Intercepted dehomologation of aldoses by N-heterocyclic carbene catalysis-a novel transformation in carbohydrate chemistry

Article abstract of DOI:10.1039/c9cc05906g

The development of an N-heterocyclic carbene (NHC) catalysed intercepted dehomologation of aldoses is reported. The unique selectivity of NHCs for aldehydes is exploited in the complex context of reducing sugars. Examples of strong substrate governance for either intercepted dehomologation or a subsequent redox-lactonisation were identified and mechanistically understood. More importantly, it was shown that catalyst design allowed the tuning of the selectivity of the reaction with structurally unbiased starting materials towards either of the two scenarios.

Full text of DOI:10.1039/c9cc05906g

Showcasing research from Markus Draskovits,
Christian Stanetty et al. from the Bioorganic Synthetic
Chemistry group, Institute of Applied Synthetic Chemistry,
TU Wien, Vienna, Austria.
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Volume 55 Number 81 18 October 2019 Pages 12115–12268
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Intercepted dehomologation of aldoses by N-heterocyclic
carbene catalysis – a novel transformation in carbohydrate
chemistry
Exploiting NHCs’ unique selectivity for aldehydes furnished
an intercepted dehomologation protocol for reducing
aldoses. Principles of substrate governance for intercepted
dehomologation or a subsequent redox-lactonisation were
identified and with structurally unbiased substrates, catalyst
design allowed tuning the selectivity towards either of these
two scenarios.
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Intercepted dehomologation of aldoses by
N-heterocyclic carbene catalysis – a novel
transformation in carbohydrate chemistry†
Cite this: Chem. Commun., 2019,
55, 12144
Received 29th July 2019,
Accepted 23rd August 2019
Markus Draskovits,
Hubert Kalaus,
Christian Stanetty * and
Marko D. Mihovilovic
DOI: 10.1039/c9cc05906g
rsc.li/chemcomm
The development of an N-heterocyclic carbene (NHC) catalysed moiety which we have just started to exploit. After the isolation
intercepted dehomologation of aldoses is reported. The unique of the first bench-stable carbene by Arduengo,9 the number of
selectivity of NHCs for aldehydes is exploited in the complex applications of NHCs has vastly increased over the last decades.
context of reducing sugars. Examples of strong substrate govern- The main areas of research have been their utilisation as ligands
ance for either intercepted dehomologation or a subsequent redox- in transition-metal catalysed reactions10 and as organocatalysts.11
lactonisation were identified and mechanistically understood. More The field of organocatalysis is dominated by processes rooted
importantly, it was shown that catalyst design allowed the tuning of in the umpolung of aldehydes,12 triggering benzoin or Stetter
the selectivity of the reaction with structurally unbiased starting type reactions13 as well as more sophisticated follow-up
materials towards either of the two scenarios.
transformations.14
The applications of NHCs within the realm of reducing sugars,
Carbohydrates are the most abundant class of all biomolecules as aldehyde species, are extremely scarce (see Scheme 1).15
formed in Nature and are found in all living organisms. They serve Wendeborn et al. attempted to perform Stetter reactions of
as structural components of cells, as energy sources within meta- fully protected reducing aldoses but instead observed dominant
bolic cycles and also play a major role in the recognition process of b-elimination towards protected 2-deoxy lactones,16 consistent
biomolecules.1 Despite their ubiquitous nature, only a limited with earlier studies on a-reducible aldehydes.17 The group of Chi
number of representatives of the family of carbohydrates are achieved the catalytic activation of fully unprotected aldoses by
readily available, requiring great synthetic efforts to provide the NHCs generating multiple nucleophilic formaldehyde equivalents
full range of carbohydrates.2 Great effort and progress have been
made in the assembly of complex oligosaccharides, often based on
elaborative protecting group chemistry to overcome the challenges
of both regio- and stereoselectivity with respect to the hydroxyl
functionalities.3 Intriguingly, the intrinsically reactive part of an
aldose, the aldehyde moiety, is targeted far less in classic carbohy-
drate chemistry.4 The established methods include addition of
organometallics (Mg, In, and Zn)5 or carbanions (Kiliani–Fischer)6
to achieve an elongation. Alternatively, also dehomologation
towards shortened carbohydrates (e.g. by the Wohl degradation)
initiate by addressing the aldehyde moiety.7 Requirements of
stoichiometric amounts of reagents and/or limited compatibility
with unprotected aldoses due to solubility and cross-reactivity with
the free hydroxyl groups are major challenges in this field.8
In this light, we perceived great potential for transforma-
tions triggered by the highly aldehyde-specific interaction of
N-heterocyclic carbenes (NHCs) with the (anomeric) carbonyl
Institute of Applied Synthetic Chemistry, TU Wien, 1060 Vienna, Austria.
Scheme 1 Examples of NHC catalysed activation of aldoses’ aldehyde
E-mail: christian.stanetty@tuwien.ac.at; Tel: +43-(1)58801-163619
moieties.
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c9cc05906g
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via a retro-benzoin reaction in an uncontrolled fashion. The
thereby achieved formylation of a,b-unsaturated compounds in
a subsequent Stetter reaction was the goal of the study, with the
sugars being utilised as a sacrificial feedstock.18
Inspired by these works and building upon the proposed
mechanism, we set out to develop an NHC controlled intercepted
dehomologation methodology of carbohydrate derivatives. See
Scheme 2 for an outline of the mechanistic consideration with
3-O-Bn-glucose 1a as an example. First, the carbene, formed
in situ from corresponding 2, attacks the aldehyde of the open-
chain form of the carbohydrate, which is in equilibrium with the
typically dominant lactol form.19 In the presence of an adjacent
OH group a retro-benzoin reaction delivers the shortened carbo-
hydrate 2-O-Bn arabinose 3. The concomitantly formed Breslow-
intermediate of formaldehyde undergoes a Stetter reaction with
a chalcone 5, thereby regenerating the catalyst (Scheme 2, bottom).
In the case of unprotected sugars the first cycle is reiterated,18
which cannot occur in the absence of an adjacent OH-group.
Nonetheless, if the intercepting group can act as a leaving group,
elimination of e.g. BnOH from the Breslow intermediate occurs,
upon activation of the carbonyl of 3. Upon the tautomerisation of
Scheme 3 Proof of concept for controlled dehomologation by NHC
activation with a strongly substrate dependent reaction outcome. (i)
3,4,5-Trimethylthiazolium iodide 2 (0.25 equiv.), K2CO3 (0.2 equiv.), chalcone
5 (2.0 equiv.), MeCN, mW, 130 1C, 15 min; (ii) Ac2O, py, DMAP, rt.
the resultant acylazolium species and displacement of the NHC by of 2-hydroxy-g-butyrolactone 9a, thus reflecting successful double
ring closure deoxy lactone 4a can be formed.16
dehomologation but with concomitant redox-lactonisation via
In our study, we were first of all aiming to deliver a principle elimination of benzaldehyde. According to our hypothesis
proof of concept of the above approach and further investigate the stability of the starting material, intermediates and final
which structural features of both substrate and/or catalyst are products as lactols is responsible for the observed differences
required to allow for high selectivity for sole dehomologation or in selectivity. Consequently, 3-O-Bn glucose 1a gave mixtures of
additional elimination. We initially evaluated several suitably the dehomologated products 2-O-Bn arabinose 3 and 2-deoxy-
semi-protected reducing sugars with the thiazolium pre-catalyst ribonolactone 4a upon NHC-catalysed elimination of BnOH
2 under general conditions.18 Compounds 6 and 8 gave the (Scheme 3, bottom) reflecting similar lactol stabilities of 1a/3.
cleanest conversions and reasonable isolated yields delivering To corroborate the above mechanism, we subjected 2-O-Bn
the desired proof of concept for successfully intercepted dehomo- arabinose 3 to the standard reaction conditions and confirmed
logation (1 and 2 carbons, respectively). However, the isolated deoxy lactone 4a as the main product. Furthermore, by instal-
products turned out to be representatives of two borderline ling a better leaving group at O3 as in 3-O-(p-nitrophenyl)
scenarios (Scheme 3, top and middle). Arabinose acetonide 620 glucose 10 the subsequent elimination to 4a was dominant
furnished the desired dehomologated product erythrose acetonide under the same reaction conditions (see the ESI†).
7a as the main product (isolated as acetate 7b). In contrast,
Our ultimate goal was to achieve catalyst control over the
treatment of benzylidene glucose 8 led to predominant formation selectivity between intercepted dehomologation and subsequent
redox-lactonisation. Therefore, we selected 3-O-Bn glucose 1a
and its 2O-epimer 3-O-Bn mannose 1b as model compounds for
the re-evaluation of the reaction conditions18 and further catalyst
development. In advance, they serve as probes for potential
influence of the relative stereochemistry at C2/C3. Both substrates
and their common reaction products (3 and 4a) are accessible in a
few chemical steps (see the ESI†). A reliable procedure for an
efficient and quantitative screening was required, given the
complexity of crude reaction mixtures. We developed a method
based on a solid phase extraction (SPE) with subsequent deriva-
tisation of all carbohydrate species to allow quantification via a
calibrated GC protocol (see details in the ESI†).21
Preliminary studies clearly showed that sub-stoichiometric
amounts of base compared to the pre-catalyst (0.20 : 0.25 equiv.)
and a sufficient reservoir of chalcone (2.0 equiv.) are mandatory
requirements. Under these conditions, the influence of solvent,
type of base as well as lower and higher temperatures has been
Scheme 2 Proposed mechanism for the NHC intercepted catalyzed
dehomologation reaction of aldoses.
evaluated which is summarized for 1b as a starting material in
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Table
1
Screening of reaction conditions of the NHC-catalyzed
Table 2 Catalyst optimisation towards increased selectivitya
dehomologationa
Deviation from
standard conditions
1bb
[%]
3ab
[%]
4ab
[%]
Sumb
[%]
Entry
Entry Starting material Catalyst 1bb [%] 3b [%] 4ab [%] Ratio 3/4a
1
2
3
4
5
6
7
8
9
None
6
0
0
48
4
9
43
63
36
30
18
4
42
44
18
96
67
45
33
78
101
67
48
Solvent:MeCNc
Solvent:DMFc
Solvent:EtOHc
Base:Li2CO3
1
2
3
4
5
6
7c
1b
1b
1b
1b
1b
1b
3
2
6
63
43
93
25
7
48
29
30
2
39
78
82
43
9
17
4
10
13
6
1.1 : 1
3.2 : 1
1.8 : 1
—
3.9 : 1
6.0 : 1
—
0
3
12
13
14
15
16
16
14
83
7
0
0
46
14
18
4
Base:DBU
T = 90 1C/320 min
T = 110 1C/80 min
T = 150 1C/10 min
2
20
—
a
a
Reaction conditions: 1b/2/base/5 = 1.00 : 0.25 : 0.20 : 2.00 (molar ratio),
Reaction conditions: 1b/precatalyst/K2CO3/5 = 1.00 : 0.25 : 0.20 : 2.00
b c
b
c
20 min. Based on calibrated GC. Reactions performed under mW (molar ratio), 20 min. Based on calibrated GC. 3 used instead of 1b.
irradiation.
dehomologated to the elimination product, and with diisopro-
pylphenyl substituted thiazolium salt 16, a 6 : 1 ratio in favour of
Table 1 (and in the ESI† for 1a which performed similarly).18
The highest recovery of identified products was generally
observed in DMSO (Table 1, entries 1–4) under conventional
heating. The second generally applicable solvent was CH3CN
which was preferred for preparative experiments under mW-
heating (vide infra). The use of stock solutions in DMSO led
to increased reproducibility and facilitated the overall work
flow. Aiming to replace insoluble K2CO3, Li2CO3 and DBU were
assessed as bases (Table 1, entries 5 and 6), however,
the reaction did not occur in the case of DBU and led to a decrease
in conversion with Li2CO3. Generally, time courses were conducted
to make sure that the reported data points were representative
ones (see the ESI†). A significant decrease of identified products
with prolonged reaction time was observed, indicating competing
not yet understood side-reactions. Experiments at higher
or lower temperatures (Table 1, entries 7–9) did not give
any improvements over the standard conditions. With the
optimized reaction conditions, we turned our attention towards
the catalysts, a usually decisive element in many previous NHC-
studies.22
We exchanged the N-alkyl thiazolium salt 2 of a family of
N-aryl-thiazolium precatalysts based on Glorius’ cycloheptyl scaf-
fold (Table 2 and ESI,† for synthesis of the catalysts) to allow for
both steric and electronic tuning of the catalyst.23 Already,
phenyl-substituted thiazolium salt 12 gave an increased ratio of
2-O-Bn arabinose 3 over lactone 4a, although with a slower
conversion. Formal substitution of the phenyl substituent with
a p-methoxy group (13) resulted in an increased reactivity (total
conversion) without a beneficial effect on the selectivity. Intro-
duction of an electron withdrawing substituent p-nitrophenyl (14)
led to no reaction, which is in good agreement with the decreased
nucleophilicity of the carbene (Table 2, entries 3 and 4).
With increased steric bulk of the aromatic substituent (Table 2,
entries 5 and 6) the selectivity and conversion improved signifi-
cantly. The mesityl substituent (15) gave a 3.9 : 1 ratio of the
the dehomologated product 2-O-Bn arabinose 3 was observed. In
a separate experiment 3 was reacted with precatalyst 16 (Table 2,
entry 7) giving no notable conversion to deoxy lactone 4a,
confirming a strong selectivity of 16 for the reaction with 1b over
3. The GC-data obtained in DMSO were validated by a preparative
experiment in MeCN and under microwave irradiation, which led
to a comparable isolated yield (1 mmol scale, Scheme 4). The fact
that the gluco-analogue 1a gave inferior results (ESI†) for us
strongly indicates competing side reactions which dominate in
the case of species of high lactol stability (low open chain
content).24 The above data was initially found to show that
increasing the steric congestion around the carbene centre
increases the selectivity for the intercepted dehomologation.
We assumed this to be due to the steric clash between the 2-O-
substituent of 3 and the diisopropyl substituent of the catalyst.
Therefore, we next evaluated triphenyl substituted triazo-
lium salts as precatalysts, initially aiming at introducing addi-
tional steric bulk around the carbene centre. We discovered
that the parent Enders’ triphenyl triazolium salt 1725 led to the
exclusive formation of the deoxy lactone 4a from 1a in high GC-
yields (Table 3, entry 2) at all obtained time points. We
attempted to achieve comparable shifts in the selectivity towards
the dehomologated product 3 within this catalyst family. Never-
theless, increasing the steric bulk near the carbene moiety via
Scheme 4 Catalyst controlled divergence in a preparative fashion.
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Table 3 Further investigations on the catalystsa
Notes and references
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Entry Starting material Catalyst 1ab [%] 3b [%] 4ab [%] Sumb [%]
1
2
3
4
1a
1a
1a
1a
2
17
18
19
5
0
22
37
13
0
5
56
80
59
36
73
80
86
79
5
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a
Reaction conditions: 1a/precatalyst/K2CO3/5 = 1.00 : 0.25 : 0.20 : 2.00
b
(molar ratio), 20 min. Based on calibrated GC.
introducing again mesityl or diisopropylphenyl on one adjacent
nitrogen atom (precatalysts 18 and 19, respectively) did not lead
to a change in chemoselectivity, as seen in the thiazolium salt
series. Instead we observed a decrease in the conversion to
product 4a, indicating that the electronic properties of the
triazolium core dominate the steric effects (Table 3, entries 3
and 4). Again, the reaction with the most promising GC-yield was
repeated with MeCN as solvent under microwave irradiation,
giving lactone in a good isolated yield (5 mmol, upon acetylation,
see Scheme 4). With both the ideal substrate/catalyst combina-
tions it was attempted to decrease catalyst loading which leads to
a significant decrease in the conversion (see the ESI†).
In summary, we have delivered a clear proof of concept
for the principle feasibility of an NHC-controlled intercepted
dehomologation of semi-protected carbohydrate derivatives.
Herein, we present the first examples of substrate-dependent
and – more importantly – catalyst-controlled divergence between
selective intercepted dehomologation based on the retro-benzoin
reaction on the one hand and the subsequent b-elimination on the
other hand. Screening of our catalysts revealed the influence of
both steric and electronic properties of carbenes identifying the
first ideal substrate/catalyst combinations. Further studies on the
scope and limitations of the current methodology are in progress
and will deliver an increased understanding of and give rise to
more means of exploitation of the fascinating interaction between
NHCs and the aldoses’ aldehyde moieties.
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¨
M. Schiffrer, K. Schlogl and A. Trpisovsky for technical support.
The Austrian Science Fund FWF (Grant P 29138-N34) is grate-
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¨
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Conflicts of interest
There are no conflicts to declare.
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