Synthesis of a new class of ligands derived from isosorbide and their application to asymmetric reduction of aromatic ketones by transfer hydrogenation

Article abstract of DOI:10.1039/c1nj20588a

A new class of β-amino alcohol and diamine ligands has been prepared from isosorbide as a chiral renewable source. The efficiency of these ligands has been evaluated for the metal-catalyzed enantioselective reduction of aromatic ketones by transfer hydrogenation, giving excellent conversion and good enantioselectivity.

Full text of DOI:10.1039/c1nj20588a

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PAPER
Synthesis of a new class of ligands derived from isosorbide and their
application to asymmetric reduction of aromatic ketones by
transfer hydrogenation
Khanh-Duy Huynh, Houssein Ibrahim, Emile Kolodziej, Martial Toffano* and
Giang Vo-Thanh*
Received (in Montpellier, France) 6th July 2011, Accepted 16th August 2011
DOI: 10.1039/c1nj20588a
A new class of b-amino alcohol and diamine ligands has been prepared from isosorbide as a
chiral renewable source. The efficiency of these ligands has been evaluated for the metal-catalyzed
enantioselective reduction of aromatic ketones by transfer hydrogenation, giving excellent
conversion and good enantioselectivity.
has recently emerged as a highly efficient method for the
Introduction
synthesis of enantiomerically enriched secondary alcohols that
Isosorbide 1, also known as (3R,3aR,6S,6aR)-hexahydro-
are key intermediates for the manufacture of a variety of
furo[3,2-b]furan-3,6-diol, is a renewable, and commercially
molecules and molecular scaffolds of biological and therapeutic
interest.6 Transition metal-catalyzed asymmetric transfer
available chiral carbohydrate. Isosorbide is basically two fused
tetrahydrofuran rings having the cis-arrangement at the ring
junction, giving a wedge-shaped molecule.1 The compound
hydrogenation of prochiral ketones provides a powerful alter-
native to asymmetric hydrogenation owing to its ease of
bears two hydroxyl groups, one at C6 having the exo-orientation
handling, the easy availability of hydrogen sources, lower cost
and safety.7 Many chiral ligands and transition metals have
with respect to the wedge-shaped molecule, and the other at C3
having the endo-orientation, which makes possible the intra-
been developed and applied to this reaction. The common
molecular hydrogen bonding with the oxygen atom of the
catalysts are rhodium, ruthenium and iridium complexes with
chiral phosphine and chiral diamine ligands.8
neighbouring tetrahydrofuran ring (Fig. 1).
Isosorbide is industrially obtained by dehydration of
As a part of our own program of studies, we have recently
D-sorbitol, and can therefore be considered as a biomass
described the rhodium-catalyzed ATH of acetophenone using
product. It was widely used for the synthesis of sophisticated
chiral N-heterocyclic carbene ligands, derived from
molecules including chiral ionic liquids,2 phase-transfer
(S)-pyroglutamic.9 We report here the synthesis of new chiral
catalysts,3 and ligands (amino alcohols, amines, mono- and
b-amino-alcohols and diamines derived from isosorbide 1, and
investigate their catalytic application to ATH of aromatic
diphosphines, diphosphites, bis-diaminophosphites, etc.).4,5
The reduction of carbonyl compounds to the corresponding
ketones.
alcohols is one of the most fundamental and useful reactions
that are important in the pharmaceutical and chemical indus-
try. The asymmetric transfer hydrogenation (ATH) of ketones
Results and discussion
Synthesis of chiral ligands
The synthesis of ligands 4a–h derived from isosorbide 1 is
summarized in Scheme 1. Our synthesis was initiated by the
selective monobenzylation of the hydroxyl group at the endo
position C3 of isosorbide. The best yield (56%) of compound 2
was obtained when performing the reaction using one equivalent
of benzyl chloride along with lithium hydride and lithium
chloride in stoichiometric quantities. The free hydroxyl group
Fig. 1 Structure of isosorbide 1.
at the exo position C6 was then activated as its sulfonate by
treatment with benzenesulfonyl chloride using an excess of
triethylamine, affording the sulfonate 3 in 99% yield. Sub-
´
Laboratoire de Catalyse Moleculaire, Institut de Chimie Moleculaire
et des Materiaux d’Orsay, UMR 8182, Universite Paris-Sud 11,
91405 Orsay Cedex, France. E-mail: giang.vo-thanh@u-psud.fr
´
sequently, the sulfonate 3 was treated with an excess of amino
alcohol in a sealed tube at 160 1C in the presence of lithium
´
´
c
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Scheme 1 Synthesis of amino alcohols 4a–h.
chloride, giving the corresponding compounds 4a–h via a SN2
substitution reaction with complete inversion of configuration.
On the other hand, amino alcohol 6 was obtained by a two-
step procedure, including a substitution of sulfonate 3 with
benzylamine, followed by a removal of the benzyl protecting
groups of 5 by hydrogenolysis in the presence of Pd/C
(Scheme 2).
Scheme 3 Synthesis of amino alcohols 7a–b.
Debenzylation of ligands 4a and 4b gave dihydroxy com-
pounds 7a and 7b, respectively, in quantitative yields
(Scheme 3).
such as stability, ease of handling, non-toxic, environmentally
friendly, inexpensive and a good solvent for many organic
compounds.
Using the similar reaction conditions previously described
for the synthesis of amino alcohol ligands 4, diamine 8 and N-
tosylated amine 9 were synthesized from sulfonate 3 with 82%
and 60% yields respectively (Scheme 4).
Next, we decided to screen catalyst precursors using i-PrOH
as a hydrogen source and t-BuOK as a promoter for the
asymmetric reduction of acetophenone. The reactions were
performed at room temperature using ligand 4a (Table 2).
Changing the arene ligand from p-cymene to benzene or
mesitylene gave a negative effect on both conversion and
enantioselectivity (entries 1 and 3). The [CpRhCl2]2 catalyst
precursor gave almost equivalent enantiomeric excess, but
lower yield compared to [RuCl2(p-cymene)]2 one (entries 4
and 2). On the other hand, the [CpIrCl2]2 catalyst precursor
gave both lower yield and enantioselectivity (entry 5).
We decided thus to pursue our studies by varying the base/
ligand/metal (B/L/M) ratio using [RuCl2(p-cymene)]2 as a
catalyst precursor and t-BuOK as a promoter in the presence
of ligand 4a (Table 3).
Asymmetric transfer hydrogenation reaction
After achieving the synthesis of these amino alcohols and
diamines, we were interested in testing their potential as
ligands for asymmetric catalysis.
The reduction of acetophenone to 1-phenylethanol by
asymmetric transfer hydrogenation was chosen as a model
reaction to explore the catalytic behaviours of complexes. The
complex formation conditions are described in detail in the
experimental section.
We have initiated by screening the hydride sources effect on
catalytic activity and asymmetric induction of the reduction of
acetophenone using the ligand 4a. The catalytic trials were
carried out using ligand 4a (5 mmol), acetophenone (1.0 mmol),
[RhCl2(p-cymene)]2 catalyst precursor (1 mol%). The reaction
Table 3 shows a crucial effect on reactivity and especially on
asymmetric induction by varying the base/ligand/metal
(B/L/M) ratio. The best conversion and enantioselectivity were
obtained at B/L/M 2/2/1. Under these conditions, the product
was obtained with 99% conversion and 70% ee after 2 h
(entry 5). Furthermore, the enantiomeric excess did not decrease
after 24 h of reaction time (entries 5 and 6). The similar results
were observed at B/L/M 4/4/1 (entries 6 and 8). Decreasing of
concentration of the base, racemic products were observed
with a deteriorated conversion (entries 1 and 2). When using
1
conversion was monitored by H NMR and the enantiomeric
excess was determined by chiral HPLC analysis. Some significant
results are presented in Table 1.
Usage of i-PrOH as a hydrogen source afforded the desired
product with 99% conversion and 70% ee after 2 h. This
conventional hydrogen source offers interesting properties
Scheme 2 Synthesis of amino alcohol 6.
c
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Scheme 4 Synthesis of diamine 8 and N-tosylated amine 9.
Table 1 ATH of acetophenone with various hydride sources
Table 4 Effect of substrate concentration on the ATH of acetophenonea
Entry Hydride source Time/h Temp./1C Solvent Conv.a/% eeb/%
Entry
Time/h
[C]b (mol)
Conv.c/%
eed/%
1c
2d
3e
HCO2H–NEt3 24
96
40
25
25
CH2Cl2 10
H2O 85
i-PrOH 99
7
46
70
1
2
3
4
5
6
2
24
2
24
2
0.1
0.1
0.2
0.2
0.4
0.4
60
67
99
99
90
93
56
70
70
70
70
65
HCO2Na
i-PrOH
2
a
b
Determined by 1H NMR. Determined by chiral HPLC analysis
c
d
using Chiralcel OD-H column. HCO2H–NEt3 (0.5 mL). HCO2Na
e
(5 mmol). t-BuOK (5 mol%) is used as a base. Ratio t-BuOK/4a/
24
a
Ru = 2/2/1. [Acetophenone] = 0.2 M in i-PrOH.
Conditions: [RuCl2(p-cymene)]2 (1.25 mol%), ligand 4a (5 mol%),
molar ratio of acetophenone/t-BuOK/ligand 4a/Ru = 40/2/2/1.
b
c
Concentration of acetophenone. Determined by 1H-NMR.
Determined by chiral HPLC analysis.
d
Table 2 ATH of acetophenone with various catalyst precursorsa
an excess of base with regard to the ligand, the enantiomeric
excess and especially the conversions dropped (entries 9
and 10). Under these optimal conditions the 2/2/1 ratio for
t-BuOK/ligand/Ru was then selected for evaluating the influ-
ence of substrate concentration (Table 4).
Entry
Time/h
Catalyst precursor
Conv.b/%
eec/%
1
2
3
4
5
2
2
24
2
[RuCl2(benzene)]2
[RuCl2(p-cymene)]2
[RuCl2(mesitylene)]2
[CpRhCl2]2
34
99
14
64
25
40
70
0
63
24
The concentration of acetophenone was changed by mod-
ifying the volume of i-PrOH. As we can observe, only 60%
conversion was obtained after 2 h of reaction time when using
0.1 M concentration of substrate (entry 1). The reaction time
was extended to 24 h in order to obtain better conversion, but
unsuccessful. With higher concentration, 0.4 M for example,
the enantiomeric excesses slightly decreased after 24 h, prob-
ably owing to the reaction reversibility (entries 5 and 6). The
best results were obtained when performing the reaction at
[substrate] = 0.2 M without any racemisation of the product
(entries 3 and 4). These conditions were applied to examine the
reaction temperature effect (Table 5).
2
[CpIrCl2]2
a
Conditions: catalyst precursor (1.25 mol%), ligand 4a (5 mol%),
molar ratio of acetophenone/t-BuOK/ligand 4a/Ru = 40/2/2/1, [aceto-
phenone] = 0.2 M in i-PrOH. Determined by 1H-NMR. Determined
by chiral HPLC analysis.
b
c
Table 3 ATH reduction of acetophenone using i-PrOH as a hydride
source and [RuCl2(p-cymene)]2 as a catalyst precursora
Table 5 Effect of temperature on ATH of acetophenonea
Entry
Time/h
Molar ratiob
Conv.c/%
eed/%
1
2
3
4
5
6
7
8
9
10
48
48
2
2
2
24
2
24
2
1/1/1
1/2/1
2/1/1
2/4/1
2/2/1
2/2/1
4/4/1
4/4/1
6/4/1
6/4/1
17
8
0
0
22
97
99
99
88
98
22
23
70
70
70
70
70
70
67
60
Entry
Time/h
Temp./1C
Conv.b/%
eec/%
1
2
3
4
2
2
40
96
25
0
0
À10
99
39
99
83
70
75
77
80
24
a
Conditions: [RuCl2(p-cymene)]2 (1.25 mol%), ligand 4a (5 mol%),
molar ratio of acetophenone/t-BuOK/ligand 4a/Ru = 40/2/2/1, [aceto-
a
Conditions: molar ratio acetophenone/Ru = 40/1, [acetophenone] =
b
0.2 M in i-PrOH. t-BuOK/ligand/Ru ratio. Determined by 1H-NMR,
c
phenone] = 0.2 M in i-PrOH. Determined by 1H-NMR. Determined
by chiral HPLC analysis.
b
c
d
no by products were observed. Determined by chiral HPLC analysis.
c
2624 New J. Chem., 2011, 35, 2622–2631
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Table 6 ATH of acetophenone with various basesa
Table 7 Variation of ligands in the ATH of acetophenonea
Entry
Time/h
Base
Conv.b/%
eec/%
1
2
3
4
5
6
2
2
3
20
2
24
t-BuOK
i-PrONa
i-PrONa
i-PrONa
KOH
99
93
96
96
28
70
70
67
67
62
70
70
Entry
Time/h
Ligand
Conv.b/%
eec/%
KOH
1
2
3
4
5
6
7
8
2
2
24
2
24
2
24
2
24
2
24
2
24
2
48
48
2
4a
4b
4b
4c
4c
4d
4d
4e
4e
4f
99
30
63
10
32
25
28
18
55
94
94
74
95
10
nde
nde
89
77
12
40
100
100
(R)-70
(R)-27
(R)-3
a
Conditions: [RuCl2(p-cymene)]2 (1.25 mol%), ligand 4a (5 mol%),
molar ratio of acetophenone/t-BuOK/ligand 4a/Ru = 40/2/2/1, [aceto-
(R)-40
(R)-36
(S)-60
(S)-47
(R)-44
(R)-35
(R)-87
(R)-91
(S)-60
(S)-60
(R)-65
—
phenone] = 0.2 M in i-PrOH. Determined by 1H-NMR. Determined
by chiral HPLC analysis.
b
c
The best enantioselectivity (80% ee) was obtained when
performing the reaction at À10 1C. However, the reaction time
dramatically increased from 2 h up to 96 h (entries 3 and 4).
It is well-known that transfer hydrogenations are sensitive
to the nature of the base. Thus, the influence of t-BuOK,
i-PrONa and KOH, used as promoters, on selectivity and
conversion was investigated. In all cases, good to excellent
conversions were observed (Table 6). Despite that the nature
of the base has limited effect on the selectivity, we observed
that longer reaction time was needed in the case of KOH. The
best conversion and enantioselectivity were obtained in the
presence of 5 mol% t-BuOK, one of the most common bases
for transfer hydrogenation (Table 6, entry 1).
9
10
11d
12
13
14
15
16
17
18f
19
20
21
22
4f
4g
4g
4h
5
6
—
7a
7a
7b
7b
10g
11h
(R)-66
(R)-65
(S)-26
(S)-26
(S)-24
(S)-29
2
2
24
1
1
a
Conditions: [RuCl2(p-cymene)]2 (1.25 mol%), ligand (5 mol%),
molar ratio of acetophenone/t-BuOK/ligand/Ru = 40/2/2/1, [aceto-
Next, the influence of the ligand nature was investigated. As
shown in Table 7, we examined 14 amino alcohol ligands 4a–h,
5, 6, 7a–b, 10, 11 under the previously optimized conditions
for the transfer hydrogenation of acetophenone.
phenone] = 0.2 M in i-PrOH. Determined by 1H-NMR. Deter-
mined by chiral HPLC analysis. Absolute configuration assigned by
comparison of the specific rotation with literature values.
b
c
d
e
f
Reaction was carried out at 0 1C. Not determined. 2 eq. LiCl
g
h
Both ligands 5 and 6 showed no activity in terms of conversion
and enantioselectivity. The distance between hydroxyl group and
amine function is probably important to assure the formation of
the Ru-complex. With the O-benzylated amino alcohol ligands
4b to 4e, enantiomeric excesses and conversions of the reduction
did not exceed 60% and 63%, respectively, compared to ligand
4a (70% ee with 99% conversion). Substituents at the a-position
of the nitrogen atom of amino alcohol have a negative influence
both on the enantioselectivity and reaction rate (compare entries
2–9 to entry 1). On the other hand, the introduction of a phenyl
group at the a-position of the oxygen atom, ligand 4f, has a
positive effect on the enantioselectivity. The asymmetric induc-
tion increased up to 91% ee without loss of catalytic activity
(94% conversion) (entries 10 and 11). However, its diastereoi-
somer 4g conducted lower enantioselectivities and conversions.
Moreover, supplementary substitution with two phenyl groups
for ligand 4h resulted in very low conversion (10%) with a slight
decrease of ee value (entry 14). Debenzylated amino alcohol
ligand 7a gave similar results as O-benzylated one 4a in terms of
conversion and enantioselectivity (entries 1 and 17). This showed
a very weak effect of free hydroxyl groups at the C3 position of
isosorbide skeleton. Surprisingly, in the case of 7b (entries 19 and
20), we observed an inversion of absolute configuration of the
product ((S)-26% ee) compared to (R)-27% ee for 4b (entries 2
and 3). More interestingly, the enantiomeric excess value did not
was added. (S)-2-Amino-2-phenylethanol 10 as ligand. (S)-2-Amino-
3-methylbutan-1-ol 11 as ligand.
decrease in time when compared to ligand 4b (26% ee for 7b and
3% ee for 4b after 24 h). Finally, when (S)-2-amino-2-phenyl-
ethanol 10 and (S)-2-amino-3-methylbutan-1-ol 11 were used as
chiral ligands for ATH of acetophenone, excellent catalytic
activities with total conversion after only 1 h of reaction time,
but moderate asymmetric induction, only 24% and 29% ee,
respectively, were observed (entries 21 and 22).
Better or similar enantioselectivities were observed with our
ligands 4b and 4d possessing an isosorbide skeleton, compared
to their analogues 11 and 10 (entries 6 and 21, 2 and 22).
Moreover, a good asymmetric induction was obtained with the
ligand 4a bearing an ethanolamine chain. These results con-
firmed that the presence of the isosorbide moiety is funda-
mental for asymmetric induction.
To extend the scope of the amino-alcohol 4a and 7a
ligand–Rh(I) complexes as chiral catalysts in this reaction,
some functionalized acetophenone derivatives which are more
difficult to hydrogenate were tested. The substrates were
selected so as to have either electron-donating or electron-
withdrawing moieties on the phenyl ring. In agreement with
the literature, no decomposition or side reactions of these
c
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substituted ketones in transfer hydrogenation have been
detected.10
presumably due to increased substrate bulk (entries 1 and
12, 13). This was confirmed when increasing the bulkiness of
the R group, next to the active center, very low or no activity
and enantioselectivity were recorded (entries 14, or 2 and 3).
The best enantiomeric excess of 82% was obtained using 3,4-
dihydronaphthalen-1(2H)-one as a substrate. However, low
conversion was observed (entry 11).
The indicated reaction times were optimized. No improve-
ment of conversion or loss of enantiomeric excesses of pro-
ducts was observed in extending reaction time.
Ligand 4a showed high capacity for transfer hydrogenation
of various ketones with good conversion and moderate to
good enantioselectivity (up to 82% ee). The steric and electro-
nic properties of substrates affected considerably the chemical
yield and enantioselectivity. Introduction of an electron-with-
drawing group or an electron-donating group on the phenyl
led to much lower yields and enantioselectivities (entries 4–10).
On the other hand, negative effects on conversion and asym-
metric induction were observed when performing the ATH
with 1- or 2-acetylnaphthalene in lieu of acetophenone,
As shown in Table 9, in general, the complex formed with
ligand 7a offers better catalytic activity, but with a little lower
in enantioselectivity when compared to ligand 4a (Tables 8
and 9). For example, 2-acetylnaphthalene was completely
reduced in 2 hours leading to 55% ee (Table 9, entry 7). On
the other hand, only 71% conversion and 65% ee were
obtained with ligand 4a in 24 hours with the same substrate
(Table 8, entry 13).
In other respect, diamine and N-tosyldiamine are well-
known as efficient ligands for ruthenium11 or iridium-
catalyzed12 ATH reaction. We started our investigation by
testing diamine 8 at reduction of acetophenone in the presence
of [RuCl2(p-cymene)]2 or Ir[(COD)Cl]2 as a pre-catalyst. The
preparation of catalysts needs to heat the system at 80 1C to
give good conversion of the substrate. However, low enantio-
selectivity was observed (ee o 23%) (Table 10).
Table 8 Asymmetric transfer hydrogenation of aromatic ketones
with ligand 4aa
Entry Ketone
Time/h Conv.b/% eec/%
1
2
R = CH3
R = i-Pr
2
48
99 (96)d
0
(R)-70
—
Next, N-monotosylated diamine 9 was evaluated as ligands
for the ATH of ketones. The complexes ligand 9–[M] give
generally better results in terms of enantioselectivity
(Table 11).
3
4
R = CH2Cl 48
0
—
X = MeO
X = Cl
2
2
54
(R)-62
Despite acceptable enantioselectivity (up to 75% ee, entry
1), long reaction time was needed with ligand 9 in all cases. For
the best result, the product was obtained with 65% conversion
and 73% ee after 24 h (entry 3). In the case of iridium-catalyzed
5
6
74
91
(R)-54
24
63
Table 9 Asymmetric transfer hydrogenation of aromatic ketones
with ligand 7aa
Entry Ketone
Time/h Conv.b/% eec/%
7
8
9
X = OMe
X = Cl
X = Br
24
2
24
3
40
75
79
93 (93)d
(R)-65
(R)-61
(R)-60
(R)-60
1
2
3
R = CH3
R = CH2Cl 48
2
89
0
(R)-66
—
(S)-33
R = CF3
3
3
32
10
X = CF3
11
12
13
2
29
26
(R)-82
(R)-59
4
99
88
(R)-56
(R)-55
24
5
6
2
24
3
71
40
(R)-65
(R)-66
2
2
35
(R)-80
(R)-55
14
7
100
a
Conditions: [RuCl2(p-cymene)]2 (1.25 mol%), ligand 4a (5 mol%),
molar ratio of acetophenone/t-BuOK/ligand 4a/Ru = 40/2/2/1, [aceto-
a
Conditions: [RuCl2(p-cymene)]2 (1.25 mol%), ligand 7a (5 mol%),
molar ratio of acetophenone/t-BuOK/ligand 7a/Ru = 40/2/2/1, [aceto-
b
phenone]
=
c
0.2
M
in i-PrOH.
T
=
25 1C. Determined by
1H-NMR. Determined by chiral HPLC analysis. Optical rotation
assigned by comparison of the specific rotation with literature values.
b
phenone]
=
c
0.2
M
in i-PrOH.
T
=
25 1C. Determined by
1H-NMR. Determined by chiral HPLC analysis. Optical rotation
assigned by comparison of the specific rotation with literature values.
d
Isolated yield.
c
2626 New J. Chem., 2011, 35, 2622–2631
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Table 10 ATH of acetophenone with ligand 8a
Entry
Pre-catalyst
Ratiob
Temp./1C
Time/h
Conv.c/%
eed/%
1
2
3
[RuCl2(p-cymene)]2
Ir[(COD)Cl]2
Ir[(COD)Cl]2
40/1/1/2
40/1/1/2
40/1/2/2
50
25
25
21 h
1 h
1 h
97
100
74
5
16
23
a
Conditions: pre-catalyst (1.25 mol%), ligand 8 (2.5 mol%), complex is prepared by heating at 80 1C for 30 min, [acetophenone] = 0.2 M in
b
c
1
d
i-PrOH. T = 25 1C. Ratio: substrate/metal/ligand/t-BuOK. Determined by H-NMR. Determined by chiral HPLC analysis.
Table 11 ATH of acetophenone with ligands 9a
Entry
Pre-catalystb
Ratioc
Temp. cat.d/1C
Time/h
Conv.e/%
eef/%
1g
2
3
4
5
6
7
8
9
Ru
Ru
Ru
Ru
Ru
Ru
Ru
Ir
40/1/1/2
40/1/1/2
40/1/1/2
40/1/1/1
40/1/1/4
40/1/1/6
40/1/1/10
40/1/1/2
40/1/1/2
80
80
25.
25
25
25
25
80
25
20
48
24
48
20
20
18
24
20
36
10
65
16
8
8
0
91
77
75
60
73
72
72
72
—
51
30
Ir
a
b
Conditions: pre-catalyst (1.25 mol%), ligand 9 (2.5 mol%), [acetophenone] = 0.2 M in i-PrOH. T = 25 1C. Ru = [Ru(p-cymene)Cl2]2, Ir =
[Ir(COD)Cl]2. Ratio: substrate/metal/ligand/t-BuOK. Temperature for preparation of complex during 30 min. Determined by 1H-NMR.
f
c
d
e
g
Determined by chiral HPLC analysis. Reaction at 50 1C.
ATH reaction, the conversion is clearly better, but enantiomeric
excesses are lower when compared to ruthenium-catalyzed reac-
tion (entries 8 and 9).
The reduction works without complication leading to the
products with moderate enantiomeric excesses (up to 70% ee,
entry 3). The conversion clearly increases in the presence of
electron-withdrawing groups such as bromide (61%, entry 1)
or trifluoromethyl (97%, entry 2). In contrast, the presence of
electron-donating groups or hindered substrates decreases the
reaction rate (entries 3, 4 and 6).
The next step was to evaluate the efficiency of ligand 9 in
ruthenium-catalyzed transfer hydrogenation. Some ketones
were tested. The results are summarized in Table 12.
Table 12 Asymmetric transfer hydrogenation of aromatic ketones
with ligand 9a
Conclusion
Entry
Ketone
Conv.b/%
ee/c%
In summary, we have described the flexible procedure for the
synthesis of new chiral amino alcohols and diamines derived
from isosorbide, a naturally renewable resource. These ligands
were obtained in moderate to excellent yields. We have also
shown that isosorbide-based amino alcohols and diamines
could be used as ligands for Ru-catalyzed asymmetric transfer
hydrogenation reaction of aromatic ketones. The reduction of
acetophenone by ATH reaction with ligand 4f gave excellent
conversion and good enantioselectivity up to 91% ee. These
results indicated clearly the efficiency of the isosorbide struc-
ture for the synthesis of new chiral ligands for asymmetric
catalysis applications. Development of new chiral compounds
derived from isosorbide as ligands or organocatalysts in
asymmetric catalysis is currently underway in our laboratory.
1
61
54
2
97
65
3
4
25
11
70
59
Experimental
5
6
a
58
0
58
—
General information
Melting points were measured on a Kofler bank. The NMR
spectra were recorded in CDCl3, DMSO-d6, MeOD-d4 or in
1
acetone-d6. H NMR spectra were recorded at 360 or 300, or
Conditions: [RuCl2(p-cymene)]2 (1.25 mol%), ligand 9 (2.5 mol%),
250 MHz. The chemical shifts (d) are reported in parts per
million relative to TMS as internal standard. J values are given
in hertz. 13C NMR spectra were recorded at 360, 300, 250 or
[acetophenone] = 0.2 M in i-PrOH. T = 25 1C, time: 24 h.
Determined by H-NMR. Determined by chiral HPLC analysis.
b
1
c
c
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62.5 MHz. IR spectra were recorded on a FT-IR Perkin–El-
mer instrument. Mass spectra were recorded on a MAT 95S
Finnigan-Thermo mass spectrometer. TLC experiments were
carried out in 0.25 mm thick silica gel plates Merck Kiesegel
F254 and visualization was accomplished by UV light or
phosphomolybdic acid solution. The columns were hand-
packed with silica gel 60 (200–300). Isopropanol was redis-
tilled over calcium hydride under an argon atmosphere. All
reagents and solvents were purchased from commercial
sources (Acros, Aldrich) and were used without further
purification. Ruthenium and iridium complexes have been gener-
ously provided by Johnson Matthey Technology Centre,
Reading.
(m, 3H, phenyl), 7.91–7.97 (m, 2H, phenyl); 13C NMR
(62.5 MHz, CDCl3) d 70.5 (CH2), 72.5 (CH2), 73.2 (CH2), 78.9
(CH), 80.6 (CH), 84.2 (CH), 85.8 (CH), 127.8, 127.9, 128.0,
128.5, 129.5, 134.1 (10CHAr), 136.3 (C), 137.5 (C). Anal. calcd
for C19H20O6S: C, 60.62; H, 5.36; O, 25.50; S, 8.52%. Found:
C, 60.44; H, 5.25; O, 25.41; S, 8.49%.
2-((3R,3aS,6R,6aR)-3-(Benzyloxy)hexahydrofuro[3,2-b]fur-
an-6-ylamino)ethanol 4a. A mixture of the sulfonate 3
(8 mmol), distilled ethanolamine (32 mmol), lithium chloride
(4 mmol) was heated in a sealed tube at 160 1C for 4 h. The
reaction mixture was brought to room temperature and
the excess of ethanolamine was then removed under vacuum. The
residual oil was purified by flash column chromatography on
silica gel (dichloromethane : methanol = 98 : 2 and 95 : 5,
consecutively) to give the product as a dark yellow oil in
75% yield.
Synthesis of ligands
(3S,3aR,6R,6aR)-6-(Benzyloxy)hexahydrofuro[3,2-b]furan-
3-ol 2. A mixture of isosorbide 1 (140 mmol, 20 g), lithium
hydride (140 mmol, 1.11 g), lithium chloride (140 mmol, 5.91 g)
in DMSO (65 mL) was stirred at 90 1C for 20 min. Benzyl
chloride (140 mmol, 16 mL) was added and the resulting
mixture was then stirred for 18 h. The reaction mixture was
acidified with 2 N HCl (65 mL) and extracted with ethyl
acetate (3 Â 150 mL). The organic phase was dried over
anhydrous MgSO4. The solvent was evaporated in vacuo and
the residual oil was purified by flash column chromatography
on silica gel (cyclohexane : ethyl acetate = 1 : 1; 5 : 5; 1.5 : 8.5)
to afford a product as white crystals in 56% yield.
25
[a]D +123.1 (c 1.1, CHCl3); IR (neat) n = 3376, 2941,
2872, 1667, 1455, 1369, 1312, 1260, 1208, 1137, 1069, 1026,
1
924, 823, 743 cmÀ1; H NMR (300 MHz, CDCl3) d 2.54 (s,
NH), 2.71–2.79 (m, 1H), 2.83–2.91 (m, 1H), 3.31–3.49 (m, 2H),
3.61–3.69 (m, 2H), 3.89 (dd, J = 6.6 and 9.0 Hz, 1H), 4.06 (dd,
J = 4.8 and 6.0 Hz, 1H), 4.11–4.17 (m, 1H), 4.40 (dd, J = 4.5
and 4.5 Hz, 1H), 4.53 (d, J = 12.0, 1H), 4.62 (dd, J = 4.5 and
4.5 Hz, 1H), 4.74 (d, J = 12.0, 1H), 7.31–7.34 (m, 5H, benzyl);
13C NMR (75.5 MHz, CDCl3) d 49.9 (CH2), 61.3 (CH2), 62.6
(CH), 71.4 (CH2), 72.6 (CH2), 72.6 (CH2), 79.7 (CH), 80.8
(CH), 81.4 (CH), 127.97, 128.5 (5CHAr), 137.7 (C). HRMS
(ESI) calcd for C15H22NO4 ([M + H]+): 280.1549, found:
280.1541.
25
Mp: 60 1C; [a]D +109.4 (c 0.83, CHCl3); IR (neat) n =
3429, 2945, 2877, 1497, 1455, 1132, 1069, 1018, 979 cmÀ1
;
1H NMR (360 MHz, CDCl3) d 2.75 (d, J = 4.7 Hz, OH), 3.59
(dd, J = 8.6 and 7.9 Hz, 1H), 3.83 (dd, J = 8.6 and 6.8 Hz, 1H),
3.90–4.07 (m, 3H), 4.25 (s, 1H), 4.38 (d, J = 4.7 Hz, 1H), 4.54
(d, J = 11.9 Hz, 1H), 4.68 (dd, J = 4.3 and 4.7 Hz, 1H), 4.75
(d, J = 11.9 Hz, 1H), 7.25–7.38 (m, 5H, benzyl); 13C NMR
(62.5 MHz, CDCl3) d 69.8 (CH2), 72.2 (CH2), 75.6 (CH2), 76.2
(CH), 79.0 (CH), 79.8 (CH), 88.1 (CH), 127.7, 128.2 (5CHAr),
137.4 (C). Anal. calcd for C13H16O4: C, 66.09; H, 6.83; O,
27.09%. Found: C, 65.98; H, 6.81; O, 27.11%.
(S)-2-((3R,3aS,6R,6aR)-3-(Benzyloxy)hexahydrofuro[3,2-
b]furan-6-ylamino)-3-methylbutan-1-ol 4b. Compound 4b was
prepared following the same procedure previously described for
the synthesis of compound 4a. The reaction time was 24 h.
The purification was carried out by flash column chromato
graphy on silica gel (cyclohexane : ethyl acetate = 1 : 1) to give
a dark yellow liquid in 50% yield from 3 and (S)-2-amino-3-
methylbutan-1-ol.
25
[a]D +115.57 (c 1.05, CHCl3); IR (neat) n = 3456, 2956,
2873, 1650, 1455, 1366, 1195, 1135, 1069, 1027, 928, 826,
(3R,3aR,6S,6aS)-3-(Benzyloxy)hexahydrofuro[3,2-b]furan-
6-yl benzenesulfonate 3. A mixture of the alcohol 2 (65 mmol,
15.4 g), triethylamine (390 mmol, 55 mL) and benzenesulfo-
nyl chloride (78 mmol, 10 mL) was stirred under an argon
atmosphere for 10 h. The reaction mixture was diluted with
water (200 mL), acidified with 5 N HCl (60 mL) and the
hydrolysis was continued for further 2 h. The resulting
mixture was extracted with dichloromethane (3 Â 120 mL).
The organic phases were washed with brine, dried over
anhydrous MgSO4 and then concentrated under reduced
pressure. The residue was purified by flash column chroma-
tography on silica gel (heptane/ethyl acetate = 1 : 1) to
afford a product as white crystals in 99% yield.
739 cmÀ1 1H NMR (300 MHz, CDCl3) d 0.89 (d, J = 6.9
;
Hz, 3H), 0.93 (d, J = 6.9 Hz, 3H), 1.63–1.74 (m, 1H),
2.35–2.41 (m, 1H), 3.37–3.47 (m, 3H), 3.60 (dd, J = 3.6 and
11.4 Hz, 1H), 3.66 (dd, J = 7.2 and 8.7 Hz, 1H), 3.90 (dd,
J = 6.6 and 8.7 Hz, 1H), 4.06–4.16 (m, 2H), 4.39 (dd, J = 4.2
and 4.2 Hz, 1H), 4.53 (d, J = 12.0 Hz, 1H), 4.62 (dd, J = 4.5
and 4.8 Hz, 1H), 4.74 (d, J = 12.0 Hz, 1H), 7.30–7.36 (m, 5H,
benzyl); 13C NMR (75.5 MHz, CDCl3) d 18.8, 19.4 (2CH3),
61.5 (CH), 62.3 (CH2), 64.1 (CH), 71.6 (CH2), 72.7 (CH2), 72.8
(CH2), 79.7 (CH), 81.4 (CH), 81.5 (CH), 127.9, 128.1, 128.5
(5CHAr), 137.7 (C). HRMS (ESI) calcd for C18H28NO4 ([M + H]+):
322.2018, found: 322.2010.
25
Mp: 93 1C; [a]D +92.7 (c 0.25, CHCl3); IR (neat) n =
3065, 3032, 2877, 1449, 1367, 1189, 1100, 1043, 971, 947, 902,
(R)-2-((3R,3aS,6R,6aR)-3-(Benzyloxy)hexahydrofuro[3,2-
b]furan-6-ylamino)-3-methylbutan-1-ol 4c. Compound 4c
was prepared following the same procedure previously
described for the synthesis of compound 4a. The reaction
time was 24 h. The purification was carried out by flash
column chromatography on silica gel (cyclohexane : ethyl
1
820, 750 cmÀ1; H NMR (250 MHz, CDCl3) d 3.57 (dd, J =
7.6 and 9.0 Hz, 1H), 3.82 (dd, J = 6.6 and 9.0 Hz, 1H),
3.95–4.08 (m, 3H), 4.52 (d, J = 4.3 Hz, 1H), 4.53 (d, J =
12.0 Hz, 1H), 4.68 (dd, J = 4.3 and 5.0 Hz, 1H), 4.73 (d, J =
12.0 Hz, 1H), 4.91 (m, 1H), 7.26–7.40 (m, 5H, benzyl), 7.54–7.71
c
2628 New J. Chem., 2011, 35, 2622–2631
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acetate = 1 : 1) to give a dark yellow liquid in 50% yield
(C). HRMS (ESI) calcd for C21H26NO4 ([M + H]+):
356.1862, found: 356.1854.
from 3 and (R)-2-amino-3-methylbutan-1-ol.
25
[a]D +136.16 (c 1.0, CHCl3); IR (neat) n = 3414, 2957,
(R)-2-((3R,3aS,6R,6aR)-3-(Benzyloxy)hexahydrofuro[3,2-
b]furan-6-ylamino)-1-phenylethanol 4f. Compound 4f was
prepared following the same procedure previously described
for the synthesis of compound 4a. The reaction time was
24 h. The purification was carried out by flash column
chromatography on silica gel (cyclohexane : ethyl acetate
= 3 : 7) to give a bright yellow solid in 43% yield from 3
and (R)-2-amino-1-phenylethanol.
2873, 1641, 1455, 1368, 1310, 1207, 1136, 1071, 1027, 930, 825,
738 cmÀ1; 1H NMR (300 MHz, CDCl3) d 0.87 (d, J = 6.9 Hz,
3H), 0.93 (d, J = 6.9 Hz, 3H), 1.20–1.25 (m, 1H), 2.38–2.43
(m, 1H), 3.30–3.44 (m, 3H), 3.52 (dd, J = 4.2 and 10.8 Hz,
1H), 3.59 (dd, J = 7.8 and 8.7 Hz, 1H), 3.86 (dd, J = 6.6 and
8.7 Hz, 1H), 4.01–4.10 (m, 2H), 4.34 (dd, J = 4.2 and 4.2 Hz,
1H), 4.49 (d, J = 12.0 Hz, 1H), 4.56 (dd, J = 4.5 and 4.5 Hz,
1H), 4.70 (d, J = 12.0 Hz, 1H), 7.30–7.36 (m, 5H, benzyl); 13
C
25
Mp: 56 1C; [a]D +99.43 (c 0.5, CHCl3); IR (KBr) n =
NMR (75.5 MHz, CDCl3) d 18.5, 19.7 (2CH3), 29.5 (CH), 60.9
(CH), 60.9 (CH2), 63.9 (CH), 71.3 (CH2), 72.6 (CH2), 73.1
(CH2), 79.9 (CH), 80.6 (CH), 81.4 (CH), 127.9, 128.0, 128.5
(5CHAr), 137.7 (C). HRMS (ESI) calcd for C6H12NO3 ([M +
H]+): 146.0817, found: 146.0811.
3311, 3028, 2869, 1668, 1492, 1452, 1346, 1258, 1207, 1115,
1084, 1025, 983, 911, 844, 748, 695 cmÀ1; 1H NMR (300 MHz,
CDCl3) d 2.26 (s, NH), 2.53, (dd, J = 9.6 and 12.3 Hz, 1H),
2.96 (dd, J = 3.3 and 12.3 Hz, 1H), 3.26–3.33 (m, 1H), 3.37
(dd, J = 8.1 and 10.1 Hz, 1H), 3.58 (dd, J = 7.5 and 9.0 Hz,
1H), 3.82 (dd, J = 6.6 and 9.0 Hz, 1H), 3.99–4.11 (m, 2H),
4.33 (dd, J = 4.5 and 4.5 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H),
4.55–4.63 (m, 2H), 4.67 (d, J = 12.0 Hz, 1H); 7.24–7.31 (10 H,
phenyl); 13C NMR (75.5 MHz, CDCl3) d 56.4 (CH2), 63.0
(CH), 71.5 (CH2), 72.3 (CH), 72.6 (2CH2), 79.7 (CH), 81.1
(CH), 81.5 (CH), 125.8, 127.6, 127.9, 128.4, 128.5 (10CHAr),
137.7 (C),142.0 (C). HRMS (ESI) calcd for C21H26NO4 ([M +
H]+): 356.1856, found: 356.1841.
(R)-2-((3R,3aS,6R,6aR)-3-(Benzyloxy)hexahydrofuro[3,2-
b]furan-6-ylamino)-2-phenylethanol 4d. Compound 4d was
prepared following the same procedure previously described
for the synthesis of compound 4a. The reaction time was 24 h.
The purification was carried out by flash column chromato-
graphy on silica gel (cyclohexane : ethyl acetate = 1 : 1) to give
a bright yellow paste in 47% yield from 3 and (S)-2-amino-2-
phenylethanol.
25
(S)-2-((3R,3aS,6R,6aR)-3-(Benzyloxy)hexahydrofuro[3,2-
b]furan-6-ylamino)-1-phenylethanol 4g. Compound 4g was
prepared following the same procedure previously described for
the synthesis of compound 4a. The reaction time was 24 h. The
purification was carried out by flash column chromatography
on silica gel (cyclohexane : ethyl acetate = 3 : 7) to give a
bright yellow solid in 52% yield from 3 and (S)-2-amino-1-
[a]D +178.15 (c 0.5, CHCl3); IR (neat) n = 3420, 2943,
2871, 1648, 1494, 1454, 1366, 1202, 1135, 1068, 1025, 845,
756 cmÀ1; 1H NMR (360 MHz, CDCl3) d 2.34 (s, NH), 3.20–3.26
(m, 1H), 3.34 (dd, J = 8.6 and 10.4 Hz, 1H), 3.52 (dd, J = 8.6
and 10.8 Hz, 1H), 3.64–3.70 (m, 2H), 3.86–3.94 (m, 3H),
4.02–4.07 (m, 1H), 4.39 (dd, J = 4.7 and 3.9 Hz, 1H),
4.49–4.52 (m, 2H), 4.69 (d, J = 11.5 Hz, 1H), 7.31–7.33 (m,
10H, phenyl); 13C NMR (90.5 MHz, CDCl3) d 60.7 (CH), 63.6
(CH), 67.7 (CH2), 71.7 (CH2), 72.7 (CH2), 72.8 (CH2), 80.0
(CH), 80.6 (CH), 81.4 (CH), 127.6, 128.0, 128.2, 128.7, 128.9
(10CHAr), 138.0 (C), 140.8 (C). HRMS (ESI) calcd for
C21H26NO4 ([M + H]+): 356.1856, found: 356.1865.
25
phenylethanol; mp: 90 1C; [a]D +180.98 (c 0.5, CHCl3); IR
(KBr) n = 3286, 3087, 2875, 1663, 1491, 1452, 1344, 1303,
1211, 1156, 1103, 1060, 934, 880, 735 cmÀ1 1H NMR (300
;
MHz, CDCl3) d 2.77 (dd, J = 8.7 and 12.0 Hz, 1H), 2.85 (dd,
J = 3.6 and 12.0 Hz, 1H), 3.33–3.40 (m, 1H), 3.42 (dd, J = 8.1
and 10.2 Hz, 1H), 3.60 (dd, J = 7.8 and 9.0 Hz, 1H), 3.86 (dd,
J = 6.6 and 9.0 Hz, 1H), 4.03–4.13 (m, 2H), 4.43 (dd, J = 4.2
and 4.5 Hz, 1H), 4.51 (d, J = 11.7 Hz, 1H), 4.59 (dd, J = 4.8
and 4.5 Hz, 1H), 4.67–4.70 (m, 1H), 4.71 (d, J = 12.0 Hz, 1H);
13C NMR (75.5 MHz, CDCl3) d 55.9 (CH2), 62.7 (CH), 71.7
(CH2), 72.3 (CH), 72.8 (CH2), 72.9 (CH2), 79.9 (CH), 80.7
(CH), 81.5 (CH), 126.0, 127.8, 128.2, 128.6, 128.7 (10CHAr),
138.0 (C), 142.1 (C). HRMS (ESI) calcd for C21H26NO4
([M + H]+): 356.1856, found: 356.1845.
(S)-2-((3R,3aS,6R,6aR)-3-(Benzyloxy)hexahydrofuro[3,2-
b]furan-6-ylamino)-2-phenylethanol 4e. Compound 4e was
prepared following the same procedure previously de-
scribed for the synthesis of compound 4a. The reaction
time was 24 h. The purification was carried out by flash
column chromatography on silica gel (cyclohexane : ethyl
acetate = 1 : 1) to give a brown solid in 48% yield from 3
and (R)-2-amino-2-phenylethanol.
25
Mp: 82 1C; [a]D +61.70 (c 1.0, CHCl3); IR (neat) n =
2-((3R,3aS,6R,6aR)-3-(Benzyloxy)hexahydrofuro[3,2-b]
furan-6-ylamino)-1,1-diphenylethanol 4h. Compound 4h was
prepared following the same procedure previously described for
the synthesis of compound 4a. The reaction time was 24 h. The
purification was carried out by flash column chromatography
on silica gel (cyclohexane : ethyl acetate = 3 : 7) to give a bright
yellow viscous liquid in 70% yield from 3 and 2-amino-1,1-
diphenylethanol.
3377, 3029, 2887, 1658, 1495, 1453, 1366, 1219, 1137, 1081,
1038, 1017, 916, 845, 752 cmÀ1; 1H NMR (360 MHz, CDCl3) d
3.06 (s, NH), 3.17–3.23 (m, 1H), 3.48 (dd, J = 8.6 and 9.7 Hz,
1H), 3.56–3.67 (m, 3H), 3.74–3.77 (m, 1H), 3.83 (dd, J = 6.8
and 8.6 Hz, 1H), 3.96–4.02 (m, 1H), 4.06 (dd, J = 7.6 and
7.9 Hz, 1H), 4.12 (dd, J = 4.7 and 4.0 Hz, 1H), 4.40 (dd, J = 4.7
and 4.7 Hz, 1H), 4.47 (d, J = 12.0 Hz, 1H), 4.67 (d, J =
12.0 Hz, 1H), 7.31–7.33 (m, 10H, phenyl); 13C NMR (90.5 MHz,
CDCl3) d 60.2 (CH), 64.0 (CH), 67.0 (CH2), 71.3 (CH2), 72.6
(CH2), 72.9 (CH2), 79.9 (CH), 80.8 (CH), 81.9 (CH), 127.5,
127.9, 128.0, 128.1, 128.5, 128.7 (10CHAr), 137.8 (C), 140.4
25
[a]D +67.52 (c 0.5, CHCl3); IR (NaCl) n = 3419, 3060,
3028, 2943, 2969, 1598, 1492, 1449, 1367, 1312, 1261, 1135,
1083, 1070, 1026, 942, 910, 826, 752, 670 cmÀ1 1H NMR
;
(360 MHz, CDCl3) d 3.11 (d, J = 12.0 Hz, 1H), 3.33–3.39 (m, 1H),
c
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2011
New J. Chem., 2011, 35, 2622–2631 2629

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3.44 (t, J = 8.76 Hz, 1H), 3.65 (dd, J = 7.3 and 8.9 Hz, 1H),
3.74 (d, J = 12.0 Hz, 1H), 3.94 (dd, J = 6.6 and 8.9 Hz, 1H),
4.10–4.15 (m, 2H), 4.46 (q, J = 4.12 Hz, 1H), 4.58 (d, J = 12.0 Hz,
1H), 4.65 (dd, J = 4.4 and 4.9 Hz, 1H), 4.79 (d, J = 12.0 Hz,
1H), 7.25–7.59 (m, 15H, 3 phenyl); 13C NMR (90.5 MHz,
CDCl3) d 57.9 (CH2), 63.7 (CH), 71.7 (CH2), 72.7, 72.8
(2CH2), 76.5 (C), 79.9 (CH), 80.9 (CH), 81.7 (CH), 126.0,
126.5, 127.1, 127.2, 128.1, 128.4, 128.5, 128.7 (15CHAr), 138.0
(C), 145.5, 145.9 (2C). HRMS (ESI) calcd for C27H30NO4
([M + H]+): 432.2169, found: 432.2173.
(250 MHz, D2O)
d
2.63–2.73 (m, 1H), 2.76–2.86
(m, 1H), 3.35–3.57 (m, 4H), 3.59–3.66 (m, 1H), 3.96
(dd, J = 6.5 and 8.8 Hz, 1H), 4.10 (dd, J = 4.8 and 5.8
Hz, 1H), 4.35–4.42 (m, 1H), 4.56 (dd, J = 4.3 and 4.8 Hz,
1H), 4.62 (dd, J = 4.0 and 4.4 Hz, 1H); 13C NMR (62.5
MHz, D2O) d 49.4 (CH2), 61.2 (CH2), 62.0, (CH), 72.0
(CH2), 72.5 (CH2), 72.9 (CH), 81.1 (CH), 83.0 (CH).
HRMS (ESI) calcd for C8H16NO4 ([M
190.1079, found: 190.1076.
+
H]+):
(3R,3aR,6R,6aR)-6-((R)-1-Hydroxy-3-methylbutan-2-ylami-
no)hexahydrofuro[3,2-b]furan-3-ol 7b. Compound 7b was pre-
pared following the same procedure previously described for
synthesis of compound 6. The reaction time was 4 days. The
purification was carried out by flash column chromatography
on silica gel (dichloromethane : methanol = 98 : 2) to give a
(3R,3aR,6R,6aS)-N-Benzyl-6-(benzyloxy)hexahydrofuro
[3,2-b]furan-3-amine 5. A mixture of the sulfonate 3 (20 mmol),
distilled benzyl amine (120 mmol), lithium chloride (10 mmol)
was heated in a sealed tube at 160 1C for 24 h. The reaction
mixture was brought to room temperature and the excess of
amine was then removed under vacuum. The residual oil was
purified by flash column chromatography on silica gel (cyclo-
hexane : ethyl acetate = 1 : 1) to give the product as a yellow
25
bright yellow liquid in 96% yield from 4b; [a]D +81.84
(c 0.75, CH3OH); IR (neat) n = 3369, 2958, 2873, 1644, 1467,
1389, 1354, 1228, 1193, 1127, 1085, 1058, 927, 826, 741 cmÀ1
;
25
oil in 70% yield. [a]D +145.3 (c 1.47, CHCl3); IR (neat) n =
3321, 3087, 3062, 3029, 2942, 2871, 1496, 1463, 1455, 1367,
1H NMR (250 MHz, D2O) d 0.85 (d, J = 7.0 Hz, 3H), 0.89
(d, J = 7.0 Hz, 3H); 1.83–1.96 (m, 1H), 2.58–2.63 (m, 1H),
3.44–3.60 (m, 3H), 3.62–3.72 (m, 2H), 3.96 (dd, J = 6.3 and
8.8 Hz, 1H), 4.14 (dd, J = 7.5 and 8.0 Hz, 1H), 4.34–4.42 (m,
1H), 4.57–4.64 (m, 2H); 13C NMR (90.5 MHz, CD3OD) d
18.9, 19.4 (2CH3), 30.2 (CH), 61.4 (CH), 62.6 (CH2), 64.5
(CH), 73.5 (CH2), 74.0 (CH), 74.9 (CH2), 82.4 (CH), 84.1
(CH). HRMS (ESI) calcd for C11H22NO4 ([M + H]+):
232.1543, found: 232.1542.
1136, 1084, 1045, 1027, 738 cmÀ1 1H NMR (250 MHz,
;
CDCl3) d 2.27 (s, NH), 3.27–3.46 (m, 2H), 3.62 (dd, J = 7.8
and 8.5 Hz, 1H), 3.72 (d, J = 12.3 Hz, 1H), 3.85 (d, J = 12.3 Hz,
1H), 3.87 (dd, J = 8.5 and 6.75 Hz, 1H), 3.98–4.11 (m, 2H), 4.40
(dd, J = 4.0 and 4.3 Hz, 1H), 4.49 (d, J = 12.0 Hz, 1H),
4.51–4.54 (m, 1H), 4.71 (d, J = 12.0 Hz, 1H), 7.14–7.40 (m,
10HAr); 13C NMR (62.5 MHz, CDCl3) d 52.3 (CH2), 62.1 (CH),
71.1 (CH2), 72.4 (CH2), 72.6 (CH2), 79.8 (CH), 80.2 (CH), 81.1
(CH), 127.0, 127.8, 128.0, 128.3 (10CHAr), 137.7 (C), 140 (C).
Anal. calcd for C20H23NO3: C, 73.82; H, 7.12; O, 14.75; N,
4.30%. Found: C, 73.52; H, 7.11; O, 14.77; N, 4.46%.
(3R,3aR,6R,6aS)-N-(2-Aminoethyl)-6-(benzyloxy)-
hexahydrofuro[3,2-b]furan-3-amine 8. To a solution of sulfo-
nate 3 (700 mg, 1.8 mmol) were added 1,2-diamino ethane
(0.72 mL, 10.8 mmol) and LiCl (38 mg, 0.9 mmol). The
solution was heated in a sealed tube at 160 1C for 24 h.
The reaction mixture was brought to room temperature and the
excess of amine was then removed under vacuum. The residual
oil was purified by flash column chromatography on silica gel
(CH2Cl2 : MeOH = 95 : 5 with 3% NEt3) to give the product
as a yellow oil in 82% yield. [a]D25 +135.4 (c = 1.02; CHCl3);
IR (NaCl) n = 3305, 3029, 2939, 2869, 1660, 1495, 1454, 1367,
(3R,3aR,6R,6aR)-6-Aminohexahydrofuro[3,2-b]furan-3-ol 6.
Amino ether 5 (5 mmol) and the same weight of palladium
10% on charcoal in 10 mL of ethanol were stirred under a 1
bar hydrogen pressure for 24 h. Filtration of the catalyst,
evaporation of the solvent and then purification of the residue
by flash chromatography on silica gel with dichloromethane/
methanol (98/2) in the presence of 1% NH3 afforded white
crystals in 96% yield. Mp: 115 1C; [a]D +110.9 (c 0.5,
1308, 1208, 1135, 1083, 1027, 825, 742, 700 cmÀ1; H NMR
25
1
CH3OH); IR (KBr) n = 3329, 2942, 2859, 1612, 1491, 1475,
(360 MHz, CDCl3) d 1.42 (s broad, NH + NH2), 2.52–2.60
(m, 1H), 2.66–2.78 (m, 3H), 3.24–3.30 (m, 1H), 3.37 (dd, J =
10.4 and 8.2 Hz, 1H), 3.58 (dd, J = 8.6 and 8.2 Hz, 1H), 3.85
(dd, J = 8.6 and 6.8 Hz, 1H), 3.99–4.09 (m, 2H), 4.38 (dd, J =
4.1 and 4.5 Hz, 1H), 4.48 (d, J = 11.8 Hz, 1H), 4.54 (dd, J =
4.1 and 5.0 Hz, 1H), 4.69 (d, J = 11.8 Hz, 1H), 7.19–7.30 (m,
5HAr). 13C NMR (90.5 MHz, CDCl3) d 42.4 (CH2), 51.4
(CH2), 63.2 (CH), 71.5 (CH2), 72.7 (CH2), 73.0 (CH2), 80.1
(CH), 80.8 (CH), 81.4 (CH), 128.0, 128.1, 128.6 (5CHAr); 138.0
(Cq). HRMS (ESI) calcd for C15H22N2O3 ([M + H]+):
279.1717, found: 279.1703.
1408, 1372, 1302, 1156, 1128, 1085, 1022, 926, 815, 777 cmÀ1
;
1H NMR (300 MHz, D2O) d 3.32 (dd, J = 8.4 and 10.2 Hz,
1H), 3.48–3.54 (m, 2H), 3.97–4.08 (m, 2H), 4.35–4.42 (m, 1H),
4.43 (dd, J = 4.5 and 4.5 Hz, 1H) , 4.55 (dd, J = 4.5 and
4.8 Hz, 1H); 13C NMR (75.5 MHz, D2O) d 54.54 (CH), 71.81
(CH2), 72.17 (CH), 72.70 (CH2), 82.21 (CH), 82.65 (CH).
HRMS (EI) calcd for C6H12NO3 ([M + H]+): 146.0817,
found: 146.0811.
(3R,3aR,6R,6aR)-6-(2-Hydroxyethylamino)hexahydro-
furo[3,2-b]furan-3-ol 7a. Compound 7a was prepared following
the same procedure previously described for the synthesis of
compound 6. The reaction time was 4 days. The purification
was carried out by flash column chromatography on silica gel
(dichloromethane : methanol = 98 : 2) to give a bright yellow
(3R,3aR,6R,6aS)-6-(Benzyloxy)-hexahydrofuro-N-(2(tosyl-
amino)ethyl)furo[3,2-b]furan-3-amine 9. Compound 9 was pre-
pared following the same procedure previously described for
synthesis of compound 8, from 3 (2.6 mmol), N-(-4-toluene-
sulfonyl)-1,2-ethylenediamine (16 mmol), and lithium chloride
(1.3 mmol). The product was purified by flash column chro-
matography on silica gel (CH2Cl2 : MeOH = 99 : 1 and 92 : 2)
25
solid in 96% yield from 4a; mp: 62 1C; [a]D +106.95 (c 0.5,
CH3OH); IR (KBr) n = 3315, 2925, 2890, 1656, 1460,
1376, 1123, 1057, 1015, 927, 825 cmÀ1
;
1H NMR
c
2630 New J. Chem., 2011, 35, 2622–2631
This journal is The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2011

View Article Online
25
to give a liquid in 60% yield. [a]D +97,3 (c = 1, CHCl3). IR
G. Rosini, Tetrahedron: Asymmetry, 2007, 18, 2923;
(c) F. W. Lui, L. Yan, J. Y. Zhang and H. M. Liu, Carbohydr.
Res., 2006, 314, 332; (d) G. De Coster, K. Vandyck, E. Van der
(NaCl) n = 3543, 3273, 3031, 2943, 2872, 1598, 1495, 1455, 1368,
1330, 1209, 1158, 1092, 1022, 817, 740, 665 cmÀ1. 1H NMR (360
MHz, CDCl3) d 1.48 (s broad, 1NH), 2.34 (s, 3H), 2.56–2.76 (m,
2H), 2.82–2.98 (m, 2H), 3.06–3.12 (m, 1H), 3.26 (dd, J = 10.0
and 8.6 Hz, 1H), 3.55 (dd, J = 8.6 and 7.7 Hz, 1H), 3.80 (dd, J
= 8.6 and 6.8 Hz, 1H), 3.93–4.01 (m, 2H), 4.24 (t, J = 4.5 Hz,
Eycken, J. Van der Eycken, M. Elseviers and H. Roper, Tetra-
¨
hedron: Asymmetry, 2002, 13, 1673.
5 Phosphorus ligands: (a) M. Dieguez, O. Pamies and C. Claver,
´
J. Org. Chem., 2005, 70, 3363; (b) K. N. Gavrilov, S. V. Zheglov,
P. A. Vologzhanin, M. G. Maksimova, A. S. Safronov,
S. E. Lyubimov, V. A. Davankov, B. Schaffner and A. Borner,
¨
¨
1H), 4.46 (d,
J
=
11.8 Hz, 1H), 4.51 (dd,
Tetrahedron Lett., 2008, 49, 3120; (c) M. T. Reetz and
T. Neugebauer, Angew. Chem., Int. Ed., 1999, 38, 179;
(d) C. Carcedo, A. Dervicsi, I. A. Fallis, L. Ooi and K. M.
A. Malik, Chem. Commun., 2004, 1236; (e) J. Bakos, B. Heil and
L. Marko, J. Organomet. Chem., 1983, 253, 249; (f) H. Zhou,
J. Hou, J. Cheng, S. Lu, H. Fu and H. Wang, J. Organomet.
Chem., 1997, 543, 227.
6 For recent selected examples, see: (a) A. Schlatter, M. K. Kundu
and W.-D. Woggon, Angew. Chem., 2004, 116, 6899 (Angew.
Chem., Int. Ed., 2004, 43, 6731); (b) D. Xue, Y.-C. Chen, X. Cui,
Q.-W. Wang, J. Zhu and J.-G. Deng, J. Org. Chem., 2005,
70, 3584; (c) X. Wu, X. Li, F. King and J. Xiao, Angew. Chem.,
2005, 117, 3473 (Angew. Chem., Int. Ed., 2005, 44, 3407);
(d) A. M. Hayes, D. J. Morris, G. J. Clarkson and M. Wills,
J. Am. Chem. Soc., 2005, 127, 7318; (e) W. Baratta, G. Chelucci,
S. Gladiali, K. Siega, M. Toniutti, M. Zanette, E. Zangrando and
P. Rigo, Angew. Chem., 2005, 117, 6370 (Angew. Chem., Int. Ed.,
2005, 44, 6214); (f) S. Enthaler, R. Jackstell, B. Hagemann,
K. Junge, G. Erre and M. Beller, J. Organomet. Chem., 2006,
691, 4652; (g) M. T. Reetz and X. Li, J. Am. Chem. Soc., 2006,
128, 1044; (h) J. Hannedouche, G. J. Clarkson and M. Wills,
J. Am. Chem. Soc., 2004, 126, 986.
7 (a) T. Ohkuma and R. Noyori, Comprehensive Asymmetric Catalysis
Supplement, ed. E. N. Jacobsen, A. Pfaltz and H. Yamamoto,
Springer, Berlin, 2004, vol. 1, p. 43; (b) S. Gladiali and E. Alberico,
Chem. Soc. Rev., 2006, 35, 226; (c) T. Ikariya and A. J. Blacker,
Acc. Chem. Res., 2007, 40, 1300; (d) X. Wu and J. Xiao, Chem.
Commun., 2007, 2449; (e) C. Wang, X. Wu and J. Xiao, Chem.–
Asian J., 2008, 3, 1750; (f) P. Paloma, D. Josefina and M. P. Gamasa,
Organometallics, 2008, 27, 2597.
8 (a) M. Kitamura and R. Noyori, Ruthenium in Organic Synthesis,
ed. S.-I. Murahashi,Wiley-VCH, Weinheim, 2004, p. 3; (b) W. He,
P. Liu, B. L. Zhang, X. L. Sun and S. Y. Zhang, Appl. Organomet.
Chem., 2006, 20, 328; (c) Y. Nishibayashi, I. Takei, S. Uemura and
M. Hidai, Organometallics, 1999, 18, 2291.
J = 5.0 and 4.5 Hz, 1H), 4.67 (d, J = 11.8 Hz, 1H), 5.15
(s large, 1NH), 7.13–7.34 (m, 7HAr), 7.66 (d, J = 8.2 Hz, 2HAr).
13C NMR (90.5 MHz, CDCl3) d 21.5 (CH3), 42.8 (CH2), 46.8
(CH2); 62.3 (CH), 71.5 (CH2), 72.5 (2CH2), 79.7 (CH), 80.5
(CH), 81.4 (CH), 127.1, 127.9, 128.4, 129.6 (9CHAr), 136.6 (Cq),
137.7 (Cq), 143.3 (Cq). HRMS (ESI) calcd for C15H22N2O3 ([M
+ H]+): 433.1810. Found: 433.1792.
General procedure for Ru-catalyzed asymmetric transfer
hydrogenation of ketones in isopropanol
In a 20 mL dry Schlenk tube under an argon atmosphere, the
in situ catalyst was prepared by stirring a solution of amino
alcohol (5 mol%) and [RuCl2(p-cymene)]2 (1.25 mol%) in
isopropanol at 25 1C for 30 min. Potassium tert-butoxide
(5 mol%) and ketone (1 mmol) were added respectively. The
1
reaction was followed by H-NMR spectroscopy analysis for
calculating the conversion. Enantiomeric excesses were mon-
itored by chiral HPLC analysis. The reaction was stopped
when no evolution of enantiomeric excesses was observed.
The obtained alcohols are known compounds and their
1H NMR and 13C NMR were identical to authentic
samples.13,14
Acknowledgements
We are grateful to the ‘Vietnamese government’ for a doctoral
fellowship to K. D. Huynh, and the ‘Ministere de l’Enseignement
Superieur et de la Recherche’ for a doctoral fellowship to H.
´
9 A. Aupoix, C. Bournaud and G. Vo-Thanh, Eur. J. Org. Chem.,
2011, 2772.
Ibrahim. The authors thank Johnson Matthey Technology Centre
of Reading for generous gift of ruthenium and iridium complexes.
10 (a) M. Bressan, N. d’Allessandro, L. Liberatore and A. Morvillo,
Coord. Chem. Rev., 1999, 185, 385; (b) S. Inoue, K. Nomura,
S. Hashiguchi, R. Noyori and Y. Izawa, Chem. Lett., 1997, 957.
11 (a) J. E. D. Martins, G. J. Clarkson and M. Wills, Tetrahedron,
2009, 11, 847; (b) T. Ikariya, K. Murata and R. Noyori, Org.
Biomol. Chem., 2006, 4, 393; (c) S. Gladiali and E. Alberico, Chem.
Soc. Rev., 2006, 35, 226.
12 (a) J. E. D. Martins, D. J. Morris and M. Wills, Tetrahedron Lett.,
2009, 50, 688; (b) J. E. D. Martins and M. Wills, Tetrahedron, 2009,
65, 5782.
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c
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