Phase Nobin

Currently, the chiral phase-transfer catalyst category remains dominated by cinchona alkaloid-derived quaternary ammonium salts that provide impressive enantioselec-tivity for a range of asymmetric reactions (see Chapter 1 to 4). In addition, Maruoka s binaphthyl-derived spiro ammonium salt provides the best results for a variety of asymmetric reactions (see Chapters 5 and 6). Recently, some other quaternary ammonium salts, including Shibasaki s two-center catalyst, have demonstrated promising results in asymmetric syntheses (see Chapter 6), while chiral crown ethers and other organocatalysts, including TADDOL or NOBIN, have also found important places within the chiral phase-transfer catalyst list (see Chapter 8). 

Crown Ethers, Taddol, Nobin and Metal(salen) Complexes as Chiral Phase-Transfer Catalysts for Asymmetric Synthesis... 

In the following sections, progress made in asymmetric phase-transfer catalysis using chiral crown ethers, taddolates, Nobin and metal(salen) complexes is surveyed. Each section is further subdivided according to the reaction being catalyzed. 

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

Scheme 8.12 Alkylation of substrate 16b using Nobin as a phase-transfer catalyst.

Under solid-liquid phase-transfer conditions, amino adds 17 and 25a,b were obtained from reactions using benzyl bromide, allyl bromide and 1-chloromethylnaphthalene, respectively, as the alkylating agents in the presence of 10 mol% of (S)-Nobin. Products 17 and 25a were obtained with >90% yield and 67-68% ee, whilst product 25b was obtained in only 60% yield and with only 18% ee, presumably due to the lower reactivity of the benzylic chloride-based alkylating agent. 

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. 

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. 

Belokon and co-workers designed a glycine-derived nickel complex 60 and examined its asymmetric addition to methyl acrylate under phase-transfer conditions. The screening of various NOBIN and iso-NOBIN derivatives in combination with NaH as a base revealed that N-pivaloyl-iso-NOBIN (62b) proved to be highly efficient catalyst, affording the product 61 in 80% yield with 96% ee, as illustrated in Scheme 4.20 [59]. 

---