Showing papers on "Glycal published in 2002"

A de Novo Enantioselective Total Synthesis of (−)-Laulimalide

Abstract: An enantioselective total synthesis of the naturally occurring anticancer agent (−)-laulimalide is described The synthesis is characterized by extensive use of new reaction methodologies based on catalytic asymmetric acyl halide−aldehyde cyclocondensation (AAC) reactions and transformations of the derived enantioenriched β-lactones The synthesis also incorporates a unique allenylstannane glycal acetate alkylation and chemoselective ring-closing metathesis reaction

C2-Amidoglycosylation. Scope and Mechanism of Nitrogen Transfer

Abstract: A one-pot C2-amidoglycosylation reaction for the synthesis of 2-N-acyl-2-deoxy-β-pyranosides from glycals is described Glycal donors activated by the reagent combination of thianthrene-5-oxide (11) and Tf2O, followed by treatment with an amide nucleophile and a glycosyl acceptor, lead to the formation of various C2-amidoglycoconjugates Both the C2-nitrogen transfer and the glycosidic bond formation proceed stereoselectively, allowing for the introduction of both natural and nonnatural amide functionalities at C2 with concomitant anomeric bond formation in a one-pot procedure Tracking of the reaction by low-temperature NMR spectroscopy employing 15N- and 18O-isotope labels suggests a mechanism involving the formation of the C2-sulfonium glycosyl imidate 39 as well as oxazoline 37 as key intermediates in this novel oxidative glycosylation process

C2-hydroxyglycosylation with glycal donors. Probing the mechanism of sulfonium-mediated oxygen transfer to glycal enol ethers.

Abstract: The C2-hydroxyglycosylation reaction employing the reagent combination of a diaryl sulfoxide and triflic anhydride offers a novel method for glycal assembly whereby a hydroxyl functionality is stereoselectively installed at the C2-position of a glycal donor with concomitant glycosylation of a nucleophilic acceptor. Mechanistic investigations into this reaction revealed a novel process for sulfonium-mediated oxidation of glycal enol ethers in which the sulfoxide oxygen atom is stereoselectively transferred to the C2-position of the glycal. 18O-labeling studies revealed that the S-to-C2 oxygen-transfer process involves initial formation of a C1−O linkage followed by O-migration to C2, leading to the generation of an intermediate glycosyl 1,2-anhydropyranoside that serves as an in situ glycosylating agent. These findings are consistent with the initial formation of a C2-sulfonium−C1-oxosulfonium pyranosyl species upon activation of the glycal donor with Aryl2SO·Tf2O.

A general approach toward the synthesis of C-nucleoside pyrazolo[1,5-a]-1,3,5-triazines and their 3', 5'-bisphosphate c-nucleotide analogues as the first reported in vivo stable P2Y1-receptor antagonists

Abstract: In our effort to identify potent purinergic P2Y(1) receptor antagonists as potent platelet aggregation inhibitors with enhanced metabolic stability, we developed an efficient route for the large-scale preparation of 2'-deoxy-C-nucleosides of pyrazolo[1,5-a]-1,3,5-triazine. The key strategic elements of this novel synthetic approach involved the following: (i) the use of a novel activating group, the N-methyl-N-phenylamino group, which was easily generated in high yield by treatment of the pyrazolo[1,5-a]-1,3,5-triazin-4-one (5) with phosphorus oxychloride and dimethylaniline under high pressure, (ii) a regio- and stereospecific palladium-mediated coupling reaction of the readily available unprotected glycal 1,4-anhydro-2-deoxy-D-erythro-pent-1-enitol (4b) and the 8-iodo derivative (16), and (iii) the stereoselective reduction of the ketone group of the furanosyl ring followed by the subsequent displacement of the N-methyl-N-phenylamino group upon treatment with methylamine. The beta configuration at the anomeric C-1' position of the glycal moieties was perfectly retained throughout this conversion. This procedure afforded 8-(2'-deoxy-beta-D-ribofuranosyl)-2-methyl-4-(N-methylamino)pyrazolo[1,5-a]-1,3,5-triazine (21) and 8-(2'-deoxy-beta-D-xylofuranosyl)-2-methyl-4-(N-methylamino)pyrazolo[1,5-a]-1,3,5-triazine (24) with an overall yield of 50% and 39%, respectively. Finally, the conversion of nucleosides 21 and 24 to the pyrazolotriazine C-nucleotides 3',5'-bisphosphate 2 and 3',5'-cyclophosphate 26 is also described herein and represents the first reported nucleotide derivatives within the pyrazolo[1,5-a]-1,3,5-triazine series. Preliminary biological testing has shown that compound 2 strongly inhibits ADP-induced human platelet aggregation and shape change and possesses significant efficacies 30 min after injection in rat, highlighting a strong P2Y(1)-receptor antagonist activity in vitro combined with a prolonged duration of action in vivo.

Anhydrodihydroartemisinin and Its 10-Trifluoromethyl Analogue: Access to Novel D-Ring-Contracted Artemisinin Trifluoromethyl Ketones

Abstract: The preparation of the 10-trifluoromethyl hydroartemisinin, followed by dehydration, afforded the trifluoromethyl analogue 2 of anhydrodihydroartemisinin 1. The reactivity of these two glycals of artemisinin were compared in epoxidation and halogenation reactions. Iodination of glycal 1 in water and the further rearrangement of the produced iodo hemiacetal provided the new D-ring-contracted aldehyde 8alpha, where the methyl at C-9 is beta. Epoxidation of 10-trifluoromethyl anhydrodihydroartemisinin 2 stereoselectively provided the beta-epoxy ether 11 in high yield. When treated with hexafluoro-2-propanol or trifluoroethanol, 11 readily underwent a rearrangement yielding to the D-ring-contracted trifluoromethyl ketone 9alpha with retention of configuration at C-9.

Stereoselective synthesis of the β-anomer of 4'-thionucleosides based on electrophilic glycosidation to 4-thiofuranoid glycals

Abstract: Three types of 4-thiofuranoid glycal with different 3,5-O-silyl protecting groups were prepared and their electrophilic glycosidation was investigated. The 3,5-bis-O-(tert-butyldimethylsilyl)-4-thiofuranoid glycal (5) was obtained through mesylation of 2-deoxy-4-thio-D-erythro-pentofuranose (4) and subsequent base-promoted elimination, while thermal elimination of sulfoxide derivatives was suitable for the preparation of 3,5-O-(tetraisopropyldisiloxane-1,3-diyl) (9) and 3,5-O-(di-tert-butylsilylene) (11) 4-thioglycals. The glycosidation reactions of these 4-thioglycals were carried out, in the presence of either PhSeCl or NIS, by using silylated derivatives of uracil, thymine, cytosine, and N(6)-benzoyladenine. Among the three 4-thioglycals, 11 was found to be an excellent glycosyl donor, forming the desired beta-anomer exclusively irrespective of the nucleobase employed.

A study of the epoxidation of 6-deoxyhex-5-enopyranosides. 1,5-Dicarbonyl derivatives and novel synthetic routes to D-xylo-hexos-5-ulose and D-lyxo-hexos-5-ulose.

Abstract: The work described deals with the isolation and characterization of epoxides from 6-deoxyhex-5-enopyranosides and preliminary exploration of their synthetic potential. Prolonged epoxidation reaction times led to their hydrolysis in situ and gave novel protected d-hexos-5-ulose derivatives (sugar 1,5-dicarbonyls). Some reactions of the hexos-5-uloses were studied, and in some cases septanoside (seven-membered-ring saccharide) derivatives were isolated. Novel routes to d-xylo-hexos-5-ulose and d-lyxo-hexos-5-ulose, of interest as intermediates in the synthesis and biosynthesis of inositols and aza sugars, are also described. The structures of the epoxides and novel hexos-5-uloses were established by NMR and X-ray crystallographic methods.

Stereocontrolled diels-alder cycloadditions of sugar-derived dihydropyranones with dienes.

Abstract: 2-Acetoxy-3,4-di-O-acetyl-d-arabinal (6), similar to its d-xylo analogue 4, reacted with benzyl alcohol by the tin(IV) chloride-promoted glycosylation to produce optically active (S)-2-benzyloxy-2H-pyran-3(6H)-one (8a). The l-arabinal derivative (5) gave 9a, the dihydropyranone enantiomer of 8a. These results indicated that the configuration of the C-4 stereocenter in the starting glycal defines the configuration of the new chiral center in the resulting dihydropyranone. The influence of other catalysts (BF3 or iodine) employed for the glycosylation on the optical purity of the dihydropyranone was studied. Enantiomerically pure dihydropyranones 8b and 9c were obtained using chiral alcohols ((R)- and (S)-2-octanol, respectively) as glycosylating agents. Compounds 8a,b and 9a,c proved to be reactive dienophiles in thermal and Lewis acid-promoted Diels−Alder reactions. The addition of 2,3-dimethylbutadiene, cyclopentadiene, and 1,3-cyclohexadiene to the β-pyranones 8a,b led to the corresponding adducts 10a,b...

Michael Addition of Thiols to Sugar Enones. Synthesis of 3-Deoxy-4-Thiohexopyranosid-2-uloses as Key Precursors of 3-Deoxy- and C-2 Branched-Chain 4-Thiosugars

Abstract: Benzyl and 2-propyl 6-O-acetyl-3,4-dideoxy-α -D-glycero-hex-3-enopyranosid-2-uloses (2) and (3) were readily prepared by the tin(IV) chloride-promoted glycosylation of glycal (1) The enone system of (2) and (3) underwent a highly diastereoselective Michael addition of thiols (ethanethiol, propane-2-thiol, and benzenemethanethiol) to afford the sulfur-containing hexopyranosid-2-ulose derivatives (4a-c) and (5a-c) in good yields Sodium borohydride reduction of the carbonyl functionalities of (4b,c) and (5b) led to the corresponding 3-deoxy-4-thiohexopyranosides having the D-xylo (6b), (6c), and (8b) or the D-lyxo (7b), (7c), and (8c) configuration Standard acetylation of these compounds gave the corresponding per-O-acetyl derivatives (10b), (10c), and (12b) and (11b), (11c), and (13b), useful for confirming all the previous configurational assignments by means of their 1H and 13C nuclear magnetic resonance spectra Furthermore the 2-ulose (5b) proved to be a key intermediate for the synthesis of C-2 branched-chain 4-thiopyranosides, such as (16) The latter was synthesized by a good yielding ammonium acetate-catalysed Knoevenagel-type condensation of malononitrile with (5b)

Nucleophilic addition of benzenethiol to 1',2'-unsaturated nucleosides: 1'-C-phenylthio-2'-deoxynucleosides as anomeric radical precursors.

Abstract: The addition reaction of benzenethiol to the glycal portion of 1‘,2‘-unsaturated uridine proceeds efficiently in the presence of Et3N. The mechanism involves nucleophilic attack of thiolate at the anomeric position in the rate-determining step, wherein conjugation between the nucleobase and the glycal portion is crucial. The derivative having a methyl group either at the 2‘- or 6-position did not undergo this addition reaction, due to their sterically prohibited coplanarity. The 1‘,2‘-unsaturated derivatives of thymine and adenine can also be used as substrates for this addition reaction. It was also shown that the resulting 1‘-C-phenylthio-2‘-deoxynucleosides serve as precursors for radical-mediated C−C bond formation at the anomeric position.

Selective preparation of glycosyl sulfone or glycal by treatment of phenyl thioglycoside of N-acetylneuraminic acid with m-chloroperbenzoic acid

Abstract: Treatment of acetylated phenyl thioglycoside of N-acetylneuraminic acid with m-chloroperbenzoic acid (MCPBA) in CH2Cl2 affords quantitatively mixtures of the respective sulfone and glycal free from the sulfoxide. The outcome of the reaction does not depend on the anomeric configuration of the starting thioglycoside. The sulfone can be selectively prepared (yield ∼100%) by oxidation with an excess of MCPBA and NaHCO3. In the presence of pyridine (2 equiv.) and MCPBA (2 equiv.), the major product is glycal (yields 81—88%). This version of the reaction can be regarded as a new method for the preparation of sialic acid glycals.

Synthesis of 1,4-Anhydro-2-deoxy-d-ribitol Derivatives from Thymidine Using Improved Preparation of Furanoid Glycals

Abstract: Preparation of furanoid glycal by elimination of the nucleobase from thymidine has been investigated. A number of catalysts for this reaction were tested, resulting in improved and scaleable synthesis. Hydrogenation of the resulting glycal afforded the 5-protected 1,4-anhydro-2-deoxy-D-ribitol derivative in a high yield.

New Aspects in the Lithiation Chemistry of Nucleosides : Anionic Migration of Silyl and Stannyl Groups

Abstract: Described herein are three types of anionic migration of silyl and stannyl groups observed during the lithiation (hydrogen-lithium exchange) of nucleosides. In the first example of 9- [2, 3, 5-tris-O- (tert-butyldimethylsilyl) -β-D-ribofuranosyl]-6-chloropurine, the 8-trimethylsilyl or 8-tributylstannyl group introduced by lithiation underwent migration to the 2-position (migration within the base) through further lithiation of the less acidic H-2. The second example was observed by using 1- (2-deoxy-D-erythro-pent-1-enofuranosyl) uracil as a substrate, wherein the lithiationbased migration took place from the 6-position of the nucleobase to the 2'-position of the sugar (furanoid glycal). The last example came from the lithiation of the 5'-O-silylated or -stannylated anti-HIV agent d 4 T (2', 3'-didehydro-3'-deoxythymidine). As a result of highly unusual vinylic lithiation in the presence of allylic hydrogen, these 5'-O-protecting groups were transferred to the 3'-position of the unsaturated sugar (migration within the sugar). Since stannyl group can be transformed in various ways, the above three examples have opened up access to nucleoside derivatives that have been difficult to be synthesized by other methods.

Glycal-Mediated Syntheses of Enantiomerically Pure Polyhydroxylated γ- and δ-Lactams.

Abstract: Syntheses of new enantiomerically pure γ-lactams 4a , b and δ-lactams 5a , b from d -glucal ( 3a ) and d -galactal ( 3b ) as starting materials are described.

New Aspects in the Lithiation Chemistry of Nucleosides: Anionic Migration of Silyl and Stannyl Groups

Abstract: Described herein are three types of anionic migration of silyl and stannyl groups observed during the lithiation (hydrogen-lithium exchange) of nucleosides. In the first example of 9- [2, 3, 5-tris-O- (tert-butyldimethylsilyl) -β-D-ribofuranosyl]-6-chloropurine, the 8-trimethylsilyl or 8-tributylstannyl group introduced by lithiation underwent migration to the 2-position (migration within the base) through further lithiation of the less acidic H-2. The second example was observed by using 1- (2-deoxy-D-erythro-pent-1-enofuranosyl) uracil as a substrate, wherein the lithiationbased migration took place from the 6-position of the nucleobase to the 2'-position of the sugar (furanoid glycal). The last example came from the lithiation of the 5'-O-silylated or -stannylated anti-HIV agent d 4 T (2', 3'-didehydro-3'-deoxythymidine). As a result of highly unusual vinylic lithiation in the presence of allylic hydrogen, these 5'-O-protecting groups were transferred to the 3'-position of the unsaturated sugar (migration within the sugar). Since stannyl group can be transformed in various ways, the above three examples have opened up access to nucleoside derivatives that have been difficult to be synthesized by other methods.

Selective Preparation of Glycosyl Sulfone or Glycal by Treatment of Phenyl Thioglycoside of N‐Acetylneuraminic Acid with m‐Chloroperbenzoic Acid.

Abstract: Treatment of acetylated phenyl thioglycoside of N-acetylneuraminic acid with m-chloroperbenzoic acid (MCPBA) in CH2Cl2 affords quantitatively mixtures of the respective sulfone and glycal free from the sulfoxide. The outcome of the reaction does not depend on the anomeric configuration of the starting thioglycoside. The sulfone can be selectively prepared (yield ∼100%) by oxidation with an excess of MCPBA and NaHCO3. In the presence of pyridine (2 equiv.) and MCPBA (2 equiv.), the major product is glycal (yields 81—88%). This version of the reaction can be regarded as a new method for the preparation of sialic acid glycals.

Reducing Oligosaccharides via Glycal Assembly: On the Remarkable Stability of Anomeric Hydroxyl Groups to Global Deprotection with Sodium in Liquid Ammonia.

Abstract: Several partially benzylated 1-hydroxy sugars were rapidly deprotected by sodium/liquid ammonia. The terminal hemiketal linkage of the substrates remained intact under these conditions and does not generate ring-opened alditols. Peracetylated glucose and glucosamine derivatives were obtained in 64–79% isolated yields.