New chiral ligands from isosorbide: application in asymmetric transfer hydrogenation

Article abstract of DOI:10.1016/j.tetasy.2008.05.033

New chiral β-amino alcohols have been designed and synthesized from isosorbide, a by-product from the starch industry. These new ligands have been synthesized in three steps from isosorbide in good yields and have been used in asymmetric transfer hydrogenation reaction with Ru^II complexes. One of these catalysts also demonstrated good catalytic activity and good enantioselectivity.

Full text of DOI:10.1016/j.tetasy.2008.05.033

Tetrahedron: Asymmetry 19 (2008) 1450–1454
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
New chiral ligands from isosorbide: application in asymmetric
transfer hydrogenation
*
Stéphane Guillarme, Thi Xuan Mai Nguyen, Christine Saluzzo
UCO2M UMR CNRS 6011, Université du Maine, Avenue O. Messiaen, 72085 Le Mans cedex 09, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 April 2008
Accepted 30 May 2008
New chiral b-amino alcohols have been designed and synthesized from isosorbide, a by-product from the
starch industry. These new ligands have been synthesized in three steps from isosorbide in good yields
and have been used in asymmetric transfer hydrogenation reaction with RuII complexes. One of these cat-
alysts also demonstrated good catalytic activity and good enantioselectivity.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
HO
O
O
O
Asymmetric catalysis is one of the most promising methods for
the synthesis of chiral compounds. Among the enantioselective
catalytic reactions promoting formation of important chiral build-
ing blocks, asymmetric reduction of prochiral ketones is one of the
most studied reactions. Although enantioselective hydrogenation1
or borane reductions2 are generally efficient to form enantiomeri-
cally pure secondary alcohols, they require the use of either high
pressure or hazardous reagents and air-sensitive catalysts. An
alternative method is the asymmetric transfer hydrogenation reac-
tion using mainly 2-propanol as the hydrogen source under mild
reaction conditions in the presence of Ru, Rh, or an Ir-based cata-
lyst.3 Furthermore, 2-propanol is a non-toxic, inexpensive, easy
and safe to handle and an environmentally friendly hydrogen do-
nor. The first chiral ligands employed in this asymmetric reduction
were chiral phosphines (DIOP,4 BINAP5 CHIRAPHOS6), but since the
beginning of the 1990s, chiral bidentate nitrogen ones have been
mainly used. Later, Noyori et al. reported the use of chiral mono-
tosylated diamine/Ru(II)-complexes.7 They also showed that the
use of b-amino alcohols as a ligand could accelerate the reaction
rate.8 Moreover, as a little modification on the structure of the li-
gand generally has a strong effect on the activity and the selectivity
of the catalyst, many research groups further developed b-amino
alcohol-based catalysts.9 Furthermore, to the best of our knowl-
edge, no carbohydrate-derived b-amino alcohols have been used
as ligands in the asymmetric transfer hydrogenation reaction.
As part of an ongoing program aimed at finding an efficient sys-
tem for the asymmetric transfer hydrogenation reaction, we were
interested by the utilization of biomass products, particularly iso-
sorbide. Isosorbide is a by-product from the starch industry formed
by the dehydration of sorbitol. Although isosorbide is commer-
NHR
O
OH
Isosorbide
O
1
OH
Scheme 1. New chiral b-amino alcohols 1 from isosorbide.
cially available, their derivatives have been extensively employed
in medicine as vasodilators10 and factor Xa inhibitors11 or in the
syntheses of biodegradable polymers.12 Few have been applied as
chiral auxiliaries13 as starting materials for a chiral phase-transfer
catalyst14 or as chiral amino alcohols.15
Herein, we report the rapid synthesis of new chiral b-amino
alcohols 1 from isosorbide (Scheme 1) along with the preliminary
results concerning their use as ligands for the RuII-catalyzed asym-
metric hydrogen transfer reduction of acetophenone.
2. Results and discussion
2.1. Synthesis of chiral ligands
A few years ago, we reported the synthesis of epoxide 2 in two
steps from isosorbide.16 The ring-opening of the oxirane group of
compound 2 with 2 equiv of primary amines led to b-amino alco-
hols 1 in moderate to excellent yields after column chromatogra-
phy (Scheme 2), (Table 1, entries 1–4 and 7–11).
Moreover, in order to perform the ring-opening reaction with
methylamine, a volatile reagent, the reaction was carried out with
a large excess of methylamine (40% aqueous solution) in dichloro-
methane at room temperature. The resulting product 1f was
formed in 62% yield (Table 1, entry 6).
* Corresponding author. Tel.: +33 (0)2 43 83 33 37; fax: +33 (0)2 43 83 39 02.
E-mail address: christine.saluzzo@univ-lemans.fr (C. Saluzzo).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.05.033

S. Guillarme et al. / Tetrahedron: Asymmetry 19 (2008) 1450–1454
1451
HO
O
O
O
O
O
1) Ref. 13a
2) Ref. 13b
RNH2
NHR
O
MeOH, 40˚C
OH
O
O
O
OH
Isosorbide
2
1
R=H
1) NaN3, H2O
2) H2, Pd/C, AcOEt
Scheme 2. Synthesis of chiral amino alcohols 1 from isosorbide.
Table 1
b-Amino alcohols 1a–k produced via Scheme 2
Table 2
Asymmetric transfer hydrogenation of acetophenone using ligands 1a
Entry
1
R
Ligand
Yielda (%)
66
OH
O
[Ru(benzene)Cl2]2
PhCH2
1a
Ph
1, i-PrOH
t-BuOK, 70˚C
Ph
4
2
3
1b
1c
80
95
Entry
Ligand
Time (h)
Conversionb (%)
eeb (%) (Config.c)
Ph
Ph
1
2d
3d
4
5
6
7
8
9
10
11
12
13
14d
15e
16d,f
17d,f
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1a
1a
1a
1a
1a
21
21
21
21
21
21
21
21
21
21
21
21
3
96
83
90
66
72
48
83
86
67
28
10
38
95
95
58
85
92
60 (R)
21 (R)
18 (R)
20 (R)
64 (R)
<5
30 (R)
6
—
24 (R)
—
—
47 (R)
57 (R)
78 (R)
74 (R)
70 (R)
4
5
6
7
8
9
Ph
H
Me
i-Pr
1d
1e
1f
1g
1h
1i
75
85
62
77
85
69
Cyclohexyl
t-Bu
10
11
1j
75
3
3
3
42
OH
a
Asymmetric reduction of acetophenone was carried out in a 0.2 M solution in 2-
propanol with [acetophenone]/[t-BuOK]/[Ligand]/[Ru] = 100/1.5/1.5/1.
1k
1l
95
98
b
Determined by chiral GC analysis.
Assigned by comparison of the specific rotation with literature values.
[acetophenone]/[t-BuOK]/[Ligand]/[Ru] = 100/2/2/1.
[acetophenone]/[t-BuOK]/[Ligand]/[Ru] = 100/4/4/1.
c
d
OH
e
f
O
Reaction was carried out at 25 °C.
12
Amine: HN
a
Isolated yield after column chromatography.
Ligands 1a, 1b, and 1c derived from benzylamines (Table 2 en-
tries 1–3) gave the best conversions of up to 80% but the absence or
the presence of a methyl group on the benzylic position had a dras-
Transformation of epoxide 2 to b-amino alcohol 1e bearing a
primary amino function was performed with sodium azide in
water, followed by reduction of the azide (overall yield: 85%)
(Scheme 2), (Table 1, entry 5).
tic effect on the enantioselectivity. With a-methylbenzylamine
derivatives 1b and 1c (entries 2 and 3), enantioselectivities of the
reduction did not exceed 21%, contrary to that with benzylamine
(60% ee).
b-Amino alcohol 1l, bearing a morpholino moiety, was obtained
in a 98% yield (Table 1, entry 12) with 1 equiv of morpholine in
methanol at 40 °C.
Moreover, no match/mismatch effects were found contrary to
what Patti et al. observed with chiral equivalent b-amino alcohols
in the ferrocenyl series.9p
The reaction with the aniline-derived b-amino alcohol 1d was
also performed but both conversion and ee were low (Table 2, en-
try 4).
2.2. Asymmetric transfer hydrogenation reaction
These b-amino alcohols 1 were then evaluated for the asym-
metric transfer hydrogenation reaction of acetophenone (Table 2).
In a typical experiment, ruthenium complexes were prepared
in situ by refluxing 0.5 mol % of [RuCl2(benzene)]2 with 1.5 mol %
of the b-amino alcohols in isopropanol at 70 °C for 1 h. The result-
ing solution was then used to reduce acetophenone in the presence
of a 1.5 mol % of tert-butoxide (0.1 M) in isopropanol at 70 °C for
21 h, using a substrate/catalyst ratio of 100.
For ligand 1e with a primary amine, although the conversion
was moderate, a similar level of enantioselectivity as for b-amino
alcohol 1a was found (Table 2, entry 5). For ligands 1f–1i with an
alkylamine moiety (Table 2, entries 6–9), various outcomes have
been observed. Surprisingly, the combination of ligand 1f with RuII
did not reduce acetophenone efficiently (entry 6). Furthermore, it
seems that introduction of a group at the
a-position of the nitrogen
atom has an influence on the enantioselectivity and sometimes on

1452
S. Guillarme et al. / Tetrahedron: Asymmetry 19 (2008) 1450–1454
the reaction rate. Indeed, as in entries 2 and 3, a similar conversion
range was observed with ligands 1g and 1h containing a secondary
carbon at the a-position of the nitrogen atom (entries 7 and 8). The
indicated by s (singlet), d (doublet), t (triplet), q (quartet), m (mul-
tiplet), or br s (broadened singlet). FT-IR spectra were performed
on an ATR Perkin–Elmer Spectrum one apparatus and only major
band positions are given in cmÀ1. Optical rotations were recorded
on a Perkin–Elmer 343 polarimeter at 25 °C. High resolution mass
spectra were performed on a Waters MicromassÒ GCT PremierTM
apparatus (oa-TOF) in CI mode. Elemental analyses have been done
at the Institut de Chimie des Substances Naturelles in Gif-sur-Yv-
ette, France.
Conversions and enantiomeric excesses for the catalytic asym-
metric reactions were determined by GC (Hewlett Pakard 6890
equipped with a FID) on a chiral Restek b-dex smTM column. Melting
points were measured on a Buchi B-540 apparatus and were
uncorrected.
best stereoinduction was detected with ligand 1g. b-Amino alcohol
1i with a bulky group on the nitrogen atom was less efficient in
terms of catalytic activity (67% conversion) and no asymmetric
induction was observed (entry 9). The same outcome was observed
by Carpentier et al. with an ephedrine series.9j
Tridentate ligands 1j and 1k were not very efficient; however, a
slight match/mismatch effect was observed in these cases (Table 2,
entries 10 and 11).
We also checked the effect of ligand 1l containing a tertiary
amine. The conversion was low and 1-phenylethanol was obtained
as a racemic mixture (Table 2, entry 12). Different research groups
have pointed out that these type of ligands were not efficient for
the asymmetric transfer hydrogenation reaction.17
4.2. General procedure for synthesis of chiral b-amino
Different investigations were then focused on the RuII–1a cata-
lyst to find the optimum conditions for the asymmetric transfer
hydrogenation of acetophenone by changing the reaction time,
the RuII/1a/base ratio, or the temperature (Table 2, entries 13–
17). When the reaction time was reduced to 3 hours, we noticed
a decrease of the enantioselectivity (entries 1 and 13). The higher
the RuII/1a/base ratio, the higher the enantioselectivity, but the
lower the conversion (entries 13–15). As expected, decreasing
the temperature to room temperature enhances the enantioselec-
tivity with a slight drop in the catalytic activity (entries 15 and
16). A longer reaction time of 42 h did not significantly change
the enantioselectivity but the conversion rose to 92% (entries 16
and 17).
alcohols 1
A solution of epoxide 2 (1 equiv) and amine (2 equiv) was
heated at 60 °C in methanol (C = 0.2 M) for 16 h. The solvent was
then removed and the crude product was purified by column
chromatography.
4.2.1. 3,6-Anhydro-1-(benzylamino)-1-deoxy-4,5-O-
isopropylidene-
D-sorbitol 1a
Yield: 66%; white solid; mp 66–71 °C; [
a
]
D = À57.5 (c 1.0,
CH2Cl2); Rf = 0.22 (eluent: CH2Cl2/MeOH (95/5)). IR 3423, 3314,
2980, 2941, 2856, 1600, 1496, 1463, 1371, 1342, 1167, 1140,
1106. 1H NMR: d 1.30 (s, 3H), 1.48 (s, 3H), 2.25 (br s, 2H), 2.79
(dd, 1H, J = 12.2, 7.8 Hz), 2.91 (dd, 1H, J = 12.2, 3.8 Hz), 3.39 (dd,
1H, J = 6.3, 3.5 Hz), 3.48 (dd, 1H, J = 10.7, 3.8 Hz), 3.78 (d, 1H,
J = 13.2 Hz), 3.64 (d, 1H, J = 13.2 Hz), 4.01 (d, 1H, J = 10.7 Hz), 4.13
(ddd, 1H, J = 7.8, 6.3, 3.8 Hz), 4.64 (dd, 1H, J = 6.0, 3.5 Hz); 4,77
(dd, 1H, J = 6.0, 3.8 Hz), 7.10–7.30 (m, 5H). 13C NMR: d 24.9, 26.4,
51.3, 54.0, 69.8, 73.0, 80.9, 81.6, 84.3, 112.5, 127.3, 128.7, 129.2,
140.5. Anal. Calcd for C16H22NO4: C, 65.51; H, 7.90; N, 4.77. Found:
C, 65.64; H, 7.99; N, 4.69.
3. Conclusion
In conclusion, we have developed the synthesis of new chiral
carbohydrate-derived b-amino alcohols. These ligands were ob-
tained in moderate to excellent yields. For the first time, we have
shown that carbohydrate-derived b-amino alcohols could be used
as ligands for the asymmetric hydrogen transfer reaction of aceto-
phenone. The conversion of acetophenone into 1-phenylethanol
was low to high (10–95%), while enantioselectivity (0–78%) is
highly dependant on the b-amino alcohol ligand structure. The chi-
ral amino alcohol 1a proved to be the most efficient ligand in the
series examined for the RuII-catalyzed asymmetric reduction of
acetophenone.
4.2.2. 3,6-Anhydro-1-((R)-
O-isopropylidene- -sorbitol 1b
Yield: 80%; white solid; mp 81–84 °C; [
a-methylbenzylamino)-1-deoxy-4,5-
D
a]
D = À17.3 (c 1.0,
CH2Cl2); Rf = 0.20 (eluent: CH2Cl2/MeOH (95/5)). IR 3400, 3334,
3200, 2934, 2845, 1455, 1380, 1372, 1205, 1165, 1103, 1057. 1H
NMR: d 1.27 (s, 3H), 1.38 (d, 3H, J = 6.6 Hz), 1.46 (s, 3H), 2.0–2.5
(br s, 2H), 2.6–2.8 (m, 2H), 3.33 (dd, 1H, J = 5.6, 3.5 Hz), 3.44 (dd,
1H, J = 10.7, 3.7 Hz), 3.78 (q, 1H, J = 6.6 Hz), 4.0–4.1 (m, 2H), 4.63
(dd, 1H, J = 6.0 Hz, J = 3.5 Hz), 4.75 (dd, 1H, J = 6.0, 3.7 Hz), 7.1–
7.3 (m, 5H). 13C NMR: d 24.7, 24.9, 26.3, 50.4, 58.9, 69.9, 70.0,
81.3, 81.7, 83.7, 112.2, 127.0, 127.3, 128.8, 146.1. Anal. Calcd for
Studies are currently in progress in order to improve the enanti-
oselectivity, and other substrates have to be tested to screen the
scope and limitations of these new catalytic systems.
4. Experimental
4.1. General
C17H25NO4: C, 66.43; H, 8.20; N, 4.56. Found: C, 66.09; H, 8.06; N,
4.42.
Moisture or air-sensitive reactions were conducted under an
atmosphere of argon in oven-dried glassware. The asymmetric
transfer hydrogenation reactions were performed in a dried and
degassed Schlenk tube, and solvents and reagents were also de-
gassed prior to use.
4.2.3. 3,6-Anhydro-1-((S)-a-methylbenzylamino)-1-deoxy-4,5-
O-isopropylidene-
D-sorbitol 1c
Yield: 95%; white solid; mp 102–105 °C; [
a]D = À90.0 (c 1.0,
CH2Cl2); Rf = 0.4 (eluent: CH2Cl2/MeOH (95/5)). IR 3443, 3314,
2973, 2937, 2861, 1492, 1474, 1453, 1380, 1342, 1203, 1167,
1151, 1107, 1093, 1051. 1H NMR: d 1.26 (s, 3H), 1.37 (d, 3H,
J = 6.5 Hz), 1.46 (s, 3H), 1.8–2.4 (br s, 2H), 2.55 (dd, 1H, J = 12.2,
7.9 Hz), 2.79 (dd, 1H, J = 12.2, 3.6 Hz), 3.35 (dd, 1H, J = 6.3,
3.6 Hz), 3.46 (dd, 1H, J = 10.8, 3.5 Hz), 3.80 (q, 1H, J = 6.5 Hz), 4.0–
4.1 (m, 1H), 4.04 (d, 1H, J = 10.8 Hz), 4.52 (dd, 1H, J = 6.0, 3.6 Hz),
4.74 (dd, 1H, J = 6.0, 3.5 Hz), 7.2–7.4 (m, 5H). 13C NMR: d 24.4,
24.5, 25.9, 49.1, 57.9, 69.0, 72.6, 80.4, 81.1, 83.6, 112.0, 126.6,
126.8, 128.3, 145.3. Anal. Calcd for C17H25NO4: C, 66.43; H, 8.20;
N, 4.56. Found: C, 66.26; H, 8.11; N, 4.37.
All anhydrous solvents were distilled calcium hydride (acetone,
acetonitrile, and isopropanol) and stored under an argon atmo-
sphere. Reactions were monitored by TLC (Macherey–Nagel Poly-
gramÒsil G/UV254). Column chromatography was performed on
silica gel (Merck, 230–400 mesh).
400 MHz 1H NMR spectra and 100.6 MHz 13C spectra were re-
corded on a Bruker AC-400 in CDCl3. 1H and 13C chemical shifts
are expressed as parts per million downfield from the internal
standards tetramethylsilane for CDCl3 solutions. Multiplicities are

S. Guillarme et al. / Tetrahedron: Asymmetry 19 (2008) 1450–1454
1453
4.2.4. 3,6-Anhydro-1-(benzeneamino)-1-deoxy-4,5-O-
isopropylidene- -sorbitol 1d
Yield: 75%; slightly yellow oil; [
8H), 1.48 (s, 3H), 1.5–2.0 (m, 5H), 2.25 (br s, 2H), 2.3–2.7 (m,
1H), 2.71 (dd, 1H, J = 11.8, 8.4 Hz), 2.93 (dd, 1H, J = 11.8, 3.6 Hz),
3.37 (dd, 1H, J = 6.3, 3.8 Hz), 3.48 (dd, 1H, J = 10.9, 3.7 Hz), 4.04
(ddd, 1H, J = 8.4, 6.3, 3.6 Hz), 4.09 (d, 1H, J = 10.9 Hz), 4,66 (dd,
1H, J = 6.3, 3.8 Hz), 4,78 (dd, 1H, J = 6.3, 3.7 Hz). 13C NMR: d 25.2,
25.3, 25.8, 26.2, 26.3, 33.4, 33.9, 48.9, 56.9, 69.1, 72.8, 81.5, 84.2,
84.5, 112.2. Anal. Calcd for C15H27NO4: C, 63.13; H, 9.54; N, 4.91.
Found: C, 63.13; H, 9.61; N, 4.79.
D
a]
D = À70.0 (c 0.25, CH2Cl2);
Rf = 0.76 (eluent: CH2Cl2/MeOH (9/1)). IR 3394, 3052, 2985, 2936,
1602, 1507, 1456, 1380, 1372, 1267, 1207, 1095. 1H NMR: d 1.34
(s, 3H), 1.51 (s, 3H), 2.9–3.1 (br s, 2H), 3.27 (dd, 1H, J = 12.8,
7.1 Hz), 3.45 (dd, 1H, J = 12.8, 4.2 Hz), 3.47–3.53 (m, 2H), 4.10 (d,
1H, J = 10.8 Hz), 4.24–4.29 (m, 1H), 4.70 (dd, 1H, J = 6.2, 3.7 Hz),
4.81 (dd, 1H, J = 6.2, 3.7 Hz), 6.68–6.76 (m, 3H), 7.14–7.21 (m,
2H). 13C NMR: d 24.5, 25.9, 46.2, 68.9, 72.5, 80.9, 81.4, 83.0,
112.4, 113.2, 117.6, 129.2, 129.3, 148.2. HRMS (CI) calcd for
4.2.9. 3,6-Anhydro-1-(tert-butylamino)-1-deoxy-4,5-O-
isopropylidene-D-sorbitol 1i
C
15H22NO4 (M+H)+, 280.1549; found, 280.1553.
Yield: 69%; white solid; mp 63.5–64.5 °C; [
a
]D = À62.3 (c 1.0,
CH2Cl2); Rf = 0.34 (eluent: CH2Cl2/MeOH (9/1)). IR 3459, 3312,
2958, 2922, 2854, 1456, 1380, 1358, 1206, 1095. 1H NMR: d 1.10
(s, 9H), 1.32 (s, 3H), 1.48 (s, 3H), 2.1–2.4 (br s, 2H), 2.65 (dd, 1H
J = 11.6, 8.1 Hz), 2.86 (dd, 1H, J = 11.6, 3.8 Hz), 3.39 (dd, 1H,
J = 6.3, 3.7 Hz), 3.50 (dd, 1H, J = 10.7, 3.7 Hz), 3.90–4.0 (m, 1H),
4.09 (d, 1H, J = 10.8 Hz), 4.68 (dd, 1H, J = 6.2, 3.5 Hz), 4.78 (dd,
1H, J = 6.2, 3.8 Hz). 13C NMR: d 24.6, 25.9, 28.9, 44.4, 50.3, 69.5,
72.6, 80.7, 81.1, 83.7, 112.2. HRMS (CI) calcd for C13H26NO4
(M+H)+, 204.1862; found, 204.1865.
4.2.5. 3,6-Anhydro-1-amino-1-deoxy-4,5-O-isopropylidene-D-
sorbitol 1e
A solution of epoxide 2 (1.86 g; 10 mmol) and sodium azide
(3.25 g; 50 mmol) in water (20 mL) was stirred at 30 °C for 14 h.
The solution was extracted twice with diethyl ether and the organ-
ic layer was dried over MgSO4. Evaporation of the solvent led to an
azide which was used without further purification and dissolved in
ethyl acetate. Pd/C 5% (60 mg) was then added and the mixture
was stirred in presence of H2 (4.5 bars) for 2 days. After filtration,
the solvent was evaporated under reduced pressure. The crude
product was purified by column chromatography to lead to 1e.
4.2.10. 3,6-Anhydro-1-[(S)-(1-hydroxybutan-2-ylamino)]-1-
deoxy-4,5-O-isopropylidene-
D-sorbitol 1j
Yield: 85% (1.73 g); white solid; mp 82–84 °C; [
a
]D = À40.0 (c 1.0,
Yield: 75%; white solid; mp 75.5–77.5 °C; [
a
]D = À35.3 (c 1.0,
CH2Cl2); Rf = 0.05 (eluent: CH2Cl2/MeOH (9/1)). IR 3328, 2998,
2933, 2847, 1564, 1424, 1372, 1340, 1202, 1059. 1H NMR: d 1.31
(s, 3H), 1.49 (s, 3H), 2,10 (br s, 3H), 2.70–3.08 (m, 2H), 3.38 (dd,
1H, J = 5.9, 3.5 Hz), 3.50 (dd, 1H, J = 10,8, 3.6 Hz), 3,90–4.06 (m,
1H) 4.10 (d, 1H, J = 10.8 Hz), 4.70 (dd, 1H, J = 6.2, 3.5 Hz), 4.77
(dd, 1H, J = 6.2, 3.6 Hz). 13C NMR: d 24.7, 26.2, 42.5, 69.4, 73.1,
81.2, 81.6, 83.1, 112.7. HRMS (CI) calcd for C9H18NO4 (M+H)+,
204.1236; found: 204.1228.
CH2Cl2); Rf = 0.2 (eluent: CH2Cl2/MeOH (95/5)). IR 3417, 3100,
2970, 2936, 1465, 1474, 1368, 1342, 1269, 1211, 1169, 1132,
1089, 1053. 1H NMR: d 0.93 (dd, 3H, J = 7.4 Hz), 1.32 (s, 3H), 1.49
(s, 3H), 1.4–1.6 (m, 2H), 2.2–2.5 (br s, 3H,), 2.5–2.6 (m, 1H), 2.74
(dd, 1H, J = 12.3, 6.8 Hz), 2.95 (dd, 1H, J = 12.3, 3.8 Hz), 3.34 (dd,
1H, J = 10.8, 3.8 Hz) 3.45 (dd, 1H, J = 5.9, 3.8 Hz), 3.49 (dd, 1H,
J = 10.8, 3.7 Hz), 3.63 (dd, 1H, J = 10.8, 3.8 Hz), 4.07 (d, 1H,
J = 10.8 Hz), 4.0–4.1 (m, 1H), 4.68 (dd, 1H, J = 6.0, 3.8 Hz), 4.79
(dd, 1H, J = 6.0, 3.7 Hz). 13C NMR: d 10.4, 24.5, 25.8, 30.9, 48.6,
60.4, 62.6, 69.5, 72.5, 80.5, 81.2, 83.4, 112.2. Anal. Calcd for
4.2.6. 3,6-Anhydro-1-(methylamino)-1-deoxy-4,5-O-
isopropylidene-
D
-sorbitol 1f
C13H25NO5: C, 56.71; H, 9.15; N, 5.09. Found: C, 56.48; H, 9.06;
Yield: 62%; white solid; mp 132.8–133.3 °C; [
a]
D = À54.2 (c 0.5,
N, 4.99.
MeOH); Rf = 0.14 (eluent: CH2Cl2/MeOH (9/1)). IR 3330, 2982,
2929, 1452, 1381, 1372, 1207, 1163, 1077. 1H NMR: d 1.30 (s,
3H), 1.47 (s, 3H), 2.79 (s, 3H), 3.28 (dd, 1H J = 12.7, 3.4 Hz), 3.32
(dd, 1H, J = 12.7, 8.7 Hz), 3.55 (dd, 1H, J = 10.7, 3.5 Hz), 3.65 (dd,
1H, J = 6.7, 3.5 Hz), 4.04 (d, 1H, J = 10.7 Hz), 4.46 (ddd, 1H, J = 8.6,
6.8, 3.4 Hz), 4.73 (dd, 1H, J = 6.2, 3.5 Hz), 4.79 (dd, 1H, J = 6.2,
3.5 Hz), 6.5–7.0 (br s, 2H). 13C NMR: d 24.4, 25.9, 33.7, 51.2, 66.4,
72.6, 80.1, 82.6, 82.6, 112.4. HRMS (CI) calcd for C10H20NO4
(M+H)+, 218.1392; found, 218.1394.
4.2.11. 3,6-Anhydro-1-[(R)-(1-hydroxybutan-2-ylamino)]-1-
deoxy-4,5-O-isopropylidene-
D-sorbitol 1k
Yield: 95%; white solid; mp 73–75 °C; [
a]
D = À64 (c 1.0, CH2Cl2);
Rf = 0.3 (eluent: CH2Cl2/MeOH (95/5)). IR 3292, 2958, 2841, 1461,
1380, 1314, 1274, 1243, 1203, 1163, 1141, 1089. 1H NMR: d 0.93
(dd, 3H, J = 7.3 Hz), 1.32 (s, 3H), 1.49 (s, 3H), 1.4–1.6 (m, 2H),
2.0–2.7 (br s, 4H), 2.7–2.9 (m, 2H), 3.33 (dd, 1H, J = 11.1, 6.0 Hz),
3.3–3.5 (m, 1H), 3.49 (dd, 1H, J = 10.6, 4.0 Hz), 3.64 (dd, 1H,
J = 10.6, 3.8 Hz), 4.08 (d, 1H, J = 11.1 Hz), 4.0–4.2 (m, 1H), 4.69
(dd, 1H, J = 6.3, 3.6 Hz), 4.80 (dd, 1H, J = 6.0, 3.6 Hz). 13C NMR: d
10.3, 23.9, 24.4, 25.8, 48.7, 60.3, 62.9, 69.4, 72.5, 80.6, 81.1, 83.5,
112.3. Anal. Calcd for C13H25NO5: C, 56.71; H, 9.15; N, 5.09. Found:
C, 56.31; H, 9.11; N, 4.89.
4.2.7. 3,6-Anhydro-1-(isopropylamino)-1-deoxy-4,5-O-
isopropylidene-D-sorbitol 1g
Yield: 77%; white solid; mp 103.5–104.1 °C; [
a]
D = À58.8 (c 1.0,
CH2Cl2); Rf = 0.24 (eluent: CH2Cl2/MeOH (9/1)). IR 3331, 3108,
2953, 2858, 1443, 1382, 1203, 1094, 1058. 1H NMR: d 1.05 (d,
6H, J = 6.3 Hz), 1.30 (s, 3H), 1.46 (s, 3H), 2.2–2.5 (br s, 2H), 2.68
(ddd, 1H J = 11.7, 8.3, 0.9 Hz), 2.80 (sept, 1H, J = 6.3 Hz), 2.88
(ddd, 1H, J = 11.7, 3.5, 0.9 Hz), 3.35 (dd, 1H, J = 6.3, 3.7 Hz), 3.47
(dd, 1H, J = 10.7, 3.7 Hz), 4.0–4.1 (m, 2H), 4.65 (dd, 1H, J = 5.8,
3.7 Hz), 4.77 (dd, 1H, J = 5.8, 4.0 Hz). 13C NMR: d 21.8, 22.1, 23.6,
24.9, 47.7, 48.2, 68.2, 71.7, 79.7, 80.3, 82.8, 111.2. HRMS (CI) calcd
for C12H24NO4 (M+H)+, 246.1705; found, 246.1710.
4.2.12. 3,6-Anhydro-1-(morpholino)-1-deoxy-4,5-O-
isopropylidene-
Yield: 85%; white solid; mp 54.2–55.3 °C; Rf = 0.44 (eluent:
CH2Cl2/MeOH; 9/1); [
D-sorbitol 1l
a
]
D = À63.8 (c 1.0, CH2Cl2). IR 3423, 2928,
2853, 1655, 1456, 1374, 1206, 1100, 1058.0 1H NMR: d 1.31 (s,
3H), 1.48 (s, 3H), 2.40–2.45 (m, 2H), 2.47 (dd, 1H, J = 12.4,
9.5 Hz), 2.62 (dd, 1H, J = 12.4, 3.5 Hz), 2.65–2.70 (m, 2H), 3.34
(dd, 1H, J = 6.9, 3.5), 3.44 (br s, 1H), 3.50 (dd, 1H, J = 11.0, 3.8 Hz),
3.6–3.7 (m, 4H), 4.08 (d, 1H, J = 11.0 Hz), 4.11 (m, 1H, J = 9.5, 6.9,
3.5 Hz), 4.65 (dd, 1H, J = 6.2, 3.5 Hz), 4.79 (dd, 1H, J = 6.2, 3.8 Hz).
4.2.8. 3,6-Anhydro-1-(cyclohexylamino)-1-deoxy-4,5-O-
isopropylidene-D-sorbitol 1h
Yield: 85%; slighly yellow crystals; mp 66–68 °C; [
a
]
D = À58.2 (c
–
13C NMR: d 24.7, 26.0, 53.9, 60.5, 66.5, 67.0, 72.7, 80.6, 81.3,
1.0, CH2Cl2); Rf = 0.22 (eluent: CH2Cl2/MeOH (95/5)). IR 3100, 2924,
84.1, 112.3. HRMS (CI) calcd for C13H24NO5 (M+H)+, 274.1654;
found, 274.1662.
2850, 1452, 1370, 1342, 1168, 1114, 1106. 1H NMR: d 1.0–1.4 (m,

1454
S. Guillarme et al. / Tetrahedron: Asymmetry 19 (2008) 1450–1454
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4.3. General procedure for the asymmetric transfer
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A Schlenk tube equipped with a stirrer bar was charged with
benzeneruthenium(II) chloride dimer (3.5 mg, 7
lmol) and ligand
1a (8.2 mg, 28 mol). The mixture was then degassed and freshly
l
dried, and degassed propan-2-ol (3 mL) was added under argon.
The solution was heated at 70 °C for 1 h. After cooling the mixture
to room temperature, it was diluted with propan-2-ol (4 mL) and t-
BuOK (280
lL, 0.1 M in propan-2-ol) was added. The resulting
solution was stirred for 10 min before acetophenone (165
lL,
1.4 mmol) was added. The reaction mixture was stirred at 70 °C
for 21 h. The conversion and ee were determined by chiral GC
(Restek b-dex sm (30 m  0.25 mm  0.25
flow 3.4 mL/min, 120 °C (0.5 min) then 0.6 °C/min until 125 °C
(1 min)): tR = 6.07 (R major), 6.33 (S minor)). [ D = +35.6 (c 1.03,
lm, gaz: He constant
a]
CH2Cl2) (1-phenylethanol isolated from entry 16, Table 2).
Acknowledgments
The authors would like to thank the University of Le Mans and
the CNRS for their financial support.
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