Synthesis of novel enantiomerically pure C3-symmetric trialkanolamine ligand containing phosphoryl groups

Article abstract of DOI:10.1055/s-2006-926349

Catalytic activity of ten metal salts in the reaction of benzhydrylamine and benzylamine with diethyl 2,3-epoxypropylphosphonate (1) was studied. Only in the presence of copper(I) iodide pure diethyl 3-benzhydrylamino- and 3-benzylamino-2-hydroxypropylpho

Full text of DOI:10.1055/s-2006-926349

PAPER
989
Synthesis of Novel Enantiomerically Pure C3-Symmetric Trialkanolamine
Ligand Containing Phosphoryl Groups
C
-Symmetric
T
ria
n
lkanolamine
d
L
igands rzej E. Wróblewski,* Anetta Hałajewska-Wosik
3
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Łódź, Muszyńskiego 1, 90-151 Łódź, Poland
Fax +44(42)6788398; E-mail: aewplld@ich.pharm.am.lodz.pl
Received 10 October 2005
This paper is respectfully dedicated to Professor John G. Verkade on the occasion of his 70th birthday.
ligands were studied as models for zinc hydrolases15 and
in chiral molecular recognition.16 Chiral C3-symmetric
ligands having a mesitylene core have also been
obtained17,18 and successfully applied as catalysts in the
Abstract: Catalytic activity of ten metal salts in the reaction of benz-
hydrylamine and benzylamine with diethyl 2,3-epoxypropylphos-
phonate (1) was studied. Only in the presence of copper(I) iodide
pure diethyl 3-benzhydrylamino- and 3-benzylamino-2-hydroxy-
propylphosphonates were produced quantitatively. Although the asymmetric addition of dialkylzinc to aldehydes.18 Very
reactions catalysed by calcium(II) triflate were the fastest, they led
recently chiral trialkanolamine-based hemicryptophanes,
to the contamination of the major products with the respective bis-
which may serve as model of enzymes, have been de-
phosphonates. Enantiomerically pure (S,S)-bis[2-(O,O-diethyl-
scribed.19
phosphorylmethyl)ethanol]amine (10) was prepared in a Ca(OTf)2-
On the other hand, chelating properties of phosphonic de-
rivatives of amino acids have been recognised and their
biomedical applications as ligands in MRI contrast agents,
fluorescent complexes and radiopharmaceuticals are well
known.20
catalysed reaction of (S)-1 (ee 94%) with 0.4 equivalent benzyl-
amine followed by hydrogenolysis. The bisphosphonate (S,S)-10
was transformed into enantiomerically pure (S,S,S)-tris[2-(O,O-di-
ethylphosphorylmethyl)ethanol]amine (2), when reacted with (S)-1
(ee 94%) or into (R,S,S)-2, when (R)-1 (ee 94%) was used.
Key words: amino alcohols, epoxides, ligands, phosphonates, ring
We have recently synthesised several enantiopure g-ami-
no-b-hydroxypropylphosphonates21–23 employing Jacob-
sen’s hydrolytic kinetic resolution (HKR)24 of diethyl 2,3-
epoxypropylphosphonate (1) and noticed the formation of
respective secondary amines, when benzhydrylamine22 or
O-benzylhydroxylamine23 were reacted with 1. These ob-
servations have prompted us to synthesise chiral tri-
alkanolamines 2 containing the O,O-diethylphosphoryl
groups at terminal carbon atoms (Scheme 1).
opening
Chiral triisopropanolamine was first synthesised by
Farina and used in stereochemical studies on trimethyl-
boratrane.1 Later Nugent and Harlow prepared other trial-
kanolamines in order to study transition metal alkoxide
complexes.2 The rigid atrane framework of these com-
plexes provides an asymmetric environment for a metal
and thus implies potential applications in asymmetric ca-
talysis.3 So far the most useful complexes in this area are
those of titanium(IV) and zirconium(IV), which are
known to catalyse sulfide to sulfoxide oxidations,4,5 meso-
epoxide ring openings,6 halohydrin synthesis7 and oxida-
tion of secondary amines to nitrones.8 Other chiral titani-
um(IV) complexes have been applied as catalysts in a
variety of oxidative processes, e.g. epoxidation of allylic
alcohols9 and N-oxidation of b-hydroxyamines.10 Also
vanadium(V) complexes have been found to efficiently
catalyse oxidation of, for example, allylic alcohols to
epoxides11 and sulfides to sulfoxides.12
O
N
CH2CHCH2P(O)(OEt)2
OH
P(O)(OEt)2
3
1
2
Scheme 1 Retrosynthetic plan
Although syntheses of chiral trialkanolamines take advan-
tage of reactions of ammonia with 3 equivalents of appro-
priate terminal epoxides1,2,13,25 or of b-amino alcohols
with two equivalents of the epoxide,2,19 we preferred a
stepwise approach, which would allow us to design syn-
thetic pathways to chiral and unsymmetrically substituted
trialkanolamine ligands (Scheme 2).
The interest in the synthesis of C3-symmetric ligands has
been increasing in recent years. For example, efficiency of
several chiral trialkanolamine-based quaternary salts in
alkylation of glycinate-benzophenone Schiff bases under
PTC conditions has been examined.13 A series of 3¢-O-si-
latranylthymidines has been prepared and shown to pos-
sess anticancer activity.14 Chiral trisoxazoline-based
CH2CH(OH)CH2R
CH2CH(OH)CH2R
N
CH2CH(OH)CH2R'
CH2CH(OH)CH2R"
HN
CH2CH(OH)CH2R'
O
H2NCH2CH(OH)CH2R
R
Scheme 2 Synthetic strategy to unsymmetrically substituted tri-
alkanolamines
SYNTHESIS 2006, No. 6, pp 0989–0994
Advanced online publication: 27.02.2006
x
x
.
x
x
.2
0
0
6
DOI: 10.1055/s-2006-926349; Art ID: P16305SS
© Georg Thieme Verlag Stuttgart · New York

990
A. E. Wróblewski, A. Hałajewska-Wosik
In this paper we describe our studies on the optimisation
of the catalyst efficient in opening of the epoxide ring in 1
with primary amines, a two-step approach to (S,S)-bis[2-
(O,O-diethylphosphorylmethyl)ethanol]amine [(S,S)-10]
and finally the syntheses of (S,S,S)- and (R,S,S)-tris[2-
(O,O-diethylphosphorylmethyl)ethanol]amines [(S,S,S)-
and (R,S,S)-2].
OH
Ph2HCHN
P(O)(OEt)2
3
O
a or b
P(O)(OEt)2
+
OH
1
Ph2CHN CH2CHCH2P(O)(OEt)2
2
4
Regiospecific opening of the epoxide 1 at C-3 with
amines was quantitatively accomplished without cata-
lysts, but it required heating at elevated temperatures
sometimes for several days.21,22 To shorten the reaction
time and to lower the reaction temperature several metal
salts, recently introduced as catalysts for the epoxide ring
opening,26–29 have been tried with the phosphonate 1 and
benzhydrylamine, selected as a model primary amine
(Scheme 3). The progress of the reactions carried out in
the presence of 5 mol% of catalysts was monitored by 31P
NMR spectroscopy and compositions of the crude prod-
ucts were calculated from 31P NMR spectra (Table 1). The
by-products 5, 6 and 7 (Figure 1) were identified based on
our recent spectroscopic characterisation.21,22
Scheme 3 Reaction of phosphonate 1 with benzhydrylamine.
Reagents and conditions: a) Ph2CHNH2 (1.1 equiv), see Table 1; or
b) Ph2CHNH2 (0.4 equiv), Ca(OTf)2 (5 mol%), 50 °C, 19 h.
(Scheme 4). Application of Cu2I2 as catalyst led to the for-
mation of the phosphonate 8 as a single product after four
hours at 50 °C. At the same temperature, in the presence
of Ca(OTf)2, the reaction of 1 with benzylamine was fin-
ished after 20 minutes. However, the major phosphonate
8 was contaminated with ca 20% of the bisphosphonate 9.
The latter transformation was also carried out at room
temperature to give an 85:15 mixture of 8 and 9 after two
hours.
Although in the reaction catalysed by copper(I) iodide the
phosphonate 3 was formed as a single product, we con-
ducted further studies using calcium triflate as catalyst,
since the epoxide ring opening in 1 could be accomplished
at room temperature in a few hours and the reaction mix-
ture was contaminated with negligible amounts of the bis-
phosphonate 4.
OH
X
P(O)(OEt)2
HO
P(O)(OEt)2
5
6
X = Cl
X = Br
7
To further shorten the reaction time benzhydrylamine was
replaced by less sterically hindered benzylamine
Figure 1 Structure of by-products 5–7
Table 1 Products of the Catalysed Epoxide Opening in the Phosphonate 1 with Benzhydrylamine
Entry
Catalyst
Conditions
Ratio of phosphonates (%)
1
3
4
6
5
0
3
3
0
6
3
3
0
0
4
3
5
0
5
0
–
0
5
5
5
0
0
0
0
0
6
0
0
5
0
0
0
0
0
4
5
0
0
0
7
0
0
0
0
6
0
0
0
9
2
0
0
0
1
2
FeSO4·7H2O
ZnCl2
50 °C; 46 h
50 °C; 24 h
50 °C; 24 h
50 °C; 24 h
50 °C; 24 h
50 °C; 2 h
50 °C; 10 h
20 °C; 12 h
50 °C; 3 h
20 °C; 4.5 h
50 °C; 21 h
50 °C; 3 h
20 °C; 6 h
1
7
0
3
0
93
83
95
91
91
73
87
82
84
45
3
ZnBr2
a
4
AgF
5
CsF
6
NiCl2·6H2O
ZrCl4
22
2
7
8
ZrCl4
10
0
9
LiBr
10
11
12
13
LiBr
48
0
Cu2I2
100
96
Ca(OTf)2
Ca(OTf)2
0
0
97
a Contains 3% of an unknown phosphonate (31P NMR: d = 29.77).
Synthesis 2006, No. 6, 989–994 © Thieme Stuttgart · New York

PAPER
C3-Symmetric Trialkanolamine Ligands
991
OH
CH2P(O)(OEt)2
H
CH2P(O)(OEt)2
H
BnHN
P(O)(OEt)2
a
HN
N
CH2C
OH
(S,S)-10
CH2C
OH
(S,S,S)-2
8
+
2
3
O
a or b
P(O)(OEt)2
OH
1
Scheme 5 Synthesis of (S,S,S)-2. Reagents and conditions: a) (S)-1
(3 equiv), Ca(OTf)2 (10 mol%), toluene, 50 °C, 20 h.
R
N CH2CHCH2P(O)(OEt)2
2
9
R = Bn
c
oxyphosphonate (R)-1 (ee 94%)21 in the presence of
Ca(OTf)2 (10 mol%) at 50 °C for 20 h. After chromato-
graphic purification, the trisphosphonate (R,S,S)-2
(Figure 2) was separated in 67% yield. Its enantiomeric
purity was proved by absence of 1H, 13C and 31P NMR res-
onances characteristic of (S,S,S)-2 in the spectra of the ob-
tained material. For example, the 31P NMR chemical
shifts for methanol solutions are well separated and ap-
peared as a single line at 31.48 ppm for (S,S,S)-2, while for
(R,S,S)-2, two lines (a 2:1 ratio) were observed at 31.70
and 31.92 ppm, respectively.
10 R = H
Scheme 4 Reaction of phosphonate 1 with benzylamine. Reagents
and conditions: a) BnNH2 (1.1 equiv), Cu2I2 or Ca(OTf)2 (5 mol%),
r.t.; or b) BnNH2 (0.4 equiv), Ca(OTf)2 (5 mol%), 50 °C, 20 min; c.
H2, Pd/C and Pd(OH)2/C, 20 h.
Syntheses of pure bisphosphonates 4 and 9 were accom-
plished by reacting the epoxyphosphonate 1 with 0.4
equivalent of the amine at 50 °C in the presence of
Ca(OTf)2. It took 19 hours for benzhydrylamine to com-
pletely react with a slight excess of 1 (Scheme 3), while
with benzylamine (Scheme 4) only one hour was needed
to produce the bisphosphonate 9 quantitatively. In both
cases, approximate 1:1 dl and meso mixtures of the re-
spective bisphosphonates were formed.
(EtO)2P(O)CH2
H
CH2P(O)(OEt)2
H
CCH2N
CH2C
HO
OH
2
Hydrogenolysis of the benzyl protecting group in 9 was
performed in the presence of a 1:1 Pd/C and Pd(OH)2/C
mixture to afford pure secondary amine 10 quantitatively
(Scheme 4). However, this compound had to be used in
further transformations as a crude material, since attempts
to purify it on silica gel led to partial decomposition.
(R,S,S)-2
Figure 2 (R,S,S)-Tris[2-(O,O-diethylphosphorylmethyl)ethanol]amine
In conclusion, among the 10 metal salts tried as catalysts
in opening of the epoxide ring in diethyl 2,3-epoxypropyl-
phosphonate (1) with benzhydrylamine and benzylamine,
only Cu2I2 cleanly gave diethyl 3-benzhydrylamino- and
3-benzylamino-2-hydroxypropylphosphonates, while in
the reactions catalysed by calcium(II) triflate, which were
the fastest, the major products were contaminated with the
respective bisphosphonates. Tagging the terminal epoxide
residue with the O,O-diethylphosphoryl group made pos-
sible identification of impurities, which were formed by
nucleophilic attack of chloride or bromide (from cata-
lysts) at terminal carbon atom.
When the epoxyphosphonate (S)-1 (ee 94%) was reacted
with 0.4 equivalent benzylamine, enantiomerically pure
(S,S)-N-benzyl-bis[2-(O,O-diethylphosphorylmethyl)eth-
anol]amine [(S,S)-9] was formed quantitatively. The
enantiomeric purity of this compound was confirmed
(within detection limits) by disappearance of signals of
meso-9 from the 1H and 13C NMR spectra of the obtained
material. The absence of a singlet at 3.75 ppm (H2CPh in
meso-9) was especially indicative. Hydrogenolysis of
(S,S)-9 led to (S,S)-bis[2-(O,O-diethylphosphorylmeth-
yl)ethanol]amine [(S,S)-10], which was pure to be used in
the next step as a crude product.
Synthesis of enantiomerically pure (S,S)-bis[2-(O,O-di-
ethylphosphorylmethyl)ethanol]amine (10) was accom-
plished in a Ca(OTf)2-catalysed reaction of the epoxy-
phosphonate (S)-1 (ee 94%) with 0.4 equivalent of benzyl-
amine followed by hydrogenolysis. Enantiomerically
pure (S,S,S)- and (R,S,S)-tris[2-(O,O-diethylphosphoryl-
methyl)ethanol]amines [(S,S,S)- and (R,S,S)-2] were ob-
tained, when the bisphosphonate (S,S)-10 was reacted
with (S)-1 (ee 94%) or with (R)-1 (ee 94%).
To synthesise the trisamine (S,S,S)-2, the enantiomerical-
ly pure bisphosphonate (S,S)-10 was reacted with three
equivalents of epoxyphosphonate (S)-1 (ee 94%) in the
presence of Ca(OTf)2 (10 mol%) at 50 °C for 20 hours
(Scheme 5). After removal of an excess (S)-1 (ee 90%)
and residual vinylphosphonate 7 as less polar materials,
(S,S,S)-tris[2-(O,O-diethylphosphorylmethyl)ethanol]amine
[(S,S,S)-2] was cleanly separated in 72% yield. Since the
1H and 13C NMR spectra of this compound exhibited sin-
gle sets of resonances for the homotopic substituents at
the nitrogen atom, we consider it as enantiomerically
pure.
1H NMR spectra were recorded with a Varian Mercury-300 spec-
trometer; chemical shifts d are given in ppm with respect to TMS;
coupling constants J are reported in Hz. 13C and 31P NMR spectra
were recorded on a Varian Mercury-300 machine at 75.5 and 121.5
MHz, respectively. IR spectra were measured on an Infinity MI-60
FT-IR spectrometer. Elemental analyses were performed by the Mi-
croanalytical Laboratory of this Faculty on a Perkin-Elmer PE 2400
CHNS analyser. Polarimetric measurements were conducted on a
Perkin-Elmer 241 MC apparatus.
To confirm this conclusion we undertook the synthesis of
(R,S,S)-2. To this end, the enantiomerically pure bisphos-
phonate (S,S)-10 was reacted with three equivalents ep-
Synthesis 2006, No. 6, 989–994 © Thieme Stuttgart · New York

992
A. E. Wróblewski, A. Hałajewska-Wosik
The following absorbents were used: column chromatography,
Merck silica gel 60 (70–230 mesh); analytical TLC, Merck TLC
9), 1.96–1.74 (m, 4 H, H2CP in meso-9 and dl-9), 1.32 (t, J = 7.1 Hz,
6 H, CH3 in dl-9), 1.32 and 1.31 (2 t, J = 7.1 Hz, 6 H, 2 CH3 in meso-
9).
plastic sheets silica gel 60 F254
.
Diethyl (R)- and (S)-2,3-epoxypropylphosphonates (1, ee 94%,
13C NMR (CDCl3): d = 138.3, 128.9, 128.2, 128.1, 127.1, 127.0,
65.0 (d, J = 4.3 Hz, CHOH in dl-9), 64.1 (d, J = 2.9 Hz, CHOH in
meso-9), 62.1, 62.0, 61.9, 61.9 (4 d, J = 6.5 Hz, COP in meso-9 and
dl-9), 61.2 and 61.2 (2 d, J = 16.3 Hz, C-N in meso-9 and dl-9), 60.3
(s, CPh in dl-9), 60.1 (s, CPh in meso-9), 31.7 (d, J = 139.7 Hz, CP
in dl-9), 31.6 (d, J = 139.7 Hz, CP in meso-9), 16.7 (d, J = 6.0 Hz,
CH3 in dl-9), 16.6 (d, J = 6.0 Hz, 2 CH3 in meso-9).
both) were prepared according to the literature procedure.21
Reaction of the Epoxyphosphonate 1 with Benzhydrylamine or
Benzylamine (1:1.1 Mixture) in the Presence of Catalysts; Gen-
eral Procedure
A mixture of the phosphonate 1 (1.00 mmol) and the amine (1.10
mmol) containing the respective catalyst (5 mol%) was stirred at
50 °C or at r.t. under argon for the time indicated in Table 1.
31P NMR (CDCl3): d = 30.81 (meso-9), 30.75 (dl-9).
Anal. Calcd for C21H39NO8P2·0.5 H2O: C, 49.99; H, 7.99; N, 2.78.
Found: C, 50.02; H, 8.02; N, 2.78.
Diethyl 3-Benzylamino-2-hydroxypropylphosphonate (8)
The crude product obtained from 1 (0.200 g, 1.03 mmol) and ben-
zylamine (0.124 mL, 1.13 mmol) in the presence of Cu2I2 (0.010 g,
0.05 mmol) was dissolved in CH2Cl2 (3 mL) and the solution was
washed with H2O (3 × 2 mL). The aqueous washings were extracted
with CH2Cl2 (2 × 2 mL) and the combined organic phases were
dried (MgSO4). After concentration, the crude product was chro-
matographed on a silica gel column with chloroform–MeOH mix-
ture (50:1) to give the phosphonate 8 (0.264 g, 85%) as a yellowish
oil.
(S,S)-N-Benzylbis[2-(O,O-diethylphosphorylmethyl)etha-
nol]amine [(S,S)-9]
The crude product obtained from 1 (0.500 g, 2.57 mmol) (ee 94%)
and benzylamine (0.112 mL, 1.03 mmol) in the presence of
Ca(OTf)2 (0.044 g, 0.13 mmol, 5 mol%) was purified as described
above to give (S,S)-9 (0.397 g, 78%) as a colourless oil; [a]D20 –35.0
(c = 1.5, CHCl3).
1H NMR (CDCl3): d = 7.30–7.20 (m, 5 H), 4.20–4.00 (m, 10 H),
3.84 (d, J = 13.8 Hz, 1 H, HaHbCPh), 3.65 (d, J = 13.8 Hz, 1 H,
HaHbCPh), 2.70–2.56 (m, 4 H, H2CN), 1.88 (dd, AB, JAB = 15.3 Hz,
J = 22.5, 8.1 Hz, 2 H, HaHbCP), 1.83 (dd, AB, JAB = 15.3 Hz,
J = 23.4, 4.8 Hz, 2 H, HaHbCP), 1.32 (t, J = 7.1 Hz, 6 H, 2 CH3).
13C NMR (CDCl3): d = 138.6, 129.1, 128.5, 127.3, 64.4 (d, J = 3.8
Hz, COH), 62.1 and 61.9 (2 d, J = 6.8 Hz, COP), 61.3 (d, J = 16.6
Hz, CN), 60.3 (s, CPh), 31.7 (d, J = 140.0 Hz, CP), 16.7 (d, J = 6.0
Hz).
IR (film): 3376, 2984, 2909, 2854, 1601, 1456, 1223, 1027, 964,
807, 747, 705 cm–1.
1H NMR (CDCl3): d = 7.34–7.23 (m, 5 H), 4.22–4.03 (m, 5 H), 3.88
(d, J = 13.2 Hz, 1 H, HaHbCPh), 3.77 (d, J = 13.2 Hz, 1 H, HaHb-
CPh), 2.83 (dd, J = 12.0, 3.6 Hz, 1 H, HaHbCN), 2.66 (dd, J = 12.0,
7.8 Hz, 1 H, HaHbCN), 2.02 (dd, AB, JAB = 15.3 Hz, J = 16.8, 8.4
Hz, 1 H, HaHbCP), 1.94 (dd, AB, JAB = 15.3 Hz, J = 18.6, 4.2 Hz, 1
H, HaHbCP), 1.32 (t, J = 7.2 Hz, 6 H).
13C NMR (CDCl3): d = 139.4, 128.5, 127.4, 127.3, 65.2, 62.1 and
62.0 (2 d, J = 6.9 Hz, COP), 55.1 (d, J = 16.0 Hz, CN), 53.7 (s,
CPh), 31.8 (d, J = 139.0 Hz, CP), 16.7 and 16.7 (2 d, J = 6.0 Hz,
CH3).
31P NMR (CDCl3): d = 30.75.
Anal. Calcd for C21H39NO8P2·0.5 H2O: C, 49.99; H, 7.99; N, 2.78.
Found: C, 49.81; H, 7.93; N, 2.76.
31P NMR (CDCl3): d = 30.37.
Bis[2-(O,O-diethylphosphorylmethyl)ethanol]amine [dl- and
meso-10]
Anal. Calcd for C14H24NO4P·0.8 H2O: C, 53.26; H, 8.20; N, 4.44.
Found: C, 53.25; H, 8.48; N, 4.20.
A solution of the phosphonate dl- and meso-9 (0.240 g, 0.520
mmol) in EtOH (2.5 mL) containing 10% Pd/C (4 mg) and
Pd(OH)2/C (4 mg) was stirred under H2 atmosphere for 20 h. Cata-
lysts were removed on a layer of Celite, and the solution was con-
centrated in vacuo to afford dl- and meso-10 (0.181 g, 86%) as a
yellowish oil.
Reaction of the Epoxyphosphonate 1 with Benzhydrylamine or
Benzylamine (1:0.4 mixture) in the Presence of Ca(OTf)2; Gen-
eral Procedure
A mixture of the phosphonate 1 (2.50 mmol) and the amine (1.00
mmol) containing Ca(OTf)2 (5 mol%) was stirred at 50 °C under ar-
gon for 19 h (benzhydrylamine) or 1 h (benzylamine).
IR (film): 3355, 2984, 2910, 1445, 1393, 1226, 1029, 964, 834 cm–1.
1H NMR (CDCl3): d = 4.22–3.98 (m, 10 H), 2.78 (dd, J = 12.3, 3.6
Hz, 1 H, HaHbCN in meso-10), 2.77 (dd, J = 12.3, 3.9 Hz, 1 H,
HaHbCN in dl-10), 2.70 (dd, J = 12.3, 8.1 Hz, 1 H, HaHbCN in meso-
10), 2.69 (dd, J = 12.3, 7.5 Hz, 1 H, HaHbCN in dl-10), 2.07–1.84
(m, 4 H, H2CP in meso-10 and dl-10), 1.34 (t, J = 7.0 Hz, 12 H, CH3
in meso-10 and dl-10).
13C NMR (CDCl3): d= 65.4 (d, J = 3.8 Hz, CHOH in meso-10), 65.3
(d, J = 3.8 Hz, CHOH in dl-10), 62.0 and 61.9 (2 d, J = 6.8 Hz, COP
in meso-10 and dl-10), 55.9 and 55.7 (2 d, J = 15.4 Hz, CN in meso-
10 and dl-10), 31.7 (d, J = 139.6 Hz, CP in meso-10), 31.7 (d,
J = 139.6 Hz, CP in dl-10), 16.6 and 16.6 (2 d, J = 6.0 Hz, CH3 in
meso-10 and dl-10).
N-Benzylbis[2-(O,O-diethylphosphorylmethyl)ethanol]amine
[dl- and meso-9]
The crude product obtained from 1 (0.500 g, 2.57 mmol) and ben-
zylamine (0.112 mL, 1.03 mmol) in the presence of Ca(OTf)2
(0.044 g, 0.13 mmol, 5 mol%) was dissolved in CH2Cl2 (5 mL) and
the solution was washed with H2O (3 × 3 mL). Aqueous washings
were back extracted with CH2Cl2 (3 mL) and the combined organic
phases were dried (MgSO4). After concentration, the crude product
was chromatographed on a silica gel column with acetone–toluene
mixture (10:1) to give dl- and meso-9 (0.457 g, 90%) as a colourless
oil.
31P NMR (CDCl3): d = 30.94 and 30.95 (meso-10 and dl-10).
IR(film): 3373, 3085, 2982, 2932, 2908, 2828, 1603, 1451, 1391,
1225, 1034, 963, 832, 806, 744, 702 cm–1.
Anal. Calcd for C14H33NO8P·0.75 H2O: C, 40.14; H, 8.30; N, 3.34.
Found: C, 40.16; H, 8.30; N, 3.22.
1H NMR (CDCl3): d = 7.30–7.20 (m, 5 H), 4.20–4.00 (m, 9 H),
4.00–3.80 (m, 1 H, CHOH in meso-9), 3.84 (d, J = 13.8 Hz, 1 H,
HaHbCPh in dl-9), 3.75 (s, 2 H, H2CPh in meso-9), 3.65 (d, J = 13.8
Hz, 1 H, HaHbCPh in dl-9), 2.74 (dd, J = 13.2, 4.2 Hz, 1 H, HaHbCN
in meso-9), 2.67–2.57 (m, 3 H, HaHbCN in meso-9 and H2CN in dl-
(S,S)-Bis[2-(O,O-diethylphosphorylmethyl)ethanol]amine
[(S,S)-10]
From the phosphonate (S,S)-9 (0.315 g, 0.680 mmol) dissolved in
EtOH (3 mL) in the presence of 10% Pd/C (6 mg) and Pd(OH)2/C
Synthesis 2006, No. 6, 989–994 © Thieme Stuttgart · New York

PAPER
C3-Symmetric Trialkanolamine Ligands
993
(6 mg), the phosphonate (S,S)-10 (0.259 g, 94%) was obtained as a
yellowish oil following the procedure described for the racemic 10;
[a]D20 +38.0 (c = 2.16, CHCl3).
1H NMR (CDCl3): d = 4.22–4.00 (m, 10 H), 2.77 (dd, J = 12.3, 3.9
Hz, 2H, HaHbCN), 2.69 (dd, J = 12.3, 7.5 Hz, 2 H, HaHbCN), 2.65–
1.90 (br s, 3 H), 2.02 (ddAB, JAB = 15.3 Hz, J = 16.8, 8.4 Hz, 2 H,
HaHbCP), 1.92 (ddAB, JAB = 15.3 Hz, J = 19.1, 4.2 Hz, 2 H,
HaHbCP), 1.34 (t, J = 7.0 Hz, 12 H).
1H NMR (CD3OD): d = 4.18–4.00 (m, 10 H), 2.75 (dd, J = 12.3, 4.1
Hz, 2 H, HaHbCN), 2.68 (dd, J = 12.3, 7.8 Hz, 2 H, HaHbCN), 2.08
(ddAB, JAB = 15.6 Hz, J = 18.6, 5.7 Hz, 2 H, HaHbCP), 2.05 (ddAB,
JAB = 15.6 Hz, J = 18.0, 7.2 Hz, 2 H, HaHbCP), 1.33 (t, J = 7.1 Hz,
12 H).
13C NMR (CDCl3): d = 65.2 (d, J = 3.0 Hz, CHOH), 62.0 and 61.9
(2 d, J = 6.8 Hz, COP), 55.7 (d, J = 15.1 Hz, CN), 31.7 (d, J = 138.8
Hz, CP), 16.6 and 16.6 (2 d, J = 6.0 Hz).
1H NMR (CD3OD): d = 4.40–4.15 (m, 12 H), 4.15–3.90 (m, 3 H),
2.72 (dd, J = 13.4, 4.4 Hz, 1 H, HaHbCN in R), 2.70 (dd, J = 13.4,
4.4 Hz, 2 H, HaHbCN in S,S), 2.66–2.54 (m, 3 H, HaHbCN), 2.15
(dd, AB, JAB = 15.4 Hz, J = 18.6, 4.5 Hz, 1 H, HaHbCP in R), 2.08
(dd, AB, JAB = 15.4 Hz, J = 18.6, 4.9 Hz, 2 H, HaHbCP in S,S), 1.94
(dd, AB, JAB = 15.4 Hz, J = 17.8, 7.8 Hz, 1 H, HaHbCP in R), 1.94
(dd, AB, JAB = 15.4 Hz, J = 17.8, 8.1 Hz, 2 H, HaHbCP in S,S), 1.33
(t, J = 6.9 Hz, 18 H).
13C NMR (CD3OD): d = 66.6 (d, J = 3.4 Hz, CHOH in R), 66.1 (d,
J = 3.4 Hz, CHOH in S,S), 64.8 (d, J = 14.6 Hz, CN in R), 64.5 (d,
J = 14.6 Hz, CN in S,S), 63.5 and 63.2 (2 d, J = 6.3 Hz, COP), 32.5
(d, J = 139.7 Hz, CP in R), 32.3 (d, J = 140.0 Hz, CP in S,S), 16.9
(d, J = 6.3 Hz).
31P NMR (CD3OD): d = 31.96 (s, 1 P in R) and 31.70 (s, 2 P in S,S).
Anal. Calcd for C21H48NO12P3: C, 42.07; H, 8.07; N, 2.34. Found:
C, 42.15; H, 7.97; N, 2.11.
13C NMR (CD3OD): d = 66.3 (d, J = 3.0 Hz, CHOH), 63.5 and 63.3
(2 d, J = 6.3 Hz, COP), 56.7 (d, J = 12.9 Hz, CN), 32.7 (d, J = 138.8
Hz, CP), 16.9 (d, J = 6.3 Hz).
Acknowledgment
Financial support from the Medical University of Łódź (503-314-1)
is gratefully acknowledged. The authors wish to express their grati-
tude to Mrs. Małgorzata Pluskota for her excellent technical assi-
stance and to Ms Izabela Sobczak, M.Sc. for her experiments in
catalyst optimisation.
31P NMR (CDCl3): d = 30.97.
31P NMR (CD3OD): d = 29.57.
Anal. Calcd for C14H33NO8P·0.25 H2O: C, 41.03; H, 8.24; N, 3.42.
Found: C, 41.06; H, 8.51; N, 3.41.
(S,S,S)-Tris[2-(O,O-diethylphosphorylmethyl)ethanol]amine
[(S,S,S)-2]
References
A mixture of the bisphosphonate (S,S)-10 (0.050 g, 0.12 mmol) and
the epoxyphosphonate (S)-1 (0.070 g, 0.36 mmol) (ee 94%) con-
taining Ca(OTf)2 (0.012 g, 0.036 mmol) in toluene (1 mL) was
stirred at 50 °C for 20 h. After concentration in vacuo, the residue
was filtered through a short pad of silica gel to remove the excess
(S)-1 (with acetone) and to collect the product (S,S,S)-2 (0.052 g,
72%) as a yellowish oil, after washing with MeOH; [a]D20 –32.3
(c = 1.0, MeOH).
1H NMR (CDCl3): d = 4.20–4.00 (m, 15 H), 2.55 (dd, J = 12.9, 1.0
Hz, 3 H, HaHbCN), 2.46 (dd, J = 12.9, 9.7 Hz, 3 H, HaHbCN), 2.20–
1.90 (br s, 3 H), 1.95 (dd, AB, JAB = 15.3 Hz, J = 17.7, 8.4 Hz, 3 H,
HaHbCP), 1.79 (dd, AB, JAB = 15.3 Hz, J = 18.6, 4.8 Hz, 3 H,
HaHbCP), 1.32 (t, J = 7.0 Hz, 18 H).
1H NMR (CD3OD): d = 4.20–4.07 (m, 12 H), 4.07–3.93 (m, 3 H),
2.65 (dd, J = 13.5, 3.5 Hz, 3 H, HaHbCN), 2.56 (dd, J = 13.5, 8.6 Hz,
3 H, HaHbCN), 2.04 (dd, AB, JAB = 15.6 Hz, J = 18.7, 5.4 Hz, 3 H,
HaHbCP), 1.96 (ddAB, JAB = 15.6 Hz, J = 17.9, 7.5 Hz, 3 H,
HaHbCP), 1.33 (t, J = 7.0 Hz, 18 H).
13C NMR (CDCl3): d = 63.8 (d, J = 3.8 Hz, CHOH), 63.7 (d,
J = 16.6 Hz, CN), 62.2 and 61.7 (2 d, J = 6.8 Hz, COP), 31.3 (d,
J = 141.2 Hz, CP), 16.7 and 16.6 (2 d, J = 6.0 Hz).
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13C NMR (CD3OD): d = 65.6 (d, J = 3.0 Hz, CHOH), 64.2 (d,
J = 15.1 Hz, CN), 63.5 and 63.3 (2 d, J = 6.8 Hz, COP), 32.2 (d,
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(R,S,S)-Tris[2-(O,O-diethylphosphorylmethyl)ethanol]amine
[(R,S,S)-2]
In a manner described for (S,S,S)-2, the bisphosphonate (S,S)-10
(0.082 g, 0.20 mmol) and the epoxyphosphonate (R)-1 (0.120 g,
0.606 mmol) (ee 94%) in the presence of Ca(OTf)2 (0.020 g, 0.061
mmol) in toluene (1.5 mL), gave the trisphosphonate (R,S,S)-2
(0.081 g, 67%) as a yellowish oil; [a]D20 –11.0 (c = 2.5, MeOH).
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Synthesis 2006, No. 6, 989–994 © Thieme Stuttgart · New York