5 (Figure 1). The gem-difluoromethylene (CF2) group was
at the C3′ position of compounds 5. Moreover, nucleosides
5 would combine the characteristics of compounds 1-4
based on the bioisosteric rationale (Figure 1).
Scheme 2
Our previous attempt to prepare L-3′-deoxy-3′,3′-difluoro-
4′-thiocytosine 5 via Pummerer reaction of compound 6
failed (Scheme 1).9 The oxidation of 6 followed by the
Scheme 1
ring opening of 13 with BnSH afforded the 1-thiofuranoside
14 as the main product, and our desired thioacetal 15 was
provided only in very low yield. More unfortunately, the
corresponding triflate 16, obtained via O-triflation of 15,
decomposed very quickly at room temperature.
Then, another strategy to thiosugar, pioneered by Mont-
gomery et al.,10 was attempted. Their method highlighted
the fact that reductive deprotection of SAc to SH with
DIBAL-H and simultaneous reduction of the methyl ester
to -CHO in the same molecule would give rise to thioactol
formation via spontaneous cyclization. Thus, developing a
practical route to thioacetate 19 starting from compound 11
was what should be first addressed (Table 1).
condensation with silyated N4-benzoylcytosine (Pummerer
recation) did not give our desired protected nucleoside 7,
but the regioisomer 8. The regiochemistry of the Pummerer
recation was determined by the kinetic acidity of the R-proton
of 4′-thiofuranose 6.
Table 1. Preparation of the Thioacetate 19
The new synthetic route was based on the supposition that
the target molecules 5 could be derived from the precursor
9 by introduction a base moiety using the glycosylation
reactions (Scheme 1). Intermediate 9 would be reached
through ring closure of the our developed versatile gem-
difluorinated synthon 10, which was easily prepared accord-
ing to our reported methodology.8a,9
entry
R
conditions
19 (%)
NRa
1
2
Ms AcSH (3 equiv)/CsF (3 equiv)/DMF/rt
Ms AcSH (3 equiv)/CsF (3 equiv)/DMF/50 °C defluorin
ationa
The construction of the special skeleton 9 appeared to be
a great challenge. Recently, Chu group reported the synthesis
of thiosugar through the corresponding riboside,7 which
stimulated us to prepare the intermediate 9 using the same
strategy. Thus, 3-deoxy-3,3-difluoro-D-arabinofuranose 12,
prepared from optically pure gem-difluorinated synthon 11
via our reported procedure,9 was converted to compound 13
by treatment with TsOH/MeOH (Scheme 2). However, the
3
Tf KSAc (3 equiv)/DMF
defluorin
ationa
72b
4
5
Tf AcSH (3 equiv)/CsF (3 equiv)/DMF/rt
Tf AcSH (5.4 equiv)/CsF (5.4 equiv)/DMF/rt 86b
a Determined by 19F NMR spectra. b Yield was based on chromatography
isolation over silica gel.
Otera and co-workers reported an efficient method of CsF/
DMF-mediated nucleophilic inversion of secondary mesyl-
ates and tosylates.11 Their strategy could be successfully
ultilized with a variety of oxygen-, sulfur-, nitrogen- and
carbo-nucleophiles. Thus, we think that thioacetate 19 could
(5) Yohimura, Y.; Kitano, K.; Yamada, K.; Satoh, H.; Watanabe, M.;
Miura, S.; Sakata, S.; Sasaki, T.; Matsuda, A. J. Org. Chem. 1997, 62, 3140.
(6) Jeong, L. S.; Moon, H. R.; Choi, Y. J.; Chun, M. W.; Kim, H. O. J.
Org. Chem. 1998, 63, 4821.
(7) Zhu, W.; Chong, Y.; Choo, H.; Mathews, J.; Schinazi, R. F.; Chu,
C. K. J. Med. Chem. 2004, 47, 1631.
(8) (a) Xu, X. H.; Qiu, X.-L.; Zhang, X.; Qing, F.-L. J. Org. Chem.
2006, 71, 2820. (b) Meng, W. D.; Qing, F.-L. Curr. Top. Med. Chem. 2006,
6, 1499.
(9) Zhang, X.; Xia, H.; Dong, X.; Jin, J.; Meng, W. D.; Qing, F.-L. J.
Org. Chem. 2003, 68, 9026.
(10) Secrist, J. A., III; Riggs, R. M.; Tiwari, K. N.; Montgomery, J. A.
J. Med. Chem. 1992, 35, 533.
(11) Otera, J.; Nakazawa, K.; Sekoguchi, K.; Orita, A. Tetrahedron 1997,
53, 13633.
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Org. Lett., Vol. 8, No. 26, 2006