Asymmetric alkylation using polymers

Special cases arc the enantioselective synthesis of chiral aldehydes using 1-phenyl-l-ethanamine under optimized conditions (see Table 5), and the remarkable asymmetric induction observed in the alkylation of polymer-bound imines at room temperature (see Table 2). 

The most evident results have been obtained in the case of monomers having the asymmetric carbon atom in a position with respect to the double bond (Table 3 and 4) on the basis of the optical activity of the polymer obtained and of the non polymerized monomer recovered, it appears that, under the polymerization conditions used, the antipode having the same absolute structure as the asymmetric alkyl group present in the catalyst (104) is polymerized more rapidly, 1.15 to 1.7 times, than the other antipode. 

Asymmetric Alkylation of Aldehydes using Polymer and Dendritic Catalysts... 

Catalytic asymmetric alkylation of 1 has also been carried out with polymer-bound glycine substrates. For example, O Donnell and coworkers used Wang resin-bound derivative 11 in combination with BEMP or BTPP and 4d, as exemplified in Scheme 2.7 [25]. Although a full equivalent of 4d was required, the promising stereoselectivities provided strong implications for further optimizations. 

The amino alcohol-dialkylzinc system can be applied to ehiral amine synthesis. Polymer-supported ephedrine was found to be an effective chiral ligand in the reaction of N-diphenylphosphinoylimines with diethylzinc (Eq. 19) [77-79]. The polymeric catalysts were, however, less efficient than monomeric model reactions. Several dendrimeric chiral ligands containing the ephedrine moiety (60, 61) have also been synthesized and used in the asymmetric alkylation of 7 -diphenylphosphinylimines by diethylzinc [80]. Both yield and enantioselectivity of the reaction were, however, lower when the dendrimeric ligands were used. 

Nonracemic Ti-BINOLate (BINOL = l,l -bi-2-naplilli()l) and Ti-TADDOLate (TADDOL = a,a,a, a -tetraaryl-2,2-dimethyl-l,3-dioxolan-4,5-dimethanol) complexes are also effechve chiral catalysts for the asymmetric alkylation of aldehydes [9-11]. Seebach developed polystyrene beads with dendritically embedded BINOL [9] or TADDOL derivatives 11 [10, 11]. As the chiral ligand is located in the core of the dendritic polymer, less steric congeshon around the catalyhc center was achieved after the treatment with Ti(OiPr)4. This polymer-supported TiTADDOLate 14 was then used for the ZnEt2 addition to benzaldehyde. Chiral 1-phenylpropanol was obtained in quantitahve yield with 96% ee (Scheme 3.3), while the polymeric catalyst could be recycled many times. 

Luis prepared polymeric monoliths 17 containing TADDOL subunits [13] these were synthesized with a thermally induced radical soluhon polymerization of a mixture containing TADDOL monomer, styrene and DVB, using toluene/1-dodecanol as the precipitating porogenic mixture and azoisobutyronitrile (AIBN) as the radical inilialor. The polymer-supported Ti-TADDOLates generated from 17 and Ti(OiPr)4 were then used for the asymmetric alkylation of benzaldehyde to give 1-phenylethanol in 60% yield and 99% ee [13]. 

The asymmetric alkylation of the ketone carbonyl groups occurred under selected reaction conditions [19]. One recent example of this involves the use of polymer-supported chiral disuUbnamide 22 as a chiral hgand (Scheme 3.6) [20]. The polymer 22- li(OiPr)4 complex was utilized for diethylzinc addition to simple... 

The asymmetric alkylation of glycine derivatives is one of the most simple methods by which to obtain optically active a-amino acids [31]. The enantioselective alkylation of glycine Schiff base 52 under phase-transfer catalysis (PTC) conditions and catalyzed by a quaternary cinchona alkaloid, as pioneered by O Donnell [32], allowed impressive degrees of enantioselection to be achieved using only a very simple procedure. Some examples of polymer-supported cinchona alkaloids are shown in Scheme 3.14. Polymer-supported chiral quaternary ammonium salts 48 have been easily prepared from crosslinked chloromethylated polystyrene (Merrifield resin) with an excess of cinchona alkaloid in refluxing toluene [33]. The use of these polymer-supported quaternary ammonium salts allowed high enantioselectivities (up to 90% ee) to be obtained. 

PEG-supported cinchona ammonium salts 54 were applied to the asymmetric alkylation of tert-butyl benzophenone Schiff base derivatives 52 [34]. The use of a water-soluble polymer support allowed the reaction to be conducted in a 1M KOH aqueous solution to give the a-amino acid derivatives 53 in high chemical yields (up to 98%). Ten different types of electrophile have been tested for the reaction, with the best enantioselectivity being obtained with o-chlorobenzylchloride (97% ee) (Scheme 3.15). 

An S—P-type chiral phosphinooxathiane was developed as an effective ligand for palladium-catalyzed allylic substitution reactions [131]. A polymer-supported chiral phosphinooxathiane 208 was also prepared and applied to asymmetric alkylations and aminations of acetate 201 [132]. Enanhoselechvihes of up to 99% ee were obtained in asymmetric Pd-catalyzed allylic amination of acetate 201 using the polymeric catalyst prepared from a PS-diethylsilyl support (Scheme 3.68). 

N-Sitylimine 89 in ether at -78°C was asymmetrically alkylated with butyl-Uthium in the presence of the diUthium alkoxide of the chiral diol 93 (76%, 62% ee) (Scheme 27) [76]. Addition of the preformed (-)-sparteine (19)-BuLi complex to benzaldehyde N-diisobutylaluminoimine 90, prepared in situ from partial reduction of benzonitrile with diisobutylaluminum hydride, in pentane at -78°C gave the primary amine 92 in good ee (70% yield, 74% ee) [77]. The use of polymer-supported amino alcohol 94 in THF at -78°C allows the asymmetric alkylation of an M-borylimine 91 to give the primary amine 92 with 44% ee [77]. 

In addition, in 2(X)4 Mamoka and co-workers [72] synthesized a recyclable fluorous chiral phase-transfer catalyst which was successfully applied for the catalytic asymmetric alkylation of a glycine-imine derivative followed by extractive recovery of the chiral phase-transfer catalyst using fluorous solvent. Later, in 2010 Itsuno and co-workers [73] published a new type of polymer-supported quarternary ammonium catalysts based on either cinchona alkaloids or Maruoka s-type catalyst bound via ionic bonds to the polymeric sulfonates. 

As with polybut-l-ene and many other vinyl monomers that contain an asymmetric carbon, isotactic, syndiotactic and atactic stmctures may be drawn. Using co-ordination catalysts such as mixtures of cobalt chlorides, aluminium alkyls, pyridine and water high-1,2 (high vinyl) polymers may be obtained. One product marketed by the Japan Synthetic Rubber Company (JSR 1,2 PBD) is 91% 1,2, and 51-66% of the 1,2 units are in the syndiotactic state. The molecular mass is said to be several hundred thousand and the ratio MJM is in the range 1.7-2.6. 

As catalysts Lewis acids such as AICI3, TiCU, SbFs, BF3, ZnCh or FeCl3 are used. Protic acids such as FI2SO4 or FIF are also used, especially for reaction with alkenes or alcohols. Recent developments include the use of acidic polymer resins, e.g. Nafion-Fl, as catalysts for Friedel-Crafts alkylations and the use of asymmetric catalysts. ... 

The aforementioned polymer-supported bis-pyridyl ligand has also been applied in microwave-assisted asymmetric allylic alkylation [140], a key step in the enantio-selective synthesis of (R)-baclofen (Scheme 7.118), as reported by Moberg and coworkers. The ( (-enantiomer is a useful agonist of the GABAb (y-aminobutyric acid) receptor, and the racemic form is used as a muscle relaxant (antispasmodic). Under microwave heating, the enantioselectivity could be improved to 89% when using toluene as solvent (see also Scheme 6.52) [140],... 

Another metal-catalyzed microwave-assisted transformation performed on a polymer support involves the asymmetric allylic malonate alkylation reaction shown in Scheme 12.4. The rapid molybdenum(0)-catalyzed process involving thermostable chiral ligands proceeded with 99% ee on a solid support. When TentaGel was used as as support, however, the yields after cleavage were low (8-34%) compared with the corresponding solution phase microwave-assisted process (monomode cavity) which generally proceeded in high yields (>85%) [30],... 

---