Dialkyl amino alcohol catalysts

In 2008, the transacylation properties of a series of dialkyl amino alcohol catalysts 53 and 54 was studied in more detail by the Wessjohann group (Fig. 7.5) [52]. 

The influence of structural and electronic parameters on the acylation and deacylation rate were separately studied (catalyst-on half cycle vs. catalyst-off half cycle cf. scheme 7.10). Through kinetic H-NMR-studies it was proven that the acylation rate of the dialkyl amino alcohol catalysts and an acyl donor (butyric anhydride) depends on the number of (carbon) spacer atoms between hydroxyl and tertiary amine, the flexibility of the molecule and the presence and position of further heteroatoms. Besides, it could be detected that the methanolysis (off-half cycle) of the formed ]3-amino ester intermediate follows a similar trend as the acylation reaction, but appeared to be rate limiting in this studies setup. The information was used for the selective auto-catalytic acylation and deacylation of complex natural antibiotics. 

Fig. 7.5 Series of dialkyl amino alcohols 53 and 54. The catalysts 54a and 54d are the most active ones [52]...

Prochiral aryl and dialkyl ketones are enantioselectively reduced to the corresponding alcohols using whole-cell bioconversions, or an Ir1 amino sulfide catalyst prepared in situ.695 Comparative studies show that the biocatalytic approach is the more suitable for enantioselective reduction of chloro-substituted ketones, whereas reduction of a,/ -unsaturated compounds is better achieved using the Ir1 catalyst. An important step in the total synthesis of brevetoxin B involves hydrogenation of an ester using [Ir(cod)(py) P(cy)3 ]PF6.696... 

Transition State Models. The stoichiometry of aldehyde, dialkylzinc, and the DAIB auxiliary strongly affects reactivity (Scheme 9) (3). Ethylation of benzaldehyde does not occur in toluene at 0°C without added amino alcohol however, addition of 100 mol % of DAIB to diethylzinc does not cause the reaction either. Only the presence of a small amount (a few percent) of the amino alcohol accelerates the organometallic reaction efficiently to give the alkylation product in high yield. Dialkyl-zincs, upon reaction with DAIB, eliminate alkanes to generate alkylzinc alkoxides, which are unable to alkylate aldehydes. Instead, the alkylzinc alkoxides act as excellent catalysts or, more correctly, catalyst dimers (as shown below) for reaction between dialkylzincs and aldehydes. The unique dependence of the reactivity on the stoichiometry indicates that two zinc atoms per aldehyde are responsible for the alkyl transfer reaction. 

Catalytic reactions have the advantage over the methods discussed so far in that the chiral catalyst need not be added in stoichiometric amounts, but only in very small quantities, which is important if not only the metal (very often a precious one) but also the chiral ligand are expensive. Among the ferrocenes, phosphines are by far the most important catalysts for stereoselective reactions, and are covered in Chapter 2 of this book. We will therefore focus here mainly on the catalytic applications of chiral ferrocenes not containing phosphine groups. Only recently, some progress has been made with such compounds, mainly with sulfides and selenides, and with amino alcohols in the side chain (for this topic, see Chapter 3 on the addition of dialkyl zinc to aldehydes). 

Though not so general as the reactions we have just seen, the catalysed addition of dialkyl zincs to certain aldehydes sets a new standard for catalysis that needs some explaining. Dialkyl zincs add to the pyrimidine aldehyde 216 under catalysis from amino alcohols, amino acids such as leucine 219, hydroxy acids, and simple secondary alcohols or amines such as 218 to give enantiomerically enriched alcohols 217. Plain sailing so far, except for the extraordinary range of catalysts. 

Very high yields of alkyl phosphorodiamidites (48), or unsymmetrical dialkyl phosphoramidites (49), are realised by treatment of tris(dialkylamino)phosphines (50) with the stoichiometric amount of alcohol in the presence of catalytic amounts of iodine.Instead of iodine, a diethylammonium diethyldithio-carbamate/diethylamine catalyst also effects the selective transformation of (50, R = Et) to (48)A series of tris(dialkyl-amino)phosphines (51) has been prepared from tris(diethylamino)-phosphine by transamination no catalyst was added, and di-ethylamine was removed by pumping. 

Extension of the enamine-mediated carbonyl a-amination strategy to the generation of quaternary stereogenic centers at the a-position of a-branched aldehydes under catalysis by prohne 1 [8, 9], pyrrolidine tetrazole 3 [10, 11], or L-azetidin-2-carboxylic acid 4 [8] has also been explored (Table 11.1). The observed enantio-selectivities ranged from essentially none to >99%. Derivatives of 2-phenylpropanal gave better enantioselectivities than a,a-dialkyl substituted aldehydes. Erase and coworkers [11] employed microwave irradiation to accelerate the rate of proline-catalyzed amination, and found that yields as well as enantioselectivity can be somewhat improved with shorter reaction times. It appears that the pyrrolidine tetrazol 3 was a more effective catalyst than L-proline 1 for the amination of 2-phenylpropanal derivatives [10,11]. Subsequent reduction of adducts and cyclization could be carried out to afford the respective a-amino alcohols or the A-amino-oxazolidinones. 

Isomers of ris-l-amino-2-indanol have attracted considerably less attention, although improved asymmetric inductions have been reported on several occasions. Diethylzinc addition to aldehydes with m-.V-disubslil tiled-1 -amino-2-indanols as catalysts yielded secondary alcohols with low enantiomeric excesses (40-50%),37 whereas r/.v-N-disubstituted-2-amino-1 -indanols led to increased selectivities (up to 80% ee) (see Section 17.3.2).46 High degrees of enantioselection were eventually achieved in the addition of diethylzinc to aliphatic and aromatic aldehydes with /raw.v-N-dialkyl-l-substituted-2-amino-l-indanols as catalysts (Scheme 17.25).47 Optimal results were obtained with bulky groups at the hydroxy-bearing carbon and at the nitrogen (R = Ph, R1 = ft-Bu), which led to the formation of (R)-l-phenylpropanol in 90% yield and 93% ee. 

V,7V-Dialkyl derivatives of 1 have been successfully applied to the asymmetric addition of dialkylzinc reagents to aldehydes, giving products of moderate enantiomeric excess.In addition, ruthenium(II) complexes of 1 have been demonstrated to be excellent catalysts for the control of the enantioselective transfer hydrogenation of ketones to alcohols at catalyst loadings as low as 1 mol The ruthenium/1 complex has been applied to a range of ketone substrates, including cyclic enones and a-amino and alkoxy substituted derivatives. 

Another example was reported in 2012 by the group of Liu. Dinuclear iridium(I) complexes with a bridging saturated dicarbene ligand turned out to be efficient catalysts for the N,N -dialkylation of phenylenediamines with various alcohols (Fig. 24). Interestingly, with simple [Ir(COD)Cl]2 as catalyst, the intermediate imino—amino compound was predominantly formed. The authors claim the much higher selectivity for the diamino product... 

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