Oxetane nucleosides

Methyl oxetane-2-carboxylate derivatives (e.g., 284), obtained by ring contraction of aldonolactones, have been employed for the synthesis (279) of the nucleoside / -noroxetanocin [9-(/ -D-eryt/iro-oxetanosyl)adenine, 304] and its a-anomer via an a-chloride obtained by a modified Hunsdiecker reaction. Displacement of chloride by adenine and debenzylation gave 304. The threo isomer of304, /J-epinoroxetanocin (305), was likewise synthesized from D-lyxono-1,4-lactone. The oxetane nucleosides display potent antiviral activity against the human immunodeficiency virus (HIV). 

Fleet and colleagues have investigated various synthetic approaches for the formation of oxetane nucleosides of which oxetanocin 48 is an important and desirable member.34 The oxetane carboxylic acids 49a are helpful precursors for a-chlorooxetanes 50 via 49b, which in turn provide oxetane... 

Substituted 2-methyleneoxetanes obtained from the j8-lactones have been shown to react with F+ as an electrophile in the presence of nucleophilic nucleobases, giving rise to the corresponding oxetane nucleosides in good yield but with low diastereoselectivity. ... 

The constrained nucleosides are of interest as leads for small-molecule therapeutics. For example, the (3-2 -0,3 -C-oxetane analogues of the antiviral 3 -azido-3 -deoxythymidine (AZT), which exist predominantly in the E-like conformation (see, for example, Equation 55), were investigated for inhibition of human immunodeficiency virus 1 (HIV-1). Neither the modified nucleosides nor their 5 -monophosphate analogues inhibit HIV-1, supporting a hypothesis that reverse transcriptase inhibitors must have conformational freedom <2001JOC4878, 2002J(P1)1655>. 

Direct UV irradiation of DNA leads to a variety of lesions at the nucleo-base. The principle products are pyrimidine cyclobutane dimers ToT, ToC, and CoC, formed in that order of preference, by [2+2] photocycloaddition of two adjacent pyrimidine nucleosides in the same oligonucleotide strand (Scheme B.21.4). With approximately 50% of the frequency of cyclobutane dimers, [2+2] dimerization involves a C=0 double bond leading to an intermediate oxetane 29, which later decomposes to the [6-4] photoproduct 30. 

The first synthesis of d4T was accomplished in 1966 by Horwitz from l-(2-deoxy-3,5-epoxy-/3-D-r/2reo-pentosyl)thymine abstraction of a proton from the 2 -position by potassium butoxide in DMSO resulted in an opening of the oxetane ring and formation of d4T. Other syntheses were based on the elimination of sulfoxide or the selenoxide moiety placed at the C-2 position in the nucleoside, which was prepared from cheap lactone 6 (O Scheme 7) [6]. 

E xides and oxetanes react readily with lithiodithiane to give derivatives of 3- or y-hydroxy aldehydes or ketones. The method has been used for the multistep synthesis of an inomycin fragment, thietane prostaglandin analogs, branched-chain nucleoside sugars, the southern hexahydrobenzctfu-ran unit avermectin, the anti-Gram-positive bacterial elaiphylin andsyn-l,3-polyols. ... 

Chemical transformations of nucleosides have resulted in the syntheses of some 2, 3 -unsaturated pyrimidine nucleosides as well as a 4, 5 -unsaturated pyrimidine nucleoside. Treatment of 3 -O-tosyl-2 -deoxy-adenosine with alkoxide produced the 2, 3 -unsaturated nucleoside as well as a smaller amount of the 3, 5 -oxetane derivative. The syntheses of 2, 3 -dideoxy-, 2, 5 -dideoxy-, and 2, 3, 5 -trideoxyadenosine have been accomplished by mono- or ditosylation of 2 -deoxyadenosine... 

L. Pearce, Approach to oxetane and furan nucleosides with an anomeric carbon substituent Nucleophilic substitution at highly hindered a-bromo-oxetane- and -tetrahydrofuran-carboxy-lates. Tetrahedron Lett., 32 (1991) 3569-3572. 

Ring-opening reactions of functionalized 1,2-cyclic sulfates and oxetanes with carbanions derived from diisopropyldifluoromethylphosphonate (115) have been reported (Scheme 40). This approach allowed an easy access to y-hydroxy-a,a -difluorophosphonates (116) as building blocks in synthesis of acyclic nucleosides. 

In a similar way it has been shown that reaction of mesylate 22, under aqueous basic conditions, affords the oxetane acid 23. This latter compound was used for a formal synthesis of the anti-viral oxetanocin. (See also Vol. 24, p. 217 and p. 176 for similar work.) The synthesis of other branched-chain nucleosides is covered in Chapter 20. 

Various 5-substituted a-D-arabinofuranosyluracils have been been prepared conventionally,27 and a full account has been given of a route to L-threofuranosyl nucleosides by ring-expansion of oxetane derivatives (see Vol. 24, p. 226). ... 

Racemic oxetan-fused nucleoside analogues of type 138 have been made by the Patemo-Biichi reaction of furan and benzoyloxyacetaldehyde, epoxidation, and reaction with silylated base. 1 1... 

Similar 0-atyl-phosphoramidate derivatives of nucleosides, bearing an amino acid residue, were prepared in several laboratories. Synthesis of such a prodrug form of l, 2 -cyclopentyl nucleosides 44 was reported from the already mentioned Qun Dang s group. Conformationally-restricted 2 -spironucleosides (bearing a 2 -oxetane motif) and their prodrugs 45 were synthesised and tested. It should be emphasised that P-diastereomerically pure compounds were evaluated. The prodrugs of a 2 -oxetane 2-amino-6-0-methylpurine nucleoside demonstrated potent anti-HCV activity in vitro. 

H. Tanaka, M. Fukui, K. Haraguchi, M. Masaki, and T. Miyasaka, Cleavage of a nucleosidic oxetane with carbanions Synthesis of a highly promising candidate for anti-HIV agents. A phosphonate isostere of AZT-5 -phoshate, Tetrahedron Lett. 30 2567 (1989). 

K. A.M. Walker, 4 -Substituted nucleosides as inhibitors of HIV An unusual oxetane derivative,... 

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