Organocatalysts cinchona alkaloid

Scheme 12.9 Synthesis of novel cinchona alkaloid organocatalysts with modified quinoline moiety. Reagents and conditions (a) Dt-BuAD, CH2CI2, rt, 2 h, 93% (b) PhNTf2, DMAP, CH2CI2 (c) 1. Pd(OAc)2, BINAP, Cs2C03, THF, Ph2C=NH, 2. citric acid, THF, H20 (d) 3,5-(CF3)2PhNCS, THF.

Johansson CCC, Bremeyer N, Ley SV, Owen DR, Smith SC, Gaimt MJ (2006) Enantioselective Catalytic Intramolecular Cyclopropanation Using Modified Cinchona Alkaloid Organocatalysts. Angew Chem Int Ed 45 6024... 

Johansson, C. C., Bremeyer, N., Ley, S. V., Owen, D. R., Smith, S. C., Gaunt, M. J. (2006). Enantioselective catalytic intramolecular cyclopropanation using modified cinchona alkaloid organocatalysts. Angewandte Chemie - International Edition, 45, 6024-6028. 

Squaramide-based dimeric cinchona alkaloid organocatalysts have also been described [92] and shown to be highly suitable for the dynamic kinetic resolution of racemic azlactones (Scheme 6.43). The dimeric squaramide derivatives were free from self-association, as indicated by the observation that the enantioselectivity was not influenced to any significant extent by the concentration of the dimeric squaramide, in contrast to the monomeric species that showed a decline in ee upon an increase in concentration. 

At almost the same time, and based on their earUer studies with cinchona alkaloid organocatalysts bearing both a Br0nsted-base and thiourea residues, Hiemstra and coworkers were able to achieve good enantioselectivities and yields in the Henry reaction between aromatic aldehydes and nitromethane [8]. With unactivated aromatic aldehydes (i.e., R = 4-MeO-Ph) longer reaction times were required (Scheme 29.3). 

Figure 44.10 Target molecules synthesized using cinchona alkaloid organocatalysts.

I.3.I. Chiral Phase-Transfer Catalysis The exploration of modified cinchona alkaloid organocatalysts for asymmetric synthesis indicates that the quaternary ammonium salt derived from cinchona alkaloids is one of the best catalysts in the asymmetric Michael reaction. In 2000, Perrard and co-workers used A/-meth-ylanthracenylquininium (or quinidinium) chloride salt (Q-a or QD-a) for catalyzing the asymmetric Michael addition of dimethyl malonate to 2-pentyl-2-cyclo-penten-l-one (Scheme 9.6). ... 

Enantioselective alcoholysis of racemic, prochiral, or meso cyclic anhydrides can be catalyzed by hydrolases, yielding the corresponding monoesters (Eigure 6.25). In most cases, the enantioselectivity was moderate ]75-77]. Organometallic catalysts or organocatalysts such as cinchona alkaloids are often more efficient than enzymes for the stereoselective ring opening of cyclic anhydrides. 

In addition to metal catalysts, organocatalysts could also be used in asymmetric cyanation reactions. Chiral Lewis bases, modified cinchona alkaloids, catalyzed asymmetric cyanation of ketones by using ethyl cyanoformate as the cyanide source (Scheme 5.34)." Similar to metal-catalyzed reactions, ethyl cyanoformate was first activated by chiral Lewis bases to form active nucleophiles. Various acyclic and cyclic dialkyl ketones were transformed into the desired products. Because of using... 

Wang and co-workers reported a novel class of organocatalysts for the asymmetric Michael addition of 2,4-pentandiones to nitro-olefms [131]. A screen of catalyst types showed that the binaphthol-derived amine thiourea promoted the enantiose-lective addition in high yield and selectivity, unlike the cyclohexane-diamine catalysts and Cinchona alkaloids (Scheme 77, Table 5). 

Cinchona Alkaloids - Natural Products as a Source of Organocatalysts Appendix 7.A [91,92,94-96,108-120]... 

Currently, the chiral phase-transfer catalyst category remains dominated by cinchona alkaloid-derived quaternary ammonium salts that provide impressive enantioselec-tivity for a range of asymmetric reactions (see Chapter 1 to 4). In addition, Maruoka s binaphthyl-derived spiro ammonium salt provides the best results for a variety of asymmetric reactions (see Chapters 5 and 6). Recently, some other quaternary ammonium salts, including Shibasaki s two-center catalyst, have demonstrated promising results in asymmetric syntheses (see Chapter 6), while chiral crown ethers and other organocatalysts, including TADDOL or NOBIN, have also found important places within the chiral phase-transfer catalyst list (see Chapter 8). 

S,y-Unsaturated a-keto esters such as tnms -MeCH=CHCOCC>2Et undergo enan-tioselective reaction with nitromethane, using new catalytic auxiliaries based on cinchona alkaloids.145 Carried out at -20 °C in DCM, the organocatalysts give high conversion, predominantly reaction at ketone only (typically <5% of product involves simultaneous addition to the alkene), and up to 97% ee. 

Cinchona alkaloids and their derivatives have been reported to catalyse the Michael addition of (V-heterocycles, such as benztriazole, to nitroalkenes in moderate to high enantioselectivities (<94% ee) 15 The thiourea derivative (149) catalysed Michael addition of thioacetic acid to a range of frafts-/f-nitrostyrenes to afford RCH(SAc)- CH2NO2 (<70% ee) 16 The thiourea derivative (149) and its congeners have been identified as efficient organocatalysts for the Michael addition of a-substituted cyano-acetates RCH(CN)C02Et to vinyl sulfones CH2=C(R)S02Ph (72-96% ee) 17 ... 

Besides the glycinate ester derivatives described above, other types of enolate-forming compounds have proved to be useful substrates for enantioselective alkylation reactions in the presence of cinchona alkaloids as chiral PTC catalysts. The Corey group reported the alkylation of enolizable carboxylic acid esters of type 57 in the presence of 25 as organocatalyst [69]. The alkylations furnished the desired a-substituted carboxylate 58 in yields of up to 83% and enantioselectivity up to 98% ee (Scheme 3.23). It should be added that high enantioselectivity in the range 94-98% ee was obtained with a broad variety of alkyl halides as alkylation agents. The product 58c is a versatile intermediate in the synthesis of an optically active tetra-hydropyran. 

Aldol reactions using a quaternary chinchona alkaloid-based ammonium salt as orga-nocatalyst Several quaternary ammonium salts derived from cinchona alkaloids have proven to be excellent organocatalysts for asymmetric nucleophilic substitutions, Michael reactions and other syntheses. As described in more detail in, e.g., Chapters 3 and 4, those salts act as chiral phase-transfer catalysts. It is, therefore, not surprising that catalysts of type 31 have been also applied in the asymmetric aldol reaction [65, 66], The aldol reactions were performed with the aromatic enolate 30a and benzaldehyde in the presence of ammonium fluoride salts derived from cinchonidine and cinchonine, respectively, as a phase-transfer catalyst (10 mol%). For example, in the presence of the cinchonine-derived catalyst 31 the desired product (S)-32a was formed in 65% yield (Scheme 6.16). The enantioselectivity, however, was low (39% ee) [65],... 

An impressive highly enantioselective route to /Mac tones in which cinchona alkaloids were used as organocatalysts was reported by Wynberg et al. in 1982... 

Polymer-supported organocatalysts have been used for cycloaddition of ketene, 127, to chloral, 128 [141]. Use of homo-acrylate polymers of cinchona alkaloids led to formation of the desired /Mactone (S)-130 with enantioselectivity up to... 

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