Enantioselective Synthesis of (−)‐CP‐55940 via Ruthenium‐ Catalyzed Asymmetric Hydrogenation of Ketones

Abstract

A new and efficient catalytic asymmetric synthesis of the potent cannabinoid receptor agonist (−)‐CP‐55940 has been developed by using ruthenium‐catalyzed asymmetric hydrogenation of racemic α‐aryl ketones via dynamic kinetic resolution (DKR) as a key step. With RuCl2‐SDPs/diamine [SDPs=7,7′‐bis(diarylphophino)‐1,1′‐spirobiindane] catalysts the asymmetric hydrogenation of racemic α‐arylcyclohexanones via DKR provided the corresponding cis‐β‐arylcyclohexanols in high yields with up to 99.3% ee and >99:1 cis‐selectivities. Both ethylene ketal group at the cyclohexane ring and ortho‐methoxy group at the phenyl ring of the substrates 6 have little effect on the selectivity and reactivity of the hydrogenations. Based on this highly efficient asymmetric ketone hydrogenation, (−)‐CP‐55940 was synthesized in 13 steps (the longest linear steps) in 14.6% overall yield starting from commercially available 3‐methoxybenzaldehyde and 1,4‐cyclohexenedione monoethylene acetal.

Advances in Stereoconvergent Catalysis from 2005 to 2015: Transition-Metal-Mediated Stereoablative Reactions, Dynamic Kinetic Resolutions, and Dynamic Kinetic Asymmetric Transformations

“…163,164,165,166 Racemic a -substituted cyclic ketones substrates were processed via this technology to establish two or three contiguous stereocenters. This approach has several advantages: the reaction is carried out on readily accessible substrates, tolerates a number of functional groups, and works well with sterically hindered substrates.…”

Catalytic Asymmetric Hydrogenation of α‐Arylcyclohexanones and Total Synthesis of (−)‐α‐Lycorane

“…However, the studies on the asymmetric hydrogenations of ketones directed towards the synthesis of natural products and pharmaceuticals are limited 3. Recently, we developed several highly efficient hydrogenations of ketones with chiral spiro ruthenium and iridium catalysts,4 which have been used for the total synthesis of natural products such as galanthamine,5 mesembrine,6 tetrahedrocannabinols,7 and centrolobine 8. In particular, the ruthenium‐catalyzed enantioselective hydrogenation of racemic α,α′‐disubstituted cycloalkanones has been developed for the synthesis of chiral diols with three contiguous stereocenters in one step, and was applied to the enantioselective total synthesis of alkaloid (+)‐γ‐lycorane 9.…”

Constructing Tertiary Alcohols with Vicinal Stereocenters: Highly Diastereo- and Enantioselective Cyanosilylation of α-Branched Acyclic Ketones and Their Kinetic Resolution

“…As supporting evidence, in contrast to the success of the synthesis of tertiary alcohols from achiral ketones, [24][25][26] no successful catalytic asymmetric C-C bond-forming reactions of racemic -branched ketones to construct vicinal stereocenters are available to date, apart from dynamic kinetic reductive amination 27 and hydrogenation reactions. [28][29][30] To exploit the desired process, we speculated that the chiral catalyst should be flexible to overcome the influence of the -substituent of the racemic ketones and recognize one enantiomer selectively to form a "matched" catalystketone complex. 31 This complex could then undergo the C-C bond-forming reaction substantially faster than the "mismatched" complex, thereby providing control of both diastereo-and enantioselectivity.…”