Synthesis of 8-amino-and N-substituted 8-aminoadenine derivatives of acyclic nucleoside and nucleotide analogs

Article abstract of DOI:10.1135/cccc20010517

8-Aminoadenine derivatives 2 were obtained from 8-bromoadenines 1 in one-pot reaction via 8-azidoadenines. Reaction of 8-bromoadenines 1 with methylamine or dimethylamine in ethanol afforded the corresponding N⁹-substituted 8-(methylamino)adeni

Full text of DOI:10.1135/cccc20010517

Acyclic Nucleoside and Nucleotide Analogs
517
SYNTHESIS OF 8-AMINO- AND N-SUBSTITUTED 8-AMINOADENINE
DERIVATIVES OF ACYCLIC NUCLEOSIDE AND NUCLEOTIDE
ANALOGS
1
,
2
Zlatko JANEBA *, Antonín HOLÝ and Milena MASOJÍDKOVÁ
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,
1
2
1
66 10Prague 6, Czech Republic; e-mail: janeba@uochb.cas.cz, holy@uochb.cas.cz
Received Jan uary 25, 2001
Accepted March 2, 2001
8
-Am in oaden in e derivatives 2 were obtain ed from 8-brom oaden in es 1 in on e-pot reaction
via 8-azidoaden in es. Reaction of 8-brom oaden in es 1 with m eth ylam in e or dim eth ylam in e in
9
eth an ol afforded th e correspon din g N -substituted 8-(m eth ylam in o)aden in es
3 an d
8
-(dim eth ylam in o)aden in es 4. Alkylation of 8-am in oaden in e (2a) with diverse alkylation
9
agen ts afforded N -substituted 8-am in oaden in e derivatives 2, an d alkylation of
8
8
9
-(dim eth ylam in o)aden in e (4a ) gave m ixtures of th e correspon din g N -substituted
3
-(dim eth ylam in o)aden in es 4 an d th eir N -substituted regioisom ers 5. 8,3′-N-An h ydro deriv-
atives
7 were prepared by tosylation of (S)-8-brom o-9-{2-[(diisopropoxyph osph oryl)-
m eth oxy]-3-h ydroxypropyl}aden in e (1c) followed by treatm en t with m eth an olic am m on ia
or m eth ylam in e solution .
Keyw ord s: Purin es; Acyclic n ucleotide an alogues; Am in es; Alkylation ; N-Cyclon ucleosides;
Nucleosides; An tivirals.
Th e im portan ce of 8-substituted purin e derivatives in n ucleoside an d n ucleo-
tide ch em istry an d th eir poten cy as biologically active com poun ds is
1
well-kn own . Of th em , 8-am in o derivatives (e.g. 8-am in oguan osin e or
2
8
-am in o-9-ben zylguan in e ) are poten tial im m un om odulators. 8-Am in o-
aden osin e, wh ich is resistan t to aden osin e deam in ase, in h ibits growth of
3
sarcom a 180 ascites cells . 8-Am in opurin e n ucleosides also attract in terest
4
because of th eir structural sim ilarity to a paralytic m arin e toxin , saxitoxin .
Th is work is a con tin uation of th e structure–biological activity relation -
sh ip (SAR) studies in th e series of N-(2,3-dih ydroxypropyl) (DHP), N-[2-
(
ph osph on om eth oxy)eth yl] (PME), an d (S)-N-[3-h ydroxy-2-(ph osph on o-
5
m eth oxy)propyl] (HPMP) derivatives of h eterocyclic bases . Th e syn th esis
of th e DHP, PME an d HPMP derivatives with various substituen ts in posi-
tion 8 of aden in e was un dertaken in order to obtain in form ation about th e
effect of substitution in th is position on th e biological activity in th ese series.
Collect. Czech. Chem. Commun. (Vol. 66) (2001)
doi: 10.1135/cccc20010517

5
18
Janeba, Holý, Masojídková:
Our recen t studies were aim ed at com poun ds derived from 8-h ydroxy-
6
aden in e (6-am in o-7H-purin e-8(9H)-on e) , 8-sulfan yladen in e (6-am in o-7H-
7
7
purin e-8(9H)-th ion e) , an d 8-(m eth ylsulfan yl)aden in e . Th is work deals
with an alogous com poun ds bearin g am in o or substituted am in o group in
position 8 of th e purin e base. It is con tin uation of a recen t prelim in ary
8
study dealin g with 8-am in oaden in e derivatives m ade in th is Laboratory .
RESULTS AND DISCUSSION
In an alogy to th e previous papers m en tion ed6,7, two prin cipal approach es
for th e syn th esis of 8-am in o derivatives were used in th is study: (i) m odifi-
cation of th e correspon din g acyclic n ucleotide derivatives in position 8 of
th e purin e m oiety or (ii) preparation of th e 8-am in o an d 8-(dim eth yl-
am in o) aden in e base an d th eir subsequen t alkylation with a suitable re-
agen t. Diverse alkylation agen ts were used in order to in vestigate
regioselectivity of th e alkylation s: m eth yl tosylate, diisopropyl [(2-ch loro-
eth oxy)m eth yl]ph osph on ate (PME reagen t)9 an d (S)-[(trityloxy)m eth yl]-
oxiran e [(S)-O-tritylglycidol], in DMF an d with sodium h ydride or cesium
carbon ate as a base.
8
-Am in oaden in e derivatives of acyclic n ucleotide an alogs 2 were pre-
1
0
pared in on e-pot reaction via 8-azido derivatives in satisfactory yields :
Treatm en t of th e correspon din g 8-brom oaden in e derivatives 1 with lith ium
azide in DMF at 110 °C followed by catalytic h ydrogen ation in m eth an ol at
1
1
room tem perature afforded 8-am in oaden in e com poun ds 2 (Sch em e 1) .
NH2
NH2
NH2
N
N
N
N
CH3
R'
N
(i), (ii)
N
(iii)
N
NH2
Br
N
N
R
N
R
N
R
N
N
2
1
3
, R' = H
4, R' = CH3
1
, 2, 4 a, R = H
-4 b, R = CH2CH2OCH2P(O)(OiPr)2
c, R = (S)-CH2CH(CH2OH)OCH2P(O)(OiPr)2
1
2
, 3, 4 d, R = CH2CH2OCH2P(O)(OH)2
(iv)
e, R = (S)-CH2CH(CH2OH)OCH2P(O)(OH)2
o
o
(
i) LiN3, DMF, 110 C; (ii) H2, Pd/C, MeOH; (iii) CH3NH2 or (CH3)2NH/EtOH, 100 C;
iv) TMSBr, MeCN
(
SCHEME 1
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Acyclic Nucleoside and Nucleotide Analogs
519
Syn th esis of com poun ds con tain in g m eth ylam in o or dim eth ylam in o
group in position 8 of th e purin e m oiety was perform ed by th e reaction of
th e appropriate 8-brom o derivative 1 with solution of m eth ylam in e or
dim eth ylam in e in eth an ol in an autoclave at 100 °C. Th e ph osph on ate
diesters afforded by cleavage un der stan dard con dition s usin g brom o-
(
trim eth yl)silan e (TMSBr) in aceton itrile followed by h ydrolysis th e free
ph osph on ates wh ich were isolated by ion -exch an ge ch rom atograph y.
Th e m odified aden in e bases n eeded for subsequen t alkylation s were pre-
pared un der sim ilar reaction con dition s as m en tion ed for tran sform ation of
acyclic n ucleotide an alogs (Sch em e 1). 8-Brom oaden in e (1a) gave, on treat-
m en t with lith ium azide in DMF followed by catalytic h ydrogen ation ,
8
-am in oaden in e (2a) in 51% overall yield. So far, 8-am in oaden in e was pre-
1
2
pared by oth er m eth ods an d ch aracterized as its salts . 8-(Dim eth yl-
am in o)aden in e (4a) was obtain ed by th e reaction of th e brom o derivative
1
a with eth an olic dim eth ylam in e in an autoclave (yield 90%). Altern a-
tively, com poun d 4a was also prepared by h eatin g of 1a with ben zylam in e
8
in DMF (ref. ). In th is case, th e reaction took about h alf of th e tim e n eeded
for th e above m en tion ed procedure wh ile th e yield of 8-(dim eth yl-
am in o)aden in e am oun ted to 66%. Th is reaction can be explain ed by tran s-
fer of form yl group from DMF to ben zylam in e followed by reaction of
liberated dim eth ylam in e with 8-brom oaden in e (1a).
In th e alkylation reaction of 8-am in oaden in e (2a) with th e above
9
alkylation reagen ts, th e N -subtituted derivatives were successfully isolated
from th e reaction m ixture as th e on ly regioisom ers (Sch em e 2). Th us, th e
9
N -m eth yl derivative 2f, th e PME derivative 2b iden tical with th e auth en tic
NH2
N
NH2
N
N
N
N
(i)
N
NH2
NH2
N
H
N
R
2a
2b,d,f-h
2
2
2
2
2
f, R = CH3
b, R = CH2CH2OCH2P(O)(OiPr)2
d, R = CH2CH2OCH2P(O)(OH)2
g, R = (S)-CH2CH(OH)CH2OTr
h, R = (S)-CH2CH(OH)CH2OH
(
ii)
(
iii)
(
if) MeOTs, DMF, NaH; (ib) ClCH2CH2OCH2P(O)(OiPr)2, DMF, NaH;
ig) (S)-O-tritylglycidol, DMF, Cs2CO3; (ii) TMSBr, MeCN; (iii) Dowex 50 (H ), 50% aq. MeOH
+
(
SCHEME 2
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

5
20
Janeba, Holý, Masojídková:
com poun d prepared by base m odification of th e correspon din g acyclic n u-
cleotide an alog (Sch em e 1), an d (S)-8-am in o-9-(2,3-dih ydroxypropyl)ade-
1
3
n in e (2h ) (ref. ; deals with th e racem ic com poun d prepared by differen t
procedures) after deprotection of th e trityl derivative 2g were obtain ed.
Con trary to com poun d 2a, alkylation of 8-(dim eth ylam in o)aden in e (4a)
9
3
gave a m ixture of N -substituted derivatives 4 an d N -substituted deriva-
tives 5 in an approxim ate ratio 1 : 1 to 1 : 2 (Sch em e 3). With sodium h y-
3
dride as a base for alkylation , N -alkyl isom ers were isolated as salts:
com poun d 5f as tosylate an d com poun d 5b as h ydroch loride. Th e trityl de-
rivatives 4g an d 5g gave on acid deprotection com poun ds 4h an d 5h , re-
spectively.
NH2
NH2
NH2
N
CH3
CH3
N
CH3
CH3
N
N
CH3
CH3
N
(i)
N
N
N
N
+
N
N
H
N
R
N
N
N
R
4a
4b,d,f-h
5b,d,f-h
f, R = CH3
b, R = CH2CH2OCH2P(O)(OiPr)2
d, R = CH2CH2OCH2P(O)(OH)2
g, R = (S)-CH2CH(OH)CH2OTr
h, R = (S)-CH2CH(OH)CH2OH
(
ii)
(
iii)
(
if) MeOTs, DMF, NaH; (ib) ClCH2CH2OCH2P(O)(OiPr)2, DMF, NaH;
ig) (S)-O-tritylglycidol, DMF, Cs2CO3; (ii) TMSBr, MeCN; (iii) Dowex 50 (H ), 50% aq. MeOH
+
(
SCHEME 3
Syn th eses of n um erous purin e N-cyclon ucleosides were reported in th e
1
4
literature . Startin g com poun ds for th e cyclization s were 8-brom opurin e
n ucleosides bearin g a leavin g group (Ms or Ts) on a carboh ydrate m oiety.
In th e precedin g studies6 , we h ave described th e preparation of th e acy-
clic n ucleotide an alogs derived from HPMPA, with O-an h ydro or S-an h ydro
,7
lin kage. An alogous com poun ds con tain in g NH-an h ydro or N(CH )-
3
an h ydro lin kages 7c an d 7d , respectively, were also obtain ed in m oderate
overall yields (17 an d 26%, respectively) by tosylation of th e brom o deriva-
tive 1c followed by treatm en t of th e crude m ixture with alcoh olic am m on ia
or m eth ylam in e, respectively, in an autoclave followed by cleavage of th e
resultin g diesters 7a an d 7b (Sch em e 4).
Th e ultim ate cleavage of ph osph on ate diesters 2b, 2c, 3b, 3c, 4b, 4c, 5b,
7
a, an d 7b was ach ieved by stan dard treatm en t with brom o(trim eth yl)sil-
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

Acyclic Nucleoside and Nucleotide Analogs
521
an e (TMSBr) in aceton itrile followed by h ydrolysis. Th e isolation of th e free
ph osph on ates 2d , 2e, 3d , 3e, 4d , 4e, 5d , 7c, an d 7d was ach ieved by
deion isation an d ion -exch an ge ch rom atograph y. Th e purified com poun ds
were fin ally crystallized from water.
NH2
N
NH2
NH2
N
N
N
N
N
N
N
R'
N
N
(i)
N
(ii)
N
Br
Br
N
OH
OTs
OCH2P(O)(OiPr)2
OCH P(O)(OR)2
2
1c
6
OCH2P(O)(OiPr)2
7
a, R' = H, R = iPr
b, R' = Me, R = iPr
c, R' = H, R = H
d, R' = Me, R = H
(iii)
o
o
(
i) TsCl, pyridine, 0 C, 2 days; (ii) NH3/MeOH or CH3NH2/EtOH, 80 C; (iii) TMSBr, MeCN
SCHEME 4
All n ew com poun ds were fully ch aracterized by H NMR (an d 13C NMR),
MS an d HR-MS or m icroan alysis. Th e structures of th e com poun ds prepared
by alkylation of startin g com poun ds 2a an d 4a were determ in ed on th e ba-
1
1
3
9
sis of proton -coupled C NMR spectra, an d N -substituted derivatives 2b
an d 4b were com pared with th e auth en tic m aterials prepared by th e m odi-
fication of acyclic n ucleotide an alogs in position 8 of th e purin e m oiety.
An exam ple of proton -coupled 13C NMR spectra is given for th e pair of
isom ers 4h an d 5h obtain ed from 8-(dim eth ylam in o)aden in e (4a) by alkyl-
ation with (S)-[(trityloxy)m eth yl]oxiran e after detritylation (Sch em e 3). Th e
9
structure of th e N -alkyl derivative 4h was con firm ed by th e sign al m ulti-
1
plicity: doublets of C-2 (δ 150.33, J(C-2,H-2) = 198.2) an d C-6 (δ 153.70,
3
3
J(C-6,H-2) = 11.7), triplet of C-5 (δ 116.38, J(C-5,NH ) = 3.9), doublet of
2
3
3
triplet of C-4 ( δ 151.31, J(C-4,H-2) = 11.7, J(C-4,H-1′) = 2.9), an d
m ultiplet of C-8 (δ 156.03, J(C-8,CH ) = J(C-8,H-1′) = 2.9). On th e oth er
h an d, th e structure of th e N -alkyl derivative 5h was determ in ed by th e
3
3
3
3
presen ce of alkylation effects (upfield sh ifts (–9 ppm ) at C-2 an d (–5 ppm )
at C-6 an d down field sh ifts (9 ppm ) at C-8 an d (5 ppm ) at C-1′) an d by th e
1
ch an ge in th e sign al m ultiplicity of C-2 (δ 141.23, J(C-2,H-2) = 209.0,
3
3
3
J(C-2,H-1′) = 4.9), C-4 (δ 151.99, J(C-4,H-2) = 6.8, J(C-4,H-1′) = 3.9), an d
3
9
C-8 (δ 164.79, J(C-8,CH ) = 2.9). Sim ilarly, th e N -alkyl derivative 2h pre-
3
pared by th e alkylation of 8-am in oaden in e (2a) (Sch em e 2) is ch aracterized
1
by th e followin g sign al m ultiplicity: doublets of C-2 (δ 148.72, J(C-2,H-2) =
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

5
22
Janeba, Holý, Masojídková:
1
98.25) an d C-6 (δ 152.23, 3J(C-6,H-2) = 10.7), triplets of C-5 (δ 116.99,
3
3
J(C-5,NH ) = 3.9) an d C-8 (δ 152.84, J(C-8,H-1′) = 2.9), an d doublet of
triplet of C-4 (δ 150.18, J(C-4,H-2) = 10.7, J(C-4,H-1′) = 3.9).
2
3
3
Hydroch loride 5b an d tosylate 5f gave appropriate elem en tal an aly-
1
sis. Sin glets of NH group were observed in H NMR spectra: 12.01 for
com pou n d 5b an d 11.60 for com poun d 5f. Proton ation at th e n itrogen
7
atom N follows from th e sign ifican tly altered ch em ical sh ifts of C-5 (δ
1
3
1
08.275 an d 108.24) an d C-8 (δ 157.17 an d 157.39) in th e C NMR
3
spectra com pared with e.g. th e N -alkyl derivative 5h (C-5 (δ 118.53) an d
C-8 (δ 164.79)).
Th e UV spectra con stitute addition al eviden ce of th e substituen t type in
position 8 of th e purin e m oiety as well as of th e ch aracter of th e corre-
spon din g alkyl regioisom ers. Th us, it is possible to distin guish between
9
(
average values of λm ax an d εm ax are given , respectively): N -substituted
8
-am inoadenine derivatives 2 (pH 2, 271 nm , 13 000; pH 12, 274 nm , 15 000);
9
N -substituted derivatives of 8-(m eth ylam in o)aden in e 3 (pH 2, 274 n m ,
1
9
2 700; pH 12, 279 n m , 15 400); N -substituted derivatives of 8-(dim eth yl-
am in o)aden in e 4 (pH 2, 281 n m , 14 000; pH 12, 278 n m , 15 000); an d
3
N -substituted derivatives of 8-(dim eth ylam in o)aden in e 5 (pH 2, 307 n m ,
2
3 100 an d 235 n m , 21 200; pH 12, 321 n m , 16 300 an d 235 n m , 11 400).
Th e CD spectra of en an tiom ers of th e ch iral acyclic n ucleoside an d n ucleo-
tide an alogs 2e, 2h , 3e, 4e, 4h , an d 5h do n ot exh ibit a m arked Cotton ef-
fect; th is reflects th e flexible ch aracter of th e aliph atic side ch ain bearin g a
ch iral carbon atom . However, in an alogy to th e O-an h ydro an d S-an h ydro
derivatives of HPMPA (refs6 ), th e CD spectra of th e NH-an h ydro derivative
,7
7
c an d th e N(CH )-an h ydro derivative 7d con tain in g rigid tricyclic system s
3
sh ow sign ifican t Cotton ban ds: (λ (∆ε)): 283 (1.24), 219 (–6.48) an d 195
–3.10) for com poun d 7c, an d 282 (–3.40), 223 (3.04) an d 201 (–1.17) for
d . In verse Cotton ban ds aroun d th e approxim ately sim ilar wavelen gth are
(
7
eviden ce of th e essen tially differen t con form ation of th e n ew rin gs in com -
poun ds 7c an d 7d . Th us, th e ch aracter of th e substitution at th e n itrogen
atom of th e an h ydro derivatives affects th e resultin g con form ation of th e
m olecule.
In con clusion , two in depen den t m eth ods were used for preparation of
alkylated aden in es bearin g am in o (or substituted am in o) group in position 8:
(
8
(
i) syn th eses of 8-am in oaden in es 2, 8-(m eth ylam in o)aden in es 3, an d
-(dim eth ylam in o)aden in es 4 from th e correspon din g 8-brom oaden in es 1,
ii) alkylation of 8-am in oaden in e (2a) an d 8-(dim eth ylam in o)aden in e (4a)
with diverse alkylation agen ts. Th e form er m eth od is direct an d con ve-
n ien t, affordin g good yields of products. Th e yields of th e base alkylation s
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

Acyclic Nucleoside and Nucleotide Analogs
523
are gen erally lower; two regioisom ers are form ed in an approxim ately
equim olar ratio in th e alkylation s of 8-(dim eth ylam in o)aden in e (4a):
3
9
9
N -alkyl derivatives 5 an d N -alkyl derivatives 4. Th e N -substituted an alogs
b an d 4b were prepared by two in depen den t routes. 8,3′-N-An h ydro deriv-
2
atives 7 were also prepared. Biological activities of th e fin al com poun ds will
be exam in ed.
EXPERIMENTAL
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 P O . Meltin g poin ts were determ in ed on a Büch i Meltin g Poin t B-545 an d are
2
5
un corrected. An alytical TLC were perform ed on Silufol UV 254 plates (Kavalier Votice,
Czech Republic) in th e system s ch loroform –m eth an ol (9 : 1) (S1), ch loroform –m eth an ol
(
(
85 : 15) (S2), ch loroform –m eth an ol (8 : 2) (S3), water–eth an ol–aceton e–eth yl acetate
1 : 1 : 1 : 4) (S4), isopropyl alcoh ol–am m on ia–water (7 : 1 : 2) (S5). Preparative TLC were car-
ried out on 40 × 17 × 0.4 cm loose-layer plates of silica gel con tain in g UV in dicator (m ade
in th e Service Laboratory of th e In stitute). Paper electroph oresis was perform ed on a
Wh atm an No. 3 MM paper at 40 V/cm for 1 h in 0.05 M trieth ylam m on ium h ydrogen -
carbon ate (TEAB) at pH 7.5; th e electroph oretical m obilities are referen ced to uridin e
3
′-ph osph ate. NMR spectra were m easured on Varian Un ity 500 spectrom eter (500 MHz for
1
13
H an d 125.7 MHz for C NMR) in h exadeuteriodim eth yl sulfoxide (DMSO-d ) referen ced
to th e solven t sign als (2.5 ppm for H an d 39.7 ppm for C NMR), or in deuterium oxide
con tain in g sodium deuteroxide with sodium 3-(trim eth ylsilyl)propan e-1-sulfon ate as an in -
6
1
13
1
13
tern al stan dard for H NMR an d dioxan e as an extern al stan dard for C NMR (δ(dioxan e)
6.86 ppm ). Mass spectra were m easured on a ZAB-EQ (VG An alytical) spectrom eter usin g
6
FAB (ion ization by Xe, acceleratin g voltage 8 kV, glycerol m atrix). UV absorption spectra
were m easured on a UV m in i-1240 Sh im adzu spectrom etr, CD spectra on a Jobin –Yvon –
Mark V in strum en t, an d IR spectra on a FT-IR spectrom etr Bruker IFS 88.
Startin g Materials an d Reagen ts
Brom o(trim eth yl)silan e, cesium carbon ate, an d m eth ylam in e an d dim eth ylam in e solution s
were purch ased from Fluka (Switzerlan d), m eth yl tosylate from Aldrich . Dim eth ylform am ide
was distilled from P O an d stored over m olecular sieves (4 Å). Aceton itrile was refluxed
2
5
with CaH2 an d distilled over m olecular sieves (4 Å).
8
-Am in oaden in e Derivatives 2. Gen eral Procedure
A m ixture of th e correspon din g 8-brom o derivative6 1 (1.5 m m ol), lith ium azide (4.5 m m ol)
an d DMF (15 m l) was h eated to 100 °C for 7 h . Th e m ixture was evaporated in vacuo, an d
th e residue was codistilled with toluen e (2 × 15 m l) an d m eth an ol (2 × 15 m l). Th e residue
was h ydrogen ated in m eth an ol (60 m l) in th e presen ce of 5% Pd-C (0.3 g) at 25 °C over-
n igh t. Th e m ixture was th en filtered th rough a Celite layer an d th e solven t was evaporated.
Th e residue was purified by preparative TLC in ch loroform –m eth an ol (5 : 1) an d crystallized
from m ixture eth an ol–eth er.
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

5
24
Janeba, Holý, Masojídková:
8
-Amino-9-{2-[(diisopropoxyphosphoryl)methoxy]ethyl}adenine (2b ). W h ite crystals, m .p.
1
1
46 °C, yield 40%, R 0.28 (S3). FAB MS, m/z (rel.%): 373 (100) [M + H]. H NMR (500 MHz,
F
DMSO-d ): 1.12 (d, 6 H, J(CH ,CH) = 6.1, CH ); 1.17 (d, 6 H, J(CH ,CH) = 6.1, CH ); 3.79 (d,
6
3
3
3
3
2
4
H, J(P,CH) = 8.3, PCH ); 3.80 (t, 2 H, J(2′,1′) = 5.3, H-2′); 4.14 (t, 2 H, J(1′,2′) = 5.3, H-1′);
2
1
3
.49 (m , 2 H, POCH); 6.41 (brs, 2 H, NH ); 6.45 (brs, 2 H, NH ); 7.90 (s, 1 H, H-2). C NMR
2
2
(
125 MHz, DMSO-d ): 23.76 (d, 2 C, J(P,C) = 4.9, CH ); 23.92 (d, 2 C, J(P,C) = 3.9, CH );
6 3 3
4
0.20 (C-1′); 64.86 (d, J(P,C) = 164.1, PC); 70.06 (d, J(P,C) = 11.7, C-2′); 70.38 (d, 2 C,
J(P,C) = 5.9, POC); 117.06 (C-5); 148.73 (C-2); 150.10 (C-4); 152.15 (C-6); 152.165 (C-8). For
C14H25N O P (372.4) calculated: 45.16% C, 6.77% H, 22.57% N, 8.32% P; foun d: 45.08% C,
6
4
6
.87% H, 22.28% N, 8.60% P.
S)-8-Amino-9-{2-[(diisopropoxyphosphoryl)methoxy]-3-hydroxypropyl}adenine (2c). Wh ite crys-
(
1
tals, m .p. 158 °C, yield 58%, RF 0.24 (S2). FAB MS, m/z (rel.%): 403 (100) [M + H]. H NMR
500 MHz, DMSO-d ): 1.15 (d, 3 H, J(CH ,CH) = 6.1, CH ); 1.18 (d, 6 H, J(CH ,CH) = 6.1,
(
6
3
3
3
CH ); 1.21 (d, 3 H, J(CH ,CH) = 6.1, CH ); 3.47 (m , 2 H, H-3′); 3.82 (m , 1 H, H-2′); 3.84 (dd,
3
3
3
1
H, J(P,CHb) = 8.6, J(gem ) = 13.9, PCHb); 3.91 (dd, 1 H, J(P,CHa) = 8.6, J(gem ) = 13.9,
PCHa); 4.03 (dd, 1 H, J(1′b,2′) = 5.4, J(gem ) = 15.1, H-1′b); 4.07 (dd, 1 H, J(1′a,2′) = 6.3,
J(gem ) = 15.1, H-1′a); 4.52 (m , 2 H, POCH); 5.07 (brs, 1 H, OH); 6.36 (brs, 2 H, NH ); 6.47
2
1
3
(
brs, 2 H, NH ); 7.91 (s, 1 H, H-2). C NMR (125 MHz, DMSO-d ): 23.75 (d, J(P,C) = 4.9,
2 6
CH ); 23.81 (d, J(P,C) = 4.9, CH ); 23.90 (d, J(P,C) = 3.9, CH ); 23.96 (d, J(P,C) = 3.9, CH );
3
3
3
3
4
1.71 (C-1′); 60.52 (C-3′); 64.01 (d, J(P,C) = 165.0, PC); 70.45 (d, J(P,C) = 6.9, POC); 70.50
(
d, J(P,C) = 5.9, POC); 80.24 (d, J(P,C) = 10.8, C-2′); 116.80 (C-5); 148.85 (C-2); 150.17 (C-4);
1
2
52.21 (C-6); 152.46 (C-8). For C15H27N O P (402.4) calculated: 44.77% C, 6.76% H,
6 5
0.89% N, 7.70% P; foun d: 44.58% C, 6.56% H, 20.68% N, 7.53% P.
8
-Am in oaden in e (2a)
Th e procedure is th e sam e as described for com poun ds 2b an d 2c. Th e residue after h ydroge-
+
n ation was dissolved in water an d applied on to a colum n of Dowex 50X8 (H form , 50 m l),
wash ed with water an d eluted with 5% aqueous am m on ia. After evaporation of an appropri-
ate UV absorbin g fraction th e residue was dried over P O Yield 51%. An alytical sam ple was
2
5.
crystallized from a m ixture water–eth an ol to afford yellowish crystals of 2a; m .p. >350 °C,
1
RF 0.49 (S4). FAB MS, m/z (rel.%): 151 (100) [M + H]. H NMR (500 MHz, DMSO-d ): 6.27 (s,
2
6
1
3
H, NH ); 6.52 (brs, 2 H, NH ); 7.90 (s, 1 H, H-2); 10.80 (br, 1 H, NH). C NMR (125 MHz,
2 2
DMSO-d ): 114.50 (C-5); 149.30 (C-4); 150.31 (C-2); 152.50 (C-6); 154.78 (C-8). For C H N
6
6
5
6
(
150.1) calculated: 40.00% C, 4.03% H, 55.97% N; foun d: 39.74% C, 4.01% H, 55.55% N.
Exact m ass (FAB HRMS) foun d: 151.0732; calculated for C H N [M + H]: 151.0732.
5
7
6
8
-(Meth ylam in o) Derivatives 3 an d 8-(Dim eth ylam in o) Derivatives 4 of Aden in e Acyclic
Nucleotide An alogues. Gen eral Procedure
A m ixture of 8-brom o derivative 1b or 1c (2 m m ol) an d m eth ylam in e or dim eth ylam in e in
eth an ol (33%, 30 m l) was h eated in an autoclave at 100 °C for 15 h . Th e solven t was evapo-
rated, th e residue was codistilled with eth an ol (2 × 15 m l) an d dried over ph osph orus
pen toxide overn igh t. Th e residue was directly treated with TMSBr un der stan dard con dition .
For th e overall yields of products 3d , 3e, 4d , 4e, see Deprotection of Ph osph on ates with
TMSBr.
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

Acyclic Nucleoside and Nucleotide Analogs
-(Dim eth ylam in o)aden in e (4a)
525
8
Procedure A: A m ixture of 8-brom oaden in e (1a; 3 g, 14 m m ol) an d dim eth ylam in e solu-
tion in eth an ol (33%, 60 m l) was h eated in autoclave to 120 °C for 18 h . Th e solid was fil-
tered off, wash ed with eth an ol (3 × 30 m l) an d eth er (3 × 20 m l). Th e filtrate was
con cen trated in vacuo an d th e precipitated solid was again filtered off an d wash ed with eth a-
n ol an d eth er. Th e com bin ed portion s of solid were dried over ph osph orus pen toxide to
give yellowish powder (2.25 g, 90%) of com poun d 4a, decom position >300 °C, R 0.52 (S4).
F
1
FAB MS, m/z (rel.%): 179 (100) [M + H]. H NMR spectrum is iden tical with th e auth en tic
m aterial . For C H10N6 (178.2) calculated: 47.18% C, 5.66% H, 47.16% N; foun d: 47.08% C,
8
7
5
.72% H, 47.04% N.
8
Procedure B (ref. ): A m ixture of 8-brom oaden in e (1a; 3 g, 14 m m ol), DMF (80 m l), an d
ben zylam in e (5 m l) was h eated to 130 °C for 9 h . Th e solven t was taken down in vacuo an d
codistilled with toluen e (3 × 20 m l) an d m eth an ol (2 × 20 m l). Crystallization from m eth a-
n ol afforded yellowish crystals (1.62 g, 66%) of com poun d 4a, decom position >300 °C.
Alkylation of 8-Am in oaden in e (2a) with Meth yl Tosylate
A m ixture of com poun d 2a (0.3 g, 2 m m ol), an d sodium h ydride (80 m g of 60% dispersion ,
2
2
m m ol) in DMF (15 m l) was stirred at 100 °C for 0.5 h . Meth yl tosylate (0.36 m l,
.4 m m ol) was added an d th e m ixture was stirred at th is tem perature for an oth er 5 h . Th e
solven t was evaporated an d th e residue purified by preparative ch rom atograph y on a silica
gel plate in isopropyl alcoh ol–am m on ia–water (S5) an d crystallized from m ixture water–
eth an ol. Yield 0.20 g (61%) of com poun d 2f.
8
-Amino-9-methyladenine (2f). Yellowish crystals, m .p. 182–185 °C, R 0.62 (S5). EI MS, m/z
F
1
(
3
rel.%): 164 (100) [M]. FAB MS, m/z (rel.%): 165 (80) [M + H]. H NMR (500 MHz, DMSO-d ):
6
1
3
.43 (s, 3 H, CH ); 6.40 (brs, 2 H, NH ); 6.44 (brs, 2 H, NH ); 7.91 (s, 1 H, H-2). C NMR
3 2 2
(
125 MHz, DMSO-d ): 27.41 (CH ); 117.18 (C-5); 148.77 (C-2); 150.15 (C-4); 152.10 (C-6);
6 3
1
1
52.65 (C-8). Exact m ass (FAB HRMS) foun d: 165.0900; calculated for C H N [M + H]:
6 9 6
65.0889. UV, λm ax (εm ax) (MeOH): 274 (14 800).
Alkylation of 2a with Diisopropyl [(2-Ch loroeth oxy)m eth yl]ph osph on ate
A m ixture of com poun d 2a (0.2 g, 1.3 m m ol) an d sodium h ydride (54 m g of 60% disper-
sion , 1.3 m m ol) in DMF (15 m l) was stirred at 110 °C for 0.5 h . Diisopropyl
9
[
(2-ch loroeth oxy)m eth yl]ph osph on ate (0.5 m l, 1.5 m m ol) was added an d th e m ixture was
stirred for an oth er 10 h . Th e solven t was evaporated an d th e residue codistilled with toluen e
2 × 15 m l). Preparative ch rom atograph y on a silica gel plate in ch loroform –m eth an ol m ix-
(
ture (4 : 1) followed by crystallization from eth an ol–eth er m ixture afforded 0.22 g (45%) of
com poun d 2b.
8
-Amino-9-{2-[(diisopropoxyphosphoryl)methoxy]ethyl}adenine (2b ). W h ite crystals, m .p.
1
13
1
42–143 °C, RF 0.28 (S3). FAB MS, H NMR an d C NMR spectra are iden tical with th e au-
th en tic com poun d.
Alkylation of 2a with (S)-[(Trityloxy)m eth yl]oxiran e [(S)-O-Tritylglycidol]
A m ixture of 8-am in oaden in e (2a; 0.8 g, 5.3 m m ol), DMF (30 m l), (S)-O-tritylglycidol (1.7 g,
5
.3 m m ol), an d cesium carbon ate (86 m g, 0.26 m m ol) was stirred at 110 °C for 20 h . Th e
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

5
26
Janeba, Holý, Masojídková:
h ot suspen sion was filtered over Celite an d th e solven t evaporated. Colum n ch rom atogra-
ph y of th e residue on silica gel followed by crystallization from aceton e–m eth an ol m ixture
gave 1.18 g (47%) of com poun d 2g.
(
S)-8-Amino-9-[2-hydroxy-3-(trityloxy)propyl]adenine (2g). Yellowish crystals, m .p. 145 °C, R
F
1
0
.54 (S3). FAB MS, m/z (rel.%): 467 (20) [M + H]; 243 (100) [Tr]. H NMR (500 MHz,
DMSO-d ): 2.93 (dd, 1 H, J(3′b,2′) = 4.9, J(gem ) = 9.5, H-3′b); 3.03 (dd, 1 H, J(3′a,2′) = 5.4,
6
J(gem ) = 9.5, H-3′a); 3.90 (dd, 1 H, J(1′b,2′) = 7.6, J(gem ) = 13.9, H-1′b); 4.06 (dd, 1 H,
J(1′a,2′) = 4.2, J(gem ) = 13.9, H-1′a); 4.11 (m , 1 H, H-2′); 5.52 (d, 1 H, J(OH,2′) = 5.6, OH);
6
6
6
.24 (brs, 2 H, NH ); 6.36 (brs, 2 H, NH ); 7.24 (t, 3 H, arom ); 7.31 (t, 6 H, arom ); 7.40 (d,
2 2
1
3
H, arom ); 7.89 (s, 1 H, H-2). C NMR (125 MHz, DMSO-d ): 44.79 (C-1′); 66.24 (C-3′);
6
8.63 (C-2′); 86.13 (C-Ph ); 117.07 (C-5); 127.12 (3 C, arom ); 127.98 (6 C, arom ); 128.49
(
6 C, arom ); 143.90 (3 C, arom ); 148.81 (C-2); 150.12 (C-4); 152.14 (C-6); 152.59 (C-8).
(
S)-8-Am in o-9-(2,3-dih ydroxypropyl)aden in e (2h )
+
A m ixture of th e trityl derivative 2g (0.4 g, 0.9 m m ol), Dowex 50X8 (H ) (5 m l), m eth an ol
(
10 m l), an d water (10 m l) was refluxed for 3 h , th en filtered wh ile h ot an d th e resin was
wash ed with m eth an ol (2 × 10 m l), eth er (3 × 10 m l), an d 5% aqueous am m on ia. Th e am -
m on ia fraction was evaporated an d th e residue crystallized from water to afford wh ite crys-
1
3
tals (0.15 g, 78%) of com poun d 2h ; m .p. 256 °C (ref. , n ot m eltin g up to 260 °C), RF 0.10
1
(
S3). FAB MS, m/z (rel.%): 225 (100) [M + H]. H NMR (500 MHz, DMSO-d ): 3.45 (m , 2 H,
6
H-3′); 3.83 (m , 1 H, H-2′); 3.84 (dd, 1 H, J(1′b,2′) = 7.3, J(gem ) = 13.2, H-1′b); 4.04 (dd, 1 H,
J(1′a,2′) = 2.5, J(gem ) = 13.2, H-1′a); 4.92 (t, 1 H, J(OH,3′) = 5.7, OH); 5.24 (d, 1 H, J(OH,2′) =
1
3
4
.6, OH); 6.25 (s, 2 H, NH ); 6.41 (s, 2 H, NH ); 7.90 (s, 1 H, H-2). C NMR (125 MHz,
2 2
DMSO-d ): 44.25 (C-1′); 63.46 (C-3′); 70.41 (C-2′); 116.99 (C-5); 148.72 (C-2); 150.18 (C-4);
6
1
52.23 (C-6); 152.84 (C-8). Exact m ass (FAB HRMS) foun d: 225.1085; calculated for
C H N O [M + H]: 225.1099. UV, λm ax (εm ax): (pH 2) 272 (13 700); (pH 12) 274 (15 800);
8
13
6
2
(
MeOH) 274 (17 000). CD, λ (∆ε) (MeOH): 255 (0.20), 222 (0.45).
Alkylation of 8-(Dim eth ylam in o)aden in e (4a) with Meth yl Tosylate
A m ixture of com poun d 4a (0.65 g, 3.6 m m ol) an d sodium h ydride (0.22 g of 60% disper-
sion , 5.4 m m ol) in DMF (20 m l) was stirred at 100 °C for 30 m in . Meth yl tosylate (0.8 m l,
5
.4 m m ol) was added an d th e m ixture was stirred 110 °C for an oth er 16 h . Th e solven t was
evaporated an d th e residue purified by preparative ch rom atograph y on a silica gel plate in
ch loroform –m eth an ol (S2) followed by crystallization from eth an ol to afford 0.13 g (19%) of
com poun d 4f an d 0.20 g (15%) of com poun d 5f.
8
-(Dimethylamino)-9-methyladenine (4f). Wh ite crystals, m .p. 261–262 °C, RF 0.51 (S2). FAB
1
MS, m/z (rel.%): 193 (100) [M + H]. H NMR (500 MHz, DMSO-d ): 2.91 (s, 6 H, NCH ); 3.56
6
3
1
3
(
s, 3 H, NCH ); 6.69 (brs, 2 H, NH ); 8.00 (s, 1 H, H-2). C NMR (125 MHz, DMSO-d ):
3 2 6
2
1
4
9.68 (NCH ); 41.46 (2 C, NCH ); 116.35 (C-5); 150.43 (C-2); 151.18 (C-4); 153.48 (C-6);
3 3
55.78 (C-8). For C H12N6 (192.2) calculated: 49.99% C, 6.29% H, 43.72% N; foun d:
8
9.97% C, 6.43% H, 43.71% N. UV, λm ax (εm ax) (MeOH): 276 (15 400).
8
-(Dimethylamino)-3-methyladenine tosylate (5f). Wh ite crystals, m .p. 280 °C, RF 0.20 (S2).
FAB MS, m/z (rel.%): 193 (100) [8-(dim eth ylam in o)-3-m eth yladen in e + H]. 1H NMR (500
MHz, DMSO-d ): 2.29 (s, 3 H, CH -arom ); 3.15 (s, 6 H, NCH ); 3.83 (s, 3 H, NCH ); 7.12 (d,
6
3
3
3
2
H, H-arom ); 7.49 (d, 2 H, H-arom ); 7.70 (br, 2 H, NH ); 8.45 (s, 1 H, H-2); 11.60 (brs, 1 H,
2
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

Acyclic Nucleoside and Nucleotide Analogs
527
NH). 13C NMR (125 MHz, DMSO-d ): 20.94 (CH -arom ); 35.72 (NCH ); 37.85 (2 C, NCH );
6
3
3
3
1
08.24 (C-5); 125.63 (2 C, C-arom ); 128.29 (2 C, C-arom ); 138.01 (C-arom ); 145.51
(
(
C-arom ); 145.70 (C-2); 147.77 (C-6); 151.08 (C-4); 157.39 (C-8). IR (KBr): 3 358, 3 184
NH ); 2 817, 1 448 (CH in NMe ); 1 671, 1 646, 1 583, 1 525 (NH an d rin g). For
2
3
2
2
C15H20N O S (364.4) calculated: 49.44% C, 5.53% H, 23.06% N, 8.80% S; foun d: 49.25% C,
6
3
5
.54% H, 22.75% N, 8.72% S. Exact m ass (FAB HRMS) foun d: 193.1234; calculated for
C H13N6 [M – TsOH + H]: 193.1202. UV, λm ax (εm ax) (MeOH): 309 (8 500).
8
Alkylation of 4a with Diisopropyl [(2-Ch loroeth oxy)m eth yl]ph osph on ate
A m ixture of com poun d 4a (0.25 g, 1.4 m m ol) an d sodium h ydride (62 m g of 60% disper-
sion , 1.5 m m ol) in DMF (10 m l) was stirred at 110 °C for 0.5 h . Diisopropyl [(2-ch loro-
9
eth oxy)m eth yl]ph osph on ate (0.35 m l, 1.5 m m ol) was added an d th e m ixture was stirred for
an oth er 15 h . Th e solven t was evaporated an d th e residue codistilled with toluen e (2 ×
1
(
5 m l). Preparative ch rom atograph y on a silica gel plate in ch loroform –m eth an ol m ixture
9 : 1) followed by crystallization from eth yl acetate afforded 90 m g (16%) of com poun d 4b
an d 185 m g (30%) of com poun d 5b.
-{2-[(Diisopropoxyphosphoryl)methoxy]ethyl}-8-(dimethylamino)adenine (4b). Yellowish crys-
9
1
tals, m .p. 152 °C, RF 0.36 (S2). FAB MS, m/z (rel.%): 401 (100) [M + H]. H NMR (500 MHz,
DMSO-d ): 1.09 (d, 6 H, J(CH ,CH) = 6.1, CH ); 1.14 (d, 6 H, J(CH ,CH) = 6.1, CH ); 2.90 (s,
6
3
3
3
3
6
H, NCH ); 3.70 (d, 2 H, J(P,CH) = 8.4, PCH ); 3.97 (t, 2 H, J(2′,1′) = 5.6, H-2′); 4.21 (t, 2 H,
3 2
1
3
J(1′,2′) = 5.6, H-1′); 4.43 (m , 2 H, POCH); 6.77 (s, 2 H, NH ); 8.01 (s, 1 H, H-2). C NMR
2
(
125 MHz, DMSO-d ): 23.68 (d, 2 C, J(P,C) = 3.9, CH ); 23.87 (d, 2 C, J(P,C) = 3.9, CH );
6 3 3
4
7
1
2.19 (NCH ); 42.65 (C-1′); 64.85 (d, J(P,C) = 163.1, PCH ); 69.22 (d, J(P,C) = 11.7, C-2′);
3 2
0.25 (d, 2 C, J(P,C) = 6.8, POC); 116.38 (C-5); 150.43 (C-2); 151.10 (C-4); 153.58 (C-6);
55.68 (C-8). For C16H29N O P (400.4) calculated: 47.99% C, 7.30% H, 20.99% N, 7.74% P;
6
4
foun d: 47.75% C, 7.28% H, 21.22% N, 7.59% P.
-{2-[(Diisopropoxyphosphoryl)methoxy]ethyl}-8-(dimethylamino)adenine hydrochloride (5b ).
3
1
Wh ite crystals, m .p. 165–167 °C, RF 0.20 (S2). FAB MS, m/z (rel.%): [M + H]. H NMR
500 MHz, DMSO-d ): 1.12 (d, 6 H, J(CH ,CH) = 6.2, CH ); 1.16 (d, 6 H, J(CH ,CH) = 6.2,
(
6
3
3
3
CH ); 3.17 (s, 6 H, NCH ); 3.79 (d, 2 H, J(P,CH) = 8.3, PCH ); 3.94 (t, 2 H, J(2′,1′) = 5.0,
3
3
2
H-2′); 4.46 (t, 2 H, J(1′,2′) = 5.0, H-1′); 4.47 (m , 2 H, POCH); 8.00 (br, 2 H, NH ); 8.42 (s,
2
1
3
1
H, H-2); 12.01 (brs, 1 H, NH). C NMR (125 MHz, DMSO-d ): 23.72 (d, 2 C, J(P,C) = 4.9,
6
CH ); 23.86 (d, 2 C, J(P,C) = 3.9, CH ); 38.02 (NCH ); 48.32 (C-1′); 64.66 (d, J(P,C) = 163.1,
3
3
3
PC); 69.05 (d, J(P,C) = 10.7, C-2′); 70. 27 (d, 2 C, J(P,C) = 6.8, POC); 108.275 (C-5); 145.60
(
C-2); 147.82 (C-6); 150.425 (C-4); 157.17 (C-8). IR (KBr): 3 299, 3 145 (NH ); 2 827, 1 450
2
(
CH3 in NMe ); 1 678, 1 642, 1 577, 1 520 (NH an d rin g); 1 391, 1 376 (CH3 in iPr); 1 178,
2
2
1
142 (iPr); 1 219 (P=O); 1 105 (COC); 1 012, 992 (POC). For C16H30ClN O P (436.9) calcu-
6 4
lated: 43.99% C, 6.92% H, 8.12% Cl, 19.24% N, 7.09% P; foun d: 43.79% C, 6.86% H,
8
.03% Cl, 18.93% N, 7.24% P.
Alkylation of 4a with (S)-[(Trityloxy)m eth yl]oxiran e [(S)-O-Tritylglycidol]
A m ixture of com poun d 4a (0.7 g, 4 m m ol), DMF (20 m l), (S)-O-tritylglycidol (1.37 g,
.5 m m ol), an d cesium carbon ate (0.13 g, 0.4 m m ol) ) was stirred at 110 °C for 15 h . Th e
4
h ot suspen sion was filtered over Celite an d evaporated. Th e residue afforded, on preparative
th ick layer ch rom atograph y on silica gel (S2), 0.37 g (17%) of com poun d 4g an d 0.41 g
(
21%) of com poun d 5g.
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

5
28
Janeba, Holý, Masojídková:
(
S)-8-(Dimethylamino)-9-[2-hydroxy-3-(trityloxy)propyl]adenine (4g). Yellowish crystals, m .p.
1
1
98–199 °C, RF 0.37 (S1). FAB MS, m/z (rel.%): 495 (40) [M + H]; 243 (100) [Tr]. H NMR
(
500 MHz, DMSO-d ): 2.87 (s, 6 H, NCH ); 2.87 (dd, 1 H, J(3′b,2′) = 5.4, J(gem ) = 9.5, H-3′b);
6
3
2
.98 (dd, 1 H, J(3′a,2′) = 5.4, J(gem ) = 9.5, H-3′a); 4.04 (dd, 1 H, J(1′b,2′) = 7.9, J(gem ) = 14.2,
H-1′b); 4.10 (dd, 1 H, J(1′a,2′) = 5.1, J(gem ) = 14.2, H-1′a); 4.37 (m , 1 H, H-2′); 5.43 (d, 1 H,
J(OH,2′) = 5.6, OH); 6.73 (brs, 2 H, NH ); 7.24 (t, 3 H, H-arom ); 7.31 (t, 6 H, H-arom ); 7.35
2
1
3
(
d, 6 H, H-arom ); 7.97 (s, 1 H, H-2). C NMR (125 MHz, DMSO-d ): 42.14 (2 C, NCH );
6 3
4
1
6.93 (C-1′); 66.27 (C-3′); 67.02 (C-2′); 86.10 (CPh ); 116.39 (C-5); 127.12 (3 C, C-arom );
27.99 (6 C, C-arom ); 128.40 (6 C, C-arom ); 143.83 (3 C, C-arom ); 150.36 (C-2); 151.09
3
(
C-4); 153.70 (C-6); 155.72 (C-8). Exact m ass (FAB HRMS) foun d: 495.2441; calculated for
C29H31N O [M + H]: 495.2509.
6
2
(
S)-8-(Dimethylamino)-3-[2-hydroxy-3-(trityloxy)propyl]adenine (5g). Wh ite crystals, m .p.
1
2
2
49 °C, R 0.13 (S1). FAB MS, m/z (rel.%): 495 (100) [M + H]. H NMR (500 MHz, DMSO-d ):
F 6
.87 (dd, 1 H, J(3′b,2′) = 6.7, J(gem ) = 9.3, H-3′b); 3.02 (dd, 1 H, J(3′a,2′) = 5.0, J(gem ) = 9.3,
H-3′a); 3.06 (s, 6 H, NCH ); 4.03 (dd, 1 H, J(1′b,2′) = 8.7, J(gem ) = 13.4, H-1′b); 4.24 (m , 1 H,
3
H-2′); 4.58 (dd, 1 H, J(1′a,2′) = 3.0, J(gem ) = 13.4, H-1′a); 5.56 (d, 1 H, J(OH,2′) = 5.0, OH);
6
7
.82 (brs, 2 H, NH ); 7.26 (t, 3 H, H-arom ); 7.33 (t, 6 H, H-arom ); 7.43 (d, 6 H, H-arom );
2
1
3
.88 (s, 1 H, H-2). C NMR (125 MHz, DMSO-d ): 38.28 (2 C, NCH ); 52.85 (C-1′); 65.76
6
3
(
C-3′); 67.24 (C-2′); 86.12 (CPh ); 120.76 (C-5); 127.20 (3 C, C-arom ); 128.06 (6 C, C-arom );
3
1
28.39 (6 C, C-arom ); 139.85 (C-2); 143.89 (3 C, C-arom ); 148.48 (C-6); 152.16 (C-4); 166.53
(
C-8). Exact m ass (FAB HRMS) foun d: 495.2561; calculated for C29H31N O [M + H]:
6
2
4
95.2509.
Deprotection of Trityl Derivatives 4g an d 5g. Gen eral Procedure
+
Th e sam e procedure as described for com poun d 2h , usin g Dowex 50X8 (H ) followed by
crystallization from eth an ol afforded com poun ds 4h (72%) an d 5h (81%).
(
S)-9-(2,3-Dihydroxypropyl)-8-(dimethylamino)adenine (4h ). Wh ite crystals, m .p. 221 °C, RF
1
0
6
.62 (S4). FAB MS, m/z (rel.%): 253 (100) [M + H]. H NMR (500 MHz, DMSO-d ): 2.91 (s,
6
H, NCH ); 3.32 (dt, 1 H, J(3′b,2′) = J(3′b,OH) = 5.9, J(gem ) = 11.2, H-3′b); 3.41 (ddd, 1 H,
3
J(3′a,2′) = 5.0, J(3′a,OH) = 5.8, J(gem ) = 11.2, H-3′a); 3.99 (dd, 1 H, J(1′b,2′) = 8.8, J(gem ) =
1
1
4.3, H-1′b); 4.07 (dd, 1 H, J(1′a,2′) = 3.8, J(gem ) = 14.3, H-1′a); 4.15 (m , 1 H, H-2′); 4.82 (t,
H, J(OH,3′) = 5.8, OH); 5.12 (d, 1 H, J(OH,2′) = 5.0, OH); 6.75 (s, 2 H, NH ); 8.00 (s, 1 H,
2
1
3
H-2). C NMR (125 MHz, DMSO-d ): 42.23 (2 C, NCH ); 46.90 (C-1′); 64.08 (C-3′); 68.89
6
3
(
(
C-2′); 116.38 (C-5); 150.33 (C-2); 151.31 (C-4); 153.70 (C-6); 156.03 (C-8). For C10H16N O
6 2
252.3) calculated: 47.61% C, 6.39% H, 33.31% N; foun d: 47.56% C, 6.47% H, 33.16% N.
UV, λm ax (εm ax): (pH 2) 282 (14 900); (pH 7) 278 (15 600); (pH 12) 278 (15 000). CD, λ (∆ε)
(
H O): 312 (–0.08), 277 (2.43), 209 (–3.19).
2
(
S)-3-(2,3-Dihydroxypropyl)-8-(dimethylamino)adenine (5h ). Wh ite crystals, m .p. 168 °C, RF
1
0
6
.53 (S4). FAB MS, m/z (rel.%): 253 (100) [M + H]. H NMR (500 MHz, DMSO-d ): 3.06 (s,
6
H, NCH ); 3.21 (dd, 1 H, J(3′b,2′) = 6.6, J(gem ) = 11.4, H-3′b); 3.38 (dd, 1 H, J(3′a,2′) = 5.2,
3
J(gem ) = 11.4, H-3′a); 3.94 (m , 1 H, H-2′); 4.11 (dd, 1 H, J(1′b,2′) = 7.2, J(gem ) = 13.7, H-1′b);
4
7
.34 (dd, 1 H, J(1′a,2′) = 3.5, J(gem ) = 13.7, H-1′a); 6.80 (br, 2 H, OH); 7.24 (brs, 2 H, NH );
2
.96 (s, 1 H, H-2). 13C NMR (125 MHz, DMSO-d ): 38.33 (2 C, NCH ); 52.02 (C-1′); 63.10
6
3
(
C-3′); 68.88 (C-2′); 118.53 (C-5); 141.23 (C-2); 148.71 (C-6); 151.99 (C-4); 164.79 (C-8). For
C10H16N O (252.3) calculated: 47.61% C, 6.39% H, 33.31% N; foun d: 47.47% C, 6.53% H,
6
2
3
3.08% N. UV, λm ax (εm ax): (pH 2) 307 (16 600), 236 (15 900); (pH 7) 307 (15 800), 236
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

Acyclic Nucleoside and Nucleotide Analogs
529
(
15 000); (pH 12) 322 (11 800), 236 (8 200). CD, λ (∆ε) (H O): 300 (0.10), 225 (–1.67),
2
2
08 (–1.69).
Syn th esis of 8,3′-N-An h ydro Derivatives 7. Gen eral Procedure
A m ixture of com poun d 1c (0.47 g, 1 m m ol), 4-(dim eth ylam in o)pyridin e (30 m g), an d
pyridin e (20 m l) was cooled to –10 °C an d tosyl ch loride (0.23 g, 1.3 m m ol) was added un -
der exclusion of m oisture. Th e m ixture was stirred at –10 °C for 2 h , left to stan d at 0 °C for
2
3
4 h an d th en at room tem perature for 24 h . Meth an ol (10 m l) was added an d, after
0 m in , th e m ixture was evaporated at 30 °C an d partition ed between eth yl acetate an d wa-
ter. Th e organ ic ph ase was dried over an h ydrous m agn esium sulfate, filtered, th e solven t
was evaporated, codistilled with toluen e (2 × 20 m l) an d th e residue was dried over P O .
2
5
Th e dry oil was dissolved in 30% m eth an olic am m on ia solution or in solution of
–
1
m eth ylam in e in eth an ol (≈5.6 m ol l , 30 m l) an d th e m ixture was h eated in an autoclave at
0 °C for 6 h . Th e solven t was evaporated an d th e crude products 7a an d 7b were directly
8
treated with TMSBr un der stan dard con dition s (see com poun ds 7c an d 7d , respectively). An -
alytical sam ple of com poun d 7b was prepared by TLC purification on silica gel.
Diisopropyl (R)-{[(4-amino-8,9-dihydro-7H-pyrimido[1,2-e]purin-8-yl)oxy]methyl}phosphonate
1
(
7b). RF 0.31 (S1). FAB MS, m/z (rel.%): 399 (100) [M + H]. H NMR (500 MHz, DMSO-d ):
6
1
.12 (d, 3 H, J(CH ,CH) = 6.1, CH ); 1.13 (d, 3 H, J(CH ,CH) = 6.1, CH ); 1.17 (d, 3 H,
3 3 3 3
J(CH ,CH) = 6.1, CH ); 1.18 (d, 3 H, J(CH ,CH) = 6.1, CH ); 3.08 (s, 3 H, NCH ); 3.53 (dd,
3
3
3
3
3
2
H, J(P,3′) = 1.6, J(3′,2′) = 3.2, H-3′); 3.88 (dd, 1 H, J(P,Hb) = 9.3, J(gem ) = 13.9, PCHb); 3.94
(
dd, 1 H, J(P,Ha) = 8.8, J(gem ) = 13.9, PCHa); 3.98 (dd, 1 H, J(1′b,2′) = 3.2, J(gem ) = 13.2,
H-1′b); 4.15 (ddd, 1 H, J(1′a,P) = 1.3, J(1′a,2′) = 2.8, J(gem ) = 13.2, H-1′a); 4.24 (quin tet, 1 H,
J = 3.1, H-2′); 4.52 (dsept, 2 H, J(CH,CH ) = 6.1, J(P,OCH) = 7.8, POCH); 6.46 (s, 2 H, NH );
3
2
7
.90 (s, 1 H, H-2). 13C NMR (125 MHz, DMSO-d ): 23.665 (d, J(P,C) = 4.9, CH ); 23.70 (d,
6
3
J(P,C) = 4.9, CH ); 23.89 (d, J(P,C) = 3.9, CH ); 23.92 (d, J(P,C) = 3.9, CH ); 43.19 (C-1′);
3
3
3
4
6
9.47 (C-3′); 62.70 (d, J(P,C) = 165.0, PC); 70.02 (d, J(P,C) = 12.7, C-2′); 70.44 (d, J(P,C) =
.9, POC); 70.495 (d, J(P,C) = 6.9, POC); 117.19 (C-5); 148.66 (C-2); 149.89 (C-8); 150.11
(
[
C-4); 151.99 (C-6). Exact m ass (FAB HRMS) foun d: 399.1889; calculated for C16H28N O P
6 4
M + H]: 399.1909.
Deprotection of Ph osph on ates with TMSBr. Gen eral Procedure
A m ixture of a ph osph on ate diester (1 m m ol), TMSBr (1 m l) an d aceton itrile (5 m l) was
stirred overn igh t at am bien t tem perature, th en evaporated an d codistilled with aceton itrile
(
10 m l). Th e residue was dissolved in water an d m ade alkalin e with aqueous am m on ia. After
evaporation in vacuo, th e residue was dissolved in water an d applied on a colum n of Dowex
+
5
0X8 (H form , 50 m l); th e colum n was wash ed with water an d eluted with 2.5% aqueous
am m on ia. After evaporation of th e UV absorbin g fraction , th e product was purified on a
Dowex 1X2 (acetate) colum n (50 m l) by elution with lin ear gradien t of acetic acid
0–0.5 m ol l– , 1 l each ). Th e UV absorbin g fraction s were evaporated in vacuo an d th e resi-
1
(
due was crystallized from water.
-Amino-9-[2-(phosphonomethoxy)ethyl]adenine (2d ). Wh ite crystals, slow decom position
8
1
over 250 °C, yield 90%, EUp 0.76. FAB MS, m/z (rel.%): 289 (100) [M + H]. H NMR
(
500 MHz, D O): 3.51 (d, 2 H, J(P,CH) = 8.5, PCH ); 3.87 (t, 2 H, J(2′,1′) = 5.1, H-2′); 4.17 (t,
2 2
2
H, J(1′,2′) = 5.1, H-1′); 7.96 (s, 1 H, H-2). UV, λm ax (εm ax): (pH 2) 271 (10 900); (pH 7) 273
(
11 300); (pH 12) 274 (14 300).
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

5
30
Janeba, Holý, Masojídková:
(
S)-8-Amino-9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine (2e). Wh ite crystals, m .p.
1
>
250 °C, yield 58%, EUp 0.78. FAB MS, m/z (rel.%): 319 (100) [M + H]. H NMR (500 MHz,
D O): 3.55 (dd, 1 H, J(P,CHb) = 8.8, J(gem ) = 12.9, PCHb); 3.59 (dd, 1 H, J(3′b,2′) = 3.9,
2
J(gem ) = 12.2, H-3′b); 3.68 (dd, 1 H, J(P,CHa) = 9.5, J(gem ) = 12.9, PCHa); 3.82 (dd, 1 H,
J(3′a,2′) = 3.9, J(gem ) = 12.2, H-3′a); 3.85 (m , 1 H, H-2′); 4.14 (dd, 1 H, J(1′b,2′) = 6.6,
J(gem ) = 15.4, H-1′b); 4.19 (dd, 1 H, J(1′a,2′) = 4.2, J(gem ) = 15.4, H-1′a); 8.01 (s, 1 H, H-2).
1
3
C NMR (125 MHz, D O): 42.65 (C-1′); 59.75 (C-3′); 66.73 (d, J(P,C) = 154.3, PCH ); 80.17
2
2
(
d, J(P,C) = 10.7, C-2′); 115.11 (C-5); 148.87 (C-2); 149.28 (C-4); 151.11 (C-6); 153.71 (C-8).
For C H N O P (318.2) calculated: 33.97% C, 4.75% H, 26.41% N, 9.73% P; foun d:
9
15
6
5
3
3.71% C, 4.68% H, 26.15% N, 9.48% P. UV, λm ax (εm ax): (pH 2) 271 (12 900); (pH 7) 273
(
14 100); (pH 12) 274 (15 400). CD, λ (∆ε) (H O): 263 (0.68), 213 (0.63).
2
8
-(Methylamino)-9-[2-(phosphonomethoxy)ethyl]adenine (3d ). Wh ite crystals, m .p. >300 °C,
1
yield 81%, EUp 0.79. FAB MS, m/z (rel.%): 303 (100) [M + H]. H NMR (500 MHz, D O): 2.99
2
(
s, 3 H, CH ); 3.49 (d, 2 H, J(P,CH) = 8.3, PCH ); 3.83 (t, 2 H, J(2′,1′) = 5.3, H-2′); 4.08 (t,
3 2
2
5
H, J(1′,2′) = 5.3, H-1′); 7.94 (s, 1 H, H-2). For C H15N O P (302.2) calculated: 35.77% C,
9 6 4
.00% H, 27.81% N, 10.25% P; foun d: 35.50% C, 5.00% H, 27.58% N, 10.25% P. UV, λm ax
(
εm ax): (pH 2) 274 (12 700); (pH 12) 279 (15 200).
S)-9-[3-Hydroxy-2-(phosphonomethoxy)propyl]-8-(methylamino)adenine (3e). Wh ite crystals,
m .p. 215 °C, yield 58%, EUp 0.75. FAB MS, m/z (rel.%): 333 (20) [M + H]; 165 (100)
(
1
[
8-(m eth ylam in o)aden in e + H]. H NMR (500 MHz, D O): 2.94 (s, 3 H, NCH ); 3.42 (dd, 1 H,
2 3
J(3′b,2′) = 4.6, J(gem ) = 12.2, H-3′b); 3.48 (d, 2 H, J(P,CH) = 8.7, PCH ); 3.70 (dd, 1 H,
2
J(3′a,2′) = 3.2, J(gem ) = 12.2, H-3′a); 3.73 (m , 1 H, H-2′); 3.98 (d, 2 H, J(1′,2′) = 5.6, H-1′);
7
.86 (s, 1 H, H-2). 13C NMR (125 MHz, D O): 28.63 (NCH ); 42.12 (C-1′); 60.08 (C-3′); 68.30
2
3
(
d, J(P,C) = 150.2, PCH ); 79.73 (d, J(P,C) = 9.7, C-2′); 115.80 (C-5); 148.50 (C-2); 149.43
2
(
C-4); 150.50 (C-6); 154.17 (C-8). For C10H17N O P (332.3) calculated: 36.15% C, 5.16% H,
6
5
2
2
5.29% N, 9.32% P; foun d: 35.99% C, 5.38% H, 25.06% N, 9.18% P. UV, λm ax (εm ax): (pH 2)
74 (12 700); (pH 12) 279 (15 500). CD, λ (∆ε) (H O): 266 (1.37), 216 (1.20).
2
8
-(Dimethylamino)-9-[2-(phosphonomethoxy)ethyl]adenine (4d ). Wh ite crystals, m .p. 183 °C,
1
yield 76%, EUp 0.84. FAB MS, m/z (rel.%): 317 (100) [M + H]. H NMR (500 MHz, D O): 3.05
2
(
s, 6 H, CH ); 3.46 (d, 2 H, J(P,CH) = 8.3, PCH ); 3.96 (t, 2 H, J(2′,1′) = 5.2, H-2′); 4.30 (t,
3 2
2
5
H, J(1′,2′) = 5.2, H-1′); 8.01 (s, 1 H, H-2). For C10H17N O P (316.3) calculated: 37.98% C,
6 4
.42% H, 26.57% N, 9.79% P; foun d: 37.94% C, 5.70% H, 26.30% N, 9.55% P. UV, λm ax
(
εm ax): (pH 2) 281 (15 300); (pH 12) 278 (15 700).
S)-8-(Dimethylamino)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine (4e). Wh ite crystals,
(
1
m .p. 147–148 °C, yield 67%, EUp 0.80. FAB MS, m/z (rel.%): 347 (100) [M + H]. H NMR
(
500 MHz, D O): 3.01 (s, 6 H, NCH ); 3.27 (dd, 1 H, J(P,CHb) = 9.9, J(gem ) = 12.2, PCHb);
2 3
3
1
.39 (dd, 1 H, J(3′b,2′) = 5.5, J(gem ) = 12.6, H-3′b); 3.40 (dd, 1 H, J(P,CHa) = 8.6, J(gem ) =
2.2, PCHa); 3.62 (dd, 1 H, J(3′a,2′) = 2.3, J(gem ) = 12.6, H-3′a); 3.91 (m , 1 H, H-2′); 4.13
(
dd, 1 H, J(1′b,2′) = 6.1, J(gem ) = 14.9, H-1′b); 4.26 (dd, 1 H, J(1′a,2′) = 7.3, J(gem ) = 14.9,
1
3
H-1′a); 8.02 (s, 1 H, H-2). C NMR (125 MHz, D O): 40.84 (2 C, NCH ); 43.58 (C-1′); 60.61
2
3
(
C-3′); 68.28 (d, J(P,C) = 150.6, PCH ); 78.83 (d, J(P,C) = 9.7, C-2′); 115.76 (C-5); 149.94
2
(
C-2); 150.30 (C-4); 152.11 (C-6); 156.91 (C-8). For C11H19N O P (346.3) calculated:
6
5
3
8.15% C, 5.53% H, 24.27% N, 8.94% P; foun d: 37.70% C, 5.62% H, 23.96% N, 8.85% P.
UV, λm ax (εm ax): (pH 2) 281 (13 500); (pH 12) 278 (13 900). CD, λ (∆ε) (H O): 278 (2.87),
2
2
32 (2.05), 204 (–2.80).
-(Dimethylamino)-3-[2-(phosphonomethoxy)ethyl]adenine (5d ). Wh ite crystals, m .p. 183 °C,
8
1
yield 76%, EUp 0.72. FAB MS, m/z (rel.%): 317 (100) [M + H]. H NMR (500 MHz, D O): 3.08
2
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

Acyclic Nucleoside and Nucleotide Analogs
531
(
2
4
s, 6 H, NCH ); 3.45 (d, 2 H, J(P,CH) = 8.6, PCH ); 3.94 (t, 2 H, J(2′,1′) = 5.0, H-2′); 4.44 (t,
3 2
H, J(1′,2′) = 5.0, H-1′); 8.12 (s, 1 H, H-2). C NMR (125 MHz, D O): 37.95 (2 C, NCH );
2 3
9.14 (C-1′); 68.84 (d, J(P,C) = 150.4, PC); 69.01 (d, J(P,C) = 9.7, C-2′); 119.96 (C-5); 141.41
1
3
(
C-2); 147.46 (C-6); 152.24 (C-4); 166.755 (C-8). IR (KBr): 3 291, 3 138 (NH ); 2 809, 1 448
2
(
CH3 in NMe ); 2 647 (OH in POH); 1 682, 1 634, 1 576, 1 520 (NH an d rin g); 1 140 (P=O);
2
2
1
3
101 (COC). Exact m ass (FAB HRMS) foun d: 317.1155; calculated for C10H18N O P [M + H]:
6 4
17.1127. UV, λm ax (εm ax): (pH 2) 307 (23 100), 235 (21 200); (pH 12) 321 (16 300), 235
(
11 400).
R)-{[(4-Amino-8,9-dihydro-7H-pyrimido[1,2-e]purin-8-yl)oxy]methyl}phosphonic acid (7c).
(
Wh ite crystals, m .p. 295–297 °C, overall yield 17%, E 0.73. FAB MS, m/z (rel.%): 301 (100)
Up
1
[
(
M + H]. H NMR (500 MHz, D O): 3.53 (dd, 1 H, J(3′b,2′) = 2.0, J(gem ) = 13.4, H-3′b); 3.55
2
dd, 1 H, J(P,CHb) = 8.7, J(gem ) = 12.6, PCHb); 3.61 (dd, 1 H, J(P,CHa) = 8.9, J(gem ) = 12.6,
PCHa); 3.76 (ddd, 1 H, J(3′a,P) = 2.3, J(3′a,2′) = 3.4, J(gem ) = 13.4, H-3′a); 4.00 (dd, 1 H,
J(1′b,2′) = 3.3, J(gem ) = 13.2, H-1′b); 4.30 (dt, 1 H, J(1′a,2′) = J(1′a,P) = 2.5, J(gem ) = 13.2,
1
3
H-1′a); 4.37 (m , 1 H, H-2′); 7.95 (s, 1 H, H-2). C NMR (125 MHz, D O): 44.44 (C-1′); 46.44
2
(
1
C-3′); 69.36 (d, J(P,C) = 149.4, PC); 71.23 (d, J(P,C) = 9.8, C-2′); 119.40 (C-5); 151.59 (C-2);
52.29 (C-4); 153.76 (C-8); 153.89 (C-6). Exact m ass (FAB HRMS) foun d: 301.0721; calcu-
lated for C H N O P [M + H]: 301.0814. UV, λ (εm ax): (pH 2) 274 (14 100); (pH 7) 281
9
14
6
4
m ax
(
(
18 000); (pH 12) 281 (17 400). CD, λ (∆ε) (H O): 283 (1.24), 262 (0.12), 246 (0.57), 219
–6.48), 205 (0.00), 195 (–3.10).
2
(
R)-{[(4-Amino-6-methyl-8,9-dihydro-7H-pyrimido[1,2-e]purin-8-yl)oxy]methyl}phosphonic acid
(
(
7d ). Wh ite crystals, m .p. 238–240 °C, overall yield 26%, E 0.74. FAB MS, m/z (rel.%): 315
Up
100) [M + H]. 1H NMR (500 MHz, D O): 3.22 (s, 3 H, NCH ); 3.70 (dd, 1 H, J(3′b,2′) = 1.8,
2
3
J(gem ) = 13.6, H-3′b); 3.80 (dd, 1 H, J(P,CHb) = 9.9, J(gem ) = 12.9, PCHb); 3.81 (dt, 1 H,
J(3′a,2′) = J(3′a,P) = 2.6, J(gem ) = 13.6, H-3′a); 3.90 (dd, 1 H, J(P,CHa) = 9.3, J(gem ) = 12.9,
PCHa); 4.02 (dd, 1 H, J(1′b,2′) = 3.3, J(gem ) = 13.9, H-1′b); 4.42 (m , 1 H, H-2′); 4.43 (dt, 1 H,
J(1′a,2′) = J(1′a,P) = 2.2, J(gem ) = 13.9, H-1′a); 8.09 (s, 1 H, H-2). Exact m ass (FAB HRMS)
foun d: 315.0867; calculated for C10H15N O P [M + H]: 315.0970. UV, λ (εm ax): (pH 2) 280
m ax
6
4
(
(
14 700); (pH 7) 284 (18 300); (pH 12) 285 (18 800). CD, λ (∆ε) (H O): 320 (0.08), 282
–3.40), 240 (1.04), 223 (3.04), 201 (–1.17).
2
This work is a part of a research project Z4055905 and it was supported by the Grant Agency of the
Czech Republic (grant No. 203/96/K001) and by Gilead Sciences (Foster City, CA, U.S.A.). The au-
thors’ thanks are due to Dr H. Votavová and Dr P. Maloň for measurement of CD spectra, Dr P.
Fiedler for measurement of IR spectra, and to the staff of the Mass Spectrometry and Analytical De-
partments of this Institute.
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