Chemoenzymatic synthesis of phosphonic acid analogues of L-lysine, L-proline, L-ornithine, and L-pipecolic acid of 99 % ee - Assignment of absolute configuration to (-)-proline

Article abstract of DOI:10.1002/ejoc.201001501

(±)-ω-Halo-α-(chloroacetoxy)phosphonates were kinetically resolved by use of a protease (Chirazyme P-2). The esters recovered at levels of conversion between 56 and 72 % furnished (S)-alcohols of 99 % ee. These were converted via azides into the phosphonic acid analogues of L-lysine, L-proline, L-ornithine and L-pipecolic acid. (-)-Phosphaproline was transformed into crystalline ureas derived from (R)- and (S)-1-phenylethyl isocyanate. X-ray structure analyses revealed that the levorotary phosphaproline has the R configuration, contrary to earlier reports. Copyright

Full text of DOI:10.1002/ejoc.201001501

FULL PAPER
DOI: 10.1002/ejoc.201001501
Chemoenzymatic Synthesis of Phosphonic Acid Analogues of
-Proline, -Ornithine, and -Pipecolic Acid of 99% ee – Assignment of
Absolute Configuration to (–)-Proline
L
-Lysine,
L
L
L
Frank Wuggenig,[a] Anna Schweifer,[a][†] Kurt Mereiter,[b] and Friedrich Hammerschmidt*[a]
Keywords: Enzymes / Enzyme catalysis / Hydrolases / Configuration determination / Chiral resolution /
Hydroxyphosphonates / Aminophosphonic acids
(Ϯ)-ω-Halo-α-(chloroacetoxy)phosphonates were kinetically
resolved by use of a protease (Chirazyme® P-2). The esters
recovered at levels of conversion between 56 and 72% fur-
nished (S)-alcohols of 99% ee. These were converted via az-
line, L-ornithine and L-pipecolic acid. (–)-Phosphaproline was
transformed into crystalline ureas derived from (R)- and (S)-
1-phenylethyl isocyanate. X-ray structure analyses revealed
that the levorotary phosphaproline has the R configuration,
contrary to earlier reports.
ides into the phosphonic acid analogues of L-lysine, L-pro-
racemic form. Additionally, we determined the absolute
configuration of levorotary phosphaproline, because this
had not previously been done rigorously.
Introduction
α-Aminophosphonic acids are structural analogues of α-
amino carboxylic acids and have diverse biological ef-
fects.[1,2] To give just a few examples, they and their deriva-
tives inhibit various enzymes of medical[3] and agricul-
tural[4] importance. Many methods for the synthesis of race-
mic[5] and chiral, nonracemic[6] α-aminophosphonic acids
have been developed, especially those with alkyl side chains.
However, the number of approaches to cyclic α-aminophos-
phonic acids and those with functionalized side chains is
rather limited. Representatives of these groups caught our
imagination. Here we present our results on the chemoen-
zymatic syntheses of the phosphonic acid analogues of two
proteinogenic examples [l-lysine (1, l-phosphalysine, Fig-
ure 1) and l-proline (2, l-phosphaproline)] and of two non-
proteinogenic ones [l-ornithine (3, l-phosphaornithine)
and l-pipecolic acid (4, l-phosphapipecolic acid)], all of
99% ee. All four aminophosphonic acids have been pre-
pared in racemic[7–10] form, but only the cyclic ones also in
homochiral[11,12] form. Dipeptides containing (Ϯ)-phos-
phaproline or (Ϯ)-phosphapipecolic acid and l-Ala or l-
Leu display plant-growth-regulating activity,[13] whereas
(Ϯ)-phosphaornithine shows antitumour[9b] activity. (S)-
Phosphaproline and its diethyl ester were recently used as
efficient organocatalysts.[11d] Phosphalysine and phos-
phaornithine have never been prepared in chiral, non-
Figure 1. Phosphonic acid analogues of l-lysine (1), l-proline (2),
l-ornithine (3), and l-pipecolic acid (4).
Results and Discussion
In preceding publications we demonstrated that various
chiral, nonracemic α-aminophosphonic acids can be pre-
pared from α-hydroxyphosphonates[14] by an approach
comprising a Mitsunobu reaction with HN3, reduction of
the azide to the amine, deprotection and purification by ion
exchange chromatography. The starting α-hydroxyphos-
phonates were obtained by lipase-[15] or protease-cata-
lysed[16] kinetic resolution of the corresponding acetates or
chloroacetates. This methodology was extended to prepare
the four aminophosphonic acids 1–4.
The envisaged starting materials – the α-hydroxyphos-
phonates (Ϯ)-6a–c (Scheme 1), each with an ω-haloalkyl
side chain – were not accessed by the standard method,
base-catalysed addition of diisopropyl phosphite to the cor-
responding aldehydes, but were easily accessible through
one-pot reactions starting from the commercially available
esters 5a–c.[15a]
[a] Institute of Organic Chemistry, University of Vienna,
Währingerstraße 38, 1090 Vienna, Austria
Fax: +43-1-4277-5291
E-mail: friedrich.hammerschmidt@univie.ac.at
[b] Institute of Chemical Technologies and Analytics, Vienna
University of Technology,
Getreidemarkt 9/164SC, 1060 Vienna, Austria
[†] Deceased December 29, 2010
1870
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1870–1879

Chemoenzymatic Synthesis of Phosphonic Acids
conversion of 45% by addition of HCl to bring the pH to
4.0. Extractive workup and flash chromatography furnished
the chiral, nonracemic α-hydroxyphosphonates (S)-6a–c to-
gether with the unreacted chloroacetates (R)-7a–c or vice
versa, depending on the hydrolase used. The chloroacetates
were transesterified (MeOH/Et3N) to give α-hydroxyphos-
phonates enantiomeric to those formed by enzymatic hy-
drolyses. The configurations and the enantiomeric excesses
of the α-hydroxyphosphonates were determined by prepara-
tion of their (R)-Mosher esters and recording of 1H and 31
P
NMR spectra.[17,18] The data are compiled in Table 1.
Table 1. Chemical shifts (δ, ppm) of 31P NMR signals of (R)-
Mosher esters derived from α-hydroxyphosphonates 6.
Entry
6
(R)-Mosher ester derived from
Δδ (ppm)[a]
(S)-6
(R)-6
1
2
3
6a
6b
6c
13.59
13.01
13.35
12.95
12.39
12.74
0.64
0.62
0.61
Scheme 1. Preparation of the chiral, nonracemic α-hydroxyphos-
phonates 6.
[a] Δδ = δ(S) – δ(R).
In summary, lipase AP 6 preferentially hydrolysed the
These were reduced with DIBAH at 78 °C in dry toluene. (S)-α-chloroacetates 7 whereas the protease preferentially
After two hours diisopropyl trimethylsilyl phosphite was hydrolysed the (R)-α-chloroacetates, to give the (S)- and
added and the mixtures were allowed to warm slowly to (R)-α-hydroxyphosphonates, respectively (Table 2). The in-
15 °C in the cooling bath, whereupon the tetrahedral inter- crease in the length of the side chain on going from
mediates collapsed with the formation of iBu2AlOR (R = Br(CH2)3 to Br(CH2)4 had more influence on the reaction
Me or Et) and aldehydes. The latter were intercepted by the rate of the protease than on that of the lipase, which was
silylated phosphite to give α-silyloxyphosphonates, which also used in larger amounts. The ee values of the α-hydroxy-
were converted on workup into the desired α-hydroxyphos- phosphonates formed on enzymatic hydrolysis are very sim-
phonates (Ϯ)-6a–c. They were chloroacetylated[14b] to give ilar for both enzymes, although the results might be some-
the esters (Ϯ)-7a–c, which displayed much higher reactivi- what better for the protease, which was therefore selected to
ties than the corresponding acetates with hydrolases.
prepare the chiral, nonracemic (S)-α-hydroxyphosphonates
From our experience in the use of lipases and proteases needed as starting materials on a preparative scale (Table 2,
in kinetic resolutions of α-acetoxy- and α-(chloroacetoxy)- Entries 6–8). To obtain high ee values for (S)-7a–c, the en-
phosphonates, we decided first to test lipase AP 6 (from As- zymatic hydrolyses were stopped at degrees of conversion
pergillus niger)[15b] and protease Chirazyme® P-2 (an alka- of 56%, 68% and 72%, respectively. The (R)-α-hydroxy-
line serine-type endoprotease)[16] on an analytical scale. The phosphonates had low ee values at this point, but the α-
substrates (Ϯ)-7a–c (1 mmol) were thus hydrolysed at room (chloroacetoxy)phosphonates (S)-7 had very high ones
temperature at pH 7.0 in a biphasic system (50 mm phos- (99%). Chemical hydrolysis of the esters (S)-7a–c furnished
phate buffer and hexanes/tert-butyl methyl ether (1:1) with the α-hydroxyphosphonates (S)-6a–c with the same ee val-
an autotitrator.[15b] The reaction was stopped at a degree of ues.
Table 2. Enantioselective hydrolysis of α-(chloroacetoxy)phosphonates (Ϯ)-7 at room temp. (22–24 °C).
Entry (Ϯ)-7
[mmol] amount[a]
Enzyme/ Time Conv.[b]
Alcohol
Ester
[α]2D0 (c)[c]
Alcohol obtained from ester by chemical hydrolysis
[h]
AP6/10 mg 4.3
P2/10 μL 4.2
AP6/21 mg 3.8
[%]
Yield [%]
[α]2D0 (c)[c] ee[d] [%] Conf. Yield [%]
Yield [%]
[α]2D0 (c)[c]
ee[d] [%]
Conf.
1
2
3
4
5
7a/1
7a/1
7b/1
7b/1
7c/1
45
45
45
47
45
56
68
72
40
36
38
38
37
37
54
50
+12.1 (1.1)
–14.1 (1.1)
+10.3 (1.3)
–10.7 (1.1)
–12.9 (1.0)
–13.6 (1.4)
–6.0 (1.0)
86
95
85
82
84
–
S
R
S
R
R
R
R
R
38
45
49
49
50
38
30
25
–16.7 (1.0)
+15.3 (1.0)
–16.5 (1.1)
+15.7 (1.2)
+13.1 (1.0)
+17.0 (1.0)
+22.5 (1.3)
+26.0 (1.1)
68
73
98
–
–4.3 (1.1)
+9.4 (1.1)
–9.6 (1.1)
–
–
R
S
R
–
78
69
–
P2/60 μL
P2/60 μL
P2/50 μL
P2/0.5 mL
20
21
20
44
21
90
84
93
99
+6.6 (1.0)
+15.4 (1.0)
+12.8 (1.0)
+14.9 (1.1)
82
99
99
99
S
S
S
S
6[e]
7[e]
8[e]
7a/18
7b/13
–
–
7c/7.6 P2/0.5 mL
–6.1 (1.0)
[a] For Chirazyme® P-2: lyophilisate or solution (600 mg of lyophilisate with protein content of 80% in 5 mL of solution). [b] Conv. =
mean value of conversion determined from 0.5 m NaOH consumed and conversion determined by 1H NMR of crude product. [c] In
acetone solution (2 mL), rounded to the nearest tenth. [d] Mean value of ee determined by 1H and 31P NMR of (R)-Mosher ester. [e] The
reaction was usually performed in phosphate buffer (50 mL) without organic solvent.
Eur. J. Org. Chem. 2011, 1870–1879
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1871

F. Wuggenig, A. Schweifer, K. Mereiter, F. Hammerschmidt
FULL PAPER
Preparation of
L
-Phosphalysine and
L
-Phosphaornithine
substitute the mesyloxy group as well, DMF at 70 °C was
required as solvent, but then dealkylation at phosphorus
occurred as a side reaction. The (S)-1-hydroxyphosphonates
(S)-6a and (S)-6b were therefore converted into the more
reactive p-nitrobenzenesulfonates (S)-11a and (S)-11b
(Scheme 3) in high yields (80% and 82%). These were
treated with NaN3 and 18-crown-6 in DMF – but not in
CH3CN – at 40 °C for 40 h to effect smooth substitution of
both leaving groups to furnish the diazides (R)-12a and (R)-
12b. Reduction with Ph3P[20] (Staudinger reaction) and de-
blocking with HCl (6 m, reflux) furnished the diaminophos-
phonic acids l-phosphaornithine [(R)-3] and l-phosphalys-
ine [(R)-1], which were isolated as their hydrobromides.
Crystals of the latter compound contained a substoichio-
metric amount (0.17 equiv.) of HBr. The ee value of the
phosphaornithine was determined by HPLC with a chiral
anion exchanger to be 99%, in agreement with that the of
starting material.[21]
l-Lysine is a basic proteinogenic amino acid. l-Ornithine
is an intermediate of the urea cycle and on decarboxylation
yields putrescine (1,4-diaminobutane),[19] required for the
biosynthesis of spermidine and spermine, two essential
components for cell growth. The phosphonic acid ana-
logues of these two amino acids were prepared similarly,
from the starting (S)-α-hydroxyphosphonates (S)-6a and
(S)-6b. We reasoned that diazidophosphonates should be
easily accessible from the α-hydroxyphosphonates 6 and
convertible into the corresponding α-aminophosphonic ac-
ids. In an exploratory experiment, we activated the OH
group of (Ϯ)-6b by mesylation (Scheme 2).
Preparation of L-Phosphaproline
The starting material for the preparation of l-phospha-
proline was the bromo-hydroxy-phosphonate (S)-6a, a
chemically unstable compound, as already established for
the racemate. When a NMR sample in CDCl3 was left for
one week at room temperature, evidently a proportion of
the compound cyclized to give diisopropyl (tetra-
hydrofuran-2-yl)phosphonate [(Ϯ)-13, ratio of 6a/(Ϯ)-13
1.6:1]. This slow cyclization reduced the yields relative to
6b whenever a reaction that produced or consumed 6a was
performed.
Scheme 2. Attempted preparation of the 1,5-diazidophosphonate
(Ϯ)-10.
The substitution of the bromide in the bromomesylate
(Ϯ)-8 (NaN3/18-crown-6 in CH3CN at reflux) was a
smooth reaction, but unfortunately that of the mesyloxy
group, to give the diazide (Ϯ)-10, did not take place. To
The α-hydroxyphosphonate (S)-6a was mesylated in 93%
yield and then selectively converted (NaN3/18-crown-6/
MeCN/24 h/reflux) into the monoazide (S)-15 in 91% yield
(Scheme 4). A Staudinger reaction with Ph3P in DMF fur-
nished the intermediate iminophosphorane (S)-16, which
cyclized to the protected l-phosphaproline (R)-17. This was
deprotected and purified by the standard procedure to yield
l-phosphaproline [(–)-2] in 87% yield. If it is assumed that
the starting (+)-6a has the S configuration, on the basis of
1
the H and 31P NMR spectra of the (R)-Mosher ester and
the plausible assumption of inversion of its configuration
upon cyclization, the levorotary proline should have the R
configuration. However, the S configuration had been as-
signed to it some years ago on the basis of analogy of the
migration properties on TLC of dipeptides consisting of
various α-aminophosphonic and α-aminocarboxylic ac-
ids.[11b] This assignment was later used to deduce the con-
figurations of the enantiomers of piperidazin-3-ylphos-
phonic acids.[11b] The diethyl ester of (S)-phosphaprol-
ine[11c] was prepared by Katritzky et al., but they did not
deblock it and correlate it with the first assignment. (S)-
Phosphaproline was recently prepared by deprotection of
the diethyl ester of (S)-phosphaproline accessed by the
method of Katritzky et al. Unfortunately, the specific rota-
tion was not given.[11d] To resolve the discrepancies relating
to the absolute configuration, we decided to derivatize
Scheme 3. Preparation of l-phosphaornithine [(R)-3] and l-phos-
phalysine [(R)-1].
1872
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1870–1879

Chemoenzymatic Synthesis of Phosphonic Acids
(–)-phosphaproline and to perform X-ray structure analyses of α-hydroxyphosphonates by NMR spectroscopic investi-
(Scheme 5). Phosphaproline [(–)-2] was silylated with gation of their Mosher esters.
TMSCl in dry pyridine and then treated with (S)-1-phenyl-
ethyl isocyanate to form a urea derivative. The phosphonic
acid group was esterified with diazomethane to give the de-
rivative 18 in an overall yield of 76%. Because it initially
could not be induced to crystallize, we also derivatized the
same phosphaproline similarly with (R)-1-phenylethyl iso-
cyanate. Luckily, we ended up with suitable crystals of both
derivatives for X-ray structure analyses, although the latter
crystals were more suited (see Figures 2 and 3). The figures
show that the levorotary phosphaproline indeed has the R
configuration and consequently that the dextrorotary form
has the S one. The previous assignment[11b] based on Rf
values thus requires revision, as do the configurations of the
(piperidazin-3-yl)phosphonic acids. Additionally, this result
lends credence to the determination of the configurations
Figure 2. X-ray structure of the (–)-proline derivative 18. Selected
interatomic distances and angles [Å (°)]: P1–C1 1.812(2), P1–O1
1.4677(13), P1–O2 1.5711(16), P1–O3 1.5861(12), C5–O4 1.232(2),
C5–N1 1.382(2), C5–N2 1.362(2), O1–P1–C1–N1 56.87(17), C5–
N2–C7–C6 156.2(2), C5–N2–C7–C8 –79.7(3), intermolecular hy-
drogen bond N2···O1 2.857(2).
Figure 3. X-ray structure of the (–)-proline derivative 19. Selected
interatomic distances and angles [Å (°)]: P1–C1 1.8145(9), P1–O1
1.4751(6), P1–O2 1.5751(7), P1–O3 1.5853(7), C5–O4 1.2371(10),
C5–N1 1.3845(11), C5–N2 1.3574(10), O1–P1–C1–N1 –64.84(7),
C5–N2–C7–C6 –143.96(8), C5–N2–C7–C8 93.24(9), intermo-
lecular hydrogen bond N2···O1 2.9368(9).
Preparation of L-Phosphapipecolic Acid
Scheme 4. Preparation of l-phosphaproline [(R)-2].
l-Pipecolic acid is on one of two alternative biodegrad-
ative routes from lysine to l-α-aminoadipic semialdehyde
ultimately leading to acetoacetyl-CoA. Here we prepared
the phosphonic acid analogue of this important intermedi-
ate.
We first tried to access racemic phosphapipecolic acid
from the α-hydroxyphosphonate (Ϯ)-6b by a very short
route as shown in Scheme 6. A Mitsunobu reaction with
HN3 furnished a mixture of the monazide (Ϯ)-20 and the
diazide (Ϯ)-21 in a ratio of 1:0.9. It was hoped that the
former might be converted into phosphapipecolic acid by a
method similar to that depicted in Scheme 3. The selectivity
of the Mitsunobu reaction could not be improved signifi-
cantly, however, so we resorted to the method used for the
preparation of l-phosphaproline (Scheme 7). The azido-
mesylate (Ϯ)-9, accessed from the α-hydroxyphosphonate
(Ϯ)-6a as in Scheme 2, was treated with Ph3P to induce a
Scheme 5. Derivatization of (–)-phosphaproline with both (S)- and
(R)-1-phenylethyl isocyanate.
Eur. J. Org. Chem. 2011, 1870–1879
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1873

F. Wuggenig, A. Schweifer, K. Mereiter, F. Hammerschmidt
FULL PAPER
Staudinger reaction, very probably giving an iminophos- phaproline derivative, but had to be done under mildly ba-
phorane. Surprisingly, though, this could not be forced to sic conditions. The isopropyl groups were removed by treat-
cyclize, either in acetonitrile at reflux or in toluene at ment with HCl (6 m, reflux). The hydrochloride of l-phos-
100 °C. However, the analogous cyclization worked phapipecolic acid was converted into the free acid by ion-
smoothly for phosphaproline.
exchange chromatography (Dowex 50, H+). Its overall yield
from the starting chloroazide (R)-22 was 55%.
Conclusions
In summary, we have demonstrated that (S)-ω-halo-α-
hydroxyphosphonates are versatile starting materials for the
preparation of phosphonic acid analogues of naturally oc-
curring amino acids. The former compounds were obtained
with ee values of 99% by protease-catalysed kinetic resolu-
tion of the corresponding chloroacetates and were then
converted into the corresponding α-aminophosphonic acids
by combinations of simple chemical reactions.
Scheme 6. Attempted preparation of the bromo azide (Ϯ)-20.
Experimental Section
General: All starting materials and enzymes were obtained from
commercial suppliers and were generally used without further puri-
fication. 1H and 13C NMR (J-modulated) spectra were recorded at
300 K in CDCl3, unless stated otherwise, with use of tetramethylsil-
ane as internal standard with a Bruker AM 400 WB instrument at
400.13 and 100.61 MHz, respectively. 31P NMR spectra were re-
corded with the same spectrometer at 161.97 MHz and with H3PO4
(85%) as external standard. In order to provide undistorted 31P
signal intensities for accurate integration, suitable relaxation times
were used without irradiation during this period to avoid NOE
enhancements. Chemical shifts (δ) are given in ppm and coupling
constants (J) in Hz. IR spectra were run with a Perkin–Elmer 1600
FT-IR spectrometer; liquid samples were measured as films be-
tween NaCl plates or on a silicon disc,[22] solids as Nujol mulls
Scheme 7. Attempted preparation of (Ϯ)-phosphapipecolic acid.
The failure of the sequence detailed in Scheme 7 was at-
tributed to sluggish intramolecular substitution of the
mesyloxy group α to the phosphonate group by the nitrogen
atom of the iminophosphorane as nucleophile. To circum-
vent this difficulty, the ω-chloro-α-hydroxyphosphonate (S)-
6c with 99% ee was transformed into the chloroazide (R)-
22 by means of a Mitsunobu reaction (Scheme 8). Unlike
the bromide in (Ϯ)-6b, however, the chloride was not re- between NaCl plates.
placed by azide. The ensuing Staudinger reaction and the
Optical rotations were measured at 20 °C with a Perkin–Elmer 341
subsequent cyclization with substitution at a primary posi-
tion were effected in acetonitrile at reflux. The P–N bond
in the cyclized product (R)-24 was very stable and could
not be cleaved under the acidic conditions used for the re-
moval of the isopropyl groups as in the case of the phos-
polarimeter in a 1 dm cell. TLC was carried out with Merck plates
(0.25 mm, silica gel 60 F254). Flash (column) chromatography was
performed with Merck silica gel 60 (230–400 mesh). Spots were vis-
ualized by dipping the plate into
a solution of (NH4)6-
Mo7O24·4H2O (24 g) and Ce(SO4)2·4H2O (1 g) in H2SO4 in water
(10%, 500 mL), followed by heating with a heat gun. TLC (iPrOH/
H2O/NH3 6:3:1) of aminophosphonic acids was also performed on
silica gel plates. Spots were visualized by dipping the plate into a
solution of ninhydrin [0.2% in ethanol (96%) or a 0.2% solution
of ninhydrin in EtOH (96%)/AcOH/collidine, 16:3:1], followed by
heating with a heat gun. A Metrohm 702 SM Titrino instrument
was used as an autotitrator. (S)-(+)-α-Methoxy-α-(trifluorometh-
yl)phenylacetyl chloride {JPS Chimie. [α]2D0 = +136.5 (c = 5.2,
CCl4), ee Ͼ 99.5%} was used for derivatization of α-hydroxyphos-
phonates. Enzymes [lyophilized preparations of lipase AP 6 and
protease Chirazyme® P-2 or a solution of it (5 mL of solution con-
tained 600 mg of lyophilisate with a protein content of 80%)] were
stored at +4 °C and used as supplied.
The α-hydroxyphosphonates (Ϯ)-6a–c were prepared by a literature
procedure[15a] and esterified[14b] with chloroacetic anhydride/pyr-
idine.
Enzymatic Hydrolysis of the α-(Chloroacetoxy)phosphonates (؎)-
7a–c (General Procedure A): A chloroacetate (Ϯ)-7 (1 mmol) was
Scheme 8. Preparation of l-phosphapipecolic acid [(R)-4].
1874
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1870–1879

Chemoenzymatic Synthesis of Phosphonic Acids
hydrolysed in a biphasic system [phosphate buffer (pH 7.0, 50 mm,
17 mL) and a hexanes/tert-butyl methyl ether mixture (1:1, 4 mL)]
at room temp. When the level of conversion had reached 45%, the
hydrolysis was stopped and the mixture was worked up as reported
(for results see Table 2).[15b] Enzymatic hydrolyses performed on a
preparative scale were performed in a 100 mL three-necked flask
with use of phosphate (50 mL) but without organic solvent (for
results see Table 2).
(؎)-Diisopropyl (5-Bromo-1-hydroxypentyl)phosphonate [(؎)-27i]:
This compound was prepared in 68% yield from ethyl 5-bromo-
pentanoate (5b, 2.51 g, 12 mmol) as a viscous colourless oil, which
crystallized at –5 °C; Rf = 0.38 (EtOAc), 0.24 (hexanes/EtOAc 1:4).
1H NMR: δ = 1.302 [d, J = 6.4 Hz, 6 H, OCH(CH3)2], 1.306 [d, J
= 6.4 Hz, 3 H, OCH(CH3)2], 1.312 [d, J = 5.9 Hz, 3 H, OCH-
(CH3)2], 1.53 (m, 1 H, CH2), 1.70 (m, 3 H, CH2), 1.88 (m, 2 H,
CH2), 3.38 (br. s, 1 H, OH), 3.39 (t, J = 6.9 Hz, 2 H, CH2Br), 3.74
(m, 1 H, CHP), 4.71 [m, 2 H, OCH(CH3)2] ppm. 13C NMR: δ =
24.0 (d, J = 4.4 Hz), 24.08 (d, J = 3.9 Hz), 24.12 (d, J = 3.6 Hz),
24.6 (d, J = 13.6 Hz), 30.4, 32.5 and 33.4, 67.8 (d, J = 161.9 Hz),
The Mosher esters 6·MTPA-(R) were prepared by a literature pro-
cedure[16] except that the α-hydroxyphosphonates 6 (approximately
0.05 mmol) were esterified with (S)-(+)-MTPACl (2.5 equiv.) and
dry pyridine (10 equiv.) in dry CH2Cl2 (0.5 mL). The solutions were
allowed to stand overnight (TLC: hexanes/EtOAc 1:4 or hexanes/
EtOAc 1:2) at room temp. and worked up as reported after the
addition of a few drops of water.
71.1 (d, J = 7.4 Hz), 71.3 (d, J = 7.2 Hz) ppm. IR (NaCl): ν =
˜
3299, 2978, 2937, 2870, 1454, 1386, 1375, 1227, 1178, 1142, 1106,
990 cm–1. C11H24BrO4P (331.19): calcd. C 39.89, H 7.30; found C
40.17, H 7.19.
(؎)-Diisopropyl (5-Chloro-1-hydroxypentyl)phosphonate [(؎)-6c]:
This compound was prepared in 62% yield from methyl 5-chloro-
pentanoate (5c, 3.01 g, 20 mmol) as a viscous colourless oil, which
Chemical Hydrolysis of the α-(Chloroacetoxy)phosphonates 7 (Gene-
ral Procedure B): A stirred solution of an α-chloroacetoxyphos-
phonate 7 in methanol (10 mL for each mmol of 7) was treated
with Et3N (2 mL for each mmol of 7) at room temp. Stirring was
continued until no starting material could be detected by TLC.
After evaporation of the solvent, the crude product was purified by
flash chromatography.
1
crystallized at –5 °C; Rf = 0.51 (EtOAc). H NMR: δ = 1.26 (d, J
= 6.0 Hz, 6 H), 1.265 (d, J = 6.0 Hz, 3 H), 1.27 (d, J = 6.0 Hz, 3
H), 1.49 (m, 1 H), 1.71 (m, 5 H), 3.48 (t, J = 6.5 Hz, 2 H), 3.56
(dd, J = 3.5, 6.0 Hz, 1 H), 3.70 (m, 1 H), 4.67 (m, 2 H) ppm. 13C
NMR: δ = 23.3 (d, J = 13.8 Hz), 24.0 (d, J = 6.1 Hz), 24.07 and
24.11 (d, J = 3.8 Hz), 30.6 and 32.3, 44.8, 67.8 (d, J = 162.1 Hz),
Preparation of the α-Azidophosphonates (General Procedure C): Di-
ethyl azodicarboxylate (1.5 equiv.) and a solution of HN3 in tolu-
ene (1.5 equiv.) were added at 0 °C under argon to a stirred mixture
of an α-hydroxyphosphonate 6 and Ph3P (1.5 equiv.) in dry toluene
(15 mL for 2 mmol of 6) and dry CH2Cl2 (3 mL for 2 mmol of
6).[14b] Stirring was continued for 30 min at 0 °C and for 1 h at
room temperature. MeOH (0.2 mL for 2 mmol of 6) was added,
and 30 min later the solvent was removed under reduced pressure.
Hexanes were added to the residue and the mixture was allowed to
stand overnight at 4 °C. The crystals were removed and the filtrate
was concentrated under reduced pressure. The crude product was
purified by flash chromatography.
71.0 and 71.2 (d, J = 7.6 Hz) ppm. IR (Si): ν = 3300, 2980, 2938,
˜
2872, 1454, 1386, 1375, 1313, 1287, 1221, 1179, 1142, 1106,
990 cm–1. C11H24ClO4P (286.74): calcd. C 46.08, H 8.44; found C
46.31, H 8.28.
(؎)-Diisopropyl [4-Bromo-1-(chloroacetoxy)butyl]phosphonate [(؎)-
7a]: Rf = 0.69 (hexanes/EtOAc 1:4); yield 82%; viscous oil. 1H
NMR: δ = 1.30 (d, J = 6.4 Hz, 3 H), 1.31 (d, J = 5.9 Hz, 3 H),
1.32 (d, J = 6.4 Hz, 6 H, 6 H), 1.92 (m, 3 H), 2.10 (m, 3 H), 3.39
(t, J = 6.2 Hz, 2 H), 4.09 (AB system, JAB = 15.0 Hz, 2 H), 4.74
(oct, J = 6.4 Hz, 2 H), 5.23 (dt, J = 3.8, 9.2 Hz, 1 H) ppm. 13C
NMR: δ = 23.8 (d, J = 4.9 Hz), 23.99 (d, J = 4.5 Hz), 24.02 and
24.2 (d, J = 3.5 Hz), 28.1 and 32.5, 28.5 (d, J = 11.8 Hz), 40.6, 69.5
(d, J = 171.1 Hz), 71.8 (d, J = 7.2 Hz), 72.0 (d, J = 6.7 Hz), 166.5
Preparation of the α-Aminophosphonic Acids (General Procedure D):
An azide (1 mmol) was dissolved in EtOH (30 mL) containing
concd. HCl (0.5 mL), and after the addition of Pd on charcoal
(50 mg, 10%) the azide was hydrogenated in a Parr apparatus
(3.4 bar) at room temp. for 4 h.[14b] The catalyst was filtered off and
the solvent was removed under reduced pressure. The residue was
dissolved in HCl (6 m, 10 mL) and heated at reflux for 5 h. After
evaporation of the solvent under reduced pressure and drying of
the residue over KOH in a desiccator, the crude product was puri-
fied by ion exchange chromatography on Dowex 50 WX8 or
50 WX4, H+ (50–100 mesh) with water as eluent. Ninhydrin-posi-
tive fractions were collected, concentrated under reduced pressure
and finally lyophilized.
(d, J = 5.8 Hz) ppm. IR (NaCl): ν = 2981, 2936, 1766, 1452, 1386,
˜
1376, 1254, 1164, 1105, 991 cm–1. C12H23BrClO5P (393.65): calcd.
C 36.61, H 5.89; found C 36.88, H 6.00.
(؎)-Diisopropyl
[5-Bromo-1-(chloroacetoxy)pentyl]phosphonate
[(؎)-7b]: Rf = 0.47 (hexanes/EtOAc 1:2); yield 88%; viscous oil. 1H
NMR: δ = 1.28 and 1.30 (d, J = 5.9 Hz, 3 H), 1.31 (d, J = 5.9 Hz,
6 H), 1.51 (m, 2 H), 1.85 (m, 4 H), 3.36 (t, J = 6.6 Hz, 2 H), 4.09
(AB system, JAB = 14.8 Hz, 2 H), 4.72 (m, 2 H), 5.21 (dt, J = 4.4,
9.3 Hz, 1 H) ppm. 13C NMR: δ = 23.8 (d, J = 4.9 Hz), 23.99 (d, J
= 5.4 Hz), 24.00 (d, J = 3.3 Hz), 24.12 (d, J = 12.2 Hz), 24.14 (d,
J = 3.4 Hz), 28.6, 32.0 and 33.0, 40.6, 70.0 (d, J = 170.5 Hz), 71.7
(d, J = 7.3 Hz), 71.9 (d, J = 6.7 Hz), 166.5 (d, J = 5.6 Hz) ppm. IR
(؎)-Diisopropyl (4-Bromo-1-hydroxybutyl)phosphonate [(؎)-6a]:
This compound was prepared in 74% yield from ethyl 4-bromobut-
anoate (5a, 5.85 g, 30 mmol), as a viscous colourless oil, which
crystallized at –5 °C and should be stored at this temperature; Rf
= 0.41 (EtOAc). 1H NMR: δ = 1.27 (d, J = 6.0 Hz, 6 H), 1.280
and 1.285 (d, J = 6.0 Hz, 3 H), 1.73 (m, 1 H), 1.91 (m, 2 H), 2.11
(m, 1 H), 2.83 (s, 1 H), 3.40 (m, 2 H), 3.74 (ddd, J = 3.5, 4.7,
(NaCl): ν = 2981, 1767, 1454, 1386, 1256, 1164, 1105, 991 cm–1.
˜
C13H25BrClO5P (407.68): calcd. C 38.30, H 6.18; found C 38.54, H
6.09.
(؎)-Diisopropyl
[5-Chloro-1-(chloroacetoxy)pentyl]phosphonate
1
[(؎)-7c]: Rf = 0.62 (EtOAc); yield 92%; viscous oil. H NMR: δ =
10.3 Hz, 1 H), 4.68 (m, 2 H) ppm. 13C NMR: δ = 23.95 (d, J = 1.33 (d, J = 6.0 Hz, 3 H), 1.34 (d, J = 5.9 Hz, 3 H), 1.35 (d, J =
2.6 Hz), 23.99 (d, J = 3.1 Hz), 24.07 (d, J = 3.8 Hz), 24.13 (d, J = 6.0 Hz, 6 H), 3.54 (t, J = 6.5 Hz, 2 H), 4.13 (AB system, JAB
=
3.1 Hz), 29.00 (d, J = 13.8 Hz), 29.8 and 33.4, 67.2 (d, J = 15.1 Hz, 2 H), 4.76 (m, 2 H), 5.25 (dt, J = 4.3, 9.3 Hz, 1 H) ppm.
162.9 Hz), 71.2 (d, J = 6.9 Hz), 71.4 (d, J = 7.6 Hz) ppm. IR 13C NMR: δ = 22.9 (d, J = 12.2 Hz), 23.8 and 23.98 (d, J = 5.3 Hz),
(NaCl): ν = 3298, 2979, 2935, 1452, 1386, 1375, 1217, 1178, 1142, 24.00 (d, J = 3.8 Hz), 24.1 (d, J = 3.1 Hz), 28.7 and 31.8, 40.6,
˜
1106, 1078, 990 cm–1. C10H22BrO4P (317.17): calcd. C 37.87, H
6.99; found C 37.82, H 6.73.
43.4, 70.1 (d, J = 170.4 Hz), 71.7 (d, J = 7.1 Hz), 71.9 (d, J =
6.6 Hz) ppm. IR (NaCl): ν = 2981, 1767, 1454, 1386, 1376, 1253,
˜
Eur. J. Org. Chem. 2011, 1870–1879
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1875

F. Wuggenig, A. Schweifer, K. Mereiter, F. Hammerschmidt
1165, 1105, 991, 889 cm–1. C13H25Cl2O5P (363.22): calcd. C 42.99, (20 mL). After the mixture had been stirred for 30 min at 0 °C and
FULL PAPER
H 6.94; found C 42.78, H 6.66.
for 2 h at room temp. (TLC: hexanes/EtOAc 1:4), water (10 mL)
and concd. HCl (1 mL) were added. The organic phase was sepa-
rated and the aqueous one was extracted twice with CH2Cl2. The
combined organic layers were washed with a sat. aq. solution of
NaHCO3, dried (MgSO4) and then concentrated under reduced
pressure. The residue was purified by flash chromatography (hex-
anes/EtOAc 1:1, Rf = 0.51). [α]2D0 = +2.8 (c = 1.1, acetone); yield
(؎)-Diisopropyl (5-Bromo-1-mesyloxypentyl)phosphonate [(؎)-8b]:
MeSO2Cl (485 mg, 4.23 mmol, 0.33 mL) and dry Et3N (4.23 mmol,
0.59 mL) were added under argon at 0 °C to a stirred solution of
the α-hydroxyphosphonate (Ϯ)-6b (934 mg, 2.82 mmol) in dry
CH2Cl2 (15 mL). After the mixture had been stirred for 30 min at
0 °C (TLC: hexanes/EtOAc 1:4), water (10 mL) and concd. HCl
(1 mL) were added. The organic phase was separated and the aque-
ous one was extracted twice with CH2Cl2. The combined organic
layers were dried (MgSO4) and concentrated under reduced pres-
sure, and the residue was purified by flash chromatography (hex-
1
82%; viscous oil. H NMR: δ = 1.19 (d, J = 6.0 Hz, 3 H), 1.21 (d,
J = 6.5 Hz, 3 H), 1.24 (d, J = 6.0 Hz, 6 H), 1.55 (m, 2 H), 1.82 (m,
4 H), 3.31 (t, J = 6.5 Hz, 2 H), 4.61 (m, 2 H), 4.81 (dt, J = 4.5,
9.0 Hz, 1 H), 8.22 (J = 9.0 Hz, 4 H, AAЈBBЈ system) ppm. 13C
NMR: δ = 23.7 and 23.9 (d, J = 4.6 Hz), 23.98 and 24.03 (d, J =
3.8 Hz), 24.2 (d, J = 10.0 Hz), 29.7, 31.93 and 32.90, 72.3 and 72.4
(d, J = 6.9 Hz), 77.9 (d, J = 172.9 Hz), 124.2 and 129.3 (each 2 C),
1
anes/EtOAc 1:4, Rf = 0.53); yield 93%, viscous oil. H NMR: δ =
1.29 (d, J = 5.5 Hz, 6 H), 1.31 (d, J = 6.0 Hz, 6 H), 1.55 (m, 1 H),
1.68 (m, 1 H), 1.83 (m, 4 H), 3.14 (s, 3 H), 3.34 (t, J = 6.8 Hz, 2
H), 4.71 (m, 3 H) ppm. 13C NMR: δ = 23.8 (d, J = 5.3 Hz), 24.0
(d, J = 5.3 Hz, 2 C), 24.1 (d, J = 10.7 Hz), 24.2 (d, J = 3.8 Hz),
29.7, 31.5 and 32.9, 39.2, 72.1 and 72.4 (d, J = 6.9 Hz), 77.0 (d, J
142.6 and 150.7 ppm. IR (NaCl): ν = 3107, 2981, 2937, 1608, 1534,
˜
1454, 1404, 1375, 1351, 1313, 1257, 1187, 1143, 1105, 991 cm–1.
C17H27BrNO8PS (516.35): calcd. C 39.54, H 5.27, N 2.71; found C
39.79, H 5.19, N 2.64.
= 171.3 Hz) ppm. IR (NaCl): ν = 2981, 2936, 2874, 1454, 1414,
˜
1387, 1360, 1255, 1225, 1175, 1143, 1104, 990 cm–1. C12H26BrO6PS
(409.27): calcd. C 35.22, H 6.40; found C 35.21, H 6.12.
(R)-(–)-Diisopropyl (1,4-Diazidobutyl)phosphonate [(R)-(–)-12a]:
The 4-nitrobenzenesulfonate (S)-(+)-11a {751 mg, 1.50 mmol,
[α]2D0 = +5.7 (c = 1.0, acetone), ee 99%} was transformed into the
diazide (R)-(–)-12a by the procedure used for the preparation of
(؎)-Diisopropyl (5-Azido-1-mesyloxypentyl)phosphonate [(؎)-9b]:
NaN3 (343 mg, 5.28 mmol) and 18-crown-6 (140 mg, 0.53 mmol)
were added under argon to a stirred solution of the mesylate (Ϯ)-
8 (1.08 g, 2.64 mmol) in dry CH3CN (25 mL). The mixture was
heated at reflux for 24 h. The solvent was evaporated under reduced
pressure and the residue was taken up in water (20 mL). The aq.
mixture was extracted three times with EtOAc. The combined or-
ganic layers were dried (MgSO4) and after removal of the solvent
the crude product was purified by flash chromatography. Rf = 0.65
(hexanes/EtOAc 1:4); yield 95%, colourless oil. 1H NMR: δ = 1.29
(d, J = 6.0 Hz, 6 H), 1.31 (d, J = 5.5 Hz, 6 H), 1.38–1.65 (m, 4 H),
1.81 (m, 2 H), 3.14 (s, 3 H), 3.23 (t, J = 6.3 Hz, 2 H), 4.70 (m, 3
H) ppm. 13C NMR: δ = 22.7 (d, J = 12.2 Hz), 23.8 (d, J = 4.6 Hz),
24.0 (d, J = 4.6 Hz, 2 C), 24.1 (d, J = 3.8 Hz), 28.2 and 30.1, 39.2,
51.0, 72.1 and 72.5 (d, J = 6.9 Hz), 77.0 (d, J = 170.6 Hz) ppm. IR
the diazide (R)-(–)-12b. Rf = 0.21 (hexanes/EtOAc 1:2). [α]2D0
=
1
–53.8 (c = 1.0, acetone); yield 82%; oil. H NMR: δ = 1.300 (d, J
= 6.5 Hz, 3 H), 1.305 (d, J = 6.0 Hz, 9 H), 1.64 (m, 2 H), 1.84 (m,
2 H), 3.29 (m, 3 H), 4.72 (m, 2 H) ppm. 13C NMR: δ = 24.0 (d, J
= 5.3 Hz, 2 C), 24.10 and 24.13 (d, J = 3.8 Hz), 26.07, 26.10 (d, J
= 13.8 Hz), 50.8, 57.4 (d, J = 157.6 Hz), 71.88 and 71.91 (d, J =
6.9 Hz) ppm. IR (NaCl): ν = 2982, 2936, 2875, 2100, 1454, 1387,
˜
1376, 1353, 1254, 1178, 1142, 1105, 990 cm–1. C10H21N6O3P
(304.29): calcd. C 39.47, H 6.96, N 27.62; found C 39.69, H 6.67,
N 27.37.
(R)-(–)-Diisopropyl (1,5-Diazidopentyl)phosphonate [(R)-(–)-12b]:
NaN3 (608 mg, 9.35 mmol) and 18-crown-6 (247 mg, 0.935 mmol)
were added under argon to a stirred solution of (S)-(+)-11b
{1.207 g, 2.34 mmol, [α]2D0 = +2.8 (c = 1.1, acetone)} in dry DMF
(25 mL). The mixture was stirred for 40 h at 40 °C. Water (20 mL)
was added and the mixture was extracted three times with EtOAc.
The combined organic layers were dried (MgSO4) and after the
evaporation of the solvent residual DMF was removed by bulb-to-
bulb distillation (bath temperature below 70 °C). The crude prod-
uct was purified by flash chromatography. Rf = 0.60 (hexanes/
EtOAc 1:2). [α]2D0 = –49.3 (c = 1.7, acetone); yield 85%; oil. 1H
NMR: δ = 1.29 (d, J = 6.0 Hz, 3 H), 1.30 (d, J = 6.0 Hz, 9 H),
1.43 (m, 1 H), 1.60 (m, 4 H), 1.80 (m, 1 H), 3.25 (m, 3 H), 4.72
(m, 2 H) ppm. 13C NMR: δ = 24.0 (d, J = 13.0 Hz), 24.1 (d, J =
3.8 Hz, 2 C), 24.4 (d, J = 4.6 Hz, 2 C), 28.2 and 28.3, 51.1, 57.7
(d, J = 156.8 Hz), 71.76 and 71.83 (d, J = 6.9 Hz) ppm. IR (NaCl):
(NaCl): ν = 2982, 2937, 2875, 2098, 1455, 1360, 1253, 1176, 1143,
˜
1105, 991 cm–1. C11H26N3O6PS (371.39): calcd. C 38.81, H 7.06, N
11.31; found C 38.88, H 6.94, N 11.39.
(S)-(+)-Diisopropyl
[4-Bromo-1-(4-nitrophenylsulfonyloxy)butyl]-
phosphonate [(S)-(+)-11a]: The α-hydroxyphosphonate (S)-(+)-6a
{650 mg 2.05 mmol, [α]2D0 = +15.4 (c = 1.0, acetone), ee 99%} was
transformed into the 4-nitrobenzenesulfonate (S)-(+)-11a by the
procedure used for the preparation of the 4-nitrobenzenesulfonate
(S)-(+)-11b; Rf = 0.54 (hexanes/EtOAc 1:1). [α]2D0 = +5.7 (c = 1.0,
acetone); yield 80%; viscous oil. 1H NMR: δ = 1.19 (d, J = 6.5 Hz,
3 H), 1.21 (d, J = 6.0 Hz, 3 H), 1.24 (d, J = 6.5 Hz, 6 H), 1.93 (m,
2 H), 2.05 (m, 2 H), 3.37 (t, J = 5.8 Hz, 2 H), 4.57 (oct, J = 6.5 Hz,
1 H), 4.65 (oct, J = 6.3 Hz, 1 H), 4.83 (m, 1 H), 8.22 (J = 9.0 Hz,
4 H, AAЈBBЈ-system) ppm. 13C NMR: δ = 23.7 and 23.9 (d, J =
5.4 Hz), 23.98 and 24.04 (d, J = 3.8 Hz), 28.2 (d, J = 10.0 Hz), 29.1
and 32.5, 72.4 and 72.5 (d, J = 7.6 Hz), 77.2 (d, J = 172.1 Hz),
ν = 2981, 2936, 2871, 2100, 1455, 1386, 1376, 1350, 1253, 1178,
˜
1142, 1106, 989 cm–1. C11H23N6O3P (318.31): calcd. C 41.50, H
7.28, N 26.40; found C 41.71, H 7.11, N 26.35.
124.2 and 129.4 (each 2 C), 142.5 and 150.8 ppm. IR (NaCl): ν =
˜
(R)-(–)-(1,4-Diaminobutyl)phosphonic Acid Hydrobromide [(R)-
Phosphaornithine·HBr, (R)-(–)-3·HBr]: The diazide (R)-(–)-12a
{301 mg, 0.99 mmol, [α]2D0 = –53.8 (c = 1.0, acetone)} was trans-
formed into (R)-(–)-3·HBr by the procedure used for the prepara-
tion of (R)-(–)-1·HBr. Melting range 110–160 °C, 274–278 °C
(dec.). [α]2D0 = –1.3 (c = 0.65, H2O); yield 67%; colourless crystals.
1H NMR (D2O): δ = 1.68–2.02 (m, 4 H), 3.01 (t, J = 7.0 Hz, 2 H),
3.23 (dt, J = 6.6, 13.2 Hz, 1 H) ppm. 13C NMR (D2O): δ = 24.3
(d, J = 7.6 Hz), 26.1, 39.3, 49.0 (d, J = 141.5 Hz) ppm. 31P NMR
3107, 2982, 2936, 1535, 1453, 1404, 1376, 1351, 1313, 1256, 1187,
1143, 1104, 993 cm–1. C16H25BrNO8PS (502.31): calcd. C 38.26, H
5.02, N 2.79; found C 38.55, H 4.86, N 2.76.
(S)-(+)-Diisopropyl [5-Bromo-1-(4-nitrophenylsulfonyloxy)pentyl]-
phosphonate [(S)-(+)-11b]: A solution of 4-nitrobenzenesulfonyl
chloride (926 mg, 4.18 mmol) in dry CH2Cl2 (5 mL), dry Et3N
(847 mg, 8.37 mmol, 1.16 mL) and DMAP (30 mg) were added un-
der argon at 0 °C to a stirred solution of (S)-(+)-6b {1.15 g,
3.47 mmol, [α]2D0 = +12.8 (c = 1.0, acetone), ee 99%} in dry CH2Cl2
(D O): δ = 13.7 ppm. IR (Nujol): ν = 3583, 1614, 1154, 1045,
˜
2
1876
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1870–1879

Chemoenzymatic Synthesis of Phosphonic Acids
917 cm–1. C4H14BrN2O3P (249.05): calcd. C 19.29, H 5.66, N 11.25,
Br 32.08; found C 19.60, H 5.39, N 11.09, Br 29.82.
2877, 2100, 1641, 1454, 1360, 1255, 1175, 1143, 1105, 990 cm–1.
C11H24N3O6PS (357.36): calcd. C 36.97, H 6.77, N 11.76; found C
36.80, H 6.52, N 11.53.
(R)-(–)-(1,5-Diaminopentyl)phosphonic Acid [(R)-Phosphalysine·
0.17HBr, (R)-(–)-1·0.17HBr]: A solution of the diazide (R)-(–)-12b
(170 mg, 0.534 mmol) and Ph3P (336 mg, 1.28 mmol) in dry tolu-
ene (3 mL) was stirred under argon for 1 h at room temp. and for
21 h at 30–40 °C.[20] The solvent was evaporated under reduced
pressure and the viscous residue was heated at reflux with HCl
(6 m, 10 mL) for 23 h. Water (20 mL) was added and the aq. sus-
pension was extracted three times with Et2O. After removal of the
solvent under reduced pressure the hydrochloride of (R)-1a was
transformed into the hydrobromide by treatment of the solid resi-
due with HBr (5 mL, 48%) and evaporation of the solvent under
reduced pressure. This process was repeated twice. The residue was
dissolved several times in water and concentrated under reduced
pressure, and was then repeatedly admixed with EtOH and concen-
trated again. The crude product, which was carefully dried under
reduced pressure, was dissolved in MeOH (2 mL), and afterwards
propene oxide (0.1 mL) was added dropwise to the stirred solution.
After 3 h the crystals were collected, washed with a small portion
of cold MeOH and dried under reduced pressure; m.p. 269–273 °C
(dec.). [α]2D0 = –9.7 (c = 0.66, H2O); yield (calculated with a formula
weight C5H16BrN2O3P·0.17HBr): 82%; colourless crystals. 1H
NMR (D2O): δ = 1.48 (m, 2 H), 1.64 (m, 3 H), 1.85 (m, 1 H), 2.94
(t, J = 7.3 Hz, 2 H), overlapping with 2.99 (m, 1 H) ppm. 13C NMR
(D2O): δ = 23.2 (d, J = 8.4 Hz), 26.7 and 28.8, 39.4, 50.4 (d, J =
(R)-(–)-(Pyrrolidin-2-yl)phosphonic Acid [(R)-Phosphaproline, (R)-
(–)-2]:
A solution of the azidomesylate (R)-(+)-15 {929 mg,
2.60 mmol, [α]2D0: = +13.9 (c = 1.2, acetone), = 99%} and Ph3P
(818 mg, 3.12 mmol) in dry DMF (20 mL) was stirred under argon
for 22 h. The solvent was removed by bulb-to-bulb distillation. The
cyclic intermediate (R)-17 {assignable signals of the NMR spectra
of crude 17 are given: 1H NMR (CD3OD): δ = 0.95, 1.10, 1.18 and
1.25 (d, J = 6.0 Hz, 3 H), 3.32 and 3.52 (m, 1 H), 3.75 (m, 1 H),
4.34 and 4.60 (m, 1 H) ppm. 13C NMR: δ = 24.4, 24.58 and 24.62
(d, J = 3.8), 24.79 (d, J = 4.6), 26.53 and 28.49 (d, J = 5.4), 52.40
(d, J = 3.1), 59.4 (dd, J = 3.1, 165.2), 74.27 and 74.30 (d, J =
6.6) ppm} was dried under reduced pressure and then heated at
reflux with HCl (6 m, 25 mL) for 22 h. Water (50 mL) was added
and the aq. solution was extracted with Et2O (3ϫ40 mL). The aq.
phase was concentrated under reduced pressure and the crude
product was purified by ion-exchange chromatography on
Dowex 50, H+ with water as eluent; m.p. 265–270 °C (dec.) (ref.
20
272–273 °C[11b]). [α]2D0 = –49.1, [α] = –51.6 (c = 1.1, 1 m NaOH)
578
20
(ref. [α] = +64 (c = 1.0, 1 m NaOH), ee 100%[11b]); yield 87%;
578
crystalline solid. 1H NMR (D2O): δ = 2.01 (m, 3 H), 2.24 (m, 1
H), 3.32 (m, 2 H), 3.51 (q, J = 9.2 Hz, 1 H) ppm. 13C NMR (D2O):
δ = 24.3 (d, J = 8.4 Hz), 26.8, 47.2 (d, J = 6.1 Hz), 56.20 (d, J =
143.8 Hz) ppm. 31P NMR (D O): δ = 13.6 ppm. IR (Nujol): ν =
˜
2
1694, 1622, 1556, 1401, 1339, 1311, 1242, 1167, 1066, 1030 cm–1.
C4H10NO3P (151.10): calcd. C 31.80, H 6.67, N 9.27; found C
31.74, H 6.42, N 9.10.
135.4 Hz) ppm. 31P NMR (D O): δ = 13.1 ppm. IR (Nujol): ν =
˜
2
3583,
2193,
1626,
1557,
1112,
1065,
974 cm–1.
C5H15N2O3P·0.17HBr (assumed, 195.91): calcd. C 30.65, H 7.74,
N 14.30, Br 6.93; found C 30.45, H 7.52, N 13.67, Br 6.99.
Derivatization of (–)-Phosphaproline with (S)-(–)- and (R)-(+)-1-
Phenylethyl Isocyanate to Give the Derivatives 18 and 19
(؎)-Diisopropyl (Tetrahydrofuran-2-yl)phosphonate [(؎)-13)]: As-
signable signals for compound (Ϯ)-13 were obtained from the
NMR spectra of a 1 to 1.6 mixture of (Ϯ)-13 and the α-hydroxy-
phosphonate (Ϯ)-6a. 1H NMR: δ = 4.01 (dt, J = 2.3, 7.8 Hz, 1
H) ppm. 13C NMR: δ = 26.1 (d, J = 6.0 Hz), 27.3, 69.7 (d, J =
7.6 Hz), 70.9 (d, J = 7.0 Hz), 71.2 (d, J = 7.2 Hz), 73.7 (d, J =
173.0 Hz) ppm.
Derivative 18:
A
mixture of (–)-phosphaproline {51 mg,
0.338 mmol, [α]2D0 = –49.1 (c = 1.1, 1 m NaOH)}, TMSCl (110 mg,
1.01 mmol, 0.128 mL, 3 equiv.) and dry pyridine (2 mL) was heated
at 60 °C until the substrate had dissolved (10 min.). The solution
was allowed to cool to room temp., (S)-(–)-1-phenylethyl isocyanate
(0.150 g, 1.014 mmol, 0.145 mL, 3 equiv.) was then added, and stir-
ring was continued for 18 h, after which a crystalline precipitate
had formed. Water (0.5 mL) was added and volatile components
were removed under reduced pressure (0.5 mbar, 30 °C). Water
(5 mL) was added to the residue. The mixture was filtered and the
filtrate was applied to Dowex 50, H+ (column: 1 cm i.d.ϫ12 cm,
elution with water, fractions of 25 mL). Product-containing frac-
tions (TLC: iPrOH/H2O/25% NH3 6:3:1; Ce(IV)/ammonium mol-
ybdate) number 1 and 2 were pooled and concentrated under re-
duced pressure. The residue was dissolved in dry MeOH and esteri-
fied with freshly distilled ethereal CH2N2. The solution was concen-
trated under reduced pressure and the residue was flash chromato-
graphed (AcOEt/MeOH 5:1, Rf = 0.68) to give the derivative 18
(083 mg, 76%) as a colourless oil; needles were obtained by al-
lowing the solvent to evaporate slowly from a solution in CH2Cl2/
hexanes; m.p. 107–108 °C. [α]2D0 = –37.69 (c = 0.65, acetone). 1H
NMR: δ = 1.44 (d, J = 6.8 Hz, 3 H), 1.77–1.87 (m, 1 H), 1.92–2.03
(m, 1 H), 2.06–2.22 (m, 2 H), 3.25 (ddd, J = 10.4, 7.6, 3.9 Hz, 1
H), 3.60–3.69 (m, 1 H), 3.73 (d, J = 10.1 Hz, 3 H), 3.74 (d, J =
10.6 Hz, 3 H), 4.07 (dd, J = 8.7, 4.0 Hz, 1 H), 4.89 (≈quint, J =
7.2 Hz, 1 H), 6.43 (br. s, 1 H), 7.16–7.39 (m, 5 H) ppm. 13C NMR:
δ = 23.4, 23.9 (d, J = 1.6 Hz), 28.0 (d, J = 1.4 Hz), 47.2 (d, J =
2.3 Hz), 50.6, 52.7 (d, J = 7.7 Hz), 54.2 (d, J = 166.0 Hz), 54.2 (d,
(S)-(+)-Diisopropyl (4-Bromo-1-mesyloxybutyl)phosphonate [(S)-
(+)-14]: Compound (S)-(+)-6a {1.05 g, 3.31 mmol, [α]2D0 = +15.4 (c
= 1.0, acetone) ee 99%} was transformed into the mesylate (S)-(+)-
69 by the procedure used for the preparation of the mesylate (Ϯ)-
8. Rf = 0.62 (hexanes/EtOAc 1:4). [α]2D0 = +13.9 (c = 1.2, acetone);
yield 93%; viscous oil. 1H NMR: δ = 1.30 (d, J = 5.7 Hz, 3 H),
1.305 (d, J = 6.0 Hz, 3 H), 1.31 (d, J = 6.0 Hz, 6 H), 1.92 (m, 2
H), 2.06 (m, 2 H), 3.15 (s, 3 H), 3.41 (m, 2 H), 4.72 (m, 3 H) ppm.
13C NMR: δ = 23.9 (d, J = 5.3 Hz), 24.0 (d, J = 3.8 Hz, 2 C), 24.2
(d, J = 3.8 Hz), 28.2 (d, J = 12.2 Hz), 29.0 and 32.7, 39.2, 72.3 (d,
J = 6.0 Hz), 72.6 (d, J = 6.9 Hz), 76.4 (d, J = 171.3 Hz) ppm. IR
(NaCl): ν = 2981, 2936, 2877, 1467, 1454, 1414, 1387, 1360, 1255,
˜
1234, 1175, 1143, 1104, 990 cm–1. C11H24BrO6PS (395.25): calcd.
C 33.43, H 6.12; found C 33.14, H 5.90.
(S)-(+)-Diisopropyl (4-Azido-1-mesyloxybutyl)phosphonate [(S)-(+)-
15]: The mesylate (S)-(+)-14 {1.18 g, 2.98 mmol), [α]2D0 = +13.9 (c
= 1.2, acetone), ee 99%} was transformed into the azidomesylate
(S)-(+)-15 by the procedure used for the preparation of the mesyl-
ate (Ϯ)-9. Rf = 0.60 (hexanes/EtOAc 1:4). [α]2D0 = +13.1 (c = 1.0,
acetone); yield 91%; viscous oil. 1H NMR: δ = 1.30 (d, J = 6.0 Hz,
6 H), 1.31 (d, J = 6.5 Hz, 6 H), 1.68 (m, 1 H), 1.76–2.00 (m, 3 H),
3.15 (s), 3.30 (m, 2 H), 4.72 (m, 3 H) ppm. 13C NMR: δ = 23.8 (d, J = 6.9 Hz), 126.0 (2 C), 126.8, 128.4 (2 C), 145.1, 157.7 ppm. 31P
J = 5.3 Hz), 24.0 (d, J = 3.8 Hz, 2 C), 24.2 (d, J = 3.8 Hz), 24.9
(d, J = 11.5 Hz), 27.7, 39.2, 50.6, 72.2 (d, J = 7.6 Hz), 72.6 (d, J =
NMR: δ = 28.9 ppm. IR (Si): ν = 3316, 2957, 1645, 1538, 1375,
˜
1223, 1182, 1030 cm–1. C15H23N2O4P (326.32): calcd. C 55.21, H
7.10, N 8.58; found C 55.34, H 6.95, N 8.55.
6.9 Hz), 76.7 (d, J = 157.6 Hz) ppm. IR (NaCl): ν = 2982, 2937,
˜
Eur. J. Org. Chem. 2011, 1870–1879
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1877

F. Wuggenig, A. Schweifer, K. Mereiter, F. Hammerschmidt
FULL PAPER
Derivative 19: (–)-Phosphaproline (66 mg, 0.437 mmol, was con-
verted into 19 (0.114 g, 80%), as a colourless oil, by use of the
procedure for the preparation of 18 except that (S)-(–)-1-phenyl-
ethyl isocyanate was replaced by the R (+) enantiomer. The crude
derivative was flash chromatographed (AcOEt/EtOH 10:1, Rf =
0.35). Colourless needles were obtained by allowing the solvent to
evaporate slowly from a solution in CH2Cl2/hexanes; m.p. 97–
X-ray Structure Determination of the (–)-Phosphaproline Derivatives
18 and 19: X-ray data were collected with a Bruker Kappa APEX-
2 CCD area detector diffractometer and use of graphite-monochro-
mated Mo-Kα radiation (λ = 0.71073 Å) and 0.5° φ- and ω-scan
frames. Corrections for absorption and λ/2 effects were applied.[23]
After structure solution with the SHELXS97 program and direct
methods, refinement on F2 was carried out with the SHELXL97
program.[24] Non-hydrogen atoms were refined anisotropically. H
atoms were placed in calculated positions and thereafter treated as
riding. The absolute structures could be unambiguously deter-
mined by anomalous dispersion effects and the Flack absolute
structure parameter (FASP). Important crystallographic data are:
1
98 °C. [α]2D0 = –108.71 (c = 1.24, acetone). H NMR: δ = 1.48 (d,
J = 6.5 Hz, 3 H), 1,76–1.86 (m, 1 H), 1.91–2.22 (m, 3 H), 3.29
(ddd, J = 10.6, 7.8, 4.0 Hz, 1 H), 3.62–3.70 (m, 1 H), 3.74 (d, J =
10.6 Hz, 3 H), 3.80 (d, J = 10.4 Hz, 3 H), 4.01 (dd, J = 8.9, 3.8 Hz,
1 H), 4.95 (quint, J = 6.5 Hz, 1 H), 7.17–7.22 (m, 1 H), 6.50 (br. s,
1 H), 7.26–7.36 (m, 4 H) ppm. 13C NMR: δ = 22.9, 23.8, 28.0 (d,
J = 1.4 Hz), 47.2 (d, J = 2.3 Hz), 50.4, 52.7 (d, J = 7.7 Hz), 54.18
(d, J = 6.5 Hz), 54.19 (d, J = 166.0 Hz), 126.1 (2 C), 126.8, 128.4
Compound 18: C15H23N2O4P, Mr = 326.32, colourless prism from
CH2Cl2/hexanes, 0.60ϫ 0.35ϫ 0.30 mm, monoclinic, space group
P21 (no. 14), a = 10.7745(8) Å, b = 7.1982(5) Å, c = 10.8448(8) Å,
(2 C), 145.0, 157.9 ppm. 31P NMR: δ = 28.8 ppm. IR (Si): ν =
˜
β = 92.538(1)°, V = 840.27(11) Å3, Z = 2, μ = 0.182 mm–1, dx
=
3306, 2956, 1636, 1540, 1375, 1223, 1031 cm–1. C15H23N2O4P
(326.32): calcd. C 55.21, H 7.10, N 8.58; found C 55.60, H 6.95, N
8.61.
1.290 gcm–3, T = 100 K. 17050 reflections collected (θmax = 30.0°)
and merged to 4246 independent data (Rint = 0.029); final R indices
(all data): R1 = 0.0447, wR2 = 0.1113, 202 parameters, FASP =
(R)-(–)-Diisopropyl (1-Azido-5-chloropentyl)phosphonate [(R)-(–)- –0.01(9). This solid showed weak superstructure reflections at low
22]: This compound was prepared by General Procedure C from
(S)-(+)-6c {500 mg, 1.74 mmol, [α]2D0 = +14.9 (c = 1.1, acetone)};
Rf = 0.26 (hexanes/acetone 5:1). [α]2D0 = –53.8 (c = 1.0. acetone);
Bragg angles and T = 100 K consistent with a C-centred unit cell
with a-axis doubled and c-axis sextupled. This superstructure was
neglected for this work and only the substructure given above is
reported. The feature essentially affects the phenyl C atoms, which
exhibit anomalously anisotropic displacement ellipsoids in the P21
1
yield 81%; oil. H NMR: δ = 1.29 (d, J = 6.0 Hz, 3 H), 1.30 (d, J
= 6.0 Hz, 9 H), 1.44–1.88 (m, 6 H), 3.26 (ddd, J = 3.0, 10.5,
12.0 Hz, 1 H), 3.48 (t, J = 6.5 Hz, 2 H), 4.72 (m, 2 H) ppm. 13C substructure.
NMR: δ = 24.0 (d, J = 4.6 Hz, 2 C) 24.11 (d, J = 3.8 Hz, 2 C),
Compound 19: C15H23N2O4P, Mr = 326.32, colourless block from
24.14 (d, J = 13.8 Hz), 27.9 and 31.9, 44.4, 57.7 (d, J = 157.6 Hz),
CH2Cl2/hexanes, 0.49ϫ 0.44ϫ 0.23 mm, orthorhombic, space
group P212121 (no. 19), a = 6.9309(6) Å, b = 10.5631(9) Å, c =
71.75 and 71.82 (d, J = 6.9 Hz) ppm. IR (NaCl): ν = 2981, 2936,
˜
2872, 2103, 1454, 1386, 1376, 1353, 1254, 1178, 1142, 1106,
989 cm–1. C11H23ClN3O3P (318.32): calcd. C 42.38, H 7.44, N
13.48; found C 42.68, H 7.23, N 13.53.
22.774(2) Å, V = 1667.3(2) Å3, Z = 4, μ = 0.184 mm–1, dx
=
1.300 gcm–3, T = 100 K. 36029 reflections collected (θmax = 30.0°)
and merged to 4865 independent data (Rint = 0.023); final R indices
(all data): R1 = 0.0238, wR2 = 0.0644, 206 parameters, FASP =
0.01(4).
(R)-(–)-(Piperidin-2-yl)phosphonic Acid [(R)-Phosphapipecolic Acid,
(R)-(–)-4]: A solution of (R)-(–)-22 {408 mg, 1.309 mmol, [α]2D0
=
–53.8, (c = 1.0, acetone)}, Ph3P (412 mg, 1.57 mmol) and dry
CH3CN (18 mL) was stirred under argon for 1 h at 40 °C and for
24 h at reflux. Evaporation of the solvent yielded the cyclic inter-
mediate (R)-24. [Assignable signals of the NMR spectra of the
crude product are given: 1H NMR (CD3OD): δ = 0.94, 1.12 and
1.30 [d, J = 6.0, 3 H, OCH(CH3)2], 1.25 [d, J = 6.5, 3 H,
OCH(CH3)2], 3.28 (m, 2 H, CH2N), 3.90 (m, 1 H, CHP), 4.39 and
4.70 [m, 1 H, OCH(CH3)2] ppm. 13C NMR (CD3OD): δ = 24.5 and
24.9 (d, J = 3.8), 24.7 (d, J = 4.6), 24.8 (d, J = 5.3), 20.6 and 25.0,
26.7 (t, J = 3.1), 47.8, 53.01 (d, J = 156.8), 74.2 and 74.8 (d, J =
7.6) ppm.] The crude product was heated with aq. NaOH (15 mL,
0.25 m) for 5 h at 100 °C. The solvent was evaporated under re-
duced pressure and the residue was taken up in HCl (6 m, 15 mL),
which was then heated at reflux for 24 h. After evaporation of the
solvent under reduced pressure and drying (KOH) of the residue
in a vacuum desiccator, the crude product was purified by ion-
exchange chromatography on Dowex 50, H+ (150 mL) with water
as eluent. Ninhydrin-positive fractions were pooled, concentrated
under reduced pressure and finally lyophilized; m.p. 254–257 °C
(dec.) (ref.[12] 230 °C). [α]2D0 = –4.3 (c = 0.7, 1 m NaOH), {ref. [α]2D0
= –4.5 (c = 1.0, 1 m NaOH), ee Ͼ 95%[12]}; yield 55%; crystalline
CCDC-780395 (for 18) and -780396 (for 19) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgments
We gratefully acknowledge financial support by the Austrian Sci-
ence Fund (FWF) (project no. P10566-CHE). We thank Boehringer
Mannheim (Germany) for generous gifts of protease Chira-
zyme® P-2 and Amano Enzyme Limited (U.K.) for lipase AP6.
[1] For reviews see: a) V. P. Kukhar, H. R. Hudson, Aminophos-
phonic and Aminophosphinic Acids – Chemistry and Biological
Activity, John Wiley, Chichester, 2000; b) V. P. Kukhar, V. A.
Soloshonok, V. A. Solodenko, Phosphorus Sulfur Silicon Relat.
Elem. 1994, 92, 239–264.
[2] For a review see: P. Kafarski, B. Lejczak, Phosphorus Sulfur
Silicon Relat. Elem. 1991, 63, 193–215.
[3] a) For a review, see: P. Kafarski, B. Lejczak, Curr. Med.
Chem. – Anti-Cancer Agents 2001, 1, 301–312; F. R. Atherton,
M. J. Hall, C. H. Hassall, R. W. Lambert, P. S. Ringrose, Anti-
microb. Agents Chemother. 1979, 15, 677–683; K. Kase, M. Ya-
mamoto, T. Koguchi, R. Okachi, M. Kasai, K. Shirahata, I:
Kawamoto, K. Shuto, A. Karasawa, Eur. Pat. Appl. EP 61172,
1982 (Chem. Abstr. 1983, 98, 107793); L. Cheng, C. A. Good-
win, M. F. Scully, V. V. Kakkar, G. Claeson, Tetrahedron Lett.
1991, 32, 7333–7336; J. Bird, R. C. De Mello, G. P. Harper,
D. J. Hunter, E. H. Karran, R. E. Markwell, A. J. Miles-Wil-
1
solid. H NMR (D2O): δ = 1.46 and 2.04 (m, 1 H), 1.62 and 1.84
(m, 2 H), 2.95 (dt, J = 3.0, 12.8 Hz, 1 H), 3.13 (dt, J = 2.7, 12.9 Hz,
1 H), 3.36 (m, 1 H) ppm. 13C NMR (D2O): δ = 22.0 (d, J =
11.5 Hz), 22.1, 24.3 (d, J = 2.3 Hz), 46.2 (d, J = 6.9 Hz), 54.7 (d,
J = 143.0 Hz) ppm. 31P NMR (D O): δ = 12.8 ppm. IR (Nujol): ν
˜
2
= 3147, 2523, 1626, 1405, 1352, 1309, 1237, 1228, 1164, 1133, 1069,
1026, 982 cm–1. C5H12NO3P (165.13): calcd. C 36.37, H 7.32, N
8.48; found C 36.15, H 7.09, N 8.35.
1878
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1870–1879

Chemoenzymatic Synthesis of Phosphonic Acids
liams, S. S. Rahman, R. W. Ward, J. Med. Chem. 1994, 37, 158–
169; S. De Lombaert, M. D. Erion, J. Tan, L. Blanchard, L.
El-Chehabi, R. D. Ghai, Y. Sakane, C. Berry, A. J. Trapani, J.
Med. Chem. 1994, 37, 498–511; Y. Song, D. Niederer, P. M.
Lane-Bell, L. K. P. Lam, S. Crawley, M. M. Palcic, M. A. Pick-
ard, D. L. Pruess, J. C. Vederas, J. Org. Chem. 1994, 59, 5784–
5793; A. I. Vovk, I. M. Mischenko, V. Y. Tanchuk, G. A. Kach-
kovskii, S. Y. Sheiko, O. I. Kolodyazhnyi, V. P. Kukhar, Bioorg.
Med. Chem. Lett. 2008, 18, 4620–4623.
L. Cui, B. Yang, P. J. Steel, J. Org. Chem. 1999, 64, 1979–1985;
d) P. Dinér, M. Amedjkouh, Org. Biomol. Chem. 2006, 4, 2091–
2096.
[12] C. Maury, Q. Wang, T. Gharbaoui, M. Chiadmi, A. Tomas, J.
Royer, H.-P. Husson, Tetrahedron 1997, 53, 3627–3636.
[13] P. Wieczorek, B. Lejczak, M. Kaczanowska, P. Kafarski, Pestic.
Sci. 1990, 30, 43–57.
[14] a) F. Hammerschmidt, F. Wuggenig, Tetrahedron: Asymmetry
1999, 10, 1709–1721, and references cited therein; b) M.
Drescher, Y.-F. Li, F. Hammerschmidt, Tetrahedron 1995, 51,
4933–4946.
[15] a) F. Hammerschmidt, W. Lindner, F. Wuggenig, E. Zarbl, Tet-
rahedron: Asymmetry 2000, 11, 2955–2964; b) Y.-F. Li, F. Ham-
merschmidt, Tetrahedron: Asymmetry 1993, 4, 109–120.
[16] F. Hammerschmidt, F. Wuggenig, Phosphorus Sulfur Silicon
Relat. Elem. 1998, 141, 231–238.
[17] M. Drescher, F. Hammerschmidt, H. Kählig, Synthesis 1995,
1267–1272.
[4] For reviews, see: a) L. Poppe, J. Rétey, Angew. Chem. 2005,
117, 3734; Angew. Chem. Int. Ed. 2005, 44, 3668–3688; b) J. E.
Franz, M. K. Mao, J. A. Sikorski, Glyphosate: A Unique Global
Herbicide, ACS Monograph 189, American Chemical Society,
Washington, DC, 1997.
[5] P. Kafarski, J. Zon´, in: Aminophosphonic and Aminophosphinic
Acids – Chemistry and Biological Activity (Eds.: V. P. Kukhar,
H. R. Hudson), John Wiley & Sons, Chichester, 2000, pp. 33–
74.
[6] For reviews, see: a) B. Dhawan, D. Redmore, Phosphorus Sulfur
Relat. Elem. 1987, 32, 119–144; b) M. Ordóñez, H. Rojas-Cab-
rera, C. Cativiela, Tetrahedron 2009, 65, 17–49.
[18] F. Hammerschmidt, Y.-F. Li, Tetrahedron 1994, 50, 10253–
10264.
[19] For a review, see: R. A. Casero Jr., L. J. Marton, Nature Rev.
Drug Discovery 2007, 6, 373–390.
[20] E. Öhler, S. Kotzinger, Liebigs Ann. Chem. 1993, 269–280.
[21] E. Zarbl, M. Lämmerhofer, F. Hammerschmidt, F. Wuggenig,
M. Hanbauer, N. M. Maier, L. Sajovic, W. Lindner, Analytica
Chim. Acta 2000, 404, 169–177.
[7] E. K. Baylis, C. D. Campbell, J. G. Dingwall, J. Chem. Soc.
Perkin Trans. 1 1984, 2845–2853.
[8] E. W. Petrillo Jr., E. R. Spitzmiller, Tetrahedron Lett. 1979, 51,
4929–4930.
[9] a) E. K. Baylis, C. D. Campbell, J. G. Dingwall, J. Chem. Soc.
Perkin Trans. 1 1984, 2845–2853; b) G. Sosnovsky, J. Lukszo,
E. Gravela, M. F. Zuretti, J. Med. Chem. 1985, 28, 1350–1354.
[10] V. A. Solodenko, V. P. Kukhar, Zh. Obshch. Khim. 1989, 59,
2684–2688 (CAN 113:24475, AN 1990: 424475).
[11] a) M. Kaname, Y. Arakawa, S. Yoshifuji, Tetrahedron Lett.
2001, 42, 2713–2716; b) B. Lejczak, P. Kafarski, P. Mastalerz,
J. Chromatography. 1985, 324, 455–461; c) A. R. Katritzky, X.-
[22] W. Mikenda, Vibrational Spectrosc. 1992, 3, 327–330.
[23] Bruker programs: APEX2, version 2009.9-0; SAINT, version
7.68 A; SADABS, version 2008/1; SHELXTL, version 2008/4,
Bruker AXS Inc., Madison, WI, 2009.
[24] G. M. Sheldrick, Acta Crystallogr., Sect. A 2008, 64, 112–122.
Received: November 9, 2010
Published Online: February 21, 2011
Eur. J. Org. Chem. 2011, 1870–1879
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1879