Stereoselective conversion of 2′,3′-dideoxydidehydro carbocyclic nucleosides into 2′-deoxy carbocyclic nucleosides

Article abstract of DOI:10.1039/a801759j

Treatment of 2′,3′-dideoxydidehydro carbocyclic nucleosides 5-9 with N-bromoacetamide in AcOH gives bromoesters 10-14 with good stereocontrol: debromination and hydrolysis furnishes 2′-deoxy carbocyclic nucleosides, e.g. 22.

Full text of DOI:10.1039/a801759j

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Stereoselective conversion of 2A,3A-dideoxydidehydro carbocyclic nucleosides
into 2A-deoxy carbocyclic nucleosides
a
a
b
a
a
James V. Barkley, Anupma Dhanda, Lars J. S. Knutsen, †‡ May-Britt Nielsen, Stanley M. Roberts* § and
David R. Varleyc
a
Department of Chemistry, Liverpool University, Liverpool, UK L69 7ZD
Novo-Nordisk A/S, Novo Nordisk Park, DK-2760, Malov, Denmark
Department of Chemistry, Exeter University, Exeter, Devon, UK EX4 4QD
b
c
Cl
N
Cl
N
Treatment of 2A,3A-dideoxydidehydro carbocyclic nucleo-
sides 5–9 with N-bromoacetamide in AcOH gives bromoe-
sters 10–14 with good stereocontrol: debromination and
hydrolysis furnishes 2A-deoxy carbocyclic nucleosides, e.g.
N
N
N
N
N
N
R1
R1
R2
R2
i
Br
22.
The preparation of 2A,3A-dideoxydidehydro carbocyclic nucleo-
sides 1 (Scheme 1) has been the subject of a great deal of
attention, owing to the biological activity of carbovir and related
AcO
5
6
7
8
9
R1 = CH2OAc, R2 = NH2
R1 = CH2OAc, R2 = H
R1 = CH2OAc, R2 = Cl
R1 = CH2OCPh3, R2 = NH2
10
11
12
13
1
compounds. The conversion of the readily-available alkenes of
general stucture 1 into structurally more complex carbocyclic
nucleosides 2 and 2A-deoxy carbocyclic nucleosides 4 has been
fraught with difficulty. For example, bis-hydroxylation of
compounds 1 tends to give an equimolar mixture of isomers
R1 = CH(OAc)CH2OAc, R2 = NH2 14
Scheme 2 Reagents and conditions: i, NBS or N-bromoacetamide, AgOAc,
2
corresponding to ribo- and lyxo-sugars 2 and 3. The preference
AcOH, 18 h, room temp.
for the formation of the carbocyclic ribonucleoside on steric
grounds is countered by a stabilizing Cieplak effect which
favours formation of the lyxo analogues.3
Treatment of the cyclopentene derivative 5 with NBS or
N-bromoacetamide and AgOAc in AcOH afforded bro-
moacetate 10 as the sole product in 68% yield (Scheme 2). This
bromoester was recrystallized and the stereochemistry con-
firmed by X-ray crystallography (Fig. 1).∑
Similarly, compounds 6–8 produced the corresponding
haloesters 11–13 in 47–69% yield.** In the latter case the NMR
spectrum of the crude product, besides the major product 13,
gave evidence of a few percent of an isomeric product, in too
small an amount to isolate. Treatment of the diester 9 under the
standard reaction conditions afforded the expected product 14
Conversion of ribo-carbocyclic nucleosides 2 into 2A-deoxy
ribo-carbocyclic nucleosides 4 [path (b)] through reaction of the
diol with AcBr in MeCN and subsequent hydrodehalogenation
is marred by the formation of the desired bromohyrins
corresponding to the ara- and isomeric xylo-bromohydrins in an
unfavourable 1:5 ratio.4
Direct conversion of carbocyclic nucleosides of type 1 into
deoxy ribo systems of type 4 [path (c)] by hydroboration was
5
investigated by Deardorff et al.; unfortunately the 3A-hydroxy
and the 2A-hydroxy compounds were both obtained, in a 2:1
(
49%) [with spectroscopic properties in accord with the
ratio.
assignments for compounds 10–13 and an isomeric substance
Herein we report a novel stereoselective method for the
transformation of alkenes 1 into the corresponding alcohols 4.
Most of the starting materials for this study (5, 6, 8 and 9)
were prepared from (±)-cis-1-acetoxy-2-(acetoxymethyl)-
cyclopent-4-ene; a typical procedure is described below.
Compound 7 was prepared from compound 5.¶
(
13%)]. We tentatively assign a 2A-acetoxy-3A-bromo structure
to the minor product on the basis of NMR spectroscopy.
The conversion of the alkenes 5–9 into the bromoesters
0–14 is reminiscent of the conversion of the cyclopentene
1
Cl(1)
base
base
N(2)
RO
RO
OH
OH
N(3)
+
C(1)
HO
OH
2
3
N(5)
N(1)
N(4)
path (a)
base
Br(1)
RO
path (b)
1
path (c)
RO
O(3)
base
O(1)
O(2)
O(4)
HO
4
Scheme 1
Fig. 1 X-Ray structure of compound 10
Chem. Commun., 1998
1117

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Cl
N
Cl
N
Cl
N
N
N
N
N
N
N
N
N
N
R1
R1
NH2
i
NH2
NH2
Br
ii
HO
from 19
AcO
AcO
HO
1
1
1
0
R1 = CH2OAc
R1 = CH(OAc)CH2OAc
R1 = CH2OH
19
20
21
22
4
8
Scheme 4 Reagents and conditions: i, Bun
CO
3
SnH, AIBN, THF, heat, 3–7 h (68–92%); ii, K
2
3
, MeOH, 2 h (96%)
derivative 15 into the dihalides 16 and 17 (ratio 8:1) (Scheme
), in that in both cases the major product is formed via the
evaporated in vacuo to give a crude yellow oil. The oil was purified by
column chromatography on silica gel eluting with CH Cl –EtOH (19:1)
2 2
giving 5 (50% yield) as a clear oil.
3
6
intermediacy of a syn-halonium ion. However, the preferential
formation of compound 16 was explained by a proposed
stabilisation of the syn-iodonium ion by the adjacent hydroxy
group, a phenomenon which is clearly impossible in our cases.
Instead we believe that the formation of the syn- and anti-
bromonium ions are reversible processes and only on formation
of the syn-bromonium ion is attack by the nucleophile possible,
from the more exposed face and distant from the heteroatom
bonded to C-1A.
Synthesis of 7. Compound 5 (224 mg, 0.728 mmol) was dissolved in
CH Cl (8 ml) and the solution was cooled to 0 °C. Me SiCl (276 ml, 2.184
2
2
3
mmol) was added followed by isopentyl nitrite (292 ml, 2.184 mmol) which
was added slowly to maintain the temperature at 0 °C. The reaction mixture
was stirred for 2 h at 0 °C and for 5 h at room temperature. Water (5 ml) was
added and the mixture was extracted with CH Cl2 (3 3 10 ml). The
2
combined organic layers were concentrated in vacuo to give a crude yellow
oil. The oil was purified by column chromatography on silica gel eluting
with EtOAc–light petroleum (2:1) giving 7 (60% yield) as a clear oil.
∑
Crystal data for 10: C15
monoclinic, P2 /n, 0.15 3 0.20 3 0.25 mm, a = 15.597(5), b = 7.077(2),
c = 17.178(2) Å, b = 96.13(2)°, V = 1885.4 Å , T = 2120 °C,
5 4
H17BrClN O , M = 446.69, colourless prism,
1
NHCO2But
HO
3
2
1
Z = 4, m(Mo-Ka) = 23.29 cm ; 3769 reflections measured, 3630 unique,
R = 0.055, R = 0.080. CCDC 182/834.
* Selected data for 11: d (300 MHz; CDCl
s, 3 H, CH of Ac), 2.55 (m, 3 H, 2 3 H-6A and H-4A), 4.35 (m, 2 H, 2 3
H-5A), 4.79 (m, 1 H, H-2A), 5.13 (m, 1 H, H-1A), 5.40 (m, 1 H, H-3A), 8.26 (s,
H, H-2), 8.70 (s, 1 H, H-8); d (75 MHz; CDCl ) 20.8 (CH , CH of Ac),
20.9 (CH , CH of Ac), 30.1 (CH , C-6A), 42.5 (CH, C-4A), 55.1 (CH, C-2A),
w
*
(
H
3 3
) 2.08 (s, 3 H, CH of Ac), 2.17
15
3
i
1
c
3
3
3
NHCO2But
NHCO2But
3
3
2
I
F
HO
HO
56.2 (CH, C-1A), 64.9 (CH , C-5A), 80.5 (CH, C-3A), 143.6 (CH), 150.8 (C),
1
†
2
+
51.6 (C), 152.0 (CH), 169.5 (C, CNO) and 170.7 (C, CNO).
† Selected data for 19: d (400 MHz; CDCl ) 1.98 (m, 1 H, H-6A), 2.08 (s,
H
3
F
I
3 H, CH of Ac), 2.09 (s, 3 H, CH of Ac), 2.30 (dd, 1 H, J 13 and 8, H-6A),
3
3
16
17
2.52–2.62 (m, 3 H, H-1A and H-2A), 4.30 (m, 2 H, H-5A), 4.90 (m, 1 H, H-1A),
.22 (m, 3 H, H-3A and NH ), 7.78 (s, 1 H, H-1A); d (100 MHz; CDCl ) 20.8
(CH , CH of Ac), 21.1 (CH , CH of Ac), 33.0 (CH , C-6A), 37.3 (CH,
C-2A), 43.6 (CH, C-4A), 54.1 (CH, C-1A), 64.8 (CH, C-5A), 75.4 (CH, C-4A),
26.0 (CH, C-5), 140.9 (C, C-8), 151.6 (C, C-4), 153.4 (C, C-6), 158.7 (C,
C-2), 170.3 (C, CNO) and 171.0 (C, CNO).
5
2
c
3
Scheme 3 Reagents and conditions: i, N-iodosuccinimide, tetrabutyl-
ammonium dihydrogen trifluoride, CH Cl
3
3
3
3
2
2
2
1
Detritylation of bromoester 13 was accomplished using aq.
AcOH to furnish the alcohol 18 in 66% yield. Treatment of
compounds 10, 14 and 18 with tri-n-butyltin hydride in hot THF
furnished the nucleoside analogues 19–21 (Scheme 4).‡‡
Methanolysis of the diester 19 provided the 2A-deoxycarbo-
cyclic nucleoside in almost quantitative yield.
1
2
V. E. Marquez, Adv. Antiviral Drug Dev., 1996, 2, 89; H. F. Olivo and
J. Yu, Tetrahedron: Asymmetry, 1997, 8, 3785; J. Chem. Soc., Perkin
Trans. 1, 1998, 391 and references therein.
S. M. Roberts and K. A. Shoberu, J. Chem. Soc., Perkin Trans. 1, 1991,
In summary, the stereocontrolled addition of Br/OAc to
2
605; E. A. Saville-Jones, S. D. Lindell, N. S. Jennings, J. C. Head and
dideoxydidehydro carbocyclic nucleosides give facile access to
M. J. Ford, J. Chem. Soc., Perkin Trans. 1, 1991, 2603; C. G. Palmer,
R. McCague, G. Ruecroft, S. Savage, S. J. C. Taylor and C. Ries,
Tetrahedron Lett., 1996, 37, 4601; see also V. K. Aggarwal and
N. Monteiro, J. Chem. Soc., Perkin Trans. 1, 1997, 2531; S. E. Ward,
A. B. Holmes and R. McCague, Chem. Commun., 1997, 2085;
B. M. Trost, R. Marsden and S. D. Guile, Tetrahedron Lett., 1997, 38,
7
2
A-bromo-2A-deoxyribo carbocyclic nucleosides.
Novo-Nordisk A/S provided studentships for A. D., M.-B. N.
and D. V. R. and this financial support is gratefully acknowl-
edged.
1
707.
Notes and References
3
N. Katagiri, Y. Ito, K. Kitano, A. Toyota and C. Kaneko, Chem. Pharm.
Bull., 1994, 42, 2653; see also G. Poli, Tetrahedron Lett., 1989, 30,
7385.
4 R. Marumoto, Y. Yoshioka, Y. Furukawa and M. Honjo, Chem. Pharm.
Bull., 1976, 24, 2624.
5 D. R. Deardorff, R. G. Linde, A. M. Martin and M. J. Shulman, J. Org.
Chem., 1989, 54, 2759.
6 A. Toyota, Y. Ono and C. Kaneko, Tetrahedron Lett., 1995, 36, 6123.
7 The corresponding nucleosides have been prepared; see L. J. S. Knutsen,
Nucleosides Nucleotides, 1992, 11, 961; it has been reported that
†
Present address, Cerebrus Ltd., Oakdene Court, 613 Reading Road,
Winnersh, Wokingham, UK RG41 5UA.
‡
§
¶
E-mail: l.knutsen@cerebrus.ltd.uk
E-mail: sj11@liverpool.ac.uk
Synthesis of 5. 2-Amino-6-chloro-9H-purine (264 mg, 1.56 mmol) and
NaH (60% dispersed in mineral oil, 68 mg, 1.71 mmol) were dissolved in
anhydrous DMF (7.0 ml) and stirred for 10 min at room temperature and at
50 °C for 10 min. The reaction mixture was added to a suspension of
(±)-(1R,2R)-1-acetoxy-2-(acetoxymethyl)cyclopent-4-ene (339 mg, 1.71
mmol) and tetrakis(triphenylphosphine)palladium (180 mg, 0.156 mmol) in
DMF (7.0 ml) using a cannula, rinsing with anhydrous THF (3 3 2.0 ml).
The reaction was excluded from light and stirred for 3 h at 50 °C. The
reaction mixture was then cooled to room temperature. Water (25 ml) was
2A-bromo-2A-deoxynucleosides
show
enhanced
stability
to
3A-exonucleases: M. Aoyagi, Y. Ueno, A. Ono and A. Matsuda, Bioorg.
Med. Chem. Lett., 1996, 6, 1573.
added and the mixture was extracted wtih CH
combined organic layers were dried with MgSO
2
Cl
4
2
(4 3 50 ml). The
and the solvent was
Received in Cambridge, UK, 3rd March 1998; 8/01759J
1118
Chem. Commun., 1998