Memapsin 2 (beta-secretase) is one of two proteases that cleave the beta-amyloid precursor protein (APP) to produce the 40-42 residue amyloid-beta peptide (Abeta) in the human brain, a key event in the progression of Alzheimer's disease. On the basis of the X-ray crystal structure of our lead inhibitor (2, OM99-2 with eight residues) bound to memapsin, we have reduced the molecular weight and designed potent memapsin inhibitors. Structure-based design and preliminary structure-activity studies have been presented.
The Pd-catalyzed hydrogenolysis of 1,1-dibromoalkenes with Bu3SnH occurs at room temperature
stereoselectively to give (Z)-1-bromo-1-alkenes. We sought to determine the optimal reaction
conditions and illustrate the scope of this method with 32 dibromoalkenes including alkenyl- and
alkynyl-conjugated 1,1-dibromo-1-alkenes 7a−h and 2,2-disubstituted 1,1-dibromo-1-alkenes 9a−f. Triphenylphosphine was the best ligand for the Pd-catalyzed hydrogenolysis. A wide range of
solvents can be used for this reaction excluding EtOH, AcOH, and CHCl3. However, the reaction
proceeds even in these solvents with the addition of a cosolvent or radical scavenger. The reaction
of 1,1-diiodo-1-alkene (3) gave a mixture of (Z)-1-iodo-1-alkene (4), (Z)-1-tributylstannyl-1-alkene
(5), and a terminal alkene 6, while that of 1,1-dichloroalkene did not occur. This selectivity can be
explained by the stereoselective insertion of Pd(0) to a trans bromine−alkenyl carbon bond,
successive transmetalation with Bu3SnH, and reductive elimination. The Suzuki and Sonogashira
couplings of the resulting (Z)-1-bromo-1-alkenes with alkenyl(dialkoxy)borane and terminal alkyne
occurred to give conjugated polyenes and enynes stereospecifically. The Pd-catalyzed hydrogenolysis
of 1,1-dibromo-1-alkene and successive cross-coupling can be carried out either in a stepwise manner
or in one-pot under the same Pd catalysis. These two processes should be useful for the synthesis
of geometrically pure polyene and enyne with a Z-alkenyl unit.
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