Asymmetric hydrogenation of dehydroamino acid derivatives catalyzed by a new aminophosphine phosphinite ligand derived from ketopinic acid

Article abstract of DOI:10.1016/S0957-4166(00)00164-6

A new chiral aminophosphine phosphinite N,O-bis(diphenylphosphino)-(1S,2R)-1-(N-methylamino) methyl-2-hydroxyl-7,7-dimethylbicyclo[2.2.1]heptane was synthesized from ketopinic acid and its application to the asymmetric hydrogenation of dehydroamino acid d

Full text of DOI:10.1016/S0957-4166(00)00164-6

Tetrahedron: Asymmetry 11 (2000) 2077±2082
Asymmetric hydrogenation of dehydroamino acid derivatives
catalyzed by a new aminophosphine phosphinite ligand
derived from ketopinic acid
Xingshu Li,a Rongliang Lou,a Chi-Hung Yeung,a,*
Albert S. C. Chana,* and Wai Kwok Wongb
aOpen Laboratory of Chirotechnology and Department of Applied Biology and Chemical Technology, The Hong Kong
Polytechnic University, Hong Kong, People's Republic of China
bDepartment of Chemistry, Hong Kong Baptist University, Hong Kong, People's Republic of China
Received 7 February 2000; accepted 1 May 2000
Abstract
A new chiral aminophosphine phosphinite N,O-bis(diphenylphosphino)-(1S,2R)-1-(N-methylamino)
methyl-2-hydroxyl-7,7-dimethylbicyclo[2.2.1]heptane was synthesized from ketopinic acid and its application
to the asymmetric hydrogenation of dehydroamino acid derivatives examined. # 2000 Elsevier Science
Ltd. All rights reserved.
1. Introduction
The asymmetric hydrogenation of dehydroamino acid derivatives is a very useful method for
the preparation of chiral amino acids.1 A host of chiral ligands have been synthesized and used
for this type of reaction. Among them, the chiral aminophosphine phosphinite (AMPP) ligands
have attracted much attention due to their easy preparation.2 The preparation of these ligands
from inexpensive starting materials is of potential industrial value. In a previous paper we
reported the synthesis of new 1,3-aminoalcohols (1S,2S)- and (1S,2R)-1-hydroxylmethyl-2-amino-
7,7-dimethylbicyclo[2.2.1]heptane from a readily available starting material, ketopinic acid, and
its application in catalytic enantioselective reduction of prochiral ketones.3 Since the readily
available ketopinic acid represents a di€erent class of chiral source from the 2-amino-1,2-diphenyl-
ethanol which we have used successfully, the preparation and application of aminophosphine
phosphinites from ketopinic acid will signi®cantly expand the scope of this chemistry. In this
paper, we report the synthesis of a chiral aminophosphine phosphinite from ketopinic acid and
* Corresponding authors. E-mail: bcachan@polyu.edu.hk
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00164-6

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X. Li et al. / Tetrahedron: Asymmetry 11 (2000) 2077±2082
the application of this new ligand in the rhodium catalyzed enantioselective hydrogenation of
dehydroamino acid derivatives.
2. Results and discussion
The reaction of ketopinic acid with thionyl chloride followed by the addition of methylamine
hydrogen chloride in the presence of pyridine produced compound 2, which was then reduced
with NaBH4 in ^20ꢀC to produce exo-3 in almost quantitative yield (Scheme 1). Compound 3
.
reacted with BH3 THF to give aminoalcohol 4 (90% yield). Finally the chiral phosphine phosphinite
5 was obtained by the reaction of 4 with two equivalents of chlorodiphenylphosphine in anhydrous
benzene in the presence of triethylamine (58% yield).
Scheme 1.
The catalytic activity and enantioselectivity of Rh-5 catalyzed hydrogenation were studied by
using methyl (Z)-2-acetamidocinnamate as the model substrate (Scheme 2) and the results are
listed in Table 1.
Scheme 2.
The e€ects of reaction temperature and pressure of H2 on the enantioselectivity of the reaction
were quite small (entries 1 and 2: the e.e. value changed from 79 to 77% when the temperature
increased from 0 to 25ꢀC; entries 2 and 3: the e.e. values were 77 and 78% under the pressure of
500 psig and 250 psig, respectively). However, the e€ect of solvents on the enantioselectivity of
the reaction was quite signi®cant. Acetone was found to be the best solvent for this reaction.
The results of hydrogenation of other dehydroamino acid derivatives (Scheme 3) catalyzed by
Rh(COD)(exo-5)BF4 are listed in Table 2. The substituents have signi®cant in¯uence on the e.e.
of the products. Electron-withdrawing groups increased the enantioselectivity of products.

X. Li et al. / Tetrahedron: Asymmetry 11 (2000) 2077±2082
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Table 1
The e€ect of solvent and reaction condition on the hydrogenation of (Z)-2-acetamidocinnamate
a
catalyzed by Rh(COD)(5)BF4
Scheme 3.
Table 2
The hydrogenation of acetamidocinnamic acid methyl ester and substituted analogues by Rh(COD)(5)BF4
a

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In conclusion, we have synthesized a new chiral aminophosphine phosphinite ligand from
readily available ketopinic acid and the new ligand was found to be e€ective in Rh-catalyzed
hydrogenation reactions leading to amino acid derivatives. Further study of other applications of
this new ligand is in progress.
3. Experimental
Unless otherwise indicated, all reactions were carried out under N2 atmosphere. Melting points
were measured using an Electrothermal 9100 apparatus in capillaries and the data were uncor-
1
rected. Optical rotations were measured on a Perkin±Elmer Model 341 polarimeter. H NMR
spectra were recorded on a Bruker DPX-400 spectrometer. Mass analyses were performed on a
Finnigan Model Mat 95 ST mass spectrometer. GLC analyses were performed using a Hewlett±
Packard HP 4890A apparatus. The ketopinic acid was prepared from camphorsulfonic chloride
according to a literature procedure4 and the other chemicals were purchased from Acros or
Aldrich and were used as received.
3.1. Preparation of (1S)-7,7-dimethylbicyclo[2.2.1]heptane-1-N-methylcarboxylamide-2-one 2
To a ¯ask containing 1.85 g (10 mmol) of (+)-ketopinic acid, 2 ml thionyl chloride was added.
The mixture was stirred at room temperature for 2 h and then at re¯ux temperature for 1 h. The
excess thionyl chloride was removed under reduced pressure and the crude acid chloride was
obtained.
Pyridine (2 ml) was added to a solution of methylamine hydrogen chloride 1.34 g (20 mmol) in
25 ml of THF at ^10ꢀC, the mixture was stirred for 30 min and the solution of acid chloride
obtained above in 10 ml of dry THF was added slowly. After the stirring was continued at the
same temperature for 1 h and then 0ꢀC for 6 h, 10 ml water and 20 ml ether were added. The
organic layer was separated and the aqueous layer was extracted with ether. The combined
organic layers were washed with brine, dried over MgSO4. The solvent was removed under
reduced pressure and the crude product was puri®ed by chromatography (silica gel, hexane:ethyl
acetate, 1:1, v/v) to a€ord colorless solid 2 1.77g (91%). Mp=59±60ꢀC, [ꢀ]D=93.9 (c=0.57,
1
CHCl3); H NMR (CDCl3): 0.967 (s, 3H), 1.27 (s, 3H), 1.38±1.61 (m, 2H), 1.92±2.20 (m, 3H),
2.45±2.57 (m, 2H), 2.83±2.84 (d, J=4.8 Hz, 3H), 7.60 (s, 1H) ppm; 13C NMR (CDCl3): 20.314,
20.928, 25.624, 27.665, 28.363, 43.096, 43.711, 50.038, 64.513, 169.684 ppm; MS (ESI): 196 (M+
+1, 100%); calcd for C11H17NO2: C, 67.66; H, 8.78; N, 7.17. Found: C, 67.47; H, 8.81; N, 7.13.
3.2. (1S,2R)-2-Hydroxyl-7,7-dimethylbicyclo[2.2.1]heptane-1-N-methylcarboxylamide 3
To a ¯ask containing 1.95 g of compound 2 (10 mmol) and 0.76 g of sodium borohydride
(20 mmol), 30 ml of absolute methanol was added at ^20ꢀC and the reaction mixture was stirred
for 8 h and then warmed to 0ꢀC. After the solvent was removed in vacuo, 10 ml of water was
added and the solution was extracted with ethyl acetate. Evaporation of solvent and puri®cation
by ¯ash chromatography gave compound 3 1.93 g (98%). Mp=133±134ꢀC, [ꢀ]D=^22.65
1
(c=0.49, CHCl3); H NMR (CDCl3): 1.03 (s, 3H), 1.06±1.24 (m, 1H), 1.28 (s, 3H), 1.30±1.35
(m, 1H), 1.77±1.83 (m, 2H), 1.87±1.91 (m, 1H), 1.92±1.96 (m, 1H), 1.97±2.12 (m, 1H), 2.85±2.87
(d, J=4.0 Hz, 3H), 4.03±4.09 (d,d, J1=3.6 Hz, J2=3.4 Hz, 1H), 4.28 (br, 1H), 6.53 (s, 1H) ppm.

X. Li et al. / Tetrahedron: Asymmetry 11 (2000) 2077±2082
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13C NMR (CDCl3): 20.792, 21.581, 25.973, 27.210, 30.116, 41.328, 45.486, 49.651, 57.161,
175.032 ppm; calcd for C11H19NO2: C, 66.97; H, 9.71; N, 7.10. Found: C, 67.13; H, 9.75; N,
6.98.
3.3. (1S,2R)-1-(N-Methyl aminomethyl)-2-hydroxyl-7,7-dimethylbicyclo[2.2.1]heptane 4
.
A solution of borane THF complex (15 ml, 1 M in THF) was added to a solution of 1.56 g
compound 3 (8 mmol in 10 ml of dry THF). The mixture was stirred at room temperature for 12
h and then was quenched with 2N hydrogen chloride. The solution was diluted with dichloro-
methane and then sodium carbonate was added to make the pH of the solution about 9±10. The
organic layer was separated and the water layer was extracted with CHCl3 (3Â15 ml). Concentration
and chromatography of the crude product (methanol:ethyl acetate, 2:1) a€orded compound 4
ꢀ
1
1.32 g (90% yield). Mp=74±76 C; [ꢀ]D=^24.2 (c=0.66, CHCl3); H NMR (400 MHz, CDCl3):
0.84 (s, 3H), 1.09±1.13 (m, 2H), 1.16 (s, 3H), 1.45±1.46 (m, 1H), 1.66±1.70 (m, 3H), 1.71±1.82 (m,
1H), 2.47 (s, 3H), 2.51±2.58 (d, J=2.612 Hz, 1H), 3.06±3.09 (d, J=2.412 Hz, 2H), 3.90±4.07 (dd,
J=3.748, 3.756 Hz, 1H); MS (ESI): 184 (M+1,100); exact mass calculated for C11H21NO:
183.1623. Found: 183.1621.
3.4. Preparation of N,O-bis(diphenylphosphino)-(1S,2R)-1-(N-methylamino)methyl-2-hydroxyl-
7,7-dimethylbicyclo[2.2.1]heptane 5
92 mg of exo-4 (0.50 mmol) was placed in a Schlenk ¯ask and an inert atmosphere was intro-
duced by three cycles of vacuum/argon. Triethylamine (0.13 ml, 0.90 mmol) in 3 ml of anhydrous
benzene was added. The reaction mixture was stirred well and cooled to 0ꢀC with an ice bath. A
solution of 0.16 ml of chlorodiphenylphosphine (0.90 mmol) in 1 ml of anhydrous benzene was
added dropwise to the mixture. After all of the chlorodiphenylphosphine was added, the ice bath
was removed and the stirring was continued at ambient temperature for 24 h. Filtration of the
triethylammonium chloride followed by ¯ash column chromatography on silica gel (benzene as
1
eluent) gave 160 mg of 5 (58%). 31P NMR (CDCl3): 74.29 (s, P (N)), 115.21 (s, P(O)) ppm; H
NMR (CDCl3): 0.86±0.92 (m, 1H), 0.93 (s, 3H), 1.06±1.09 (m, 1H), 1.24 (s, 3H), 1.45±1.52 (m,
1H), 1.85±1.86 (m, 1H), 2.46±2.47 (d, J=4.12 Hz, 3H), 3.37±3.45 (dd, J=14.61, 15.54 Hz, 1H),
3.67±3.74 (dd, J=12.65, 12.59 Hz), 4.26±4.28 (m, 1H), 7.08±7.66 (m, 20H) ppm. C35H39NOP2
(551.6483), calcd: C, 76.21; H, 7.13; N, 2.54; P, 11.23. Found: C, 75.94; H, 7.18; N, 2.52; P,
11.16.
3.5. Typical procedures for the prepation of catalyst and for asymmetric catalytic hydrogenation
In an inert atmosphere glove box, [Rh(COD)2]BF4 (4.1 mg, 0.01 mmol) and exo-5 (5.9 mg,
0.0105 mmol) were dissolved in 1 ml of anhydrous acetone. After 10 min of stirring, the solution
of [Rh(COD)(exo-5)]BF4 obtained was ready for use in asymmetric hydrogenation. In a 50 ml
stainless steel autoclave were added the substrate methyl (Z)-2-acetaminocinnamate (0.1 mmol),
0.1 ml (0.001 mmol) of catalyst solution prepared above and 1 ml of the degassed acetone under
nitrogen atmosphere. The vessel was pressurized with 500 psi of H2 and the reaction was carried
out at room temperature for 7 h. The e.e. value and the conversion level were determined
by chiral GLC analysis with a Chirasil-L-Val column or HPLC analysis with a Chiralcel OD
column.

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Acknowledgements
We thank the Hong Kong Polytechnic University ASD fund and the Research Grants Council
of Hong Kong (project number ERB003) for ®nancial support of this study.
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