Quinine-derived catalysts Michael addition

The Soos group, in 2005, prepared the first thiourea derivatives from the cinchona alkaloids quinine QN (8S, 9R-121), dihydroquinidine DHQD (8S, 9S-122), C9-epi-QN (8S, 9P-123), and quinidine QD (SR, 9R-124) via an experimentally simple one-step protocol with epimerization at the C9-position of the alkaloid starting material (Figure 6.39) [278]. The catalytic efficiency of these new thiourea derivatives and also of unmodified QN and C9-epi-QN was evaluated in the enan-tioselective Michael addition [149-152] of nitromethane to the simple model chal-cone 1,3-diphenyl-propenone resulting in adduct 1 in Scheme 6.119. After 99h reaction time at 25 °C in toluene and at 10 mol% catalyst loading QN turned out to be a poor catalyst (4% yield/42% ee (S)-adduct) and C9-epi-QN even failed to accelerate the screening reaction. In contrast, the C9-modified cinchona alkaloid... 

Tandem intramolecular Michael addition - intramolecular alkylation can lead to cyclopropanes. Matthew J. Gaunt of the University of Cambridge has shown (Angew. Chem. Int. Ed. 2004,43, 2681) that this intramolecular Michael addition also responds to organocatalysis. In this case, the catalyst, a quinine-derived amine, covalently binds to the substrate, then is released at the end of the reaction. 

Michael additions of C-nudeophiles such as the indanone 1 have been the subject of numerous further studies For example, the reaction between the indanone 1 and methyl vinyl ketone was effected by a solid-phase-bound quinine derivative in 85% yield and with remarkable 87% ee by d Angelo, Cave et al. [5], Co-polymers of cinchona alkaloids with acrylonitrile effected the same transformation Kobaya-shi and Iwai [6a] achieved 92% yield and 42% ee and Oda et al. [6b] achieved almost quantitative yield and up to 65% ee. Similarly, partially resolved 2-(hydroxy-methyl)quinudidine was found to catalyze the reaction between 1 and acrolein and a-isopropyl acrolein with induction of asymmetry, but no enantiomeric excesses were determined [7]. As shown in Scheme 4.4, the indanone 7 could be added to MVK with up to 80% ee under phase-transfer conditions, by use of the Cinchona-derived PT-catalysts 9a and 9b, affording the Michael-product 8 or enf-8, respectively [8]. The adducts 8 or ent-8 were intermediates in the stereoselective Robinson anellation of a cydohexenone ring to the indanone 7 [8],... 

Modified cinchona alkaloids 18 and 19, derived from quinine and quinidine, respectively, were utilized by Deng and co-workers for the catalytic asymmetric Michael additions of malonates to nitroolefins [49]. These catalysts effectively promoted the conjugate additions of methylmalonate to a variety of aromatic (90-99% yield 96-98% ee), heteroaromatic (97-99% yield 96-98% ee) and aliphatic (71-86% yield 94% ee) -substituted nitroolefins (Table 6.7). As the two alkaloids... 

Further reports on asymmetric synthesis in the presence of Cinchona alkaloids have been made.142 " For example, hydrogenation of methyl pyruvate with a platinum-alumina catalyst containing quinine gives (+)-(/ )-methyl lactate in 87% optical yield.1426 Asymmetric induction with optical yields up to 36 and 26% has been observed in the Michael addition of thiols and nitro-alkanes to ct/ -unsaturated ketones in the presence of quaternary salts derived from the Cinchona alkaloids.142"... 

In 2006, Deng and coworkers reported that quinine/quinidine-derived catalysts (64a,b) bearing a free OH group at the C6 -position and bulky phenanthryl moiety at the 9( Opposition quite efficiently promoted the Michael addition of the a-substituted P-ketoesters 65 to the a,P-unsaturated ketones 66 (Scheme 9.21) [18]. The reaction with as little as 1.0mol% of catalyst 64 afforded excellent stereoselectivity and chemical yields (up to 98% ee with quantitative yield) for a wide range of both donors and acceptors. 

The Plaquevent group achieved a new and efficient method for the approach to both enantiomers of methyl dihydrojasmonate 47 by asymmetric Michael addition under solid-liquid phase-transfer catalysis. The main advantages of their procedure are the solvent-free system and the creation of two contiguous stereogenic centres in one step. The authors proposed a plausible mechanism with a transition state composed of substrate 45 and catalyst, quinine-, or quinidine-derived PTC catalyst (48a, 49a), in which hydrogen bonding ensures the proximity of the reactive centres and significantly stabilises the transition state (Scheme 16.14). ... 

Scheme 16.16 Enantioselective Michael addition of FBSM to chalcone using sterically demanding quinine-derived PTC catalysts 49b and 48c.

Squaramide (244) with two quinine-derived units has been developed as a catalyst (2mol%) for Michael addition of nitroalkanes RCH2NO2 (R=Me, Et) to R CH=CHN02 (R = aryl, alkyl, heteroaryl), which occurs in CH2CI2 at —20 °C with <95 5 dr and 97% ee ... 

Other catalytic reactions. The quinine-derived quinazoline (394) has been shown to catalyse the Michael addition of a-substituted nitro acetates (395) to nitroalkenes, affording the dinitro derivatives (396) with 94-98% ee and 89 11 to 99 1 dr, which were then converted into pyrazolines or y-lactams. The reaction proceeds at 0 °C and is remarkable by the low catalyst loading (1 mol%). ... 

The present situation with regard to non-supported catalysts has been admirably reviewed recently, with Wynberg s excellent articlebeing particularly informative. To date virtually all the work has employed quarternary ammonium salts based either on ephedrine [l] and its relatives or the cinchona alkaloids, notably quinine [II], as the active chiral catalyst. Some confusion still remains in the literature concerning the effectiveness of these catalystsi. However, the results of a number of Michael additions seem to be genuine and have been reproduced in more than one laboratory. For example, a chemical yield of100% in the addition of the cyclohexanone derivative, [III], to methyl... 

A chiral quinine-derived squaramide catalysed the highly enantioselective Michael addition of malononitrile to chalcones. The reactions take place at a very low catalyst loading (0.5 mol%) and provide the Michael adducts with high yields and good enan-tioselectivities (up to 96% ee). Chiral bifunctional squaramides have also been used as multiple hydrogen-bond donor-acceptor organocatalysts for the asymmetric Michael addition of nitroolefins to 1,3-dicarbonyl compounds. ... 

Michael addition of a-substituted a-nitroallylphosphonates (293) to various nitroolefins (299) have been shown to produce o,y-diaminophos-phonic esters (300) in the presence of a quinine-derived thiourea catalyst (298), with high diastereo- and enantioselectivity (Scheme 100). ... 

Based on the experiences on the Diels-Alder reaction of 2-pyrones [20], Deng et al. have investigated the stereoselective Diels-Alder reaction of 2-pyrones and a,(3-unsaturated ketones. They also found that primary amines lo and lp derived from quinine and quinidine, respectively, werethe optimal iminium catalysts (5 mol%). The acid additive has a crucial effect on the efficiency of the reaction. TFA (20 mol%) gave the best results, and the Michael reaction, as a side reaction, could also be prohibited. 

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