Microwave-assisted organocatalytic anomerization of α-C- glycosylmethyl aldehydes and ketones

Article abstract of DOI:10.1021/jo701959b

(Chemical Equation Presented) The use of L-proline (30 mol %) and MW irradiation (13 W) with cooling promotes in a few hours the almost quantitative anomerization of α-C-glycosylmethyl aldehydes into β-isomers. An open-chain enamine-based mechanism is pos

Full text of DOI:10.1021/jo701959b

compounds such as C-glycopeptides4 and C-oligosaccharides5
as well as modified PNAs.6 Nevertheless, while stereoselective
syntheses of R-anomers 1-2 are straightforward for the most
common C-glycopyranosides with gluco, galacto, and manno
configuration, synthetic procedures to the corresponding â-ano-
mers appear to be much more complicated in terms of number
of steps, stereoselectivity, and general applicability.7 Therefore,
a facile as well as efficient anomerization of R-C-glycosides
1-2 to the â-anomers 3-4 is quite attractive. The group of
Zou has recently addressed this issue reporting on the use of
MeONa/Zn(OAc)2 mixture in a first instance8a and then, more
simply, MeONa alone as anomerization promoting agent.8b
Nevertheless, reported yields are not always satisfactory and
isolation of target â-C-glycosylmethyl aldehydes 3 appears often
impractical as demonstrated by the need for in situ reduction
to the corresponding alcohols. Additionally, the proposed
methodology is incompatible with the presence of base sensitive
functionalities installed in the sugar fragments such as the ester
protective groups (Ac, Bz, Piv, Lev, etc.). Therefore, with the
aim to overcome these major limitations, we thought it quite
convenient to replace the stoichiometric, strongly basic MeONa
promoter with a mild and almost neutral catalyst. Accordingly,
we hypothesized that an R-C-glycosylmethyl aldehyde 1 or
ketone 2 (kinetic product) can react with L-proline (Figure 1)
to generate an intermediate enamine I capable of promoting
â-elimination via intramolecular hydrogen-bonding activation
and form an acyclic R,â-unsaturated carbonyl protected species
II. The less crowded and more stable â-C-glycosylmethyl
carbonyl derivative 3 or 4 (thermodynamic product) would then
result from an intramolecular hetero-Michael reaction through
the intermediate III in a domino process, being the proline
catalyst released via hydrolysis.
Microwave-Assisted Organocatalytic
Anomerization of r-C-Glycosylmethyl Aldehydes
and Ketones
Alessandro Massi,* Andrea Nuzzi, and Alessandro Dondoni*
Dipartimento di Chimica, Laboratorio di Chimica Organica,
UniVersita` di Ferrara, Via L. Borsari 46, I-44100 Ferrara, Italy
adn@unife.it; msslsn@unife.it
ReceiVed September 6, 2007
The use of L-proline (30 mol %) and MW irradiation (13
W) with cooling promotes in a few hours the almost
quantitative anomerization of R-C-glycosylmethyl aldehydes
into â-isomers. An open-chain enamine-based mechanism
is postulated for this transformation. The anomerization of
R-ketones was instead achieved by the pyrrolidine/TFA
couple and MW irradiation at 120 °C (enamine mechanism)
and by DBU as Brønsted base (enolate mechanism).
The number of studies based on organocatalytic strategies
has expanded exponentially within the last 7 years.1 However,
despite this widespread interest, the use of organocatalysis in
carbohydrate chemistry is still quite scanty. Two main topics
can be identified in this area. The first involves the development
of biomimetic strategies for the de novo carbohydrate synthesis;2
the second deals with the use of sugar derivatives as readily
available chiral scaffolds for the preparation of new classes of
organocatalysts.3 Very recently, our group has embarked on a
still-neglected research topic via organocatalysis that is the
preparation of carbohydrate-based building blocks and biologi-
cally relevant glycoconjugates. As a first example of our
incoming work we report herein the results on the organocata-
lyzed anomerization of R-C-glycosylmethyl aldehydes 1 and
ketones 2 to their corresponding â-isomers 3 and 4 (Figure 1).
These simple C-glycosides in both anomeric forms are known
to be valuable precursors to important nonnatural complex
A study of the designed proline-catalyzed anomerization
process was initially carried out using the perbenzylated R-C-
galactosylmethyl aldehyde8 1a as a model substrate (Table 1).
Experiments in different solvents with 30 mol % of catalyst at
room temperature (entries 1-4) showed variable extents of
anomerization and the formation of two byproducts 5 and 6.
The former was tentatively assigned as a diastereomeric mixture
of C-glycosylmethyl 1-oxapyrrolizidines as shown. On the basis
of previous observations,9 compounds 5 may be formed through
an azomethine ylide intermediate arising from the addition of
(4) (a) Eniade, A.; Murphy, A. V.; Landreau, G.; Ben, R. N. Bioconjugate
Chem. 2001, 12, 817-823. (b) Arya, P.; Barkley, A.; Randell, K. D. J.
Comb. Chem. 2002, 4, 193-198. (c) Debenham, S. D.; Snyder, P. W.;
Toone, E. J. J. Org. Chem. 2003, 68, 5805-5811. (d) Liu, S.; Ben, R. N.
Org. Lett. 2005, 7, 2385-2388. (e) Dondoni, A.; Massi, A.; Aldhoun, M.
J. Org. Chem., 2007, 72, 7677-7687.
(5) (a) Lin, C.-C.; Mor´ıs-Varas, F.; Weitz-Schmidt, G.; Wong, C.-H.
Bioorg. Med. Chem. 1999, 7, 425-433. (b) Kaila, N.; Thomas, B. E.;
Thakker, P.; Alvarez, J. C.; Camphausen, R. T.; Crommie, D. Bioorg. Med.
Chem. Lett. 2001, 11, 151-155. (c) Postema, M. H. D.; Piper, J. L.; Liu,
L.; Shen, J.; Faust, M.; Andreana, P. J. Org. Chem. 2003, 68, 478-475.
(6) Hamzavi, R.; Dolle, F.; Tavitian, B.; Dahl, O.; Nielsen, P. E.;
Bioconjugate Chem. 2003, 14, 941-954.
(7) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
4976-4978. For a detailed discussion on the synthesis of â-C-glycosides,
see also ref. 8.
(1) (a) Berkessel, A.; Gro¨ger, H.; MacMillan, D. W. C. Asymmetric
Organocatalysis; Wiley-VCH: Weinheim, Germany, 2005; pp 1-454. For
reviews, see: (b) List, B. Chem. Commun. 2006, 819-824. (c) Taylor, M.
S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520-1543.
(2) A selection: (a) Northrup, A. B.; Mangion, I. K.; Hettche, F.;
MacMillan, D. W. C. Angew. Chem., Int. Ed. 2004, 43, 2152-2154. (b)
Suri, J. T.; Mitsumori, S.; Albertshofer, K.; Tanaka, F.; Barbas, C. F., III.
J. Org. Chem. 2006, 71, 3822-3828. (c) Ibrahem, I.; Zou, W.; Xu, Y.;
Co´rdova, A. AdV. Synth. Catal. 2006, 348, 211-222. (d) Grondal, C.;
Enders, D. AdV. Synth. Catal. 2007, 349, 694-702. For a review, see: (e)
Kazmaier, U. Angew. Chem,. Int. Ed. 2005, 44, 2186-2188.
(8) (a) Shao, H.; Wang, Z.; Lacroix, E.; Wu, S.-H.; Jennings, H. J.; Zou,
W. J. Am. Chem. Soc. 2002, 124, 2130-2131. (b) Wang, Z.; Shao, H.;
Lacoix, E.; Wu, S.-H.; Jennings, H. J.; Zou, W. J. Org. Chem. 2003, 68,
8097-8105.
(9) Dambruoso, P.; Massi, A.; Dondoni, A. Org. Lett. 2005, 7, 4657-
4660.
(3) (a) Dwivedi, N.; Bisht, S. S.; Tripathi, R. P. Carbohydr. Res. 2006,
341, 2737-2743. (b) Becker, C.; Hoben, C.; Kunz, H. AdV. Synth. Catal.
2007, 349, 417-424.
10.1021/jo701959b CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/16/2007
J. Org. Chem. 2007, 72, 10279-10282
10279

FIGURE 1. Envisaged catalytic cycle for anomerization of R-C-glycosylmethyl aldehydes and ketones 1 and 2.
TABLE 1. Optimization of the Reaction Conditions for the
Anomerization of 1aa
window by keeping the mixture of 1a and proline in MeOH at
0 °C for 1 h and then warming the reaction mixture at 30 °C
for 24 h (entry 7). Under these optimized conditions, the R- to
â-anomer conversion was excellent (â/R 19:1) and the formation
of 6 was suppressed so that the isolated yield of 3a was excellent
as well (95%).10
As indicated by the yellow color of the solution at 0 °C, the
enamine intermediate I can be generated at low temperature,
whereas the ring opening/closure process necessitates more
thermal energy. In addition, it appears that the anomerization
process as a whole is faster than the self-aldolization of 3a under
optimized conditions. Accordingly, a longer reaction time (48
h) or higher loading of the catalyst (50 mol %) afforded
appreciable amounts of 6 (entries 8-9). The anomerization of
1a was also carried out with pyrrolidine and pyrrolidine/AcOH
couple as the catalysts (entries 10-11). Both catalysts induced
the anomerization to a great extent but gave rise also to the
formation of the self-aldolization product 6, thus resulting in
low yields of isolated 3a.10 Quite notably, with the tertiary amine
base triethylamine in catalytic and even stoichiometric amount
no epimerization did take place (entries 12-13). This result
excluded a reaction mechanism via enolate generation while
the proposed mechanism via enamine intermediate by proline
catalysis appears quite reasonable.
entry
catalyst
L-prolined
solvent time â/Rb 3ac 5c
6c
1
2
DMF
24h
1:2 20 15
1:2 15 18
19:1 45
8:1 40
0:1
5:1 70
19:1 95
19:1 65
19:1 51
19:1 65
19:1 72
0:1
L-prolined
L-prolined
L-prolined
L-prolinee
L-prolinef
L-prolinef
L-prolinef
L-prolinef,g
pyrrolidinef
DMSO 24h
MeOH 24h
MeOH 8h
MeOH 24h
MeOH 12h
MeOH 24h
MeOH 48h
MeOH 24h
MeOH 24h
3
17
8
4
5
6
7
8
10
12
10
8
9
10
11
12
13
pyrrolidine/ AcOHf,h MeOH 24h
Aiming at decreasing the long reaction time needed to carry
out the anomerization of 1a, we considered the use of microwave
(MW) dielectric heating in the warming step of our protocol.
The beneficial effect of MW irradiation on the rate enhancement
of organocatalytic reactions has been described in three reports
from different laboratories.11 A recent revisitation of earlier
studies by Kappe and co-workers demonstrated that the results
Et3Nd
MeOH 24h
MeOH 24h
Et3Nd,i
0:1
a All reactions were run with 0.40 mmol of 1a and 30 mol % of catalyst.
b Determined by 1H NMR analysis of the crude reaction mixture. c Isolated
yield (see note 10). d Reaction run at room temperature. e Reaction run at
0 °C. f Reaction run at 0 °C for 1 h then at 30 °C for the stated time.
g Reaction run with 50 mol % of catalyst. h Ratio amine-protic acid 1:1.
i Reaction run with 100 mol % of catalyst.
(10) The reported yields of â-C-glycosyl methyl aldehydes and ketones
3 and 4 refer to their isolation by aqueous work up of the crude reaction
mixtures when â/R ratio was higher than 10:1. A chromatographic
purification was performed to isolate the pure â-anomers for lower â/R
ratios and when by-products and the DBU promoter contaminated the
anomerization mixtures.
(11) (a) Westermann, B.; Neuhaus, C. Angew. Chem., Int. Ed. 2005, 44,
4077-4079. (b) Rodriguez, B.; Bolm, C. J. Org. Chem. 2006, 71, 2888-
2891. (c) Mosse´, S.; Alexakis, A. Org. Lett. 2006, 8, 3577-3580.
proline to the aldehyde 1a and decarboxylation, followed by
1,3-dipolar cycloaddition of the ylide to the carbonyl of a second
molecule of 1a. The formation of 6 should instead arise from
the consumption of 3a via self-aldolization and dehydration.
While the decrease of the reaction time and temperature (entries
4-5) had marked negative effects, we found a suitable reaction
10280 J. Org. Chem., Vol. 72, No. 26, 2007

TABLE 2. MW-Assisted Proline-Catalyzed Anomerization of 1aa
TABLE 3. Proline-Catalyzed Anomerization of r-Aldehydes 1a
mol% of
catalyst
powerb
(W)
time
(min)
tempc
(°C)
entry
â/Rd
3ae
6e
1
2
3
4
5
6
7
8
9
30f
30f
30f
30f
30f
10f
10f
30g
30g
30i
45
120
60
120
60
60
240
60
100
58
58
22
50
19:1
19:1
19:1
0:1
19:1
1:2
41
65
78
20
10
5
15
15
10
13
13
13
13
13
95
22
75
95
95
95
50
50
5:1
50
19:1
19:1
18:1
60
60
61h
61h
10
a All reactions were run with 0.40 mmol of 1a and the stated amount of
L-proline in MeOH at 0 °C for 1 h; then the mixture was warmed by MW
irradiation for the stated time. b Application of a constant power. c All
temperatures were measured externally by an IR sensor; simultaneous air-
cooling was applied using compressed air with a constant pressure of 4
bar. d Determined by 1H NMR analysis of the crude reaction mixture.
e Isolated yield (see note 10). f Experiment run in Biotage Initiator.
g Experiment run in CEM Discover. h Temperature measured with internal
fiber-optic probe. i Experiment run in a conventional preheated oil bath.
obtained with MW irradiation can be reproduced at the same
reaction temperature and time simply by heating the reaction
in an oil bath.12 The results of our study on the MW-assisted
anomerization of 1a are summarized in Table 2. All experiments
were conducted under optimized conditions (L-proline 30 mol
%, MeOH, 0 °C for 1 h, and then warming) in septum-sealed
reaction vessels with the single-mode cavity dedicated reactor
Biotage Initiator. All reaction temperatures were measured
externally on the outside vessel wall by an IR sensor, as
permitted only by the conventional setup of the above MW
reactor. With a temperature-controlled program at 100 °C the
maximum conversion (â/R 19:1) was observed after only 45
min, but a low yield of 3a was obtained owing to the formation
of 6 (entry 1). Consequently, we adopted irradiation at constant
power using simultaneous external cooling of the vial by
compressed air. After some experimentations (entries 2-4) we
found that with a MW power of 13 W (50 °C) for 1 h the sole
â-anomer 3a was obtained in almost quantitative yield (entry
5).10 This transformation was performed up to 1 gram scale.
Hence the absence of byproducts and the high anomeric ratio
(â/R 19:1) enable the use of 3a in preparative experiments just
after a simple aqueous work up without the need of any
chromatographic purification.10 This is a significant result due
to the substantial degradation of â-aldehydes 3 over silica gel.
Triggered by previous observations on the beneficial effect of
MW irradiation on the reduction of catalyst amount in orga-
nocatalyzed reactions,11b we next performed the above optimized
procedure using 10 mol % of L-proline. Unfortunately, low
levels of conversion were detected within reasonable reaction
times (entries 6-7).
a All reactions were run with 0.40 mmol of R-aldehyde. b Determined
by 1H NMR analysis of the crude reaction mixture. c Isolated yield (see
note 10). d Homogeneous by chromatography.
11 °C was detected with the two different probes in the presence
of simultaneous cooling of the vial by compressed air (entries
8-9). Hence, the final run was performed for 1 h in a oil bath
preheated at 61 °C (entry 10). The results of this experiment
almost exactly matched the data from optimized MW experi-
ments (entries 5 and 8-9) in terms of both isolated 3a and â/R
ratio, thus excluding the occurrence of any possible nonthermal
MW effects in this type of transformation.
With the above information in hand, we examined the
substrate generality of the anomerization reaction with respect
to the sugar configuration and the hydroxyl protective groups
(Table 3). To our great delight, exposure of perbenzylated R-C-
glucosylmethyl aldehyde13 1b and R-C-mannosylmethyl alde-
hyde8 1c to the optimized reaction conditions established for
1a did indeed provide high levels of conversion into the
corresponding â-anomers 3b and 3c and no formation of any
byproduct (entries 2-3). Significantly, the evaluation of mono
and peracetylated R-C-galactosylmethyl aldehydes 1d14 and 1e15
revealed the compatibility of the proposed anomerization
procedure with ester protective groups of the sugar moiety, as
the target â-aldehydes 3d and 3e were recovered in high yields.10
Our final experiment involved performing in a preheated oil
bath the run conducted under optimal MW conditions. Since
an accurate measurement of the internal reaction temperature
was needed for this comparative study, preliminary experiments
(entries 8-9) consisted in reproducing optimized results (entry
5) by using the CEM Discover single-mode MW reactor
equipped with either the conventional IR sensor for external
measurement of reaction temperature or a fiber-optic probe for
direct monitoring of the internal temperature. A difference of
The proline-catalyzed anomerization strategy was next applied
to R-C-glycosylmethyl ketones 2. The substrate generality was
examined with respect to the nonsugar residue linked to the
carbonyl group. Hence R-linked methyl, allyl, and phenyl
(13) (a) Sparks, M. A.; Panek, J. S. Tetrahedron Lett. 1989, 30, 4017-
410. (b) Nolen, E. G.; Watts, M. M.; Fowler, D. J. Org. Lett. 2002, 4,
3963-3965.
(14) This aldehyde was prepared from the R-C-allyl precursor of 1a by
selective 6-O-acetolysis as detailed in Supporting Information.
(15) Liu, S.; Ben, R. N. Org. Lett. 2005, 7, 2385-2388.
(12) Hosseini, M.; Stiasmi, N.; Barbieri, V.; Kappe, C. O. J. Org. Chem.
2007, 72, 1417-1424.
J. Org. Chem, Vol. 72, No. 26, 2007 10281

TABLE 4. Anomerization of r-C-Glycosylmethyl Ketones 2 under
B). Finally we observed that anomerization induced by pyrro-
lidine/TFA couple was compatible with the peracetylated
galactosyl residue of 2d, whereas the use of DBU as a strong
base resulted in substantial degradation of the formed â-anomer
4d (entry 4).
Lewis- and Brønsted-Base Catalysisa
In summary, anomerization of O-Bn and O-Ac R-C-glyco-
sylmethyl aldehydes and ketones has been shown to occur in
good yields under a set of optimized, MW-assisted organocata-
lytic conditions.
Experimental Section
General Procedure for the Anomerization of Aldehydes 1a-
e. A 0.5-2.0 mL process vial was filled with the sugar aldehyde
1 (0.40 mmol) and MeOH (1.5 mL). The resulting solution was
cooled to 0 °C, and then L-proline (14 mg, 0.12 mmol) was added
in one portion. The vial was sealed with the Teflon septum and
aluminum crimp by using an appropriate crimping tool. The mixture
was then vigorously stirred at 0 °C for 1 h, and then the vial was
placed in its correct position in the Biotage Initiator cavity where
irradiation at constant power (13 W) was performed for the stated
time (Table 3) with simultaneous cooling of the vial by means of
pressurized air (4 bar). After the full irradiation sequence was
completed, the vial was cooled to room temperature and then
opened. The mixture was diluted with AcOEt (80 mL) and washed
with saturated NaHCO3 (2 × 15 mL) and brine (2 × 5 mL). The
organic phase was dried (Na2SO4), filtered, and concentrated to
give crude aldehyde 3 (â/R ratio reported in Table 3).10
General Procedure for the Anomerization of Ketones 2a-d.
Method A. A 0.5-2.0 mL process vial was filled with the sugar
ketone 2 (0.40 mmol), pyrrolidine (10 µL, 0.12 mmol), trifluoro-
acetic acid (9 µL, 0.12 mmol), and DMF (1.5 mL). The vial was
sealed with the Teflon septum and aluminum crimp by using an
appropriate crimping tool. The vial was then placed in its correct
position in the Biotage Initiator cavity where irradiation for 4 h at
120 °C was performed. After the full irradiation sequence was
completed, the vial was cooled to room temperature and then
opened. The mixture was diluted with AcOEt (80 mL) and washed
with saturated NaHCO3 (2 × 15 mL) and brine (2 × 5 mL). The
organic phase was dried (Na2SO4), filtered, and concentrated to
give crude ketone 4 (â/R ratio reported in Table 4).10 Method B.
A 0.5-2.0 mL process vial was filled with the sugar ketone 2 (0.40
mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (59 µL, 0.40 mmol) and
DMF (1.5 mL). The vial was sealed with the Teflon septum and
aluminum crimp by using an appropriate crimping tool. The vial
was then placed in its correct position in the Biotage Initiator cavity
where irradiation for 4 h at 120 °C was performed. After the full
irradiation sequence was completed, the vial was cooled to room
temperature and then opened. The mixture was diluted with Et2O
(80 mL) and washed with H2O (2 × 15 mL). The organic phase
was dried (Na2SO4), filtered, and concentrated to give crude ketone
4 (â/R ratio reported in Table 4).10
a All reactions were run with 0.40 mmol of R-ketone. b Method A:
pyrrolidine/TFA (1:1, 30 mol %), DMF, MW, 120 °C, 4 h. Method B:
DBU (100 mol %), MW, 120 °C, DMF, 2 h. c Determined by 1H NMR
analysis of the crude reaction mixture. d Isolated yield (see note 10).
e Reaction time 1 h. f Reaction time 2 h.
C-galactosylmethyl ketones 2a-d shown in Table 4 were
prepared as detailed in the Supporting Information. Quite
disappointedly, the anomerization of the model ketone 2a did
not take place at all under the optimized conditions established
for the conversion of the R-aldehydes 1 (Table 2, entry 5). After
some experimentations (see Supporting Information, Table 1S),
we found that the couple pyrrolidine/TFA (30 mol %) in DMF
at 120 °C, MW, 4 h promoted the anomerization of 2a to 4a to
a significant extent (Table 4, entry 1, method A). Aiming at
increasing the efficiency of the process, we also considered the
use of organic Brønsted bases of different strength (DABCO,
quinine, PS-BEMP, and DBU) to catalyze the epimerization of
ketones 2 through enolate generation.16 Only stoichiometric
DBU (DMF, MW, 120 °C, 2 h) promoted the anomerization of
2a to 4a, although with low efficiency (â/R 2:1, entry 1, method
B).
Methods A and B were then applied to ketones 2b-d. As
expected on the basis of Zou results,8 under both Lewis and
Brønsted base catalysis, double bond migration took place in
the allyl ketone 2b to form the more stable conjugated derivative
7 (entry 2) although with still preferential R-configuration. The
evaluation of the phenyl ketone 2c demonstrated the incompat-
ibility of enamine catalysis with the anomerization of aromatic
R-glycosylmethyl ketones. Nevertheless, an almost complete
conversion into the target â-anomer 4c was achieved via enolate
intermediate using DBU as the base promoter (entry 3, method
Acknowledgment. We gratefully acknowledge University
of Ferrara for financial support and Centro RMN. Thanks are
due to Dr. Stefano Neodo for preliminary experiments. We also
thank Dr. Andrea Rota from CEM for making available to us
the CEM Discover reactor for MW experiments.
Supporting Information Available: Experimental procedures,
characterization data, and selected examples of temperature, pres-
sure, and MW power profiles. This material is available free of
charge via the Internet at http://pubs.acs.org.
(16) Anomerization of 2a through the enolate has been reported using
NaOMe (ref. 8). Similarly, K2CO3 and KOH were used in an earlier time
for the anomerization of R-C-glucosyl acetone: Allevi, P.; Anastasia, M.;
Ciuffredda, P.; Fiecchi, A.; Scala, A. J. Chem. Soc., Perkin Trans. 1 1989,
1275-1280.
JO701959B
10282 J. Org. Chem., Vol. 72, No. 26, 2007