(+)-Neplanocin F, 2′-fluoroneplanocin, and a 6′-isoneplanocin via a common versatile cyclopentenol precursor

Article abstract of DOI:10.1016/j.tetlet.2011.07.059

Reductive (diisobutylaluminum hydride) ring opening of an acetal protected cyclopentenol has provided a precursor adaptable to uniquely substituted carbocyclic nucleosides. To illustrate the broad implication of this process the preparation of unnatural (

Full text of DOI:10.1016/j.tetlet.2011.07.059

Tetrahedron Letters 52 (2011) 4931–4933
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Tetrahedron Letters
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(+)-Neplanocin F, 20-fluoroneplanocin, and a 60-isoneplanocin
via a common versatile cyclopentenol precursor
⇑
Chong Liu, Qi Chen, Stewart W. Schneller
The Molette Laboratory for Drug Discovery, Department of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849-5312, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Reductive (diisobutylaluminum hydride) ring opening of an acetal protected cyclopentenol has provided
a precursor adaptable to uniquely substituted carbocyclic nucleosides. To illustrate the broad implication
of this process the preparation of unnatural (+)-neplanocin F, an ara-like 20-fluoroneplanocin, and a
Received 12 June 2011
Revised 6 July 2011
Accepted 12 July 2011
Available online 22 July 2011
60- isomeric
L-like neplanocin analog is described.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Carbocyclic nucleosides
Mitsunobu reaction
Diisobutylaluminum hydride ring-opening
For a number of years our laboratories at Auburn have been
engaged in embellishing known adenine derived carbocyclic
nucleosides as biological entities.1 In that effort, there continues
to be a need for access to uniquely substituted cyclopentyl repre-
sentatives. We recognized that, perhaps, the frequently used 20O/
30O acetal/ketal protecting partner in carbocyclic nucleoside syn-
theses could be partially opened in such a way that a fragment
of the protector would be retained as a removable ether substitu-
ent availing versatile carbocyclic nucleoside precursors. Our inves-
tigations led us to the reaction of diisobutylaluminum hydride2
with acetals.
To assess this idea we began with the protected cyclopentenol
13 (Scheme 19) and found that 5 equiv of DIBAH yielded 24 (64%)
as a possible precursor to neplanocin cohorts that require a free
20-hydroxyl for development. To build on this achievement for
the stated goals, the known,5a but structurally unique, (+)-neplano-
cin F (3) was sought. Thus, the treatment of 2 with t-butyldimeth-
ylsilyl chloride (TBSCl) (to 4) followed by Mitsunobu coupling with
N6(bisBoc) protected adenine6 provided 5. However, complete
deprotection of 5 (to 3) could not be accomplished with the
isopropoxyl substituent remaining after a number of conditions
were attempted.
was accomplished by relating its COSY analysis to that previously
described for 2.4
As presented in the detailed synthetic steps of Scheme 3,11 it
was possible to move 16 forward to (+)-neplanocin F (3).5a To fur-
ther explore 16 as a versatile precursor to other carbocyclic nucleo-
sides, its conversion to the ara-like 2-fluoroneplanocin (17)7 and
the L
-like 60-isoneplanocin (18)8 are likewise specifically shown
in Scheme 3.
N(Boc)2
N
N
TrO
N
N
TBSO
OTr
OR
OH
c
O
on 4
O
2, R=H
4, R=TBS
b
5
NH2
a to 2
N
N
N
TrO
HO
OH
This result led to the consideration of using the benzylidene
protected 2,3-diol 6 (prepared via Scheme 210) for our stated
purposes with the hope that debenzylation would be more produc-
tive. In that direction, treatment of 6 with DIBAH as before
(5 equiv) led to the requisite 16. Structural confirmation for 16
OH
N
O
O
OH
13
3
⇑
Corresponding author. Tel.: +1 334 844 6947; fax: +1 334 844 5748.
E-mail address: schnest@auburn.edu (S.W. Schneller).
Scheme 1. Reagents and conditions: (a) 5 equiv DIBAH, CH2Cl2, 64%; (b) TBSCl,
imidazole, CH2Cl2, 82%; (c) PPh3, DIAD, Ad(Boc)2, THF, 77%. (TBSCl = tBuMe2SiCl).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.059

4932
C. Liu et al. / Tetrahedron Letters 52 (2011) 4931–4933
OH
O
O
O
O
O
OR
OH
HO
TrO
TrO
e
TrO
b
c
d
on mixture
O
O
O
O
O
O
O
O
of 8a and 8b
R1 R2
R1 R2
R1 R2
R1 R2
8
9
10
11, R=H
a R1=H, R2=Ph or
b, R1=Ph, R2=H
12, R=TBS
f on 12
a
O
O
X
TrO
HO
j
i
TrO
OR
TrO
OH
O
OH
OH
on 15
HO
OH
O
BnO
O
O
R1 R2
7
R1 R2
16
6
13, R=TBS; X=O
g
h
14, R=TBS; X=CH2
15, R=H; X=CH2
Scheme 2. Reagents and conditions: (a) ZnCl2, PhCHO, 67% for mixture; (b) DMF, trityl chloride, DMAP, NEt3, 91%; (c) DIBAH, THF, ꢁ78 °C, 67%; (d) vinylmagnesium bromide,
THF, ꢁ78 °C, 95%; (e) TBSCl, imidazole, CH2Cl2, 78%; (f) oxalyl chloride, DMSO, CH2Cl2, NEt3, 94%; (g) n-BuLi, Ph3PCH3Br, THF; (h) TBAF, THF, 90%; (i) 2nd generation Grubbs
cat., CH2Cl2, 83%; (j) 5 equiv DIBAH, CH2Cl2, 61%. (TBSCl = tBuMe2SiCl).
N(Boc)2
NH2
N
N
N
N
N
N
N
TBSO
OTr
HO
TrO
b
c
N
a
OTBS
OH
16
BnO
OBn
OH
d
OH
19
3
20
g
O
TrO
N(Boc)2
N
NH2
b
f
N
N
OTr
OH
N
N
RO
e
O
on 22
N
N
N
21, R=Bn
22, R=H
TrO
BnO
OR
O
O
HO
18
OH
23
X
24, R=Bz; X=OH
25, R=Bz; X=F
26, R=H; X=F
h
N(Boc)2
NH2
N
N
N
N
N
N
N
i
b
on 26
c
N
TrO
BnO
HO
F
HO
F
17
27
Scheme 3. Reagents and conditions: (a) TBSCl, CH2Cl2–DMF, imidazole, 85%; (b) PPh3, DIAD, Ad(Boc)2, THF, 77% for 20, 87% for 23, 88% for 27; (c) (i) BCl3, CH2Cl2, (ii) HCl/
MeOH, 81% for 3, 77% for 17; (d) TsOH, 2,2-dimethoxypropane, acetone, 94%; (e) BF3ꢀEt2O, CH2Cl2, 76%; (f) HCl/MeOH, 83%; (g) BzCl, pyridine, 78%; (h) DAST, CH2Cl2, 74%; (i)
NaOH, MeOH, 77%. (TBSCl = tBuMe2SiCl).
Further investigations are underway to expand this method to
other neplanocin derivatives (e.g., 20-deoxy), aristeromycin ana-
logs, free 30-hydroxy frameworks resembling 16, and 50-homo
products.
Acknowledgment
Support from the Molette Fund and Auburn University is
appreciated.

C. Liu et al. / Tetrahedron Letters 52 (2011) 4931–4933
4933
MeOH), d 8.20 (s, 1H), 8.12 (s, 1H), 5.91 (td, J = 1.6, 2.0 Hz, 1H), 5.50 (m, 1H),
4.62 (d, J = 6.0 Hz, 1H), 4.39 (t, J = 6.0 Hz, 1H), 4.32 (m, 2H); 13C NMR (100 MHz,
MeOH) d 155.7, 151.9, 150.0, 149.9, 140.0, 124.0, 119.1, 77.3, 72.7, 65.1, 58.9;
HRMS calcd for C11H13N5O3 [M+H]+ 264.1097, found 264.1093.
References and notes
1. For recent references see: (a) Yin, X.-q.; Li, W.-k.; Yang, M.; Schneller, S. W.
Bioorg. Med. Chem. 2009, 17, 3126–3129; (b) Ye, W.; He, M.; Schneller, S. W.
Tetrahedron Lett. 2009, 50, 7156–7158.
2. (a) Ishihara, K.; Mori, A.; Arai, I.; Yamamoto, H. Tetrahedron Lett. 1986, 26, 983–
986; (b) Mori, A.; Ishihara, K.; Yamamoto, H. Tetrahedron Lett. 1986, 27, 987–
990; (c) Mori, A.; Fujiwara, J.; Maruoka, K.; Yamamoto, H. J. Organomet. Chem.
1985, 285, 83–94.
6. Dey, S.; Garner, P. J. Org. Chem. 2000, 65, 7697–7699.
7. Chu, C. K.; Cho, J. H.; Kim, H. J. U.S. Patent 0,270,431, 2009. Selected data for 17:
white solid; 1H NMR (400 MHz, MeOH), d 8.22 (s, 1H), 8.00 (s, 1H), 5.97 (m, 1H),
5.87 (m, 1H), 5.12 (ddd, J = 2.8, 5.6, 48 Hz, 1H), 4.97 (m, 1H), 4.35 (m, 2H); 13C
NMR (100 MHz, MeOH) d 157.5,153.4 (d, J = 6 Hz), 153.3, 151.1, 141.7,122.4,
120.2, 97.8 (d, J = 194 Hz), 79.3 (d, J = 26 Hz), 59.8, 59.1 (d, J = 17 Hz); HRMS
calcd for C11H12FN5O2 [M+H]+ 266.1053, found 266.1044.
3. Cho, J. H.; Bernard, D. L.; Sidwell, R. W.; Kern, E. R.; Chu, C. K. J. Med. Chem. 2006,
49, 1140–1148.
8. Selected data for 18: white solid; 1H NMR (400 MHz, MeOH), d 8.17 (s, 1H), 8.11
(s, 1H), 6.11 (s, 1H), 5.51 (d, J = 5.6 Hz, 1H), 4.69 (m, 1H), 4.60 (t, J = 5.6 Hz, 1H),
3.02–3.14 (m, 2H); 13C NMR (100 MHz, MeOH) d 155.9, 152.2, 149.6, 144.6,
140.9, 129.6, 119.2, 76.4, 71.9, 65.4, 58.2; HRMS calcd for C11H13N5O3 [M+H]+
264.1097, found 264.1094.
4. The structural assignment for 2 was accomplished by a 1H COSY experiment in
the following way: the H-1 vinyl proton at d 6.00 ppm correlated with the H-5
proton, which, in turn, correlated with its hydroxyl proton. With this data, H-3
and H-4 could be identified and only H-4 showed correlation with a hydroxyl
hydrogen, rendering the C-3 center with the isopropoxyl substituent.
1
9. For leading references for the less customary procedures see Ref. 1b.
10. For leading references for the less customary procedures see Refs. 1, 2 and (a)
Yin, X.-q.; Schneller, S. W. Tetrahedron Lett. 2005, 46, 1927–1929; (b) Yang, M.;
Ye, W.; Schneller, S. W. J. Org. Chem. 2004, 69, 3993–3996.
11. For leading references for the less customary procedures see Ref. 1 and (a) Yin,
X.-q.; Schneller, S. W. Tetrahedron 2005, 61, 1839–1843; (b) Zhou, J.; Yang, M.;
Akdag, A.; Wang, H.; Schneller, S. W. Tetrahedron 2008, 64, 433–438.
5
TrO
2
OH
3 4
O
OH
2
5. (+)-Neplanocin F: (a) Comin, M. J.; Leitofuter, J.; Rodriguez, J. B. Tetrahedron
2002, 58, 3129–3136 (b) Selected data for 3: white solid; 1H NMR (400 MHz,