Facile Entry to an Efficient and Practical Enantioselective Synthesis of a Polycyclic Cholesteryl Ester Transfer Protein Inhibitor

An efficient enantioselective synthesis
of the chiral polycyclic
cholesteryl ester transfer protein (CETP) inhibitor 1 has been developed. The synthesis was rendered practical for large
scale via the development of a modified Hantzsch-type reaction to
prepare the sterically hindered pyridine ring, enantioselective hydrogenation
of hindered ketone 6 utilizing novel BIBOP-amino-pyridine
derived Ru complex, efficient ICl promoted lactone formation, and
a BF3 mediated hydrogenation process for diastereoselective
lactol reduction. This efficient route was successfully scaled to
produce multikilogram quantities of challenging CETP drug candidate 1.