Development of a New and Practical Route to Chiral 3,4-Disubstituted Cyclopentanones:  Asymmetric Alkylation and Intramolecular Cyclopropanation as Key C−C Bond-Forming Steps

Abstract

An efficient and practical asymmetric synthesis of (+)-trans-3-hydroxymethyl-4-(3-fluorophenyl)cyclopentanone (1) is described. An asymmetric Mo-catalyzed alkylation reaction was used to establish the first stereocenter and a Cu-catalyzed intramolecular diastereoselective cyclopropanation reaction was used to set the second stereocenter. The last step involved a one-pot ring-opening/deprotection/hydrolysis/decarboxylation sequence that furnished the desired product in good yield.

Stereoselective synthesis of an anti-HIV drug candidate

“…9 Details of this methodology were recently reported, and this route was used to produce greater than 2 kg of cyclopentanone 3 with an ee of 98%.…”

“…Therefore, we needed to develop a new scalable route to enantiopure cyclopentanone 3. 9 Herein, we describe alternative approaches for the preparation of 3, preparation of the pyrazole 2, and the reductive aminations that assemble the three components into drug candidate 1.…”

Enantioselective Allylic Substitutions in Natural Product Synthesis

“…The synthesis of an important clinical candidate intermediate was selected because of the demonstrated robustness of this process [11]. Starting with racemic carbonate 22, the sodium salt of dimethyl malonate afforded functionalized product 23 in 84À91% yield (batch dependent) with 19:1 branched to linear selectivity in 97% ee (Scheme 10).…”

Molybdenum-Catalyzed Asymmetric Allylic Alkylations

“…Palucki et al 27 used a Mo-catalyzed dynamic kinetic asymmetric transformation (DYKAT) together with an intramolecular cyclopropanation to form a new chiral 3,4-disubstituted cyclopentanone, a key intermediate in the synthesis of a new drug candidate at Merck & Co (Scheme 4). The DYKAT proceeded with high regio-and enantioselectivity (19:1 branched-to-linear ratio and 96-97% ee) in a multikilo scale.…”