Access to Oxetane-Containing psico-Nucleosides from 2-Methyleneoxetanes: A Role for Neighboring Group Participation?

Abstract

The first psico-oxetanocin analogue of the powerful antiviral natural product, oxetanocin A, has been readily synthesized from cis-2-butene-1,4-diol. Key 2-methyleneoxetane precursors were derived from β-lactones prepared by the carbonylation of epoxides. F(+)-mediated nucleobase incorporation provided the corresponding nucleosides in good yield but with low diastereoselectivity. Surprisingly, attempted exploitation of anchimeric assistance to increase the selectivity was not fruitful. A range of 2-methyleneoxetane and related 2-methylenetetrahydrofuran substrates was prepared to explore the basis for this. With one exception, these substrates also showed little stereoselectivity in nucleobase incorporation. Computational studies were undertaken to examine if neighboring group participation involving fused [4.2.0] or [4.3.0] intermediates is favorable.

Nucleophilic Addition to Silyl-Protected Five-Membered Ring Oxocarbenium Ions Governed by Stereoelectronic Effects

“…The product was purified by flash column chromatography on silica gel (1:5:94 Et 3 N:EtOAc:hexanes) to give 35 as a colorless oil (1.5 g, 97%). The spectral data obtained matched the reported values for this compound: 32 1 H NMR (600 MHz, CDCl 3 ) δ 3.80 (dd, J = 11.8, 4.2, 2H), 3.72 (dd, J = 11.8, 6.1, 2H), 3.15–3.12 (m, 2H), 0.91 (s, 18H), 0.09 (s, 6H), 0.08 (s, 6H); 13 C NMR (150 MHz, CDCl 3 ) δ 62.0, 57.1, 26.1, 18.5, −5.0, −5.2; HRMS (TOF MS ES+) m / z calcd for C 16 H 37 O 3 Si 2 (M + H) + 333.2281, found 333.2284.…”

Oxetanes: Recent Advances in Synthesis, Reactivity, and Medicinal Chemistry

“…This was achieved through electrophilic addition of F + followed by nucleophilic attack of the nucleobase (Scheme ). From 2-methyleneoxetane 313 , selectfluor gave a good yield for nucleobase incorporation, but both N7 ( 314 ) and competing N9 alkylation ( 315 ) occurred. After multiple purifications, 314 was obtained as a 37:63 mixture (α:β epimers, 42% yield) and 315 as a 23:77 mixture (α:β epimers, 34% yield), with both favoring the desired β-isomers.…”

2-(Aryl-sulfonyl)oxetanes as designer 3-dimensional fragments for fragment screening: synthesis and strategies for functionalisation

“…19 Substituted oxetanes have also been generated from exo-methylene oxetanes. 20 However, these approaches are unsuitable for our targets, particularly due to the instability of the often required a-sulfonyl oxy-anion intermediate. 21 To incorporate the 2-sulfonyl group, we envisaged a strategy involving C-C bond formation, as opposed to the usual C-O bond formation (Fig.…”