Polymer modification, enantioselective

Duxbury and coworkers recently developed a new chiral enzyme-responsive polymer based on enantioselective polymer modification [151]. With the aid of two alcohol dehydrogenases that show opposite enantioselectivities in the reduction of ketones (ADH-LB and ADH-T), the two enantiomers of p-vinylpheny-lethanol were obtained in excellent yield and ee. Copolymers of these monomers with styrene using free radical polymerization afforded random block copolymers... 

This initial observation by Inoue et al. triggered intensive research in this area. Most of the efforts were dedicated to structural variation of the catalyst and to elucidation of the catalytic mechanism. With regard to the former, the many structural variations produced mainly confirmed 1 as the optimum catalyst. Variation of the aromatic amino acids involved [25, 26], side-chain methylation and/or modification [27], N-methylation [28], etc., all afforded catalysts of lower selectivity. In contrast, incorporation of a-Me-Phe led to diketopiperazines of activity and selectivity comparable with those derived from non-methylated Phe (for example 1) [29]. Similarly, attachment to Merrifield-resin or polysiloxane polymers proved detrimental to the enantioselectivity of the Inoue-catalyst 1 [30, 31]. Upon incorporation into a silicon based sol-gel glass matrix, however, the excellent enantioselectivity of the cyclic peptide 1 is preserved, and separation of the spent catalyst can easily be achieved by, e.g., filtration, centrifugation or simply decantation [32], Unfortunately, further catalytic cycles afforded much lower ee (ca. 30-35% max.) [32],... 

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 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. 

Since the first report on Ti-TADDOLate-mediated Diels-Alder reactions [97,98] several studies of the same reaction have been reported these have shown that Ti-TADDOLate is an efficient chiral Lewis acid in enantioselective Diels-Alder reactions. Polymer- and dendrimer-supported Ti-TADDOLates have been reported and their catalytic activity in several enantioselective reactions has been evaluated [59]. Various kinds of polymeric TADDOLs were prepared both by chemical modification (Eq. 22) and by copolymerization (Eq. 23). 

It has recently been demonstrated that this reaction could be used for the epoxidation of a broader class of enones and excellent enantioselectivities were obtained provided the enone was substituted at the 3-position [48,49,50]. However, essentially no asymmetric induction was observed with cyclic enones [51]. Further practical improvements in this reaction have recently been made. Roberts found that the use of anhydrous urea-hydrogen peroxide with DBU in THF as a two-phase system (polymer and organic phase) resulted in rapid epoxidation with high levels of asymmetric induction [52]. This modification solves many of the problems associated with the original procedure (oxidant decomposition, long reaction times, work up) and provides a very practical oxidation system (Scheme 17). 

One of the most studied polymerization systems employs alkyllithium initiators that are modified by chiral amine ligands for the polymerization of sterically bulky methacrylates [8,38,39,40,41], acrylates [42],crotonates [43], and acrylamides [44]. A primary example is the reaction of triphenylmethyl methacrylate with an initiator derived from 9-fluorenyllithium and (-)-sparteine (3) at -78 °C (Scheme 4). The resultant isotactic polymer is optically active, and is postulated to adopt a right-handed helix as it departs from the polymerization site. This polymer has been particularly successful as a chiral stationary phase for the chromatographic resolution of atropisomers [8]. Many modifications of the or-ganolithium initiator/chiral ligand system have been explored. Recently, Okamo-to has applied enantiopure radical initiators for the enantioselective polymerization of bulky methacrylate monomers [45]. 

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. 

Ephedrine and pseudoephedrine auxiliaries are cheap commercially available compounds and readily accessible without any further modification. Procter and coworkers developed a polymer-supported pseudoephedrine auxiliary for asymmetric alkylations on solid phase." The resin-bound amide 109 is deprotonated and alkylated with benzyl bromide to provide enantiopure 110. Treating later with different reagents resulted in the enantioselective formation of various alcohols, acids, and amide in 31-55% yield (overall yields), with ee ranging from 78% to 92% (Scheme 7.23). 

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