Enzymes in organic chemistry. Part 9: Chemo-enzymatic synthesis of phosphonic acid analogues of L-valine, L-leucine, L-isoleucine, L-methionine and L-α-aminobutyric acid of high enantiomeric excess

Article abstract of DOI:10.1016/S0957-4166(99)00152-4

Diisopropyl α-chloroacetoxyphosphonates derived from propanal, isobutanl, 3-methylmercaptopropanal, 3-methylbutanal and (S)-2-methylbutanal were resolved by enzyme-catalysed hydrolysis. Lipases preferentially hydrolysed the (S)-esters and protease Chirazyme P-2 the (R)-esters. Replacing the isopropyl groups by t-butyl groups reduced the reaction rate; replacing them by a 2,2-dimethylpropane-1,3-diyl group increased the reaction rate. (S)-α-Hydroxyphosphonates (ee 92-99%), obtained with the protease except one, were transformed into phosphonic acid analogues of L-valine, L- leucine, L-isoleucine, L-methionine and L-α-aminobutyric acid. Their enantiomeric purity was determined by HPLC on a chiral stationary phase after derivatisation at nitrogen.

Full text of DOI:10.1016/S0957-4166(99)00152-4

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1709–1721
1
Enzymes in organic chemistry. Part 9: Chemo-enzymatic
synthesis of phosphonic acid analogues of L-valine, L-leucine,
L-isoleucine, L-methionine and L-α-aminobutyric acid of high
enantiomeric excess
∗
Friedrich Hammerschmidt and Frank Wuggenig
Institut für Organische Chemie der Universität Wien, Währingerstraße 38, A-1090 Wien, Austria
Received 18 March 1999; accepted 19 April 1999
Abstract
Diisopropyl α-chloroacetoxyphosphonates derived from propanal, isobutanal, 3-methylmercaptopropanal, 3-
methylbutanal and (S)-2-methylbutanal were resolved by enzyme-catalysed hydrolysis. Lipases preferentially
®
hydrolysed the (S)-esters and protease Chirazyme P-2 the (R)-esters. Replacing the isopropyl groups by t-butyl
groups reduced the reaction rate; replacing them by a 2,2-dimethylpropane-1,3-diyl group increased the reaction
rate. (S)-α-Hydroxyphosphonates (ee 92–99%), obtained with the protease except one, were transformed into
phosphonic acid analogues of L-valine, L-leucine, L-isoleucine, L-methionine and L-α-aminobutyric acid. Their
enantiomeric purity was determined by HPLC on a chiral stationary phase after derivatisation at nitrogen. © 1999
Elsevier Science Ltd. All rights reserved.
1. Introduction
Certain α-amino acids are important intermediates of metabolism and building blocks of biopolymers.
The synthesis of phosphonic acid analogues of proteinogenic and non-proteinogenic amino acids — the
phosphonic group is considered to be an isosteric replacement of the carboxyl group — has gained
momentum during recent years. α-Aminophosphonic acids themselves and oligopeptides containing
2
them display various interesting biological activities. As the absolute configuration at the α-position of
the substituted phosphonic acids influences their biological properties, a number of strategies have been
3
developed for the preparation of chiral, non-racemic α-aminophosphonic acids. The more prominent
3
4
5
synthetic methods include chemical and enzymatic resolution, enantioselective addition of phosphites
6
7
8
to achiral imines, addition of phosphites to homochiral imines, acyliminium ions and nitrones,
∗
Corresponding author. Fax: 0043-1-31367-2280; e-mail: frha@felix.orc.univie.ac.at
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00152-4

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F. Hammerschmidt, F. Wuggenig / Tetrahedron: Asymmetry 10 (1999) 1709–1721
9
,10
alkylation of α-lithiated homochiral enamines
derived from α-aminomethylphosphonic acid, and
11,12
manipulation
available for the synthesis of chiral, non-racemic α-hydroxyphosphonates.
We have pioneered lipase-catalysed kinetic resolution of α-acyloxyphosphonates to produce op-
of α-hydroxyphosphonates. The latter approach benefits from attractive methods
13
14
tically active α-hydroxyphosphonates. Five of them were transformed into the α-amino- and α-
aminooxyphosphonic acids. Recently, we found that proteases mediate the preferential hydrolysis of
R)-α-chloroacetoxyphosphonates, which is in contrast to the enantioselectivity of the lipases tested
before. The enantiomeric excesses with Chirazyme P-2, an alkaline endoprotease of serine type, for
various substrates, notably with branched alkyl groups, were significantly better than those with lipase
AP 6 (from Aspergillus niger).
15
(
1
®
These results prompted us to prepare phosphonic acid analogues of L-valine, L-leucine, L-isoleucine,
L-methionine, and L-α-aminobutyric acid of high enantiomeric excesses chemoenzymatically. These α-
aminophosphonic acids have nonpolar side chains and biological effects. Phosphonic acid analogues
of methionine and leucine were used as C-termini of pentapeptides which were tested as enkephalin
16
analogues for analgesic acitivity. Phosphonic acid analogues of (ꢀ)-valine, (ꢀ)-α-aminobutyric acid
and L- and D-leucine were studied as inhibitors of leucine aminopeptidase from porcine kidney and had
17
K (µM) of 3.6, 1.2, 0.23 and 220, respectively. Not surprisingly, L-phosphaleucine is about 1000 times
i
as effective as D-phosphaleucine. When a series of five α-aminophosphonic acids was tested towards
possible use as seed dressing agents, the α-aminopropylphosphonic acid was found to be the most
18
promising. Chiral, nonracemic phosphaisoleucine has not yet been prepared. Furthermore, the t-butyl
and 2,2-dimethylpropane-1,3-diyl groups were studied as protecting groups at phosphorus.
2. Results and discussion
The α-chloroacetoxyphosphonates (ꢀ)-2a–f and (1RS,2S)-2g used as substrates for the enzyme-
catalysed resolutions, were prepared by esterification of the corresponding α-hydroxyphosphonates with
19
chloroacetic anhydride/pyridine (Scheme 1).
Scheme 1. Chloroacetylation of α-hydroxyphosphonates
0 21 21
2
Racemic phosphonates (ꢀ)-1a–c, f
and (ꢀ)-2a–c
were synthesised by the Abramov reaction from 3-
methylmercaptopropional and diisopropyl and di-t-butyl phosphite, respectively. A different approach
are known compounds. α-
2
0 12
Hydroxyphosphonates (ꢀ)-1d, e

F. Hammerschmidt, F. Wuggenig / Tetrahedron: Asymmetry 10 (1999) 1709–1721
1711
was selected for α-hydroxyphosphonate (1RS,2S)-1g (Scheme 2). Diisopropyl trimethylsilyl phosphite
was added to base-labile, crude (S)-2-methylbutanal prepared by oxidation of (S)-2-methylbutanol
22
with TEMPO/NaOCl. The optically active, commercially available alcohol was assessed for its
1
enantiomeric excess by H NMR spectroscopy of its (R)-MTPA ester and that of the racemic alcohol.
A sample from Aldrich had an ee of only 94%. The methylene hydrogens of the CH O group of the
2
(S)-alcohol give a doublet (δ=4.15 ppm, J=5.9 Hz), and the corresponding hydrogens of the (R)-alcohol
an AB system coupling with 2-H (δ=4.15 ppm, JAB=10.8 Hz, J=5.9, 6.4 Hz). The sample obtained
from Fluka did not contain a detectable amount of the (R)-alcohol (ee >99%) and was used for the
preparation of (S)-2-methylbutanal. The intermediate α-silyloxyphosphonate was not isolated, but
deprotected immediately to give α-hydroxyphosphonates (1RS,2S)-1g as a mixture of two diastereomers
in equal amounts which could not be separated by flash chromatography or HPLC (signals were only
partially resolved). The diastereomeric α-chloroacetoxyphosphonates (1RS,2S)-2g behaved similarly
(
one signal by HPLC). The diastereomeric ratios of samples of (1RS,2S)-1g and 2g or mixtures thereof
1
as obtained by enzymatic hydrolysis could be determined easily by H NMR spectroscopy, as the
signals of the hydrogens at C-1 were well separated. To detect a possible partial racemisation of (S)-2-
methylbutanal, occurring during its preparation or reaction with phosphite, the mixture of diasteromeric
α-hydroxyphosphonates (1RS,2S)-1g and its racemate, prepared from racemic 2-methylbutanol, were
31
derivatised with (S)-MTPACl. The P NMR spectrum of the Mosher ester of (1RS,2S)-1g shows
two singlets, at 18.06 and 17.21 ppm, respectively. The signal at lower field was assigned to the
2
3
Mosher ester of the α-hydroxyphosphonate with (S)-configuration at C-1 on the basis of precedence.
31
The P NMR spectrum of the Mosher ester of all four stereoisomers of (1RS,2RS)-1g shows four
singlets of equal intensity; the ones at 18.06 and 17.21 ppm, and two additional ones at 17.71 and
1
7.60 ppm, respectively. These are assigned to the Mosher esters of the α-hydroxyphosphonates with
(R)-configuration at C-2 and (S) and (R) at C-1, respectively. On the basis of this NMR spectroscopic
investigation, we can exclude a partial racemisation of (S)-2-methylbutanal. Consequently, the two
diasteromeric α-hydroxyphosphonates (1RS,2S)-1g are enantiomerically pure (ee >99%).
Scheme 2. Preparation of α-hydroxyphosphonate (1RS,2S)-1g
In preliminary experiments to find the best enzymes for the different substrates, the hydrolyses of
the chloroacetates were carried out on a 1 mmol scale in a biphasic system to a conversion of about
4
5%, using a protease and lipases. The results as obtained by methods reported previously are given
20
in Table 1. Lipase SP 524 (lipase from a selected fungus which was expressed in Aspergillus oryzae
as a host organism, from Novo Nordisk) which was found to be best suited of all enzymes tested for
the kinetic resolution of racemic diisopropyl α-acetoxyethylphosphonate, was also very effective for
15
substrate (ꢀ)-2a (entry 1). Merely 1.5 mg of enzyme were sufficient to give a conversion of 49%
in 1 h. The α-hydroxyphosphonate formed had (S)-configuration and an ee of 96%. The protease
®
Chirazyme P-2 preferentially hydrolysed the (R)-enantiomer of α-chloroacetoxyphosphonate (ꢀ)-2a
furnishing α-hydroxyphosphonate (−)-1a with an enantiomeric excess of 80% (entry 2). The results of
®
the Chirazyme P-2 catalysed resolution on an analytical scale of substrates (ꢀ)-2b and c have already
been published in the preceding paper. α-Hydroxyphosphonates (R)-(−)-1b and c were obtained with
enantiomeric excesses of 85 and 96%, respectively. α-Chloroacetoxyphosphonate (ꢀ)-1d needed to
prepare the starting material for the synthesis of phosphamethionine was tested with lipase AP 6 (lipase

1712
F. Hammerschmidt, F. Wuggenig / Tetrahedron: Asymmetry 10 (1999) 1709–1721
®
from Aspergillus niger) and protease Chirazyme P-2 (entries 3 and 4). The α-hydroxyphosphonates
isolated had virtually the same enantiomeric excesses (77 and 75%), but opposite absolute configurations.
The hydrolysis of α-chloroacetoxyphosphonates (1RS,2S)-2g produced α-hydroxyphosphonate (1R,2S)-
1g diastereoselectively (de 84%, entries 8 and 9). The additional stereogenic centre seems to influence
only the reaction rate, but not the selectivity at C-1. The only difference between the two experiments is
the absence of organic solvent during hydrolysis in entry 9, which caused a fourfold increase in reaction
rate. We have not tested whether this effect is a general trend for other substrates as well.
2
In all the substrates studied so far, the protecting group R at phosphorus was isopropyl which proved
very successful for enantioselective hydrolysis, transformations at C-1 and removal in the past. To
evaluate the influence of other protecting groups we have also used, in two cases, the more bulky t-
2
butyl and the less bulky 2,2-dimethylpropane-1,3-diyl group for both R over the isopropyl group. The
®
reaction rate for di-t-butyl phosphonate (ꢀ)-2e was decreased relative to (ꢀ)-2d for Chirazyme P-2
and lipase AP 6 by factors of roughly 10 and 20, respectively (entries 3 to 6). The ee was unchanged
(75%) in the former case and decreased significantly (55 versus 75%) in the latter (entries 4 and 6).
Furthermore, the substitution of the hydroxyl group for azide by the Mitsunobu reaction did not proceed
as cleanly with 1e as with diisopropyl phosphonate 1d as will be shown later. These drawbacks do
not outweigh the anticipated easier removal of the t-butyl over the isopropyl group. The use of this
protecting group was, therefore, abandoned. Replacing the two isopropyl substituents of (ꢀ)-2b by a
®
2
2
,2-dimethylpropane-1,3-diyl group gives (ꢀ)-2f. This chloroacetate was hydrolysed by Chirazyme P-
20
by a factor of about 30 times faster than diisopropyl chloroacetoxyphosphonate (ꢀ)-2b (entry 7).
Concomitantly, the selectivity changed from (R) to (S), assuming that the principles underlying the
determination of the absolute configuration by NMR spectroscopy of the Mosher ester are not affected by
23
31
the cyclic structure. The shift difference in the P NMR spectrum is only 0.044 ppm (δ 12.59/12.55)
as compared to 0.15 ppm for the diastereomeric (R)-MTPA-esters of (ꢀ)-2b, which is already very
20
low. Chloroacetate (ꢀ)-2f was also hydrolysed by various lipases, but the enantioselectivity was low
as judged from the consumption of base as function of time. Lipase AP 6 is a very efficient catalyst for
the hydrolysis of different substrates, but did not seem to show any selectivity in this case. The extreme
stability of the 2,2-dimethylpropane-1,3-diyl group towards removal (see later) in combination with its
negative influence on the enantioselectivity did not justify more experiments.
Finally, α-chloroacetoxyphosphonates (ꢀ)-2a–d and (1RS,2S)-2g were resolved enzymatically on a
®
preparative scale (4–6 mmol), using lipase SP 524 for (ꢀ)-2a and protease Chirazyme P-2 for the
others (entries 10–14). As we planned to prepare phosphonic acid analogues of L-amino acids, the
starting α-hydroxyphosphonates had to have (S)-configuration. Because the enantiomeric excess of an
enzymatic resolution depends on the conversion, the reactions were stopped at appropriate times. α-
Hydroxyphosphonate (S)-(+)-1a obtained with lipase SP 524 at a conversion of 44% had an enantiomeric
excess of 97%. The kinetic resolutions with protease Chirazyme® P-2 were stopped at conversions
between 56 and 64% to get the (S)-esters of high enantiomeric excess, which were hydrolysed chemically
by NEt in dry MeOH to give the corresponding (S)-α-hydroxyphosphonates [ee 92–99% for 1b–d,
3
1
de 98% for (1S,2S)-1g]. The de of chloroacetoxyphosphonate (1S,2S)-2g as determined by H NMR
spectroscopy was 99.5%, the de of the corresponding α-hydroxyphosphonates (1S,2S)-1g was 97.8%.
We attribute the very small decrease in diastereomeric excess to a small amount of racemisation, possibly
during chemical ester cleavage with NEt in methanol.
3
The transformation of α-hydroxyphosphonates (S)-1a–d and (1S,2S)-1g into the aminophosphonic
acids was straightforward (Scheme 3). The hydroxyl group was replaced by azide with inversion of
1
4
configuration using Ph P/diethyl azodicarboxylate (DEAD)/HN (Mitsunobu reaction). Azides 4 were
3
3
14
reduced catalytically (Pd/C/H ; 5 h) in the presence of hydrochloric acid, except sulfur containing azide
2

F. Hammerschmidt, F. Wuggenig / Tetrahedron: Asymmetry 10 (1999) 1709–1721
1713

1714
F. Hammerschmidt, F. Wuggenig / Tetrahedron: Asymmetry 10 (1999) 1709–1721
(
R)-4d, which was reduced with triphenylphosphine (Staudinger reaction).24 The crude reaction products
were deprotected with refluxing 6 N HCl (5 h). Under these conditions the iminophosphorane derived
from (R)-4d was split into amine and triphenylphosphine oxide as well. The α-aminophosphonic acid
hydrochlorides, except the one of phosphamethionine, were purified by ion-exchange chromatography
+
on Dowex 50, H with water as eluent to give free aminophosphonic acids (R)-5a–c and (1R,2S)-5e.
Crystalline phosphamethionine (R)-5d was obtained by treating a solution of the hydrochloride in ethanol
24
with propylene oxide.
Scheme 3. Transformation of α-hydroxyphosphonates into α-aminophosphonic acids
Additionally, two more α-hydroxyphosphonates with different protecting groups at phosphorus were
subjected to the Mitsunobu reaction. The reaction rate of di-t-butyl phosphonate (ꢀ)-1e was very low
(
Scheme 4) and the unsaturated phosphonate 7 was formed as a side product25 along with the desired
azide (ꢀ)-6. The two bulky t-butyl groups shield C-1 against nucleophilic attack by azide and thus
elimination leading to 7 becomes an alternative pathway.
Scheme 4. Mitsunobu reaction of α-hydroxyphosphonate (ꢀ)-1e
Hoping that the chloroacetate of (ꢀ)-1f could be resolved by hydrolases, a preliminary experiment was
carried out with racemic material to determine the stability of the protecting group (Scheme 5). Thus,
12
α-hydroxyphosphonate (ꢀ)-1f was smoothly transformed by the method of Gajda into crystalline azide
(
ꢀ)-8 which was reduced catalytically and then refluxed in 6 N HCl. Samples were withdrawn at intervals
1
of 24 to 48 h, concentrated in vacuo and investigated as solutions in D O by H NMR spectroscopy. The
2
protecting group at phosphorus was extremely resistant towards hot hydrochloric acid and was removed
only after 8 days, which disqualifies it for further application. Workup and purification afforded racemic
phosphavaline (ꢀ)-5b in 69% yield.
The substitution of the hydroxyl group by azide in the Mitsunobu reaction is an S 2 process and
N
the ee (de) of the α-aminophosphonic acids (R)-4a–d [(1R,2S)-5e] should be the same as that of the
starting α-hydroxyphosphonates. Nevertheless, we wanted to prove it by an independent method, because

F. Hammerschmidt, F. Wuggenig / Tetrahedron: Asymmetry 10 (1999) 1709–1721
1715
Scheme 5. Transformation of α-hydroxyphosphonate (ꢀ)-1f into α-aminophosphonic acid (ꢀ)-5b
in the case of the 1-aminopropylphosphonic acid (R)-5a the specific optical rotation of our product
2
0
20
(
[α]5 =−17.8 (0.9, 1 N NaOH) was lower than that reported in the literature10 ([α] =−21.6, 1.0, 1 N
7
8
5
7
8
NaOH, ee 98%). The α-aminophosphonic acids (R)-5a–c were derivatised at nitrogen and investigated by
26
HPLC on a chiral stationary phase. The enantiomeric excesses were found to be 98% for (R)-5a (ee of
starting α-hydroxyphosphonate 97%), 92% for (R)-5b (92%), and 99% (R)-5c (99%), respectively. The
transformation of chiral, nonracemic α-hydroxyphosphonates into α-aminophosphonic acids via azides
prepared by the Mitsunobu reaction proceeds stereospecifically with inversion of configuration without
neighbouring group participation of the P_O group.
3. Conclusions
We have demonstrated that racemic (and one diastereomeric mixture) diisopropyl α-
chloroacetoxyphosphonates can be resolved on a preparative scale using protease Chirazyme®
P-2 to furnish (R)-α-hydroxyphosphonates and (S)-α-chloroacetoxyphosphonates of high enantiomeric
purity (diastereomeric purity). The latter are hydrolysed chemically and transformed into phosphonic
acid analogues of L-valine, L-leucine, L-isoleucine, L-methionine and L-α-aminobutyric acid of the
same ee as the starting material, as proven for three of them by HPLC on a chiral stationary phase.
4. Experimental
4.1. General
All starting materials and enzymes were obtained from commercial suppliers and were generally used
1
13
without further purification. H and C NMR (J modulated) spectra were recorded in CDCl , unless
3
otherwise given, using tetramethylsilane as internal standard on a Bruker AM 400 WB spectrometer
31
at 400.13 and 100.61 MHz, respectively. P NMR spectra were recorded on the same spectrometer at
31
1
61.97 MHz using H PO (85%) as external standard. In order to get undistorted P signal intensities
3 4
for an accurate integration, adequate 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 hertz.
IR spectra were run on a Perkin–Elmer 1600 FT-IR spectrometer; liquid samples were measured as
films between NaCl plates or on a silicon disc,27 solids as Nujol mulls between NaCl plates. Optical
rotations were measured at 20°C on a Perkin–Elmer 341 polarimeter in a 1 dm cell. TLC was carried

1716
F. Hammerschmidt, F. Wuggenig / Tetrahedron: Asymmetry 10 (1999) 1709–1721
out on 0.25 mm thick Merck plates, silica gel 60 F254. Flash chromatography was performed with Merck
silica gel 60 (230–400 mesh). Spots were visualised by dipping the plate into a solution of 24 g of
(
NH ) Mo O ·4H O and 1 g of Ce(SO ) ·4H O in 500 ml of 10% H SO in water, followed by heating
4
6
7
24
2
4 2
2
2
4
with a hot gun. A Metrohm 702 SM Titrino instrument was used as an autotitrator. (S)-(+)-α-Methoxy-
2
0
α-(trifluoromethyl)phenylacetyl chloride {JPS Chimie; [α] =+136.5 (c 5.2, CCl ), ee >99.5%} was
D
4
used for derivatisation of α-hydroxyphosphonates. Enzymes [lyophilised preparations of lipases SP
®
5
24 and AP 6 and protease Chirazyme P-2 or a solution of it (5 ml of solution contains 600 mg of
lyophilisate with a protein content of 80%)] were stored at +4°C and used as supplied. Abbreviations
used: MC=methylene chloride; EA=ethyl acetate, PE=petroleum ether, AC=acetone, ee=enantiomeric
excess.
4.2. (ꢀ)-Diisopropyl 1-hydroxy-3-(methylthio)propylphosphonate (ꢀ)-1d
Yield 89%; oil; R =0.13 (MC:EA, 5:3); (R)-MTPA-(S)-1d/(R)-MTPA-(R)-1d: 31P NMR: δ
f
−1
1
9
(
2
7.34/16.79; IR (NaCl): ν
cm : 3288, 2978, 2920, 1439, 1386, 1375, 1224, 1178, 1142, 1106, 1075,
max
1
90; H NMR: δ 4.68 (two oct overlap to non, J=6.4, 2H, OCH), 3.92 (dt, J=4.7, 9.2, 1H, CHP), 3.40
br.s, 1H, OH), 2.65 (AB system, JAB=13.1, J=2×6.5, 2×7.6, 2H, SCH ), 2.04 (s, 3H, SMe), 1.91 (m,
2
13
H, CH ), 1.28 (d, J=6.4, 3H, Me), 1.26 (d, J=6.4, 9H, Me); C NMR: δ 71.32 (d, J=7.2), 71.14 (d,
2
J=7.3), 66.55 (d, J=163.5), 30.64 (d, J=1.5), 30.38 (d, J=15.4), 24.11 (d, J=3.2), 24.07 (d, J=3.2), 23.95
(
d, J=4.7, 2C), 15.25. Anal. calcd for C H O PS: C, 44.43; H, 8.58. Found: C, 44.64; H, 8.58.
10 23 4
4.3. (ꢀ)-Di-t-butyl 1-hydroxy-3-methylthiopropylphosphonate (ꢀ)-1e
Yield 48%; colourless crystals; R =0.39 (PE:EA, 1:2); mp 68–70°C (PE); (R)-MTPA-(S)-1e/(R)-
f
3
1
−1
MTPA-(R)-1e: P NMR: δ 10.98/10.59; IR (Si) ν
cm : 3299, 2979, 2919, 1435, 1476, 1394, 1370,
max
1
1
(
2
3
258, 1230, 1168, 1078, 1039, 990; H NMR: δ 3.82 (dt, J=3.4, 9.8, CHP), 3.40 (br.s, 1H, OH), 2.67
AB system, J =13.3, J=5.4, 3×7.9, 2H, SCH ), 2.07 (s, SMe), 1.93 (m, 2H, CH ), 1.48 and 1.47 (2s,
AB
2
2
13
×9H, t-Bu); C NMR: δ 82.78 and 82.74 (d, J=9.1), 67.88 (d, J=166.6), 31.11, 30.61 (d, J=13.8),
0.52 (d, J=4.0, 6C), 15.29. Anal. calcd for C H O PS: C, 48.30; H, 9.12. Found: C, 48.52; H, 9.01.
12
27
4
4.4. (1RS,2S)-Diisopropyl 1-hydroxy-2-methylbutylphosphonate (1RS,2S)-1g
2
0
(
S)-(−)-2-methylbutanol (1.76 g, 20 mmol) {[α] =−6.3ꢀ0.3 (10.0, ethanol) for product from Fluka;
D
2
0
22
[
α] =−5.8 (neat) for product from Aldrich} was oxidised by a known procedure. Diisopropyl
D
trimethylsilyl phosphite (4.75 g, 20 mmol) was added to the dried solution of the aldehyde in MC. The
solution was stirred for 5 h under argon at room temperature. Then 4 ml of methanol and 4 drops of
concentrated HCl were added and stirring was continued for 2 h. The organic phase was extracted with
saturated NaHCO , dried with MgSO and concentrated in vacuo. The crude product was purified by
3
4
flash chromatography.
−1
Yield 51%; viscous oil; R =0.19 (PE:EE, 2:1); IR (NaCl) ν
386, 1187, 1178, 1107, 987; H NMR [(1R,2S)-1g in brackets were distinguishable]: δ 4.72 (m, 4H,
cm : 3301, 2977, 2949, 2935, 1466,
max
f
1
1
OCH), 3.72 (dd, J=3.8, 8.3, 1H, CHP), [3.56 (t, J=6.3, 1H, CHP)], 2.85 (s, 1H, OH), 2.75 (s, 1H, OH),
1.76 (m, 3H), [1.51 (m, 1H)], 1.30 (d, J=5.9, 12H, CH ), 1.298 (d, J=6.4, 12H, CH ), 1.20–1.00 (m,
3 3
2
H), 1.00 (d, J=6.4, 3H, CH CH), [0.99 (d, J=5.9, 3H, CH CH)], 0.88 (t, J=7.4, 3H, CH CH ), [0.87 (t,
3
3
3
2
13
J=7.4, 3H, CH CH )]; C NMR: δ [72.59 (d, J=156.4)], 71.16 (d, J=157.9), 70.92 (d, J=7.6, 3C), 70.85
3
2
(d, J=6.1), [36.75 (d, J=1.5)], 36.29 (d, J=2.3), 26.66 (d, J=12.2), [24.50 (d, J=8.4)], 24.13 (d, J=3.8),

F. Hammerschmidt, F. Wuggenig / Tetrahedron: Asymmetry 10 (1999) 1709–1721
1717
24.09 (d, J=3.0), 23.94 (d, J=3.8), [15.67 (d, J=6.9)], 14.05 (d, J=4.6), 11.60, [10.98]. Anal. calcd for
C H O P: C, 52.37; H, 9.99. Found: C, 52.26; H, 9.80.
11
25
4
4.5. (ꢀ)-2-(1-Chloroacetoxy-2-methylpropyl)-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one (ꢀ)-2f
Compound 1f (3.15 g, 14.2 mmol) was esterified using chloroacetic anhydride/pyridine and purified by
flash chromatography (MC:EA, 1:1, as eluent, R =0.55) to give 3.55 g (84%) of (ꢀ)-2f as a very viscous
f
−1
1
oil; IR (NaCl) ν
cm : 2970, 1762, 1473, 1281, 1164, 1062, 1000; H NMR: δ 5.24 (dd, J=7.6, 14.5,
max
1
H, CHP), 4.13 (s, 2H, CH Cl), 4.13–3.92 (m, 4H, OCH ), 2.35 (m, 1H, PCCH), 1.14 (s, 3H, Me), 1.06
2 2
13
(
(
d, J=6.9, 3H, Me), 1.04 (d, J=6.9, 3H, Me), 1.01 (s, 3H, Me); C NMR: δ 166.53 (d, J=5.3), 76.68
d, J=6.9), 76.33 (d, J=6.1), 73.74 (d, J=161.0), 40.47, 32.52 (d, J=6.9), 29.18 (d, J=1.5), 21.65, 21.11,
19.41 (d, J=8.4), 18.22 (d, J=6.6). Anal. calcd for C H ClO P: C, 44.23; H, 6.75. Found: C, 44.24; H,
11 20 5
6.71.
4.6. (ꢀ)-Diisopropyl 1-chloroacetoxy-3-(methylthio)propylphosphonate (ꢀ)-2d
−
1
Yield 81%; oil; R =0.53 (MC:EE, 5:3); IR (NaCl) ν
cm : 2980, 2934, 1769, 1438, 1386, 1376,
max
f
1
1
248, 1163, 1105, 989; H NMR: δ 5.37 (dt, J=4.9, 9.3, 1H, CHP), 4.73 (m, 2H, OCH), 4.09 (AB system,
JAB=14.8, 2H, CH Cl), 2.53 (AB system, J =13.3, J=5.3, 6.9, 2×8.4, 2H, SCH ), 2.12 (m, 2H, CH ),
2
AB
2
2
13
2
1
.07 (s, SMe), 1.32 (d, J=5.9, 6H, Me), 1.31 (d, J=6.4, 3H, Me), 1.30 (d, J=5.9, 3H, Me); C NMR: δ
66.38 (d, J=4.5), 71.99 (d, J=6.7), 71.80 (d, J=7.3), 69.25 (d, J=170.4), 30.12 (d, J=13.5), 29.14, 24.13
and 24.00 (d, J=3.6), 23.97 (d, J=4.7), 23.82 (d, J=4.9), 15.37. Anal. calcd for C H ClO PS: C, 41.56;
12
24
5
H, 6.97. Found: C, 41.67; H, 6.95.
4.7. (ꢀ)-Di-t-butyl 1-chloroacetoxy-3-(methylthio)propylphosphonate (ꢀ)-2e
−
1
Yield 72%; viscous oil; R =0.67 (PE:EE, 1:2); IR (NaCl) ν
cm : 2980, 2934, 1766, 1476, 1429,
max
f
1
1
394, 1370, 1327, 1260, 1168, 1040, 986; H NMR: δ 5.21 (ddd, J=3.8, 7.8, 9.7, 1H, CHP), 4.04 (AB
system, JAB=14.8, 2H, CH Cl), 2.48 (AB system, J =13.3, J=5.4, 6.9, 8.4, 8.9, 2H, SCH ), 2.03 (s,
2
AB
2
13
SMe), 2.20–1.91 (m, 2H, CH ), 1.45 and 1.44 (2s, 2×9H, t-Bu); C NMR: δ 166.55 (d, J=4.8), 83.97
2
(
(
d, J=8.4), 83.82 (d, J=9.7), 70.87 (d, J=174.0), 40.74, 30.45 (d, J=3.9, 3C), 30.28 (d, J=3.8, 3C), 30.27
d, J=13.5), 29.53, 15.37. Anal. calcd for C H ClO PS: C, 44.86; H, 7.53. Found: C, 45.15; H, 7.27.
14
28
5
4.8. (1R,2S)- and (1S,2S)-Diisopropyl 1-chloroacetoxy-2-methylbutylphosphonate (1RS,2S)-2g
−
1
Yield 94%; viscous oil; R =0.76 (PE:EE, 1:4); IR (NaCl) ν
cm : 2979, 2952, 2938, 1769, 1466,
max
f
1
1
(
402, 1386, 1254, 1164, 1105, 991; H NMR [(1R,2S)-2g in brackets were distinguishable]: δ 5.22
dd, J=4.4, 10.3, 1H, CHP), [5.09 (dd, J=7.4, 9.3, 1H, CHP)], 4.72 (m, 4H, OCH), 4.09 (AB system,
JAB=15.3, 4H, CH Cl), 1.97 (m, 2H, CH ), [1.64 (m, 1H, CH )], 1.45 (m, 1H, CH ), 1.32–1.26
2
2
2
2
(
3
overlapping d, J=∼6.0, 24H, CH ), 1.20 (m, 2H, CH ), 1.02 (d, J=6.9, 6H, CH CH), 0.90 (t, J=7.4,
3
2
3
13
H, CH CH ), [0.86 (t, J=7.4, 3H, CH CH )]; C NMR: δ 166.54 (d, J=7.0), 166.48 (d, J=5.3), (d,
3
2
3
2
J=4.6), [74.37 (d, J=167.8)], 73.07 (d, J=168.6), 71.56 (d, J=5.7), [71.50 (d, J=6.3)], 71.39 (d, J=7.4),
71.36 (d, J=7.5)], [40.65], 40.60, 35.64, [35.52], 26.69 (d, J=11.1), [24.76 (d, J=7.9)], 24.18 (d, J=2.3),
4.10–23.93 (overlapping d), 23.78 (d, J=2.3), [15.56 (d, J=6.1)], 14.69 (d, J=4.6), 11.42, [10.84]. Anal.
calcd for C H ClO P: C, 47.49; H, 7.97. Found: C, 47.22; H, 8.05.
[
2
13
26
5

1718
F. Hammerschmidt, F. Wuggenig / Tetrahedron: Asymmetry 10 (1999) 1709–1721
4.9. (R)-(−)-Diisopropyl 1-azidopropylphosphonate (R)-(−)-4a
2
0
−1
Yield 84%; oil; R =0.30 (PE:AC, 5:1); [α] =−54.0 (1.0, AC); IR (NaCl) ν
cm : 2980, 2937,
max
f
D
1
2
103, 1465, 1386, 1381, 1251, 1178, 1142, 1106, 987; H NMR: δ 4.74 (m, 2H, OCH), 3.20 (dt,
J=3.6, 11.4, 1H, CHP), 1.88 (m, 1H, CH ), 1.63 (m, 1H, CH ), 1.33 (d, J=6.4, 6H, Me), 1.324 and
.321 (d, J=6.4, 3H, Me), 1.06 (t, J=7.4, 3H, Me); C NMR: δ 71.66 (d, J=7.3), 71.59 (d, J=8.4),
9.55 (d, J=156.8), 24.12 (d, J=3.5, 2C), 23.94 (d, J=4.7, 2C), 22.12, 11.48 (d, J=14.2). Anal. calcd for
2
2
13
1
5
C H N O P: C, 43.37; H, 8.09; N, 16.86. Found: C, 43.47; H, 7.81; N, 17.07.
9
20
3
3
4.10. (R)-(−)-Diisopropyl 1-azido-2-methylpropylphosphonate (R)-(−)-4b
2
0
−1
Yield 68%; oil; R =0.33 (PE:AC, 5:1); [α] =−56.0 (1.1, AC); IR (Si) ν
cm : 2980, 2936, 2104,
max
f
D
1
1
467, 1387, 1257, 1178, 1142, 1106, 991; H NMR: δ 4.76 (m, 2H, OCH), 3.21 (dd, J=5.4, 12.8, 1H,
CHP), 2.13 (m, 1H, CHMe ), 1.34 (d, J=6.4, 3H, Me), 1.33 (d, J=5.9, 6H, Me), 1.32 (d, J=5.9, 3H, Me),
.03 and 1.08 (d, J=7.4, 3H, Me); C NMR: δ 71.57 (d, J=7.6), 71.47 (d, J=8.0), 64.59 (d, J=156.1),
9.30, 24.20 (d, J=3.6), 24.13 (d, J=3.4), 23.97 (d, J=4.8), 23.92 (d, J=5.0), 21.08 (d, J=10.5), 18.64 (d,
2
13
1
2
J=6.5). Anal. calcd for C H N O P: C, 45.62; H, 8.42; N, 15.96. Found: C, 45.58; H, 8.48; N, 16.14.
10
22
3
3
4.11. (R)-(−)-Diisopropyl 1-azido-3-methylbutylphosphonate (R)-(−)-4c
2
0
−1
Yield 77%; oil; R =0.35 (PE:AC, 5:1); [α] =−56.6 (1.1, AC); IR (Si) ν
cm : 2980, 2112, 1467,
max
f
D
1
1
387, 1261, 1178, 1142, 1106, 989; H NMR: δ 4.75 (m, 2H, OCH), 3.34 (ddd, J=3.4, 11.8, 12.8, 1H,
CHP), 1.82 (m, 1H, CHMe ), 1.60 (m, 2H, CH ), 1.33 (d, J=6.4, 12H, Me), 0.95 (d, J=6.7, 3H, Me),
.90 (d, J=6.9, 3H, Me); C NMR: δ 71.72 (d, J=7.3), 71.59 (d, J=7.2), 55.83 (d, J=156.7), 36.80, 25.04
d, J=13.6), 24.14 (d, J=3.6), 24.11 (d, J=3.4), 23.97 and 23.93 (d, J=4.2), 23.15, 20.85. Anal. calcd for
C H N O P: C, 47.64; H, 8.72; N, 15.15. Found: C, 47.91; H, 8.53; N, 14.88.
2
2
13
0
(
11
24
3
3
4.12. (R)-(−)-Diisopropyl 1-azido-3-(methylthio)propylphosphonate (R)-(−)-4d
2
0
−1
Yield 90%; oil; R =0.61 (ether); [α] =−83.8 (1.1, AC); IR (Si) ν
cm : 2981, 2922, 2100, 1453,
max
f
D
1
1
386, 1376, 1263, 1178, 1142, 1106, 987; H NMR: δ 4.76 (m, 2H, OCH), 3.64 (dt, J=3.3, 11.5, 1H,
CHP), 2.64 (AB system, JAB=13.4, J=4.4, 7.4, 2×7.9 and long range coupling with phosphorus, J=1.0,
1
3
2
7
H, SCH ), 2.07 (s, 3H, SMe), 2.04 and 1.86 (m, 1H, CH ), 1.33 (d, J=5.9, 12H, Me); C NMR: δ
2
2
1.88 (d, J=7.3), 71.85 (d, J=7.0), 56.04 (d, J=157.9), 30.81 (d, J=15.1), 30.38 (d, J=15.4), 24.12 and
2
4.11 (d, J=3.8), 23.97 and 23.96 (d, J=4.6), 15.18. Anal. calcd for C H N O PS: C, 40.67; H, 7.51;
10
22
3
3
N, 14.23. Found: C, 40.43; H, 7.23; N, 13.98.
4.13. (1R,2S)-(−)-Diisopropyl 1-azido-2-methylbutylphosphonate (1R,2S)-(−)-4e
To a stirred solution of 252 mg (1.0 mmol) of (+)-2e and 524 mg (2.0 mmol) of triphenylphosphine in
5
ml of dry toluene, 0.31 ml (348 mg, 2.0 mmol) of diethyl azodicarboxylate were added under argon and
cooling with an ice bath. After addition of 1 ml of a 1.06 M solution of HN in toluene, a precipitate was
3
formed and another 0.9 ml of the HN solution was added at room temperature. Stirring was continued for
3
4
h. Then 1 ml of methanol was added and after 1 h the solvent was removed in vacuo. Hexane was added
to the residue and the mixture was allowed to stand overnight. The crystalline solid was removed and the
filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography.

F. Hammerschmidt, F. Wuggenig / Tetrahedron: Asymmetry 10 (1999) 1709–1721
−1
1719
2
0
Yield 79%; oil; R =0.25 (PE:AC, 5:1); [α] =−58.2 (1.0, AC); IR (Si) ν
cm : 2979, 2104, 1453,
max
f
D
1
1
386, 1254, 1178, 1142, 1106, 986; H NMR: δ 4.73 (m, 2H, OCH), 3.40 (dd, J=4.0, 14.0, CHP of trace
of diastereomeric azide), 3.20 (dd, J=6.5, 13.0, 1H, CHP), 1.82 and 1.70 (m, 1H, CH ), 1.30 (d, J=6.0,
2
3
9
H, Me), 1.28 (d, J=5.5, 3H, Me), 1.03 (t, J=7.0, 3H, Me), 0.84 (d, J=7.4, 3H, Me); 1 C NMR: δ 71.16
and 70.98 (d, J=7.6), 63.36 (d, J=155.3), 35.42, 24.95 (d, J=7.6), 24.18 (d, J=2.3), 24.15 (d, J=3.8),
23.95 (d, J=5.3), 23.93 (d, J=5.3), 16.83 (d, J=8.4), 10.58. Anal. calcd for C H N O P: C, 47.65; H,
11 24 3 3
8.72; N, 15.15. Found: C, 47.86; H, 8.52; N, 14.99.
4.14. (R)-(−)-1-Aminopropylphosphonic acid (R)-(−)-5a
1
0
20
20
Yield 79%; crystalline solid; mp 263–264°C (decomp.) (lit. : 276°C); [α] =−18.0, [α] =−17.8
D
578
10
20
−1
(
1
(
0.9, 1 M NaOH) {lit. : [α] 78=−21.6 (1.0, 1 M NaOH), ee 98%}; IR (Nujol mull) νmax cm : 1629,
5
1
537, 1155, 1077, 1019, 921; H NMR (D O, NaOD): δ 2.26 (dt, J=3.3, 10.2, 1H, CHP), 1.63 and 1.17
2
m, 1H, CH ), 0.83 (t, J=7.4, 3H, Me). Anal. calcd for C H NO P: C, 25.91; H, 7.25; N, 10.07. Found:
2 3 10 3
C, 26.14; H, 6.95; N, 9.89.
.15. (R)-(+)-1-Amino-2-methylpropylphosphonic acid (R)-(+)-5b
4
2
8
20
20
Yield 68%; crystalline solid; mp 265–268°C (decomp.) (lit. : 272–273°C); [α] =+0.4, [α] =+0.4
D
578
28
20
−1
(
1
1
0.9, 1 M NaOH) {lit. : [α] 78=+0.6 (1.0, 1 M NaOH)}; IR (Nujol mull) νmax cm : 1624, 1532, 1233,
5
1
167, 1061, 934; H NMR (D O): δ 3.04 (dd, J=6.0, 13.7, 1H, CHP), 2.18 (m, 1H, CHMe ), 1.07 and
2
2
.03 (d, J=6.4, 3H, Me).
4.16. (R)-(−)-1-Amino-3-methylbutylphosphonic acid (R)-(−)-5c
6
20
Yield 85%; crystalline solid; mp 273–276°C (decomp.) (lit. : 281–283°C); [α] =−31.6 (0.9, 1 M
D
6
20
−1
NaOH) {lit. : [α] =−25.0 (0.7, 1 M NaOH), ee ≥99%}; IR (Nujol mull) ν
cm : 1614, 1203, 1015,
D
max
1
9
0
42, 934; H NMR (D O): δ 3.25 (ddd, J=5.0, 9.0, 13.9, 1H, CHP), 1.78–1.52 (m, 3H, CH and CH ),
2
2
.91 and 0.87 (d, J=6.4, 3H, Me).
4.17. (R)-(−)-1-Amino-3-(methylthio)propylphosphonic acid (R)-(−)-5d
2
0
20
Yield 59%; crystalline solid; mp 263–265°C (decomp.); [α] =−26.8 (0.9, H O), [α] =−43.5 (1.0,
D
2
D
8
20
20
0
.25 M NaOH) {lit. : [α] =−17.2 (1.1, H O), [α] =30.5 (1.1, 0.25 M NaOH), ee 76.8%, see also
D D
2
6
−1
1
Smith III et al. }; IR (Nujol mull) ν
cm : 2282, 1648, 1537, 1183, 1029, 1003; H NMR (D O,
2
max
NaOD): δ 3.19 (ddd, J=4.4, 8.9, 13.0, 1H, CHP), 2.65 (AB system, JAB=13.9, J=5.9, 2×7.3, 8.4, 2H,
CH ), 2.16 (m, 1H, CH ), 2.08 (s, 3H, Me), 1.90 (m, 1H, CH ), 0.83 (t, J=7.4, 3H, Me).
2
2
2
4.18. (1R,2S)-(−)-1-Amino-2-methylbutylphosphonic acid (1R,2S)-(−)-5e
2
0
Yield 68%; crystalline solid; mp 256–258°C (decomp.); [α] =−8.5 (1.0, 1 M NaOH); IR (Nujol mull)
D
−
1
1
νmax cm : 1599, 1531, 1167, 1022, 928; H NMR (D O, NaOD): δ 2.64 (dd, J=2.8, 13.8, CHP of trace
2
of other diastereomer), 2.50 (dd, J=4.5, 12.5, 1H, CHP), 1.76 (m, 2H), 1.11 (m, 1H), 1.04 (d, J=6.7, Me),
13
0
.92 (t, J=7.3, 3H, Me); C NMR (D O, NaOD): δ 55.73 (d, J=136.9), 36.13, 24.28 (d, J=4.6), 17.68
2
(
d, J=9.2), 11.49; 31P NMR (D O, NaOD): δ 22.45. Anal. calcd for C H NO P: C, 35.93; H, 8.44; N,
2
5
14
3
8
.38. Found: C, 36.12; H, 8.17; N, 8.26.

1720
F. Hammerschmidt, F. Wuggenig / Tetrahedron: Asymmetry 10 (1999) 1709–1721
4.19. (ꢀ)-Di-t-butyl 1-azido-3-(methylthio)propylphosphonate (ꢀ)-6
−
1
Yield of (ꢀ)-6 59% and of byproduct 7 15%; R =0.37 (MC:EE, 10:1); IR (NaCl) ν
cm : 2981,
max
f
1
2
934, 2099, 1394, 1371, 1268, 1170, 1038, 983; H NMR: δ 3.44 (dt, J=3.1, 10.9, 1H, CHP), 2.64 (AB
system, JAB=13.2, J=4.4, 7.4, 2×7.9 and long range coupling with phosphorus, J=1.0, 2H, SCH ), 2.07
2
13
(
s, 3H, SMe), 2.14–2.01 and 1.85 (m, 1H, CH ), 1.52 and 1.51 (s, 9H, Me); C NMR: δ 83.90 (d,
J=9.9), 83.65 (d, J=9.0), 57.39 (d, J=159.4), 31.01 (d, J=14.7), 30.49 (d, J=3.9, 3C), 30.46 (d, J=3.8,
cm : 2980, 2919, 1631, 1394, 1370,
max
260, 1173, 1039, 979; H NMR: δ 6.49 (ddt, J=7.2, JAB=16.7, JPH=20.7, 1H, CH_CHP), 5.74 (ddt,
J=1.2, JAB=16.7, JPH=18.7, 1H, CHP), 3.13 (dt, J=1.2, 7.2, 2H, CH S), 2.00 (s, 3H, SCH ), 1.45 (s,
2
−
1
3
1
C), 28.25, 15.21. Crude 7 was isolated as byproduct; IR (Si) ν
1
2
3
1
8H, t-Bu). (ꢀ)-6: Anal. calcd for C H N O PS: C, 44.57; H, 8.10. Found: C, 44.83; H, 7.86.
12
26
3
3
4.20. (ꢀ)-2-(1-Azido-2-methylpropyl)-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one (ꢀ)-8
12
The azide was prepared from 0.99 g (4 mmol) of (ꢀ)-1f by the method of Gajda. The crude product
was purified by flash chromatography using diethyl ether (R =0.22) as eluent to give 0.80 g (81%) of
f
−1
crystalline azide; mp 73–74°C (PE/few drops of MC); IR (Nujol mull) ν
cm : 2107, 1272, 1055,
max
1
1
1
005; H NMR: δ 4.14 (m, 2H, OCH ), 3.98 (m, 2H, OCH ), 3.47 (dd, J=4.9, 13.3, 1H, CHP), 2.25 (m,
2
2
13
H, PCCH), 1.08 (d, J=7.9, 3H, Me), 1.07 and 1.02 (2 s, each 3H, Me), 1.01 (d, J=5.4, 3H, Me);
C
NMR: δ 76.31 (d, J=6.9), 76.08 (d, J=6.9), 64.43 (d, J=152.6), 32.60 (d, J=6.9), 29.42, 21.65, 21.33,
2
0.90 (d, J=11.2), 18.41 (d, J=6.0). Anal. calcd for C H N O P: C, 43.69; H, 7.33; N, 17.06. Found: C,
9 18 3 3
43.98; H, 7.14; N, 17.06.
Azide (ꢀ)-8 (0.70 g, 2.83 mmol) was catalytically reduced and then deblocked by refluxing in 30 ml
of 6 N HCl for 8 days. Removal of volatiles in vacuo and purification of the residue by ion exchange
+
chromatography (Dowex 50, H ) with water as eluent afforded 0.3 g (69%) of racemic aminophosphonic
acid (ꢀ)-5b.
Acknowledgements
We thank the Fonds zur Förderung der wissenschaftlichen Forschung (project no. P13017-CHE and
®
6
537C) for financial support, Boehringer Mannheim for generous gifts of protease Chirazyme P-2,
Amano Enzyme Europe Ltd (England) for lipase AP 6 and Novo Nordisk (Denmark) for lipase SP 524,
and M. Hanbauer for carrying out the enzymatic hydrolysis of chloroacetoxyphosphonate (ꢀ)-2f.
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2
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1721
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1
1
1
1
1
2
2
2
2
2
2
2
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