Efficient synthesis of several methylene-expanded oxetanocin nucleoside analogues

Article abstract of DOI:10.1016/S0040-4039(00)00467-6

S-Glycidol 4 has been converted by a direct route via the dihydrofuran- 3-methanols 9ab into a series of methylene-expanded oxetanocin nucleoside analogues, e.g., analogues of the normal nucleosides 2 and the known antiviral nucleosides, AZT, FdT, and ddC, 3. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00467-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3577–3581
Efficient synthesis of several methylene-expanded oxetanocin
nucleoside analogues
Michael E. Jung ∗ and Akemi Toyota
Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095-1569, USA
Received 7 February 2000; revised 15 March 2000; accepted 17 March 2000
Abstract
S-Glycidol 4 has been converted by a direct route via the dihydrofuran-3-methanols 9ab into a series of
methylene-expanded oxetanocin nucleoside analogues, e.g., analogues of the normal nucleosides 2 and the known
antiviral nucleosides, AZT, FdT, and ddC, 3. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: nucleoside synthesis; anhydro nucleosides; cyclic stereocontrol; alkoxyepoxide chemistry.
Several modified nucleosides have become useful agents for the treatment of viral diseases due to their
good antiviral activity.1 In particular, nucleosides with somewhat abnormal structures, e.g., L-nucleosides
or isonucleosides, have been shown to be very useful antiviral agents.2 Recently we published a general
synthesis of several ‘methylene-expanded’ oxetanocin isonucleosides 1 in which a methylene group
was inserted between the ring oxygen and the carbon bearing the base. One of these — the thymidine
analogue 1a — showed quite good antiviral activity (TI>250).3 We now report a very efficient synthesis
of a different class of ‘methylene-expanded’ oxetanocin analogues 2, in which the methylene group is
inserted between the oxygen and the carbon bearing the hydroxymethyl group. In addition we report the
synthesis of several modified nucleosides in this class, namely those containing azido, fluoro, or hydrido
groups in place of the secondary hydroxyl, 3. This de novo synthesis uses a novel approach, in which all
of the asymmetry required is derived from the inexpensive precursor S-glycidol 4.
Sharpless asymmetric epoxidation of allyl alcohol using D-(+)-DIPT and cumyl hydroperoxide affor-
ded S-glycidol 4 in 43% yield and >90% ee4 (Scheme 1). This compound has been prepared in a very
large scale by an industrial application of this process.5 Treatment of the anion of 4 with 2-chloroethenyl
phenyl sulfone 5 (prepared in three steps and 82% overall yield from 1,1,2-trichloroethane)6 afforded
the addition–elimination product, the 2-alkoxyvinyl sulfone 6, in 78% yield.6 Treatment of 6 with
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00467-6
tetl 16747

3578
Scheme 1.
LHMDS gave in 60% yield the cyclized product 7, the alcohol of which was protected as either the
tert-butyldiphenylsilyl (TBDPS) or monomethoxytrityl (MMTr) ether, 8ab, in quantitative yield. Sodium
amalgam reduction gave the desired enol ethers 9ab also in quantitative yield.
Scheme 2.
Epoxidation with dimethyl dioxirane gave the epoxides 10ab as the major isomers as an 8:1 ratio with
the opposite diastereomers 11ab in quantitative yield. These two key compounds were then converted
into the desired modified nucleosides as shown in Schemes 2–5. Both of the ethers 10ab could be opened
with excess bis-silylated thymine to give in good yields the protected nucleoside analogues 12ab, the
latter of which could be hydrolyzed to give 2T in quantitative yield (Scheme 2). The cytidine analogue
2C could also be prepared by treatment of the epoxide 10a with excess bis-silylated uracil to give the
protected nucleoside analogue 13a in 75% yield (Scheme 3). Protection of the secondary alcohol as the
TBDPS ether and conversion of the amide into the triazole afforded the bis-silyl ether triazole 14a in
80% yield. Final conversion to the cytosine ring and deprotection of both silyl ethers gave the cytidine
analogue 2C in 91% yield. The purine analogues were prepared by a different route again starting with
the enol ether 9b (Scheme 4). Dihydroxylation using catalytic osmium tetroxide and NMO followed by
acetylation gave a quantitative yield of a 20:1 ratio of the two isomeric diacetates 15, as a 1.5:1 mixture
of α- and β-anomers, and 16 as only the α-anomer. Reaction of this mixture with the N6-benzoyl bis-
Scheme 3.

3579
Scheme 4.
silylated adenine in the presence of trimethylsilyl triflate (TMSOTf) afforded in 93% yield the desired
β-anomer 17 which was debenzoylated and then deprotected to give the adenosine analogue 2A. Finally
a similar route afforded the guanosine analogue (Scheme 5). Thus the known carbamate 18 (prepared in
two steps from guanine by acetylation followed by O-acylation with diphenylcarbamoyl chloride)7 was
bis-silylated using bis(trimethylsilyl)acetamide and then treated with the diacetate 15 and TMSOTf to
give a mixture of the MMTr ether and the alcohol 19ab in yields of 72% and 19%, respectively. These
compounds were both treated with ammonium hydroxide and then the protecting groups were removed
to give the guanosine analogue 2G.
Scheme 5.
In addition to preparing the simple analogues of the natural nucleosides, we also wished to prepare
several analogues which resembled more closely the well known antiviral agents, such as AZT, FdT,
Scheme 6.

3580
Scheme 7.
ddC, etc. Therefore we decided to prepare the three analogues, 3abc, in which azido, fluoro, and
hydrido groups replaced the secondary hydroxyl group of the appropriate nucleosides. The syntheses
of these compounds are shown in Schemes 6–8. Thus, an internal Mitsunobu reaction on the two
protected thymidine analogues 12ab using diisopropyl azodicarboxylate (DIAD) afforded the 10,20-
anhydronucleosides 20ab in excellent yield. Opening of the silyl ether 20a with excess lithium azide
in DMF at 125°C furnished the azidothymidine 21 in 77% yield along with 17% recovered starting
material. Cleavage of the TBDPS protecting group afforded the desired AZT analogue 3a in quantitative
yield. The preparation of the fluoro analogue was somewhat more difficult since we were unable to get
clean opening of either 10,20-anhydronucleoside with fluoride ion (e.g., by using the method of Green and
Blum).8 Therefore we had to use a longer but more certain route as follows (Scheme 7). Basic hydrolysis
of the anhydro nucleoside 20b afforded the secondary alcohol of retained stereochemistry 22 in 92%
yield. The protecting group on the primary alcohol was exchanged for a benzoate in two steps to give
the alcohol 23. Treatment of this alcohol 23 with excess DAST gave a 42% yield of the inverted fluoride
25 along with 33% of the elimination product 24. The desired nucleoside analogue of FdT 3b was then
prepared in quantitative yield by basic hydrolysis of the benzoate of 25.
Scheme 8.
The final analogue, the ddC analogue 3c, was prepared as shown in Scheme 8. The monomethoxytrityl
ether of the uridine analogue 13b was deoxygenated by a Barton–McCombie procedure,9 namely
by formation of the phenyl thionocarbonate and treatment with excess tributylstannane to give the

3581
deoxygenated compound 26 in 80% yield for the two steps. Exchange of the trityl protecting group
for an acetate was effected in two steps and 93% yield to give the acetate 27. Final transformation of the
uridine to the cytidine via the normal triazole procedure gave the desired ddC analogue 3c in 50% yield.
The details of the synthesis and the results of testing of some of these novel compounds will be reported
in due course. The preparation of novel nucleoside analogues is currently underway in our laboratories.
Acknowledgements
We thank the National Institutes of Health (GM47228) and the Universitywide AIDS Research
Program (R97-LA-139) for generous financial support.
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