Synthesis of novel hydroxymethyl substituted analogues related to carbovir and neplanocin A

Article abstract of DOI:10.1081/NCN-120006528

Two enantiomerically pure hydroxymethyl substituted cyclopentene nucleoside analogues (42 and 53) related to carbovir and neplanocin A, respectively, were prepared from the chiral pool of iridoid glucosides. In addition two saturated hydroxymethylated ana

Full text of DOI:10.1081/NCN-120006528

Nucleosides, Nucleotides and Nucleic Acids
ISSN: 1525-7770 (Print) 1532-2335 (Online) Journal homepage: http://www.tandfonline.com/loi/lncn20
SYNTHESIS OF NOVEL HYDROXYMETHYL
SUBSTITUTED ANALOGUES RELATED TO CARBOVIR
AND NEPLANOCIN A
Henrik Franzyk , Søren Rosendal Jensen , Carl Erik Olsen & Jon Holbech
Rasmussena
To cite this article: Henrik Franzyk , Søren Rosendal Jensen , Carl Erik Olsen & Jon Holbech
Rasmussena (2002) SYNTHESIS OF NOVEL HYDROXYMETHYL SUBSTITUTED ANALOGUES
RELATED TO CARBOVIR AND NEPLANOCIN A, Nucleosides, Nucleotides and Nucleic Acids, 21:1,
23-43, DOI: 10.1081/NCN-120006528
To link to this article: http://dx.doi.org/10.1081/NCN-120006528
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Date: 05 November 2015, At: 15:42

NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 21(1), 23ꢀ43 (2002)
SYNTHESIS OF NOVEL HYDROXYMETHYL
SUBSTITUTED ANALOGUES RELATED
TO CARBOVIR AND NEPLANOCIN A
Henrik Franzyk,a,* Søren Rosendal Jensen,a Carl Erik Olsen,b
and Jon Holbech Rasmussena
aDepartment of Organic Chemistry, Technical University of
Denmark, Building 201, DK-2800 Lyngby, Denmark
bDepartment of Chemistry, The Royal Danish Veterinary and
Agricultural University, Thorvaldsensvej 40, DK-1871
Frederiksberg C, Denmark
ABSTRACT
Two enantiomerically pure hydroxymethyl substituted cyclopentene
nucleoside analogues (42 and 53) related to carbovir and neplanocin A,
respectively, were prepared from the chiral pool of iridoid glucosides.
In addition two saturated hydroxymethylated analogues (44 and 45)
were obtained from a protected intermediate.
INTRODUCTION
During the last three decades carbocyclic nucleoside analogues have
been recognized as potent and increasingly important antiviral agents. Car-
bocyclic analogues of active nucleosides frequently appear to be inactive,
which may in part be due to the lack of the anomeric effect and the inter-
actions between the ring-oxygen and the hydroxyl groups present. Never-
theless, in recent years several carbocyclic analogues with altered carbon-
skeletons and unusual substitution patterns (Figure 1) have been found to
*Corresponding author. Present address: Department of Medicinal Chemistry, The Royal
Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
23
Copyright # 2002 by Marcel Dekker, Inc.
www.dekker.com

24
FRANZYK ET AL.
Figure 1. Carbocyclic nucleoside analogues related to 1-3 (A ¼ adenine-9-yl, G ¼
guanine-9-yl).

ANALOGUES OF CARBOVIR AND NEPLANOCIN A
25
possess activity against a number of viral infections1. Particularly the anti-
HIV active carbovir (1)2 and (-)-BCA (2)3, but also the antitumoral nepla-
nocin A (3)4 still attract considerable synthetic interest5,6 as does the
development of enantioselective preparative methodologies towards carbo-
cyclic nucleoside analogues7ꢀ9. Since the enantioselective synthesis10 of 1, its
pure enantiomer11 and a number of base-modified analogues12 including the
anti-HIV agent Ziagen113, have been reported. In addition the 5-homologues
4a and 4b (the latter as two racemates) as well as the halogenated 5a and 5b,
and the hydroxymethyl substituted 6 have been prepared14ꢀ18. Also 50-hetero
compounds19ꢀ21 (7aꢀc) and analogues (8) with a 10-methylene bridge22 have
appeared. Racemic analogues having a transposed23 (i.e., 9) or an additional
hydroxymethyl group24 (i.e., 10 and 11) as well as optically pure 40-alkylated
analogues25 (12aꢀc) have been synthesized. Compound 13 may be regarded
either as an L-type analogue of carbovir (1) or as an 20-nor-analogue of
(-)-BCA (2)26. Likewise, many analogues of neplanocin A (3) have appeared
in recent years. Hence, both the corresponding antileishmanial 50-nor-
compound27,28 (14), the antiviral 5-substituted analogues (15aꢀe)29, satu-
rated homologues (16aꢀc)29ꢀ31 as well as unsaturated 5-homologues
(17aꢀe)29,31,32, and 50-carboxylic acid derivatives (18aꢀd) have been repor-
ted33. The enantiomer34 of 3 as well as its diepimer5 (19) have also been
prepared. Other modifications seen in neplanocin A analogues include
fluorination35 (i.e., racemic 20), methoxy substitution36 (i.e., racemic 21),
deoxygenation37,38 (i.e., 22aꢀb), hydroxymethylation18,39 (i.e., 22c and 23)
and transposition of the double bond40 (i.e., 24). Introduction of hydro-
xymethyl groups instead of hydroxyls has become a common approach to
obtain increased structural diversity of carbocyclic nucleoside analogues.
Examples are compounds 25aꢀ28b41ꢀ47, whereas compounds 29ꢀ32b con-
tain an extra hydroxymethyl group40,48,49
.
Only a few previous reports on the use of iridoid glucosides as cyclo-
pentanoid building blocks in syntheses of nucleoside analogues have
appeared50ꢀ52. In the present work either catalpol (33), or more conveniently
its cinnamoyl ester 34, was selected as a readily available starting material53.
Preliminary investigations had shown that these iridoids after only a few
modification and protection steps (i.e., to give 35) could be converted into a
partially protected cyclopentanoid polyol (36) using an ozonolytic procedure
(Scheme 1)54. The polyol (36) was envisaged to be a potential intermediate in
the synthesis of novel hydroxymethyl substituted analogues related to car-
bovir (1) and neplanocin A (3), which we report here.
RESULTS AND DISCUSSION
Initial attempts to perform either selective acylation or silylation of the
primary hydroxyl groups in triol 36 resulted in rather complex mixtures of

26
FRANZYK ET AL.
Scheme 1. Synthesis of nucleoside analogues from iridoid-derived building blocks.
mono-, di- and fully protected products. In order to overcome this obstacle,
triol 36 was subjected to acetonation with 2,2-dimethoxypropane (2,2-DMP)
under mild conditions, which provided diacetonide 37 in good yield (82%).
The nucleoside base was introduced by way of a Mitsunobu reaction of
alcohol 37 with 6-chloropurine (Scheme 1.). But in addition to the desired
product (38) a substantial amount of elimination product (39) was also
obtained (ca. 1:1 ratio). When polymer-bound triphenylphosphine was
employed and no nucleophile was added under Mitsunobu conditions,
dehydration of 37 to 39 could be accomplished in good yield (74%). It
should be noted that the above seven-membered acetonides seem quite stable
towards prolonged reaction time in neutral to weakly acidic conditions, and

ANALOGUES OF CARBOVIR AND NEPLANOCIN A
27
they may be purified by vacuum liquid chromatography (VLC) using TLC-
mesh silica even when eluents without added base are employed. To be able
to introduce a double bond between C-10 and C-50 in the cyclopentane moiety
(in 38) by dehydration of the tertiary alcohol, the isopropylidene protecting
groups were exchanged for acyl groups at the primary positions. This was
performed as a one-pot hydrolysis-acetylation procedure. However, due to a
competing methanolysis of the 6-chloro functionality in the purine moiety,
the desired product (40) and the 6-methoxypurine derivative (41) were
obtained in a 5:1 ratio. Dehydration of triacetate 40 was best achieved with
phosphorus oxychloride in pyridine at room temperature. Even though the
reaction proceeded sluggishly under these conditions, a higher selectivity for
the less substituted olefin was observed as compared to e.g., thionyl chloride
in pyridine-dichloromethane at low temperature, where the selectivity was
reverse (i.e., the precursor of 43 was predominant). Subsequently, the inse-
parable olefinic product mixture was simultaneously deacylated and con-
verted into the adenine nucleoside analogues 42 and 43 by ammonolysis. The
former compound could be obtained in essentially isomer-free state by
repeated reverse-phase chromatography. Structurally, compound 42 is rela-
ted to the (inactive) carbovir analogue 618. Also a uracil substituted 70-
homologue of 42 has been reported (no biological data were given)50. So far,
only a mixture of 42 and 43 has been examined for antiviral activity, and it
was found to be inactive against HIV and HSV-1.
The intermediate 38 was further elaborated into saturated nucleoside
analogues 44 and 45 (Scheme 1). First, diacetonide 38 was ammonolyzed to
give the corresponding adenine diacetonide that was hydrolyzed directly to
yield bis(hydroxymethyl) substituted carbocyclic deoxyadenosine 44 in 84%
yield. Next, periodate oxidation of the vicinal diol functionality to give the
corresponding ketone proved somewhat problematic as the keto compound
was prone to undergo -elimination of the purine moiety during chromato-
graphy. To avoid alkaline conditions (also promoting b-elimination) during
reduction, we used sodium triacetoxyborohydride together with acetonitrile
as co-solvent55. Thus, when the ketone, prepared in aqueous solution at 0ꢁC,
was added directly to a cooled suspension of NaBHðOAcÞ3 in acetonitrile, the
-hydroxy compound (45) was obtained as the only product in 77% yield. The
20- and=or the 30-hydroxymethyl group probably participating56 to give the
observed stereospecificity. A NOESY experiment corroborated the stereo-
chemistry of analogue 45 (as shown in Figure 2.). Strong interactions were
seen between H-10 and the two H-60 while the H-10=H-20 interaction was weak
and both the H-10=H-40 and H-10=H-30 interactions were practically absent.
Moreover, H-40 exhibited strong interactions with H-20 and H-30 as well as
medium interactions with the protons at C-50. The three large to medium
coupling constants (10.8, 9.2 and 7.6 Hz) for H-40 together with the size of the
coupling constants for H-10 (9.0, 6.7 and 2.9 Hz) indicates that an envelope
conformation with the adenine substituent in a pseudoequatorial position is

28
FRANZYK ET AL.
Figure 2. Correlations (left) obtained for compound 45 from a NOESY experiment (in
CD3OD, 400 MHz). Selected coupling constants pointing to an envelope conformation.
predominating (Figure 2.). To our knowledge, only one compound of closely
related structure has been reported so far, namely the 60--hydroxymethyl
carbocyclic thymidine, which was studied for its effect on the stability of
DNA=RNA duplexes57.
Finally, the synthesis of a bis(hydroxymethyl)-analogue (53) of nepla-
nocin A (3) was undertaken (Scheme 2.). The protected cyclopentanol 37
from above was subjected to Mitsunobu inversion using 4-nitrobenzoic acid
Scheme 2. Synthesis of a bis(hydroxymethyl)-analogue of neplanocin A.

ANALOGUES OF CARBOVIR AND NEPLANOCIN A
29
as nucleophile, and this yielded the expected 4-nitrobenzoate 46 together
with the elimination product 39 (83% and 14%, respectively). Deacylation of
46 followed by introduction of the purine moiety via a Mitsunobu coupling
with 6-chloropurine resulted only in a low yield (approx. 15%) of the desired
product (49) while the main product (59%) was an olefin (48). Ammonolysis
of the slightly impure 6-chloropurine derivative (49) afforded the crystalline
adenine compound (50), which subsequently was N6-benzoylated58 to give
51. Acid hydrolysis followed by acetylation furnished triacetate 52. Dehy-
dration of the tertiary alcohol in triacetate 52 was accomplished with phos-
phorus oxychloride. Only one elimination product was obtained, and this
was deprotected with methanolic sodium methoxide at slightly elevated
temperature for 5 hours (a long reaction time59 and the necessity for heat-
ing60 have been reported for N6-debenzoylation) to give neplanocin A ana-
logue 53. The analogues 44 and 45 as well as cyclopentene 53 have been
submitted to biological evaluation, which will be reported in due course.
EXPERIMENTAL SECTION
General Experimental Procedures. PPTS (pyridinium p-toluenesulpho-
nate) and DEAD (diethyl azodicarboxylat) were purchased from Aldrich
Chemical Co.; 2,2-DMP (2,2-dimethoxypropane), POCl3; NaIO4; BzCl, and
6-chloropurine were from Fluka Chemie AG, while Ph3P was from Merck.
Acetone was distilled and then stirred with CaCl2, filtered, and stored over
3A molecular sieves. THF was freshly distilled from Na. All concentrations
were performed invacuo. Optical rotations were measured on a Perkin-Elmer
241 polarimeter. Elemental analyses were performed by the Microanalytical
Department at the H. C. Ørsted Institute (University of Copenhagen).
Melting points are uncorrected. TLC was performed on Merck Si gel 60 F254
aluminum sheets with detection by charring with H2SO4 or by UV light when
applicable. MPLC was performed on Merck Lobar Lichroprep RP18 col-
umns (size B or C). Vacuum liquid chromatography (VLC) was performed
on predried (120ꢁC; > 24 h) Merck Si gel 60H; the column size is given as
height  diameter (cm). NMR spectra were recorded on Varian Inova 500
and Mercury 300 or Bruker Avance 400 spectrometers. Chemical shifts
are given in ppm, using the solvent peaks as internal standards (D2O :
dH ¼ 4:75; CD3OD : dH ¼ 3:31; dC ¼ 49:0; DMSO-d6 : dH ¼ 2:50; dC ¼ 39:5;
CDCl3 : dH ¼ 7:27; dC ¼ 77:0). Coupling constants (J-values) are given in
hertz (Hz). The subscripts a and b indicate the low field and high field pro-
tons, respectively, in methylene groups. Primes (0) are used to denote the
0
cyclopentanoid moities of the nucleoside analogues. For all compounds, H
NMR signals were assigned by COSY experiments, while 13C NMR signals
were assigned from HSQC and HMBC spectra. HRFAB-MS were recorded
on a JEOL JMS-AX505W instrument using a bis(hydroxyethyl)disulfide

30
FRANZYK ET AL.
matrix. Carbocyclic nucleoside analogues were tested against HIV and
HSV-1 at the Department of Virology, The Danish Serum Institute,
Copenhagen61ꢀ63
.
(1S,3R,4S,5R)-1,6:7,8-bis-O-Isopropylidene-1,4,5-tris-hydroxymethyl-cy-
clopentane-1,3-diol (37). Acetonide 3654 (4.47 g, 19.3 mmol) was treated
with 2,2-DMP (2.36 mL, 19.3 mmol) in dry acetone (130 mL) in the presence
of anhydrous CuSO4 (2.36 g) and PPTS (0.236 g). After 1 h at room tem-
perature, Et3N (4 mL) was added, and the volume was reduced to ca. 50 mL,
which was mixed with silica gel 60 (17 g, 0.040ꢀ0.063 mm) and more Et3N
(1 mL) was added. The solvent was evaporated in vacuo, and then the re-
sulting silica gel was loaded onto a VLC column (7 Â 7 cm). Gradient elution
with hexane, and then hexaneꢀMe2CO (10:1 to 4:1) yielded diacetonide 37
(4.30 g, 82%): mp 84ꢀ85ꢁ (hexaneꢀMe2CO); [a]21D ꢀ 3.0 ꢁ (c 0.73, MeOH);
1H NMR (CD3OD, 500 MHz): d 4.14 (1H, d, J ¼ 9:0 Hz, H-6a), 4.11 (1H, dt,
J ¼ 8:1; 2 Â 5:5 Hz, H-3), 3.79 (1H, dd, J ¼ 12:4, 3.4 Hz, H-7a), 3.69 (1H, d,
J ¼ 9:0 Hz, H-6b), 3.66 (1H, dd, J ¼ 12:4, 4.5 Hz, H-8a), 3.62 (2H, m, H-7b
and H-8b), 2.29 (1H, br dt, J ¼ 2 Â 7:5, 4.5 Hz, H-5), 2.26 (1H, dd, J ¼ 14:5,
8.1 Hz, H-2a), 2.19 (1H, m, H-4), 1.84 (1H, br dd, J ¼ 14.5, 5.5 Hz, H-2b),
1.37, 1.35, 1.32, 1.27 (each 3H, s, 26(CH3)2C<); 13C NMR (CD3OD,
75 MHz): d 109.3, 102.7 (2 Â ðCH3Þ2C <Þ, 88.8 (C-1), 71.4 (C-3), 70.6 (C-6),
61.5 (C-7), 60.4 (C-8), 52.0 (C-4), 51.6 (C-5), 47.1 (C-2), 27.3, 27.0, 25.3, 24,5
(26(CH3<)2C<); anal. C 61.57%, H 9.07%, calcd for C14H24O5 (Mw
272.34), C 61.74%, H 8.88%.
(1S; 2R; 3R; 4S)-1,6:7,8-bis-O-Isopropylidene-4-(6-chloro-purin-9-yl)-1,2,
3-tris-hydroxymethyl-cyclopentanol (38). To a solution of cyclopentanol 37
(1.28 g, 4.70 mmol), Ph33P (2.47 g, 264.70 mmol) and 6-chloropurine (1.45 g,
264.70 mmol) in dry THF (20 mL) was slowly added a solution of DEAD
(1.42 mL, 1.9564.70 mmol) in dry THF (5 mL). The mixture was kept at
room temperature for 17 h, when the reaction mixture was concentrated. The
residue was dissolved in CH2Cl2 (15 mL) and loaded onto a VLC column
(565 cm). Gradient elution with hexane and then hexane-Me2CO (50:1 to
8:1) yielded impure fractions of 39 (0.73 g) and 38 (1.15 g), which were
purified by repeated VLC to give almost pure 39 (hexaneꢀMe2CO 100:1,
0.56 g, 47%, see below for characterization) and 38 (hexaneꢀMe2CO 10:1,
0.87 g, 45%). Diacetonide 38: mp 153ꢀ154 ꢁC (hexaneꢀMe2CO); [a]21
D
ꢀ 60.5 ꢁ (c 0.65, MeOH); 1H NMR (CD3OD, 500 MHz): d 8.74 (1H, s, H-2),
8.68 (1H, br s, H-8), 5.36 (1H, dt, J ¼ 11:8; 2 Â 8:1 Hz, H-40), 4.39, 4.04 (each
1H, d, J ¼ 9:0 Hz, 26H-60), 3.97 (1H, dd, J ¼ 13:0, 6.8 Hz, H-7a0), 3.89 (1H,
dd, J ¼ 13:0, 3.8 Hz, H-7b0), 3.42 (1H, dd, J ¼ 12:8, 6.8 Hz, H-8a0), 3.33 (1H,
br d, J ¼ 12:8 Hz, H-8b0), 3.08 (1H, dd, J ¼ 13:5, 11.8 Hz, H-5a0), 2.95
(1H, m, H-30), 2.52 (1H, dd, J ¼ 13:5, 8.1 Hz, H-5b0), 2.45 (1H, dt,
J ¼ 2 Â 6:8, 3.8 Hz, H-20), 1.42, 1.39 (each 3H, s, (CH3)2C<), 1.20 (6H, s,

ANALOGUES OF CARBOVIR AND NEPLANOCIN A
31
(CH3)2C<); 13C NMR (CD3OD, 75 MHz): d 153.9 (C-6), 152.8 (C-2), 151.1
(C-4), 147.8 (C-8), 132.5 (C-5), 109.9, 103.0 (26(CH3)2C <), 88.0 (C-10), 71.0
(C-60), 60.8 (C-70), 60.4 (C-80), 56.6 (C-40), 52.8 (C-20), 46.2 (C-30), 41.2 (C-50),
27.2, 27.1, 25.4, 23.9 (26(CH3)2C<); anal. C 55.92%, H 6.03%, N 13.70%
calcd for C19H25N4O4Cl (Mw 408.89), C 55.81%, H 6.16%, N 13.70%.
(1S; 4S; 5R)-1,6:7,8-bis-O-Isopropylidene-1,4,5-tris-hydroxymethyl-cy-
clopent-2-enol (39). To cyclopentanol 37 (0.65 g, 2.39 mmol), Ph3P (1.59 g,
262.39 mmol; polymer-bound, Aldrich, 3 mmol P=g resin) in dry THF
(20 mL) was added DEAD (0.41 mL, 1.162.39 mmol) in THF (5 mL). After
24 h more DEAD (0.20 mL) was added, and the mixture was kept at room
temperature for an additional 4 days. Then EtOAc (150 mL) was added and
the resin subsequently filtered off on a bed of Na2SO4. Concentration yielded
a residue, which was purified on a VLC column (565 cm). Elution with
hexane and then hexaneꢀMe2CO (100:1) gave 39 (0.45 g, 74%): mp
36 ꢀ 37 ꢁC (hexaneꢀMe2CO); [a]21 þ105 ꢁ (c 0.84, MeOH); 1H NMR
D
(CD3OD, 500 MHz): d 5.83 (2H, s, H-2 and H-3), 4.53 (1H, d, J ¼ 9:0 Hz, H-
6a), 4.00 (1H, dd, J ¼ 13:2, 3.4 Hz, H-8a), 3.88 (1H, dd, J ¼ 13:2, 2.4 Hz, H-
8b), 3.73 (1H, d, J ¼ 9:0 Hz, H-6b), 3.58 (1H, dd, J ¼ 12:4, 4.7 Hz, H-7a),
3.33 (1H, dd, J ¼ 12:4, 11.1 Hz, H-7b), 2.93 (1H, ddd, J ¼ 11:1, 7.6, 4.7 Hz,
H-4), 2.28 (1H, br dt, J ¼ 7:6; 2 Â 2:8 Hz, H-5), 1.40, 1.38, 1.34, 1.26 (each
3H, s, 26(CH3)2C<); 13C NMR (CD3OD, 75 MHz): d 137.7 (C-2), 134.3 (C-
3), 108.8, 103.1 (26(CH3)2C<), 93.7 (C-1), 71.2 (C-6), 64.9 (C-7), 59.2 (C-8),
51.6 (C-5), 49.6 (C-4), 27.1, 26.5, 25.3, 24.2 (26(CH3)2C<); anal. C 65.79%,
H 9.00%, calcd for C14H22O4 (Mw 254.32), C 66.12%, H 8.72%.
(1S; 2R; 3R; 4S)-6,7,8-Tri-O-acetyl-4-(6-chloro-purin-9-yl)-1,2,3-tris-hy-
droxymethyl-cyclopentanol (40) and (1S; 2R; 3R; 4S)-6,7,8-tri-O-acetyl-4-(6-
methoxy-purin-9-yl)-1,2,3-tris-hydroxymethyl-cyclopentanol (41). Diaceto-
nide 38 (0.79 g) was dissolved in MeOH (35 mL), and aqueous 12M HCl
(0.5 mL) was added slowly. After the mixture was stirred at room tempera-
ture for 3 h, more 12M HCl (0.250 mL) was added. Upon a further 3 h,
pyridine (2 mL) was added to the reaction mixture, and after concentration
in vacuo, the residue was dried on an oil-pump for 0.5 h. The residue was
dissolved in pyridineꢀCH2Cl2 (1:1, 30 mL), and upon cooling of the mixture
to 0ꢁC, Ac2O (15 mL) was added. After 3 h, excess Ac2O was quenched with
ice (10 g). Then EtOAc (150 mL) was added, and the organic layer was se-
parated and subsequently washed with saturated aqueous NaHCO2
(3625 mL). Each of the washings was extracted back with EtOAc
(2650 mL). The combined EtOAc phases were dried (Na2SO4) and then
concentrated. The residue was purified on a VLC column (464 cm). Gra-
dient elution with hexane and then hexaneꢀMe2CO (4:1 to 2:1) afforded 40
(0.66 g, 75%) followed by 41 (0.13 g, 15%). Triacetate 40: white foam,
1
[a]24D ꢀ 30.5 ꢁ (c 0.90, MeOH); H NMR (CDCl3, 500 MHz): d 8.76 (1H, s,

32
FRANZYK ET AL.
H-2), 8.14 (1H, s, H-8), 5.46 (1H, ddd, J ¼ 11:5, 8.5, 7.8 Hz, H-40), 4.44 (1H,
dd, J ¼ 12:0, 7.2 Hz, H-7a0), 4.41 (1H, dd, J ¼ 12:0, 7.0 Hz, H-7b0), 4.39, 4.31
(each 1H, d, J ¼ 11:5 Hz, 26H-60), 4.02 (1H, dd, J ¼ 12:0, 5.0 Hz, H-8a0),
3.76 (1H, dd, J ¼ 12:0, 8.5 Hz, H-8b0), 3.42 (1H, dq, J ¼ 3 Â 8:5, 5.0 Hz, H-
30), 3.05 (1H, dd, J ¼ 13:3, 11.5 Hz, H-5a0), 2.76 (1H, q-like, J ¼ 7:3 Hz, H-
20), 2.53 (1H, br s, 10-OH), 2.38 (1H, dd, J ¼ 13:3, 7.8 Hz, H-5b0), 2.18, 2.11,
1.74 (each 3H, s, 36OCOCH3); 13C NMR (CDCl3, 75 MHz): d 170.8, 170.4,
169.8, (36COCH3), 152.3 (C-6), 151.7 (C-2), 151.3 (C-4), 144.9 (C-8), 131.9
(C-5), 78.9 (C-10), 67.8 (C-60), 60.9 (C-70), 60.6 (C-80), 55.6 (C-40), 49.3 (C-20),
41.9 (C-30), 39.3 (C-50), 20.9, 20.8, 20.3 (36COCH3); anal. C 49.89%, H
5.11%, N 12.10% calcd for C19H23N4O7Cl (Mw 454.87), C 50.17%, H
5.10%, N 12.32%. 6-methoxypurin-9-yl derivative 41: white foam,
1
[a]25D ꢀ 36.5 ꢁ (c 0.59, MeOH); H NMR (CDCl3, 500 MHz): d 8.55 (1H, s,
H-2), 8.05 (1H, br s, H-8), 4.21 (3H, s, 6-OCH3), 5.43 (1H, ddd, J ¼ 11:5, 8.5,
8.0 Hz, H-40), 4.47, 4.42 (each 1H, dd, J ¼ 11:9, 7.3 Hz, 26H-70), 4.39, 4.31
(each 1H, d, J ¼ 11:5 Hz, 26H-60), 3.98 (1H, dd, J ¼ 12:0, 5.5 Hz, H-8a0),
3.78 (1H, dd, J ¼ 12:0, 8.5 Hz, H-8b0), 3.41 (1H, dq, J ¼ 368.5, 5.5 Hz, H-
30), 3.06 (1H, dd, J ¼ 13:2, 11.5 Hz, H-5a0), 2.75 (1H, q-like, J ¼ 7:3 Hz, H-
20), 2.62 (1H, br s, 10-OH), 2.36 (1H, dd, J ¼ 13:2, 8.0 Hz, H-5b0), 2.17, 2.10,
1.77 (each 3H, s, 36OCOCH3); 13C NMR (CDCl3, 75 MHz): d 170.8, 170.4,
169.9 (36COCH3), 161.1 (C-6), 152.4 (C-4), 152.0 (C-2), 141.8 (C-8), 121.8
(C-5), 54.3 (6-OCH3), 79.0 (C-10), 67.9 (C-60), 61.1 (C-70), 60.7 (C-80), 55.3
(C-40), 49.3 (C-20), 41.9 (C-30), 39.4 (C-50), 20.9, 20.8, 20.4 (36COCH3); anal.
C 53.17%, H 5.76%, N 12.36% calcd for C20H26N4O8 (Mw 450.45),
C 53.33%, H 5.82%, N 12.44%.
(3S; 4R; 5S)-3-(6-Amino-purin-9-yl)-4,5-bis-hydroxymethyl-cyclopent-1-
enyl]-methanol (42). Triacetate 40 (0.66 g, 1.45 mmol) was dissolved in dry
CH2Cl2 (20 mL), and upon cooling to 0ꢁC, pyridine (4 mL) followed by a
solution of POCl2 (1.33 mL in 4 mL CH2Cl2) were added. After 48 h at room
temperature, EtOAc (150 mL) was added. Excess POCl3 was quenched by a
slow addition of saturated aqueous NaHCO3 (15 mL) under cooling to 0ꢁC.
Then H2O (10 mL) was added, and the organic layer was separated and
subsequently washed with more H2O (10 mL) and dried (Na2SO4). Con-
centration of the EtOAc phase yielded a residue that was dissolved in CH2Cl2
(3 mL) and loaded onto a VLC column (363 cm). Elution with hexane and
then hexaneꢀMe2CO (10:1 to 2:1) gave a slightly impure mixture of elim-
ination products (0.39 g, 61%; HRES-MSþ [MþH]þ 437.1265, calcd for
C19H22N4O6Cl 437.1228) followed by recovered 40 (85 mg, 13%). An aliquot
of the elimination products (0.28 g) was dissolved in THF (2 mL), and then
liquid NH3 (20 mL) was added. This solution was placed in a tube in a sealed
steel vessel and was heated to 60ꢁC for 5 days. After evaporation of the
solvents, the resulting residue was purified on an RP-18 column (size B),
which was eluted with H2OꢀMeOH mixtures (1:0 to 5:1). This afforded a

ANALOGUES OF CARBOVIR AND NEPLANOCIN A
33
5:1-mixture of cyclopentene triols 42 and 43 (0.17 g, 91%); HRFAB-MSþ
[MþH]þ 292.1380, calcd for C13H18N5O3 292.1409. Repeated rechromato-
graphy (H2O-MeOH 7:1) afforded a pure sample of 42: white hygroscopic
foam, [a]20 ꢀ 33.4 ꢁ(c 0.50, MeOH); 1H NMR (d6-DMSO, 500 MHz): d 8.16
D
(1H, s, H-8), 8.14 (1H, s, H-2), 7.17 (2H, br s, 6-NH2), 5.74 (1H, br s, H-20),
5.55 (1H, br d, J ¼ 7:7 Hz, H-30), 4.93 (1H, t, J ¼ 5:0 Hz, 60-OH), 4.78 (1H, t,
J ¼ 4:5 Hz, 80-OH), 4.51 (1H, t, J ¼ 5:0 Hz, 70-OH), 4.28, 4.14 (each 1H, dd,
J ¼ 15:0, 5.0 Hz, 26H-60), 3.66, 3.61 (each 1H, dt, J ¼ 11:1, 264.5 Hz,
26H-80), 3.28, 3.14 (each 1H, m, 26H-70), 2.89 (1H, m, H-40), 2.82 (1H, m,
H-50); 13C NMR (d6-DMSO, 75 MHz): d 155.9 (C-6), 152.1 (C-2), 150.0
(C-4), 139.8 (C-8), 118.4 (C-5), 154.2 (C-10), 121.4 (C-20), 59.2 (C-60), 59.0 (C-
80), 58.4 (C-30), 57.7 (C-70), 48.1 (C-50), 46.4 (C-40); anal. C 52.14%, H 5.92%,
N 23.35% calcd for C13H17N5O3ꢂ1=2H2O (Mw 291.31), C 51.99%, H 6.04%,
N 23.32%. [(30R,40S)-4-(6-Amino-purin-9-yl)-20,30-bis-hydroxymethyl-cyclo-
1
pent-10-enyl]-methanol (43): H NMR (d6-DMSO, 500 MHz): d 8.14 (1H, s,
H-2), 8.06 (1H, s, H-8), 7.16 (2H, br s, 6-NH2), 5.15 (1H, q-like, J ¼ 7:6 Hz,
H-40), 4.72 (1H, t, J ¼ 5:2 Hz, 60-OH), 4.68 (1H, t, J ¼ 5:3 Hz, 70-OH), 4.34
(1H, t, J ¼ 4:5 Hz, 80-OH), 4.20-4.00 (4H, m, 26H-60 and 26H-70), 3.22-3.14
(2H, m, 26H-80), 3.20 (1H, obsc., H-30), 3.11 (1H, br dd, J ¼ 15:8, 8.0 Hz, H-
5a0), 2.86 (1H, dd, J ¼ 15:8, 8.0 Hz, H-5b0); 13C NMR (d6-DMSO, 75 MHz):
d 155.9 (C-6), 152.0 (C-2), 149.6 (C-4), 140.4 (C-8), 118.6 (C-5), 137.8 (C-20),
136.2 (C-10), 58.7 (C-80), 56.7 (C-60), 55,7 (C-70), 53.9 (C-40), 51.4 (C-30), 37.9
(C-50).
(1S; 2R; 3R; 4S)-4-(6-Amino-purin-9-yl)-1,2,3-tris-hydroxymethyl-cyclo-
pentanol (44). Diacetonide 38 (0.80 g) was treated with NH3ꢀTHF (10:1,
22 mL) in a steel vessel at 60ꢁC for 48 h. The solvents were allowed to eva-
porate, and the residue was then dissolved in MeOH (40 mL) with 12M
aqueous HCl (0.6 mL) and stirred for 12 h at 4 ꢁC. The mixture was allowed
to warm to room temperature when more 12M aqueous HCl (0.5 mL) and
H2O (10 mL) were added. After an additional 3 h, the mixture was neu-
tralized with aqueous saturated NaHCO3. The MeOH was removed invacuo,
and the residual aqueous solution was then applied to an RP-18 column (size
C). Gradient elution with H2OꢀMeOH mixtures (1:0 to 8:1) yielded tetrol 44
(0.51 g, 84%). An analytical sample was obtained upon VLC with
1
CHCl3ꢀMeOH mixtures: white foam, [a]21 ꢀ 34.9ꢁ (c 0.41, MeOH); H
D
NMR (d6-DMSO, 500 MHz): d 8.19 (1H, s, H-2), 8.11 1H, s, H-8), 7.12 (2H,
br s, 6-NH2), 5.20 (1H, ddd, J ¼ 11:5, 8.5, 8.0 Hz, H-40), 4.75 (1H, t,
J ¼ 5:0 Hz, 60-OH), 4.66 (1H, t, J ¼ 5:5 Hz, 70-OH), 4.34 (1H, t, J ¼ 5:0 Hz,
80-OH), 3.76, 3.70 (each 1H, dt, J ¼ 10:9, 5.0 Hz, 26H-60), 3.57 (2H, m,
26H-70), 3.20 (1H, ddd, J ¼ 11:0, 7.7, 5.0 Hz, H-8a0), 3.06 (1H, dt, J ¼ 11:0,
265.0 Hz, H-8b0), 2.81 (1H, m, H-30), 2.65 (1H, dd, J ¼ 12:8, 11.5 Hz, H-
5a0), 2.22 (1H, dt, J ¼ 7:7, 266.0 Hz, H-20), 1.96 (1H, dd, J ¼ 12:8, 8.0 Hz,
H-5b0); 13C NMR (d6-DMSO, 75 MHz): d 155.9 (C-6), 152.1 (C-2), 150.1

34
FRANZYK ET AL.
(C-4), 140.1 (C-8), 119.0 (C-5), 79.8 (C-10), 65.4 (C-60), 57.7 (C-70þ), 57.5 (C-
80), 53.5 (C-40), 52.0 (C-20), 44.4 (C-30), 40.9 (C-50); HRFAB-MS [MþH]þ
310.1468, calcd for C13H20N5O4 310.1515.
(1S; 2R; 3R; 4S)-4-(6-Amino-purin-9-yl)-2,3-bis-hydroxymethyl-cyclopen-
tanol (45). Tetrol 44 (158 mg, 0.511 mmol) was treated with NaIO4
(118 mg, 0.552 mmol) in H2O (10 mL) at 0ꢁC for 0.5 h. This reaction mix-
ture was then added to a suspension of NaBH(OAc)3 (1.015 g, 4.79 mmol)
in MeCN (50 mL) at 0ꢁC. After 1 h, the cooling bath was removed, and
after an additional 2 h the reaction mixture was concentrated with MeOH
twice. The residue was dissolved in EtOHꢀMeOHꢀEt3N (4:4:1, 9 mL) and
loaded onto a VLC column (464 cm). Elution with hexane, CHCl3, and
then with CHCl3ꢀMeOH (10:1 to 3:1) yielded impure 45 (227 mg), which
was chromatographed on an RP-18 column (size B); elution with
H2OꢀMeOH (1:0, 10:1 to 5:1) afforded triol 45 (110 mg, 77%): white hy-
1
groscopic foam; [a]21D ꢀ 35.2 ꢁ (c 0.64, MeOH); H NMR (d4-methanol,
400 MHz): d 8.28 (1H, s, H-2), 8.20 (1H, s, H-8), 5.32 (1H, ddd, J ¼ 10:8,
9.2, 7.6 Hz, H-40), 4.37 (1H, ddd, J ¼ 9:0, 6.7, 2.9 Hz, H-10), 3.92 (1H, dd,
J ¼ 10:8, 5.3 Hz, H-6a0), 3.87 (1H, dd, J ¼ 10:8, 7.9 Hz, H-6b0), 3.53, 3.18
(each 1H, dd, J ¼ 11:7, 4.1 Hz, 26H-70), 3.02 (1H, ddd, J ¼ 13:4, 10.8,
9.0 Hz, H-5a0), 2.74 (1H, m, H-30), 2.38 (1H, m, H-20), 2.14 (1H, ddd,
1
J ¼ 13:4, 9.2, 2.9 Hz, H-5b0); H NMR (d6-DMSO, 500 MHz): d 8.16 (1H,
s, H-2), 8.11 (1H, s, H-8), 7.15 (2H, br s, 6-NH2), 5.14 (1H, br q-like,
J ¼ 9:4 Hz, H-40), 4.75 (1H, t, J ¼ 5:1 Hz, 10-OH), 4.56 (1H, t, J ¼ 4:5 Hz,
70-OH), 4.54 (1H, t, J ¼ 4:5 Hz, 60-OH), 4.12 (1H, m, H-10), 3.67 (2H, m,
26H-60), 3.26, 3.02 (each 1H, dt, J ¼ 11:1, 264.5 Hz, 26H-70), 2.81 (1H,
ddd, J ¼ 12:8, 10.7, 8.1 Hz, H-5a0), 2.56 (1H, m, H-30), 2.18 (1H, m, H-20),
1.95 (1H, ddd, J ¼ 12:8, 9.0, 2.6 Hz, H-5b0); 13C NMR (d6-DMSO,
75 MHz): d155.8 (C-6), 152.0 (C-2), 149.8 (C-4), 140.0 (C-8), 118.7 (C-5),
70.7 (C-10), 59.7 (C-60), 56.9 (C-70), 54.5 (C-40), 52.4 (C-20), 44.4 (C-30), 38.4
(C-50); HRFAB-MSþ [MþH]þ 280.1427, calcd for C12H18N5O3 280.1409;
anal. C 48.28%, H 6.31%, N 23.38% calcd for C12H17N5O3ꢂH2O (Mw
279.30), C 48.48%, H 6.44%, N 23.56%.
(1S; 3S; 4S; 5R)-1,6:7,8-bis-O-Isopropylidene-3-O-(40-nitrobenzoyl)-1,4,5-
tris-hydroxymethyl-cyclopentane-1,3-diol (46). Diacetonide 37 (3.39 g,
12.45 mmol), Ph3P (4.89 g, 1.5612.45 mmol) and p-NO2-BzOH (3.12 g,
1.5612.45 mmol) were dissolved in dry THF (100 mL), and then DEAD
(2.74 mL, 1.4612.45 mmol) in THF (5 mL) was added dropwise to the ice-
cooled mixture. After 0.5 h, the cooling bath was removed, and the mixture
was stirred for an additional 17 h at room temperature. The mixture was
concentrated, and the residue was dissolved in CH2Cl2 (20 mL) and loaded
onto a VLC column (767 cm). Elution with hexane and then hex-
aneꢀMe2CO (150:1 to 20:1) afforded successively cyclopentene 39 (0.44 g,

ANALOGUES OF CARBOVIR AND NEPLANOCIN A
35
14%) and 46 (4.34 g, 83%). Ester 46: white foam; [a]21D ꢃ 0ꢁ (c 1.2, MeOH);
1H NMR (CD3OD, 500 MHz): d 5.60 (1H, br q-like, J ¼ 7:3 Hz, H-3), 4.41,
3.91 (each 1H, d, J ¼ 9:0 Hz, 26H-6), 3.92 ꢀ 3.85 (3H, m, H-7a and 26H-8),
3.81 (1H, dd, J ¼ 12:8, 4.0 Hz, H-7b), 2.69 (1H, dq-like, J ¼ 367.5, 4.0 Hz,
H-4), 2.47 (1H, dd, J ¼ 14:5, 7.7 Hz, H-2a), 2.30 (1H, m, H-5), 2.13 (1H, dd,
J ¼ 14:5, 7.0 Hz, H-2b), 1.38, 1.37, 1.30, 1.23 (each 3H, s, 26(CH3)2C<),
8.32, 8.24 (each 2H, br d, J ¼ 9:0 Hz, p-NO2-Ph-CO); 13C NMR (CD3OD,
75 MHz): d 165.7 (p-NO2-Ph-CO), 152.0, 136.9, 131.8, 124.6 (p-NO2-Ph-CO),
109.4, 102.9 (26(CH3)2C<), 88.1 (C-1), 76.8 (C-3), 71.6 (C-6), 60.7 (C-8),
60.6 (C-7), 51.9 (C-5), 46.4 (C-4), 44.9 (C-2), 27.1, 27.0, 25.4, 24.2
(26(CH3)2C<); anal. C 59.89%, H 6.41%, N 3.35% calcd for C21H27NO8
(Mw 421.45), C 59.85%, H 6.46%, N 3.32%.
(1S; 3S; 4S; 5R)-1,6:7,8-bis-O-Isopropylidene-1,4,5-tris-hydroxymethyl-
cyclopentane-1,3-diol (47). The ester 46 (4.11 g, 9.75 mmol) was dissolved
in MeOH (100 mL) and 1M methanolic NaOMe (3 mL) was added. After 1 h
at room temperature, the mixture was neutralized with HOAc (0.15 mL) and
then concentrated. The residue was dissolved in EtOAc (100 mL), and HOAc
(50 mL) followed by Et3N (2 mL) were added. The mixture was then washed
with H2O (25 mL), dried (Na2SO4) and concentrated. The residue was sus-
pended in CH2Cl2 (30 mL) and loaded onto a VLC column (667 cm). Elu-
tion with hexane followed by hexaneꢀMe2CO (30:1 to 5:1) gave alcohol 47
(2.55 g, 96%): white foam; [a]21D þ48.3ꢁ (c 0.60, MeOH); 1H NMR (CD3OD,
500 MHz): d 4.44 (1H, d, J ¼ 9:0 Hz, H-6a), 4.39 (1H, dt, J ¼ 8:5, 267.3 Hz,
H-3), 3.93, 3.85 (each 1H, dd, J ¼ 13:0, 3.4 Hz, 26H-8), 3.83 (1H, d,
J ¼ 9:0 Hz, H-6b), 3.77 (1H, dd, J ¼ 12:8, 5.4 Hz, H-7a), 3.73 (1H, dd,
J ¼ 12:8, 10.0 Hz, H-7b), 2.38 (1H, m, H-4), 2.16 (1H, dd, J ¼ 14:1, 7.3 Hz,
H-2a), 2.16 (1H, obsc., H-5), 1.85 (1H, dd, J ¼ 14:1, 8.5 Hz, H-2b), 1.35,
1.34, 1.31, 1.30 (each 3H, s, 26(CH3)2C<); 13C NMR (CD3OD, 75 MHz):
d108.9, 102.9 (26(CH3)2C <), 88.3 (C-1), 72.6 (C-6), 72.1 (C-3), 61.1 (C-7),
60.3 (C-8), 51.7 (C-5), 48.0 (C-4), 47.3 (C-2), 27.2, 26.8, 25.3, 24.5
(26(CH3)2C<); anal. C 61.58%, H 8.86%, calcd for C14H24O5 (Mw 272.34),
C 61.74%, H 8.88%.
(1S; 2R; 3R; 4R)-1,6:7,8-bis-O-Isopropylidene-4-(6-amino-purin-9-yl)-1,2,3-
tris-hydroxymethyl-cyclopentanol (50). To a solution of alcohol 47 (1.98 g,
7.27 mmol), Ph3P (3.81 g, 267.27 mmol) and 6-chloropurine (2.25 g,
267.27 mmol) in dry THF (20 mL) was slowly added a solution of DEAD
(2.17 mL, 1.967.27 mmol) in dry THF (5 mL). The mixture was kept at
room temperature for 1.5 h and subsequently at 4 ꢁC for 22 h, at which point
the reaction mixture was concentrated. The residue was dissolved in CH2Cl2
(15 mL) and loaded onto a VLC column (665 cm). Gradient elution with
hexane and then hexaneꢀMe2CO (50:1 to 8:1) yielded impure fractions of
48 (1.69 g) and 49 (0.88 g), which were purified by repeated VLC to give

36
FRANZYK ET AL.
pure 48 (hexaneꢀMe2CO 100:1, 1.10 g, 59%), slightly impure 49 (hex-
aneꢀMe2CO 10:1, 0.51 g, 17%; still contaminated with a small amount of
hydrazine diethyldicarboxylate), and recovered 47 (hexaneꢀMe2CO 10:1,
86 mg, 4%). (1S; 2R)-1,6:7,8-Bis-O-isopropylidene-1,2,3-tris-hydroxymethyl-
1
cyclopent-3-enol (48): colorless syrup; [a]24Dþ23.6 ꢁ (c 1.1, MeOH); H
NMR (CD3OD, 500 MHz): d 5.48 (1H, m, H-4), 4.24 (1H, ddq, J ¼ 13:7,
3.0, 361.5 Hz, H-8a), 4.02 (1H, d, J ¼ 9:0 Hz, H-6a), 4.00 (1H, d,
J ¼ 13:7 Hz, H-8b), 3.81 (1H, dd, J ¼ 11:5, 5.1 Hz, H-7a), 3.70 (1H, dd,
J ¼ 11:5, 10.7 Hz, H-7b), 3.70 (1H, d, J ¼ 9:0 Hz, H-6b), 2.97 (1H, m, H-2),
2.63 (1H, ddt, J ¼ 16:4, 3.8, 262.1 Hz, H-5a), 2.51 (1H, ddt, J ¼ 16:4, 2.6,
261.3 Hz, H-5b), 1.37, 1.35, 1.34, 1.33 (each 3H, s, 26(CH3)2C<); 13C
NMR (CD3OD, 75 MHz): d 144.4 (C-3), 124.1 (C-4), 109.7, 103.6
(26(CH3)2C<), 90.4 (C-1), 71.6 (C-6), 62.2 (C-8), 61.8 (C-7), 56.3 (C-2),
45.5 (C-5), 27.1, 26.8, 25.2, 24.8 (26(CH3)2C<); anal. C 65.94%, H 8.99%,
1
calcd for C14H22O4 (Mw 254.32), C 66.12%, H 8.72%. Diacetonide 49: H
NMR (CD3OD, 500 MHz): d 8.75 (1H, s, H-2), 8.74 (1H, s, H-8), 5.47 (1H,
ddd, J ¼ 10:9, 8.1, 4.3 Hz, H-40), 4.20, (1H, d, J ¼ 9:4 Hz, H-6a0), 3.95 (1H,
dd, J ¼ 13:2, 2.1 Hz, H-8a0), 3.90 (1H, d, J ¼ 9:4 Hz, H-6b0), 3.72 (1H, dd,
J ¼ 12:4, 10.2, H-7a0), 3.64 (1H, br dd, J ¼ 12:4, 4.5 Hz, H-7b0), 3.49 (1H,
dd, J ¼ 13:2, 3.8 Hz, H-8b0), 2.81 (1H, m, H-30), 2.72 (1H, dd, J ¼ 14:9,
10.9 Hz, H-5a0), 2.50 (1H, m, H-20), 2.28 (1H, ddd, J ¼ 14:9, 4.3, 1.7 Hz, H-
5b0), 1.48, 1.45, 1.39, 1.33 (each 3H, s, 26(CH3)2C<); 13C NMR (CD3OD,
75 MHz): d 153.5 (C-6), 152.9 (C-2), 151.2 (C-4), 147.1 (C-8), 132.1 (C-5),
110.5, 103.2 (26(CH3)2C <), 89.3 (C-10), 69.3 (C-60), 60.6 (C-70), 60.5 (C-
80), 54.8 (C-40), 53.4 (C-20), 52.4 (C-30), 44.1 (C-50), 27.5, 26.9 25.2, 24.6
(26(CH3)2C<); FAB-MSþ [MþH]þ 409.16, calcd for C19H26N4O4Cl
409.16. An aliquot of 49 (386 mg, 0.94 mmol) was treated with NH3 (20 mL)
in THF (5 mL) at 60ꢁC for 3 days. The solvents were allowed to evaporate,
and the residue was dissolved in EtOAc (10 mL) and loaded onto a VLC
column (464 cm). Elution with hexane and then hexaneꢀMe2CO (3:1 to
1.5:1) afforded (adenin-9-yl)-derivative 50 (326 mg, 89%): mp 218ꢀ220ꢁC
1
(hexaneꢀMe2CO); [a]24 ꢀ 23.9 ꢁ (c 0.60, MeOH); H NMR (CD3OD,
D
500 MHz): (8.35 (1H, s, H-2), 8.21 (1H, s, H-8), 5.29 (1H, ddd, J ¼ 10:2, 8.1,
4.3 Hz, H-40), 4.18 (1H, d, J ¼ 9:4 Hz, H-6a0), 3.94 (1H, dd, J ¼ 12:8,
2.6 Hz, H-8a0), 3.88 (1H, d, J ¼ 9:4 Hz, H-6b0), 3.71 (1H, dd, J ¼ 12:6,
10.0 Hz, H-7a0), 3.63 (1H, dd, J ¼ 12:6, 4.5 Hz, H-7b0), 3.47 (1H, dd,
J ¼ 12:8, 4.0, H-8b0), 2.77 (1H, m, H-30), 2.67 (1H, dd, J ¼ 14:9, 10.2 Hz, H-
5a0), 2.47 (1H, m, H-20), 2.18 (1H, ddd, J ¼ 14:9, 4.3, 1.7 Hz, H-5b0), 1.45,
1.43, 1.37, 1.33 (each 3H, s, 26(CH3)2C<); 13C NMR (CD3OD, 75 MHz):
d 157.3 (C-6), 153.7 (C-2), 151.0 (C-4), 141.4 (C-8), 119.8 (C-5), 110.4, 103.1
(26(CH3)2C <), 89.3 (C-10), 69.5 (C-60), 60.6 (C-70), 60.5 (C-80), 53.9 (C-40),
53.3 (C-20), 52.2 (C-30), 44.5 (C-50), 27.5, 26.9, 25.2, 24.6 (26(CH3)2C<);
anal. C 58.63%, H 6.99%, N 17.92% calcd for C19H27N5O4 (Mw 389.46), C
58.60%, H 6.99%, N 17.98%.

ANALOGUES OF CARBOVIR AND NEPLANOCIN A
37
(1S; 2R; 3R; 4R)-6,7,8-Tri-O-acetyl-4-(6-benzamido-purin-9-yl)-1,2,3-tris-
hydroxymethyl-cyclopentanol (52). (Adenin-9-yl)-derivative 50 (205 mg,
0526 mmol) was dissolved in pyridine (3 mL), and upon cooling to 0ꢁC, BzCl
(125 mL, 260526 mmol) in pyridine (0.5 mL) was added dropwise. After 0.5 h
at 0ꢁC the cooling bath was removed. Upon an additional 1.5 h the mixture
was cooled to 0ꢁC, and then H2O (0.5 mL) was added. After a further 5 min,
25% aqueous ammonia (1 mL) was added. The mixture was then stirred for
0.5 h at 0ꢁC followed by 15 min at room temperature, when EtOAc (50 mL)
and saturated aqueous NaHCO3 (50 mL) were added. The organic layer was
washed with H2O (2625 mL), dried (Na2SO4) and concentrated with
toluene. The residue was dissolved in CH2Cl2 (4 mL) and loaded onto a VLC
column (463 cm). Elution with hexane, and then with hexaneꢀMe2CO (5:1
to 3:1) gave an impure fraction of 51 (237 mg), which was rechromato-
graphed to give almost pure 51 (205 mg, 79%): 1H NMR (CD3OD,
500 MHz): d 8.72 (1H, s, H-2), 8.63 (1H, s, H-8), 8.09 (2H, br d, J ¼ 7:3 Hz,
NH-CO-Ph), 7.66 (1H, br t, J ¼ 7:3 Hz, NH-CO-Ph), 7.57 (2H, br t,
J ¼ 7:3 Hz, NH-CO-Ph), 5.47 (1H, ddd, J ¼ 10:7, 8.0, 4.0 Hz, H-40), 4.20
(1H, d, J ¼ 9:4 Hz, H-6a0), 3.97 (1H, dd, J ¼ 13:0, 2.6 Hz, H-8a0), 3.91 (1H,
d, J ¼ 9:4 Hz, H-6b0), 3.74 (1H, dd, J ¼ 12:6, 10.2 Hz, H-7a0), 3.65 (1H, dd,
J ¼ 12:6, 4.3 Hz, H-7b0), 3.51 (1H, dd, J ¼ 13:0, 3.9 Hz, H-8b0), 2.81 (1H, m,
H-30), 2.73 (1H, dd, J ¼ 15:4, 10.7 Hz, H-5a0), 2.50 (1H, m, H-20), 2.27 (1H,
ddd, J ¼ 15:4, 4.0, 1.3 Hz, H-5b0), 1.48, 1.45, 1.40, 1.34 (each 3H, s,
26(CH3)2C<); 13C NMR (CD3OD, 75 MHz):d 168.1 (Ph-CO-NH), 153.9
(C-4), 153.1 (C-2), 150.9 (C-6), 144.7 (C-8), 124.7 (C-5), 135.0, 133.8, 129.7,
129.4 (Ph-CO-NH), 110.4, 103.2 (26(CH3)2C<), 89.3 (C-10), 69.4 (C-60),
60.6 (C-70), 60.5 (C-80), 54.2 (C-40), 53.4 (C-20), 52.4 (C-30), 44.2 (C-50), 27.5,
26.9, 25.2, 24.6 (26(CH3)2C<); HRFAB-MSþ [MþH]þ 494.2420, calcd for
C26H32N5O5 494.2403. An aliquot of 51 (154 mg) was treated with 12M
aqueous HCl (0.14 mL) in MeOH (7 mL) for 3 h at room temperature, when
additional 12M aqueous HCl (0.14 mL) was added. After a further 3.5 h at
room temperature, pyridine (1 mL) was added, and the mixture concentrated.
The residue was dried on an oil-pump for 0.5 h, and then it was partially
dissolved in pyridineꢀCH2Cl2 (3:2, 5 mL). After addition of Ac2O (3 mL) the
mixture was kept at room temperature for 2 h, when ice and saturated
aqueous NaHCO3 (25 g and 50 mL, respectively) were added. Then EtOAc
(100 mL) was added, and the organic layer was washed with more saturated
NaHCO3 (25 mL). The organic phase was dried (Na2SO4) and concentrated.
The residue was subsequently concentrated with toluene and CH2Cl2. The
residue (190 mg) was dissolved in CH2Cl2 (4 mL) and loaded onto a VLC
column (3.563 cm). Elution with hexane, and then hexaneꢀMe2CO (4:1 to
1
1:1) afforded triacetate 52 (127 mg, 76%): [a]20 þ7.9 ꢁ (c 0.89, MeOH); H
D
NMR (CDCl3, 300 MHz): d 8.73 (1H, s, H-2), 8.24 (1H, s, H-8), 8.01 (2H, br
d, J ¼ 7:5 Hz, NH-CO-Ph), 7.59 (1H, br t, J ¼ 7:5 Hz, NH-CO-Ph), 7.49
(2H, br t, J ¼ 7:5 Hz, NH-CO-Ph), 4.94 (1H, ddd, J ¼ 11:8, 9.6, 3.4 Hz,

38
FRANZYK ET AL.
H-40), 4.37 (1H, d, J ¼ 11:6 Hz, H-6a0), 4.22 (3H, m, H-7a and 26H-80), 4.11
(1H, d, J ¼ 11:6 Hz, H-6b0), 4.10 (1H, dd, J ¼ 12:4, 4.5 Hz, H-7b0), 3.50 (1H,
m, H-30), 2.72 (1H, dd, J ¼ 15:6, 11.8 Hz, H-5a0), 2.68 (1H, m, H-20), 2.33
(1H, ddd, J ¼ 15:6, 3.4, 1.8 Hz, H-5b0), 2.14, 2.11, 1.81 (each 3H, s,
36OCOCH3); 13C NMR (CDCl3, 75 MHz): d 170.9, 170.5, 170.0 (36CH3-
CO), 164.8 (Ph-CO), 151.6 (C-2), 150.3 (C-4), 150.0 (C-6), 143.4 (C-8), 123.4
(C-5), 133.3, 132.9, 128.8, 127.9 (Ph-CO), 80.3 (C-10), 67.3 (C-60), 63.0 (C-80),
61.0 (C-70), 58.2 (C-40), 49.3 (C-20), 45.4 (C-30), 42.0 (C-50), 21.1, 20.8, 20.6
(36CH3-CO); HRFAB-MSþ [MþH]þ 540.2048, calcd for C26H30N5O8
540.2094.
[(3R; 4R; 5S)-3-(6-Amino-purin-9-yl)-4,5-bis-hydroxymethyl-cyclopent-1-
enyl]-methanol (53). Triacetate 52 (92 mg, 0.171 mmol) was dissolved in dry
CH2Cl2ꢀpyridine (2:1, 6 mL). After cooling to 0 ꢁC, POCl3 (160 mL,
1060.171 mmol) in dry CH2Cl2 (1 mL) was added, and the cooling bath
removed. After 23 h at room temperature more POCl3 (80 mL,
560.171 mmol) was added. The mixture was kept at room temperature for 2
days more when it was poured into iceꢀsaturated aqueous NaHCO3 (15 g
and 30 mL, respectively) under stirring. The resulting mixture was extracted
with EtOAc (2650 mL). The combined organic layers were washed with
brine (20 mL), dried (Na2SO4) and concentrated. The residue was con-
centrated successively with toluene and CH2Cl2, and was then dissolved in
CH2Cl2 (4 mL) and loaded onto a VLC column (3.563 cm). Elution with
hexane and then with hexane-Me2CO (5:1 to 3.5:1) gave almost pure elim-
ination product (34 mg), which was treated with 0.1M NaOMeꢀMeOH
(5 mL) for 3.5 h at room temperature followed by 1.5 h at 45ꢁC. Then HOAc
(50 mL) followed by Et3N (50 mL) were added. The mixture was concentrated,
and the residue was dissolved in saturated aqueous NaHCO3 (3 mL) and
loaded onto an RP-18 column (size B), which was eluted with H2OꢀMeOH
(1:0, 6:1 and 5:1) to give triol 53 (17 mg, 34%): white solid; [a]20D ꢀ 126 ꢁ (c
0.53, MeOH); 1H NMR (D2O, 500 MHz): d 8.06 (1H, s, H-8), 8.05 (1H, s, H-
2), 5.79 (1H, br s, H-20), 5.38 (1H, dm, J ¼ 8:1 Hz, H-30), 4.27, 4.23 (each 1H,
br d, J ¼ 15:4 Hz, 26H-60), 3.88 (1H, dd, J ¼ 11:5, 7.9 Hz, H-7a0), 3.75 (2H,
m, 26H-80), 3.73 (1H, dd, J ¼ 11:5, 6.0 Hz, H-7b0), 3.07 (1H, m, H-50), 2.74
(1H, dq-like, J ¼ 368.0, 6.0 Hz, H-40); 13C NMR (CD3OD, 75 MHz): d157.3
(C-6), 153.5 (C-2), 150.7 (C-4), 141.1 (C-8), 120.3 (C-5), 151.8 (C-10), 125.9
(C-20), 63.1 (C-30), 61.1 (C-70), 60.8 (C-60 and C-80), 54.0 (C-40), 49.7 (C-50);
HRFAB-MSþ [MþH]þ 292.1388, calcd for C13H18N5O3 292.1409.
ACKNOWLEDGMENTS
This work was supported by the Danish National Research Councils
(grant. no. 9501145) to H.F. and J.H.R. We thank Dr. C. Nielsen for per-
forming the antiviral tests.

ANALOGUES OF CARBOVIR AND NEPLANOCIN A
39
REFERENCES
1. Mansour, T.S.; Storer, R. Antiviral Nucleosides. Curr. Pharm. Design 1997, 3,
227ꢀ264.
2. Vince, R.; Hua, M. Synthesis and Anti-HIV Activity of Carbocyclic 20,30-Dide-
hydro-20,30-dideoxy 2,6-Disubstituted Purine Nucleosides. J. Med. Chem. 1990,
33, 17ꢀ21.
3. Katagiri, N.; Toyota, A.; Shiraishi, T.; Sato, H.; Kaneko, C. Synthesis
of (1R; 4S; 5R)-9-(4,5-Bishydroxymethylcyclopent-2-en-1-yl)-9H-adenine [( ꢀ )-
BCA] and Selective Inhibition of Human Immunodeficiency Virus. Tetrahedron
Lett. 1992, 33, 3507ꢀ3510.
4. Arita, M.; Adachi, K.; Ito, Y.; Sawai, H.; Ohno, M. Enantioselective Synthesis
of the Carbocyclic Nucleosides ( ꢀ )-Aristeromycin and ( ꢀ )-Neplanocin A by a
Chemicoenzymatic Approach. J. Am. Chem. Soc. 1983, 105, 4049ꢀ4055.
5. Trost, B.M.; Madsen, R.; Guile, S.D.; Brown, B. Palladium-Catalyzed Enan-
tioselective Synthesis of Carbanucleosides. J. Am. Chem. Soc. 2000, 122,
5947ꢀ5956.
6. Yoshida, N.; Kamikubo, T.; Ogasawara, K. A Concise Synthesis of ( ꢀ )-
Neplanocin A. Tetrahedron Lett. 1998, 39, 4677ꢀ4678.
7. Crimmins, M.T. New Developments in the Enantioselective Synthesis of Cyclo-
pentyl Carbocyclic Nucleosides. Tetrahedron 1998, 54, 9229ꢀ9272.
8. Zhu, X.-F. The Latest Progress in the Synthesis of Carbocyclic Nucleosides.
Nucleosides, Nucleotides & Nucleic Acids 2000, 19, 651ꢀ690.
9. Crimmins, M.T.; Zuercher, W.J. Solid-Phase Synthesis of Carbocyclic
Nucleosides. Org. Letters 2000, 2, 1065ꢀ1067.
10. Taylor, S.J.C.; Sutherland, A.G.; Lee, C.; Wisdom, R.; Thomas, S.; Roberts,
S.M.; Evans, C. Chemoenzymatic Synthesis of ( ꢀ )-Carbovir Utilizing a Whole
Cell Catalysed Resolution of 2-Azabicyclo[2.2.1]hept-5-en-3-one. J. Chem. Soc.,
Chem. Commun. 1990, 1120ꢀ1121.
11. Brown, B.; Hegedus, L.S. A Novel, One-Pot Ring Expansion of Cyclobutanones.
Synthesis of Carbovir and Aristeromycin. J.Org.Chem. 2000, 65, 1865ꢀ1872.
12. Vince, R.; Kilama, J.; Pham, P.T.; Beers, S.A. 6-Substituted Derivatives of Car-
bovir: Anti-HIV Activity. Nucleosides & Nucleotides 1995, 14, 1703ꢀ1708.
13. Daluge, S.M.; Martin, M.T.; Sickles, B.R.; Livingston, D.A. An Efficient, Scal-
able Synthesis of the HIV Reverse Transcriptase Inhibitor Ziagen1 (1592U89).
Nucleosides, Nucleotides & Nucleic Acids 2000, 19, 297ꢀ327.
14. Olivo, H.F.; Yu, J. Enantioselective Syntheses of 50-homo-Carbocyclic Nucleo-
sides. Tetrahedron: Asymmetry 1997, 8, 3785ꢀ3788.
15. An, G.; Rhee, H. A Facile Synthesis of cis-9-[4-(1,2-Dihydroxyethyl)-cyclo-
pent-2-enyl]guanine and its Derivative. Nucleosides, Nucleotides & NucleicAcids
2000, 19, 1111ꢀ1122.
16. Toyota, A.; Nishimura, A.; Kaneko, C. a-Fluorination of 6-Phenylsulfinyl-2-
azabicyclo[2.2.1]heptan-3-one and Synthesis of 20-Fluoro Substituted Carbovir.
Tetrahedron Lett. 1998, 39, 4687ꢀ4690.
17. Toyota, A.; Nishimura, A.; Kaneko, C. Stereoselectivity in Addition of Phenyl-
selenyl Chloride to Bicyclo[2.2.1]hept-2-ene derivatives and Synthesis of
30-Chloro Substituted Carbovir. Heterocycles 1997, 45, 2105ꢀ2108.

40
FRANZYK ET AL.
18. Wachtmeister, J.; Classon, B.; Samuelsson, B.; Kvarnstrom, I. Synthesis of
¨
20,30-Dideoxycyclo-20-pentenyl-30-C-hydroxymethyl Carbocyclic Nucleoside
Analogues as Potential Anti-viral Agents. Tetrahedron 1995, 51, 2029ꢀ2038.
19. Dyatkina, N.; Costisella, B.; Theil, F.; von Janta-Lipinski, M. Synthesis of the
Four Possible Stereoisomeric 50-Nor Carbocyclic Nucleosides from One Com-
mon Enantiomerically Pure Starting Material. Tetrahedron Lett. 1994, 35,
1961ꢀ1964.
20. Mulvihill, M.J.; Miller, M.J. Syntheses of Novel Hydroxylamine Carbanucleo-
sides. Tetrahedron 1998, 54, 6605ꢀ6626.
21. Ghosh, A.; Ritter, A.R.; Miller, M.J. Synthesis of Enantiomerically Pure 50-
Aza Noraristeromycin Analogs. J. Org. Chem. 1995, 60, 5808ꢀ5813.
22. Balo, C.; Blanco, J.M.; Fernandez, F.; Lens, E.; Lopez, C. Synthesis of Novel
´ ´
Carbocyclic Nucleosides with a Cyclopentenyl Ring: Homocarbovir and Ana-
logues. Tetrahedron 1998, 54, 2833ꢀ2842.
23. Besada, P.; Santana, L.; Teijeira, M.; Uriarte, E. Nucleoside Analogues of Pur-
ine with a 1,2-Disubstituted Cyclopentene Ring. Nucleosides & Nucleotides
1999, 18, 725ꢀ726.
24. Katagiri, N.; Nomura, M.; Sato, H.; Tameda, C.; Kurimoto, A.; Arai, S.;
Toyota, A.; Kaneko, C. Synthesis of Purine Bases Having a Di(hydroxy-
methyl)cyclopentenyl Group by Means of High-Pressure Reaction and their
Anti-HIV Activity. Nucleic Acids Symp. Ser. 1991, 27, 5ꢀ6.
25. Kato, K.; Suzuki, H.; Tanaka, H.; Miyasaka, T.; Baba, M.; Yamaguchi, K.;
Akita, H. Stereoselective Synthesis of 40-a-Alkylcarbovir Derivatives Based
on an Asymmetric Synthesis or Chemoenzymatic Procedure. Chem. Pharm.
Bull. 1999, 47, 1256ꢀ1264.
26. Wang, P.; Gullen, B.; Newton, M.G.; Cheng. Y.; Schinazi, R.F.; Chu, C.K.
Asymmetric Synthesis and Antiviral Activities of L-Carbocyclic 20,30-Didehy-
dro-20,30-dideoxy and 20,30-Dideoxy Nucleosides. J. Med. Chem. 1999, 42,
3390ꢀ3399.
27. Da Silva, A.D.; Coimbra, E.S.; Fourrey, J.-L.; Machado, A.S.; Robert-Gero,
´
M. Expeditious Enantioselective Synthesis of Carbocyclic Nucleosides with
Antileishmanial Activity. Tetrahedron Lett. 1993, 34, 6745ꢀ6748.
28. Borcherding, D.R.; Scholtz, S.A.; Borchardt, R.T. Synthesis of Analogues of
Neplanocin A: Utilization of Optically Active Dihydroxycyclopentenones
Derived from Carbohydrates. J. Org. Chem. 1987, 52, 5457ꢀ5461.
29. Shuto, S.; Obara, T.; Toriya, M.; Hosoya, M.; Snoeck, R.; Andrei, G.; Balzar-
ini, J.; De Clerq, E. New Neplanocin Analogues. 1. Synthesis of 60-Modified
Neplanocin A Derivatives as Broad-Spectrum Antiviral Agents. J. Med. Chem.
1992, 35, 324ꢀ331.
30. Shuto, S.; Obara, T.; Saito, Y.; Andrei, G.; Snoeck, R.; De Clerq, E.;
Matsuda, A. New Neplanocin Analogues. 6. Synthesis and Potent Antiviral
Activity of 60-Homoneplanocin A. J. Med. Chem. 1996, 39, 2392ꢀ2399.
31. Shuto, S.; Obara, T.; Saito, Y.; Yamashita, K.; Tanaka, M.; Sasaki, T.; Andrei,
G.; Snoeck, R.; Neyts, J.; Padalko, E.; Balzarini, J.; De Clerq, E.; Matsuda, A.
New Neplanocin Analogues. VIII. Synthesis and Biological Activity of 60-C-
Ethyl, -Ethenyl, and -Ethynyl Derivatives of Neplanocin A. Chem. Pharm.
Bull. 1997, 45, 1163ꢀ1168.

ANALOGUES OF CARBOVIR AND NEPLANOCIN A
41
32. Shuto, S.; Niizuma, S.; Matsuda, A. One-Pot Conversion of a,b-Unsaturated
Alcohols into the Corresponding Carbon-Elongated Dienes with a Stable Phos-
phorus YlideꢀBaMnO4 System. Synthesis of 60-Methylene Derivatives of Ne-
planocin A as Potential Antiviral Nucleosides. New Neplanocin Analogues.
11. J. Org. Chem. 1998, 63, 4489ꢀ4493.
33. Obara, T.; Shuto, S.; Saito, Y.; Toriya, M.; Ogawa, K.; Yaginuma, S.; Shigeta,
S.; Matsuda, A. New Neplanocin Analogues. V. A Potent Adenosylhomocys-
teine Hydrolase Inhibitor Lacking Antiviral Activity. Synthesis and Antiviral
Activity of 60-Carboxylic Acid Derivatives of Neplanocin A. Nucleosides &
Nucleotides 1996, 15, 1157ꢀ1167.
34. Hegedus, L.S.; Geisler, L. Synthesis of (þ)-Neplanocin A from a Chromium-
Carbene Complex-Derived Optically Active Butenolide. J. Org. Chem. 2000,
65, 4200ꢀ4203.
35. Biggadike, K.; Borthwick; A.D. 40-Modification of Carbocyclic Nucleosides:
Synthesis of 40-a-Fluoro, 40-a-Hydroxy and 40,60-Unsaturated Derivatives of
the Antiviral Agent 20-ara-Fluoro Carbocyclic Guanosine. J. Chem. Soc.,
Chem. Commun. 1990, 1380ꢀ1382.
36. Kraus, G.A.; Begey, T.; Wang, X. Synthesis of a Novel Carbocyclic Nucleo-
side. Nucleosides & Nucleotides 1997, 16, 1961ꢀ1965.
37. Marquez, V.E.; Tseng, C.K.H.; Treanor, S.P.; Driscoll, J.S. Synthesis of 20,30-
Dideoxycyclopentenyl Carbocyclic Nucleosides as Potential Drugs for the
Treatment of AIDS. Nucleosides & Nucleotides 1987, 6, 239ꢀ244.
38. Arita, M.; Okumoto, T.; Saito, T.; Hoshino, Y.; Fukukawa, K.; Shuto, S.; Tsuji-
no, M.; Sakakibara, H.; Ohno, M. Enantioselective Synthesis of New Analogs of
Neplanocin A and their Biological Activity. Carbohydr.Res. 1987,171, 233ꢀ258.
39. Marquez, V.E.; Bodenteich, M. Psicoplanocin A. A Synthetic Carbocyclic Nu-
cleoside with the Combined Structural Features of Neplanocin A and Psicofur-
anine. Nucleosides & Nucleotides 1991, 10, 311ꢀ314.
40. Bindu Madhavan, G.V.; McGee, D.P.C.; Rydzewski, R.M.; Boehme, R.;
Martin, J.C.; Prisbe, E.J. Synthesis and Antiviral Evaluation of 60-Substituted
Aristeromycins: Potential Mechanism-Based Inhibitors of S-Adenosylhomo-
cysteine Hydrolase. J. Med. Chem. 1988, 31, 1798ꢀ1804.
41. Buenger, G.S.; Marquez, V.E. Carbocyclic Ring-Enlarged Oxetanocin Analo-
gues. Tetrahedron Lett. 1992, 33, 3707ꢀ3710.
42. Boumchita, H.; Legraverend, M.; Bisagni, E. Synthesis of Ring-Enlarged
Cyclobut-A and Cyclobut-G Analogues as HIV Inhibitors. Part 4. Hetero-
cycles 1991, 32, 1785ꢀ1792.
43. Bonnal, C.; Chavis, C.; Lucas, M. Synthesis of meso-20,30-Dideoxy-30b-hydro-
xymethyl Carbocyclic Nucleosides as Potential Antiviral Drugs. Unusual Com-
petitive 2-O- versus N1-Alkylation of 3-Substituted Pyrimidines under
Mitsunobu Conditions. J. Chem. Soc., Perkin Trans 1 1994, 1401ꢀ1410.
44. Rosenquist, A.; Kvarnstrom, I.; Svensson, S.C.T.; Classon, B.; Samuelsson, B.
¨
Synthesis of Carbocyclic 20,30-Dideoxy-20-C-hydroxymethyl Nucleosides as Po-
tential Inhibitors of HIV. J. Org. Chem. 1994, 59, 1779ꢀ1782.
45. Wachtmeister, J.; Classon, B.; Kvarnstrom, I.; Samuelsson, B. Synthesis of
¨
Novel Fluoro Carbocyclic Purine Nucleoside Analogues. Nucleosides & Nu-
cleotides 1997, 16, 809ꢀ814.

42
FRANZYK ET AL.
46. Wachtmeister, J.; Muhlman; A.; Classon, B.; Samuelsson, B. Synthesis of 4-
¨
Substituted Carbocyclic 2,3-Dideoxy-3-C-hydroxymethyl Nucleoside Analo-
gues as Potential Anti-viral Agents. Tetrahedron 1999, 55, 10,761ꢀ10,770.
47. Legraverend, M.; Huel, C.; Bisagni, E. Synthesis of ( ꢄ )-Carbocyclic-30-deoxy-
40-(hydroxymethyl)-adenosine and ( ꢄ )-Carbocyclic-30-deoxy-40-(hydroxy-
methyl)-guanosine as Potential Antiviral Agents. J. Chem. Res. (S) 1990,
102ꢀ103.
0
48. Hrebabecky , H.; Holy´
, A. Synthesis of Carba Analogues o-fD2eoxy-40-C-
´
(hydroxymethyl)nucleosides. Collect. Czech. Chem. Commun. 1999, 64,
1485ꢀ1496.
49. Roy, A.; Chakrabarty, K.; Dutta, P.K.; Bar, N.C.; Basu, N.; Achari, B.;
Mandal, S.B. Chiral Carbocyclic Nucleosides from D-Glucose: Enantiodiver-
gent Synthesis and One-Pot Entry of Dimethylamino Functionality in the Pur-
ine Rings. J. Org. Chem. 1999, 64, 2304ꢀ2309.
50. Bianco, A.; Mazzei, R.A. Synthesis of a New Carbocyclic Nucleoside Analog.
Tetrahedron Lett. 1997, 38, 6433ꢀ6436.
51. Franzyk, H.; Rasmussen, J.H.; Mazzei, R.A.; Jensen, S.R. Synthesis of
Carbocyclic Homo-N-Nucleosides from Iridoids. Eur. J. Org. Chem. 1998,
2931ꢀ2935.
52. Franzyk, H.; Stermitz, F.R. Stereoselective Hydrogenation and Ozonolysis of
Iridoids. Conversion into Carbocyclic Nucleoside Analogues. J. Nat. Prod.
1999, 62, 1646ꢀ1654.
53. Franzyk, H. Synthetic Aspects of Iridoid Chemistry. In: Herz, W.; Falk, H.;
Kirby, G.W.; Moore, R.E. (eds) Prog. Chem. Org. Nat. Prod. (Springer Verlag,
Wien, New York), 2000, vol. 79, pp. 1ꢀ114.
54. Franzyk, H.; Rasmussen, J.H.; Jensen, S.R. Ozonolysis of Protected Iridoid
Glucosides. Eur. J. Org. Chem. 1998, 365ꢀ370.
55. Walker II, J.A.; Chen, J.J.; Hinkley, J.M.; Wise, D.S.; Townsend, L.B. Novel
20-Deoxy Pyrazine C-Nucleosides Synthesized via Palladium-Catalyzed Cross-
Couplings. Nucleosides & Nucleotides 1997, 16, 1999ꢀ2012.
56. Borthwick, A.D.; Crame, A.J.; Exall, A.M.; Weingarten, G.G. An Efficient
Synthesis of a Chiral Carbocyclic 20-Deoxyribonucleoside Synthon by Directed
Reduction. Tetrahedron Lett. 1994, 35, 7677ꢀ7680.
57. Altmann, K.-H.; Kesselring, R.; Pieles, U. 60-Carbon-Substituted Carbocyclic
Analogs of 20-Deoxyribonucleosides-Synthesis and Effect on DNA=RNA
Duplex Stability. Tetrahedron 1996, 52, 12,699ꢀ12,722.
58. McLaughlin, L. W.; Piel, N.; Hellmann, T. Preparation of Protected Ribo-
nucleosides Suitable for Chemical Oligoribonucleotide Synthesis. Synthesis
1985, 322ꢀ323.
59. Yoshikawa, M.; Nakae, T.; Cha, B.C.; Yokokawa, Y.; Kitagawa, I. Syntheses
of (þ)-Cyclaradine and (þ)-9-pseudo-b-L-Xylofuranosyladenine, Two Opti-
cally Active Cyclopentane Analogs of Nucleoside. Chem. Pharm. Bull. 1989,
37, 545ꢀ547.
60. Kapeller, H.; Baumgartner, H.; Griengl, H. Synthetic Studies towards ( ꢄ )-
Aristeromycin and its 50-homo-Analogue. Monatsh.Chem. 1997, 128, 191ꢀ200.
61. Vestergaard, B.F.; Jensen, O. Diagnosis and Typing of Herpes Simplex Virus in
Clinical Specimens by the Enzyme-Linked Immunosorbent Assay (ELISA).

ANALOGUES OF CARBOVIR AND NEPLANOCIN A
43
In: Nahmias, A.J.; Dowdle, W.R.; Schinazi, R.V., (eds) The Human Herpes
V|rus, an InterdisciplinaryPerspective (Elsevier, New York), 1981, pp. 391ꢀ394.
62. Nielsen, C.M.; Bygbjerg, I.C.; Vestergaard, B.F. Detection of HIV Antigens in
Eluates from Whole Blood Collected on Filter Paper (Letter). Lancet 1987,
566ꢀ567.
63. El-Barbary, A.A.; Khodair, A.I.; Pedersen, E.B.; Nielsen, C. S-Glucosylated
Hydantoins as New Antiviral Agents. J. Med. Chem. 1994, 37, 73ꢀ77.
Received September 5, 2001
Accepted November 5, 2001