Cinchona, quaternary ammonium salts

The catalytic construction of heteroatom-substituted stereocenters has been an important and challenging task in asymmetric synthesis. Various synthetic methods for this issue have been developed. Among them, a-hydroxylation and a-halogena-tion via asymmetric phase-transfer catalytic reactions by cinchona quaternary ammonium salts are described here. 

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... 

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... 

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.

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... 

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... 

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],... 

Phase-transfer catalysis has been widely been used for asymmetric epoxidation of enones [100]. This catalytic reaction was pioneered by Wynberg et al., who used mainly the chiral and pseudo-enantiomeric quaternary ammonium salts 66 and 67, derived from the cinchona alkaloids quinine and quinidine, respectively [101-105],... 

Chiral phase transfer catalysts have been exploited in a wide range of reactions which involve anionic intermediates. Remarkably, quaternary ammonium salts of 1 and 2 have been shown to induce asymmetry in many different synthetic reactions, and the cinchona alkaloids appear to be a charmed template for the design of effective phase transfer catalysts [14],... 

A first attempt to realize catalytic asymmetric fluorination under phase transfer conditions goes back to attempts by Cahard et al. [20] Quaternary ammonium salts of cinchona alkaloids were used as catalysts in the presence of TosNFtBu as F-source and 23 was employed as substrate. Unfortunately, enantioselectivities remained rather low. Very recently, Kim and Park have described a closely related system (Scheme 4) [21]. 

Hodge, P., Khoshdel, E. and Waterhouse, J. Michael reactions catalyzed by polymer-supported quaternary ammonium-salts derived from cinchona and ephedra alkaloids, J. Chem. Soc., Perkin Trans. 1, 1983, 2205-2209. 

As mentioned above, quaternary ammonium salts derived from cinchona alkaloids have occupied the central position as efficient PTCs in various organic transformations, especially in the asymmetric a-substitution reaction of carbonyl derivatives. A cinchona alkaloidal quaternary ammonium salt, which acts as a PTC in various organic reactions, is prepared by a simple and easy chemical transformation of the bridgehead tertiary nitrogen with a variety of active halides, mainly arylmethyl halides. Other moieties of cinchona alkaloids (the 9-hydroxy, the 6 -methoxy, or the 10,11-vinyl) are occasionally modified for the enhancement of both chemical and optical yields (Figure 6.4). 

Figure 6.4 Quaternary ammonium salts derived from cinchona alkaloids.

As shown in Scheme 8.2, chiral P-hydroxy-a-amino adds can be obtained by the Mukaiyama-type aldol reaction of aldehydes with glycine-derived enol silyl ethers using cinchona-based quaternary ammonium salts. In 2004, Castle and coworkers [9] found that dnchona-based quaternary ammonium salts such as 13 are also able to catalyze the dired aldol readion of aldehydes with the glydne donor 14 in the presence of a phosphazene base such as BTTP (t-butyliminotri(pyrrolidino)phos-... 

As discussed above, all of the cinchona-based quaternary ammonium salts used as catalysts gave only poor to moderate diastereoselectivities and enantioselectivities for direct aldol reactions. Quite recently, a highly enantioselective, catalytic, direct aldol reaction was realized by adopting the enamine catalysis approach [12], in which 9-amino-epi-cinchona alkaloids are employed as aminocatalysts [13, 14]. 

---