Stereoselective synthesis of novel types of cyclopropyl carbocyclic nucleosides containing quaternary stereogenic centers

Article abstract of DOI:10.1021/jo025599v

Versatile and stereocontrolled synthetic entries to novel types of cyclopropyl carbocyclic nucleosides are described. The target products have been synthesized from suitable cyclopropane precursors obtained, in turn, from olefinic compounds derived from D-glyceraldehyde as a chiral precursor. Selective manipulation of the functional groups has allowed the preparation of enantiopure nucleosides, some of them displaying opposite chirality. All these molecules contain a quaternary stereogenic carbon at C-1 or C-3 of the cyclopropane ring and bear an amino, a hydroxymethyl, or a methyl group as an additional substituent. In one instance, thymine is directly linked to the cyclopropane. A methylene unit serves as the spacer in the other synthesized nucleosides.

Full text of DOI:10.1021/jo025599v

4520
J . Org. Chem. 2002, 67, 4520-4525
Ster eoselective Syn th esis of Novel Typ es of Cyclop r op yl
Ca r bocyclic Nu cleosid es Con ta in in g Qu a ter n a r y Ster eogen ic
Cen ter s
Elena Muray, J oan Rife´, Vicenc¸ Branchadell, and Rosa M. Ortun˜o*
Departament de Quı´mica, Universitat Auto`noma de Barcelona, 08193 Bellaterra, Barcelona, Spain
rosa.ortuno@uab.es
Received February 6, 2002
Versatile and stereocontrolled synthetic entries to novel types of cyclopropyl carbocyclic nucleosides
are described. The target products have been synthesized from suitable cyclopropane precursors
obtained, in turn, from olefinic compounds derived from D-glyceraldehyde as a chiral precursor.
Selective manipulation of the functional groups has allowed the preparation of enantiopure
nucleosides, some of them displaying opposite chirality. All these molecules contain a quaternary
stereogenic carbon at C-1 or C-3 of the cyclopropane ring and bear an amino, a hydroxymethyl, or
a methyl group as an additional substituent. In one instance, thymine is directly linked to the
cyclopropane. A methylene unit serves as the spacer in the other synthesized nucleosides.
Ch a r t 1
In tr od u ction
The discovery of the potent antileukemic (-)-arystero-
mycin,1 a naturally occurring nucleoside analogue in
which a methylene group has replaced the ring oxygen
atom, marked a new field in synthetic and bio-organic
chemistry. In general, carbocyclic nucleosides are more
resistant to enzymatic hydrolysis and degradation than
classic nucleosides, and this property confers on them a
promising usefulness in the search for new therapeutic
agents. Several natural or designed carbocyclic nucleo-
sides have shown, indeed, antineoplasic or antiviral
activity, and these properties have stimulated synthetic
chemists to develop new and efficient methods to prepare
novel nucleosides in order to test their biological activi-
ties.2 Thus, different sized carbocyclic nucleosides con-
taining cyclohexane, cyclopentane, cyclobutane, or cyclo-
propane rings have been prepared. Regarding the
cyclopropyl derivatives, several structural modifications
have been made in order to improve or enhance the
antiviral activity found for some of them. Chart 1
summarizes the most significant structural types of
cyclopropyl carbocyclic nucleosides described by other
authors.
tivity than acyclovir.4 Moreover, the inclusion of other
substituents such as halogen atoms has also been con-
sidered.5 The introduction of spacers, i.e., additional CH2
units between the heterocyclic base6 or the hydroxy-
methyl group at C-17 and the cyclopropane, has also been
investigated. Spacered cyclopropyl nucleosides of types
D (n ) 1) and E are more flexible than those of type A
avoiding the high rigidity that seems to be unfavorable
either for the interaction with phosphorylating enzymes
or for interaction of the corresponding triphosphate with
viral DNA polymerases.8 Very recently, methylenecyclo-
propane analogues of purine nucleosides (type F) have
been described as potent antiviral agents of broad
selectivity.9
One of the most usual modifications is the incorpora-
tion of a second hydroxymethyl group, either in a geminal
position at C-3 (type B) or C-1 (type D) of the cyclopro-
pane ring or in a vicinal position at C-2 (type C).3 A new
compound of type B has been prepared showing an
antiviral activity 40 times more potent and better selec-
Therefore, the acknowledgment of the interest of these
products has prompted chemists to develop synthetic
(1) (a) Kusaka, T.; Yamamoto, H.; Shibata, M.; Muroi, M.; Kishi,
T.; Mizuno, K. J . Antibiot. 1968, 21, 255. (b) 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) For reviews on the synthesis and activities of carbocyclic nucleo-
sides, see: (a) Zhu, X.-F. Nucleosides, Nucleotides Nucleic Acids 2000,
19. (b) Agrofolio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, R.;
Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611. (c) De Clercq, E.
Nucleosides Nucleotides 1994, 13, 1271. (d) Huryn, D. M.; Okabe, M.
Chem. Rev. 1992, 92, 1745.
(4) 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) Csuk, R.; Eversmann, L. Tetrahedron 1998, 54, 6445. (b)
Csuk, R.; Thiede, G. Tetrahedron 1999, 55, 739.
(6) (a) Me´vellec, L.; Huet, F. Tetrahedron Lett. 1995, 36, 7441. (b)
Csuk, R.; Kern, A. Tetrahedron 1999, 55, 8409.
(7) Yang, T.-F.; Kim, H.; Kotra, L. P.; Chu, C. K. Tetrahedron Lett.
1996, 49, 8849.
(8) Harnden, M. R.; J arvest, R. L.; Bacon, T. H.; Boyd, M. R. J . Med.
Chem. 1987, 30, 1636.
(3) Maag, H.; Nelson, J . T.; Steiner, J . L. R. Prisbe, E. J . J . Med.
Chem. 1994, 37, 431.
(9) Chen X.; Zemlika, J . J . Org. Chem. 2002, 67, 286 and references
therein.
10.1021/jo025599v CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/08/2002

Synthesis of Cyclopropyl Carbocyclic Nucleosides
J . Org. Chem., Vol. 67, No. 13, 2002 4521
Sch em e 1
Resu lts a n d Discu ssion
(-)-(Z)-2,3-Methanohomoserine, 5, previously synthe-
sized in our laboratory on a multigram scale,11 is the
common precursor to nucleosides 1 and 2 that display
different chirality. The synthetic routes leading to these
products are shown in Scheme 2. The strategies to
introduce the heterocyclic base are different. For 1, the
thymine ring is constructed around an amino group
already present in the precursor 5. In contrast, in the
synthesis of 2 the introduction of the adenine core
involves the nucleophilic displacement of mesylate from
the intermediate 12.12
For the synthesis of 1, the methyl ester 5 was reduced
with LiBH4 to afford diol 8,13 which was protected as a
TBDMS diether. Then, the amine was deprotected by
hydrogenolysis of the benzyl carbamate, in the presence
of Pd(OH)2 on charcoal as a catalyst, to afford compound
10. Creation of the thymine heterocycle was accomplished
according to the standard methodology14 through the
reaction of 10 and 3-methoxy-2-methylacryloyl isocyan-
ate. This reagent was generated in situ from 3-methoxy-
2-methylacryloyl chloride and silver isocyanante. Cy-
clization of the acryloyl urea to the thymine ring and
deprotection of diol was achieved in one single step by
treatment of 11 with 0.2 M HCl to afford nucleoside 1 in
16% overall yield from 5.
The synthetic route for nucleoside 2 involved mesyl-
ation of alcohol 5 to give 12, which was reacted with
adenine in the presence of K2CO3 and 18-crown-6 in DMF
as a solvent, at 80 °C for 10 h, to provide isomer-free
compound 13 in 47% yield. The N-9-alkylated derivative
was produced as the major compound along with the N-7
regioisomer (85:15 ratio) when NaH was used as a base
even in the presence of a crown ether. The structures
approaches leading to different kinds of cyclopropyl
nucleosides, in enantiomerically pure form or as race-
mates.3-7,9,10 However, the protocols employed usually
involve long synthetic sequences and cyclopropanation
methods that often display low stereoselectivity.
1
were assigned by H and 13C NMR and by comparison of
the spectra with those of similar compounds in the
literature.15 The structural homogeneity of 13 was as-
sessed by TLC and by its 13C NMR spectrum showing
one only set of signals. Finally, subsequent reduction of
the methyl ester to give 14 followed by catalytic hydro-
genation of the Cbz protecting group afforded nucleoside
2 in 27% overall yield from 5. UV of 2 (λmax 256, ꢀ 14 000)
compares well with that of adenosine (λ max 260, ꢀ 15 000)
in good agreement with the structure of the N-9 regio-
isomer.
We describe in this paper the easy and efficient
stereoselective syntheses of the new cyclopropyl nucleo-
sides 1-4 (Scheme 1). The synthetic strategy is based
on the selective manipulation of functional groups start-
ing from suitable cyclopropane derivatives and it provides
a versatile entry to several types of nucleosides with
different substituents and with controlled stereochem-
istry. The four compounds 1-4 bear a gem-disubstitution
at C-1 (compounds 2 and 3) or at C-3 (compounds 1 and
4). In 2, such a substitution contains a â-amino alcohol
function. Furthermore, whereas the base is directly
linked to the cyclopropane in 1, adenine is spacered from
the carbocyclic ring by a methylene group in 2-4. It is
noteworthy that chirality of 1 and 4 is opposite at C-3
with respect to 2 and 3. Moreover, in 2 and 3, the
hydroxymethyl group and the base are in a trans disposi-
tion. The cyclopropane derivatives 5-7 are the key
precursors to the target molecules, and they have been
synthesized, in turn, through the highly stereoselective
cyclopropanation of convenient chiral olefins prepared
from D-glyceraldehyde acetonide, which is the primary
source of chirality.
The synthesis of nucleoside 3 is outlined in Scheme 3.
Cyclopropanation of (E)-pentenoate 15 and subsequent
hydrolysis of the acetonide provided compound 16, as
previously described by us.16 Cleavage of the diol by the
action of NaIO4 afforded aldehyde 17 that was reduced
to alcohol 6. This product is the key intermediate in the
preparation of 3. Reaction of 6 with mesyl chloride in the
presence of triethylamine gave a mesylate that was made
to react with adenine under the conditions described
above. In this way, compound 18 was obtained in 55%
(11) J ime´nez, J . M.; Rife´, J .; Ortun˜o, R. M. Tetrahedron: Asymmetry
1996, 7, 537.
(12) Rife´, J .; Ortun˜o, R. M. Org. Lett. 1999, 1, 1221.
(13) Rife´, J .; Ortun˜o, R. M. Tetrahedron: Asymmetry 1999, 10, 4245.
(14) (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.
(15) J ung, M. E.; Kiankarimi, M. J . Org. Chem. 1998, 63, 8133.
(16) Muray, E.; AÄ lvarez-Larena, A.; Piniella, J . F.; Branchadell, V.;
Ortun˜o, R. M. J . Org. Chem. 2000, 65, 388.
(10) (a) Csuk, R.; von Scholz, Y. Tetrahedron 1994, 50, 10431. (b)
Csuk, Y.; von Scholz, Y. Tetrahedron 1995, 51, 7193. (c) Zhao, Y.; Yang,
T.; Lee, D.; Newton, M. G.; Chu, C. K. J . Org. Chem. 1995, 60, 5236.
(d) Lee, G.; Du, J . F.; Chun, M. W.; Chu, C. K. J . Org. Chem. 1997, 62,
1991. (e) Gauvry, N.; Huet, F. Tetrahedron 1999, 55, 1321.

4522 J . Org. Chem., Vol. 67, No. 13, 2002
Muray et al.
Sch em e 2
Sch em e 3
Sch em e 4
yield for the two steps. Reduction of the methyl ester with
LiBH4 furnished nucleoside 3 in 37% overall yield from
diol 16.
The synthesis of nucleoside 4 was envisioned from (Z)-
pentenoate 22 (Scheme 4). Following the methodology of
our laboratory, cyclopropane 23 was obtained in 65%
yield.16 The order of manipulation of the functional
groups was crucial for success. Thus, starting from 23,
attempts to transform the diol function into a hy-
droxymehyl group failed in the deprotection step since
hydrolysis of the acetonide with 2 M HCl led to lactone
19. The use of 90% acetic acid allowed the preparation
of diol 20 without cyclization. Nevertheless, lactone 21
was obtained after oxidative cleavage of 20 and subse-
quent reduction of the resulting aldehyde.17 Lactones 19
and 21 remained unaltered under several reaction condi-
tions, being unsuitable to achieve the synthetic goal.
Therefore, the methyl ester in 23 was reduced to the
primary alcohol 7, and then the adenine core was
introduced as described above for the synthesis of 2 and
3. From compound 24, the synthesis of 4 was successfully
achieved through hydrolysis of the ketal and oxidation
of the resultant diol 25 to aldehyde 26. Subsequent
reduction with NaBH4 to alcohol led to nucleoside 4 in
26% yield from precursor 23.
In conclusion, we have synthesized several types of
nucleosides, in enantiomerically pure form, from easily
available cyclopropane derivatives. The synthetic routes
presented herein involve simple chemical transforma-
tions of functional groups, and they are also useful for
(17) For a very related case, see: Mart´ın-Vila`, M.; Hanafi, N.;
J ime´nez, J . M.; AÄ lvarez-Larena, A.; Piniella, J . F.; Branchadell, V.;
Oliva, A.; Ortun˜o, R. M. J . Org. Chem. 1998, 63, 3581.

Synthesis of Cyclopropyl Carbocyclic Nucleosides
J . Org. Chem., Vol. 67, No. 13, 2002 4523
NMR (CDCl3) -5.24, -5.19, 8.79, 14.88, 18.26, 23.18, 25.93,
25.96, 29.65, 37.93, 61.44, 62.91, 65.36, 106.80, 154.09, 158.35,
168.45.
the preparation of nucleosides containing bases other
than adenine and thymine. The antiviral and the anti-
tumoral biological activities of the synthesized products
is being investigated and results will be published
elsewhere.
Compound 11 (85 mg, 0.2 mmol) in (10:1) 0.2 M HCl-EtOH
(11 mL) was heated to reflux overnight. The solvents were
evaporated to dryness affording a dark and very dense oil
which was purified by successive elutions through a C18
reversed-phase cartridge (water) and on silica gel (8:1 EtOAc-
MeOH) to give the thymine derivative 1 (28 mg, 68% yield):
crystals; mp 180-182 °C (MeOH-EtOAc); [R]D -44.0 (c 0.50,
MeOH); IR (KBr) 3600-3200 (broad), 1689, 1670; 1H NMR
(methanol-d4) 0.89 (dd, J ) 6.6, J ′ ) 5.8, 1H), 1.20 (dd, J )
9.5, J ′ ) 5.8, 1H), 1.56 (m, 1H), 1.86 (s, 3H), 3.05 (d, J ) 11.7,
1H), 3.20-3.43 (complex absorption, 2H), 4.12 (d, J ) 11.7,
1H), 7.34 (s, 1H); 13C NMR (D2O) 12.03, 14.91, 25.47, 49.00,
61.30, 66.17, 111.67, 145.40, 153.78, 167.66. Anal. Calcd for
Exp er im en ta l Section
Flash column chromatography was carried out on silica gel
(240-400 mesh) or on Baker silica gel (400 mesh) for acid-
sensitive products. Melting points were determined on a hot
stage apparatus and are uncorrected. Distillation of small
amounts of material was effected in a bulb-to-bulb distillation
apparatus, with oven temperatures (ot) being reported. Signals
in IR spectra are reported in cm-1. In 250-MHz 1H and in 62.5-
MHz 13C NMR spectra, chemical shifts are given on the δ scale.
Coupling constants (J ) are given in Hz. Electron impact mass
spectra were recorded at 70 eV.
C
10H14N2O4: C, 53.09; H, 6.24; N, 12.38. Found: C, 53.15; H,
6.18; N, 12.57.
Meth yl (1S,2R)-1-N-Ben zyloxyca r bon yla m in o-2-m eth -
a n esu lfon yloxycyclop r op a n eca r boxyla te, 12. Freshly dis-
tilled TEA (415 µL, 3.0 mmol) and mesyl chloride (275 µL, 3.0
mmol) were successively added to a stirred and ice-cooled
solution of alcohol 511 (415 mg, 1.5 mmol) in dry dichloro-
methane (10 mL) under nitrogen atmosphere. After the
mixture was stirred at 0 °C for 10 min, water (6 mL) was
added, and the layers were separated. The aqueous phase was
extracted with dichloromethane (3 × 6 mL), the combined
organic extracts were dried (MgSO4), and solvent was removed
at reduced pressure. The residue was chromatographed (2:1
hexanes-EtOAc) to afford mesylate 12 (502 mg, 95% yield):
crystals; mp 56-58 °C (EtOAc-pentane); [R]D -7.7 (c 1.30,
CHCl3); IR (KBr) 3303 (broad, 1754, 1698; 1H NMR (acetone-
d6) 1.29 (dd, J ) 7.4, J ′ ) 5.4, 1H), 1.66 (dd, J ) 9.4, J ′ ) 5.4,
1H), 2.20 (dddd, J ) 9.4, J ′ ) 7.4, J ′′ ) 7.3, J ′′′ ) 7.1, 1H),
3.09 (s, 3H), 3.65 (s, 3H), 4.21 (dd, J ) 11.0, J ′ ) 7.1, 1H),
4.41 (dd, J ) 11.0, J ) 7.3, 1H), 5.10 (coalescent AB system,
J ) 11.2, 2H), 7.07 (broad s, 1H), 7.34 (complex absorption,
5H); 13C NMR (acetone-d6) 20.03, 25.49, 36.49, 38.44, 51.87,
65.98, 68.88, 127.56, 127.74, 128.28, 137.06, 156.91, 171.81.
Anal. Calcd for C15H19NO7S: C, 50.41; H, 5.36, N, 3.92; S, 8.97.
Found: C, 50.34; H, 5.40; N, 3.90; S, 8.84.
Met h yl (1S,2R)-2-(6-Am in o-9H -p u r in ylm et h yl)-1-(N-
ben zyloxyca r bon yla m in o)cyclop r op a n eca r boxyla te, 13.
A solution of mesylate 13 (286 mg, 0.8 mmol) in anhydrous
DMF (5 mL) was added to a mixture of adenine (113 mg, 0.8
mmol), 18-crown-6 (211 mg, 0.8 mmol), and K2CO3 (121 mg,
0.9 mmol) in anhydrous DMF (8 mL) under nitrogen atmo-
sphere. After being stirred at 80 °C for 15 h, the reaction
mixture was cooled to rt, brine (15 mL) was added, and
extractions with EtOAc (5 × 10 mL) were performed. The
combined organic extracts were dried (MgSO4), and solvents
were removed at reduced pressure. The residue was chromato-
graphed on silica gel (mixtures of dichloromethane-MeOH as
eluents) to afford 149 mg (47% yield) of compound 13 as a
colorless oil: [R]D +10.7 (c 0.75, MeOH); IR (film) 3324, 1724,
1644, 1598; 1H NMR (CDCl3) 1.23 (m, 1H), 1.93 (complex
absorption, 2H), 3.59 (s, 3H), 4.07 (dd, J ) 14.6, J ′ ) 9.5, 1H),
4.45 (dd, J ) 14.6, J ′ ) 2.9, 1H), 5.19 (s, 2H), 6.00 (s, 2H),
7.32-7.39 (complex absorption, 5H), 7.78 (s, 1H), 8.33 (s, 1H),
8.60 (broad s, 1H); 13C NMR (CDCl3) 20.32, 27.83, 38.33, 43.00,
52.65, 66.78, 119.70, 127.79, 127.94, 128.41, 136.61, 140.29,
149.64, 152.73, 155.82, 157.55, 172.40. Anal. Calcd for
(1S,2R)-1-N-Ben zyloxycar bon ylam in o-1,2-bis(ter t-bu tyl-
d im et h ylsilyloxym et h yl)cyclop r op a n e, 9. DMAP (1.1 g,
9.3 mmol) and tert-butyldimethylsilyl chloride (0.9 g, 4.6 mmol)
were successively added to a stirred and ice-cooled solution of
diol 813 (390 mg, 1.5 mmol) in anhydrous dichloromethane
under nitrogen atmosphere. After 5 min, the mixture was
stirred at rt for 15 h. Then solvent was removed at reduced
pressure, and the residue was chromatographed on Baker
silica (2:1 hexanes-ether) to afford 0.7 g (89% yield) of diether
9 as an oil: [R]D +21.6 (c 1.80, CHCl3); IR (film) 3500-2900
(broad), 1733, 1494, 1468, 1255, 1223; 1H NMR (CDCl3) -0.01
(s, 6H), 0.04 (s, 6H), 0.76 (m, 1H), 0.84 (s, 9H), 0.87 (s, 9H),
0.96, (m, 1H), 1.26 (m, 1H), 3.30 (d, J ) 10.2, 1H), 3.39 (dd, J
) 10.9, J ′ ) 9.5, 1H), 3.91 (complex absorption, 2H), 5.06 (s,
2H), 5.50 (broad s, 1H), 7.32 (m, 5H); 13C NMR (CDCl3) -5.46,
-5.37, -5.14, 15.47, 18.18, 18.27, 23.36, 25.92, 38.50, 63.52,
66.12, 66.35, 127.94, 128.44, 136.67, 156.58. Anal. Calcd for
C
25H45NO4Si2: C, 62.58, H, 9.45, N, 2.92. Found: C, 62.66; H,
9.53; N, 2.95.
(1S,2R)-1-Am in o-1,2-b is(ter t-b u t yld im et h ylsilyloxy-
m eth yl)cyclop r op a n e, 10. Carbamate 9 (300 mg, 0.6 mmol)
in MeOH (10 mL) was hydrogenated under 4 atm of pressure
for 17 h in the presence of 20% Pd(OH)2/C (27 mg). The mixture
was filtered through Celite, and the solvent was removed
under reduced pressure. The residue was chromatographed
on Baker silica gel to furnish amine 10 (199 mg, 92% yield) as
a colorless oil: [R]D +9.52 (c 2.05, CHCl3); IR (film) 3500-2700
(broad); 1H NMR (CDCl3) 0.02 (s, 6H), 0.03 (s, 6H), 0.38 (dd, J
) 5.8, J ′ ) 5.1, 1H), 0.56 (dd, J ) 8.4, J ′ ) 5.1, 1H), 0.87 (s,
18H), 0.94 (m, 1H), 2.03 (broad s, 2H), 3.42 (s, 1H), 3.43 (s,
1H), 3.68 (dd, J ) 10.9, J ′ ) 8.0, 1H), 3.85 (dd, J ) 10.9, J ′ )
5.1, 1H); 13C NMR (CDCl3) -5.23, -5.11, 15.44, 18.33, 24.30,
25.94, 39.30, 62.68, 71.06. Anal. Calcd for C17H39NO2Si2: C,
59.07; H, 11.37; N, 4.05. Found: C, 59.28; H, 11.55; N, 4.00.
(1′S,2′R)-(Z)-1-[1′,2′-Bis(dih ydr oxym eth yl)cyclopr opyl]-
5-m eth yl-(1H)-p yr im id in e-2,4-d ion e, 1. Oxalyl chloride (120
µL, 1.4 mmol) was added dropwise to an ice-cooled and stirred
solution of 3-methoxy-2-methylacrylic acid (146 mg, 1.3 mmol)
in anhydrous benzene (8 mL). After the mixture was stirred
at rt for 1 h, dry silver cyanate (380 mg, 2.5 mmol) was added,
and the mixture was heated to reflux for 30 min under
nitrogen atmosphere. Then the mixture was cooled to rt and
added dropwise to a solution of amine 10 (199 mg, 0.6 mmol)
in anhydrous dichloromethane (4 mL), cooled at -78 °C, under
nitrogen atmosphere. The resultant mixture was stirred at
-78 °C for 30 min and at 0 °C for 3 h. The solvent was
removed, and the residue was chromatographed on Baker
silica (mixtures of hexanes-ether as eluents) to afford 85 mg
(30% yield) of (1′S,2′R)-(E)-1-(3-methoxy-2-methylacryloyl)-3-
[1′,2′-bis(tert-butyldimethylsilyloxymethyl)cyclopropyl]urea, 11,
as a colorless oil that was identified by its spectroscopic data:
IR (film) 3500-3000 (broad), 1689, 1662, 1010; 1H NMR
(CDCl3) -0.02 (s, 6H), -0.03 (s, 6H), 0.68 (dd, J ) 6.6, J ′ )
5.8, 1H), 0.87 (s, 9H), 0.98 (s, 9H), 1.01 (dd, J ) 8.8, J ′ ) 5.8,
1H), 1.25 (m, 1H), 1.73 (s, 3H), 3.57-3.76 (complex absorption,
4H), 3.82 (s, 3H), 7.32 (broad s, 1H), 9.04 (broad s, 1H); 13C
C
19H20N6O4: C, 57.57; H, 5.09; N, 21.20. Found: C, 57.19; H,
5.31; N, 21.53.
(1S,2R)-2-(6-Am in o-9H-p u r in ylm eth yl)-1-N-ben zyloxy-
ca r bon yla m in o-2-h yd r oxym eth ylcyclop r op a n e, 14. A 1
M solution of LiBH4 (1.4 mL, 1.4 mmol) was added to a stirred
solution of compound 13 (139 mg, 0.4 mmol) in anhydrous THF
(10 mL) cooled at -78 °C under nitrogen atmosphere. The
resultant mixture was stirred at rt for 20 h. MeOH was then
slowly added to destroy excess hydride, and solvents were
removed at reduced pressure. The residue was poured into
water (6 mL) and ethyl acetate (6 mL), and the layers were
separated. The aqueous phase was extracted with EtOAc (5
× 6 mL), the combined organic phases were dried (MgSO4),

4524 J . Org. Chem., Vol. 67, No. 13, 2002
Muray et al.
and solvent was evaporated. The residue was eluted (water)
through a C18 reversed-phase cartridge to afford pure alcohol
14 (116 mg, 90% yield): crystals; mp 152-154 °C (MeOH-
H2O); [R]D +24.0 (c 1.00, MeOH); IR (KBr) 3500-2900 (broad),
3329, 1710, 1650, 1601, 1508; 1H NMR (methanol-d4) 0.83 (dd,
J ) 6.6, J ′ ) 5.8, 1H), 1.07 (dd, J ) 9.5, J ′ ) 5.8, 1H), 1.59 (m,
1H), 3.47-3.57 (complex absorption, 2H), 4.25 (d, J ) 7.3, 2H),
5.05 (s, 2H), 7.31-7.35 (complex absorption, 5H), 8.21 (s, 1H),
8.46 (s, 1H); 13C NMR (methanol-d4) 15.79, 22.96, 40.82, 44.54,
66.46, 67.60, 119.80, 128.87, 129.03, 129.48, 138.10, 142.64,
149.72, 153.49, 155.62, 159.06. Anal. Calcd for C19H20N6O4: C,
58.69; H, 5.47; N, 22.18. Found: C, 58.52; H, 5.31; N, 23.01.
(1S,2R)-2-(6-Am in o-9H -p u r in ylm et h yl)-1-a m in o-2-h y-
d r oxym eth ylcyclop r op a n e, 2. Working as described above
for the hydrogentation of carbamate 9, pure product 2 was
prepared in 87% yield after elution (water) through a C18
reversed-phase cartridge: crystals; mp 197-199 °C (MeOH-
H2O); [R]D +22.5 (c 0.80, MeOH); IR (KBr) 3600-2600 (broad),
3329, 1646, 1601, 1515; 1H NMR (methanol-d4) 0.63 (t, J )
5.1, 1H), 0.84 (dd, J ) 9.5, J ′ ) 5.1, 1H), 1.39 (m, 1H), 3.34 (s,
2H), 4.27 (dd, J ) 8.0, J ′ ) 7.3, 1H), 4.45 (dd, J ) 14.6, J ′ )
5.8, 1H), 8.18 (s, 1H), 8.49 (s, 1H); 13C NMR (methanol-d4)
15.65, 23.03, 41.14, 44.15, 70.08, 120.10, 142.57, 150.69,
153.68, 157.27. Anal. Calcd for C10H14N6O: C, 51.27; H, 6.02;
N, 35.87. Found: C, 51.08; H, 6.28; N, 36.04.
Eth yl (1R,2R)-2-Hydr oxym eth yl-1-m eth ylcyclopr opan e-
ca r boxyla te, 6. NaIO4 (884 mg, 4.2 mmol) was added to a
stirred and ice-cooled solution of diol 1616 (600 mg, 3.2 mmol)
in 10:3 THF-H2O (13 mL), and the resultant mixture was
stirred for 10 min. The produced precipitate was filtered off,
and most of THF was removed at reduced pressure. Then 5
mL of water was added, and the aqueous solution was
extracted with dichloromethane (4 × 10 mL). The combined
organic extracts were dried (MgSO4), and solvent was removed
to afford ethyl (1R,2R)-2-formyl-1-methylcyclopropanecarbox-
ylate, 17 (456 mg, 91% yield), as a highly volatile liquid that
was identified by their spectroscopic data: [R]D -231.2 (c 1.47,
CHCl3); IR (film) 1729, 1708; 1H NMR (CDCl3) 1.21 (t, J )
7.3, 3H), 1.39 (s, 3H), 1.46 (dd, J )6.6, J ′ ) 4.4, 1H), 1.67 (dd,
J ) 8.8, J ′ ) 4.4, 1H), 2.47 (m, 1H), 4.10 (q, J ) 7.3, 2H), 9.45
(d, J ) 4.4, 1H); 13C NMR (CDCl3) 13.71, 14.00, 21.39, 29.45,
35.21, 61.32, 172.70, 198.75; MS m/z 157 (M + 1, 1), 110 (52),
83 (100), 55 (58).
a 2 M solution of LiBH4 in THF (1.5 mL, 2.9 mmol) under
nitrogen atmosphere. The mixture was allowed to reach rt and
then was heated to reflux for 24 h. The reaction mixture was
cooled to rt, and MeOH, water, and EtOAc were successively
added. Layers were separated, and the aqueous phase was
extracted with EtOAc (6 × 10 mL). The combined organic
phases were dried (MgSO4), and solvents were removed at
reduced pressure to afford 3 (136 mg, 80% yield). The analyti-
cal sample was prepared by further purification on preparative
TLC (9:1 dichloromethane-MeOH): crystals; mp 147-150 °C
(MeOH-CH2Cl2-pentane); [R]280 +2217.9 (c 1.32, MeOH); IR
1
(KBr) 3349 (broad), 1667, 1614; H NMR (methanol-d4) 0.51
(t, J ) 5.0, 1H), 0.83 (dd, J ) 8.8, J ′ ) 5.0, 1H), 1.34 (s, 3H),
1.42 (m, 1H), 3.29 (d, J ) 11.1, 1H), 3.52 (d, J ) 11.1, 1H),
4.35-4.38 (m, 2H), 8.42 (s, 1H), 8.57 (s, 1H); 13C NMR
(methanol-d4) 13.99, 14.74, 20.21, 22.40, 43.62, 69.47, 118.36,
140.60, 150.75, 151.93, 155.60; HRMS calcd for C11H15N5O (M)
233.1277, found 233.1287; calcd for C11H14N5 (M - OH)
216.1249, found 216.1233.
(1S,2R,4′S)-1-Meth yl-2-(2′,2′-d im eth yl-1′,3′-d ioxola n -4′-
yl)h yd r oxym eth ylcyclop r op a n e, 7. Compound 2316 was
reduced, according to the same procedure as described above
for the reduction of 18, to afford alcohol 7 in 90% yield: oil; ot
60-70 °C (0.01 Torr); [R]D -29.4 (c 1.22, CHCl3); IR (film)
3113-3716; 1H NMR (CDCl3) 0.57 (t, J ) 5.2, 1H), 0.66 (dd, J
) 8.1, J ′ ) 4.8, 1H), 0.82 (m, 1H), 1.13 (s, 3H), 1.32 (s, 3H),
1.41 (s, 3H), 3.39 (d, J ) 11.3, 1H), 3.62-3.73 (complex
absorption, 2H), 3.84 (m, 1H), 4.12 (dd, J ) 7.9, J ′ ) 5.7, 1H);
13C NMR (CDCl3) 16.35, 22.18, 22.63, 25.75, 26.46, 26.77,
66.91, 70.04, 77.18, 108.61. Anal. Calcd for C10H18O3: C, 64.49;
H, 9.74. Found: C, 64.29; H, 9.74.
(1S,2R,4′S)-2-(6-Am in o-9H -p u r in ylm et h yl)-1-(2′,2′-d i-
m eth yl-1′,3′-dioxolan -4′-yl)-2-m eth ylcyclopr opan e, 24. Fol-
lowing the same procedures as described above for the
preparation of 12 and 13, compound 24 was synthesized in
52% yield for the two steps: crystals; mp 153-155 °C (MeOH-
CH2Cl2-pentane); [R]D -13.3 (c 0.75, CHCl3); IR (KBr) 1667,
1
1595, 1579; H NMR (CDCl3) 0.74 (dd, J ) 7.5, J ′ ) 3.8, 1H),
0.91-1.03 (complex absorption, 2H), 1.01 (s, 3H), 1.36 (s, 3H),
1.42 (s, 3H), 3.65 (t, J ) 7.7, 1H), 4.06-4.25 (complex
absorption, 3H), 4.38 (d, J ) 14.3, 1H), 5.84 (broad s, 2H), 7.89
(s, 1H), 8.34 (s, 1H); 13C NMR (CDCl3) 16.20, 20.86, 23.25,
25.82, 26.66, 27.23, 47.72, 70.14, 74.95, 109.28, 119.29, 140.40,
150.52, 152.96, 155.52. Anal. Calcd for C15H21N5O2: C, 59.39;
H, 6.98; N, 23.09. Found: C, 59.44; H, 7.23; N, 23.28.
(1S,2R,1′S)-2-(6-Am in o-9H-p u r in ylm eth yl)-1-(1′,2′-d ih y-
d r oxyeth yl)-2-m eth ylcyclop r op a n e, 25. A solution of com-
pound 24 (181 mg, 0.6 mmol) in 80% acetic acid (10 mL) was
stirred at rt for 24 h and then evaporated to dryness under
reduced pressure. The residue was purified by elution (MeOH)
through a C18 reversed-phase cartridge to afford diol 25 (146
mg, 94% yield) as a foam unsuitable for microanalysis: [R]D
+4.3 (c 2.34, CHCl3); IR (film) 3320, 3177 (broad), 1647, 1600;
1H NMR (methanol-d4) 0.72 (dd, J ) 8.4, J ′ ) 4.7, 1H), 0.97-
1.14 (complex absorption, 2H), 1.06 (s, 3H), 3.64-3.76 (complex
absorption, 3H), 4.19 (d, J ) 14.3, 1H), 4.61 (d, J ) 14.3, 1H),
8.28 (s, 1H), 8.29 (s, 1H); 13C NMR (methanol-d4) 16.14, 21.28,
22.50, 28.70, 48.25, 66.92, 71.61, 118.70, 141.85, 150.14,
152.67, 156.27; MS m/z 263 (M, 2), 246 (4), 232 (30), 202 (10),
136 (100), 108 (27).
A mixture of 17 (450 mg, 2.9 mmol) and NaBH4 (142 mg,
3.7 mmol) in absolute ethanol (5 mL) was stirred at 0 °C for
20 min. The solvent was evaporated to dryness, the residue
was slowly poured into saturated aqueous NH4Cl (2 mL), and
the solution was extracted with dichloromethane (4 × 10 mL).
The combined organic phases were dried (MgSO4), and solvent
was removed. The residue was chromatographed on silica gel
(1:4 hexanes-EtOAc) to afford alcohol 6 as an oil (430 mg,
94% yield): ot 65-70 °C (0.1 Torr); [R]D -40.5 (c 1.08, CHCl3);
IR (film) 3718-3064, 1722; 1H NMR (CDCl3) 0.50 (dd, J ) 6.6,
J ) 4.4, 1H), 1.18 (t, J ) 7.3, 3H), 1.29 (s, 3H), 1.35 (dd, J )
8.0, J ) 4.4, 1H), 1.74 (m, 1H), 3.46 (dd, J ) 11.7, J )8.0,
1H), 3.76 (dd, J ) 11.7, J ′ ) 5.8, 1H), 4.05 (q, J ) 7.3, 2H); 13
C
NMR (CDCl3) 13.65, 14.06, 20.21, 22.65, 28.33, 60.62, 62.03,
175.61. Anal. Calcd for C8H14O3: C, 60.74; H, 8.92. Found: C,
60.78; H, 8.87.
Eth yl (1R,2R)-2-(6-Am in o-9H-p u r in ylm eth yl)-1-m eth yl-
cyclop r op a n eca r boxyla te, 18. Following the same protocols
as described above for the preparation of 12 and 13, compound
18 was synthesized from 6 in 55% yield for the two steps:
crystals; mp 139-141 °C (CH2Cl2-pentane); [R]D -29.2 (c 0.68,
CHCl3); IR (KBr) 3276, 1715, 1680, 1609; 1H NMR (CDCl3)
0.73 (dd, J )5.9, J ′ ) 4.4, 1H), 1.20 (t, J ) 7.3, 3H), 1.41 (s,
3H), 1.48 (dd, J ) 9.5, J ′ ) 4.4, 1H), 2.02 (m, 1H), 4.08 (q, J )
7.3, 2H), 4.23 (complex absorption, 2H), 5.90 (broad s, 2H),
7.84 (s, 1H), 8.33 (s, 1H); 13C NMR (CDCl3) 14.09, 14.15, 21.15,
23.36, 25.15, 43.18, 61.03, 119.53, 139.67, 150.06, 153.06,
155.53. Anal. Calcd for (C13H17N5O2)‚1/2H2O: C, 54.92; H, 6.38;
N, 24.63. Found: C, 55.00; H, 6.11; N, 24.48.
(1R ,2S )-2-(6-Am in o-9H -p u r in ylm e t h yl)-1-for m yl-2-
m eth ylcyclop r op a n e, 26. Diol 25 was cleaved according to
the same oxidative method as described above for the synthesis
of 17. Thus, aldehyde 26 resulted in 87% yield: crystals; mp
145-148 °C (MeOH-CH2Cl2-pentane); [R]D -128.0 (c 0.93,
1
CHCl3); IR (KBr) 1695, 1647, 1600; H NMR (CDCl3) 1.11 (s,
3H), 1.18 (dd, J ) 7.9, J ′ ) 5.0, 1H), 1.73 (t, J ) 5.0, 1H), 2.07
(m, 1H), 4.32 (d, J ) 14.7, 1H), 4.45 (d, J ) 14.7, 1H), 5.99
(broad s, 2H), 7.70 (s, 1H), 8.32 (s, 1H), 9.97 (d, J ) 3.0, 1H);
13C NMR (CDCl3) 22.57, 22.60, 31.34, 35.26, 45.34, 119.17,
140.25, 150.39, 152.92, 155.68, 200.66; HRMS Calcd for
C
11H13N5O (M) 231.1120, obsd 231.1116; calcd for C11H13N3O
(1R ,2R )-2-(6-Am in o-9H -p u r in ylm e t h yl)-1-h yd r oxy-
m eth ylcyclop r op a n e, 3. To a solution of 18 (200 mg, 0.7
mmol) in anhydrous THF (20 mL) cooled at -78 °C was added
(M - NH2) 203.1059, obsd 203.1085.
(1R ,2S )-2-(6-Am in o-9H -p u r in ylm e t h yl)-2-m e t h ylh y-
d r oxym eth ylcyclop r op a n e, 4. The reduction of 26 was

Synthesis of Cyclopropyl Carbocyclic Nucleosides
J . Org. Chem., Vol. 67, No. 13, 2002 4525
achieved following the same procedure as described above for
the synthesis of 6. Thus, nucleoside 4 was prepared in 71%
yield: crystals; mp 200-201 °C (MeOH-CH2Cl2-pentane);
[R]300 -117.8 (c 0.14, MeOH); IR (KBr) 3502-2727 (broad),
E t h yl (1S,2R,1′S)-2-(1′,2′-Dih yd r oxyet h yl)-1-m et h yl-
cyclop r op a n eca r boxyla te, 20. Following a similar procedure
as described above for 19 but stirring acetonide 23 with 90%
AcOH for 4 h, diol 20 was obtained as a yellowish oil (200 mg,
76% yield) whose spectroscopic data follow: IR (film) 3044-
3711 (broad), 1722 1H NMR (CDCl3) 0.87 (dd, J ) 8.6, J )
4.5, 1H), 1.09 (m, 1H), 1.19-1.24 (complex absorption, 6H),1.43
(dd, J ) 6.8, J ) 4.5, 1H), 3.49 (m, 2H), 3.66 (dt, J ) 7.2, J ′ )
3.2, 1H), 4.09 (q, J ) 7.2, 2H); 13C NMR (CDCl3) 14.13, 19.57,
21.02, 23.74, 31.82, 61.00, 66.40, 70.35, 174.7.
1
1681, 1614, 1571; H NMR (methanol-d4) 0.72 (m, 2H), 1.02
(s, 3H), 1.27 (m, 1H), 3.67 (dd, J ) 12.0, J ′ ) 9.7, 1H), 4.08
(dd, J ) 12.0, J ′ ) 5.2, 1H), 4.39 (m, 2H), 8.28 (s, 1H), 8.42 (s,
1H); 13C NMR (methanol-d4) 15.20, 20.76, 21.92, 27.81, 46.97,
61.67, 118.77, 142.48, 149.87, 152.55, 156.35; HRMS calcd for
C
11H15N5O (M) 233.1277, obsd 233.1282; calcd for C10H12N5 (M
- CH2OH) 202.1093, obsd 202.1097.
(1S,5R,4S)-4-H yd r oxym et h yl-1-m et h yl-3-oxa b icyclo-
[3,1,0]h exa n -2-on e, 19. A solution of acetonide 23 (94 mg,
0.4 mmol) in 3 mL of 2 N HCl was stirred at rt for 1.5 h and
then diluted with EtOH, and solvents were removed under
reduced pressure. The residue was chromatographed on silica
gel (1:4 hexane/EtOAc) to afford pure 19 (45.5 mg, 78% yield):
crystals; mp 67-70 °C (EtOAc-pentane); [R]D -79.4 (c 0.71,
Ack n ow led gm en t. Financial support from DGESIC
through Project PB97-0214 and from DGR (1999SGR
00092) is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Physical constants
and spectroscopic data of compounds 11, 17, 19, and 20. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
CHCl3); IR (film) 3494, 3276 (broad), 1778; H NMR (CDCl3)
0.93 (dd, J ) 7.5, J ′ ) 5.0, 1H), 1.09 (t, J ) 4.7, 1H), 1.39 (s,
3H), 2.01 (m, 1H), 2.09 (broad s, 1H), 3.71 (m, 2H), 4.64 (m,
1H); 13C NMR (CDCl3) 14.03, 15.49, 23.70, 24.50, 63.06, 78.35,
177.89. Anal. Calcd for C7H10O3: C, 59.14; H, 7.09. Found: C,
58.76; H, 7.14.
J O025599V