Stereoselective synthesis, solution structure and metal complexes of (1S,2S)-2-amino-1-hydroxyalkylphosphonic acids

Article abstract of DOI:10.1016/S0957-4166(03)00278-7

The highly stereoselective synthesis of (1S,2S)-2-amino-1-hydroxyalkylphosphonic acids was achieved by addition of dimethyl phosphite to N-protected aminoaldehydes. Relative configuration and solution conformations of (1S,2S)-2-amino-1-hydroxy-alkylphosphonic acids (in D₂O) and their dimethyl esters (in CDCl₃ and CD₃OD) were established by means of NMR basing on the dependence between observed values of coupling constants (³J_HH, ³J_PC, ³J_HP) and corresponding dihedral angles. Potentiometric and spectroscopic methods were used for the evaluation of the structure of the complexes of (1S,2S)-2-amino-1-hydroxy-alkylphosphonic acids with Zn(II) and Cu(II) ions in aqueous solutions.

Full text of DOI:10.1016/S0957-4166(03)00278-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1837–1845
Stereoselective synthesis, solution structure and metal complexes
of (1S,2S)-2-amino-1-hydroxyalkylphosphonic acids
Marcin Drag,a Rafal Latajka,a Elzbieta Gumienna-Kontecka,b Henryk Kozlowskib and
Pawel Kafarskia,*
aInstitute of Organic Chemistry, Biochemistry and Biotechnology, University of Technology, Wybrzeze Wyspianskiego 27,
50-370 Wroclaw, Poland
bFaculty of Chemistry, University of Wroclaw, F. Joliot Curie 14, 50-383 Wroclaw, Poland
Received 17 March 2003; accepted 26 March 2003
Abstract—The highly stereoselective synthesis of (1S,2S)-2-amino-1-hydroxyalkylphosphonic acids was achieved by addition of
dimethyl phosphite to N-protected aminoaldehydes. Relative configuration and solution conformations of (1S,2S)-2-amino-1-
hydroxy-alkylphosphonic acids (in D2O) and their dimethyl esters (in CDCl3 and CD3OD) were established by means of NMR
3
3
basing on the dependence between observed values of coupling constants (3JHH, JPC, JHP) and corresponding dihedral angles.
Potentiometric and spectroscopic methods were used for the evaluation of the structure of the complexes of (1S,2S)-2-amino-1-
hydroxy-alkylphosphonic acids with Zn(II) and Cu(II) ions in aqueous solutions. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
logues of b-amino-a-hydroxyphosphonates have been
satisfactorily achieved in recent years, the literature
reports describing the synthesis of 2-amino-1-hydroxy-
alkylphosphonates bearing aliphatic substituents in
their side chains are rather scarce.4,8,9 Additionally,
their conformations in aqueous solutions as well as
their abilities to coordinate metal ions have not been
described so far, although these properties are known
to have significant influence on the biological activity
exerted by aminophosphonic acids.
Phosphonic acids bearing heteroatoms in the a and b
positions have attracted considerable interests because
of their well recognized interesting biological proper-
ties.1 Most importantly, they act as inhibitors of prote-
olytic enzymes, such as renin2 and human
immunodeficiency virus (HIV) protease,3 as agents
affecting the growth of plants4 or as haptens for the
development of catalytic antibodies.5 They also repre-
sent structural analogues of statine and bestatine, the
compounds of potential use as anti-cancer agents and
potent inhibitors of proteases involved in apoptosis, as
well as might be considered as interesting and promis-
ing analogues of non-terpenic fragment of paclitaxel
and docetaxel—one of the most important natural anti-
cancer agents.6 Moreover, the presence of neighboring
amino and hydroxy groups close to each other makes
them interesting chelating agents able to bind zinc ions
present in the active centers of metalloproteases.7
In this paper we have described the stereocontrolled
synthesis and properties of optically active (1S,2S)-2-
amino-1-hydroxyalkanephosphonic acids, determina-
tion of their structure by means of NMR spectroscopy
basing on the dependence between observed values of
coupling constants (3JHH, 3JPC, 3JHP) and corresponding
dihedral angles,10 as well as evaluation of complexing
abilities of these new ligands towards Zn(II) and Cu(II)
ions.
These properties have stimulated the studies on their
synthesis with special attention paid to their stereoselec-
tive synthesis. Although, the synthesis of aromatic ana-
2. Results and disscussion
2.1. Stereoselective synthesis
The (S)-a-amino acids were transformed into their
methyl ester hydrochlorides followed by protection of
their amino groups with Boc2O. N-Protected esters
* Corresponding author. Tel.: +048-71-320-36-82; fax: +048-71-328-
40-64; e-mail: kafarski@kchf.ch.pwr.wroc.pl
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00278-7

1838
M. Drag et al. / Tetrahedron: Asymmetry 14 (2003) 1837–1845
Scheme 1. Reagents and conditions used during synthesis of 3a–c (R=-CH3, -CH2CH(CH3)2, -CH(CH3)(CH2CH3)).
were then reduced to the appropriate alcohols 1 by
treatment with NaBH4/LiCl in THF/EtOH. All the
steps in the preparation of N-protected amino alcohols
were carried out according to literature procedures.11
The synthesis of the aliphatic (S)-N-Boc-a-amino alde-
hydes 2 was performed by the oxidation of the (S)-N-
Boc-a-amino alcohols 1 using DMSO–oxalyl chloride
in dry CH2Cl2 (Swern oxidation)12 (Scheme 1). To
avoid the undesired decomposition and racemisation of
the aldehydes, the obtained crude products were used
immediately in the next step of the synthesis. According
to our experience, the racemisation of (S)-N-Boc-a-
amino aldehydes 2 occurs at 5–7% per hour upon silica
gel during their purification.13
They show, that the presence of a bulky side chain
improved the stereoselectivity of addition of dimethyl
phosphite to (S)-N-Boc-a-aminoaldehyde 2, which in
turn indicates, that the stereoselectivity in this reaction
is not only dependent on reaction conditions, but also
on the structure of the substrate.14 The obtained mix-
tures of dimethyl-[Boc-amino]-1-hydroxyalkylphospho-
nic esters 3 were then sequentially deprotected and
recrystallised to yield the desired (1S,2S)-2-amino-1-
hydroxyalkylphosphonic acids 5 (Scheme 2). Reaction
of esters 3 with 6 M hydrogen chloride in methanol
(saturated solution) led to dimethyl (1S,2S)/(1R,2S)-2-
amino-1-hydroxyalkylphosphonate hydrochlorides
4
with quantitative yields. In the next step, the obtained
hydrochlorides 4 were deprotected by refluxing in 8 M
HCl to give the desired 2-amino-1-hydroxyalkylphos-
phonic acids 5 as mixtures of two diastereomers with
the ratio of (1S,2S) to (1R,2S) isomers being identical
to that for the Boc-protected methyl esters 3. The
separation of the pure diastereomers of (1S,2S)-5a,b
and (1S,2S,3S)-5c was achieved by fractional crystalli-
sation. According to the interest in the synthesis of
5-syn (1S,2S) derivatives, and the observed small
amount of the 5-anti (1R,2S) diastereomers formed, we
have not undertook efforts to obtain the second ones as
pure enantiomers.
The appropriate (S)-N-Boc-a-aminoaldehyde 2 was
treated with dimethyl phosphite in DMF using solid
KF as a catalyst to give the mixture of dimethyl
(1S,2S)/(1R,2S)-2-(Boc-amino)-1-hydroxyalkylphos-
phonates 3, in which the syn adduct predominates
(Table 1).14a This method was chosen because its suc-
cesful application for the stereoselective synthesis of
a-hydroxyphosphonates bearing cycloaliphatic side-
chains was reported earlier.14 The observed stereoselec-
tive course of the reaction is in a good agreement with
literature where the strong dominance of production of
syn-diastereomers upon addition of various nucleo-
philic species to N-monosubstitued a-amino aldehydes
was reported. This is, on the other hand, in contrast to
N,N-disubstitued a-amino aldehydes, where anti-iso-
mers predominate.15 Ratios of syn- to anti-diastereoiso-
mers established from the 31P NMR spectra are shown
in Table 1.
In order to prove that there is a lack of racemisation of
the aldehyde 2 upon addition of dimethyl phosphite, we
coupled the obtained mixture of dimethyl (1S,2S)/
(1R,2S)-2-amino-1-hydroxypropylphosphonate hydro-
chloride 4a with (S)-Boc-phenylalanine (Scheme 3).
This was done in order to incorporate an additional,
defined stereogenic center into the molecule, which in
turn should result in appearance of additional peaks in
31P NMR spectra if the racemisation of substrate 2
would take place.16 To avoid undesired racemisation of
the substrates during the coupling step, the reaction
was performed by mixed carboxylic–carbonic anhy-
dride procedure (with the use of isobutyl chlorofor-
mate) at −20°C in dry THF and in the presence of
N-methylmorpholine. 31P NMR spectra of the mixture
Table 1. Diastereoselectivity of the addition of dimethyl
phosphite to (S)-N-Boc-a-aminoaldehydes 2
Entry
R
Stereoselectivity syn:anti Yield (%)
3a
3b
3c
-CH3
80:20
78
81
82
-CH2CH(CH3)2 88:12
CH(CH3)(CH2C 83:17
H3)
Scheme 2. Deprotection of phosphonate 3.

M. Drag et al. / Tetrahedron: Asymmetry 14 (2003) 1837–1845
1839
Scheme 3. Preparation of phosphonodipeptide 6.
Table 2. Values of the coupling constants (Hz) found for syn-esters 3 and 4
R
Entry
3JCP (Hz)
3JHP (Hz)
CDCl3
CD3OD
D2O
CDCl3
CD3OD
D2O
-CH3
-CH3
-CH2CH(CH3)2
-CH2CH(CH3)2
CH(CH3)(CH2CH3)
CH(CH3)(CH2CH3)
3a
4a
3b
4b
3c
4c
8.2
Insolouble
10.6
4.9
11.8
9.6
9.8
9.8
10.4
12.8
10.7
Insolouble
10.6
Insolouble
8.5
Insolouble
9.4
9.8
Insolouble
9.8
9.0
10.0
10.0
8.1
10.2
9.5
10.5
10.2
Insolouble
10.1
Insolouble
9.5
Insolouble
10.5
4.2
9.8
of isomers of peptide 6 showed the presence of two
dominating signals at 25.28 ppm (16%) and 25.48 ppm
(84%) corresponding to (1S,2S,2%S) and (1R,2S,2%S)
diastereoisomers, and only traces (less than 1%) of the
second pair of diastereomers at 25.62 and 25.78 ppm.
D2O) solvents and compared the results with those
obtained for phosphonic acids 5 in D2O. In order to
eliminate the possible formation of intermolecular
hydrogen bonding, we have performed NMR investiga-
tions in dilute solutions (concentration of phospho-
nates=5 mg/ml). We have also limited conformational
analysis only to the dominant syn (1S,2S)-
diastereomers. This is because the presence of only a
small amount of anti (1R,2S)-diastereomers in the mix-
tures caused problems with exact determination of cou-
pling constants values, which is indispensable step in
such studies. Coupling constants determined for syn-
esters 3 and 4 are shown in Table 2, whereas those
found for respective acids 5 in Table 3. Interpretation
of the experimental data was based on the dependence
Our results are in accordance with earlier report of
Tao, who had performed a similar reaction, in which
dimethyl
(2S)-amino-1-hydroxy-4-methylpentylphos-
phonate hydrochloride 4b was coupled with (S)-Cbz-
Leucine gave the final product as a mixture of only two
desired diastereomers.16 This allowed us to postulate,
that the aliphatic (S)-N-Boc-a-amino aldehydes 2 did
not racemise in applied reaction conditions (DMF, KF,
HPO(OMe)2).
3
3
of the observed coupling constants JHP and JPC for
3
3
3
esters 3 and 4, and JHH, JPC, JHP for acids 5, on
respective values of dihedral angles between these
atoms, which enabled us to assign tentative absolute
configurations, as well as the most probable conforma-
tions of the studied molecules in solution.10
2.2. Determination of absolute configuration and confor-
mational analysis
In order to assign a tentative absolute configuration to
the obtained compounds we have used NMR confor-
mational analysis of esters 3 and 4 and acids 5 basing
on our recent studies, which were done in order to
study the influence of hydrogen bonding on conforma-
tional behavior of diethyl (1R,2S)-2-amino-1-hydroxy-
2-arylalkylphosphonates.10
Table 3. Values of the coupling constants (Hz) found for
syn-acids 5
Entry
R
D2O solution
3JPC
3JHH 2JHP
3JHP
The presence of amino, hydroxyl and phosphonyl
groups in the same molecule creates the possibility of
various hydrogen bonds, of which the dominating ones
determine the molecule conformation in the solution. In
the case of compounds 3–5 we would expect a competi-
tion in the formation of hydrogen bonds between three
functional groups present in the molecule, namely
amino, hydroxy and phosphonate moieties. In order to
determine, which one predominates we have performed
measurements of NMR spectra for dimethyl esters 3
and 4 in non-polar (CDCl3) and polar (CD3OD and
5a
5b
5c
-CH3
-CH2CH(CH3)2
CH(CH3)(CH2CH3)
8.7
9.6
10.7
5.3
2.2
2.0
5.8
4.6
5.2
8.9
10.5
11.3
In Tables 4 and 5 the comparison of the coupling
constants determined for (1S,2S) and (1R,2S)
diastereomers (2S-center was predetermined by using

1840
M. Drag et al. / Tetrahedron: Asymmetry 14 (2003) 1837–1845
Table 4. Conformational analysis—comparison of calculated and experimental data for dimethyl 2-amino-1-hydroxyalkyl-
phosphonates 3 and 4
Table 5. Conformational analysis—comparison of calculated and experimental data for 2-amino-1-hydroxyalkylphosphonic
acids 5
appropriate isomer of amino acid as substrate)
obtained with those calculated from conformational
analysis of three sets of species having their conforma-
tions constrained by the presence of hydrogen bonding
are collected. The first set was established assuming the
formation of hydrogen bond between hydroxyl- and
amino-moieties, in the second set the formation of such
a bond between amino- and phosphonate groups was
proposed, whereas the third set considers the possibility
of formation of hydrogen bonds between hydroxyl and

M. Drag et al. / Tetrahedron: Asymmetry 14 (2003) 1837–1845
1841
phosphonyl functions. The last set considers free rota-
tion around the PꢀC bond (both groups are attached to
the same carbon atom) and the presented results are
limited to the most energetically probable conformers
with hydrogen atoms being trans to each other. Forma-
tion of hydrogen bonds results in fixing the dihedral
angles, which is reflected by certain values of the corre-
3
sponding coupling constants. For JPC these values fall
into two categories: 0–8 Hz for gauche like conforma-
tions and >8 Hz for trans conformations, whereas for
3
3JHH and JHP they lie in narrow defined ranges (see
Tables 4 and 5).
Scheme 4. (S)-O-Methyl mandelate derivative of 3a.
by the NMR experiments (1S,2S) cofiguration.
Results of the analysis suggests the formation of hydro-
gen bonds between either (NH2)···(PꢁO) or
(NH2)···(OH) moieties in (1S,2S) esters and acids.
From the obtained results we can not determine, which
of the two bonds predominate and thus establish the
strict conformation of these compounds in the solution.
The similar environment of both conformations rather
suggests the existence of a dynamic equilibrium between
them. Anyway, the presence of trans conformation and
the lack of a gauche like one was shown to exist in all
the solutions of esters and acids. In the case of acids 5
we have obtained an acceptable agreement between
experimental and calculated data only for (1S,2S) iso-
mers, which confirms the expected steric course of the
reaction and provides tentative absolute configuration
for the major isomer obtained in this work.
The absolute configuration of the obtained acids 5 was
additionally confirmed by comparision of the specific
rotation and spectroscopic parameters of (1S,2S)-2-
amino-1-hydroxypropylphosphonic acid 5a, with the
data reported for this compound earlier.19
2.3. Coordination studies
An inhibitory effect of phosphonic acids with hetero-
atoms (hydroxy, amino) in a and b positions may result
from the good binding abilities of these groups to metal
ions present in the active centers of enzymes. Therefore,
we have studied complexing abilities of the obtained
acids 5 for Cu(II) and Zn(II) ions.
IR spectra of the acids showed broad bands in the
region of 3100–2400 cm−1, which is very characteristic
for strongly hydrogen-bonding systems, particularly
The obtained results show that each ligand behaves as
the H2L acid with two protonation constants at amino
(log K=10.88–11.31) and phosphonic group (5.65–5.85)
(Table 6). The second protonation at the phosphonic
group occurs below pH 1.5 and therefore the pK value
could not be evaluated. The basicity of the amino
donor is higher for 5b and 5c having large substituents
adjacent to the amino group.
NH3 ···X− system.17 The lack of strong absorption at
+
3500 cm−1 indicates involvement of the hydroxyl group
in hydrogen bonding, which suggests the formation of a
hydrogen bond between amino and hydroxyl groups in
crystalline state in the case of acids.
In order to confirm the tentative assignment of the
absolute configuration of the obtained compounds, we
have performed an additional experiment, namely ester-
ification (NMR scale experiment) of 3a with (S)-O-
methyl mandelic acid upon action of DCC, according
to the procedure described by Kozlowski.18 In our case,
the application of the proposed model would result in
shielding of the phosphorus atom in the case of
(1R,1%S,2S)-ester and thus its signal shifting upfield in
31P NMR spectra relative to the (1S,1%S,2S)-ester
(Scheme 4). This in the case of (S)-O-methyl mandelate
derivatised alcohols should enlarge the distance
between peaks of the observed diastereomers in the 31P
NMR spectra comparing to the non-esterified alcohols.
The obtained experimental results confirm this assump-
tion, because the Dl between diastereomers of alcohol
3a is 0.51 ppm (25.62 ppm (1R,2S), 26.13 ppm
(1S,2S)), whereas for its (S)-O-methyl mandelates 0.74
ppm (19.61 ppm (1R,1%S,2S), 20.35 ppm (1S,1%S,2S)).
Our data are in a good agreement with those reported
by Kozlowski and enabled us to assign determine tenta-
tively the absolute configuration of dimethyl (1S,2S)/
(1R,2S)-2-amino-1-hydroxylakanephosphonate 3a and
confirm that major isomer appears to have ascertained
Cu(II) forms two major complex species with the stud-
ied acids 5 (Table 6). The stabilities of the equimolar
complexes (log K=9.64–9.78) and bis-complexes
(log i=16.74–17.39) are relatively high indicating the
strong coordination ability of all three acids. In the case
of ligands 5a and 5b, which form slightly weaker bis-
complexes than 5c, the [CuL2]2− species underwent
Table 6. Stability constants of the proton (log K) for cop-
per(II) and zinc(II) complexes (log i) of acids 5 at 25°C
and I=0.1 M (KNO3)
Ligand
5a
5b
5c
a-Ala-P
Log K(HL) 10.88(1)
Log K(H2L) 5.85(1)
11.20(1)
5.65(1)
9.64(1)
17.10(2)
5.77(5)
13.56(3)
6.26(6)
–
11.31(1)
5.68(1)
9.78(2)
17.39(2)
–
13.53(2)
6.39(3)
–
10.11
5.55
8.29
14.94
–
11.79
5.99
–
[CuL]
9.75(1)
16.74(1)
4.91(10)
13.36(3)
6.45(2)
[CuL2]2−
[CuH−1L2]3
[ZnHL]+
[ZnL]
[ZnH−1L]−
1.59(2)

1842
M. Drag et al. / Tetrahedron: Asymmetry 14 (2003) 1837–1845
deprotonation to [CuH−1L2]3− complex at pH above 10.
The energy of the d–d transitions at 715 nm (Table 7)
for equimolar species clearly indicate the involvement
of one amino group in the Cu(II) ion coordination.
Thus, the chelation of the metal ion involves the [NH2,
PO32−] donor set.20 Also EPR parameters (Table 7)
agree with such a coordination mode. The coordination
of the second ligand shifts the d–d transition energy to
632–665 nm region (Table 7), which is characteristic for
coordination of two amino nitrogen atoms and two
phosphonate oxygen atoms to Cu(II) ion.20a,b The
changes in the EPR parameters also well agree with this
binding mode.
hydes 2. The subsequent deprotection and purification
of the obtained compounds resulted in pure syn-
diastereomers of 2-amino-1-hydroxyalkylphosphonic
acids of (1S,2S) configuration in the case of 5a,b and
(1S,2S,3S) in the case of 5c. Additionally, we have
shown that esters 4 could be easily converted into
phosphono
dipeptides
with
a
very
good
stereoselectivity.
The configuration of the obtained compounds was
determined by both conformational analysis of their
dilute solutions, as well as by analysis of NMR spectra
of their derivatives with (S)-O-methylmandelic acid, the
methods, which have been recently standardly used for
the assignment of absolute configurations of optically
active hydroxyalkylphosphonates.9d,19,21 In our case the
configuration of major isomer appeared as (1S,2S).
Table 7. Spectroscopic parameters for copper(II) com-
plexes formed by studied acids 5
Ligand
u
m
AII
g
The coordination abilities of acids 5 towards Cu(II) and
Zn(II) prove that they are potent chelating agents bind-
ing these ions stronger than structurally related simple
aminophosphonic acids. This suggests vital role of
hydroxyl moiety in complex formation.
5a
[CuL]
715
665
665
54
74
74
155
170
170
2.32
2.26
2.26
[CuL2]2−
[CuH−1L2]3−
5b
[CuL]
713
632
632
54
68
68
152
167
167
2.32
2.26
2.26
[CuL2]2−
[CuH−1L2]3−
5c
4. Experimental
[CuL]
704
653
653
57
82
82
155
170
170
2.32
2.26
2.26
4.1. General remarks
[CuL2]2−
[CuH−1L2]3−
Unless otherwise noted, all reagents were obtained from
commercial suppliers and used without further purifica-
tion. Dichloromethane was dried over P2O5 and dis-
tilled. THF was dried over sodium with benzophenone
as indicator and distilled. Reaction progress was moni-
tored by thin-layer chromatography on Merck 60 F254
0.1 m silica plates. Unless otherwise specified, extracts
were dried over MgSO4 and solvents were removed
with a rotary evaporator. IR spectra were recorded
with Perkin–Elmer 1600 Series Fourier transform spec-
trometer as thin films or KBr pellets. NMR spectra
were recorded on a Bruker Avance DRX 300 MHz
instrument, operating at 300.13 MHz (1H), 121.499
MHz (31P) and 75.46 MHz (13C). Measurements were
made in CDCl3 (99.5 at.% D), CD3OD (99.5 at.% D)
and D2O (99.8 at.% D) solutions containing 3,5 mg of
sample in 0.7 ml of solvent at temperature 300 K, all
solvents were supplied by Dr Glaser AG (Basel,
Switzerland). Proton decoupling was achieved by power
gated decoupling using the Waltz 16 sequence. Chemi-
cal shifts are reported in parts per million relative to
TMS, and coupling constants are reported in hertz.
Melting points were determined on a Electrothermal
9200 apparatus and are reported uncorrected. Elemen-
tal analyses were performed at Chemistry Department
of the University of Wroclaw and Wroclaw University
of Technology on Perkin Elmer 2400 CHN. Electro-
spray mass spectra were recorded at Chemistry Depart-
ment of the University of Wroclaw using Finnigan Mat
TSQ 700 Electrospray mass spectrometer. Titrations
involved an ionic background of 0.1 M KNO3, ligand
concentration of 2 mM and metal-to-ligand ratios of
1:2, 1:3, 1:4 and 1:5 were applied. Initial solutions of 2
mL were titrated with sodium hydroxide delivered by a
Zn(II) ions form two major complexes as well.
However, the species formed are equimolar with
stability constants for [ZnL] species distinctly lower
than those obtained for the Cu(II) ions (Table 6). In the
protonated complexes [ZnHL]+ proton sits most likely
on the amino group causing that ligand binds to metal
ion via monodentate coordination through the
phosphonate oxygen. In the high pH the [ZnL] complex
(L=5a) deprotonates into [ZnH−1L]− species. The
proton dissociation with log K ꢀ8 occurs most likely
from the bound water molecule. In the two other cases
potentiometric titration were performed only up to pH
around 7 due to precipitation of the zinc complex.
All the studied ligands are much more effective in
Cu(II) ion coordination than, for example, phosphonic
analogues of simple amino acids. This could suggest
some role of hydroxyl group in stabilization of the
complexes formed. In the case of Zn(II) ions only
equimolar species are formed, while for phosphonic
analogue of alanine also ZnL2 complexes were found.20a
The bulky substituent as well as some involvement of
hydroxyl group could protect the binding of the second
aminophosphonate to Zn(II) ion.
3. Conclusions
We have performed highly stereoselective synthesis of
2-amino-1-hydroxyalkylphosphonic esters by the addi-
tion of dimethyl phosphite to (S)-N-Boc-a-amino alde-

M. Drag et al. / Tetrahedron: Asymmetry 14 (2003) 1837–1845
1843
0.25 mL micrometer syringe previously calibrated by
weight titrations and titrations of standard materials.
The pH-metric titrations were performed at 25oC in pH
range 2.5–11.0 using a MOLSPIN automatic titration
system with a Russell CMAW 711 microcombined elec-
trode calibrated daily in hydrogen-ion concentration
using HNO3.22 Titrations were performed in triplicate
and the SUPERQUAD computer program was used
for calculations of stability constants (ipqr=[MpHrLq]/
[M]p[H]r[L]q).23 Standard deviations quoted refer to ran-
dom errors only. They are, however, a good indication
of the importance of a particular species in the equi-
librium. Absorpion spectra were recorded on a Beck-
man DU 650 spectrophotometer. Electron para-
magnetic resonance (EPR) spectra were performed in
ethylene glycol–water (1:2 v/v) solution at 77 K on a
Bruker ESP 300E spectrometer at the X-band fre-
quency (about 9.45 GHz) and equipped with the Bruker
NMR gaussmetter ER 035M and the Hewlett–Packard
microwave frequency counter HP 5350B. The concen-
trations used in the spectroscopic measurements were
the same as those used in potentiometric titrations.
4.3.1. N-Boc-(S)-a-aminoalaninal, 2a. 82% yield, 1H
NMR (CDCl3): l=1.34 (d, 3H, 3J(H,H)=7.3 Hz,
CH3), 1.46 (s, 9H, Boc), 4.23 (m, 1H, CH), 6.88 (bs,
1H, NH) 9.56 (s, 1H, formyl).
4.3.2. N-Boc-(S)-a-aminoleucinal, 2b. 66% yield, 1H
NMR (CDCl3): l=0.96 (d, 6H, 3J(H,H)=6.3 Hz,
CH3), 1.37 (m, 1H, CH), 1.45 (s, 9H, Boc), 1.66 (m, 2H,
CH2), 4.23 (m, 1H, CH), 6.95 (bs, 1H, NH) 9.58 (s, 1H,
formyl).
1
4.3.3. N-Boc-(S)-a-amino-i-leucinal, 2c. 63% yield, H
NMR (CDCl3): l=0.89 (m, 6H, 2×CH3), 1.19 (m, 1H,
CH), 1.38 (s, 9H, Boc), 1.41 (m, 2H, CH2), 4.22 (m, 1H,
CH), 7.10 (bs, 1H, NH), 9.59 (s, 1H, formyl).
4.4. General procedure for the synthesis of dimethyl
(1S,2S)/(1R,2S)-(2-tert-butoxycarbonyloamino-1-
hydroxy)alkylphosphonates 3
N-Boc-a-amino aldehyde 2 (0.01 mol) was dissolved in
50 ml of DMF and dimethyl phosphite (0.01 mol) and
KF (0.05 mol) were added. The mixture was stirred for
24 h, solid components were filtered off and solvent
removed under reduced pressure. The oily residue was
dissolved in dichloromethane and washed with: 10%
aqueous citric acid solution (50 ml), water (50 ml) and
brine (50 ml). After drying and removal of solvent final
product was obtained as yellowish oil of satisfactory
purity. Because of the low ratio of the minor
diastereomer 3-(1R,2S), their peaks in 1H and 13C
spectra are hidden under the peaks of major epimer
(1S,2S), and therefore the detail determination of these
signals was omitted during analysis.
4.2. General procedure for the synthesis of N-Boc-a-
amino alcohols 1
The methyl ester of the appriopriate N-Boc-a-
aminoacid (0.08 mol) was dissolved in THF (100 ml)
followed by addition of lithium chloride (0.16 mol) and
sodium borohydride (0.16 mol). After addition of dry
ethanol (150 ml), the mixture was stirred overnight.
When the reaction was completed (TLC), the mixture
was cooled in an ice–water bath and pH adjusted to 3
by addition of 10% citric acid. After concentration in
vacuo, water was added (200 ml), and extraction with
dichloromethane (4×70 ml) performed. Standard work-
up of the organic phase gave desired product 1. Spec-
tral and analytical data for N-Boc-a-amino alcohols
were identical with those published earlier for 1a,11e
1b11f and 1c.11d
4.4.1. Dimethyl (1S,2S)/(1R,2S)-(2-tert-butoxycarbonyl-
oamino-1-hydroxy)propylphosphonate (80/20 mixture),
3a. 78% yield, IR: w=1048, 1118, 1248, 1367, 1523,
1
1697, 2935, 2978, 3327 cm−1. H NMR (CDCl3): l=
3
1.27 (d, 3H, J(H,H)=6.3 Hz, CH3), 1.43 (s, 9H, Boc)
4.3. General procedure for the synthesis of N-Boc-a-
amino aldehydes 2
3.49 (dd, 1H, 3J(H,H)=5.1 Hz, 2J(H,P)=11.5 Hz,
CH), 3.82 and 3.91 (2d, 6H, 3J(H,P)=10.5 Hz, 2×
OCH3), 4.04 (m, 1H, CH), 5.65 (d, 1H, 3J(H,H)=
12.1Hz, NH) 13C NMR (CDCl3): l=17.23 (d,
3J(C,P)=8.2 Hz), 28.32 (s), 47.59 (s), 53.20 (d,
Oxalyl chloride (0.035 mol) was dissolved in 100 ml of
dry dichloromethane and cooled to −60°C. Then dry
DMSO (0.105 mol) in 10 ml of dichloromethane was
added dropwise. After 5 min, N-Boc-a-amino alcohol 1
(0.03 mol) in 10 ml of dichloromethane was added
dropwise and the mixture was stirred intensively for 1
h, while the temperature was maintained between −60
and −50°C. After completion of the reaction (TLC),
triethylamine (0.15 mol) was added and the mixture
was stirred for additional 15 min. Next, 100 ml of
saturated aqueous solution of ammonium chloride and
100 ml of water were added and the mixture was stirred
for additional 5 min. The mixture was left to reach
room temperature. Then the organic phase was washed
with: 5% aqueous solution of citric acid (2×70 ml),
water and brine. Standard work-up of the organic
phase gave desired product 2 as yellowish solid, which
was immediately used for the next step without further
purification.
2
2J(C,P)=6.2 Hz), 54.02 (d, J(C,P)=6.0 Hz), 71.36 (d,
1J(C,P)=164.2 Hz), 79.60 (s), 155.15 (s); 31P NMR:
l=25.62 (1R,2S), 26.13 (1S,2S); ESI=283.9, 305.8
(M+Na)+.
4.4.2. Dimethyl (1S,2S)/(1R,2S)-(2-tert-butoxycarbonyl-
oamino-1-hydroxy-4-methyl)pentylphosphonate
(88/12
mixture), 3b. 81% yield, IR: w=1043, 1173, 1249, 1367,
1
1505, 1713, 2871, 2958, 3335 cm1. H NMR (CDCl3):
3
l=0.86 (d, 6H, J(H,H)=4.4 Hz, 2×CH3), 1.37 (s, 9H,
Boc), 1.57 (m, 3H, CH, CH2), 3.74 and 3.79 (2d, 6H,
3J(H,P)=10.6 Hz, 2×OCH3), 3.89 (m, 2H, 2×CH), 5.40
(d, 1H, 3J(H,H)=9.0 Hz, NH). 13C NMR (CDCl3):
l=21.58 (s), 22.14 (s), 28.31 (s), 40.60 (d, 3J(C,P)=10.6
Hz), 49.73 (s), 53.20 (d, 2J(C,P)=6.8 Hz), 53.58 (d,
2J(C,P)=6.0 Hz), 70.2 (d, 1J(C,P)=161.8 Hz), 79.31

1844
M. Drag et al. / Tetrahedron: Asymmetry 14 (2003) 1837–1845
(s), 156.17 (s). 31P NMR: l=25.87 (1R,2S), 26.41
(1S,2S); ESI=325.8, 347.9 (M+Na)+.
62.10 (s), 66.97 (d, 1J(C,P)=167.8 Hz). 31P NMR:
l=24.29 (1R,2S,3S), 25.11 (1S,2S,3S); ESI=226.
4.4.3. Dimethyl (1S,2S,3S)/(1R,2S,3S)-(2-tert-butoxy-
carbonyloamino-1-hydroxy-3-methyl)pentylphosphonate
(83/17 mixture), 3c. 82% yield, IR: w=1044, 1176, 1250,
1367, 1506, 1714, 2875, 2958, 3329 cm1. 1H NMR
(CDCl3): l=0.90 (m, 6H, 2×CH3), 1.13 (m, 1H, CH)
1.42 (s, 9H, Boc), 1.5 (m, 2H, CH2), 3.54 (m, 1H, CH),
4.6. General procedure for the synthesis of (1S,2S)-2-
amino-1-hydroxyalkylphosphonates 5
The dimethyl (2-amino-1-hydroxy)alkylphosphonate
hydrochloride 4 was refluxed in 50 ml of 8 M HCl for
8–10 h. After evaporation of the volatile products in
vacuo, the residue was dissolved in 100 ml of ethanol
and treated with propylene oxide (pH=6). The precipi-
tated acid was filtered off and recrystallized 3–5 times
from water to give pure syn diastereomer of 5. In the
case of 5c the final product was obtained by the recrys-
tallisation from water and isopropanol.
3
3.80 (d, 6H, J(H,P)=10.6 Hz, 2×OCH3), 3.84 (m, 1H,
3
CH), 5.60 (d, 1H, J(H,H)=8.2 Hz, NH). 13C NMR
(CDCl3): l=11.12 (s), 15.64 (s), 25.40 (s), 28.33 (s),
35.85 (d, 3J(C,P)=11.8 Hz), 53.16 (d, 2J(C,P)=7.4 Hz),
53.75 (d, 2J(C,P)=7.0 Hz), 55.24 (s), 67.64 (d,
1J(C,P)=163.1 Hz), 79.17 (s), 156.34 (s). 31P NMR:
l=25.41 (1R,2S,3S), 26.02 (1S,2S,3S); ESI=325.8,
347.6 (M+Na)+.
4.6.1. (1S,2S)-(2-Amino-1-hydroxy)propyl phosphonic
acid, 5a. 72% yield, mp=247–250°C, [h]2D6.7=+19.3 (c 1,
water), IR: w=916, 1040, 1096, 1143, 1509, 1628, 2361,
4.5. General procedure for the synthesis of dimethyl
(2-amino-1-hydroxy)alkylphosphonates hydrochlorides 4
1
3
3154 cm−1. H NMR (D2O): l=1.28 (d, 3H, J(H,H)=
3
6.6 Hz, CH3), 3.47 (ddq, 1H, J(H,H)=5.3 Hz, 6.6 Hz,
3
The
dimethyl
(2-tert-butoxycarbonyloamino-1-
2J(H,P)=5.8 Hz, CH), 3.60 (dd, 1H, J(H,H)=5.3 Hz,
hydroxy)alkylphosphonate 3 was stirred in 6 M hydro-
gen chloride saturated in methanol for 30 min. The
solvent was removed under reduced pressure, and the
residue treated with diethyl ether (20 ml). Evaporation
of this solvent on rotary evaporator gave compound 4
in quantitative yield as white semisolid.
3J(H,P)=8.9, CH). 13C NMR (D2O): l=15.4 (d,
3J(C,P)=8.7 Hz), 49.02 (s), 68.41 (d, 1J(C,P)=156.2
Hz). 31P NMR (D2O): l=17.27. Anal. calcd for
C3H10NO4P: C, 23.23; H, 6.45; N, 9.03. Found: C,
23.21; H, 6.08; N, 8.77%.
4.6.2.
(1S,2S)-(2-Amino-1-hydroxy-4-methyl)pentyl
4.5.1. Dimethyl (1S,2S)/(1R,2S)-(2-amino-1-hydroxy)-
propylphosphonate hydrochloride (81/19 mixture), 4a.
IR: w=1051, 1185, 1242, 1370, 1507, 1611, 2959, 3329
phosphonic acid, 5b. 78% yield, mp=235.5–238.5°C,
[h]2D5.9=+8.7 (c 1, water), IR: w=937, 1015, 1076, 1134,
1526, 1618, 2881, 3145 cm−1. H NMR (D2O): l=0.84
1
1
3
3
cm−1. H NMR (CD3OD): l=1.43 (d, 3H, J(H,H)=
6.7 Hz, CH3), 3.74 (m, 1H, CH), 3.82 (d, 6H, 3J(P,H)=
10.6 Hz, 2×OCH3), 3.92 (m, 1H, CH), 8.08 (bs, 4H,
(d, 6H, J(H,H)=7.0 Hz, 2×CH3), 1.42 (m, 1H, CH),
1.57 (m, 2H, CH2), 3.50 (m, 1H, CH), 3.71 (dd, 1H,
3J(H,H)=2.2 Hz, J(H,P)=10.5 Hz, CH). 13C NMR
3
OH, NH3 ) 13C NMR (CD3OD): l=15.10 (d,
(D2O): l=21.38 (s), 23.56 (s), 38.18 (d, J(C,P)=9.6
+
3
1J(C,P)=9.8 Hz), 52.37 (d, J(C,P)=6.2 Hz), 54.05 (d,
Hz), 57.37 (s), 65.83 (d, J(C,P)=155.4 Hz). 31P NMR
2
1
2
2J(C,P)=7.4 Hz), 54.48 (d, J(C,P)=7.5 Hz), 66.73 (d,
(D2O): l=17.57. Anal. calcd for C6H16NO4P: C, 36.52;
H, 8.11; N, 7.10. Found: C, 36.43; H, 7.89; N, 6.88%.
1J(C,P)=167.1 Hz). 31P NMR (CD3OD): l=23.73
(1R,2S), 24.56 (1S,2S); ESI=184.0.
4.6.3. (1S,2S,3S)-(2-Amino-1-hydroxy-3-methyl)pentyl
phosphonic acid, 5c. 66% yield, mp=216–220°C.
[h]2D8.3=+8.2 (c 1, water), IR: w=942, 1013, 1080, 1134
4.5.2. Dimethyl (1S,2S)/(1R,2S)-(2-amino-1-hydroxy-4-
methyl)pentylphosphonate hydrochloride (88/12 mixture),
1
1
4b. IR: w=1050, 1216, 1470, 1506, 1608, 2960 cm−1. H
1528, 1616, 2881, 3145 cm−1. H NMR (D2O): l=0.76
3
3
3
NMR (CDCl3): l=0.98 (d, 6H, J(H,H)=5.0 Hz, 2×
(t, 3H, J(H,H)=7.3 Hz, CH3), 0.83 (d, 3H, J(H,H)=
6.7 Hz, CH3), 1.05 (m, 1H, CH), 1.60 (m, 2H, CH2),
3.12 (m, 1H, CH), 3.86 (dd, 1H, 3J(H,H)=2.0 Hz,
3J(H,P)=11.3 Hz, CH). 13C NMR (D2O): l=9.82 (s),
CH3), 1.57 (m, 2H, CH2), 1.74 (m, 1H, CH), 3.82 (2d,
3
6H, J(H,P)=10.5 Hz, 2×OCH3), 4.02 (m, 2H, 2×CH),
6.10 (bs, 4H, NH3 , OH). 13C NMR (CDCl3): l=22.65
+
3
(s), 24.26 (s), 38.02 (d, 3J(C,P)=4.9 Hz), 53.61 (d,
14.19 (s), 24.22 (s), 33.86 (d, J(C,P)=10.1 Hz), 56.40
2J(C,P)=7.0 Hz), 54.76 (d, J(C,P)=7.0 Hz), 65.75 (d,
(s), 63.92 (d, 1J(C,P)=155.1 Hz). 31P NMR (D2O):
l=17.10. Anal. calcd for C6H16NO4P: C, 36.52; H,
8.11; N, 7.10. Found: C, 36.52; H, 8.13; N, 6.77%.
2
1J(C,P)=166.6 Hz). 31P NMR: l=24.77 (1R,2S), 24.93
(1S,2S); ESI=225.6.
4.5.3. Dimethyl (1S,2S,3S)/(1R,2S,3S)-(2-amino-1-
hydroxy-3-methyl)pentylphosphonate hydrochloride (83/
17 mixture), 4c. IR: w=1050, 1216, 1371, 1471, 1508,
4.7. Synthesis of Boc-(S)-Phe-(S)-Ala-PO3Me2, 6
Boc-(S)-phenylalanine (5 mmol) was dissolved in 10 ml
of dry THF and 12 mmol of N-methylmorpholine was
added dropwise to the mixture. The mixture was then
cooled in an ice–water bath to −20°C and 5.5 mmol of
isobutyl chloroformate was added. After 1 h, 5 mmol of
(1S,2S)/(1R,2S) dimethyl (2-amino-1-hydroxy)propyl-
phosphonate hydrochloride 3a was added and the mix-
ture was stirred overnight at room temperature. THF
1
1610, 2961 cm−1. H NMR (CDCl3): l=1.12 (m, 6H,
2×CH3), 1.22 (m, 1H, CH), 1.59 (m, 2H, CH2), 3.76 (m,
3
1H, CH), 3.81 (d, 3H, J(H,P)=10.3 Hz, OCH3), 3.86
3
(d, 3H, J(H,P)=10.5 Hz, OCH3), 4.02 (m, 1H, CH),
6.11 (bs, 4H, NH3 , OH). 13C NMR (CDCl3): l=12.82
+
(s), 18.36 (s), 24.02 (s), 35.27 (d, 3J(C,P)=4.2 Hz),
2
2
52.57 (d, J(C,P)=7.0 Hz), 53.08 (d, J(C,P)=7.0 Hz),

M. Drag et al. / Tetrahedron: Asymmetry 14 (2003) 1837–1845
1845
was removed on rotary evaporator and the residue was
dissolved in 40 ml of ethyl acetate and washed with
10% aqueous solution of citric acid, saturated solution
of NaHCO3, water and brine. Drying and evaporation
of the solvent gave crude 6, which was purified by
means of column chromatography on silica gel using
CH2Cl2/MeOH (50:2, v/v) as eluent. Pure phosphono-
peptide 6 was obtained as a white solid.
6. Nicolaou, K. C.; Dai, W. M.; Guy, R. K. Angew. Chem.,
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Mixture of two diastereoisomers: (1S,2S,2%S), 84%;
(1R,2S,2%S), 16%; 38% yield, mp=45–49°C. IR: w=
978, 1023, 1070.60, 1173, 1225, 1445, 1479, 1527, 1651,
1
1691, 2982, 3339 cm−1. H NMR (CDCl3): l=1.26 (d,
3
3H, J(H,H)=5.7 Hz, CH3), 1.37 (s, 9H, Boc), 3.01 (m,
3
2H, CH2), 3.82 (d, 6H, J(P,H)=10.5 Hz, 2×OCH3),
3.89 (dd, 1H, 3J(H,H)=3.8 Hz, 2J(H,P)=8.9, CH),
4.27 (m, 2H, 2×CH), 7.02 (d, 1H, NH), 7.23–7.31 (m,
5H, aromat.); 13C NMR for (1S,2S,2%S) (CDCl3): l=
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3
17.6 (d, J(C,P)=9.7 Hz), 28.22 (s), 38.50 (s), 47.46 (s),
53.50 (d, 2J(C,P)=7.0 Hz), 56.50 (s), 70.74 (d,
1J(C,P)=161.4 Hz), 80.20 (s), 126.8 (s), 128.51 (s),
129.40 (s), 136.67 (s), 155.37 (s), 172.04 (s). 31P NMR:
l=25.28 (1R,2S,2%S), 25.48 (1S,2S,2%S). Anal. calcd for
C19H31N2O7P: C, 52.98; H, 7.20; N, 6.51. Found: C,
53.21; H, 7.40; N, 6.77%. ESI=430.5, 452 (M+Na)+.
4.8. Derivativation of 3b with (S)-O-methylmandelic acid
To a solution of 3b (30 mg) in 1 ml of CH2Cl2 (S)-O-
methylmandelic acid (15.4 mg, 1 equiv.) was added
followed by addition of small crystal of DMAP and
DCC (24 mg, 1.3 equiv.). After 24 h of stirring DCU
was filtered off, solvent removed under reduced pres-
sure and the sample subjected to 1H and 31P NMR
(CDCl3) analysis without purification.
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Acknowledgements
This work was supported by Komitet Badan
Naukowych grant no. 6 P04B 021 18. The authors also
thank Radoslaw Lipinski, MSc. for helpful assistance.
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