Synthetic studies on glycosphingolipids from protostomia phyla: synthesis of neogala-series glycolipid analogues containing a mannose residue from the earthworm Pheretima hilgendorfi.

Two kinds of glycosphingolipid analogues from the earthworm Pheretima hilgendorfi were synthesized as follows: the trisaccharide 2-(tetradecyl)hexadecyl alpha-D-mannopyranosyl-(1-->4)-beta-D-galactopyranosyl-(1-->6)-beta-D- galactopyranoside (13) and the tetrasaccharide 2-(tetradecyl) hexadecyl alpha-D-galactopyranosyl-(1-->6)-[alpha-D-mannopyranosyl-(1-->4)]-beta-D - galactopyranosyl-(1-->6)-beta-D-galactopyranoside (20) were synthesized by stepwise condensation of suitably protected monosaccharide units. A 2-(trimethylsilyl)ethyl 2,3,4-tri-O-benzoyl-beta-D-galactopyranoside derivative (5) was used as the glycosyl acceptor and thiophenyl derivatives of D-galactose and D-mannose were used as donors respectively.     

Synthesis of a new glycosphingolipid from the marine ascidian Microcosmus sulcatus using a one-pot glycosylation strategy

A novel neutral glycosphingolipid found in Microcosmus sulcatus containing a β-d-Galp(1→4)[α-d-Fucp-(1→3)]β-d-Glcp-(1→)Cer motif was synthesized. Trisaccharide derivatives were synthesized using trimethylsilyltrifluoromethanesulfanate (TMSOTf) and N-iodosuccimide (NIS)/trifluoromethane sulfonic acid (TfOH) as the promoters. Synthesis was achieved with an efficient one-pot glycosylation strategy. This is the first report of a one-pot glycosylation strategy using the procedure of Boons et al. for the synthesis of a natural product. Coupling of trisaccharide derivative 19 and ceramide derivative 20 by TMSOTf afforded the glycosphingolipid derivative 21. The fully protected glycoside was deprotected to give the target glycosphingolipid 2.     

Synthetic studies on glycosphingolipids from protostomia phyla: synthesis of amphoteric glycolipid analogues from the porcine nematode,Ascaris suum

A novel amphoteric glycosphingolipid, cholinephosphoryl-(-->6)-beta-D-GlcpNAc-(1-->3)-beta-D-Manp-(1-->4)-beta-D-Glcp-(1-->)-Cer, isolated from the porcine parasitic nematode, Ascaris suum, may be expected to be involved in host-parasite interactions. This glycosphingolipid analogue containing octyl residue in place of ceramide was synthesized as follows: The key reaction of this synthetic procedure is the formation of a intramolecular aglycon delivery (IAD) approach for beta-selective mannosylation. Then, a coupling of phosphocholine group at the position C-6' of 16 was attempted using 2-chloro-2-oxo-1,3,2-dioxaphospholane, followed by reaction of the resulting cyclic phosphate intermediate with anhydrous trimethylamine to give 17. Subsequent debenzylation and debenzylidenation afforded target compound (2).     

Synthetic anthracyclines: regiospecific total synthesis of D-ring thiophene analogues of daunomycin

The key anhydride 2-acetoxy-[2-carboxy-5-(trimethylsilyl)thiophen-3-yl]acetic acid anhydride (8), prepared from (2-carboxythiophen-3-yl)acetic acid (5), underwent a strong base-induced cycloaddition reaction with the chloroquinone acetal (11) to give the 7,7-ethylenedioxy-2-trimethylsilyl-6,7,8,9- tetrahydroanthra[2,3-b]thiophene-5,10-dione (12) regioselectively. Similarly, the regioisomeric 8,8-ethylenedioxy-2-trimethylsilyl-6,7,8,9-tetrahydroanthra[2,3-b] thiophene- 5,10-dione (30) was obtained by the strong base-induced cycloaddition reaction of 8 with the chloroquinone acetal (29). These cycloadducts (12 and 30) were converted to D-ring thiophene analogues (28 and 38) of daunomycin (1a). Another D-ring thiophene analogue (42) which has a trimethylsilyl substituent in the D-ring was also prepared.     

Studies on imidazole derivatives and related compounds. 4. Synthesis of O-glycosides of 4-carbamoylimidazolium-5-olate

Ribosylation of trimethylsilyl derivative of 1-(4-nitrobenzyl)-5-carbamoylimidazolium-4-olate ( 5 ) with 1,2,3,5-tetra-O-acetyl-β- D -ribofuranose in the presence of stannic chloride and trimethylsilyl trifluoromethanesulfonate afforded no 5-O-glycosides but N-1 ribosylated compound ( 6 ). However, 5-O-riboside ( 7a ) and its orthoamide derivative ( 8 ) were given by glycosylation of tri-n-butylstannyl derivative of 5 with 2,3,5-tri-O-acetyl-β- D -ribofuranosyl chloride in the presence of silver trifluoromethanesulfonate. This procedure was successfully applied to other sugars and 5-O-glucuronide ( 11 ), a possible metabolite of 1 in vivo, was obtained as one of the 5-O-glycoside derivatives.     

Synthesis of bromo-, boryl-, and stannyl-functionalized 1,2-bis(trimethylsilyl)benzenes via Diels-Alder or C-H activation reactions

1,2-Bis(trimethylsilyl)benzenes are key starting materials for the synthesis of benzyne precursors, Lewis acid catalysts, and certain luminophores. We have developed efficient, high-yield routes to functionalized 4-R-1,2-bis(trimethylsilyl)benzenes, starting from either 1,2-bis(trimethylsilyl)acetylene/5-bromopyran-2-one (2) or 1,2-bis(trimethylsilyl)benzene (1)/bis(pinacolato)diborane. In the first reaction, 5 (R = Br) is obtained through a cobalt-catalyzed Diels-Alder cycloaddition. The second reaction proceeds via iridium-mediated C-H activation and provides 8 (R = Bpin). Besides its use as a Suzuki reagent, compound 8 can be converted into 5 with CuBr(2) in i-PrOH/MeOH/H(2)O. Lithium-bromine exchange on 5, followed by the addition of Me(3)SnCl, gives 10 (R = SnMe(3)), which we have applied for Stille coupling reactions. A Pd-catalyzed C-C coupling reaction between 5 and 8 leads to the corresponding tetrasilylbiphenyl derivative. The bromo derivative 5 cleanly undergoes Suzuki reactions with electron-rich as well as electron-poor phenylboronic acids.     

Synthesis and reactions of silicon containing cyclic α-amino acid derivatives

A simple synthesis of a new amino acid derivative 5,6-bis(trimethylsilyl)indanylglycine via cobalt mediated [2 + 2 + 2] cycloaddition strategy is described. Co-trimerization of diyne building block containing amino acid moiety with bis(trimethylsilyl)acetylene in presence of CpCo(CO)₂ catalyst afforded the silylated indane-based α-amino acid (AAA) derivative. Electrophilic aromatic substitution reaction, ipso to the trimethylsilyl group gave highly functionalised indane-based AAA derivatives.     

[2+3]Cycloaddition reaction of a kinetically stabilized distibene with a nitrile oxide leading to the formation of a unique heterocyclic compound

The synthesis of a 1-oxa-5-aza-2,3-distibacyclopent-4-ene derivative by the [2+3]cycloaddition reaction of a kinetically stabilized distibene, BbtSb=SbBbt (Bbt = 2,6-bis[bis(trimethylsilyl)methyl]-4-[tris-(trimethylsilyl)methyl]phenyl), with MesCNO (Mes = mesityl) has been performed. Dedicated to Prof. Dr. E. Lukevics on the occasion of his 70th birthday __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1880–1887, December, 2006.     

The synthesis of imidazole-2-thione nucleosides

Ribosylation of the trimethylsilyl derivative ( 1b ) of imidazole-2-thione ( 1a ) using either stannic chloride or silver perchlorate as catalyst resulted in the formation of the acylated derivatives of 1-(β-D-ribofuranosyl)imidazole-2-thione ( 3c ) and 1,3-di-(β-D-ribofuranosyl)imidazole-2-thione ( 4c ) with the latter predominating ( 4c:3c , ca. 2:1 ). The diribosylated nucleoside 4c was shown to be the N,N-disubstituted product rather than the N,S-disubstituted product by ¹H nmr and ¹³C nmr spectroscopy. Employment of the iodine-catalyzed fusion procedure reversed the aforementioned product ratios and provided the monoriboside 3c in excellent yield. When the trimethylsilyl derivative ( 5b ) of 2-methylthioimidazole ( 5a ) was reacted with 2,3,5-tri-O-benzoyl-D-ribofuranosyl bromide ( 2d ) in acetonitrile, the major product was 1,3-di-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-imidazole-2-thione ( 4b ). The formation of 4b in this reaction is thought to arise via the Hilbert-Johnson mechanism.     

(4-Methoxyphenyl)amine and its derivatives in the synthesis of <Emphasis Type="Italic">O</Emphasis>-silylurethanes,ureas, and formamides

Reactions of (4-methoxyphenyl)amine and its trimethylsilyl derivative with organosilicon isocyanates and phenylisocyanate have been studied. (4-Methoxyphenyl)formamide was first synthesized by the reaction of (4-methoxyphenyl)amine with ethyl formate. The structure of trimethylsilyl(4-methoxyphenyl)-carbamate and N-(4-methoxyphenyl)formamide was determined by X-ray diffraction (XRD) analysis.     

Applications of 4,4'-(Me3Si)2-BINAP in transition-metal-catalyzed asymmetric carbon-carbon bond-forming reactions

[structure: see text] A recently developed BINAP derivative with trimethylsilyl substituents on the 4- and 4'-positions of the binaphthyl skeleton, 2,2'-bis(diphenylphosphino)-4,4'-bis(trimethylsilyl)-1,1'-binaphthyl (tms-BINAP), was used in a variety of transition-metal-catalyzed asymmetric carbon-carbon bond-forming reactions. In pi-allylpalladium-mediated reactions, tms-BINAP gave better enantioselectivity than the unsubstituted BINAP, and the origin of the improved enantioselectivity was gained from an X-ray structural study of [Pd(eta(3)-C(3)H(5))((R)-tms-BINAP)]ClO(4).     

Synthesis of Enantiomerically Pure Bis(hydroxymethyl)-Branched Cyclohexenyl and Cyclohexyl Purines as Potential Inhibitors of HIV

The synthesis of the enantiomerically pure bis(hydroxymethyl)-branched cyclohexenyl and cyclohexyl purines is described. Racemic trans-4,5-bis(methoxycarbonyl)cyclohexene [(+/-)-6] was reduced with lithium aluminum hydride to give the racemic diol (+/-)-7. Resolution of (+/-)-7 via a transesterification process using lipase from Pseudomonas sp. (SAM-II) gave both diols in enantiomerically pure form. The enantiomerically pure diol (S,S)-7was benzoylated and epoxidized to give the epoxide 9. Treatment of the epoxide 9 with trimethylsilyl trifluoromethanesulfonate and 1,5-diazabicyclo[5.4.0]undec-5-ene followed by dilute hydrochloric acid gave (1R,4S,5R)-4,5-bis[(benzoyloxy)methyl]-1-hydroxycyclohex-2-ene (10). Acetylation of 10 gave (1R,4S,5R)-1-acetoxy-4,5-bis[(benzoyloxy)methyl]cyclohex-2-ene (11). (1R,4S,5R)-1-Acetoxy-4,5-bis[(benzoyloxy)methyl]cyclohex-2-ene (11) was converted to the adenine derivative 12 and guanine derivative 13 via palladium(0)-catalyzed coupling with adenine and 2-amino-6-chloropurine, respectively. Hydrogenation of 12 and 13 gave the correspondning saturated adenine derivative 14 and guanine derivative 15. (1R,4S,5R)-4,5-Bis[(benzoyloxy)methyl]-1-hydroxycyclohex-2-ene (10) was converted to the adenine derivative 16 and guanine derivative 17 via coupling with 6-chloropurine and 2-amino-6-chloropurine, respectively, using a modified Mitsunobu procedure. Hydrogenation of 16 and 17 gave the corresponding saturated adenine derivative 18 and guanine derivative 19. Compounds 12-19 were evaluated for activity against human immunodeficiency virus (HIV), but were found to be inactive. Further biological testings are underway.     

Synthesis and crystal structure of an O-silylated hexahomotriazacalix[3]arene

The first synthesis of an O-silylated derivative of a hexahomotriazacalix[3]arene has been achieved using 1-(trimethylsilyl)imidazole (TMSIM), 1,1,1,3,3,3-hexamethyldisilazane (HMDS), or bis(trimethylsilyl)trifluoroacetamide (BSTFA) in acetronitrile. The cone isomer was formed selectively using TMSIM and HMDS; whereas a cone/partial cone mixture was obtained using BSTFA.     

Synthesis of 1-(2′-O-methyl-β-d-ribofuranosyl)-uracil (2′-O-methyluridine) and 3-(2′-O-methyl-β-d-ribofuranosyl)uracil

1-O-Acetyl-3,5-di-O-benzoyl-2-O-methyl-β-d-ribofuranose has been prepared in five steps from benzyl 2-O-methyl-β-d-ribopyranoside. Reaction of the furanose derivative with 2,4-bis-(trimethylsilyl)uracil in the presence of stannic chloride provides a new synthesis of 2′-O-methyl uridine and also yields the hitherto unknown 3-(2′-O-methyl-β-d-ribofuranosyl)uracil.     

Studies on the Thioglycosides of N-Acetylneuraminic Acid 7: Synthesis of S-(α-Sialyl)-(2↠6)-β-D-Hexopyranosyl and -(2↠6)-β-D-Lactosyl Ceramides and their Biological Activity

ABSTRACT

The coupling of the sodium salt of methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-3, 5-dideoxy-2-thio-D-glycero-α-D-galacto-2-nonulopyranosonate (17) with 2-(trimethylsilyl)ethyl 2,3,4-tri-O-acetyl-6-bromo-6-deoxy-β-D-galactopyranoside (5), glucopyranoside (10), and 2-(trimethylsilyl)ethyl 2,3,6,2′,3′,4′-hexa-O-acetyl-6′-bromo-6′-deoxy-β-D-lactoside (16), gave the corresponding α-thioglycosides 18, 21, and 24 of the 2-thio-N-acetyl-neuraminic acid derivative in good yields, which were converted, via selective removal of the 2-(trimethylsilyl)ethyl group, trichloroacetimidation, and coupling with (2S,3R,4E)-2-azido-3-O-benzoyl-4-octadecene-1,3-diol (27), into the ß-glycosides 28, 32, and 36, respectively.

Compounds 28, 32, and 36 were transformed, via selective reduction of the azide group, coupling with octadecanoic acid, O-deacetylation, and de-esterification, into the title compounds 31, 35, and 39, which showed potent inhibitory effect for sialidases from influenza and other viruses.     

Determination of lovastatin acid in serum by gas chromatography/mass spectrometry

The acid form of lovastatin, an HMG-CoA reductase inhibitor, was analyzed by gas chromatography/negative-ion chemical ionization mass spectrometry after derivatization with pentafluorobenzyl bromide and bis-(trimethylsilyl)trifluoroacetamide (BSTFA). Mass spectrometry of this derivative produced a dominant [M-181]- ion under chemical ionization conditions using ammonia as the reagent gas. The limit of detection was approximately 2 pg injected on column.     

Fluorous (trimethylsilyl)ethanol: a new reagent for carboxylic acid tagging and protection in peptide synthesis

Starting with a fluorous analogue of 2-(trimethylsilyl)ethanol, we have designed an easy method for preparing a new fluorous tag ((F)TMSE) for the protection of carboxylic acids. Because mild conditions are employed in the tag cleavage (TBAF in the presence of 4 A molecular sieves, which prevent racemization), this tag can be advantageously used in the synthesis of peptides and modified peptides, as we have demonstrated with several examples, including the fluorous synthesis of short alpha- and beta-peptides as well as of modified fluorinated retropeptides.     

Synthesis of 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]-1,2,4-triazole-3- and 5-carboxamides

Coupling of trimethylsilyl derivative of methyl 1,2,4-triazole-3-carboxylate with 2-$\text{O}$-(chloromethyl)-1,3-di-$\text{O}$-benzyl glycerol, followed by amination and removal of the protecting groups afforded 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]-1,2,4-triazole 3- and 5-carboxamides, 1a and 1b, respectively.     

Determination of 6-(2'-chlorophenyl)-4-hydroxy-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxamide, a mixed agonist-antagonist anxiolytic agent, in human plasma and urine by gas chromatography-negative-ion chemical-ionization mass spectrometry

A simple, sensitive and specific assay was developed for the determination in plasma and urine of 6-(2'-chlorophenyl)-4-hydroxy-4H-imidazo[1,5-alpha] [1,4]benzodiazepine- 3-carboxamide, compound I, a mixed agonist-antagonist anxiolytic agent. A hexadeuterated analogue of the compound was added to plasma or urine as the reference standard. The titled compound was extracted with benzene at pH 11. Following evaporation of the solvent, the residue was reacted with pentafluoropropionic anhydride in the presence of triethylamine. The derivatizing reagents were evaporated, and the carbonitrile derivative of the analyte was extracted into ethyl acetate at pH 11. The residue remaining after removal of the ethyl acetate was silylated with bis(trimethylsilyl)trifluoroacetamide, and a portion of this solution was analyzed by gas chromatography-negative-ion chemical-ionization mass spectrometry. The mass spectrometer was set to monitor, in the gas chromatographic effluent, the M-. ion of the titled compound and its hexadeuterated reference standard. The ratio of these two ions was calculated and converted to a concentration of analyte using a calibration curve that was generated from the analyses of control plasma fortified with various amounts of analyte and a fixed amount of the hexadeuterated reference standard. The limit of quantitation of the assay was 1 ng/ml for plasma and urine.     

Oligonucleotide incorporation of 8-thio-2'-deoxyguanosine

[reaction: see text] 8-Thio-2'-deoxyguanosine (SdG) is a useful analogue of the abundant promutagen 8-oxo-2'-deoxyguanosine (OdG). Its synthesis and DNA incorporation using standard phosphoramidite chemistry is reported. To prevent oxidation during DNA synthesis, the sulfur was protected as a 2-(trimethylsilyl)ethyl sulfide. Subsequent treatment with TBAF yielded the desired 8-thiocarbonyl functionality. Melting studies with SdG revealed almost equal stabilities of SdG:dC and SdG:dA base pairs, lending insight into the base-pairing preferences of OdG.