New glycosyl-α-aminotetrazole-based catalysts for highly enantioselective aldol reactions

Article abstract of DOI:10.1016/j.tet.2013.04.043

Direct aldol reactions of acetone with aromatic aldehydes have been achieved in high yielding and enantioselective processes using glycosyl-α-aminotetrazoles as a new class of organocatalysts. Computational studies at DFT level have been performed to account for the experimental observations.

Full text of DOI:10.1016/j.tet.2013.04.043

Tetrahedron 69 (2013) 4899e4907
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New glycosyl-
a
-aminotetrazole-based catalysts for highly
enantioselective aldol reactions
,
b
a
,
,b,
*
Lucie Wynands a , Sebastien Delacroix b, Albert Nguyen Van Nhien a
,
ꢀ
c
c
a,b
ꢀ
Elena Soriano , Jose Marco-Contelles , Denis Postel
a
ꢀ
ꢀ
Laboratoire des Glucides-FRE3517, Universite de Picardie Jules Verne, Faculte des sciences, 33 rue Saint Leu, 80039 Amiens, France
b Institut de Chimie de Picardie, FR3085 CNRS, 33 rue Saint Leu, 80039 Amiens cedex 1, France
c
ꢀ
Laboratorio de Química Medical (IQOG, CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Direct aldol reactions of acetone with aromatic aldehydes have been achieved in high yielding and
Received 24 November 2012
Received in revised form 9 April 2013
Accepted 12 April 2013
enantioselective processes using glycosyl-a-aminotetrazoles as a new class of organocatalysts. Compu-
tational studies at DFT level have been performed to account for the experimental observations.
Ó 2013 Elsevier Ltd. All rights reserved.
Available online 16 April 2013
Keywords:
a
-Aminotetrazole
Aldolisation
Carbohydrate
DFT calculation
1. Introduction
auxiliary agents to anchor acyclic diamines derived from a-amino
acids in organocatalytic addition of acetylacetone to trans-b-
Amino acid organocatalysis have recently received much at-
nitrostyrene.8aed Organocatalysts derived from the combination of
carbohydrates and cinchona alkaloid have also been used in
tention since the discovery1,2 that
L-proline is able to catalyze direct
intermolecular aldol or Mannich reactions. Although these trans-
formations are highly enantioselective, they all rely on fairly polar
asymmetric synthesis of tertiary a L-
-hydroxy phosphonates.8e
proline attached to carbohydrate (catalyst IV) also demonstrated
that the hydroxyl group presumably promotes the coordination
leading to aldol derivatives in good yields and moderate enantio-
solvents, such as DMSO, due to the insoluble nature of
L-proline
itself, as well as on large amounts of -proline to achieve reasonable
L
yields. Consequently, small synthetic organic molecules with
greater solubility in conventional solvents would be highly desir-
selectivity.9 Glycosyl-
b
-amino acids V10 and
D-glucosamine de-
rivatives VI11 have also been studied in catalytic asymmetric aldol
able as an alternative to
L-proline. Based on these grounds, most
reactions.
investigations have focused on
L
-proline derivatives, such as ami-
notetrazole catalysts. This is the case of (S)-5-(pyrrolidin-2-yl)-1H-
tetrazole I3a,b (Fig. 1) that has promoted remarkable selectivity
compared to
N
L
-proline in organocatalytic Mannich4 reactions,
N
H2N
N
N
H
N
N
alanine-tetrazole II,5 and cyclopentylamine-tetrazole III (Fig. 1).6a,b
However, no glycosyl substituted tetrazole has been described as a
catalytic system in related synthetic transformations, and this
is very surprising, because carbohydrates have been largely used
as chiral ligands in the search for high catalytic activities and
enantioselectivities.7 Recently, carbohydrates have been used as
HN
HN
N
N
N
II
N
HN
I
NH2
III
HO
HO
O
O
O
H2N
HOOC
OMe
O
O
O
HO
HN
O
Ph
O
BnO
OMe
V
O
HO
NH2
IV
Fig. 1. Organocatalysts.
VI
* Corresponding author. Tel.: þ33 3 22827569; fax: þ33 3 22827568; e-mail
address: albert.nguyen-van-nhien@u-picardie.fr (A. Nguyen Van Nhien).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.043

4900
L. Wynands et al. / Tetrahedron 69 (2013) 4899e4907
Table 1
With these precedents in mind, we report here that the new
glycosyl- -aminotetrazoles (1d, 2d, and 3b) (Fig. 2) promote high
yielding and enantioselective direct asymmetric aldol reactions of
different aromatic aldehydes with acetone.
Direct asymmetric aldol reaction of 4-nitrobenzaldehyde with acetone catalyzed by
a
chiral amino acids (1c, 2c) and aminotetrazoles (1d, 2d)a
OH
O
O
O
cat.
+
H
60 °C, 24 h
O2N
O
O
O
O
O
O
BnO
O2N
Entry
O
O
O
HOOC
HOOC
NH2
NH2
NH2
Catalyst (mol %)
Yielda (%)
ee (%)b
O
O
O
TBDMSO
1c
2c
1
2
3
4
5
6
7
1c (20)
2c (20)
1d (20)
2d (20)
2d (5)c
2d (10)
3b (10)
19
3
14 (R)
ndd
N
NH2
O
O
O
O
O
O
BnO
N
NH
36
89
87
89
98
95 (R)
88 (R)
82 (R)
87 (R)
81 (R)
N
3b
O
N
N
N
NH2
N
NH
NH
N
N
2d
1d
a
Yield of product isolated by column chromatography.
The ee value of the product was determined by HPLC analysis using a chiral
Fig. 2. The synthesized catalysts.
b
column (chiralpak AS-H, Daicel Chemical Industries).
c
The absolute configuration was determined by comparison of the HPLC re-
2. Results and discussion
tention time of the product with reported data.17 48 h of reaction time.
d
nd: not determined.
In the first exploratory experiments we tested our recently re-
ported GlycoAminoAcids (GAAs)12 1c and 2c (Fig. 2), readily pre-
pared from precursors 113 and commercially available 2 (Scheme 1).
Oxidation using PDC afforded crude uloses, which were submitted
In order to clearly understand the role of the carbohydrate
moiety, we synthesized catalyst 3b in a similar way, but starting
from 5-O-tert-butyldimethylsilyl-1,2-O-isopropylidene-
a-D-xylo-
furanose 3,18 in 41% yield from 3a (Scheme 2).
to our modified Strecker reaction leading stereoselectively to
a-
aminonitriles 1a14 and 2a15 in 70% and 98% yields, respectively. A
€
BucherereBergs reaction led almost quantitatively to the spiranic
i) PDC, Ac O
TBDMSO
N
molecular sieves
CH Cl , reflux
O
O
O
iii) Bu SnO
TMSN
TBDMSO
TBDMSO
hydantoïns 1b and 2b. Finally, GAAs 1c and 2c were obtained by
ring opening using barium oxide, whereas the bioisostere tetrazole
derivatives 1d and 2d were synthesized from 1a and 2a using
TMSN3/Bu2SnO in toluene at 100 ꢀC in 66% and 70% yields, re-
spectively (Fig. 2).
O
O
O
O
O
O
ii) a) Ti(OiPr)
NH -MeOH 7N
b) TMSCN
NC
toluene, 100°C
N
NH
NH
HO
NH
N
3
3a (91%)
3b (41%)
Scheme 2.
i) PDC, Ac2O
Screening the reaction of 4-nitrobenzaldehyde with acetone
using catalyst 3b (entry 7, Table 1), the aldol product was nicely
obtained in an almost quantitative yield (98%) and 81% ee.
Having established the critical effect on both enantioselectivity
and yield, by changing the carboxylic group to tetrazole, we next
investigated the potent and readily available catalyst 3b in the aldol
reaction of differently substituted benzaldehydes with acetone, in
order to test the scope and generality of the reaction.
O
O
O
molecular sieves
CH2Cl2, reflux
O
O
O
O
O
O
R
iii) (NH4)2CO3
R
R
O
NH
O
NC
MeOH
H2O, 70°C
ii) a) Ti(OiPr)4
NH3-MeOH7N
b) TMSCN
HN
NH2
HO
1
R= CH2OBn
1b (95%)
1a (70%)
2a (98%)
O
2 R=
2b (97%)
O
iv) a) Ba(OH)2.8H2O
v) Bu2SnO
H2O
TMSN3
b) CO2
toluene, 100°C
dowex resin 50W-X8
O
O
O
As shown in Table 2, different types of substituted aromatic
aldehydes were found suitable reaction substrates, the corre-
sponding aldol adducts being isolated in good yields and high
O
O
O
R
N
R
N
HOOC
NH2
NH2
NH
N
1d (66%)
2d (70%)
1c (91%)
2c (72%)
Table 2
Direct asymmetric aldol reaction of aldehyde with acetone catalyzed by chiral
aminotetrazole (3b)
Scheme 1.
OH
*
O
3b
O
(10 mol%)
O
+
R
With these compounds in hands, first, we carried out the re-
action of 4-nitrobenzaldehyde with acetone, catalyzed by GAAs 1c
and 2c (20 mol %), under different experimental conditions.16 At
room temperature no reaction was observed, but after heating at
60 ꢀC, (R)-4-hydroxy-4-(4-nitrophenyl)butan-2-one was obtained
in only 19% and 3% yields (entries 1 and 2, Table 1). Next, and view
of these results we used tetrazoles 1d and 2d (Fig. 2). To our delight,
and under the same experimental conditions, the aldol was isolated
in 36% and 89% yields, respectively (entries 3 and 4) showing
ees>>88%. A reduction on the amount of the catalyst used (entries
5 and 6) afforded the aldol derivative in a similar range of yields
(87e89%) and ee (82e87%), except when the catalyst was loaded at
5 mol %, the aldolisation requiring then longer reaction times
(48 h).
60 °C, 24 h
R
H
Entry
R
Yielda (%)
ee (%)b
1
2
3
4
5
6
7
3-ClC6H4
34
46
99
73
86
98
99
98 (R)
77 (R)
92 (S)
96 (R)
75 (R)
81 (R)
83 (R)
2-Naphtyl
2-Cle6-FC6H3
3-FC6H4
2,5-F2C6H3
4-NO2C6H4
4-CNC6H4
a
Yield of product isolated by column chromatography.
b
The ee value of the product was determined by HPLC analysis using a chiral
column (chiralpak AS-H, AD-H Daicel Chemical Industries). The absolute configu-
ration was determined by comparison of the HPLC retention time of the product
with reported data.17

L. Wynands et al. / Tetrahedron 69 (2013) 4899e4907
4901
enantioselectivities. One intriguing result is the fact that the S-
isomer (entry 3) was obtained while the other substrates afforded
R-isomer. In order to rationalize the substrate’s influence and sugar
skeleton on the asymmetric induction, aminotetrazole catalyst
with modified substituent at C-5 were examined (Scheme 3).
tetrazole ring can exist in two different tautomers (2H and 3H). The
calculations indicate that 2-tautomer is more stable than the 3-
tautomer form by 1.6 and 1.9 kcal/mol for the anti and syn-en-
amine of 3b, respectively. Similar conclusions on the higher sta-
bility of the 2-tautomer have been reported by Domingo et al.20
Moreover, because the transition structures that involve intra-
molecular proton catalysis would be the more energetically viable,
we discard 3H-tautomer as operative intermediate.21
O
H2N
O
O
O
O
O
Bu2SnO
TMSN3
O
O
O
R
N
a) PPh3, THF/H2O
N
b) NH3-MeOH
R
N
At this point, we have analyzed the transition states that allow
for intramolecular acid catalysis from the tetrazole proton of the 2-
tautomer to the aldehyde acceptor. For each enamine, anti and syn,
at least four possible transition structures can be envisaged
depending of the incoming benzaldehyde: two transition struc-
tures depending on the attack face of the aldehyde (Re- or Si-face),
and two more depending on the dihedral angle between the un-
saturated reactive groups, alkene of enamine and carbonyl group of
the aldehyde (þ60ꢀ and ꢁ60ꢀ, Fig. 4).
NC
N
NH2
NH2
toluene, 100°C
NH2
NH
NH
N
N
4a
4 R = CH2OTr
R = CH2N3
(57%)
6 (52%)
5
5a (99%)
Scheme 3.
Catalysts 4a and 5a were obtained in 57% and 99% yield, re-
spectively from 413 and 5. Reduction of 5a with triphenylphosphine
led to the diamino-tetrazole 6 in 52% yield. Those catalysts were
also submitted to the aldol reaction and the results are summarized
in Table 3.
In order to get insights into the origin of the striking enantio-
selectivity found for the asymmetric aldol reaction of 4-
nitrobenzaldehyde catalyzed by 3b, firstly, we have calculated the
Table 3
Influence of C-5 substituent
Entry
Ar
4a
2d
5a
6
1d
Yield (%)
ee (%)
Yield (%)
ee (%)
Yield (%)
ee (%)
Yield (%)
ee (%)
Yield (%)
ee (%)
1
2
3
4
5
6
7
3-ClC6H4
32
15
44
32
99
97
70
81 (R)
69 (R)
89 (S)
92 (R)
80 (R)
91 (R)
88 (R)
90
38
55
54
88
89
90
67 (R)
84 (R)
97 (S)
95 (R)
75 (R)
87 (R)
91 (R)
53
53
99
54
92
91
82
96 (R)
82 (R)
96 (S)
96 (R)
80 (R)
88 (R)
88 (R)
47
nda
25
35
30
18
34
98 (R)
nda
14 (S)
97 (R)
<1 (R)
9 (R)
64
27
45
<10
76
36
91 (R)
91 (R)
98 (S)
nda
90 (R)
95 (R)b
90 (R)
2-Naphtyl
2-Cle6-FC6H3
3-FC6H4
2,5-F2C6H3
4-NO2C6H4
4-CNC6H4
6 (R)
42
a
Not determined.
Catalyst (20 mol %) was added.
b
As expected, all the catalysts gave similar results in ee% excepted
plausible transition structures. Table 4 summarizes the relative free
energies and main geometric parameters found. The data show that
the transition structures showing additional H-bond between the
carbonyl and the enamine were notably favored.17a,22 Transition
states, which lack this interaction are higher in energy by
6.8e9.5 kcal/mol. In addition, the preferred Re-face attack of the
benzaldehyde poses the aryl group facing out. This minimizes the
steric interaction between the aldehyde substituent and the methyl
or substituents of the sugar ring of the enamine (Fig. 5), placing the
substituent in a pseudoequatorial conformation.23 Accordingly, this
attack mode also shows a more perfect staggering of substituents
around the forming CeC bond. Since this intermolecular step is
exothermic, the earlier the transition state, the lower the energy
barrier and the longer the distance of the forming CeC bond. Thus,
the favored transition structure involves the attack of the anti-en-
amine on the Re-face of the aldehyde in an approaching angle of
ꢁ60ꢀ and shows the longer forming CeC bond length while the
tetrazole proton is only slightly transferred. This kinetically pre-
ferred structure drives to the R-enantiomer, in agreement with
experiment.
for catalyst 6, which afforded poor ee%. Substrate 2-Cle6-FC6H3
favors in all cases S-isomer showing in this case that the aldol
compound is not catalyst-dependent.
In order to rationalize these results including the observed
asymmetric induction, we undertook a DFT study. The focus of our
investigation was to determine why the R-isomer is favored in most
cases, and for the most efficient catalyst 3b in particular, and why
this trend is not followed for substrate 2-Cle6-FC6H3 whatever the
catalyst. Initially, we have explored the possible transition struc-
tures for different aromatic aldehydes. Organocatalyzed aldol re-
action is presumed to proceed via an enamine intermediate.19
Therefore, the model system we have studied involves the re-
action of the anti or syn-enamines of 3b with acetone (Fig. 3). The
anti and syn refer to orientation of the enamine with respect to the
tetrazole.
Fig. 3. Enamines of the tetrazole-based organocatalyst and acetone.
For 3b, the conformer anti is 3.3 kcal/mol more stable than the
rotamer syn because of unstabilizing steric interactions between
the methyl group and R in the syn-enamine. On other hand, the
Fig. 4. Plausible transition structures depending on the carbonyl approaching angle.

4902
L. Wynands et al. / Tetrahedron 69 (2013) 4899e4907
Table 4
ꢁ
Relative free energies (kcal/mol) and main geometric parameters (A) of the possible
transition structures for the addition of 4-nitro and 2-chloro-6-fluorobenzaldehyde
to enamine of 3b
4-Nitro
2-Cl, 6-F
DDG# CeC OeH NeH DDG# CeC OeH NeH
anti þ60 Si
anti þ60 Re
anti ꢁ60 Si
anti ꢁ60 Re
syn þ60 Re
syn þ60 Si
syn ꢁ60 Re
syn ꢁ60 Si
S
R
S
R
R
S
R
S
6.8
9.3
1.8
0.0
9.2
9.5
7.7
6.3
1.73 1.35 1.17 2.8
1.72 1.33 1.17 7.2
1.82 1.62 1.06 0.0
1.88 1.61 1.06 2.4
1.75 1.37 1.16 5.7
1.80 1.52 1.10 8.0
1.77 1.38 1.15 7.6
1.81 1.46 1.11 3.0
1.77 1.36 1.17
1.74 1.32 1.19
1.94 1.74 1.04
1.89 1.59 1.07
1.78 1.39 1.15
1.89 1.63 1.11
1.73 1.32 1.19
1.83 1.46 1.11
The data computed for the possible transition structures for
other differently substituted benzaldehydes catalyzed by 3b show
similar trends. In general, the transition structures showing the
additional H-bond between the carbonyl and the enamine were
notably favored (for instance, for 3-F and 3-Cl, see Fig. 6). For all the
aldehydes but for 2-Cle6-FC6H3, the transition structures involving
the anti- are favored over the syn-enamine due to the lower dis-
tortion to accommodate the proton transfer from the tetrazole unit
to the developing alkoxide, and also to the unfavorable steric in-
teractions between the methyl moiety of the enamine with the C-5
moiety and the aryl group. Moreover, the attack on the Si-face of the
aldehyde involves steric contacts that force change from the ideal
staggered substituents to more eclipsed arrangements around the
forming CeC bond. In contrast, the attack on the Re-face avoids
steric interactions with the aryl moiety and leads to the kinetically
favored enantiomer R, consistent with the experimental
observations.
Fig. 6. Relative free energies (kcal/mol) of the most favorable transition structures
leading to the enantiomers R (right) and S (left) for the addition of the enamine of 3b to
3-fluoro- (top) and 3-chlorobenzaldehyde (bottom).
enough to revert the selectivity and favor the Si-face attack over the
Re-face attack. Remarkably, the rotation of the aryl ring along the
CeC(O) bond drives to a transition structure 5.8 kcal/mol higher in
energy due to unfavorable steric interactions between the chlorine
atom and the methyl group (Fig. 7). Finally, it should be noted that
this 2,6-halo-substitution involves stronger electrostatic XeO re-
ꢁ
ꢁ
However, for substrate 2-Cle6-FC6H3 we have observed that the
Si-face attack on the anti-enamine is favored because of the elec-
trostatic stabilizing interaction between the fluorine substituent of
the aromatic ring and the proton of the methyl group of the en-
pulsions in the Re-face attacking (FeO¼2.76 A and CleO¼3.05 A in
ꢁ
0
the best cases TSD and TSD-4 , respectively, vs 2.94 and 3.23 A, for
-4
0
TSD and TSD-3 , respectively, for the Si-face attack; see Fig. 7)
-3
because of the shorter CeC forming bond and higher pyramidali-
zation of the carbonyl carbon. Therefore, the opposite
amine, as the FeH distance suggest (2.59 A).24 This effect is strong
ꢁ
Fig. 5. Relative free energies (kcal/mol) of the possible transition structures for the addition of the anti- (top) and syn-enamine (bottom) of 3b and 4-nitrobenzaldehyde. Some
schematic Newman projections along the forming CeC bond have been depicted for clarity purpose.

L. Wynands et al. / Tetrahedron 69 (2013) 4899e4907
4903
Fig. 8. Relative free energies (kcal/mol) of the most favorable transition structures for
the attack of anti-enamine of 3b to the Re-face (top) and Si-face attack (bottom) of 2,5-
F2C6H3. Plausible rotamers (right) are shown for comparison.
Fig. 7. Relative free energies (kcal/mol) of the most favorable transition structures for
the attack of anti-enamine of 3b to the Si-face (top) and Re-face attack (bottom) of 2-
Cle6-FC6H3. Plausible rotamers (right) are shown for comparison.
2.1 for 1d, in good agreement with the experimental higher ster-
eoselectivity. It is attributable to a lack of unfavorable interactions
between the proton-donor group and the C-5 substituent, which
allows a more staggered CeC forming bond for the Si-face attack
(45ꢀ for 1c vs 39ꢀ for 1d), and to the H-bond between the incipient
carboxylated oxygen of the enamine of 1c and the aromatic ring of
the benzaldehyde in the formation of the S-enantiomer (Fig. 9).
In summary, the calculations provide a stereochemical model
that rationalizes the experimental results. Thus, viable hydrogen-
bond donors can stabilize the aldolisation transition state. The
enantioselectivity is proposed to arise from intra- and in-
termolecular interactions in the staggered transition structures
between the carbohydrate and the benzaldehyde. Our data suggest
that subtle changes in both units can strongly affect the stereo-
selectivity outcome.
stereoselectivity for the acceptor 2-Cle6-FC6H3 is probably due to
the favorable weak H-bond,25 and the less significant electrostatic
XeO interactions for the Si-face attack.
For other catalysts, substrate 2-Cle6-FC6H3 also favors S-isomer,
probably because of analogous gauche interactions around the
forming CeC bond.
According to these considerations, the aldolisation with the
benzaldehyde 2,5-F2C6H3 would afford the S-enantiomer by
attacking of the anti-enamine on the Si-face. Nevertheless, calcu-
lations indicate once again that the R-enantiomer alcohol is favored
over the S-isomer, in agreement with the experimental evidences.
The energetically favored transition structure implies minimized
unfavorable steric interactions with the enamine in a nearly perfect
staggering around the forming CeC bond, as for other benzalde-
hydes related above (Figs. 5 and 6).
Moreover, we observed the formation, for the Re-face attack, of
an H-bond between the alkene proton at the enamine and the
ꢁ
fluorine atom (Fig. 8), shorter (2.46 A) than the H-bond with the
ꢁ
alkane for the Si-face attack (2.59 A), and hence probably stronger,
due to the higher acidity of the alkene proton. Contrarily to the 2,6-
dihalosubstituted aldehyde, the free rotation around the CeC(O)
bond connecting the aldehyde and aryl groups avoids unfavorable
electrostatic FeO contacts, thus restoring the Re-face attack pref-
erence. These observations can account for the computed relative
free energy values of the transition structures, 2.2 kcal/mol lower
for the Re-face attack, which agrees with the experimental data.
An important aspect of this model is that the transition state is
stabilized through hydrogen bondings and involves a proton
transfer. Therefore, a small change in the pKa value of an organic
compound would affect its catalytic activity and selectivity in the
aldol reactions.23b,26 In addition, although tetrazoles and carboxylic
acids have similar pKa values, the tetrazole group is much more
lipophilic and does not suffer from solvation issues in organic sol-
vents. Thus, we performed calculations on the differences between
catalysts 1c and 1d, which provides yields of 19 and 64%, re-
spectively, for substrate 3-Cl, and ee% of 14 (R-) and 91 (R-). The
computed results reveal a free energy of activation 1.6 kcal/mol
higher for 1c than for its isostere 1d. The most stable transition
structure for the formation of the R-enantiomer is only 1.0 below
than that for the S-enantiomer for 1c. This difference increases to
Fig. 9. Optimized transition structures for the attack of anti-enamine of 1d (left) and
1c (right) to the Si-face of 3-CleC6H4.
Next, we turned our attention to investigate our catalysts in
a one-pot reaction including aldolisation and Michael addition
starting from aldehydes. Asymmetric Michael additions of nitro-
alkanes to
a,b-unsaturated ketones is one of the most powerful
atom-economical carbonecarbon bond formation. The de-
velopment of organocatalytic systems has been successfully ap-
plied to Michael addition.27 For example,
L-proline has been used
for the addition of 2-nitropropane on aromatic -unsaturated
a,b
ketone but Et3N (50 mol %) was necessary to achieve the reaction in
37% yield with <5% ee.27a Also, recently, Yu et al. demonstrated that
immobilized Candida antarctica lipase B (CAL-B) lead in presence of
aniline to
a,b-unsaturated ketones starting from aromatic alde-
hydes via the formation of aldol derivatives.28
Keeping in mind those results, we undertook to use catalyst 6 in
order to achieve the three steps sequence including, (i) CAL-B to

4904
L. Wynands et al. / Tetrahedron 69 (2013) 4899e4907
achieve the aldolisation reaction, (ii) an amino group in catalyst 6 to
generate the -unsaturated ketone, (iii) the -aminotetrazole
group in 6 for Michael addition.
To realize the reaction, we replaced acetone by ethyl acetoace-
tate, which lead to the enolate through decarboxylation.28 The re-
sults are summarized in Table 5. The different nitro-Michael
compounds (9aec) were obtained in modest yields (5e16%) and
improvements. Regarding the structural diversity in carbohydrates,
we believe that the -aminotetrazole catalytic system can be sup-
ported by a wide range of sugar skeletons with a diversity of chiral
centers.
Computational studies to account for the experimental obser-
vations reveal that the preferred transition structures involve sta-
bilizing anti-enamine H-bond and that the enantioselectivity
results from the steric and electrostatic interactions around the
forming CeC bond. The Re-face attack generally features a more
perfect staggering of substituents around the CeC bond as this
attack mode poses the aryl group facing out, thus minimizing the
steric interaction between the aldehyde substituent and the methyl
or substituents of the sugar ring of the enamine.
a
,b
a
a
accompanied with the
a,b-unsaturated ketone intermediate
(8aec). For all the nitro derivatives, the enantioselectivities are in
the range 3e82% ee. Despite some modest results in this one-pot
three steps sequence, catalyst 6 appears to be efficient in order to
dehydrate the aldol product and to assist the Michael addition. This
last was easily demonstrated in the direct addition of 2-
nitropropane on the
a,b-unsaturated ketone 8a (Scheme 4). In
this experiment, nitro derivative 9a was obtained in 29% yield (vs
16% yield) demonstrating that the Michael addition step was the
limiting step in the one-pot sequence. Moreover, the second amino
group in catalyst 6 is essential because catalysts 1d, 2d, and 3b in
the same conditions could not afford the nitro-Michael addition.
4. Experimental section
4.1. Computational
Calculations were performed with Gaussian09.29 All geome-
tries were optimized using B3LYP/6-31G(2d,p). DFT calculations
predict good transition state geometries.30 The stationary points
thus obtained were characterized by means of harmonic anal-
ysis, and for all the transition structures, the normal mode re-
lated to the imaginary frequency corresponds to the nuclear
motion along the reaction coordinate under study. The vibra-
tional zero-point and thermal corrections to the thermodynamic
results were taken from the frequency calculations. The CPCM
solvation model31 was applied selecting the UAKS radii. Single-
point calculations were performed on the B3LYP geometries32
with M06/6-311þg(3d,2p). M06 provides more accurate selec-
tivities and thermodynamic values and incorporates dispersion
effects.33
The a-aminotetrazole group could also be helpful in the aldolisa-
tion step as demonstrated in the first paragraph.
Table 5
One-pot aldolisationeMichael addition with ethyl acetoacetate catalyzed by CAL-B
and 6
O
O2N
R
O
O
O
6, CAL-B
O
+
+
R
R
H
2-nitropropane
CH3CN/H2O
EtO
7a-c
8a-c
9a-c
,d
Entrya
R
8, Yieldb (%)
9, Yieldb (%)
ee (%)c
1
2
3
4-NO2C6H4
3-ClC6H4
2-Naphtyl
8a (16)
8b (10)
8c (29)
9a (16)
9b (6)
9c (5)
3 (S)
70 (R)
82 (R)
4.2. General
Materials and methods. Melting points are uncorrected. Optical
rotations were recorded in CHCl3, CH2Cl2, acetone or H2O solutions.
1H NMR (300.13 MHz) and 13C NMR (75.47 MHz) spectra were
recorded in CDCl3, D2O, DMSO-d6 or MeOD-d4 (internal Me4Si),
respectively. TLC was performed on Silica F254 and detection by UV
light at 254 nm or by charring with phosphomolybdic-H2SO4 re-
agent. FTIR spectra were obtained on a AVATARÔ 320 neat using
ATR and are reported in cmꢁ1. Mass spectral data were acquired on
a WATERS Micromass Q-TOFF spectrometer. HPLC analysis was
a
Reaction conditions:
7 (0.66 mmol), ethyl acetoacetate (0.78 mmol), 6
(30 mol %), CAL-B 66 mg, 2-nitropropane/CH3CN/H2O ratio (2.8/1.0/0.04), 50 ꢀC.
b
Yield of product isolated by column chromatography.
c
The ee value of the product was determined by HPLC analysis using a chiral
column (chiralpak AD-H Daicel Chemical Industries).
d
The absolute configuration was determined by comparison of the HPLC
retention time of the product with reported data.
O
O2N
performed on Waters-Breeze (2487 Dual
l Absorbance Detector
O
and 1525 Binary HPLC Pump). Chiralpak AS-H columns were pur-
chased from Daicel Chemical Industries. Column chromatography
was effected on Silica Gel 60 (230 mesh). Cyclohexane and ethyl
acetate were distilled before use.
6
(30 mol%), CAL-B
2-nitropropane
CH3CN/H2O, 50°C
O2N
O2N
8a
9a (29%)
x
4.2.1. 5-O-Benzyl-1,2-O-isopropylidenespiro[3-deoxy-a-D-erythro-
1d 2d 3b
,
or
pentofuranose-3,50-imidazolidine]-20,40-dione (1b). To a solution of
compound 1a (8.0 g, 26.29 mmol) in MeOH (120 mL) was added
(NH4)2CO3 (24.0 g, 250 mmol) and H2O (120 mL). After stirring at
70 ꢀC for 1 h and cooling at room temperature, the reaction
mixture was filtered and the solvent eliminated under reduced
Scheme 4.
3. Conclusions
pressure. After flash chromatography (EtOAc/cyclohexane, 40/60),
20
To sum up, a series of new and easily available glycosyl-based
substituted tetrazoles have been prepared, and their efficiency in
enantioselective aldol reactions clearly demonstrated, as high en-
antiomeric excesses and good to excellent yields have been ob-
tained. Moreover, catalyst 6 showed interesting results in the one-
pot three steps sequence including Michael addition. Despite some
modest results in terms of yield, this example represents a prom-
ising collaboration between biocatalysis and organocatalysis
few described in the literature and paved the way for further
compound 1b (8.7 g, 95%) was obtained as a syrup. [
0.33, CHCl3); IR (ATR)
1055 cmꢁ1 1H NMR (300.13 MHz, CDCl3)
a]
þ68 (c
D
n
2988, 2900, 1724, 1405, 1384, 1234, 1179,
8.74 (s, 1H, NH), 7.21
;
d
(m, 5H, Ph), 6.08 (s, 1H, NH), 5.92 (d, J1,2¼3.7 Hz, 1H, H-1), 4.46 (d,
1H, H-2), 4.42 (s, 2H, OCH2Ph),4.27 (t, J4,5a¼5.8 Hz, 1H, H-4), 3.70
(dd, J5a,5b¼10.4 Hz, 1H, H-5a), 3.57 (dd, J4,5b¼5.8 Hz, 1H, H-5b),
1.48, 1.28 (s, 6H, 2ꢂ CH3); 13C NMR (75.47 MHz, CDCl3)
d 172.3
(CO), 156.6 (CO), 137.6, 128.8, 128.5, 128.2 (Ph), 114.0 [OC(CH3)2],
105.3 (C-1), 81.3 (C-2), 78.7 (C-4), 74.2 (OCH2Ph), 71.2 (C-3), 68.0

L. Wynands et al. / Tetrahedron 69 (2013) 4899e4907
4905
(C-5), 27.1, 26.9 (2ꢂ CH3); HRMS: C18H24N2O5Na calcd 371.1583,
NMR (300.13 MHz, DMSO-d6)
d
7.30 (m, 5H, Ph), 6.16 (d, J1,2¼3.7 Hz,
found 371.1576.
1H, H-1), 4.92 (d, 1H, H-2), 4.48 (dd, J4,5a¼2.2 Hz, 1H, H-4), 4.40 (d,
JA,B¼12.4 Hz, 1H H-A OCH2Ph), 4.36 (d, 1H, H-B OCH2Ph), 3.67 (dd,
J5a,5b¼10.9 Hz, 1H, H-5a), 2.83 (dd, J4,5b¼7.5 Hz, 1H, H-5b), 2.50 (s,
2H, NH2), 1.60, 1.35 (s, 6H, 2ꢂ CH3); 13C NMR (75.47 MHz, DMSO-d6)
4.2.2. 1,2:5,6-Di-O-isopropylidenespiro[3-deoxy-a-D-ribo-hexofur-
anose-3,50-imidazolidine]-20,40-dione (2b). To a solution of com-
pound 2a (0.5 g, 1.76 mmol) in MeOH (10 mL) was added (NH4)2CO3
(1.70 g, 17.6 mmol) and H2O (10 mL). After stirring at 70 ꢀC for 2 h
and cooling at room temperature, the reaction mixture was filtered
and the solvent eliminated under reduced pressure. After crystal-
lization in diethyl ether, compound 2b (0.56 g, 97%) was obtained as
d
157.3 (C]N), 138.7, 129.1, 128.4 (Ph), 113.8 [OC(CH3)2], 105.6 (C-1),
83.0 (C-2), 80.2 (C-4), 73.3 (OCH2Ph), 68.8 (C-5), 61.6 (C-3), 27.2,
27.1 (2ꢂ CH3); HRMS: C16H21N5O4Na calcd 370.1491, found
370.1494.
a solid. Mp¼232e236 ꢀC; [
a
]
20 þ56 (c 0.76, CHCl3); IR (ATR)
n
2985,
4.2.6. 3-Amino-3-deoxy-1,2:5,6-di-O-isopropylidene-3-C-(1H-tetra-
zol-5-yl)-a-D-glucofuranose (2d). To a solution of 2a (6.8 g,
D
2902,1784,1721,1381,1225,1075,1017 cmꢁ1; 1H NMR (300.13 MHz,
CDCl3)
d
8.77 (s, 1H, NH), 6.16 (s, 1H, NH), 5.91 (d, J1,2¼3.6 Hz, 1H, H-
24.12 mmol) in toluene (50 mL) was added Bu2SnO (6.60 g,
26.53 mmol) and TMSN3 (6.46 mL, 48.24 mmol). After stirring for
2 h at 100 ꢀC, the solvent was removed and the residue was purified
by flash chromatography (20/80 to 50/50 EtOAC/MeOH) to afford
1), 4.55 (d, 1H, H-2), 4.17 (ddd, J4,5¼9.1 Hz, 1H, H-5),4.06 (d,
J5,6a¼3.4 Hz, 1H, H-6a), 3.96 (d, J5,6b¼3.4 Hz, 1H, H-6b), 3.96 (d, 1H,
H-4), 1.54, 1.36, 1.33, 1.24 (s, 12H, 4ꢂ CH3); 13C NMR (75.47 MHz,
CDCl3)
d
172.1 (CO), 156.2 (CO), 113.6 [OC(CH3)2], 104.8 (C-1), 81.5
2d as a white solid (5.49 g, 70%). Mp¼94e95 ꢀC; [
a
]
20 þ29 (c 0.15,
D
(C-2), 79.6 (C-4), 74.1 (C-5), 71.2 (C-3), 67.9 (C-6), 26.8, 26.6, 26.4,
24.8 (4ꢂ CH3); HRMS: C14H20N2O7Na calcd 351.1168, found
351.1168.
acetone); IR (ATR) n 2987, 2928, 2852, 1608, 1529, 1452, 1377, 1213,
1163, 1070, 1049, 1003 cmꢁ1 1H NMR (300.13 MHz, DMSO-d6)
;
d
6.14 (d, J1,2¼3.5 Hz,1H, H-1), 4.82 (d,1H, H-2), 4.36 (d, J4,5b¼3.6 Hz,
1H, H-4), 4.00 (m, 1H, H-5), 3.05 (dd, J5,6a¼6.2 Hz, J6a,6b¼8.2 Hz, 1H,
H-6a), 2.80 (t, J5,6b¼J6a,6b¼8.2 Hz, 1H, H-6b), 1.57, 1.36, 1.30, 1.17 (s,
4.2.3. 3-Amino-5-O-benzyl-3-C-carboxy-3-deoxy-1,2-O-iso-
propylidene-
a-
D-ribofuranose (1c). To a solution of compound 1b
12H, 4ꢂ CH3); 13C NMR (75.47 MHz, DMSO-d6)
d 156.7 (C]N), 113.1,
(3.13 g, 9.0 mmol) in H2O (100 mL) was added Ba(OH)2$8H2O
(8.50 g, 27.0 mmol). After stirring for 7 days at reflux, CO2 was
bubbling into the flask, then the reaction mixture was filtered and
the salt washed with hot water. After removal of the solvent, the
crude was purified by flash chromatography (EtOAc/MeOH/acetic
108.2 [OC(CH3)2], 105.4 (C-1), 83.2 (C-2), 80.8 (C-4), 73.4 (C-5), 63.3
(C-6), 61.9 (C-3), 27.0, 26.9, 26.6, 25.3 (4ꢂ CH3); HRMS: C13H22N5O5
calcd 328.1621, found 328.1623.
4.2.7. 3-Amino-3-C-cyano-3-deoxy-1,2-O-isopropylidene-5-O-tert-
acid, 80/19/1) to afford compound 1c (2.63 g, 91%) as a solid.
butyldimethylsily-
a-D-ribofuranose (3a). To a solution of 1,2-O-iso-
20
Mp¼193e194 ꢀC; [
a
]
D
þ13 (c 0.18, H2O); IR (ATR)
n
2987, 2901,
propylidene- -xylose (10.5 g, 55 mmol) in pyridine (150 mL) was
a-D
1634, 1556, 1407, 1393, 1242, 1226, 1077 cmꢁ1
;
1H NMR
added TBDMSCl (10 g, 66 mmol). After stirring for 3 h, the solvent
was removed under vacuo and the residue extracted with CH2Cl2
and H2O. The organic layer was dried over Na2SO4, filtered and
evaporated to afford compound 3 (15 g, 88%) as a syrup, which was
used in the next step without further purification. To a solution of
compound 3 (15 g, 49 mmol) in CH2Cl2 (140 mL) was added mo-
lecular sieves (one spatula) and Ac2O (18 mL, 183 mmol). The re-
action mixture was heated at reflux then PDC (12.8 g, 34 mmol) was
added portionwise. After 4 h and elimination of the solvent under
vacuo, the residue was dissolved in EtOAc and filtered through
a silica pad. Evaporation of the solvent afforded crude ulose in
a quantitative yield (14.8 g, >99%), which was used the next step.
Crude ulose (14.8 g, 49 mmol) was dissolved in a methanolic so-
lution of ammonia (7 N, 150 mL) and Ti(OiPr)4 (28 mL, 93 mmol)
was added. After stirring overnight at room temperature, TMSCN
(7.9 mL, 59 mmol) was added and the reaction mixture was stirred
for 15 h. After addition of water (<10 mL) and EtOAc, the solvent
was removed under vacuo. EtOAc was added and the residue was
filtered through a silica pad. After evaporation of the solvent,
compound 3a (14.6 g, 91%) was obtained as a white solid.
(300.13 MHz, D2O)
d
7.32 (m, 5H, Ph), 5.92 (d, J1,2¼3.6 Hz, 1H, H-1),
4.69 (s, 2H, OCH2Ph), 4.48 (d, 1H, H-2), 4.10 (dd, J4,5a¼3.0 Hz, 1H, H-
4), 3.66 (dd, J5a,5b¼11.0 Hz, 1H, H-5a), 3.45 (dd, J4,5b¼8.3 Hz, 1H, H-
5b), 1.45, 1.28 (s, 6H, 2ꢂ CH3); 13C NMR (75.47 MHz, D2O)
d 173.1
(CO), 137.4, 129.1, 128.9, 128.7 (Ph), 113.8 [OC(CH3)2], 106.0 (C-1),
82.4 (C-2), 81.3 (C-4), 73.7 (OCH2Ph), 69.2 (C-5), 67.3 (C-3), 26.1,
25.7 (2ꢂ CH3); HRMS: C16H21NO6Na calcd 346.1267, found
346.1282.
4.2.4. 3-Amino-3-C-carboxy-3-deoxy-1,2:5,6-di-O-isopropylidene-
a-
D-allofuranose (2c). To solution of compound 2b (0.30 g,
a
0.86 mmol) in H2O (12 mL) was added Ba(OH)2$8H2O (0.86 g,
2.73 mmol). After stirring for 7 days at reflux, CO2 was bubbling into
the flask, then the reaction mixture was filtered and the salt
washed with hot water. After removal of the solvent, the crude was
purified by flash chromatography (EtOAc/MeOH/acetic acid, 80/19/
1) to afford compound 2c (0.20 g, 72%) as a solid. Mp¼173e175 ꢀC;
[
a]
20 þ34 (c 0.22, H2O); IR (ATR)
n
1643, 1555, 1376, 1253, 1217, 1071,
5.90 (d, J1,2¼3.5 Hz, 1H, H-
D
1003 cmꢁ1; 1H NMR (300.13 MHz, D2O)
d
1), 4.75 (d, 1H, H-2), 4.11 (ddd, J5,6a¼6.4 Hz, 1H, H-5),4.02 (dd,
J6a,6b¼8.8 Hz, 1H, H-6a), 3.91 (d, J4,5¼7.0 Hz, 1H, H-4), 3.86 (d,
J5,6b¼4.7 Hz, 1H, H-6b), 1.47, 1.35, 1.29, 1.25 (s, 12H, 4ꢂ CH3); 13C
Mp¼35e37 ꢀC; [
a
]
20 þ7 (c 1.19, CH2Cl2); IR (ATR)
n
2929, 1474, 1385,
D
1374,1097 cmꢁ1; 1H NMR (300.13 MHz, CDCl3)
d
5.91 (d, J1,2¼3.7 Hz,
1H, H-1), 4.70 (d, 1H, H-2), 4.07 (dd, J4,5a¼9.2 Hz, J4,5b¼13.9 Hz, 1H,
H-4), 3.92e3.88 (m, 2H, H-5), 2.02 (br s, 2H, NH2), 1.57, 1.36 (s, 6H,
2ꢂ CH3), 0.90 (s, 9H, t-Bu), 0.13, 0.12 (s, 6H, 2ꢂ SiCH3); 13C NMR
NMR (75.47 MHz, D2O)
d 172.9 (CO), 114.1 [OC(CH3)2], 110.5
[OC(CH3)2], 106.0 (C-1), 82.6 (C-2), 81.9 (C-4), 74.3 (C-5), 68.2 (C-3),
66.1 (C-6), 26.2, 25.9, 25.7, 24.2 (4ꢂ CH3); HRMS: C13H21NO7Na
calcd 326.1216, found 326.1220.
(75.47 MHz, CDCl3)
d 118.7 (CN), 113.6 [OC(CH3)2], 104.1 (C-1), 83.4
(C-2), 80.8 (C-4), 62.7 (C-5), 26.6, 26.4 (2ꢂ CH3), 25.9 (t-Bu),18.3 (Cq
t-Bu), ꢁ5.7, ꢁ5.6 (2ꢂ SiCH3); HRMS: C15H28N2O4SiNa calcd 351.
1716, found 351.1709.
4.2.5. 3-Amino-5-O-benzyl-3-deoxy-1,2-O-isopropylidene-3-C-(1H-
tetrazol-5-yl)-a-D-ribofuranose (1d). To a solution of 1a (1.35 g,
4.43 mmol) in toluene (40 mL) was added Bu2SnO (1.32 g,
5.31 mmol) and TMSN3 (1.19 mL, 8.86 mmol). After stirring for 2 h
at 100 ꢀC, the solvent was removed and the residue was purified by
flash chromatography (20/80 to 50/50 EtOAC/MeOH) to afford 1d as
4.2.8. 3-Amino-5-O-tert-butyldimethylsilyl-3-deoxy-1,2-O-iso-
propylidene-3-C-(1H-tetrazol-5-yl)-a-D-ribofuranose (3b). To a solu-
tion of 3a (5.5 g, 16.76 mmol) in toluene (50 mL) was added Bu2SnO
(4.59 g, 18.43 mmol) and TMSN3 (4.50 mL, 33.52 mmol). After
stirring for 2 h at 100 ꢀC, the solvent was removed and the residue
was purified by flash chromatography (20/80 to 50/50 EtOAC/
a slight brown solid (1.02 g, 66%). Mp¼97e99 ꢀC; [
a
]
D
20 þ25 (c 0.12,
CHCl3); IR (ATR)
n
2975, 1508, 1378, 1217, 1162, 1086, 1026 cmꢁ1; 1H

4906
L. Wynands et al. / Tetrahedron 69 (2013) 4899e4907
MeOH). After crystallization in EtOAc/cyclohexane, pure compound
2.64 (dd, 1H, H-5b), 1.55, 1.36 (s, 6H, 2ꢂ CH3); 13C NMR (75.47 MHz,
3b was isolated as a white solid (2.56 g, 41%). Mp¼127e128 ꢀC;
DMSO-d6) d 157.3 (C]N), 112.8 [OC(CH3)2], 105.3 (C-1), 83.5 (C-2),
[
a]
20 þ50 (c 0.12, acetone); IR (ATR)
n
2953, 2856, 1599, 1525, 1464,
80.9 (C-4), 62.1 (C-3), 50.7 (C-5), 27.0, 26.9 (2ꢂ CH3); HRMS:
D
1388, 1375, 1253, 1217, 1163, 1078, 1024, 1003 cmꢁ1
;
1H NMR
C9H14N8O3Na calcd 305.1087, found 305.1075.
(300.13 MHz, DMSO-d6)
d
6.10 (d, J1,2¼3.6 Hz, 1H, H-1), 4.84 (d, 1H,
H-2), 4.26 (d, J4,5b¼8.3 Hz, 1H, H-4), 3.87 (d, J5a,5b¼11.7 Hz, 1H, H-
4.2.12. 3,5-Diamino-3,5-dideoxy-1,2-O-isopropylidene-3-C-(1H-tet-
razol-5-yl)-a-D-ribofuranose (6). To a solution of 5a (1.0 g,
5a), 2.81 (dd, 1H, H-5b), 1.56, 1.41 (s, 6H, 2ꢂ CH3), 0.81 (s, 9H, t-Bu),
0.02 (s, 6H, 2ꢂ SiCH3); 13C NMR (75.47 MHz, DMSO-d6)
d
156.4 (C]
3.54 mmol) in 20 mL of a mixture of THF/H2O (4/1) was added PPh3
(1.02 g, 3.90 mmol). After stirring at room temperature overnight,
the solvent was eliminated under vacuo. After extraction with
water and diethyl ether (ꢂ3) and elimination of H2O from the
aqueous layer, a methanolic solution of ammonia (7 N, 100 mL) was
added. After stirring overnight at room temperature, the solvent
was eliminated under vacuo. After extraction with water and EtOAc
N), 112.9 [OC(CH3)2], 105.3 (C-1), 83.1 (C-2), 82.3 (C-4), 62.8 (C-5),
61.4 (C-3), 26.9, 26.8 (2ꢂ CH3), 26.2 (t-Bu), 18.4 (Cq t-Bu), ꢁ4.7, ꢁ4.8
(2ꢂ SiCH3); HRMS: C15H30N5O4Si calcd 372.2067, found 372.2077.
4.2.9. 3-Amino-5-azido-3-C-cyano-3,5-dideoxy-1,2-O-iso-
propylidene-
isopropylidene-
a
-
D
-ribofuranose (5). To a solution of 5-azido-1,2-O-
-xylofuranose (24 g, 111.6 mmol) in CH2Cl2
a-
D
(ꢂ2) and elimination of water under vacuo, compound 6 (0.47 g,
20
(200 mL) was added molecular sieves (one spatula) and Ac2O
(36.7 mL, 390.7 mmol). The reaction mixture was heated at reflux
then PDC (29.4 g, 78.1 mmol) was added portionwise. After 4 h and
elimination of the solvent under vacuo, the residue was dissolved in
EtOAc and filtered through a silica pad. Evaporation of the solvent
afforded crude ulose in a quantitative yield, which was used in the
next step. Crude ulose was dissolved in a methanolic solution of
ammonia (7 N, 150 mL) and Ti(OiPr)4 (28 mL, 93 mmol) was added.
After stirring overnight at room temperature, TMSCN (7.9 mL,
59 mmol) was added and the reaction mixture was stirred for 15 h.
After addition of water (<10 mL) and EtOAc, the solvent was re-
moved under vacuo. EtOAc was added and the residue was filtered
52%) was obtained as an amorphous solid. [
a
]
D
þ53 (c 0.45, ace-
tone); IR (ATR)
n
2987, 2933, 2100, 1593, 1533, 1514, 1454, 1375,
1217, 1163, 1086 cmꢁ1
;
1H NMR (300.13 MHz, DMSO-d6)
d
6.18 (d,
J1,2¼3.0 Hz, 1H, H-1), 4.92 (br s, 5H, NH, 2ꢂ NH2), 4.78 (d, 1H, H-2),
4.21 (dd, J4,5a¼3.0 Hz, J4,5b¼9.0 Hz,1H, H-4), 3.03 (dd, J5a,5b¼15.0 Hz,
1H, H-5a), 2.34 (dd, 1H, H-5b), 1.63, 1.44 (s, 6H, 2ꢂ CH3); 13C NMR
(75.47 MHz, DMSO-d6) d 160.4 (C]N), 112.2 [OC(CH3)2], 105.1 (C-1),
84.4 (C-2), 80.1 (C-4), 62.7 (C-3), 39.6 (C-3), 25.6, 25.2 (2ꢂ CH3);
HRMS: C9H16N6O3Na calcd 279.1192, found 279.1187.
4.2.13. 4-(4-Nitrophenyl)-3-buten-2-one (8a) and 4-(4-
nitrophenyl)-5-methyl-5-nitrohexan-2-one (9a). To a solution of
through a silica pad. After evaporation of the solvent, compound 5
the aldehyde 7a (0.66 mmol) in 325
(87/13) was added 99 L (0.78 mmol) of ethyl acetoacetate, 66 mg
of CAL-B immobilized on acrylic resin, 30 mol % of 6 (51 mg,
0.2 mmol) and 795 L of 2-nitropropane (14 mmol). The suspension
mL of a mixture of CH3CN/H2O
20
(14.6 g, 91%) was obtained as a white solid. Mp¼133e134 ꢀC; [
a
]
m
D
þ6 (c 0.17, CH2Cl2); IR (ATR)
n 3367, 3305, 2097, 1377, 1388, 1269,
1220, 1166, 1104, 1090, 1060, 1014 cmꢁ1
CDCl3)
;
1H NMR (300.13 MHz,
m
d
5.96 (d, J1,2¼3.7 Hz, 1H, H-1), 4.64 (d, 1H, H-2), 3.86 (dd,
was stirred for 5 days at 50 ꢀC. The reaction was then concentrated
under reduced pressure and the crude material was purified by
flash chromatography using cyclohexane/EtOAc (100/0 to 90/10) to
afford successively 8a34 (20 mg, 16%) as a white solid and 9a35
(30 mg, 16%) as a pale yellow solid. Enantiomeric excess of 9a
was determined by chiral HPLC (AD-H column, 8/2 hexane/iPrOH,
J4,5a¼7.2 Hz, J4,5b¼5.0 Hz, 1H, H-4), 3.76 (dd, J5a,5b¼12.8 Hz, 1H, H-
5a), 3.63 (dd, 1H, H-5b), 1.95 (br s, 2H, NH2), 1.56, 1.37 (s, 6H, 2ꢂ
CH3); 13C NMR (75.47 MHz, CDCl3)
d 117.8 (CN), 113.8 [OC(CH3)2],
104.1 (C-1), 83.0 (C-2), 80.0 (C-4), 61.8 (C-3), 50.7 (C-5), 26.6, 26.4
(2ꢂ CH3); HRMS: C9H14N5O3 calcd 240.10912, found 240.10930.
flow rate 1 mL/min, tmajor¼16.0 min, tminor¼24.3 min, ¼254 nm).
l
4.2.10. 3-Amino-3-deoxy-1,2-O-isopropylidene-3-C-(1H-tetrazol-5-
yl)-5-O-trityl-
a
-
D
-ribofuranose (4a). To a solution of 4 (0.75 g,
4.2.14. 4-(3-Chlorophenyl)-3-buten-2-one (8b) and 4-(3-
chlorophenyl)-5-methyl-5-nitrohexan-2-one (9b). To a solution of
1.64 mmol) in toluene (20 mL) was added Bu2SnO (0.45 g,
1.81 mmol) and TMSN3 (0.44 mL, 3.29 mmol). After stirring for 2 h
at 100 ꢀC, the solvent was removed and the residue was purified by
the aldehyde 7b (0.66 mmol) in 325
(87/13) was added 99 L (0.78 mmol) of ethyl acetoacetate, 66 mg
of CAL-B immobilized on acrylic resin, 30 mol % of 6 (51 mg,
0.2 mmol) and 795 L of 2-nitropropane (14 mmol). The suspension
mL of a mixture of CH3CN/H2O
m
flash chromatography (20/80 to 70/30 EtOAC/MeOH)to afford
20
compound 4a as a white solid (0.47 g, 57%). Mp¼78e79 ꢀC; [
a
]
m
D
þ15 (c 0.15, acetone); IR (ATR)
n
1597, 1491, 1448, 1377, 1217, 1163,
was stirred for 5 days at 50 ꢀC. The reaction was then concentrated
under reduced pressure and the crude material was purified by
flash chromatography using cyclohexane/EtOAc (100/0 to 90/10) to
afford successively 8b36 (13 mg, 10%) as a pale yellow liquid and
9b27d (11 mg, 6%) as a pale yellow solid. Enantiomeric excess of 9b
was determined by chiral HPLC (AD-H column, 99/1 hexane/iPrOH,
1070, 1003 cmꢁ1; 1H NMR (300.13 MHz, DMSO-d6)
d 7.30 (m, 15 H,
3ꢂ Ph), 6.07 (s, 1H, H-1), 4.69 (s, 1H, H-2), 4.31 (d, J4,5a¼9.0 Hz, 1H,
H-4), 3.86 (br s, 4 H, H-5a, NH, NH2), 3.25 (d, J5a,5b¼12.0 Hz, 1H, H-
5b), 1.61, 1.37 (s, 6H, 2ꢂ CH3); 13C NMR (75.47 MHz, DMSO-d6)
d
158.1 (C]N), 144.1, 128.7, 128.3, 127.4 (3ꢂ Ph), 112.2 [OC(CH3)2],
105.2 (C-1), 86.5 (Cq trityl), 83.9 (C-2), 82.1 (C-4), 63.7 (C-5), 61.7 (C-
3), 27.2, 27.0 (2ꢂ CH3); HRMS: C28H29N5O4Na calcd 522.2117, found
522.2138.
flow rate 1 mL/min, tmajor¼22.4 min, tminor¼28.1 min, ¼254 nm).
l
4.2.15. 4-(2-Naphtalenyl)-3-buten-2-one (8c) and 4-(2-
naphtalenyl)-5-methyl-5-nitrohexan-2-one (9c). To a solution of
4.2.11. 3-Amino-5-azido-3,5-dideoxy-1,2-O-isopropylidene-3-C-(1H-
the aldehyde 7c (0.66 mmol) in 325
(87/13) was added 99 L (0.78 mmol) of ethyl acetoacetate, 66 mg of
CAL-B immobilized on acrylic resin, 30 mol % of 6 (51 mg, 0.2 mmol)
and 795 L of 2-nitropropane (14 mmol). The suspension was stirred
mL of a mixture of CH3CN/H2O
tetrazol-5-yl)-
a-D
-ribofuranose (5a). To a solution of 5 (5.0 g,
m
20.92 mmol) in toluene (100 mL) was added Bu2SnO (5.72 g,
23.01 mmol) and TMSN3 (6.16 mL, 46.02 mmol). After stirring for 2 h
at 100 ꢀC, the solvent was removed and the residue was purified by
flash chromatography (20/80 to 40/60 EtOAC/MeOH) to afford
compound 5a as a slight yellow solid (5.91 g, 99%). Mp¼137e138 ꢀC;
m
for 5 days at 50 ꢀC. The reaction was then concentrated under re-
duced pressure and the crude material was purified by flash chro-
matography using cyclohexane/EtOAc (100/0 to 90/10) to afford
successively 8c34 (30 mg, 29%) as a pale yellow liquid and 9c (10 mg,
5%) as a pale yellow solid. Enantiomeric excess of 9c was determined
by chiral HPLC (AD-H column, 8/2 hexane/iPrOH, flow rate 1 mL/
[a]
20 þ78 (c 0.31, acetone); IR (ATR)
n 2989, 2929, 2098, 1602, 1510,
D
1377, 1265, 1222, 1163, 1080 cmꢁ1; 1H NMR (300.13 MHz, DMSO-d6)
d
6.12 (d, J1,2¼6.0 Hz, 1H, H-1), 5.66 (br s, 3H, NH, NH2), 4.83 (d, 1H,
H-2), 4.31 (d, J4,5b¼9.0 Hz,1H, H-4), 3.43 (d, J5a,5b¼15.0 Hz,1H, H-5a),
min, tmajor¼7.2 min, tminor¼6.3 min,
l
¼254 nm). Compound 9c: 1H

L. Wynands et al. / Tetrahedron 69 (2013) 4899e4907
4907
15. Nguyen Van Nhien, A.; Domínguez, L.; Tomassi, C.; Rosario Torres, M.; Len, C.;
Postel, D.; Marco-Contelles, J. Tetrahedron 2004, 60, 4709.
16. In a typical experiment, 100 mg of aldehyde and 10 mol % of catalyst were
stirred in neat acetone (5 mL) at 60 ꢀC for 24 h. After evaporation of the solvent
and flash chromatography, the aldol derivative was obtained.
17. (a) Tang, Z.; Jiang, F.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5755; (b) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.;
Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. 2004, 101, 5755; (c)
Gandhi, S.; Singh, V. K. J. Org. Chem. 2008, 73, 9411.
NMR (300.13 MHz, CDCl3) d (ppm) 7.82e7.78 (3H, m, Haro), 7.66 (1H,
d, J¼1.7 Hz, Haro), 7.50e7.46 (2H, m, Haro), 7.32 (1H, dd, J¼1.9 Hz,
J¼8.5 Hz, Haro), 4.11 (1H, dd, J¼3.5 Hz, J¼10.6 Hz, CH), 3.22 (1H, dd,
J¼10.6 Hz, J¼17.0 Hz, Ha CH2), 2.80 (1H, dd, J¼3.5 Hz, J¼17.0 Hz, Hb
CH2), 2.03 (3H, s, CH3CO), 1.61, 1.53 (3H, s, CH3(CNO2)), 13C NMR
(75 MHz, CDCl3)
d (ppm) 205.3 (CO), 143.66 (]CeCH*), 129, 128.9,
128.6, 128.5, 128.2, 127.8, 127.2, 126.6, 126.5 (Caro), 91.4 (CNO2),
49.21(CH*), 44.48 (CH2), 30.59 (CH3CO), 26.35, 22.78 (CH3eCNO2);
HRMS: C17H19NO3Na calcd 308.1263, found 308.1270.
18. Muraoka, O.; Yoshikai, K.; Takahashi, H.; Minematsu, T.; Lu, G.; Tanabe, G.;
Wang, T.; Matsuda, H.; Yoshikawa, M. Bioorg. Med. Chem. 2006, 14, 500.
€
19. Cheong, P. H.-Y.; Legault, C. Y.; Um, J. M.; C¸ elebi-Olhum, N.; Houk, K. N. Chem.
Rev. 2011, 111, 5042.
20. Arno, M.; Zaragoza, R. J.; Domingo, L. R. Tetrahedron: Asymmetry 2005, 16, 2764.
21. Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16.
22. Xu, X.-Y.; Tang, Z.; Wang, Y.-Z.; Luo, S.-W.; Cun, L.-F.; Gong, L.-Z. J. Org. Chem.
2007, 72, 9905.
Acknowledgements
ꢀ
A.N.V.N. thanks the Conseil Regional de Picardie and the FEDER
23. (a) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123, 12911; (b) Bahmanyar,
S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc. 2003, 125, 2475.
24. (a) Desiraju, G. R.; Steiner, T. The Weak Hydrogen Bond; Oxford University: New
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25. For other results on the impact of CeH./F interactions on the stereo-
selectivity of reactions: (a) Armstrong, A.; Washington, I.; Houk, K. N. J. Am.
Chem. Soc. 2000, 122, 6297; (b) Um, J. M.; DiRocco, D. A.; Noey, E. L.; Rovis, T.;
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for financial support.
Supplementary data
Supplementary data related to this article can be found online at
http://dx.doi.org/10.1016/j.tet.2013.04.043.
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