Polymer oxazaborolidine

Another soluble polymer-enlarged catalyst was synthesized and tested by Wandrey et a/.[57] The catalyst was prepared by a coupling of an oxazaborolidine via a hydrosilylation reaction to a methyl hydrosiloxane-dimethylsiloxane copolymer (Figure 4.40). The catalyst was used in the enantioselective borane reduction of ketones. 

The use of such an oxazaborolidine system in a continuously operated membrane reactor was demonstrated by Kragl et /. 58] Various oxazaborolidine catalysts were prepared with polystyrene-based soluble supports. The catalysts were tested in a deadend setup (paragraph 4.2.1) for the reduction of ketones. These experiments showed higher ee s than batch experiments in which the ketone was added in one portion. The ee s vary from 84% for the reduction of propiophenone to up to >99% for the reduction of L-tetralone. The catalyst showed only a slight deactivation under the reaction conditions. The TTON could be increased from 10 for the monomeric system to 560 for the polymer-bound catalyst. 

Cross-linked polymers bearing IV-sulfonyl amino acids as chiral ligands were converted to polymer bound oxazaborolidine catalysts by treatment with borane or bromoborane. In the cycloaddition of cyclopentadiene with methacrolein, these catalysts afforded the same enantioselectivities as their non-polymeric counterparts238. 

A modified oxazaborolidine 2 catalyzing the enantioselective reduction of acetophenone or tetralone with borane proved to give ttn values in the same order of magnitude [10, 11]. Using a special hydroxyproUne-based polymer-enlarged oxazaborolidine 3, a ttn of 1400 for the reduction of tetralone was achieved (Fig. 3.1.3, 3) [5, 12]. 

A polymer-enlarged homogeneously soluble oxazaborolidine catalyst for the asymmetric reduction of ketones by borane, Tetrahedron Asymm. 1997, 8, 1975-1977. 

A polymer-bound oxazaborolidine catalyst enantioselective borane reductions of ketones, Tetrahedron Asymm. 1995, 6, 2755-2766. 

Y. Y. Chu, Y. Synthetic studies on d-biotin, part 6 an expeditious and enantiocontrolled approach to the total synthesis of d-biotin via a polymer-supported chiral oxazaborolidine-cata-lyzed reduction of meso-cyclic imide strategy. Synthesis 2003, 2155-2160. 

In reactions with polymer-bound catalysts, a mass-transfer limitation often results in slowing down the rate of the reaction. To avoid this disadvantage, homogenous organic-soluble polymers have been utilized as catalyst supports. Oxazaborolidine 5, supported on linear polystyrene, was used as a soluble immobilized catalyst for the hydroboration of aromatic ketones in THF to afford chiral alcohols with an ee of up to 99% [40]. The catalyst was separated from the products with a nanofiltration membrane and then was used repeatedly. The total turnover number of the catalyst reached as high as 560. An intramolecularly cross-linked polymer molecule (microgel) was also applicable as a soluble support [41]. 

Oxazaborolidines have been found to be a unique catalyst for asymmetric borane reduction of ketones and imines [35,36]. Coordination of BH3 to the nitrogen atom of 24 serves to activate BH3 as a hydride donor and to increase the Lewis acidity of the boron atom (Eq. 9). The Lewis acidity of the boron atom in the oxazaborolidine plays an important role in the reduction. Several types of polymer-supported oxazaborolidine have been reported and are considered to be polymer-supported boron-based Lewis acids. 

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... 

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 same reaction has also been catalyzed by chiral oxazaborolidinones derived from amino acids and boranes. They proved to be efficient catalysts for enantioselec-tive Diels-Alder reaction [91,92]. The polymer-supported chiral oxazaborolidinones 75 were reported to be efficient catalysts [93]. These polymer-supported chiral oxaza-borolidinone ligands were prepared both by chemical modification and by the copolymerization shown in Sch. 5 [94]. The polymer-supported chiral ligands were then reacted with borane to give the oxazaborolidines which were used as catalysts in Diels-Alder reaction of cyclopentadiene with methacrolein. 

However, also in this case enantio-selectivities never exceeded the values obtained with the oxazaborolidine in solution, probably because of diffusional limitations within the polymer support, which enhanced the contribution of the non-selective, direct borane reduction of the ketone. In spite of the rather low imprinting effects obtained in these initial attempts, we feel that this approach still represents a most interesting application of molecularly imprinted polymers in catalysis and deserves further attention in the near future. 

The use of membrane reactors is favorable not only with respect to an increase in the total turnover number. In certain cases the selectivity can also be increased by applying high concentrations of the soluble catalyst together with making use of the behavior of a continuously operated stirred-tank reactor. Basically, this is also possible with a catalyst coupled to an insoluble support, but here the maximum volumetric activity is limited by the number of active sites per mass unit of the catalyst. This has been shown for the enantioselective reduction of ketones (eq. (2)) such as acetophenone 5 with borane 6 in the presence of polymer-enlarged oxazaborolidines 8 and 9 [65-67]. 

Price, M. D., Sui, J. K., Kurth, M. J., Schore, N. E. Oxazaborolidines as Functional Monomers Ketone Reduction Using Polymer-Supported Corey, Bakshi, and Shibata Catalysts. J. Org. Chem. 2002, 67, 8086-8089. 

A disulfide-linked bis(aminoethanol) 82 prepared from L-cystine also catalyzes the borane reduction of ketones. Other oxazaborolidine derivatives are obtained from 83, 84, " and 85, " and polymer-bound species. Those derived from the ephedra bases find use in the asymmetric reduction of imines. bicyclic oxazaborolidine generated... 

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... 

The influence of temperature on the selectivity of the reduction of acetophenone and cyclohexylmethylketone by various oxazaborolidines 3.71 (Ar = Ph, R = Me, Bu, Ph) has been examined [S5]. The use of polymer-bound 3.71 has also been proposed [FS3]. Some mechanistic [DTIJ and theoretical investigations of the reductions have also been carried out [DLl, LS6, N4, NU2, QBl]. 

Other polymer-supported oxazaborolidine catalysts (e.g., 71 Fig. 6) have also been used for the ketone reductions [107,108]. 

Homogeneous, Soluble Polymer-Supported Oxazaborolidine Catalysts... 

Linear polymers carrying chiral oxazaborolidine as a pendant group were prepared from a methylhydrosiloxane-dimethylsiloxane copolymer [72]. Borane reduction using the polymeric oxazaborolidine 25 gave (i )-phenylethylalcohol of 97% ee which is as high as in analogous reaction with non-polymeric catalyst. This chiral polymer can be retained by a nanofiltration membrane thus will be suitable for use in a continuously operated membrane reactor. 

The use of oxazaborolidine catalysts in asymmetric reductions of ketones has been extensively studied by Corey et al. Recently, a polymer-bound oxazaborolidine Scheme 3.6.5) was developed and successfully used in the asymmetric reduction of acetophenone. 1-Phenylethanol was obtained in 93% yield and 98% enantiomeric excess. 

The enantioselective reduction of ketones has become a key reaction not only for the production of chiral alcohols, but for the production of fimctionalized compounds in general, thanks to the versatility of the hydroxyl fimctionality. The oxazaborolidine-catalyzed borane reduction of ketones [2] has become an important reaction due to the fact that the stereochemistry of the alcohols can be predicted and because of the wide substrate acceptance of this catalytic system (it works with aromatic as well as with aliphatic ketones). Among all the known oxazaboroUdine catalysts, the proline-based one is very interesting not only because it is one of the most selective catalysts, but also because another related reagent, the 4-hydroproline, is commercially available and possesses a functional group which could be used for the linkage to a polymer. 

Application of polymer-supported oxazo-type compounds (mainly, oxazo-lidinone, oxazoline, and oxazaborolidine derivatives) to asymmetric reactions 05CJ01039. 

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