Highly Enantioselective Michael Addition of Pyrazolin‐5‐ones Catalyzed by Chiral Metal/N,N′‐Dioxide Complexes: Metal‐Directed Switch in Enantioselectivity

Abstract

Make the switch: The first example of a switch in enantioselectivity in the asymmetric Michael addition of pyrazolin‐5‐ones to 4‐oxo‐4‐arylbutenoates that is controlled by the metal center of the catalyst is reported. By using the same N,N′‐dioxide ligand L with different metals the respective enantiomers of various 4‐substituted 5‐pyrazolone derivatives were obtained. Tf=trifluoromethanesulfonyl.

Recent developments in enantioselective yttrium-catalyzed transformations

“…Later, related ligand 70 was combined to Y(OTf) 3 to promote the highly enantioselective Michael addition of 4-substituted pyrazolones 71a-g to 4-oxo-4-arylbutenoates 72a-k to give a range of chiral 4-substituted-5-pyrazolone derivatives 73a-q as almost single diastereomers (> 96% de) in good to high yields (75-95%) and general excellent enantioselectivities of up to 98% ee [61]. As shown in Scheme 24, the ester group of the alkyl 4-oxo-4-arylbutenoates 72a-d exhibited little effect on the enantioselectivity of the reaction (90-98% ee for products 73a-d) but they did influence the reactivity of the substrates (82-95% yields for products 73a-d).…”

Asymmetric, Three‐Component, One‐Pot Synthesis of Spiropyrazolones and 2,5‐Chromenediones from Aldol Condensation/NHC‐Catalyzed Annulation Reactions

“…Encouragedb yt his result,s everal chiral NHC pre-catalysts 4b-4f were employed (entries 2-6) revealing that the catalyst 4b provides the best ee of 94 %w ith 49 %y ield (entry 2). The screening of different bases (entries [7][8][9][10][11][12] showedt hat except for DBU, only KOtBu provided promising results in terms of ee;h owever,t he product was isolated in lower yield (entry 9). Further optimizationw as carried out by screening different solvents using DBU as base (entries 12-18).…”

“…[5] Given the prevalence of the pyrazolone moiety in biologically active compounds and the known methods to assembler elateds pirocyclicp yrazolones in multistep reactions by employing special reagents, [6] organocatalytic strategies are the method of choice to concisely construct this important moiety. [7] Most of these methods rely on the synthesis of six-membered carbocyclic spiropyrazolones. However,t he synthesis of spiropyrazolones bearing ac yclopentane ring is less explored, though this core structure was found recently to have type-4 phosphodiesterase inhibitor activities.…”

From Palladium to Brønsted Acid Catalysis: Highly Enantioselective Regiodivergent Addition of Alkoxyallenes to Pyrazolones

“…[2] Multifarious products can be furnished regioselectively from the same set of starting materials by this strategy,t hus providing much more efficient atom/stepeconomical protocols to facilitate chemical synthesis. [6] Herein, we report the success of highly enantioselective regiodivergent additions of pyrazolones and alkoxyallenes. [4, 5] Forexample,the neuroprotective agent bearing aphenzaone core skeleton, synthesized by Ludwig Knorr in 1883, was the first synthetic antipyretic and analgesic drug, [5a,b] and other important pyrazolone-containing pharmaceuticals include antibacterial agents,t he strongest antipyretic drug,a nd p38 inhibitors,etal.…”

“…[4,5] Forexample,the neuroprotective agent bearing aphenzaone core skeleton, synthesized by Ludwig Knorr in 1883, was the first synthetic antipyretic and analgesic drug, [5a,b] and other important pyrazolone-containing pharmaceuticals include antibacterial agents,t he strongest antipyretic drug,a nd p38 inhibitors,etal. [6] Herein, we report the success of highly enantioselective regiodivergent additions of pyrazolones and alkoxyallenes. [6] Herein, we report the success of highly enantioselective regiodivergent additions of pyrazolones and alkoxyallenes.…”