Unprecedented Lability of the 5‘-O-tert-Butyldimethylsilyl Group from 3‘-Spiro-5‘ ‘-(4‘ ‘-acylamino-1‘ ‘,2‘ ‘-oxathiole-2‘ ‘,2‘ ‘-dioxide) Nucleoside Derivatives via Neighboring Group Participation of the 4‘ ‘-Acylamino Residue

Abstract

Scarce examples of exceptionally mild desilylation of tert-butyldimethylsilyl (TBDMS) ether groups by neighboring group participation have been previously described. Here, we investigate, in detail, the discovery of the unusual lability of the 5'-TBDMS group on 4' '-acylamino TSAO derivatives in DMSO solution. The synthesis and comparative chemical stability studies in different solvents of a variety of 4' '-substituted TSAO derivatives bearing different carbonyl functionalities are reported. Modifications have also been performed at the 5'-position of the TSAO molecule to gain insight into the structural requirements for the desilylation to occur. The role of the solvent has also been studied. Additionally, NMR and theoretical investigations have been carried out to get further insight into the conformational, geometric, and/or electronic parameters that may play a role in the "spontaneous" release of the 5'-TBDMS group. A silyl hydrolysis mechanism involving neighboring group participation of the 4' '-acylamino group is proposed.

4′′-Benzoylureido-TSAO Derivatives as Potent and Selective Non-Nucleoside HCMV Inhibitors. Structure−Activity Relationship and Mechanism of Antiviral Action

“…Reaction of 1 12 with tetrabutylammonium fluoride in THF afforded the fully deprotected derivative 3 (72% yield) that was silylated (TBDMSCl/pyridine) to give the 5′-O-TBDMS compound 4. Next, compounds substituted with other silyl groups at 5′ or 2′ positions (Scheme 2), such as 5′-O-or 2′-thexyldimethylsilyl (TDS) (12 or 13) and 5′-O-triisopropylsilyl (TIPS) (14), were prepared in good yields (64-98%) by reaction of the corresponding 5′-O-or 2′-O-TBDMS-protected TSAO derivatives 5, 14 or 6, 15 or 7 14 with benzoyl isocyanate, in dry acetonitrile in a pressure tube at 100 °C. The 2′,5′-bis-O-thexyldimethylsilyl derivative (15) was prepared from the 2′,5′-O-deprotected TSAO derivative 8 16 as follows.…”

“…Also, removal of the TBDMS moiety at 2′ (4) or 5′ (2) or both 2′-and 5′-position (3) annihilated the antiviral activity of the parent compound. When one of the silylated substituents at 2′ or 5′ were replaced by the silicium containing TDS (12,13,15) or TIPS (14) substituents, the anti-HCMV activity of the test compounds was preserved. As also observed for the prototype compound 1, the silylated derivatives 12-15 were devoid of significant cytotoxic or cytostatic activity in the HEL cell cultures.…”

Structure−Activity Relationships of [2‘,5‘-Bis-O-(tert-butyldimethylsilyl)-β-d-ribofuranosyl]- 3‘-spiro-5‘ ‘-(4‘ ‘-amino-1‘ ‘,2‘ ‘-oxathiole-2‘ ‘,2‘ ‘-dioxide)thymine Derivatives as Inhibitors of HIV-1 Reverse Transcriptase Dimerization

“…Inhibitors. All TSAO compounds were synthesized as described previously. − The syntheses of compounds 2 , 15 , 16 , 17 , and 21 will be published in a separate paper. Efavirenz was obtained from the NIH AIDS Research and Reference Reagent Program.…”

Nucleophilic Aliphatic Substitution

“…The mechanism of the S N hydrolysis reaction at silicon removing the 5 -t-butyldimethylsilyl group of 3-spiro-5 -(4 -acylamino-1 , 2 -oxathiole-2 , 2 -dioxide) nucleoside derivatives (51) involves neighbouring group participation by the N-H hydrogen of the 4 -acylamino group (Scheme 22). 73 Calculations at the B3LYP/6-31+(d) level of theory on modified substrates showed that the 4 -N-H bond was longer, the H-O distance from the 4 -N-H to the O of the 5 -silyloxy group was shorter, and the 5 -Si-O bond was longer in the substrates with a more electron-withdrawing group on the oxygen on the 4 -carbonyl group. All of these factors should increase the reactivity in agreement with experiment.…”

“…108 Both the gas phase and acetone reactions occur with inversion, rather than retention, of configuration. However, the transition states and products are different in the gas phase and in solution; methyl thiocyanate is formed in the gas phase by transition state (72) whereas methyl isothiocyanate is formed much more slowly in acetone via the looser transition state (73). The mechanism for the fluorination of methanol by diethylaminosulfur triflouride (74) has been investigated in the gas phase and in dichloromethane using the RHF and B3LYP methods with the 6-31G+** basis set and truncated structures for the reactants.…”