The Fluoro-Pauson–Khand Reaction in the Synthesis of Enantioenriched Nitrogenated Bicycles Bearing a Quaternary C–F Stereogenic Center

Abstract

A variety of enantioenriched fluorinated 6H-cyclopenta[c]pyridin-6-one bicycles, a scaffold present in several classes of monoterpenic alkaloids with varied biological activity, were synthesized in just five steps starting from simple aldehyde starting materials. The synthesis presented wide functional group tolerance and moderate to high yields and diastereoselectivities, and could be carried out at gram-scale. These products were suitable for further transformations, such as hydrogenation and deprotection of the tert-butyl sulfonyl protecting group.

Asymmetric Synthesis of Fluorinated Monoterpenic Alkaloid Derivatives from Chiral Fluoroalkyl Aldimines via the Pauson‐Khand Reaction

“…[24] Unfortunately, after several attempts, the catalytic version of the Pauson-Khand could not be applied to the synthesis of this class of previously reported quaternary CÀ F containing bicycles, such as 5 n (Scheme 4). [6,23] The mechanism of the Pauson-Khand reaction catalyzed by Co 2 (CO) 8 was initially proposed by Magnus in 1985, [25] and the same mechanism has since been supported by theoretical studies. [26] In our case, 1,7-enyne 4 reacts with Co 2 (CO) 8 through a ligand exchange reaction to form the alkyne-coordinated Co 2 (CO) 6 complex I upon release of two molecules of CO (Scheme 5).…”

“…To this end, the allylation reaction of the homopropargyl sulfonamine 3 a was carried out with 2‐fluoroallyl mesylate 6 to afford enyne 4 n (Scheme ) . For the cyclisation of this enyne derivative, we followed the reaction conditions previously applied by our group in analogous fluoro‐Pauson‐Khand reactions, in which DMSO is used as the promoter instead of NMO . It is worth noting that this transformation involves the asymmetric construction of a carbon‐fluorine quaternary stereogenic centre, a goal that constitutes remarkable interest in organic synthesis .…”

“…It is worth noting that this transformation involves the asymmetric construction of a carbon‐fluorine quaternary stereogenic centre, a goal that constitutes remarkable interest in organic synthesis . Unfortunately, after several attempts, the catalytic version of the Pauson‐Khand could not be applied to the synthesis of this class of previously reported quaternary C−F containing bicycles, such as 5 n (Scheme ) …”

“…[4,5] In terms of fluorinated derivatives, our group recently reported the synthesis of similar bicyclic structures via fluoro-Pauson-Khand reaction, resulting in a stereogenic bridgehead CÀ F bond (Scheme 1). [6] In addition, Bonnet-Delpon and co-workers briefly explored the synthesis of racemic trifluoromethylated derivatives of the same heterobicylic skeleton (Scheme 1). [7] This, incidentally, is the only documented example of the propargylation of fluorinated imines, to the best of our knowledge.…”

“…[22] For the cyclisation of this enyne derivative, we followed the reaction conditions previously applied by our group in analogous fluoro-Pauson-Khand reactions, in which DMSO is used as the promoter instead of NMO. [6,23] It is worth noting that this transformation involves the asymmetric construction of a carbon-fluorine quaternary stereogenic centre, a goal that constitutes remarkable interest in organic synthesis. [24] Unfortunately, after several attempts, the catalytic version of the Pauson-Khand could not be applied to the synthesis of this class of previously reported quaternary CÀ F containing bicycles, such as 5 n (Scheme 4).…”