Stereoselective Synthesis of 1‘-<i>C</i>-Branched Arabinofuranosyl Nucleosides via Anomeric Radicals Generated by 1,2-Acyloxy Migration

Stereoselective C−C bond formation at the anomeric position of uracil and adenine nucleoside has been accomplished through reaction of the anomeric radical, generated by 1,2-acyloxy migration, with a radical acceptor. The present method consists of the following steps:  (1) electrophilic addition (bromo-pivaloyloxylation) to 3‘,5‘-O-(1,1,3,3-tetraisopropyldisiloxane-1,3-diyl)-protected 1‘,2‘-unsaturated nucleoside, (2) tin radical-mediated reaction of the resulting adduct with a radical acceptor. The use of allyl(tributyl)tin gave the 1‘-C-allylated uracil nucleoside 14 in 66% yield together with the unrearranged 2‘-C-allylated product 15 (6%). Radical acceptors such as styryl(tributyl)tin and 3-bromo-2-methylacrylonitrile can also be used in the reaction of 5, giving 16 (70%) and 17 (76%) without the formation of unrearranged product. The radical-mediated C−C bond formation of the adenine counterpart 12 was also investigated

Cyclization Reactions of Nucleoside Anomeric Radical with Olefin Tethered on Base: Factors That Induce Anomeric Stereochemistry

Nucleoside anomeric radicals were formed through 1,5-translocation of vinyl radicals generated from the 2,2-dibromovinyl group tethered at the uracil 6-position (1, 2, and 4) by tin radical. The anomeric radicals attacked the resulting C-6 vinyl group in a 5-endo-trig manner to afford anomeric spiro nucleosides (11−13, 21, 23, and 24) with the 6,1‘-etheno bridge as the major cyclized products. The anomeric stereochemistry of the cyclization was found to be affected by the 2‘-substituent. To consider the structure of the intermediate anomeric radical, the reaction using α-6-(2,2-dibromovinyl)-2‘-deoxyuridine 9 was investigated. The same anomeric β/α-stereoselectivity as the counterpart of 2 showed that the nucleoside anomeric radical would have nearly a planar structure and the C1‘−N1 bond rotation in the radical is much faster than cyclization. The origin of the minor spiro nucleosides (14−20, 22, and 25−28) with the 6,1‘-ethano bridge has also been investigated and appeared to be (E)-6-(2-bromovinyl)uridine 7E, a reduced form of 1a, but not (Z)-6-(2-bromovinyl)uridine 7Z, which gave a novel type of unstable compound with 6-exomethylene structure 29 through a different reaction pathway. 6-Chloro-8-(2,2-dibromovinyl)purine nucleoside 10 was next studied, and not only 1,5- but also 1,6-translocated products were isolated

Synthesis and Anti-Human Immunodeficiency Virus Activity of 4‘-Branched (±)-4‘-Thiostavudines

Motivated by our recent finding that 4‘-ethynylstavudine (4) is a promising anti-human immunodeficiency virus type 1 (HIV-1) agent, we synthesized its 4‘-thio analogue, as well as other 4‘-thiostavudines having a carbon substituent at the 4‘-position, as racemates in this study. Methyl 3-oxo-tetrahydrothiophen-2-carboxylate (5) was used as a starting material to construct the requisite 4-thiofuranoid glycal (13). Introduction of a thymine base was carried out by an electrophilic addition reaction to 13 using N-iodosuccinimide (NIS) and bis(trimethylsilyl)thymine. The desired β-anomer (16β) obtained as a major product in this reaction underwent ready elimination with activated Zn to give the 4‘-carbomethoxy derivative (18). By using 18 as a common intermediate, 4‘-carbon-substituted (CH2OH, CO2Me, CONH2, CHCH2, CN, and C⋮CH) 4‘-thiostavudines were prepared. Among these six compounds, 4‘-cyano (28) and 4‘-ethynyl (29) analogues were found to show inhibitory activity against HIV-1 with ED50 values of 7.6 and 0.74 μM, respectively. The activity of 29 was comparable to that of stavudine, but 29 was not as active as 4. Optical resolution of 29 was briefly examined

5-<i>Exo</i> versus 6-<i>Endo</i> Cyclization of Nucleoside 2-Sila-5-hexenyl Radicals: Reaction of 6-(Bromomethyl)dimethylsilyl 1‘,2‘-Unsaturated Uridines

The mode of cyclization of 2-sila-5-hexen-1-yl radicals generated from 6-(bromomethyl)dimethylsilyl-1‘,2‘-unsaturated uridines was investigated. In contrast to the case of the 2‘-unsubstituted 6-silicon-tethered substrate (4), which undergoes exclusive 6-endo-cyclization, reactions of the 2‘-substituted (Me, CO2Me, OBz, and Cl) derivatives (14, 20, 22, and 24) uniformly proceeded in preferential or exclusive 5-exo-mode. The Tamao oxidation of the resulting cyclized products was also carried out to synthesize the corresponding 1‘-C-hydroxymethyl derivatives

Stereoselective Synthesis of the β-Anomer of 4‘-Thionucleosides Based on Electrophilic Glycosidation to 4-Thiofuranoid Glycals

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 N6-benzoyladenine. Among the three 4-thioglycals, 11 was found to be an excellent glycosyl donor, forming the desired β-anomer exclusively irrespective of the nucleobase employed

Catalytic Asymmetric Allylation of 3,4-Dihydroisoquinolines and Its Application to the Synthesis of Isoquinoline Alkaloids

A catalytic asymmetric allylation of 3,4-dihydroisoquinoline was carried out with allyltrimethoxylsilane-Cu as the nucleophile in the presence of DTBM-SEGPHOS as the chiral ligand to afford corresponding chiral 1-allyltetrahydroisoquinoline derivatives in good yield and stereoselectivity. The allyl adduct thus obtained was applied to the synthesis of several isoquinoline alkaloids such as crispine A and homolaudanosine. The reaction was further used for the synthesis of the isoquinoline moiety of schulzeine A