Chiral aminoalcohols

The molecular modelling approach, taking into account the pyruvate—cinchona alkaloid interaction and the steric constraints imposed by the adsorption on the platinum surface, leads to a reasonable explanation for the enantio-differentiation of this system. Although the prediction of the complex formed between the methyl pyruvate and the cinchona modifiers have been made for an ideal case (solvent effects and a quantum description of the interaction with the platinum surface atoms were not considered), this approach proved to be very helpful in the search of new modifiers. The search strategy, which included a systematic reduction of the cinchona alkaloid structure to the essential functional parts and validation of the steric constraints imposed to the interaction complex between modifier and methyl pyruvate by means of molecular modelling, indicated that simple chiral aminoalcohols should be promising substitutes for cinchona alkaloid modifiers. Using the Sharpless symmetric dihydroxylation as a key step, a series of enantiomerically pure 2-hydroxy-2-aryl-ethylamines... 

Not so long ago, the general opinion was that high enantioselectivity can only be achieved with natural, structurally unique, complex modifiers as the cinchona alkaloids. Our results obtained with simple chiral aminoalcohols and amines demonstrate the contrary. With enantiomeric excesses exceeding 80%, commercially available naphthylethylamine is the most effective chiral modifier for low-pressure hydrogenation of ethyl pyruvate reported to... 

The latter effect has been demonstrated by Meijer et al., who attached chiral aminoalcohols to the peripheral NH2-groups of polypropylene imine) dendrimers of different generations [100]. In the enantioselective addition of diethyl-zinc to benzaldehyde (mediated by these aminoalcohol appendages) both the yields and the enantioselectivities decreased with increasing size of the dendrimer (Fig. 28). The catalyst obtained from the 5th-generation dendrimer carrying 64 aminoalcohol groups at its periphery showed almost no preference for one enantiomer over the other. This behavior coincides with the absence of measurable optical rotation as mentioned in Sect. 3 above. The loss of activity and selectivity was ascribed to multiple interactions on the surface which were... 

Carpentier and coworkers studied the asymmetric transfer hydrogenation of /f-keloeslers using chiral ruthenium complexes prepared from [(// -p-cyrriene)-RuC12]2 and chiral aminoalcohols based on norephedrine. During this study, these authors became aware of substrate inhibition when ketoesters carrying 4-halo-substituents were used. It transpired that this was caused by formation of a complex between the substrate and the catalyst [28]. 

A number of groups have reported the preparation and in situ application of several types of dendrimers with chiral auxiliaries at their periphery in asymmetric catalysis. These chiral dendrimer ligands can be subdivided into three different classes based on the specific position of the chiral auxiliary in the dendrimer structure. The chiral positions may be located at, (1) the periphery, (2) the dendritic core (in the case of a dendron), or (3) throughout the structure. An example of the first class was reported by Meijer et al. [22] who prepared different generations of polypropylene imine) dendrimers which were substituted at the periphery of the dendrimer with chiral aminoalcohols. These surface functionalities act as chiral ligand sites from which chiral alkylzinc aminoalcoholate catalysts can be generated in situ at the dendrimer periphery. These dendrimer systems were tested as catalyst precursors in the catalytic 1,2-addition of diethylzinc to benzaldehyde (see e.g. 13, Scheme 14). 

Chiral aminoalcohols both catalyze reactions of simple dialkylzinc reagents with aldehydes and also induce a high degree of enantioselectivity, even when used in only catalytic amounts. Two examples are given below. Indicate how the aminoalcohols can have a catalytic effect. Suggest transition states for the examples show which would be in accord with the observed enantioselectivity. 

In 1996, Enders and coworkers reported the asymmetric epoxidation of ( )-enones 91 in the presence of stoichiometric amounts of diethylzinc and (lR,2R)-A-methylpseudo-ephedrine (120) under an oxygen atmosphere to give fraw -epoxides 92 with excellent yields (94-99%), almost complete diastereoselectivity (>98% de) and with very good enantioselectivities (61-92%) (Scheme 54) . For the same reaction Pu and coworkers utilized achiral polybinaphthyl 121 as ligand (in excess) instead of the chiral aminoalcohol. For each substrate, only one diastereomer was formed, but in most cases yields were lower than observed with the Enders system. Enders catalyst shows high asymmetric induction for alkyl-substituted enones (ee 82-92%), but for substrates bearing only aromatic substituents only modest enantioselectivity was obtained (R = R = Ph ... 

Chiral aminoalcohols (45), derived from (2S, 4S)-4-hydroxyproline and (S)-proline, respectively, were found to be superior catalysts for the enantioselective 1,4-addition of arylthiols to 2-cyclohexen-l-one to yield 3-arylthiocyclohexanones (46) 82). 

The thiolester group was used for deracemization of terpenic esters [254]. Racemic 5-phenyl thiocyclogeranate was deprotonated by n-BuLi, and the resulting enolate was protonated by a chiral aminoalcohol, ( )-N-isopropylephedrine. The thiolester was obtained with the highest enantioselectivity (99% e.e.) reported for such a process (carried out on a 40 g scale). With a sulfur group a selective (Z)-enolate was formed and protonation was slower than for esters. 

A substoichiometric or stoichiometric amount of chiral aminoalcohol accelerates the enantioselective addition of diethylzinc to enones even without Ni(acac)2 in up to 94% ee.31... 

An interesting version of the transesterification reactions was reported by Movassaghi et al., with the amidation of unactivated esters with amino alcohols (Scheme 9.27) [73]. The amidation was explained by carbene-alcohol interactions. A nucleophilic activation of the hydroxyl group of the aminoalcohol 90 by the catalyst 11 is followed by transesterification to the ester 91 which is in-situ-converted to the amide 92 through a N —> O acyl transfer. Various aliphatic and aromatic esters with different functionalities, as well as chiral aminoalcohols, are suitable for this reaction. 

Scheme 12 Option. The oxynitrilase-catalyzed HCN addition to the aldehyde Xin appeared to offer an attractive prospect presuming that the R-cyanohydrin (XIV) could be formed, and this then converted to dilevalol via intermediates XV and XVI. Although the oxynitrilase-catalyzed formation of chiral aromatic and aliphatic cyanohydrins and their reduction to chiral aminoalcohols has been known for some time,16 the selective reduction of XIV to XV and the likelihood of 100% induction in the reduction of the Schiff base XVI raised many questions.

Fig. 10.40. Catalytic asymmetric addition of Et2Zn to Ph— C(=0)H. Chiral amplification through a mutual kinetic resolution of the (auxiliary/ZnEt)2 complex which is produced from two molecules of chiral aminoalcohol and diethylzinc each.

In 1981, Hirao and others reported that the chiral borane-amine complex 25a, derived from (S)-prolinol and 1 equivalent of BH3 THF, enantioselec-tively reduced propiophenone to afford (R )-l -phenyl-1 -propanol (26) in 44% ee9 (Scheme 4.3h). The chiral complex 25b was even better than 25a, affording the same secondary alcohol in 60% ee. Two years after the initial disclosure, Hirao et al. uncovered a new catalyst system that improved the previous experimental conditions dramatically10 (Scheme 4.3i). When the chiral aminoalcohol 27, prepared from (S)-valine methyl ester hydrochloride and phenylmagnesium bromide, was used along with 2 equivalents of BH3 THF, the enantioselectivity of the alcohol 26 jumped to 94% ee. In addition, the reaction time was shortened to 2 hours. 

In our previous studies, we supported a chiral aminoalcohol, (-)-ephedrine, on Mesoporous Templated Silicas (MTS).8 10 The enantioselective alkylation of benzaldehyde by diethylzinc (Model reaction) was performed using catalytic amounts of the supported aminoalcohol. Our first results8 were in good agreement with precedent results by Soai and al. using silica gel and alumina supported (-)-ephedrine.7 Lower rates, selectivities and enantioselectivities were obtained compared with homogeneous catalysis. 

Among the very few papers published after the above review appeared, two deserve some comment. The asymmetric protonation of the lithium enolate of a thiopyranic thioester by an ephedrine-derived chiral aminoalcohol described by Ward and coworkers leads to the desired enantiomer in 99% yield and 82% e.e., provided the reaction was performed in carefully designed conditions (Scheme 79)373. 

Even the very efficient enantioselective catalysts used in organozinc addition reactions to carbonyl compounds failed to catalyze the corresponding addition reactions to nonactivated imines such as A-silyl-, A-phenyl-, or iV-benzyl-imines. However, enantioselective additions of diaUcylzinc compounds to more activated imines, like iV-acyl- or iV-phosphinoyl-imines, in the presence of catalytic or stoichiometric amounts of chiral (see Chiral) aminoalcohols, have been recently reported. For example, in presence of 1 equiv of (A,A-dibutylnorephedrine) (DBNE) diethylzinc reacts with masked A-acyl imines like A-(amidobenzyl)benzotriazoles, to give chiral A-(l-phenylpropyl)amides with up to 76% e.e. (equation 68). 

Similar yield and enantioselectivity were obtained with chalcones when Co(acac)2 was substituted for Ni(acac)2 catalysts under otherwise identical reaction conditions. However, the cobalt-catalyzed reaction was significantly slower and produced a significant amount of reduced by-product (5%) compared to reactions catalyzed by nickel. For both the cobalt- and nickel-catalyzed reactions, both (—)DAIB and (+)DAIB were shown to be superior to several chiral aminoalcohols for enantioselectivity. 

Related Reagents. Chiral aminoalcohols (prolinol, cinchoni-dine, quinidine) and polystyrene-attached analogs of (—)DAIB. 

An efficient synthesis of new chiral phosphonylated thiazolines (332), readily accessible from phosphonodithioacetate and commercial chiral aminoalcohols via intermediate (333), has been described. (Scheme 88). These thiazolinephos-phonates (332) were then involved in H-W-E reactions to give asymmetric vinylic thiazolines. ... 

The same conversion is successfully catalyzed by using in-situ generated complexes of Ti(OPr )4 and tridentate Schiff bases (Stmcture 54), which are derived from substituted salicylaldehydes with chiral aminoalcohols [85]. Another similar chiral reagent is derived from reaction of titanium tetraisopropoxide and the Schiff base of 3,5-di-tert-butylsalicylaldehyde and (5)-valinol. The mechanism and stereoselectivity of these chiral Lewis acids are discussed by Corey and co-workers. Other chiral Ti Schiff base complexes have been employed in asymmetric TMSCN addition to benzaldehyde [85]. 

Breakthrough was brought by using an ephedrine-derived chiral aminoalcohol 8 to effect conjugate addition of organolithiums with over 90% enantioselectivity (Eq. (12.14)) [37]. The relationships between cluster structure and enantiofacial selection are a matter of discussion [38]. The sense of the observed enantiofacial selection was rationalized by the model 9. 

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