Chiral N-spiro

Maruoka and coworkers designed a new and highly efficient chiral N-spiro-type quaternary ammonium salt (S)-70 with dual functions for the asymmetric epoxidation of various enone substrates (Scheme 5.44) [45]. The exceedingly high asymmetric induction is ascribable to the molecular recognition ability of the catalyst toward enone substrates by virtue of the appropriately aligned hydroxy functionality, as well as the chiral molecular cavity. Indeed, the observed enantioselectivity depends heavily... 

Ooi and Maruoka developed an efficient phase transfer catalyst (46a-e), which consisted of chiral N-spiro ammonium salts with binaphthalene skeleton. 3,3 -(3,4,5-Trifluorophenyl)ammonium salt (46e) provided a perfect stereoselection in benzylation of benzophenone Schiffbase of glycine terf-butyl ester (47) (Scheme 5.13, Table 5.5) [19]. The perfect stereoselective alkylation is applicable for a variety of alkyl bromides in the presence of 1 mol% of the catalyst (46e). Not only monoalkylation but also the consecutive double alkylation of 49 was successful to give 50 in excellent enantioselectivities (Scheme 5.14) [20]. The protocol is useful for the enantioselective aldol reaction of 47 with aldehyde (51) [21] and a-imino ester [22], in which catalysts (46f) and (46g) were effective (Scheme 5.15) [23]. 

Figure 12.8 Maruoka s chiral N-spiro binaphthyl-modified quaternary ammonium salt phase-transfer catalysts.

Conformational rigidity and flexibility are two key features for the development of an efficient chiral catalyst. Ma and coworkers developed a new generation of chiral dinuclear phase-transfer catalysts 47 by connecting two structurally rigid BINOL-derived chiral N-spiro quaternary ammonium salts with a flexible linker [80]. These catalysts were proven to act via dual activation of both nucleophiles and electrophiles and to be very efficient catalysts for the conjugate addition of hindered nitroalkanes to enones. Notably, a completely reversed enantioselectivity could be easily switched with catalysts (S,S)-47a and (S,S)-47b, which differ in the length of the methylene chain of the linker but not in the chiral element of backbone. 

The Park group developed the highly enantioselective monoalkylation of 1,3-dicarbonyl compounds 90a and 90b under the phase-transfer conditions. The chiral N-spiro quaternary ammonium bromide (S,S)-31c delivered the alkylated products 91a and 91b in high yield with excellent enantioselectivity [122]. Accordingly, both 91a and 91b could be further converted into the dmg (—)-paroxetine and natural product (—)-isonitramine (Scheme 12.16). 

Maruoka and coworkers also investigated the substantial reactivity enhancement of N-spiro chiral quaternary ammonium salt and simplification of its structure, the aim being to establish a truly practical method for the asymmetric synthesis of a-amino acids and their derivatives. As ultrasonic irradiation produces homogenization (i.e., very fine emulsions), it greatly increases the reactive interfacial area, which may in turn deliver a substantial rate acceleration in the liquid-liquid phase-transfer reactions. Indeed, sonication of the reaction mixture of 2, methyl iodide and (S,S)-lc (1 mol%) in toluene-50% KOH aqueous solution at 0 °C for 1 h gave rise to the corresponding alkylation product in 63% yield with 88% ee. Hence, the reaction was speeded up markedly, and the chemical yield and enantioselectivity were comparable with those of the reaction with simple stirring (0°C for 8h 64%, 90% ee) (Scheme 5.5) [10]. 

Although the conformationally rigid, N-spiro structure created by two chiral binaphthyl subunits represents a characteristic feature of 1 and related catalyst 9, Maruoka and coworkers have generally used their (S,S)- and (R,R)-isomers. Surprisingly, however, when the diastereomeric (R,S)-lc was used for asymmetric benzyla-tion of 2, the reaction was found to proceed very slowly, such that even after 60 h the... 

On the other hand, Maruoka and coworkers were intrigued with the preparation of symmetrical N-spiro-type catalysts to avoid the independent synthesis of two different binaphthyl-modified subunits required for 1. Along this line, 4,4, 6,6 -tetra-arylbinaphthyl-substituted ammonium bromide (S, S)-13 was assembled through the reaction of aqueous ammonia with bis-bromide (S)-14 on the basis of previous studies on the substituent effect of this type of salt. The evaluation of (S,S)-13 as a chiral phase-transfer catalyst in the alkylation of 2 uncovered its high catalytic and chiral efficiency (Scheme 5.9) [9]. 

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). 

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. 

Maruoka and coworkers recently developed an efficient, highly diastereo- and enantioselective direct aldol reaction of glycine Schiff base 2 with a wide range of aliphatic aldehydes under mild phase-transfer conditions employing N-spiro chiral quaternary ammonium salt li as a key catalyst, as shown in Table 5.12 [41a]. 

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],... 

Highly enantioselective Michael addition of silyl nitronates (105) to cyclic o /3-unsaturated ketones (106 n = 0-2) has been accomplished by the utilization of N-spiro C2-symmetric chiral quaternary ammonium bifluoride (108) as an organocatalyst, offering a new route to the enol silyl ethers of scalemic y-nitro ketones (107 70-90% ee).156... 

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]. 

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 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>. 

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. 

Excellent results were also reported recently by Maruoka and coworkers by using 50% aqueous NaOH in toluene and a (5)-BINAP-derived C2-symmetric ammonium catalyst 14 [64]. The steric and/or electronic properties of this new class of catalysts can be finely tuned in order to improve reactivity and enantioselectivity. The N-spiro structure along with their high lipophilicity make such catalysts much more reactive than the traditional PTC catalysts, e.g., Bu4N+Br, in otherwise identical conditions [65]. Excellent ees are usually obtained in short reaction times with 1 % of catalyst only moreover, they should be more stable under basic conditions than ammonium salt derived from Cinchona alkaloids since they do not undergo Hofmann elimination resulting from lack of yS-hydrogens. However, they are not as easily prepared as Cinchona ammonium catalysts and are expected to be quite expensive since they are not derived from the chiral pool. On... 

Waser M, Gratzer K, Herchl R, Miiller N (2012) Design, Synthesis, and Application of Tartaric Acid Derived N-Spiro Quaternary Ammoniiun Salts as Chiral Phase-Transfer Catalysts. Org Biomol Chem 10 251... 

By using low-temperature P-NMR spectroscopy and X-ray crystallographic analysis, Uraguchi et al. have revealed that chiral R-spiro imino-phosphorane (123) and 3,5-Cl2C6H30H (ArOH) assemble into three types of molecular associations (124-126) of general formula 123 [2] , (n= 1-3) in solution by simply adjusting the stoichiometry of ArOH (Scheme 31). ... 

The 1,6-addition of azalactones (174) to monosubstituted dienyl N-acylpyrroles (175) has been realised with essentially complete control of regio-, diastereo- and enantioselectivities in the presence of chiral P-spiro triaminoimino-phosphorane (176) as a strong organic base catalyst (Scheme 64)7 ... 

Inspired by Maruoka s success in using axially chiral C2-symmetric binaphthyl-based N-spiro quaternary ammonium salts, both the Arai [83] and Waser [84] groups developed tartaric acid-derived N-spiro quaternary ammonium salts 51 and 52, respectively. These catalysts could promote the asymmetric alkylation and conjugate addition with good enantioselectivities. 

The regiochemical course reacting saturated ketones depended on the substitution pattern of the a-positions. In most cases, the intermediate oxime had an anti N-OH function with respect to the chain branched a-position. Consequently, the more substituted alkyl group preferentially migrates. This advantage was utilized for synthesizing the spiro a-amino-e-caprolactam (202 203, Scheme 38) [12c], the Mexican bean beetle azamacrolide allomone (205 206, Scheme 39) [44 a], in a key step of the chiral synthesis of benzomorphanes... 

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