An alternative method suitable for a large scale synthesis of 4'-ethynyl-2',3'-didehydro-3'-deoxythymidine.
Reaction of 4', 5'-unsaturated thymine nucleoside 1 with Pb(OBz)4 gave the 4'-benzoyloxy derivative 9 as a diastereomeric mixture in 79% yield. When 9 was treated with Me3Al in CH2Cl2 at 0 degrees C, spiro-derivative 10 was formed as the major product in 76% yield. On the other hand, the use of Me2AlCl led to the formation of the 4'-chlorinated product 11, which was subjected to in situ treatment with Me3Al to give the 4'-alpha-methyl derivative 12 (15%) as well as the 4'-beta-methyl counterpart 13 (38%). Formation of 11 was also observed during the reaction between 9 and EtAl(Cl)C[triple bond]CTMS, prepared from EtAlCl2 and LiC[triple bond]CTMS. From this reaction, the 4'-ethynyl nucleoside 14 was obtained stereoselectively in 56% yield.
Haraguchi
Kazuhiro
K
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
Sumino
Masanori
M
Takeda
Shingo
S
Tanaka
Hiromichi
H
D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D018119:Stavudine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D013936:Thymidine / Q000138:chemical synthesis* / Q000737:chemistry
C486840:2',3'-didehydro-3'-deoxy-4'-ethynylthymidine; D018119:Stavudine; D013936:Thymidine