The asymmetric synthesis of chiral cyclic α-hydroxy phosphonates and quaternary cyclic α-hydroxy phosphonates

Article abstract of DOI:10.1039/c1ob06669b

A highly practical, catalytic enantioselective cyclic phosphite addition to aldehydes and ketones was developed. The reaction rate of the asymmetric hydrophosphonylation was significantly enhanced by the addition of silver carbonate. Particularly, signifi

Full text of DOI:10.1039/c1ob06669b

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PAPER
The asymmetric synthesis of chiral cyclic α-hydroxy phosphonates and
quaternary cyclic α-hydroxy phosphonates†
Chubei Wang‡, Chao Xu, Xiaosong Tan,* Hao Peng and Hongwu He*
Received 2nd October 2011, Accepted 21st November 2011
DOI: 10.1039/c1ob06669b
A highly practical, catalytic enantioselective cyclic phosphite addition to aldehydes and ketones was
developed. The reaction rate of the asymmetric hydrophosphonylation was significantly enhanced by the
addition of silver carbonate. Particularly, significant improvement has been achieved on the asymmetric
hydrophosphonylation of unactivated ketones, giving quaternary α-hydroxy phosphonates with excellent
enantioselectivity (up to 99% ee).
efficient Al-Schiff base complexes catalysing the asymmetric
Introduction
hydrophosphonylation of a simple ketone4g with moderate enan-
The α-hydroxy phosphonates and α-hydroxy phosphonic acids
are an important class of molecules that have exhibited intriguing
biological activities,1 and are widely applied in pharmaceutical
chemistry, pesticide chemistry and enzyme inhibition. Numerous
studies have demonstrated that the biological activity of these
compounds depends largely on their stereo configurations,1f–h
hence the synthesis of chiral α-hydroxy phosphonates with high
enantioselectivity is focus of research interest.2–5
The base-catalysed hydrophosphonylation of aldehydes or
imines (Pudovik reaction)2a is a convenient and widely used
method for the synthesis of α-hydroxy phosphonates.2 Since the
pioneering work of Shibuya3a and Spilling,3b much attention has
been paid to developing enantioselective catalysts for the syn-
thesis of chiral α-hydroxy phosphonates 1.3 Chiral aluminium
complexes are the most successful among the chiral catalysts.4
Inspired by the tremendous success of Al(salen) and Al(salcyen)
asymmetric catalysts, Al-Schiff base complexes4f have been
developed for catalysing the asymmetric addition reaction.
Feng first prepared chiral quaternary α-hydroxy phosphonates
2 by hydrophosphonylation of α-ketoesters in the presence of
organocatalysts.5 The α-ketoesters could be converted to the
chiral tertiary α-hydroxy phosphonates 2 in high yield and high
enantioselectivity. The catalytic enantioselective addition of
dialkyl phosphite with ketones was another approach to achieve
the chiral quaternary α-hydroxy phosphonates 3. Feng reported
tioselectivity (55% ee). It was the first example of the catalytic
asymmetric hydrophosphonylation of an unactivated ketone.
They later reported the catalytic enantioselective hydrophospho-
nylation of trifluoromethyl ketones4h. Takashi Ooi reported enan-
tioselective hydrophosphonylation of ynones4i by using chiral
tetraaminophosphonium phosphite as the catalyst and achieved
high enantioselectivity. Despite these works, enantioselectivity
for the asymmetric hydrophosphonylation of unactivated ketones
have not been achieved so far. Because the carbonyl of the
ketoester can be activated by the ester group, the reactivity of
ketoesters is much higher than that of ketones, so their enantio-
selectivity is also higher than that for ketones. Therefore, there is
still substantial room for improvement in terms of efficiency and
substrate scope for asymmetric hydrophosphonylations. In order
to find novel bioactive molecules, we have synthesized a series
of α-substituted phosphonates and examined their biological
activities. In this paper, we describe the catalytic asymmetric
synthesis of chiral cyclic α-hydroxy phosphonates 7 and quatern-
ary cyclic α-hydroxy phosphonates 8 via the enantioselective
hydrophosphonylation of aldehydes and unactivated ketones
using tridentate Schiff base Al(III) complexes as the catalyst
(Scheme 1).
‡Current address: Institute of Energy and Fuel, Xinxiang University,
Xinxiang, Henan 453003, P. R. China
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education,
College of Chemistry, Central China Normal University, Wuhan, Hubei,
430079, P. R. China. E-mail: he1208@mail.ccnu.edu.cn, txs3542@mail.
ccnu.edu.cn; Fax: +86 27 67867960; Tel: +86 27 67867960
†Electronic supplementary information (ESI) available: Experimental
procedures and analytical data. CCDC reference number 806532. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c1ob06669b
Results and discussion
As excellent chiral scaffolds, tridentate Schiff base metal com-
plexes, especially those of vanadium, chromium and iron,6 have
1680 | Org. Biomol. Chem., 2012, 10, 1680–1685
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Table 1 Effects
of
complexes
10
on
asymmetric
hydrophosphonylation of benzaldehydea
Ligands 9
Entry
Catalyst
Yieldb [%]
eec [%]
R1
R2
Scheme 1 Asymmetric hydrophosphonylation of aldehydes and
ketones with Al(III) complexes 10 as catalyst.
1
2
3
4
5
6
7
8
(S)-10a
(S)-10b
(S)-10c
(S)-10d
(S)-10e
(S)-10f
(R)-10e
(R)-10f
Isopropyl
Benzyl
Phenyl
Isobutyl
Isopropyl
Isobutyl
Isopropyl
Isobutyl
Isobutyl
Isobutyl
Isobutyl
Isobutyl
Adamantyl
Adamantyl
Adamantyl
Adamantyl
82
84
83
83
81
82
80
82
86 (S)
67 (S)
87 (S)
91 (S)
94 (S)
99 (S)
94 (R)
99 (R)
a Reactions were carried out under nitrogen: benzaldehyde (10 mmol),
cyclic phosphate (12 mmol), a mixture of 4 mL CH2Cl2 and 6 mL THF.
b Isolated yield. c Determined by HPLC analysis.
Table 2 Effects
of
inorganic
salts
on
asymmetric
hydrophosphonylation of benzaldehydea
Scheme 2 Synthesis of Al(III) complexes 10.
been successfully applied in many asymmetric reactions. Al(III)
complexes catalysed the asymmetric Pudovik reaction and the
ligands can be synthesized easily.7 Tridentate Schiff base ligands
9 reacted in situ with Et2AlBr to form complexes 10 (Scheme 2)
that effectively catalyse the asymmetric hydrophosphonylation
of aldehydes and ketones.
Entry
Salt
[mol%]
Time [h]
Yieldb [%]
eec [%]
1
2
3
4
5
6
7
8
K2CO3
K2CO3
K2CO3
K2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
10
20
30
40
1
2
3
4
5
1
2
2/6/12
2/6/12
2/6/12
2/6/12
2/4/8
2/4/8
2/4
2/4
2/4
2/12/24
2/12/24
2/12/24
2/12/24
2/12/24
40/68/80
45/76/82
67/82/82
75/81/83
30/58/79
44/60/78
71/82
82/82
82/81
20/61/80
23/67/79
23/68/80
24/69/78
23/67/79
99
99
99
99
99
99
99
99
99
99
99
99
99
99
To improve the enantioselectivity of the reaction, the steric
effects based on ligands 9 were examined (Table 1).
As shown in Table 1, the steric hindrance of substituent R1
and R2 affected the enantioselectivity principally. Ligands with
bulky groups, such as R1 = tert-butyl and R2 = adamantyl, could
achieve the highest enantioselectivity (99% ee; Table 1, entries 6
and 8). It is noteworthy that not only the size of substituent R1,
but also the distance between the bulky group and the chiral
centre, had notable effect on the enantioselectivity. Although the
size of phenyl is larger than that of isopropyl, the effect on enan-
tioselectivity of both phenyl and isopropyl are almost the same
(Table 1, entries 1 and 3). When R1 was benzyl there was a
methylene inserted between the phenyl and the chiral carbon,
which put the phenyl far from the chiral centre, and accordingly
the enantioselectivity significantly decreased (67% ee, Table 1,
entry 2).
9
10
11
12
13
14
3
4
5
phosphite.8 There is now substantial agreement among chemists
that the accepted mechanism for the Pudovik reaction involves
deprotonation of the dialkyl phosphonate by a base to form the
catalytically active dialkyl phosphite anion.3e Inorganic bases,
such as potassium carbonate, which have a relatively weak basi-
city and low solubility in organic solvents, would generate an
active phosphite anion at an appropriate rate and enhance the
hydrophosphonylation without reducing the enantioselectivity.4e
We expected to determine the role of the inorganic salts. Potass-
ium carbonate, silver carbonate and silver nitrate were employed
for experiment (Table 2). Indeed, the addition of 0.30–0.40
equivalents of potassium carbonate could effectively increase the
reaction rate (Table 2, entries 3–4). It was most surprising that
the addition of 0.04 equivalents of silver carbonate could signifi-
cantly speed up the reaction. The reaction was completed in 2 h
However, the steric hindrance of substituent R1 and R2 had no
obvious effect on the reactivity (81–84% yield, Table 1, entries
1–8). The ligands 9 afforded the same absolute configuration of
products. The S or R product with the same ee value could be
obtained by changing the absolute configuration of (S)-10 to
(R)-10 (Table 1, entries 5–8)
Dialkyl phosphonates undergo phosphite–phosphonate tauto-
merism and exist in two tautomeric forms: phosphonate and
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Table 3 Asymmetric hydrophosphonylation of aldehydesa
Table 4 Asymmetric hydrophosphonylation of ketonesa
Entry
Product
R
Yieldb [%]
eec [%]
Confd
Entry
Product
R
Yieldb [%]
eec [%]
Confd
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
7g
7h
7i
Ph
82
84
83
75
82
79
77
72
76
68
79
99
99
99
99
96
92
99
99
99
99
99
S
S
S
S
S
S
S
S
S
S
S
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-BrC6H4
3-BrC6H4
4-FC6H4
68
70
68
70
71
70
67
68
98
97
99
95
95
96
98
97
S
S
S
S
S
S
S
S
4-MeC6H4
3-MeC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4
2,4-diClC6H3
2,3-diClC6H3
3,4-diClC6H3
2-Furyl
8g
8h
4-MeOC6H4
2-Thienyl
9
10
11
a Reactions were run under the conditions of entry 8 in Table 2.
b Isolated yield. c Determined by HPLC analysis. d 8d was confirmed by
the crystal structure and others were determined by comparison with 8d.
7j
7k
2-Thienyl
a Reactions were run under the conditions of entry 8 in Table 2.
b Isolated yield. c Determined by HPLC analysis. d 7g was confirmed by
the crystal structure and others were determined by comparison with 7g.
(Table 2, entry 8). But silver nitrate, which has a weak acidity,
had a slight negative effect on the reactivity (Table 2, entries
10–14). This evidence supports the suggestion that basic con-
ditions are favourable for the formation of phosphite anion.
However, the addition of all three inorganic salts had no negative
effect on the enantioselectivity (Table 2).
Under the optimized conditions, a series of aldehydes were
examined, and the corresponding products 7 were given in high
yields with excellent enantioselectivities by the asymmetric
hydrophosphonylation of aldehydes 4 with cyclic phosphite 6
(Table 3).
As shown in Table 3, the disubstituted aldehydes could react
smoothly with cyclic phosphite 6 and the corresponding pro-
ducts were given with 99% ee (Table 3, entries 7–9). p-Methoxy-
Fig. 1 Molecular structure of catalyst (S)-10d.
benzaldehyde showed
a
slightly reduced reactivity and
The relationship between the enantiomeric excess of Schiff
base ligand and the product was tested by Feng and co-
workers.4f The results indicated a strong positive nonlinear
effect, which implied that the reaction occurred in the presence
of a polymeric aluminium active species. Additionally the pres-
ence of dimeric aluminium species was observed by HR-MS
analysis. However, the configuration of the catalyst was still
unclear.
enantioselectivity (Table 3, entry 6). Excellent enantioselectiv-
ities were also achieved in the asymmetric hydrophosphonylation
of heteroaromatic aldehydes (up to 99% ee; Table 3, entries 10
and 11). It can be noted that both the electronic properties and
the steric hindrance of the substitution at the aromatic ring of
aldehydes had no obvious effect on the enantioselectivities
(Table 3). The absolute configuration of compound 7g was
confirmed by the single-crystal X-ray analysis9a and others were
determined by comparison with 7g.
To expand the application of the present synthetic strategy, we
examined the asymmetric hydrophosphonylation of unactivated
ketones under the same catalytic reaction system. The quaternary
cyclic α-hydroxy phosphonates 8 were obtained in good yields
with high enantioselectivities (Table 4).
Although the ketones showed a slightly reduced reactivity
(Table 4 vs. Table 3), it is noteworthy that excellent enantioselec-
tivities were achieved for the first time in the asymmetric hydro-
phosphonylation of unactivated ketones by the use of chiral
tridentate Schiff base Al(III) complexes 10 as the catalyst (up to
99% ee; Table 4). The absolute configuration of compound 8d
was confirmed by the single-crystal X-ray analysis9b and others
were determined by comparison with 8d.
Fortunately, we obtained single crystals of catalyst (S)-10d9c
(Fig. 1). As shown in Fig. 1, the oxygen atom of the alcohol
group acts as a bridge in the dimeric aluminum species. Though
the exact transition state for the reaction is unclear, the crystal
structure may provide us some valuable information to under-
stand the catalytic mechanism of the reaction. The two Br ions
of the dimer are substituted by the phosphite ions. Consequently,
the possibility might be that reaction proceeds via two pathways:
monometallic catalysis or bimetallic catalysis. Perhaps the cata-
lyst is capable of bringing both substrate and reagent together
at a single metal centre or one metal centre may activate the
phosphorus reagent whilst the other metal centre activates
the carbonyl. The steric hindrance of substituent R2 could force
the carbonyl towards the chiral centre of the ligand, and the
larger substituent R1 would provide a more favourable chiral
1682 | Org. Biomol. Chem., 2012, 10, 1680–1685
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environment. Therefore, ligands with bulkier groups could
achieve higher enantioselectivities.
column chromatography on silica gel (acetone : petroleum ether
= 1 : 2).
7a: (S)-2-[Hydroxy(phenyl)methyl]-5,5-dimethyl-1,3,2-dio-
xaphosphinane-2-one. White solid; yield 82% (99% ee); mp
Conclusions
20
1
154.1–155.3 °C; [α]D = −78.3° (c = 1.0, CHCl3); H NMR
(600 MHz, CDCl3): δ 0.80 (s, 3H), 1.11 (s, 3H), 3.97–4.06
(m, 4H), 5.16 (d, J = 11.4 Hz, 1H), 7.31–7.38 (m, 3H), 7.50
In conclusion, we have developed an efficient method for the
synthesis of chiral cyclic α-hydroxy phosphonates and quatern-
ary cyclic α-hydroxy phosphonates in good yields with excellent
enantioselectivity. We found that the addition of silver carbonate
significantly enhanced the reaction rate of the Al-Schiff base
complexes catalysed asymmetric hydrophosphonylation. Particu-
larly, significant improvement has been achieved on the asym-
metric hydrophosphonylation of unactivated ketones, giving
quaternary α-hydroxy phosphonates with excellent enantioselec-
tivity (up to 99% ee).
1
(d, J = 7.2 Hz, 2H). The H NMR data were consistent with
literature data.10a
7b: (S)-2-[Hydroxy(4-methylphenyl)methyl]-5,5-dimethyl-1,3,
2-dioxaphosphinane-2-one. White solid; yield 84% (99% ee);
20
mp 170.3–172.1 °C; [α]D = −60.7° (c = 0.49, CHCl3); 1H
NMR (600 MHz, CDCl3): δ 0.84 (s, 3H), 1.11 (s, 3H), 2.34
(s, 3H), 3.98–4.05 (m, 4H), 5.12 (d, J = 10.8 Hz, 1H), 7.18
(d, J = 7.2 Hz, 2H), 7.38 (d, J = 6.6 Hz, 2H). The 1H NMR data
were consistent with literature data.10a
Experimental
7c: (S)-2-[Hydroxy(3-methylphenyl)methyl]-5,5-dimethyl-1,3,
2-dioxaphosphinane-2-one. White solid; yield 83% (99% ee);
General
mp 175.9–176.9 °C; [α]D = −59.2° (c = 0.39, CHCl3); 1H
20
Melting points were recorded on a hot-plate microscope appar-
atus and uncorrected. 1H NMR spectra were measured on
Varian-Mercury 600 (600 MHz) spectrometers. Chemical shifts
were recorded in δ (ppm) relative to tetramethylsilane (TMS)
or residual solvent signals as the internal standard (CHCl3, δ =
7.26, DMSO-d6, δ = 2.50). Spectra were reported as follows:
Chemical shifts (δ ppm), multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet), coupling constants (Hz),
integration, and assignment. 13C NMR spectra were collected on
Varian-Mercury 600 (150 MHz) spectrometers with complete
proton decoupling. Chemical shifts were reported in ppm from
TMS with the solvent resonance as internal standard (DMSO-d6,
δ = 39.5). Infrared spectra were obtained as a KBr disc on a
Perkin-Elmer PE-983 infrared spectrometer. The X-ray diffrac-
tion data were collected on a Bruker SMARTAXS CCD diffract-
ometer. Mass spectra were measured on a Finnigan Trace MS
spectrometer. Elementary analyses were taken on a Vario EL III
elementary analysis instrument. Optical rotations were measured
NMR (600 MHz, CDCl3): δ 0.83 (s, 3H), 1.12 (s, 3H), 2.36
(s, 3H), 3.99–4.07 (m, 4H), 5.11 (d, J = 11.4 Hz, 1H), 7.12
1
(d, J = 7.2 Hz, 1H), 7.28 (m, 3H). The H NMR data were con-
sistent with literature data.10a
7d: (S)-2-[Hydroxy(4-chlorophenyl)methyl]-5,5-dimethyl-1,3,
2-dioxaphosphinane-2-one. White solid; yield 75% (99% ee);
20
mp 175.3–176.8 °C; [α]D = −60.4° (c = 0.56, CHCl3); 1H
NMR (600 MHz, CDCl3): δ 0.84 (s, 3H), 1.10 (s, 3H),
3.99–4.11 (m, 4H), 5.14 (d, J = 12.0 Hz, 1H), 7.33 (d, J = 7.8
1
Hz, 2H), 7.42 (d, J = 7.2 Hz, 2H). The H NMR data were con-
sistent with literature data.10a
7e: (S)-2-[Hydroxy(4-bromophenyl)methyl]-5,5-dimethyl-1,3,
2-dioxaphosphinane-2-one. White solid; yield 82% (96% ee);
20
mp 189.1–191.6 °C; [α]D = −59.6° (c = 0.39, CHCl3); IR
(KBr): 3233, 2978, 1483, 1247, 1202, 1180, 826 cm−1 1H
;
NMR (600 MHz, CDCl3): δ 0.84 (s, 3H), 1.10 (s, 3H),
3.99–4.12 (m, 4H), 5.12 (d, J = 12 Hz, 1H), 7.36 (d, J = 7.2 Hz,
2H), 7.48 (d, J = 8.4 Hz, 2H); 13C NMR (150 MHz, DMSO-d6):
δ 20.0, 21.5, 32.1, 68.8, 68.9, 69.9, 77.4, 78.0, 120.8, 129.4,
131.0, 138.1; MS (EI) (m/z): 334 (M+); Anal. Calcd. for
C12H16BrO4P: C 43.01, H 4.81; Found: C 43.20, H 4.67.
T
on JASCO P-1020 polarimeter and reported as follows: [α]D
(c = g per 100 mL, solvent). The enantiomeric excesses (ee)
of the products were determined by HPLC analysis on a chiral
DAICEL CHIRALPAK AS-H column at 254 nm unless
specially indicated. All reagents are commercial reagents and
were used as received. Solvents were purified by standard tech-
niques. The chiral ligands 9a–f were prepared according to litera-
ture reported.7b,c The progress of reaction was monitored by
TLC.
7f: (S)-2-[Hydroxy(4-methoxyphenyl)methyl]-5,5-dimethyl-
1,3,2-dioxaphosphinane-2-one. White solid; yield 79% (92%
ee); mp 186.4–187.9 °C; [α]D20 = −59.6° (c = 0.42, CHCl3); 1H
NMR (600 MHz, CDCl3): δ 0.86 (s, 3H), 1.12 (s, 3H), 3.81
(s, 3H), 4.03–4.05 (m, 4H), 5.10 (d, J = 10.2 Hz, 1H), 6.91
(d, J = 8.4 Hz, 2H), 7.43 (d, J = 7.2 Hz, 2H). The 1H NMR data
were consistent with literature data.10a
Asymmetric hydrophosphonylation of aldehydes
Et2AlBr (1 mmol) was added to a solution of ligand (S)-9f
(1 mmol) in CH2Cl2 (4 mL) under nitrogen. After stirring at
room temperature for 30 min, the aldehyde 4 (10 mmol) in THF
(6 mL) and silver carbonate (0.4 mmol) were added and stirred
for a further 30 min. The cyclic phosphite 6 (12 mmol) was
added at −15 °C, and the reaction solution was stirred for 2 h.
The reaction were quenched by diluted hydrochloric acid (v/v =
1/15). The pure α-hydroxy phosphonate 7 was afforded by
7g: (S)-2-[Hydroxy(2,4-dichlorophenyl)methyl]-5,5-dimethyl-
1,3,2-dioxaphosphinane-2-one. Whitesolid;yield77%(99%ee);
20
mp 188.4–189.2 °C; [α]D = −63.1° (c = 0.52, CHCl3); 1H
NMR (600 MHz, CDCl3): δ 0.87 (s, 3H), 1.10 (s, 3H),
3.96–4.10 (m, 4H), 5.62 (d, J = 12.0 Hz, 1H), 7.31 (d, J = 8.4
1
Hz, 1H), 7.39 (s, 1H), 7.70 (d, J = 7.2 Hz, 1H). The H NMR
data were consistent with literature data.10a
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7h: (S)-2-[Hydroxy(2,3-dichlorophenyl)methyl]-5,5-dimethyl-
1,3,2-dioxaphosphinane-2-one. White solid; yield 72% (99%
(600 MHz, CDCl3): δ 0.86 (s, 3H), 1.07 (s, 3H), 1.88 (d, J =
15.6 Hz, 3H), 3.96–4.09 (m, 4H), 7.34 (d, J = 8.4 Hz, 2H), 7.57
(m, 2H); 13C NMR (150 MHz, DMSO-d6): δ 20.0, 21.4, 25.5,
32.0, 74.6, 75.6, 78.0, 78.5, 127.7, 128.1, 131.8, 142.0; MS (EI)
(m/z): 304 (M+); Anal. Calcd. for C13H18ClO4P: C 51.24, H
5.95; Found: C 50.96, H 5.90.
20
ee); mp 193.1–194.5 °C; [α]D = −61.8° (c = 0.51, CHCl3); IR
1
(KBr): 3221, 2970, 1375, 1237, 1185, 749, 683 cm−1; H NMR
(600 MHz, CDCl3): δ 0.87 (s, 3H), 1.10 (s, 3H), 3.98–4.11
(m, 4H), 5.71 (d, J = 12.0 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H),
7.44 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H); 13C NMR
(150 MHz, DMSO-d6): δ 19.9, 21.3, 32.0, 67.3, 68.4, 77.8,
78.0, 128.0, 128.3, 129.7, 131.4, 138.9, 139.0; MS (EI) (m/z):
324 (M+); Anal. Calcd. for C12H15Cl2O4P: C 44.33, H 4.65;
Found: C 44.36, H 4.59.
8b: (S)-2-[1-Hydroxy-1-(3-chlorophenyl)ethyl]-5,5-dimethyl-
1,3,2-dioxaphosphinane-2-one. White solid; yield 70% (97%
20
ee); mp 142.0.3–143.6 °C; [α]D = −53.7° (c = 0.51, CHCl3);
1
IR (KBr): 3229, 2969, 1486, 1222, 1138, 787, 691 cm−1; H
NMR (600 MHz, DMSO-d6): δ 0.85 (s, 3H), 1.15 (s, 3H), 1.74
(d, J = 15.6 Hz, 3H), 3.89–3.93 (m, 1H), 4.03–4.08 (m, 1H),
4.39–4.40 (m, 1H), 4.47–4.49 (m, 1H), 7.37–7.43 (m, 2H),
7.54–7.60 (m, 2H); 13C NMR (150 MHz, DMSO-d6): δ 20.0,
21.4, 25.6, 32.0, 74.6, 75.6, 78.0, 78.5, 124.9, 125.8, 126.9,
129.7, 132.6, 145.5; MS (EI) (m/z): 304 (M+); Anal. Calcd. for
C13H18ClO4P: C 51.24, H 5.95; Found: C 50.98, H 5.91.
7i: (S)-2-[Hydroxy(3,4-dichlorophenyl)methyl]-5,5-dimethyl-
1,3,2-dioxaphosphinane-2-one. White solid; yield 76% (99%
20
ee); mp 189.8–191.5 °C; [α]D = −60.2° (c = 0.48, CHCl3); IR
1
(KBr): 3273, 2967, 1466, 1247, 1193, 885, 822 cm−1; H NMR
(600 MHz, CDCl3): δ 0.88 (s, 3H), 1.12 (s, 3H), 4.04–4.15
(m, 4H), 5.14 (d, J = 12.6 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H),
7.43 (d, J = 8.4 Hz, 1H), 7.61 (s, 1H); 13C NMR (150 MHz,
DMSO-d6): δ 19.9, 21.5, 32.2, 68.1, 69.2, 77.6, 78.0, 127.5,
129.0, 130.2, 130.3, 130.8, 139.9; MS (EI) (m/z): 324 (M+);
Anal. Calcd. for C12H15Cl2O4P: C 44.33, H 4.65; Found:
C 44.56, H 4.68.
8c: (S)-2-[1-Hydroxy-1-(2-chlorophenyl)ethyl]-5,5-dimethyl-
1,3,2-dioxaphosphinane-2-one. White solid; yield 68% (99%
20
ee); mp 145.9–147.8 °C; [α]D = −58.4° (c = 0.52, CHCl3); IR
(KBr): 3241, 2970, 1489, 1222, 1138, 768 cm−1 1H NMR
;
(600 MHz, DMSO-d6): δ 0.85 (s, 3H), 1.14 (s, 3H), 1.74 (d, J =
15.6 Hz, 3H), 3.87–3.92 (m, 1H), 4.03–4.07 (m, 1H), 4.37–4.39
(m, 1H), 4.47–4.48 (m, 1H),7.44 (d, J = 7.8 Hz, 2H), 7.59
(m, J = 7.2 Hz, 2H); 13C NMR (150 MHz, DMSO-d6): δ 20.0,
21.4, 25.5, 32.0, 74.5, 75.6, 77.9, 78.4, 127.6, 128.0, 131.8,
141.9; MS (EI) (m/z): 304 (M+); Anal. Calcd. for C13H18ClO4P:
C 51.24, H 5.95; Found: C 51.06, H 5.89.
7j: (S)-2-[Hydroxy(furan-2-yl)methyl]-5,5-dimethyl-1,3,2-
dioxaphosphinane-2-one. White solid; yield 68% (99% ee);
20
mp 202.4–203.4 °C; [α]D = −64.1° (c = 0.53, CHCl3); 1H
NMR (600 MHz, CDCl3): δ 0.89 (s, 3H), 1.21(s, 3H), 4.00–4.04
(m, 2H), 4.24–4.25 (m, 2H), 5.20 (d, J = 13.2 Hz, 1H), 6.38
1
(s, 1H), 6.52 (s, 1H), 7.43 (s, 1H). The H NMR data were con-
sistent with literature data.10b
8d: (S)-2-[1-Hydroxy-1-(4-bromophenyl)ethyl]-5,5-dimethyl-
1,3,2-dioxaphosphinane-2-one. White solid; yield 70% (95%
7k: (S)-2-[Hydroxy(thiophen-2-yl)methyl]-5,5-dimethyl-1,3,2-
dioxaphosphinane-2-one. Yellowish solid; yield 79% (99%
20
ee); mp 148.5–150.2 °C; [α]D = −64.8° (c = 0.56, CHCl3); IR
(KBr): 3239, 2970, 1486, 1222, 1138, 830 cm−1 1H NMR
;
20
ee); mp 226.0–227.4 °C; [α]D = −62.1° (c = 0.42, CHCl3); IR
1
(KBr): 3215, 2968, 1469, 1237, 1079, 825, 722 cm−1; H NMR
(600 MHz, CDCl3): δ 0.84 (s, 3H), 1.06 (s, 3H), 1.85
(d, J = 15.6 Hz, 3H), 4.00–4.01 (m, 4H), 7.49 (m, 4H); 13C
NMR (150 MHz, DMSO-d6): δ 19.8, 21.3, 25.4, 31.8, 74.5,
75.5, 77.8, 78.3, 120.3, 128.3, 130.4, 142.2; MS (EI) (m/z): 348
(M+); Anal. Calcd. for C13H18BrO4P: C 44.72, H 5.20; Found:
C 44.51; H 5.31.
(600 MHz, CDCl3): δ 0.88 (s, 3H), 1.19 (s, 3H), 4.02–4.25
(m, 4H), 5.41 (d, J = 12.0 Hz, 1H), 7.01 (t, J = 4.2 Hz, 1H),
7.20 (s, 1H), 7.32 (d, J = 4.8 Hz, 1H); 13C NMR (150 MHz,
DMSO-d6): δ 20.0, 21.6, 32.1, 65.8, 66.9, 77.6, 78.0, 125.6,
125.9, 126.8, 141.8; MS (EI) (m/z): 262 (M+); Anal. Calcd. for
C10H15O4PS: C 45.80, H 5.76; Found: C 45.61; H 5.72.
8e: (S)-2-[1-Hydroxy-1-(3-bromoophenyl)ethyl]-5,5-dimethyl-
1,3,2-dioxaphosphinane-2-one. White solid; yield 71% (95%
20
ee); mp 162.3–163.5 °C; [α]D = −74.0° (c = 0.41, CHCl3); IR
Asymmetric hydrophosphonylation of ketones
1
(KBr): 3233, 2969, 1477, 1225, 1139, 777, 690 cm−1; H NMR
Et2AlBr (1 mmol) was added to a solution of ligand (S)-9f
(1 mmol) in CH2Cl2 (4 mL) under nitrogen. After stirring at
room temperature for 30 min, the ketone 5 (10 mmol) in THF
(6 mL) and silver carbonate (0.4 mmol) were added and stirred
for a further 30 min. The cyclic phosphite 6 (12 mmol) was
added at −15 °C, and the reaction solution was stirred for 2 h.
The reaction were quenched by diluted hydrochloric acid (v/v =
1/15). The pure α-hydroxy phosphonate 8 was afforded by
column chromatography on silica gel (acetone : petroleum ether
= 1 : 2).
(600 MHz, CDCl3): δ 0.87 (s, 3H), 1.10 (s, 3H), 1.89 (d, J =
15.6 Hz, 3H), 3.96–4.11 (m, 4H), 7.27 (m, 1H), 7.45 (d, J = 7.8
Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 1.8 Hz, 1H); 13C
NMR (150 MHz, DMSO-d6): δ 20.0, 21.4, 25.7, 32.0 (d, J =
8.55 Hz), 74.5, 75.6, 78.0, 78.6, 121.3, 125.2, 128.7, 129.8,
130.0, 145.8; MS (EI) (m/z): 348 (M+); Anal. Calcd. for
C13H18BrO4P: C 44.72, H 5.20; Found: C 44.39, H 5.48.
8f: (S)-2-[1-Hydroxy-1-(4-fluorophenyl)ethyl]-5,5-dimethyl-
1,3,2-dioxaphosphinane-2-one. White solid; yield 70% (95%
20
ee); mp 168.7–169.9 °C; [α]D = −65.0° (c = 0.64, CHCl3); IR
8a: (S)-2-[1-Hydroxy-1-(4-chlorophenyl)ethyl]-5,5-dimethyl-
1,3,2-dioxaphosphinane-2-one. White solid; yield 68% (98%
(KBr): 3220, 2974, 1510, 1374, 1223, 1135, 828 cm−1 1H
;
NMR (600 MHz, CDCl3): δ 0.86 (s, 3H), 1.07 (s, 3H), 1.89 (d, J
= 15.6 Hz, 3H), 3.92–4.10 (m, 4H), 7.06 (m, 2H), 7.61 (m, 2H);
13C NMR (150 MHz, DMSO-d6): δ 20.0, 21.4, 25.6, 31.9, 74.4,
20
ee); mp 149.8–151.6 °C; [α]D = −53.4° (c = 0.54, CHCl3); IR
(KBr): 3241, 2970, 1489, 1222, 1138, 829 cm−1 1H NMR
;
1684 | Org. Biomol. Chem., 2012, 10, 1680–1685
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10d: C42H66Al2Br2N2O4·2CH2Cl2, M = 1046.60, orthorhombic, C2221,
a = 12.9848(17), b = 17.0304(17), c = 24.393(3) Å, α = 90, β = 90,
γ = 90°, V = 5394.2(11) Å3, Z = 4, T = 298 K; 18 710 measured reflec-
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54.17, H 6.29; Found: C 54.19, H 6.51.
8g: (S)-2-[1-Hydroxy-1-(4-methoxyphenyl)ethyl]-5,5-dimethyl-
1,3,2-dioxaphosphinane-2-one. White solid; yield 67% (98%
20
ee); mp 155.6–156.3 °C; [α]D = −48.1° (c = 0.48, CHCl3); IR
(KBr): 3329, 2969, 1513, 1251, 1230, 1137, 830 cm−1 1H
;
NMR (600 MHz, CDCl3): δ 0.88 (s, 3H), 1.10 (s, 3H), 1.90 (d, J
= 15.6 Hz, 3H), 3.82 (s, 3H), 3.90–4.08 (m, 4H), 6.93 (d, J =
8.4 Hz, 2H), 7.56 (d, J = 6.6 Hz, 2H); 13C NMR (150 MHz,
DMSO-d6): δ 20.1, 21.5, 25.6, 32.0 (d, J = 7.05 Hz), 55.1, 74.4,
75.5, 77.7, 78.2, 113.1, 127.4, 134.7, 158.3; MS (EI) (m/z): 300
(M+); Anal. Calcd. for C14H21O5P: C 56.00, H 7.05; Found: C
55.72, H 7.28.
8h: (S)-2-[1-Hydroxy-1-(thiophen-2-yl)ethyl]-5,5-dimethyl-
1,3,2-dioxaphosphinane-2-one. White solid; yield 68% (97%
20
ee); mp 152.0–153.8 °C; [α]D = −63.0° (c = 0.57, CHCl3); IR
(KBr): 3234, 2967, 1468, 1372, 1224, 1128, 1064, 836 cm−1
;
1H NMR (600 MHz, DMSO-d6): δ 0.84 (s, 3H), 1.17 (s, 3H),
1.78 (d, J = 15.6 Hz, 3H), 3.92–4.05 (m, 2H), 4.43–4.45
(m, 2H), 6.70 (d, J = 18 Hz, 1H), 7.04 (d, J = 18 Hz, 2H), 7.47
(s, 1H); 13C NMR (150 MHz, DMSO-d6): δ 20.0, 21.4, 26.3,
32.0, 73.9, 75.0, 78.1, 78.5, 124.4, 125.2, 126.9, 147.8; MS (EI)
(m/z): 276 (M+); Anal. Calcd. for C11H17O4PS: C 47.82, H 6.20;
Found: C 47.72, H 6.02.
Acknowledgements
The present work was supported by the National Basic Research
Program of China (No. 2010CB126100) and the National
Natural Science Foundation of China (No. 21172090 and
21002037). This work was supported in part by the PCSIRT
(No. IRT0953).
Notes and references
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This journal is © The Royal Society of Chemistry 2012
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