Glycosylation Enabled by Successive Rhodium(II) and Br?nsted Acid Catalysis

Article abstract of DOI:10.1021/jacs.9b04619

Herein, we reported on a highly efficient glycosylation reaction comprising two chronological meticulously designed catalytic cycles: (1) rhodium-catalyzed formation of sulfonium ylide and (2) Br?nsted acid-catalyzed formation of sulfonium ion. This protocol highlighted an effective and robust tactic to prepare a glycosyl sulfonium ion from a glycosyl sulfonium ylide precursor amenable for glycosylation.

Full text of DOI:10.1021/jacs.9b04619

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Communication
Glycosylation Enabled by Successive
Rhodium(II) and Brønsted Acid Catalysis
Lingkui Meng, Peng Wu, Jing Fang, Ying Xiao, Xiong Xiao,
Guangsheng Tu, Xiang Ma, Shuang Teng, Jing Zeng, and Qian Wan
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b04619 • Publication Date (Web): 17 Jul 2019
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Glycosylation Enabled by Successive Rhodium(II) and Brønsted Acid
Catalysis
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Lingkui Meng,† Peng Wu,† Jing Fang,† Ying Xiao,† Xiong Xiao,† Guangsheng Tu,† Xiang Ma,† Shuang
Teng,† Jing Zeng,† Qian Wan*,†
†Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Huazhong University
of Science and Technology, 13 Hangkong Road, Wuhan, Hubei 430030, China
Supporting Information Placeholder
(86%) and sulfide 9 (83%). The extension of reaction duration to
24 hours rendered O-glycoside 6b as the major product while the
Stevens rearrangement product C-glycoside 6c was not observed.9a
The formation of O-glycoside 6b was speculated to be the rear-
rangement product of zwitterion 5’; which in turn pointed to the
intermediacy of glycosyl ylide 5 formed during the activation.13a,b
ABSTRACT: Herein, we reported on a highly efficient glycosyla-
tion reaction comprises two chronological meticulously-designed
catalytic cycles: 1) rhodium-catalyzed formation of sulfonium ylide;
2) Brønsted acid-catalyzed formation of sulfonium ion. This proto-
col highlighted an effective and robust tactic to prepare glycosyl sul-
fonium ion from glycosyl sulfonium ylide precursor amenable for
glycosylation.
Scheme 1. Transformations within Sulfide, Sulfonium Ylide and Sul-
fonium Ion
Sulfonium ylides are conventionally prepared via (i) deprotona-
tion of sulfonium salts under strong basic conditions or (ii) reac-
tions of sulfides and carbenes or metal carbenoids (Scheme 1a, path
A and B).1,2 Alternatively, conjugate addition of nucleophiles to vi-
nylsulfonium salts provide sulfonium ylide intermediates which
upon protonation form sulfonium ions that also serve as valuable
intermediates in multifarious synthetic pathways.3 This appealing
reaction mode was seminally explored by Gosselck,4a and further
advanced by Aggarwal,4b and Xiao4c et al. In 2008, Aggarwal demon-
strated an elegant synthesis of morpholines initiated by conjugate
addition of -amino alcohols to vinylsulfonium salts (Scheme 1b).5a
An ensuing proton transfer from a tethered hydroxy group to the in
situ generated sulfonium ylide-I produces a zwitterionic intermedi-
ate. The resulting nucleophilic alkoxide then facilitates a ring clo-
sure by displacement of the sulfonium leaving group.5 Intriguingly,
the formation of sulfonium intermediates via the protonation of
sulfonium ylides can be viewed as a reverse process of deprotona-
tion of sulfonium salts.6
Thioglycosides in carbohydrate chemistry offer distinct ad-
vantages7 and the formation of glyco-sulfonium ions underlies the
success of glycosylation.8 As opposed to the well-established meth-
ods to generate glyco-sulfonium ions, the methodical studies of the
chemistry of glyco-sulfonium ylides receives less attention.9a-c Gal-
vanized on the Kametani9a, Porter9b-c and Aggarwal’s works5a, we
devised a novel glycosylation reaction10 constitutes of successive
Rh(II)-catalyzed sulfonium ylide formation11 and Brønsted acid-
catalyzed sulfonium formation12 which facilely affords oxocarbe-
nium ion susceptible for nucleophilic attack of acceptors (Scheme
1c).
Enlisting armed 1a-d as donors and 2a-b as the acceptors (Table
1), initial developmental trials for the titled reaction were per-
formed at 0 °C to suppress the undesirable Stevens rearrange-
ment.9a At the outset of this investigation, thio-donor 1a alone was
treated with rhodium(II) octanoate dimer (Rh2(oct)4) and methyl
4-chlorophenyldiazoacetate 3a. The reaction was quenched after an
hour upon complete consumption of 1a to isolate hemiacetal 6a
At the same time, we reckoned the generation of oxo-carbenium
species from glycosyl sulfonium ylide 5 could be difficult as the pos-
itively charged glycosyl sulfur atom was stabilized by the neighbor-
ing carbanion, rendering it a poor leaving group. Accordingly, cat-
alytic amount of Brønsted acid was added to facilitate the formation
of active sulfonium ion. We first pursued the reaction in a “one-shot”
activation mode for coupling between 1a and 2a in the presence of
diazo compound 3a (3.0 equiv) (Table 1, procedure A). Gratify-
ingly, the disaccharide 4a was isolated in 89% yield, together with
two by-products 7 and 8 instead of 9 (entry 1). These by-products
could be derived from the Stevens rearrangement of ylide which
was generated from a competitive reaction between the in situ re-
leased sulfide 9 and rhodium carbenoid. To verify this hypothesis,
a stepwise reaction (procedure B) was investigated; wherein the
amount of the 3a was reduced to 1.2 equiv. and the Brønsted acid
was added until the yellow color of 3a disappeared (entry 2). This
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modification resulted in formation of 4a and co-product 9 in 86%
and 89% yield respectively while that of 7
On the basis of experimental results and prior reports,11b a plau-
sible pathway for the successive rhodium(II)- and Brønsted acid-
catalyzed glycosylation was illustrated in Scheme 2. In the first cat-
alytic circle, Rh2(oct)4 promotes the decomposition of 3a and forms
a rhodium carbenoid (A), which is subsequently attacked by the
sulfide 1 to provide the glycosyl ylide (B) and regenerates active
Rh(II) species (Scheme 2, cycle 1). In the second catalytic
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4
Table 1. Reaction Development
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Scheme 2. Mechanistic Proposal
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Table 2. Reaction Scope for Armed/Superarmed Thioglycosides.a,b
Entry
1
proce-
dures
1/2 (ratio)
1a/2a (1:1)
4 a,b
bypro-
ducta
A
4a (89%)
7 (52%)
8 (36%)
9 (89%)
2
3
4
5
6
7
8
9
B
A
A
A
A
A
A
B
1a/2a (1:1)
1a/2a (1:1)
4a (86%)
4a (23%)c
d
-
d
1a/2a (1.2/1) 4a (95%)
1b/2a (1.2/1) 4a (89%)
1c/2a (1.2/1) 4a (82%)
1d/2a (1.2/1) 4a (90%)
1a/2b (1.2/1) 4b (12%)
1a/2b (1.2/1) 4b (96%)
-
d
-
d
-
d
-
10 (81%)
d
-
Procedure A: to the mixture of 1, 2 and 3 (3.0 equiv) in CH2Cl2 at
0 °C, Rh2(oct)4 (0.5 mol%) in CH2Cl2 and TfOH·DTBMP (5.0
mol%) in CH2Cl2 were added, the resulting mixture was stirred at
0 °C until the reaction was completed. Procedure B: the reaction
mixture of 1, 3 (1.2-1.5 equiv) and Rh2(oct)4 (0.5 mol%) in CH2Cl2
was stirred at 0 °C until the yellow color was disappeared, then 2
and TfOH·DTBMP (5.0 mol%) were added to the mixture. a Iso-
lated yields based on 2a-b. b Isolated as a mixture of / anomers. c
Without TfOH·DTBMP. d by-products were not collected.
and 8 was completely inhibited. In view of the ease of operation,
further optimizations were carried out based on procedure A. In the
absence of TfOH·DTBMP, the yield of disaccharide 4a was ham-
pered to 23% even with longer reaction time (entry 3). Slight excess
of 1a (1.2 equiv.) promoted the yield up to 95% (entry 4). Screen-
ing of donors 1a-d revealed that -SPh was the optimal anomeric
leaving group and the coupling efficiency was unaffected by the
anomeric configuration of the donor (entries 5-7). However, when
primary alcohol 2b was used as the acceptor with procedure A, sig-
nificant amount of carbene O-H insertion by-product 10 was ob-
tained (81%, entry 8).14 In this case, reaction with procedure B fur-
nished the desired product 4b in excellent yield (96%, entry 9).
This implied that “one-shot” activation mode was not suitable for
the reaction with highly reactive alcohols as acceptors and the step-
wise activation mode was recommended correspondingly.
a
b
Yield of isolated product. Unless otherwise specified, the reac-
tions were carried out according to Procedure A: to the solution of
1 (1.2 equiv, R = Tol), 2 and 3 (3.0 equiv) in CH2Cl2 at 0 °C, were
added the solutions of Rh2(oct)4 (0.5 mol%) and TfOH·DTBMP
c
d
e
(5.0 mol%) in CH2Cl2. 1 (R = Ph). Rh2(oct)4 (1.0 mol%).
1
(1.5 equiv). f Procedure B (stepwise activation): 3a (1.5 equiv), the
acceptor and TfOH·DTBMP were added after the formation of gly-
cosyl ylide.
cycle, protonation of the carbanion of glycosyl ylide (B) with cata-
lytic amount of Brønsted acid furnishes the active sulfonium ion
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(C), the precursor of oxocarbenium ion.15 Interception of the oxo-
1
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4
5
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8
carbenium ion or analogous intermediate by acceptor 2 produces
the glycoside 4 and restores H+. The H+ released from acceptor 2
completes the second catalytic cycle (Scheme 2, cycle 2). Note-
worthily, the protonation of ylide in second catalytic cycle not only
provides active sulfonium species but also avoids the accumulation
of H+ which is crucial for accommodating acid labile substrates
(vide infra). Both catalytic cycles are maneuvered under very mild
conditions; which augurs well for the preparation of acid sensitive
substrates or chemical manipulation of stagnant glycosylations.16
With two sets of optimal conditions in hand, we then set out to
study the universality and versatility of current novel glycosylation
reaction by coupling a manifold of armed/superarmed thioglyco-
sides with acceptors bearing different protecting groups (details see
Table S1). Wide variety of glycosidic bonds could be formed in
good to excellent yields (4c-s, Table 2). Most coupling reactions
proceeded with “one-shot” procedure (Table 1, procedure A). Of
note, carbonyl groups, acetonide, benzylidene, silyl group, 4-meth-
oxyphenyl group, p-nitrobenzenesulfonyl (Ns) amide group and io-
dide demonstrated exquisite compatibility with the glycosylation
conditions. Current chemistry was also well undertaken by acid
sensitive substrates to afford 6-deoxyl sugars (4g-h, 4l, 4n-o, 4q-r),
2-deoxyl sugars (4i-l), 2,6-dideoxyl-L-fucose (4l, 4k) and electron
rich substrates (4f, 4m-n, 4q-r); attesting to the geniality and gen-
erality of the protocols.
Exceptionally, this new activation method was applicable for the
synthesis of phenolic glycosides (4m-r).17 Phenolic O-glycosylation
are conventionally associated with long-standing challenges with
the first being the poor nucleophilicity of phenols bearing electron-
withdrawing group especially under acidic conditions. As for phe-
nols with electron-donating substituents, Fries-type rearrangement
of O-aryl glycosides to C-glycosides often precedes the desired O-
glycosylation.18 Lastly, the steric encumbrance posed by substitu-
ents on the phenol rings often jeopardize the glycosylation effi-
ciency.19 In our study, electron-rich phenols (4-methoxyphenol 2l,
2,6-dimethoxyphenol 2m, o-((p-methoxyphenyl)ethynyl)phenol
(MPEP) 2p and 3,5-dimethyl-4-(2’-phenylethynylphenyl)phenol
(EPP) 2q), electron-poor phenol (2-iodophenol 2o), sterically hin-
dered phenol (2m) and ortho-(cyclopropylethynyl)benzoic
(CPEBz) acid 2r were auspiciously glycosylated with various do-
nors following “step-wise” or “one-shot” activation procedure in ex-
cellent yields (Table 2). More importantly, the synthetically signif-
icant MPEP glycoside20 4p, EPP glycoside21 4q and CPEBz glyco-
side16e 4s were obtained in excellent yields in a single step from sim-
ple thioglycosides. While Sun’s20 studies evinced the synthetic in-
feasibility to obtain the active MPEP glycosyl donors directly from
the super electron rich phenol 2p due to its inherent high reactivity;
current method presented an alternative straightforward approach
towards MPEP, EPP and CPEBz glycosides.
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a Yield of isolated product. b Rh2(oct)4 (0.5 mol%). c Reaction mix-
ture of donor 1, acceptor 2, diazo compound 3 and Rh(II), in
CH2Cl2 was stirred at 0 °C, then TfOH (20 mol%) was added while
the yellow color of 3a disappeared. d Reaction mixture of donor 1,
diazo compound 3a and Rh(II) in CH2Cl2 was stirred at 0 °C, then
acceptor 2 and TfOH (20 mol%) was added while the yellow color
disappeared. e Rh2(oct)4 (1.0 mol%). f 1 (2.0 equiv), 3a (4.0 equiv),
g
h
Rh(II) (10.0 mol%). S-Methyl donor 1x was used. ortho-
i
Hexynylbenzoic acid 2t (1.3 equiv) and 3a (1.3 equiv) was used.
Rh2(oct)4 (4.0 mol%).
favored the desired reaction course and provided 4t and co-prod-
uct 11 in 96% and 93% isolated yields respectively. Hereupon, di-
versified secondary alcohols or sterically hindered acceptors were
efficiently glycosylated with disarmed thioglycosides (details see
table S2) in generally good yields (4t-z). In these reactions, the in-
terference of the less reactive hydroxyl groups with the formation
of the sulfonium ylides was virtually absent which allowed either
pre-mixing of acceptors with donors at the beginning or addition of
acceptors just before the acidic treatment. For acceptors bearing
primary hydroxy group (2b, 2u, 2x, 2y, 2za and 2zb), mercaptan (2z),
sulfide (2za, 2zb), glycan (2y), olefin (2v, 2x), alkyne and acid func-
tionalities (2w), the addition of acceptors after complete formation
of sulfonium ylides became mandatory. Adopting the “stepwise”
procedure, compounds 4za-zi were prepared in good to excellent
yields. Prominently, disarmed ortho-alkynylbenzoate (ABz) donor
4ze, pentenyl donor 4zf trisaccharide thiodonor 4zh22 and latent
OPTB glycoside23 4zi were directly prepared from thioglycoside.
Since 2008, gold-catalyzed glycosylation with Yu’s alkynyl donors
became integral in the synthesis of many complex natural prod-
ucts.24 Usually, the ABz donors are prepared as a mixture of α/β
anomers in two steps, followed by removal of temporary anomeric
protecting groups and subsequent coupling with ortho-alkynylben-
zoic acid. Nonetheless, Yu and co-workers have demonstrated the
Having determined the breadth of reaction scope with respect to
armed/superamred thioglycosides, the compatibility of disarmed
thioglycosides was evaluated next. The disarmed 1p was hardly ac-
tivated under conditions established afore. Upon replacement of
the phenyl moiety of 1p to an ethyl group, 1q was successfully acti-
vated but only orthoester 4t’ was isolated in 59% yield with the cus-
tomary TfOH·DTBMP (5.0 mol%). Given that disarmed sugars are
non-acid sensitive and resistant to strong acidic conditions, 20 mol%
of TfOH instead of TfOH·DTBMP was introduced into the reac-
tion mixture. To our delights, this
Table 3. Reaction scope for 2-Acyl Thiolglycosides.a,b
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Springer, Cham, 2017; Vol. 177, pp 73−166. (b) Lu, L.-Q.; Li, T.-R.; Wang,
Q.; Xiao, W.-J. Beyond Sulfide-centric Catalysis: Recent Advances in the
Catalytic Cyclization Reactions of Sulfur Ylides. Chem. Soc. Rev. 2017, 46,
α-ABz donors could provide much better β-selectivities in manno-
sylations.25 In this work, we accomplished the assembly of ABz gly-
coside 4ze (α/β 3.3:1) and 4s (a single α-isomer, table 1) directly
from the corresponding thioglycosides 1q and 1m in good yields
with an α-favored selectivity.
1
2
3
4
5
6
7
8
4135−4149. (c) Sun, X.-L.; Tang, Y. Acc. Chem. Res., 2008, 41, 937−948. (d)
Aggarwal, V. K.; Winn, C. L. Catalytic, Asymmetric Sulfur Ylide-Mediated
Epoxidation of Carbonyl Compounds: Scope, Selectivity, and Applications
in Synthesis. Acc. Chem. Res. 2004, 37, 611−620. (e) Li, A.-H.; Dai, L-X.;
Aggarwal, V. K. Asymmetric Ylide Reactions: Epoxidation, Cyclopropana-
tion, Aziridination, Olefination, and Rearrangement. Chem. Rev. 1997, 97,
2341−2372.
(3) Review see: Mondal, M.; Chen, S.; Kerrigan, N. J. Recent Develop-
ments in Vinylsulfonium and Vinylsulfoxonium Salt Chemistry. Molecules
2018, 23, 738.
(4). (a) Gosselck, J.; Béress, L.; Schenk, H. Reaction of Substituted Vi-
nylsulfonium Salts with CH-Acidic Compounds. A New Route to Polysub-
stituted Cyclopropanes. Angew. Chem. Int. Ed. 1966, 5, 596−597. (b) Yar,
M.; McGarrigle, E. M.; Aggarwal, V. K. Sulfonium, Ethenyldiphenyl-1,1,1-
Trifluoromethanesulfonate. In e-EROS Encyclopedia of Reagents for Organic
Synthesis; John Wiley & Sons, Ltd.: Hoboken, NY, USA, 2012; pp 1−6. (c)
An, J.; Chang, N.-J.; Song, L.-D.; Jin, Y.-Q.; Ma, Y.; Chen, J.-R.; Xiao, W.-
J. Efficient and General Synthesis of Oxazino[4,3-α]indoles by Cascade Ad-
dition-cyclization Reactions of (1H-indol-2-yl)methanols and Vinyl Sul-
fonium Salts. Chem.Commun. 2011, 47, 1869−1871.
(5) (a) Yar, M.; McGarrigle, E. M.; Aggarwal, V. K. An Annulation Re-
action for the Synthesis of Morpholines, Thiomorpholines, and Piperazines
from -Heteroatom Amino Compounds and Vinyl Sulfonium Salts. Angew.
Chem. Int. Ed. 2008, 47, 3784−3786. (b) Yar, M.; McGarrigle, E. M.; Ag-
garwal, V. K. Bromoethylsulfonium Salts-A More Effective Annulation
Agent for the Synthesis of 6- and 7-Membered 1,4-Heterocyclic Com-
pounds. Org. Lett. 2009, 11, 257−260. (c) Riches, S. L.; Saha, C.; Filgueira,
N. F.; Grange, E.; McGarrigle, E. M.; Aggarwal, V. K. On the Mechanism
of Ylide-Mediated Cyclopropanations: Evidence for a Proton-Transfer Step
and Its Effect on Stereoselectivity. J. Am. Chem. Soc. 2010, 132, 7626−7630.
(6) Selected examples see: (a) Chen, J.; Palani, V.; Hoye, T. R. Reactions
of HDDA-Derived Benzynes with Sulfides: Mechanism, Modes, and Three-
Component Reactions. J. Am. Chem. Soc. 2016, 138, 4318−4321. (b)
Lakhdar, S.; Appel, R.; Mayr, H. How Does Electrostatic Activation Con-
trol Iminium-Catalyzed Cyclopropanations? Angew. Chem. Int. Ed. 2009, 48,
5034−5037. (c) Chou, S.-S. P.; Liu, J. H. Reactions of Methylphenylvinyl-
sulfonium Tetrafluoroborate with Ketone Enolates. J. Chin. Chem. Soc. 1987,
34, 49−55. (d) Nakayama, J.; Hoshino, K.; Hoshino, M. Carbon-Sulfur
Bond Cleavage by Benzyne Generated from 2-Carboxybenzenediazonium
Chloride. Chem. Lett. 1985, 677−678. (e) Nakayama, J.; Fujita, T.; Hoshino,
M. Reactions of Benzyne with Sulfides Having a Carboxyl Group. A Novel
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J. P. N.; Heaney, H.; Ward, T. J. Aryne Chemistry. Part XVII. The Reaction
of Tetrahalogenobenzynes with Thioanisole. J. Chem. Soc. (C) 1969,
355−356.
In summary, for the first time a generally applicable thioglyco-
sides activation was realized via an unprecedented sequential rho-
dium- and Brønsted acid-catalyzed glycosylation. The rhodium-
catalyzed glycosyl ylide formation and successive protonation
paved a brand-new route to activate conventional thioglycosides.
Under this novel strategy, the ylide served as the precursor or the
reservoir of sulfonium ion. The low catalyst loading and mild reac-
tion conditions were attractive features of this method. The ap-
plicability of protocol was substantiated by well tolerance of various
acid sensitive and sterically-demanding substrates. A number of
useful glycosyl donors were also facilely prepared from simple thio-
glycosides. We foresee current protocol to be soon adopted in the
synthetic toolbox of chemists alike in the studies of carbohydrate
chemistry and natural products synthesis.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Experimental procedures, NMR spectroscopic and analytical data
for all compounds (PDF)
Crystallographic data for 8 (CIF)
AUTHOR INFORMATION
Corresponding Author
wanqian@hust.edu.cn
ORCID
Qian Wan: 0000-0001-9243-8939
Jing Zeng: 0000-0001-9116-9861
Lingkui Meng: 0000-0001-6159-2511
Notes
The authors declare no competing financial interests.
(7) (a) Lian, G.; Zhang, X.; Yu, B. Thioglycosides in Carbohydrate Re-
search. Carohydr. Res. 2015, 403, 13−22. (b) Zhong, W.; Boons, G.-J. Gly-
coside Synthesis from 1-Sulfur/Selenium-Substituted Derivatives. In Hand-
book of Chemical Glycosylation; Demchenko, A. V., Ed.; Wiley-VCH: Wein-
heim, Germany, 2008; pp 261−303.
ACKNOWLEDGMENT
Financial support from National Natural Science Foundation of
China (201877043, 21702068, 21672077, 21761132014), Wuhan
Creative Talent Development Fund, Fundamental Research Funds
for the Central Universities (2017KFYXJJ150) are greatly appreci-
ated. We would like to give our truthful thanks to Prof. Biao Yu
(Shanghai Institute of Organic Chemistry) for providing 2’-iodo-
2,6-dimethyl-[1,1’-biphenyl]-4-ol. We thank Mr. Xiaodi Yang
(Shanghai University of Traditional Chinese Medicine) for X-ray
testing and analysis. We also thank Analytical and Testing Center
of HUST for NMR tests. This paper is dedicated to Prof. Claudine
Augé (Universtié Paris-Sud).
(8) (a) Nokami, T. Sulfonium Ions as Reactive Glycosylation Interme-
diates. Trends Glycosci. Glycotech. 2012, 24, 203−214. (b) Nokami, T.;
Nozaki, Y.; Saigusa, Y.; Shibuya, A.; Manabe, S.; Ito, Y.; Yoshida, J.-I. Gly-
cosyl Sulfonium Ions as Storable Intermediates for Glycosylations. Org. Lett.
2011, 13, 1544−1547. (c) Fang, T.; Huang, W.; Boons, G.-J. Mechanism of
Glycosylation of Anomeric Sulfonium Ions. J. Am. Chem. Soc. 2016, 138,
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