Asymmetric Michael additions of a chiral phosphite to nitroalkenes and knoevenagel acceptors

Article abstract of DOI:10.1055/s-2006-926437

The diastereoselective Michael addition of an enantiopure phosphite to nitroalkenes and α,β-unsaturated malonates is described. High asymmetric inductions were obtained using a readily available TADDOL auxiliary. Racemization-free cleavage of the auxiliar

Full text of DOI:10.1055/s-2006-926437

PAPER
1447
Asymmetric Michael Additions of a Chiral Phosphite to Nitroalkenes and
Knoevenagel Acceptors
Asymmetric
P
hosp
i
ha-Mi
e
A
ddi
t
Institut für Organische Chemie, RWTH Aachen, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received 23 November 2005
in a highly stereoselective manner. Racemization-free re-
moval of the chiral auxiliary from the addition products
provided either b-nitrophosphonic acids or b-phosphono-
malonates in good yields and high enantiomeric excesses.
Abstract: The diastereoselective Michael addition of an enan-
tiopure phosphite to nitroalkenes and a,b-unsaturated malonates is
described. High asymmetric inductions were obtained using a readi-
ly available TADDOL auxiliary. Racemization-free cleavage of the
auxiliary led to a-substituted b-nitro phosphonates and b-substitut-
ed b-phosphono malonates in good yields and high enantiomeric
excesses, respectively. An extension of the method to the synthesis
of a,b-disubstituted b-nitrophosphonates with two new neighboring
stereogenic centers is also reported.
O
O
O
O
O
H
Me
Me
P
Key Words: Michael addition, nitroalkenes, phosphonates, P–C
bond formation, asymmetric synthesis
(R,R)-1
Phosphonates are a class of compounds with extraordi-
nary biological properties.1 Their structural analogy to
phosphates, in combination with the hydrolytic stability
of the phosphorus–carbon bond enables them to act as en-
zyme inhibitors in a variety of processes. Phosphonates
show significant neurotoxic activity, are used as antibiot-
ics,2 herbicides,3 blood pressure regulators4 and antiviral
agents.5 Recently, phosphonates with antiviral activity
such as Viread® or Hepsera™, both inhibitors of reverse
transcriptase, have proved to be highly efficient drugs in
the treatment of HIV–1 and hepatitis B infections. The
main synthetic approaches to phosphonates involve either
the Michaelis–Arbusov rearrangement6 or the addition of
phosphites to multiple bonds, a transformation initially re-
ported by the Russian chemist Pudovik7 in the 1950’s and
often referred to as the Pudovik reaction.8 However, de-
spite the importance of enantiomerically pure phospho-
nates, only a few methods for their asymmetric synthesis
have been described. They are generally limited to asym-
metric hydrophosphonylation of aldehydes and imines or
to a few examples of the asymmetric Michaelis–Arbusov
rearrangement.9
Figure 1
We now wish to report in detail our investigations on the
reactivity of (R,R)-1 and an extension of our protocol. As
previously described,11 the title phosphite was prepared in
nearly quantitative yield in a two-step procedure starting
from (R,R)-4,5-bis(diphenylhydroxymethyl)-2,2-dimeth-
yl-1,3-dioxolane (TADDOL).14 Its reactivity towards the
nitroalkenes 2a–f was tested under different sets of condi-
tions (Scheme 1).
Ph
Ph
Ph
NO2
2a–f
Ph
R
O
O
O
O
O
O
O
O
H
Me
Me
Me
.
P
P
method
A, B or C
Me
NO2
O
O
R
Ph
Ph
Ph
Ph
3a–f
(R,R)-1
Scheme 1 Reagents and conditions: Method A: n-BuLi, THF, 0 °C,
40 h. Method B: Et2Zn, THF, –78 °C to r.t., 12 h. Method C: Et2Zn,
TMEDA, THF, –78 °C, 12 h.
In two recent communications we reported the asymmet-
ric Michael addition10 of the enantiopure phosphite
(3aR,8aR)-2,2-dimethyl-4,4,8,8-tetraphenylperhydro-
6l5-[1,3]dioxolo-[4,5-e][1,3,2]dioxaphosphepin-6-one,
(R,R)-1, to nitroalkenes11 and a,b-unsaturated malonates12
as a general method to access enantiomerically enriched
bifunctional phosphonates via a P–C bond forming reac-
tion.13 According to our procedure, the metalated phos-
phite (R,R)-1 was added to the desired Michael acceptors
The stereoselectivity of the reaction as well as the abso-
lute configuration of the newly formed stereogenic center
turned out to be highly dependent on both the metal base
used and the reaction temperature. In the first series of ex-
periments (Scheme 1, Table 1) the phosphite (R,R)-1 was
metalated in THF at 0 °C using n-butyllithium (method
A). The resulting P–nucleophile underwent conjugate ad-
dition to the nitroalkenes 2a–f to give the a-substituted b-
nitrophosphonates 3a–f. Although the Michael adducts
3a–f were obtained in good yields (70–84%), the reactiv-
ity of the lithiated phosphite was low. It added sluggishly
to the nitroalkenes with reaction times up to 40 hours.
Moreover, even though the addition step occurred stereo-
SYNTHESIS 2006, No. 9, pp 1447–1460
x
x
.
x
x
.2
0
0
6
Advanced online publication: 11.04.2006
DOI: 10.1055/s-2006-926437; Art ID: Z22805SS
© Georg Thieme Verlag Stuttgart · New York

1448
D. Enders et al.
PAPER
selectively the diastereomeric excesses of the products
were only moderate (de = 32–55%). As established by X-
ray crystal structure analysis, the absolute configuration
of the newly formed stereogenic center for the major dia-
stereoisomer was S.
Table 2 Temperature Effect on the n-BuLi Mediated Asymmetric
phospha-Michael Addition to Nitroalkenes 2c and 2f
3
R
T
(°C)
Me-
thod
Yield de
(%)a
(%)a
MeO
MeO
(R,R,S)-3c
0
A
84
47
Table 1 n-BuLi Mediated Asymmetric Michael Addition of Phos-
phite (R,R)-1 to Nitroalkenes 2a–f to Afford the b-Nitrophosphonates
3a–f
OMe
(R,R,R)-3c
(R,R,S)-3c
(R,R,S)-3f
–78
66
0
A
A
A
78
28
81
40
50
35
3
R
Method Yield (%) de (%)a
(R,R,S)-3a
A
75
32
Fe
(R,R,S)-3b
(R,R,S)-3c
A
70
38
(R,R,R)-3f
(R,R,S)-3f
–78
66
A
A
77
22
32
37
A
84
47
MeO
MeO
a Determined by 1H NMR and HPLC (Whelk 01, cyclohexane–2-pro-
panol, 9:1).
OMe
(R,R,S)-3d
(R,R,S)-3e
A
A
72
77
35
55
the use of diethylzinc as the metal source. In this case the
phospha-Michael addition proceeded smoothly even at
low temperature (12 h at –78 °C, then 1 h at r.t.) and the
R-configured b-nitrophosphonates 3a–f were obtained in
high yields and diastereomeric excesses (Scheme 1,
Method B, Table 3). The reaction of diethylzinc with
(R,R)-1 led to the formation of a reactive organozinc phos-
phorus adduct, which in analogy to previous reports by
Noltes et al.15 turned out to be very reactive, but insoluble.
Indeed, after Et2Zn was added to (R,R)-1 at 0 °C and the
solution was cooled to –78 °C, the precipitation of a col-
orless solid was observed. This completely redissolved
only when the solution was allowed to warm to 0 °C. Con-
sequently, some of the nucleophiles reacted with the cor-
responding nitroalkene only at higher temperature.
Me
(R,R,S)-3f
A
81
35
Fe
a Determined by 31P NMR and HPLC (Whelk 01, cyclohexane–2-pro-
panol, 9:1).
In order to improve the stereoselectivity of the conjugate
addition, the effect of the temperature was investigated
using 2c and 2f as model substrates. (R,R)-1 was metalat-
ed with n-butyllithium in THF at 0 °C and, after subse-
quent addition of the nitroalkene, the resulting solution
was either cooled to –78 °C or heated to reflux. As shown
in Table 2, low temperatures did not have any beneficial
effect on the diastereoselectivity. The diastereomeric ex-
cesses were comparable with those achieved at 0 °C, but
a reversal of facial selectivity was observed for both ni-
troalkenes, resulting in b-nitrophosphonates 3c and 3f
with R-configurations at the new stereogenic centers. At
–78 °C the reactivity of (R,R)-1 was significantly lower
than at 0 °C, with reaction times of up to one week, while
heating the solution to reflux produced a slight increase of
diastereomeric excess but led to very poor yields, due to
hydrolysis of (R,R)-1 at high temperature to recoverable
TADDOL.
To enhance the solubility of the reactive intermediate the
addition of Et2Zn was carried out in the presence of a
chelating amine such as TMEDA. Under these conditions
the conjugate addition of (R,R)-1 reached completion at
–78 °C and, as a result, improved yields (86–91%) and
diastereomeric excesses (de = 84–96%) could be
achieved (Scheme 1, Method C, Table 3).
The absolute configuration of the newly formed stereo-
genic center in 3b was determined to be R by X-ray crys-
tallography (Figure 2).11 Assuming a uniform reaction
mechanism, all examples described should possess the
same configuration.
We hoped to extend this methodology to the preparation
of b-nitrophosphonates with two new stereogenic centers.
The asymmetric conjugate addition of (R,R)-1 to a,b-di-
substituted nitroalkenes was investigated (Scheme 2,
Table 4). In this case, the second stereogenic center is
generated through stereoselective protonation of the inter-
mediate nitronate, generated by addition of the phospho-
rus nucleophile onto the double bond of nitroalkenes 4a–
c. For this reason, besides typical quenching reagents such
The conjugate additions were then carried out in the pres-
ence of different bases such as sodium or potassium hy-
dride, n-butyllithium in the presence of copper salts,
dibutylmagnesium or diethylzinc. With alkali metals as
counterions, less reactive P–nucleophiles were produced,
whereas in the presence of copper or magnesium no reac-
tion could be observed at all. A breakthrough came with
Synthesis 2006, No. 9, 1447–1460 © Thieme Stuttgart · New York

PAPER
Asymmetric phospha-Michael Additions
1449
1) a
Table 3 Et2Zn-Mediated Asymmetric Michael Addition of Phos-
phite (R,R)-1 to Nitroalkenes 2a–f to Afford the 1,4-Adducts 3a–f
NO2
R
Ph
Ph
2)
Ph
Ph
Ph
Me
4a–c
O
O
O
O
Method Yield (%) de (%)a
Me
Me
Me
O
O
O
O
3
R
3) b or c
Me
Me
P
O
.
P
NO2
H
O
(R,R,R)-3a
B
C
81
89
84
89
72–87%
R
Ph
Ph
Ph
(R,R,R,S)-5a–c
(R,R)-1
de = 46–75%
(R,R,R)-3b
(R,R,R)-3c
B
C
84
88
87
92
Scheme 2 Reagents and conditions: (a) Et2Zn, TMEDA, THF,
–78 °C, 12 h; (b) NH4Cl (aq); (c) 4-bromo-2,6-di-tert-butylphenol.
B
C
88
91
77
88
MeO
MeO
tion of the new stereogenic center, as well as the absolute
configuration, was established via NOE experiments
based on the known configuration of the chiral auxiliary.
OMe
(R,R,R)-3d
(R,R,R)-3e
B
C
86
86
82
96
Table 4 Asymmetric phospha-Michael Addition of (R,R)-1 to Ni-
troalkenes 4a–c to Afford a,b-Disubstituted b-Nitrophosphonates
5a–c
Me
B
C
95
87
93
93
5
R
Meth- Yield
de
od
(%)
(%)a
(R,R,R)-3f
B
C
75
86
63
84
Fe
MeO
MeO
(R,R,R,S)-5a
B
C
81
72
57
75
a Determined by 1H NMR and HPLC (Whelk 01, cyclohexane–2-pro-
panol, 9:1).
OMe
(R,R,R,S)-5b
(R,R,R,S)-5c
B
C
87
77
69
46
B
C
81
75
62
67
O
a Determined by 1H NMR and HPLC (Whelk 01, cyclohexane–2-pro-
panol, 9:1).
To complete the reaction sequence, the chiral auxiliary
was removed from the 1,4-addition products 3a–f. As pre-
viously reported, cleavage of the auxiliary occurred under
neutral, racemization-free conditions upon treatment with
trimethylsilylchloride and sodium iodide in acetonitrile to
yield a-substituted b-nitrophosphonic acids 6a–f
(Scheme 3, Table 5).
1) TMSCl, NaI,
MeCN, reflux
2) CH2Cl2, H2O
Ph
Ph
Figure 2 X-ray crystal structure of 3b
O
P
.
O
O
O
O
Me
Me
P
HO
NO2
NO2
.
65–94%
O
HO
as aqueous ammonium chloride, the use of bulky proton
donors such as 4-bromo-2,6-di-t-butylphenol at low tem-
perature was employed.
R
R
Ph
Ph
(R)-6a–f
(R,R,R)-3a–f
(ee = 81–95%)
The addition of (R,R)-1 to a,b-disubstituted nitroalkenes
4a–c proceeded smoothly under the optimized conditions
described above, affording the corresponding a,b-disub-
stituted b-nitrophosphonates 5a–c in good yields (72–
87%) and moderate diastereomeric excesses (de = 46–
75%, Table 4). The best results were obtained in the case
of nitroalkene 4a when the reaction was quenched at
–78 °C with 4-bromo-2,6-di-tert-butylphenol and allowed
to warm to room temperature. The anti relative configura-
Scheme 3
With the purpose of extending the scope of our methodol-
ogy, we proceeded to investigate the conjugate addition of
phosphite (R,R)-1 to other Michael acceptors, such as a,b-
unsaturated malonates. Since derivatives of b-phosphono-
malonic acid have shown promising in vitro anti-tumor
activity,16 the synthesis of enantiomerically pure ana-
logues of this type was particularly desirable.
Synthesis 2006, No. 9, 1447–1460 © Thieme Stuttgart · New York

1450
D. Enders et al.
PAPER
Table 5 Cleavage of the Chiral Auxiliary from b-Nitrophospho-
nates 3a–f to Yield b-Nitrophosphonic Acids 6a–f
Table 6 Asymmetric phospha-Michael Addition of (R,R)-1 to a,b-
Unsaturated Malonates 7a,b,d to Afford a,b-Disubstituted b-Nitro-
phosphonates 8a,b,d (Preliminary Investigations)
6
R
Method
A
Yield (%) ee (%)a
8
R
Method Yield (%) de (%)a
(R)-6a
87
92
Me
(R,R,S)-8a
A
89
67
Me
(R)-6b
(R)-6c
A
A
88
88
(R,R,S)-8a
(R,R,S)-8b
B
A
93
81
13
75
92
86
MeO
MeO
(R,R,S)-8b
(R,R,S)-8d
B
A
88
79
75
76
OMe
(R)-6d
(R)-6e
A
A
94
65
95
91
Me
(R,R,S)-8d
B
82
69
a Determined by 31P NMR and HPLC (Daicel OD, Daicel AD 2,
Whelk 01).
(R)-6f
A
85
81
Fe
role in the stereochemical course of the addition. After ex-
amining a variety of metal oxides, we showed that inex-
pensive Fe2O3–KOH as a solid base in dichloromethane in
the presence of small amounts of water provided high dia-
stereomeric excesses (de = 82–94%, Table 7).
a Measured by chiral HPLC of the dimethylphosphonate derivatives
(Daicel OD).
Based on observations by Koenig et al.,17 that the conju-
gate addition of diethylphosphite to a,b-unsaturated ke-
tones could be carried out under heterogeneous
conditions, using KOH on aluminium oxide as a solid
base, we studied the reactivity of (R,R)-1 towards Knoev-
enagel acceptors 7a–f under both homogeneous and het-
erogeneous conditions (Scheme 4).
Table 7 Michael Addition of Phosphite (R,R)-1 to a,b-Unsaturated
Malonates 7b–f Using Fe2O3–KOH as Base
8
R
Reaction Yield (%) de (%)a
time (h)
(R,R,S)-8b
(R,R,S)-8c
(R,R,S)-8d
4
5
4
64
67
63
86
91
94
O
CO2Me
Ph
Ph
Ph
Ph
R
CO2Me
O
O
O
7a–f
.
O
O
O
P
O
CO2Me
O
O
O
Me
Me
Me
Me
.
P
S
CO2Me
method
A or B
H
O
R
Ph
Ph
Ph
Ph
(R,R)-1
.
.
(R,R,S)-8a–f
(R,R,S)-8e
(R,R,S)-8f
3
4
75
71
82
89
Scheme 4 Method A: Et2Zn, TMEDA, THF, –78 °C, 12 h. Method
B: Al2O3–KOH, CH2Cl2, r.t., 2 h.
Me
MeO
The desired b-substituted b-phosphonomalonates could
be obtained under both sets of conditions (Table 6). Com-
parable results where obtained in the case of aromatic ma-
lonates. In contrast, when the aliphatic malonate 7a was
used as a substrate in the heterogeneous system, even if
the reaction product was obtained in high yield (93%),
only poor stereoselectivity (de = 13%) could be observed.
MeO
OMe
a Determined by 31P NMR and by HPLC (Daicel OD, AD2).
The absolute configuration of the newly formed stereo-
genic center was determined to be S by X-ray crystal
structure analysis in the case of product 8e (Figure 3).18
Assuming a uniform reaction mechanism, all cases de-
scribed should possess the same configuration. This is
also supported by the observation that addition of (R,R)-1
to Knoevenagel acceptors showed the same relative topi-
city encountered in the case of nitroalkenes.
Considering the advantages of heterogeneous asymmetric
phospha-Michael additions (room temperature, faster re-
action times, no dry solvents required), we were interested
in developing suitable reaction conditions under which
the stereoselectivity of the reaction would be maximized.
Our previous investigations showed that the metal oxide
on which potassium hydroxide is adsorbed plays a crucial
Synthesis 2006, No. 9, 1447–1460 © Thieme Stuttgart · New York

PAPER
Asymmetric phospha-Michael Additions
1451
With the desired b-substituted b-phosphonomalonates
8a–f in the hand, we proceeded to remove the chiral aux-
iliary, which was accomplished as previously reported
upon treatment with trimethylsilyl chloride and sodium
iodide in acetonitrile (Scheme 5).
1. TMSCl, NaI,
Ph
MeCN, ∆
2. CH2Cl2, H2O
3. CH2N2, MeOH
Ph
Ph
O
P
CO2Me
CO2Me
CO2Me
CO2Me
.
O
O
O
O
.
Me
Me
.
P
MeO
MeO
O
72–86%
R
R
Ph
(S)-9b–f
(R,R,S)-8b–f
ee = 84–94%
de = 82–94%
Scheme 5
To facilitate the workup procedure, the resulting free ac-
ids were treated with diazomethane and isolated as the
corresponding methyl esters. The enantiomeric excesses
of the b-substituted b-phosphonomalonates 9b–f were de-
termined via HPLC over chiral stationary phase and were
comparable with the diastereomeric excessesof 8b–f, in-
dicating that no racemization occurred during the cleav-
age of the chiral auxiliary.
Figure 3 X-ray crystal structure of 8e
During our preliminary investigations, we noticed that the
diastereomeric excess of the Michael adducts 7b–f was
time-dependent; increasing with longer reaction times. In
order to quantify this observation we monitored the course
of addition of (R,R)-1 to alkylidene malonate 7d. The dia-
stereomeric excess was measured at regular intervals via
31P NMR spectroscopy. The phospha-Michael addition
was carried out using Fe2O3–KOH as a base in either dry
dichloromethane or in a dichloromethane–water system.
Surprisingly, in the presence of water, the diastereomeric
excess increased from the initial value of 62% to >96% af-
ter several hours, while it remained constant when the re-
action was carried out in dry dichloromethane (Figure 4).
Table 8 Cleavage of the TADDOL Auxiliary to Yield b-Phospho-
nomalonates (S)-9b–f
9
R
31P NMR d Yield ee (%)a
(ppm)
(%)
(R,R,S)-9b
(R,R,S)-9c
(R,R,S)-9d
27.8
72
84
92
94
27.9
27.8
86
77
O
O
Deuteration experiments seem to suggest that, in the
Fe2O3–KOH–H2O system, the reaction product undergoes
retro-Michael addition. This establishes an equilibrium,
which leads to virtually complete conversion of the start-
ing materials into the major diastereoisomer.
(R,R,S)-9e
(R,R,S)-9f
28.0
27.9
74
82
84
90
Me
MeO
MeO
OMe
a Determined by chiral HPLC (Daicel OD 2, Daicel AD 2).
In conclusion, we have developed a very efficient asym-
metric synthesis of b-functionalised phosphonic acids or
phosphonates, with very good diastereomeric and enan-
tiomeric excesses. Our approach constitutes a first broadly
applicable method of asymmetric P–C bond formation via
conjugate addition. Additionally, a heterogeneous version
of the reaction, which occurs under very mild conditions,
has been developed. Therefore, considering the impor-
tance of functionalized phosphonates as biologically ac-
tive compounds and synthetic building blocks, our study
Figure 4 Conjugate addition of (R,R)-1 to a,b-unsaturated malonate
7d using Fe2O3–KOH as base in anhydrous (red circles) or wet (blue
squares) CH2Cl2
Unfortunately, excessively long reaction times cause par-
tial decomposition of starting materials and products, re-
sulting in poorer yields.
Synthesis 2006, No. 9, 1447–1460 © Thieme Stuttgart · New York

1452
D. Enders et al.
PAPER
by filtration and the filtrate concentrated under reduced pressure.
The crude product was diluted with CH2Cl2 (3 mL/mmol) and H2O
(10 mL/mmol) and stirred at r.t. for 2 h. After separation of the or-
ganic phase, the crude β-phosphonomalonic acid was obtained as a
colorless solid from the aqueous phase by lyophilisation. The phos-
phonic acid was dissolved in MeOH–H2O (10:1, v/v) and treated
with a solution of diazomethane in ether at r.t. until a yellow color
remained and no further nitrogen was developed. After concentra-
tion under reduced pressure, the crude product was purified by col-
umn chromatography to yield the phosphonomalonates 9.
may be an important starting point for further develop-
ments in this field.
All moisture-sensitive reactions were carried out using standard
Schlenk techniques. Reactions involving sensitive phosphorus in-
termediates were carried out in dried and degassed solvents (N2).
Solvents were dried and purified by conventional methods prior to
use. THF was freshly distilled from sodium–lead alloy under argon.
Reagents of commercial quality were used from freshly opened
containers or purified by common methods. n-BuLi (1.6 M in hex-
ane) was purchased from Merck, Darmstadt and Et2Zn (1.0 M in
heptane) was purchased from Fluka. Preparative column chroma-
tography: Merck silica gel 60, particle size 0.040–0.063 mm (230–
240 mesh, flash). Analytical TLC: silica gel 60 F254 plates from
Merck, Darmstadt. Optical rotation values were measured on a Per-
kin–Elmer P241 polarimeter. Microanalyses were obtained with a
Vario EL element analyzer. Mass spectra were acquired on a Finni-
gan SSQ7000 (CI 100 eV; EI 70 eV) spectrometer. High-resolution
mass spectra were recorded on a Finnigan MAT95 spectrometer. IR
spectra were taken on a Perkin–Elmer FT/IR 1760. 1H and 13C NMR
spectra were recorded on Gemini 300 or Varian Inova 400 and all
measurements were performed with tetramethylsilane as internal
standard. Melting points were determined on a Tottoli melting point
apparatus and are uncorrected.
(3aR,8aR)-2,2-Dimethyl-4,4,8,8-tetraphenylperhydro-6l5-
[1,3]dioxolo-[4,5-e][1,3,2]dioxaphosphepin-6-one [(R,R)-1]
TADDOL (40.2 g, 86 mmol) was added over 60 min via canula to
a solution of PCl3 (9.7 mL, 111 mmol) and Et3N (31.1 mL) in THF
(345 mL) at 0 °C. After 2 h, the precipitated colorless solid was sep-
arated by filtration under argon and a previously degassed mixture
of H2O (1.5 mL), Et3N (15.5 mL) and THF (5 mL) was added to the
filtrate. After 1 h the precipitated colorless solid was separated off
by filtration under argon and the crude product was purified by col-
umn chromatography (n-pentane–Et2O, 3:2) to give the phosphite
(R,R)-1 as a colorless solid.
Yield: 95%; mp 225–227 °C; [a]D26 –301.8 (c 1.00, CHCl3).
IR (KBr): 3062 (w), 3036 (w), 2987 (w), 2933 (w), 2906 (w), 2441
(w), 1495 (m), 1448 (m), 1383 (w), 1372 (w), 1275 (s), 1241 (m),
1218 (m), 1167 (m), 1113 (m), 1094 (s), 1080 (s), 1053 (m), 1034
(s), 1021 (m), 1002 (m), 952 (s), 902 (m), 859 (w), 747 (s), 727 (m),
700 (s), 673 (w), 654 (w), 641 (w), 584 (w), 497 (w) cm–1.
Asymmetric phospha-Michael Addition to Nitroalkenes; Gen-
eral Procedure (GP 1)
The chiral phosphite 1 (1 equiv) was dissolved in dry THF (2 mL/
mmol) and the solution was cooled to –78 °C. Et2Zn (1 equiv) and
TMEDA (1 equiv) were added dropwise, followed by the nitroal-
kene 2 (1 equiv) dissolved in THF (2 mL/mmol). After stirring for
12 h the mixture was allowed to reach r.t. and was then quenched
with sat. aq NH4Cl (4 mL/mmol). The aqueous layer was extracted
with Et2O (3 × 100 mL). Drying the combined organic layers
(Na2SO4) and concentration in vacuo gave the crude product, which
was purified by column chromatography.
1H NMR (400 MHz, CDCl3): d = 0.57 (s, 3 H, CCH3), 0.76 (s, 3 H,
CCH3), 5.21 (d, 3JH–H = 8.2 Hz, 1 H, OCH), 5.36 (d, 3JH–H = 8.0 Hz,
1
1 H, OCH), 7.08 (d, JP–H = 726.8 Hz, 1 H, PH), 7.25–7.43 (m,
12 H, m-ArH and p-ArH), 7.57–7.61 (m, 8 H, o-ArH).
13C NMR (100 MHz, CDCl3): d = 26.2, 26.7, 79.8, 80.6, 88.6 (d,
2JC–P = 4.6 Hz, POCHCH), 88.7, 114.4, 126.8, 126.9, 127.3, 127.5,
127.9, 128.0, 128.2, 128.3, 128.5, 128.6, 128.7, 128.8, 138.9, 139.1,
143.2, 143.6.
Asymmetric phospha-Michael Addition to Knoevenagel Accep-
tors; General Procedure (GP 2)
31P NMR (162 MHz, CDCl3): d = –3.35.
MS (EI, 70 eV): m/z (%) = 512 (4) [M+], 497 (6), 454 (7), 431 (15),
430 (32), 373 (44), 355 (33), 344 (100), 330 (27), 208.2 (25), 207.2
(83), 183.0 (5), 179.2 (9), 178.2 (9), 165.1 (6).
The phosphite 1 (1.0 equiv) and the Knoevenagel acceptor 7 (1.0
equiv) were stirred in CH2Cl2 (1.0 mL/mmol) in the presence of
Fe2O3–KOH (5.25 g/g phosphite), prepared by addition of methan-
olic KOH (0.7 M, 10 mL) to a vigorously stirred suspension of
Fe2O3 (2.30 g, 14.4 mmol) in MeOH (50 mL), removal of the sol-
vent and drying at 120 °C in high vacuum. After the reaction was
complete (TLC, 31P NMR), the suspension was filtered and the res-
idue washed with CH2Cl2 (3 × 20 mL). After concentration under
reduced pressure, the crude product was purified by column chro-
matography.
Anal. Calcd for C31H29O5P: C, 72.65; H, 5.70. Found: C, 72.68; H,
5.99.
(3aR,8aR)-2,2-Dimethyl-6-[(1R)-(2-nitro-1-phenylethyl)]-
4,4,8,8-tetra-phenylperhydro-6l5-[1,3]dioxolo[4,5-e][1,3,2]di-
oxaphosphepin-6-one (3a)
Prepared according to GP 1 using phosphite (R,R)-1 (2.56 g,
5 mmol), TMEDA (0.75 mL, 5mmol), Et2Zn (1 N in hexane; 5 mL,
5 mmol) and nitroalkene 2a (0.745 g, 5 mmol) in THF (20 mL). The
crude product was purified by column chromatography (n-pentane–
Et2O, 7:3) to give pure 3a as a colorless solid.
Removal of the Chiral Auxiliary; General Procedure (GP 3)
To a single-neck flask, charged with the β-nitrophosphonate 3 (1.0
equiv) in MeCN (4 mL/mmol) was added a solution of NaI (1.0
equiv) and TMSCl (1.0 equiv). After refluxing for 10 h, the NaCl
formed was removed by filtration and the filtrate concentrated un-
der reduced pressure. The crude product was diluted with CH2Cl2
(3 mL/mmol) and H2O (10 mL/mmol) and the solution was stirred
at r.t. for 2 h. After separation of the organic phase, the aqueous
phase was concentrated to afford the crude nitrophosphonic acid by
lyophilization. Purification by recrystallization (MeOH) gave 6 as a
colorless solid.
26
Yield: 89%; mp 202–210 °C; [a]D –195.5 (c 1.0, CHCl3);
de = 89% (31P NMR).
IR (KBr): 3676 (w), 3652 (w), 3432 (m), 3062 (m), 3033 (m), 2989
(m), 2931 (m), 2869 (w), 1736 (w), 1602 (w), 1560 (s), 1496 (s),
1449 (s), 1375 (s), 1326 (w), 1264 (s), 1215 (s), 1167 (s), 1107 (s),
1089 (s), 1054 (s), 1038 (s), 1019 (s), 987 (s), 939 (s), 902 (m), 881
(m), 860 (w), 746 (s), 727 (m), 699 (s), 653 (w), 641 (m), 578 (w),
544 (w), 526 (w), 506 (w) cm–1.
1H NMR (400 MHz, CDCl3): d = 0.43 (s, 3 H, CH3), 0.80 (s, 3 H,
CH3), 4.13 (dt, 3JH–H = 7.9 Hz, 2JP–H = 26.1 Hz, 1 H, PCH), 5.02 (m,
3 H, CH2 and CHO), 5.47 (d, 3JH–H = 8.0 Hz, 1 H, CHO), 6.91–7.59
(m, 25 H, ArH).
Removal of the Chiral Auxiliary; General Procedure (GP 4)
To a single-neck flask charged with the β-phosphonomalonic acid 8
(1.0 equiv) in MeCN (4 mL/mmol) was added NaI (4.2 equiv) and
TMSCl (4.2 equiv). After 8 h reflux, the NaCl formed was removed
Synthesis 2006, No. 9, 1447–1460 © Thieme Stuttgart · New York

PAPER
Asymmetric phospha-Michael Additions
1453
3
13C NMR (100 MHz, CDCl3): d = 26.7, 27.4, 44.4 (d, 1JC–P = 145.7
(d, JH–H = 7.8 Hz, 1 H, CHO), 6.47 (d, 2 H, J = 2.2 Hz,
CHCOCH3), 7.03–7.52 (m, 20 H, ArH).
2
Hz, POCH), 74.5 (d, JC–P = 6.8 Hz, POCHCH), 79.2, 79.2, 79.7,
87.7, 91.6, 114.2, 126.6, 126.9, 127.5, 127.5, 128.0, 128.2, 128.4,
128.5, 128.6, 128.7, 128.8, 129.0, 129.0, 129.1, 129.1, 129.9, 131.8,
139.4, 139.5, 143.4, 144.1.
31P NMR (162 MHz, CDCl3): d = 16.80 (minor), 17.05 (major).
MS (CI, isobutane): m/z (%) = 662 (54) [M+], 616 (14), 615 (32),
449 (8), 432 (31), 431 (100), 391 (10), 373 (8), 267 (16), 236 (7),
208 (5), 207 (16), 160 (5), 150 (44), 135 (8), 123 (26), 105 (5), 104
(12), 86 (10).
13C NMR (100 MHz, CDCl3): d = 26.4, 26.9, 44.2 (d, 1JC–P = 148.8
2
Hz, POCH), 56.0, 60.8, 75.1, 78.5, 79.61, 87.2 (d, JC–P = 8.4 Hz,
POCHCH), 91.6, 105.8, 113.7, 126.4, 126.8, 127.1, 127.1, 127.7,
127.8, 128.1, 128.2, 128.2, 128.4, 129.4, 137.9, 138.8, 138.9, 139.0,
143.1, 144.2, 144.9, 153.3.
31P NMR (160 MHz, CDCl3): d = 16.87.
MS (EI, 70 eV): m/z (%) = 751 (19) [M+], 430 (6), 344 (13), 304 (5),
303 (43), 267 (6), 266 (6), 265 (21), 256 (14), 208 (10), 207 (33),
195 (16), 194 (100), 193 (7), 183 (9), 180 (7), 179 (40), 178 (19),
167 (17), 166 (7), 165 (14), 151 (5), 149 (9), 111 (6), 105 (10), 97
(6), 91 (5), 85 (8), 83 (7), 77(5), 73 (7), 71 (10), 69 (6), 60 (12), 59
(5), 57 (22), 56 (6), 55 (14).
Anal. Calcd for C39H36NO7P: C, 70.79; H, 5.48; N, 2.12. Found: C,
70.51; H, 5.55; N, 1.94.
(3aR,8aR)-2,2-Dimethyl-6-[(1R)-2-nitro-(4-phenylphenyl)eth-
yl]-4,4,8,8-tetraphenylperhydro-6l5-[1,3]dioxolo[4,5-e][1,3,2]-
dioxaphosphepin-6-one (3b)
Prepared according to GP 1 using phosphite (R,R)-1 (2.56 g,
5 mmol), TMEDA (0.75 mL, 5 mmol), Et2Zn (1 N in hexane, 5 mL,
5 mmol) and nitroalkene 2b (1.125 g, 5mmol) in THF (20 mL). The
crude product was purified by column chromatography (n-pentane–
Et2O, 1:1) to give pure 3b as a colorless solid.
HRMS (EI): m/z [M + H]+ calcd for C42H42NO10P: 751.254; found:
751.254.
(3aR,8aR)-2,2-Dimethyl-6-[(1R)-1-(4-methylphenyl)-2-nitro-
ethyl]-4,4,8,8-tetraphenylperhydro-6l5-[1,3]dioxolo[4,5-
e][1,3,2]dioxaphosphepin-6-one (3d)
Prepared according to GP 1 using phosphite (R,R)-1 (2.56 g,
5 mmol), TMEDA (0.75 mL, 5mmol), Et2Zn (1 N in hexane, 5 mL,
5 mmol) and nitroalkene 2d (0.815 g, 5 mmol) in THF (20 mL). The
crude product was purified by column chromatography (n-pentane–
Et2O, 7:3) to give pure 3d as a colorless solid.
26
Yield: 88%; mp 155 °C, [a]D –155.5 (c 1.0, CHCl3); de = 87%
(31P NMR).
IR (KBr): 3433 (m), 3061 (m), 3031 (m), 2990 (m), 2956 (m), 2927
(m), 2879 (m), 2318 (w), 1601 (m), 1561 (vs), 1494 (s), 1448 (s),
1373 (s), 1264 (vs), 1216 (m), 1167 (m), 1106 (m), 1089 (m), 1054
(vs), 1039 (vs), 1020 (vs), 1006 (vs), 985 (vs), 940 (s), 924 (m), 901
(m), 887 (m), 864 (w), 849 (w) 803 (w), 790 (w), 762 (m) 674 (w)
cm–1.
1H NMR (400 MHz, CDCl3): d = 0.43 (s, 3 H, CH3), 0.80 (s, 3 H,
CH3), 4.21 (dt, 3JH–H = 7.1 Hz, 2JP–H = 26.1 Hz, 1 H, PCH), 5.04 (m,
3 H, PCCH2 and CHO), 5.47 (d, 3JH–H = 8.0 Hz, 1 H, CHO), 6.95–
7.61 (m, 29 H, ArH).
26
Yield: 87%; mp 231 °C; [a]D –187.3 (c 1.00, CHCl3); de = 96%
(31P NMR).
IR (KBr): 3435 (w), 3060 (m), 3031 (m), 2989 (m), 2957 (m), 2929
(m), 2869 (w), 1602 (w), 1561 (s), 1516 (m), 1496 (m), 1448 (s),
1374 (s), 1336 (w), 1322 (w), 1261 (s), 1215 (m), 1170 (s), 1115
(m), 1088 (m), 1053 (s), 1038 (s), 1018 (s), 980 (s), 941 (s), 926 (s),
901 (m), 884 (m), 863 (w), 841 (w), 792 (w), 747 (s), 726 (s), 699
(s), 652 (w), 641 (w), 585 (m), 550 (w) cm–1.
13C NMR (100 MHz, CDCl3): d = 26.2, 27.9, 43.6 (d, 1JC–P = 145.7
1H NMR (400 MHz, CDCl3): d = 0.45 (s, 3 H, CCH3), 0.82 (s, 3 H,
2
4
Hz, POCH), 78.7 (d, JC–P = 2.3 Hz, POCHCH), 79.2, 79.7, 87.3,
CCH3), 2.33 (d, JH–H = 1.6 Hz, 3 H, ArCH3), 4.10 (dt, 3JH–H = 8.0
114.2, 126.2, 126.8, 127.0, 127.1, 127.1, 127.2, 127.4, 127.6, 127.7,
128.0, 128.0, 128.1, 128.3, 128.3, 128.7, 129.0, 129.0, 129.5, 130.3,
138.9, 139.0, 140.1, 140.9, 142.9, 143.7.
31P NMR (162 MHz, CDCl3): d = 15.50.
Hz, 2JP–H = 26.1 Hz, 1 H, CHP), 5.00 (m, 3 H, CH2, CHO), 5.47 (d,
3JH–H = 8.0 Hz, 1 H, CHO), 6.94–7.60 (m, 24 H, ArH).
13C NMR (100 MHz, CDCl3): d = 21.5, 26.6, 27.4, 44.1 (d,
1JC–P = 145.7 Hz, POCH), 74.6 (d, 2JC–P = 6.8 Hz, POCHCH), 79.3,
79.8, 87.6, 91.4, 114.2, 126.6, 127.4, 127.5, 128.0, 128.1, 128.4,
128.4, 128.5, 128.5, 128.7, 128.8, 129.0, 129.7, 129.9, 138.2, 138.2,
139.4, 139.5, 143.5, 144.2.
Anal. Calcd for C45H40NO7P: C, 73.26; H, 5.46; N, 1.90. Found: C,
72.93; H, 5.77; N, 1.80.
(3aR,8aR)-2,2-Dimethyl-6-[(1R)-2-nitro-(3,4,5-trimethoxyphe-
nyl)ethyl]-4,4,8,8-tetraphenylperhydro-6l5-[1,3]dioxolo[4,5-e]-
[1,3,2]dioxaphosphepin-6-one (3c)
Prepared according to GP 1 using phosphite (R,R)-1 (2.56 g, 5
mmol), TMEDA (0.75 mL, 5mmol), Et2Zn (1 N in hexane, 5 mL,
5mmol) and nitroalkene 2c (1.196 g, 5mmol) in THF (20 mL). The
crude product was purified by column chromatography (n-pentane–
Et2O, 3:7) to give 3c as a colorless solid.
31P NMR (160 MHz, CDCl3): d = 17.22.
MS (CI, isobutane): m/z (%) = 677 (25) [M + H]+, 676 (57) [M+],
630 (22), 629 (61), 449 (10), 432 (17), 431 (46), 373 (5), 267 (19),
264 (12), 207 (14), 183 (5), 174 (10), 165 (9), 164 (100), 160 (16),
149 (8), 148 (10), 137 (16), 120 (7), 119 (21), 118 (54), 86 (19).
Anal. Calcd for C40H38NO7P: C, 71.10; H, 5.67; N, 2.07. Found: C,
71.13; H, 5.93; N, 1.91.
26
Yield: 91%; mp 117–127 °C; [a]D –203.3 (c 1.0, CHCl3);
(3aR,8aR)-2,2-Dimethyl-6-[(1R)-(1-naphthyl)-2-nitroethyl]-
4,4,8,8-tetraphenylperhydro-6l5-[1,3]dioxolo[4,5-e][1,3,2]di-
oxaphosphepin-6-one (3e)
Prepared according to GP 1 using phosphite (R,R)-1 (2.56 g,
5 mmol), TMEDA (0.75 mL, 5 mmol), Et2Zn (1 N in hexane, 5 mL,
5 mmol) and nitroalkene 2e (0.995 g, 5mmol) in THF (20 mL). The
crude product was purified by column chromatography (n-pentane–
Et2O, 2:3) to give pure 3e as a colorless solid.
de = 88% (31P NMR).
IR (CHCl3): 3092 (w), 3063 (m), 3011 (s), 2965 (m), 2938 (s), 2840
(m), 1593 (s), 1559 (s), 1510 (s), 1497 (s), 1463 (s), 1449 (s), 1427
(s), 1374 (s), 1335 (s), 1246 (s), 1218 (s), 1188 (s), 1167 (s), 1129
(s), 1107 (s), 1090 (s), 1054 (s), 1039 (s), 1019 (s), 1005 (s), 986 (s),
941 (s), 924 (s), 910 (m), 889 (m), 864 (w), 845 (w), 803 (w), 752
(s), 727 (s), 700 (s), 666 (s), 659 (s), 641 (m) cm–1.
26
1H NMR (400 MHz, CDCl3): d = 0.49 (s, 3 H, CH3CCH3), 0.86 (s,
3 H, CH3CCH3), 3.72 (s, 6 H, m-OCH3), 3,84 (s, 3 H, p-OCH3),
Yield: 87%; mp 131 °C; [a]D –219.3 (c 1.00, CHCl3); de = 93%
(31P NMR).
3
3
2
4.17 (ddd, JH–H = 4.9 Hz, JH–H = 10.7 Hz, JP–H = 25.3 Hz, 1 H,
IR (KBr): 3448 (w), 3060 (m), 3038 (w), 2987 (m), 2934 (w), 2866
(w), 1599 (w), 1560 (s), 1514 (w), 1496 (m), 1448 (s), 1373 (s),
CHP), 4.98 (m, 2 H, CH2), 5.08 (d, 3JH–H = 7.8 Hz, 1 H, CHO), 5.53
Synthesis 2006, No. 9, 1447–1460 © Thieme Stuttgart · New York

1454
D. Enders et al.
PAPER
1331 (w), 1269 (s), 1217 (s), 1167 (s), 1112 (m), 1089 (s), 1053 (s),
1037 (s), 1019 (s), 984 (s), 939 (s), 923 (s), 901 (m), 878 (m), 859
(m), 792 (m), 776 (s), 744 (s), 727 (s), 699 (s), 672 (w), 655 (w)
cm–1.
1H NMR (400 MHz, CDCl3): d = 0.41 (s, 3 H, CH3), 0.77 (s, 3 H,
CH3), 4.94 (m, 1 H, CHCH2), 5.06 (m, 1 H, CHO), 5.15 (m, 2 H,
CHCH2), 5.50 (m, 1 H, CHO), 6.67–7.86 (m, 27 H, ArH).
(3aR,8aR)-2,2-Dimethyl-6-[3-nitro-1-(3,4,5-trimethoxyphenyl)-
pentyl]-4,4,8,8-tetraphenylperhydro[1,3]dioxolo[4,5-e][1,3,2]di-
oxaphosphepin-2-one (5a)
Prepared according to GP 1 using phosphite (R,R)-1 (512 mg,
1 mmol), TMEDA (0.15 mL, 5 mmol), Et2Zn (1 N in hexane,1 mL,
1 mmol) and nitroalkene 4a (267 mg, 1 mmol) in THF (4 mL). The
crude product was purified by column chromatography (n-pentane–
Et2O, 1:3) to give 5a as a colorless solid.
13C NMR (100 MHz, CDCl3): d = 26.2, 26.7, 37.8 (d, 1JC–P = 144.2
26
Yield: 66%; mp 126 °C; [a]D –194.0 (c 0.92, CHCl3); de = 75%
2
Hz, POCH), 75.0 (d, JC–P = 5.3 Hz, POCHCH), 78.8, 79.6, 87.7,
(31P NMR).
90.3, 114.0, 122.6, 124.0, 125.5, 125.8, 126.0, 126.7, 126.8, 127.1,
127.2, 127.7, 127.8, 127.9, 128.3, 128.5, 128.7, 128.8, 128.9, 128.9,
129.1, 131.7, 131.7, 133.9, 138.5, 139.2, 142.8, 143.3.
31P NMR (162 MHz, CDCl3): d = 15.18.
MS (EI, 70 eV): m/z (%) = 711 (0.3) [M+], 471 (5), 445 (6), 265
(18), 234 (7), 233 (46), 208 (27), 207 (100), 191 (19), 183 (13), 180
(6), 179 (39), 178 (27), 168 (6), 167 (28), 166 (7), 165 (12), 155 (6),
154 (36), 153 (22), 152 (10), 105 (16), 102 (5), 77 (5), 57 (8), 55 (6).
IR (KBr): 3447 (m), 3062 (m), 3027 (w), 2936 (s), 2839 (m), 1592
(s), 1557 (s), 1509 (s), 1498 (s), 1461 (s), 1449 (s), 1425 (s), 1384
(m), 1373 (s), 1332 (s), 1249 (s), 1217 (s), 1189 (s), 1167 (s), 1129
(s), 1090 (s), 1053 (s), 1037 (s), 1014 (s), 971 (s), 938 (s), 902 (m),
883 (m), 859 (m), 802 (w), 789 (w), 745 (s), 727 (m), 699 (s), 660
(m), 642 (m), 577 (w), 556 (m), 540 (w), 488 (w), 467 (m) cm–1.
1H NMR (400 MHz, CDCl3): d = 0.51 (s, 3 H, CCH3), 0.83 (s, 3 H,
CCH3), 0.95 (t, 3JH–H = 7.4 Hz, 3 H, CH2CH3), 1.98 (m, 1 H, CH2),
2.5 (m, 1 H, CH2), 3.74 (s, 6 H, OCH3), 3.78 (dd, 3JH–H = 6.59 Hz,
2JP–H = 20.2 Hz, 1 H, PCH), 3.82 (s, 3 H, OCH3), 5.1 (d, 3JH–H = 8.2
Hz, 1 H, OCH), 5.16 (m, 1 H, CHNO2), 5.59 (d, 3JH–H = 8.0 Hz, 1 H,
OCH), 6.50 (s, 2 H, ArH), 6.8–7.8 (m, 20 H, ArH).
13C NMR (100 MHz, CDCl3): d = 11.0, 26.8, 27.3, 27.3, 44.2 (d,
1JC–P = 148.8 Hz, POCH), 56.0, 60.8, 78.6, 80.2, 87.5 (d, 2JC–P = 8.4
Hz, POCHCHNO2), 91.9, 92.3, 105.8, 113.7, 126.4, 126.8, 127.1,
127.1, 127.7, 127.8, 128.1, 128.2, 128.2, 128.4, 129.4, 129.5, 129.6,
137.9, 138.7, 138.9, 139.0, 143.1, 144.2, 153.3.
+
HRMS (EI): m/z [M + 1] calcd for C43H38NO7P: 711.23; found:
711.239.
(3aR,8aR)-2,2-Dimethyl-6-[(1R)-2-nitro-1-ferrocenyl-ethyl]-
4,4,8,8-tetraphenylperhydro-6l5-[1,3]dioxolo [4,5-e][1,3,2]di-
oxaphosphepin-6-one (3f)
Prepared according to GP 1 using phosphite (R,R)-1 (2.56 g,
5 mmol), TMEDA (0.75 mL, 5 mmol), Et2Zn (1 N in hexane, 5 mL,
5 mmol) and nitroalkene 2f (1.225 g, 5 mmol) in THF (20 mL). The
crude product was purified by column chromatography (n-pentane–
Et2O, 3:2) to give pure 3f as a yellow-orange solid.
31P NMR (160 MHz, CDCl3): d = 18.93.
Yield: 86%; mp 93–95 °C; [a]D26 –84.4 (c 1.00, CHCl3); de = 84%
MS (EI, 70 eV): m/z (%) = 780 (10) [M+], 779 (21), 331 (8), 302 (5),
265 (15), 223 (14), 222 (100), 208 (7), 207 (33), 191 (5), 179 (19),
178 (11), 167 (12), 105 (5).
HRMS (EI): m/z [M + 1] + calcd for C44H46NO10P: 779.285; found:
779.283.
(31P NMR).
IR (CHCl3): 3063 (w), 3010 (m), 1561 (s), 1496 (m), 1448 (s), 1374
(m), 1257 (s), 1217 (s), 1167 (m), 1107 (m), 1090 (m), 1053 (s),
1039 (s), 1020 (s), 1004 (s), 982 (s), 940 (m), 925 (m), 902 (m), 880
(w), 820 (w), 804 (w), 756 (s), 727 (s), 700 (s), 668 (m), 642 (w),
576 (w), 484 (m), 465 (w) cm–1.
Anal. Calcd for C44H46NO10P: C, 67.78; H, 5.95; N, 1.80. Found: C,
68.19; H, 6.25; N, 1.59.
1H NMR (400 MHz, C6D6): d = 0.53 (s, 3 H, CCH3), 0.78 (s, 3 H,
CCH3), 3.78 (m, 1 H), 3.83 (m, 1 H), 3.89 (s, 1 H), 3.92 (m, 1 H),
3.90 (s, 5 H, C5H5), 4.10 (dt, 2JH–P = 23.6 Hz, 3JH–H = 6.5 Hz, 1 H,
PCH), 4.76 (ddd, 3JH–H = 6.6 Hz, 2JH–H = 13.7 Hz, 3JH–P = 16.5 Hz,
(3aR,8aR)-2,2-Dimethyl-6-[1-(1-naphthyl)-3-nitropropentyl]-
4,4,8,8-tetraphenylperhydro[1,3]dioxolo[4,5-e][1,3,2]dioxa-
phosphepin-2-one (5b)
Prepared according to GP 1 using phosphite (R,R)-1 (512 mg,
1 mmol), TMEDA (0.15 mL, 5 mmol), Et2Zn (1 N in hexane, 1 mL,
1 mmol) and nitroalkene 4b (227 mg, 1 mmol) in THF (4 mL). The
crude product was purified by column chromatography (n-pentane–
Et2O, 4:3) to give 5b as a colorless solid.
3
2
3
1 H, PCCH), 4.99 (ddd, JH–H = 6.3 Hz, JH–H = 13.7 Hz, JH–
P = 13.7 Hz, 1 H, PCCH), 5.37 (d, 3JH–H = 8.1 Hz, 1 H, OCH), 5.89
(d, 3JH–H = 8.1 Hz, 1 H, OCH), 7.05–7.96 (m, 20 H, ArH).
1
13C NMR (100 MHz, C6D6): d = 26.6, 27.1, 38.9 (d, JC–P = 145.7
Hz, POCH), 66.3, 67.9, 68.1, 69.4, 69.3, 74.7, 79.2, 79.8, 81.8, 86.9,
91.8, 113.8, 127.0, 127.2, 127.3, 127.7, 127.9, 128.2, 128.2, 128.3,
128.4, 129.1, 130.4, 139.8, 140.0, 144.0, 144.91.
26
Yield: 87%; mp 138 °C; [a]D –183.0 (c 0.71, CHCl3); de = 69%
(31P NMR).
31P NMR (162 MHz, C6D6): d = 17.69.
IR (KBr): 3651 (w), 3449 (m), 3061 (m), 2986 (m), 2933 (m), 1599
(m), 1558 (s), 1496 (m), 1448 (s), 1372 (s), 1260 (s), 1216 (s), 1167
(s), 1105 (m), 1088 (s), 1053 (s), 1037 (s), 1018 (s), 979 (s), 938 (s),
923 (s), 882 (m), 810 (m), 790 (m), 776 (m), 744 (s), 728 (s), 699
(s), 673 (w), 657 (m), 641 (m), 583 (m), 557 (w), 541 (m), 522 (w),
505 (w), 489 (w) cm–1.
1H NMR (400 MHz, CDCl3): d = 0.54 (s, 3 H, CCH3), 0.83 (s, 3 H,
CCH3), 1.02 (t, 3JH–H = 7.4 Hz, 3 H, CH2CH3), 1.98 (m, 2 H, CH2),
4.98 (m, 2 H, PCH and OCH), 5.13 (m, 1 H, CHNO2), 5.59 (d,
3JH–H = 8.0 Hz, 1 H, OCH), 6.81–8.02 (m, 27 H, ArH).
MS (EI, 70 eV): m/z (%) = 770.6 (8), 769.5 (45) [M+], 722.5 (12),
722.4 (15) [M+ – HNO2], 431.4 (8), 430.3 (5), 345.4 (8), 344.4 (7),
340.3 (13), 339.1 (92), 337.2 (6), 321.1 (11), 305.2 (5), 293.2 (10),
292.2 (72), 291.4 (6), 290.2 (5), 274.1 (27), 268.4 (7), 267.3 (16),
265.3 (8), 252.2 (5), 237.2 (10), 227.2 (6), 213.1 (14), 212.1 (100)
[FcCHCH2]+, 211.1 (10), 210.2 (10), 209.3 (9), 208.2 (19), 207.2
(62), 195.2 (6), 191.2 (6), 184.0 (13), 183.2 (5), 180.2 (12), 179.2
(70), 178.2 (75), 168.2 (11), 167.2 (79), 166.2 (10), 165.1 (28),
152.1 (10), 121.2 (13), 105.2 (30), 102.2 (7), 91.3 (11), 77.2 (6).
Anal. Calcd for C43H40NO7P: C, 67.11; H, 5.24; N, 1.82. Found: C,
67.48; H, 5.53; N, 1.35.
13C NMR (100 MHz, CDCl3): d = 12.2, 26.0, 28.1, 28.3, 44.2 (d,
2
1JC–P = 147.2 Hz, POCH), 78.6, 80.2, 86.5 (d, JC–P = 8.1 Hz,
POCHCHNO2), 91.7, 105.4, 113.7, 126.4, 126.8, 127.1, 127.1,
127.7, 127.8, 128.1, 128.2, 128.2, 128.4, 129.4, 129.5, 129.6, 137.9,
138.8, 138.9, 139.0, 143.1, 144.2, 153.3.
31P NMR (162 MHz, CDCl3): d = 18.93.
Synthesis 2006, No. 9, 1447–1460 © Thieme Stuttgart · New York

PAPER
Asymmetric phospha-Michael Additions
31P NMR (160 MHz, CD3OD): d = 19.75.
1455
MS (EI, 70 eV): m/z (%) = 739 (0.2) [M+], 499 (6), 473 (7), 274
(12), 265 (17), 262 (6), 261 (15), 219 (13), 208 (21), 207 (100), 191
(7), 183 (7), 182 (26), 181 (8), 180 (6), 179 (26), 178 (18), 167 (20),
166 (5), 165 (9), 155 (7), 153 (13), 105 (8).
MS (FAB, negative ions): m/z (%) = 229 (38), 180 (15), 126 (5), 94
(5), 78 (100), 62 (8).
Anal. Calcd for C8H10NO5P: C, 41.57; H, 4.67; N, 6.06. Found: C,
41.34; H, 4.95; N, 6.11.
Anal. Calcd for C45H42NO7P: C, 73.06; H, 5.72; N, 1.89. Found: C,
72.89; H, 5.41; N, 1.66.
2-Nitro-1-(4-phenylphenyl)ethylphosphonic Acid (6b)
Prepared according to GP 3 using nitrophosphonate 3b (2.065 g, 2.8
mmol), NaI (0.851 g, 5.7 mmol) and TMSCl (0.71 mL, 5.7 mmol)
in MeCN (10 mL). The crude product was purified by recrystalliza-
tion (MeOH) to give 6b as a colorless solid.
(3aR,8aR)-6-[1-(4-Benzyloxyphenyl)-3-nitropenthyl]-2,2-di-
methyl-4,4,8,8-tetraphenylperhydro[1,3]dioxolo[4,5-e][1,3,2]di-
oxaphosphepin-2-one (5c)
Prepared according to GP 1 using phosphite (R,R)-1 (1.024 g,
2 mmol), TMEDA (0.30 mL, 2 mmol), Et2Zn (1 N in hexane, 2 mL,
2 mmol) and nitroalkene 4c (0.566 mg, 2 mmol) in THF (8 mL). The
crude product was purified by column chromatography (n-pentane–
Et2O, 1:1) to give 5c as a colorless solid.
26
Yield: 88%; mp 102 °C; [a]D +11.2 (c 0.91, MeOH); ee = 88%
(HPLC; Daicel OD; n-heptane–i-PrOH, 9.5:0.5).
IR (KBr): 3501 (s), 3029 (m), 2915 (m), 2311 (w), 1667 (s), 1543
(s), 1521 (s), 1496 (s), 1455 (m), 1435 (m), 1377 (s), 1327 (w), 1158
(s), 1084 (m), 989 (s), 941 (s), 844 (m), 786 (m), 733 (m), 710 (s),
575 (w), 545 (m) cm–1.
26
Yield: 81%; mp 163 °C; [a]D –198.2 (c 1.31, CHCl3); de = 61%
(31P NMR).
IR (KBr): 3463 (w), 3062 (m), 3034 (m), 2985 (m), 2934 (m), 1736
(w), 1610 (m), 1584 (m), 1556 (s), 1511 (s), 1496 (s), 1449 (s), 1373
(s), 1354 (m), 1303 (m), 1251 (s), 1222 (s), 1181 (s), 1167 (s), 1107
(s), 1089 (s), 1053 (s), 1038 (s), 1017 (s), 979 (s), 938 (s), 921 (s),
902 (m), 883 (m), 861 (m), 840 (m), 801 (w), 744 (s), 727 (s), 698
(s), 672 (w), 641 (m), 583 (m), 548 (m), 507 (w), 488 (w) cm–1.
3
3
1H NMR (400 MHz, CD3OD): d = 3.81 (ddd, JH–H = 5.0 Hz, JH–
2
H = 11.8 Hz, JP–H 23.2 Hz, 1 H, CHP), 4.88 (m, 2 H, CH2), 7.31–
7.56 (m, 9 H, ArH).
1
13C NMR (100 MHz, CD3OD): d = 44.9 (d, JP–C = 133.5 Hz,
2
POCH), 76.0 (d, JP–C = 4.5 Hz, POCHCH), 127.2, 127.5, 128.5,
1H NMR (400 MHz, CDCl3): d = 0.43 (s, 3 H, CH3), 0.86 (s, 3 H,
128.9, 131.1, 134.2, 135.2.
31P NMR (162 MHz, CD3OD): d = 20.1.
3
CH3), 0.92 (t, JH–H = 7.4 Hz, 3 H, CH3), 1.98 (m, 2 H, CH2), 2.48
3
3
(m, 2 H, CH2), 3.74 (dd, JH–H = 12.1 Hz, JP–H = 20.1 Hz, 1 H,
PCH), 5.01 (s, 2 H, CH2), 5.02 (d, 3JH–H = 6.32 Hz, 1 H, OCH), 5.12
(m, 1 H, CHNO2), 5.57 (d, 3JH–H = 7.97 Hz, 2 H, OCH), 6.84–7.61
(m, 29 H, ArH).
MS (FAB, negative ions): m/z (%) = 305 (43), 272 (27), 2.01 (23),
145 (15), 126 (5), 94 (5), 69 (100), 62 (8).
Anal. Calcd for C14H14NO5P: C, 54.73; H, 4.59; N, 4.56. Found: C,
54.40; H, 4.91; N, 4.20.
13C NMR (100 MHz, CDCl3): d = 10.5, 26.1, 26.7, 26.9, 48.1, 69.8,
78.4, 79.4, 87.2, 91.0, 91.5, 113.6, 114.7, 124.7, 127.0, 127.2,
127.6, 127.6, 127.7, 127.8, 127.9, 128.0, 128.4, 128.5, 129.5, 130.3,
136.5, 139.2, 139.3, 139.5, 139.8, 143.1, 143.7.
2-Nitro-1-(3,4,5-trimethoxyphenyl)ethylphosphonic Acid (6c)
Prepared according to GP 3 using nitrophosphonate 3c (2.253 g, 2.8
mmol), NaI (0.851 g, 5.7 mmol) and TMSCl (0.71 mL, 5.7 mmol)
in MeCN (10 mL). The crude product was purified by recrystalliza-
tion (MeOH) to give 6c as a colorless solid.
31P NMR (162 MHz, CDCl3): d = 18.34.
MS (EI, 70 eV): m/z (%) = 795 (0.01) [M+], 432 (16), 431 (50), 373
(20), 348 (14), 347 (65), 345 (26), 318 (23), 317 (18), 286 (14), 284
(13), 271 (24), 269 (25), 265 (70), 238 (24), 220 (32), 208 (8), 207
(61), 205 (100), 177 (10), 150 (7), 149 (72), 147 (8), 145 (13), 141
(14), 131 (16), 128 (13), 127 (10), 119 (14), 115 (14), 111 (17), 105
(23), 102 (10), 98 (10), 97 (28), 95 (15), 91 (12), 85 (29), 83 (29),
81 (16), 71 (30), 70 (13), 69 (22), 59 (13), 57 (62), 56 (12), 55 (22),
49 (21).
26
Yield: 92%; mp 89 °C; [a]D +9.8 (c 2.5, MeOH); ee = 86%
(HPLC; Daicel OD; n-heptane–i-PrOH, 9.8:0.2).
IR (KBr): 3508 (m), 3011 (w), 2946 (w), 2846 (w), 1595 (s), 1548
(s), 1511 (m), 1459 (m), 1431 (s), 1374 (m), 1336 (m), 1318 (w),
1291 (w), 1252 (s), 1236 (s), 1186 (m), 1154 (m), 1124 (s), 1034 (s),
1015 (s), 988 (s), 941 (s), 909 (m), 857 (m), 814 (w), 776 (w), 651
(m), 537 (m), 455 (m) cm–1.
1H NMR (400 MHz, CD3OD): d = 3.72 (s, 3 H, p-ArCH3), 3.81 (s,
6 H, m-ArCH3), 3.92 (ddd, J = 5.2 Hz, J = 10.7 Hz, J = 23.9 Hz,
1 H, CH), 4.96–5.05 (m, 2 H, CH2), 6.67 (d, J = 2.5 Hz, 2 H, ArH).
13C NMR (100 MHz, CD3OD): d = 44.7 (d, JP–C = 135.2 Hz,
POCH), 55.5, 59.9, 75.7 (d, JP–C = 4.6 Hz, POCHCH), 106.3,
129.7, 133.0, 134.4.
31P NMR (162 MHz, CD3OD): d = 20.48.
Anal. Calcd for C48H46NO8P: C, 72.44; H, 5.83; N, 1.76. Found: C,
72.27; H, 6.11; N, 1.95.
2-Nitro-1-phenylethylphosphonic Acid (6a)
1
Prepared according to GP 3 using nitrophosphonate 3a (1.877 g, 2.8
mmol), NaI (0.851 g, 5.7 mmol) and TMSCl (0.71 mL, 5.7 mmol)
in MeCN (10 mL). The crude product was purified by recrystalliza-
tion (MeOH) to give 6a as a colorless solid.
2
26
Yield: 86%; mp 77 °C; [a]D +9.2 (c 0.83, MeOH); ee = 92%
MS (FAB, negative ions): m/z (%) = 320 (96), 306 (5), 181 (6), 79
(100).
(HPLC; Daicel OD; n-heptane–i-PrOH, 9.5:0.5).
IR (KBr): 3418 (s), 3034 (m), 2923 (m), 2323 (w), 1656 (s), 1556
(s), 1496 (m), 1455 (m), 1435 (m), 1377 (s), 1327 (w), 1158 (s),
1084 (m), 989 (s), 941 (s), 838 (m), 776 (m), 751 (m), 701 (s), 596
(w), 545 (m) cm–1.
Anal. Calcd for C11H16NO8P: C, 41.13; H, 5.02; N, 4.36. Found: C,
41.26; H, 5.37; N, 4.01.
1-(4-Methylphenyl)-2-nitroethylphosphonic Acid (6d)
Prepared according to GP 3 using nitrophosphonate 3d (2.298 g, 3.4
mmol), NaI (1.020 g, 6.8 mmol) and TMSCl (0.85 mL, 6.8 mmol)
in MeCN (10 mL). The crude product was purified by recrystalliza-
tion (MeOH) to give 6d as a colorless solid.
3
1H NMR (400 MHz, CD3OD): d = 3.92 (ddd, JH–H = 4.4 Hz,
2
3JH–H = 11.3 Hz, JP–H 23.9 Hz, 1 H, CHP), 4.95–5.09 (m, 2 H,
CH2), 7.22–7.37 (m, 5 H, ArH).
1
13C NMR (100 MHz, CD3OD): d = 44.9 (d, JP–C = 133.5 Hz,
26
2
Yield: 94%; mp 83 °C; [a]D +15.3 (c 2.5, MeOH); ee = 95%
POCH), 76.0 (d, JP–C = 4.5 Hz, POCHCHNO2), 127.5, 128.5,
(HPLC; Daicel OD; n-heptane–i-PrOH, 9.5:0.5).
128.9, 134.2.
Synthesis 2006, No. 9, 1447–1460 © Thieme Stuttgart · New York

1456
D. Enders et al.
PAPER
3
IR (KBr): 3433 (m), 3033 (m), 2924 (s), 2312 (w), 1637 (m), 1558
(s), 1515 (m), 1479 (w), 1437 (m), 1377 (s), 1158 (s), 1000 (s), 939
(s), 849 (m), 822 (m), 737 (w), 717 (w), 681 (m), 561 (s), 500 (m)
cm–1.
PCCHCO2CH3), 5.30 (d, JH–H = 8.0 Hz, 1 H, OCH), 5.61 (d,
3JH–H = 8.0 Hz, 1 H, OCH), 7.20–7.77 (m, 20 H, ArH).
13C NMR (100 MHz, CDCl3): d = 21.0, 21.5, 26.9, 27.0, 28.0, 44.7
(d, 1JP–C = 145.7 Hz, POCH), 52.6 (d, 2JP–C = 29.1 Hz, POCHCH),
52.6, 78.5, 79.3, 86.9, 91.1, 113.3, 126.8, 126.9, 127.1, 127.2,
127.3, 127.6, 127.6, 127.7, 127.7, 128.8, 128.9, 129.9, 139.7, 139.9,
143.9, 144.80, 167.9, 168.0.
1H NMR (400 MHz, CD3OD): d = 2.27 (s, 3 H, CH3), 3.88 (ddd,
3
2
3JH–H = 4.4 Hz, JH–H = 11.5 Hz, JP–H 23.9 Hz, 1 H, CHP), 4.90–
5.03 (m, 2 H, CH2), 7.12 (d, 3JH–H = 8.0 Hz, 2 H, o-ArH), 7.23 (dd,
3JH–H = 1.6 Hz, J = 8.0 Hz, 2 H, m-ArH).
31P NMR (162 MHz, CDCl3): d = 24.53.
13C NMR (100 MHz, CD3OD): d = 20.1, 44.4 (d, 1JP–H = 135.0 Hz,
MS (EI, 70 eV): m/z (%) = 252 (10), 251 (100), 219 (17), 207 (16),
179 (11), 178 (8), 123 (5), 105 (7).
2
POCH), 75.9 (d, JP–H = 4.6 Hz, POCHCH), 128.7, 129.1, 130.8,
137.4.
MS (CI, 100 eV): m/z (%) = 699 (100), 471 (6), 463 (14), 460 (6),
459 (21), 447 (10), 432 (18), 431 (60), 269 (58), 251 (28), 155 (7).
31P NMR (160 MHz, CD3OD): d = 20.38.
MS (FAB, negative ions): m/z (%) = 243 (80), 209 (6), 180 (11),
158 (6), 78 (100), 62 (6).
Anal. Calcd for C40H43O9P: C, 68.76; H, 6.20. Found: C, 68.60; H,
6.29.
Anal. Calcd for C9H12NO5P: C, 44.09; H, 4.93; N, 5.71. Found: C,
44.32; H, 5.30; N, 5.55.
2-{(S)-1-[(3aR,8aR)-2,2-Dimethyl-6-oxo-4,4,8,8-tetraphenyl-
perhydro-6l5-phosphepino[4,5-d][1,3]dioxol-6-yl]-1-phenyl-
methyl}malonic Acid Dimethyl Ester (8b)
1-(1-Naphthyl)-2-nitroethylphosphonic Acid (6e)
Prepared according to GP 3 using nitrophosphonate 3e (2.133 g, 3.0
mmol), NaI (0.899 g, 6.0 mmol) and TMSCl (0.75 mL, 6.0 mmol)
in MeCN (10 mL). The crude product was purified by recrystalliza-
tion (MeOH) to give 6e as a colorless solid.
Prepared according to GP 2 using 2-benzylidene malonic acid di-
methylester 7b (220 mg, 1.0 mmol), phosphite (R,R)-1 (512 mg, 1.0
mmol) and Fe2O3/KOH (2.698 g, 2.5 equiv KOH) in H2O (92 mL).
The crude product was purified by column chromatography (n-pen-
tane–Et2O, 1:1) to give 8b as a colorless solid.
26
Yield: 65%; mp 105 °C; [a]D +8.7 (c 0.93, MeOH); ee = 91%
26
(HPLC; Daicel OD; n-heptane–i-PrOH, 9.5:0.5).
Yield: 64%; mp 210 °C; [a]D –147.3 (c 1.00, CHCl3); de = 86%
(31P NMR).
IR (KBr): 3551 (s), 3474 (s), 3415 (s), 3050 (w), 2924 (w), 2290
(w), 1637 (m), 1619 (s), 1598 (m), 1556 (s), 1512 (m), 1479 (w),
1435 (w), 1397 (w), 1377 (s), 1334 (w), 1258 (m), 1164 (m), 980
(s), 943 (s), 825 (w), 798 (m), 777 (s), 728 (w), 682 (w), 639 (w),
614 (w), 560 (w), 504 (m) cm–1.
1H NMR (400 MHz, CD3OD): d = 4.96–5.33 (m, 3 H, CH2CHP),
7.30–8.23 (m, 7 H, ArH).
IR (KBr): 3445 (m), 362 (m), 3028 (m), 2986 (m), 2960 (m), 2922
(m), 2195 (w), 1742 (vs), 1705 (m), 1658 (m), 1639 (m), 1602 (m),
1561 (m), 1543 (m), 1525 (m), 1497 (s), 1458 (s), 1431 (m), 1380
(m), 1328 (m), 1290 (s), 1261 (vs), 1229 (vs), 1205(s), 1170 (s),
1155 (s), 1116 (s), 1088 (s), 1055 (s), 1036 (vs), 1010 (vs), 962 (vs),
940 (vs), 920 (s), 901 (s), 883 (s), 806 (m), 791 (s), 745 (s), 726 (s),
699 (vs), 673 (m), 641 (m), 616 (w), 581 (m), 562 (m), 540 (m), 518
(m), 499 (m), 483 (w), 465 (w) cm–1.
1
13C NMR (100 MHz, CD3OD): d = 44.9 (d, JP–C = 133.5 Hz,
2
POCH), 76.0 (d, JP–C = 4.5 Hz, POCHCH), 124.9, 125.7, 126.0,
1H NMR (300 MHz, CDCl3): d = 0.32 (s, 3 H, CCH3), 0.76 (s, 3 H,
127.5, 128.5, 128.6, 128.9, 134.2, 134.6, 138.9.
31P NMR (160 MHz, CD3OD): d = 20.17.
CCH3), 3.36 (s, 3 H, CO2CH3), 3.52 (s, 3 H, CO2CH3), 4.09–4.37
3
(m, 2 H, PCHCH), 4.87 (d, JH–H = 8.0 Hz, 1 H, OCH), 5.46 (d,
3JH–H = 8.0 Hz, 1 H, OCH), 6.90–7.46 (m, 25 H, ArH).
MS (FAB, negative ions): m/z (%) = 281 (4), 280 (40), 277 (5), 199
13C NMR (100 MHz, CDCl3): d = 25.8, 26.3, 44.9 (d, 1JC–P = 122.1
Hz, POCH), 52.7 (d, 2JC–P = 23.7 Hz, POCHCH), 52.9, 86.5, 86.6,
88.6, 89.9, 113.0, 126.2, 126.4, 126.7, 126.8, 127.0, 127.0, 127.1,
127.3, 127.4, 127.5, 127.7, 127.7, 127.8, 128.0, 128.0, 128.3, 128.5,
129.2, 133.1, 139.5, 143.1, 143.2, 166.6, 166.9.
(5), 181 (17), 159 (6), 127 (11), 95 (5), 79 (100), 63 (9).
Anal. Calcd for C12H12NO5P: C, 51.26; H, 4.30; N, 4.98. Found: C,
51.45; H, 4.11; N, 5.28.
2-{(S)-1-[(3aR,8aR)-2,2-Dimethyl-6-oxo-4,4,8,8-tetraphenyl-
perhydro-6l5-phosphepino[4,5-d][1,3]dioxol-6-yl]-2-methyl-
propyl}malonic Acid Dimethyl Ester (8a)
Prepared according to GP 1 using phosphite (R,R)-1 (512 mg,
1 mmol), TMEDA (0.15 mL, 1 mmol), Et2Zn (1 N in hexane, 1 mL,
1 mmol) and the a,b-unsaturated malonate 7a (186 mg, 1 mmol) in
THF (4 mL). The crude product was purified by column chromatog-
raphy (n-pentane–Et2O, 2:3) to give 8a as a colorless oil.
31P NMR (162 MHz, CDCl3): d = 20.06.
MS (EI, 70 eV): m/z (%) = 467 (7), 286 (13), 285 (100), 265 (6), 253
(12), 208 (6), 207 (23), 179 (12), 178 (9), 167 (6), 165 (5), 131 (5),
105 (6).
MS (CI, 100 eV): m/z (%) = 163 (6), 119 (7), 117 (14), 93 (10), 89
(100), 75 (50), 73 (54), 61 (17).
Yield: 89%; [a]D26 –192.2 (c 1.00, CHCl3); de = 67% (31P NMR).
Anal. Calcd for C43H41O9P: C, 70.48; H, 5.64. Found: C, 70.88; H,
5.21.
IR (KBr): 3458 (m), 3059 (m), 3026 (m), 2989 (m), 2935 (m), 2879
(m), 2340 (w), 2199 (w), 1763 (vs), 1742 (vs), 1688 (m), 1676 (w),
1602 (m), 1497 (s), 1449 (s), 1435 (s), 1383 (m), 1372 (m), 1305 (s),
1263 (vs), 1225 (vs), 1169 (vs), 1137 (s), 1112 (s), 1089 (s), 1054
(s), 1039 (vs), 1017 (vs), 975 (vs), 937 (vs), 917 (vs), 901 (s), 877
(s), 804 (m), 787 (m), 745 (vs), 726 (s), 700 (vs), 675 (m), 652 (m),
641 (m), 617 (w), 591 (m), 581 (m), 560 (m), 535 (m), 519 (m), 487
(m), 464 (w) cm–1.
2-{(S)-1-[(3aR,8aR)-2,2-Dimethyl-6-oxo-4,4,8,8-tetraphenyl-
perhydro-6l5-phosphepino[4,5-d][1,3]dioxol-6-yl]-1-(1,3-ben-
zodioxol-5-yl)methyl}malonic Acid Dimethyl Ester (8c)
Prepared according to GP 2 using 7c (264 mg, 1.0 mmol), phosphite
(R,R)-1 (512 mg, 1.0 mmol) and Fe2O3/KOH (2.698 g, 2.5 equiv
KOH) in H2O (92 mL). The crude product was purified by column
chromatography (n-pentane–Et2O, 2:3) to give 8c as a colorless sol-
id.
1H NMR (300 MHz, CDCl3): d = 0.52 (s, 3 H, CCH3), 0.83 (s, 3 H,
3
CCH3), 1.09 [d, JH–H = 6.6 Hz, 3 H, CH(CH3)2], 1.11 [d,
26
Yield: 67%; mp 110 °C; [a]D –130.3 (c 1.00, CHCl3); de = 91%
3JH–H = 6.9 Hz, 3 H, CH(CH3)2], 2.20 (m, 1 H, PCH), 2.96 [dt,
3JH–H = 5.8 Hz, 1 H, (CH3)2CH], 3.38 (s, 3 H, CO2CH3), 3.54 (s,
(31P NMR).
3
3
3 H, CO2CH3), 3.89 (dd, JH–H = 6.9 Hz, JP–H = 18.3 Hz, 1 H,
Synthesis 2006, No. 9, 1447–1460 © Thieme Stuttgart · New York

PAPER
Asymmetric phospha-Michael Additions
1457
IR (KBr): 3466 (w), 3061 (m), 3028 (m), 2991 (m), 2952 (m), 2902
(m), 1763 (s), 1743 (vs), 1608 (w), 1490 (s), 1447 (s), 1384 (m),
1373 (m), 1348 (m), 1249 (vs), 1219 (s), 1166 (s), 1105 (m), 1089
(s), 1052 (vs), 1038 (vs), 1019 (vs), 984 (s), 936 (s), 884 (m), 819
(w), 804 (w), 744 (s), 728 (s), 700 (s), 672 (w), 655 (m), 642 (m),
574 (w), 548 (w), 510 (w), 454 (w) cm–1.
MS (CI, 100 eV): m/z (%) = 809 (100), 459 (9), 432 (8), 431 (24),
380 (9), 379 (49), 361 (24), 325 (5), 297 (17), 265 (28), 239 (14).
Anal. Calcd for C49H45O9P: C, 72.76; H, 5.61. Found: C, 72.38; H,
6.01.
2-{(S)-1-[(3aR,8aR)-2,2-Dimethyl-6-oxo-4,4,8,8-tetraphenyl-
perhydro-6l5-phosphepino[4,5-d] [1,3]dioxol-6-yl]-1-(4-phenyl-
methyl)methyl}malonic Acid Dimethyl Ester (8e)
Prepared according to GP 2 using 7e (234 mg, 1.0 mmol), phosphite
(R,R)-1 (512 mg, 1.0 mmol) and Fe2O3/KOH (2.698 g, 2.5 equiv
KOH) in H2O (92 mL). The crude product was purified by column
chromatography (n-pentane–Et2O, 1:1) to give 8e as a colorless sol-
id.
1H NMR (300 MHz, CDCl3): d = 0.35 (s, 3 H, CCH3), 0.92 (s, 3 H,
CCH3), 3.47 (s, 3 H, CO2CH3), 3.52 (s, 3 H, CO2CH3), 4.16 (dd,
2
3JH–H = 12.1 Hz, JP–H = 20.6 Hz, 1 H, PCH), 4.87 (dd,
2
3
3JH–H = 9.7 Hz, JP–H = 10.3 Hz, 1 H, PCCH), 4.94 (d, JH–H = 8.2
3
Hz, 1 H, OCH), 5.47 (d, JH–H = 7.8 Hz, 1 H, OCH), 5.89 (d,
3JH–H = 1.4 Hz, 1 H), 5.93 (d, JH–H = 1.6 Hz, 1 H, OCH2), 6.57–
2
7.35 (m, 23 H, ArH).
1
26
13C NMR (100 MHz, CDCl3): d = 25.9, 27.0, 44.7 (d, JC–P = 147.2
Yield: 75%; mp 205–206 °C; [a]D –136.9 (c 1.00, CHCl3);
Hz, POCH), 52.6, 52.7 (d, 2JC–P = 25.9 Hz, POCHCH), 86.5, 86.6,
88.6, 89.9, 100.9, 110.2, 110.1, 113.2, 126.6, 126.4, 126.9, 127.0,
127.4, 127.4, 127.6, 127.6, 127.7, 127.9, 128.6, 129.3, 139.1, 139.6,
143.3, 143.7, 146.7, 147.2, 166.6, 166.8.
de = 82% (31P NMR).
IR (KBr): 3454 (m), 3061 (m), 3027 (m), 2988 (m), 2954 (m), 2930
(m), 1747 (vs), 1602 (w), 1515 (m), 1496 (m), 1449 (s), 1433 (m),
1383 (m), 1373 (m), 1321 (m), 1266 (vs), 1222 (vs), 1168 (s), 1107
(s), 1090 (s), 1053 (s), 1037 (vs), 1015 (vs), 980 (s), 964 (s), 939 (s),
922 (s), 900 (m), 645 (m), 616 (w), 585 (m), 565 (m), 532 (m), 504
(w), 485 (w), 467 (w) cm–1.
31P NMR (162 MHz, CDCl3): d = 20.09.
MS (EI, 70 eV): m/z (%) = 330 (7), 329 (45), 328 (100), 297 (8), 283
(6), 269 (12), 268 (9), 265 (11), 237 (6), 207 (19), 201 (9), 196 (5),
179 (31), 175 (11), 165 (40), 146 (5), 145 (6), 131 (6), 125 (6), 119
(6), 109 (6), 105 (20), 97 (12), 91 (8), 85 (18), 83 (19), 73 (10), 69
(24), 57 (41), 51 (8), 45 (27).
1H NMR (300 MHz, CDCl3): d = 0.33 (s, 3 H, CCH3), 0.93 (s, 3 H,
CCH3), 2.32 (s, 3 H, ArCH3), 3.42 (s, 3 H, CO2CH3), 3.53 (s, 3 H,
3
2
CO2CH3), 4.23 (dd, JH–H = 11.9 Hz, JP–H = 21.8 Hz, 1 H, PCH),
4.40 (dd, 3JH–H = 10.7 Hz, 3JP–H = 11.9 Hz, 1 H), 4.92 (d, 3JH–H = 7.8
Hz, 1 H, OCH), 5.47 (d, 3JH–H = 7.8 Hz, 1 H, OCH), 6.57–7.35 (m,
24 H, ArH).
MS (CI, 100 eV): m/z (%) = 779 (12), 778 (17), 777(100), 265 (15),
207 (27).
Anal. Calcd for C44H41O11P: C, 68.04; H, 5.32. Found: C, 67.83; H,
5.54.
13C NMR (100 MHz, CDCl3): d = 21.1, 25.8, 27.0, 44.6 (d,
1JC–P = 146.8 Hz, POCH), 52.6, 52.8 (d, JC–P = 29.0 Hz,
2
POCHCH), 78.1, 80.2, 86.7, 90.0, 113.1, 126.3, 126.8, 127.0,
127.3, 127.5, 127.5, 127.7, 127.7, 127.8, 128.6, 128.7, 129.3, 130.1,
136.8, 139.4, 143.4, 143.9, 166.8, 167.0.
31P NMR (162 MHz, CDCl3): d = 20.24.
2-{(S)-1-[(3aR,8aR)-2,2-Dimethyl-6-oxo-4,4,8,8-tetraphenyl-
perhydro-6l5-phosphepino[4,5-d] [1,3]dioxol-6-yl]-1-
(4-phenylphenyl)methyl}malonic Acid Dimethyl Ester (8d)
Prepared according to GP 2 using 7d (296 mg, 1.0 mmol), phosphite
(R,R)-1 (512 mg, 1.0 mmol) and Fe2O3/KOH (2.698 g, 2.5 equiv
KOH) in H2O (92 mL). The crude product was purified by column
chromatography (n-pentane–Et2O, 2:3) to give 8d as a colorless sol-
id.
MS (EI, 70 eV): m/z (%) = 300 (15), 299 (100), 267 (15), 207 (19),
203 (6), 179 (14), 178 (12), 171 (7), 167 (6), 145 (7), 135 (12), 105
(7), 57 (6).
MS (CI, 100 eV): m/z (%) = 749 (17), 748 (32), 299 (6), 236 (14),
235 (100), 177 (59).
26
Yield: 63%; mp 154 °C; [a]D –138.9 (c 1.00, CHCl3); de = 94%
(31P NMR).
Anal. Calcd for C44H43O9P: C, 70.77; H, 5.80. Found: C, 70.93; H,
6.18.
IR (KBr): 3448 (m), 3060 (m), 3030 (m), 2990 (m), 2951 (s), 2935
(m), 2866 (m), 2340 (m), 2191 (m), 1763 (vs), 1743 (vs), 1687 (m),
1676 (w), 1655 (m), 1638 (m), 1618 (m), 1601 (m), 1585 (m), 1495
(s), 1449 (s), 1435 (s), 1384 (m), 1374 (m), 1352 (s), 1321 (s), 1264
(vs), 1217 (vs), 1166 (vs), 1107 (s), 1089 (s), 1053 (vs), 1038 (vs),
1018 (vs), 982 (vs), 938 (s), 902 (s), 883 (s), 862 (m), 844 (m), 762
(m), 744 (s), 728 (s), 699 (vs), 672 (m), 641 (m), 581 (m), 561 (m),
521 (m), 504 (m), 457 (m) cm–1.
2-{(S)-1-[(3aR,8aR)-2,2-Dimethyl-6-oxo-4,4,8,8-tetraphenyl-
perhydro-6l5-phosphepino[4,5-d] [1,3]dioxol-6-yl]-1-(3,4,5-tri-
methoxyphenyl)methyl}malonic Acid Dimethyl Ester (8f)
Prepared according to GP 2 using phosphite (R,R)-1 (512 mg,
1 mmol), 7f (0.31 g, 1 mmol) and Fe2O3/KOH (2.698 g, 2.5 equiv
KOH) in H2O (92 mL). The crude product was purified by column
chromatography (n-pentane–Et2O, 3:7) to give 8f as a colorless sol-
id.
1H NMR (300 MHz, CDCl3): d = 0.32 (s, 3 H, CCH3), 0.91 (s, 3 H,
CCH3), 3.42 (s, 3 H, CO2CH3), 3.53 (s, 3 H, CO2CH3), 4.32 (dd,
2
3
3JH–H = 11.8 Hz, JP–H = 18.9 Hz, 1 H, PCH), 4.40 (dd, JH–H = 1.1
Hz, 2JP–H = 12.1 Hz, 1 H), 4.92 (d, 3JH–H = 7.8 Hz, 1 H, OCH), 5.47
(d, 3JH–H = 7.8 Hz, 1 H, OCH), 6.57–7.35 (m, 29 H, ArH).
26
Yield: 71%; mp 162 °C; [a]D –126.3 (c 1.00, CHCl3); de = 89%
(31P NMR).
IR (KBr): 3449 (m), 3061 (m), 2992 (m), 2938 (m), 2839 (m), 1763
(s), 1743 (vs), 1591 (s), 1509 (s), 1498 (s), 1449 (s), 1431 (s), 1384
(m), 1374 (m), 1332 (s), 1257 (vs), 1216 (s), 1165 (s), 1128 (vs),
1090 (s), 1053 (s), 1036 (vs), 1017 (vs), 938 (s), 884 (m), 744 (s),
728 (m), 700 (s), 659 (m), 641 (m), 557 (w), 536 (w), 488 (w), 466
(w) cm–1.
13C NMR (100 MHz, CDCl3): d = 25.8, 27.0, 44.3 (d, 1JC–P = 146.5
Hz, POCH), 52.4, 52.9 (d, 2JC–P = 29.9 Hz, POCHCH), 79.0, 80.1,
86.7, 90.0, 113.2, 126.6, 126.3, 126.6, 126.6, 127.7, 127.0, 127.2,
127.4, 127.5, 127.6, 127.6, 127.8, 127.9, 127.5, 128.6, 129.3, 132.3,
139.0, 139.9, 140.1, 143.2, 143.7, 166.6, 166.8.
31P NMR (162 MHz, CDCl3): d = 19.98.
1H NMR (300 MHz, CDCl3): d = 0.38 (s, 3 H, CCH3), 1.02 (s, 3 H,
MS (EI, 70 eV): m/z (%) = 362 (19), 361 (100), 360 (33), 329 (8),
315 (6), 301 (14), 300 (5), 265 (11), 238 (8), 233 (5), 208 (6), 207
(23), 197 (15), 179 (18), 178 (16), 167 (8), 165 (8), 105 (8).
CCH3), 3.46 (s, 3 H, CO2CH3), 3.50 (s, 3 H, CO2CH3), 4.25 (dd,
2
3JH–H = 11.2 Hz, JP–H = 21.6 Hz, 1 H, PCH), 4.41 (dd, 3JH–H = 10.7
Hz, 3JP–H = 11.9 Hz, 1 H), 4.97 (d, 3JH–H = 8.2 Hz, 1 H, OCH), 5.55
(d, 3JH–H = 7.8 Hz, 1 H, OCH), 6.48 (d, 4JH–H = 2.2 Hz, 2 H, ArH),
6.57–7.35 (m, 20 H, ArH).
Synthesis 2006, No. 9, 1447–1460 © Thieme Stuttgart · New York

1458
D. Enders et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 26.4, 26.7, 44.2 (d, 1JC–P = 148.8
Hz, POCH), 56.0, 60.8, 75.1, 78.5, 79.6, 87.2, 91.6, 105.8 (d,
2JC–P = 6.1 Hz, POCHCH), 113.7, 126.4, 126.8, 127.1, 127.1, 127.7,
127.8, 128.1, 128.2, 128.2, 128.4, 129.4, 137.9, 138.8, 138.9, 139.0,
143.0, 144.2, 144.9, 153.3.
1H NMR (400 MHz, CDCl3): d = 3.50 (s, 3 H, CO2CH3), 3.55 (d,
3
3JP–H = 10.7 Hz, 3 H, POCH3), 3.69 (d, JP–H = 11.3 Hz, 3 H,
3
POCH3), 3.80 (s, 3 H, CO2CH3), 3.91 (dd, JH–H = 11.8 Hz,
2JP–H = 20.3 Hz, 1 H, PCH), 4.14 (dd, 3JP–H = 10.4 Hz, 3JH–H = 11.5
Hz, 1 H, PCCH), 6.74–6.86 (m, 3 H, ArH).
1
MS (EI, 70 eV): m/z (%) = 824 (18), 823 (32), 391 (5), 375 (32), 374
(100), 346 (33), 343 (16), 315 (9), 314 (6), 311 (9), 279 (6), 265
(13), 252 (16), 247 (10), 237 (19), 211 (24), 208 (9), 207 (28), 205
(5), 196 (9), 195 (8), 191 (6), 179 (38), 167 (27), 155 (5), 152 (8),
149 (9), 141 (7), 139 (8), 137 (6), 135 (6), 133 (6), 131 (5), 129 (7),
125 (13), 119 (12), 115 (8), 111 (24), 107 (5), 105 (27), 104 (7), 97
(34), 91 (11), 87 (8), 83 (39), 79 (8), 77 (15), 73 (21), 71 (44), 69
(44), 64 (16), 60 (40), 57 (88), 55 (66), 46 (20), 45 (55).
13C NMR (100 MHz, CDCl3): d = 43.2 (d, JC–P = 139.6 Hz,
POCH), 52.6, 53.0, 53.2, 53.8 (d, 2JC–P = 6.9 Hz, POCHCH), 101.1,
108.2, 109.8, 122.9, 126.4, 147.1, 147.5, 166.6, 167.3.
31P NMR (160 MHz, CDCl3): d = 27.86.
MS (EI, 70 eV): m/z (%) = 375 (6), 374 (42) [M+], 342 (11), 315
(18), 314 (10), 311 (18), 310 (46), 284 (13), 283 (100), 282 (7), 233
(9), 206 (21), 201 (12), 175 (21), 173 (6), 166 (6), 165 (55), 147 (5),
146 (8), 145 (20), 135 (7), 117 (11), 109 (10), 93 (30), 89 (18), 79
(7), 63 (8), 59 (10).
MS (CI, 100 eV): m/z (%) = 825 (7), 824 (16), 312 (16), 311 (100),
310 (7), 279 (9), 253 (8), 237 (11).
Anal. Calcd for C15H19O9P: C, 48.14; H, 5.12. Found: C, 48.25; H,
5.07.
Anal. Calcd for C46H47O12P: C, 67.15; H, 5.76. Found: C, 66.78; H,
5.81.
2-[(Dimethoxyphosphoryl)(4-phenylphenyl)methyl]malonic
Acid Dimethyl Ester (9d)
Prepared according to GP 4 using β-phosphonomalonate 8d (809
mg, 1.0 mmol), NaI (601 mg, 4.0 mmol) and TMSCl (0.5 mL, 4.0
mmol) in MeCN (4 mL). The crude product was purified by column
chromatography (n-heptane–i-propanol, 4:1) to give 9d as a color-
less solid.
2-[(Dimethoxyphosphoryl)phenylmethyl]malonic Acid
Dimethyl Ester (9b)
Prepared according to GP 4 using β-phosphonomalonate 8b (732
mg, 1.0 mmol), NaI (601 mg, 4.0 mmol) and TMSCl (0.5 mL, 4.0
mmol) in MeCN (4 mL). The crude product was purified by column
chromatography (n-heptane–i-propanol, 4:1) to give 9b as a color-
less solid.
Yield: 77%; mp 70–75 °C; [a]D26 +12.1 (c 0.82, MeOH).
26
Yield: 72%; mp 78 °C; [a]D +7.2 (c 0.94, MeOH); ee = 84%
IR (KBr): 3464 (m), 3032 (m), 3002 (m), 2954 (s), 2872 (m), 2849
(m), 1735 (vs), 1601 (w), 1522 (m), 1489 (s), 1436 (s), 1413 (m),
1344 (m), 1307 (s), 1254 (vs), 1215(s), 1183 (s), 1156 (s), 1053 (vs),
1024 (vs), 936 (m), 855 (s), 826 (s), 804 (s) cm–1.
(HPLC; Daicel OD; n-heptane–i-PrOH, 9.5:0.5).
IR (KBr): 3469 (br w), 3032 (w), 2960 (m), 2858 (w), 1738 (vs),
1497 (m), 1455 (m), 1434 (m), 1326 (m), 1301 (m), 1253 (vs), 1214
(s), 1185 (m), 1153 (s), 1091 (m), 1065 (s), 1024 (s), 980 (w), 855
(m), 841 (m), 803 (m), 764 (w), 699 (m), 559 (m) cm–1.
1H NMR (400 MHz, CDCl3): d = 3,45 (s, 3 H, CO2CH3), 3.54 (d,
3
3JP–H = 10.7 Hz, 3 H, POCH3), 3.70 (d, JP–H = 11.0 Hz, 3 H,
1H NMR (400 MHz, CDCl3): d = 3.42 (s, 3 H, CO2CH3), 3.49 (d,
2
POCH3), 3.82 (s, 3 H, CO2CH3), 4.06 (dd, JP–H = 20.3 Hz,
2
2JC–P = 10.4 Hz, 3 H, POCH3), 3.68 (d, JC–P = 11.0 Hz, 3 H,
3
3JH–H = 11.8 Hz, 1 H, PCH), 4.27 (dd, JH–H = 11.8 Hz, 3JP–H = 9.9
3
CO2CH3), 3.82 (s, 3 H, CO2CH3), 4.01 (dd, JH–H = 11.8 Hz,
Hz, 1 H, PCCH), 7.30–7.59 (m, 9 H, ArH).
2JP–H = 20.3 Hz, 1 H, PCH), 4.24 (dd, 3JH–H = 11.8 Hz, 3JP–H = 10.2
1
13C NMR (100 MHz, CDCl3): d = 43.2 (d, JC–P = 139.6 Hz,
Hz, 1 H, PCCH), 7.25–7.36 (m, 5 H, ArH).
POCH), 52.6, 53.0, 53.0, 53.8 (d, 2JC–P = 6.1 Hz, POCHCH), 126.8,
1
13C NMR (100 MHz, CDCl3): d = 43.6 (d, JC–P = 138.9 Hz,
127.0, 127.3, 128.6, 129.7, 131.9, 140.1, 140.4, 166.7, 167.4.
31P NMR (162 MHz, CDCl3): d = 27.86.
POCH), 52.5, 52.9, 53.0, 53.7 (d, 2JC–P = 6.1 Hz, POCHCH), 127.7,
128.4, 129.4, 132.9, 166.6, 167.4.
MS (EI, 70 eV): m/z (%) = 407 (10), 406 (43) [M+], 374 (12), 347
(34), 343 (12), 342 (36), 316 (19), 315 (100), 265 (11), 238 (9), 233
(6), 221 (6), 207 (16), 205 (6), 198 (7), 197 (49), 179 (12), 178 (35),
176 (5), 172 (7), 167 (5), 165 (15), 152 (7), 109 (7), 93 (16), 59 (7).
31P NMR (162 MHz, CDCl3): d = 27.82.
MS (EI, 70 eV): m/z (%) = 331 (6), 330 (34) [M+], 299 (10), 298 (9),
297 (7), 272 (8), 271 (61), 267 (14), 266 (26), 240 (14), 239 (100),
211 (6), 189 (35), 162 (7), 161 (13), 157 (10), 145 (19), 135 (5), 131
(51), 121 (56), 117 (5), 115 (6), 109 (15), 103 (25), 102 (7), 93 (14),
91 (11), 79 (7), 77 (14), 63 (5), 59 (11).
Anal. Calcd for C20H23O7P: C, 59.11; H, 5.70. Found: C, 58.83; H,
5.92.
Anal. Calcd for C14H19O7P: C, 50.91; H, 5.80. Found: C, 50.96; H,
5.96.
2-[(Dimethoxyphosphoryl)(4-methylphenyl)methyl]malonic
Acid Dimethyl Ester (9e)
Prepared according to GP 4 using β-phosphonomalonate 8e (747
mg, 1.0 mmol), NaI (601 mg, 4.0 mmol) and TMSCl (0.5 mL, 4.0
mmol) in MeCN (4 mL). The crude product was purified by column
chromatography (n-heptane–i-propanol, 4:1) to give 9e as a color-
less solid.
2-[(1,3-Benzodioxol-5-yl)(dimethoxyphosphoryl)methyl]mal-
onic Acid Dimethyl Ester (9c)
Prepared according to GP 4 using β-phosphonomalonate 8c (777
mg, 1.0 mmol), NaI (601 mg, 4.0 mmol) and TMSCl (0.5 mL, 4.0
mmol) in MeCN (4 mL). The crude product was purified by column
chromatography (n-heptane–i-propanol, 4:1) to give 9c as a color-
less solid.
26
Yield: 74%; mp 103 °C; [a]D +6.7 (c 0.63, MeOH); ee = 84%
(HPLC; Daicel OD2; n-heptane–i-PrOH, 9:1).
26
IR (KBr): 2957 (m), 2857 (w), 1768 (vs), 1735 (m), 1514 (m), 1439
(m), 1354 (m), 1311 (s), 1250 (vs), 1225 (m), 1210 (m), 1179 (m),
1140 (s), 1056 (vs), 1025 (vs), 966 (m), 936 (w), 851 (s), 828 (m),
816 (m), 767 (s), 719 (w), 563 (s), 524 (w) cm–1.
Yield: 86%; mp 94 °C; [a]D +5.2 (c 1.32, MeOH); ee = 92%
(HPLC; Daicel AD2; n-heptane–i-PrOH, 9.5:0.5).
IR (KBr): 3005 (w), 2957 (m), 2889 (m), 2853 (w), 1736 (vs), 1510
(s), 1491 (s), 1442 (s), 1346 (m), 1313 (m), 1252 (vs), 1214 (s),
1155 (vs), 1105 (m), 1057 (vs), 1034 (vs), 931 (m), 878 (m), 840 (s),
762 (s), 627 (s), 526 (m), 479 (w) cm–1.
1H NMR (400 MHz, CDCl3): d = 2.31 (s, 3 H, ArCH3), 3.43 (s, 3 H,
3
CO2CH3), 3.50 (d, JP–H = 10.7 Hz, 2 H, POCH3), 3.67 (d,
3JP–H = 10.7 Hz, 3 H, POCH3), 3.80 (s, 3 H, CO2CH3), 3.97 (dd,
2
3
3JH–H = 11.9 Hz, JP–H = 20.2 Hz, 1 H, PCH), 4.18 (dd, JP–H = 9.9
Synthesis 2006, No. 9, 1447–1460 © Thieme Stuttgart · New York

PAPER
Asymmetric phospha-Michael Additions
1459
Hz, 3JH–H = 11.8 Hz, 1 H), 7.11 (d, J = 8.2 Hz, 2 H, ArH), 7.22 (dd,
J = 2.2 Hz, J = 8.2 Hz, 2 H, ArH).
(2) (a) Christiansen, B. G.; Leanza, W. J.; Beattie, T. R.;
Patchett, A.; Arison, B. H.; Ormond, R. E.; Kuehl, F. A.;
Albers-Schonberg, G.; Jardetzky, O. Science 1969, 166,
123. (b) Glamowski, E. J.; Gal, G.; Purick, R.; Davidson, A.
J.; Sletzinger, M. J. Org. Chem. 1970, 35, 3510.
(c) Giordano, C.; Castaldi, G. J. Org. Chem. 1989, 54, 1470.
(d) Allen, J. G.; Atherton, F. R.; Hall, M. J.; Hassal, C. H.;
Holmes, S. W.; Lambert, R. W.; Nisbet, L. J.; Ringrose, P.
S. Nature 1978, 272, 56.
1
13C NMR (100 MHz, CDCl3): d = 21.1, 43.2 (d, JP–C = 138.9 Hz,
POCH), 52.5, 53.0, 53.1, 53.7 (d, 2JP–C = 6.1 Hz, POCHCH), 129.1,
129.3, 129.8, 137.4, 166.7, 167.5.
31P NMR (162 MHz, CDCl3): d = 28.07.
MS (EI, 70 eV): m/z (%) = 345 (7), 344 (40) [M+], 313 (8), 312 (7),
286 (6), 285 (45), 281 (12), 280 (35), 254 (13), 253 (100), 225 (8),
203 (13), 175 (5), 171 (6), 159 (10), 145 (23), 136 (5), 135 (53), 117
(9), 116 (7), 115 (16), 109 (8), 93 (16), 91 (10), 59 (7).
(3) (a) Duke, S.; Lydon, J. Weed Technol. 1987, 1, 122.
(b) Leason, M.; Cunliffe, D.; Parklin, D.; Lea, P. J.; Miflin,
B. J. Phytochemistry 1982, 21, 855. (c) Diddens, H.;
Zähner, H.; Kraas, E.; Göhring, W.; Jung, W. G. Eur. J.
Biochem. 1976, 66, 11.
Anal. Calcd for C15H21O7P: C, 52.33; H, 6.15. Found: C, 52.64; H,
6.40.
(4) Kido, Y.; Hamakado, T.; Anno, M.; Miyagawa, E.; Motoki,
Y. J. Antibiot. 1984, 37, 965.
2-[(Dimethoxyphosphoryl)(3,4,5-trimethoxyphenyl)meth-
yl]malonic Acid Dimethyl Ester (9f)
Prepared according to GP 4 using β-phosphonomalonate 8f (822
mg, 1.0 mmol), NaI (601 mg, 4.0 mmol) and TMSCl (0.5 mL, 4.0
mmol) in MeCN (4 mL). The crude product was purified by column
chromatography (n-heptane–i-propanol, 4:1) to give 9f as a color-
less solid.
(5) (a) Van Herrewege, Y.; Penne, L.; Vereecken, C.; Fransen,
K.; Van Der Groen, G.; Kestens, L.; Balzarini, J.; Vanham,
G. Aids Res. Human Retroviruses 2002, 18, 1091. (b)Guan,
H.-P.; Qiu, Y.-L.; Ksebati, M. B.; Kern, E. R.; Zemlicka, J.
Tetrahedron 2002, 58, 6047. (c) Aquaro, S.; Calio, R.;
Balzarini, J.; Bellocchi, M. C.; Garaci, E.; Perno, C. F.
Antiviral Res. 2002, 55, 209.
(6) (a) Michaelis, A.; Kaehne, R. Ber. Dtsch. Chem. Ges. 1898,
31, 1048. (b) Arbusov, B. A. Pure Appl. Chem. 1964, 9,
307. (c) Kosolapoff, G. M. Org. React. (N. Y.) 1951, 6, 273.
(d) Pommer, H. Angew. Chem. 1960, 72, 811.
(7) (a) Pudovik, A. N.; Arbuzov, B. A. Dokl. Akad. Nauk SSSR
1950, 73, 327. (b) Pudovik, A. N. Dokl. Akad. Nauk SSSR
1950, 73, 499. (c) Pudovik, A. N.; Arbuzov, B. A. Zh.
Obshch. Khim. 1951, 21, 382. (d) Pudovik, A. N.; Arbuzov,
B. A. Zh. Obshch. Khim. 1951, 21, 423. (e) Pudovik, A. N.;
Arbuzov, B. A. Zh. Obshch. Khim. 1951, 21, 1837.
(f) Pudovik, A. N.; Arbuzov, B. A. Zh. Obshch. Khim. 1952,
22, 462.
26
Yield: 82%; mp 95 °C; [a]D +9.8 (c 1.02, MeOH); ee = 90%
(HPLC; Daicel AD2; n-heptane–i-PrOH, 9:1).
IR (KBr): 3001 (m), 2954 (m), 2849 (m), 1757 (vs), 1590 (s), 1510
(m), 1462 (s), 1428 (s), 1331 (m), 1299 (s), 1259 (vs), 1177 (s),
1125 (vs), 1061 (s), 1038 (vs), 1006 (s), 915 (m), 874 (m), 827 (m),
652 (m), 613 (w), 532 (m) cm–1.
1H NMR (400 MHz, CDCl3): d = 3.48 (s, 3 H, p-ArOCH3), 3.54 (d,
3
3JP–H = 10.7 Hz, 3 H, POCH3), 3.70 (d, JP–H = 10.7 Hz, 3 H,
POCH3), 3.81 (s, 3 H, CO2CH3), 3.82 (s, 3 H, CO2CH3), 3.85 (s,
3
6 H, m-ArOCH3), 3.93 (dd, JH–H = 11.8 Hz, 2JP–H = 20.3 Hz, 1 H,
3
3
PCH), 4.21 (dd, JP–H = 10.4 Hz, JH–H = 11.7 Hz, 1 H, PCHCH),
6.58 (s, 2 H, ArH).
1
13C NMR (100 MHz, CDCl3): d = 43.7 (d, JP–C = 139.6 Hz,
(8) For a review, see: Pudovik, A. N.; Konovalova, I. V.
Synthesis 1979, 793.
POCH), 52.7, 52.9, 53.0, 53.9 (d, 2JP–C = 6.9 Hz, POCHCH), 56.1,
(9) (a) Tollefson, M. B.; Li, J. J.; Beak, P. J. Am. Chem. Soc.
1996, 118, 9052. (b) Jugé, S.; Waksleman, M.; Genêt, J. P.
Tetrahedron Lett. 1990, 31, 4442. (c) Jugé, S.; Genêt, J. P.
Tetrahedron Lett. 1989, 30, 2783.
60.8, 106.9, 128.3, 138.8, 152.9, 166.6, 167.3.
31P NMR (162 MHz, CDCl3): d = 27.9.
MS (EI, 70 eV): m/z (%) = 421 (14), 420 (77) [M+], 361 (11), 360
(14), 357 (20), 356 (45), 341 (8), 330 (15), 329 (100), 328 (6), 313
(7), 311 (14), 310 (8), 289 (12), 279 (14), 252 (17), 247 (14), 237
(15), 235 (7), 212 (6), 211 (50), 205 (5), 181 (10), 178 (5), 177 (10),
163 (6), 151 (5), 149 (8), 135 (6), 119 (5), 109 (16), 93 (35), 79 (8),
59 (9).
(10) For recent reviews on asymmetric Michael additions, see:
(a) Xu, L.-W.; Xia, C.-G. Eur. J. Org. Chem. 2005, 633.
(b) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org.
Chem. 2002, 1877. (c) Alexakis, A.; Benhaim, C. Eur. J.
Org. Chem. 2002, 3221. (d) Krause, N.; Hoffmann-Röder,
A. Synthesis 2001, 171. (e) Sibi, M. P.; Manyem, S.
Tetrahedron 2000, 56, 8033. (f) Leonard, J.; Diez-Barra, E.;
Merino, S. Eur. J. Org. Chem. 1998, 2051. (g) Yamamoto,
Y.; Pyne, S. G.; Schinzer, D.; Feringa, B. L.; Jansen, J. F. G.
A. In Houben Weyl – Methoden der Organischen Chemie,
4th ed., Vol. E21b; Helmchen, G.; Hoffmann, R. W.;
Mulzer, J.; Schaumann, E., Eds.; Thieme: Stuttgart, 1995,
Chap. 1.5.2. (h) Rossiter, B. E.; Swingle, N. M. Chem. Rev.
1992, 92, 771For a review on phospha-Michael additions
see:. (i) Enders, D.; Saint-Dizier, A.; Lannou, M.-I.; Lenzen,
A. Eur. J. Org. Chem. 2006, 29.
(11) Enders, D.; Tedeschi, L.; Bats, J. W. Angew. Chem. Int. Ed.
2000, 39, 4605; Angew. Chem. 2000, 112, 4774.
(12) Tedeschi, L.; Enders, D. Org. Lett. 2001, 3, 3515.
(13) For the application of 1 in nucleophilic acylations of
unsaturated amides, see: Nahm, M. R.; Linghu, X.; Potnick,
J. R.; Yates, C. M.; White, P. S.; Johnson, J. S. Angew.
Chem. Int. Ed. 2005, 44, 2377; Angew. Chem. 2005, 117,
2429.
Anal. Calcd for C17H25O10P: C, 48.58; H, 5.99. Found: C, 48.72; H,
5.99.
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 380, Graduiertenkolleg 440) and the Fonds der Chemischen
Industrie. We thank Degussa AG, BASF AG and Bayer AG for the
donation of chemicals. The X-ray structure determinations by Dr. J.
W. Bats, University of Frankfurt, and the NOE measurements by
Dr. J. Runsink, RWTH Aachen, are gratefully acknowledged.
References
(1) (a) Horiguchi, M. Biochim. Biophys. Acta 1972, 261, 102.
(b) Hildebrand, R. L. The Role of Phosphonates in Living
Systems; Hildebrand, R. L., Ed.; CRC Press: Boca Raton,
1983.
Synthesis 2006, No. 9, 1447–1460 © Thieme Stuttgart · New York

1460
D. Enders et al.
PAPER
(17) (a) Semenzin, D.; Etemad-Moghadam, G.; Albouy, D.;
(14) (a) Beck, A. K.; Bastani, B.; Plattner, D. A.; Petter, W.;
Seebach, D.; Braunschweig, H.; Gysi, P.; La Vecchia, L.
Chimia 1991, 45, 238. (b) Seebach, D.; Beck, A. K.; Heckel,
A. Angew. Chem. Int. Ed. 2001, 40, 92; Angew. Chem. 2001,
113, 96.
(15) (a) Noltes, J. G. Recl. Trav. Chim. Pays-Bas 1965, 84, 782.
(b) Boersma, J.; Noltes, J. G. Recl. Trav. Chim. Pays-Bas
1973, 92, 229.
Diallo, O.; Koenig, M. J. Org. Chem. 1997, 62, 2414.
(b) Albouy, D.; Laspéras, M.; Etemad-Moghadam, G.;
Koenig, M. Tetrahedron Lett. 1999, 40, 2311.
(18) The crystal structure of 8e has been deposited as
supplementary publication no. CCDC-281444 at the
Cambridge Crystallographic Data Centre. Copies of the data
can be obtained free of charge on application to CCDC 12
Union Road Cambridge CB2 1EZ UK [fax: +44(1223)
336033; e-mail: deposit@ccdc.cam.ac.uk or
(16) Patel, V. D.; Schmidt, R. J.; Biller, S. A.; Gordon, E. M.;
Robinson, S. S.; Manne, V. J. Med. Chem. 1995, 38, 2906.
http//www.ccdc.cam.ac.uk].
Synthesis 2006, No. 9, 1447–1460 © Thieme Stuttgart · New York