Enantioselective addition 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 R2Zn to aldehydes. Corey and Hannon2 have prepared the diamino benzylic alcohol 1 from (S)-proline and (lS,2R)-( + )-ephed-rine and report that the chelated lithium salt of 1 is an effective catalyst for enantioselective addition of diethylzinc to aromatic aldehydes. Thus benzaldehyde can be converted into (S)-( - )-3 with 95% ee, via an intermediate tridentate lithium complex such as 2 formed from 1. Similar reactions, but catalyzed by diastereomers of 1, show that the chirality of addition of dialkylzincs to aldehydes is controlled by the chirality of the benzylic alcohol center of 1. 

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)-)... 

This enantioselective preparation of allylic alcohols has been applied to the synthesis of the side chain of prostaglandins . The addition to functionalized aldehydes, such as 483, allows the synthesis of C2-symmetrical 1,4-diols, such as 484, with excellent diastereoselectivity and enantioselectivity . An extension of this method allows the synthesis of C3-symmetrical dioF . Aldol-type products result from the catalytic enantioselective addition of functionalized dialkylzincs to 3-TIPSO-substituted aldehydes, such as 485, followed by a protection-deprotection and oxidation sequence affording 486 in 70% yield and 91% ee (Scheme 118) . The addition to a-alkoxyaldehydes provides a... 

SCHEME 118. Enantioselective addition of functionalized dialkylzincs to functionalized aldehydes... 

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. 

Nowadays, this chemistry includes a wide range of applications. The organozinc compounds employed in the enantioselective addition include dialkylzincs, dialkenylzincs, dialkynylzincs, diarylzincs and the related unsymmetrical diorganozincs. Electrophiles have been expanded to aldehydes, ketones and imines. Asymmetric amplification has been observed in the enantioselective addition of organozincs. Recently, asymmetric autocatalysis, i.e. automultiplication of chiral compounds, has been created in organozinc addition to aldehydes. 

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... 

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