac s, and known o be po en
inhibi o s o in es inal glycosidases [20]. These sul onium glycomime ics a e he e o e
p omising candida es o he ea men o diabe es [21].
In his con ex , Takashima e al. hypo hesized [22] ha he inco po a ion o a hyd o-
phobic moie y in o he side chain o salacinol could enhance i s inhibi o y ac i i y agains
glycosidases h ough a o able an de Waals in e ac ions. To es his hypo hesis, de i -
a i es 19‒24 we e p epa ed (Scheme 4), he alkyla ion o O-p o ec ed hiosuga 17 using
cyclic sul a es 18 being he key s ep. The inal compounds we e e alua ed as inhibi o s o
a mal ase, suc ose and isomal ase, as well as human mal ase. While no clea effec s o
he hyd oca bon esidue we e obse ed on mal ase o isomal ase inhibi ion, suc ose inhi-
bi ion displayed a leng h-dependen inhibi o y ac i i y, wi h longe appendages yielding
he mos po en compounds (IC50 = 0.15‒0.73 µM o 19–22, 1.4 and 0.38 µM o 23 and 24).
This esul ed in an up o en- old inc ease in ac i i y compa ed o pa en salacinol [22].
Scheme 3. Syn hesis o S-linked u ona e de i a i es and o ma ion o he hio u onoside 16. Reagen s
and condi ions: (a) PhSH, BnSH; (b) BnSH, he mal/pho o-ini i a o ; (c) AlCl3, oluene, 48 h.
A amily o hiosuga s ha has gained conside able a en ion is he sul onium-
con aining ca bohyd a es, as hey a e analogues o he na u ally occu ing ko alanol and
salacinol (Figu e 2), bo h isola ed om Salacia e icula a ex ac s, and known o be po en
inhibi o s o in es inal glycosidases [
20
]. These sul onium glycomime ics a e he e o e
p omising candida es o he ea men o diabe es [21].
In his con ex , Takashima e al. hypo hesized [
22
] ha he inco po a ion o a hy-
d ophobic moie y in o he side chain o salacinol could enhance i s inhibi o y ac i i y
agains glycosidases h ough a o able an de Waals in e ac ions. To es his hypo he-
sis, de i a i es 19–24 we e p epa ed (Scheme 4), he alkyla ion o O-p o ec ed hiosuga
17 using cyclic sul a es 18 being he key s ep. The inal compounds we e e alua ed as
inhibi o s o a mal ase, suc ose and isomal ase, as well as human mal ase. While no
clea e ec s o he hyd oca bon esidue we e obse ed on mal ase o isomal ase inhi-
bi ion, suc ose inhibi ion displayed a leng h-dependen inhibi o y ac i i y, wi h longe
appendages yielding he mos po en compounds (IC
50
= 0.15–0.73
µ
M o 19–22, 1.4 and
0.38
µ
M o 23 and 24). This esul ed in an up o en- old inc ease in ac i i y compa ed o
pa en salacinol [
22
]. Addi ionally, de-O-sul ona ed analogues a C-3
′
posi ion (23 and 24)
exhibi ed signi ican ly s onge inhibi ion agains isomal ase han 19–22, ega dless o he
hyd oca bon esidue leng h.
Wi h he aim o e alua ing whe he he 5-membe ed hiosuga is essen ial o he
α
-glucosidase inhibi o y ac i i y exhibi ed by sul onium-based hiosuga s, Tanabe e al.
ecen ly syn hesized [
23
] ing-clea ed salacinol analogues (25–28) and unca ed salacinol
analogues (29–31) (Figu e 3). This in es iga ion was p omp ed by a p e ious epo [
24
]
demons a ing ha some acyclic analogues de i ed om 1-deoxynoji imycin, a po en
α
-glucosidase inhibi o , e ained ac i i y, indica ing ha he i e-membe ed ing may no be
c ucial o he inhibi o y e ec . The esul s o he ing-clea ed salacinol analogues e ealed
ha hese compounds we e inac i e, highligh ing he essen ial ole o he 5-membe ed
hiosuga in hei po en ac i i y.
Molecules 2025,30, 2053 5 o 54
Molecules 2025, 30, x FOR PEER REVIEW 5 o 58
Addi ionally, de-O-sul ona ed analogues a C-3′ posi ion (23 and 24) exhibi ed signi i-
can ly s onge inhibi ion agains isomal ase han 19–22, ega dless o he hyd oca bon
esidue leng h.
Scheme 4. P epa a ion o salacinol de i a i es wi h an elonga ed side chain.
Wi h he aim o e alua ing whe he he 5-membe ed hiosuga is essen ial o he α-
glucosidase inhibi o y ac i i y exhibi ed by sul onium-based hiosuga s, Tanabe e al. e-
cen ly syn hesized [23] ing-clea ed salacinol analogues (25–28) and unca ed salacinol
analogues (29–31) (Figu e 3). This in es iga ion was p omp ed by a p e ious epo [24]
demons a ing ha some acyclic analogues de i ed om 1-deoxynoji imycin, a po en α-
glucosidase inhibi o , e ained ac i i y, indica ing ha he i e-membe ed ing may no
be c ucial o he inhibi o y effec . The esul s o he ing-clea ed salacinol analogues
e ealed ha hese compounds we e inac i e, highligh ing he essen ial ole o he 5-mem-
be ed hiosuga in hei po en ac i i y.
Figu e 3. Ring-clea ed salacinol analogues.
A equen d awback ound in he syn hesis o sul onium hiosuga s as po en ial an-
idiabe ic agen s is he limi ed dias e eoselec i i y ound in he alkyla ion eac ion on he
sul u a om, hampe ing he scale-up o he p ocess. Tanabe e al. epo ed [25] he alkyla-
ion o O-p o ec ed hiosuga s wi h epoxides in hexa luo oisop opanol (HFIP), yielding a
oughly 90% dias e eome ic a io (~26:1 α/β), which cons i u es a 3- old imp o emen
compa ed o con en ional me hodologies. The excellen dias e eoselec i i y ound was
a ibu ed o a coope a i e mechanism composed o e e sible S-alkyla ion and he mal
isome iza ion. Using his me hodology, de i a i es 32 (Figu e 4) we e accessed and es ed
Scheme 4. P epa a ion o salacinol de i a i es wi h an elonga ed side chain.
Molecules 2025, 30, x FOR PEER REVIEW 5 o 58
Addi ionally, de-O-sul ona ed analogues a C-3′ posi ion (23 and 24) exhibi ed signi i-
can ly s onge inhibi ion agains isomal ase han 19–22, ega dless o he hyd oca bon
esidue leng h.
Scheme 4. P epa a ion o salacinol de i a i es wi h an elonga ed side chain.
Wi h he aim o e alua ing whe he he 5-membe ed hiosuga is essen ial o he α-
glucosidase inhibi o y ac i i y exhibi ed by sul onium-based hiosuga s, Tanabe e al. e-
cen ly syn hesized [23] ing-clea ed salacinol analogues (25–28) and unca ed salacinol
analogues (29–31) (Figu e 3). This in es iga ion was p omp ed by a p e ious epo [24]
demons a ing ha some acyclic analogues de i ed om 1-deoxynoji imycin, a po en α-
glucosidase inhibi o , e ained ac i i y, indica ing ha he i e-membe ed ing may no
be c ucial o he inhibi o y effec . The esul s o he ing-clea ed salacinol analogues
e ealed ha hese compounds we e inac i e, highligh ing he essen ial ole o he 5-mem-
be ed hiosuga in hei po en ac i i y.
Figu e 3. Ring-clea ed salacinol analogues.
A equen d awback ound in he syn hesis o sul onium hiosuga s as po en ial an-
idiabe ic agen s is he limi ed dias e eoselec i i y ound in he alkyla ion eac ion on he
sul u a om, hampe ing he scale-up o he p ocess. Tanabe e al. epo ed [25] he alkyla-
ion o O-p o ec ed hiosuga s wi h epoxides in hexa luo oisop opanol (HFIP), yielding a
oughly 90% dias e eome ic a io (~26:1 α/β), which cons i u es a 3- old imp o emen
compa ed o con en ional me hodologies. The excellen dias e eoselec i i y ound was
a ibu ed o a coope a i e mechanism composed o e e sible S-alkyla ion and he mal
isome iza ion. Using his me hodology, de i a i es 32 (Figu e 4) we e accessed and es ed
Figu e 3. Ring-clea ed salacinol analogues.
A equen d awback ound in he syn hesis o sul onium hiosuga s as po en ial
an idiabe ic agen s is he limi ed dias e eoselec i i y ound in he alkyla ion eac ion on he
sul u a om, hampe ing he scale-up o he p ocess. Tanabe e al. epo ed [
25
] he alkyla-
ion o O-p o ec ed hiosuga s wi h epoxides in hexa luo oisop opanol (HFIP), yielding
a oughly 90% dias e eome ic a io (~26:1
α
/
β
), which cons i u es a 3- old imp o emen
compa ed o con en ional me hodologies. The excellen dias e eoselec i i y ound was
a ibu ed o a coope a i e mechanism composed o e e sible S-alkyla ion and he mal
isome iza ion. Using his me hodology, de i a i es 32 (Figu e 4) we e accessed and es ed
agains human in es inal mal ase. Those isome s wi h an o ho-subs i u ion pa e n exhib-
i ed s ong inhibi o y p ope ies (IC
50
= 0.11–0.58
µ
M).
In i o
assays in mice e ealed
a high capaci y o supp ession o blood glucose, compa able o he an idiabe ic d ug
oblibose [25].
Molecules 2025, 30, x FOR PEER REVIEW 6 o 58
agains human in es inal mal ase. Those isome s wi h an o ho-subs i u ion pa e n exhib-
i ed s ong inhibi o y p ope ies (IC50 = 0.11‒0.58 µM). In i o assays in mice e ealed a
high capaci y o supp ession o blood glucose, compa able o he an idiabe ic d ug o-
blibose [25].
Figu e 4. Salacinol analogues wi h s ong α-glucosidase inhibi ion.
2.2. Thioglycosides
Thioglycosides a e one o he mos popula glycosyl dono s in glycosyla ion eac-
ions, widely used in he syn hesis o oligosaccha ides o u nish 1,2-cis- and ans-link-
ages [26]. O-glycosides ha e also been ob ained [27] in a s e eoselec i e ashion s a ing
om 1-me cap o-ca bohyd a es by eac ion wi h an acid and a Cu o Co ca alys
(Cu(acac)2, Co(acac)2), Ag2CO3 as he oxidan agen , and unde mic owa e i adia ion.
As a o emen ioned, hioglycosides exhibi a conside ably highe s abili y owa ds
acidic and enzyma ic hyd olysis compa ed o na u al glycosidic linkages; his ea u e is
impo an o inc easing hei bioa ailabili y when inco po a ed in bioac i e compounds.
Fo ins ance, Banisalman e al. p epa ed [28] glycopep ides 33 by conjuga ing mono-
and disaccha ides o he cys eine esidues o he pep ide h ough a disul ide linkage, in-
ol ing he glycosidic posi ion o he ca bohyd a e esidue (Figu e 5).
Figu e 5. Gene al s uc u e o disul ide-linked glycopep ides.
Inco po a ion o S-linked Manα1→2Man e mini in o oligomannose glycans (Man3,
Man4) led o comple e s abili y owa ds enzyma ic hyd olysis media ed by Xan homonas
maniho is mannosidase [29]. 1-S-α-Galp(1 → 3)-β-Galp mo i was inco po a ed [30] in o
oligosaccha ides, leading o he isos e ic uni o he epi ope ecognized by ly ic an ibodies
in T. c uzi, he pa asi ic agen esponsible o he Chagas disease.
An ample a ie y o hioglycosides ha e been epo ed as an iplasmodial [31] and
an i i al agen s [32], inhibi o s o bac e ial glycan biosyn hesis [33], me abolic decoys o
glycosyla ion [34], o hepa anase inhibi o s [35], among o he s; he la e ones a e S-linked
polysaccha ides ob ained ia chemoenzyma ic syn hesis (hepa osan syn hase). Couma in
S-glycosides, ob ained by hioglycoligase-media ed connec ion o 7-me cap o-4-me hyl-
couma ins and p-ni ophenyl-D-glycopy anosides we e claimed [36] o be po en ially use-
ul in bioimaging, due o hei enhanced luo escence emission p ope ies compa ed o
he pa en couma in.
A ele an example o he imp o emen o biological ac i i y achie ed by isos e ic
oxygen-sul u subs i u ion a he glycosidic posi ion was ecen ly epo ed by Gademann
and cowo ke s [37]. The au ho s enhanced he acid s abili y o he na u al glycosyla ed
Figu e 4. Salacinol analogues wi h s ong α-glucosidase inhibi ion.

Molecules 2025,30, 2053 6 o 54
2.2. Thioglycosides
Thioglycosides a e one o he mos popula glycosyl dono s in glycosyla ion e-
ac ions, widely used in he syn hesis o oligosaccha ides o u nish 1,2-cis- and ans-
linkages [
26
]. O-glycosides ha e also been ob ained [
27
] in a s e eoselec i e ashion s a ing
om
1-me cap o-ca bohyd a es
by eac ion wi h an acid and a Cu o Co ca alys (Cu(acac)
2
,
Co(acac)2), Ag2CO3as he oxidan agen , and unde mic owa e i adia ion.
As a o emen ioned, hioglycosides exhibi a conside ably highe s abili y owa ds
acidic and enzyma ic hyd olysis compa ed o na u al glycosidic linkages; his ea u e is
impo an o inc easing hei bioa ailabili y when inco po a ed in bioac i e compounds.
Fo ins ance, Banisalman e al. p epa ed [
28
] glycopep ides 33 by conjuga ing mono-
and disaccha ides o he cys eine esidues o he pep ide h ough a disul ide linkage,
in ol ing he glycosidic posi ion o he ca bohyd a e esidue (Figu e 5).
Molecules 2025, 30, x FOR PEER REVIEW 6 o 58
agains human in es inal mal ase. Those isome s wi h an o ho-subs i u ion pa e n exhib-
i ed s ong inhibi o y p ope ies (IC50 = 0.11‒0.58 µM). In i o assays in mice e ealed a
high capaci y o supp ession o blood glucose, compa able o he an idiabe ic d ug o-
blibose [25].
Figu e 4. Salacinol analogues wi h s ong α-glucosidase inhibi ion.
2.2. Thioglycosides
Thioglycosides a e one o he mos popula glycosyl dono s in glycosyla ion eac-
ions, widely used in he syn hesis o oligosaccha ides o u nish 1,2-cis- and ans-link-
ages [26]. O-glycosides ha e also been ob ained [27] in a s e eoselec i e ashion s a ing
om 1-me cap o-ca bohyd a es by eac ion wi h an acid and a Cu o Co ca alys
(Cu(acac)2, Co(acac)2), Ag2CO3 as he oxidan agen , and unde mic owa e i adia ion.
As a o emen ioned, hioglycosides exhibi a conside ably highe s abili y owa ds
acidic and enzyma ic hyd olysis compa ed o na u al glycosidic linkages; his ea u e is
impo an o inc easing hei bioa ailabili y when inco po a ed in bioac i e compounds.
Fo ins ance, Banisalman e al. p epa ed [28] glycopep ides 33 by conjuga ing mono-
and disaccha ides o he cys eine esidues o he pep ide h ough a disul ide linkage, in-
ol ing he glycosidic posi ion o he ca bohyd a e esidue (Figu e 5).
Figu e 5. Gene al s uc u e o disul ide-linked glycopep ides.
Inco po a ion o S-linked Manα1→2Man e mini in o oligomannose glycans (Man3,
Man4) led o comple e s abili y owa ds enzyma ic hyd olysis media ed by Xan homonas
maniho is mannosidase [29]. 1-S-α-Galp(1 → 3)-β-Galp mo i was inco po a ed [30] in o
oligosaccha ides, leading o he isos e ic uni o he epi ope ecognized by ly ic an ibodies
in T. c uzi, he pa asi ic agen esponsible o he Chagas disease.
An ample a ie y o hioglycosides ha e been epo ed as an iplasmodial [31] and
an i i al agen s [32], inhibi o s o bac e ial glycan biosyn hesis [33], me abolic decoys o
glycosyla ion [34], o hepa anase inhibi o s [35], among o he s; he la e ones a e S-linked
polysaccha ides ob ained ia chemoenzyma ic syn hesis (hepa osan syn hase). Couma in
S-glycosides, ob ained by hioglycoligase-media ed connec ion o 7-me cap o-4-me hyl-
couma ins and p-ni ophenyl-D-glycopy anosides we e claimed [36] o be po en ially use-
ul in bioimaging, due o hei enhanced luo escence emission p ope ies compa ed o
he pa en couma in.
A ele an example o he imp o emen o biological ac i i y achie ed by isos e ic
oxygen-sul u subs i u ion a he glycosidic posi ion was ecen ly epo ed by Gademann
and cowo ke s [37]. The au ho s enhanced he acid s abili y o he na u al glycosyla ed
Figu e 5. Gene al s uc u e o disul ide-linked glycopep ides.
Inco po a ion o S-linked Man
α
1
→
2Man e mini in o oligomannose glycans (Man3,
Man4) led o comple e s abili y owa ds enzyma ic hyd olysis media ed by Xan homonas
maniho is mannosidase [
29
]. 1-S-
α
-Galp(1
→
3)-
β
-Galp mo i was inco po a ed [
30
] in o
oligosaccha ides, leading o he isos e ic uni o he epi ope ecognized by ly ic an ibodies
in T. c uzi, he pa asi ic agen esponsible o he Chagas disease.
An ample a ie y o hioglycosides ha e been epo ed as an iplasmodial [
31
] and
an i i al agen s [
32
], inhibi o s o bac e ial glycan biosyn hesis [
33
], me abolic decoys
o glycosyla ion [
34
], o hepa anase inhibi o s [
35
], among o he s; he la e ones a e
S-linked polysaccha ides ob ained ia chemoenzyma ic syn hesis (hepa osan syn hase).
Couma in S-glycosides, ob ained by hioglycoligase-media ed connec ion o 7-me cap o-4-
me hylcouma ins and p-ni ophenyl-D-glycopy anosides we e claimed [
36
] o be po en ially
use ul in bioimaging, due o hei enhanced luo escence emission p ope ies compa ed o
he pa en couma in.
A ele an example o he imp o emen o biological ac i i y achie ed by isos e ic
oxygen-sul u subs i u ion a he glycosidic posi ion was ecen ly epo ed by Gademann
and cowo ke s [
37
]. The au ho s enhanced he acid s abili y o he na u al glycosyla ed
mac olac one Fidaxomicin (Fdx), app o ed o he Clos idioides di icile (C. di .) in ec ions;
he au ho s eplaced he O-glycosidic bond by he co esponding hioglycoside. Al hough
he na u al compound has shown p omising ac i i ies agains o he pa hogenic agen s,
i s clinical use in o he pa hogens a he han C. di . is hampe ed by i s limi ed acid
s abili y, making i di icul o ea , o example, s omach in ec ions. T ea men o Fdx wi h
Cu(ClO
4
)
·
6H
2
O as ca alys and he co esponding O-p o ec ed-1-me cap o ca bohyd a e,
u nished a mix u e o h ee egioisome ic glycosyla ed p oduc s (modes yields) a C-11
(<5%), C-13 (10%) and C-15 (24%) posi ions, wi h conse ed
β
-con igu a ion. Figu e 6
displays he s uc u e o he hio-isos e o Fdx, ob ained as a mino compound. Deg a-
da ion s udies in me hanolic HCl e ealed ha , whe eas Fdx unde wen deg ada ion
( 1/2 = 62.7 min),
S-Fdx was s able o e a pe iod o 540 min [
37
]. Addi ionally, al hough
he subs i u ion sligh ly educed he an ibac e ial ac i i y, S-Fdx e ained po en e icacy
agains C. di . (Minimum inhibi o y concen a ions (MIC) anges o 0.12–4
µ
g/mL) and
Clos idium pe ingens (MIC anges o 0.06–0.5
µ
g/mL). Regioisome ic hioglycosides a
C-13 and C-15 posi ions demons a ed o be inac i e.
Molecules 2025,30, 2053 7 o 54
Molecules 2025, 30, x FOR PEER REVIEW 7 o 58
mac olac one Fidaxomicin (Fdx), app o ed o he Clos idioides difficile (C. diff.) in ec-
ions; he au ho s eplaced he O-glycosidic bond by he co esponding hioglycoside. Al -
hough he na u al compound has shown p omising ac i i ies agains o he pa hogenic
agen s, i s clinical use in o he pa hogens a he han C. diff. is hampe ed by i s limi ed
acid s abili y, making i difficul o ea , o example, s omach in ec ions. T ea men o
Fdx wi h Cu(ClO4)·6H2O as ca alys and he co esponding O-p o ec ed-1-me cap o ca -
bohyd a e, u nished a mix u e o h ee egioisome ic glycosyla ed p oduc s (modes
yields) a C-11 (<5%), C-13 (10%) and C-15 (24%) posi ions, wi h conse ed β-con igu a-
ion. Figu e 6 displays he s uc u e o he hio-isos e o Fdx, ob ained as a mino com-
pound. Deg ada ion s udies in me hanolic HCl e ealed ha , whe eas Fdx unde wen
deg ada ion ( 1/2 = 62.7 min), S-Fdx was s able o e a pe iod o 540 min [37]. Addi ionally,
al hough he subs i u ion sligh ly educed he an ibac e ial ac i i y, S-Fdx e ained po en
efficacy agains C. diff. (Minimum inhibi o y concen a ions (MIC) anges o 0.12–4
µg/mL) and Clos idium pe ingens (MIC anges o 0.06‒0.5 µg/mL). Regioisome ic hi-
oglycosides a C-13 and C-15 posi ions demons a ed o be inac i e.
Figu e 6. S uc u e o hio-Fidaxomicin.
Classical syn he ic me hodologies epo ed o he p epa a ion o hioglycosides in-
clude eac ion o hiols wi h pe -O-ace yla ed ca bohyd a es, using Lewis acids as ca a-
lys s, eac ion o hiola es wi h ace ohalosuga s, o 1- hioglycode i a i es wi h alkyl hal-
ides. The building blocks in ol ed in such ans o ma ions a e depic ed in Scheme 5.
Scheme 5. Classical p ocedu es o p epa ing hioglycosides.
In he sea ch o eco- iendly me hods o syn hesize hioglycosides, Luo and cowo k-
e s de eloped [38] an inno a i e me hodology based on he use o phospho ungs ic acid
(PTA) as a ca alys o he eac ion o pe -O-ace yla ed saccha ides 34 (D-galac ose, D-xy-
lose, L- ucose) and hiols unde mic owa e-assis ed condi ions (Scheme 6). No ably, PTA
Figu e 6. S uc u e o hio-Fidaxomicin.
Classical syn he ic me hodologies epo ed o he p epa a ion o hioglycosides in-
clude eac ion o hiols wi h pe -O-ace yla ed ca bohyd a es, using Lewis acids as ca alys s,
eac ion o hiola es wi h ace ohalosuga s, o 1- hioglycode i a i es wi h alkyl halides. The
building blocks in ol ed in such ans o ma ions a e depic ed in Scheme 5.
Molecules 2025, 30, x FOR PEER REVIEW 7 o 58
mac olac one Fidaxomicin (Fdx), app o ed o he Clos idioides difficile (C. diff.) in ec-
ions; he au ho s eplaced he O-glycosidic bond by he co esponding hioglycoside. Al -
hough he na u al compound has shown p omising ac i i ies agains o he pa hogenic
agen s, i s clinical use in o he pa hogens a he han C. diff. is hampe ed by i s limi ed
acid s abili y, making i difficul o ea , o example, s omach in ec ions. T ea men o
Fdx wi h Cu(ClO4)·6H2O as ca alys and he co esponding O-p o ec ed-1-me cap o ca -
bohyd a e, u nished a mix u e o h ee egioisome ic glycosyla ed p oduc s (modes
yields) a C-11 (<5%), C-13 (10%) and C-15 (24%) posi ions, wi h conse ed β-con igu a-
ion. Figu e 6 displays he s uc u e o he hio-isos e o Fdx, ob ained as a mino com-
pound. Deg ada ion s udies in me hanolic HCl e ealed ha , whe eas Fdx unde wen
deg ada ion ( 1/2 = 62.7 min), S-Fdx was s able o e a pe iod o 540 min [37]. Addi ionally,
al hough he subs i u ion sligh ly educed he an ibac e ial ac i i y, S-Fdx e ained po en
efficacy agains C. diff. (Minimum inhibi o y concen a ions (MIC) anges o 0.12–4
µg/mL) and Clos idium pe ingens (MIC anges o 0.06‒0.5 µg/mL). Regioisome ic hi-
oglycosides a C-13 and C-15 posi ions demons a ed o be inac i e.
Figu e 6. S uc u e o hio-Fidaxomicin.
Classical syn he ic me hodologies epo ed o he p epa a ion o hioglycosides in-
clude eac ion o hiols wi h pe -O-ace yla ed ca bohyd a es, using Lewis acids as ca a-
lys s, eac ion o hiola es wi h ace ohalosuga s, o 1- hioglycode i a i es wi h alkyl hal-
ides. The building blocks in ol ed in such ans o ma ions a e depic ed in Scheme 5.
Scheme 5. Classical p ocedu es o p epa ing hioglycosides.
In he sea ch o eco- iendly me hods o syn hesize hioglycosides, Luo and cowo k-
e s de eloped [38] an inno a i e me hodology based on he use o phospho ungs ic acid
(PTA) as a ca alys o he eac ion o pe -O-ace yla ed saccha ides 34 (D-galac ose, D-xy-
lose, L- ucose) and hiols unde mic owa e-assis ed condi ions (Scheme 6). No ably, PTA
Scheme 5. Classical p ocedu es o p epa ing hioglycosides.
In he sea ch o eco- iendly me hods o syn hesize hioglycosides, Luo and cowo k-
e s de eloped [
38
] an inno a i e me hodology based on he use o phospho ungs ic acid
(PTA) as a ca alys o he eac ion o pe -O-ace yla ed saccha ides 34
(D-galac ose, D-xylose,
L- ucose)
and hiols unde mic owa e-assis ed condi ions (Scheme 6). No ably, PTA p o ed
o be highly eusable, main aining yields o 84–88% ac oss mul iple eac ions wi h a e-
co e y e iciency exceeding 80%. Fu he mo e, me hanolic PTA was success ully u i-
lized o he one-po de-O-ace yla ion o ace oxy compounds o gi e ully unp o ec ed
hioglycosides 35.
Molecules 2025, 30, x FOR PEER REVIEW 8 o 58
p o ed o be highly eusable, main aining yields o 84‒88% ac oss mul iple eac ions wi h
a eco e y efficiency exceeding 80%. Fu he mo e, me hanolic PTA was success ully u i-
lized o he one-po de-O-ace yla ion o ace oxy compounds o gi e ully unp o ec ed
hioglycosides 35.
Scheme 6. One-po p ocess o he hioglycoside o ma ion and de-O-ace yla ion. Reagen s and
condi ions: (a) PTA, HSR, DCM, MW, 30 min, 40 °C.; (b) PTA, MeOH, 90 °C, 4 h.
In o de o a oid handling alkyl hiols, which a e equen ly malodo ous and oxic,
Dong and cowo ke s de eloped [39] an efficien and en i onmen ally iendly p o ocol
ha consis ed o he eac ion o sodium alkane hiola es wi h pe -O-ace yla ed ca bohy-
d a es 34 in he p esence o BF3·OE 2 unde sol en less condi ions (Scheme 7). In e es -
ingly, 1,2- ans- hioglycosides 35 could be isome ized in o challenging 1,2-cis species 36
by ea men wi h T OH in non-pola sol en s and unde mild condi ions (Scheme 7).
Scheme 7. Syn hesis o hioalkylglycosides.
Pd-ca alyzed c oss-coupling eac ions ha e also been used o accessing hioglyco-
sides. In his con ex , Domingues e al. employed [40] he hi d-gene a ion Buchwald
p eca alys (Pd-G3 Xan phos palladacycle) o unc ionalizing benzo-2,1,3- hiadiazole
(BTD) a he C-5 posi ion wi h 1-me cap o suga s 37 o gi e 39 (Scheme 8); he in e es in
such he e ocyclic mo i lies in he ac ha i can be used as a luo escen ma ke . The
scope o he eac ion was analyzed on py anoses (D-Glc, D-Man, D-Gal, D-Xyl, L-A a),
u anoses (D-Rib) and disaccha ides (mal ose, lac ose), and was ound o p oceed unde
mild condi ions and o be compa ible wi h an ample a ie y o unc ional g oups. The
yields we e om good o almos quan i a i e, excep o pe -O-ace yla ed D-mannopy a-
nose and D- ibo u anose, whose hioglycosides we e ob ained in modes yields; e en ion
o he β-con igu a ion was obse ed. The lowes yields could be signi ican ly inc eased by
changing he ca alys o Pd G3-Mo Dalphos. P oduc s we e dep o ec ed using Zemplen-
ype condi ions.
Scheme 8. Pd-ca alyzed C–S c oss-coupling eac ion be ween hiosuga s and BTD. Reagen s and
condi ions: (a) Pd ca alys 4-5 mol%, E 3N, 1,4-dioxane, 90 °C; (b) K2CO3 (ca .), MeOH.
Scheme 6. One-po p ocess o he hioglycoside o ma ion and de-O-ace yla ion. Reagen s and
condi ions: (a) PTA, HSR, DCM, MW, 30 min, 40 ◦C.; (b) PTA, MeOH, 90 ◦C, 4 h.
In o de o a oid handling alkyl hiols, which a e equen ly malodo ous and oxic,
Dong and cowo ke s de eloped [
39
] an e icien and en i onmen ally iendly p o ocol ha
consis ed o he eac ion o sodium alkane hiola es wi h pe -O-ace yla ed ca bohyd a es
34 in he p esence o BF
3·
OE
2
unde sol en less condi ions (Scheme 7). In e es ingly,
Molecules 2025,30, 2053 8 o 54
1,2- ans- hioglycosides
35 could be isome ized in o challenging 1,2-cis species 36 by ea -
men wi h T OH in non-pola sol en s and unde mild condi ions (Scheme 7).
Molecules 2025, 30, x FOR PEER REVIEW 8 o 58
p o ed o be highly eusable, main aining yields o 84‒88% ac oss mul iple eac ions wi h
a eco e y efficiency exceeding 80%. Fu he mo e, me hanolic PTA was success ully u i-
lized o he one-po de-O-ace yla ion o ace oxy compounds o gi e ully unp o ec ed
hioglycosides 35.
Scheme 6. One-po p ocess o he hioglycoside o ma ion and de-O-ace yla ion. Reagen s and
condi ions: (a) PTA, HSR, DCM, MW, 30 min, 40 °C.; (b) PTA, MeOH, 90 °C, 4 h.
In o de o a oid handling alkyl hiols, which a e equen ly malodo ous and oxic,
Dong and cowo ke s de eloped [39] an efficien and en i onmen ally iendly p o ocol
ha consis ed o he eac ion o sodium alkane hiola es wi h pe -O-ace yla ed ca bohy-
d a es 34 in he p esence o BF3·OE 2 unde sol en less condi ions (Scheme 7). In e es -
ingly, 1,2- ans- hioglycosides 35 could be isome ized in o challenging 1,2-cis species 36
by ea men wi h T OH in non-pola sol en s and unde mild condi ions (Scheme 7).
Scheme 7. Syn hesis o hioalkylglycosides.
Pd-ca alyzed c oss-coupling eac ions ha e also been used o accessing hioglyco-
sides. In his con ex , Domingues e al. employed [40] he hi d-gene a ion Buchwald
p eca alys (Pd-G3 Xan phos palladacycle) o unc ionalizing benzo-2,1,3- hiadiazole
(BTD) a he C-5 posi ion wi h 1-me cap o suga s 37 o gi e 39 (Scheme 8); he in e es in
such he e ocyclic mo i lies in he ac ha i can be used as a luo escen ma ke . The
scope o he eac ion was analyzed on py anoses (D-Glc, D-Man, D-Gal, D-Xyl, L-A a),
u anoses (D-Rib) and disaccha ides (mal ose, lac ose), and was ound o p oceed unde
mild condi ions and o be compa ible wi h an ample a ie y o unc ional g oups. The
yields we e om good o almos quan i a i e, excep o pe -O-ace yla ed D-mannopy a-
nose and D- ibo u anose, whose hioglycosides we e ob ained in modes yields; e en ion
o he β-con igu a ion was obse ed. The lowes yields could be signi ican ly inc eased by
changing he ca alys o Pd G3-Mo Dalphos. P oduc s we e dep o ec ed using Zemplen-
ype condi ions.
Scheme 8. Pd-ca alyzed C–S c oss-coupling eac ion be ween hiosuga s and BTD. Reagen s and
condi ions: (a) Pd ca alys 4-5 mol%, E 3N, 1,4-dioxane, 90 °C; (b) K2CO3 (ca .), MeOH.
Scheme 7. Syn hesis o hioalkylglycosides.
Pd-ca alyzed c oss-coupling eac ions ha e also been used o accessing hioglycosides.
In his con ex , Domingues e al. employed [
40
] he hi d-gene a ion Buchwald p eca alys
(Pd-G3 Xan phos palladacycle) o unc ionalizing benzo-2,1,3- hiadiazole (BTD) a he C-5
posi ion wi h 1-me cap o suga s 37 o gi e 39 (Scheme 8); he in e es in such he e ocyclic
mo i lies in he ac ha i can be used as a luo escen ma ke . The scope o he eac ion
was analyzed on py anoses (D-Glc, D-Man, D-Gal, D-Xyl, L-A a), u anoses (D-Rib) and
disaccha ides (mal ose, lac ose), and was ound o p oceed unde mild condi ions and o
be compa ible wi h an ample a ie y o unc ional g oups. The yields we e om good o
almos quan i a i e, excep o pe -O-ace yla ed D-mannopy anose and D- ibo u anose,
whose hioglycosides we e ob ained in modes yields; e en ion o he
β
-con igu a ion was
obse ed. The lowes yields could be signi ican ly inc eased by changing he ca alys o Pd
G3-Mo Dalphos. P oduc s we e dep o ec ed using Zemplen- ype condi ions.
Molecules 2025, 30, x FOR PEER REVIEW 8 o 58
p o ed o be highly eusable, main aining yields o 84‒88% ac oss mul iple eac ions wi h
a eco e y efficiency exceeding 80%. Fu he mo e, me hanolic PTA was success ully u i-
lized o he one-po de-O-ace yla ion o ace oxy compounds o gi e ully unp o ec ed
hioglycosides 35.
Scheme 6. One-po p ocess o he hioglycoside o ma ion and de-O-ace yla ion. Reagen s and
condi ions: (a) PTA, HSR, DCM, MW, 30 min, 40 °C.; (b) PTA, MeOH, 90 °C, 4 h.
In o de o a oid handling alkyl hiols, which a e equen ly malodo ous and oxic,
Dong and cowo ke s de eloped [39] an efficien and en i onmen ally iendly p o ocol
ha consis ed o he eac ion o sodium alkane hiola es wi h pe -O-ace yla ed ca bohy-
d a es 34 in he p esence o BF3·OE 2 unde sol en less condi ions (Scheme 7). In e es -
ingly, 1,2- ans- hioglycosides 35 could be isome ized in o challenging 1,2-cis species 36
by ea men wi h T OH in non-pola sol en s and unde mild condi ions (Scheme 7).
Scheme 7. Syn hesis o hioalkylglycosides.
Pd-ca alyzed c oss-coupling eac ions ha e also been used o accessing hioglyco-
sides. In his con ex , Domingues e al. employed [40] he hi d-gene a ion Buchwald
p eca alys (Pd-G3 Xan phos palladacycle) o unc ionalizing benzo-2,1,3- hiadiazole
(BTD) a he C-5 posi ion wi h 1-me cap o suga s 37 o gi e 39 (Scheme 8); he in e es in
such he e ocyclic mo i lies in he ac ha i can be used as a luo escen ma ke . The
scope o he eac ion was analyzed on py anoses (D-Glc, D-Man, D-Gal, D-Xyl, L-A a),
u anoses (D-Rib) and disaccha ides (mal ose, lac ose), and was ound o p oceed unde
mild condi ions and o be compa ible wi h an ample a ie y o unc ional g oups. The
yields we e om good o almos quan i a i e, excep o pe -O-ace yla ed D-mannopy a-
nose and D- ibo u anose, whose hioglycosides we e ob ained in modes yields; e en ion
o he β-con igu a ion was obse ed. The lowes yields could be signi ican ly inc eased by
changing he ca alys o Pd G3-Mo Dalphos. P oduc s we e dep o ec ed using Zemplen-
ype condi ions.
Scheme 8. Pd-ca alyzed C–S c oss-coupling eac ion be ween hiosuga s and BTD. Reagen s and
condi ions: (a) Pd ca alys 4-5 mol%, E 3N, 1,4-dioxane, 90 °C; (b) K2CO3 (ca .), MeOH.
Scheme 8. Pd-ca alyzed C–S c oss-coupling eac ion be ween hiosuga s and BTD. Reagen s and
condi ions: (a) Pd ca alys 4-5 mol%, E 3N, 1,4-dioxane, 90 ◦C; (b) K2CO3(ca .), MeOH.
Pd-ca alyzed Migi a c oss-coupling eac ion be ween a acemic mix u e o o-iodo
S- i luo ome hyl-S-a ylsul oximines 41
and a g ea a ie y o 1-me cap o suga s
(mono-,
di- and isaccha ides) has been used in he p epa a ion o hioglycosides 42/43 [
41
]. Fo
ha pu pose, PdG3-Xan Phos was used as he ca alys , and E
3
N as base (Scheme 9).
A single
β
-anome was ob ained, in a 1:1 dias e eome ic mix u e, ha was e icien ly
sepa a ed by ei he c ys alliza ion o HPLC.
Molecules 2025, 30, x FOR PEER REVIEW 9 o 58
Pd-ca alyzed Migi a c oss-coupling eac ion be ween a acemic mix u e o o-iodo S-
i luo ome hyl-S-a ylsul oximines 41 and a g ea a ie y o 1-me cap o suga s (mono-,
di- and isaccha ides) has been used in he p epa a ion o hioglycosides 42/43 [41]. Fo
ha pu pose, PdG3-Xan Phos was used as he ca alys , and E 3N as base (Scheme 9). A
single β-anome was ob ained, in a 1:1 dias e eome ic mix u e, ha was efficien ly sepa-
a ed by ei he c ys alliza ion o HPLC.
Scheme 9. Migi a c oss-coupling eac ion o he syn hesis o hioglycosides. Reagen s and condi-
ions: (a) PdG3-Xan Phos, E 3N (1.5 equi ), dioxane, 15‒30 min.
O-P o ec ed 1- hio-mono- and disaccha ides 37 we e efficien ly coupled [42] wi h
a yl-naph hoquinones 44 (Scheme 10) in he p esence o 45, a chi al squa amide as he
o ganoca alys . The co esponding axially chi al hioglycosides 46 we e ob ained, in gen-
e al, wi h high dias e eoselec i i y (14:1 o >19:1 d ). I was claimed ha he hyd ogen
bonding es ablished be ween he bi unc ional o ganoca alys and he quinone had a pi -
o al ole in he ac i a ion o he subs a e and he s e eocon ol, locking a majo con o -
ma ion o he biphenyl esidue a he ansi ion s a e wi h he lowes s e ical hind ance.
Scheme 10. S e eoselec i e syn hesis o naph hoquinone hioglycosides using a squa amide-based
o ganoca alys .
Iso hiou onium sal s a e in e es ing syn he ic in e media es, and can be ob ained
om ully O-ace yla ed ca bohyd a es 34 by ea men wi h BF3·OE 2 o gi e en a i ely a
1,2-acyloxonium ion [43]. Reac ion o he la e wi h hiou ea as a nucleophile, affo ds he
co esponding iso hiou onium de i a i e 47, exclusi ely wi h he 1,2- ans-a angemen
(Scheme 11). Hyd olysis o 47 unde weakly basic condi ions (E 3N) gi es access o a an-
sien hiola e (48), which exe s a 1,6 nucleophilic addi ion on p-quinone me hide, wi h he
subsequen o ma ion o dia ylme hyl hioglycosides 49.
Scheme 9. Migi a c oss-coupling eac ion o he syn hesis o hioglycosides. Reagen s and condi ions:
(a) PdG3-Xan Phos, E 3N (1.5 equi ), dioxane, 15–30 min.
O-P o ec ed 1- hio-mono- and disaccha ides 37 we e e icien ly coupled [
42
] wi h
a yl-naph hoquinones 44 (Scheme 10) in he p esence o 45, a chi al squa amide as he
Molecules 2025,30, 2053 9 o 54
o ganoca alys . The co esponding axially chi al hioglycosides 46 we e ob ained, in
gene al, wi h high dias e eoselec i i y (14:1 o >19:1 d ). I was claimed ha he hyd ogen
bonding es ablished be ween he bi unc ional o ganoca alys and he quinone had a pi o al
ole in he ac i a ion o he subs a e and he s e eocon ol, locking a majo con o ma ion
o he biphenyl esidue a he ansi ion s a e wi h he lowes s e ical hind ance.
Molecules 2025, 30, x FOR PEER REVIEW 9 o 58
Pd-ca alyzed Migi a c oss-coupling eac ion be ween a acemic mix u e o o-iodo S-
i luo ome hyl-S-a ylsul oximines 41 and a g ea a ie y o 1-me cap o suga s (mono-,
di- and isaccha ides) has been used in he p epa a ion o hioglycosides 42/43 [41]. Fo
ha pu pose, PdG3-Xan Phos was used as he ca alys , and E 3N as base (Scheme 9). A
single β-anome was ob ained, in a 1:1 dias e eome ic mix u e, ha was efficien ly sepa-
a ed by ei he c ys alliza ion o HPLC.
Scheme 9. Migi a c oss-coupling eac ion o he syn hesis o hioglycosides. Reagen s and condi-
ions: (a) PdG3-Xan Phos, E 3N (1.5 equi ), dioxane, 15‒30 min.
O-P o ec ed 1- hio-mono- and disaccha ides 37 we e efficien ly coupled [42] wi h
a yl-naph hoquinones 44 (Scheme 10) in he p esence o 45, a chi al squa amide as he
o ganoca alys . The co esponding axially chi al hioglycosides 46 we e ob ained, in gen-
e al, wi h high dias e eoselec i i y (14:1 o >19:1 d ). I was claimed ha he hyd ogen
bonding es ablished be ween he bi unc ional o ganoca alys and he quinone had a pi -
o al ole in he ac i a ion o he subs a e and he s e eocon ol, locking a majo con o -
ma ion o he biphenyl esidue a he ansi ion s a e wi h he lowes s e ical hind ance.
Scheme 10. S e eoselec i e syn hesis o naph hoquinone hioglycosides using a squa amide-based
o ganoca alys .
Iso hiou onium sal s a e in e es ing syn he ic in e media es, and can be ob ained
om ully O-ace yla ed ca bohyd a es 34 by ea men wi h BF3·OE 2 o gi e en a i ely a
1,2-acyloxonium ion [43]. Reac ion o he la e wi h hiou ea as a nucleophile, affo ds he
co esponding iso hiou onium de i a i e 47, exclusi ely wi h he 1,2- ans-a angemen
(Scheme 11). Hyd olysis o 47 unde weakly basic condi ions (E 3N) gi es access o a an-
sien hiola e (48), which exe s a 1,6 nucleophilic addi ion on p-quinone me hide, wi h he
subsequen o ma ion o dia ylme hyl hioglycosides 49.
Scheme 10. S e eoselec i e syn hesis o naph hoquinone hioglycosides using a squa amide-based
o ganoca alys .
Iso hiou onium sal s a e in e es ing syn he ic in e media es, and can be ob ained
om ully O-ace yla ed ca bohyd a es 34 by ea men wi h BF
3·
OE
2
o gi e en a i ely a
1,2-acyloxonium ion [43]. Reac ion o he la e wi h hiou ea as a nucleophile, a o ds he
co esponding iso hiou onium de i a i e 47, exclusi ely wi h he 1,2- ans-a angemen
(Scheme 11). Hyd olysis o 47 unde weakly basic condi ions (E
3
N) gi es access o a
ansien hiola e (48), which exe s a 1,6 nucleophilic addi ion on p-quinone me hide, wi h
he subsequen o ma ion o dia ylme hyl hioglycosides 49.
Molecules 2025, 30, x FOR PEER REVIEW 10 o 58
Scheme 11. Syn hesis o dia ylme hyl hioglycosides.
A yldiazonium sal s a e known o hei inhe en elec ophilici y, and ha e been
used in he o ma ion o C–S bonds. Building on his p ope y, Venka esh e al. de eloped
[44] a eac ion be ween hiosuga s 40 and ac i a ed a yldiazonium sal s 50 (Scheme 12) o
efficien ly o m C‒S bonds (S-a yla ion, compounds 51). The op imized condi ions in-
ol ed he use o CuCl as he ca alys , DBU as he base, low empe a u es (0‒5 °C) and
sho eac ion imes (<5 min). Unde hese condi ions, diazosul ide (R-S-N=N-A ) is no
obse ed, and only small amoun s o he compe ing dime (R-S-S-R) was ob ained. The
eac ion was compa ible wi h an ample numbe o p o ec ing g oups (NHAc, Ac, Bn, Bz),
and e en wi h unp o ec ed ca bohyd a es; howe e , in his case, he a io o he undesi ed
dime ic disul ides inc eased [44]. I was pos ula ed ha he key in e media e is a ee ad-
ical, ob ained upon eac ion o he a yldiazonium sal wi h he Cu(I) ca alys . This mech-
anism was demons a ed by he addi ion o a ee adical sca enge (TEMPO), u nishing
only aces o 51 [44].
Scheme 12. Syn hesis S-a yl hioglycosides. Reagen s and condi ions: (a) CuCl (5%), DBU (1 eq),
MeCN, 0‒5 °C.
This app oach enabled he success ul syn hesis o hio-analogues o bioac i e com-
pounds, including he an idiabe ic agen dapagli lozin (52) [45,46], and he y osinase in-
hibi o a bu in (53) (Figu e 7).
Figu e 7. Thio-analogues o dapagli lozin and a bu in.
A s e eospeci ic me al- ee syn hesis o a yl hioglycosides 51 was achie ed by using
a bo on ca alys o p omo ing a educ i e deoxygena ion coupling eac ion be ween O-
p o ec ed α-ace ob omohexoses 54 (also di- and isaccha ides) and sul onyl chlo ides 55
(Scheme 13) [47]; B2pin2 (Bis(pinacola o)dibo on) and PPh3 we e used as addi i es. This a -
Scheme 11. Syn hesis o dia ylme hyl hioglycosides.
A yldiazonium sal s a e known o hei inhe en elec ophilici y, and ha e been used
in he o ma ion o C–S bonds. Building on his p ope y, Venka esh e al. de eloped [
44
]
a eac ion be ween hiosuga s 40 and ac i a ed a yldiazonium sal s 50 (Scheme 12) o
e icien ly o m C–S bonds (S-a yla ion, compounds 51). The op imized condi ions in ol ed
he use o CuCl as he ca alys , DBU as he base, low empe a u es (0–5
◦
C) and sho
eac ion imes (<5 min). Unde hese condi ions, diazosul ide (R-S-N=N-A ) is no obse ed,
and only small amoun s o he compe ing dime (R-S-S-R) was ob ained. The eac ion was
compa ible wi h an ample numbe o p o ec ing g oups (NHAc, Ac, Bn, Bz), and e en
wi h unp o ec ed ca bohyd a es; howe e , in his case, he a io o he undesi ed dime ic
disul ides inc eased [
44
]. I was pos ula ed ha he key in e media e is a ee adical,
Molecules 2025,30, 2053 16 o 54
Molecules 2025, 30, x FOR PEER REVIEW 16 o 58
Scheme 18. Syn hesis o pseudo-disaccha ides om 1- hio-β-D-mannosides and 1- hio-β-L- hamno-
sides.
Pho oini ia ed hiol-ene coupling eac ions we e used by Bo bás and co-wo ke s o
p epa ing S-linked pseudo-disaccha ides [61]. These glycomime ics we e ob ained by
UV-induc ion o hyd o hiola ion eac ions be ween unsa u a ed suga s bea ing an exocy-
clic double bond a C1, C2, C3, C4, C5 and C6 posi ions and a hiol-con aining suga
(Scheme 19). 2,2-Dime hoxy-2-phenylace ophenone (DPAP) was used as he pho oini ia-
o . Reac ion p oceeds in a wo-s ep pa hway: e e sible addi ion o he hiyl ee adical,
and he i e e sible dona ion o hyd ogen a om om a hiol; al hough he s e eoselec i i y
s ongly depends on he ca bohyd a e in ol ed, a p e e en ial axial H- ans e is e-
quen ly obse ed, wi h he hiol subs i uen occupying he equa o ial posi ion [61].
Scheme 19. Reac ions o enopy anoses bea ing an exocyclic double bond.
Using his me hodology, he sialyl hioglycoside 86 was ob ained in good yield
(Scheme 20).
Scheme 19. Reac ions o enopy anoses bea ing an exocyclic double bond.
Using his me hodology, he sialyl hioglycoside 86 was ob ained in good yield
(Scheme 20).
Molecules 2025, 30, x FOR PEER REVIEW 17 o 58
O
OH
HO
HO
OH
S
O
OH
OH
OMe
HO
O
OH
HO
HO
OH
S
O
OH
OH
OMe
HO
O
OR
N
NHT BuOCl (1.1 eq.)
THF, 20 °C
O
OR
N
NHT
RSH (80 eq.)
5 °C
O
OR
Cl-
87 88 89
SR
90 91
O
OH
HO
HO
OH
F
HS
O
OH
OH
OMe
HO
+
AcS
O
OH
OH
OMe
HO
92 93 94
Scheme 20. Syn hesis o hiosuga s om suga -de i ed i yl hyd azones.
A s aigh o wa d al e na i e o p epa ing O-unp o ec ed S-linked pseudo-disac-
cha ides consis s o he p epa a ion o suga -de i ed i yl hyd azones 87, which upon
ea men wi h BuOCl gene a e a chlo o-azo in e media e on he suga moie y [62]. The -
molysis o such in e media e in he p esence o an excess o simple hiols gene a es hi-
oe he s 89 in up o almos quan i a i e yield (Scheme 20).
This me hodology was applied o he p epa a ion o pseudo-disaccha ides 90 and 91,
which we e ob ained by ea men o i yl hyd azone 87 wi h AcSH o gi e 94, ollowed
by hyd olysis o he ace yl moie y, and coupling o he co esponding 3- hiols 93 wi h
glucopy anosyl luo ide 92 (Scheme 20) [62].
Au oma ed syn heses ha e also been applied o he selec i e inco po a ion o S-gly-
cosides in o oligomannopy anosides [63] using an in e se glycosyla ion p o ocol ins ead
o he con en ional me hodology. The syn hesis o isaccha ide 97 was accomplished
wi h good yield (73%) employing eac i e glycosyl accep o 95, glycosyl dono 96, and
TMSOT as he p omo e (Scheme 21). The p ocess comp ised h ee sequen ial cycles o
glycosyla ion coupling, dep o ec ion, and pu i ica ion. The au oma ed p o ocol was exe-
cu ed on a pla o m equipped wi h a obo ic a m and dual sy inge pumps, enabling p e-
cise deli e y o eagen s o an a ay o double-jacke ed eac ion essels. The eac ion se up
was main ained unde an ine a mosphe e, ensu ing con olled and ep oducible condi-
ions o each s ep o he syn hesis [63].
Scheme 20. Syn hesis o hiosuga s om suga -de i ed i yl hyd azones.
A s aigh o wa d al e na i e o p epa ing O-unp o ec ed S-linked pseudo-disaccha ides
consis s o he p epa a ion o suga -de i ed i yl hyd azones 87, which upon ea men
wi h BuOCl gene a e a chlo o-azo in e media e on he suga moie y [
62
]. The molysis o
such in e media e in he p esence o an excess o simple hiols gene a es hioe he s 89 in up
o almos quan i a i e yield (Scheme 20).
This me hodology was applied o he p epa a ion o pseudo-disaccha ides 90 and 91,
which we e ob ained by ea men o i yl hyd azone 87 wi h AcSH o gi e 94, ollowed
by hyd olysis o he ace yl moie y, and coupling o he co esponding 3- hiols 93 wi h
glucopy anosyl luo ide 92 (Scheme 20) [62].

Molecules 2025,30, 2053 17 o 54
Au oma ed syn heses ha e also been applied o he selec i e inco po a ion o S-
glycosides in o oligomannopy anosides [
63
] using an in e se glycosyla ion p o ocol ins ead
o he con en ional me hodology. The syn hesis o isaccha ide 97 was accomplished
wi h good yield (73%) employing eac i e glycosyl accep o 95, glycosyl dono 96, and
TMSOT as he p omo e (Scheme 21). The p ocess comp ised h ee sequen ial cycles
o glycosyla ion coupling, dep o ec ion, and pu i ica ion. The au oma ed p o ocol was
execu ed on a pla o m equipped wi h a obo ic a m and dual sy inge pumps, enabling
p ecise deli e y o eagen s o an a ay o double-jacke ed eac ion essels. The eac ion
se up was main ained unde an ine a mosphe e, ensu ing con olled and ep oducible
condi ions o each s ep o he syn hesis [63].
Molecules 2025, 30, x FOR PEER REVIEW 17 o 58
O
OH
HO
HO
OH
S
O
OH
OH
OMe
HO
O
OH
HO
HO
OH
S
O
OH
OH
OMe
HO
O
OR
N
NHT BuOCl (1.1 eq.)
THF, 20 °C
O
OR
N
NHT
RSH (80 eq.)
5 °C
O
OR
Cl-
87 88 89
SR
90 91
O
OH
HO
HO
OH
F
HS
O
OH
OH
OMe
HO
+
AcS
O
OH
OH
OMe
HO
92 93 94
Scheme 20. Syn hesis o hiosuga s om suga -de i ed i yl hyd azones.
A s aigh o wa d al e na i e o p epa ing O-unp o ec ed S-linked pseudo-disac-
cha ides consis s o he p epa a ion o suga -de i ed i yl hyd azones 87, which upon
ea men wi h BuOCl gene a e a chlo o-azo in e media e on he suga moie y [62]. The -
molysis o such in e media e in he p esence o an excess o simple hiols gene a es hi-
oe he s 89 in up o almos quan i a i e yield (Scheme 20).
This me hodology was applied o he p epa a ion o pseudo-disaccha ides 90 and 91,
which we e ob ained by ea men o i yl hyd azone 87 wi h AcSH o gi e 94, ollowed
by hyd olysis o he ace yl moie y, and coupling o he co esponding 3- hiols 93 wi h
glucopy anosyl luo ide 92 (Scheme 20) [62].
Au oma ed syn heses ha e also been applied o he selec i e inco po a ion o S-gly-
cosides in o oligomannopy anosides [63] using an in e se glycosyla ion p o ocol ins ead
o he con en ional me hodology. The syn hesis o isaccha ide 97 was accomplished
wi h good yield (73%) employing eac i e glycosyl accep o 95, glycosyl dono 96, and
TMSOT as he p omo e (Scheme 21). The p ocess comp ised h ee sequen ial cycles o
glycosyla ion coupling, dep o ec ion, and pu i ica ion. The au oma ed p o ocol was exe-
cu ed on a pla o m equipped wi h a obo ic a m and dual sy inge pumps, enabling p e-
cise deli e y o eagen s o an a ay o double-jacke ed eac ion essels. The eac ion se up
was main ained unde an ine a mosphe e, ensu ing con olled and ep oducible condi-
ions o each s ep o he syn hesis [63].
Scheme 21. Au oma ed app oach o he syn hesis o oligomannopy anosides.
2.3. 3-Thiosuga s
Inco po a ion o a sul u a om a C-3 posi ion o a suga esidue has been used
o accessing aluable syn he ic in e media es, as well as o p epa ing de i a i es wi h
po en ial biological ac i i ies [
64
]. Despi e ha , his kind o sul u -con aining ca bohyd a es
is signi ican ly less s udied compa ed o o he posi ions on he suga , like he endocyclic
oxygen, o he glycosidic posi ion. A equen app oach o accessing 3- hiosuga s is he
eac ion o glycals wi h di e en hiols and ca alys s, as displayed in his sec ion.
Mukhe jee e al. epo ed [
65
] he biomime ic syn hesis o a amily o 3- hiosuga s
(100, Scheme 22)
ia eac ion o 2-ke ophenyl-glycals 98,99 (D-glucal, D-galac al, L- hamnal)
wi h di e en hiols. The egio- and s e eoselec i e displacemen o he ace oxy g oup
a he C-3 posi ion o he glycal was achie ed using a oma ic and cyclic alipha ic hiols
unde mild basic condi ions (E
3
N), u nishing excellen axial selec i i y. The p esence
o a ca bonyl g oup a C-2 was ound o be c ucial [
65
]. I was hypo hesized ha he
hiol a acks he ca bonyl g oup a C-2, and hen i unde goes a 1,3-mig a ion h ough he
opposi e ace o he ace oxy g oup a C-3. This p ocess was inspi ed by he hiola ion o
glucosamine by cy osolic es e ases.
Molecules 2025, 30, x FOR PEER REVIEW 18 o 58
Scheme 21. Au oma ed app oach o he syn hesis o oligomannopy anosides.
2.3. 3-Thiosuga s
Inco po a ion o a sul u a om a C-3 posi ion o a suga esidue has been used o
accessing aluable syn he ic in e media es, as well as o p epa ing de i a i es wi h po-
en ial biological ac i i ies [64]. Despi e ha , his kind o sul u -con aining ca bohyd a es
is signi ican ly less s udied compa ed o o he posi ions on he suga , like he endocyclic
oxygen, o he glycosidic posi ion. A equen app oach o accessing 3- hiosuga s is he
eac ion o glycals wi h diffe en hiols and ca alys s, as displayed in his sec ion.
Mukhe jee e al. epo ed [65] he biomime ic syn hesis o a amily o 3- hiosuga s
(100, Scheme 22) ia eac ion o 2-ke ophenyl-glycals 98, 99 (D-glucal, D-galac al, L- ham-
nal) wi h diffe en hiols. The egio- and s e eoselec i e displacemen o he ace oxy g oup
a he C-3 posi ion o he glycal was achie ed using a oma ic and cyclic alipha ic hiols
unde mild basic condi ions (E 3N), u nishing excellen axial selec i i y. The p esence o
a ca bonyl g oup a C-2 was ound o be c ucial [65]. I was hypo hesized ha he hiol
a acks he ca bonyl g oup a C-2, and hen i unde goes a 1,3-mig a ion h ough he op-
posi e ace o he ace oxy g oup a C-3. This p ocess was inspi ed by he hiola ion o glu-
cosamine by cy osolic es e ases.
Scheme 22. Syn hesis o a lib a y o 3-a yl/alkyl hiosuga s p epa ed om 2-ke oglycals. Reagen s
and condi ions: (a) E 3N (1 equi .), MeCN, . .
Liu and cowo ke s epo ed [66] he s e eo- and egioselec i e syn hesis o hiosuga s
by eac ion o 3,4-O-ca bona e glycals 101 wi h diffe en hiols; compe i i e expe imen s
e ealed ha he hiol g oup eac ed wi h o al chemoselec i i y in he p esence o o he
nucleophilic moie ies, like alcohols, phenols, amides, o amines. A egiodi e gen ap-
p oach was de eloped, as depending on he ca alys employed, ei he 3- hiosuga s (wi h
Co(BF4)2, axial posi ion, compound 102) o 1- hiosuga s (wi h Pd2(dba)3, equa o ial posi-
ion, compound 103) we e ob ained, wi h gene al good yields (Scheme 23). Based on com-
pu a ional calcula ions, i was hypo hesized ha unde Pd ca alysis, he hiol g oup es-
ablished hyd ogen bonding on he op ace wi h he oxygen a om a C-4 posi ion. Ne e -
heless, coo dina ion wi h Co ook place h ough he bo om ace.
Scheme 23. Syn hesis o 1- and 3- hiosuga s using Co and Pd-based ca alys s. Reagen s and condi-
ions: (a) RSH, Co(BF4)2 ca alys , CH2Cl2, 35 °C; (b) RSH, Pd2(dba)3 ca alys , 100 °C.
Scheme 22. Syn hesis o a lib a y o 3-a yl/alkyl hiosuga s p epa ed om 2-ke oglycals. Reagen s
and condi ions: (a) E 3N (1 equi .), MeCN, . .
Molecules 2025,30, 2053 18 o 54
Liu and cowo ke s epo ed [
66
] he s e eo- and egioselec i e syn hesis o hiosuga s
by eac ion o 3,4-O-ca bona e glycals 101 wi h di e en hiols; compe i i e expe imen s
e ealed ha he hiol g oup eac ed wi h o al chemoselec i i y in he p esence o o he
nucleophilic moie ies, like alcohols, phenols, amides, o amines. A egiodi e gen app oach
was de eloped, as depending on he ca alys employed, ei he 3- hiosuga s (wi h Co(BF
4
)
2
,
axial posi ion, compound 102) o 1- hiosuga s (wi h Pd
2
(dba)
3
, equa o ial posi ion, com-
pound 103) we e ob ained, wi h gene al good yields (Scheme 23). Based on compu a ional
calcula ions, i was hypo hesized ha unde Pd ca alysis, he hiol g oup es ablished
hyd ogen bonding on he op ace wi h he oxygen a om a C-4 posi ion. Ne e heless,
coo dina ion wi h Co ook place h ough he bo om ace.
Molecules 2025, 30, x FOR PEER REVIEW 18 o 58
Scheme 21. Au oma ed app oach o he syn hesis o oligomannopy anosides.
2.3. 3-Thiosuga s
Inco po a ion o a sul u a om a C-3 posi ion o a suga esidue has been used o
accessing aluable syn he ic in e media es, as well as o p epa ing de i a i es wi h po-
en ial biological ac i i ies [64]. Despi e ha , his kind o sul u -con aining ca bohyd a es
is signi ican ly less s udied compa ed o o he posi ions on he suga , like he endocyclic
oxygen, o he glycosidic posi ion. A equen app oach o accessing 3- hiosuga s is he
eac ion o glycals wi h diffe en hiols and ca alys s, as displayed in his sec ion.
Mukhe jee e al. epo ed [65] he biomime ic syn hesis o a amily o 3- hiosuga s
(100, Scheme 22) ia eac ion o 2-ke ophenyl-glycals 98, 99 (D-glucal, D-galac al, L- ham-
nal) wi h diffe en hiols. The egio- and s e eoselec i e displacemen o he ace oxy g oup
a he C-3 posi ion o he glycal was achie ed using a oma ic and cyclic alipha ic hiols
unde mild basic condi ions (E 3N), u nishing excellen axial selec i i y. The p esence o
a ca bonyl g oup a C-2 was ound o be c ucial [65]. I was hypo hesized ha he hiol
a acks he ca bonyl g oup a C-2, and hen i unde goes a 1,3-mig a ion h ough he op-
posi e ace o he ace oxy g oup a C-3. This p ocess was inspi ed by he hiola ion o glu-
cosamine by cy osolic es e ases.
Scheme 22. Syn hesis o a lib a y o 3-a yl/alkyl hiosuga s p epa ed om 2-ke oglycals. Reagen s
and condi ions: (a) E 3N (1 equi .), MeCN, . .
Liu and cowo ke s epo ed [66] he s e eo- and egioselec i e syn hesis o hiosuga s
by eac ion o 3,4-O-ca bona e glycals 101 wi h diffe en hiols; compe i i e expe imen s
e ealed ha he hiol g oup eac ed wi h o al chemoselec i i y in he p esence o o he
nucleophilic moie ies, like alcohols, phenols, amides, o amines. A egiodi e gen ap-
p oach was de eloped, as depending on he ca alys employed, ei he 3- hiosuga s (wi h
Co(BF4)2, axial posi ion, compound 102) o 1- hiosuga s (wi h Pd2(dba)3, equa o ial posi-
ion, compound 103) we e ob ained, wi h gene al good yields (Scheme 23). Based on com-
pu a ional calcula ions, i was hypo hesized ha unde Pd ca alysis, he hiol g oup es-
ablished hyd ogen bonding on he op ace wi h he oxygen a om a C-4 posi ion. Ne e -
heless, coo dina ion wi h Co ook place h ough he bo om ace.
Scheme 23. Syn hesis o 1- and 3- hiosuga s using Co and Pd-based ca alys s. Reagen s and condi-
ions: (a) RSH, Co(BF4)2 ca alys , CH2Cl2, 35 °C; (b) RSH, Pd2(dba)3 ca alys , 100 °C.
Scheme 23. Syn hesis o 1- and 3- hiosuga s using Co and Pd-based ca alys s. Reagen s and condi-
ions: (a) RSH, Co(BF4)2ca alys , CH2Cl2, 35 ◦C; (b) RSH, Pd2(dba)3ca alys , 100 ◦C.
Chen and co-wo ke s no iced [
67
] ha pe -O-ace yla ed unna u al monosaccha ides
and he cys eine esidues on p o eins unde go an a ypical glycosyla ion p ocess, yielding
3- hiola ed suga s in hei hemiace al o m. In hei s udy, he au ho s elucida ed an
elimina ion-addi ion mechanism, which in ol es a base-p omo ed
β
-elimina ion s ep
ollowed by a Michael addi ion o he cys eine esidue o he
α
,
β
-unsa u a ed aldehyde.
(Scheme 24). This p ocess, called S-glycosyla ion, migh comp omise he speci ici y o he
me abolic glycan labelling (MGL) used, o example, in glycan agging wi h luo opho es.
Molecules 2025, 30, x FOR PEER REVIEW 19 o 58
Chen and co-wo ke s no iced [67] ha pe -O-ace yla ed unna u al monosaccha ides
and he cys eine esidues on p o eins unde go an a ypical glycosyla ion p ocess, yielding
3- hiola ed suga s in hei hemiace al o m. In hei s udy, he au ho s elucida ed an elim-
ina ion-addi ion mechanism, which in ol es a base-p omo ed β-elimina ion s ep ol-
lowed by a Michael addi ion o he cys eine esidue o he α,β-unsa u a ed aldehyde.
(Scheme 24). This p ocess, called S-glycosyla ion, migh comp omise he speci ici y o he
me abolic glycan labelling (MGL) used, o example, in glycan agging wi h luo opho es.
Scheme 24. P oposed wo-s ep elimina ion–addi ion mechanism o S-glyco-modi ica ion.
2.4. O he Thiosuga s
1,6-Anhyd o-1- hio-β-D-hexopy anose de i a i es a e ele an molecules in Medici-
nal and Syn he ic Chemis y, unc ioning as p ecu so s o glycomime ics. Mis a’s g oup
has de eloped [68] a as , effec i e, and scalable me hod o hei syn hesis by ea men
o p o ec ed 6-O- osyla ed glycopy anosyl b omide de i a i es 104 wi h Na2S·9H2O (2
equi .) and CS2 (2 equi .) a (Scheme 25). The eac ion was comple ed in jus 5 min,
yielding he co esponding hiole oglucosan de i a i es 105 wi h yields anging om
82% o 92%.
Scheme 25. Syn hesis o 6-anhyd o-1- hio-β-D-hexopy anose de i a i es. Reagen s and condi ions:
(a) Na2S·9H2O (2 equi ), CS2 (2 equi ), DMF, . .
Using he same combina ion o eac an s, he au ho s ex ended [69] he me hodology
o syn hesize unsymme ical glycosyl disul ides di ec ly om glycosyl b omides by in-
co po a ing symme ical disul ides. Unde op imized condi ions, a se ies o anome ic gly-
cosyl b omides 54 we e ea ed wi h symme ical alkyl, a yl, and glycosyl disul ides, a -
o ding unsymme ical β-glycosyl disul ides 106 in yields anging om 72% o 90%
(Scheme 26).
Scheme 26. Syn hesis o unsymme ical glycosyl disul ides. Reagen s and condi ions: (a) CS2 (2
equi .), Na2S·9H2O (2 equi .), RSSR, DMF, 0 °C, , 5‒20 min.
Scheme 24. P oposed wo-s ep elimina ion–addi ion mechanism o S-glyco-modi ica ion.
2.4. O he Thiosuga s
1,6-Anhyd o-1- hio-
β
-D-hexopy anose de i a i es a e ele an molecules in Medicinal
and Syn he ic Chemis y, unc ioning as p ecu so s o glycomime ics. Mis a’s g oup has
de eloped [
68
] a as , e ec i e, and scalable me hod o hei syn hesis by ea men o
p o ec ed 6-O- osyla ed glycopy anosyl b omide de i a i es 104 wi h Na
2
S
·
9H
2
O (2 equi .)
and CS
2
(2 equi .) a (Scheme 25). The eac ion was comple ed in jus 5 min, yielding he
co esponding hiole oglucosan de i a i es 105 wi h yields anging om 82% o 92%.
Molecules 2025,30, 2053 19 o 54
Molecules 2025, 30, x FOR PEER REVIEW 19 o 58
Chen and co-wo ke s no iced [67] ha pe -O-ace yla ed unna u al monosaccha ides
and he cys eine esidues on p o eins unde go an a ypical glycosyla ion p ocess, yielding
3- hiola ed suga s in hei hemiace al o m. In hei s udy, he au ho s elucida ed an elim-
ina ion-addi ion mechanism, which in ol es a base-p omo ed β-elimina ion s ep ol-
lowed by a Michael addi ion o he cys eine esidue o he α,β-unsa u a ed aldehyde.
(Scheme 24). This p ocess, called S-glycosyla ion, migh comp omise he speci ici y o he
me abolic glycan labelling (MGL) used, o example, in glycan agging wi h luo opho es.
Scheme 24. P oposed wo-s ep elimina ion–addi ion mechanism o S-glyco-modi ica ion.
2.4. O he Thiosuga s
1,6-Anhyd o-1- hio-β-D-hexopy anose de i a i es a e ele an molecules in Medici-
nal and Syn he ic Chemis y, unc ioning as p ecu so s o glycomime ics. Mis a’s g oup
has de eloped [68] a as , effec i e, and scalable me hod o hei syn hesis by ea men
o p o ec ed 6-O- osyla ed glycopy anosyl b omide de i a i es 104 wi h Na2S·9H2O (2
equi .) and CS2 (2 equi .) a (Scheme 25). The eac ion was comple ed in jus 5 min,
yielding he co esponding hiole oglucosan de i a i es 105 wi h yields anging om
82% o 92%.
Scheme 25. Syn hesis o 6-anhyd o-1- hio-β-D-hexopy anose de i a i es. Reagen s and condi ions:
(a) Na2S·9H2O (2 equi ), CS2 (2 equi ), DMF, . .
Using he same combina ion o eac an s, he au ho s ex ended [69] he me hodology
o syn hesize unsymme ical glycosyl disul ides di ec ly om glycosyl b omides by in-
co po a ing symme ical disul ides. Unde op imized condi ions, a se ies o anome ic gly-
cosyl b omides 54 we e ea ed wi h symme ical alkyl, a yl, and glycosyl disul ides, a -
o ding unsymme ical β-glycosyl disul ides 106 in yields anging om 72% o 90%
(Scheme 26).
Scheme 26. Syn hesis o unsymme ical glycosyl disul ides. Reagen s and condi ions: (a) CS2 (2
equi .), Na2S·9H2O (2 equi .), RSSR, DMF, 0 °C, , 5‒20 min.
Scheme 25. Syn hesis o 6-anhyd o-1- hio-
β
-D-hexopy anose de i a i es. Reagen s and condi ions:
(a) Na2S·9H2O (2 equi ), CS2(2 equi ), DMF, . .
Using he same combina ion o eac an s, he au ho s ex ended [
69
] he me hodology
o syn hesize unsymme ical glycosyl disul ides di ec ly om glycosyl b omides by inco -
po a ing symme ical disul ides. Unde op imized condi ions, a se ies o anome ic glycosyl
b omides 54 we e ea ed wi h symme ical alkyl, a yl, and glycosyl disul ides, a o ding
unsymme ical β-glycosyl disul ides 106 in yields anging om 72% o 90% (Scheme 26).
Molecules 2025, 30, x FOR PEER REVIEW 19 o 58
Chen and co-wo ke s no iced [67] ha pe -O-ace yla ed unna u al monosaccha ides
and he cys eine esidues on p o eins unde go an a ypical glycosyla ion p ocess, yielding
3- hiola ed suga s in hei hemiace al o m. In hei s udy, he au ho s elucida ed an elim-
ina ion-addi ion mechanism, which in ol es a base-p omo ed β-elimina ion s ep ol-
lowed by a Michael addi ion o he cys eine esidue o he α,β-unsa u a ed aldehyde.
(Scheme 24). This p ocess, called S-glycosyla ion, migh comp omise he speci ici y o he
me abolic glycan labelling (MGL) used, o example, in glycan agging wi h luo opho es.
Scheme 24. P oposed wo-s ep elimina ion–addi ion mechanism o S-glyco-modi ica ion.
2.4. O he Thiosuga s
1,6-Anhyd o-1- hio-β-D-hexopy anose de i a i es a e ele an molecules in Medici-
nal and Syn he ic Chemis y, unc ioning as p ecu so s o glycomime ics. Mis a’s g oup
has de eloped [68] a as , effec i e, and scalable me hod o hei syn hesis by ea men
o p o ec ed 6-O- osyla ed glycopy anosyl b omide de i a i es 104 wi h Na2S·9H2O (2
equi .) and CS2 (2 equi .) a (Scheme 25). The eac ion was comple ed in jus 5 min,
yielding he co esponding hiole oglucosan de i a i es 105 wi h yields anging om
82% o 92%.
Scheme 25. Syn hesis o 6-anhyd o-1- hio-β-D-hexopy anose de i a i es. Reagen s and condi ions:
(a) Na2S·9H2O (2 equi ), CS2 (2 equi ), DMF, . .
Using he same combina ion o eac an s, he au ho s ex ended [69] he me hodology
o syn hesize unsymme ical glycosyl disul ides di ec ly om glycosyl b omides by in-
co po a ing symme ical disul ides. Unde op imized condi ions, a se ies o anome ic gly-
cosyl b omides 54 we e ea ed wi h symme ical alkyl, a yl, and glycosyl disul ides, a -
o ding unsymme ical β-glycosyl disul ides 106 in yields anging om 72% o 90%
(Scheme 26).
Scheme 26. Syn hesis o unsymme ical glycosyl disul ides. Reagen s and condi ions: (a) CS2 (2
equi .), Na2S·9H2O (2 equi .), RSSR, DMF, 0 °C, , 5‒20 min.
Scheme 26. Syn hesis o unsymme ical glycosyl disul ides. Reagen s and condi ions: (a) CS
2
(2 equi .), Na2S·9H2O (2 equi .), RSSR, DMF, 0 ◦C, , 5–20 min.
3. Se-Con aining Ca bohyd a es
The inco po a ion o selenium in o o ganic amewo ks has led o he de elopmen
o po en bioac i e compounds wi h an ioxidan [
70
], an i i al [
71
], an ipa asi ic [
72
],
an i-Alzheime ’s [
73
–
75
], o an icance p ope ies [
76
–
80
], among o he s. Combining he
di e se biological ac i i ies o selenium wi h he unique s uc u al ea u es o ca bohy-
d a es o e s a p omising s a egy o he design o no el d ug candida es wi h enhanced
he apeu ic po en ial.
3.1. 4′- and 5′-Selenosuga s
In e es in eplacing he endocyclic oxygen a om in ca bohyd a es by selenium da es
back o he 1970’s. Howe e , mos ea ly a emp s we e unsuccess ul, ei he yielding unde-
si ed by-p oduc s, o p oducing he desi ed selenosuga s in e y low yields (e.g., de i a i e
107 (Figu e 11) [
81
]. La e , Schiesse and co-wo ke s, in he sea ch o wa e -soluble an ioxi-
dan s, pionee ed [
82
] a mo e p ac ical app oach o syn hesizing selenosuga s (108–110).
This was achie ed h ough he he molysis o pe -O-bezyla ed-5-benzylseleno o ma es o
D- ibo-, xylo- and a abino-con igu a ions. Thei me hod in ol ed an in amolecula a ack
o he benzylseleno sca old, and elimina ion o CO2and phenylselenoa e.
To p epa e educing selenosuga s, he same g oup epo ed [
82
] he SmI
2
-media ed
ans o ma ion o O-p o ec ed 5-benzylseleno aldoses in o de i a i es 111–113 ia an in-
amolecula homoly ic subs i u ion [
83
]. Ne e heless, only D-a abino-con igu ed 113 was
ob ained in pu e o m and wi h mode a e yield. Un o una ely, none o such compounds
could be success ully dep o ec ed.
Liu and Pin o de eloped [
84
] a p ocedu e o achie ing unp o ec ed seleno u anoses
and py anoses by using ace als as p o ec ing g oups in hei e o s o syn hesize selenon-
ium sul a es as analogues o na u al salacinol and ko alanol (Figu e 2), po en
α
-glucosidase
inhibi o s. Thei s a egy o accessing he selenosuga s was based on ou s eps: app op i-
a e O-p o ec ion o he s a ing ca bohyd a e wi h isop opylidene g oups, educ ion o he
la en aldehyde o he educing suga , di-O-mesyla ion and double nucleophilic displace-
men wi h in si u gene a ed Na
2
Se ( ea men o elemen al selenium wi h he app op ia e
numbe o equi alen s o NaBH
4
), as depic ed in Scheme 27 [
84
]. This simple syn he ic
Molecules 2025,30, 2053 20 o 54
pa hway inspi ed Schiesse ’s and o he g oups o access a wide a ie y o py anoses and
u anoses wi h di e se con igu a ions. These included compounds like 114–116,118 [
83
,
85
],
which a e e icien sca enge s o hypohalous acids and 117, a good mime ic o glu a hione
pe oxidase (GPx) [86].
Molecules 2025, 30, x FOR PEER REVIEW 20 o 58
3. Se-Con aining Ca bohyd a es
The inco po a ion o selenium in o o ganic amewo ks has led o he de elopmen
o po en bioac i e compounds wi h an ioxidan [70], an i i al [71], an ipa asi ic [72], an i-
Alzheime ’s [73–75], o an icance p ope ies [76–80], among o he s. Combining he di-
e se biological ac i i ies o selenium wi h he unique s uc u al ea u es o ca bohyd a es
offe s a p omising s a egy o he design o no el d ug candida es wi h enhanced he a-
peu ic po en ial.
3.1. 4′- and 5′-Selenosuga s
In e es in eplacing he endocyclic oxygen a om in ca bohyd a es by selenium da es
back o he 1970’s. Howe e , mos ea ly a emp s we e unsuccess ul, ei he yielding un-
desi ed by-p oduc s, o p oducing he desi ed selenosuga s in e y low yields (e.g., de-
i a i e 107 (Figu e 11) [81]. La e , Schiesse and co-wo ke s, in he sea ch o wa e -sol-
uble an ioxidan s, pionee ed [82] a mo e p ac ical app oach o syn hesizing selenosuga s
(108–110). This was achie ed h ough he he molysis o pe -O-bezyla ed-5-benzylseleno
o ma es o D- ibo-, xylo- and a abino-con igu a ions. Thei me hod in ol ed an in amo-
lecula a ack o he benzylseleno scaffold, and elimina ion o CO2 and phenylselenoa e.
To p epa e educing selenosuga s, he same g oup epo ed [82] he SmI2-media ed
ans o ma ion o O-p o ec ed 5-benzylseleno aldoses in o de i a i es 111–113 ia an in-
amolecula homoly ic subs i u ion [83]. Ne e heless, only D-a abino-con igu ed 113
was ob ained in pu e o m and wi h mode a e yield. Un o una ely, none o such com-
pounds could be success ully dep o ec ed.
Figu e 11. S uc u es o some o ep esen a i e examples o selenosuga s.
Liu and Pin o de eloped [84] a p ocedu e o achie ing unp o ec ed seleno u anoses
and py anoses by using ace als as p o ec ing g oups in hei effo s o syn hesize sele-
nonium sul a es as analogues o na u al salacinol and ko alanol (Figu e 2), po en α-glu-
cosidase inhibi o s. Thei s a egy o accessing he selenosuga s was based on ou s eps:
app op ia e O-p o ec ion o he s a ing ca bohyd a e wi h isop opylidene g oups, educ-
ion o he la en aldehyde o he educing suga , di-O-mesyla ion and double nucleophilic
displacemen wi h in si u gene a ed Na2Se ( ea men o elemen al selenium wi h he ap-
p op ia e numbe o equi alen s o NaBH4), as depic ed in Scheme 27 [84]. This simple
syn he ic pa hway inspi ed Schiesse ’s and o he g oups o access a wide a ie y o py a-
noses and u anoses wi h di e se con igu a ions. These included compounds like 114‒
Figu e 11. S uc u es o some o ep esen a i e examples o selenosuga s.
Molecules 2025, 30, x FOR PEER REVIEW 21 o 58
116, 118 [83,85], which a e efficien sca enge s o hypohalous acids and 117, a good mi-
me ic o glu a hione pe oxidase (GPx) [86].
119
OOH
(HO)n
MeO OMe
ace one, PTSA
ó
OMe
DMF, PTSA
OOH
OO
(1) NaBH4
(2) MsCl
OMs OMs
OO
120
121
(1) Se, NaBH4
(2) TFA, CH2Cl2
122
Se
(HO)n
Scheme 27. Gene al p ocedu e o he p epa a ion o unp o ec ed selenosuga s.
Undoub edly, due o i s syn he ic accessibili y, he mos ex ensi ely s udied com-
pound in his se ies is 1,4-anhyd o-4-seleno-D- ali ol (SeTal, 118, Figu e 11). I has been
conside ed as a p i ileged s uc u e because o he di e se biological p ope ies i exhibi s.
This wa e -soluble compound has demons a ed [87] po en sca enging ac i i y agains
oxidizing agen s, like HOCl and HOB , he o me being p oduced by he enzyme
myelope oxidase (MPO) o elimina e pa hogens om in lamed issues. Alongside o he
analogues wi h diffe en con igu a ions, SeTal and i s de i a i es ha e shown an ioxidan
po ency up o wice ha o hei sul u -coun e pa s. Mo eo e , 118 has been shown o
epai damaged skin issues in animal models, including diabe ic wounds [87]. SeTal ex-
hibi s ema kable s abili y unde acidic condi ions (as hose ound when d ugs ha e an
o al adminis a ion) and also in a i icial gas ic o in es inal luids, achie ing s eady-s a e
in acellula concen a ions anging 2–10 µM. Howe e , he exac in e naliza ion mecha-
nism emains unde e mined [88]. In i o expe imen s ha e e ealed ha SeTal p o ec s
agains oxida i e damage in human co ona y a e y cells and mouse ao ic ings [88]. In-
e es ingly, opical applica ion o 118 o induced skin inju ies in mice modula ed in lam-
ma o y ma ke s [89]. Fu he mo e, i s inco po a ion in o gela in and algina e polyme ic
ilms, ei he alone, o in combina ion wi h hyd oco isone o i amin C, has ecen ly
shown p omise as a ea men o a opic de ma i is [90]. S udies on i s po en ial hepa o ox-
ici y e ealed [91] ha SeTal only affec s hepa ic cells iabili y a e y high concen a-
ions, much highe han i s po en ial he apeu ic dose, making i a p omising candida e
o d ug de elopmen .
Ano he signi ican con ibu ion o he ield o wa e -soluble selenosuga s was made
by Iwaoka and Tomoda. They syn hesized ans-dihyd oxy selenonane 124 (DHS ed) and
diselenane 126 by nucleophilic opening o acemic 1,3-bu adiene diepoxide wi h NaHSe
o Na2Se2, espec i ely (Scheme 28) [92]. DHS ed was shown o mimic he ca aly ic cycle o
GPX by educing H2O2 in he p esence o a hiol-con aining compound as a co ac o such
as di hio h ei ol (DTT) [93]. GPx is a me alloenzyme ha main ains he homeos asis in
Reac i e Oxygen Species (ROS) le els by elimina ing H2O2 and alkyl pe oxides, wi h glu-
a hione (GSH) as a co ac o . The p oposed ca aly ic cycle in aqueous media in ol es he
slow oxida ion o DHS ed wi h H2O2 o p oduce he selenoxide 128, which is subsequen ly
educed by DTT o gi e DSH ed [93] (Scheme 29A).
Scheme 27. Gene al p ocedu e o he p epa a ion o unp o ec ed selenosuga s.
Undoub edly, due o i s syn he ic accessibili y, he mos ex ensi ely s udied compound
in his se ies is 1,4-anhyd o-4-seleno-D- ali ol (SeTal,118, Figu e 11). I has been conside ed
as a p i ileged s uc u e because o he di e se biological p ope ies i exhibi s. This wa e -
soluble compound has demons a ed [
87
] po en sca enging ac i i y agains oxidizing
agen s, like HOCl and HOB , he o me being p oduced by he enzyme myelope oxidase
(MPO) o elimina e pa hogens om in lamed issues. Alongside o he analogues wi h
di e en con igu a ions, SeTal and i s de i a i es ha e shown an ioxidan po ency up o
wice ha o hei sul u -coun e pa s. Mo eo e , 118 has been shown o epai damaged
skin issues in animal models, including diabe ic wounds [
87
]. SeTal exhibi s ema kable
s abili y unde acidic condi ions (as hose ound when d ugs ha e an o al adminis a-
ion) and also in a i icial gas ic o in es inal luids, achie ing s eady-s a e in acellula
concen a ions anging 2–10
µ
M. Howe e , he exac in e naliza ion mechanism emains
Molecules 2025,30, 2053 21 o 54
unde e mined [
88
].
In i o
expe imen s ha e e ealed ha SeTal p o ec s agains oxida i e
damage in human co ona y a e y cells and mouse ao ic ings [
88
]. In e es ingly, opical
applica ion o 118 o induced skin inju ies in mice modula ed in lamma o y ma ke s [
89
].
Fu he mo e, i s inco po a ion in o gela in and algina e polyme ic ilms, ei he alone, o in
combina ion wi h hyd oco isone o i amin C, has ecen ly shown p omise as a ea men
o a opic de ma i is [
90
]. S udies on i s po en ial hepa o oxici y e ealed [
91
] ha SeTal only
a ec s hepa ic cells iabili y a e y high concen a ions, much highe han i s po en ial
he apeu ic dose, making i a p omising candida e o d ug de elopmen .
Ano he signi ican con ibu ion o he ield o wa e -soluble selenosuga s was made
by Iwaoka and Tomoda. They syn hesized ans-dihyd oxy selenonane 124 (DHS
ed
) and
diselenane 126 by nucleophilic opening o acemic 1,3-bu adiene diepoxide wi h NaHSe
o Na
2
Se
2
, espec i ely (Scheme 28) [
92
]. DHS
ed
was shown o mimic he ca aly ic cycle
o GPX by educing H
2
O
2
in he p esence o a hiol-con aining compound as a co ac o
such as di hio h ei ol (DTT) [
93
]. GPx is a me alloenzyme ha main ains he homeos asis
in Reac i e Oxygen Species (ROS) le els by elimina ing H
2
O
2
and alkyl pe oxides, wi h
glu a hione (GSH) as a co ac o . The p oposed ca aly ic cycle in aqueous media in ol es he
slow oxida ion o DHS
ed
wi h H
2
O
2
o p oduce he selenoxide 128, which is subsequen ly
educed by DTT o gi e DSH ed [93] (Scheme 29A).
Molecules 2025, 30, x FOR PEER REVIEW 22 o 58
Scheme 28. P epa a ion o ans-dihyd oxy selenonanes and diselenanes and lipophilic de i a i es.
Scheme 29. Ca aly ic cycles o he GPx-like ac i i y o DHS ed (A) and DSTox (B).
DSH ed exhibi ed supe io ROS sca enging capaci y compa ed o i s non-cyclic iso-
me . The enhanced ac i i y was a ibu ed o inc eased HOMO ene gy due o he s ain
caused by he cyclic s uc u e [94], acili a ing oxida ion. Unexpec edly, when GPx-like
ac i i y was es ed in MeOH, he eac ion became much mo e complex. O e -oxidized
species, like hyd oxyselenonium and hyd oxy pe hyd oxyselane we e sugges ed o play
an ac i e ole in he sca enging p ocess [95].
DHS ed also demons a ed [96] adio-p o ec i e effec s in mice when adminis a ed
in ape i oneally be o e and a e he i adia ion wi h 60Co. Reduced DNA damage, de-
c eased lipid pe oxida ion, and down- egula ion o p o-in lamma o y genes we e ob-
se ed [96]. These effec s we e simila o hose exhibi ed by he seleno-amino acid SeMe .
The mechanism included GPx-dependen DNA epai enhancemen [97].
Monoes e i ica ion o DHS ed wi h acid chlo ides de i ed om p opionic, lau ic,
my is ic, palmi ic, and s ea ic acids yielded a y acid conjuga es (125), wi h lipid pe oxide
Scheme 28. P epa a ion o ans-dihyd oxy selenonanes and diselenanes and lipophilic de i a i es.
DSH
ed
exhibi ed supe io ROS sca enging capaci y compa ed o i s non-cyclic isome .
The enhanced ac i i y was a ibu ed o inc eased HOMO ene gy due o he s ain caused
by he cyclic s uc u e [
94
], acili a ing oxida ion. Unexpec edly, when GPx-like ac i i y
was es ed in MeOH, he eac ion became much mo e complex. O e -oxidized species, like
hyd oxyselenonium and hyd oxy pe hyd oxyselane we e sugges ed o play an ac i e ole
in he sca enging p ocess [95].
DHS
ed
also demons a ed [
96
] adio-p o ec i e e ec s in mice when adminis a ed in-
ape i oneally be o e and a e he i adia ion wi h
60
Co. Reduced DNA damage, dec eased
lipid pe oxida ion, and down- egula ion o p o-in lamma o y genes we e obse ed [
96
].
These e ec s we e simila o hose exhibi ed by he seleno-amino acid SeMe . The mecha-
nism included GPx-dependen DNA epai enhancemen [97].
Monoes e i ica ion o DHS
ed
wi h acid chlo ides de i ed om p opionic, lau ic,
my is ic, palmi ic, and s ea ic acids yielded a y acid conjuga es (125), wi h lipid pe oxide
(LOOH) sca enging ac i i y in leci hin/choles e ol liposome memb anes [
98
]. The my is-
a e de i a i e displayed in e acial edox ac i i y. Amphiphilic diselenides (127) we e also
syn hesized [99].

Molecules 2025,30, 2053 22 o 54
Molecules 2025, 30, x FOR PEER REVIEW 22 o 58
Scheme 28. P epa a ion o ans-dihyd oxy selenonanes and diselenanes and lipophilic de i a i es.
Scheme 29. Ca aly ic cycles o he GPx-like ac i i y o DHS ed (A) and DSTox (B).
DSH ed exhibi ed supe io ROS sca enging capaci y compa ed o i s non-cyclic iso-
me . The enhanced ac i i y was a ibu ed o inc eased HOMO ene gy due o he s ain
caused by he cyclic s uc u e [94], acili a ing oxida ion. Unexpec edly, when GPx-like
ac i i y was es ed in MeOH, he eac ion became much mo e complex. O e -oxidized
species, like hyd oxyselenonium and hyd oxy pe hyd oxyselane we e sugges ed o play
an ac i e ole in he sca enging p ocess [95].
DHS ed also demons a ed [96] adio-p o ec i e effec s in mice when adminis a ed
in ape i oneally be o e and a e he i adia ion wi h 60Co. Reduced DNA damage, de-
c eased lipid pe oxida ion, and down- egula ion o p o-in lamma o y genes we e ob-
se ed [96]. These effec s we e simila o hose exhibi ed by he seleno-amino acid SeMe .
The mechanism included GPx-dependen DNA epai enhancemen [97].
Monoes e i ica ion o DHS ed wi h acid chlo ides de i ed om p opionic, lau ic,
my is ic, palmi ic, and s ea ic acids yielded a y acid conjuga es (125), wi h lipid pe oxide
Scheme 29. Ca aly ic cycles o he GPx-like ac i i y o DHS ed (A) and DSTox (B).
Diselenides such as 127 (Scheme 28) we e shown [
100
] o mimic p o ein disul ide iso-
me ases (PDIs), enzymes c i ical o edox homeos asis in he endoplasmic e iculum and in
he p e en ion o amyloid plaque pa hogenici y. Fu he mo e, GPx-like ac i i y was obse ed
o 126 and 127. Depending on hei hyd ophilic (R = H, C3) o hyd ophobic (R = C6–C14)
na u e, GPx1- o GPx4-like ac i i y p edomina ed [
99
], espec i ely. These compounds e-
duced H
2
O
2
o lipid pe oxides (LOOH) o ha mless H
2
O and an alcohol (LOH), espec i ely
(Scheme 29B). An ioxidan p ope ies we e also con i med in cul u ed cells [
99
]. A simila
beha io was p oposed o DHS ed (124) and monoes e s coun e pa s (125) [101].
Mugesh and co-wo ke s desc ibed [
102
] he syn hesis o enan iome ically pu e ans-
dihyd oxy diselenide (126) and selenyl sul ide (136) as an ioxidan s o p o ec e y h ocy es
(RBCs, Red Blood Cells) om oxida i e s ess-induced e yp osis (p og ammed RBC dea h).
The syn hesis in ol ed ea men o 1,4-di-O- osyl-2,3-O-isop opylidene-L- h ei ol 131 wi h
subs oichiome ic selenol 133 (ob ained by educ ion o p-me hoxybenzyl diselenide 132)
o gi e benzyl selenide 134. Subsequen nucleophilic displacemen o he second osyla e
wi h KSAc, ollowed by I
2
-media ed oxida ion a o ded O-p o ec ed selenyl sul ide 135
(Scheme 30). Final dep o ec ion unde acidic condi ions u nished 136. Al e na i ely,
ea men o di osyla ed 131 wi h an excess o selenol 133 ga e he dibenzylselenide 137.
Final oxida ion and dep o ec ion led o he expec ed diselenide 126 [102].
When RBCs we e exposed o H
2
O
2
o simula e se e e oxida i e s ess, ea men
wi h 126 and 127 educed ROS le els, demons a ing e ec i e an ioxidan ac i i y in cells.
S uc u al aspec s p o ed c i ical; dec easing con o ma ional lexibili y ( ia isop opilidene
p o ec ion) o eplacing selenium a oms wi h sul u impai ed ac i i y [
102
]. O-p o ec ed
de i a i es exhibi ed high oxici y, e en wi hou H
2
O
2
. Inhibi ion o glu a hione educ ase
(GR), leading o educed glu a hione (GSH) le els, signi ican ly diminished he p o ec i e
e ec s o 126 and 136. This con i med ha hei an ioxidan ac i i y p ima ily elies on
GPx-like mechanisms, wi h GSH as a co ac o [102].
Molecules 2025,30, 2053 23 o 54
Molecules 2025, 30, x FOR PEER REVIEW 23 o 58
(LOOH) sca enging ac i i y in leci hin/choles e ol liposome memb anes [98]. The
my is a e de i a i e displayed in e acial edox ac i i y. Amphiphilic diselenides (127)
we e also syn hesized [99].
Diselenides such as 127 (Scheme 28) we e shown [100] o mimic p o ein disul ide
isome ases (PDIs), enzymes c i ical o edox homeos asis in he endoplasmic e iculum
and in he p e en ion o amyloid plaque pa hogenici y. Fu he mo e, GPx-like ac i i y
was obse ed o 126 and 127. Depending on hei hyd ophilic (R = H, C3) o hyd ophobic
(R = C6‒C14) na u e, GPx1- o GPx4-like ac i i y p edomina ed [99], espec i ely. These
compounds educed H2O2 o lipid pe oxides (LOOH) o ha mless H2O and an alcohol
(LOH), espec i ely (Scheme 29B). An ioxidan p ope ies we e also con i med in cul u ed
cells [99]. A simila beha io was p oposed o DHS ed (124) and monoes e s coun e pa s
(125) [101].
Mugesh and co-wo ke s desc ibed [102] he syn hesis o enan iome ically pu e ans-
dihyd oxy diselenide (126) and selenyl sul ide (136) as an ioxidan s o p o ec e y h o-
cy es (RBCs, Red Blood Cells) om oxida i e s ess-induced e yp osis (p og ammed RBC
dea h). The syn hesis in ol ed ea men o 1,4-di-O- osyl-2,3-O-isop opylidene-L- h ei ol
131 wi h subs oichiome ic selenol 133 (ob ained by educ ion o p-me hoxybenzyl
diselenide 132) o gi e benzyl selenide 134. Subsequen nucleophilic displacemen o he
second osyla e wi h KSAc, ollowed by I2-media ed oxida ion affo ded O-p o ec ed
selenyl sul ide 135 (Scheme 30). Final dep o ec ion unde acidic condi ions u nished 136.
Al e na i ely, ea men o di osyla ed 131 wi h an excess o selenol 133 ga e he diben-
zylselenide 137. Final oxida ion and dep o ec ion led o he expec ed diselenide 126 [102].
OTs
OTs
O
O
OMe
Se
Se
MeO
NaBH4
DMF
SeH
MeO
131
132
133
OTs
SePMB
O
O
134
(1) KSAc
18-c own-6
(2) KOH, E OH SH
SePMB
O
O
135
(0.95 equi .)
133
(2.1 equi .)
(1) I2
(2) p-TsOH
X
Se
HO
HO
SePMB
SePMB
O
O
137
(1) I2
(2) p-TsOH
126 (X = Se)
136 (X = S)
Scheme 30. Syn hesis o ans-dihyd oxy diselenide 126 and selenenyl sul ide 136.
When RBCs we e exposed o H2O2 o simula e se e e oxida i e s ess, ea men wi h
126 and 127 educed ROS le els, demons a ing effec i e an ioxidan ac i i y in cells.
S uc u al aspec s p o ed c i ical; dec easing con o ma ional lexibili y ( ia isop opi-
lidene p o ec ion) o eplacing selenium a oms wi h sul u impai ed ac i i y [102]. O-p o-
ec ed de i a i es exhibi ed high oxici y, e en wi hou H2O2. Inhibi ion o glu a hione
educ ase (GR), leading o educed glu a hione (GSH) le els, signi ican ly diminished he
p o ec i e effec s o 126 and 136. This con i med ha hei an ioxidan ac i i y p ima ily
elies on GPx-like mechanisms, wi h GSH as a co ac o [102].
Selenosuga s ha e been conjuga ed wi h hyd oxycinnamic acids, known o hei po-
en an ioxidan agen s, ia a Mi sunobu eac ion o achie e syne gic effec s [103]. Ini-
ially, he au ho s in ended [104] o use L-suga s ( he C-4 epime o 139), ob ained om D-
ibose h ough a 6-s ep syn he ic pa hway: isop opylidene p o ec ion o he C-2 and C-3
Scheme 30. Syn hesis o ans-dihyd oxy diselenide 126 and selenenyl sul ide 136.
Selenosuga s ha e been conjuga ed wi h hyd oxycinnamic acids, known o hei
po en an ioxidan agen s, ia a Mi sunobu eac ion o achie e syne gic e ec s [
103
]. Ini-
ially, he au ho s in ended [
104
] o use L-suga s ( he C-4 epime o 139), ob ained om
D- ibose h ough a 6-s ep syn he ic pa hway: isop opylidene p o ec ion o he C-2 and C-3
posi ions, TBDPS p o ec ion a C-5, educ ion o la en aldehyde, di-O-mesyla ion, nucle-
ophilic displacemen wi h NaHSe and acidic emo al o TBDPS p o ec ing g oup. Howe e ,
unexpec edly, when he C-4 epime o 139 was subjec ed o he Mi sunobu eac ion wi h
monoacey la ed hyd oquinone, a con igu a ional in e sion occu ed a C-4, esul ing in
aD-suga ins ead [
104
]. Al e na i ely, D-con igu ed selenosuga 139 can be ob ained in a
5-s ep me hodology s a ing om O-p o ec ed D- ibonolac one 138 [
104
]: mesyla ion o C-5
posi ion, in e sion o con igu a ion on C-4 p omo ed by KOH, TBDPS-p o ec ion o C-5,
educ ion o he lac one moie y, di-O-mesyla ion, nucleophilic displacemen wi h NaHSe,
and C-5 dep o ec ion. Subsequen ly, p-couma ic, ca eic and elu ic acids we e a ached o
he ee OH a C-5 h ough a Mi sunobu eac ion (gi ing compounds 140–142) [
103
,
104
], in
he p esence o diisop opyl azodica boxila e (DIAD) and PPh3(Scheme 31).
Final dep o ec ion o he isop opylidene p o ec ing g oup unde acidic condi ions
a o ded conjuga es 143–145. These conjuga es exhibi ed no able ee- adical sca enging
p ope ies, educed oxici y a concen a ions up o 100
µ
M, and p omising wound-healing
p ope ies in ke a inocy es (
in i o
sc a ch wound model), making hem po en ial cosme-
ceu ical ing edien s [
103
,
104
]. Unp o ec ed de i a i es 144 and 145, de i ed om p-ca eic
and e ulic acids, demons a ed dose-dependen healing ac i i y, a lowe doses compa ed
o he co esponding unconjuga ed cinnamic acids. The au ho s did no ind a co ela ion
be ween a highe cellula up ake and he wound healing p ope ies, sugges ing in e ac ion
wi h ou e cell memb ane componen s [103].
Using a simila app oach wi h he C-4-epime o 139, conjuga e 146 was syn he-
sized [
105
] using diace yla ed es e a ol in a Mi sunobu- ype eac ion (Scheme 31). ans-
Res e a ol, a na u al phy oalexina ound in g apes and ed wine, exhibi s nume ous
biological p ope ies like an ioxidan , an i-in lamma o y, ca dio- and neu op o ec i e,
and an idiabe ic e ec s [
106
]. Ca eic acid and es e a ol conjuga es 144 and 146 we e
loaded on a hyd oxyl ilm o de elop a pH-sensi i e deli e y sys em o accele a ing
skin wound healing. Fo his pu pose, a copolyme comp ised o poly(e hyleneglycol
diac yla e) (PEGDA) and poly(hyd oxye hyl me hac yla e) (HEMA), in a 1:4.2 mola a io,
was used. Compound 144 was eleased a pH 7.4, sui able o acu e wounds, whe eas
es e a ol-con aining 146 was eleased a pH 9.6, op imal o ch onic wounds [
105
]. The
Molecules 2025,30, 2053 24 o 54
pH-depending selec i e elease was a ibu ed o weak in e ac ions be ween he selenocon-
juga es and he hyd oxyl g oups o HEMA [105].
Molecules 2025, 30, x FOR PEER REVIEW 24 o 58
posi ions, TBDPS p o ec ion a C-5, educ ion o la en aldehyde, di-O-mesyla ion, nucle-
ophilic displacemen wi h NaHSe and acidic emo al o TBDPS p o ec ing g oup. How-
e e , unexpec edly, when he C-4 epime o 139 was subjec ed o he Mi sunobu eac ion
wi h monoacey la ed hyd oquinone, a con igu a ional in e sion occu ed a C-4, esul ing
in a D-suga ins ead [104]. Al e na i ely, D-con igu ed selenosuga 139 can be ob ained in
a 5-s ep me hodology s a ing om O-p o ec ed D- ibonolac one 138 [104]: mesyla ion o
C-5 posi ion, in e sion o con igu a ion on C-4 p omo ed by KOH, TBDPS-p o ec ion o
C-5, educ ion o he lac one moie y, di-O-mesyla ion, nucleophilic displacemen wi h
NaHSe, and C-5 dep o ec ion. Subsequen ly, p-couma ic, caffeic and elu ic acids we e
a ached o he ee OH a C-5 h ough a Mi sunobu eac ion (gi ing compounds 140‒142)
[103,104], in he p esence o diisop opyl azodica boxila e (DIAD) and PPh3 (Scheme 31).
Scheme 31. P epa a ion o selenosuga -phenolic acid conjuga es h ough a Mi sunobu eac ion.
Final dep o ec ion o he isop opylidene p o ec ing g oup unde acidic condi ions
affo ded conjuga es 143‒145. These conjuga es exhibi ed no able ee- adical sca enging
p ope ies, educed oxici y a concen a ions up o 100 µM, and p omising wound-heal-
ing p ope ies in ke a inocy es (in i o sc a ch wound model), making hem po en ial
cosmeceu ical ing edien s [103,104]. Unp o ec ed de i a i es 144 and 145, de i ed om
p-caffeic and e ulic acids, demons a ed dose-dependen healing ac i i y, a lowe doses
compa ed o he co esponding unconjuga ed cinnamic acids. The au ho s did no ind a
co ela ion be ween a highe cellula up ake and he wound healing p ope ies, sugges -
ing in e ac ion wi h ou e cell memb ane componen s [103].
Using a simila app oach wi h he C-4-epime o 139, conjuga e 146 was syn hesized
[105] using diace yla ed es e a ol in a Mi sunobu- ype eac ion (Scheme 31). ans-
Res e a ol, a na u al phy oalexina ound in g apes and ed wine, exhibi s nume ous
biological p ope ies like an ioxidan , an i-in lamma o y, ca dio- and neu op o ec i e,
and an idiabe ic effec s [106]. Caffeic acid and es e a ol conjuga es 144 and 146 we e
loaded on a hyd oxyl ilm o de elop a pH-sensi i e deli e y sys em o accele a ing skin
wound healing. Fo his pu pose, a copolyme comp ised o poly(e hyleneglycol
diac yla e) (PEGDA) and poly(hyd oxye hyl me hac yla e) (HEMA), in a 1:4.2 mola a io,
Scheme 31. P epa a ion o selenosuga -phenolic acid conjuga es h ough a Mi sunobu eac ion.
The same g oup ecen ly de eloped [
107
] a second gene a ion o selenosuga -cinnamic
acid conjuga es as cosmeceu ical agen s, in oducing an ace oxy g oup a he pseudo-
anome ic posi ion o enhance cellula up ake. This s uc u al ea u e was inco po a ed ia a
seleno-Pumme e ea angemen o selenoxide 148 upon hea ing in Ac
2
O (Scheme 32). This
eac ion has been used ex ensi ely by Iwaoka’s g oup o accessing selenonucleosides [
108
]
(see Sec ion 3.2). Subsequen silyl-O-dep o ec ion, ollowed by Mi sunobu eac ion wi h
he same phenolic acids as desc ibed in Scheme 32, and inal O-dep o ec ion u nished
conjuga es 151–153.
Compa ed o he i s gene a ion coun e pa s, he ace oxy de i a i es 151–153 dis-
played a dose-dependen cy o oxici y, po en ially a ec ing mi ochond ia edox ac i i y
a concen a ions abo e 25
µ
M [
107
]. Among hese, 153 exhibi ed a 7.5- old inc ease in
cell memb ane pe meabili y compa ed o 145, which lacks he ace oxy g oup (HaCaT
cells). The ca eoyl de i a i e 152 showed he s onges p o ec i e e ec agains H
2
O
2
,
while selenosuga s de i ed om p-couma ic and e ulic acids (151 and 153) demons a ed
p o-oxidan p ope ies.
Using a pe cu aneous abso p ion assay, i s gene a ion compounds, wi hou he
ace oxy g oup, gene ally exhibi ed highe skin pene a ion [
107
]. Compound 144 displayed
he as es pene a ion a e. Howe e , 152 (de i ed om ca eic acid) was he only second-
gene a ion compound ound in he ecep o luid laye .
Molecules 2025,30, 2053 25 o 54
Molecules 2025, 30, x FOR PEER REVIEW 25 o 58
was used. Compound 144 was eleased a pH 7.4, sui able o acu e wounds, whe eas
es e a ol-con aining 146 was eleased a pH 9.6, op imal o ch onic wounds [105]. The
pH-depending selec i e elease was a ibu ed o weak in e ac ions be ween he
selenoconjuga es and he hyd oxyl g oups o HEMA [105].
The same g oup ecen ly de eloped [107] a second gene a ion o selenosuga -
cinnamic acid conjuga es as cosmeceu ical agen s, in oducing an ace oxy g oup a he
pseudo-anome ic posi ion o enhance cellula up ake. This s uc u al ea u e was
inco po a ed ia a seleno-Pumme e ea angemen o selenoxide 148 upon hea ing in
Ac2O (Scheme 32). This eac ion has been used ex ensi ely by Iwaoka’s g oup o
accessing selenonucleosides [108] (see Sec ion 3.2). Subsequen silyl-O-dep o ec ion,
ollowed by Mi sunobu eac ion wi h he same phenolic acids as desc ibed in Scheme 32,
and inal O-dep o ec ion u nished conjuga es 151‒153.
Scheme 32. P epa a ion o he second-gene a ion selenosuga -phenolic acid conjuga es.
Compa ed o he i s gene a ion coun e pa s, he ace oxy de i a i es 151‒153
displayed a dose-dependen cy o oxici y, po en ially affec ing mi ochond ia edox
ac i i y a concen a ions abo e 25 µM [107]. Among hese, 153 exhibi ed a 7.5- old
inc ease in cell memb ane pe meabili y compa ed o 145, which lacks he ace oxy g oup
(HaCaT cells). The caffeoyl de i a i e 152 showed he s onges p o ec i e effec agains
H2O2, while selenosuga s de i ed om p-couma ic and e ulic acids (151 and 153)
demons a ed p o-oxidan p ope ies.
Using a pe cu aneous abso p ion assay, i s gene a ion compounds, wi hou he
ace oxy g oup, gene ally exhibi ed highe skin pene a ion [107]. Compound 144
displayed he as es pene a ion a e. Howe e , 152 (de i ed om caffeic acid) was he
only second-gene a ion compound ound in he ecep o luid laye .
3.2. Selenonucleosides
The inco po a ion o selenium in o nucleosides has been p oposed as a s a egy o
modula e o enhance hei an icance o an i i al p ope ies [10]. He ein we ocused spe-
ci ically on eplacing he endocyclic oxygen a om in he ca bohyd a e moie y wi h sele-
nium. P e ious s udies explo ing selenium subs i u ion wi hin he ni ogen base ha e
been comp ehensi ely e iewed [10].
Scheme 32. P epa a ion o he second-gene a ion selenosuga -phenolic acid conjuga es.
3.2. Selenonucleosides
The inco po a ion o selenium in o nucleosides has been p oposed as a s a egy o
modula e o enhance hei an icance o an i i al p ope ies [
10
]. He ein we ocused
speci ically on eplacing he endocyclic oxygen a om in he ca bohyd a e moie y wi h
selenium. P e ious s udies explo ing selenium subs i u ion wi hin he ni ogen base ha e
been comp ehensi ely e iewed [10].
Mos epo ed examples o selenonucleosides desc ibe he syn hesis o he 4
′
-
selenosuga moie y 154 ia a double nucleophilic displacemen eac ion using in si u
gene a ed NaHSe on a di-O-mesyla ed de i a i e, as illus a ed in Scheme 27. Subse-
quen ly, he ni ogen base is usually in oduced in o he selenosuga amewo k h ough
wo main s a egies (Scheme 33). Pa hway A: ea men o a selenoxide (155) di ec ly wi h
a silyla ed ni ogen base in he p esence o TMSOT and E
3
N. Pa hway B: ia seleno-
Pumme e ea angemen wi h Ac
2
O ollowed by N-glycosyla ion wi h a ni ogen base
(Vo b üggen glycosyla ion). In his app oach, he selenoxide unde goes hea ing in he
p esence o Ac
2
O o p oduce he ace oxy de i a i e 157, ha ac s as he glycosyl dono .
The ace oxy in e media es hen eac wi h he app op ia e ni ogen base in he p esence o
N,O-bis( ime hylsilyl)ace amide (BSA) and TMSOT (Scheme 33).
Molecules 2025, 30, x FOR PEER REVIEW 26 o 58
Mos epo ed examples o selenonucleosides desc ibe he syn hesis o he 4′-seleno-
suga moie y 154 ia a double nucleophilic displacemen eac ion using in si u gene a ed
NaHSe on a di-O-mesyla ed de i a i e, as illus a ed in Scheme 27. Subsequen ly, he ni-
ogen base is usually in oduced in o he selenosuga amewo k h ough wo main s a -
egies (Scheme 33). Pa hway A: ea men o a selenoxide (155) di ec ly wi h a silyla ed
ni ogen base in he p esence o TMSOT and E 3N. Pa hway B: ia seleno-Pumme e e-
a angemen wi h Ac2O ollowed by N-glycosyla ion wi h a ni ogen base (Vo b uggen
glycosyla ion). In his app oach, he selenoxide unde goes hea ing in he p esence o Ac2O
o p oduce he ace oxy de i a i e 157, ha ac s as he glycosyl dono . The ace oxy in e -
media es hen eac wi h he app op ia e ni ogen base in he p esence o N,O-bis( ime-
hylsilyl)ace amide (BSA) and TMSOT (Scheme 33).
Scheme 33. Gene al p ocedu e o he p epa a ion o selenonucleosides.
In he sea ch o no el an i hepa i is C i us agen s (HCV), Jeong and co-wo ke s
p epa ed Se-analogues o So osbu i , an o al d ug ha is p esc ibed o he ea men o
ch onic HCV [109]. I was claimed ha he p esence o selenium migh inc ease he lipo-
philici y compa ed o he 4′-oxo nucleosides, hus enabling hese compounds o be ans-
po ed ac oss cell memb anes; u he mo e, he bulkie cha ac e o he selenium a om
can also affec he nucleoside con o ma ion [109]. Comme cially a ailable 2-C-me hyl-D-
ibono-γ-lac one 158 was ans o med in o he key 4′-seleno u anose 159 in a 5-s ep p o-
cedu e, which included basic-p omo ed epime iza ion a C-4′ and nucleophilic displace-
men o a ansien di-O-mesyla e by selenide as he key s eps. Then, wo amilies o sele-
nonucleosides we e ob ained [109] om 159 (Scheme 34): 4′-selenopy imidine and pu ine
nucleosides. The o me amily (161‒163) was ob ained ollowing he pa hway A o
Scheme 33; MCPBA-p omo ed oxida ion o 159 o gi e he glycosyl dono 160 ollowed
by ea men wi h he app op ia e py imidine base, TMSOT and E 3N u nished he co -
esponding O-p o ec ed nucleosides in a oughly 1:2.5 α:β a io [109]. Dep o ec ion a -
o ded de i a i es 161‒163 (Scheme 34).
Scheme 33. Gene al p ocedu e o he p epa a ion o selenonucleosides.
Molecules 2025,30, 2053 32 o 54
gene a ed selenide and p ima y O-dep o ec ion. The nucleobase was in oduced in his
case ia an S
N
2 eac ion p io mesyla ion o 204 [
120
]. Again, he bes compound in he
se ies wi hin 205 inco po a ed a Cl a om a C-2 and a 3-iodobenzyl moie y a N
6
. This
compound beha ed as a po en PPAR
γ
pa ial agonis (Ki = 2.8
µ
M) and a PPAR
δ
an ag-
onis (Ki = 43 nM). Addi ionally, i imp o ed he p oduc ion o adiponec in, a ho mone
sec e ed o con olling he me abolism o a y acids and glucose, inc easing sensi i i y o
insulin. This e ec demons a es ha he syne gic modula ion o bo h ecep o s can lead
o p omising agen s o he ea men o me abolic diso de s, speci ically hose associa ed
wi h hypoadiponec inemia [120].
Molecules 2025, 30, x FOR PEER REVIEW 32 o 58
o he Skp2 (S-Phase Kinase Associa ed P o ein 2) exp ession in PC-3-Pa cells, a hi he o
unknown a ge o selenonucleosides [117].
Figu e 14. S uc u e o he an icance selenonucleoside LJ-2618.
A empla e ha has been ex ensi ely s udied is 4′-selenoadenosine in connec ion
wi h pe oxisome p oli e a o -ac i a ed and A3 adenosine ecep o s (PPAR and A3AR, e-
spec i ely). PPARs (classi ied as PPARα, γ and δ, depending on he issue dis ibu ion
and speci ic unc ion), ha e a key ole in main aining he me abolic homeos asis, wi h a
di ec in ol emen in he me abolism o lipids and glucose, adipogenesis, and also in in-
lamma o y esponses [118]. Acco dingly, PPARs a e in e es ing he apeu ic a ge s o
me abolic diso de s and in lamma o y diseases, like in lamma o y bowel disease. Jeon,
Noh and co-wo ke s de eloped a se ies o selenoadenosine nucleosides (203, Figu e 15)
by modi ica ion o he subs i uen s a C-2 (H, Cl) and C-6 posi ions N6-(cycloalkyl, a yl,
halobenzyl) o he base [119]. In e es ingly, de i a i e 203, deco a ed wi h a Cl a om a C-
2 and a 3-iodobenzyl moie y a N6 exhibi ed an enhanced an agonis ac i i y agains
PPARδ compa ed o i s 4′-oxo and 4′- hio coun e pa s. This beha iou was a ibu ed o
he unusual Sou h con o ma ion; docking simula ions con i med addi ional hyd ogen
bonding wi hin he hyd ophobic pocke o he enzyme, wha was lacking in i s o he chal-
cogen isos e s [119].
Figu e 15. S uc u e o 5′-N-me hylca bamoyl-4′-selenoadenosines and unca ed/homologa ed an-
alogues.
Figu e 15. S uc u e o 5
′
-N-me hylca bamoyl-4
′
-selenoadenosines and unca ed/homologa ed
analogues.
Bioisos e ic eplacemen o oxygen and sul u in p e ious nucleosides by selenium led
o A
3
AR agonis s, a ea u e ha can allow he de elopmen o new d ugs o he ea men
o in lamma o y and au oimmune diseases. In his con ex , de i a i e 205 bea ing a H a
H-2 and a N
6
-3-iodobenzyl moie y (Figu e 15), beha ed as a subnanomola agonis o such
ecep o (K
i
= 0.57 nM) [
121
]. This ep esen s an ou s anding selec i i y compa ed o A
1
AR
and A
3
AR (selec i i y index > 800 and 1900, espec i ely). S uc u al analysis e ealed ha
hese selenonucleosides exhibi again a Sou h u anose pucke ing, and a syn o ien a ion
o he nucleobase; su p isingly, p e ious A
3
AR agonis exhibi he comple e opposi e
con o ma ional p e e ence. The lead compound also showed an imp o ed inhibi ion o he
MCP-1 induced mic oglial chemo axis, sugges ing po en ial an i-s oke p ope ies [121].
Fu he S uc u e-Ac i i y s udies conduc ed on adenosine ecep o s led o he p epa-
a ion o selenonucleosides 206, wi h a unca ed s uc u e [
122
], and 207 [
123
], wi h a
disubs i u ed ni ogen a om on he ca boxamido mo i (Figu e 15). Compounds 206 ex-
hibi ed s ong binding o A3AR, wi hin he nanomola ange. Su p isingly, he wo mos
po en compounds (R
1
= Cl) inco po a ed alkyl g oups on R
2
posi ions (Me and cycloalkyl,
K
i
= 5.2 and 5.7 nM). Compu a ional calcula ions demons a ed ha he Sou h pucke ing
o he ca bohyd a e esidue allowed a close loca ion wi hin he binding si e o OH-3 o
Th 94, compa ed o 4
′
-oxo nucleosides [
122
]. Fu he mo e, an agonis e ec was obse ed,
unlike hei unca ed oxygen and sul u coun e pa s, which beha ed as an agonis o
his ecep o .

Molecules 2025,30, 2053 33 o 54
Rema kably, he addi ion o a second me hyl o he ca boxamido moie y (207) shi ed
he ac i i y o he 4-‘selenonucleosides o an agonism, wi h medium o high binding a in-
i y [
123
]. The bes compounds lacked a chlo ine a om a he 2-posi ion o he nucleobase,
and he lead one was deco a ed wi h a 3-iodobenzyl sca old a N
6
-posi ion (K
i
= 22.7 nM).
The same beha iou , and simila binding a ini ies we e ound o isos e ic 4
′
-oxo and
4
′
- hionucleosides. Theo e ical calcula ions e ealed he essen ial ole o he NH moie y o
exhibi ing agonis ac i i y [123].
3.3. Selenoglycosides
The subs i u ion o he oxygen a om in he glycosidic bond wi h selenium has eme ged
as a p ominen s a egy in glycomime ic syn hesis. This isos e ic modi ica ion enables
he de elopmen o biomime ics wi h enhanced me abolic s abili y compa ed o hei na -
u al coun e pa s, while main aining dynamic and con o ma ional p ope ies simila o
hose o hioglycosides [
124
]. Selenoglycosides, h ough
77
Se-NMR, X- ay c ys allog a-
phy o calo ime y i a ions, a e widely used in s uc u al s udies [
124
–
127
], pa icula ly
o gaining deepe insigh s in o ca bohyd a e ecogni ion by p o ein ecep o s, such as
lec ins. No able examples o hese glycomime ics include he seleno- and diselenodiglyco-
sides
208–210 [124,126,127],
which ha e been s udied o hei binding o human galec ins
1- and 3,
as well as Se-sialoside 211, a mime ic o sialyl
α
(2,6) and
α
(2,3)-galac ose epi opes,
ele an o in es iga ing glycan-pa hogen in e ac ions (Figu e 16). Nume ous selenogly-
cosides also exhibi ele an biological p ope ies; o ins ance, Comini and co-wo ke s
e alua ed [
128
] an ample panel o selenoglycosides as po en ial an ipa asi ic agen s agains
ypanosomiasis; he lead compounds exhibi ed ac i i y wi hin he submic omola ange,
and good selec i i y.
Molecules 2025, 30, x FOR PEER REVIEW 34 o 58
simila o hose o hioglycosides [124]. Selenoglycosides, h ough 77Se-NMR, X- ay c ys-
allog aphy o calo ime y i a ions, a e widely used in s uc u al s udies [124–127], pa -
icula ly o gaining deepe insigh s in o ca bohyd a e ecogni ion by p o ein ecep o s,
such as lec ins. No able examples o hese glycomime ics include he seleno- and dise-
lenodiglycosides 208‒210 [124,126,127], which ha e been s udied o hei binding o hu-
man galec ins 1- and 3, as well as Se-sialoside 211, a mime ic o sialyl α(2,6) and α(2,3)-
galac ose epi opes, ele an o in es iga ing glycan-pa hogen in e ac ions (Figu e 16).
Nume ous selenoglycosides also exhibi ele an biological p ope ies; o ins ance,
Comini and co-wo ke s e alua ed [128] an ample panel o selenoglycosides as po en ial
an ipa asi ic agen s agains ypanosomiasis; he lead compounds exhibi ed ac i i y
wi hin he submic omola ange, and good selec i i y.
Figu e 16. Rep esen a i e selenoglycosides o s uc u al s udies.
The g owing in e es in selenoglycosides has d i en he need o p ac ical and s e e-
oselec i e syn he ic me hods. Mos o hese app oaches a e based on nucleophilic dis-
placemen s ca ied ou by Se-based nucleophiles (Scheme 41) on glycosyl halides (212),
i la es, ace a es (215) and glycals (216). Fo ins ance, he ea men o glycosyl halides
wi h p-me hylselenobenzoic anhyd ide in he p esence o Cs2CO3 and pipe idine, gene -
a es p-me hylselenobenzoa e in si u, which hen unde goes a SN2 eac ion a he anome ic
posi ion, wi h in e sion o con igu a ion, yielding p-me hylbenzoylselenoglycoside 213
(Scheme 41, pa hway A). Fu he eac ion wi h alkyl halides, including hose con aining
suga esidues, unde basic condi ions enables he p epa a ion o he co esponding se-
lenoglycosides [125,129]. Using his me hodology as one o he key s eps, Mu phy and
cowo ke s accomplished [129] he p epa a ion o 219 (Figu e 17), he Se-isos e o he im-
munos imulan α-GalCe . In hei syn he ic pa hway, TiCl4 was used o isome ize an
equa o ial β-selenoglycoside in o i s axial α-coun e pa .
Figu e 17. Rele an selenoglycosides.
Figu e 16. Rep esen a i e selenoglycosides o s uc u al s udies.
The g owing in e es in selenoglycosides has d i en he need o p ac ical and s e e-
oselec i e syn he ic me hods. Mos o hese app oaches a e based on nucleophilic dis-
placemen s ca ied ou by Se-based nucleophiles (Scheme 41) on glycosyl halides (212),
i la es, ace a es (215) and glycals (216). Fo ins ance, he ea men o glycosyl halides wi h
p-me hylselenobenzoic anhyd ide in he p esence o Cs
2
CO
3
and pipe idine, gene a es p-
me hylselenobenzoa e in si u, which hen unde goes a S
N
2 eac ion a he anome ic posi ion,
wi h in e sion o con igu a ion, yielding p-me hylbenzoylselenoglycoside
213 (Scheme 41,
pa hway A). Fu he eac ion wi h alkyl halides, including hose con aining suga
esidues, unde basic condi ions enables he p epa a ion o he co esponding selenoglyco-
sides [
125
,
129
]. Using his me hodology as one o he key s eps, Mu phy and cowo ke s
accomplished [
129
] he p epa a ion o 219 (Figu e 17), he Se-isos e o he immunos im-
ulan
α
-GalCe . In hei syn he ic pa hway, TiCl
4
was used o isome ize an equa o ial
β-selenoglycoside in o i s axial α-coun e pa .
Molecules 2025,30, 2053 34 o 54
Molecules 2025, 30, x FOR PEER REVIEW 35 o 58
O
n(RO)
SeR
O
n(AcO)
OAc
10% InB 3
Phenyl 1,2- ans-
selenoglycosides
O
n(RO)
X
(1) KSeCN
(2) NaBH4
Ac2O
X = B , I
Y = B , I, OT
R: Alkyl, glycosyl
O
n(RO)
SeAc
RY
Py olidine
High s e eoselec i i y
(RSe)2
NH2-NH2
KOH
O
n(RO)
B
R-SeCN
NaBH4
ó NaBH4
O
Ph2Se2
TMSN3
BAIB
R=Ph
O
n(BnO)
BF3K
(PhSe)2
Blue LED
R=Ph
I
N
N
N
N Bu
Bu
F F
F3C
F
F
CF3PF6-
Pho oca alys
Pho oca alys
O
Se
O
Pipe idine, CsCO3
O
n(RO)
Se
H3CCH3
O
CH3R-X
A
B
C
D
O
n(RO)
SnBu3
CuCl, KF
(RSe)2
Ph-SeH E
F
G
212
213
214 212
215
216
217
218
Cs2CO3, pipe azine
H
Azido-phenyl
selena ion eac ion
Scheme 41. Main syn he ic p ocedu es o he p epa a ion o selenoglycosides.
A ansien p-me hylselenobenzoa e in e media e was also used [130] in c oss-cou-
pling eac ions by ea men wi h he e oa yl and alkenyl halides using a Pd-based ca alys
(PdG3 Xan Phos) unde mild condi ions. This p ocess u nished he unp eceden ed o -
ma ion o a C(sp2)-Se bond, like in 220 (Figu e 17). This me hodology p o ed o be com-
pa ible wi h a a ie y o unc ional g oups, including aldehydes, ke ones, o ni iles,
among o he s. Howe e , i was claimed [131] ha , despi e being an elegan app oach, i
lacks a om economy, as he acyl moie y in 213 is no inco po a ed in o he inal s uc u e.
This issue was o e come by Liang and cowo ke s by using modi ied condi ions o he
Cas ellani eac ion (Scheme 42), o iginally en isioned o he syn hesis o a enes, and
based on Pd/no bo nene (NBE) coope a i e ca alysis [132]. They epo ed he unp ece-
den ed use o wo-componen Cas allani- ype eac ion o coupling p-me hylbenzoylse-
lenoglycosides 213 wi h (he e o)a yl iodides o u nish selenoglycosides upon o ma ion
o a new C(sp2)-Se bond, and concomi an Se‒C(=O) b eaking. A simila p ocedu e was
also employed o accessing he co esponding hioisos e s. This s a egy p o ed o ha e
a b oad scope, being effec i e in O-p o ec ed py anoses and u anoses ( ibose, glucose,
mannose, galac ose, xylose, a abinose), including disaccha ides like cellobiose and mal -
ose, and ole a es a a ie y o unc ional g oups (Ac, Pi , Bn, TBDPS, Me). A en a i e
ca aly ic cycle (adap ed om he one epo ed o hioglycosides) is illus a ed in Scheme
42. (Pd(MeCN)2Cl2 is used as he Pd(II) sou ce, and P(p-Cl-C6H4)3 as he ligand; he o -
ma ion o he selenoglycoside is pos ula ed o ake place h ough se en s eps [131]: oxi-
da i e addi ion o Pd(0) in o a yl iodides, mig a o y inse ion o 5-no bo nene-2-ca boni-
ile, o ho C-H ac i a ion o gi e he i e-membe ed palladacycle 227, oxida i e addi ion
o p-me hylbenzoylselenoglycoside 213, educ i e elimina ion, no bo nene ex usion, and
a second educ i e elimina ion o gi e selenoglycoside 231, whe e no loss o a oms has
aken place. The main conce ns o his app oach a e he high empe a u es (95–100 °C)
and he long eac ion imes (16 h).
Scheme 41. Main syn he ic p ocedu es o he p epa a ion o selenoglycosides.
Molecules 2025, 30, x FOR PEER REVIEW 34 o 58
simila o hose o hioglycosides [124]. Selenoglycosides, h ough 77Se-NMR, X- ay c ys-
allog aphy o calo ime y i a ions, a e widely used in s uc u al s udies [124–127], pa -
icula ly o gaining deepe insigh s in o ca bohyd a e ecogni ion by p o ein ecep o s,
such as lec ins. No able examples o hese glycomime ics include he seleno- and dise-
lenodiglycosides 208‒210 [124,126,127], which ha e been s udied o hei binding o hu-
man galec ins 1- and 3, as well as Se-sialoside 211, a mime ic o sialyl α(2,6) and α(2,3)-
galac ose epi opes, ele an o in es iga ing glycan-pa hogen in e ac ions (Figu e 16).
Nume ous selenoglycosides also exhibi ele an biological p ope ies; o ins ance,
Comini and co-wo ke s e alua ed [128] an ample panel o selenoglycosides as po en ial
an ipa asi ic agen s agains ypanosomiasis; he lead compounds exhibi ed ac i i y
wi hin he submic omola ange, and good selec i i y.
Figu e 16. Rep esen a i e selenoglycosides o s uc u al s udies.
The g owing in e es in selenoglycosides has d i en he need o p ac ical and s e e-
oselec i e syn he ic me hods. Mos o hese app oaches a e based on nucleophilic dis-
placemen s ca ied ou by Se-based nucleophiles (Scheme 41) on glycosyl halides (212),
i la es, ace a es (215) and glycals (216). Fo ins ance, he ea men o glycosyl halides
wi h p-me hylselenobenzoic anhyd ide in he p esence o Cs2CO3 and pipe idine, gene -
a es p-me hylselenobenzoa e in si u, which hen unde goes a SN2 eac ion a he anome ic
posi ion, wi h in e sion o con igu a ion, yielding p-me hylbenzoylselenoglycoside 213
(Scheme 41, pa hway A). Fu he eac ion wi h alkyl halides, including hose con aining
suga esidues, unde basic condi ions enables he p epa a ion o he co esponding se-
lenoglycosides [125,129]. Using his me hodology as one o he key s eps, Mu phy and
cowo ke s accomplished [129] he p epa a ion o 219 (Figu e 17), he Se-isos e o he im-
munos imulan α-GalCe . In hei syn he ic pa hway, TiCl4 was used o isome ize an
equa o ial β-selenoglycoside in o i s axial α-coun e pa .
Figu e 17. Rele an selenoglycosides.
Figu e 17. Rele an selenoglycosides.
A ansien p-me hylselenobenzoa e in e media e was also used [
130
] in c oss-coupling
eac ions by ea men wi h he e oa yl and alkenyl halides using a Pd-based ca alys (PdG3
Xan Phos) unde mild condi ions. This p ocess u nished he unp eceden ed o ma ion o
a C(sp
2
)-Se bond, like in 220 (Figu e 17). This me hodology p o ed o be compa ible wi h a
a ie y o unc ional g oups, including aldehydes, ke ones, o ni iles, among o he s. How-
e e , i was claimed [
131
] ha , despi e being an elegan app oach, i lacks a om economy, as
he acyl moie y in 213 is no inco po a ed in o he inal s uc u e. This issue was o e come
by Liang and cowo ke s by using modi ied condi ions o he Cas ellani eac ion (Scheme 42),
o iginally en isioned o he syn hesis o a enes, and based on Pd/no bo nene (NBE) coop-
Molecules 2025,30, 2053 35 o 54
e a i e ca alysis [
132
]. They epo ed he unp eceden ed use o wo-componen Cas allani-
ype eac ion o coupling p-me hylbenzoylselenoglycosides 213 wi h (he e o)a yl iodides
o u nish selenoglycosides upon o ma ion o a new C(sp
2
)-Se bond, and concomi an Se–
C(=O) b eaking. A simila p ocedu e was also employed o accessing he co esponding
hioisos e s. This s a egy p o ed o ha e a b oad scope, being e ec i e in O-p o ec ed
py anoses and u anoses ( ibose, glucose, mannose, galac ose, xylose, a abinose), including
disaccha ides like cellobiose and mal ose, and ole a es a a ie y o unc ional g oups
(Ac, Pi , Bn, TBDPS, Me). A en a i e ca aly ic cycle (adap ed om he one epo ed o
hioglycosides) is illus a ed in Scheme 42. (Pd(MeCN)
2
Cl
2
is used as he Pd(II) sou ce,
and P(p-Cl-C
6
H
4
)
3
as he ligand; he o ma ion o he selenoglycoside is pos ula ed o ake
place h ough se en s eps [
131
]: oxida i e addi ion o Pd(0) in o a yl iodides, mig a o y
inse ion o 5-no bo nene-2-ca boni ile, o ho C-H ac i a ion o gi e he i e-membe ed
palladacycle 227, oxida i e addi ion o p-me hylbenzoylselenoglycoside 213, educ i e
elimina ion, no bo nene ex usion, and a second educ i e elimina ion o gi e selenoglyco-
side 231, whe e no loss o a oms has aken place. The main conce ns o his app oach a e
he high empe a u es (95–100 ◦C) and he long eac ion imes (16 h).
Azeem and Mandal desc ibed [
133
] he a om-economic and g am-scale syn hesis
o unsymme ical gem-dia ylme hyl( hio)seleno glycosides. Fo his pu pose, glycosyl
hio(seleno) ace a es and o he acyla ed de i a i es 232 (analogues o 213) we e ea ed
wi h Cs
2
CO
3
and p-quinone me hides (p-QMs). I was hypo hesized ha Cs
2
CO
3
p o-
mo es he clea age o he X-C(=O) bond, gene a ing a ansien hiola e/selenola e ha
unde goes a 1,6-addi ion on he p-QMs and an acyl ans e ia a conce ed mechanism
(Scheme 43). Reac ions p oceeded smoo hly ( ), wi h sho eac ion imes (30 min-2 h), and
he selenoglycosides 233 we e isola ed in a oughly 1:1 dias e ome ic a io.
1,2- ans-Selenoglycosides (alkyl, a yl, glycosyl) can be ob ained [
134
] h ough he
nucleophilic a ack o selenides (Scheme 41, Pa hway B), which a e gene a ed ia he
educ i e clea age o symme ical diselenides. These selenides hen eac wi h pe -O-
ace yla ed glycosyl b omides unde phase ans e ca alysis. Using a simila app oach,
Osca son and cowo ke s epo ed [
135
] he p epa a ion o selenoglycosides bea ing a
luo ine a om as use ul ools o s udying p o ein-ca bohyd a e in e ac ions wi h
19
F and
77Se-NMR spec oscopy.
Ano he app oach o p epa e selenoglycosides om glycosyl halides 212 is illus a ed
in Scheme 41, Pa hway C. T ea men wi h KSeCN a o ds glycosyl selenocyana es, ypi-
cally wi h in e sion o con igu a ion. Reduc ion o he selenocyana o mo i wi h NaBH
4
gene a es a con igu a ionally s able selenide, which is subsequen ly apped h ough
ace yla ion (214). Fu he eac ion wi h alkyl halides unde basic condi ions leads o he
o ma ion o he co esponding selenoglycoside [
136
] in good yields, and sho eac ion
imes (10–20 min). Disaccha ides, like 221, we e also ob ained wi h his p ocedu e.
Glycosyl b omides 212 we e also ea ed wi h a yl selenides, gene a ed ia he NaBH
4
-
media ed educ ion o he co esponding a yl selenocyana es (Scheme 41, Pa hway D). This
s a egy was used by Angeli and cowo ke s [
137
] o de elop no el sul onamides bea ing a
selenoglycoside linkage, like 222, designed o a ge ing seizu es associa ed wi h glucose
anspo e ype 1 de iciency synd ome (GLUT1-DS).
Reac ions in ol ing Se-based nucleophiles can also ake place in pe -O-ace yla ed
aldoses, using benzene selenol and InB
3
as a mois u e-s able Lewis acid (Scheme 41,
Pa hway E) [
138
]. This s a egy a o ds 1,2- ans selenoglycosides, due o neighbou ing
g oup pa icipa ion, in mode a e o almos quan i a i e yields. The me hodology is also
applicable o he p epa a ion o phenyl hioglycosides.
Molecules 2025,30, 2053 36 o 54
Molecules 2025, 30, x FOR PEER REVIEW 36 o 58
Scheme 42. Ca aly ic cycle o he Cas ellani- ype eac ion o he syn hesis o (he e o)a yl selenogly-
cosides.
Azeem and Mandal desc ibed [133] he a om-economic and g am-scale syn hesis o
unsymme ical gem-dia ylme hyl( hio)seleno glycosides. Fo his pu pose, glycosyl
hio(seleno) ace a es and o he acyla ed de i a i es 232 (analogues o 213) we e ea ed
wi h Cs2CO3 and p-quinone me hides (p-QMs). I was hypo hesized ha Cs2CO3 p omo es
he clea age o he X-C(=O) bond, gene a ing a ansien hiola e/selenola e ha unde -
goes a 1,6-addi ion on he p-QMs and an acyl ans e ia a conce ed mechanism (Scheme
43). Reac ions p oceeded smoo hly ( ), wi h sho eac ion imes (30 min-2 h), and he
selenoglycosides 233 we e isola ed in a oughly 1:1 dias e ome ic a io.
Scheme 42. Ca aly ic cycle o he Cas ellani- ype eac ion o he syn hesis o (he e o)a yl selenogly-
cosides.
Ni an ie and cowo ke s epo ed [
139
] he he e ogeneous and ep oducible 2-azido-
phenylselenyla ion o 3,5,6- i-O-ace yl-D-galac al wi h Ph
2
Se
2
and TMSN
3
(Scheme 41,
Pa hway F) in he p esence o he hype alen iodine compound BAIB (PhI(OAc)
2
,
[bis(ace oxy)iodo]benzene). This eac ion a o ded c ys alline phenyl 3,4,6- i-O-ace yl-
2-azido-2-deoxy-1-seleno-
α
-D-galac opy anoside (223), used o he p epa a ion o galac-
osamine building blocks. Con e sely, he use o D-glucal did no p oceed wi h s e e-
oselec i i y, esul ing in a mix u e o D-gluco and D-manno selenoglycosides. The use
o low chemis y allowed a educ ion o side-p oduc s, and he eac ion ime, com-
pa ed o he ba ch p ocess [
140
]; op imised condi ions led o he p oduc ion o he abo e
2-azidoselenoglycoside
in 1.2 mmol/h a e, a o ding he p ocessing o 5 mmol o galac al
o e a 3 h-pe iod.
Al e na i ely, Walczak and cowo ke s epo ed he s e eo e en i e syn hesis o seleno-
glycosides s a ing om glycosyl ibu yl s annanes and symme ical diselenides in he
Molecules 2025,30, 2053 37 o 54
p esence o CuCl and KF (Scheme 41, Pa hway G) [
141
]. No di ec ing g oups a e equi ed,
and he eac ion p oceeds success ully wi h ee hyd oxyl g oups (e.g., 224), a o ding a
b oad scope ha enabled he p epa a ion o a as lib a y o compounds. I was hypo h-
esized ha he ibu yl s annane unde goes a s e eo e en i e ansme alla ion eac ion
wi h CuCl, enabled by he p esence o F
−
. Then, he glycosyl o ganocoppe in e media e
eac s wi h he diselenide, collapsing o he co esponding selenoglycoside [
141
]. The main
limi a ions a e he empe a u es (110 ◦C) and haza dous o gano in eagen s.
Molecules 2025, 30, x FOR PEER REVIEW 37 o 58
Scheme 43. P epa a ion o unsymme ical gem-dia ylme hyl hio(seleno)glycosides.
1,2- ans-Selenoglycosides (alkyl, a yl, glycosyl) can be ob ained [134] h ough he
nucleophilic a ack o selenides (Scheme 41, Pa hway B), which a e gene a ed ia he e-
duc i e clea age o symme ical diselenides. These selenides hen eac wi h pe -O-ace -
yla ed glycosyl b omides unde phase ans e ca alysis. Using a simila app oach, Osca -
son and cowo ke s epo ed [135] he p epa a ion o selenoglycosides bea ing a luo ine
a om as use ul ools o s udying p o ein-ca bohyd a e in e ac ions wi h 19F and 77Se-NMR
spec oscopy.
Ano he app oach o p epa e selenoglycosides om glycosyl halides 212 is illus-
a ed in Scheme 41, Pa hway C. T ea men wi h KSeCN affo ds glycosyl selenocyana es,
ypically wi h in e sion o con igu a ion. Reduc ion o he selenocyana o mo i wi h
NaBH4 gene a es a con igu a ionally s able selenide, which is subsequen ly apped
h ough ace yla ion (214). Fu he eac ion wi h alkyl halides unde basic condi ions leads
o he o ma ion o he co esponding selenoglycoside [136] in good yields, and sho e-
ac ion imes (10‒20 min). Disaccha ides, like 221, we e also ob ained wi h his p ocedu e.
Glycosyl b omides 212 we e also ea ed wi h a yl selenides, gene a ed ia he
NaBH4-media ed educ ion o he co esponding a yl selenocyana es (Scheme 41, Pa h-
way D). This s a egy was used by Angeli and cowo ke s [137] o de elop no el sul ona-
mides bea ing a selenoglycoside linkage, like 222, designed o a ge ing seizu es associ-
a ed wi h glucose anspo e ype 1 de iciency synd ome (GLUT1-DS).
Reac ions in ol ing Se-based nucleophiles can also ake place in pe -O-ace yla ed al-
doses, using benzene selenol and InB 3 as a mois u e-s able Lewis acid (Scheme 41, Pa h-
way E) [138]. This s a egy affo ds 1,2- ans selenoglycosides, due o neighbou ing g oup
pa icipa ion, in mode a e o almos quan i a i e yields. The me hodology is also applica-
ble o he p epa a ion o phenyl hioglycosides.
Ni an ie and cowo ke s epo ed [139] he he e ogeneous and ep oducible 2-azido-
phenylselenyla ion o 3,5,6- i-O-ace yl-D-galac al wi h Ph2Se2 and TMSN3 (Scheme 41,
Scheme 43. P epa a ion o unsymme ical gem-dia ylme hyl hio(seleno)glycosides.
The same g oup ecen ly de eloped a p ocedu e o he s e eo e en i e c oss-coupling
eac ion o 2-deoxysuga s bea ing anome ic i luo obo a es. The main a ge s we e C-
a yla ion and e he i ica ion eac ions unde pho o edox condi ions ( ia a single elec on
ans e mechanism) [
142
]. As he only example o a selenoglycoside, hey desc ibed he
p epa a ion o phenyl 2-deoxy-3,4,6- i-O-benzyl-
α
-D-glucopy anoside wi h o al e en ion
o con igu a ion (Scheme 41, Pa hway H).
Co zana and cowo ke s epo ed [
143
] he p epa a ion o S- and Se-mime ics o a
GalNAc glycopep ide (compound 238, Scheme 44) de i ed om mucin MUC1, an O-
glycop o ein o e exp essed in a se ies o umou s. This glycopep ide ac s as a umou -
associa ed an igen, and hus, is po en ially use ul in he de elopmen o cance accines.
The subs i u ion o oxygen by bulkie S and Se a oms inc eases he dis ance be ween he
saccha ide esidue and he oligopep ide, and also al e s he o ien a ion o he glycosidic
bond. These s uc u al modi ica ions allowed he glycopep ide 238 and i s sul u isos e o
adop a p e-o ganized con o ma ion ha imp o ed binding o he MUC1 an ibody [
143
].
The p epa a ion o selenoglycoside 237, a key syn he ic in e media e la e subjec ed o
solid-phase pep ide syn hesis, in ol ed a nucleophilic displacemen exe ed by a selenium
nucleophile (Scheme 44). Unlike p e ious examples, in his case he diselenide mo i was
loca ed a he anome ic posi ion. This was achie ed s a ing om pe -O-ace yla ed GalNAc,

Molecules 2025,30, 2053 38 o 54
which upon ea men wi h Woolin’s eagen a o ded a ansien selenoamide ha e ol ed
o bicyclic 2-me hylselenazoline 235 h ough a spon aneous in amolecula nucleophilic
cycliza ion. Subsequen ea men wi h TFA u nished diselenide 236 which was hen
educed and coupled o an iodina ed de i a i e o L- h eonine [143].
Molecules 2025, 30, x FOR PEER REVIEW 39 o 58
Scheme 44. Syn hesis o Se-GalNAc-glycopep ide as a umou -associa ed an igen.
Scheme 45. Use o selenoglycosides in glycosyla ion eac ions.
Al e na i ely, Li and co-wo ke s con e ed he 2-azido unc ionali y in 239 (O-benzyl
p o ec ed) in o 2-deoxy-2-(2,4-dini obenzenesul onyl)amino (DNsNH) (compound 241,
Scheme 45) [146], which in u n can be ea ed wi h hioace ic acid and DMAP o gi e an
ace amido mo i . Ac i a ion o 2-deoxy-2-DNsNH phenyl selenoglycoside 241 wi h a
combina ion o PhSeCl and AgOT , ollowed by he addi ion o he glycosyl accep o a
low empe a u es affo ded disaccha ide 242 wi h good β-s e eoselec i i y. This p o ocol
p o ed o be efficien e en wi h s e ically hinde ed glycosyl accep o s, wi h educed nu-
cleophilic p ope ies. The combina ion o 241 wi h sequen ial hioglycoside-based dono s
enabled he p epa a ion o β-(1→6)-linked i- and hexasaccha ides wi h po en ial in e es
as an igens in he sea ch o accines agains mic obial in ec ions [146].
Scheme 44. Syn hesis o Se-GalNAc-glycopep ide as a umou -associa ed an igen.
Selenoglycosides a e no only ele an o s uc u al s udies o o he de elopmen
o bioac i e compounds, bu hey a e also aluable in e media es in o ganic syn hesis, as
hey can be used as glycosyl dono s wi h di e en alcohols (including pa ially p o ec ed
saccha ides) and p omo e s. This s a egy has also been used in he p epa a ion o complex
oligosaccha ides [
144
]. Phenyl
α
-selenoglycosides, ob ained ia an azido-phenyl selena ion
eac ion om glycals as depic ed in Scheme 41 (Pa hway F) we e ac i a ed using classi-
cal glycosyla ion condi ions wi h NIS and TMSOT , and ea ed wi h ei he p ima y o
seconda y (suga -de i ed) alcohols (Scheme 45); in he la e case, disaccha ides we e ob-
ained [
145
]. 2-Azido mo i s a e he p ecu so s o amino and ace amido sca olds, p esen
in nume ous bioac i e glycans. When D-gluco-con igu ed selenoglycosides we e used
(e.g., 240), a good
α
:
β
selec i i y was obse ed (3–5:1); in e es ingly, mannopy anosides
a o ded α-linked glycosides exclusi ely.
Al e na i ely, Li and co-wo ke s con e ed he 2-azido unc ionali y in 239 (O-benzyl
p o ec ed) in o 2-deoxy-2-(2,4-dini obenzenesul onyl)amino (DNsNH) (compound 241,
Scheme 45) [
146
], which in u n can be ea ed wi h hioace ic acid and DMAP o gi e
an ace amido mo i . Ac i a ion o 2-deoxy-2-DNsNH phenyl selenoglycoside 241 wi h a
combina ion o PhSeCl and AgOT , ollowed by he addi ion o he glycosyl accep o a low
empe a u es a o ded disaccha ide 242 wi h good
β
-s e eoselec i i y. This p o ocol p o ed
o be e icien e en wi h s e ically hinde ed glycosyl accep o s, wi h educed nucleophilic
p ope ies. The combina ion o 241 wi h sequen ial hioglycoside-based dono s enabled he
p epa a ion o
β
-(1
→
6)-linked i- and hexasaccha ides wi h po en ial in e es as an igens
in he sea ch o accines agains mic obial in ec ions [146].
Molecules 2025,30, 2053 39 o 54
Molecules 2025, 30, x FOR PEER REVIEW 39 o 58
Scheme 44. Syn hesis o Se-GalNAc-glycopep ide as a umou -associa ed an igen.
Scheme 45. Use o selenoglycosides in glycosyla ion eac ions.
Al e na i ely, Li and co-wo ke s con e ed he 2-azido unc ionali y in 239 (O-benzyl
p o ec ed) in o 2-deoxy-2-(2,4-dini obenzenesul onyl)amino (DNsNH) (compound 241,
Scheme 45) [146], which in u n can be ea ed wi h hioace ic acid and DMAP o gi e an
ace amido mo i . Ac i a ion o 2-deoxy-2-DNsNH phenyl selenoglycoside 241 wi h a
combina ion o PhSeCl and AgOT , ollowed by he addi ion o he glycosyl accep o a
low empe a u es affo ded disaccha ide 242 wi h good β-s e eoselec i i y. This p o ocol
p o ed o be efficien e en wi h s e ically hinde ed glycosyl accep o s, wi h educed nu-
cleophilic p ope ies. The combina ion o 241 wi h sequen ial hioglycoside-based dono s
enabled he p epa a ion o β-(1→6)-linked i- and hexasaccha ides wi h po en ial in e es
as an igens in he sea ch o accines agains mic obial in ec ions [146].
Scheme 45. Use o selenoglycosides in glycosyla ion eac ions.
3.4. Miscellaneous Selenosuga s
O he suga mime ics con aining selenium ha e been epo ed, besides selenosuga s,
selenonucleosides and selenoglycosides. Figu e 18 shows some ecen examples o such
s uc u es. Thus, López and co-wo ke s epo ed [
74
] he p epa a ion o suga -de i ed
bicyclic 1,3-selenazolines bea ing ei he an alkylamino (243) o alkoxy (244) esidue a he
C-2 posi ion o he he e ocyclic mo i . Such s uc u es we e designed as dual inhibi o s o
cholines e ases and O-GlcNAcase (OGA), wo enzymes ha a e conside ed as alida ed
a ge s agains Alzheime ’s disease; i was pos ula ed ha he p esence o a Se a om migh
con ibu e o main ain he edox homeos asis. De i a i es 243, and pa icula he de i a i e
wi h R = P exhibi ed he bes bioac i i ies. This compound ac ed as a submic omola
selec i e inhibi o o bu y ylcholines e ase (p edominan in ad anced s ages o he disease;
IC
50
= 0.46
µ
M) and a nanomola selec i e inhibi o o human OGA (IC
50
= 53 nM), while
showing no signi ican ac i i y agains glycosidases o cy o oxici y [74].
Fan’s g oup designed p od ugs de i ed om he an i umou d ug gemci abine
and a 1,2-diselenolane moie y connec ed h ough a ca bama e linke (Se-Gem,245,
Figu e 18) [147].
This compound, which ac ed as a suicide p od ug, imp o ed he an ip o-
li e a i e ac i i y o gemci abine (up o 6- old, IC
50
= 0.11–0.88
µ
M). I was ac i a ed by
glu a hione (GSH), eleasing gemci abine and he diselenide, deple ing GSH and inc easing
he oxida i e s ess, wha in u n induced cell-dea h by apop osis [147].
Using O-p o ec ed monosaccha ides deco a ed wi h a selenocyana o mo i ei he
a C-4 o C-6 posi ion, Mis a’s g oup accomplished he p epa a ion o non-symme ical
and non-glycosidic pseudodisaccha ides connec ed h ough a selenide (246) [
148
] o a
diselenide (247) [
149
] e he (Figu e 18). In bo h cases, he key s ep is he educ ion o he
selenocyana o g oup wi h hyd azine hyd a e o gi e a ansien and eac i e suga selenide,
which aps a suga iodide o i la e o 246, o a symme ical suga diselenide o gi e 247.
Addi ionally, ea men o a 6-iodo suga de i a i e wi h a symme ical suga diselenide,
CS
2
and Na
2
S
·
9H
2
O a o ded a pseudo disaccha ide wi h a S-Se linkage (e.g., 248) [
150
].
When he lea ing g oup is loca ed on he anome ic posi ion (ace ob omo aldoses), eac ion
Molecules 2025,30, 2053 40 o 54
wi h suga diselenides a o ded compounds like 249, wi h exclusi e o ma ion o he
β-anome . This me hodology p o ed o be scalable, odou less and high-yielding [150].
Molecules 2025, 30, x FOR PEER REVIEW 40 o 58
3.4. Miscellaneous Selenosuga s
O he suga mime ics con aining selenium ha e been epo ed, besides selenosuga s,
selenonucleosides and selenoglycosides. Figu e 18 shows some ecen examples o such
s uc u es. Thus, López and co-wo ke s epo ed [74] he p epa a ion o suga -de i ed
bicyclic 1,3-selenazolines bea ing ei he an alkylamino (243) o alkoxy (244) esidue a he
C-2 posi ion o he he e ocyclic mo i . Such s uc u es we e designed as dual inhibi o s o
cholines e ases and O-GlcNAcase (OGA), wo enzymes ha a e conside ed as alida ed
a ge s agains Alzheime ’s disease; i was pos ula ed ha he p esence o a Se a om migh
con ibu e o main ain he edox homeos asis. De i a i es 243, and pa icula he de i a-
i e wi h R = P exhibi ed he bes bioac i i ies. This compound ac ed as a submic omola
selec i e inhibi o o bu y ylcholines e ase (p edominan in ad anced s ages o he dis-
ease; IC50 = 0.46 µM) and a nanomola selec i e inhibi o o human OGA (IC50 = 53 nM),
while showing no signi ican ac i i y agains glycosidases o cy o oxici y [74].
Figu e 18. Miscellaneous selenosuga s.
Fan’s g oup designed p od ugs de i ed om he an i umou d ug gemci abine and
a 1,2-diselenolane moie y connec ed h ough a ca bama e linke (Se-Gem, 245, Figu e 18)
[147]. This compound, which ac ed as a suicide p od ug, imp o ed he an ip oli e a i e
ac i i y o gemci abine (up o 6- old, IC50 = 0.11‒0.88 µM). I was ac i a ed by glu a hione
(GSH), eleasing gemci abine and he diselenide, deple ing GSH and inc easing he oxi-
da i e s ess, wha in u n induced cell-dea h by apop osis [147].
Using O-p o ec ed monosaccha ides deco a ed wi h a selenocyana o mo i ei he a
C-4 o C-6 posi ion, Mis a’s g oup accomplished he p epa a ion o non-symme ical and
non-glycosidic pseudodisaccha ides connec ed h ough a selenide (246) [148] o a
diselenide (247) [149] e he (Figu e 18). In bo h cases, he key s ep is he educ ion o he
selenocyana o g oup wi h hyd azine hyd a e o gi e a ansien and eac i e suga sele-
nide, which aps a suga iodide o i la e o 246, o a symme ical suga diselenide o
gi e 247. Addi ionally, ea men o a 6-iodo suga de i a i e wi h a symme ical suga
diselenide, CS2 and Na2S·9H2O affo ded a pseudo disaccha ide wi h a S-Se linkage (e.g.,
248) [150]. When he lea ing g oup is loca ed on he anome ic posi ion (ace ob omo al-
Figu e 18. Miscellaneous selenosuga s.
4. Te-Con aining Ca bohyd a es
Tellu ium was i s iden i ied by on Reichs ein in 1782, while he syn hesis o he
i s o gano ellu ium compounds (dialkyl ellu ides) was achie ed in 1840 by Wöhe [
151
].
Howe e , signi ican ad ances in he ield o o gano ellu ium chemis y did no occu un il
he 1980s, oughly a decade a e o ganoselenium chemis y did [
152
]. This delay can be
a ibu ed o he ac ha low-molecula weigh o gano ellu ium de i a i es a e ypically
ola ile, malodo ous and pe cei ed as oxic subs ances [
152
]. Ini ially conside ed as an
ex ension o Se-con aining isome s, o gano ellu ium chemis y has since unlocked new
syn he ic possibili ies [
153
]. The syn hesis and applica ions o o gano ellu ium de i a i es
a e cu en ly being explo ed in a wide ange o a eas, including o gano- and me al-based
ca alysis [
154
,
155
], bioca alys s [
156
], Ma e ial Science [
157
–
159
], and Medicinal Chem-
is y [160,161], among o he s.
4.1. Tellu osuga s
When i comes o ca bohyd a e mime ics, he numbe o ellu ium-con aining sac-
cha ides is signi ican ly smalle compa ed o hei hio- and seleno coun e pa s. In hese
de i a i es, ellu ium has been inco po a ed in di e en posi ions o he ca bohyd a e
skele on, such as he endocyclic posi ion, he aglycon esidue, o o he speci ic si es, like
he C-5 posi ion o xylo u anoses (p o ec ing agen s agains oxida i e s ess in
in i o
expe imen s) [162], o C-2 and C-6 posi ions o cyclodex ins (as GPx mimics) [163].
Inspi ed by he p omising an ioxidan p ope ies o selenosuga s, Schiesse and co-
wo ke s epo ed [
11
,
164
] he p epa a ion o isos e ic 4- ellu o u anoses (252,255,257–259),
5- ellu opy anoses 260–262 and 6- ellu epane 256 as wa e soluble ca bohyd a e mimics.
These compounds we e accessed using na u ally occu ing ca bohyd a es wi h di e en
con igu a ion as s a ing ma e ials. They key s ep o hei syn heses in ol ed a double
nucleophilic subs i u ion eac ion on dimesyla ed aldi ols (e.g., 250,253,254) exe ed by
eshly p epa ed NaHTe (Scheme 46). NaHTe was in u n ob ained by educing elemen al Te
Molecules 2025,30, 2053 41 o 54
wi h NaBH
4
. The nucleophilic displacemen eac ion was ound o p oceed mo e e icien ly
when poly e hylene glycol (PEG-400) was used as sol en . Addi ionally, he choice o
he p o ec ing g oup played a c ucial ole in he ou come o he eac ion. Whe eas O-
benzyla ed ellu osuga s 260–262 could no be dep o ec ed [
164
] o yield he co esponding
unp o ec ed ca bohyd a e mimics, ace als we e success ully emo ed upon ea men wi h
TFA. 5-Tellu opy anose 260 was ound o be highly uns able, e en when p ese ed in
he eeze , and spon aneously unde wen decomposi ion, wi h elease o elemen al Te;
in o de o demons a e he o ma ion o 260, i was ans o med in o dib omo ellu ium
de i a i e 261, upon eac ion wi h B 2.
Molecules 2025, 30, x FOR PEER REVIEW 42 o 58
D-Mannose
OMs
O
OOMs
H
O
O
Te + NaBH4
NaHTe
Te
OO
H
O
O
PEG-400
TFA
H2OCH2Cl2
Te
HO OH
H
HO
OH
250 251 252
(34% om 250)
D-Galac ose OMs
O
OOMs
H
O
O
253
+
OMs
MsO
O
O
O
O
Te
HO OH
H
HO
OH
255
(32% om 253)
254
Te
OH
HO
OH
HO
256
(53% om 254)
Te
HO OH
H
HO
OH
257
( om L-mannose)
Te
HO OH
H
HO
OH
258
( om D-gulonic acid 1,4-
lac one, uns able)
Te
HO OH
H
HO
259
( om 2,3-di-O-isop opylidene-
D- ibonic acid 1,4-lac one)
X
OBn
OBn
BnO
260 (X = Te)
( om D-a abinose)
261 (X = TeB 2)
Te
OBn
OBn
BnO
262
( om L-a abinose)
B 2
Scheme 46. P epa a ion o ellu osuga s by nucleophilic subs i u ion on di-O-mesylaldi ols.
Addi ionally, acemic ans-3,4-dihyd oxy-1- ellu olane 263 was ob ained [11] in al-
mos quan i a i e yield by nucleophilic eac ion o bu a-1,3-diene bisepoxide 123 wi h aq.
NaHTe (Scheme 47). Al e na i ely, Cappe ucci and cowo ke s epo ed [165] he syn he-
sis o 263 unde on wa e condi ions and using ongali e (sodium hyd oxyme hanesul-
ina e) o educe in si u elemen al Te o Na2Te as he nucleophile (Scheme 47). Compound
263 is he Te-isos e o DHS ed 124, a selenosuga mime ics endowed wi h s ong an ioxi-
dan p ope ies, as conside ed in he p eceden sec ion.
Scheme 47. P epa a ion o ans-3,4-dihyd oxy-1- ellu olane 263.
Tellu osuga s 252, 256, 257, 259 and 263 we e assayed [11] o hei sca enging p op-
e ies agains common oxidan agen s like hypochlo ous, hypob omous and pe oxy-
ni ous acids (HOCl, HOB and ONOOH, espec i ely), gene a ed by he in lamma o y
enzyme myelope oxidase. An ioxidan p ope ies agains HOCl and HOB we e de e -
mined using a compe i ion kine ics assay, while s opped- low spec oscopy was used o
Scheme 46. P epa a ion o ellu osuga s by nucleophilic subs i u ion on di-O-mesylaldi ols.
Addi ionally, acemic ans-3,4-dihyd oxy-1- ellu olane 263 was ob ained [
11
] in al-
mos quan i a i e yield by nucleophilic eac ion o bu a-1,3-diene bisepoxide 123 wi h aq.
NaHTe (Scheme 47). Al e na i ely, Cappe ucci and cowo ke s epo ed [
165
] he syn hesis
o 263 unde on wa e condi ions and using ongali e (sodium hyd oxyme hanesul ina e)
o educe in si u elemen al Te o Na
2
Te as he nucleophile (Scheme 47). Compound 263
is he Te-isos e o DHS
ed
124, a selenosuga mime ics endowed wi h s ong an ioxidan
p ope ies, as conside ed in he p eceden sec ion.
Tellu osuga s 252,256,257,259 and 263 we e assayed [
11
] o hei sca enging p ope -
ies agains common oxidan agen s like hypochlo ous, hypob omous and pe oxyni ous
acids (HOCl, HOB and ONOOH, espec i ely), gene a ed by he in lamma o y enzyme
myelope oxidase. An ioxidan p ope ies agains HOCl and HOB we e de e mined using
a compe i ion kine ics assay, while s opped- low spec oscopy was used o moni o ing
eac ion wi h ONOOH. 3,4-Dihyd oxy-1- ellu olane 263 exhibi ed he bes an ioxidan
p o ile agains HOCl and ONOOH, whe eas 4- ellu o u anose 259 was he bes sca enge
Molecules 2025,30, 2053 48 o 54
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