Novel carbohydrate-based bifunctional organocatalysts for nucleophilic addition to nitroolefins and imines

Article abstract of DOI:10.1039/c0ob01240h

Glucosamine has been selected as a cheap and readily available chiral scaffold for the synthesis of a series of novel enantiomerically pure bifunctional organocatalysts bearing a tertiary amino group in proximity to a (thio)urea group. The catalytic behav

Full text of DOI:10.1039/c0ob01240h

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 3295
www.rsc.org/obc
PAPER
Novel carbohydrate-based bifunctional organocatalysts for nucleophilic
addition to nitroolefins and imines†
Alessandra Puglisi,a Maurizio Benaglia,*a Laura Raimondi,a Luigi Lay*b and Laura Polettia
Received 23rd December 2010, Accepted 21st February 2011
DOI: 10.1039/c0ob01240h
Glucosamine has been selected as a cheap and readily available chiral scaffold for the synthesis of a
series of novel enantiomerically pure bifunctional organocatalysts bearing a tertiary amino group in
proximity to a (thio)urea group. The catalytic behaviour of these compounds, both as neutral and
N-protonated species, was investigated using the addition of acetylacetone to b-nitrostyrene as a model
reaction. Under optimized experimental conditions, chemical yields up to 93% and enantioselectivities
up to 89% were obtained. Semiempirical (AM1) computational studies allowed to find a theoretical
rationale for the chemical and stereochemical behaviour of the catalyst of choice. These catalysts were
also preliminarily investigated as promoters in the addition of diethyl malonate to the N-Boc imine of
benzaldehyde, affording the product in up to 81% ee.
In this context, however, it must be noted that only a very
limited set of chiral scaffolds have been used for the construction
The development of new and efficient chiral catalytic systems
of such catalytic systems, which were mostly derived from 1,2-
Introduction
represents a tumultuously expanding area in present day organic
chemistry. In particular, the design of chiral efficient multifunc-
tional organocatalysts has received a great deal of attention.1
diamino cyclohexane, cinchona alkaloids, and 1,1¢-binaphthyl
2,2¢-diamine. Since all of these scaffolds have some drawbacks,
mostly in term of cost and the necessity of complex synthetic
Several approaches to achieve this goal were inspired by Nature’s
manipulation, the search for alternative chiral structures suitable
extraordinarily efficient enzyme-catalyzed transformations, in
for the design of novel multifunctional organocatalysts is still a
which multistep processes are readily performed, in sharp contrast
topic of front-line interest.
to the lengthy and tedious procedures of organic synthesis. The
Carbohydrates are primarily involved in inflammatory pro-
key elements that are able to guarantee enzymes’ extraordinary
cesses, bacterial and viral invasions, tumour growth and metas-
tasis, and many other crucial biological events.4 Due to their
enormous structural diversity, oligo- and polysaccharides play
a fundamental role in signal transduction and vital molecular
recognition phenomena, thus offering exciting new therapeutic
opportunities in biomedical fields.5 Due to their crucial biological
roles carbohydrates, especially mono- and disaccharides, possess
a unique set of chemical and structural features that make them
particularly attractive as molecular scaffolds. They are readily
available in a variety of diastereomeric forms, chiral and conforma-
tionally rigid molecules providing a well defined three-dimensional
spatial arrangement of substituents and various multi-configured
hydroxyl groups for chemical modification. We therefore reasoned
that carbohydrates could offer extraordinary possibilities as basic
structures onto which new metal-free catalysts can be developed,
for their low cost, potential polyfunctionalization, and easy
possibility of different modifications for fine tuning of steric,
electronic and solubility properties. To the best of our knowledge,
there is only one report describing the use of D-glucosamine as
starting material for the synthesis of a new class of bifunctional
catalysts able to promote the Strecker and Mannich reaction
with imines.6 In this pioneering work Kunz et al. explored the
preparation of carbohydrate-based organocatalysts, where the
efficiency are poly-functionalization, pre-organization and co-
operativity. Like many other groups, we have been actively engaged
in the attempt to reproduce Nature’s efficiency in performing
catalytic transformations by building new bifunctionalized chiral
catalysts, where two organic residues will co-operate to promote
stereoselective reactions and thus perform as polyfunctional,
synergic organocatalysts.2 Examples of highly successful catalytic
systems developed in the last few years are bifunctional (thio)urea–
tertiary amine organocatalysts, employed in a great variety of
stereoselective transformations.3
aDipartimento di Chimica Organica e Industriale, CISI, Universita´ degli
Studi di Milano, via Golgi 19, I-20133, Milano, Italy. E-mail: maurizio.
benaglia@unimi.it; Fax: +390250314159
bISTM-CNR, Universita´ degli Studi di Milano, via Golgi 19, I-20133,
Milano, Italy
† Electronic supplementary information (ESI) available: Synthesis and
characterization of bifunctional catalysts 13 and 16. Characterization
details of bifunctional catalysts 10, 12, and 14. Copies of 1H and 13C
1
NMR spectra of compounds 3, 7, 10–14, and 16. H-NMR spectra and
HPLC chromatograms on chiral stationary phase of the products of the
catalytic addition of acetylacetone to different nitrostyrenes and of diethyl
malonate to imines. See DOI: 10.1039/c0ob01240h
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 3295–3302 | 3295
©

View Article Online
Fig. 1 Novel saccharide-based chiral bifunctional organocatalysts.
monosaccharide effectively replaced the more frequently used 1,2-
diamino cyclohexane scaffold and was the only stereocontrolling
element present in the molecule.7
More recently, a few contributions have explored the use
of saccharide-substituted chiral thiourea–amine compounds as
promoters of stereoselective Michael additions to nitroolefins,8
and aza-Henry reactions.9 It must be noted, however, that in
these catalysts either the chiral 1,2-diamino cyclohexane or other
amino acid-derived enantiopure diamine scaffolds were retained
as the crucial element for the stereocontrol of the reaction, while
carbohydrates have, in all cases, been introduced only as an
additional element possibly useful for a fine tuning of the catalytic
properties of the molecule.
Based on these considerations and inspired by the seminal
work by Kunz et al.,6 we decided to investigate the synthesis of
a new family of (thio)urea–amine organocatalysts,10 where both
catalytic residues were connected by an enantiomerically pure
saccharide-based scaffold, as an alternative chiral skeleton to
diamino cyclohexane (Fig. 1).
Scheme 1 The synthesis of glycosyl azides. (a) NaOMe, MeOH (qu.); (b)
TESOTf, sym-collidine, DMF (3: 97%, 5: 97% over 2 steps); (c) MeI, NaH,
DMF (82%); (d) PhCH(OMe)2, (+)-b-camphorsulfonic acid, CHCl3 (qu).
TES = triethylsilyl.
Results and discussion
When designing the novel metal-free catalysts, we selected as a
starting material the cheap, readily available in large quantities
D-glucosamine, which, by introduction of a second amino func-
tion, allows the construction of a bifunctional amine–(thio)urea-
containing catalyst. Its polyfunctionalization offers several pos-
sible structural modifications to be explored for the development
and fine tuning of the novel enantiomerically pure organocatalysts
(Fig. 1).
The bifunctional catalysts of type B were synthesized ac-
cording to the following strategy (Scheme 1). First, com-
mercial D-glucosamine was converted into the 1-azido-2-N-
allyloxycarbonyl derivative 1 as previously described.6 Next,
Zemple`n O-deacetylation of glycosyl azide 1 provided 2, and the
3, 4, and 6-hydroxyls were suitably functionalised with various
protecting groups, in order to modulate the polarity, the rigidity
and the hydrogen-bonding ability of the saccharide scaffold,
and to evaluate their influence on the behaviour of the result-
ing organocatalysts. Accordingly, the highly polar O-acetylated
scaffold 1, and its deacetylated derivative 2, both suitable to act
as hydrogen-bonding acceptors, were employed for the synthesis
of organocatalysts 10 and 13, respectively. On the other hand,
silyl and alkyl ether protecting groups dampen the polarity of
the saccharide scaffold and might interfere with its hydrogen-
bonding capacity. Intermediate 2 was therefore converted into 3
by treatment with triethylsilyl trifluoromethanesulfonate in the
presence of sym-collidine (Scheme 1).
Moreover, since semiempirical calculations suggested that the
steric hindrance of the substituents on the glycosyl moiety may
play a crucial role in the catalytic activity, small size alkyl ethers,
such as methyl groups were introduced on 2 under classical
Williamson conditions to afford 4. Finally, the importance of
the rigidity of the saccharide scaffold was investigated with the
preparation of glycosyl azide 5 by introduction of the 4,6-O-
benzylidene acetal followed by 3-O-silylation (Scheme 1).
Having the properly protected saccharide scaffolds in our hands,
we approached their conversion into bifunctional organocatalysts
of type B reported in Fig. 2. Preliminary investigations suggested
that the best sequence was the initial installation of the (thio)ureido
linkage, followed by the generation of the tertiary amine. Since
our aim was to mimic the Takemoto catalyst (A in Fig. 1), glycosyl
azide 1 was reacted with triphenylphosphine followed by the addi-
tion of 3,5-bis-trifluoromethyl phenylisothiocyanate (Scheme 2).
3296 | Org. Biomol. Chem., 2011, 9, 3295–3302
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Scheme 2 The synthesis of glucosaminylurea-based organocatalysts. (a) PPh3, ArNCS, THF (6: 45%, 7: 60%, 8: 36%, 14: 71%); (b) Pd(PPh3)4, Bu3SnH,
AcOH, CH2Cl2, then HCHO, NaCNBH3, THF (9: 67%, 10: 52%, 11: 47%, 12: 61%); (c) NaOMe, MeOH, (qu).
Scheme 3 Synthesis of glucosaminylthiourea organocatalyst 16. (a)
Pd(PPh3)4, Bu3SnH, AcOH, CH2Cl2, then HCHO, NaCNBH3, THF
(57%); (b) H2, Pd/C, ArNCS, THF (46%).
Fig. 2 The proposed stereoselection model for acetylacetone addition to
b-nitrostyrene.
was performed in the presence of the aryl isothiocyanate to afford
We observed the exclusive generation of the urea-linked compound
6, which was confirmed by NMR spectroscopy as well as by mass
spectrometry (ESI source) analysis. In particular, in the 13C-NMR
spectrum the signal corresponding to the quaternary carbon of the
new linkage appeared at 158 ppm, a chemical shift fully consistent
with a urea function.11
Eventually, organocatalyst 10 was achieved by palladium(0)-
catalyzed removal of the Aloc group and subsequent N-
dimethylation by reductive amination with formaldehyde and
sodium cyanoborohydride (Scheme 2). The same sequence was
successfully applied to glycosyl azides 3 and 5, leading to
glucosaminylurea-based organocatalysts 11 and 12 via 7 and 8,
respectively, while organocatalyst 13 was obtained by standard O-
deacetylation of 10. In contrast, O-methylated organocatalyst 14
was achieved from 4 in higher yield when N-dimethylation was
performed before the formation of the ureido linkage.
glucosaminylthiourea organocatalyst 16 (Scheme 3).
Partial epimerization of the transient anomeric amine, however,
occurred during the hydrogenation step, and organocatalyst 16
was obtained as an a,b mixture, evidenced by NMR analysis.12
In the next stage of our endeavor, the catalytic properties of
the bifunctional organocatalyst were tested in the stereoselective
addition of activated nucleophiles to nitroolefins.13
The catalytic activity of compounds 10–14 and 16 was first
evaluated in the model reaction between trans b-nitrostyrene
17 and acetylacetone (Scheme 4); the reaction was typically
performed in the presence of 10 mol% of catalyst for 18 h in
dichloromethane at room temperature; the results obtained with
chiral bifunctional catalysts of type B are reported in Table 1.
The poly-acetylated compound 10 was able to promote the
reaction in modest yield and stereoselectivity. Derivatives bearing
less sterically demanding hydroxyl groups were shown to catalyze
the acetylacetone addition with improved efficiency; better yields
were obtained with catalysts 14 and 13, although with low enan-
tioselectivity. The possibility that coordinating hydroxyl groups
may interfere with the action of the bifunctional catalyst that
should activate the reactive substrates by realizing a hydrogen
Finally, we investigated a different route to obtain the
(thio)ureido-linked organocatalyst. The silylated saccharide scaf-
fold 3 was converted into glycosyl azide 15 by deprotection of
the 2-amino group and N-dimethylation in 57% yield over two
steps. Next, catalytic hydrogenation of the anomeric azide onto 15
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 3295–3302 | 3297
©

View Article Online
Scheme 4 Addition of acetylacetone to b-nitrostyrenes.
Table 1 The stereoselective addition of acetylacetone to b-nitrostyrene
17 at RT in DCMa
Table 2 Optimization studies for the organocatalytic addition of acety-
lacetone to b-nitrostyrene 17a
Entry
Catalyst
Yield%b
ee%c
Entry
Catalyst
Solvent
Yield%b
ee%c
1
2
3
4
10
14
13
11
16
12
11
13
11
35
40
57
25
27
36
21
83
70
28
50
20
89
55
40
57
45
45
1
2
3
4
10
11
11
11
11
11
11
11
11
Et2O
DCM
Et2O
Toluene
neat
DCM
DCM
DCM
DCM
27
25
21
23
30
n.d.
27
25
93
18
89
59
79
51
—
71
57
83
5
5d
6d
7e
8f
9g
6
7d
8e
9e
a Typical experimental conditions: 0.1 mol equiv. of catalyst, 1 mol equiv.
of b-nitrostyrene, 1 mol equiv. of acetylacetone, 18 h reaction time in
DCM at 25 ◦C. b Yields of isolated products. c As determined by HPLC
on a chiral stationary phase; yields and ee are the average of duplicate
experiments. d Reaction was run in the presence of 0.1 mol equiv. of acetic
acid. e Reaction was run without solvent.
a Typical experimental conditions: 0.1 mol equiv. of catalyst, 1 mol equiv. of
b-nitrostyrene, 1 mol equiv. of acetylacetone, 18 h reaction time in DCM
at 25 ◦C. b Yields of isolated products. c As determined by HPLC on a
chiral stationary phase; yields and ee are average of duplicate experiments.
◦
d Reaction was run at 0 C. e Reaction was run with 30% mol amount of
catalyst. f Reaction was run with 10 mol equiv. of acetylacetone for 1 mol
equiv. of nitrostyrene. g Reaction was run with 5 mol equiv. of nitrostyrene
for 1 mol equiv. of acetylacetone.
bond network, was considered responsible for the disappointing
results. Indeed, the use of sugar-derived compounds with non-
coordinating protecting groups at the hydroxy residues, such as
silyl ethers afforded better results. Catalyst 11 promoted the
reaction in 89% ee, a level of stereoselection comparable to
that obtained with the Takemoto catalyst; in this case the urea
derivative was shown to behave better than the corresponding
thiourea-based catalyst 16.14 Unfortunately, also in this case, the
addition product was isolated in low chemical yield. In the attempt
to further improve the methodology the reaction was performed
without solvent, in the presence of a large excess of acetylacetone.
As expected, the product was obtained in higher yields, both
with persilylated catalyst 11 and catalyst 13 and the same level of
stereoselectivity (45% ee). A more polar reaction medium (such as
acetylacetone) compared to dichloromethane negatively affected
the coordination action of the catalyst towards the nitrostyrene.
By looking for the best experimental conditions, the catalytic
behavior of the catalyst of choice 11 was investigated in different
solvents (Table 2). Dichloromethane and toluene proved to be
the solvents of choice; lower stereoselectivities were observed in
more polar solvents like diethyl ether or by running the reaction
in acetylacetone as solvent, even when the reaction temperature
was lowered.
Table 3 The addition of acetylacetone to b-nitrostyrenes catalyzed by 11a
Entry
R
Product
Yield%b
ee%c
1
2
3
4
5
H
18
20
22
24
26
93
71
67
84
78
83
82
55
84
85
Me
OMe
Cl
CF3
a Typical experimental conditions: 0.1 mol equiv. of catalyst, 5 mol equiv.
of b-nitrostyrene, 1 mol equiv. of acetylacetone, 18 h reaction time in DCM
at 25 ◦C. b Yields of isolated products. c As determined by HPLC on a chiral
stationary phase; yields and ee are average of duplicate experiments.
Table 2). However, the chemical yield was successfully improved
by employing a five equivalent excess of nitrostyrene (see below
for the discussion of this result); by running the reaction at 25 ◦C
for 18 h the product was obtained in 93% yield and with only
marginally decreased enantioselectivity (83% ee, entry 9, Table 2).
The general applicability of the catalyst of choice, 11, was then
briefly investigated. Differently substituted nitrostyrene deriva-
tives were prepared and tested in the organocatalyzed reaction
with acetylacetone (Table 3).
Catalyst 11 promoted the addition to the differently substituted
nitroolefins in comparable chemical yields; generally, substrates
bearing electron withdrawing substituents, such as halogens or a
trifluoromethyl group, gave higher enantioselectivities than those
Unfortunately, the chemical yield was not improved either by
increasing the catalyst loading up to 30% (entry 7, Table 2) or
by performing the reaction with a great excess of acetylacetone
in DCM (entry 8, Table 2); in this case the product was isolated
with an even lower enantioselectivity (57% ee vs. 89% ee, entry 2
3298 | Org. Biomol. Chem., 2011, 9, 3295–3302
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
with nitroolefins bearing electron donating groups (see entries 4–5
of Table 3 in comparison with entry 3).
plexes A and B (0.03 kcal mol-1) increases to 2.9 kcal mol-1 when
the complexes of (R) and (S)-18 with catalyst 11 are considered
(structures A¢ and B¢ in Fig. 4), favoring the (R) product. Another
feature of the reaction is revealed by these calculations: the
complexes between reaction product (R) or (S)-18 and catalyst
11 are extremely stable; in particular, decomplexation of A¢ to
give (R)-18 and catalyst 11 requires about 8 kcal mol-1. For this
reason, probably, an excess of trans b-nitrostyrene is recommended
to obtain a reasonable reaction yield, in accordance with the
experimental findings in Table 2.
At this stage it is very difficult to propose any hypothesis of
rationalization of the stereochemical course of the reaction, also in
view of the fact that the present multifunctionalized catalysts prob-
ably present more than one possible mechanism of action. These
compounds are thought to operate as bifunctional catalysts; for
example for the addition of acetylacetone to trans b-nitrostyrene
it is quite reasonable to postulate a transition state depicted in
Fig. 2. The nitrostyrene activation through double hydrogen bond
coordination with the urea group and deprotonation of the 1,3-
diketone by the basic amino group of the 1,2-diaminocylohexane
moiety should keep the two reagents close enough to allow the
catalyst to control the absolute stereochemistry of the process.
Working on this hypothesis, we performed some preliminary
calculations with MM as well as with semiempirical methods,
and were able to underline some critical features for the reaction
promoted by sugar-derived catalysts.
A complete conformational analysis15 of catalysts 10 and
11, performed with an MMFFS force field, as included in
the MacroModel package,16 revealed the reason for the scarce
stereoselectivity of the reaction promoted by catalyst 6: in fact,
not only the basic dimethylamino group, but also the three acetyl
moieties can act as Lewis bases in this case.
With the acetylacetone enolate binding in four different posi-
tions, and thus four different relative orientations of the reactants
being accessible, a significant lack of facial stereoselectivity is
predicted, in agreement with the experimental data (Tables 1 and
2). On the other hand, oxygen atoms protected as silyl ethers are
not basic, thus other catalysts such as 11, 12 and 16 are much more
stereoselective.
To further investigate the origin of the reaction stereoselectivity,
theoretical calculations were performed on the two adducts be-
tween catalyst 11, trans b-nitrostyrene and acetylacetone enolate,
leading to the (R) and (S) products. Due to the size of the
problem, the semiempirical AM1 Hamiltonian was selected.17
In an exploratory study performed on the Takemoto catalyst
(Fig. 1), we observed a significant correspondence between the
energy difference of the two diastereoisomeric ternary adducts
and the final enantioselection in the addition of ethyl malonate to
trans b-nitrostyrene. In the case of the sugar-derived catalyst 11,
two structures A and B were fully optimized, and characterized
as minima, for the adducts leading to products (R) and (S),
respectively (Fig. 3).18
Fig. 4 AM1 structures A¢ and B¢ for the complexes of (R) and (S)-18 with
catalyst 11, respectively.
In order to further explore the catalytic behavior of this novel
class of catalysts in more challenging transformations, the addition
of activated nucleophiles to imines was studied; in particular, we
focused our attention on reactions of imines with 1,3-dicarboxylic
esters.
The addition of diethyl malonate to the N-Boc imine of ben-
zaldehyde was investigated; the reaction was typically performed
in dichloromethane at room temperature for 12 h in the presence of
10 mol% of catalyst to afford the corresponding Mannich product
27, that was isolated by flash chromatography; the results are
reported in Scheme 5.
Once again, compounds bearing hydroxyl groups able to act
as hydrogen bonding acceptors, like catalyst 14, promoted the
reaction with low enantioselectivity, although in good chemical
yield. In contrast, molecules bearing more sterically demanding
hydroxyl protecting groups catalyzed the addition to Boc-imines
in lower yields. However, for this transformation the silyl ether
was shown to be the protecting group of choice, in order to
guarantee good levels of stereoselection. With catalysts 16 and
12 the product was isolated with good enantioselectivity with 75%
and 77% ee, respectively, but it was with catalyst 11 that the best
results were observed: the expected b-amino ester was obtained in
81% enantioselectivity after an 18 h reaction at room temperature.
In conclusion, the synthesis of a new family of chiral bifunc-
tional organocatalysts was successfully realized, starting from a
readily available, cheap, enantiomerically pure material such as D-
glucosamine. For the first time, the saccharide unit was employed
as a chiral scaffold alternative to 1,2-trans-diaminocyclohexane,
bearing two catalytic residues located in a well defined spatial
arrangement. The activity of the novel catalysts was investigated in
a model reaction: the addition of acetylacetone to nitrostyrene; in
the best conditions, enantioselectivities up to 89% were obtained.
The same metal-free catalysts were then employed in the addition
of activated nucleophiles to imines: in the reaction of diethyl
malonate with N-Boc imines and the products were isolated in up
to 81% ee. An attempt to rationalize the stereochemical outcome
Fig. 3 AM1 structures A and B for the ternary complexes leading to the
(R) and (S) adducts, respectively.
The origin of the stereoselection seems to depend upon the
steric hindrance due to the silylated protecting groups of the
carbohydrate oxygens; the small energy difference between com-
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 3295–3302 | 3299
©

View Article Online
Scheme 5 The addition of diethyl malonate to N-Boc imines.
of the reaction and the behaviour of the novel catalysts was also
proposed on the basis of preliminary semiempirical (AM1) studies.
We believe that these results represent only the first step towards
the development of new carbohydrate-based metal-free catalytic
systems, which may offer several attractive features, like ready
availability, low cost, polyfunctionalization, the presence of several
well defined stereocenters and the possibility of different facile
modifications for the fine tuning of their catalytic properties.
were obtained on a polarimeter at 589 nm using a 5 mL cell with a
length of 1 dm. HPLC for ee determination was performed under
the conditions reported below. High resolution mass spectra (MS)
were performed at CIGA (Centro Interdipartimentale Grandi
Apparecchiature), with Mass Spectrometer APEX II & Xmass
software (Bruker Daltonics). Mass spectra (MS) were performed
on a hybrid quadrupole time of flight mass spectrometer equipped
with an ESI ion source.
Experimental Section
2-N-allyloxycarbonyl-2-amino-2-deoxy-b-D-glucopyranosyl azide
(2)
Computational
Compound 1 (1.95 g, 4.7 mmol)6 was dissolved in dry methanol
under an inert atmosphere and a 1 M soln of MeONa in
MeOH was added at rt until basic pH was reached. After
the disappearance of the starting material (TLC analysis), the
reaction was quenched with IR-120 resin (H+ form), filtered and
concentrated under reduced pressure, obtaining compound 2 as
a yellow glass (1.35 g, qu). The complete removal of the acetyl
groups was ascertained by NMR analysis and the compound was
used in the following steps without further characterization.
All MMFFS calculations were run with the MacroModel package;
conformational analyses were performed with the stochastic
MCMM method, with all exocyclic dihedral angles set as variables;
convergence was considered achieved when all structures within
3 kcal mol-1 from the global minimum were sampled several times.
AM1 calculations were run with the Gaussian03 package.19 All
located structures were characterized as minima by means of a
full vibrational analysis.
General
2-N-allyloxycarbonyl-2-amino-2-deoxy-3,4,6-tri-O-triethylsilyl-b-
D-glucopyranosyl azide (3)
All reactions were carried out in oven-dried glassware with
magnetic stirring under a nitrogen atmosphere, unless otherwise
stated. All commercially available reagents, including dry solvents,
were used as received. Organic extracts were dried over sodium
sulfate, filtered, and concentrated under vacuum using a rotatory
evaporator. Nonvolatile materials were dried under high vacuum.
Reactions were monitored by thin-layer chromatography on pre-
coated Merck silica gel 60 F254 plates and visualized either by
UV or by staining with a solution of cerium sulfate (1 g) and
ammonium heptamolybdate tetrahydrate (27 g) in water (469 mL)
and concentrated sulfuric acid (31 mL). Flash chromatography
was performed on Fluka silica gel 60. Proton NMR spectra were
recorded at 300 K (unless otherwise stated) on spectrometers
operating at 300, 400 or 500 MHz. Proton chemical shifts are
reported in ppm (d) with the solvent reference relative to tetram-
ethylsilane (TMS) employed as the internal standard (CDCl3 d =
7.26 ppm). Carbon chemical shifts are reported in ppm (d) relative
to TMS with the respective solvent resonance as the internal
standard (CDCl3, d = 77.0 ppm). In 13C NMR spectra, signals
corresponding to aromatic carbons are omitted. Optical rotations
Compound 2 (705 mg, 2.45 mmol) was dissolved in dry DMF
◦
under an inert atmosphere and cooled to -20 C. Sym-collidine
(3.89 mL, 29.4 mmol) and TESOTf (3.05 mL, 3.47 mmol) were
slowly dropped into the solution. After 24 h the reaction was
quenched by pouring it into NaHCO3 saturated soln and extracted
with EtOAc. The combined organic layers were washed with water,
dried (Na2SO4), filtered and concentrated under reduced pressure.
The crude product was purified by flash chromatography (eluent
Hex/AcOEt 9 : 1) providing compound 3 (1.50 g, 97%) as a glassy
solid.
aD = -32.15◦ (c 0.1, CHCl3); H NMR (400 MHz, CDCl3) d
1
5.88–6.00 (m, 1H, CHvin), 5.55 (d, 1H, JNH–2 = 9.4 Hz, NH), 5.37–
5.205 (m, 2H, CH2 vin), 4.98 (d, 1H, J1–2 = 4.8 Hz, H-1), 4.61–4.58
(m, 2H, CH2 all), 4.15 (bt, 1H, J1–2 = 9.5 Hz, H-6a), 3.91 (t, 1H, J =
3.8 Hz, H-4), 3.88–3.79 (m, 2H, H-6b, H-3), 3.74–3.69 (m, 1H, H-
5), 3.63-3.58 (m, 1H, H-2), 1.03–0.92 (m, 27H, CH3 TES), 0.73–0.50
(m, 18H, CH2 TES); 13C NMR (100.6 MHz, CDCl3) d 117.5, 88.0,
80.1, 72.7, 69.3, 65.7, 62.5, 54.5, 6.8, 4.7. ESI-MS 654.2 g mol-1
3300 | Org. Biomol. Chem., 2011, 9, 3295–3302
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
(+Na). Anal. calcd for C28H58N4O6Si3 (631.04): C, 47.27; H, 6.71;
N, 16.96%; Found: C, 47.31; H, 6.68; N, 17.00%.
64.7, 41.9, 7.2, 6.9, 6.4, 5.3, 5.2, 3.9; ESI-MS 804.3 g mol-1; Anal.
calcd for C35H63F6N3O5Si3 (804.14): C, 52.28; H, 7.90; N, 5.23%;
Found: C, 52.34; H, 7.85; N, 5.31%.
Synthesis of glucosaminyl ureas – general procedure
General procedure for the Michael addition reaction of
The glucosyl azide (1 mmol) and triphenylphosphine (1.1 mmol)
were dissolved in dry THF under a nitrogen atmosphere and
stirred overnight at rt. 3,5-Bis-trifluorometilphenyl isothiocianate
(1 mmol) was added and the reaction was stirred for a further 3 h.
The solvent was evaporated under reduced pressure and the crude
product was purified by flash chromatography, obtaining the pure
urea derivative.
2,4-pentanedione with trans-b-Nitrostyrene
Bifunctional catalyst (0.02 mmol, 0.1 eq.) and trans-b-nitrostyrene
(30 mg, 0.20 mmol, 1 eq. or 1 mmol, 5 eq., see text) were charged
in a 10 mL round bottom flask under nitrogen. DCM (0.5 mL)
was added and, after 5 min stirring at 23 ◦C, 2,4-pentanedione
(0.023 mL, 0.22 mmol, 1.1 eq.) was added via syringe. The reaction
was stirred at 23 ◦C for 18 h, then the solvent was evaporated
in vacuo and the crude product was purified by flash chromato-
graphy on silica gel (1 ¥ 16 cm silica, petroleum ether : AcOEt
7 : 3, Rf 0.25) to afford pure 3-((R)-2-nitro-1-phenylethyl)pentane-
2,4-dione.
1H-NMR (300 MHz, CDCl3): d 7.35–7.1 (m, 5H), 4.65–4.55
(m, 2H), 4.3 (d, J = 10.9 Hz, 1H), 4.2 (m, 1H), 2.3 (s, 3H), 1.9
(s, 3H). HPLC (Daicel Chiralpak AD, hexane : i-propanol 80 : 20,
flow rate = 1 mL min-1, P = 21 bar, l = 210 nm): tminor = 8.69 min,
tmajor = 11.14 min. [a]2D0 = -13.98◦ (c = 0.1, CHCl3).
N-[N-allyloxycarbonyl-2-amino-2-deoxy-3,4,6-tri-O-triethylsilyl-
b-D-glucopyranosyl], N¢-(3,5-bis-trifluoromethyl)phenyl urea (7)
Chromatographic purification of urea 7 was performed using
Hex/EtOAc 95 : 5 + 1% TEA as eluent (yield 60%).
aD = -3,69◦ (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) d
1
7.91 (s, 2H, Ar), 7.74 (s, 1H, Ar), 7.49 (bd, 1H, NH), 6.36 (bs, 1H,
NH), 5.96–5.88 (m, 1H, Hvin), 5.65 (bs, 1H, NH), 5.36–5.23 (m, 2H,
CH2 vin), 4.68–4.56 (m, 3H, CH2 all, H-6a), 4.38 (bs, 1H, H-6b), 4.08
(bt, 1H, H-1), 3.95–3.83 (m, 2H, H-2, H-3), 3.57 (bs, 1H, H-5), 3.44
(d, 1H, J = 2.7 Hz, H-4), 1.06–0.95 and 0.83 (m, 27H, CH3 TES),
0.72–0.63 (m, 18H, CH2 TES); 13C NMR (100.6 MHz, CDCl3) d
157.2, 117.8, 81.8, 71.0, 68.8, 68.4, 66.3, 58.7, 52.3, 6.7, 6.4, 4.5,
4.0; ESI-MS 883.5 g mol-1 (+Na); Anal. calcd for C37H63F6N3O7Si3
(860.16): C, 51.66; H, 7.38; N, 4.89%; Found: C, 51.69; H, 7.35;
N, 4.80%.
General procedure for the Mannich reaction of diethyl malonate
with imines
Bifunctional catalyst (0.019 mmol, 0.1 eq.) and Boc-imine
(0.19 mmol, 1 eq.) were charged in a 10 mL round bottom
flask under nitrogen. DCM (0.5 mL) was added and, after 5 min
stirring at the indicated temperature, diethyl malonate (0.058 mL,
0.38 mmol, 2 eq.) was added via syringe. The reaction was stirred
at 25 ◦C for 18 h, then the solvent was evaporated in vacuo and the
crude product was purified by flash chromatography on silica gel.
(1 ¥ 16 cm silica, petroleum ether : AcOEt 7 : 3, Rf 0.25)
1H-NMR (300 MHz, CDCl3): d 7.3 (m, 5H), 6.25 (brs, 1H),
5.4 (brs, 1H), 4.35–4.25 (m, 4H), 4.1 (d, 1H), 3.7 (s, 3H), 1.5 (t,
3H), 1.25 (t, 9H), 1.15 (t, 3H). [a]2D0 = -5.7◦ (c = 0.1, CHCl3) (R)
enantiomer.
Removal of the Aloc group and N,N-dimethylation – general
procedure
The starting urea (1 eq.) was dissolved in dry dichloromethane,
then Pd(PPh3)4 (0.02 eq.), AcOH (2.4 eq.) and Bu3SnH (1.1 eq.)
were sequentially added to the solution. After 30 min the solvent
was removed under reduced pressure, the residue was dissolved
in THF and paraformaldehyde aq. 37% solution (35 eq.) and
NaCNBH3 (8 eq.) were added. The reaction was stirred at rt for
2 h, then AcOH was added until pH 4–5. After stirring for a further
3 h, the reaction mixture was cooled to 0 ◦C and aq. NaOH 5% was
added until basic pH was reached. The mixture was extracted with
EtOAc, the combined organic layers were washed with water and
brine, dried (Na2SO4), filtered and concentrated under reduced
pressure. The crude product was purified by flash chromatography,
obtaining pure bifunctional organocatalyst.
HPLC (Daicel Chiralpak AD, hexane : i-propanol 90 : 10, flow
rate = 0.8 mL min-1, P = 15 bar, l = 225 nm) tmajor = 18.63 min,
tminor = 23.36 min.
Acknowledgements
This work was supported by MIUR (Nuovi metodi catalitici
stereoselettivi e sintesi stereoselettiva di molecole funzionali).
We also gratefully acknowledge Comune di Milano for financial
support (Convenzione 55/2008).
N-[2-N,N-dimethylamino-2-deoxy-3,4,6-tri-O-triethylsilyl-b-D-
glucopyranosyl], N¢-(3,5-bis-trifluoromethyl)phenyl urea (11)
References
Chromatographic purification of urea 11 was performed using
Hex/EtOAc 98 : 2 + TEA 1% as eluent (yield 47%).
1 C. Zhong and X. Shi, Eur. J. Org. Chem., 2010, 2999.
aD = -2.8◦ (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.83
(bs, 1H, NH), 7.58 (s, 2H, Ar), 7.28 (bs, 1H, Ar), 6.42 (d, 1H, J =
10.3 Hz, NH), 5.62 (t, 1H, J = 10.2 Hz, H-1), 3.93 (dd, 1H, J =
2.8, 10.6 Hz, H-6a), 3.84–3.78 (m, 2H, H-3, H-5), 3.66 (t, 1H, J =
9.6 Hz, H-6b), 3.41 (bt, 1H, H-4), 2.49–2.45 (m, 7H, H-2, NMe2),
1.70–0.99 (m, 18H, 6 CH3 TES), 0.82 (t, 9H, J = 7.9 Hz, 3 CH3 TES),
0.76–0.66 (m, 12H, 6 CH2 TES), 0.41 (q, 6H, J = 7.9 Hz, 3 CH2 TES);
13C NMR (100.6 MHz, CDCl3) d 153.8, 80.7, 78.2, 75.2, 74.0, 70.6,
2 A. Puglisi, R. Annunziata, M. Benaglia, F. Cozzi, A. Gervasini, V.
Bertacche and M. C. Sala, Adv. Synth. Catal., 2009, 351, 219. For an
excellent recent review see: E. L. Margelefsky, R. K. Zeidan and M. E.
Davis, Chem. Soc. Rev., 2008, 37, 1118.
3 Reviews: (a) Y. Takemoto, Org. Biomol. Chem., 2005, 3, 4299; (b) S.
J. Connon, Chem.–Eur. J., 2006, 12, 5418; (c) A. G. Doyle and E.
N. Jacobsen, Chem. Rev., 2007, 107, 5713; (d) S. J. Connon, Chem.
Commun., 2008, 2499. For recent examples of the use of bi-functional
tertiary amine/thiourea catalysts see: (e) J. M. Andres, R. Manzano
and R. Pedrosa, Chem.–Eur. J., 2008, 14, 56116–5119; (f) L.-Q. Lu,
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 3295–3302 | 3301
©

View Article Online
Y.-J. Cao, X.-P. Liu, J. An, C.-J. Yao, Z.-H. Ming and W.-J. Xiao,
J. Am. Chem. Soc., 2008, 130, 6946–6948; (g) S. E. Reisman, A.
G. Doyle and E. N. Jacobsen, J. Am. Chem. Soc., 2008, 130, 7198–
7199.
4 A. Varki, Glycobiology, 1993, 3, 97–130; R. A. Dwek, Chem. Rev., 1996,
96, 683–720.
5 B. Ernst and J. L. Magnani, Nat. Rev. Drug Discovery, 2009, 8, 661–
677.
6 C. Becker, C. Hoben and H. Kunz, Adv. Synth. Catal., 2007, 349, 417.
7 For another recent contribution about a stereoselective organocatalytic
Strecker reaction see: M. Negru, D. Schollmeyer and H. Kunz, Angew.
Chem., Int. Ed., 2007, 46, 9339.
8 (a) K. Liu, H.-F. Cui, J. Nie, K.-Y. Dong, X.-J. Li and J.-A. Ma, Org.
Lett., 2007, 9, 923; (b) X. Li, K. Liu, H. Ma, J. Nie and J.-A. Ma,
Synlett, 2008, 3242; (c) P. Gao, C. Wang, Y. Wu, Z. Zhou and C. Tang,
Eur. J. Org. Chem., 2008, 4563; (d) A. Lu, P. Gao, Y. Wu, C. Wang,
Z. Zhou and C. Tang, Org. Biomol. Chem., 2009, 7, 3141; (e) X. Pu, P.
Li, F. Peng, X. Li, H. Zhang and Z. Shao, Eur. J. Org. Chem., 2009,
4622; (f) X. Pu, F. Peng, H. Zhang and Z. Shao, Tetrahedron, 2010, 66,
3655.
9 C. Wang, Z. Zhou and C. Tang, Org. Lett., 2008, 10, 1707. See also;
A. Tsutsui, H. Takeda, M. Kimura, T. Fujimoto and T. Machinami,
Tetrahedron Lett., 2007, 48, 5213.
10 For our contribution in the field see: (a) A. Puglisi, M. Benaglia, R.
Annunziata and D. Rossi, Tetrahedron: Asymmetry, 2008, 19, 2258;
(b) A. Puglisi, L. Raimondi, M. Benaglia, M. Bonsignore and S. Rossi,
Tetrahedron Lett., 2009, 50, 4340.
11 A reasonable explanation for this result is that the initially-formed
triphenyl phosphinimine A is transformed into the carbodiimide B
via an aza Wittig-type reaction with the arylisothiocyanate. The
subsequent aqueous work-up delivered the glycosyl urea 6.
12 The separation of the components of the anomeric mixture and the
isolation of an anomerically pure thiourea was unfeasible. Moreover,
any attempt to generate the anomerically pure glucosyl amine to be
coupled with the aryl isothiocyanate failed.
13 For a recent reviews see (a) S. B. Tsogoeva, Eur. J. Org. Chem.,
2007, 1701; (b) D. Almasi, D. A. Alonso and C. Najera, Tetrahedron:
Asymmetry, 2007, 18, 299; (c) J. L. Vicario, D. Badia and L. Carrillo,
Synthesis, 2007, 2065.
14 A 70/30 a/b mixture of anomers was employed.
15 (a) T. A. Halgren, J. Comput. Chem., 1996, 17, 490–641; (b) T. A.
Halgren, J. Comput. Chem., 1999, 20, 720–748.
16 All molecular mechanics calculations were run with standard pro-
cedures implemented in the MacroModel/Batchmin 7.2 package
(Schroedinger, 2001). Original reference for Macro-Model: F. Mo-
hamadi, N. G. J. Richards, C. Guida, R. Liskamp, C. Lipton, C.
Caufield, G. Chang, T. Hendrickson and W. C. Still, J. Comput. Chem.,
1990, 11, 440–467.
17 For a discussion of AM1 features with respect to other semiempirical
Hamiltonians, see: A. R. Leach, Molecular Modelling. Prentice Hall,
New Jersey, 2001.
18 T. Okino, Y. Hoashi and Y. Takemoto, J. Am. Chem. Soc., 2003, 125,
12672.
19 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb,
J. R. Cheeseman, J. A. Montgomery Jr., T. Vreven, K. N. Kudin, J. C.
Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone, B. Mennucci,
M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M.
Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T.
Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E.
Knox, H. P. Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo,
R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi,
C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth,
P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, V. Dapprich, A. D.
Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K.
Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S.
Clifford, J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, A. Piskorz,
I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y.
Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W.
Chen, M. W. Wong, C. Gonzalez, J. A. Pople, GAUSSIAN 03, Revision
D.01, Gaussian, Wallingford, CT, 2004.
3302 | Org. Biomol. Chem., 2011, 9, 3295–3302
This journal is
The Royal Society of Chemistry 2011
©