Asymmetric hydrogenation of enamides in aqueous media with a new water-soluble chiral rhodium-α,α-trehalose-derived phosphine-phosphinite catalyst

Article abstract of DOI:10.1016/S0957-4166(02)00569-4

A new chiral rhodium catalyst with α,α-trehalose-derived phosphine-phosphinite (α,α-TREHAPPN) ligand, [(TREHAPPN)Rh(cod)]BF₄ 8 has been prepared. This catalyst is soluble in water and is an effective chiral catalyst for asymmetric hydrogenation

Full text of DOI:10.1016/S0957-4166(02)00569-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2155–2160
Asymmetric hydrogenation of enamides in aqueous media with a
new water-soluble chiral rhodium-a,a-trehalose-derived
phosphine–phosphinite catalyst
Kouichi Ohe,* Kiyoharu Morioka, Koji Yonehara and Sakae Uemura*
Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Sakyo-ku,
Kyoto 606-8501, Japan
Received 21 August 2002; accepted 11 September 2002
Abstract—A new chiral rhodium catalyst with a,a-trehalose-derived phosphine–phosphinite (a,a-TREHAPPN) ligand, [(TRE-
HAPPN)Rh(cod)]BF4 8 has been prepared. This catalyst is soluble in water and is an effective chiral catalyst for asymmetric
hydrogenation of N-acyldehydroamino acids in aqueous media to give enantiomerically enriched a-amino acid derivatives with R
configuration. The simple decantation allows retrieval of the catalyst from the reaction mixture, the recovered catalyst being
re-used without marked loss of enantioselectivity. © 2002 Elsevier Science Ltd. All rights reserved.
catalysts bearing 1a and 1b as ligands allows the cata-
lytic reaction to be completed under aqueous conditions
and recycling of the catalyst by decantation after one
cycle. On the other hand, diphosphine 2, also prepared
from a,a-trehalose, is less soluble in water despite hav-
ing the same number of hydroxy moieties in this
molecule like 1a and 1b.7 Thus, its applicability was
restricted to non-aqueous conditions. Our continuous
efforts to prepare new water-soluble ligands have been
based upon the use of a,a-trehalose as a readily avail-
able chiral source, and herein, we wish to report a new
water-soluble ligand, 2-(diphenylphosphino)-2-deoxy-3-
O-(diphenylphosphino)trehalose 3 derived from a,a-
trehalose. This approach widens the utility of a,a-tre-
halose as a chiral source with a hydrophilic function,
and allows the synthesis of (R)-a-amino acids from
enamides by rhodium-catalyzed asymmetric hydrogena-
tion in aqueous media. Additionally, catalyst recovery
and re-use is possible.
1. Introduction
The enantioselective hydrogenation of N-acyl-
dehydroamino acids and their esters constitutes a stan-
dard tool for the synthesis of optically active amino
acids. In particular, rhodium catalysis has been well
investigated, and a plethora of efficient chiral ligands
has been developed for this purpose.1 While the major-
ity of the development in this area involves bidentate
phosphine, phosphite, and phosphinite ligands, or
mixed phosphine–phosphite2 ligands, the corresponding
phosphine–phosphinite ligands have only rarely been
exploited.3 A wide range of carbohydrate-derived phos-
phinites and phosphines have been prepared and suc-
cessfully applied to homogeneous catalysis in several
enantioselective syntheses.4,5 On the basis of our studies
pursuing water-soluble and recyclable chiral catalysts,
we have developed carbohydrate scaffolding phospho-
rus ligands.6 We found that diphosphinite ligand 1a
(a,a-TREHAP), derived from the naturally occurring
disaccharide a,a-trehalose, is an effective ligand for
rhodium-catalyzed enantioselective hydrogenation of
enamides in aqueous media (Scheme 1).6a,b We also
demonstrated that the analogous diphosphinite 1b
(1b,1%b-anomer, b,b-TREHAP) prepared from b,b-tre-
halose was a much more effective ligand than com-
2. Results and discussion
A preparative method for the novel water-soluble
rhodium complex 8, having an a,a-trehalose-derived
phosphine–phosphinite ligand 3 is shown in Scheme 2.
Initially, partial protection of the 4,6:2%,3%:4%,6%-positions
of a,a-trehalose with isopropylidene followed by purifi-
cation (acylation and hydrolysis) provided 2,3:4,6-di-O-
pound
1a
for
the
same
enantioselective
hydrogenation.6a,b The high water-solubility of rhodium
isopropylidene-a-
D-glucopyranosyl-(1,1)-4,6-O-isopropyl-
* Corresponding authors.
idene-a-
D
-glucopyranoside 48 in 35% yield. In the sec-
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00569-4

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K. Ohe et al. / Tetrahedron: Asymmetry 13 (2002) 2155–2160
Scheme 1. Diphosphinite 1a, 1b, diphosphine 2, and phosphine–phosphinite 3 derived from a,a-trehalose.
Scheme 2. Reagents and conditions: (a) (i) Me2C(OMe)2, cat. p-TsOH·H2O, DMF, 90°C, 48 h; (ii) Ac2O, C5H5N, rt, 8 h, 44% (two
steps); (iii) K2CO3, MeOH, rt, 1 h, 80%. (b) MsCl, C5H5N, rt, 24 h, 92%. (c) Na/EtOH–2-PrOH, acetone, 10°C, 16 h, 75%. (d)
KPPh2, THF, rt, 2 h, 60%. (e) Ph2PCl, cat. DMAP, Et3N–THF, rt, 15 min, 47%. (f) (i) [Rh(acac)(cod)], THF, rt, 15 min; (ii) 40%
aqueous HBF4, rt, 1 h, 51% (two steps).
phosphino)-a- -altropyranoside)(cod)]BF4 8 bearing six
D
ond step of the synthesis, mesylation of 4 with MsCl
(MeSO2Cl) gave 2,3:4,6 - di - O - isopropylidene - a -
glucopyranosyl - (1,1) - 4,6-O-isopropylidene-2,3-di-O-
mesyl-a- -glucopyranoside 5 in 92% yield. Treatment
of 5 with Na/EtOH–iPrOH9 gave 2,3:4,6-di-O-iso-
propylidene-a- -glucopyranosyl-(1,1)-2,3-anhydro-4,6-
O-isopropylidene-a-
-allopyranoside 610 in 75% yield
free hydroxy groups in 51% yield. In the 31P NMR
spectrum of 8 resonance peaks of the two phosphorus
nuclei as a doublet of doublet [l 19.2 (dd, JP–P=49,
D
-
D
JP–Rh=147 Hz) and 120.5 (dd, JP–P=49, JP–Rh=165
Hz) ppm] show that the phosphine–phosphinite 3 coor-
dinates to rhodium in a bidentate fashion. Gratifyingly,
complex 8 has good solubility in water (ca. 1 g/100 mL
at 20°C) and polar organic solvents such as methanol,
dichloromethane, 1,2-dichloroethane, and THF, while
it is less soluble in non-polar organic solvents such as
hexane or toluene.
D
D
and ring-opening of the epoxide moiety of 6 with
KPPh2 in tetrahydrofuran (THF) afforded 2,3:4,6-di-O-
isopropylidene - a -
propylidene-2-(diphenylphosphino)-2-deoxy-a-
pyranoside 711 in 60% yield. Reaction of 7 with Ph2PCl
then gave 2,3:4,6-di-O-isopropylidene-a- -glucopyran-
osyl-(1,1)-4,6-O-isopropylidene-2-(diphenylphosphino)-
-altropyranoside
D
- glucopyranosyl - (1,1) - 4,6 - O - iso-
D
-altro-
D
Asymmetric hydrogenation of methyl (Z)-a-acetami-
docinnamate 9a as a test substrate was carried out
using the water-soluble rhodium complex 8. The effects
of different reaction parameters, such as solvent and
hydrogen pressure, on the efficiency of the catalyst were
investigated. The results are summarized in Table 1.
Enantioselective hydrogenation proceeded under atmo-
2-deoxy-3-O-(diphenylphosphino)-a-
D
3% in 47% yield. Finally, the reaction of 3% with
[Rh(acac)(cod)] followed by treatment with 40%
12
aqueous HBF4
afforded [Rh(a-D-glucopyranosyl-
(1,1)-2-(diphenylphosphino)-2-deoxy-3-O-(diphenyl-

K. Ohe et al. / Tetrahedron: Asymmetry 13 (2002) 2155–2160
Table 1. Enantioselective hydrogenation of enamides 9a using a catalyst 8a
2157
Entry
Solvent
8 (mol%)
H2 (atm)
Time (h)
Conv. (%)
ee (%)b
1
2
3
4
5
6
7
8
9
THF
1
1
1
1
2.5
2.5
2.5
2.5
1
1
1
1
50
10
30
50
70
50
50
4
1
0.5
2
24
24
24
24
77
100
100
88
63
37
69
33
–
CH2Cl2
ClCH2CH2Cl
ClCH2CH2Cl
H2O
H2O
H2O
H2O
MeOH
H2O–AcOEt (1:1)
0
100
100
100
100
100 (100)d
13
72
62
50
9
10
2
12 (24)c
73 (70)d
a Reaction conditions: 9a (0.1 mmol), solvent (2 mL) at room temperature.
b Enantiomeric excess of methyl N-acetylphenylalanate with (R)-configuration was determined by HPLC.
c Reaction time in the second cycle using recovered aqueous phase containing the catalyst.
d The value obtained from the second cycle.
spheric pressure of hydrogen in THF, dichloromethane,
and 1,2-dichloroethane to give (R)-methyl N-
acetylphenylalanate with moderate enantioselectivities
(37–69% ee, entries 1–3). Both the enantioselectivity
and activity of the hydrogenation in 1,2-dichloroethane
diminished when the hydrogen pressure was raised from
1 to 50 atm (entry 4). The hydrogenation of 9a was
sluggish in H2O, no hydrogenated product being
obtained at hydrogen pressures below 10 atm (entry 5).
Interestingly, both the enantioselectivity and activity
were notably enhanced when the hydrogen pressure was
raised from 10 to 30 and 50 atm, respectively [13% ee
(30 atm) and 72% ee (50 atm)] (entries 6 and 7). This
contrasts with the usual decrease in enantioselectivity
observed with bidentate ligands when the hydrogen
pressure is raised.13,14 Much higher pressure of H2 (70
atm), on the other hand, decreased the enantioselectiv-
ity (62% ee, entry 8). Hydrogenation in MeOH instead
of H2O proceeded more smoothly and was complete
within 9 h, but the enantioselectivity was lower (50%
ee) than that in H2O (entry 9). This result is in sharp
contrast with the fact that the rhodium complexes with
ligands 1a,b afforded the best enantioselectivity when
MeOH was used as a solvent or a cosolvent.6a In a
biphasic system (1:1 H2O–AcOEt), the reaction also
took place to give the product with 73% ee (entry 10).
In these aqueous systems, after the reaction was com-
plete, the organic phase including the product was
easily separated by decantation. The recovered aqueous
phase containing the catalyst could be re-used in the
second cycle hydrogenation to give almost the same
enantiomeric excess (70% ee), although the prolonged
reaction time (24 h) was required. In the third cycle,
both enantioselectivity and activity for the hydrogena-
tion were diminished, probably due to the catalyst
decomposition (63% conv., 50% ee after 72 h).15
Next, the asymmetric hydrogenation of several N-
acyldehydroamino acids and their esters 9b–g was car-
ried out in H2O or a mixed solvent of H2O and EtOAc
under H2 (50 atm). The results are shown in Table 2.
Hydrogenation of enamides (entries 1–4) in a biphasic
system (1:1 H2O–AcOEt) under identical conditions to
those used for methyl (Z)-a-acetamidocinnamate gave
the corresponding a-amino acid derivatives in good
yield with fair to good enantioselectivities (50–67% ee).
The addition of MeOH was required for the hydro-
genation of dehydro N-acetyl-3-(1-naphthyl)alanine
methyl ester 9e because of the low solubility of the
substrate in H2O–EtOAc (entry 4). Hydrogenation of
a-N-acetamidoacrylic acid 9f and its methyl ester 9g
took place in aqueous media but with very low enan-
tioselectivity for each substrate (entries 5 and 6).
Results summarized in Tables 1 and 2 show that the
catalyst 8 having a (2S,3R)-2-deoxyaltropyranoside
backbone provides a-amino acids with R configuration
predominantly. In general, one of the perceived limita-
tions of natural products as chiral sources is the
scarcity of one of the enantiomers. Thus, it is worth
noting that the present transformation to the catalyst 8
from a,a-trehalose complementarily compensates for
the reverse selectivity of our previous catalyst having 1a
as a ligand16 in asymmetric hydrogenation of enamides.
In the previous study, we have found that some surfac-
tants notably enhance the enantioselectivity in the
hydrogenation of enamides and itaconic acid in water
using rhodium catalysts involving ligands 1a,b.6b There-
fore, we examined the effect of surfactants, such as
sodium dodecyl sulfate (SDS), cetyltrimethylammo-
nium hydrogensulfate (CTA–HSO4), and Brij 58 on
enantioselectivity in hydrogenation of 9a in water using

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K. Ohe et al. / Tetrahedron: Asymmetry 13 (2002) 2155–2160
Table 2. Enantioselective hydrogenation of enamides 9 using catalyst 8a
Entry
9
R1
R2
Solvent
Conv. (%)
ee (%)b
Config.c
1
2
3
4
5
6
b
c
d
e
f
Ph
H
H2O–EtOAc (1:1)
H2O–EtOAc (1:1)
H2O–EtOAc (1:1)
H2O–MeOH–EtOAc (0.6:0.4:1)
H2O
100
71
100
100
100
100
50d
66
67
R
R
R
R
R
R
4-MeOC6H4
3-ClC6H4
1-Naphthyl
H
Me
Me
Me
H
51
10d
18
g
H
Me
H2O–EtOAc (1:1)
a Reaction conditions: enamide (0.1 mmol), catalyst 8 (0.2×102 mmol), H2 (50 atm), solvent (2 mL), rt, 24 h.
b Determined by HPLC.
c Determined by comparing with authentic samples.
d Determined as its methyl ester.
the catalyst 8. Each surfactant accelerated the rate of
hydrogenation, but the observed enantioselectivities
were lower (0% ee with SDS, 5% ee with CTA–HSO4,
and 21% ee with Brij 58) than in the absence of
surfactants.
except for an N-acetylalanine methyl ester. Melting
points are uncorrected. Mass spectra (FAB LRMS or
HRMS) were obtained with a JEOL JMX-SX 102A
spectrometer. 2,3:4,6-Di-O-isopropylidene-a-
D-glucopy-
-glucopyran-
ramosyl-(1,1)-4,6-O-isopropylidene-a-
D
oside 4 was prepared according to the reported
procedure.8 a,a-Trehalose dihydrate was purchased
from Hayashibara Corporation.
In conclusion, we have developed a novel water-soluble
cationic rhodium complex 8 having a phosphine–phos-
phinite (a,a-TREHAPPN) ligand derived from a,a-tre-
halose. This complex was found to be an effective
catalyst for the enantioslective hydrogenation of dehy-
droamino acids and their esters in aqueous media. Since
the catalyst can be immobilized in the aqueous phase,
the aqueous phase containing the catalyst can be recov-
ered by simple phase separation and re-used for the
next cycle. We have also demonstrated that the ligand
3, derived from a,a-trehalose, afforded unnatural types
of a-amino acid derivatives with the opposite sense of
enantioselectivity to ligand 1.
3.2. 2,3:4,6-Di-O-isopropylidene-a-D-glucopyranosyl-
(1,1)-4,6-O-isopropylidene-2,3-di-O-mesyl-a-D-glucopy-
ranoside, 5
To a solution of 4 (0.90 g, 1.95 mmol) in pyridine (50
mL) was added methanesulfonyl chloride (0.56 g, 4.85
mmol) at 0°C, and the mixture was stirred at room
temperature for 24 h. The reaction mixture was poured
into ice-water (50 mL) and extracted with CHCl3 (3×50
mL). The organic layer was dried over MgSO4. The
solvent was removed under vacuum and the orange
residue was subjected to column chromatography on
SiO2 with hexane–EtOAc (v/v=1:1) as an eluent to give
the title compound 5 (1.11 g, 1.79 mmol, 92%) as a
white solid: mp 102.0–103.0°C; [h]2D3=+103.0 (c 0.5,
3. Experimental
3.1. General
1
CHCl3); H NMR (400 MHz, CDCl3) l 1.42 (s, 3H),
Tetrahydrofuran (THF) and diethyl ether were distilled
from sodium benzophenone ketyl under argon.
Dichloromethane, triethylamine, and N,N-dimethylfor-
mamide were distilled from calcium hydride. Methanol
was distilled over Mg(OMe)2. Analytical thin-layer
chromatographies (TLC) were performed with silica gel
60 Merck F-254 plates or aluminum oxide 60 Merck
F-254. Column chromatographies were performed with
Merck silica gel 60 or ICN Alumina Akt I (neutral).
NMR spectra were measured on JEOL EX-400, AL-
300, and JNM-GSX-270 spectrometers for solutions in
CDCl3 or CD3OD with Me4Si as an internal standard
(1H and 13C) or with P(OMe)3 as an external standard
(31P): the following abbreviations are used; s: singlet, d:
doublet, t: triplet, q: quartet, m: multiplet. Optical
rotations were recorded at 589 nm. Enantiomeric ratios
were determined by HPLC with Daicel Chiralcel OJ or
OD column (4.6×250 mm) (at 254 or 210 nm) at 40°C
1.46 (s, 3H), 1.49 (s, 3H), 1.50 (s, 3H), 1.51 (s, 3H), 1.54
(s, 3H), 3.12 (s, 3H), 3.19 (s, 3H), 3.57 (dd, J=2.9, 9.3
Hz, 1H), 3.70–3.86 (m, 4H), 3.89–4.05 (m, 4H), 4.14 (t,
J=9.3 Hz, 1H), 4.67 (dd, J=3.9, 9.8 Hz, 1H), 4.88 (t,
J=9.8 Hz, 1H), 5.36 (d, J=2.9 Hz, 1H), 5.40 (d, J=3.9
Hz, 1H); 13C NMR (67.5 MHz, CDCl3) l 19.2, 19.3,
26.1, 26.8, 28.9, 38.8, 38.8, 61.8, 61.9, 63.7, 66.3, 72.0,
73.3, 73.7, 75.1, 76.2, 77.8, 94.4, 94.6, 99.6, 100.0, 111.9
ppm. HRMS (FAB) calcd for C23H39O15S2 (M+H+):
619.1730. Found: 619.1719.
3.3. 2,3:4,6-Di-O-isopropylidene-a-D-glucopyranosyl-
(1,1)-2,3-anhydro-4,6-O-isopropylidene-a-D-allopyran-
oside, 6
To a solution of 5 (1.11 g, 1.79 mmol) in acetone (50
mL) was added a mixture of sodium alkoxides gener-
ated from Na (0.23 g, 10 mmol) in 2-PrOH and EtOH

K. Ohe et al. / Tetrahedron: Asymmetry 13 (2002) 2155–2160
2159
(v/v=3:1, 40 mL) at 10°C. The mixture was stirred at
the same temperature for 16 h. After removing the
solvent under vacuum, water (20 mL) was added and
then the product was extracted with CHCl3 (3×20 mL).
The organic layer was dried over MgSO4. The solvent
was removed under vacuum and the orange residue was
subjected to column chromatography on SiO2 with
petroleum ether–EtOAc (v/v=3:2) as an eluent to give
the title compound 6 (0.60 g, 1.35 mmol, 75%) as a
white solid: mp 76.4–77.5°C; [h]2D3=+73.8 (c 0.5,
stirred at room temperature for 15 min under Ar. The
solvent was removed under vacuum, and the white
residue was subjected to column chromatography on
Al2O3 with CHCl3 as an eluent to give the title com-
pound 3% (0.069 g, 0.085 mmol, 47%) as a white solid:
mp 90.3–92.0°C; [h]2D3=+40.4 (c 0.25, CHCl3); 1H
NMR (400 MHz, CDCl3) l 0.98 (s, 3H), 1.07 (s, 3H),
1.37 (s, 3H), 1.44 (s, 3H), 1.53 (s, 3H), 1.54 (s, 3H), 3.25
(s, 1H), 3.29–3.34 (m, 1H), 3.39 (dd, J=4.9, 10.5 Hz,
1H), 3.49 (dd, J=3.2, 9.0 Hz, 1H), 3.63 (t, J=10.5 Hz,
1H), 3.72 (t, J=10.5 Hz, 1H), 3.82–3.89 (m, 2H),
4.06–4.10 (m, 2H), 4.29 (m, 1H), 4.46 (m, 1H), 4.84 (d,
J=6.8 Hz, 1H), 5.33 (d, J=2.9 Hz, 1H), 7.13–7.71 (m,
20H); 13C NMR (75 MHz, CDCl3) l 19.2, 19.2, 26.1,
26.8, 28.5, 29.2, 59.4, 60.0, 62.0, 62.3, 65.5, 70.0 (d,
J=4.4 Hz), 73.7, 74.0, 76.3, 77.2, 92.2, 93.4, 94.0 (d,
J=24.9 Hz), 99.7, 111.6, 127.8–135.6 (22 carbons),
143.7, 143.9; 31P NMR (161.9 Hz, CDCl3) l −18.3,
117.9 ppm. HRMS (FAB) calcd for C45H53O10P2 (M+
H+): 815.3114. Found: 815.3122.
1
CHCl3); H NMR (400 MHz, CDCl3) l 1.45 (s, 6H),
1.46 (s, 3H), 1.51 (s, 3H), 1.52 (s, 3H), 1.55 (s, 3H), 3.40
(m, 1H), 3.48 (dd, J=2.9, 9.3 Hz, 1H), 3.54 (dd, J=2.9,
9.3 Hz, 1H), 3.63–3.72 (m, 2H), 3.81–3.91 (m, 3H), 3.93
(t, J=9.3 Hz, 1H), 4.00–4.02 (m, 2H), 4.18 (t, J=9.8
Hz, 1H), 5.24 (d, J=2.9 Hz, 1H), 5.44 (d, J=2.9 Hz,
1H); 13C NMR (67.5 MHz, CDCl3) l 18.9, 19.1, 26.2,
26.8, 29.0, 50.7, 52.8, 61.1, 62.1, 62.3, 65.9, 70.2, 73.4,
73.8, 76.5, 91.0, 94.1, 99.7, 100.0, 111.7 ppm. HRMS
(FAB) calcd for C21H33O10 (M+H+): 445.2074. Found:
445.2061.
3.6. [Rh(a-D-glucopyranosyl-(1,1)-2-(diphenylphosphino)-
3.4. 2,3:4,6-Di-O-isopropylidene-a-
(1,1)-4,6-O-isopropylidene-2-(diphenylphosphino)-2-
deoxy-a- -altropyranoside, 7
D-glucopyranosyl-
2-deoxy-3-O-(diphenylphosphino)-a-
D
-altropyranoside)-
(1,5-cyclooctadiene)]+BF4 , 8
−
D
[Rh(acac)(cod)] (13.3 mg, 0.043 mmol) and 3% (36 mg,
0.045 mmol) were dissolved in degassed dry THF (1.0
mL) under Ar and the mixture was stirred for 15 min.
Aqueous 40% HBF4 solution (0.2 mL) was added to the
mixture and the reaction mixture was stirred at room
temperature for 1 h. Degassed dry Et2O (30 mL) was
added, and then the yellow solid was precipitated. The
supernatant solution was removed by syringe, and the
title complex 8 (21.8 mg, 0.022 mmol, 51%) was
obtained as yellow crystals: mp 230.0–231.5°C; 31P
To a solution of 6 (0.20 g, 0.45 mmol) in degassed THF
(10 mL) was added dropwise a solution of 0.5 M
potassium diphenylphosphide (1.35 mL, 0.68 mmol) in
THF at −78°C. The mixture was stirred at room tem-
perature for 2 h under Ar. To the reaction mixture was
added NH4Cl (1.0 g) and the mixture was stirred for 0.5
h. After removal of excess NH4Cl insoluble in THF, the
solvent was removed under vacuum, and the residue
was subjected to column chromatography on SiO2 with
CHCl3–AcOEt (v/v=1:3) as an eluent to give the title
compound 7 (0.17 g, 0.27 mmol, 60%) as a white solid:
mp 104.3–106.0°C; [h]2D3=+78.9 (c 0.5, CHCl3); 1H
NMR (270 MHz, CDCl3) l 1.42 (s, 3H), 1.46 (s, 3H),
1.48 (s, 3H), 1.48 (s, 3H), 1.52 (s, 6H), 3.22–3.34 (m,
2H), 3.42–3.53 (m, 2H), 3.66 (t, J=10.7 Hz, 1H),
3.82–3.91 (m, 4H), 4.07 (t, J=9.3 Hz, 1H), 4.17 (m,
2H), 4.87 (d, J=5.5 Hz, 1H), 5.32 (d, J=3.3 Hz, 1H),
7.37–7.87 (m, 10H); 13C NMR (67.5 MHz, CDCl3) l
19.1, 19.2, 26.2, 26.7, 29.0, 29.1, 44.6 (d, J=16.1 Hz),
59.6, 61.8, 62.4, 65.9, 66.9 (d, J=16.1 Hz), 69.6 (d,
J=7.3 Hz), 73.4, 73.7, 75.8, 92.2, 94.0 (d, J=21.8 Hz),
99.6, 99.9, 111.8, 128.8, 128.9, 129.0, 129.0, 129.6,
130.0, 130.6, 130.7, 132.8 (d, J=21.8 Hz), 133.5 (d,
J=21.8 Hz), 134.9 (d, J=13.0 Hz), 135.3 (d, J=14.5
Hz); 31P NMR (161.9 Hz, CDCl3) l −20.5 ppm. HRMS
(FAB) calcd for C33H44O10P (M+H+): 631.2672. Found:
631.2692.
NMR (161.9 Hz, CD3OD) l 19.2 (dd, JP–P=49, JP–Rh
=
147 Hz), 120.5 (dd, JP–P=49, JP–Rh=165 Hz) ppm.
LRMS (FAB) m/z 905 (M+−BF4). HRMS (FAB) calcd
for C44H52O10P2Rh (M+−BF4): 905.2091. Found:
905.2096.
3.7. A typical procedure for the hydrogenation of dehy-
droamino acids in an aqueous/organic medium (H2O–
EtOAc) using the complex 8
The Rh complex 8 (2.0 mg, 0.20×10−2 mmol) was
dissolved in degassed H2O (1.0 mL), and the solution
was injected into a stainless steel autoclave with glass
container by a syringe under Ar. To this solution was
added a solution of methyl a-acetamide (Z)-cinnamate
(21.8 mg, 0.10 mmol) in degassed EtOAc (1.0 mL) by a
syringe under Ar, and the mixture was stirred vigor-
ously under H2 pressure (50 atm). When the reaction
was complete (as confirmed by GLC, TLC, or 1H
NMR) the organic layer was separated by decantation,
and the removal of solvent under vacuum gave the
crude product as a pale yellow oil. Purification of the
crude product by column chromatography on SiO2 with
petroleum ether–EtOAc (v/v=1:10) as eluent gave N-
acetylphenylalanine methyl ester. The enantiomeric
excess was determined by HPLC using a Daicel Chiral-
cel OJ column [1.0 mL/min, 10% 2-PrOH/hexane; (R)
3.5. 2,3:4,6-Di-O-isopropylidene-a-
(1,1)-4,6-O-isopropylidene-2-(diphenylphosphino)-2-
deoxy-3-O-(diphenylphosphino)-a- -altropyranoside, 3%
D-glucopyranosyl-
D
To a solution of 7 (0.11 g, 0.18 mmol), 4-(N,N-
dimethylamino)pyridine (DMAP) (2.0 mg, 0.24 mmol),
and triethylamine (1.0 mL, 7.1 mmol) in degassed THF
(1.0 mL) was slowly added chlorodiphenylphosphine
(0.03 mL, 0.20 mmol) and the reaction mixture was

2160
K. Ohe et al. / Tetrahedron: Asymmetry 13 (2002) 2155–2160
t1=10.0 min, (S) t2=13.0 min]. The separation of
racemic mixtures under HPLC conditions is as follows:
N-acetyl-3-(4-methoxyphenyl)alanine methyl ester (OJ,
1.0 mL/min, 10% 2-PrOH/hexane), (R) t1=16.0 min,
(S) t2=27.5 min; N-acetyl-3-(3-chlorophenyl)alanine
methyl ester (OJ, 1.0 mL/min, 10% 2-PrOH/hexane),
(R) t1=10.2 min, (S) t2=12.5 min; N-acetyl-3-(1-naph-
thyl)alanine methyl ester (OJ, 0.5 mL/min, 10% 2-
PrOH/hexane), (R) t1=27.8 min, (S) t2=32.5 min;
N-acetylalanine methyl ester (OD, 1.0 mL/min, at
25°C, 1% 2-PrOH/hexane), (R) t1=53.5 min, (S) t2=
71.7 min.
Processes; Doyle, M. P., Ed.; JAI Press: Greenwhich,
1998; Vol. 2, p. 1.
5. For recent advances in this area, see: (a) Die´guez, M.;
Ruiz, A.; Claver, C. J. Org. Chem. 2002, 67, 3796; (b)
Park, H.; RajanBabu, T. V. J. Am. Chem. Soc. 2002, 124,
734; (c) RajanBabu, T. V.; Yan, Y.-Y.; Shin, S. J. Am.
Chem. Soc. 2001, 123, 10207; (d) Li, W.; Zhang, Z.; Xiao,
D.; Zhang, X. J. Org. Chem. 2000, 65, 3489; (e) Shin, S.;
RajanBabu, T. V. Org. Lett. 1999, 1, 1229.
6. (a) Yonehara, K.; Hashizume, T.; Mori, K.; Ohe, K.;
Uemura, S. J. Org. Chem. 1999, 64, 5593; (b) Yonehara,
K.; Ohe, K.; Uemura, S. J. Org. Chem. 1999, 64, 9381; (c)
Hashizume, T.; Yonehara, K.; Ohe, K.; Uemura, S. J.
Org. Chem. 2000, 65, 5197.
7. Yonehara, K.; Hashizume, T.; Ohe, K.; Uemura, S.
Acknowledgements
Tetrahedron: Asymmetry 1999, 10, 4029.
8. Wallace, P. A.; Minnikin, D. E. Carbohydr. Res. 1994,
263, 43.
9. The use of NaOEt in EtOH–acetone instead of a mixed
base resulted in lower yield of 6 along with many by-
products.
This work was supported by a Grants-in-Aid for Scien-
tific Research (C) (No. 12839009) from the Japan Soci-
ety for the Promotion of Science. We are grateful to
Mr. Yasuaki Hisamoto in our department for measur-
ing HRMS spectra.
10. For the related synthesis of 2,3-anhydro-4,6-O-benzyli-
dene-a-
D
-allopyransyl 2,3-anhydro-4,6-O-benzylidene-a-
D
-allopyranoside, see: Hough, L.; Munroe, P. A.;
Richardson, A. C. J. Chem. Soc. (C) 1971, 1090.
11. It was reported that ring-opening reaction of methyl
References
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D-allopyranoside with
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D
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14. Recently other groups have reported that both enantiose-
lectivity and activity were enhanced when the hydrogen
pressure was raised in rhodium-catalyzed hydrogenations
with
a monodentate phosphramidite and bidentate
diphosphite ligands, see: (a) van den Berg, M.; Minnaard,
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into EtOAc is therefore unlikely (no coloring of the
organic phase was visibly observed). It is tempting to
speculate that the loss of reactivity and selectivity is
related to the decomposition of 8 causing leaching of the
ligand portion into the organic phase under the recycling
conditions.
16. The ligands 1a and 1b having a (2R,3S)-glucopyranoside
backbone provide (S)-a-amino acid derivatives in the
asymmetric hydrogenation of enamides, although they
form seven-membered complexes with rhodium, see: Ref.
6a.
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