R. L. Mackman et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1116–1119
1117
adenosine deaminase type II.9 Attempts to oxidize 12
to the 50-carboxylic acid without protection of the gua-
nosine base proved difficult. Therefore, the 2-amino
group was protected once again as the 2-N-isobutyryl
amide 13. Acetylation of the ribose hydroxyl groups,
followed by Mitsunobu mediated installation of the 6-
O benzyl ether, and subsequent removal of the acetyl
groups yielded the base protected intermediate 14.11 14
was converted to acid 15, using platinum-catalyzed oxi-
dation in 37% yield.12 Decarboxylative dehydration of
acid 15 by heating in the presence of DMF-dineopentyl-
alcohol formed the intermediate glycal 16, which, with-
out purification, was activated with PhSeCl and
converted to phosphonate 17.13 The instability of the
glycal intermediate was also a challenge in this synthetic
route and care had to be used to avoid extensive depu-
rination and furan formation. Oxidation of selenium
by O3 followed by elimination provided olefin derivative
18. Finally, 18 was treated with TMSI in DMF and
2,4,6-collidine at 45 °C to simultaneously remove both
the phosphonate ester groups and the 6-O benzyl ether.
Treatment with concentrated ammonium hydroxide to
remove the isobutyryl group then yielded the ammo-
nium salt of guanosine phosphonate 19.
NHpiv
NH2
N
N
N
N
N
N
N
(i)-(iii)
O
Et2O3P
O
O
O
N
H2O3P
F
PhSe
F
5
6, 2'-FddAP
Scheme 1. Reagents and conditions: (i) n-Bu3SnH, AIBN, benzene; (ii)
NaOMe, MeOH, 100%; (iii) TMSBr, DMF, lutidine, 50 °C, then
NH4OH.
(Scheme 2 and 3). The focus was directed specifically to
purine analogs since earlier pyrimidine analogs of 4
demonstrated poor resistance profiles toward key HIV
mutations.7 Guanosine analog 19 was prepared from
the fluoro sugar 7 according to Scheme 2. Initially, con-
version of 7 to the anomeric bromide, by treatment with
HBr,2 was followed by the attempted addition of 2-N-
isobutyryl amide, 6-O diphenylcarbamoyl protected
guanine to provide 8. Unfortunately, the addition was
low-yielding and also resulted in significant amounts
of the N-7 substituted product that made efficient isola-
tion of the desired N-9 product problematic. Explora-
tion of alternative guanine precursors identified 2,6-
dichloropurine as the optimal precursor, which coupled
with the anomeric bromide to yield intermediate 9 in
64% yield.8 Treatment of 9 with sodium azide in reflux-
ing EtOH resulted in 10 which was then reduced and
debenzoylated using NaBH4 in ethanol to provide diam-
inopurine nucleoside 11.9,10 Diaminopurine 11 was then
enzymatically converted to guanosine analog 12, by
A logical approach to the 2,6-diaminopurine phospho-
nate analog 24 was to utilize the 2,6-diaminopurine
nucleoside 11, but attempts to form the corresponding
glycal intermediate, after oxidiation to the 50-carboxylic
acid, were unsuccessful. Therefore, an alternative route
from 2,6-dichloro intermediate 9 was pursued (Scheme
R
NH2
N
O
N
N
N
N
N
N
N
NH
R
O
OBz
i, ii
iii
O
O
N
R1
N
NH2
v
BzO
BzO
iv
O
N
BzO
BzO
HO
HO
F
F
HO
F
HO
12 R = NH2
13 R = NHCOiPr
F
7
11
8
9
R = OCON(Ph)2, R1 = NHCOiBu
R = R1 = Cl
10 R = R1 = N3
vi
vii-ix
OBn
N
OBn
N
OBn
N
OBn
N
N
N
O
N
N
N
N
N
O
O
O
O
xi
O
N
N
H
x
N
O
F
N
N
O
N
N
HO
O
N
N
Et2O3P
O
HO
H
H
H
HO
F
HO
15
F
PhSe
F
14
17
16
xii
O
N
OBn
N
N
N
N
NH
NH2
O
xiii-xiv
O
O
N
H2O3P
O
O
N
N
H
Et2O3P
F
F
19, 2'-Fd4GP
18
Scheme 2. Reagents and conditions: (i) HBr, AcOH; (ii) NaH, CH3CN, 2,6-dichloropurine, 64%; (iii) NaN3, EtOH, reflux, 1 h, 100%; (iv) NaBH4,
EtOH , dioxane; (v) adenosine deaminase type II, rt, 16 h, 100%; (vi) TMSCl, pyridine, (iPrCO)2O, concd NH4OH, 70%; (vii) Ac2O, Py, 71%; (viii)
t
Ph3P, BnOH, DIAD, dioxane; (ix) NaOMe, MeOH, rt, 44% (two steps); (x) O2, 10% Pt/C, H2O, 60 °C, 24 h, 37%; (xi) a—Me2NCH(OCH2 Bu)2,
CH3SO3H, 100 °C; b—PhSeCl, HOCH2P(O)(OEt)2, AgClO4; (xii) O3, CH2Cl2, 0–45 °C; (xiii) TMSI, 2,4,6-collidine, DMF, 45 °C; (xiv) concd
NH4OH, 45 °C, 5 h.