Copper(II) triflate: A versatile catalyst for the one-pot preparation of orthogonally protected glycosides

Article abstract of DOI:10.1002/adsc.201100228

The development of general and expedient methodologies for the preparation of orthogonally protected glycoside building blocks is essential for the efficient synthesis of complex oligosaccharides. Herein, we describe a new approach that uses copper(II) triflate as a versatile catalyst for the one-pot preparation of orthogonal protected thio- and O-glycosides from the corresponding unprotected counterparts. The conditions are mild, easy to handle and applicable to two and three one-pot tandem transformations, which include arylidene acetalation, esterification, regioselective reductive acetal ring opening, glycosylation and silylation processes. Copyright

Full text of DOI:10.1002/adsc.201100228

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DOI: 10.1002/adsc.201100228
Copper(II) Triflate: AVersatile Catalyst for the One-Pot
Preparation of Orthogonally Protected Glycosides
Anh-Tuan Tran,a Rachel A. Jones,a Julien Pastor,a Julien Boisson,a Nichola Smith,b
and M. Carmen Galana,*
a
School of Chemistry, University of Bristol, Bristol BS8 1TS, U.K.
Fax : (+44)-(0)117-929-8611; phone: (+44)-(0)117-928-7654; e-mail: M.C.Galan@bristol.ac.uk
Novartis Institute for Biomolecular Research, Novartis Horsham Research Centre, Horsham RH12 5AB, U.K.
b
Received: March 29, 2011; Revised: June 8, 2011; Published online: October 10, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100226.
Abstract: The development of general and expedi-
ent methodologies for the preparation of orthogo-
nally protected glycoside building blocks is essential
for the efficient synthesis of complex oligosacchar-
ides. Herein, we describe a new approach that uses
copper(II) triflate as a versatile catalyst for the one-
pot preparation of orthogonal protected thio- and
O-glycosides from the corresponding unprotected
counterparts. The conditions are mild, easy to
handle and applicable to two and three one-pot
tandem transformations, which include arylidene
acetalation, esterification, regioselective reductive
acetal ring opening, glycosylation and silylation pro-
cesses.
building blocks with suitable leaving groups[1a] that
can be manipulated under different reaction condi-
tions. However, the synthesis of these differentially
protected monosaccharide moieties is still a very
labour-intensive process, as it is typically accom-
plished by the introduction of each functional group
in a stepwise fashion. This process tends to increase
the linearity and decrease the efficiency of the overall
synthesis.
Most methodologies developed for the assembly of
complex oligosaccharide structures are aimed at in-
vestigating new, improved promoters to catalyze the
glycosylation reaction[5] or more efficient coupling
strategies such as: one-pot multistep glycosylation re-
actions,[6] polymer-supported,[7] fluorous tag[8] or ionic
liquid-supported[9] oligosaccharide syntheses. Howev-
er, little effort has been devoted to the development
of efficient approaches that can be applied to the
preparation of orthogonally protected monosacchar-
ide building blocks.[4] In the last few years, very ele-
gant Lewis acid-catalyzed one-pot regioselective pro-
Keywords: carbohydrates; catalysis; copper(II) tri-
flate; oligosaccharide synthesis; one-pot procedure
Recent developments in glycobiology and glycomedi- tection strategies by the groups of Beau[10] and
cine research have made carbohydrates and their gly- Hung[11] have been reported. Still, their approaches
coconjugates increasingly popular as lead compounds require the use of labile per-O-trimethylsilyl ether
in drug and vaccine discovery.[1] Furthermore, carbo- glucosides as their starting materials, since their strat-
hydrate scaffolds have also been employed as chiral egy is not suitable for unprotected glucosides.
precursors in natural product synthesis with good suc-
Herein, we report the first successful application of
(OTf)2] to catalyze arylidene
cess.[2] The preparation of structurally defined oligo- copper(II) triflate [Cu
AHCTUNGTRENNUNG
saccharide scaffolds has remained a major obstacle in acetalation reactions. Furthermore, we show the ver-
the field. The development of expedient methods to satility of this catalyst in the application of sequential
efficiently prepare these complex molecules remains one-pot catalyzed orthogonal functionalization of un-
essential to make oligosaccharide synthesis available protected glycosides that includes up to three distinct
to main stream chemists and for understanding glycan steps.
diversity and function.[3]
In the last decade, Cu
Oligosaccharide synthesis relies on the ability to tery of extended synthetic applications, including nu-
link monosaccharide units in a chemo-, regio- and ste- merous examples where Cu(OTf)2 gives better results
reoselective manner. This is typically accomplished by than other popular metal triflates such as Yb(OTf)3
the use of orthogonal protecting groups[4] and of and Sc(OTf)3.[12] Furthermore, Cu
(OTf)2 has been
ACHTUNGRTEN(NUNG OTf)2 has been used in a bat-
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
N
ACHTUNGTRENNUNG
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found in a variety of highly useful applications in car- chain or an acid labile 1,2-ortho ester (compounds 9–
bohydrate chemistry. For instance, CuACHTNUTRGNE(NUG OTf)2 has been 11), were prepared. These two series of compounds
used to catalyze acetylation reactions,[13] and more re- were subjected to the same reaction conditions previ-
cently was used as a mild glycosylation promoter.[14] ously described in Scheme 1. In general, the reactions
In general, CuACHTUNGTRENNUNG(OTf)2 is used in catalytic amounts and proceeded cleanly, were complete within 10–30 min at
is water-stable, hence it can be easily recycled and room temperature under sonication conditions and
reused without loss of activity,[15] which makes it very products 12–20 were isolated in yields of 85–98%
attractive for the synthetic chemist.
(Table 1).
The use of 4,6-O-arylidene acetalations as a pro-
tecting group strategy is widely spread on carbohy-
drate templates in combination with esterification at
C-2 and C-3, as it provides a versatile orthogonal pro-
tection that allows for regio- and stereocontrol in oli-
gosaccharide assembly. 4,6-O-Arylidene acetals can
either undergo regioselective ring opening to provide
a free 4-OH or 6-OH, or afford both free hydroxy
groups upon acetal hydrolysis or hydrogenolysis.[4]
4,6-O-Arylidenation is often performed under harsh
acidic conditions and the use of a Lewis acid to cata-
lyze acetalation reactions is rarely reported.[16,17] In
those instances, the benzaldehyde is used in large
excess (i.e., as reaction solvent)[16] or the reaction pro-
ceeds slowly requiring long reaction times for comple-
tion.[17]
Table 1. CuACHTNUTRGNENG(U OTf)2-catalyzed 4,6-O-arylidene acetalations.
Due to its coordinating as well as Lewis acid prop-
erties,[12a] we speculated that Cu
ACTHNUGTRNE(UNG OTf)2 could be a
good catalyst for the arylidene acetalation of glyco-
sides, while still providing a mild reaction medium.
With that in mind, we decided to test our hypothe-
sis with a simple 4,6-O-arylidene acetalation of com-
mercial methyl b-d-glucopyranoside 1 in the presence
of CuACHTUNGTRENNUNG(OTf)2 (0.05 equiv.) and the corresponding di-
methyl arylidene acetal (1.2 equiv.) in CH3CN
(Scheme 1). Conversion to product was achieved
within 20 min at room temperature under sonication
conditions and 4,6-O-benzylidene acetal derivative 2a
and 4,6-O-p-benzylidene acetal 2b were obtained in
excellent yields of 90% and 97%, respectively.
Encouraged by these results, we then turned our at-
tention to explore the scope of the reaction with
other frequently used thio- and O-glycosides.[18] To
that end, a series of synthetic thiophenyl glycosides,
including examples containing allyl protecting groups
Entry
Ar
Substrate
Product
Yield[b] [%]
1
2
3
4
5
6
7
8
Ph
3
3
4
5
5
6
7
7
8
9
10
11
12a
12b
13a
14a
14b
15a
16a
16b
17a
18a
19a
20
94[c]
85
PMP[a]
Ph
and
a
series of common N-protecting groups
98[c]
90
(NHTroc, NPhth, NHAc) (compounds 3–8) were pre-
pared. In addition, a series of O-glycosides bearing
either a 1-O-alkyl azide chain, a 1-O-alkyl halide
Ph
PMP
Ph
Ph
PMP
Ph
Ph
Ph
Ph
86
70[d]
85[c]
85
9
90[c]
95
10
11
12
91[c]
45
[a]
PMP=p-methoxyphenyl.
Isolated yield.
The reaction was carried out in a gram-scale.
Performed with 2 equivalents of PhCH(OMe)2
[b]
[c]
[d]
AHCTUNGTRENNUNG
Scheme 1. CuACHTUNGTRENNUNG(OTf)2-catalyzed 4,6-O-arylidene acetalations.
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Copper(II) Triflate: A Versatile Catalyst for the One-Pot Preparation of Orthogonally Protected Glycosides
In all cases, the reactions proceeded with excellent
regioselectivity with only the 4,6-O-arylidene product
observed, without any trace of the undesired 3,4-O-
acetal in the case of galactosides 5 and 10 (entries 4, 5
and 11, Table 1) or 2,3-O-acetal in the case of manno-
side 6 (entry 6, Table 1).[19] Moreover, the reaction
conditions are compatible with different protecting
groups such as allyl ethers (entry 3, Table 1) and
amino protecting groups (entries 7–10, Table 1) dem-
onstrating the generality of use of this approach. In-
terestingly, when orthoester 11 was treated with
CuACHTUNGTRENNUNG(OTf)2 in the presence of benzaldehyde dimethyl
acetal, concomitant formation of the 4,6-O-acetal
with orthoester rearrangement gave the unexpected
product 20, containing the 4,6-O-benzylidene, an
acetyl group at C-2 and a free 3-OH, in a moderate
yield of 45%. This exciting outcome offers a very
useful and non-toxic entry into selective C-2/C-3 gly-
coside functionalization that is otherwise generally
achieved by toxic stannylene
Scheme 2. One-pot CuCAHTUNGTERN(UGNN OTf)2-catalyzed tandem acetalation/
[a]
acetylation reactions.
gram-scale.
The reaction was carried out in a
These encouraging results combined with our inter-
est in developing new and improved approaches for
the preparation of versatile glycoside building blocks,
led us to the investigation of a new, general and effi- a moderate yield of 50%. It is noteworthy that p-me-
cient multistep synthesis of orthogonally functional- thoxybenzylidene acetals, which undergo acid hydrol-
ized glycosides.
ysis 10 times faster than the benzylidene counter-
One-pot synthetic strategies offer a very attractive parts,[26] could withstand the reaction conditions and
alternative to sequential approaches, since several products 24b and 26b were isolated in yields of 73%
synthetic steps can be performed in the same reaction and 70%, respectively, demonstrating that our mild
vessel, without any need for work-up and purification set of conditions are compatible with this more labile
between the steps. One-pot 4,6-arylidene acetalation/ class of acetals. Moreover, the tandem one-pot reac-
acetylation of sugar derivatives has been reported tion was also compatible with the use of amino pro-
[21]
under acidic conditions using immobilized HClO4
tecting groups, as demonstrated for substrates 7 and 9
and H2SO4,[22] respectively, or p-toluenesulfonic which afforded products 26a and 27 in yields of 76%
acid.[23] However, all of these strategies are based on and 70%, respectively. In addition allyl ether bearing
the use of harsh, and in some cases, difficult to handle 23 was obtained in 92% yield from 4.
acidic systems to catalyze the reactions. Our group
has recently reported the iodine (I2)-catalyzed one- protic acid or CuAHCTNUGTRENNNUG
Et3SiH is frequently used in the presence of a
(OTf)2 as a hydride source in reduc-
pot tandem acetalation/esterification reaction of un- tive 4,6-O-benzylidene ring opening of carbohydrates
protected thio- and O-glycosides.[24] However, to form 4-OH, 6-OBn bearing derivatives.[27] Based
0.4 equivalents of I2 were needed to drive the reaction on our preliminary data, we proposed that a 4,6-O-
to completion and catalytic 4-dimethylaminopyridine benzylidene reductive opening step could be incorpo-
was required to accelerate the esterification step.
Having shown that acetal formation could be effec- syl 3, galactosyl 5 and NHTroc protected glucosaminyl
tively catalyzed by Cu(OTf)2, we decided to apply the 7 thioglycosides, were subjected to the one-pot
developed conditions to the preparation of orthogo- Cu(OTf)2-catalyzed acetalation/esterification condi-
rated into the one-pot sequence. Consequently, gluco-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
nally protected glycosides in one-pot acetalation/ace- tions previously described, once the two-step process
tylation tandem reactions. To that purpose, glycosides was complete as shown by TLC, Et3SiH was added to
1, 3–7 and 9 were first subjected to the CuACHTNUTRGNE(NUG OTf)2-cat- the reaction mixture and the expected products 28, 29
alyzed acetalation reaction. Upon completion as and 30 were obtained cleanly in yields of 50–60%
shown by TLC, acetic anhydride (Ac2O)[25] and anoth- over the 3-step conversion (Scheme 3). It is important
er 0.05 equivalents of CuACHTNUTRGNEUNG(OTf)2 were added to the re- to note that the strategy affords, in one-pot and at
action mixture, which was left stirring at room tem- room temperature, thioglycoside products that are dif-
perature overnight to afford products 21–27 ferentially protected, that is, each orthogonal protect-
(Scheme 2). Reactions proceeded in good to excellent ing group can be chemoselectively unmasked. For in-
yields ranging from 70–92% over 2 steps, with the ex- stance, the C-3 acetate group is base labile, while the
ception of mannose derivative 25 that was obtained in C-6 benzyl group is susceptible to hydrogenolysis and
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Scheme 3. One-pot CuACHTNUTRGENNG(U OTf)2-catalyzed tandem acetalation/acetylation/reductive opening reactions.
Scheme 4. One-pot CuACTHNUTRGNE(NUG OTf)2-catalyzed tandem acetalation/silylation and acetalation/glycosylation processes.
the glycosides are ready to be used as both glycosyl N3) and scalable to gram quantitities. This approach
donors and acceptors.[5b]
simplifies greatly the preparation of orthogonally pro-
Another synthetically useful protecting group com- tected building blocks ready to be used in oligosac-
bination is that of acetalation/silylation. This was charide assembly and represents a significant step for-
achieved by acetalation of 7 in the presence of ward towards simplifying oligosaccharide synthesis
CuACHTUNGTRENNUNG(OTf)2 followed by addition of chloro(tert-butyl)di- and making it more accessible to main stream chem-
methylsilane and imidazole to afford 31 in 76% isolat- ists.
ed yield, after two steps.
In order to showcase further the versatility of
Cu
G
tion was also investigated. For that purpose, benzyli-
denation of NHTroc protected glycosaminyl 7 was General Procedure for 4,6-O-Arylidenation
carried out with CuACHTUNTRGNEUNG(OTf)2 as described before. Upon
To a mixture of benzaldehyde (or 4-methoxybenzaldehyde)
dimethyl acetal (1.2 mmol) in CH3CN (10 mL) and the un-
protected saccharide (1 mmol) was added CuACHTUNGTRENNUNG(OTf)2
(0.05 mmol) and the system was sonicated at room tempera-
ture (10–30 min) under a nitrogen atmosphere. Upon com-
pletion as monitored by TLC, the solvent was concentrated
and the residue was purified by flash chromatography to
give the 4,6-arylidene product with the corresponding yield
as shown in Table 1.
completion of the 4,6-O-acetalation, glycosyl donor
32 and TMSOTf (0.05 equiv.) were added at 08C
(Scheme 4). Disaccharide 33 was obtained after 1
hour in a yield of 51% over the 2 steps.[29]
These results highlight the wide range of transfor-
mations possible in the presence of mild Cu
In summary, we have shown a versatile and fast
one-pot Cu(OTf)2-catalyzed strategy for the orthogo-
ACHTUNGERTN(NUNG OTf)2.
ACHTUNGTRENNUNG
nal protection of O- and thio-glycosides. The condi-
tions are mild, easy to handle and applicable to two-
and three-step one-pot tandem transformations, in-
cluding arylidene acetalation, esterification, reductive
acetal ring-opening, silylation and glycosylation pro-
cesses. The reaction conditions are tolerant of most
General Procedure for One-Pot 4,6-O-Arylidenation/
Acetylation Reaction
To a mixture of benzaldehyde (or 4-methoxybenzaldehyde)
dimethyl acetal (1.2 mmol) and the unprotected saccharide
(1 mmol) in CH3CN (10 mL) was added CuACHTUNGTRENNUNG(OTf)2
common amino protecting groups (Ac, Phth, Troc and (0.05 mmol) and the system was sonicated at room tempera-
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Copper(II) Triflate: A Versatile Catalyst for the One-Pot Preparation of Orthogonally Protected Glycosides
ture (10–30 min) under a nitrogen atmosphere. Acetic anhy-
dride (5 mmol, 5 equiv.) was then added and the obtained
solution was stirred for a further 18 h. The reaction was
quenched with Et3N (0.1 mL) and the solvent was evaporat-
ed. The crude product was purified by flash chromatography
to give the protected monosaccharides with corresponding
yields as shown in Scheme 2.
obtained residue in CH2Cl2 (1.0 mL), the donor 32 (46 mg,
0.093 mmol) in dry CH2Cl2 (0.5 mL) was added followed by
4 ꢂ MS. The reaction mixture was stirred for 1 h at room
temperature before being cooled to 08C and TMSOTf (10%
in CH2Cl2, 8.0 mL) was then added. The reaction was kept at
08C for 1 h, quenched with Et3N (50 mL, 0.36 mmol) and pu-
rified by flash chromatography (Tol/EtOAc, 9:1!8:2, v/v),
to afford disaccharide 33; yield: 36 mg (51%) and phenyl
2,3,4,6-tetra-O-acetyl-1-thio-b-d-galactopyranoside;[30] yield:
10 mg (28%).
General Procedure for One-Pot 4,6-O-Arylidenation/
Acetylation/Reductive Ring Opening Reaction
1
Data for 33: [a]22: ꢀ13 (c 1.0, CH2Cl2); H NMR (CDCl3,
400 MHz): d=7.50D–7.46 (m, 4H, Ph), 7.39–7.36 (m, 3H, Ph),
7.35–7.31 (m, 3H, Ph), 5.54 (s, 1H, PhCH), 5.36 (d, 1H,
To a mixture of benzaldehyde (or 4-methoxybenzaldehyde)
dimethyl acetal (1.2 mmol) and the unprotected saccharide
(1 mmol) in CH3CN (10 mL) was added CuACTHNURGTNEUNG(OTf)2
(0.05 mmol) and the system was sonicated at room tempera-
ture (10–30 min) under a nitrogen atmosphere. Acetic anhy-
dride (5 mmol, 5 equiv) was then added and the obtained
solution was stirred for a further 18 h. Upon complete acety-
lation as shown by TLC, Et3SiH (10 mmol, 10 equiv.) was
J
NH,2 =8.0 Hz, NH), 5.30 (bd, 1H, J4’,3’ =3.5 Hz, H-4’), 5.19
(dd, 1H, J2’,1’ =8.0 Hz, J2’,3’ =10.5 Hz, H-2’), 5.18 (d, 1H,
1,2 =10.5 Hz, H-1), 4.93 (dd, 1H, H-3’), 4.83 (d, 1H, d, 1H,
J=12.0 Hz, CHH Troc), 4.73 (d, 1H, J=12.0 Hz, CHH
Troc), 4.70 (d, 1H, H-1’), 4.38 (dd, 1H, J6a,5 =5.0 Hz, J6a,6b
J
=
10.5 Hz, H-6a), 4.30 (t, 1H, J3,2 =J3,4 =9.5 Hz, H-3), 4.05 (dd,
1H, J6a’,5’ =8.0 Hz, J6a’,6b’ =11.0 Hz, H-6a’), 3.83 (dd, 1H,
added at 08C before adding a further quantity of CuACTHNUTRGNEUNG(OTf)2
(0.05 mmol). The mixture was kept at room temperature for
3–4 h. After quenching the reaction with Et3N (0.1 mL), the
solvent was concentrated and the residue was purified by
flash chromatography to give the 4-OH, 6-OBn products.
J
6b’,5’ =6.0 Hz, H-6b’), 3.81 (t, 1H, J6b,5 =J6b,6a =10.5 Hz, H-
6b), 3.66 (t, 1H, J4,3 =J4,5 =9.5 Hz, H-4), 3.63 (dd, 1H, H-5’),
5.55 (ddd,1H, H-5), 3.38 (m, 1H, H-2). 2.11, 2.00, 1.96, 1.95
(4 s, 4ꢁ3H, 4ꢁCH3, 4ꢁOAc); 13C NMR (CDCl3, 100 MHz):
d=170.2, 170.1, 169.4 (CO, Ac), 153.6 (CO, Troc), 136.9,
(Cq, Ph), 132.9, 131.7, 129.3, 129.1, 129.0, 128.4, 128.3, 128.2
126.0 (CH, Ph), 101.3 (CHPh), 100.7, (C-1’), 95.3 (CCl3,
Troc), 86.0 (C-1), 79.8 (C-4), 79.0 (C-3), 74.4 (CH2 Troc),
70.9 (C-3’), 70.5 (C-5’), 70.4 (C-5), 69.3 (C-2’), 68.5 (C-6),
66.7 (C-4’), 60.8 (C-6’), 56.4 (C-2), 20.7, 20.6, 20.6, 20.5
(CH3, OAc); ESI-HR-MS: m/z=886.1076, calcd. for
C36H40Cl3NNaO15S+ (M+Na)+: 886.1082.
Procedure for One-Pot CuACHTNUTRGNENG(U OTf)2-Catalyzed Tandem
Acetalation/Silylation Reaction; Synthesis of 31
To a solution of monosaccharide 6 (86 mg, 0.193 mmol), and
benzaldehyde dimethyl acetal (35 mL, 0.232 mmol) in dry
CH3CN (2.0 mL) was added CuACTHNUGTRNENUG(OTf)2 (3.5 mg, 9.65 mmol).
The reaction mixture was then sonicated for 30 min.
Chloro(tert-butyl)dimethylsilane (146 mg, 0.967 mmol) and
imidazole (66 mg, 0.967 mmol) were added and the reaction
mixture was stirred for 2 h at 608C. The solution was con-
centrated under reduced pressure and the residue was puri-
fied by flash chromatography (n-hexane/EtOAc, 95:5, v/v)
to give the title product 31; yield: 95 mg (76%); [a]2D2: ꢀ15
Acknowledgements
We gratefully acknowledge financial support from Novartis,
EPSRC and The Royal Society.
1
(c 0.9, CH2Cl2). H NMR (CDCl3, 400 MHz): d=7.50–7.46
(m, 4H, Ph), 7.38–7.30 (m, 6H, Ph), 5.52 (s, 1H, PhCH),
5.19 (d, 1H, JNH,2 =9.0 Hz, NH), 5.07 (d, 1H, J1,2 =10.5 Hz,
H-1), 4.78 (d, 1H, J=12.0 Hz, CHH, Troc), 4.71 (d, 1H, J=
12.0 Hz, CHH, Troc), 4.37 (dd, 1H, dd, 1H, J6a,5 =4.5 Hz,
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J
6a,6b =10.5 Hz, H-6a), 4.06 (t, 1H, J3,2 =J3,4 =9.0 Hz, H-3),
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Procedure for One-Pot CuACHTNUTRGNENG(U OTf)2-Catalyzed Tandem
Acetalation/Glycosylation Processes: Synthesis of 33
To a solution of 7 (37 mg, 0.08 mmol) and benzaldehyde di-
methyl acetal (14 mL, 0.095 mmol) in dry CH3CN (0.8 mL)
was added CuACHTUNGTRENNUNG(OTf)2 (1.5 mg, 3.95 mmol) and the solution
was sonicated for 30 min. The solvents were then carefully
evaporated under reduced pressure. After redissolving the
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