Enantiospecific synthesis of 5′,5′,5′-trifluoro-5′- deoxyneplanocin A

Article abstract of DOI:10.1016/j.tetlet.2005.10.064

(-)-(1S,4R)-4-Hydroxy-2-cyclopenten-1-yl acetate provided a convenient entry point for a 12-step chiral preparation of 5′,5′,5′- trifluoro-5′-deoxyneplanocin A.

Full text of DOI:10.1016/j.tetlet.2005.10.064

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8913–8915
Enantiospecific synthesis of 50,50,50-trifluoro-50-deoxyneplanocin A
Atanu Roy and Stewart W. Schneller*
Department of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849-5312, USA
Received 24 September 2005; accepted 17 October 2005
Available online 4 November 2005
Abstract—(À)-(1S,4R)-4-Hydroxy-2-cyclopenten-1-yl acetate provided a convenient entry point for a 12-step chiral preparation of
50,50,50-trifluoro-50-deoxyneplanocin A.
Ó 2005 Elsevier Ltd. All rights reserved.
Inhibition of S-adenosyl-L-homocysteine (AdoHcy)
hydrolase, an enzyme with major responsibilities in
modulating biological methylations dependent on S-
adenosylmethionine (AdoMet), has served as a point
of convergence for antiviral drug design.1 From these
efforts, two structural features have arisen as meaning-
ful: nucleosides with (i) a carbocyclic framework2 and
(ii) C-50 fluorination.3 Neplanocin A (1) represents a
prominent entity in this area.4 Of particular relevance
to our program based on 1 (Fig. 1), and its saturated
derivative aristeromycin (2), for antiviral therapy re-
search was the report from De Clercqꢀs laboratory that
50-fluoro-50-deoxyneplanocin A has broad spectrum
potential.3a From this, and the fact that a C-50 poly-
flourinated adenosine has displayed mechanism-based
inhibition of AdoHcy hydrolase,3b we sought access to
the 50,50,50-trifluoro-50-deoxyneplanocin analogue (3).
This route is communicated herein.
The synthesis of 3 began with (À)-(1S,4R)-4-hydroxy-2-
cyclopenten-1-yl acetate (4)5 and its conversion to 5 in
high yield through a sequence of reactions (Scheme 1):
(i) hydroxyl protection, (ii) glycolization, (iii) isopropyl-
idenation, (iv) deacetylation, and (v) pyrdinium chloro-
chromate oxidation. Compound 5 was then transformed
to the trifluoromethyl derivative 6 by, first, reaction with
Ruppertꢀs reagent6,7 (CF3SiMe3) in the presence of a
catalytic amount of tetrabutylammonium fluoride
(0 °C) followed by desilylation with tetrabutylammo-
nium fluoride (room temperature). While the ultimate
stereochemical outcome of the 1,2-addition reaction
(Scheme 1, step b (i)) is not relevant to the goal of
obtaining 3, the configuration shown is likely because
of the hindered bottom face of 5 that blocks the a-addi-
tion of the trifluoromethyl group.
Based on the success of the Mitsunobu coupling reac-
tion for preparing carbocyclic nucleosides,8 the allylic
alcohol 9 was sought. This required the precursor
ketone 8 that, in turn, was expected to be accessible by
subjecting 6 to an oxidation followed by elimination
procedure.9 In that direction, oxidation of 6 with pyrid-
inium chlorochromate was found to produce 7 in 78%
yield (reaction conditions not specified in the scheme).
A similar result was also obtained when 6 was oxidized
with Dess–Martin periodinane reagent. The trifluoro-
methyl enone 8 was then obtained in 50% yield from 7
by reaction with methanesulfonyl chloride and triethyl-
amine (Scheme 1). In order to improve the yield of 8
from diol 6, a literature precedent was followed.10 In this
regard, a modified Pfitzner–Moffatt oxidation11 of 6
afforded a mixture of 7 in 40% yield and 8 in 36% yield.
However, when this reaction was left for 6 days in the
presence of excess oxidizing agent (8 equiv), compound
8 was obtained as the only product in high yield (80%).
NH2
N
NH2
N
N
N
N
N
N
HOH2C
N
R
OH
OH
HO
HO
1, R = CH2OH
3, R = CF3
2
Figure 1.
Keywords: Carbocylic nucleosides; Oxidation and elimination;
Mitsunobu coupling.
*
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.2005.10.064

8914
A. Roy, S. W. Schneller / Tetrahedron Letters 46 (2005) 8913–8915
AcO
OH
F3C
HO
OH
F3C
HO
OTBDPS
O
O
a
c
b
O
O
O
O
O
O
45
6
5
7
d
NH2
N
N
N
N
F3C
O
F3C
F3C
g
e
f
3
OH
O
O
O
O
O
O
10
9
8
Scheme 1. Reagents and conditions: (a) (i) TBDPSCl, imidazole, DMF, rt, 95%; (ii) OsO4, NMO, THF–H2O, acetone (8:1:1), rt, 90%; (iii)
Me2C(OMe)2, acetone, H+, rt, 94%; (iv) satd NH3 in MeOH, 100 °C, 92%; (v) PCC, CH2Cl2, rt, 90%; (b) (i) CF3SiMe3, TBAF (cat), THF, 0 °C; (ii)
TBAF, rt, 81% for two steps; (c) DMSO, CH2Cl2, EDC, HCl, pyridinium trifluoroacetate, 10 °C then rt for 36 h: 40% for 7, 36% for 8; for 6 days
with 8 equiv of oxidizing agent, only 8 (80%); (d) MsCl, Et3N, CH2Cl2, rt, 50%; (e) NaBH4, CeCl3Æ7H2O, MeOH, 0 °C, 78%; (f) (i) PPh3, DIAD,
6-chloropurine; (ii) satd NH3 in MeOH, 68% for two steps; (g) Dowex H+, MeOH, H2O(19:1), 90 °C, 80%. EDC = N-(3-dimethylaminopropyl)-
N0-ethylcarbodiimide.
Reduction of the trifluoromethyl enone 8 with sodium
borohydride in methanol (using the Luche method)
yielded the alcohol 9. Mitsunobu reaction of 9 with
6-chloropurine followed by ammonolysis provided
10. Acidic deprotection of 10 furnished the target 3.12
ysis of 3 is underway and will be presented in a full paper
on this nucleoside derivative.
Acknowledgments
A proposed pathway to 8 from 6 is presented in Scheme
2 and follows from the initial oxidation to the key inter-
mediate 7 and calls upon the work of Moffatt and his
collaborators13 to evoke the N-(3-dimethylaminoprop-
yl)-N0-ethylcarbodiimide hydrochloride (EDC)-DMSO
adduct (11). The transformation of 13 into 8 would be
favored by a six-membered transition state.
This research was supported by funds from the NIH (AI
56540).
References and notes
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In conclusion, a highly efficient synthetic route to 50-
deoxy-50,50,50-trifluoro neplanocin
A 3 has been
described via a key intermediate 8. The biological anal-
H+
H+
F3C
R
RHN
Me
C
O
S
N
Et
O
N
C N Et
HO
O
Me
O
O
S
Me Me
7
11
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H
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3996.
F3C
F3C
H2C
Me
O
Me
Me
8
-H+
O
S
S
O
O
O
O
O
O
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13
12
R=(CH2)3NMe2
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Scheme 2.

A. Roy, S. W. Schneller / Tetrahedron Letters 46 (2005) 8913–8915
8915
11. Agouridas, C.; Denis, A.; Auger, J.-M.; Benedetti, Y.;
Bonnefoy, A.; Bretin, F.; Chantot, J.-F.; Dussarat, A.;
30-H), 5.47 (1H, d, J 7.6, 20-OH), 5.70 (1H, d, J 7.2,
30-OH), 6.57 (1H, d, J 2.1, 60-H), 7.46 (2H, br s, 6-NH2),
8.25 (1H, s, 8-H), 8.35 (1H, s, 2-H); dC (100 MHz; DMSO-
d6; Me4Si) 53.2 (q, JC1,F 26.6), 69.0, 72.1, 109.7 (q, JC,F
3.3) 119.1, 127.2 (q, JC,F 277.1), 138.4, 139.8, 149.4,
153.5, 156.2; dF(250 MHz; DMSO-d6; CF3C6H5) À71.1 (d,
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`
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24:3
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22.8. C11H10F3N5O2Æ0.17H2Orequires C, 43.4; H, 3.4; N,
23.0); dH (400 MHz; DMSO-d6; Me4Si) 3.56–3.66 (1H,
m, 10-H), 4.28 (1H, q, J 7.30, 20-H), 5.11 (1H, t, J 6.7,
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