Tert-butyldimethylsilyl Group Research Articles

Methylene-2-ethynylcyclopropanes: synthesis and biological activity of ( Z)- and ( E)-9-{[2-ethynyl-2-(hydroxymethyl)cyclopropylidene]methyl}adenine and -guanine

Synthesis of methylene-2-ethynylcyclopropane analogues of nucleosides 12a, 12b, 13a, and 13b is described. Ethyl methylenecyclopropane carboxylate 14 was hydroxymethylated to give alcohol 15, which was reduced to diol 16. Selective protection with tert-butyldimethylsilyl group gave derivative 17, which was oxidized to aldehyde 18. Wittig reaction with CBr 4 gave dibromoalkene 19. Elimination of both bromine atoms afforded methylene-2-ethynylcyclopropane 20. Bromoselenenylation using N-bromosuccinimide and diphenyldiselenide gave intermediate 21. Alkylation of adenine and 2-amino-6-chloropurine with 21 provided the Z, E-isomeric mixtures 22a and 22c. Oxidation afforded selenoxides 23a and 23c. Mild thermolysis furnished methylenecyclopropanes Z-24a , E-24a , and 24c. Deprotection and separation of Z, E-isomers gave adenine analogues 12a and 13a, and 2-amino-6-chloropurine intermediates 12c and 13c. Hydrolytic dechlorination of 12c and 13c afforded guanine analogues 12b and 13b. Adenine Z-isomer 12a inhibits replication of Epstein-Barr virus through its cytotoxicity. The E-isomer 13a is a substrate for adenosine deaminase.

Regioselective Silylation of N-Phthaloylchitosan with TBDMS and TBDPS Groups

N-Phthaloylchitosan represents a key intermediate for the regioselective modification of chitosan in organic media. Chemoselective protection of primary alcohols on N-phthaloylchitosan was achieved with tert-butyldimethylsilyl (TBDMS) and tert-butyldiphenylsilyl (TBDPS) groups in imidazole/DMF and DMAP/pyridine. Influence of experimental conditions such as solvent, choice of base, stoichiometry, temperature, and time of reaction was studied regarding the degree of substitution (ds) of silyl groups. TBDMS groups allow higher ds than TBDPS groups. Higher reaction temperatures in different conditions led to lower ds and incomplete substitution. However, regioselective silylation of N-phthaloylchitosan was realized with ds up to 0.92 at room temperature. Silylated derivatives were characterized by elemental analysis, IR, and CP/MAS 13C NMR spectroscopies.

Gas‐chromatographic approach to probe the absence of molecular inclusion in enantioseparations by carbohydrates. Investigation of linear dextrins (“acyclodextrins”) as novel chiral stationary phases

Acetylated/silylated maltooligosaccharides with different degrees of oligomerization have been tested as chiral stationary phases for enantioselective gas chromatography. The acyclic dextrin derivatives carrying tert-butyldimethylsilyl groups at the primary hydroxyl sites and acetyl groups at the secondary hydroxyl sites showed an unexpected ability for the enantioseparation of alpha-amino acid derivatives and halogenated compounds, in addition to some underivatized chiral compounds. Some examples of an improved enantioselectivity invoked by the linear CSPs as compared to that of cyclic oligosaccharides are demonstrated in this work. The results highlight the role of the polar external surface of the selector in lieu of the well-established inclusion mechanism of enantiorecognition by cyclic dextrins. Thus, the enantioseparation of chiral compounds on linear dextrin derivatives--devoid of a molecular cavity--sheds a new light on the mechanisms of enantiorecognition by cyclodextrin derivatives. In contrast to cyclodextrins, linear dextrins are readily accessible in both enantiomeric forms.

Asymmetric Modular Synthesis of Highly Functionalized Medium-Sized Carbocycles and Lactones via Ring-Closing Metathesis of Sulfoximine-Substituted Trienes

A modular asymmetric synthesis of medium-sized carbocycles and lactones has been developed that affords highly substituted 7-, 9-, and 11-membered rings. The key steps are (1) the highly diastereoselective synthesis of sulfoximine-substituted homoallylic alcohols from allylic sulfoximines and unsaturated as well as saturated aldehydes, (2) an E-stereoselective alkylation and hydroxyalkylation of sulfoximine-substituted alkenyllithium derivatives, (3) the esterification of sulfoximine-substituted homoallylic alcohols, and (4) the ring-closing metathesis reaction of sulfoximine-substituted trienes with the ruthenium catalyst 8. Two examples for the further synthetic elaboration of the sulfoximine-substituted carbocycles are provided. The selective cleavage of the tert-butyldimethylsilyl group of 12 in the presence of the triethylsilyl group afforded the allylic alcohol 18 which was oxidized to enone 19. A cross-coupling reaction of the sulfoximine-substituted carbocycle 9 with LiCuMe2 furnished the methyl-substituted derivative 20.

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

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.

Syntheses of 19-[ O-(carboxymethyl)oxime] haptens of epipregnanolone and pregnanolone

O-(Carboxymethyl)oximes 1 and 2 derived from two epimeric 5β-pregnanolones (3β-hydroxy-5β-pregnan-20-one and 3α-hydroxy-5β-pregnan-20-one) in position 19 were prepared. Two synthetic routes were employed, both using protection of the 20-keto group after reduction into the (20R)-alcohol in the form of acetate. In the first route, (20R)-19-hydroxy-5β-pregnan-3β,20-diyl diacetate ( 3) was transformed into the corresponding 19-[ O-(carboxymethyl)oxime] methyl ester 6, then deacetylated by acid and partially silylated with tert-butyldimethylsilyl chloride. The desired 3- O-silylated derivative 8 was separated, oxidized to the 20-ketone and protecting groups were sequentially removed to give the first title hapten 1. The second route started from (20R)-19-hydroxy-3-oxopregn-4-en-20-yl acetate ( 11), which was hydrogenated in the presence of base to the 5β-pregnan-3-one derivative 12, protected in position 19 with tert-butyldimethylsilyl group and reduced with borohydride. The prevailing 3α-alcohol 15 was separated, protected in position 3 with a methoxymethyl group, deprotected in position 19 and transformed into the 19-[ O-(carboxymethyl)oxime] 19. After deacetylation, esterification with diazomethane and oxidation in position 20, the pregnanolone skeleton was regenerated. Final deprotection steps gave the second title hapten 2. Both haptens, i.e., (19E)-3β- and -3α-hydroxy-20-oxo-5β-pregnan-19-al 19-[ O-(carboxymethyl)oxime], were designed for the development of immunoassays of the corresponding parent neuroactive steroids.

Formation of Tetra(ethylene oxide) Terminated Si−C Linked Monolayers and Their Derivatization with Glycine: An Example of a Generic Strategy for the Immobilization of Biomolecules on Silicon

Surface modification with oligo(ethylene oxide) functionalized monolayers terminated with reactive headgroups constitutes a powerful strategy to provide specific coupling of biomolecules with simultaneous protection from nonspecific adsorption on surfaces for the preparation of biorecognition interfaces. To date, oligo(ethylene oxide) functionalized monolayer-forming molecules which can be activated for attachment of biomolecules but which can selectively form monolayers onto hydrogen terminated silicon have yet to be developed. Here, self-assembled monolayers (SAMs) containing tetra(ethylene oxide) moieties protected with tert-butyl dimethylsilyl groups were formed by thermal hydrosilylation of alkenes with single-crystal Si(111)-H. The protection group was used to avoid side reactions with the hydride terminated silicon surface. Monolayer formation was carried out using solutions of the alkene in the high-boiling-point solvent 1,3,5-triethylbenzene. The protecting group was removed under very mild acidic conditions to yield a free hydroxyl functionality, a convenient surface moiety for coupling of biological entities via carbamate bond formation. The chemical composition and structure of the monolayers before and after deprotection were characterized by X-ray photoelectron spectroscopy (XPS) and X-ray reflectometry. To demonstrate the utility of this surface for covalent modification, two reagents were compared and contrasted for their ability to activate the surface hydroxyl groups for coupling of free amines, carbonyl diimidazole (CDI), and disuccinimidyl carbonate (DSC). Analysis of XP spectra before and after activation by CDI or DSC, and after subsequent reaction with glycine, provided quantitative information on the extent of activation and overall coupling efficiencies. CDI activated surfaces gave poor coupling yields under various conditions, whereas DSC mediated activation followed by aminolysis at neutral pH was found to be an efficient method for the immobilization of amines on tetra(ethylene oxide) modified surfaces.

Enhanced Stereocontrol in Disyndiotactic-specific Group Transfer Polymerization of Methyl Crotonate—Stereochemical Evidence of Group Transfer

Group transfer polymerization (GTP) of methyl crotonate was examined by using a ketene silyl acetal with tert-butyldimethylsilyl group in the presence of HgI2 and tert-butyldimethylsilyl iodide as a catalyst and a co-catalyst, respectively. Under optimized conditions, the GTP produced disyndiotactic polymers with narrow molecular weight distribution in quantitative yields. The trialkylsilyl group in the initiator components was found to exert control over the stereochemical process of the GTP; the bulky tert-butyldimethylsilyl group leads to the highest disyndiotacticity. The results provide a direct evidence for the transferring silyl group to be involved in the propagation steps in the GTP.

Facile Sythesis of Dioscin and Its Analogues

Abstract Three representative spirostanol saponins that have typical structure of the sugar moiety, diosgenyl 2,3-di-O-α-l-rhamnopyranosyl-β-d-glucopyranoside, diosgenyl 2,4-di-O-α-l-rhamnopyranosyl-β-d-glucopyranoside (dioscin), and diosgenyl 2,6-di-O-α-l-rhamnopyranosyl-β-d-glucopyranoside, were synthesized in a facile way. An approach to selectively mask the C3-hydroxyl of diosgenyl 4,6-O-benzylidene β-d-glucopyranoside was described. A procedure using cerium(IV) ammonium nitrate for selective removal of tert-butyldimethylsilyl group while retaining levulinyl group is afforded.

The tert-butyl dimethyl silyl group as an enhancer of drug cytotoxicity against human tumor cells

In this study, we synthesized a series of enantiomerically pure (2 R,3 S)-disubstituted tetrahydropyranes with diverse functional groups using known methodologies. In addition to the tert-butyl dimethyl silyl group, other common protecting groups for hydroxyl groups such as allyl, acetate, and benzoate were used to obtain appropriate derivatives. Pure compounds were evaluated in vitro against HL60 human leukemia cells and MCF7 human breast cancer cells. From the growth inhibition data a structure–activity relationship was obtained. Overall the results point to the relevant role of the tert-butyl dimethyl silyl group in the modulation of cytotoxic activity.

Synthesis of a 2‘-Deoxyguanosine Adduct of cis-2-Butene-1,4-dial, a Reactive Metabolite of Furan

Furan is a liver and kidney toxicant and a hepatocarcinogen in rodents. Its reactive metabolite, cis-2-butene-1,4-dial, reacts with nucleosides to form adducts in vitro. The reaction with 2'-deoxyguanosine generates 3-(2'-deoxy-beta-D-erythropentafuranosyl)-3,5,6,7-tetrahydro-6-hydroxy-7-(ethane-2"-al)-9H-imidazo[1,2-alpha]purine-9-one as the major reaction product. A synthetic approach to this adduct is presented in this report. The key step in this synthesis is the preparation of 2'-deoxy-3',5'-O-bis(tert-butyldimethylsilyl)-1-(1,2,5,6-tetrahydroxyhexan-3-yl)guanosine. Treatment of this intermediate with sodium periodate gave three reaction products: a one-substituted adduct, 2'-deoxy-3',5'-O-bis(tert-butyldimethylsilyl)-1-(2,5-dihydroxy-tetrahydrofuran-3-yl)guanosine; a 1,N(2)-cyclic adduct, 3-[2'-deoxy-3',5'-O-bis(tert-butyldimethylsilyl)-beta-D-erythropentafuranosyl]-6-hydroxy-8-formyl-5,6,7,8-tetrahydropyrimidino[1,2-alpha]purin-10(3H)-one; and the 1,N(2)-bicyclic adduct, 3-[2'-deoxy-3',5'-O-bis(tert-butyldimethylsilyl)-beta-D-erythropentafuranosyl]-3,5,6,7-tetrahydro-6-hydroxy-7-(ethane-2"-al)-9H-imidazo[1,2-alpha]purine-9-one. The one-substituted and 1,N(2)-cyclic reaction products were unstable and rearranged over time to yield the 1,N(2)-bicyclic 2'-deoxyguanosine adducts. The desired reaction product was obtained as a mixture of four diastereomers by removing the tert-butyldimethylsilyl groups with hydrogen fluoride. This synthetic approach to the cis-2-butene-1,4-dial-derived dGuo adducts confirms our previous structural characterization of the in vitro cis-2-butene-1,4-dial-dGuo reaction product. These studies demonstrate that the observed 1,N(2) bicyclic structure is the thermodynamically stable isomer, supporting our previous observations that this adduct is the major product formed in vitro. Finally, these studies provide the necessary groundwork for the preparation of oligonucleotides with site specifically incorporated cis-2-butene-1,4-dial-derived adducts.

Synthesis of AZA Analogues of TSAO

AbstractFor Abstract see ChemInform Abstract in Full Text.

Conformation inversion of an inositol derivative by use of silyl ethers: a modified route to 3,6-di-O-substituted-L-ido-tetrahydroxyazepane derivatives.

The trans-diequatorial 3,4-diol of 2,5-di-O-benzyl-D-chiro-inositol cleaved selectively with the periodate ion in the presence of the trans-diaxial 1,6-diol to give a dialdehyde (dialdose) from which 3,6-di-O-benzyl-D-manno-tetrahydroxyazepane (1) was made. The trans-diaxial 1,6-diol of 3,4-di-O-allyl-2,5-di-O-benzyl-D-chiro-inositol was not cleaved satisfactorily by periodate, but replacement of the allyl substituents with tert-butyldimethylsilyl groups caused conformational inversion of the inositol ring, and the resulting trans-diequatorial 1,6-diol cleaved efficiently to give a dialdehyde from which 3,6-di-O-benzyl-L-ido-tetrahydroxyazepane (2) can be prepared.

Structure-activity relationship studies on a novel family of specific HIV-1 reverse transcriptase inhibitors.

We have previously reported the discovery and preliminary structure-activity relationships of a new class of specific HIV-1 reverse transcriptase (RT) inhibitors whose prototype compound is the 1-[2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3-N-[(carboxy) methyl]-thymine. In an attempt to increase the inhibitory efficacy against HIV-1 RT of this new class of nucleosides, and to further explore the structural features required for anti-HIV-1 activity, different types of modifications have been carried out on the prototype compound. These include substitution of the tert-butyldimethylsilyl groups by other liphophilic groups, replacement of the carboxy group at the N-3 position of the nucleobase by other functional groups, change in the length of the spacer between the thymine and the carboxylic acid residue and substitution of the thymine moiety by other pyrimidine (uracil, 5-ethyluracil) or purine (hypoxanthine) nucleobases. In addition, the most salient structural features of this new class of HIV-1-specific nucleosides have been incorporated into classical HIV RT nucleoside inhibitors such as ddl, AZT, d4T. Our studies demonstrate that both the carboxymethyl moiety at the nucleobase and tert-butyldimethylsilyl groups at the sugar are important structural components since deletion of either of them is detrimental to the antiviral activity.

Synthesis of AZA Analogues of TSAO

TSAO derivatives which were first synthesized in 1992 have shown strong inhibitory effect and selectivity against HIV-1 (Camarasa, M.J.; Pérez-Pérez, M.J.; San-Félix, A.; Balzarini, J.; De Clercq, E. J. Med. Chem. 1992, 35, 2721–2727). The structure-activity relationship of these derivatives has shown strong binding between the amino acids constituting the reverse transcriptase and the different pharmacophore (tert-butyldimethylsilyl group, amino and sulfonate groups of the TSAO derivatives) (Camarasa, M.J.; San-Félix, A.; Pérez-Pérez, M.J.; Velázquez, S., Alvarez, R.; Chamorro, C.; Jimeno, M.L.; Pérez, C.; Gago, F.; De Clercq, E.; Balzarini, J. J. Carbohydr. Chem. 2000, 19, 6403–6406). We described the synthesis of an original TSAO analogue where, basically, the O-1″ atom is replaced by a nitrogen atom.

Retention of carbon and alteration of expected 13C-tracer enrichments by silylated derivatives using continuous-flow combustion-isotope ratio mass spectrometry.

Continuous-flow inlets from oxidation reactors are commonly used systems for biological sample introduction into isotope ratio mass spectrometers (IRMS) to measure 13C enrichment above natural abundance. Because the samples must be volatile enough to pass through a gas chromatograph, silylated derivatization reactions are commonly used to modify biological molecules to add the necessary volatility. Addition of a tert-butyldimethylsilyl (TBDMS) group is a common derivatization approach. However, we have found that samples do not produce the expected increment in measured 13C abundance as the TBDMS derivatives. We have made measurements of 13C enrichment of leucine and glutamate standards of known 13C enrichment using derivatives without silicon (N-acetyl n-propyl ester), with silicon (TBDMS), and an intermediate case. The measurements of 13C in amino acids derivatized without silicon were as expected. The 13C enrichment measurements using the TBDMS derivative were higher than expected but could be corrected to produce the expected 13C enrichment measurement by IRMS if one carbon was removed per silicon. We postulate that the silicon in the derivative forms silicon carbide compounds in the heated cupric oxide reactor, rather than forming silicon dioxide. Doing so reduces the amount of CO2 formed from the carbon in the sample. Silylated derivatives retain carbon with the silicon and must be used carefully and with correction factors to measure 13C enrichments by continuous-flow IRMS.

Stereoselective (2-naphthyl)methylation of sugar hydroxyls by the hydrogenolysis of diastereoisomeric dioxolane-type (2-naphthyl)methylene acetals

The cis axial/equatorial OH groups of methyl α- l- and ethyl 1-thio-α- l-rhamnopyranoside, 1,6-anhydro-β- d-mannopyranose, and 1,6-anhydro-β- d-galactopyranose were reacted with 2-naphthaldehyde dimethyl acetal to diastereomeric dioxolane-type 2,3 -O-(2-naphthyl)methylene or 3,4 -O-(2-naphthyl)methylene acetals. The glycosides yielded the exo- and endo-isomers in nearly 1:1 ratio, 1,6-anhydro-β- d-mannopyranose gave predominantly the endo-, and 1,6-anhydro-β- d-galactopyranose exclusively endo-isomer. The acetals and some of their fully protected derivatives bearing benzyl or tert-butyldimethylsilyl groups were hydrogenolised with AlH 3 (3LiAlH 4-AlCl 3) or with Me 3N·BH 3–AlCl 3 reagents. The endo-isomers were cleaved by both reagents to give axial NAP ethers, the exo-isomers of pyranosides furnished equatorial NAP ethers. However, the exo-isomers of pyranoses gave irregular axial ethers with a >30-fold enhancement of the reaction rates with respect to the endo-isomer.

New Negative-Type Photosensitive Polyimide Based on Hyperbranched Poly(ether imide), a Cross-Linker, and a Photoacid Generator

Abstract A new negative working photosensitive polyimide, based on hyperbranched poly(ether imide) (1), 4,4′-methylenebis[2,6-bis(hydroxymethyl)]phenol (2) as a cross-linker, and a photoacid generator diphenyliodonium 9,10-dimethoxyanthracene-2-sulfonate (3) has been developed. 1 was prepared by polycondensation of N-[3,5-di-(tert-butyldimethylsilyloxy)phenyl]-4-fluorophthalimide (4), followed by deprotection of tert-butyldimethylsilyl group with KF-HBr. The photosensitive polyimide containing 1 (70 wt%), 2 (20 wt%) and 3 (10 wt%) gave a clear negative pattern when it was exposed to 365 nm light and postbaked at 120 °C, followed by developing with a 2.38 wt% aqueous tetramethylammonium hydroxide (TMAH) solution at room temperature.

Synthesis and characterization of DNA duplexes containing an N(4)C-ethyl-N(4)C interstrand cross-link.

Short DNA duplexes containing an N(4)C-ethyl-N(4)C interstrand cross-link, C-C, were synthesized on controlled pore glass supports. Duplexes having two, three, or four A/T base pairs on either side of the C-C cross-link and terminating with a C(4) overhang at their 5'-ends were prepared. The cross-link was introduced using a convertible nucleoside approach. Thus, an oligonucleotide terminating at its 5'-end with O(4)-triazoyl-2'-deoxyuridine was first prepared on the support. The triazole group of support-bound oligomer was displaced by the aminoethyl group of 5'-dimethoxytrityl-3'-O-tert-butyldimethylsilyl-N(4)-(2-aminoethyl)deoxycytidine to give the cross-link. The dimethoxytrityl group was removed, and the upper and lower strands of the duplex were extended from two 5'-hydroxyl groups of the cross-link using protected nucleoside 3'-phosphoramidites. The tert-butyldimethylsilyl group of the resulting partial duplex was then removed, and the chain was extended in the 3'-direction from the resulting 3'-hydroxyl of the cross-link using protected nucleoside 5'-phosphoramidites. The cross-linked duplexes were purified by HPLC and characterized by enzymatic digestion and MALDI-TOF mass spectrometry. Duplexes with three or four A/T base pairs on either side of the C-C cross-link gave sigmoidal shaped A(260) profiles when heated, a behavior consistent with cooperative denaturation of the A/T base pairs. Each cross-linked duplex could be ligated to an acceptor duplex using T4 DNA ligase, a result that suggests that the C-C cross-link does not interfere with the ligation reaction, even when it is located only two base pairs from the site of ligation. The ability to synthesize duplexes with a defined interstrand cross-link and to incorporate these duplexes into longer pieces of DNA should enable preparation of substrates that can be used for a variety of biophysical and biochemical experiments, including studies of DNA repair.

Studies in polyphenol chemistry and bioactivity. 3.(1,2) stereocontrolled synthesis of epicatechin-4alpha,8-epicatechin, an unnatural isomer of the B-type procyanidins.

Oligomeric procyanidins containing 4alpha-linked epicatechin units are rare in nature and have hitherto not been accessible through stereoselective synthesis. We report herein the preparation of the prototypical dimer, epicatechin-4alpha,8-epicatechin (6), by reaction of the protected 4-ketones 11a,b with aryllithium reagents derived by halogen/metal exchange from the aryl bromides 26a,b. Removal of the 4-hydroxyl group from the resulting tertiary benzylic alcohols 27a,b was effected by tri-n-butyltin hydride and trifluoroacetic acid in a completely stereoselective manner, resulting in hydride delivery exclusively from the beta face. If benzyl was chosen for protection of the 3-hydroxyls, all protective groups could subsequently be removed in a single step by hydrogenolysis. tert-Butyldimethylsilyl groups, on the other hand, permitted selective deprotection of the 3-hydroxyls in preparation for their subsequent acylation with tri-O-benzylgalloyl chloride. Only monogalloylation at the "bottom" 3-hydroxyl took place when 28c was acylated under the previously reported conditions, reflecting the increased steric hindrance of the "top" 3-hydroxyl group in 28c compared with its 4beta,8-isomer 3. The preparation of compounds 14 and 17 containing phloroglucinol trimethyl ether in the 4alpha and 4beta linkages to epicatechin is also described. The 8-position of the bromine atom in 19, previously conjectured in analogy to the structurally characterized tetramethyl ether 20, was confirmed by transformation of both compounds into the common derivative 25.