Asymmetrie hydrophosphonylation of α-ketoesters catalyzed by cinchona-derived thiourea organocatalysts

Article abstract of DOI:10.1002/chem.200802237

A study was conducted to demonstrate asymmetric hydrophosphonylation of αketoesters, catalyzed by cinchona-derived thiourea organocatalysts. It was demonstrated that chiral cinchona-derived thioureas are a type of bifunctional organocatalyst that combine a basic bridge-head nitrogen, with a tunable hydrogen-bonding group that originates from the 9-amino functionality. It was also demonstrated that these organocatalysts have emerged as powerful tools for the asymmetric construction of chiral molecules. The investigation proceeded by screening the organocatalysts, derived from cinchona alkaloids, to evaluate their ability to promote the addition of methyl phenylglyoxylate with dimethyl phosphite at 0°C in toluene. A variety of variables, including the choice of solvent, catalyst loading, reaction concentration, and the ester group of phosphite and phenylglyoxylate were investigated, to obtain the optimal conditions for the investigations.

Full text of DOI:10.1002/chem.200802237

COMMUNICATION
DOI: 10.1002/chem.200802237
Asymmetric Hydrophosphonylation of a-Ketoesters Catalyzed by Cinchona-
Derived Thiourea Organocatalysts
Fei Wang,[a] Xiaohua Liu,[a] Xin Cui,[a] Yan Xiong,[a] Xin Zhou,[a] and
Xiaoming Feng *[a, b]
The asymmetric reaction between a carbonyl compound
hydroxy phosphonates and phosphonic acids, therefore re-
search into this area remains significant. Herein, we wish to
describe the asymmetric hydrophosphonylation of a-keto-
and a phosphite is a powerful synthetic tool for the con-
[1]
À
struction of C P bonds in organic chemistry, providing ef-
ficient access to chiral a-hydroxy phosphonates and phos-
phonic acids, which show biological activity and have appli-
cations in the pharmaceutical industry.[2] In recent years, sev-
eral efficient, catalytic, and enantioselective methods to per-
form this reaction have been described. Typically, an
aldehyde is treated with a phosphite in the presense of a
chiral metal complex to obtain a-hydroxy phosphonates and
phosphonic acids with good to excellent optical purities.[3–7]
Shibasaki et al. reported the first highly enantioselective hy-
drophosphonylation by using heterobimetallic complexes,[3]
Kee et al. studied the catalytic performance of chiral [Al-
ACHTUNGTRENNUNG
of bifunctional organocatalyst that combine a basic bridge-
head nitrogen with a readily tunable hydrogen-bonding
group, which originates from the 9-amino functionality, and
have emerged as powerful tools for the asymmetric con-
struction of chiral molecules. Accordingly, our initial investi-
gation began by screening thiourea organocatalysts 1a–h de-
rived from cinchona alkaloids to evaluate their ability to
promote the addition of methyl phenylglyxoylate (2a) with
dimethyl phosphite (3) at 08C in toluene. As shown in
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
E
E
N
ACHTUNGTRENNUNG
quently, our group has found that both the tridentate Schiff
base and 1,1’-bi-2-naphthol (BINOL)-derivative AlIII com-
plexes effectively catalyze the hydrophosphonylation of al-
dehydes.[6] Despite these successes, there have been few re-
ports of the hydrophosphonylation of a-ketoesters to give a-
[a] Dr. F. Wang, Dr. X. Liu, X. Cui, Dr. Y. Xiong, Dr. X. Zhou,
Prof. Dr. X. Feng
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry
Sichuan University
Chengdu 610064 (P.R. China)
Fax : (+86)28-8541-8249
E-mail: xmfeng@scu.edu.cn
Table 1, the cinchonidine- and quinine-derived thioureas
1a–d preferentially gave the dextrogyrous S compounds,
whereas the quinidine- and cinchonine-derived thioureas
1e–h gave the levorotatory R compounds (for discussion of
the absolute configuration, see below; Table 1, entries 1–4
[b] Prof. Dr. X. Feng
State Key Laboratory of Biotherapy, Sichuan University
Chengdu 610041 (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802237.
Chem. Eur. J. 2009, 15, 589 – 592
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
589

Table 1. Asymmetric hydrophosphonylation of methyl phenylglyxoylate
with dimethyl phosphite.
Table 2. Catalyst 1a-promoted asymmetric hydrophosphonylation of a-
ketoesters with dimethyl phosphite under optimum conditions.
Entry[a]
R
Product
Yield [%][b]
ee [%][c]
Entry[a]
Catalyst
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Ph
(+)-4a
(+)-4b
(+)-4c
(+)-4d
(+)-4e
(+)-4 f
(+)-4g
(+)-4h
(+)-4i
(+)-4j
92
92
90
90
94
90
85
87
91
86
90
90
90
91
90
90
90
90
91
88
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1a
1g
1a
1g
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
94
93
90
92
95
95
94
92
94
93
92
94
85
75
80
3-CH3C6H4
4-CH3C6H4
4-CH3OC6H4
3-FC6H4
72
À76
À66
À82
À73
87
4-FC6H4
4-ClC6H4
4-BrC6H4
2-thiophenyl
2-naphthyl
9
10
9
10
11[d]
12[e]
THF
THF
THF
À84
90
[a] Reactions were carried out with a-ketoester (0.1 mmol) and dimethyl
phosphite (0.2 mmol) in THF (0.4 mL). [b] Isolated yield. [c] Determined
by HPLC analysis (Chiralpak AD-H).
À88
[a] Reactions were carried out with methyl phenylglyxoylate (0.1 mmol)
and dimethyl phosphite (0.2 mmol) in solvent (0.4 mL). [b] Isolated yield.
[c] Determined by HPLC analysis (Chiralpak AD-H). The minus means
that the product is a levorotatory compound according to the optical ro-
tation. [d] Reaction was carried out by using 15 mol% of 1a. [e] Reac-
tion was carried out by using THF (0.6 mL) as the solvent.
gave the corresponding products with 90–91% ee (Table 2,
entries 2–4). The electron-withdrawing (-F, -Cl, -Br) substi-
tuted methyl phenylglyoxylates were also suitable substrates,
and good isolated yields with excellent enantioselectivities
(up to 90% ee) were obtained (Table 2, entries 5–8). Fur-
thermore, even the heteroaromatic and fused-ring a-ketoest-
ers could be smoothly converted to the desired products
with 91 and 88% ee, respectively (Table 2, entries 9 and 10).
It is well known that levorotatory and dextrogyrous com-
pounds have different biological activities. To our delight,
the treatment of methyl phenylglyxoylate and 3 gave the
adduct (À)-4a with the opposite configuration, promoted by
catalyst 1g, as shown in Table 3. Compound 3 reacted with
the electron-donating (-CH3, -OCH3) substituted methyl
phenylglyoxylates to provide the corresponding products
with 81–90% ee (Table 3, entries 2–4). However, 80–90% ee
were obtained when electron-withdrawing (-F, -Cl) substitut-
ed methyl phenylglyoxylates were used (Table 3, entries 5–
vs. 5–8). The presence of a methoxyl group on the aromatic
ring has a detrimental effect on enantioselectivities (Table 1,
entries 1 and 2 vs. entries 3 and 4; entries 5 and 6 vs. en-
tries 7 and 8). With regards to the thiourea moiety, com-
pounds 1a and 1g, which have a phenyl group attached,
gave promising ee values of 85 and 82%, respectively
(Table 1, entries 1 and 7). However, when 1b and 1h, which
possess a bulky 3,5-bis(trifluoromethyl)phenyl group, were
used, the ee values decreased appreciably (Table 1, entries 2
and 8).
To obtain the optimal conditions, a variety of variables in-
cluding the choice of solvent, catalyst loading, reaction con-
centration, and the ester group of the phosphite and phenyl-
glyoxylate were systematically explored (see the Supporting
Information for details). A survey of various solvents re-
vealed that THF gave the product with better reactivities
and enantioselectivities (Table 1, entries 9 and 10). The
change of the ester group of the phosphite and phenylgly-
Table 3. Catalyst 1g-promoted asymmetric hydrophosphonylation of a-
ketoesters with dimethyl phosphite under optimum conditions.
ACHTUNGTRENNUNGoxyACHTUNGTRENNUNGlate was not beneficial to the ee value of the product.
Subsequently, we examined the effects of catalyst loading
and the reaction concentration. The reaction in the presence
of the cinchonidine-derived thiourea 1a (15 mol%) and 2a
(0.25m) in THF gave (+)-4a in 92% yield with 90% ee
(Table 1, entry 11), and the enantiomer of the hydrophos-
phonylation product (À)-4a could also be obtained in 94%
yield with 88% ee in a reaction catalyzed by the cinchonine-
derived thiourea 1g (20 mol%) and 2a (0.167m) in THF
(Table 1, entry 12).
Under the optimized conditions, a diverse array of aro-
matic a-ketoesters was examined, and the corresponding
products were formed in high yields with good to excellent
enantioselectivities. As shown in Table 2, methyl phenylgly-
Entry[a]
R
Product
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
Ph
(À)-4a
(À)-4b
(À)-4c
(À)-4d
(À)-4e
(À)-4 f
(À)-4g
(À)-4i
(À)-4j
94
91
91
84
95
92
85
90
86
88
90
87
81
90
86
80
84
84
3-CH3C6H4
4-CH3C6H4
4-CH3OC6H4
3-FC6H4
4-FC6H4
4-ClC6H4
2-thiophenyl
2-naphthyl
[a] Reactions were carried out with a-ketoester (0.1 mmol) and dimethyl
phosphite (0.2 mmol) in THF (0.6 mL). [b] Isolated yield. [c] Determined
by HPLC analysis (Chiralpak AD-H).
ACHTUNGTRENNUNGoxACHTUNGTRENNUNGylates with electron-donating (-CH3, -OCH3) substituents
590
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Chem. Eur. J. 2009, 15, 589 – 592

Bifunctional Thiourea Organocatalysts
COMMUNICATION
7). Moreover, ee values of 84% were also attained in the
case of heteroaromatic and fused-ring substrates (Table 3,
entries 8 and 9).
nuclidine nitrogen atom and the hydrogen on the phosphite.
Then the desired S product could be produced by the Si-
face attack of the activated a-ketoester.
With the (R)-nitroaldol product 5 in hand,[10] we found it
could be further elaborated into the chiral a-hydroxy acid
(R)-6a ([a]2D5 =À5.0) through treatment with sodium nitrite
in acetic acid and DMSO.[11] However, the adduct (+)-4a
from the reaction between 2a and 3 could also be easily
converted into the chiral a-hydroxy acid (S)-6a ([a]2D5 =
+5.3). The absolute configuration of (+)-4a as the S enan-
tiomer was assigned from the optical rotation value correla-
tion results (Scheme 1).
In conclusion, we have developed the first cinchona-de-
rived thiourea organocatalyst that catalyzes the hydrophos-
phonylation of a-ketoesters. Aromatic and heteroaromatic
a-ketoesters were converted in high yields (up to 95%) with
high enantioselectivies (up to 91% ee). The S and R prod-
ucts were attained with the readily available cinchonidine-
and cinchonine-derived catalysts 1a and 1g, respectively.
This contribution provides a simple and practical synthetic
strategy for the direct formation of a-hydroxy phosphonates
and phosphonic acids from a-ketoesters. Current studies are
underway to investigate the synthetic utility of the hydro-
phosphonylation products.
Experimental Section
Typical experimental procedures: Methyl phenylglyoxylate (15 mL,
0.1 mmol) was added to
a stirred solution of catalyst 1a (6.5 mg,
0.015 mmol) in anhydrous THF (0.4 mL) at 08C, then dimethyl phosphite
(19 mL, 0.2 mmol) was added. The resulting mixture was stirred at 08C
for 36–40 h. The mixture was purified by flash chromatography by using
EtOAc/petroleum ether (1:1) as the eluent to afford (+)-4a as a pale-
yellow liquid (25.2 mg, 92% yield, 90% ee).
Scheme 1. Determination of the absolute configuration of (+)-4a.
Methyl phenylglyoxylate (15 mL, 0.1 mmol) was added to a stirred solu-
tion of catalyst 1g (8.6 mg, 0.020 mmol) in anhydrous THF (0.6 mL) at
08C, then dimethyl phosphite (19 mL, 0.2 mmol) was added. The resulting
mixture was stirred at 08C for 36–40 h. The mixture was purified by flash
chromatography by using EtOAc/petroleum ether (1:1) as the eluent to
afford (À)-4a as a pale-yellow liquid (25.7 mg, 94% yield, 88% ee).
Based on the absolute configuration of (+)-4a, a plausi-
ble catalytic model for the reaction of 2a and 3 has been
proposed (Scheme 2). The a-ketoester is activated by the
Acknowledgements
We are grateful to the National Natural Science Foundation of China
(nos. 20732003, 20602025) for financial support. We also thank Sichuan
University Analytic & Testing Center for NMR spectroscopy analysis.
Keywords: asymmetric catalysis
·
enantioselectivity
·
hydrophosphonylation · ketoesters · thiourea
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Published online: December 10, 2008
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