Isomers of neplanocin A and 2′-deoxyneplanocin A possessing a C-1′/C-6′ double bond

Article abstract of DOI:10.1016/j.tetlet.2005.01.061

Missing among the unsaturated carbocyclic nucleosides is the 1′,6′-double bond isomer of neplanocin A. A practical synthesis of this compound and its 2′-deoxy derivative is reported from readily accessible cyclopentenols.

Full text of DOI:10.1016/j.tetlet.2005.01.061

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1927–1929
Isomers of neplanocin A and 20-deoxyneplanocin A possessing
a C-10/C-60 double bond
Xue-qiang Yin and Stewart W. Schneller*
Department of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849-5312, USA
Received 16 December 2004;revised 12 January 2005;accepted 13 January 2005
Abstract—Missing among the unsaturated carbocyclic nucleosides is the 10,60-double bond isomer of neplanocin A. A practical
synthesis of this compound and its 20-deoxy derivative is reported from readily accessible cyclopentenols.
Ó 2005 Elsevier Ltd. All rights reserved.
Considerable evidence has shown that the introduction
of a rigid structural element into the cyclopentyl moiety
of carbocyclic nucleosides can lead to compounds with
interesting biological properties.1 The most studied
examples in this class are neplanocin A (1),2 fused cyclo-
propyl derivatives (as represented by 23), and 20,30-dide-
hydro-20,30-dideoxy derivatives of carbaguanosine.4
These results prompted our interest in the neplanocin
C-10/C-605a alkenic isomer 3, which presents a planar
arrangement at the C-10 center. Such derivatives6,7 lend
themselves to interesting biological studies by present-
ing, for example, an unexplored structural dimension
for mono-, oligo-, and polymeric nucleosidic
compositions.1,5b,8
ponent of neplanocin A, 3 and the 20-deoxy 4 were
selected to serve as the platform from which to develop
this series. A preliminary account of the preparation of 3
and 4 is reported here (Fig. 1).
The key feature of our plan to 3 and 4 was to place a
leaving group at C-605a of a requisite adenine derivative
and conduct a 1,2-elimination procedure between C-10
and C-60. Epoxides were envisioned as offering stereo-
chemically and functionally versatile synthetic frame-
works for this purpose.
The preparation of 3 began with allylic alcohol 5,9 which
was converted to the b-alcohol 6 by, first, a Mitsunobu
reaction followed by ammonolysis (Scheme 1). The cru-
cial precursor for this investigation, 7, was then pre-
pared from 6 following a literature procedure10 and
protected as its p-methoxybenzyl derivative 8. Direct
epoxidation of 8 gave exclusively b-epoxide rather than
Our initial goal in investigating this class of nucleosides
was to develop a general synthetic procedure that would
be adaptable to a variety of heterocyclic base deriva-
tives. In this direction, because adenine is the base com-
NH2
NH2
N
NH2
N
N
N
N
N
N
N
N
N
6'
N
N
HOH2C
HOH2C
HOH2C
1'
OH
X
HO
HO
HO
2
3, X=OH
4, X=H
1
Figure 1.
Keywords: Carbocyclic nucleosides;Neplanocin analogs;Epoxide ring opening;Antiviral.
*
Corresponding author. Tel.: +1 334 844 5737;fax: +1 334 844 5748;e-mail: schnest@auburn.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.061

1928
X. Yin, S. W. Schneller / Tetrahedron Letters 46 (2005) 1927–1929
OH
RO
ref. 10
a
OH
O
O
O
O
O
O
59
6
7, R=H
8, R=pMBn
b
c
NH2
NH2
N
N
N
N
N
RO
HO
O
N
N
N
RO
d
+
6'
O
O
RO
OH
O
O
9
O
O
R=pMBn (p-methoxybenzyl)
10
11
e
f
NH2
NH2
N
N
N
N
N
N
HO
HO
N
N
g
3
HO
RO
OH
12
O
O
13
Scheme 1. Reagents and conditions: (a) (i) p-nitrobenzoic acid, DIAD, Ph3P, THF;(ii) NH 3, MeOH (81% for two steps);(b) pMBnCl, NaH, DMF
(86%);(c) (i) HCl, MeOH;(ii) mCPBA, CH2Cl2;(iii) Me 2C(OMe)2, acetone, pTSA (80% for three steps);(d) adenine, NaH, 15-crown-6, DMF ( 10,
43%; 11, 39%);(e) (i) TFA;(ii) 1 N HCl (83%);(f) (i) HC(OMe) 2NMe2, DMF;(ii) MsCl, DMAP, CH 2Cl2;(iii) NaOMe, THF/MeOH, reflux;(iv)
MeOH, reflux (60% for four steps);(g) (i) 10% TFA, CH 2Cl2;(ii) 1 N HCl (51% for two steps).
the a-isomer 9, which was desired for purine nucleo-
philic ring opening.11 Since formation of the b-isomer
could be rationalized by invoking iso-propylidene steric
control embodied within the Henbest rule,11,12 the fol-
lowing sequence to 9 as the only product was employed:
deprotection of the iso-propylidene of 8 (to the 2,3-diol),
epoxidation with mCPBA, and re-introduction of the
iso-propylidene (step c, Scheme 1). Nucleophilic opening
of 9 with adenine gave, after careful silica gel column
chromatographic separation (MeOH/EtOAc, 1:30), 10
(43%) and 11 (39%). A similar result was achieved with
sodium azide as nucleophilic source on a substrate anal-
ogous to 9.11,13
nol provided 13 (4 steps, 65% yield from 10).
Debenzylation of 13 with trifluoroacetic acid and, subse-
quent acidic deketalization completed the synthesis of
3
14 (Scheme 1). Structural confirmation for 3 came from
a proton NMR analysis15: (i) appearance of a peak at d
6.60 is in the expected region16 for H-60;(ii) H-6 of iso-
0
meric neplanocin A has been reported to appear at d
0
5.6915b;and (iii) presence of an H-4 peak for 3 (d
2.79) while there was, of course, no corresponding peak
for neplanocin A.15b
The synthesis of 4 began with a Tamao oxidation of 1417
(Scheme 2) followed by selective trityl protection of the
resultant primary alcohol to give 15 in 65% yield. Epox-
idation11 of 15 followed by methoxybenzylation affor-
ded 16. Nucleophilic opening18 of 16 with adenine
resulted in the desired, single product 17.18 Following
the same steps for converting 10–3 (steps f and g of
Scheme 1), target 414b,19a was obtained from 17 (via 18).
The structure of 10 was established by comparing NMR
spectra: (i) compound 10 with a similarly C-50 protected
aristeromycin11 and (ii) compound 12, from deprotec-
tion of 10, with a racemic analog.11 Compound 11 was
confirmed by using a proton–proton COSY NMR
analysis, which will be detailed in the full paper on
this research.
The regiochemistry of 4 was confirmed by analyzing its
1H NMR spectrum,19 which was substantially different
from the isomeric 20-deoxyneplanocin.19,20 Particularly
diagnostic was its H-60 absorption (d 6.48), which is very
similar to 3, while the H-60 for 20-deoxyneplanocin exists
further upfield (d 5.75).
Introduction of a mesylate to C-60 of 10 was sought to
provide the desired leaving group at this center. How-
ever, direct mesylation of 10 using methylsulfonyl chlo-
ride failed. In view of this, blocking the C-6 purine
amine of 10 with N,N-dimethylformamide dimethyl ace-
tal then allowed smooth mesylate formation. Refluxing
this amino protected compound (not shown) with so-
dium methoxide in tetrahydrofuran followed by metha-
The biological analysis of 3 and 4 is underway and will
be presented in the full paper on this new class of nucleo-
side derivatives.

X. Yin, S. W. Schneller / Tetrahedron Letters 46 (2005) 1927–1929
1929
NH2
NH2
N
N
R
N
N
TrO
N
b
c
d
O
HO
N
N
N
6'
TrO
HO
R
pMBnO
16
4'
2'
14, R=Si(Me)2OiPr17
15, R=OTr
R'O
a
pMBnO
17
18, R=OTr; R'=pMBn
4, R=OH; R'=H
e
Scheme 2. Reagents and conditions: (a) (i) KF, KHCO3, H2O2, MeOH/THF (v/v, 50%), 75%;(ii) TrCl, pyridine, DMAP, 86%;(b) (i) mCPBA,
CH2Cl2, 75%;(ii) pMBnCl, NaH, DMF, 94%;(c) adenine, NaH,15-crown-6, DMF, 91%;(d) (i) HC(OMe) 2NMe2, DMF;(ii) MsCl, DMAP, CH 2Cl2;
(iii) NaOMe, THF/MeOH, reflux;(iv) MeOH, reflux (65% for four steps);(e) (i) 10% TFA, CH 2Cl2;(ii) 1 N HCl (55% for two steps).
12. Henbest, H. B.;Wilson, R. A. L. J. Chem. Soc. 1957,
1958–1965.
Acknowledgements
13. Yin, X.;Schneller, S.W., unpublished results.
14. (a) HRMS for compound 3, 263.1014 (calcd 263.1018);(b)
satisfactory microanalytical data was obtained for com-
pounds 3 and 4.
This research was supported by funds from the NIH (AI
56540).
1
References and notes
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1H), 8.20 (s, 1H), 7.35 (br s, 2H), 6.60 (d, J = 1.75 Hz, 1H,
H-60), 5.30 (d, J = 4.25 Hz, 1H), 4.95 (t, J = 6.50 Hz, 1H),
4.83 (d, J = 7.0 Hz, 1H), 4.14 (m, 1H), 3.85 (m, 1H), 3.67
(m, 1H), 3.42 (m, 1H), 2.79 (m, 1H, H-40). 13C (DMSO-d6)
d 161.6, 158.4, 154.7, 143.9, 143.3, 125.0, 124.5, 77.9, 76.4,
67.3, 57.8;(b) NMR data for neplanocin21: 1H (DMSO-d6)
d 8.11 (s, 1H), 8.05 (s, 1H), 7.20 (br s, 2H), 5.69 (s, 1H, H-
60), 5.33 (br d, J = 2.5 H, 1H), 5.16–4.92 (br s, 3H), 4.42
(d, J = 5.4 Hz, 1H), 4.30 (t, J = 5.4 Hz, 1H), 4.11 (m, 2H).
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´
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´
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