Phenylpropanols, alkylation with

An interesting example of alkylation with alcohols is the selective transformation of isomeric phenylpropanols under appropriate reaction conditions 199... 

Scheme 3.15 illustrates a different auxiliary derived from camphor, and which has similar design features, but which affords higher diastereoselectivity [75]. Additionally, Scheme 3.15 illustrates the selective formation of either an E(0)- or Z(0)-enoIate based on the presence or absence of HMPA in the reaction mixture. Thus, deprotonation of the ester with LICA is 98% selective for the fO>enolate and deprotonation in the presence of HMPA is 96% selective for the ZfO]-enolate. Alkylation with benzyl bromide is more selective for the E(0)-enolate than for the Z(0), but after diastereomer separation, reduction gives enantiomerically pure R-or S-2-methyl-3-phenylpropanol, opposite enantiomers from the same auxiliary... 

Both enantiomers of 2-methylamino-l-phenylpropanol (ephedrine, 1), which are commercially available and relatively inexpensive, have been used as auxiliaries in many syntheses of chiral compounds. Ephedrine can be used for amide alkylations both directly1-3, or as derived heterocyclic compounds (see Sections 1.1.1.3.3.4.2.1. and 1.1.1.3.3.4.2.2.). Acyclic derivatives of ephedrine are discussed in this section. For example, either enantiomer of ephedrine gives A-acylephedrines 2 in good yield without epimerization if treated with an anhydride at 65 °C for 10 minutes2. 

An amino alcohol was found to accelerate the addition reaction of diethlylzinc to aldehyde [8], and then chiral amino alcohols were proved to be efficient chiral catalysts for asymmetric alkylation by using dialkylzinc reagents [9], Oguni reported a remarkable asymmetric amplification in chiral amino alcohol-promoted alkylation (Scheme 9.4). In the presence of (-)-l-piperidino-3,3-dimethyl-2-butanol (5) of 11% ee, benzaldehyde is alkylated enantioselectively to give (/ )-l-phenylpropanol with 82% ee [10]. Asymmetric amplification was also observed by Noyori using partially resolved (2.S )-3-exo-(dimethylamino)isobomeol (6) [11]. 

In the optical resolution of cyanohydrins, it was first found that brucine (4) is a suitable host for the cyanohydrins which substituted with one aromatic group and one bulky alkyl group. In this case, not only a simple enantiomer separation of rac-cyanohydrin but also its transformation to one enantiomer occurred and one pure enantiomer was obtained in a yield of more than 100%. For example, when a solution of rac-l-cyano-2,2-dimethyl-l-phenylpropanol (61a) (1.0 g, 5.3 mmol) and 4 (2.1 g, 5.3 mmol) in MeOH (2 ml) was kept in a capped flask for 12 h, a 1 1 brucine complex of (+)-61a (2.08 g, 134%, mp 112-114 °C) separated out as colorless prisms. Decomposition of the complex with dil HC1 gave (+)-61a of 97% ee (0.67 g, 134%). From the filtrate, rac-61a (0.33 g, 33%) was obtained.273 The... 

Surprisingly, the introduction of the pyridine ring not only influences the velocity of the enzymatic transformations, but also induces promising stereochemical effects (Table 1). For instance, at 40% conversion (R)-phenylethanol is obtained from the pyridyl acetate 25 with 73 % ee, whereas the value for the corresponding phenylacetate is only 28%. Also, the secondary alcohol liberated from the ester 26 displays 98% ee at 40% conversion, whereas the respective phenylacetate leads to 1-phenylpropanol with 94% ee but at a conversion rate of 12% only [19,20]. These results demonstrate that the stereoselecting properties of penicillin acylase may be enhanced by appropriate engineering of the substrate. This is of particular interest since this enzyme has already been used for the kinetic resolution of various chiral alcohols [21-24], e.g. furyl alkyl carbinols [24], which are valuable precursors for the de novo synthesis, with moderate to high ee values, of carbohydrates. 

Nonracemic Ti-BINOLate (BINOL = l,l -bi-2-naplilli()l) and Ti-TADDOLate (TADDOL = a,a,a, a -tetraaryl-2,2-dimethyl-l,3-dioxolan-4,5-dimethanol) complexes are also effechve chiral catalysts for the asymmetric alkylation of aldehydes [9-11]. Seebach developed polystyrene beads with dendritically embedded BINOL [9] or TADDOL derivatives 11 [10, 11]. As the chiral ligand is located in the core of the dendritic polymer, less steric congeshon around the catalyhc center was achieved after the treatment with Ti(OiPr)4. This polymer-supported TiTADDOLate 14 was then used for the ZnEt2 addition to benzaldehyde. Chiral 1-phenylpropanol was obtained in quantitahve yield with 96% ee (Scheme 3.3), while the polymeric catalyst could be recycled many times. 

The tri-2-phenylpropylborane formed can be oxidized and hydrolyzed to 2-phenylpropanol-l, thus representing [as with aluminum alkyls (146)] an overall anti-Markownikoff hydration of a-olefins. Besides employing trialkylboranes as a source of boron hydrides, similar additions have been accomplished by heating olefins with boron hydride-amine complexes. As the latter are not as oxygen-sensitive, they are easier to handle (73) ... 

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