Organocatalytic Glycosylation by Using Electron-Deficient Pyridinium Salts

Article abstract of DOI:10.1002/anie.201503156

A new organocatalytic glycosylation method based on electron-deficient pyridinium salts is reported. At ambient temperature and catalyst loadings as low as 1 mol %, 2-deoxyglycosides were formed from benzyl- and silyl-protected glycals and primary or secondary glycosyl acceptors, with excellent yields and anomeric selectivity. Mechanistic investigations point to alcohol-pyridinium conjugates (1,2-addition products) as key intermediates in the catalytic cycle.

Full text of DOI:10.1002/anie.201503156

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201503156
German Edition: DOI: 10.1002/ange.201503156
Organocatalytic Glycosylation
Organocatalytic Glycosylation by Using Electron-Deficient Pyridinium
Salts**
Somnath Das, Daniel Pekel, Jçrg-M. Neudçrfl, and Albrecht Berkessel*
Dedicated to Professor David Milstein
Abstract: A new organocatalytic glycosylation method based
on electron-deficient pyridinium salts is reported. At ambient
temperature and catalyst loadings as low as 1 mol%, 2-
deoxyglycosides were formed from benzyl- and silyl-protected
glycals and primary or secondary glycosyl acceptors, with
excellent yields and anomeric selectivity. Mechanistic inves-
tigations point to alcohol–pyridinium conjugates (1,2-addition
products) as key intermediates in the catalytic cycle.
G
lycosylation is arguably one of the most important yet
difficult reactions in carbohydrate chemistry.[1] In particular,
the stereoselective synthesis of 2-deoxyglycosides remains
a challenge owing to the absence of any directing group at the
2-position and the inherent susceptibility of the product
towards hydrolysis.[2] 2-Deoxyglycosides are important build-
ing blocks for many bioactive natural products.[3] They also
occur frequently in antibiotics and anticancer agents, and play
an important role in the bioactivity of various drugs.[4] One
direct approach to synthesize these molecules involves the
addition of alcohols to glycals, that is, the acetalization of
a vinyl ether. Although there have been several recent reports
on organocatalytic acetalizations,[5] only two publications by
Galan and co-workers appear to deal with the glycosylation of
glycals.[6] In their approach, thioureas serve as organocatalysts
to promote alcohol addition to glycals, albeit with a rather
limited substrate scope.[6,7]
Scheme 1. Organocatalysis by thioureas and pyridinium salts: a) halide
À
binding and C C bond formation between a-chloroethers and silyl
ketene acetals; b) oxyanion stabilization in the addition of alcohols to
vinyl ethers.
We have recently shown that the electron-deficient
pyridinium salts 4·BPh4 act as anion-binding catalysts for
the addition of silyl ketene acetals (such as 2) to 1-
chloroisochroman (1), a transformation initially introduced
by Jacobsen et al. through the use of the thiourea catalyst 3
(Scheme 1a).[8,9] Organocatalytic transformations based on
thioureas are by now manifold,[10] and the similarity in
reactivity between pyridinium salts and thioureas in terms
of anion binding made us wonder whether it might be possible
to extend the scope of pyridinium catalysis beyond halide
binding. Specifically, we focused our attention on the
tetrahydropyranyl (THP) protection of alcohols, as developed
by Schreiner et al. (Scheme 1b).[11] The latter transformation
proceeds efficiently at thiourea catalyst loadings as low as
0.001 mol%. Experimental and computational evidence
points to two-fold hydrogen bonding of thiourea 8 to the
alcohol component as the key mechanistic feature: the acidity
of the alcohol is enhanced as the developing negative charge
on oxygen is stabilized by the thiourea oxyanion hole.[11] We
wondered whether an analogous oxyanion stabilization, and
thus organocatalytic acetalization, might be effected by the
pyridinium salts 4·X instead of thioureas.[12]
[*] S. Das, D. Pekel, Dr. J.-M. Neudçrfl,[+] Prof. Dr. A. Berkessel
Cologne University, Department of Chemistry, Organic Chemistry
Greinstrasse 4, 50939 Cologne (Germany)
E-mail: berkessel@uni-koeln.de
As a first set of experiments, we studied the THP
protection of benzyl alcohol. To our delight, the pyridinium
bromide salts 4a–d·Br efficiently catalyzed this reaction at RT
in dichloromethane (DCM; Scheme 2). For the most electron-
deficient pyridinium salt 4a·Br, only 1 mol% loading was
enough to give full conversion and high yield (88%) of the
THP-protected product 7a. Other pyridinium salts, such as
the bis(trifluoromethanesulfonyl)imide 4d·NTf2, the tetra-
Homepage: http://www.berkessel.de
[+] X-Ray crystallography
[**] Support from SusChemSys[19] and by the Fonds der Chemischen
Industrie is gratefully acknowledged. Preparative support by Florian
Berger, Benjamin Zonker, and Ines Schmidt is gratefully acknowl-
edged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201503156.
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acetonide-protected d-galactose 6c (primary alcohol) and
secondary acceptors derived from d-fructose (6d), d-glucose
(6e), and d-galactose (6 f). Entries 1–5 of Table 1 summarize
the results achieved with benzyl-protected galactal 10a.
We were delighted to see that not only primary acceptors
[MeOH (6b) and 6c; entries 1,2], but also the secondary ones
(6d–f, entries 3–5) reacted smoothly at 1–2 mol% catalyst
loading and efficiently provided the glycoside products 12ab–
af. For the electron-rich acceptors 6c–e, quantitative con-
version was reached within 24 h (entries 2–4), whereas the
benzoyl-protected acceptor reacted somewhat more slowly
(entry 5). Note that 12ac–af were exclusively formed as the a-
anomers. The results obtained with the silyl-protected galactal
10b are summarized in entries 6–8. When combined with
primary (6c) and secondary (6d,e) acceptors, the silyl-
protected donor 10b also afforded high glycosylation yields,
with only the a-anomer detectable. Under our standard
reaction conditions, the acetyl-protected galactal 10c did not
undergo alcohol addition, even with methanol (6b; entry 9).
This deactivating effect of acetyl protection has been
observed before.[6a] In the more challenging glucal series,
the benzyl-protected donor 11a reacted smoothly with the
primary acceptor galactose acetonide 6c with very high
anomeric selectivity (entry 10).[14a,b] The same holds for the
silyl-protected glucal 11b (entry 11), although the yield of
isolated glycoside was somewhat lower (63% vs. quantita-
tive). As in the case of the galactal 10c, the acetyl-protected
glucal 11c did not undergo alcohol addition (entry 12). Note
that Ferrier rearrangement products were not detected for
any of the examples reported in Table 1.
Scheme 2. Tetrahydropyranyl protection of benzyl alcohol (6a), as
catalyzed by the pyridinium salts 4·X.
phenylborate 4d·BPh4, and the chloride 4d·Cl were catalyti-
cally active as well.[13] Interestingly, the N-(pentafluoroben-
zyl)pyridinium bromide 9·Br, which has no electron-with-
drawing substituents at the pyridine ring, failed to promote
product formation. Note that this importance of electron
deficiency for catalytic activity is in line with our earlier
observations on pyridinium catalytic activity/inactivity in silyl
ketene acetal additions to a-chloroethers.[8]
After successful establishment of the THP protection of
benzyl alcohol, we turned our attention towards the more
challenging glycosylations (Table 1). As glycal components,
we chose benzyl-, silyl-, and acetyl-protected galactals (10a–
c) and glucals (11a–c). As glycosyl acceptors, we selected bis-
The remarkable activity of electron-deficient pyridinium
salts in glycosylation prompted us to investigate the mecha-
nism of catalysis. We selected the addition of methanol (6b)
to the benzyl-protected d-glucal 11a as the model trans-
formation. We speculated that the combination of pyridinium
salt and alcohol might generate some kind of alcohol–
pyridinium complex/conjugate that is acidic enough to effect
catalysis. With this in mind, we first synthesized the ammo-
nium salts 16–18 and tested them in the acetalization of d-
glucal 11a (see the Supporting Information for the synthesis
and crystal structures of 16–18).
Table 1: Addition of alcohols to the glycals 10a–c and 11a–c in the
presence of the pyridinium salt 4a·Br.
Entry[a] Glycal Alcohol Cat. loading
[mol%]
Conv.
[%][b]
Product, Yield
[%][c,d]
1
2
3
4
5
6
7
8
10a
10a
6b
6c
1
1
2
2
2
2
2
2
2
2
2
2
quant.
quant.
quant.
quant.
66
quant.
quant.
quant.
0
12ab, 89 [5.9:1]
12ac, 94 [a only]
12ad, 97 [a only]
12ae, 97 [a only]
12af, 60 [a only]
12bc, 96 [a only]
12bd, 82 [a only]
12be, 88 [a only]
n.a.
10a[e] 6d
10a[e] 6e
10a[e] 6 f
It was found that the piperidinium salt 16 was much less
reactive than its corresponding diester analogue 17 (Table 2,
entries 1 and 2). This result parallels the reactivity of the
related pyridinium salts 9·Br vs. 4d·Br. Also, N-(cyanome-
thyl)piperidinium chloride (18) was found to be more reactive
than its N-pentafluorobenzyl analogue 16 (Table 2, entry 1 vs.
entries 3,4). These results indicate that electron-deficient
ammonium salts, but not simple trialkyl ones, are acidic
enough to promote acetalization.[14c]
10b
6c
10b[e] 6d
10b[e] 6e
10c[e] 6b
11a[e] 6c
11b[e] 6c
11c[e] 6b
9
10
11
12
quant.
quant.
0
13ac, 89 [33:1]
13bc, 63 [a only]
n.a.
[a] 3 equiv of MeOH (6b) were used, all other alcohol nucleophiles were
used at 1.2 equiv. [b] From 1H NMR spectroscopy of the crude reaction
mixture. [c] Isolated product after column chromatography. [d] a/b ratios
in brackets from H NMR spectroscopy. [e] Reaction was carried out at
408C.
Our next concern was to exclude free HX as a potential
catalyst. We did so by deliberately performing the acetaliza-
tion of d-glucal 11a in the presence of 10 mol% of HBr and
1
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Table 2: Addition of methanol to the glycals 10a and 11a in the presence
of the pyridinium salts 4d·Br and 4d·Cl and other catalyst candidates.
deuterated DCM, we observed quantitative formation of the
addition product 19, with exclusive 1,2-regioselectivity
(Scheme 3, see the Supporting Information for full character-
ization of 19).[15,16] We were also able to crystallize the 2-
addition product 19 and determine its structure (Figure 1).[17]
We observed addition in the 2-position for other alcohol
nucleophiles, as well as for benzyl amine. Benzyl thiol, on the
other hand, gave mixtures of the 2- and 4-addition products
(see the Supporting Information).[18]
Entry[a]
Glycal
Catalyst
Temperature
Conversion [%][b]
1
2
3
4
5
6
7
8
11a
11a
11a
11a
11a
11a
11a
11a
10a
10a
11a
16
17
18
18
408C
408C
RT
408C
408C
408C
408C
408C
RT
0
quant.
30
quant.
71
4d·Br
4d·Cl
HBr
HCl
82
quant.
quant. (22)[c]
Scheme 3. 1,2-Addition of benzyl alcohol (6a) to the pyridinium salt
4d·Br affords the hemiaminal 19 (DEAM-PS= diethylaminomethyl
polystyrene).
[d]
9
10
11
–
0
0
0
8
8
RT
408C
[a] 3 equiv of methanol were used in all reactions. [b] From 1H NMR
spectroscopy of the crude reaction mixture (conversion to the products
12 and 13); the product anomeric ratio was typically ca. 5.5–6 (a/b) for
the methyl galactoside 12ab and ca. 4.5 for the glucoside 13ab. [c] The
amount of Ferrier rearrangement product 15ab is given in brackets.
[d] Carried out in the presence of 10 mol% of pentafluorobenzyl bromide
or pentafluorobenzoic acid.
HCl, and comparing the product distribution with that
resulting from the use of 4d·Cl and 4d·Br (Table 2, entries 5,6
vs. entries 7,8). If a free acid generated from the pyridinium
salts was the sole catalyst, the product distribution obtained
for a Brønsted acid HX should be similar to that obtained
from the pyridinium salt 4·X. While 4d·Cl and 4d·Br show
similar reactivities for this transformations, HBr and HCl
behaved quite differently. HBr gave quantitative conversion
of 11a to the product 13ab (Table 2, entry 7); in contrast, HCl
gave substantial amounts of the Ferrier rearrangement
product 15ab, along with the glycosylation product 13ab
(Table 2, entry 8). This result speaks against free HX as the
catalyst and points to a crucial role for the pyridinium salt
itself. N-Dealkylation of the pyridinium catalysts by the
alcohol nucleophile could also be a potential source of HX.
However, even 10 mol% of pentafluorobenzyl bromide did
not lead to any product formation (Table 2, entry 9). Like-
wise, no product formation occurred when 10 mol% of
pentafluorobenzoic acid (pKa 1.60) was used (Table 2,
entry 9). In summary, the above control experiments strongly
argue against catalysis by adventitious HX and thus support
a specific mechanism of catalysis involving pyridinium
cations. Under our reaction conditions, thiourea 8 did not
promote methanol addition to the glycals 10a or 11a
(entries 10,11).
Figure 1. X-ray crystal structure of the hemiaminal 19; note the tight
stacking of the phenyl/pentafluorophenyl rings.
Combining all of these observations, we propose a step-
wise catalytic mechanism as demonstrated for dihydropyran
(5) in Scheme 4 (left). The first step involves addition of the
alcohol to the 2-position of the pyridinium salt 4·X to form the
protonated hemiaminal I. The enol ether 5 is then protonated
by the ammonium cation I to give the oxonium ion II. The
latter is captured by a second alcohol molecule in an
intermolecular fashion to give the product acetal III, with
Addition of the solid-phase-bound base diethylamino-
methyl polystyrene (DEAM-PS) to the reaction mixture
prevents acetal formation, and the 1,2-addition product of the
alcohol nucleophile to the pyridine nucleus of, for example,
4d·Br, can be detected (1H NMR). Analogously, when the
pyridinium bromide 4d·Br was exposed to an equimolar
amount of benzyl alcohol in the presence of DEAM-PS in
Scheme 4. Proposed mechanism for the addition of alcohol to the
cyclic vinyl ether 5, as catalyzed by a pyridinium salt 4·X.
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concomitant regeneration of the ammonium ion I. An
intramolecular variant of this mechanism (Scheme 4, right)
may be envisaged in which proton transfer from the
ammonium cation I to the enol ether 5 is followed by
alcoholate transfer from the aminal. A clear distinction
between the intermolecular and intramolecular mechanisms
cannot be put forward at this point. However, the catalytic
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the pyridinium salts. For both mechanistic alternatives, enol
ether activation rests on b-protonation. Consequently, it is not
surprising that the deprotonated neutral aminal 19 does not
promote acetal formation.
In conclusion, we report a new organocatalytic glycosyl-
ation method based on electron-deficient pyridinium salts.
The addition of alcohol nucleophiles to glycals proceeds
efficiently at low catalyst loading. The method provides
excellent yields of isolated glycosylation products and high
anomeric selectivity, and prevents the formation of byprod-
ucts, for example, from Ferrier rearrangement. Mechanistic
studies point to 2-addition of the alcohol nucleophile to the
pyridinium catalyst as the crucial step. Further work in this
laboratory aims at the exploitation of this mechanism for the
promotion of other addition reactions across polar double
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Experimental Section
Glycosylation of the d-galactal 10a with 1,2:3,4-di-O-isopropylidene-
a-d-galactopyranose (6c) as the glycosyl acceptor: In a screw-capped
vial and under Ar atmosphere, d-galactal 10a (110 mg, 0.26 mmol,
1.0 equiv) was dissolved in 5.0 mL dry DCM. To this solution, catalyst
4a·Br (0.8 mg, 2.6 mmol, 0.01 equiv) was added, followed by the
glycosyl acceptor 6c (82 mg, 0.31 mmol, 1.2 equiv), and the cap was
closed tightly. The reaction mixture was stirred at RT for 24 h and
then the solvent was evaporated under vacuum. The remaining crude
product was purified by column chromatography on silica gel to give
the galactoside 12ac as a clear oil. Yield: 166 mg (94%); Rf = 0.29
1
(20% EtOAc in c-hex); H NMR (500 MHz, CDCl3): d = 7.39–7.18
(m, 15), 5.52 (d, J = 5.0 Hz, 1H), 5.03 (d, J = 2.9 Hz, 1H), 4.92 (d, J =
11.6 Hz, 1H), 4.67–4.55 (m, 3H), 4.48 (d, J = 11.8 Hz, 1H), 4.42 (d, J =
11.8 Hz, 1H), 4.30 (dd, J = 4.8, 2.2 Hz, 1H), 4.20 (dd, J = 7.9, 1.7 Hz,
1H), 4.00–3.92 (m, 4H), 3.70–3.63 (m, 1H), 3.69–3.65 (m, 1H), 3.65–
3.60 (m, 1H), 3.55–3.51 (m, 1H), 2.12 (m, 1H), 2.03 (m, 1H), 1.51 (s,
3H), 1.42 (s, 3H), 1.32 (s, 6H) ppm; 13C NMR (125 MHz, CDCl3): d =
139.1, 138.7, 138.3, 128.5, 128.4, 128.3, 127.9, 127.8, 127.6, 127.4, 109.4,
108.6, 97.7, 96.5, 74.8, 74.4, 73.5, 73.0, 71.2, 70.8, 70.7, 70.5, 69.8, 69.3,
66.0, 65.7, 31.3, 26.3, 26.1, 25.1, 24.7 ppm; IR (ATR): n˜ = 2985, 2933,
2910, 1454, 1209, 1166, 1093, 1064, 999, 732, 696 cmÀ1; HRMS (ESI):
calcd. for C39H48O10Na ([M + Na]+) 699.3139, found 699.3141. Proton
and carbon NMR spectra of the product 12ac were fully consistent
with the literature (Ref. [6a]).
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[12] Pyridinium catalysis has been reported earlier for the acetaliza-
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10, 4935 – 4938; b) B. Procuranti, L. Myles, N. Gathergood, S. J.
Connon, Synthesis 2009, 4082 – 4086.
[13] The tetraphenylborate salts 4·BPh4 were found to be of limited
stability in DCM. Therefore, further transformations with
pyridinium tetraphenylborate salts as catalysts were not
attempted.
[14] a) Tribenzyl-protected d-glucal 11a was reported to give sub-
stantial amounts of Ferrier rearrangement product and poor
anomeric selectivity when thiourea 8 was used as the catalyst:
see Ref. [6]; b) See the Supporting Information for the addition
of benzyl alcohol, methanol, 2-propanol and tert-butanol to 10a
and 11a; c) Trialkylammonium salts, such as triethylammonium
Keywords: acetals · anion binding · glycosylation ·
organocatalysis · pyridinium cations
How to cite: Angew. Chem. Int. Ed. 2015, 54, 12479–12483
Angew. Chem. 2015, 127, 12656–12660
[1] a) S. C. Ranade, A. V. Demchenko, J. Carbohydr. Chem. 2013,
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Glycosylation: Advances in Stereoselectivity and Therapeutic
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chloride, are reported in Ref. [6a] (see the Supporting Informa-
tion) to be catalytically inactive in this transformation.
[18] Note that in Ref. [12a], Connon et al. proposed a mechanism
based on the 4-addition of the alcohol to a pyridinium salt to
generate HBr.
[15] Related 1,2-additions to pyridinium cations were recently
ˇ
ˇ
reported: J. Sturala, S. Bohµcovµ, J. Chudoba, R. Metelkovµ,
[19] The project “Sustainable Chemical Synthesis (SusChemSys)” is
co-financed by the European Regional Development Fund
(ERDF) and the State of North Rhine-Westphalia, Germany,
under the Operational Programme “Regional Competitiveness
and Employment” 2007–2013.
R. Cibulka, J. Org. Chem. 2015, 80, 2676 – 2699.
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P. E. Floreancig, Org. Lett. 2007, 9, 5385 – 5388; b) G. Li, F. R.
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[17] CCDC 1057632 (17), 1057633 (S6), 1057634 (16), 1057635 (19),
1057636 (4d·NTf2), and 1067637 (18) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre.
Received: April 6, 2015
Published online: July 16, 2015
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