2
674
G. Zoidis et al. / Tetrahedron Letters 50 (2009) 2671–2675
defined at 1.75 ppm and 1.65 ppm due to their correlations with H-
and H-11. Proton H-10b was identified at 1.65 ppm through the
of the 1,2-annulated oxetane 4, which is a useful intermediate
for the preparation of bioactive adamantane derivatives.
9
NOE peaks observed with both H-14b and H-8b. The assignment of
H-10a at 1.75 ppm was also confirmed by its NOE correlations with
H-12b and H-13b.
Acknowledgments
The NMR spectra of compound 6 (Fig. 1B) show a number of
similarities with those of 5 as was expected, and the conforma-
tional assignment was accomplished in an analogous way. The
Dr. Zoidis would like to thank the State Scholarship Foundation
of Greece for financial support. L.N. acknowledges the technical
assistance from Leentje Persoons and Frieda Demeyer.
1
13
H and C chemical shifts of 6 are summarized in Table 3. Only
weak differences in chemical shifts between compounds 5 and 6
were observed. A downfield shift of 0.7 ppm for C-2 and 1.0 ppm
for C-6 of compound 6 was apparent. The corresponding protons
experience an upfield shift of 0.82 ppm for H-2 and an average of
Supplementary data
0
.60 ppm for the H-6 methylene protons. Additionally, C-8 shows
a 0.9 ppm downfield shift although the H-8 methylene protons
seem to be less affected with an average upfield shift of
References and notes
0
.13 ppm (Table 3).
Theoretical calculations were performed to rationalize the ob-
1
.
(a) Kolocouris, N.; Foscolos, G. B.; Kolocouris, A.; Marakos, P.; Pouli, N.; Fytas,
G.; Ikeda, S.; De Clercq, E. J. Med. Chem. 1994, 37, 2896–2902; (b) Kolocouris, N.;
Kolocouris, A.; Foscolos, G. B.; Fytas, G.; Neyts, J.; Padalko, E.; Balzarini, J.;
Snoeck, R.; Andrei, G.; De Clercq, E. J. Med. Chem. 1996, 39, 3307–3318; (c)
Zoidis, G.; Kolocouris, N.; Foscolos, G. B.; Kolocouris, A.; Fytas, G.; Karayannis,
P.; Padalko, E.; Neyts, J.; De Clercq, E. Antiviral Chem. Chemother. 2003, 14, 153–
served NMR differences and elucidate the orientation of the thio-
carbonyl group of 5. Ab initio single point calculations were
performed on AM1 preoptimized geometries at the restricted HF
level of theory using the 6-31(d,p) basis set for compounds 5-eq
164; (d) De Clercq, E. Nat. Rev. Drug Discovery 2006, 5, 1015–1025; (e) Fytas, G.;
Stamatiou, G.; Foscolos, G. B.; Kolocouris, A.; Kolocouris, N.; Witvrouw, M.;
Pannecouque, C.; De Clercq, E. Bioorg. Med. Chem. Lett. 1997, 7, 1887–1890; (f)
Kolocouris, N.; Zoidis, G.; Foscolos, G. B.; Fytas, G.; Prathalingham, S. R.; Kelly, J.
M.; Naesens, L.; De Clercq, E. Bioorg. Med. Chem. Lett. 2007, 17, 4358–4362; (g)
Zoidis, G.; Tsotinis, A.; Kolocouris, N.; Kelly, J. M.; Prathalingam, S. R.; Naesens,
L.; De Clercq, E. Org. Biomol. Chem. 2008, 6, 3177–3185; (h) Maryanoff, B. E.;
Costanzo, M. J.; Shank, R. P.; Schupsky, J. J.; Ortegon, M. E.; Vaught, J. L. Bioorg.
Med. Chem. Lett. 1993, 3, 2653–2656; (i) Xiao, Z.; Han, S.; Bastow, K. F.; Lee, K. H.
Bioorg. Med. Chem. Lett. 2004, 14, 1581–1584.
(
with S@O in equatorial orientation), 5-ax (with S@O in axial ori-
entation), and 6. All C and H chemical shifts were determined with-
in the GIAO approach as implemented in the GAUSSIAN98 program
2
5
and are summarized in Table 3. Large deviations were noticed for
C-2 (6.7 ppm), and C-6 (6.0 ppm) between the two conformations
of 5, which demonstrate the influence of the thiocarbonyl orienta-
tion on the chemical shift, while for all the other carbons the differ-
ence varied from À1.0 to 0.8 ppm. Moreover the C-2 and C-6
calculated chemical shifts of 5-eq are nearly identical with the cor-
responding values of dioxane 6. More specifically, in the case of
conformer 5-eq, carbons C-2 and C-6 are shifted upfield by only
2.
Gish, D. T.; Kelly, R. C.; Camiener, G. W.; Wechter, W. J. J. Med. Chem. 1971, 14,
1159–1162.
3. Wood, G.; Miskow, M. H. Tetrahedron Lett. 1969, 1109–1112.
4
5
6
.
.
.
Cazaux, L.; Maroni, P. Tetrahedron Lett. 1969, 3667–3670.
Cazaux, L.; Chassaing, G.; Maroni, P. Tetrahedron Lett. 1975, 2517–2520.
Mustoe, F. J.; Hencher, J. L. Can. J. Chem. 1972, 50, 3892–3899.
0
.8 and 0.5 ppm being close to the overall average difference. In
7. van Woerden, H. F.; Cerfontain, H.; Green, C. H.; Reijerkerk, R. J. Tetrahedron
Lett. 1968, 6107–6110.
contrast, in the case of conformer 5-ax, the calculated chemical
shifts of C-2 and C-6 are 7.5 and 6.5 ppm upfield with respect to
the corresponding carbons of dioxane 6, while all the other carbons
differ by 0.4 ppm on average. These calculated chemical shift dif-
ferences between 5-ax and 6 as well as the calculated and experi-
mentally observed similarities of the corresponding values
between 5-eq and 6, suggest that the thiocarbonyl moiety adopts
an equatorial orientation.
The proposed configuration is in agreement with Virtanen et
al.,11 who have described that 2-oxo-1,3,2 dioxathianes, when
substituted with large alkyl groups such as isopropyl and tert-bu-
tyl, exist preferentially in the chair conformation with an equato-
8.
Eccleston, G.; Hamblin, P. C.; Pethrick, R. A.; White, R. F. M.; Wyn-Jones, E.
Trans. Faraday Soc. 1970, 66, 310–315.
9. Overberger, C. G.; Kurtz, T.; Yaroslavsky, S. J. Org. Chem. 1965, 30, 4363–4364.
1
0. Edmundson, R. S. Tetrahedron Lett. 1965, 1649–1652.
11. Virtanen, T.; Nikander, H.; Pihlaja, K.; Rahkamaa, E. Tetrahedron 1982, 38,
2821–2830.
12. van Oyen, J. W. L.; Hasekamp, R. C. D. E.; Verschoor, G. C.; Romers, C. Acta
Crystallogr., Sect. B 1968, 24, 1471–1477.
1
1
3. Pihlaja, K.; Nikander, H.; Jordan, D. M. Adv. Mass Spectrom. 1980, 821.
4. (a) Acheson, R. M. An Introduction to the Chemistry of Heterocyclic Compounds;
Interscience: New York, 1962; (b) Hudrlik, P. F.; Wan, C.-N. J. Org. Chem. 1975,
40, 2963–2965. and references cited therein.
15. (a) Schneider, G.; Weisz-Vincze, I.; Vass, A.; Kovacs, K. Chem. Commun. 1972,
713; (b) Darko, L. L.; Cannon, J. G. J. Org. Chem. 1967, 32, 2352–2354; (c)
Reinenke, M. G.; Kray, L. R. J. Org. Chem. 1964, 29, 1736–1739; (d) Kovacs, O.;
Weisz, I.; Zoller, P.; Fodor, G. Helv. Chim. Acta 1956, 39, 99–110; (e) Searles, S.,
Jr.; Gregory, V. P. J. Am. Chem. Soc. 1954, 76, 2789–2790; (f) Searles, S. J. Am.
Chem. Soc. 1951, 73, 124–125.
rial S@O group. Moreover, our findings are in accordance with
NMR data reported recently by Garcia-Granados et al.,26 for two
cyclic sulfite derivatives of the eudesmane natural product. These
two compounds differing only in the S@O orientation were struc-
turally characterized by X-ray crystallography and NMR spectros-
copy. Carbon chemical shift differences were only observed for
16. Kolocouris, N.; Zoidis, G.; Fytas, C. Synlett 2007, 1063–1066.
17. Farcasius, D. J. Am. Chem. Soc. 1976, 98, 5301–5305.
1
8. (a) Fames, J.; Warren, S. Tetrahedron Lett. 1996, 37, 3525–3528; (b) Moon Kim,
B.; Sharpless, K. B. Tetrahedron Lett. 1990, 31, 4317–4320.
9. Oxetane 4 (viscous oil) 1H NMR (400 MHz, CDCl
1
3
), d: 1.35–1.38 (m, 2H, H-6b,
the atoms in
c positions relative to the exocyclic oxygen atom.
H-12b), 1.48 (m, 1H, H-6a), 1.57 (m, 1H, H-10b), 1.70 (m, 1H, H-8b), 1.79 (m,
2
1
H, H-8a, H-11a), 1.85–1.93 (m, 2H, H-1, H-11b), 1.93–2.01 (m, 2H, 7-H, H-
The chemical shifts of carbons C-2 and C-6 of compound 5 are in
complete agreement with the corresponding carbons in eudes-
mane cyclic sulfite (84.2 and 72.5 ppm, respectively) with the
S@O in the equatorial position. In the axial isomer, the correspond-
0a), 2.04 (m, 1H, H-9), 2.60 (m, 1H, H-12a), 3.25 (d, J = 11.2 Hz, 1H, H-4b), 4.55
13
(
3
d, J = 11.0 Hz, 1H, H-4a), 5.00 (br s, 1H, H-2) ppm. C NMR (CDCl , 100 MHz),
d: 27.0 (C-9), 27.5 (C-7), 30.0 (C-10), 31.3 (C-1), 34.1 (C-12), 34.3 (C-5), 38.1 (C-
6
C
), 36.9 (C-11), 36.9 (C-8), 67.3 (C-4), 73.6 (C-2) ppm. HRMS (ESI, m/z) calcd for
11
H16O [M ] 164.2468, found 164.2484.
+
ing atoms were shielded as rationalized by the c-gauche effect and
2
0. Dioxathiane 5, mp 83 °C (ether-n-pentane); HRMS (ESI, m/z) calcd for
+
predicted by our calculations in the case of the 5-ax conformer.
In conclusion, 1,2-annulated adamantane dioxathiane was syn-
thesized, structurally characterized, and examined for its antiviral
activity. NMR data suggest that the cyclic sulfite moiety exists in a
chair conformation with the S@O group equatorially oriented. The
antiviral properties of 5 should trigger future research on cyclic
sulfite derivatives and possibly the discovery of new antiviral
drugs. Furthermore, we describe a facile and effective synthesis
C11H16O S [M ] 228.3116, found 228.3193.
3
3
,7
21. 2-Bromo-1-tricyclo[3.3.1.1 ]decanemethyl bromide (7):
A
solution of
triphenyldibromophosphorane was prepared by the dropwise addition of Br
2
(
(
2.78 g, 17.4 mmol) in benzonitrile (12 mL) to a solution of triphenylphosphine
4.57 g, 17.4 mmol) in benzonitrile (15 mL) and the resulting solution was
stirred at 122 °C under an argon atmosphere. To this solution, was added in one
portion, the oxetane derivative 4 (2.26 g, 13.7 mmol) and the mixture was
heated at 127 °C for 4 h. The mixture was cooled to room temperature, n-
pentane was added, and the precipitate formed was removed by filtration and
washed with n-pentane. The washings were combined and the upper layer was