Chemoenzymatic Synthesis of Racemic and Enantiomerically Pure Phosphaaspartic Acid and Phosphaarginine

Article abstract of DOI:10.1002/ejoc.201700948

Diisopropyl allyloxymethylphosphonate prepared by a one-pot procedure was isomerized to give racemic 1-hydroxy-3-butenylphosphonate with LDA by a [2,3]-sigmatropic rearrangement. Chloroacetylation delivered an ester, which was resolved in a two-phase system by using the lipase from Thermomyces lanuginosus. Racemic and (S)-α-hydroxyphosphonate 6 were converted to (±)- and (R)-phosphaaspartic acid by functional-group manipulation. (±)-, (R)- and (S)-6 were first esterified with 4-nitrobenzenesulfonyl chloride before hydroboration to transform the double bond into a hydroxyethyl group. The hydroxyl group was manipulated to give a guanidinyl group and the 4-nitrobenzenesulfonyloxy to give an amino group. Global deprotection of the α-aminophosphonates yielded the desired phosphaamino acids.

Full text of DOI:10.1002/ejoc.201700948

A Journal of
Accepted Article
Title: Chemoenzymatic Synthesis of Racemic and Enantiomerically
Pure Phosphaaspartic Acid and Phosphaarginine
Authors: Friedrich Hammerschmidt, Renzhe Qian, Edyta Kuliszewska,
and Elena Macoratti
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700948
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European Journal of Organic Chemistry
10.1002/ejoc.201700948
FULL PAPER
Chemoenzymatic Synthesis of Racemic and Enantiomerically
Pure Phosphaaspartic Acid and Phosphaarginine
Renzhe Qian, Edyta Kuliszewska, Elena Macoratti, and Friedrich Hammerschmidt*[a]
Abstract: Diisopropyl allyloxymethylphosphonate prepared by a one
pot procedure was isomerized to racemic 1-hydroxy-3-
butenylphosphonate with LDA by a [2,3]-sigmatropic rearrangement. RESULTS and DISCUSSION
Chloroacetylation delivered an ester which was resolved in a two-
phase system using the lipase from Thermomyces lanuginosus.
Racemic and (S)-α-hydroxyphosphonate 6 were converted to (±)-
and (R)-phosphaaspartic acid by functional group manipulation. (±)-,
We envisaged to use racemic diisopropyl 1-hydroxy-3-
butenylphosphonate (±)-6 (see Scheme 1) as starting material
for the synthesis of both phosphaaspartic acid and
phosphaarginine as racemates as well as the enantiomers. The
isopropyl group was selected as protective group for phosphorus
as it is more stable toward nucleophilic attack than the more
often used ethyl group. The hydroxyl group can be replaced by
an amino group via azide and the double bond allows many
transformations. Initially, we thought that it could be prepared in
three steps from commercially available vinylacetic acid. It is first
converted to the vinylacetyl chloride, then to the corresponding
α-ketophosphonate (Arbusov reaction with triisopropyl
phosphite), which is reduced to the α-hydroxyphosphonate with
(R)- and (S)-6 were first esterified with 4-nitrobenzenesulfonyl
chloride before hydroboration to transform double bond into a
hydroxyethyl group. The hydroxyl group was manipulated to give a
guanidinyl group and the 4-nitrobenzenesulfonyloxy to give an amino
group. Global deprotection of the α-aminophosphonates yielded the
desired phosphaamino acids.
INTRODUCTION
4
NaBH . The diethyl analog of (±)-6 was prepared by allylation of
α-Aminophosphonic acids are a class of α-amino (carboxlic)acid
analogs, which have attracted the attention of organic chemists
during the last decades for various reasons.[1] They are more
acidic than the respective amino acids and the P-C bond is
chemically and biologically very stable. While the carboxyl group
is planar, the phosphonic group is tetrahedral and therefore an
isosteric replacement of the tetrahedral intermediate involved in
reactions of carboxyl acid derivatives.[2] The combination of
these properties and the various biological activities makes α-
aminophosphonic acids[3] and the peptides containing them
THP-protected diethyl hydroxymethylphosphonate.[10] This
approach was not attractive as it comprised four steps and
chromatographic purification. The method used for the
preparation of 5 by Kolyamshin et al. was not attractive either as
it involved chloromethyl allyl ether as starting material.[11]
The alternative we used is a three step sequence with the first
two steps being performed as a one pot reaction (Scheme 1).
[4]
[1]
interesting synthetic targets . Many methods have been
[5]
developed to access them in racemic and chiral, non-racemic
[
6]
form . Not surprisingly, phosphonic acid analogs of amino acids
without functional groups in the side chain can be prepared fairly
easily by a variety of procedures. However, the syntheses of
those with functional groups comprise many steps and suffer
from a lack of methods for enantiomerically pure compounds.
[
7]
We delineate here the syntheses of known racemic and (R)-
phosphaaspartic acid[8] and racemic, (R)- and (S)-
phosphaarginine. The latter has previously been prepared as
racemate or component of a phosphapeptide, using as key step
the Kabachnik Fields protocol to synthesize
a protected
phosphaornithine, which was guanidinylated.[9] However,
phosphaarginine has never been prepared as enantiomer to the
best of our knowledge.
Scheme 1. Synthesis of racemic 1-chloroacetoxy-but-2-enylphosphonate (±)-7.
[
a]
Dr. R. Qian, Dr. E. Kuliszewska, Ing. Elena Macoratti, and Prof. Dr.
F. Hammerschmidt
Institut für Organische Chemie
Universität Wien
E-mail: friedrich.hammerschmidt@univie.ac.at
It is reminiscent of the protocol used by Collignon et al. to
prepare diethyl allyloxymethylphosphonate.[
12]
Our sequence
Supporting information for this article is given via a link at the end of
the document.
started with the DBU-catalyzed exothermic reaction between
paraformaldehyde and neat diisopropyl phosphite (Pudovik
reaction). The hydroxymethylphosphonate
3
formed was
1
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European Journal of Organic Chemistry
10.1002/ejoc.201700948
FULL PAPER
subsequently reacted with allyl bromide in aqueous NaOH under
(hexanes/tBuOMe, 1:1) by the lipase from Thermomyces
lanuginosus, using an autotitrator to add 0.5 M NaOH to
maintain the pH constant at 7.0.[15] When 40% of the substrate
had been hydrolyzed based on the consumption of 0.5 M NaOH,
the mixture was extracted with EtOAc. The hydroxyphosphonate
and the chloroacetate were separated by flash chromatography.
The ee and the configuration of the hydroxyphosphonate were
determined by NMR spectroscopy of the (R)-Mosher ester in
analogy to a literature procedure.[18] The ee was found to be
97% and the configuration to be (S). Consequently, the
recovered chloroacetate had to have (R) configuration and a low
ee because of a conversion of only 40%. To increase its ee to
more than 95%, this chloroacetate was subjected to a second
lipase-catalyzed hydrolysis with lipase from Thermomyces
lanuginosus under similar conditions. The consumption of base
decreased and finally stopped, when all (S)-chloroacetate had
been consumed. The left (R)-chloracetate was extracted,
phase transfer conditions with BnNEt
3
Cl. Extraction with CH
2 2
Cl
and bulb-to-bulb distillation delivered
homogeneous
allyloxymethylphosphonate 5 in an overall yield of 80% in
batches of 15-20 g. LDA-mediated [2,3]-Wittig rearrangement at
‒78 °C furnished 1-hydroxyphophonate (±)-6 (94% yield),
containing up to 3mol% of diisopropyl phosphite. The latter was
evidently formed by decomposition (retro-Pudovik reaction) of
the intermediate alkoxide. This labile compound was formed by
rearrangement of (±)-6 after metalation with LDA and
disintegrated to the respective aldehyde and the lithium salt of
diisopropyl phosphite, which is protonated on quenching with
HCl. The literature-known [2,3]-Wittig rearrangement of
allyloxmethylphosphonates was first studied in the racemic[12,13]
and later in the enantioselective[14] series as well.
For the synthesis of the enantiomers of phosphaaspartic acid
and phosphaarginine the enantiomers of diisopropyl 1-hydroxy-
3-butenylphosphonate were needed. In order to obtain them with
3
purified and chemically hydrolyzed in MeOH/Et N. This time, the
a high ee the racemate was resolved by enzyme-catalyzed
hydrolysis of the respective chloroacetate.[15] Therefore, the α-
ee was determined to be 99% by using (R)-(+)-
[19]
tbutyl(phenyl)phosphinothioic acid
as chiral solvating agent
hydroxyphosphonate
chloroacetic anhydride/pyridine (see Scheme 1). Hydrolytic
(±)-6
was
chloroacetylated
with
and 31P NMR spectroscopy. It is noteworthy, that Ganti et al.
needed for the resolution of racemic diethyl 1-acetoxy-3-
butenylphosphonate 200 mg/mmol of lipase PL from Amano and
obtained at 50% conversion in 24 h an ee of 97% for the α-
hydroxyphosphonate.[10]
With α-hydroxyphosphonates (±)-6 and virtually enantiomerically
pure (R)- and (S)-6 in our hands, we opted first for the
preparation of racemic and (R)-phosphaaspartic acid. These
phosphonic acids are analogs of the racemic and the
proteinogenic (S)-form (the different descriptors are caused by
the fact that CO
compared to NH according to the CIP rules) of aspartic acid
Scheme 3). The hydroxyl group of (±)- and (S)-6 was replaced
2 3 2
H has lower and PO H higher priority
2
(
Scheme 2. Lipase-catalyzed resolution of chloroacetate (±)-7.
enzymes (esterases and lipases) have been used in a plethoria
of cases for resolution of alcohols.[16] Enantiomers of α- and β-
hydroxyphosphonates have been obtained from the racemates
using lipases for (1) enantioselective esterification[17] or (2)
enantioselective hydrolyses of esters.[15] In the latter case
chloroacetates were preferred as they were more reactive than
the acetates. Additionally, diisopropyl acyloxyphosphonates
delivered enantiomers of higher ee than the diethyl analogs. We
tested a series of lipases (SAM-I and -II, AP 6, FAP 15, SP 523,
Chirazyme L9, and from Candida antarctica, Candida
cylindracea, and Thermomyces lanuginosus) and found that the
lipase from Thermomyces lanuginosus was best (Scheme 2).
Briefly, chloroacetate (±)-7 was hydrolyzed in a vigorously stirred
biphasic system of phosphate buffer pH 7.0 and organic solvent
Scheme 3. Synthesis of (±)- and (R)-phosphaaspartic acid 10.
2
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European Journal of Organic Chemistry
10.1002/ejoc.201700948
FULL PAPER
replaced by the azide group with inversion of configuration,
using the Mitsunobu reaction [Ph
3
P/diisopropyl azodicarboxylate
(
DIAD)/HN
3
].[15,20] The conversion of the azides to the
phosphaaspartic acids was performed without characterization
of the intermediate products. The double bond was oxidatively[21]
cleaved with RuCl ×H O/NaIO and delivered β-azidocarboxylic
3 2 4
acids (±)- and (R)-9, respectively. These were reduced to
amines with two equivalent methods, catalytic hydrogenation
(
Pd/C/H
reduction [HS(CH
aminophosphonic acids were deblocked at phosphorus with
refluxing HCl and purified by cation exchange
chromatography. final crystallization afforded the
phosphaaspartic acids (±)- and (R)-10 as colorless crystals in
1% and 59% overall yield for the three steps, respectively.[15]
2
) for the racemate and 1,3-propanedithiol-mediated
)
3
SH/Et
3
N] for the enantiomer.[22] The
2
6
M
A
6
The ee of (R)-10 was determined by HPLC on a chiral stationary
anion exchange phase (unmodified OH-QN-AX column) based
on quinine.[23] (±)- and (R)-10 were pre-column deriviatized with
Sanger´s reagent for sensitive detection. The ee of the
enantiomeric compound after cation exchange purification was
found to be 98.3% and 98.5% after additional crystallization
(
Figure 1).
Scheme 4. Nosylation and hydroboration of (±)-, (R)- and (S)- 6 to obtain ω-
hydroxyphosphonates (±)-, (R)- and (S)-12, respectively.
1
0
8
6
a: 1.18
ee
R
(before crystallization): 98.4 %
ee
R
(after crystallization): 99.2 %
8
3
2.81
0.70
(±)-12 and several byproducts. Addition of catecholborane to the
S
5
.69
R
double bond, catalyzed by Wilkinson´s catalyst, did not increase
6
.43
.45
the yield.[24] The complexation of BH
3
to the P=O group might
S
5.71
6
interfere with its anti-Markovonikov addition to the double bond.
The enantiomers (R)- and (S)-6, both of ee >99% as determined
by chiral HPLC of the corresponding nosylates, were converted
to (R)- and (S)-12 by the protocol used for (±)-6 and in yields
similar to (±)-12.
The racemate and the enantiomers of 12 were transformed into
the corresponding phosphaarginines by functional group
manipulation (Scheme 5). The steps were optimized in the
4
2
0
0.65
6
.45
5.66 0.12
5.75
5
5.25
5.5
6
6.25
5
6
7
8
9
10
Time [min]
racemic series. Mitsunobu reaction of ω-hydroxyphosphonate
Figure 1. Chiral separation of 2,4-dinitrophenyl-derivatized (±)- and (R)-
phosphaaspartic acid on an unmodified OH-QN-AX column before (red) and
after crystallization (green). Peak areas are in bold and retention times are in
italic.
P/DIAD/bisBoc-protected guanidine[
25,26,27]
as acid
(
±)-12 with Ph
3
furnished ω-guanidinophosphonate (±)-14 in 86% yield in a
smooth reaction at room temperature. We assume that the Boc-
protected guanidino group has the same structure as the one
found
in
a
3-tributylstannylphenylmethyl-substituted
compound[
27]
by single crystal X-ray structure analysis. The
The synthesis of phosphaarginines necessitated the
transformation of the allyl into a 3-hydroxypropyl side chain in 6
as first step. Before doing that, the hydroxyphosphonates were
converted to 4-nitrobenezenesulfonyl esters (nosylates) 11
displacement reaction of 4-nitrobenzenesulfonyloxy group with 3
equiv of NaN had to be performed in the presence of 1.5 equiv
of 15-crown-5 at 60 °C to generate azide (±)-15 in 79% yield
with inversion of configuration. It was reduced to amine (±)-16 in
3
(
Scheme 4). The nosyloxy group had three functions. It was (1)
protecting group, (2) good leaving group allowing
a
a
3
89% yield under mild conditions using 1,3-propanedithiol/Et N in
displacement by azide at a later stage and (3) facilitated enantio-
separation on a chiral stationary phase to determine the ee by
dry MeOH at room temperature. Refluxing with 6 M HCl
removed all protecting groups (iPr, Boc). The crude
hydrochloride was dissolved in ethanol. Dropwise addition of
methyloxirane induced precipitation of the monohydrochloride in
67% as colorless crystals.
The ω-hydroxyphosphonates (R)- and (S)-12 of ee >99% were
converted to phosphaarginines (S)- and (R)-16 by the same
reaction sequence as the racemate, comprising Mitsunobu
HPLC. Hydroboration of (±)-11 with 1.4 equiv of H
C followed by oxidative work-up with H /NaHCO
mixture of three hydroxyphosphonates (ratio by
.0:0.16:0.26). Easy separation by flash chromatography gave
3
B·THF at 0
3
delivered a
°
2
O
2
3
1
P NMR:
1
desired homogeneous (±)-12 (60% yield, anti-Markovnikov
product) and a mixture of diastereomers (±)-13a,b (26% yield,
Markovnikov product). The yield of (±)-12 and ratio of
hydroxyphosphonates in favor of (±)-12 could not be improved.
Hydroboration with 9-BBN yielded only 16% of (±)-12,
reaction, substitution reaction with NaN
3
with inversion of
configuration, reduction of azide to amine and global
deprotection. Contrary to the racemate, the enantiomers of
phosphaarginine were obtained as heavy oils as likely
2
cyclohexylBH gave a mixture of products containing 51% of
3
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European Journal of Organic Chemistry
10.1002/ejoc.201700948
FULL PAPER
280
260
240
220
200
180
160
140
a: 1.28
ee : 99.2 % ee
S
S
R
: 98.5 %
19.37
8784.37
7646.21
R
19.36
2
4.19
24.42
58.67
33.69
17.5
20
22.5
25
27.5
0
10
20
Time [min]
30
40
Figure 2. Chiral Separation of phosphaarginines (R) and (S)-17 after
derivatization with 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate on an
unmodified OH-QN-AX column. Peak areas are in bold and retention times are
in italic.
Conclusions
In summary, we have accomplished the synthesis of racemic
and enantiomeric phosphaarginine and phosphaaspartic acid.
The starting material was racemic diisopropyl 1-hydroxy-3-
butenylphosphonate
obtained
by
[2,3]-sigmatropic
rearrangement of allyloxymethylphosphonate. Lipase-catalyzed
resolution of the corresponding chloroacetate furnished both
enantiomers of high ee. The hydroxyl group and the double
bond were manipulated to yield the respective phosphaamino
acids.
Experimental Details
General Information. H, 13C (J-modulated) and 31P NMR spectra were
1
1
13
recorded in CDCl
3
or D
2
O on a Bruker AV 400 ( H: 400.13 MHz, C:
31
1
13
1
00.61 MHz, P: 161.98 MHz), AV III 400 ( H: 400.27 MHz, C: 100.65
MHz, P: 162.03 MHz), AV III 600 ( H: 600.25 MHz, C: 150.93 MHz,
P: 242.99 MHz), and AV III HD 700 ( H: 700.40 MHz, C: 176.12 MHz)
at 25 °C. Chemical shifts (δ) are reported in parts per million (ppm)
relative to internal residual CDCl (δ 7.24; δ 77.00), C CD H (
.09), HOD (δ 4.80) and external H PO (85%; δ 0.00) and coupling
31
1
13
31
1
13
3
H
C
D
6 5
2
H
2
H
3
4
P
Scheme 5. Synthesis of racemate and enantiomers of phosphaarginine from
1
constants (J) in Hz. Data for H NMR spectra are reported as follows:
chemical shift, multiplicity (br = broad, s = singlet, d = doublet, t = triplet,
q = quartet, sep = septet, m = multiplet), coupling constants, and
integration). IR spectra were recorded on a Bruker VERTEX 70 IR
spectrometer in ATR mode or of films[ on a silicon disk. Melting points
were measured on a Leica Galen III Thermovar instrument and are
uncorrected. Optical rotations were measured on a Perkin-Elmer 341
polarimeter in a 1 dm quartz cell. Anhydrous THF was refluxed over
potassium and distilled prior to use. Pyridine was dried by refluxing over
12.
28]
dihydrochlorides containing still some water after removal of the
M HCl. Extensive drying at 0.5 mbar gave glassy products.
6
Unfortunately, they could not be isolated in crystalline form as
the racemate on treatment with methyloxirane in ethanol. The
enantiomeric excesses for (R)- and (S)-17 were 98.2% and
2
powdered CaH , then distilled and stored over molecular sieves (4 Å). All
other solvents, also dry ones, and chemicals were used as purchased
from Sigma-Aldrich, Acros, Fluka or Merck. Flash (column)
chromatography was performed over Silica 60 M (particle size 0.040-
99.0%, respectively, as determined by HPLC on a chiral anion
chromatography column (Figure 2). Advantageously, this
approach to phosphaarginines allows to easily prepare peptides
with phosphaarginine as component as well. The intermediate
amines (R)- and (S)-16 can be coupled with amino acids in α-
position prior to global deprotection with HBr in AcOH.
0.063 mm) from Macherey-Nagel. Reactions were monitored by
analytical thin layer chromatography (TLC) using precoated silica gel
plates from Macherey-Nagel (TLC Silica gel 60 F254, 250 μm thickness).
Spots were visualised by UV and/or dipping into
NH Mo O (25.0 g) and Ce(SO ∙4H O (1.0 g) in 10% aqueous
SO (500 mL), followed by heating with a heat gun.
a solution of
(
4
)
6
7
O24∙4H
2
4
)
2
2
H
2
4
Determination of ee by chiral HPLC
Ee determination of 1-(4-nitrobenzenesulfonyloxy)-3-butenyl-
phosphonates: Shimadzu system comprising components LC-20AT,
SIL-20A HT, CTO-20AC, SPD-20A, CMB-20A, column: Chiralpak IA (250
×
4.6 mm, particle size 5 μm), software: LC solutions.
4
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European Journal of Organic Chemistry
10.1002/ejoc.201700948
FULL PAPER
Ee determination of phosphaaspartic acid and phosphaarginines:
Phosphaarginine was derivatized with 6-aminoquinolyl-N-hydroxy-
succinimidyl carbamate (AQC; AccQ) and phosphaaspartic acid with 2,4-
dinitrofluorobenzene (2,4-DNFB, Sanger’s reagent) prior to enantiomeric
excess determination using an in-house prepared underivatized OH-QN-
AX column[23] (150 mm × 4 mm, 5 μm; CSP1) employing as mobile
78 °C) was removed and HCl (10 mL, 12 M) was added in one portion,
followed by water (50 mL) 5 min later, when the ice had dissolved. The
organic phase was separated and the aqueous one was extracted with
EtOAc (2 × 50 mL). The combined organic layers were washed with brine
(40 mL), dried (Na
2 4
SO ) and concentrated under reduced pressure. The
1-hydroxy-3-butenylphosphonate (±)-6 was obtained as
a
nearly
phase 2 M aqueous H
triethylamine) at a flow rate of 1 mL/min and a column temperature of
3
PO
4
/MeOH (1:9, (v/v)), pH 4.0 (adjusted with
colorless oil (8.368 g, 94%, contained 3mol% of diisopropyl phosphite)
which proved to be pure enough (by 1H and 31P NMR spectroscopy) as
starting material for the next step. The analytical sample was obtained as
4
1
0 °C. Liquid chromatographic analysis was performed with an Agilent
100 Series HPLC system equipped with a binary pump with column
colorless oil by flash chromatography (EtOAc, R
1H NMR (400.13 MHz, CDCl
): δ = 5.88 (tdd, J = 17.1, 10.1, 7.0 Hz, 1H,
=CH), 5.16 (qd, J = 17.1, 1.5 Hz, 1H, =CH ), 5.13 (dd, J = 10.1, 1.5 Hz,
1H, =CH ), 4.81-4.67 (m, 2H, OCH), 3.86-3.78 (m, 1H, CHP), 2.59-2.48
(m, 2H, CH , OH), 2.46-2.35 (m, 1H, CH ), 1.33 (d, J = 6.2 Hz, 3H, CH ),
1.324 (d, J = 6.2 Hz, 3H, CH ), 1.318 (d, J = 6.2 Hz, 6H, CH
); 13C NMR
(100.61 MHz, CDCl ): δ = 133.9 (d, J = 14.3 Hz, =CH), 118.2 (=CH ),
71.24 (d, J = 7.0 Hz, OCH), 71.19 (d, J = 7.3 Hz, OCH), 67.5 (d, J =
163.4 Hz, CHP), 36.1 (CH ), 24.1 (d, J = 3.8 Hz, 2C, CH ), 24.0(d, J =
4.7 Hz, 2C, CH ): δ = 23.6. IR (Si):  =
); 31P NMR (161.98 MHz, CDCl
f
= 0.36).
oven, autosampler, multi-wavelength detector (MWD; 254 nm) and
fluorescence detector (FLD; gain 10; excitation: 254 nm; emission: 395
nm) from Agilent (Waldbronn, Germany).
3
2
2
Since quinine and quinidine type chiral selectors are per se fluorescence
active, a thorough column rinse with the mobile phase prior to analysis
was essential. Note that sample injection was only performed after base
line drift was significantly reduced. Nonetheless, a slight drift in the
baseline can still be seen in Figures 1 and 2. The (S)-enantiomers of
both, AQC-derivatized phosphaarginine and DNP-phosphaaspartic acid,
eluted before their (R)-enantiomers. For DNP-phosphaaspartic acid a
separation factor of 1.18 and for AQC-derivatized phosphaarginine a
separation factor of 1.28 was achieved.
2
2
3
3
3
3
2
2
3
3
3
‒1
3306, 2980, 2936, 1387, 1224, 1107, 989 cm . C10
21 4
H O P (236.25):
calcd. C 50.84, H 8.96; found C 50.74, H 8.70.
(
±)-Diisopropyl 1-chloroacetoxy-3-butenylphosphonate [(±)-7]: 1-
Hydroxy-3-butenylphosphonate (±)-6 (7.650 g, 32.38 mmol) and dry
pyridine (8.150 g, 8.32 mL, 103.03 mmol) were dissolved in dry CH Cl
30 mL) at 0 °C under argon atmosphere. Chloroacetic anhydride (7.757
g, 45.33 mmol, 1.40 equiv, 95%; dissolved in 20 mL of dry CH Cl ) was
Dervatization
of
phosphaaspartic
acids
with
2,4-
dinitrofluorobenzene (Sangers reagent):[
29]
To 200 µL of
2
2
phosphaaspartic acid (20 mM) in 0.1 M carbonate buffer (pH 9.5), 100 µL
of Sanger´s reagent (Sigma Aldrich, Germany) at a concentration of
(
2
5
.5% in acetonitrile (v/v) was added. The reaction mixture was heated at
0 °C for 15 min. After reaching room temperature, 500 µL of mobile
2
2
added drop wise at 0 °C and the solution was stirred at that temperature
for 1.5 h. Water (50 mL) was then added and the organic layer was
separated after 15 min. The aq layer was extracted with EtOAc (2 × 30
mL). The combined organic layers were washed with 2 M HCl (2 × 15
mL), water (10 mL), a saturated aqueous solution of NaHCO
dried (Na SO ) and concentrated under reduced pressure. The residue
was purified by flash chromatography (hexanes/EtOAc, 2:1, R = 0.25) to
yield α-chloroacetoxyphosphonate (±)-7 (9.469 g, 94%) as colorless oil.
phase was added.
Derivatization of phosphaarginines with 6-aminoquinolyl-N-
hydroxysuccinimidyl carbamate (AQC):[30] To 70 µL 0.2 M borate
buffer (pH 8.5), 10 µL phosphaarginine (20 mM in water) was added,
followed by the addition of 20 µL AQC-reagent (Synchem, Germany) at a
concentration of 3 mg/mL in dry acetonitrile. The reaction mixture was
heated for 10 min at 55 °C. Samples were analyzed without further
treatment.
3
(10 mL),
2
4
f
1
H NMR (400.27 MHz, CDCl
1H, =CH), 5.23 (ddd, J = 10.2, 8.9. 3.7 Hz, 1H, PCH), 5.09 (qd, J = 17.0,
1.5 Hz, 1H, =CH ), 5.04 (br. d, J = 10.1 Hz, 1H, =CH ), 4.78-4.63 (m, 2H,
OCH), 4.03 (s, 2H, CH Cl), 2.68-2.56 (m, 1H, CH ), 2.54-2.40 (m, 1H,
CH ), 1.29 (d, J = 6.1 Hz, 6H, CH ), 1.28 (d, J = 6.1 Hz, 3H, CH ), 1.27 (d,
J = 6.1 Hz, 3H, CH ); C NMR (100.61 MHz, CDCl ): δ = 166.4 (d, J =
6.1 Hz, C=O), 132.4 (d, J = 13.9 Hz, =CH), 118.8 (=CH ), 71.9 (d, J = 6.7
Hz, OCH), 71.7 (d, J = 7.1 Hz, OCH), 69.2 (d, J = 170.7 Hz, CHP), 40.6
3
): δ = 5.68 (dddd, J = 17.0, 10.1, 7.9, 6.1 Hz,
Diisopropyl allyloxymethylphosphonate (5): DBU (15 drops) was
added to a stirred mixture of diisopropyl phosphite (13.29 g, 80 mmol)
and paraformaldehyde (2.52 g, 84 mmol, 1.05 equiv) at room
temperature. An exothermic reaction (fume cupboard!) started which was
not cooled and the reaction mixture became clear. After 1 hr NaOH (9.60
2
2
2
2
2
3
3
13
3
3
g, 240 mmol, dissolved in 32 mL of H
2
O, cooled), allyl bromide (11.61 g,
2
8.31 mL, 96 mmol, 1.2 equiv) and benzyltriethylammonium chloride (71
mg, 0.31 mmol) were added. After stirring vigorously for 3-4 h at room
temperature, the hydroxymethylphosphonate was consumed (TLC:
(ClCH
2
), 34.1 (CH
2
), 24.1 (d, J = 3.3 Hz, CH
3
), 24.0 (d, J = 4.0 Hz, CH
3
),
31
24.0 (d, J = 5.3 Hz, CH
3
), 23.8 (d, J = 5.2 Hz, CH
3
); P NMR (162.03
EtOAc,
hydroxymethylphosphonate). Water (32 mL) was added and the mixture
was extracted with CH Cl (3 × 30 mL). The combined organic layers
were washed with brine (20 mL), dried (Na SO ) and concentrated under
R
f
=
0.58 for allyloxymethylphosphonate;
R
f
=
0.17 for
MHz, CDCl ): δ = 16.7. IR (Si):  = 2981, 2349, 1768, 1645, 1465, 1388,
3
1261, 1165, 1105, 989 cm‒1. C H ClO P (312.73): calcd. C 46.09, H
12
22
5
2
2
7.09; found C 46.13, H 6.74.
2
4
reduced pressure. Bulb to bulb distillation (95 – 110 ˚C/0.6 mbar)
furnished allyloxymethylphosphonate 5 (15.12 g, 80%) as a colourless
Lipase-catalyzed enzymatic resolution of (±)-diisopropyl 1-
chloroacetoxy-3-butenylphosphonate [(±)-7]: Diisopropyl 1-
20
[11]
20
liquid; n
H NMR (400.13 MHz, CDCl
D
1.4327 (lit. : n
D
1.4312).
chloroacetoxy-3-butenylphosphonate (±)-7 (7.509 g, 24.01 mmol) was
dissolved in a mixture of hexanes (25 mL), tBuOMe (25 mL) and
phosphate buffer (125 mL, 25 mM, pH 7.0). The mixture was stirred
vigorously and 0.5 M NaOH was added by the autotitrator to maintain pH
1
3
: δ = 5.83 (tdd, J = 17.3, 10.4, 5.7 Hz, 1H,
=
1
CH), 5.25 (qd, J = 17.3, 1.5 Hz, 1H, =CH
H, =CH ), 4.71 (septd, J = 7.7, 6.2 Hz, 2H, OCH), 4.05 (td, J = 5.7, 1.5
), 3.66 (t, J = 8.7 Hz, 2H, PCH ), 1.30 (d, J = 6.2 Hz, 6H,
), 1.29 (d, J = 6.2 Hz, 6H, CH ): δ =
); 13C NMR (100.61 MHz, CDCl
33.7 (=CH), 118.1 (=CH ), 73.8 (d, J = 12.9 Hz, OCH ), 70.9 (d, J = 6.7
Hz, 2POCH), 64.4 (d, J = 168.5 Hz, PCH ), 24.0 (d, J = 3.8 Hz, 2CH ),
3.9 (d, J = 4.6 Hz, 2CH ): δ = 19.6. IR
); 31P NMR (162.03 MHz, CDCl
Si):  = 2981, 1387, 1260, 1108, 989 cm‒1. C10
P (236.25): calcd. C
0.84, H 8.96; found C 50.73, H 8.86.
2
), 5.18 (qd, J = 10.4, 1.5 Hz,
2
Hz, 2H, OCH
CH
1
2
2
7
.0.[31] Lipase from Thermomyces lanuginosus (≥100,000 U/g, 0.2 mL of
3
3
3
commercial solution from Sigma Aldrich) was added, pH was again
adjusted to 7.0, and kept there by automatic addition of 0.5 M NaOH at
room temperature. When the conversion was 40% based on the
consumption of base after 3.5 h, EtOAc (30 mL) was added. The organic
phase was separated, if necessary facilitated by centrifugation, and the
aqueous one extracted with EtOAc (3 × 60 mL). Centrifugation was used
to ease separation of phases. The combined organic layers were washed
2
2
2
3
2
(
5
3
3
21 4
H O
(±)-Diisopropyl 1-hydroxy-3-butenylphosphonate [(±)-6]: n-BuLi
with brine (30 mL), dried (Na
pressure. The residue was purified by flash chromatography
hexanes/EtOAc, 1:1 for chloroacetate, EtOAc for hydroxyphosphonate).
2 4
SO ) and concentrated under reduced
(18.92 mL, 2.5 M solution in hexanes) was drop wise added to a stirred
solution of iPr
35 °C under argon atmosphere. After 15 min, this freshly prepared LDA
was added to a solution of distilled allyloxymethylphosphonate 5 (8.941 g,
7.85 mmol) in dry THF (35 mL) under argon at ‒78 °C. The reaction
mixture was stirred for 2 h at ‒78 °C (TLC: heptanes/EtOAc, 2:1;
developed twice, 0.20 for starting material, 0.11 for
hydroxyphosphonate). EtOAc (50 mL) was added, the cooling bath (‒
2
NH (4.595 g, 45.41 mmol, 6.36 mL) in dry THF (6.8 mL) at
(
‒
to yield (R)-chloroacetate (R)-7 (4.05 g, 54%) and (S)-α-
hydroxyphosphonate (S)-6 (2.076 g, 37%) as colorless oils; (S)-6: [α] 2
0
D
3
=
+22.8 (c = 2.10, acetone).
R
f
=
5
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700948
FULL PAPER
The α-hydroxyphosphonate (S)-6 was converted to the (R)-Mosher ester
Ru) after cooling (0 °C). The reaction mixture was stirred vigorously for
17 h, allowing the temperature in the cooling bath to rise to room
temperature. Water (7 mL) and HCl (3 mL, 2 M) were added and the
organic phase was separated. The aq phase was extracted with EtOAc
according to a literature procedure; ee 97%. 31P NMR (161.98 MHz,
): δ = 15.9 for (R)-Mosher ester of (S)-6 and 15.4 of (R)-6.[18a]
CDCl
3
(
3 × 10 mL). To ease phase separation, centrifugation was advantageous.
The combined organic layers were washed with a mixture of brine (5 mL)
and HCl (2 mL, 2M), dried (Na SO ) and concentrated under reduced
Preparation of enantiomerically pure (R)-(‒)-diisopropyl 1-hydroxy-
-butenylphosphonate [(R)-6]: Diisopropyl 1-chloroacetoxy-3-
butenylphosphonate [(R)-7] (8.423 g, 26.93 mmol, ee 68%, recovered
from resolutions to obtain (S)-hydroxyphosphonate of high ee) was
subjected to a second resolution with the lipase from Thermomyces
lanuginosus (25 mL of hexanes/25 mL of tbutyl methyl ether/125 mL of
3
2
4
pressure. The somewhat dark colored residue (632 mg, 92%) (±)-3-
azido-3-(diisopropoxyphosphinyl)propanoic acid [(±)-9] crystallized, when
1
left overnight in the fridge. It was used in the next step after recording H
31
and P NMR spectra.
Similarly, (R)-1-azido-3-butenylphosphonate (R)-8 (1.462 g, 5.60 mmol)
was converted to (R)-azidocarboxylic acid (±)-9 (1.397 g, 89%). The
spectroscopic data were identical to those of the racemate.
25 mM phosphate buffer/1 mL of lipase/autotitrator) using the method to
obtain (S)-1-hydroxy-3-butenylphosphonate (S)-6. The reaction mixture
was worked up after 48 h at a conversion of 16%, when addition of
NaOH had stopped. Flash chromatography (hexanes/EtOAc, 1:1, R =
f
1H NMR (400.27 MHz, CDCl
3 2
): δ = 8.25 (br. s, 1H, CO H), 4.86-4.73 (m,
2
H, POCH), 4.00 (ddd, J = 12.3, 10.9, 3.2 Hz, 1H, PCH), 2.73 (AB part of
ABX system coupling with phosphorus, JAB = 17.1 Hz, JAX = 3.2 Hz, JAP
.3 Hz, JBX = 10.8 Hz, JBP = 8.0 Hz, 2H, CH ), 1.358 (d, J = 6.2 Hz, 6H,
); 31P NMR (162.03 MHz, CDCl
CH ), 1.355 (d, J = 6.1 Hz, 6H, CH ): δ =
8.4.
0
.27) furnished (R)-(‒)-1-chloroacetoxyphosphonate (R)-7 (5.560 g, 66%)
=
20
as colorless oil; [α]
D
= −13.5 (c = 1.5, acetone).
7
2
A solution of (R)-diisopropyl 1-chloroacetoxy-3-butenylphosphonate [(R)-
] (3.390 g, 10.84 mmol) in dry methanol (30 mL) with Et N (1.306 g, 1.7
mL, 12.9 mmol, 1.2 equiv) was stirred overnight at RT and quenched with
water (10 mL). CH Cl (20 mL) was added and the organic layer was
separated. The aqueous layer was extracted with CH Cl (2 × 10 mL).
The combined organic layers were washed with brine, dried (Na SO
and concentrated under reduced pressure. The residue was purified by
flash chromatography (EtOAc, 0.36) to yield (‒)-
hydroxyphosphonate (R)-7 (2.174 g, 85%) as colorless oil; [α]
c = 1.4, acetone).
3
3
3
7
3
1
2
2
Preparation of (±)-10: (±)-3-Azido-3-(diisopropoxyphosphinyl)propanoic
prepared from 642 mg, 2.457 mmol of 1-azido-3-butenylphosphonate
±)-9] was dissolved in dry ethanol. Water (5 ml), concentrated HCl (7
2
2
[
(
2
4
)
drops) and Pd/C (90 mg, 10%) were added and the mixture was
hydrogenated (50 psi) in a Parr apparatus at room temperature for 3 h.
The mixture was filtered through Celite. The clear solution was
concentrated under reduced pressure. HCl (20 mL, 6 M) was added to
the residue. The mixture was refluxed for 4 h and then concentrated after
cooling under reduced pressure. The residue was dried over KOH in a
R
f
=
20
D
= −23.3
(
The ee (99%) was determined using (R)-(+)-tert-butyl(phenyl)-
phosphinothioic acid as chiral shift reagent (2 equiv) and only
1
31
resonances of (R)-enantiomer were found in H and P NMR spectrum,
spiking with racemate gave two signals in the 31P NMR spectrum;[19a] 31
NMR (162.03 MHz, toluene-D ): δ = 23.1 for (S)-hydroxyphosphonate,
2.8 for (R)-hydroxyphosphonate; 1H NMR (400.27 MHz, toluene-D
),
significant resonances: δ = 4.07 (ddd, J = 8.5, 5.3, 3.6 Hz, PCH) for (R)-
vacuum desiccator for 18
chromatography (Dowex 50W × 8, H , o. d. 2 cm × 38 cm, elution with
h
and purified by cation exchange
P
+
8
f
water, fractions of 10 mL; R = 0.30). Ninhydrin-positive fractions were
pooled and concentrated under reduced pressure to give racemic
phosphaaspartic acid [(±)-10] [236 mg, 61% combined yield for three
steps starting from azide (±)-6]; mp 227-229 °C (decomp.) (lit.[7d]: 226
2
8
hydroxyphosphonate, 3.90 (td,
hydroxyphosphonate.
J
=
10.0, 3.6 Hz, PCH) for (S)-
°C).
(
(
(
±)- and (R)-(‒)-Phosphaaspartic acid
±)- and (R)-(‒)-diisopropyl 1-azido-3-butenylphosphonate [(±) and
R)-8]: (±)-1-Hydroxy-3-butenylphosphonate (±)-6 (1.979 g, 8.38 mmol)
Preparation of (R)-(‒)-10: 1,3-Propanedithiol (667 mg, 0.6 ml, 6.16
mmol) and Et N (626 mg, 0.86 ml, 6.19 mmol) were added to a solution
of 3-azidopropanoic acid (R)-9 (575 mg, 2.06 mmol) in methanol (9 mL)
under argon atmosphere at room temperature. After stirring for 18 h,
volatile components were removed under reduced pressure (0.5 mbar).
3
and Ph
30 mL) under argon. At 0 °C, DIAD (2.343 g, 2.3 mL, 10.89 mmol, 1.30
equiv, dissolved in 3 mL of dry toluene) was added, followed by HN (8.7
mL, 10.88 mmol, 1.25 M in toluene). The solution was stirred for 30 min
at 0 °C and 3 h at ambient temperature (TLC: hexanes/EtOAc, 1:1, R
.62 for azide). After the addition of MeOH (5 drops) and cold hexanes
25 mL), the flask was allowed to stand for a few h in the fridge (4 °C).
The crystals (Ph PO and DIADH ) were collected and thoroughly washed
3
P (2.856 g, 10.89 mmol, 1.3 equiv) were dissolved in dry toluene
(
3
Water (10 mL) and CH
separated and the aq one was extracted with CH
2
Cl
2
(10 mL) were added. The organic layer was
Cl (2 × 10 mL). The
2
2
f
=
combined organic layers were concentrated under reduced pressure.
Then 6 M HCl (20 mL) was added to the residue and the solution was
refluxed for 4 h, and concentrated under reduced pressure. The residue
0
(
3
2
+
was purified by ion exchange chromatography (Dowex 50 W × 8, H ,
with hexanes. The combined filtrates were concentrated under reduced
pressure. The residue was flash chromatographed (hexanes/EtOAc, 1:1,
water as eluens, fractions of 25 mL). Ninhydrin-positive fractions were
combined and concentrated under reduced pressure to yield
aminophosphonic acid (R)-10 (205 mg, 59%) as colorless crystals; mp
R
f
= 0.62) to yield racemic azide (±)-8 (1.620 g, 74%) as oil.
Similarly, (S)-(+)-1-hydroxy-3-butenylphosphonate (S)-6 (1.912 g, 8.09
mmol, 97% ee) was converted to azide (R)-8 (1.670 g, 79%); [α] 20
= –
1.0 (c = 1.33, acetone).
The spectroscopic data of (±)- and (R)-8 were identical. H NMR (400.27
MHz, CDCl ): δ = 5.84 (tdd, J = 17.0, 10.2, 6.7 Hz, 1H, =CH), 5.20 (qd, J
17.0, 1.3 Hz, 1H, =CH ), 5.15 (br. d, J = 10.2 Hz, 1H, =CH ), 4.84-4.70
m, 2H, OCH), 3.36 (td, J = 11.7, 3.4 Hz, 1H, PCH), 2.67-2.56 (m, 1H,
CH ), 2.45-2.33 (m, 1H, CH ), 1.35 (d, J = 6.2 Hz, 9H, CH ), 1.34 (d, J =
.2 Hz, 3H, CH ); C NMR (100.61 MHz, CDCl ): δ = 133.4 (d, J = 15.1
Hz, =CH), 118.4 (=CH ), 71.9 (d, J = 7.5 Hz, OCH), 71.8 (d, J = 7.0 Hz,
OCH), 57.2 (d, J = 156.9 Hz, CHP), 33.0 (CH ), 24.12 (d, J = 3.6 Hz,
CH ), 24.11 (d, J = 3.7 Hz, CH ), 23.9 (d, J = 4.7 Hz, 2CH
161.98 MHz, CDCl ): δ = 20.7. IR (Si): ν = 3475, 2983, 2937, 2121,
33-235 °C (water/ethanol) (lit.[8b]: 234-237 °C); [α]
20
2
D
= –34.1 (c = 0.98,
D
water) {lit.[8b]: [α]
25
D
= –33.6 (c = 1.0, water)}.
3
The NMR spectra of (±)- and (R)-10 were identical and identical to one in
the literature[32] but different[33] to another one. 1H NMR (400.13 MHz,
1
3
D
2
O): δ = 3.71 (ddd, J = 14.0, 10.2, 3.7 Hz, 1H, CHP), 3.05 (A part of
ABX-sys, JAB = 18.0 Hz, J = 8.6, J = 3.7 Hz, 1H, CH ), 2.85 (B part of
ABX-sys, JAB = 18.0 Hz, J = 10.2, J = 7.1 Hz, 1H, CH
); 13C NMR (100.61
MHz, D O): δ = 174.6 (d, J = 15.0 Hz, CO), 46.0 (d, J = 143.0 Hz, PCH),
); 31P NMR (161.98 MHz, D
3.1 (CH O): δ = 11.4. C NO (169.07):
=
(
2
2
2
2
2
3
2
13
6
3
3
2
2
3
2
2
H
3 8
5
2
calcd. C 21.31, H 4.77, N 8.28; found for (±)-10: C 21.38, H 4.90, N 8.05;
found for (R)-10: C 21.46, H 4.68, N 8.15.
31
3
3
3
); P NMR
(
3
‒1
2
102, 1387, 1377, 1258, 1105, 991, 914 cm . C10H N O P (261.26)
20 3 3
calcd. C 45.97, H 7.72, N 16.0; found C 46.12, H 7.73, N 15.90.
(±)-, (R)- and (S)-diisopropyl 1-(4-nitrobenzenesulfonyloxy)-3-
butenyl-phosphonate [(±)-, (R)- and (S)-11]: 4-Nitrobenzenesulfonyl
chloride (3.616 g, 16.32 mmol), DMAP (1.329 g, 10.88 mmol, dissolved
(
(
(
±)-
and
(R)-(–)-3-amino-3-phosphonopropanoic
acid
phosphaaspartic acid) [(±)- and (R)-(‒)-10] - (±)- and (R)-3-azido-3-
diisopropoxyphosphinyl)propanoic acid [(±)- and (R)-9]: Racemic 1-
in 5 mL of dry CH
added to a solution of 1-hydroxy-3-butenylphosphonate (±)-6 (2.570 g,
0.88 mmol) dissolved in dry CH Cl (30 mL) at ‒35 °C under argon
atmosphere. The reaction mixture was allowed to warm slowly in the
2 2 3
Cl ) and Et N (2.202 g, 3.03 mL, 21.76 mmol) were
azidophosphonate (±)-8 (642 mg, 2.46 mmol) was dissolved in a CCl
4.9 mL). CH CN (4.9 mL), H O (7.3 mL) and NaIO (2.366 g, 11.06
mmol, 4.5 equiv) were added, followed by RuCl ×H O (28 mg, 45-55%
4
1
2
2
(
3
2
4
3
2
6
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700948
FULL PAPER
cooling bath to room temperature in 18 h. HCl (30 mL, 2 M) was added
and the organic layer was separated after stirring for 15 min. The
CH
23.2 (d, J = 4.9 Hz, CH
MHz, CDCl ): δ = 14.9. IR (ATR): ν = 3396, 2981, 2936, 2875, 1534,
9
1374, 1351, 1240, 1186, 992 cm . C16H26NO PS (439.42): calcd. C
43.73, H 5.96, N 3.19, O 32.77, S 7.30; found C 43.50, H 5.89, N 3.09, O
32.77, S 6.91.
2
), 27.19 (CH
2
), 24.00 (d, J = 4.6 Hz, CH
3
), 23.9 (d, J = 3.8 Hz, CH
3
),
); 31P NMR (242.99
3
), 23.7 (d, J = 4.9 Hz, CH
3
aqueous layer was extracted with CH
organic layers were washed with brine (20 mL), dried (Na
concentrated under reduced pressure. The residue was purified by flash
chromatography (hexanes/EtOAc, 2:1, R = 0.25) to yield nosylate (±)-11
4.166 g, 91%) as colorless crystals, mp 79-80 °C (heptanes).
Similarly, (S)-(+)-hydroxyphosphonate (S)-6 (2.201 g, 9.32 mmol, [α]
22.1 (c = 1.1, acetone) gave (S)-(+)-nosylate (S)-11 (3.528 g, 77%),
2
Cl
2
(2 × 30 mL). The combined
3
‒1
2
SO ) and
4
f
(
20
Racemic 3-hydroxyphosphonates (±)-13a,b: 1H NMR (600.25 MHz,
CDCl ): ratio of major product/minor product B, 36:64: δ = 8.39-8.35 (m,
3
4H, Har, A, B), 8.19-8.16 (m, 2H, Har, B), 8.16-8.12 (m, 2H, Har, A), 5.15
(ddd, J = 10.7, 8.9, 3.0 Hz, 1H, PCH, B), 5.01 (ddd, J = 11.3, 7.1, 5.5 Hz,
1H, PCH, A), 4.75-4.66 (m, 2H, POCH, A), 4.69-4.62 (m, 1H, POCH, B),
4.64-4.56 (m, 1H, POCH, B), 4.06-3.99 (m, 1H, OCH, A), 3.97-3.90 (m,
D
=
+
20
[
α]
D
= +4.7 (c = 1.2, acetone), 99.3% ee by chiral HPLC.
Similarly, (R)-(‒)-hydroxyphosphonate (R)-6 {2.173 g, 9.20 mmol, [α]
20
D
=
‒
23.3 (c = 1.4, acetone)} was converted to (R)-(‒)-nosylate (R)-11 (2.89
20
g, 75%) as heavy oil; [α]
D
= ‒5.7 (c = 0.95, acetone), ee >99% by chiral
HPLC.
1H, OCH, B), 2.77 (br. s, 2H, OH, A, B), 2.06-1.97 (m, 1H, CH
1.82 (m, 1H of A, 2H of B, CH ), 1.30-1.25 (overlapping d, 12H of A, 6H
of B, CH ), 1.23 (d, J = 6.4 Hz, 3H, CH , B), 1.22 (d, J = 6.3 Hz, 3H, CH
B), 1.21 (d, J = 5.9 Hz, 3H, CH , B), 1.13 (d, J = 6.2 Hz, CH
, A); 13
NMR (150.93 MHz, CDCl ): δ = 150.73 (C , A), 150.72 (C , B), 142.5 (C
A), 142.2 (C , B), 129.5 (2HCar, B), 129.3 (2HCar, A), 124.3 (2HCar, A),
124.1 (2HCar, B), 75.54 (d, J = 172.5 Hz, PCH, B), 75.5 (d, J = 171.6 Hz,
PCH, A), 72.84 (d, J = 7.2 Hz, POCH, A), 72.81 (d, J = 6.8 Hz, POCH,
A), 72.4 (d, J = 6.8 Hz, POCH, B), 72.3 (d, J = 7.0 Hz, POCH, B), 63.4 (d,
2
, A), 1.95-
1
The NMR spectra of (±)-, (S)- and (R)-11 were identical. H NMR (400.27
MHz, CDCl
2
3
): δ = 8.37-8.32 (m, 2H, Har), 8.16-8.10 (m, 2H, Har), 5.72
3
3
3
,
(dddd, J = 17.1, 10.1, 7.2, 6.9 Hz, 1H, =CH), 5.06 (qd, J = 17.1 Hz, J =
3
3
C
1.4 Hz, 1H, =CH
4.4 Hz, 1H, PCH), 4.70 (sepd, J = 7.1, 6.2 Hz, 1H, OCH), 4.65 (sepd, J =
7.2, 6.2 Hz, 1H, OCH), 2.72-2.61 (m, 1H, CH ), 2.60-2.49 (m, 1H, CH ),
1.30 (d, J = 6.2 Hz, 6H, CH ), 1.26 (d, J = 6.2 Hz, 3H, CH ), 1.25 (d, J =
6.2 Hz, 3H, CH
); 13C NMR (100.61 MHz, CDCl
2
), 5.03 (br. d, J = 10.1 Hz, 1H, =CH
2
), 4.88 (td, J = 9.1,
3
q
q
q
,
q
2
2
3
3
3
3
): δ = 150.7 (C
q
), 142.8
(
(
C
q
), 131.8 (d, J = 11.4 Hz, =CH), 129.4 (2HCar), 124.1 (2HCar), 119.5
=CH ), 77.5 (d, J = 170.7 Hz, CHP), 72.5 (d, J = 6.7 Hz, POCH), 72.4 (d,
), 24.1 (d, J = 4.6 Hz, CH ), 24.0 (d, J = 4.9
), 23.9 (d, J = 5.1 Hz, CH ), 23.7 (d, J = 4.9 Hz, CH
); 31P NMR
162.03 MHz, CDCl ): δ = 14.328. IR (Si, (S)-nosylate): ν = 2984, 1536,
377, 1351, 1260, 1187, 1104, 995 cm‒1. C16
PS (421.40): calcd.
J = 6.2 Hz, HOCH, A), 62.6 (d, J = 12.0 Hz, HOCH, B), 40.1 (CH
39.5 (CH , B), 24.0 (d, J = 3.5 Hz, CH , A), 23.99 (d, J = 3.6 Hz, CH
23.97 (d, J = 3.6 Hz, CH , B), 23.92 (d, J = 3.8 Hz, CH , B), 23.85 (d, J =
4.9 Hz, CH , A), 23.8 (d, J = 5.1 Hz, CH3, A), 23.699 (d, J = 5.2 Hz, CH
A), 23.694 (d, J = 4.7 Hz, CH , B), 23.5 (CH , B), 23.3 (CH
, A); 31P NMR
(242.99 MHz, CDCl ): δ = 15.7, 15.5. IR (ATR): ν = 3383, 2981, 2936,
1534, 1376, 1349, 1228, 1188, 1096, 989, 939 cm‒1. C16
PS
439.42): calcd. C 43.73, H 5.96, N 3.19, O 32.77, S 7.30; found C 44.01,
H 6.09, N 3.18, O 32.67, S, 7.26.
2
, A),
2
2
3
3
, A),
J = 7.2 Hz, POCH), 35.1 (CH
Hz, CH
(
1
2
3
3
3
3
3
3
3
3
,
3
3
3
3
H24NO
8
3
C 45.60, H 5.74, N 3.32; found C 45.58, H 5.79, N 3.34.
H26NO
9
(
(
±)-,
sulfonyloxy)butylphosphonate [(±)-, (R)- and (S)-12] and 13a,b]:
BH ×THF (12.76 mL, 1 M, 1.4 equiv.) was added dropwise to a stirred
solution of racemic 1-nosyloxy-3-butenylphosphonate (±)-11 (3.840 g,
.11 mmol) in dry THF (28 mL) under argon atmosphere at 0 °C. After
stirring for 1.5 h at 0 °C and 0.5 h at RT, dry MeOH (5 mL) was added at
°C. 15 min later, the reaction mixture was concentrated to one third of
its volume under reduced pressure. Then THF (27.5 mL), H (3.6 mL)
and a saturated aqueous solution of NaHCO (3.45 mL) were added at
°C. After stirring for 30 min at 0 °C and 1.5 h at room temperature,
(R)-
and
(S)-diisopropyl
4-hydroxy-1-(4-nitrobenzene-
3
(±)-, (R)-(‒)- and (S)-(+)-diisopropyl 4-[N,N´-bis(tert-butoxy-carbonyl)-
guanidino)]-1-(4-nitrobenzenesulfonyloxy)butylphosphonate [(±)-,
(R)- and (S)-13]: Racemic diisopropyl 4-hydroxy-1-(4-nitrobenzene-
sulfonyloxy)butylphos-phonate [(±)-12] (3.976 g, 9.05 mmol), N,N´-
bis(tert-butoxycarbonyl)guanidine (3.520 g, 13.76 mmol, 1.5 equiv) and
9
0
O
2 2
3
Ph P (3.609 g, 13.76 mmol) were dissolved in dry THF (36 mL) under
3
argon and cooled at 0 °C. DIAD (2.782 g, 13.76 mmol, 2.71 mL, 1.5
equiv) was dropwise added to the stirred solution. After stirring at room
temperature for 6 h, water (0.5 mL) was added and 10 min later the
mixture was concentrated under reduced pressure. The residue was
0
water (25 mL) and pentaerythritol (1.737 g, 12.76 mmol) were added.
The mixture was vigorously stirred for 10 min. EtOAc (25 mL) was added,
the organic phase was separated and the aq one was extracted with
EtOAc (2 × 25 mL). The combined organic layers were washed with
water (10 mL) and brine (20 mL), dried (Na SO ) and concentrated under
2 4
reduced pressure (water bath only of room temperature! to prevent
cyclization of product). The residue was flash chromatographed [ratio of
diluted with iPr
DIADH to crystallize. The crystals were collected and washed with iPr
The mother liquor was concentrated under reduced pressure and flash
chromatographed (hexanes/EtOAc, 2:1, 0.27) to yield
2
O (36 mL) and kept at 4 °C for 18 h to allow Ph
3
PO and
2
2
O.
R
f
=
guanidinophosphonate (±)-14 (5.293 g, 86%) as colorless foam
containing some EtOAc which could not be removed at 0.5 mbar.
Similarly, (R)-4-hydroxy-1-(4-nitrobenzenesulfonyloxy)butylphosphonate
hydroxyphosphonates
heptanes/EtOAc, 1:2, R
mixture of (±)-13a,b (1.033 g, 26%) as solid and ω–hydroxyphosphonate
±)-12 (2.402 g, 60%) as heavy oil; ratio: 32:88.
Similarly, (R)-(‒)-nosylate (R)-11 (2.89 g, 6.86 mmol) was converted to
ω–hydroxynosylate (R)-12 (1.44 g, 48%), [α] 20
= ‒10.3 (c = 0.93,
by
31P
NMR:
12/13a,b,
70:(11:19);
f
= 0.23 for (±)-13a,b, 0.09 for (±)-12] to give a
(R)-12 (1.44 g, 3.28 mmol, ee >99%) was converted to
guanidinophosphonate (R)-14 (1,807 g, 81%) as a colorless foam; [α] 1
8
(
D
= +1.4 (c = 1.5, acetone).
Similarly, (S)-4-hydroxy-1-(4-nitrobenzenesulfonyloxy)butylphosphonate
D
acetone), heavy oil. Ratio of hydroxyphosphonates in crude product by
31P NMR: 12/13a,b, 70:(11:19).
(S)-12] (928 mg, 2.11 mmol, ee >99%) was converted to
18
guanidinophosphonate (S)-14 (1,30 g, 90%) as a colorless foam; [α]
‒1.8 (c = 0.95, acetone).
D
=
Similarly, (S)-(+)-nosylate (S)-11 (1.99 g, 4.72 mmol) was converted to
ω-hydroxynosylate (S)-12 (0.958 g, 46%), [α] 20
= +9.5 (c = 0.95,
The spectroscopic data of (±)-, (R)- and (S)-14 were identical. 1H NMR
(600.25 MHz, CDCl ): δ = 9.37 (br. s, 1H, NH ), 9.17 (br s, 1H, NH ),
D
acetone), heavy oil. Ratio of hydroxyphosphonates in crude product by
31P NMR: 12/13a,b, 72:(11:17).
The spectroscopic data of (±)-, (R)- and (S)-12 were identical. 1H NMR
3
2
2
8.39-8.34 (m, 2H, Har), 8.20-8.14 (m, 2H, Har), 4.97-4.91 (m, 1H, CHP),
4.67 (oct, J = 6.2 Hz, 1H, POCH), 4.59 (oct, J = 6.2 Hz, 1H, POCH),
(
4
600.25 MHz, CDCl
.94 (td, J = 9.1, 4.5 Hz, 1H, PCH), 4.67 (sepd, J = 7.0, 6.2 Hz, 1H,
POCH), 4.60 (sepd, J = 7.1, 6.2 Hz, 1H, POCH), 3.67-3.60 (m, 2H,
OCH ), 2.29 (br. s, 1H, OH), 2.09-2.00 (m, 1H, CH ), 195-1.84 (m, 1H,
CH ), 1.81-1.73 (m, 1H, CH ), 1.70-1.61 (m, 2H, CH ), 1.27 (d, J = 6.2
Hz, 6H, CH ), 1.21 (d, J = 6.2 Hz, 3H,
CH ), 142.6 (C ), 129.4
2HCar), 124.2 (2HCar), 78.0 (d, J = 171.0 Hz, PCH), 72.4 (d, J = 6.8 Hz,
POCH), 72.3 (d, J = 7.2 Hz, POCH), 61.7 (HOCH ), 28.3 (d, J = 9.6 Hz,
3
): δ = 8.38-8.34 (m, 2H, Har), 8.17-8.14 (m, 2H, Har),
3.96-3.83 (m, 2H, NCH
CH ), 1.51 (s, 9H, tBu), 1.48 (s, 9H, tBu), 1.27 1.26, 1.24, 1.22 (4 d, each
J = 6.2 Hz, 3H, CH ): δ = 163.8 (C=N),
); 13C NMR (150.93 MHz, CDCl
160.5 (C=O), 154.9 (C=O), 150.6 (C ), 142.69 (C ), 129.4 (2HCar), 124.2
(2HCar), 84.0 (OC), 78.8 (OC), 78.1 (d, J = 171.5 Hz, PCH), 72.3 (d, J =
6.8 Hz, POCH), 72.2 (d, J = 7.3 Hz, POCH), 43.6 ( NCH ), 28.3 (3C,
tBu), 28.0 (3C, tBu), 27.6 (CH ), 24.9 (d, J = 10.2 Hz, CH ), 24.1 (d, J =
3.5 Hz, CH ), 23.98 (d, J = 3.8 Hz, CH ), 23.94 (d, J = 5.0 Hz, CH ),
23.71 (d, J = 4.9 Hz, CH ): δ = 14.7. IR
);31P NMR (242.99 MHz, CDCl
2 2
), 1.91-1.74 (m, 3H, CH ), 1.74-1.64 (m, 1H,
2
3
3
2
2
q
q
2
2
2
3
), 1.23 (d, J = 6.2 Hz, 3H, CH
3
2
); 13C NMR (150.93 MHz, CDCl
3
3
): δ = 150.7 (C
q
q
2
2
(
3
3
3
2
3
3
7
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700948
FULL PAPER
(
1
Si): ν = 3385, 2982, 1714, 1611, 1536, 1370, 1274, 1254, 1187, 1148,
100, 993 cm‒1. C27
12PS (680.71): calcd. C 47.64, H 6.66, N 8.23;
found C 47.62, H 6.74, N 8.10.
(OC), 78.6 (OC), 70.3 (d, J = 5.7 Hz, POCH), 70.3 (d, J = 5.6 Hz, POCH),
45 4
H N O
48.6 (d, J = 151.6 Hz, CH), 44.1 (CH
(3C, tBu), 25.1 (d, J = 12.4 Hz, CH ), 24.1 (d, J = 4.2 Hz, 3CH
d, J = 6.1 Hz, CH ): δ = 27.3. IR (Si): ν =
); 31P NMR (242.99 MHz, CDCl
3382, 2977, 2932, 1710, 1608, 1509, 1367, 1272, 1239, 1143, 1102,
2 2
), 28.3 (3C, tBu), 28.1 (CH ), 28.0
2
3
), 24.11
(
3
3
(
±)-, (S)-(+)- and (R)-(‒)-Diisopropyl 1-azido-4-[N,N´-bis(tert-
butoxycarbonyl)-guanidino)]butylphosphonate [(±)-, (S)- and (R)-15]:
Dry CH CN (19 mL) was added to the mixture of (±)-4-(1,3-bis(tert-
butoxycarbonyl)guanidino)-1-(4-nitrobenzenesulfonyloxy)butylphospho-
nate (±)-14 (2.13 g, 3,13 mmol), powdered NaN (610 mg, 9.39 mmol, 3
-
1
43 4 7
975cm . C21H N O P (494.57): calcd. C 51.00, H 8.76, N 11.33; found
3
C 50.99, H 9.27, N 11.21.
3
(±)-, (S)-(+)- and (R)-(‒)-1-amino-4-guanidinobutylphosphonate [(±)-,
equiv) and 15-crown-5 (1.034 g, 0.93 mL, 4.70 mmol, 1.5 equiv) under
argon. The mixture was stirred at 60 °C for 7 h, cooled and concentrated
(S)-
and
(R)-17]:
(±)-1-Amino-4-[N,N´-bis(tert-butoxycarbonyl)-
guanidino)]butylphospho-nate (±)-16 (765 mg, 1.55 mmol) was dissolved
in HCl (30 mL, 6 M) and refluxed for 5 h. After cooling to room
temperature, the solution was concentrated under reduced pressure. The
residue was dissolved in water and lyophilized. The residue was
dissolved in ethanol/few drops of water if necessary at all. Dropwise
addition of methyloxirane induced precipitation of (±)-1-amino-4-
guanidinobutylphosphonic acid mono-hydrochloride (±)-17 (0.256 g,
67%) as colorless crystals; mp. 157-158 °C (lit. : 160 °C). Elemental
5 17 4 4
analysis calcd (%) for C H N O P×HCl: C 22.69, H 6.86, N 21.17, Cl
13.40; found: C 22.35, H 6.62, N 20.43, Cl 13.46 (see lit.[9b]).
under reduced pressure. Water (20 mL) and CH
and the organic layer was separated. The aq one was extracted with
CH Cl (2 × 15 mL). The combined organic layers were dried (Na SO
and concentrated under reduced pressure. The residue was purified by
flash chromatography (heptanes/EtOAc, 1:1, 0.38) to yield
2 2
Cl (20 mL) were added
2
2
2
4
)
R
f
=
azidophosphonate (±)-15 (1.287 g, 79%) as colorless oil, which
contained a few % of starting nosylate. They could not be separated as
they were of the same polarity.
[
7a]
Similarly, 1-(4-nitrobenzenesulfonyloxy)butylphosphonate (R)-14 (1.653 g,
2
.43 mmol) was converted to azidophosphonate (S)-15 (1.176 g, 93%)
Similarly, 1-aminobutylphosphonate (S)-16 (873 mg, 1.77 mmol) was
converted to likely 1-aminophosphonic acid dihydrochloride (S)-17
(quantitative yield) as colorless glassy product by drying sample to
19
as colorless oil; [α]
Similarly, 1-(4-nitrobenzenesulfonyloxy)butylphosphonate (S)-14 (1.30 g,
D
= +36.4 (c = 0.81, acetone).
25
1.91 mmol) was converted to azidophosphonate (R)-15 (0.937 g, 94%)
constant weight; [α]
D
2
= ‒3.4 (c = 1.85, H O) after drying sample to
19
as colorless oil; [α]
The spectroscopic data of (±)-, (S)- and (R)-15 were identical. 1H NMR
D
= ‒37.5 (c = 1.4, acetone).
constant weight.
Similarly, 1-aminobutylphosphonate (R)-16 (760 mg, 1.54 mmol) was
converted to likely α-aminophosphonic acid dihydrochloride (R)-17
(quantitative yield) as colorless glassy product by drying sample to
(
700.40 MHz, CDCl
3
): δ = 9.36 (br. s, 1H, NH
.76 (sept, J = 6.2 Hz, 1H, POCH), 4.75 (sept, J = 6.2 Hz, 1H, POCH),
.99-3.87 (m, 2H, NCH ), 3.45 (td, J = 11.5 Hz, J = 2.9 Hz, 1H, PCH),
.89-1.77 (m, 2H, CH ), 1.73-1.66 (m, 1H, CH ), 1.64-1.57 (m, 1H, CH ),
.51 (s, 9H, tBu), 1.46 (s, 9H, tBu), 1.33 (d, J = 6.2 Hz, 9H, CH ), 1.32 (d,
); 13C NMR (176.11 MHz, CDCl
): δ = 163.8 (C=N),
60.5 (C=O), 154.9 (C=O), 83.9 (OC), 78.7 (OC), 71.7 (d, J = 7.3 Hz,
POCH), 71.65 (d, J = 7.3 Hz, POCH), 57.3 (d, J = 156.8 Hz, PCH), 43.7
2 2
), 9.17 (br. s, 1H, NH ),
4
3
1
1
25
2
constant weight, which could not be crystallized; [α]
O).
The NMR spectroscopic data of (±)-, (S)- and (R)-17 were identical. 1H
NMR (600.25 MHz, D O): δ = 3.29 (td, J = 13.0, 6.5 Hz, 1H, PCH), 3.22
(t, J = 6.5 Hz, 1H, NCH ), 2.01-1.88 (m, 1H, CH ), 1.88-1.69 (m, 3H,
CH O): δ = 156.7 (C ), 48.4 (d, J = 144.5 Hz,
); 13C NMR (150.93 MHz, D
CH), 40.5 (CH ), 25.6 (CH ), 24.9 (d, J = 7.9 Hz, CH
); 31P NMR (242.99
MHz, D O): δ = 13.6.
D
= +3.8 (c = 1.85,
2
2
2
H
2
3
J = 6.2 Hz, 3H, CH
1
3
3
2
2
2
2
2
q
(
(
4
3
NCH
CH ), 24.2 (d, J = 2.1 Hz, CH
.3 Hz, 2CH
); 31P NMR (242.99 MHz, CDCl
384, 2981, 2102, 1712, 1608, 1509, 1267, 1247, 1144, 1101, 983 cm‒1.
P (520.57): calcd. C 48.45, H 7.94, N 16.14, O 21.51, P 5.95;
found C 48.96, H 7.73, N 15.46, O 22.00.
2
), 28.3 (3C, tBu), 28.0 (3C, tBu), 26.0 (d, J = 13.4 Hz, CH
), 24.2 (d, J = 2.3 Hz, CH ), 25.0 (d, J =
): δ = 20.2. IR (ATR): ν =
2
), 25.7
2
2
2
2
3
3
2
3
3
21 41 6 7
C H N O
Acknowledgements
(
±)-, (S)-(+)- and (R)-(‒)-diisopropyl 1-amino-4-[N,N´-bis(tert-
butoxycarbonyl)-guanidino)]butylphosphonate [(±)-, (S)- and (R)-16]:
,3-Propanedithiol (526 mg, 4.86 mmol, 0.49 mL, 3 equiv) and Et N (492
The authors thank Amano Enzyme Limited (SAM I, AP 6, F-AP
15), Novo Nordisk (SP 523), and pharma biotechnologie
hannover (lipase from Candida cylindracea) for gifts of lipases,
S. Felsinger for recording NMR spectra, J. Horak for the
determination of the ee of phosphaaspartic acid and
phosphaarginine, and J. Theiner for combustion analyses.
1
3
mg, 4.86 mmol, 0.68 mL) were added to a solution of 1-azido-4-(N,N´-
bis(tert-butoxycarbonyl)guanidino)butylphosphonate (±)-15 (841 mg, 1.62
mmol) in dry MeOH (10 mL) under argon atmosphere at room
temperature. The mixture was stirred for 21 h and concentrated under
reduced pressure (0.5 mbar). The residue was dissolved in CH
ml) and water (10 mL). The organic phase was separated and the aq one
was extracted with CH Cl (2 × 10 mL). The combined organic layers
were dried (Na SO ), filtered through Celite and concentrated under
reduced pressure. The residue was flash chromatographed
2 2
Cl (20
Conflict of interest
The authors declare no conflict of interest.
2
2
2
4
Keywords: phosphaaspartic acid
• phosphaarginine • α-
2 2 f
(CH Cl /EtOH, 20:1, R = 0.20) to deliver α-aminophosphonate (±)-16
hydroxyphosphonate • lipase • chiral HPLC
(711 mg, 89%) as colorless heavy oil.
Similarly, 1-azido-4-(N,N´-bis(tert-butoxycarbonyl)guanidino)butylphos-
phonate (S)-15 (1.190 g, 2.29 mmol) was converted to α-amino-
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D
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(150.93 MHz, D O): δ = 163.7 (C=N), 160.5 (C=O), 155.0 (C=O), 83.7
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This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700948
FULL PAPER
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10.1002/ejoc.201700948
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A [2,3]-sigmatropic rearrangement and a lipase do it together: They transform allyloxymethyl-
phosphonate into (±)-, (R)- and (S)-1-hydroxy-3-butenylphophonate, which serve as starting substrates
for the synthesis of (±)-, (R)- and (S)-arginine and -phosphaaspartic acid. A combination of functional
group manipulations delivers the racemic and enantiomerically pure α-aminophosphonic acids. The
enantiomers of phosphaarginine were prepared for the first time.
1
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