Atsushi Kittaka

Nucleoside anomeric radicals via 1,5-translocation: Facile access to anomeric spiro nucleosides

Abstract A method for generating anomeric radicals of nucleosides was developed based on a 1,5-translocation strategy. A vinyl radical derived from uracil nucleosides having a β,β-dibromovinyl group at the C6 position under-goes the 1,5-translocation to form an anomeric radical, which then cyclizes with the resulting CHCHBr group in a 5-endo-trig manner. The whole sequence has disclosed a facile access to anomeric spiro derivatives. A similar reaction of a 6-chloro-9-(β- d -ribofuranosyl)purine derivative was also briefly examined.

Design and Synthesis of Regioisomeric Analogues of a Specific Anti-HIV-1 Agent 1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT)

Abstract Regioisomeric analogues of the anti-HIV-1 lead 1-[(2-hydroxy-ethoxy)methyl]-6-(phenylthio)thymine (1: HEPT) have been synthesized. These compounds, having an ethoxymethyl side chain at C-5 and an ethyl group at the N-1 position of the uracil ring, also possess activity against HIV-1.

An Intramolecular Anionic Migration of a Stannyl Group from the 6-Position of 1-(2-Deoxy-d-erythro-pent-1-enofuranosyl)uracil to the 2′-Position: Synthesis of 2′-Substituted 1′,2′-Unsaturated Uridines

Abstract Lithiation of 1-[3,5-bis-O-(tert-butyldimethylsilyl)-2-deoxy- d -erythro-pent-1-enofuranosyl)uracil (1) takes place exclusively at the 6-position of the uracil base. The 6-tributylstannyl (or 6-trimethylsilyl) derivative prepared by quenching the C6-lithiated species with Bu3SnCl (or Me3SiCl) was found to undergo an intramolecular anionic migration to the 2′-positon of the furanoid glycal portion. By manipulation of the 2′-stannyl group, 2′-halogeno and 2′-carbon-substituted 1′,2′-unsaturated uridines were prepared for the first time. In contrast to the reported instability of 1 during deprotection, the 2′-substituted analogs synthesized in the present study gave the corresponding free nucleosides uniformly in high yields upon treatment with NH4F in MeOH.

Tandem Radical Cyclization-Oxygenation of 6-(2,2-Di-bromovinyl)-1-(2-deoxy-d-erytho-pent-1-enofuranosyl)-uracil: Synthesis of Anomeric Spiro Nucleosides Having Arabino and Ribo Configurations

Abstract Radical-mediated 5-exo-trig cyclization of 6-(2,2-dibromovinyl)-1-(2-deoxy-D-erythro-pent-1-enofuranosyl)uracil, when carried out in the presence of oxygen, furnished an anomeric spiro nucleoside having arabino-configuration. The corresponding ribofuranosyl analogue was also synthesized via the 2′-keto derivative. This paper is dedicated to Dr. Yoshihisa Mizuno, one of the founders of nucleic acids chemistry in Japan, on the occasion of his 75th birthday.

SYNTHESIS OF ANOMERIC SPIRO URACIL NUCLEOSIDES WITH AN ORTHOESTER STRUCTURE : STEREOSELECTIVE CYCLIZATION CONTROLLED BY THE C6-SUBSTITUENT

Abstract Uracil nucleosides having an anomeric orthoester structure were synthesized from 2′-deoxy-6-(hydroxyalkyl)uridines through hypoiodite-initiated cyclization. The hydroxyalkyl substituent at the 6-position was found to control the anomeric stereochemistry (β/α= 7 1 ∼ 1 46 ) of the cyclization. The transition state geometry of the reaction was postulated based on the X-ray crystallographic structure of the cyclized product 7α elucidate the observed stereoselectivity.

1,5-Translocation Strategy for Nucleoside Anomeric Radicals

Abstract A new method for generating nucleoside anomeric radicals utilizing radical 1,5-translocation was developed. Two kinds of β-halogenovinyl groups at the C6-position of uracil nucleosides were found to be a good radical source, which subsequently forms a nucleoside anomeric radical. The following 5-endo-trig cyclization gave anomeric spiro nucleosides as products.

Face selective 6,1′-(1-oxo)ethano bridge formation of uracil nucleosides under hypoiodite reaction conditions

Synthesis of novel spiro uracil nucleosides with an anomeric orthoester structure in a stereoselective manner under the hypoio dite reaction conditions of Heusler-Kalvoda and Suarez is fully described. While 2′-deoxy-6-(hydroxymethyl)uridine 2 and 2′-deoxy-6-[(1-hydroxy-1-methyl)ethyl]uridine 4 gave β- and α-spiro nucleosides in 43–68% yields with low βα selectivity (11.3∼31), the secondary ary alcohols 3a and 3b showed 68–79% chemical yields with significantly better βα selectivity (6.51∼146). The βα orientation of the 6-(hydroxyalkyl)uridine counterparts 6–8, 16–17, and 19 seemed to be controlled not only by the 2′-substituent but also by the chirality at the C7-stereocenter of the C6-side chain like in the 2′-deoxyuridine series. The transition state geometries of the reaction were postulated based on the X-ray crystallographic structures of cyclized products 20α and 24β.

Stannyl migration from the base to the sugar portion of 1′,2′-unsaturated uridine: the first example of substitution at the 2′-position

Abstract We report that TBDMS-protected 1-(2-deoxy-D- erythro -pent-1-enofuranosyl)-6-(tributyl-stannyl)uracil, when treated with LDA or LTMP, undergoes an anionic stannyl migration to yield the 2′-stannylated product. Optimization of the reaction conditions has disclosed an efficient entry to compounds variously substituted at the 2′-position. Desilylation of these compounds caused no further elimination, and furnished a hitherto unknown series of nucleoside analogues.

Reactions Of 2′-Deoxy-2′-halouridines and O 2,2′-Cyclouridine with Lithium Dialkylamides: Formation of 1′,2′-Unsaturated Derivatives

Abstract Treatment of 2′-deoxy-2′-halouridine derivatives with lithium diisopropylamide (LDA) resulted in partial formation of the 1′,2′-unsaturated nucleosides, no lithiation being observed in the base moiety of the recovered starting material. Reactions of an O2,2′-cyclouridine derivative with LDA or lithium 2,2,6,6-tetramethyl-piperidide (LTMP) were also examined.

Radical-Mediated Cyclization of A 6-Chloro-9-(2-Deoxy--d erythro-pent-1-enofuranosyl)-8-(2,2-dibromovinyl) purine

Abstract A vinyl radical generated from a 6-chloro-9-(2-deoxy--d eryrhro-pent-l-enofuranosyl)-8-(2,2-dibromovinyl) purine effected cyclization either at the 1′-or at the 2′-position. The result is discussed in comparison with our previous study of the corresponding uracil derivative.