New class of chiral ligands derived from isosorbide: First application in asymmetric transfer hydrogenation

Article abstract of DOI:10.1016/j.tetasy.2010.04.065

A new class of β-amino alcohol and diamine ligands was prepared from isosorbide as a chiral renewable resource. The original wedge-shaped structure of isosorbide offers an interesting chiral pocket to promote the metal-catalyzed enantioselective reduction of ketones by transfer hydrogenation.

Full text of DOI:10.1016/j.tetasy.2010.04.065

Tetrahedron: Asymmetry 21 (2010) 1542–1548
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
New class of chiral ligands derived from isosorbide: first application
in asymmetric transfer hydrogenation
*
*
Khanh-Duy Huynh, Houssein Ibrahim, Martial Toffano , Giang Vo-Thanh
Institut de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO—UMR 8182), Laboratoire de Catalyse Moléculaire, Université Paris-Sud 11, 91405 Orsay, Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A new class of b-amino alcohol and diamine ligands was prepared from isosorbide as a chiral renewable
resource. The original wedge-shaped structure of isosorbide offers an interesting chiral pocket to pro-
mote the metal-catalyzed enantioselective reduction of ketones by transfer hydrogenation.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 8 March 2010
Accepted 21 April 2010
Available online 11 June 2010
Dedicated to Henri Kagan on the occasion of
his 80th birthday anniversary
1. Introduction
Other amino-alcohol derivatives are obtained from transformation
of isosorbide and partial destruction of the original structure.4a,b
From an economic and environmental point of view, catalysis
appears to be an interesting solution to develop selective chemis-
try, sophisticated molecules, and to minimize atom and energy
consumption. However, the necessary chiral organometallic com-
plexes are often obtained from ligands prepared by sophisticated
and expensive processes or starting materials. The high costs of
precious ligands required to achieve satisfactory yields of the ex-
pected products are dissuasive for an economical development of
metal-catalyzed processes. Therefore, the development of new li-
gands for catalytic asymmetric transformations becomes crucial.
Given the very restricted range of efficient catalysts, the develop-
ment of easily available, inexpensive, modular, and innovative cat-
alysts is expected to be a key for expanding the reaction scope and
the synthetic potential of the field. According to the ‘Sustainable
Chemistry’ guide to preserve resources, to use them more effi-
ciently, and to minimize our footprint, we propose to develop ori-
ginal catalysts, starting from renewable natural resources and
more precisely from isosorbide 1.
We think that its original wedge-shaped structure could offer an
interesting chiral pocket to coordinate a metal. The chemical sta-
bility of these chiral structures is an important property to develop
chiral ligands. In our strategy, structural modification could be eas-
ily and efficiently obtained by taking advantage of the two hydro-
xyl groups. Transformations of the diol groups are easily accessible
by classical organic synthetic procedures and the structure can be
modified by varying the steric and/or electronic effects.
Herein we report the synthesis of new chiral b-amino-alcohols
and diamines derived from isosorbide and their primary evaluation
as ligands in the Ru-catalyzed asymmetric transfer hydrogenation of
acetophenone.
2. Results and discussions
2.1. Synthesis of chiral ligands
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.2a The
free hydroxyl group 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
(Scheme 1).
Subsequently, the sulfonate 3 was treated with an excess of amino
alcohol in a sealed tube at 160 °C in the presence of lithium chloride,
giving the corresponding compounds 4a–h via an SN2 substitution
reaction with complete inversion of configuration (Table 1).
We observed a significant drop in the yields and the formation
of elimination product 5 (Fig. 1) in the case of substituted amino
alcohols, suggesting the importance of steric hindrance in the
Isosorbide, also known as (3R,3aR,6S,6aR)-hexahydrofuro[3,2-
b]furan-3,6-diol, is industrially obtained by the dehydration of D-
sorbitol and can therefore be considered as a biomass product.1 It
represents a commercially available and inexpensive chiral starting
material for the synthesis of sophisticated molecules including chi-
ral ionic liquids,2 phase-transfer catalysts,3 and phosphorus ligands
(mono- and diphosphines, diphosphites, bis-diaminophosphites,
etc.).4,5 This starting material provides an easy and cost effective ac-
cess to enantiomerically pure functionalized compounds such as
ligands.
Furthermore, only a few examples of amino alcohol ligands de-
rived from isosorbide retain the original skeleton of the bicycle.4c,d
* Corresponding authors. Tel.: +33 1 69 15 78 91; fax: +33 1 69 15 46 80 (G.V.T.).
E-mail address: giang.vo-thanh@u-psud.fr (G. Vo-Thanh).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.065

K.-D. Huynh et al. / Tetrahedron: Asymmetry 21 (2010) 1542–1548
1543
HO
BnO
BnO
H
H
H
H
PhSO2Cl
O
O
O
BnCl, LiH, LiCl
3
6
DMSO
56%
NEt3, 10h
99%
O
O
O
H
H
OH
OH
OSO2Ph
1
2
3
Scheme 1. Synthesis of phenylsulfonate 3.
Table 1
Amino alcohol 7 was obtained by two-step procedure, including
a substitution of sulfonate 3 with benzylamine, followed by
removal of the benzyl-protecting groups of 6 (Scheme 2).
Debenzylation of ligands 4a and 4e gave dihydroxy compounds
8a and 8b, respectively, in good yields (Scheme 3).
The inversion of configuration in the substitution reaction of 3
with an amine was confirmed by 1H NMR analysis based on the
observation of the Ha, Hb coupling constant of products 4a–h. For
compounds 3, proton Ha appears as a doublet corresponding to a
trans-coupling JHa–Hb = 0 Hz. The signal turns to a doublet of
doublet for compounds 4a–h corresponding to a cis-coupling
JHa–Hb = 5 Hz (Fig. 2).
Synthesis of amino alcohols 4a–h
BnO
BnO
H
H
H
RNH2
160°C, 24h
O
O
O
O
H
NHR
OSO2Ph
4a-h
3
Entry
1
RNH2
Ligands 4
Isolated yield (%)
75
OH
OH
4a
H2N
H2N
Diamino compound 9 and N-tosylated ligand 10 were obtained
in the same reaction conditions from sulfonate 3 in 82% and 60%
yields, respectively (Scheme 4).
2
3
4
5
4b
4c
4d
4e
55
50
47
40
i-Pr
OH
2.2. Asymmetric transfer hydrogenation reaction
H2N
H2N
H2N
i-Pr
OH
Enantioselective reduction of ketones to enantiopure secondary
alcohols is one of the most studied transformations, because of the
importance of these alcohols, as intermediate for the preparation
of more sophisticated molecules.6 Asymmetric transfer hydrogena-
tion (ATH) is a practical, simple, selective reaction and tolerates
several functional groups. If chiral diamine ligands offer an impor-
tant development in the ATH reaction,7,8 amino alcohols represent,
for their part, good ligands for this application.4a,9 The ATH reac-
tion offers an interesting and common tool to evaluate the activity
of these new ligands. At this point of our investigation, we were
interested in screening different parameters for transfer hydroge-
nation such as hydride sources and pre-catalysts.
Ph
OH
Ph
OH
6
7
4f
43
52
H2N
H2N
H2N
Ph
OH
4g
Ph
OH
Ph
Ph
The catalytic system using ligand 4a [RuCl2(p-cymene)]2 in the
presence of t-BuOK was first chosen to select the hydride source
and the optimized reaction conditions for the reduction of aceto-
phenone. The best results are reported in Table 2.
8
4h
70
Using i-PrOH as the hydride source afforded the desired product
with 99% conversion and 70% ee after 2 h. This conventional hydro-
gen source offers interesting properties such as stability, ease to
handle, nontoxic, environmentally friendly, inexpensive, and a
good solvent for many organic compounds. We then decided to
screen a number of different metal pre-catalysts using isopropanol
as a hydrogen source and t-BuOK as a base for the ATH reduction of
acetophenone at room temperature in the presence of ligand 4a
(Table 3).
BnO
H
H
O
5
O
Figure 1. Formation of 5 by an elimination reaction.
Changing the arene ligand from p-cymene to benzene or mesit-
ylene gave a negative effect on both conversion and enantioselec-
tivity (entries 1 and 3). Other rhodium catalysts gave a similar
enantiomeric excess, but lower yield compared to some ruthenium
reaction. This observation was confirmed by the unsuccessful
substitution of 3 with secondary or aromatic amines.
BnO
HO
H
BnO
H
H
BnNH2
H2, Pd/C
O
O
O
160°C, 24h
70%
EtOH
99%
O
O
O
Ph
H
H
H
HN
NH2
OSO2Ph
3
6
7
Scheme 2. Synthesis of amino alcohol 7.

1544
K.-D. Huynh et al. / Tetrahedron: Asymmetry 21 (2010) 1542–1548
new ligands. Further improvements of the application of these
ligands in asymmetric transfer hydrogenation are currently under-
way in our laboratory.
OH
OH
BnO
HO
H
H
H
R =
R =
HN
HN
8a
8b
H
2, Pd/C
O
O
O
EtOH
O
H
R
R
4. Experimental section
4.1. General information
4a,e
i-Pr
Scheme 3. Synthesis of amino alcohols 8a–b.
Melting points were measured on a Kofler bank. The NMR spec-
tra were recorded in CDCl3, DMSO-d6, MeOD-d4, or in acetone-d6.
1H NMR spectra were recorded at 360 or 300, or 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 spec-
tra were recorded at 360, 300, 250, or 62.5 MHz. IR spectra were
recorded on an FT-IR Perkin–Elmer 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 Kieselgel 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 redistilled
over calcium hydride under an argon atmosphere. All reagents
and solvents were purchased from commercial sources (Acros, Al-
drich) and were used without further purification.
BnO
BnO
H
H
O
O
O
O
OSO2Ph
NHR
Ha
Ha
Hb
Hb
Jtrans = 0 Hz
Jcis = 5 Hz
3
4a-h
Figure 2. 1H NMR studies for 3 and 4a–h.
catalysts (entries 4 and 2). On the other hand, iridium gave both
lower yield and enantioselectivity (entry 5).
3. Conclusion
4.2. Characterization of ligands
In summary, we have designed and synthesized a new class of
chiral amino alcohol and diamine compounds derived from isosor-
bide, a naturally renewable resource. The synthesis of these com-
pounds is easy and practical due to the commercially inexpensive
available startingmaterial. These ligands were obtained in moderate
to excellent yields. We have also showed that isosorbide-1,2-amino
alcohol derivatives could be used as ligands for the Ru-catalyzed
enantioselective reduction of aromatic ketones by asymmetric
transfer hydrogenation. As preliminary results, the reduction of ace-
tophenone by ATH using ligand 4a gave excellent conversion and
enantiomeric excess up to 70%. These results clearly indicated the
efficiency of the chiral isosorbide structure for the preparation of
4.2.1. (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), and lithium chloride (140 mmol, 5.91 g) in
DMSO (65 mL) was stirred at 90 °C 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 M HCl
(65 mL) and extracted with ethyl acetate (3 ꢀ 150 mL). The organic
phase was successively 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 ace-
BnO
BnO
H
BnO
H
H
H
NHTs
H2N
H2N
NH2
O
O
O
NHTs
NH2
O
O
160°C, 24h
60%
O
160°C, 24h
82%
H
H
OSO2Ph
HN
HN
10
3
9
Scheme 4. Synthesis of diamine 9 and N-tosylated 10 ligands.
Table 2
ATH of acetophenone with various hydride sourcesa
O
OH
[RuCl2(p-cymene)]2 / 4a
Ph
Ph
Hydride source
Entry
Hydride source
Time (h)
Temp (°C)
Solvent
Conv.b (%)
eec (%)
1d
2e
3f
HCOOH–NEt3
HCOONa
i-PrOH
24
96
2
40
25
25
CH2Cl2
H2O
i-PrOH
10
85
99
7
46
70
a
b
c
d
e
f
Conditions: 0.125 mol % of [RuCl2(p-cymene)]2 and 2.5 mol % of ligand 4a, acetophenone (1 mmol).
Determined by 1H NMR.
Determined by chiral HPLC analysis using Chiralcel OD-H column.
HCOOH–NEt3 (0.5 mL).
HCOONa (5 mmol).
t-BuOK (2.5 mol %) is used as base. Ratio t-BuOK/4a/Ru = 2:2:1. [Acetophenone] = 0.2 M in i-PrOH.

K.-D. Huynh et al. / Tetrahedron: Asymmetry 21 (2010) 1542–1548
1545
Table 3
CHCl3); IR (neat)
m
= 3321, 3087, 3062, 3029, 2942, 2871, 1496,
1H NMR
ATH of acetophenone with various pre-catalystsa
1463, 1455, 1367, 1136, 1084, 1045, 1027, 738 cmꢂ1
;
(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
O
OH
[Cat] / 4a
Ph
Ph
i-PrOH /t-BuOK
25°C
Entry
Time (h)
Pre-catalysts
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
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.
2
[CpIrCl2]2
4.2.4. (3R,3aR,6R,6aR)-6-Aminohexahydrofuro[3,2-b]furan-3-ol
7
a
Conditions: 0.125 mol % of pre-catalyst and 2.5 mol % of ligand 4a, molar ratio
of acetophenone/base/ligand 4a/Ru = 40:2:2:1. [Substrate] = 0.2 M in i-PrOH.
b
Determined by 1H NMR.
Determined by chiral HPLC analysis.
Amino ether 6 (5 mmol) and the same weight of palladium 10%
on charcoal in 10 mL of ethanol were stirred under a 1 bar hydro-
gen pressure for 24 h. Filtration of the catalyst, evaporation of the
solvent, and then purification of the residue by flash chromatogra-
phy on silica gel with dichloromethane/methanol (98:2) in the
presence of 1% NH3 afforded white crystals in 96% yield. Mp:
c
tate = 1:1; 5:5; 1.5:8.5) to afford the product as white crystals in
56% yield. Mp: 60 °C; ½a D25
¼ þ109:4 (c 0.83, CHCl3); IR (neat)
ꢁ
115 °C; ½a 2D5
ꢁ
¼ þ110:9 (c 0.5, CH3OH); IR (KBr)
m = 3329, 2942,
m
= 3429, 2945, 2877, 1497, 1455, 1132, 1069, 1018, 979 cmꢂ1
;
2859, 1612, 1491, 1475, 1408, 1372, 1302, 1156, 1128, 1085,
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.
1022, 926, 815, 777 cmꢂ1 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.
4.2.5. 2-((3R,3aS,6R,6aR)-3-(Benzyloxy)hexahydrofuro[3,2-
b]furan-6-ylamino)ethanol 4a
4.2.2. (3R,3aR,6S,6aS)-3-(Benzyloxy)hexahydrofuro[3,2-b]furan-
6-yl benzenesulfonate 3
A mixture of the sulfonate 3 (8 mmol), distilled ethanolamine
(32 mmol), and lithium chloride (4 mmol) was heated in a sealed
tube at 160 °C 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 chro-
matography on silica gel (dichloromethane/methanol = 98:2 and
95:5, consecutively) to give the product as a dark yellow oil in
A mixture of the alcohol 2 (65 mmol, 15.4 g), triethylamine
(390 mmol, 55 mL), and benzenesulfonyl chloride (78 mmol,
10 mL) was stirred under an argon atmosphere for 10 h. The reac-
tion 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 ꢀ 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 chromatogra-
phy on silica gel (heptane/ethyl acetate = 1:1) to afford a product
75% yield. ½a 2D5
ꢁ
¼ þ123:1 (c 1.1, CHCl3); IR (neat)
m = 3376, 2941,
2872, 1667, 1455, 1369, 1312, 1260, 1208, 1137, 1069, 1026,
924, 823, 743 cmꢂ1 1H 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 Hz, 1H), 4.62 (dd, J = 4.5 and 4.5 Hz, 1H),
4.74 (d, J = 12.0 Hz, 1H), 731–7.34 (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 (EI) calcd for C15H22NO4
([M+H]+): 280.1549, found: 280.1541.
as white crystals in 99% yield. Mp: 93 °C; ½a D25
¼ þ92:7 (c 0.25,
ꢁ
CHCl3); IR (neat)
m = 3065, 3032, 2877, 1449, 1367, 1189, 1100,
1043, 971, 947, 902, 820, 750 cmꢂ1 1H 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 (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, 60.54; H, 5.25; O, 25.41; S, 8.49.
4.2.6. (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 pre-
viously 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 = 1:1) to
give a dark yellow liquid in 50% yield from 3 and (S)-2-amino-3-
4.2.3. (3R,3aR,6R,6aS)-N-Benzyl-6-
(benzyloxy)hexahydrofuro[3,2-b]furan-3-amine 6
A mixture of the sulfonate 3 (20 mmol), distilled benzyl amine
(120 mmol), and lithium chloride (10 mmol) was heated in a
sealed tube at 160 °C 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 chro-
matography on silica gel (cyclohexane/ethyl acetate = 1:1) to give
methylbutan-1-ol;
= 3456, 2956, 2873, 1650, 1455, 1366, 1195, 1135, 1069, 1027,
928, 826, 739 cmꢂ1 1H NMR (300 MHz, CDCl3)
0.89 (d,
½
a 2D5
ꢁ
¼ þ115:6 (c 1.05, CHCl3); IR (neat)
m
;
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,
the product as a yellow oil in 70% yield. ½a D25
¼ þ145:3 (c 1.47,
ꢁ

1546
K.-D. Huynh et al. / Tetrahedron: Asymmetry 21 (2010) 1542–1548
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 (EI) calcd for
HRMS (ESI) calcd for
356.1854.
C
21H26NO4 ([M+H]+): 356.1862, found:
4.2.10. (R)-2-((3R,3aS,6R,6aR)-3-(Benzyloxy)hexahydrofuro[3,2-
b]furan-6-ylamino)-1-phenylethanol 4f
C
18H28NO4 ([M+H]+): 322.2018, found: 322.2010.
Compound 4f was prepared following the same procedure pre-
viously 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-
4.2.7. (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 pre-
viously 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 = 1:1) to
give a dark yellow liquid in 50% yield from 3 and (R)-2-amino-3-
phenylethanol; mp: 56 °C; ½a D25
¼ þ99:4 (c 0.5, CHCl3); IR (KBr)
ꢁ
m
= 3311, 3028, 2869, 1668, 1492, 1452, 1346, 1258, 1207, 1115,
1084, 1025, 983, 911, 844, 748, 695 cmꢂ1 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 (10H, 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.
methylbutan-1-ol;
= 3414, 2957, 2873, 1641, 1455, 1368, 1310, 1207, 1136, 1071,
1027, 930, 825, 738 cmꢂ1 1H NMR (300 MHz, CDCl3) d 0.87 (d,
½
a 2D5
ꢁ
¼ þ136:2 (c 1.0, CHCl3); IR (neat)
m
;
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); 13C 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.
4.2.11. (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 pre-
viously 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-
4.2.8. (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 pre-
viously 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 = 1:1) to
give a bright yellow paste in 47% yield from 3 and (S)-2-amino-
phenylethanol; mp: 90 °C; ½a D25
¼ þ181 (c 0.5, CHCl3); IR (KBr)
ꢁ
m
= 3286, 3087, 2875, 1663, 1491, 1452, 1344, 1303, 1211, 1156,
1103, 1060, 934, 880, 735 cmꢂ1 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
2-phenylethanol;
½
a 2D5
ꢁ
¼ þ178:15 (c 0.5, CHCl3); IR (neat)
m
= 3420, 2943, 2871, 1648, 1494, 1454, 1366, 1202, 1135, 1068,
1025, 845, 756 cmꢂ1
;
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).
(C), 142.1 (C). HRMS (ESI) calcd for
356.1856, found: 356.1845.
C
21H26NO4 ([M+H]+):
HRMS (ESI) calcd for
356.1865.
C
21H26NO4 ([M+H]+): 356.1856, found:
4.2.12. 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 pre-
viously 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-ami-
4.2.9. (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 pre-
viously 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 = 1:1) to
give a brown solid in 48% yield from 3 and (R)-2-amino-2-phenyl-
no-1,1-diphenylethanol; ½a D25
¼ þ67:5 (c 0.5, CHCl3); IR (NaCl)
ꢁ
m
= 3419, 3060, 3028, 2943, 2969, 1598, 1492, 1449, 1367, 1312,
1261, 1135, 1083, 1070, 1026, 942, 910, 826, 752, 670 cmꢂ1 1H
;
ethanol; mp: 82 °C; ½a D25
ꢁ
¼ þ61:7 (c 1.0, CHCl3); IR (neat)
m = 3377,
NMR (360 MHz, CDCl3) d 3.11 (d, J = 12.0 Hz, 1H), 3.33–3.39 (m,
1H), 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.
3029, 2887, 1658, 1495, 1453, 1366, 1219, 1137, 1081, 1038, 1017,
916, 845, 752 cmꢂ1; 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 (C).

K.-D. Huynh et al. / Tetrahedron: Asymmetry 21 (2010) 1542–1548
1547
4.2.13. (3R,3aR,6R,6aR)-6-(2-Hydroxyethylamino)hexahydrof
uro[3,2-b]furan-3-ol 8a
1209, 1158, 1092, 1022, 817, 740, 665 cmꢂ1
.
1H NMR (360 MHz,
CDCl3) d 1.48 (s broad, 1 NH), 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, 1H), 4.46 (d,
J = 11.8 Hz, 1H), 4.51 (dd, J = 5.0 and 4.5 Hz, 1H), 4.67 (d,
J = 11.8 Hz, 1H), 5.15 (s large, 1 NH), 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.
Compound 8a was prepared following the same procedure pre-
viously described for the synthesis of compound 7. 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 solid in 96% yield from 4a; mp: 62 °C;
½
a 2D5
ꢁ
¼ þ106:95 (c 0.5 CH3OH); IR (KBr)
m
= 3315, 2925, 2890,
1656, 1460, 1376, 1123, 1057, 1015, 927, 825 cmꢂ1
;
1H NMR
(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
(250 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+H]+): 190.1079, found: 190.1076.
4.3. General procedure for the asymmetric transfer
hydrogenation of ketones in isopropanol
At first, 0.125 mol % of [RuCl2(p-cymene)]2 and 2.5 mol % of the
amino alcohol ligand in isopropanol were stirred at 25 °C for
30 min; 2.5 mol % of potassium tert-butoxide, 0.1 M in isopropanol
(0.5 mL), and ketone (1 mmol) were added, respectively. The reac-
tion was followed by 1H NMR spectroscopy analysis for calculating
the conversion. Enantiomeric excess was monitored with chiral
HPLC analysis at 2 h and 24 h reaction times. The reaction was
stopped when no evolution of enantiomeric excesses was
observed.
4.2.14. (3R,3aR,6R,6aR)-6-((R)-1-Hydroxy-3-methylbutan-2
ylamino)hexahydrofuro[3,2-b]furan-3-ol 8b
Compound 8b was prepared following the same procedure pre-
viously described for synthesis of compound 7. The reaction time
was 4 days. The purification was carried out by flash column chro-
matography on silica gel (dichloromethane/methanol = 98:2) to
give a bright yellow liquid in 96% yield from 4e; ½a D25
¼ þ81:8 (c
ꢁ
0.75, CH3OH); IR (neat)
m = 3369, 2958, 2873, 1644, 1467, 1389,
1354, 1228, 1193, 1127, 1085, 1058, 927, 826, 741 cmꢂ1 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
Acknowledgments
We are grateful to the ‘Vietnamese government’ for a doctoral
fellowship to K. D. Huynh and the ‘Ministère de l’Enseignement
Supérieur et de la Recherche’ for a doctoral fellowship to H. Ibra-
him. We also thank E. Kolodziej for technical support of the HPLC
analysis.
(CH), 84.1 (CH). HRMS (ESI) calcd for
232.1543, found: 232.1542.
C
11H22NO4 ([M+H]+):
References
4.2.15. (3R,3aR,6R,6aS)-N-(2-Aminoethyl)-6-(benzyloxy)-
hexahydrofuro[3,2-b]furan-3-amine 9
1. Sheldon, R. A. Chirotechnology: Industrial Synthesis of Optically Active Compounds;
Marcel Dekker: New York, 1993. p 145.
To a solution of sulfonate 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 °C 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
2. (a) Nguyen Van Buu, O.; Aupoix, A.; Doan Thi Hong, N.; Vo-Thanh, G. New J.
Chem. 2009, 33, 2060; (b) Nguyen Van Buu, O.; Aupoix, A.; Vo-Thanh, G.
Tetrahedron 2009, 65, 2260; (c) Nguyen Van Buu, O.; Vo-Thanh, G. Lett. Org.
Chem. 2007, 4, 158; (d) Kumar, V.; Olsen, C. E.; Schaffer, S. J. C.; Parmar, V. S.;
Malhotra, S. V. Org. Lett. 2007, 9, 3905.
3. Kumar, S.; Ramachandran, U. Tetrahedron 2005, 61, 4141.
4. Amino-alcohols, diamines: (a) Guillarme, S.; Nguyen, T. X. M. Tetrahedron:
Asymmetry 2008, 19, 1450; (b) Paolucci, C.; Rosini, G. Tetrahedron: Asymmetry
2007, 18, 2923; (c) Lui, F. W.; Yan, L.; Zhang, J. Y.; Liu, H. M. Carbohydr. Res. 2006,
314, 332; (d) De Coster, G.; Vandyck, K.; Van der Eycken, E.; Van der Eycken, J.;
Elseviers, M.; Röper, H. Tetrahedron: Asymmetry 2002, 13, 1673.
5. Phosphorus ligands: (a) Diéguez, M.; Pàmies, O.; Claver, C. J. Org. Chem. 2005, 70,
3363; (b) Gavrilov, K. N.; Zheglov, S. V.; Vologzhanin, P. A.; Maksimova, M. G.;
Safronov, A. S.; Lyubimov, S. E.; Davankov, V. A.; Schäffner, B.; Börner, A.
Tetrahedron Lett. 2008, 49, 3120; (c) Reetz, M. T.; Neugebauer, T. Angew. Chem.,
Int. Ed. 1999, 38, 179; (d) Carcedo, C.; Dervicsi, A.; Fallis, I. A.; Ooi, L.; Malik, K. M.
A. Chem. Commun. 2004, 1236; (e) Bakos, J.; Heil, B.; Marko, L. J. Organomet.
Chem. 1983, 253, 249; (f) Zhou, H.; Hou, J.; Cheng, J.; Lu, S.; Fu, H.; Wang, H. J.
Organomet. Chem. 1997, 543, 227.
6. Malacea, R.; Poli, R.; Manoury, E. Coord. Chem. Rev. 2010, 254, 729.
7. (a) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1997,
117, 8738; (b) Hashiguchi, S.; Fujii, A.; Haack, K.; Matsumura, K.; Ikariya, T.;
Noyori, R. Angew. Chem., Int. Ed. 1997, 36, 288.
8. (a) Cortez, N. A.; Aguirre, G.; Parra-Hake, M.; Somanathan, R. Tetrahedron Lett.
2007, 48, 4335; (b) Martins, J. E. D.; Morris, D. J.; Tripathi, B.; Wills, M. J.
Organomet. Chem. 2008, 693, 3527; (c) Martins, J. E. D.; Clarkson, G. J.; Wills, M.
Org. Lett. 2009, 11, 847; (d) Limanto, J.; Karska, S. W.; Dorner, B. T.; Vazquez, E.;
Yoshikawa, N.; Tan, L. Org. Lett. 2010, 12, 512; (e) Liu, J.; Wu, Y.; Li, X.; Chan, A. S.
C. J. Organomet. Chem. 2008, 693, 2177; (f) Cortez, N. A.; Aguirre, G.; Parra-Hake,
M.; Somanathan, R. Tetrahedron: Asymmetry 2008, 19, 1304.
82% yield. ½a 2D5
ꢁ
¼ þ135:4 (c 1.02, CHCl3); IR (NaCl)
m = 3305,
3029, 2939, 2869, 1660, 1495, 1454, 1367, 1308, 1208, 1135,
1083, 1027, 825, 742, 700 cmꢂ1 1H NMR (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.
4.2.16. (3R,3aR,6R,6aS)-6-(benzyloxy)-hexahydrofuro-N-
(2(tosylamino)ethyl)furo[3,2-b]furan-3-amine 10
Compound 10 was prepared following the same procedure pre-
viously described for synthesis of compound 9, from 3 (2.6 mmol),
N-(-4-toluenesulfonyl)-1,2-ethylenediamine (16 mmol), and lith-
ium chloride (1.3 mmol). The product was purified by flash column
chromatography on silica gel (CH2Cl2/MeOH = 99:1 and 92:2) to
9. (a) Wu, X.; Li, X.; McConvill, M.; Saidi, O.; Xiao, J. J. Mol. Catal. 2006, 247, 153; (b)
Alza, E.; Bastero, A.; Jansat, S.; Perica, M. A. Tetrahedron: Asymmetry 2008, 19,
374; (c) Cheug, F. K.; Hayes, A. M.; Hannedouche, J.; Yim, A. S. Y.; Wills, M. J. Org.
Chem. 2005, 70, 3188; (d) Hannedouche, J.; Clarkson, G. J.; Wills, M. J. Am. Chem.
Soc. 2004, 126, 986; (e) Mao, J.; Wan, B.; Wu, F.; Lu, S. Tetrahedron Lett. 2005, 46,
7341; (f) Palmer, M. J.; Kenny, J. A.; Walsgrove, T.; Kawamoto, A. M.; Wills, M. J.
Chem. Soc., Perkin Trans. 1 2002, 416; (g) Petra, D. G. I.; Reek, J. N. H.; Handgraaf,
give the product in 60% yield. ½a D25
¼ þ97:3 (c 1, CHCl3). IR (NaCl)
ꢁ
m
= 3543, 3273, 3031, 2943, 2872, 1598, 1495, 1455, 1368, 1330,

1548
K.-D. Huynh et al. / Tetrahedron: Asymmetry 21 (2010) 1542–1548
J.-W.; Meijer, E. J.; Dierkes, P.; Kamer, P. C. J.; Brussee, J.; Schoemaker, H. E.; Van
A.; Mann, I.; Houson, I.; Campbell, L.; Walsgrove, T.; Wills, M. Tetrahedron 2006,
62, 1864; (l) Everaere, K.; Mortreux, A.; Carpentier, J.-F. Adv. Synth. Catal. 2003,
345, 67; (m) Everaere, K.; Mortreux, A.; Bulliard, M.; Brussee, J.; Van der Gen, A.;
Nowogrocki, G.; Carpentier, J.-F. Eur. J. Org. Chem. 2001, 275.
Leeuwen, P. W. N. M. Chem. Eur. J. 2000, 6, 2818; (h) Alonso, D. A.; Nordin, S. J.
M.; Roth, P.; Tarnai, T.; Andersson, P. G. J. Org. Chem. 2000, 65, 3116; (i) Patti, A.;
Pedotti, S. Tetrahedron: Asymmetry 2003, 14, 597; (j) Brandt, P.; Roth, P.;
Andersson, P. G. J. Org. Chem. 2004, 69, 4885; (k) Peach, P.; Cross, D. J.; Kenny, J.