Synthesis of novel cyclopropyl carbocyclic nucleosides from (-)-(Z)-2,3-methanohomoserine

Article abstract of DOI:10.1021/ol990203w

(matrix presented) The new cyclopropyl carbocyclic nucleosides 1 and 2 have been synthesized by following short and efficient routes starting from conveniently protected (-)-(Z)-methanohomoserine derivative 3. Both products 1 and 2 bear a quaternary stere

Full text of DOI:10.1021/ol990203w

ORGANIC
LETTERS
1999
Vol. 1, No. 8
1221-1223
Synthesis of Novel Cyclopropyl
Carbocyclic Nucleosides from
(−)-(Z)-2,3-Methanohomoserine
Joan Rife´ and Rosa M. Ortun˜o*
Departament de Qu´ımica, UniVersitat Auto`noma de Barcelona,
08193 Bellaterra, Barcelona, Spain
rosa.ortuno@uab.es
Received August 2, 1999
ABSTRACT
The new cyclopropyl carbocyclic nucleosides 1 and 2 have been synthesized by following short and efficient routes starting from conveniently
protected (−)-(Z)-methanohomoserine derivative 3. Both products 1 and 2 bear a quaternary stereogenic center and have opposite chirality.
Moreover, the adenine derivative 2 belongs to a new class of cyclopropyl nucleoside showing an amino alcohol function at C-1 in addition to
a methylene spacer between the base and the carbocyclic ring.
Carbocyclic nucleosides have received great attention since
the isolation from natural sources of (-)-aristeromycin1 and
(-)-neplanocine2 and the verification of their remarkable
biologic activities. Among the differently sized carbocyclic
nucleosides, the cyclopropane derivatives have focused the
interest of chemists and biologists in the past decade due to
the potent antiviral properties of some of them. Several
structural modifications have been made in order to improve
or enhance this activity, the most representative being shown
in Figure 1. One of the most usual modifications consists of
the incorporation of a second hydroxymethyl group, either
in a geminal position at C-1 of the carbocyclic ring (type C)
or in a vicinal position at C-2 (type D).3 Very recently, a
new compound bearing a geminal disubstitution at C-3 (type
E) has been prepared showing an activity 40 times more
potent than acyclovir and better selectivity.4 The introduction
(1) Kusaka, T.; Yamamoto, H.; Shibata, M.; Muroi, M.; Kishi, T.;
Mizuno, K. J. Antibiot. 1968, 21, 255. Yaginuma, S.; Tsujino, M.; Muto,
N.; Otani, M.; Hatashi, M.; Ishimura, F.; Fujii, T.; Watanabe, S.; Matsuda,
T.; Watanabe, T.; Abe, J. Curr. Chemother. Infect. Dis., Int. Congr. 1980,
2, 1558.
(2) Yaginuma, S.; Tsujino, M.; Muto, N.; Otani, M.; Hatashi, M.;
Ishimura, F.; Fujii, T.; Watanabe, S.; Matsuda, T.; Watanabe, T.; Abe, J.
Curr. Chemother. Infect. Dis., Int. Congr. 1980, 2, 1558.
(3) Maag, H.; Nelson, J. T.; Steiner, J. L. R.; Prisbe, E. J. J. Med. Chem.
1994, 37, 431.
Figure 1.
10.1021/ol990203w CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/23/1999

of spacers, i.e., additional methylene groups between the
heterocyclic base5 or the hydroxymethyl group at C-16 and
the cyclopropane has also been investigated. Spacered
cyclopropyl nucleosides of types B and C are more flexible
than those of type A, avoiding the high rigidity that seems
to be unfavorable either for the interaction with phospho-
rylating enzymes or for the interaction of the corresponding
triphosphate with viral DNA polymerases.7 Finally, the
incorporation of other substituents such as halogen atoms
has also been considered.8
Scheme 1
Therefore, keeping the interest of such products in mind,
several synthetic approaches have been reported for the
obtention of these different kinds of cyclopropyl nucleosides,
as pure enantiomers or as racemates.3-6,8,9 Nevertheless, the
described protocols often involve long synthetic sequences
and cyclopropanation methods with rather low stereoselec-
tivity.
In this Letter, we describe the concise and efficient
stereoselective syntheses of the new cyclopropyl carbocyclic
nucleosides 1 and 2. Compound 2 represents a new kind of
nucleoside showing a gem-disubstituion, as a â-amino
alcohol function, at C-1 and a methylene spacer between
the base and the cyclopropane ring. As additional structural
features, the hydroxymethyl group is trans with respect to
the base-containing chain at C-3, and the quaternary center
bears an amino group. On the other hand, nucleoside 1
contains a pyrimidine-family base while nucleoside 2
presents a purine-type one. Both products are enentiomeri-
cally pure and have been obtained from conveniently
protected (-)-(Z)-2,3-methanohomeserine, 3, as an appropri-
ate precursor which affords the chirality of the cyclopropane
stereogenic centers and presents functional groups suitable
for the transformations into the target molecules. This
homoserine methanolog has been synthesized in our labora-
tory, in multigramme scale, through the highly stereoselective
cyclopropanation of a suitable olefinic substrate, readily
available from D-glyceraldehyde, and has successfully been
used for the synthesis of other cyclopropane amino acids.10
The synthetic routes to 1 and 2 are outlined in Schemes 1
and 2, respectively. The strategies to introduce the hetero-
cyclic base are different for each nucleoside. In the case of
1, the thymine ring is built from an amino group present in
the precursor, following a standard methodology previously
described.11 Adenine, in contrast, is incorporated through
nucleophilic displacement of mesylate anion.
Scheme 2
Thus, the methyl ester in methanohomoserine derivative
3 was reduced with lithium borohydride to afford, in nearly
quantitative yield, diol 412 which was protected as bis(silyl)
ether 5. The amine was deprotected by hydrogenation of
benzyl carbamate in the presence of Pd(OH)2 on charcoal
as catalyst. Creation of the thymine system to afford
compound 7 was accomplished through the reaction between
6 and 3-methoxy-2-methylacryloyl isocyanate. This last
reagent was generated in situ from 3-methoxy-2-methylacryl-
oyl chloride and silver isocyanate.
(4) Sekiyama, T.; Hatsuya, S.; Tanaka, Y.; Uchiyama, M.; Ono, N.;
Iwayama, S.; Oikawa, M.; Suzuki, K.; Okunishi, M.; Tsuji, T. J. Med. Chem.
1998, 41, 1284.
(5) (a) Me´vellec, L.; Huet, F. Tetrahedron Lett. 1995, 36, 7441. (b) Csuk,
R.; Kern, A. Tetrahedron 1999, 55, 8409.
(6) Yang, T.-F.; Kim, H.; Kotra, L. P.; Chu, C. K. Tetrahedron Lett.
1996, 49, 8849.
(7) Harnden, M. R.; Jarvest, R. L.; Bacon, T. H.; Boyd, M. R. J. Med.
Chem. 1987, 30, 1636.
(8) (a) Csuk, R.; Eversmann, L. Tetrahedron 1998, 54, 6445. (b) Csuk,
R.; Thiede, G. Tetrahedron 1999, 55, 739.
Cyclization of the acryloyl urea to the thymine ring and
deprotection of diol was achieved in one single step by
treatment of 7 with 0.2 M HCl. In this way, nucleoside 1
was obtained as a solid, mp 180-182 °C and [R]D -44.0,
in 16% overall yield from 3.
(9) (a) Gauvry, N.; Huet, F. Tetrahedron 1999, 55, 1321. (b) Zhao, Y.;
Yang, T.; Lee, M.; Lee, D.; Newton, M. G.; Chu, C. K. J. Org. Chem.
1995, 60, 5236. (b) Lee, G.; Du, J. F.; Chun, M. W.; Chu, C. K. J. Org.
Chem. 1997, 62, 1991.
(10) Jime´nez, J. M.; Rife´, J.; Ortun˜o, R. M. Tetrahedron: Asymmetry
1999, 7, 537.
(11) (a) Shaw, G.; Warrener, R. N. J. Chem. Soc. 1958, 153. (b) Shealy,
Y. F.; O’Dell, C. A.; Thorpe, M. C. J. Heterocycl. Chem. 1981, 18, 383.
(c) D´ıaz, M.; Ortun˜o, R. M. Tetrahedron: Asymmetry 1997, 8, 3421.
(12) All new products were fully charaterized by their physical constants
and spectroscopic data and gave satisfactory microanalysis.
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Org. Lett., Vol. 1, No. 8, 1999

In the second synthetic route, mesylate 8, obtained from
3 in the usual way,10 was reacted with adenine in the presence
of potassium carbonate and 18-crown-6 at 80 °C for 10 h to
give compound 9 in 47% yield.13 This method afforded better
results than the use of NaH as a base even in the presence
of a crown ether.14,15 Intermediate 9 incorporates the
heterocyclic base present in the target nucleoside but still
retains the amino acid function provided by the precursor.
Reduction of the methyl ester to give 10 followed by
deprotection of the amino group under catalytic hydrogena-
tion led to the obtention of nucleoside 2 as solid, mp 197-
199 °C and [R]D +22.5 (27% overall yield from 3).
In conclusion, we have shown the usefulness of (-)-(Z)-
methanohomoserine as a precursor of different types of
cyclopropyl nucleosides. Versatile and straightforward syn-
thetic routes have allowed the obtention of two new
compounds whose biological evaluation is in progress.
(13) In a typical run, a solution of mesylate 810 (286 mg, 0.8 mmol) in
anhydrous DMF (5 mL) was added to a mixture of adenine (113 mg, 0.8
mmol), K2CO3 (121 mg, 0.9 mmol), and 18-crown-6 (211 mg, 0.8 mmol)
in DMF (8 mL) under a nitrogen atmosphere. The resulting mixture was
stirred at 80 °C for 10 h and then cooled to room temperature. Saturated
aqueous NaCl (15 mL) was added, and the solution was extracted with
EtOAc (5 × 10 mL). The combined organic extracts were dried over
MgSO4, and solvents were removed at reduced pressure. The residue was
chromatographed on silica gel (mixtures of CH2Cl2-methanol as eluent)
to afford compound 9 (149 mg, 47% yield).
Acknowledgment. J.R. thanks the Generalitat de Cata-
lunya for a predoctoral fellowship. Financial support from
DGESIC trhough the project PB97-0214 is gratefully
acknowledged.
(14) In the last cases the N-9 alkylated product was produced along with
the N-7 regioisomer (85:15 ratio). The structures were assigned by
comparison of their 1H and 13C NMR spectroscopic data with those of
similar compounds in the literature.15 Moreover, UV of 2 (λmax 256, ꢀ 14000)
compares well with that of adenosine (λmax260, ꢀ 15000), thus discarding
the presence of the N-3 regioisomer.
OL990203W
(15) See, for instance: Jung, M. E.; Kiankarimi, M. J. Org. Chem. 1998,
63, 8133.
Org. Lett., Vol. 1, No. 8, 1999
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