Phase-transfer, chiral anion

The phosphonium salt 21 having a multiple hydrogen-bonding site which would interact with the substrate anion was applied to the phase transfer catalyzed asymmetric benzylation of the p-keto ester 20,[18 191 giving the benzylated P-keto ester 22 in 44% yield with 50% ee, shown in Scheme 7 Although the chemical yield and enantiomeric excess remain to be improved, the method will suggest a new approach to the design of chiral non-racemic phase transfer catalysts. 

Attempts to produce chiral cyanhydrins under phase-transfer catalytic conditions (3.3.9) using ephedrinium or cinchoninium catalysts has been singularly unsuccessful [21,22]. Optical purities varying from 0 to 60% have been recorded [22], but verification of the reproducibility of the higher values is needed. Similarly, nucleophilic attack on a carbonyl group by the trichloromethyl anion under phase-transfer catalytic conditions (see Section 7.4) in the presence of benzylquininium chloride produces a chiral product, but only with an enantiomeric excess of 5.7% [23]. The veracity of this observation has also been questioned [24],... 

These observations showed that the reaction can be simplified by preformation of the indanone enolate in toluene/50% NaOH and subsequent addition of catalyst and CH3CI (Figure 12). This eliminates the "induction period and most importantly the high sensitivity of rate and ee to the catalyst/indanone ratio. Detailed kinetic measurements on this preformed enolate methylation in toluene/50% NaOH determined that the reaction is 0.55 order in catalyst. This is consistent with our finding that the catalyst goes into solution as a dimer which must dissociate prior to com-plexation with the indanone anion. If the rate has a first order dependence on the monomer, the amount of monomer is very small, and the equilibration between dimer and monomer is fast, then the order in catalyst is expected to be 0.5. The 0.5 order in catalyst is not due to the preformation of solid sodium indanone enolate but is a peculiarity of this type of chiral catalyst. Vlhen Aliquat 336 is used as catalyst in this identical system the order in catalyst is 1. Finally, in the absence of a phase transfer catalyst less than 2% methylation was observed in 95 hours. 

There are only a few reports on chiral phase transfer mediated alkylations". This approach, which seems to offer excellent opportunities for simple asymmetric procedures, has been demonstrated in the catalytic, enantioselective alkylation of racemic 6,7-dichloro-5-methoxy-2-phenyl-l-indanone (1) to form ( + )-indacrinone (4)100. /V-[4-(tnfluoromethyl)phenylmethyl]cinchoninium bromide (2) is one of the most effective catalysts for this reaction. The choice of reaction variables is very important and reaction conditions have been selected which afford very high asymmetric induction (92% cc). A transition state model 3 based on ion pairing between the indanone anion and the benzylcinchoninium cation has been proposed 10°. 

Enantioselective aldol reactions also can be used to create arrays of stereogenic centers. Two elegant ot-amino anion approaches have recently been published. Fujie Tanaka and Carlos F. Barbas III of the Scripps Institute, La Jolla, have shown (Org. Lett. 2004,6,3541) that L-proline catalyzes the addition of the aldehyde 6 to other aldehydes with high enantio- and diastereocontroJ. Keiji Maruoka of Kyoto University has developed (J. Am. Chem. Soc. 2004,126,9685) a chiral phase transfer catalyst that mediates the addition of the ester 9 to aldehydes, again with high enantio- and diastcrcocontrol. 

Chiral a-methoxy aldehydes.2 The anion of 1 undergoes 1,2-addition to bcnzaldehyde in quantitative yield. The adduct can be methylated under phase-transfer conditions and then reduced3 to give the dithioacetal 2, from which the aldehyde 3 is liberated by reaction with I2 and NaIlC03.4 The optical yield of 3 is >70%. 

Alkylation Alkylation of the phenylindanone 31 with catalyst 3a by the Merck group demonstrates the reward that can accompany a careful and systematic study of a particular phase-transfer reaction (Scheme 10.3) [5d,5f,9,36], The numerous reaction variables were optimized and the kinetics and mechanism of the reaction were studied in detail. It has been proposed that the chiral induction step involves an ion-pair in which the enolate anion fits on top of the catalyst and is positioned by electrostatic and hydrogen-bonding effects as well as 71—71 stacking interactions between the aromatic rings in the catalyst and the enolate. The electrophile then preferentially approaches the ion-pair from the top (front) face, because the catalyst effectively shields the bottom-face approach. A crystal structure of the catalyst as well as calculations of the catalyst-enolate complex support this interpretation [9a,91]. Alkylations of related active methine compounds, such as 33 to 34 (Scheme 10.3), have also appeared [10,11]. 

Enantioselective catalytic alkylation is a versatile method for construction of stereo-genic carbon centers. Typically, phase-transfer catalysts are used and form a chiral ion pair of type 4 as an key intermediate. In a first step, an anion, 2, is formed via deprotonation with an achiral base this is followed by extraction in the organic phase via formation of a salt complex of type 4 with the phase-transfer organocata-lyst, 3. Subsequently, a nucleophilic substitution reaction furnishes the optically active alkylated products of type 6, with recovery of the catalyst 3. An overview of this reaction concept is given in Scheme 3.1 [1],... 

In the Michael-addition, a nucleophile Nu is added to the / -position of an a,fi-unsaturated acceptor A (Scheme 4.1) [1], The active nucleophile Nu is usually generated by deprotonation of the precursor NuH. Addition of Nu to a prochiral acceptor A generates a center of chirality at the / -carbon atom of the acceptor A. Furthermore, the reaction of the intermediate enolate anion with the electrophile E+ may generate a second center of chirality at the a-carbon atom of the acceptor. This mechanistic scheme implies that enantioface-differentiation in the addition to the yfi-carbon atom of the acceptor can be achieved in two ways (i) deprotonation of NuH with a chiral base results in the chiral ion pair I which can be expected to add to the acceptor asymmetrically and (ii) phase-transfer catalysis (PTC) in which deprotonation of NuH is achieved in one phase with an achiral base and the anion... 

In the phase-transfer processes discussed in Section 11.2 it is assumed that the anionic hydride source, i.e. borohydride or a hypervalent hydrosilicate, forms an ion-pair with the chiral cationic phase-transfer catalyst. As a consequence, hydride transfer becomes enantioselective. An alternative is that the nucleophilic activator needed to effect hydride transfer from a hydrosilane can act as the chiral inducer itself (Scheme 11.6). 

Chiral phase transfer catalysts have been exploited in a wide range of reactions which involve anionic intermediates. Remarkably, quaternary ammonium salts of 1 and 2 have been shown to induce asymmetry in many different synthetic reactions, and the cinchona alkaloids appear to be a charmed template for the design of effective phase transfer catalysts [14],... 

Two different epoxidation reactions have been studied using chiral phase transfer catalysts. The salts 22 and 23 have been used to catalyse the nucleophilic epoxidation of enones (e.g. 24) to give either enantiomer of epoxides such as 25 (Scheme 9) [17]. Once again, the large 9-anthracenylmethyl substituent is thought to have a profound effect on the enantio selectivity of the process. A similar process has been exploited by Taylor in his approach to the Manumycin antibiotics (e.g. Manumycin C, 26) [18]. Nucleophilic epoxidation of the quinone derivative 27 with tert-butyl hydroperoxide anion, mediated by the cinchonidinium salt la, gave the tx,/ -epoxy ketone 28 in >99.5% ee (Scheme 10). 

The enantio-determining step of nucleophilic additions to a-bromo-a,y -unsaturated ketones is mechanistically similar to those of nucleophilic epoxidations of enones, and asymmetry has also been induced in these processes using chiral phase-transfer catalysts [20]. The addition of the enolate of benzyl a-cyanoacetate to the enone 31, catalysed by the chiral ammonium salt 32, was highly diastereoselective and gave the cyclopropane 33 in 83% ee (Scheme 12). Good enantiomeric excesses have also been observed in reactions involving the anions of nitromethane and an a-cyanosulfone [20]. 

An exciting addition to the armoury of asymmetric phase transfer catalysed reactions has been the oxidative cyclisation of 1,5-dienes (Scheme 13) [21]. This tandem reaction process leads to the formation of tetrahydrofurans such as 35 in a single step from the open chain dienes 34. The step which determines the sense of asymmetry is the initial attack of permanganate anion, and this chiral information is efficiently relayed in the cyclisation to give products with three new stereogenic centres. For example, oxidation of the di-enone 34 with potassium permanganate, catalysed by the salt 36, gave the tetrahydrofuran 35 in 72% ee. 

Several families of efficient chiral phase transfer catalysts are now available for use in asymmetric synthesis. To date, the highest enantiomeric excesses (>95% ee) are obtained using salts derived from cinchona alkaloids with a 9-anthracenylmethyl substituent on the bridgehead nitrogen (e.g. lb, 2b). These catalysts will be used to improve the enantiose-lectivity of existing asymmetric PTC reactions and will be exploited in other anion-mediated processes both in the laboratory and industrially. 

The insertion of the N(2)-G(3) unit in reduced isoquinolines remains a topic of interest, especially stereoselective examples. The iminoglycinate 43 undergoes reaction with the dibromo 44 in the presence of the -symmetric chiral quaternary ammonium bromide phase-transfer catalyst (Equation 130) <2001S1716>. A high-yielding tetrahydro-isoquinoline resulted in excellent enantioselectivity. Reaction of the chiral anion generated from 45 with benzylidene also produces chiral tetrahydroisoquinolines (Equation 131) <1999EJO503>. 

Weak acid-base chiral complex formation represents hydrogen bond catalysis (see Chapter 9) and deprotonation followed by cation/anion association under homogeneous, and also under phase-transfer conditions (see Chapter 4) [14, 65],... 

Carter C, Fletcher S, Nelson A (2003) Towards phase-transfer catalysts with a chiral anion inducing asymmetry in the reactions of cations. Tetrahedron Asymmetry 14 1995-2004... 

Alkylation of phthalimide anion can be carried out under solid-liquid phase-transfer conditions, using phosphonium salts or ammonium salts. In the reaction systems using hexadecyltributylphosphonium bromide, alkyl bromides and alkyl methanesulfonate are more reactive than alkyl chlorides. Octyl iodide is less reactive than the corresponding bromide and chloride. ( )-2-Octyl methanesulfonate was converted into (S)-2-octylamine with 92.5% inversion. Kinetic resolution of racemic ethyl 2-bromopro-pionate by the use of a chiral quaternary ammonium salt catalyst has been reported. Under liquid-liquid phase-transfer conditions, A -alkylation of phthalimide has been reported to give poor results. ... 

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