Asymmetrie hydrogenation of α,ss-unsaturated esterphosphonates

Article abstract of DOI:10.1002/adsc.200900051

The rhodium-catalyzed asymmetric hydrogenation of readily available α,ss-unsaturated esterphosphonates affords the corresponding α-chiral phosphonates in excellent yield and ee. The resulting products are useful multifunctional building blocks applied in

Full text of DOI:10.1002/adsc.200900051

FULL PAPERS
DOI: 10.1002/adsc.200900051
Asymmetric Hydrogenation of a,b-Unsaturated Ester-
Phosphonates
Yange Huang,a Florian Berthiol,a Bart Stegink,a Michael M. Pollard,a,b
and Adriaan J. Minnaarda,*
a
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
Fax : (+31)-50-363-4296; phone: (+31)-50-363-4258; e-mail: A.J.Minnaard@rug.nl
Current address: Department of Chemistry, York University, 4700 Keele Street, Toronto, Ontario, Canada M3J 1P3
b
Received: January 23, 2009; Published online: May 27, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900051.
Abstract: The rhodium-catalyzed asymmetric hydro- applied in the synthesis of physiologically active
genation of readily available a,b-unsaturated ester- compounds.
phosphonates affords the corresponding a-chiral
phosphonates in excellent yield and ee. The resulting Keywords: asymmetric hydrogenation; homogeneous
products are useful multifunctional building blocks catalysis; phosphonates; rhodium
Introduction
kinsonꢀs disease because of their enhanced selectivity
for glutamate receptors.[3] In addition, phosphonates
Compounds containing phosphonic acids and alkyl are excellent chelators of calcium and magnesium,
phosphonates are frequently encountered in the field and as such they find application in the treatment of
of medicinal chemistry.[1] As phosphonic acids and osteoporosis, bone cancer and calcium metabolism.[4]
phosphonates act as isosteres of carboxylic acids and
Fosmidomycin (Figure 1) is an effective inhibitor of
esters, respectively, these functional groups are em- 1-deoxy-d-xylulose 5-phosphate reducto-isomerase.[5]
ployed to improve the activity or availability of phys- A derivative of fosmidomycin, FR900098, is currently
iologically active compounds. In addition, phosphonic on the market as a drug against malaria. It has been
acids act as non-hydrolyzable phosphate mimics.[2]
shown recently, however, that fosmidomycin ana-
Phosphonate analogues of glutamic acid are being logues substituted next to the phosphonic acid moiety
studied in the treatment of diseases of the central are more active than fosmidomycin itself.[6] As these
nervous system such as Huntingtonꢀs disease and Par- derivatives were tested as racemates, it would be very
interesting to study their single enantiomers.
Whereas the asymmetric synthesis of a-amino- and
a-hydroxy-phosphonates has been thoroughly studied
because of their structural resemblance to amino
acids and hydroxy acids, the asymmetric synthesis of
other chiral phosphonates, especially those with a ste-
reogenic center next to phosphorus, has received
much less attention. To address the deficit in asym-
metric methods to prepare this important class of
molecules, we initiated a study of the asymmetric hy-
drogenation of functionalized phosphonates 2 to pro-
vide compounds of type 3 (Scheme 1). These com-
pounds are multifunctional building blocks containing
a stereogenic center next to phosphorus and an ester
group amendable for further manipulation at the b-
position. Nevertheless, compounds like 2 are not trivi-
al extensions of known substrates for asymmetric rho-
Figure 1. The natural substrate of 1-deoxy-d-xylulose 5-
phosphate reducto-isomerase and its corresponding phos-
phonate inhibitors.
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Yange Huang et al.
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with a series of aliphatic and aromatic acid chlorides
afforded the corresponding a-oxo-phosphonates 1 in
moderate to good yields.[13] It became clear that sub-
sequent treatment of the products with methyl or tert-
butyl (triphenylphosphoranylidene)acetate in a Wittig
reaction afforded the substrates 2 selectively in the E-
stereochemistry[14] in good to high yields. This route is
very flexible as it allows the variation of all reaction
partners, the alkyl phosphites, the acid chlorides and
Scheme 1. Asymmetric hydrogenation of unsaturated ester
phosphonates.
dium-catalyzed hydrogenation as their structure dif- the Wittig reagent.
fers considerably from the dehydro amino acids, ita-
An initial study on the hydrogenation of 2 focused
conic acids, and cinnamic acids, established substrates on substrate 2b. Using RhACHTUNRTGNEUNG(COD)2BF4 as the rhodium
for asymmetric hydrogenation.[7]
precursor and MonoPhos[15] (L12, Figure 2) as the
Only a few studies have been devoted to the asym- ligand, dichloromethane was found to be a suitable
metric synthesis of 3. Conjugate addition of chiral solvent – using 40 bar of H2 (gas) at room tempera-
enantiopure phosphites to Knoevenagel adducts has ture, 3b was obtained in 53% ee at full conversion. In-
been reported by Enders et al.,[8] whereas Wyatt et al. creasing the pressure of the H2 (gas) did not lead to a
reported a single example of a diastereoselective alky- higher ee. To increase the enantioselectivity, the hy-
lation of an enantiopure benzyldiazaphosphine oxide drogenation was studied using a series of catalysts
with tert-butyl bromoacetate, which upon hydrolysis based on the chiral ligands depicted in Figure 2
afforded the corresponding phosphonic acid.[9] In a (Table 1). In the monodentate phosphoramidite series
recent and extensive study, Jørgensen et al. reported the highest enantioselectivity was found using Pip-
the asymmetric organocatalytic phosphonylation of Phos (L11). Shifting to bidentate phosphines did not
a,b-unsaturated aldehydes.[10] Although this ap- show much improvement, as both TolBINAP[16] L1
proach turned out to be effective, the ees did not pass and JosiPhos-type[17] ligand L4 afforded 33% ee (full
the 90% mark, and an excess of aldehyde had to be conversion). A marked increase in enantioselectivity
used.
To the best of our knowledge, only one report has
was found using L5 and especially L3, L8 and L10.
We were pleased to see, however, that the hydroge-
appeared studying the asymmetric hydrogenation of nation of 2c using a catalyst containing L6, a ligand of
2. Bargon et al. used Rh/BPPM in the hydrogenation the JosiPhos family, gave 3c in an excellent 95% ee
of 2a (Scheme 2) and found a 42% ee.[11] A somewhat with full conversion. The increase in enantioselectivity
related asymmetric hydrogenation of b-substituted observed upon changing from L3 to L6 is noteworthy
unsaturated phosphonates was very recently reported and most probably caused by the steric bulk of the
by the group of Zheng.[12] Excellent ees were obtained tert-butyl groups.
using a ferrocene-based phosphoramidite ligand.
As we wondered whether the use of a bidentate
ligand was essential to achieve a high enantioselectivi-
ty in the asymmetric hydrogenation of this novel sub-
strate class, we continued studying monodentate phos-
phoramidite ligands and finally were rewarded when
Results and Discussion
We started our study by developing an efficient two- L7 was used. The catalyst containing this ligand
step procedure for the synthesis of 2 (Scheme 2). An showed excellent enantioselectivity (95%) in the hy-
arbuzov reaction of trimethyl or triethyl phosphite drogenation of 2c, and gave full conversion.
Scheme 2. Synthesis of compounds 1 and 2.
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Asymmetric Hydrogenation of a,b-Unsaturated Ester-Phosphonates
FULL PAPERS
Figure 2. Ligands used in the rhodium catalyzed hydrogenation of 2.
Table 1. Asymmetric hydrogenation of 2c.[a]
Upon changing from methyl to ethyl phosphonate
esters, the enantioselectivity of the hydrogenation
seemed to increase slightly using L6 as the ligand,
(91% versus 94%, entries 1 and 3), however, when R2
was a phenyl moiety there was no difference (both
95%). When R2 =Ph, the shift from R3 =Me to a
bulky tert-butyl ester decreased the ee to 86%
(entry 18). Using L6 as the ligand, catalyst loadings
could be decreased to 2 mol% maintaining full con-
version and a similar ee (entries 5 and 6), whereas fur-
ther reductions in the catalyst loading led to incom-
plete conversions (entry 7). The high enantioselectivi-
ty found amongst the range of derivatives we tested
with a variety of groups at the a-position of the phos-
phonate (R2) suggests that this selectivity is quite gen-
eral. Especially using L6 as the ligand, high to excel-
lent enantioselectivities were obtained with both ali-
phatic and aromatic substitutents. Changing the sub-
stituent adjacent to the phosphonate from a methyl to
a propyl led to only a small reduction in the ee (93%,
entry 16). Both electron withdrawing (Cl) and elec-
tron donating (OMe) substituents on the phenyl ring
did not influence the enantioselectivity (94–95%, en-
tries 10 and 12). The thienyl containing substrate
showed a small decrease in ee to 89%. High isolated
yields were obtained consistently for all these reac-
tions. The enantioselectivities of the hydrogenation
Entry
Ligand
Conv.[%][b]
ee [%][c]
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
100
0
33
–
100
100
100
100
100
100
100
100
100
100
100
85
33
65
95
95
79
19
83
60
53
-43
9
L9
10
11[d]
12[e]
13[d]
L10
L11
L12
L13
[a]
Reactions were performed on a 0.2-mmol scale.
Conversions were determined by H NMR.
The ee was determined by chiral HPLC, see Supporting
Information.
25 bar H2 pressure was used and 2b was the substrate.
2b was the substrate.
[b]
[c]
1
[d]
[e]
With two highly selective catalysts in hand, we com- using the catalyst based on phosphoramidite L7 were
menced studying the generality of the high enantiose- clearly less consistent with regard to substrate varia-
lectivity. A series of substrates was hydrogenated tion; excellent enantioselectivities were only obtained
using catalysts derived from L6 and L7 and, at least in the hydrogenation of 2c and the thienyl-substituted
with L6, enantioselectivities were mostly above 90% substrate 2g.
with complete conversion (Table 2).
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Table 2. Hydrogenation of 2 with ligand L6 and L7.
Entry
Subst.[a]
Ligand
R1
R2
Conversion [%][b]
ee [%][c,h]
1
2
3
4
5
6
7
8
2a
2a
2b
2c
2c
2c
2c
2c
2d
2e
2e
2f
2f
2g
2g
2h
2h
2i
L6
L7
L6
Me
Me
Et
Et
Et
Et
Et
Et
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
Me
Me
Me
100 (73)
100
100 (85)
100 (95)
100 (90)
100
91 (À)
63
94 (À)
95 (À)
95
93
93
95 (+)
95 (À)
95 (À)
40
L6
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
4-Cl-C6H4
4-Cl-C6H4
4-MeO-C6H4
4-MeO-C6H4
Thienyl
Thienyl
n-Propyl
n-Propyl
Phenyl
L6[d]
L6[e]
L6[f]
L7
77
100
9
L6
L6
L7
L6
L7
L6
L7
L6
100 (96)
100 (94)
100
100 (95)
100
100 (90)
100
100 (87)
100
10
11
12
13
14
15
16
17
18[g]
94 (À)
65
89 (À)
89 (+)
93 (+)
71
L7
L6
100
86 (À)
[a]
Reactions were performed on a 0.2-mmol scale.
Conversions were determined by H NMR spectroscopy; numbers in parenthesis are isolated yields.
[b]
[c]
[d]
[e]
[f]
1
The ee was determined by chiral HPLC.
3 mol% of catalyst was used.
2 mol% of catalyst was used.
1 mol% of catalyst was used.
R3 is tert-butyl.
[g]
[h]
The absolute configuration of the products is not known, the sign of the determined optical rotation is given in brackets.
on silica gel (Aldrich 60, 230–400 mesh). TLC was per-
Conclusions
formed on silica gel 60/Kieselguhr F254. 1H and 13C NMR
spectra were recorded on a Varian AMX 400 [399.93 MHz
1
for H, 100.59 MHz for 13C and 161.9 MHz (1H-decoupled)
In summary, we have developed the first highly enan-
tioselective catalytic preparation of a-chiral phospho-
for 31P] spectrometer in CDCl3 unless stated otherwise.
nate esters of type 3 by the asymmetric hydrogenation Carbon assignments are based on APT 13C experiments.
Mass spectra (HR-MS) were performed on a Jeol JMS-
600H. HPLC analysis was performed on a Shimadzu HPLC
system equipped with two LC-10AD solvent delivery sys-
tems, a DGU-14 A degasser, a SIL-10AD vp auto injector,
an SPD-M10 A vp diode array detector, a CTO-10 A vp
column oven, and an SCL-10 A vp system controller using
the columns indicated for each compound separately. Opti-
cal rotations were measured on a Schmidt+Haensch polar-
imeter (Polartronic MH8) with a 10 cm cell (c given in g/
100 mL). Ligand L7 was prepared according to the literature
procedure.[21,22]
of readily available vinyl phosphonate precursors
(two steps). Using a rhodium/bisphosphine catalyst,
very high enantioselectivities and yields are obtained
with a range of substituents adjacent to phosphonate.
The resulting products are useful multifunctional
building blocks for application in the synthesis of
physiologically active compounds including enantio-
pure analogues of fosmidomycin.
Experimental Section
General Procedure for the Synthesis of Compounds
1a–1h
General Experimental Details
Starting materials were purchased from Aldrich, Alfa Aesar
or Acros and used as received unless stated otherwise. All
solvents were reagent grade and, if necessary, dried and dis-
tilled prior to use. Column chromatography was performed
The compounds 1a–1h were synthesized via an Arbuzov re-
action.[12] The corresponding acyl chloride (24mmol) was
added to trimethyl or triethyl phosphite (20mmol) at 08C
under a nitrogen atmosphere. The mixture was stirred for
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Asymmetric Hydrogenation of a,b-Unsaturated Ester-Phosphonates
FULL PAPERS
24h at room temperature. Unreacted phosphite was re-
moved under vacuum, and further purification by column
chromatography (SiO2, 4/1, heptane/EtOAc) gave the corre-
sponding products in 54–70% yield.
(5 mmol) in benzene (40 mL) was treated with sodium
amide (10 mmol) at room temperature for 24 h. The sodium
bromide formed and the unreacted sodium amide were fil-
tered off under a nitrogen flow. Compound 1 (5 mmol) was
then added dropwise to the solution of the phosphorane at
08C and the mixture was allowed to react at room tempera-
ture for 24 h. Benzene was removed under vacuum and the
residue was purified by crystallization of the triphenylphos-
phine oxide from heptane/toluene and its removal by filtra-
tion. Further purification by column chromatography (SiO2,
1/1, heptane/EtOAc) gave the corresponding products 2;
yield: 73–85%.
Dimethyl acetylphosphonate (1a):[13] Pale yellow liquid;
yield: 60%; 1H NMR (CDCl3): d=3.61 (d, 3JP, H =10.8 Hz,
6H), 2.23 (d, 3JP, H =5.2 Hz, 3H); 13C NMR (CDCl3): d=
2
208.1 (d, JP, C =169.8 Hz), 54.0 (d, JP, C =7.2 Hz, 2C), 20.9 (d,
2JP, C =36.0 Hz); 31P NMR (CDCl3): d=À0.35 (s).
Diethyl acetylphosphonate (1b):[13] Pale yellow liquid;
1
yield: 63%; H NMR (CDCl3): d=3.95–4.03 (m, 4H), 2.24
(d, 3JP, H =5.1 Hz, 3H), 1.14 (t, J=7.1 Hz, 6H); 13C NMR
(CDCl3): d=208.8 (d, JP, C =171 Hz), 63.7 (d, 2JP, C =7.3 Hz,
2C), 30.6 (d, 2JP, C =59.4 Hz), 16.4 (d, 3JP, C =5.5 Hz, 2C);
31P NMR (CDCl3): d=À2.1 (s).
(E)-Methyl 3-(dimethoxyphosphoryl)but-2-enoate (2a):[11]
1
Pale yellow liquid; yield: 73%; H NMR (CDCl3): d=6.64
3
[dq, J=1.7, 24.3 (3JP, H ) Hz, 1H], 3.77 (d, JP, H =10.8 Hz, 6H),
Diethyl benzoylphosphonate (1c):[18] Green liquid; yield:
65%; 1H NMR (CDCl3): d=8.24 (AA’BB’C, Japp =7.8 Hz,
2H), 7.61 (AA’BB’C, Japp =7.4 Hz, 1H), 7.48 (AA’BB’C,
3.75 (s, 3H), 2.26 [dd, J=1.7, 15.5 (3JP, H ) Hz, 3H); 31P NMR
(CDCl3): d=21.7 (s).
(E)-Methyl 3-(diethoxyphosphoryl)but-2-enoate (2b):[11]
1
J
app =7.4 Hz, 2H), 4.22–4.29 (m, 4H), 1.36 (t, J=7.0 Hz,
Pale yellow liquid; yield: 77%; H NMR (CDCl3): d=6.56
6H); 13C NMR (CDCl3): d=199.2 (d, JP, C =175 Hz), 135.8
[dq, J=1.7, 24.3ACTHNUTRGNEUNG
(3JP, H) Hz, 1H], 3.98–4.08 (m, 4H), 3.68 (s,
2
2
3H), 2.19 [dd, J=1.7, 15.5ACHTNUGRTNEUNG
(3JP, H ) Hz, 3H], 1.26 (t, J=7.1 Hz,
(d, JP, C =63.4 Hz), 135.0, 130.1, 129.1, 64.2 (d, JP, C =7.3 Hz,
2C), 16.6 (d, JP, C =5.9 Hz, 2C); 31P NMR (CDCl3): d=À0.2
3
6H); 31P NMR (CDCl3): d=18.7 (s).
(s).
(E)-Methyl 3-(diethoxyphosphoryl)-3-phenylacrylate (2c):
Dimethyl benzoylphosphonate (1d):[13] Green liquid;
1
Green liquid; yield: 83%; H NMR (CDCl3): d=7.18–7.28
yield: 64%; 1H NMR (CDCl3): d=8.04 (AA’BB’C, Japp
=
(m, 5H), 6.81 (d, 3JP, H =23.0 Hz, 1H), 3.95–4.05 (m, 4H),
3.49 (s, 3H), 1.18 (t, J=7.0 Hz, 6H); 13C NMR (CDCl3): d=
6.5 Hz, 2H), 7.40 (AA’BB’C,
Japp =7.0 Hz, 1H), 7.28
3
3
(AA’BB’C, Japp =7.8 Hz, 2H), 3.71 (d, JP, H =10.9 Hz, 6H);
165.1 (d, JP,C =28.8 Hz), 145.3 (d, JP, C =172.9 Hz), 134.2 (d,
13C NMR (CDCl3): d=198.0 (d, JP, C =175.1 Hz), 135.4 (d,
3
2JP, C =6.8 Hz), 132.0 (d, 2JP, C =11.3 Hz), 128.5 (d, JP, C
=
2JP, C =63.4 Hz), 135.1, 129.8, 129.1, 54.3 (d, JP, C
=
2
2
2.1 Hz), 128.2, 128.2, 63.1 (d, JP, C =6.1 Hz, 2C), 51.9, 16.4
7.4 Hz,2C); 31P NMR (CDCl3): d=1.6 (s).
(d, JP, C =6.2 Hz, 2C); 31P NMR (CDCl3): d=15.0 (s); HR-
3
Dimethyl 4-chlorobenzoylphosphonate (1e):[19] Green
liquid; yield: 54%; 1H NMR (CDCl3): d=7.82 (AA’BB’,
MS (EI+): m/z=299.1044, calcd. for C14H20O5P: 299.1043.
(E)-Methyl
3-(dimethoxyphosphoryl)-3-phenylacrylate
J
app =8.6 Hz, 2H), 7.10 (AA’BB’, Japp =8.6 Hz, 2H), 3.56 (d,
1
(2d): Green liquid; yield: 81%; H NMR (CDCl3): d=7.19–
3JP, H =10.9 Hz, 6H); 13C NMR (CDCl3): d=197.1 (d, JP, C
=
3
7.30 (m, 5H), 6.84 (d, 3JP, H =23.2 Hz, 1H), 3.65 (d, JP, H
=
2
177.2 Hz), 141.3, 133.78 (d, JP, C =64.8 Hz), 131.1, 129.2, 64.1
11.1 Hz, 6H), 3.51 (s, 3H); 13C NMR (CDCl3): d=165 (d,
(d, JP, C =6.5 Hz, 2C); 31P NMR (CDCl3): d=1.0 (s).
2
3JP, C =29.0 Hz), 144.0 (d, JP, C =173.3 Hz), 134.0 (d, JP, C
=
2
Dimethyl 4-methoxybenzoylphosphonate (1f):[19] Green
6.8 Hz), 132.8 (d, 2JP, C =11.1 Hz), 128.7, 128.3, 128.1 (d,
3JP, C =5.4 Hz), 53.4 (d, 2JP,C =6.1 Hz, 2C), 52.0; 31P NMR
(CDCl3): d=17.8 (s); HR-MS (EI+): m/z=271.0729, calcd.
for C12H16O5P: 271.0730,.
liquid; yield: 70%; 1H NMR (CDCl3): d=7.92 (AA’BB’,
J
app =8.7 Hz, 2H), 6.65 (AA’BB’, Japp =8.6 Hz, 2H), 3.59 (d,
3JP, H =10.9 Hz, 6H), 3.54 (s, 3H); 13C NMR (CDCl3): d=
195.6 (d, JP, C =173.6 Hz), 165.1, 132.3 (d, 3JP, C =1.4 Hz),
128.7 (d, 2JP, C =65.7 Hz), 114.2, 55.6, 54.0 (d, 2JP, C =7.3 Hz,
2C); 31P NMR (CDCl3): d=2.2 (s).
(E)-Methyl 3-(4-chlorophenyl)-3-(dimethoxyphosphoryl)-
1
acrylate (2e): Green liquid; yield: 85%; H NMR (CDCl3):
d=7.28 (AA’BB’, Japp =8.1 Hz, 2H), 7.15 (AA’BB’, Japp
=
=
Diethyl thiophene-3-carbonylphosphonate (1g): Green
liquid; yield: 59%; 1H NMR (CDCl3): d=8.36- 8.38 (m,
1H), 7.76- 7.79 (m, 1H), 7.14- 7.17 (m, 1H), 4.17- 4.25 (m,
4H), 1.31 (t, J=7.0 Hz, 6H); 13C NMR (CDCl3): d=190.6
(d, JP, C =183.3 Hz), 143.4 (d, 2JP, C =80.8 Hz), 138.2, 137.3,
3
8.4 Hz, 2H), 6.83 (d, 3JP, H =23.1 Hz, 1H), 3.66 (d, JP, H
11.0 Hz, 6H), 3.54 (s, 3H); 13C NMR (CDCl3): d=164.7 (d,
3JP, C =28.7 Hz), 143.1 (d, JP, C =174.7 Hz), 134.8, 133.1 (d,
2
2JP, C =11.3 Hz), 132.4, 129.7 (d, JP, C =5.4 Hz), 128.6, 53.5 (d,
2JP, C =6.1 Hz, 2C), 52.1; 31P NMR (CDCl3): d=17.3 (s); HR-
MS (EI+): m/z=305.0339, calcd. for C12H15O5P35Cl:
305.0340.
3
2
129.2 (d, JP, C =1.1 Hz), 64.4 (d, JP, C =7.1 Hz, 2C), 16.5 (d,
3JP, C =5.8 Hz, 2C); 31P NMR (CDCl3): d=À1.40 (s); HR-MS
(EI+): m/z=249.0344, calcd. for C9H14O4P32S: 249.0345.
Diethyl butyrylphosphonate (1h):[20] Pale yellow liquid;
(E)-Methyl 3-(dimethoxyphosphoryl)-3-(4-methoxyphen-
yl)acrylate (2f): Green liquid; yield: 77%; 1H NMR
1
yield: 64%; H NMR (CDCl3): d=3.90–3.97 (m, 4H), 2.53
(CDCl3): d=7.18 (AA’BB’,
Japp =8.7 Hz, 2H), 6.84
(dt, J=1.5 Hz, 7.1 Hz, 2H), 1.32–1.40 (m, 2H), 1.09 (t, J=
7.1 Hz, 6H), 0.65 (t, J=7.4 Hz, 3H); 31P NMR (CDCl3): d=
À2.06 (s).
(AA’BB’, Japp =8.9 Hz, 2H), 6.80 (d, 3JP, H =23.2 Hz, 1H),
3.75 (s, 3H), 3.67 (d, 3JP, H =11.0 Hz, 6H), 3.56 (s, 3H);
13C NMR (CDCl3): d=165.2 (d, JP, C =29.0 Hz), 160.1, 143.2
3
2
3
(d, JP,C =173.2 Hz), 132.2 (d, JP, C =11.9 Hz), 129.7 (d, JP, C
=
=
2
2
5.6 Hz), 125.8 (d, JP, C =7.2 Hz), 113.9, 55.4, 53.4 (d, JP, C
General Procedure for the Synthesis of the
Compounds 2a–i via a Wittig reaction
6.1 Hz, 2C), 52.0; 31P NMR (CDCl3): d=18.4 (s); HR-MS
(EI+): m/z=301.0836, calcd. for C13H18O6P: 301.0836.
(E)-Methyl 3-(diethoxyphosphoryl)-3-(thiophen-3-yl)acry-
Methoxycarbonylmethyltriphenylphosphonium or tert-bu-
1
toxycarbonylmethyltriphenylphosphonium
bromide
late (2g): Green liquid; yield: 81%; H NMR (CDCl3): d=
Adv. Synth. Catal. 2009, 351, 1423 – 1430
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asc.wiley-vch.de
1427

Yange Huang et al.
FULL PAPERS
7.40 (d, J=5.1 Hz, 1H), 7.30 (m, 1H), 7.03 (dd, J=4.0 Hz,
4.7 Hz, 1H), 6.90 (d, 3JP, H =22.96 Hz, 1H), 4.04–4.19 (m,
4H), 3.70 (s, 3H), 1.29 (t, J=7.1 Hz, 6H); 13C NMR
3.63 [ddd, J=22.5 (2JP, H ), 10.3, 4.8 Hz, 1H], 3.57 (s, 3H),
3.05–3.13 (m, 1H), 2.91–3.00 (m, 1H), 1.27 (t, J=7.0 Hz,
3H), 1.11 (t, J=7.0 Hz, 3H); 13C NMR (CDCl3): d=171.6
(CDCl3): d=165.5 (d, 3JP, C =27.5 Hz), 135.7 (d, JP, C
=
3
2
3
(d, JP,C =19.1 Hz), 135.4 (d, JP, C =6.9 Hz), 129.2 (d, JP, C
6.5 Hz), 128.7 (d, JP, C =2.3 Hz), 127.6 (d, JP, C =3.0 Hz), 63.0
=
2
2
5
4
175.9 Hz), 133.6 (d, JP, C =9.5 Hz), 131.9 (d, JP, C =10.8 Hz),
129.9 (d, 3JP, C =6.3 Hz), 128.4, 127.1, 63.1 (d, 2JP, C =5.8 Hz,
2
2
(d, JP, C =6.96 Hz), 62.3 (d, JP,C =7.3 Hz), 52.1, 40.1 (d, JP, C
=
=
2C), 52.1, 16.3 (d, JP, C =6.1 Hz, 2C); 31P NMR (CDCl3): d=
3
140.4 Hz), 35.2, 16.6 (d, 3JP, C =6.0 Hz), 16.4 (d, JP, C
3
5.9 Hz); 31P NMR (CDCl3): d=28.2 (s); [a]D: À4.2 (c 0.7,
CHCl3, 95% ee); HR-MS (EI+): m/z=301.1199, calcd. for
C14H22O5P: 301.1199; chiral HPLC (Chiralpak AD-H, 408C,
heptane/IPA 95:5, 0.5 mLminÀ1): tr =34.4 min (minor 3c),
37.7 min (major 3c).
14.9 (s); HR-MS (EI+): m/z=305.0607, calcd. for
C12H18O5P32S: 305.0607.
(E)-Methyl 3-(diethoxyphosphoryl)hex-2-enoate (2h):
1
Pale yellow liquid; yield: 77%; H NMR (CDCl3): d=6.55
3
(d, JP, H =24.3 Hz, 1H), 4.0–4.10 (m, 4H), 3.68 (s, 3H), 2.60
[dt, J=7.8 Hz, 20.7 (3JP, H) Hz, 2H], 1.47–1.55 (m, 2H), 1.27
Methyl
3-(dimethoxyphosphoryl)-3-phenylpropanoate
(t, J=7.0 Hz, 6H), 0.90 (t, J=7.3 Hz, 3H); 13C NMR
(3d):[9] Colourless oil; 1H NMR (CDCl3): d=7.20–7.33 (m,
(CDCl3): d=165.3 (d, 3JP, C =32.1 Hz), 148.8 (d, JP, C
=
3
5H), 3.64 (d, JP, H =10.7 Hz, 3H), 3.59–3.68 (m, 1H), 3.52 (s,
167.2 Hz), 130.2 (d, 2JP, C =12.5 Hz), 62.5 (d, 2JP, C =5.9 Hz,
3
3H), 3.45 (d, JP,H =10.6 Hz, 3H), 2.99–3.07 (m, 1H), 2.86–
2
3
2.96 (m, 1H); 13C NMR (CDCl3): d=171.5 (d, JP, C
=
3
2C), 51.7, 30.9 (d, JP,C =6.7 Hz), 22.8, 16.4 (d, JP, C =6.2 Hz,
2C), 14.4; 31P NMR (CDCl3): d=19.1 (s); HR-MS (EI+):
m/z=265.1197, calcd. for C11H22O5P: 265.1199.
18.8 Hz), 135.1 (d, 2JP, C =7.2 Hz), 129.2 (d, 3JP, C =6.6 Hz),
128.8 (d, 5JP, C =2.4 Hz), 127.8 (d, 4JP, C =3.1 Hz), 53.8 (d,
2JP, C =7.0 Hz), 53.1 (d, 2JP,C =7.2 Hz), 52.1, 40.1 (d, JP, C
=
(E)-tert-Butyl
3-(diethoxyphosphoryl)-3-phenylacrylate
1
140.4 Hz), 35.1; 31P NMR (CDCl3): d=30.6 (s); [a]D: À10.4
(c 0.5, CHCl3, 95% ee); HR-MS (EI+): m/z=273.0889,
calcd. for C12H18O5P: 273.0886; chiral HPLC (Chiralpak AS-
H, 408C, heptane/IPA 95:5, 0.5 mLminÀ1): tr =25.4 min
(major 3d), 30.0 min (minor 3d).
(2i): Green liquid; yield: 79%; H NMR (CDCl3): d=7.17–
7.27 (m, 5H), 6.72 (d, 3JP, H =23.2 Hz, 1H), 3.95–4.05 (m,
4H), 1.18 (t, J=7.0 Hz, 6H), 1.14 (s, 9H); 13C NMR
(CDCl3): d=164.2 (d, 3JP, C =27.5 Hz), 142.2 (d, JP, C
=
173.5 Hz), 134.9 (d, 2JP, C =6.6 Hz), 134.6 (d, 2JP, C =6.9 Hz),
2
128.4, 128.2, 128.1, 81.8, 62.8 (d, JP, C =6.1 Hz, 2C), 27.7 (d,
Methyl 3-(4-chlorophenyl)-3-(dimethoxyphosphoryl)pro-
3JP, C =8.6 Hz, 2C), 16.4 (3C); 31P NMR (CDCl3): d=15.8
(s); HR-MS (EI+): m/z=341.1514, calcd. for C17H26O5P:
341.1512.
1
panoate (3e): Colourless oil; H NMR (CDCl3): d=7.27 (s,
3
4H), 3.68 (d, JP, H =10.6 Hz, 3H), 3.56–3.65 (m, 1H), 3.55 (s,
3
3H), 3.52 (d, JP,H =10.6 Hz, 3H), 2.99–3.08 (m, 1H), 2.84–
3
2.92 (m, 1H); 13C NMR (CDCl3): d=171.3 (d, JP, C
=
=
3
19.1 Hz), 133.8 (d, 2JP, C =7.1 Hz), 133.7, 130.5 (d, JP, C
4
2
General Procedure for the Hydrogenation
6.4 Hz), 129.1 (d, JP, C =2.5 Hz), 53.9 (d, JP, C =7.0 Hz), 53.2
(d, 2JP, C =7.4 Hz), 52.2, 39.57 (d,
JP, C =141.0 Hz), 35.0;
The standard operating procedure for hydrogenation using
an autoclave was as follows: To a glass reaction vessel was
added 0.20 mmol of substrate, bidentate ligand (0.010 mmol)
31P NMR (CDCl3): d=30.0 (s); [a]D: À8.8 (c 0.5, CHCl3,
95% ee); HR-MS (EI+): m/z=307.0497, calcd. for
C12H17O5P35Cl: 307.0497; chiral HPLC (Chiralpak AS-H,
408C, heptane/IPA 95:5, 0.5 mLminÀ1): tr =27.6 min (major
3e), 30.0 min (minor 3e).
or monodentate ligand (0.020 mmol), RhACTHUNGTRNEUNG(COD)2BF4
(0.010 mmol) and 4.0 mL of solvent. The reaction vessel was
placed in the autoclave and purged 4 times with nitrogen
followed by purging with hydrogen, and finally pressurized
to 40 bar of hydrogen. The sample was stirred at 700 rpm
for 24 h. The reaction mixture was filtered over a silica plug
(1/1, EtOAc/heptane) after which the conversion and ee
were determined by 1H NMR spectroscopy and chiral
HPLC, respectively.
Methyl
3-(dimethoxyphosphoryl)-3-(4-methoxyphenyl)-
1
propanoate (3f): Colourless oil; H NMR (CDCl3): d=7.25
(AA’BB’, Japp =8.4 Hz, 2H), 6.84 (AA’BB’, Japp =8.1 Hz,
2H), 3.76 (s, 3H), 3.67 (d, JP, H =10.7 Hz, 3H), 3.58–3.63 (m,
3
3
1H), 3.55 (s, 3H), 3.49 (d, JP, H =10.5 Hz, 3H), 2.98–3.06 (m,
1H), 2.84–2.93 (m, 1H); 13C NMR (CDCl3): d=171.6 (d,
3JP, C =19.6 Hz), 159.2 (d, 5JP, C =3.1 Hz), 130.2 (d, JP, C
=
3
Methyl 3-(dimethoxyphosphoryl)butanoate (3a):[11] Col-
ourless oil; 1H NMR (CDCl3): d=3.69 (d, 3JP, H =10.6 Hz,
6H), 3.63 (s, 3H), 2.64–2.76 (m, 1H), 2.30–2.44 (m, 1H),
2.20–2.30 (m, 1H), 1.15 [dd, J=7.1, 18.2 (3JPÀH) Hz, 3H];
31P NMR (CDCl3): d=36.05 (s); [a]D: À4 (c 0.35, CHCl3,
91% ee); Chiral HPLC (Chiralpak AD-H, 408C, heptane/
IPA 97:3, 0.5 mLminÀ1): tr =34.7 min (major 3a), 38.8 min
(minor 3a).
2
4
6.3 Hz), 126.9 (d, JP,C =7.4 Hz), 114.3 (d, JP, C =2.3 Hz), 55.4,
2
2
53.8 (d, JP, C =6.9 Hz), 53.1 (d, JP, C =7.4 Hz), 52.1, 39.3 (d,
J
P, C =141.4 Hz), 35.3; 31P NMR (CDCl3): d=30.9 (s); [a]D:
À8 (c 0.25, CHCl3, 94% ee); HR-MS (EI+): m/z=303.0991,
calcd. for C13H20O6P: 303.0992; chiral HPLC (Chiralpak
AD-H, 408C, heptane/IPA 90:10, 0.5 mLminÀ1): tr =28.3 min
(minor 3f), 30.0 min (major 3f).
Methyl 3-(diethoxyphosphoryl)butanoate (3b):[11] Colour-
less oil; 1H NMR (CDCl3): d=4.04–4.07 (m, 4H), 3.65 (s,
3H), 2.64–2.80 (m, 1H), 2.20–2.41 (m, 2H), 1.27 (t, J=
7.0 Hz, 6H), 1.13 [dd, J=7.0, 18.3 (3JP, H ) Hz, 3H]; 31P NMR
(CDCl3): d=33.52 (s); [a]D: À2.75 (c 0.8, CHCl3, 94% ee);
chiral HPLC (Chiralpak AD-H, 408C, heptane/IPA 97:3,
0.5 mLminÀ1): tr =31.9 min (major 3b), 35.5 min (minor 3b).
Methyl 3-(diethoxyphosphoryl)-3-phenylpropanoate (3c):
Colourless oil; 1H NMR (CDCl3): d=7.37–7.23 (m, 5H),
3.98–4.08 (m, 2H), 3.86–3.93 (m, 1H), 3.70–3.80 (m, 1H),
Methyl
3-(diethoxyphosphoryl)-3-(thiophen-3-yl)propa-
1
noate (3g): Colourless oil; H NMR (CDCl3): d=7.19 (d, J=
5.1 Hz, 1H), 7.03 (t, J=3.4 Hz, 1H), 6.94 (t, J=4.2 Hz, 1H),
4.01- 4.09 (m, 2H), 3.85–4.01 (m, 3H), 3.61 (s, 3H), 3.05–
3.13 (m, 1H), 2.85- 2.94 (m, 1H), 1.28 (t, J=7.1 Hz, 3H),
1.18 (t, J=7.1 Hz, 3H); 13C NMR (CDCl3): d=171.3 (d,
3JP, C =17.9 Hz), 137.4 (d, 2JP, C =8.2 Hz), 127.1 (d, JP, C
=
4
3
3
3.3 Hz), 127.0 (d, JP, C =7.8 Hz), 125.1 (d, JP, C =3.8 Hz), 63.3
2
2
(d, JP, C =6.9 Hz), 62.7 (d, JP, C =7.1 Hz), 52.2, 36.6, 36.0 (d,
3
J
P, C =145.6 Hz), 16.6 (d, 3JP,C =6.1 Hz), 16.5 (d, JP, C
=
1428
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Asymmetric Hydrogenation of a,b-Unsaturated Ester-Phosphonates
FULL PAPERS
6.1 Hz); 31P NMR (CDCl3): d=26.1 (s); [a]D: À41 (c 0.7,
CHCl3, 89% ee); HR-MS (EI+): m/z=307.0764, calcd. for
C12H20O5P32S: 307.0764; chiral HPLC (Chiralpak OJ-H,
408C, heptane/IPA 95:5, 0.5 mLminÀ1): tr =29.0 min (major
3g), 52.4 min (minor 3g).
[4] a) R. Emkey, W. Koltun, K. Beusterien, L. Seidman, A.
Kivitz, V. Devas, Curr. Med. Res. Opin. 2005, 21, 1895;
b) Y. Q. Yang, S. Z. Luo, M. F. Pu, J. H. He, W. Z. Bing,
G. Q. Wang, J. Radioanal. Nucl. Chem. 2003, 1, 133.
[5] H. Jomaa, J. Wiesner, B. Sanderbrand, B. Altincicek, C.
Weidemeyer, M. Hintz, I. Tꢂrbachova, M. Eberl, J. Zei-
dler, H. K. Lichtenthaler, D. Soldati, E. Beck, Science
1999, 285, 1573. 1-Deoxy-d-xylulose 5-phosphate reduc-
to-isomerase is a key enzyme of the DOXP/MEP path-
way of isoprenoid biosynthesis present in protozoans
but not in mammals.
[6] T. Haemers, J. Wiesner, R. Busson, H. Jomaa, S. V. Cal-
enbergh, Eur. J. Org. Chem. 2006, 3856–3863, and ref-
erences cited therein.
[7] Handbook of Homogeneous Hydrogenation, (Eds.:
J. G. de Vries, C. J. Elsevier), Wiley-VCH, New York,
2007.
[8] L. Laurenco, D. Enders, Org. Lett. 2001, 3, 3513.
[9] a) S. Gardner, M. Motevalli, K. Shastri, A. C. Sullivan,
P. B. Wyatt, New. J. Chem. 2002, 26, 433. In a more
recent paper the unexpected conjugated ethyl transfer
from diethylaluminum chloride to a chiral enantiopure
3-phosphonopropenoyl derivative was reported, with
unknown diastereoselectivity; b) E. W. C. Cheng, R. T.
Mandalia, M. Motevalli, B. Mothia, Y. Patanwadia,
P. B. Wyatt, Tetrahedron 2006, 62, 12398.
Methyl 3-(diethoxyphosphoryl)hexanoate (3h): Colourless
1
oil; H NMR (CDCl3): d=4.01–4.08 (m, 4H), 3.64 (s, 3H),
2.58–2.70 (m, 1H), 2.29–2.40 (m, 2H), 1.61–1.75 (m, 2H),
1.32–1.44 (m, 2H), 1.26 (t, J=7.0 Hz, 6H), 0.86 (t, J=
3
6.9 Hz, 3H); 13C NMR (CDCl3): d=172.7 (d, JP, C
=
2
2
14.1 Hz), 61.98 (d, JP, C =6.7 Hz), 61.9 (d, JP, C =6.9 Hz), 52.0,
33.9 (d, 2JP, C =2.3 Hz), 32.7 (d, JP, C =142.3 Hz), 31.3 (d,
2JP, C =3.6 Hz), 20.8 (d, JP,C =9.9 Hz), 16.60 (d, JP, C =5.9 Hz,
2C), 14.2; 31P NMR (CDCl3): d=33.5 (s); [a]D: +4.4 (c 0.9,
CHCl3, 93% ee); HR-MS (EI+): m/z=267.1354, calcd. for
C11H24O5P: 267.1356; chiral HPLC (Chiralpak AD-H, 408C,
heptane/IPA 97:3, 0.5 mLminÀ1): tr =29.2 min (major 3h),
31.6 min (minor 3h).
3
3
tert-Butyl
3-(diethoxyphosphoryl)-3-phenylpropanoate
(3i): Colourless oil; 1H NMR (CDCl3): d=7.22–7.34 (m,
5H), 3.98–4.06 (m, 2H), 3.86–3.95 (m, 1H), 3.71–3.81 (m,
1H), 3.56 [ddd, J=22.5 (2JP, H), 10.99, 4.7 Hz, 1H], 2.94–3.01
(m, 1H), 2.81–2.91 (m, 1H), 1.26 (t, J=7.1 Hz, 3H), 1.23 (s,
9H), 1.10 (t, J=7.1 Hz, 3H); 13C NMR (CDCl3): d=170.3
3
2
3
(d, JP, C =20.0 Hz), 135.5 (d, JP, C =6.95 Hz), 129.4 (d, JP, C
=
5
4
6.3 Hz), 128.6 (d, JP,C =2.6 Hz), 127.5 (d, JP, C =3.3 Hz), 81.1,
2
2
62.9 (d, JP,C =6.95 Hz), 62.3 (d, JP, C =7.3 Hz), 41.0 (d, JP, C
=
139.6 Hz), 36.4, 28.0 (3C), 16.6 (d, 3JP, C =5.9 Hz), 16.5 (d,
3JP, C =5.7 Hz); 31P NMR (CDCl3): d=28.5 (s); [a]D: À9 (c
1.4, CHCl3, 86% ee); HR-MS (EI+): m/z=343.1670, calcd.
for C17H28O5P: 343.1669; chiral HPLC (Chiralpak AS-H,
408C , heptane/IPA 95:5, 0.5 mLminÀ1): tr =8.7 min (major
3i), 10.0 min (minor 3i).
[10] E. Maerten, S. Cabrera, A. Kjærsgaard, K. A. Jørgen-
sen, J. Org. Chem. 2007, 72, 8893–8903.
[11] a) R. Kadyrov, R. Selke, R. Giernoth, J. Bargon, Syn-
thesis 1999, 1056–1062. BPPM=N-tert-butoxycarbon-
yl-2-diphenylphoshino-4-methylene-diphenylphosphino
pyrrolidine. Hydrogenation of the isomeric vinyl phos-
phonate gave 98% ee, for the use of a different catalyst
in this reaction see b) J. Holz, R. Kadyrov, S. Borns, D.
Heller, A. Bçrner, J. Organomet. Chem. 2000, 603, 61.
[12] Z. C. Duan, X. P. Hu, D. Y. Wang, J. D. Huang, S. B.
Yu, J. Deng, Z. Zheng, Adv. Synth. Catal. 2008, 350,
1979.
Acknowledgements
E. P. Schudde and T. Tiemersma-Wegman are acknowledged
for technical assistance. A generous gift of a Josiphos ligand
kit by Solvias, Basel, is gratefully acknowledged.
[13] M. Yamashita, M. Kojima, H. Yoshida, T. Ogata, S. In-
okawa, Bull. Chem. Soc. Jpn. 1980, 53, 1625.
[14] The E-stereochemistry was determined by 1H NMR
spectroscopy via the JP, H, see: G. L. Kenyon, F. H.
Westheimer, J. Am. Chem. Soc. 1966, 88, 3557. In addi-
tion, no NOE was observed between the vinylic H and
the R2 substituent.
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Adv. Synth. Catal. 2009, 351, 1423 – 1430
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1429

Yange Huang et al.
FULL PAPERS
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1430
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ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 1423 – 1430