Asymmetric phase-transfer catalysis alkylation

FIG. 7 Asymmetric phase transfer catalysis alkylation of glycine imine esters. 

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 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 phase-transfer benzylation of 2 with the catalyst (S)-12a having [1-naphthyl group on the 3,3 -position of the flexible biphenyl moiety proceeded smoothly at 0 °C to afford the corresponding alkylation product (R)-3 in 85% yield with 87% ee after 18 h. The origin of the observed chiral efficiency could be ascribed to the considerable difference in catalytic activity between the rapidly equilibrated, diaste-reomerichomo- and heterochiral catalysts namely, homochiral (S,S)-12a is primarily responsible for the efficient asymmetric phase-transfer catalysis to produce 3 with high enantiomeric excess, whereas the heterochiral (R,S)-12a displays low reactivity and stereoselectivity. 

Asymmetric phase-transfer catalysis with (S,S)-lg can be successfully extended to the stereoselective N-terminal alkylation of Gly-Ala-Phe derivative 61 (i.e., the asymmetric synthesis of tripeptides), where (S,S)-lg turned out to be a matched catalyst in the benzylation of DL-61, leading to the almost exclusive formation of DDL-62. This tendency for stereochemical communication was consistent in the phase-transfer alkylation of DDL-63, and the corresponding protected tetrapeptide DDDL-64 was obtained in 90% yield with excellent stereochemical control (94% de) (Scheme 5.30) [31]. 

Scheme 8.1 also illustrates an important feature of asymmetric phase-transfer catalysis, namely that the catalyst is involved in two different steps of the mechanism. Thus, the rate of reaction increases because the catalyst accelerates the substrate deprotonation step, but the asymmetric induction occurs during the subsequent enolate alkylation step. 

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. 

Some other very important events in the historic development of asymmetric organocatalysis appeared between 1980 and the late 1990s, such as the development of the enantioselective alkylation of enolates using cinchona-alkaloid-based quaternary ammonium salts under phase-transfer conditions or the use of chiral Bronsted acids by Inoue or Jacobsen for the asymmetric hydro-cyanation of aldehydes and imines respectively. These initial reports acted as the launching point for a very rich chemistry that was extensively developed in the following years, such as the enantioselective catalysis by H-bonding activation or the asymmetric phase-transfer catalysis. The same would apply to the development of enantioselective versions of the Morita-Baylis-Hillman reaction,to the use of polyamino acids for the epoxidation of enones, also known as the Julia epoxidation or to the chemistry by Denmark in the phosphor-amide-catalyzed aldol reaction. ... 

One class of application that readily highlights the enormous potential of asymmetric phase-transfer catalysis is the stereoselective ot-alkylation of different carbanion nucleophiles, in particular enolates. Although these types of transformations are most important in organic chemistry, there are stiU only a limited number of stereoselective catalytic methods available and the use of chiral PTCs represents one of the most versatile strategies to achieve such transformations. One example of special interest is the asymmetric a-alkylation of glycine Schiffbase 374 (Scheme 85)... 

The paramount importance of Michael additions as versatile C-C bond forming transformations was discussed in some detail earlier in this volume. Thus, it is not surprising that, besides the use of chiral PTCs in asymmetric a-alkylation reactions, their use for stereoselective Michael additions is one of the most carefully investigated reactions in asymmetric phase-transfer catalysis (328, 329). Accordingly, the additional use of this methodology in asymmetric total synthesis has been reported on several occasions. 

Martins, E. R Pliego, R. Jr. Unraveling the Mechanism of the Cinchoninium Ion Asymmetric Phase-Transfer-Catalyzed Alkylation Reaction. ACS Catalysis 2013,3,613-616. 

Efficient Asymmetric Alkylations via Chiral Phase-Transfer Catalysis Applications and Mechanism... 

Jew, Park and coworkers performed systematic investigations to develop a more efficient system for the asymmetric synthesis of a-alkylalanines by chiral phase-transfer catalysis [31]. Eventually, sterically more demanding 2-naphthyl aldi-mine tert-butyl ester 14 was identified as a suitable substrate, and its alkylation in the presence of stronger base rubidium hydroxide (RbOH) and 0(9)-allyl-N-2, 3, 4 -trifluorobenzyldihydrocinchonidinium bromide (6a) at lower reaction temperature led to the highest enantioselectivity (Scheme 2.11). 

Enantioselective Michael addition of glycine derivatives by means of chiral phase-transfer catalysis has been developed to synthesize various functionalized a-alkyl-a-amino acids. Corey utilized 4d as catalyst for asymmetric Michael addition of glycinate Schiff base 1 to a,(3-unsaturated carbonyl substrates with high enantioselectivity (Scheme 2.15) [35,36]. With methyl acrylate as an acceptor, the a-tert-butyl-y-methyl ester of (S)-glutamic acid can be produced, a functionalized glutamic acid... 

The chiral phase-transfer catalysis of le was further applied to the facile synthesis of L-Dopa ester and its analogue, which usually have been prepared by either asymmetric hydrogenation of eneamides or enzymatic processes, and tested as potential drugs for the treatment of Parkinson s disease. Phase-transfer-catalyzed alkylation of 2 with the requisite benzyl bromide 35a in toluene-50% KOH aqueous solution proceeded smoothly at 0 °C under the influence of (R,R)-le to furnish fully protected L-Dopa tert-butyl ester this was subsequently hydrolyzed to afford the corresponding amino ester 36a in 81% yield with 98% ee. Debenzylation of 36a under... 

Since the aldimine Schiff base 21 can be readily prepared from glycine, direct stereoselective introduction of two different side chains to 21 by appropriate chiral phase-transfer catalysis would provide an attractive, yet powerful, strategy for the asymmetric synthesis of structurally diverse a,a-dialkyl-a-amino acids. This possibility of a one-pot asymmetric double alkylation has been realized by using N-spiro chiral quaternary ammonium bromide le (Scheme 5.21). 

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. 

Whilst simple alkylations of enolates and Michael additions have been successfully catalyzed by phase-transfer catalysts, aldol-type processes have proved more problematic. This difficulty is due largely o the reversible nature of the aldol reaction, resulting in the formation of a thermodynamically more stable aldol product rather than the kinetically favored product. However, by trapping the initial aldol product as soon as it is formed, asymmetric aldol-type reactions can be carried out under phase-transfer catalysis. This is the basis of the Darzens condensation (Scheme 8.2), in which the phase-transfer catalyst first induces the deprotonation of an a-halo... 

Further, Jew and Park successfully applied the efficient phase-transfer catalysis of 32e to the asymmetric synthesis of a-alkyl serines using phenyl oxazoline derivative 55a as a requisite substrate. The reaction is general, and provides a practical access to a variety of optically active a-alkyl serines through acidic hydrolysis, as exemplified in Scheme 4.18 [52]. 

Enantioselective Michael addition of glycine derivatives by means of chiral phase-transfer catalysis has been developed to synthesize various functionalized a-alkyl-amino acids. Corey and colleagues utilized 30d as a catalyst for the asymmetric... 

Dolling UH, Davis P, Grabowski EJJ (1984) Efficient catalytic asymmetric alkylations, 1. Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysis. J Am Chem Soc 106 446... 

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. 

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... 

Dolling, U.-H. Davis, P. Grabowski, E. J. J., Efficient Catalytic Asymmetric Alkylations. 1. Enan-tioselective Synthesis of (+)-Indacrinone via Chiral Phase-Transfer Catalysis. / Am. Chem. Soc. 1984, 106, 446. 

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