T-butyldimethylsilyl Group Research Articles

Structural Development of Silicon‐Containing Retinoids: Structure–Activity Relationship Study of the Hydrophobic Pharmacophore of Retinobenzoic Acids Using Silyl Functionalities

We designed and synthesized a series of retinobenzoic acids bearing various silyl functionalities in order to explore in detail the structure-activity relationship (SAR) at the hydrophobic moiety of retinoids. Among the synthesized compounds, 24 c bearing a t-butyldimethylsilyl (TBS) group at the hydrophobic site exhibited potent retinoid activity comparable to that of the lead compound Am555S (4). Compound 24 c exhibited transcription-promoting activity towards all three subtypes of retinoic acid receptor (RAR), but showed the highest activity towards RARγ, in contrast to the high RARα-selectivity of Am80 (3) and Am555S (4). The SARs presented here should be helpful in the development of subtype-selective retinoids, and in particular 24 c might be a promising lead compound for new RARγ ligands.

Investigation of Transfer Group, Tether Proximity, and Alkene Substitution for Intramolecular Silyloxypyrone-Based [5 + 2] Cycloadditions.

Systematic investigation of intramolecular silyloxypyrone-based [5 + 2] cycloadditions revealed three significant factors impacting conversion to cycloadduct: (1) the silyl transfer group has a substantial influence on the rate of reaction, and the robust t-butyldiphenylsilyl group was found to be more effective overall than the conventional t-butyldimethylsilyl group; (2) α,β-unsaturated esters were generally more reactive than terminal olefins and afforded appreciable quantity of cycloadduct even at room temperature; and (3) the proximity of the tether to the silyl transfer group revealed a critical alignment trend between the pyrone and the alkene. Taken together, these investigations provided insight regarding the steric and electronic parameters that impact the scope and limitation of these reactions.

Synthesis of a protected ribonucleoside phosphoramidite-linked spin label via an alkynyl chain at the 5′ position of uridine

New, spin-labeled nucleosides, and an efficient synthetic route for a modified uridine amidite, were developed. The spin-labeled part was the 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) group, which was linked via an alkynyl chain at the 5 position of uridine. Three typical protecting groups, the t-butyldimethylsilyl (TBDMS) group at 2′, the dimethoxytrityl (DMTr) group at 5′, and the phosphoramidite group at 3′, were introduced to produce an automated nucleic acid synthesizer. The TEMPO group at the 5 position in the uridine structure affected introduction of bulky protecting groups, such as the DMTr group at the 5′ position and the TBDMS group at the 2′ position. The electron paramagnetic resonance (EPR) data revealed a nitroxyl radical in the structure of synthetic nucleoside compounds; however, RNA produced by automated synthesis using a TEMPO-linked uridine phosphoramidite building block was EPR silent.

Chemoselective Deprotection of Aryl tert-Butyldimethylsilyl Ethers Promoted by Phosphates

A facile protocol to the chemoselective deprotection of aryl t-butyldimethylsilyl (TBDMS) ethers using Na3PO4 · 12H2O as promoter is described. From aryl TBDMS ethers to the corresponding phenols, the TBDMS group could be cleaved in the presence of 0.5 equivalent of Na3PO4 · 12H2O in dimethylformamide at room temperature with good to excellent yields in the presence of other common protecting and functional groups. K3PO4 · 3H2O was also found to be useful for the selective deprotection reaction. This is, to our knowledge, the first report on chemoselective deprotection of aryl TBDMS ethers using phosphates.

ChemInform Abstract: Synthesis of 6-Hydroxyalkylidenepenicillanates.

Allyl (5R)-(Z)- and (5R)-(E)-6-[(2S)-2,3-isopropylidenedioxypropylidene]Penicillanate(10a and 10b) were prepared from allyl (5R)-dibromopenicillanate(6) via a sequence of reactions involving condensation with 2,3-O-isopropylidene-D-glyceraldehyde, reduction with , and Mitsunobu elimination. Deprotection of isopropylidene and allyl groups of 10a gave potassium (5R)-(Z)-6-[(2S)-2,3-dihydroxypropylidene]penicillanate(4). However, deprotection of isopropylidene group of 10b afforded -unsaturated-lactone(12). Allyl (5R)-(Z)- and (5R)-(E)-6-[(2S)-2-(t-butyldimethlsilyloxy)propylidene]penicillanate(18a and 18b) were prepared from ally (5R)-dibromopenicillanate(6) via a sequence of reactions involving condensation with (2S)-2-(t-butyldimethylsilyloxy)propanal(15), reduction with and Mitsunobu elimination or mesylation-elimination. Deprotection of t-butyldimethylsilyl and allyl groups of 18a and 18b gave potassium (5R)-(Z)- and (5R)-(E)-6-[(2S)-2-hydroxypropylidene]penicillanate(5a and 5b), respectively.

ChemInform Abstract: Facile Cleavage of Carbohydrate Benzyl Ethers and Benzylidene Acetals Using the NaBrO3/Na2S2O4 Reagent under Two-Phase Conditions.

Abstract Benzyl ether and benzylidene acetal carbohydrate protecting groups can be selectively cleaved by reaction with sodium bromate/sodium dithionite in ethyl acetate/water. Under the mild (room temperature, short reaction time) conditions needed, a variety of other protecting functionalities such as acetyl, chloroacetyl, benzoyl, pivaloyl, tosyl, t-butyldimethylsilyl, trityl, and isopropylidene groups remain unaffected.

Protecting Groups Transfer: Unusual Method of Removal of Tr and Tbdms Groups by Transetherification

The triphenylmethyl (Tr) group undergoes a transfer (transetherification or disproportionation) between the molecules of 5′-O-Tr-2′-deoxynucleosides in a process mediated by anhydrous sulfates of Cu+2, Fe+2, or Ni+2 to yield mixtures of 3′,5′-bis-O-Tr and 3′-O-Tr products. If phenylmethanol is present in a reaction medium, detritylation results with concomitant formation of phenylmethyl triphenylmethyl ether. The behavior of t-butyldimethylsilyl (TBDMS) group in 5′-O-TBDMS-2′-deoxynucleosides is exactly the same. Such type of transetherifications was not observed before for the O-Tr and O-TBDMS groups.

Exomethylene pyranonucleosides: Efficient synthesis and biological evaluation of 1-(2,3,4-trideoxy-2-methylene-β- d- glycero-hex-3-enopyranosyl)thymine

A new series of unsaturated pyranonucleosides with an exocyclic methylene group and thymine as heterocyclic base have been designed and synthesized. d-Galactose ( 1) was readily transformed in three steps into the corresponding 1-(β- d-galactopyranosyl)thymine ( 2). Selective protection of the primary hydroxyl group of 2 with a t-butyldimethylsilyl (TBDMS) group, followed by specific acetalation, and oxidation gave 1-(6- O- t-butyldimethylsilyl-3,4- O-isopropylidene-β- d- lyxo-hexopyranosyl-2-ulose)thymine ( 5). Wittig reaction of the ketonucleoside 5, deprotection and tritylation of the 6′-hydroxyl group gave 1-(2-deoxy-2-methylene-6- O-trityl-β- d- lyxo-hexopyranosyl)thymine ( 9). Exomethylene pyranonucleoside 9 was converted to the olefinic derivative 10, which after detritylation afforded the title compound 1-(2,3,4-trideoxy-2-methylene-β- d- glycero-hex-3-enopyranosyl)thymine ( 11). These novel synthesized compounds were evaluated for antiviral activity against rotaviral infection and cytotoxicity in colon cancer. As compared to AZT, compounds 1-(2-deoxy-2-methylene-β- d- lyxo-hexopyranosyl)thymine ( 7) and 1-(β- d- lyxo-hexopyranosyl-2-ulose)thymine ( 8) showed to be more efficient, in rotavirus infections and in treatment of colon cancer.

Deprotection of a Silyl Group with Mesoporous Silica

The triethylsilyl (TES) group of silyl ethers of several types is selectively and easily removed in the presence of a t-butyldimethylsilyl (TBDMS) group with a mesoporous silica MCM-41/MeOH heterogeneous system. Comparison of the efficiency was carried out among several solvents, and among such promoters as common zeolites and ion-exchange resins. Furthermore, FSM-16, another mesoporous silica, was examined for the possibility of recycling by re-calcination at 400 degrees C after the reaction.

An Easy Conversion of the Baylis—Hillman Adducts into tert‐Butyldimethylsilyl Ethers with tert‐Butyldimethylsilyl Chloride and Li2S.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A Remarkable Zirconium(IV) Chloride Catalyzed Highly Selective Deprotection of t-Butyldimethylsilyl (TBS) Ethers in Presence of t- Butyldiphenylsilyl (TPS) Ethers

A highly selective and efficient method for the chemoselective deprotection of t-butyldimethylsilyl (TBS) ethers using 20 mol% of zirconium(IV) chloride as Lewis acid in isopropanol is reported. Remarkable selectivity was observed towards the TBS group deprotection while TPS remains unaffected. The reaction is fast and the conditions are tolerable to a variety of protecting groups, carbohydrates and terpenes. The products are obtained in excellent yields.

AN EASY CONVERSION OF THE BAYLIS-HILLMAN ADDUCTS INTO tert-BUTYLDIMETHYLSILYL ETHERS WITH tert-BUTYLDIMETHYLSILYL CHLORIDE AND Li2S

The hydroxy group of the Baylis-Hillman adducts is protected with the t-butyldimethylsilyl (TBDMS) group using the reaction of adducts 1a–h with tert-butyldimethylsilyl chloride (TBDMSCl) in the presence of lithium sulfide under nearly acidic reaction conditions.

Examination of protecting groups in the synthesis of nucleosides by intramolecular glycosylation

Influence of carbohydrate protecting groups on intramolecular glycosylation was examined, and it was found that the use of 4-methoxybenzyl group as the protection for the 4-O position as well as t-butyldimethylsilyl group at the 3-O position was necessary to obtain desired beta-nucleosides in good yields.

Development of a Method for the Detection and Confirmation of the alpha-2 Agonist Amitraz and Its Major Metabolite in Horse Urine

Amitraz (N'-(2,4-dimethylphenyl)-N-[[(2,4-dimethylphenyl)imino]methyl]-N-methyl-methanimidamide) is an alpha-2 adrenergic agonist used in veterinary medicine primarily as a scabicide- or acaricide-type insecticide. As an alpha-2 adrenergic agonist, it also has sedative/tranquilizing properties and is, therefore, listed as an Association of Racing Commissioners International Class 3 Foreign Substance, indicating its potential to influence the outcome of horse races. We identified the principal equine metabolite of amitraz as N-2,4-dimethylphenyl-N'-methylformamidine by electrospray ionization(+)-mass spectrometry and developed a gas chromatographic-mass spectrometric (GC-MS) method for its detection, quantitation, and confirmation in performance horse regulation. The GC-MS method involves derivatization with t-butyldimethylsilyl groups; selected ion monitoring (SIM) of m/z 205 (quantifier ion), 278, 261, and 219 (qualifier ions); and elaboration of a calibration curve based on ion area ratios involving simultaneous SIM acquisition of an internal standard m/z 208 quantifier ion based on an in-house synthesized d(6) deuterated metabolite. The limit of detection of the method is approximately 5 ng/mL in urine and is sufficiently sensitive to detect the peak urinary metabolite at 1 h post dose, following administration of amitraz at a 75-mg/horse intravenous dose.

Synthetic Organic Chemistry with Mesoporous Silicas

AbstractFor Abstract see ChemInform Abstract in Full Text.

メソポーラスシリカを利用する有機合成反応

Ti-HMS, MCM-41 and FSM-16, which are typical hexagonal mesoporous silicas, were attempted to use as a promoter for organic synthesis. Ti-HMS, which possesses Lewis acid sites due to Ti-atom, was found to accelerate deprotection of benzyl groups, which is a typical protective group of hydroxyl group, selectively under hydrogenolytic conditions with palladium catalyst even in the presence of acid-sensitive functional groups such as silyl ether and acetal moieties in the molecule. MCM-41 proved to deprotect triethylsilyl (TES) group, which is another typical protective group of hydroxyl group, selectively and easily in the presence of t-butyldimethylsilyl (TBS) group. FSM-16 was found to accelerate several photo-reaction such as oxidative photodecarboxylation of α-hydroxy carboxylic acid, oxidation of arylmethylhalides and arylmethylalcohols, and oxidative cleavage of styrenes. Efficiency of these reactions was investigated concerning the solvent effect and activities of the promoters including common zeolites and ion-exchange resins.

Synthetic organic reactions with mesoporous silicas

Some hexagonal mesoporous silicas were attempted to use as a promoter for fine organic synthesis. Ti-HMS, a Ti-loaded hexagonal mesoporous silica, which possesses Lewis acid sites due to Ti-atom, was found to accelerate deprotection of benzyl ethers under hydrogenolytic conditions with palladium catalyst. Such acid-sensitive functional groups as silyl ether and acetal moieties in the molecule were little affected by Ti-HMS. MCM-41, a hexagonal mesoporous silica, /MeOH heterogeneous system was found to remove selectively and easily triethylsilyl (TES) group of silyl ethers of several types in the presence of t-butyldimethylsilyl (TBS) groups. FSM-16, another hexagonal mesoporous silica, was found to catalyze oxidative photodecarboxylation of alpha-hydroxy carboxylic acid and phenyl acetic acid derivatives to afford the corresponding carbonyl compounds. Furthermore, FSM-16 proved to be reuseable by recalcination at 450 degrees C after the reaction. Efficiency of these reactions was investigated concerning the solvent effect and activities of the promoters including common zeolites and ion-exchange resins.

Selective Protecting Method for the Individual Hydroxyl Groups of Kdn

ABSTRACT Selective protection for the individual hydroxyl groups of methyl (phenyl 3-deoxy-2-thio-β-D-glycero-D-galacto-2-nonulopyranosid)onate (2) was examined. The 4-, 5-, and 7-hydroxyl groups of methyl (phenyl 3-deoxy-8,9-O-isopropylidene-2-thio-β-D-glycero-D-galacto-2-nonulopyranosid)onate (3) were found selectively to be protected by t-butyldimethylsilyl, methoxymethyl, and benzoyl groups, respectively. In order to obtain the 8- and 9-hydroxyl derivatives selectively, methyl (phenyl 4,5,7-tri-O-acetyl-9-O-t-butyldimethylsilyl-3-deoxy-2-thio-β-D-glycero-D-galacto-2-nonulopyranosid)onate (12) and methyl (phenyl 4,5,7,8-tetra-O-benzyl-9-O-triphenylmethyl-3-deoxy-2-thio-β-D-glycero-D-galacto-2-nonulopyranosid)onate (19) were prepared in moderate yields.

Synthesis and Anti-HIV Activity of Sulfated Polysaccharides Containing Acetamido Groups.

A series of stereoregular azido group-containing copolymers such as poly [3-azido-2-O-t-butyldimethylsilyl-3-deoxy-(1→5)-α-D-xylofuranose-co-2, 3-di-O-t-butyldimethylsilyl-(1→5)-α-D-ribofuranose] [copoly (A3ASX-ADSR)] were synthesized by selective ring-opening polymerization of 1, 4-anhydro-3-azido-2-O-t-butyldimethylsilyl-3-deoxy-α-D-xylopyranose (A3ASX) and 1, 4-anhydro-2, 3-di-O-t-butyldimethylsilyl-α-D-ribopyranose (ADSR) with BF3•OEt2 catalyst. The number-average molecular weights (_??_n) were in a range of 3.5×104_??_4.2×104. The optical rotations ([α] D) increased from +119°to+143° with increasing mole fraction of the xylofuranosidic units in the copolymers from 30% to 78%.Reduction of the azido group in the copolymer into an amino group, acetylation of the amino group into an acetamido group, and removal of the t-butyldimethylsilyl group afforded poly [3-acetamido-3-deoxy-(1→5)-α-D-xylofuranose-co-(1→5)-α-D-ribofuranose] [copoly (A3AAdX-R)] with _??_n 9.0×103 and [α] D of +150.8°. Sulfation of the 3AAdXF and copoly (A3AAdX-R) produced a sulfated 3-acetamido-3-deoxy-(1→5)-α-D-xylofuranan with _??_n of 17.1×103, and a sulfated poly _??_3-acetamido-3-deoxy-(1→5)-α-D-xylofuranose-co-(1→5)-α-D-ribofuranose_??_ with _??_n of 10.9×103. The degrees of sulfation of homo- and co-polymers were 0.72 and 1.03, respectively. The four kinds of sulfated acetamido group-containing polypentoses exhibited medium-to-high anti-HIV (human immunodeficiency virus) activities in the range of EC50 of from 0.42μg/mL to 62.86μg/mL, while they showed low anticoagulant activities in the range of 0 to 6unit/mg.

Synthesis of 1,5-Anhydro-D-Mannitol Nucleosides with a Purine Base Moeety

D-Mannitol nucleosides with a purine base moiety have been conveniently synthesized strating from 1,5-anhydro-4,6-O-benzylidene-D-glucitol. The 3-OH function of 1,5-anhydro-4,6-O-benzylidene-D-glucitol was selectively protected with t-butyldimethylsilyl group and subsequently converted to the corresponding 0-triflate derivative for the introduction of the nucleobase moietes. These nucleoside derivatives were transformed to 1,5-Anhydro-6-O-MMTr-2-(N6-benzoyladenin-9-yl)-2-deoxy-3-O-TBDMS-D-mannitol and 1,5-Anhydro-6-O-MMTr-2-(N2-isobutyryl-guanin-9-yl)-2-deoxy-3-O-TBDMS-D-mannitol, useful as the building blocks for oligonucleotide synthesis. Also, the synthesis of the corresponding fully deprotected anhydrohexitol nucleosides were achieved for evaluation of antiviral activity test.