Phase benzophenone imines

Preparation of 0-Allyl-N-(9)-anthracenylmethylcinchonidinium Bromide as a Phase Transfer Catalyst for the Enantioselective Alkylation of Glycine Benzophenone Imine tert-Butyl Ester. 

Having optimized the catalytic enantioselective phase-transfer alkylation system, the group explored the scope and limitations. A variety of electrophiles were reacted with the benzophenone imine glycine tert-butyl ester 1 catalyzed by 5 mol% of the selected chiral dimeric PTCs, benzene-linked-l,3-dimeric PTC 37, 2 -F-benzene-linked-1,3-dimeric PTC 41, and naphthalene-linked-2,7-dimeric PTC 39, at reaction temperatures of 0°C or — 20 °C (Scheme 4.8). 

The solid-phase synthesis of a-amino acids via alkaloid-catalyzed alkylation has been investigated by the O Donnell group [64, 65]. The solid-phase based synthetic approach is particularly useful for rapid preparation of a-amino acids for combinatorial application. The concept of this solid-phase synthetic approach, which comprises three key steps, is shown in Scheme 3.22 (for formation of (R) enantiomers). First, solid-phase bound glycine, 51, is converted into its benzophenone imine de-... 

In an attempt to develop a PEG-supported version of a chiral phase-transfer catalyst the Cinchona alkaloid-derived ammonium salt 15 used by Corey and Lygo in the stereoselective alkylation of amino acid precursors was immobilized on a modified PEG similar to that used in the case of 13. The behaviour of the catalyst obtained 16, however, fell short of the expectations (Danelli et al. 2003). Indeed, while this catalyst (10 mol%) showed good catalytic activity promoting the benzy-lation of the benzophenone imine derived from tert-butyl glycinate in 92% yield (solid CsOH, DCM, -78 to 23 °C, 22 h), the observed ee was only 30%. Even if this was increased to 64% by maintaining the reac-... 

PREPARATION OF 0-ALLYL-N-(9-ANTHRACENYLMETHYL) CINCHONIDINIUM BROMIDE AS A PHASE TRANSFER CATALYST FOR THE ENANTIOSELECTIVE ALKYLATION OF GLYCINE BENZOPHENONE IMINE tert-BUTYL ESTER (4S)-2-(BENZHYDRYLIDENAMINO)PENTANEDIOIC ACID, 1-tert-BUTYL ESTER-5-METHYL ESTER... 

In 1978, O Donnell and coworkers developed the benzophenone imines of glycine alkyl esters 4 as glycine anion equivalents, which have been found to be perfed to use in the phase-transfer catalysis [10]. An essential feature of this reaction system lies in the selective mono substitution of the starting Schiff base, the O Donnell substrate 4. This can be possible because of the significant difference in acidity of a-hydrogen between starting substrate 4 p/C,(DMSO) 18.7 (R=Et)] and a-monosubstituted produd S p/C,(DMSO) 22.8 (R=Et, E = Me), 23.2 (R=Et, E = CH2Ph)] [11]. This dramatic acidity difference makes it possible for selective formation of only monoalkylated product without concomitant production of undesired dialkylated produd or racemization. 

A few years ago Cahard reported a series of studies on the use of immobilized cinchona alkaloid derivatives in asymmetric reactions with phase-transfer catalysts [17[. Two types of polymer-supported ammonium salts of cinchona alkaloids (types A and B in Scheme 8.4) were prepared from PS, and their activity was evaluated. The enantioselectivity was found to depend heavily on the alkaloid immobilized, with the type B catalysts usually giving better results than the type A catalysts. By performing the reaction in toluene at -50 °C in the presence of an excess of solid cesium hydroxide and 0.1 mol equiv of catalyst 10, benzylation of the tert-butyl glycinate-derived benzophenone imine afforded the expected (S)-product in 67% yield with 94% ee, a value very close to that observed with the nonsupported catalyst. (Scheme 8.4, Equation b) Unfortunately-and again, inexplicably-the pseudoenantiomer of 10 proved to be much less stereoselective, affording the R)-product in only 23% ee. No mention of catalyst recycling was reported [18]. 

Another approach to the synthesis of p hydroxy-a-amino acids is by aldol reaction of imines derived from amino adds. The benzophenone imine of glycine (7.102) undergoes highly enantioselective aldol addition with a range of aliphatic aldehydes, including (7.71) xmder phase-transfer conditions in the presence of the bromide salt of phase-transfer catalyst (7.103). A similar transformation is catalysed, in low to moderate ee, by the bimetallic catalysts developed by Shibasaki and CO workers. ... 

Scheme 5.8 Enantioselective Michael reaction of glycinate benzophenone imines with several enones in solid phase and in solution.

In a sealable glass vial, bromo[2.2]paracyclophane (1.02 g, 3.56 mmol), (rac)-BlNAP (55 mg, 0.08 mmol), tris(dibenzylideneacetone)dipalladium(0) (22 mg, 0.03 mmol), and sodium tert-butoxide (840 mg, 8.75 mmol) was dissolved in dry toluene (11 mL), and benzophenone imine (0.9 mL, 5.2 mmol) was added. The reaction was stirred at reflux for 3 d. The same amounts of BINAP, tris(dibenzylideneacetone)dipalladium(0), and sodium /ert-butoxide were added, and the reaction was stirred at reflux temperature for another 4 d. The mixture was allowed to cool to ambient temperature and was filtered over silica with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was dissolved in methanol (5 mL). Hydrogen chloride (2 M, 2 mL) was added and the suspension was stirred at 100 °C for 3 h. The reaetion was allowed to cool to ambient temperature and sat. sodium carbonate (5 mL) was added. The reaction was extracted with diethyl ether (3 x 10 mL), and the combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography (silica, cyclohexane/dichloromethane 1 1) to yield the title compound as a brown solid (0.31 g, 1.30 mmol, 37%). The compound can be recrystallized from dichloromethane/hexane mp 243 °C (capillary) Rf 0.28 (cyclohexane/ethyl acetate, 1 1). ... 

Alkylation and deprotection of N-protected aminomethylphosphonate esters 6 are shown in Scheme 6. The nitrogen is protected as the imine derived from benzophenone or a benz-aldehyde, and a variety of conditions are used for deprotonation and alkylation (Table 2). The benzaldehyde imine of aminomethylphosphonate can be deprotonated with LDA and alkylated with electrophilic halides (entries 1 and 2). For the best yields, saturated alkyl bromides require an equivalent of HMPA as an additive. 36 Allylic esters can be added to the carbanion with palladium catalysis (entries 3-7). 37,38 For large-scale production, phase-transfer catalysis appears to be effective and inexpensive (entries 8-12). 39,40 ... 

The Schiff s base derived from ethyl glycinate and benzophenone has been alkylated under both anhydrous and phase transfer conditions yielding, after hydrolysis, a-amino acids. Under phase transfer conditions, alanine, a-aminobutyric acid, valine, leucine and phenylalanine were prepared in 91%, 86%, 61%, and 55% yields, based on starting imine. 

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