Synthesis of chiral β-aminophosphonates via Rh-catalyzed asymmetric hydrogenation of β-amido-vinylphosphonates

Article abstract of DOI:10.1016/j.tetasy.2008.04.019

The Rh-catalyzed asymmetric hydrogenation of prochiral β-N-acetylamino-vinylphosphonates allows the preparation of chiral β-N-acetylamino-phosphonates with excellent yields (up to 100%) and high enantioselectivities (up to 92% ee). The reaction is strongl

Full text of DOI:10.1016/j.tetasy.2008.04.019

Tetrahedron: Asymmetry 19 (2008) 1189–1192
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Tetrahedron: Asymmetry
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Synthesis of chiral b-aminophosphonates via Rh-catalyzed asymmetric
hydrogenation of b-amido-vinylphosphonates
b
c
a
a,b,
*
Renat Kadyrov a, Jens Holz b, , Benjamin Schäffner , Odalys Zayas , Juan Almena , Armin Börner
*
a Evonik Industries, Rodenbacher Chaussee 4, 63457 Hanau, Germany
b Leibniz-Institut für Katalyse an der Universität Rostock e.V., A.-Einstein-Str. 29a, 18059 Rostock, Germany
c Institut für Chemie der Universität Rostock, A.-Einstein-Str. 3a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 February 2008
Accepted 16 April 2008
The Rh-catalyzed asymmetric hydrogenation of prochiral b-N-acetylamino-vinylphosphonates allows the
preparation of chiral b-N-acetylamino-phosphonates with excellent yields (up to 100%) and high enantio-
selectivities (up to 92% ee). The reaction is strongly dependent on the chiral bidentate phosphorus ligand
and the solvent employed. In several cases an inversion of the induced chirality was noted by using the
corresponding E- or Z-isomeric substrates.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
NH
R2
NH
*
R3
H2, chiral catalyst
R3
OR1
OR1
Phosphorus analogues of amino acids display highly interesting
properties in biochemistry and medicine. By replacement of
natural a- or b-amino acids in proteins by the corresponding
aminophosphonic acids structure and binding properties are
significantly altered, hence new insights in biochemical process
are possible as well as new medicinal applications emerge.1 In this
view, b-aminophosphonic acids are isosters of b-amino acids.2 Up
to now they have seen applications as antibacterial agents,3
enzyme inhibitors,4 haptens for catalytic antibodies5 und anti-
HIV agents.6
OR1
OR1
P
R2
P
O
O
1
2
Figure 1. Asymmetric hydrogenation of prochiral b-enamidophosphonates.
In spite of these results up to now there is no report for the
asymmetric hydrogenation of prochiral enamidophosphonates of
type 1 which would directly lead to the formation of chiral b-amido-
phosphonates 2 (Fig. 1). The only known examples of a hydro-
genation approach concern the diastereoselective reduction of
optically active b-enaminophosphonates with NaBH4 or H2/Pd/C
to give diastereomeric 2-amino-2-alkyl-ethan-1-ylphosphonates
in 20–90% de.14
This situation is quite astonishing since the asymmetric hydro-
genation of pertinent dehydroamino acid derivatives with chiral
transition metal catalysts, preferentially based on Rh-, Ru-, or
Ir-complexes, is one of the most established methods for the prep-
aration of chiral a-15 and b-amino acids.16 Moreover, the reduction
of these olefins is usually employed as a benchmark reaction to test
the catalytic performance of chiral catalysts, and therefore is the
focus of numerous mechanistic investigations.17,18 Also the asym-
metric hydrogenation of a-dehydroamino phosphonates is known
to proceed with high enantioselectivity with Rh-catalysts based
on phosphorus ligands.7,19
Recently, Palacios1 and Ma7 summarized methods for the prep-
aration of b-aminophosphonates. These compounds can be pre-
pared via formation of C–C–, C–N–, and C–P–bonds, ring opening
reactions or rearrangements. Other venues are based on the selec-
tive reduction of unsaturated functionalities such as amides8 or
thioamides9 with boranes or the hydrogenation of oximes with
molecular hydrogen in the presence of Raney-nickel10 and Pd/
C,11 respectively. Further methods rely on the reduction of azides,
nitriles, or nitro compounds.1
In most cases b-aminophosphonates are chiral.7 Therefore, in
recent time growing research activities are dedicated to the enan-
tioselective preparation of synthetic precursors, which can be eas-
ily transformed into b-aminophosphonates.12 For example,
Kolodiazhnyi et al. reported on the diastereoselective reduction
of chiral b-keto phosphonates with the NaBH4/tartaric acid system
to afford the corresponding b-hydroxy phosphonates with high
diastereoselectivity.13
2. Results and discussion
Herein, we report our results on the first enantioselective
* Corresponding authors.
hydrogenation of b-enamidophosphonates generating chiral
E-mail address: armin.boerner@catalysis.de (A. Börner).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.04.019

1190
R. Kadyrov et al. / Tetrahedron: Asymmetry 19 (2008) 1189–1192
b-amidophosphonates with a huge potential for biochemical and
medicinal applications. Moreover, reaction products can be used
as coupling reagents in Horner–Wadsworth–Emmons-reactions,
hence those chiral amines can be derived which are not easily
accessible by other methods.20
which are acylated with acetic anhydride or acetyl chloride to give
the desired dehydroamidophosphonates of type 6.
According to these conditions, we obtained E/Z-mixtures of
compounds 6a,b which were subsequently separated into the
individual isomers by flash chromatography.
The required prochiral substrates for asymmetric hydrogena-
tion can be prepared by different pathways. For example, reaction
of a-halo ketones with trialkylphosphites affords b-ketophospho-
nates which can be converted by condensation with ammonia or
primary amines into enaminophosphonates.21 Final acetylation
affords the desired enamides as a mixture of E- and Z-isomers.22
The composition of the mixture is dependent on the substitution
pattern and the solvent used.23 The addition of primary amines
or ammonia to unsaturated phosphonates (1-alkenylphos-
phonates24 or allenyl-phosphonates14,25) likewise yields prochiral
enamides.
Preliminary individual trials of the asymmetric hydrogenation
under conditions usually successful in the hydrogenation of
a- and b-dehydroacetamido acid derivatives (e.g., ambient
pressure)15,16 gave disappointing results. In order to speed up the
screening process in the next stage, we investigated the reaction
in a high-throughput (HTS) approach considering 20 chiral Rh-
complexes in three solvents at an initial hydrogen pressure of
35–40 bar (0.1 mmol substrate in 0.5 mL solvent, S/C = 100)
(Fig. 3). Precatalysts were prepared in situ by mixing
[Rh(COD)2]BF4 with an equimolar amount of the bidentate phos-
phorus ligand. Among these 240 trials Rh-catalysts based on
ligands 8–11 performed best. Superior results were achieved in
both dichloromethane and THF as solvent.27,28 Subsequent up-scal-
We followed the route suggested by the groups of Palacios and
Oh.26a–c In their approach nitriles
4
are reacted with
methyldiethylphosphonate 3 in the presence of n-BuLi (Fig. 2).
Subsequent hydrolysis gives 2-amino-alkenylphosphonates 5,
H2 (35-40 bar),
R
R
[Rh(COD)2]BF4 + PP*
*
OEt
OEt
OEt
OEt
or
AcHN
P
O
AcHN
P
O
R
H2 (40, 90 bar),
[Rh(COD)(PP*)]BF4
solvent
n-BuLi
MeP(O)(OEt)2
+
R C N
OEt
P
O
H2N
6a,b
7a,b
OEt
3
4a,b
PP*:
5a,b
PPh2
N
P(
t
Bu)2
a: R = Ph
b: R = i-Pr
Ac2O
Fe
Fe
PPh2
or AcCl
PPh2
R
Chromatographic
separation
(
R)-(
S
)-BoPHOZ 8
(R)-(S
)-DPPFtBP 9
OEt
P
O OEt
NHAc
O
PCy2
Ph2P
Fe
6a,b
O
O
PPh2
PPh2
R
AcHN
R
OEt
OEt
OEt
+
AcHN
-6a,b
P
O
P
O
-6a,b
OEt
O
E
Z
(
S)-(
R
)-JOSIPHOS 10
(R)-SYNPHOS 11
Figure 2. Synthesis of isomeric b-enamidophosphonates 6.
Figure 3. Rh-catalyzed asymmetric hydrogenation and the best ligands.
Table 1
Results of the asymmetric hydrogenation of b-enamidophosphonates Z-6a,b and E-6a,ba
Entries
Substr.
PP*
40 bar, THF
Conv.b (%)
40 bar, CH2Cl2
90 bar, THF
Conv.b (%)
90 bar, CH2Cl2
eec (%)
Conv.b (%)
eec (%)
eec (%)
Conv.b (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Z-6a
Z-6a
Z-6a
Z-6a
E-6a
E-6a
E-6a
E-6a
Z-6b
Z-6b
Z-6b
Z-6b
E-6b
E-6b
E-6b
E-6b
8
9
10
11
8
100
100
100
100
100
100
92
62
92
69
100
100
100
100
100
100
67 (À)
35 (À)
90 (+)
22 (À)
82 (À)
14 (+)
24 (+)
70 (+)
62 (+)
59 (+)
89 (À)
22 (À)
65 (+)
50 (À)
29 (À)
70 (À)
100
80
100
57
100
100
100
65
80
75
93
57
72 (À)
78 (À)
83 (+)
23 (À)
76 (À)
32 (+)
42 (+)
92 (+)
86 (+)
84 (+)
72 (À)
23 (À)
61 (+)
78 (À)
58 (À)
55 (À)
100
100
100
100
100
100
100
71
71 (À)
36 (À)
89 (+)
10 (À)
82 (À)
17 (+)
25 (+)
73 (+)
71 (+)
68 (+)
91 (À)
10 (À)
66 (+)
56 (À)
34 (À)
63 (À)
100
100
100
100
91
100
90
66
67 (À)
79 (À)
77 (+)
23 (À)
76 (À)
35 (+)
41 (+)
90 (+)
91 (+)
90 (+)
75 (À)
23 (À)
67 (+)
69 (À)
63 (À)
81 (À)
9
10
11
8
85
52
78
87
9
10
11
8
9
10
11
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
0.33 mmol of substrate, 0.0033 mmol of [Rh(PP*)(COD)]BF4 at 25 °C, 24 h in 4 mL of solvent.
a
b
c
The determination of the conversion was carried out by 1H- or 31P NMR spectroscopy.
The enantiomeric excess was determined by HPLC (CHIRALPAK AD-H, 15 cm), 6a: hexane/ethanol = 95:5, 1.5 mL/min, tR = 10.9 min for (À)-enantiomer, tR = 17.5 min for
(+)-enantiomer; 6b: hexane/ethanol = 92:8, 0.8 mL/min, tR = 5.0 min for (+)-enantiomer, tR = 6.1 min for (À)-enantiomer; in brackets the sign of the specific rotation of the
hydrogenation product.

R. Kadyrov et al. / Tetrahedron: Asymmetry 19 (2008) 1189–1192
1191
ing experiments were carried out with isolated precatalysts of the
type [Rh(COD)(PP*)]BF4 at 40 and 90 bar, respectively, initial
hydrogen pressure. No differences in the catalytic results in depen-
dence on the nature of the precatalyst preparation (in situ vs iso-
lated precatalyst) were noted.
(7.90 g, 94%). 1H NMR (acetone-d6) d 7.62 (m, 2H, arom. H), 7.43
(m, 3H, arom. H), 6.63 (s (br), 2H, NH2); 4.08 (m, J = 11.9 Hz, 1H,
@CH), 4.00 (m, 4H, OCH2), 1.27 (d, J = 6.9 Hz, 6H, CH3); 13C NMR
(acetone-d6) d 163.4 (N–C@), 139.7 (arom. C), 127.0, 129.3, 130.6
(arom. CH), 73.9 (d, J = 191 Hz, @CH), 61.2 (OCH2), 16.7 (CH3); 31P
NMR (acetone-d6) d +28.0; Anal. Calcd for C12H18NO3P (255.25):
C, 56.47; H, 7.11; N, 5.49. Found: C, 56.28; H, 7.01; N, 5.29.
Results of the optimized trials, which were performed with
0.5 mmol of the substrate are listed in Table 1.29 Our results give
evidence that Rh-catalyzed asymmetric hydrogenation is a power-
ful methodology for the preparation of the desired chiral target
compounds. With the exception of a few trials, most reactions
were complete after 24 h. In dependence on the catalyst, solvent
and hydrogen pressure used up to 92% ee could be achieved (entry
8, 40 bar, CH2Cl2). In contrast to most asymmetric hydrogenations
of related b-dehydroacylamido acid derivatives also with Z-b-acet-
ylamido-vinylphosphonates as substrates, good ee-values can be
achieved (up to 91% ee). It is remarkable to note that the applica-
tion of ligands 9 and 10 gave in the hydrogenation of Z-substrates
products with the opposite configuration in the product. In con-
trast by employment of E-olefins the same configuration was in-
duced. There is no uniform correlation between H2-pressure and
enantioselectivity, neither with E- nor with Z-substrates. More-
over, a comparison of results obtained with different substrates
is not possible. Small changes in the structure of the substrate or
ligand structure influence the catalytic result significantly. This
finding is in contrast to the tendencies noted several times with
related unsaturated b-amino acid substrates in hand.17b
4.3. (Z)-Diethyl-2-amino-2-isopropylvinylphosphonate 5b
The compound was prepared by the same procedure as de-
scribed for 5a using isobutyronitrile (2.28 g, 33 mmol). After evap-
oration of solvent, 5b was obtained as white solid in analytically
pure form (5.60 g, 77%). Mp = 58–60 °C; 1H NMR (acetone-d6) d
6.28 (s (br), 2H, NH2), 3.91 (q, J = 7.1 Hz, 4H, OCH2), 3.57 (d,
J = 13.0 Hz, @CH), 2.37 (m, 1H, CH), 1.23 (d, J = 7.1 Hz, 6H, CH3),
1.13 (d, J = 7.1 Hz, 6H, CH3); 13C NMR (acetone-d6) d 172.4 (d,
J = 5 Hz, N–C@), 68.7 (d, J = 192 Hz, @CH), 60.8 (d, J = 5 Hz, OCH2),
36.6 (d, J = 19 Hz, CH), 21.7 (CH3), 16.7 (d, J = 6 Hz, CH3); 31P NMR
(acetone-d6) d +29.0; Anal. Calcd for C9H20NO3P (221.23): C,
48.86; H, 9.11; N, 6.33. Found: C, 49.2; H, 9.29; N, 6.30.
4.4. Diethyl 2-acetamino-2-phenylvinylphosphonate 6a
To a solution of the enamide phosphonate 5a (25 mmol, 6.38 g)
in dry THF (100 mL) were added pyridine (50 mmol, 3.96 g) and
acetic acid anhydride (125 mmol, 12.76 g). The solution was re-
fluxed for 24 h. After cooling to ambient temperature, a saturated
aq Na2CO3 solution (100 mL) was added and the solution was ex-
tracted with ethyl acetate (3 Â 100 mL). The combined organic
phases were washed with saturated aq Na2CO3 solution and brine
(100 mL, respectively). The solvents were removed under vacuo,
and the residue was separated and purified by column chromato-
graphy (AcOEt/EtOH = 15:1). Z-Isomer Z-6a: Rf-value 0.70;
m = 7.20 g (65%) of pale yellow oil; 1H NMR (acetone-d6) d 10.18
(s (br), 1H, NH); 7.43 (m, 2H, arom. H), 7.35 (m, 3H, arom. H),
5.02 (d, J = 11.3 Hz, 1H, @CH), 4.08 (m, 4H, OCH2), 2.04 (s, 3H,
CH3), 1.30 (dt, J = 7,0 Hz, 0.5 Hz, 6H, CH3); 13C NMR (acetone-d6) d
168.5 (C@O), 157.2 (d, J = 3 Hz, N–C@), 138.3 (d, J = 18 Hz, arom.
C), 130.0, 128.7, 127.7 (arom. CH), 97.8 (d, J = 182 Hz, @CH), 62.4
(d, J = 5 Hz, OCH2), 24.3 (CH3), 16.6 (d, J = 5 Hz, CH3); 31P NMR
(acetone-d6) d +19.1; Anal. Calcd for C14H20NO4P (297.29): C,
56.56; H, 6.78; N, 4.71. Found: C, 56.79; H, 6.73; N, 4.44; E-isomer
E-6a: Rf-value 0.55; m = 2.00 g (18%) of white crystals; mp = 118–
121 °C; 1H NMR (acetone-d6) d 8.88 (s (br), 1H, NH); 7.49 (m, 2H,
arom. H), 7.39 (m, 3H, arom. H), 6.89 (d, 1H, J = 11.8 Hz, @CH), 3.72
(m, 4H, OCH2), 2.10 (s, 3H, CH3), 1.29 (dt, J = 6.9, 0.5 Hz, 6H, CH3);
13C NMR (acetone-d6) d 170.7 (C@O), 151.9 (d, J = 16 Hz, N–C@),
137.5 (arom. C), 130.1, 129.9, 128.7 (arom. CH), 99.9 (d, J = 200 Hz,
@CH), 61.3 (d, J = 6 Hz, OCH2), 24.7 (CH3), 16.4 (d, J = 6 Hz, CH3);
3. Conclusions
In conclusion for the first time the asymmetric hydrogenation of
b-acetylamido-vinylphosphonates was successfully performed to
give the chiral b-acetylamido phosphonates in up to 92% ee. Fur-
ther work is in progress to elucidate the mechanism of the
reaction.
4. Experimental
4.1. General procedure
Solvents were dried and freshly distilled under argon before
use. All reactions were performed under an argon atmosphere.
Thin-layer chromatography was performed on precoated TLC
plates (silica gel). Flash chromatography was carried out with Silica
Gel 60 (particle size 0.040–0.063 mm). Melting points are uncor-
rected. NMR spectra were recorded at a Bruker ARX 400 spectrom-
eter at the following frequencies: 400.13 MHz (1H), 100.63 MHz
(
13C), 161.98 MHz (31P). Chemical shifts of 1H and 13C NMR spectra
are reported in ppm downfield from TMS as internal standard.
Chemical shifts of 31P NMR spectra are referred to H3PO4 as exter-
nal standard. Signals are quoted as s (singlet), d (doublet), br
(broad) and m (multiplet). The chiral ligands were purchased from
STREM and ALFA AESAR.
31P NMR (acetone-d6)
d +19.5; Anal. Calcd for C14H20NO4P
(297.29): C, 56.56; H, 6.78; N, 4.71; Found: C, 56.70; H, 6.67; N, 4.41.
4.5. Diethyl 2-acetamino-2-isopropylvinylphosphonate 6b
4.2. (Z)-Diethyl-2-amino-2-phenylvinylphosphonate 5a
The compound was prepared by the same procedure as de-
scribed for 6a using enamide 5b (25 mmol, 5.53 g). The purification
and isolation were realized by column chromatography (AcOEt/
EtOH = 9:1). Z-Isomer Z-6b: Rf-value 0.80; m = 4.2 g (59%) of a col-
orless oil; 1H NMR (CDCl3) d 10.53 (s (br), 1H, NH); 4.45 (d,
J = 9.9 Hz, 1H, @CH), 4.01 (m, 4H, OCH2), 3.85 (m, 1H, CH), 2.07
(s, 3H, CH3), 1.30 (dt, J = 7.0, 0.5 Hz, 6H, CH3), 1.08 (d, J = 6.8 Hz,
6H, CH3); 13C NMR (CDCl3) d 168.3 (C@O), 167.6 (N–C@), 85.9 (d,
J = 186 Hz, @CH), 61.7 (d, J = 5 Hz, OCH2), 30.2 (d, J = 16 Hz, CH),
25.4 (CH3), 21.4 (CH3), 16.2 (d, J = 6 Hz, CH3); 31P NMR (CDCl3) d
+22.7; Anal. Calcd for C11H22NO4P (263.27): C, 50.18; H, 8.42; N,
A 250 mL flask was charged with diethylmethylphosphonate
(33 mmol, 5.02 g) in dry THF (90 mL). At À78 °C, a 1.6 M n-BuLi/
hexane-solution (36.3 mmol, 22.7 mL) was slowly added and the
solution was stirred for 1 h. After addition of 1 equiv of benzo-
nitrile (33 mmol, 3.41 g), stirring was continued for 15 min at this
temperature and further 2 h at 0 °C. After quenching the reaction
with water (25 mL), the mixture was evaporated on a rotavapor
to remove the THF. The aqueous residue was extracted with dichlo-
romethane (3 Â 30 mL), the combined extracts were dried
(Na2SO4), and concentrated to yield 5a as a pale yellow oil

1192
R. Kadyrov et al. / Tetrahedron: Asymmetry 19 (2008) 1189–1192
5.32. Found: C, 50.08; H, 8.19; N, 5.20; E-isomer E-6b: Rf-value
0.50; m = 0.7 g (10%) of white crystals, mp = 151–155 °C; 1H NMR
(CDCl3) d 7.07 (s (br), 1H, NH); 6.54 (d, J = 12.3 Hz, 1H, @CH),
4.00 (m, 4H, OCH2), 3.68 (m, 1H, CH), 2.11 (s, 3H, CH3), 1.27 (d,
J = 7.0 Hz, H, CH3), 1.10 (d, J = 7.0 Hz, 6H, CH3); 13C NMR (CDCl3) d
169.9 (C@O), 157.2 (d, J = 20 Hz, N–C@), 95.4 (d, J = 199 Hz, @CH),
61.2 (d, J = 5 Hz, OCH2), 30.5 (d, J = 6 Hz, CH), 25.0 (CH3), 20.2
(CH3), 16.2 (d, J = 6 Hz, CH3); 31P NMR (CDCl3) d +21.6; Anal. Calcd
for C11H22NO4P (263.27): C, 50.18; H, 8.42; N, 5.32. Found: C,
49.89; H, 8.28; N, 5.19.
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Gladiali, S.; Beller, M. Org. Process Res. Dev. 2007, 11, 568–577; (b) Monti, C.;
Gennari, C.; Piarulli, U.; de Vries, J. G.; de Vries, A. H. M.; Lefort, L. Chem. Eur. J.
2005, 11, 6701–6717; (c) Dai, Q.; Yang, W.; Zhang, X. Org. Lett. 2005, 7, 5343–
5345; (d) Reetz, M. T.; Li, X. Angew. Chem., Int. Ed. 2005, 44, 2959–2962. and
references cited therein.
17. (a) Brown, J. M. In The Handbook of Homogeneous Hydrogenation; de Vries, J. G.,
Elsevier, C. J., Eds.; Wiley-VCH: Weinheim, 2007; pp 1073–1103. Chapter 31;
(b) Drexler, H.-J.; You, J.; Zhang, S.; Fischer, C.; Baumann, W.; Spannenberg, A.;
Heller, D. Org. Process Res. Dev. 2003, 7, 355–361.
18. For the preparation of other functionalized phosphonates by Rh- and Ru-
catalyzed asymmetric hydrogenation, see: (a) Wang, D.-Y.; Hu, Y.-P.; Huang, J.-
D.; Deng, J.; Yu, S.-B.; Duan, Z.-D.; Xu, X.-F.; Zeng, Z. Angew. Chem., Int. Ed. 2007,
46, 8002–8005; (b) Badkar, P. A.; Rath, N. P.; Spilling, C. D. Org. Lett. 2007, 9,
3619–3622.
4.6.2. Optimization
The asymmetric hydrogenation was carried out with an auto-
matic hydrogenation device hosting 8 autoclaves (HP-ChemScan
HEL-Group). The Rh-catalyst (3.3 lmol) and the substrate
(0.33 mmol) were transferred into the autoclaves and kept under
argon. The solvent (4 mL) was added and the autoclaves were pres-
surized with hydrogen to the appropriate pressure after reaching
the temperature of 25 °C. The gas uptake was monitored over a
period of 24 h.
19. (a) Wang, D.-Y.; Huang, J.-D.; Hu, X.-P.; Deng, J.; Yu, S.-B.; Duan, Z.-C.; Zheng, Z.
J. Org. Chem. 2008, 73, 2011–2014; (b) Gridnev, I. D.; Yasutake, M.; Imamoto, T.;
Beletskaya, I. P. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5385–5390; (c) Holz, J.;
Stürmer, R.; Schmidt, U.; Drexler, H.-J.; Heller, D.; Krimmer, H.-P.; Börner, A.
Eur. J. Org. Chem. 2001, 4615–4624; (d) Burk, M. J.; Stammers, T. A.; Straub, J. A.
Org. Lett. 1999, 1, 387–390; (e) Dwars, T.; Schmidt, U.; Fischer, C.; Grassert, I.;
Kempe, R.; Froehlich, R.; Drauz, K.; Oehme, G. Angew. Chem., Int. Ed. 1998, 27,
2851–2853; (f) Schmidt, U.; Oehme, G.; Krause, H.-W. Synth. Commun. 1996,
26, 777–781.
20. For example: (a) Rozalski, M.; Krajewska, U.; Panczyk, M.; Mirowski, M.;
Rozalska, B.; Wasek, T.; Janecki, T. Eur. J. Med. Chem. 2007, 42, 248–255; (b)
Wasek, T.; Olczak, J.; Janecki, T. Synlett 2006, 1507–1510; (c) Okada, Y.;
Minami, T.; Miyamoto, M.; Tsuneyuki, O.; Sumiko, S.; Junji, S. Heteroatom Chem.
1995, 6, 195–210.
4.7. rac-Diethyl 2-acetamino-2-phenylethylphosphonate rac-7a
Pale yellow oil; 1H NMR (CDCl3) d 7.30–7.12 (m, 5H, arom. H),
5.30 (1H, m, CH–N), 3.97 (m, 2H, OCH2), 3.69 (m, 2H, OCH2), 2.36
(s (br), 1H, NH); 2.36–2.12 (2H, m, CH2-P), 1.95 (s, 3H, CH3), 1.22
(t, 3H, J = 7.1 Hz, CH3), 1.00 (t, 3H, J = 7.0 Hz, CH3); 13C NMR (CDCl3)
d 169.2 (C@O), 141.2 (d, J = 8 Hz, arom. C), 128.3, 127.2, 126.0
(arom. CH), 61.7 (d, J = 7 Hz, OCH2), 61.4 (d, J = 6 Hz, OCH2), 48.2
(d, J = 5 Hz, CH–N), 32.1 (d, J = 139 Hz, CH2P), 23.1 (CH3), 16.2 (d,
J = 6 Hz, CH3), 15.9 (d, J = 6 Hz, CH3); 31P NMR (CDCl3) d +27.9; Anal.
Calcd for C14H22NO4P (299.30): C, 56.18; H, 7.41; N, 4.68. Found: C,
56.63; H, 7.53; N, 4.32.
21. (a) Johnson, A.-L.; Slaett, J.; Janosik, T.; Bergman, J. Heterocycles 2006, 68, 2165–
2170; (b) Pietruszka, J.; Witt, A. Synthesis 2006, 4266–4268.
22. Sakhibullina, V. G.; Polezhaeva, N. A.; Bagautdinova, D. A.; Arbuzov, B. A. Zh.
Obshch. Khim. 1991, 61, 2421–2427.
4.8. rac-Diethyl 2-acetamino-2-isopropylethylphosphonate
rac-7b
23. (a) Sakhibullina, V. G.; Polezhaeva, N. A.; Bagautdinova, D. A.; Arbuzov, B. A. Zh.
Obshch. Khim. 1989, 59, 983–986; (b) Alikin, A. Yu.; Liorber, B. G.; Sokolov, M.
P.; Razumov, A. I.; Zykova, T. V.; Salakhutdinov, R. A. Zh. Obshch. Khim. 1982, 52,
316–322.
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25. (a) Khusainova, N. G.; Mostovaya, O. A.; Berdnikov, E. A.; Litvinov, I. A.;
Krivolapov, D. B.; Cherkasov, R. A. Russ. J. Org. Chem. 2005, 41, 1260–1264; (b)
Palacios, F.; Aparicio, D.; Garcia, J. Tetrahedron 1996, 52, 9609–9628.
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2004, 69, 8767–8774; (b) Palacios, F.; Garcia, J.; Ochoa de Retana, A. M.;
Oyarzabal, J. Heterocycles 1995, 41, 1915–1922; (c) Shin, W. S.; Lee, K.; Oh, D. Y.
Tetrahedron Lett. 1995, 36, 281–282.
27. All results of the HTS can be obtained from the authors on request.
28. It should be noted, however, when in an individual trial 3 mmol of Z-6b was
hydrogenated with [Rh((R)-SYNPHOS)(COD)]BF4 in methanol, the chiral
product was obtained in quantitative yield and in 94% ee. Obviously in some
cases the HTS-approach can give some misleading results. Currently, this
aspect is under investigation.
Pale yellow oil; 1H NMR (CDCl3) d 6.32 (d (br), 1H, NH); 4.10–
3.88 (m, 5H, CH–N, OCH2), 2.02–1.80 (3H, m, CH, CH2P), 1.91 (s,
3H, CH3), 1.24 (dt, J = 7.1, 3.1 Hz, 6H, CH3), 0.85 (d, J = 6.8 Hz, 3H,
CH3), 0.83 (d, J = 6.8 Hz, 3H, CH3); 13C NMR (CDCl3) d 169.4
(C@O), 61.6 (d, J = 7 Hz, OCH2), 61.1 (d, J = 6 Hz, OCH2), 49.7 (d,
J = 4 Hz, CH–N), 31.9 (d, J = 10 Hz, CH), 27.2 (d, J = 140 Hz, CH2P),
23.0 (CH3), 18.5 (CH3), 18.3 (CH3), 16.1 (d, CH3, JC,P = 6 Hz); 31P
NMR (CDCl3) d +30.1; Anal. Calcd for C11H24NO4P (265.29): C,
49.80; H, 9.12; N, 5.28. Found: C, 50.18; H, 9.23; N, 5.07.
Acknowledgments
29. Up to now correlation of the sign of the specific rotation with the absolute
configuration cannot be given. A comparison with the specific rotation of
known chiral b-substituted b-amino-ethan-1-ylphosphonates indicates that a
positive sign correlates with an (S)-configuration.
We are grateful for the skilled technical assistance by Mrs. H.
Borgwaldt and Mrs. G. Wenzel. We acknowledge financial support
by the Graduate School 1213 of DFG.