Synthesis of novel chiral binaphthyl phosphorus ligands and their applications in Rh-catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1016/S0040-4039(02)00877-8

A series of new chiral mono- or bidentate phosphorus ligands were efficiently prepared through a key intermediate (S)-4-chloro-4,5-dihydro-3H-4-phosphacyclohepta[2,1-a;3,4-a′] binaphthalene and its derivatives. These ligands were applied in the Rh-catalyzed asymmetric hydrogenation of α-dehydro amino acids, enol acetates, itaconates, and enamides. Good to excellent enantioselectivities were obtained (up to 99.5% ee).

Full text of DOI:10.1016/S0040-4039(02)00877-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4849–4852
Synthesis of novel chiral binaphthyl phosphorus ligands and their
applications in Rh-catalyzed asymmetric hydrogenation
Yongxiang Chi and Xumu Zhang*
Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA
Received 5 March 2002; accepted 6 May 2002
Abstract—A series of new chiral mono- or bidentate phosphorus ligands were efficiently prepared through a key intermediate
(S)-4-chloro-4,5-dihydro-3H-4-phosphacyclohepta[2,1-a;3,4-a%]binaphthalene and its derivatives. These ligands were applied in the
Rh-catalyzed asymmetric hydrogenation of a-dehydro amino acids, enol acetates, itaconates, and enamides. Good to excellent
enantioselectivities were obtained (up to 99.5% ee). © 2002 Elsevier Science Ltd. All rights reserved.
Discovery of new chiral phosphorus ligands plays a
critical role in asymmetric catalysis.1 Atropisomeric 1,1%-
binaphthalene core is the parent framework of steadily
increasing families of chiral ligands for asymmetric
reactions.2 Reetz3 and Pringle4 prepared chelating chiral
phosphites using readily accessible Binaphthol (BINOL)
as the starting material and demonstrated that they are
excellent ligands for Rh-catalyzed asymmetric hydro-
genation of dehydroamino acids. Feringa5 has developed
a variety of chiral phosphoramidites from BINOL and
high enantioselectivities (up to 98% ee) were achieved in
Michale addition of cyclic enones. Gladiali6 and Stelzer7
made several mono- or bidentate chiral phosphanes as
well as the corresponding racemic chelating derivatives
bearing the 1,1%-binaphthyl core. However, only limited
applications of these ligands for asymmetric catalysis
were reported.6a
asymmetric hydrogenation of b-substituted-a-aryl-
enamides and Ir-catalyzed asymmetric hydrogenation of
acyclic imines. By using NaH as the base, condensation
of (R)-2,2%-dichloromethyl-1,1%-binaphthyl with 1,2-bis-
(phosphino)benzene or 1,1%-bis(phosphino)ferrocene
yielded BINAPHANE or f-BINAPHANE in good
yields. The (R)-2,2%-dichloromethyl-1,1%-binaphthyl was
synthesized from (R)-BINOL through four-step reac-
tions in 63% overall yield. However, this synthetic route
is not flexible for generating a variety of structurally
diverse of ligands and is too long for making these chiral
ligands.
Herein, we report a simple and efficient new pathway for
making chiral phosphorus ligands. Using (S)-2,2%-
dimethyl-1,1%-binaphthyl and it’s 3,3%-diphenyl deriva-
tive, an array of new chiral mono- or bidentate
phosphorus ligands (S)-1–(S,S)-5 (Fig. 2) were efficiently
synthesized through a dilithiated species (S)-7 and (S)-4-
chloro-4,5-dihydro-3H-4-phosphacyclohepta[2,1-a;3,4-
a] binaphthalene (S)-8.
Recently, we prepared two chiral chelating phosphane
ligands, BINAPHANE8 and f-BINAPHANE9 (Fig. 1),
which gave excellent enantioselectivities for Rh-catalyzed
P
Fe
P
P
P
(S,S)-f-BINAPHANE
(S,S)-BINAPHANE
Figure 1.
* Corresponding author. Fax: +1-814-863-8403; e-mail: xumu@chem.psu.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00877-8

4850
Y. Chi, X. Zhang / Tetrahedron Letters 43 (2002) 4849–4852
Figure 2.
R
R
R
Li
Li
ii
i
P Cl
40 %
50-60 %
R
R
R
(S)-6a : R=H
(S)-7a : R=H
(S)-8: R=H
(S)-6b : R=Ph
(S)-7b : R=Ph
Scheme 1. Synthesis of synthon (S)-8. Reagents and conditions: (i) n-BuLi, Et2O, −78°C to rt, 30 min; rt, 24 h; −78°C, 3 h; (ii)
PCl3, hexane, rt, 12 h.
Scheme 2. Synthesis of phosphorus ligands 1–5. Reagents and conditions: (i) diethylamine, Et3N, toluene, −40°C, 12 h; (ii) phenol,
Et3N, toluene, −40°C, 12 h; (iii) t-BuMgBr, THF, rt, 12 h; (iv) (S,S)- or (R,R)-1,2-diaminocyclohexane, Et3N, toluene, −40°C, 12
h; (v) hexane, rt, 12 h.

Y. Chi, X. Zhang / Tetrahedron Letters 43 (2002) 4849–4852
4851
attack of 1,2-bis(dichlorophosphine)ethane with (S)-7
provided an efficient way to prepare bidentate phosphane
ligands (S,S)-5.
The key synthon, (S)-4-chloro-4,5-dihydro-3H-4-phos-
phacyclohepta[2,1-a;3,4-a%] binaphthalene (S)-8 for the
synthesis of many phosphorus ligands 1–4, can be
prepared as shown in Scheme 1. The starting material,
(S)-2,2%-dimethyl-1,1%-binaphthyl (S)-6a, was easily pre-
pared through two-step operations from (S)-BINOL
according to recent literatures methods.8,10 (S)-3,3%-
Diphenyl-2,2%-dimethyl-1,1%-binaphthyl (S)-6b was made
by the method of Maruoka.11 2,2%-Dimethyl-1,1%-binaph-
thyl (S)-6a was lithiated with 2.5 equiv. of n-butyllithium
in ether and the dilithium salt (S)-7a was separated under
N2 asredpowderin60%yield.12 Anotherdilithiumspecies
(S)-7b was prepared in the same way from (S)-6b in 50%
yield. Reaction of (S)-7a with phosphine trichloride in
hexane at rt overnight, followed by recrystallization from
CH2Cl2/hexane, yielded the pure synthon 8 as yellow
powder.
We have used monodentate phosphorus ligands (S)-1–3
fortheRh-catalyzedasymmetrichydrogenationofmethyl
2-acetamido acrylates. The hydrogenation reaction was
performed at ambient temperature under 60 psi of H2 in
MeOH for 24 h. Using Rh(COD)2SbF6–(S)-1–3 (1:2) as
an in-situ catalyst with a substrate to metal ratio of 100:1,
quantitative conversions were obtained for hydrogena-
tion reactions. Low and moderate ee’s were achieved
(59.3% ee for (S)-1, 55.8% ee for (S)-2), 6.3% ee for (S)-3).
The R-enantiomer is the preferred product in all cases.
In order to investigate the cooperative effect of the
1,1%-binaphthyl motif and trans-1,2-diaminocyclohexane.
Two phosphoramidite ligands (S,S,S,S)-4 and (S,R,R,S)-
4 were employed for Rh-catalyzed hydrogenation of
several substrates (Table 1). In comparison with ligand
(S,S,S,S)-4, (S,R,R,S)-4 was found to be more effective
for asymmetric hydrogenation (Table 1, entry 5 versus
entry 2, entry 6 versus entry 4).
As shown in Scheme 2, chiral phosphoramidite ligands
(S)-1, (S,S,S,S)-4 or (S,R,R,S)-4, and phosphite ligand
(S)-2 were synthesized by nucleophilic substitution of
(S)-8. RecrystallizationfromCH2Cl2/hexanegavedesired
ligands as white powder in satisfactory yields. The
reaction of the synthon (S)-8 with t-butyl Grignard
reagent in THF afforded the monodentate phosphane
ligand (S)-3 in 60% yield. However, owing to the difficulty
of preparation of XMgCH2CH2MgX, this route is not
applicable for the synthesis of ligand 5. Nucleophilic
Bidentate chiral phosphane ligands (S,S)-5a and 5b were
used for the Rh-catalyzed asymmetric hydrogena-
tion of enamides 9a–g, Table 2 shows the experimental
results. Although Rh-(S,S)-5a only offers good enan-
tioselectivity for hydrogenation of a-arylenamides with-
out a substitution in the b-position (entry 1, 77.2% ee;
entry 2, 93.5% ee), it is effective for reducing b-substi-
tuted-a-arylenamides (entries 3–7, 93.1–99.5% ee). This
Table 1. Asymmetric hydrogenation of enamide 9a, enol
acetate 10, itaconate 11 with Rh-(S,S,S,S)-4 or Rh-
(S,R,R,S)-4 catalysta
Table 2. Asymmetric hydrogenation of enamide 9 by Rh-
(S,S)-5a
NHAc
9a
NHAc
(S)-12a
Rh-(S,S,S,S)-4
or
Rh-(S,R,R,S)-4
(1mol%)
Rh-(S,S)-5
(1mol%)
NHAc
H2, MeOH
R
R
R
+
OAc
Ar
NHAc
(R)-12b
OAc
Ar
NHAc Ar
Z-9
E-9
(S)-13
10
H2, MeOH
CH3O2CCH2
Ee (%)c
CH3O2CCH2
Entry
Substrate
Ar, R
Ligand
H3CO2C
H3CO2C
1
2
3
4
9a
9b
9c
9d
C6H5, H
2-Np, H
C6H5, CH3
C6H5,
CH(CH3)2
4-MeO-C6H5,
CH3
4-CF3-C6H5,
CH3
2-Np, CH3
C6H5, H
(S,S)-5a
(S,S)-5a
(S,S)-5a
(S,S)-5a
77.2
93.5
97.5
97.7
(R)-14
11
Entry
Substrate
Ligand
Ee (%)b
Configurationc
5
6
9e
9f
(S,S)-5a
(S,S)-5a
99.5
93.1
1
2
3
4
5
6
9a
10
11
9a
10
11
(S,S,S,S)-4
(S,S,S,S)-4
(S,S,S,S)-4
(S,R,R,S)-4
(S,R,R,S)-4
(S,R,R,S)-4
44.3
77.0
65.9
70.9
90.4
85.5
S
S
R
S
S
R
7
8
9g
9a
(S,S)-5a
(S,S)-5b
99.5
49.3
a The reaction was carried out at room temperature under an initial
hydrogen pressure of 40 psi for 24 h. The catalyst was made in situ
by stirring a solution of Rh(NBD)2SbF6 and chiral ligand (S,S)-5 in
MeOH [substrate (0.5 mmol)]:[Rh]:(S,S)-5=100:1:1.1. The reaction
proceeded in quantitative yield.
a The reaction was carried out at room temperature under an initial
hydrogen pressure of 40 psi for 24 h. The catalyst was made in situ
by stirring a solution of Rh(COD)2SbF6 and chiral ligand 4 in
MeOH. The reaction proceeded in quantitative yield.
b Enantiomeric excesses were determined by chiral GC with a Supelco
chiral select 1000 column (for 12a and 13), or a gamma dex 225
column (for 14).
b
The configurations were determined by comparison of optical
rotations with reported data.
c Enantiomeric excesses were determined by chiral GC with a Supelco
chiral select 1000 column, or Chiral HPLC with a Regis (S,S)-
Whelk-01 column.13
c
The configurations were determined by comparison of optical
rotations with reported data.

4852
Y. Chi, X. Zhang / Tetrahedron Letters 43 (2002) 4849–4852
catalytic system can tolerate the E- and Z-mixture
substrates of enamides. A small electronic effect was
observed. For example, hydrogenation of 9e bearing an
electron-donating 4-methoxy substituent in the aryl
group proceeded with the higher enantioselectivity
(entry 8, 99.5% ee) than the result obtained with 9c
(entry 3, 97.5% ee). Hydrogenation of 9f bearing an
electron-withdrawing 4-CF3 substituent in the aryl
group proceeded with the lower enantioselectivity
(entry 6, 93.1% ee). Compared with Rh-(S,S)-5a, Rh-
(S,S)-5b gave a poor enantioselectivity for hydrogena-
tion of a-arylenamide (entry 8, 49.3% ee). The effect of
3,3%-diphenyl substituent in binaphthyl backbone for
the Rh-catalyzed hydrogenation currently is under
investigation.
References
1. (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994; (b) Catalytic Asymmetric Synthe-
sis; Ojima, I., Ed.; VCH: New York, 1999; (c) Comprehen-
sive Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H., Eds.; Springer: Berlin, 1999; (d) Handbook
of Enantioselective Catalysis; Brunner, H.; Zettlmeier, W.,
Eds.; VCH: New York, 1993.
2. (a) Whitesell, J. K. Chem. Rev. 1989, 1581; (b) Rosini, C.;
Franzini, L.; Raffaelli, A.; Salvadori, P. Synthesis 1992,
503; (c) Pu, L. Chem. Rev. 1998, 98, 2405.
3. (a) Reetz, M. T.; Sell, T. Tetrahedron Lett. 2000, 41, 6333;
(b) Reetz, M. T. Pure Appl. Chem. 1997, 71, 1503; (c) Reetz,
M. T.; Neugebauer, T. Angew. Chem., Int. Ed. 1999, 38,
179; (d) Reetz, M. T.; Gosberg, A. Tetrahedron: Asymme-
try 1999, 10, 2129; (e) Reetz, M. T.; Gosberg, A.; Goddard,
R.; Kyung, S.-H. Chem. Commun. 1998, 2077.
4. Claver, C.; Fernandez, E.; Gillon, A.; Heslop, K.; Hyett,
D. J.; Martorell, A.; Orpen, A. G.; Pringle, P. G. Chem.
Commun. 2000, 961.
5. Arnold, L. A.; Imbos, R.; Mandoli, A.; deVries, A. H. M.;
Massz, R.; Feringa, B. L. Tetrahedron 2000, 56, 2865.
6. (a) Gladiali, S.; Dore, A.; Fabbri, D.; Lucchi, O. D.;
Manassero, M. Tetrahedron: Asymmetry 1994, 511; (b)
Gladiali, S.; Dore, A.; Fabbri, D. J. Org. Chem. 1994, 59,
6363; (c) Gladiali, S.; Fabbri, D. Chem. Ber. 1997, 130, 543.
7. Bitterer, F.; Herd, O.; Kuhnel, M.; Stelzer, O.; Werferling,
N.; Sheldrick, W. S.; Hahu, J.; Nagel, S.; Rosch, N. Inorg.
Chem. 1998, 37, 6408.
In conclusion, a simple and effective route for prepar-
ing phosphorus ligands bearing an 1,1%-binaphthyl
motif was established. An array of new chiral mono- or
bidentate phosphorus ligands (S)-1–(S,S)-5 were
efficiently obtained through a dilithiated species (S)-7
and (S)-4-chloro-4,5-dihydro-3H-4-phosphacyclohepta-
[2,1-a;3,4-a%]binaphthalene (S)-8. The applications of
ligands 1–5 in Rh-catalyzed asymmetric hydrogenation
were tested. Excellent enantioselectivities (93–99% ee)
have been observed in hydrogenation of an isomeric
mixture of E- and Z-b-substituted-a-arylenamides by
using Rh-(S,S)-5a as the catalyst. Other applications of
ligands 1–5 for asymmetric catalysis will be disclosed in
due course.
8. Xiao, D.; Zhang, Z.; Zhang, X. Org. Lett. 1999, 1, 1679.
9. Xiao, D.; Zhang, X. Angew. Chem., Int. Ed. 2001, 40, 3425.
10. Mecca, T.; Superchi, E. G.; Rosini, C. Tetrahedron: Asym-
metry 2001, 12, 1225.
Acknowledgements
11. Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc.
We gratefully acknowledge the support by the National
Institutes of Health and a Camille and Henry Dreyfus
Teacher–Scholar Award. We also thank Johnson
Matthey Inc. for a generous loan of precious metals
and Supelco and Regis for a gift of chiral columns.
1999, 121, 6519.
12. Klein, H.; Jackstell, R.; Wiese, K.-D.; Borgmann, C.;
Buller, M. Angew. Chem., Int. Ed. 2001, 40, 3408.
13. Zhu, G.; Zhang, X. J. Org. Chem. 1998, 63, 9590.