Alkylation asymmetric phase-transfer

K. Manabe, Asymmetric Phase-Transfer Alkylation Catalyzed by a Chiral Quaternary Phosphonium Salt with a Multiple Hydrogen-Bonding Site , Tetrahedron Lett. 1998, 39, 5807-5810. 

K. Manabe, Synthesis of Nobel Chiral Quaternary Phosphonium Salts with a Multiple Hydrogen-Bonding Site, and Their Application to Asymmetric Phase-Transfer Alkylation , Tetrahedron 1998, 54, 14465-14476. 

This asymmetric phase-transfer method has been applied to enantio-selective Robinson annelation as shown in Scheme 14 (41). First, alkylation of a 1-indanone derivative with the Wichtetie reagent as a methyl vinyl ketone equivalent in the presence of p-CF3BCNB gives the S-alkylation product in 92% ee and 99% yield. With 1 -(p-trifluoro-methylbenzyl)cinchonidinium bromide, a pseudo-enantiomeric diaste-reomer of p-CF3BCNB, as catalyst, the -alkylation product is obtained in 78% ee and 99% yield. These products are readily convertible to the... 

Lygo and Wainwright recently reported a detailed study of the asymmetric phase-transfer mediated epoxidation of a variety of acyclic a,P-unsaturated ketones of the chalcone type. The third-generation cinchona-derived quats (8c and 7c), related to those discussed earlier in the alkylation section and Scheme 10.4, gave the best inductions (89% ee, 88 to 89, Scheme 10.13 and 86% ee for the pseudoenantiomeric catalyst 7c to give, as product, the enantiomer of 89). 

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 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... 

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. 

Scheme 4.1 Synthesis of a-alkyl-a-amino acids via asymmetric phase-transfer catalytic alkylation ofbenzophenone imine glycine ester (A).

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... 

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. 

Table 5.5 Asymmetric phase-transfer alkylation of glycine amide Schiff base 22. 

Table 5.6 Asymmetric phase-transfer alkylation of protected glycine weinreb amides 23.

Despite numerous efforts to develop the asymmetric phase-transfer-catalyzed alkylation of 2 into a powerful method for the synthesis of natural and unnatural a-amino adds, the stereochemistry of the alkylation of 2 with chiral electrophiles has scarcely been addressed. 

The vast synthetic utility of the asymmetric phase-transfer alkylation of glycine Schiff base 2 has been realized by its successful application to the synthesis of various useful amino acid derivatives and natural products. 

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 6.2 Catalytic asymmetric phase-transfer alkylation of various electrophiles.

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... 

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. 

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]. 

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. 

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

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