Conversion of the enantiomers of spiro[4.4]nonane-1,6-diol into both epimeric carbaspironucleosides having natural C1′ absolute configuration

Article abstract of DOI:10.1021/ol0340033

(Matrix presented) The enantiomers of spiro[4.4]nonane-1,6-diol have been transformed by different reaction pathways into the two possible carbaspironucleoside epimers with natural C1′ absolute stereochemistry.

Full text of DOI:10.1021/ol0340033

ORGANIC
LETTERS
2003
Vol. 5, No. 6
869-871
Conversion of the Enantiomers of
Spiro[4.4]nonane-1,6-Diol into Both
Epimeric Carbaspironucleosides Having
Natural C1′ Absolute Configuration
Leo A. Paquette,* Ryan E. Hartung, and David J. France
Department of Chemistry, EVans Chemical Laboratories, The Ohio State UniVersity,
Columbus, Ohio 43210
paquette.1@osu.edu
Received January 2, 2003
ABSTRACT
The enantiomers of spiro[4.4]nonane-1,6-diol have been transformed by different reaction pathways into the two possible carbaspironucleoside
epimers with natural C1′ absolute stereochemistry.
The discovery made more than 15 years ago of the effective-
ness of 2′,3′-dideoxyinosine and 2′,3′-dideoxycytidine for the
treatment of AIDS1 can be singled out as the initiator of an
intense search for related therapeutic agents.2 Indeed, the
generation of new, structurally novel nucleosides continues
unabated to the present time. In this connection, we have
recently initiated an investigation of the effect of structural
preorganization in a spirocyclic manner on the pharmaco-
logical properties of nucleosides having this unprecedented
architectural feature.3,4 The several attractive characteristics
associated with the 1-oxaspiro[4.4]nonanyl diastereomers 1
and 2, which are conformationally biased but not confor-
mationally locked systems, have previously been outlined.3c
This paper reports on the synthesis of their carbocyclic
analogues 3 and 4 by a route that incorporates the novel
feature involving the merger of stereochemistries originating
from reactants possessing different absolute configuration.
(1) Mutsuya, H.; Broder, S. Proc. Natl. Acad. Sci. U.S.A. 1986, 83 1911.
(2) Huryn, D. M.; Okabe, M. Chem. ReV. 1992, 92, 1745.
(3) (a) Paquette, L. A.; Bibart, R. T.; Seekamp, C. K.; Kahane, A. L.
Org. Lett. 2001, 3, 4039. (b) Paquette, L. A.; Owen, D. R.; Bibart, R. T.;
Seekamp, C. K. Org. Lett. 2001, 3, 4043.
(4) For additional background studies, consult: (a) Paquette, L. A.; Owen,
D. R.; Bibart, R. T.; Seekamp, C. K.; Kahane, A. L.; Lanter, J. C.; Corral,
M. A. J. Org. Chem. 2001, 66, 2828. (b) Paquette, L. A.; Lanter, J. C.;
Owen, D. R.; Fabris, F.; Bibart, R. T.; Alvarez, M. Heterocycles 2001, 54,
49. (c) Paquette, L. A.; Brand, S.; Behrens, C. J. Org. Chem. 1999, 64,
2010.
In the past several years, interest in the carbocyclic
nucleoside field has become particularly intense.5 This class
(5) Reviews: (a) Ferrero, M.; Gotor, V. Chem. ReV. 2000, 100, 4319.
(b) Crimmins, M. T. Tetrahedron 1998, 54, 9229. (c) Borthwick, A. D.;
Biggadike, K. Tetrahedron 1992, 48, 571.
10.1021/ol0340033 CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/26/2003

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.
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R.; Williamson, C.; Cameron, J. M. AntiViral Res. 1991, 15, 161. (b) Vince,
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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.
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870
Org. Lett., Vol. 5, No. 6, 2003

(-)-enantiomer. Recourse to phosphorus oxychloride served
well as before, with (+)-9 now resulting (Scheme 3). The
pursuit of proper regiodirected hydration of (+)-9 soon
focused on the effective steric bulk of the hydroborating
agent. After some experimentation, disiamylborane proved
to be a reasonable compromise in that 17 and 18 were
produced in 19% and 51% yield, respectively. For the
purpose of maximizing the availability of 18, the Mitsunobu
reaction was again applied, this time to bring about con-
figurational inversion in 17. At this point, practical crossover
to the diastereomeric manifold had been achieved and the
ultimate generation of 19 and 20 was accomplished in a
manner similar to that developed earlier. The structural
assignments to 15/16 and 19/20 are based on extensive
mechanistic precedent14,19 and conform to their NMR spectral
properties.
Scheme 3
To sum up, the enantiomers of 8 have been transformed
by different synthetic pathways into epimeric spirocytidines
and spirothymidines. The rather novel “merger of chirality”
illustrated here holds sufficient potential generality that it is
expected to find application in the solution of other problems
in organic stereochemistry.
Acknowledgment. We thank the S.T. Li Foundation for
generous financial support.
Supporting Information Available: Spectral character-
ization for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
uneventful, proceeding with clean inversion of configuration
to deliver the targeted levorotatory spirocyclic carbanucleo-
sides 15 and 16.
The next phase of this undertaking called again for the
initial dehydration of 8, although now in the form of the
OL0340033
(19) Hughes, D. L. Org. React. 1992, 42, 335.
Org. Lett., Vol. 5, No. 6, 2003
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