Synthesis of a novel spiro bisphosphinamidite ligand for highly enantioselective hydrogenation

Article abstract of DOI:10.1016/j.tetlet.2004.07.137

A novel chiral bisphosphinamidite ligand SpiroNP has been synthesized. The rhodium complex of this ligand has been found to be highly active and enantioselective in the asymmetric hydrogenation of (Z)-2-acetamidoacrylic acid derivatives and α,β-unsaturated carboxylic acid derivatives.

Full text of DOI:10.1016/j.tetlet.2004.07.137

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7379–7381
Synthesis of a novel spiro bisphosphinamidite ligand for highly
enantioselective hydrogenation
Ching Wen Lin, Chi-Ching Lin, Louis F.-L. Lam, Terry T.-L. Au-Yeung and
Albert S. C. Chan*
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
Received 20 May 2004; revised 20 July 2004; accepted 23 July 2004
Available online 19 August 2004
Abstract—A novel chiral bisphosphinamidite ligand SpiroNP has been synthesized. The rhodium complex of this ligand has been
found to be highly active and enantioselective in the asymmetric hydrogenation of (Z)-2-acetamidoacrylic acid derivatives and a,b-
unsaturated carboxylic acid derivatives.
Ó 2004 Elsevier Ltd. All rights reserved.
Ligands containing chiral bisphosphorus donors are the
most sought-after targets in asymmetric catalysis due to
the relative ease of manipulation of both the electronic
and steric properties about the phosphorus centre and
the extensive range of reactions in which they can be em-
ployed.1 Whilst bidentate phosphorus ligands possessing
stereogenic biaryl linkages have attracted much atten-
tion, the study of chiral ligands composed of other forms
of axial chirality, namely spiral compounds, is relatively
rare. Notable seminal reports in recent years include the
use of fructose-derived ketone 1 in epoxidation,2 chiral
spiro ammonium salts 3 in phase transfer catalysis,3
SPRIXs 4 in tandem Wacker-type cyclization,4 Siphos
5 in the hydrogenation of prochiral enamides,5 and
SDP 6 in the hydrogenation of unsymmetrical ketones.6
We have also contributed in this area by demonstrating
that bisphosphinite (R)-SpirOP 2 is highly efficient in
transferring stereochemical information to enamides
and (Z)-dehydroamino acid derivatives in catalytic
hydrogenation to give the corresponding amides and
a-amino acid derivatives, respectively, with good to
excellent enantioselectivities.7 We contended that the
potency of ligand 2 arises from the highly skewed and
a rigid conformation, a property which is also consid-
ered important to give rise to the effectiveness of BINAP
and related systems,8 of the spiro backbone.
R
O
Br
H
OPPh2
OPPh2
O
N
O
O
H
O
R
SpirOP 2
3
1
N
P
O
PAr2
PAr2
O
R
R
R
R
N
N
O
O
Siphos 5
SPRIXs 4
SDP 6
*
Corresponding author. Tel.: +852 2766 5608; fax: +852 2364 9932; e-mail: bcachan@polyu.edu.hk
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.137

7380
C.W.Lin et al./ Tetrahedron Letters 45 (2004) 7379–7381
HO
MsO
H
H
N3
H
H
N3
N3
H
H
(i)
(ii)
+
HO
(1S,5R,6S)-7
MsO
(1S,5R,6S)-8
H
(1R,5R,6R)-9
(1R,5R)-10
(iii)
H
H
NHPPh2
NHPPh2
NH2
NH2
(iv)
H
H
(1R,5R,6R)-12
(1R,5R,6R)-11
Scheme 1. Reagents and conditions: (i) MsCl, pyridine, 0°C—rt, 5h, 94%; (ii) NaN3, DMF, 80°C, 36h, 55%; (iii) Pd/C, H2, EtOH, RT, 2h, 98%;
(iv) (a) n-BuLi, THF À40°C; (b) Ph2PCl, À40°C—rt; (c) saturated NH4Cl(aq), 73%.
In search of a novel bisphosphinamidite ligand and fur-
ther exploiting the use of the enantiopure spiro[4.4]non-
ane skeleton, herein, we wish to report a short-route
synthesis of 12 (abbreviated (R)-SpiroNP) and its appli-
cations in the asymmetric hydrogenation of various ole-
finic substrates as a testing ground for its effectiveness.
was transformed to the corresponding spirodiamine 11
via Pd/C reduction with molecular hydrogen. Subse-
quent lithiation of 11 followed by the addition of chlo-
rodiphenylphosphine afforded (1R,5R,6R)-12 in a good
yield.
The active cationic rhodium complex [12-Rh(COD)]BF4
for hydrogenation was prepared directly by mixing
[Rh(COD)2]BF4 and (1R,5R,6R)-12 in dichloromethane
at room temperature, followed by solvent removal once
the complex was formed as judged by 31P NMR. Rou-
tine screening of solvents for the enantioselective hydro-
genation of methyl (Z)-acetamidocinnamate revealed
that the best solvent was acetone.
The overall synthesis for bisphosphinamidite 12 is illus-
trated in Scheme 1. The requisite (1S,5R,6S)-diol 7 was
first prepared according to our previously reported
method,9 which was then converted to the dimesylate
8. Treatment of 8 with sodium azide gave the
(1R,5R,6R)-diazide 9 (in a maximum of 55% yield)
and the mono-azido product 10. Several attempts were
made to eliminate the formation of 10 but were not suc-
cessful. The two products, however, could be readily
separated by flash chromatography. The spirodiazide 9
In the ensuing investigation, a number of methyl esters
of (Z)-2-acetamidoacrylic acid were hydrogenated with
0.2mol% [12-Rh(COD)]BF4 catalyst (Table 1) at room
temperature under 1atm H2. Quantitative conversion
was achieved within 1h for all the substrates studied
(Table 1) with enantioselectivities reaching over 99%
(Table 1: entries 2, 4–8). Various substitutions on the
phenyl ring of the acetamidocinnamate had almost
Table 1. The hydrogenation of various methyl esters of 2-acetamido-
acrylic acid and (Z)-2-acetamido-3-arylacrylic acids with [12-
Rh(COD)]BF4
[12-Rh(COD)]BF4
CO2Me
NHAc
CO2Me
NHAc
(0.2 mol%)
H2
(1 atm)
+
acetone, RT, 1h
R
R
Table 2. The hydrogenation of various 2-acetamidoacrylic acid and
(Z)-2-acetamido-3-arylacrylic acids with [12-Rh(COD)]BF4
Entry
R
H
ee (%)a,b
1
95 (>99.9)
[12-Rh(COD)]BF4
CO2H
NHAc
CO2H
NHAc
2Ph
3
>99 (96)
(0.2 mol%)
H2
(1 atm)
+
o-Chloro-phenyl
96
>99
ethanol, RT, 1.5 h
R
R
4
m-Chloro-phenyl
p-Chloro-phenyl
p-Bromo-phenyl
p-Fluoro-phenyl
p-Methoxy-phenyl
p-Methyl-phenyl
p-Nitro-phenyl
3,4-Methylene-
dioxyphenyl
5
>99 (94)
>99 (96)
>99 (96)
>99 (96)
>98 (96)
94
Entry
R
ee (%)a,b
78
6
1
H
7
2Ph
3
>98 (98)
8
o-Chloro-phenyl
m-Chloro-phenyl
o-Methoxy-phenyl
96 (97)
95 (97)
84
9
4
10
11
5
>98 (95)
6
3,4-Methylene-dioxyphenyl
3-Methoxy-4-acetophenyl
92
94
7
-Furfuryl
122
>99 (97)
a The ee values were determined by GC using a Chrompack Chiralsil-L-
Val capillary column. (R) product configuration was observed in all
cases.
b The number in parenthesis is the enantioselectivity obtained using
[(R)-2-Rh(COD)]BF4 catalyst under otherwise identical conditions.
a The ee values were determined by GC using a Chrompack Chiralsil-L-
Val capillary column. (R) product configuration was observed in all
cases.
b The number in parenthesis is the enantioselectivity obtained using
[(R)-2-Rh(COD)]BF4 catalyst under otherwise identical conditions.

C.W.Lin et al./ Tetrahedron Letters 45 (2004) 7379–7381
7381
Table 3. Asymmetric hydrogenations of a,b-unsaturated carboxylic
acid derivatives by [12-Rh(COD)]BF4
In conclusion, a new chiral bisphosphinamidite ligand,
SpiroNP, based on a spiro backbone has been developed
via a short-path synthesis. The cationic rhodium com-
plex of SpiroNP was found to be an excellent catalyst
for the synthesis of chiral amino acid and acrylic acid
derivatives under mild conditions, giving products of
up to >99% ee.
a
Entry
1
Substrate
Product
ee (%), configuration
CO2H
CO2H
68, S
CO2H
CO2Me
CO2Me
CO2H
CO2Me
CO2Me
2
3
4
93, S
96, R
97, R
Acknowledgements
CO2Me
CO2Me
We thank the University Grants Committee Areas of
Excellence Scheme in Hong Kong (AoE P/10-01) and
The Hong Kong Polytechnic University Area of Strate-
gic Development Fund for financial support of this
study.
OC(O)Me
OC(O)Me
CO2Et
CO2Et
OC(O)Me
OC(O)Me
a S/C = 250; [Sub] = 0.2M; pressure of H2 = 1atm; 1.5h; room tem-
perature; solvent = THF.
References and notes
1. (a) Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley–
VCH: USA, 2000; (b) Jacobson, E. N.; Pfaltz, A.; Yama-
moto, H. In Comprehensive Asymmetric Catalysis; Springer:
Germany, 1999; Vol. I–III.
2. Tu, Y.; Wang, Z.-X.; Shi, Y. J.Am.Chem.Soc. 1996, 118,
9806–9807.
negligible effect on the resulting enantioselectivities. It
should be noted that the enantioselectivities obtained
in this study were observed to be even higher than those
obtained by using the highly effective SpirOP-Rh(I)
catalyst.7
3. Ooi, T.; Kameda, M.; Maruoka, K. J.Am.Chem.Soc.
1999, 121, 6519–6520.
4. Arai, M. A.; Kuraishi, M.; Arai, T.; Sasai, H. J.Am.Chem.
Soc. 2001, 123, 2907–2908.
5. Hu, A.-G.; Fu, Y.; Xie, J.-H.; Zhou, H.; Wang, L.-X.;
Zhou, Q.-L. Angew.Chem,. Int.Ed. 2002, 41, 2348–2350.
6. Xie, J.-H.; Wang, L.-X.; Fu, Y.; Zhu, S.-F.; Fan, B.-M.;
Direct catalytic asymmetric conversion of (Z)-2-acetam-
ido-3-acrylic acids into their corresponding amino acids
is also feasible with [12-Rh(COD)]BF4 (Table 2). In this
case, the protic solvent ethanol was the optimal solvent
furnishing the hydrogenation products in excellent con-
version with good to excellent enantioselectivity, except
for 2-acetamidoacrylic acid (entry 1).
Duan, H.-F.; Zhou, Q.-L. J.Am.Chem.Soc.
4404–4405.
2003, 125,
7. (a) Chan, A. S. C.; Hu, W.-H.; Pai, C.-C. J.Am.Chem.Soc.
1997, 119, 9570–9571; (b) Hu, W.-H.; Yan, M.; Lau, C.-P.;
Yang, S. M.; Chan, A. S. C. Tetrahedron Lett. 1999, 40,
973–976; (c) Li, X.-S.; Yeung, C.-H.; Chan, A. S. C.; Lee,
D.-S.; Yang, T.-K. Tetrahedron: Asymmetry 1999, 10,
3863–3867.
8. Ohta, H.; Takaya, H.; Noyori, R. Inorg.Chem. 1988, 27,
566.
9. Lin, C.-W.; Lin, C.-C.; Li, Y.-M.; Chan, A. S. C.
Tetrahedron Lett. 2000, 401, 4425–4429.
To further probe the effectiveness of 12, the hydrogena-
tion of another class of substrates was also investigated.
Again, the rhodium complex of 12 was sufficiently
active to promote the complete hydrogenation of a,b-
unsaturated carboxylic acid derivatives (Table 3) under
atmospheric hydrogen pressure within 1.5h. The enan-
tioselectivity ranged from moderate to excellent.