Synthesis of Oxepane Ring Containing Monocyclic, Conformationally Restricted Bicyclic and Spirocyclic Nucleosides from D-Glucose: A Cycloaddition Approach (original) (raw)
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Carbohydrate Research, 2005
The dioxepanofuranose derivatives 4 and 12, obtained through the cyclization of the 3-(2-hydroxyethyl) ether of a D D-xylo-pentodialdose derivative, were appropriately functionalized and elaborated to the first examples of the new class of 3 0-O, and 5 0-O-bicyclic nucleoside analogues 9, 10, and 14 with a fused seven-membered ring. Reactions carried out through the intermediacy of the D D-xylo-pentodialdose derivative 5 yielded racemic products, while prior protection of the 4-formyl group (as in 7) before deprotection of the 1,2-hydroxyl groups led to optically active analogues.
Organic & biomolecular chemistry, 2017
A novel type of nucleoside analogue in which the sugar part is replaced by a new tricycle, 3,7,10-trioxa-11-azatricyclo[5.3.1.0(5,11)]undecane has been prepared by substrate-controlled asymmetric synthesis. 1,5-Dialdehydes obtained from properly protected or unprotected uridine, ribothymidine, cytidine, inosine, adenosine and guanosine by metaperiodate oxidation reacted readily with tris(hydroxymethyl)aminomethane to provide the corresponding tricyclic derivatives with three new stereogenic centers. Through a double cyclisation cascade process the tricyclic compounds were obtained in good to high yields, with very high diastereoselectivity. Formation of one stereoisomer, out of the eight possible, was observed in all cases. The absolute configuration of the new stereotriad-containing tricyclic systems was aided by conventional NMR experiments followed by chemical shift calculations using an X-ray crystal structure as reference that was in good agreement with H-H distances obtained f...
Tetrahedron, 1994
Absbw~ Intramolecular 1,Mipolar cycloaa'diton reactions of a number of &-akenyl nitrones of nucleoside derivatives 7.9.19 and28 afforded 2'-and 3'-hypemwdiJied tricyclic nucleoside derivatives 10 (56%), II (43%). 20 (91%) and 29 (75%). respectively. The solutian structures of these tricyclic nucleoside derivatives have been investigated using the 3JRR (JH at 500 MHz) and the NiUR-derived torsion angle constrained energy minimizations with the aid of MacroModel's AMBER force field. Subsequent Tamao oxidation of the hypermodtifid nucleoside derivatives 20 and 29 gave spire-4(7)-substituted isoxazolidine-nucleoside akrivatives 21 and 30, respectively. A recent report by Camarasa and coworkers1 has indicated that nucleosides with a 3'-Spiro-unit, in conjunction with other structural features, possess anti-HIV-l activity. Studies by Tronchet and coworkers2*3 have described the synthesis of a 3'-deoxy-3'-N-hydroxyaminonucleoside derivative which has been tested to be moderately active against HIV-l and may still prove to be a new lead compound in the combat against HIV infection. It was these reports that prompted us to investigate the synthesis of both 2'-and 3'-spironucleosides through the intermediacy of an N-methylnitrone. Recent work carried out in this laboratory4 has employed the use of an intermolecular 1,3-dipolar cyclisation of a 2'-or 3'-N-methylnitrone, with both electron-deficient and electron-rich dipolarophiles, to produce 5-substituted Spiro-isoxazolidine nucleosides. The intramolecular 1,3-dipolar cycloaddition reaction of both oximes and nitrones with various dipolarophiles has been used extensively in the synthesis of fused 4-substituted isoxazolidines,sa-c and in particular with the synthesis of many natural products&-c In this paper, we report the first synthesis of &-fused 4-substituted isoxazolidines as a means to introduce C2' or C3' functionality to nucleosides, by way of an intramolecular cycloaddition reaction of a tethered olefin with a vicinal N-methylnitrone. The use of the N-methylnitrone as the dipole clearly overcame the problem encountered by Tronchet et a1,7s where the 2'-oxime employed in their system underwent intramolecular nucleophilic reactions with the aglycone. This report constitutes the first synthesis of an isomeric pair of tricyclic cis-fused-Spiro-isoxazolidine nucleosides 10 and 11. They occured smoothly through a tandem intramolecular 13-dipolar cycloadditiotts of the isomeric pair of 2'-or 3'-N-methylnitrones 7 and 9, generated in situ from their parent ketones (2 + 6 + 7 + 10 and 3-+ 8 + 9 + ll), and were found to be both regio and diastereospecific in their formation. It is 4921 4922 J. RONG et al. worth pointing out that these tricyclic fused systems 10 and 11 were extremely rigid molecules which allowed for the assignment of their configuration and conformation (vide i&z). While the synthesis of hypermodified nucleosides 10 and 11 clearly illustrated the facility and stereospecfic nature of the above cy cloaddition reaction they could not, however, be used further for the stereospecific synthesis of new 4-substituted Spiro-isoxazolidine nucleosides. Work also carried out in this laboratoryc has successfully shown the utility of the silyl-tether approach to stereospecifically direct an intramolecular free-radical trapping reaction by an olefin. We herein extend our above synthesis of tricyclic-Spiro-isoxazolidme thymidines 10 and 11, by incorporating a silyl-tethered alkene into the isoxazolidine synthesis (Scheme 2). This approach utilized the existing bhydroxy functional group, as in 18 or 27, to undergo first silylation with a suitable vinylchlorosilane to give intermediary 19 or 28, respectively, which in turn undergoes an in situ intramolecular cycloaddition reaction. The products resulting from this approach, 20 and 29, have silicon containing heterocycles which are readily cleavable under the Tamao oxidation conditions. toa-e The products of this oxidative cleavage, the 4(7>substituted-[l(9), 2(10)-isoxazolidines] 21 and 30, are unique 1,3-dihydroxy functionalizcd nucleoside derivatives (note that the actual numbering of all atoms used for NMR and NOE assignments are shown in parenthesis and are also shown in the formulae in Schemes 1 and 2). This 4(7)-hydroxyl group of the Spiro moiety of both 20 and 29, which is not accessible by an intermolecular means, is then amenable to further modification. Result aud Discussion Synthesis of an isomeric pair of bicyclic ck-fused-Spiro-koxazolidine nuckosides 10 and 11. The precursors for the intramolecular nitrone-olefin cycloaddition reaction were the 2'-and 3'-O-ally1 nucleosides 2 (30%) and 3 (44%), respectively, and were readily synthesized by the opening of the 2',3'-epoxy ring of l-(S-O-MMTr-2',3'-O-anhydro-~-D-lyxofuranosyl)thyminec (1) with ally1 alcohol (2:3 ratio, NMR) under a basic condition at room temperature, followed by simple column chromatography. The assignment of regio and stereochemistry of 2 and 3 was based on a comparison with an authentic sample of the 2'Gallyl derivative 2, which was obtained from 3',5'-0-isopropylidine-xylothymidine (4), via specific 2'-0-allylation, removal of the isopropylidine group under an acidic condition and subsequent protection of the S-hydroxyl group as the 4-monomethoxytrityl ether [4 + 5 + 21. Oxidation of the nucleosides 2 and 3, using the reaction conditions described by Hansske et uJ.ll afforded the corresponding 2'-and 3'ulosides 6 and 8. Treatment of the crude 2'-or 3'-O-ally1 ulosides 6 and 8 with Nmethylhydroxylamine hydrochloride in pyridine at 0°C gave the corresponding putative N-methylnitrones 7 and 9, which underwent in situ intramolecular cycloaddition to afford the corresponding isomeric pair of tricyclic cis-fused-Spiro-isoxazolidine nucleosides 10 (56%) and 11 (43%), respectively. Of particular interest to US was the regio and stereochemical outcome of this cyclisation reaction. 1H NMR spectroscopy of these derivatives indicated that the cis-fused products were isolated in each case as the sole product. Confirmation of the regiochemical and hence the stereochemical outcome of the reaction was on the basis of 1D NOE difference spectroscopy (vide infra). Removal of the 5'-0-MMTr-protecting group from the tricyclic nucleosides 10 and 11 was affected by stirring each nucleoside with an 80% aqueous acetic acid mixture at room temperature overnight. The respective nucleoside derivatives 12 (93%) and 13 (91%) were isolated as the sole product of the deprotection reaction and were characterised on the basis of their spectral characteristics. Again, the regio and 2'-And 3'-hypennodified tricyclic nucleosides
Stereocontrolled Syntheses of Carbocyclic C-Nucleosides and Related Compounds
The Journal of Organic Chemistry, 2001
Carbocyclic 9-deazapurine nucleosides (1-4), a spiranic pyrimidone carbocyclic compound (5), and an unusual carbocyclic isonucleoside (6) were prepared as enantiomerically pure compounds via the key intermediates 10 and 21 from 1,4-γ-ribonolactone. The key intermediate 10 was prepared by stereoselective reduction with Bu 3 SnH and then converted to carbocyclic C-ribonucleosides 1, 3, and 4. 2′,3′-Didehydro-2′,3′-dideoxycarbocyclic 9-deazainosine (2) was prepared from a 2′,3′dimesylate 17 by treatment with Li 2 Te followed by an acidic deprotection. The key bicyclic intermediate 21 was prepared from a diol 20 by an intramolecular cyclization using CHI 3-Ph 3 Pimidazole and converted to the spiranic compound 5 and an olefinic nucleoside 6 by the construction of the heterocyclic moiety followed by deprotection.
2017
A novel type of nucleoside analogue in which the sugar part is replaced by a new tricycle, 3,7,10-trioxa-11-azatricyclo[5.3.1.0 5,11 ]undecane has been prepared by substrate-controlled asymmetric synthesis. 1,5-Dialdehydes obtained from properly protected or unprotected uridine, ribothymidine, cytidine, inosine, adenosine and guanosine by metaperiodate oxidation reacted readily with tris(hydroxymethyl)aminomethane to provide the corresponding tricyclic derivatives with three new stereogenic centers. Through a double cyclisation cascade process the tricyclic compounds were obtained in good to high yields, with very high diastereoselectivity. Formation of one stereoisomer, out of the eight possible, was observed in all cases. The absolute configuration of the new stereotriad-containing tricyclic systems was aided by conventional NMR experiments followed by chemical shift calculations using an X-ray crystal structure as reference that was in good agreement with H-H distances obtained from a new ROESY NMR method. The synthesis was compatible with silyl, trityl and dimethoxytrityl protecting groups. A new reagent mixture containing ZnCl 2 , Et 3 SiH and hexafluoroisopropanol was developed for detritylation of the acid-sensitive tricyclano nucleosides.
Advances in the enantioselective synthesis of carbocyclic nucleosides
Chemical Society Reviews, 2013
Carbocyclic nucleosides are nucleoside analogues in which the furanosidic moiety has been replaced by a carbocycle. Several members of this family have been isolated from natural sources and include a 5-membered ring carbocycle. The aim of this review is to examine critically the different methodologies for the enantioselective construction of 3-to 6-membered rings, with a particular focus on 5-membered rings and their modifications. The procedures for bonding the heterocyclic moiety and the carbohydrate are treated separately. The methods for synthesising the carbocyclic moiety mainly focus on the construction of the cycle, although precise details about the functionalisation are provided in some cases. The selected methods aim to provide an overview of the synthesis of carbocycles related to the synthesis of carbocyclic nucleosides. The methods of synthesis of 5-membered rings are classified into two types: methods in which the cyclopentane ring is formed by ring closing reactions (CQC and C-C formation) and methods that start from preformed 5-membered rings, based mainly on cycloaddition reactions. With respect to the methods of synthesis of 3-, 4-and 6-membered ring carbocyclic nucleosides, a selection of the more relevant enantioselective procedures is presented in a systematic manner.