Glycine asymmetric alkylation

A further example of the use of a chiral anion in conjunction with a chiral amine was recently reported by Melchiorre and co-workers who described the asymmetric alkylation of indoles with a,P-unsaturated ketones (Scheme 65) [212]. The quinine derived amine salt of phenyl glycine (159) (10-20 mol%) provided the best platform with which to perform these reactions. Addition of a series of indole derivatives to a range of a,P-unsaturated ketones provided access to the adducts with excellent efficiency (56-99% yield 70-96% ee). The substrates adopted within these reactions is particularly noteworthy. For example, use of aryl ketones (R = Ph), significantly widens the scope of substrates accessible to iminium ion activation. Expansion of the scope of nucleophiles to thiols [213] and oximes [214] with similar high levels of selectivity suggests further discoveries will be made. 

The synthesis of substituted glutamic acid analogues has been pursued by many routest94-106 using asymmetric alkylation, Simmons-Smith reactions, Diels-Alder reactions, and nickel complexes of glycine or alanine equivalents. 

The fate of the onium carbanion Q+R incorporated into the organic phase depends on the electrophilic reaction partner. The most studied area in the asymmetric phase-transfer catalysis is that of asymmetric alkylation of active methylene or methine compounds with alkyl halides, in an irreversible manner. The reaction mechanism illustrated above is exemplified by the asymmetric alkylation of glycine Schiff base (Scheme 1.5) [8]. 

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... 

Catalytic asymmetric alkylation of 1 has also been carried out with polymer-bound glycine substrates. For example, O Donnell and coworkers used Wang resin-bound derivative 11 in combination with BEMP or BTPP and 4d, as exemplified in Scheme 2.7 [25]. Although a full equivalent of 4d was required, the promising stereoselectivities provided strong implications for further optimizations. 

In addition to the glycinate Schiff base 1, glycine amide derivatives can be used as prochiral substrates for asymmetric alkylation under phase-transfer conditions. Kumar and Ramachandran examined the benzylation of various Schiff bases of... 

The salient feature of le as a chiral phase-transfer catalyst is its ability to catalyze the asymmetric alkylation of glycine methyl and ethyl ester derivatives 4 and 5 with excellent enantioselectivities. Since methyl and ethyl esters are certainly more susceptible towards nucleophilic additions than tert-butyl ester, the synthetic advantage of this process is clear, and highlighted by the facile transformation of the alkylation products (Scheme 5.3) [8],... 

The Maruoka group s further efforts toward simplification of the catalyst have led to the design of new, polyamine-based chiral phase-transfer catalysts of type 15, with expectation of the multiplier effect of chiral auxiliaries, as illustrated in Scheme 5.10 [13]. The chiral efficiency of such polyamine-based chiral phase-transfer catalysts (S)-15 was examined by carrying out an asymmetric alkylation of glycine derivative 2 under phase-transfer conditions. Among various commercially available polyamines, spermidine- and spermine-based polyammonium salts were found to show moderate enantioselectivity. In particular, the introduction of a 3,4,5-trifluor-ophenyl group at the 3,3 -positions of chiral binaphthyl moieties showed excellent asymmetric induction. 

Metal-based asymmetric phase-transfer catalysts have mainly been used to catalyze two carbon-carbon bond-forming reactions (1) the asymmetric alkylation of amino acid-derived enolates and (2) Darzens condensations [5]. The alkylation ofprochiral glycine or alanine derivatives [3] is a popular and successful strategy for the preparation of acyclic a-amino acids and a-methyl-a-amino acids respectively (Scheme 8.1). In order to facilitate the generation of these enolates and to protect the amine substituent, an imine moiety is used to increase the acidity of the a-hydrogens, and therefore allow the use of relatively mild bases (such as metal hydroxides) to achieve the alkylation. In the case of a prochiral glycine-derived imine (Scheme 8.1 R3 = H), if monoalkylation is desired, the new chiral methine group... 

The very short reaction times required for the alkylation of substrate 11a with benzylic bromides using Nobin as an asymmetric phase-transfer catalyst are important for the synthesis of 18F-fluorinated amino adds for use in positron-emission tomography (PET)-imaging studies. Thus, Krasikova and Belokon have developed a synthesis of 2-[18F]fluoro-L-tyrosine and 6-[18F]fluoro-L-Dopa employing a (S)-Nobin-catalyzed asymmetric alkylation of glycine derivative 11a as the key step, as shown in Scheme 8.14 [29]. The entire synthesis (induding semi-preparative HPLC purification) could be completed in 110 to 120 min, which corresponds to one half-life of18 F. Both the chemical and enantiomeric purity of the final amino acids were found to be suitable for clinical use. 

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

The asymmetric alkylation of cyclic ketones, imines of glycine esters, and achiral, enolizable carbonyl compounds in the presence of chiral phase-transfer organoca-talysts is an efficient method for the preparation of a broad variety of interesting compounds in the optically active form. The reactions are not only highly efficient, as has been shown impressively by, e.g., the synthesis of enantiomerically pure a-amino acids, but also employ readily available and inexpensive catalysts. This makes enantioselective alkylation via chiral phase-transfer catalysts attractive for large-scale applications also. A broad range of highly efficient chiral phase-transfer catalysts is also available. 

Further great advances in the field of asymmetric alkylation reactions have been made by several groups working on chiral phase-transfer-catalyzed alkylation of glycinates (see also Section 3.1). A pioneer in this field is the O Donnell group [53, 54] who developed the first a-amino acid ester synthesis using this methodol-... 

Despite the great achievements made over the years in alkaloid-type asymmetric alkylation of glycinates, however, to the best of our knowledge commercial application of this method on an industrial scale for production of optically active a-amino acids has not yet been reported. Nevertheless, because of the high efficiency achieved by use of the state of the art of this methodology, the prerequisite for applications on industrial scale have now been realized, and commercial applications can be expected in the future. 

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. 

Asymmetric alkylations of the glycine derivative 3 have become the standard by which chiral phase transfer catalysts are judged, and enable the preparation of a wide range of unnatural... 

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 addition to the high efficiency and broad generality, the characteristic feature of the 32e-catalyzed asymmetric alkylation strategy is visualized by direct stereoselective introduction of two different side chains to glycine-derived aldimine... 

Scheme 8 Asymmetric alkylation of N-(diphenylmethylene)glycine isopropyl ester with benzyl bromide catalyzed by the dendronized catalysts shown in Fig. 25...

D-Glucose-derived oxazinones, which can be considered as chiral glycine derivatives, were also employed in asymmetric alkylation reactions [155]. The oxazinone represents a rigid... 

SCHEME 10.70 Chiral glycine derivatives such as d-glucose-derived oxazinones are useful in asymmetric alkylation reactions. 

Asymmetric alkylation of A-pro tec ted glycine ester 26 under phase-transfer catalysis conditions is the well-known method for the syntheses of a-amino acids [19]. Scheme... 

Using a IM KOH aq solution, it is possible to perform the asymmetric alkylation of the benzophenone glycine Schiff base with benzyl bromide using 10 mol% of 15 at room temperature, as shown in Figure 14. 

The asymmetric alkylation of glycine derivatives is one of the most simple methods by which to obtain optically active a-amino acids [31]. The enantioselective alkylation of glycine Schiff base 52 under phase-transfer catalysis (PTC) conditions and catalyzed by a quaternary cinchona alkaloid, as pioneered by O Donnell [32], allowed impressive degrees of enantioselection to be achieved using only a very simple procedure. Some examples of polymer-supported cinchona alkaloids are shown in Scheme 3.14. Polymer-supported chiral quaternary ammonium salts 48 have been easily prepared from crosslinked chloromethylated polystyrene (Merrifield resin) with an excess of cinchona alkaloid in refluxing toluene [33]. The use of these polymer-supported quaternary ammonium salts allowed high enantioselectivities (up to 90% ee) to be obtained. 

Scheme 11.5 Asymmetric alkylation of glycine Dpm amide Schiff base 28.

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