Synthesis of (±) cis-substituted cyclohexenyl and cyclohexanyl nucleosides via a double Mitsunobu-type reaction

Article abstract of DOI:10.1016/S0040-4039(01)02107-4

This letter describes the synthesis of (±) cis-substituted cyclohexenyl and cyclohexanyl nucleosides. The synthesis of cis isomers was successfully achieved by the use of two consecutive Mitsunobu reactions involving an inversion of configuration and a sugar-base condensation.

Full text of DOI:10.1016/S0040-4039(01)02107-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 81–84
Synthesis of ( ) cis-substituted cyclohexenyl and cyclohexanyl
nucleosides via a double Mitsunobu-type reaction
Karine Barral,a Philippe Halfon,b Ge´rard Pe`pea and Michel Camploa,*
aGroupe de Chimie Organique et des Mate´riaux Mole´culaires (UMR-CNRS 6114), Faculte´ des Sciences de Luminy, case 901,
F-288 Marseille cedex 09, France
bGenoScience, Marseille, France
Received 5 October 2001; revised 2 November 2001; accepted 6 November 2001
Abstract—This letter describes the synthesis of ( ) cis-substituted cyclohexenyl and cyclohexanyl nucleosides. The synthesis of cis
isomers was successfully achieved by the use of two consecutive Mitsunobu reactions involving an inversion of configuration and
a sugar–base condensation. © 2001 Elsevier Science Ltd. All rights reserved.
The development of new modified nucleosides as antivi-
ral agents has remained a very active field of research.
Despite the fact that the carbocyclic nucleosides have
been extensively studied, few efforts have been directed
toward the synthesis of six-membered carbocyclic ana-
logues.1 However, two recent publications describe the
potent antiviral activity of such compounds.2
selective protection of the primary alcohol function of
the analogue 4, provided 5 in 58% yield from com-
pound 3. The preparation of the trans derivative 6 was
accomplished using a Mitsunobu-type reaction on the
allylic alcohol 5. Thus, the introduction of a benzoyl
protective group allowed an inversion of configuration.7
The allylic alcohol 5 was reacted with benzoic acid in
the presence of diethyl azodicarboxylate (DEAD) and
triphenylphosphine (PPh3) in dry THF to give 6. Alka-
line hydrolysis of 6 afforded in 93% yield the trans
allylic alcohol 7.8
The major reasons which highlight the importance of
six-membered carbocyclic nucleosides are:
– the protection from resistance to hydrolysis since
glycosidic bond cleavage is a frequently encountered
degradative pathway of nucleoside antivirals, particu-
larly for the 2%,3%-dideoxynucleosides;3
– the cyclohexene ring on nucleosides has been
shown to be a (bio)isostere of the saturated furanose
ring.4
The corresponding cis-cyclohexenyl nucleosides were
obtained by the use of a second Mitsunobu-type reac-
tion between the allylic alcohol 7 and pyrimidine and
purine bases.9 The synthesis of the cytosin-1-yl (10),
thymin-1-yl (13), adenin-9-yl (17) and guanin-9-yl (19)
derivatives are illustrated in Schemes 2 and 3.
In this article, we describe the syntheses of several ( )
cis-substituted
cyclohexenyl
and
cyclohexanyl
Condensation of the common intermediate, allylic alco-
hol 7, respectively, with N4-benzoylcytosine and N3-
benzoylthymine10 in the presence of DEAD and
triphenylphosphine in THF gave the cis racemic
cytosine and thymine derivatives 8 and 11 in 55 and
nucleosides (I and II, Fig. 1), starting from the com-
mercially available precursor 1 (racemic 3-cyclohexene-
1-carboxylic acid). The known allylic alcohol derivative
7 (Scheme 1) is a requisite for the Mitsunobu coupling
reaction of various nucleoside bases.5 Iodolactoniza-
tion, followed by elimination of the iodide 2 using
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), afforded the
unsaturated lactone 3 in quantitative yield.6 Reduction
of 3 with lithium aluminium hydride, followed by the
HO
Base
HO
Base
(±)-cis II
(±)-cis I
Base : cytosin-1-yl (I, II); thymin-1-yl (I, II);
adenin-9-yl (I, II); guanin-9-yl (I only)
Keywords: cyclohexenyl and cyclohexanyl nucleosides; carbocyclic
nucleosides; Mitsunobu reaction.
* Corresponding author. Tel.: 33 (0)4 91 82 95 86; fax: 33 (0)4 91 82
95 82; e-mail: camplo@luminy.univ-mrs.fr
Figure 1.
0040-4039/02/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02107-4

82
K. Barral et al. / Tetrahedron Letters 43 (2002) 81–84
O
O
O
O
O
HO
OH
HO
c
b
a
quant.
quant.
I
(±)-1
(±)-2
(±)-3
(±)-cis 4
58%
d
TBDMSO
OH
TBDMSO
OBz
TBDMSO
OH
e
f
78%
93%
(±)-trans 7
(±)-trans 6
(±)-cis 5
Scheme 1. Reagents and conditions: (a) Aq. NaHCO3, then aq. KI/I2; (b) DBU, toluene, reflux, 10 h; (c) AlLiH4, THF, rt, 2 h;
(d) TBDMSCl, imidazole, DMF, rt, 5 h; (e) DEAD, PPh3, BzOH, THF, rt, 5 h; (f) NH3/MeOH, NaOH 2N, rt, 3 h.
45% yield (Scheme 2).11 Compounds 8 and 11 were
converted to compounds 9 and 12 by treatment with
TBAF in THF followed by a saturated ammonia solu-
tion in MeOH. The overall yields starting from 8 and
11 were 34 and 36%, respectively. Hydrogenation of
compounds 9 and 12 in EtOAc over 10% palladium on
carbon gave the saturated cytosine derivative 10 and
the saturated thymine derivative 13 in 56 and 77%
yield, respectively.12,13
2-amino-6-chloropurine gave the protected 6-chloro-
purines derivatives 14 and 18 in 39 and 40% yield,
respectively (Scheme 3).14
Building of the adenine ring from 14 was accomplished
by treatment with methanolic ammonia in a sealed
reaction vessel for 1 day to give 15 in 52% yield. The
material was converted to pure adenine cyclohexene
nucleoside 16 by treatment with TBAF in THF. The
2-amino-6-chloropurine derivative 18 was converted to
the guanine cyclohexene nucleoside 19 by treatment
with TFA–H2O (3:1). Under these conditions, the
Using the same conditions, the Mitsunobu-type reac-
tion on the allylic alcohol 7 with 6-chloropurine and
TBDMSO
OH
(±)-trans 7
55% 45%
TBDMSO
O
N
b
NHBz
N
a
Bz
N
O
O
TBDMSO
N
(±)-cis 11
(±)-cis 8
c
36%
c
34%
NH2
O
N
NH
O
HO
N
O
HO
N
(±)-cis 12
(±)-cis 9
d
77%
56%
d
O
NH2
N
NH
O
O
HO
N
HO
N
(±)-cis 13
(±)-cis 10
Scheme 2. Reagents and conditions: (a) N4-Benzoylcytosine, DEAD, PPh3, THF rt, 18 h; (b) N3-benzoylthymine, DEAD, PPh3,
THF, rt, 18 h; (c) TBAF, THF, 3 h, then satd NH3/MeOH, 20 h; (d) 10% Pd/C, H2, EtOAc, 24 h.

K. Barral et al. / Tetrahedron Letters 43 (2002) 81–84
83
TBDMSO
OH
(±)-trans 7
39% 40%
b
a
Cl
N
N
N
Cl
N
N
N
N
N
NH2
TBDMSO
TBDMSO
(±)-cis 18
(±)-cis 14
d
36%
O
c
52%
N
NH
NH2
NH2
N
N
N
HO
N
N
TBDMSO
N
(±)-cis 19
(±)-cis 15
f
O
30%
e
N
NH
NH2
N
N
NH2
HO
N
N
N
HO
N
(±)-cis 16
f
67%
NH2
N
N
N
HO
N
(±)-cis 17
Scheme 3. Reagents and conditions: (a) 6-Chloropurine, DEAD, PPh3, THF, rt, 18 h; (b) 2-amino-6-chloropurine, DEAD, PPh3,
dioxane, rt, 48 h; (c) NH3/MeOH, 80°C, 24 h; (d) TFA/H2O (3/1), rt, 72 h; (e) TBAF, THF, 4 h; (f) 10% Pd/C, H2, EtOH, rt,
24 h.
TBDMS protecting group was simultaneously removed
with an overall yield of 36%. Hydrogenation of com-
pound 16 over palladium on activated carbon gave the
saturated adenine derivative 17 in 67% yield. However,
hydrogenation in MeOH of compound 19 led to
decomposition and the use of EtOAc was inappropriate
since 19 was unsoluble in this solvent. Structural assign-
ments of the products 9, 10, 12, 13, 16, 17 and 19 were
HO
H2'
Base
H3'
H1'
1
based on 1D and 2D H NMR studies. Ring conforma-
tion and relative stereochemistry of the base and the
NOE effects
3%-hydroxymethyl group were determined by examina-
1
tion of 2D H–1H NOESY spectra. In all cases, strong
Figure 2.
NOE interactions were observed between H1%, H2% and
H3% suggesting the cis configuration (H1% –H3% ) of the
Acknowledgements
ax
ax
nucleosides (Fig. 2).
This work was supported by GenoScience, Marseilles,
France. We wish to thank Dr. Robert Faure (St Je´roˆme
University, Marseilles) for conducting the NMR experi-
Antiviral activity of these new series of nucleosides will
be reported in due course.

84
K. Barral et al. / Tetrahedron Letters 43 (2002) 81–84
ments and for his expertise. We also thank Dr. Nicolas
Mourier (FOB synthesis, Boston, USA) and Dr. Martin
Bouygues (Emory university, Atlanta, USA) for helpful
discussions.
5. Murahashi, S.-I.; Taniguchi, Y.; Imada, Y.; Tanigawa, Y.
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6. Goldsmith, D. J.; John, T. K.; Van Middlesworth, F.
Synth. Commun. 1980, 10, 551–557.
7. Mitsunobu, O. Synthesis 1981, 1–28.
8. Partial hydrolysis was achieved with ammonia solution
independently of time. Use of sodium hydroxide was
necessary to involve the total hydrolysis.
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