Conversion of the cellular isoform of the prion protein (PrP C ) into the pathogenic isoform (PrP Sc ) is thought to be the causative event in prion diseases. Biochemically, PrP Sc differs from PrP C in its partial resistance to proteinase K (PK). The amino acid sequence AGAAAAGA, comprising residues 112-119 of the murine PrP C , has been shown to be amyloidogenic and evolutionarily conserved. To assess the effect of mutations at and around this hydrophobic sequence on protease resistance, the sequence was replaced either by alanines or by glycines and, in a third mutant, a large part surrounding this region was removed. The PrP mutant carrying substitutions of glycines for alanines showed PK resistance and aberrant proteolytic processing. Tetracycline-induced expression of this mutant indicated that resistance to protease is acquired concurrent with the synthesis of the protein. These findings indicate that mutations in the central hydrophobic region lead to immediate alterations in PrP structure and processing.

No abstract

A highly selective asymmetric domino allylation of aliphatic ketones is described. When methyl ketones 1 a ± g, the chiral trimethylsilyl ether 2, and allylsilane 3 react in the presence of catalytic amounts of trifluoromethanesulfonic acid, the homoallylic ethers 4 a ± g are produced with up to 24:1 diastereoselectivity and 89 % yield. Cleavage of the obtained tertiary homoallylic ethers 4 using lithium or sodium in liquid ammonia gives the homoallylic alcohols 5 in 75 to 95 % yield and up to 92 % ee. Even ethyl methyl ketone 1 a, the most difficult example, showed a stereoselectivity of 9:1 at À 78 8C and 24:1 at À 109 8C. In addition, the allylation of protected hydroxyalkyl methyl ketones 7 a ± j was investigated to give the corresponding homoallylic ethers 8 a ± j with a diastereoselectivity of up to b 24:1 and 98 % yield. In contrast, ethyl alkyl ketones 1 h ± j have a low selectivity.

Reaction of aliphatic aldehydes 1 and allylsilane 3 at -78 °C in the presence of the norpseudoephedrine derivative 2a and catalytic amounts of trifluoromethanesulfonic acid trimethylsilyl ester gives the homoallylic ethers 4 with >98% diastereoselectivity. The ethers 4 can be transformed into the corresponding homoallylic alcohols 5 having an enantiomeric excess >98% using sodium in liquid ammonia. On-line NMR spectroscopy indicates that the mixed acetal 7 and the oxazolidinium ion 12 are intermediates in the formation of 4. At higher temperature proton transfer occurs to give the oxazolidinium ion 18, which does not react with allylsilane, but gives the oxazolidine 17 on aqueous workup. Protonation of 17 with trifluoromethanesulfonic acid leads to 18 but not to the oxazolidinium ion 12. Thus, an allylation starting from 17 is not possible.

No abstract