N,O-Nucleosides from Ene Reaction of (Nitrosocarbonyl)mesitylene with Crotyl Alcohol: Selectivity, Scope, and Limitations

Abstract

The (nitrosocarbonyl)mesitylene intermediate undergoes an ene reaction with crotyl alcohol, affording two regioisomeric adducts in fair yields. The sterically demanding (nitrosocarbonyl)mesitylene slightly shifts the C2/Markovnikov orientation towards a C3/anti-Markovnikov pathway, affording a 5-hydroxyisoxazolidine that serves as a synthon for the preparation of N,O-nucleoside analogues through the Vorbrüggen protocol. The selectivity of the ene reaction is discussed in the light of C=C bond polarization and steric effects. The structures of the N,O-nucleosides are assigned and discussed on the basis of spectroscopic observations and X-ray analysis.

Ene Reactions of Nitrosocarbonyl Intermediates with Trisubstituted Cycloalkenes: “Cis Effect” and Steric and Conformational Factors Drive the Selectivity

“…The TSs shown in Figures 2 and 3 are part of more complex mechanism already accounted in previous works. 9,10 The addition step leads to polarized diradicals, which readily undergo H abstraction to yield the ene adducts (Figure 4). The polarized diradicals are also connected through a cyclization TS to the aziridine N -oxides, but the cyclization path is more difficult than H-transfer, presumably because the N -acyl substituent substantially destabilizes the aziridine N -oxides, which bear a positive charge on the nitrogen atom.…”

“…Recently, we have reported the intriguing and remarkable changes in the regioselectivity of the ene reactions of trisubstituted alkenes upon variation of the nitrosocarbonyl substituent as well as the remarkable “cis” selectivity of these ene reactions, 9 with important applications in the design and synthesis of N , O -nucleoside analogues. 10…”

Ene Reaction of Nitrosocarbonyl Mesitylene with the Cinnamyl Alcohol: Metabolic Activity and Apoptosis of the Synthetized 6-Chloropurine N,O-Nucleoside Analogues

“…4 The ene reactions of aromatic nitrosocarbonyl intermediates 1 with allylic alkoxy olefins offered an alternative pathway for the synthesis of N,O-nucleoside analogues. 5 This methodology relies upon the mild oxidation of aromatic nitrile oxides with tertiary amine N-oxides to generate the nitrosocarbonyl intermediates 1. 6 When these intermediates are in-situgenerated in the presence of the highly reactive 3-methyl-2buten-1-ol representative of the category of the trisubstituted allylic alcohols, they undergo ene reaction by extracting exclusively the allylic hydrogens on the more congested side of the alkene (the "cis effect") (Scheme 1).…”

DEAE-cellulose-catalyzed synthesis of 5-hydroxy-isoxazolidines and their synthetic uses towards nucleoside analogues

“…The process can somewhat be considered catalytic due to the fact that the amount of ammonium residues on the cellulose skeleton depends on the manufacturers and the loading values are substantially lower than the amount of reagents used for conducting the reactions. In previous works 3, [10][11][12] we prepared and evaluated from their biological activities some nucleoside analogues bearing aromatic or aliphatic substituents on the carbon atom C3 of the heterocyclic moiety as shown in Figure 1. In order to have further insights on the SAR, we envisioned to pursue the investigation on the nucleoside analogues obtained from a "clean" isoxazolidine ring where carbon C3 is just a methylene; the absence of substituents at this point on the heterocyclic ring could offer more information on how to increase or modify the apoptotic activity of these N,O-nucleosides.…”

“…The fully characterized product was then submitted to heterobase insertion reaction by adapting the Vorbrüggen protocol (Table 3). The reaction were conducted according to the method already used in previous works 3,[10][11][12] and compounds 15a-d were obtained from fair to good yields.…”