Chiral diphosphites derived from D-glucose: new highly modular ligands for the asymmetric catalytic hydrogenation.

Article abstract of DOI:10.1021/jo0255429

A series of novel diphosphite ligands derived from readily available D-(+)-glucose have been synthesized. These ligands were screened in the Rh-catalyzed hydrogenation of a series of alpha,beta-unsaturated carboxylic acid derivatives. Both excellent enantioselectivities (ee up to >99%) and activities were achieved. The advantage of these ligands is that their modular nature allows an easy systematic variation in the configuration of the stereocenters (C-3, C-5) at the ligand backbone and in the biaryl substituents, so the optimum configuration for maximum enantioselectivity in asymmetric hydrogenation can be determined. Results show that enantiomeric excesses depend strongly on the absolute configuration of C-3 and slightly on the stereocenter carbon C-5, while the sense of the enantiodiscrimination is predominantly controlled by the configuration of the biaryls at the phosphite moieties. Moreover, the presence of bulky substituents at the ortho-positions of the biaryl diphosphite moieties has a positive effect on enantioselectivity.

Full text of DOI:10.1021/jo0255429

3
796
J . Org. Chem. 2002, 67, 3796-3801
Ch ir a l Dip h osp h ites Der ived fr om D-Glu cose: New High ly
Mod u la r Liga n d s for th e Asym m etr ic Ca ta lytic Hyd r ogen a tion
Montserrat Di e´ guez,* Aurora Ruiz, and Carmen Claver
Departament de Qu ı´ mica F ı´ sica i Inorg a` nica, Universitat Rovira i Virgili, Pl. Imperial T a` rraco 1,
4
3005 Tarragona, Spain
dieguez@quimica.urv.es
Received J anuary 21, 2002
A series of novel diphosphite ligands derived from readily available D-(+)-glucose have been
synthesized. These ligands were screened in the Rh-catalyzed hydrogenation of a series of R,â-
unsaturated carboxylic acid derivatives. Both excellent enantioselectivities (ee up to >99%) and
activities were achieved. The advantage of these ligands is that their modular nature allows an
easy systematic variation in the configuration of the stereocenters (C-3, C-5) at the ligand backbone
and in the biaryl substituents, so the optimum configuration for maximum enantioselectivity in
asymmetric hydrogenation can be determined. Results show that enantiomeric excesses depend
strongly on the absolute configuration of C-3 and slightly on the stereocenter carbon C-5, while
the sense of the enantiodiscrimination is predominantly controlled by the configuration of the biaryls
at the phosphite moieties. Moreover, the presence of bulky substituents at the ortho-positions of
the biaryl diphosphite moieties has a positive effect on enantioselectivity.
In tr od u ction
The asymmetric hydrogenation of functionalized pro-
phite ligands.4a,b Therefore, it is important to develop new
phosphite ligands and to scope their applicability in the
hydrogenation reaction.
chiral olefins is one of the most important applications
of asymmetric catalysis. Over many years, the scope of
this reaction has been gradually extended in both reac-
For this purpose, chiral auxiliaries from the chiral pool
are particularly advantageous. Of them, sugar-derived
ligands have provided good conversions and excellent
1
tant structure and catalyst efficiency. Many chiral
diphosphines1 and diphosphinites have been synthe-
,2
3
enantioselectivities in different types of catalytic
reactions.3
c,4a,5f,i,7
Particularly, some 1,2-protected fura-
sized as ligands for enantioselective metal-catalyzed
hydrogenation. Recently, a group of less electron-rich
phosphorus compoundssphosphite ligandsshas received
noses derived from D-(+)-xylose and D-(+)-glucose have
been shown to be successful ligands for asymmetric
catalysis.5
e,f,i,l,8
However, the success of these ligands
4
more attention. Phosphite ligands are a very attractive
highly depends on the studied reaction. For example, in
diphosphite furanoside ligands 1 and 2 (Figure 1), the
introduction of a stereogenic center at the C-5 position
(ligands 3-6a ,b, Figure 2) improved the rate and enan-
tioselectivity in the Rh-catalyzed asymmetric hydro-
formylation of styrene,5 while it hardly affected the
enantioselectivity in the Pd-catalyzed asymmetric allylic
group of compounds for catalysis and have been success-
fully applied in other transition-metal-catalyzed reactions
such as hydroformylation, hydrocyanation, and allylic
alkylation. They have many advantages; for example,
they are easy to prepare from readily available starting
5
e,f
materials, and they are less sensitive to air than
phosphines.5j,6 However, only Reetz et al. have reported
5
i,l
alkylation of rac-1,3-diphenyl-2-propenyl acetate. As far
a successful enantioselective hydrogenation using phos-
(
1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
(5) See, for example: (a) Babin, J . E.; Whiteker, G. T. (Union Carbide
Chemical and Plastics Technology Co.). WO 93/03839, 1993; Chem.
Abstr. 1993, 119, P159872h. (b) Buisman, G. J . H.; van deer Veen, L.
A.; Klootwijk, A.; de Lange, W. G. J .; Kamer, P. C. J .; van Leeuwen,
P. W. N. M.; Vogt, D. Organometallics 1997, 16, 2929. (c) Nozaki, K.;
Sakai, N.; Nanno, T.; Higashijima, T.; Mano, S.; Horiuchi, T.; Takaya,
H. J . Am. Chem. Soc. 1997, 119, 4413. (d) Franci o` , G.; Leitner, W.
Chem. Commun. 1999, 1663. (e) Di e´ guez, M.; P a` mies, O.; Ruiz, A.;
Castill o´ n, S.; Claver, C. Chem. Commun. 2000, 1607. (f) Di e´ guez, M.;
P a` mies, O.; Ruiz, A.; Castill o´ n, S.; Claver, C. Chem. Eur. J . 2001, 7,
3086. (g) Pr e´ t oˆ t, R.; Pfaltz, A. Angew. Chem., Int. Ed. 1998, 37, 323.
(h) Selvakumar, K.; Valentini, M.; Pregosin, P. S.; Albinati, A.
Organometallics 1999, 18, 4591. (i) Di e´ guez, M.; J ansat, S.; Gomez,
M.; Ruiz, A.; Muller, G.; Claver, C. Chem. Commun. 2001, 1132. (j)
Baker, M. J .; Pringle, P. G. J . Chem. Soc., Chem. Commun. 1991, 1292.
(k) Horiuchi, T.; Shirakawa, E.; Nozaki, K.; Takaya, H. Tetrahedron:
Asymmetry 1997, 8, 57. (l) P a` mies, O.; van Strijdonck, G. P. F.; Di e´ guez,
M.; Deerenberg, S.; Net, G.; Ruiz, A.; Claver, C.; Kamer, P. C. J .; van
Leeuwen, P. W. N. M. J . Org. Chem. 2001, 66, 8867.
Wiley: New York, 1994. (b) Catalytic Asymmetric Synthesis; Ojima,
I., Ed.; Wiley: New York, 2000. (c) Comprehensive Asymmetric
Catalysis; J acobsen, E. N., Pfaltz, A., Yamamoto, H. H., Eds.;
Springer: Berlin, 1999; Vol. 1.
(
2) See for instance: (a) Brunner, H.; Zettlmeier, W. Handbook of
Enantioselective Catalysis; VCH: Weinheim, Germany, 1993. (b)
Nettekoven, U.; Kamer, P. C. J .; van Leeuwen, P. W. N. M.; Widhalm,
M.; Speck, A. L.; Lutz, M. J . Org. Chem. 1999, 64, 3996. (c) Barens,
U.; Burk, M. J .; Gerlach, A.; Hems, W. Angew. Chem., Int. Ed. 2000,
3
9, 1981.
3) (a) Chan, A. S. C.; Hu, W.; Pai, C. C.; Lau, C. P. J . Am. Chem.
(
Soc. 1997, 119, 9570. (b) Ayers, T. A.; RajanBabu, T. V. Process Chem.
Pharm. Ind. 1999, 327. (c) Selke, R. J . Organomet. Chem. 1989, 370,
2
49. (d) RajanBabu, T. V.; Radetich, B.; You, K. K.; Ayers, T. A.;
Casalnuovo, A. L.; Calabrese, J . C. J . Org. Chem. 1999, 64, 3429.
4) (a) Reetz, M. T.; Neugebauer, T. Angew. Chem., Int. Ed. 1999,
(
3
3
8, 179. (b) Reetz, M. T.; Mehler, G. Angew. Chem., Int. Ed. 2000, 39,
889. (c) Brunner, H.; Pieronczyk, W. J . Chem. Res., Synop. 1980, 76.
(
9
d) Kadyrov, R.; Heller, D.; Selke, R. Tetrahedron: Asymmetry 1998,
, 329. (e) P a` mies, O.; Net, G.; Ruiz, A.; Claver, C. Eur. J . Inorg. Chem.
000, 1287. (f) P a` mies, O.; Net, G.; Ruiz, A.; Claver, C. Tetrahedron:
(6) (a) Baker, M. J .; Harrison, K. N.; Orpen, A. G.; Shaw, G.; Pringle,
P. G. J . Chem. Soc., Chem. Commun. 1991, 803. (b) Pignolet, L. H.
Homogeneous Catalysts with Metal Phosphine Complexes; Plenum:
New York, 1983.
2
Asymmetry 2000, 11, 1097.
1
0.1021/jo0255429 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/01/2002

Chiral Diphosphates Derived from D-Glucose
J . Org. Chem., Vol. 67, No. 11, 2002 3797
Sch em e 1. Syn th esis of Liga n d s 3-6a
a
Reagents and conditions: (a) ref 5f; (b) Py, toluene, 100 °C.
F igu r e 1.
Resu lts a n d Discu ssion
Liga n d Design . Ligands 3-6 consist of chiral 1,2-O-
protected furanoside backbones, which determine their
underlying structure, and two hydroxyl groups at the C-3
and C-5 positions. Several phosphoric acid biaryl esters
7
were attached to these basic frameworks (Scheme 1).
The influence of the different groups attached to the
ortho- and para-positions of the biphenyl moieties on
enantioselectivity was investigated using ligands 3a -c,
which have the same configuration on the carbon atoms
C-3 and C-5.
We studied the effects of the stereogenic carbon atoms
C-3 and C-5 on enantioselectivity and the possibility of
a cooperative effect between them by comparing diaster-
eomeric ligands 3-6.
To determine whether there is a cooperative effect
between the stereocenters of the ligand backbone and the
configuration of the biaryl phosphite moieties, we pre-
pared a series of enantiomerically pure binaphthol-based
ligands 3d -g.
Liga n d Syn th esis. The new ligands 3c-g and 4c
were synthesized very efficiently in one step from the
corresponding diols, which were prepared on a large scale
from D-(+)-glucose, as previously described for ligands
F igu r e 2.
3
a ,b and 4a ,b (Scheme 1).5f Therefore, reaction of the
as the asymmetric hydrogenation reaction is concerned,
ligands 1 and 2 provided moderate results.4e,f
corresponding diol with 2 equiv of the desired in situ
formed phosphorochloridite 7c-g in the presence of base
afforded the desired ligands.
The objective of the study presented here is 2-fold: (a)
to test whether introducing a stereocenter at the carbon
C-5 position would improve enantioselectivity in the Rh-
catalyzed asymmetric hydrogenation reaction and (b) to
investigate the existence of a cooperative effect between
the stereogenic centers of the ligand backbone and the
stereogenic biaryl substituents. Such effects have recently
All the ligands were stable during purification on
neutral silica gel under an atmosphere of argon and were
isolated in moderate-to-good yields (45-80%) as white
31
solids. The P NMR spectra of ligands 3c-g show two
singletssone for each phosphorus moiety, while for ligand
4
c, two doubletssone for each phosphorusswere ob-
5
b,9
been described for other ligands
and were beneficial.
served. The large J PP value for ligand 4c is similar to
With these purposes, we synthesized the new chiral
diphosphite ligands 3-6c-g (Figure 2) so that the
complete family of ligands 3-6a -g combine the system-
atic variation of the configurations at C-3 and C-5 of the
ligand backbone and different substituents and configu-
rations in the biaryl phosphite moieties. This allows the
optimum configuration for maximum enantioselectivity
to be determined and may provide some insight into the
origin of the stereochemistry of the reaction.
5f
those of the related diphosphite ligands 4a and 4b.
Moroever, due to the axial chirality of the biphenyl
groups, two pairs of signals should be expected for ligands
3
c and 4c. However, the existence of a single set of
signals for each phosphorus atom for ligands 3c and 4c
31
in the variable-temperature P NMR suggested rapid
ring inversions (atropoisomerization) of the seven-
membered dioxaphosphepin rings on the NMR time
10
scale.
Asym m et r ic Hyd r ogen a t ion of r,â-Un sa t u r a t ed
Ca r boxylic Acid Der iva tives. The catalytic perfor-
mance of ligands 3-6 was thoroughly explored in the
enantioselective rhodium-catalyzed hydrogenation reac-
tion. In a first set of experiments, we used these ligands
in the rhodium-catalyzed hydrogenation of dimethyl
itaconate (8). The reaction proceeded smoothly at room
temperature. In general, the catalysts were prepared in
situ by adding the corresponding diphosphite ligands to
(
7) See also, for instance: (a) RajanBabu, T. V.; Ayers, T. A.
Tetrahedron Lett. 1994, 35, 4295. (b) RajanBabu, T. V.; Casalnuovo,
A. L. Pure Appl. Chem. 1994, 94, 149. (c) Yonehara, K.; Hashizuma,
T.; Mori, K.; Ohe, K.; Uemura, S. Chem. Commun. 1999, 415. (d) Clyne,
D. S.; Mermet-Bouvier, Y. C.; Nomura, N.; RajanBabu, T. V. J . Org.
Chem. 1999, 64, 7601. (e) Yonehara, K.; Ohe, K.; Uemura, S. J . Org.
Chem. 1999, 64, 937. (f) Park, H.; RajanBabu, T. V. J . Am. Chem. Soc.
2
002, 124, 734.
8) See also, for instance: (a) P a` mies, O.; Net, G.; Ruiz, A.; Claver,
(
C. Eur. J . Inorg. Chem. 2000, 2011. (b) P a` mies, O.; Di e´ guez, M.; Net,
G.; Ruiz, A.; Claver, C. Tetrahedron: Asymmetry 2000, 11, 4377. (c)
P a` mies, O.; Di e´ guez, M.; Net, G.; Ruiz, A.; Claver, C. Chem. Commun.
2 4
the catalyst precursor [Rh(cod) ]BF .
2
000, 2383. (d) P a` mies, O.; Di e´ guez, M.; Net, G.; Ruiz, A.; Claver, C.
J . Org. Chem. 2001, 66, 8364.
9) Cser e´ pi-Sz u¨ cs, S.; T o´ th, I.; P a´ rk a´ nyi, L.; Bakos, J . Tetrahedron:
Asymmetry 1998, 9, 3135.
(
(10) Pastor, D. D.; Shum, S. P.; Rodebaugh, R. K.; Debellis, A. D.;
Clarke, F. H. Helv. Chim. Acta 1993, 76, 900.

3
798 J . Org. Chem., Vol. 67, No. 11, 2002
Di e´ guez et al.
Ta ble 1. Asym m etr ic Hyd r ogen a tion of Dim eth yl
Ta ble 2. Rh -ca ta lyzed Asym m etr ic Hyd r ogen a tion of 8
a
Usin g Dip h osp h ites 3-6a
Ita con a te 8 Usin g Rh /Dip h osp h ite 3a
PH2,
bar
% convnb
(t, h)
% convnb
(t, h)
entry
solvent
% eec
entry
ligand
% eec
1
2
3
4
5
6
7
8
toluene
CH2Cl2
AcOEt
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
5
5
5
5
1
16 (8)
90 (8)
8 (8)
99 (8)
100 (20)
66 (8)
90 (3)
100 (0.8)
89 (8)
90 (8)
2 (S)
90 (R)
2 (R)
12 (R)
10 (R)
90 (R)
90 (R)
91 (R)
90 (R)
90 (R)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
4a
4b
4c
5a
5b
6a
6b
1a
2a
90 (8)
82 (8)
100 (6)
50 (8)
46 (8)
100 (8)
100 (8)
100 (8)
98 (8)
100 (8)
87 (8)
80 (8)
73 (8)
69 (8)
12 (8)
28 (8)
90 (R)
85 (R)
97 (R)
50 (S)
52 (R)
90 (S)
92 (R)
2 (R)
2
10
30
5
d
9
0
2 (R)
3 (R)
d
1
5
10
1
1
1
1
1
1
1
2
3
4
5
6
67 (R)
63 (R)
29 (R)
27 (R)
22 (R)
64 (R)
a
Amount of [Rh(cod)2]BF4 0.01 mmol, ligand/Rh ) 1.1, substrate/
b
Rh ) 100, amount of solvent 6 mL, T ) 25 °C. Percent conversion
c
measured by GC. Percent enantiomeric excess measured by GC
d
e
using a Chiraldex G-TA column. Ligand/Rh ) 2. Using pre-
formed complex [Rh(cod)(3a)]BF4 (0.01 mmol).
a
The effects of different reaction parameters (i.e., sol-
vent, hydrogen pressure, catalyst preparation, ligand-to-
rhodium ratio, and temperature) were investigated for
the catalytic precursor containing ligand 3a . The results
are summarized in Table 1.
Amount of [Rh(cod)2]BF4 0.01 mmol, ligand/Rh ) 1.1, substrate/
Rh ) 100, amount of CH2Cl2 6 mL, PH ) 5 bar, T ) 25 °C.
2
b
Percent conversion measured by GC. c Percent enantiomeric
excess measured by GC using a Chiraldex G-TA column.
presence of trimethylsilyl groups in the ortho-positions
of the biphenyl moieties (ligand 3c) had a positive effect
on both activity and enantioselectivity (97% ee, entry 3).
Ligands 3d and 3e, which contain stereogenic binaphthyl
moieties, resulted in lower activity and enantioselectivity
The results show that the efficiency of the process
depended strongly on the nature of the solvent (entries
1
-4). Thus, the catalyst performance (activity and enan-
tioselectivity) was best when dichloromethane was used
(entry 2).
(
entries 4 and 5). Ligand 3d , which has (S)-binaphthyl
Interestingly, both enantioselectivity and activity were
moieties, resulted in an ee of 50% (S), whereas diaste-
reomer 3e, which has (R)-binaphthyl moieties, resulted
in an ee of 52 (R). We can therefore conclude that the
sense of the enantiodiscrimination is predominantly
controlled by the configuration of the biaryl at the
phosphite moieties.
notably enhanced when the hydrogen pressure was raised
from 1 to 2 bar (entry 5 vs entry 6). However, though
increasing the hydrogen pressure further had a positive
effect on activity, enantioselectivity remained the same
(entries 7 and 8). This contrasts with the usual decrease
in enantioselectivity with bidentate ligands when the
hydrogen pressure is raised.1
a,11
As with ligand 3c, ligands 3f and 3g, which contain
bulky trimethylsilyl groups in the ortho-positions of the
binaphthyl moieties, led to higher reaction rates and
enantioselectivities (entries 6 and 7) than the less steric
nonsubstituted binaphthyl ligands 3d and 3e. Thus, both
enantiomers of 9 can be obtained in good enantioselec-
tivities (entries 6 and 7). The enantioselectivity observed
for the catalytic system Rh/3c, which was higher than
for Rh/3f and Rh/3g, can be attributed to the different
dihedral angles of the biphenyl and binaphthyl moieties,
which affect the characteristics of the phosphorus and
therefore the geometry of the species responsible for the
catalytic activity.5b
Using preformed catalyst precursor [Rh(cod)(3a )]BF
cod ) 1,3-cyclooctadiene) did not affect the efficiency of
4
(
the process (entry 10). Also, adding a 1-fold excess of
ligand did not affect the outcome of the reaction (entry
9
).
For comparison purposes, the rest of the ligands were
tested under “standard” conditions (a ligand-to-rhodium
ratio of 1.1, a hydrogen pressure of 5 bar, and dichlo-
romethane as a solvent). The results are shown in Table
2
.
Using ligand 3b with methoxy groups instead of tert-
butyl groups in the para-positions of the biphenyl moi-
eties led to lower enantioselectivity and activity than
those of catalytic system Rh/3a (entry 1 vs entry 2).12 The
Ligands 4a -c, whose configuration of carbon atom C-3
is opposite that of ligands 3 (Figure 2), produced slightly
better activities, but the enantioselectivity dropped con-
siderably (entries 8-10).
(11) (a) Pfaltz, A.; Brown, J . M. In Houben-Weyl Methods of Organic
Chemisty; Helchem, G., Hoffmann, R. W., Mulzer, J ., Schaumann, E.,
Eds.; Thieme: Stuttgart, Germany, 1995; Vol. E21, Section D.2.5.1.2.
Ligands 5, which resulted from changing the configu-
ration of carbon C-5 from R to S in ligands 3, led to a
slightly lower activity and a lower enantioselectivity than
the catalytic systems Rh/3 (entries 1 and 2 vs entries 11
and 12).
(b) Zhang, X. Enantiomer 1999, 4, 541. (c) Burk, M. J .; Bienewald, F.
In Transition Metals For Organic Synthesis; Beller, M., Bolm, C., Eds.;
Wiley-VCH: Weinheim, Germany, 1998; Vol. 2; Chapter 1.1.2. (d) van
den Berg, M.; Minnaard, A. J .; Schudde, E. P.; van Esch, J .; de Vries,
A. H. M.; de Vries, J . G.; Feringa, B. L. J . Am. Chem. Soc. 2000, 122,
1
1539.
12) This behavior contrasts with the positive effect on enantio-
(
Ligands 6, whose configuration of carbon atom C-3 is
opposite to that of ligands 5 (Figure 2), produced lower
activities and enantioselectivities (entries 11 and 12 vs
entries 13 and 14).
selectivity observed in the Rh-catalyzed hydroformylation and Pd-
catalyzed allylic alkylation reactions for ligands containing methoxy
substituents in the para-positions of the biphenyl moieties; see refs 5f
and 5i.

Chiral Diphosphates Derived from D-Glucose
J . Org. Chem., Vol. 67, No. 11, 2002 3799
Ta ble 3. Asym m etr ic Hyd r ogen a tion of Meth yl
Ta ble 4. Asym m etr ic Hyd r ogen a tion w ith Low Ca ta lyst
Loa d in g a t Eleva ted P r essu r e Usin g [Rh (cod )2]BF 4/3c
a
(
N)-Acetyla m in oa cr yla te (10) a n d Meth yl (Z)-(N)-
a
Acetyla m in ocin n a m a te (12) w ith [Rh (cod )2]BF 4/3-6
%
convnb
entry
substrate
T, °C
(t, min)
% eec
1
2
3
4
5
6
8
10
12
8
10
12
25
25
25
5
5
5
99 (25)
100 (25)
95 (25)
97 (R)
98 (S)
97 (S)
>99 (R)
>99 (S)
>99 (S)
100 (240)d
d
100 (240)
100 (240)d
%
convnb
(t, h)
entry
substrate
ligand
% eec
a
Amount of [Rh(cod)2]BF4 0.01 mmol, ligand/Rh ) 1.1, substrate/
b
Rh ) 1000, amount of CH2Cl2 6 mL, PH ) 30 bar. Percent
2
1
2
3
4
5
6
7
8
9
10
12
10
12
10
12
10
12
10
12
3a
3a
3c
3c
4a
4a
5a
5a
6a
6a
98 (8)
96 (8)
92 (S)
91 (S)
97 (S)
98 (S)
3 (S)
c
conversion measured by GC. Percent enantiomeric excess mea-
sured by GC. d Reaction time not optimized.
100 (6)
100 (6)
100 (8)
100 (8)
97 (8)
opposite that of the hydrogenated product 9, but they
have the same spatial arrangement. The catalyst
precursor with ligand 3c produced the highest enantio-
meric excess (98%, entry 4).
Also, we performed the hydrogenation of substrates 8,
2 (S)
16
71 (S)
70 (S)
29 (S)
32 (S)
98 (8)
92 (8)
96 (8)
1
0
1
0, and 12 at high pressure and low catalyst concentra-
a
Amount of [Rh(cod)2]BF4 0.01 mmol, ligand/Rh ) 1.1, substrate/
Rh ) 100, amount of CH2Cl2 6 mL, PH ) 5 bar, T ) 25 °C.
tion (0.1 mol %) using ligand 3c in dichloromethane (see
Table 4). Under these conditions, the reactions proceeded
2
c
b
Percent conversion measured by GC. Percent enantiomeric
excess measured by GC using a Permabond L-Chiralsil-Val
column.
-1
fast (TOF > 2500 h ) with enantioselectivities up to 98%
entries 1-3). An increase in enantioselectivity (ee >
9%) combined with good activity was found for all
substrates by lowering the reaction temperature (Table
, entries 4-6).
(
9
Comparison of entries 1, 8, 11, and 13 clearly shows
that the enantiomeric excesses depend strongly on the
absolute configuration of C-3 and depend slightly on the
stereocenter carbon C-5 of the carbohydrate backbone.
The best enantioselectivities were obtained therefore with
allofuranoside ligands 3 with R configuration on both C-3
and C-5 stereocenters.13 Further evidence is provided by
using related diphosphite ligands 1a and 2a with xylo-
and ribofuranoside backbones (Figure 1).14 Ligand 2a ,
with R configuration on C-3, produced a better enanti-
oselecitivity than ligand 1a with opposite configuration
on C-3 (entry 15 vs entry 16). Moreover, the similar
enantioselecitivities obtained with ligands 2a and 5a
suggest that they both adopt a similar spatial arrange-
ment around the metal center in the species responsible
for the catalytic activity. This is also true for ligands 1a
and 6a . Interestingly, in contrast with the hydroformy-
lation results,5f the sense of enantioselectivity, in the
biphenyl-based ligands, is not controlled by the absolute
configuration of the stereogenic carbon atom C-3. Thus,
in all cases the (R)-9 enantiomer is predominantly formed
4
Con clu sion s
We have designed a series of diphosphite ligands 3-6
based on the simple but highly effective furanoside
backbone. These ligands have been easily prepared in few
steps from readily available D-(+)-glucose. The possibility
and necessity of tuning the ligand was demonstrated by
the synthesis of 14 diphosphite ligands and their ap-
plication in the Rh-catalyzed asymmetric hydrogenation
of several R,â-unsaturated carboxylic acid derivatives.
Both excellent enantioselectivities (ee up to >99%) and
activities were achieved. Systematic variation of stereo-
centers C-3 and C-5 at the ligand backbone revealed that
enantiomeric excesses depend strongly on the absolute
configuration of C-3 and slightly on that of the stereo-
center carbon C-5. Therefore, enantioselectivities were
best with ligands 3 with R configuration on both C-3 and
C-5 stereocenters. Variation in chirality at the axial
chiral binaphthyl substituents in ligands 3 indicates that
the sense of the enantiodiscrimination is predominantly
controlled by the configuration of the biaryls at the
phosphite moieties. The presence of bulky substituents
at the ortho-positions of the biaryl diphosphite moieties
has a positive effect on enantioselectivity. The highest
enantiomeric excess was found for allofuranoside ligand
(
entries 1-3 and 9-16).
We can also conclude that the presence of a methyl
substituent on the carbon C-5 significantly increased the
activity (entries 1-14 vs entries 15 and 16).
We subsequently applied these new highly efficient
diphosphites 3-6 in the Rh-catalyzed hydrogenation of
other benchmark dehydroamino acid derivatives 10 and
1
5
1
2. The results are summarized in Table 3. The results
3
c, which have o-trimethylsilyl substituents in the bi-
followed the same trend as observed for substrate 8, but
the activities were somewhat higher. The absolute con-
figuration of the hydrogenated products 11 and 13 is
phenyl moieties.
The systematic variation in the configuration of the
stereocenters at the ligand backbone and in the biaryl
substituents provides therefore a rational approach to the
optimum ligand parameters for high activity and enan-
tioselectivity (ee up to >99%). Exploiting the fact that
these sugar ligands can be easily modified, further
research into other types of hydrogenation reactions is
now in progress.
(13) This behavior contrasts with the high copperative effect between
stereocenters C-3 and C-5 observed in the Rh-catalyzed hydroformy-
lation, which results in a matched combination for ligands with gluco-
and talofuranoside backbones; see ref 5f.
(
14) For comparative purposes diphosphite ligands 1a and 2a were
tested in the Rh-catalyzed enantioselective hydrogenation of 8 under
the same reaction conditions.
(
15) Similar behavior has been observed in the Rh-catalyzed asym-
metric hydrogenation using related diphosphine ligands. See: Di e´ guez,
M.; P a` mies, O.; Ruiz, A.; Castill o´ n, S.; Claver, C. Tetrahedron:
Asymmetry 2000, 11, 4701.
(16) Cahn, R. S.; Ingold, C. K.; Prelog, V. Angew. Chem., Int. Ed.
Engl. 1966, 5, 385.

3
800 J . Org. Chem., Vol. 67, No. 11, 2002
Di e´ guez et al.
Exp er im en ta l Section
3e, which was purified by flash chromatography (eluent
toluene, R 0.45) to produce 0.39 g (48%) of a white powder.
f
Gen er a l Com m en ts. All syntheses were performed using
standard Schlenk techniques under an argon atmosphere.
Solvents were purified by standard procedures. Ligands 1a
Anal. Calcd for C49
38 9 2
H O P : C, 70.67; H, 4.60. Found: C, 70.39,
H, 4.68. 3 P NMR: δ 140.3 (s), 146.3 (s). H NMR: δ 1.05 (d,
1
1
1
7
3
4
f
3H, H-6, J 6-5 ) 6.4 Hz), 1.31 (s, 3H, CH
3
), 1.55 (s, 3H, CH
3
),
and 2a were prepared according to the literature procedures.
Compounds 3a ,b, 4a ,b, 5a ,b, and 6a ,b were prepared by
4
.12 (m, 1H, H-4), 4.28 (m, 2H, H-2, H-3), 4.59 (m, 1H, H-5),
3
13
5
f
5.62 (d, 1H, H-1, J 1-2 ) 3.2 Hz), 6.8-7.8 (m, 24H, CHd).
NMR: δ 17.1 (d, C-6, J C-P ) 3 Hz), 26.7 (CH ), 26.9 (CH
71.0 (m, C-5), 72.0 (C-3), 79.0 (d, C-2, J C-P ) 1.9 Hz), 81.2 (m,
C-4), 103.7 (C-1), 113.5 (CMe ), 121.5 (CHd), 121.7 (CHd),
C
previously described methods. 6-Desoxy-1,2-O-isopropylidene-
3
3
),
R-D-allofuranose (14) and 6-desoxy-1,2-O-isopropylidene-R-D-
glucofuranose (15) were synthesized as previously described.5f
2
Phosphorochloridites 7c-g were prepared in analogy with
5
b,18
1
121.9 (CHd), 124.8 (CHd), 124.9 (CHd), 125.0 (CHd),
126.1 (CHd), 126.3 (CHd), 126.8 (CHd), 126.9 (CHd), 127.0
literature procedures.
All other reagents were used as
13
1
31
1
commercially available. H, C{ H}, and P{ H} NMR spectra
(
CHd), 128.1 (CHd), 128.3 (CHd), 128.4 (CHd), 128.5
were recorded using a 400 MHz spectrometer. Chemical shifts
1
13
(CHd), 129.6 (CHd), 130.3 (CHd), 132.5 (C), 132.5 (C), 132.6
(C), 132.7 (C), 146.8 (C), 147.4 (C), 147.7 (C), 148.5 (C).
are relative to that of SiMe
4
( H and C) as internal standard
3
1
or H PO ( P) as external standard. All assignments in NMR
3 4
3
,5-Bis[((S)-3,3′-bis(tr im eth ylsilyl)-1,1′-bin a p h th yl-2,2′-
spectra were determined by COSY and HETCOR spectra.
Hydrogenation reactions were carried out in a homemade 100
mL stainless steel autoclave.
d iyl)p h osp h it e]-6-d eoxy-1,2-O-isop r op ylid en e-r-D-a llo-
fu r a n ose (3f). Treatment of in situ formed phosphorochlo-
ridite 7f (2.2 mmol) and 14 (0.21 g, 1 mmol) as described for
compound 3c afforded diphosphite 3f, which was purified by
3
,5-Bis[(3,3′-bis(tr im eth ylsilyl)-1,1′-bip h en yl-2,2′-d iyl)-
p h osp h it e]-6-d eoxy-1,2-O-isop r op ylid en e-r-D-a llofu r a -
n ose (3c). In situ formed phosphorochloridite 7c (2.2 mmol)
was dissolved in toluene (5 mL) to which pyridine (0.36 mL,
flash chromatography (eluent toluene, R
g (35%) of a white powder. Anal. Calcd for C61
f
0.50) to produce 0.39
Si : C,
5.33; H, 6.29. Found: C, 65.45; H, 6.37. P NMR: δ 145.1
H
70
O
9
P
2
4
3
1
6
4
.6 mmol) was added. 14 (0.21 g, 1 mmol) was azeotropically
1
(
1
3
s, 1P), 145.5 (s, 1P). H NMR, δ: 0.31 (s, 9H, CH Si), 0.34 (s,
dried with toluene (3 × 1 mL) and dissolved in toluene (10
mL) to which pyridine (0.18 mL, 2.3 mmol) was added. The
diol solution was transferred slowly over 30 min to the solution
of phosphorochloridite at room temperature. The reaction
mixture was stirred overnight at reflux, and the pyridine salts
were removed by filtration. Evaporation of the solvent gave a
white foam which was purified by flash chromatography
3
8H, CH
3
Si), 0.36 (s, 9H, CH
), 1.32 (s, 3H, CH
.19 (d, 1H, H-2, J 2-1 ) 3.6 Hz), 4.50 (m, 1H, H-3), 4.55 (m,
3
Si), 1.04 (d, 3H, H-6, J 6-5 ) 7.2
Hz), 1.11 (s, 3H, CH
4
1
3
3
), 4.01 (m, 1H, H-4),
3
3
H, H-5), 5.69 (d, 1H, H-1, J 1-2 ) 3.6 Hz), 6.8-8.0 (m, 20H,
1
3
CHd). C NMR: δ -1.0 (CH
3
Si), -0.2 (CH
Si), 18.2 (C-6), 26.3 (CH ), 26.5 (CH
4.3 (m, C-3), 82.4 (C-4), 82.9 (C-2), 103.9 (C-1), 110.9 (CMe
24.1 (CHd), 124.3 (CHd), 124.6 (CHd), 124.8 (CHd),
3
Si), 0.1 (CH
), 69.5 (m, C-5),
),
3
Si),
0
7
1
.5 (CH
3
3
3
2
(
eluent toluene, R
f
0.85) to produce 0.79 g (86%) of a white
Si C, 58.67; H, 6.78.
Found: C, 58.76; H, 6.89. P NMR: δ 145.0 (s), 145.5 (s). H
NMR: δ 0.24 (s, 9H, CH Si), 0.26 (s, 9H, CH Si), 0.27 (s, 9H,
CH Si), 0.35 (s, 9H, CH
.25 (s, 3H, CH ), 1.51 (s, 3H, CH
.6 Hz, J 2-3 ) 3.6 Hz), 4.05 (d, 1H, H-4, J 4-5 ) 6.8 Hz), 4.36
powder. Anal. Calcd for C45
H
62
O
9
P
2
4
:
3
1
1
125.3 (CHd), 125.7 (CHd), 125.9 (CHd), 127.1 (CHd),
27.5 (CHd), 127.7 (CHd), 128.1 (CHd), 128.5 (CHd), 128.5
1
3
3
3
(CHd), 130.1 (C), 130.2 (C), 130.3 (C), 130.6 (C), 132.1 (C),
132.5 (C), 133.0 (C), 133.2 (C), 133.4 (C), 134.0 (C), 136.7
(CHd), 136.9 (CHd), 137.4 (CHd), 137.3 (CHd), 150.9 (C),
151.1 (C), 151.3 (C).
3,5-Bis[((R)-3,3′-bis(tr im eth ylsilyl)-1,1′-bin a p h th yl-2,2′-
d iyl)p h osp h it e]-6-d eoxy-1,2-O-isop r op ylid en e-r-D-a llo-
fu r a n ose (3g). Treatment of in situ formed phosphorochlo-
ridite 7g (2.2 mmol) and 14 (0.21 g, 1 mmol) as described for
compound 3c afforded diphosphite 3g, which was purified by
3
3
Si), 0.63 (d, 3H, H-6, J 6-5 ) 7.2 Hz),
3
1
3
(
3
3
), 3.88 (t, 1H, H-2, J 2-1 )
3
3
3
m, 1H, H-3), 4.48 (m, 1H, H-5), 5.56 (d, 1H, H-1, J 1-2 ) 3.6
13
Hz), 7.1-7.5 (m, 12H, CHd). C NMR: δ 0.1 (CH
Si), 0.2 (CH Si), 16.9 (C-6), 27.1 (CH ), 27.3 (CH
2.9 (d, C-3, J C-P ) 6.4 Hz), 78.9 (C-2), 83.1 (m, C-4), 104.8
C-1), 113.8 (CMe ), 124.7 (CHd), 124.8 (CHd), 124.9 (CHd),
30.8 (C), 130.9 (C), 131.1 (C), 132.3 (CHd), 132.5 (CHd), 132.6
3
Si), 0.2 (CH
3
-
3
3
3
), 71.2 (C-5),
7
(
1
(
2
flash chromatography (eluent toluene, R
g (32%) of a white powder. Anal. Calcd for C61
f
0.50) to produce 0.35
Si : C,
5.33; H, 6.29. Found: C, 65.27; H, 6.45. P NMR: δ 146.2
CHd), 134.8 (CHd), 135.1 (CHd), 135.3 (CHd), 150.9 (C),
51.1 (C), 151.2 (C).
,5-Bis[((S)-1,1′-bin aph th yl-2,2′-diyl)ph osph ite]-6-deoxy-
,2-O-isop r op ylid en e-r-D-a llofu r a n ose (3d ). Treatment of
in situ formed phosphorochloridite 7d (2.2 mmol) and 14 (0.21
g, 1 mmol) as described for compound 3c afforded diphosphite
H
70
O
9
P
2
4
1
3
1
6
3
1
(s, 1P), 148.0 (s, 1P). H NMR: δ 0.34 (s, 9H, CH
3
Si), 0.39 (s,
Si), 0.92 (s,
), 0.99 (d, 3H, H-6, J 6-5 ) 7.2 Hz), 1.28 (s, 3H, CH ),
1
9
3
4
5
H, CH
H, CH
3 3 3
Si), 0.41 (s, 9H, CH Si), 0.42 (s, 9H, CH
3
3
3
.12 (m, 1H, H-4), 4.38 (m, 2H, H-2, H-3), 4.51 (m, 1H, H-5),
3
d , which was purified by flash chromatography (eluent
toluene, R 0.45) to produce 0.42 g (51%) of a white powder.
Anal. Calcd for C49 : C, 70.67; H, 4.60. Found: C, 70.84;
3
13
.41 (d, 1H, H-1, J 1-2 ) 3.6 Hz), 7.0-8.0 (m, 20H, CHd).
Si), -0.5 (CH Si), 0.1 (CH Si), 0.3 (CH
18.7 (br, C-6), 27.4 (CH ), 27.5 (CH ), 71.4 (m, C-5), 77.5 (m,
C-3), 82.1 (C-4), 82.9 (m, C-2), 104.3 (C-1), 112.1 (CMe ),
C
f
NMR: δ -0.8 (CH
3
3
3
3
Si),
38 9 2
H O P
3
1
1
3
3
H, 4.78. P NMR: δ 144.4 (s), 147.9 (s). H NMR: δ 1.22 (d,
3
2
3
4
(
2
7
(
H, H-6, J 6-5 ) 7.2 Hz), 1.32 (s, 3H, CH
3
), 1.53 (s, 3H, CH
3
),
3
125.1 (CHd), 125.2 (CHd), 125.3 (CHd), 125.5 (CHd),
127.0 (CHd), 127.1 (CHd), 127.6 (CHd), 127.8 (CHd),
127.9 (CHd), 128.1 (CHd), 128.4 (CHd), 128.5 (CHd), 128.7
.08 (d, 1H, H-4, J 4-5 ) 7.2 Hz), 4.50 (m, 2H, H-2, H-3), 4.62
3
m, 1H, H-5), 5.63 (d, 1H, H-1, J 1-2 ) 3.2 Hz), 7.0-8.0 (m,
1
3
4H, CHd). C NMR: δ 18.3 (C-6), 26.8 (CH
0.6 (d, C-5, J C-P ) 12.9 Hz), 73.2 (d, C-3, J C-P ) 9.1 Hz), 79.3
), 121.8 (CHd),
21.9 (CHd), 121.9 (CHd), 122.2 (CHd), 124.7 (CHd), 124.8
3 3
), 26.9 (CH ),
(CHd), 130.4 (C), 130.5 (C), 130.6 (C), 130.8 (C), 131.9 (C),
1
1
32.1 (C), 132.5 (C), 132.7 (C), 132.8 (C), 133.9 (C), 134.1 (C),
36.5 (CHd), 136.6 (CHd), 137.1 (CHd), 137.2 (CHd), 137.4
C-2), 80.7 (m, C-4), 103.6 (C-1), 113.3 (CMe
2
1
(CHd), 151.2 (C), 151.3 (C), 151.5 (C), 151.6 (C).
(
(
(
1
(
CHd), 125.0 (CHd), 125.1 (CHd), 125.3 (CHd), 126.8
CHd), 127.0 (CHd), 128.1 (CHd), 128.3 (CHd), 128.9
CHd), 129.4 (CHd), 129.7 (CHd), 130.3 (CHd), 131.0 CHd),
31.5 (CHd), 132.2 (C), 132.6 (C), 132.7 (C), 132.8 (C), 146.9
C), 147.4 (C), 147.9 (C), 148.4 (C).
,5-Bis[((R)-1,1′-bin aph th yl-2,2′-diyl)ph osph ite]-6-deoxy-
,2-O-isop r op ylid en e-r-D-a llofu r a n ose (3e). Treatment of
in situ formed phosphorochloridite 7e (2.2 mmol) and 14 (0.21
g, 1 mmol) as described for compound 3c afforded diphosphite
3
,5-Bis[(3,3′-bis(tr im eth ylsilyl)-1,1′-bip h en yl-2,2′-d iyl)-
p h osp h ite]-6-d eoxy-1,2-O-isop r op ylid en e-r-D-glu cofu r a -
n ose (4c). Treatment of in situ formed phosphorochloridite
7
c (2.2 mmol) and 15 (0.21 g, 1 mmol) as described for
compound 3c afforded diphosphite 4c, which was purified by
flash chromatography (eluent toluene, R 0.85) to produce 0.80
86%) of a white powder. Anal. Calcd for C45 Si : C,
8.67; H, 6.78. Found: C, 58.87; H, 6.86. P NMR: δ 146.2
3
f
1
(
5
H
62
O
9
P
2
4
3
1
6
6
1
(
d, 1P, J P-P ) 23 Hz), 147.3 (d, 1P, J P-P ) 23 Hz). H NMR:
δ 0.35 (s, 18H, CH Si), 0.36 (s, 9H, CH Si), 0.41 (s, 9H, CH
Si), 1.02 (s, 3H, CH
H, CH ), 3.38 (d, 1H, H-2, J 2-1 ) 3.6 Hz), 4.03 (dd, 1H, H-4,
3
3
3
-
(
17) Buisman, G. J . H.; Martin, M. E.; Vos, E. J .; Klootwijk, A.;
Kamer, P. C. J .; van Leeuwen, P. W. N. M. Tetrahedron: Assymetry
995, 6, 719.
18) Buisman, G. J . H.; Kamer, P. C. J .; van Leeuwen, P. W. N. M.
Tetrahedron: Asymmetry 1993, 4, 1625.
3
3
), 1.08 (d, 3H, H-6, J 6-5 ) 6 Hz), 1.38 (s,
3
3
3
1
3
3
(
J 4-5 ) 7.6 Hz, J 4-3 ) 2.4 Hz), 4.68 (m, 1H, H-5), 4.70 (dd,
3
3
1H, H-3, J 3-4 ) 2.4 Hz, J 3-P ) 5.2 Hz), 5.41 (d, 1H, H-1, J 1-2

Chiral Diphosphates Derived from D-Glucose
3.6 Hz), 7.0-7.6 (m, 12H, CHd). 13C NMR: δ -0.2 (CH
J . Org. Chem., Vol. 67, No. 11, 2002 3801
)
3
Si),
),
)
then stirred under H
the catalyst, the solution was placed on a short silica gel
column and eluted with CH Cl . Conversion and enantiomeric
2
(5 atm) at room temperature. To remove
0
6
4
1
1
.1 (CH Si), 0.2 (CH Si), 19.7 (C-6), 25.7 (CH ), 26.4 (CH
8.6 (C-5), 76.4 (d, C-3, J C-P ) 9.2 Hz), 82.7 (9 (t, C-4, J C-P
.8 Hz), 83.8 (C-2), 104.6 (C-1), 111.4 (CMe ), 124.4 (CHd),
24.6 (CHd), 124.9 (CHd), 130.9 (C), 131.1 (C), 131.2 (C),
32.0 (CHd), 132.2 (CHd), 132.5 (CHd), 134.9 (CHd), 135.1
3
3
3
3
2
2
2
excesses were determined by gas chromatography.
Ack n ow led gm en t. We thank the Spanish Ministe-
rio de Educaci o´ n, Cultura y Deporte, and the Generali-
tat de Catalunya (CIRIT) for their financial support
Grant PB97-0407-CO5-01). We thank Prof. P. W. N.
M. van Leeuwen for his suggestions and comments.
(CHd), 153.4 (C), 153.5 (C), 153.6 (C).
Asym m etr ic Hyd r ogen a tion Rea ction s. In a typical
experiment, the autoclave was filled with a dichloromethane
solution (6 mL) of substrate (1 mmol), [Rh(cod) ]BF (4.95 mg,
.01 mmol), and ligand (0.011 mmol). This was then purged
(
2
4
0
2
three times with H and a vacuum. The reaction mixture was
J O0255429