Synthesis of acyclic carba-nucleoside phosphonates, structural analogues to natural deoxyribonucleotides

Article abstract of DOI:10.1002/(SICI)1099-0690(199904)1999:4<931::AID-EJOC931>3.0.CO;2-R

Acyclic carba-nucleoside phosphonates, modelled on natural deoxyribonucleotides have been prepared starting from DNA nucleobases and tert-butyl acrylate. The products obtained from a Michael-type reaction were elongated to β-oxo esters that were first reduced to β-hydroxy esters and then transformed into protected β-hydroxy aldehydes. Wittig-Homer-Emmons reaction with the anion of tetraisopropyl methylenebisphosphonate gave, after deprotection, the desired 4-hydroxy-6-purinyl- or -6-pyrimidinyl-1- hexenylphosphonic acids. A dimer, potential precursor of acyctic polynucleotides (APN), homomorphous with DNA, was also prepared.

Full text of DOI:10.1002/(SICI)1099-0690(199904)1999:4<931::AID-EJOC931>3.0.CO;2-R

FULL PAPER
Synthesis of Acyclic Carba-Nucleoside Phosphonates, Structural Analogues to
Natural Deoxyribonucleotides
Annamaria Esposito,[a] Maria Grazia Perino,[a] and Maurizio Taddei*[a]
Keywords: Nucleosides / Phosphonates / Nucleophilic additions / C–C coupling / Reduction
Acyclic carba-nucleoside phosphonates, modelled on natural
deoxyribonucleotides have been prepared starting from
Wittig–Horner–Emmons reaction with the anion of
tetraisopropyl methylenebisphosphonate gave, after
DNA nucleobases and tert-butyl acrylate. The products deprotection, the desired 4-hydroxy-6-purinyl- or -6-
obtained from a Michael-type reaction were elongated to β-
oxo esters that were first reduced to β-hydroxy esters and
then transformed into protected β-hydroxy aldehydes.
pyrimidinyl-1-hexenylphosphonic acids. A dimer, potential
precursor of acyclic polynucleotides (APN), homomorphous
with DNA, was also prepared.
Since the discovery of Acyclovir (ACV), the synthesis of
The retrosynthetic scheme proposed for the preparation
acyclic nucleosides has attracted the interest of several or- of compounds of type 1 is shown in Scheme 2.
ganic and medicinal chemists.[1] The extensive work of Holy
and De Clercq has demonstrated that, amongst the large
number of molecules proposed as potentially active, the
most promising structure for the discovery of effective anti-
viral agents should present a purine ring linked to an ali-
phatic chain bearing one OH and/or one phosphonate
group as possible site of triphosphorylation.[2][3]
Following our interest in the synthesis of DNA chi-
merae,[4] we considered the possibility of preparing acyclic
carba analogues of nucleosides homomorphous with the
natural system.[5]
Scheme 2. B ϭ adenine, cytosine, thymine
The vinyl phosphonic acid 1 can be prepared from a Wit-
tigϪHornerϪEmmons reaction starting from the β-alde-
hyde 2 that can be related, through a simple series of
chemoselective reductions, with β-oxo ester 3. As several
methods are reported the enantioselective reduction of the
carbonyl group of a β-oxo ester, we decided to use this reac-
tion for control of the stereochemistry of the products.
Compound 3 could be prepared according to a common
Scheme 1. B ϭ A, T, C, G
strategy based on the introduction of the nucleobase on the
carbon skeleton with a Michael-type reaction. Two se-
quences of events are possible: addition of the nucleobase
to the unsaturated β-oxo ester 4 or Michael reaction of a
Our idea was to remove the ribose oxygen atom, main-
nucleobase with an acrylate followed by a Claisen-type re-
tain the phosphorus atom in the molecule as a phosphonic
action.
acid and to introduce a double bond to give a certain level
As the first approach appeared more convergent, we de-
of conformational rigidity to the molecule.[6]
cided to prepare compound 4 by reaction of the ethyl lithio-
We report here a general synthesis of compounds of type 1
carrying adenine, cytosine, and thymine as nucleobases and
a model oligomerisation reaction of 1 that could be em-
acetate with acrolein followed by oxidation of the allylic
alcohol 6 with the Jones reagent.[8] Product 4 was isolated
by vacuum distillation in good yield and was immediately
submitted to Michael reaction with adenine (Scheme 3).
The addition of nucleobases to α,β-unsaturated carbonyl
ployed for the preparation of acyclic polynucleotides (APN)
homomorphous with DNA.[7]
compounds has been described to take place under basic
conditions[9] that partially deprotonated the acidic methyl-
ene group of 4. The desired addition product 3 could be
obtained albeit in 12% yield only in case when Cs2CO3 in
[a]
`
Dipartimento di Chimica, Universita di Sassari,
Via Vienna 2, I-07100 Sassari, Italy
E-mail: mtad@ssmain.uniss.it
Eur. J. Org. Chem. 1999, 931Ϫ936
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/0404Ϫ0931 $ 17.50ϩ.50/0
931

A. Esposito, M. G. Perino, M. Taddei
FULL PAPER
DMSO at room temperature for 28 h was employed ditions, compound 16 was hydrolysed to give the guanylpro-
(Scheme 3).
panoic acid 20.
Scheme 3. a) EtOAc, LDA, THF, Ϫ78°C, 73%; b) Jones oxidation,
61%; c) adenine, Cs2CO3, DMSO, 12%
The preparation of 3 was then attempted according to
the second approach. tert-Butyl acrylate was chosen as the
Michael acceptor and several different reaction conditions
were tested to obtain good yields of products 7؊10. The
protocol proposed by Pandit,[10] who described the use of
a molar excess of the heterocyclic compound in refluxing
methanol in the presence of 10 mol-% of sodium, proved
quite general and gave modest to good yields of the desired
products 7؊10 together with minor amounts (10Ϫ25%) of
compound 11, obtained by addition of methanol to the
acrylate.
Scheme 5
Scheme 4
C-Alkylation of carboxylic acids 17؊19 was carried out
under neutral conditions converting the acid into the corre-
sponding acylimidazole with carbonyldiimidazole (CDI) in
THF followed by in situ treatment with the magnesium salt
of monomethyl malonate.[12] The product β-oxo esters
21؊23 were obtained decomplexed with magnesium and
could therefore be isolated by column chromatography on
silica gel in excellent yields.
Compounds 7؊10, after purification by crystallisation
from water, require protection at the exocyclic NH2 group
(7, 8, and 9) or at the acidic NH thymine ring (10).
Using the adenyl derivative as the model compound, we
decided to prepare the corresponding N6-benzoyl derivative.
According to a literature procedure,[11] reaction with ben-
zoyl chloride (2.5 equiv.) in pyridine unexpectedly gave a
mixture of the monobenzoyl compound 12 and the diben-
zoyl derivative 13 in a 70:30 ratio. Use of 1 equiv. of benzoyl
chloride also gave the same product ratio (obviously with
lower chemical yields). Better results were obtained using
benzoic anhydride in pyridine or benzoyl chloride/pyridine
in acetonitrile with a catalytic amount of DMAP. The puri-
fication of 12 was straightforward using the second pro-
cedure; hence this was applied to the preparation of com-
pounds 14؊16 (62Ϫ79%).
Hydrolysis of esters 12, 14, and 15 was achieved by stir-
ring in dry 3  HCl in EtOAc at room temperature for 12
h to give the corresponding carboxylic acids 17؊19
Scheme 6
Unfortunately, the carboxylic derivative 20 did not react
(61Ϫ82%). In this transformation the concentration of the as it was completely insoluble in THF or in other aprotic
acid had a crucial role as, at higher concentrations, the ni- solvents. Attempts to carry out the alkylation in DMF,
trogen atom was deprotected. However under these con- where 20 was soluble, also failed.
932
Eur. J. Org. Chem. 1999, 931Ϫ936

Acyclic Carba-Nucleoside Phosphonates
FULL PAPER
Compound 21 was used once again as the model for en-
The deprotection of 30 with TBAF gave compound 31,
antioselective reduction of the carbonyl group. The enantio- which was purified by column chromatography on silica gel
selective reduction of differently functionalized β-oxo esters and fully characterised. The stereochemistry of the double
has been successfully achieved with high ee using homo- bond was confirmed by the trans-alkene coupling constant
geneous transition metal catalyst hydrogenation in the pres- (14 Hz, determined after decoupling the CH2 at δ ϭ 2.2).
ence of (binap)Ru or by applying reduction mediated by
Compounds 30 and 31 were employed to prepare the di-
BakerЈs yeast.[13] As the second approach appeared simple, mer 33. Compound 30 was refluxed in THF with 1 equiv.
attempts were made to reduce compound 21 using dry yeast of PCl5 for 3 h.[18] The solvent was removed under vacuum
in an organic solvent,[14] in an aqueous medium after pre- and crude 32 was treated with a solution of 31 in the pres-
vious fermentation[15] or without fermentation.[16] How- ence of 5 equiv. of triethylamine to give 33. After aqueous
ever, under none of the attempted conditions was the for- workup, the reaction producut was desilylated with TBAF
mation of the alcohol 25 observed. The application of to give compound 31 in 34% yield (as a mixture of dia-
(binap)Ru-catalysed hydrogenation did not give better re- stereoisomers).
sults.[17]. Reduction of 21 took place only with NaBH4 in
MeOH/THF to give product 25 (as a racemate) in 63%
yield. The same procedure applied to oxo esters 22 and 23
gave alcohols 26 and 27 in 61 and 57% yields, respectively.
Scheme 7
Although the formation of a racemic mixture cannot be
considered a satisfactory result, we decided to undertake
Scheme 9
the synthetic sequence with the adenyl derivative 25, as a
model study. Alcohol 25 was protected as tert-butyldimeth-
ylsilyl ether with TBDMSCl/imidazole/DMF at 60°C and
the corresponding product 28 was reduced to the aldehyde
29 with DIBAL-H at Ϫ78°C. The reduction proceeded
smoothly at low temperature going to completion after 4 h
at Ϫ78°C. The excess of DIBAL-H was destroyed at Ϫ78°C
with MeOH and product 29 isolated, after the usual aque-
Product 33 is formally an acyclic dinucleotide (in pro-
tected form) which is topologically related to DNA and to
PNA as it presents two atoms between the nucleobase and
the chain and six atoms between the carbon atoms that
carry the pendant nucleobases.[19]
Compounds 25؊33 are currently subjected to antiviral
activity tests. As the synthetic strategy has proved to be
successful, we are currently persuing the synthesis of the
asymmetric analogue of 33.
ous workup, by column chromatography. Although alde-
hyde 29 was sufficiently stable and could be stored at 0°C
for several weeks, we used it immediately for the Wit-
tigϪHornerϪEmmons reaction with tetraisopropyl methyl-
enebisphosphonate with LDA (0°C to room temperature, 3
9-(2-tert-Butoxycarbonylethyl)adenine (7). ؊ General Procedure: To
h) to give product 30.
Experimental Section
a solution of adenine (4.0 g, 29.6 mmol), dissolved in dry MeOH
(100 mL), sodium (0.15 g, 6.5 mmol) was added and the mixture
refluxed for 2 h under nitrogen. tert-Butyl acrylate (9.2 g, 71.6
mmol) was added and the mixture refluxed for additional 18 h. The
solvent was evaporated and the crude residue dissolved in water.
Product 7 separated as a fine precipitate that was filtered and crys-
tallised from hot water to give 5.6 g of 7 (74% yield), m.p.
183Ϫ185°C. Ϫ 1H NMR (300 MHz, [D6]DMSO): δ ϭ 1.40 (s, 9
H), 2.83 (t, J ϭ 6 Hz, 2 H), 4.45 (t, J ϭ 6 Hz, 2 H), 5.64 (br. s, 2
H), 7.90 (s, 1 H), 8.36 (s, 1 H). Ϫ C12H17N5O2 (263.30): calcd. C
54.74, H 6.51, N 26.60; found C 54.47, H 6.43, N 26.35.
2-Amino-9-(2-tert-butoxycarbonylethyl)-6-chloropurine (8): 43%
1
yield, m.p. 163Ϫ165°C. Ϫ H NMR (300 MHz, [D6]DMSO): δ ϭ
1.42 (s, 9 H), 2.75 (t, J ϭ 6 Hz, 2 H), 4.35 (t, J ϭ 6 Hz, 2 H), 5.90
(br. s, 2 H), 8.41 (s, 1 H). Ϫ C12H16ClN5O2 (297.74): calcd. C 48.41,
H 5.42, N 23.52; found C 48.30, H 5.42, N 23.40.
Scheme 8. a) TBDMSCl, imidazole, DMF, 60°C; b) DIBALH,
toluene, Ϫ78°C; c) CH2[PO(OiPr)2]2, LDA, THF, 0°C; d) TBAF,
THF, room temp.
Eur. J. Org. Chem. 1999, 931Ϫ936
933

A. Esposito, M. G. Perino, M. Taddei
FULL PAPER
1-(2-tert-Butoxycarbonylethyl)cytosine (9): 63% yield, m.p.
(d, J ϭ 8 Hz, 1 H), 7.50, 7.61 and 8.10 (m, 5 H), 9Ϫ10 (br. s, 2
185Ϫ188°C. Ϫ 1H NMR (300 MHz, [D6]DMSO): δ ϭ 1.35 (s, 9 H). Ϫ 13C NMR (75 MHz, [D6]DMSO): δ ϭ 35.8, 45.9, 98.7, 121.6,
H), 2.55 (t, J ϭ 6 Hz, 2 H), 3.76 (t, J ϭ 6 Hz, 2 H), 5.58 (d, J ϭ
127.0, 128.4, 129.0, 131.9, 158.6, 161.6, 171.7, 177.9 Ϫ C14H13N3O4
7 Hz, 1 H), 7.00 (s, 2 H), 7.51 (d, J ϭ 7 Hz, 1 H). Ϫ C11H17N3O3 (287.27): calcd. C 58.53, H 4.56, N 14.63; found C 58.64, H 4.66,
(239.27): calcd. C 55.22, H 7.16, N 17.56; found C 55.10, H 7.11, N 14.73.
N 17.66.
N3-Benzoyl-1-(2-carboxyethyl)thymine (19): 79% yield, m.p.
1
1-(2-tert-Butoxycarbonylethyl)thymine (10): 65% yield m.p.
190Ϫ191°C. Ϫ 1H NMR (300 MHz, [D6]DMSO): δ ϭ 1.40 (s, 9
H), 2.00 (s, 3 H), 2.80 (t, J ϭ 6 Hz, 2 H), 4.12 (t, J ϭ 6 Hz, 2 H),
7.35 (s, 1 H), 8.27 (br. s, 1 H). Ϫ C12H18N2O4 (254.29): calcd. C
56.68, H 7.13, N 11.02; found C 56.43, H 7.06, N 11.12.
165Ϫ167°C. Ϫ H NMR (300 MHz, [D6]DMSO): δ ϭ 1.94 (s, 3
H), 2.70 (t, J ϭ 6 Hz, 2 H), 3.91 (t, J ϭ 6 Hz, 2 H), 7.75 (s, 1 H),
7.6, 7.8, and 7.90 (m, 5 H), 10 (br. s, 1 H). Ϫ 13C NMR (75 MHz,
[D6]DMSO): δ ϭ 15.9, 31.6, 43.8, 109.7, 121.6, 127.0, 128.4, 129.0,
134.8, 155.5, 165.7, 169.7, 177.0. Ϫ C15H14N2O5 (302.29): calcd. C
59.60, H 4.67, N 9.27 Found C 59.70, H 4,46, N 9.73.
N6-Benzoyl-9-(2-tert-butoxycarbonylethyl)adenine (12). ؊ General
Procedure: To a solution of 7 (5.6 g, 21.2 mmol) in dry MeCN (22
mL) at 0°C, dry pyridine (9 mL) was added followed by freshly
distilled benzoyl chloride (7.53 g, 54.8 mmol). The mixture was
refluxed for 12 h, then cooled to room temp. and poured into a
flask containing melting ice and conc. HCl (5 mL). The formed
precipitate was filtered, washed with water and crystallised from
hot water to give 7.2 g of 12 (88% yield), m.p. 127Ϫ128°C. Ϫ IR
9-(2-Carboxyethyl)guanine (20): 78% yield, m.p. 235Ϫ238°C (dec.).
1
Ϫ H NMR (300 MHz, [D6]DMSO): δ ϭ 2.80 (t, J ϭ 7 Hz, 2 H),
4.17 (t, J ϭ 7 Hz, 2 H), 7.10 (br. s, 2 H), 7.88 (s, 1 H), 10 (br. s, 1
H). Ϫ C8H9N5O3 (223.19): calcd. C 43.05, H 4.06, N 31.38; found
C 43.11, H 4.09, N 31.45.
N6-Benzoyl-9-(4-ethoxycarbonyl-3-oxobutyl)adenine (21). ؊ General
Procedure: To a solution of acid 17 (2.0 g, 6.36 mmol) in dry THF
(32 mL) under nitrogen and magnetic stirring CDI (1.09 g, 6.7
mmol) was added and the mixture stirred at room temperature for
6 h. Magnesium ethyl malonate, prepared from monoethyl malon-
ate[20] (5.83 g, 44.2 mmol) and magnesium ethoxide (2.52 g, 22.0
mmol) in THF (110 mL), was added and the mixture stirred for
additional 20 h. The solvent was evaporated under vacuum and
the crude residue purified by column chromatography on silica gel
(eluent CHCl3 followed by CHCl3/EtOH, 10:1). Obtained 2.22 g of
21 (91% yield), m.p. 85Ϫ86°C. Ϫ IR (KBr): ν˜ ϭ 3400, 1730, 1710,
(KBr): ν˜ ϭ 3450, 1740, 1670, 1610 cmϪ1. Ϫ H NMR (300 MHz,
1
CDCl3): δ ϭ 1.39 (s, 9 H), 2.83 (t, J ϭ 6 Hz, 2 H), 4.47 (t, J ϭ 6
Hz, 2 H), 7.45, 7.55, and 8.11 (m, 5 H), 8.00 (s, 1 H), 8.33 (s, 1 H),
9.3 (br. s, 1 H). Ϫ C19H21N5O3 (367.41): calcd. C 62.11, H 5.36, N
19.06; found C 62.33, H 6.26, N 19.22.
N4-Benzoyl-1-[(2-tert-butoxycarbonyl)ethyl]cytosine (14): 54% yield,
m.p. 175Ϫ179°C. Ϫ IR (KBr): ν˜ 3440, 1720, 1660, 1600 cmϪ1. Ϫ
1H NMR (300 MHz, CDCl3): δ ϭ 1.41(s, 9 H), 2.29 (t, J ϭ 6 Hz,
2 H), 4.11 (t, J ϭ 6 Hz, 2 H), 7.42 (d, J ϭ 8 Hz, 1 H), 8.03 (d, J ϭ
8 Hz, 1 H), 7.51, 7.66, and 8.14 (m, 5 H), 8.98 (br. s, 1 H). Ϫ
C18H21N3O4 (343.38): calcd. C 62.96, H 6.16, N 12.24; found C
62.77, H 6.06, N 12.18.
1
1660, 1610 cmϪ1. Ϫ H NMR (300 MHz, [D6]DMSO): δ ϭ 1.21
(t, J ϭ 7 Hz, 3 H), 3.27 (t, J ϭ 6 Hz, 2 H), 3.44 (s, 2 H), 4.13 (q,
J ϭ 7 Hz, 2 H), 4.57 (t, J ϭ 6 Hz, 2 H), 7.5, 7.6, and 8.00 (m, 5
H), 8.14 (s, 1 H), 8.78 (s, 1 H), 9.1 (br. s, 1 H). Ϫ 13C NMR (75
MHz, [D6]DMSO): δ ϭ 14.9, 39.7, 41.8, 48.9, 59.8, 127.6, 128.7,
129.7, 131.6, 133.8, 144.6, 147.3, 152.6, 154.7, 167.8, 171.7, 202.2.
Ϫ C19H19N5O4 (381.39): calcd. C 59.84, H 5.02, N 18.36; found C
59.75, H 5,06, N 18.43.
N3-Benzoyl-1-(2-tert-butoxycarbonylethyl)thymine (15): 84% yield,
m.p. 168Ϫ169°C. Ϫ IR (KBr): ν˜ ϭ 3450, 1730, 1660, 1610 cmϪ1
.
1
Ϫ H NMR (300 MHz, CDCl3): δ ϭ 1.40 (s, 9 H), 1.92 (s, 3 H),
2.70 (t, J ϭ 6 Hz, 2 H), 3.95 (t, J ϭ 6 Hz, 2 H), 7.20 (s, 1 H), 7.46,
7.59, and 8.11 (m, 5 H). Ϫ C19H22N2O5 (358.39): calcd. C 63.67,
H 6.19, N 7.82; found C 63.77, H 6.26, N 7.78.
N4-Benzoyl-1-(4-ethoxycarbonyl-3-oxobutyl)cytosine (22): 86%
yield, m.p. 149Ϫ150°C. Ϫ IR (KBr): ν˜ ϭ 3430, 1730, 1705, 1650,
1640, 1610 cmϪ1. Ϫ 1H NMR (300 MHz, [D6]DMSO): δ ϭ 1.27
(t, J ϭ 7 Hz, 3 H), 3.20 (t, J ϭ 7 Hz, 2 H), 3.48 (s, 2 H), 4.10 (t,
J ϭ 7 Hz, 2 H), 4.20 (q, J ϭ 7 H, 2 H), 7.51 (d, J ϭ 8 Hz, 1 H),
7.7, 7.8, and 7.9 (m, 5 H), 7.95 (d, J ϭ 8 Hz, 1 H), 8.7 (s, 1 H). Ϫ
13C NMR (75 MHz, [D6]DMSO): δ ϭ 14.9, 38.9, 40.8, 47.8, 58.1,
99.7, 121.3, 126.5, 127.8, 130.1, 133.7, 138.9, 161.7, 166.1, 174.3,
201.1. Ϫ C18H19N3O5 (357.37): calcd. C 60.50, H 5.36, N 11.76;
found C 60.55, H 5,46, N 11.43.
2-Benzoylamino-9-(2-tert-butoxycarbonylethyl)-6-chloropurine
(16): 49% yield, m.p. 113Ϫ115°C. Ϫ IR (KBr): ν˜ ϭ 3450, 1730,
1660, 1610 cmϪ1. Ϫ H NMR (300 MHz, CDCl3): δ ϭ 1.39 (s, 9
1
H), 2.70 (t, J ϭ 6 Hz, 2 H), 4.58 (t, J ϭ 6 Hz, 2 H), 7.49, 7.55,
and 8.18 (m, 5 H), 8.31 (s, 1 H), 9.19 (br. s, 1 H). Ϫ C19H20ClN5O3
(401.85): calcd. C 56.79, H 5.02, Cl 8.82, N 7.82; found C 56.77,
H 5.10, Cl 8.90, N 7.79.
N6-Benzoyl-9-(2-carboxyethyl)adenine (17). ؊ General Procedure:
Compound 12 (3.7 g, 10.1 mmol) was dissolved in a solution of
dry HCl in EtOAc (67 mL of a 3.5  solution) and stirred at room
temp. for 24 h. A white solid was separated and filtered. The filtrate
was diluted with ether (50 mL) to precipitate additional product
which was collected, mixed with the first crop and crystallised from
water. Obtained 1.9 g of 17 (61% yield), m.p. 198Ϫ200°C. Ϫ IR
N3Benzoyl-1-(4-ethoxycarbonyl-3-oxobutyl)thymine (23): 91% yield,
m.p. 122Ϫ123°C. Ϫ IR (KBr): ν˜ ϭ 1740, 1710, 1650Ϫ1640, 1610
cmϪ1. Ϫ 1H NMR (300 MHz, [D6]DMSO): δ ϭ 1.26 (t, J ϭ 7 Hz,
3 H), 1.93 (s, 3 H), 3.07 (t, J ϭ 6 Hz, 2 H), 3.46 (s, 2 H), 3.98 (t,
J ϭ 6 Hz, 2 H), 4.18 (q, J ϭ 7 Hz, 2 H), 7.33 (s, 1 H), 7.4, 7.6,
and 7.9 (m, 5 H). Ϫ 13C NMR (75 MHz, [D6]DMSO): δ ϭ 13.9,
19.7, 36.9, 42.8, 44.8, 55.1, 101.7, 121.3, 125.5, 127.8, 130.1, 133.7,
155.7, 159.7, 164.1, 173.3, 203.1. Ϫ C19H20N2O6 (383.41): calcd. C
61.28, H 5.41, N 7.52; found C 61.10, H 5,52, N 7.27.
(KBr): ν˜ ϭ 3450Ϫ2700, 1710, 1660, 1610 cmϪ1. Ϫ H NMR (300
1
MHz, [D6]DMSO): δ ϭ 2.96 (t, J ϭ 6 Hz, 2 H), 4.50 (t, J ϭ 6 Hz,
2 H), 7.54, 7.65, and 8.01 (m, 5 H), 8.75 (s, 1 H), 8.85 (s, 1 H),
9Ϫ10 (br. s, 2 H). Ϫ 13C NMR (75 MHz, [D6]DMSO) δ 34.9, 47.2,
127.0, 128.4, 129.0, 131.9, 133.5, 144.8, 148.9, 152.0, 155.0, 168.3,
177.0. Ϫ C15H13N5O3 (311.90): calcd. C 57.87, H 4.21, N 22.50;
found C 57.74, H 4.16, N 22.37.
N6-Benzoyl-9-(4-ethoxycarbonyl-3-hydroxybutyl)adenine (25).
؊
General Procedure: To a solution of NaBH4 (0.1 g, 2.6 mmol), in
EtOH (15 mmol), compound 21 (1.0 g, 2.6 mmol) in THF (5 mL)
was added. The mixture was stirred for 2 h, the solvent evaporated,
N4-Benzoyl-1-(2-carboxyethyl)cytosine (18): 82% yield, m.p.
213Ϫ215°C. Ϫ 1H NMR (300 MHz, [D6]DMSO): δ ϭ 2.70 (t, J ϭ and the crude residue purified by flash chromatography (eluent:
6 Hz, 2 H), 4.00 (t, J ϭ 6 Hz, 2 H), 7.25 (d, J ϭ 7 Hz, 1 H), 8.15
CHCl3). Obtained 0.62 g of a waxy material (62% yield). Ϫ IR
Eur. J. Org. Chem. 1999, 931Ϫ936
934

Acyclic Carba-Nucleoside Phosphonates
(KBr): ν˜ ϭ 3400Ϫ3200, 1725, 1650, 1610 cmϪ1. Ϫ H NMR (300
FULL PAPER
1
was added and the product extracted with CHCl3 (15 mL). The
MHz, [D6]DMSO): δ ϭ 1.4 (m, 3 H), 2.2 (m, 2 H), 2.5 (m, 1 H), organic layer was separed, dried with anhydrous Na2SO4 and the
2.8 (br. s, 1 H), 3.2 (m, 1 H), 4.02 (t-like, 3 H), 4.2 (m, 1 H) 4.4 solvent evaporated. The crude residue (0.52 g) was divided in two
(m, 2 H), 7.5, 7.6, and 8.0 (m, 5 H), 8.03 (s, 1 H), 8.81 (s, 1 H), portions of 0.25 g each. One portion was washed several times with
9.12 (s, 1 H). Ϫ 13C NMR (75 MHz, [D6]DMSO): δ ϭ 14.9, 39.7, diethyl ether to give product 30 sufficiently pure to be used in the
41.8, 48.9, 59.8, 61.6, 127.6, 128.7, 129.7, 132.6, 133.1, 144.9, 149.0,
152.8, 155.7, 166.6, 173.3. Ϫ C19H21N5O4 (383.41): calcd. C 59.52,
H 5.52, N 18.27; found C 60.00, H 5,42, N 18.47.
next step (FAB/MS; m/z: 615.3). The other portion was dissolved
in THF (5 ml) and TBAF (0.17 g, 0.53 mmol) was added. The
mixture was stirred at room temp. for 12 h, the solvent evaporated
and the product 31 isolated by column chromatography on silica
gel (eluent: CHCl3/EtOH, 8:1). Obtained 0.06 g (54% yield, based
N4-Benzoyl-1-(4-ethoxycarbonyl-3-hydroxybutyl)cytosine (26): 61%
yield. Ϫ IR (KBr): ν˜ ϭ 3400Ϫ3100, 1715, 1650, 1640, 1610 cmϪ1
Ϫ
.
1
on 0.22 mmol of starting compound 29). Ϫ H NMR (300 MHz,
1H NMR (300 MHz, [D6]DMSO): δ ϭ 1.2 (m, 3 H), 2.2Ϫ2.4
CDCl3): δ ϭ 1.3 (m, 12 H), 2.2 (m, 2 H), 2.3Ϫ2.5 (m, 3 H), 4.4
(m, 1 H), 4.5Ϫ4.8 (m, 4 H), 5.75, (dd, J ϭ 18 and 14 Hz, 1 H),
6.6Ϫ6.8 (m, 1 H), 7.5, 7.6, and 8.0 (m, 5 H), 8.78 (s, 1 H), 9.12 (s,
1 H), 9.78 (s, 1 H). Ϫ 13C NMR (75 MHz, CDCl3): δ ϭ 22.9, 39.7
(d), 48.9, 59.8, 61.6, 71.6, 113.9 (d), 127.6, 128.7, 129.7, 132.6, 133.1
(d), 144.9, 149.0, 150.7, 152.8, 155.7, 166.6. Ϫ C24H32N5O5P
(501.52): calcd. C 57.48, H 6.43, N 13.96; found C 57.57, H 6.37,
N 13.7.
(m, 2 H), 3.2Ϫ3.5 (m, 3 H), 3.9Ϫ4.1 (m, 2 H), 4.10 (t-like, 2 H),
7.50 (d, J ϭ 8 Hz, 1 H), 7.7, 7.8, and 7.9 (m, 5 H), 7.85 (d, J ϭ 8
Hz, 1 H), 8.3(s, 1 H). Ϫ 13C NMR (75 MHz, [D6]DMSO): δ ϭ
12.9, 32.9, 40.0, 45.8, 57.1, 63.3, 99.0, 121.3, 126.5, 127.8, 130.1,
137.7, 157.7, 166.9, 175.7. Ϫ C18H21N3O5 (359.38): calcd. C 60.16,
H 5.89, N 11.69; found C 60.01, H 5.96, N 11.73.
N3-Benzoyl-1-(4-ethoxycarbonyl-3-hydroxybutyl)thymine (27): 57%
1
yield. Ϫ IR (KBr): ν˜ ϭ 3200, 1710, 1650Ϫ1640, 1610 cmϪ1. Ϫ H
Dimer 33 (Not Optimized Procedure): A solution of the crude phos-
phonate 30 (0.2 g, 0.32 mmol) in dry THF (0.7 mL), containing
PCl5 (0.1 g, 0.45 mmol), was heated in a sealed vial at 70°C for 5
h. After cooling to room temp., the solvent was removed at room
temp. under vacuum and the remaining crude product was dis-
solved in 1 mL of dry THF and this solution added to a cooled
(0°C) solution of alcohol 31 (0.16 g, 0.32 mmol) and Et3N (0.5 g,
5 mmol) in dry THF (1 mL). The mixture was stirred for 12 h. The
solid was filtered off and to the solution TBAF (0.31 g, 1 mmol)
in THF (1 mL) was added and the mixture stirred for additional 3
h. The solvent was evaporated and the product 33 isolated by col-
umn chromatography on silica gel (eluent: CHCl3). Obtained 0.21
g (34% yield). Ϫ 1H NMR (300 MHz, CDCl3): δ ϭ 1.3Ϫ1.4 (m,
18 H), 2.1Ϫ2.6 (br. m, 9 H), 4.2Ϫ4.4 (m, 2 H), 4.6Ϫ4.8 (m, 7 H),
7.5Ϫ7.9 (m, 10 H), 8.6 (br. s, 1 H), 8.7 (br. s, 1 H), 8.9 (br. s, 1 H),
NMR (300 MHz, [D6]DMSO): δ ϭ 1.2 (m, 3 H), 1.96 (s, 3 H),
1.9Ϫ2.4 (m, 5 H), 3.3 (m, 2 H), 3.9 (m, 1 H), 4.14(m, 2 H), 7.19
(s, 1 H), 7.4, 7.6, and 7.9 (m, 5 H). Ϫ 13C NMR (75 MHz,
[D6]DMSO): δ ϭ 14.9, 18.7, 36.0, 42.0, 43.8, 50.1, 68.9, 101.7,
121.3, 125.5, 127.8, 130.1, 138.7, 155.7, 159.7, 164.1, 173.3. Ϫ
C19H22N2O6 (374.39): calcd. C 60.95, H 5.92, N 7.48; found C
61.01, H 5.92, N 7.47.
N6-Benzoyl-9-[3-(tert-butyldimethylsilyloxy)-4-ethoxycarbonyl-
butyl]adenine (28): To a solution of 25 (0.360 g, 0.94 mmol) in dry
DMF (0.7 mL) imidazole (0.18 g, 2.6 mmol) was added followed
by TBDMSCl (0.17 g, 1.13 mmol). The vial was sealed and the
mixture stirred for 72 h at 70°C (oil bath). The solvent was evapo-
rated and the product purified by column chromatography on silica
gel (eluent: CHCl3). Obtained 0.32 g (69% yield). Ϫ 1H NMR (300
MHz, CDCl3): δ ϭ 0.09 (s, 3 H), 0.11 (s, 3 H), 0.92 (s, 9 H), 1.22
(t, J ϭ 7 Hz, 3 H), 2.1Ϫ2.3 (m, 2 H), 2.5 (m, 2 H), 4.10 (q, J ϭ 7
Hz, 2 H), 4.25 (m, 1 H), 4.35 (m, 2 H), 7.4, 7.6, and 8.0 (m, 5 H),
8.76 (s, 1 H), 8.86 (s, 1 H), 9.02 (s, 1 H). Ϫ C25H35N5O4Si (497.67):
calcd. C 60.34, H 7.09, N 14.07; found C 60.44, H 7.06, N 14.19.
9.2 (br. s,
1 H), 9.4 (br. s 2 H). Ϫ HRMS: calcd. for
C45H56N10O9P2; m/z: 942.3707, found 942.3712.
Acknowledgments
N6-Benzoyl-9-[3-(tert-butyldimethylsilyloxy)-5-oxopentyl]adenine
(29): Compound 28 (0.25 g, 0.5 mmol) was dissolved in dry CH2Cl2
(0.7 mL) and this solution cooled to Ϫ78°C. DIBAL-H in toluene
(0.6 mL of a 1  solution) was added and the mixture stirred at
Ϫ78°C for 4 h. Methanol (0.5 mL) was added to destroy the excess
of DIBAL-H than the mixture was warmed to room temp., diluted
with additional CH2Cl2 and washed with a saturated solution of
NH4Cl. The organic phase was separated, dried with Na2SO4, and
the solvent evaporated to give 0.2 g of the crude aldehyde as a
waxy material that was immediately employed in the next step (87%
This work was financially supported by MURST (Rome) within
the project “Chimica dei Composti Organici di Interesse Bio-
logico”.
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1
yield). Ϫ IR (neat): ν˜ ϭ 3450, 2860, 2740, 1730, 1620 cmϪ1. Ϫ H
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adenine (31): To a solution of tetraisopropyl methylenediphosphon-
ate (0.34 g, 1 mmol) in dry THF (1 mL), cooled to 0°C, LDA (1.1
mL of a 1  solution in THF) was added and the mixture stirred
at room temp. for 3 h. After cooling again to 0°C, 29 (0.2 g, 0.44
mmol), dissolved in THF (1 mL), was added and the mixture was
stirred at room temperature for 5 h. A saturated solution of NH4Cl
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