Catalytic, Enantioselective Petasis Reaction

The enantioselective, organocatalytic variant of the Petasis reaction, developed by Takemoto and coworkers from the University of Kyoto, represents a breakthrough in the synthesis of enantiopure 1,2-dihydroquinolines. As mentioned before, this structural unit is present in many natural products and biologically active compounds, and therefore an effective and short synthetic route via the Petasis-type reaction to enantiopure compounds in this class is a major leap forwards. Screening of the new thiourea catalysts in the Takamoto group resulted in a highly effective catalyst 13, specifically designed for the Petasis reaction. 

Thiourea derivatives are a specific group of organocatalysts. Most of them were developed by the groups of Jacobsen [23,24] and Takemoto [25,26], and designed for enantioselective or chiral variants of classic synthetic reactions, such as the Mannich reaction, Michael addition, the aza-Henry reaction, Strecker cyanide addition and some others. 

In this reactimi, the chiral thiourea moiety acts as a Bronsted acid and activates both the N-acylated quinolonium salt XXIV and unsaturated boronic acid III, enhancing the electrophilic character of the quinohnium unit in the ate catalytic complex with bifurcal hydrogen bond. Such activation of the two reaction partners permits enantioselective formation of the C-C IxMid at the stereogenic centre C(2) as a result of interaction between the nucleophilic terminal carbon of the C=C bond in boronic acid and the electrophilic C(2)-atom a- to the ammonium cation in the quinolonium unit. 

The broad application of the organocatalytic Petasis reaction is revealed by the total syntheses of quinoline alkaloids and their congeners with biological activity. The enantiomeric purity obtained in this reaction of 1,2-dihydroquinolines with the 

Broad biological potential of enantiopure 1,2-dihydroquinolines prompted the recently reported organocatalytic, asymmetric Petasis reaction, catalyzed by chiral biphenols [31]. Since it was observed that chiral biphenol derivatives XXVI-XX-VIII serve as proficient catalysts for asymmetric reactions involving boronates [32, 33], the authors postulated that they could be used as ligands in multi-component condensation reactions, and the Petasis reaction in particular. 

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The chiral thiourea organocatalyst for the catalytic enantioselective Petasis reaction... 

Yamaoka, Y, Miyabe, H. and Takemoto, Y. (2007) Catalytic enantioselective Petasis-type reaction of quinolines catalyzed by a newly designed thiourea catalyst. Journal of the American Chemical Society, 129, 6686-6687. 

Figure 6.4 Products derived from the catalytic enantioselective Petasis-Akritopoulou reaction of quinolones catalyzed by a thiourea catalyst, as described by Takemoto s group [65].

In this chapter that highlights the synthesis of arylamines, we will discuss the most recent and relevant developments in the catalytic arylations of imine substrates, which incidentally are mostly enantioselective. The application of organomet2Jlic cat2dysts bearing Pd, Rh, Ru, and other metal catalysts will be considered, as well as the recent multicomponent Petasis reaction. 

The same catalyst has been used by this research group in synthesis of j -amino-aldehydes (146) by combining two catalytic reactions, i.e. a Ni(II) complex-catalyzed isomerization of a double bond and a chiral phosphoric acid (127)-catalyzed aza-Petasis-Ferrier rearrangement in a highly dia-stereo- and enantioselective manner (Scheme 39). ... 

Subsequently, the same group demonstrated an asymmetric synthesis of 3-amino aldehydes via catalytic double-bond isomerization/enantioselective aza-Petasis-Ferrier rearrangement reaction (Scheme 2.93) [128]. Similarly, the hemiaminal allyl ether substrates 346 were first isomerized by Ni(II) complexes to stereoselectively form Z-configured vinyl ethers 347, which then underwent a phosphoric acid-catalyzed... 

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