Polymer amino alcohol

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. 

Polymer-supported amino alcohols and quaternary ammonium salts catalyze the enan-tioselective addition of dialkylzinc reagents to aldehydes (Table 31). When the quaternary ammonium salt F is used in hexane, it is in the solid state, and it catalyzes the alkylation of benzaldehyde with diethylzinc in good chemical yield and moderate enantioselectivity. On the other hand, when a mixture of dimethylformamide and hexane is used as solvent, the ammonium salt is soluble and no enantioselectivity is observed21. 

The polymer-bound catalysts A-C. (Table 31) are prepared by reaction of the corresponding amino alcohols with partially chloromethylated 1 -2% cross-linked polystyrene. In the case of A, the enantioselectivity of the addition of dialkylzincs to aldehydes is higher than with the corresponding monomeric ephedrine derivatives (vide supra). Interesting insights into the mechanism of the alkylation of aldehydes by dialkylzinc reagents can be obtained from the experi-... 

Many bacterial polysaccharides contain phosphoric ester groups. There is a limited number of examples of monoesters. More common are phosphoric diesters, connecting an amino alcohol or an alditol to the polysaccharide chain. Another possibility is that oligosaccharide or oligosaccharide-alditol repeating units are connected to a polymer by phosphoric diester linkages. In addition to the intracellular teichoic acids, several bacteria, for example, different types of Streptococcus pneumoniae, elaborate extracellular polymers of this type. These polymers are generally discussed in connection with the bacterial polysaccharides. 

In 1982 Cardillo used a three-step sequence involving two supported reagent systems to convert /i-iodoamines into amino alcohols (Scheme 2.23) [45]. Polymer-supported acetate ions were used for the substitution of the iodide which immediately underwent acyl transfer to the amine. The resulting compound (10) was directly treated with hydrochloric acid to cleave the amide and the free base was subsequently obtained from the reaction by treatment with a resin-bound carbonate. This was of particularly synthetic value because of the high water solubiHty of these amino alcohol compounds that would have made aqueous work-up challenging. 

Various polymer-bound (polystyrene-bound) oxazaboroHdine catalysts for the reduction of secondary alcohols were reported [128]. These can simply be prepared by condensation of the resin-bound boronic acid with chiral 1,2-amino alcohols. The best results as far as enatioselectivity is concerned were obtained with oxaza-borohdine (59) (Scheme 4.36). 

In a soluble polymer strategy comparable to resin-capture [145], Janda reported a MeO-PEGsooo-supported dialkyl borane reagent (31) that was used in the purification of a solution-phase library of y9-amino alcohols [146]. Purification was achieved by simply adding (31) to the crude reaction mixture followed by subsequent precipitation of the polymer with diethyl ether to give polymer-supported 1,3,2-oxazaboroU-dine (32) (Scheme 5.2). The /9-amino alcohol product could then be released from the soluble support by treatment with acid. In a two-step synthetic strategy that is readily amendable to automation, the isolation of a small library of /9-amino alcohols was accomplished with all compounds obtained in >80% purity. 

Enantioselective reduction of jS-keto nitriles to optically active 1,3-amino alcohols has been carried out in one step using an excess of borane-dimethyl sulfide complex as a reductant and a polymer-supported chiral sulfonamide as a catalyst with moderate to high enantioselectivity (Figure 3.11). The facile and enantioselective method to prepare optically active 1,3-amino alcohols has been used to prepare 3-aryloxy-3-arylpropylamine type antidepressant drugs, for example (l )-fluoxetine. 

Phthalimidoglutaric acid (18), readily prepared from glutamic acid and phthalic anhydride, has served as a precursor for the preparation of several interesting condensation polymers (76MI1110l). For example, it is readily transformed (Scheme 7) into diisocyanate (19), which was utilized for the preparation of a number of optically active polyureas (by reaction with diamines), polyurethanes (by reaction with diols) and polyurea-urethanes (by reaction with amino alcohols). 

Scheme 13) (35). This high selectivity can be obtained with the 1 2 amino alcohol-borane reagent, however, the 1 1 reagent is less reactive and affords only low stereoselectivity (36). The continuous-flow reaction using a polymer-bound amino alcohol provides evidence for the catalytic nature of the reduction with respect to the chiral ancillary. The reduction is accelerated by the presence of the amino alcohol-borane adduct, and the product is not bound to the complex. 

The amino alcohol-catalyzed enantioselective addition of dialkylzincs to aldehydes, detailed in Chapter 5 (27), is accomplished with polymer catalysts containing DAIB, a camphor-derived auxiliary, and other chiral amino alcohols (28). Reactions that involve matrix isolation of the catalyst not only result in operational simplicity but also greatly facilitate understanding of the reaction mechanism. In solution, the catalytic chiral alkylzinc alkoxide derived from a dialkylzinc and DAIB exists primarily as dimer (27) however, when immobilized, its monomeric structure can be maintained. 

When considering the easy recovery and reuse of chiral catalysts, or simple separation process of the product from chiral catalyst, polymer-supported catalysts are very attractive [1,3]. For the enantioselective ethylation using dialkylz-inc, Frechet and Itsuno s group and our group developed polystyrene-supported amino alcohols [1]. 

Several poly(urea urethane) oligomers 28 (Figure 12) were prepared by one-component polycondensation of iV-(hydroxyalkyl)-2 -oxo-1,3-diazepane-l-carboxamides, which act as intramolecular blocked isocyanates <2005PLM 1459>. These oligomers are semicrystalline materials and their melting points show the odd/even effect observed earlier for [ ]-polyamides, [ ]-polyurethanes, poly(ester amide)s, and poly (amide urethane)s. Further analysis showed that the polymers are stable up to ca. 205-230 °C, the polymers with the lower number of methylene groups in the amino alcohol decomposing at the lowest temperature. 

The first enantioselective process within the flow domain was the reduction of valerophenone (5) by borane in the presence of the polymer-supported amino alcohol catalyst 6 (Scheme 4.52) as reported by Itsuno [100]. Solutions of 5 and borane were mixed into the bottom of the column using long syringe needles, and the product 7 flowed from the top. Following washing with TH F and water, acidic workup and bulb-to-bulb distillation, 1.8 g of 7 was isolated in 84% yield and in 83-91% ee, depending on the fraction analyzed. 

A further example used the supported amino alcohols 45,46 and 47 (Scheme 4.76), where the reagents were pumped up from the bottom of the polymer using a pair of long needles connected to peristaltic pumps. The product was collected from the top using another pump and quenched in a solution of dilute hydrochloric acid. For the first run with catalyst 46, the yields and ee were excellent (94% yield in 97% ee), but when 46 was recovered and reused, the yield dropped to 75% and the ee to 50%. This was ascribed to degradation of both the chiral and backbone sites of the polymer by diethyl zinc, again demonstrating that not only do the solid supports need to be mechanically sound but both the backbone support and active site must be also chemically resistant to the reaction conditions [171]. 

Among the types of ultraviolet absorbers that may be used as stabilizers are salicylates, o-hydroxybenzophenones, o-hydroxyarylbenzotri-azoles, and certain acrylonitriles. The stabilization of polystyrene by other additives has also been reported. Matheson and Boyer (10) found that certain aliphatic amines and amino alcohols improved the light stability of the polymer. 

Yashima and co-workers reported the memory of macromolecular helicity of poly((4-carboxyphenyl)acetylene) (poly-98). Poly-98 itself possesses a large number of short helical units with many helix-reversal points, and is therefore achiral. However, in the presence of optically active amine 99, which can interact with the polymer s carboxyl groups, one-handed macromolecular helicity is induced in the polymer. When achiral amino alcohol 100 is added to the helical complex, chiral amine 99 bound to poly-98 is replaced by stronger base 100. Nevertheless, the newly formed complex still shows a one-handed helical conformation. Even after the removal of 99 by gel permeation chromatography, the poly-98-100 complex retains a one-handed helical conformation without a loss of helical intensity. Thus the helicity of poly-98 induced by complexation with a chiral amine was memorized after replacement by an achiral one. The half-life of the chiral memory is as long as four years at room temperature.48... 

Quinine-acrylonitrile copolymer. Cinchona alkaloids can be copolymerized with another vinyl monomer such as acrylonitrile with AIBN as initiator. The highest yield of polymer in the case of quinine is obtained when the quinine/acrylonitrile ratio is 1 20. This method was used to obtain a polymeric form of the alkaloid in which the crucial part of the molecule for asymmetric reactions—the amino alcohol unit—is free. The polymers are stable, light yellow solids, soluble in polar aprotic solvents (DMF and DMSO), but insoluble in common organic solvents. 

Preparation of Polymeric Catalyst. A c inindAcrylonitrile copolymer has been successfully synthesized via radical polymerization using Azobisisobutyronitrile (AIBN) as initiator (eq 15). The polymer can be prepared such that the vinyl group is the connecting site and the amino alcohol portion can either be free or protected. These copolymers are thermally stable and are soluble in polar aprotic solvents such as DMF and DMSO, but insoluble in common organic solvents. Preliminary experiments have shown that these copolymers can be used as asymmetric catalysts. ... 

In the solid phase, Sc(OTf)3 also effectively catalyzed Mannich-type three-component reactions of aldehydes, amines, and PSSEEs to afford polymer-supported /3-amino thioesters (Eq. 22). Reductive cleavage from the supports gave the amino alcohols in good to high yields [85b]. /3-Amino acid and /3-lactam libraries are also constructed according by this method (Eq. 23). 

The first report of a polymer-supported oxazaborolidine appeared in 1985 [37]. The polymer-supported chiral ligand amino alcohol (27) was prepared by reaction of chlor-omethylated polystyrene resin and enantiopure amino alcohol 26 with a phenolic hydroxyl group (Eq. 10). Borane reduction of ketones by use of polymer-supported oxazaborolidines proceeded very smoothly to give the corresponding chiral alcohol in quantitative yield. For example, the reduction of butyl phenyl ketone afforded 1-phe-nylpentan-l-ol in 97 % ee (27, Eq. 11). This is somewhat higher than that obtained by... 

The above mentioned polymer-supported oxazaborolidines are prepared from polymeric amino alcohols and borane. Another preparation of polymer-supported oxazaborolidines is based on the reaction of polymeric boronic acid with chiral amino alcohol. This type of polymer can be prepared only by chemical modification. Lithiation of the polymeric bromide then successive treatment with trimethyl borate and hydrochloric acid furnished polymer beads containing arylboronic acid residues 31. Treatment of this polymer with (li ,2S)-(-)-norephedrine and removal of the water produced gave the polymer-supported oxazaborolidine 32 (Eq. 14) [41 3]. If a,a-diphenyl-2-pyrrolidinemetha-nol was used instead of norephedrine the oxazaborolidine polymer 33 was obtained. The 2-vinylthiophene-styrene-divinylbenzene copolymer, 34, has been used as an alternative to the polystyrene support, because the thiophene moiety is easily lithiated with n-butyl-lithium and can be further functionalized. The oxazaborolidinone polymer 37 was then obtained as shown in Sch. 2. Enantioselectivities obtained by use of these polymeric oxazaborolidines were similar to those obtained by use of the low-molecular-weight counterpart in solution. For instance, acetophenone was reduced enantioselectively to 1-phe-nylethanol with 98 % ee in the presence of 0.6 equiv. polymer 33. Partial elimination of... 

The slow nucleophilic addition of dialkylzinc reagents to aldehydes can be accelerated by chiral amino alcohols, producing secondary alcohols of high enantiomeric purity. The catalysis and stereochemistry can be interpreted satisfactorily in terms of a six-membered cyclic transition state assembly [46,47], In the absence of amino alcohol, dialkylzincs and benzaldehyde have weak donor-acceptor-type interactions. When amino alcohol and dialkylzinc are mixed, the zinc atom acts as a Lewis acid and activates the carbonyl of the aldehyde. Zinc in this amino alcohol-zinc complex is regarded as a kind of chirally modified Lewis acid. Various kinds of polymer-supported chiral amino alcohol have recently been prepared and used as ligands in dialkylzinc alkylation of aldehydes. 

The first report of a polymer-supported approach to this reaction appeared in 1987 [48]. Enantiopure amino alcohols such as ephedrine, prolinol, and 3-exo-amino-isoborneol were attached to Merrifield polymer. The use of polymer-supported 3-exo-aminoisoborneol 40 resulted in quite high enantioselectivity ( 95 % ee) in the ethylation of aldehydes with diethylzinc (Eq. 15), a result comparable with those obtained from the corresponding low-molecular-weight catalyst system (Eq. 16). A similar system was also reported in 1989, this time using ephedrine derivatives (41,42) and prolinol derivative (43) [49]. A methylene spacer was introduced between the polymer and the amino alcohol to improve activity [50]. Despite this the selectivity was always somewhat lower than that obtained from the low-molecular-weight catalyst (44). These chiral polymers were all prepared by the chemical modification method using Merrifield polymer. 

Chiral amino alcohols can be prepared by reaction of chiral epoxides with amines. Enantiopure (25, 3.R)-2,3-epoxy-3-phenylpropanol anchored to Merrifield resin has been used for ring-opening with secondary amines in the presence of lithium perchlorate to afford polymer-supported chiral amino alcohols 47 (Eq. 18) [56], By analogy, (2i ,35)-3-(cis-2,6-dimethylpiperidino)-3-phenyl-l,2-propanediol has been anchored to a 2-chlorotrityl chloride resin (48). Although this polymer had high catalytic activity in the enantioselective addition of diethylzinc to aldehydes, the selectivity of the corresponding monomeric catalyst was higher (97 % ee) in the same reaction. 

Not only polystyrene supports, also other polymer supports were used in the preparation of polymeric amino alcohol ligands for dialkylzinc alkylation. For example, a vinylferrocene derivative with A,N -disubstituted norephedrine was copolymerized with vinylferrocene [60]. This polymeric chiral ligand (53) was used in the ethylation of aldehydes with moderate activity. Brown has reported that chiral oxazaborolidines have catalytic activity in the addition of diethyl zinc to aldehydes [61]. Polymers bearing chiral oxazaborolidines 37 were also active in the reaction and result on moderate enantioselectivity (<58 % ee) [62]. Enantiopure a,a -diphenyl-L-prolinol coupled to a copolymer prepared from 2-hydroxyethylmethacrylate and octadecyl methacrylate... 

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