Novel Water-Soluble Bisphosphinite Chiral Ligands Derived from α,α- And β,β-Trehalose. Application to Asymmetric Hydrogenation of Dehydroamino Acids and Their Esters in Water or an Aqueous/ Organic Biphasic Medium

Article abstract of DOI:10.1021/jo990448m

Novel 2,3:4,6-di-O-isopropylidene-α-D-glucopyranosyl-(1,1)-4,6-O-isopropylidene- 2,3-di-O-diphenylphosphino-α-D-glucopyranoside (2), 2,3:4,6-di-O-cyclohexylidene-α-D-glucopyranosyl-(1,1)-4,6-O- cyclohexylidene-2,3-di-O-diphenylphosphino-α-D-glucopyranoside (4), and 2,3:4,6-di-O-cyclohexylidene-β-D-glucopyranosyl-(1,1)-4,6-O- cyclohexylidene-2,3-di-O-diphenylphosphino-β-D-glucopyranoside (11) were prepared from the corresponding α,α- or β,β-trehalose. The ligands were transformed into cationic Rh complexes, such as [Rh(α-D-glucopyranosyl-(1,1)-2,3-di-O-diphenylphosphino-α-D- glucopyranoside)(cod)]BF₄ (3) and [Rh(β-D-glucopyranosyl-(1,1)-2,3-di-O-diphenylphosphino-β-D- glucopyranoside)(cod)]BF₄ (12) bearing free hydroxy groups. These complexes were soluble in water and were efficient catalysts for the asymmetric hydrogenation of dehydroamino acids and their esters in water or an aqueous/organic biphasic medium with high enantioselectivity (up to 99.9% ee). Aqueous biphasic systems offer an easy separation of the aqueous catalyst phase from the product phase and allow recycling of the catalyst phase without the loss of enantioselectivity.

Full text of DOI:10.1021/jo990448m

J . Org. Chem. 1999, 64, 5593-5598
5593
Novel Wa ter -Solu ble Bisp h osp h in ite Ch ir a l Liga n d s Der ived fr om
r,r- a n d â,â-Tr eh a lose. Ap p lica tion to Asym m etr ic Hyd r ogen a tion
of Deh yd r oa m in o Acid s a n d Th eir Ester s in Wa ter or a n Aqu eou s/
Or ga n ic Bip h a sic Med iu m
Koji Yonehara, Tomohiro Hashizume, Kenji Mori, Kouichi Ohe,* and Sakae Uemura*
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University,
Sakyo-ku, Kyoto 606-8501, J apan
Received March 11, 1999
Novel 2,3:4,6-di-O-isopropylidene-R-D-glucopyranosyl-(1,1)-4,6-O-isopropylidene-2,3-di-O-diphe-
nylphosphino-R-D-glucopyranoside (2), 2,3:4,6-di-O-cyclohexylidene-R-D-glucopyranosyl-(1,1)-4,6-O-
cyclohexylidene-2,3-di-O-diphenylphosphino-R-D-glucopyranoside (4), and 2,3:4,6-di-O-cyclohexylidene-
â-D-glucopyranosyl-(1,1)-4,6-O-cyclohexylidene-2,3-di-O-diphenylphosphino-â-D-glucopyranoside (11)
were prepared from the corresponding R,R- or â,â-trehalose. The ligands were transformed into
cationic Rh complexes, such as [Rh(R-D-glucopyranosyl-(1,1)-2,3-di-O-diphenylphosphino-R-D-
glucopyranoside)(cod)]BF
glucopyranoside)(cod)]BF
4
(3) and [Rh(â-D-glucopyranosyl-(1,1)-2,3-di-O-diphenylphosphino-â-D-
(12) bearing free hydroxy groups. These complexes were soluble in water
4
and were efficient catalysts for the asymmetric hydrogenation of dehydroamino acids and their
esters in water or an aqueous/organic biphasic medium with high enantioselectivity (up to 99.9%
ee). Aqueous biphasic systems offer an easy separation of the aqueous catalyst phase from the
product phase and allow recycling of the catalyst phase without the loss of enantioselectivity.
In tr od u ction
Homogeneous catalysts have many attractive advan-
tages over their heterogeneous counterparts, because the
former have well-defined active sites with steric and
electronic properties influenced by their ligands. There-
fore, higher activities and selectivities are exhibited
1
under milder operating reaction conditions. Industrial
large-scale applications of homogeneous catalysts, how-
ever, encounter serious drawbacks, such as the cumber-
some separation of the expensive catalysts from reaction
products and the quantitative recovery of the catalyst in
an active form. In many cases, the separation of the
product phase from the miscible molecular catalyst phase
includes thermal operation, such as distillation, decom-
position, transformation, and rectification, which nor-
mally causes thermal stress on the catalyst, sacrificing
the catalytic activity. As a way of solving these problems,
an aqueous biphasic system using a water-soluble com-
2
plex has attracted a great deal of interest. Ruhrchemie/
3
Rh oˆ ne-Poulenc’s oxo process is a benchmark in the field
of homogeneous catalyst in aqueous media, and its
success stimulated the application of this principle to a
broad spectrum of catalytic reactions. The principle of
this biphasic catalytic system is depicted in Figure 1.
Generally, after the reaction the water-soluble organo-
F igu r e 1. General principle of biphasic catalysis in an
aqueous/organic medium.
metallic complex loaded as a catalyst and the reaction
product are maintained in an aqueous phase and an
organic phase, respectively. This intrinsic nature of phase
separation can facilitate the isolation of the product from
the catalyst and the recycle of the catalyst phase. In
addition, since water is used as solvent, this system is
economically and environmentally attractive.
Solubilization of transition-metal complexes in aqueous
media has been usually accomplished by the attachment
of charged or polar substituents, such as sulfonate,
carboxylate, ammonium, phosphonium, and polyether, to
their ligands. Complexes bearing such ligands have been
(
1) Parshall, G. W.; Ittel, S. D. Homogeneous Catalysis, 2nd ed.; J ohn
Wiley: New York, 1992.
2) (a) Cornils, B.; Herrmann, W. A. Aqueous-Phase Organometallic
(
Catalysis; VCH: New York, 1998. (b) Cornils, B.; Herrmann, W. A.
Applied Homogeneous Catalysis with Organometallic Compounds;
VCH: New York, 1996. (c) J o o´ , F.; Kath o´ , AÄ . J . Mol. Catal. A: Chem.
1
1
1
997, 116, 3. (d) Papadogianakis, G.; Sheldon, R. A. New J . Chem.
996, 20, 175. (e) Cornils, B. Angew. Chem., Int. Ed. Engl. 1995, 34,
575. (f) Beller, M.; Cornils, B.; Frohning, C. D.; Kohlpaintner, C. W.
J . Mol. Catal. A: Chem. 1995, 104, 17. (g) Herrmann, W. A.;
Kohlpaintner, C. W. Angew. Chem., Int. Ed. Engl. 1993, 32, 1524.
(3) Kuntz, E. G. Chemtech 1987, 17, 570.
1
0.1021/jo990448m CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/02/1999

5
594 J . Org. Chem., Vol. 64, No. 15, 1999
Yonehara et al.
applied to various reactions in water.2 Furthermore,
several water-soluble chiral ligands incorporating these
substituents have been developed as well over the past
decade, providing fair to good enantioselectivity in the
4
5
hydrogenation and hydroformylation of alkenes and the
hydrogenolysis of epoxides.6
In contrast, water-soluble ligands incorporating poly-
7
hydroxy groups have been used to a lesser extent. For
this reason, transformation of carbohydrates, especially
monosaccharides, into water-soluble ligands now receives
8
increased attention. Carbohydrates have some advan-
tages for ligand synthesis, since they are ubiquitously
present in nature, and therefore readily available. More-
over, since they contain both many chiral centers and
hydroxy groups in their skeletons, they are applicable to
the synthesis of a variety of water-soluble chiral ligands.
Recently, Selke, Oehme, and co-workers reported the
application of the water-soluble or sparingly water-
soluble rhodium complexes derived from R- or â-D-glucose
F igu r e 2. Concept for the water-soluble disaccharide chiral
ligand.
based on monosaccharides, their use as ligands of transi-
tion-metal catalysts may allow the asymmetric reaction
in an immiscible biphasic system.
Resu lts a n d Discu ssion
9
to asymmetric reactions. Although such complexes were
We initially chose the R,R-trehalose (R-D-glucopyrano-
syl-(1,1)-R-D-glucopyranoside) as a starting material and
planned to synthesize the Rh complex 3 in which R-D-
glucopyranosyl-(1,1)-2,3-di-O-diphenylphosphino-R-D-glu-
copyranoside was introduced as a poly-hydroxy chiral
ligand. R,R-Trehalose is found in many bacteria and
fungi, in plants, and in the blood of most insects. In
addition to its ready availability, we could take advantage
of some features of it for the synthesis of a water-soluble
poly-hydroxy chiral ligand: (i) 2,3-Di-O-diphenylphos-
phino-R,R-trehaloses which are protected in the 4,6:2′,3′:
active in asymmetric hydrogenation of dehydroamino
acids and their derivatives in water, the addition of a
surfactant was still necessary to achieve high reactivity
9
a,b
as well as high enantioselectivity.
In this paper, we report the synthesis of novel water-
soluble disaccharide chiral ligands in which one sugar
moiety is attached to the 2,3-diphosphinite glucopyrano-
side moiety at the anomeric position by a glycosid linkage
in order to increase the water-solubility (Figure 2). Their
application to asymmetric hydrogenation of dehydroam-
ino acids and their esters in water or an aqueous/organic
biphasic medium will be described. Since the catalysts
having such ligands are more soluble in water than those
4
′,6′ positions by cyclic acetals can be synthesized, and
these protecting groups can be easily removed under
acidic conditions. (ii) Because R,R-trehalose does not
contain a reducing sugar in its structure, both D-glucopy-
ranosyl structures may not be influenced by the isomer-
ization under acidic conditions. The preparative sequence
for such ligand and complex is depicted in Scheme 1.
(4) (a) Lensink, C.; Rijnberg, E.; de Vries, J . G. J . Mol. Catal. A:
Chem. 1997, 116, 199. (b) Ding, H.; Hanson, B. E.; Bakos, J . Angew.
Chem., Int. Ed. Engl. 1995, 34, 1645. (c) J ones, A.; Roberts, D. L.;
Davis, M. E. Nature 1994, 370, 449. (d) Wan, K. T.; Davis, M. E.
Tetrahedron: Asymmetry, 1993, 4, 2461. (e) T o´ th, I.; Hanson, B. E.
Organometallics, 1993, 12, 1506. (f) Laghmari, M.; Sinou, D. J .
Organomet. Chem. 1992, 438, 213. (g) Lensink, C.; de Vries, J . G.
Tetrahedron: Asymmetry 1992, 3, 235. (h) Bakos, J .; Orosz, A.; Heil,
B.; Laghmari, M.; Lhoste, P.; Sinou, D. J . Chem. Soc., Chem. Commun.
First, 2,3:4,6-di-O-isopropylidene-R-D-glucopyranosyl-
10
(
1,1)-4,6-O-isopropylidene-R-D-glucopyranoside (1) was
prepared and then was transformed into 2,3:4,6-di-O-
isopropylidene-R-D-glucopyranosyl-(1,1)-4,6-O-isopropy-
lidene-2,3-di-O-diphenylphosphino-R-D-glucopyranoside
1
1
991, 1684. (i) Sinou, D.; Safi, M.; Claver, M.; Masdeu, A. J . Mol. Catal.
991, 68, L9. (j) T o´ th, I.; Hanson, B. E.; Davis, M. E. Tetrahedron:
Asymmetry 1990, 1, 913. (k) T o´ th, I.; Hanson, B. E.; Davis, M. E. J .
Organomet. Chem. 1990, 396, 363. (l) T o´ th, I.; Hanson, B. E.; Davis,
M. E. Catal. Lett. 1990, 5, 183. (m) Amrani, Y.; Lecomte, L.; Sinou,
D.; Bakos, J .; T o´ th, I.; Hell, B. Organometallics 1989, 8, 542. (n)
Lecomte, L.; Sinou, D. J . Mol. Catal. 1989, 52, L21. (o) Alario, F.;
Amrani, Y.; Colleuille, Y.; Dang, T. P.; J enck, J .; Morel, D.; Sinou, D.
J . Chem. Soc., Chem. Commun. 1986, 202. (p) Nagel, U.; Kinzel, E.
Chem. Ber. 1986, 119, 1731. (q) Amrani, Y.; Sinou, D. J . Mol. Catal.
(
2) by treatment with Ph
(2)(acac)] was formed in situ by the reaction of [Rh(acac)-
cod)] with chiral ligand 2 in degassed THF under Ar,
and then 40% aqueous HBF was added to this solution
at 50 °C. After 4 h, degassed dry Et O was added and a
separated orange syrup was rinsed with degassed Et
2 3
PCl and Et N. A complex [Rh-
(
4
2
2
O
1
986, 36, 319. (r) Benhazma, R.; Amrani, Y.; Sinou, D. J . Organomet.
Chem. 1985, 288, C37. (s) Amrani, Y.; Sinou, D. J . Mol. Catal. 1984,
4, 231.
5) Eckl, R. W.; Priermeier, T.; Herrmann, W. A. J . Organomet.
Chem. 1997, 532, 243.
6) Bakos, J .; Orosz, AÄ .; Cser e´ pi, S.; T o´ th, I.; Sinou, D. J . Mol. Catal.
A: Chem. 1997, 116, 85.
7) (a) Hoye, P. A. T.; Pringle, P. G.; Smith, M. B.; Worboys, K. J .
to give a water-soluble cationic Rh complex 3 in 76% yield
(Scheme 1, Path A). On the other hand, we previously
reported the synthesis of 2,3:4,6-di-O-cyclohexylidene-R-
D-glucopyranosyl-(1,1)-4,6-O-cyclohexylidene-2,3-di-O-
diphenylphosphino-R-D-glucopyranoside (5) from R,R-
trehalose via the compound 4 and its application to the
asymmetric hydrogenation of dehydroamino acids and
2
(
(
(
Chem. Soc., Dalton Trans. 1993, 269. (b) Ellis, J . W.; Harrison, K. N.;
Hoye, P. A. T.; Orpen, A. G.; Pringle, P. G.; Smith, M. B. Inorg. Chem.
1
992, 31, 3026. (c) Harrison, K. N.; Hoye, P. A. T.; Orpen, A. G.; Pringle,
11
their esters. Then, we could prepare the complex 3 from
P. G.; Smith, M. B. J . Chem. Soc., Chem. Commun. 1989, 1096. (d)
Chatt, J .; Leigh, R. M.; Slade, R. M. J . Chem. Soc., Dalton Trans. 1973,
5
(Scheme 1, Path B). If two protection methods were
2
021. (e) Issleib, K.; M o¨ bius, M. Chem. Ber. 1961, 94, 102.
8) (a) Ferrara, M. L.; Oranona, I.; Ruffo, F.; Funicello, M.; Panunzi,
compared, the efficiency of the tri-protection step by
cyclohexylidene groups was higher (53%, 2 steps) than
that by isopropylidene groups (20%, 2 steps), while the
deprotection step of alkylidene groups from the Rh
complex of 2 and 5 proceeded similarly in both cases. As
(
A. Organometallics 1998, 17, 3832. (a) Beller, M.; Krauter, J . G. E.;
Zpaf, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 772. (b) Sawamura,
M.; Kitayama, K.; Ito, Y. Tetrahedron: Asymmetry 1993, 4, 1829. (c)
Mitchell, T. N.; Heesche-Wagner, K. J . Organomet. Chem. 1992, 436,
4
3.
(
9) (a) Kumar, A.; Oehme, G.; Roque, J . P.; Schwarze, M.; Selke, R.
Angew. Chem., Int. Ed. Engl. 1994, 33, 2197. (b) Oehme, G.; Paetzold,
E.; Selke, R. J . Mol. Catal. 1992, 71, L1. (c) Selke, R. J . Organomet.
Chem. 1989, 370, 241.
(10) Wallace, P. A.; Minnikin, D. E. Carbohydr. Res. 1994, 263, 43.
(11) Yonehara, K.; Hashizume, T.; Ohe, K.; Uemura, S. Bull. Chem.
Soc. J pn. 1998, 71, 1967.

Novel Bisphosphinite Chiral Ligands
J . Org. Chem., Vol. 64, No. 15, 1999 5595
Sch em e 1a
a
(
i) Me2C(OMe)2, cat. p-TsOH‚H2O, DMF, 80 °C, 6 h; (ii) Ac2O, C5H5N, rt, overnight, 20% (2 steps); (iii) K2CO3, MeOH, rt, 1 h, 70%.
(
b) Ph2PCl, cat. DMAP, Et3N-THF, rt, 15 min, 63%. (c) (i) [Rh(acac)(cod)], THF, rt, 20 min; (ii) 40% aqueous HBF4, 50 °C, 4 h, 76% (2
steps). (d) 1,1-dimethoxycyclohexane, cat. p-TsOH‚H2O, DMF, 80 °C, 6 h; (ii) Ac2O, C5H5N, rt, overnight, 53% (2 steps); (iii) K2CO3, MeOH,
rt, 1 h, 68%. (e) Ph2PCl, cat. DMAP, Et3N-THF, rt, 15 min, 65%. (f) (i) [Rh(acac)(cod)], THF, rt, 20 min; (ii) 40% aqueous HBF4, 50 °C, 4
h, 72% (2 steps).
Ta ble 1. Asym m etr ic Hyd r ogen a tion of Meth yl
identical conditions. The best result (76% ee) in a biphasic
system was obtained when the reaction was carried out
r-Aceta m id ocin n a m a te Usin g 3 in Wa ter or a n Aqu eou s/
a
Or ga n ic Med iu m
in H
same ee value (75% ee) was also observed in a homoge-
neous system (H O-MeOH ) 3:2) (entry 5).
2
O-MeOH-AcOEt ) 0.6:0.4:1 (entry 4). Almost the
2
Next, we tried to synthesize the analogous water-
soluble Rh complex (12) from â,â-trehalose (â-D-glucopy-
ranosyl-(1,1)-â-D-glucopyranoside)12 (Scheme 2). The â,â-
trehalose is not nature’s reserve sugar but it can be easily
prepared from penta-O-acetyl-â-D-glucopyranoside by the
following procedures. After the bromination of penta-O-
acetyl-â-D-glucopyranoside (6) at the anomeric position
with 25% HBr/AcOH,13 the obtained compound 7, 2,3,4,6-
tetra-O-acetyl-R-D-glucopyranosyl bromide, was treated
cat.
(mol %) (h)
time ee (%)b
(S)c
entry
1
solvent
H2O
H2O
5
1
2
1
1
6
1
55
d
2
90
68 (66)e
3
4
5
H2O/AcOEt ) 1/1
H2O/CH3OH/AcOEt ) 0.6/0.4/1
H2O/CH3OH ) 3/2
1.5
3
1.5 75
76
a
Complete conversion of 3 in all cases. b The ee (%) values were
determined by HPLC. The absolute configuration was deter-
mined by optical rotation. Sodium dodecyl sulfate (10 mol %) was
added. The enantiomeric excess obtained from the second use of
with H
glucopyranoside (8). Glycosidation of 8 with phenyl
,3,4,6-tetra-O-acetyl-1-thio-â-D-glucose using N-iodosuc-
2 2 3
O and Ag CO to give 2,3,4,6-tetra-O-acetyl-â-D-
c
14
d
2
e
cinimide/cat. trifluoromethanesulfonic acid (TfOH) as an
the catalyst aqueous solution is shown in parentheses.
activator15 followed by deacetylation gave â,â-trehalose
(
9). The compound 9 was dissolved in dry DMF, and the
can be expected, the complex 3 was soluble in water, at
ca. 5 g/100 mL at 20 °C.
Asymmetric hydrogenation of methyl R-acetamidocin-
namate (13) was carried out using the complex 3 in water
or an aqueous/organic biphasic medium at room temper-
ature under H pressure (5 atm) (eq 1). The results are
2
summarized in Table 1.
2
The reaction proceeded even in H O to give moderate
solution was stirred at 80 °C in the presence of 1,1-
dimethoxycyclohexane and a catalytic amount of p-
toluenesulfonic acid. After 4 h, isolation of the mixture
followed by acetylation produced crude 2,3:4,6-di-O-
cyclohexylidene-â-D-glucopyranosyl-(1,1)-4,6-O-cyclohex-
ylidene-2,3-di-O-acetyl-â-D-glucopyranoside. Deacetyla-
tion of this compound gave 2,3:4,6-di-O-cyclohexylidene-
â-D-glu copyr a n osyl-(1,1)-4,6-O-cycloh exyliden e-â-D-
glucopyranoside (10). Treatment of 10 with Ph
Et N afforded 2,3:4,6-di-O-cyclohexylidene-â-D-glucopy-
ranosyl-(1,1)-4,6-O-cyclohexylidene-2,3-di-O-diphenylphos-
phino-â-D-glucopyranoside (11). The rhodium complex
selectivity (55% ee) (entry 1). The addition of sodium
dodecyl sulfate (SDS) as an amphiphile improved its
selectivity to 90% ee (entry 2). In a biphasic system
2
PCl and
3
(
H
2
O-AcOEt ) 1:1), the reaction also occurred smoothly
to give higher ee value (68% ee) than that in H O (entry
). Furthermore, after the reaction was completed the
2
3
(
12) Cook, S. J .; Khan, R.; Brown, J . M. J . Carbohydr. Chem. 1984,
, 343.
(13) Hudson, C. S.; Dale, J . K. J . Am. Chem. Soc. 1918, 40, 992.
organic phase including the product was easily separated
by decantation. The aqueous phase containing the cata-
lyst could be reused for the same hydrogenation to give
almost the same enantiomeric excess (66% ee), albeit,
with lower catalytic activity (70% conversion) under
3
(
(
14) Allen, P. Z. Methods Carbohydr. Chem. 1962, 1, 372.
15) (a) Konradsson, P. K.; Udodong, U. E.; Fraster-Reid, B.
Tetrahedron Lett. 1990, 31, 4313. (b) Veeneman, G. H.; van Leeuwen,
S. H.; van Boom, J . H. Tetrahedron Lett. 1990, 31, 1331.

5
596 J . Org. Chem., Vol. 64, No. 15, 1999
Yonehara et al.
Sch em e 2a
a
(a) 25% HBr/AcOH, CH2Cl2, rt, 12 h, 90%. (b) Ag2CO3, H2O, 0 °C, 1 h, 85%. (c) (i) phenyl 2,3,4,6-tetra-O-acetyl-1-thio-â-D-glucose,
NIS(N-iodosuccinimide), cat. TfOH, MS 4A, CH2Cl2, rt, 30 min; (ii) NaOMe, MeOH, reflux, 15 min, 36% (2 steps). (d) (i) 1,1-
dimethoxycyclohexane, cat. p-TsOH, DMF, 80 °C, 4 h; (ii) Ac2O, C5H5N, rt, overnight; (iii) K2CO3, MeOH, rt, 1 h, 32% (3 steps). (e)
Ph2PCl, cat. DMAP, Et3N-THF, rt, 15 min, 65%. (f) (i) [Rh(acac)(cod)], THF, rt, 20 min; (ii) 40% aqueous HBF4, 50 °C, 4 h, 79% (2 steps).
Ta ble 2. Asym m etr ic Hyd r ogen a tion of Deh yd r oa m in o Acid s Usin g 12 in Wa ter or a n Aqu eou s/Or ga n ic Med iu m a
b
cat.
(mol %)
time
(h)
ee (%)
(S)
c
entry
1
substrate
solvent
13
13
13
13
13
14
14
15
15
16
16
17
17
18
H2O
H2O
5
1
2
1
1
1
1
1
1
1
1
1
1
2
6
1
1.5
3
1.5
3
1.5
3
1.5
3
3
3
88
d
2
99.9
87 (85)
98
94
96
e
3
4
5
6
7
8
9
H2O/AcOEt ) 1/1
H2O/CH3OH/AcOEt ) 0.6/0.4/1
H2O/CH3OH ) 3/2
f
H2O/CH3OH/AcOEt ) 0.6/0.4/2
H2O/CH3OH ) 3/2
f
95
H2O/CH3OH/AcOEt ) 0.6/0.4/1
H2O/CH3OH ) 3/2
92
90
98
98
96
95
80
1
1
1
1
1
0
1
2
3
4
H2O/CH3OH/AcOEt ) 0.6/0.4/1
H2O/CH3OH ) 3/2
H2O/CH3OH/AcOEt ) 0.6/0.4/1
H2O/CH3OH ) 3/2
3
1.5
H2O
a
Complete conversion of alkenes in all cases. b The ee (%) values were determined by HPLC. c The absolute configuration was determined
by optical rotation. d Sodium dodecyl sulfate (10 mol %) was added. The enantiomeric excess obtained from the second use of the catalyst
aqueous solution is shown in parentheses. The ee (%) values were determined on its methyl ester.
e
e
[
(
Rh(11)(acac)] formed in situ by the reaction of [Rh(acac)-
cod)] with the chiral ligand 11 in degassed THF under
under the same conditions.9a,b When the hydrogenation
was carried out in H O-AcOEt ) 1:1 biphasic system,
2
Ar was treated with 40% aqueous HBF
4
at 50 °C for 4 h
the ee value of product was 87%. The aqueous phase
containing the complex 12 could be reused after the
separation. The same level of enantiomeric excess of the
product was maintained in 85% ee, although the conver-
sion of the starting material was decreased to 82% (entry
3). The ee value was improved to 98% when the reaction
to give a cationic Rh complex (12) in 79% yield. The water
solubility of the complex 12 was almost the same as that
of the complex 3, being ca. 4.3 g/100 mL at 20 °C.
The results of asymmetric hydrogenation of dehy-
droamino acids and their esters (13-18) using the
complex 12 in water or an aqueous/organic biphasic
was carried out in H
phasic system (entry 4). In H
2
O-MeOH-AcOEt ) 0.6:0.4:1 bi-
O-MeOH ) 3:2 homoge-
medium at room temperature under H
2
pressure (5 atm)
2
(eq 2) are listed in Table 2. The hydrogenation of 13
neous system, the ee value was 94% (entry 5). In this
case, the product could be extracted with AcOEt after the
reaction and the catalyst phase was separated by a
simple phase separation. The hydrogenation of 14 bear-
2
proceeded smoothly in H O and the enantiomeric excess
(
(
88% ee) was higher than in the case of the complex 3
entry 1). Moreover, complete enantioselectivity (99.9%
ee) could be achieved in the presence of SDS as an
amphiphile (entry 2). This ee value was much higher
than that obtained by monosaccharide chiral ligands
ing a carboxylic acid group also proceeded both in H
MeOH-AcOEt ) 0.6:0.4:2 and in H O-MeOH ) 3:2 with
96% ee and 95% ee, respectively (entries 6 and 7). Several
2
O-
2

Novel Bisphosphinite Chiral Ligands
J . Org. Chem., Vol. 64, No. 15, 1999 5597
dehydroamino acid derivatives (15-17) were effectively
hydrogenated with good enantioselectivities (90-98% ee)
under homogeneous and heterogeneous conditions (en-
tries 8-13). Since the compound 18 was quite soluble in
water, the reaction proceeded completely in water within
was recrystallized from methanol/ethanol and dried under
vacuum. Pure compound 9 (1.8 g, 5.4 mmol, 36%) was obtained
as a white solid. NMR data were consistent with those of the
reported ones.
2
,3:4,6-Di-O-cycloh exylid en e-â-D-glu cop yr a n osyl-(1,1)-
,6-O-cycloh exylid en e-â-D-glu cop yr a n osid e (10). To the
compound 9 (0.51 g, 1.5 mmol) in dry DMF (10 mL) were added
,1-dimethoxycyclohexane (1.0 g, 6.9 mmol) and a catalytic
4
1
8
.5 h even in the absence of methanol as a cosolvent with
0% ee (entry 14). The reason for the high selectivity and
1
the high reactivity observed in asymmetric hydrogenation
using the catalyst 12 in water or aqueous solvent without
surfactant might be ascribed to a high solubility as well
as an ability of effective micelle formation of 12 in water.
amount of p-toluenesulfonic acid, and the mixture was stirred
at 80 °C for 4 h. If necessary, more 1,1-dimethoxycyclohexane
was added. After the mixture was cooled, solid NaHCO was
3
added to quench the reaction. Solvent was removed under
vacuum. The resulting crude syrup was dissolved in dry
pyridine (15 mL), and then acetic anhydride (5 mL) was added.
This solution was stirred overnight and then poured into ice-
Su m m a r y
water. The product was extracted with CHCl
layer was washed successively with aqueous CuSO
saturated aqueous NaCl, and dried over MgSO . The solvent
was evaporated under vacuum, and the residue was subjected
to column chromatography on SiO
3
, and the organic
We successfully prepared the novel disaccharide chiral
ligands 2, 5, and 11 from natural reserve sugars. The
water-soluble cationic Rh complexes 3 and 12 possessing
free poly-hydroxy groups could be synthesized by the
reaction of [Rh(cod)(acac)] with the ligands 2, 5, and 11
derived from R,R- or â,â-trehalose, followed by treatment
4
and
4
2
with petroleum ether-
AcOEt (v/v ) 8:3) as an eluent to give crude 2,3:4,6-di-O-
cyclohexylidene-â-D-glucopyranosyl-(1,1)-4,6-O-cyclohexylidene-
2
,3-di-O-acetyl-â-D-glucopyranoside. To a solution of this
4
with 40% aqueous HBF . These complexes were effective
compound in methanol (10 mL) was added K CO (0.1 g, 0.7
2
3
catalysts for the hydrogenation of dehydroamino acids
and their esters in water or an aqueous/organic biphasic
medium with high enantiomeric excesses (up to 99.9%
ee). In the present biphasic system, the catalysts are
immobilized in the aqueous phase. The catalyst could be
recovered by simple phase separation. The aqueous
catalyst phase could be reused for further operation in
hydrogenation to give almost the same enantiomeric
excesses. These results show that origosaccharides are
applicable to the synthesis of water-soluble chiral ligands.
Although the addition of MeOH as a cosolvent to the
biphasic system was required, the highest enantiomeric
excess (98% ee), which has never been accomplished in
an aqueous medium using other water-soluble chiral
ligands, could be obtained.
mmol), and the mixture was stirred for 1 h. The solvent was
evaporated under vacuum and the residue was subjected to
column chromatography on SiO
(v/v ) 1:1) as an eluent to give 10 (0.28 g, 0.48 mmol, 32%) as
2
with petroleum ether-AcOEt
2
4
a white solid: mp 157.2-157.3 °C; [R] ) -43.5° (c ) 0.5,
D
1
CHCl
3
); H NMR (400 Mz, CDCl
3
) δ 1.30-2.40 (m, 30H), 3.31
(
3
1
m, 2H), 3.42 (t, J ) 8.5 Hz, 1H), 3.54 (t, J ) 8.0 Hz, 1H),
.59-3.72 (m, 3H), 3.82-3.97 (m, 5H), 4.72 (d, J ) 6.9 Hz,
H), 5.00 (d, J ) 8.0 Hz, 1H) ppm; 13C NMR (100 Mz, CDCl
3
)
δ 22.5, 22.7, 22.8, 23.5, 24.9, 25.5, 27.7, 27.8, 35.8, 36.1, 37.7,
3
9
7.8, 61.1, 61.3, 68.0, 70.4, 71.6, 71.8, 73.7, 73.9, 98.6, 99.8,
9.9, 100.0, 113.1 ppm; IR (KBr) 1100, 3484 cm ; HRMS
-1
+
(FAB) calcd for C H47O11 (M+H ) 583.3118, found 583.3109.
3
0
A Typ ica l P r oced u r e for Syn th esis of a Dip h en ylp h os-
p h in ite Com p ou n d . To a solution of 1 (0.23 g, 0.5 mmol) and
a catalytic amount of 4-(dimethylamino)pyridine in 2 mL of
degassed THF/Et N (v/v ) 1:1) was added chlorodiphenylphos-
3
phine (0.2 mL, 1.1 mmol) at room temperature, and the
mixture was stirred for 15 min. The mixture was concentrated
to dryness and the residue was subjected to column chroma-
Exp er im en ta l Section
Gen er a l. Tetrahydrofuran (THF) and diethyl ether were
distilled from sodium benzophenone ketyl under argon. Dichlo-
romethane, N,N-dimethylformamide (DMF), and triethylamine
were distilled from calcium hydride. NMR spectra were
tography on Al
2
O
3
2 2
with degassed hexane-CH Cl (v/v ) 1:2)
as an eluent to give 2,3:4,6-di-O-isopropylidene-R-D-glucopy-
ranosyl-(1,1)-4,6-O-isopropylidene-2,3-di-O-diphenylphosphino-
R-D-glucopyranoside (2) (0.27 g, 0.32 mmol, 63%) as a white
measured for solutions in CDCl
3
, d
4
-MeOH, or d
8
-THF with
2
D
4
1
1
13
solid: mp 86.5-86.8 °C; [R] ) + 59.4° (c ) 0.27, CHCl
3
); H
) δ 0.92 (s, 3H), 1.11 (s, 3H), 1.39 (s, 3H),
.46 (s, 3H), 1.49 (s, 3H), 1.53 (s, 3H), 3.5-3.8 (m, 7H), 3.92
t, J ) 9.3 Hz, 1H), 4.0-4.1 (m, 2H), 4.18 (t, J ) 9.3 Hz, 1H),
Me
4
Si as an internal standard ( H and C) or with P(OMe)
3
3
1
NMR (400 Mz, CDCl
3
as an external standard ( P). Melting points are uncorrected.
Elemental analyses were performed at Microanalytical Center
of Kyoto University. R,R-Trehalose dihydrate was purchased
from Hayashibara Corporation. Pentaacetyl-â-D-glucopyrano-
side was purchased from Tokyo Chemical Industry Co, Ltd.
â-D-Glu cop yr a n osyl-(1,1)-â-D-glu cop yr a n osid e (â,â-tr e-
h a lose) (9). This compound was prepared by the modified
1
(
4
1
1
7
.45 (m, 1H), 5.14 (d, J ) 2.3 Hz, 1H), 5.30 (d, J ) 2.4 Hz,
H), 7.0-7.6 (m, 20H) ppm; 13C NMR (100 Mz, CDCl
) δ 17.9,
3
9.2, 26.2, 26.8, 28.6, 28.9, 61.9, 62.2, 63.8, 66.1, 73.6, 73.7,
6.5, 77.6 (dd, J ) 5.5, 12.9 Hz), 80.1 (dd, J ) 3.7, 20.2 Hz),
1
2
94.7, 96.0 (d, J ) 5.6 Hz), 99.3, 99.4, 111.8, 127.7-130.9 (12
procedure of Brown et al. The phenyl 2,3,4,6-tetra-O-acetyl-
-thio-â-D-glucose (6.6 g, 15 mmol) and alcohol 8 (5.2 g, 15
mmol) were dissolved in dry CH Cl under argon, and N-
carbons), 140.5 (d, J ) 16.5 Hz), 142.0 (d, J ) 22.0 Hz), 142.6
1
(
d, J ) 12.9 Hz), 143.6 (d, J ) 20.2 Hz) ppm; 31P NMR (161.9
1
2
2
-
Mz, CDCl ) δ 111.9, 115.1 ppm; IR (KBr) 1434 cm ; HRMS
3
iodosuccinimide (3.8 g, 17 mmol) and pulverized MS4A (5 g)
were added to the solution. A solution of trifluoromethane-
sulfonic acid in CH Cl (ca. 0.15 M) was added dropwise to
2 2
this solution until TLC indicated that the substrate had been
consumed. After filtration through a Celite pad, the solution
+
(FAB) calcd for C45
H
52
O
11
P
2
M
830.2985, found 830.2969.
C, 65.05; H, 6.31; P, 7.46.
Anal. Calcd for C45
H
52
O
11
P
2
:
Found: C, 65.33; H, 6.38; P, 7.12.
2,3:4,6-Di-O-cycloh exylid en e-â-D-glu cop yr a n osyl-(1,1)-
4,6-O-cycloh exylid en e-2,3-d i-O-d ip h en ylp h osp h in o-â-D-
glu cop yr a n osid e (11). 65% yield, a white solid; mp 116.1-
was washed with aqueous NaHCO
Na and dried over MgSO . The solvent was evaporated
under vacuum and the residue was subjected to column
chromatography on SiO with CHCl -AcOEt (v/v ) 1:1) as an
eluent to give a crude octaacetyl â,â-trehalose. To this crude
product was added a small amount of Et O to precipitate a
3
followed by aqueous
2
S
2
O
3
4
2
D
4
1
116.2 °C; [R] ) -38.5° (c ) 0.24, CHCl
3
); H NMR (400 Mz,
2
3
CDCl ) δ 0.60-2.20 (m, 30H), 2.61 (t, J ) 9.3 Hz, 1H), 3.03
3
(dt, J ) 4.9, 9.3 Hz, 1H), 3.33 (dt, J ) 5.8, 10.4 Hz, 1H), 3.42
(t, J ) 9.3 Hz, 1H), 3.50 (t, J ) 9.3 Hz, 1H), 3.57 (t, J ) 9.3
Hz, 1H), 3.67 (t, J ) 10.4 Hz, 1H), 3.77-3.82 (m, 2H), 3.86
(dd, J ) 5.8, 10.4 Hz, 1H), 4.24-4.28 (m, 2H), 4.78 (d, J ) 9.3
Hz, 1H), 4.93 (d, J ) 7.3 Hz, 1H), 7.01-7.52 (m, 20H) ppm;
2
pure octaacetyl â,â-trehalose (3.9 g, 5.7 mmol). To methanolic
NaOMe (2.6 mL, 0.1 M) was added a solution of octaacetyl
â,â-trehalose in hot methanol, and this solution was refluxed
for 15 min. The solvent was removed under vacuum. The solid
1
3
C NMR (100 Mz, CDCl ) δ 22.1, 22.4, 22.7, 23.5, 25.0, 25.4,
3

5
598 J . Org. Chem., Vol. 64, No. 15, 1999
Yonehara et al.
2
7
2
5.5, 26.4, 28.0, 35.8, 36.2, 37.4, 37.7, 61.2, 67.0, 69.6, 71.4,
1.7, 76.5, 77.2, 82.9 (dd, J ) 3.7, 23.9 Hz), 83.1 (dd, J ) 5.5,
0.2 Hz), 96.4, 96.8, 99.7, 99.8, 112.5, 127.6-131.5 (12
A Typ ica l P r oced u r e for th e Hyd r ogen a tion of Deh y-
d r oa m in o Acid s in a n Aqu eou s/Or ga n ic Med iu m . H
2
O-
MeOH-AcOEt System . The Rh complex 3 [or 12] (1.5 mg,
-
2
carbons), 142.3 (d, J ) 11.1 Hz), 142.5 (d, J ) 11.0 Hz), 143.9
0.15 × 10 mmol) was dissolved in H O-MeOH ) 3:2 solution
2
3
1
(
d, J ) 11.0 Hz), 144.6 (d, J ) 9.2 Hz) ppm; P NMR (161.9
(
1.0 mL), and the solution was injected to a stainless steel
-
1
Mz, CDCl ) δ 109.9, 115.5 ppm; IR (KBr) 1435 cm ; HRMS
(
3
autoclave with glass container by a syringe under Ar. To this
solution was added a solution of the substrate (0.15 mmol) in
AcOEt (1.0-2.0 mL) by a syringe under Ar, and the mixture
+
FAB) calcd for C54
H
H
64
O
11
P
2
M
:
950.3924, found 950.3931.
C, 68.20; H, 6.78; P, 6.51.
Anal. Calcd for C54
Found: C, 68.29; H, 7.00; P, 6.52.
A Typ ica l P r oced u r e for Syn th esis of a Wa ter -Solu ble
Rh Com p lex. [Rh(acac)(cod)] (15.5 mg, 0.05 mmol) and 2 (41.5
mg, 0.05 mmol) [or 5 (47.6 mg, 0.05 mmol)] were dissolved in
degassed dry THF (1.0 mL) and the mixture was stirred under
64
O
11
P
2
2
was stirred vigorously under H pressure (5 atm). After the
1
end of the reaction was confirmed by GLC, TLC, or H NMR,
the organic phase was separated by decantation and the
solvent was evaporated under vacuum to give the product (85-
9
3% yield). The enantiomeric excess was determined by HPLC
Ar. After 20 min, 40% aqueous HBF
and the mixture was stirred at 50 °C for 4 h. Degassed dry
Et O (5.0 mL) was added, and the complex was separated out
as an orange syrup. The supernatant solution was decanted,
and degassed dry Et O (5.0 mL) was again added to the
obtained syrup. The product, [Rh(R-D-glucopyranosyl-(1,1)-2,3-
di-O-diphenylphosphino-R-D-glucopyranoside)(cod)]BF (3), was
crystallized as an orange powder (36.0-38.0 mg, 0.036-0.038
4
was added to the solution
using either a Daicel Chiralcel OD or OJ column (4.6 × 250
mm) at 40 °C.
2
2
H O-MeOH System . To the Rh complex 3 [or 12] (1.5 mg,
-
2
0.15 × 10 mmol) and substrate (0.15 mmol) in a stainless
steel autoclave with glass container was added a H O-MeOH
) 3:2 solution (2.0 mL) by a syringe under Ar, and the mixture
was stirred vigorously under H pressure (5 atm). After the
2
2
4
2
3
1
1
mmol, 72-76%): P NMR (161.9 MHz, d
4
-MeOH) δ 131.0 (dd,
end of the reaction was confirmed by GLC, TLC, or H NMR,
1
2
1
J (Rh, P) ) 180 Hz, J (P, P) ) 28 Hz), 138.7 (dd, J (Rh, P)
AcOEt (1.5 mL) and H O (0.5 mL) were added and the mixture
2
2
+
)
BF
180 Hz, J (P, P) ) 28 Hz) ppm; LRMS (FAB) m/z 921 (M -
).
R h (â-D-glu cop yr a n osyl-(1,1)-2,3-d i-O-d ip h en ylp h os-
was stirred vigorously for 10 min. The organic phase was
separated by decantation and the solvent was evaporated
under vacuum to give the product (80-90% yield). The
enantiomeric excess was determined by HPLC using either a
Daicel Chiralcel OD or OJ column (4.6 × 250 mm) at 40 °C.
4
[
3
1
4
p h in o-â-D-glu cop yr a n osid e)(cod )]BF (12). P NMR (161.9
MHz, d
Hz), 132.5 (dd, J (Rh, P) ) 177 Hz, J (P, P) ) 24 Hz) ppm;
LRMS (FAB) m/z 921 (M -BF
1
2
8
-THF) δ 131.6 (dd, J (Rh, P) ) 177 Hz, J (P, P) ) 24
1 2
+
4
).
J O990448M