Remote Activation of Disarmed Thioglycosides in Latent-Active Glycosylation via Interrupted Pummerer Reaction

Article abstract of DOI:10.1021/jacs.6b08305

S-glycosides, S-2-(2-propylthio)benzyl (SPTB) glycosides, were converted to the corresponding oxidized glycosyl donors, S-2-(2-propylsulfinyl)benzyl (SPSB) glycosides, by simple and selective oxidation. Treatment of disarmed SPSB donor and various acceptors with triflic anhydride provided the desired glycosides in good to excellent yields. Meanwhile, observation of thiosulfinate, thiosulfonate, and disulfide suggested that the leaving group was activated via an interrupted Pummerer reaction. The disarmed SPSB thioglycosyl donors could be selectively activated in the presence of various thioglycosides with remote activation mode. Finally, two natural hepatoprotective glycosides, Leonoside E and Leonuriside B, were efficiently synthesized in a convergent manner with this newly developed method.

Full text of DOI:10.1021/jacs.6b08305

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Article
Remote Activation of Disarmed Thioglycosides in Latent-
Active Glycosylation via Interrupted Pummerer Reaction
Xiong Xiao, Yueqi Zhao, Penghua Shu, Xiang Zhao, Yan
Liu, Jiuchang Sun, Qian Zhang, Jing Zeng, and Qian Wan
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b08305 • Publication Date (Web): 12 Sep 2016
Downloaded from http://pubs.acs.org on September 13, 2016
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Remote Activation of Disarmed Thioglycosides in Latent-Active Gly-
cosylation via Interrupted Pummerer Reaction
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Xiong Xiao,† Yueqi Zhao,† Penghua Shu,† Xiang Zhao,† Yan Liu,† Jiuchang Sun,† Qian Zhang,† Jing
Zeng,† Qian Wan*,†,‡
†Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Huazhong Universiꢀ
ty of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, P. R. of China
‡Institute of Brain Research, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030,
P. R. of China
ABSTRACT: Sꢀglycosides, Sꢀ2ꢀ(2ꢀpropylthio)benzyl (SPTB) glycosides, were converted to the corresponding oxidized glycosyl
donors, Sꢀ2ꢀ(2ꢀpropylsulfinyl)benzyl (SPSB) glycosides, by a simple and selective oxidation. Treatment of disarmed SPSB donor
and various acceptors with triflic anhydride provided the desired glycosides in good to excellent yields. Meanwhile, the observation
of thiosulfinate, thiosulfonate and disulfide suggested that the leaving group was activated via an interrupted Pummerer reaction.
The disarmed SPSB thioglycosyl donors could be selectively activated in the presence of various thioglycosides with remote activaꢀ
tion mode. Finally, two natural hepatoprotective glycosides, Leonoside E and Leonuriside B, were efficiently synthesized in a conꢀ
vergent manner with this newly developed method.
■ INTRODUCTION
Huang,11e Wang,11f Demchenko,11g Yu11h and our own.11i The
advantage of latentꢀactive strategy may streamline the global
efficiency of oligosaccharide assembly process.10
Although 1ꢀthioglycosides occur rarely in nature, they are
widely used as important glycosylation donors in constructing
a broad range of glycosidic linkages.1 Ever since the first glyꢀ
cosylation reaction with a thioglycosyl donor was reported in
1973,2 the improvement of corresponding leaving groups, varꢀ
ious promoters, different activation conditions and strategies
etc. has become a prominent subject in carbohydrate research.3
In most of the reported cases, the initial activation takes place
on the anomeric sulfur atom (direct activation),4 whereas actiꢀ
vation of thioglycosides in remote mode is rare.5 Nearly twenꢀ
ty years ago, Kunz and Leuck employed Sꢀpentꢀ4ꢀenyl thioꢀ
glycosides as donors to construct Oꢀglycosyl amino acids.6
Because soft electrophiles can be either attacked by the anoꢀ
meric sulfur atom or by the tethered double bond, the real
mode of activation remains unsolved. In 2012, based on the
success of Yu glycosylation,7 Yu and coꢀworkers reported an
Au(I)ꢀcatalyzed glycosylation in a remote activation mode
with orthoꢀalkynylphenyl thiolglycosides.8a Later, Zhu group
succeeded in using Sꢀbutꢀ3ꢀynyl thioglycoside as thioglycosyl
donor.8b,c Most recently, Ragains et al. designed a novel Sꢀ
Recently, our research laboratories have developed an Oꢀ
benzyl glycoside, Oꢀ2ꢀ(2ꢀpropylthio)benzyl (OPTB) glycoꢀ
side, and an oxidized Oꢀbenzyl glycoside, Oꢀ2ꢀ(2ꢀ
propylsulfinyl)benzyl (OPSB) glycoside, which can be emꢀ
ployed in the synthesis of oligosaccharides with latentꢀactive
concept.11i The latent glycosides can be converted to the correꢀ
sponding active oxidized glycosides by a simple and efficient
oxidation.11c, 11i, 12 Treatment of the oxidized Oꢀbenzyl glycoꢀ
sides and acceptors with triflic anhydride provided desired
glycosidic linkages in good to excellent yields (Scheme 1a).
We revealed that the leaving group was remotely activated by
an interrupted Pummerer reaction.13,14,15 Despite significant
progress, only armed and superarmed glycosyl donors16 bearꢀ
ing the oxidized Oꢀbenzyl leaving group can be successfully
activated to unleash the desired oxocarbenium. In contrast, the
disarmed glycosides usually yield unproductive side products:
intermolecular Pummerer reaction adducts.17
Herein, we disclose a novel strategy combines oxidized Sꢀ
benzyl glycosides, namely S-2ꢀ(2ꢀpropylsulfinyl)benzyl glycoꢀ
sides (SPSB), and remote activation via interrupted Pummerer
reaction to efficiently construct glycosidic bonds with disꢀ
armed glycosyl donors. In this report, we will provide detailed
information about a strategy for selective thioether oxidation,
mechanistic studies of remote activation, the scope of this
glycosylation, and convergent assemblies of Leonuriside B
and Leonoside E.18
butenyl
glycosyl
donor,
4ꢀpꢀmethoxyphenylꢀ3ꢀ
butenylthioglucoside, for a remote activation approach.8d In
this method, the armed and superarmed Sꢀbutenyl glycosyl
donors could be activated efficiently under visibleꢀlight irradiꢀ
ation in the presence of stoichiometric amount of Umemoto’s
reagent.
Another milestone in this field was made in 1992 by Roy and
his colleagues who introduced a latentꢀactive glycosyl syntheꢀ
sis strategy arising from the investigation of pꢀ
acetamidophenyl thioglycosides and pꢀnitrophenyl thioglycoꢀ
side.9 In this strategy, a latent leaving group (LG) is inert to
the activation condition of the active LG, and is able to be
activated in the subsequent glycosylation under appropriate
conditions.10 In the past twenty years, this concept has been
further enriched by FraserꢀReid,11a Boons,11b,c Kim,11d
■ RESULTS AND DISCUSSION
First, we evaluated the reactivity of the oxidized Sꢀbenzyl
glycosyl donor 2a with glycosyl acceptor 3b. Following a
previously established activation protocol for superarmed
OPSB glycosyl donor 1, triflic anhydride (Tf2O, 1.2 equiv)
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was added to a solution of 2a (1.2 equiv) and 3b (1.0 equiv) in suggested that the in situ produced disulfide 10 is a possible
CH2Cl2 in the presence of 4 Å molecular sieves (M.S.) at 0 oC.
The reaction completed in 30 min and provided the desired
disaccharide 4b in 97% yield, along with compounds 6ꢀ8 deꢀ
rived from glycosyl donor’s leaving group (scheme 1b). After
a thorough investigation, the side products were assigned as
thiosulfinate 6 (12%), symmetric disulfide 7 (44%) and thioꢀ
sulfonate 8 (40%), the combined yield of these materials relatꢀ
ed to the leaving group PSBꢀSH is 96%. These results indicatꢀ
ed that the disarmed SPSB glycoside is an eligible glycosyl
donor, but the mechanism of activation may be much more
complex compare to those of OPSB glycosyl donor11i and traꢀ
ditional anomeric sulfoxide donors.19,20,21
precursor of products 6, 7 and 8.27 We then investigated that
whether the anomeric thioether could be activated by intermeꢀ
diate D or 9 by a competitive glycosylation reaction between
two thioglycosyl donors 2a and 11 in the presence of 3b and
1.0 equivalent of Tf2O at 0 oC (Scheme 2c). As expects, disacꢀ
charide 4b was isolated in 95% yield accompanied with 97%
recovered 11. These results clearly indicated that the glycosyl
donor was activated in a tandem fashion initiated from the
remote sulfur atom rather than directly activation at the anoꢀ
meric sulfur atom.
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Scheme 2. Original Hypothesis for Activation
Scheme 1. Remote Activation of Oxidized O/S-benzyl Gly-
cosides
a Yield of isolated product based on the amount of acceptor. b
Yield of isolated product based on the amount of donor.
In 1989, Kahne’s group reported a successful glycosylation
reaction with glycosyl sulfoxides as donors.22a Since then,
application of sulfoxide donors and related sulfonate reagents
in chemical glycosylation has become an intensely pursued
research area. Many outstanding reactions (Kahne glycosylaꢀ
tion,22a Crich βꢀmannosylation,22b Gin oxidative glycosylaꢀ
tion22c and Gin dehydrative glycosylation22d) have been estabꢀ
lished in this field. Based on the elegant mechanistic investigaꢀ
tions of the previous reports,20 a proposed activation pathway
of SPSB donors is illustrated in Scheme 2a. The first step of
the reaction is the activation of phenyl sulfoxide by triflic anꢀ
hydride to form a trifloxylsulfonium ion A. The attack of
anomeric sulfur atom to the cationic sulfur atom leads to a
dithia dication species23 B via an interrupted Pummerer reacꢀ
tion.24 Intermediate B subsequently generates the key oxoꢀ
carbenium ion C and a thiosulfonium ion D which is equivaꢀ
lent to benzyl sulfenyl triflate 9.25 Usually, sulfenyl triflates
are powerful electrophiles1a and they react with the sulfoxide
more rapidly than Tf2O.20a Thus, a putative sulfonium ion E is
possibly formed. The anomeric sulfur atom of intermediate E
then attacks the less hindered cationic sulfur, resulting asymꢀ
metric disulfide 10 and thiosulfinate 6, which may be accountꢀ
able for the generation of disulfide 7 and thiosulfonate 8 via a
disproportionation.26 Given no direct observation of compound
10 in the reaction mixture, we synthesized 10 according to
Scheme S1. Upon treatment with Tf2O and standard workꢀup,
compounds 6, 7 and 8 were isolated in a similar ratio to that in
the glycosylation reaction (Scheme 2b). These observations
The species 9 and its equivalent, thiosulfonium D, were proꢀ
posed as key active species in the aforementioned mechanistic
proposal. The evidences for the formation of these reactive
intermediates were obtained by a trapping experiment
(Scheme 3a).20c When scavenger 12 was added to the glycoꢀ
sylation mixture, episulfonium 13 was detected by highꢀ
resolution MS and subsequent hydrolysis led to the formation
of compound 14 (35%) and 15 (30%). In this experiment, we
were pleased to find that the glycosidic bond generation was
not disturbed by addition of the scavenger, which made 12 an
excellent additive for sensitive substrates. Based on the proꢀ
posed activation mode (scheme 2a), it would be possible to
use substoichiometric Tf2O for the glycosylation reaction.28
However, when triflic anhydride was reduced to 0.5 equivalent,
the glycosylation proceeded in 52% yield, and 46% of SPSB
donor 2a and 47% of acceptor 3b were recovered (Scheme 3b).
These results indicated that Tf2O is the predominant activator
in the glycosylation. Despite highly reactive towards scavenꢀ
ger 12, benzyl sulfenyl triflate 9 and thiosulfonium intermediꢀ
ate D are much less effective than Tf2O in terms of promoting
the desired glycosylation. In light of these findings, we proꢀ
pose that Tf2O first activates the SPSB donor and the resulting
dithia dication ion B decomposes to generate oxocarbenium
ion C and thiosulfonium ion D (Scheme 3c). Subsequent conꢀ
densation between thiosulfonium ion D and sulfenyl triflate 9
provides a new dithia dication ion F (path a), which is responꢀ
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sible for the formation of thiosulfinate 6 upon aqueous workꢀ
up. The sulfenyl triflate 9 could be also hydrolyzed during the
quenching process to form corresponding sulfenic acid H. It is
well know that sulfenic acid condense with themselves to form
thiosulfinate 6 (path b).29 The same disproportionation reaction
provides symmetric disulfide 7 and thiosulfonate 8.
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Scheme 3. Preliminary Mechanistic Proposal
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b
a Yield of isolated product based on two steps. Yield of isoꢀ
lated product based on three steps from 19b: 1) K2CO3 (0.3
equiv), MeOH, rt, 1 h, 2) CSA (0.2 equiv), PhCH(OCH3)2 (1.2
equiv), dry CH3CN, overnight, 3) BzCl (2.4 equiv), NEt3 (3.0
equiv), DMAP (0.1 equiv), dry CH2Cl2. DTT = 1,4ꢀ
dithiothreitol, DMA = dimethylacetamide, CSA = camphorsulꢀ
fonic acid, BzCl = benzoyl chloride.
Table 2. Preparation of Oxidized Thiobenzyl Glycosides:
S-2-(2-propylsulfinyl)benzyl Glycosides.a
a
b
Yield of isolated product. PIFA (1.0ꢀ1.2 equiv), wet
CH3CN, rt, 10 min. cmꢀCPBA (1.0 equiv), dry CH2Cl2, ꢀ20 oC,
30 min. PIFA = bis(trifluoroacetoxy)iodobenzene, mꢀCPBA =
3ꢀchloroperbenzoic acid.
After mechanistic investigation, we turned our attention to
evaluate the application potentials of our methodology. The
preparation of latent Sꢀ2ꢀ(2ꢀpropylthio)benzyl (SPTB) glycoꢀ
sides 19aꢀj, and active SPSB glycosides 2aꢀj were outlined in
table 1 and table 2. Following the procedure recently develꢀ
oped by our group,30 the Sꢀacetyl group of 16aꢀi was selectiveꢀ
ly removed by transthioesterification with 1.5 equivalent of
1,4ꢀdithiothreitol (DTT) in the presence of catalytic amount of
NaHCO3 in DMA. Then the resulting glycosyl thiols 17aꢀi
was Sꢀalkylated with benzyl iodide 18 under basic condition.
In two steps, the disarmed SPTB glycosides 19aꢀi were preꢀ
pared with good to excellent yields. The benzylidene acetal
protected SPTB glycoside 19j was prepared from 19b followꢀ
ing routine protecting group manipulations in three steps.
Table 3. Scope of Reaction.a,b
With latent SPTB glycosides 19aꢀj in hand, we began to inꢀ
vestigate selective oxidation of the phenyl thioethers. In our
previous work, we have demonstrated that OPTB glycoside
could be selectively oxidized to the corresponding OPSB glyꢀ
cosyl donor leaving an Sꢀmethyl group intact by PIFA (1.2
equiv).17 Although it is a daunting task to differentiate a pheꢀ
nyl thioether group from an anomeric methyl thioether group,
we were delight to find that the desired SPSB glycosides 2aꢀj
could be prepared smoothly by selective oxidation with PIFA
or mꢀCPBA.31
Table 1. Preparation of Thiobenzyl Glycosides: S-2-(2-
propylthio)benzyl Glycosides.a
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VIII) there was no unpleasant odor released from the reaction.
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Most importantly, the oxidized SPSB glycosyl donors were
able to couple with thioglycoside, OꢀPTB glycoside and Sꢀ
PTB glycoside to yield corresponding new glycosyl donors (4f
and 4n) or latent O/S benzyl glycosides (4j and 4r), which
could be used in the subsequent glycosylation.
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Scheme 4. Completion of Total Synthesis of Leonuriside B
(28a) and Leonoside E (28c)
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a Yield of isolated product, 2 (1.2 equiv). b Tf2O (1.2 equiv) was
added to the mixture of the glycosyl donor and the acceptor in
o
c
DCM, 0 C, 30 min. Tf2O (1.2 equiv) was added to the solution
of glycosyl donor, ADMB (3.0 equiv) and DTBMP at 0oC, folꢀ
lowed by the addition of acceptor. Additional DTBMP (1.2
d
To further demonstrate the power of this new glycosyl donor
in the synthesis of complex oligosaccharides, we embarked the
total synthesis of Leonoside E, and Leonuriside B (scheme 4).
Leonoside E, F and Leonuriside B were isolated from Chinese
motherwort (Leonurus japonicus Houtt).18 These three natural
products bear a trisaccharide moiety and a phenylethanoid
aglycon. Recently, we have reported a total synthesis and
structural revision of leonoside F, a branched trisaccharide,
with latent and active Oꢀbenzyl glycosides.11i Unfortunately,
we failed to prepare leonoside E, a linear trisaccharide, with
the same strategy because disarmed oxidized Oꢀbenzyl donor
was not able to be activated properly. This time, a convergent
[3+1] approach and two pairs of latentꢀactive glycosides are
equiv) was used. DTBMP = 2,6ꢀdiꢀtert-butylꢀ4ꢀmethylpyridine,
ADMB = 4ꢀallylꢀ1,2ꢀdimethoxybenzene.
Next, we investigated the scope of this new glycosylation
method by coupling of a variety of disarmed SPSB donors 2aꢀ
j with different acceptors (oxoꢀ and mecaptoꢀnucleophiles,
table S4). Many glycosidic bonds could be formed between
the newly developed disarmed glycosyl donors (Glu 2b, Gal
2c, 2ꢀaminoꢀGlu 2d, Man 2e, LꢀRha 2f, lactose 2g and Xyl 2i)
and acceptors (natural occurring steroids, Gluoꢀ2, Gluo-3, Gluoꢀ4,
Gluoꢀ6, Rhaoꢀ4 and Manoꢀ2, Ribofuranoseoꢀ5, Galoꢀ6 and even
Galsꢀ6) in good to excellent yields. From these examples, it is
worth noting that: I) there are some acetyl group migrations
between the donors and acceptors (primary alcohols), and
replacement of the acetyl groups by benzoyl groups inhibited
these side reactions (4l, 4n, 4o, 4s and 4t); II) the less reactive
nucleophiles such as 3a, 3e and 3g could be glycosylated in
excellent yields; III) acid sensitive groups such as acetonide
(4f, 4l, 4s and 4t) and benzylidene (4i, 4j and 4o) were toleraꢀ
ble under current conditions; IV) the thioether groups (4f, 4j,
4n, 4r and 4t) remained intact during the glycosylation; V) the
formation of 4t represented a rare but efficient transthioglycoꢀ
sylation which was hard to achieve by traditional methods;32,1b
VI) in certain cases, when the acceptors were highly sensitive
to electrophiles (diosgenin and cholesterol etc.), the sulfenyl
triflate scavenger 12 was required for optimal yield (4p); VII)
incorporated into our retrosynthesis design. First, the active Lꢀ
arabinosyl SPSB glycoside 2h was coupled with the latent Lꢀ
rhamnosyl OPTB glycoside 20 under the standard reaction
condition to form the αꢀ(1ꢀ›2)ꢀdisaccharide 21 (91%), which
was then oxidized to the active armed OPSB glycosyl donor
22 (90%) by the hypervalent iodine reagent. The resulting
active OPSB donor 22 was coupled with the latent SPTB glyꢀ
coside 23 in the presence of triflic anhydride and a bulky base
(DTBMP) to give αꢀ(1ꢀ›3)ꢀtrisaccharide 24a (73%) along with
an unwanted βꢀ(1ꢀ›3)ꢀtrisaccharide 24b (16%). The latent triꢀ
saccharide 24a was then selectively oxidized to SPSB donor
25 (89%) by treatment of mꢀCPBA at ꢀ20oC. Subsequent glyꢀ
cosylations between the active SPSB donor 25 and aglycons
(26a-c) in a convergent manner produced the phenylethanoid
trisaccharides 27a (95%), 27b (96%) and 27c (95%), respecꢀ
o
o
most reactions were carried out at 0 C rather than ꢀ78 C, a
common practice for complex carbohydrate synthesis;21 and
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(4) Selected references: a) Yu, Y.; Xiong, D.ꢀC.; Mao, R.ꢀZ.; Ye,
tively. Finally, global deprotection furnished the leonuriside B
X.ꢀS. J. Org. Chem. 2016, 81, 7134ꢀ7138; b) Mao, R.ꢀZ.; Xiong, D.ꢀ
C.; Guo, F.; Li, Q.; Duan, J.; Ye, X.ꢀS. Org. Chem. Front. 2016, 3,
737ꢀ743; c) Goswami, M.; Ashley, D. C.; Baik, M.ꢀH.; Pohl, N, L. B.
J. Org. Chem. 2016, 81, 5949ꢀ5962; d) Mao, R.ꢀZ.; Guo, F.; Xiong,
D.ꢀC.; Li, Q.; Duan, J.; Ye, X.ꢀS. Org. Lett. 2015, 17, 5606–5609; e)
Chu, A.ꢀH. A.; Minciunescu, A.; Bennett, C. S. Org. Lett. 2015, 17,
6262ꢀ6265; f) Goswami, M.; Ellern, A.; Pohl, N. L. B. Angew. Chem.
Int. Ed. 2013, 52, 8441ꢀ8445.
(5) Selected Reviews: a) Ranade, S. C.; Demchenko, A. V. J. Car-
bohydr. Chem. 2013, 32, 1ꢀ43; b) El Ashry, E. S. H.; Awad, L. F.;
Atta, A. I. Tetrahedron 2006, 62, 2943ꢀ2998; selected reference: c)
Kaeothip, S.; Pornsuriyasak, P.; Rath, N. P.; Demchenko, A. V. Org.
Lett. 2009, 11, 799ꢀ802. Note: in the literature, the remote activating
sites are usually less than 3 bonds far away from the anomeric posiꢀ
tion.
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(28a, 78%), proposed leonoside E (28b, 83%) and revised
leonoside E (28c, 86%) in three steps.33
■ CONCLUSIONS
We have discovered Sꢀ2ꢀ(2ꢀpropylsulfinyl)benzyl (SPSB)
glycoside as a novel glycosyl donor which can be efficiently
activated in a tandem remote mode. The SPSB glycoside can
be derived from the corresponding SPTB glycoside by an effiꢀ
cient and selective oxidation. By employing Sꢀ2ꢀ(2ꢀ
propylsulfinyl)benzyl (SPSB) group as a new leaving group,
glycosylations of disarmed glycosyl donors are successfully
achieved. Integration of OPSB leaving group and this newly
discovered SPSB leaving group allows rapid oligosaccharide
assembly by latentꢀactive strategy. Finally, we have demonꢀ
strated that this novel methodology is applicable to natural
product syntheses in a convergent manner.
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ASSOCIATED CONTENT
1
Experimental details, H and 13C NMR spectra for all new
compounds, and 2D NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* wanqian@hust.edu.cn
Author Contributions
All authors have given approval to the final version of the manuꢀ
script.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research is partially supported by National Natural Science
Foundation of China (21272082, 21402055, 21472054), the State
Key Laboratory of Bioꢀorganic and Natural Products Chemistry
(SKLBNPC13425), Natural Science Funds of Hubei Province for
Distinguished Young Scholars (2015CFA035), “Thousand Talꢀ
ents Program” Young Investigator Award, Wuhan Creative Talent
Development Fund and Huazhong University of Science and
Technology (2014ZZGH015) for support. We thank Professor
Suwei Dong (Peking University) and Professor Yu Yuan (Univerꢀ
sity of Central Florida) for helpful discussions. This paper is dediꢀ
cated to Professor Samuel J. Danishefsky on the occasion of his
80th birthday.
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