Conformationally locked 4',6'-cyclopropane-fused carbocyclic nucleoside analogues. The compounds are prepared by condensing a cyclopropane-fused carbocyclic allylic alcohol with substituted purine or pyrimidine bases. The condensation products are then modified to produce the adenosine, guanosine, cytidine, thymidine and uracil nucleoside analogues. The compounds are therapeutically useful as antimetabolites, or in the preparation of anti-metabolic agents.

FIELD OF THE INVENTION 
This invention relates to nucleoside analogues and methods for their 
synthesis. More specifically, it relates to nucleoside analogues 
containing a cyclopropane-fused carbocyclic ring. 
BACKGROUND OF THE INVENTION 
Nucleoside analogues, such as those species lacking the 3'hydroxyl group or 
both the 2' and 3'hydroxyl groups, of the naturally-occurring nucleosides 
can act as chain terminators of the DNA into which they are incorporated. 
Intense effort has focused on the design and use of these compounds as 
inhibitors of viral replication (Van Roey et al., (1990) Ann. NY Acad. 
Sci., 616: 29). Although the conformation of the sugar moiety in these 
analogues is believed to play a critical role in modulating biological 
activity, including the anti-HIV 1 activity mediated by derivatives such 
as 3'-azido-3'-deoxythymidine (AZT) and dideoxyinosine (ddI), the main 
problem encountered in attempting to correlate a specific type of sugar 
conformation with the biological activity of nucleoside analogues is that 
the sugar ring is quite flexible and its conformation in solution can 
differ markedly from its conformation in the solid state (Jagannadh, et 
al., (1991) Biochem. Biophys. Res. Commun., 179: 386; Plavec et al., 
(1992) Biochem. Biophys. Methods, 25: 253.). Thus, any structure-function 
analysis based solely on solid state conformational parameters would be 
inaccurate unless it was previously determined that both solution and 
solid-state conformations were the same. Some [3.1.0]-fused 2',3'-modified 
cyclopropane-fused dideoxynucleosides (FIG. 1A; Wu and Chattopadhyaya, 
(1990) Tetrahedron Lett., 46: 2587; Okabe and Sun, (1989) Tetrahedron 
Lett., 30: 2203; Beard et al., (1990) Carbohyd. Res., 205: 87; Codington 
et al., (1962) J. Org. Chem., 27:163) appear quite rigid and their altered 
sugar moiety shows the same conformational preference in solution as in 
the solid state. However, the conformation of the furanose ring in these 
compounds is well outside the typical range of the Northern (N) or 
Southern (S) geometry conformations that are characteristic of nucleosides 
(Koole et al., (1991) J. Org. Chem., 56: 6884). A different type of 
[3.1.0] fusion, an epoxide ring between carbons 4' and 6', is found in the 
naturally-occurring carbocyclic nucleoside analogue neplanocin C 
(Kinoshita et al., (1985) Nucleosides & Nucleotides, 4: 661), which allows 
this compound to adopt a rigid N-geometry. 
In solution there is a dynamic equilibrium between N and S type furanose 
conformers (Taylor et al., (1990) Antiviral Chem. Chemother., 1: 163-173). 
The conformations of nucleosides and their analogues can be described by 
the geometry of the glycosyl link (syn or anti), the rotation about the 
exocyclic C4'-C5' bond and the puckering of the sugar ring leading to 
formation of the twist and envelope conformations. Two conformations are 
preferred for ribose ring puckering: C3'-endo (N) and C2'-endo (S). The 
endo and exo refer to displacement of the atom above or below the plane of 
the ribose ring, respectively. The torsion angles .chi.[C2-N1-C1'-04' 
(pyrimidines) or C4-N9-C1'-04' (purines)] and .gamma. (C3'-C4'-C5'-05') 
describe, respectively, the orientations of the base and the 5'-hydroxyl 
group relative to the ribose ring. 
In ribonucleosides and 2'-deoxyribonucleosides, two types of sugar 
puckering are generally energetically preferred, namely the C3'-endo (N) 
and the C2'-endo (S) conformations. In DNA duplexes, a 2'-endo (S) 
conformation of the repeating nucleoside unit confers upon the double 
helix a B-conformation, whereas the 3'-endo (N) conformation induces an 
A-conformation double helix. The A and B forms of DNA differ in the number 
of base pairs per turn, the amount of rotation per base pair, the vertical 
rise per base pair and the helical diameter. In addition, in stretches of 
DNA containing alternating purines and pyrimidines, a left-handed helix 
called Z-DNA may form. 
Since DNA in solution may exist in several different conformations, the 
present invention provides a means of locking DNA into a specific 
conformation. This can be useful in elucidating the structural 
requirements influencing DNA-protein, DNA-DNA and DNA-RNA interactions and 
the development of valuable therapeutics able to specifically block these 
interactions. 
SUMMARY OF THE INVENTION 
The present invention provides conformationally locked compounds having the 
formula 
##STR1## 
wherein R.sub.1 is adenine, guanine, cytosine, thymine, uracil or a 
derivative thereof and R.sub.2 and R.sub.3 are independently H or OH. In a 
preferred embodiment, the compounds are locked in the Northern 
configuration. In various embodiments of the present invention either 
R.sub.2 .dbd.R.sub.3 .dbd.H, R.sub.2 .dbd.OH and R.sub.3 .dbd.H or R.sub.2 
.dbd.R.sub.3 .dbd.OH. According to a preferred embodiment of the 
invention, there are provided 
carbocyclic-4',6'-cyclopropane-fused-2',3'-derivatives of dideoxypurines, 
dideoxypyrimidines, deoxypurines, deoxypyrimidines, purine 
ribonucleosides, and pyrimidine ribonucleosides. The invention also 
includes the corresponding conformationally locked nucleotides. According 
to another aspect of the invention there are provided oligonucleotides 
comprising one or more of the aforementioned compounds and 
oligonucleotides consisting essentially of the aforementioned compounds. 
According to another aspect of the invention there is provided a process 
for preparing the adenosine and guanosine species of the above compounds 
comprising providing a carbocyclic alcohol, comprising a cyclopropanated 
allylic alcohol, condensing the allylic alcohol with a 6-halopurine or a 
2-amino-6-halopurine to form a condensation product wherein said purine 
derivative is linked to said allylic alcohol through a C1'-N9 bond, and 
then displacing the halo group of the 2-amino-6-halopurine with an amino 
group to form an adenosine analogue or with an hydroxyl group to form a 
guanosine analogue. In a particular embodiment of the process, the 
carbocyclic alcohol is a dihydroxy cyclopropanated allylic alcohol, and 
the condensation product is a purine ribonucleoside analogue. 
According to another aspect of the invention, there is provided a process 
for preparing conformationally locked pyrimidine nucleoside analogues of 
the invention, comprising the steps of providing a carbocyclic alcohol, 
comprising a cyclopropanated allylic alcohol, and condensing the 
carbocyclic alcohol with an N3-protected thymine or an N3 protected uracil 
to form a condensation product wherein the thymine or uracil derivative is 
linked to the carbocyclic alcohol through a C1'-N1 bond. A corresponding 
cytidine analogue is formed by the further steps of protecting the 
hydroxyl groups of a uracil analogue of the invention, prepared as 
described above, treating that analogue to form a triazole intermediate at 
C4 of uracil, and displacing the triazole group by aminolysis to form the 
cytidine analogue. In a particular embodiment of this aspect of the 
invention, the carbocyclic alcohol is a protected dihydroxycyclopropanated 
allylic alcohol, and the condensation product comprises a pyrimidine 
ribonucleoside analogue. 
Deoxynucleoside analogues of the conformationally locked nucleoside 
analogues of the invention are prepared by a radically-induced 
deoxygenation of the C-2'hydroxyl function of the corresponding ribose 
nucleoside analogue. 
The present invention also provides the compound 
##STR2## 
wherein R is selected from the group consisting of alkyl, aryl, alkylaryl 
and aroyl. 
Still another embodiment of the invention is a method for preparing the 
above compound, comprising the steps of: 
(a) providing 
##STR3## 
(b) reacting the compound of step (a) with trimethyl aluminum to form 
tert-butyloxy and hydroxy substituents at the 4' and 5' positions, 
respectively; 
(c) protecting the hydroxy group at the 1' position by silylating the 
compound of step (b) with a bulky group; 
(d) forming an O-(methylthio)thiocarbonyloxy group at the 5' position; 
(e) removing said O-(methylthio) thiocarbonyloxy group; 
(f) removing said silyl group from the 1' position to form an allylic 
alcohol; and 
(g) cyclopropanating said allylic alcohol to form a carbocyclic alcohol.

DETAILED DESCRIPTION OF THE INVENTION 
The compounds of the present invention represent the first examples of 
carbocyclic dideoxynucleosides that in solution exist locked in a defined 
N-geometry (C3'-endo) conformation typical of conventional nucleosides. 
These analogues exhibit increased stability due to the cyclopropane-fused 
group and the substitution of carbon for oxygen in the ribose ring. The 
dideoxyadenosine analogue exhibits anti-HIV activity in vitro. As used 
herein, the terms oligonucleoside and oligonucleoside refer to two or more 
contiguous nucleosides or nucleotides in 3'-5' phosphodiester linkage. In 
a chemical synthesis, the term "protection" refers to the addition of a 
chemical substituent prior to a reaction in order to prevent the group to 
which the substituent is attached from reacting. "Deprotection" refers to 
the removal of the protecting group. This invention includes 
4',6'-cyclopropane-fused carbocyclic dideoxynucleosides, 
2'-deoxynucleosides and ribonucleosides as well as oligonucleotides 
derived from these analogues. These oligonucleotides may be synthesized 
exclusively from the nucleoside analogues of the present invention. In 
addition, oligonucleotides derived from one or more of the nucleoside 
analogues in combination with the naturally-occurring nucleosides are also 
within the scope of the present invention. These compounds comprise the 
five naturally-occurring nitrogenous bases adenine, guanine, cytosine, 
thymine and uracil. The present invention also includes methods of 
synthesis of these dideoxynucleoside analogues as well as the 
corresponding 2'-deoxyribonucleosides and ribonucleosides. 
The synthetic scheme for preparing the adenosine, guanosine, cytidine, 
thymidine and uridine dideoxynucleoside analogues of the present invention 
is described in the following example. These analogues contain the 
naturally-occurring nitrogenous bases found in DNA and RNA in either N9 
(purines) or N1 (pyrimidines) linkage to the cyclopropane-fused 
carbocyclic ribose ring. The synthesis and utilization of 
cyclopropane-fused carbocyclic nucleoside analogues containing modified 
bases by virtue of substitution of the purine and pyrimidine rings is also 
within the scope of the present invention. 
The salient features of the nucleoside analogue synthetic scheme that is 
exemplified include a "hydroxyl-directed" cyclopropanation of a 
5'-OH-protected allylic alcohols 10 and 29 via a samarium (2+) carbenoid 
intermediate (Molander and Etter, (1987) J. Org. Chem. 52: 3942; Molander 
and Harring, (1989) J. Org. Chem., 54: 3525) to generate 
4',6'-cyclopropane-substituted carbocyclic alcohols 11 and 30 (Examples 
1,2,21). This chemistry can be carried out analogously using 2',3',5'--OH 
protected carbocyclic compounds. 
The 2'-deoxynucleoside analogs are prepared according to the same synthetic 
schemes as the dideoxynucleoside analogs, with the exception that the 
carbocyclic alcohol contains a tert-butyl group at the 4 position 
(corresponding to the 3 position in the corresponding deoxynucleoside) 
which protects the OH group during the reaction steps. Since this 
tert-butyl-substituted carbocyclic alcohol 30 is a chiral material, no 
optical resolution of the synthesis products is required to separate out 
the active isomer from a racemic mixture. The synthesis of the tert-butyl 
carbocyclic alcohol is briefly described below, and in detail in Examples 
16-22. 
(1S,4R,5S)-3-[(benzyloxy)methyl]-4,5-O-isopropylidene-2-cyclopenten-1-ol 
(24) is prepared from the 1-carbonyl (23) according to the procedure of 
Marquez et al., (J. Org. Chem., 53:5709, 1988). Although a benzyloxy group 
was present at position 3, the use of any 3-aryloxy, alkyloxy, 
alkylaryloxy or aroyloxy group for the subsequent synthetic steps is 
within the scope of the present invention. Compound 24 is then reacted 
with trimethylaluminum to form Compound 25 containing tert-butyloxy and 
hydroxy substituents at the 4 and 5 positions, respectively. The 
tert-butyl group effectively protects the 4-hydroxy group in all 
subsequent synthetic steps. Compound 25 is then silylated to protect the 
hydroxy group at the 1 position, forming compound 26. It is important that 
the silylating agent be a large, bulky chemical group in order to 
effectively repel the tert-butyl group, thus allowing the next synthetic 
step to proceed efficiently. Compound 26 is reacted with methyl iodide and 
carbon disulfide to form a (methylthio) carbonyloxy group at the 5 
position (Compound 27). This bulky group is able to fit between the silyl 
and tert-butyl group due to repulsive forces acting between the bulky 
groups. The entire O-(methylthio) carbonyloxy group is then removed with 
tri-n-butyltin hydride to form compound 28. The silyl group is then 
removed with tetrabutylammonium fluoride to form the allylic alcohol 29. 
The allylic alcohol is then cyclopropanated as described above to form the 
cyclopropanated carbocyclic alcohol 30 containing a tertbutyl substituent 
at the 4 position which protects the hydroxy group at this position. 
The purine nucleoside analogues are then prepared as described in Examples 
3-10. Both carbocyclic alcohols 11 and 30 are used as starting materials 
for purine synthesis. The carbocyclic alcohol 11 is reacted with a 
6-halo-substituted purine ring in a Mitsunobu-type condensation 
(Mitsunobu, (1980) Synthesis 1,; Jenny et al., (1991) Tetrahedron Lett. 
32: 7029; Jenny et al., (1992) Helv. Chim. Acta. 75: 1944) to form 
halogenated intermediates 13 (Example 5) and 14 (Example Although 
6-chloropurine and 2-amino-6-chloropurine were used, it is envisioned that 
other substitutions at the 6-position could be incorporated into the 
synthetic scheme to generate modified purine analogues. Furthermore, the 
use of other halogen-substituted purines is also contemplated. The 
substituent chlorine group is then displaced by ammonia to generate the 
5'-OH protected adenosine 16 (Example 7) or displaced by benzylate to 
generate the 5' -OH and 6 OH protected guanosine 17 (Example 8) 
derivatives which are then deblocked to generate the adenosine and 
guanosine derivatives 5 (Example 9) and 6 (Example 10). The main features 
of the pyrimidine analogue synthetic scheme are described in Examples 
11-15. This scheme includes condensation of N-3 protected uracil or N-3 
protected thymine with carbocyclic alcohols 11 or 30 to generate the 
protected Mitsunobu condensation products 18 (Example 11) and 19 (Example 
12). The use of substituted N-3 protected bases is also within the scope 
of the present invention. Compounds 18 and 19 are then deprotected to 
generate the thymidine analogue 7 (Example 13) and the uracil analogue 8 
(Example 14). The 5'-OH group of compound 8 is then protected with an 
acetyl group to generate intermediate 21 (Example 15) and the resulting 
compound is derivatized with a triazole group at C4 of the pyrimidine 
ring, although the use of a number of groups for this derivatization is 
contemplated. The triazole group is then displaced by ammonia to generate 
the cytidine derivative 9 (Example 15). 
Synthesis of Conformationally Locked Ribonucleosides 
The ribonucleoside species of the invention are prepared by replacing the 
carbocyclic allylic alcohol of Examples 3, 4, 9, and 10 with a the 
equivalent isopropylidene-protected carbocyclic allylic alcohol formed 
from D-ribose according to the procedure set forth in Marquez, V. et al. 
(Compound 8a in J. Org. Chem. (1988), 53: 5709-5714). This compound is 
then cyclopropanated as described in Example 1. The remainder of the 
synthetic steps are the same commencing with the Mitsunobu coupling 
reaction as described in Examples 3, 4, 9, and 10. 
One of ordinary skill in the art will appreciate that there are a number of 
alternative ways in which to perform certain synthetic steps of the 
present invention using well known reactions. 
The dideoxynucleoside analogue compounds of the present invention are 
incapable of forming oligonucleotides, DNA or RNA due to the absence of a 
3'hydroxyl group necessary for chain elongation; however the 
ribonucleoside and deoxyribonucleoside species, having the 3'-hydroxyl 
present, can react to form the polynucleotides in the manner of the 
naturally occurring nucleoside species. 
Once these 2'-deoxyribonucleoside and ribonucleoside analogues are 
synthesized, and phosphoramidites of the base analogues, which will react 
like conventional phosphoramidites, are prepared, one of ordinary skill 
will be able to synthesize oligodeoxyribonucleotides and 
oligoribonucleotides using readily available automated synthesizers by 
methods well known in the art (Gait, M.J. ed., Oligonucleotide Synthesis: 
A Practical Approach, Washington, D.C.: IRL Press, 1984). In addition, the 
preparation of the corresponding nucleotides containing attached phosphate 
groups using well known chemical methods is also within the scope of the 
present invention. 
These 2'-deoxyribonucleoside and ribonucleoside analogues are expected to 
adopt a rigid N-geometry conformation in solution. The 
2'-deoxyribonucleoside and ribonucleoside analogues are useful for the 
same purposes as are conventional nucleosides. They can be used, for 
example, to synthesize nucleic acid coding sequences, regulatory sequences 
known to interact with DNA binding proteins, and to synthesize probes for 
hybridization analysis. These oligonucleotide analogues can also be 
inserted into expression vectors from which functional sequences will be 
transcribed. Each analogue is thus useful in forming functional DNA or RNA 
oligonucleotide analogues. DNA and RNA oligonucleotides containing the 
2'-deoxynuceoside and ribonucleoside analogs will exhibit increased 
stability and will be useful as antisense molecules for inhibiting mRNA 
translation for a gene of interest. Furthermore, the nucleoside analogues 
can be used as a scientific tool to synthesize and lock DNA into the 
A-conformation thus allowing subsequent discoveries. 
The synthesis of 2'-deoxyribonucleoside and ribonucleoside analogues will 
allow the preparation of molecules which will interact more strongly with 
proteins and enzymes requiring Northern conformers for substrates. Since 
the conformation of a particular nucleic acid is an equilibrium 
conformation, the overall interaction of DNA and RNA binding proteins with 
DNA and RNA, respectively, is the sum of the interactions with the various 
conformations. DNA and RNA with nucleotide units locked in the N-geometry 
conformation will be useful in elucidating the interactions between 
nucleic acids and nucleic acid binding proteins. This will lead to novel 
therapeutics which can inhibit specific DNA-protein interactions thus 
inhibiting the synthesis of deleterious gene products and/or increasing 
the synthesis of beneficial gene products. It is also envisioned that 
other types of cyclopropane-fused nucleosides prepared using this 
technology will generate compounds locked in the opposite (S) 
configuration by simply changing the relative position of the base and the 
hydroxymethyl groups. 
Compared to conventional oligonucleotides, oligonucleotides synthesized 
using the nucleoside analogues of the present invention will have a 
significantly smaller entropy change upon duplex formation due to their 
rigidity. This will result in a more favorable negative free energy change 
upon hybridization relative to conventional DNA fragments. Using this new 
methodology, by combining natural nucleosides with the analogues of the 
present invention, DNA fragments can be constructed to create a specific 
"bend" in the double helix which may lead to either increased or decreased 
binding to proteins and/or nucleic acids. 
The foregoing examples are intended to be illustrative rather than limiting 
with the full scope of the invention being defined by the following 
appended claims. 
All chemical reagents were obtained from commercial sources. Silica gel 
column chromatography was performed on silica gel 60, 230-400 mesh 
(Merck). Analytical thin layer chromatography (TLC) was performed on 
Analtech Uniplates silica gel GF. Proton and .sup.13 C-NMR spectra were 
recorded in a Brucker AC-250 instrument at 250 and 62.9 MHz, respectively. 
NMR conformational studies were performed in a Brucker AMX-500 instrument 
at 500 MHz. Chemical shifts are expressed as .delta. values with reference 
to tetramethylsilane. Positive-ion fast bombardment (FAB) mass spectra 
were obtained on a VG 7070E mass spectrometer equipped with a FAB ion 
source. The sample was dissolved in a glycerol matrix, and ionization was 
effected by a beam of xenon atoms. Elemental analyses were performed by 
Atlantic Microlab, Inc., Norcross, Ga. UV spectra were recorded in a 
Shimadzu Model UV-2101PC spectrophotometer. These values are listed after 
each synthetic step described below. A convergent approach was used to 
incorporate the purine and pyrimidine bases onto the carbocyclic moiety in 
one step. Mitsunobu-type condensations with the appropriate bases were 
performed using the common intermediate carbocyclic alcohol, 
(+/-)-5-[(benzyloxy)methyl]-2-hydroxy-cis-bicyclo[3.1.0]hexane (11, 
Schemes 1 and 2). 
The present invention is described below in detail using the following 
examples, but the methods described are broadly applicable for the 
preparation of all of the nucleoside analogues described herein and are 
not limited to the examples given below. 
EXAMPLE 1 
Synthesis of the Intermediate Carbocyclic Alcohol 
1-Benzyloxymethyl-cis-bicyclo[3.1.0]hexane-4-ol 11 
Samarium metal (5.04 g, 33.6 mmol) was added to a dry round-bottomed flask 
which was simultaneously flushed with argon and flamed dry. Anhydrous 
tetrahydrofuran (THF; 50 ml) was then added followed by a solution of 
mercuric chloride (HgCl.sub.2 ; 0.88 g, 3.2 mmol) in 10 ml THF. The 
mixture was stirred for 10 min followed by addition of allylic alcohol 10 
(1.52 g, 7.45 mmol). The reaction mixture was cooled to -78.degree. C. 
followed by addition of chloroiodomethane (CH.sub.2 ICl; 2.32 ml, 32 mmol) 
and the mixture was stirred at -78.degree. C. overnight. The mixture was 
allowed to warm to room temperature and stirred for one hour. The reaction 
was quenched with 300 ml saturated Na.sub.2 CO.sub.3 and extracted several 
times with methylene chloride. The combined organic layers were washed 
with brine, dried over MgSO.sub.4, filtered and evaporated yielding pure 
compound 11 as a colorless oil in nearly theoretical yield. The product 
was used in the next step without further purification. 
FAB MS (m/z, %) =201 ({MH-H.sub.2 O}+,9);91 (100); 71 (98). .sup.1 H-NMR 
(CDCl.sub.3) .delta.=0.47 (dd, J =5.2, 8.0 Hz, 1H, H-6 exo); 0.85 (t, 
J=5.2 Hz, 1H, H-6 endo); 1.40 (m, 1H, H-5); 3.42 (s, 2H, H-7); 4.50 (s, 
2H, PhCH.sub.2 --); 4.55 (m, 1H, H-4); 7.25-7.40 (m, 5H, aromatic 
protons). .sup.-- C-NMR (CDCl.sub.3) .delta.=8.93 (C-6); 27.17 (C-5); 
27.51 (C-3); 28.25 (C-1); 29.64 (C-2); 72.39 (C-7); 73.60 (C-4); 74.42 
(C-8); 127.36 (C-3' & C-4'); 128.17 (C-2') 138.35 (C-1'). 
EXAMPLE 2 
4-Acetoxy-l-benzyloxy-cis-bicyclo-[3.1.0]-hexane 12 
A solution of compound 11 (109 mg, 0.5 mmol) in 3 ml anhydrous pyridine was 
treated with 2 ml acetic anhydride and the mixture was stirred overnight 
at room temperature. The solvent was evaporated and the residue purified 
by flash chromatography eluting with hexane-ethyl acetate (4:1) to yield 
mg of the stable acetate derivative 12. 
Results from the NOE difference .sup.1 H-NMR spectra for the acetate 12 
(FIG. 2) agreed well with the disposition of the bicyclic system as 
inferred by the mode of cyclopropanation. 
.sup.1 H-NMR (CDCL.sub.3) .delta.=0.54 (dd, J=5.4, 8.0 Hz, 1H, H-6 exo); 
0.85 (t, J=5.4 Hz, 1H, H-6 endo); 1.53 (m, 1H, H-5); 2.02 (s, 3H, 
COCH.sub.3); 3.43 (s, 2H, H-7); 4.50 (s, 2H, PhCH.sub.2 --); 5.30 (dt, 
J=4.7, 8.2 H, 1H, H-4); 7.30 (m, 5H, aromatic protons). .sup.13 C-NMR 
(CDCl.sub.3) .delta.=9.99 (C-6); 21.12 (COCH.sub.3); 24.49 (C-5); 26.36 
(C-3); 27.05 (C-C-2); 28.50 (C-1); 72.52 (C-7); 74.19 (C-S); 76.77 (C-4); 
127.41 (C-3' & C-4'); 128.23 (C-2'); 138.32 (C-1'); 171.23 (CO) . Anal. 
Calculated for C.sub.16 H.sub.20 O.sub.3 =C 73.82 H 7.74. Found C 73.71, H 
7.79. 
##STR4## 
EXAMPLE 3 
5'-Benzyloxy-4',6'-cyclopropyl-2',3 '-dideoxy-6-chloroadenosine 13 
To a suspension of 6-chloropurine (148 mg, 0.96 mmol) in 3 ml anhydrous THF 
was added diethylazodicarboxylate (DEAD; 206 mg, 0.96 mmol) and the 
resulting mixture was stirred vigorously for 10 min. Alcohol 11 was then 
added (218 mg, 1 mmol in 5 ml THF) and the reaction was stirred overnight 
at room temperature. The solvent was evaporated and the residue was 
adsorbed on silica gel and purified by column chromatography. The products 
eluted with hexane:ethyl acetate (3:2) resulting in 75 mg (21% yield) of 
pure compound 13 as a white solid and 24 mg of 7-N derivative 15 as a pale 
yellow oil. 
Compound 13, m.p. =118.degree.-119.degree. C. FAB MS (m/z, %) =357 (12), 
355 (MH+, 35), 247 (11), 155 (34) 91 (100). .sup.1 H-NMR (CDCl.sub.3) 
.delta.= = = 0.76 (m, 2H, H-7'); 1.56 (dd, J=4.3, 8.2 Hz, 1H, H-6'); 
1.65-2.00 (m, 3H, H-2' & H-3'.alpha.); 2.25 (m, 1H, H-3'.beta.); 3.29 (d, 
J=9.9 Hz, 1H, H-5a'); 3.95 (d, J=9.9 Hz, 1H, H-5b'); 4.63 (s, 2H, 
PhH.sub.2 -); 5.22 (d. J=5.5 Hz, H-1'); 7.36 (m, 5H, aromatic protons); 
8.74 (s, 1H, H-8); 9.00 (s, 1H, H-2). .sup.13 C-NMR (CDCl.sub.3 
.delta.=12.30 (C-7'); 26.22 (C-6'); 26.28 (C-2'); 30.26 (C-3' & 4'); 56.94 
(C-1'); 72.86 (C-5'); 73.20 (PhCH.sub.2 --); 127.49 (C-4"); 127.64 (C-2"); 
128.52 (C-2"); 131.74 (C-5); 137.95 C-1"); 144.78 (C-8); 150.65 (C-4); 
151.30 (C-6); 151.51 (C-2). Anal. Calculated for C.sub.19 H.sub.19 
ON.sub.4 CL=C 64.38, H 5.41, N 15.82, Cl 19.87; Found C 64.43, H 5.47, N 
15.82, Cl 9.80. 
EXAMPLE 4 
Carbocyclic-5'-benzyl-4',6'-cyclopropyl-2',3'-dideoxy-6-chloroquanine 14 
To a suspension of triphenylphosphine (Ph.sub.3 P; 2.672 g, 10.24 mmol) and 
2-amino-6-chloropurine in 60 ml anhydrous THF was added DEAD (1.76 ml, 
11.26 mmol) under an argon atmosphere and the resulting yellow mixture was 
stirred for 10 minutes at room temperature. A solution of compound 11 (670 
mg, 3.07 mmol) in 5 ml THF was added and the mixture was stirred for 18 
hours at room temperature. The solvent was evaporated and the residue 
absorbed on silica gel and purified by column chromatography eluting with 
hexane-ethyl acetate to obtain 435 mg (38% yield) of compound 14 as a 
white solid. 
m.p. =135.degree.-137.degree. C. FAB MS (m/z, %) =372 (15); 370 (MH+, 42); 
172 (14); 170 (43); 91 (100). .sup.1 H-NMR (CDCl.sub.3 .delta.=0.69 (m, 
2H, H-7'); 1.50 (dd, J=3.9, 8.4 Hz, 2H, H-5'); 3.30 (d, J=9.9 Hz, 1H, 
H5a'); 3.88 (d, J=9.9 Hz, 1H, H5b'); 4.60 (AB q. J=14.8 Hz, 2H, PhCH.sub.2 
--); 4.95 (d, J=5.3 Hz, 1H, H-1'); 5.05 (s, 2H, --NH2); 7.35 (m. 5H, 
aromatic protons); 8.56 (s. 1H, H-8). .sup.13 C-NMR (CDCl.sub.3) 
.delta.=12.21 (C-7'); 26.29 (C-6'); 26.46 (C-2'); 30.19 (C-3')*; 30.26 
(C-4')*; 56.26 (C-1'); 73.00 (C-5'); 73.17 (PhCH.sub.2 --); 125.54 (C-5); 
127.65 (C-4"); 127.75 (C-3"); 128.51 (C-2"); 138.09 C-1"); 141.84 (C-8); 
150.99 (C-6); 153.29 (C-2); 158.76 (C-4. Anal. Calculated for C.sup.19 
H.sub.20 ON.sub.5 Cl.2/3H.sub.2 O - C 59.76, H 5.63, N 18.34, Cl 9.28. 
Found 
C 59.56, H 5.46, N 18.47, C1 9. 53. 
EXAMPLE 5 
Carbocyclic-5'-benzyloxy-4',6'-cyclopropyl-2',6'-dideoxyadenosine 16 
Compound 13 (215 mg) was treated with 5 ml of a saturated solution of 
ammonia in methanol in a sealed tube and stirred at 70.degree. C. 
overnight. The mixture was cooled to room temperature and the solvent was 
evaporated. The residue was purified by column chromatography on silica 
gel and eluted with CHCl.sub.3 -isopropanol (9:1) yielding 109 mg (54% 
yield) of pure compound 16 as a white solid. 
m.p. =170.degree. C. .sup.1 H-NMR (CD.sub.3 OD) .delta.=0.76 (m, 2H, H-7'); 
1.59 (t, J=6 Hz, 1H, H-6'); 1.65-2.00 (m. 3H, H-2' & H-3'.alpha.); 2.20 
(m, 1H, H-3'.beta.); 3.40 (d, J=10.0 Hz, 1H, H5a'); 3.97 (d, J=10.0 Hz, 
1H, H.sub.5 b'); 4.57 (s, 2H, PhCH.sub.2 --); 5.02 (d, J=5.7 Hz, 1H, 
H-1'); 7.2-7.4 (m, 5H, aromatic protons); 8.18 (s, 1H, H-8); 8.60 (s, 1H, 
H-2). .sup.13 C-NMR (CD.sub.3 OD) .delta.=12.72 (C-7'); 27.27 (C-6'); 
27.54 (C-2'); 31.12 (C-3'); 31.36 (C-4'); 57.96 (C-1'); 74.23 (C-5'); 
74.80 (PhCH.sub.2 --); 120.06 (C-5); 128.64 (C-4"); 128.70 (C-2"); 129.50 
(C-2"); 139.80 C-1"); 141.08 (C-8); 149.99 (C-4); 153.50 (C-2); 157.27 
(C-6) . 
Anal. Calculated for C.sub.19 H.sub.21 ON.sub.5 =C 68.04, H 6.31, N 20.88; 
Found C 67.86, H 6.34, N 20.80. 
EXAMPLE 6 
Carbocyclic-5'-benzyl-4',6'-cyclopropyl-2',3'-dideoxy- 6-benzylquanidine 17 
Anhydrous benzyl alcohol (PhCH.sub.2 OH) was treated with 100 mg sodium and 
the suspension was vigorously stirred under an argon atmosphere until no 
sodium metal remained. Compound 14 was treated with 1.5 ml sodium 
benzylate and stirred for 10 min. The reaction was quenched with 25 ml 
water followed by the addition of 30 ml methylene chloride. The organic 
layer was washed with water until pH=7, dried with MgSO.sub.4 and 
evaporated. The residue was purified by flash chromatography eluting with 
hexane-ethyl acetate (1:1) to yield 161 mg (77% yield) of pure compound. 
17 as a white solid. 
m.p. =171.degree. C. FAB MS (m/z, %)=442 (MH+, 49); 242 (34); 91 (100). 
.sup.1 H-NMR (CDCl.sub.3 .delta.=0.66 (m, 2H, H-7'); 1.49 (dd, J=3.8 8.4 
Hz, 1H, H-6'); 3.36 (d, J=9.9 Hz, 1H, H-5a'); 3.82 (d, J=9.9 Hz, 1H, 
H-5b'); 4.58 (AB q. J=14.0 Hz, 2H, PhCH.sub.2 -- at 0-5'); 4.84 (s, 2H, 
--NH.sub.2); 4.93 (d, J=5.2 Hz, 1 H, H-1'); 5.58 (AB q, J=14.8 Hz, 2 H, 
PhCH.sub.2 -- at C-6); 7.26-7.54 (m. 10H, aromatic protons); 8.24 (s. 1H, 
H-8). .sup.13 C-NMR (CDCl.sub.3) .delta.=12.16 (C-7'); 26.47 (C-2'); 26.70 
(C-6'); 30.26 (C-3' & C-4'); 55.78 (C-1'); 67.91 (PhCH.sub.2.sub.2 -- at 
C-6); 73.09 (C-5); 73.23 (PhCH.sub.2 -- at 0-5'); 115.69 (c-5); 127.56, 
127.63 (C-4"); 127.45, 128.18 (C-2"); 128.30, 128.45 (C-2"), 136.61 (C-8); 
138.21, 138.63 C-1"); 153.65 (C-6); 158.90 (C-2); 1'60.90 (C-4). Anal. 
Calculated for C.sub.26 H.sub.27 ON.sub.2 N.sub.5 =C 70.73, H 6.16, N 
15.86. Found C 70.72, 6.21, N 15.83. 
EXAMPLE 7 
Carbocyclic-4',6'-cyclopropyl-2',3'-dideoxyadenosine 5 
Palladium on 10% charcoal (300 mg) was purged with argon for 15 min 
followed by addition of 50 mg compound 16 dissolved in 5 ml methanol. The 
resulting mixture was treated with 1 g ammonium formate and refluxed for 3 
hours. The mixture was allowed to cool to room temperature, filtered and 
the solvent was evaporated. The residue was purified using a reverse phase 
column eluted with water to yield 12 mg (33% yield) of pure compound 5 as 
a pale yellow solid. 
m.p. =251.degree. C. (d) . UV (MeOH) .epsilon..sub.max 260.7 
(.epsilon.15200). FAB MS (m/z, %) =338 ({MH+glycerine}+, 12), 246(MH+, 
100), 136 (84), 500 MHz .sup.1 H-NMR (DMSO-d.sub.6) .delta.=0.66 (m, 2H, 
H-7'); 1.48 (dd, J=3.9, 8.3 Hz, 1H, H-6'); 1.58 (dd, J=8.2, 14.3 Hz, 1H, 
H-3'.alpha.); 1.67 (dd, J=8.0, 12.5 Hz, 1H, H-2'.beta.); 1.84 (m, 1H, 
H-2'.alpha.); 2.07 (dt, J=8.0, 12.0 Hz, 1H, H-3'.beta.); 3.37 (dd, J=11.4 
Hz, J=5.1 Hz, 1 H, H-5a'); 3.86 (dd, J=11.4 Hz, J=5.1 Hz, 1 H, H-5b'); 
4.90 (d, J=6.0 Hz, 1H, H-1'); 4.99 (t, J=5.2 Hz, 1H, -0H); 7.17 (s, 2H, 
--NH.sub.2); 8.11 (s, 1H, H-8); 8.37 (s, 1H, H-2) . .sup.13 C-NMR 
(CD.sub.3 OD-D.sub.2 O) .delta.=12.51 (C-7'); 26.88 (C-6'); 27.11 (C-2'); 
30.95 (C-3'); 32.99 (C-4'); 58.34 (C-1'); 66.21 (C-5'); 119.84 (C-5); 
141.05 (C-8); 149.57 (C-4); 153.25 (C-2); 156.84 (C-6) . Anal. Calculated 
for C.sub.12 H.sub.15 ON.sub.5 =C 58.76, H 6.16, N 28.55; Found C 58.63, H 
6.19, N 28.52. 
EXAMPLE 8 
Carbocyclic-4',6'-cyclopropyl-2',3'-dideoxyquanosine 6 
A solution of compound 17 (154 mg, 0.35 mmol) in 35 ml anhydrous methylene 
chloride was cooled at -78.degree. C. under an argon atmosphere, treated 
with 3.0 ml 1.0M boron trichloride (BCl3) and stirred for 6 hours at 
-78.degree. C. The solvent was evaporated and the residue dissolved in 30 
ml CH.sub.2 Cl.sub.2. The organic layer was washed with saturated 
NaHCO.sub.3 (3.times.30 ml ) and water (2.times.30 ml ) , dried with 
MgSO.sub.4 and evaporated. The residue was purified using a reverse phase 
column eluted with water to yield 50 mg (55% yield) of pure compound 6 as 
a white solid. 
m.p.&gt;300.degree. C. UV (MeOH) .lambda..sub.max 254.4 (.epsilon.10500). FAB 
MS (m/z, %) =354 ({MH+glycerine}+, 14), 262(MH+, 100), 152 (66). .sup.1 
H-NMR (DMSO-d.sub.6) .delta.=0.60 (m, 1H, H-7' exo); 0.84 (m, 1H, H-7' 
endo); 1.40 (dd, J=3.7, 8.1 Hz, H-6'); 3.81 (dd, J=5.2, 10.4 Hz, 1H, 
H-5a'); 4.13 (dd, J=5.2, 10.4 Hz, 1H, H-5b'); 4.64 (d, J=5.8 Hz, 1H, H-1); 
4.95 (t, J=5.2 Hz, 1H, -OH); 6.60 (s, 2H, --NH.sub.2); 7.94 (s, 1H, H-8); 
10.66 (s, 1H, H-1). .sup.13 C-NMR (DMSO-d.sub.6) .delta.=11.03 (C-7'); 
25.50 (C-2'); 25.87 (C-6'); 29.73 (C-4'); 31.89 (C-3'); 55.31 (C-1'); 
63.80 (C-5'); 116.52 (C-5); 135.19 (C-8); 150.44 (C-6); 153.53 (C-2) 
;56.79 (C-4). Anal. Calculated for C.sub.12 H.sub.15 O.sub.2 N.sub.5 1/6=C 
54.54, H 5.85, N 26.50; Found C 54.5II. 
The pyrimidine derivatives were also synthesized under Mitsunobu conditions 
in comparable yields using protected N-3-benzoyl thymine or N-3-benzoyl 
uracil (Cruickshank et al., (1984) s. Tetrahedron Lett., 681) as described 
in the following examples 9-13. 
##STR5## 
EXAMPLE 9 
Carbocyclic-5'-benzoyloxy-4',6'-cyclopropyl-2',3'-dideoxy-3-benzoylthymidin 
e 18 
To a solution of triphenylphosphine (Ph.sub.3 P; 1,340 g, 5.10 mmol) in 16 
ml anhydrous THF was added DEAD (860 .mu.l, 5.0 mmol). The mixture was 
stirred for 30 min at 0.degree. C. then cooled to 45.degree. C. To this 
suspension was added a solution of 3-N-benzoylthymine (N-3-BzThy; 920 mg, 
4 mmol) and carbocyclic alcohol 11 (460 mg, 2.10 retool) in 16 ml THF over 
45 rain and the mixture was stirred overnight at 45.degree. C. The mixture 
was warmed to room temperature and the solvent was evaporated. The residue 
was purified by flash chromatography, eluting with hexane-ethyl acetate 
(7:3) yielding a mixture of N-alkylation and O-alkylation products. This 
mixture was repurified by silica gel column chromatography, eluting with 
CH.sub.2 Cl.sub.2 -ether (97.5:2.5) to yield 330 mg (36% yield) of the 
desired N-alkylation product 18 as a white solid and 400 mg (44% yield ) 
of the undesired O-alkylation product 20 as an oil. In this solvent 
system, compound 18 eluted faster than compound 20. 
m.p. =182.degree.-184.degree. C. FAB MS (m/z, %) =431 (MH+, 30), 323 (6), 
231 (13), 105 (100), 91 (79). .sup.1 H-NMR (CDCl.sub.3) .delta.=0.58 (m, 
1H, H-7' exo); 0.71 (m, 1H, H-7' endo); 1.32 (dd, J=3.7, 8.8 Hz, 1H, 
H-6'); 1.55 (d, J=0.8 Hz, 3H, Me at C-5); 1.60-1.90 (m, 3H, H-2' & 
H-3'.alpha.); 2.25 (m, 1H, H-3'.beta.); 3.26 (d, J=9.9 Hz, 1H, H-5a'); 
4.05 (d, J=9.9 Hz, 1H, H-5b'); 4.57 (AB q, J=16.5Hz, 2H, PhCH.sub.2 --); 
4.98 (d, J=5.8 Hz, 1H, H-1'); 7.35 (m, 5H, benzylic protons); 7.50 (t, 
J=7.4 Hz, 2H, H-2'"); 7.62 (t, J=7.4 Hz, 1H, H-4'"); 7.91 (d, J=7.4 Hz, 
2H, H-2'"); 8.00 (d. j=0.8 Hz, 1H, H-6). .sup.13 C-NMR (CDCl.sub.3) 
.delta.=11.77 (Me at C-5); 12.18 (C-7'); 25.71 (C-2'); 26.31 (C-6'); 30.34 
(C-3'); 31.02 (C-4'); 57.48 (C-1'); 73.53 (C-5')*; 73.65 (PhCH.sub.2 --)*; 
110.25 (C-5); 127.99 (C-2'"); 128.53 (C-3", C-4" & C-3'"); 129.00 (C-2"); 
130.37 (C-4'"); 134.73 (C-1'"); 137.90 (C-6); 138.19 C-1"); 149.95 (C-2); 
162.90 (C-4); 169.46 (C.dbd.O). Anal. Calculated for C.sub.26 H.sub.26 
O.sub.4 N.sub.2 1/10 CH.sub.2 CL.sub.2 =C 71.41, H 6.02, N 6.38. Found C 
72.46, H 5.98, N 6.39. 
EXAMPLE 10 
Carbocyclic-5'-benzyloxy-4',6'-cyclopropyl-2',3'-dideoxy-3-benzoyluridine 
19 
To a solution of Ph.sub.3 P (857 mg, 3.26 mmol) in 10 ml anhydrous THF was 
added DEAD (0.500 ml, 3.2 mmol ). The mixture was stirred at 0.degree. C. 
for 30 min and cooled to -78.degree. C. A suspension of 3-N-benzoyluracil 
(N-3-BzUr; 550 mg, 2.56 mmol) and carbocyclic alcohol 11 (280 mg, 1.27 
mmol) in 25 ml THF was added to the reaction mixture over 10 min. The 
mixture was stirred overnight at 50.degree. C., allowed to warm to room 
temperature and the solvent evaporated. The residue was purified by column 
chromatograph(silica gel) using CH.sub.2 Cl.sub.2 -ether (98:2) as eluent 
to yield 150 mg (28% yield) of pure compound 19 as a colorless oil. 
FAB MS (m/z, %) =417 (MH+, 48), 309 (9), 217 (9), 105 (100), 91 (76). 
.sup.1 H-NMR (CDCl.sub.3) .delta.=0.61 (dd, J=3.5, 5.7 Hz 1 H, H-7' exo); 
0.74 (dd, J=5.7, 8.5 Hz 1H, H-7' endo); 1.31 (dd, J=3.5, 8.5 Hz, 1H, 
H-6'); 1.60-1.90 (m, 3H, H-2' & H-3'.alpha.); 2.20 (m, 1H, H-3'.beta.); 
3.28 (d, J=9.9 Hz, 1H, H-5a'); 4.07 (d, J=9.9 Hz, 1H, H-5b'); 4.51 (AB q, 
J=16.5Hz, 2H, PhCH.sub.2 --); 4.95 (d, J=5.4 Hz, 1H, H-1'); 5.42 (d, J=8.1 
Hz, 1H, H-5.sub.-- ; 7.30-7.40 (m, 5H, benzylic protons); 7.47 (t, J=7.4 
Hz, 2H, H-3'"); 7.62 (dt, J=7.4, 1.0 Hz, 1H, H-4'"); 7.92 (dt, J=7.4, 1.0 
Hz, 1H, H-2'"); 8.26 (d. j=8.1 Hz, 1H, H-6). .sup.13 C-NMR (CDCl.sub.3) 
.delta.=12.25 (C-7'); 25.29 (C-2'); 26.18 (C-6'); 30.22 (C-3'); 30.98 
(C-4'); 57.83 (C-1'); 73.28 (C-5') *; 73.59 (PhCH.sub.2 --) *; 101.35 
(C-5); 127.45 (C-4"); 127.88 (C-3)*; 128.44 (C-2")*; 128.98 (C-2'")*; 
130.30 (C-3'"); 131.55 (C-4'"); 134.80 (C-1'"); 137.95 (C-1"); 142.45 
(C-6); 149.88 (C-2); 162.14 (C-4); 169.14 (CO). Anal. Calculated for 
C.sub.25 H.sub.24 O.sub.4 N.sub.2 =C 72.10, H 5.81, N 6.73. Found C 71.84, 
H 5.89, N 6.59. 
EXAMPLE 11 
Carbocyclic-4',6'-cyclopropyl -2',3'-dideoxythymidine 7 
Compound 18 (150 mg, 0.3S mmol) was suspended in 100 ml methanol. 
Concentrated ammonia (4 ml) was then added and the mixture was stirred at 
room temperature for 16 hours. The solvent was evaporated and the residue 
was dissolved in 30 ml CH.sub.2 Cl.sub.2. The organic layer was washed 
with saturated NaHCO.sub.3 (3.times.30 ml ) and water (2.times.30 ml ) , 
dried with MgSO.sub.4 and evaporated. The residue was purified by flash 
chromatography (silica gel) using CH.sub.2 Cl.sub.2 -isopropanol (97:3) as 
eluent to obtain 105 mg (92% yield) of the N-3 deblocked intermediate as a 
white solid. 
A solution of the N-3 deblocked intermediate (85 mg in 20 ml anhydrous 
CH.sub.2 Cl.sub.2 ) cooled to -78 .degree.C. under argon was treated with 
BCl.sub.3 (1.0M in hexane, 1.80 ml) and stirred for 6 hours at -78.degree. 
C. Methanol (4.0 ml) was added at the same temperature and the mixture was 
allowed to warm to room temperature. The solvent was evaporated and 4 ml 
methanol was again added followed by evaporation of the solvent. This 
procedure was repeated 6 times. The residue was purified by C-18 reverse 
phase chromatography eluting with water to yield 28 mg (46% yield) of pure 
compound 7 as a white solid. 
m.p. =205.degree.-207.degree. C. .sup.1 H-NMR (CDCl.sub.3) .delta.=0.57 
(dd, J=4.0, 5.6 Hz, 1H, H-7' exo); 0.68 (dd, J=5.6, 7.8 Hz, 1H, H-7' 
endo); 1.27 (dd, J=4.0, 7.7 Hz, 1H, H-6'); 1.54 (d, J=1.0 Hz, 3 H, Me at 
C-6); 1.65-1.90 (m, 3H, H-2' & H-3'.alpha.); 2.20 (m, 1H, H-3'.beta.); 
3.34 (d, J=9.9 Hz, 1H, H-5a'); 4.01 (d, J=9.9 Hz, 1H, H-5b'); 4.55 (AB q. 
J=16.5 Hz, 2H, PhCH.sub.2 --); 4.98 (d, J=6.1 Hz, 1H, H-1'); 7.34 (m, 5H, 
aromatic protons) , 7.88 (d, J=1.0 Hz, 1H, H-6); 8.15 (s, 1H, NH) . 
.sup.13 C-NMR 9CDCl.sub.3) .delta.=11.78 (Me at C-5); 12.14 (C-7'); 25.78 
(C-2'); 26.34 (C-6'); 30.25 (C-3'); 30.96 (C-4'); 57.16 (C-1'); 73.47 
(C-5')*; 73.63 (PhCH.sub.2 --)*; 110.22 (C-5); 127.92 (C-4"); 128.50 
(C-2"); 128.56 (C-2"); 137.94 (C-6); 138.39 C-1"); 151.01 (C-2). Anal. 
Calculated for C.sub.19 H.sub.22 O.sub.3 N.sub.2 - C 69.92, H 6.79, N 
8.58. Found C 69.78, H 6.85, N 8.53. 
EXAMPLE 12 
Carbocyclic-4',6'-cyclopropyl -2',3'-dideoxyuridine 8 
A solution of compound 19 (120 mg, 0.29 mmol) in 60 ml methanol was treated 
with concentrated ammonia and the mixture was stirred for 16 hours at room 
temperature. The solvent was evaporated and the residue was purified by 
flash chromatography eluting with CH.sub.2 Cl.sub.2 -isopropanol (97:3) to 
obtain 77 mg (86% yield) of the N-3 deblocked intermediate as a white 
solid. 
A solution of this N-3 deblocked intermediate (67 mg, 0.21 mmol) in 16 ml 
anhydrous CH.sub.2 Cl.sub.2 was cooled at -78.degree. C. under argon was 
treated with 1.50 ml 1.0M BCl.sub.3 in hexane and stirred for 6 hours at 
-78.degree. C. The reaction was quenched as described for compound 7. The 
residue was purified by flash chromatography using CH.sub.2 Cl.sub.2 
-isopropanol (9:1) as solvent to yield 41 mg (87% yield) of pure compound 
8 as a white solid. 
m.p. --154.degree.-156.degree. C. .sup.1 H-NMR (CDCl.sub.3) .delta.=0.59 
(dd, J=3.8, 5.7 Hz, 1H, H-7' exo); 0.72 (dd, J=5.7, 8.7 Hz, 1H, H-7' 
endo); 1.26 (dd, J=3.8, 8.7 Hz, 1H, H-6'); 1.55-1.90 (m, 3H, H-2' & 
H-3'.alpha.); 2.15 (m, 1H, H-3'.beta.); 3.27 (d, J=9.9 Hz, 1H, H-5a'); 
4.40 (d, J=9.9 Hz, 1H, H-5b');4.52 q. J=16.4 Hz, 2H, PhCH.sub.2 --); 5.00 
(d, J=5.8 Hz, 1H, H-1'); 5.37 (dd, J=1.4, 8.0 Hz, 1H, H-5); 8.11 (d, J=8.0 
Hz, 1H, H-6); 9.90 (d, J=1.4 Hz, 1H, --NH); .sup.13 C-NMR (CDCl.sub.3) 
.delta.=12.19 (C-7'); 25.42 (C-2'); 26.24 (C-6'); 30.16 (C-3'); 30.92 
(C-4'); 57.35 (C-1'); 73.25 (C-5') *; 73.62 (PhCH.sub.2 --) *; 101.59 
(C-5); 127.39 (C-4"); 127.83 (C-2"); 128.42 (C-2"); 137.96 C-1"); 142.58 
(C-6); 151.21 (C-2); 163.74 (C-4). Anal. Calculated for C.sub.18 H.sub.20 
O.sub.3 N.sub.2 - c 69.21, h 6.45, n 8.97. Found C 69.13, H 6.44, N 9.02. 
EXAMPLE 13 
Carbocyclic-4',6'-cyclopropyl-2',3'-dideoxycytidine 9 
Compound 8 (120 mg, 0.54 mmol) was dissolved in 3 ml anhydrous pyridine, 
treated with 2 ml acetic anhydride and stirred overnight. Evaporation of 
the solvent produced the 5'-monoacetyl derivative 21 in almost theoretical 
yield. This compound was used in the next step without further 
purification. 
Triethylamine (Et.sub.3 N; 540 .mu.l, 3.88 mmol) was added to a mixture of 
1,2,4-triazole (280 mg, 4.05 mmol), phosphorous oxychloride (POCl.sub.3 ; 
81 .mu.l, 0.867 mmol) and anhydrous acetonitrile (2.3 ml) under argon. 
Compound 21 (100 mg, 0.45 mmol) in 2.0 ml acetonitrile was then added and 
the reaction mixture was stirred at room temperature for 24 hours. Eton 
(375 .mu.l, 2.67 mmol) and water (97 .mu.l ) were then added, the mixture 
was stirred for 10 min and the solvent was evaporated. The residue was 
partitioned between CH.sub.2 Cl.sub.2 (50 ml) and saturated NaHCO.sub.3 
(50 ml). The organic layer was removed and the aqueous layer was extracted 
with CH.sub.2 Cl.sub.2 (2.times.50 ml). The combined organic layers were 
dried with MgSO.sub.4 and the solvent evaporated to obtain compound 22 
which was used in the next step without purification. 
The residue was dissolved in 10 mo dioxane, treated with 1.6 ml aqueous 
ammonia and stirred overnight. The solvent was evaporated and the residue 
was treated with methanolic ammonia (saturated at -70.degree. C. and 
stirred for 20 hours at room temperature. The solvent was evaporated and 
the residue purified by preparative TLC using CH.sub.2 Cl.sub.2 
-isopropanol-Et.sub.3 N (70:30:1) as eluent to obtain 31 mg (37% yield) of 
pure compound 9 as a white solid. 
m.p. =222.degree.-224.degree. C. UV (MeOH) .lambda..sub.max 276.5 
(.epsilon.8400). FAB MS (m/z, %) =314 ({MH +glycerine}+,9); 222 (MH+, 90); 
152 (7); 112 (100. .sup.1 H-NMR (DMSOd.sub.6) .delta.--0.50 (dd, J=3.7, 
5.1 Hz, 1H, H-7' exo); 0.60 (dd, J=5.1, 8.6 Hz, 1H, H-7' endo); 1.15 (dd, 
J=3.7, 8.6 Hz, 1H, H-6'); 3.32 (dd, J=5.0, 11.4 Hz, 1H, H-5a'); 3.78 (dd, 
J=5.0, 11.4 Hz, 1H, H-5b'); 4.77 (d, J=6.3 Hz, 1H, H-1'); 4.89 (t, J=5.0 
Hz, 1H, --OH); 5.67 (d, J=7.3 Hz, 1H, H-5); 7.08 (broad, 2H, --NH.sub.2); 
7.86 (d, J=7.3 Hz, 1H, H-6). .sup.13 C-NMR (DMSOd6) .delta.=11.07 (C-7'); 
24.85 (C-2'); 25.75 (C-6'); 29.70 (C-3') , 32.51 (C-4'); 57.11 (C-1'); 
63.78 (C-5'); 92.99 (C-5); 142.72 (C-6); 154.88 (C-2); 164.59 (C-4 ).d 
Anal. Calculated for C.sub.11 H.sub.15 O.sub.3 N.sub.2.1/3H.sub.2 O - C 
58.14, H 6.95, N 18.49. Found C 58.14, H 6.88, N 18.41. 
EXAMPLE 14 
Conformational analysis of dideoxynucleoside analogues 
With the exception of signals corresponding to the individual aglycons, the 
.sup.1 H NMR spectra of compounds 5-9 were nearly identical and no 
apparent changes in the coupling constants were observed between 
25.degree. C. and 80.degree. C. This indicated that these compounds had a 
highly similar rigid conformation in solution. Using compound 5 as a 
prototype, the pseudoanomeric signal appeared as a doublet with a coupling 
constant of 6.0 Hz centered at .delta.=4.90. To understand the 
multiplicity of this signal, models of N- and S-conformers of 5 were 
constructed using the QUANTA program version 3.2.4 using CHARMm version 21 
with the standard parameter set. The structures were minimized by 
systematic conformational search and the implicated torsion angles were 
measured for both conformers. For the N-conformer the values were: 
H6'-C6'-C1'-H1' (-86.1.degree.), H1'-C1'-C2'-H2'.beta. (91.3.degree.) and 
H1'-C1'-C2'-H2'.alpha.(-23.9.degree.). 
Although the Karplus equation, defined as an empirically-derived 
correlation between the coupling constant J for the H/H interaction in a 
H-C1-C2-H system and the dihedral angle (.theta.) formed between the 
planes that contain H-C1-C2 and C1-C2-H, may not apply perfectly due to 
the distortion produced by the fused cyclopropane ring, the torsion angle 
values measured for the N-conformer suggest that two of the three coupling 
constants should be very close to zero. Conversely, none of the same 
torsion angles measured for the S-conformer approached 90.degree. 
(-134.7.degree.,175.7.degree. C. and 60.9.degree.). Thus, the torsion 
angles measured for the N-geometry agree better with the multiplicity 
observed for the pseudoanomeric signal of 5 (doublet, J=6 Hz), in the 
.sup.1 H NMR spectrum. These torsion angles are also similar to those 
measured from the crystal structure of neplanocin C, suggesting that 
structures 5-9 have equivalent N-geometries in solution. The N-geometry in 
compounds 5-9 can only be achieved if the bicyclo[3.1.0] hexane system 
exists as a pseudoboat, since a pseudochair conformation would correspond 
to the S-geometry. A search for compounds containing unrestricted 
bicyclo[3.1.0]hexanes in the Cambridge Structural Data Base (Allen, et 
al., (1979) Acta. Crystallogr., B35, 2331) revealed that in the seven 
examples found the pseudoboat was the only form of puckering observed. 
EXAMPLE 15 
Evaluation of anti-HIV activity of dideoxynucleosides 
Compounds 5-9 were evaluated against HIV-1 in immortalized OKT4.sup.+ 
T-cells (ATH.sub.8 cells) by the cytopathic effect assay (Mitsuya and 
Broder, (1986) Proc. Natl. Acad. Sci. U.S.A., 83: 1911). Compound 5, the 
adenosine derivative, was the only analogue which exhibited anti-HIV 
activity. A dose-dependent increase in the number of viable cells was 
observed from 5-50 .mu.M, although the drug itself exhibited some toxicity 
in this range (FIG. 3). Since compound 5 is a racemic mixture, it is 
anticipated that separation of the two enantiomers will result in one 
responsible for toxicity and one responsible for the antiviral effect. 
The synthetic approach for the 2' tert-butyl-substituted carbocyclic 
alcohol 30 is shown in Scheme 3 and described in Examples 16-21 below. 
##STR6## 
EXAMPLE 16 
(1S,4R,5S)-3-[(Benzyloxy)methyl]-4,5-O-isopropylidene-2-cyclopenten-1-ol 24 
Compound 24 was prepared from compound 23 according to 5 the procedure of 
Marquez et al., J. Org. Chem., 53:5709 (1988). 
EXAMPLE 17 
(1S,4R,5S)-3-[(Benzyloxy)methyl]-4-tert-butyloxy-5-hydroxy-2-cyclopenten-1- 
ol 25 
A solution of 24 (0.61 g, 2.20 mmol) was stirred in anhydrous CH.sub.2 
Cl.sub.2 (25 ml) at -78.degree. C. and treated with a solution of 
trimethylaluminum in toluene (2M, 7.8 ml, 15.6 mmol). After the addition, 
the reaction was allowed to reach room temperature and stirring was 
continued for 18 hours. The reaction mixture was cooled again to 
-78.degree. C. and quenched with an aqueous saturated solution of NH.sub.4 
Cl (10 ml). Since this is a very exothermic process, the addition of 
NH.sub.4 Cl was done slowly. The mixture was filtered after reaching room 
temperature and the solid was washed with CHCl.sub.3. The filtrate was 
extracted with CHCl.sub.3 (3.times.50 ml) and the combined organic extract 
was washed with water (50 ml), dried (Na.sub.2 SO.sub.4), and concentrated 
under vacuum. The crude product was purified by flash column 
chromatography over silica gel with a 0-50% gradient of ethyl acetate in 
hexane as eluant to give 0.349 g (54%) of compound 25 as a thick oil. 
Analysis calculated for C.sub.17 H.sub.24 O.sub.4 : C, 69.83; H, 8.27. 
Found: C, 69.57; H, 8.27. 
EXAMPLE 18 
(1S,4R,5S)-1-(tert-Butyldimethylsilyloxy)-3-{[(Benzoyloxy) 
methyl]}-4-tert-butyloxy-5-hydroxy-2-cyclopentene 26 
A solution of 25 (8.04 g, 27.5 mmol) and imidazole (7.05 g, 103.55 mmol) in 
anhydrous DMF (80 ml) was treated with tert-butyldimethylsilyl chloride 
(6.70 g, 44.45 mmol). The mixture was stirred at room temperature under a 
blanket of argon for 40 min and quenched by the addition of water (100 
ml). The reaction mixture was extracted with ethyl acetate (3.times.100 
ml), and the combined organic extract was washed with brine (2.times.100 
ml) and dried over Na.sub.2 SO.sub.4. The solvent was evaporated and the 
product purified by flash column chromatography over silica gel to give 
9.77 g (87.4%) of pure 26 as an oil. Analysis calculated for C.sub.23 
H.sub.38 O.sub.4 Si.0.5 H.sub.2 O: C, 66.46; H, 9.46. Found: C, 66.41; H, 
9.31. 
EXAMPLE 19 
(1S,4R,5S)-1-(tert-Butyldimethylsilyloxy)-3-[(Benzyloxy)methyl]-4-tert-buty 
loxy-5-[(methylthio)thiocarbonyloxy-2-cyclopentene 27 
A solution of 26 (9.77 g), 24.02 mmol) in anhydrous THF (100 ml) was 
treated with carbon disulfide (10.2 ml, 168.8 mmol). The mixture was 
stirred at 0.degree. C. for 5 min, and NaH (80% suspension in oil, 2.2 g, 
73.3 mmol) was added in portions. The mixture was stirred at room 
temperature for 30 min. Methyl iodide (19.5 ml, 313.2 mmol) was added, and 
after further stirring for 30 min, the reaction mixture was cooled to 
0.degree. C., and excess NaH was destroyed by the slow addition of water 
(very exothermic process). The organic layer was separated and the aqueous 
extract was dried (Na.sub.2 SO.sub.4) and concentrated under vacuum. The 
crude product was purified by flash column chromatography over silica gel 
using a 0-5% gradient of ethyl acetate in hexane to give 9.83 g (82.4%) of 
pure 27 as an oil. Analysis calculated for C.sub.25 H.sub.40 O.sub.4 
S.sub.2 Si.0.25 H.sub.2 O: C, 59.90; H, 8.10; S, 12.77. Found: C, 59.84; 
H, 8.10; S, 12.72. 
EXAMPLE 20 
(1S,4R)-1-(tert-Butyldimethylsilyloxy)-3-[(Benzyloxy)methyl]-4-tert-butyl-2 
-cyclopentene 28 
A solution of 27 (9.82 g, 19.76 mmol) and azobis(isobutyronitrile) (AIBN, 
2.04 g, 12.42 mmol) in anhydrous toluene (100 ml) under a blanket of argon 
was heated to ca. 50.degree. C. and treated slowly with tri-n-butyltin 
hydride (22 ml, 81.8 mmol). After the addition was complete, the mixture 
was heated (oil bath temp. 120.degree. C.) for 1.5 hours and cooled to 
room temperature. The solvent was evaporated and the crude product was 
purified by flash column chromatography over silica gel with a gradient of 
0-5% ethyl acetate in hexane to give compound 28 (5.94 g, 77%) as an oil. 
Analysis calculated for C.sub.23 H.sub.38 O.sub.3 Si.0.5H.sub.2 O: C, 
69.12; H, 9.83. Found: C, 69.21; H, 9.71. 
EXAMPLE 21 
(1S,4R)-3-[(Benzyloxy)methyl]-4-tert-butyloxy-2-cyclopenten-1-ol 29 
A solution of 28 (4.82 g, 12.36 mmol) in anhydrous THF (80 ml) was treated 
with a solution of tetrabutylammonium fluoride in THF (1M, 51 ml) and the 
resulting mixture was stirred at room temperature overnight. The solvent 
was evaporated and the residue treated with water and extracted with ethyl 
acetate (3.times.100 ml). The combined organic extract was washed with 
brine (2.times.100 ml) and dried (Na.sub.2 SO.sub.4). The solvent was 
removed under reduced pressure and the crude product purified by flash 
column chromatography over silica gel using a gradient of 50-66% ethyl 
acetate in hexane to give compound 29 (3.152 g, 92%) as a clear oil. 
Analysis calculated for C.sub.17 H.sub.24 O.sub.3.0.75H.sub.2 O: C, 70.43; 
H, 8.86. Found: C, 70.62; H, 8.54. 
EXAMPLE 22 
(1R,2S,4R,5S)-1-[(Benzoyloxy)methyl]-2-tert-butyloxy-4hydroxybicyclo[3.1.0] 
hexane 30 
Samarium metal (4.40 g, 29.3 mmol) was placed in a flask and dried with a 
flame under a stream of argon. Anhydrous THF (30 ml) and a solution of 
mercuric chloride (0.76 g, 2.8 mmol) in 10 ml THF were added and the 
mixture was stirred for 10 min prior to the addition of a solution of 
compound 29 (1.80 g, 6.50 mmol) in THF (30 ml). The reaction mixture was 
cooled to -78.degree. C. and treated with chloroiodomethane (2.20 ml, 30 
mmol). The resulting mixture was stirred continuously starting at 
-78.degree. C. and allowing the temperature to reach room temperature 
during the course of the night. The following day, the reaction was 
quenched with a saturated solution of potassium carbonate (200 ml) and 
extracted with methylene chloride (3.times.100 ml). The combined organic 
extract was washed with brine (100 ml), dried (Na.sub.2 SO.sub.4), 
filtered and evaporated to give nearly pure compound 30 quantitatively as 
a colorless oil. This product was used in the condensation steps described 
in the purine and pyrimidine synthetic steps described above. 
Compounds 31 and 32 corresponding to the thymidine and adenosine analogs, 
respectively, were synthesized using compound 30 as the starting material 
following reaction Schemes 2 and 1, respectively, starting with the step 
following cyclopropanation. 
(1R,2S,4S,5S)-1-Hydroxymethyl-4-(5-methyl-2,4(1H,3H)-dioxopyrimidin-1-yl)bi 
cyclo[3.1.0]hexane 31 
The thymidine analog 31 was obtained as a white crystalline product having 
the following parameters: melting point =239.degree.-241.degree. C.; 
[.alpha.].sub.D 25=+47.14; FAB MS m/z (relative intensity) 253 (MH+, 100) 
, 127 (b+2H, 40) . Analysis calculated for C.sub.12 H.sub.16 O.sub.4 
N.sub.2.0.33H.sub.2 O: C, 55.81; H, 6.50; N, 10.85. Found: C, 55.91; H, 
6.51; N, 10.73. 
(1R,2S,4S,SS) 2-hydroxy-4-(6-amino-9-purinyl)bicyclo [3.1.0]hexane 32 
The adenosine analog 32 was obtained as a white solid, melting point 
259-261.degree. C.; FAB MS m/z (relative intensity) 262 (MH+, 100), 136 (b 
+2H, 58). 
In the final step of the purine synthetic scheme (Scheme 1), and in the 
thymidine/uracil synthetic step of the pyrimidine synthetic scheme (Scheme 
2), the benzyl protecting groups are removed by cleavage with BCl.sub.3. 
This same treatment removes the tert-butyl group at the 2' position when 
compound 30 is used as the starting material for synthesis of the 
nucleoside analogs, thus leaving a 2'-0H group. 
The description above is illustrative and not restrictive. Accordingly, 
many variations of the invention will be apparent to one skilled in the 
art on review of this disclosure, and the invention can be embodied in 
these various specific forms without departing from it in spirit or 
essential characteristics. For example, it should be apparent from the 
foregoing that various purine and pyrimidine analogues can be substituted 
in the Examples to achieve similar results. The scope of the invention is 
therefore indicated by the appended claims rather than by the foregoing 
description.