Synthesis and resolution of diastereomers of (R,R)-1,2- cyclohexylenediamino-di-phenylmethylphosphonates

Article abstract of DOI:10.1016/j.tetasy.2012.04.007

Salen-like compounds, such as bis-aminophosphonic systems bearing a (R,R)-1,2-diamino-cyclohexyl (DACH) moiety, were synthesized by the addition of dialkyl phosphites to the azomethine bond of N,N′-dibenzylidene-1,2- diaminocyclohexane 2. Five bis-aminophosphonates, dimethyl, diethyl, diisopropyl, dibenzyl, and diallyl derivatives, were obtained in high diastereoselectivity. Three of these compounds, dimethyl 3a, diethyl 3b, and diisopropyl 3c derivatives, had the predominant diastereoisomers separated. A hypothetical explanation of the diastereoselectivity is also reported.

Full text of DOI:10.1016/j.tetasy.2012.04.007

Tetrahedron: Asymmetry 23 (2012) 482–488
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis and resolution of diastereomers
of (R,R)-1,2-cyclohexylenediamino-di-phenylmethylphosphonates
Jarosław Lewkowski a, , Paweł Tokarz , Tadeusz Lis , Katarzyna Slepokura
⇑
a
b
b
´
a
´
´
Department of Organic Chemistry, Faculty of Chemistry, University of Łódz, Tamka 12, 91-403 Łódz, Poland
b Faculty of Chemistry, University of Wrocław, F. Joliot-Curie 14, 50-383 Wrocław, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 February 2012
Accepted 5 April 2012
Salen-like compounds, such as bis-aminophosphonic systems bearing a (R,R)-1,2-diamino-cyclohexyl
(DACH) moiety, were synthesized by the addition of dialkyl phosphites to the azomethine bond of
N,N0-dibenzylidene-1,2-diaminocyclohexane 2. Five bis-aminophosphonates, dimethyl, diethyl, diisopro-
pyl, dibenzyl, and diallyl derivatives, were obtained in high diastereoselectivity. Three of these com-
pounds, dimethyl 3a, diethyl 3b, and diisopropyl 3c derivatives, had the predominant diastereoisomers
separated. A hypothetical explanation of the diastereoselectivity is also reported.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
are widely used in pharmaceutical applications.8,9 Therefore, much
effort has been directed toward the development of the asymmet-
Salen-ligands 1 constitute a group of compounds with a broad
range of applications. They have been used as catalysts in the ster-
eoselective Strecker synthesis of amino acids,1 and also in the
asymmetric catalysis of modifications of the Mannich reaction
such as the Kabatchnik-Fields reaction.2–6 Recently,7 the use of sat-
urated derivatives of salen-ligands, such as DACH-based, N-tosylat-
ed tetramines 1, was reported. They were applied to the
asymmetric Henry reaction as Cu(I) complexes and turned out to
be very much stereoselective.
ric hydrophosphonylation of carbonyl and imine compounds.
All of these facts prompted us to perform a study on the
catalytic properties of chiral salen-ligand derivatives bearing phos-
phonic moieties that had saturated, sp3 nitrogen atoms. Our aim
was to construct
a-aminophosphonates, whose structure would
resemble salen-like ligand derivatives and would combine the
chelating abilities of aminophosphonic groups with the strong ste-
reodivergence action of salen compounds.
Therefore, we performed the addition of phosphites to salen-like
compounds in order to obtain aminophosphonic derivatives of
salen-ligands, that is, bis-aminophosphonic systems bearing a
(R,R)-1,2-diaminocyclohexyl (DACH) moiety. We expected that
the presence of this optically active moiety would have a great
influence on the stereoselectivity of the addition. These bis-amino-
phosphonic systems bearing the (R,R)-DACH moiety have the po-
tential to asymmetrically catalyze the Henry reaction and
possibly also the Kabachnik–Fields reaction.
NH HN
Ph
Ph
NHTs
TsHN
1
2. Results and discussion
It is well known that aminophosphonic derivatives bearing
more than one amino- and more than one phosphonic moiety
are as good ligands for coordinating metal ions. While the phos-
phonic analogue of EDTA is the most well known, there are many
other aminophosphonic chelating agents.
As a result, a large number of salen applications involve amino-
phosphonic acids because optically active aminophosphonic acids
and their derivatives are biologically active compounds, which
For the model compounds, we chose the benzaldehyde deriva-
tives to prevent any of the substituents of the phenyl ring from
having an additional influence on the stereochemistry. (R,R)-1,2-
Diaminocyclohexane was isolated from a commercially available
mixture of cis- and trans-isomers by crystallization of the (R,R)-iso-
mer as its (+)-tartaric acid salt. Using the published procedure,10
the condensation of (R,R)-cyclohexane-1,2-diammonium mono-
(+)-tartrate with benzaldehyde was performed to give optically
active N,N0-dibenzylidene-1,2-diaminocyclohexane 2, which was
easily identified by comparison with the literature data.10,11
⇑
Corresponding author.
E-mail address: jlewkow@uni.lodz.pl (J. Lewkowski).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.04.007

J. Lewkowski et al. / Tetrahedron: Asymmetry 23 (2012) 482–488
483
HP(O)(OR)2
3a-e
N
N
NH HN
(RO)2P
O
P(OR)2
O
2
4a-e
a
b
c
d
R = CH3
dr from10:1:1 to 10:3:3
R = CH2CH3
R = CH(CH3)2
R = CH2Ph
e R = CH2CH=CH2
Scheme 1. Addition of phosphites 3a–e to diimine 2.
Table 1
Results of addition of phosphites 3a–e to N,N0-dibenzylidene-1,2-diaminocyclohexane 2
No.
R
Y (%)
dr
31P NMR
A single isomera
31P NMR
½ ꢁ
a 2D0
4a
4b
4c
4d
4e
CH3
57
10:3:3
10:3:3
10:2:2
10:2:2
100:9:9
26.20, 27.31, 27.53
23.90, 24.08, 24.15
22.27, 22.46, 22.73
24.77, 25.03, 25.48
24.46, 24.54, 24.65
26.20
23.90
22.27
—
ꢂ74.5 (c 1, CH2Cl2)
CH2CH3
CH(CH3)2
CH2Ph
53b
19b
68
ꢂ69.4 (c 1, CH2Cl2)
ꢂ55.7 (c 1, CH2Cl2)
—
—
CH2CH@CH2
37
—
a
Spectroscopic data of the separated diastereoisomer.
Yield of a single diastereoisomer.
b
The Schiff base 2 was then subjected to the addition of several
N–Hꢀ ꢀ ꢀO@P hydrogen bonds, which may stabilize the conformation
adopted in the molecule (Fig. 1, Table 2). Different structural
phenomena were seen for tetra-iso-propyl (R,R)-1,2-cyclohexylene-
diamino-di-(S,S)-phenylmethylphosphonate 4c, as it crystallized as
a monohydrate with two different 4c molecules (A and B) and two
different water molecules in the asymmetric part of the unit cell. As
shown in Fig. 2, each water molecule forms two O–Hꢀ ꢀ ꢀO@P hydro-
gen bonds with two different phosphonate groups of the same mol-
ecule A or B. Therefore, water molecules, acting as linkers between
the two phosphonate groups of the same molecule, influence their
mutual orientation and hence play an important role in the
stabilization of the molecular structures of 4c-A and 4c-B. In addi-
tion to these intermolecular phosphonateꢀ ꢀ ꢀwaterꢀ ꢀ ꢀphosphonate
interactions, the intramolecular N–Hꢀ ꢀ ꢀO and N–Hꢀ ꢀ ꢀN bonds also
stabilize the molecular conformation of both 4c-A and 4c-B.
For elemental analysis, bis-aminophosphonate 4c was recrys-
tallized from hexane to remove water molecules because of techni-
cal issues. The question concerning the mechanism with regards to
the stereochemistry of this reaction appears logical. To answer it,
we analyzed the conformation of the starting imine and considered
model phosphites 3a–e, which lead to the formation of five bis-
aminophosphonates: tetramethyl 4a, tetraethyl 4b, tetraisopropyl
4c, tetrabenzyl 4d, and tetraallyl 4e ones (Scheme 1). Due to the
influence of the optically active (R,R)-1,2-diaminocyclohexyl
substituent, we expected that the additions would be diastereose-
lective. In all cases, analysis of the post-reaction mixture demon-
strated the occurrence of one diastereoisomer in large excess
with the diastereomeric ratio varying from 3:3:10 in the case of
tetrabenzyl ester 4d, up to 9:9:100 for the tetraallyl derivative
4b. The diastereoisomeric ratios together with 31P NMR data, are
shown in Table 1. After preliminary purification of the product
reaction mixtures, we made attempts to separate the diastereoiso-
mers of products 4a–e by column chromatography or fractional
crystallization. However, the resolutions of the stereoisomers of
tetrabenzyl 4d and tetraallyl 4e bis-aminophosphonates were
unsuccessful, because in each fraction, the predominant diastereo-
isomer was accompanied by two others and we were unable to iso-
late any of them. However, the column chromatography of
tetramethyl bis-aminophosphonate 4a as well as the crystalliza-
tion of tetraethyl 4b and tetraisopropyl 4c bis-aminophosphonates,
allowed us to isolate the pure predominant diastereoisomers of
these three compounds. While the predominant diastereoisomer
of tetramethyl bis-aminophosphonate 4a was isolated as a dense
oil, the main stereoisomers of tetraethyl 4b and tetraisopropyl 4c
bis-aminophosphonates were isolated as crystals, and so their
structures were studied by X-ray single crystal diffraction.
The X-ray studies of these two predominant stereomeric forms
of bis-aminophosphonates 4b,c indicated clearly an (S,S)-configu-
ration for the newly formed stereogenic centers for both bis-amin-
ophosphonate 4b (Fig. 1) and 4c (Fig. 2). We suspect that
tetramethyl bis-aminophosphonate 4a as well as bis-aminophos-
phonates 4d-e also occurred predominantly as the (S,R,R,S)-
diastereoisomers.
that imine 2 adopted a syn–syn conformation (Fig. 3) as reported by
12
´
Gawronski et al. Their calculations suggested that the syn–syn
conformer was of the lowest energy and at a global energy
minimum.
The mechanism of the bis-addition of phosphite molecules to
two azomethine bonds of bis-imines has been analyzed in the lit-
erature.13,14 It was suggested that the reaction occurred in two
steps; firstly attack on the first azomethine bond and then, on
the second one. Taking this suggestion into account, we applied
this mechanism to our case. The first step is determined by the spa-
tial orientation of the azomethine bond in the syn–syn conformer.
A molecule of the phosphite attacks the first azomethine bond
from the less hindered si face. The representation using a Newman
projection of the conformational state 3 shows that predominant
The X-ray study of tetraethyl (R,R)-1,2–cyclohexylenediamino-
di-(S,S)-phenylmethylphosphonate 4b revealed two intramolecular
attack comes from the site opposite to the largest,
substituent, which is in accordance with the Felkin model. Thus,
p-conjugated

484
J. Lewkowski et al. / Tetrahedron: Asymmetry 23 (2012) 482–488
Figure 1. The X-ray structure of tetraethyl (R,R)-1,2–cyclohexylenediamino-di-(S,S)-phenylmethylphosphonate 4b with the intramolecular N–Hꢀ ꢀ ꢀO hydrogen bonds (dashed
lines). Displacement ellipsoids are shown at the 50% probability level. [Selected torsion angles: O1–P1–C7–N1 ꢂ41.94(9)°; O4–P2–C8–N2 44.47(10)°.]
the predominant isomer of an imino-aminophosphonate 5 occurs
in the (S)-configuration at the newly formed stereogenic center.
The predominant attack onto the second azomethine bond of the
intermediates 5b,c of a phosphite molecule, which is depicted by
the use of a Newman projection, comes from a si face too, that is,
from the site opposite to the largest substituent, according to the
Felkin model. Therefore, the predominant diastereoisomers, that
is, (R,R)-1,2–cyclohexylenediamino-di-(S,S)-phenylmethyl-phos-
phonates 4b,c occur with an (S,S)-configuration around the newly
formed stereogenic centers (Fig. 3).
the 2 h of heating might be shortened or even neglected without a
significant decrease in the yield. The crude product was crystallized
from hexane yielding 80% of pure compound. Mp: 101–104 °C, lit11
98–100 °C. 1H NMR (CDCl3, 200 MHz): d 8.21 (s, CH@N, 2H); 7.61–
7.56 (m, PhH, 4H); 7.34–7.29 (m, PhH, 6H); 3.49–3.35 (m,
NCHc-hex, 2H); 1.89–1.78 ðm; CH2c-hex; 6HÞ; 1.55–1.46 ðm; CHc2-hex; 6HÞ.
4.3. General procedure for the synthesis of phosphonates 4a–e
A 10 ml flask was charged with 2 mmol of imine and 4.4 mmol
(or 6–7 mmol in a case of dimethyl phosphite due to the low solu-
bility of the imine in it) of the appropriate phosphite. It was heated
with stirring on a water bath for 2–3 min until all of the imine was
dissolved in phosphite. Then the mixture was irradiated using
microwaves (100 W) for 2–3 min. It should be noted that the irra-
diation was not needed in a case of diallyl phosphite. Purification
was performed as described below.
3. Conclusion
We have performed the bis-addition of several phosphites to azo-
methine bonds of a salen-like, imine 2 bearing (R,R)-1,2-diaminocy-
clohexane moiety, whose reactions were diastereoselective. In two
cases, we managed to separate the predominant diastereoisomer,
whose X-ray studies demonstrated its configuration on the newly
formed stereogenic centers to be (S,S). In other cases, the separation
of the predominant diastereoisomers was unsuccessful, but we can
suppose, per analogiam, that the stereochemicalbehavior is, in these
cases, similar and the predominant diastereoisomers also have (S,S)-
configurations. We made some attempts, based on the literature, to
give the most probable explanation for the stereochemistry of this
reaction. The separated isomers of bis-aminophosphonates 4a, 4b,
and 4c will be further investigated as catalysts in the Tsuji-Trost
reaction,15 Henry reaction,7 and the Kabachnik–Fields reaction.6
4.3.1. Tetramethyl (R,R)-1,2–cyclohexylenediamino-di-
phenylmethylphosphonate 4a
The post-reaction mixture was dissolved in dichloromethane
and washed five times with a sodium bicarbonate saturated water
solution. The solvent was removed in vacuo and the residual oil
was purified on a short chromatography column with Et2O/MeOH
12:1 as an eluent. The procedure yielded 580 mg (57% based on
imine) of a colorless oil. Elemental analysis: Calcd for C24H36N2-
O6P2: C, 56.47; H, 7.11; N, 5.49. Found: C, 56.27; H, 7.14; N, 5.41.
Predominant diastereoisomer: ½a D20
ꢁ
¼ ꢂ74:5 (c 1, CH2Cl2); 1H
4. Experimental
4.1. General
NMR (CDCl3, 200 MHz): d 7.48–7.32 (m, PhH, 10H); 4.22 (d,
2JPH = 21.2 Hz, CHP, 2H); 3.70 and 3.63 (2 d, JPH = 10.4 Hz,
3
P(OCH3)2, 12H); 2.54–2.42 (m, NCHc-hex
,
2H); 2.06–1.96
ðm; CH2c-hex, 2H; 1.61–1.52 ðm; CH2c-hex, 2H; 1.09–0.86 ðm;CHc2-hex
;
4HÞ. 13C NMR (CDCl3, 150 MHz): d 136.10 (C-ipso); 128.78 (d,
All solvents were routinely distilled and dried prior to use.
Reagents were purchased by Aldrich and used as received. NMR
spectra were recorded on a Bruker Avance III 600 MHz apparatus
operating at 600 MHz (1H NMR) and 243 MHz (31P NMR). Rotatory
power was measured with a 241 MC Perkin-Elmer polarimeter.
Elemental analyses were performed in the Microanalysis
3JPC = 6.3 Hz, Cortho); 128.53 (Carom); 128.50 (Carom); 53.86
2
2
(d, JPC = 6.8 Hz, POC); 53.57 (d, JPC = 6.6 Hz, POC); 57.45, 57.35
(Cchex); 57.12 (d, JPC = 153.1 Hz, PCN); 30.17, 24.42 (Cchex). 31P
1
NMR (CDCl3, 81 MHz): d 26.20. IR (KBr): 3447 (NH); 2951, 2928
(C–Harom); 1494, 1454 (C@Carom); 1244 (P@O); 1106 (P–O); 1057,
1030. ESI-MS: m/z = 533.3 [M+Na]+; 451.3 [M-4CH3]+; 423.3
[M+Na-2P(O)(OCH3)2]+. Two minor diastereoisomers; 1H NMR
´
Laboratory of the CMMS PAS in Łódz.
4.2. N,N0-Dibenzylidene-(R,R)-1,2-diaminocyclohexane 2
(CDCl3, 200 MHz):
d
7.43–7.30 (m, PhH, 10H); 4.28 (d,
2
2JPH = 21.4 Hz, CHPId, 2H); 4.10 (d, JPH = 21.2 Hz, CHPIId, 2H); 3.83
The imine was synthesized following the described procedure.10
The general method was unchanged, although it was noticed that
Id
3
and 3.77 (2d, JPH = 10.8 Hz, PðOCH3Þ2 , 12H); 3.54 and 3.52 (2d,
3JPH = 10.2 Hz, PðOCH3Þ2IId, 12H); 2.54–2.25 (m, NCHc-hex, 2H);

J. Lewkowski et al. / Tetrahedron: Asymmetry 23 (2012) 482–488
485
Fig. 2. The X-ray structures of two crystallographically independent molecules
A (a) and B (b) of tetra-iso-propyl (R,R)-1,2–cyclohexylenediamino-di-(S,S)-phen-
ylmethylphosphonate 4c (in the crystal of 4cꢀH2O) joined with water molecules via O–Hꢀ ꢀ ꢀO hydrogen bonds (dashed lines). Intermolecular hydrogen contacts – dashed lines.
The disorder of two isopropoxyl groups in molecule B is omitted for the sake of clarity. Displacement ellipsoids are shown at the 50% probability level. [Selected torsion
angles: O1A–P1A–C7A–N1A 69.81(11)°; O4A–P2A–C8A–N2A 53.57(11)°; O1B–P1B–C7B–N1B 53.16(12)°; O4B–P2B–C8B–N2B 76.19(12)°.]
2.16–1.90 ðm; CHÞ2c-hex; 2HÞ; 1.65–1.39 ðm; CHÞ2c-hex; 2HÞ; 1.09–
0.96 ðm; CHÞ2c-hex; 4HÞ. 31P NMR (CDCl3, 81 MHz): d 27.53, 27.31.
PhH, 2H); 4.19 (d, JPH = 21.6 Hz, CHP, 2H); 4.07–4.01 (m,
POCH2CH3, 6H); 3.97–3.90 (m, POCH2CH3, 2H); 2.45 (large s, NH,
2H); 2.05–2.00 (m, CHc2-hex, 4H); 1.60–1.58 (m, NCHc-hex, 2H); 1.25
2
3
4.3.2. Tetraethyl (R,R)-1,2–cyclohexylenediamino-di-(S,S)-
phenylmethylphosphonate 4b
and 1.20 (2t, JHH = 7.2 Hz, P(OCH2CH3)2, 2ꢃ6H); 1.03–0.99
ðm; CHÞ2c-hex; 2HÞ; 0.87–0.82 ðm; CHÞ2c-hex; 2HÞ. 13C NMR (CDCl3,
3
A post-reaction mixture was vigorously scratched with a glass
rod inside the flask followed by standing at ambient temperature
for two days, after which it was found that most of the mixture
had solidified. As much as possible of the residual oil was removed
on a filter funnel. The residue was washed a few times with hexane
and then crystallized from hexane. The procedure yielded 605 mg
(53.4%) of a pure, single diastereoisomer as colorless needle crys-
tals. Once the crystals are obtained they can be used for the direct
nucleation of the crude post-reaction mixture. Mp = 109 °C.
Elemental analysis: Calcd for C28H44N2O6P2: C, 59.37; H, 7.87; N,
4.94. Found: C, 59.57; H, 7.57; N, 5.09. Predominant diastereoiso-
150 MHz): d 136.10 (C-ipso); 128.86 (d, JPC = 5.8 Hz, Cortho);
2
128.34 (Carom); 127.68 (Carom); 63.10 (d, JPC = 6.9 Hz, POC); 62.80
(d, JPC = 6.7 Hz, POC); 57.48 (d, JPC = 152.4 Hz, PCN); 57.57,
2
1
3
57.46, 30.17, 24.42 (Cchex); 16.43 (d, JPC = 6.3 Hz, POC-C); 16.39
3
(d, JPC = 5.5 Hz, POC-C). 31P NMR (CDCl3, 243 MHz): d 23.88. IR
(KBr): 3432 (NH); 2982, 2929 (C–Harom); 1601, 1485, 1458
(C@Carom); 1235 (P@O); 1102 (P–O); 1058, 1024. ESI-MS: m/z =
589.3 [M+Na]+; 567.3 [M+H]+. Two minor diastereoisomers; 1H
NMR (CDCl3, 600 MHz): d 7.49–7.47 (m, PhH, 4H); 7.37–7.35
2
(m, PhH, 4H); 7.30–7.28 (m, PhH, 2H); 4.12 (d, JPH = 21.6 Hz,
2
CHP, 2H); 4.06 (d, JPH = 20.4 Hz, CHP, 2H); 3.99–3.95 ðm;POCH2
mer: ½a 2D0
ꢁ
¼ ꢂ69:4 (c 1, CH2Cl2); 1H NMR (CDCl3, 600 MHz): d
CHI3d; 6HÞ; 3.84–3.80 ðm;POCH2CHIId; 6HÞ; 3.79–3.74 ðm; POCH2
3
7.49–7.47 (m, PhH, 4H); 7.37–7.35 (m, PhH, 4H); 7.30–7.28 (m,
CHId; 2HÞ; 3.70–3.66 ðm; POCH2CHIId; 6HÞ; 2.10–2.04 ðm; CHc2-hex
;
3
3

486
J. Lewkowski et al. / Tetrahedron: Asymmetry 23 (2012) 482–488
Table 2
Geometry of hydrogen bonds and close contacts for 4b and 4c (Å, °)
Symmetry codes: (i) xꢂ1, y, z; (ii) ꢂx+1, yꢂ1/2, ꢂz+1/2.
/intramolecular—red, intermolecular—blue.
N
N
syn-syn 2
OH
Ph
H
RO
RO
H
P
PO3R2
N
Ph
N
Ph
N
N
H
Ph
2
5
OH
P
Ph
H
PO3R2
NH
H
RO
RO
H
N
Ph
PO3R2
PO3R2
Ph
N
N
H
Ph
3
Figure 3. The probable mechanism of stereocontrol of the phosphite addition to 2.
4HÞ; 1.48–1.41 and 1.58–1.53 (2 m, NCHc-hex, 2H); 1.30 and 1.13
mixture. Elemental analysis: Calcd for C32H52N2O6P2: C, 61.72; H,
8.42; N, 4.50. Found: C, 61.47; H, 8.60; N, 4.41. Mp: 76–80 °C. Pre-
Id
3
3
(2t, JHH = 7.2 Hz, PðOCH2CH3Þ2 ; 12H); 1.28 and 1.12 (2t, JHH
=
7.2 Hz, PðOCH2CH3ÞIId; 12H); 1.08–1.05 ðm; CHc2-hex; 2HÞ; 0.74–0.71
dominant diastereoisomer; ½a D20
ꢁ
¼ ꢂ55:7 (c 1, CH2Cl2); 1H NMR
2
ðm;CH2c-hex; 2HÞ. 31P NMR (CDCl3, 243 MHz): d 24.15 and 24.08.
(CDCl3, 600 MHz): d 7.50–7.49 (m, PhH, 4H); 7.35–7.33 (m, PhH,
4H); 7.28–7.26 (m, PhH, 2H); 4.67–4.62 (m, POCH(CH3)2, 2H);
2
4.3.3. Tetraisopropyl (R,R)-1,2–cyclohexylenediamino-di-
phenylmethylphosphonate 4c
4.60–4.54 (m, POCH(CH3)2, 2H); 4.11 (d, JPH = 22.2 Hz, CHP, 2H);
2.42 (large s, NH, 2H); 2.03–2.01 (m, CHc2-hex, 4H); 1.60–1.58 (m,
3
The post-reaction mixture was partially purified by using a
short chromatography column using Et2O/hexane 3:1 as an eluent.
Fractions containing the product were merged and the solvents
were removed in vacuo. The residue was kept in high vacuum for
5 h until small crystals appeared in the mixture. The flask was then
left at ambient temperature and pressure for one night for further
solidification. Crystals were obtained from this mixture using the
method described for diethyl phosphate, yielding a pure, single
diastereoisomer. Once the crystals are obtained they can be used
for nucleation of the initially purified post-reaction mixture. It
was found, that crystals cannot grow in a crude post-reaction
NCHc-hex
,
2H); 1.28, 1.25, 1.22 and 1.09 (4d, JHH = 6.6 Hz,
POCH(CH3)2, 4ꢃ6H); 1.03–0.99 ðm;CHc2-hex; 2HÞ; 0.81–0.80
ðm;CH2c-hex; 2HÞ. 13C NMR (CDCl3, 150 MHz): d 136.45 (C-ipso);
3
129.09 (d, JPC = 5.9 Hz, Cortho); 128.13 (Carom); 127.43 (Carom);
1
71.32 (POC); 71.13 (POC); 57.75 (d, JPC = 154.2 Hz, PCN); 57.66,
3
57.55, 30.12, 24.46 (Cchex); 24.22 (d, JPC = 3.0 Hz, POC-C); 24.15
3
3
(d, JPC = 4.7 Hz, POC-C); 23.85 (d, JPC = 5.4 Hz, POC-C); 23.63 (d,
3JPC = 5.3 Hz, POC-C). 31P NMR (CDCl3, 243 MHz): d 22.31. IR
(KBr): 3448 (NH); 2978, 2929 (C–Harom); 1636, 1455 (C@Carom);
1245 (P@O); 1106 (P–O); 994. ESI-MS: m/z = 645.5 [M+Na]+. Two
minor diastereoisomers; 1H NMR (CDCl3, 600 MHz): d 7.50–7.48

J. Lewkowski et al. / Tetrahedron: Asymmetry 23 (2012) 482–488
487
(m, PhH, 2H); 7.35–7.33 (m, PhH, 4H); 7.28–7.23 (m, PhH, 4H);
4.4. Crystal structure determination
Id
4.75–4.72 and 4.69–4.61 (2m, POCHðCH3Þ2 , 2H); 4.56–4.46 and
4.44–4.40 (2m, POCHðCH3ÞIId, 2H); 4.13 (2d, JPH = 21.0 Hz, CHP,
The crystallographic measurements for 4b and 4c were performed
2
2
2H); 4.06 (2d, JPH = 20.4 Hz, CHP, 2H); 2.03–2.01 (m, CHc-hex
,
on a
j-geometry Xcalibur PX four-circle diffractometer with graphite-
2
2
4H); 1.60–1.58 (m, NCHc-hex, 2H); 1.32–1.23 (2m, POCH(CH3)2,
3ꢃ6H); 1.08–1.06 (2m, POCH(CH3)2, 1ꢃ6H); 1.02–0.98 (m,
monochromatized Mo K
a
radiation ( and scans). Data were cor-
x
u
rected for Lorentz and polarization effects. Data collection, cell refine-
ment, and data reduction and analysis were carried out with the
Xcalibur PX software, CRYSALIS CCD, and CRYSALIS RED, resp.16 Analytical
absorption corrections were applied to the data with the use of CRY-
SALIS RED. The structures were solved by direct methods with the SHEL-
XS-97 program,17 and refined using SHELXL-9717 with anisotropic
thermal parameters for non-H-atoms (except for low-occupied posi-
tionsofdisordered atomsin4c). The Hatoms were found indifference
Fourier maps. In the final refinement cycles, all C-bonded H atoms
were treated as riding atoms in geometrically optimized positions,
with C–H = 0.95–1.00 Å, and with Uiso(H) = 1.2Ueq(CH,CH2) or
1.5Ueq(CH3). N-bonded H atoms in both 4b and 4c were refined iso-
tropically. H atoms from fully occupied water molecules in 4c were
refined with Uiso(H) = 1.5Ueq(O). Those from partially occupied water
molecules were not found in the difference Fourier maps.
The asymmetric unit of crystal 4cꢀH2O contains two crystallo-
graphically independent molecules of 4c (A and B shown in Fig. 2)
and two water molecules. The highest peak in difference Fourier
map was included into the final model and treated as 4% of water
O atom. One of diisopropylphosphonate groups in molecule B is dis-
ordered and has both isopropoxyl groups at two positions (with
s.o.f. = 0.77(1) and 0.23(1)). Therefore, in the final model, some
geometrical restraints (SAME instructions in SHELXL-9717), and con-
straints on the fractional coordinates and anisotropic displacement
parameters (EXYZ and EADP instructions) were applied to this
disordered region. The figures showing the molecular and crystal
structures of 4b and 4c were made using the Diamond program.18
Crystallographic data for the structural analysis have been
deposited with the Cambridge Crystallographic Data Center [ref.
CCDC 856983 and 856984]. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif or by e-mailing
deposit@ccdc.cam.ac.uk.
CHc2-hex
, ,
2H); 0.85–0.80 (m, CHc2-hex 2H). 31P NMR (CDCl3,
243 MHz): d 22.73, 22.46.
4.3.4. Tetrabenzyl (R,R)-1,2–cyclohexylenediamino-di-
phenylmethylphosphonate 4d
The post-reaction mixture was dissolved in methylene chloride.
Next, elemental iodide was added in small portions and if the solu-
tion was discolored within 10 min, further portions of iodine were
added. If after the addition, the mixture remained brown, it was
stirred for another 10 min with heating on a water bath. The
mixture was then washed once with 50 ml of saturated aqueous
sodium thiosulfate and 5 times with 50 ml of saturated aqueous
sodium bicarbonate. The organic layer was separated and dried
over sodium sulfate. The solvent was removed in vacuo. The crude
product obtained was purified by chromatography on silica gel
using Et2O/n-hexane (3:1) as a mobile phase. Elemental analysis:
Calcd for C48H52N2O6P2: C, 70.75; H, 6.43; N, 3.44. Found: C,
70.67; H, 6.66; N, 3.56. Asterisk denotes predominant diastereoiso-
mer; 1H NMR (CDCl3, 200 MHz): d 7.50–7.49 (m, PhH, 4H); 7.31–
7.21 (m, PhH, 22H); 7.15–7.10 (m, PhH, 4H); 5.08–4.97 (m,
2
POCH2Ph, 4H); 4.90 and 4.71 (part of AMX system, JHH = 12.0 Hz,
3JPH = 8.4 and 8.2 Hz, POCH2Ph); 4.95⁄ and 4.79⁄ (part of AMX sys-
2
3
tem, JHH = 12.6 Hz, JPH = 8.4 and 7.8 Hz, POCH2Ph); 4.82 and 4.63
2
3
(part of AMX system, JHH = 12.0 Hz, JPH = 8.4 and 7.2 Hz,
POCH2Ph); 4.28 (d, 2JPH = 20.4 Hz, CHP, 2H); 4.21⁄ (d, 2JPH = 20.4 Hz,
CHP, 2H); 4.10 (d, 2JPH = 19.8 Hz, CHP, 2H); 2.49–2.46 (m, NCHc-hex
,
2H); 2.42–2.39 (m, NCHc-hex, 2H); 2.14–2.11⁄ (m, NCHc-hex, 2H);
2.02–2.00⁄ (m, CH2c-hex, 2H); 1.92–1.90⁄ (m, CHc2-hex, 2H); 1.64–
1.62 (m, CH2c-hex, 2ꢃ2H); 1.53–1.51⁄ (m, CHc2-hex, 2H); 1.47–1.43
(m, CHc2-hex, 2ꢃ2H); 1.09–0.97 (m, CHc2-hex, 2ꢃ2H); 0.95–0.91⁄ (m,
CHc2-hex, 2H); 0.67–0.66 (m, CHc2-hex
,
2ꢃ2H). 31P NMR (CDCl3,
81 MHz): d 25.03, 24.97, 24.77⁄ (2:2:10). IR (KBr): 3451 (NH);
3030, 2927 (C–Harom); 1600, 1496, 1455 (C@Carom); 1242 (P@O);
1105 (P–O); 1080. ESI-MS: m/z = 837.7 [M+Na]+.
Crystal data for 4b. C28H44N2O6P2, M = 566.59, colorless
needlelike block, crystal dimensions: 0.40 ꢃ 0.20 ꢃ 0.13 mm3;
orthorhombic, space group P212121; a = 8.679(2), b = 18.219(4),
c = 19.013(4) Å; V = 3006.4(11) Å3; T = 100(2) K; Z = 4; qcalc
=
4.3.5. Tetraallyl (R,R)-1,2–cyclohexylenediamino-di-
phenylmethylphosphonate 4e
1.252 g cmꢂ3
1216; reflections collected = 27716; reflections independent =
12287 [Rint = 0.028]; reflections observed = 9405 [I > 2 (I)]; h range
; l a, k = 0.71073 Å); F(000) =
= 0.19 mmꢂ1 (for Mo K
A post-reaction mixture was purified by chromatography, using
Et2O/hexane 3:1 as an eluent. Fractions containing the product
were merged and solvents were removed in vacuo. Elemental
analysis: Calcd for C32H44N2O6P2: C, 62.53; H, 7.22; N, 4.56. Found:
C, 62.38; 7.23; N, 4.32. Asterisk denotes predominant diastereoiso-
mer; 1H NMR (CDCl3, 200 MHz): d 7.49–7.48 (m, PhH, 4H);
7.38–7.35 (m, PhH, 4H); 7.31–7.28 (m, PhH, 2H); 6.01–5.93 (m,
POCH2CH@CH2, 2H); 5.88 (ddt, 3JHH = 5.4, 10.8, 17.4 Hz,
POCH2CH@CH2, 2H); 5.81⁄ (ddt, 3JHH = 5.4, 10.8, 17.4 Hz,
POCH2CH@CH2, 2H); 5.68–5.62 (m, POCH2CH@CH2, 2H); 5.39–
r
2.48–38.57°; h, k, l range: ꢂ13 6 h 6 12, ꢂ27 6 k 6 26, -32 6
l 6 23; full-matrix least-squares on F2; parameters = 351;
restraints = 0; R1 = 0.040; wR2 = 0.084 [F2 > 2 (F2)]; GooF = S =
r
1.01; largest difference in peak and hole,
Dqmax and Dqmin = 0.53
and ꢂ0.23 e Åꢂ3; Flack parameter = ꢂ0.02(4).
Crystal data for 4cꢀH2O. C32H52N2O6P2ꢀH2O, M = 641.15, colorless
block, crystal dimensions: 0.48 ꢃ 0.41 ꢃ 0.27 mm3; orthorhombic,
space group P212121; a = 14.340(4), b = 19.109(4), c = 26.148(6) Å;
V = 7165(3) Å3; T = 85(2) K; Z = 8;
q
calc = 1.189 g cmꢂ3
;
l =
3
5.26 (m, POCH2CH@CH2, 8H); 5.26⁄ (ddt, JHH = 1.2, 1.8, 17.4 Hz,
0.17 mmꢂ1 (for Mo K
lected = 41667; reflections independent = 20404 [Rint = 0.030]; reflec-
tions observed = 16815 [I > 2 (I)]; h range 2.56–30.06°; h, k, l range:
a, k = 0.71073 Å); F(000) = 2770; reflections col-
POCH2CH@CH2, 4H); 5.22⁄ (ddt, 3JHH = 1.2, 1.8, 17.4 Hz, POCH2CH@
3
CH2, 4H); 5.17 (ddt, JHH = 1.2, 1.8, 10.8 Hz, POCH2CH=CH2, 2H);
r
3
5.14⁄ (ddt, JHH = 1.2, 1.8, 10.8 Hz, POCH2CH=@CH2, 2H); 4.62–
ꢂ19 6 h 6 17, -26 6 k 6 26, ꢂ27 6 l 6 35; full-matrix least-squares
4.60 (m, POCH2CH@CH2, 8H); 4.56–4.55 (m, POCH2CH@CH2, 8H);
4.49–4.47⁄ (m, POCH2CH@CH2, 6H); 4.37–4.30⁄ (m, POCH2CH@CH2,
2H); 4.26–4.22 (m, CHP, 2H); 2.45 (large s, NH, 2H); 2.06–2.00⁄
on F2; parameters = 837; restraints = 66; R1 = 0.038; wR2 = 0.083 [F2
>2
and
r
(F2)]; GooF = S = 1.03; largest difference in peak and hole,
D
qmax
Dq
min = 0.34 and ꢂ0.32 e Åꢂ3; Flack parameter = 0.01(3).
ðm;CHc2ꢂhex; 4HÞ; 1:73 ꢂ 1:72ðm;CHc2ꢂhex; 4HÞ; 1.60–1.59⁄ ðm;CHc2-hex
;
2HÞ; 1.54–1.14 ðm;CHc2-hex; 12HÞ; 1.03–1.00⁄ ðm;CHc2-hex; 2HÞ; 0.94–
0.86 ðm;CH2c-hex; 4HÞ; 0.84–0.82⁄ ðm;CH2c-hex; 2HÞ. 31P NMR (CDCl3,
81 MHz): d 24.65, 24.59, 24.46⁄ (9:9:100). IR (KBr): 3466 (NH);
3026, 2928 (C–Harom); 1648 (C@C); 1601, 1494, 1455 (C@Carom);
1242 (P@O); 1100 (P-O); 1023. ESI-MS: m/z = 637.4 [M+Na]+.
Acknowledgements
Paweł Tokarz is a participant in the project entitled ‘Doktor-
anci—Regionalna Inwestycja w Młodych naukowców—Akronim
D-RIM’, which is co-financed by the EU from the European Social

488
J. Lewkowski et al. / Tetrahedron: Asymmetry 23 (2012) 482–488
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