Conformationally locked nucleosides. Synthesis of 3(R,S)-(adenin-9-y1)-1- and 3(R,S)-(cytosin-1-y1)-1-hydroxymethylbicyclo[2,1,1]hexanes

Article abstract of DOI:10.1016/S0040-4039(00)01246-6

3,3-Di(isopropoxycarbonyl)-1,1-dimethoxycyclobutane (1) was converted, in multi-steps, to 3-(1,3-dithiacyclohex-2-yl)-1,1-di(p-tosyloxymethyl)cyclobutane (7), which was subjected to a butyllithium-mediated cyclization to give the bicyclo[2,1,1]hexane ring system 8. Further transformations afforded 1-(t-butyldimethylsilyloxymethyl)-3(R,S)-hydroxybicyclo[2,1,1]hexanes (11), which were condensed with 6-chloropurine and 4-acetylcytosine via Mitsunobu reactions to give, after further treatment, 3(R,S)-(adenin-9-yl)- and 3(R,S)-(cytosin-1-yl)-1-hydroxymethylbicyclo[2,1,1]hexanes (14 and 17), respectively. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01246-6

Tetrahedron Letters 41 (2000) 7139±7143
Conformationally locked nucleosides. Synthesis of 3(R,S)-
(adenin-9-yl)-1- and 3(R,S)-(cytosin-1-yl)-1-
hydroxymethylbicyclo[2,1,1]hexanes
Guangyi Wang*
Chemistry Laboratory, ICN Pharmaceuticals, Inc., 3300 Hyland Avenue, Costa Mesa, California 92626, USA
Received 29 June 2000; revised 20 July 2000; accepted 21 July 2000
Abstract
3,3-Di(isopropoxycarbonyl)-1,1-dimethoxycyclobutane (1) was converted, in multi-steps, to 3-(1,3-
dithiacyclohex-2-yl)-1,1-di(p-tosyloxymethyl)cyclobutane (7), which was subjected to a butyllithium-mediated
cyclization to give the bicyclo[2,1,1]hexane ring system 8. Further transformations a€orded 1-(t-butyl-
dimethylsilyloxymethyl)-3(R,S)-hydroxybicyclo[2,1,1]hexanes (11), which were condensed with 6-chloro-
purine and 4-acetylcytosine via Mitsunobu reactions to give, after further treatment, 3(R,S)-(adenin-9-yl)-
and 3(R,S)-(cytosin-1-yl)-1-hydroxymethylbicyclo[2,1,1]hexanes (14 and 17), respectively. # 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: bicyclic aliphatic compounds; cyclization; nucleosides; stereochemistry.
Conformationally restricted nucleosides have recently received medicinal chemists' attention as
these nucleosides adopt certain desired, restricted geometrical shapes and are potentially useful as
small molecule inhibitors or as building blocks of modi®ed oligonucleotides. Partially rigid 20,30-
didehydro-20,30-dideoxyribonucleoside analogues such as carbovir (a) and d4T (b), which have
shown potent antiviral activities against HIV,1,2 may be considered as the earlier examples in this
class. Conformationally restricted nucleosides (c) containing the Northern bicyclo[3,1,0]hexane3
as the sugar moiety were found potent against HSV-1, HSV-2, HCMV, and EBV.4,5 The triphos-
phate of the conformationally restricted AZT analogue (d) having the bicyclo[3,1,0]hexane ring
as the sugar moiety is an equipotent inhibitor of HIV reverse transcriptase.6 However, the
Southern isomers (not shown) did not show much activity against these viruses. Apparently, the
restricted, Northern conformation is crucial to the activities of these nucleosides. A few other
nucleosides having rigid sugar moieties were also reported, but their biological activity was either
weak or not reported.7 10 Recently, nucleosides containing small, rigid methylenecyclopropanes
or spiropentanes were also synthesized and found active against certain DNA viruses.11,12 If
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01246-6

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nucleosides containing unnatural `sugar moieties', like acyclovir, can be selectively phosphorylated
by viral nucleoside kinases, they may have a favorable toxicity pro®le. In fact, carbovir inhibits
HIV infection in T cells at concentrations 200±400 times below its cytotoxic levels.1 Similarly, the
nucleosides (c) containing the Northern bicyclo[3,1,0]hexane ring also showed favorable selectivity
pro®le.4,5 It seems that conformationally rigid nucleosides deserve further exploration. It was also
reported that 20,40-bridged nucleosides dramatically increased hybridization of the modi®ed
oligonucleotides to complementary RNA and DNA,13 15 which was attributed to their favorable,
conformationally locked, C30-endo sugar pucker. Whether these 20,40-bridged nucleosides possess
antiviral activity has not been reported so far. It seems that the known 20,40-bridged nucleosides14,16
might be slightly larger than a favorable size to be a good substrate of nucleoside kinases. Can the
20,40-bridge be shortened? It means that highly strained, 20,40-one-atom-bridged nucleosides such
as e and f need to be synthesized. In continuation of our e€orts on conformationally locked
nucleosides, we recently explored the synthetic feasibility of 20,40-one-atom-bridged nucleosides.
In this communication, synthesis of 3(R,S)-(adenin-9-yl)- and 3(R,S)-(cytosin-1-yl)-1-hydroxy-
methylbicyclo[2,1,1]hexanes (14 and 17) is described.
The carbocyclic nucleosides e containing a bicyclo[2,1,1]hexane ring as the sugar moiety were
prepared from condensation of the nucleoside bases and 1-(t-butyldimethylsilyloxymethyl)-
3(R,S)-hydroxybicyclo[2,1,1]hexanes 11 as shown in Schemes 1 and 2. The synthesis of 11 started
with 3,3-di(isopropoxycarbonyl)-1,1-dimethoxycyclobutane 1, which was prepared from
Scheme 1. (a) LAH, THF, rt, 1.5 h, 66%; (b) TFA/CHCl3, rt, 1 h; (c) TBS-Cl, pyridine, 45ꢀC, 1 h, 53% (two steps);
ꢀ
ꢀ
.
(d) Ph3PˆCH2, ether, 0 C, 1 h, 100%; (e) (1) BH3 SMe2, THF, rt, 1 h; (2) NaBO3, dioxane/water, 60 C, 2 h, 77%;
(f) DMT-Cl, pyridine, 40ꢀC, 2 h; (g) TBAF, THF, 40ꢀC, 1 h; (h) TsCl, pyridine, 50ꢀC, 0.5 h; (i) 80% AcOH, 50ꢀC, 0.5
h, 79% (four steps); (j) DMSO, DCC, TFA, pyridine, rt, 15 h, 91%; (k) 1,3-propanedithiol, SOCl2/silica, CH2Cl2, rt, 2
h, 93%; (l) BuLi, THF, rt, 1 h, 42%; (m) NaOH, dioxane/water, 90ꢀC, 3 days, 74%; (n) TBDMS-Cl, pyridine, rt, 1 h;
(o) Hg(ClO4)2, Ca(CO3)2, THF, rt, 1 h, 83% (two steps); (p) LAH, THF, 0ꢀC, 0.5 h, 84%

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Scheme 2. (a) DEAD, Ph3P, THF, rt, 2±3 days, 69% for 13, 70% for 16; (b) TBAF, THF, rt, 1 h; (c) NH3/MeOH,
80ꢀC, 15 h, 60% for 14 (two steps); (d) same as (c), 55ꢀC, 24 h, 73% for 17 (two steps)
condensation of 1,3-dibromo-2,2-dimethoxypropane17 and diisopropyl malonate according to a
published procedure.18 Compound 1 was reduced with lithium aluminum hydride (LAH) to give
a 3,3-di(hydroxymethyl) derivative, which was treated with tri¯uoroacetic acid (TFA) to give the
keto derivative 2 in good yield. An attempt to convert 3,3-di(p-tosyloxymethyl)cyclobutanone
(prepared from 2, not shown) to the corresponding 1-methylene derivative via Wittig reaction
failed due to the instability of the tosyl group. After protection of the hydroxyls of 2 with t-
butyldimethylsilyl (TBS) group, a Wittig reaction16 converted the keto intermediate to the
methylenecyclobutane derivative 3. The hydroboration of 3 gave a hydroxymethyl intermediate,
which was protected with dimethoxytrityl (DMT) group to give 4. The TBS groups of 4 were
removed and then replaced with two p-tosyl groups to give 5. After removal of DMT from 5, the
resulting hydroxyl was oxidized to give the aldehyde 6. Treatment of 6 with 1,3-propanedithiol
and SOCl2/silica19 a€orded the dithiane 7, which was subjected to a cyclization in the presence of
butyllithium.20 This was the key step to the synthesis of the bicyclo[2,1,1]hexane ring system.
With excess butyllithium (3 equivalents) at ambient temperature for 1 h, a moderate yield
(ꢁ40%) of 8 was obtained. The side reactions included the removal of one or two tosyl groups
and the formation of a spiro ring system from the monotosyl by-product. In an attempt to
optimize the cyclization, the tosyl groups of 8 were replaced by mesyl. In this case, no desired
product was formed and the side reactions predominated. Compound 8 was subjected to a vig-
orous hydrolysis with aqueous sodium hydroxide at 90ꢀC, and fortunately, the bicyclo[2,1,1]ring
system well survived the hydrolytic condition. The hydrolytic product was protected with TBS to
give 9 in good yield. Removal of 1,3-dithiane was achieved by treatment with mercury(II) per-
chlorate21 in THF in the presence of calcium carbonate to give the keto product 10. Reduction of
10 with LAH a€orded the desired 11 in good yield. Theoretically, the reduction of the symmetrical
keto compound 10 should give a mixture of equal amounts of the 3(R)- and 3(S)-isomers, which
formed an enantiomeric mixture and could not be distinguished by NMR. It was our interest to
make both isomers and therefore a separation was not attempted.
Compound 11 was successfully condensed with 6-chloropurine 12 and 4-acetylcytosine 15,
respectively, via Mitsunobu reaction.22,23 A typical procedure was as follow: DEAD (1.0 mmol)
was added to a stirred mixture of nucleoside base (1.0 mmol) and triphenylphosphine (1.0 mmol)

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in anhydrous THF (5 mL). The mixture was stirred at room temperature for 10 min, and a
solution of 11 (0.5 mmol) in THF (1 mL) was added. The reaction mixture was stirred under
argon for 2±3 days, evaporated, and subjected to a ¯ash chromatography. Compound 13 was
obtained in good yield and further converted to the adenosine analogue by treatment with
ammonia-saturated methanol in a steel bomb. The condensation of 11 with 4-acetylcytosine
a€orded a good yield of 16, which was subjected to removal of the TBS and acetyl to give the
cytidine analogue 17. Other purine and pyrimidine nucleosides containing 1-hydroxymethyl-
3(R,S)hydroxybicyclo[2,1,1]hexanes are being synthesized in this laboratory.
The sugar moiety of the bicyclonucleosides 14 and 17 consists of a pair of the enantiomers as
mentioned above, and therefore the nucleosides prepared from this `sugar' are also a mixture of
two enantiomers since the nucleoside bases do not have any chiral center. These compounds may
be analogously named d- and l-nucleosides. In this case, the 30-(R)-isomer is a b-d-nucleoside
and the 30(S)-isomer is a b-l-nucleoside as shown below.
In summary, this letter, has reported, for the ®rst time the synthesis of nucleosides having
1-hydroxymethyl-3(R,S)-bicyclo[2,1,1]hexanes as the sugar moiety. The successful synthesis of
1-hydroxymethyl-3(R,S)-hydroxybicyclo[2,1,1]hexanes would encourage the exploration of
nucleosides containing compact bicyclic ring systems. In this laboratory, the optimization of the
synthetic route to the bicyclo[2,1,1]hexane ring system and synthesis of the 20,40-methylene
nucleosides are under way.
Acknowledgements
The author would like to thank Dr. Esmir Gunic for improving the yield of the reduction of
compound 1 with LAH.
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