Phase-transfer catalysis chiral, asymmetric

Early work on the use of chiral phase-transfer catalysis in asymmetric Darzens reactions was conducted independently by the groups of Wynberg [38] and Co-lonna [39], but the observed asymmetric induction was low. More recently Toke s group has used catalytic chiral aza crown ethers in Darzens reactions [40-42], but again only low to moderate enantioselectivities resulted. 

There have been several examples of multi-phase systems in asymmetric syntheses, notably a polymeric chiral rhodium hydrogenation catalyst for selectively producing i -amino-acids, and the use of phase-transfer catalysis in asymmetric carbon-carbon bond formation. The incorporation of optically active cinchona alkaloids, e.g. quinine (29), into a polymer by virtue of their vinyl group has been described, with preliminary results on application to asymmetric syntheses. At the other extreme of structural complexity, enzymes themselves have been incorporated into polymers to some advantage. ... 

In contrast the progress of asymmetric synthesis by use of chiral non-racemic phase transfer catalysts had been slow compared to the ordinary phase transfer catalysis. However, recent achievements in this particular area are noteworthy and efficient asymmetric phase transfer catalysis has been increasingly explored.17 101... 

Asymmetric a-hydroxylation of ketones 97 through phase transfer catalysis under alkaline conditions was realized by use of the Merck catalyst 7 (R=4-CF3, X=Br)[721 as well as the chiral azacrown ether 98[731 in conjunction with molecular oxygen, as shown in Scheme 30. The highest enantioselectivity of 79% ee was attained in the a-hydroxylation of the tetralone 100 by use of the Merck cata-... 

Numbers of asymmetric phase transfer catalysis can now be accomplished efficiently to give a variety of chiral non-racemic products with high enantiomeric excesses. Thus, asymmetric phase transfer catalysis has grown up into practical level in numbers of reactions and some optically pure compounds can be effectively produced on large scale by use of chiral phase transfer catalysts. 

In contrast to the maturity of asymmetric synthesis utilizing chiral transition metal catalysts, asymmetric phase transfer catalysis is still behind it and covers organic reactions to lesser extent. Thus, it is further necessary in wide range to explore efficient asymmetric phase transfer catalysis keeping its superiority of easy operation, mild reaction conditions, and environmental binignancy. 

Asymmetric phase-transfer catalysis using chiral nonra-cemic onium salts or crown ethers has now grown into a practical method whereby a large number of reactions can be performed and some optically pure compounds can be produced effectively on a large scale. 

Efficient Asymmetric Alkylations via Chiral Phase-Transfer Catalysis Applications and Mechanism... 

The epoxidation of enones using chiral phase transfer catalysis (PTC) is an emerging technology that does not use transition metal catalysts. Lygo and To described the use of anthracenylmethyl derivatives of a cinchona alkaloid that are capable of catalyzing the epoxidation of enones with remarkable levels of asymmetric control and a one pot method for oxidation of the aUyl alcohol directly into... 

Jew, Park and coworkers performed systematic investigations to develop a more efficient system for the asymmetric synthesis of a-alkylalanines by chiral phase-transfer catalysis [31]. Eventually, sterically more demanding 2-naphthyl aldi-mine tert-butyl ester 14 was identified as a suitable substrate, and its alkylation in the presence of stronger base rubidium hydroxide (RbOH) and 0(9)-allyl-N-2, 3, 4 -trifluorobenzyldihydrocinchonidinium bromide (6a) at lower reaction temperature led to the highest enantioselectivity (Scheme 2.11). 

Enantioselective Michael addition of glycine derivatives by means of chiral phase-transfer catalysis has been developed to synthesize various functionalized a-alkyl-a-amino acids. Corey utilized 4d as catalyst for asymmetric Michael addition of glycinate Schiff base 1 to a,(3-unsaturated carbonyl substrates with high enantioselectivity (Scheme 2.15) [35,36]. With methyl acrylate as an acceptor, the a-tert-butyl-y-methyl ester of (S)-glutamic acid can be produced, a functionalized glutamic acid... 

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. 

The phase-transfer benzylation of 2 with the catalyst (S)-12a having [1-naphthyl group on the 3,3 -position of the flexible biphenyl moiety proceeded smoothly at 0 °C to afford the corresponding alkylation product (R)-3 in 85% yield with 87% ee after 18 h. The origin of the observed chiral efficiency could be ascribed to the considerable difference in catalytic activity between the rapidly equilibrated, diaste-reomerichomo- and heterochiral catalysts namely, homochiral (S,S)-12a is primarily responsible for the efficient asymmetric phase-transfer catalysis to produce 3 with high enantiomeric excess, whereas the heterochiral (R,S)-12a displays low reactivity and stereoselectivity. 

The chiral phase-transfer catalysis of le was further applied to the facile synthesis of L-Dopa ester and its analogue, which usually have been prepared by either asymmetric hydrogenation of eneamides or enzymatic processes, and tested as potential drugs for the treatment of Parkinson s disease. Phase-transfer-catalyzed alkylation of 2 with the requisite benzyl bromide 35a in toluene-50% KOH aqueous solution proceeded smoothly at 0 °C under the influence of (R,R)-le to furnish fully protected L-Dopa tert-butyl ester this was subsequently hydrolyzed to afford the corresponding amino ester 36a in 81% yield with 98% ee. Debenzylation of 36a under... 

Since the aldimine Schiff base 21 can be readily prepared from glycine, direct stereoselective introduction of two different side chains to 21 by appropriate chiral phase-transfer catalysis would provide an attractive, yet powerful, strategy for the asymmetric synthesis of structurally diverse a,a-dialkyl-a-amino acids. This possibility of a one-pot asymmetric double alkylation has been realized by using N-spiro chiral quaternary ammonium bromide le (Scheme 5.21). 

The catalytic asymmetric epoxidation of electron-deficient olefins, particularly a,P-unsaturated ketones, has been the subject of numerous investigations, and as a result a number of useful methodologies have been elaborated [44], Among these, the method utilizing chiral phase-transfer catalysis occupies a unique position in terms of its practical advantages. Moreover, it also allows the highly enantioselective epoxidation of trans-a,P-unsaturated ketones, particularly chalcone. 

A biphenyl and ct-methylnaphthylamine-derived chiral quaternary ammonium salt 23d, which was shown by Lygo to be effective for the asymmetric alkylation of Schiffs base 20, was also effective in the Michael reaction (Scheme 7.12) [43]. Notably, the enantioselectivity was highly dependent on the reaction conditions and substrates used. The Michael reaction of imine esters such as benzhydryl and benzyl esters with a,p-unsaturated ketones under solid-liquid phase-transfer catalysis conditions afforded the Michael adduct in up to 94% ee and 91% ee, respectively, while the tert-butyl ester showed moderate enantioselectivity (Scheme 7.12). Interestingly, in contrast to earlier reports, acrylate [42] and acrylamides failed to undergo the Michael reaction under these optimized conditions. 

Asymmetric epoxidation catalyzed by chiral phase-transfer catalysts is another reaction which has been extensively studied following an initial report by Wynberg [2,44]. Shioiri et al. further improved the enantioselective epoxidation of naphthoquinones under cinchona alkaloid-derived chiral phase-transfer catalysis [45],... 

Neutral cyclodextrins have been used as chiral phase-transfer catalysts for an interesting inverse phase-transfer catalysis reaction [50]. The Markovnikovhydration of the double bond by an oxymercuration-demercuration reaction has been demonstrated in the presence of cyclodextrins as chiral phase-transfer catalysts to obtain products in low to moderate enantioselectivity (Scheme 7.16). The mercuric salts are water-soluble, and remain in the aqueous phase, whereas the neutral alkenes prefer an organic phase. A neutral cyclodextrin helps to bring the alkenes into the aqueous phase in a biphasic reaction, and also provides the necessary asymmetric environment. 

In the following sections, progress made in asymmetric phase-transfer catalysis using chiral crown ethers, taddolates, Nobin and metal(salen) complexes is surveyed. Each section is further subdivided according to the reaction being catalyzed. 

The aim of this book is to provide a concise and comprehensive treatment of this continuously growing field of catalysis, focusing not only on the design of the various types of chiral phase-transfer catalyst but also on the synthetic aspects of this chemistry. In addition, the aim is to promote the synthetic applications of these asymmetric phase-transfer reactions by giving solid synthetic evidence. Clearly, despite recent spectacular advances in this area, there is still plenty of room for further continuous development in asymmetric phase-transfer catalysis. 

In the Michael-addition, a nucleophile Nu is added to the / -position of an a,fi-unsaturated acceptor A (Scheme 4.1) [1], The active nucleophile Nu is usually generated by deprotonation of the precursor NuH. Addition of Nu to a prochiral acceptor A generates a center of chirality at the / -carbon atom of the acceptor A. Furthermore, the reaction of the intermediate enolate anion with the electrophile E+ may generate a second center of chirality at the a-carbon atom of the acceptor. This mechanistic scheme implies that enantioface-differentiation in the addition to the yfi-carbon atom of the acceptor can be achieved in two ways (i) deprotonation of NuH with a chiral base results in the chiral ion pair I which can be expected to add to the acceptor asymmetrically and (ii) phase-transfer catalysis (PTC) in which deprotonation of NuH is achieved in one phase with an achiral base and the anion... 

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],... 

In the metal-free epoxidation of enones and enoates, practically useful yields and enantioselectivity have been achieved by using catalysts based on chiral electrophilic ketones, peptides, and chiral phase-transfer agents. (E)-configured acyclic enones are comparatively easy substrates that can be converted to enantiomeri-cally highly enriched epoxides by all three methods. Currently, chiral ketones/ dioxiranes constitute the only catalyst system that enables asymmetric and metal-free epoxidation of (E)-enoates. There seems to be no metal-free method for efficient asymmetric epoxidation of achiral (Z)-enones. Exocyclic (E)-enones have been epoxidized with excellent ee using either phase-transfer catalysis or polyamino acids. In contrast, generation of enantiopure epoxides from normal endocyclic... 

Lygo, B. and Andrews, B.I. (2004) Asymmetric phase-transfer catalysis utilizing chiral quaternary ammonium salts asymmetric alkylation of glycine imines. Ace. Chem. Res., 37, 518. 

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