Highly enantioselective synthesis of α-hydroxy phosphonic acid derivatives by Rh-catalyzed asymmetric hydrogenation with phosphine- phosphoramidite ligands

Article abstract of DOI:10.1002/anie.200702924

(Chemical Equation Presented) A class act: Unsymmetrical hybrid phosphine-phosphoramidite ligands with central and axial chirality are applied to the highly enantioselective hydrogenation of various enol ester phosphonates (see scheme; cod = cycloocta-1,5-diene). Enantioselectivities up to 99.9% ee are obtained for all classes of β-aryl, β-alkoxy, and β-alkyl substrates.

Full text of DOI:10.1002/anie.200702924

Communications
DOI: 10.1002/anie.200702924
Asymmetric Catalysis
Highly Enantioselective Synthesis of a-Hydroxy Phosphonic Acid
Derivatives by Rh-Catalyzed Asymmetric Hydrogenation with
Phosphine–Phosphoramidite Ligands**
Dao-Yong Wang, Xiang-Ping Hu,* Jia-Di Huang, Jun Deng, Sai-Bo Yu, Zheng-Chao Duan,
Xue-Feng Xu, and Zhuo Zheng*
Optically active a-hydroxy phosphonic acid derivatives are
widely used as enzyme inhibitors, antibacterial agents, anti-
viral agents, antibiotics, anticancer agents, and pesticides, as
well as useful building blocks for the synthesis of many other
important a-functionalized optically active phosphonates.[1]
Therefore, an enantioselective synthesis of these compounds
is highly desirable. Asymmetric catalysis has provided several
novel solutions for the synthesis of chiral a-hydroxy phos-
phonic acid derivatives, including asymmetric reduction of
ketophosphonates[2] and phosphonylation of carbonyl com-
pounds.[3]
For its inherent efficiency and atom economy, much effort
in the past few years has been directed toward the develop-
ment of an asymmetric hydrogenation of a-enol esters of
phosphonate substrates.[4] By this means, b-alkyl-substituted
a-acyloxy phosphonates were hydrogenated with good enan-
tioselectivities by using Rh catalysts bearing DuPHOS (1,2-
bis((2R,5R)-2,5-dialkylphospholano)benzene), BisP* ((S,S)-
1,2-bis(alkylmethylphosphino)ethane), MiniPHOS (R,R-
bis(alkylmethylphosphino)methane),and phosphine–phos-
phite ligands. However, catalyst performance for b-aryl- and
b-alkoxy-substituted substrates was less than satisfactory, as
moderate enantioselectivities or low conversions were
observed in most cases.
hydrogenation of this class of substrates, in which 87% ee
was obtained.[4c] Therefore, the highly enantioselective syn-
thesis of a-hydroxy phosphonate derivatives by asymmetric
hydrogenation of a-enol ester phosphonates, especially those
bearing b-aryl or b-alkoxy substituents, is still a significant
challenge for organic chemists. Herein, we report a new chiral
phosphine–phosphoramidite ligand derived from (Rc)-1,2,3,4-
tetrahydro-1-naphthylamine (Rc = central chirality), which
promoted unprecedented enantioselectivities (up to
99.9% ee) in Rh-catalyzed asymmetric hydrogenation across
a broad range of substrates bearing b-aryl, b-alkoxy, and b-
alkyl substituents.
Ligand design has played a pivotal role in the develop-
ment of efficient metal-catalyzed asymmetric reactions.
Although a large number of bidentate phosphorus ligands
with C2 symmetry or two closely related binding sites have
been prepared and examined for asymmetric hydrogenation,
significantly fewer unsymmetrical hybrid bidentate phospho-
rus ligands were disclosed.[5] We[6] and others[7] have recently
revealed that chiral phosphine–phosphoramidite ligands are
highly efficient for the asymmetric hydrogenation of various
functionalized olefins, including a- and b-dehydroamino acid
esters, itaconate, and enamides. In our ongoing efforts toward
the development of new and practical chiral ligands for use in
the hydrogenation of challenging substrates, we designed a
class of rigid chiral phosphine–phosphoramidite ligands with
a 1,2,3,4-tetrahydronaphthalene backbone.
Recently, Pizzano and co-workers[4d,f] reported that the
use of a phosphine–phosphite/Rh catalyst could give rise to an
ee value of up to 92% in the asymmetric hydrogenation of b-
aryl-substituted substrates, although only the b-phenyl-sub-
stituted substrate afforded an ee value over 90% under full
conversion. As for the hydrogenation of b-alkoxy-substituted
substrates, there is only one report on the asymmetric
The phosphine–phosphoramidite ligands 1 can be readily
prepared from optically pure (Rc)-1,2,3,4-tetrahydro-1-naph-
thylamine ((Rc)-2) through a concise synthetic procedure
(Scheme 1). The initial step involves functionalization of
[*] D.-Y. Wang, Dr. X.-P. Hu, J.-D. Huang, J. Deng, S.-B. Yu, Z.-C. Duan,
X.-F. Xu, Prof. Dr. Z. Zheng
Dalian Institute of Chemical Physics
Chinese Academy of Sciences
457 Zhongshan Road, Dalian 116023 (China)
Fax: (+86)411-8468-4746
E-mail: xiangping@dicp.ac.cn
zhengz@dicp.ac.cn
D.-Y. Wang, J.-D. Huang, J. Deng, S.-B. Yu, Z.-C. Duan
Graduate School of Chinese Academy of Sciences
Beijing 100039 (China)
[**] We are grateful for the financial support from the National Natural
Science Foundation of China (20472083). X.-P.H. thanks Bo Zheng
and Prof. Huai-Ming Hu for solving the X-ray crystal structure.
Scheme 1. Synthesis of phosphine–phosphoramidite ligands (Rc,Ra)-1a
and (Rc,Sa)-1b: a) 1. nBuLi, ClSiMe3, Et2O, 08C; 2. nBuLi, ClPPh2, Et2O,
ꢀ308C!RT, 52%; b) (Ra)-4-chloro-3,5-dioxa-4-phosphacyclohepta[2,1-
a’;3,4-a’]dinaphthalene, Et3N, CH2Cl2, 08C–RT, 89%.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Asymmetrichydrogenation of b-aryl substrates 4.[a]
position 8 of (Rc)-2 by a directed metalation reaction to form
the key aminophosphine intermediate (Rc)-3.[8] This com-
pound is then converted into the corresponding phosphine–
phosphoramidite ligand (Rc,Ra)-1a (Ra = axial chirality) in
high yields by reaction with (Ra)-binol-derived chlorophos-
phite (binol = 1,1’-binaphthalene-2,2’-diol) in CH2Cl2 at 08C
in the presence of Et3N. By a similar procedure, diastereo-
meric ligand (Rc,Sa)-1b was also prepared in good yields.
Besides their ready availability, another salient and practical
feature of these phosphine–phosphoramidite ligands is their
excellent air and moisture stability, which makes the syn-
thesis, use, and storage of these ligands very convenient.
To establish the conformational orientation of the chiral
phosphine–phosphoramidite ligand in its coordinated forms, a
crystal of the complex [Rh(cod){(Rc,Ra)-1a}]BF4 (cod =
cycloocta-1,5-diene) prepared from [Rh(cod)2]BF4 and
(Rc,Ra)-1a in CH2Cl2 was grown and subjected to X-ray
diffraction analysis.[9] As shown in Figure 1, a seven-mem-
bered heterometallacyclic ring was formed by the chelate
coordination of the phosphine and phosphoramidite P atoms
of (Rc,Ra)-1a to rhodium, with a P-Rh-P bite angle of 89.58.
Entry
Substrate, Ar
Solvent
ee [%]
1
4a, Ph
4a, Ph
4a, Ph
4a, Ph
CH2Cl2
CH2Cl2
iPrOH
toluene
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
CH2Cl2
CH2Cl2
99.4
60.3
99.5
n.d.[c]
99.9
99.9
99.6
99.2
99.9
99.8
99.3
99.9
99.2
99.3
99.4
2[b]
3
4
5
6
7
8
9
10
11
12
13
14
15[d]
4b, p-FC6H4
4c, p-ClC6H4
4d, p-BrC6H4
4e, p-NO2C6H4
4 f, p-MeOC6H4
4g, m-MeOC6H4
4h, m-ClC6H4
4i, o-ClC6H4
4j, 1-naphthyl
4k, 2-thienyl
4a, Ph
[a] All reactions were carried out with 0.25 mmol of substrate in 2 mL of
the indicated solvent for 12 h under the conditions given in the equation
and with 100% conversion, unless otherwise specified. Degrees of
conversion were determined by 1H NMR spectroscopy. The ee values
were determined by HPLC on a chiral column (Chiralpak AD, Chiralcel
OD-H, or Chiralcel OJ-H). [b] (Rc,Sa)-1b was used instead of (Rc,Ra)-1a
[c] Conversion and ee value were not determined because of low
conversion. [d] Substrate/[Rh(cod)2]BF4 =1000:1, H2 (20 bar).
Subsequent solvent-screening experiments revealed that
the nature of the solvent had a profound effect on the
catalytic reaction. The hydrogenation reactions performed in
CH2Cl2 and iPrOH gave comparable results (Table 1,
entries 1 and 3). However, very low conversion was observed
when the reaction was carried out in toluene, probably
because of the low solubility of the ligand and the resulting
catalyst in toluene (Table 1, entry 4). With these encouraging
results, we proceeded to investigate the scope of this
challenging reaction on various b-aryl enol ester phospho-
nates, with iPrOH as the standard solvent. As the b-2-thienyl
substrate has a low solubility in iPrOH, in this case CH2Cl2
was selected as the reaction medium.
Figure 1. Crystal structure of [Rh(cod)((Rc,Ra)-1a)]BF4. The counter
anion (BF4ꢀ), hydrogen atoms, and solvent are omitted for clarity.
These novel phosphine–phosphoramidite ligands were
then tested in the Rh-catalyzed asymmetric hydrogenation of
enol ester phosphonates. For the initial screening and
optimization process, the highly challenging b-phenyl enol
ester phosphonate 4a was selected as substrate, and the
As shown in Table 1, a wide range of substituted b-phenyl
enol ester phosphonates were hydrogenated to provide the
corresponding b-aryl-a-hydroxy phosphonic acid derivatives
results are summarized in Table 1. To our delight, we found at high conversions and extremely high enantioselectivities
that the catalyst generated by mixing [Rh(cod)2]BF4
(1.0 mol%) with ligand (Rc,Ra)-1a (1.1 mol%) in CH2Cl2
under a H2 pressure of 10 bar led to full conversion of 4a
into 5a with an unprecedented ee value of 99.4%, which
suggests the high potential of this catalytic system in the
hydrogenation of enol ester phosphonates (Table 1, entry 1).
In contrast, ligand (Rc,Sa)-1b with an (Sa)-binaphthyl frag-
ment displayed low enantioselectivity and favored a hydro-
genation product with a configuration the same as that
(ee values of over 99.0% for all substrates tested) under mild
conditions (10 bar H2, room temperature; Table 1, entries 5–
12). These results indicate that the reaction system has a high
tolerance to the substitution pattern and electronic properties
of the substrates.
The best enantioselectivities were obtained in the hydro-
genation of 4b, 4c, 4 f, and 4i, which afforded the corre-
sponding hydrogenation product with 99.9% ee (Table 1,
entries 5, 6, 9, and 12). The b-1-naphthyl-substituted substrate
obtained with (Rc,Ra)-1a (Table 1, entry 2). These results led to the corresponding hydrogenation product with
demonstrate that the central chirality has more influence in
determining the absolute configuration of the predominant
hydrogenation product, and the matched stereogenic ele-
ments are Rc (central chirality) and Ra (axial chirality).
99.2% ee (Table 1, entry 13). An outstanding enantioselec-
tivity of 99.3% ee was also observed in the hydrogenation of
the substrate containing a thienyl group (Table 1, entry 14).
To further demonstrate the efficiency of the present catalytic
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Communications
system, the hydrogenation of 4a was also performed with
reduced catalyst loadings (0.1 mol%); in this reaction, the
(20 bar) was needed to complete the reaction at lower catalyst
loadings of 0.05 mol% (Table 2, entry 8), which is the lowest
excellent enantioselectivity remained (Table 1, entry 15). To amount of catalyst used to date. As reported by Burk et al.,[4a]
the best of our knowledge, these results represent the highest
catalytic activities and enantioselectivities in the asymmetric
hydrogenation of enol ester phosphonates reported so far.
Having established a highly enantioselective hydrogena-
tion of b-aryl enol ester phosphonates 4, we decided to apply
this efficient methodology to the hydrogenation of b-alkoxy
the a-benzoyloxy phosphonates can be simply deprotected by
K2CO3 in methanol at room temperature to afford the
corresponding a-hydroxy phosphonates with no apparent
loss of optical purity.
In conclusion, new unsymmetrical hybrid phosphine–
phosphoramidite ligands have been developed and applied to
enol ester phosphonates 6 (Table 2). The hydrogenation of the enantioselective hydrogenation of various enol ester
phosphonates, including b-aryl-, b-alkoxy-, and b-alkyl-sub-
stituted substrates. Unprecedented enantioselectivities (up to
Table 2: Asymmetrichydrogenation of b-alkoxy and b-alkyl substrates 6
and 7.[a]
99.9% ee) have been observed in the hydrogenation of all
classes of substrates tested, which represents the best results
obtained in the asymmetric hydrogenation of enol ester
phosphonates reported so far. Optimization and application
of these phosphine–phosphoramidite ligands will be reported
in due course.
Entry
Substrate, R
Solvent
ee [%]
1
2
3
4
5
6
6a, OMe
6b, OEt
6c, OiPr
7a, H
7b, Me
7c, Et
CH2Cl2
CH2Cl2
CH2Cl2
iPrOH
iPrOH
iPrOH
CH2Cl2
CH2Cl2
99.7
99.9
98.9
99.5
99.8
99.9
99.7
99.1
Received: July 2, 2007
Published online: September 11, 2007
Keywords: asymmetric catalysis · enantioselectivity ·
.
hydrogenation · P ligands · rhodium
7[b]
8[c]
7a, H
7a, H
[a] All reactions were carried out with 0.25 mmol of substrate in 2 mL of
the indicated solvent for 12 h under the conditions given in the equation,
unless otherwise specified. Full conversions were achieved in all
reactions. The ee values were determined by HPLC on a chiral column
(Chiralpak AD or Chiralcel OD-H). [b] Substrate/catalyst=1000:1.
[c] Substrate/catalyst=2000:1, H2 (20 bar).
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pare Table 2, entries 4 and 7), although a higher H2 pressure
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