New class of β-aminoalcohol ligands derived from isosorbide and isomannide: Application in hydrogen transfer reduction of prochiral ketones

Article abstract of DOI:10.1016/j.tet.2010.09.060

Starting from isosorbide and isomannide, two by-products from the starch industry, a family of chiral functionalized β-aminoalcohols presenting a THF ring has been synthesized as potential ligands for hydrogen transfer reduction of prochiral ketones. Unde

Full text of DOI:10.1016/j.tet.2010.09.060

Tetrahedron 66 (2010) 8893e8898
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New class of
b
-aminoalcohol ligands derived from isosorbide and isomannide:
application in hydrogen transfer reduction of prochiral ketones
*
Tin Thanh Le, Stéphane Guillarme, Christine Saluzzo
UMR CNRS 6011, Faculté des Sciences, Université du Maine, Av. 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 27 May 2010
Received in revised form 9 September 2010
Accepted 17 September 2010
Available online 22 September 2010
Starting from isosorbide and isomannide, two by-products from the starch industry, a family of chiral
functionalized
b-aminoalcohols presenting a THF ring has been synthesized as potential ligands for
hydrogen transfer reduction of prochiral ketones. Under optimal conditions, more than 70% ee with an
excellent conversion were obtained for the HTR of the acetophenone.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Homogeneous catalysis
Enantioselective catalysis
Asymmetric hydrogen transfer reduction
b
-Aminoalcohols
Biomass
1. Introduction
Our goal in this work was to promote biomass products for ca-
talysis, particularly isosorbide and isomannide, two by-products
Chiral secondary alcohols are one of the most valuable in-
termediates in organic synthesis. For their formation, one of the
most attractive route, which has recently emerged consists in cat-
alytic asymmetric transfer hydrogenation reduction (HTR) of ke-
tones using mainly isopropanol as the hydrogen donor. This
reduction, occurring under very mild conditions, is a very useful
alternative to the classical catalytic reduction of ketones using
molecular hydrogen and is able to give very high enantioselectiv-
ities in some examples.1e4
from the starch industry. The dinitro derivative of isosorbide has
been extensively used in medicine as vasodilator18e20 and some
aminoalcohol derivatives have shown glycosidase inhibitory ac-
tivity.21 Otherwise, isosorbide and isomannide derivatives were
considered as factor Xa inhibitors22,23 and isommanide pseudo-
peptides derivatives as serine protease inhibitors.24 Isosorbide and
isomannide were also used in the synthesis of biodegradable pol-
ymers,25e28 amphiphiles,29 chiral auxiliaries30e34 or as starting
material for catalyst used for enantioselective alkylation35,36 or in
chiral phase transfer catalysis.37,38 Isomannide has found applica-
tion as precursor of chiral ionic liquids for chiral discrimination and
optical resolution of racemates.39,40
Close to the use of chiral monotosylated diamine/Ru(II)-com-
plexes leading to enantioelectivities higher than 90%,2,5e12 Noyori
showed that the use of
b
-aminoalcohols as ligand could accelerate
the reaction rate.13e15 Thus, numerous
b
-aminoalcohols/Ru(II)
We present here their rapid and easy transformation into a large
systems have been performed because these ligands are ready
available and easy to functionalize. In general, they have shown
height enantioselectivities and activities.16 Moreover, some of them
have been heterogeneized in order to isolate the catalytic system
from the reaction mixture and to reuse it.17
series of modular unsymmetrical chiral b-aminoalcohols ligands
and their applications in hydrogen transfer reduction of various
prochiral ketones.
2. Results and discussion
To the best of our knowledge, no carbohydrate-derived b-ami-
noalcohols have been used as ligands in the asymmetric transfer
hydrogenation reaction.
In 2001, we developed an efficient method to prepare chiral
epoxides
3 and 4, respectively, from isosorbide and iso-
mannide.29,41,42 Reacting these readily available epoxides with
various primary amines at 40 ꢀC in methanol led to a series of
b-aminoalcohols 5e11 with moderate to good reaction yields
(Scheme 1, Table 1). We have only observed the product resulting
from the ring opening reaction at the less hindered carbon. It is
* Corresponding author. Tel.: þ33 2 43833337; fax: þ33 2 43833902; e-mail
address: Christine.saluzzo@univ-lemans.fr (C. Saluzzo).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.060

8894
T.T. Le et al. / Tetrahedron 66 (2010) 8893e8898
O
O
O
O
O
O
O
O
HO
O
3 : 91 %
TMSCl/NaI (2 eq.)
Me CO (2 eq)
NaH,THF
R3NH2
MeOH, Δ
or
0 °C 1 h then rt 5 h
2
CH CN, 12 h, rt.
3
R2
O
I
O
NHR3
O
R1
O
O
R2
R2
1
R1
R1
2a : 79 %
2b : 56 %
5
R3 = CH2Ph
a R1 = OH, R2 = H
b R1 = H, R2 = OH
6
7
8
9
R3 = (R) -CH(Me)Ph
R3 = (S) -CH(Me)Ph
R3 = -CH2Ph(o-Me)
R3 = cyclohexyl
O
O
4 : 86 %
10 R3 = i-Pr
11 R3 = t-Bu
Scheme 1.
b-Aminoalcohol syntheses.
O
OH
Table 1
[Ru(benzene)Cl2]2
Formation of b-aminoalcohols byepoxide ring opening with various amines (2 equiv)
5-11, i-PrOH
t-BuOK, 70°C
Ph
Ph
*
Entry
Substrate
Amine
Ligand
Time (h)
Yield (%)
11
1
2
3
4
5
6
7
8
3
4
3
4
3
4
3
4
3
4
3
4
3
4
PhCH2NH2
PhCH2NH2
5a
5b
6a
6b
7a
7b
8a
8b
9a
9b
10a
10b
11a
11b
16
16
21
21
21
16
21
21
16
16
21
21
21.5
21.5
66
56
80
87
95
85
64
65
85
88
77
65a
69
67
Scheme 2. Hydrogen transfer reduction of acetophenone.
PhCH(Me)NH2 (R)
PhCH(Me)NH2 (R)
PhCH(Me)NH2 (S)
PhCH(Me)NH2 (S)
(o-Me)PhCH2NH2
(o-Me)PhCH2NH2
Cyclohexylamine
Cyclohexylamine
i-PrNH2
Table 2
Ruthenium assisted asymmetric HTR of acetophenone catalyzed by [Ru(benzene)
Cl2]2 associated with ligands 5e11
9
Entry
Ligand
Conv.a (%)
eea (%) (config.)
10
11
12
13
14
1
2
3
4
5
6
7
8
5a
5b
6a
6b
7a
7b
8a
8b
9a
9b
10a
10b
11a
11b
97
94
83
79
90
89
93
57
67
48
83
75
67
71
66 (R)
70 (S)
21 (R)
34 (S)
18 (R)
54 (S)
57 (R)
5 (S)
24 (R)
51 (S)
30 (R)
29 (S)
<5 (R)
<5 (S)
i-PrNH2
t-BuNH2
t-BuNH2
a
86% yield is obtained with 5 equiv of amine.
9
noteworthy that the moderate yields observed with the benzyl-
amine derivatives 5 and 8 are due to the difficulties encountered
during the chromatography purifications (entries 1, 2, 7, and 8). For
isopropylamine and tert-butylamine derivatives 10 and 11, the
yields have not been optimized (entries 11e14). The volatility of the
amine reagent is responsible of the moderate yields observed: if
the ring opening reaction is performed with 5 equiv of isopropyl-
amine the resulting product was formed in 86% yield (Table 1, entry
12 note a).
10
11
12
13
14
a
Determined by GC analyses on Rt-
bDEX smÔ column.
All ligands (5e11, Table 2) were shown to be rather efficient in
the asymmetric HTR reaction under the reaction conditions used.
Conversion of 1-phenylethanol ranged from 48 to 97%.
The pure b
-aminoalcohols from the a43 and b series were iso-
lated and fully characterized via 1H and 13C NMR spectroscopic
methods, high resolution mass spectrometry, and microanalysis.
These compounds from the a and b series differ only in the con-
figuration of the hydroxyl group on the side chain of the THF ring,
the three stereocenters of the ring presenting the same absolute
configuration.
The ruthenium complexes of these aminoalcohols were pre-
pared in situ, under argon, by reacting [Ru(benzene)Cl2]2 with
2 equiv of these corresponding ligands in anhydrous isopropanol at
70 ꢀC for 1 h. Color changes were observed from yellow to deep
orange or deep red, showing the formation of the complex. The so-
formed complexes with [Ru(benzene)Cl2]2 were then studied for
the asymmetric HTR reaction of acetophenone (Scheme 2, Table 2).
The catalysis was carried out under argon at 70 ꢀC for 21 h, under
free water conditions, in isopropanol in the presence of t-BuOK
with a ratio of acetophenone/Ru/ligand/t-BuOK of 100:1:2:2. For
ligand 5a, this ratio gave the best results in terms of catalytic
activity and enantioselectivity.43
The stereogenic center bearing the hydroxyl group, located in the
side chain part of the THF ring, is responsible of the absolute con-
figuration of the 1-phenylethanol, ligands 5ae11a leading mainly to
the R isomer, whereas ligands 5be11b gave the S one (Table 2 en-
tries 1, 3, 5, 7, 9,11,13 and 2, 4, 6, 8,10,12,14, respectively). The same
phenomenon was already observed with chiral 2-methylamino-1,2-
phenylethanol44 or with
b-aminoalcohols ligands derived from
tartaric acid45 in the case of HTR of prochiral ketones.
Moreover, it is noteworthy that in our case, the stereochemistry
of the chiral center located on the position 2 of the THF ring of
a and b series seemed to have no influence on the enantiose-
lectivity of the HTR of ketones, as it has been observed by Paolucci
and Rosini for the asymmetric addition of diethylzinc to benzal-
dehyde36 with THF ring substituted in position 2 with
alcohol functionality.
b-amino-
Except for ligands 8 and 9, a similar catalytic activity is observed
for ligands a and b bearing the same amino group (Table 2 entries 1
and 2, 3 and 4, 5 and 6, 11 and 12, 13 and 14).

T.T. Le et al. / Tetrahedron 66 (2010) 8893e8898
8895
For ligands 5e7, the enantioselectivity depends not only on the
absolute configuration on the hydroxyl group but also on the
presence or the absence of a methyl group in the benzylic position
of the amino group. It is noteworthy that isomannide ligands (series
b) gave higher enantioselectivities than isosorbide ones (series a)
(entries 1e6).
100:1:2:2. After 21 h at 25 ꢀC, conversion did not exceed 57% for
71% ee contrary to the experiment performed at 70 ꢀC where 89% of
conversion was observed with only 54% ee (entries 1 and 2). At
25 ꢀC, a change of the reaction time has no effect on the enantio-
selectivity and no significative increase of the conversion is found
(entries 2e4).
Moreover, the presence of the methyl group resulted in a detri-
mental effect on the enantioselectivity of the ligand but this effect
is less important with ligand 7b.
Contrary to ligands 6a and 7a (entries 3 and 5), presenting, re-
spectively, 21% and 18% ee, a match/mismatch effect was noticed
with ligands 6b and 7b (entries 4 and 6), which gave, respectively,
34% and 54% ee.46
For ligands 8a and 8b, which contain a methyl group located on
the ortho position of the phenyl group of the benzyl moiety, an
important difference in the catalytic activities and in the enantio-
selectivities have been observed: 93% and 57% conversions and 57%
and 5% ee, respectively (entries 7 and 8). This is probably the result
of a steric hindrance due to the methyl group.
It is also noteworthy that the influence of the alkylamine moiety
on the catalytic activity and enantioselectivity depends on whether
the ligands belong to the isosorbide or the isomannide series.
For ligands 10 and 11, containing a linear alkylamine moiety,
conversions and enantioselectivities are similar: around 80% of
conversion and 30% ee for 10a and 10b, and around 70% of conver-
sion and quite no stereoselection for 11a and 11b (entries 11, 12 and
13, 14 respectively). If ligands present a cyclic amine moiety such as
ligands 9, a drastic decrease in conversion from 67% to 48% is ob-
served along an important rise in enantioselection from 24% to 51%
ee for 9a and 9b, respectively (entries 9 and 10). To summarize, these
observed activity differences are probably due to steric factors.
We then studied the influence of the nature of the catalytic
precursor. We observed that [Ru(p-cymene)Cl2]2 or [Ru(benzene)
Cl2]2 associated with ligands 5a or 5b do not have the same in-
fluence on the catalytic activity and selectivity (Table 3). [Ru(p-
cymene)Cl2]2 is less efficient in terms of enantioselectivity and
conversion than [Ru(benzene)Cl2]2 in combination with ligand 5a
(entries 1 and 2) contrary to what was observed with ligand 5b,
which gave similar efficiency but with a better selectivity (entries 3
and 4). Previous results have reported this phenomenon with
2-methylamino-1,2-diphenylethanol as ligands.44
We finally study the efficiency of the best ligand 5 of isomannide
series using [Ru(benzene)Cl2]2 as the catalytic precursor on the
asymmetric HTR of various prochiral ketones: acetophenone,
p-methoxy, p- and m-nitro and trifluoromethylacetophenone
(Table 5).
Table 5
Asymmetric HTR of various prochiral ketones catalyzed by [Ru(benzene)Cl2]2, as-
sociated with ligand 5b. Reaction conditions: Ru/5b/t-BuOK/ketone¼1/2/2/100 at
70 ꢀC for 21 h
Entry
Substrate
Conv. (%)
ee (%)
O
O
1
100a
37a
O2N
2
3
29a
94a
<5a
MeO
O
70a
O
4
100b
41b
CF3
O
O2N
5
63c
<5c
a
determined by chiral GC column: Rt-
determined by chiral GC column: Rt-
determined by chiral HPLC chiracel-OD column (isooctane/i-PrOH 99:1).
b
DEX smÔ.
b
c
gDEX.
Table 3
Compared to the HTR of acetophenone, a drastic decrease in
Influence of the nature of the catalyst precursor associated with ligands 5 on the
reaction rate and selectivity of the HTR of acetophenone. Reaction conditions: Ru/5/
t-BuOK/ketone¼1/2/2/100 at 70 ꢀC for 21 h
the stereoselection was observed if an electrodonating group or
an electrowithdrawing group is present at the para position of the
phenyl group (entries 1e3). Compared to the acetophenone HTR,
an electrowithdrawing group such as a nitro gave similar con-
version with moderate enantioselectivity (100% conv., 37% ee),
and an electrodonating group, such as methoxy, led to a drastic
decrease in conversion and also in enantioselection (29% conv.,
<5% ee). Introduction of a trifluoromethyl group instead of the
methyl group of the acetophenone gave almost the same result as
the one obtained with the para nitro group: total conversion with
moderate enantioselectivities (respectively 37% ee and 41% ee,
entries 1 and 4). In the case of a nitro group at the meta position
the conversion is moderate with very low enantioselectivity
(entry 5).
Entry
Ligand
Precursor
Conv.a (%)
eea (%) (config.)
1
2
3
4
5a
[Ru(benzene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(benzene)Cl2]2
[Ru(p-cymene)Cl2]2
97
84
94
96
66 (R)
53 (R)
70 (S)
75 (S)
5b
a
Determined by GC analyses on Rt-
b
DEX smÔ column.
The influence of the temperature and the reaction time have
also been examined with ligand 7b associated with [Ru(benzene)
Cl2]2 (Table 4) with a ratio of acetophenone/Ru/ligand/t-BuOK of
Table 4
Influence of the temperature and the reaction time on the enantioselective HTR of
acetophenone
3. Conclusion
Entry
Ligand
Time (h)
T (ꢀC)
Conv.a(%)
eea (%)
In conclusion, we have developed two series of epimeric
-aminoalcohols easily prepared from isosorbide and isomannide.
Their Ru(II) complexes have been synthesized and evaluated for the
reduction of acetophenone and other prochiral ketones. The
complexes have shown modest to interesting enantioselectivity.
1
2
3
4
7b
21
21
63
70
25
25
25
89
57
59
60
54 (S)
71 (S)
71 (S)
71 (S)
b
116
a
determined by chiral GC column: Rt-
b
DEX smÔ.

8896
T.T. Le et al. / Tetrahedron 66 (2010) 8893e8898
Ligands 5a and 5b with N-benzyl amino group gave rise to catalysts
that induced the best enantioselectivities. 75% ee has been reached
when ligand 5b associated with Ru[(p-cymene)Cl2]2 was used for
the reduction of acetophenone. The search for more active and
selective ligands derived from these dianhydrohexitols for asym-
metric catalysis is ongoing in our laboratory.
d 24.7, 26.0, 52.3, 53.8, 67.6, 72.9, 80.6, 80.7, 83.8, 112.1, 127.1, 128.2,
128.4, 139.7; IR (cmꢁ1) (ATR): 3000e3300, 2916, 2841, 1495, 1455,
1380, 1271, 1204, 1168, 1095, 1065, 1052, 1029, 987, 909, 891, 861,
810; HRMS: (CIþ NH3) m/z found: 294.1688, C16H24NO4 [MþH]þ
requires: 294.1705.
4.2.2. 3,6-Anhydro-1-((1R)-phenylethylamino)-1-deoxy-4,5-O-iso-
4. Experimental
4.1. General
propylidene
D
-mannitol 6b. Reagent amounts: epoxide 4 (300 mg,
1.61 mmol), (þ)-(R)-(
a
)-méthylbenzylamine (413 L, 3.22 mmol),
m
time 21 h. Column chromatography (CH2Cl2/MeOH 98:2). Yield:
87%; viscous colorless oil; Rf¼0.30 (CH2Cl2/MeOH 9:1); [
a
]
20 þ3.6 (c
D
Unless otherwise stated, commercial reagents were used with-
out purification. Acetonitrile, isopropanol, methanol were distilled
over calcium hydride and acetone over calcium sulfate. Dry THF
was obtained by filtration through an activated alumina gel of
a Glass Technology GTS100All apparatus. t-BuOK was sublimated.
Analytical thin-layer chromatography (TLC) was carried out on
MachereyeNagel PolygramÒsil G/UV254. Column chromatography
0.495, CHCl3).
1H NMR:
d
1.32 (s, 3H), 1.37 (d, 3H, J¼6.6), 1.46 (s, 3H), 2.55 (dd,
1H, J¼12.1, 8.3), 2.6e2.8 (br s, 2H), 2.84 (dd, 1H, J¼12.1, 3.4), 3.25
(dd,1H, J¼8.1, 3.5), 3.40 (dd,1H, J¼10.8, 3.5), 3.79 (q,1H, J¼6.6), 3.97
(d, 1H, J¼10.8), 4.01 (ddd, 1H, J¼8.3, 8.1, 3.4), 4.72 (dd, 1H, J¼6.2,
3.5), 4.75 (dd, 1H, J¼6.2, 3.5), 7.1e7.4 (m, 5H); 13C NMR:
d 24.3, 24.7,
26.0, 50.6, 58.1, 68.0, 72.9, 80.7, 80.8, 83.8, 112.2, 126.5, 126.9, 128.5,
145.3; IR (cmꢁ1) (film): 3200e3600, 2977, 2934, 2849, 1493, 1452,
1371, 1270, 1206, 1165, 1098, 1077, 1059, 988, 964, 910, 884, 860,
815; HRMS: (CIþ NH3) m/z found: 308.1859, C17H26NO4 [MþH]þ
requires: 308.1862.
was performed on silica gel 60 (40e63
mm, Merck). Air- and
moisture-sensitive reactions were performed under inert atmo-
sphere techniques. Melting points were determined on a Reichert
Thermoval apparatus and are uncorrected. FT-IR spectra were
performed on a Nicolet AVATAR 370 DTGS Thermo Electron Cor-
poration apparatus and band positions are given in cmꢁ1. NMR
spectra were recorded with a Bruker Avance 400 spectrometer, in
CDCl3 and referenced as following: 1H (400 MHz) 13C (100.6 MHz),
4.2.3. 3,6-Anhydro-1-((1S)-phenylethylamino)-1-deoxy-4,5-O-iso-
propylidene
D
-mannitol 7b. Reagent amounts: epoxide 4 (205 mg,
1.10 mmol), (ꢁ)-(S)-(
a
)-methylbenzylamine (284 L, 2.20 mmol),
m
internal SiMe4 at
d
¼0.00 ppm. Multiplicities are indicated by s
time 16 h. Column chromatography (CH2Cl2/MeOH 98:2). Yield:
(singlet), d (doublet), t (triplet), q (quartet), m (multiplet) or br s
(broadened singlet). High resolution mass spectra were recorded
on a Waters MicromassÒ GCT PremierÔ. Optical rotations values
were recorded using a PerkineElmer 343 polarimeter. Conversion
and enantiomeric excesses were determined by GC using a capillary
85%. White solid, mp 87.9e89.8 ꢀC; Rf¼0.30 (CH2Cl2/MeOH 9:1);
[a
]
20 ꢁ67.2 (c 0.555, CHCl3).
D
1H NMR:
d
1.32 (s, 3H), 1.39 (d, 3H, J¼6.6), 1.45 (s, 3H), 2.3e2.5
(br s, 2H), 2.64 (dd, 1H, J¼11.9, 8.1), 2.80 (dd, 1H, J¼11.9, 3.5), 3.31
(dd,1H, J¼8.0, 2.8), 3.44 (dd,1H, J¼10.7, 3.1), 3.78 (q,1H, J¼6.6), 3.92
(ddd, 1H, J¼8.1, 8.0, 3.5), 3.99 (d, 1H, J¼10.7), 4.7e4.8 (m, 2H),
Rt-
b
DEX smÔ column (30 mꢂ0.5 mmꢂ0.25
mm) or a capillary Rt-
m) column or by HPLC using a chir-
g
dex (30 mꢂ0.25 mmꢂ0.25
m
7.2e7.3 (m, 1H), 7.3e7.4 (m, 4H); 13C NMR:
d 24.3, 24.6, 26.0, 51.0,
acel-OD (25 cmꢂ0.46 cm) column.
58.6, 68.3, 72.8, 80.7e80.8, 83.7, 112.2, 126.6, 126.9, 128.5, 145.4; IR
(cmꢁ1) (ATR): 3306, 2980, 2968, 2932, 2843, 1456, 1368, 1253,1212,
1161, 1111, 1100, 1086, 1057, 1027, 1005, 981, 964, 914, 872, 852, 832;
HRMS: (CIþ NH3) m/z found 308.1857, C17H26NO4 [MþHþ] requires:
308.1862.
Epoxides 3 and 4 were prepared, respectively, from isosorbide
and isomannide according to the literature procedure.29,41,42
4.2. General procedure for the synthesis of chiral
b-aminoalcohols 5e10
4.2.4. 3,6-Anhydro-1-(2-methyl-benzylamino)-1-deoxy-4,5-O-iso-
A solution of epoxide 3 or 4 (1 equiv) and amine (2e5 equiv)
propylidene
1.11 mmol), 2-methyl benzylamine (280
Column chromatography (CH2Cl2/MeOH 97:3 then 95:5). Yield:
D
-sorbitol 8a. Reagent amounts: epoxide 3 (207 mg,
were heated at 40 ꢀC in methanol (3 mL/mmol of epoxide) for
16e21 h. Solvent was then removed and the crude product was
purified by column chromatography.
mL, 2.25 mmol), time 21 h.
20
64%, visquous yellowish oil; Rf¼0.33 (CH2Cl2/MeOH 90:10); [
a]
D
3,6-Anhydro-(1-benzylamino)-1-deoxy-4,5-O-isopropylidene
sorbitol 5a, 3,6-anhydro-(1(R)-phenyl ethylamino)-1-deoxy-4,5-O-
isopropylidene -sorbitol 6a, 3,6-anhydro-(1(S)-phenyl ethylamino)-
1-deoxy-4,5-O-isopropylidene -sorbitol 7a, 3,6-anhydro-(1-cyclo-
hexylamino)-1-deoxy-4,5-O-isopropylidene -sorbitol 9a, 3,6-anhy-
dro-(1-isopropylamino)-1-deoxy-4,5-O-isopropylidene -sorbitol
10a, 3,6-anhydro-(1-terbutylamino)-1-deoxy-4,5-O-isopropylidene
D-
ꢁ42.5 (c 1.0, CHCl3).
1H NMR:
d 1.29 (s, 3H), 1.47 (s, 3H), 2.32 (s, 3H), 2.5e2.6 (br s,
D
2H), 2.82 (dd, 1H, J¼12.1, 7.6), 2.98 (dd, 1H, J¼12.1, 3.7), 3.42 (dd, 1H,
J¼6.2, 3.6), 3.48 (dd,1H, J¼10.7, 3.8), 3.78 (d,1H, J¼13.3), 3.86 (d,1H,
J¼13.3), 4.05 (d, 1H, J¼10.7), 4.14 (ddd, 1H, J¼7.5, 6.3, 3.8), 4.66 (dd,
1H, J¼6.2, 3.6), 4.78 (dd, 1H, J¼6.2, 3.7), 7.14e7.20 (m, 3H),
D
D
D
7.29e7.34 (m, 1H); 13C NMR:
d 19.0, 24.6, 26.0, 51.2, 51.4, 69.1, 72.7,
D
-sorbitol 11a, already been described, were prepared according to
80.8, 81.3, 83.5, 112.3, 126.0, 127.2, 128.6, 130.3, 136.4, 137.7; IR
(cmꢁ1) (ATR): 3200e3500, 2984, 2935, 2854, 1605, 1456, 1372,
1272, 1206, 1165, 1098, 1059, 987, 911, 857, 815, 740; HRMS: (FDþ)
m/z found 307.1797C17H25NO4 requires: 307.1784.
the literature procedure using epoxide 3.43
4.2.1. 3,6-Anhydro-1-(benzylamino)-1-deoxy-4,5-O-isopropylidene
D-mannitol 5b. Reagent amounts: epoxide 4 (297.6 mg,1.60 mmol),
benzylamine (384 L, 3.50 mmol); time 16 h. Column chroma-
m
4.2.5. 3,6-Anhydro-1-(2-methyl-benzylamino)-1-deoxy-4,5-O-iso-
tography (CH2Cl2/MeOH 95:5). Yield: 56%; orange solid,
propylidene
1.07 mmol), 2-methyl benzylamine (268
Column chromatography (CH2Cl2/MeOH 95:5). Yield: 65%, visquous
D
-mannitol 8b. Reagent amounts: epoxide 4 (201 mg,
20
mp¼52.5e55.3 ꢀC; Rf¼0.26 (CH2Cl2/MeOH 9:1); [
a
]
ꢁ28.2 (c
mL, 2.16 mmol), time 21 h.
D
1.085, CHCl3).
20
1H NMR:
d
1.34 (s, 3H), 1.48 (s, 3H), 2.5e2.6 (br s, 2H), 2.78 (dd,
yellowish oil; Rf 0.25 (CH2Cl2/MeOH 90:10); [
a
]
ꢁ14.5 (c 1.07,
D
1H, J¼12.2, 8.1), 2.99 (dd, 1H, J¼12.2, 3.4), 3.34 (dd, 1H, J¼7.9, 3.5),
3.47 (dd, 1H, J¼10.7, 3.4), 3.83 (d, 1H, J¼13.3), 3.85 (d, 1H, J¼13.3),
4.02 (d, 1H, J¼10.7), 4.04 (ddd, 1H, J¼8.1, 7.9, 3.4), 4.76 (dd, 1H,
J¼6.3, 3.4), 4.79 (dd, 1H, J¼6.3, 3.5), 7.2e7.4 (m, 5H); 13C NMR:
CHCl3).
1H NMR:
d 1.34 (s, 3H), 1.49 (s, 3H), 2.2e2.4 (br s, 2H), 2.35 (s,
3H), 2.81 (dd, 1H, J¼12.2, 8.1), 3.02 (dd, 1H, J¼12.2, 3.4), 3.35 (dd,
1H, J¼8.0, 3.4), 3.48 (dd, 1H, J¼10.8, 3.4), 3.79 (d, 1H, J¼13.2), 3.84

T.T. Le et al. / Tetrahedron 66 (2010) 8893e8898
8897
(d, 1H, J¼13.2), 4.04 (ddd, 1H, J¼7.8, 7.8.3.4), 4.76 (dd, 1H, J¼6.1, 3.4),
4.79 (dd, 1H, J¼6.1, 3.4), 7.1e7.2 (m, 3H), 7.2e7.3 (m, 2H); 13C NMR:
aliquot was taken off and filtered through a pad of silica gel in order
to follow the advancement of the reaction. After dilution in acetone
(1 mL), GC or HPLC analysis of the sample is carried on in order to
determine the conversion and the enantiomeric excess.
d
19.3, 24.7, 26.0, 58.4, 58.7, 66.8, 73.0, 80.7, 80.8, 83.8, 112.2, 125.8,
127.4, 130.2, 130.5, 136.4, 137.2; IR (cmꢁ1) (ATR): 3200e3500, 2934,
2854, 1605, 1456, 1372, 1270, 1207, 1165, 1095, 987, 963, 909, 859,
815, 742; HRMS: (FDþ) m/z found 307.1791C17H25NO4 requires:
307.1784.
For the reduction of the acetophenone chiral GC conditions are:
Rt-b
DEX smÔ column, oven: 120 ꢀC for 0.5 min then 0.6 ꢀC/min to
125 ꢀC, 1 min at that temperature: tR¼5.9 min, tS¼6.1 min.
For the reduction of the p-nitroacetophenone chiral GC condi-
4.2.6. 3,6-Anhydro-1-(cyclohexylamino)-1-deoxy-4,5-O-iso-
tions are: Rt-b
DEX smÔ column, oven: 100 ꢀC for 2 min then 1 ꢀC/
propylidene
D-mannitol 9b. Reagent amounts: epoxide 4 (305 mg
min to 180 ꢀC, 2 min at that temperature: tR¼58.7 min, tS¼59.3 min.
For the reduction of the p-methoxyacetophenone chiral GC
1.64 mmol), cyclohexylamine (400
mL, 3.48 mmol), time 16 h. Col-
umn chromatography (CH2Cl2/MeOH 95:5). Yield: 88%. White solid,
conditions are: Rt-b
DEX smÔ column, oven: 80 ꢀC for 5 min then
20
mp 83.7e86.9 ꢀC; Rf 0.34 (CH2Cl2/MeOH 9:1); [
a
]
ꢁ30.9 (c 0.97,
1
ꢀC/min to 140 ꢀC, 1 min at that temperature: tR¼43.5 min,
D
CHCl3).
tS¼44.0 min.
1H NMR:
d
1.0e1.4 (m, 5H), 1.34 (s, 3H), 1.49 (s, 3H), 1.5e1.9 (m,
For the reduction of the p-trifluoromethylacetophenone chiral
5H), 2.42 (tt, 1H, J¼10.4, 3.8), 2.4e2.6 (br s, 2H), 2.69 (dd, 1H, J¼12.1,
8.4), 2.99 (dd, 1H, J¼12.1, 3.5), 3.31 (dd, 1H, J¼8.4, 3.5), 3.48 (dd, 1H,
J¼10.8, 3.5), 3.95 (ddd, 1H, J¼8.4, 8.4, 3.5), 4.02 (d, 1H, J¼10.4), 4.76
GC conditions are: column Rt-g
DEX, oven: 100 ꢀC for 5 min then
1
ꢀC/min to 140 ꢀC, 1 min at that temperature: tR¼31.4 min,
tS¼33.7 min.
(dd, 1H, J¼6.3, 3.5), 4.80 (dd, 1H, J¼6.3, 3.5); 13C NMR:
d
24.6, 25.0,
For the reduction of the m-nitroacetophenone chiral HPLC
conditions are: HPLC chiracel-OD column; isooctane/i-PrOH 99:1,
1 mL/min, 254 nm, tr are 102.8 min and 111.0 min.
26.0, 26.1, 33.6, 49.7, 56.7, 67.6, 73.0, 80.7, 80.8, 84.0,112.1; IR (cmꢁ1
)
(ATR): 3050e3200, 2975, 2924, 2848, 1450, 1384, 1370, 1325, 1301,
1272, 1250, 1210, 1168, 1100, 1078, 1057, 1030, 988, 902, 853, 842,
812; HRMS: (FI) m/z found 285.1961, C15H27NO4 [M]þ requires:
285.1940.
Acknowledgements
We are grateful to the Ministère de la Recherche et de la Tech-
nologie and the CNRS for financial supports.
4.2.7. 3,6-Anhydro-1-(isopropylamino)-1-deoxy-4,5-O-iso-
propylidene
1.86 mmol), isopropylamine (800
umn chromatography (CH2Cl2/MeOH 95:5). Yield: 86%, visquous
D
-mannitol 10b. Reagent amounts: epoxide 4 (347 mg,
mL, 9.30 mmol), time 21 h. Col-
Supplementary data
20
yellow oil; Rf 0.26 (CH2Cl2/MeOH 85:15); [
a]
ꢁ36.1 (c 0.985,
D
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.09.060. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
CHCl3).
1H NMR:
d
1.10 (d, 6H, J¼6.3), 1.34 (s, 3H), 1.49 (s, 3H), 2.71 (dd,
1H, J¼12.1, 8.4), 2.8e2.9 (br s, 2H), 2.85 (sept, 1H, J¼6.3), 2.98 (dd,
1H, J¼12.1, 3.4), 3.34 (dd, 1H, J¼8.1, 3.5), 3.49 (dd, 1H, J¼10.5, 3.5),
4.00 (ddd, 1H, J¼8.4, 8.1, 3.4), 4.03 (d, 1H, J¼10.5), 4.77 (dd, 1H,
References and notes
J¼6.3, 3.5), 4.81 (dd, 1H, J¼6.3, 3.5); 13C NMR:
d 22.8, 22.9, 24.6,
26.0, 48.9, 50.1, 67.7, 73.0, 80.7, 80.8, 83.9, 112.2; IR (cmꢁ1) (ATR):
3200e3600, 2964, 2933, 2849, 1456, 1371, 1338, 1270, 1208, 1166,
1098, 1073, 989, 964, 909, 855, 815; HRMS: (CIþ NH3) m/z found
246.1701, C12H24NO4 [MþH]þ requires: 246.1705.
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less oil; Rf 0.30 (CH2Cl2/MeOH 95:5); [
a
]
20 ꢁ26.9 (c 0.405, CHCl3).
D
1H NMR:
d
1.18 (s, 9H), 1.34 (s, 3H), 1.48 (s, 3H), 2.73 (dd, 1H,
J¼11.9, 8.4), 3.01 (dd, 1H, J¼11.9, 3.4), 3.36 (dd, 1H, J¼8.0, 3.4), 3.49
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J¼10.6), 4.76 (dd, 1H, J¼6.1, 3.5), 4.80 (dd, 1H, J¼6.1, 3.4); 13C NMR:
d
24.6, 26.0, 28.5, 45.5, 51.7, 67.3, 73.0, 80.6 (2C), 84.0, 112.2; IR
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260.1862.
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m
b-ami-
m
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