Inter- and Intramolecular Annulation Strategies to a Cyclopentanone Building Block Containing an All-Carbon Quaternary Stereogenic Center

Abstract

Synthesis of (S)-2-methyl-3-fluorophenyl cyclopentanone methyl ester (1S)-1 has been achieved by both inter- and intramolecular alkylation reactions on multigram scale, using chiral pool reagents. The intramolecular variant is a novel example of a chiral bis-electrophile reacting with a carbon nucleophile to form an enantiomerically pure all-carbon quaternary center.

A concise access to bridged [2,2,1] bicyclic lactones with a quaternary stereocenter via stereospecific hydroformylation

“…In 2015, Dominguez developed a synthetic route to chiral bridged [2,2,1] bicyclic lactones by using chiral alcohol as starting material (Fig. 2a ) 15 . In 2018, Zhu et al developed a copper-catalyzed enantioselective arylative desymmetrization reaction of prochiral cyclopentenes, and then followed by hydrolysis and intramolecular iodolactonlization to generate bridged [2,2,1] bicyclic lactones.…”

Enantiosective synthesis of a substituted cyclopentanone with all-carbon quaternary stereocenter

“…17,18 There are significantly fewer examples of efficient control of the stereogenic process and stereochemistry of the newly formed quaternary center directed by chiral center or centers present initially in the starting materials. [19][20][21] Nevertheless, using the substrate-controlled stereo-induction of an easily accessible stereogenic center is a very attractive strategy to create another one that is more difficult to establish by conventional methods. We surmised that the advantages of this approach could additionally be shown using an annulation reaction by intramolecular dipolar [3+2] cycloaddition of silyl nitronates generated from chiral unsaturated nitro compounds.…”

Stereospecific Hydroformylation of 1-Substituted Cyclopent-3-en-1-ols: A Concise Access to Bridged [2, 2, 1] Bicyclic Lactones With A Quaternary Stereocenter

“…In 2015, Dominguez developed a new synthetic route to chiral bridged [2,2,1] bicyclic lactones by using chiral alcohol as starting material (Figure 2, a). 15 In 2018, Zhu and co-workers developed a copper-catalyzed enantioselective arylative desymmetrization of prochiral cyclopentenes, and then followed by hydrolysis and intramolecular iodolactonlization to generate bridged [2,2,1] bicyclic lactones. However, the installation and removal of an amide direction group were essential to this synthetic route, which resulted in relatively low atom econmy (Figure 2, b).…”