Chiral compounds phase-transfer catalysts

Of course, the most practical and synthetically elegant approach to the asymmetric Darzens reaction would be to use a sub-stoichiometric amount of a chiral catalyst. The most notable approach has been the use of chiral phase-transfer catalysts. By rendering the intermediate etiolate 86 (Scheme 1.24) soluble in the reaction solvent, the phase-transfer catalyst can effectively provide the enolate with a chiral environment in which to react with carbonyl compounds. 

In the following example, although the synthesis of the azoniaspirocycle does not involve an acyclic compound, the reaction itself is very similar to those described in this section, hence its inclusion here (Equation 34). Maruoka and co-workers have designed a C2-symmetric chiral quarternary ammonium salt, which is then employed as a phase-transfer catalyst in an enantioselective alkylation <1999JA6519, 2001JFC(112)95, 2004TA1243>. 

Numbers of asymmetric phase transfer catalysis can now be accomplished efficiently to give a variety of chiral non-racemic products with high enantiomeric excesses. Thus, asymmetric phase transfer catalysis has grown up into practical level in numbers of reactions and some optically pure compounds can be effectively produced on large scale by use of chiral phase transfer catalysts. 

W. Nerinckx, M. Vandewalle, Asymmetric Alkylation of a-Aryl Substituted Carbonyl Compounds by Means of Chiral Phase Transfer Catalysts. Applications for the Synthesis of (+)-Podocarp-8(14)-en-13-one and of (-)-Wy-16,225, A Potent Analgesic Agent , Tetrahedron Asymmetry 1990,1, 265-276. 

Acyloxy-l-cyanoalkanes [45, 46], which can be used as precursors for ketones [47], a-hydroxy ketones [48] and 1,4-dicarbonyl compounds [47], are prepared in one pot from the appropriate aldehyde, sodium or potassium cyanide, and the acylating agent under phase-transfer catalytic conditions [47-49]. Attempts to synthesize chiral cyanhydrins using chiral phase-transfer catalysts have been unsuccessful (see Section 12.3). 

Quaternary ammonium salts of heterocyclic compounds have been used in liquid-liquid phase-transfer syntheses. When these compounds are achiral, they show a behavior very similar to that of other quaternary ammonium salts. For example, 2-dialkylamino-l-alkylpyridinium tetrafluoroborates have been used by Tanaka and Mukayama282 in the alkylation of active methylene compounds PhCH2CN, PhCH(Et)CN, and PhCH(Me)COPh. However, comparative studies of the efficiency of the catalysts show that alkylpyridinium bromides283 or N-alkyl-Af-benzyl-piperidinium chloride284 have a smaller catalytic activity compared to tetraalkylammonium halides. McIntosh285 has described the preparation of azapropellane salts 186 as potential chiral phase transfer catalysts. 

As mentioned above, the enantioselective Michael addition of P-keto esters to a,P-unsaturated carbonyl compounds represents a useful method for the construction of densely functionalized chiral quaternary carbon centers. One characteristic feature of designer chiral phase-transfer catalyst lh in this type of transformation is that it enables the use of a,p-unsaturated aldehydes as an acceptor, leading to the... 

The use of chiral crown ethers as asymmetric phase-transfer catalysts is largely due to the studies of Bako and Toke [6], as discussed below. Interestingly, chiral crown ethers have not been widely used for the synthesis of amino acid derivatives, but have been shown to be effective catalysts for asymmetric Michael additions of nitro-alkane enolates, for Darzens condensations, and for asymmetric epoxidations of a,P-unsaturated carbonyl compounds. 

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. 

Use of an organocatalyst in a highly diastereoselective nitroaldol reaction was reported by the Corey group in the synthesis of 123 [128]. This compound is a key building block in the synthesis of the HIV-protease inhibitor amprenavir. The alkaloid-based fluoride salt, 122, was used as an efficient chiral phase-transfer catalyst (this type of catalyst was developed by the same group [129-131]) and led to formation of the (2R,3S) diastereomer (2H,3S)-123 in 86% yield and with a diastereo-meric ratio of d.r. = 17 1 (Scheme 6.53) [128], It is worthy of note that a much... 

A procedure for alkylation of C=0 double bonds in the presence of (metal-free) organocatalysts and non-metallic nucleophiles has been reported by the Iseki group for trifluoromethylation of aldehydes and ketones [185]. On the basis of a previous study of the Olah group [186, 187] which showed the suitability of non-chiral phase-transfer catalysts for trifluoromethylation of carbonyl compounds, Iseki et al. investigated the use of N-benzylcinchonium fluoride, 182, as a chiral catalyst. The reaction has been investigated with several aldehydes and aromatic ketones. Trifluoromethyltrimethylsilane, 181, was used as nucleophile. The reaction was, typically, performed at —78 °C with a catalytic amount (10-20 mol%) of 182, followed by subsequent hydrolysis of the siloxy compound and formation of the desired alcohols of type 183 (Scheme 6.82). 

Asymmetric Alkylation. 7Y-[4-(Trifluoromethyl)benzyl]-cinchoninium bromide (1) has been used as chiral phase-transfer catalyst in the alkylation of indanones (eq 1). For the alkylation of a-aryl-substituted carbonyl compounds the diastere-omeric 7Y-[4-(trifluoromethyl)benzyl]cinchonidinium bromide (2) was used to obtain the opposite stereochemistry (eqs 2 and 3). The asymmetric alkylation of oxindoles was used as the key step in an asymmetric synthesis of (—)-physostigmine (eq 4). ... 

Until recently, little success had been achieved in developing a highly enantioselective version of the Darzens reaction. Several investigations of chiral phase-transfer catalysts for this condensation, in which low or modest asymmetric induction is obtained, have been reported. These include the use of N-alky -N-methylephedrinium halides, the quinine-derived salt (120), and polyamino acids. A related study has examined the use of achiral phase-transfer catalysts in the condensations of carbonyl compounds and the asymmetric chloromethylsulfonate ester (121). The same group of researchers subsequently reported similar studies employing the sulfonamides (122)-(124). ... 

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