Constructing chiral bicyclo[3.2.1]octanes via palladium-catalyzed asymmetric tandem Heck/carbonylation desymmetrization of cyclopentenes

Abstract

Transition-metal-catalyzed tandem Heck/carbonylation reaction has emerged as a powerful tool for the synthesis of structurally diverse carbonyl molecules, as well as natural products and pharmaceuticals. However, the asymmetric version was rarely reported, and remains a challenging topic. Herein, we describe a palladium-catalyzed asymmetric tandem Heck/carbonylation desymmetrization of cyclopentenes. Alcohols, phenols and amines are employed as versatile coupling reagents for the construction of multifunctional chiral bicyclo[3.2.1]octanes with one all-carbon quaternary and two tertiary carbon stereogenic centers in high diastereo- and enantioselectivities. This study represents an important progress in both the asymmetric tandem Heck/carbonylation reactions and enantioselective difunctionalization of internal alkenes.

Palladium-catalyzed enantioselective carbonylation reactions

“…This reaction exhibited good functional group tolerance, and it has been implemented as a key step in the syntheses of the natural product coixspirolactam A and of an effective CRTH2 receptor antagonist. Indeed, They pro- In 2020, Lin and Yao et al [52] reported a Pd-catalyzed asymmetric tandem Heck/carbonylation desymmetrization of cyclopentenes that produced bicyclo[3.2.1]-octanes, which are found in several bioactive natural products. Employing Pd 2 (dba) 3 •CHCl 3 (or Pd(dba) 2 ) as the catalyst and (S)-difluorphos as the ligand, various chiral bicyclo[3.2.1] octane products bearing one all-carbon quaternary and two tertiary carbon stereogenic centers were synthesized in 50%-98% yields and 88%-97% ee.…”

Palladium-Catalyzed Asymmetric Domino Heck/Carbocyclization/Suzuki Reaction: A Dearomatization of Nonactivated Naphthalenes

“…Palladium-catalyzed asymmetric domino Heck reaction is one of the most powerful methods for the construction of quaternary stereocenters. 26,27 Through trapping of the in situ generated alkyl-PdX intermediate, various enantioselective domino reactions, including Heck tandem coupling with azoles, 28,29 (dearomative) Heck-Sonogashira reaction, [30][31][32] Heck-Suzuki reaction, 33,34 and Heck-carbonylative reaction [35][36][37][38] have been developed for the synthesis of valuable structures (Scheme 1A). Alternatively, by switching the cross-coupling of alkyl-PdX to reductive elimination, intriguing reductive Heck and Heck carboiodination reactions have been reported (Scheme 1A).…”

Pd-Catalyzed Enantioselective Tandem C–C Bond Activation/Cacchi Reaction between Cyclobutanones and o-Ethynylanilines

“…1 Intramolecular enantioselective carbopalladation of 1,1-disubstituted C−C double bond represents an elegant approach to generating chiral σ-alkylpalladium species, which can be in situ trapped by various nucleophiles such as cyanide, azole, and hydride as reported by the groups of Zhu, 2−7 Lautens, 8 Jia, 9−11 Diaz, 12 Zhou, 13,14 Tong, 15,16 Zhang, 17−20 Lu, 21 and Lin and Yao (Scheme 1a). 22,23 Transition-metal catalyzed C−C σ-bond activation has received considerable attention in the past decade. 24−29 Owing to the inherent high ring strain, C−C σ-bond of cyclobutanones can be easily cleaved, and Rh-and Ni-catalyzed enantioselective C−C bond activation of prochiral cyclobutanones has been established by the groups of Murakami, 30−32 Cramer, 33−35 and Dong.…”