Palladium-Catalyzed Enantioselective C_sp³–C_sp³Cross-Coupling for the Synthesis of (Poly)fluorinated Chiral Building Blocks

Abstract

A general method for the enantioselective synthesis of carbo- and heterocyclic carbonyl compounds bearing fluorinated α-tetrasubstituted stereocenters using palladium-catalyzed decarboxylative allylic alkylation is described. The stereoselective Csp3 –Csp3 cross-coupling reaction delivers five- and six-membered ketone and lactam products bearing (poly)fluorinated tetrasubstituted chiral centers in high yields and enantioselectivities. These fluorinated, stereochemically rich building blocks hold potential value in medicinal chemistry and are prepared using an orthogonal and enantioselective approach into such chiral moieties compared to traditional approaches, often without the use of electrophilic fluorinating reagents.

Recent Advances in the Construction of Quaternary Stereocenters via Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation

“…27 In 2018, the Stoltz group reported the first examples of the synthesis of fluorine-containing tetrasubstituted stereocenters via Pd-catalyzed DAAA (Scheme 6). 36 Electrondeficient (S)-(CF 3 ) 3 -t-BuPHOX ligand L3 was the optimal chiral ligand. This strategy can be applied to a variety of fluoro, -fluoroalkyl, and -fluoroallyl substrates, generating five-and six-membered ketones and lactams containing fluorinated stereocenters in up to 99% yields and 97% ee.…”

“…Scheme 5 Construction of α, α-disubstituted piperazin-2-ones and tetrahydropyrimidin-2-ones Incorporation of fluorine substituted functional groups into molecules is one useful strategy frequently applied in agrochemical and pharmaceutical industry. 35,36 38 electron-deficient (S)-(CF3)3-t-BuPHOX ligand L3 was the optimal chiral ligand. This strategy can be applied to a variety of α-fluoro-, α-fluoroalkyl-, and αfluoroallyl substrates, generating five-and six-membered ketones and lactams containing fluorinated stereocenters in up to 99% yields and 97% ee.…”

Base-Mediated Claisen Rearrangement of CF3-Containing Bisallyl Ethers

“…On the basis of this successful as well as convenient proton shift process starting from the CF3-containing allylic alcohols 1, we envisaged its interesting extension from the synthetic point of view: thus, our idea was that the bisallylic ethers 2 possibly readily synthesized by way of the O-allylation of 1 were recognized as the potential substrates for the Claisen rearrangement as long as the proton shift of 3 to 4 was possible. It is worthwhile to note that, except for our previous report [9], there are no such examples to prepare the compounds 5 by way of Claisen rearrangement irrespective of the substituents R 2 , while there are some reports on the alkylation methods to alternatively get access to 5 [10][11][12][13]. We thus started our research for the novel utilization of the CF3-containing bisallylic ethers 3 as the potent substrates for the [3,3]-sigmatropic rearrangement via the facile isomerization to the corresponding allyl Scheme 1.…”

Synthesis, Structure, and Catalytic Reactivity of Pd(II) Complexes of Proline and Proline Homologs

“…Figure 11. ORTEP plot of cis-bis-(L-pipecolinato)palladium(II), (7). Thermal ellipsoids are shown at the 50% probability level.…”

“…Oxidative coupling reactions are some of the most utilized reactions in modern synthetic chemistry, and transition metal catalyzed oxidations are well known [1]. Palladium(II) oxidative coupling catalysis is a huge field [1][2][3][4][5][6], and this introduction cannot give even a cursory overview of it [7][8][9][10][11][12][13]. Some recent reviews may be the best way of relaying important background information.…”