Cinchona ammonium salts

PEG-supported cinchona ammonium salts 54 were applied to the asymmetric alkylation of tert-butyl benzophenone Schiff base derivatives 52 [34]. The use of a water-soluble polymer support allowed the reaction to be conducted in a 1M KOH aqueous solution to give the a-amino acid derivatives 53 in high chemical yields (up to 98%). Ten different types of electrophile have been tested for the reaction, with the best enantioselectivity being obtained with o-chlorobenzylchloride (97% ee) (Scheme 3.15). 

Cinchona ammonium salt and 2,6-napthylsulfonate. ° In 2009, the novel chiral polymer 14c (henzylation, 86% enantiomeric excess), involving dimeric chiral quaternary ammonium repeating units internally connected hy two C(9)-OH groups prepared from dihalide via a repeated Williamson ether synthesis, was developed by the same research group. ... 

On the other hand, several intramolecular aza-Michael additions have been successfully developed. As an example, Bandini et al. have reported the first enantioselective synthesis of 3,4-dihydropyrazino[l,2-a]indol-l(2//)-ones through an intramolecular phase-transfer-catalysed aza-Michael addition. This highly enantioselective process was performed in the presence of a chiral cinchona ammonium salt and could be successfully applied to a range of substrates, as shown in Scheme 1.84. 

Arai and co-workers have used chiral ammonium salts 89 and 90 (Scheme 1.25) derived from cinchona alkaloids as phase-transfer catalysts for asymmetric Dar-zens reactions (Table 1.12). They obtained moderate enantioselectivities for the addition of cyclic 92 (Entries 4—6) [43] and acyclic 91 (Entries 1-3) chloroketones [44] to a range of alkyl and aromatic aldehydes [45] and also obtained moderate selectivities on treatment of chlorosulfone 93 with aromatic aldehydes (Entries 7-9) [46, 47]. Treatment of chlorosulfone 93 with ketones resulted in low enantioselectivities. 

Cinchona alkaloids now occupy the central position in designing the chiral non-racemic phase transfer catalysts because they have various functional groups easily derivatized and are commercially available with cheap price. The quaternary ammonium salts derived from cinchona alkaloids as well as some other phase transfer catalysts are... 

The asymmetric Darzens condensation, which involves both carbon-carbon and carbon-oxygen bond constructions, was realized by use of the chiral azacrown ether 75als2,s ,ss and the quaternary ammonium salts derived from cinchona alka-loids159"621 under phase transfer catalyzed conditions. The a,p-epoxy ketone 80 (R=Ph) was obtained with reasonable enantioselectivity by the reaction of... 

O Donnell (1989), Corey/Lygo (1997) cinchona alkaloid-derived quaternary ammonium salts Lewis Base Cataiysis... 

New catalyst design further highlights the utility of the scaffold and functional moieties of the Cinchona alkaloids. his-Cinchona alkaloid derivative 43 was developed by Corey [49] for enantioselective dihydroxylation of olefins with OsO. The catalyst was later employed in the Strecker hydrocyanation of iV-allyl aldimines. The mechanistic logic behind the catalyst for the Strecker reaction presents a chiral ammonium salt of the catalyst 43 (in the presence of a conjugate acid) that would stabilize the aldimine already activated via hydrogen-bonding to the protonated quinuclidine moiety. Nucleophilic attack by cyanide ion to the imine would give an a-amino nitrile product (Scheme 10). 

Alkylation of Schiff bases, derived from amino acid and non-optically active aromatic aldehydes by phase-transfer catalysis in the presence of cinchona alkaloid derived quaternary ammonium salts, gave ce values of up to 50% l42. 

Very successful results have been obtained with functionalized quaternary ammonium salts derived from cinchona alkaloids. An example... 

Corey employed a cinchona alkaloid-derived ammonium salt 5 for the solid-liquid phase transfer catalyst, and attained 99% ee in the addition of a glycine-derived imine to 2-cyclohexenone (Scheme 6) [13,14]. 

In 1989, O Donnell and coworkers successfully utilized cinchona alkaloid-derived chiral quaternary ammonium salts for the asymmetric synthesis of a-amino acids using tert-butyl glycinate benzophenone Schiff base 1 as a key substrate [5]. The asymmetric alkylation of 1 proceeded smoothly under mild phase-transfer... 

As reviewed in this chapter, cinchona alkaloids have played a crucial role in the development of asymmetric phase-transfer catalysis since its advent, and today constitute a privileged structural motif that may be widely utilized for the design of new chiral quaternary ammonium salts. These benefits are due not only to the... 

In particular, it is not only the cinchona alkaloids that are suitable chiral sources for asymmetric organocatalysis [6], but also the corresponding ammonium salts. Indeed, the latter are particularly useful for chiral PTCs because (1) both pseudo enantiomers of the starting amines are inexpensive and available commercially (2) various quaternary ammonium salts can be easily prepared by the use of alkyl halides in a single step and (3) the olefin and hydroxyl functions are beneficial for further modification of the catalyst. In this chapter, the details of recent progress on asymmetric phase-transfer catalysis are described, with special focus on cinchona-derived ammonium salts, except for asymmetric alkylation in a-amino acid synthesis. 

A wide variety of catalytic asymmetric transformations have been achieved in the above investigations, which clearly indicates that quaternary ammonium salts derived from cinchona alkaloids are still powerful reagents, despite their limited structural diversity. Moreover, as PTC chemistry has been recognized as a highly practical approach, further progress should be expected in this area of research. 

Cinchona alkaloids, of course, have occupied the central position in the design of chiral PTCs. By employing a simple chemical transformation of the tertiary amine ofthe natural cinchona alkaloids to the corresponding quaternary ammonium salts, using active halides (e.g., aryl-methyl halides), a basic series of PTCs can be readily prepared. Cinchona alkaloid-derived PTCs have proved their real value in many types of catalytic asymmetric synthesis, including a-alkylation of modified a-amino acids for the synthesis of higher-ordered a-amino acids [2], a-alkylation of... 

It is generally considered that a quaternary ammonium salt derived from cinchona alkaloids has an imaginary tetrahedron composed of four carbon atoms adjacent to the bridgehead nitrogen. As shown in Figure 4.2, in order to serve as an efficient... 

Figure 4.2 Origin of stereoselectivity of cinchona-derived quaternary ammonium salts.

Scheme 4.2 General synthetic scheme for cinchona-derived dimeric quaternary ammonium salts, (a) bis(Bromomethyl)-linkers (0.5 equiv.), EtOH-DMF-CHCI3 (5 6 2), r.t. or reflux, (b) Allyl bromide or benzyl bromide (6.0 equiv.), 50% KOH (10.0 equiv.), CH2CI2, r.t.

As (—)-cinchonidine-derived ammonium salts have been mainly used as chiral PTCs in monomeric cinchona-PTCs via the asymmetric alkylation of 1, and have generally shown better results than those of others [e.g., derived from (+)-cinchonine, (—(-quinine, and (+)-quinidine], the Park-Jew group primarily prepared (—) -cinchonidine derivatives to identify both the optimal linker and best relationship of attachment for the two cinchona units, and to compare catalytic efficiency with that of monomeric cinchona-PTCs. 

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). 

Non-cinchona alkaloid-derived quaternary ammonium salts 1 [10] and 2 [11] were each shown to promote asymmetric alkylation reactions, with enantioselectivity of up to 48% and 94% ee, respectively (Scheme 7.1). 

In continuation with their studies on the synthesis of new analogues of cinchona alkaloids, Dehmlow et al. prepared quaternary ammonium salt 14, which is a... 

Currently, this area is not as well developed as the use of cinchona alkaloid derivatives or spiro-ammonium salts as asymmetric phase-transfer catalysts, and the key requirements for an effective catalyst are only just becoming apparent. As a result, the enantioselectivities observed using these catalysts rarely compete with those obtainable by ammonium ion-derived phase-transfer catalysts. Nevertheless, the ease with which large numbers of analogues - of Taddol, Nobin, and salen in particular- can be prepared, and the almost infinite variety for the preparation of new, chiral metal(ligand) complexes, bodes well for the future development of more enantioselective versions of these catalysts. 

Both experimental and theoretical studies have been reported of fluoro-denitration and fluoro-dechlorination reactions using anhydrous tetrabutylammonium fluoride in DMSO. The absences of ion pairing and strong solvation are critical in contributing to the reactivity of the fluorinating agent24 Quaternary ammonium salts derived from cinchona alkaloids have been shown to be effective catalysts in an improved asymmetric substitution reaction of /1-dicarbonyl compounds with activated fluoroarenes. The products may be functionalized to yield spiro-oxindoles.25... 

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