Highly enantioselective hydrophosphonylation of aldehydes catalyzed by tridentate Schiff base aluminum(III) complexes

Article abstract of DOI:10.1002/anie.200704116

(Chemical Equation Presented) Active in dimeric form: A tridentate Schiff base aluminum(III) complex has been applied in the asymmetric hydrophosphonylation of various aldehydes, giving the corresponding products in good yields with good to excellent ee v

Full text of DOI:10.1002/anie.200704116

Communications
DOI: 10.1002/anie.200704116
Asymmetric Catalysis
Highly Enantioselective Hydrophosphonylation of Aldehydes
Catalyzed by Tridentate Schiff Base Aluminum(III) Complexes**
Xin Zhou, Xiaohua Liu, Xu Yang, Deju Shang, Junguo Xin, and Xiaoming Feng*
Chiral a-hydroxy phosphonates and phosphonic acids are
widely applied in the pharmaceutical industry owing to their
biological activity,[1] and intense efforts have been made on
the asymmetric hydrophosphonylation of aldehydes. To our
knowledge, the first highly enantioselective hydrophospho-
nylation was realized by the Shibasaki group using hetero-
bimetallic complexes ([LaLi3(binaphthoxide)3], [AlLi(bi-
naphthoxide)2]) as tailor-made catalysts.[2] Recently, Kee
and co-workers studied the catalytic performance of chiral
[Al(salcyen)] and [Al(salcyan)] complexes.[3] Subsequently,
the Katsuki group developed an interesting and highly
Scheme 1. Chiral ligands used in the study. Ad=adamantyl.
efficient C1-symmetric [Al(salalen)] complex for the reac-
tion.[4] An aluminum–binaphthyl Schiff base complex was also
found to be effective for the reaction.[5] Although a number of
Table 1: Asymmetric hydrophosphonylation ofbenzaldehyde with diethyl
phosphite under the indicated conditions.
works have appeared on the synthesis of chiral a-hydroxy
phosphonates,[6] searching for a catalyst system that could
achieve high reactivity and enantioselectivity is still challeng-
ing and interesting. As excellent chiral scaffolds, tridentate
Schiff base metal complexes, especially those of vanadium,
chromium, and iron, have successfully been applied in many
asymmetric reactions.[7] Herein, we present a highly efficient
asymmetric hydrophosphonylation of various aldehydes cat-
alyzed by chiral tridentate Schiff base AlIII complexes.
Initially, tridentate Schiff base 1a (Scheme 1), derived
from l-valinol and 3,5-di-tert-butylsalicylaldehyde, reacted in
situ with various aluminum(III) reagents to form complexes
that catalyze the asymmetric hydrophosphonylation (Table 1,
entries 1–3). The counterions of 1a–AlIII complexes showed a
decisive effect on the enantioselectivity.[3a,8] Complex 1a–
Et2AlCl catalyzed the reaction smoothly, giving the desired
Entry[a] Al source
L
Solvent
T [8C] Yield [%][b] ee [%][c]
1
2
Et2AlCl 1a THF
Al(OiPr)3 1a THF
0
88
50
60
68
71
48
81
30
59
53
36
80
86 (S)
30 (R)
0
0
0
3
4
5
6
7
8
9
10
11
12[d]
AlEt3
1a THF
1b THF
1c THF
1d THF
1e THF
Et2AlCl
Et2AlCl
Et2AlCl
Et2AlCl
Et2AlCl
Et2AlCl
Et2AlCl
Et2AlCl
Et2AlCl
0
0
0
0
0
0
0
ꢀ20
60 (S)
73 (S)
43 (S)
86 (S)
35 (R)
92 (S)
94 (S)
97 (S)
96 (S)[e]
2
THF
1a CH2Cl2
1e CH2Cl2
1e CH2Cl2
1e CH2Cl2/THF ꢀ15
[a] All reactions were carried out under nitrogen: diethyl phosphite
(0.3 mmol), benzaldehyde (0.25 mmol) in 1.0 mL solvent. [b] Yield of
isolated product. [c] Determined by HPLC analysis. [d] The catalyst was
prepared in situ in 0.4 mL CH2Cl2. [e] The R product with the same ee
value could be obtained by changing the absolute configuration of 1e to
R.
[*] X. Zhou, Dr. X. H. Liu, X. Yang, D. J. Shang, J. G. Xin,
Prof. Dr. X. M. Feng
Key Laboratory ofGreen Chemistry & Technology (Sichuan
University)
Ministry ofEducation
College ofChemistry
Sichuan University
Chengdu 610064 (China)
Fax: (+86)28-8541-8249
E-mail: xmfeng@scu.edu.cn
products with 86% ee, while only a racemate product was
obtained in the presence of 1a–AlEt3 (Table 1, entry 1 vs. 3).
It was interesting that catalyst 1a–Al(OiPr)3 showed an
opposite absolute sense of stereoinduction (Table 1, entry 2).
The disparate results were probably caused by the different
steric and electronic properties of the counterions (Cl, Et, and
OiPr), which each exhibited a different action in the catalytic
cycle.[9b,d]
To further improve the enantioselectivity of the reac-
tion,[9a] the steric and electronic effects based on 1 were
examined (Table 1, entries 1 and 4–8). As shown in Table 1,
electron-donating groups at the position para to the OH
Prof. Dr. X. M. Feng
State Key Laboratory ofBiotherapy
Sichuan University
Chengdu 610041 (China)
[**] We appreciate the National Natural Science Foundation ofChina
(No. 20732003) for financial support. We also thank Sichuan
University Analytical & Testing Center for NMR analysis and the
State Key Laboratory ofBiotherapy of r HRMS analysis.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
392
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Chemie
Table 2: Substrate scope for the catalytic asymmetric hydrophosphonyl-
ation ofaldehydes.
group increased the enantioselectivities and the reactivities
(Table 1, entries 4–6). Furthermore, ligands with bulkier
ortho groups, such as tert-butyl and adamantyl, could achieve
higher enantioselectivities (up to 86% ee; Table 1, entry 5 vs.
entries 1 and 7). Although ligands 1e and 2 have the same
absolute backbone configuration, the hydrogenated Schiff
base 2 afforded an opposite configuration of product with a
poor ee value (Table 1, entry 8 vs. 7).
A survey of various solvents revealed that THF provided
the product with good reactivity and enantioselectivity
(Table 1, entry 1).[9e] However, CH2Cl2 showed a strong
solvent effect in which a higher ee value was obtained
(Table 1, entry 9). Furthermore, discrimination on the stereo-
inducing capability between 1a–Et2AlCl and 1e–Et2AlCl was
also exhibited by using CH2Cl2 as the solvent (Table 1, entry 9
vs. 10), and 1e–Et2AlCl showed better enantioselectivity (up
to 94% ee). When the temperature of the reaction was
lowered, the enantioselectivity further improved, but the
yield was rather poor (Table 1, entry 11 vs. 10). Fortunately,
using THFas a cosolvent dramatically improved the reactivity
while the enantioselectivity was maintained (96% ee; Table 1,
entry 12 vs. 11).
Entry[a]
R
Product
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Ph
5a
5b
5c
5d
5e
5 f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
96
93
95
89
79
88
81
87
87
94
87
85
86
82
83
88
83
95 (S)[d]
96
2-MeC6H4
3-MeC6H4
4-MeC6H4
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
4-FC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-BrC6H4
4-CNC6H4
4-PhC6H4
96
97 (S)[d]
94
94
92
95
93
9
10
11
12
13
14
15
16
17
97 (S)[d]
97
95
92
95 (S)[d]
97
89
95
Under the optimized conditions, a series of aldehydes
were examined, and the corresponding products were given in
high yields with good to excellent enantioselectivities
(Table 2). It is interesting to note that not only the electronic
properties of the substitution at the aromatic ring, but also the
steric hindrance, had no obvious effect on the enantioselec-
tivity (Table 2, entries 1–18). While the condensed-ring alde-
hydes (1-naphthaldehyde and 2-naphthaldehyde) reacted
smoothly with diethyl phosphite, giving the products with
96% ee (Table 2, entries 19 and 20),[6g] the a,b-unsaturated
aldehyde (cinnamaldehyde) showed a slightly reduced reac-
tivity and enantioselectivity (Table 2, entry 21). Though both
nonbranched and branched aliphatic aldehydes gave high
enantioselectivities, aldehydes with more steric hindrance
generally gave the corresponding a-hydroxy phosphonates
with higher ee values (up to 91% ee; Table 2, entries 24–27).
It is noteworthy that excellent enantioselectivities have been
achieved for the first time in the asymmetric hydrophospho-
nylation of heteroaromatic aldehydes (up to 94% ee; Table 2,
entries 22 and 23).[6f]
18
5r
82
97
19
20
1-naphthyl
2-naphthyl
5s
5t
87
89
96
96
21
5u
73
85
22
23
24
25
26
27
2-thienyl
2-furyl
PhCH2CH2
nBu
iPr
tBu
5v
5w
5x
5y
5z
90
89
93
92
87
73
93 (S)[d]
94 (S)[d]
87
85[e]
90[e]
5aa
91[e]
[a] All reactions were carried out under nitrogen: aldehyde (0.25 mmol),
diethyl phosphite (0.3 mmol), a mixture of0.4 mL CH Cl2 and 0.6 mL
2
THF; the catalyst was prepared in situ in 0.4 mL CH2Cl2. [b] Yield of
isolated product. [c] Determined by HPLC analysis. [d] The absolute
configurations were determined by comparison with literature data.[6f,g]
[e] Determined by HPLC analysis after conversion of the product into the
corresponding benzoate.
To gain insight into the origin of the enantioselectivity, the
relationship between the enantiomeric excess of Schiff base
1e and the product 5a was tested (Figure 1).[10] The results
indicate a strong positive nonlinear effect, which implies that
the reaction occurs in the presence of a polymeric aluminum
active species. Direct evidence of the dimeric species was
observed by HRMS analyses and deduced from experimental
observations.[9b,c] The strong positive nonlinear effect makes it
possible that the high enantioselectivity of the reacton can be
achieved using a moderate ee value of 1e. HRMS analyses
show that the two Clꢀ ions of dimeric 1e–Et2AlCl are
substituted by phosphite ions,[9b] which suggests that the
counterion Clꢀ does not function as the bridge of dimeric 1e–
Et2AlCl. On the basis of previous reports,[11] we propose that
the oxygen atom of the flexible alcohol group acts as a bridge
in the dimeric aluminum species, while it seems impossible
that the oxygen atom of the phenol group could act as a bridge
Figure 1. Nonlinear effect in the enantioselective hydrophosphonyl-
ation ofaldehyde 3a.
owing to the sterically demanding adamantyl group. Though
the exact transition state for the reaction is unclear, it is
believed that dimeric 1e–Et2AlCl possesses an excellent
chiral environment which tolerates a wide range of substrates.
Angew. Chem. Int. Ed. 2008, 47, 392 –394
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393

Communications
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In conclusion, we have developed a new chiral tridentate
Schiff base AlIII complex for the asymmetric hydrophospho-
nylation of aldehydes. Significant progress has been obtained
with an extremely broad substrate scope, giving chiral a-
hydroxy phosphonates in good yields with excellent enantio-
selectivities (up to 97% ee). Further studies of the reaction
mechanism and the application of this catalyst to other
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Experimental Section
Typical experimental procedure: Et2AlCl (0.025 mmol) was added to
a solution of 1e (0.025 mmol) in CH2Cl2 (0.4 mL) under nitrogen.
After stirring at 308C for 30 min, the aldehyde (0.25 mmol) in THF
(0.3 mL) was added and stirred for a further 30 min. The diethyl
phosphite (0.3 mmol) in THF (0.3 mL) was added at ꢀ158C, and the
reaction was stirred for 60 h. The pure a-hydroxy phosphonate was
afforded by column chromatography on silica gel (ethyl acetate/
petroleum ether 1:1!9:1)
[8] Some selected reports on counterions: a) C. Bonaccorsi, A.
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[9] a) Other phosphites were also examined; see the Supporting
Information. b) The HRMS analyses of the reaction solution
showed a high level at 1119.6494, which was relative to the
diphosphite-substituted dimeric 1e–Et2AlCl; ESI-HRMS calcd
for [C60H94Al2N2O10P2 + H]+: 1119.6093. c) Using enantiopure
1e as the chiral ligand, the catalyst 1e–Et2AlCl, prepared in situ
in CH2Cl2, was soluble; using chiral ligand 1e which was not
Received: September 6, 2007
Published online: November 14, 2007
Keywords: aluminum · asymmetric catalysis ·
.
hydrophosphonylation · hydroxy phosphonates · Schiff bases
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394
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