Amino acid derivatives quaternary ammonium catalysts

Aldol and Related Condensations As an elegant extension of the PTC-alkylation reaction, quaternary ammonium catalysts have been efficiently utilized in asymmetric aldol (Scheme 11.17a)" and nitroaldol reactions (Scheme ll.lTb) for the constmction of optically active p-hydroxy-a-amino acids. In most cases, Mukaiyama-aldol-type reactions were performed, in which the coupling of sUyl enol ethers with aldehydes was catalyzed by chiral ammonium fluoride salts, thus avoiding the need of additional bases, and allowing the reaction to be performed under homogeneous conditions. " It is important to note that salts derived from cinchona alkaloids provided preferentially iyw-diastereomers, while Maruoka s catalysts afforded awh-diastereomers. 

The group of Arai and Nishida investigated the catalytic asymmetric aldol reaction between tert-butyl diazoacetate and various aldehydes under phase-transfer conditions with chiral quaternary ammonium chloride 4c as a catalyst. The reactions were found to proceed smoothly in toluene, even at —40°C, when using 50% RbOH aqueous solution as a base, giving rise to the desired aldol adducts 23 with good enantioselectivities. The resulting 23 can be stereoselectively transformed into the corresponding syn- or anti-P-hydroxy-a-amino acid derivatives (Scheme 2.20) [42],... 

The symmetrical quaternary ammonium salts 5-6 have also been shown to be effective reagents for the enantioselective alkylation of the Schiff base 3 under mild phase-transfer conditions [6]. Although results with the C2-symmetrical quaternary ammonium salt 5 were disappointing (entry 6, Table 1), the more rigid spiro ammonium salts 6 were much more effective catalysts. The rate and enantioselectivity of the benzylation of 3 was found to depend critically on the substituent R. With the ammonium salt 6c (R = / -Np), the reaction was complete within 30 min at 0 °C (entry 9, Table 1) and gave the amino acid derivative 4 with 95% ee, whereas the unsubstituted catalyst 6a (R = H) required a longer reaction time and gave 4 in only 79% ee (entry 7, Table 1). 

The power of this methodology lies in the ability to prepare unnatural amino acid derivatives by asymmetric alkylation of prochiral enolates. Several asymmetric alkylations of the alanine derivative 7, catalysed by the C2-symmetrical quaternary ammonium salt 6d, have been reported these reactions yield unnatural amino acids such as 8 in high enantiomeric excess (Scheme 2) [7]. The chiral salen complex 9 has also been shown to be an effective catalyst for the preparation of a,a-dialkyl a-amino acids [8, 9]. For example, benzylation of the Schiff base 10 gave the a-methyl phenylalanine derivative 11 in 92% ee (Scheme 3) [8]. Similar reactions have been catalysed by the TADDOL 12, and also give a,a-dialkyl a-amino acids in good enantiomeric excess [10]. 

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]. 

In the presence of chiral quaternary ammonium salt catalysts, not only amino acid-derived Schiff bases but also other active methine and methylene compounds can be alkylated under biphasic conditions in an enantioselective manner as exemplified in the first report on the successful... 

Five years later, a similar cinchona alkaloid-derived quaternary ammonium salt was applied for the alkylation of N-(diphenylmethylene) glycine tert-butyl ester by O Donnell et al. [17]. By using either 11b or 12a, both enantiomers of the alkylated products, which could be hydrolyzed to afford the chiral a-amino acids, were obtained in high yield with a maximum of 66% ee. Further optimization indicated that, with the corresponding 9-OH-protected catalyst 11c, the enantioselectivity could be enhanced to 81% ee [6bj. 

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 asymmetric alkylation of glycine derivatives constitutes a general means of accessing a wide range of natural and unnatural oc-amino acids.111 Recently it has been established that the quaternary ammonium salt, (lS,2S,4S,5/ ,l / )-l-anthracen-9-yl)methyl-2-[benzyloxy(quinolin-4-yl)methyl]-5-ethyl-l-azoniabicyclo [2.2.2]octane bromide, is a highly effective catalyst in the asymmetric liquid-liquid phase-transfer alkylation of tert-butyl AI-(diphenylmethylene)glycinate. Subsequent hydrolysis of the imine provides access to a wide range of a-amino acid fcrt-butyl... 

Generally, the chiral quaternary ammonium salts, derived from cinchona alkaloids [26, 28, 29, 46, 56-60] and C2-symmetric chiral binaphthyl or biaryl structures [61-68, 71-73, 77], were demonstrated to be very enantioselective catalysts for the asymmetric alkylation of 65a, and provided the corresponding chiral a-amino acids in over 95% ee in most cases. The tartaric acid-derived catalysts 48a [81] and 52 [84] and chiral guanidinium salts 53 [85] and 54 [86] were also found to be suitable for this alkylation reaction. However, in terms of catalytic activity, only a... 

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