Diethylaminosulfur Trifluoride Research Articles

Synthesis of 3′-Fluoro-3′-deoxyadenosine Starting from Adenosine

A new synthesis of 3′-fluoro-3′-deoxyadenosine is described. Start- ing from adenosine via a suitably protected intermediate by triflate activation and nucleophilic displacement with sodium acetate, the "xylo" epimer is obtained in two cases with different silyl groups protecting the 2′-position. Treatment of the xylo derivatives with diethylaminosulphur trifluoride gives the corresponding 3′-fluoro derivatives with inversion of the configuration. The reaction se- quence affords protected derivatives allowing selective deblocking of the 5′ or 2′-position.

Amikacin analogs with a fluorinated amino acid side chain.

The synthesis and biological activity of kanamycin A derivatives with an omega-amino-alpha-fluoroalkanoyl side chain on the 1-amino group are described. The fluorinated amino acids (4) for the side chain were prepared by fluorination of the alpha-hydroxy esters (2) with diethylaminosulfur trifluoride (DAST) with accompanying the Walden inversion. The reaction products varied with the amino protective groups employed, chain length of the alkanoic acids and the presence or absence of base. The fluorinated side chain was introduced to 1-free-NH2 kanamycin A (12) by the conventional active ester method and subsequent deblocking reactions afforded the desired final products (13-17). Of the derivatives prepared, 1-N-[(S)-4-amino-2-fluorobutyryl]kanamycin A (2'''-deoxy-2'''-fluoroamikacin, 14) showed the best overall activity profile, nearly the same as that of amikacin. Preparation and antibacterial activity of several aminoglycoside antibiotics with the 1-N-(S)-4-amino-2-fluorobutyryl side chain are also discussed.

Chemistry of novel compounds with multifunctional carbon structure. VI. Synthetic studies and 19F-nuclear magnetic resonance investigation of novel .ALPHA.,.ALPHA.-disubstituted fluoroacetates.

As a part of our work on synthetic studies of chiral monofluoro compounds and molecular design of efficient reagents for optical purity determination, we focused on novel α, α-disubstituted α-fluoroacetic acids (8a-d) (R1=Me, Ph; R2=C≡CPh, Me, Bu). The ethyl esters (13a-d) were prepared by introduction of alkyl groups into the appropriate α-keto acids (9a, b) followed by fluorination of the corresponding hydroxy-esters (12a-d) with diethylaminosulfur trifluoride (DAST). For comparison with Mosher's reagent (2-methoxy-2-trifluoromethylphenylacetic acid, (MTPA)), the ethyl esters (13a-d) were converted into three representative diastereoisomers, (14a-d), (15a-d), and (16a-d), and 19F-nuclear magnetic resonance (19F-NMR) chemical shift differences between pairs of diastereoisomers (Δδ) were obtained. These α, α-disubstituted α-fluoroacetate derivatives have much larger Δδ values than the corresponding derivatives of MTPA, which strongly indicates that the acids (8a-d) can potentially be better reagents for ee determination than MTPA. The influence on the Δδ values of the steric effects which arise upon introduction of the two substituents (R1 and R2) on the fluorine-bearing chiral center is also discussed.

Fluoro carbocyclic nucleosides: synthesis and antiviral activity of 2'- and 6'-fluoro carbocyclic pyrimidine nucleosides including carbocyclic 1-(2-deoxy-2-fluoro-.beta.-D-arabinofuranosyl)-5-methyluracil and carbocyclic 1-(2-deoxy-2-fluoro-.beta.-D-arabinofuranosyl)-5-iodouracil

The racemic carbocyclic 2'-fluoroarabinosyl pyrimidine nucleosides 8, 9 (C-FIAU), 12, and 13 (C-FMAU) and the 2'-fluororibosyl pyrimidine nucleosides 17, 20, and 21 were prepared from their respective protected 2'-fluoro amino diols 5 and 14. The carbocyclic 2'-2'-difluorothymidine analogue 27 was obtained from the protected difluoro amino diol 24 which was prepared from the ketone 23 and (diethylamino)sulfur trifluoride (DAST). The chiral carbocyclic 2'-deoxy-6'-fluorouridines 33, 34, 38, and 39 were synthesized from the protected 6'-fluoro amino diols 30 and 36, which were prepared by reduction of the azides 28 and 35. C-FMAU (13) and C-FIAU (9) were active in vitro against HSV-1 with ID50 values of 4.4 and 11 micrograms/mL, respectively, but they were inactive against HSV-2. The cytidine analogues 12 and 20 displayed modest activity in vitro against HSV-1 and HSV-2 but were inactive against human influenza A virus.

Synthesis and antiviral activity evaluation of 3′-fluoro-3′-deoxyribonucleosides: broad-spectrum antiviral activity of 3′-fluoro-3′-deoxyadenosine

Five 3′-fluorinated ribonucleosides were prepared and evaluated for their inhibitory properties against different viruses. The synthesis of these compounds was achieved by treatment of 2′,5′-di- O-tritylated nucleoside analogues possessing a xylo-configuration with diethylaminosulfur trifluoride, followed by deprotection. 3′-Fluoro-3′-deoxyadenosine was active against a broad range of viruses, encompassing both DNA viruses [pox (vaccinia)], single-stranded (+) RNA viruses [picorna (polio, Coxsackie B), toga (sindbis, Semliki Forest)] and double-stranded RNA viruses (reo). In its antiviral activity spectrum 3′-fluoro-3′-deoxyadenosine clearly differed from those adenosine analogues that are known as inhibitors of S-adenosylhomocysteine hydrolase. 3′-Fluoro-3′-deoxyadenosine also proved effective in vivo, in inhibiting tail lesion formation in mice inoculated intravenously with vaccinia virus.

2′, 3′‐Dideoxy‐3′‐fluorotubercidin and Related Dideoxyribonucleosides:. Synthesis via a 2′‐deoxy‐3′‐oxoribofuranoside intermediate and conformation studies

AbstractAn efficient synthesis of the unknown 2′‐deoxy‐D‐threo‐tubercidin (1b) and 2′, 3′‐dideoxy‐3′‐fluorotubercidin (2) as well as of the related nucleosides 9a, b and 10b is described. Reaction of 4‐chloro‐7‐(2‐deoxy‐β‐D‐erythro‐pentofuranosyl)‐7H‐pyrrolo[2,3‐d]pyrimidine (5) with (tert‐butyl)diphenylsilyl chloride yielded 6 which gave the 3′‐keto nucleoside 7 upon oxidation at C(3′). Stereoselective NaBH4 reduction (→8) followed by deprotection with Bu4NF(→9a)and nucleophilic displacement at C(6) afforded 1b as well as 7‐deaza‐2′‐deoxy‐D‐threo‐inosine (9b). Mesylation of 4‐chloro‐7‐{2‐deoxy‐5‐O‐[(tert‐butyl)diphenylsilyl]‐β‐D‐threo‐pentofuranosyl}‐7H‐pyrrolo[2,3‐d]‐pyrimidine (8), treatment with Bu4NF (→12a) and 4‐halogene displacement gave 2′, 3′‐didehydro‐2′, 3′‐dideoxy‐tubercidin (3) as well as 2′, 3′‐didehydro‐2′, 3′‐dideoxy‐7‐deazainosne (12c). On the other hand, 2′, 3′‐dideoxy‐3′‐fluorotubercidin (2) resulted from 8 by treatment with diethylamino sulfurtrifluoride (→10a), subsequent 5′‐de‐protection with Bu4NF (→10b), and Cl/NH2 displacement. 1H‐NOE difference spectroscopy in combination with force‐field calculations on the sugar‐modified tubercidin derivatives 1b, 2, and 3 revealed a transition of the sugar puckering from the 3′T2′ conformation for 1b via a planar furanose ring for 3 to the usual 2′T3′ conformation for 2.

ChemInform Abstract: Nucleic Acid‐Related Compounds. Part 54. Fluorination at C5′ of Nucleosides. Synthesis of the New Class of 5′‐Fluoro‐5′‐S‐aryl (Alkyl) Thionucleosides from Adenosine.

AbstractThe thioadenosine S‐oxides (V), generated from adenosine (I), are treated with diethylaminosulfur trifluoride (DAST) to produce mixtures of the diastereomeric α‐fluoro sulfides (VI).

Synthesis of 5‐fluoroalkyl‐5‐methyloxazolidine‐2,4‐diones and their 18F‐labeled analogs as potential indicators of tissue pH

Abstract5‐Fluoromethyl‐, 5‐(2′‐fluoroethyl)‐ and 5‐(3′‐fluoropropyl)‐5‐methyloxazolidine‐2,4‐diones (4a,b,c) were prepared as potential indicators of tissue pH, based on the fluorinative dehydroxylation with diethylaminosulfur trifluoride and/or the displacement reaction with fluoride ion. 5‐(3′‐[18F]Fluoropropyl)‐5‐methyloxazolidine‐2,4‐dione (4d) was obtained by tosylate displacement in 14‐16% radiochemical yield in a synthesis time of 40 min from start of the radiofluorination. The other two congeners labeled with 18F resisted our efforts to prepare them using [18F]fluoride ion.

Synthesis of Derivatives of 2,6-Dideoxy-2,2-Difluoro-3-O-Methyl-l-Arabinopyranose (2,2-Difluorooleandrose)

Abstract L-Oleandrose is the carbohydrate constituent of the potent anthelmintic agents the avermectins. Diethylaminosulfur tri-fluoride treatment of appropriate uloses did not give gem-difluoro sugars. Trifluorofluoroxymethane or xenon difluoride addition to the double bond of 4-O-benzoyl-6-deoxy-2-fluoro-3-O-methyl-L-glucal produced protected 2,2-difluorooleandrose derivatives activated at their anomeric center and ready for glycosidation.

Aminosulfur trifluorides: relative thermal stability [1

The fluorinating reagent, DAST (diethylaminosulfur trifluoride, 1b), has the potential to decompose violently when heated and presents a hazard if not properly handled. This investigation has shown that the decomposition occurs in two steps. First, a non-energetic disproportionation occurs to give sulfur tetrafluoride and bis(diethylamino) sulfur difluoride ( 3b). The less stable difluoride thus formed then undergoes a vigorous exothermic decomposition (detonation). The relative stabilities of DAST and several of its analogs were determined by differential thermal analysis. Morpholinosulfur trifluoride ( 1g, morpho-DAST) was the most stable of the aminosulfur trifluorides examined, and its use in place of the less stable DAST is recommended for fluorinations of alcohols.

2,3′‐Difluoro‐and 3′‐Azido‐2′‐Fluoro Substituted Dideoxypyrimidines as Potential Anti‐HIV Agents

Abstract2′‐Deoxy‐2′‐fluorouridine (2) was obtained by reaction of the arabinofuranosyl nucleoside 1 with diethylaminosulfur trifluoride followed by detritylation. After inversion of the configuration at the 3′‐position, 4 was used as starting material for the preparation of the 2′,3′‐disubstituted derivatives 6, 7, 8 and 10.

An unusual hydroxyl inversion mediated by dast

Trans -3-hydroxy-4-(2-oxopyrrolidin-1-yl) benzopyrans have been shown to undergo inversion to cis -3-hydroxy-4-(2-oxopyrrolidin-1-yl) benzopyrans in moderate yield on treatment with diethylaminosulphur trifluoride (DAST).

Synthetic studies towards (−)-carba-3′-deoxy-3′-fluorothymidine.

Stereospecific synthesis of (−)-carba-3′-deoxy-3′-fluorothymidine (−)- 11 is reported from the protected (−)-carbocyclic 3′-epi-thymidine (−)- 7 using diethylaminosulfur trifluoride. Under the conditions used, extensive dehydration of the blocked precursor into 10 and formation of the 4′-fluoro analogue ( 9 ) were also observed. An attempted simplification of our methodology based on (+)-(1R, 5S)-2-oxabicyclo[3.3.0]oct-6-en-3-one failed, but a novel cyclopentane ( 2 ) ring expansion to tetrahydropyran ( 18 ) was discovered.

Synthesis of 3'-Fluoro-3'-Deoxyribonucleosides; Anti-HIV-1 and Cytostatic Properties

Abstract It has generally proven difficult to synthesize ribonucleosides with sugar modifications at the 3′ position. We now present a practical route for the synthesis of ribonucleosides with a 3′ fluorine substituent. Nucleosides with the xylo configuration were prepared by sugar-base condensation. Tritylation of the unprotected nucleosides gave a mixture of 2′,5′ and 3′,5′ bistritylated nucleosides which were difficult to characterize. Therefore the necessary precursors were synthesized in a step-wise fashion, starting with selective deprotection of the 2′-acyl group, followed by tritylation. This gave the 2′,5′-tritylated xylonucleosides in good yield. Reaction with diethylaminosulfur trifluoride and deprotection with 80 % acetic acid provided the 3′-fluoro-3′-deoxyribonucleosides 1, 2 and 4. The cytidine derivative was synthesized from 1 by reaction with trifluoromethanesulfonic anhydride followed by ammonia. Treatment of 4 with adenosine deaminase yielded 5.

Synthesis of Nucleosides Fluorinated in the Sugar Moiety. The Application of Diethylaminosulfur Trifluoride to the Synthesis of Fluorinated Nucleosides

Abstract A survey is given of the different methods that have been used for the synthesis of nucleosides fluorinated in the carbohydrate moiety. In this article we describe the use of diethylaminosulfur trifluoride (DAST) as a fluorinating agent in the nucleoside field.

ChemInform Abstract: A Stereocontrolled Access to Vicinal Difluoroalkanes.

AbstractAn expedient method for the preparation of diastereomerically pure vicinal difluoroalkanes (IV) involves a ring opening of an oxirane, e.g. (II) obtained from the Z‐dodecene (I), by addition of HF and subsequent treatment of the resulting fluorohydrine with diethylaminosulfur trifluoride (→ meso‐(IV)).

ChemInform Abstract: Use of Diethylaminosulfur Trifluoride (DAST) in the Preparation of Synthons of Carbocyclic Nucleosides.

AbstractThe title compound (II) converts the protected pseudo sugars (Ia), (Ib) or (VIII) (available from the compound (VII)) into the products indicated in the scheme.

Synthesis of methyl 6″-deoxy-6′-fluoro-α-isomaltoside and of the corresponding trisaccharide

Methyl 6- O-(6- O-acetyl-2,3,4-tri- O-benzyl-α- d-glucopyranosyl)-2,3,4-tri- O-benzyl-α- d-glucopyranoside ( 5) was formed with high stereoselectivity when the condensation of methyl 2,3,4-tri- O-benzyl-α- d-glucopyranosyl ( 1) with 6- O-acetyl-2,3,4-tri- O-benzyl-α- d-glucopyranosyl chloride in ether was promoted with silver perchlorate in the presence of 2,4,6-trimethylpyridine. O-Deacetylation of 5, followed by treatment of the formed 6, containing only HO-6′ unsubstituted, with diethylaminosulfur trifluoride (DAST) or dimethylaminosulfur trifluoride (methyl DAST) gave the per- O-benzyl derivative ( 9) of methyl 6′-deoxy-6′-fluoro-α-isomaltoside. Compound 9 was also obtained by condensation of 1 with 2,3,4-tri- O-benzyl-6-deoxy-6-fluoro-β- d-glucopyranosyl fluoride ( 4) in the presence of silver perchlorate and anhydrous stannous chloride. The fully benzylated methyl α-glycoside ( 15) of 6-deoxy-6-fluoro-isomaltotriose, was obtained by condensation of 6 with 4. Hydrogenolysis of 9 and 15 gae the methyl α-glycosides of isomaltose and isomaltotriose fluorinated at C-6 of their (nonreducing) d-glucosyl group. Fluoride-ion displacements involving DAST and methyl DAST gave practically identical results, but mixtures arising from reactions involving the latter reagent were lighter-colored and easier to resolve by chromatography. The isolation of methyl α-glycosides of 6′-deoxy-6′-fluorogentiobiose and of 6′- O-(6-deoxy-6-fluoro-β- d-glucopyranosyl) isomaltose is also described.

ChemInform Abstract: Reaction of Epoxides with Diethylaminosulfur Trifluoride.

AbstractReaction of the cycloalkene oxides (Ia) and (Ib), styrene oxide (IVa), and cis‐ (IVb) or trans‐stilbene oxide (IVc) with diethylaminosulfur trifluoride yields the fluorinated products as summarized in the reaction scheme.

General methods for modification of sialic acid at C-9. Synthesis of N-acetyl-9-deoxy-9-fluoroneuraminic acid

Methyl 5-acetamido-3,5-dideoxy-2- O-methyl- d- glycero- d- galacto-2-nonulopyranosate was converted into the 9- O-trityl derivative and the remaining hydroxyl groups were protected as benzyl ethers. Removal of the trityl group, followed by treatment with diethylaminosulfur trifluoride gave the 9-deoxy-9-fluoro derivative, and deprotection N-acetyl-9-deoxy-9-fluoroneuraminic acid ( 8). In another procedure, coupling of 2-acetamido-2,6-dideoxy-6-fluoro- d-glucopyranose with potassium di( tert-butyl) oxaloacetate, followed by hydrolysis and decarboxylation gave 8. Some of the derivatives were active as inhibitors of growth of mouse mammary adenocarcinoma (TA 3) and L1210 cells in culture.