Stereoselective synthesis of (-)-ara-cyclohexenyl-adenine

Article abstract of DOI:10.1016/j.tetlet.2007.03.031

A stereoselective synthesis leading to (-)-ara-cyclohexenyl-adenine is described. The synthesis starts from methyl-α-d-glucopyranose and involves an isomerization step, selective protection/deprotection chemistry, a Ferrier rearrangement and a Mitsunobu r

Full text of DOI:10.1016/j.tetlet.2007.03.031

Tetrahedron Letters 48 (2007) 3621–3623
Stereoselective synthesis of (ꢀ)-ara-cyclohexenyl-adenine
*
´
´
Andras Horvath, Bart Ruttens and Piet Herdewijn
Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Minderbroedersstraat 10, 3000 Leuven, Belgium
Received 8 February 2007; revised 28 February 2007; accepted 6 March 2007
Available online 12 March 2007
Abstract—A stereoselective synthesis leading to (ꢀ)-ara-cyclohexenyl-adenine is described. The synthesis starts from methyl-a-D-
glucopyranose and involves an isomerization step, selective protection/deprotection chemistry, a Ferrier rearrangement and a Mit-
sunobu reaction. This is the first total synthesis of an enantiomeric pure ara-type cyclohexenyl nucleoside.
Ó 2007 Elsevier Ltd. All rights reserved.
Modified nucleosides represent the most important class
of antiviral compounds.1,2 In the category of nucleoside
analogues with a ‘six-membered’ carbohydrate mimic
potent antiherpes activity has been found in the series
of cyclohexenyl nucleosides.3
NH2
NH2
N
N
N
N
N
N
N
HO
N
HO
The synthesis of ( )-ara-cyclohexenyl-adenine4 and of
( )-ribo-cyclohexenyl-adenine5 has been described
(Fig. 1). These nucleoside analogues were synthesized,
likewise, because of their potential biological impor-
tance as antiviral agent. The obtained racemic mix-
tures4,5 can be used for a first antiviral screening
assay, but are neither useful for incorporation studies
in oligonucleotides nor for enzymatic studies. The ap-
proach of separating a racemic mixture into enantiomers
was less appealing for compound 1 as its total synthesis
from furan and acrylic acid4 had several drawbacks, a.o.
the non-selectivity of protection–deprotection chemistry
for the secondary alcohol groups and the time consump-
tion and low yield of some reactions.
HO
OH
HO
OH
ara-cyclohexenyl-A
ribo-cyclohexenyl-A
1
2
Figure 1. Structure of ara-cyclohexenyl-adenine and ribo-cyclohex-
enyl-adenine.
cyclophellitol from D-mannose.7 Our variant on this
carbohydrate-based approach starts from commercially
available and inexpensive methyl-a-D-glucopyranose (3).
First, the 4- and 6-OH groups of methyl-a-D-glucopyran-
ose were protected with a benzylidene group (Scheme 1),
followed by a two-step selective benzoylation of the
2-OH group via a stannylidene intermediate.8 The free
3-OH group was protected with the acid labile tetrahy-
dropyranyl group. After removing the benzoyl protect-
ing group in basic circumstances, the free 2-OH was
oxidized to a keto function and converted into a methyl-
ene group using Wittig conditions. The intermediate
keto compound 9 was not purified.
Therefore, we envisaged a stereoselective synthesis of
compound 1, starting from naturally occurring carbo-
hydrates. Initially, our synthetic approach was based
on the palladium catalyzed asymmetric allylic alkylation
reaction, described for the synthesis of (+)- and (ꢀ)-
cyclophellitol.6 However, we were not very successful
in carrying out this reaction in good and reproducible
yields. The synthesis of the cyclohexenyl scaffold, which
is used for the synthesis of the nucleoside analogues, is
based on the work of Jung and Choe who synthesized
During the hydroboration reactions of 10 (Scheme 2),
the tetrahydropyranyl group was partially removed to
give a mixture of unprotected and protected com-
pounds. Therefore, we preferred to change the 3-OH
protecting group. The tetrahydropyranyl group was
*
Corresponding author. Tel.: +32 16 337387; fax: +32 16 337340;
e-mail: piet.herdewijn@rega.kuleuven.be
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.031

3622
A. Horva´th et al. / Tetrahedron Letters 48 (2007) 3621–3623
Ph
BzCl, Et3N/dioxane
4h, rt, 72%
O
Ph
O
OH
Ph
O
Bu2SnO
O
O
O
PhCH(OMe)2/DMF
1h, 60°C, 79%
O
O
O
O
Toluene-MeOH(10:1)
HO
HO
HO
O
O
HO
14h, 55°C, 98%
OMe
O
OBz
Sn
OMe
OH
OH
OMe
OMe
6
4
5
3
Ph
Ph
O
Ph
O
Ph
O
[MePPh3]Br
TFAA, DMSO
ET3N/DCM
O
O
n-BuLi/THF
O
CH2
NaOMe/MeOH
DHP, pTsOH/DCM
1h, rt, 95%
O
O
O
THPO
O
O
THPO
THPO
-78°C,
-78°C, 84%
2 steps yield
2h, rt, 96%
THPO
OH
O
OMe
OBz
OMe
OMe
OMe
7
9
8
10
Scheme 1.
Ph
O
O
O
BnO
Ph
O
Ph
O
BH3 Me3S/THF
NaOH, H2O2
Ph
O
AcOH-THF-H2O
4:2:1
BnBr, NaH/ DMF
O
OMe
OH
OH
O
O
O
THPO
O
O
HO
+
O
BnO
1h, rt, 89%
1h, 50
˚
C, 91%
24h, 93%
Ph
CH2
CH2
OMe
OMe
CH
2OMe
O
O
11
10
BnO
12
OMe
13
Ph
O
Ph
O
Ph
NaBH4
EtOH-THF (1:1)
10 min, 0˚C, 92%
O
O
BnBr, NaH/ DMF
O
O
O
BnO
O
O
BnO
BnO
1h, rt, 78%
oxalyl-Cl
DMSO/DCM
OMe
OH
O
OMe
OBn
OMe
H
+
O
15
16
Ph
O
ET3N/DCM
7d, rt, 94%
4h, -78˚C, 69%
H
O
O
BnO
OMe
14
Scheme 2.
I
OH
PPh3, I2, imidazole
toluene
O
Cu(OTf)2, BH3
1h, 66%
O
O
DBU/THF
BnO
BnO
BnO
BnO
BnO
BnO
16
reflux, 60%
3h, reflux, 86%
OMe
OBn
OMe
OBn
OMe
OBn
19
17
18
NaBH4, CeCl3.7H2O
EtOH-THF (1:1)
O
HgCl2
acetone-H2O
O
MsCl, cat. DAMP/py
24h, rt, 53%
BnO
BnO
BnO
BnO
OH
(4:1)
1h, reflux, 93%
10 min, -78˚C, 96%
OBn
OBn
21
20
HO
BnO
BnO
OBn
BzO
HO
BzCl, pyr, 0˚C
16h, rt, 86%
K2CO3, MeOH
16h, rt, 96%
22a
BnO
BnO
BnO
BnO
+
OBn
OBn
BnO
BnO
23
22a
OH
OBn
22b
Scheme 3.
selectively removed using mild acidic conditions and
reprotected using benzyl bromide/NaH to give com-
pound 12. Hydroboration of 12 gives a 1:1 mixture of
diastereomers with a 2-hydroxymethyl group in the [R]
or [S] configuration. Since we only need the compound
with an equatorial hydroxymethyl group ([R] configura-

A. Horva´th et al. / Tetrahedron Letters 48 (2007) 3621–3623
3623
NH2
N
N
BCl3, CH2Cl2
N
BnO
N
adenine, Ph3P
1
BnO
HO
BnO
BnO
-78˚, 1.5h
0˚C, 2.5h
97%
(-) isomer
DIAD, dioxane
24h, rt
OH
OBn
OBn
BnO
37%
BnO
OBn
22a
24
Scheme 4.
tion), we carried out an isomerization step to convert the
2-[S] stereogenic centre into a 2-[R] stereogenic centre.
Therefore, the mixture of primary alcohols (13) was oxi-
dized and the obtained mixture of aldehydes (14) was
isomerized under mild basic conditions followed by
reduction using sodium borohydride. This approach
was previously described by Jung and Choe.7 It should
be noted that the success of this approach is highly
dependent on the purity of the starting materials (other-
wise the isomerization reaction is getting very slow). The
primary hydroxyl group was protected with a benzyl
group to obtain compound 16.
References and notes
1. De Clercq, E. J. Clin. Virol. 2001, 22, 73.
2. Perigaud, C.; Gosselin, G.; Imbach, J.-L. Nucleosides
Nucleotides 1992, 11, 903.
3. Wang, J.; Froeyen, M.; Hendrix, C.; Andrei, G.; Snoeck,
R.; De Clercq, E.; Herdewijn, P. J. Med. Chem. 2000, 43,
736–745.
4. Wang, J.; Vina, D.; Busson, R.; Herdewijn, P. J. Org.
Chem. 2003, 68, 4499.
5. Vijgen, S.; Nauwelaerts, K.; Wang, J.; Van Aerschot, A.;
Lagoja, I.; Herdewijn, P. J. Org. Chem. 2005, 70, 4591.
6. Trost, B. M.; Patterson, D. E.; Hembre, E. J. Chemistry
2001, 7, 3768.
7. Jung, M. E.; Choe, S. W. T. J. Org. Chem. 1995, 60, 3280.
8. Munavu, R. M.; Szmant, H. H. J. Org. Chem. 1976, 41,
1832.
9. Shie, C.-R.; Tzeng, Z.-H.; Kulkarni, S. S.; Uang, B.-J.;
Hsu, C.-Y.; Hung, S.-C. Angew. Chem., Int. Ed. 2005, 44,
1665.
Selective cleavage of the benzylidene-acetal bond was
achieved using BH3ÆTHF and Cu(OTf)2 (Scheme 3),
without observing the formation of the 6-O-benzyl pro-
tected side compound.
9
This selective deprotection is needed to obtain the exo-
cyclic methylene compound 19 by an iodination-elimi-
nation step (Scheme 3). The desired enone 21 is then
obtained by a Ferrier rearrangement7,10 followed by
an elimination reaction. Selective reduction of the keto
group of 21 was, however, not absolute and a mixture
of two diastereoisomers 22a and 22b were obtained in
a ratio of 94:6. As the separation of 22a and 22b by col-
umn chromatography is tedious, we preferred to protect
the free HO group by benzoylation which resulted into
a more easily separable mixture of compounds. Re-
moval of the benzoyl protecting group of 23 yielded
22a.
10. Ferrier, R. J.; Middleton, S. Chem. Rev. 1993, 93, 2779.
11. Mitsunobu, O. Synthesis 1981, 1–28.
12. Haines, D. R.; Tseng, C. K. H.; Marquez, V. E. J. Med.
Chem. 1987, 30, 943.
13. Compound 1: A 1 M solution of BCl3 in CH2Cl2 (7.4 ml,
7.4 mmol) was added to a stirred solution of compound 24
(270 mg, 0.493 mmol) in CH2Cl2 (9.9 ml) at ꢀ78 °C.
Stirring was continued under N2 at ꢀ78 °C for 1.5 h.
Then, the mixture was allowed to warm slowly to 0 °C
over 2.5 h. Next, it was cooled again to ꢀ78 °C and
MeOH was added (5 ml). After 5 min, the cooling was
removed and the mixture was concentrated. The residue
was concentrated three times from MeOH to remove all
B(OMe)3. The residue was chromatographed (CH2Cl2–
MeOH: 4/1) to give compound 1 as a white, amorphous
solid (132 mg, 97%). HRMS: 278.1238 (M+H+), calcd:
278.1253. 1H NMR (500 MHz, CD3OD): d 8.20 (s, 1H, H-
20 or H-80), 8.16 (s, 1H, H-20 or H-80), 6.10 (ddd, J = 1.4,
2.6, 9.9 Hz, 1H, H-5), 5.85 (ddd, J = 2.7, 4.6, 9.9 Hz, 1H,
H-6), 5.46 (m, 1H, H-1), 3.99 (dd, J = 5.2, 9.3 Hz, 1H, H-
2), 3.91 (dd, J = 4.0, 10.6 Hz, 1H, H-7a), 3.84–3.89 (m,
2H, H-3, H-7b), 2.38 (m, 1H, H-4) ppm. 13C NMR
(125 MHz, CD3OD): d 157.25, 151.60, 119.96 (C-40, C-50,
C-60), 153.46, 142.61 (C-20, C-80), 135.82 (C-5), 124.09 (C-
6), 72.33 (C-2), 68.69 (C-3), 62.73 (C-7), 54.57 (C-1), 47.99
(C-4) ppm. [a]D ꢀ83.0 (CH3OH, c 1). Elem. Anal. Calcd
for C12H15N5O3 (MW 277.1): C, 51.96; H, 5.46; N, 25.27.
Found: C, 51.87; H, 5.40; N, 25.31.
Introduction of the adenine base moiety was carried out
under Mitsunobu type conditions11 (Scheme 4) and all
the benzyl protecting groups can be removed smoothly
using BCl3 in CH2Cl2.12 The obtained ara-cyclohexyl-
A is a mimic of a natural nucleoside in the D-configura-
tion and shows an [a]D value of ꢀ83.0 (CH3OH, c 1).13
When tested in the replicon system (HCV) the com-
pound proved to be inactive.
In conclusion, the first stereoselective total synthesis of
an ara-type cyclohexenyl nucleoside is described, start-
ing from a commercially available carbohydrate.