Enantioselective addition of dialkylzincs

The tridentate ligands C, L and M are effective catalysts for the enantioselective addition of dialkylzincs to aromatic aldehydes16,17. In particular, ligands L and M qualify as members of the chemical enzyme (chemzyme) class of synthetic reagents17, since they function in a predictable, clear-cut mechanistic way. As demonstrated by X-ray diffraction, the actual catalyst is a monomeric zinc chelate 2 formed in toluene at 50 C by reaction of L or M with one equivalent of diethylzinc. 

In the reported enantioselective additions of dialkylzincs and diphenylzinc to aldehydes, a great variety of structurally different ligands with different kinds of chirality have been used. A very detailed account of major developments in this area up to the year of 2001 can be found in a review of L. Pu and H.-B. Yu.2 0 The majority of... 

Enantioselective additions of dialkylzincs and diphenylzinc to enones and related compounds were accomplished using catalytic amounts of Gu salts and optically active ligands, including biphenol-based phosphoramidites301-304... 

Enantioselective addition of diethylzinc to benzaldehyde has been promoted by indole-containing chiral oxazolidines (which are able to use both O and N atoms to effect metal coordination in the transition state), and by chiral o-hydroxyphenyl diaza-phospholidine oxide,and by chiral aziridino alcohols.Enantioselective addition of dialkylzinc to prostereogenic ketones has been promoted using chiral camphorsul-fonamide derivatives. 

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... 

B. Enantioselective Addition of Dialkylzincs using Lewis Acid Catalysts. 559... 

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. 

On the other hand, in the presence of Lewis acid, addition of dialkylzinc to ketones occurs (equation 14)45. A stoichiometric amount of Ti(OPr-i)4 and a catalytic amount of camphorsulfonamide 33 enable an enantioselective addition of dialkylzincs to ketones46. Later, bis(sulfonamide) ligand 34 was found to be a more enantioselective catalyst in this... 

Also in 1992, Soai and coworkers reported the enantioselective addition of dialkylzincs to N. /V-di phenylphosphinyI i m incs using DBNE (1) and its analogue 55 as chiral ligands... 

As described in the preceding section, asymmetric amplification has been reported in the non-autocatalytic enantioselective addition of dialkylzincs. In asymmetric autocatalysis, amplification of has a more significant role, because the product of the asymmetric autocatalysis itself is capable of acting as the asymmetric autocatalyst. Once the product, i.e. the asymmetric autocatalyst with an enhanced , is formed in the asymmetric autocatalytic reaction, the product catalyzes the formation of itself with higher . From the viewpoint of the molecule, an asymmetric autocatalyst with dominant absolute configuration catalyzes... 

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. 

Chiral diol 52 [52] and ferrocenyl alkanol 54 [53] also work as asymmetric autocatalysts in the enantioselective addition of dialkylzincs to the corresponding dialdehyde 51 and ferrocene-carbaldehyde 53, respectively (Scheme 9.26). 

High enantioselectivity has been achieved on addition of diethylzinc to benzaldehyde catalysed by a chiral diamine, (,S )-2-(A,A -disubstitutcd aminomethyl)pyrrolidine,116 and by chiral helical titanate complexes of tetradentate ligands.117 Enantioselective additions of dialkylzinc reagents to A,-(diphcnylphosphiiioyl)imines, promoted by aziridino alcohols,118 and to the carbon-nitrogen double bond of the nitrone 3,4-dihydroisoquinoline A-oxide, promoted by dicyclopentyl(R,R)-tartrate,119 have also been reported. 

The enantioselective addition of dialkylzinc to inline derivatives has been performed using copper,118,119 titanium,120 and rhodium catalysts 121 high yields and excellent enantiocontrol (up to 99% ee) have been achieved. 

While f -amino alcohols have been widely studied as chiral auxiliaries, a series of (S)-amino alcohols - built into norbornane frameworks - have been examined as catalysts of enantioselective addition of dialkylzincs to benzaldehydes.236... 

Various phosphorus catalysts have been employed in enantioselective addition of dialkylzinc reagents to sulfonylimines.123 125... 

Enantioselective addition of (CiHs)2Zn to RCHO. These are the first secondary amino alcohols known to effect efficient enantioselective addition of dialkylzincs to aromatic and aliphatic aldehydes. 

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... 

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