Diethylzinc enantioselective addition

Keywords A-diphenylphosphinoylimine, diethylzinc, enantioselective addition, A-diphenylphosphinoylamine... 

The first reported chiral catalysts allowing the enantioselective addition of diethylzinc to aryl aldehydes in up to 60% cc were the palladium and cobalt complexes of 1,7,7-trimethylbicy-clo[2.2.1. ]heptane-2,3-dione dioxime (A,B)3. A number of other, even more effective catalysts, based on the camphor structure (C K, Table 26) have been developed. 

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. 

Although it is known that in some cases the lithium salts of chiral amino alcohols are even better catalysts than the chiral ligands themselves, the use of metals other than lithium has rarely been investigated. The oxazaborolidines A and B and the aluminum analog C have been used as catalysts for the enantioselective addition of diethylzinc to benzaldehyde35 (Table 32). 

The enantioselective addition of organometallic reagents to, V-(trimethylsilyl)benzaldehyde imine (1) in the presence of enantiomerically pure modifiers has been investigated. The best result is obtained with butyllithium (the corresponding Grignard reagent affords both lower yield and selectivity, 1 fails to react with diethylzinc) and two equivalents of the enantiomerically pure diol 2 in diethyl ether. It should be noted that the choice of the solvent is crucial for the stereoselectivity of the reaction1 2 3 5 7 8 9. 

A polymer-supported version of our optimal ligand was also developed [52]. Its preparation involves attachment of aziridine carbinols to polymer-bound triphenylchloromethane (Scheme 40). This polymer-bound ligand 53 was almost equally effective in the enantioselective addition of diethylzinc to aromatic and aliphatic aldehydes with ee s ranging from 77-97% for the latter type of substrate [52]. It is of practical interest that this polymer-supported ligand could be reused without losing much of its efficiency. 

The use of cyclic a,p-unsaturated ketones as starting materials in the enantioselective addition of dimethyl- and diethylzinc reagents catalysed by the HOCSAC ligand was introduced by Walsh and Jeon, in 2003. As shown in Scheme 4.16, the corresponding cyclic tertiary alcohols were formed in high enantioselectivities of up to 99% ee. 

On the other hand, S/O ligands have been developed to a lesser extent, but their efficient use as chiral ligands was proven in the enantioselective addition of diethylzinc to aldehydes and also in the copper-catalysed asymmetric conjugate addition. 

Attached to the periphery of a lst-generation dendrimer, Ti(OCHMe2)2-com-plexes of the six TADDOL moieties in 84 catalyze - in homogeneous solution -the enantioselective addition of diethylzinc to benzaldehyde with about the same selectivity ((S) (R) 97 3) as do six monomeric TADDOL units [105],but, with a molecular weight of only 3833 Da, dendrimer 84 had to be separated by column chromatography rather than by ultrafiltration methods. 

Seebach and co-workers copolymerized a dendritically modified TADDOL ligand with styrene (Figure 9). When associated with Ti(OiPr)4, the immobilized catalyst gave a very high ee (98%) for more than 20 runs in the enantioselective addition of diethylzinc to benzaldehyde95 96... 

Figure 9 Supported Ti-TADDOLate catalyst for enantioselective addition of diethylzinc to benzaldehyde...

The optically active reagent (5)-l-methyl-2-(diphenylhydroxymethyl)-azitidine [(5)-114] has also been reported to catalyze the enantioselective addition of diethylzinc to various aldehydes. The resulting chiral secondary alcohols 115 are obtained in up to 100% ee under mild conditions (Scheme 2-44).111 Furthermore, most of the 114-type ligands have also been used in the ox-... 

Chiral quaternary ammonium salts in solid state have also been used as catalysts for the enantioselective addition of diethylzinc to aldehydes (Scheme 2-45).112 In most cases, homogeneous chiral catalysts afford higher enantio-selectivities than heterogeneous ones. Scheme 2-45 presents an unusual asymmetric reaction in which chiral catalysts in the solid state afford much higher enantioselectivities than its homogeneous counterpart.112... 

The optically active //-amino alcohol (1 / . 3 R. 5 / )-3-(di phenyl hydroxymethyl )-2-azabicyclo[3.3.0]octane [(li ,3i ,5i )-121], can be derived from a bicyclic proline analog. It catalyzes the enantioselective addition of diethylzinc to various aldehydes. Under mild conditions, the resulting chiral secondary alcohols are obtained in optical yields up to 100%. The bicyclic catalyst gives much better results than the corresponding (S )-proline derivative (S )-122 (Scheme 2-47).114... 

Scheme 2-49. TADDOL and its analogs as titanium ligands in enantioselective addition of diethylzinc reagents to benzaldehyde.

In Scheme 2 51, species 133 is formed from the precatalyst 132 and TifOPr )4. It is then converted to complex G upon addition of diethylzinc. Reaction between species G and an aldehyde furnishes intermediate E, which accomplishes the enantioselective addition of the nucleophile to the carbonyl group. Intervention of two molecules of Ti(OPr )4 releases the alkylated product, regenerates the active catalyst 133, and also completes the catalytic cycle. This cycle explains the fact that at least one equivalent of Ti(OPr )4 is required for an effective reaction. 

Similarly, Ramon and Yus140 reported the enantioselective addition of diethylzinc and dimethylzinc to prochiral ketones catalyzed by camphorsulfona-mide-titanium alkoxide derivatives as shown in Scheme 2-54. 

K. Soai, M. Watanabe, Chiral Quaternary Ammonium Salts as Solid State Catalysts for the Enantioselective Addition of Diethylzinc to Aldehydes , J. Chem Soc, Chern. Commun 1990, 43-44. 

Enantioselective addition of CjH zZn to aldehydes.1 Addition of diethylzinc to either aromatic or aliphatic aldehydes catalyzed by 1 (6 mole %) results in (S)-secondary alcohols in generally 90-95% ee. Although several chiral amino alcohols are known to effect enantioselective addition of R2Zn to aromatic aldehydes, this one is the first catalyst to be effective for aliphatic aldehydes. The dibutylamino group of 1 is essential for the high enantioselectivity the dimethylamino analog of 1, (lS,2R)-N-methylephedrine, effects this addition in only about 60% ee. 

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. 

The same laboratory has prepared three tridentate zinc chelates from chiral tertiary amino phenolic alcohols and used them for enantioselective addition of diethylzinc to aryl aldehydes in 70-87% ee. Results with the ligand 4 [from (1S,2S)-(+ )-pseudoephedrine] are typical. 

DOLate was formed which was tested in the Lewis acid catalyzed enantioselective addition of diethylzinc to benzaldehyde. The authors note that the catalyst can be recovered by simple filtration and was active for at least more than twenty runs (refer also to Section 4.2.3) [102]. 

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. 

On the other hand, approaches to the use of catalytic amounts of chiral ligands have been developed. Thus, the use of a sub-stoichiometric amount (50 mol%) of DBNE (1) affords A,A-diphenylphosphinylamine with 85% in 69% yield121a. Similarly, 25 mol% of chiral aziridinyl alcohol 56 (R = - ) affords (V,(V-diphenylphosphinylamine with 65% in 60% yield123. In the enantioselective addition reaction of diethylzinc to a nitrone, 20 mol% of the metal alkoxide of diisopropyl tartrate 62 catalyzed the formation of a... 

In the enantioselective addition of diethylzinc to benzaldehyde, a wide variety of chiral catalysts 3, 4, 16, 23, 47, 66-73 exhibits asymmetric amplification (equation 36 and Table 1). 

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