Bifunctional acyclic nucleoside phosphonates. 1. Symmetrical 1,3-bis[(phosphonomethoxy)propan-2-yl] derivatives of purines and pyrimidines

Article abstract of DOI:10.1135/cccc20060543

We report here a general method for the synthesis of new symmetrical bis-phosphonates of acyclic nucleosides. 1,3-Bis[(diisopropoxyphosphoryl) methoxy] derivatives of purine and pyrimidine bases were prepared by their reaction with 1,3-bis[(diisopropoxyphosphoryl)-methoxy]propan-2-yl tosylate. Cytosine, uracil and thymine provided regiospecifically N¹-isomers. This alkylation regiospecificity applies to several other tosylates of primary and secondary alcohols as well. 6-Chloropurine and 2-amino-6-chloropurine were alkylated in N⁹ position. Resulting bis-phosphonates were converted to the respective free phosphonic acids and tested for antiviral and cytostatic activity. Despite the fact that no biological activity was found so far, the outcome of this work can serve as a useful tool in synthesis of novel groups of acyclic nucleoside phosphonates (ANPs).

Full text of DOI:10.1135/cccc20060543

Bifunctional Acyclic Nucleoside Phosphonates
543
BIFUNCTIONAL ACYCLIC NUCLEOSIDE PHOSPHONATES.
1. SYMMETRICAL 1,3-BIS[(PHOSPHONOMETHOXY)PROPAN-2-YL]
DERIVATIVES OF PURINES AND PYRIMIDINES
1,
2
3
Silvie VRBOVSKÁ *, Antonín HOLÝ , Radek POHL and Milena MASOJÍDKOVÁ
Centre for Novel Antivirals and Antineoplastics, Institute of Organic Chemistry and Biochemistry,
Academy of Sciences of the Czech Republic, 166 10 Prague 6, Czech Republic;
1
2
3
e-mail: vrbovska@uochb.cas.cz, holy@uochb.cas.cz, pohl@uochb.cas.cz
Received Decem ber 29, 2005
Accepted Jan uary 18, 2006
Dedicated to Professor Jaroslav Podlaha on the occasion of his 70th birthday.
We report h ere a gen eral m eth od for th e syn th esis of n ew sym m etrical bis-ph osph on ates
of acyclic n ucleosides. 1,3-Bis[(diisopropoxyph osph oryl)m eth oxy] derivatives of purin e an d
pyrim idin e bases were prepared by th eir reaction with 1,3-bis[(diisopropoxyph osph oryl)-
m eth oxy]propan -2-yl tosylate. Cytosin e, uracil an d th ym in e provided regiospecifically
N1-isom ers. Th is alkylation regiospecificity applies to several oth er tosylates of prim ary an d
secon dary alcoh ols as well. 6-Ch loropurin e an d 2-am in o-6-ch loropurin e were alkylated in N9
position . Resultin g bis-ph osph on ates were con verted to th e respective free ph osph on ic acids
an d tested for an tiviral an d cytostatic activity. Despite th e fact th at n o biological activity
was foun d so far, th e outcom e of th is work can serve as a useful tool in syn th esis of n ovel
groups of acyclic n ucleoside ph osph on ates (ANPs).
Keyw ord s: Acyclic n ucleotide an alogues; Acyclic n ucleoside ph osph on ates; ANP; Purin es;
Pyrim idin es; Ph osph on om eth yl eth ers; Biph osph on ates; An tivirals.
Acyclic n ucleoside ph osph on ates (ANP) deserve proper atten tion owin g to
th eir sign ifican t biological activity. Th is is particularly im portan t, th ough
by n o m ean s lim ited to th e suppression of DNA virus an d/or retrovirus rep-
lication . Th ree com poun ds (each of th em represen tin g on e of th e structural
classes with diverse substituen ts at th e β-position of th e alkyl ch ain s) were
approved an d m arketed: cidofovir, Vistide® with a wide ran ge of an ti-DNA
virus activity an d th e can didate for sm allpox ch em oth erapy in case of its
crim in al artificial outbreak; adefovir, aim ed at th e th erapeutic use in h epa-
titis B, specifically for lam ivudin e-resisten t m utan ts of th e HBV, an d
ten ofovir, a very successful drug used in th e HAART com bin ation of AIDS
th erapy. Wh ile th e first drug m en tion ed is used for in fusion , th e oral form s
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 4, pp. 543–566
© 2006 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc20060543

544
Vrbovská, Holý, Pohl, Masojídková:
of th e oth er two ANPs with in creased in testin al absorption con tain pro-
drugs of th e above active prin ciples: adefovir dipivoxil (Hepsera®) an d
ten ofovir disoproxil fum arate (Viread®, Truvada®), respectively. On ce
tran sported in to th e cell, th e liberated ANP un dergo m etabolic tran sform a-
tion to th e α-m odified triph osph ate an alogues – th e active an tim etabolites.
Th ese dNTP an alogues th en in h ibit th e DNA syn th esis de n ovo actin g as
ch ain term in ators (2 an d 3) or as altern ative substrates/in h ibitors 1 capable
of lim ited in corporation wh ich is followed by appropriate con sequen ces.
Th ere are two recen t reviews on th e syn th etic m eth ods, m ech an ism of ac-
tion , m etabolic tran sform ation s an d biological effects of ANP 1,2
.
Ph osph on om eth yl eth er group is on e of th e ch aracteristic features of th e
ph arm acoph ore in biologically active ANP. To our kn owledge, th ere are
on ly two com poun ds described in th e literature wh ich bear two such
groups in th e m olecule: th e asym m etric 3-ph osph on om eth yl eth er (5) of
HPMPA, 9-[3-h ydroxy-2-(ph osph on om eth oxy)propyl)aden in e3 (4), an d
2-am in o-4,6-bis[2-(ph osph on om eth oxy)eth oxy]pyrim idin e (7), a sym m etri-
cal ANP from th e n ovel class of “rin g-open ” com poun ds4. Wh ile com poun d
5 is devoid of an y an tiviral activity in con trast to its paren t com poun d, th e
an tiviral activity dem on strated by th e paren t pyrim idin e derivative 6 re-
m ain s preserved followin g th e in troduction of an addition al 2-ph osph on o-
m eth yl group in 7. Obviously, h igh polarity itself is n ot h in dran ce for th e
m em bran e tran sport of th e com poun d in to th e cell as is th e ch arge distri-
bution in th e m olecule. Th erefore, we decided to syn th esize an d study bio-
logical activity an d oth er properties of th e sim plest sym m etrical 1,3-bis-
NH2
N
NH2
NH2
N
N
N
N
N
N
N
O
N
N
R
OH
OH
OH
OH
OH
O
O
O
P
O
P
O
P
O
HO
HO
HO
1
2 R = H
3 R = CH3
4
NH2
N
O
N
N
OH
O
O
N
O
O
N
N
N
N
O
O
OH
HO
O
P
H2N
OH
OH NH2
O
P
O
P
OH
HO
O
HO
O
O
P
OH
P
OH
6
5
7
OH
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 4, pp. 543–566

Bifunctional Acyclic Nucleoside Phosphonates
545
(ph osph on om eth yl)eth er derived from glycerol wh ose secon dary h ydroxy
fun ction is replaced by h eterocyclic base residue boun d at its N1 (pyrim i-
din e) or N9 (purin e) position . Form ally, th ese com poun ds could be also
taken for double PME (2-(ph osph on om eth oxy)eth yl) m olecules. In addition
to th eir poten tial biological activity, th ese com poun ds m igh t be in terestin g
objects for ph ysico-ch em ical in vestigation : due to th e repulsion of n ega-
tively ch arged groups, th eir con form ation sh ould depen d on proxim ate pH
of th eir aqueous solution s.
Th e syn th esis of th e bis-ph osph on ate alkylatin g agen t proceeded as de-
picted in Sch em e 1. 2-(Ben zyloxy)propan e-1,3-diol (10) can be syn th esized
by kn own m eth ods5–7, h owever, we used an altern ative approach . 2-Ph en yl-
1,3-dioxan -5-ol (8) was prepared by th e kn own procedure8 an d purified by
crystallization from cycloh exan e. It was subsequen tly con verted to its O-
ben zyl derivative 9. Th e ben zyliden e protectin g grou p was rem oved by
acid-catalyzed h ydrolysis (Dowex 50X8, H+ form ) to provide 2-(ben zyl-
oxy)propan e-1,3-diol (10). Th is in term ediate was furth er alkylated with
(diiisopropoxyph osph oryl)m eth yl tosylate to form com poun d 11. It was
subsequen tly h ydrogen ated an d th e th us obtain ed in term ediate 12 was
un der stan dard con dition s fin ally con verted to 1,3-bis[(diisopropoxy-
ph osph oryl)m eth oxy]propan -2-yl tosylate (13).
OH
OBn
OBn
OBn
(ii)
(i)
(iii)
O
P
O
P
O
O
O
O
O
O
O
O
O
O
OH OH
Ph
Ph
8
10
11
9
(iv)
OH
OTs
(v)
O
P
O
P
O
O
P
O
O
O
O
O
O
O
O
O
P
O
O
O
12
13
(i) NaH, Bn Br, THF; (ii) Dowex 50X8 (H+ form ), 80% MeOH, reflux; (iii) TsOCH2P(O)(OiPr)2,
NaH, DMF, 0 °C; (iv) H2/10% Pd/C, MeOH, HCl, r.t.; (v) TsCl, Et3N, DMAP, CH2Cl2, 0 °C
SCHEME 1
Syn th esis of bis-ph osph on ate alkylatin g agen t
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546
Vrbovská, Holý, Pohl, Masojídková:
Alkylation of n ucleobases with com poun d 13 was perform ed un der stan -
dard con dition s (0.5 equivalen t of Cs2CO3, DMF, h eatin g). Alkylation of
purin es is depicted in Sch em e 2. Th e reaction of 6-ch loropurin e 14a an d
2-am in o-6-ch loropurin e 14b proceeded at N9 position of th e rin g to give
com poun ds 15a an d 15b on ly. Essen tially n o N7-regioisom er form ation was
observed.
Th e in term ediates 15 were furth er con verted to oth er base-m odified
ph osph on ates: th us, aden in e 16a an d 2,6-diam in opurin e 16b derivatives
were prepared by th e am m on olysis with m eth an olic am m on ia; h ypo-
xan th in e derivative 17b was obtain ed in reaction of 16a with 3-m eth yl-
butyl n itrite in 80% acetic acid wh ile acid h ydrolysis of 15b led to guan in e
derivative 17b. Replacem en t of ch lorin e atom in th e 6-ch loro derivatives 15
by sulfan yl group in com poun ds 19a an d 19b was ach ieved by th e reaction
with th iourea. We h ave also prepared th e 6-(cyclopropylam in o) derivatives
R2
Cl
N
N
N
N
N
N
Cl
R1
N
N
R1
N
N
(ii)-(vi)
(i)
O
P
O
P
R1
N
O
P
O
P
N
H
RO
RO
OR
OR
RO
RO
OR
OR
O
O
O
O
14a,b
16a,b R2 = NH2
17a,b R2 = OH
15a,b
18a,b R2 = cyclopropylamino
19a,b R2 = SH
In compounds 15-19, R = iPr,
In compounds 14-23, a R1 = H, b R1 = NH2
(vii)
R2
N
N
20a,b R2= NH2
21a,b R2 = OH
R1
N
N
O
P
O
P
22a,b R2 = cyclopropylamino
23a,b R2 = SH
HO
HO
OH
OH
O
O
(i) 8, Cs2CO3, DMF, 90 °C; (ii) for com poun ds 16, m eth an olic am m on ia, 100 °C; iii) for 17a:
16a, 3-m eth ylbutyl n itrite, 80% CH3COOH, r.t.; iv) for 17b : 16b , 80% CH3COOH, r.t.;
(v) for 18: cyclopropylam in e, dioxan e, reflux; (vi) for 19: th iourea, eth an ol, reflux; (vii) for
20–23: TMSBr in aceton itrile, r.t.
SCHEME 2
Alkylation of purin e bases
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Bifunctional Acyclic Nucleoside Phosphonates
547
18a an d 18b by reaction of tetraester 15a an d 15b with cyclopropylam in e
in dioxan e because cyclopropylam in o group possesses very in terestin g
feature. It is catabolized in th e cells to 6-oxo derivative. 2-Am in o-6-(cyclo-
propylam in o)purin es can th erefeore serve as guan in e prodrugs9,10
.
Subsequen t deprotection of com poun ds 16–19 with brom otrim eth yl-
silan e in aceton itrile followed by h ydrolysis yielded th e correspon din g free
bis-ph osph on ic acids 20–23 th at were ultim ately purified as deion ized
crude m aterials by ion exch an ge ch rom atograph y.
Th e reaction of cytosin e an d 5-m eth ylcytosin e derivatives 24a an d 24b
with in term ediate 13 un der th e above con dition s afforded a m ixture of
O2-regioisom er (25; yield 7%,) an d N1-regioisom er (26; yield 14%), wh ich
were furth er con verted to th e correspon din g free bis-ph osph on ic acids 27
an d 28 as sh own in Sch em e 3. O2- an d N1-isom ers in th e pyrim idin e series
can be readily distin guish ed by 13C NMR spectroscopy. Th e
ph osph on ate-bearin g th ree-carbon ch ain lin ked via its position 2 to oxygen
sh ows δCH 72 ppm wh ile in th at boun d to N δCH 54 ppm (cf. Experim en tal).
RO
NH2
O
RO
NH2
NH2
N
R1
P
R1
R1
O
N
N
(i)
N
O
+
O
O
N
O
N
H
O
P
O
O
O
P
RO
RO
OR
OR
24a,b
25a,b
O
OR
OR
P
26a,b
In compounds 25 and 26: R = iPr
In compounds 24-28: a R1 = H, b R1 = CH3
(ii)
HO
NH2
O
HO
R1
P
NH2
N
N
R1
O
O
N
O
N
O
P
O
O
O
P
+
HO
HO
OH
OH
O
O
P
OH
OH
27a,b
28a,b
(i) 13, Cs2CO3, DMF, 90 °C; (ii) TMSBr in aceton itrile, r.t.
SCHEME 3
Alkylation of cytosin e derivatives
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548
Vrbovská, Holý, Pohl, Masojídková:
Sch em e 4 sh ows th e course of alkylation of uracil 29a an d th ym in e 29b
with syn th on 13 un der stan dard con dition s. Of th e th ree products form ed
in both cases (O2-30, N1-31 an d bis-N1,N3-isom er 32) th e N1-isom er 31 was
always th e m ajor product. It was isolated in about 15% yield wh ile th e
O2-isom er an d bis-N1,N3-substituted com poun d were obtain ed on ly in 1.1
an d 0.5% yields, respectively. Th e subsequen t deprotection of tetraester 31
with brom otrim eth ylsilan e in aceton itrile followed by h ydrolysis yielded
m esoform s of th e correspon din g free ph osph on ic acids 33 th at were iso-
lated from th e deion ized product by ion exch an ge ch rom atograph y.
Bis-N1,N3 derivative 32 was iden tified usin g 1H NMR spectroscopy by th e
absen ce of th e sign al of NH group. In 13C NMR, th e residue boun d to py-
rim idin e base provides two sign als with δC,H 50 an d 40 ppm for N1 an d N3,
respectively. Th is also clearly in dicates a double substitution of th e pyrim i-
din e rin g.
O
R1
HN
In compounds 30-32: R = iPr
In compounds 29-33: a R1 = H, b R1 = CH3
O
N
H
29a,b
(i)
OR
P
OR
RO
O
O
O
N
O
P
R1
RO
O
N
O
N
O
HN
R1
O
R1
HN
+
O
O
OR
OR
O
O
O
P
O
O
P
RO
RO
OR
OR
O
N
O
P
O
+
RO
RO
O
O
P
O
O
P
31a,b
(ii)
P
OR
RO
RO
OR
32a,b
30a,b
O
N
R1
HN
O
P
O
O
P
HO
HO
OH
OH
O
O
33a,b
(i) 13, Cs2CO3, DMF, 90 °C; (ii) TMSBr in aceton itrile, r.t.
SCHEME 4
Alkylation of uracil an d th ym in e
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 4, pp. 543–566

Bifunctional Acyclic Nucleoside Phosphonates
549
Our results are th erefore in agreem en t with th e kn own fact th at N1 posi-
tion of th e th ym in e an d uracil rin g is th e prefered alkylation target un der
given con dition s11,12. Bis-N1,N3- an d O-isom er are our m in or products.
N3-Isom er, th at is preferen tially form ed in alkylation of uridin e an d th ym -
idin e, is n ot form ed in our case at all13. To verify th e gen eral validity of th is
ph en om en on we h ave briefly exam in ed th e regiospecificity of alkylation s
of th ym in e with th e tosyl derivatives of various prim ary an d secon dary
alcoh ols (Sch em e 5). Th e results sum m arized in Table I clearly dem on strate
th at – un der th e reaction con dition s used – th e m ajor product of th e reac-
tion is th e N1-isom er both with th e prim ary an d secon dary tosylates.
All tosylates of prim ary alcoh ols (No. 1, 2, an d 3) provide m ixtures of N1
an d bis-N1,N3 derivatives in th e ratio ca. 3:1. Wh en tosylate of secon dary
alcoh ols is used (No. 4), N1 derivative is preferen tially form ed. Also, th e re-
action with “bis-ph osph on ate precursor” (No. 5) gives th e sam e result. In
all th ese cases O derivative is form ed as m in or product.
It sh ould be also con sidered th at, wh ile th e n ucleosidation s are m ain ly
SN1 reaction s, th e m ech an ism of alkylation by tosylates is eviden tly SN2.
Th ough th e advan tage of th e 4-O-alkyl protection 4-m eth oxypyrim idin -
2(1H)-on es) of uracil, th ym in e an d related pyrim idin es, wh ich are gen erally
used for such tran sform ation s, con sists in im proved yields of alkylation s
due to good solubility of th e alkylation substrates, th e above fin din g on th e
regiospecificity of th e alkylation reaction of free pyrim idin e bases in DMF
in th e presen ce of cesium carbon ate could be useful in th ose cases wh ere
th e correspon din g 4-m eth oxypyrim idin -2(1H)-on es are n ot accessible at all
or with difficulties on ly, as it can be, e.g., in th e case of m in ute reaction
scales (labeled com poun ds) or with bases sen sitive to th e reaction con di-
tion s required for th e 4-m eth oxypyrim idin -2(1H)-on e preparation . To con -
trol th e reaction it is advisable to perform it at m ild tem perature an d with a
sm all excess of th e reagen t on ly, to avoid th e form ation of th e bis-alkylated
product.
O
O
O
O
N
CH3
CH3
R
O
CH3
CH3
HN
HN
N
HN
RO
Cs2CO3, DMF
R-OTs
+
+
O
N
R
O
N
H
N
R
34a-38a
34c-38c
34b-38b
SCHEME 5
Alkylation of th ym in e with prim ary an d secon dary alkyl tosylates
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 4, pp. 543–566

550
Biological Activity
Vrbovská, Holý, Pohl, Masojídková:
Biological activity of th e bis-ph osph on ates both in th e purin e an d pyrim i-
din e series is lim ited by th eir h igh polarity. Th ey are in active both in th e
an tiviral assays of DNA viruses, RNA viruses an d retroviruses, specifically
again st h epatitis B an d C viruses an d again st HIV, again st h erpesviruses
(HSV-1 an d HSV-2, VZV an d CMV) an d RNA virus m odels of h um an path o-
TABLE I
Yields of alkylation s of th ym in e with prim ary an d secon dary alkyl tosylates
No.
1
Tosylates
TsO
N1-derivative Bis-N1,N3-derivative
O-derivative
39%
10%
1%
O
O
34
35
36
34a
34b
34c
TsO
OCH3
O
2
3
4
5
31%
10%
1%
O
O
35a
35b
35c
O
P
TsO
O
32%
10%
1%
O
O
36a
36b
36c
BnO
25%
<4%
1%
OTs
37a
37b
37c
37
38
OTs
23%
<1%
1%
O
O
Ph
38a
38b
38c
Collect. Czech. Chem. Commun. 2006, Vol. 71, No. 4, pp. 543–566

Bifunctional Acyclic Nucleoside Phosphonates
551
gen s. Nor was th ere an y activity observed on an y of th e four h um an tran s-
form ed cell lin es tested. Non eth eless, th e data are n ot con sidered to be
con clusive, sin ce som e tests are still in progress. Also, it is n ecessary to con -
vert at least som e of th e com poun ds presen ted in th is paper to th eir
lipoph ilic derivatives, e.g. to m on o- or diesters with lon g-ch ain aliph atic al-
coh ols to en h an ce th eir tran sport across th e cellular m em bran e. Th is study
is curren tly bein g carried out.
Conclusion
In con clusion , we h ave developed a gen eral m eth od for th e syn th esis of
sym m etrical bifun ction al ph osph on ates of acyclic n ucleoside as a n ovel
group of ANP. Selected purin e an d pyrim idin e derivatives were prepared
an d ch aracterized. On th is occasion we h ave discovered th at uracil an d th y-
m in e are alkylated by tosylates of prim ary an d secon dary alcoh ols
regiospecifically in th e position N1.
EXPERIMENTAL
Materials an d Meth ods
Un less oth erwise stated, solven ts were evaporated at 40 °C/2 kPa, an d com poun ds were
dried at 2 kPa over P2O5. Meltin g poin ts were determ in ed on a Büch i m eltin g poin t appara-
tus. NMR spectra were m easured on an FT NMR spectrom eter Varian Un ity 500 (1H at 500
MHz an d 13C at 125.7 MHz frequen cy). Ch em ical sh ifts are given in ppm (δ-scale), couplin g
con stan ts (J) in Hz. Mass spectra were m easured on a ZAB-EQ (Microm ass, Man ch ester, U.K.)
spectrom eter usin g FAB (ion ization by Xe, acceleratin g voltage 8 kV, glycerol m atrix) or
usin g EI (electron en ergy 70 eV). UV spectra (λ in n m ) were taken on a Beckm an DU-65
spectroph otom eter in m eth an ol solution . Elem en tal an alyses were carried out on a Perkin –
Elm er CHN An alyser 2400, Series II Sys (Perkin –Elm er, Norwolk, CT, U.S.A.). Ch em icals
were purch ased from Sigm a–Aldrich (Prague, Czech Republic). Dim eth ylform am ide an d
aceton itrile were distilled from P2O5 an d stored over m olecular sieves (4Å). Tetrah ydrofuran
was distilled with CaH2 an d stored over m olecular sieves (4Å).
2-Ph en yl-1,3-dioxan -5-ol (8)
Con cen trated H2SO4 (3 drops) was added to a solution of glycerol (113 g, 1227 m m ol) an d
ben zaldeh yde (100 g, 942 m m ol) in toluen e (450 m l). Th e m ixture was refluxed in m odified
Dean –Stark apparatus for 4 h (88% of water separated). Th e reaction m ixture was th en
cooled to room tem perature an d th e solven t was evaporated. Th e residue was dissolved in
eth er (500 m l) an d wash ed th ree tim es with water (500 m l). Th e organ ic layer was dried
over an h ydrous MgSO4, filtered an d evaporated. Crystallization from n-h exan e provided
com poun d 8 as a wh ite solid (yield 92 g, 55%). M.p. 61.9–63.3 °C. For C10H12O3 (180.2) cal-
culated: 66.65% C, 6.71% H; foun d: 66.44% C, 6.63% H. FAB MS: 181.1 (MH+) (100).
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552
Vrbovská, Holý, Pohl, Masojídková:
1H NMR (500 MHz, DMSO-d6 + DAc): 7.40–7.30 (m , 10 H, arom .); 5.53 an d 5.41 (2 × s, 2 ×
1 H, 2 × O-CH-O); 5.24 an d 5.01 (2 × d, 2 × 1 H, J = 2 × 5.2, 2 × OH); 4.13 (dd, 2 H, J = 5.1
an d 11.0, O-CH2); 3.48 (t, 2 H, J = 10.6 an d 10.6, O-CH2); 4.04 (dd, 2 H, J = 1.5 an d 11.8,
O-CH2); 3.95 (dd, 2 H, J = 1.2 an d 11.8, O-CH2); 3.72 (tq, 1 H, J = 3 × 5.2 an d 2 × 10.3,
O-CHax); 3.50 (m , 1 H, O-CHeq). 13C NMR (125.7 MHz, DMSO-d6 + DAc): 139.25; 138.57;
129.01; 128.92; 128.35 (2 C); 128.28 (2 C); 126.60 (2 C); 126.54 (2 C); 100.64 an d 100.60
(2 × O-CH-O); 72.02 (2 C, O-CH2); 71.76 (2 C, O-CH2); 62.76 an d 60.57 (O-CH).
5-(Ben zyloxy)-2-ph en yl-1,3-dioxan e (9)
Un der argon atm osph ere 2-ph en yl-1,3-dioxan -5-ol (90 g, 499 m m ol) was added at 0 °C to
a suspen sion of NaH (20 g of 60% suspen sion in m in eral oil, 499 m m ol, prewash ed with n-
h exan e) in dry THF (550 m l). Th e reaction m ixture was th en cooled to –10 °C an d ben zyl
brom ide (94 g, 549 m m ol) in THF (200 m l) was added dropwise durin g 1 h . Th e m ixture was
stirred for 30 m in at –10 °C an d at room tem perature overn igh t un der argon . Wh en th e re-
action was com plete (TLC), m eth an olic am m on ia (30 m l) was added. After stirrin g th e solu-
tion for 1 h , th e solven t was evaporated. Th e residue was dissolved in ch loroform (500 m l)
an d wash ed with water (500 m l). Th e organ ic layer was dried with an h ydrous MgSO4, fil-
tered an d evaporated to yield crude product 9, wh ich was used with out furth er purification .
2-(Ben zyloxy)propan e-1,3-diol (10)
A solution of crude 9 in 80% m eth an ol (500 m l) was refluxed with Dowex 50X8 in H+ form
(10 g) for 4 h . Th e resin was filtered off, th e solution n eutralized with aqueous am m on ia
an d th e solven t was evaporated. Th e crude product was purified by silica gel colum n ch ro-
m atograph y, usin g ch loroform –m eth an ol gradien t 0–5%, to yield 74 g (80%) of pure 10 as
colorless solid. M.p. 38.1–39.6 °C. For C10H14O3 (182.2) calculated: 65.91% C, 7.74% H;
foun d: 65.87% C, 7.68% H. MS (EI), m/z: 182.2 (M+). 1H NMR (500 MHz, DMSO-d6): 7.34
(m , 5 H, arom .); 4.61 (s, 2 H, CH2-ben zyl); 4.58 (t, 2 H, OH, JOH,CH2 = 5.6); 3.52 (dt, 2 H,
JCH2,CH ~ JCH2,OH = 5.4, O-CH2); 3.45 (dt, 2 H, Jgem = 11.2, O-CH2); 3.38 (q, 2 H, J = 5.2,
O-CH). 13C NMR (125.7 MHz, DMSO-d6): 139.47; 128.27 (2 C); 127.61 (2 C); 127.35; 81.12
(O-CH); 70.96 (CH2-O-Ph ); 61.05 (O-CH2).
2-(Ben zyloxy)-1,3-bis[(diisopropoxyph osph oryl)m eth oxy]propan e (11)
A solution of 10 (20 g, 110 m m ol) in dry DMF (50 m l) was added dropwise at 0 °C to a
stirred suspen sion of NaH (11 g of 60% suspen sion in m in eral oil, 274 m m ol, prewash ed
with n-h exan e) in dry DMF (450 m l) un der a CaCl2 protectin g tube. (Diisopropoxyph os-
ph oryl)m eth yl tosylate (88 g, 252 m m ol) was added dropwise an d th e m ixture was stirred
with a m ech an ical stirrer at room tem perature for 8 h . Th e reaction m ixture was n eutralized
with 4.5 M HCl in DMF, th e solven t evaporated, th e residue was co-evaporated with toluen e,
dissolved in eth yl acetate (300 m l) an d wash ed th ree tim es with water (300 m l). Th e organ ic
layer was dried with an h ydrous MgSO4 an d evaporated. Th e residue was purified by silica gel
colum n ch rom atograph y, usin g ch loroform –m eth an ol gradien t 0–3%, to yield 37 g (65%) of
pure 11 as yellowish oil. For C24H44O9P2 (538.6) calculated: 53.52% C, 8.23% H, 11.50% P;
foun d: 53.23% C, 8.39% H, 11.75% P. FAB MS: 539.2 (M+) (40). 1H NMR (500 MHz, CDCl3):
7.37–7.30 (m , 5 H, arom .); 4.74 (m , 4 H, CH-iPr, JH,P = 7.7, Jvic = 6.2); 4.69 (s, 2 H,
CH2-O-Ph ); 3.78 (tt, 1 H, J1′,2′ = 5.7 an d 4.8, H-1′); 3.78 an d 3.72 (2 × dd, 2 × 2 H, Jgem
=
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Bifunctional Acyclic Nucleoside Phosphonates
553
13.9, JH,P = 8.3, H-3′); 3.68 (dd, 2 H, Jgem = 10.3, J2′a,1′ = 5.7, H-2′a); 3.72 (dd, 2 H, Jgem
=
10.3, J2′b,1′ = 4.8, H-2′b); 1.34, 1.32 an d 1.30 (3 × d, 24 H, Jvic = 6.2, CH3-iPr). 13C NMR
(125.7 MHz, CDCl3): 128.29; 127.71; 127.55; 76.94 (CH-1′); 73.31 (d, JC,P = 11.0, CH2-2′);
72.25 (CH2-ben zyl); 70.97 (d, JC,P = 7.0, CH-iPr); 66.36 (d, JC,P = 167.0, CH2-3′); 24.10 an d
24.09 (d, JC,P = 4.0, CH3-iPr).
1,3-Bis[(diisopropoxyph osph oryl)m eth oxy]propan -2-ol (12)
Palladium on activated ch arcoal (10% Pd, 1 g) an d con cen trated HCl (1 m l) were added to a
solution of 11 (34 g, 63 m m ol) in m eth an ol (300 m l). Th e reaction m ixture was h ydroge-
n ated at atm osph eric pressure an d room tem perature overn igh t. Th e catalyst was filtered off
th rough a Celite pad, th e filtrate was n eutralized with Et3N an d evaporated to give crude
product 12, wh ich was directly used in th e subsequen t reaction . FAB MS: 449.1 (MH+) (60).
1H NMR (500 MHz, DMSO-d6): 4.93 (bs, 1 H, OH); 4.59 (tt, 1 H, J1′,2′ = 7.4 an d 4.5, H-1′);
4.50 (m , 4 H, CH-iPr); 3.78 an d 3.76 (2 × dd, 2 × 2 H, Jgem = 13.8, JH,P = 8.1, H-3′); 3.48 (dd,
2 H, Jgem = 10.0, J2′a,1′ = 7.6, H-2′a); 3.43 (dd, 2 H, Jgem = 10.0, J2′b,1′ = 4.8, H-2′b); 1.24, 1.23
an d 1.21 (3 × d, 24 H, Jvic = 6.2, CH3-iPr). 13C NMR (125.7 MHz, DMSO-d6): 74.55 (d, JC,P
=
10.7, CH2-2′); 70.26 (d, JC,P = 6.4, CH-iPr); 68.47 (CH-1′); 65.56 (d, JC,P = 164.6, CH2-3′);
24.01 an d 23.90 (d, JC,P = 4.0, CH3-iPr).
1,3-Bis[(diisopropoxyph osph oryl)m eth oxy]propan -2-yl Tosylate (13)
A m ixture of crude 12, 4-(dim eth ylam in o)pyridin e (0.7 g) an d Et3N (8 g) in dry dich loro-
m eth an e (200 m l) was stirred at 0 °C with a CaCl2 protectin g tube. Tosyl ch loride (15 g) in
dich lorom eth an e (100 m l) was added dropwise. Th e m ixture was stirred at 0 °C for 1 h an d
th en kept in refrigerator overn igh t. Th e organ ic solution was diluted with ice water (300 m l)
an d th e layers separated. Th e organ ic layer was dried with an h ydrous MgSO4, filtered an d
evaporated in vacuo. Th e residue was purified by colum n ch rom atograph y on silica gel, us-
in g ch loroform –m eth an ol gradien t 0–2%, to yield 30 g (78%) of pure 13 as yellowish oil. For
C
24H44O11P2S (602.6) calculated: 47.83% C, 7.36% H, 10.28% P, 5.32% S; foun d: 47.50% C,
7.38% H, 10.53% P, 5.57% S. FAB MS: 602.9 (MH+) (75). 1H NMR (500 MHz, DMSO-d6): 7.80
an d 7.46 (d, 2 × 2 H, arom ); 4.70 (tt, 1 H, J1′,2′ = 7.4 an d 4.5, H-1′); 4.56 (m , 4 H, CH-iPr);
3.79 an d 3.75 (2 × dd, 2 × 2 H, Jgem = 13.8, JH,P = 8.1, H-3′); 3.67 (dd, 2 H, Jgem = 10.3,
J2′a,1′ = 7.4, H-2′a); 3.64 (dd, 2 H, Jgem = 10.3, J2′b,1′ = 4.5, H-2′b); 2.41 (s, 3 H, CH3-tosyl);
1.23, 1.22 an d 1.21 (3 × d, 24 H, Jvic = 6.2, CH3-iPr). 13C NMR (125.7 MHz, DMSO-d6):
144.94; 133.48; 130.18 (2 C); 127.79 (2 C); 79.32 (CH-1′); 70.93 (d, JC,P = 10.2, CH2-2′);
70.37 (d, JC,P = 5.9, CH-iPr); 65.40 (d, JC,P = 164.1,CH2-3′); 23.97 an d 23.85 (d, JC,P = 3.6,
CH3-iPr); 21.27 (CH3).
Gen eral Procedure for Alkylation of Nucleobases with Com poun d 13
A solution of an appropriate n ucleobase (14a, 14b; 24a, 24b; 29a, 29b; 7–10 m m ol) in dry
DMF (50 m l) was treated with Cs2CO3 (0.5 equiv.) at room tem perature un der a CaCl2
protectin g tube for 1 h . Th e reaction m ixture was th en h eated at 60 °C an d syn th on 13
(1.0 equiv.) was added. Th e m ixture was th en stirred at 90 °C for 24 h . Solven t was taken
down an d th e residue was co-evaporated with toluen e. Th e residue in ch loroform was fil-
tered th rough a Celite pad, evaporated an d purified on a silica gel colum n in ch loroform –
m eth an ol.
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554
Vrbovská, Holý, Pohl, Masojídková:
9-{1,3-Bis[(diisopropoxyphosphoryl)methoxy]propan-2-yl}-6-chloro-9H-purine (15a). Colum n
ch rom atograph y (silica gel, ch loroform –m eth an ol gradien t 0–6%) afforded th e product as
yellowish oil (yield 25%). FAB MS: 585.9 (MH+) (70). 1H NMR (500 MHz, DMSO-d6): 8.79 (s,
1 H, H-2); 8.76 (s, 1 H, H-8); 5.14 (tt, 1 H, J1′,2′ = 8.1 an d 4.3, H-1′); 4.41 (m , 4 H, CH-iPr);
4.16 (dd, 2 H, Jgem = 10.5, J2′a,1′ = 8.1, H-2′a); 3.95 (dd, 2 H, Jgem = 10.5, J2′b,1′ = 4.3, H-2′b);
3.80 an d 3.73 (2 × dd, 2 × 2 H, Jgem = 14.0, JH,P = 8.3, H-3′); 1.13, 1.12, 1.10 an d 1.05 (4 × d,
24 H, Jvic = 6.2, CH3-iPr). 13C NMR (125.7 MHz, DMSO-d6): 152.35 (CH-2); 151.59 (C-6);
149.20 (C-4); 146.76 (CH-8); 130.99 (C-5); 70.45 (d, JC,P = 11, CH2-2′); 70.30 an d 70.26 (d,
JC,P = 6, CH-iPr); 64.98 (d, JC,P = 164.0, CH2-3′); 54.85 (CH-1′); 23.87, 23.75, 23.64 an d 23.62
(d, JC,P = 4.0, CH3-iPr).
9-{1,3-Bis[(diisopropoxyphosphoryl)methoxy]propan-2-yl}-6-chloro-9H-purin-2-amine (15b). Col-
um n ch rom atograph y (silica gel, ch loroform –m eth an ol gradien t 0–6%) afforded th e product
as yellowish foam (yield 30%). FAB MS: 600.5 (MH+) (100). 1H NMR (500 MHz, DMSO-d6):
8.17 (s, 1 H, H-8); 6.88 (bs, 2 H, NH2); 4.80 (tt, 1 H, J1′,2′ = 7.9 an d 4.4, H-1′); 4.46 (m , 4 H,
CH-iPr); 4.05 (dd, 2 H, Jgem = 10.3, J2′a,1′ = 7.9, H-2′a); 3.87 (dd, 2 H, Jgem = 10.3, J2′b,1′ = 4.4,
H-2′b); 3.79 an d 3.72 (2 × dd, 2 × 2 H, Jgem = 13.9, JH,P = 8.2, H-3′); 1.10, 1.09, 1.07 an d 1.06
(4 × d, 24 H, Jvic = 6.2, CH3-iPr). 13C NMR (125.7 MHz, DMSO-d6): 159.81 (C-2); 154.49
(C-6); 149.44 (C-4); 142.17 (CH-8); 123.43 (C-5); 70.67 (d, JC,P = 12, CH2-2′); 70.38 an d
70.27 (d, JC,P = 6, CH-iPr); 65.05 (d, JC,P = 164.0, CH2-3′); 53.70 (CH-1′); 23.87, 23.82, 23.75
an d 23.70 (d, JC,P = 4.0, CH3-iPr).
2-({[1,3-Bis(diisopropoxyphosphoryl)methoxy]propan-2-yl}oxy)pyrimidin-4-amine (25a). Colum n
ch rom atograph y (silica gel, ch loroform –m eth an ol gradien t 0–12%) afforded th e product as
yellowish oil (7%). FAB MS: 542.4 (MH+) (40). 1H NMR (500 MHz, DMSO-d6): 7.83 (d, 1 H,
JH6,H5 = 5.8, H-6); 6.82 (bs, 2 H, NH2); 6.06 (d, 1 H, JH5,H6 = 5.8, H-5); 5.28 (tt, 1 H, J1′,2′
8.2 an d 4.8, H-1′); 4.58 (m , 4 H, CH-iPr); 3.78 (dd, 2 H, Jgem = 13.9, J2′a,1′ = 8.2, H-2′a); 3.74
(dd, 2 H, Jgem = 13.9, J2′b,1′ = 4.8, H-2′b); 3.71 an d 3.70 (2 × dd, 2 × 2 H, Jgem = 13.9, JH,P
=
=
8.5, H-3′); 1.22, 1.21, 1.20 an d 1.19 (4 × d, 24 H, Jvic = 6.2, CH3-iPr). 13C NMR (100.6 MHz,
DMSO-d6): 165.60 (C-4); 164.38 (C-2); 156.29 (C-6); 99.69 (C-5); 72.40 (CH-1′); 71.55 (d,
JC,P = 11.7, CH2-2′); 70.46 an d 70.35 (d, JC,P = 6.3, CH-iPr); 65.48 (d, JC,P = 164.1, CH2-3′);
23.96, 23.94, 23.85 an d 23.81 (d, JC,P = 4.0, CH3-iPr).
4-Amino-1-{[1,3-bis(diisopropoxyphosphoryl)methoxy]propan-2-yl}pyrimidin-2(1H)-one (26a).
Colum n ch rom atograph y (silica gel, ch loroform –m eth an ol gradien t 0–12%) afforded th e
product as yellowish oil (14%). FAB MS: 542.3 (MH+) (40). 1H NMR (500 MHz, DMSO-d6):
7.53 (d, 1 H, JH6,H5 = 7.3, H-6); 6.97 (bs, 2 H, NH2); 5.63 (d, 1 H, JH5,H6 = 7.3, H-5); 4.70 (tt,
1 H, J1′,2′ = 7.4 an d 4.8, H-1′); 4.54 (m , 4 H, CH-iPr); 3.84 (dd, 2 H, Jgem = 10.5, J2′a,1′ = 7.4,
H-2′a); 3.68 (dd, 2 H, Jgem = 10.5, J2′b,1′ = 4.8, H-2′b); 3.75 an d 3.70 (2 × dd, 2 × 2 H, Jgem
14.0, JH,P = 8.2, H-3′); 1.22, 1.21, 1.20 an d 1.19 (4 × d, 24 H, Jvic = 6.1, CH3-iPr). 13C NMR
(100.6 MHz, DMSO-d6): 165.54 (C-4); 155.93 (C-2); 142.70 (C-6); 93.32 (C-5); 70.67 (d, JC,P
=
=
11.2, CH2-2′); 70.37 an d 70.46 (d, JC,P = 6.3, CH-iPr); 65.00 (d, JC,P = 163.6, CH2-3′); 54.50
(CH-1′); 23.96, 23.94, 23.86 an d 23.81(d, JC,P = 4.3, CH3-iPr).
2-({[1,3-Bis(diisopropoxyphosphoryl)methoxy]propan-2-yl}oxy)-5-methylpyrimidin-4-amine (25b).
Colum n ch rom atograph y (silica gel, ch loroform –m eth an ol gradien t 0–12% afforded th e
product as yellowish oil (7%). FAB MS: 556.0 (MH+) (100). 1H NMR (500 MHz, DMSO-d6):
7.74 (q, 1 H, JH6,CH3 = 1.0, H-6); 6.65 (bs, 1 H, NH2); 5.36 (tt, 1 H, J1′,2′ = 8.2 an d 4.9, H-1′);
4.56 (m , 4 H, CH-iPr); 3.78 (dd, 2 H, Jgem = 13.9, J2′a,1′ = 8.2, H-2′a); 3.73 (dd, 2 H, Jgem
=
13.9, J2′b,1′ = 4.9, H-2′b); 3.53 an d 3.49 (2 × dd, 2 × 2 H, Jgem = 12.8, JH,P = 8.4, H-3′); 1.80 (d,
3 H, JCH3 H6
,
= 1.0, CH3); 1.22, 1.21, 1.20 an d 1.19 (4 × d, 24 H, Jvic = 6.1, CH3-iPr). 13C NMR
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Bifunctional Acyclic Nucleoside Phosphonates
555
(100.6 MHz, DMSO-d6): 164.33 (C-4); 163.10 (C-2); 154.91 (C-6); 107.02 (C-5); 72.31
(CH-1′); 71.61 (d, JC,P = 11.7, CH2-2′); 70.36 an d 70.30 (d, JC,P = 6.3, CH-iPr); 65.48 (d, JC,P
164.5, CH2-3′); 23.86, 23.85, 23.83 an d 23.81 (d, JC,P = 4.2, CH3-iPr); 13.13 (CH3).
=
4-Amino-1-{[1,3-bis(diisopropoxyphosphoryl)methoxy]propan-2-yl}-5-methylpyrimidin-2(1H)-one
(26b). Colum n ch rom atograph y (silica gel, ch loroform –m eth an ol gradien t 0–15%) afforded
th e product as yellowish oil (14%). FAB MS: 556.1 (MH+) (100). 1H NMR (500 MHz,
DMSO-d6): 7.43 (q, 1 H, JH6,CH3 = 1.0, H-6); 6.87 (bs, 2 H, NH2); 4.80 (tt, 1 H, J1′,2′ = 7.7 an d
4.8, H-1′); 4.53 (m , 4 H, CH-iPr); 3.84 (dd, 2 H, Jgem = 10.5, J2′a,1′ = 7.7, H-2′a); 3.68 (dd, 2 H,
Jgem = 10.5, J2′b,1′ = 4.8, H-2′b); 3.75 an d 3.70 (2 × dd, 2 × 2 H, Jgem = 13.9, JH,P = 8.5, H-3′);
1.82 (d, 3 H, JCH3 H6 = 1.0, CH3); 1.21, 1.20, 1.19 an d 1.18 (4 × d, 24 H, Jvic = 6.1, CH3-iPr).
,
13C NMR (100.6 MHz, DMSO-d6): 164.78 (C-4); 155.55 (C-2); 142.70 (C-6); 100.66 (C-5);
70.65 (d, JC,P = 11.2, CH2-2′); 70.47 an d 70.46 (d, JC,P = 6.3, CH-iPr); 64.98 (d, JC,P = 164.1,
CH2-3′); 53.88 (CH-1′); 24.01, 23.98, 23.86 an d 23.82 (d, JC,P = 4.1, CH3-iPr); 13.35 (CH3).
2-({[1,3-Bis(diisopropoxyphosphoryl)methoxy]propan-2-yl}oxy)pyrimidin-4(3H)-one
(30a ).
Colum n ch rom atograph y (silica gel, ch loroform –m eth an ol gradien t 0–10%) afforded th e
product as yellowish oil (1%). FAB MS: 543.2 (MH+) (60). 1H NMR (500 MHz, DMSO-d6):
7.75 (d, 1 H, JH6,H5 = 8.0, H-6); 5.64 (d, 1 H, JH5,H6 = 8.0, H-5); 5.01 (tt, 1 H, J1′,2′ = 8.1 an d
4.5, H-1′); 4.55 (m , 4 H, CH-iPr); 3.78 (dd, 2 H, Jgem = 10.7, J2′a,1′ = 8.1, H-2′a); 3.74 (dd, 2 H,
Jgem = 10.7, J2′b,1′ = 4.5, H-2′b); 3.72 an d 3.70 (2 × dd, 2 × 2 H, Jgem = 14.0, JH,P = 8.3, H-3′);
1.22, 1.21, 1.20 an d 1.19 (4 × d, 24 H, Jvic = 6.2, CH3-iPr). 13C NMR (100.6 MHz, DMSO-d6):
163.40 (C-4); 162.46 (C-2); 155.32 (C-6); 106.19 (C-5); 72.62 (CH-1′); 71.25 (d, JC,P = 12.00,
CH2-2′); 70.44 an d 70.31 (d, JC,P = 6.0, CH-iPr); 65.42 (d, JC,P = 164.0, CH2-3′); 23.95, 23.93,
23.86 an d 23.89 (d, JC,P = 4.1, CH3-iPr).
1-{[1,3-Bis(diisopropoxyphosphoryl)methoxy]propan-2-yl}pyrimidine-2,4(1H,3H)-dione (31a).
Colum n ch rom atograph y (silica gel, ch loroform –m eth an ol gradien t 0–8%) afforded th e
product as yellowish oil. Crystallization from eth yl acetate/petroleum eth er gave wh ite solid
(12%). FAB MS: 543.2 (MH+) (65). 1H NMR (500 MHz, DMSO-d6): 11.28 (bs, 1 H, NH); 7.64
(d, 1 H, JH6,H5 = 8.0, H-6); 5.56 (d, 1 H, JH5,H6 = 8.0, H-5); 4.80 (tt, 1 H, J1′,2′ = 8.1 an d 4.5,
H-1′); 4.57 (m , 4 H, CH-iPr); 3.86 (dd, 2 H, Jgem = 10.7, J2′a,1′ = 8.1, H-2′a); 3.78 (dd, 2 H,
Jgem = 10.7, J2′b,1′ = 4.5, H-2′b); 3.74 an d 3.70 (2 × dd, 2 × 2 H, Jgem = 14.0, JH,P = 8.3, H-3′);
1.22, 1.21, 1.20 an d 1.19 (3 × d, 24 H, Jvic = 6.2, CH3-iPr). 13C NMR (100.6 MHz, DMSO-d6):
163.29 (C-4); 151.46 (C-2); 143.13 (C-6); 101.11 (C-5); 70.42 (d, JC,P = 12.00, CH2-2′); 70.40
an d 70.21 (d, JC,P = 6.0, CH-iPr); 64.98 (d, JC,P = 164.0, CH2-3′); 54.12 (CH-1′); 23.95, 23.93,
23.85 an d 23.89 (d, JC,P = 4.1, CH3-iPr).
1,3-Bis{[1,3-bis(diisopropoxyphosphoryl)methoxy]propan-2-yl}pyrimidine-2,4(1H,3H)-dione
(32a). Colum n ch rom atograph y (silica gel, ch loroform –m eth an ol gradien t 0–4%) afforded
th e product as yellowish oil (0.5%). FAB MS: 973.2 (MH+) (45). 1H NMR (500 MHz,
DMSO-d6): 8.28 (d, 1 H, JH6,H5 = 5.7, H-6); 6.52 (d, 1 H, JH5,H6 = 5.7, H-5); 5.42 an d 5.34 (tt,
1 H, J1′,2′ = 6.1 an d 5.0, H-1′); 4.57 (m , 4 H, CH-iPr); 3.87 an d 3.85 (dd, 2 H, Jgem = 10.1,
J2′a,1′ = 6.1, H-2′a); 3.78 an d 3.76 (dd, 2 H, Jgem = 10.7, J2′b,1′ = 5.0, H-2′b); 3.48 an d 3.43 (4 ×
dd, 4 × 2 H, Jgem = 14.0, JH,P = 8.4, H-3′); 1.22, 1.21, 1.20 an d 1.19 (8 × d, 48 H, Jvic = 6.2,
CH3-iPr). 13C NMR (100.6 MHz, DMSO-d6): 163.26 (C-4); 151.97 (C-2); 143.65 (C-6); 101.15
(C-5); 70.23 an d 70.19 (d, JC,P = 12.00, CH2-2′); 70.41 an d 70.21 (d, JC,P = 6.3, 4 × CH-iPr);
64.83 an d 64.79 (d, JC,P = 164.6, CH2-3′); 53.11 an d 45.46 (CH-1′); 23.95, 23.93, 23.91 an d
23.89 (d, JC,P = 4.1, CH3-iPr).
2-({[1,3-Bis(diisopropoxyphosphoryl)methoxy]propan-2-yl}oxy)-5-methylpyrimidin-4(3H)-one
(30b). Colum n ch rom atograph y (silica gel, in ch loroform –m eth an ol gradien t 0–9%) afforded
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Vrbovská, Holý, Pohl, Masojídková:
th e product as yellowish oil (1.1%). FAB MS: 557.1 (MH+) (60). 1H NMR (500 MHz,
DMSO-d6): 7.53 (q, 1 H, JH6,CH3 = 1.0, H-6); 4.90 (tt, 1 H, J1′,2′ = 8.2 an d 4.6, H-1′); 4.53 (m ,
4 H, CH-iPr); 3.85 (dd, 2 H, Jgem = 10.7, J2′a,1′ = 8.2, H-2′a); 3.71 (dd, 2 H, Jgem = 10.7, J2′b,1′
4.6, H-2′b); 3.72 an d 3.70 (2 × dd, 2 × 2 H, Jgem = 14.0, JH,P = 8.2, H-3′); 1.82 (d, 3 H,
JCH3 H6
= 1.0, CH3); 1.22, 1.21, 1.20 an d 1.19 (4 × d, 24 H, Jvic = 6.2, CH3-iPr). 13C NMR
=
,
(100.6 MHz, DMSO-d6): 163.91 (C-4); 162.46 (C-2); 139.01 (C-6); 108.19 (C-5); 71.62
(CH-1′); 70.45 (d, JC,P = 12.00, CH2-2′); 70.38 an d 70.31 (d, JC,P = 6.0, CH-iPr); 65.22 (d,
JC,P = 164.0, CH2-3′); 23.95, 23.93, 23.85 an d 23.89 (d, JC,P = 4.1, CH3-iPr).
1-{[1,3-Bis(diisopropoxyphosphoryl)methoxy]propan-2-yl}-5-methylpyrimidine-2,4(1H,3H)-dione
(31b). Colum n ch rom atograph y (silica gel, ch loroform –m eth an ol gradien t 0–7%) afforded
th e product as yellowish oil (12%). FAB MS: 557.0 (MH+) (65). 1H NMR (500 MHz,
DMSO-d6): 11.20 (bs, 1 H, NH); 7.52 (q, 1 H, JH6,CH3 = 1.0, H-6); 4.80 (tt, 1 H, J1′,2′ = 8.3 an d
4.6, H-1′); 4.53 (m , 4 H, CH-iPr); 3.86 (dd, 2 H, Jgem = 10.5, J2′a,1′ = 8.3, H-2′a); 3.69 (dd, 2 H,
Jgem = 10.5, J2′b,1′ = 4.6, H-2′b); 3.77 an d 3.72 (2 × dd, 2 × 2 H, Jgem = 14.0, JH,P = 8.3, H-3′);
1.82 (d, 3 H, JCH3 H6 = 1.0, CH3); 1.22, 1.21, 1.20 an d 1.19 (4 × d, 24 H, Jvic = 6.1, CH3-iPr).
,
13C NMR (100.6 MHz, DMSO-d6): 163.89 (C-4); 151.46 (C-2); 138.72 (C-6); 108.63 (C-5);
70.41 (d, JC,P = 11.2, CH2-2′); 70.38 an d 70.09 (d, JC,P = 6.4, CH-iPr); 64.95 (d, JC,P = 164.1,
CH2-3′); 53.74 (CH-1′); 23.95, 23.90, 23.86 an d 23.85 (d, JC,P = 4.1, CH3-iPr); 23.76 (CH3).
1,3-Bis{[1,3-bis(diisopropoxyphosphoryl)methoxy]propan-2-yl}-5-methylpyrimidine-2,4(1H,3H)-
dione (32b ). Colum n ch rom atograph y (silica gel, ch loroform –m eth an ol gradien t 0–4%)
afforded th e product as yellowish oil (0.5%). FAB MS: 987.2 (MH+) (45). 1H NMR (500 MHz,
DMSO-d6): 7.43 (q, 1 H, JH6,CH3 = 1.0, H-6); 5.40 an d 5.31 (tt, 1 H, J1′,2′ = 6.1 an d 5.0, H-1′);
4.56 (m , 4 H, CH-iPr); 3.87 an d 3.85 (dd, 2 H, Jgem = 10.1, J2′a,1′ = 6.1, H-2′a); 3.78 an d 3.72
(dd, 2 H, Jgem = 10.7, J2′b,1′ = 5.0, H-2′b); 3.48 an d 3.43 (4 × dd, 4 × 2 H, Jgem = 14.0, JH,P
=
8.4, H-3′); 1.81 (d, 3 H, JCH3,H6 = 1.0, CH3) 1.22, 1.21, 1.20 an d 1.19 (8 × d, 48 H, Jvic = 6.2,
CH3-iPr). 13C NMR (100.6 MHz, DMSO-d6): 163.91 (C-4); 151.45 (C-2); 139.23 (C-6); 108.15
(C-5); 70.23 an d 70.19 (d, JC,P = 12.00, CH2-2′); 70.41 an d 70.21 (d, JC,P = 6.3, 4 × CH-iPr);
64.83 an d 64.56 (d, JC,P = 164.6, CH2-3′); 51.17 an d 43.56 (CH-1′); 23.95, 23.93, 23.91 an d
23.89 (d, JC,P = 4.1, CH3-iPr).
9-{1,3-Bis[(diisopropoxyph osph oryl)m eth oxy]propan -2-yl}-9H-purin e-6-am in e (16a)
A solution of 15a (940 m g, 1.6 m m ol) in m eth an olic am m on ia (50 m l) was stirred an d
h eated (100 °C) in an autoclave for 3 days. Th e solven t was evaporated an d th e residue was
purified by colum n ch rom atograph y on silica gel with ch loroform –m eth an ol gradien t 0–6%
to yield th e product as yellowish oil (80%). FAB MS: 566.5 (MH+) (100). 1H NMR (500 MHz,
DMSO-d6): 8.16 (s, 1 H, H-2); 8.11 (s, 1 H, H-8); 7.20 (bs, 2 H, NH2); 4.93 (tt, 1 H, J1′,2′ = 7.4
an d 4.7, H-1′); 4.45 (m , 4 H, CH-iPr); 4.09 (dd, 2 H, Jgem = 10.3, J2′a,1′ = 7.4, H-2′a); 3.90 (dd,
2 H, Jgem = 10.3, J2′b,1′ = 4.7, H-2′b); 3.79 an d 3.72 (2 × dd, 2 × 2 H, Jgem = 13.9, JH,P = 8.2,
H-3′); 1.15, 1.13, 1.10 an d 1.09 (4 × d, 24 H Jvic = 6.2, CH3-iPr). 13C NMR (125.7 MHz,
DMSO-d6): 156.15 (C-6); 152.36 (CH-2); 149.82 (C-4); 139.99 (CH-8); 118.88 (C-5); 70.95 (d,
JC,P = 12, CH2-2′); 70.36 an d 70.35 (d, JC,P = 6.3, CH-iPr); 65.02 (d, JC,P = 163.6, CH2-3′);
53.64 (CH-1′); 23.89, 23.85, 23.78 an d 23.72 (d, JC,P = 3.7, CH3-iPr).
9-{1,3-Bis[(diisopropoxyph osph oryl)m eth oxy]propan -2-yl}-9H-purin e-2,6-diam in e (16b)
A solution of 15b (980 m g, 1.6 m m ol) in m eth an olic am m on ia (50 m l) was stirred an d
h eated (100 °C) in an autoclave for 3 days. Th e solven t was evaporated an d th e residue was
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Bifunctional Acyclic Nucleoside Phosphonates
557
purified by colum n ch rom atograph y on silica gel with ch loroform –m eth an ol gradien t
0–10% to yield th e product as yellowish foam (70%). FAB MS: 581.3 (MH+) (100). 1H NMR
(500 MHz, DMSO-d6): 7.73 (s, 1 H, H-8); 6.63 (bs, 2 H, NH2-C6); 5.71 (bs, 2 H, NH2-C2); 4.68
(tt, 1 H, J1′,2′ = 7.3 an d 4.8, H-1′); 4.50 (m , 4 H, CH-iPr); 4.00 (dd, 2 H, Jgem = 10.3, J2′a,1′
=
7.3, H-2′a); 3.84 (dd, 2 H, Jgem = 10.3, J2′b,1′ = 4.8, H-2′b); 3.78 an d 3.72 (2 × dd, 2 × 2 H,
Jgem = 13.9, JH,P = 8.3, H-3′); 1.19, 1.17, 1.15 an d 1.14 (4 × d, 24 H, Jvic = 6.2, CH3-iPr).
13C NMR (125.7 MHz, DMSO-d6): 160.26 (C-2); 156.26 (C-6); 152.01 (C-4); 136.38 (CH-8);
113.24 (C-5); 71.12 (d, JC,P = 12, CH2-2′); 70.43 an d 70.40 (d, JC,P = 6, CH-iPr); 65.10 (d, JC,P
= 164.0, CH2-3′); 23.95, 23.81, 23.74 an d 23.79 (d, JC,P = 4.0, CH3-iPr); 52.79 (CH-1′).
9-{1,3-Bis[(diisopropoxyph osph oryl)m eth oxy]propan -2-yl}-1H-purin -6(9H)-on e (17a)
3-Meth ylbutyl n itrite (10 equiv.) was added to a solution of com poun d 16a (450 m g, 0.8 m m ol)
in 80% acetic acid (20 m l) an d th e m ixture was stirred at room tem perature overn igh t an d
th en at 70 °C for 2 h . After evaporation of volatiles th e residue was codistilled with water
an d purified by colum n ch rom atograph y on silica gel with ch loroform –m eth an ol gradien t
0–12% to yield th e product as yellowish foam (77%). FAB MS: 567.4 (MH+) (100). 1H NMR
(500 MHz, DMSO-d6): 12.25 (bs, 1 H, NH); 8.13 (s, 1 H, H-2); 8.04 (s, 1 H, H-8); 4.92 (tt,
1 H, J1′,2′ = 7.8 an d 4.3, H-1′); 4.46 (m , 4 H, JH,P = 7.8, Jvic = 6.2, CH-iPr); 4.06 (dd, 2 H,
Jgem = 10.4, J2′a,1′ = 7.8, H-2′a); 3.88 (dd, 2 H, Jgem = 10.4, J2′b,1′ = 4.3, H-2′b); 3.79 an d 3.73
(2 × dd, 2 × 2 H, Jgem = 13.9, JH,P = 8.3, H-3′); 1.17, 1.16, 1.15 an d 1.13 (4 × d, 24 H, Jvic
=
6.2, CH3-iPr). 13C NMR (100.6 MHz, DMSO-d6): 156.80 (C-6); 148.70 (C-4); 145.47 (CH-2);
139.41 (CH-8); 124.03 (C-5); 71.00 (d, JC,P = 11.2, CH2-2′); 70.38 an d 70.35 (d, JC,P = 6.3,
CH-iPr); 65.02 (d, JC,P = 164.1, CH2-3′); 54.02 (CH-1′); 23.89, 23.87, 23.78 an d 23.72 (d,
JC,P = 4.0, CH3-iPr).
2-Am in o-9-{1,3-bis[(diisopropoxyph osph oryl)m eth oxy]propan -2-yl}-
1H-purin -6(9H)-on e (17b)
A solution of 15b (620 m g, 1.0 m m ol) in 80% acetic acid (20 m l) was refluxed for 6 h . Th e
solven t an d excess of acetic acid was th en evaporated. Th e residue was co-evaporated with
toluen e an d eth an ol an d purified by colum n ch rom atograph y on silica gel ch loro-
form –m eth an ol gradien t 0–15% to yield th e product as yellowish foam (75%). FAB MS:
582.4 (MH+) (100). 1H NMR (500 MHz, DMSO-d6): 10.56 (bs, 1 H, NH); 7.73 (s, 1 H, H-8);
6.42 (bs, 2 H, NH2); 4.66 (tt, 1 H, J1′,2′ = 7.4, 4.7, H-1′); 4.50 (m , 4 H, JH,P = 7.7, Jvic = 6.2,
CH-iPr); 3.97 (dd, 2 H, Jgem = 10.3, J2′a,1′ = 7.4, H-2′a); 3.82 (dd, 2 H, Jgem = 10.3, J2′b,1′ = 4.7,
H-2′b); 3.78 an d 3.72 (2 × dd, 2 × 2 H, Jgem = 13.9, JH,P = 8.3, H-3′); 1.19, 1.17, 1.15 an d 1.14
(4 × d, 24 H, Jvic = 6.2, CH3-iPr). 13C NMR (100.6 MHz, DMSO-d6): 156.96 (C-6); 153.56
(C-2); 151.45 (C-4); 136.28 (CH-8); 116.54 (C-5); 71.11 (d, JC,P = 12, CH2-2′); 70.44 an d
70.40 (d, JC,P = 6.0, CH-iPr); 65.10 (d, JC,P = 164.0, CH2-3′); 53.07 (CH-1′); 23.93, 23.89,
23.78 an d 23.76 (d, JC,P = 4.0, CH3-iPr).
9-{1,3-Bis[(diisopropoxyph osph oryl)m eth oxy]propan -2-yl}-N-cyclopropyl-
9H-purin -6-am in e (18a)
A solution of 15a (430 m g, 0.7 m m ol) an d cyclopropylam in e (7 equiv.) in dioxan e (15 m l)
was refluxed for 7 h . Th e solven t an d excess of am in e were th en evaporated to dryn ess an d
codistilled with toluen e. Th e residue was purified by colum n ch rom atograph y on silica gel
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Vrbovská, Holý, Pohl, Masojídková:
with ch loroform –m eth an ol gradien t 0–6% to yield yellowish oil (84%). FAB MS: 606.3 (MH+)
(100). 1H NMR (500 MHz, DMSO-d6): 8.21 (s, 1 H, H-2); 8.16 (s, 1 H, H-8); 7.85 (bs, 1 H,
NH); 4.95 (tt, 1 H, J1′,2′ = 7.8 an d 4.5, H-1′); 4.45 (m , 4 H, CH-iPr); 4.09 (dd, 2 H, Jgem = 10.4,
J2′a,1′ = 7.8, H-2′a); 3.90 (dd, 2 H, Jgem = 10.4, J2′b,1′ = 4.6, H-2′b); 3.79 an d 3.72 (2 × dd, 2 ×
2 H, Jgem = 13.9, JH,P = 8.2, H-3′); 3.04 (bm , 1 H, CH-cyclopropyl); 1.16, 1.15, 1.12 an d 1.10
(4 × d, 24 H, Jvic = 6.2, CH3-iPr); 0.71 an d 0.59 (2 × m , 2 × 2 H, CH2-cyclopropyl). 13C NMR
(125.7 MHz, DMSO-d6): 155.75 (C-6); 152.27 (CH-2); 149.61 (C-4); 139.84 (CH-8); 119.26
(C-5); 70.94 (d, JC,P = 12, CH2-2′); 70.37 an d 70.32 (d, JC,P = 6, CH-iPr); 65.01 (d, JC,P = 164,
CH2-3′); 53.61 (CH-1′); 23.88, 23.81, 23.73 an d 23.71 (d, JC,P = 4, CH3-iPr an d CH-cyclo-
propyl); 6.56 (CH2-cyclopropyl).
9-{1,3-Bis[(diisopropoxyph osph oryl)m eth oxy]propan -2-yl}-N6-cyclopropyl-
9H-purin e-2,6-diam in e (18b)
A solution of 15b (490 m g, 0.8 m m ol) an d cyclopropylam in e (7 equiv.) in dioxan e (15 m l)
was refluxed for 7 h an d worked up as described for com poun d 18a. Purification by silica
gel ch rom atograph y yielded yellowish oil (75%). FAB MS: 621.5 (MH+) (100). 1H NMR
(500 MHz, DMSO-d6): 7.73 (s, 1 H, H-8); 7.60 (bs, 1 H, NH); 5.79 (bs, 2 H, NH2); 4.70 (tt,
1 H, J1′,2′ = 7.3 an d 4.6, H-1′); 4.48 (m , 4 H, CH-iPr); 4.00 (dd, 2 H, Jgem = 10.3, J2′a,1′ = 7.3,
H-2′a); 3.84 (dd, 2 H, Jgem = 10.3, J2′b,1′ = 4.6, H-2′b); 3.78 an d 3.72 (2 × dd, 2 × 2 H, Jgem
=
13.9, JH,P = 8.3, H-3′); 3.05 (bm , 1 H, CH-cyclopropyl); 1.18, 1.16, 1.14 an d 1.13 (4 × d,
24 H, Jvic = 6.1, CH3-iPr); 0.65 an d 0.57 (2 × m , 2 × 2 H, CH2-cyclopropyl). 13C NMR (125.7
MHz, DMSO-d6): 160.19 (C-2); 150.07 (C-6); 149.92 (C-4); 136.14 (CH-8); 113.51 (C-5);
71.12 (d, JC,P = 11.7, CH2-2′); 70.42 an d 70.39 (d, JC,P = 6.3, CH-iPr); 65.10 (d, JC,P = 163.6,
CH2-3′); 52.74 (CH-1′); 23.94, 23.92, 23.88 an d 23.80 (d, JC,P = 3.9, CH3-iPr an d CH-cyclo-
propyl); 6.56 (CH2-cyclopropyl).
9-{1,3-Bis[(diisopropoxyph osph oryl)m eth oxy]propan -2-yl}-
1H-purin e-6(9H)-th ion e (19a)
A solution of com poun d 15a (350 m g, 0.6 m m ol) an d th iourea (3 equiv.) in eth an ol (20 m l)
was refluxed for 3 h , cooled an d m ade alkalin e with trieth ylam in e. Th e m ixture was evapo-
rated, refluxed with ch loroform , an d filtered wh ile h ot. Th e filtrate was evaporated an d puri-
fied on of silica gel colum n with ch loroform –m eth an ol gradien t 0–10% to yield th e product
as yellowish foam (52%). FAB MS: 583.0 (MH+) (80). 1H NMR (500 MHz, DMSO-d6): 13.70
(bs, 1 H, NH); 8.33 (s, 1 H, H-2); 8.32 (s, 1 H, H-8); 4.95 (tt, 1 H, J1′,2′ = 7.8 an d 4.3, H-1′);
4.45 (m , 4 H, JH,P = 7.8, Jvic = 6.2, CH-iPr); 4.07 (dd, 2 H, Jgem = 10.5, J2′a,1′ = 7.8, H-2′a); 3.90
(dd, 2 H, Jgem = 10.5, J2′b,1′ = 4.3, H-2′b); 3.79 an d 3.73 (2 × dd, 2 × 2 H, Jgem = 13.9, JH,P
=
8.3, H-3′); 1.19, 1.15, 1.11 an d 1.10 (4 × d, 24 H, Jvic = 6.2, CH3-iPr). 13C NMR (100.6 MHz,
DMSO-d6): 176.12 (C-6); 144.94 (CH-2); 144.49 (C-4); 142.06 (CH-8); 135.11 (C-5); 70.80 (d,
JC,P = 11.7, CH2-2′); 70.36 an d 70.30 (d, JC,P = 6.3, CH-iPr); 65.10 (d, JC,P = 164.1, CH2-3′);
54.21 (CH-1′); 23.89, 23.88, 23.79 an d 23.73 (d, JC,P = 4.0, CH3-iPr).
2-Am in o-9-{1,3-Bis[(diisopropoxyph osph oryl)m eth oxy]propan -2-yl}-
1H-purin e-6(9H)-th ion e (19b)
A solution of com poun d 15b (360 m g, 0.6 m m ol) an d th iourea (3 equiv.) in eth an ol (20 m l)
was refluxed for 3 h an d worked up as described for com poun d 19a. Purification by silica
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Bifunctional Acyclic Nucleoside Phosphonates
559
gel ch rom atograph y yielded yellowish oil (60%). FAB MS: 598.0 (MH+) (100). 1H NMR (500
MHz, DMSO-d6): 11.70 (bs, 1 H, NH); 7.93 (s, 1 H, H-8); 6.80 (bs, 2 H, NH2); 4.67 (tt, 1 H,
J1′,2′ = 7.8 an d 4.3, H-1′); 4.48 (m , 4 H, JH,P = 7.8, Jvic = 6.2, CH-iPr); 3.99 (dd, 2 H, Jgem
=
10.4, J2′a,1′ = 7.8, H-2′a); 3.84 (dd, 2 H, Jgem = 10.4, J2′b,1′ = 4.3, H-2′b); 3.78 an d 3.72 (2 × dd,
2 × 2 H, Jgem = 13.9, JH,P = 8.3, H-3′); 1.18, 1.16, 1.14 an d 1.13 (4 × d, 24 H, Jvic = 6.2,
CH3-iPr). 13C NMR (100.6 MHz, DMSO-d6): 175.07 (C-6); 152.99 (C-2); 148.20 (C-4); 139.33
(CH-8); 128.28 (C-5); 70.89 (d, JC,P = 11.7, CH2-2′); 70.42 an d 70.40 (d, JC,P = 6.3, CH-iPr);
65.10 (d, JC,P = 164.1, CH2-3′); 53.28 (CH-1′); 23.92, 23.91, 23.82 an d 23.76 (d, JC,P = 4.1,
CH3-iPr).
Gen eral Procedure for Preparation of Free Ph osph on ic Acids
Th e startin g [1,3-bis(diisopropoxyph osph oryl)m eth oxy]propan -2-yl derivative (16–19, 25,
26 an d 31, 1 m m ol, co-distilled with aceton itrile), aceton itrile (20 m l) an d BrSiMe3 (3 m l)
were stirred at room tem perature overn igh t. After evaporation an d co-distillation with aceto-
n itrile, th e residue was treated with water an d aqueous am m on ia. Th e m ixture was evapo-
rated to dryn ess, an d th e residue dissolved in water was applied on to a colum n of Dowex
50X8 in H+ form an d wash ed with water. Elution with water an d evaporation in vacuo af-
forded th e product as th e free ph osph on ic acid (20–23, 27, 28 an d 33).
9-[1,3-Bis(phosphonomethoxy)propan-2-yl]-9H-purin-6-amine (20a). Wh ite solid (yield 70%),
m .p. 256–257 °C (dec.). For C10H17N5O8P2·H2O (415.2) calculated: 28.93% C, 4.61% H,
16.87% N, 14.92% P; foun d: 29.14% C, 4.44% H, 16.71% N, 15.01% P. FAB MS: 398.3 (MH+)
(100). 1H NMR (500 MHz, D2O + NaOD, refdioxan e = 3.75): 8.48 (s, 1 H, H-8); 8.23 (s, 1 H,
H-2); 5.04 (tt, 1 H, J1′,2′ = 7.4 an d 4.4, H-1′); 4.13 (dd, 2 H, Jgem = 11.0, J2′a,1′ = 7.4, H-2′a);
4.04 (dd, 2 H, Jgem = 11.0, J2′b,1′ = 4.4, H-2′b); 3.47 an d 3.45 (2 × dd, 2 × 2 H, Jgem = 12.6,
JH,P = 8.5, H-3′). 13C NMR (125.7 MHz, D2O + NaOD, refdioxan e = 69.3): 158.31 (C-6); 155.17
(CH-2); 152.00 (C-4); 144.86 (CH-8); 121.12 (C-5); 73.73 (d, JC,P = 10, CH2-2′); 72.12 (d,
JC,P = 150, CH2-3′); 57.48 (CH-1′). UV: (0.01 M HCl) λm ax = 259 (εm ax = 14302); (H2O) λm ax
260 (εm ax = 13756); (0.01 M NaOH) λm ax = 261 (εm ax = 13837).
=
9-[1,3-Bis(phosphonomethoxy)propan-2-yl]-9H-purine-2,6-diamine (20b ). Wh ite solid (yield
65%), m .p. 237–238 °C (dec.). For C10H18N6O8P2·1/2H2O (421.2) calculated: 28.51% C,
4.55% H, 19.95% N, 14.71% P; foun d: 28.55% C, 4.58% H, 19.70% N, 14.81% P. FAB MS:
413.1 (MH+) (90). 1H NMR (40 MHz, D2O, refdioxan e = 3.75): 8.17 (s, 1 H, H-8); 4.84 (tt, 1 H,
J1′,2′ = 7.2 an d 4.6, H-1′); 4.04 (dd, 2 H, Jgem = 11.0, J2′a,1′ = 7.2, H-2′a); 3.98 (dd, 2 H, Jgem
=
11.0, J2′b,1′ = 4.6, H-2′b); 3.49 an d 3.44 (2 × dd, 2 × 2 H, Jgem = 13.7, JH,P = 8.6, H-3′).
13C NMR (125.7 MHz, D2O, refdioxan e = 69.3): 156.28 (C-2); 155.17 (C-6); 151.55 (C-4);
139.52 (CH-8); 112.93 (C-5); 71.22 (d, JC,P = 10.8, CH2-2′); 69.56 (d, JC,P = 149.9, CH2-3′);
54.03 (CH-1′). UV: (0.01 M HCl) λm ax = 288 (εm ax = 9070); (H2O) λm ax = 282 (εm ax = 8807);
(0.01 M NaOH) λm ax = 281 (εm ax = 10059).
9-[1,3-Bis(phosphonomethoxy)propan-2-yl]-1H-purin-6(9H)-one (21a). Wh ite solid (72%), m .p.
107–109 °C (dec.). For C10H16N4O9P2·3/2H2O (425.2) calculated: 28.25% C, 4.50% H,
13.18% N, 14.57% P; foun d: 28.46% C, 4.45% H, 13.23% N, 14.71% P. FAB MS: 399.2 (MH+)
(10). 1H NMR (500 MHz, D2O, refdioxan e = 3.75): 8.32 (s, 1 H, H-8); 8.14 (s, 1 H, H-2); 4.99
(tt, 1 H, J1′,2′ = 7.3 an d 4.6, H-1′); 4.09 (dd, 2 H, Jgem = 11.0, J2′a,1′ = 7.3, H-2′a); 4.02 (dd,
2 H, Jgem = 11.0, J2′b,1′ = 4.6, H-2′b); 3.46 an d 3.43 (2 × dd, 2 × 2 H, Jgem = 12.7, JH,P = 8.6,
H-3′). 13C NMR (125.7 MHz, D2O, refdioxan e = 69.3): 165.59 (C-6); 151.68 (C-4); 149.84
(CH-2); 140.46 (CH-8); 123.08 (C-5); 71.15 (d, JC,P = 10.3, CH2-2′); 69.45 (d, JC,P = 149.9,
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560
Vrbovská, Holý, Pohl, Masojídková:
CH2-3′); 54.70 (CH-1′). UV: (0.01 M HCl) λm ax = 250 (εm ax = 9797); (H2O) λm ax = 249 (εm ax
9555); (0.01 M NaOH) λm ax = 254 (εm ax = 10080).
=
2-Amino-9-[1,3-bis(phosphonomethoxy)propan-2-yl]-1H-purin-6(9H)-one (21b ). Wh ite solid
(yield 74%), m .p. 220–221 °C (dec.). For C10H17N5O9P2·1/2H2O (422.2) calculated: 28.45% C,
4.30% H, 16.59% N, 14.67% P; foun d: 28.73% C, 4.55% H, 16.68% N, 14.79% P. FAB MS:
414.1 (MH+) (90). 1H NMR (500 MHz, D2O, refdioxan e = 3.75): 8.98 (s, 1 H, H-8); 5.14 (tt,
1 H, J1′,2′ = 6.5 an d 4.0, H-1′); 4.21 (dd, 2 H, Jgem = 11.0, J2′a,1′ = 6.5, H-2′a); 4.08 (dd, 2 H,
Jgem = 11.0, J2′b,1′ = 4.0, H-2′b); 3.47 an d 3.45 (2 × dd, 2 × 2 H, Jgem = 13.4, JH,P = 8.8, H-3′).
13C NMR (125.7 MHz, D2O, refdioxan e = 69.3): 155.17 (C-6); 155.28 (C-2); 150.25 (C-4);
137.34 (CH-8); 107.44 (C-5); 70.16 (d, JC,P = 12.2, CH2-2′); 66.76 (d, JC,P = 157.7, CH2-3′);
55.31 (CH-1′). UV: (0.01 M HCl) λm ax = 255 (εm ax = 11352); (H2O) λm ax = 251 (εm ax = 11635);
(0.01 M NaOH) λm ax = 267 (εm ax = 10464).
9-[1,3-Bis(phosphonomethoxy)propan-2-yl]-N-cyclopropyl-9H-purin-6-amine (22a). Yellowish
h ygroscopic solid (yield 69%), m .p. 142–144 °C (dec.). For C13H21N5O8P2·H2O (455.3) calcu-
lated: 34.29% C, 5.09% H, 15.38% N, 13.61% P; foun d: 34.52% C, 5.25% H, 15.29% N,
13.72% P. FAB MS: 438.0 (MH+) (80). 1H NMR (500 MHz, D2O, refdioxan e = 3.75): 8.55 an d
8.46 (2 × s, 2 × 1 H, H-2 an d H-8); 5.16 (tt, 1 H, J1′,2′ = 7.3 an d 4.3, H-1′); 4.18 (dd, 2 H,
Jgem = 11.0, J2′a,1′ = 7.3, H-2′a); 4.06 (dd, 2 H, Jgem = 11.0, J2′b,1′ = 4.3, H-2′b); 3.70 an d 3.65
(2 × dd, 2 × 2 H, Jgem = 13.4, JH,P = 8.7, H-3′); 2.89 (bm , 1 H, CH-cyclopropyl); 1.09 an d 0.88
(2 × m , 2 × 2 H, CH2-cyclopropyl). 13C NMR (125.7 MHz, D2O, refdioxan e = 69.3): 152.66
(C-6); 150.49 (C-4); 146.66 (CH-2 an d CH-8); 120.95 (C-5); 73.55 (d, JC,P = 12, CH2-2′); 69.50
(d, JC,P = 158, CH2-3′); 57.69 (CH-1′); 25.45 (CH-cyclopropyl); 9.35 (CH2-cyclopropyl). UV:
(0.01 M HCl) λm ax = 268 (εm ax = 17655); (H2O) λm ax = 269 (εm ax = 16 968); (0.01 M NaOH)
λm ax = 271 (εm ax = 18301).
9-[1,3-Bis(phosphonomethoxy)propan-2-yl]-N6-cyclopropyl-9H-purine-2,6-diamine (22b). Wh ite
solid (60%), m .p. 164–166 °C (dec.). For C13H22N6O8P2·H2O (470.3) calculated: 33.20% C,
5.14% H, 17.87% N, 13.17% P; foun d: 33.18% C, 5.24% H, 17.57% N, 13.32% P. FAB MS:
453.3 (MH+) (100). 1H NMR (500 MHz, D2O, refdioxan e = 3.75): 8.21 (s, 1 H, H-8); 4.92 (tt,
1 H, J1′,2′ = 7.3 an d 4.1, H-1′); 4.10 (dd, 2 H, Jgem = 11.0, J2′a,1′ = 7.3, H-2′a); 4.00 (dd, 2 H,
Jgem = 11.0, J2′b,1′ = 4.1, H-2′b); 3.71 an d 3.65 (2 × dd, 2 × 2 H, Jgem = 13.3, JH,P = 8.7, H-3′);
2.82 (bm , 1 H, CH-cyclopropyl); 1.03 an d 0.83 (2 × m , 2 × 2 H, CH2-cyclopropyl). 13C NMR
(125.7 MHz, D2O, refdioxan e = 69.3): 157.40 (C-2); 152.59 (C-6); 150.52 (C-4); 140.95 (CH-8);
114.35 (C-5); 70.77 (d, JC,P = 12.2, CH2-2′); 66.88 (d, JC,P = 157.2, CH2-3′); 54.50 (CH-1′);
22.71 (CH-cyclopropyl); 6.75 (CH2-cyclopropyl). UV: (0.01
M HCl) λm ax = 294 (εm ax =
12 584.6); (H2O) λm ax = 291 (εm ax = 12 059.4); (0.01 M NaOH) λm ax = 284 (εm ax = 14 119.8).
9-[1,3-Bis(phosphonomethoxy)-2-propyl]-1H-purine-6(9H)-thione (23a). Yellow solid (84%),
m .p. 109–110 °C (dec.). For C10H16N4O8P2S·3/2H2O (441.3) calculated: 27.22% C, 4.34% H,
12.70% N, 14.04% P, 7.27% S; foun d: 27.44% C, 4.18% H, 12.41% N, 14.15% P, 7.42% S.
FAB MS: 415.0 (MH+) (10). 1H NMR (500 MHz, D2O, refdioxan e = 3.75): 8.46 (s, 1 H, H-8);
8.30 (s, 1 H, H-2); 5.02 (tt, 1 H, J1′,2′ = 7.2 an d 4.5, H-1′); 4.10 (dd, 2 H, Jgem = 11.0, J2′a,1′
=
7.2, H-2′a); 4.03 (dd, 2 H, Jgem = 11.0, J2′b,1′ = 4.5, H-2′b); 3.47 an d 3.43 (2 × dd, 2 × 2 H,
Jgem = 12.8, JH, = 8.5, H-3′). 13C NMR (125.7 MHz, D2O, refdioxan e = 69.3): 177.16 (C-6);
P
150.77 (CH-2); 146.17 (C-4); 142.37 (CH-8); 135.26 (C-5); 71.03 (d, JC,P = 10.2, CH2-2′);
69.45 (d, JC,P = 149.9, CH2-3′); 54.58 (CH-1′). UV: (0.01 M HCl) λm ax = 323 (εm ax = 18927);
(H2O) λm ax = 322 (εm ax = 20321); (0.01 M NaOH) λm ax = 310 (εm ax = 18099).
2-Amino-9-[1,3-bis(phosphonomethoxy)propan-2-yl]-1H-purine-6(9H)-thione (23b). Yellowish
solid (91%), m .p. 183–184 °C (dec.). For C10H17N5O8P2S·3/2H2O (456.3) calculated: 26.32% C,
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Bifunctional Acyclic Nucleoside Phosphonates
561
4.42% H, 15.35% N, 13.58% P, 7.03% S; foun d: 26.08% C, 4.35% H, 15.19% N, 13.62% P,
7.23% S. FAB MS: 430.0 (MH+) (40). 1H NMR (500 MHz, D2O, refdioxan e = 3.75): 9.15 (s, 1 H,
H-8); 5.09 (tt, 1 H, J1′,2′ = 6.5 an d 4.0, H-1′); 4.16 (dd, 2 H, Jgem = 11.0, J2′a,1′ = 6.7, H-2′a);
4.03 (dd, 2 H, Jgem = 11.0, J2′b,1′ = 4.0, H-2′b); 3.72 an d 3.685 (2 × dd, 2 × 2 H, Jgem = 13.3,
JH,P = 8.8, H-3′). 13C NMR (125.7 MHz, D2O, refdioxan e = 69.3): 174.72 (C-6); 154.69 (C-2);
146.31 (C-4); 139.96 (CH-8); 119.97 (C-5); 70.16 (d, JC,P = 12.2, CH2-2′); 67.00 (d, JC,P
=
157.2, CH2-3′); 55.28 (CH-1′). UV: (0.01 M HCl) λm ax = 345 (εm ax = 19008); (H2O) λm ax = 341
(εm ax = 22280.6); (0.01 M NaOH) λm ax = 319 (εm ax = 17654.8).
2-{[1,3-Bis(phosphonomethoxy)propan-2-yl]oxy}pyrimidin-4-amine (27a). Wh ite h ygroscopic
solid (80%), m .p. 118–119 °C (dec.). For C9H17N3O9P2·H2O (391.2) calculated: 27.63% C,
4.90% H, 10.74% N, 15.83% P; foun d: 27.50% C, 5.10% H, 10.54% N, 15.95% P. FAB MS:
374.1 (MH+) (30). 1H NMR (500 MHz, D2O, refdioxan e = 3.75): 7.83 (d, 1 H, JH6,H5 = 7.2, H-6);
6.43 (d, 1 H, JH5,H6 = 7.2, H-5); 5.68 (tt, 1 H, J1′,2′ = 6.0 an d 4.0, H-1′); 3.96 (dd, 2 H, Jgem
=
11.8, J2′a,1′ = 6.0, H-2′a); 3.93 (dd, 2 H, Jgem = 11.8, J2′b,1′ = 4.0, H-2′b); 3.83 an d 3.74 (2 × dd,
2 × 2 H, Jgem = 13.6, JH,P = 8.6, H-3′). 13C NMR (125.7 MHz, D2O, refdioxan e = 69.3): 166.45
(C-2); 157.68 (C-4); 142.93 (C-6); 100.07 (C-5); 76.33 (CH-1′); 70.66 (d, JC,P = 11.2, CH2-2′);
66.70 (d, JC,P = 157.7, CH2-3′). UV: (0.01 M HCl) λm ax = 259 (εm ax = 8282); (H2O) λm ax = 260
(εm ax = 8181); (0.01 M NaOH) λm ax = 271 (εm ax = 6969).
4-Amino-1-[1,3-bis(phosphonomethoxy)propan-2-yl] pyrimidin-2(1H)-one (27b ). Wh ite solid
(70%), m .p. 130–131 °C (dec.). For C9H17N3O9P2·H2O (391.2) calculated: 27.63% C, 4.90% H,
10.74% N, 15.84% P; foun d: 27.80% C, 5.12% H, 10.60% N, 15.92% P. FAB MS: 374.1 (MH+)
(30). 1H NMR (500 MHz, D2O, refdioxan e = 3.75): 8.08 (d, 1 H, JH6,H5 = 7.8, H-6); 6.20 (d, 1 H,
JH5,H6 = 7.2, H-5); 5.02 (tt, 1 H, J1′,2′ = 7.2 an d 4.2, H-1′); 3.99 (dd, 2 H, Jgem = 11.2, J2′a,1′
=
7.2, H-2′a); 3.52 (dd, 2 H, Jgem = 11.2, J2′b,1′ = 4.2, H-2′b); 3.68 an d 3.64 (2 × dd, 2 × 2 H,
Jgem = 13.4, JH,P = 8.8, H-3′). 13C NMR (125.7 MHz, D2O, refdioxan e = 69.3): 158.94 (C-4);
149.41 (C-2); 147.53 (C-6); 94.61 (C-5); 69.83 (d, JC,P = 12.2, CH2-2′); 66.82 (d, JC,P = 157.7,
CH2-3′); 52.96 (CH-1′). UV: (0.01 M HCl) λm ax = 282 (εm ax = 15473); (H2O) λm ax = 280 (εm ax
= 10484); (0.01 M NaOH) λm ax = 274 (εm ax = 8201).
2-{[1,3-Bis(phosphonomethoxy)propan-2-yl]oxy}-5-methylpyrimidin-4-amine (28a). Wh ite h y-
groscopic solid (75%), m .p. 154–155 °C (dec.). For C10H19N3O9P2·H2O (405.2) calculated:
29.64% C, 5.22% H, 10.37% N, 15.29% P; foun d: 29.42% C, 5.32% H, 10.46% N, 15.17% P.
FAB MS: 388.2 (MH+) (100). 1H NMR (500 MHz, D2O, refdioxan e = 3.75): 7.77 (q, JH6,CH3
=
1.0, 1 H, H-6); 6.34 (tt, 1 H, J1′,2′ = 6.2 an d 4.9, H-1′); 3.86 (dd, 2 H, Jgem = 10.5, J2′a,1′ = 6.2,
H-2′a); 3.83 (dd, 2 H, Jgem = 10.5, J2′b,1′ = 4.9, H-2′b); 3.53 an d 3.49 (2 × dd, 2 × 2 H, Jgem
=
12.8, JH,P = 8.4, H-3′); 2.10 (d, JCH3,H6 = 1.0, 3 H, CH3). 13C NMR (125.7 MHz, D2O,
refdioxan e = 69.3): 164.99 (C-2); 164.68 (C-4); 154.55 (C-6); 108.92 (C-5); 74.29 (CH-1′); 71.61
(d, JC,P = 11.2, CH2-2′); 69.70 (d, JC,P = 150.4, CH2-3′); 12.14 (CH3). UV: (0.01 M HCl) λm ax
=
264 (εm ax = 7918); (H2O) λm ax = 264 (εm ax = 8100); (0.01 M NaOH) λm ax = 275 (εm ax = 7009).
4-Amino-1-[1,3-bis(phosphonomethoxy)propan-2-yl]-5-methylpyrimidin-2(1H)-one (28b). Wh ite
solid (80%), m .p. 124–126 °C (dec.). For C10H19N3O9P2·H2O (405.2) calculated: 29.64% C,
5.22% H, 10.37% N, 15.29% P; foun d: 29.38% C, 5.30% H, 10.54% N, 15.27% P. FAB MS:
388.3 (MH+) (100). 1H NMR (500 MHz, D2O, refdioxan e = 3.75): 7.70 (q, JH6,CH3 = 1.0, 1 H,
H-6); 5.06 (tt, 1 H, J1′,2′ = 7.3 an d 4.3 H-1′); 3.87 (dd, 2 H, Jgem = 11.2, J2′a,1′ = 7.3, H-2′a);
3.52 (dd, 2 H, Jgem = 11.2, J2′b,1′ = 4.3, H-2′b); 3.50 an d 3.49 (2 × dd, 2 × 2 H, Jgem = 12.8,
JH,P = 8.4, H-3′); 1.99 (d, JCH3,H6 = 1.0, 3 H, CH3). 13C NMR (125.7 MHz, D2O, refdioxan e
=
69.3): 160.29 (C-4); 156.50 (C-2); 138.93 (C-6); 104.53 (C-5); 71.25 (d, JC,P = 10.2, CH2-2′);
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562
Vrbovská, Holý, Pohl, Masojídková:
69.49 (d, JC,P = 148.9, CH2-3′); 53.96 (CH-1′); 12.14 (CH3). UV: (0.01 M HCl) λm ax = 289
(εm ax = 14241); (H2O) λm ax = 288 (εm ax = 9837); (0.01 M NaOH) λm ax = 280 (εm ax = 7898).
1-[1,3-Bis(phosphonomethoxy)propan-2-yl]pyrimidine-2,4(1H,3H)-dione (33a). Wh ite solid
(80%), m .p. 105–106 °C (dec.). For C9H16N2O10P2·H2O (392.2) calculated: 27.56% C, 4.63% H,
7.14% N, 15.80% P; foun d: 27.30% C, 4.58% H, 6.98% N, 15.53% P. FAB MS: 375.0 (MH+)
(10). 1H NMR (500 MHz, D2O + NaOD, refdioxan e = 3.75): 7.55 (d, 1 H, JH6,H5 = 7.5, H-6);
5.82 (d, 1 H, JH5,H6 = 7.5, H-5); 5.03 (tt, 1 H, J1′,2′ = 7.3 an d 5.1, H-1′); 3.87 (dd, 2 H, Jgem
=
11.0, J2′a,1′ = 7.3, H-2′a); 3.84 (dd, 2 H, Jgem = 11.0, J2′b,1′ = 5.1, H-2′b); 3.47 an d 3.44 (2 × dd,
2 × 2 H, Jgem = 12.7, JH,P = 8.5, H-3′). 13C NMR (125.7 MHz, D2O + NaOD, refdioxan e = 69.3):
162.64 (C-4); 155.60 (C-2); 144.96 (C-6); 104.38 (C-5); 73.07 (d, JC,P = 10.7, CH2-2′); 71.45
(d, JC,P = 149.9, CH2-3′); 56.93 (CH-1′). UV: (0.01 M HCl) λm ax = 266 (εm ax = 8484); (H2O)
λm ax = 264 (εm ax = 8161); (0.01 M NaOH) λm ax = 265 (εm ax = 8444).
1-[1,3-Bis(phosphonomethoxy)propan-2-yl]-5-methylpyrimidine-2,4(1H,3H)-dione (33b). Yellow-
ish solid (80%), m .p. 96–97 °C (dec.). For C10H18N2O10P2·H2O (406.2) calculated: 29.57% C,
4.96% H, 6.90% N, 15.25% P; foun d: 29.30% C, 4.72% H, 6.85% N, 15.59% P. FAB MS:
389.0 (MH+) (10). 1H NMR (500 MHz, D2O + NaOD, refdioxan e = 3.75): 7.77 (q, 1 H, JH6,CH3
=
1.0, H-6); 5.14 (tt, 1 H, J1′,2′ = 7.3 an d 5.1, H-1′); 3.96 (dd, 2 H, Jgem = 11.0, J2′a,1′ = 7.3,
H-2′a); 3.84 (dd, 2 H, Jgem = 11.0, J2′b,1′ = 5.1, H-2′b); 3.47 an d 3.44 (2 × dd, 2 × 2 H, Jgem
=
12.7, JH,P = 8.6, H-3′); 1.19 (d, 3 H, JCH3,H6 = 6.1, CH3). 13C NMR (125.7 MHz, D2O + NaOD,
refdioxan e = 69.3): 156.80 (C-4); 154.90 (C-2); 139.46 (C-6); 111.34 (C-5); 70.57 (d, JC,P = 11.2,
CH2-2′); 69.34 (d, JC,P = 149.9, CH2-3′); 54.90 (CH-1′); 12.08 (CH3). UV: (0.01 M HCl) λm ax
=
270 (εm ax = 8444); (H2O) λm ax = 271 (εm ax = 8150); (0.01 M NaOH) λm ax = 271 (εm ax = 8320).
Gen eral Procedure for Alkylation of Th ym in e with Prim ary an d Secon dary
Alkyl Tosylates (34–39)
A solution of th ym in e (0.5 g) in dry DMF (20 m l) was treated with Cs2CO3 (0.5 equiv.) at
room tem perature un der a CaCl2 protectin g tube for 1 h . Th e reaction m ixture was th en
h eated at 60 °C an d syn th on (34–39, 1.0 equiv.) was added. Th e m ixture was th en stirred at
90 °C for 24 h . Solven t was taken down an d th e residue was co-evaporated with toluen e.
Th e residue in ch loroform was filtered th rough a Celite pad, evaporated an d purified on a
preparative th in layer ch rom atograph y (silica gel).
5-Methyl-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]pyrimidine-2,4(1H,3H)-dione (34a). Pre-
parative TLC (ch loroform –8% m eth an ol) afforded th e product as wh ite solid (39%). FAB MS:
241.09 (MH+) (65). 1H NMR (500 MHz, DMSO-d6): 11.30 (bs, 1 H, NH); 7.45 (q, 1 H, JH6,CH3
=
1.0, H-6); 4.28 (m , 1 H, H-2′); 3.99 (dd, 1 H, J3a′,2′ = 8.7 an d 6.6, H-3a′); 3.79 (dd, 1 H,
J1a′,2′ = 14.0 an d 4.3, H-1a′); 3.72 (dd, 1 H, J1b′,2′ = 14.0 an d 6.6, H-1b′); 3.66 (dd, 1 H, J3b′,2′
=
8.7 an d 5.6, H-3b′); 2.01 (d, 3 H, JCH3,H6 = 1.0, CH3); 1.32 an d 1.24 (2 × s, 3 H, CH3).
13C NMR (100.6 MHz, DMSO-d6): 164.44 (C-4); 151.36 (C-2); 142.42 (C-6); 109.00 (CH-iPr);
108.27 (C-5); 73.57 (C-2′); 66.13 (C-3′); 49.54 (C-1′); 26.68 an d 25.35 (CH3-iPr); 12.11 (CH3).
5-Methyl-1,3-bis[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]pyrimidine-2,4(1H,3H)-dione (34b ).
Preparative TLC (h exan e–eth yl acetate 1:1) afforded th e product as yellowish oil (10%).
FAB MS: 355.12 (MH+) (45). 1H NMR (500 MHz, DMSO-d6): 8.13 (q, 1 H, JH6,CH3 = 1.0, H-6);
4.40 (m , 1 H, H-2′); 4.29 (dd, 1 H, J1a′,2′ = 11.2 an d 1.6, H-1a′); 4.22 (dd, 1 H, J1b′,2′ = 11.2
an d 2.3, H-1′b); 4.07 an d 4.06 (dd, 1 H, J3a′,2′ = 8.4 an d 6.6, H-3a′); 3.79 an d 3.73 (dd, 1 H,
J3b′,2′ = 8.4 an d 6.2, H-3b′); 2.01 (d, 3 H, JCH3,H6 = 1.0, CH3); 1.34, 1.29 an d 1.28 (s, 12 H,
CH3). 13C NMR (100.6 MHz, DMSO-d6): 168.65 (C-4); 162.93 (C-2); 157.78 (C-6); 110.93
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(C-5); 109.03 an d 108.96 (CH-iPr); 73.47 (2 C, C-2′); 67.65 an d 66.61 (C-3′); 65.94 an d 65.61
(C-1′); 26.82, 26.68, 25.55 an d 11.58 (CH3).
2-[(2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy]-5-methylpyrimidin-4(3H)-one (34c). Preparative
TLC (ch loroform –10% m eth an ol) afforded th e product as yellowish oil (1%). FAB MS: 241.11
(MH+) (45). 1H NMR (500 MHz, DMSO-d6): 7.65 (q, 1 H, JH6,CH3 = 1.0, H-6); 4.28 (m , 1 H,
H-2′); 3.86 (dd, 1 H, J3a′,2′ = 8.7 an d 6.6, H-3a′); 4.25 (dd, 1 H, J1a′,2′ = 14.0 an d 4.3, H-1a′);
3.72 (dd, 1 H, J1b′,2′ = 14.0 an d 6.6, H-1b′); 3.66 (dd, 1 H, J3b′,2′ = 8.7 an d 5.6, H-3b′); 1.95 (d,
3 H, JCH3,H6 = 1.0, CH3); 1.32 an d 1.24 (2 × s, 3 H, CH3). 13C NMR (100.6 MHz, DMSO-d6):
164.44 (C-4); 151.36 (C-2); 142.42 (C-6); 109.00 (CH-iPr); 108.27 (C-5); 73.57 (C-2′); 70.21
(C-1′); 66.13 (C-3′); 26.68 an d 25.35 (CH3-iPr); 12.11 (CH3).
1-[(Tetrahydro-4-methoxy-2,2-dimethylfuro[3,4-d][1,3]dioxol-6-yl)methyl]-5-methylpyrimidine-
2,4(1H,3H)-dione (35a). Preparative TLC (ch loroform –8% m eth an ol) afforded th e product as
wh ite solid (31%). FAB MS: 313.35 (MH+) (65). 1H NMR (500 MHz, DMSO-d6): 11.34 (bs,
1 H, NH); 7.51 (q, 1 H, JH6,CH3 = 1.0, H-6); 4.95 (s, 1 H, H-1′); 4.72 (bd, 1 H, J3′,4′ = 1.0 an d
J3′,2′ = 6.0, H-3′); 4.62 (d, 1 H, J2′,3′ = 6.0, H-2′); 4.32 (bt, 1 H, J4′,3′ = 1.0 an d J4′,5′ = 7.3, H-4′);
3.87 (dd, 1 H, J5a′,4′ = 13.9 an d 7.6, H-5a′); 3.55 (dd, 1 H, J5b′,4′ = 13.9 an d 7.2, H-5b′); 3.28
(s, 3 H, OCH3); 1.75 (d, 3 H, JCH3,H6 = 1.2, CH3); 1.36 an d 1.24 (2 × s, 3 H, CH3). 13C NMR
(100.6 MHz, DMSO-d6): 164.35 (C-4); 151.21 (C-2); 141.93 (C-6); 111.89 (CH-iPr); 109.35
(C-1′); 108.79 (C-5); 84.76 (C-4′); 83.69 (C-2′); 81.31 (C-3′); 55.09 (OCH3); 50.25 (C-5′);
26.44 an d 24.91 (iPr); 12.11 (CH3).
1,3-Bis[(tetra hydro-4-methoxy-2,2-dimethylfuro[3,4-d][1,3]dioxol-6-yl)methyl]-5-methyl-
pyrimidine-2,4(1H,3H)-dione (35b). Preparative TLC (h exan e–eth yl acetate 1:1) afforded th e
product as colorless oil (10%). FAB MS: 499.32 (MH+) (65). 1H NMR (500 MHz, DMSO-d6):
7.62 (q, 1 H, JH6,CH3 = 1.0, H-6); 4.95 an d 4.94 (2 × s, 1 H, H-1′); 4.74 an d 4.68 (2 × bd, 1 H,
J3′,4′ = 1.0, H-3′); 4.63 an d 4.60 (2 × d, 1 H, J2′,3′ = 6.0, H-2′); 4.37 an d 4.23 (2 × dd, 1 H, J4′,5′
=
7.3, 4.8 an d 9.6, H-4′); 4.07 an d 3.96 (2 × dd, 1 H, J5a′,4′ = 9.6 an d 7.6, H-5a′); 3.65 an d 3.48
(2 × dd, 1 H, J5b′,4′ = 7.2 an d 4.8, Jgem = 13.9 an d 13.0, H-5b′); 3.28 an d 3.27 (2 × s, 3 H,
OCH3); 1.75 (d, 3 H, JCH3,H6 = 1.2, CH3); 1.36, 1.33, 1.24, an d 1.20 (4 × s, 6 H, CH3).
13C NMR (100.6 MHz, DMSO-d6): 163.30 (C-4); 151.44 (C-2); 140.95 (C-6); 111.85 an d
111.69 (CH-iPr); 109.49 (C-5); 108.06 an d 108.85 (C-1′); 84.88 an d 84.75 (C-4′); 83.52 an d
83.51 (C-2′); 81.84 an d 81.34 (C-3′); 55.16 an d 54.71 (OCH3); 51.39 an d 43.41 (C-5′); 26.47,
26.43, 24.92 an d 24.91 (iPr); 12.72 (CH3).
2-[(Tetrahydro-4-methoxy-2,2-dimethylfuro[3,4-d][1,3]dioxol-6-yl)methoxy]-5-methylpyrimidin-
4(3H)-one (35c). Preparative TLC (ch loroform –8% m eth an ol) afforded th e product as color-
less oil (1%). FAB MS: 313.21 (MH+) (35). 1H NMR (500 MHz, DMSO-d6): 7.51 (q, 1 H,
JH6,CH3 = 1.0, H-6); 4.98 (s, 1 H, H-1′); 4.74 (bd, 1 H, J3′,4′ = 1.0 an d J3′,2′ = 6.0, H-3′); 4.62 (d,
1 H, J2′,3′ = 6.0, H-2′); 4.35 (bt, 1 H, J4′,3′ = 1.0 an d J4′,5′ = 7.3, H-4′); 3.85 (dd, 1 H, J5a′,4′
=
13.9 an d 7.6, H-5a′); 3.65 (dd, 1 H, J5b′,4′ = 13.9 an d 7.2, H-5b′); 3.25 (s, 3 H, OCH3); 1.75 (d,
3 H, JCH3,H6 = 1.2, CH3); 1.36 an d 1.24 (2 × s, 3 H, CH3). 13C NMR (100.6 MHz, DMSO-d6):
164.35 (C-4); 151.21 (C-2); 141.93 (C-6); 111.89 (CH-iPr); 109.35 (C-1′); 108.79 (C-5); 84.76
(C-4′); 83.69 (C-2′); 81.31 (C-3′); 71.13 (C-5′); 55.09 (OCH3); 26.44 an d 24.91 (iPr); 12.11
(CH3).
1-({Bis[(diisopropoxy)phosphoryl]methoxy}ethyl)-5-methylpyrimidine-2,4(1H,3H)-dione (36a).
Preparative TLC (ch loroform –10% m eth an ol) afforded th e product as wh ite solid (32%). FAB
MS: 349.25 (MH+) (65). 1H NMR (500 MHz, DMSO-d6): 11.25 (bs, 1 H, NH); 7.43 (q, 1 H,
JH6,CH3 = 1.0, H-6); 4.55 (m , 2 H, CH-iPr); 3.81 (t, 2 H, H-1′); 3.76 (d, 2 H, J = 8.4, H-3′); 3.68
(t, 2 H, J = 5.0, H-2′); 1.75 (d, 3 H, JCH3,H6 = 1.2, CH3); 1.21 an d 1.19 (2 × d, 6 H, J = 6.2,
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CH3). 13C NMR (100.6 MHz, DMSO-d6): 164.49 (C-4); 151.05 (C-2); 142.25 (C-6); 108.04
(C-5); 70.34 (2 C, J = 6.4, CH-iPr); 70.14 (d, J = 11.7, C-2′); 64.84 (d, J = 164.1, C-3′); 46.97
(C-1′); 23.97, 26.43, 23.83 an d 23.25 (iPr); 12.15 (CH3).
1,3-Bis({bis[(diisopropoxy)phosphoryl]methoxy}ethyl)-5-methylpyrimidine-2,4(1H,3H)-dione
(36b). Preparative TLC (ch loroform –10% m eth an ol) afforded th e product as colorless oil
(10%). FAB MS: 571.23 (MH+) (45). 1H NMR (500 MHz, DMSO-d6): 7.51 (q, 1 H, JH6,CH3
=
1.0, H-6); 4.55 (m , 2 H, CH-iPr); 4.07 an d 3.81 (2 × t, 2 H, J = 6.0 an d 5.0, H-1′); 3.76 an d
3.74 (2 × d, 2 H, J = 8.4, H-3′); 3.72 an d 3.68 (2 × t, 2 H, J = 6.0 an d 5.0, H-2′); 1.75 (d, 3 H,
JCH3,H6 = 1.2, CH3); 1.22, 1.21, 1.20 an d 1.19 (4 × d, 6 H, J = 6.1, CH3). 13C NMR (100.6
MHz, DMSO-d6): 163.26 (C-4); 150.99 (C-2); 141.02 (C-6); 107.24 (C-5); 70.34 (4 C, CH-iPr,
J = 6.3); 70.00 an d 68.97 (d, J = 12.2, C-2′); 64.83 an d 64.68 (d, J = 164.6, C-3′); 48.11 an d
39.46 (C-1′); 23.97, 23.94, 23.83 an d 23.80 (iPr); 12.75 (CH3).
2-({Bis[(diisopropoxy)phosphoryl]methoxy}ethoxy)-5-methylpyrimidin-4(3H)-one (36c). Prepara-
tive TLC (ch loroform –10% m eth an ol) afforded th e product as yellowish oil (1%). FAB MS:
349.12 (MH+) (25). 1H NMR (500 MHz, DMSO-d6): 7.43 (q, 1 H, JH6,CH3 = 1.0, H-6); 4.55 (m ,
2 H, CH-iPr); 3.79 (t, 2 H, H-1′); 3.75 (d, 2 H, J = 8.4, H-3′); 3.66 (t, 2 H, J = 5.0, H-2′); 1.75
(d, 3 H, JCH3,H6 = 1.2, CH3); 1.21 an d 1.19 (2 × d, 6 H, J = 6.2, CH3). 13C NMR (100.6 MHz,
DMSO-d6): 164.49 (C-4); 151.05 (C-2); 142.25 (C-6); 108.04 (C-5); 70.34 (2 C, J = 6.4,
CH-iPr); 70.14 (d, J = 11.7, C-2′); 65.13 (C-1′); 64.84 (d, J = 164.1, C-3′); 23.97, 26.43, 23.83,
23.54 (iPr); 12.15 (CH3).
1-[1-(Benzyloxy)propan-2-yl]-5-methylpyrimidine-2,4(1H,3H)-dione (37a). Preparative TLC
(ch loroform –5% m eth an ol) afforded th e product as wh ite solid (25%). FAB MS: 275.21
(MH+) (65). 1H NMR (500 MHz, DMSO-d6): 11.20 (bs, 1 H, NH); 7.54 (q, 1 H, JH6,CH3 = 1.0,
H-6); 7.30–7.24 (m , 5 H, arom .); 4.75 (m , 1 H, H-1′); 4.50 an d 4.42 (2 × d, 2 H, J = 12.2,
Bn OCH2); 3.62 an d 3.51 (2 × dd, 2 H, J = 10.5 an d 8.2, 10.5 an d 4.6, OCH2); 1.75 (d, 3 H,
JCH3,H6 = 1.2, CH3); 1.21 (d, 3 H, J = 7.1, CH3). 13C NMR (100.6 MHz, DMSO-d6): 163.95
(C-4); 151.29 (C-2); 138.30 (C); 138.12 (C-6); 128.45 (2 C); 127.69 (C); 127.58 (2 C); 108.83
(C-5); 71.98 an d 71.94 (OCH2); 49.89 (C-1′); 15.66 (CH3); 12.27 (CH3).
1,3-Bis[1-(benzyloxy)propan-2-yl]-5-methylpyrimidine-2,4(1H,3H)-dione (37b). Preparative TLC
(h exan e–eth yl acetate 7:3) afforded th e product as wh ite solid (3.5%). FAB MS: 423.52 (MH+)
(45). 1H NMR (500 MHz, DMSO-d6): 7.59 (q, 1 H, JH6,CH3 = 1.0, H-6); 7.30-7.24 (m , 10 H,
arom .); 5.20 an d 4.81 (m , 1 H, H-1′); 4.48, 4.45, 4.40 an d 4.37 (4 × d, 4 H, J = 12.2,
Bn OCH2); 3.93 an d 3.64 (2 × dd, 2 H, J = 9.5 an d 8.2, 9.5 an d 6.1, OCH2); 3.62 an d 3.35
(2 × dd, 2 H, J = 10.5 an d 8.2, 10.5 an d 4.8, OCH2); 1.75 (d, 3 H, JCH3,H6 = 1.2, CH3); 1.30
an d 1.21 (d, 3 H, J = 7.1, CH3). 13C NMR (100.6 MHz, DMSO-d6): 163.95 (C-4); 151.29 (C-2);
138.61 (C); 136.84 (C-6); 136.52, 138.26, 129.66, 129.33 an d 128.35 (4 C); 127.64 (2 C);
127.52 (2 C); 127.58 (2 C); 109.0 (C-5); 71.98, 71.90, 70.92, 70.54 (OCH2); 50.94 an d 50.90
(C-1′); 15.58, 14.71 an d 12.97 (CH3).
2-[1-(Benzyloxy)propan-2-yloxy]-5-methylpyrimidin-4(3H)-one (37c). Preparative TLC (chloroform –
5% m eth an ol) afforded th e product as wh ite solid (1%). FAB MS: 275.31 (MH+) (55). 1H NMR
(500 MHz, DMSO-d6): 7.54 (q, 1 H, JH6,CH3 = 1.0, H-6); 7.30–7.24 (m , 5 H, arom .); 4.75 (m , 1 H,
H-1′); 4.52 an d 4.42 (2 × d, 2 H, J = 12.2, Bn OCH2); 3.61 an d 3.51 (2 × dd, 2 H, J = 10.5 an d
8.2, 10.5 an d 4.6, OCH2); 1.75 (d, 3 H, JCH3,H6 = 1.2, CH3); 1.21 (d, 3 H, J = 7.1, CH3).
13C NMR (100.6 MHz, DMSO-d6): 163.95 (C-4); 151.29 (C-2); 138.30 (C); 138.12 (C-6);
128.45 (2 C); 127.69 (C); 127.58 (2 C); 108.83 (C-5); 71.98 an d 71.94 (OCH2); 65.85 (C-1′);
15.66 (CH3); 12.27 (CH3).
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5-Methyl-1-(2-phenyl-1,3-dioxan-5-yl)pyrimidine-2,4(1H,3H)-dione (38a). Preparative TLC
(h exan e–eth yl acetate 7:3) afforded th e product as wh ite solid (23%). FAB MS: 335.12 (MH+)
(65). 1H NMR (500 MHz, DMSO-d6): 11.38 (bs, 1 H, NH); 8.16 (q, 1 H, JH6,CH3 = 1.0, H-6);
7.42–7.24 (m , 5 H, arom .); 5.73 (s, 1 H, O-CH-O); 4.42 an d 4.25 (bd, 4 H, Jgem = 12.6, H-2′,
2′′); 4.37 (bt, 1 H, JCH,CH2 = 2.0 H-1′); 1.80 (d, 3 H, JCH3,H6 = 1.2, CH3). 13C NMR (100.6
MHz, DMSO-d6): 163.95 (C-4); 151.29 (C-2); 139.37 (C-6); 138.19; 129.28; 128.51 (2 C);
126.25 (2 C); 108.28 (C-5); 101.04 (O-CH-O); 68.86 (2 C, C-2′, 2′′); 47.53 (C-1′); 12.73 (CH3).
5-Methyl-1,3-bis(2-phenyl-1,3-dioxan-5-yl)pyrimidine-2,4(1H,3H)-dione (38b). Preparative TLC
(h exan e–eth yl acetate 7:3) afforded th e product as wh ite solid (1%). FAB MS: 451.23 (MH+)
(45). 1H NMR (500 MHz, DMSO-d6): 8.16 (q, 1 H, JH6,CH3 = 1.0, H-6); 7.50–7.30 (m , 10 H,
arom .); 5.67 an d 5.66 (s, 1 H, O-CH-O); 5.10 an d 4.90 (pen t, 2 H, JCH,CH2 = 1.6, H-1′); 4.28
(m , 8 H, H-2′, 2′′); 2.10 (d, 3 H, JCH3,H6 = 1.2, CH3). 13C NMR (100.6 MHz, DMSO-d6): 168.36
(C-4); 162.55 (C-2); 157.99 (C-6); 138.68; 138.60, 128.96; 128.84, 128.22 (2 C); 128.18 (2 C);
126.31 (2 C); 126.18 (2 C); 111.29 (C-5); 100.32 an d 100.13 (O-CH-O); 68.54 an d 68.38
(2 C, C-2′, 2′′); 68.17 an d 67.88 (C-1′); 11.68 (CH3).
2-(2-Phenyl-1,3-dioxan-5-yloxy)-5-methylpyrimidin-4(3H)-one (38c). Preparative TLC (h exan e–
eth yl acetate 7:3) afforded th e product as colorless oil (1%). FABMS: 335.13 (MH+) (45).
1H NMR (500 MHz, DMSO-d6): 8.16 (q, 1 H, JH6,CH3 = 1.0, H-6); 7.42-7.24 (m , 5 H, arom .);
5.69 (s, 1 H, O-CH-O); 4.37 (bt, 1 H, JCH,CH2 = 2.0 H-1′); 4.32 an d 4.25 (bd, 4 H, Jgem = 12.6,
H-2′, 2′′); 1.80 (d, 3 H, JCH3,H6 = 1.2, CH3). 13C NMR (100.6 MHz, DMSO-d6): 163.95 (C-4);
151.29 (C-2); 139.37 (C-6); 138.19; 129.28; 128.51 (2 C); 126.25 (2 C); 108.28 (C-5); 101.04
(O-CH-O); 69.12 (C-1′); 68.86 (2 C, C-2′, 2′′); 12.73 (CH3).
The authors’ thanks are due to Dr I. Votruba of this Institute for performing the tests of cytostatic
activity. This study was performed as a part of the research project Z 440250506 of this Institute and
within the frame of the programme of Centre for New Antivirals and Antineoplastics 1M0508. It was
also supported by the Programme of Targeted Projects of the Academy of Sciences of the Czech
Republic IQS 5400550501 and by Descartes Prize of the European Union. The financial support of
Gilead Sciences (Foster City, CA, USA) is greatly appreciated.
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