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

Abstract

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.

P-Chiral Phosphorus Ligands Based on a 2,3-Dihydrobenzo[d][1,3]oxaphosphole Motif for Asymmetric Catalysis

“…In a kilogram-scale enantioselective synthesis of polycyclic cholesteryl ester transfer protein inhibitor 69 , the catalyst Ru–( R , R , R , R )-MeO-BIBOP–ampy (Ru– ent - L3 –ampy) provided excellent enantioselectivity (>98% ee) and high TON (10 000) in the asymmetric hydrogenation of pyridine ketone 67 , affording chiral alcohol 68 with >98% ee in 98% yield (Figure ). Likewise, WingPhos was efficient in producing chiral β-arylamines by asymmetric hydrogenation. The reduction of 70 proceeded smoothly in the presence of 0.1 mol % Rh–WingPhos (Rh– L3 ) to form chiral amide 71 , a key intermediate for the α1-adrenoceptor antagonist silodosin ( 72 ), with 96% ee .…”

Synthesis of P-Chiral Dihydrobenzooxaphosphole Core for BI Ligands in Asymmetric Transformations

“…In 2010, our laboratories discovered a new series of P -chiral mono- and bisphosphine ligands containing a unique dihydrobenzooxaphosphole (BOP) core 1 that are structurally rigid, electronically and sterically tunable, and air-stable. These unique chiral BOP ligands have demonstrated superior reactivity and selectivity for various asymmetric transformations (Scheme ) including for (1) asymmetric Suzuki–Miyaura cross-coupling reactions, (2) asymmetric hydrogenation of enamide, , ketones, unfunctionalized alkenes, and substituted pyridine, (3) asymmetric proprogylation , and allenylation, , (4) asymmetric addition to ketone, imine, and nitroalkene, (5) asymmetric ring-opening, (6) asymmetric hydroboration, (7) asymmetric dearomative and reductive alkynone cyclization, (8) asymmetric hydroformylation, and (9) asymmetric alkene oxyarylation . More significantly, these chiral BOP ligands were successfully applied to the syntheses of complex chiral drug candidates for cholesteryl ester transfer protein (CETP) inhibitor, HIV integrase inhibitor, and 11β-HSD-1 inhibitor programs at Boehringer Ingelheim (Figure ).…”

“…These unique chiral BOP ligands have demonstrated superior reactivity and selectivity for various asymmetric transformations (Scheme ) including for (1) asymmetric Suzuki–Miyaura cross-coupling reactions, (2) asymmetric hydrogenation of enamide, , ketones, unfunctionalized alkenes, and substituted pyridine, (3) asymmetric proprogylation , and allenylation, , (4) asymmetric addition to ketone, imine, and nitroalkene, (5) asymmetric ring-opening, (6) asymmetric hydroboration, (7) asymmetric dearomative and reductive alkynone cyclization, (8) asymmetric hydroformylation, and (9) asymmetric alkene oxyarylation . More significantly, these chiral BOP ligands were successfully applied to the syntheses of complex chiral drug candidates for cholesteryl ester transfer protein (CETP) inhibitor, HIV integrase inhibitor, and 11β-HSD-1 inhibitor programs at Boehringer Ingelheim (Figure ). Furthermore, these ligands are effectively used for other nonasymmetric transformations such as sterically hindered Suzuki and Negishi cross-coupling, amination, and borylation …”

“…The syntheses of various mono- and bisphosphine ligands ( 2 – 7 in Scheme ) using this key building block 1 have been previously reported from our laboratory and others. − …”

“…In summary, an efficient and practical synthesis of enantiomerically pure P -chiral dihydrobenzooxaphosphole core 1 is developed, which has been used to produce multikilogram quantities of this ligand series for asymmetric transformations on large scale. These unique chiral phosphine ligand families have been successfully applied to the asymmetric syntheses of drug candidates ,, on scale.…”