Organic Letters
Letter
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Scheme 4. 3TC and FTC Synthesis by One-Pot Reduction of
Nucleoside Precursors 8 and 9
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60:1]. Eventually, one-pot addition of NaBH4 and K2HPO4 to
the crude reaction mixture gave lamivudine (1) in an excellent
95% overall yield and with a high anomeric selectivity (β:α >
50:1). The same protocol, repeated on nucleoside 9b, provided
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In summary, we have provided a first look at the synthetic
potential of Et3SiH/I2 and PMHS/I2 as novel N-glycosidation
reagents, as exemplified by the synthesis of the antiviral drugs
oxathiolane nucleosides 3TC and FTC. Because of the low cost
and high stability of the reagents, the chemical efficiency, and the
exceedingly high stereoselectivity of the reactions, this approach
can be reasonably considered as an effective alternative to the
existing methodologies and reagents devoted to the same end.
Crucial in influencing the stereochemical reaction outcome, an
unprecedented role played by the N4 protective groups of
(fluoro)cytosine has been also observed and rationalized on the
basis of their capacity to increase nucleobase softness. Far beyond
the scope of this work, this last finding opens up new
opportunities in the stereoselective synthesis of β-nucleosides
not relying on the presence of stereodirecting groups. A more
comprehensive investigation on this topic aimed at studying
scope and limitations of silane/I2 in nucleoside synthesis is
ongoing and will be published elsewhere.
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(23) An average cost of ca. 0.2 €/g has been estimated according to the
main suppliers of chemicals (Mar 3, 2015).
(24) The structures of (2R,5R)-5b and (2S,5S)-5b were established by
1D and 2D NMR studies (see the Supporting Information) and
confirmed by NMR and [α]D comparison with literature data (ref 11).
(25) Jeong, L. S.; Shinazi, R. F.; Beach, J. W.; Kim, H. O.; Nampalli, S.;
Shanmuganathan, K.; Alves, A. J.; McMillan, A.; Chu, C. K.; Mathis, R. J.
Med. Chem. 1993, 36, 181−195.
(26) In this case, complete reaction mixture discoloration was
observed, suggesting quantitative reduction of starting I2.
(27) Barciszewski, J.; Markiewicz, W. T.; Adamska, E.; Plitta, B.; Giel-
Pietraszuk, M.; Wyszko, E.; Markiewicz, M.; Fedoruk-Wyszomirska, A.;
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2011.
(28) A considerable amount (28%) of a side product, which NMR
signals were consistent with the structure of the regioisomeric N3-
nucleoside, was also formed.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and copies of NMR spectra. The
Supporting Information is available free of charge on the ACS
AUTHOR INFORMATION
Corresponding Author
■
Notes
The authors declare no competing financial interest.
REFERENCES
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