Cinchona alkaloid catalysts alkylation

One example is the optically active amino acid derivative (S)-20n which contains a bipyridyl substituent (Scheme 3.14). The alkylation reaction in the presence of the cinchona alkaloid catalyst 33 proceeds with 53% ee (83% yield of (S)-20n) and gave the desired enantiomerically pure a-amino acid ester (S)-20n in >99% ee after re-crystallization [43]. Subsequent hydrolysis of the optically pure (S)-20n furnished the desired unprotected a-amino acid 35. A different purification method, subsequent enzymatic resolution, reported by Bowler et al., furnished the a-amino acid product 35 with enantioselectivity of 95% ee [44],... 

The asymmetric synthesis of a-alkyl-a-amino acids using a chiral catalyst is a useful method for the preparation of both natural and unnatural amino acids. O Donnell et al. developed the cinchona alkaloid-catalyzed alkylation of glycine derivatives [49]. However, almost all of the chiral phase-transfer catalysts were restricted to cinchona alkaloid derivatives. In 1999, Maruoka and co-workers designed a chiral ammonium salt bearing a binaphthyl backbone as a chiral phase-transfer catalyst (10a) (Figure 10.11), and demonstrated its catalytic activity... 

Alkylation of protected glycine derivatives is one method of a-amino acid synthesis (75). Asymmetric synthesis of a D-cx-amino acid from a protected glycine derivative by using a phase-transfer catalyst derived from the cinchona alkaloids (8) has been reported (76). 

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. 

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. 

In 1997 the Corey [1] and Lygo [2] groups disclosed the use of N-(anthracenyl)methyl-modified Cinchona alkaloids (e.g., 1) as catalysts in phase transfer alkylations, which afforded remarkable enantiomeric excesses of up to 99%. During the ensuing years, these groups have expanded the scope and limitations of these catalysts, as summarized below. 

These reports have accelerated research investigations into improving the asymmetric alkylation of 1 in terms of catalytic activity and stereoselectivity, the result being the emergence of a series of appropriately modified cinchona alkaloid-based catalysts. The performance of the representative monomeric catalysts in the asymmetric benzylation and allylation of 1 are summarized in Table 2.1, in order to provide an overview of the relationship between the structure, activity and enantioselectivity. 

Table 2.1 Cinchona alkaloid-derived monomeric catalysts and their performance in the phase-transfer-catalyzed alkylation of 1. 

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. 

Consequently, Dehmlow and coworkers modified the cinchona alkaloid structure to elucidate the role of each ofthe structural motifs of cinchona alkaloid-derived chiral phase-transfer catalysts in asymmetric reactions. Thus, the quinoline nucleus of cinchona alkaloid was replaced with various simple or sterically bulky substituents, and the resulting catalysts were screened in asymmetric reactions (Scheme 7.2). The initial results using catalysts 8-11 in the asymmetric borohydride reduction of pivalophenone, the hydroxylation of 2-ethyl-l-tetralone and the alkylation of SchifF s base each exhibited lower enantiomeric excesses than the corresponding cinchona alkaloid-derived chiral phase-transfer catalysts [14]. 

Dehmlow and coworkers [17] compared the efficiency of monodeazadnchona alkaloid derivatives 14a-c in the enantioselective epoxidation of naphthoquinone 50 with that of cinchona alkaloid-derived chiral phase-transfer catalysts 15a-c (Table 7.7) (for comparison of the alkylation reaction, see Table 7.1). Interestingly, the non-natural cinchona alkaloid analogues 14a-c afforded better results than natural cinchona alkaloids 15a-c. The deazacinchonine derivatives 14a,b produced epoxidation product 51 in higher enantioselectivity than the related cinchona alkaloids 15a,b. Of note, catalyst 14c, which possessed a bulky 9-anthracenylmethyl substituent on the quaternary nitrogen, afforded the highest enantioselectivity (84% ee). 

The intramolecular alkylation of the enolate derived from phenylalanine derivatives 22a,b to form P-lactams 23a,b has also been achieved using Taddol as a chiral phase-transfer catalyst (Scheme 8.11) [23]. In this process, the stereocenter within enantiomerically pure starting material 22 is first destroyed and then regenerated, so that the Taddol acts as a chiral memory relay. Taddol was found to be superior to other phase-transfer catalysts (cinchona alkaloids, binol, etc.) in this reaction, and under optimal conditions (50 mol % Taddol in acetonitrile with BTPP as base), P-lactam 23b could be obtained with 82% et. The use of other amino acids was also studied, and the... 

Esters 16b,c are used in reactions catalyzed by cinchona alkaloid-based phase-transfer catalysts, since the size of the ester is important for efficient asymmetric induction in these reactions [35], However, the syntheses of esters 16b,c adds considerable cost to any attempt to exploit this chemistry on a commercial basis. Fortunately, it was possible to develop reaction conditions which allowed the readily available and inexpensive substrate 16a to be alkylated with high enantios-electivity using catalyst 33 and sodium hydroxide, as shown in Scheme 8.18 [36]. The key feature of this modified process is the introduction of a re-esterification step following alkylation of the enolate of compound 16a. It appears that under... 

The development of dimeric cinchona alkaloids as very efficient and practical catalysts for asymmetric alkylation of the N-protected glycine ester 18 was reported... 

Besides the glycinate ester derivatives described above, other types of enolate-forming compounds have proved to be useful substrates for enantioselective alkylation reactions in the presence of cinchona alkaloids as chiral PTC catalysts. The Corey group reported the alkylation of enolizable carboxylic acid esters of type 57 in the presence of 25 as organocatalyst [69]. The alkylations furnished the desired a-substituted carboxylate 58 in yields of up to 83% and enantioselectivity up to 98% ee (Scheme 3.23). It should be added that high enantioselectivity in the range 94-98% ee was obtained with a broad variety of alkyl halides as alkylation agents. The product 58c is a versatile intermediate in the synthesis of an optically active tetra-hydropyran. 

Catalytic asymmetric alkylations of 28 have also been carried out with polymer-bound glycine substrates [43], or in the presence of polymer-supported cinchona alkaloid-derived ammonium salts as immobilized chiral phase-transfer catalysts [44], both of which feature their practical advantages especially for large-scale synthesis. 

In an attempt to develop a PEG-supported version of a chiral phase-transfer catalyst the Cinchona alkaloid-derived ammonium salt 15 used by Corey and Lygo in the stereoselective alkylation of amino acid precursors was immobilized on a modified PEG similar to that used in the case of 13. The behaviour of the catalyst obtained 16, however, fell short of the expectations (Danelli et al. 2003). Indeed, while this catalyst (10 mol%) showed good catalytic activity promoting the benzy-lation of the benzophenone imine derived from tert-butyl glycinate in 92% yield (solid CsOH, DCM, -78 to 23 °C, 22 h), the observed ee was only 30%. Even if this was increased to 64% by maintaining the reac-... 

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