Tert-butyldimethylsilyl Ethers Research Articles

Synthesis and structure–activity relationship of 3- O-acylated (–)-epigallocatechins as 5α-reductase inhibitors

A series of 3- O-acylated (–)-epigallocatechins were synthesized and their inhibition of steroid 5α-reductase was studied. They were prepared from the reaction of EGCG with tert-butyldimethylsilyl chloride followed by reductive cleavage of the ester bond. The resultant (–)-epigallocatechins penta- O- tert-butyldimethylsilyl ether was esterified with different fatty acids then desilylated to provide the corresponding products. The activity of 3- O-acylated (–)-epigallocatechins increased with the increasing carbon numbers of the fatty acid moiety, reaching maximum for 16 carbon atoms (compound 4h) with an IC 50 of 0.53 μM, which was ∼12-fold more potent than EGCG (IC 50 = 6.29 μM). Introduction of monounsaturated fatty acid provided the most potent compound 6 (IC 50 = 0.48 μM), which showed moderate anti-tumor activity in vivo.

Catalytic removal of tert-butyldimethylsilyl (TBS) and tetrahydropyranyl (THP) groups from protected alcohols by NO+BF4 − in methanol

An effective, catalytic method has been developed to remove TBS and THP groups from protected alcohols. TBS and THP ethers were selectively cleaved using a catalytic amount of NO+BF4 − (5 mol%) in methanol at room temperature.

ChemInform Abstract: A Practical Synthesis of Flavones from Methyl Salicylate.

Abstract A facile synthetic method has been developed for the conversion of methyl salicylate (5) into flavones 1a-i in high yields. Compound 5 on treatment with t-butyldimethylsilyl chloride (6) gave the O-silyl protected ester 7. Condensation of this ester 7 with the lithium anion generated from acetophenones 3a-i yielded the 1.3-diarylpropane-1,3-diones 8a-i, which on treatment with glacial acetic acid containing 0.5% H2SO4 for 3 h at 95-100 °C provided the desired flavones 1a-i in 83–94% yields.

ChemInform Abstract: Improved Protocols for the Selective Deprotection of Trialkylsilyl Ethers Using Fluorosilicic Acid.

Improvements for the application of aqueous fluorosilicic acid to the selective cleavage of tert-butyldimethylsilyl ethers in the presence of triisopropylsilyl ethers are described. Deprotection conditions have been optimized for cleavage selectivity, tolerance by acid-labile compounds, and cleavage rate. Mechanistic features of the desilylation reaction are discussed

ChemInform Abstract: Solid Acid Catalysts: Modification of Acid Sites and Effect on Activity and Selectivity Tuning in Various Reactions

AbstractReview: 80 refs.

Erratum to “A mild and chemoselective method for the deprotection of tert-butyldimethylsilyl (TBDMS) ethers using iron(III) tosylate as a catalyst” [Tetrahedron Lett. 51 (2010) 1056–1058

Erratum Erratum to ‘‘A mild and chemoselective method for the deprotection of tert-butyldimethylsilyl (TBDMS) ethers using iron(III) tosylate as a catalyst” [Tetrahedron Lett. 51 (2010) 1056–1058] Jason M. Bothwell, Veronica V. Angeles, James P. Carolan, Margaret E. Olson, Ram S. Mohan * Laboratory for Environmentally Friendly Organic Synthesis, Department of Chemistry, Bloomington, IL 61701, United States

A General Method for the Synthesis of 2,2-[60]Fullerenoalkanals: The Reaction of [60]Fullerene with 2-Bromoenol Silyl Ethers

Five kinds of 2,2-[60]fullerenoalkanals were synthesized by the fluoride ion-mediated reaction of [60]fullerene with 2-bromoenol silyl ethers, which were easily prepared by 2-bromination of the corresponding enol silyl ethers. The reactivity differed significantly depending on the stability of the 2-bromoenol silyl ethers. High yield and selectivity were achieved for the reaction of 2-bromoenol trimethylsilyl ethers under mild conditions (KF/18-crown-6-ether). The reaction of stable 2-bromoenol tert-butyldimethylsilyl ethers, on the other hand, required the use of more reactive tetra­butylammonium fluoride as a fluoride ion source.

Enantioselective Inhibition of Squalene Synthase by Aziridine Analogues of Presqualene Diphosphate

Squalene synthase catalyzes the conversion of two molecules of (E,E)-farnesyl diphosphate to squalene via the cyclopropylcarbinyl intermediate, presqualene diphosphate (PSPP). Since this novel reaction constitutes the first committed step in sterol biosynthesis, there has been considerable interest and research on the stereochemistry and mechanism of the process and in the design of selective inhibitors of the enzyme. This paper reports the synthesis and characterization of five racemic and two enantiopure aziridine analogues of PSPP and the evaluation of their potencies as inhibitors of recombinant yeast squalene synthase. The key aziridine-2-methanol intermediates (6-OH, 7-OH, and 8-OH) were obtained by N-alkylations or by an N-acylation-reduction sequence of (+/-)-, (2R,3S)-, and (2S,3R)-2,3-aziridinofarnesol (9-OH) protected as tert-butyldimethylsilyl ethers. S(N)2 displacements of the corresponding methanesulfonates with pyrophosphate and methanediphosphonate anions afforded aziridine 2-methyl diphosphates and methanediphosphonates bearing N-undecyl, N-bishomogeranyl, and N-(alpha-methylene)bishomogeranyl substituents as mimics for the 2,6,10-trimethylundeca-2,5,9-trienyl side chain of PSPP. The 2R,3S diphosphate enantiomer bearing the N-bishomogeranyl substituent corresponding in absolute stereochemistry to PSPP proved to be the most potent inhibitor (IC(50) 1.17 +/- 0.08 muM in the presence of inorganic pyrophosphate), a value 4-fold less than that of its 2S,3R stereoisomer. The other aziridine analogues bearing the N-(alpha-methylene)bishomogeranyl and N-undecyl substituents, and the related methanediphosphonates, exhibited lower affinities for recombinant squalene synthase.

Synthesis and self‐assembly of well‐defined cyclodextrin‐centered amphiphilic A14B7 multimiktoarm star copolymers based on poly(ε‐caprolactone) and poly(acrylic acid)

AbstractNovel amphiphilic A14B7 multimiktoarm star copolymers composed of 14 poly(ε‐caprolactone) (PCL) arms and 7 poly(acrylic acid) (PAA) arms with β‐cyclodextrin (β‐CD) as core moiety were synthesized by the combination of controlled ring‐opening polymerization (CROP) and atom transfer radical polymerization (ATRP). 14‐Arm star PCL homopolymers (CDSi‐SPCL) were first synthesized by the CROP of CL using per‐6‐(tert‐butyldimethylsilyl)‐β‐CD as the multifunctional initiator in the presence of Sn(Oct)2 at 125 °C. Subsequently, the hydroxyl end groups of CDSi‐SPCL were blocked by acetyl chloride. After desilylation of the tert‐butyldimethylsilyl ether groups from the β‐CD core, 7 ATRP initiating sites were introduced by treating with 2‐bromoisobutyryl bromide, which further initiated ATRP of tert‐butyl acrylate (tBA) to prepare well‐defined A14B7 multimiktoarm star copolymers [CDS(PCL‐PtBA)]. Their molecular structures and physical properties were in detail characterized by 1H NMR, SEC‐MALLS, and DSC. The selective hydrolysis of tert‐butyl ester groups of the PtBA block gave the amphiphilic A14B7 multimiktoarm star copolymers [CDS(PCL‐PAA)]. These amphiphilic copolymers could self‐assemble into multimorphological aggregates in aqueous solution, which were characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM) and atomic force microscopy (AFM). © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 2961–2974, 2010

ChemInform Abstract: A Mild, Efficient, Inexpensive, and Selective Cleavage of Primary tert-Butyldimethylsilyl Ethers by Oxone in Aqueous Methanol.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Total Synthesis of Englerin A

Total synthesis of englerin A, a recently reported sesquiterpenoid exhibiting potent and selective growth inhibition against renal cancer cell lines, has been accomplished. The successful strategy featured a [5 + 2] cycloaddition reaction to cast the seven-membered oxabicyclic key intermediate in both racemic and optically active forms. Synthetic (+/-)-englerin A, (+/-)-englerin B, (+/-)-englerin B acetate, a hydroxy acetate, a tert-butyldimethylsilyl ether, and hydrogenated (+/-)-englerin A (31) were tested for their cytotoxicity against a selected panel of cancer cell lines, and the results are path-pointing to more focused structure-activity relationship studies.

Selective cleavage of phenolic tert-butyldimethylsilyl ethers using simple organic nitrogen bases

Simple organic nitrogen bases, such as Et 3N, pyridine, DBU, etc., were found to be convenient and useful reagents for deprotection of TBDMS groups on acidic hydroxyl groups. The efficiency of these bases has an apparent order: 1° amine > 2° amine > 3° amine and aliphatic base > aromatic base. In aqueous DMSO and at room temperature, phenolic TBDMS ethers were removed selectively in the presence of alcoholic TBDMS ethers. And catalytic base can make these reactions complete. This method is high-yielding, fast, clean, safe and cost-effective.

Substitution‐ and Elimination‐Free Phosphorylation of Functionalized Alcohols Catalyzed by Oxidomolybdenum Tetrachloride

AbstractAmong 14 oxidometallic species examined for catalytic phosphorylation of the tested alcohols, oxidomolybdenum tetrachloride (MoOCl4) was found to be the most efficient with a negligible background reaction mediated by triethylamine (Et3N). The new catalytic protocol can be applied to the chemoselective phosphorylations of primary, secondary and tertiary alcohols as well as the substitution‐free phosphorylations of allylic, propargylic, and benzylic alcohols. Functionalized alcohols bearing acetonide, tetrahydropyranyl ether, tert‐butyldimethylsilyl ether, or ester group are also amenable to the new catalytic protocol. The most difficult scenarios involve substitution‐free phosphorylations of 1‐phenylethanol and 1‐(2‐naphthyl)ethanol which can be effected in 95 and 90% yields, respectively. ESI‐MS, IR, 1H, and 31P NMR spectroscopic analyses of the reaction progress suggest the intermediacy of an alkoxyoxidomolybdenum trichloride‐triethylamine adduct such as [(RO)Mo(O)Cl3‐Et3N] to be responsible for the catalytic turnover.

A mild and chemoselective method for the deprotection of tert-butyldimethylsilyl (TBDMS) ethers using iron(III) tosylate as a catalyst

The most common method for the deprotection of TBDMS ethers utilizes stoichiometric amounts of tetrabutylammonium fluoride, n-Bu4N + F (TBAF), which is highly corrosive and toxic. We have developed a mild and chemoselective method for the deprotection of TBDMS, TES, and TIPS ethers using iron(III) tosylate as a catalyst. Phenolic TBDMS ethers, TBDPS ethers and the BOC group are not affected under these conditions. Iron(III) tosylate is an inexpensive, commercially available, and non-corrosive reagent.

Abstract A89: Synthesis and structure-activity relationship of 3-O-acylated (−)-epigallocatechins as 5α-reductase inhibitors

Abstract A series of 3-O-acylated (−)-epigallocatechins were synthesized and their inhibition of steroid 5α-reductase was studied. They were prepared by the reaction of EGCG with tert-butyldimethylsilyl chloride followed by reductive cleavage of the ester bond. The resultant (−)-epigallocatechins penta-O-tert-butyldimethylsilyl ether was esterified with different fatty acids using DCC and DMAP and then desilylated with aqueous HF to provide the corresponding products. For 3-O-acylated (−)-epigallocatechins with saturated fatty acids, the 5α-reductase inhibitory activity increased with the increasing numbers of carbon atoms at the C3-O position, reaching maximum for 16 carbon atoms (compound 4h, with palmitic acid) with an IC50 of 0.53 µM, which was ∼12-fold more potent than EGCG (IC50 = 6.29 M). Introduction of monounsaturated fatty acid to the C3-O position of (−)-epigallocatechins enhanced the activity, providing the most potent compound 6 (IC50 = 0.48 µM, with palmitoleic acid), which showed moderate anti-tumor activity in a PC-3 prostate cancer xenograft model. Replacement of the ester moiety at C3-O with carbamate, or permethylation or peracylation of hydroxyl groups diminished 5α-reductase inhibitory activity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A89.

Di‐ and Dodeca‐Mitsunobu Reactions on C60 Derivatives: Post‐Functionalization of Fullerene Mono‐ and Hexakis‐Adducts

The diverse addition patterns of fullerene adducts make them attractive molecules, generating widespread application. Firstly, in terms of the latter, mono-adducts are extensively used in opto-electronic devices, owing to the fullerene core s capacity to accept up to six electrons. A second important application involves the utilization of fullerene adducts as structural components in material sciences. With their octahedral topology, Th-symmetric hexakis-adducts, are particularly intriguing. Amongst others, the latter have been used in C60-based star polymers. [5] In the aforementioned contexts, the relatively stable methanofullerene adducts obtained through Bingel cyclopropanation reactions are of particular interest. However, this functionalization approach—primarily developed by A. Hirsch and later optimized by Y.-P. Sun—suffers from two critical weaknesses. One is its effectively exclusive limitation to malonates; only a few exceptions are known. The other is a structural concern. In fact, quite often only the use of fairly simple malonates leads to the desired fullerene adducts in reasonable yields without tedious purifications. In order to overcome these problems, several groups have developed post-functionalizations of methanofullerene adducts. For instance, J.F. Nierengarten adapted the copper-mediated Huisgen 1,3dipolar cycloaddition reaction and applied it to the preparation of complex hexasubstituted fullerenes. A. Hirsch developed a selective deprotection–functionalization sequence of fullerene e,e,e-trisadducts. Our own group derivatized hexakis methanofullerenes by using several organometallic cross-coupling reactions. This article outlines the use of the Mitsunobu reaction as an efficient tool for the post-functionalization of fullerene monoand hexakis-adducts. The mild, virtually neutral conditions under which this dehydrative coupling of an alcohol with a pronucleophile (generally an acid) proceeds, prompted our group to use this reaction for the derivatization of fullerene adducts. To this end, we have prepared a C60 mono-adduct bearing 2 hydroxyl groups and a hexakisadduct with 12 hydroxyl functions. The preparation of hexakis compound 4 is depicted in Scheme 1. Ethylene glycol was mono-protected as tert-butyldimethylsilyl ether according to a previously reported procedure. Subsequent diesterification of malonic acid was performed in the presence of DCC in 97% yield. Hexakis-adduct 3 was then readily synthesized by using the optimized conditions

Solid Acid Catalysts: Modification of Acid Sites and Effect on Activity and Selectivity Tuning in Various Reactions

The effects of acidity and variation in concentration of acid sites of dodecatungstophosphoric acid (DTP), supported DTP and montmorillonite-K catalysts were studied for various organic reactions such as the hydroxyalkylation of phenols to bisphenols, intramolecular rearrangement of benzyl phenyl ether (BPE) to 2-benzyl phenol (2-BP) and selective cleavage of tert-butyldimethylsilyl (TBDMS) ether into the corresponding alcohol. Both dodecatungstophosphoric acid (DTP) impregnated on silica (SiO2) and montmorillonite catalysts showed the highest catalyst activity with 90–95% selectivity to bisphenol for the hydroxyalkylation of phenols to give bisphenol. Temperature Programmed Desorption (TPD) of ammonia and activity results of various catalysts showed that an appropriate combination of both strong and weak acidic sites in the catalyst was highly desirable for high bisphenol selectivity. A 10% DTP/SiO2 catalyst was found to be highly selective for the cleavage of TBDMS ether into the corresponding alcohol at room temperature giving a high TON of 9.5 × 105 even after the 4th recycle. DTP was also found to be a promising solid acid catalyst for the intramolecular rearrangement of BPE giving 2-BP.

Asymmetric [3,3]- and [1,3]-Sigmatropic Rearrangements of γ-Allyloxy Vinylogous Urethanes

Vinylogous urethanes derived from condensation of prolinol or prolinol tert-butyldimethylsilyl ether with 4-allyloxyketoester were found to undergo a thermal [3,3]-sigmatropic rearrangement, providing compounds with N-substituted quaternary carbon centers. Cyclizations (subsequently or in situ) of the rearranged products generated hexahydro-3,4-dioxa-8a-aza-as-indacen-2-ones. Various terminally substituted allyloxy ketoesters and arylmethoxy ketoesters were found to generate tricyclic compounds via [1,3]-sigmatropic rearrangement. Finally, tricyclic lactones were transformed successfully into lactams.

A ratiometric fluorescent probe for fluoride ion employing the excited-state intramolecular proton transfer

A ratiometric fluorescent probe 1 for fluoride ion was developed based on modulation of the excited-state intramolecular proton transfer (ESIPT) process of 2-(2′-hydroxyphenyl)benzimidazole (HPBI) through the hydroxyl group protection/deprotection reaction. The probe 1 was readily prepared by the reaction of HPBI with tert-butyldimethylsilyl chloride (TBS-Cl) and shows only fluorescence emission maximum at 360 nm. Upon treatment with fluoride in aqueous DMF solution, the TBS protective group of probe 1 was removed readily and ESIPT of the probe was switched on, which resulted in a decrease of the emission band at 360 nm and an increase of a new fluorescence peak around 454 nm. The fluorescent intensity ratio at 454 and 360 nm ( I 454/ I 360) increases linearly with fluoride ion concentration in the range 0.3–8.0 μmol L −1 and the detection limit is 0.19 μmol L −1. The proposed probe shows excellent selectivity toward fluoride ion over other common anions. The method has been successfully applied to the fluoride determination in toothpaste and tap water samples.

Molecular Solids from Symmetrical Bis(piperazine-2,5-diones) with Open- and Closed-Monomer Conformations

The design, synthesis and solid state structures of a new class of xylylene-linked bis(1,4- piperazine-2,5-diones) are reported in an effort to extend the molecular framework of piperazine-2,5-diones. These compounds were derived from piperazine-2,5-dione as the core structure, synthesized via a new efficient route, and their crystal structures were determined. We examined the effects of side chain substitution on conformations of the linked bis-DKPs. Crystallization of 3,3'-[1,4-phenylenebis(methylene)]-bis[6-(hydroxymethyl)-1,4-dimethylpiperazine-2,5-dione] yielded molecular solids with an unusual network of "C"-shaped monomers held together by four intermolecular hydrogen bonds per asymmetric unit. Similarly, intermolecular interactions between the iodomethyl groups in 3,3'-[1,4-phenylenebis(methylene)]-bis[6-(iodomethyl)-1,4-dimethyl-piperazine-2,5-dione] result in the monomers adopting a "C"-shape in the solid state. Assembly of the monomers with side chains converted to methyl groups or tert-butyldimethylsilyl ethers, thereby lacking these stabilizing intermolecular interactions, results in an infinite array of "S"-shaped conformations. These results suggest that the interplay between the attractive intermolecular interactions and repulsive steric interactions of the substituents at the C6 and C6' positions of the diketopiperazine rings is important in determining the solid-state conformations of xylylene-linked bis(piperazine-2,5-diones).