Addition of Et2Zn, to aldehydes

In a seminal study various libraries of chiral ligands and activators in the addition of Et2Zn to aldehydes (51) were investigated (Scheme 11).87,89... 

The disulfonamide library was tested in the TifO PrC-mcdiatcd addition of Et2Zn to aldehydes, a known process using the bis-trifluoromethylsulfonamide of 1,2-diaminocyclohexane.106 The tests were run in 30 different reaction vessels in parallel format. In order to increase throughput, each vessel was charged with four different aldehydes, and the enantioselectivities of the four reaction products were determined by conventional GC analysis of the crude mixtures. The idea of using a given catalyst to screen combinatorially the reactions of different substrates had previously been proposed but in a different context.45 In the present case each mixture required about one hour to be screened, which means that about 96 ee-determinations of products (52) (Scheme 11) could be performed per day.105 A total of 120 results were collected, the best ees being >90%. 

Since the pioneering studies of asymmetric catalysis with core-functionalized dendrimers reported by Brunner (88) and Bolm (89), several noteworthy investigations have been described in this field. Some examples of the dendritic effects observed in enantioselective catalysis with dendrimers having active sites in the core were discussed in Section II, such as the catalytic experiments with TADDOL-cored dendrimers described by Seebach et al. (59) the asymmetric addition of Et2Zn to aldehydes catalyzed by core-functionalized phenylacetylene-containing dendrimers reported by Hu et al (42)-, the asymmetric hydrogenation investigations with (R)-BINAP core-functionalized dendrimers synthesized by Fan et al. (36) or the results... 

Ti TG, PS-micro sulfonamide asymmetric addition of Et2Zn to aldehydes [64]... 

The synthesis of a new enantiopure, conformationally constrained 1,4-amino alcohol (25) has been reported, starting from commercially available reagents from the chiral pool.107 This 1,4-amino alcohol has been used as a chiral ligand in the addition of Et2Zn to aldehydes (best ee 98%) and in the synthesis of chiral propargylic alcohols (best ee 70%) by alkynylzinc species. 

A study of enantio-selective addition of Et2Zn to aldehydes with the use of Schiff bases (18) as chiral ligands has probed steric effects in the transition state, the... 

The enantioselective addition of dialkylzinc reagents to aldehydes is not limited to the homonuclear zinc complexes described above. Seebach has shown that Ti-TADDOL complexes can be effective catalysts for the preparation of a wide range of secondary alcohols (Equation 16) [102], The addition of Et2Zn to aldehydes is carried out with catalyst 165 in combination with 1.2 equiv Ti(Oi-Pr)4 to furnish products in 82-99% ee [17. 103). The use of excess Ti(Oi-Pr)4 is noteworthy, as it is of mechanistic significance. Catalyst turnover is only observed in this system because of the ability of the Ti(Oi-Pr)4 to serve as a reservoir for the alkoxide product. It is remarkable, however, that the presence of excess Ti(Oi-Pr)4 does not lead to any diminution in the enantioselectivity of the product formed. This represents a dramatic example of ligand-accelerated catalysis in C-C bond-forming reactions. 

Tandem 1,4-addition to cycloalkenones constitutes an extremely versatile and elegant methodology for the synthesis of 2,3-disubstituted cycloalkanones, as is evident from its application in areas such as prostaglandin synthesis. Noyori et al. have reported the use of organozinc reagents in copper-catalyzed tandem additions [64]. The zinc enolate resulting from the catalytic enantioselective 1,4-addition of Et2Zn to cyclohexenone reacts readily with an aldehyde in a subsequent aldol condensation. 

A series of chiral (3i ,5 RHlihvdroxypiperidine derivatives have been conveniently prepared from trans -4-hvdrox v- r.-proline and applied to the catalytic enantioselective addition of diethylzinc to benzaldehyde and heptanal.110 The compound (31) has been found to show the best asymmetric induction in promoting the addition of Et2Zn to various aldehydes, providing (R)-secondary alcohols in up to 98% ee. 

The addition of Ph2Zn to aldehydes has been investigated by DFT calculations.103 The experimentally observed increase in enantioselectivity upon addition of Et2Zn to the reaction mixture was rationalized from calculations of all isomeric transition states. 

In accessing chiral allyl vinyl ethers for Claisen rearrangement reactions, Nelson et al. employed the iridium-mediated isomerization strategy. Thus, the requisite enantioenriched diallyl ether substrate 28 was synthesized via a highly enantioselective diethylzinc-aldehyde addition protocol10 (Scheme 1.1k). The enantioselective addition of Et2Zn to cinnamaldehyde catalyzed by (—)-3-exo-morpholinoisobomeol (MIB 26)11 provided an intermediate zinc alkoxide (27). Treatment of 27 with acetic acid followed by 0-allylation in the presence of palladium acetate delivered the 28 in 73% yield and 93% ee. Isomerization of 28 with a catalytic amount of the iridium complex afforded the allyl vinyl ether... 

Scheme 3. Influence of various chiral ligands on the enantioselective addition of Et2Zn to an aliphatic aldehyde...

The asymmetrie addition of Et2Zn to different aromatic and aliphatic aldehydes using the functioimalized Barlos resin 146 was also studied and both conversions (> 82%) and ee s (>86 %) were high. 

Terminal alkynes have been added enantioselectively to aromatic aldehydes, using a Ti-(7 )-BINOL/diethylzinc protocol. An A-3,5-bis(trifluoromethyl)benzenesul-fonamido-D-glucosamine derivative (88) catalyses Ti(OPr-04/Et2Zn-promoted addition of phenylacetylene to aldehydes in up to 92% ee ... 

Scheme 5.22 Addition of Et2Zn to biaryl hydroxy aldehydes.

In 1986, Noyori disclosed a true breakthrough in the field (Equation 15) [94]. The camphor-derived -amino alcohol 147 ((-)-3-exo-(dimethylamino) isoborneol, DIAB) was found to mediate the addition of Et2Zn to aromatic and unsaturated aldehydes to afford secondary alcohols with high enantio-selectivity (cf 149, 99% ee). 

Soai developed the/5-amino alcohol N,N-dibutylnorephedrine (DBNE, 159) which is readily available in both enantiomeric forms (Scheme 2.18) [99]. This ligand generates a catalyst for the addition of Et2Zn to both aliphatic and aromatic aldehydes with excellent optical purity ( 90%). As an example of the high stereocontrol induced by the chiral catalyst, either enantiomer of DBNE overrules the induction by the stereocenter in the a-chiral aldehyde 158 to furnish the diastereomeric products 160 and 161, respectively, with impressive stereoselectivity [100]. 

Et2Zn also participates in the reductive coupling as a formal hydride source. Results for the Ni-catalyzed, Et2Zn-promoted homoallylation of carbonyl compounds with isoprene are summarized in Table 7 [30]. Et2Zn is so reactive that for the reaction with reactive aromatic aldehydes it causes direct ethylation of aldehydes, and the yields of homoallylation are diminished (runs 1 and 2). Unsaturated aldehydes seem to be subject to the Michael addition of Et2Zn. Accordingly, for the reaction with cinnamaldehyde, none of the expected homoallylation product is produced instead, the 1,4-addition product of Et2Zn, 3-phenylpentanal is produced exclusively (run 3). 

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