Chiral quaternary ammonium bromide

Phenoxy acid herbicides, sulfonyl ureas, quaternary ammonium derivatives (quats), and aryloxy propanoic acids are the main classes of compounds subjected to capillary zone electrophoresis (CZE). Triazines are also separated using nonaqueous CZE, while low pfCa characterized chlorotriazines require an ion-pair-like solubilization using cationic surfactants (tetradecylammonium bromide, dodecyltrimethyl-ammonium bromide). Chiral selectors are added in CZE for obtaining enantioselectivity. Chiral selectors used for herbicide enantiomeric discrimination are vancomycin, y-cyclodextrin, ethyl carbonate -cyclo-dextrin, cyclohexyl-alkyl-)S-D-maltoside, sulpropyl ether a-cyclodextrin, and hexakis(2,3-di-0-methyl)-a-cyclodextrin. 

The ammonium catalyst can also influence the reaction path and higher yields of the desired product may result, as the side reactions are eliminated. In some cases, the structure of the quaternary ammonium cation may control the product ratio with potentially tautomeric systems as, for example, with the alkylation of 2-naph-thol under basic conditions. The use of tetramethylammonium bromide leads to predominant C-alkylation at the 1-position, as a result of the strong ion-pair binding of the hard quaternary ammonium cation with the hard oxy anion, whereas with the more bulky tetra-n-butylammonium bromide O-alkylation occurs, as the binding between the cation and the oxygen centre is weaker [11], Similar effects have been observed in the alkylation of methylene ketones [e.g. 12, 13]. The stereochemistry of the Darzen s reaction and of the base-initiated formation of cyclopropanes under two-phase conditions is influenced by the presence or absence of quaternary ammonium salts [e.g. 14], whereas chiral quaternary ammonium salts are capable of influencing the enantioselectivity of several nucleophilic reactions (Chapter 12). 

Asymmetric induction in the Neber rearrangement was also obtained under phase-transfer conditions with chiral quaternary ammonium bromides 544 as catalysts (equation 243). Moderate enantioselectivities (30-70% ee, 60-95% yield) were observed, but there is still an opportunity for extending the full synthetic utility of this classical rearrangement. 

With this information at hand, Maruoka and coworkers developed a new C2-symmetric chiral quaternary ammonium bromide 12 which incorporated an achiral, conformationally flexible biphenyl subunit (Scheme 5.8) [12]. 

This unique phenomenon provides a powerful strategy in the molecular design of chiral catalysts that is, the requisite chirality can be served by the simple binaphthyl moiety, while an additional structural requirement for fine-tuning of reactivity and selectivity can be fulfilled by an easily modifiable achiral biphenyl structure. This certainly obviates the use of two chiral units, and should be appreciated in the synthesis of a variety of chiral catalysts with different steric and/or electronic properties. Actually, quaternary ammonium bromide possessing a sterically demanding substituent such as (S)-12b can be easily prepared, and benzylation with (S)-12b as catalyst gave 9 in 95% yield with 92% ee. Further, theenantioselectivity was enhanced to 95% ee with (S)-12c as a catalyst [12]. 

Table 5.4 Asymmetric monoalkylation of 21 under phase-transfer conditions catalyzed by chiral quaternary ammonium bromide (R,R)-le or (R)-16Aa.

By using glycine diphenylmethyl (Dpm) amide-derived Schiff base 22 as a key substrate and N-spiro chiral quaternary ammonium bromide lg as an ideal catalyst, a high enantioselectivity was achieved, even in the alkylation with less-reactive simple secondary alkyl halides, as shown in Table 5.5 [21]. This system offers a facile access to structurally diverse optically active vicinal diamines in combination with the subsequent reduction (Scheme 5.14) [21]. 

Since the aldimine Schiff base 21 can be readily prepared from glycine, direct stereoselective introduction of two different side chains to 21 by appropriate chiral phase-transfer catalysis would provide an attractive, yet powerful, strategy for the asymmetric synthesis of structurally diverse a,a-dialkyl-a-amino acids. This possibility of a one-pot asymmetric double alkylation has been realized by using N-spiro chiral quaternary ammonium bromide le (Scheme 5.21). 

Upon facing the difficulty of stereochemical control in peptide alkylation events, Maruoka and coworkers envisaged that the chiral phase-transfer catalyst should play a crucial role in achieving an efficient chirality transfer, and consequently examined the alkylation of the dipeptide, Gly-L-Phe derivative 57 (Scheme 5.28) [31]. When a mixture of 57 and tetrabutylammonium bromide (TBAB, 2 mol%) in toluene was treated with a 50% KOH aqueous solution and benzyl bromide at 0°C for 4h, the corresponding benzylation product 58 was obtained in 85% yield with the diastereo-meric ratio (DL-58 LL-58) of 54 46 (8% de). In contrast, the reaction with chiral quaternary ammonium bromide (S,S)-lc under similar conditions gave rise to 58 with 55% de. The preferential formation of LL-58 in lower de in the reaction with (R,R)-lc indicated that (R,R)-lc is a mismatched catalyst for this diastereofacial differentiation of 57. Changing the 3,3 -aromatic substituent (Ar) of the catalyst 1 dramatically increased the stereoselectivity, and almost complete diastereocontrol was realized with (S,S)-lg. 

Efficient, highly enantioselective construction of quaternary stereocenter on P-keto esters under phase-transfer conditions has been achieved using N-spiro chiral quaternary ammonium bromide lh as catalyst [32]. This system has a broad generality in terms of the structure of P-keto esters 65 and alkyl halides (Scheme 5.31). 

A highly enantioselective alkylation of 3,5-diaryloxazolidin-2,4-diones 70 with N-spiro chiral quaternary ammonium bromide (S,S)-69 was achieved under mild phase-transfer conditions. With this methodology in hand, a wide range of tertiary a-hydroxy-a-aryl carboxylic acid derivatives may easily be obtained in good yields and high enantiomeric excesses (Scheme 5.34) [35]. 

Jew and Park achieved a highly enantioselective synthesis of (2S)-a-(hydroxy-methyljglutamic acid, a potent metabotropic receptor ligand, through the Michael addition of 2-naphthalen-l-yl-2-oxazoline-4-carboxylic acid tert-butyl ester 72 to ethyl acrylate under phase-transfer conditions [38]. As shown in Scheme 5.36, the use of BEMP as a base at —60 °C with the catalysis of N-spiro chiral quaternary ammonium bromide le appeared to be essential for attaining an excellent selectivity. 

Phase-transfer-catalyzed direct Mannich reaction of glycine Schiff base 2 with a-imino ester 79 was achieved with high enantioselectivity by the utilization of N-spiro chiral quaternary ammonium bromide le as catalyst (Table 5.14) [42],... 

The nitroaldol reaction of silyl nitronates with aldehydes promoted by ammonium fluorides, which was originally introduced by Seebach and Colvin in 1978 [24], is a useful method for the preparation of 1,2-functionalized nitroalkanols. Recently, the present authors have succeeded in developing an asymmetric version of high efficiency and stereoselectivity by using a designer chiral quaternary ammonium bifluoride of type 6 as catalyst, which was readily prepared from the corresponding bromide by the modified method C in Scheme 9.5 [25]. 

Very recently, Maruoka and co-workers described a new N-spiro quaternary ammonium bromide with two chiral biphenyl structures as easily modifiable subunits [37]. These phase-transfer catalysts with biphenyl subunits, containing methyl groups in the 6,6 -position for inducing chirality, and additionally bulky substituents in the 4-position, efficiently catalyzed the alkylation of protected glycinate with high enantioselectivity of up to 97% ee. The substrate range is broad, for example (substituted) benzyl bromide and allylic and propargylic bromides are tolerated [37]. 

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>. 

Ooi T, Kameda M, Maruoka K (2003) Design of N-spiro C2-symmetric chiral quaternary ammonium bromides as novel chiral phase-transfer catalysts synthesis and application to practical asymmetric synthesis of a-amino acids. J Am Chem Soc 125 5139-5151... 

The Neber route has been noted to be mildly influenced by the introduction of chiral auxiliaries. Thus, rearrangement of the tosyl oxime 860 (formed in situ from the oxime 859) in the presence of catalytic amounts of the chiral quaternary ammonium bromide 858 led to the formation of enantiomerically enriched amino ketone 863, which is presumed to arise from the preferential formation of the intermediate 2//-azirine 862. Association of the cationic chiral auxiliary with an anionic intermediate (i.e, 861) has been invoked to rationalize the stereochemical outcome (Scheme 215) <2002JA7640>. 

The a-hydroxy acid-derived 2,4-oxazolidinediones have been successfully utilized as substrates for asymmetric alkylations with a chiral phase-transfer catalyst (Scheme 40). Using 1 mol% of the N-spiro chiral quaternary ammonium bromide catalyst 153, oxazolidinedinone 152 was alkylated in high yield and enantioselectivity and hydrolyzed in situ to give a-hydroxy amides 154 <2006AGE3839>. 

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. ... 

The first example of a fully recyclable fluorous chiral metal-free catalyst was reported by Maruoka and coworkers, who described the enantioselective alkylation of a protected glycine derivative (Scheme 5.17) with various benzyl- and alkyl bromides, in the presence of the quaternary ammonium bromide 62 as a phase-transfer catalyst [77]. Reactions were performed in a 50% aqueous KOH/toluene biphasic system in which 62 was poorly soluble. Nevertheless, the alkylated products were obtained in good yields (from 81 to 93%), with enantioselectivity ranging from 87 to 93% ee. Catalyst 62 was recovered by extraction with FC-72, followed by evaporation of the solvent, and could be used at least three times without any loss of activity and selectivity. 

Further, N-spiro chiral quaternary ammonium bromide 9e was successfully applied by Jew and Park to the asymmetric synthesis of a-alkyl serines using... 

A phase-transfer-catalyzed direct Mannich reaction of glycinate Schiff base 5 with a-itnino ester 78 was achieved with high enantioselectivity by the use of N-spiro chiral quaternary ammonium bromide 9e as catalyst (Scheme 11.21) [62]. This method enabled the catalyhc asymmetric synthesis of differentiatly protected 3-aminoaspartate, a nitrogen analogue of dialkyl tartrate, the utility of which was demonstrated by the conversion of product (sy -79) into a precursor (80) of strep-tohdine lactam. 

Low to moderate optical yields are reported for the reaction of cyclohexene with chiral quaternary ammonium bromides, the enantiomeric excess <36% being too low for most practical applications147. 

The most common surfactants used in MECC are anionic and cationic, for example, SDS and cetyltrimethyl ammonium bromide (CTAB). Subtle changes in the solute miscelle interactions giving enhanced resolution have been achieved by using a variety of organic modifications, e.g. chiral selectors such as cyclodextrins and crown ethers [88] and quaternary anions for ion pairing. 

It is interesting that the condensation between electron-rich phenol, amine, and a chiral a -A, A -dibenzylamino aldehyde has been reported to be temperature sensitive, with high syn selectivity at high reaction temperatures while high anti selectivity is observed at low reaction temperatures. Similar to the Aldol Condensation, the Mannich reaction can be promoted or catalyzed by either acid or base. Furthermore, different protic acids or Lewis acid alone or in combination with a different chiral ligand or auxiliary group is used to enhance the stereoselectivity of the Mannich reaction, such as proline, (,S )-amino sulfonamide, BINOL phosphate," At-spiro chiral quaternary ammonium bromide, and dodecylbenzenesulfonic acid" as well as Lewis acids, such as Cu(OAc)2, CuC104, " Cu(OTf)2-chiral diamine complexes,... 

Scheme 5.43 Af-spiio-Cj-symmetrical chiral quaternary ammonium bromide in the Mannich reaction...

Subsequently, Arai and Shioiri used a-chloro sulfones 104 as new carbon nucleophiles for the Darzens reaction that can be transformed more effectively to Darzens products due to the closer distance between the reactive carbanion and the chiral quaternary ammonium cation in the ionic complex. In 2007, Jew and coworkers succeeded in obtaining more optically pure a,B-epoxy sulfones 105 by using N-(2,3,4-trifluorobenzynquinidinium bromide 49f (Scheme 16.35). °... 

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