Aldehydes dialkylzinc addition

BINOL and related compounds have proved to be effective catalysts for a variety of reactions. Zhang et al.106a and Mori and Nakai106b used an (R)-BINOL-Ti(OPr )4 catalyst system in the enantioselective diethylzinc alkylation of aldehydes, and the corresponding secondary alcohols were obtained with high enantioselectivity. This catalytic system works well even for aliphatic aldehydes. Dialkylzinc addition promoted by TifOPr1 in the presence of (R)- or (A)-BINOL can give excellent results under very mild conditions. Both conversion of the aldehyde and the ee of the product can be over 90% in most cases. The results are summarized in Table 2-14. 

Kitamura and Noyori have reported mechanistic studies on the highly diastere-omeric dialkylzinc addition to aryl aldehydes in the presence of (-)-i-exo-(dimethylamino)isoborneol (DAIB) [33]. They stated that DAIB (a chiral (i-amino alcohol) formed a dimeric complex 57 with dialkylzinc. The dimeric complex is not reactive toward aldehydes but a monomeric complex 58, which exists through equilibrium with the dimer 57, reacts with aldehydes via bimetallic complex 59. The initially formed adduct 60 is transformed into tetramer 61 by reaction with either dialkylzinc or aldehydes and regenerates active intermediates. The high enantiomeric excess is attributed to the facial selectivity achieved by clear steric differentiation of complex 59, as shown in Scheme 1.22. 

Since the discovery of amino alcohol induced dialkylzinc addition to aldehydes, many new ligands have been developed. It has recently been reported that chiral amino thiols and amino disulfides can form complexes or structurally strained derivatives with diethylzinc more favorably than chiral amino alcohols and thus enhance the asymmetric induction. Table 2 15 is a brief summary of such chiral catalysts. 

Another significant development in oxazoline chemistry is the application of oxazoline-containing ligands for asymmetric catalysis, such as palladium-catalyzed allylic substimtions, Heck reactions, hydrogenations, dialkylzinc additions to aldehydes, and Michael reactions. The discovery of diastereoselective metalation of chiral ferrocenyloxazolines has further expanded the availability of chiral ligands for metal-catalytic reactions. 

Transition State Models. The stoichiometry of aldehyde, dialkylzinc, and the DAIB auxiliary strongly affects reactivity (Scheme 9) (3). Ethylation of benzaldehyde does not occur in toluene at 0°C without added amino alcohol however, addition of 100 mol % of DAIB to diethylzinc does not cause the reaction either. Only the presence of a small amount (a few percent) of the amino alcohol accelerates the organometallic reaction efficiently to give the alkylation product in high yield. Dialkyl-zincs, upon reaction with DAIB, eliminate alkanes to generate alkylzinc alkoxides, which are unable to alkylate aldehydes. Instead, the alkylzinc alkoxides act as excellent catalysts or, more correctly, catalyst dimers (as shown below) for reaction between dialkylzincs and aldehydes. The unique dependence of the reactivity on the stoichiometry indicates that two zinc atoms per aldehyde are responsible for the alkyl transfer reaction. 

Scheme 1 Chiral amino alcohol catalyzed asymmetric dialkylzinc addition to aldehydes...

The key point of this scenario is to assume a priori that XY promotes the product of opposite configuration to X. In addition, additive dimers and not monomers are considered as catalytically active species, opposing the commonly accepted mechanism for typical dialkylzinc additions to aldehydes catalyzed by Vamino alcohols [ 18]. 

Only few reports deal with the use of mineral supports for immobilising chiral auxiliaries able to. activate dialkylzinc addition to aldehyde (Scheme 10). 

In addition to amino alcohols, numerous other ligands such as amines, amino thiols, diols, disulfides, and dis-elenides have been developed and tested. Several have shown a very good enantioselectivity for dialkylzinc additions to a variety of aldehydes. In contrast, the addition of aryl-, vinyl-, and alkynylzinc compounds was not so extensively studied and more work is stiU needed in... 

The dialkylzinc additions catalyzed by N,N-di-n-alkylnorephedrines (most typically DBNE) are not limited to primary organometallic reagents. Diisopropylzinc (with a secondary alkyl substituent) adds to benzaldehyde in the presence of a catalytic amount of DBNE to afford the corresponding alcohol with high ee (entry 4). The reaction of diisopropylzinc in the presence of other types of catalysts may result in the reduction of aldehydes. 

Stereoselective Addition of Dialkylzincs to Chiral Aldehydes. Stereoselective addition of dibutylzinc to racemic 2-phenylpropanal using (1S,2J )-DBNE as a chiral catalyst affords optically active alcohols (84% ee, 92% ee) as a result of the si face attack of the aldehyde regardless of its configuration (eq 21). ... 

Chiral Lewis acidic catalysts derived from p-amino alcohols constitute a major field of recent development. These reagents have been used for enantioselective reduction of ketones and for dialkylzinc additions to aldehydes. 

A very similar model can be invoked to explain the results of catalytic enantioselective dialkylzinc additions to aldehydes. The catalysts used in these reactions are invariably lithium- or zinc-centered Lewis acids. The transition structure shown in Figure has been put forward by several groups... 

Figure 52 A model for catalytic asymmetric dialkylzinc additions to aldehydes...

One of the earUest demonstrations of the viability of a combinatorial approach in the discovery of asymmetric reactions was reported by Elhnan in 1995 [7]. The Berkeley team s selection of the dialkylzinc addition to aldehydes (Scheme 2) to gauge the potential utility of a combinatorial approach was based on several factors ... 

This aldehyde had already been converted (26) to methyl nonactate and methyl 8-epinonactate with high selectivity using titanium tetrachloride catalysed addition of dimethyl zinc and lithium dimethylcuprate, respectively. Lygo also found that dialkylzinc addition under different Lewis acid conditions gave different diastereoisomers with high selectivity (Scheme 15). 

In this section, the asymmetric synthesis of the vicinal thio- and selenoalcohols 42 — 45 is described based on the highly enantio- and diastereoselective addition of diethylzinc reagent to racemic a-thio- and selenoaldehydes 41, catalyzed by 20o (( —)-DFPE) and S,R)-2Qo ((+)-DFPE) (Scheme 3-20). Although the enantio-selective addition of dialkylzinc reagents to achiral aldehydes using chiral catalysts has been well investigated [10], there are no known catalytic enantio- and di-asteroselective dialkylzinc additions to aldehydes with chiral centers, except for the alkylation of a-methyl- [58, 59], a-chloro- [59], and j5-alkoxyaldehydes [60]. The reaction of diethylzinc with racemic a-thio- and selenoaldehydes 41 was carried out in the presence of 20o or (S,il)-20o (5 — 50 mol%) in hexane at room temperature for 12 —16h. The results are summarized in Table 3-11. 

A complementary reaction towards the construction of secondary alcohols consists of a dialkylzinc addition to aldehydes in the presence of substoichiometric amounts of suitable chiral ligands, mostly amino alcohols [42-44]. For this reaction, which already is one of the classical asymmetric catalytic syntheses, three structurally related catalyst precursors have been described. 

The ionic liquids, [BMIMjBr, [BMIM][BF4], [BMIMjlPFe], [BDMIM][BF4], and [BPY][BF4], were examined as the solvent media for dialkylzinc addition to aldehydes giving the corresponding alcohols. The ionic liquid [BPY][BF4] was found to be the solvent of choice, giving the best yields, and was found to be easily recovered and reused [226] (Scheme 5.2-95). It was found that the imidazoUum salts react with diethyl zinc to form a carbene complex of zinc, but the 2-methylimidazolium or pyridinium salts did not react and hence could be recycled. 

Figure 6.1 Mechanism of catalysed dialkylzinc addition to aldehyde...

To the best of our knowledge, this phenomenon is tmprecedented in catalytic asymmetric synthesis. In addition to our previous results [56, 57] of the enantioselectivity reversal based on the addition of achiral catalyst, these results should be possibly understood that the heterochiral aggregate acts as the catalytic species in the enantioselective dialkylzinc addition to the aldehydes. 

Ishihara et al. reported that conjugate Lewis acid-Lewis base catalysis was highly effective in enantioselective dialkylzinc addition to a series of aromatic, aliphatic, and heteroaromatic aldehydes (Scheme 4.48) [42]. Bifunctional BINOL ligands bearing phosphine oxides [P(=0)R2] (136), phosphonates [P(=0)(0R)2] (137) or phosphoramides [P(=0)(NMe2)2] (138) at the 3,3 positions were developed. The coordination of a NaphO-Zn(II)-R center as a Lewis acid to a carbonyl group... 

EtjZn is among the most reactive organozinc reagents. Addition of higher homologues to aldehydes therefore often necessitates the use of very active catalysts [90], This requirement is fulfilled by the C2-symmetric disulfonamide 168 in combination with Ti(Oi-Pr)4, as reported by Ohno [106]. The resulting Ti complex with 168 effects enantioselective dialkylzinc additions to both aliphatic and aromatic aldehydes with superb stereocontrol [105]. 

Since the addition of dialkylzinc reagents to aldehydes can be performed enantioselectively in the presence of a chiral amino alcohol catalyst, such as (-)-(1S,2/ )-Ar,A -dibutylnorephedrine (see Section 1.3.1.7.1.), this reaction is suitable for the kinetic resolution of racemic aldehydes127 and/or the enantioselective synthesis of optically active alcohols with two stereogenic centers starting from racemic aldehydes128 129. Thus, addition of diethylzinc to racemic 2-phenylpropanal in the presence of (-)-(lS,2/ )-Ar,W-dibutylnorephedrine gave a 75 25 mixture of the diastereomeric alcohols syn-4 and anti-4 with 65% ee and 93% ee, respectively, and 60% total yield. In the case of the syn-diastereomer, the (2.S, 3S)-enantiomer predominated, whereas with the twtf-diastereomer, the (2f ,3S)-enantiomer was formed preferentially. 

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