Asymmetric PTCs

M. J. O Donnell, Asymmetric PTC Reactions. Part 1 Amino Acids , Phases - The Sachem Phase Transfer Catalysis Review 1998, Issue 4, pp. 5-8. 

Y. N. Belokon , K Kochetkov, T. D. Churkina, N. S. Ikonnikov, A A Chesnokov, O. V. Larionov, V. S. Parm ar, R. Kumar, H. R Kagan, Asymmetric PTC C-Alkylation Mediated by TADDOL-Novel Route to Enantiomeric-ally Enriched a-Alkyl-a-Amino Adds , Tetrahedron Asymmetry 1998, 9, 851-857. 

A powerful approach to the synthesis of a,p-epoxy carbonyls and related compounds is found in the Darzens reaction (Scheme 11.18b). In this context, the groups of and Arai " have investigated the asymmetric PTC-... 

Other chiral PTC alkylations of active methylene compounds leading to amino acid derivatives have been reported [24] as have other alkylations [25]. Several reported asymmetric PTC alkylations have been disputed [26-29]. 

The catalytic asymmetric epoxidation of electron-deficient olefins has been regarded as one of the most representative asymmetric PTC reactions, and various such systems have been reported (Scheme 3.12). Lygo reported the asymmetric epoxidation of chalcone derivatives through the use of NaOCl [30,31], while Shioiri and Arai used aqueous H202 as an oxidant, their results indicating hydrogen bonding between the catalyst and substrates because an OH functionality in the catalyst was essential... 

Several families of efficient chiral phase transfer catalysts are now available for use in asymmetric synthesis. To date, the highest enantiomeric excesses (>95% ee) are obtained using salts derived from cinchona alkaloids with a 9-anthracenylmethyl substituent on the bridgehead nitrogen (e.g. lb, 2b). These catalysts will be used to improve the enantiose-lectivity of existing asymmetric PTC reactions and will be exploited in other anion-mediated processes both in the laboratory and industrially. 

Catalytic Michael additions of a-nitroesters 38 catalyzed by a BINOL (2,2 -dihydroxy-l,r-bi-naphthyl) complex were found to yield the addition products 39 as precursors for a-alkylated amino acids in good yields and with respectable enantioselectivities (8-80%) as shown in Scheme 9 [45]. Asymmetric PTC (phase transfer catalysis) mediated by TADDOL (40) as a chiral catalyst has been used to synthesize enantiomeri-cally enriched a-alkylated amino acids 41 (up to 82 % ee) [46], A similar strategy has been used to access a-amino acids in a stereoselective fashion [47], Using azlactones 42 as nucleophiles in the palladium catalyzed stereoselective allyla-tion addition, compounds 43 were obtained in high yields and almost enantiomerically pure (Scheme 9) [48]. The azlactones 43 can then be converted into the a-alkylated amino acids as shown in Scheme 4. 

Another optimization study by Lygo s group revealed that only 1 mol% of catalyst 4 is sufficient to give almost the same results (Scheme 5.5) [7]. Under asymmetric PTC conditions using 4 as a catalyst, Lygo also reported that allyl alcohols with aromatic and aliphatic side chains could be converted directly to epoxyketones with moderate to good ee values [8]. 

We thank our colleagues at Hokkaido University and Kyoto University for the personal and scienhfic collaborations, and whose names appear in the references. Without their enthusiasm for orgarhc chemistry, our research in the field of asymmetric PTC would not have been achieved. 

Despite the great impact of PTC in organic synthesis since its discovery, catalytic asymmetric synthesis using chiral phase transfer catalysts has been poorly investigated for quite a long time, but has taken a fast growing pace in the last few years [58,59]. Only isolated examples [60] of asymmetric PTC appeared in the literature until O Donnell in 1989 reported the enantioselective PTC alkylation of the benzophenoneimine of glycine derivatives catalyzed by Cinchona alkaloid-derived ammonium salts (Scheme 14) [61]. 

The use of optically resolved PTC catalysts for the synthesis of enantiomerically pure compounds is no doubt an attractive field. Asymmetric PTC has become an important tool for both laboratory syntheses and industrial productions of enantiomerically enriched compounds. Recently, Lygo and coworkers [207-216] reported a new class of Cinchona alkaloid-derived quaternary ammonium PTC catalysts, which have been applied successfully in the enantioselective synthesis of a-amino acids, bis-a-amino acids, and bis-a-amino acid esters via alkylation [207-213] and in the asymmetric epoxidation of a/p-unsaturated ketones [214-216]. 

Asymmetric PTC is an important method in the synthesis of a-alkyl and a-amino acids. Belokon et al. [7] reported that the compound (47 ,57 )-2,2-dimethyl-Q ,Q ,Q , Q -tetra-phenyl-l,3-dioxolane-4,5-dimethanol (TADDOL) was used to catalyze the C-alkylation of C-H acids with alkyl halides to the asymmetric synthesis of a-methyl-substituted a-amino acids under PTC conditions. The alkylations of the substrate C-H acids with benzyl bromide or allyl bromide were conducted in dry toluene at ambient temperature with NaH or solid NaOH as base and TADDOL as a chiral promoter. The type of base is important in the asymmetric C-alkylation of C-H acids. 

More recent studies on asymmetric PTC Michael reactions involving ketones, have sown that the A-alkylated cinchonidinium cation 61 mediates the enantioselective conjugate addition of acetophenone to chalcones (Scheme 2.34) [103]. In the proposed transition state of the reaction, the acetophenone enolate and the a,P-enone are contact... 

Scheme 2.127 Asymmetric PTC intramolecular conjugate addition of indoles...

On the basis of the previous results. Park, Jew, and co-workers [101] developed in 2009 an efficient synthetic methodology for enantiomerically pure a-alkyl-a,3-diaminopropionic acid. They described the asymmetric PTC alkylation of Af(l)-Boc-2-phenyl-2-imidazoline-4-carboxylic acid /cr/-butyl esters (52) with propargyl, allyl, and substituted benzyl bromides under catalysis with the binaphthalene-derived PTC XXV (Scheme 8.19). Alkylated products were obtained in high yields with excellent enantioselectivities and their acidic hydrolysis furnished corresponding optically active a-alkyl-a,(3-diaminopropionic acids. Another example of PTC alkylation of heterocyclic compounds, namely 1-cyanotetrahydro-(3-carbolines using a binaphthyl-modified V-spiro-type catalyst L, was reported by Maruoka and co-workers [103]. 

Recently, asymmetric PTC using chiral quaternary ammonium salt 110 has proven to be an effective method for the enantioselective a-arylation of a-imino acid derivatives 108 via asymmetric nucleophilic aromatic substitution, to give a,a-disubstituted a-amino acids 111 in good to high enantiomeric purity (Scheme 8.22) [86]. 

Lygo et al. reported the asymmetric a-alkylation of 14 with allyl bromide 77 to obtain the almost enantiopure 78 as a key intermediate for the synthesis of aroylalanine derivatives like kynurenine (79) [32a]. This approach illustrates the high potential of asymmetric PTCs as it represents a powerful and direct protocol to access important naturally occurring L-tryptophan metabolites like kynurenine (79). Interestingly, the oxidative cleavage of... 

Over the past few decades, the increasing demand for optically pure compounds has stimulated the development of asymmetric PTC. The examination of asymmetric PTC by the use of structurally well-defined chiral, nonracemic catalysts began in the mid-1970s [4], and has continued at a fast pace to become one of the most active fields in asymmetric catalysis. Today, a large number of chiral phase-transfer catalysts with diverse structures have been developed, and their applications in asymmetric PTC have resulted in notable achievements. 

The aim of this chapter is to provide a general overview of this continuously growing field, focusing not only on the design of various types of chiral phase-transfer catalysts but also on their representative applications. In addition, the aim is to encourage chemists to direct their efforts toward further continuous development in asymmetric PTC. It is inevitable that some chiral phase-transfer catalysts and their appHcations are still missed in this chapter since there exists a vast amount of hterature on asymmetric PTC covering them. Fortunately, many previous books [5] and reviews [6] on this field may alleviate this problem. 

The development of efficient chiral phase-transfer catalysts is at the center of asymmetric PTC. Over the past 30 years, numerous chiral phase-transfer catalysts have been reported, and most of them can be divided into several different categories based on their activation modes and structures. 

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