Mechanism investigations of the activation process of S-2-[(propan-2-yl)sulfinyl]benzyl (SPSB) glycosides

Article abstract of DOI:10.1080/07328303.2018.1541998

In our recently developed interrupted Pummerer reaction mediated (IPRm) glycosylation with S-2-[(propan-2-yl)sulfinyl] benzyl (SPSB) glycosides as glycosyl donors, the anomeric leaving groups were recovered in the forms of thiosulfinate, disulfide and thi

Full text of DOI:10.1080/07328303.2018.1541998

Journal of Carbohydrate Chemistry
ISSN: 0732-8303 (Print) 1532-2327 (Online) Journal homepage: https://www.tandfonline.com/loi/lcar20
Mechanism investigations of the activation
process of S-2-[(propan-2-yl)sulfinyl]benzyl (SPSB)
glycosides
Wei Chen, Jing Zeng, Zhiwen Liao, Shuang Teng, Xiong Xiao, Lingkui Meng &
Qian Wan
To cite this article: Wei Chen, Jing Zeng, Zhiwen Liao, Shuang Teng, Xiong Xiao, Lingkui
Meng & Qian Wan (2019): Mechanism investigations of the activation process of S-2-
[(propan-2-yl)sulfinyl]benzyl (SPSB) glycosides, Journal of Carbohydrate Chemistry, DOI:
10.1080/07328303.2018.1541998
To link to this article: https://doi.org/10.1080/07328303.2018.1541998
Published online: 20 Feb 2019.
Submit your article to this journal
Article views: 8
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=lcar20

JOURNAL OF CARBOHYDRATE CHEMISTRY
https://doi.org/10.1080/07328303.2018.1541998
Mechanism investigations of the activation process of
S-2-[(propan-2-yl)sulfinyl]benzyl (SPSB) glycosides
Wei Chena, Jing Zenga , Zhiwen Liaoa, Shuang Tenga, Xiong Xiaoa,
Lingkui Menga, and Qian Wana,b
aHubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of
b
Pharmacy, Huazhong University of Science and Technology, Wuhan, Hubei, China; Institute of
Brain Research, Huazhong University of Science and Technology, Wuhan, Hubei, China
ABSTRACT
ARTICLE HISTORY
Received 5 August 2018
Accepted 25 October 2018
In our recently developed interrupted Pummerer reaction
mediated (IPRm) glycosylation with S-2-[(propan-2-yl)sulfinyl]
benzyl (SPSB) glycosides as glycosyl donors, the anomeric
leaving groups were recovered in the forms of thiosulfinate,
disulfide and thiosulfonate. These products were presumed to
be obtained by the hydrolysis and disproportionation of a cyc-
lic thio-sulfonium intermediate. In this study, mass spectrom-
etry and 1H NMR studies were carried out which confirmed
that the cyclic thio-sulfonium intermediate exists. Further 18O
isotopic labeling reactions revealed that the cyclic thio-sulfo-
nium ion was hydrolyzed to thiosulfinate which further dispro-
portionated to disulfide and thiosulfonate. This study clarifies
the activation process of the SPSB glycosides involved glycosy-
lation reactions.
KEYWORDS
Glycosylation; sulfoxide;
interrupted Pummerer
reaction; isotopic labeling;
disproportionation
GRAPHICAL ABSTRACT
CONTACT Qian Wan
wanqian@hust.edu.cn
Hubei Key Laboratory of Natural Medicinal Chemistry and
Resource Evaluation, School of Pharmacy; Institute of Brain Research, Huazhong University of Science and
Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lcar.
ß 2018 Taylor & Francis Group, LLC

2
W. CHEN ET AL.
Scheme 1. Selected glycosylation reactions with OPSB and SPSB glycosyl donors.
Introduction
Sulfoxides have long been widely used in chemical synthesis but were not
introduced in carbohydrate chemistry as glycosyl donors until the 1980s by
Kahne and co-workers.[1] Since then, activation of glycosyl sulfoxides has
become one of the most powerful methods for construction of glycosidic
bonds.[2–4] However, the commonly used glycosyl sulfoxide donors always
incorporated the sulfinyl groups at the anomeric position which sometimes
resulted in instability problems. Recently, we have developed two kinds of
new sulfoxide donors with sulfinyl groups located at a site remote to the
anomeric position: O-2-[(propan-2-yl)sulfinyl]benzyl (OPSB) glycosides
(1a) applicable for armed and super-armed glycosides[5–7] and S-2-
[(propan-2-yl)sulfinyl]benzyl (SPSB) glycosides (1b) suitable for dis-armed
glycosides (see Scheme 1).[8–10] These two sulfoxide donors exhibited high
efficiency in the construction of glycosidic bonds especially in the synthesis
of complex oligosaccharides and glycoconjugates, due to their comparative
stability and the ability to employ latent-active glycosylation strategies. We
have successfully synthesized a series of bioactive phenylethanoid glyco-
sides[5,11] and we are currently working on the total synthesis of complex
macrolide resin glycosides using these glycosyl donors.[12]
A proposed simplified activation pathway of O/S-PSB donors is illustrated
in Scheme 2 (eq a). The initial step is the activation of phenyl sulfoxide by
Tf2O to form a transient intermediate A. The attack of the benzylic oxygen
or sulfur atom on the cationic sulfur atom via an interrupted Pummerer
reaction (IPR) pathway yields oxocarbenium ion B and cyclic sulfonium
intermediate 4a or 4b. In these glycosylation reactions with OPTB glycosides,
the O-2-[(propan-2-yl)sulfinyl]benzyl group was transformed to 2-[(propan-
2-yl)sulfanyl]benzyl alcohol 5 (Scheme 2b), while the glycosylation reaction
with SPSB glycosides delivered the S-2-[(propan-2-yl)sulfinyl]benzyl group to
thiosulfinate 7, thiosulfonate 8 and disulfide 9. Thiosulfonate 8 and disulfide

JOURNAL OF CARBOHYDRATE CHEMISTRY
3
Scheme 2. Proposed mechanism for activation of OPSB and SPSB glycosyl donors.
9 were always isolated in nearly a 1:1 ratio (Scheme 2c). We have demon-
strated that cyclic oxo-sulfonium ion 4a was hydrolyzed to furnish 5 (PSB-
OH) during the work-up process.[13] Despite high structural similarity of
thio-sulfonium ion 4b and oxo-sulfonium ion 4a, the further transformation
of 4b during the glycosylation and work-up process is much more complex
than that of 4a. In our original research paper,[8] we have proposed two
plausible pathways to generate thiosulfinate 7, thiosulfonate 8 and disulfide
9. Herein, we describe our further studies on the formation and transform-
ation of 4b based on MS, NMR, and isotopic labeling studies.
Results and discussion
The thiosulfonium 4b and sulfenyl triflate 4b0 were proposed as key in situ
generated electrophiles during the activation of remote sulfoxide. When an
electrophile scavenger 10, 4-allyl-1, 2-dimethoxybenzene (ADMB), was
added to the glycosylation reaction between 1b and 2b under the standard
reaction conditions, the desired disaccharide 3b was obtained in excellent
yield and the glycosidic bond generation was not disturbed by addition of
10. In addition, an episulfonium ion 11 was detected in this reaction by
high resolution mass spectrometry (Scheme 3a). The coupling of SPSB
glycoside 1b and thiosugar 12 in a one-pot procedure provided thio-disac-
charide 13 in moderate yield (Scheme 3b). This result indicated that the
electrophilic 4b and 4b0 were much less active than the well-known phenyl
sulfenyl triflate (PhSOTf) and can be orthogonal with thioglycoside.

4
W. CHEN ET AL.
Scheme 3. Capture the cyclic thio-sulfonium ion intermediate.
Meanwhile, electrophilic 4b or 4b0 could be trapped by nucleophilic thiol
12. Consequently, an asymmetric disulfide 14 was isolated in 25% yield.
Upon exposure of the SPSB glycoside 1b alone to Tf2O, the resulting reac-
tion mixture was subjected directly to MS detection. A peak at 197.0468
(m/z) was observed. It was a match to the calculated molecular weight
(197.0453) of 4b (Scheme 3c). This observation suggested that 4b was very
likely to be generated in the reaction system and it was quite stable.
However, the presence of sulfenyl triflate 4b0 could not be excluded based
on the aforementioned experiments.
In our previous studies,[8] it was found that activation of sulfoxide 15
with Tf2O followed by quenching with water also furnished thiosulfinate 7,
thiosulfonate 8 and disulfide 9 with similar isolated yields. This phenom-
enon indicated that the activation of SPSB glycosides and sulfoxide 15
might form the same intermediate 4b (Figure 1(a)). Later, this speculation
was confirmed by the observation of MS peak at 197.0477 (m/z). The activa-
tion of asymmetric sulfoxide 15 with Tf2O in CD2Cl2 at 0 ˚C was measured
1
by H NMR (Figure 1(b)). It was found that a clean and single compound
was presented in the NMR tube after 30min activation (Figure 1(e)). The
1H NMR spectra showed that the signal of isopropyl proton moved down-
0
00
field from 2.86 ppm (Ha) and 3.28ppm (Ha ) respectively to 3.97 ppm (Ha ),
and the signal of benzylic proton moved downfield from 3.72 (Hb) ppm and
0
00
3.95ppm (Hb ) respectively to 4.98 ppm (Hb ). These results suggested that
isopropyl group in the intermediate was linked to a sulfur atom with a

JOURNAL OF CARBOHYDRATE CHEMISTRY
5
Figure 1. NMR study on cyclic thio-sulfonium ion intermediate 4b: (a) Alternative pathway to
generate 4b from sulfoxide 15 (b) Activation of 15 in CD2Cl2 leads to 4b; (c) IPRm glycosylation
1
1
of 16 with 17 (d) H NMR spectrum of sulfoxide 15; (e) H NMR spectrum of cyclic thiol-sulfo-
1
nium 4b; (f) H NMR spectrum of glycosylation of 16 with 17.
positive charge and the structure of the intermediate was most likely to be
stable cyclic thio-sulfonium 4b.[14] At this stage, the presence of reactive sul-
1
fenyl triflate 4b0 in quantities detected by H NMR could be excluded defini-
1
tively. Additionally, a H NMR spectrum of coupling reaction between SPSB
glycoside 16 and acceptor 17 was measured. In this experiment, all the sig-
nals of 4b were clearly found in the spectrum of the reaction mixture.
Consequently, we could conclude that the leaving group SPSB was trans-
ferred to a stable cyclic thio-sulfonium intermediate 4b after activation.

6
W. CHEN ET AL.
Scheme 4. (a) Quenching of the thio-sulfonium intermediate 4b with H218O; (b) Outline of acti-
vation of SPSB glycoside.
Having confirmed the existence of the cyclic thio-sulfonium 4b in the
glycosylation reactions, we then commenced to determine the transform-
ation process from the intermediate 4b to thiosulfinate 7, thiosulfonate 8
and disulfide 9. To this end, H218O was introduced as an isotopic labeling
reagent to quench the intermediate. HRMS analysis of the reaction mixture
revealed the formation of the thiosulfinate 70, thiosulfonate 80 and disulfide
9. Among them, it was found that almost all the oxygen atoms of thiosulfi-
nate 70 and thiosulfonate 80 had been labeled by 18O.[15] This result indi-
cated that thiosulfinate and thiosulfonate were generated by hydrolysis of
the cyclic thio-sulfonium intermediate 4b. Considering that the thiosulfo-
nate 8 and disulfide 9 were always isolated in a 1:1 ratio and thiosulfinate
essentially prior to disproportionation,[16–19] it was reasonable to deduce
that these two compounds were produced from thiosulfinate 7 by dispro-
portionation. This disproportionation reaction was observed upon standing
of the thiosulfinate 7. The isotopic labeling of thiosulfinate 7 also implied
that H2O attacked the benzylic sulfur atom of intermediate 4b to produce
sulfenic acid 6. Then, a self-condensation of acid 6 possibly occurred to
form thiosulfinate 7 (Scheme 4a).[16,20]
Finally, based on the above observations, we concluded that, in the gly-
cosylation reaction with SPSB glycosides, the SPSB leaving group was trans-
formed to cyclic thio-sulfonium ion 4b upon activation with Tf2O through
an interrupted Pummerer reaction pathway. This intermediate might fur-
ther hydrolyze to sulfenic acid 6 which underwent self-condensation to

JOURNAL OF CARBOHYDRATE CHEMISTRY
7
produce thiosulfinate 7. Further disproportionation of thiosulfinate 7 gen-
erated thiosulfonate 8 and disulfide 9. The NMR, HRMS and isotopic label-
ing studies provided substantial evidence for the existence of the cyclic
thio-sulfonium ion intermediate and its hydrolysis process, which clarified
the activation mode of SPSB glycosides (Scheme 4b).
Experimental section
General experimental methods
NMR spectra were recorded on Bruker AM-400 spectrometer (400 MHz)
1
and Bruker Ascend TM-600 spectrometer (600 MHz), and the H and 13C
NMR chemical shifts were referenced to the solvent or solvent impurity
peaks for CDCl3 at d H 7.24 and d C 77.23, CD2Cl2 at d H 5.23 and d C
54.00 High resolution mass spectras were recorded on a Bruker micro TOF
II spectrometer using electrospray ionization (ESI). All reagents and sol-
vents were of pure analytical grade. Thin layer chromatography (TLC) was
performed on silica-gel-coated TLC plates (Yantai Chemical Industry
Research Institute) and revealed with either a UV lamp (kmax ¼ 254 nm) or
by spraying with 10% H2SO4 (10% H2SO4 in ethanol) and subsequent char-
ring by heating. Column chromatography was performed using silica gel
(Qingdao Marine Chemical Inc., China).
Materials
Prior to running the glycosylation reactions, all reagents except Tf2O and
those with low boiling point (<180 ꢀC) were dried by repeated azeotropic
removal of water using toluene and
a
rotary solvent purifier.
Trifluoromethanesulfonic anhydride (Tf2O) was purchased from Adamas
and TCI. H218O was purchased from J&K Scientific. Other reagents were
purchased from Adamas or Acros Company.
Detection of the cyclic thio-sulfonium ion intermediate 4b by activation of
asymmetric sulfoxide 15
The asymmetric sulfoxide (15) (12 mg, 0.030 mmol) was dissolved in
CD2Cl2 (0.6 mL) at 0 ꢀC, followed by addition of Tf2O (6.0 mL,
1
0.036 mmol), after 30 min, the H NMR, 13C NMR spectrum and HMQC
1
were acquired. H NMR (400 MHz, CD2Cl2): d 7.91 (1H, d, J ¼ 8.0 Hz),
7.73-7.56 (3H, m), 4.98 (2H, brs), 3.97 (1H, h, J ¼ 6.4 Hz), 1.34 (6H, brs).
13C NMR (100 MHz, CD2Cl2): d 143.0, 134.8, 131.1, 128.6, 128.2, 127.5,
59.8, 45.8, 17.5 (low-intensity multiplet). HRMS calcd for C10H13S2 [M]þ
197.0453, found 197.0477.

8
W. CHEN ET AL.
Funding
We thank the National Natural Science Foundation of China [21672077, 21761132014,
21772050, 21702068], the State Key Laboratory of Bio-organic and Natural Products
Chemistry [SKLBNPC7425], Natural Science Funds of Hubei Province for Distinguished
Young Scholars [2015CFA035], Wuhan Creative Talent Development Fund, “Thousand
Talents Program” Young Investigator Award, and Huazhong University of Science and
Technology for support.
ORCID
Jing Zeng
Qian Wan
http://orcid.org/0000-0001-9116-9861
http://orcid.org/0000-0001-9243-8939
References
[1] Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. Glycosylation of unreactive sub-
strates. J. Am. Chem. Soc. 1989, 111, 6881–6882. DOI: 10.1021/ja00199a081.
[2] Aversa, M. C.; Barattucci, A.; Bonaccorsi, P. Glycosulfoxides in carbohydrate chem-
istry. Tetrahedron, 2008, 64, 7659–7683. DOI: 10.1016/j.tet.2008.05.051.
[3] Fascione, M. A.; Brabham, R.; Turnbull, W. B. Mechanistic investigations into the
application of sulfoxides in carbohydrate synthesis. Chem. Eur. J. 2016, 22,
3916–3928. DOI: 10.1002/chem.201503504.
[4] Crich, D.; Bowers, A.-A. Sulfoxides, Sulfimides and Sulfones. In Handbook of
Chemical Glycosyaltion; Demchenko, A.-V., Eds.; Wiley-VCH Verlag Gmbh & Co.
KGaA: Weinheim, 2008, pp 303–329.
[5] Shu, P.; Xiao, X.; Zhao, Y.; Xu, Y.; Yao, W.; Tao, J.; Wang, H.; Yao, G.; Lu, Z.;
Zeng, J.; Wan, Q. Interrupted Pummerer reaction in latent-active glycosylation: gly-
cosyl donors with a recyclable and regenerative leaving group. Angew. Chem. Int.
Ed. 2015, 54, 18432–18436. DOI: 10.1002/anie.201507861.
[6] Shu, P.; Wang, H.; Xiao, X.; Sun, J.; Zhao, X.; Zhao, Y.; Xu, Y.; Tao, J.; Yao, G.;
Zeng, J.; Wan, Q. Glycosylation via remote activation of anomeric leaving groups:
development of 2-(2-propylsulfinyl)benzyl glycosides as novel glycosyl donors. Org.
Chem. Front. 2016, 3, 177–183. DOI: 10.1039/C5QO00359H.
[7] Zeng, J.; Sun, G.; Zhu, Y.; Wang. R.; Cai, L.; Liu, K.; Zhang, Q.; Liu, X.; Wan. Q. 3-
Aminodeoxypyranoses in Glycosylation: diversity-oriented synthesis and assembly in
oligosaccharides. Angew. Chem. Int. Ed. 2017, 56, 5227–5231. DOI: 10.1002/
anie.201700178.
[8] Xiao, X.; Zhao, Y.; Shu, P.; Zhao, X.; Liu, Y.; Sun, J.; Zhang, Q.; Zeng, J.; Wan, Q.
Remote activation of disarmed thioglycosides in latent-active glycosylation via inter-
rupted Pummerer reaction. J. Am. Chem. Soc. 2016, 138, 13402–13407. DOI:
10.1021/jacs.6b08305.
[9] Xu, Y.; Zhang, Q.; Xiao, Y.; Wu, P.; Chen, W.; Song, Z.; Xiao, X.; Meng, L.; Zeng,
J.; Wan, Q. Practical synthesis of latent disarmed S-2-(2-propylthio) benzyl glyco-
sides for interrupted Pummerer reaction mediated glycosylation. Tetrahedron Lett.
2017, 58, 2381–2384. DOI: 10.1016/j.tetlet.2017.05.014.
[10] Meng, L.; Zeng, J.; Wan, Q. Interrupted Pummerer reaction in latent/active glycosy-
lation. Synlett 2018, 29, 148–156. DOI: 10.1055/s-0036-1588582.

JOURNAL OF CARBOHYDRATE CHEMISTRY
9
[11] Jimenez, C.; Riguera, R. Phenylethanoid glycosides in plants: structure and biological
activity. Nat. Prod. Rep. 1994, 11, 591–606. DOI: 10.1039/NP9941100591.
[12] Lilia, C.; Rogelio, P.-M.; Mabel, F.-S.; Nadia, J.-H.; Glenn, W, K.; Simon, G.
Inhibitors of bacterial multidrug efflux pumps from the resin glycosides of ipomoea
murucoides. J. Nat. Prod. 2008, 71, 1037–1045. DOI: 10.1021/np800148w.
[13] Chen, W.; Zeng, J.; Wang, H.; Xiao, X.; Meng, L.; Wan, Q. Tracking the leaving
group in the remote activation of O-2-[(propan-2-yl)sulfinyl]benzyl (OPSB) glyco-
side. Carbohydr. Res. 2017, 452, 1–5. DOI: 10.1016/j.carres.2017.09.07.
[14] Morgan, D. L.; Stokes, C. D. Meierhoefer, M. A.; Storey, R. F. Sulfonium ion
adducts from quasiliving polyisobutylene and mono- or disulfides. Macromol., 2009,
42, 2344–2352. DOI: 10.1021/ma802812m.
[15] The 18O labeled thiosulfinate 7’ transformed to 16O-thiosulfinate 7 after purification
by column chromatography on silica gel.
[16] Davis, F. A.; Jenkins, R. H. Acids chemistry of sulfenic acids. 2. Formation of hydro-
gen peroxide from sulfenic acids. J. Am. Chem. Soc. 1980, 102, 7967–7971. DOI:
10.1021/ja00547a039.
[17] Kice, J. L.; Large, G. B.; Synthesis of optically active phenyl benzenethiolsulfinate by
asymmetric oxidation of phenyl disulfide. Tetrahedron Lett. 1965, 6, 3537–3541.
DOI: 10.1016/S0040-4039(01)99535-8.
[18] Moore, T. L.; O’Connor, D. E. Reaction of methanesulfenyl chloride with alkoxides
and alcohols. Preparation of aliphatic sulfenate and sulfinate esters. J. Org. Chem.
1966, 31, 3587–3592. DOI: 10.1021/jo01349a027.
[19] Ju, T.-L.; Kice, J. L.; Venier, C. G. Mechanisms of reactions of thiolsulfinates (sul-
fenic anhydrides). 4. Acid- and sulfide-catalyzed decomposition of tert-butyl benze-
nethiolsulfinate. J. Org. Chem. 1979, 44, 610–614. DOI: 10.1021/jo01318a026.
[20] Graber, D. R.; Morge, R. A.; Sih, J. C. Reaction of 2-(alkylsulfinyl)-, 2-(arylsulfinyl)-,
and 2-(aralkylsulfinyl)benzimidazoles with thiols: a convenient synthesis of unsym-
metrical disulfides. J. Org. Chem. 1987, 52, 4620–4646. DOI: 10.1021/jo00229a039.