Cinchonidine-derived catalysts

A cursory examination of the Cinchona catalysts used in O Donnell-type alkylation [90] of methyl (diphenylimino)glycinate (Appendix 7.A) reveals that only minor modifications to the Cinchona scaffold are required for the synthesis of a catalyst the 8-substituent on the quinuclidine core may either be a vinyl group (as in the parent alkaloids, quinine and quinidine) or can be an ethyl substituent, introduced by hydrogenation. The quinoline system at the 2-position ofthe quinuclidine ring can be unsubstituted if the catalyst is derived from quinine or quinidine, but can contain a 6-methoxy group ifit is derived from cinchonine or cinchonidine. The 3-position ofthe quinuclidine ring may contain either a hydroxy group or else a vinyloxy or benzyloxy... 

A characteristic feature of this solid-phase amino acid synthesis is the use of the phosphazene bases 53 and 54 for the PTC alkylation reaction [64, 65]. Because these compounds, which are soluble in organic media, do not react with alkyl halides, both alkyl halide and phosphazene bases can be added together at the start of the reaction, which is useful practically [65], Cinchonine and cinchonidine-derived salts, e.g. 25, were found to be very efficient catalysts. Under optimum conditions the alkylation proceeds with enantioselectivity in the range 51-99% ee, depending on the alkyl halide component [65], Seventeen different alkyl halides were tested. After subsequent hydrolysis with trifluoroacetic acid the corresponding free amino acids were obtained in high yield (often >90%). 

Use of the preformed Z-silyl enol ether 18 results in quite substantial anti/syn selectivity (19 20 up to 20 1), with enantiomeric purity of the anti adducts reaching 99%. The chiral PT-catalyst 12 (Schemes 4.6 and 4.7) proved just as efficient in the conjugate addition of the N-benzhydrylidene glycine tert-butyl ester (22, Scheme 4.8) to acrylonitrile, affording the Michael adduct 23 in 85% yield and 91% ee [10]. This primary product was converted in three steps to L-ornithine [10]. The O-allylated cinchonidine derivative 21 was used in the conjugate addition of 22 to methyl acrylate, ethyl vinyl ketone, and cydohexenone (Scheme 4.8) [12]. The Michael-adducts 24-26 were obtained with high enantiomeric excess and, for cydohexenone as acceptor, with a remarkable (25 1) ratio of diastereomers (26, Scheme 4.8). In the last examples solid (base)-liquid (reactants) phase-transfer was applied. 

Asymmetric nucleophilic addition to C=C double bonds (see also Chapter 4) can also proceed highly stereoselectively. Several examples of enantio- and diastereo-selective Michael additions with 99% ee for the resulting products have been described by the Corey group [19]. A cinchonidine-derived phase-transfer organo-catalyst (10 mol%) was used. 

Dehmlow and coworkers screened several analogues of dnchona-based PTCs bearing an N-(9-anthracenylmethyl) group [17]. Especially, in the case of 2-isopropyl naphthoquinones, the nonnatural deazacinchonidine derivative catalyst 11 showed better results compared to those obtained with the natural cinchonidine-derived analogue 12, in terms of both the catalytic activity and the enantioselectivity (84% ee) in this reaction (Scheme 5.12). 

Asymmetric Michael additions can also be performed under phase-transfer conditions with an achiral base in the presence of a chiral quaternary ammonium salt as a phase-transfer agent. Conn and coworkers conducted the Michael addition of 2-propyl-l-indanone (13) to methyl vinyl ketone under biphasic conditions (aq 50% NaOH/toluene) using the cinchonine/cinchonidine-derived chiral phase-transfer catalysts (PTCs), 14a and 14b, as a catalyst (Scheme 9.5). However, only low to... 

Using molecular oxygen as the oxidizing agent, the Itoh group has achieved the enantioselective preparation of 3-allyl-3-hydroxyoxindole 90 (85% ee) under phase-transfer conditions with the cinchonidine derived catalyst 89 [54]. The oxindole 90 was further manipulated to a key intermediate that has been applied in a prior synthesis of the hexahydropyrroloindole CPC-1 [55] (Scheme 24). 

Chiral y-amino acids and y-nitroesters have been prepared, under PTC conditions, from 4-nitro-5-styrylisoxazoles, derivatives efficiently used as cinnamate equivalents in the asymmetric Michael reaction with nitroalkanes[181]. The reaction is catalyzed by Cinchonidine-derived catalyst 122 (2-5 mol%) at low temperatures (-30 to 0°C) affording high selectivities not only with nitromethane but also with secondary and tertiary nitroalkanes as nucleophiles. As seen in Scheme 2.66, the... 

Cinchonidine-derived catalyst 173 (10 mol%) has been also employed in the asymmettic synthesis of 4-alkytiden glutamic acid derivatives through a tandem conjugate addition-eUminalion reaction between the Schiff base of glycine tm-butyl ester and activated aUytic acetates under PTC conditions using CsOHH O as base [276]. The reaction, which is performed at -78°C in allows the preparation... 

In 2009, Bernadi and Adamo designed 4-nitro-5-sttyrylisoxazole (66) as a novel Michael acceptor. The asymmetric conjugate addition of nitroalkanes to 66 in the presence of cinchonidine-derived PTC catalyst 8o afforded the addition adduct 67 with high enantioselectivity (97% enantiomeric excess). The 4-nitroisoxazole eore serves as an activator of the conjugated alkene and is readily derivatised to pharmaceutically valuable compounds, such as y-nitroesters and y-amino acids (Scheme 16.20). " ... 

In 2008, Itoh and co-workers [66] successfully developed the first organocata-lyzed a-aminoxylation of oxyindoles using a cinchonidine-derived phase-transfer catalyst 29 and molecular oxygen (Scheme 12.7). In 2010, Barbas III and co-workers [67] designed a new dimeric quinidine catalyst 28 to synthesize the same kind of... 

The Au(I)- or Ag(I)-catalysed intermolecular hetero-Diels—Alder cycloaddition of push-pull l,3-dien-5-ynes (76) with aldimines or silylaldimines (77) produced 5,6-dihydropyridin-2-ones (78) with high diastereo- and regio-selectivities (Scheme 24). A copper-catalysed intramolecular aza-Diels—Alder reaction has been used to produce dihydrochromeno[4,3-Mpyrrolo[3,2-/ quinolmes in good yields. The cinchonidine-derived quaternary ammonium catalyst, A-2, 3, 4 -trifluorobenzyl-0-benzylcinchonidinum bromide (79), catalysed the aza-Diels—Alder reactions between... 

An organocatalytic asymmetric hydroxylation of oxindoles by molecular oxygen as an oxidant using a phase-transfer catalyst was reported by Itoh et ai, in 2008. The use of O2 as the oxidant was a paramount process, because it is inexpensive and environmentally benign. In these conditions, the reaction of a series of 3-substituted oxindoles in the presence of a cinchonidine-derived... 

A combined system of PhjP and a cinchonidine-derived primary amine has been identified as an ideal catalyst for the Michael addition of aliphatic aldehydes to iV-aryl maleimides (with <99% ee). Mechanistic investigation, involving UV-vis, fluoreseenee emission (FL), NMR, circular dichroism (CD), and ESI-MS, revealed the existenee of the molecular assembly of phosphine and amine (248) with an arene-arene staeking, which is believed to play the key role ... 

Complementary to the above-presented enantioselective sequences Michael addition/a-alkylation of bromomalonates, a related powerful gem-dialkylative process was also proposed recently [38]. a-Dialkylation of imines 25 with 1,4-dihalo-but-2-ene 26 using a cinchonidine derivative J as phase-transfer catalyst proceeded smoothly in the presence of aqueous NaOH to give the (l/ ,25)-l-amino-2-vinylcyclopropanecarboxylic acid derivatives 27 with generally good diastereose-lectivity but with enantiomeric excesses not exceeding 80% (Scheme 5.10). 

Making use of the stereochemically matched combination of a chiral auxiliary and a chiral ammonium catalyst, Minakata and coworkers succeeded in developing a highly diastereoselective aziridination of electron-deficient alkenes with iV-carbamate chloramine salts [60]. For example, in the presence of a cinchonidine-derived ammonium salt as an organocatalyst, the reaction of the enone that has L-mentho-pyrazole moiety as an auxiliary with iV-Boc chloramine salt gave diastereochemicaUy pure aziridine in 77% yield (Scheme 2.39). 

SCHEME 35.29. Asymmetric epoxidation of enones 106 using cinchonidine-derived, phase-transfer catalyst 105. 

The extension of the thiourea-tertiary amine concept to the cinchona alkaloids was reported by several groups independently in 2005. The general usefulness of cinchona alkaloids as bifunctional catalysts was recognized by several groups even before this date [9]. The focus herein is on (thio)urea and squaramide catalysts since they are prototypes of more efficient catalysts. The Chen and the Dixon groups screened cinchonine and cinchonidine-derived thiourea catalysts for conjugate... 

Figure 12.3 Cinchonine- and cinchonidine-derived quaternary ammonium salt phase-transfer catalysts.

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