Asymmetric phase-transfer catalysts

B. Lygo, P. G. Wainwright, A New Class of Asymmetric Phase-Transfer Catalysts Derived from Cinchona Alkaloids - Application in the Enantioselective Synthesis of a-Amino Acids , Tetrahedron Lett., 1997, 38, 8595-8598. 

Since asymmetric phase-transfer catalysts normally contain highly lipophilic chiral organic frameworks, and are reluctant to enter the aqueous phase, the Makosza interfacial mechanism seems plausible. 

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 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. 

Bako later prepared mannose-derived crown ethers 3 in which the macrocyde and six-membered ring are cis-fused [12]. Crown ethers 3 were also found to be highly enantioselective phase-transfer catalysts, and compound 3a catalyzed the asymmetric synthesis of compound 5a in 37% yield and with 92% ee in favor of the (S)-enantiomer. In contrast, crown ethers 4 - which lack a fused ring junction -were found to be relatively poor asymmetric phase-transfer catalysts for the reaction shown in Scheme 8.3. The best results in this case were also obtained with the N-unsubstituted compound 4a, which gave compound 5a in 38% yield and with just 67% ee [13]. 

Whilst the use of Taddol as an asymmetric phase-transfer catalyst for asymmetric Michael reactions was only moderately successful, it was much more enantioselec-tive in catalyzing alkylation reactions. For this study, Belokon and Kagan employed alanine derivatives lib and 16a-c as substrates, and investigated their alkylation with benzyl bromide under solid-liquid phase-transfer conditions in the presence of 10 mol % of Taddol to form a-methyl phenylalanine, as shown in Scheme 8.8. The best results were obtained using the isopropyl ester of N-benzylidene alanine 16b as substrate and sodium hydroxide as the base. Under these conditions, (R)-a-methyl phenylalanine 17 could be obtained in 81% yield and with 82% ee [19]. Under the same reaction conditions, substrate 16b reacted with allyl bromide to give (R)-Dimethyl allylglycine in 89% yield and with 69% ee, and with (l-naphthyl)methyl chloride to give (R)-a-methyl (l-naphthyl)alanine in 86% yield and with 71% ee [20]. 

The use ofTaddol as an asymmetric phase-transfer catalyst has been adopted by other research groups. For example, Jaszay has used Taddol for Michael additions to a-aminophosphonate derivative 20, as shown Scheme 8.10 [22]. A range ofTaddol derivatives was investigated, but the best results were again obtained with the same catalyst employed by Belokon and Kagan. Thus, phosphoglutamic acid derivative 21 was obtained in 95% yield and with 72% ee when tert-butyl acrylate was employed as the Michael acceptor. 

Use of Nobin and Related Species as Asymmetric Phase-Transfer Catalysts... 

A major breakthrough in the use of Nobin as an asymmetric phase-transfer catalyst came when Belokon and coworkers applied it to the alkylation of glycine-derived nickel(II) complex 11a under the conditions shown in Scheme 8.13 [25], Representative results are given in Table 8.1, which illustrate that benzylic and allylic halides react very rapidly and highly enantioselectively to produce a-amino acids. Intrigu-ingly, in this case (R)-Nobin catalyzes the formation of (R)-amino acids, which is the opposite enantioselectivity to that observed for the alkylation of alanine derivative 16b [21,24],... 

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 use of iso-Nobin derivatives 27 as asymmetric phase-transfer catalysts for the alkylation of substrate 11a was also investigated [30], The N-acylated derivatives 27c and 27d were again found to be the most enantioselective catalysts and, under identical conditions to those employed for Nobin (see Scheme 8.13), were only slightly less enantioselective than Nobin 24. Thus, catalyst 27d generated phenylalanine in 70% yield and with 92% ee, compared to a 90% yield with 97% ee obtained with Nobin 24, both after an 8- to 9-min reaction time in DCM. However, whereas when Nobin was used as the catalyst, the (R)-enantiomcr of the catalyst generated (R)-amino acids, the use of the (S)-enantiomers of catalysts 27b-d gave (R)-amino acids. 

The first metal(salen) complex investigated as an asymmetric phase-transfer catalyst was methionine-derived sulfonium salt 29. It was anticipated that the sulfonium salt... 

The low level of asymmetric induction obtained with nickel(salen) complexes was not synthetically usefiil, but did prove that the concept of using metal(salen) complexes as asymmetric phase-transfer catalysts was feasible. Fortunately, changing... 

Table 8.2 Use of complexes 29-32 as asymmetric phase-transfer catalysts for the benzylation of substrate 16b.

Table 8.3 U se of complex 33 as an asymmetric phase-transfer catalysts for the alkylation of substrate 16a.

Since both nickel(II) and copper(II)(salen) complexes have been found to form asymmetric phase-transfer catalysts, the use of other metal(salen) complexes was investigated. Cobalt(salen) complexes 42a-d provided an opportunity to probe the influence of the oxidation state of the metal on the catalytic activity of the complex [42]. Hence, each of these complexes was prepared and tested as a catalyst for the benzylation of substrate 16a, according to the conditions specified in Scheme 8.18. 

Very recently, Belokon and North have extended the use of square planar metal-salen complexes as asymmetric phase-transfer catalysts to the Darzens condensation. These authors first studied the uncatalyzed addition of amides 43a-c to aldehydes under heterogeneous (solid base in organic solvent) reaction conditions, as shown in Scheme 8.19 [47]. It was found that the relative configuration of the epoxyamides 44a,b could be controlled by choice of the appropriate leaving group within substrate 43a-c, base and solvent. Thus, the use of chloro-amide 43a with sodium hydroxide in DCM gave predominantly or exclusively the trans-epoxide 44a this was consistent with the reaction proceeding via a thermodynamically controlled aldol condensation... 

Currently, this area is not as well developed as the use of cinchona alkaloid derivatives or spiro-ammonium salts as asymmetric phase-transfer catalysts, and the key requirements for an effective catalyst are only just becoming apparent. As a result, the enantioselectivities observed using these catalysts rarely compete with those obtainable by ammonium ion-derived phase-transfer catalysts. Nevertheless, the ease with which large numbers of analogues - of Taddol, Nobin, and salen in particular- can be prepared, and the almost infinite variety for the preparation of new, chiral metal(ligand) complexes, bodes well for the future development of more enantioselective versions of these catalysts. 

Research by M. Ikunaka showed that C2-symmetrical chiral quaternary ammonium salts can serve as asymmetric phase-transfer catalysts." To prepare significant quantities of (R)-3,5-dihydro-4/-/-dinaphth[2,1-c T,2 -e]azepine, a novel short and scalable synthetic approach was undertaken. The synthesis commenced with the triflation of (R)-binol to give the b/s-O-triflate. The Kumada cross-coupling was used to install two methyl groups in good yield. 

This reaction is a step in the synthesis of the diuretic indacrinone (Hughes et al., 1987) and uses a quaternary salt of a cinchona alkaloid (E) as an asymmetric phase-transfer catalyst (Wynberg, 1986). The product enolate (F) formed from the ketone is a precursor of indacrinone... 

The benefits of phase transfer catalysts (PTCs) within organic synthesis have been well-documented for some time and it is the mild reaction conditions required, along with their environmental compatibility, and the ability to scale up these processes, which has established PTCs as useful reagents. Asymmetric phase transfer catalysts have also found extensive utility, particularly in intermolecular alkylation... 

Cinchona Alkaloid Derivatives as Asymmetric Phase-transfer Catalysts... 

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