Simple transformation of thymine 1-[3-hydroxy-2-(phosphonomethoxy)propyl] derivatives to their 1-[3-fluoro-2-(phosphonomethoxy)propyl] counterparts

Article abstract of DOI:10.1135/cccc20051465

A novel method of transformation of HOCH₂ group to FCH ₂ was successfully applied to the preparation of fluorine-containing pyrimidine acyclic nucleoside phosphonates (FPMP compounds) such as (S)- and (R)-1-[3-fluoro-2-(phosphonometh

Full text of DOI:10.1135/cccc20051465

Transformation of Thymine Derivatives
1465
SIMPLE TRANSFORMATION OF THYMINE 1-[3-HYDROXY-2-(PHOSPHONO-
METHOXY)PROPYL] DERIVATIVES TO THEIR 1-[3-FLUORO-2-
(PHOSPHONOMETHOXY)PROPYL] COUNTERPARTS
1,
2
3
4
Karel POMEISL *, Radek POHL , Antonín HOLÝ and Ivan VOTRUBA
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,
1
Flemingovo nám. 2, CZ-166 10, Prague 6, Czech Republic; e-mail: pomeislk@uochb.cas.cz,
2
3
4
pohl@uochb.cas.cz, holy@uochb.cas.cz, votruba@uochb.cas.cz
Received April 11, 2005
Accepted Jun e 9, 2005
A n ovel m eth od of tran sform ation of HOCH2 group to FCH2 was successfully applied to th e
preparation of fluorin e-con tain in g pyrim idin e acyclic n ucleoside ph osph on ates (FPMP com -
poun ds) such as (S)- an d (R)-1-[3-fluoro-2-(ph osph on om eth oxy)propyl]th ymine (7a, 7b) (FPMPT).
Th e key displacem en t of h ydroxy group with fluorin e in 1-{2-[(diisopropoxyph osph oryl)-
m eth oxy]-3-h ydroxypropyl}-4-m eth oxy-5-m eth ylpyrim idin-2(1H)-on e (5a, 5b) was perform ed
usin g perfluorobutan e-1-sulfon yl fluoride in th e presen ce of DBU. Novel pyrim idin e acyclic
n ucleoside ph osph on ates were in vestigated as in h ibitors of th ym idin e ph osph orylase.
Keyw ord s: Acyclic n ucleoside ph osph on ates; Acyclic n ucleotide an alogues; Th ym idin e
ph osph orylase; Deoxyfluorin ation s; Th ym in e; Pyrim idin es; An tivirals.
Acyclic n ucleoside ph osph on ates1 (ANPs) con tain in g fluorin e atom in th e
ph osph on ate-bearin g side ch ain exh ibit sign ifican t biological activity. It is
docum en ted by th e an tiretroviral effect of 9-[3-fluoro-2-(ph osph on o-
m eth oxy)propyl]aden in e2 (FPMPA) an d som e of its con gen ers m odified at
th e h eterocyclic base. In con trast to 9-[2-(ph osph on om eth oxy)eth yl] (PME)
or 9-[3-h ydroxy-2-(ph osph on om eth oxy)propyl] (HPMP) purin e derivatives,
FPMP com poun ds possess n o activity again st DNA viruses; th e h ydroxy
group displacem en t with fluorin e results in th e ch an ge of “quality” of an ti-
viral effect. In an alogy to PME or HPMP derivatives, also FPMP com poun ds
are ph osph orylated in th e cell to give diph osph ates wh ich term in ate th e
DNA ch ain 3 growth . However, th e FPMP com poun ds are less toxic to h ost
cells in vitro com pared with th e PME derivatives2. Despite th eir activity
wh ich was con firm ed by in vivo experim en ts with an im al viruses h om olo-
gous to HIV, th e FPMP derivatives n ever foun d th e way to practical devel-
opm en t. On e of th e reason s for th is n eglection m ay well be th eir difficult
accessibility.
Collect. Czech. Chem. Commun. (Vol. 70) (2005)
doi:10.1135/cccc20051465

1466
Pomeisl, Pohl, Holý, Votruba:
Fluorin e-con tain in g substituen ts are also powerful m odifiers of ch em ical
an d biological properties of n ucleosides (e.g. FIAU, FIAC, FMAU etc.)4. Th eir
syn th eses in clude various fluorin ation m eth ods. Th e m ost useful reagen ts
for primary or secondary hydroxy group displacement in saccharide-containing
n ucleosides with fluorin e are DAST 5, Olah ’s reagen t6, fluoroalkylam in e re-
agen ts7 (FAR), etc. In addition , preform ed syn th on s con tain in g fluoro sub-
stituen ts can be used for glycosylation 8 or alkylation 2a,9 of h eterocyclic
bases.
Fluorin ation of n ucleosides an d ANPs 9 h as been also a subject of our re-
search . In th is report, we describe th e syn th eses of several fluorin ated
side-ch ain m odified pyrim idin e ANPs wh ich sh ow poten t in vitro in h ibition
of th ym idin e ph osph orylase10 (dTh dPase).
In our studies, we were particularly in terested in th e side-ch ain fluorin a-
tion of th e h ydroxy group in pyrim idin e 1-[3-h ydroxy-2-(ph osph on o-
m eth oxy)propyl] derivatives in order to replace th e existin g m eth od of
FPMP syn th esis by better available HPMP derivatives as startin g m aterials.
As m odels we were usin g en an tiom eric th ym in e com poun ds 5a an d 5b. For
th is purpose, we h ave elaborated an im proved syn th esis of startin g
en an tiom eric n on -fluorin ated side-ch ain m odified com poun ds 11a, 11b
an d 15a, 15b. Th e oth er aim of our study is search for n ovel efficien t in h ib-
itors of th ym idin e ph osph orylase in vitro2; we h ave prepared both th e opti-
cal isom ers an d th e racem ate to com pare th eir activity.
In our previous syn th eses of C-3′-fluorin ated ANP derivatives (FPMP com -
poun ds), we were usin g fluorin ated syn th on s obtain ed by m ultistep reac-
tion s2a,9. For th e preparation of 7a–7c we used weakly corrosive perfluoro-
butan e-1-sulfon yl fluoride11 as a n ucleoph ilic fluorin ation agen t in th is
study. Th is reagen t is stable an d little m oisture-sen sitive at room tem pera-
ture, an d th erefore easy to h an dle. Th e key in term ediates 5a–5c for th is
kin d of side-ch ain fluorin ation were obtain ed in several reaction steps from
4-m eth oxy-5-m eth ylpyrim idin -2(1H)-on e12 (Sch em e 1): N1-alkylation of th e
h eterocyclic base with various oxiran es13 1a–1d takes place un der th e con -
dition s used in m eth ods A or B. Both reaction s were carried out in
dim eth ylform am ide in th e presen ce of cesium carbon ate as catalyst an d
afforded h ydroxy derivatives 2a–2c in acceptable yields. Furth erm ore,
m eth od B in cludes even m eth an olysis14 of in term ediary product 3 . Subse-
quen t tritylation proceeded by reaction with trityl ch loride in pyridin e in
th e presen ce of 4-(N,N-dim eth ylam in o)pyridin e.
For th e preparation of 4a–4c we h ave used gen eral procedures reported
previously14,15. A m ixture of startin g com pon en ts 2a–2c an d [(diiso-
propoxyph osph oryl)m eth oxy]m eth yl tosylate in th e presen ce of sodium
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

Transformation of Thymine Derivatives
1467
Method B
OCH3
CH3
OC(O)C3H7
O
N
(i)
1d
O
N
2b
(ii)
Cs2CO3
DMF,100°C
OC(O)C3H7
a, (S)-derivatives
OCH3
OH
b, (R)-derivatives
c, racemic
derivatives
CH3
N
3
O
N
H
OCH3
Method A
OCH3
CH3
CH3
OTr
O
1a-1c
N
N
(iii)
O
N
O
N
Cs2CO3
DMF,80°C
OTr
P(O)(OiPr)2
OTr
O
OH
2a-2c
4a-4c
O
OCH3
CH3
OCH3
CH3
CH3
HN
N
N
(iv)
(v)
(vi)
O
N
O
N
O
N
F
P(O)(OH)2
F
P(O)(OiPr)2
OH
O
O
O
P(O)(OiPr)2
5a-5c
6a-6c
7a-7c
(i) MeONa, MeOH; (ii) TrCl, DMAP, Py, rt; (iii) TsCH2P(O)(OiPr)2, NaH, THF, –20°C→rt;
(iv) method C: H2, Pd/C, 99% AcOH, MeOH, 5a and 5b; method C: 80%AcOH, 5c;
(v) C4F9SO2F, DBU, toluene, rt→90°C; (vi) (CH3)3SiBr, CH3CN, rt
SCHEME 1
h ydride was first stirred in tetrah ydrofuran at –20 °C; th e reaction th en pro-
ceeded at 25–30 °C. Th e ch oice of adsorben t was sh own to be im portan t for
ch rom atograph ic separation of reaction products. Wh ile th e isolation of
3-h ydroxy derivatives was successful with n eutral alum in um oxide, th e
C-4-m eth oxy group of th e (S)-en an tiom er 4a was com pletely rem oved by
silica gel colum n ch rom atograph y (Sch em e 2). On th e oth er h an d, com -
poun d 9 wh ich resulted from th is reaction sequen ce was applicable to
side-ch ain fluorin ation . However, th e displacem en t of th e C-3′-h ydroxy
group with fluorin e could be com plicated if a h eterocyclic base con tain s la-
bile proton in th e N3-position .
Th erefore we h ave deprotected th e side ch ain of com poun ds 4a–4c to
give 5a–5c: th e trityl group was rem oved by m ild h ydrogen ation
in m eth an ol over 5% palladium on ch arcoal in th e presen ce of acetic
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1468
Pomeisl, Pohl, Holý, Votruba:
acid (m eth od C). Likewise, selective deprotection of racem ic derivative 4c
with excess of 80% acetic acid with out h ydrogen ation was also tested14
(m eth od D). Th is reaction afforded sim ilar results provided th at th e reac-
tion m ixture was perform ed in th e tem perature ran ge of 40–70 °C.
O
CH3
N
(ii)
O
N
O
N
OCH3
CH3
O
P(O)(OiPr)2
10
CH3
HN
N
(i)
O
O
N
O
OR
OTr
CH3
O
P(O)(OiPr)2
O
P(O)(OiPr)2
HN
4a
8, R = Tr
9, R = H
O
N
(iii)
(iv)
OH
P(O)(OH)2
O
O
11a
CH3
HN
(iv)
O
N
5b
OH
P(O)(OH)2
O
11b
(i) H+,H2O, SiO2; (ii) C4F9SO2F, DBU, toluene, rt→90°C; (iii) Dowex 50 (H+), MeOH, H2O, reflux;
(iv) (CH3)3SiBr, CH3CN, rt
SCHEME 2
For n ucleoph ilic fluorin ation usin g perfluorobutan e-1-sulfon yl fluoride it
is essen tial to fin d a suitable base an d solven t16. Th e base h as to be a good
proton acceptor with a low n ucleoph ilicity an d m oderately basic to avoid
elim in ation reaction . We tested th e reaction with N-eth ylpiperidin e (NEP)
an d 1,8-diazabicyclo[5.4.0]un dec-7-en e (DBU), wh ich was foun d useful for
th is type of fluorin e displacem en t. Th e reaction with NEP was reported to
give better fluorin ation results in th e syn th eses of sacch aride-con tain in g
n ucleosides16. However, in th is case th e reaction s proceeded better in th e
presen ce of DBU to reach good con version of ANP in term ediates 5a–5c. Th e
reaction was carried out in toluen e at room tem perature. Alth ough th e fluo-
rin ation afforded 49–58% yields of 6a–6c, th e reaction rate was slow. Sign if-
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

Transformation of Thymine Derivatives
1469
ican t reduction of th e reaction tim e was ach ieved wh en th e m ixture was
h eated at 90 °C. Con version of 9 obtain ed by h ydrolysis of com poun d 8 on
Dowex 50 (H+ form ) was n ot successful. Un desirable N3-deproton ation of
th e th ym in e base resulted in th e closure of six-m em bered rin g un der th e
form ation of com poun d 10. Th e obtain ed com poun ds 5b, 6a–6c an d 9
were fin ally deprotected by th e reaction with brom otrim eth ylsilan e in ace-
ton itrile followed by h ydrolysis to give 7a–7c an d 11a, 11b.
In order to assess th e effect of fluorin e at th e side ch ain of ANP on
dTh dPase in h ibition , we also syn th esized n on -fluorin ated ANPs 15a an d
15b lackin g fluorin e in th e side ch ain (Sch em e 3). Th us, 4-m eth oxy-
5-m eth ylpyrim idin -2(1H)-on e was con verted in to en an tiom ers of N1-deriva-
tives 13a an d 13b by reaction with ph osph on ate syn th on s15 12a an d 12b
in th e presen ce of sodium h ydride. However, th e in itial alkylation reaction
proceeded with low regioselectivity as was docum en ted by O2-alkyl in ter-
m ediates 14a an d 14b (see Experim en tal). Th e structures of both regio-
isom ers were con firm ed by 13C NMR spectroscopy an d H,C-HBMC experi-
m en ts. 13C NMR spectra of 13a an d 13b exh ibit ch aracteristic ch em ical
sh ifts for CH2N fragm en t an d 4-m eth oxy-5-m eth yl-2-pyrim idin -2(1H)-on e
m oiety (for num bering see Fig. 1). In addition, H,C-HMBC spectra show cross-
peaks of CH2-1′ (3.50 ppm ) to CH-6 (145.97 ppm ) an d C-2 (156.79 ppm ).
In con trast, ch aracteristic values for CH2O fragm en t an d arom atic pyrim i-
OCH3
CH3
N
O
N
a, (S)-derivatives
b, (R)-derivatives
CH3
O
P(O)(OiPr)2
OCH3
CH3
14a,14b
(i)
N
O
N
O
N
H
OCH3
CH3
CH3
CH3
HN
N
O
O
N
(ii)
CH3
O
P(O)(OH)2
O
P(O)(OiPr)2
15a,15b
13a,13b
(i) TsOCH2CH(CH3)OCH2P(O)(OiPr)2 (S)-12a, (R)-12b, NaH, DMF, rt→80-100°C;
(ii) (CH3)3SiBr, CH3CN, rt
SCHEME 3
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1470
Pomeisl, Pohl, Holý, Votruba:
din e m oiety of isom ers 14a, 14b an d cross-peaks of CH2-1′ (4.23 an d 4.29
ppm ) to only C-2 (163.41 ppm ) confirm ed the structure of O2-isom er. Finally,
in term ediates 13a an d 13b were deprotected by reaction with brom o-
trim eth ylsilan e un der usual con dition s.
Th e structures of all prepared com poun ds were con firm ed by NMR with
com plete proton an d carbon assign m en t usin g H,C-h eterocorelated experi-
m en ts (HSQC an d HMBC). In addition , th e optical purity of en an tiom eric
products 2a, 2b, 4a, 4b, 5a, 5b, 6a, 6b an d 8 was ch ecked by 1H NMR
m easurem en t of dyn am ic com plex with ch iral solvatin g agen t (–)-(R)-
1-(9-an th ryl)-2,2,2-trifluoroeth an -1-ol17 in CDCl3 an d com pared with th e
diastereom eric m ixtures of correspon din g racem ic com poun ds. Th e optical
purity was determ in ed to be >98% ee in all cases. Racem ates for th is study
were eith er syn th esized or obtain ed by m ixin g of in dividual en an tiom ers.
TABLE I
In h ibition of th ym idin e ph osph orylases by ANP
In h ibition of th ym idin e ph osph orylasea, Vi/V0
Com poun d
Escherichia coli
h um an expressed SD-lym ph om a
h um an placen ta
PMET
1.00
0.92
0.93
0.91
0.98
1.05
1.00
1.02
0.91
0.82
0.95
0.84
0.92
0.98
0.27
0.29
0.11
0.25
0.31
0.35
0.47
0.85
0.83
0.56
0.75
0.84
0.74
0.79
(S)-FPMPT (7a)
(R)-FPMPT (7b)
(S)-HPMPT (11a)
(R)-HPMPT (11b)
(S)-PMPT (15a)
(R)-PMPT (15b)
a
100 µM [3H]-2′-deoxyth ym idin e, 250 µM Pi, tested com poun d 10 µm ol l–1, pH 6.7; an ap-
propriate am oun t of en zym e, 10 m in in cubation at 37 °C.
O
OCH3
4
OCH3
4
4
3
HN
CH3
3'
CH3
CH3
N
2
N
2
5
6
5
6
5
6
2
O
N1
O
N
3'
O
N1
1
3'
1'
R1
1'
1'
R1
R1
2'
2'
2'
P(O)(OR2)2
P(O)(OR2)2
O
P(O)(OR2)2
O
O
4'
4'
4'
FIG. 1
Gen eral n um berin g sch em e for assign m en t of NMR sign als
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

Transformation of Thymine Derivatives
1471
Com poun ds 7a, 7b, 11a, 11b, 15a an d 15b h ave sh owed a con siderable
inhibitory potency of thymidine phosphorylase. The data comprized in Table I
wh ich were taken in part from our recen tly publish ed paper18 dem on strate
an in terestin g differen ce in th e respon se to diverse in h ibitors of ANP type
by th ym idin e ph osph orylases isolated from differen t sources of origin . Th e
m ost sen sitive en zym e is th at of th e T-cell lym ph om a; th e m ost active com -
poun ds 7b an d 7a in h ibit th is en zym e with Ki/KdTh d = 0.0026 an d
m
Ki/KdTh d = 0.0048, respectively.
m
Non e of th e com poun ds presen ted in th is study possesses sign ifican t
cytostatic activity in vitro estim ated in m ouse lym ph ocytic leukem ia L1210
cells (ATCC CCL 219), CCRF-CEM T lym ph oblastoid cells (h um an acute
lym ph oblastic leukem ia, ATCC CCL 119), h um an prom yelocytic leukem ia
HL-60 cells (ATCC CCL 240) an d h um an cervix carcin om a HeLa S3 cells
(ATCC CCL 2.2) at a con cen tration 10 µm ol l–1
.
In con clusion , th e preparation of 7a an d 7b usin g perfluorobutan e-
1-sulfon yl fluoride represen ts a n ovel direct fluorin ation m eth od of th y-
m in e ANPs. In con trast to kn own syn th eses of fluorin ated buildin g
blocks2a,9 usually usin g potassium fluoride th is kin d of fluorin ation requires
m ild con dition s. However, th e dan ger of racem ization by sim ple displace-
m en t of h ydroxy group with fluorin e is n ot quite excluded; th e exact m ech -
an ism of th e reaction is n ot kn own . Th e described procedure open s th e pre-
parative way to FPMP derivatives of bases wh ich do n ot bear am in o fun c-
tion (s). Th e appropriate startin g HPMP derivatives are well an d reproduc-
ibly accessible, th eir tran sform ation to th e fluorin e con tain in g com pouds is
easy an d th e isolation is un com plicated. However, it rem ain s to be furth er
search ed for con dition s wh ich would m ake possible to tran sform th e am in o
group con tain in g HPMP derivatives, in order to give th is m eth od a gen eral
ch aracter.
EXPERIMENTAL
Un less stated oth erwise, solven ts were evaporated at 40 °C/0.5–2 kPa an d com poun ds were
dried at 50 °C/13 Pa. Meltin g poin ts were determ in ed on a Kofler block an d are un corrected.
Optical rotation s were m easured on a AUTOPOL IV polarim eter (Rudolph Research An alyti-
cal, U.S.A.) at 25 °C; [α]D values are given in 10–1 deg cm 2 g–1. IR spectra were recorded on a
FTIR Spectrom eter Bruker IFS 55 (Equin ox) in KBr, CCl4 an d CDCl3. An alytical TLC was car-
ried out on Silufol UV254 plates (Kavalier Votice, Czech Republic). Colum n ch rom atograph y
was perform ed on n eutral alum in um oxide 150 m esh 58 Å with 3% water addition (Aldrich )
an d silica gel 60 µm (Fluka). Preparative TLC was carried out on 45 × 18 × 0.4 cm loose-layer
silica gel con tain in g UV in dicator (system S1). NMR spectra were recorded on a Bruker
Avan ce 400, Bruker Avan ce 500 or Varian Un ity 500 spectrom eters (1H at 400 or 500, 13C at
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1472
Pomeisl, Pohl, Holý, Votruba:
100.6 or 125.8 an d 19F at 470.2 MHz) in CDCl3 with in tern al stan dard tetram eth ylsilan e an d
trich lorofluorom eth an e; DMSO-d6 solution s (referen ced to th e solven t sign al at δ 2.50) or in
D2O solution s with dioxan e as an in tern al stan dard (3.75 ppm for 1H an d 67.19 ppm for
13C). Ch em ical sh ifts (δ, ppm ) an d couplin g con stan ts (J, Hz) were obtain ed by first-order
an alysis of th e spectra. Th e n um berin g system for assign m en t of NMR sign als is outlin ed in
Fig. 1. Mass spectra were m easured on a ZAB-EQ (VG An alytical) spectrom eter usin g FAB
(ion ization with xen on , acceleratin g voltage 8 kV, glycerol m atrix). Reversed-ph ase HPLC
was perform ed on a Waters Delta 600 (Xterra , Prep RP18 Colum n 10 µm , 10 × 150 m m ,
system S2; RP18 Colum n 5 µm 3.9 × 150 m m , system S3) in 0.05 M trieth ylam m on ium
h ydrogen carbon ate buffer (TEAB).
Materials an d Ch em icals
Stan dard ch em icals, ion -exch an ge resin Dowex 50WX8-200 an d activated ch arcoal were pur-
ch ased from Sigm a–Aldrich (Czech Republic). Ion -exch an ge resin Seph adex A-25-120 DEAE was
purch ased from Fluka. Perfluorobutan e-1-sulfon yl fluoride was obtain ed from Fluoroch em
(Wesley Street, Old Glossop). 4-Meth oxy-5-m eth yl-2-pyrim idin -2(1H)-on e an d 4-m eth oxy-
2-pyrim idin -2(1H)-on e were prepared as described in ref.12 Oxiran es 1a, 1b an d 1d were ob-
tain ed from Daiso Co. Ltd. [(Trityloxy)m eth yl]oxiran e (1c) was prepared by tritylation of
glycidol as described in ref.19 [(Diisopropoxyph oryl)m eth yl] tosylate was syn th esized as de-
scribed in ref.14, (R)- an d (S)-en an tiom eric ph osph on ates 10a an d 10b were prepared accord-
in g to ref.15 Diisopropyl [(2-ch loroeth oxy)m eth yl]ph osph on ate was obtain ed accordin g to
ref.20 Dim eth ylform am ide, tetrah ydrofuran , an d aceton itrile were dried by distillation from
calcium h ydride an d stored over m olecular sieves (4 Å).
Syn th esis of 4-Meth oxy-5-pyrim idin -2(1H)-on es 2a–2c. Gen eral Procedure
A m ixture of 4-m eth oxy-5-m eth ylpyrim idin -2(1H)-on e (5.2 g, 37.2 m m ol), [(trityloxy)m eth yl]-
oxiran e 1a or 1b or 1c (11.8 g, 37.2 m m ol) an d cesium carbon ate (1.2 g, 3.7 m m ol) in di-
m eth ylform am ide (300 m l) was h eated at 70–80 °C for 19 h . Th e m ixture was con cen trated
in vacuo to a m in im um volum e. Th e residue was ch rom atograph ed in th e below-m en tion ed
system s. Th e product 2 con tain in g isom ers were evaporated to dryn ess in vacuo. Com poun d
2c was th en crystallized from ch loroform –eth yl acetate.
(S)-1-[2-Hydroxy-3-(trityloxy)propyl]-4-methoxy-5-methylpyrimidin-2(1H)-one (2a). Yield 11.4 g
(70%), wh ite sirupy product. Colum n ch rom atograph y was perform ed on silica gel (toluen e–
m eth an ol–eth yl acetate–trieth ylam in e 7:1:1.5:1). IR, νm ax (CCl4): 3357, 1670, 1644, 1598,
1491, 1449, 1541, 1476, 1399, 1368, 1333, 1099. [α]D –38.7 (c 0.311 g/100 m l, CHCl3). For
C
28H28N2O4 (456.6) calculated: 73.66% C, 6.18% H, 6.14% N; foun d: 73.29% C, 6.30% H,
5.99% N. FAB MS, m/z: 457 [MH]+ (2), 243 (100), 215 (8), 197 (10), 165 (18), 141 (7).
1H NMR (400 MHz, DMSO-d6): 1.81 d, 3 H, J(CH3,6) = 1.0 (CH3); 2.89 dd, 1 H, J(gem ) = 9.5,
J(3′b,2′) = 5.3 (H-3′b); 2.96 dd, 1 H, J(gem ) = 9.5, J(3′a,2′) = 4.9 (H-3′a); 3.54 dd, 1 H,
J(gem ) = 12.9, J(1′b,2′) = 8.2 (H-1′b); 3.83 s, 3 H (OCH3); 3.97 m , 1 H (H-2′); 4.04 dd, 1 H,
J(gem ) = 12.9, J(1′a,2′) = 4.1 (H-1′a); 5.26 d, 1 H, J(OH,2′) = 5.7 (OH); 7.26 m , 3 H (p-H-Ph );
7.33 m , 6 H (m-H-Ph ); 7.41 m , 6 H (o-H-Ph ); 7.63 q, 1 H, J(6,CH3) = 1.0 (H-6). 13C NMR
(100.6 MHz, DMSO-d6): 11.69 (CH3-5); 53.08 (CH2-1′); 54.02 (OCH3); 66.20 (CH2-3′); 67.07
(CH-2′); 86.04 (C-Tr); 101.69 (C-5); 127.20 (p-CH-Ph ); 128.06 (m-CH-Ph ); 128.44 (o-CH-Ph );
143.90 (i-C-Ph ); 147.55 (CH-6); 155.67 (C-2); 170.09 (C-4).
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Transformation of Thymine Derivatives
1473
(RS)-1-[2-Hydroxy-3-(trityloxy)propyl]-4-methoxy-5-methylpyrimidin-2(1H)-one (2c). Yield 10.3 g
(63%), wh ite crystals, m .p. 89–91 °C. Colum n ch rom atograph y was perform ed on n eutral
alum in um oxide (ch loroform –m eth an ol 25:1). For C28H28N2O4 (456.6) calculated: 73.66% C,
6.18% H, 6.14% N; foun d: 73.47% C, 6.14% H, 6.06% N. FAB MS, m/z: 457 [MH]+ (1), 243
(100), 215 (8), 197 (18), 165 (35), 141 (14), 105 (10), 57 (8). 1H, 13C NMR an d IR data were
iden tical with com poun d 2a.
(R)-1-[2-Hydroxy-3-(triph en ylm eth oxy)propyl]-4-m eth oxy-5-m eth ylpyrim idin -
2(1H)-on e (2b)
A m ixture of 4-m eth oxy-5-m eth ylpyrim idin -2(1H)-on e (6 g, 42.8 m m ol), (R)-oxiran ylm eth yl
butan oate (1d ; 6.8 g, 42.8 m m ol) an d cesium carbon ate (1.4 g, 4.0 m m ol) in dim eth ylform -
am ide (300 m l) was h eated at 100 °C for 10 h . Th e m ixture was con cen trated to a m in im um
volum e. Th e residue was codistilled with toluen e (50 m l) an d left stan din g with 0.05
M
m eth an olic sodium m eth oxide (100 m l) for 9 h . Th e m ixture was stirred in ch loroform –
m eth an ol 25:1 an d th en n eutralized with acetic acid. Th e residue was con cen trated in vacuo
an d th en dissolved in dim eth ylform am ide (150 m l) an d pyridin e (70 m l). 4-(Dim eth yl-
am in o)pyridin e (2.9 g, 23.7 m m ol) an d trityl ch loride (18 g, 64.2 m m ol) were added to a so-
lution an d th e resultin g m ixture was stirred at 50 °C for 28 h . Th e solven ts were evaporated
in vacuo an d th e residue was codistilled with toluen e (2 × 50 m l). Th e m ixture was dissolved
in ch loroform (200 m l) an d wash ed with water (50 m l). Th e organ ic layer was wash ed with
saturated sodium ch loride solution (50 m l) an d dried with an h ydrous m agn esium sulfate.
After evaporation of th e solven t th e residue was ch rom atograph ed on n eutral alum in um
oxide (eth er, eth yl acetate an d eth yl acetate–m eth an ol 18:1). Yield 6.5 g (30%) of 2b as a
wh ite solid. [α]D +40.2 (c 0.512 g/100 m l, CHCl3). FAB MS, m/z: 457 [MH]+ (2), 243 (100),
197 (6), 165 (14), 141 (6). For C28H28N2O4·H2O (474.6) calculated: 70.86% C, 6.37% H,
5.90% N; foun d: 70.60% C, 6.48% H, 5.70 N. 1H, 13C NMR an d IR data were iden tical with
com poun d 2a.
Syn th esis of 1-{2-[(Diisopropoxyph osph oryl)m eth oxy)]-3-(trityloxy)propyl}pyrim idin -
2(1H)-on e Derivatives 4a–4c. Gen eral Procedure
A m ixture of com poun d 2 (10.3 g, 22.6 m m ol), [(diisopropoxyph osph oryl)m eth oxy]m eth yl
tosylate (9.5 g, 27.1 m m ol) an d 60% sodium h ydride dispersion (1.4 g, 35 m m ol) in tetra-
h ydrofuran (300 m l) was stirred at –20 °C. Th e suspen sion was allowed to warm to 20–30 °C
for 1 h an d stirred at room tem perature overn igh t. Th e m ixture was filtered th rough a Celite
pad an d con cen trated in vacuo. Th e residue was ch rom atograph ed on n eutral alum in um
oxide (ch loroform –m eth an ol 25:1).
(S)-1-{2-[(Diisopropoxyphosphoryl)methoxy]-3-(trityloxy)propyl}-4-methoxy-5-methylpyrimidin-
2(1H)-one (4a). Yield 12.5 g (87%) of a yellowish sirupy product. IR, νm ax (CCl4): 1676, 1656,
1599, 1541, 1491, 1475, 1450, 1399, 1332, 1259, 1106, 1009, 901. [α]D –6.4 (c 0.202 g/100 m l,
CHCl3). HR MS (FAB): for C35H44N2O7P foun d: 635.2918, calculated: 635.2886. 1H NMR
(400 MHz, CDCl3): 1.26, 1.27, 1.29 an d 1.31 4 × d, 4 × 3 H, J(vic) = 6.0 (CH3-i-Pr); 1.88 d,
3 H, J(CH3,6) = 1.1 (CH3-5); 3.09 dd, 1 H, J(gem ) = 10.7, J(3′b,2′) = 4.0 (H-3′b); 3.40 dd, 1 H,
J(gem ) = 10.7, J(3′a,2′) = 3.4 (H-3′a); 3.57 dd, 1 H, J(gem ) = 13.5, J(H,P) = 10.2 (H-4′b);
3.80 dd, 1 H, J(gem ) = 13.5, J(1′b,2′) = 8.0 (H-1′b); 3.87 dd, 1 H, J(gem ) = 13.5, J(H,P) = 8.6
(H-4′a); 3.91 m , 1 H (H-2′); 3.96 s, 3 H (OCH3); 4.26 dd, 1 H, J(gem ) = 13.5, J(1′a,2′) = 3.8
(H-1′a); 4.69 m , 2 H (CH-i-Pr); 7.24 m , 3 H (p-H-Ph ); 7.31 m , 7 H (H-6) an d (m-H-Ph );
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

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Pomeisl, Pohl, Holý, Votruba:
7.44 m , 6 H (o-H-Ph ). 13C NMR (100.6, CDCl3): 11.95 (CH3-5); 23.90 d, J(C,P) = 4.7
(CH3-i-Pr); 23.96 d, J(C,P) = 4.8 (CH3-i-Pr); 23.99 d, J(C,P) = 4.0 (CH3-i-Pr); 24.00 d, J(C,P) =
4.2 (CH3-i-Pr); 51.18 (CH2-1′); 54.40 (OCH3); 62.28 (CH2-3′); 64.85 d, J(C,P) = 169.1 (CH2-4′);
70.79 d, J(C,P) = 6.7 (CH-i-Pr); 70.97 d, J(C,P) = 6.5 (CH-i-Pr); 78.87 d, J(C,P) = 12.6 (CH-2′);
86.78 (C-Tr); 103.66 (C-5); 127.12 (p-CH-Ph ); 127.88 (m-CH-Ph ); 128.55 (o-CH-Ph ); 143.48
(i-C-Ph ); 147.98 (CH-6); 156.62 (C-2); 170.78 (C-4).
(R)-1-{2-[(Diisopropoxyphosphoryl)methoxy]-3-(trityloxy)propyl}-4-methoxy-5-methylpyrimidin-
2(1H)-one (4b). Yield 7.9 g (55%) of a yellowish sirupy product. [α]D +37.7 (c 0.136 g/100 m l,
CHCl3). HR MS (FAB): for C35H44N2O7P foun d: 635.2825, calculated: 635.2886. 1H, 13C NMR
an d IR data were iden tical with com poun d 4a.
(RS)-1-{2-[(Diisopropoxyphosphoryl)methoxy]-3-(trityloxy)propyl}-4-methoxy-5-methylpyrimidin-
2(1H)-one (4c). Yield 10.5 g (73%) of a wh ite sirupy product. HR MS (FAB): for C35H44N2O7P
foun d: 635.2905, calculated: 635.2886. 1H, 13C NMR an d IR data were iden tical with com -
poun d 4a.
Syn th esis of 1-[3-Hydroxy-2-(ph osph on om eth oxy)propyl]pyrim idin -2(1H)-on e
Derivatives 5a an d 5b. Gen eral Procedure
Com poun d 4a or 4b (4.3 g, 6.7 m m ol) in m eth an ol (60 m l) an d glacial acetic acid (1 m l)
was h ydrogen ated over 5% palladium on ch arcoal (1.5 g) at room tem perature for 24 h un til
th e con version of startin g ph osph on ate to 5a or 5b was com plete (TLC in ch loroform –
m eth an ol 25:1). Th e m ixture was th en n eutralized with solid sodium h ydrogen carbon ate
an d filtered th rough a Celite pad. Th e filtrate was con cen trated to a m in im um volum e, th e
residue was ch rom atograph ed on n eutral alum in ium oxide (ch loroform an d ch loroform -
m eth an ol 25:1).
(S)-1-{2-[(Diisopropoxyphosphoryl)methoxy]-3-hydroxypropyl}-4-methoxy-5-methyl-pyrimidin-
2(1H)-one (5a). Yield 1.6 g (62%) of a colorless oil. IR, νm ax (CCl4): 3395, 1671, 1643, 1540,
1477, 1399, 1386, 1375, 1336, 1253, 1105, 1013, 994. [α]D –6.4 (c 0.202 g/100 m l, CHCl3).
HR MS (FAB): for C16H29N2O7P foun d: 393.1800, calculated: 393.1791. FAB MS, m/z: 393
[MH]+ (100). 1H NMR (400 MHz, DMSO-d6): 1.16, 1.19, 1.20 an d 1.22 4 × d, 4 × 3 H, J(vic) =
6.2 (CH3-i-Pr); 1.86 d, 3 H, J(CH3,6) = 1.0 (CH3); 3.45 dd, 1 H, J(gem ) = 11.9, J(3′b,2′) = 4.4
(H-3′b); 3.51 dd, 1 H, J(gem ) = 11.9, J(3′a,2′) = 4.4 (H-3′a); 3.70 m , 3 H (H-4′ an d H-1′b);
3.84 s, 3 H (OCH3); 3.87 dd, 1 H, J(gem ) = 14.0, J(1′a,2′) = 8.1 (H-1′a); 4.02 m , 1 H (H-2′);
4.53 dh , 2 H, J(H,P) = 7.7, J(vic) = 6.2 (CH-i-Pr); 4.82 bs, 1 H (OH); 7.65 q, 1 H, J(6,CH3) =
1.0 (H-6). 13C NMR (100.6, DMSO-d6): 11.75 (CH3-5); 23.72, 23.82, 23.89 an d 23.93 d,
J(C,P) = 4.8 (CH3-i-Pr); 50.24 (CH2-1′); 54.03 (OCH3); 62.37 (CH2-3′); 63.66 d, J(C,P) = 164.8
(CH2-4′); 70.25 d, J(C,P) = 6.2 (CH-i-Pr); 79.61 d, J(C,P) = 11.0 (CH-2′); 101.96 (C-5); 147.47
(CH-6); 155.71 (C-2); 170.14 (C-4).
(R)-1-{2-[(Diisopropoxyphosphoryl)methoxy]-3-hydroxypropyl}-4-methoxy-5-methylpyrimidin-
2(1H)-one (5b). Yield 1.3 g (51%) of a colorless oil. [α]D +3.6 (c 0.312 g/100 m l, CHCl3).
HR MS (FAB): for C16H29N2O7P foun d: 393.1781, calculated: 393.1791. FAB MS, m/z: 393
[MH]+ (100). 1H, 13C NMR an d IR data were iden tical with com poun d 5a.
(RS)-1-{2-[(Diisopropoxyphosphoryl)methoxy]-3-hydroxypropyl}-4-methoxy-5-methylpyrimidin-
2(1H)-one (5c). A solution of com poun d 4c (9.4 g, 14.8 m m ol) in 80% acetic acid (40 m l)
was h eated at 40 °C for 2 h . Th e m ixture was th en h eated to 70 °C for 4 h un til th e con ver-
sion of startin g ph osph on ate 4c to 5c was com plete (TLC in ch loroform –m eth an ol 25:1).
Th e m ixture was con cen trated in vacuo an d th en codistilled with ligh t petroleum . Th e resi-
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Transformation of Thymine Derivatives
1475
due was ch rom atograph ed on silica gel (ch loroform an d ch loroform –m eth an ol 25:1). Yield
4.1 g (70%) of 5c as a colorless oil. IR, νm ax (CCl4): 3394, 1670, 1645, 1540, 1477, 1399,
1386, 1375, 1336, 1253, 1105, 1012, 994. HR MS (FAB): for C16H29N2O7P foun d: 393.1748,
calculated: 393.1791. FAB MS, m/z: 393 [MH]+ (100). 1H, 13C NMR an d IR data were iden tical
with com poun d 5a.
Syn th esis of 1-[3-Fluoro-2-(ph osph on om eth oxy)propyl]pyrim idin -2(1H)-on e
Derivatives 6a–6c. Gen eral Procedure
A m ixture of 1,8-diazabicyclo[5.4.0]un dec-7-en e (0.8 g, 5.1 m m ol) an d 92% perfluorobutan e-
1-sulfon yl fluoride (1.1 g, 3.7 m m ol) was stirred in toluen e (3 m l) at room tem perature for
10 m in . A solution of com poun d 5 (1 g, 2.5 m m ol) in toluen e (7 m l) was added an d th e
resultin g m ixture was stirred at room tem perature overn igh t or h eated at 90 °C for 4 h un til
th e con version of startin g ph osph on ate to 6 was com plete (TLC in ch loroform –m eth an ol
25:1). Th e m ixture was con cen trated in vacuo, filtered over n eutral alum in um oxide (ch loro-
form an d ch loroform –m eth an ol 20:1). After evaporation of solven ts th e residue was
ch rom atograph ed on preparative TLC (S1, ch loroform –m eth an ol 20:1).
(S)-1-{2-[(Diisopropoxyphosphoryl)methoxy]-3-fluoropropyl}-4-methoxy-5-methylpyrimidin-2(1H)-
one (6a). Yield 482 m g (48%) of a colorless oil. [α]D –75.1 (c 0.865 g/100 m l, CHCl3). For
C
16H28FN2O6P (394.4) calculated: 48.73% C, 7.16% H, 4.82% F, 7.10% N, 7.85% P; foun d:
48.57% C, 7.38% H, 4.63% F, 6.77% N, 7.64% P. FAB MS, m/z: 395 [MH]+ (100). 1H NMR
(500 MHz, CDCl3): 1.30, 1.31 an d 1.32 4 × d, 4 × 3 H, J(vic) = 6.2 (CH3-i-Pr); 1.95 d, 3 H,
J(CH3,6) = 1.1 (CH3); 3.71 dd, 1 H, J(gem ) = 13.7, J(H,P) = 9.3 (H-4′b); 3.79 dd, 1 H, J(gem ) =
13.8, J(1′b,2′) = 7.4 (H-1′b); 3.90 dd, 1 H, J(gem ) = 13.7, J(H,P) = 8.7 (H-4′a); 3.99 s, 3 H
(OCH3); 4.04 m , 1 H (H-2′); 4.18 ddd, 1 H, J(gem ) = 13.8, J(1′a,2′) = 4.3, J(H,F) = 0.6 (H-1′a);
4.45 ddd, 1 H, J(H,F) = 47.3, J(gem ) = 10.7, J(3′b,2′) = 4.8 (H-3′b); 4.70 m , 3 H (H-3′a an d
CH-i-Pr); 7.37 q, 1 H, J(6,CH3) = 1.1 (H-6). 13C NMR (125.8 MHz, CDCl3): 11.96 (CH3-5);
23.89, 23.93, 24.02 an d 24.03 d, J(C,P) = 4.4 (CH3-i-Pr); 50.02 d, J(C,F) = 9.1 (CH2-1′); 54.53
(OCH3); 65.47 d, J(C,P) = 168.6 (CH2-4′); 71.08 an d 71.20 d, J(C,P) = 6.6 (CH-i-Pr); 78.49 dd,
J(C,F) = 18.3, J(C,P) = 10.9 (CH-2′); 82.55 d, J(C,F) = 173.0 (CH2-3′); 104.28 (C-5); 145.62
(CH-6); 156.69 (C-2); 171.07 (C-4). 13F NMR (470.2 MHz, CDCl3): –232.72 dt, J(F,H-3′) =
47.3, J(F,H-2′) = 23.2 (CH2F). IR data were iden tical with 6b.
(R)-1-{2-[(Diisopropoxyphosphoryl)methoxy]-3-fluoropropyl}-4-methoxy-5-methylpyrimidin-2(1H)-
one (6b). Yield 362 m g (36%) of a colorless oil. IR, νm ax (CCl4): 1676, 1655, 1540, 1476,
1399, 1386, 1376, 1335, 1255, 1106, 1010, 992. [α]D +70.8 (c 0.237 g/100 m l, CHCl3). FAB
MS, m/z: 395 [MH]+ (100). 1H, 13C an d 19F NMR data were iden tical with com poun d 6a.
(RS)-1-{2-[(Diisopropoxyphosphoryl)methoxy]-3-fluoropropyl}-4-methoxy-5-methylpyrimidin-
2(1H)-one (6c). Yield 583 m g (58%) of a colorless oil. HR MS (FAB): for C16H28FN2O6P foun d:
395.1725, calculated: 394.1747. MS (FAB), m/z: 395 [MH]+ (72). 1H, 13C, 19F NMR an d IR
data were iden tical with com poun d 6a. or 6b.
Syn th esis of 1-[3-Fluoro-2-(ph osph on om eth oxy)propyl]pyrim idin -2(1H)-on e Derivatives
7a–7c. Gen eral Procedure
A m ixture of com poun d 6 (493 m g, 1.25 m m ol), aceton itrile (10 m l) an d brom otrim eth yl-
silan e (1.8 m l) was stirred at room tem perature overn igh t. Th e m ixture was con cen trated in
vacuo an d th en codistilled with water (2 × 5 m l). Th e residue in water (20 m l) was h eated
with Dowex 50X8 (H+ form ) (3 m l) at 80 °C for 3 h . Th e m ixture was cooled to room tem -
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1476
Pomeisl, Pohl, Holý, Votruba:
perature an d th en filtered. Accordin g to paper electroph oresis of a h ydrolyzed sam ple, th e
reaction was quan titative. Th e filtrate was con cen trated in vacuo an d ch rom atograph ed by
preparative HPLC (S2) or purified on Seph adex (in Cl– form , activated with 0.02 M TEAB,
40 m l) with subsequen t deion ization on activated ch arcoal. Th e relevan t fraction s were com -
bin ed, evaporated in vacuo an d codistilled with water (3 × 10 m l). Th e residue was dissolved
in water (3 m l), applied on to a Dowex 50X8 (Li+ form , 30 m l) an d th en th e colum n was
wash ed with water. Th e appropriate UV absorbin g fraction con tain in g product 6 was evapo-
rated to dryn ess in vacuo. Th e residue was dissolved in water an d lyoph ilized. Th e followin g
com poun ds were obtain ed as dilith ium salts:
(S)-1-[3-Fluoro-2-(phosphonomethoxy)propyl]thymine (7a). Yield 215 m g (56%) of a wh ite
solid, m .p. 233–235 °C. IR, νm ax (KBr): 3199, 3058, 1691, 1469, 1438, 1385, 1352, 1230,
1182, 1098, 1074, 996, 924, 552, 455, 422. [α]D –22.5 (c 0.561 g/100 m l, H2O). HPLC: 98%
(S3). For C9H12FLi2N2O6P·H2O (326.1) calculated: 33.15% C, 4.33% H, 5.83% F, 8.59% N,
9.50% P; foun d: 33.43% C, 4.74% H, 6.05% F, 8.49% N, 9.36% P. FAB MS, m/z: 309 [MH]+
(18). 1H NMR (400 MHz, D2O): 1.88 d, 3 H, J(CH3,6) = 1.2 (CH3); 3.62 dd, 1 H, J(gem ) =
12.8, J(H,P) = 9.2 (H-4′b); 3.71 dd, 1 H, J(gem ) = 12.8, J(H,P) = 9.2 (H-4′a); 4.00 m , 3 H (H-1′
an d H-2′); 4.52 ddd, 1 H, J(H,F) = 46.5, J(gem ) = 10.7, J(3′b,2′) = 3.6 (H-3′b); 4.70 ddd, 1 H,
J(H,F) = 47.7, J(gem ) = 10.7, J(3′a,2′) = 3.0 (H-3′a); 7.57 q, 1 H, J(6,CH3) = 1.2 (H-6). 13C NMR
(100.6 MHz, D2O): 11.89 (CH3-5); 48.38 d, J(C,F) = 7.5 (CH2-1′); 67.81 d, J(C,P) = 154.3
(CH2-4′); 78.27 dd, J(C,F) = 18.3, J(C,P) = 10.9 (CH-2′); 83.00 d, J(C,F) = 167.6 (CH2-3′);
111.23 (C-5); 144.48 (CH-6); 153.06 (C-2); 167.72 (C-4). 19F NMR (470.2 MHz, D2O):
–231.48 dt, J(F,H-3′) = 47.1, J(F,H-2′) = 25.9 (CH2F).
(R)-1-[3-Fluoro-2-(phosphonomethoxy)propyl]thymine (7b). Yield 223 m g (58%) of a wh ite
am ourph ous solid. IR, νm ax (KBr): 3191, 3062, 1689, 1475, 1439, 1385, 1353, 1226, 1178,
1074, 1113, 995, 924,787, 715, 547, 465, 429, 418. [α]D +19.3 (c 0.429 g/100 m l, H2O).
HPLC: 96% (S3). For C9H12FLi2N2O6P·3/5H2O (318.9) calculated: 33.90% C, 4.14% H, 5.96%
F, 8.79% N, 9.71% P; foun d: 33.90% C, 4.15% H, 5.87% F, 8.62% N, 9.48% P. FAB MS, m/z:
309 [MH]+ (21). 1H, 13C an d 19F NMR data were iden tical with com poun d 7a.
(RS)-1-[3-Fluoro-2-(phosphonomethoxy)propyl]thymine (7c). Yield 146 m g (38%) of a wh ite
am orph ous solid. HPLC: 95% (S3). HR MS (FAB): for C9H12FN2O6P foun d: 309.0820, calcu-
lated: 309.0815. For C9H12FLi2N2O6P·H2O (326.1) calculated: 33.15% C, 4.33% H, 5.83% F,
8.59% N, 9.50% P; foun d: 33.42% C, 4.17% H, 6.07% F, 8.16% N, 9.77% P. FAB MS, m/z:
309 [MH]+ (8). 1H, 13C, 19F NMR an d IR data were iden tical with com poun d 7a.
(S)-1-{2-[(Diisopropoxyph osph oryl)m eth oxy]-3-(trityloxy)propyl}th ym in e (8)
A m ixture of com poun d 2a (4 g, 8.8 m m ol), [(diisopropoxyph osph oryl)m eth oxy]m eth yl
tosylate (4.1 g, 11.7 m m ol) an d 60% sodium h ydride dispersion (591 m g, 14.8 m m ol) in
tetrah ydrofuran (150 m l) was stirred at –20 °C. Th e suspen sion was let to warm to room
tem perature for 1 h an d th en stirred overn igh t. Th e m ixture was filtered th rough a Celite
pad an d con cen trated in vacuo. Th e residue was filtered on silica gel (toluen e–eth yl acetate–
m eth an ol–trieth ylam in e 7:1.5:1:1), relevan t fraction s were com bin ed an d evaporated to dry-
n ess in vacuo. Th e crude product was th en ch rom atograph ed on silica gel (ch loroform –
trieth ylam in e 200:1 an d ch loroform –m eth an ol–trieth ylam in e 26:1:1). Yield 4.0 g (73%) of 8
as a wh ite sirupy product. IR, νm ax (CCl4): 3412, 1715, 1694, 1655, 1386, 1375, 1257, 1107,
1009, 991. HR MS (FAB): for C34H41N2O7P foun d: 620.2675, calculated: 620.2651. FAB MS,
m/z: 379 [M + H – Ph 3C]+ (16), 295 (13), 243 (100), 165 (12), 137 (25), 109 (10), 96 (6), 61
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Transformation of Thymine Derivatives
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(5). 1H NMR (400 MHz, CDCl3): 1.27, 1.29, 1.31 an d 1.32 4 × d, 4 × 3 H, J(vic) = 6.2
(CH3-i-Pr); 1.85 d, 3 H, J(CH3,6) = 1.2 (CH3-5); 3.12 dd, 1 H, J(gem ) = 10.7, J(3′b,2′) = 4.2
(H-3′b); 3.34 dd, 1 H, J(gem ) = 10.7, J(3′a,2′) = 4.0 (H-3′a); 3.61 dd, 1 H, J(gem ) = 13.6,
J(H,P) = 9.5 (H-4′b); 3.72 dd, 1 H, J(gem ) = 13.9, J(1′b,2′) = 7.5 (H-1′b); 3.80 dq, 1 H, J(2′,1′) =
7.5, 4.0, J(2′,3′) = 4.2, 4.0 (H-2′); 3.86 dd, 1 H, J(gem ) = 13.6, J(H,P) = 8.6 (H-4′a); 4.10 dd,
1 H, J(gem ) = 13.9, J(1′a,2′) = 4.0 (H-1′a); 4.71 dh , 2 H, J(H,P) = 7.7, J(vic) = 6.2 (CH-i-Pr);
7.14 q, 1 H, J(6,CH3) = 1.2 (H-6); 7.25 m , 3 H (p-H-Ph ); 7.31 m , 6 H (m-H-Ph ); 7.43 m , 6 H
(o-H-Ph ); 7.98 bs, 1 H (NH). 13C NMR (100.6 MHz, CDCl3): 12.25 (CH3-5); 23.98 d, J(C,P) =
4.7 (CH3-i-Pr); 24.07 d, J(C,P) = 4.8 (CH3-i-Pr); 49.54 (CH2-1′); 62.22 (CH2-3′); 64.87 d,
J(C,P) = 168.9 (CH2-4′); 70.94 d, J(C,P) = 6.6 (CH-i-Pr); 71.06 d, J(C,P) = 6.6 (CH-i-Pr);
79.10 d, J(C,P) = 11.4, CH-2′); 87.02 (C-Tr); 109.68 (C-5); 127.27 (p-CH-Ph ); 127.97
(m-CH-Ph ); 128.54 (o-CH-Ph ); 142.21 (CH-6); 143.42 (i-C-Ph ); 150.58 (C-2); 163.75 (C-4).
(S)-1-{2-[(Diisopropoxyph osph oryl)m eth oxy]-3-h ydroxypropyl}th ym in e (9)
A solution of com poun d 8 (2.4 g, 3.8 m m ol) in m eth an ol (150 m l) was h eated with Dowex
50X8 (H+ form , 20 m l) at 80 °C for 11 h un til th e con version of startin g ph osph on ate to 9
was com plete (TLC, ch loroform –m eth an ol 12:1). Th e m ixture was th en filtered an d con cen -
trated in vacuo. Th e residue was ch rom atograph ed on n eutral alum in um oxide (ch loroform –
m eth an ol 12:1). Yield 971 m g (70%) of 9 as a colorless oil. IR, νm ax (CCl4): 3410, 3400,
1716, 1693, 1387, 1376, 1257, 1104, 1011, 994. [α]D –66.4 (c 0.440 g/100 m l, CHCl3). For
C
15H27N2O7P (378.4) calculated: 47.62% C, 7.19% H, 7.40% N, 8.19% P; foun d: 47.39% C,
7.37% H, 7.02% N, 8.50% P. FAB MS, m/z: 379 [MH]+ (70). 1H NMR (400 MHz, DMSO-d6):
1.19, 1.20, 1.21 an d 1.23 4 × d, 4 × 3 H, J(vic) = 6.2 (CH3-i-Pr); 1.74 d, 3 H, J(CH3,6) = 1.2
(CH3-5); 3.41–3.54 m , 2 H (H-3′); 3.58 dd, 1 H, J(gem ) = 13.8, J(1′b,2′) = 8.1 (H-1′b); 3.65 m ,
1 H (H-2′); 3.73 dd, 1 H, J(gem ) = 14.0, J(H,P) = 9.3 (H-4′b); 3.88 dd, 1 H, J(gem ) = 13.8,
J(1′a,2′) = 3.9 (H-1′a); 3.89 dd, 1 H, J(gem ) = 14.0, J(H,P) = 8.1 (H-4′a); 4.54 m , 2 H (CH-i-Pr);
4.82 t, 1 H, J(OH,3′) = 5.6 (OH-3′); 7.37 q, 1 H, J(6,CH3) = 1.2, H-6); 11.24 s, 1 H (NH).
13C NMR (100.6 MHz, DMSO-d6): 12.21 (CH3-5); 23.91 d, J(C,P) = 4.8 (CH3-i-Pr); 48.66
(CH2-1′); 60.27 (CH2-3′); 63.62 d, J(C,P) = 164.6 (CH2-4′); 70.28 d, J(C,P) = 6.6 (CH-i-Pr);
79.90 d, J(C,P) = 10.7 (CH-2′); 107.92 (C-5); 142.69 (CH-6); 151.22 (C-2); 164.53 (C-4).
(S)-[3-(Diisopropoxyph osph oryl)m eth oxy]-7-m eth yl-3,4-dih ydro-
2H-pyrim ido[2,1-b][1,3]oxazin -8(9H)-on e (10)
A m ixture of 1,8-diazabicyclo[5.4.0]un dec-7-en e (400 m g, 2.6 m m ol) an d 92% perfluorobutan e-
1-sulfon yl fluoride (800 m g, 2.6 m m ol) in toluen e (5 m l) was stirred at room tem perature
for 10 m in . A solution of com poun d 9 (330 m g, 0.9 m m ol) in toluen e (10 m l) was added.
Th e resultin g m ixture was stirred at room tem perature overn igh t un til th e con version of
startin g ph osph on ate to 10 was com plete (TLC in ch loroform –m eth an ol 2:1). Th e m ixture
was evaporated to dryn ess in vacuo an d separated by preparative TLC (S1, ch loroform –
m eth an ol 2:1). Yield 350 m g (53%) of 10 as a wh ite sirupy product. IR, νm ax (CHCl3): 1668,
1648, 1629, 1527, 1496, 1388, 1377, 1255, 1103, 1018, 1000. HR MS (FAB): for C15H26N2O6P
foun d: 361.1554, calculated: 361.1529. 1H NMR (500 MHz, CDCl3): 1.26, 1.30, 1.32 an d 1.36
4 × d, 4 × 3 H, J(vic) = 6.2 (CH3-i-Pr); 1.92 d, 3 H, J(CH3,6) = 1.2 (CH3-5); 3.79 dd, 1 H,
J(gem ) = 14.0, J(H,P) = 8.1 (H-4′b); 3.91 dd, 1 H, J(gem ) = 14.0, J(H,P) = 8.7 (H-4′a); 4.01 dt,
1 H, J(gem ) = 12.9, J(1′b,2′) = 2.5, J(1′b,3′a) = 2.5 (H-1′b); 4.23 dd, 1 H, J(gem ) = 12.9,
J(1′a,2′) = 3.1 (H-1′a); 4.28 p, 1 H, J(2′,1′) = 3.1, 2.5, J(2′,3′) = 2.7, 1.9 (H-2′); 4.52 dd, 1 H,
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Pomeisl, Pohl, Holý, Votruba:
J(gem ) = 12.3, J(3′b,2′) = 1.9 (H-3′b); 4.58 dt, 1 H, J(gem ) = 12.3, J(3′a,2′) = 2.7, J(3′a,1′b) =
2.5 (H-3′a); 4.66 an d 4.72 2 ( dh , 2 ( H, J(H,P) = 7.6, J(vic) = 6.2 (CH-i-Pr); 6.86 q, 1 H,
J(6,CH3) = 1.2 (H-6). 13C NMR (125.8 MHz, CDCl3): 13.36 (CH3-5); 23.82, 23.96 an d 24.00 d,
J(C,P) = 4.8 (CH3-i-Pr); 51.02 (CH2-1′); 64.05 d, J(C,P) = 168.8 (CH2-4′); 66.75 (CH2-3′);
69.15 d, J(C,P) = 8.1 (CH-2′); 71.59 an d 71.81 d, J(C,P) = 6.8 (CH-i-Pr); 119.93 (C-5); 137.54
(CH-6); 154.02 (C-2); 171.56 (C-4).
Dilith ium Salt of (R)- an d (S)-1-[3-Hydroxy-2-(ph osph on om eth oxy)propyl]th ym in e
(11a) an d (11b)
Com poun ds 11a an d 11b were obtain ed as dilith ium salts by th e sam e procedure reported
for 7a–7c.
(S)-1-[3-Hydroxy-2-(phosphonomethoxy)propyl]thymine (11a). A m ixture of com pound 9 (257 m g,
0.68 m m ol) in aceton itrile (10 m l) an d brom otrim eth ylsilan e (0.90 m l) afforded 123 m g
(61%) of 11a as a wh ite solid, m .p. > 300 °C. IR, νm ax (KBr): 3423, 3199, 3057, 2954, 1686,
1474, 1437, 1386, 1353, 1225, 1172, 1102, 1077, 998, 916, 579, 552, 475, 425. [α]D –23.0
(c 0.321 g/100 m l, H2O). HPLC: 98% (S3). For C9H13Li2N2O7P (306.1) calculated: 35.32% C,
4.28% H, 9.15% N, 10.12% P; foun d: 35.30% C, 4.68% H, 8.84% N, 9.81% P. 1H NMR
(500 MHz, D2O): 1.82 d, 3 H, J(CH3,6) = 1.2 (CH3-5); 3.48 dd, 1 H, J(gem ) = 12.4, J(3′b,2′) =
4.8 (H-3′b); 3.50 dd, 1 H, J(gem ) = 12.6, J(H,P) = 9.5 (H-4′b); 3.54 dd, 1 H, J(gem ) = 12.6,
J(H,P) = 9.0 (H-4′a); 3.65 dddd, 1 H, J(2′,3′) = 7.3, 3.4, J(2′,1′) = 6.7, 4.8 (H-2′); 3.72 dd, 1 H,
J(gem ) = 12.4, J(3′a,2′) = 3.4 (H-3′a); 3.80 dd, 1 H, J(gem ) = 14.5, J(1′b,2′) = 6.7 (H-1′b);
3.89 dd, 1 H, J(gem ) = 14.5, J(1′a,2′) = 4.8 (H-1′a); 7.49 q, 1 H, J(6,CH3) = 1.2 (H-6). 13C NMR
(125.8 MHz, D2O): 11.92 (CH3-5); 49.14 (CH2-1′); 61.03 (CH2-3′); 67.53 d, J(C,P) = 155.1
(CH2-4′); 80.54 d, J(C,P) = 11.5 (CH-2′); 111.08 (C-5); 144.66 (CH-6); 153.09 (C-2); 167.73
(C-4).
(R)-1-[3-Hydroxy-2-(phosphonomethoxy)propyl]thymine (11b ). A m ixture of com poun d 5b
(331 m g, 0.84 m m ol) in aceton itrile (15 m l) an d brom otrim eth ylsilan e (1.1 m l) afforded
136 m g (53%) of 11b as a wh ite solid, m .p. > 300 °C. IR: νm ax (KBr) 3432, 3265, 3051, 1691,
1474, 1438, 1356, 1225, 1104, 1080, 995, 912, 787, 762, 553, 463. [α]D +25.2 (c 0.228 g/
100 m l, H2O). HPLC: 97% (S3). For C9H13Li2N4O7P·0.75H2O (319.6) calculated: 33.82% C,
4.54% H, 8.77% N, 9.69% P; foun d: 33.92% C, 4.69% H, 8.36% N, 9.31% P. FAB MS, m/z:
307 [MH]+ (22). 1H, an d 13C NMR data were iden tical with com poun d 11a.
Syn th esis of 1-[2-(Ph osph on om eth oxy)propyl]th ym in e Derivatives 13 an d 14.
Gen eral Procedure
A m ixture of 4-m eth oxy-5-m eth ylpyrim idin -2(1H)-on e (800 m g, 5.7 m m ol) an d 60% sodium
h ydride dispersion (228 m g, 5.7 m m ol) in dim eth ylform am ide (20 m l) was stirred at room
tem perature for 1 h . Com poun d 12a or 12b (2.3 g, 5.7 m m ol) in dim eth ylform am ide (10 m l)
was added an d th e resultin g m ixture was h eated at 80 °C for 4.5 h . Th e m ixture was th en
h eated at 100 °C for 8 h . Th e m ixture was con cen trated in vacuo an d th e residue was dis-
solved in eth er (60 m l). Th e precipitate was filtered off th rough a Celite an d wash ed with
eth er (60 m l). Th e filtrate was con cen trated in vacuo an d th e residue was ch rom atograph ed
on n eutral alum in um oxide (ch loroform –m eth an ol 25:1).
(S)-1-{2-[(Diisopropoxyphosphoryl)methoxy]propyl}-4-methoxy-5-methylpyrimidin-2(1H)-one
(13a). Yield 774 m g (36%) of a yellowish oil, RF 0.25. [α]D +90.6 (c 0.587 g/100 m l, CHCl3).
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Transformation of Thymine Derivatives
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HR MS (FAB): for C16H30N2O6P foun d: 377.1830, calculated: 377.1841. FAB MS, m/z: 377
[MH]+ (78). 1H NMR (400 MHz, CDCl3): 1.22 d, 3 H, J(vic) = 6.3 (CH3-2′); 1.27 d, 6 H,
J(vic) = 6.2 (2 × CH3-i-Pr); 1.30 d, 3 H, J(vic) = 6.2 (CH3-i-Pr); 1.31 d, 3 H, J(vic) = 6.2
(CH3-i-Pr); 1.94 d, 3 H, J(CH3,6) = 1.1 (CH3-5); 3.45–3.54 m , 2 H (H-1′b an d H-4′b); 3.77 dd,
1 H, J(gem ) = 13.4, J(H,P) = 9.3 (H-4′a); 3.88 m , 1 H (H-2′); 3.98 s, 3 H (OCH3); 4.20 dd, 1 H,
J(gem ) = 13.8, J(1′a,2′) = 2.6 (H-1′a); 4.68 dh , 2 H, J(H,P) = 7.7, J(vic) = 6.2 (CH-i-Pr); 7.37 q,
1 H, J(6,CH3) = 1.1 (H-6). 13C NMR (100.6 MHz, CDCl3): 12.02 (CH3-5); 16.52 (CH3-2′);
23.93, 23.96 an d 24.04 d, J(C,P) = 4.7 (CH3-i-Pr); 54.49 (OCH3); 54.50 (CH2-1′); 63.65 d,
J(C,P) = 170.2 (CH2-4′); 70.83 an d 70.96 d, J(C,P) = 6.6 (CH-i-Pr); 76.15 d, J(C,P) = 13.1
(CH-2′); 103.68 (C-5); 145.97 (CH-6); 156.79 (C-2); 170.84 (C-4).
(R)-1-{2-[(Diisopropoxyphosphoryl)methoxy]propyl}-4-methoxy-5-methylpyrimidin-2(1H)-one
(13b). Yield, 300 m g (14%) of a yellowish oil, RF 0.25. [α]D –83.4 (c 0.225 g/100 m l, CHCl3).
HR MS (FAB): for C16H30N2O6P foun d: 377.1836, calculated: 377.1841. FAB MS, m/z: 377
[MH]+ (100). 1H an d 13C NMR data were iden tical with th ose of com poun d 13a.
(S)-2-{2-[(Diisopropoxyphosphoryl)methoxy]propoxy}-4-methoxy-5-methylpyrimidine (14a). Yield
858 m g (40%) of a yellowish oil, RF 0.50. [α]D +8.1 (c 0.744 g/100 m l, CHCl3). IR, νm ax
(CCl4): 1608, 1575, 1475, 1425, 1397, 1386, 1375, 1295, 1259, 1107, 1011, 990. HR MS
(FAB): for C16H30N2O6P foun d: 377.1859, calculated: 377.1841. FAB MS, m/z: 377 [MH]+
(76). 1H NMR (400 MHz, CDCl3): 1.29 d, 3 H, J(vic) = 6.4 (CH3-2′); 1.31, 1.32, 1.33 an d 1.34
4 × d, 4 × 3 H, J(vic) = 6.2 (4 × CH3-i-Pr); 2.05 d, 3 H, J(CH3,6) = 0.9 (CH3-5); 3.87 dd, 1 H,
J(gem ) = 13.5, J(H,P) = 9.3 (H-4′b); 3.92 dd, 1 H, J(gem ) = 13.5, J(H,P) = 9.1 (H-4′a); 3.97 m ,
1 H (H-2′); 3.97 s, 3 H (OCH3); 4.23 dd, 1 H, J(gem ) = 11.2, J(1′b,2′) = 4.7 (H-1′b); 4.39 dd,
1 H, J(gem ) = 11.2, J(1′a,2′) = 6.3 (H-1′a); 4.75 dh , 2 H, J(H,P) = 8.0, J(vic) = 6.2 (CH-i-Pr);
7.95 q, 1 H, J(6,CH3) = 0.9 (H-6). 13C NMR (100.6 MHz, CDCl3): 11.84 (CH3-5); 16.95
(CH3-2′); 23.95 d, J(C,P) = 4.7 (CH3-i-Pr); 24.10 d, J(C,P) = 3.7 (CH3-i-Pr); 53.84 (OCH3);
64.19 d, J(C,P) = 168.4 (CH2-4′); 70.19 (CH2-1′); 70.96 an d 71.03 d, J(C,P) = 6.8 (CH-i-Pr);
76.00 d, J(C,P) = 12.3 (CH-2′); 111.18 (C-5); 156.91 (CH-6); 163.41 (C-2); 169.58 (C-4).
(R)-2-{2-[(Diisopropoxyphosphoryl)methoxy]propoxy}-4-methoxy-5-methylpyrimidine (14b). Yield
365 m g (17%) of a yellowish oil, RF 0.50. HR MS (FAB): for C16H30N2O6P foun d: 377.1838,
calculated: 377.1841. FAB MS, m/z: 377 [MH]+ (89). 1H, 13C NMR an d IR data were iden tical
with com poun d 14a.
Syn th esis of 1-[2-(Ph osph on om eth oxy)propyl]th ym in e Derivatives 15a an d 15b.
Gen eral Procedure
A m ixture of com poun ds 13a or 13b (2.18 m m ol) in aceton itrile (25 m l) an d brom otri-
m eth ylsilan e (3 m l) afforded derivatives 15a an d 15b wh ich were obtain ed as dilith ium salts
by th e sam e procedure as for 7a–7c.
(S)-1-[2-(phosphonomethoxy)propyl]thymine (15a). Yield 164 m g (26%) of a wh ite solid, m .p.
> 300 °C. IR, νm ax (KBr): 3205, 3058, 2978, 1691, 1473, 1438, 1386, 1350, 1230, 1100, 1074,
995, 923, 785, 714, 579, 556, 454, 422. [α]D +28.4 (c 0.343 g/100 m l, H2O). HPLC: 99% (S3).
HR MS (FAB): for C9H13Li2N2O6P foun d: 291.0903, calculated: 291.0910. For C9H13Li2N2O6P·
2/5H2O (297.3) calculated: 36.36% C, 4.64% H, 9.42% N, 10.41% P; foun d: 36.78% C,
4.88% H, 9.13% N, 10.00% P. FAB MS, m/z: 291 [MH]+ (82). 1H NMR (500 MHz, D2O):
1.11 d, 3 H, J(vic) = 6.15 (CH3-2′); 1.81 d, 3 H, J(CH3,6) = 1.2 (CH3-5); 3.43 dd, 1 H, J(gem ) =
13.0, J(H,P) = 9.4 (H-4′b); 3.58 dd, 1 H, J(gem ) = 13.0, J(H,P) = 9.3 (H-4′a); 3.71 dd, 1 H,
J(gem ) = 13.8, J(1′b,2′) = 6.6 (H-1′b); 3.78 m , 1 H (H-2′); 3.82 dd, 1 H, J(gem ) = 13.8,
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Pomeisl, Pohl, Holý, Votruba:
J(1′a,2′) = 3.6 (H-1′a); 7.48 q, 1 H, J(6,CH3) = 1.2 (H-6). 13C NMR (125.8 MHz, D2O): 11.91
(CH3-5); 16.70 (CH3-2′); 52.63 (CH2-1′); 66.09 d, J(C,P) = 156.00 (CH2-4′); 76.56 d, J(C,P) =
11.3 (CH-2′); 110.93 (C-5); 144.79 (CH-6); 153.21 (C-2); 167.76 (C-4).
(R)-1-[2-(Phosphonomethoxy)propyl]thymine (15b). Yield 10.3 g (63%) of a wh ite solid, m .p.
> 300 °C. IR, νm ax (KBr): 3260, 3055, 2980, 1688, 1476, 1438, 1385, 1351, 1227, 1107, 1081,
922, 785, 716, 562, 465. [α]D –27.5 (c 0.202 g/100 m l, H2O). HPLC: 98% (S3). HR MS (FAB):
for C9H13Li2N2O6P foun d: 291.0918, calculated: 291.0910. FAB MS, m/z: 291 [MH]+ (10). 1H
an d 13C NMR data were iden tical with th ose of com poun d 15a.
The study has been supported by grant No. 203/03/0089 (Grant Agency of the Czech Republic) as a
part of research project Z 40550506 of the Institute of Organic Chemistry and Biochemistry and by
Descartes Prize HPAW-CT-2002-9001. The authors thank Dr J. Günter, Dr M. Krečmerová for valu-
able discussions and to Analytical Department of the Institute for assistance (Dr K. Ubik, Head).
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Transformation of Thymine Derivatives
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