SYNTHESIS OF 9-(2-PHOSPHONOMETHOXYETHYL)ADENINE AND RELATED COMPOUNDS

Article abstract of DOI:10.1135/cccc19941870

Alkyl 2-chloroethoxymethyl(diethoxymethyl)phosphinates VII and XIII were prepared by reaction of silyl esters of dialkoxymethylphosphinic acid with 2-chloroethyl chloromethyl ether.Adenine was alkylated with VII and XIII to give <2-(adenin-9-yl)ethoxy>met

Full text of DOI:10.1135/cccc19941870

1870
Alexander, Holy, Masojidkova:
SYNTHESIS OF 9-(2-PHOSPHINOMETHOXYETHYL)ADENINE
AND RELATED COMPOUNDS
Petr ALEXANDER, Antonin HOLY and Milena MASOJIDKOVA
Institute of Organic Chemistry and Biochemistry,
Academy of Sciences of the Czech Republic, 166 10 Prague 6, The Czech Republic
Received November 10, 1993
Accepted April 11, 1994
Alkyl 2-chloroethoxymethyl(diethoxymethyl)phosphinates VII and XIII were prepared by reaction of
silyl esters of dialkoxymethylphosphinic acid with 2-chloroethyl chloromethyl ether. Adenine was
alkylated with VII and XIII to give [2-(adenin-9-yl)ethoxy]methyl(diethoxymethyl)phosphinates VIII
and XIV, bearing the dialkoxymethyl protecting group on the phosphorus atom. Acid hydrolysis of
compounds VIII and XIV afforded 9-(2-phosphinoethoxymethyl)adenine (X). Alkyl dialkoxymethyl-
phosphinates V and XI reacted with paraformaldehyde to give hydroxymethylphosphinates XV and
XIX which were converted into the synthons XVI, XVII and XVIII capable of introducing a protected
hydroxymethylphosphino group on a hydroxy or amino group.
Phosphonate derivatives represent important analogs with modified phosphate function-
ality. Particularly important are phosphonomethoxy derivatives of acyclic nucleosides
among which a series of extraordinarily biologically active compounds has been
found1. In these compounds the phosphomonoester bond, present in nucleotides, is re-
placed by the chemically as well as enzymatically very stable P−C bond. They possess
high inhibitory activity also against mutants or strains of DNA viruses that are resistant
toward nucleoside antivirals due e.g. to reduced activity of some phosphorylation
enzymes.
Within the framework of our studies of potential prodrugs of 9-(2-phosphonomethoxy-
ethyl)adenine2 (PMEA, I), which is recently undergoing clinical tests3 against AIDS, we
tried to prepare derivatives of the corresponding acyclic nucleoside analogs II in which
the phosphonate group is replaced by the phosphinate group. These compounds, analo-
gous to nucleoside phosphites with respect to the oxidation state of the phosphorus
atom, have not been described so far in the chemistry of nucleic acid analogs. Nucleo-
side phosphites4,5 are widely used in the synthesis of oligonucleotides6 or other nucleo-
tide esters7. Phosphites of some nucleoside analogs are biologically active8. The
chemical reactivity, together with the possible activation of phosphinate analogs, could
lead to new synthetic approach to nucleoside phosphonates, in analogy with methods
using nucleoside phosphites in the phosphate series.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

9-(2-Phosphinomethoxyethyl)adenine
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The simplest approach to the desired compounds could consist in reduction of deri-
vatives of compound I by some of the methods applied already to aliphatic phospho-
nates9. However, the reduction of diethyl ester of compound I with lithium aluminium
hydride or sodium bis(2-methoxyethyl)aluminium hydride (Synhydride) leads directly
to the phosphine intermediate which is cleaved under the reaction conditions to give
9-(2-hydroxyethyl)adenine III as the sole reaction product. The corresponding phospho-
nochloridate (generated from the phosphonate group by thionyl chloride) is reduced
under milder conditions with NaBH4, as described for alkyl phosphonates10. In the case
of compound I, however, even this reaction failed.
Another possibility how to obtain compound II consists in using a suitable phos-
phorus derivative that bears structural elements of the target phosphonate and a protect-
ing group which upon removal affords the P−H bond. This method is recently used in
the chemistry of phosphonopeptides11; it was also employed by Hata and Sekine in the
synthesis of nucleoside phosphites12 or optically active dinucleoside phosphothioates13.
Of groups with suitable properties we chose the dialkoxymethyl group which can be
removed from the phosphorus atom by acid hydrolysis14. In the series of PME deriva-
tives, 2-chloroethyl chloromethyl ether15 (IV) is the most accessible compound capable
of forming the required skeleton between the phosphorus atom and the amino nitrogen.
This ether easily undergoes Arbuzov reaction with trivalent phosphorus compounds16.
By treatment of the ether IV with silylated ethyl diethoxymethylphosphinate VI we
prepared synthon VII containing a halogen-activated alkyl moiety with protected phos-
phinate functionality (see Scheme 1). The required silyl ester was prepared according
to a described procedure14 by reaction of phosphorous acid with triethyl orthoformate,
catalyzed with trifluoroacetic acid, and subsequent silylation of the arising phosphonite
V with hexamethyldisilazane17. Compound VII is sufficiently stable in anhydrous al-
kaline as well as weakly acidic media and can be used for alkylation of corresponding
bases under formation of phosphinates VIII. However, alkylation of sodium salt of
adenine at elevated temperatures resulted mainly in undesired alkylation of adenine
with the ester-bonded ethyl group. Thus, under standard conditions2 (at 100 °C in di-
methylformamide in the presence of potassium carbonate), the reaction gave predomi-
nantly 9-ethyladenine (IX). In spite of this, we also isolated the desired ethyl
[2-(adenin-9-yl)ethoxymethyl]phosphinate (VIII) in 10% yield. As expected, on heating
in 80% trifluoroacetic acid this compound lost the dialkoxymethyl group to give 9-(2-
phosphinomethoxyethyl)adenine [(2-(adenin-9-yl)ethoxymethylphosphinic acid) (X)].
Because of the mentioned alkylation side-reaction, tris(2-propyl) orthoformate was
converted analogously into synthon XIII which on reaction with adenine afforded phos-
phinate XIV without any side reaction. Also the derivative XIV was hydrolyzed into the
free phosphinate X.
As alternative synthons for attaching of the mentioned phosphinomethyl ether
functionality to hydroxy or amino groups in other compounds, we also prepared the
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

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Alexander, Holy, Masojidkova:
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

9-(2-Phosphinomethoxyethyl)adenine
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tosyl- or methanesulfonyloxymethylphosphinates XVI, XVII and XVIII (Scheme 2).
Base-catalyzed reaction of ethyl diethoxymethylphosphinate (V) with paraformalde-
hyde afforded the corresponding hydroxymethyl derivative XV which was then
smoothly converted into the tosyl or mesyl derivative (XVI and XVII, respectively).
Reaction of these compounds with 9-(2-hydroxyethyl)adenine in the presence of three
equivalents of sodium hydride in dimethylformamide at room temperature2 afforded
compound VIII in an acceptable yield. The corresponding methanesulfonyl derivative
of the 2-propyl ester, XVIII, reacted with N-benzoyl-9-(2-hydroxyethyl)adenine to give
phosphinate XIV in very good yield.
SCHEME 2
Compounds XVI, XVII and XVIII, containing a sulfonyl group-activated hydroxy-
methylphosphinate moiety, represent universal synthons suitable for preparation of
analogous phosphinates derived from other alcohols.
According to preliminary results, compound X exhibits neither antiviral18 nor antitu-
mor activity.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)