Prolines polymer-supported

Metal ion complexes. These classic CSPs were developed independently by Davankov and Bernauer in the late 1960s. In a typical implementation, copper (II) is complexed with L-proline moieties bound to the surface of a porous polymer support such as a Merrifield resin [28-30]. They only separate well a limited number of racemates such as amino acids, amino alcohols, and hydroxy acids. 

In 2001, Sarko and coworkers disclosed the synthesis of an 800-membered solution-phase library of substituted prolines based on multicomponent chemistry (Scheme 6.187) [349]. The process involved microwave irradiation of an a-amino ester with 1.1 equivalents of an aldehyde in 1,2-dichloroethane or N,N-dimethyl-formamide at 180 °C for 2 min. After cooling, 0.8 equivalents of a maleimide dipo-larophile was added to the solution of the imine, and the mixture was subjected to microwave irradiation at 180 °C for a further 5 min. This produced the desired products in good yields and purities, as determined by HPLC, after scavenging excess aldehyde with polymer-supported sulfonylhydrazide resin. Analysis of each compound by LC-MS verified its purity and identity, thus indicating that a high quality library had been produced. 

Very recently, Portnoy et al. described the design and synthesis of insoluble polymer-supported dendrimers bearing proline end groups for asymmetric aldol reachons [123]. The zeroth- to third-generahon supported dendrimer catalysts were prepared by ahaching (2S,4R)-4-hydroxyproline onto the insoluble PS-bound... 

On the other hand, polymer-supported task-specific ILs in which the imidazolium cations couple L-proline via the ionic-pair interaction have also been synthesized and applied in metal scavenging and heterogeneous catalysis. The novel materials displayed considerable ability for metal scavenging onto their surface [e.g., Cul, Pd(OAc)2, Pd and IrCh] without the aid of a non-immo-bilized ionic liquid. Moreover, attempts to use these materials in the Cul-cat-alyzed N-arylation of nitrogen-containing heterocycles revealed that these systems are characterized by a much higher activity and recycling ability than... 

Preparation of amidine [31] Polymer-supported reagent 21 (780 mg), proline 26 (29.7 pL, 0.3 mmol), and EtsN (208 pL, 1.5 mmol) were stirred in dry THF (4 mL) at 60 °C for 24 h. After completion of the reaction (TLC monitoring), the mixture was filtered, the resin on the filter was washed with THF (2x2 mL) and methanol (3x4 mL), and the combined filtrates were concentrated in vacuo. The residue was taken up in water (5 mL) and passed through a column of Amberhte IRA-400 (hydroxide form, 10 mL), eluting with water. The eluate was cooled to -30 °C and lyophilized to afford proline-N-carboxamidine 29 (31 mg, 0.245 mmol, 82%) as a light-green adhesive solid. 

Scheme 10.21 Polymer-supported proline and related catalysts and their use.

Of the inorganic supports, best results were reported for a mesoporous MCM-41 [337]. Support on ionic-liquid phases has been studied by different groups with variable results [338, 339], Of the non-conventional organic polymers, non-covalent immobilization on poly(diallyldimethylammonium) is notable [340], Catalysts 133 (15 mol.%) promoted the aldol reaction of acetone and benzaldehydes to afford the corresponding (i-hydroxyketones in 50-98% yields and 62-72% ee, which are clearly lower than those reported for other polymer-supported systems. Recycling of the catalysts was possible at least six times without loss of efficiency. More recently, proline has been attached to one DNA strand while an aldehyde was tethered to a complementary DNA sequence and made to react with a non-tethered ketone [341], To date, the work has focused more on conceptual development than on the analysis of its practical applications in organic synthesis. 

L-proline was reduced to prolinol, and conversion with benzyl chloride into N-benzyl substituted prolinol 17 followed. Subsequent complex formation was achieved by the usage of Cr(CO)6. Irradiabon of complex 18 in the presence of polystyrene-diphenylphosphine gave the polymer-supported chiral auxiliary 19 (Scheme 12.10). 

As shown in Scheme 4.3.4, several substituted hydroxybenzaldehydes 226 were attached to Wang resin 84 via an alkylaryl ether linkage through a Mitsunobu reaction to give 227. These polymer-supported aldehydes were allowed to react with an a-amino ester 228 and maleimide 229 in DMF to give immobilised proline analogues 230 that were liberated from the resin by treatment with 50% TFA to afford 231. The dipolar cycloaddition provided mixtures of diastereoisomers, which could be separated by HPLC. 

FIGURE 3.13 Polymer-supported synthesis of a series of peptides containing proline analogues. 

Gulin, O.P., Rabanal, F. and Giralt, E. (2006) Efficient preparation of proline A -carboxyanhy-dride using polymer-supported bases. Organic Letters, 8, 5385-5388. 

Using these methods we more recently reported the synthesis of another isoquinoline alkaloid, (-)-norarmepavine (Scheme IS.IO). " This was accomplished by coupling the amine 26 with the ester 27 to give an intermediate amide (28). This was best done using focused microwave irradiation under solvent-free conditions. Next, 28 was converted to a Bischler-Napieralski product by using a combination of triflic anhydride and PS-DMAP. This was followed by scavenging with polymer-supported A(-(2-aminoelhyl)aminomethyl polystyrene to remove any excess anhydride. The intermediate triflate was then converted to the free base 29 with PS-BEMP (7), mentioned earlier. Finally, a proline-derived reductant... 

Difficulties in attachment and lower yields have been encountered with certain specific amino acids such as A -Boc-nitroarginine and N-Boc-proline. Difficulties in linking the first amino acids to the polymer support have also been observed in case of A -Boc-methionine and A -Boc-N -benzylhistidine. For methionine, the difficulty is due to the formation of suifonium derivatives. This was overcome by using methionine, as its sulfoxide, and then reducing the sulfoxide to its thioether by sodium iodide and acetyl chloride in DMF (Norris et aL, 1971). The two last-named amino acids can be linked without any difficulty to the hydroxymethyl polymers and the problem circumvented. 

Since the discovery of proline-catalyzed enantioselective aldol reactions, an extensive research program to explore chiral secondary amine catalysts has been pursued. Several polymer-supported chiral amines have been synthesized for aldol, Mannich, and related reactions. Polystyrene is a popular solid phase for use in place of silica gel in the proline-based organocatalysis. In contrast, silica gel displays a slightly acidic character and has a hydrogen-bond donor or acceptor, which may change the catalytic activity and chiral space of the organocatalyst. Flow enantioselective aldol [158-161], Mannich [162], Michael [163], and related reactions... 

Proline has also been attached to a polymer support. Takemoto et al. described the first example of this approach [141]. Hydroxyproline vas linked... 

SCHEME 11.16 Asymmetric Mannich reaction catalyzed by a polymer-supported proline catalyst. 

Figure 23.3 Functional monomers for preparation of polymer-supported prolines by copolymerization.

---