Enantioselective Addition of Dialkylzincs to Aldehydes

Soai et al. [62a] first reported the use of sihca gel or alumina as a heterogeneous support for chiral catalysts in the enantioselective addition of dialkylzincs to aldehydes. Chiral N-alkyhrorephedrines (R = Me, Et, n-Pr) were immobilized covalently on (3-chloropropyl)silyl-functionalized alumina or silica gel via a nucleophilic substitution. However, the catalytic activities and enantioselectivities were only moderate (24—59% ee) in comparison with those of homogeneous and polymer- 

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CATALYTIC ENANTIOSELECTIVE ADDITION OF DIALKYLZINCS TO ALDEHYDES USING (2S)-(-)-3-exo-(DIMETHYLAMINO)ISOBORNEOL [(2S)-DAIB] (S)-I-PHENYL-I-PROPANOL (Benzenemethanol, a-ethyl-, (S)-)... 

A. Enantioselective Addition of Dialkylzincs to Aldehydes using Lewis... 

Chirality plays a central role in the chemical, biological, pharmaceutical and material sciences. Owing to the recent advances in asymmetric catalysis, catalytic enantioselective synthesis has become one of the most efficient methods for the preparation of enantiomer-ically enriched compounds. An increased amount of enantiomerically enriched product can be obtained from an asymmetric reaction using a small amount of an asymmetric catalyst. Studies on the enantioselective addition of dialkylzincs to aldehydes have attracted increasing interest. After the chiral amino alcohols were developed, highly enantioselective and reproducible —C bond forming reactions have become possible. 

On the other hand, Soai and coworkers found that chiral thiophosphoramidate 27 formed a complex with Ti( OPr- )4 and that the chiral complex catalyzed the enantioselective addition of dialkylzincs to aldehydes to afford enantioenriched. sec-alcohols in high enantiomeric excess31. In particular, the addition of dicyclopropylzinc exhibits very high enantioselectivity (up to 97% )32. 

The amino alcohol-catalyzed enantioselective addition of dialkylzincs to aldehydes, detailed in Chapter 5 (27), is accomplished with polymer catalysts containing DAIB, a camphor-derived auxiliary, and other chiral amino alcohols (28). Reactions that involve matrix isolation of the catalyst not only result in operational simplicity but also greatly facilitate understanding of the reaction mechanism. In solution, the catalytic chiral alkylzinc alkoxide derived from a dialkylzinc and DAIB exists primarily as dimer (27) however, when immobilized, its monomeric structure can be maintained. 

In the course of the continuing study [9a,b] on the enantioselective addition of dialkylzincs to aldehydes by using chiral amino alcohols such as diphenyl(l-methyl-2-pyrrolidinyl)methanol (45) (DPMPM) [48] A. A -dibutylnorephedrine 46 (DBNE) [49], and 2-pyrrolidinyl-l-phenyl-1-propanol (47) [50] as chiral catalysts, Soai et al. reacted pyridine-3-carbaldehyde (48) with dialkylzincs using (lS,2/ )-DBNE 46, which gave the corresponding chiral pyridyl alkanols 49 with 74-86% ee (Scheme 9.24) [51]. The reaction with aldehyde 48 proceeded more rapidly (1 h) than that with benzaldehyde (16 h), which indicates that the product (zinc alkoxide of pyridyl alkanol) also catalyzes the reaction to produce itself. This observation led them to search for an asymmetric autocatalysis by using chiral pyridyl alkanol. 

The enantioselective addition of dialkylzinc to aldehydes catalysed by chiraPp-aminoalcohol has also excellent chemoselectivities which are not usually achieved with Grignard reagents and alkyllithiums both of which have excess reactivities. Thus enantio- and chemoselective addition of dialkylzincs... 

Heterogeneous chiral catalysts are useful because of the easier separation of catalyst from the product and recovery process than homogeneous chiral catalysts. Heterogeneous chiral catalysts supported on polystyrene-type resin catalyse the highly enantioselective addition of dialkylzincs to aldehydes.17... 

Catalytic Enantioselective Addition of Dialkylzincs to Aldehydes. DPMPM (1) is a chiral amino alcohol which is a precursor to a chiral catalyst for the enantioselective addition of dialkylzincs to aldehydes. In the presence of 2 mol % of (.S)-(l), optically active alcohols of up to 100% ee are obtained from the enantioselective addition of dialkylzincs to aldehydes (eq 1, Table 1). When benzaldehyde is allowed to react with Diethylzinc using (5)-(l) (2 mol %), (5)-l-phenylpropan-l-ol with 97% ee is obtained in quantitative yield (entry 1). When the lithium alkoxide of (5)-(l) (5 mol %) is employed as a chiral ligand in the addition to aromatic aldehydes, ee s of the alcohols obtained increase... 

Enantioselective Addition of Dialkylzincs to Aldehydes Using Chiral Amino Alcohols Derived from Ephedrine. Nucleophilic addition of dialkylzinc to aldehydes is usually very slow. Amino alcohols facilitate the addition of Diethylzinc to benzalde-hyde to afford l-phenylpropanol. When chiral amino alcohols possessing the appropriate stracture are used as a precatalyst, optically active secondary alcohols are obtained. Highly enantioselective chiral catalysts derived from ephedrine are known. (lR,25)-N-Isopropylephedrine functions as a precatalyst for the enantioselective addition of diethylzinc to benzaldehyde to afford (R)-l-phenylpropanol with 80% ee in 72% yield. The use of an excess amount of diethylzinc increases the enantioselectivity up to 97% ee (eq 17). ... 

The dilithium salt of a chiral diaminodiol derived from ephedrine mediates the enantioselective addition of dialkylzinc to aldehydes to afford (f )-l-phenylethanol with 85% ee (eq 19). ... 

Enantioselective Addition of Dialkylzincs to Aldehydes with Functional Groups. Enantioselective and chemoselective addition of dialkylzincs to formyl esters using (15,2R)-DBNE as a catalyst affords optically active hydroxy esters. The subsequent hydrolysis of the esters affords the corresponding optically active alkyl substituted lactones with up to 95% ee (eq 13). ... 

Enantioselective Addition of Dialkylzinc to Aldehydes Catalyzed by Chiral Ferrocenyl Aminoalcohols... 

Optically active ferrocene derivatives, particularly ferrocenyl phosphines, have hitherto been utilized as chiral ligands for a wide range of asymmetric synthesis. We have now revealed that the ferrocene moiety can easily be incorporated in amino alcohol ligands instead of phosphinic ligands. The preparative methods for several types of ferrocenylamino alcohols were developed and they were successfully used to catalyze enantioselective addition of dialkylzinc to aldehydes with high enantio-selectivity. In particular, 1,2-disubstituted ferrocenyl amino alcohols with planar... 

As for the reduction of the ketones, the amphoteric catalysts featuring acidic-basic sites have been found to be very effective for the enantioselective catalysis of C-C bond formation. Thus, Soai et al. were the first to report the enantioselective addition of dialkylzincs to aldehydes using enantiomerically pure phosphin-amides and analogues as chiral catalysts in the presence of titanium tetraiso-propoxide. Numerous chiral organophosphorus compounds have been prepared and applied in a test reaction between benzaldehyde and diethylzinc [48, 49]. An important difference in terms of enantioselectivity was observed between the behavior of P=S (47-48) and P=0 (49) groups. Thus, the enan-... 

Enantioselective addition of dialkylzinc to aldehydes of pyridines, pyrimidines, and quinolines leading to chiral hetarylalkanoles which act as asymmetric autocatalysts 04BCJ1063. 

Recently, Soai et al. reported the synthesis of series of chiral dendrimer amino alcohol ligands based on PAMAM, hydrocarbon and carbosilane dendritic backbones (Figure 4.31) [99-102]. These chiral dendrimers were used as catalysts for the enantioselective addition of dialkylzincs to aldehydes and N-diphenylphosphi-nylimines (Scheme 4.25). The molecular structures of the dendrimer supports were shown to have a significant influence on the catalytic properties. The negative dendrimer effect for the PAMAM-bound catalysts was considered due to the fact that the nitrogen and oxygen atoms on the dendrimer skeleton could coordinate to zinc. 

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