Two-step Chemo-Enzymatic Synthesis of a Key Chiral Intermediate En Route to Anti-Alzheimer Drug BMS299897

Alzheimer's disease (AD) is one the most common type of dementia, caused by pathological lesion and plaque-accumulation of amyloid-β peptide, due to the activity of β- and γ-secretases. Several drugs are available to date for the treatment of AD. γ-Secretase inhibitor BMS299897 is among one of the most effective ones.1 Key chiral intermediates involved for the synthesis of this drug, however, are usually obtained through several steps, and making use of volatile organic solvents (VOCs).2 Building on our interest in developing truly sustainable synthetic catalytic and stoichiometric methodologies,3 in this communication we report on an unprecedented two-step tandem bioreduction of prochiral ketone 1 followed by a palladium-catalyzed Negishi cross-coupling reaction4 of the resulting chiral nonracemic secondary alcohol (S)-2a (50-98% ee, 60-98% yield) with the organozinc bromide 2b, to provide stereodefined key chiral adduct (S)-3, en route to BMS299897, in up to 98% enantiomeric excess (ee) and 70-80% yield, minimizing purification procedures and the isolation of intermediates (Scheme 1). These results follow a systematic screening of bio- (whole-cells and isolated enzymes)5 and metal-catalysts and organometallic complexes in several environmentally responsible media.4b