Polymer chiral amino alcohol

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. 

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. 

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. 

Kobayashi et al. developed chiral Lewis acids derived from A -benzyldiphenylproli-nol and boron tribromide and used these successfully as catalysts in enantioselective Diels-Alder reactions [89]. The corresponding polymeric catalyst 71 was prepared and used for the Diels-Alder reaction of cyclopentadiene with methacrolein [90]. Different polymeric catalysts 72, 73, 74 were prepared from supported chiral amino alcohols and diols fimctionalized with boron, aluminum and titanium [88,90]. In these polymers copolymerization of styrene with a chiral auxiliary containing two polymerizable groups is a new approach to the preparation of crosslinked chiral polymeric ligands. This chiral monomer unit acts as chiral ligand and as a crosslink. 

One of the most powerful asymmetric catalytic reductions of ketones is borane reduction with oxazaborolidine catalyst [92, 93]. Various types of polymer-supported chiral amino alcohols have been prepared and used for the formation... 

Norephedrine and its derivahves are efficient chiral ligands of the catalyst for asymmetric transfer hydrogenation. By using a 7 3 copolymer of a PEG ester and a hydroxyethyl ester, polymer-supported norephedrine 171 was prepared. The polymeric norephedrine/Ru(II) complex catalyzed the reduction of acetophenone in up to 95% yield and 81% ee (Scheme 3.52) [102]. Polymer-supported chiral amino alcohol 172 was also used for the same reaction [103]. 

A polyacetylene-type helical polymer having chiral amino alcohol pendant groups has also been prepared by the polymerization of chiral (S )-threonine-based... 

Other polymer-supported catalysts for the asymmetric Diels-Alder reaction include aluminum and titanium complexes of chiral amino alcohols [74],... 

The addition of diethylzinc to aldehydes produces secondary alcohols. This process can be stereoselectively catalyzed by chiral amino alcohols that form Schiff-base zinc complexes with the aldehyde and the metal. With the aim of simplifying the work-up of these reactions and to use continuous-flow processes, the polymer-supported amino alcohols 115 and 116 were synthesized (Scheme 21) [91]. The polymers were obtained by co-polymerization of the chiral monomer 117 and styrene 58 in the presence of divinylbenzene (118) or cross-tinldng agent 119 containing a flexible oxyethylene chain. The latter was used to ensure sufficient flexibility within the cross-linked network of the polymer and to further activate the nucleophile by coordination of the oxyethylene chain to the metal. 

Many supported or heterogeneous catalysts used for Diels-Alder reactions are known to give better results than their non-supported analogues. Nevertheless, chiral catalysts for asymmetric Diels-Alder reactions are scarce. Mayoral, Luis and coworkers studied the use of a variety of chiral polymer-bound amino alcohols as catalysts in cycloaddition reactions. Reaction of cyclopentadiene with methacrolein in the presence of (S)-prolinol-derived resin 81 proceeded with excellent yield (98%) but poor enantioselectivity (14% e.e.) as shown in Scheme 3.6.8. Once again, extrapolation from solution phase chemistry to a solid-supported reaction proved difficult. 

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]. 

Similar polymeric chiral ligand of N-sulfonylated amino alcohol (171) was developed by Gau et al. [74]. The polymeric chiral ligand (171) was prepared by two methods chemical modification method and polymerization method (Scheme 19.35). Chemical modification of chlorosulfonylated polystyrene with chiral amino alcohol, (1R,2S)-2-amino-1,3-dipheny 1-1-propanol, afforded (171). The copolymerization of the chiral N-sulfonylated amino alcohol monomer with styrene in the presence of divinylbenzene also yielded the polymer (171). These polymers were complexed with Ti(O Pr)4 to apply to ZnEt2 addition to benzaldehyde. Higher enantioselectivity was obtained by using (171) prepared by polymerization method. 

Few chiral reagents bound to polymers have succeeded in asymmetric syntheses with high enantiomeric excess (ee). Chiral amino alcohol reagent (42), prepared from (S)-tyrosine, and 2.0 molar equivalents of borane in THF at 30 °G, reduced alkyl phenyl ketones to secondary alcohols in 76-97% ee and quantitative yield and reduced acetophenone 0-methyloxime to 1-phenyl-ethylamine in 99% ee and 85-95% yield as shown in Scheme 15. Reagent (42) was easily recycled. 

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). 

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. 

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]. 

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]. 

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... 

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 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. 

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... 

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. 

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