Expanding the scope of the elpaN-type library: Glucose-derived bis(pyridine-2-carboxamide) ligands (elpaN-Py) for molybdenum-catalyzed asymmetric allylic alkylations

Article abstract of DOI:10.1016/j.tet.2013.03.075

The elpaN-Py family of ligands, which represents a subset of the elpaN-type library based on d-glucose, is described. The ligands are structural analogs of the privileged bis(pyridine-2-carboxamides) derived from trans-1,2- diaminocyclohexane, and differ

Full text of DOI:10.1016/j.tet.2013.03.075

Tetrahedron 69 (2013) 4061e4065
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Tetrahedron
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Expanding the scope of the elpaN-type library: glucose-derived
bis(pyridine-2-carboxamide) ligands (elpaN-Py) for molybdenum-
catalyzed asymmetric allylic alkylations
,
b
,
,
,
a,b,
Matteo Lega a c, Rosario Figliolia a b, Christina Moberg c , Francesco Ruffo
*
*
a
ꢀ
Dipartimento di Scienze Chimiche, Universita di Napoli ‘Federico II’, Complesso Universitario di Monte S. Angelo, Via Cintia, 80126 Napoli, Italy
b
ꢀ
Consorzio Interuniversitario di Reattivita Chimica e Catalisi, Italy
c KTH School of Chemical Science and Engineering, Department of Chemistry, Organic Chemistry, SE 10044 Stockholm, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
The elpaN-Py family of ligands, which represents a subset of the elpaN-type library based on D-glucose,
Received 21 January 2013
Received in revised form 26 February 2013
Accepted 18 March 2013
is described. The ligands are structural analogs of the privileged bis(pyridine-2-carboxamides) derived
from trans-1,2-diaminocyclohexane, and differ for the type of substitution in the coordinating functions
present in positions 1 and 2. Their ability to induce high enantioselectivity in asymmetric allylic alkyl-
ations promoted by molybdenum under microwave irradiation has been successfully demonstrated,
starting from both a linear (ee up to 99%) and a branched substrate (ee up to 96%). The multifunctional
nature of the sugar scaffold was exploited for the preparation of a polar ligand, through deprotection of
the hydroxyl groups in positions 3, 4 and 6. In this version, it was possible to verify the performance in
catalysis in alternative solvents, such as ionic liquids and water.
Available online 22 March 2013
Keywords:
Asymmetric catalysis
Molybdenum
Carbohydrates
Allylation
Ó 2013 Elsevier Ltd. All rights reserved.
Microwave reactions
1. Introduction
Moreover, when AAA catalyzed by Mo are performed under
microwave irradiation (MW), Mo(CO)6 can be used directly without
Asymmetric allylic alkylations (AAA) have been widely studied
in recent years due to their high synthetic versatility. The reactions
are catalyzed by complexes of several different metals1 (Pd, Mo, Ir,
Cu, etc.), and a variety of substrates and nucleophiles may be used,
leading to CeC and CeX (X¼H, O, S, P) bond formation.2 The stereo-
and regiochemistry of the product are a function of the metal, the
ligand, the nucleophile, and the substrate, thereby making it pos-
sible to access alternative reactivity by switching between different
catalytic systems.
any pretreatment and the product is usually obtained in less than
10 min with high regio- and stereoselectivity.7 On this basis, Mo-
catalyzed AAA have been successfully employed in a variety of
synthetic applications.8 A number of bis(pyridine-2-carboxamide)
derivatives, obtained from 1,2-diaminocyclohexanes and pyridine
carboxylic acids, have been successfully used as ligands in the Mo-
catalyzed reaction.9 Particularly high stereo- and regioselectivity
have been observed with ligands substituted with
p-donor groups
on the pyridine nucleus.10
Among available catalytic systems, those based on Pd have been
most widely explored,3 but since Mo4 and Ir5 catalysts exhibit
complementary regiochemistry when unsymmetrically substituted
allyl derivatives are used, catalysts containing these metals are
valuable. Typically, Pd complexes afford the achiral linear products
from monosubstituted allylic substrates,1 while Ir or Mo catalysts
preferentially lead to the branched chiral products. Ir complexes
have a wider scope,5a,6 but the cheap catalyst precursor Mo(CO)6 in
combination with easily accessible bis(pyridine-2-carboxamides)
ligands is attractive due to its low cost and high stability.4a
Attracted by the structural analogy between trans-1,2-
diaminocyclohexane and 2,3-disubstituted glucose, we previously
designed sugar versions11 of the original ligands and described12
their successful application in different catalytic reactions (Naple-
type library in Fig. 1).
* Corresponding authors. Fax: þ39 081 674090 (F.R.); fax: þ46 8 7912333 (C.M.);
e-mail addresses: kimo@kth.se (C. Moberg), ruffo@unina.it (F. Ruffo).
Fig. 1. The Naple-type library.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.075

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M. Lega et al. / Tetrahedron 69 (2013) 4061e4065
In particular, we prepared and employed the bis(pyridine-2-
carboxamide) ligand Naple-py12f (X¼NH, L¼L0¼CO-o-py in Fig. 1)
with excellent results in the AAA promoted by Mo.
A general problem encountered with ligands derived from
naturally occurring compounds, like the Naple-type ligands, is that
they usually can afford only one of the possible enantiomers of the
product. In order to access also to the opposite enantioselectivity,
we recently designed the library of elpaN-type ligands.13 These
ligands are pseudo-enantiomers of the Naple-type ligands as a re-
sult of the shift of the coordinating functions at C1 and C2 of the
sugar backbone (Fig. 2).
Fig. 2. Naple-type versus elpaN-type ligands.
This approach already led to successful results. In a preliminary
study,13 asymmetric allylic substitutions catalyzed by palladium
yielded chiral products with high ee, and with opposite configu-
ration with respect to those achieved with the original Naple-type
library.
Scheme 1. Synthesis of the elpaN-Py ligands. (i) AcBr, 3 d; (ii) Me3SiN3, t-BuOK, THF,
18 h; (iii) DMAP, RCO2H, DCC, DCM; (iv) PMe3, DCM; (v) NH3, MeOH.
In this report, we describe the synthesis of a new subset of the
elpaN-type bouquet (elpaN-Py series of Fig. 3), and its application
in the Mo-catalyzed AAA promoted by MW.
(DCC) and 4-dimethylaminopyridine (DMAP). Compound 3 was
converted into the ligand by a Staudinger reaction, using PMe3 and
the appropriate activated ester (step iv). This procedure is neces-
sary because anomerization at C1 was usually observed when the
azide was reduced to the amine by H2 over Pd/C.
Finally, the acetate groups of the elpaN-py ligand were conve-
niently deprotected by stirring a methanolic solution of the ligan-
d in the presence of ammonia to yield a ligand with free
hydroxyl groups (step v). The deprotected ligand elpaN-py0 is sol-
uble in water and ionic liquids (RTILs), but almost insoluble in
DCM and toluene and was synthesized in order to explore the
feasibility of
a
Mo-promoted AAA under unconventional
conditions.15
2.2. Mo-catalyzed asymmetric allylic alkylations
Fig. 3. The elpaN-Py series.
The catalytic reactions (Scheme 2) were performed by using
both a linear 4 and a branched allylic carbonate rac-5, which are
crucial substrates because the knowledge of their reactivity pro-
vides the necessary information for assessing the qualities of the
ligands.16e18
2. Results and discussion
2.1. Preparation of the ligands
The key intermediate in the synthesis of the ligands is the
known 1-azido-2-aminoglucose derivative 2,14 whose synthesis
from bromide 1 (step ii in Scheme 1) was significantly improved
within this study. In fact, the dangerous silver azide, originally used
for providing Nꢀ3 and capturing Brꢀ, was safely substituted by the
couple trimethylsilyl azide/t-BuOK, the latter acting as base, acti-
vator of the organic azide, and source of Kþ (CAUTION: azides are
highly energetic and potentially explosive compounds).
The amino group of compound 2 was condensed with the de-
sired acid (step iii), employing N,N0-dicyclohexylcarbodiimide
Scheme 2. Molybdenum-catalyzed AAA.

M. Lega et al. / Tetrahedron 69 (2013) 4061e4065
4063
According to experimental conditions previously developed,12f
Mo(CO)6, ligand, allylic carbonate 4, dimethyl malonate, and N,O-
bis-(trimethylsilyl)acetamide (BSA) were mixed in THF and heated
at 160 ꢁC in the microwave cavity under air. After the desired re-
action time, conversions and branched/linear ratios were de-
termined by 1H NMR spectroscopy, and enantioselectivities by
chiral HPLC.
The different performances of the ligands were assessed by
using 4 mol % of Mo catalyst, a ligand/metal ratio of 1.3:1 and
a nucleophile/substrate ratio of 1.1:1. The results of the reactions of
the linear substrate 4 are shown in Table 1. As expected, Naple-
type12f and elpaN-type ligands afforded products with opposite
absolute configurations, the latter leading preferentially to the (S)-B
product. Except for the ligand containing a quinoline group (entry
4), which was expected to be the less active and selective,16 good
conversions, yields, regioselectivity, and stereoselectivity were
observed.
Table 2
Molybdenum-catalyzed asymmetric substitutions of rac-5 using elpaN-Py ligandsa
Entry elpaN-Py
Time
Cat.
Conv.b Isolated
B/Lc
eed (%)
ligand
(min) (mol %) (%)
yieldb (%)
1
2
3
4
5
-py
6
6
6
6
4
4
4
4
1
94
92
100
51
65
70
72
45
16
14:1 98 (S)
25:1 99 (S)
6:1 97 (S)
15:1 90 (S)
14:1 97 (S)
-py-p-OMe
-py0
-qui
-py-p-OMe 30
23
a
Reaction conditions: dimethyl malonate (0.77 mmol), allylic carbonate rac-5
(0.71 mmol), Mo(CO)6 (0.026 mmol, 4 mol %), ligand (0.034 mmol), BSA (208
mL),
THF (2 mL), 160 ꢁC, 6 min.
b
Determined by NMR spectroscopy of the crude reaction mixture.
Yield of product isolated by column chromatography (EtOAc/petroleum
c
ether¼1:5).
d
Determined by chiral HPLC Daicel OD-H (0.46 cm i.d. 25 cm) column.
main product obtained from the allylic carbonate 4, as well as from
the corresponding acetate, consisted of a mixture of the branched
and linear alcohols. The hydrolysis was, at least in part, catalyzed by
the metal complex as shown by the formation of only the linear
product from the Mo-free background reaction, thus suggesting
Table 1
Molybdenum-catalyzed asymmetric substitutions of 4 using elpaN-Py ligandsa
a
p-allylic intermediate in the hydrolysis. In the ionic liquid
Entry
elpaN-py
ligand
Conversionb
(%)
Isolated
B/La
eed (%)
bmimBF4, the allylic carbonate afforded the allylic ether in racemic
form, mainly as product of a background decarboxylation, while the
allylic acetate did not react.
yieldc (%)
1
2
3
4
-py
94
78
73
67
72
66
55
41
17:1
21:1
6:1
96 (S)
95 (S)
86 (S)
90 (S)
-py-p-OMe
-py0
-qui
24:1
3. Conclusions
a
Reaction conditions: dimethyl malonate (0.77 mmol), allylic carbonate
L), THF (2 mL), 160 ꢁC.
Determined by NMR spectroscopy of the crude reaction mixture.
4
(0.71 mmol), BSA (208
m
This work demonstrates the validity of a strategy, namely that it
is possible to prepare libraries of pseudo-enantiomeric ligands
from easily accessible natural compounds, with both synthetic and
economic benefits.11b,12b,19
b
c
Yield of product isolated by column chromatography (EtOAc/petroleum
ether¼1:5).
d
Determined by chiral HPLC Daicel OD-H (0.46 cm i.d. 25 cm) column.
In particular, the library elpaN-type, based on 1,2-disubstituted
D
-glucose, was expanded through the preparation of the bis(pyr-
In analogy with the results obtained for the ligands derived from
1,2-diaminocyclohexane,17 the presence of
-donating substituents
in the 4-position of the pyridyl rings increased the enantio- and site
selectivity.10 Thus, ligand elpaN-py-p-OMe was more selective than
elpaN-py (entries 1 vs 2).
idine-2-carboxamide) derivatives elpaN-Py. The ligands were ob-
tained in both protected and deprotected versions, and this has
allowed us to verify their ability in the AAA promoted by Mo under
traditional and non-conventional conditions. High enantiose-
lectivities were accomplished in the former case, starting from both
a linear and a branched allylic substrates. In water, although the
enantioselective process was almost ineffective, a peculiar re-
activity was disclosed, that could be the subject of further future
research.
p
A catalyst containing the deprotected ligand elpaN-py0 resulted
in a similar activity, but lower regio- and stereoselectivity com-
pared to the acetylated ligand (entries 1 vs 3). As expected, lower
amounts of catalyst resulted in lower conversion and lower regio-
selectivity (entries 1 vs 5), although the enantioselectivity was still
good (97% ee).
4. Experimental section
4.1. General
Branched substrates, such as rac-5, often react with lower
enantioselectivity than their linear isomers as a result of a memory
effect,17 explained on the basis of the known mechanism of the Mo-
promoted AAA.18 The allylic carbonate reacts with the Mo precursor
by oxidative addition leading to a (h
3-allyl)molybdenum complex.
THF and toluene were dried by using a Glass-contour solvent
dispensing system. Dichloromethane was distilled from CaH2. The
microwave heating was performed with a Smith CreatorTM single
mode cavity from Personal Chemistry AB, Uppsala, Sweden
equipped with magnetic stirrer and automatic temperature control.
1H and 13C NMR spectra were recorded, respectively, at 400 or
200 MHz, and 100.6 and 50.3 MHz. The 1H and 13C chemical shifts
are reported using CHCl3 (for spectra recorded in CDCl3), HDO (for
proton spectra recorded in water) or dioxane (for carbon spectra
recorded in water) as internal standards.
This reaction proceeds through a stereospecific syn displacement of
the carbonate, and for this reason the two enantiomers of 5 pro-
duce two diastereoisomeric complexes. The system will equilibrate
via h3 h1 3 isomerization, and if this process is slow compared to
e eh
the nucleophilic attack, which also occurs by a syn mechanism,
a memory effect may be observed, leading to lower enantiose-
lectivity. The results for reactions of substrate rac-5 are reported in
Table 2.
As expected, the branched substrate 5 resulted in lower enantio-
and regioselectivity than the linear substrate, but still acceptable
levels of enantioselectivity (88e96% ee (S)). Conversions observed
for this substrate were lower but still good in all cases. The trend
was analogous to that experienced for substrate 4, except that li-
gand elpaN-qui gave the highest branched/linear ratio (entry 4).
The performance of ligand elpaN-py0 was also tested in water
and in hydrophilic RTIL, taking advantage of its solubility in these
solvents. Disappointingly, when water was used as solvent, the
4.2. Synthesis of 3,4,6-tri-O-acetyl-1-b-azido-D-glucosamine (2)
Compound 114 (6.17 g, 13.7 mmol) was dissolved in THF
(100 mL). TMSN3 (1.30 mL, 10.0 mmol) and t-BuOK (2.36 g,
21.0 mmol) were added, and the system was stirred for 18 h at rt
(CAUTION: azides are highly energetic and potentially explosive
compounds). The suspension was filtered and the solvent was

4064
M. Lega et al. / Tetrahedron 69 (2013) 4061e4065
3
3
J6-H,6 -H¼12.4 Hz, 1H, 6-H), 4.15 (dd, J6 -H,5-H¼1.9 Hz, 1H, 60-H),
0
0
removed under reduced pressure, leading to a slightly yellow solid.
This solid was dissolved in DCM (5 mL), the solution was filtered,
and petroleum ether was added, affording pure compound 2 as
4.03 (q, 1H, 2-H), 3.83e3.79 (m, 1H, 5-H), 2.06 (s, 3H, AcO), 1.98 (s,
3H, AcO), 1.87 (s, 3H, AcO); 13C NMR (100.6 MHz, CDCl3):
d¼170.8,
a slightly yellow solid (yield: 4.24 g, 95%). [
a
] ꢀ8.0 (c 1.0, 586 nm,
170.6, 169.5, 164.8, 148.9, 148.3, 137.6, 126.8, 122.7, 88.7, 74.2, 72.0,
25 ꢁC, CHCl3); lit. (ꢀ11.5).14
68.4, 62.0, 54.3, 20.9, 20.8, 20.7. 3-py-p-OMe: 1H NMR (400 MHz,
CDCl3):
d
¼8.31 (d, 3J¼5.6 Hz, 1H, aromatic), 8.21 (d, 3JNH,2-H¼8.2 Hz,
4.3. Synthesis of the activated esters, R[-py and -qui
1H, NH), 7.69 (dd, 3J¼2.4, 12.7 Hz, 1H, aromatic), 6.94e6.90 (m, 1H,
aromatic), 5.46 (t, 3J3-H,2-H¼3J3-H,4-H¼9.5 Hz, 1H, 3-H), 5.14 (t, 3J4-H,3-
2-Pyridine carboxylic acid or 2-quinoline carboxylic acid
(5.0 mmol), DCC (1.03 equiv), and N-hydroxysuccinimide
(1.0 equiv) were suspended in THF (50 mL) and the solution was
stirred overnight. The suspension was filtered, and the solvent was
evaporated under reduced pressure. The crude product was dis-
solved in DCM and precipitated as a yellow solid by the addition of
petroleum ether. The resulting product was used without any fur-
ther purification (yield: 41 and 65%, respectively, 0.46 g and 0.90 g).
¼3J4-H,5-H, 1H, 4-H), 4.97 (d, 3J1-H,2-H¼9.2 Hz, 1H, 1-H), 4.31 (dd, 3J6-
H
¼4.8 Hz, 3J6-H,6 -H¼12.4 Hz, 1H, 6-H), 4.20 (dd, 3J6 -H,5-H¼2.1 Hz,
0
0
H,5-H
1H, 60-H), 4.07 (q, 1H, 2-H), 3.90 (s, 3H, OMe), 3.88e3.83 (m, 1H, 5-
H), 2.11 (s, 3H, AcO), 2.03 (s, 3H, AcO), 1.93 (s, 3H, AcO); 13C NMR
(100.6 MHz, CDCl3)
d
¼171.1, 170.8, 169.8, 167.4, 165.1, 151.2, 149.7,
113.9, 108.1, 89.0, 74.5, 72.3, 68.8, 62.3, 56.0, 54.6, 21.1, 21.0, 20.9. 3-
qui: 1H NMR (400 MHz, CDCl3):
d
¼8.35 (d, 3JNH,2-H¼9.0 Hz, 1H, NH),
8.25 (q, 3J¼8.5 Hz, 2H, aromatic), 8.07 (d, 3J¼8.5 Hz, 1H, aromatic),
7.83 (d, 3J¼8.1 Hz, 1H, aromatic), 7.73 (t, 3J¼7.7 Hz, 1H, aromatic),
Activated Ester-py: 1H NMR (400 MHz, CDCl3):
d
¼8.83 (d, 3J¼4.6 Hz,
3
1H, aromatic), 8.21 (d, 3J¼7.8 Hz, 1H, aromatic), 7.91 (td, 3J¼1.4,
7.58 (t, 3J¼7.5 Hz, 1H, aromatic), 5.51 (t, J3-H,2-H¼3J3-H,4-H¼9.9 Hz,
3
3
7.8 Hz, 1H, aromatic), 7.59 (dd, 3J¼4.6, 7.8 Hz, 1H, aromatic), 2.92 (s,
1H, 3-H), 5.14 (t, J4-H,3-H¼3J4-H,5-H, 1H, 4-H), 5.02 (d, J1-H,2-
3
3
4H); 13C NMR (100.6 MHz, CDCl3):
d
¼169.2, 160.8, 150.9, 144.5,
¼9.2 Hz, 1H, 1-H), 4.30 (dd, J6-H,5-H¼4.7 Hz, J6-H,6 -H¼12.4 Hz,
0
H
137.7, 128.9, 127.1, 26.1. Activated Ester-qui: 1H NMR (400 MHz,
1H, H-6), 4.17 (dd, J6 ,5-H¼1.8 Hz, 1H, 60-H), 4.09 (q, 1H, 2-H), 3.86
3
0
CDCl3):
d
¼8.36 (d, 3J¼8.5 Hz, 1H, aromatic), 8.31 (d, 3J¼8.5 Hz, 1H,
(m, 1H, 5-H), 2.09 (s, 3H, AcO), 2.00 (s, 3H, AcO), 1.88 (s, 3H, AcO);
aromatic), 8.21 (d, 3J¼8.5 Hz, 1H, aromatic), 7.92 (d, 3J¼8.5 Hz, 1H,
aromatic), 7.83 (t, 3J¼7.6 Hz, 1H, aromatic), 7.71 (t, 3J¼7.6 Hz, 1H,
13C NMR (100.6 MHz, CDCl3)
d
¼171.1, 170.9, 169.8, 165.4, 149.0,
146.8, 138.1, 130.7, 130.2, 130.0, 128.6, 128.1, 119.2, 89.0, 74.5, 72.3,
68.8, 62.3, 54.7, 21.1, 21.0, 20.9.
aromatic), 2.95 (s, 4H); 13C NMR (100.6 MHz, CDCl3)
d¼169.0, 160.9,
147.9, 143.9, 137.7, 131.1, 131.0, 129.9, 130.0, 127.8, 121.7, 25.9. R¼-py-
p-OMe: The acid (5.0 mmol), DCC (2.5 equiv), and N-hydrox-
ysuccinimide (1.1 equiv) were suspended in THF (130 mL) and the
solution was stirred overnight. The suspension was filtered, and the
solvent was evaporated under reduced pressure. The crude product
was extracted twice with boiling n-hexane in order to remove ex-
cess DCC. The solid was dissolved in EtOAc (50 mL), the solution
was filtered, and then washed with EtOAc (2ꢂ25 mL). The solvent
was removed under reduced pressure, leading to the crude product
that was used with no further purification (yield: 580 mg, 45%). 1H
4.5. Synthesis of the elpaN ligands
The desired intermediate 3 (1.35 mmol) and the desired acti-
vated ester (1.25 equiv) were dissolved in dry DCM (15 mL) under
inert atmosphere. The solution was cooled to ꢀ78 ꢁC and a solution
of 0.89 M PMe3 in dry toluene (1.50 mL, 1.69 mmol) was slowly
added. The system was warmed to rt, and when evolution of N2(g)
ceased, the reaction was quenched by the addition of a saturated
solution of Na2CO3 (15 mL). The organic phase was separated, and
the water was extracted with DCM (2ꢂ20 mL). The combined or-
ganic phases were dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was precipitated by
slow addition of petroleum ether and washed twice with the same
solvent. The compounds were isolated as white solids by flash
chromatography (silica/crude¼50:1 w/w).
NMR (400 MHz, CDCl3):
d
¼8.65 (d, 3J¼5.7 Hz, 1H, aromatic), 7.72 (d,
1H, 3J¼2.5 Hz, aromatic), 7.09 (dd, 3J¼2.5, 5.7 Hz,1H, aromatic), 3.94
(s, 3H, OMe), 2.91 (s, 4H); 13C NMR (100.6 MHz, CDCl3)
187.0, 166.9, 160.6, 151.7, 141.4, 113.3, 56.0, 25.9.
d
¼171.9,
4.4. Synthesis of 3
Compound 2 (1.32 g, 4.00 mmol) was dissolved in DCM (25 mL)
for the synthesis of 3-py and 3-qui, or THF (50 mL) for the synthesis
of 3-py-p-OMe. DMAP (49 mg, 0.40 mmol), the desired acid
(4.20 mmol) and DCC (1.24 g, 6.00 mmol) were added in this order,
and the solution was stirred for the desired time. DCU was removed
by filtration, and the solution was concentrated under reduced
pressure. The crude product was precipitated by slow addition of
petroleum ether, and washed twice with the same solvent. The
compound was extracted twice with boiling n-hexane and isolated
as a white solid after further purification by flash chromatography
(silica/crude¼50:1 w/w).
Product
Eluent ratio
(EtOAc/PEþ3% TEA)
1:0
1:0
2:1
Yield (%)
elpaN-py
elpaN-py-p-OMe
elpaN-qui
58
41
67
Compound elpaN-py: [
a
] ꢀ38.4 (c 1.0, 586 nm, 25 ꢁC, CH2Cl2);
ꢁ
mp 107 C; nmax (Nujol): 1751 (C]O ester), 1669 (C]O
amide) cmꢀ1. 1H NMR (400 MHz, CDCl3):
d
¼9.06 (d, 3JNH,1-H¼9.6 Hz,
1H, NH), 8.57 (d, 3J¼4.7 Hz, 1H, aromatic), 8.33 (d, 3J¼4.7 Hz, 1H,
aromatic), 8.31 (d, JNH,2-H¼9.6 Hz, 1H, NH), 8.10 (d, 3J¼7.8 Hz, 1H,
3
aromatic), 8.00 (d, 3J¼7.8 Hz, 1H, aromatic), 7.70 (m, 2H, aromatic),
Product
Reaction
time (h)
Eluent ratio
(EtOAc/PEþ3% TEA)
Yield (%)
7.33 (m, 2H, aromatic), 5.57 (t, J1-H,NH¼3J1-H-2-H, 1H, 1-H), 5.47 (t,
3
3J3-H,2-H¼3J3-H,4-H¼10.0 Hz, 1H, 3-H), 5.24 (t, J4-H,3-H¼3J4-H,5-H, 1H,
3
3-py
3-py-p-OMe
3-qui
2
18
18
1:1
3:1
3:2
68
57
60
4-H), 4.58 (q, 1H, 2-H), 4.36 (dd,3J6-H,5-H¼4.2 Hz, 3J6-H,6 -H¼12.4 Hz,
0
1H, 6-H), 4.14 (dd, 3JH6 ,5-H¼2.0 Hz, 1H, 60-H), 4.10e3.90 (m, 1H, 5-
0
H), 2.09 (s, 3H, AcO), 2.05 (s, 3H, AcO), 1.94 (s, 3H, AcO); 13C NMR
Compound 3-py: 1H NMR (400 MHz, CDCl3):
d
¼8.49 (d,
(100.6 MHz, CDCl3)
d
¼170.8 (2C), 169.5, 165.3, 165.2, 148.8, 148.6,
3J¼4.2 Hz, 1H, aromatic), 8.12 (d, 3JNH,2-H¼7.9 Hz, 1H, NH), 7.79 (td,
3J¼1.4, 7.7 Hz, 1H, aromatic), 7.40e7.32 (m, 1H, aromatic), 5.41 (t,
148.4, 148.2, 137.0 (2C), 126.6, 126.4, 122.6, 122.2, 79.9, 73.7, 73.1,
68.3, 62.0, 52.9, 20.8, 20.7, 20.6. HRMS (ESI) calcd for C24H26N4NaO9
3
3J3-H,2-H¼3J3-H,4-H¼9.9 Hz, 1H, 3-H), 5.10 (t, J4-H,3-H¼3J4-H,5-H, 1H,
[MþNa]þ: 537.1597, found 537.1581. elpaN-py-p-OMe: [
] ꢀ7.4 (c
a
3
3
1.0, 586 nm, 25 ꢁC, CH2Cl2); mp 102 ꢁC; nmax (Nujol): 1739 (C]O
4-H), 4.93 (d, J1-H,2-H¼9.2 Hz, 1H, 1-H), 4.26 (dd, J6-H,5-H¼4.8 Hz,

M. Lega et al. / Tetrahedron 69 (2013) 4061e4065
4065
ester), 1652 (C]O amide) cmꢀ1. 1H NMR (200 MHz, CDCl3):
d
¼8.97
25 cm) column, 0.05:99.5 isopropanol/hexane, UV 254 nm, re-
tention times: (S)-B: 19 min; (R)-B: 35 min. The structures of the
products were confirmed by comparison with published spectro-
(d, 3JNH,1-H¼9.3 Hz, 1H, NH), 8.58 (d, 3J¼5.6 Hz, 1H, aromatic), 8.22
(d, 3JNH,2-H¼9.4 Hz,1H, NH), 8.11 (d, 3J¼5.6 Hz,1H, aromatic), 7.57 (s,
1H, aromatic), 7.51 (s, 1H, aromatic), 6.83e6.78 (m, 1H, aromatic),
scopic data:18 1H NMR (400 MHz, CDCl3):
d
¼7.25e7.14 (m, 5 Hz,
3
6.75e6.69 (m, 1H, aromatic), 5.46 (t, J1-H,NH¼3J1-H,2-H, 1H, 1-H),
aromatic), 5.92 (ddd, 3J¼17.0, 10.2, 8.2 Hz, 1H), 5.06 (d, 3J¼17.0 Hz,
1H), 5.02 (d, 3J¼10.2 Hz, 1H), 4.04 (dd, 3J¼11.0, 8.2 Hz, 1H), 3.80 (d,
3J¼11.0 Hz, 1H), 3.68 (s, 3H), 3.42 (3H).
5.38 (t, 3J3-H,2-H¼3J3-H,4-H¼9.9 Hz,1H, 3-H), 5.17 (t, 3J4-H,3-H¼3J4-H,5-H
,
3
3
0
1H, 4-H), 4.47 (q, 1H, 2-H), 4.29 (dd, J6-H,5-H¼4.1 Hz, J6-H,6 -
¼12.4 Hz, 1H, 6-H), 4.07 (dd, 3J6 -H,5-H¼1.8 Hz, 1H, 60-H), 3.93e3.88
0
H
(m, 1H, 5-H), 3.76 (s, 6H, 2OMe) 2.06 (s, 3H, AcO), 1.98 (s, 3H, AcO),
1.88 (s, 3H, AcO); 13C NMR (50.3 MHz, CDCl3)
d¼171.2, 171.1, 169.9,
Acknowledgements
167.2, 167.1, 165.7, 165.6, 151.1, 151.0, 149.9, 149.7, 113.6, 113.4, 108.3,
108.0, 80.3, 74.1, 73.4, 68.7, 62.4, 55.9 (2C), 53.4, 21.2, 21.1, 21.0.
HRMS (MALDI) calcd for C26H30N4O11 [M]þ: 574.1911, found
ꢀ
We are grateful to the Ministero dell’Istruzione, dell’Universita e
della Ricerca (Progetti di Ricerca di Interesse Nazionale e Bando
2009) for financial support, which allowed M.L. to perform work in
Stockholm. The authors thank Dr. Mikhail Gorlov, Department of
Chemistry, KTH, for a generous gift of some RTILs.
574.5331. elpaN-qui: [
a
] ꢀ150 (c 1.0, 586 nm, 25 ꢁC, CH2Cl2); mp
117 ꢁC; nmax (Nujol): 1742 (C]O ester), 1674 (C]O amide) cmꢀ1. 1H
NMR (400 MHz, CDCl3):
d
¼9.36 (d, 3JNH,1-H¼9.2 Hz,1H, NH), 8.48 (d,
3JNH,2-H¼9.5 Hz, 1H, NH), 8.22 (d, 3J¼8.8 Hz, 1H, aromatic),
8.15e8.10 (m, 2H, aromatic), 8.05e7.99 (m, 2H, aromatic), 7.83 (d,
3J¼8.5 Hz, 1H, aromatic), 7.76e7.70 (m, 2H, aromatic), 7.65 (d,
3J¼8.8 Hz, 1H, aromatic), 7.58e7.53 (m, 2H, aromatic), 7.45 (t,
3J¼7.5 Hz, 1H, aromatic), 5.66 (t, 3J1-H,NH¼3J1-H,2-H, 1H, 1-H), 5.54 (t,
3J3-H,2-H¼3J3-H,4-H¼9.9 Hz, 1H, 3-H), 5.27 (t, 3J4-H,3-H¼3J4-H,5-H, 1H, 4-
References and notes
1. Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 258e297.
2. Trost, B. M.; Zhang, T.; Sieber, J. D. Chem. Sci. 2010, 1, 427e440.
3. Trost, B. M.; Crawley, M. L. Top. Organometal. Chem. 2012, 38, 321e340.
4. (a) Belda, O.; Moberg, C. Acc. Chem. Res. 2004, 37, 159e167; (b) Moberg, C. Top.
Organometal. Chem. 2012, 38, 209e234.
3
3
0
H), 4.69 (q, 1H, 2-H), 4.37 (dd, J6-H,5-H¼4.2 Hz, J6-H,6 -H¼12.4 Hz,
1H, 6-H), 4.07 (dd, 3J6 -H,5-H¼1.8 Hz, 1H, 60-H), 3.92e3.88 (m, 1H, 5-
0
€
5. (a) Helmchen, G.; Dahnz, A.; Dubon, P.; Schelwies, M.; Weihofen, R. Chem.
H), 2.07 (s, 3H, AcO), 2.04 (s, 3H, AcO), 1.91 (s, 3H, AcO); 13C NMR
Commun. 2007, 675e691; (b) Liu, W.-B.; Xia, J.-B.; You, S.-L. Top. Organometal.
Chem. 2012, 38, 155e208.
6. Bartels, B.; Garcia-Yebra, C.; Rominger, F.; Helmchen, G. Eur. J. Inorg. Chem. 2002,
2569e2586.
7. Kaiser, N. F. K.; Bremberg, U.; Larhed, M.; Moberg, C.; Hallberg, A. Angew. Chem.,
Int. Ed. 2000, 39, 3595e3598.
8. See for example: (a) Trost, B. M.; Andersen, N. G. J. Am. Chem. Soc. 2002, 124,
14320e14321; (b) Belda, O.; Lundgren, S.; Moberg, C. Org. Lett. 2003, 5,
2275e2278.
(100.6 MHz, CDCl3)
d
¼171.2, 170.0, 169.0, 166.0 (2C), 148.8, 148.7,
146.9, 146.6, 137.7, 137.6, 130.7, 130.5, 130.4, 130.4, 129.8, 129.6,
128.6, 128.4, 127.9, 127.8, 119.3, 119.0, 80.6, 74.3, 73.6, 68.8, 62.4,
53.6, 21.1, 21.0, 20.9. HRMS (ESI) calcd for C32H31N4O9 [MþH]þ:
615.2091, found 615.2071.
9. (a) Trost, B. M.; Hachiya, I. J. Am. Chem. Soc. 1998, 120, 1104e1105; (b) Belda, O.;
Moberg, C. Coord. Chem. Rev. 2005, 249, 727e740.
4.6. Synthesis of elpaN-py0
10. (a) Belda, O.; Kaiser, N.-F.; Bremberg, U.; Larhed, M.; Hallberg, A.; Moberg, C. J.
Org. Chem. 2000, 65, 5868e5870; (b) Belda, O.; Moberg, C. Synthesis 2002,
1601e1606.
11. We decided to use carbohydrates as building blocks for chiral ligands for
various reasons: they are easily available, they are ‘naturally chiral’, they are
highly functionalized, and their chemistry is extremely developed. For recent
reviews on this topic see: (a) Steinborn, D.; Junicke, H. Chem. Rev. 2000, 100,
The elpaN-py ligand (0.50 mmol) was dissolved in MeOH
(10 mL) under a NH3 atmosphere. After 20 h the solvent was re-
moved under vacuum, affording the pure product as a solid in
quantitative yield. Relevant NMR data: elpaN-py0: [
a
] ꢀ26.0 (c 1.0,
586 nm, 25 ꢁC, CH2Cl2); nmax (Nujol): 1669 (C]O amide) cmꢀ1. 1H
ꢀ
ꢀ
ꢀ
4283e4317; (b) Dieguez, M.; Pamies, O.; Ruiz, A.; Diaz, Y.; Castillon, S.; Claver, C.
NMR (400 MHz, D2O):
d
¼8.42 (m, 2H, aromatic), 7.75 (m, 2H, aro-
ꢀ
ꢀ
Coord. Chem. Rev. 2004, 248, 2165e2192; (c) Dieguez, M.; Pamies, O.; Claver, C.
Chem. Rev. 2004, 104, 3189e3215; (d) Diaz, Y.; Castillon, S.; Claver, C. Chem. Soc.
Rev. 2005, 34, 702e713; (e) Dieguez, M.; Claver, C.; Pamies, O. Eur. J. Org. Chem.
2007, 4621e4634; (f) Boysen, M. M. K. Chem.dEur. J. 2007, 13, 8648e8659; (g)
Dieguez, M.; Pamies, O. Chem.dEur. J. 2008, 14, 944e960; (h) Benessere, V.; De
Roma, A.; Del Litto, R.; Ruffo, F. Coord. Chem. Rev. 2010, 254, 390e401; (i)
3
matic), 7.41 (m, 2H, aromatic), 5.37 (d, J1-H,NH¼3J1-H-2-H¼9.65 Hz,
ꢀ
ꢀ
1H, 1-H), 4.18 (t, 3J2-H,NH¼9.9 Hz, 1H, 2-H), 3.81 (m, 2H, 6-H and 3-
ꢀ
H), 3.70 (dd, 3J6 -H,5-H¼4.9 Hz, 1H, 60-H), 3.58 (m, 2H, 5-H and 4-H);
0
ꢀ
ꢀ
13C NMR (100.6 MHz, D2O)
d
¼171.0, 170.5, 151.8, 151.6, 151.3, 150.7,
ꢁ
ꢀ
Dieguez, M.; Pamies, O.; Woodward, S. Coord. Chem. Rev. 2010, 254, 2007e2030.
12. (a) Borriello, C.; Cucciolito, M. E.; Panunzi, A.; Ruffo, F. Tetrahedron: Asymmetry
2001, 12, 2467e2471; (b) Borriello, C.; Del Litto, R.; Panunzi, A.; Ruffo, F.
Tetrahedron: Asymmetry 2004, 15, 681e686; (c) De Roma, A.; D’Errico, A.; Del
Litto, R.; Magnolia, S.; Ruffo, F. Tetrahedron: Asymmetry 2006, 17, 2265e2269;
(d) De Roma, A.; Ruffo, F.; Woodward, S. Chem. Commun. 2008, 5384e5386; (e)
Benessere, V.; De Roma, A.; Ruffo, F. ChemSusChem 2008, 1, 425e430; (f) Ben-
essere, V.; Del Litto, R.; Moberg, C.; Ruffo, F. Eur. J. Org. Chem. 2009, 1352e1356;
(g) Benessere, V.; Ruffo, F. Tetrahedron: Asymmetry 2010, 21, 171e176; (h)
Benessere, V.; Lega, M.; Ruffo, F.; Silipo, A. Tetrahedron 2011, 67, 4826e4831.
13. Benessere, V.; De Roma, A.; Del Litto, R.; Lega, M.; Ruffo, F. Eur. J. Org. Chem.
2011, 5779e5782.
141.2 (2C), 130.6, 130.2, 125.7, 125.5, 82.0, 80.8, 76.8, 72.5, 63.5, 57.8.
HRMS (ESI) calcd for C18H20N4NaO6 [MþNa]þ: 411.1281, found
411.1279.
4.7. Microwave-assisted allylic alkylations
General procedure: two different stock solutions were pre-
pared: solution N, containing the nucleophile, was prepared by
adding dimethyl malonate (880 mL, 7.70 mmol) to a suspension of
60% NaH in mineral oil (27 mg, 0.68 mmol) in THF (10 mL), and
solution S, containing the substrate, was prepared by dissolving the
allylic carbonate (4 or 5) (7.1 mmol) in THF (10 mL). Then the ap-
propriate ligand (0.034 mmol) and Mo(CO)6 (6.9 mg, 0.026 mmol)
were transferred to a flame-dried SmithProcess VialTM. Solution N
ꢁ ꢁ
14. Bertho, A.; Revesz, A. Liebigs Ann. Chem. 1953, 581, 11e16.
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Germany, 2005.
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A.; Palucki, M.; Yasuda, N.; Reider, P. J. Angew. Chem., Int. Ed. 2002, 41,
1929e1932.
17. Hughes, D. L.; Palucki, M.; Yasuda, N.; Reamer, R. A.; Reider, P. J. J. Org. Chem.
2002, 67, 2762e2768.
(1 mL), solution S, and BSA (208 mL, 0.85 mmol) were added in this
order, and the suspension was heated in the microwave cavity at
160 ꢁC for the desired time. The brown solution obtained was di-
luted with Et2O to a total volume of 10 mL, resulting in a dark
precipitate. A sample of the solution was filtered through silica gel
and analyzed by 1H NMR spectroscopy to determine the conversion
and the regioselectivity. The crude product was then purified by
chromatography on silica gel (eluent: petroleum ether/EtOAc, 5:1).
The ees were determined by HPLC using a Daicel OD-H (0.46 cm i.d.
18. (a) Hughes, D. L.; Lloyd-Jones, G. C.; Krska, S. W.; Gouriou, L.; Bonnet, V. D.; Jack,
K.; Sun, Y.; Mathre, D. J.; Reamer, R. A. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5379e5384; (b) Krska, S. W.; Hughes, D. L.; Reamer, R. A.; Mathre, D. J.; Palucki,
M.; Yasuda, N.; Sun, Y.; Trost, B. M. Pure Appl. Chem. 2004, 76, 625e633; (c)
Lloyd-Jones, G. C.; Krska, S. W.; Hughes, D. L.; Gouriou, L.; Bonnet, V. D.; Jack, K.;
Sun, Y.; Reamer, R. A. J. Am. Chem. Soc. 2004, 126, 702e703.
19. (a) Rajanbabu, T. V.; Ayers, T. A.; Casalnuovo, A. L. J. Am. Chem. Soc. 1994, 116,
ꢁ
ꢁ
4101e4102; (b) Khiar, N.; Suarez, B.; Valdivia, V.; Fernandez, I. Synlett 2005,
2963e2967; (c) Grugel, H.; Albrecht, F.; Minuth, T.; Boysen, M. M. K. Org. Lett.
2012, 14, 3780e3783.