of compounds has been targeted because of the potent
antiviral and antitumor properties of select members. The
strong inhibitory capability of neplanocin A on S-adenosyl-
L-homocysteine hydrolase6 and the notable inhibitory proper-
ties of carbovir triphosphate against HIV transcriptase7 are
exemplary.8 This structural modification is also recognized
to offer improved metabolic stability in view of the absence
of a glycosidic linkage.
pyridine11 under optimized conditions (0 °C f rt) afforded
9 in 56% yield with diminished operation of competing
Wagner-Meerwein rearrangement (ca. 25%) (Scheme 2).
Scheme 2
Retrosynthetic evaluation of 3 and 4 led us back to readily
available (()-spiro[4.4]nonane-1,6-dione,9 the reduction of
which with Lit-Bu(i-Bu)2AlH has previously been shown to
deliver exclusively the racemic cis,cis-diol.10 The latter can
be efficiently resolved with generation of (-)-5 and (+)-5
via ketalization with (1R)-(+)-camphor.10 The levorotatory
enantiomer of 5 was expected to serve as a reliable precursor
to 3 in view of the absolute configurational features of this
pair of compounds (Scheme 1). To secure 6, we envisioned
Scheme 1
This unsaturated spirocycle was subjected to the chromium
trioxide-3,5-dimethylpyrazole complex11,12 in such a fashion
that 10 emerged without suffering loss of structural integrity.
Application of the Luche reduction13 to 10 proceeded with
no evidence of π-facial selectivity to deliver 11 and 12 in a
1:1 diastereomeric ratio. However, since these allylic alcohols
are amenable to ready chromatographic separation, the
tandem transformation of 11 into 12 by the Mitsunobu
protocol14 constituted a convenient means for generating
appreciable amounts of the latter epimer.
This accomplished, 12 was subjected in turn to catalytic
hydrogenation, SN2 displacement with N4-benzoylcytosine
and N3-benzoylthymine,15,16 diisopropyl azodicarboxylate,
and triphenylphosphine in tetrahydrofuran or dioxane,17
ammonolysis,18 and desilylation. These reactions proved
suitable monoprotection, dehydration to the cyclopentene,
and allylic oxidation as a prelude to utilization of the
Mitsunobu reaction. Fruitful deployment of dextrorotary 5
was likewise seen to involve the elimination of water to
generate a monounsaturated intermediate. Subsequent regio-
selective hydroboration-oxidation would culminate in overall
1,2-transposition of the OH group (see 7) and ultimately the
delivery of 4 by way of SN2 displacement.
The same nonbonded steric compression that facilitated
the monosilylation of 5 was expected to complicate the
dehydration of 8, and this proved to be the case. Nevertheless,
recourse to the oxophilic phosphorus oxychloride reagent in
(6) Borchardt, R.; Keller, B.; Patel-Thrombe, U. J. Biol. Chem. 1984,
259, 4353.
(7) (a) Coates, J. A. V.; Inggall, H. J.; Pearson, B. A.; Penn, C. R.; Storer,
R.; Williamson, C.; Cameron, J. M. AntiViral Res. 1991, 15, 161. (b) Vince,
R.; Hua, M.; Brownell, J.; Daluge, S.; Lee, F.; Shannon, W. M.; Lavelle,
G. C.; Qualls, J.; Weislow, O. S.; Kiser, R.; Canonico, P. G.; Schultz, R.
H.; Narayanan, V. L.; Mayo, J. G.; Shoemaker, R. H.; Boyd, M. R. Biochem.
Biophys. Res. Commun. 1988, 156, 1046.
(8) For reports detailing activity against other viruses, see: (a) Slusarchyk,
W. A.; Young, M. G.; Bisacchi, G. S.; Hockstein, D. R.; Zahler, R.
Tetrahedron Lett. 1989, 30, 6453. (b) Borthwick, A. D.; Kirk, B. E.;
Biggadike, K.; Exall, A. M.; Butt, S.; Roberts, S. M.; Knight, D. J.; Coates,
J. A. V.; Ryan, D. M. J. Med. Chem. 1991, 34, 907. (c) Price, P. M.;
Banerjee, R.; Jeffrey, A. M.; Acs, G. Hepatology 1992, 16, 8.
(9) (a) Nieman, J. A.; Keay, B. A.; Kubicki, M.; Yang, D.; Rauk, A.;
Tsankov, D.; Wieser, H. J. Org. Chem. 1995, 60, 1918. (b) Nieman, J. A.;
Keay, B. A. Tetrahedron: Asymmetry 1993, 4, 1973.
(11) Wright, J.; Drtina, G. J.; Roberts, R. A.; Paquette, L. A. J. Am.
Chem. Soc. 1988, 110, 5806.
(12) (a) Salmond, W. G.; Barta, M. A.; Havens, J. L. J. Org. Chem.
1978, 43, 2057. (b) Kok, P.; De Clercq, P. J.; Vandewalle, M. E. J. Org.
Chem. 1979, 44, 4553.
(13) Luche, J. L. J. Am. Chem. Soc. 1978, 100, 2226.
(14) Georg, G. I.; Kant, J.; Gill, H. S. J. Am. Chem. Soc. 1987, 109,
1129.
(15) Cruickshank, K. A.; Jiricny, J.; Reese, C. B. Tetrahedron Lett. 1984,
25, 681.
(16) Brown, D. M.; Todd, A.; Varadarajan, S. J. Chem. Soc. 1956, 2384.
(17) Jenny, T. F.; Previsani, N.; Benner, S. A. Tetrahedron Lett. 1991,
32, 7029.
(18) Wang, P.; Gallen, B.; Newton, M. G.; Cheng, Y.; Schinazi, R. F.;
Chu, C. K. J. Med. Chem. 1999, 42, 3390.
(10) Nieman, J. A.; Keay, B. A. Synth. Commun. 1999, 29, 3829.
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