Synthesis of new cholesteryl and adenosinyl esters of 2-furyl-N- phenylaminophosphonous acids

Article abstract of DOI:10.1080/10426500701672903

The synthesis of novel 2-furyl N-arylaminomethanephosphonous acids 2a, b and their cholesteryl and adenosinyl esters 3a, b and 4a, b, respectively, is presented. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500701672903

Phosphorus, Sulfur, and Silicon, 183:1455–1460, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701672903
Synthesis of New Cholesteryl and Adenosinyl Esters of
2-Furyl-N-phenylaminophosphonous Acids
Jaroslaw Lewkowski,1 Rafl Karpowicz,1
1
2
´
Romuald Skowronski, and Ewa Stronka-Lewkowska
1Department of Organic Chemistry, University of Lꢀ o´dz´, Lꢀ o´dz´, Poland
2Department of Chemical Didactics, University of Lꢀ o´dz´, Lꢀ o´dz´, Poland
The synthesis of novel 2-furyl N-arylaminomethanephosphonous acids 2a,b and
their cholesteryl and adenosinyl esters 3a,b and 4a,b, respectively, is presented.
Keywords Adenosinyl aminophosphonites; aminophosphonous acids; cholesteryl
aminophosphonites; formation of aminophosphonites
INTRODUCTION
The important biological function of aminophosphonic acids is well
recognized.1,2 Equally, the importance of 2-substituted furan deriva-
tives as bioactive compounds is commonly known,3 just to men-
tion a series of nitrofurfural derived drugs such as nitrofurazone or
nifurantoine4 or the efficient anti-histamine agent ranitidine.5
Biological substances often bear in their structure a phosphory-
lated alcohol group, e.g., phospholipids, oligonucleotides, or carbohy-
drate phosphates.6 Among them the synthesis and properties of mono-
or dicholesteryl phosphites7,8 has attracted much interest.
The synthesis of phosphites or phosphonates of various nucleo-
sides is also of interest as they are derivatives of AMP, which could
act as antimetabolites. The preparation of monophosphites of uridine
and thymidine,6,9 adenosine10,11 or even mono-adenosinyl and mono-
uridinyl esters of 1aminoethane phosphonic acid12 was reported.
Received 26 April 2007; accepted 9 September 2007.
Dedicated to Professor Jan Epsztajn from the University of Lꢀ o´dz´, Poland, on the oc-
casion of his 75th birthday.
The financial support of the Polish State Committee for Scientific Research (KBN) is
kindly acknowledged.
Address correspondence to Jaroslaw Lewkowski, Department of Organic Chem-
istry, University of Lꢀ o´dz´, Narutowicza 68, 90-136 Lꢀ o´dz´, Poland; E-mail: jlewkow@
uni.lodz.pl
1455

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J. Lewkowski et al.
We have also contributed to this topic. In one of our previous pa-
pers, we reported the synthesis of cholesteryl and adenosinyl esters of
N-substituted 2-furyl aminomethanephosphonous acids.13 These com-
pounds bear both furanic and aminophosphonous functions in their
molecules combined with a biomolecule moiety and might be inves-
tigated with respect to their anti-metabolic action. As a continua-
tion of our study, we report the synthesis of cholesteryl and O,Oꢀ-
isopropylideneadenosinyl 2-furyl Narylaminomethanephosphonites,
which were chosen in order to verify the reactivity of Naryl Schiff
bases vs. the addition of hypophosphorous acid and the reactivity of
Narylaminophosphonous acids vs. their condensation with cholesterol
and adenosine.
RESULTS AND DISCUSSION
2-Furyl aminophosphonous acids 2a,b were synthesized following the
published procedure2,12 in a two-step reaction. Furfural was reacted
with an aromatic amine to give the Schiff bases 1a,b, which on addi-
tion of hypophosphorous acid afforded aminophosphonous acids 2a,b
in satisfactory yields (Scheme 1). The acids 2a,b are new and were
properly characterized by means of NMR spectroscopy and elemental
analysis.
SCHEME 1

Esters of Phenylaminophosphonous Acids
1457
The condensation of the acids 2a,b with cholesterol was carried out in
the presence of dicyclohexylcarbodiimide (DCC) as a condensing agent
in dichloromethane as solvent. The condensations of the acids 2a,b
with O,Oꢀ-isopropylidene adenosine were carried out under identical
conditions. The reaction mixtures were refluxed for several days (up to
5 days).
The above reactions led either to the cholesteryl 2-furyl N-
arylaminomethanephosphonites 3a,b or to the adenosinyl (2-furyl)-N-
arylaminomethanephosphonites 4a,b in yields varying from 65 to 85%.
In the case of the cholesteryl phosphonites 3a,b, the 31P NMR spec-
tra showed four signals (two sets of two signals with similar chemical
shifts). Similarly, in the 1H NMR spectra corresponding sets of signals
for the P H and P C H protons were observed. This demonstrated the
formation of four diastereoisomers, which was expected, because of the
appearance of a second center of asymmetry situated at the phospho-
rus atom. The diastereoisomers were formed in unequal ratios, which
would suggest the chiral assistance of the optically active cholesterol.
However, in case of the adenosinyl phosphonites 4a,b, the 31P NMR
1
spectra showed only one broad signal. Also in the H NMR spectra,
only one set of signals for the P H and P C H protons was observed.
This indicates the exclusive formation of two diastereoisomers demon-
strating the high chiral assistance of the adenosine molecule in the
formation of a new center of chirality at phosphorus.
Unfortunately, the separation of the diastereoisomers failed because
compounds 3a,b and 4a,b decomposed on silica gel and aluminum
oxide.
EXPERIMENTAL
All solvents (POCh, Poland) were routinely distilled and dried prior
to use. Amines, furfural, and O,Oꢀ-isopropylidene adenosine as well as
cholesterol (Aldrich) were used as received. NMR spectra were recorded
on a Varian Gemini 200 BB apparatus operating at 200 MHz (1H NMR)
and 81 MHz (31P NMR). Elemental analyses were performed in the Cen-
ter for Molecular and Macromolecular Science of the Polish Academy
of Science in Lꢀ o´dz´. Schiff bases 1a,b were synthesized following the
known procedures.14,15
Synthesis of Acids 2a,b: General Procedure
To furfural (1.92 g, 0.02 mol), the respective amine (0.02 mol) was added.
After 1.5 h, 20 mL of methanol were added and the mixture was stirred
at room temperature for 24 h. The solvent was evaporated in vacuo,

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J. Lewkowski et al.
the residue was dissolved in 20 mL of dichloromethane and dried over
anhydrous MgSO4. The inorganic salt was filtered off and solvent was
evaporated to give the Schiff base 1a,b as light-brown oil in quanti-
tative yield, which was dissolved in dioxane (20 mL). To this solution,
hypophosphorous acid (1.32 g, 0.02 mol) was added, the mixture was
refluxed for 5 h and stirred at room temperature for 24 h. The solid
formed was collected by filtration, washed with 30 mL of dioxane and
dried to give the acids 2a,b.
N-(p-Methoxyphenyl)amino-2-furyl-methanephosphonous
Acid (2a)
Yield: 2.20 g (44%); m.p. 172–174◦C. Calcd. for C12H14NO4P: C,
1
53.94; H, 5.28; N, 5.24%. Found: C, 53.68; H, 5.30; N, 5.17%. H NMR
(NaOD/D2O): δ = 7.39 (m, 1H, H5fur); 6.78 (broad s, 4H, p-C6H4); 6.97
(d, JPH = 531.1 Hz, 1H, PH); 6.31 (m, 2H, H3fur, H4fur); 4.55 (d, JPH
17.0 Hz, 1H, CHP); 3.66 (s, 3H, OCH3). 31P NMR (D2O): δ = 20.6.
=
1
2
N-(p-Methylphenyl)amino-2-furyl-methanephosphonous
Acid (2b)
Yield: 3.08 g (61%); m.p. 168–174◦C. Calcd. for C12H14NO3P: C,
1
57.37; H, 5.62; N, 5.58%. Found: C, 57.18; H, 5.78; N, 5.54%. H NMR
(NaOD/D2O): δ = 7.37 (m, 1H, H5fur); 6.98 (d, J = 8.1 Hz, 2H, p-C6H4);
1
6.72 (d, J = 8.1 Hz, 2H, p-C6H4); 6.95 (d, JPH = 531.3 Hz, 1H, PH);
6.29 (m, 2H, H3fur, Hf4ur); 4.59 (d, 2 JPH = 17.4 Hz, 1H, CHP); 2.11 (s, 3H,
CH3). 31P NMR (NaOD/D2O): δ = 20.7.
Synthesis of Esters 3a,b and 4a,b: General Procedure
To a suspension of the aminophosphonous acid 2a–d (5 mmol) in
dichloromethane (20 mL), 0.01 mol of cholesterol or isopropylidene
adenosine and 5 mmol (1.04 g) of DCC were added. The mixture was
then refluxed for 10 h with vigorous stirring, then stirred overnight at
room temperature and this procedure was repeated during the next 7
days. The reaction mixture was filtered, the solid residue was washed
with 20 mL of dichloromethane and then discarded. The filtrate was
evaporated in vacuo, the residue was re-dissolved in 30 mL of chlo-
roform, shaken with charcoal, filtered, and the eluent evaporated to
obtain the pure product 3a,b and 4a,b.
Cholesteryl N-(p-Methoxyphenyl)amino-2-
furyl-methanephosphonite (3a)
Yield: 3.01 g (95%); m.p. = 105–108◦C. Calcd. for C39H58NO4P: C,
1
73.67; H, 9.19; N, 2.20%. Found: C, 73.56; H, 9.21; N, 2.35%. H NMR

Esters of Phenylaminophosphonous Acids
1459
(CDCl3): δ = 7.41 (m, 1H, Hf5ur); 6.76 (d, J = 8.8 Hz, 2H, p-C6H4); 6.66
(d, J = 8.8 Hz, 2H, p-C6H4); 7.24 (d, 1 JPH = 567.6 Hz, 1H, PH); 7.15 (d,
1 JPH = 569.4 Hz, 1H, PH); 6.37 (m, 2H, H4fur, H3fur); 5.35 (m, 1H, HC=C);
4.79 (d, 2 JPH = 17.1 Hz, 1H, PCH); 4.73 (d, 2 J = 16.8 Hz, 1H, PCH);
PH
4.21 (m, 1H, O-CHcholest); 3.72 (s, 3H, OCH3); 2.39 (m, 2H, CH2cholest);
1.97–1.79 (m, 8H, CHcholest); 1.6–1.3 (m, 8H, CHcholest); 1.11 (m, 10H,
CHcholest); 1.01 (s, 3H, CH3); 0.98 (d, J = 9.0 Hz, 3H, CH3); 0.86 (d, J =
6.6 Hz, 6H, CH3); 0.67 (s, 3H, CH3). 31P NMR (CDCl3): δ = 28.4, 28.3,
25.3, 25.2 (5:5:3:3).
Cholesteryl N-(p-Methylphenyl)amino-2-
furyl-methanephosphonite (3b)
Yield: 2.93 g (94%); m.p. 99–103◦C. Calcd. for C39H58NO3P: C, 75.57;
H, 9.43; N, 2.26%. Found: C, 75.09; H, 9.40; N, 2.35%. 1H NMR (CDCl3):
δ = 7.41 (m, 1H, H5fur); 6.99 (d, J = 8.2 Hz, 2H, p-C6H4); 6.63 (d, J =
8.2 Hz, 2H, p-C6H4); 7.24 (d, 1 JPH = 566.8 Hz, 1H, PH); 7.16 (d, 1 JPH
=
569.6 Hz, 1H, PH); 6.36 (m, 2H, H4fur, H3 ); 5.35 (m, 1H, HC=C); 4.85 (d,
2 JPH = 17.0 Hz, 1H, PCH); 4.80 (d, 2 JPfHur= 16.5 Hz, 1H, PCH); 4.23 (m,
1H, O-CHcholest); 2.40 (m, 2H, CH2cholest); 2.23 (s, CH3, 3H); 1.97–1.81
(m, 8H, CHcholest); 1.6–1.3 (m, 8H, CHcholest); 1.10 (m, 10H, CHcholest);
1.01 (s, 3H, CH3); 0.99 (d, J = 9.0 Hz, 3H, CH3); 0.89 (d, J = 6.6 Hz,
6H, CH3); 0.67 (s, 3H, CH3). 31P NMR (CDCl3): δ = 28.4, 28.3, 25.3, 25.2
(5:5:3:3).
O,O’-Isopropylideneadenosinyl N-(p-Methoxyphenyl)amino-
2-furyl-methanephosphonite (4a)
Yield: 2.73 g (98%); m.p. 69–72◦C. Calcd. for C25H29N6O7P: C, 53.96;
H, 5.25; N, 15.10%. Found: C, 53.75; H, 5.48; N, 15.44. 1H NMR (DMSO-
d6): δ = 8.38 (s, 1H, Ha2de); 8.18 (s, 1H, Ha8de); 7.64 (m, 2H, NH2); 7.57
(m, 1H, H5fur); 7.00 (broad d, 1 JPH = 541.2 Hz, 1H, PH); 6.73 (d, J = 9.3
Hz, 2H, p-C6H4); 6.66 (d, J = 9.3 Hz, 2H, p-C6H4); 6.37 (m, 2H, Hf3ur
,
H4fur); 6.13 (d, J = 2.9 Hz, 1H, Hr1ib); 5.34 (dd, J = 6.1 and 3.1 Hz, 1H,
Hr2ib); 4.96 (dd, J = 6.1 and 2.3 Hz, 1H, Hr3ib); 4.76 (d, JPH = 18.9 Hz,
2
1H, CHP); 4.23 (m, 1H, Hr4ib); 3.61 (s, 3H, OCH3); 3.54 (dd, JPH = 2.7
3
Hz, J = 4.7 Hz, 2H, H5 ); 1.54 (s, 3H, CH3); 1.32 (s, 3H, CH3). 31P
3
HH
rib
NMR (CDCl3): δ = 22.1.
O,O’-Isopropylideneadenosinyl N-(p-Methylphenyl)amino-
2-furyl-methane phosphonite (4b)
Yield: 2.60 g (96%); m.p. 74–78◦C. Calcd. for C25H29N6O6P: C, 55.55;
H, 5.41; N, 15.55%. Found: C, 55.87; H, 5.78; N, 15.31%. 1H NMR

1460
J. Lewkowski et al.
(DMSO-d6): δ = 8.38 (s, 1H, H2ade); 8.19 (s, 1H, Ha8de); 7.61 (m, 2H, NH2);
7.58 (m, 1H, H5fur); 7.00 (broad d, JPH = 541.2 Hz, 1H, PH); 6.86 (d,
1
J = 8.0 Hz, 2H, p-C6H4); 6.66 (d, J = 8.0 Hz, 2H, p-C6H4); 6.37 (m, 2H,
Hf3ur, H4fur); 6.13 (d, J = 2.8 Hz, 1H, Hr1ib); 5.34 (dd, J = 6.0 and 3.0 Hz,
1H, H2rib); 4.96 (dd, J = 6.0 and 2.1 Hz, 1H, H3rib); 4.81 (d, JPH = 18.9
2
Hz, 1H, CHP); 4.23 (m, 1H, H4rib); 3.55 (dd, JPH = 2.2 Hz, JHH = 3.8
3
3
Hz, 2H, H5rib); 2.11 (s, 3H, CH3); 1.54 (s, 3H, CH3); 1.32 (s, 3H, CH3). 31
P
NMR (CDCl3): δ = 22.1.
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