Alkylations, asymmetric ammonium salt

The rearrangement of ammonium ylides 27 derived from chiral amines affords chiral 3-butenals 28 in modest yield120. Critical to the observed diaslereoface selectivity of the rearrangement is the substrate-directed alkylation of amines 26 to afford asymmetric ammonium salts. The observed asymmetric induction is consistent with rearrangement through a transition state conformation in which the more substituted carbon (RL) of the auxiliary occupies an exo orientation. 

In 1994, Kawara and Taguchi reported on the apphca-tion of the chiral alkyl quaternary ammonium salt derived from Z>-prohne in the asymmetric Michael addition of malonate to cychc enone. The enone moiety was activated via electrophilic iminium ion formation. The results indicated that the facial selectivity of enone at the time of... 

SCHEME 9.8. The chiral alkyl quaternary ammonium salt derived from L-proline in the asymmetric Michael addition of malonate to cychc enone. 

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. 

The first practical and efficient asymmetric alkylation by use of chiral phase-transfer catalysts was the alkylation of the phenylindanone 15 (R1=Ph), reported by the Merck research group in 1984.114-161 By use of the quaternary ammonium salt 7 (R=4-CF3i X=Br) derived from cinchonine, the alkylated products 16 were obtained in excellent yield with high enantiomeric excess, as shown in... 

The importance of chiral thiols and thioether linkages in biological systems has prompted intense investigation of the use of chiral amines [see e.g. 5-11] and ammonium salts [see e.g. 12] as agents for asymmetric induction in the Michael-type addition reaction. Considerable success has been achieved using chinchona alkaloids and their A-alkyl derivatives (see Chapter 12). 

Some organic reactions can be accomplished by using two-layer systems in which phase-transfer catalysts play an important role (34). The phase-transfer reaction proceeds via ion pairs, and asymmetric induction is expected to emerge when chiral quaternary ammonium salts are used. The ion-pair interaction, however, is usually not strong enough to control the absolute stereochemistry of the reaction (35). Numerous trials have resulted in low or only moderate stereoselectivity, probably because of the loose orientation of the ion-paired intermediates or transition states. These reactions include, but are not limited to, carbene addition to alkenes, reaction of sulfur ylides and aldehydes, nucleophilic substitution of secondary alkyl halides, Darzens reaction, chlorination... 

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... 

Rozwadowska and coworkers carried out the asymmetric alkylation of isoquino-line Reissert compounds under phase-transfer conditions using cinchonine-derived quaternary ammonium salts as catalysts. The best enantioselectivity was achieved in the benzylation and allylation of 1 -cyano-2-phenoxy carbonyl-1,2-dihydroisoquinoline (17) catalyzed by 2a (Scheme 2.14) [34]. 

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. 

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... 

As (—)-cinchonidine-derived ammonium salts have been mainly used as chiral PTCs in monomeric cinchona-PTCs via the asymmetric alkylation of 1, and have generally shown better results than those of others [e.g., derived from (+)-cinchonine, (—(-quinine, and (+)-quinidine], the Park-Jew group primarily prepared (—) -cinchonidine derivatives to identify both the optimal linker and best relationship of attachment for the two cinchona units, and to compare catalytic efficiency with that of monomeric cinchona-PTCs. 

In the Park-Jew group s systematic investigation, two types of catalyst - the 1,3-phenyl- and 2,7-naphthyl-based dimeric ammonium salts - were selected as an efficient skeleton of chiral PTCs for the catalytic asymmetric phase-transfer alkylation... 

Maruoka and coworkers also investigated the substantial reactivity enhancement of N-spiro chiral quaternary ammonium salt and simplification of its structure, the aim being to establish a truly practical method for the asymmetric synthesis of a-amino acids and their derivatives. As ultrasonic irradiation produces homogenization (i.e., very fine emulsions), it greatly increases the reactive interfacial area, which may in turn deliver a substantial rate acceleration in the liquid-liquid phase-transfer reactions. Indeed, sonication of the reaction mixture of 2, methyl iodide and (S,S)-lc (1 mol%) in toluene-50% KOH aqueous solution at 0 °C for 1 h gave rise to the corresponding alkylation product in 63% yield with 88% ee. Hence, the reaction was speeded up markedly, and the chemical yield and enantioselectivity were comparable with those of the reaction with simple stirring (0°C for 8h 64%, 90% ee) (Scheme 5.5) [10]. 

Scheme 6.15 Catalytic asymmetric alkylation using 2,2 -bimorpholinium ammonium salts.

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). 

Being inspired by Maruoka s results with the C2-symmetric binaphthyl-derived quaternary ammonium salt [21], Lygo and colleagues designed a quaternary ammonium salt 23, comprising conformationally flexible biphenyl units and commercially available chiral secondary amines [22], A library of 40 quaternary ammonium salt was synthesized and evaluated for their catalytic efficiency in the asymmetric alkylation of... 

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. 

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. 

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]. 

Lygo has extended his asymmetric alkylation methodology to the synthesis of bis-a-amino acids (Scheme 4) [11], Bis-amino acids, such as meso-diaminopirnelic acid, dityrosine and isodityrosine, are found in nature and are thought to act as cross-linking agents which stabilise structural proteins in plants and bacteria. For example, asymmetric alkylation of the Schiff base 3 with the dibromide 13, catalysed by the quaternary ammonium salt le, gave the bis-amino acid derivative 14 in >95% ee. 

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. 

The asymmetric organocatalytic transformation of a ketone into an alcohol may be realized with the combination achiral silanexhiral phase-transfer catalyst, such a quaternary ammonium salt. The final alcohol is then recovered by an additional hydrolytic step. The asymmetric reduction of aryl alkyl ketones with silanes has been reported (ee-values up to 70%), the catalysts utilized being ammonium fluorides prepared from the quinine/quinidine series (e.g., 18 in Scheme 11.6) [19]. (For experimental details see Chapter 14.21.1). The more appropriated silanes were (Me3SiO)3SiH or (MeO)3SiH (some examples are... 

Starting with enantioselectivities of below 10% ee at the beginning, a subsequent increase of the asymmetric induction was achieved when using individually made chinchona-derived quarternary ammonium salts. While /V-bcnzylchinchonium reached approximately 30% ee, the use of analogue p-substituted derivatives led to enantioselecivities of up to 60% ee. Subsequent process development led to an efficient enan-tioselective alkylation process with enantioselectivities of up to 94% ee... 

The nucleophilic character ofdialkyl sulfides is illustrated by their nucleophilic addition reaction with alkyl halides to form the corresponding sulfonium salts (35) (Scheme 13). Asymmetric sulfonium salts (36) have a tetrahedral configuration therefore, like the analogous chiral saturated carbon compounds, they can be resolved into optical enantiomers (see Chapter 6, p. 81). They are, however, generally less optically stable than sulfoxides, but in sulfonium salts the unshared electron pair can hold its configuration at ordinary temperatures, unlike nitrogen in quaternary ammonium salts, enabling their resolution to be achieved. 

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