We describe the development of statine-based peptidomimetic inhibitors of human beta-secretase (BACE). The conversion of the peptide inhibitor 1 into cell-permeable peptidomimetic inhibitors of BACE was achieved through an iterative strategy of conceptually subdividing 1 into three regions: an N-terminal portion, a central statine-containing core, and a C-terminus. Replacement of the amino acid residues of 1 with moieties with less peptidic character was done with retention of BACE enzyme inhibitory activity. This approach led to the identification of the cell-permeable BACE inhibitor 38 that demonstrated BACE-mechanism-selective inhibition of Abeta secretion in human embryonic kidney cells.

GC-MS analysis of extracts from temporal gland secretions of an African elephant has revealed the presence of several farnesol-related sesquiterpenes. Among these are (E)-2, 3-dihydrofarnesol (3), a bumblebee pheromone not seen before in mammals, and a rare component of a Greek tobacco, drimane-8alpha, 11-diol (4), never observed before in an animal.

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A series of vinyl sulfonamides was synthesized using the Horner reaction of aldehydes and diphenylphosphorylmethanesulfonamide. The sulfonamide reagent was easily prepared and can be stored indefinitely. The trans orientation about the double bond of the vinyl sulfonamides was the only isomer observed.Recently, we were interested in the synthesis of aromatic vinyl sulfonamides as potential drug candidates for antiinflammatory programs. 2 The sulfonamide is a useful functionality because it can act as a carbonyl bioisostere 3 making key interactions with receptor proteins as well as providing aqueous solubility. Previous routes to vinyl sulfonamides have involved generating the vinyl sulfonate ester, 4 which is then converted to the sulfonyl chloride and subsequently reacted with various amides. 5 Other methods include Heck coupling of the ethylenesulfonamide and aryl chlorides 6 or a Peterson olefination reaction of a silyl-substituted sulfonamide. 7 After reviewing this literature, we found ourselves interested in developing a general route to vinyl sulfonamides that involved minimal steps and utilized readily available starting materials. Herein, we describe the synthesis of a phosphoryl sulfonamide that reacts with aldehydes in a Horner 8 reaction to generate vinyl sulfonamides. We anticipate that this facile method will complement the existing sulfonamide procedures.The synthesis of the sulfonamide reagent starts with the generation of tert-butyl sulfonyl carbamate 3. We found through initial experiments that a protecting group on the sulfonamide was essential for substrate solubility and facile sulfonamide deprotonation. The synthesis of 3 was straightforward starting with tert-butyl pyrocarbonate and commercially available methyl sulfonamide 9 (Scheme 1).Treating the Boc-sulfonamide 3 with LDA in THF at -78°C, followed by addition of diphenylphosphinic chloride at the same temperature provided 4 as a crystalline solid in 78% yield (Scheme 1). When the phosphoryl sulfonamide 4 was mixed with sodium hydride in DMF followed by the addition of benzaldehyde, the only product observed was the Boc-protected vinyl sulfonamide 5 (Scheme 2). This adduct was deprotected using TFA in dichloromethane at room temperature to yield the vinyl sulfonamide 6 in 82% yield (over the two steps).We then explored the generality of the reaction and found that a variety of aldehydes yielded the respective vinyl sulfonamides. Sodium hydride and potassium carbonate are effective bases for the deprotonation of the phosphoryl reagent. The Boc deprotection conditions were either TFA in CH 2 Cl 2 or hot DMSO, 10 depending on the functionality in the molecule. The overall yields of the sulfonamides for the two step sequence were moderate 11 to good (Table 1). All sulfonamides isolated had the trans orientation about the double bond as determined by NMR coupling constants; the cis isomer was not observed in any of the examples described. We believe that the preference for the trans vinyl sulfonamide is due to steric hindrance encountered in...

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