Phase cinchonidine-derived

A characteristic feature of this solid-phase amino acid synthesis is the use of the phosphazene bases 53 and 54 for the PTC alkylation reaction [64, 65]. Because these compounds, which are soluble in organic media, do not react with alkyl halides, both alkyl halide and phosphazene bases can be added together at the start of the reaction, which is useful practically [65], Cinchonine and cinchonidine-derived salts, e.g. 25, were found to be very efficient catalysts. Under optimum conditions the alkylation proceeds with enantioselectivity in the range 51-99% ee, depending on the alkyl halide component [65], Seventeen different alkyl halides were tested. After subsequent hydrolysis with trifluoroacetic acid the corresponding free amino acids were obtained in high yield (often >90%). 

Use of the preformed Z-silyl enol ether 18 results in quite substantial anti/syn selectivity (19 20 up to 20 1), with enantiomeric purity of the anti adducts reaching 99%. The chiral PT-catalyst 12 (Schemes 4.6 and 4.7) proved just as efficient in the conjugate addition of the N-benzhydrylidene glycine tert-butyl ester (22, Scheme 4.8) to acrylonitrile, affording the Michael adduct 23 in 85% yield and 91% ee [10]. This primary product was converted in three steps to L-ornithine [10]. The O-allylated cinchonidine derivative 21 was used in the conjugate addition of 22 to methyl acrylate, ethyl vinyl ketone, and cydohexenone (Scheme 4.8) [12]. The Michael-adducts 24-26 were obtained with high enantiomeric excess and, for cydohexenone as acceptor, with a remarkable (25 1) ratio of diastereomers (26, Scheme 4.8). In the last examples solid (base)-liquid (reactants) phase-transfer was applied. 

Asymmetric nucleophilic addition to C=C double bonds (see also Chapter 4) can also proceed highly stereoselectively. Several examples of enantio- and diastereo-selective Michael additions with 99% ee for the resulting products have been described by the Corey group [19]. A cinchonidine-derived phase-transfer organo-catalyst (10 mol%) was used. 

Asymmetric Michael additions can also be performed under phase-transfer conditions with an achiral base in the presence of a chiral quaternary ammonium salt as a phase-transfer agent. Conn and coworkers conducted the Michael addition of 2-propyl-l-indanone (13) to methyl vinyl ketone under biphasic conditions (aq 50% NaOH/toluene) using the cinchonine/cinchonidine-derived chiral phase-transfer catalysts (PTCs), 14a and 14b, as a catalyst (Scheme 9.5). However, only low to... 

Using molecular oxygen as the oxidizing agent, the Itoh group has achieved the enantioselective preparation of 3-allyl-3-hydroxyoxindole 90 (85% ee) under phase-transfer conditions with the cinchonidine derived catalyst 89 [54]. The oxindole 90 was further manipulated to a key intermediate that has been applied in a prior synthesis of the hexahydropyrroloindole CPC-1 [55] (Scheme 24). 

In 2008, Itoh and co-workers [66] successfully developed the first organocata-lyzed a-aminoxylation of oxyindoles using a cinchonidine-derived phase-transfer catalyst 29 and molecular oxygen (Scheme 12.7). In 2010, Barbas III and co-workers [67] designed a new dimeric quinidine catalyst 28 to synthesize the same kind of... 

An organocatalytic asymmetric hydroxylation of oxindoles by molecular oxygen as an oxidant using a phase-transfer catalyst was reported by Itoh et ai, in 2008. The use of O2 as the oxidant was a paramount process, because it is inexpensive and environmentally benign. In these conditions, the reaction of a series of 3-substituted oxindoles in the presence of a cinchonidine-derived... 

This synthesis, which was reported by a group of development chemists, represents a remarkably efficient application of asymmetric alkylation by chiral phase transfer catalysis (PTC) (see section 6.1.1). Reaction of indanone (77) and allylic halide (78) under PTC conditions in the presence of only a few per cent of chiral cinchonidine derivative... 

Complementary to the above-presented enantioselective sequences Michael addition/a-alkylation of bromomalonates, a related powerful gem-dialkylative process was also proposed recently [38]. a-Dialkylation of imines 25 with 1,4-dihalo-but-2-ene 26 using a cinchonidine derivative J as phase-transfer catalyst proceeded smoothly in the presence of aqueous NaOH to give the (l/ ,25)-l-amino-2-vinylcyclopropanecarboxylic acid derivatives 27 with generally good diastereose-lectivity but with enantiomeric excesses not exceeding 80% (Scheme 5.10). 

Recently, Lamaty and coworkers [70] demonstrated asymmetric phase-transfer catalyzed alkylation of fert-butyl glycinate-benzophenone Schiff base under solvent-free ball milling conditions (Scheme 21.33). The reaction proceeds with different alkylating agents in the presence of the cinchonidine-derived ammonium salt (10mol%) with very high yields (91-97%). This protocol reduces the reaction time however, the enantioselectivity (36-75% ee) is lower compared to conventional method with solvents (>90% ee) [71]. 

SCHEME 35.29. Asymmetric epoxidation of enones 106 using cinchonidine-derived, phase-transfer catalyst 105. 

Figure 12.3 Cinchonine- and cinchonidine-derived quaternary ammonium salt phase-transfer catalysts.

Epoxidation is another important area which has been actively investigated on asymmetric phase transfer catalysis. Especially, the epoxidation of various (i.)-a,p-unsaturated ketones 68 has been investigated in detail utilizing the ammonium salts derived from cinchonine and cinchonidine, and highly enantioselective and diastereoselective epoxidation has now been attained. When 30 % aqueons H202 was utilized in the epoxidation of various a, 3-unsaturated ketones 68, use of the 4-iodobenzyl cin-choninium bromide 7 (R=I, X=Br) together with LiOH in Bu20 afforded the a,p-epoxy ketones 88 up to 92% ee,1641 as shown in Table 5. The O-substituted... 

A limited study has been made of the role of the structure of the catalyst in the phase-transfer epoxidation reaction (77). The catalysts tried were mainly salts of quinine (3a-g), cinchonidine (4), ephedrine (5), and a camphor derivative (6) (Figure 14). The conclusions were as follows ... 

In simple experiments, particulate silica-supported CSPs having various cin-chonan carbamate selectors immobilized to the surface were employed in an enantioselective liquid-solid batch extraction process for the enantioselective enrichment of the weak binding enantiomer of amino acid derivatives in the liquid phase (methanol-0.1M ammonium acetate buffer pH 6) and the stronger binding enantiomer in the solid phase [64]. For example, when a CSP with the 6>-9-(tcrt-butylcarbamoyl)-6 -neopentoxy-cinchonidine selector was employed at an about 10-fold molar excess as related to the DNB-Leu selectand which was dissolved as a racemate in the liquid phase specified earlier, an enantiomeric excess of 89% could be measured in the supernatant after a single extraction step (i.e., a single equilibration step). This corresponds to an enantioselectivity factor of 17.7 (a-value in HPLC amounted to 31.7). Such a batch extraction method could serve as enrichment technique in hybrid processes such as in combination with, for example, crystallization. In the presented study, it was however used for screening of the enantiomer separation power of a series of CSPs. 

Murugan and Siva developed a new procedure for such asymmetric aziridination reactions to achieve an excellent level of enantioselectivity using new chiral phase-transfer catalysts 2f and 4m derived from cinchonidine and cinchonine, respectively (Scheme 2.25) [47]. 

Dimeric phase-transfer catalysts were also reported by Najera et al., who used cinchonidine- and cinchonine-derived ammonium salts bearing a dimethyl-anthracenyl bridge as a spacer [32]. In the presence of these catalysts high enantioselectivity of up to 90% ee was obtained. 

Aldol reactions using a quaternary chinchona alkaloid-based ammonium salt as orga-nocatalyst Several quaternary ammonium salts derived from cinchona alkaloids have proven to be excellent organocatalysts for asymmetric nucleophilic substitutions, Michael reactions and other syntheses. As described in more detail in, e.g., Chapters 3 and 4, those salts act as chiral phase-transfer catalysts. It is, therefore, not surprising that catalysts of type 31 have been also applied in the asymmetric aldol reaction [65, 66], The aldol reactions were performed with the aromatic enolate 30a and benzaldehyde in the presence of ammonium fluoride salts derived from cinchonidine and cinchonine, respectively, as a phase-transfer catalyst (10 mol%). For example, in the presence of the cinchonine-derived catalyst 31 the desired product (S)-32a was formed in 65% yield (Scheme 6.16). The enantioselectivity, however, was low (39% ee) [65],... 

Three chiral stationary phases that were prepared by derivatizing y-mercaptopropylsilanized silica gel with quinine (CSP II), quinidine (CSP III), and cinchonidine (CSP IV), have been used for the successful resolution of N-acyl derivatives of fl-hydroxyphenethylamines [25]. UV and CD detectors set at 270 nm were used in series. The effectiveness of the separation and the detection are illustrated in Figure 6 for the resolution of the N-(3,5-dinitrobenzoyl) derivative of phenylethanolamine on CSP III. 

Using (2) as catalyst provided the (R) enantiomer in 99% yield, 78% ee. The key introduction of asynunetry during the synthesis of (+)-podocarp-8(14)-en-13-one was the phase-transfer-catalyzed Robinson annulation of 6-methoxy-l-methyl-2-tetralone with ethyl vinyl ketone. The authors carried out a comparative study of the A/-(4-trifluoromethyl)benzyl derivatives of cinchonine, cinchonidine, dihydrocinchonine, and dihydrocinchonidine and found that (5) produced the highest ee of the desired (S) enantiomer at —45 °C using toluene and 60% aq KOH (eq 10). ... 

As the cinchona alkaloids contain a nucleophilic nitrogen center, they can be alkylated at this position. Thus, cinchonidine reacts with benzyl chlorides to form quaternary salts, e.g., 9 and 108, which are useful as chiral phase-transfer catalysts (see Section D.1.5.2.4. for enantioselec-tive additions to azaenolates, and D.4.1. for the oxidation of enolates). Further modification by catalytic reduction of the double bond (hydrogen/platinum) leads to the corresponding dihydrocinchonidine derivatives. 

For many years applications of the Bradsher reaction were restricted due to its limited substrate scope and requirement for harsh reaction conditions. However, after the advancement of the arene oxide concept concerning the metabolism of polycyclic aromatic hydrocarbons, synthesis of all the nuclear monohydroxylated derivatives of 7,12-dimethylbenz[a]-anthracene (DMBA), diol epoxide metabolites of DMBA, and fluoro derivatives of DMBA was undertaken for carcinogenicity and mutagenicity determination studies. " Interest in the Bradsher reaction has increased greatly as a consequence of the need to construct these polycyclic aromatic hydrocarbons. Development of fluoroanthracenylmethyl cinchonidine as an efficient phase-transfer catalyst for asymmetric glycine alkylation also expanded the scope of the Bradsher reaction. ... 

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