RESUMO
The reactions of N-(alkoxycarbonyl)-2-azabicyclo[2.2.0]hex-5-enes 5 with halonium ion electrophiles were studied in polar and nonpolar aprotic solvents and also in protic media with the aim of controlling nitrogen neighboring group participation. Specifically, for bromonium ions nitrogen participation is facilitated by the polar aprotic solvent nitromethane and by the poorly nucleophilic protic solvent acetic acid. Alkene 5b and bromine/nitromethane afford only the rearranged anti,anti-5,6-dibromo-2-azabicyclo[2.1.1]hexane 6b, and NBS/acetic acid gives an 8:1 mixture favoring rearranged 5-bromo-6-acetate 6f. Conversely, pyridinium bromide perbromide/CH(2)Cl(2) is selective for only unrearranged 5,6-dibromide 7. Iodonium and phenylselenonium ions react with alkenes 5 to give only unrearranged 1,2-addition products 9 and 10, regardless of solvent. Chloronium and fluoronium ions react with alkenes 5 to give 4-aminomethyl-3-hydroxycyclobutene 11, derived by ring cleavage.
RESUMO
Among the proteinogenic amino acids, only proline is a secondary amine and only proline has a saturated ring. Electronegative substituents on C-4 (that is, C(gamma)) have a substantial effect on the trans/cis ratio of the prolyl peptide bond and the pucker of the pyrrolidine ring. 2-Azabicyclo[2.1.1]hexane is, in essence, a proline analogue with two C(gamma) atoms, one in each of the two prevalent ring puckers of proline. Here, 2-azabicyclo[2.1.1]hexane analogues of 2S-proline, (2S,4S)-4-hydroxyproline, and (2S,4S)-4-fluoroproline residues were synthesized, and their trans/cis ratios were shown to be invariant in a particular solvent. Thus, the substitution of a proline residue on C-4 affects the trans/cis ratio by altering the pucker of its pyrrolidine ring. This finding has implications for the conformation of collagen, which has an abundance of 2S-proline and (2S,4R)-4-hydroxyproline residues, and can be stabilized by (2S,4R)-4-fluoroproline and (2S,4S)-4-fluoroproline residues.